PMID- 23980189 TI - Embracing the principles of the San Francisco Declaration of Research Assessment: Robert Balaban's editorial. PMID- 23980188 TI - Are interventions to reduce interruptions and errors during medication administration effective?: a systematic review. AB - BACKGROUND: Medication administration errors are frequent and lead to patient harm. Interruptions during medication administration have been implicated as a potential contributory factor. OBJECTIVE: To assess evidence of the effectiveness of interventions aimed at reducing interruptions during medication administration on interruption and medication administration error rates. METHODS: In September 2012 we searched MEDLINE, EMBASE, CINAHL, PsycINFO, Cochrane Effective Practice and Organisation of Care Group reviews, Google and Google Scholar, and hand searched references of included articles. Intervention studies reporting quantitative data based on direct observations of at least one outcome (interruptions, or medication administration errors) were included. RESULTS: Ten studies, eight from North America and two from Europe, met the inclusion criteria. Five measured significant changes in interruption rates pre and post interventions. Four found a significant reduction and one an increase. Three studies measured changes in medication administration error rates and showed reductions, but all implemented multiple interventions beyond those targeted at reducing interruptions. No study used a controlled design pre and post. Definitions for key outcome indicators were reported in only four studies. Only one study reported kappa scores for inter-rater reliability and none of the multi ward studies accounted for clustering in their analyses. CONCLUSIONS: There is weak evidence of the effectiveness of interventions to significantly reduce interruption rates and very limited evidence of their effectiveness to reduce medication administration errors. Policy makers should proceed with great caution in implementing such interventions until controlled trials confirm their value. Research is also required to better understand the complex relationship between interruptions and error to support intervention design. PMID- 23980190 TI - Evaluation of scientific productivity and excellence in the NHLBI Division of Intramural Research. PMID- 23980191 TI - Of antisense, antibodies, K+ channels, and jejunal metabolism. PMID- 23980192 TI - A gating charge interaction required for late slow inactivation of the bacterial sodium channel NavAb. AB - Voltage-gated sodium channels undergo slow inactivation during repetitive depolarizations, which controls the frequency and duration of bursts of action potentials and prevents excitotoxic cell death. Although homotetrameric bacterial sodium channels lack the intracellular linker-connecting homologous domains III and IV that causes fast inactivation of eukaryotic sodium channels, they retain the molecular mechanism for slow inactivation. Here, we examine the functional properties and slow inactivation of the bacterial sodium channel NavAb expressed in insect cells under conditions used for structural studies. NavAb activates at very negative membrane potentials (V1/2 of approximately -98 mV), and it has both an early phase of slow inactivation that arises during single depolarizations and reverses rapidly, and a late use-dependent phase of slow inactivation that reverses very slowly. Mutation of Asn49 to Lys in the S2 segment in the extracellular negative cluster of the voltage sensor shifts the activation curve ~75 mV to more positive potentials and abolishes the late phase of slow inactivation. The gating charge R3 interacts with Asn49 in the crystal structure of NavAb, and mutation of this residue to Cys causes a similar positive shift in the voltage dependence of activation and block of the late phase of slow inactivation as mutation N49K. Prolonged depolarizations that induce slow inactivation also cause hysteresis of gating charge movement, which results in a requirement for very negative membrane potentials to return gating charges to their resting state. Unexpectedly, the mutation N49K does not alter hysteresis of gating charge movement, even though it prevents the late phase of slow inactivation. Our results reveal an important molecular interaction between R3 in S4 and Asn49 in S2 that is crucial for voltage-dependent activation and for late slow inactivation of NavAb, and they introduce a NavAb mutant that enables detailed functional studies in parallel with structural analysis. PMID- 23980193 TI - Functional contributions of HCN channels in the primary auditory neurons of the mouse inner ear. AB - The hyperpolarization-activated current, Ih, is carried by members of the Hcn channel family and contributes to resting potential and firing properties in excitable cells of various systems, including the auditory system. Ih has been identified in spiral ganglion neurons (SGNs); however, its molecular correlates and their functional contributions have not been well characterized. To investigate the molecular composition of the channels that carry Ih in SGNs, we examined Hcn mRNA harvested from spiral ganglia of neonatal and adult mice using quantitative RT-PCR. The data indicate expression of Hcn1, Hcn2, and Hcn4 subunits in SGNs, with Hcn1 being the most highly expressed at both stages. To investigate the functional contributions of HCN subunits, we used the whole-cell, tight-seal technique to record from wild-type SGNs and those deficient in Hcn1, Hcn2, or both. We found that HCN1 is the most prominent subunit contributing to Ih in SGNs. Deletion of Hcn1 resulted in reduced conductance (Gh), slower activation kinetics (taufast), and hyperpolarized half-activation (V1/2) potentials. We demonstrate that Ih contributes to SGN function with depolarized resting potentials, depolarized sag and rebound potentials, accelerated rebound spikes after hyperpolarization, and minimized jitter in spike latency for small depolarizing stimuli. Auditory brainstem responses of Hcn1-deficient mice showed longer latencies, suggesting that HCN1-mediated Ih is critical for synchronized spike timing in SGNs. Together, our data indicate that Ih contributes to SGN membrane properties and plays a role in temporal aspects of signal transmission between the cochlea and the brain, which are critical for normal auditory function. PMID- 23980194 TI - E258K HCM-causing mutation in cardiac MyBP-C reduces contractile force and accelerates twitch kinetics by disrupting the cMyBP-C and myosin S2 interaction. AB - Mutations in cardiac myosin binding protein C (cMyBP-C) are prevalent causes of hypertrophic cardiomyopathy (HCM). Although HCM-causing truncation mutations in cMyBP-C are well studied, the growing number of disease-related cMyBP-C missense mutations remain poorly understood. Our objective was to define the primary contractile effect and molecular disease mechanisms of the prevalent cMyBP-C E258K HCM-causing mutation in nonremodeled murine engineered cardiac tissue (mECT). Wild-type and human E258K cMyBP-C were expressed in mECT lacking endogenous mouse cMyBP-C through adenoviral-mediated gene transfer. Expression of E258K cMyBP-C did not affect cardiac cell survival and was appropriately incorporated into the cardiac sarcomere. Functionally, expression of E258K cMyBP C caused accelerated contractile kinetics and severely compromised twitch force amplitude in mECT. Yeast two-hybrid analysis revealed that E258K cMyBP-C abolished interaction between the N terminal of cMyBP-C and myosin heavy chain sub-fragment 2 (S2). Furthermore, this mutation increased the affinity between the N terminal of cMyBP-C and actin. Assessment of phosphorylation of three serine residues in cMyBP-C showed that aberrant phosphorylation of cMyBP-C is unlikely to be responsible for altering these interactions. We show that the E258K mutation in cMyBP-C abolishes interaction between N-terminal cMyBP-C and myosin S2 by directly disrupting the cMyBP-C-S2 interface, independent of cMyBP-C phosphorylation. Similar to cMyBP-C ablation or phosphorylation, abolition of this inhibitory interaction accelerates contractile kinetics. Additionally, the E258K mutation impaired force production of mECT, which suggests that in addition to the loss of physiological function, this mutation disrupts contractility possibly by tethering the thick and thin filament or acting as an internal load. PMID- 23980195 TI - Life and death of a cardiac calcium spark. AB - Calcium sparks in cardiac myocytes are brief, localized calcium releases from the sarcoplasmic reticulum (SR) believed to be caused by locally regenerative calcium induced calcium release (CICR) via couplons, clusters of ryanodine receptors (RyRs). How such regeneration is terminated is uncertain. We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed). Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium. Spark termination by local SR depletion was not robust: under some conditions, sparks could be greatly and variably prolonged, terminating by stochastic attrition-a phenomenon we dub "spark metastability." Spark fluorescence rise time was not a good surrogate for the duration of calcium release. Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates. The conditions for spark metastability resemble those produced by known mutations of RyR2 and CASQ2 that cause life-threatening triggered arrhythmias, and spark metastability may be mitigated by altering the kinetics of the RyR in a manner similar to the effects of drugs known to prevent those arrhythmias. The model was unable to explain the distributions of spark amplitudes and rise times seen in chemically skinned cat atrial myocytes, suggesting that such sparks may be more complex events involving heterogeneity of couplons or local propagation among sub-clusters of RyRs. PMID- 23980196 TI - Hydrophobic interactions between the voltage sensor and pore mediate inactivation in Kv11.1 channels. AB - Kv11.1 channels are critical for the maintenance of a normal heart rhythm. The flow of potassium ions through these channels is controlled by two voltage regulated gates, termed "activation" and "inactivation," located at opposite ends of the pore. Crucially in Kv11.1 channels, inactivation gating occurs much more rapidly, and over a distinct range of voltages, compared with activation gating. Although it is clear that the fourth transmembrane segments (S4), within each subunit of the tetrameric channel, are important for controlling the opening and closing of the activation gate, their role during inactivation gating is much less clear. Here, we use rate equilibrium free energy relationship (REFER) analysis to probe the contribution of the S4 "voltage-sensor" helix during inactivation of Kv11.1 channels. Contrary to the important role that charged residues play during activation gating, it is the hydrophobic residues (Leu529, Leu530, Leu532, and Val535) that are the key molecular determinants of inactivation gating. Within the context of an interconnected multi-domain model of Kv11.1 inactivation gating, our REFER analysis indicates that the S4 helix and the S4-S5 linker undergo a conformational rearrangement shortly after that of the S5 helix and S5P linker, but before the S6 helix. Combining REFER analysis with double mutant cycle analysis, we provide evidence for a hydrophobic interaction between residues on the S4 and S5 helices. Based on a Kv11.1 channel homology model, we propose that this hydrophobic interaction forms the basis of an intersubunit coupling between the voltage sensor and pore domain that is an important mediator of inactivation gating. PMID- 23980197 TI - Functional interactions of voltage sensor charges with an S2 hydrophobic plug in hERG channels. AB - Human ether-a-go-go-related gene (hERG, Kv11.1) potassium channels have unusually slow activation and deactivation kinetics. It has been suggested that, in fast activating Shaker channels, a highly conserved Phe residue (F290) in the S2 segment forms a putative gating charge transfer center that interacts with S4 gating charges, i.e., R362 (R1) and K374 (K5), and catalyzes their movement across the focused electric field. F290 is conserved in hERG (F463), but the relevant residues in the hERG S4 are reversed, i.e., K525 (K1) and R537 (R5), and there is an extra positive charge adjacent to R537 (i.e., K538). We have examined whether hERG channels possess a transfer center similar to that described in Shaker and if these S4 charge differences contribute to slow gating in hERG channels. Of five hERG F463 hydrophobic substitutions tested, F463W and F463Y shifted the conductance-voltage (G-V) relationship to more depolarized potentials and dramatically slowed channel activation. With the S4 residue reversals (i.e., K525, R537) taken into account, the closed state stabilization by F463W is consistent with a role for F463 that is similar to that described for F290 in Shaker. As predicted from results with Shaker, the hERG K525R mutation destabilized the closed state. However, hERG R537K did not stabilize the open state as predicted. Instead, we found the neighboring K538 residue to be critical for open state stabilization, as K538R dramatically slowed and right-shifted the voltage dependence of activation. Finally, double mutant cycle analysis on the G V curves of F463W/K525R and F463W/K538R double mutations suggests that F463 forms functional interactions with K525 and K538 in the S4 segment. Collectively, these data suggest a role for F463 in mediating closed-open equilibria, similar to that proposed for F290 in Shaker channels. PMID- 23980198 TI - Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization- and voltage-activated current in mouse spermatozoa. AB - During passage through the female reproductive tract, mammalian sperm undergo a maturation process termed capacitation that renders sperm competent to produce fertilization. Capacitation involves a sequence of changes in biochemical and electrical properties, the onset of a hyperactivated swimming behavior, and development of the ability to undergo successful fusion and penetration with an egg. In mouse sperm, the development of hyperactivated motility is dependent on cytosolic alkalization that then results in an increase in cytosolic Ca(2+). The elevation of Ca(2+) is thought to be primarily driven by the concerted interplay of two alkalization-activated currents, a K(+) current (KSPER) composed of pore forming subunits encoded by the Kcnu1 gene (also termed Slo3) and a Ca(2+) current arising from a family of CATSPER subunits. After deletion of any of four CATSPER subunit genes (CATSPER1-4), the major remaining current in mouse sperm is alkalization-activated KSPER current. After genetic deletion of the Slo3 gene, KSPER current is abolished, but there remains a small voltage-activated K(+) current hypothesized to reflect monovalent flux through CATSPER. Here, we address two questions. First, does the residual outward K(+) current present in the Slo3 (-/-) sperm arise from CATSPER? Second, can any additional membrane K(+) currents be detected in mouse sperm by patch-clamp methods other than CATSPER and KSPER? Here, using mice bred to lack both SLO3 and CATSPER1 subunits, we show conclusively that the voltage-activated outward current present in Slo3 (-/-) sperm is abolished when CATSPER is also deleted. Any leak currents that may play a role in setting the resting membrane potential in noncapacitated sperm are likely smaller than the pipette leak current and thus cannot be resolved within the limitation of the patch-clamp technique. Together, KSPER and CATSPER appear to be the sole ion channels present in mouse sperm that regulate membrane potential and Ca(2+) influx in response to alkalization. PMID- 23980199 TI - Ramifications of single-port laparoscopic surgery: measuring differences in task performance using simulation. AB - INTRODUCTION: Single-port laparoscopic surgery imposes unique psychomotor challenges. We used surgical simulation to define performance differences between surgeons with and without single-port clinical experience and examined whether a short course of training resulted in improved performance. METHODS: Study participants were assigned to 3 groups: resident group (RES), experienced laparoscopic surgeons with (SP) and without (LAP) prior single-port laparoscopic experience. Participants performed the Fundamentals of Laparoscopic Surgery precision cutting task on a ProMIS trainer through conventional ports or with articulating instruments via a SILS Port (Covidien, Inc). Two iterations of each method were performed. Then, 6 residents performed 10 successive single-port iterations to assess the effect of practice on task performance. RESULTS: The SP group had faster task times for both laparoscopic (P = .0486) and single-port (P = .0238) methods. The LAP group had longer path lengths for the single-port task than for the laparoscopic task (P = .03). The RES group was slower (P = .0019), with longer path length (P = .0010) but with greater smoothness (P = .0186) on the single-port task than the conventional laparoscopic task. Resident performance task time (P = .005) and smoothness (P = .045) improved with successive iterations. DISCUSSION: Our data show that surgeons with clinical single-port surgery experience perform a simulated single-port surgical task better than inexperienced single-port surgeons. Furthermore, this performance is comparable to that achieved with conventional laparoscopic techniques. Performance of residents declined dramatically when confronted with the challenges of the single-port task but improved with practice. These results suggest a role for lab-based single-port training. PMID- 23980200 TI - Endoscopic therapies for leaks and fistulas after bariatric surgery. AB - Bariatric surgery is the most effective treatment for the medical comorbidities associated with morbid obesity. Though uncommon, staple line or anastomotic leaks after bariatric surgery are highly morbid events and challenging to treat. In selected patients without severe sepsis or distant pollution, endoscopic transluminal peritoneal drainage may provide source control. For leaks within 3 days of surgery, endoscopic stenting does not appear to speed closure but does permit oral nutrition. In uncomplicated situations, the risk of migration and resulting complications of enteric stents appear to overshadow the benefits. Initial treatment failures and leaks presenting more than 48 hours after surgery respond to enteric diversion by endoscopic stenting. Occlusion of the leak by injection of fibrin glue also shows promise; however, these case series are limited to a small number of patients. Endoclips may work best to occlude leaks and close fistulas if the epithelium is debrided. As suturing technology improves, direct internal closure of fistulas may prove feasible. Therapeutic endoscopy offers several technologies that can assist in the closure of early leaks and that are essential to the treatment of late leaks and fistulas after bariatric surgery. PMID- 23980202 TI - A late presentation of Loeys-Dietz syndrome: joint hypermobility is not always benign. PMID- 23980201 TI - Spontaneous mesotheliomas in F344/N rats are characterized by dysregulation of cellular growth and immune function pathways. AB - Aged male Fischer 344/N rats are prone to developing spontaneous peritoneal mesotheliomas that arise predominantly from the tunica vaginalis of the testes. A definitive cause for the predominance of this neoplasm in F344/N rats is unknown. Investigation of the molecular alterations that occur in spontaneous rat mesotheliomas may provide insight into their pathogenesis as well enable a better understanding regarding the mechanisms underlying chemically induced mesothelioma in rodents. Mesothelial cell function represents a complex interplay of pathways related to host defense mechanisms and maintenance of cellular homeostasis. Global gene expression profiles of spontaneous mesotheliomas from vehicle control male F344/N rats from 2-year National Toxicology Program carcinogenicity bioassays were analyzed to determine the molecular features of these tumors and elucidate tumor-specific gene expression profiles. The resulting gene expression pattern showed that spontaneous mesotheliomas are associated with upregulation of various growth factors, oncogenes, cytokines, pattern recognition response receptors, and pathogen-associated molecular patterns receptors, and the production of reactive oxygen and nitrogen species, as well as downregulation of apoptosis pathways. Alterations in these pathways in turn trigger molecular responses that stimulate cell proliferation and promote tumor survival and progression. PMID- 23980203 TI - Imp3 unfolds stem structures in pre-rRNA and U3 snoRNA to form a duplex essential for small subunit processing. AB - Eukaryotic ribosome biogenesis requires rapid hybridization between the U3 snoRNA and the pre-rRNA to direct cleavages at the A0, A1, and A2 sites in pre-rRNA that liberate the small subunit precursor. The bases involved in hybridization of one of the three duplexes that U3 makes with pre-rRNA, designated the U3-18S duplex, are buried in conserved structures: box A/A' stem-loop in U3 snoRNA and helix 1 (H1) in the 18S region of the pre-rRNA. These conserved structures must be unfolded to permit the necessary hybridization. Previously, we reported that Imp3 and Imp4 promote U3-18S hybridization in vitro, but the mechanism by which these proteins facilitate U3-18S duplex formation remained unclear. Here, we directly addressed this question by probing base accessibility with chemical modification and backbone accessibility with ribonuclease activity of U3 and pre-rRNA fragments that mimic the secondary structure observed in vivo. Our results demonstrate that U3-18S hybridization requires only Imp3. Binding to each RNA by Imp3 provides sufficient energy to unfold both the 18S H1 and the U3 box A/A' stem structures. The Imp3 unfolding activity also increases accessibility at the U3-dependent A0 and A1 sites, perhaps signaling cleavage at these sites to generate the 5' mature end of 18S. Imp4 destabilizes the U3-18S duplex to aid U3 release, thus differentiating the roles of these proteins. Protein-dependent unfolding of these structures may serve as a switch to block U3-pre-rRNA interactions until recruitment of Imp3, thereby preventing premature and inaccurate U3-dependent pre-rRNA cleavage and folding events in eukaryotic ribosome biogenesis. PMID- 23980204 TI - S6:S18 ribosomal protein complex interacts with a structural motif present in its own mRNA. AB - Prokaryotic ribosomal protein genes are typically grouped within highly conserved operons. In many cases, one or more of the encoded proteins not only bind to a specific site in the ribosomal RNA, but also to a motif localized within their own mRNA, and thereby regulate expression of the operon. In this study, we computationally predicted an RNA motif present in many bacterial phyla within the 5' untranslated region of operons encoding ribosomal proteins S6 and S18. We demonstrated that the S6:S18 complex binds to this motif, which we hereafter refer to as the S6:S18 complex-binding motif (S6S18CBM). This motif is a conserved CCG sequence presented in a bulge flanked by a stem and a hairpin structure. A similar structure containing a CCG trinucleotide forms the S6:S18 complex binding site in 16S ribosomal RNA. We have constructed a 3D structural model of a S6:S18 complex with S6S18CBM, which suggests that the CCG trinucleotide in a specific structural context may be specifically recognized by the S18 protein. This prediction was supported by site-directed mutagenesis of both RNA and protein components. These results provide a molecular basis for understanding protein-RNA recognition and suggest that the S6S18CBM is involved in an auto-regulatory mechanism. PMID- 23980205 TI - Type I IFN inhibits innate IL-10 production in macrophages through histone deacetylase 11 by downregulating microRNA-145. AB - Innate immune responses must be tightly regulated to avoid overactivation and subsequent inflammatory damage to host tissue while eliminating invading pathogens. IL-10 is a crucial suppressor of inflammatory responses and its expression is under precise regulation involving complex regulatory networks and multiple feedback loops. MicroRNAs are now emerging as critical regulators in immune response. Our previous work showed that miR-143/145 cluster was markedly downregulated in macrophages upon vesicular stomatitis virus infection. However, the particular role of miR-143/145 cluster in the regulation of innate immune response remains unknown. In this study, we found that miR-143/145 cluster expression was also downregulated dramatically by TLR signals in macrophages, which was dependent on the subsequent type I IFN (IFN-I) production and downstream IFN-I receptor-JAK1-STAT1 signal cascade. Further studies demonstrated that miR-145, but not miR-143, promoted IL-10 expression in TLR4-triggered macrophages through directly targeting the epigenetic Il10 gene silencer histone deacetylase 11. Therefore, we demonstrate that miR-145, downregulated by IFN-I, targets histone deacetylase 11 to promote innate IL-10 expression in macrophages. Our findings suggest a new IFN-I-mediated negative feedback loop in the fine tuning of innate IL-10 production that creates precise coordination of innate immune responses. PMID- 23980206 TI - Tapasin facilitation of natural HLA-A and -B allomorphs is strongly influenced by peptide length, depends on stability, and separates closely related allomorphs. AB - Despite an abundance of peptides inside a cell, only a small fraction is ultimately presented by HLA-I on the cell surface. The presented peptides have HLA-I allomorph-specific motifs and are restricted in length. So far, detailed length studies have been limited to few allomorphs. Peptide-HLA-I (pHLA-I) complexes of different allomorphs are qualitatively and quantitatively influenced by tapasin to different degrees, but again, its effect has only been investigated for a small number of HLA-I allomorphs. Although both peptide length and tapasin dependence are known to be important for HLA-I peptide presentation, the relationship between them has never been studied. In this study, we used random peptide libraries from 7- to 13-mers and studied binding in the presence and absence of a recombinant truncated form of tapasin. The data show that HLA-I allomorphs are differentially affected by tapasin, different lengths of peptides generated different amounts of pHLA-I complexes, and HLA-A allomorphs are generally less restricted than HLA-B allomorphs to peptides of the classical length of 8-10 aa. We also demonstrate that tapasin facilitation varies for different peptide lengths, and that the correlation between high degree of tapasin facilitation and low stability is valid for different random peptide mixes of specific lengths. In conclusion, these data show that tapasin has specificity for the combination of peptide length and HLA-I allomorph, and suggest that tapasin promotes formation of pHLA-I complexes with high on and off rates, an important intermediary step in the HLA-I maturation process. PMID- 23980207 TI - Retinoid X receptor agonists modulate Foxp3+ regulatory T cell and Th17 cell differentiation with differential dependence on retinoic acid receptor activation. AB - Retinoic acid (RA) enhances TGF-beta-dependent differentiation of Foxp3(+) inducible regulatory T cells (iTregs) and inhibits Th17 differentiation by binding to the RA receptor (RAR)/retinoid X receptor (RXR) heterodimer. The major physiologic RA, all-trans-RA, binds to RAR but not to RXR at physiological concentrations. It remained unclear whether RXR-mediated stimulation affected the iTregs and Th17 differentiation. We found in this study that the RXR agonists, PA024 and tributyltin, augmented the ability of all-trans-RA or the RAR agonist Am80 to enhance CD4(+)CD25(-) T cells to acquire Foxp3 expression and suppressive function. However, they failed to enhance Foxp3 expression in the presence of the RAR antagonist LE540, suggesting that the effect depends on RAR-mediated signals. They exerted the effect largely by augmenting the ability of all-trans-RA to suppress the production of IL-4, IL-21, and IFN-gamma that inhibited Foxp3 expression. Agonists of peroxisome proliferator-activated receptors and liver X receptors (LXRs), permissive partners of RXR, failed to enhance Foxp3 expression. In contrast, RXR agonists and LXR agonists suppressed IL-17 expression. The RXR mediated suppression was not canceled by blocking RAR stimulation but was likely to involve permissive activation of LXRs. All-trans-RA and an agonist of RXR or LXR additively suppressed IL-17 expression when the all-trans-RA concentration was low. RXR agonists also suppressed Ccr6 expression that is essential for Th17 cells to enter the CNS. Accordingly, tributyltin treatment of mice ameliorated experimental autoimmune encephalomyelitis through regulating Th17 cell activities. These results suggest that RXR stimulation modulates Foxp3(+) iTreg and Th17 differentiation with differential dependence on RAR-mediated stimulation. PMID- 23980208 TI - Insights into the role of Bcl6 in follicular Th cells using a new conditional mutant mouse model. AB - The transcriptional repressor Bcl6 controls development of the follicular Th cell (T(FH)) lineage, but the precise mechanisms by which Bcl6 regulates this process are unclear. A model has been proposed whereby Bcl6 represses the differentiation of T cells into alternative effector lineages, thus favoring T(FH) cell differentiation. Analysis of T cell differentiation using Bcl6-deficient mice has been complicated by the strong proinflammatory phenotype of Bcl6-deficient myeloid cells. In this study, we report data from a novel mouse model where Bcl6 is conditionally deleted in T cells (Bcl6(fl/fl)Cre(CD4) mice). After immunization, programmed death -1 (PD-1)(high) T(FH) cells in Bcl6(fl/fl)Cre(CD4) mice are decreased >90% compared with control mice, and Ag-specific IgG is sharply reduced. Residual PD-1(high)CXCR5(+) T(FH) cells in Bcl6(fl/fl)Cre(CD4) mice show a significantly higher rate of apoptosis than do PD-1(high)CXCR5(+) T(FH) cells in control mice. Immunization of Bcl6(fl/fl)Cre(CD4) mice did not reveal enhanced differentiation into Th1, Th2, or Th17 lineages, although IL-10 expression by CD4 T cells was markedly elevated. Thus, T cell-extrinsic factors appear to promote the increased Th1, Th2, and Th17 responses in germline Bcl6 deficient mice. Furthermore, IL-10 may be a key target gene for Bcl6 in CD4 T cells, which enables Bcl6 to promote the T(FH) cell phenotype. Finally, our data reveal a novel mechanism for the role of Bcl6 in promoting T(FH) cell survival. PMID- 23980209 TI - T cell CD3zeta deficiency enables multiorgan tissue inflammation. AB - Although a population of T cells with CD3zeta chain deficiency has been found in patients with systemic lupus erythematosus, rheumatoid arthritis, cancer, and infectious disease, the role of CD3zeta chain in the disease pathogenesis remains unknown. To understand the contribution of CD3zeta deficiency to the expression of organ injury, we have performed the following studies. We used CD3zeta deficient mice to investigate the role of CD3zeta in the pathogenesis of organ tissue inflammation. We found that the CD3zeta(-/-) mice can spontaneously develop significant organ inflammation that can be accelerated following the administration of polyinosinic:polycytidylic acid or allogeneic cells (graft versus host). T cells from CD3zeta(-/-) mice display increased expression of the adhesion molecules CD44 and CCR2 and produce increased amounts of IFN-gamma blockade, which mitigates tissue inflammation. Our results demonstrate that CD3zeta deficiency bestows T cells with the ability to infiltrate various tissues and instigate inflammation. Decreased CD3zeta expression noted in T cells from various diseases contributes independently to tissue inflammation and organ damage. Approaches to restore CD3zeta expression of the surface of T cells should be expected to mitigate tissue inflammation. PMID- 23980211 TI - Dynamic sonographic evaluation of posterior shoulder dislocation secondary to brachial plexus birth palsy injury. PMID- 23980210 TI - The CD226/CD155 interaction regulates the proinflammatory (Th1/Th17)/anti inflammatory (Th2) balance in humans. AB - CD226 costimulatory signals strongly promote Th1 differentiation, enhancing IFN gamma production by naive T cells. We recently reported that knockdown of CD226 on human T cells resulted in a decrease in T-bet and IFN-gamma expression. However, the role of CD226 on Th2 and Th17 cells remains unknown. In this study, we found that CD226 and its ligand CD155 were decreased on Th2-polarized naive T cells, whereas both were highly expressed under Th17 conditions. Most IFN-gamma- and IL-17-producing cells expressed high levels of CD226, but production of IL-13 did not correlate with CD226 expression. CD226 knockdown by lentiviral transduction resulted in increased STAT-6 phosphorylation, enhanced GATA3 expression, and consequently higher production of IL-4 and IL-13. Under Th17 conditions, CD226-depleted cells showed slightly impaired IL-17 secretion, suggesting that CD226 contributes, in part, to IL-17 production but is dispensable for Th17 cell generation. In line with these results, CD226 blockade with neutralizing Abs efficiently inhibited T cell activation and proliferation and production of IFN-gamma and IL-17, whereas IL-13 secretion remained functional. Taken together, our results establish an important role for CD226 in differentially regulating the proinflammatory (Th1/Th17)/anti-inflammatory (Th2) balance, suggesting that the CD226/CD155 interaction could potentially be targeted in therapeutic approaches to human autoimmune diseases. PMID- 23980212 TI - Evaluation of the temporal stability of Definity using double passive cavitation detection. PMID- 23980213 TI - Comparative study evaluating the role of color Doppler sonography and computed tomography in predicting chest wall invasion by lung tumors. AB - OBJECTIVES: To analyze qualitative and quantitative parameters of lung tumors by color Doppler sonography, determine the role of color Doppler sonography in predicting chest wall invasion by lung tumors using spectral waveform analysis, and compare color Doppler sonography and computed tomography (CT) for predicting chest wall invasion by lung tumors. METHODS: Between March and September 2007, 55 patients with pleuropulmonary lesions on chest radiography were assessed by grayscale and color Doppler sonography for chest wall invasion. Four patients were excluded from the study because of poor acoustic windows. Quantitative and qualitative sonographic examinations of the lesions were performed using grayscale and color Doppler imaging. The correlation between the color Doppler and CT findings was determined, and the final outcomes were correlated with the histopathologic findings. RESULTS: Of a total of 51 lesions, 32 were malignant. Vascularity was present on color Doppler sonography in 28 lesions, and chest wall invasion was documented in 22 cases. Computed tomography was performed in 24 of 28 evaluable malignant lesions, and the findings were correlated with the color Doppler findings for chest wall invasion. Of the 24 patients who underwent CT, 19 showed chest wall invasion. The correlation between the color Doppler and CT findings revealed that color Doppler sonography had sensitivity of 95.6% and specificity of 100% for assessing chest wall invasion, whereas CT had sensitivity of 85.7% and specificity of 66.7%. CONCLUSIONS: Combined qualitative and quantitative color Doppler sonography can predict chest wall invasion by lung tumors with better sensitivity and specificity than CT. Although surgery is the reference standard, color Doppler sonography is a readily available, affordable, and noninvasive in vivo diagnostic imaging modality that is complementary to CT and magnetic resonance imaging for lung cancer staging. PMID- 23980214 TI - Clinical outcomes of pediatric patients with acute abdominal pain and incidental findings of free intraperitoneal fluid on diagnostic imaging. AB - OBJECTIVES: The presence of free intraperitoneal fluid on diagnostic imaging (sonography or computed tomography [CT]) may indicate an acute inflammatory process in children with abdominal pain in a nontraumatic setting. Although clinical outcomes of pediatric trauma patients with free fluid on diagnostic examinations without evidence of solid-organ injury have been studied, similar studies in the absence of trauma are rare. Our objective was to study clinical outcomes of children with acute abdominal pain of nontraumatic etiology and free intraperitoneal fluid on diagnostic imaging (abdominal/pelvic sonography, CT, or both). METHODS: We conducted a retrospective review of medical records of children aged 0 to 18 years presenting to a pediatric emergency department with acute abdominal pain (nontraumatic) between April 2008 and March 2009. Patients with intraperitoneal free fluid on imaging were divided into 2 groups: group I, imaging suggestive of an intra-abdominal surgical condition such as appendicitis; and group II, no evidence of an acute surgical condition on imaging, including patients with equivocal studies. Computed tomograms and sonograms were reviewed by a board-certified radiologist, and the free fluid volume was quantitated. RESULTS: Of 1613 patients who underwent diagnostic imaging, 407 were eligible for the study; 134 (33%) had free fluid detected on diagnostic imaging. In patients with both sonography and CT, there was a significant correlation in the free fluid volume (r = 0.79; P < .0005). A significantly greater number of male patients with free fluid had a surgical condition identified on imaging (57.4% versus 25%; P < .001). Children with free fluid and an associated condition on imaging were more likely to have surgery (94.4% versus 6.3%; P < .001). CONCLUSIONS: We found clinical outcomes (surgical versus nonsurgical) to be most correlated with a surgical diagnosis on diagnostic imaging and not with the amount of fluid present. PMID- 23980215 TI - Fusion imaging-guided percutaneous biopsy of focal hepatic lesions with poor conspicuity on conventional sonography. AB - OBJECTIVES: The purpose of this study was to evaluate the effectiveness of real time fusion imaging (sonography combined with computed tomography or magnetic resonance imaging) for percutaneous sonographically guided biopsy of focal hepatic lesions with poor sonographic conspicuity. METHODS: This study was conducted as a retrospective analysis of a prospective database and was approved by the Institutional Review Board. Patients who had target lesions with poor conspicuity on B-mode sonography for percutaneous biopsy were enrolled in the study. Lesion conspicuity was assessed by conventional B-mode sonography first and then by fusion imaging later in the same session. We compared lesion conspicuity and detection rates between B-mode sonography and fusion imaging and evaluated how many cases of initially invisible lesions on B-mode sonography became visible on fusion imaging. The technical success rate was evaluated on the basis of the final diagnoses, which were established by pathologic examination of the biopsy specimens as well as follow-up clinical and radiologic examinations. RESULTS: A total of 22 patients were enrolled in the study. On fusion imaging, lesion conspicuity was increased in 63.6% of focal hepatic lesions (14 of 22). Moreover, 66.7% of lesions (6 of 9) that were invisible on B-mode sonography became visible on fusion imaging. The true-positive detection rate was significantly different between B-mode sonography and fusion imaging (9 of 22 versus 19 of 22; P = .0044). Percutaneous biopsy was performed for all lesions, including 3 target lesions that were invisible even on fusion imaging. The technical success rate was 95.5% (21 of 22). CONCLUSIONS: Fusion imaging is effective for percutaneous biopsy of focal hepatic lesions with poor sonographic conspicuity. PMID- 23980216 TI - Role of preoperative sonography in the diagnosis and pathologic staging of pseudomyxoma peritonei. AB - OBJECTIVES: The purpose of this study was to analyze the sonographic features of pseudomyxoma peritonei and the ability of preoperative sonography to assess the pathologic grades of this disease. METHODS: Nineteen patients with pseudomyxoma peritonei who underwent preoperative sonographic examinations were included (9 male and 10 female; age range, 31-70 years). Four patients presented with disseminated peritoneal adenomucinosis, 7 with peritoneal mucinous carcinomatosis with intermediate or discordant features (intermediate-grade disease), and 8 with peritoneal mucinous carcinomatosis. The sonographic characteristics, clinical features, and serum tumor marker levels were recorded and compared among the 3 grades. RESULTS: Clinical symptoms and carcinoembryonic antigen, cancer antigen 125 (CA-125), CA-19-9, CA-724, and CA-153 levels were not significantly different among the 3 pathologic grades (P > .05). Ascites, scalloping of the visceral margin, invasive parenchymal nodules, and peritoneal masses were detected in all grades. Disseminated peritoneal adenomucinosis occurred without the finding of an omental cake. The presence of enlarged lymph nodes was more common in peritoneal mucinous carcinomatosis. The diagnosis of pseudomyxoma peritonei was made by preoperative sonography in 1 case. Four cases were diagnosed as ovarian mucinous cystadenoma with rupture. One case was diagnosed as a mucinous appendiceal cyst. Four cases were diagnosed as ascites or encapsulated effusion. One case was misdiagnosed as lymphoma. The others were diagnosed as celiac masses. CONCLUSIONS: Preoperative sonography can be used to diagnose pseudomyxoma peritonei as long as radiologists are familiar with the imaging features. Although there are overlaps in the sonographic findings among the different grades, some features may aid in separating them. PMID- 23980217 TI - Evaluation of screening whole-breast sonography as a supplemental tool in conjunction with mammography in women with dense breasts. AB - OBJECTIVES: The purpose of this study was to evaluate the use and performance of supplemental screening whole-breast sonography in conjunction with mammography in asymptomatic women with dense breast tissue. METHODS: A total of 28,796 asymptomatic women underwent screening mammography. Among 20,864 women with dense breasts (72%), 8359 underwent additional sonography as part of their screening examinations. We classified women with mammographically dense breasts into mammography-only and mammography-plus-sonography groups. The reference standard was a combination of pathologic results and clinical follow-up at 2 years. We compared the recall rate, cancer detection yield, sensitivity, specificity, and positive predictive value in each group. RESULTS: Among the 20,864 women with dense breasts, 35 cancers were diagnosed, with a mean size of 13 mm. The cancer detection yield was 0.480 per 1000 women in the mammography-only group and increased to 2.871 in the mammography-plus-sonography group. Of 24 cancers detected in the mammography-plus-sonography group, the mean size was 11 mm, and the axillary lymph nodes were negative in 19 of 20. The sensitivity was significantly higher in the mammography-plus-sonography group than the mammography-only group (100% versus 54.55%; P = .002). The positive predictive values of sonographically prompted biopsy were 11.1% for the mammography-plus sonography group and 50% for the mammography-only group. CONCLUSIONS: Supplemental screening whole-breast sonography increases the cancer detection yield by 2.391 cancers per 1000 women with dense breast tissue over that of mammography alone. It is beneficial for increased detection of breast cancers that are predominantly small and node negative; however, it also raises the number of false-positive results. PMID- 23980218 TI - Improving antenatal prediction of small-for-gestational-age neonates by using customized versus population-based reference standards. AB - OBJECTIVES: The purpose of this study was to evaluate whether the use of customized fetal reference standards improves the prenatal detection of intrauterine growth restriction. METHODS: We conducted a retrospective cohort study. Singleton pregnancies with a diagnosis of a small-for-gestational-age (SGA) fetus based on the in utero reference standard of Hadlock et al (Am J Obstet Gynecol 1985; 151:333-337; Radiology 1991; 181:129-133) were identified from our ultrasound database, and customized percentiles were calculated by adjusting for maternal height, weight, ethnicity, parity, and sex. RESULTS: A total of 300 pregnancies were identified as SGA by both the Hadlock and customized standards, and 60 were identified as SGA by the Hadlock standard only. Small-for-gestational age pregnancies identified by the Hadlock standard only were significantly less likely to have any abnormal sonographic findings, including an elevated head to abdominal circumference ratio (8.3% versus 21.7%; P = .019), oligohydramnios (3.3% versus 13%; P = .027), abnormal umbilical artery Doppler findings (3.4% versus 14.7%; P = .017), maternal hypertensive disease (3.3% versus 12.7%; P = .041), and preterm delivery (6.7% versus 27.7%; P < .001). There was no difference in neonatal intensive care unit admission rates; however, neonates identified as SGA by the Hadlock standard only were less likely to have a postnatal diagnosis of SGA (9.1% versus 78.3%; P < .001) and had a shorter neonatal intensive care unit stay (median, 2 versus 8 days; P < .001). CONCLUSIONS: Using a customized standard, we have identified a population of pregnancies with low rates of antenatal complications and sonographic findings associated with pathologic growth. Adoption of customized standards to improve our antenatal detection rate of intrauterine growth restriction may decrease the need for intervention in healthy but constitutionally small fetuses. PMID- 23980219 TI - Routine sonographic measurement of the near-field lateral ventricle during second trimester morphologic scans. AB - OBJECTIVES: The purpose of this study was to determine whether measurement of the near-field lateral ventricular diameter can be reliably obtained within a practical time frame during second-trimester obstetric scans by angling the fetal head approximately 30 degrees away from the horizontal image axis such that the posterior aspect of the fetal head lies closer to the transducer. METHODS: Fifty consecutive singleton pregnancies presenting for a routine-second trimester scan were recruited for this study. The far-field lateral ventricular diameter was measured, followed by the near-field lateral ventricular diameter using the proposed technique. The measurements were repeated by a second operator who was blinded to the first measurement. Both operators recorded the measurements taken and scored the level of visibility of the near-field lateral ventricle. The difference between the two operators' measurements was compared by a kappa analysis. RESULTS: The near-field lateral ventricle was visualized in 49 of 50 cases (98%). There was no statistically significant difference in the measurement of the near-field lateral ventricular diameter by the two operators (P = .34). There was, however, a statistically significant difference in the time it took each operator to obtain the near-field measurement after the far-field measurement (P = .01). CONCLUSIONS: Manipulating the transducer to position the falx of the fetal head approximately 30 degrees away from the horizontal image axis allows the near-field lateral ventricle to be routinely visualized and measured with a high degree of interoperator agreement and within a practical time frame once the operator is experienced in performing the technique. PMID- 23980220 TI - Efficiency of first-trimester uterine artery Doppler, a-disintegrin and metalloprotease 12, pregnancy-associated plasma protein a, and maternal characteristics in the prediction of preeclampsia. AB - OBJECTIVES: The purpose of this study was to estimate the efficiency of first trimester uterine artery Doppler, A-disintegrin and metalloprotease 12 (ADAM12), pregnancy-associated plasma protein A (PAPP-A), and maternal characteristics in the prediction of preeclampsia. METHODS: We conducted a prospective cohort study of patients presenting for first-trimester aneuploidy screening between 11 and 14 weeks' gestation. Maternal serum ADAM12 and PAPP-A levels were measured by an immunoassay, and mean uterine artery Doppler pulsatility indices were calculated. Outcomes of interest included preeclampsia, early preeclampsia (defined as requiring delivery at <34 weeks' gestation), and gestational hypertension. Logistic regression analysis was used to model the prediction of preeclampsia using ADAM12 multiples of the median (MoM), PAPP-A MoM, and uterine artery Doppler pulsatility index MoM, either individually or in combination. The sensitivity, specificity, and area under the receiver operating characteristic curves were used to compare the screening efficiency of the models using nonparametric U statistics. RESULTS: Among 578 patients with complete outcome data, there were 54 cases of preeclampsia (9.3%) and 13 cases of early preeclampsia (2.2%). Median ADAM12 levels were significantly lower in patients who developed preeclampsia compared to those who did not (0.81 versus 1.01 MoM; P = .04). For a fixed false-positive rate of 10%, ADAM12, PAPP-A, and uterine artery Doppler parameters in combination with maternal characteristics identified 50%, 48%, and 52% of patients who developed preeclampsia, respectively. Combining these first-trimester parameters did not improve the predictive efficiency of the models. CONCLUSIONS: First-trimester ADAM12, PAPP-A, and uterine artery Doppler characteristics are not sufficiently predictive of preeclampsia. Combinations of these parameters do not further improve their screening efficiency. PMID- 23980221 TI - Formative assessment based on an audit and feedback improves nuchal translucency ultrasound image quality. AB - OBJECTIVES: The purpose of this work was to study the impact of an audit and feedback on the quality of routine first-trimester nuchal transparency ultrasound images. METHODS: Eighty-eight sonographers were each sent 2 different series of 30 consecutive nuchal translucency images at a mean interval of 3 months to a dedicated, protected server for remote double-blind independent analysis based on the new College Francais d'Echographie Foetale/Centre National de la Recherche Scientifique image-scoring method (https://www.cfef.org/evaluation/ISMCFEFCNRS.pdf). The sonographers were classified as low (score below the median) or high (score above the median) scorers for each series. Before their second evaluation, 73 of the 88 sonographers received a feedback report on their first series of images, whereas the other 15 participants received no feedback. The baseline characteristics of the participants who did and did not receive feedback were comparable. RESULTS: Participants who received feedback increased their average score significantly, from a mean +/- SD of 11.1 +/- 1.3 to 13.4 +/- 1.4 among low scorers (P < .00001) and from 15.1 +/- 1.2 to 16.0 +/- 1.4 among high scorers (P < .001), whereas no significant change was seen among participants who received no feedback (low scorers, 10.9 +/- 1.5 to 12.1 +/- 2.0; P = .11; high scorers, 14.7 +/- 1.3 to 14.6 +/- 1.3; P = .99). The proportion of satisfactory images increased by 48% among low scorers who received feedback. CONCLUSIONS: Formative assessment based on a moderately intensive audit and feedback is feasible and effective for improving the quality of routine first-trimester nuchal transparency ultrasound images. PMID- 23980222 TI - Efficacy of the genetic sonogram in a stepwise sequential protocol for down syndrome screening. AB - OBJECTIVES: The purpose of this study was to evaluate the efficacy of the genetic sonogram in Down syndrome screening for women who have received the stepwise sequential test. METHODS: This retrospective cohort study included women with singleton pregnancies who underwent stepwise sequential (first-trimester combined and second-trimester serum) screening and then had a genetic sonogram between March 2005 and January 2010. Stepwise sequential Down syndrome risks were multiplied by either a positive or negative likelihood ratio based on the second trimester sonographic findings to determine the final Down syndrome risk. A final Down syndrome risk of 1:270 or higher was considered screen positive. RESULTS: A total of 6286 women fulfilled our criteria, including 17 with Down syndrome affected fetuses. After stepwise sequential testing, the Down syndrome detection rate was 88.2% (15 of 17), and after the genetic sonogram, there was a non significant reduction in detection to 82.4% (14 of 17; P > .05). For the 6269 unaffected pregnancies, the genetic sonogram converted 58 screen-negative results (1%) to positive and 183 screen-positive results (3.1%) to negative. The net effect was a change in the false-positive rate from 6.2% (390 of 6269) after stepwise sequential screening to 4.2% (266 of 6269) after the genetic sonogram. CONCLUSIONS: The genetic sonogram should be applied cautiously for women who have received prior prenatal screening tests. Women with screen-positive results need to be counseled that a negative sonographic result can be falsely reassuring. Conversely, for women with screen-negative results who have a risk close to the cutoff, a sonographic examination could assist in the decision of whether to accept or reject amniocentesis. PMID- 23980223 TI - Effect of B-mode optimization techniques on fetal bowel echogenicity using computerized image analysis. AB - OBJECTIVES: The purpose of this study was to provide and compare measurable parameters for normal fetal bowel echogenicity under predefined B-mode scanning presets. METHODS: Forty healthy fetuses underwent 14- to 17-week ultrasound scans, and 40 underwent 21- to 25-week scans. Sagittal, coronal, and axial fetal abdominal images were tested using predefined B-mode presets. The presets differed from fundamental imaging by isolated activation of harmonic imaging, compound resolution imaging, speckle reduction imaging, focus and frequency composite imaging, and coded excitation imaging features. A transabdominal probe was used in all fetuses, and transvaginal images were added for the 14- to 17 week scans. The images were studied with custom-developed software, which provided a grayscale analysis of the pixels in the region of interest within the image. The mean brightness of the pixels from the fetal bowel area was calculated. RESULTS: The 14- to 17-week transabdominal scans showed significantly higher mean brightness on harmonic imaging compared to fundamental imaging (P < .01). Activation of coded excitation and compound resolution imaging in these scans resulted in a significant decrease in the mean brightness compared to fundamental imaging. Mean bowel brightness values on the 21- to 25-week transabdominal scans did not differ significantly with the use of the different imaging presets compared to fundamental imaging. CONCLUSIONS: Transabdominal harmonic imaging in the early second trimester may significantly increase the mean brightness of the fetal bowel tissue. Contrarily, compound resolution imaging and coded excitation imaging produce the opposite effect on bowel echogenicity. PMID- 23980224 TI - Reference values for the right and left fetal choroid plexus at 11 to 13 weeks: an early sign of "developmental" laterality? AB - OBJECTIVES: The purpose of this study was to establish reference values for the length, area, and circumference of the right and left fetal choroid plexus at 11 to 13 weeks with respect to the fetal biparietal diameter and to compare the right to the left side. METHODS: We conducted a prospective study on 114 fetuses at 11 to 13 weeks undergoing first-trimester screening for aneuploidy and structural fetal abnormalities. After the establishment of the fetal situs, the plane of the "butterfly" was obtained on all fetuses, from which the length, area, and circumference of both the right and left choroid plexus were obtained and the right and left sides compared. Using a paired t test, analysis of variance, scatterplots, and linear and logarithmic fittings, reference ranges and charts for the length, area, and circumference of the choroid plexus were then formulated according to their relationship to the fetal biparietal diameter. P < .05 was considered statistically significant. RESULTS: Reference values for the length, area, and circumference of the fetal choroid plexus, with respect to the fetal biparietal diameter, were established. There was a statistically significant difference between the right and left sides for all parameters, with all measurements statistically greater on the left side (P < .0001). CONCLUSIONS: Reference values for the length, area, and circumference of the fetal choroid plexus at 11 to 13 weeks are presented. These may prove to be of clinical importance in the early screening for central nervous system abnormalities. In addition, the statistically significant difference between the right and left sides may be an early sign of "developmental" laterality. PMID- 23980225 TI - Medial or lateral location of the whirlpool sign in adnexal torsion: clinical importance. AB - OBJECTIVES: The whirlpool sign is used as a sonographic marker for adnexal torsion. The aims of this study were to describe the location of the whirlpool sign (lateral or medial to the ovary) and to evaluate the clinical importance of the location. METHODS: Thirty patients with a confirmed surgical diagnosis of torsion and a positive whirlpool sign on sonography before surgery were included. We examined the sonographic clips of these patients. Classic signs of adnexal torsion were determined: ovarian edema, the presence of a mass, pelvic free fluid, and ovarian ischemia on Doppler imaging. The whirlpool sign was detected on grayscale and color Doppler sonography by moving the transducer to and fro along the axis of suspected torsion. RESULTS: Sixteen of 30 patients had right sided torsion. Of these, 7 had a lateral whirlpool sign. All 7 of these patients had an ovarian or paraovarian mass. Nine of these 16 patients had a medial whirlpool sign. Of these, 7 had an ovarian or paraovarian mass, and 2 had no mass. Of the 14 patients with left-sided torsion, all had a medial whirlpool sign. Nine of 14 these patients had an ovarian or paraovarian mass, and 5 had no mass. The mean volume of the masses among cases with the lateral whirlpool sign was significantly greater compared to those with the medial whirlpool sign (304 versus 108 cm(3); P = .035). In 25 of 30 cases, the torsed components included the ovary. CONCLUSIONS: The lateral whirlpool sign is associated with enlarged masses in comparison to the medial whirlpool sign. This finding indicates the need to search meticulously for the lateral whirlpool sign in cases with enlarged masses to decide whether to operate on these patients emergently. PMID- 23980226 TI - Potential role of strain elastography for detection of the extent of large-scar endometriosis. AB - OBJECTIVES: The purpose of this study was to evaluate the clinical value of strain elastography for detection of the lesion extent of large-scar endometriosis and compare it to conventional sonography and magnetic resonance imaging (MRI). METHODS: Eight patients suspected of having large-scar endometriosis underwent transabdominal sonography, strain elastography, and MRI. The mass was located and assessed for its size, imaging appearance, and, especially, widest boundary and vertical extent. After wide surgical excision and pathologic diagnosis, lesions in the central area shown on conventional sonography and the extended area shown on strain elastography underwent immunohistochemical examination. RESULTS: Nodules were always deep in the subcutaneous plane, in contact with the fascia or muscle. Horizontally, the mean lesion size shown on conventional sonography was mainly consistent with the size on MRI in all cases, but it was obviously smaller on sonography than on strain elastography in 7 cases. Vertically, the lesion depth was mainly consistent with the depth on MRI in 7 cases, but it was more infiltrative on strain elastography in 6 cases. The vertical and horizontal infiltration scales of the postoperative specimens were consistent with strain elastography in all cases. All 8 patients showed strong collagen type I expression in the central area of the lesions; 6 patients showed strong collagen type I expression and the other 2 showed moderate expression in the extended area. CONCLUSIONS: Strain elastography can elevate the diagnostic accuracy of large-scar endometriosis, the extent of which may be evaluated insufficiently by transabdominal sonography and MRI. PMID- 23980228 TI - Sonography as a tool for identifying engaging Hill-Sachs lesions: preliminary experience. AB - Engaging Hill-Sachs lesions can be a factor predictive of recurrent anterior shoulder instability, yet no method has been recognized as an effective means to predict engagement. We evaluated the ability of sonography to identify engaging Hill-Sachs lesions by using a transaxillary approach and dynamic scanning. In patients with engaging lesions, there was an abrupt change in the contour of the humeral head when the shoulder was in 90 degrees of abduction and 90 degrees of external rotation. Sonography therefore has the potential to be a useful preoperative tool in determining which patients may benefit from a surgical repair that also addresses Hill-Sachs lesions. PMID- 23980227 TI - Sonographic visualization of the first branch of the lateral plantar nerve (baxter nerve): technique and validation using perineural injections in a cadaveric model. AB - OBJECTIVES: The primary purpose of this investigation was to document the ability of high-resolution sonography to accurately identify the first branch of the lateral plantar nerve (FBLPN) using sonographically guided perineural injections in an unembalmed cadaveric model. METHODS: single experienced operator completed sonographically guided perineural FBLPN injections in 12 unembalmed cadaveric specimens (6 right and 6 left) obtained from 10 donors (5 male and 5 female) aged 47 to 95 years (mean, 71 years) with an average body mass index of 24.2 kg/m(2) (range, 17.2-31.6 kg/m(2)). All injections were completed using 22-gauge, 38-mm stainless steel needles to deliver 1 mL of 50% diluted colored latex adjacent to the FBLPN in the abductor hallucis-quadratus plantae (AH-QP) interval. Six injections were completed using a cart-based ultrasound (US) machine and a 17-5 MHz transducer, and 6 were completed using a portable US machine and a 12-3-MHz transducer. Nerve conspicuity was graded on a 4-point scale (1, poor; 4, excellent). After a minimum of 24 hours, study coinvestigators dissected each specimen to assess injectate placement. RESULTS: All 12 injections accurately placed latex onto the FBLPN within the AH-QP interval, with 11 of 12 (91%) resulting in complete nerve coverage. Proximal latex overflow to the lateral plantar nerve occurred in 82% of cases (10 of 12). The average distance between the plantar fascia and injected latex was 1.2 cm (range, 1.0-1.75 cm). No vascular injury was seen in any specimen. The average nerve conspicuities were 3.7 (range, 3-4) using the cart-based US machine and 1.8 (range, 1-4) using the portable US machine. CONCLUSIONS: Sonographic visualization of the FBLPN in the AH-QP interval is feasible and should be considered for diagnostic and therapeutic purposes in patients presenting with chronic or atypical heel pain syndromes. Further clinical experience should refine the role of FBLPN sonography and explore the utility of sonographically guided diagnostic and therapeutic FBLPN perineural injections. PMID- 23980229 TI - Evaluating lesion segmentation on breast sonography as related to lesion type. AB - Breast sonography currently provides a complementary diagnosis when other modalities are not conclusive. However, lesion segmentation on sonography is still a challenging problem due to the presence of artifacts. To solve these problems, Markov random fields and maximum a posteriori-based methods are used to estimate a distortion field while identifying regions of similar intensity inhomogeneity. In this study, different initialization approaches were exhaustively evaluated using a database of 212 B-mode breast sonograms and considering the lesion types. Finally, conclusions about the relationship between the segmentation results and lesions types are described. PMID- 23980230 TI - Power M-mode transcranial Doppler examination of the ophthalmic artery in pregnancy: standard operating procedure and review of the literature. AB - Our aim was to describe the standard operating procedure for transcranial Doppler investigation of the ophthalmic artery in pregnancy, determine the interobserver and intraobserver variability using power M-mode technology, and review the existing literature. Accordingly, 27 healthy pregnant or immediately postpartum women were enrolled and underwent transcranial Doppler investigation of the ophthalmic artery using power M-mode technology. Good interobserver and intraobserver variability was observed for both, especially with respect to the clinically important indices. Transcranial Doppler power M-mode examination of the ophthalmic artery is easy and reproducible and holds a great deal of potential for investigation in pregnancy. PMID- 23980231 TI - Intracranial translucency and spinal cord defects: early prenatal diagnosis of diastematomyelia. PMID- 23980232 TI - Three-dimensional sonography of sirenomelia at 10 and 12 weeks' gestation. PMID- 23980233 TI - Isolated umbilical vein varix with a poor outcome despite close fetal surveillance. PMID- 23980234 TI - Viable delivery after conservative management of a cesarean scar pregnancy. PMID- 23980235 TI - Motivating factors and perceived barriers to participating in continuing professional development: a national survey of veterinary surgeons. AB - Although continuing professional development (CPD) is regarded as mandatory by the Royal College of Veterinary Surgeons, it is not yet a statutory requirement. To understand what motivates veterinary surgeons to engage in CPD and perceived barriers to participation, a national survey was administered to a sample of the profession. The study sought to report overall opinion and to compare the views of different groups in terms of decade of graduation, gender, employment status, area of employment and position in the workplace. The results of the study are encouraging in that recent graduates would like to engage in more CPD, compared with their predecessors, and are the most intrinsically and extrinsically motivated. However, significant barriers to participation exist, including personal barriers, a lack of workplace support and a lack of CPD activities at a suitable time, location or level. Part-time workers reported higher barriers than full-time workers. Although the majority (90 per cent) of respondents receive all or part of their CPD funding from employers, a significant proportion (41 per cent) are required to fund at least part of their CPD. First-opinion practitioners reported significantly less access to a professional library, which has implications for lifelong learning and the practice of evidence-based veterinary medicine. PMID- 23980236 TI - Clinicopathological analysis of patients with non-muscle-invasive bladder cancer: prognostic value and clinical reliability of the 2004 WHO classification system. AB - OBJECTIVE: The aim of this study was to clarify the prognostic value and clinical reliability of the 2004 World Health Organization classification system of non muscle-invasive bladder cancer. METHODS: Between January 1995 and November 2010, 153 patients were diagnosed with non-muscle-invasive bladder cancer. We used a substage system that discerns T1-microinvasive (T1m, 42 patients) and T1 extensive-invasive (T1e, 37 patients) cancers. RESULTS: There were 2 (1.3%), 89 (58.2%) and 62 (40.5%) cases of Grade 1-3 urothelial carcinoma, respectively, on the basis of the 1973 World Health Organization classification system. Of these, 37 (24.2%) and 116 (75.8%) were graded as low and high on the basis of the 2004 World Health Organization classification system. All of the cases with progression (15 patients) were diagnosed as high grade at the time of primary transurethral resection of the bladder tumor. Based on the Kaplan-Meier analysis, the 2004 World Health Organization classification system accurately predicted tumor recurrence (P = 0.029) and progression (P = 0.031). The 5-year recurrence free survival rates in patients with low-grade and high-grade tumors were 68.7 and 47.1%, and the 5-year progression-free survival rates were 100 and 89.0%, respectively. In the high-grade T1 cases, the substage (T1m or T1e) was a significant predictor of tumor recurrence (P = 0.001) and progression (P = 0.020). CONCLUSIONS: The 2004 World Health Organization classification system accurately predicts the risk of recurrence in primary non-muscle-invasive bladder cancer cases and has the same accuracy when predicting the risk of progression as the 1973 World Health Organization classification. Furthermore, the substaging system for high-grade T1 tumors is useful in predicting both recurrence and progression. PMID- 23980237 TI - Effect of drink carbohydrate content on postexercise gastric emptying, rehydration, and the calculation of net fluid balance. AB - The purpose of this study was to examine the gastric emptying and rehydration effects of hypotonic and hypertonic glucose-electrolyte drinks after exercise induced dehydration. Eight healthy males lost ~1.8% body mass by intermittent cycling and rehydrated (150% of body mass loss) with a hypotonic 2% (2% trial) or a hypertonic 10% (10% trial) glucose-electrolyte drink over 60 min. Blood and urine samples were taken at preexercise, postexercise, and 60, 120, 180, and 240 min postexercise. Gastric and test drink volume were determined 15, 30, 45, 60, 90, and 120 min postexercise. At the end of the gastric sampling period 0.3% (2% trial) and 42.1% (10% trial; p < .001) of the drinks remained in the stomach. Plasma volume was lower (p < .01) and serum osmolality was greater (p < .001) at 60 and 120 min during the 10% trial. At 240 min, 52% (2% trial) and 64% (10% trial; p < .001) of the drinks were retained. Net fluid balance was greater from 120 min during the 10% trial (p < .001). When net fluid balance was corrected for the volume of fluid in the stomach, it was greater at 60 and 120 min during the 2% trial (p < .001). These results suggest that the reduced urine output following ingestion of a hypertonic rehydration drink might be mediated by a slower rate of gastric emptying, but the slow gastric emptying of such solutions makes rehydration efficiency difficult to determine in the hours immediately after drinking, compromising the calculation of net fluid balance. PMID- 23980238 TI - "Choosing wisely" to reduce low-value care: a conceptual and ethical analysis. AB - The American Board of Internal Medicine (ABIM) Foundation has recently initiated a campaign called "Choosing Wisely," which is aimed at reducing "low-value" care services. Lists of low-value care services are being developed and the ABIM Foundation is urging the American Medical Association and other organizations to get behind the lists, disseminate them, and implement them. Yet, there are many ethical questions that remain about the development, dissemination, and implementation of these low-value care lists. In this paper I argue for conceptual clarity with respect to the label "low-value care." Thus far it has not been precisely defined, and I argue that there are actually 10 distinct categories of low-value care. I discuss the ethical challenges and considerations associated with each category. I also provide arguments that can be used to justify the reduction of some of these categories of low-value care. These arguments rely on Rawlsian and Hegelian notions of justice, as well as on concepts about the fiduciary obligations of physicians. Finally, I outline the various mechanisms that could be utilized for the reduction of low-value care (i.e., incentives, punishments, nonrational influences such as appeals to social norms, emotions, or ego, and creation of conditions that make avoidance easy such as defaults and reminders). I provide normative guidelines for the use of each. PMID- 23980239 TI - The effect of a caffeinated mouth-rinse on endurance cycling time-trial performance. AB - The purpose of this study was to investigate if acute caffeine exposure via mouth rinse improved endurance cycling time-trial performance in well-trained cyclists. It was hypothesized that caffeine exposure at the mouth would enhance endurance cycling time-trial performance. Ten well-trained male cyclists (mean +/- SD: 32.9 +/- 7.5 years, 74.7 +/- 5.3 kg, 176.8 +/- 5.1cm, VO2peak = 59.8 +/- 3.5 ml.kg 1.min-1) completed two experimental time-trials following 24 hr of dietary and exercise standardization. A randomized, double-blind, placebo-controlled, cross over design was employed whereby cyclists completed a time-trial in the fastest time possible, which was equivalent work to cycling at 75% of peak aerobic power output for 60 min. Cyclists were administered 25 ml mouth-rinses for 10 s containing either placebo or 35 mg of anhydrous caffeine eight times throughout the time-trial. Perceptual and physiological variables were recorded throughout. No significant improvement in time-trial performance was observed with caffeine (3918 +/- 243 s) compared with placebo mouth-rinse (3940 +/- 227 s). No elevation in plasma caffeine was detected due to the mouth-rinse conditions. Caffeine mouth rinse had no significant effect on rating of perceived exertion, heart rate, rate of oxygen consumption or blood lactate concentration. Eight exposures of a 35 mg dose of caffeine at the buccal cavity for 10s does not significantly enhance endurance cycling time-trial performance, nor does it elevate plasma caffeine concentration. PMID- 23980240 TI - Short- and long-term conditioning of a temperate marine diatom community to acidification and warming. AB - Ocean acidification and greenhouse warming will interactively influence competitive success of key phytoplankton groups such as diatoms, but how long term responses to global change will affect community structure is unknown. We incubated a mixed natural diatom community from coastal New Zealand waters in a short-term (two-week) incubation experiment using a factorial matrix of warming and/or elevated pCO2 and measured effects on community structure. We then isolated the dominant diatoms in clonal cultures and conditioned them for 1 year under the same temperature and pCO2 conditions from which they were isolated, in order to allow for extended selection or acclimation by these abiotic environmental change factors in the absence of interspecific interactions. These conditioned isolates were then recombined into 'artificial' communities modelled after the original natural assemblage and allowed to compete under conditions identical to those in the short-term natural community experiment. In general, the resulting structure of both the unconditioned natural community and conditioned 'artificial' community experiments was similar, despite differences such as the loss of two species in the latter. pCO2 and temperature had both individual and interactive effects on community structure, but temperature was more influential, as warming significantly reduced species richness. In this case, our short-term manipulative experiment with a mixed natural assemblage spanning weeks served as a reasonable proxy to predict the effects of global change forcing on diatom community structure after the component species were conditioned in isolation over an extended timescale. Future studies will be required to assess whether or not this is also the case for other types of algal communities from other marine regimes. PMID- 23980241 TI - Ocean acidification and rising temperatures may increase biofilm primary productivity but decrease grazer consumption. AB - Climate change may cause ecosystems to become trophically restructured as a result of primary producers and consumers responding differently to increasing CO2 and temperature. This study used an integrative approach using a controlled microcosm experiment to investigate the combined effects of CO2 and temperature on key components of the intertidal system in the UK, biofilms and their consumers (Littorina littorea). In addition, to identify whether pre-exposure to experimental conditions can alter experimental outcomes we explicitly tested for differential effects on L. littorea pre-exposed to experimental conditions for two weeks and five months. In contrast to predictions based on metabolic theory, the combination of elevated temperature and CO2 over a five-week period caused a decrease in the amount of primary productivity consumed by grazers, while the abundance of biofilms increased. However, long-term pre-exposure to experimental conditions (five months) altered this effect, with grazing rates in these animals being greater than in animals exposed only for two weeks. We suggest that the structure of future ecosystems may not be predictable using short-term laboratory experiments alone owing to potentially confounding effects of exposure time and effects of being held in an artificial environment over prolonged time periods. A combination of laboratory (physiology responses) and large, long-term experiments (ecosystem responses) may therefore be necessary to adequately predict the complex and interactive effects of climate change as organisms may acclimate to conditions over the longer term. PMID- 23980242 TI - The stunting effect of a high CO2 ocean on calcification and development in sea urchin larvae, a synthesis from the tropics to the poles. AB - The stunting effect of ocean acidification on development of calcifying invertebrate larvae has emerged as a significant effect of global change. We assessed the arm growth response of sea urchin echinoplutei, here used as a proxy of larval calcification, to increased seawater acidity/pCO2 and decreased carbonate mineral saturation in a global synthesis of data from 15 species. Phylogenetic relatedness did not influence the observed patterns. Regardless of habitat or latitude, ocean acidification impedes larval growth with a negative relationship between arm length and increased acidity/pCO2 and decreased carbonate mineral saturation. In multiple linear regression models incorporating these highly correlated parameters, pCO2 exerted the greatest influence on decreased arm growth in the global dataset and also in the data subsets for polar and subtidal species. Thus, reduced growth appears largely driven by organism hypercapnia. For tropical species, decreased carbonate mineral saturation was most important. No single parameter played a dominant role in arm size reduction in the temperate species. For intertidal species, the models were equivocal. Levels of acidification causing a significant (approx. 10-20+%) reduction in arm growth varied between species. In 13 species, reduction in length of arms and supporting skeletal rods was evident in larvae reared in near-future (pCO2 800+ uatm) conditions, whereas greater acidification (pCO2 1000+ uatm) reduced growth in all species. Although multi-stressor studies are few, when temperature is added to the stressor mix, near-future warming can reduce the negative effect of acidification on larval growth. Broadly speaking, responses of larvae from across world regions showed similar trends despite disparate phylogeny, environments and ecology. Larval success may be the bottleneck for species success with flow-on effects for sea urchin populations and marine ecosystems. PMID- 23980243 TI - Bioturbation determines the response of benthic ammonia-oxidizing microorganisms to ocean acidification. AB - Ocean acidification (OA), caused by the dissolution of increasing concentrations of atmospheric carbon dioxide (CO2) in seawater, is projected to cause significant changes to marine ecology and biogeochemistry. Potential impacts on the microbially driven cycling of nitrogen are of particular concern. Specifically, under seawater pH levels approximating future OA scenarios, rates of ammonia oxidation (the rate-limiting first step of the nitrification pathway) have been shown to dramatically decrease in seawater, but not in underlying sediments. However, no prior study has considered the interactive effects of microbial ammonia oxidation and macrofaunal bioturbation activity, which can enhance nitrogen transformation rates. Using experimental mesocosms, we investigated the responses to OA of ammonia oxidizing microorganisms inhabiting surface sediments and sediments within burrow walls of the mud shrimp Upogebia deltaura. Seawater was acidified to one of four target pH values (pHT 7.90, 7.70, 7.35 and 6.80) in comparison with a control (pHT 8.10). At pHT 8.10, ammonia oxidation rates in burrow wall sediments were, on average, fivefold greater than in surface sediments. However, at all acidified pH values (pH <= 7.90), ammonia oxidation rates in burrow sediments were significantly inhibited (by 79-97%; p < 0.01), whereas rates in surface sediments were unaffected. Both bacterial and archaeal abundances increased significantly as pHT declined; by contrast, relative abundances of bacterial and archaeal ammonia oxidation (amoA) genes did not vary. This research suggests that OA could cause substantial reductions in total benthic ammonia oxidation rates in coastal bioturbated sediments, leading to corresponding changes in coupled nitrogen cycling between the benthic and pelagic realms. PMID- 23980244 TI - The other ocean acidification problem: CO2 as a resource among competitors for ecosystem dominance. AB - Predictions concerning the consequences of the oceanic uptake of increasing atmospheric carbon dioxide (CO2) have been primarily occupied with the effects of ocean acidification on calcifying organisms, particularly those critical to the formation of habitats (e.g. coral reefs) or their maintenance (e.g. grazing echinoderms). This focus overlooks direct and indirect effects of CO2 on non calcareous taxa that play critical roles in ecosystem shifts (e.g. competitors). We present the model that future atmospheric [CO2] may act as a resource for mat forming algae, a diverse and widespread group known to reduce the resilience of kelp forests and coral reefs. We test this hypothesis by combining laboratory and field CO2 experiments and data from 'natural' volcanic CO2 vents. We show that mats have enhanced productivity in experiments and more expansive covers in situ under projected near-future CO2 conditions both in temperate and tropical conditions. The benefits of CO2 are likely to vary among species of producers, potentially leading to shifts in species dominance in a high CO2 world. We explore how ocean acidification combines with other environmental changes across a number of scales, and raise awareness of CO2 as a resource whose change in availability could have wide-ranging community consequences beyond its direct effects. PMID- 23980245 TI - Adaptation and acclimatization to ocean acidification in marine ectotherms: an in situ transplant experiment with polychaetes at a shallow CO2 vent system. AB - Metabolic rate determines the physiological and life-history performances of ectotherms. Thus, the extent to which such rates are sensitive and plastic to environmental perturbation is central to an organism's ability to function in a changing environment. Little is known of long-term metabolic plasticity and potential for metabolic adaptation in marine ectotherms exposed to elevated pCO2. Consequently, we carried out a series of in situ transplant experiments using a number of tolerant and sensitive polychaete species living around a natural CO2 vent system. Here, we show that a marine metazoan (i.e. Platynereis dumerilii) was able to adapt to chronic and elevated levels of pCO2. The vent population of P. dumerilii was physiologically and genetically different from nearby populations that experience low pCO2, as well as smaller in body size. By contrast, different populations of Amphiglena mediterranea showed marked physiological plasticity indicating that adaptation or acclimatization are both viable strategies for the successful colonization of elevated pCO2 environments. In addition, sensitive species showed either a reduced or increased metabolism when exposed acutely to elevated pCO2. Our findings may help explain, from a metabolic perspective, the occurrence of past mass extinction, as well as shed light on alternative pathways of resilience in species facing ongoing ocean acidification. PMID- 23980246 TI - Effects of acidification on olfactory-mediated behaviour in freshwater and marine ecosystems: a synthesis. AB - For many aquatic organisms, olfactory-mediated behaviour is essential to the maintenance of numerous fitness-enhancing activities, including foraging, reproduction and predator avoidance. Studies in both freshwater and marine ecosystems have demonstrated significant impacts of anthropogenic acidification on olfactory abilities of fish and macroinvertebrates, leading to impaired behavioural responses, with potentially far-reaching consequences to population dynamics and community structure. Whereas the ecological impacts of impaired olfactory-mediated behaviour may be similar between freshwater and marine ecosystems, the underlying mechanisms are quite distinct. In acidified freshwater, molecular change to chemical cues along with reduced olfaction sensitivity appear to be the primary causes of olfactory-mediated behavioural impairment. By contrast, experiments simulating future ocean acidification suggest that interference of high CO2 with brain neurotransmitter function is the primary cause for olfactory-mediated behavioural impairment in fish. Different physico-chemical characteristics between marine and freshwater systems are probably responsible for these distinct mechanisms of impairment, which, under globally rising CO2 levels, may lead to strikingly different consequences to olfaction. While fluctuations in pH may occur in both freshwater and marine ecosystems, marine habitat will remain alkaline despite future ocean acidification caused by globally rising CO2 levels. In this synthesis, we argue that ecosystem-specific mechanisms affecting olfaction need to be considered for effective management and conservation practices. PMID- 23980247 TI - Ocean acidification and climate change: advances in ecology and evolution. PMID- 23980248 TI - Emiliania huxleyi increases calcification but not expression of calcification related genes in long-term exposure to elevated temperature and pCO2. AB - Increased atmospheric pCO2 is expected to render future oceans warmer and more acidic than they are at present. Calcifying organisms such as coccolithophores that fix and export carbon into the deep sea provide feedbacks to increasing atmospheric pCO2. Acclimation experiments suggest negative effects of warming and acidification on coccolithophore calcification, but the ability of these organisms to adapt to future environmental conditions is not well understood. Here, we tested the combined effect of pCO2 and temperature on the coccolithophore Emiliania huxleyi over more than 700 generations. Cells increased inorganic carbon content and calcification rate under warm and acidified conditions compared with ambient conditions, whereas organic carbon content and primary production did not show any change. In contrast to findings from short term experiments, our results suggest that long-term acclimation or adaptation could change, or even reverse, negative calcification responses in E. huxleyi and its feedback to the global carbon cycle. Genome-wide profiles of gene expression using RNA-seq revealed that genes thought to be essential for calcification are not those that are most strongly differentially expressed under long-term exposure to future ocean conditions. Rather, differentially expressed genes observed here represent new targets to study responses to ocean acidification and warming. PMID- 23980251 TI - A study of disequilibrium between 220Rn and 216Po for 220Rn measurements using a flow-through Lucas scintillation cell. AB - Lucas-type scintillation cells (LSCs) are commonly used for rapid measurements of (220)Rn concentrations in flow-through mode in field and for calibration experiments in laboratories. However, in those measurements, equilibrium between (220)Rn and (216)Po is generally assumed and two alpha particles are considered to be emitted per (220)Rn decay due to very short half-life of (216)Po. In this paper, a small, yet significant disequilibrium existing between (220)Rn and (216)Po has been examined and shown that less than two alpha particles are actually emitted per (220)Rn decay in the cell when flow is maintained. A theoretical formula has been derived for the first time for a correction factor (CF) to be applied to this measured concentration to account for the disequilibrium. The existence of this disequilibrium has been verified experimentally and is found to increase with the increase in the ratio of flow rate to cell volume. The reason for the disequilibrium is attributed to the flushing out of (216)Po formed in the cell before its decay due to the flow. Uncertainties in measured concentrations have been estimated and the estimated CF values have been found to be significant for the flow rates considered above 5 dm(3) min(-1) for a cell of volume 0.125 dm(3). The calculated values of the CF are about 1.055 to 1.178 in the flow rate range of 4 to 15 dm(3) min(-1) for the cell of volume 0.125 dm(3), while the corresponding experimental values are 1.023 to 1.264. This is a systematic error introduced in (220)Rn measurements using a flow-through LSC, which can be removed either by correct formulation or by proper design of a measurement set-up. PMID- 23980250 TI - Sex-specific associations between screen time and lipoprotein subfractions. AB - BACKGROUND: Time spent in sedentary activities (such as watching television) has previously been associated with several risk factors for cardiovascular disease (CVD) such as increased low-density lipoprotein cholesterol (LDL-C). Little is known about associations with lipoprotein subfractions. Using television and computer screen time in hours per day as a measure of sedentary time, we examined the association of screen time with lipoprotein subfractions. METHODS: Data were used from men and women forming the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study population. Mixed linear models specified lipoprotein measures as the outcome, and screen time as the predictor for fourteen lipoprotein subfraction measures, and included age, smoking status, pedigree, and fat, carbohydrate daily alcohol and energy intake as covariates. Analyses were run separately for men (n = 623) and women (n = 671). A step-down Bonferroni correction was applied to results. The analysis was repeated for significant results (p < .05), additionally controlling for body mass index (BMI) and moderate and vigorous physical activity. RESULTS: Linear models indicated that screen time was associated with five lipoprotein parameters in women: the concentration of large VLDL particles (p = .01), LDL particle number (p = .01), concentration of small LDL particles (p = .04), the concentration of large HDL particles (p = .04), and HDL diameter (p = .02). All associations remained after controlling for moderate or vigorous physical activity and BMI. CONCLUSIONS: We show that sedentary time is associated with lipoprotein measures, markers of cardiometabolic disease, independently of physical activity and BMI, in women but not men. PMID- 23980249 TI - Long-term effects of warming and ocean acidification are modified by seasonal variation in species responses and environmental conditions. AB - Warming of sea surface temperatures and alteration of ocean chemistry associated with anthropogenic increases in atmospheric carbon dioxide will have profound consequences for a broad range of species, but the potential for seasonal variation to modify species and ecosystem responses to these stressors has received little attention. Here, using the longest experiment to date (542 days), we investigate how the interactive effects of warming and ocean acidification affect the growth, behaviour and associated levels of ecosystem functioning (nutrient release) for a functionally important non-calcifying intertidal polychaete (Alitta virens) under seasonally changing conditions. We find that the effects of warming, ocean acidification and their interactions are not detectable in the short term, but manifest over time through changes in growth, bioturbation and bioirrigation behaviour that, in turn, affect nutrient generation. These changes are intimately linked to species responses to seasonal variations in environmental conditions (temperature and photoperiod) that, depending upon timing, can either exacerbate or buffer the long-term directional effects of climatic forcing. Taken together, our observations caution against over emphasizing the conclusions from short-term experiments and highlight the necessity to consider the temporal expression of complex system dynamics established over appropriate timescales when forecasting the likely ecological consequences of climatic forcing. PMID- 23980253 TI - Dietary intake at competition in elite Olympic combat sports. AB - The purpose of the current study was to investigate elite female (n = 21) and male (n = 47) combat sports athletes' (n = 68; mean age (+/- SD) 21.3 +/- 3.8 years; mean height 177 +/- 10.2 cm) dietary intake between weigh-in and the first bout in Olympic combat sports. The data were collected at 6 separate tournaments and measurements included estimated food records, time for recovery, and body weight (BW) at weigh-in and first match. In total, 33 athletes participated in wrestling and taekwondo, sports with extended recovery times, and 35 athletes in judo and boxing, sports with limited recovery time. The results displayed that despite a mean consumption of food and drinks corresponding to 4.2 kg, the athletes only regained an average of 1.9 kg BW during recovery. Water accounted for 86% of the total intake. For each liter of water consumed, athletes gained 0.57 kg BW, when excluding heavy weight athletes (n = 5). Carbohydrate consumption was 5.5 g/kg BW, compared with the recommended 8-10 g/kg BW. In total, one-quarter of the consumed water originated from carbohydrate-rich drinks. Given the average recovery time of 18 (wrestling, taekwondo) versus 8 hr (judo, boxing), the former group consumed twice the amount of water, carbohydrates, protein, and fat as the latter group. In conclusion, a large proportion of the participants did not meet the recovery nutrition guidelines for carbohydrates. In addition, the discrepancy between nutrient intake and weight gain points to the physiological barriers to retaining fluids during a limited recovery time after engaging in weight making practices. PMID- 23980254 TI - The effect of feeding during recovery from aerobic exercise on skeletal muscle intracellular signaling. AB - We previously reported an increase in skeletal muscle protein synthesis during fasted and fed recovery from nonexhaustive aerobic exercise (Harber et al., 2010). The current study examined skeletal muscle intracellular signaling in the same subjects to further investigate mechanisms of skeletal muscle protein metabolism with and without feeding following aerobic exercise. Eight males (VO2peak: 52 +/- 2 ml-1.kg-1.min-1) performed 60-min of cycle ergometry at 72 +/- 1% VO2peak on two occasions in a counter-balanced design. Exercise trials differed only in the postexercise nutritional intervention: EX-FED (5 kcal, 0.83 g carbohydrate, 0.37 g protein, 0.03 g fat per kg body weight) and EX-FAST (noncaloric, isovolumic placebo) ingested immediately and one hour after exercise. Muscle biopsies were obtained from the vastus lateralis at rest (on a separate day) and two hours postexercise to assess intracellular signaling via western blotting of p70S6K1, eEF2, 4EBP1, AMPKalpha and p38 MAPK. p70S6K1 phosphorylation was elevated (p < .05) in EX-FED relative to REST and EX-FAST. eEF2, 4EBP1, AMPKalpha and p38 MAPK signaling were unaltered at 2 h after exercise independent of feeding status when expressed as the ratio of phosphorylated to total protein normalized to actin. These data demonstrate that feeding after a nonexhaustive bout of aerobic exercise stimulates skeletal muscle p70S6K1 intracellular signaling favorable for promoting protein synthesis which may, as recent literature has suggested, better prepare the muscle for subsequent exercise bouts. These data provide further support into the role of feeding on mechanisms regulating muscle protein metabolism during recovery from aerobic exercise. PMID- 23980255 TI - ECG Quiz. Rapid repetitive electric signals in a 12-lead ECG and in telemetry. PMID- 23980256 TI - Electrocardiogram artifacts may be helpful in recognition of haloperidol's side effects. PMID- 23980257 TI - The X-HALE Awards: Stubbing out youth smoking in Ireland. PMID- 23980258 TI - Evidence for an interaction between proinsulin C-peptide and GPR146. AB - Microvascular diseases, such as retinopathies, neuropathies, and nephropathies, are a devastating consequence of type 1 and type 2 diabetes. The etiology of diabetes-associated microvascular dysfunction is poorly understood, and, likewise, treatment modalities for these disorders are limited. Interestingly, proinsulin C-peptide has been shown to play a protective role against diabetes associated complications in experimental animals and in diabetic humans and is thus an attractive therapeutic target. However, an important step in the development of C-peptide-based therapeutics is identification of the C-peptide receptor, which is likely a G protein-coupled receptor (GPCR). Using a unique Deductive Ligand-Receptor Matching Strategy, we sought to determine whether one of the known orphan GPCRs is essential for C-peptide signaling. Knockdown of GPR146, but not GPR107 or GPR160, blocked C-peptide-induced cFos expression in KATOIII cells. Furthermore, stimulation with C-peptide caused internalization of GPR146, and examples of punctate colocalization were observed between C-peptide and GPR146 on KATOIII cell membranes. These data indicate that GPR146 is likely a part of the C-peptide signaling complex and provide a platform for the elucidation of the C-peptide signalosome. PMID- 23980259 TI - Dr. Claudepierre and Dr. Thomas reply. PMID- 23980260 TI - Dr. Hardcastle, et al reply. PMID- 23980261 TI - Dr. Wallace and Dr. Stone reply. PMID- 23980262 TI - Flu shot may prevent heart attacks and stroke. PMID- 23980263 TI - CDX-1401 combined with TLR agonist: positive phase 1 results. PMID- 23980264 TI - Three MRSA vaccines in early clincial trials. PMID- 23980265 TI - Ovarian cancer vaccine candidate DPX-Survivac: positive interim results from phase 1. PMID- 23980266 TI - Chinese biotech partnership brings first hepatitis E vaccine to the market. PMID- 23980267 TI - Therapeutic vaccine for treatment of genital herpes enters phase 2. PMID- 23980268 TI - Visionary concept: printable vaccines. PMID- 23980269 TI - In vivo confocal microscopy of climatic droplet keratopathy. AB - We describe the corneal microstructural changes in a patient with spheroidal degeneration using in vivo confocal microscopy. Multiple hypo- and hyper reflective spherical lesions were observed in the anterior corneal stroma and Bowman's layer ranging from 45 to 220 mm in size. The corneal epithelium, posterior stroma and endothelium were otherwise unaffected. In vivo confocal microscopy demonstrates good correlation with excised histological samples in climatic droplet keratopathy. It provides a non-invasive technique to examine the living cornea for degenerative disease and acts as a bridge between clinical and laboratory observations. PMID- 23980270 TI - [Impact of surface modifications of dental implants on their integration potential]. PMID- 23980271 TI - Neurologic disability: a hidden epidemic for India. PMID- 23980272 TI - Author Response. PMID- 23980274 TI - [Depression - Good family life protects against anxiety and depression]. PMID- 23980273 TI - Author's reply: To PMID 23287081. PMID- 23980275 TI - [Internet Addiction - Immediate psychological effects of Internet use]. PMID- 23980276 TI - ?70 billion on the horizon for European researchers. PMID- 23980277 TI - [Eating Disorders in Childhood - estimated extent]. PMID- 23980278 TI - [Of electronic servers]. PMID- 23980279 TI - Studies seek to find answers about Gulf oil spill legacy. PMID- 23980280 TI - Response to letter regarding article, ''anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis''. PMID- 23980281 TI - Reply to Ollinger et al.: Remote sensing of leaf nitrogen and emergent ecosystem properties. PMID- 23980282 TI - Reply to Bogdan et al.: "Cubic ice" in cirrus clouds under dry and wet conditions. PMID- 23980283 TI - Current world literature. Anesthesia outside the operating room. PMID- 23980284 TI - Retraction. Neuroimaging in metabolic disorders of children. PMID- 23980285 TI - Regarding the relationship between the inflammatory marker C-reactive protein and coronary heart disease. PMID- 23980286 TI - Notification of occupational disease and risk of work disability--how concerned should we be? PMID- 23980287 TI - Avoid yelling "stop thief!" and work disability prevention due to an occupational disease. PMID- 23980288 TI - Notification of occupational disease and risk of work disability--authors' response to commentaries. PMID- 23980289 TI - Validation of maternal and neonatal tetanus elimination in United Republic of Tanzania, 2012. PMID- 23980290 TI - Cholera, 2012. PMID- 23980291 TI - Monthly report on dracunculiasis cases, January -- May 2013. PMID- 23980292 TI - Treatment. Perceived respect affects appointment adherence. PMID- 23980293 TI - WHO revised treatment guidelines urge earlier antiretroviral initiation. PMID- 23980294 TI - Testing. HIV-positive under 45 less likely to receive sustained care. PMID- 23980295 TI - New HIV infections in children down by half in 7 countries. PMID- 23980296 TI - Restriction on HIV funds violates First Amendment rights. PMID- 23980297 TI - Jails. Settlement with county barred future HIV medication claims. PMID- 23980298 TI - PrEP reduces HIV infection in injection drug users. PMID- 23980299 TI - Criminal. Convicted man fails to show transmission law is overbroad. PMID- 23980300 TI - SSI. ALJ's omission harmless mistake; disability denial upheld. PMID- 23980301 TI - Correlation between waist circumference and carotid intima-media thickness in women from Shanghai, China. AB - OBJECTIVE: To evaluate whether waist circumference (WC) >=85 cm is related to asymptomatic preclinical atherosclerosis in women from Shanghai, China. METHODS: A total of 2365 females aged >=20 years recruited from 4 communities underwent physical examination and carotid artery scanning. Their carotid intima-media thickness (C-IMT) was measured. RESULTS: The C-IMT was significantly higher in overweight or obese women with their BMI >=25.0 kg/m2(P<0.01) and in those with their WC >=85 cm than in those with their WC <85 cm (P<0.01). Spearman and partial correlation analysis showed that the C-IMT was significantly correlated with WC which was independent of menopausal status. The C-IMT significantly increased with the increasing WC and reached to a platform in about 85 cm. An increment tendency was found in the subgroup with its WC <85 cm (P<0.01) while no significant tendency was found in the subgroup with its WC>=85 cm (P=0.07).Multiple stepwise regression analysis showed that the WC was an independent risk factor for C-IMT. In logistic regression model, the odd ratio of WC >=80 cm, >=80 cm and <85 cm and >=85 cm for evaluating the risk of C-IMT elevation was 1.632, 1.501, and 1.878, respectively. CONCLUSION: WC is significantly correlated with C-IMT in women from Shanghai, China, and WC>=85 cm may be used in identifying the risk of subclinical carotid atherosclerosis. PMID- 23980302 TI - Natural disasters and environmental health. PMID- 23980303 TI - The effects of the Great Recession on health insurance: changes in the uninsured population from 2007 to 2009. AB - The economic recession that began in California in 2008 did not affect all counties equally. Using data from several years of the California Health Interview Survey, this policy brief examines the differences between 2007 and 2009 for the populations who were uninsured "for all or part of the prior year." During this time period, counties with high unemployment and lower household income saw the highest growth in the uninsured population, due to a large drop in job-based coverage and only a small increase in public coverage. Compared to the uninsured population in California in 2007, Californians who were uninsured for all or part of 2009 were older, more likely to be U.S.-born citizens, had lower household incomes, and were more likely to be unemployed and looking for work. PMID- 23980304 TI - [List of items in a health examination for new employees and how to handle the information]. PMID- 23980305 TI - Challenges and rewards--a career as a generalist. AB - The generalist approach to medical practice has existed for thousands of years, alongside the specialist approach. Proponents and critics of both approaches have existed as well, but with overall societal trends towards reductionism and specialisation there had been a perception that the generalist approach was under threat and in crisis. At the same time, research was finding that healthcare systems with strong primary care, where generalists operate as the first point-of contact within the healthcare system, were more efficient and had better health outcomes. In addition, demographic trends with ageing populations have resulted in more patients with chronic multisystem diseases that require a generalist approach. PMID- 23980306 TI - Tap water iontophoresis versus glycopyrrolate iontophoresis. PMID- 23980307 TI - Tap water iontophoresis versus glycopyrrolate iontophoresis. Reply. PMID- 23980308 TI - [Work related education of employees to prevent occupational accidents]. PMID- 23980309 TI - Hidden wildlife: Ohio authorities getting a sense of captive wildlife population. PMID- 23980310 TI - Rise in snake fungal disease draws researchers' attention. PMID- 23980311 TI - Tornado takes toll on horses: Oklahoma response reflects preparedness. PMID- 23980312 TI - The authors of a recent study. PMID- 23980313 TI - The authors respond. PMID- 23980314 TI - Workforce issues. PMID- 23980315 TI - The AVMA responds. PMID- 23980316 TI - More on the veterinary workforce. PMID- 23980317 TI - As a 2006 graduate. PMID- 23980318 TI - The AVMA responds. PMID- 23980319 TI - BRICS and global health: a call for papers. PMID- 23980320 TI - The ears have it. PMID- 23980321 TI - Foreign veterinary school accreditation. PMID- 23980322 TI - [Overseas business trip of a newly hired employee seen as On the Job Training]. PMID- 23980323 TI - The AVMA responds. PMID- 23980324 TI - [Liability of the employer for a management-level employee who suffered a cerebrovascular accident due to work overload outside the company premises after work hours]. PMID- 23980325 TI - [Cases of employees who refuse to leave work in a timely manner due to poor productivity]. PMID- 23980326 TI - [Case of a taxi driver with various medical conditions]. PMID- 23980327 TI - [Case of an employee taking company financial data home to work on despite the regulation]. PMID- 23980328 TI - Symposium on cardiovascular emergencies and their treatment. 1956. PMID- 23980329 TI - Problems of amoebic dysentery. 1961. PMID- 23980330 TI - Chondro-osteo-dystrophy (Morquios disease) 1961. PMID- 23980331 TI - Ophthalmic problems in children. 1961. PMID- 23980332 TI - Anaemia in pregnancy. 1970. PMID- 23980333 TI - Infectious hepatitis--a clinico-pathological study. 1970. PMID- 23980334 TI - Abuse of steroidal drugs by homoeopaths and hakims. 1981. PMID- 23980335 TI - The role of H2-receptors in Ch. pharyngitis? 1991. PMID- 23980336 TI - Dubai syndrome in Karachi. 1991. PMID- 23980338 TI - Caring for the aging patient. PMID- 23980337 TI - To boldly go..... PMID- 23980339 TI - Open house: CDSF Clinic opens doors to dignitaries, dental community. PMID- 23980340 TI - Volunteers bring smiles to Special Olympians. PMID- 23980341 TI - If you offer Botox, don't skimp on training. PMID- 23980342 TI - Follow those who lead by example. PMID- 23980343 TI - Kelly Skerrett finds her outlet through abstract art. PMID- 23980344 TI - The passion of John Sachs. Eric Family Health Center honors the contributions and commitment of Dr. Sachs. PMID- 23980345 TI - Bringing up baby. PMID- 23980346 TI - Is ownership 9/10 of the law? PMID- 23980347 TI - [Where will Chinese medicine disease names go?]. AB - The statistical survey of "Clinical Articles", one column of Journal of Traditional Chinese Medicine (24 volumes in total) showed that, of the 151 academic exploration on diseases, Western disease (WM) names were used in 145 articles, constituting 96.03% of the entire column. Obviously, Chinese medicine (CM) disease names were not basically used by CM physicians. Taking Chinese Internal Medicine (2nd edition), a national textbook for students in CM universities, as an example, we could find that the use of disease names was in a chaos logically, disease, syndrome, and symptom were not used clearly. In the general knowledge part, when mentioning a disease, the book sometimes used "disease", sometimes "disease-syndrome". In the classified parts, some diseases were simply named as "A or B syndrome", and when talking about a specific disease, it referred to the symptom-based disease as a kind of "disease syndrome". Throughout the whole book, the disease names named after symptoms or heavily colored by symptoms amounted to 31, accounting for 59.6% of the listed 52 common diseases. In clinical practices, using CM disease names ran the risk of making wrong diagnosis or failing to diagnose patients in time, and therefore, leading to improper treatment or loss of treatment time. For critical diseases, these names can't reveal the serious situations and help to get rid of possible dangers. For chronic diseases, using these names can't lead to early recognition and prevention of diseases. Considering that CM disease names can't go with clinical practices, and lag behind the development of integrative medicine, the author suggested that we should borrow as many WM disease names as possible in CM, because when compared with CM, WM has a much clearer and more objective knowledge of the location, cause, mechanisms, diagnosis, treatment, and prevention of diseases. The classification and naming of diseases in WM is the result of negotiation of WHO and its member countries (including China), and therefore, more generally accepted. How to do that? We should start from the present clinical practice, refer to the tradition, face the future, and work hard. Borrowing WM disease names is of great significance. It will help to bring the theory of Zang-Fu organs back to its origin, clinically help to deepen the combination of disease and syndrome, disease and formula, promote the objectification and micronization of syndrome differentiation in CM, and possibly bring about new theories of CM which will in return promote clinical development. CM will be able to occupy an important position in the field of world medicine and make its own contributions to the health of the global population. PMID- 23980348 TI - [Jinshuibao capsule combined losartan potassium intervened early renal damage of hypertension patients of yin and yang deficiency: a clinical research]. AB - OBJECTIVE: To observe the effects of Jinshuibao Capsule (JC) combined losartan potassium on some indices of early renal damage of hypertension patients of yin and yang deficiency syndrome (YYDS), such as levels of serum cystatin C (Cys C), beta2-microglobulin (beta2-MG), hypersensitive C-reactive protein (hs-CRP), uric acid (UA), blood pressure, blood lipids, and fasting blood glucose (FBG), and to explore their protective effects on early renal damage of hypertension patients and on the metabolisms of blood lipids and blood glucose. METHODS: Totally 106 hypertension patients of YYDS were randomly assigned to two groups, 53 patients in the control group (treated by losartan potassium) and 53 patients in the treatment group (treated by JC + losartan potassium). The treatment lasted for 16 weeks. The serum changes of UA, Cys C, beta2-MG, hs-CRP, blood lipids [including total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C)], and FBG levels were measured to evaluate the renal protective effects and to assess their effect on the metabolisms of blood lipids and blood glucose. RESULTS: Compared with before treatment in the same group, the systolic blood pressure (SBP) decreased in the two groups after treatment, showing statistical difference (P < 0.05, P < 0.01), but there was no statistical difference between the two groups (P > 0.05). The diastolic blood pressure (DBP) was not obviously declined in the two groups after treatment, showing no statistical difference. Compared with before treatment in the same group, the LDL-C level decreased obviously after treatment in the control group. But there was no obvious change in FBG, TC, HDL-C, and TG in the control group, showing no statistical difference when compared with before treatment (P < 0.05). The FBG, TC, and LDL-C obviously decreased in the treatment group more obviously after treatment than before treatment, showing statistical difference (P < 0.05, P < 0.01). There was no statistical difference when compared with the control group after treatment (P > 0.05). Compared with before treatment in the same group, the levels of UA, Cys C, beta2-MG, and hs-CRP all decreased in the two groups, showing statistical difference (P < 0.05, P < 0.01). The SCr level decreased in the treatment group more obviously after treatment than before treatment, showing statistical difference (P < 0.05). Compared with the control group after treatment, the levels of Cys C, beta2-MG, and hs-CRP decreased more obviously after treatment in the treatment group, showing statistical difference (P < 0.05). CONCLUSIONS: JC combined losartan potassium showed better effects in treating early renal damage of hypertension patients of YYDS. They could protect and stabilize the renal functions more effectively. JC could regulate blood lipids and blood glucose. PMID- 23980349 TI - [Treatment of hyperlipoidemia by xiaozhi capsule: a clinical efficacy research]. AB - OBJECTIVE: To observe the clinical effect and efficacy of Xiaozhi Capsule (XZC), a Chinese medicine preparation for tonifying Gan-Shen, invigorating Pi to dissipate dampness (TGSIPDD) on total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), and endothelin (ET) in treating patients with hyperlipidemia. METHODS: Totally 120 primary hyperlipidemia patients were randomly assigned to the treatment group (80 cases) and the control group (40 cases). Those in the treatment group took XZC, while those in the control group took Xuezhikang Capsule (XZKC). The serum TC, TG, HDL-C, LDL-C, and ET were detected and evaluated after 8 weeks of treatment. RESULTS: In the treatment group TC was reduced by 25.60%, TG by 33.70%, LDL-C by 32.90%, and ET by 11.02%, while HDL-C was elevated by 24.20%. In the control group, TC was reduced by 24.80%, TG by 33.50%, LDL-C by 31.30%, and ET by 12.05%, while HDL-C was elevated by 20.90%. There was statistical difference in the two groups when compared with before treatment (P < 0.01). But there was no statistical difference in the aforesaid indices between the two groups after treatment (P > 0.05). The integrals for main symptoms after treatment obviously decreased in the two groups, showing statistical difference when compared with before treatment in the same group (P < 0.01). But there was no statistical difference in the aforesaid indices between the two groups (P > 0.05). After 8 weeks of treatment, symptoms such as vertigo, heavy sensation of head, palpitation, chest distress, dry mouth and thirsty were obviously improved after treatment. There was statistical difference in the improvement of tinnitus after treatment in the treatment group (P < 0.01). The total effective rate was 86.25% in the treatment group and 82.50% in the control group, showing no statistical difference (P > 0.05). CONCLUSIONS: XZC showed certain effects on each blood lipid index and ET of hyperlipidemia patients. It had better improvement of clinical symptoms with reliable efficacy. PMID- 23980350 TI - [Effect of clinical pathways based on integrative medicine for patients with chronic heart failure: a multi-center research]. AB - OBJECTIVE: To assess a multi-center study effectiveness of clinical pathways based on integrative medicine (IM) for chronic heart failure (CHF) patients. METHODS: A combined method of historical control study and clinical study on concurrent control was used. After the standard management for clinical pathways was carried out in four hospitals at home, the effects on hospitalization days, medical expenses, clinical efficacy, patient satisfaction, and quality of life were assessed. RESULTS: Results of non-concurrent historical control study showed that: the hospital stay was significantly shorter in the pathways group than in the retrospective group (12.59 days vs 18.44 days), and the total cost of hospitalization was significantly reduced in the pathways group (yen 9 051.90 vs yen 11 978.40), showing statistical difference (P < 0.01). Moreover, the effect on the heart function was better in the pathways group than in the retrospective group (the markedly effective rate: 45.60% vs 21.90%; the total effective rate: 96.80% vs 86.10%), showing statistical difference (P < 0.01). Results of clinical study on concurrent control showed that the hospital stay was significantly shorter in the pathways group than in the control group (11.19 days vs 13.21 days), showing statistical difference (P < 0.05). The average total cost of hospitalization was significantly lower in the pathways group than in the control group (yen 8 656.80 vs yen 11 609.70), showing statistical difference (P < 0.01). As for clinical efficacy of Chinese medical syndrome, the total effective rate was higher in the pathways group than in the control group (97.10% vs 93.62%), showing statistical difference (P < 0.05). The markedly effective rate of heart function was better in the pathways group than in the control group, showing statistical difference (49.30% vs 38.30%, P < 0.05). The overall satisfaction was higher in the pathways group than in the conventional group (P < 0.01). There was no statistical difference in the mortality within 3 months after discharge from hospital, and the readmission rate due to heart failure between the two groups (P > 0.05). But there was statistical difference in the quality of life (P < 0.05). CONCLUSION: The pathway could shorten the hospitalization time, decrease the cost of hospitalization, improve the clinical efficacy, improve patients' quality of life and satisfaction, therefore, it could be spread nationwide. PMID- 23980351 TI - [Treatment of sixty-one patients with coronary slow flow phenomenon by yiqi huoxue recipe combined Western drugs: a clinical research]. AB - OBJECTIVE: To observe the clinical efficacy of treating patients with coronary slow flow phenomenon by Yiqi Huoxue Recipe (YHR) combined Western drugs, thus providing clinical evidence for further studies. METHODS: Totally 61 patients with coronary slow flow phenomenon were randomly assigned to the treatment group (31 cases) and the control group (30 cases). Patients in the control group were treated with basic treatment of Western medicine, while those in the treatment group were treated with basic treatment of Western medicine and YHR. The therapeutic course for all was two months. Clinical symptoms were observed, and electrocardiogram examinations taken, and left ventricular ejection fraction (LVEF) were evaluated before treatment and at two months after treatment. RESULTS: Patients' clinical symptoms and electrocardiogram examinations were significantly improved in the treatment group. Its effective rate of improved symptoms was 90.32% in the treatment group, superior to that in the control group (76.67%, P < 0.05). The effective rate of electrocardiogram examinations was 87.10% in the treatment group, superior to that in the control group (73.33%, P < 0.05). But there was no statistical difference in LVEF between the two groups (P > 0.05). CONCLUSION: YHR combined Western drugs could improve clinical symptoms and electrocardiographic ischemia in patients with coronary slow flow phenomenon. PMID- 23980352 TI - [Effects of resolving method of Chinese medicine on the lipid metabolism in polycystic ovary syndrome accompanied with non-alcoholic fatty liver disease]. AB - OBJECTIVE: To observe the therapeutic effect of resolving method of Chinese medicine (CM) on the lipid metabolism in polycystic ovary syndrome (PCOS) patients accompanied with non-alcoholic fatty liver disease (NAFLD), to analyze the correlation between PCOS and NAFLD, and to study its mechanisms. METHODS: Totally 70 female PCOS patients in the reproductive age (20 -40 years old) were recruited. Among them, 35 PCOS patients accompanied with NAFLD were recruited as Group A, and 35 PCOS patients without complicated NAFLD were recruited as Group B. At the same time, 20 healthy female volunteers were recruited as the control group. All subjects had their personal medical records after relevant questionnaire. Their clinical data including body height (BH), body weight (BW), body mass index (BMI), waist circumference (WC), hip circumference (HC), testosterone (T), prolactin (PRL), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), leptin, fasting blood glucose (FBG), fasting insulin (FINS), 2 h postprandial blood glucose (2 h PBG), homeostatic model assessment for insulin resistance (HOMA-IR), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), etc. were detected. Patients in Group A were treated by the resolving method for 3 months. The follow-up was continued for 6 months after ending treatment. RESULTS: The levels of BW, BMI, WHR, T, LH, LH/FSH, leptin, FINS, 2 h PBG, HOMA-IR, and LDL-C were significantly higher in Group B than in the control group (P < 0.05). The level of FSH was significantly lower in Group B than in the control group (P < 0.05). The levels of BW, BMI, WC, HC, waist-hip-ratio (WHR), leptin, FINS, 2 h PBG, HOMA-IR, TG, LDL-C, ALT, and AST were significantly higher in Group A than in Group B (P < 0.05). The HDL-C level was significantly lower in Group A than in Group B (P < 0.05). In Group A after treatment by resolving method of CM, the menstrual cycle was recovered in 83.87% patients (26/31 cases), reduced fatty liver degree or disappearance of fatty liver degree occurred in 32.26% patients (10/31 cases), with the total effective rate being 85.71% (24/28 cases).48.28% (14/29) patients were pregnant. The levels of BW, BMI, FBG, leptin, TG, ALT, and AST significantly decreased when compared with those before treatment (P < 0.05). The level of SHBG significantly increased (P < 0.05). There was no significant difference in the levels of HOMA IR, FINS, T, FSH, LH, or LH/FSH between before and after treatment (P > 0. 05). CONCLUSIONS: The metabolic disorder of glycolipid exists in PCOS patients, and more serious in PCOS patients accompanied with NAFLD. Resolving method can effectively restore the metabolic disturbance in PCOS patients accompanied with NAFLD, recover their fatty liver degrees, recover normal menstrual cycles, and elevate their pregnancy rates. Further studies are necessary on whether its mechanisms lie on lowering leptin levels and correcting lipid metabolisms to relieve patient's clinical symptoms. PMID- 23980353 TI - [Treatment of irritable bowel syndrome by Chinese medicine and pharmacy: an analysis of data mining on experiences of experts]. AB - OBJECTIVE: The pathogenesis of irritable bowel syndrome (IBS), a functional gastrointestinal disorder, is poorly understood. Treatment by Chinese medicine and pharmacy (CMP) is superior to treatment by Western medicine (WM). Therefore, we aimed to analyze Chinese medical experts' experiences in treating IBS by data mining. METHODS: By retrieving related literatures from 1994 to 2012 from CNKI, we chose proved cases and screened effective medical records to establish a database using structural electronic medical case collecting system and data mining. The thinking ways of modern physicians in diagnosis and treatment of IBS were analyzed. RESULTS: Totally 116 medical cases from 46 Chinese medical experts were recruited and analyzed. Results showed that Gan depression and Pi deficiency were most basic syndrome elements. In addition, cold dampness, damp heat, yang deficiency, and Shen deficiency were main elements for the development of diarrhea predominant IBS (IBS-D). Qi stagnation, yin deficiency, qi deficiency, and blood stasis were main elements for the development of constipation predominant IBS (IBS-C). Soothing Gan-qi and strengthening Pi was the most important treatment method. White peony root, prepared atractylodes, prepared licorice, tangerine peel, poria, bupleurum, Radix sileris, lanceolata, and Radix aucklandiae were the most common Chinese herbs used in treating IBS. CONCLUSIONS: (1) Gan depression and Pi deficiency was the main pathogenesis for IBS. Diagnosis and treatment of IBS should be performed clinically according to its development. Tongxie Yao-fang should be used as the basic prescription with modification according to syndrome differentiation. (2) Data mining will have a wide application prospect in studying medical cases. PMID- 23980354 TI - [Effects of acupuncture combined general anesthesia on endorphin and hemodynamics of laparoscopic cholecystectomy patients in the perioperative phase]. AB - OBJECTIVE: To observe the effects of different anesthesia ways on endorphin and hemodynamics of laparoscopic cholecystectomy patients in the perioperative phase. METHODS: A total of 90 laparoscopic cholecystectomy patients, 29 to 80 years old, were randomly assigned to Group A (treated with electroacupuncture at acupoints combined general anesthesia), Group B (treated with electroacupuncture at non acupoints combined general anesthesia), and Group C (treated with general anesthesia) according to American Society of Anesthesiologists (ASA) I-II, 30 cases in each group. All patients were induced by 3 microg/kg Fentanyl (Fen), 2 mg/kg Propofol (Pro), and 0.1 mg/kg Vecuronium (Vcr). Bispectral index (BIS), being 40 -65, indicated the state of general anesthesia. The anesthesia was maintained by intravenous injecting Pro, interruptedly intravenous injecting Fen and Vcr. Each patient received patient controlled intravenous analgesia (PCIA) after operation. On these bases, patients in Group A received electrical acupuncture at bilateral Hegu (LI4), Neiguan (PC6), Quchi (Ll11), Zusanli (ST36), and Yanglingquan (GB34). Patients in Group B received electrical acupuncture at the points beside acupoints. The electroacupuncture was lasted from 15 -30 min before anesthesia induction to the end of the operation in Group A and B. The heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), cardiac output (CO), systemic vascular resistance index (SVRI), and acceleration index (ACI) were recorded before anesthesia induction, immediate before pneumoperitoneum, 5 min after pneumoperitoneum, excision of gallbladder, and at the end of operation. The time consumption from discontinuation to spontaneously breathing recovery, analeptic, and extubation were recorded. The blood samples (3 mL each time) were collected from the peripheral vein before anesthesia induction, 2 h after operation, the 1st day after operation, and the 3rd day after operation to detect the beta-endorphin (beta-EP) level. The visual analogue scale (VAS) were observed and recorded in the 3 groups at post-operative 4, 6, 8, 24, and 44 h, respectively. RESULTS: (1) Compared with before anesthesia induction in the same group, the CI, CO, ACI of all patients decreased significantly at 5 min after pneumoperitoneum and at excision of gallbladder (P < 0.01, P < 0.05). The HR, MAP, SVRI obviously increased in Group B and Group C at each time point (P < 0.05, P < 0.01). Less change happened in Group A. Compared with Group C, the increment of MAP was less in Group A at 5 min after pneumoperitoneum, showing statistical difference (P < 0.05). (2) The time consumption from discontinuation to analeptic and extubation was obviously shorter in Group A than in Group B and Group C (P < 0.05, P < 0.01). (3) The level of beta-EP on the 1st day of operation was significantly lower in Group A than in Group B (P < 0.05) and Group C (P < 0.01). (4) The VAS score at post-operative 44 h was significantly lower in Group A than in Group B and Group C (P < 0.05). CONCLUSIONS: Electroacupuncture at acupoints combined general anesthesia could maintain the stabilization of haemodynamics, and relieve the stress reaction after pneumoperitoneum and operation, and prolong it to early post-operative period, and strengthen the effects of post-operative analgesia. The post-operative recovery was fast, safe, and reliable. PMID- 23980355 TI - [Effects of xuebijing on nitric oxide and VEGF-A in exhaled breath condensate of patients with ALI/ARDS]. AB - OBJECTIVE: To observe the clinical significance of changes of nitric oxide (NO) and vascular endothelial growth factor A (VEGF-A) in exhaled breath condensate (EBC) of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) after they were treated by Xuebijing (XBJ), and to evaluate the effect of the EBC detection technology. METHODS: Totally 32 ALI/ARDS patients receiving mechanical ventilation at intensive care unit (ICU) were randomly assigned to the treatment group and the control group, 16 cases in each group. Patients in the control group were treated by routine therapy, while those in the treatment group were treated by routine therapy + XBJ. The therapeutic course for all was 5 days. The EBC sample was collected by improved EcoScreen condenser within 24 h after confirmed diagnosis of ALI/ARDS and on the fifth day of medication. The levels of NO and VEGF-A were measured by EIA in EBC and serum. The changes of NO and VEGF-A in EBC were observed before and after treatment. RESULTS: Compared with before treatment, the level of NO in EBC and serum decreased and VEGF-A increased after treatment, showing statistical difference (P < 0.05, P < 0.01). After treatment the level of NO in EBC and serum was lower in the treatment group than in the control group (P < 0.05). The VEGF-A in EBC was higher in the treatment group than in the control group (P < 0.05). There was no statistical difference in the serum VEGF-A level between the two groups (P > 0.05). CONCLUSIONS: XBJ was an effective therapeutic drug capable to control the in vivo inflammation reaction in patients with ALI/ARDS. The detection of changes of VEGF-A and NO levels by EBC could judge the inflammatory reaction degree in ALI/ARDS patients, and help evaluating the therapeutic effect. PMID- 23980356 TI - [Significance of serum MMP-3, TIMP-1, and monocyte CD147 in rheumatoid arthritis patients of damp-heat Bi-syndrome and of cold-damp Bi-syndrome]. AB - OBJECTIVE: To explore the clinical significance of serum matrix metalloproteinase 3 (MMP-3), tissue inhibitor of metalloproteinase-1 (TIMP-1), and monocyte CD147 in rheumatoid arthritis (RA) patients of damp-heat Bi-syndrome (DHBS) and of cold damp Bi-syndrome (CDBS). METHODS: The clinical data of 22 patients from inpatients and outpatients with RA were collected, and their peripheral blood was withdrawal. The disease activity scores [DAS28(4)] were assessed. The serum levels of MMP-3 and TIMP-1 were detected by double antibody sandwich enzyme linked immunosorbent assay (ELISA). The mean fluorescence intensity (MFI) and the expression percentage of CD147 on CD14+ monocytes were detected by flow cytometry. The difference of each index between RA patients of DHBS and RA patients of CDBS was analyzed. RESULTS: The level of serum MMP-3 and the MFI of CD147 on the monocyte surface were obviously higher in RA patients of DHBS than in those of CDBS and the normal control group (P < 0.05). The concentration of serum TIMP-1 was obviously higher in RA patients of DHBS than in those of the normal control group (P < 0.05), while there was no statistical difference between the two syndrome types. The percentage of CD147 expression was obviously lower in DHBS than in those of CDBS and the normal control group (P < 0.05). CONCLUSIONS: Increased serum MMP-3 level of RA patients of DHBS might result in destroy of joint cartilages and sclerotin. The significant increase of MFI and decreased expression percentage of monocyte CD147 might be the results of increased disease activity of RA and monocyte migration to the synovial membrane tissue. PMID- 23980357 TI - [Effects of expression ways and traits of anger emotion on autonomic nerve in the emotion recovery stage]. AB - OBJECTIVE: To explore the effects of expression ways and traits of anger emotion on autonomic nerve in the emotion recovery stage. METHODS: The 48 healthy undergraduate students were recruited as subjects, who were assigned to four groups, i.e., anger-out of high trait group, anger-in of high trait group, anger out of low trait group, anger-in of low trait group, 12 in each group. The changes of autonomic nerve in emotion recovery stage [mainly including heart rate (HR), finger pulse volume (FPV), heart rate variability (HRV), and galvanic skin response (GSR)] were observed in an experimental paradigm processed dynamically by emotion induction (by watching movie clips) and emotion regulation (by phraseology chewing and regulating body reaction to anger). RESULTS: In the emotion recovery stage all increased data of vegetative reactions decreased in the four groups. The decrease extent of HR, FPV, and GSR was lower in the anger in groups than that in the anger-out groups (P < 0.05). The HRV showed a decreasing trend, but with no statistical significance (P > 0.05). The decrease extent of HR was lower in the low-anger groups than in the high-anger group (P < 0.05). CONCLUSIONS: Both expression ways and traits of anger exerted influence on the autonomic nerve in the emotion recovery stage. The former influenced more broadly. The influence of anger-in on the autonomic nerve would be more sustainable. PMID- 23980358 TI - [The role of MAPK signal pathway in the regulation of AQP3 expression induced by compound danshen injection in human amniotic epithelial cells]. AB - OBJECTIVE: To investigate the role of mitogen-activated protein kinases (MAPKs) extracellular signal regulated kinase1/2 (ERK1/2) signal pathway in the regulation of Compound Danshen Injection (CDI) induced AQP3 expression in the human amniotic epithelial cells (hAECs). METHODS: hAECs of term pregnancy with normal amniotic fluid volume (AFV) or isolated oligohydramnios were primarily cultured. And the cells were equally divided into four groups, i.e., the vehicle control group, the U0126 group, the CDI group, the CDI + U0126 group. The expressions of phosphorylated ERK1/2 (p-ERK1/2) and AQP3 in hAECs were detected using Western blot analysis. RESULTS: (1) When compared with the control group, the expression level of p-ERK1/2 in hAECs in those with normal AFV and oligohydramnios obviously decreased in the U0126 group (P < 0.05). The expression level of p-ERK1/2 could be elevated in the CDI group (P < 0.05). The expression level of p-ERK1/2 in hAECs was higher in the CDI +U0126 group than in the U0126 group, but lower in the CDI + U0126 group than in the CDI group (P < 0.05). (2) There was no obvious change in AQP3 expression in hAECs with normal AFV between the U0126 group and the vehicle control group (P > 0.05). There was no statistical difference in the expression level of AQP3 between the CDI group and the U0126 +CDI group (P > 0.05), but they were higher than those in the vehicle control group (P < 0.05). (3) Compared with the vehicle control group, the expression level of AQP3 in hAECs with oligohydramnios significantly decreased in the U0126 group and increased in the CDI group (P < 0.05). The expression level of AQP3 was lower in the U0126 + CDI group than in the CDI group, but higher in the U0126 +CDI group than in the U0126 group (P < 0.05). CONCLUSION: CDI could regulate AQP3 expression level in hAECs with oligohydramnios via activating the MAPK-ERK1/2 signal transduction pathway. PMID- 23980359 TI - [Effects of xinfuli granule on cardiomyocyte apoptosis in rats with dilated heart failure induced by adriamycin]. AB - OBJECTIVE: To investigate the effects of Xinfuli Granule (XG) on cardiomyocyte apoptosis in rats with adriamycin-induced dilated cardiomyopathy (DCM). METHODS: Seventy-two male SD rats were randomly divided into 6 groups, i.e., the normal control group, the model group, the irbesartan group, the low dose XG group, the medium dose XG group, and the high dose XG group. The DCM heart failure rat model was established using peritoneal injection of ADR. Equal volume of normal saline was injected to those in the normal control group, once per week for 6 consecutive weeks. The medication was started from the 5th week by gastrogavage. XG was dispensed into 0.5 g/mL suspension with distilled water. The XG was administered at the daily dose of 0.675 g/kg, 1.350 g/kg, and 2.700 g/kg to those in the low dose XG group, the medium dose XG group, and the high dose XG group, respectively. Irbesartan was administered to rats in the irbesartan group at the daily dose of 50 mg/kg. Equal volume of normal saline was administered to those in the normal control group and the model group by gastrogavage, once in the morning for 4 consecutive weeks. Myocardial apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and the expressions of the Bcl-2 and Bax protein of cardiomyocytes were measured by immunohistochemical assay. RESULTS: Compared with the normal control group, the cardiomyocyte apoptosis rate and Bax expression level obviously increased, but the expression of Bcl-2 and the Bcl-2/Bax ratio decreased significantly in the model group (P < 0.05). Compared with the model group, the expression of Bax and the Bcl-2/Bax ratio increased significantly in the high dose XG group and the irbesartan group (P < 0.01). The Bax expression level obviously decreased in all groups except the normal control group (P < 0.01). CONCLUSIONS: XG could obviously attenuate cardiomyocyte apoptosis in the adriamycin-induced DCM rats, and reverse the occurrence and development of heart reconstruction. The underlying mechanism might be related to regulating and controlling the expressions of Bax and Bcl-2. PMID- 23980360 TI - [Effects of preconditioning of wufu jingfang on ischemia/reperfusion injury induced apoptosis in rats]. AB - OBJECTIVE: To observe the protective effect of Wufu Jingfang (WJ, containing Aconitum carmichaeli Debx, Radix Aconiti Lateralis Preparatae, Rhizoma Pinelliae, and snakegourd fruit) on myocardial ischemia-reperfusion injury (I/R) of rats, thus exploring the feasibility of recipes containing eighteen incompatible pairs for specific pathological conditions. METHODS: Fifty male Wistar rats were randomly divided into five groups, i.e., the sham-operative control group (the SH group), the I/R group, the low dose WJ I/R group (the I/R +JFL group), the middle dose WJ I/R group (the I/R +JFM group), the high dose WJ I/R group (the I/R +JFH group), 10 in each group. Rats in the latter three groups were administered with WJ at 0.75 mL/100 g, 1.50 mL/100 g, and 3.00 mL/100 g body weight for 14 consecutive days by gastrogavage. All groups except the SH group received ligation of left anterior descending branch of coronary artery for 30-min ischemia followed by 120-min reperfusion. The micro-structural changes of myocardial mitochondria were observed by transmission electron microscope. The ischemic cardiomyocyte apoptosis was detected in each group using one-step terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL). The mRNA expressions of B-cell leukemia/lymphoma 2 (Bcl-2) and Bcl-2 associated x protein (Bax) were detected by RT-PCR. The activities of lactic dehydrogenase (LDH) and creatine kinase (CK) were detected using ELISA. The myocardial infarct size was detected. RESULTS: Compared with the I/R group, WJ pretreatment significantly suppressed the release of LDH and CK (Besides, the release of LDH and CK reduced along with increased dose.), reduced the myocardial infarct size, and lowered myocardial apoptosis index (P < 0.05). WJ pretreatment also modulated Bcl-2/Bax ratio by up-regulating Bcl-2 expression level while decreasing Bax expression level. CONCLUSIONS: WJ pretreatment might protect the heart from I/R injury via decreasing myocardial cell apoptosis. The results suggested that eighteen incompatible pairs is not absolute, but relative. Chinese medical preparation containing opposite Chinese herbs could be used in specific pathological states such as ischemic cardiomyopathy. PMID- 23980361 TI - [Chinese herbs for shen invigorating and blood activating activated MMP-9 signaling pathway to mobilize rats' bone marrow EPCs: a molecular mechanism research]. AB - OBJECTIVE: To explore the effect of Chinese herbs for Shen invigorating and blood activating (CHSIBA) on the number of endothelial progenitor cells (EPCs) in the bone marrow and the peripheral blood and the signaling pathway of bone marrow matrix metalloproteinase 9 (MMP-9) of the myocardial infarction (MI) model rats. METHODS: The MI rat model was established by ligation. Thirty successfully modeled rats were randomly divided into the high dose CHSIBA group, the low dose CHSIBA group, and the model group, 10 in each group. Besides, another 10 normal rats were recruited as the blank group. Rats in the high dose CHSIBA group and the low dose CHSIBA group were administered with CHSIBA at 3 g/kg and 1.5 g/kg body weight by gastrogavage (by adding them in 4 mL physiological saline), once daily. Rats in the model group and the blank group were administered with 4 mL physiological saline once daily. The EPCs were collected from the bone marrow and the peripheral blood 4 weeks later. Seven days later the CD34/CD133 phenotype was identified in collected sticking wall cells using flow cytometry. The MMP-9 and water soluble Kit ligand (sKitL) were detected using Western blot. The expressions of vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1alpha (SDF-1alpha) were detected using ELISA. RESULTS: The CD34/CD133 positive rate and the EPC quantity in the bone marrow and the peripheral blood were higher in the high dose CHSIBA group and the low dose CHSIBA group than in the model group (P < 0.05, P < 0.01). Besides, the expressions of VEGF, SDF 1alpha, MMP-9, and sKitL in the bone marrow and the peripheral blood were also higher in the high dose CHSIBA group and the low dose CHSIBA group than in the model group (P < 0.05, P < 0.01). CONCLUSION: CHSIBA could activate MMP-9 signaling pathway, increase its upstream and downstream signal expression levels, and mobilize EPCs in the bone marrow to enter the blood circulation. PMID- 23980362 TI - [An animal model establishment of social stress and its effect evaluation]. AB - OBJECTIVE: To establish a social defeat stress model for simulating the human mental disease, thus laying a foundation for in-depth laboratory research on depression. METHODS: Eight C57BL/6J mice (abbreviated as C57 mice) were recruited as the stress group. They were subject to psychological stress of social defeat for 10 successive days. Besides, another 8 C57 mice were selected as the normal control group (receiving no stress). The Noldus Ethovision was used to evaluate the depressive behavior of mice. The date was acquired in the case of with or without aggressive CD-1 mice in the social defeat open field (SDOF), and it included the two groups of mice's trajectory in the SDOF and the first time of the two groups of mice's entry into the interactive area of the SDOF, the residence time of the two groups of mice in the interactive area of the SDOF, the first time of the two groups of mice's entry into the corner areas of the SDOF and the residence time of the two groups of mice in the corner areas of the SDOF. All data were used to analyze the changes in the behavior of the C57, mice, thus inferring the psychological changes of C57 mice. RESULTS: The mice in the social stress group showed significant behavioral differences when compared with the normal control group. Their trajectories in the interactive area of the SDOF were significantly reduced. The trajectories of the mice in the social stress group were mainly distributed in the corner areas of the SDOF and its surrounding area within the smaller range. The residence time of mice in the social stress group in the interactive area of the SDOF was shortened (P < 0.05). The first time for the mice in the social stress group to enter the interactive area of the SDOF was extended (P < 0.05). Their residence time in the corner areas of the SDOF was shortened (P < 0.05). The first time for mice in the social stress group to enter the corner areas of the SDOF was extended (P < 0.05). CONCLUSION: An animal model of depressive behavior can be established by social defeat stress, which was consistent with human depression. PMID- 23980363 TI - [Study on inhibitory effects of Taxus chinensis var. mairei aqueous extract on the proliferation of tumor cells]. AB - OBJECTIVE: To study the inhibitory effects of Taxus chinensis var. mairei Aqueous Extract (TAE) on SGC-7901 and MCF-7 cells, and to explore its mechanisms. METHODS: The inhibitory effects of TAT and Paclitaxel on the proliferation of SGC 7901 and MCF-7 cells were tested by MTT method. Their effects on the morphology of SGC-7901 and MCF-7 cells were observed by microscope. Its effects on the cell apoptosis were detected by flow cytometry. RESULTS: The TAE had inhibitory effects on the proliferation of tumor cells, and its mechanisms were correlated to inducing the apoptosis of tumor cells. CONCLUSION: TAE had inhibitory effects on the proliferation of tumor cells. PMID- 23980364 TI - [Curcumin combined FOLFOX induced cell apoptosis of gastric cancer and its mechanism research]. AB - OBJECTIVE: To observe the effect of curcumin combined folinic acid fluorouracil oxaliplatin (FOLFOX) on the gastric adenocarcinoma cell line BGC-823 and to explore its possible mechanisms. METHODS: Cells were divided into five groups, i.e. the blank control group, the curcumin group, the FOLFOX group (0.1 mmol/L 5 FU +5 micromol/L oxaliplatin), and the curcumin combined FOLFOX group. CCK-8 was used to detect cell activity. The cell apoptosis was observed using Hoechst dyeing. Caspase-3 test kit was applied to test Caspase-3 vitality. The mRNA expressions of Bcl-2 and Bax were detected by real time fluorescent quantitative PCR. The expressions of Bcl-2 and Bax protein were determined by Western blot. RESULTS: The BGC-823 cells' proliferation could be inhibited, apoptosis induced, the Caspase-3 activity increased, expressions of Bcl-2 mRNA and Bcl-2 protein lowered, while Bax mRNA and Bax protein expressions increased in each medicated group. Besides, the efficacy of the curcumin combined FOLFOX group was superior to that of the curcumin group and the FOLFOX group, showing statistical difference (P < 0.01). CONCLUSION: Curcumin combined FOLFOX could significantly inhibit the proliferation of BGC-823 cells possibly via promoting Bax expression and Caspase-3 activity, inhibiting Bcl-2 expression, thus inducing apoptosis. PMID- 23980365 TI - [Effects of dioscornin tablet containing serum on NF-kappaB p65, STAT3, and VEGF mRNA expressions in rats' synovial cell strain RSC-364 induced by IL-17 and TNF alpha]. AB - OBJECTIVE: To observe the effects of Dioscornin Tablet (DT) containing serum on nuclear factor of kappa B (NF-kappaB) p65, signal transducer and activator of transcription 3 (STAT3), and vascular endothelial growth factor (VEGF) mRNA expressions in rats' synovial cell strain 364 (RSC-364) induced by interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-alpha), and to investigate the underlying mechanisms for DT to inhibit angiogenesis of rheumatoid arthritis (RA). METHODS: In this experiment, the vehicle control group, the cell model group, the DT containing serum group, and the positive control group (Tripterygium containing serum) were set up. The DT containing serum and the Tripterygium containing serum were prepared. The RA cell model was established by IL-17 combined TNF-alpha induced injury in RSC-364. The RA cells were intervened by DT containing serum and Tripterygium containing serum respectively. The DNA binding activity of NF-kappaB p65 was detected using TransAM NF-kappaB p65. The expression of STAT3 was observed using Western blot. The VEGF mRNA expressions were detected by real-time quantitative PCR. RESULTS: Compared with the vehicle control group, the NF-kappaB p65 activity, the expressions of STAT3 and VEGF mRNA increased significantly in RSC-364 induced by IL-17 +TNF-alpha (P < 0.01, P < 0.05). Compared with the model group, the NF-kappaB p65 activity, the expressions of STAT3 and VEGF mRNA decreased significantly in the DT containing serum group and the positive control group (P < 0.01, P < 0.05). There was no statistical difference between the two groups (P > 0.05). CONCLUSION: DT inhibited the VEGF mRNA expression through inhibiting the NF-kappaB p65 activity and the STAT3 protein expression in the Janus kinase (JAK)-signal transducer and activating transcription factor pathway, thus inhibiting the angiogenesis of RA. PMID- 23980366 TI - [Effects of diterpene phenol extract of Rosmarinus officinalis on TGFbeta1 and mRNA expressions of its signaling pathway molecules in the lung tissue of pulmonary fibrosis rats]. AB - OBJECTIVE: To investigate the regulative mechanism of the diterpene phenol extract of Rosmarinus Officinalis (DERO) on the imbalance of collagen metabolism of the lung tissue in pulmonary fibrosis rats. METHODS: Fifty healthy Sprague Dawley rats were randomly divided into the normal saline group (NS), the bleomycin-induced lung injury group (BLM), the low dose DERO group (at the daily dose of 50 mg/kg), the moderate dose DERO group (at the daily dose of 100 mg/kg), and the high dose DERO group (at the daily dose of 200 mg/kg), 10 in each group (abbreviated as DERO 1, 2, 3, respectively). The pulmonary fibrosis rat model was prepared by disposable intratracheal instillation of bleomycin. DERO was administered by gastrogavage as intervention during the repairing process of lung injury. On the morning of the 29th day, the rats' lung tissue was extracted. The karyocyte number, collagen protein, type I collagen (collagen I) and transforming growth factor-beta type II receptor (TGFbetaR II), Smad4 mRNA expressions were semi-quantitatively determined using tissue microarray, HE staining, collagen fiber dyeing, immunohistochemical assay, and in situ hybridization. Using real time fluorescent quantification RT-PCR, the mRNA expression of transforming growth factor-beta1 (TGF-beta1) were detected. RESULTS: Compared with the NS group, the collagen deposition of the lung tissue was obvious and the inflammatory infiltration was more severe in the BLM group (P < 0.05, P < 0.01). There was no statistical difference in the aforesaid 4 indices between the DERO1 group and the BLM group (P > 0.05). The collagen deposition and the inflammatory infiltration were obviously alleviated in the DERO2 and DERO3 groups (P < 0.05, P < 0.01). Compared with the NS group, the mRNA expressions of collagen-I, TGF beta1 R II, Smad4, and TGF-beta1 were obviously up-regulated in the BLM group (P < 0.05, P < 0.01). Compared with the BLM group, the aforesaid four indices were not statistically changed in the DERO1 group (P > 0.05). But the mRNA expressions of collagen-I, TGF-beta1 R II, Smad4, and TGF-beta1 were obviously downregulated in the DERO2 and DERO3 groups (P < 0.05, P < 0.01). But the down-regulation of Smad4 expression was not obvious in the DERO2 and the DERO3 groups (P > 0.05). Compared with the DERO1 group, the mRNA expressions of collagen-I, TGF-beta1, R II, TGFbeta1 were all obviously lower in the DERO2 and the DERO3 groups (P < 0.05). But there was no statistical difference in the aforesaid 4 indices between the DERO2 group and the DERO3 group (P > 0.05). CONCLUSIONS: DERO could regulate imbalanced collagen metabolism of pulmonary fibrosis. It could inhibit excessive deposition of collagen fibers, especially excessive deposition of collagen- I. Its mechanisms might be realized by inhibiting up-regulation of TGF-beta1 and TGFbetaR II mRNA expressions, thus interfering the activation of TGF-beta-Smad signaling pathway on target genes, especially on type I procollagen target gene. PMID- 23980367 TI - [Evaluation of the key indicators in the pituitary-target gland axes in the animal model with shenyang deficiency syndrome using factor analysis]. AB - OBJECTIVE: To evaluate the key indicators in the pituitary-target gland axes in the animal model of Shen-yang deficiency syndrome (SYDS). METHODS: The 8 biological indicators [thyroid stimulating hormone (TSH), 3, 3', 5 triiodothyronine (T3), thyroxine (T4), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), adrenocorticotropic hormone (ACTH), and cortisol (CORT)] in the pituitary-target gland axes were grouped using factor analysis. Then the sensitivity of every indicator was calculated according to the sensitivity function defined in this paper, so as to find all the most sensitive indicators in every group as key indicators of SYDS. RESULTS: The key indicators in the early period of SYDS were T, LH, T4, and CORT. The key indicators in the middle period were LH,T, CORT, and ACTH. The key indicators in the late period were LH, T, CORT, and FSH. CONCLUSIONS: T, LH, and CORT were the common key indicators of the three periods, and other different key indicator of SYDS in the early, middle and late period were T4, ACTH, and FSH respectively, which changed from the thyroid axis to the adrenal axis and then to the gonadal axis as the period changed. The key indicators in the late period were mainly in the gonadal axis, showing gonadal dysfunction in the late period. PMID- 23980368 TI - [Effects of total paeony glucosides on mRNA expressions of Toll receptors and interleukin-33 in the brain tissue of D-galactose induced aging rats: an experimental research]. AB - OBJECTIVE: To investigate effects of total paeony glucosides (TPGs) on the expressions of Toll receptors (TLR4) and interleukin-33 (IL-33) in the brain tissue of D-galactose-induced aging rats. METHODS; Fifty SD rats were randomly divided into 5 groups, i.e., the blank control group, the model group, the high dose TPG group, the middle dose TPG group, and the low dose TPG group, 10 in each group. Equal volume of normal saline was subcutaneously injected to rats in the blank control group, while 10% D-galactose was subcutaneously injected to rats in the rest groups at 0.125 mL/g, once a day for 8 successive weeks to induce the aging rat model. TPG was administered at 300 mg/kg, 150 mg/kg, and 75 mg/kg to rats in the high, middle, and low dose TPG groups while injecting D-galactose from the 5th week of model preparation, once daily for 4 successive weeks. Equal volume of normal saline was administered to rats in the blank control group and the model group, once daily. The capability for learning and memory was detected using Morris water. The mRNA expressions of TLR4 and IL-33 in the brain tissue were detected using ELISA. RESULTS: Compared with the blank control group, the capability for learning and memory decreased in the model group with statistical difference (P < 0.05). Compared with the model group, the capability for learning and memory was obviously improved in all the medicated groups in a dose-dependent manner, showing statistical difference (P < 0.05). Compared with the blank control group, mRNA expressions of TLR4 and IL-33 in the brain tissue obviously increased after medication in the model group, showing statistical difference (P < 0.05). Compared with the model group, mRNA expressions of TLR4 and IL-33 in the brain tissue obviously decreased after medication in all the medicated groups in a dose-dependent manner, showing statistical difference (P < 0.05). CONCLUSION: TPGs improved D-galactose induced aging rats' capability for learning and memory through regulating changes of TLR4 and IL-33 expressions. PMID- 23980369 TI - [Homoharringtonine combined arsenic trioxide induced apoptosis in human multiple myeloma cell line RPMI 8226: an experimental research]. AB - OBJECTIVE: To clarify the effects and mechanisms of homoharringtonine (HHT) monomer therapy or combination therapy with arsenic trioxide (ATO) on human multiple myeloma (MM) cell line RPMI 8226 in in vitro researches. METHODS: Effects of HHT, ATO, and HHT combined ATO on the growth of MM cell line RPMI 8226 were detected using MTT assay. The morphological changes of cell apoptosis were detected by Hoechst staining. The early apoptosis rate was detected using flow cytometry. Expressions of Caspase-3, Caspase-9, poly-ADP-ribose polymerase (PARP), Bcl-2, Mcl-1, Bcl-xl, and AKT protein were detected by Western blot. RESULTS: HHT and ATO inhibited the proliferation of RPM1 8226 cell line in a time and dose-dependent manner (P < 0.05). Synergistic effects was shown in the combination group (Cl < 1). HHT and ATO induced the apoptosis of RPMI 8226 in a dose-dependent manner with typical morphological changes of apoptosis and higher early stage apoptosis rate. The enhancement in apoptotic induction was seen when two agents were combined. HHT activated expressions of Caspase-3 and PARP in a dose dependent manner at 24 h. HHT at 40 ng/mL and ATO at 8.5 micromol/L could significantly activate expressions of Caspase-3 and Caspase-9, and down-regulate expressions of anti-apoptotic proteins Bcl-xl and Mcl-1. In addition, the combination therapy of HHT at 40 ng/mL and ATO at 8.5 micromol/L inhibited phosphorylation of AKT in a time-dependent manner. CONCLUSION: HTT, ATO, and combination therapy of HHT and ATO induced the apoptosis of RPMI 8226 cell line possibly through activating Caspase pathways, regulating expressions of Bcl-2 families, and inhibiting phosphorylation of AKT. PMID- 23980370 TI - [Oxymatrine could promote mesenchymal stem cell therapy in hepatic fibrosis rats: an experimental research]. AB - OBJECTIVE: To investigate whether oxymatrine (OM) could promote mesenchymal stem cell (MSC) therapy in CCl4-induced hepatic fibrosis (HF) in rats and to initially explore its mechanisms. METHODS: Totally 50 male SD rats were randomly divided into five groups,i.e., the normal control group, the model group, the MSC therapy group, the OM therapy group, and the MSC combined OM therapy group, 10 in each group. Except the normal control group, the HF model was duplicated by CCl4 induction. After successful modeling, rats in the MSC therapy group received 5 x10(6) MSCs by intravenous injection via caudal vein, once a week. Rats in the OM therapy group received 50 mg/kg OM by intramuscular injection, three times a week. Rats in MSC combined OM therapy group received 5 x 10(6) MSCs by intravenous injection via caudal vein, once a week and 50 mg/kg OM by intramuscular injection three times a week. Equal volume of normal saline was given to those in the normal control group and the model group. All medication lasted for 8 weeks. Serum levels of ALT and AST were detected 8 weeks later. The hepatic histopathological injury and extracellular matrix deposit were assessed using HE and Masson staining. Expressions of serum interleukin-4 (IL-4) and interleukin-10 (IL-10) were detected using enzyme linked immunosorbent assay (ELISA). RESULTS: (1) Compared with the normal control group, serum levels of ALT and AST significantly increased in the model group (P < 0.05). Compared with the model group, serum levels of ALT and AST significantly decreased in the OM therapy group, the MSC therapy group, and the MSC combined OM therapy group at the end of 8 weeks of treatment (P < 0.05). But serum levels of ALT and AST were significantly lower in the MSC combined OM therapy group than in the OM therapy group and the MSC therapy group (P < 0.05). (2) Compared with the model group, the hepatic injury was significantly lessened and the area of extracellular matrix deposit was significantly reduced in the OM therapy group, the MSC therapy group, and the MSC combined OM therapy group (P < 0.05). Besides, they wer more significant in the MSC combined OM therapy group (P < 0.05). (3) Compared with the model group, the serum IL-4 level was significantly higher in the MSC therapy group and the MSC combined MO group (P < 0.05). It was higher in the MSC combined MO group (P < 0.05). Although the serum IL-4 level also increased in the OM therapy group, but with no statistical difference (P > 0.05). (4) The serum IL-10 level significantly increased in the OM therapy group, the MSC therapy group, and the MSC combined OM therapy group (P < 0.05), and it was the highest in the MSC combined OM therapy group among the three groups (P < 0.05). (5) Two-photon fluorescence imaging showed no signals of MSCs in liver with or without OM injection. CONCLUSION: OM could promote mesenchymal stem cell therapy in hepatic fibrosis rats, which might be involved in increasing serum levels of IL-4 and IL 10. PMID- 23980371 TI - [Clinical experience and thinking of treating abdominal compartment syndrome by dachaihu decoction]. AB - The descriptions about Dachaihu Decoction (DD) were retrieved from ancient and modern literatures. A feeling of being oppressed in stomach or abdomen was raised to be a main symptom of Dachaihu Decoction syndrome (DDS). The pathogenesis of DDS includes failure of shaoyang to flow upward, abnormality of gallbladder and stomach, and inner stagnation of heat. The main clinical feature of abdominal compartment syndrome is severe abdominal distension, which is similar to that of DDS. Significant effects could be achieved by using DD. The clinical use of classical prescriptions should focus on main symptoms and grasp the pathogenesis. PMID- 23980372 TI - [Current state of Chinese medical objective research on chronic heart failure]. PMID- 23980373 TI - [Progress for researches on peri-operative gastroenterological function recovery by Chinese medicine and pharmacy]. PMID- 23980374 TI - [Progress for researches on radiotherapy resistance mechanisms for reversing ovarian cancer by active components of Chinese materia medic]. PMID- 23980375 TI - [Infrasound from wind turbines--an overlooked health hazard]. PMID- 23980376 TI - [Encountering and handling of mentally ill outside of hospitals. The police--an important collaborator]. PMID- 23980377 TI - [ESBL-CARBA can become a problem in Swedish health care]. PMID- 23980378 TI - [Doubts about HES. The European Medicines Agency withdraws the marketing permit until further notice]. PMID- 23980379 TI - [Carbapenem-resistant Escherichia coli now exist in Sweden]. PMID- 23980380 TI - [Interview study on the living conditions of the very old. Elderly acquire more health problems, but they manage everyday life better]. PMID- 23980381 TI - [Vascular ultrasound in stroke]. PMID- 23980382 TI - [Methylphenidate and cannabinoids may have a place in palliative care. Literature review and clinical experience provides evidence]. PMID- 23980383 TI - [Increased mortality in young women with personality disorders]. PMID- 23980384 TI - [Scientific work during internship: An integral part--not an odd bird]. PMID- 23980385 TI - [Greater clarity on scientific competence is needed]. PMID- 23980386 TI - [Help is available]. PMID- 23980387 TI - Associations between body morphology, mating success and mate preferences among Slovak males and females. AB - Human body morphology is thought to be correlated with sexual behaviour and sociosexuality (defined as an increased willingness to engage in sex without commitment) influences the perception of certain cues of physical attractiveness. Based on a sample of Slovak university students, we investigated relationships between 1) male and female mating success and reported body morphology (body mass index, BMI and waist-to-hip ratio, WHR) and 2) mate preference characteristics and mating success. Both males and females reported a similar number of long-term sexual partners and frequency of engaging in extra-pair copulation (EPC). The mating success of both sexes was positively mediated by self-perceived attractiveness. However, female BMI was inversely associated with mating success whereas increasing BMI was positively associated with male mating success (the total number of lifetime sexual partners) as well as with the likelihood of engaging in EPC. Unrestricted sociosexuality positively correlated with direct and indirect benefits from mating and negatively with the religious/political background of a potential mate and with the desire for a home/ children. These results confirm the hypothesis that human body morphology is associated with sexual behaviour and that cues of direct/indirect benefits in a potential mate positively correlate with sociosexuality. PMID- 23980388 TI - Assessing the applicability of the digital laser rangefinder GLM Professional Bosch 250 VF for anthropometric field studies. AB - The digital laser rangefinder GLM Professional BoscH 250 VF was tested as a modified preproduction model with regard to its applicability of quantifying humans' height. The aim of this investigation was to determine and evaluate the instrument's precision, as well as its manageability within anthropometric field studies. Data collected by the digital laser rangefinder did not show a significant difference to data of control by an anthropometer. Furthermore, more than 96% of the difference values are located within area of agreement. Nevertheless, the GLM Professional is a highly sensitive instrument and mean SD within threefold data acquisition is twice as high as SD resulting from data collection by an anthropometer. However, due to the minimal percentage differences within data acquisition and compared to the standard method, the GLM Professional is proved to be a reliable instrument and to be highly applicable for anthropometric field studies. Furthermore, due to its excellent manageability and compact size, the GLM Professional shows a very good applicability even for less trained anthropometrists and thus ameliorates the possibilities of collecting reliable data within anthropometric field studies. PMID- 23980389 TI - Reliability of anthropometric parameters in the prediction of the visceral fat area among adult women. AB - Visceral fat accumulation is a risk factor for cardiometabolic diseases. Magnetic resonance imaging (MRI) and computed tomography (CT) provided the most accurate techniques of abdominal fat assessment, but these methods are very expensive. The aim of this study was to examine and compare the predictive ability of simple anthropometric parameters for visceral fat area (VFA) among adult women in different age and obesity status groups. The sample consisted of 133 adult women (aged 18-76 years). All subjects underwent anthropometric measurements. Body composition and VFA were determined with a multi-frequency bioimpedance analyzer (BIA). 16.9% of the younger women (age < 45) were obese with a body-mass index (BMI) > or = 30.0 kg/m2, and 23.2% of the older individuals (age > 45) had BMI > or = 30 kg/m2. After age and BMI adjustment, the best correlation was observed between VFA and waist circumference (WC) in younger women (R = 0.347, p = 0.002). In the case of the older women, the best correlation efficient values were for SAD (R = 0.560, p < 0.001) and hip circumference (R = 0.550, p < 0.001). The partial correlation coefficients were consistently higher for younger subjects with excessive fat accumulation (overweight & obese subgroup; individuals with WC > 80 cm) compared to women without obesity. Results of the multiple linear stepwise regression analyses showed the significance of age and BMI in prediction of VFA. In addition, hip circumference (HC) was one of the methods that best reflected VFA in older women independently from obesity status. Using single anthropometric parameters is not usually sufficient for predicting with good accuracy the VFA, but the convenient combination of these parameters could be a suitable way for the reliable prediction in Hungarian women. PMID- 23980390 TI - Prediction of nutritional status from skinfold thickness in undernourished Santal children of Purulia district, India. AB - The present study was undertaken to explore whether the skinfold thickness can be used in assessing the nutritional status in 5-12 years aged Santal children of Purulia district of West Bengal and to determine the sensitivity of these parameters for measuring the nutritional status. Height, weight and skinfold thickness of triceps (TRSF), biceps, suprailiac, subscapula (SBSF) and calf of Santal children were measured. Growth curves of TRSF-forage and SBSF-for-age in Santal children are placed at lower level of reference values indicating prevailed undernutrition in surveyed children. The SBSF for boys and TRSF for girls are significantly associated with nutritional status. Present study suggests that SBSF for boys and TRSF for girls are more sensitive than other skinfold thickness for the assessment of nutritional status in Santal children. Relationship of growth pattern of skinfold thickness is different in undernourished Santal children compared to well-nourished Santal children. PMID- 23980391 TI - Cross-sectional reference values for BMI among Khasi tribal adolescents of Meghalaya, India. AB - Body mass index (BMI) is a useful tool to assess nutritional status and may be applied to study undernutrition and overweight/obesity in distinct ethnic populations like Khasi tribal children to derive cross sectional reference values for undernutrition, overweight and obesity. Cross-sectional methods of anthropometric measurements in 957 Khasi children (467 boys, 490 girls) of age 11 to 17 years were used to derive BMI (kg/m2), which were compared with national and international standards. Smoothed Khasi specific BMI percentiles were generated by the LMS method and International Obesity Task Force (IOTF) criteria were applied as for Asian children. Mean BMI in Khasi children were below those of national and international reference standards. Girls achieved higher BMI in late adolescence, but boys remained thin throughout. Smoothed percentile charts were constructed for boys and girls and IOTF criteria for undernutrition, overweight and obesity were applied corresponding to 11, 77.4 and 90.5 percentiles for boys and 13.4, 74 and 91.2 percentiles for girls, respectively. Undernutrition was more prevalent in boys than in girls, particularly at age 14 and 15 years (p < 0.001). There was a small prevalence of obesity, 5.1% in boys and 9.5% in girls at age 17 years. BMI values in pubertal Khasi boys and girls are different from commonly used standards. BMI percentiles specific to Khasi children in puberty are advocated to track changing trends over time. PMID- 23980392 TI - Nutritional status, fertility and factors associated with anaemia: a cross sectional study among a rural population of Muslim women in Assam, India. AB - In the present study an attempt has been made to report on the nutritional status of the Assamese Muslim women of Dadara and Agyathuri villages of the Kamrup district in Assam, India on their basis of body mass index (BMI) and haemoglobin (hb) content. Cross sectional data on 1034 women belonging to the age group of 19 years and above were collected following internationally accepted standards. The fertility of mothers by BMI range was found to be highest (6.50 (mean) +/- 0.14 (SE) and range being 1-11) amongst underweight mothers. The one-way analysis of variance (ANOVA) test of BMI and fertility shows significant relation between different BMI groups withp < 0.01. Highest haemoglobin levels were recorded in the age group of < or = 23 years with a mean of 11.61 +/- 0.06 g/dl, the range being 9.8-13.9 g/dl. Whereas lowest levels of haemoglobin were found in the age groups of 44+ years having a mean value of 10.26 +/- 0.04 g/dl and a range of 9.2 11.8 g/dl. The ANOVA analysis for haemoglobin content and corresponding fertility rates show significant difference between different hemoglobin levels with their live births at p < 0.01. The summary of ANOVA analysis for haemoglobin and BMI range shows the significant difference between groups i.e., normal, overweight and underweight. The t-value and F-ratio is 118.61 and 14068.42, respectively, which is significant at 1% probability. The authors conclude a general trend in the study population of women with high fertility having poor nutritional status. These findings might be important in formulating responsive health policies in an underdeveloped region. PMID- 23980393 TI - Premenstrual syndrome, body fat and bitter taste receptor gene TAS2R38 among adult Kullu females of Himachal Pradesh, India. AB - OBJECTIVE: Premenstrual syndrome (PMS) is still a poorly understood and accepted condition. We evaluate the phenotypic variations at TAS2R38 gene locus in relation to PMS severity and adiposity measures among adult women. This is the first ever report describing association of PTC taste genetic locus with the PMS susceptibility. METHODS: The study was based on a cross-sectional sample of 105 adult rural women from the Kullu district, Himachal Pradesh. Retrospective approach was used to assess PMS. PTC tasting ability was assessed after Harris & Kalmus (1949). Each subject was measured for height, weight and body fat measures. RESULTS: 19.05% of the females were PTC non-tasters and 80.95% were tasters. Prevalence of PMS was 45.71%. Prevalence of severe type of PMS was very low, varying from 0-6%. Severity was highest in PMS-A type characterized by anxiety/irritability, tension, clumsiness, mood swings, nervousness, and insomnia. Females who tasted PTC bitter at lower concentrations had lowest PMS prevalence, while those who tasted PTC at higher concentration had highest PMS prevalence. Stature and body weight decreased with increase in PTC taste sensitivity. However, one-way ANOVA revealed that all the F-ratios were insignificant between the three discrete categories of low, medium and high PTC thresholds. CONCLUSION: Our results are compatible with the hypothesis that the bitter receptor gene TAS2R38 could not serve as a significant predictor of anthropometric measurements though some indirect pathways may not be ruled out, but the gene is significantly correlated with PMS susceptibility and severity. PMID- 23980394 TI - Hominin evolution and gene flow in the Pleistocene Africa. AB - Africa demonstrates a complex process of the hominin evolution with a series of adaptive radiations during several millions of years that led to diverse morphological forms. Recently, Hammer et al. (2011) and Harvati et al. (2011) provided integrated morphological and genetic evidence of interbreeding between modern humans and unknown archaic hominins in Africa as recently as 35,000 years ago. However, a genetic evidence of hybridization between hominin lineages during the Lower and Middle Pleistocene epochs is unknown and the direct retrieval of DNA from extinct lineages of African hominins remains elusive. The availability of both nuclear and mitochondrial genome sequences from modern humans, Neanderthals, and Denisovans allows collecting nuclear DNA sequences of mitochondrial origin (numts) inserted into the nuclear genome of the ancestral hominin lineages and drawing conclusions about the hominin evolution in the remote past. The mtDNA and numt analysis uncovered a deep division of mtDNA lineages that existed in African hominins in the Middle Pleistocene. The first cluster included the human and Neanderthal-like mtDNA sequences while the second consisted of DNA sequences that are known today as mtAncestor-1, a nuclear fossil of the mtDNA, and the Denisova mtDNA isolated from a bone and a tooth found in southern Siberia. The two groups initially diverged 610,000-1,110,000 years ago. Approximately 220,000 years after the primary split, the Denisova - mtAncestor-1 mtDNA lineages mixed with the mtDNA pool of an ancestral population of Neanderthals and modern humans. This admixture after the profound division is demonstrated by the transposition of the Denisova-like mtDNA sequence into the nuclear genome of an ancestor of Neanderthals and modern humans. This finding suggests the matrilineal genetic structure among the Middle Pleistocene hominins as well as the existence of gene flow between African hominin lineages. Through paleogenomic analyses, it is impossible to exclude the theory that population structure and gene flow in African hominins influenced the admixture pattern observed in the nuclear genomes of non-Africans. PMID- 23980395 TI - Dietary reconstruction from trace element analysis and dental microwear in an Early Medieval population from Gan (Galanta district, Slovakia). AB - The aim of the study was to determine the diet of an historical human population using the trace elements in dental tissues and dental buccal microwear. Although 38 individuals had been buried in the cemetery, preservation of the remains did not allow analysis of all of them. A total of 13 individuals were analysed, of which the samples for trace-element analysis consisted of 12 permanent premolars from 12 individuals. Buccal microwear was studied in a sample of nine teeth from nine individuals. Both trace-element and microwear analyses were performed on eight individuals. All analyzed teeth were intact, with fully developed roots, without dental calculus and macro-abrasion. Concentrations of Sr, Zn, and Ca, and their ratios, were used to determine the relative proportions of plant and animal protein in the diet. Samples were analyzed using optical emission spectrometry with inductively coupled plasma. The values of the Sr and Zn concentrations indicate that a diet of the investigated population was of a mixed character with approximately the same proportion of plants and meat in their food. Buccal microwear was studied in molds ofbuccal surfaces and observed at 100x magnification with a scanning electron microscope (SEM). Length and orientation of striations were determined with the SigmaScan Pro 5.0 image analysis program. The results obtained from microwear analysis correspond with those from trace element analysis and showed that the population consumed a mixed diet. The density of the scratches indicates that the diet contained a considerable vegetable component. The high number of vertical scratches and their high average length suggest that individuals also consumed a large portion of meat. The results of both analyses showed that there were also individuals whose diet had probably been poor, i.e. richer in animal protein, which probably could be related to their health or social status in the population. PMID- 23980397 TI - Flexibility, fun and family. PMID- 23980396 TI - Mission of Mercy treats 1,136; provides $903,000 in care. PMID- 23980398 TI - Suspending orthodontic treatment due to non-payment. PMID- 23980399 TI - ADA terminates relationship with sharecare.com. PMID- 23980401 TI - Coding for extraoral bitewing images. PMID- 23980400 TI - Say 'cheese': using employee photos on practice websites. PMID- 23980402 TI - MDA seminars help you keep up with health insurance reform. PMID- 23980403 TI - Saving you money every day...MDA Insurance and MDA Services. PMID- 23980404 TI - One-year clinical evaluation of Quixfil and Gradia Direct composite restorative materials in posterior teeth. AB - OBJECTIVE: The purpose of this study was to evaluate and compare the 12 month clinical performances of two different posterior composites in Class I and Class II restorations. METHODS: Class I and class II cavities of 62 patients, 74 Quixfil (Dentsply/ Xeno V) and 68 Gradia Direct (GC America/G bond) composite restorations were placed by two dentists. Only small and medium-sized cavities were included in the study. Independent evaluations were performed at baseline (one week), after three months, six months, and one year, by one trained examiner using the modified U.S. Public Health Service rating criteria. Color match, marginal integrity, anatomical form, surface roughness, marginal or interfacial staining, postoperative sensitivity, and secondary caries were evaluated. RESULTS: Both restorative materials showed only minor changes, and no differences were detected between their performance at baseline and after 12 months. Postoperative sensitivity was observed in only one Quixfil restoration. In regard to the clinical performance, there was no statistically significant difference between the materials used. CONCLUSIONS: Both materials showed good clinical results with dominant alpha scores at the end of 12 months. PMID- 23980405 TI - Locally-delivered antibiotics for management of periodontitis: current understanding. AB - The primary etiology of periodontitis is bacterial plaque in a susceptible host. In an attempt to eradicate or reduce periopathogenic bacterial levels, locally delivered antibiotic (LDA) agents have been suggested and have shown promising results. By applying the antibiotics locally, clinicians are able to overcome some of the disadvantages of systemic antibiotics in the management of periodontal patients. However, selecting a specific LDA to treat periodontitis out of the many available agents is not an easy task. Furthermore, timing of when to apply these agents can also be challenging. This literature review discusses the current understanding of the use of LDA in the management of periodontitis. A decision tree was developed in an attempt to guide the clinician in understanding the indications for the use of controlled delivery antimicrobial agents as an adjunct or alternative to traditional treatment modalities. PMID- 23980406 TI - A dual diagnosis: better late than never. PMID- 23980407 TI - A realistic look at managing debt. PMID- 23980408 TI - New aspects in natural product synthesis: methodology and strategy. PMID- 23980409 TI - Regioselective hydroxylation and glucosylation of alpha- and beta-pinenes with cultured cells of Eucalyptus perriniana. AB - Cultured plant cells of Eucalyptus perriniana regioselectively hydroxylated (+)- and (-)-alpha-pinenes to the corresponding (+)- and (-)-verbenols. In addition, (+)- and (-)-verbenols were converted into mono-beta-D-glucosides. On the other hand, (+)- and (-)-beta-pinenes were transformed into (+)- and (-)-pinocarveol 3 O-beta-D-glucosides via (+)- and (-)-pinocarveols. PMID- 23980410 TI - Synthesis of sterically-crowded olefins, gem-dihaloalkenes, butatrienes, and thioketenes through the reaction of substituted bornane-2-thiones or bornane-2 selones with conventional carbenes or metal carbenoids. AB - Reaction of highly-substituted bornane-2-selones with a diazoalkane in the presence of either Rh2(OAc)4 or CuCl formed sterically-crowded exo-methylenic products, and similar treatment of the thiones or selones with dihalocarbenes or a propadienylidene carbene also formed dihaloalkenes, butatrienes, and thioketenes. All these reactions were assumed to proceed through a pathway involving the in situ formation and subsequent ring closure of chalcogenocarbonyl ylides. PMID- 23980411 TI - Modification of valencene by bio- and chemical transformation. AB - Highly efficient production is discussed of nootkatone, the most important fragrant component of grapefruit and which possesses anti-obesity activity, from valencene, obtained from Valencia orange, by the green alga, Chlorella, and the fungi, Mucor, Botryospaeria and Botryodiplodia. The microorganisms introduce an oxygen atom at an allylic position to give secondary hydroxyl and keto groups. The presented methods are a cheap one step reaction, non-hazardous and very useful for the production of fragrant components from commercially available natural sesquiterpene hydrocarbons. PMID- 23980412 TI - Enantioselective synthesis of natural trinorsesquiterpene tetralones by chemo enzymatic approaches. AB - The enantioselective syntheses of both the enantiomeric forms of the four natural tetralones 1a-d are here described. The aforementioned trinorsesquiterpenes were prepared starting either from substituted (S)-3-arylbutanols 5a-c or from substituted (S)-2-arylpropanols 7a-c. The latter chiral building blocks were in turn obtained through two different kinds of enzymatic transformations consisting of the baker's yeast mediated reduction of substituted (E)-3-aryl-but-2-enals 4a c and the lipase-mediated resolution of racemic 2-arylpropanols 7a-c, respectively. Further key steps of the presented syntheses were C1 and C2 homologation procedures as well as the ring closure of the substituted 4-aryl pentanoic acids 3a-c. By these means the target compounds were obtained in good yields and with very high stereoisomeric purity. In addition, the trinorsesquiterpene schiffnerone-B was synthesized for the first time and its absolute configuration was unambiguously assigned. PMID- 23980413 TI - Structural factors in the odor of alpha-santalol derivatives. AB - Alpha-Santalol is a sesquiterpene that is a major constituent of sandalwood (Santalum album L.), and is responsible for its distinctive woody odor. We replaced the polycyclic moiety and hydroxyl group of alpha-santalol with other moieties, and we compared the odors of the E/Z-isomers and their saturated analogues. Our previous study of the structure-odor relationships of alpha santalols bearing hydroxyl, formyl, formyloxy, and acetoxy functional groups showed there was a similarity in odor between the Z-isomer and its saturated analogue. We synthesized alpha-santalols with a benzyl group in place of the hydroxyl group, because many benzyl compounds have strong characteristic odors. We found similar odors for the E-isomer and its saturated analogue. In contrast, the odors of the alpha-santalol derivatives with a hydroxyl, formyl, formyloxy, or acetoxy group were different. We also replaced the bulky polycyclic moiety with a linear alkyl chain. The polycyclic moiety was the most important structural factor in the characteristic sandalwood odor. The synthesis of derivatives and the evaluation of their odor allowed us to identify the key structural factors in the odor of alpha-santalol. PMID- 23980414 TI - Second generation synthesis of the neo-clerodane diterpenoid methyl barbascoate. AB - The second generation total synthesis of the neo-clerodane diterpenoid, methyl barbascoate, was accomplished in seven or nine linear steps via double enol triflation and subsequent palladium catalyzed double carbonylation, followed by regioselective samarium diiodide mediated conjugate reduction. PMID- 23980415 TI - Synthesis of a key intermediate, 10-acetyl-7-(t-butyldiphenylsilyloxymethyl)-4 methylbicyclo[5.3.0]dec-4-en-1-ol, in the synthesis of pseudolaric acid A. AB - 10-Acetyl-7-(t-butyldiphenylsilyloxymethyl)-4-methylbicyclo[5.3.0]dec-4-en-1-ol was synthesized by aldol cyclization to a five-membered ring, epoxidation, samarium diiodide-induced ring opening, and the RCM reaction to the seven membered carbocycle. This method has succeeded in constructing the desired stereochemistry in the synthesis of pseudolaric acid A. PMID- 23980416 TI - Use of RCM reactions for construction of eight-membered carbocycles and introduction of a hydroxy group at the juncture between five- and eight-membered carbocycles. AB - Model studies for total synthesis of YW3699 were carried out in order to introduce a hydroxy group at the ring juncture between 5- and 8-membered carbocycles. The five-membered ring part, hydrazone, and aldehyde with a cyclohexane ring were connected by the Shapiro reaction, followed by conversion to diketones, which were treated with IBX to afford hydroxylated models. PMID- 23980417 TI - Synthetic approach toward alpha-aminomethyl-gamma-butyrolactones from beta-lactam synthons elaborated by SmI2-mediated reductive coupling reactions. AB - A simple and straightforward synthetic approach was developed to access a biologically important class of alpha-aminomethyl-gamma-butyrolactones via a beta lactam synthon strategy involving successive ring-opening and lactonization processes from alpha-hydroxyethyl-substituted beta-lactams that were elaborated by SmI2-mediated reductive coupling reaction. PMID- 23980418 TI - Formal synthesis of (+)-madindoline A, a potent IL-6 inhibitor, utilizing enzymatic discrimination of quaternary carbon. AB - A formal synthesis of (+)-madindoline A was achieved. The Sunazuka's key intermediate, (4R,5S)-(-)-3-butyl-4-(tert-butyldimethylsiloxy)-5-methoxycarbonyl 2,5-dimethyl-2-cyclopentenone, was synthesized from easily available (2S,3S)-3 acetoxy-2-ethenyl-2-methylcyclopentanone. The starting material was reliably supplied by a chemo-enzymatic procedure in enantiomerically pure form. The synthesis was performed by straightforward transformations involving enone formation and regioselective introduction of the two alkyl side chains. PMID- 23980419 TI - Glucosylation of taxifolin with cultured plant cells. AB - Cultured plant cells of Eucalyptus perriniana glucosylated taxifolin to its 3'- and 7-O-beta-D-glucosides and 3',7-O-beta-D-diglucoside. On the other hand, taxifolin was converted into 3'- and 7-O-beta-D-glucosides by cultured cells of Nicotiana tabacum and Catharanthus roseus. PMID- 23980420 TI - Regioselective hydroxylation and glucosylation of flavanones with cultured plant cells of Eucalyptus perriniana. AB - Cultured plant cells of Eucalyptus perriniana catalyzed reduction, regioselective hydroxylation, and regioselective glycosylation of flavanones. (2S)-Flavanone was converted into (2S)-flavan-4-ol, (2S)-flavan-4,7-diol, (2S)-flavan-7-ol, (2S) flavan-7-yl glucoside, and (2S)-flavan-7-yl gentiobioside. The cells glucosylated (2S)-flavan-6-ol to (2S)-flavan-6-yl glucoside. (2S)-Flavan-2'-ol was transformed to (2S)-flavan-2',4-diol, (2S)-flavan-2',7-diol, (2S)-flavan-2'-yl glucoside. In addition, (2S)-flavan-4'-ol was transformed to (2S)-flavan-4,4'-diol, (2S)-flavan 4',7-diol, (2S)-flavan-4'-yl glucoside. PMID- 23980421 TI - Synthesis of resveratrol glycosides by cultured plant cells. AB - Incubation of cultured cells of Glycine max with trans-resveratrol gave its 3-O beta-D- and 4'-O-beta-D-glucosides. Cultured Gossypium hirsutum cells glycosylated trans-resveratrol to its 3-O-beta-D-, 4'-O-beta-D-, and 3,4'-O-beta D-diglucosides. On the other hand, trans-resveratrol was converted into cis resveratrol 4'-O-beta-D-glucoside, together with trans-resveratrol 3-O-beta-D glucoside and trans-resveratrol 4'-O-beta-D-glucoside, by Eucalyptus perriniana. PMID- 23980422 TI - Synthesis of 3-farnesyl salicylic acid, a novel antimicrobial from Piper multiplinervium. AB - Both 3-farnesyl salicylic acid and 3-geranyl salicylic acid were synthesized from 2,6-dibromophenol and showed low levels of antimicrobial activity against E. coli strains. PMID- 23980423 TI - Total synthesis of bisbibenzyl dibenzofuran asterelin A via intramolecular oxidative coupling. AB - Total synthesis of asterelin A was accomplished by applying intramolecular Suzuki Miyaura and oxidative couplings to the formation of an 18-membered macrocyclic ring and a dibenzofuran, respectively. PMID- 23980424 TI - Cyclopentanoids from cyclopentadiene: synthesis of (-)-methyl jasmonate and (+) 12-oxophytodienoic acid. AB - Linoleic acid metabolites, (-)-methyl jasmonate and (+)-12-oxophytodienoic acid ((+)-12-oxo-PDA), were prepared from the same precursor (1,2-trans, 1,3-cis, 2'Z) 2-(pent-2'-enyl)-cyclopent-4-en-1,3-diol, which was obtained by regioselective pent-2-enylation of cyclopentadiene and following photooxidation to cis-1,3-diol. A methoxycarbonylmethyl substituent was introduced to the cyclopentane ring via alkylation of the pi-allyl palladium intermediate derived from (1R,2S,3S,2'Z)-3 acetoxy-2-(pent-2'-enyl)cyclopent-4-ene-1-ol with dimethyl malonate for (-) methyl jasmonate. The alpha-chain was introduced to the cyclopentane ring via the S(N)2 type nucleophilic substitution of (1S,2R,3R,2'Z)-3-acetoxy-2-(pent-2' enyl)cyclopent-4-ene-1-ol with a dialkylcuprate for (+)-12-oxo-PDA. PMID- 23980425 TI - Synthesis of both enantiomers of 12-methyl-13-tridecanolide and 14-methyl-15 pentadecanolide (muscolide). AB - Both enantiomers of 12-methyl-13-tridecanolide{(R)-(+)-1, (S)-(-)-1} and 14 methyl-15-pentadecanolide (muscolide) {(R)-(+)-2, (S)-(-)-2} were synthesized from either (S)-(+)- or (R)-(-)-3-bromo-2-methyl-1-propanol 8 as a chiral building block. PMID- 23980426 TI - A new variant of fused cyclic ether synthesis based on Ireland-Claisen rearrangement and RCM. AB - A new variant of fused cyclic ether synthesis based on Ireland-Claisen rearrangement and ring-closing olefin metathesis (RCM) was developed. The Ireland Claisen rearrangement of a (Z)-3-alkoxyprop-2-en-1-yl glycolate ester having a cyclic ether on the oxygen at C3 of the (Z)-prop-2-en-1-yl group stereoselectively produced an anti-alpha,beta-dialkoxyester, which was successfully transformed to a fused bicyclic ether via a reaction sequence including RCM. PMID- 23980427 TI - Carvone as a versatile chiral building block for total syntheses of heterocyclic sesquiterpenoids. AB - This review article is focused on the total syntheses of heterocyclic sesquiterpenoids starting from carvone since 1996. PMID- 23980428 TI - Synthesis of a hydrindenone in rings C and D of YW3699. AB - A hydrindenone in rings C and D of YW3699 was synthesized starting from (-) isocarvone. The stereochemical requirement in this ring was successfully achieved by Eschenmoser-Claisen rearrangement followed by alkylation and the aldol reaction to afford the desired hydrindenone, which can be used for further elaboration of YW3699. PMID- 23980429 TI - Collective total synthesis of PPAPs: total synthesis of clusianone via intramolecular cyclopropanation. AB - The total synthesis of clusianone was accomplished through the stereoselective construction of a bicyclo[3.3.1]nonane derivative via a three-step sequence, which has been utilized for the total syntheses of nemorosone, garsubellin A, and hyperforin: intramolecular cyclopropanation, formation of a geminal dimethyl group, and regioselective ring opening of cyclopropane. Further elaboration, including chemo- and stereoselective hydrogenation to generate the C7 stereogenic center and cross-metathesis to construct prenyl groups in the side-chains, was employed to complete the total synthesis ofclusianone. PMID- 23980430 TI - Synthetic approaches to tetracyclic pyrrole imidazole marine alkaloids. AB - Oroidin derived, pyrrole imidazole marine alkaloids (PIAs) are attractive targets for synthetic organic chemists because of their structural complexity and diversity, as well as their interesting biological activities. A number of efforts have been carried out to develop strategies for the synthesis of these natural products. Members of PIAs (eg., 2-7), which contain tetracyclic ring systems possessing characteristic cyclic guanidine or urea moieties, show significant biological activities including anticancer activity and agonistic activity against the adrenoceptor. In this review, investigations of the total synthesis of the representative tetracyclic PIAs, dibromophakellin (2) and dibromophakellstatin (3), are described. PMID- 23980431 TI - Lyngbouilloside and related macrolides from marine cyanobacteria. AB - Lyngbouilloside and the related macrolides lyngbyaloside, lyngbyaloside B and lyngbyaloside C have attracted a lot of attention over the past decade due to their intriguing architecture, their natural scarcity and their potential biological activities. This review aims to showcase the various strategies that have been used to access these natural products. PMID- 23980432 TI - Enantioselective total synthesis of otteliones A and B, novel and powerful antitumor agents from the freshwater plant Ottelia alismoides. AB - Otteliones A and B, isolated from the freshwater plant Ottelia alismoides, have attracted significant attention because of their potential as novel anticancer agents. In this review, four independent enantioselective total syntheses and one formal synthesis of these natural products are presented with particular focus on their methodology and strategy. PMID- 23980433 TI - A new approach to the synthesis of chiral blocks for cyclopentanoids. AB - A microreview is presented of the development by the authors of the original preparation of enantiomerically pure cyclopentane blocks from the racemic [2+2] cycloadducts of 1,3-cyclopentadiene and its derivatives with dichloroketene. PMID- 23980434 TI - Stereocontrolled total synthesis of tetrodotoxin from myo-inositol and D-glucose by three routes: aspects for constructing complex multi-functionalized cyclitols with branched-chain structures. AB - This report describes the stereocontrolled total synthesis of the multi functionalized cyclitol derivative, tetrodotoxin, containing eight asymmetric carbons and different types of branched-chains, from myo-inositol and D-glucose using three different methods. The tetrodotoxin derivatives possess a relatively small molecular weight but unique structural and chemical properties. Selection of the appropriate synthetic method may be useful not only for compounds related to TTX (including related derivatives), but also for other highly complex multi functionalized cyclitols containing branched-chains. PMID- 23980435 TI - Development of a second generation palladium-catalyzed cycloalkenylation and its application to bioactive natural product synthesis. AB - A novel palladium-catalyzed intramolecular oxidative alkylation of unactivated olefins is described. This protocol was devised to solve one of the drawbacks of the original palladium-catalyzed cycloalkenylation that we developed. We call this new procedure the 'second generation palladium-catalyzed cycloalkenylation'. This protocol has been applied to the total syntheses of cis-195A, trans-195A, boonein, scholareins A, C, D, and alpha-skytanthine. PMID- 23980436 TI - Stereoselective aminopalladation and oxypalladation and their application to the synthesis of natural products. AB - Stereoselective aminopalladation and oxypalladation are very important approaches for the synthesis of various natural products which contain N- and O-hetero alicycles. The author has reviewed recent progress of synthesis of natural products using Pd(II)-catalyzed aminopalladation and oxypalladation, including our work within this decade. PMID- 23980437 TI - Evolution of the total syntheses of batzellasides, the first marine piperidine iminosugar. AB - Batzellasides A-C are C-alkylated piperidine iminosugars isolated from a sponge, Batzella sp. The first total synthesis of (+)-batzellaside B was achieved by employing a chiral pool approach starting from L-arabinose for the construction of a piperidine ring system. Subsequently, a practical second-generation synthesis was developed by utilizing a Sharpless asymmetric dihydroxylation for the preparation of the common piperidine intermediate elaborated in the first generation synthesis. The overall yield of batzellaside B was improved to 3.3% by introducing the exocyclic C8 stereocenter via facial selective hydride addition to a linear ketone. These syntheses allowed for the determination of the absolute stereochemistry of this natural product as well as for providing precious samples, which would pave the way for further biological studies. PMID- 23980438 TI - Recent applications and developments of organic azides in total synthesis of natural products. AB - Organic azides have been exploited since their discovery because of their high reactivities. Various organic reactions using azides have been synthetically applied in chemical biology, pharmaceuticals, medicinal, and agricultural areas. In this review, we present some recent applications and developments of organic azides in the total synthesis of natural products (mostly within five years), especially alkaloids. We focus not only on application examples of organic azides, but also show their preparation methods including recently reported procedures concerning their decomposing and reducing methods in the syntheses of bioactive molecules. PMID- 23980439 TI - [Make research misconduct punishable!]. PMID- 23980440 TI - [New policy for police assistance in the county of Vastra Gotaland. Mentally ill might not receive care]. PMID- 23980441 TI - [Physician level of commitment crucial for critically ill patients. Procedures for monitoring of vital functions in a hospital department must be improved]. PMID- 23980442 TI - [Latex allergy is a problem for both health professionals and patients. Perhaps the climax has been reached thanks to preventive measures]. PMID- 23980443 TI - [Distribution of naloxone to prevent death from heroin overdose. Study of opioid dependent patients' attitudes to be part of the antidote program]. PMID- 23980444 TI - [Health communicators can contribute to better health among people born abroad]. PMID- 23980445 TI - [You should listen to the patient. Unusual cause of heart failure was discovered after 40 years]. PMID- 23980446 TI - [Toxic hepatitis most likely triggered by dalteparin]. PMID- 23980447 TI - [Critically ill hospitalized patients must get help in time. Measure, evaluate, act is the foundation--supported by ALERT, MEWS and MIG]. PMID- 23980448 TI - [New treatment options for vascular Ehlers-Danlos syndrome]. PMID- 23980449 TI - [Physician, where is your LGBT patient?]. PMID- 23980450 TI - [Increased methodological knowledge more important than experiments]. PMID- 23980451 TI - [Political decisions must be based on sound data]. PMID- 23980452 TI - [Physicians should not prescribe drugs to themselves]. PMID- 23980453 TI - [The white coat--does it play a role?]. PMID- 23980454 TI - "The government's focus must be on patient safety". PMID- 23980455 TI - Nursing stuck in subservient past. PMID- 23980456 TI - The Keogh review. PMID- 23980457 TI - "Trust boards must be obliged to publish their actual staffing levels". PMID- 23980458 TI - "Nurses and doctors must stop acting like a divorced couple". PMID- 23980459 TI - Using clerical staf free up ward sister time. AB - The head and neck unit at Nottingham University Hospitals Trust trialled the introduction of a ward administrator. This role takes on some of the ward sister's administrative and clerical tasks, enabling the sister to spend more time on the ward, be a visible leader to staff and patients, and monitor standards. This article outlines how the role was introduced and the key outcome measures used to evaluate its impact on patient and staff satisfaction, complaint reduction and nursing metrics. PMID- 23980460 TI - Does hands-free drinking improve patient hydration? AB - Hospital patients are at risk of dehydration, especially if they cannot drink unaided due to physical or mental incapacity. Dehydration may lead to complications and result in costly interventions. A sports-style bottle has been developed into a hands-free drinking system by fitting a drinking tube into the screw top. We trialled the bottle on acute wards and in the community to test claims that it improves hydration and reduces infection risks and length of hospital stays. The Hydrant is useful and even transformative for some patients. However, it is less suitable for older people, especially those in rehabilitation programmes. PMID- 23980461 TI - Feverish illness in children under five. PMID- 23980462 TI - Nurses' role in care home rehabilitation. AB - BACKGROUND: Increasing numbers of older people are living in long-term residential care. Due to their often complex physical and medical conditions, there is a need for nursing rehabilitation to improve or maintain their functional status. AIM: The aim of this study was to explore nurses' perceptions of their role in the rehabilitation of older people in long-term care residences. METHODS: Ten nurses working in two long-term care residences participated in this qualitative descriptive design study. Data was collected through semistructured interviews and its thematic content was then analysed. FINDINGS: The nurses considered their roles in caring and promoting enablement and independence to be important, but reported that time constraints and the physical and cognitive limitations in older people made the successful implementation of rehabilitation more difficult. They were positive about multidisciplinary collaboration and reported that multiple skills were needed in rehabilitation nursing, expressing a need for further education and training. They were aware of the need for a sense of homeliness to exist in long-term residences and welcomed working with families to achieve this. CONCLUSION: Rehabilitation nursing of older people in long-term residences focuses on caring and enablement. Participants acknowledged challenges relating to age and infirmities but considered multidisciplinary collaboration, homeliness and families to be important to successful rehabilitation nursing. PMID- 23980463 TI - 60 seconds with Sarah Wheatland. PMID- 23980464 TI - Value from difficult times. PMID- 23980465 TI - How to run a great student placement. PMID- 23980466 TI - [Analysis of selenometabolome and tellurometabolome by speciation]. PMID- 23980467 TI - [New research initiatives in the regulatory mechanisms of heterotrimeric G protein signaling]. PMID- 23980468 TI - [Amyloidogenicity and pathogenicity of Abeta43 in Alzheimer's disease]. PMID- 23980469 TI - [Complete metabolic pathway of sphingosine 1-phosphate and its importance as a metabolic intermediate]. PMID- 23980470 TI - [Molecular mechanisms involved in the diverse actions of ghrelin]. PMID- 23980471 TI - [Sensory mechanism of pain and novel analgesics]. PMID- 23980472 TI - [Heterochromatin assembly and RNA silencing]. PMID- 23980473 TI - [Mechanisms and functions underlying neuronal activity-dependent alternative pre mRNA splicing]. PMID- 23980474 TI - [Molecular mechanism of magnesium transport in renal tubule]. PMID- 23980475 TI - [Development of hyper-thermostable chitinolytic enzymes by gene hunting and functional analysis]. PMID- 23980476 TI - [Molecular regulatory mechanisms of epithelial structure and barrier function]. PMID- 23980477 TI - [Utilize the specific medical checkup and health guidance in the action against chronic kidney disease]. PMID- 23980479 TI - [Japanese guidelines of the management of hematuria]. PMID- 23980478 TI - [Special issue: Evidence-based practice guideline for the treatment of CKD]. PMID- 23980480 TI - [Long-term prognosis of patients with steroid-dependent nephrotic syndrome treated with rituximab]. AB - Rituximab, an anti-CD2O monoclonal antibody, is an emerging and effective option for the treatment of patients with refractory steroid-dependent nephrotic syndrome (SDNS), but few studies have assessed the long-term prognosis in these patients. We therefore evaluated the efficacy of rituximab in 35 patients, aged 4 21 years, who experienced SDNS while being treated with immunosuppressants. Patients were monitored for 24-63 months. After the first infusion of rituximab, the number of relapses and the dose of prednisolone were significantly reduced, and the steroid withdrawal period was significantly increased. However, 22 patients (63%) required retreatment with rituximab owing to relapses. At the last observation, only three patients (9%) could discontinue immunosuppressants completely and only three continued to show remission during the observation period. Although rituximab could not induce a complete cure of refractory SDNS, it resulted in longer remission times when immunosuppressants were continued after rituximab therapy, indicating the effectiveness of rituximab followed by immunosuppressants. We also found that patients who experienced more relapses before rituximab therapy were more likely to relapse earlier after rituximab therapy. PMID- 23980481 TI - [Effect of an educational admission program for patients at the conservative phase of chronic kidney disease (CKD)]. AB - PURPOSE: We have been conducting a 1-week educational admission program for patients at the conservative phase of chronic kidney disease (CKD) since 2006. In this study we evaluated the effect of the program. METHODS: We retrospectively reviewed 469 patients who could be followed for 12 months after a 1-week educational admission program for CKD out of a total of 700 patients who attended the program between October 2006 and April 2012. We compared the rates of decrease in renal function before and after the program. In addition, we divided the patients into two groups of diabetic nephropathy and non-diabetic nephropathy. We compared the rate of decrease in renal function in each group. RESULTS: The rate of decrease in renal function 12 months after discharge was improved compared with that 6 months before admission. (before: 0.316 mL/min/1.73 m2/month; after: 0.001 mL/min/1.73 m2/month.) The rate of decrease in renal function 6 months before admission of the diabetic nephropathy group was 72.3 times faster than that of the non-diabetic nephropathy group. However, the rate of decrease in renal function 12 months after admission was improved in both groups. CONCLUSION: It was revealed that the educational admission program is effective for preserving the renal function on patients at the conservative phase of CKD. PMID- 23980482 TI - [A case of acute kidney injury during warfarin therapy]. AB - The patient was an 82-year-old female. She had been treated with warfarin for atrial fibrillation that developed after a heart valve replacement operation. She was admitted because of a progressive loss of renal function together with persistent microscopic hematuria and proteinuria. Although the renal biopsy showed only focal mononuclear cell infiltration and mild mesangial expansion in the glomeruli, the occlusive red blood cell casts were remarkable in the tubules and were accompanied by inflammatory and edematous changes in the surrounding interstitial area. After the adjustment of an excessively extended prothrombin time, her renal function gradually improved in parallel with the marked decrease in the microhematuria. It was assumed that an acute kidney injury observed in this case was caused by the occlusive red blood cell casts as a result of abnormal hemorrhage in the glomeruli due to focal glomerulonephritis and a warfarin overdose. The present case, therefore, suggests that a warfarin overdose is a potential risk factor for acute kidney injury in the presence of coexisting glomerular injury. PMID- 23980483 TI - [Questionnaire about the intake of and hypersensitivity to fruits, vegetables and nuts including birch pollen related foods]. AB - BACKGROUND: In Hokkaido and Scandinavia, birch pollen allergic persons are common and they often report oral and pharyngeal hypersensitivity to fruits and vegetables (oral allergy syndrome, OAS), because of immunological cross reactivity. In Scandinavia, nuts as well as Rosaceae fruits such as apples were the foods most often reported to elicit symptoms. On the other hand, nuts are minor foods causing hypersensitivity in Japan. Even in Japan, regional differences of foods causing hypersensitivity have been reported, which may be related to the regional differences of elementary habit and pollen dispersion. In the present study, we evaluated the intake history of the foods and the frequency of food hypersensitivity in adults from the general population. METHODS: Three hundreds and thirty nine subjects (20-67 years old) took part in the study. With a questionnaire survey, we asked them about their intake history and hypersensitive symptoms for 33 kinds of fruit, vegetables, and nuts. RESULTS: 30% of subjects had eaten Brazil nuts, 80% had eaten pomegranates, and 81% had eaten hazelnuts. And over 95% of subjects had eaten the other 30 foods. Those who had lived in Hokkaido for more than 20 years had a higher frequency of plum consumption than the others. Those who had lived in Hokkaido for more than 20 years had a lower frequency of loquat, fig and pomegranate consumption than the others. Food hypersensitivity was found in 52 subjects (15.3%). The most common symptom was OAS (46 subjects, 13.6%), and foods most frequently causing OAS were peach (21 subjects, 6.2%), cherry (19 subjects, 5.6%) and apple (17 subjects, 5.0%). 26 subjects (7.7%) reported OAS to Rosaceae fruits. The ratio of having OAS to consuming Rosaceae fruits was 11.0% in the group who had lived in Hokkaido for more than 20 years, which was higher than the group who has lived in Hokkaido for less than 20 years. The intake history of hazelnuts and Brazil nuts was very low, with a correspondingly low frequency of food hypersensitivity associated with these nuts. CONCLUSION: The frequency of intake and hypersensitivity of some foods differ among different regions. PMID- 23980484 TI - [Effect of septoplasty and turbinectomy on obstructive sleep apnea syndrome]. AB - Obstructive sleep apnea syndrome (OSAS) is thought to be closely related to nasal airway resistance, which accounts for approximately one half of total upper airway resistance. This retrospective study aimed at elucidating the effect of endoscopic endonasal surgery on OSAS. Nine consecutive patients with OSAS complaining of nasal obstruction who underwent endoscopic endonasal surgery were enrolled. They were 8 men and 1 woman ranging from 34-73 years of age with an average of 53.2 years. All patients had chronic hypertrophic rhinitis and nasal septal deviation, and underwent septoplasty and submucous turbinectomy. The severity of OSAS was assessed by 8 sleep apnea indices of polysomnography before and after surgery. The indices included the apnea-hypopnea index (AHI), maximum apnea time, mean apnea time, minimum blood oxygen saturation, mean blood oxygen saturation, blood oxygen saturation decline index, awakening response index, and ratio of snoring time to sleep time. Significant decrease in the AHI (27.6 +/- 5.3 vs. 20.7 +/- 5.5/hr; p = 0.033), in the awakening response index (30.5 +/- 3.3 vs. 21.2 +/- 5.3/hr; p = 0.028), and increase in the mean blood oxygen saturation (95.1 +/- 0.7 vs. 96.0 +/- 0.7%; p = 0.023) were observed postoperatively. There was no significant change in the other 5 indices. In addition, nasal airflow resistance measured by acoustic rhinometry had significantly reduced during the periods of both inhalation (474.4 +/- 49.0 vs. 842.7 +/- 50.2cm3/s; p = 0.002) and exhalation (467.3 +/- 57.3 vs. 866.0 +/- 80.6 cm3/s; p = 0.004). The pre- and postoperative body mass indices did not differ statistically from each other. These results indicate that endoscopic endonasal surgery alone has a potential effect on sleep-disordered breathing in OSAS patients with nasal obstruction. We should be aware of such a positive impact of endonasal surgery upon the management of OSAS. PMID- 23980485 TI - [Preoperative diagnosis of nonrecurrent inferior laryngeal nerve--usefulness of CT and ultrasonography]. AB - BACKGROUND AND OBJECT: The right nonrecurrent inferior laryngeal nerve (NRILN), which is usually associated with the right aberrant subclavian artery, is a risk factor of nerve injury during thyroid surgery. Therefore the presence of the NRILN should be diagnosed if possible before surgery. The aim of this study was to investigate the usefulness of computed tomography (CT) and ultrasonography (US) for preoperative diagnosis of the right-sided NRILN. SUBJECTS AND METHODS: We reviewed 1,561 patients who underwent thyroid surgery, during which the right inferior laryngeal nerve was exposed, at Yamashita thyroid and parathyroid clinic from April 2006 to April 2012. All medical records, CT findings and ultrasonograms of these patients were reviewed retrospectively. RESULTS: We recognized 11 patients who had the right-sided NRILN from the total of 1561 patients (0.71%). Ten of 1086 patients who underwent CT, had a right aberrant subclavian artery. CT findings were enabled us to predict the existence of the right NRILN before surgery. The sensitivity and specificity of CT for detection of the right-sided NRILN were 100% and 100%. On the other hand, we could detect the bifurcation of the innominate artery in 116 of 140 patients with cervical US before surgery, and therefore could confirm that the right inferior laryngeal nerve of the 116 patients was normal. The bifurcation of the other patients was not detectable and one of the 24 patients only had the right-sided NRILN during surgery. The sensitivity and specificity of cervical US for detection of the right-sided NRILN were 100% and 83.5% respectively. CONCLUSIONS: Although CT is extremely useful for preoperative diagnosis of the right-sided NRILN because of its accuracy, cervical US is also a good method for making sure that the right inferior laryngeal nerve is normal. PMID- 23980486 TI - [A case of chronic active Epstein-Barr virus infection with a pharyngeal ulcer]. AB - Chronic active Epstein-Barr virus infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms, such as fever, extensive lymphadenopathy, and hepatosplenomegaly. A 44-year-old women visited our ENT clinic with a four-month history of fever and throat pain. She was diagnosed as having CAEBV based on the findings of fever, liver dysfunction, lymphadenopathy, pharyngeal ulcer, the titer for IgG to the EBV capsid and pathological findings. The whole-blood EBV DNA levels were high and above 3.7 x 10(3) copies/mL. After administration of intravenous predonine (1000 mg/day for 3 days) and oral predonine (1.5 mg/kg. 60 mg/day), the liver dysfunction and pharyngeal ulcer improved. Since the prognosis is poor in adult cases of CAEBV, chemotherapy is scheduled for this case. PMID- 23980487 TI - Emergency mental health. PMID- 23980488 TI - Experiences of chronic stress one year after the Gulf oil spill. AB - One of the largest oil spills in world history happened off the Alabama Gulf coast in April of 2010. One year later the Gulf Coast community was still trying to recover and reestablish itself as a major source for the shipping, tourism, fishing and energy industries. Although this disaster did not physically destroy communities and families, it did take an economic and psychological toll. Researchers conducted focus groups with mental health professionals employed by Project Rebound, a state sponsored response to disasters in Alabama to explore the mental health effects of the Gulf Oil Spill on two gulf coast communities one year after the spill. Project Rebound clinicians were the front line of the mental health response to the spill and collaborated with community service agencies to provide support to adults, children, and families in the Gulf Coast community. The semi-structured focus groups allowed staff to discuss the extent of mental health treatment utilization as well as provide valuable input as to what can be done to better prepare communities and agencies for future disasters. PMID- 23980489 TI - Incident-related television viewing and psychiatric disorders in Oklahoma City bombing survivors. AB - The objective of this study was to examine terrorism media coverage and psychiatric outcomes in directly-exposed terrorism survivors. The study used (1) self-report questionnaires to retrospectively assess event-related media behaviors and reactions in a cross sectional design and (2) longitudinal structured diagnostic interviews to assess psychopathologic outcomes. The participants were 99 directly-exposed Oklahoma City bombing survivors who were initially studied six months after the 1995 incident. Though a fear reaction to bombing-related television coverage and fear-driven discontinuation of bombing related media contact were associated with diagnostic outcomes, the number of hours viewing bombing-related television coverage in the first week after the event was not associated with the prevalence of bombing-related posttraumatic stress disorder or post-bombing major depressive disorder during the seven years post event. The results raise doubt about the effects of quantified incident related television viewing on clinically-significant emotional outcomes in directly-exposed terrorism survivors. PMID- 23980490 TI - Trauma and stress-related disorders in German emergency physicians: the predictive role of personality factors. AB - Emergency medical personnel (EMP) are repeatedly exposed to traumatic and stressful events with possible consequences on their mental wellbeing. Out of the group of EMP, we chose German Emergency Physicians (EP), because they represent a distinct group within the German pre-hospital emergency services. In this group, we studied the prevalence rates of posttraumatic stress disorder (PTSD), burnout and depression. We specifically focussed on the role of personality and other factors of vulnerability. Four hundred eighty-seven German EPs answered questionnaires with scales assessing probable PTSD, burnout, depression, and personality factors. Additionally, we asked for biographic, occupational and mental health information. More than 90% of the participants reported at least one traumatic event. We found low to moderate levels of stress-related disorders with 16.8% of participants meeting the criteria for probable PTSD, 4.1% for burnout, and 3.1% for clinical depression. We identified four clusters of personalities that were related to the prevalence of PTSD and depression. The type of personality seems to be more predictive of the development of trauma and stress-related disorders than the EPs' traumatic experiences. PMID- 23980491 TI - Elite firefighter/first responder mindsets and outcome coping efficacy. AB - The present study examined coping strategies used by firefighters, the relationship between appraisals and coping strategies used, and the relationship between transitional coping strategies used and outcome coping efficacy for mental preparedness. Firefighter coping strategies of problem focused coping and seeking social support were found to have positive significant relationships to outcome coping efficacy, after transitioning from one critical incident to a second. The coping strategies of blamed self wishful thinking, and avoidance appear to have a negative significant relationship to outcome coping efficacy. Additionally, the appraisals of challenge and positive reappraisal to meet the challenge appear to have a positive significant relationship to problem focused coping and seeking social support. These findings on outcome coping efficacy may be of help to firefighters for rehabilitative efforts after traumatic incidents when used in the Peer Support Review intervention model. PMID- 23980492 TI - The changing role of leadership in the fire service. AB - The role of the modem fire service is evolving drastically and today's leaders must have the courage, tenacity, and perseverance to embrace and prepare for substantial change in an industry heavily steeped in almost two centuries of tradition that's historically resistant to new ways of doing things. Moreover, from an individual perspective, fire service professionals must personally prepare themselves to lead the emergency response industry in the years ahead. Fire service leaders will be faced with new and different challenges. The roles and responsibilities of our profession are changing and becoming more complex. Many common practices currently done in the fire service today will require innovative solutions in the future. To lead our firefighters, not only into dangerous environments, but through these changing times, the professional fire officer will need to be functionally educated, current with new tactics to combat changing conditions, and possess an understanding of leadership principles such as emotional intelligence, leadership style, and leadership theory. This foundation will help today's fire officers become tomorrow's fire service professionals. PMID- 23980493 TI - Introducing embedded indigenous psychological support teams: a suggested addition to psychological first aid in an international context. AB - The current article introduces Embedded Indigenous Psychological Support Teams (IPST) as a possible addition to current disaster relief efforts. This article highlights psychological first aid in an international context by drawing on mainstream disaster relief models such as The American Red Cross, Critical Incident Stress Management, and Flexible Psychological First Aid. IPST are explained as teams utilizing techniques from both CISM and FPFA with a focus on resiliency. It is currently theorized that in utilizing IPST existing disaster relief models may be more effective in mitigating negative physical or mental health consequences post-disaster. PMID- 23980494 TI - Just show up: the importance of caring attachments in emergency services. AB - Caring attachments to others are important for health, well-being, and longevity. This is no less true when EMS are providing needed medical services to victims at a vulnerable moment in the victims' lives. This article reviews the recent medical and behavioral science findings of the psychological and physiological benefits of caring attachments. Special attention is paid to the societal state of anomie and individuals' differing levels of optimal stimulation. The review then focuses on how attachments can be utilized by EMS as they provide services to victims and how these same health benefits may accrue to their colleagues onsite as well. PMID- 23980496 TI - The healing effect of stem cells loaded in nanofibrous scaffolds on full thickness skin defects. AB - In this study, we have evaluated the wound-healing effects of unrestricted somatic stem cells loaded in chitosan-cross linked PHBV nanofibrous scaffold, implanted into the full thickness skin defects of rats. Afterwards, the scaffolds were evaluated by structural, microscopic, physical and mechanical assays and cell culture analyses. Defects were treated with the scaffolds without and with USSCs. MTT assay, immunostaining, and wound pathology were performed for groups twenty one days after implantation. SEM images showed the average diameter of about 100 nm for the nanofibrous scaffolds, increasing up to 500 nm after chitosan-crosslinking. Results of physical and mechanical analyses also showed a good resilience and compliance with movement as a skin graft. Cellular experiments showed a better cell adhesion, growth and proliferation inside the cross-linked nanofibrous scaffolds compared to un-cross linked ones. In animal models, all groups, excluding the control group, exhibited the most pronounced effect on wound closure, with the statistically significant improvement in wound healing being seen at post-operative day 21. Histological and immunostaining examinations of healed wounds from all groups, especially the groups treated with stem cells. Thus, the grafting of chitosan-cross-linked nanofibrous scaffold loaded with USSC showed better results during the healing process of skin defects in rat models. PMID- 23980497 TI - Nanohydroxyapatite incorporated electrospun polycaprolactone/polycaprolactone polyethyleneglycol-polycaprolactone blend scaffold for bone tissue engineering applications. AB - The present work is a comparative evaluation of physical and biological properties of electrospun biodegradable fibrous scaffolds based on polycaprolactone (PCL) and its blend with polycaprolactone-polyethyleneglycol polycaprolactone (CEC) with and without nanohydroxyapatite (nHAP) particles. The fiber morphology, porosity, surface wettability, and mechanical properties of electrospun PCL were distinctly influenced by the presence of both copolymer CEC and nHAP. The degradation in hydrolytic media affected both morphological and mechanical properties of the scaffolds and the tensile strength decreased by 58% for PCL, 83% for PCL/CEC, 36% for PCL/nHAP and 75% for PCL/CEC/nHAP in 90 days of PBS ageing. MTT assay using mouse fibroblast L929 cells proved all the scaffolds to be non-cytotoxic. An overall enhanced performance was shown by PCL/CEC/nHAP scaffold in cell viability (LPH) and proliferation (Picogreen). Simultaneously, ELF assay of ALP activity (bone marker) confirmed the presence of osteogenic induced Rabbit adipose-derived mesenchymal stem cells (ADMSCs) on all the scaffolds. In comparison, the results reveal the potential of the cytocompatible PCL/CEC/nHAP scaffold for the fabrication of living bony constructs for tissue engineering applications. PMID- 23980495 TI - Entering the era of nanoscience: time to be so small. AB - The field of nanoscience has produced more hype than probably any other branch of materials science and engineering in its history. Still, the potentials of this new field largely lay undiscovered ahead of us; what we have learnt so far with respect to the peculiarity of physical processes on the nanoscale is only the tip of an iceberg. Elaborated in this critical review is the idea that the surge of interest in physical chemistry of phenomena at the nanoscale presents a natural consequence of the spatial refinement of the human ability to controllably manipulate the substratum of our physical reality. Examples are given to illustrate the sensitivity of material properties to grain size on the nanoscale, a phenomenon that directly contributed to the rise of nanoscience as a special field of scientific inquiry. Main systemic challenges faced by the present and future scientists in this field are also mentioned. In part, this perspective article resembles standing on the constantly expanding seashore of the coast of nanoscience and nanoengineering and envisioning the parts of the island where the most significant advances may be expected to occur and where, therefore, most of the attention of scientist in this field is to be directed: (a) crossing the gap between life science and materials science; (b) increasing experimentation sensitivity; (c) crisscrossing theory and experiments; and (d) conjoining top down and bottom-up synthetic approaches. As for materials and the application areas discussed, a special emphasis is placed on calcium phosphate nanoparticles and their usage in controlled drug delivery devices and other applications of biomedical relevance. It is argued that the properties of nanoparticles as drug carriers often comprise the critical determinant for- the efficacy of the drug therapy. Therefore, the basic properties of nanoparticles to be optimized for the purpose of maximizing this efficacy are discussed: size, size distribution, morphology, polymorphic nature, crystallinity, biocompatibility, biodegradability, drug elution profiles, and aggregation propensity. PMID- 23980498 TI - Bi-layer composite dressing of gelatin nanofibrous mat and poly vinyl alcohol hydrogel for drug delivery and wound healing application: in-vitro and in-vivo studies. AB - Present investigation involves the development of a bi-layer dressing of gelatin nanofibrous mat loaded with epigallocatechin gallate (EGCG)/poly vinyl alcohol (PVA) hydrogel and its in-vivo evaluation on full-thickness excision wounds in experimental Wistar rats. Nanomorphological observation, porosity, effect of crosslinking on tensile strength, physical stability and drug release profile in phosphate buffer and biocompatibility aspects of electrospun nanomat were investigated by various physico-chemical tools. EGCGa release profile was found to increase from 2-4 days with decreasing crosslinking time from 15 to 5 min. PVA hydrogels were prepared by freeze-thaw method and has been utilized as a protective and hydrating outer layer of the bi-layer dressing. Topical application of bi-layer composite dressing loaded with EGCG improve the healing rate in experimental rats as acute wounds model which was evidenced by significant increase in DNA (approximately 42%), total protein (approximately 32%), hydroxyproline (approximately 26%) and hexosamine approximately 24%) contents. A faster wound contraction was observed in wounds treated with composite dressing from approximately 14% to 47%. Histopathological examination revealed significant improvement in angiogenesis, re-epithelialization and less inflammatory response in comparison to control. Van-Gieson's collagen stains revealed matured, compact and parallel deposition of collagen fibrils on day 12. These results were supported by up-regulated expressions of matrix metalloproteinase (MMPs-2 and 9) by gelatin zymography. Control release of EGCG, 3D porous architecture of nanofibrous scaffolds as well as moist microenvironment provides ideal conditions for uninterrupted wound healing. PMID- 23980499 TI - Magnetite nanoparticle with positively charged surface for immobilization of peptide nucleic acid and deoxyribonucleic acid. AB - We herein report the surface modification of magnetite nanoparticle (MNP) with the (co)polymer of poly(ethylene glycol) methyl ether methacrylate (PEGMA) and/or diethylamino ethyl methacrylate (DEAEMA) via atom transfer radical polymerization (ATRP) for use as anion exchanger solid support for detection of DNA sequence using peptide nucleic acid (PNA) probe. Molar ratio of the PEGMA:DEAEMA (co)polymer was systematically varied to tune the positive charges on the particle surface. Kinetic studies of the (co)polymerizations were investigated via 1HNMR to disclose the relative reactivity of the (co)polymers in the reaction. Zeta potential of the (co)polymer-grafted MNP was analyzed by photo correlation spectroscopy (PCS). Transmission electron microscopy (TEM) and PCS indicated an improvement in the particle dispersibility in water upon quaternization of the DEAEMA entities grafted on the particle surface. From the preliminary results, these (co)polymer-grafted MNPs can be used as a nanosolid support to differentiate between full match and single-base mismatch DNA sequences using an acpcPNA probe. These novel cationic MNPs might be efficiently applicable for use as a magnetically guidable tool for detection of DNA sequences. PMID- 23980500 TI - Fluconazole loaded chitin nanogels as a topical ocular drug delivery agent for corneal fungal infections. AB - Poor bioavailability of antifungal drugs due to the various protective mechanisms of the eye is a serious concern for the treatment of corneal fungal infections in today's world. The use of nanosystems that can improve the bioavailability of these antifungal drugs is relatively a new idea being conceived and here we have synthesized fluconazole loaded chitin nanogels (Flu-CNGs) which can be used for the treatment of corneal fungal infections. These nanogels were characterized using DLS, Zeta potential, SEM, FTIR and TG/DTA. The prepared Flu-CNGs have controlled release pattern which is ideal for the continuous availability of fluconazole over a longer period of time for an effective fungal treatment. Flu CNGs are haemocompatible, cytocompatible and also showed very good cell uptake in human dermal fibroblast cells and penetration to the deeper sections of the porcine cornea with no signs of destruction or inflammation to corneal cells as shown in ex vivo permeation studies. PMID- 23980501 TI - Increased proliferation and differentiation of pre-osteoblasts MC3T3-E1 cells on nanostructured polypyrrole membrane under combined electrical and mechanical stimulation. AB - Polypyrrole (PPy), as an electrical conductive polymer, has been widely investigated in biomedical fields. In this study, PPy membrane at nanoscale was electrically deposited on indium-tin oxide glass slide with sodium p toluenesulfonate as supporting electrolyte. Electropolymerization of PPy was performed under a constant 800 mV voltage for 10 seconds. Chemical compositions and morphology were characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The results showed that the nanoscaled PPy particles distributed uniformly and the average diameter of PPy particles was 62 nm. Since bone cells can respond to both electrical and mechanical stimulation in vivo, pre-osteoblasts MC3T3-E1 cells were cultured ort nanostructured PPy membrane under the combined electrical and mechanical stimulation. The nano-PPy membrane was conducive to transferring uniform electrical stimulation and applying steady mechanical stimulation. It is suggested that the combined stimulation did not affect cells morphologies significantly. However, cell proliferation tested by MTT, alkaline phosphatase activities, and gene expression of Collagen-I indicated that combined stimulation can enhance the proliferation and differentiation of MC3T3-E1 cells more efficiently than single electrical stimulation or single mechanical stimulation. The combined stimulation through a nano-PPy membrane may provide a highly potential stimulated method in bone tissue engineering. PMID- 23980502 TI - PCL and PCL-gelatin nanofibers as esophageal tissue scaffolds: optimization, characterization and cell-matrix interactions. AB - Nanofiber based scaffolds offer great promise in regeneration of various tissues including esophagus. Diseases of the esophagus such as malignancy and strictures require surgical intervention to repair the affected region using an appropriate substitute. Long gap esophageal atresia poses a clinical challenge to bridge the gap. In this study, nanofibrous scaffolds made of PCL and PCL-gelatin were fabricated through electrospinning. The average diameter of PCL and PCL-gelatin nanofibers were found to be 324 +/- 50 nm and 242 +/- 30 nm respectively. PCL gelatin nanofibers was characterized using FTIR, DSC, UTM, Goniometer, suture retention strength and in vitro degradation and the results were compared with the PCL nanofibers. PCL nanofiber characterization results showed that it exhibited higher tensile strength, suture retention strength, contact angle and slower degradation when compared with the PCL-gelatin nanofibers. Further, the interaction of human esophageal epithelial cells with PCL and PCL-gelatin nanofibrous scaffold was determined by cell adhesion, proliferation and gene expression studies. Our results demonstrated that the epithelial cells adhered and proliferated well on both PCL and PCL-gelatin nanofibrous scaffolds and also exhibited the characteristic cobblestone morphology. Cell proliferation on PCL gelatin nanofibrous scaffold was significantly higher than the PCL nanofibrous scaffold (*p <0.05). Therefore, these scaffolds could be explored as potential candidates for regeneration of functional esophagus. PMID- 23980503 TI - Dynamic investigation of interaction of biocompatible iron oxide nanoparticles with epithelial cells for biomedical applications. AB - Magnetic nanoparticles have emerged as important players in current research in modern medicine since they can be used in medicine for diagnosis and/or therapeutic treatment of diseases. Among many therapeutic applications of iron based nanoparticles, drug delivery and photothermal therapy are of particular interest. At cellular level their uptake has been studied and the mechanism by which nanoparticles enter into the cell has important implication not only for their fate but also for their impact on the biological systems. We present here a dynamic investigation of interaction of biocompatible iron oxide nanoparticles coated with L-3,4-dihydroxyphenylalanine and labeled with tetra-methylrhodamine 5/6-isothiocyanate with lung epithelial cells. Our data show that after macropinocytosis-mediated internalization, nanoparticles in form of vesicles approach the nucleus and converge in the more acidic compartments of the cells in a microtubule-dependent manner. During progression the nanoparticles aggregate. Finally, we have demonstrated that a converging laser radiation on the cells, causes the increase in the local temperature and thus damages the cells, suggesting that these nanoparticles may be applied for photothermal therapy studies. PMID- 23980504 TI - Antimicrobial activity of caO nanoparticles. AB - The high degree of microbial diseases and their multidrug resistant properties make the researchers to develop new class of antimicrobial agents. A modern and innovative approach of drug development is the use of metallic nanoparticles as new formulations of antimicrobial agents. In this study, microwave irradiated CaO nanoparticles (CaO-NPs) were used to determine their antimicrobial efficacy against gram negative and gram positive bacteria, as well as pathogenic yeast. The physiochemical properties of CaO-NPs were characterized by means of X-ray diffraction (XRD) and high resolution transmission electron microscopy (HRTEM). The nanoparticles consist of well dispersed agglomerates of grains with a narrow size distribution of 14-24 nm. The prepared CaO-NPs showed much higher antimicrobial activity against Pseudomonas aeruginosa (ATCC 27853) and Staphylococcus epidermidis (MTCC 435) in comparision to Candida tropicalis (NCIM 3110). The minimum inhibitory concentration (MIC) value of CaO-NPs was found within the range of 2-8 mM for all the above tested strains. This bioactive nanoparticle also inhibits the biofilm formation and may have future applications cheap and non toxic as antimicrobial drug for skin care product development. PMID- 23980505 TI - New oil-in-water magnetic emulsion as contrast agent for in vivo magnetic resonance imaging (MRI). AB - Nowadays, bio-imaging techniques are widely applied for the diagnosis of various diseased/tumoral tissues in the body using different contrast agents. Accordingly, the advancement in bionanotechnology research is enhanced in this regard. Among contrast agents used, superparamagnetic iron oxide nanoparticles were developed by many researchers and applied for in vive magnetic resonance imaging (MRI). In this study, a new oil-in-water magnetic emulsion was used as contrast agent in MRI, after being characterized in terms of particle size, iron oxide content, magnetic properties and colloidal stability using dynamic light scattering (DLS), thermal gravimetric analysis (TGA), vibrating sample magnetometer (VSM) and zeta potential measurement techniques, respectively. The hydrodynamic size and magnetic content of the magnetic colloidal particles were found to be 250 nm and 75 wt%, respectively. In addition, the used magnetic emulsion possesses superparamagentic properties and high colloidal stability in aqueous medium. Then, the magnetic emulsion was highly diluted and administered intravenously to the Sprague dawley rats to be tested as contrast agent for in vivo MRI. In this preliminary study, MRI images showed significant enhancement in contrast, especially for T2 (relaxation time) contrast enhancement, indicating the distribution of magnetic colloidal nanoparticles within organs, like liver, spleen and kidneys of the Sprague dawley rats. In addition, it was found that 500 microL of the highly diluted magnetic emulsion (0.05 wt%) was found adequate for MRI analysis. This seems to be useful for further investigations especially in theranostic applications of magnetic emulsion. PMID- 23980506 TI - A novel approach for systematic delivery of a hydrophobic anti-leukemia agent tamibarotene mediated by nanostructured lipid carrier. AB - The present work evaluated the feasibility of nanostructured lipid carriers (NLC) for the intravenous delivery of tamibarotene (Am80), a poorly water-soluble drug for the treatment of acute promyelocytic leukemia (APL). The objective of this research was to develop a suitable drug delivery system in vivo which could improve therapeutic efficacy and decrease side effects. The tamibarotene-loaded NLC (Am80-NLC) nanosuspension was formulated by the method of melt-emulsification at a high temperature and solidified by ice bath. Based on the optimized results of single-factor screening experiment, the Am80-NLC was found to be relatively uniform in size (189.38+/- 8.07 nm) with a narrow poly-dispersity index (PI) (0.27+/-0.02) and a negative zeta potential (-34.69+/-3.05 mV). The average drug entrapment efficiency and loading capacity was 90.85+/- 1.03% and 9.08+/- 0.10%, respectively. The differential scanning calorimetry (DSC) analysis indicated that Am80 was not in crystalline state in Am80-NLC. The in vitro release profile of Am80-NLC possessed a sustained release characteristic and the release behavior was in accordance with the Ritger-Peppas equation. In vivo, after intravenous injection to mice, Am80-NLC showed a longer retention time and higher AUC values compared with the Am80 solution. In addition, biodistribution results clearly demonstrated that Am80-NLC preferentially decreased the drug distribution in kidney and liver of mice after intravenous injection. These results revealed that injectable Am80-NLC may serve as a promising carrier for Am80 to increase therapeutic efficacy on APL and reduce adverse events. PMID- 23980507 TI - Response of monocultured and co-cultured human microvascular endothelial cells and mesenchymal stem cells to macroporous granules of nanostructured hydroxyapatite agglomerates. AB - Recent studies have shown that hydroxyapatite (HA) nanocrystalline have better functional properties that are important to create suitable local conditions for bone formation, when implanted in an osseous environment. Bone formation depends on several complex processes, including a tight communication between endothelial cells and osteoblasts and mesenchymal stem cells. This study examined the interaction between human dermal microvascular endothelial cells (HDMEC) and human mesenchymal stem cells (HMSC), in monoculture and co-culture on,macroporous granules of nanostructured-hydroxyapatite agglomerates. Cell viability/proliferation was assessed through MTT and DNA quantification assays. CLSM and SEM observations allow the study of cell morphology and growth pattern of cells. The angiogenic and osteogenic genes expression were studied using real time PCR and cell differentiation was assessed by ALP activity and matrix mineralization assays. Matrigel tube-like formation assay was also used. Increased expression levels of genes related with osteogenesis and angiogenesis was evident. The osteoblastic phenotype was clearly promoted, as evidenced by the over-expression of osteoblastic genes, increased ALP activity and matrix mineralization. The work clearly demonstrated that the nanostructured-HA granules were able to support cell type's survival, proliferation and individual functionality in a monoculture and co-culture system, for 21 days. HMSC seeded on the granules were able to differentiate into osteoblastic phenotype. The results achieved suggest that nano-structured HA granules may be considered promising implants for bone regeneration and tissue engineering application, in which the granules can be pre-seeded with these two types of autologous cells, before bone graft implant. PMID- 23980508 TI - Decreased 5-hydroxymethylcytosine (5-hmC) is an independent poor prognostic factor in gastric cancer patients. AB - DNA methylation at the 5 position of cytosine (5-mC) is a key epigenetic mark that is involved in various biological and pathological processes. 5-mC can be converted to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation (TET) family of DNA hydroxylases. Increasing evidence suggests that large-scale loss of 5-hmC is an epigenetic hallmark of several human cancers. However, the value of 5-hmC in diagnosis and prognosis of human cancers, including gastric cancer (GC), remains largely unknown. The aim of this study is to determine 5-hmC levels in GCs and explore its association with clinicopathological characteristics and clinical outcome of GC patients. Using immunohistochemistry (IHC) and dot-blot assays, we demonstrated that 5-hmC was dramatically decreased in GCs compared with matched normal tissues. We also found a strong link between decreased 5-hmC and the reduction of TET1 gene expression, but not TET2 or 3, suggesting that decreased TET1 expression might be one of the mechanisms underlying 5-hmC loss in GCs. Wilcoxon tests showed that 5-hmC content was significantly associated with most of clinicopathological characteristics, such as tumor size (P = 0.016), Bormman type (P < 0.0001), tumor invasion (P = 0.001), TNM stage (P < 0.0001), the number of lymph nodes metastasis (P = 0.002), and survival status (P < 0.0001). It is noteworthy that decreased 5-hmC was significantly associated with poor survival of GC patients. Collectively, our findings indicate that decreased 5-hmC may be crucial to the clinical pathology of GC and is a strong and independent poor prognostic factor in GCs. PMID- 23980509 TI - Intravitreal administration of dexamethasone-loaded PLGA-TPGS nanoparticles for the treatment of posterior segment diseases. AB - The purpose of this research was to investigate the possibility of dexamethasone (DEX)-loaded PLGA-TPGS nanoparticles (NPs) in rabbits after intravitreal administration for the treatment of posterior segment diseases. The DEX-loaded PLGA-TPGS NPs were fabricated and characterized in terms of surface morphology, particle size and size distribution, entrapment efficiency, and in vitro drug release. The animals were classified randomly into two groups: experimental group with thirty rabbits, and control group with eighteen rabbits. Rabbits in the experimental group received intravitreal injections of 0.1 mL of DEX-loaded PLGA TPGS NPs suspension and the control rabbits received intravitreal injection of 0.1 mL DEX (20 g/L in saline). The DEX concentrations in plasma and the ocular tissues such as the cornea, aqueous humor, lens, iris, vitreous humor, and chorioretina were determined by HPLC. The DEX-loaded PLGA-TPGS nanoparticle suspension were transparent and maintained a sustained release of DEX for about 45 days in vitreous and provided relatively constant DEX levels for more than 30 days with a mean concentration of 3.93 mg/L. Based on the area-under-the-curve (AUC), the bioavailability of DEX in the experimental group was significantly higher than that in the control group administrated with regular DEX. These results suggest that intravitreal administration of DEX-loaded PL.3A-TPGS NPs leads to a sustained release of DEX with a high bioavailability, providing a basis for a novel approach to treat posterior segment diseases. PMID- 23980510 TI - Silver nanoparticles inhibit vaccinia virus infection by preventing viral entry through a macropinocytosis-dependent mechanism. AB - Silver nanoparticles have been shown to inhibit viruses. However, very little is known about the mechanism of antiviral activity. This study tested the hypothesis that 25-nm silver nanoparticles inhibited Vaccinia virus replication by preventing viral entry. Plaque reduction, confocal microscopy, and beta galactosidase reporter gene assays were used to examine viral attachment and entry in the presence and absence of silver nanoparticles. To explore the mechanism of inhibition, viral entry experiments were conducted with silver nanoparticles and small interfering RNAs designed to silence the gene coding for p21-activated kinase 1, a key mediator of macropinocytosis. The silver nanoparticles caused a 4- to 5-log reduction in viral titer at concentrations that were not toxic to cells. Virus was capable of adsorbing to cells but could not enter cells in the presence of silver nanoparticles. Virus particles that had adsorbed to cells in the presence of silver nanoparticles were found to be infectious upon removal from the cells, indicating lack of direct virucidal effect. The half maximal inhibitory concentration for viral entry in the presence of silver nanoparticles was 27.4+/-3.3 microg/ml. When macropinocytosis was blocked, this inhibition was significantly reduced. Thus, macropinocytosis was required for the full antiviral effect. For the first time, this study points to the novel result that a cellular process involved in viral entry is responsible for the antiviral effects of silver nanoparticles. PMID- 23980511 TI - Long-circulating, pH-sensitive liposomes versus long-circulating, non-pH sensitive liposomes as a delivery system for tumor identification. AB - Bombesin (BBN) is a tetradecapeptide that binds specifically to gastrin-releasing peptide receptors in humans. Several forms of cancer, including lung, prostate, breast, and colon over-express receptors for bombesin-like peptides. Therefore, radiolabeled bombesin analogs might be useful for tumor identification. Nevertheless, it is well known that higher tumor uptake can yield images in higher quality. Hence, drug delivery systems, such as liposomes, can be used to achieve a higher concentration of radiotracer in tumor site, and also improve the radiotracer stability, since peptides can suffer easily degradation in vivo by natural plasma and tissue peptides. In this paper, we prepared long-circulating, pH-sensitive liposomes and long-circulation, non-pH sensitive liposomes. Both formulations were able to encapsulate the radiolabeled bombesin derivative (99mTc BBN(7_14)), and also showing high in vitro stability. Biodistribution studies were performed in Ehrlich tumor bearing-mice to compare the ability of pH sensitive and non-pH sensitive liposomes to deliver 99mTc-BBN(7_14) to tumor site. Results showed higher tumor uptake (2-fold) when pH-sensitive liposomes were used, suggesting that these vesicles can facilitate the access to the tumor by releasing the diagnostic agent into the ideal area. As a result, tumor-to muscle ratio achieved with pH-sensitive liposomes was higher than that obtained with non-pH-sensitive formulation. In addition, scintigraphic images for pH sensitive liposomes showed evident tumor uptake, corroborating with biodistribution data. Therefore, the results presented in this paper suggest that pH-sensitive liposomes are able to deliver more efficiently the radiolabeled bombesin analog. This finding poses a new possibility to improve images quality, since the tumor-to-muscle ratio was strongly enhanced. PMID- 23980512 TI - Synthesis and characterization of pullulan-polycaprolactone core-shell nanospheres encapsulated with ciprofloxacin. AB - Nanosphere-encapsulated drugs offer a means to overcome many drug delivery limitations by localizing the site of delivery and providing controlled release. This research details the synthesis and encapsulation of ciprofloxacin in pullulan-polycaprolactone (PCL) core shell nanospheres and the characterization of these materials by 1H-NMR, UV spectroscopy, dynamic light scattering (DLS) and scanning electron microscopy (SEM).1H-NMR results confirm that the pullulan-PCL grafted copolymer was successfully synthesized. UV spectroscopy showed that the ciprofloxacin loaded nanospheres contain 35-40% ciprofloxacin by weight. DLS and SEM results indicate that the loaded nanospheres are spherical in shape and approximately 142+/-12 nm in size. Under in vitro test conditions, approximately 20% of the ciprofloxacin is released in the first 4 hours, with additional release over 10 days. The nanoparticles demonstrate bioactivity against Escheria coli and do not affect the proliferation of two human cell lines. These results demonstrate the potential of pullulan-PCL core-shell nanospheres as delivery vehicles of hydrophobic drugs, including antibiotics for localized treatments applicable to a wide-range of human bacterial infections. PMID- 23980517 TI - Saturation-recovery EPR with nitroxyl radical-Dy(III) spin pairs: distances and orientations. AB - We describe a method for measuring the distance between a radical and a Dy(III) ion using saturation-recovery electron paramagnetic resonance (EPR) and demonstrate its application using four chemically modified DNA duplexes. The four DNA duplexes contain a terminal nitroxide spin-label and a midsequence, EDTA bound Dy(III) ion but differ in the nitroxyl radical (NO)-Dy(III) distance. Distances can be determined with high precision because of their sixth-root dependence on the experimentally determined dipolar rate constant. Furthermore, the orientation of the NO-Dy(III) interspin vector in the Dy(III) g-tensor reference frame can be determined for two of the DNA duplexes. The shortest mean NO-Dy(III) distance, 18.3 +/- 0.3 A, and the longest, 50.3 +/- 2.4 A, are near the lower and upper distance limits of what can be measured with the NO EDTA(Dy(III)) pair at X-band. These methods are applicable to structural studies of nucleic acids, proteins, and their complexes. PMID- 23980518 TI - Resource need and use of multiethnic caregivers of elders in their homes. AB - AIMS: The aim of this study was to predict South Florida family caregivers' need for and use of informal help or formal services, specifically, to explore the predictive power of variables suggested by the Caregiver Identity Theory and the literature and develop and test a structural model. BACKGROUND: In the USA, most of the care to older adults is given by family members. Caregivers make economic and social sacrifices that endanger their health. They feel burdened, if they receive no assistance with their tasks; however, services available are not sufficiently used. DESIGN: This cross-sectional correlational study was a survey of family caregivers in their home, using standardized and/or pre-tested scales and a cognitive status test of their patients. METHODS: A random sample of 613 multiethnic caregivers of frail elders were recruited in home care and community agencies. The interviews were held between 2006-2009. Analyses involved correlation and regression analyses and structural equation modelling. Outcome measures were need and use of family help and formal services. RESULTS/FINDINGS: The model yielded excellent fit indices replicated on three random samples of 370. The patients' functional limitations yielded the strongest predictive coefficients followed by caregiver stress. Cultural indicators played a minor role. CONCLUSION: The lack of a link between resource need and use suggested access barriers. Important for policy makers and service providers are the delivery of high-quality services and the use of a personal and individualized approach with all ethnicities. Quality service includes understanding the caregiving situations and requires a trusting relationship with family caregivers. PMID- 23980519 TI - PTEN hypermethylation profiles of Chinese Kazakh patients with esophageal squamous cell carcinoma. AB - Aberrant DNA methylation of promoter region CpG islands may serve as an alternative mechanism to genetic defects in the inactivation of tumor suppressor genes (TSGs) in human malignancies. The aim of this study was to examine the promoter methylation status of the PTEN TSG and its association with esophageal squamous cell carcinoma (ESCC) carcinogenesis in a Chinese Kazakh population, which is known to have a relatively high ESCC incidence and mortality. The methylation status of the PTEN promoter region was determined in patients with ESCC (n = 95) and healthy individuals (n = 65) using highly sensitive Sequenom Epityper assays. The methylation level of the PTEN gene was significantly higher in patients with ESCC than in healthy controls. The median methylation level was 10.0% (interquartile range [IQR]: 7.0-11.0%) in patients with ESCC and 6.0% in controls (IQR: 4.0-9.0%; P = 0.001). PTEN methylation levels were higher in male patients with ESCC than in male controls, whereas a trend toward significance was observed between female patients with ESCC and female controls (P = 0.005 and P = 0.086, respectively). The PTEN methylation level was associated with histopathological grade and lymph node metastasis in patients with ESCC (P = 0.002 and P = 0.009, respectively). To our knowledge, this is the first report to show the presence of PTEN promoter CpG hypermethylation in ESCC and its association with tumor metastasis. PMID- 23980520 TI - From kids, through kids, to kids: examining the social influence strategies used by adolescents to promote prevention among peers. AB - Recent technological advances have increased the interest and ability of lay audiences to create messages; however, the feasibility of incorporating lay multimedia messages into health campaigns has seldom been examined. Drawing on the principle of cultural grounding and narrative engagement theory, this article seeks to examine what types of messages adolescents believe are most effective in persuading their peers to resist substance use and to provide empirical data on the extent to which audience-generated intervention messages are consistent with the associated campaign philosophy and branding. Data for the current study are prevention messages created by students as part of a four-lesson substance use prevention "booster" program delivered to eighth-grade students in 20 rural schools in Pennsylvania and Ohio during 2010-2011. Content analysis results indicate that didactic message strategies were more common in audience-generated messages than narrative strategies, although strategy was somewhat dependent on the medium used. Two of the most common strategies that adolescents used to persuade peers not to use substances were negative consequences and identity appeals, and messages varied in the degree to which they were consistent with the theoretical underpinnings and program philosophy of the prevention campaign. Implications of the current study for understanding the social construction of substance use prevention messages among adolescents and incorporating audience generated messages in health communication campaigns are discussed. PMID- 23980522 TI - Unprecedented synthesis of alkynylphosphine-boranes through room-temperature oxidative alkynylation. AB - An original and user-friendly synthesis of alkynylphosphine-boranes, useful building blocks in organic synthesis, based on an oxidative P-alkynylation reaction with readily available copper acetylides is reported. The ability of a secondary phosphine protected with a borane to undergo oxidative coupling without oxidation of the P-moiety is demonstrated for the first time. The reaction, which proceeds at room temperature, is applicable to the preparation of enantioenriched and structurally complex alkynylphosphine-boranes. PMID- 23980521 TI - Distinct quantitative computed tomography emphysema patterns are associated with physiology and function in smokers. AB - RATIONALE: Emphysema occurs in distinct pathologic patterns, but little is known about the epidemiologic associations of these patterns. Standard quantitative measures of emphysema from computed tomography (CT) do not distinguish between distinct patterns of parenchymal destruction. OBJECTIVES: To study the epidemiologic associations of distinct emphysema patterns with measures of lung related physiology, function, and health care use in smokers. METHODS: Using a local histogram-based assessment of lung density, we quantified distinct patterns of low attenuation in 9,313 smokers in the COPDGene Study. To determine if such patterns provide novel insights into chronic obstructive pulmonary disease epidemiology, we tested for their association with measures of physiology, function, and health care use. MEASUREMENTS AND MAIN RESULTS: Compared with percentage of low-attenuation area less than -950 Hounsfield units (%LAA-950), local histogram-based measures of distinct CT low-attenuation patterns are more predictive of measures of lung function, dyspnea, quality of life, and health care use. These patterns are strongly associated with a wide array of measures of respiratory physiology and function, and most of these associations remain highly significant (P < 0.005) after adjusting for %LAA-950. In smokers without evidence of chronic obstructive pulmonary disease, the mild centrilobular disease pattern is associated with lower FEV1 and worse functional status (P < 0.005). CONCLUSIONS: Measures of distinct CT emphysema patterns provide novel information about the relationship between emphysema and key measures of physiology, physical function, and health care use. Measures of mild emphysema in smokers with preserved lung function can be extracted from CT scans and are significantly associated with functional measures. PMID- 23980523 TI - Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load <= 100 000 copies/mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials. AB - OBJECTIVES: These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naive, HIV-1-infected adults with viral load (VL) <= 100 000 HIV-1 RNA copies/mL receiving rilpivirine or efavirenz. METHODS: ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. RESULTS: Baseline characteristics were comparable between the rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) -1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres , a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance associated mutations (RAMs). Among those with VFres , more patients in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208-240) cells/MUL in the rilpivirine group and by 206 (188-225) cells/MUL in the efavirenz group. Treatment-related grade 2-4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for efavirenz (P < 0.0001). CONCLUSIONS: Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naive adults with baseline VL <= 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz. PMID- 23980524 TI - A diversity index for model space selection in the estimation of benchmark and infectious doses via model averaging. AB - In chemical and microbial risk assessments, risk assessors fit dose-response models to high-dose data and extrapolate downward to risk levels in the range of 1-10%. Although multiple dose-response models may be able to fit the data adequately in the experimental range, the estimated effective dose (ED) corresponding to an extremely small risk can be substantially different from model to model. In this respect, model averaging (MA) provides more robustness than a single dose-response model in the point and interval estimation of an ED. In MA, accounting for both data uncertainty and model uncertainty is crucial, but addressing model uncertainty is not achieved simply by increasing the number of models in a model space. A plausible set of models for MA can be characterized by goodness of fit and diversity surrounding the truth. We propose a diversity index (DI) to balance between these two characteristics in model space selection. It addresses a collective property of a model space rather than individual performance of each model. Tuning parameters in the DI control the size of the model space for MA. PMID- 23980526 TI - Optimal design of the hydrodynamic multi-arc bearing in a centrifugal blood pump for the improvement of bearing stiffness and hemolysis level. AB - The purpose of the present study is to establish an optimal design of the multi arc hydrodynamic bearing in a centrifugal blood pump for the improvement of bearing stiffness and hemolysis level. The multi-arc bearing was designed to fulfill the required specifications: (i) ensuring the uniform bearing stiffness for various bearing angles; (ii) ensuring a higher bearing stiffness than the centrifugal force to prevent impeller whirl; and (iii) adjusting the bearing clearance as much as possible to reduce hemolysis. First, a numerical analysis was performed to optimize three design parameters of the multi-arc bearing: number of arcs N, bearing clearance C, and groove depth H. To validate the accuracy of the numerical analysis, the impeller trajectories for six pump models were measured. Finally, an in vitro hemolysis test was conducted to evaluate the hemolytic property of the multi-arc bearing. As a result of the numerical analysis, the optimal parameter combination was determined as follows: N=4, C=100 MUm, and H >= 100 MUm. In the measurements of the impeller trajectory, the optimal parameter combination was found to be as follows: N=4, C=90 MUm, and H=100 MUm. This result demonstrated the high reliability of the numerical analysis. In the hemolysis test, the parameter combination that achieved the smallest hemolysis was obtained as follows: N=4, C=90 MUm, and H=100 MUm. In conclusion, the multi-arc bearing could be optimized for the improvement of bearing stiffness and hemolysis level. PMID- 23980525 TI - The membrane protein LeuT in micellar systems: aggregation dynamics and detergent binding to the S2 site. AB - Structural and functional properties of integral membrane proteins are often studied in detergent micellar environments (proteomicelles), but how such proteomicelles form and organize is not well understood. This makes it difficult to evaluate the relationship between the properties of the proteins measured in such a detergent-solubilized form and under native conditions. To obtain mechanistic information about this relationship for the leucine transporter (LeuT), a prokaryotic homologue of the mammalian neurotransmitter/sodium symporters (NSSs), we studied the properties of proteomicelles formed by n dodecyl-beta,D-maltopyranoside (DDM) detergent. Extensive atomistic molecular dynamics simulations of different protein/detergent/water number ratios revealed the formation of a proteomicelle characterized by a constant-sized shell of detergents surrounding LeuT protecting its transmembrane segments from unfavorable hydrophobic/hydrophilic exposure. Regardless of the DDM content in the simulated system, this shell consisted of a constant number of DDM molecules (~120 measured at a 4 A cutoff distance from LeuT). In contrast, the overall number of DDMs in the proteomicelle (aggregation number) was found to depend on the detergent concentration, reaching a saturation value of 226+/-17 DDMs in the highest concentration regime simulated. Remarkably, we found that at high detergent-to-protein ratios we observed two independent ways of DDM penetration into LeuT, both leading to a positioning of the DDM molecule in the second substrate (S2) binding site of LeuT. Consonant with several recent experimental studies demonstrating changes in functional properties of membrane proteins due to detergent, our findings highlight how the environment in which the membrane proteins are examined may affect the outcome and interpretation of their mechanistic features. PMID- 23980527 TI - Effects of pollen availability and the mutation bias on the fixation of mutations disabling the male specificity of self-incompatibility. AB - The evolution of self-compatibility (SC) by the loss of self-incompatibility (SI) is regarded as one of the most frequent transitions in flowering plants. SI systems are generally characterized by specific interactions between the male and female specificity genes encoded at the S-locus. Recent empirical studies have revealed that the evolution of SC is often driven by male SC-conferring mutations at the S-locus rather than by female mutations. In this study, using a forward simulation model, we compared the fixation probabilities of male vs. female SC conferring mutations at the S-locus. We explicitly considered the effects of pollen availability in the population and bias in the occurrence of SC-conferring mutations on the male and female specificity genes. We found that male SC conferring mutations were indeed more likely to be fixed than were female SC conferring mutations in a wide range of parameters. This pattern was particularly strong when pollen availability was relatively high. Under such a condition, even if the occurrence of mutations was biased strongly towards the female specificity gene, male SC-conferring mutations were much more often fixed. Our study demonstrates that fixation probabilities of those two types of mutation vary strongly depending on ecological and genetic conditions, although both types result in the same evolutionary consequence-the loss of SI. PMID- 23980528 TI - Investigating the function of [2Fe-2S] cluster N1a, the off-pathway cluster in complex I, by manipulating its reduction potential. AB - NADH:quinone oxidoreductase (complex I) couples NADH oxidation and quinone reduction to proton translocation across an energy-transducing membrane. All complexes I contain a flavin to oxidize NADH, seven iron-sulfur clusters to transfer electrons from the flavin to quinone and an eighth cluster (N1a) on the opposite side of the flavin. The role of cluster N1a is unknown, but Escherichia coli complex I has an unusually high-potential cluster N1a and its reduced flavin produces H2O2, not superoxide, suggesting that cluster N1a may affect reactive oxygen species production. In the present study, we combine protein film voltammetry with mutagenesis in overproduced N1a-binding subunits to identify two residues that switch N1a between its high- (E. coli, valine and asparagine) and low- (Bos taurus and Yarrowia lipolytica, proline and methionine) potential forms. The mutations were incorporated into E. coli complex I: cluster N1a could no longer be reduced by NADH, but H2O2 and superoxide production were unaffected. The reverse mutations (that increase the potential by ~0.16 V) were incorporated into Y. lipolytica complex I, but N1a was still not reduced by NADH. We conclude that cluster N1a does not affect reactive oxygen species production by the complex I flavin; it is probably required for enzyme assembly or stability. PMID- 23980529 TI - Upregulated baseline plasma CCL19 and CCR7 cell-surface expression on monocytes in early rheumatoid arthritis normalized during treatment and CCL19 correlated with radiographic progression. AB - OBJECTIVES: The aim of this study was to measure, in early rheumatoid arthritis (RA) patients, the concentration of CC-chemokine ligand 19 (CCL19) in plasma and the cell-surface expression of CC-chemokine receptor 7 (CCR7) on circulating monocytes and CD4+ T lymphocytes and to analyse correlations with disease activity and 5-year radiographic progression. METHOD: In disease-modifying anti rheumatic drug (DMARD)-naive RA patients (disease duration < 6 months), we measured plasma CCL19 by enzyme-linked immunosorbent assay (ELISA) (n = 160) and CCR7 cell-surface expression on monocytes and CD4+ T lymphocytes by flow cytometry (n = 40) at baseline and after 1 year of treatment with methotrexate (MTX) or methotrexate+cyclosporin A (MTX/CyA). Radiographic progression was scored by the van der Heijde-modified Total Sharp Score (TSS) from 0 to 5 years. RESULTS: Increased baseline CCL19 (median 85 pg/mL, range 31-1008 pg/mL, p = 0.01) decreased after 1 year (median 31 pg/mL, range 31-1030 pg/mL, p < 0.001) and 5 years (median 31 pg/mL, range 31-247 pg/mL, p < 0.001) to a level below the controls (n = 45) (median 60 pg/mL, range 31-152 pg/mL). Baseline plasma CCL19 levels [p = 0.011, 95% confidence interval (CI) 0.0030-0.0176], anti-cyclic citrullinated peptide (anti-CCP) antibody status (p = 0.002, 95% CI 0.61-2.38), and TSS > 0 at baseline (p < 0.001, 95% CI 1.21-3.16) were independent predictors of 5-year radiographic progression evaluated by multiple logistic regression in contrast to never smoked, C-reactive protein (CRP), gender, age, number of tender (NTJ) and swollen joints (NSJ), and 28-joint Disease Activity Score (DAS28). Increased CCR7 expression on monocytes (p = 0.008) correlated to CRP (p = 0.006, r = 0.52) and normalized (n = 15) after 1 year (p = 0.02). CONCLUSIONS: In DMARD naive RA patients, CCL19 plasma level and CCR7 surface expression on monocytes were upregulated and normalized after 1 year of treatment. Increased baseline plasma CCL19 level, anti-CCP antibody status, and TSS > 0 at baseline correlated independently with 5-year radiographic progression. PMID- 23980530 TI - Fatal wounds sustained from "falling bullets": maintaining a high index of suspicion in a forensic setting. AB - Celebratory gunfire injuries from "falling bullets" occur when guns are fired into the air during celebrations without realizing that this can cause serious injuries or even fatalities. Fatal celebratory gunfire injury is an uncommonly reported event in the continental United States. Our electronic database was queried for homicides occurring within days of July 4th and December 31st over a 14-year period. We describe two cases of fatal gunfire injury due to celebratory gunfire occurring during New Year's Eve in Southern Florida. The relevant literature is reviewed. These case reports illustrate that fatal gunfire injuries sustained from "falling bullets" may pose as an unexpected mimic to sudden natural deaths especially in patients with prior medical history. A high index of suspicion to recognize such injury is required particularly during holidays. PMID- 23980531 TI - Preventive effect of agaro-oligosaccharides on non-steroidal anti-inflammatory drug-induced small intestinal injury in mice. AB - BACKGROUND AND AIM: Non-steroidal anti-inflammatory drugs (NSAIDs), which are commonly used in clinical medicine, cause erosion, ulcers, and bleeding in the gastrointestinal tract. No effective agent for the prevention and treatment of small intestinal injury by NSAIDs has been established. This study investigates the effects of agaro-oligosaccharides (AGOs) on NSAID-induced small intestinal injury in mice. METHODS: Mice were treated with indomethacin, an NSAID, to induce intestinal injury. The respective degrees of mucosal injury of mice that received AGO and control mice were compared. Heme oxygenase-1 (HO-1) expression using quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and immunohistochemistry were measured. The expression of keratinocyte chemoattractant (KC) was measured using qRT-PCR and enzyme-linked immunosorbent assay. RESULTS: AGO administration induced HO-1 expression in mouse small intestinal mucosa. Induction was observed mainly in F4/80 positive macrophages. The increased ulcers score, myeloperoxidase activity, and KC expression by indomethacin were inhibited by AGO administration. Conversely, HO inhibitor cancelled AGO-mediated prevention of intestinal injury. In mouse peritoneal macrophages, AGOs enhanced HO-1 expression and suppressed lipopolysaccharide induced KC expression. Furthermore, AGOs enhanced the expressions of alternatively activated macrophage markers arginase-1, mannose receptor-1, and chitinase 3-like 3. CONCLUSIONS: Results suggest that oral administration of AGOs prevents NSAID-induced intestinal injury. PMID- 23980532 TI - Functional and oncologic outcomes of graded bladder neck preservation during robot-assisted radical prostatectomy. AB - PURPOSE: To describe our bladder neck dissection during robot-assisted radical prostatectomy (RARP), to describe the degrees of robot-assisted bladder neck preservation (R-BNP) we have encountered, and to determine the effect of increasing R-BNP on postoperative continence and positive surgical margin (PSM) rates. PATIENTS AND METHODS: We performed a retrospective analysis of 599 patients who underwent robot-assisted radical prostatectomy (RARP) by a single surgeon (DIL). All bladder neck dissections were graded between 1 and 4; higher grades corresponded to an increasing degree of robot-assisted bladder neck preservation (R-BNP). After grouping patients by R-BNP grade, postoperative continence and positive surgical margin (PSM) rates were compared. The association between R-BNP and continence was also assessed using multivariate binary logistic regression models. RESULTS: Similar outcomes were seen for two definitions of continence (0 pads per day [ppd]; 0 ppd or security pad, respectively). A higher proportion of patients were continent at 3 months postoperatively who received grade 4 compared with grade 1 (P=0.043; P=0.001) and grade 2 (P=0.006; P=0.009); and grade 3 compared with grade 1 (P=0.048; P=0.002) and grade 2 (P=0.009; P=0.030) R-BNP. There was no difference between grade 1 and 2 (P=0.541; P=0.064), and grade 3 and 4 (P=0.898; P=0.584) R-BNP. At 1 year postoperatively, there was no difference among the four groups in continence rate (P=0.771; P=0.411). R-BNP was an independent predictor of continence at 3 months (odds ratio [OR] [95% confidence interval (CI)]=1.33 [1.06-1.67]; OR [95% CI]=1.45 [1.1-1.82]), but not at 1 year (OR [95% CI]=1.07 [0.82-1.39]; OR (95% CI)=1.30 [0.92-1.85]). There was no difference among the four groups in PSM rates (P=0.946). CONCLUSIONS: R-BNP is a graded, rather than all-or-none outcome. An increasing degree of R-BNP is associated with an earlier return to continence, without compromising oncologic outcomes. PMID- 23980533 TI - Profile and activities of a rural home-based psychiatric treatment service in Ireland. AB - OBJECTIVES: This study described the profile, activities and patient-related outcomes of a long-established home-based treatment (HBT) service in Ireland. METHODS: A retrospective descriptive study design was adopted to review and describe the activities of the Cavan HBT team over a 5-year period. Data including demographics, referral details, duration of admissions and outcome/disposal were retrospectively collected from the home treatment team mental health register of admissions between 2006 and 2010. Data were analysed using SPSS version 15 for windows. RESULTS: A total of 783 patients were referred to the team over the study period, of which 722 were admitted for home treatment. Most referrals (51%) were from General Practitioners and the commonest reason for referral/admission for home treatment was low mood (26%). While 10% required stepped-up care to the psychiatric inpatient unit, 77% were successfully discharged to the out-patient clinic for routine follow-up care. CONCLUSIONS: Common psychiatric illnesses can be safely and effectively managed with HBT within the context of a spectrum of therapeutic options in a community psychiatric service. PMID- 23980534 TI - An open-label trial of duloxetine in patients with irritable bowel syndrome and comorbid generalized anxiety disorder. AB - OBJECTIVE: Irritable bowel syndrome (IBS) is commonly comorbid with generalized anxiety disorder (GAD). We evaluated whether duloxetine would lead to improvement in symptoms and quality of life in patients with both conditions. METHOD: A 12 week, open-label trial of duloxetine was conducted in 13 subjects with IBS and GAD. The primary outcome measure was the Clinical Global Impression (CGI) Scale. Secondary measures included the Hamilton Anxiety Rating Scale, IBS Quality of Life (IBS-QOL) Scale, and IBS Symptom Severity Scale (IBS-SSS). RESULTS: Repeated measures ANOVA was used to examine the effect of treatment with duloxetine on ratings of anxiety and IBS. Significant improvement was observed on the CGI Improvement (F = 14.19, df = 1,12, p < 0.001) and Severity scales (F = 16.16, df = 1,12, p < 0.001). Secondary measures revealed significant reduction in symptoms of anxiety (F = 11.66, df = 1,12, p < 0.01), etap(2) = 0.56, and IBS-SSS (F = 6.05, df = 1,12, p < 0.001), etap(2) = 0.34, in addition to IBS-QOL improvements (F = 11.66, df = 1,12, p < 0.01), etap(2) = 0.56. CONCLUSION: Results of this pilot study support the efficacious use of duloxetine in comorbid IBS and GAD. Participants reported significant reductions in IBS components, as well as improvement in GAD. PMID- 23980535 TI - The effects of group psychoeducational programme on family burden in caregivers of Iranian patients with schizophrenia. AB - This study was aimed at assessing the impact of group psychoeducation therapy on family burden in caregivers of Iranian patients with schizophrenia during the acute phase of the disease. Using a randomized-controlled trial design, 71 caregivers of patients with schizophrenia were randomly assigned to either a 4 week group psychoeducational programme (n = 36) or the control group (n = 35). Family burden was assessed by Family Burden Index Schedule (FBIS) at the beginning, and after a month of psychoeducation therapy as a follow-up. FBIS assesses family burden in six different dimensions with score ranging from 0 to 48, higher scores indicating higher burdens. At baseline mean, FBIS score was not significantly different between the cases and the controls. After the intervention, the mean total FBIS score was significantly lower in the case group compared with the control group (P < 0.001). In the intervention group, FBIS score change was significant through the study in all dimensions as well as the total score (P < 0.001). A significant reduction in family burden has been achieved by implementing group psychoeducational programmes for inpatients with acute phase schizophrenia in Iranian population. PMID- 23980536 TI - Browning of white adipose tissue: role of hypothalamic signaling. AB - Two types of fat, white adipose tissue (WAT) and brown adipose tissue (BAT), exist in mammals including adult humans. While WAT stores excess calories and an excessive accumulation of fat causes obesity, BAT dissipates energy to produce heat through nonshivering thermogenesis for protection against cold environments and provides the potential for the development of novel anti-obesity treatments. The hypothalamus plays a central role in the control of energy balance. Specifically, recent observations indicate the importance of the dorsomedial hypothalamus (DMH) in thermoregulation. We have found that the orexigenic neuropeptide Y (NPY) in the DMH has distinct actions in modulating adiposity and BAT thermogenesis. Knockdown of NPY in the DMH elevates the thermogenic activity of classic BAT and promotes the development of brown adipocytes in WAT, leading to increased thermogenesis. These findings identify a novel potential target for combating obesity. PMID- 23980537 TI - Analysis of the levels of tumour necrosis factor (TNF), autoantibodies to TNF, and soluble TNF receptors in patients with rheumatoid arthritis. AB - OBJECTIVES: To evaluate the potential contribution made by autoantibodies against tumour necrosis factor (TNF) to the pathogenesis of rheumatoid arthritis (RA). METHOD: We used affinity chromatography methods and a magnetic separation procedure to purify human autoantibodies specific to TNF. The autoantibodies were used as calibration material to determine the absolute content of autoantibodies to TNF using an enzyme-linked immunosorbent assay (ELISA). TNF content and the levels of soluble TNF receptors types I and II (sTNF-RI and sTNF-RII) were determined using commercial ELISA test kits. RESULTS: We demonstrated significant increases in the levels of TNF, sTNF-RI, and sTNF-RII in the sera of patients with acute RA and in patients with RA who had responded positively to therapy compared with healthy controls. Levels of autoantibodies of the immunoglobulin (Ig)G2, IgG3, and IgG4 subclasses were significantly higher in sera from patients with acute RA than in sera from healthy controls. Level of autoantibodies of the IgG2 subclass were significantly higher in sera from patients with acute RA than in RA patients who had responded positively to therapy. CONCLUSIONS: Acute RA is associated with changes in levels of TNF and soluble receptors for TNF and also in levels of autoantibodies to TNF. Given the magnitude of the changes in levels of different subclasses of autoantibodies to TNF, we propose that these autoantibodies might contribute to the pathogenesis of RA. PMID- 23980542 TI - Early outcomes of thulium laser versus transurethral resection of the prostate for managing benign prostatic hyperplasia: a systematic review and meta-analysis of comparative studies. AB - PURPOSE: To assess the efficacy and safety of thulium laser resection of the prostate (TmLRP) vs transurethral resection of the prostate (TURP) for treating patients with benign prostatic hyperplasia (BPH). METHODS: A systematic search of the electronic databases, including Medline, Scopus, China National Knowledge Infrastructure, and the Cochrane Library was performed up to May 1, 2013. The pooled outcomes of interest assessing the two techniques included demographic and clinical baseline characteristics, perioperative variables, complications, and postoperative efficacy including maximum flow rate (Qmax), postvoid residual (PVR), quality of life (QoL) and International Prostate Symptom Score (IPSS). RESULTS: Nine trials assessing TmLRP vs. TURP were considered suitable for meta analysis including three randomized controlled trials (RCTs), two prospective, and four retrospective studies. Compared with TURP, although TmLRP needed a longer operative time (weighted mean difference [WMD]: 9.00 min; 95% confidence interval [CI], 2.53-15.47; P=0.006), patients having TmLRP might benefit from significantly less serum sodium decreased (-3.58 mmol/L; 95% CI, -4.04 to -3.12; P<0.001), less serum hemoglobin decreased (WMD: -0.94 mmol/L; 95% CI, -1.44 to 0.44; P<0.001), shorter time of catheterization (WMD: -2.07 days; 95% CI, -2.66 to -1.49; P<0.001), shorter length of hospital stay (WMD: -1.87 days; 95% CI, 2.41 to -1.33; P<0.001), and fewer total complications (odds ratio [OR]: 0.29; 95% CI, 0.20-0.41; P<0.001). During the 1, 3, 6, and 12 months of postoperative follow-up, the procedures did not demonstrate a significant difference in Qmax, IPSS, PVR, and QoL. CONCLUSIONS: Our data suggest that as a promising minimally invasive technique, TmLRP appears to be a safe, feasible, and efficient alternative to TURP for treating patients with BPH with reliable perioperative safety, fewer complications, and comparable efficacy in relation to Qmax, PVR, QoL, and IPSS. Because of the inherent limitations of the included studies, further large sample prospective, multicentric, long-term follow-up studies and RCTs should be undertaken to confirm our findings. PMID- 23980543 TI - Dynamics of water confined in reversed micelles: multidimensional vibrational spectroscopy study. AB - Here we perform a comprehensive study of ultrafast molecular and vibrational dynamics of water confined in small reversed micelles (RMs). The molecular picture is elucidated with two-dimensional infrared (2D IR) spectroscopy of water OH stretch vibrations and molecular dynamics simulations, bridged by theoretical calculations of linear and 2D IR vibrational spectra. To investigate the effects of intermolecular coupling, experiments and modeling are performed for isotopically diluted (HDO in D2O) and undiluted (H2O) water. We put a separation of water inside RMs into two subensembles (water-bound and surfactant-bound molecules), observed by many before, on a solid theoretical basis. Water molecules fully attached to the lipid interface ("shell" water) are decoupled from one another and from the central water nanopool ("core" water). The environmental fluctuations are largely "frozen" for the shell water, while the core waters demonstrate much faster dynamics but still not as fast as in the bulk case. A substantial nanoconfinement effect on the dynamics of the core water is observed after disentanglement of the shell water contribution, which is fully confirmed by the simulations of 2D IR spectra. Current results provide new insights into interaction between biological objects like membranes or proteins with the surrounding aqueous bath, and highlight peculiarities in vibrational energy redistribution near the lipid surface. PMID- 23980544 TI - Pd(II)-catalyzed intramolecular 1,2-aminoalkylation of conjugated 1,3-dienes for the synthesis of pyrrolizidines. AB - A palladium(II)-catalyzed tandem cyclization reaction involving an intramolecular 1,2-aminoalkylation of N-4,6-dienyl beta-keto amides has been developed. This process provides an efficient method for the rapid assembly of pyrrolizidines starting from linear substrates in moderate to good yields and high to excellent diastereoselectivities. PMID- 23980545 TI - Glycosylation and functionality of recombinant beta-glucocerebrosidase from various production systems. AB - The glycosylation of recombinant beta-glucocerebrosidase, and in particular the exposure of mannose residues, has been shown to be a key factor in the success of ERT (enzyme replacement therapy) for the treatment of GD (Gaucher disease). Macrophages, the target cells in GD, internalize beta-glucocerebrosidase through MRs (mannose receptors). Three enzymes are commercially available for the treatment of GD by ERT. Taliglucerase alfa, imiglucerase and velaglucerase alfa are each produced in different cell systems and undergo various post translational or post-production glycosylation modifications to expose their mannose residues. This is the first study in which the glycosylation profiles of the three enzymes are compared, using the same methodology and the effect on functionality and cellular uptake is evaluated. While the major differences in glycosylation profiles reside in the variation of terminal residues and mannose chain length, the enzymatic activity and stability are not affected by these differences. Furthermore, the cellular uptake and in-cell stability in rat and human macrophages are similar. Finally, in vivo studies to evaluate the uptake into target organs also show similar results for all three enzymes. These results indicate that the variations of glycosylation between the three regulatory approved beta-glucocerebrosidase enzymes have no effect on their function or distribution. PMID- 23980546 TI - Biomonitoring of perfluoroalkyl acids in human urine and estimates of biological half-life. AB - Perfluoroalkyl acids (PFAAs) are persistent and bioaccumulative compounds that have been associated with adverse health outcomes. In human blood, PFAAs exist as both linear and branched isomers, yet for most linear homologues, and for all branched isomers, elimination rates are unknown. Paired blood and urine samples (n = 86) were collected from adults in China. They were analyzed by a sensitive isomer-specific method that permitted the detection of many PFAAs in human urine for the first time. For all PFAAs except perfluoroundecanoate (PFUnA), levels in urine correlated positively with levels in blood. Perfluoroalkyl carboxylates (PFCAs) were excreted more efficiently than perfluoroalkane sulfonates (PFSAs) of the same carbon chain-length. In general, shorter PFCAs were excreted more efficiently than longer ones, but for PFSAs, perfluorooctanesulfonate (PFOS, a C8 compound) was excreted more efficiently than perfluorohexanesulfonate (PFHxS, a C6 compound). Among PFOS and perfluorooctanoate (PFOA) isomers, major branched isomers were more efficiently excreted than the corresponding linear isomer. A one-compartment model was used to estimate the biological elimination half-lives of PFAAs. Among all PFAAs, the estimated arithmetic mean elimination half-lives ranged from 0.5 +/- 0.1 years (for one branched PFOA isomer, 5m-PFOA) to 90 +/- 11 years (for one branched PFOS isomer, 1m-PFOS). Urinary excretion was the major elimination route for short PFCAs (C <= 8), but for longer PFCAs, PFOS and PFHxS, other routes of excretion likely contribute to overall elimination. Urinary concentrations are good biomarkers of the internal dose, and this less invasive strategy can therefore be used in future epidemiological and biomonitoring studies. The very long half-lives of long-chain PFCAs, PFHxS, and PFOS isomers in humans stress the importance of global and domestic exposure mitigation strategies. PMID- 23980547 TI - The role of vimentin intermediate filaments in the progression of lung cancer. AB - There is an accumulation of evidence in the literature demonstrating the integral role of vimentin intermediate filaments (IFs) in the progression of lung cancers. Vimentin IF proteins have been implicated in many aspects of cancer initiation and progression, including tumorigenesis, epithelial-to-mesenchymal transition (EMT), and the metastatic spread of cancer. Specifically, vimentin IFs have been recognized as an essential component regulating EMT, major signal transduction pathways involved in EMT and tumor progression, cell migration and invasion, the positioning and anchorage of organelles, such as mitochondria, and cell-cell and cell-substrate adhesion. In tumorgenesis, vimentin forms a complex with 14-3-3 and beclin 1 to inhibit autophagy via an AKT-dependent mechanism. Vimentin is a canonical marker of EMT, and recent evidence has shown it to be an important regulator of cellular motility. Transcriptional regulation of vimentin through hypoxia-inducible factor-1 may be a potential driver of EMT. Finally, vimentin regulates 14-3-3 complexes and controls various intracellular signaling and cell cycle control pathways by depleting the availability of free 14-3-3. There are many exciting advances in our understanding of the complex role of vimentin IFs in cancer, pointing to the key role vimentin IFs may play in tumor progression. PMID- 23980548 TI - Near infrared (NIR) lanthanide emissive Langmuir-Blodgett monolayers formed using Nd(III) directed self-assembly synthesis of chiral amphiphilic ligands. AB - The incorporation of chiral amphiphilic lanthanide-directed self-assembled Nd(III) complexes (Nd.13 and Nd.23) into stable Langmuir monolayers, and the subsequent Langmuir-Blodgett film formation of these, is described. The photophysical properties of the enantiomeric pair of ligands 1 and 2 in the presence of Nd(CF3SO3)3 were also investigated in CH3CN solutions using UV-vis, fluorescence, and lanthanide luminescence spectroscopies. Analysis of the resulting self-assembly processes revealed that two main species were formed in solution,1:1 and 1:3 Nd:L self-assembly complexes, with the latter being the dominant species upon the addition of 0.33 equivalents of Nd(III). Excited state lifetime measurements of Nd.13 and Nd.23 in CH3OH and CD3OD and CH3CN were also evaluated. The formation of the self-assembly in solution was also monitored by observing the changes in the circular dichroism (CD) spectra; and large differences were observed between the 1:3 and other stoichiometries in the spectra, allowing for correlation to be made with that seen in the emission studies of these systems. Surface pressure-area and surface pressure-time isotherms evidenced the formation of stable Langmuir monolayers of Nd.13 and Nd.23 at an air-water interface, and the deposition of these monolayers onto a quartz solid substrate (Langmuir-Blodgett films) gave rise to immobilized chiral monomolecular films which exhibited Nd(III) NIR luminescence upon excitation of the ligand chromophore, demonstrating efficient energy transfer to the Nd(III) excided state (sensitized) with concomitant emission centered at 800 and 1334 nm. PMID- 23980549 TI - Deamination, oxidation, and C-C bond cleavage reactivity of 5 hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine. AB - Three new cytosine derived DNA modifications, 5-hydroxymethyl-2'-deoxycytidine (hmdC), 5-formyl-2'-deoxycytidine (fdC) and 5-carboxy-2'-deoxycytidine (cadC) were recently discovered in mammalian DNA, particularly in stem cell DNA. Their function is currently not clear, but it is assumed that in stem cells they might be intermediates of an active demethylation process. This process may involve base excision repair, C-C bond cleaving reactions or deamination of hmdC to 5 hydroxymethyl-2'-deoxyuridine (hmdU). Here we report chemical studies that enlighten the chemical reactivity of the new cytosine nucleobases. We investigated their sensitivity toward oxidation and deamination and we studied the C-C bond cleaving reactivity of hmdC, fdC, and cadC in the absence and presence of thiols as biologically relevant (organo)catalysts. We show that hmdC is in comparison to mdC rapidly oxidized to fdC already in the presence of air. In contrast, deamination reactions were found to occur only to a minor extent. The C-C bond cleavage reactions require the presence of high concentration of thiols and are acid catalyzed. While hmdC dehydroxymethylates very slowly, fdC and especially cadC react considerably faster to dC. Thiols are active site residues in many DNA modifiying enzymes indicating that such enzymes could play a role in an alternative active DNA demethylation mechanism via deformylation of fdC or decarboxylation of cadC. Quantum-chemical calculations support the catalytic influence of a thiol on the C-C bond cleavage. PMID- 23980550 TI - Commentary on the symposium on the theory and practice of engaging youth in prevention message creation. AB - The symposium articles address a variety of assumptions concerning interventions in which youth create prevention messaging. These articles help confirm that young people left to themselves are likely to engage in self-persuasion through such message creation but are less likely to create messages persuasive to others. However, with youth working collaboratively with persons more expert in message production, effective messaging can be created. Symposium articles also provide important and useful theoretical frameworks for the effective design of such interventions and for understanding the persuasive effects of personal narratives. PMID- 23980551 TI - People with intellectual disabilities must be designated a medically underserved population. PMID- 23980552 TI - Latin-American Special Olympics athletes: evaluation of oral health status, 2010. AB - OBJECTIVES: The purpose of this study was to evaluate the oral health status and dental needs of the athletes with intellectual disabilities from Latin-American and Caribbean countries who were participating in the II Latin-American Special Olympics games held in Puerto Rico, February 2010. METHODS: There were 930 athletes who participated in the games, of whom 445 received a dental examination, including 367 from Latin-American and 78 from Caribbean countries. Forty-four trained and standardized dental professionals performed dental screenings of athletes with intellectual disabilities, following Special Olympic Special Smiles and CDC protocols. These criteria were used to record untreated caries, missing and filled teeth, and gingival status. Socio-demographics, existence, and severity of pain and oral hygiene habits were assessed by questionnaire. Statistical analysis was performed using EPI-INFO and SPSS Statistical Program to produce descriptive statistics and chi-square test. RESULTS: Untreated dental caries was recorded for more than half of the examined athletes. Missing teeth were noted in more than one-third of the athletes. More than half of the participants had signs of gingival disease and half needed preventive mouth guards. Statistics for each Latin-American country suggests a dissimilar trend of dental decay and treatment needs among nations. CONCLUSIONS: While the Special Olympic athletes may not be representative of the entire population of individuals with intellectual disabilities in their specific country, the general consistency of the oral health status of these athletes from the 31 countries supports the certainty of the need for increased dental services for individuals with intellectual disability in the respective countries. PMID- 23980553 TI - Behavior guidance techniques in Pediatric Dentistry: attitudes of parents of children with disabilities and without disabilities. AB - This study compared the parental acceptance of pediatric behavior guidance techniques (BGT). Forty parents of children without disabilities (Group A) and another 40 parents of children with disabilities (Group B) were selected. Each BGT was explained by a single examiner and it was presented together with a photograph album. After that parents evaluated the acceptance in: totally unacceptable, somewhat acceptable, acceptable, and totally acceptable. Results indicated that in Group A, the BGT based on communicative guidance was accepted by most participants. In Group B, just one mother considered totally unacceptable the voice control method and other two, tell-show-do. For both groups, the general anesthesia was the less accepted BGT. There was statistically significant difference in acceptance for protective stabilization with a restrictive device in Group B. Children's parents with and without disabilities accepted behavioral guidance techniques, but basic techniques showed higher rates of acceptance than advanced techniques. PMID- 23980554 TI - Oral health status and needs of homebound elderly in an urban home-based primary care service. AB - OBJECTIVES: This study assessed the oral health status, dental utilization and dental needs of the homebound elderly (HBE) care patients within the Mount Sinai Visiting Doctor program. METHODS: Of the 334 eligible patients, 57% agreed to participate and 95.4% completed the clinical examinations, the Dental Utilization and Needs survey and Geriatric Oral Health Assessment Index conducted in each subject's home by a trained research team. RESULTS: Among 75% who were dentate subjects, 40% needed restorative dental care, 45.6% needed dental extractions, and 33% complained of current oral pain. Overall, 92.0% needed some type of dental care and 96% stated that they had not seen a dentist since they became homebound (mean number of years in program = 3.2 +/- 2.58). CONCLUSION: Findings show the oral health status of these homebound elderly was poor and their quality of life was significantly affected by the lack of basic dental care. PMID- 23980555 TI - Integrated versus incidental dental care in nursing homes. AB - PURPOSE/AIM: In most of the 334 Dutch nursing homes, incidental dental care is provided upon indication by the medical and nursing staff. However, more and more nursing homes offer integrated dental care, where a dentist works on a structural basis in facilities within the home. METHODS: To evaluate the costs and effects of integrated versus incidental care, we studied the oral status and treatment needs in two nursing homes in the same city with 175 and 120 residents an average age of 81.7 and 79.3 years, respectively. RESULTS: In the integrated care home, the dentist spent an average 2.2 hours/year per resident at a cost of ?229 for the dentist's work and ?143 for laboratory costs. In the incidental care home, these values were 0.1 hours/year per resident at a cost of ?15 for the dentist's work and ?20 for laboratory costs. CONCLUSIONS: With integrated care, 55.6% of the residents had no oral treatment need versus 13.1% for incidental care, more edentulous residents wore dentures, and residents had less soft tissue pathology. PMID- 23980556 TI - Variation in oral health parameters between older people with and without mental disorders. AB - This study investigated the variation in the oral examination findings and the subjective oral complaints between older people with and without mental disorders. An interview and an oral investigation were performed in a group of older patients with mental disorders with a mean age of 71.9 years and in a group of older people without mental disease with a mean age of 70.2 years. The analysis did not reveal any statistically significant differences in the dental status of the participants and in the prevalence of oral ulcers and stomatitis. However xerostomia, burning mouth, dysgeusia, and oral malodor complaints were more frequent in patients with mental disorders, whereas general chewing complaints were less frequent. The multiple logistic regression analysis revealed that psychiatric illness was significantly associated with more complaints of dysgeusia and fewer chewing complaints. The increased prevalence of specific oral complaints in the older patients with mental disorders revealed the significant psychopathological compound of these symptoms. PMID- 23980557 TI - Oral health in older adults with dementia living in different environments: a propensity analysis. AB - This study was to compare oral health in dementia patients living in different environments. One hundred two dementia patients living in the community, assisted living facilities and nursing homes (NH) were retrospectively selected from a community-based dental clinic. Participants' sociodemographics, medical, dental, functional, and cognitive assessment were documented at arrival. Poisson and negative-binomial regressions were developed to assess impacts of residential status on the number of missing teeth and number of caries/retained roots, respectively. Oral health was poor in study participants, regardless of their residential status. Nearly 30% of NH residents were edentulous, about two times higher than those in the community. Dentate participants averaged about 5.9 caries/retained roots at arrival. Forty-four percent of community-dwelling participants and 54% of NH residents presented with five or more caries/retained roots. Holding other factors constant, living environment was not associated with oral health measures, indicating oral health had declined in dementia patients before they were placed into NH. PMID- 23980558 TI - Marfan syndrome: a review of the literature and case report. AB - Marfan syndrome (MFS) is a connective tissue disorder of variable inheritance that affects multiple organ systems. Cardiovascular, ocular, and skeletal abnormalities are cardinal features of the syndrome. Orofacially, MFS patients typically exhibit skeletal class II malocclusion, dolichofacial growth pattern, mandibular retrognathia, malar hypoplasia, high arched palate, dental crowding, and root anomalies. The purpose of this paper is to provide a review of the literature, as well as describe an 11-year-old female with MFS diagnosed at the age of 10.5 years. This report emphasizes the orofacial findings in MFS and highlights particularities of dental treatment when social deficits and intellectual disabilities are also implicated. PMID- 23980559 TI - Temporomandibular disorder in a patient with pseudoxanthoma elasticum: a case report and review. AB - Pseudoxanthoma elasticum (PXE) is a disorder characterized by progressive degeneration of elastic fibers and ectopic mineralization. Cutaneous manifestations are a hallmark of this disease and organs that may be affected by the disease process include cardiovascular, central nervous system, ocular and gastrointestinal systems. Oral manifestations of PXE have been previously reported as intramucosal nodules observed on various intraoral surfaces. We present a case of a 46-year-old female with PXE diagnosed with temporomandibular disorder (TMD). To our knowledge, this is the first report of a patient with TMD coexisting with PXE in the scientific literature. PMID- 23980560 TI - Validation of standard times and influencing factors during the development of the Workload Indicator for Nursing. AB - BACKGROUND: A tool to assist in optimal allocation of available nursing resources is of paramount importance. AIMS: The goals of this study were as follows: (1) to determine whether the standard time values of the Belgian Nursing Minimum Dataset are a valid basis for the development of a Workload Indicator for Nursing; (2) to quantify the impact of factors that most influence nursing workload; and (3) to examine the cross-impact of items of the Belgian Nursing Minimum Dataset. DESIGN: This research project is a prospective observational study with exploratory aspects. METHODS: The data for this prospective study were collected during September 2010 from a convenience sample of 23 nursing units in four hospitals in Belgium. The data collection included three parts: (1) the registration of the items of the Belgian Nursing Minimum Dataset; (2) the amount of time committed to direct patient care; and (3) analysis of variables, which influence the nursing workload at patient and unit level. RESULTS: The correlation coefficients for the sum of Direct and Indirect Patient Care and the Workload Indicator for Nursing score of the surgical, internal medicine and intensive care units were 0.85, 0.88 and 0.89 respectively. Significant differences in standard time utilization for nursing activities at the patient level are directly related to the level of mobility assistance required. Units needing significantly more time for Direct and Indirect Patient Care than predicted by the Workload Indicator for Nursing score had a higher mean number of complex nursing activities per patient. CONCLUSIONS: The high correlation coefficients between the total time utilized for direct patient care and the WiN-score indicate that the standard time values of the Belgian Nursing Minimum Dataset are valid. PMID- 23980561 TI - Differences between blood and a Newtonian fluid on the performance of a hydrodynamic bearing for rotary blood pumps. AB - Assuming that blood has a constant viscosity is a common practice when designing rotary blood pumps (RBPs), where shear stresses are generally higher than in the human body. This eases the design and allows numerical simulations and bench top experiments to be performed with Newtonian fluids. However, specific flow conditions may cause a change in cell distribution leading to an apparent lower blood viscosity. It has been observed that decreasing the vessel diameters and increasing flow velocities contribute to this effect. Because a hydrodynamic bearing operates under flow conditions following this pattern, it is important to verify whether this effect also takes place when this type of bearing is applied to a RBP. Because the operation of a hydrodynamic bearing depends directly on the fluid viscosity, a local change in cell distribution in the bearing gap can be reflected in changes in the bearing performance. In this work, a spiral groove hydrodynamic bearing was tested with porcine blood in a specially built test rig. The generated suspension force, cross flow, and bearing torque were recorded and compared with the reference response when using a solution of water and glycerol. Experiments with porcine blood yielded lower suspension forces, lower flows, and lower bearing torques than when using the glycerol solution. An explanation could be a lower apparent viscosity due to inhomogeneity of blood cell concentrations. Therefore, it is crucial to consider the effective blood viscosity when designing hydrodynamic bearings for RBPs and performing experiments. PMID- 23980562 TI - Intrafamilial phenotypic variability in four families with Anderson-Fabry disease. AB - We analysed the clinical history of 16 hemizygous males affected by Anderson Fabry Disease, from four families, to verify their intrafamilial phenotypic variability. Seven male patients, ranging from 26 to 61 years of age, died, whereas nine (age range 23-55) are alive. Eleven patients have undergone enzyme replacement therapy (ERT) for a period of 5-10 years. We have found a wide range of intrafamilial phenotypic variability in these families, both in terms of target-organs and severity of the disease. Overall, our findings confirm previous data from the literature showing a high degree of intrafamilial phenotypic variability in patients carrying the same mutation. Furthermore, our results underscore the difficulty in giving accurate prognostic information to patients during genetic counselling, both in terms of rate of disease progression and involvement of different organs, when such prognosis is solely based on the patient's family history. PMID- 23980563 TI - Endocytoscopy can provide additional diagnostic ability to magnifying chromoendoscopy for colorectal neoplasms. AB - BACKGROUND AND AIM: Pit pattern (PIT) diagnosis with magnifying chromoendoscopy is effective diagnostic method for predicting a massively invasive submucosal colorectal cancer (SMm) which has possibility of metastasis, whereas endocytoscopy (EC) is recently reported to provide excellent diagnostic ability by enabling in vivo cellular visualization. The aim was to assess the additional diagnostic value of EC to PIT for diagnosing colorectal lesions. METHODS: We conducted a retrospective comparative analysis using a prospectively recorded database in a referral hospital. The subjects were 538 patients who were detected of a colorectal lesion with use of a magnifying colonoscope with EC capability. Each detected lesion was initially diagnosed by PIT findings followed by EC diagnosis by the on-site endoscopist. The diagnostic abilities in predicting neoplastic change and SMm were compared between PIT and PIT plus EC. RESULTS: Overall, 514 lesions from 455 patients were available for analysis. Of them, there were 58 non-neoplastic lesions, 352 adenomas, 15 slightly invasive submucosal cancers, and 89 SMm. The diagnostic abilities of predicting neoplastic change were comparable between PIT and PIT plus EC: sensitivity was 97.8% versus 97.4%, specificity was 91.4% versus 89.7%, and accuracy was 97.1% versus 96.5%. Regarding those of predicting SMm, PIT plus EC showed additional specificity and accuracy to PIT: specificity was 99.1% versus 97.6% (P = 0.041), and accuracy was 96.3% versus 93.8% (P = 0.004). CONCLUSIONS: Though PIT has feasible diagnostic ability for predicting both neoplastic change and SMm, EC provides additional diagnostic value to PIT diagnosis for predicting SMm. PMID- 23980564 TI - Acute kidney injury caused by tenofovir disoproxil fumarate and diclofenac co administration. AB - OBJECTIVES: The renal elimination of tenofovir (TFV) may be subject to renal drug drug interactions that may increase the risk of kidney injury. Case reports indicated that diclofenac might increase TFV-associated nephrotoxicity via a drug drug interaction, leading to an increased intracellular TFV concentration in proximal tubular cells. METHODS: A retrospective analysis of data for all patients from the Frankfurt HIV Cohort (FHC) who had diclofenac prescriptions between January 2008 and June 2012 was carried out. RESULTS: Among 89 patients with diclofenac use, 61 patients (68.5%) were treated with tenofovir disoproxil fumarate (TDF) and 28 patients (31.5%) were treated with TDF-sparing combination antiretroviral therapy (cART). Thirteen patients (14.6%) developed acute kidney injury (AKI) shortly after initiating diclofenac treatment. AKI occurred exclusively in TDF-treated patients, although all had previously stable renal function. All cases were accompanied by new onset of at least two parameters indicating proximal tubular damage, such as normoglycaemic-glucosuria and hypophosphataemia. TFV-associated nephrotoxicity was demonstrated by renal biopsy in four cases. Additionally, 11.5% of patients on TDF treatment developed new onset proximal tubular damage, while having a preserved glomerular filtration rate. In contrast, diclofenac did not affect renal function in patients with TDF sparing cART, as only one case of isolated hypophataemia was observed in these patients. In univariate analysis, risk factors for AKI were TDF-containing cART (P = 0.0076) and pre-existing hypophosphataemia (P = 0.0086). CONCLUSIONS: Drug drug interaction caused by diclofenac could exacerbate TFV-associated nephrotoxicity. Diclofenac should be used with caution in patients on TDF therapy, especially in those with hypophosphataemia. Our findings need to be confirmed in larger studies. PMID- 23980565 TI - Application of high-frequency ultrasound in esophageal atresia with distal fistula. AB - The present study was designed to evaluate the accuracy of preoperative ultrasonography (US) in depicting the structure of esophageal atresia with distal fistula (EA-DF) and to determine its role in planning the surgical strategy by digitally measuring the interpouch distance (ID). Thirty-six neonates (20 males and 16 females) born with EA-DF were included in this study. After obtaining chest radiographs of the neonates with a coiled nasogastric tube in the upper esophageal pouch, longitudinal esophageal high-frequency US was performed. The esophageal structures were displayed, and the IDs measured on US images were compared with the surgical findings. With the use of US, the structure of EA-DF was accurately depicted, and the ID detected by US correlated well with the surgical findings. Statistical analysis demonstrated no significant difference in the ID as assessed by US and surgery (R = 0.99, P < 0.001).). US findings were crucial for planning the surgical strategy in 9 (25.0%) patients. Preoperative US could provide more accurate information on the structure of EA-DF and play a crucial role in planning the surgical strategy. PMID- 23980566 TI - A qualitative study into the attitudes of patients and staff towards violence and aggression in a high security hospital. PMID- 23980567 TI - Fatalities due to indigenous and exotic species in Florida. AB - Florida's climate is suitable for many potentially hazardous animals, including both indigenous and exotic species, which are frequently kept as in zoos or as pets. This has resulted in many unforeseen fatal encounters between animals and the ever expanding human population. While the literature and knowledge pool for more common types of deaths referred to medical examiner/coroner's offices is abundant, the appreciation of wildlife and exotic pet-related deaths is far less widespread. We report seven animal attack-related deaths that occurred in Florida. The inflicted injuries included blunt and sharp force injuries, asphyxia, drowning, and envenomation. The underlying cause of death, however, was always a result of the human/animal interaction and in many cases related to human error and failure to appreciate the potentially dangerous behavior of nondomesticated species. These cases illustrate the varied circumstances and pathophysiologies associated with deaths due to indigenous and exotic species and the importance of the multidisciplinary approach in the medicolegal investigation of these cases. PMID- 23980568 TI - Seasonal increase in sea temperature triggers pancreas disease outbreaks in Norwegian salmon farms. AB - Pancreas disease (PD) is a viral disease causing negative impacts on economy of salmon farms and fish welfare. Its transmission route is horizontal, and water transport by ocean currents is an important factor for transmission. In this study, the effect of temperature changes on PD dynamics in the field has been analysed for the first time. To identify the potential time of exposure to the virus causing PD, a hydrodynamic current model was used. A cohort of salmon was assumed to be infected the month it was exposed to virus from other infective cohorts by estimated water contact. The number of months from exposure to outbreak defined the incubation period, which was used in this investigation to explore the relationship between temperature changes and PD dynamics. The time of outbreak was identified by peak in mortality based on monthly records from active sites. Survival analysis demonstrated that cohorts exposed to virus at decreasing sea temperature had a significantly longer incubation period than cohorts infected when the sea temperature was increasing. Hydrodynamic models can provide information on the risk of being exposed to pathogens from neighbouring farms. With the knowledge of temperature-dependent outbreak probability, the farmers can emphasize prophylactic management, avoid stressful operations until the sea temperature is decreasing and consider removal of cohorts at risk, if possible. PMID- 23980569 TI - Weak impact of fine-scale landscape heterogeneity on evolutionary potential in Arabidopsis lyrata. AB - Microhabitat heterogeneity can lead to fine-scale local adaptation when gene flow is restricted, which may be important for the maintenance of genetic variation within populations. This study tested whether microhabitat heterogeneity was associated with trait differences in a population of Arabidopsis lyrata and studied its impact on the genetic variance-covariance (G) matrix. Maternal seed families were collected from dune tops and bottoms, two microhabitats known to vary significantly in water availability. In a common garden experiment, replicate individuals per family were raised under wet and dry conditions, and physiological, morphological and life-history traits were assessed. Plants from the two microenvironments differed in their response to treatment in two performance components, in stomata density and most strongly in flowering time. Under wet conditions, plants originating from dune bottoms flowered 4 weeks earlier than those from dune tops. Only one of three G-matrix comparisons revealed that habitat heterogeneity and evolutionary potential were positively linked. The number of independent trait dimensions was larger in the entire population than within subpopulations separated by microhabitat under wet conditions. However, the size of the G-matrix was no larger in the entire population than within subpopulations separated by microhabitat, and trait correlation structure between microhabitats and treatments was not significantly different. These results indicate that fine-scale habitat heterogeneity likely led to local adaptation, which weakly affected levels of across-trait genetic variation. PMID- 23980570 TI - Yo-Yo intermittent recovery test performances within an entire football league during a full season. AB - The study examined Yo-Yo intermittent recovery level 2 (YYIR2) and submaximal YYIR1 test performances in 172 male semi-professional football players (age; 25.8 +/- 4.1 years) representing all teams in a top league at pre-season, start season, mid-season and end-season. YYIR2 performance was 847 +/- 227 m (+/-SD) at pre-season and rose (P < 0.05) by 128 +/- 113 m to 975 +/- 205 m at start of season and further (P < 0.05) by 59 +/- 102 m to 1034 +/- 211 m at mid-season. Submaximal YYIR1 HR was 90.9 +/- 4.2% HR(max) at pre-season, which was higher (P < 0.05) than at start, mid and end of season (87.0 +/- 3.9, 85.9 +/- 4.1 and 87.0 +/- 3.7% HR(max), respectively). Peak YYIR2 performance and minimum YYIR1 HR were 1068 +/- 193 m and 85.1 +/- 3.8% HR(max), respectively, with ~50% of the players peaking at mid-season. Top-teams and middle-teams had higher (P < 0.05) peak YYIR2 scores (1094 +/- 205 and 1121 +/- 152 m, respectively) than bottom-teams (992 +/- 185 m). YYIR2 performance was 16% higher (P < 0.05) and YYIR1 HR was 1.4% HR(max) lower (P < 0.05) for regular players than non-regular players at pre season and remained lower (P < 0.05) throughout the season. Central defenders had poorer (P < 0.05) YYIR performances compared to other positional roles. In conclusion, YYIR performances are highly variable within a football league over a season and are influenced by league ranking, regularity of competitive play and playing position. PMID- 23980573 TI - Conformation-directed catalysis and coupled enzyme-substrate dynamics in Pin1 phosphorylation-dependent cis-trans isomerase. AB - Human peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is an essential enzyme in numerous phosphorylation-dependent regulatory pathways and has been implicated in many diseases, including cancer and Alzheimers. Pin1 specifically catalyzes cis-trans isomerization of prolyl-peptide bonds preceded by phosphorylated serine or phosphorylated threonine in its protein substrates. Yet, little is known about the catalytic mechanism of Pin1 in atomistic detail. Here, we present results from accelerated molecular dynamics simulations to show that catalysis occurs along a restricted path of the backbone configuration of the substrate, selecting out specific conformations of the substrate in the active site of Pin1. We show that the dynamics of Pin1 and the enzyme-substrate interactions are intricately coupled to isomerization during catalysis. The strength of the interactions between the phosphate binding pocket of Pin1 and the phosphate moiety of the substrate is dictated by the state of the substrate during catalysis. We also show that the transition-state configuration of the substrate binds better than the cis and trans states to the catalytic domain of Pin1, suggesting that Pin1 catalyzes its substrate by noncovalently stabilizing the transition state. These results suggest an atomistic detail understanding of the catalytic mechanism of Pin1 that is necessary for the design of novel inhibitors and the treatment of several diseases. PMID- 23980574 TI - Ultrasonography of carotid plaque for the prevention of stroke. AB - A carotid ultrasonography is a non-invasive technique that provides an accurate and reliable characterization of the broad spectrum of carotid arteriosclerosis, from the intima-media thickness to the atherosclerotic plaque. Carotid ultrasonography has become a useful tool for identifying patients at high risk of stroke and selecting those who can benefit most from revascularization therapies such as carotid endarterectomy and stenting. In addition to the degree of stenosis, plaque echomorphology has emerged in recent years as an important contributory factor to stroke risk. Changes in plaque echogenicity, as measured by the quantitative computer-assisted ultrasonography index, could be a marker of plaque instability as well as an indicator of plaque remodeling, thereby providing the means for monitoring anti-atherosclerosis drugs such as statins. PMID- 23980575 TI - Reversible surface two-electron transfer reactions in square wave voltcoulommetry: application to the study of the reduction of polyoxometalate [PMo12O40]3- immobilized at a boron doped diamond electrode. AB - Reversible surface two-electrons transfer reactions (stepwise processes) are analyzed using square wave voltcoulommetry (SWVC), which is a variety of square wave techniques based on the measurement of the transferred charge. Such reversible surface redox processes are exhibited by many two-redox center and multicenter biomolecules (proteins, enzymes, ...) and inorganic molecules like polyoxometalates (POMs), which have very interesting applications, mainly as electrocatalysts. Because of the stationary character of the response obtained, the key parameters that govern the cooperativity degree of the two reversible electron transfers (ETs) are the difference between their formal potentials, DeltaE(0), and the square wave amplitude, |E(SW)|, whose combined effect sets the two peaks -> one peak transition in the response. Working curves based on the variation of the peak parameters (peak potentials, half-peak widths, and peak heights) with DeltaE(0) and |E(SW)| are given, from which the formal potentials and the total surface excess can be accurately determined. SWVC has been applied to the study of the reduction of polyoxometalate [PMo12O40](3-) adsorbed at a boron doped diamond electrode (BDD), for which three stable and well-defined reversible charge peaks, corresponding to three cooperative EE processes, are obtained in the interval (0.6, -0.2) V by using low square wave frequencies. From the analysis of these peaks, the values of the total surface excess and the formal potentials of the six ETs have been obtained in aqueous media for two electrolytes: HClO4 and LiClO4. PMID- 23980577 TI - Why (1 0 0) terraces break and make bonds: oxidation of dimethyl ether on platinum single-crystal electrodes. AB - A surface structural preference for (1 0 0) terraces of fcc metals is displayed by many bond-breaking or bond-making reactions in electrocatalysis. Here, this phenomenon is explored in the electrochemical oxidation of dimethyl ether (DME) on platinum. The elementary C-O bond-breaking step is identified and clarified by combining information obtained from single-crystal experiments and density functional theory (DFT) calculations. Experiments on Pt(1 0 0), Pt(5 1 0), and Pt(10 1 0) surfaces show that the surface structure sensitivity is due to the bond-breaking step, which is unfavorable on step sites. DFT calculations suggest that the precursor for the bond-breaking step is a CHOC adsorbate that preferentially adsorbs on a square ensemble of four neighboring atoms on Pt(1 0 0) terraces, named as "the active site". Step sites fail to strongly adsorb CHOC and are, therefore, ineffective in breaking C-O bonds, resulting in a decrease in activity on surfaces with increasing step density. Our combined experimental and computational results allow the formulation of a new mechanism for the electro oxidation of DME as well as a simple general formula for the activity of different surfaces toward electrocatalytic reactions that prefer (1 0 0) terrace active sites. PMID- 23980576 TI - Respiratory distress and early neonatal lethality in Hspa4l/Hspa4 double-mutant mice. AB - Heat shock proteins HSPA4L and HSPA4 are closely related members of the HSP110 family and act as cochaperones. We generated Hspa4l(-/-)Hspa4(-/-) mice to investigate a functional complementarity between HSPA4L and HSPA4 during embryonic development. Hspa4l(-/-)Hspa4(-/-) embryos exhibited marked pulmonary hypoplasia and neonatal death. Compared with lungs of wild-type, Hspa4l(-/-), and Hspa4(-/-) embryos, Hspa4l(-/-)Hspa4(-/-) lungs were characterized by diminished saccular spaces and increased mesenchymal septa. Mesenchymal hypercellularity was determined to be due to an increased cell proliferation index and decreased cell death. A significant increase in expression levels of prosurvival protein B cell leukemia/lymphoma 2 may be the cause for inhibition of apoptotic process in lungs of Hspa4(-/-)Hspa4l(-/-) embryos. Accumulation of glycogen and diminished expression of surfactant protein B, prosurfactant protein C, and aquaporin 5 in saccular epithelium suggested impaired maturation of type II and type I pneumocytes in the Hspa4l(-/-)Hspa4(-/-) lungs. Further experiments showed a significant accumulation of ubiquitinated proteins in the lungs of Hspa4l(-/ )Hspa4(-/-) embryos, indicating an impaired chaperone activity. Our study demonstrates that HSPA4L and HSPA4 collaborate in embryonic lung maturation, which is necessary for adaptation to air breathing at birth. PMID- 23980578 TI - Fusion at the non-K-region of pyrene: an alternative strategy to extend the pi conjugated plane of pyrene. AB - A large fused pyrene derivative TTTP was facilely developed through fusion at the non-K-region of pyrene, which represents the first example of extending such a pi conjugated plane at its non-K-region. The investigation of its photophysical properties and other characterizations indicated that TTTP exhibited strong aggregation behaviors and self-assembled into highly ordered one-dimensional nanowires due to its large pi-conjugated plane. PMID- 23980579 TI - Evaluating adult patients' sleep: an integrative literature review in critical care. AB - BACKGROUND: Patients in a critical care unit sleep quite poorly even when they appear to be sleeping. Sleep is light and fragmented. Acute lack of sleep causes patients suffering in the form of fatigue, irritability, disorientation and hallucinations. It may also affect their recovery and immune defence. To promote sleep, nurses must be able to evaluate patients' sleep reliably. AIM AND OBJECTIVES: Our aim was to form a comprehensive overview of the sleep evaluation methods in critical care. Our objectives were to determine the content and the quality of the methods as reported by the researchers. This overview hopefully improves the use of the sleep evaluation methods as part of sleep promoting nursing interventions and practices. METHOD: The literature search was performed from the Ovid MEDLINE, CINAHL, an 'All EBM Reviews', and PsycINFO databases. The search terms sleep, evaluating sleep and critical care were used. An integrative review method was used to analyse the data. RESULTS: According to the 52 articles of this review, there is a wide variety of methods to evaluate patients' sleep in critical care by observation, by asking for patient's own perception and by objective measures. Most instruments evaluate only total sleep time or the quality of sleep in general. The validity and reliability of the instruments has been insufficiently reported. Some questionnaires for patients' perception have been tested and used in several studies. CONCLUSION: Sleep evaluation instruments do not cover all dimensions of sleep since they mostly measure total sleep time or estimate the overall quality of sleep. The quality of the sleep evaluation instruments varies from scientifically tested tools to untested instruments. This review will allow nurses to recognise the strengths and limitations of sleep evaluation instruments when selecting one to be used in critical care. Valid information about patients' sleep enables nurses to facilitate it. PMID- 23980580 TI - Addition of lidocaine to bupivacaine for spinal anaesthesia compared with bupivacaine spinal anaesthesia and local infiltration anaesthesia. AB - BACKGROUND: Two spinal anaesthesia techniques were compared with local infiltration anaesthesia (LIA) to test the hypothesis that the addition of lidocaine to bupivacaine would decrease the spinal block's duration and provide shorter recovery to discharge. METHODS: Ninety-three patients undergoing outpatient herniorrhaphy were randomised into three groups. Spinal anaesthesia: the BL Group (bupivacaine-lidocaine) received 2 ml hyperbaric bupivacaine (10 mg) + 0.6 ml 1% lidocaine (6 mg), the BS Group (bupivacaine-saline) received 2 ml hyperbaric bupivacaine (10 mg) + 0.6 ml saline. LIA: the LIA group received plain bupivacaine + lidocaine. Resolution of the nerve blocks were compared between spinal anaesthesia groups, and post-operative pain scores, analgesic requirements, post-anaesthesia care unit (PACU) time, and discharge time were compared among all groups. RESULTS: Spinal block resolved faster in the BL group vs. the BS group: 194.8 [standard deviation (SD) 29.2] min vs. 236.8 (SD 36.5) min (P = 0.000). PACU and discharge time were shortest in the LIA group [PACU time: 108.7 (SD 27.6) min vs. 113.0 (SD 39.4) min and 151.9 (SD 43.7) min in the BL and BS groups (P = 0.000), and discharge time 108.5 (SD 29.5) min vs. 145.8 (SD 37.3) min and 177.1 (SD 32.0) min in the BL and BS groups, respectively (P = 0.000)]. Pain scores and analgesic consumption were lower, with the time to first analgesic intake being longer in the LIA group. CONCLUSION: Addition of lidocaine to bupivacaine reduced the duration of the spinal block and was associated with shorter recovery times. However, LIA provided the fastest recovery to discharge after outpatient inguinal herniorrhaphy. PMID- 23980581 TI - The theory of active involvement: processes underlying interventions that engage adolescents in message planning and/or production. AB - Adolescence is a time of increased risk taking, and recent intervention strategies have included adolescents planning or producing antirisk messages for their peers. Although these projects may generate enthusiasm, we know little about message planning or production as a strategy for changing adolescent decision-making and behavior. This article articulates the Theory of Active Involvement (TAI) to describe and explain the processes through which these active involvement interventions influence adolescents. TAI is based on social cognitive theory's notion of self-regulation and examines multiple perspective taking and activating the self-reflection processes. The theory specifically describes the process of cognitive changes experienced by participants in active involvement interventions. The sequence is conceptualized as starting when engagement with the intervention (arousal and involvement) produces skill and knowledge gains (immediate outcomes) that lead to reflection (perceived discrepancy) and then other cognitions (expectancies, norms, intentions), with the ultimate outcome being behavior change. Engaging the target audience in a process of self-reflection is conceptualized as the crucial ingredient for meaningful and sustainable change in cognitions and behavior. This article provides valuable insight into how active involvement strategies function and how to best design these interventions, particularly those targeting adolescents. PMID- 23980582 TI - Polyelectrolyte adsorption on solid surfaces: theoretical predictions and experimental measurements. AB - This work utilizes a combination of theory and experiments to explore the adsorption of two different cationic polyelectrolytes onto oppositely charged silica surfaces at pH 9. Both polymers, poly(diallyldimethylammonium chloride), PDADMAC, and poly(4-vinyl N-methylpyridinium iodide), PVNP, are highly charged and highly soluble in water. Another important aspect is that a silica surface carries a relatively high surface charge density at this pH level. This means that we have specifically chosen to investigate adsorption under conditions where electrostatics can be expected to dominate the interactions. Of specific focus in this work is the response of the adsorption to the addition of simple salt (i.e., a process where electrostatics is gradually screened out). Theoretical predictions from a recently developed correlation-corrected classical density functional theory for polyelectrolytes are evaluated by direct quantitative comparisons with corresponding experimental data, as obtained by ellipsometry measurements. We find that, at low concentrations of simple salt, the adsorption increases with ionic strength, reaching a maximum at intermediate levels (about 200 mM). The adsorption then drops but retains a finite level even at very high salt concentrations, indicating the presence of nonelectrostatic contributions to the adsorption. In the theoretical treatment, the strength of this relatively modest but otherwise largely unknown nonelectrostatic surface affinity was estimated by matching predicted and experimental slopes of adsorption curves at high ionic strength. Given these estimates for the nonelectrostatic part, experimental adsorption data are essentially captured with quantitative accuracy by the classical density functional theory. PMID- 23980583 TI - Axial ligand replacement mechanism in heme transfer from streptococcal heme binding protein Shp to HtsA of the HtsABC transporter. AB - The heme-binding protein Shp of Group A Streptococcus rapidly transfers its heme to HtsA, the lipoprotein component of the HtsABC transporter, in a concerted two step process with one kinetic phase. Heme axial residue-to-alanine replacement mutant proteins of Shp and HtsA (Shp(M66A), Shp(M153A), HtsA(M79A), and HtsA(H229A)) were used to probe the axial displacement mechanism of this heme transfer reaction. Ferric Shp(M66A) at high pH and Shp(M153A) have a pentacoordinate heme iron complex with a methionine axial ligand. ApoHtsA(M79A) efficiently acquires heme from ferric Shp but alters the reaction mechanism to two kinetic phases from a single phase in the wild-type protein reactions. In contrast, apoHtsA(H229A) cannot assimilate heme from ferric Shp. The conversion of pentacoordinate holoShp(M66A) into pentacoordinate holoHtsA(H229A) involves an intermediate, whereas holoHtsA(H229A) is directly formed from pentacoordinate holoShp(M153A). Conversely, apoHtsA(M79A) reacts with holoShp(M66A) and holoShp(M153A) in mechanisms with one and two kinetic phases, respectively. These results imply that the Met79 and His229 residues of HtsA displace the Met66 and Met153 residues of Shp, respectively. Structural docking analysis supports this mechanism of the specific axial residue displacement. Furthermore, the rates of the cleavage of the axial bond in Shp in the presence of a replacing HtsA axial residue are greater than that in the absence of a replacing HtsA axial residue. These findings reveal a novel heme transfer mechanism of the specific displacement of the Shp axial residues with the HtsA axial residues and the involvement of the HtsA axial residues in the displacement. PMID- 23980584 TI - CPAP-induced mania in bipolar disorder: a case report. AB - OBJECTIVE: In this case report we present our clinical observations of two patients with bipolar disorder with comorbid obstructive sleep apnea (OSA) who were treated with continuous positive airway pressure (CPAP) for their sleep apnea. BACKGROUND: Bipolar disorder is a psychiatric disorder characterized by the presence of one or more episodes of mania and frequent episodes of depression. This disorder affects approximately 0.8% of the adult population, with estimates from community samples ranging between 0.4% and 1.6%. OSA syndrome is a severe sleep disorder with a prevalence of 2-4% in the general population, the risk of which is increased by obesity. The prevalence of OSA is expected to be high in bipolar disorder due to high comorbid obesity. It is expected that improvement in OSA in patients with bipolar disorder with CPAP will improve mood and other symptoms of bipolar disorder. However, there is a relative lack of data examining this aspect. RESULTS: In both cases of bipolar disorder, CPAP was started after a polysomnographic diagnosis of OSA and CPAP titration study indicating that most of the apneas/hypopneas were eliminated with a significant improvement in oxygen saturation. To our surprise, we noted that in both of these cases initiation of CPAP resulted in manic symptoms. CONCLUSIONS: Clinicians need to monitor patients with bipolar disorder closely for worsening of manic symptoms when they are started on CPAP for underlying OSA. PMID- 23980585 TI - Relationship between inosine triphosphate genotype and outcome of extended therapy in hepatitis C virus patients with a late viral response to pegylated interferon and ribavirin. AB - BACKGROUND AND AIM: It is not yet clear which factors are associated with the outcome of 72-week treatment with pegylated-interferon and ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. METHODS: In 66 patients with HCV genotype 1 who had a late viral response (LVR) to 72-week treatment of pegylated-interferon and RBV, we examined the factors that determined the outcome, including single nucleotide polymorphisms of interleukin-28B and inosine triphosphatase (ITPA) genes. RESULTS: Thirty seven of 66 (56%) patients with LVR achieved a sustained viral response (SVR). The mean age of these 37 SVR patients was 55, compared with 61 in 29 relapsed patients (P = 0.009). Twenty six of 54 (48%) patients with the CC genotype and 11 of 12 (92%) with the CA/AA genotype of ITPA rs1127354 achieved SVR (P = 0.006). The SVR rates were 79%, 40%, 60%, and 33% in patients with undetectable HCV RNA on weeks 16, 20, 24, and 28 or later, respectively (P = 0.014). Finally, serum RBV concentration at week 44 of treatment was significantly higher in the SVR group (2651 ng/mL) than in the relapse group (1989 ng/mL, P = 0.002). In contrast, the rate of the interleukin 28B genotype was not different between the groups. Multiple regression analysis showed that age < 60 years, ITPA CA/AA genotype, and serum RBV concentration were significant independent predictive factors for SVR. CONCLUSIONS: Our findings elucidated the association of four factors, including ITPA genotype, with the outcome of 72-week treatment in LVR patients. PMID- 23980586 TI - PIK3R1 mutations in SHORT syndrome. AB - SHORT syndrome (OMIM 269880) is a rare autosomal-dominant disorder characterized by short stature, hyperextensibility of joints, hernias, ocular depression, ophthalmic anomalies (Rieger anomaly, posterior embryotoxon, glaucoma), teething delay, partial lipodystrophy, insulin resistance and facial dysmorphic signs. Heterozygous mutations in PIK3R1 were recently identified in 14 families with SHORT syndrome. Eight of these families had a recurrent missense mutation (c.1945C>T; p.Arg649Trp). We report on two unrelated patients with typical clinical features of SHORT syndrome and additional problems such as pulmonary stenosis and ectopic kidney. Analysis of PIK3R1 revealed the mutation c.1945C>T; p.Arg649Trp de novo in both patients. These two patients not only provide additional evidence that PIK3R1 mutations cause SHORT syndrome, but also broaden the clinical spectrum of this syndrome and further confirm that the amino acid exchange c.1945C>T; p.Arg649Trp is a hotspot mutation in this gene. PMID- 23980587 TI - Short-term neurodevelopmental outcome of babies operated on for low-risk esophageal atresia: a pilot study. AB - Data on the neurodevelopmental outcome of esophageal atresia (EA) survivors are scarce, controversial, and based on small samples. This is an observational prospective longitudinal study on a selected cohort of low-risk EA survivors. We considered a low-risk EA survivor a patient with the following characteristics: gestational age >32 weeks, no long gap, no genetic or chromosomic anomaly associated with neurodevelopmental delay, and no further major surgical congenital anomalies. Infants were evaluated with scales derived from the Bayley Scales of Infant and Toddler Development - 3rd Edition at 6 and 12 months, with a score of 100 considered normal for each scale. Analysis of variance was used to assess differences of cognitive and motor development. Linear regression was used to assess the impact of the following clinical and sociodemographic variables: gender, birthweight, gestational age, length of hospital stay, number of surgeries and number of esophageal dilatations during first hospitalization, days of mechanical ventilation, weight at follow up, number of surgeries and esophageal dilatations at follow up, parental age, educational level, and socioeconomic status. Thirty children form the object of the study. The mean (standard deviation [SD]) cognitive scale's score was 93.7 (7.5) and 98.2 (9.6) at 6 and 12 months, respectively (P < 0.05). The mean (SD) motor scale's score was 97.6 (9.3) and 98.0 (12.1) at 6 and 12 months, respectively (P = n.s.). Children with a body weight <5 degrees percentile at 12 months showed a mean (SD) cognitive score significantly lower when compared with those with a body weight >5 degrees percentile: 88.8 (6.3) and 100.5 (8.9), respectively. At 12 months, children with unemployed mothers had a mean (SD) motor score significantly lower when compared with those in the other socioeconomic classes: 87.7 (9.8) and 100.6 (12.4), respectively. In conclusion, parents of babies operated on for low-risk EA can be reassured about neurodevelopmental outcome at least up to 1 year of age. When offering a multidisciplinary follow-up program, underweight patients should deserve particular attention to promote their quality of life and support their global development. PMID- 23980588 TI - Evaluation of single port access gastropexy and ovariectomy using articulating instruments and angled telescopes in dogs. AB - OBJECTIVE: To describe in dogs, a technique for single port access gastropexy and ovariectomy (SPAGO) using a commercially available multitrocar port and to evaluate short-term outcome. DESIGN: Retrospective case series. ANIMALS: Dogs (n = 18). PROCEDURES: A commercially available multitrocar port was inserted into the abdomen lateral to the rectus abdominis muscle and 2-5 cm caudal to the right rib. Dogs were tilted 45 degrees in both left and right recumbency and bilateral ovariectomy performed using articulating graspers, a bipolar vessel sealing device and a 30 degrees telescope. The laparoscopic assisted incisional gastropexy was performed after ovariectomy at the multitrocar port insertion site by grasping the antral portion of the stomach with a 10 mm DuVall forceps and suturing the seromuscular layer of the antral region of the stomach to the transversus abdominis muscle. RESULTS: Eighteen dogs (median weight, 34.5 kg; range, 14.7-59.2 kg) met the inclusion criteria. Median surgical time for SPAGO was 65 minutes (range, 50-225 minutes). Intra-operative complications included, incorrect multitrocar port placement location (n = 3) and mild hemorrhage from a splenic laceration (1) All dogs recovered from surgery and were discharged from the hospital. CONCLUSIONS: Single port access gastropexy and ovariectomy is a feasible procedure to provide prophylaxis against gastric dilation-volvulus and a simultaneous means of sterilization in female dogs. Careful and accurate initial multitrocar port insertion is necessary to have optimal operative viewing as well as to reduce the chances of inadvertent splenic laceration. PMID- 23980590 TI - Erik von Willebrand. PMID- 23980591 TI - Laparoscopy-assisted versus open total gastrectomy for gastric cancer: a meta analysis. AB - BACKGROUND: It remains controversial whether laparoscopy-assisted total gastrectomy (LATG) is a safe or better alternative to open total gastrectomy (OTG) for the treatment of gastric cancer. We aimed to evaluate the safety and efficacy of LATG by pooling comparative studies of LATG and OTG in a meta analysis. MATERIALS AND METHODS: Original articles comparing LATG and OTG for gastric cancer, published in the English language since 1990, were searched for in PubMed, Embase, Medline, and the Cochrane Library. The outcome variables analyzed were number of harvested lymph nodes, postoperative complications, postoperative mortality, 5-year survival, operative time, blood loss, time of analgesic use, first flatus day, and postoperative hospital stay. RESULTS: Eight studies were considered suitable for the meta-analysis, for a total of 1161 patients (409 LATG and 752 OTG). Compared with OTG, LATG showed a similar number of lymph nodes harvested, morbidity, and postoperative mortality. There was also no difference in 5-year overall and disease-specific survival between groups, according to two enrolled studies where such data were available. LATG required longer operative times than OTG but also resulted in significantly less blood loss, earlier return of bowel function, less time of analgesics use, and shorter postoperative hospital stay. CONCLUSIONS: This meta-analysis suggests that LATG in the treatment of gastric cancer is similar in safety and efficacy to OTG. LATG has the advantages of less blood loss and faster postoperative recovery, at the expense of a longer operative time. PMID- 23980592 TI - Clipless minilaparoscopic cholecystectomy: a study of 1,096 cases. AB - PURPOSE: Low conversion rate, high safety, and good cosmetic result with less medical cost are chased by all laparoscopic surgeons. We used general laparoscopic instruments and combined with absorbable thread trying to perform a clipless minilaparoscopic cholecystectomy for benign gallbladder patients and got all the above-mentioned results. SUBJECTS AND METHODS: From January 2008 to February 2011, 1096 minilaparoscopic cholecystectomies were performed for patients with uncomplicated or complicated benign gallbladder disease by our treatment team. The three-port technique with the help of an electrocautery hook, forceps, and suction was applied for laparoscopy cholecystectomy, and the cystic duct and vessels were ligated by absorbable thread rather than hemostasis clips and Harmonic((r)) scalpels (Ethicon, Cincinnati, OH). The operative time, blood loss, subhepatic drain, conversion rate, drainage time, and hospital stay were reviewed and statistically analyzed. RESULTS: Our conversion rate was 0.18%, which was much lower than those reported by many studies. The mean operating time was 28 minutes (range, 11-70 minutes). Mean blood loss was 12 mL (range, 5-200 mL). A subhepatic drain was placed in 63 patients, with a mean drainage time of 1.7 days (range, 1-6 days). The mean postoperative hospital stay was 2.5 days (range, 2-7 days). No postoperative bleeding, biliary leakage, intraabdominal infection, umbilical site infection, umbilical incision herniation, biliary duct or bowel injury, or mortality occurred. CONCLUSIONS: Minilaparoscopic cholecystectomy using absorbable thread instead of clips and Harmonic scalpels offers a safe, effective, and economical surgical alternative for benign gallbladder patients. PMID- 23980593 TI - Reduction in absorption of gallium maltolate in adult horses following oral administration with food: chemistry and pharmacokinetics. AB - Gallium (Ga) is under study for the treatment of osteolytic disorders in equines. Previous studies indicate that oral gallium maltolate (GaM) would provide a higher bioavailability than oral Ga salts. However, oral administration to adult horses of 2 mg/kg of GaM, in the form of a solution mixed with food, did not lead to detectable Ga levels in plasma. Therefore, a study was performed to model the chemical behaviour of GaM in the digestive tract. The equilibrium formation constants for Ga(III) and maltol were calculated by means of UV-visible measurements and validated by 1H-NMR measurements at selected pH values. Data indicate that the dissociation of GaM in aqueous solutions is very rapid, while the re-association is slower. Based on these results, poor Ga absorption seems to be due to the equilibrium dissociation of GaM in the stomach and to its slow formation rate in the intestine. The concomitant presence of high concentrations of phytates (strong charged metal chelating agents, which represent about 1% of dry matter in vegetables) might also explain the low absorption of GaM by the gastrointestinal tract. Methods of optimizing Ga absorption after oral administration of GaM require further investigation. PMID- 23980589 TI - Prognostic significance of the interval between the initiation of antiretroviral therapy and the initiation of anti-tuberculosis treatment in HIV/tuberculosis coinfected patients: results from the TREAT Asia HIV Observational Database. AB - OBJECTIVES: We evaluated the effect of the time interval between the initiation of antiretroviral therapy (ART) and the initiation of tuberculosis (TB) treatment on clinical outcomes in HIV/TB-coinfected patients in an Asian regional cohort. METHODS: Adult HIV/TB-coinfected patients in an observational HIV-infected cohort database who had a known date of ART initiation and a history of TB treatment were eligible for study inclusion. The time interval between the initiation of ART and the initiation of TB treatment was categorized as follows: TB diagnosed while on ART, ART initiated <= 90 days after initiation of TB treatment ('early ART'), ART initiated > 90 days after initiation of TB treatment ('delayed ART'), and ART not started. Outcomes were assessed using survival analyses. RESULTS: A total of 768 HIV/TB-coinfected patients were included in this study. The median CD4 T-cell count at TB diagnosis was 100 [interquartile range (IQR) 40-208] cells/MUL. Treatment outcomes were not significantly different between the groups with early ART and delayed ART initiation. Kaplan-Meier analysis indicated that mortality was highest for those diagnosed with TB while on ART (3.77 deaths per 100 person-years), and the prognoses of other groups were not different (in deaths per 100 person-years: 2.12 for early ART, 1.46 for delayed ART, and 2.94 for ART not started). In a multivariate model, the interval between ART initiation and TB therapy initiation did not significantly impact all-cause mortality. CONCLUSIONS: A negative impact of delayed ART in patients coinfected with TB was not observed in this observational cohort of moderately to severely immunosuppressed patients. The broader impact of earlier ART initiation in actual clinical practice should be monitored more closely. PMID- 23980594 TI - The importance of multidisciplinary teamwork and team climate for relational coordination among teams delivering care to older patients. AB - AIM: To identify predictors of relational coordination among professionals delivering care to older patients. BACKGROUND: Relational coordination is known to enhance quality of care in hospitals. The underlying mechanisms, however, remain poorly understood. DESIGN: This cross-sectional study was part of a larger evaluation study examining the opportunity to prevent loss of function in older patients due to hospitalization in the Netherlands. METHODS: This study was performed in spring 2010 among team members delivering care to older hospitalized patients (192 respondents; 44% response rate) in one hospital. Relational coordination was measured by the Relational Coordination survey; team climate by the Team Climate Inventory and questions were asked about participation in multidisciplinary team meetings and disciplines represented in these meetings. To account for the hierarchical structure, a multilevel analysis was performed. RESULTS: Correlation analysis revealed a positive relationship among being female, being a nurse and relational coordination; medical specialists showed a negative relationship. The number of disciplines represented during multidisciplinary team meetings and team climate were positively related with relational coordination. The multilevel analysis showed a positive relationship between the number of disciplines represented during multidisciplinary team meetings and team climate with relational coordination. CONCLUSIONS: The enhancement of team climate and attendance of diverse professionals during multidisciplinary team meetings are expected to improve relational coordination. Furthermore, this study underscores the importance of enhancing relational coordination between medical specialists and other professionals. PMID- 23980596 TI - No correlation between multi-locus heterozygosity and fitness in the common buzzard despite heterozygote advantage for plumage colour. AB - Correlations between heterozygosity and fitness are frequently found but rarely well understood. Fitness can be affected by single loci of large effect which correlate with neutral markers via linkage disequilibrium, or as a result of variation in genome-wide heterozygosity following inbreeding. We explored these alternatives in the common buzzard, a raptor species in which three colour morphs differ in their lifetime reproductive success. Using 18 polymorphic microsatellite loci, we evaluated potential genetic differences among the morphs which may lead to subpopulation structuring and tested for correlations between three fitness-related traits and heterozygosity, both genome wide and at each locus separately. Despite their assortative mating pattern, the buzzard morphs were found to be genetically undifferentiated. Multilocus heterozygosity was only found to be correlated with a single fitness-related trait, infection with the blood parasite, Leucocytozoon buteonis, and this was via interactions with vole abundance and age. One locus also showed a significant relationship with blood parasite infection and ectoparasite infestation. The vicinity of this locus contains two genes, one of which is potentially implicated in the immune system of birds. We conclude that genome-wide heterozygosity is unlikely to be a major determinant of parasite burden and body condition in the polymorphic common buzzard. PMID- 23980604 TI - Generation of a phage-display library of single-domain camelid VH H antibodies directed against Chlamydomonas reinhardtii antigens, and characterization of VH Hs binding cell-surface antigens. AB - Single-domain antibodies (sdAbs) are powerful tools for the detection, quantification, purification and subcellular localization of proteins of interest in biological research. We have generated camelid (Lama pacos) heavy chain-only variable VH domain (VH H) libraries against antigens in total cell lysates from Chlamydomonas reinhardtii. The sdAbs in the sera from immunized animals and VH H antibody domains isolated from the library show specificity to C. reinhardtii and lack of reactivity to antigens from four other algae: Chlorella variabilis, Coccomyxa subellipsoidea, Nannochloropsis oceanica and Thalassiosira pseudonana. Antibodies were produced against a diverse representation of antigens as evidenced by sera ELISA and protein-blot analyses. A phage-display library consisting of the VH H region contained at least 10(6) individual transformants, and thus should represent a wide range of C. reinhardtii antigens. The utility of the phage library was demonstrated by using live C. reinhardtii cells to pan for VH H clones with specific recognition of cell-surface epitopes. The lead candidate VH H clones (designated B11 and H10) bound to C. reinhardtii with EC50 values <= 0.5 nm. Treatment of cells with VH H B11 fused to the mCherry or green fluorescent proteins allowed brilliant and specific staining of the C. reinhardtii cell wall and analysis of cell-wall genesis during cell division. Such high-complexity VH H antibody libraries for algae will be valuable tools for algal researchers and biotechnologists. PMID- 23980605 TI - Specific anion effect in water-nonaqueous solvent mixtures: interplay of the interactions between anion, solvent, and polymer. AB - Ethanol (EtOH) and dimethylsulfoxide (DMSO) are polar protic and aprotic organic solvents, respectively. In the present work, we have investigated the anion specific lower critical solution temperature (LCST) and upper critical solution temperature (UCST) behaviors of poly(N-isopropylacrylamide) (PNIPAM) in the H2O EtOH and H2O-DMSO mixtures. The turbidity and differential scanning calorimetry studies show that the LCST for the anions follows the Hofmeister series at the molar fraction of EtOH (xE) or DMSO (xD) of 6%. At xE of 26%, the UCST for the anions also follows the Hofmeister series because the dominating interactions for the UCST behavior are similar to that for the LCST behavior in the H2O-EtOH mixtures. In the H2O-DMSO mixture at xD of 70%, an inverted V-shaped anion series is observed for the UCST behavior of PNIPAM. Our studies demonstrate that the specific anion effect on the phase transition behaviors of PNIPAM is influenced not only by the anionic polarization of hydrogen bonding between solvent molecules and PNIPAM but also by the anion adsorption on the PNIPAM chain surface. PMID- 23980595 TI - Identification of a developmental gene expression signature, including HOX genes, for the normal human colonic crypt stem cell niche: overexpression of the signature parallels stem cell overpopulation during colon tumorigenesis. AB - Our goal was to identify a unique gene expression signature for human colonic stem cells (SCs). Accordingly, we determined the gene expression pattern for a known SC-enriched region--the crypt bottom. Colonic crypts and isolated crypt subsections (top, middle, and bottom) were purified from fresh, normal, human, surgical specimens. We then used an innovative strategy that used two-color microarrays (~18,500 genes) to compare gene expression in the crypt bottom with expression in the other crypt subsections (middle or top). Array results were validated by PCR and immunostaining. About 25% of genes analyzed were expressed in crypts: 88 preferentially in the bottom, 68 in the middle, and 131 in the top. Among genes upregulated in the bottom, ~30% were classified as growth and/or developmental genes including several in the PI3 kinase pathway, a six transmembrane protein STAMP1, and two homeobox (HOXA4, HOXD10) genes. qPCR and immunostaining validated that HOXA4 and HOXD10 are selectively expressed in the normal crypt bottom and are overexpressed in colon carcinomas (CRCs). Immunostaining showed that HOXA4 and HOXD10 are co-expressed with the SC markers CD166 and ALDH1 in cells at the normal crypt bottom, and the number of these co expressing cells is increased in CRCs. Thus, our findings show that these two HOX genes are selectively expressed in colonic SCs and that HOX overexpression in CRCs parallels the SC overpopulation that occurs during CRC development. Our study suggests that developmental genes play key roles in the maintenance of normal SCs and crypt renewal, and contribute to the SC overpopulation that drives colon tumorigenesis. PMID- 23980606 TI - Classification systems for stalking behavior. AB - Stalking is a complex behavioral phenomenon that is unique in that it necessarily involves a prolonged dyadic relationship between both a perpetrator and a victim. Since criminalization of stalking behavior in the 1990s, different conceptual typologies have attempted to classify this behavior to assess risk and aid in management decisions. The authors reviewed the current literature regarding the most recent and accepted stalking classification systems. The three predominant stalker typologies currently in use include Zona's stalker-victim types, Mullen's stalker typology, and the RECON stalker typology. Of these, the RECON classification system alone was developed in an attempt to separate stalkers into groups based on previously known risk factors for behaviorally based phenomenon such as propensity for violence. Understanding and simplifying these classification systems may enhance the potential that new research will lead to evidence-based management and treatment strategies in the stalking situation. PMID- 23980607 TI - A review of current therapies used in the treatment of congestive heart failure. AB - Congestive heart failure is the leading cause of hospitalizations for patients older than 65 years. There are almost 700,000 new cases of heart failure annually and re-hospitalization rates are as high as 50% within the first few months of initial discharge. These statistics translate to healthcare costs that nearly reached US$40 billion in 2010. Understanding the therapeutic agents that can not only help decrease mortality and morbidity but also decrease the rate of re hospitalizations is vital in the management of congestive heart failure. Here, the authors highlight the various classes of drugs used in the treatment of heart failure. They then provide a focused review examining the multiple clinical trials that have emphasized the evaluation of mortality, morbidity and hospitalization rates in heart failure patients who are receiving the different types of therapeutic agents. PMID- 23980608 TI - Mechanism study of copper-mediated one-pot reductive amination of aryl halides using trimethylsilyl azide. AB - Reaction mechanisms of the copper-mediated amination of aryl halides with trimethylsilyl azide (TMSN3) were analyzed on the basis of the time-course study using reaction monitoring FT-IR, trapping an intermediary aryl azide by the Huisgen reaction, and the analysis of the generated N2 gas during the reaction. This amination would proceed through multiple pathways via aryl radicals and copper(I) azide. PMID- 23980610 TI - Mixed aggregates of an alkyl lithium reagent and a chiral lithium amide derived from N-ethyl-O-triisopropylsilyl valinol. AB - The crystal structure of a mixed aggregate containing lithiated (S)-N-ethyl-3 methyl-1-(triisopropylsilyloxy)butan-2-amine derived from (S)-valinol and cyclopentyllithium is determined by X-ray diffraction. The mixed aggregate adopts a ladder structure in the solid state. The ladder-type mixed aggregate is also the major species in a toluene-d8 solution containing an approximately 1:1 molar ratio of the lithiated chiral amide to cyclopentyllithium. A variety of NMR experiments including diffusion-ordered NMR spectroscopy (DOSY) with diffusion coefficient-formula (D-FW) weight correlation analyses and other one- and two dimensional NMR techniques allowed us to characterize the complex in solution. Solution state structures of the mixed aggregates of n-butyl, sec-butyllithium, isopropyllithium with lithiated (S)-N-ethyl-3-methyl-1 (triisopropylsilyloxy)butan-2-amine are also reported. Identical dimeric, ladder type, mixed aggregates are the major species at a stoichiometric ratio of 1:1 lithium chiral amide to alkyllithium in toluene-d8 solution for all of the different alkyllithium reagents. PMID- 23980611 TI - Bronsted base catalyzed [2,3]-Wittig/phospha-Brook tandem rearrangement sequence. AB - A Bronsted base catalyzed rearrangement reaction of 2-allyloxy-2-phosphonoacetate derivatives was developed. This reaction proceeded via a [2,3]-Wittig rearrangement followed by a phospha-Brook rearrangement. This is the first example of a catalytic [2,3]-Wittig rearrangement initiated by a Bronsted base. PMID- 23980609 TI - Mechanical ventilation causes pulmonary mitochondrial dysfunction and delayed alveolarization in neonatal mice. AB - Hyperoxia inhibits pulmonary bioenergetics, causing delayed alveolarization in mice. We hypothesized that mechanical ventilation (MV) also causes a failure of bioenergetics to support alveolarization. To test this hypothesis, neonatal mice were ventilated with room air for 8 hours (prolonged) or for 2 hours (brief) with 15 MUl/g (aggressive) tidal volume (Tv), or for 8 hours with 8 MUl/g (gentle) Tv. After 24 hours or 10 days of recovery, lung mitochondria were examined for adenosine diphosphate (ADP)-phosphorylating respiration, using complex I (C-I) dependent, complex II (C-II)-dependent, or cytochrome C oxidase (C-IV)-dependent substrates, ATP production rate, and the activity of C-I and C-II. A separate cohort of mice was exposed to 2,4-dinitrophenol (DNP), a known uncoupler of oxidative phosphorylation. At 10 days of recovery, pulmonary alveolarization and the expression of vascular endothelial growth factor (VEGF) were assessed. Sham operated littermates were used as control mice. At 24 hours after aggressive MV, mitochondrial ATP production rates and the activity of C-I and C-II were significantly decreased compared with control mice. However, at 10 days of recovery, only mice exposed to prolonged-aggressive MV continued to exhibit significantly depressed mitochondrial respiration. This was associated with significantly poorer alveolarization and VEGF expression. In contrast, mice exposed to brief-aggressive or prolonged-gentle MV exhibited restored mitochondrial ADP-phosphorylation, normal alveolarization and pulmonary VEGF content. Exposure to DNP fully replicated the phenotype consistent with alveolar developmental arrest. Our data suggest that the failure of bioenergetics to support normal lung development caused by aggressive and prolonged ventilation should be considered a fundamental mechanism for the development of bronchopulmonary dysplasia in premature neonates. PMID- 23980612 TI - Conceptions of mental health care--from the perspective of parents' of adult children suffering from mental illness. AB - The aim of this study was to describe parents' conceptions of the mental health care provided to adult children suffering from mental illness. Data were collected using qualitative research interviews with a purposive sample of sixteen mothers and ten fathers. Phenomenographic analysis was used to identify conceptions and formulate descriptive categories. The first category, questioning the availability of care, describes mental health care as being unequal in terms of accessibility and lacking in continuity. The second category, disapproval of parental exclusion, illustrates conceptions that mental healthcare professionals disregard parents and do not provide them with adequate information. The third category, questioning the quality of care, encompasses conceptions of lack of trust in the professionals' competence, an unsatisfactory environment as well as inadequate cooperation with other healthcare providers and authorities. Positive aspects, such as being seen and confirmed, were mentioned as valuable by the parents. PMID- 23980613 TI - Narrative means to preventative ends: a narrative engagement framework for designing prevention interventions. AB - This article describes a Narrative Engagement Framework (NEF) for guiding communication-based prevention efforts. This framework suggests that personal narratives have distinctive capabilities in prevention. The article discusses the concept of narrative, links narrative to prevention, and discusses the central role of youth in developing narrative interventions. As illustration, the authors describe how the NEF is applied in the keepin' it REAL adolescent drug prevention curriculum, pose theoretical directions, and offer suggestions for future work in prevention communication. PMID- 23980614 TI - A comparison of sagittal short T1 inversion recovery and T2-weighted FSE sequences for detection of multiple sclerosis spinal cord lesions. AB - PURPOSE: Multiple sclerosis (MS) is the most common disabling CNS disease of young adults. MRI is routinely used for the detection of MS plaques in the brain and spinal cord. A significant portion of patients with MS demonstrates spinal cord lesions at the time of initial workup, and these lesions are an important part of the McDonald criteria for diagnosis. However, whereas brain imaging sequences are now fairly standardized, there continues to be debate about the optimal sequences for imaging the spinal cord. The short T1 inversion recovery (STIR) sequence has been shown in the current literature to improve lesion detection with its additive T1/T2 weighting, but current spinal cord imaging protocols from the Consortium on MS Center Consensus Guidelines do not include the STIR sequence. We demonstrate that not only do STIR sequences improve lesion detection when compared directly with conventional T2-weighted sequences, but that they also significantly improve lesion conspicuity, facilitating earlier positive diagnosis and management. MATERIALS AND METHODS: Dedicated MR spinal cord imaging of twenty-nine sequential patients with clinically confirmed multiple sclerosis was retrospectively analyzed by two independent neuroradiologists in a novel study design. Sagittal T2-weighted and STIR sequence images from the same study for each patient were examined for MS plaques using a double-blinded review of individual images 'separated in time and space', such that STIR and T2 image pairs were never analyzed simultaneously. Number of lesions and lesion conspicuity for each lesion, using a subjective scale (1-5), were tallied for each sequence. Averages for each observer were compared using a paired t-test analysis for statistical significance, and assessment of inter rater agreement was assessed using Cohen's kappa index. RESULTS: Significantly, more MS lesions were detected on STIR than on T2-weighted sequences for both observers (P = 0.001 and P = 0.005). In seven patients, the conventional T2 sequence detected no lesions at all, whereas STIR sequences showed significant cord involvement. Lesion conspicuity was also significantly better on STIR for both observers (P < 0.0005). This improved conspicuity leads to more uniform lesion detection. On the conventional T2-weighted sequence, there was a statistically significant difference in the number of lesions detected between the two observers (P = 0.003), but there was no statistically significant difference on STIR (P = 0.43). The kappa index showed greater interobserver agreement in both lesion count and lesion conspicuity on the STIR sequence as compared with T2. CONCLUSIONS: Short T1 inversion recovery sequence imaging not only significantly improves detection of MS lesions within the spinal cord, but also provides better contrast and conspicuity of visible lesions, creating a more confident diagnostic measure of MS extent and progression. Short T1 inversion recovery sequences of the spinal cord should be routinely obtained during initial and routine follow-up of MS. PMID- 23980615 TI - Molecular dynamics simulations of liquid phase interfaces: understanding the structure of the glycerol/water-dodecane system. AB - Modern spectroscopic techniques such as time-resolved second-harmonic-generation spectroscopy allow molecules to be examined selectively directly at phase interfaces. Two-phase systems formed by glycerol/water and alkane layers have previously been studied by time-resolved second-harmonic-generation spectroscopic measurements. In this molecular dynamics study, a triphenylmethane dye was inserted at the glycerol/water-alkane interface and was used as a probe for local properties such as viscosity. We now show how extensive simulations over a wide range of concentrations can be used to obtain a detailed view of the molecular structure at the glycerol/water-alkane interface. Glycerol is accumulated in a double layer adjacent to the alkane interface, which results in increased viscosity of the glycerol/water phase in the direct vicinity of the interface. We also show that conformational ensembles created by classical molecular-dynamics simulations can serve as input for QM/MM calculations, yielding further information such as transition dipoles, which can be compared with spectroscopic measurements. PMID- 23980616 TI - Effect modification of body mass index and body fat percentage on fatty liver disease in a Japanese population. AB - BACKGROUND AND AIM: No previous study has performed multivariate analysis of the risk factors of fatty liver disease (FL), focusing on the effect of weight gain of >= 10 kg since the age of 20, and no analysis model exists that simultaneously evaluates body mass index (BMI) and body fat percentage (BFP) as adjustment variables. METHODS: To investigate these, we collected anthropometric data from health checkups, and conducted a cross-sectional study (targeting 1851 males and 1259 females aged 30 years or over). RESULTS: Regardless of sex, weight gain of >=10 kg since the age of 20 was positively associated with FL. Our stratified analysis of BFP into two categories, to evaluate the interaction between BMI and BFP in FL, indicated an approximately fivefold increase in the odds ratio in the male group with high BMI and BFP values compared to those with low BMI and BFP values, with a synergy index of 1.77 > 1. On the other hand, females demonstrated no significant additive interaction, with a synergy index of 0.49 < 1. CONCLUSIONS: We revealed that weight gain >= 10 kg since the age of 20 is significantly associated with FL regardless of sex. In addition, by performing a synergy index (S), we showed that the additive interaction between BMI and BFP in FL differs according to gender. PMID- 23980617 TI - Discrimination of RNA from DNA by polynucleotide phosphorylase. AB - Polynucleotide phosphorylase (PNPase) plays synthetic and degradative roles in bacterial RNA metabolism; it is also thought to participate in bacterial DNA transactions. Here we used chimeric polynucleotides, composed of alternating RNA and DNA tracts, to analyze whether and how Mycobacterium smegmatis PNPase discriminates RNA from DNA during the 3'-phosphorolysis reaction. We find that a kinetic block to 3'-phosphorolysis of a DNA tract within an RNA polynucleotide is exerted when resection has progressed to the point that a 3'-monoribonucleotide flanks the impeding DNA segment. The position of the pause one nucleotide before the first deoxynucleotide encountered is independent of DNA tract length. However, the duration of the pause is affected by DNA tract length, being transient for a single deoxynucleotide and durable when two or more consecutive deoxynucleotides are encountered. Substituting manganese for magnesium as the metal cofactor allows PNPase to "nibble" into the DNA tract. A 3'-phosphate group prevents RNA phosphorolysis when the metal cofactor is magnesium. With manganese, PNPase can resect an RNA 3'-phosphate end, albeit 80-fold slower than a 3'-OH. We discuss the findings in light of the available structures of PNPase and the archaeal exosome.RNA.phosphate complex and propose a model for catalysis whereby the metal cofactor interacts with the scissile phosphodiester and the penultimate ribose. PMID- 23980618 TI - Bipolar II disorder is associated with thinning of prefrontal and temporal cortices involved in affect regulation. AB - OBJECTIVES: The neurobiological substrate of bipolar II disorder (BD-II) remains largely unknown. A few previous studies have found evidence for cerebral cortical thinning in mixed samples of BD-II and bipolar I disorder patients; however, no study of cortical thickness or surface area has been limited to BD-II. In the present study, we compared magnetic resonance imaging (MRI)-based indices of cortical thickness and surface area between individuals with BD-II and healthy controls. METHODS: Thirty-six individuals with a DSM-IV diagnosis of BD-II and 42 controls underwent 3T MRI. Comparisons of thickness and relative surface areal expansion across the cerebral cortical mantle were performed using Freesurfer. RESULTS: Individuals with BD-II showed significant thinning in two prefrontal clusters primarily comprising the left subgenual anterior cingulate cortex, left perigenual ventromedial prefrontal cortex (PFC), bilateral dorsomedial PFC, and bilateral dorsolateral PFC (p < 0.0002 for both clusters, cluster size corrected) and in a left temporal cluster involving the superior, middle, and inferior temporal gyrus (p = 0.006, cluster size corrected). No group differences in cortical surface area were found. No significant effect of medication, mood state, illness duration, or family history of bipolar disorders on cortical thinning was observed. CONCLUSIONS: These results indicate that BD-II is associated with thinning of prefrontal and temporal cortices implicated in the expression and regulation of negative and positive affect. Longitudinal studies are needed to clarify whether cortical thinning is a stable trait of BD-II, an illness effect that might progress during the course of the disease, or a combination of the two. PMID- 23980619 TI - Vulnerability to opiate intake in maternally deprived rats: implication of MeCP2 and of histone acetylation. AB - We previously showed that maternal deprivation predisposes male rats to anxiety, accompanied with an increase in their opiate consumption. In the present report, we searched for brain epigenetic mechanisms that possibly underlie this increase. For that, we examined the expression of the methyl-CpG-binding protein MeCP2 and of the histone deacetylases HDAC2 and HDAC3, as well as the acetylation status of histone H3 and H4 in mesolimbic structures of adult maternally deprived rats, using immunohistochemistry and Western blot analysis. A long-lasting increase in MeCP2 expression was found throughout the striatum of deprived rats. Enhanced HDAC2 expression and increased nuclear HDAC activity in the nucleus accumbens of deprived rats were associated with lower acetylation levels of histone H3 and H4. Treatment for 3 weeks with the HDAC inhibitor sodium valproate abolished HDAC activation together with the decrease in the acetylation levels of histone H4, and was accompanied with normalized oral morphine consumption. The data indicate that epigenetic mechanisms induced by early adverse environment memorize life experience to trigger greater opiate vulnerability during adult life. They suggest that sodium valproate may lessen vulnerability to opiate intake, particularly in subgroups of individuals subjected to adverse postnatal environments. PMID- 23980620 TI - A randomized clinical trial comparing metabolic parameters after 48 weeks of standard- and low-dose stavudine therapy and tenofovir disoproxil fumarate therapy in HIV-infected South African patients. AB - OBJECTIVES: Low-dose stavudine therapy may have a lower toxicity profile compared with standard dose. A randomized controlled trial comparing these two doses of stavudine with tenofovir disoproxil fumarate (tenofovir DF) was performed to assess the effects on anthropometry, markers of inflammation, and lipid and glucose metabolism in Black South African patients. METHODS: Sixty patients were randomized 1:1:1 to either standard-dose (30-40 mg) or low-dose (20-30 mg) stavudine or tenofovir DF (300 mg), each combined with lamivudine and efavirenz, for 48 weeks. Anthropometry, markers of inflammation, and lipid and glucose metabolism were assessed using standard techniques. RESULTS: In all three treatment arms, there was a significant increase in lipid levels over the study period. At 48 weeks, fasting glucose level (P < 0.005) and homeostasis model assessment (HOMA) score (P < 0.05) increased significantly in the standard-dose stavudine arm, as did insulin and C-peptide levels in both the standard- and low dose stavudine arms. At week 48, a significant decrease (P < 0.05) in adiponectin was noted in the standard-dose stavudine arm, but there was an increase (P < 0.005) in the tenofovir DF arm. In both the stavudine arms, significant increases in anthropometric measures occurred at 24 weeks but these decreased by week 48. Mitochondrial toxicities occurred in both the stavudine arms. Immunological and virological outcomes were similar for all three arms. CONCLUSIONS: This study highlights the occurrence of metabolic abnormalities with both stavudine and tenofovir DF treatment. Awareness of the potential increased cardiovascular risk should be of concern with the use of both these therapies. PMID- 23980621 TI - Acute adverse events associated with ventral slot decompression in 546 dogs with cervical intervertebral disc disease. AB - OBJECTIVE: To report the frequency, types, and risk factors for acute perioperative adverse events (AEs) in dogs that had ventral slot decompression (VSD) for cervical intervertebral disc disease (IVDD). DESIGN: Retrospective, case-control study. ANIMALS: Dogs (n = 546) with cervical IVDD treated by VSD; 54 cases experiencing AE and 492 controls. METHODS: Historical, clinical, diagnostic, operative, and outcome data were collected. AE were graded using a Spine Adverse Events Severity (SAVES) system. Associations between the development of AE and hypothesized risk factors were analyzed using bi- and multi variable analyses. RESULTS: AE were observed in 54 dogs (9.9%). Minor AE (SAVES Grade 1-2) occurred in 3.5% (19 dogs) and major (SAVES Grades 3-5) AE in 6.4% (35 dogs). Deterioration in neurologic status (n = 13), persistent pain (12), and intraoperative hemorrhage (7) were common major AE. NSAID administration, surgeon experience, C7-T1 disc location, and intraoperative hypotension were significantly associated with AE in multivariate analyses. Improvement of AE occurred in 48/54 (88.9%) of cases, although reoperative neurosurgery was required in 48.5% (17/35) of dogs experiencing major AE. Dogs with major AE had significantly longer hospitalization and worse outcomes than dogs with minor AE or controls. No fatal AE occurred, although 0.7% (4/546) of dogs were euthanatized postoperatively. CONCLUSIONS: AE occurred in 9.9% of dogs that had VSD, and were significantly associated with perioperative hypotension, C7-T1 disc extrusions, surgeon experience, and NSAID usage. Identification of a major postoperative AE is an indication for immediate diagnostic imaging studies, as 50% of dogs experiencing major AE required reoperation. PMID- 23980622 TI - Clinical significance of plasma fibrinogen level as a predictive marker for postoperative recurrence of esophageal squamous cell carcinoma in patients receiving neoadjuvant treatment. AB - Among multidisciplinary therapies developed for advanced esophageal cancer, neoadjuvant chemotherapy and chemoradiotherapy have been established as standard treatments. To deliver cautious follow up and intense treatment for high-risk patients, a simple and instructive biomarker for the postoperative recurrence needs to be identified. Fibrinogen, a common component of hemostasis, has been suggested to not only play an important role in cancer metastasis, but also correlate with tumor recurrence. We aim to clarify the validity of plasma fibrinogen as a marker for predicting the postoperative recurrence of esophageal squamous cell carcinoma patients who received neoadjuvant treatment. We reviewed 72 consecutive patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy or chemoradiotherapy, followed by esophagectomy at the Keio University Hospital from 2001 to 2010. Of them, we retrospectively examined 68 patients who underwent plasma fibrinogen examination before and after neoadjuvant treatment and underwent transthoracic radical esophagectomy. We investigated patient characteristics, clinicopathological factors, neoadjuvant treatment effects, postoperative course, and plasma fibrinogen levels. We investigated pretreatment and preoperative (postneoadjuvant treatment) plasma fibrinogen levels, as well as changes in fibrinogen levels before and after neoadjuvant treatment. Patients with preoperative hyperfibrinogenemia (>350 mg/dL) and patients with increased plasma fibrinogen levels during neoadjuvant treatment showed significantly shorter postoperative disease-free survival (DFS) (P = 0.002 and P = 0.037, respectively). Moreover, we classified these patients into three classes on the basis of their preoperative fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment. Patients who had both high preoperative plasma fibrinogen and increased fibrinogen levels showed significantly shorter DFS than others. In contrast, patients who had normal preoperative plasma fibrinogen and decreased fibrinogen levels showed significantly longer DFS. Based on this fibrinogen classification, we could differentiate between significantly favorable and poor prognosis patients group. Overall, this classification (hazard ratio = 1.812, P = 0.013) and the response to neoadjuvant treatment (hazard ratio = 0.350, P = 0.007) were found to be significant determining factors for postoperative DFS. With the validity of preoperative plasma fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment, the plasma fibrinogen level was found to be a possible biomarker for postoperative recurrence in advanced esophageal cancer patients who received neoadjuvant treatment. Moreover, plasma fibrinogen classification could be a simple and valuable predictive marker for postoperative follow up. PMID- 23980624 TI - Effects of eight vehicles on transdermal lidocaine penetration in sheep skin in vitro. AB - This study investigated the effects of vehicles on penetration and retention of lidocaine applied to sheep skin in vitro. Thoracic skin from two sheep was clipped of wool and stored at -20 degrees C, until used. Skin samples were defrosted and mounted in Franz-type diffusion cells, and then one of the following formulations, each saturated with lidocaine, was added: sodium lauryl sulphate (SLS) 0.5% in water, SLS 1% in water, dimethyl sulphoxide (DMSO) 50% in water (wt/wt), DMSO 100%, isopropyl myristate 100% (IPM), water alone, diethylene glycol monoethyl ether (DGME) 50% in water (wt/wt) and DGME 100%. The penetration of lidocaine in each skin sample was measured over 8 h. Significantly greater lidocaine skin concentrations and flux (J(SS)) were achieved with the nonaqueous vehicles, DMSO 100% (P < 0.00001 and P < 0.01, respectively), followed by DGME 100% and IPM (P < 0.00001 and P < 0.01, respectively). The lag time (t(lag)) for lidocaine penetration in the DMSO 100% vehicle was significantly shorter (P < 0.01) compared with all other vehicles except water. Improved transdermal penetration of lidocaine in the DMSO 100% vehicle was likely due to skin barrier disruption, as determined by differences in pre- and post-treatment transepidermal water loss (TEWL). This study has shown that nonaqueous vehicles enhanced penetration of lidocaine in sheep skin to a greater extent than aqueous vehicles, which has implications for topically applied local anaesthesia in sheep. PMID- 23980623 TI - Distinct Ca2+ channels maintain a high motility state of the sperm that may be needed for penetration of egg jelly of the newt, Cynops pyrrhogaster. AB - Activation state of sperm motility named "hyperactivation" enables mammalian sperm to progress through the oviductal matrix, although a similar state of sperm motility is unknown in non-mammalian vertebrates at fertilization. Here, we found a high motility state of the sperm in the newt Cynops pyrrhogaster. It was predominantly caused in egg jelly extract (JE) and characterized by a high wave velocity of the undulating membrane (UM) that was significantly higher at the posterior midpiece. An insemination assay suggested that the high motility state might be needed for sperm to penetrate the egg jelly, which is the accumulated oviductal matrix. Specific characteristics of the high motility state were completely abrogated by a high concentration of verapamil, which blocks the L type and T-type voltage-dependent Ca(2+) channels (VDCCs). Mibefradil, a dominant blocker of T-type VDCCs, suppressed the wave of the UM at the posterior midpiece with separate wave propagation from both the anterior midpiece and the posterior principal piece. In addition, nitrendipine, a dominant L-type VDCC blocker, weakened the wave of the UM, especially in the anterior midpiece. Live Ca(2+) imaging showed that, compared with the intact sperm in the JE, the relative intracellular Ca(2+) level changed especially in the anterior and posterior ends of the midpiece of the blocker-treated sperm. These suggest that different types of Ca(2+) channels mediate the intracellular Ca(2+) level predominantly in the anterior and posterior ends of the midpiece to maintain the high motility state of the newt sperm. PMID- 23980625 TI - miR172 regulates soybean nodulation. AB - Micro-RNAs (miRNAs) play a pivotal role in the control of gene expression and regulate plant developmental processes. miRNA 172 (miR172) is a conserved miRNA in plants reported to control the expression of genes involved in developmental phase transition, floral organ identity, and flowering time. However, the specific role of miR172 in legume nodulation is undefined. Ectopic expression of soybean miR172 resulted in an increase in nodule numbers in transgenic roots and an increase in the expression of both symbiotic leghemoglobin and nonsymbiotic hemoglobin. These nodules showed higher levels of nitrogenase activity. Further analysis revealed a complex regulatory circuit in which miR156 regulates miR172 expression and controls the level of an AP2 transcription factor. The latter, either directly or indirectly, controls the expression of nonsymbiotic hemoglobin, which is essential for regulating the levels of nodulation. PMID- 23980626 TI - Iron, oxidative stress, and virulence: roles of iron-sensitive transcription factor Sre1 and the redox sensor ChAp1 in the maize pathogen Cochliobolus heterostrophus. AB - The gene SRE1, encoding the GATA transcription factor siderophore biosynthesis repressor (Sre1), was identified in the genome of the maize pathogen Cochliobolus heterostrophus and deleted. Mutants were altered in sensitivity to iron, oxidative stress, and virulence to the host. To gain insight into mechanisms of this combined regulation, genetic interactions among SRE1 (the nonribosomal peptide synthetase encoding gene NPS6, which is responsible for extracellular siderophore biosynthesis) and ChAP1 (encoding a transcription factor regulating redox homeostasis) were studied. To identify members of the Sre1 regulon, expression of candidate iron and oxidative stress-related genes was assessed in wild-type (WT) and sre1 mutants using quantitative reverse-transcription polymerase chain reaction. In sre1 mutants, NPS6 and NPS2 genes, responsible for siderophore biosynthesis, were derepressed under iron replete conditions, whereas the high-affinity reductive iron uptake pathway associated gene, FTR1, was not, in contrast to outcomes with other well-studied fungal models. C. heterostrophus L-ornithine-N(5)- monooxygenase (SIDA2), ATP-binding cassette (ABC6), catalase (CAT1), and superoxide dismutase (SOD1) genes were also derepressed under iron replete conditions in sre1 mutants. Chap1nps6 double mutants were more sensitive to oxidative stress than either Chap1 or nps6 single mutants, while Chap1sre1 double mutants showed a modest increase in resistance compared with single Chap1 mutants but were much more sensitive than sre1 mutants. These findings suggest that the NPS6 siderophore indirectly contributes to redox homeostasis via iron sequestration, while Sre1 misregulation may render cells more sensitive to oxidative stress. The double-mutant phenotypes are consistent with a model in which iron sequestration by NPS6 defends the pathogen against oxidative stress. C. heterostrophus sre1, nps6, Chap1, Chap1nps6, and Chap1sre1 mutants are all reduced in virulence toward the host, compared with the WT. PMID- 23980627 TI - Novel biomarkers for heart failure. AB - Heart failure (HF) has proven to be a major burden on the health system. The continuing prevalence of the condition and its rising associated costs and care, has amplified the need for earlier diagnosis, better risk stratification and cost effective treatment to cut rates of hospitalization. Biomarkers seem poised to undertake such tasks, with biomarker management of patients with HF quickly evolving over the past several years. Biomarker guided diagnosis and treatment has become vital, especially during the acute setting in which the majority of patients with HF, were initially present. An adequate assessment of risk requires a multi-marker approach to a given HF patient. Established markers including brain natriuretic peptide and NT-proBNP are a significant clinical aid to physicians, though their utility is limited. In the past few years, momentous effort has been put into the discovery of new biomarkers. These endeavors have led to the emergence of several capable and promising biomarkers for HF management including troponins, mid-regional pro-adrenomedullin, GDF-15, C reactive protein, Galectin-3, IL-6, ST-2, neutrophil gelatinase-associated lipocalin, copeptin and procalcitonin. This review will offer an insight into the novel biomarkers considered as the cutting-edge in the diagnosis and management of HF. PMID- 23980628 TI - Multicoloured greenbeards, bacteriocin diversity and the rock-paper-scissors game. AB - Greenbeard genes identify copies of themselves in other individuals and cause their bearer to behave nepotistically towards those individuals. Bacterial toxins (bacteriocins) exemplify the greenbeard effect because producer strains carry closely linked genes for immunity, such that toxicity is limited to nonproducer strains. Bacteriocin producers can be maintained in a dynamic polymorphism, known as rock-paper-scissors (RPS) dynamics, with immune and susceptible strains. However, it is unclear whether and how such dynamics will be maintained in the presence of multiple toxin types (multiple beard 'colours'). Here, we analyse strain dynamics using models of recurrent patch colonization and population growth. We find that (i) polymorphism is promoted by a small number of founding lineages per patch, strong local resource competition and the occurrence of mutations; (ii) polymorphism can be static or dynamic, depending on the intensity of local interactions and the costs of toxins and immunity; (iii) the occurrence of multiple toxins can promote RPS dynamics; and (iv) strain diversity can be maintained even when toxins differ in toxicity or lineages can exhibit multitoxicity/multi-immunity. Overall, the factors that maintain simple RPS dynamics can also promote the coexistence of multiple toxin types (multiple beard colours), thus helping to explain the remarkable levels of bacteriocin diversity in nature. More generally, we contrast these results with the maintenance of marker diversity in genetic kin recognition. PMID- 23980629 TI - Genealogy as a critical toolbox: deconstructing the professional identity of nurses. AB - AIM: To discuss the Foucauldian concept of genealogy as a framework for understanding and transforming nurses' professional identity. BACKGROUND: The professional identity of nurses has primarily been defined by personal and interpersonal attributes and by the intradisciplinary dimensions of nursing, leading to its conceptualization as a universal, monolithic phenomenon. The Foucauldian genealogical perspective offers a critical lens to examine what constitutes this professional identity; Spanish nursing offers a historical case study of an active effort to impose an identity that fits the monolithic ideal. DATA SOURCES: Five of the 33 professional conduct manuals for nurses' training published from 1956-1976 during the Franco dictatorship in Spain and six interviews with nursing instructors or students at the time were analysed using a theoretical framework drawn from Foucault's writing. DISCUSSION: Foucault's genealogical framework considers practices of normalization and resistance as a means of understanding knowledge continuities and discontinuities, clarifying practices that constitute nurses' professional identity in a particular way in specific contexts and analysing the implications of this theoretical frame. IMPLICATIONS FOR NURSING: The genealogy concept offers valuable tools to determine how professional identities are constituted, questions assumptions about the profession and its professionals and envisions alternative approaches. This theoretical approach helps both scholars and practitioners understand, question and transform their practices as needed. CONCLUSION: The genealogical approach prioritizes analysis of the phenomenon over its description and challenges many unknown, forgotten, excluded and/or unquestioned aspects of identity from a position of diversity and complexity. PMID- 23980630 TI - Perspectives and future directions of human pluripotent stem cell-based therapies: lessons from Geron's clinical trial for spinal cord injury. AB - Halting the first clinical trial on the use of embryonic stem cell derivatives for spinal cord injury resulted in disappointment and created concerns about the future use of pluripotent stem cell-based therapy in the treatment of human diseases. This article presents reflections and concerns related to the halted embryonic stem cell-based clinical trial and discusses some important and controversial issues for achieving safe and successful cell therapy. This manuscript highlights two important points for successful translation of pluripotent stem cell-based therapy in clinics: (i) reproducible xeno-free growth and differentiation of pluripotent stem cells in good manufacturing practice conditions as the prerequisites to ensure a defined and controlled cell source and (ii) extensive studies in small and large animal models and comprehensive basic studies to determine any adverse or toxic effects of transplanted cells, especially teratoma formation, in addition to improving surgical procedure and cell delivery system. PMID- 23980631 TI - One-step preparation of O-(alpha-bromoacyl) cyanohydrins by minor enantiomer recycling: synthesis of 4-amino-2(5H)-furanones. AB - O-(alpha-Bromoacyl) cyanohydrins were prepared in a single step from a range of different aldehydes in combination with alpha-bromoacyl cyanides. By the use of a cyclic procedure where the two minor diastereoisomers from a chiral Lewis acid catalyzed reaction undergo Candida antarctica lipase B (CALB)-catalyzed hydrolysis followed by dehydrocyanation to regenerate the starting material, the products were obtained in good to high yields and in most cases with excellent diastereoselectivites. The synthetic importance of these compounds was demonstrated by the synthesis of 4-amino-2(5H)-furanones, a class of compounds that have shown both biological activity and utility as synthetic intermediates. This transformation was achieved by an intramolecular Blaise reaction, which gave the products in high to excellent yields and enantiomeric ratios. PMID- 23980632 TI - Thermal modifications of root transparency and implications for aging: a pilot study. AB - Root transparency has proven to be related to age and has been considered by different odontological methods for age estimation. Very little is known concerning possible variations of root transparency with heat, although the applicability of the method to burnt remains depends on the possible modifications of this specific variable. This pilot study presents the results of an experiment performed on 105 teeth obtained from dental patients and autopsy material, heated in an industrial oven at 50 degrees C, 100 degrees C, 150 degrees C and 200 degrees C. Root transparency was measured before and after the charring experiment. The heating process proved to radically modify root transparency, which decreased in 20% of samples at 50 degrees C, in 34.6% at 100 degrees C, in 50% at 150 degrees C, in 77% at 200 degrees C. The overall correlation index (CI) between decrease in root transparency and increase in temperature amounted to 0.96. These results show that heat may modify root transparency and suggest caution in using methods based on root transparency for age estimation. PMID- 23980633 TI - Biomineralization of hydroxyapatite on DNA molecules in SBF: morphological features and computer simulation. AB - The hydroxyapatite (HA) formation on the DNA molecules in SBF was examined. After immersion for four weeks in SBF at 36.5 degrees C, the HA crystallites of ~1-14 MUm in diameter grew on the surface of DNA molecules. Various morphologies were successfully observed through scanning electron microscopy analysis. The Ca/P mol ratio (1.1-1.5) in HA was estimated by energy dispersive X-ray analysis. Original peaks of both of DNA and HA were characterized by Fourier transform infrared spectroscopy. The molecular orbital computer simulation has been used to probe the interaction of DNA with two charge-balancing ions, i.e., CaOH(+) and CaH2PO4(+). The adsorption enthalpy of the two ions on ds-DNA and/or ss-DNA having large negative value (~ -60 kcal/mol per charge-balancing ion) was the evidence for the interface in mineralization of HA in SBF. PMID- 23980634 TI - Ventral onlay buccal mucosa urethroplasty: a 10-year experience. AB - OBJECTIVE: To report our experience, and to evaluate the long-term outcomes and complication profiles of ventral onlay buccal mucosal graft urethroplasty (BMU) after prior urological intervention. METHODS: We retrospectively reviewed 114 consecutive patients between February 2001 and April 2009 who underwent buccal mucosal graft urethroplasty for recurrent anterior urethral stricture disease. Seven patients were excluded for incomplete data. The remaining 107 patients comprised the study cohort. The mean follow-up time was 39.3 months (range 6.6 127.3 months). All patients had prior urological attempts at operative management. RESULTS: The mean stricture length was 3.14 cm (range 1.0-8.0 cm). Indications for buccal mucosal graft urethroplasty included: lichen sclerosis (2.8%), iatrogenic (24.3%), infection (4.7%) and perineal trauma/straddle injury (20.6%). Of these patients, 78 had bulbo-membranous stricture disease, 20 had penile involvement and nine were multifocal strictures. The average number of prior urological procedures was 2.83 (range 1-9). The overall graft failure rate was 6.5%. Importantly, the re-operation rate was 20.6%, primarily for stricture recurrence (18), meatal stenosis (3) and urethral diverticulum. The mean time to complication was 10.8 months. CONCLUSIONS: Ventral onlay buccal mucosal graft urethroplasty offers satisfactory results in the setting of recurrent and complicated urethral stricture disease. Graft failures and complications generally occur within the first year after surgery. Bulbar strictures enjoy greater graft patency and lower complication rates than other stricture locations. In particular, guarded expectations should be given for stricture length >4 cm and multifocal disease. PMID- 23980635 TI - Predictors of executive complaints and executive deficits in multiple sclerosis. AB - OBJECTIVES: To investigate executive complaints and objective executive deficits and their relations to both depression and neurological function in multiple sclerosis (MS). MATERIALS AND METHODS: One hundred and twenty MS patients participating in multidisciplinary rehabilitation underwent assessment with the Expanded Disability Status Scale (EDSS), neuropsychological tests of executive function, self-report measures of executive function (BRIEF-A), and depression (BDI-II). RESULTS: Multivariate regression analysis showed that moderate depression and above (BDI-II > 20) significantly predicted a high degree of subjective executive complaints. Multivariate regression analysis showed that EDSS scores above 4.3 significantly predicted executive cognitive deficit, measured by neuropsychological tests. CONCLUSION: Among the study variables, depression was the strongest predictor of executive complaints. A high degree of neurological disability was the strongest predictor for executive deficit, measured by neuropsychological tests. PMID- 23980636 TI - Correlational selection does not explain the evolution of a behavioural syndrome. AB - Correlated suites of behaviours, or behavioural syndromes, appear to be widespread, and yet few studies have explored how they arise and are maintained. One possibility holds that correlational selection can generate and maintain behavioural syndrome if certain behavioural combinations enjoy greater fitness than other combinations. Here we test this correlational selection hypothesis by comparing behavioural syndrome structure with a multivariate fitness surface based on reproductive success of male water striders. We measured the structure of a behavioural syndrome including dispersal ability, exploration behaviour, latency to remount and sex recognition sensitivity in males. We then measured the relationship between these behaviours and mating success in a range of sex ratio environments. Despite the presence of some significant correlational selection, behavioural syndrome structure was not associated with correlational selection on behaviours. Although we cannot conclusively reject the correlational selection hypothesis, our evidence suggests that correlational selection and resulting linkage disequilibrium might not be responsible for maintaining the strong correlations between behaviours. Instead, we suggest alternative ways in which this behavioural syndrome may have arisen and outline the need for physiological and quantitative genetic tests of these suggestions. PMID- 23980638 TI - Tunable visible light emission of self-assembled rhomboidal metallacycles. AB - Supramolecular coordination complexes (SCCs) have been proposed for applications necessitating photon emitting properties; however, two critical characteristics, facile tunability and high emission quantum yields, have yet to be demonstrated on SCC platforms. Herein, a series of functionalized D2h [D2A2] rhomboids (D = 2,6-bis(4-ethynylpyridine)aniline-based ligands; A = 2,9-bis[trans Pt(PEt3)2NO3]phenanthrene) is described with emission wavelengths spanning the visible region (lambdamax = 476-581 nm). Tuning was achieved by simple functional group modifications para to the aniline amine on the donor building block. Steady state absorption and emission profiles were obtained for each system and are discussed. When the Hammett sigma(para) constants for the functional groups para to the aniline amine were plotted versus the wavenumber (cm(-1)) for the lambdamax of the emission profile, a linear relationship was observed. By utilizing this relationship, the emission wavelength of a given rhomboid can be predetermined on the basis of the Hammett constant of the functionality employed on the donor precursor. This range of visible light emission for a suite of simple rhomboids along with the predictive nature of the wavelength of emission is unprecedented for these types of systems. PMID- 23980639 TI - HLA-DP and gamma-interferon receptor-2 gene variants and their association with viral hepatitis activity in chronic hepatitis B infection. AB - BACKGROUND AND AIM: Studies show that polymorphisms in human leukocyte antigen (HLA)-DP loci and certain gamma-interferon (IFN-gamma) signaling pathway genes are related to persistence of hepatitis B virus (HBV) infection and viral load in chronic HBV (CHB) infection respectively. Our study aims to determine whether single-nucleotide polymorphisms (SNPs) linked to HLA-DP loci and IFN-gamma signaling pathway are associated with HBV activities. METHODS: We compared the SNPs in the HLA-DPA1 gene (rs3077) and the IFN-gamma receptor-2 gene (rs2284553 and rs9808753) of 100 treatment-naive hepatitis B e antigen (HBeAg)-negative CHB patients with undetectable HBV DNA with 100 age- and sex-matched controls with HBV DNA > 2000 IU/mL. RESULTS: The median age of the study group was 47.9 years, and 61% were male patients. The distribution of the three polymorphisms was in Hardy-Weinberg equilibrium. Both rs3077 and rs2284553 polymorphisms were not associated with HBV viral load in terms of allelic frequency, genotypic frequency, dominant/recessive gene action. rs9808753 (G allele) was associated with a reduced chance of "undetectable HBV DNA" for patients below the age of 50 years in allelic frequency analysis (odds ratio 0.562; 95% confidence interval, 0.326-0.967; P value = 0.037). IFN-gamma receptor-2 gene haplotype block (rs2284553/rs9808753) was not associated with HBV viral activity. CONCLUSION: There was no significant association between HLA-DP polymorphism (rs3077) and IFN gamma receptor-2 gene polymorphism (rs2284553) with viral activity in HBeAg negative CHB patients. Further studies are required to confirm the association between IFN-gamma receptor-2 gene polymorphism (rs9808753) and reduced chance of having "undetectable HBV DNA" in young CHB patients. PMID- 23980640 TI - Five-year oncological outcomes of endoscopic extraperitoneal radical prostatectomy (EERPE) for prostate cancer: results from a medium-volume UK centre. AB - OBJECTIVE: To determine the 5-year oncological outcomes of endoscopic extraperitoneal radical prostatectomy (EERPE) from a medium-volume centre, thereby providing much needed data on outcomes from the UK. PATIENTS AND METHODS: From January 2006 to January 2012, 575 patients underwent EERPE for localized prostate cancer, performed by a single surgeon who had completed a modular training programme. Follow-up was as per local hospital policy and data were collected in our prospective database. A retrospective review of patient demographics, prostate-specific antigen (PSA) levels, pathological T stages, Gleason scores, surgical margin status and biochemical recurrence (BCR) data was performed. BCR was defined as PSA >0.2 MUg/L. RESULTS: The mean (range) patient age was 62 (40.3-76.5) years and the mean (range) follow-up was 30 (12-72) months. The median (interquartile range [IQR]) operating time was 135 (120-170) min and the median (IQR) blood loss was 200 (100-250) mL. Of the 575 patients, 135 (23.5%) had positive surgical margins (PSMs). The PSM rate for pT2 disease was 66/406 patients (16.3%) and for pT3 disease it was 68/168 patients (40.5%). Overall BCR-free survival at 5-years was 81.5%. Multivariate Cox analysis showed that PSMs, Gleason score, D'Amico risk category and pT stage were independent predictors of BCR-free survival. CONCLUSIONS: This assessment of the oncological results of EERPE, which included the surgical learning curve, shows that the adoption of EERPE after mentored fellowship training translates into mid-term oncological outcomes in line with those of retropubic/transperitoneal laparoscopic approaches and with large-volume centres worldwide which have pioneered laparoscopic radical prostatectomy. The study shows that EERPE in a medium-volume second generation laparoscopic centre (that introduced EERPE after adequate training in pioneering centres) produces results with good 5-year oncological outcomes, similar to those of other major series, for patients in the UK. PMID- 23980637 TI - A BAC physical map of aus rice cultivar 'Kasalath', and the map-based genomic sequence of 'Kasalath' chromosome 1. AB - Comparative analysis using available genomic resources within closely related species is an effective way to investigate genomic sequence and structural diversity. Rice (Oryza sativa L.) has undergone significant physiological and morphological changes during its domestication and local adaptation. We present a complete bacterial artificial chromosome (BAC) physical map for the aus rice cultivar 'Kasalath', which covers 90% of the sequence of temperate japonica rice cultivar 'Nipponbare'. Examination of physical distances between computational and experimental measurements of 'Kasalath' BAC insert size revealed the presence of more than 500 genomic regions that appear to have significant chromosome structural changes between the two cultivars. In particular, a genomic region on the long arm of 'Kasalath' chromosome 11 carrying a disease-resistance gene cluster was greatly expanded relative to the 'Nipponbare' genome. We also decoded 41.37 Mb of high-quality genomic sequence from 'Kasalath' chromosome 1. Extensive comparisons of chromosome 1 between 'Kasalath' and 'Nipponbare' led to the discovery of 317,843 single-nucleotide polymorphisms (SNPs) and 66,331 insertion/deletion (indel) sites. Nearly two-thirds of the expressed genes on rice chromosome 1 carried natural variations involving SNPs and/or indels that resulted in substitutions, insertions or deletions of amino acids in one cultivar relative to the other. We also observed gain and loss of genes caused by large indels. This study provides an important framework and an invaluable dataset for further understanding of the molecular mechanisms underlying the evolution and functions of the rice genome. PMID- 23980642 TI - Biomechanical evaluation of the helica femoral implant system using traditional and modified techniques. AB - OBJECTIVE: To determine the effect of implant placement on proximal femoral axial bone strains, implant subsidence, implant motion, and failure mechanical properties of Helica implants. STUDY DESIGN: In vitro biomechanical study. SAMPLE POPULATION: Cadaveric canine femora (n = 8 pairs). METHODS: Femora instrumented with strain gauges and kinematic markers were cyclically loaded in axial compression before (intact femora) and after implantation with a Helica prosthesis that engaged only cancellous bone (traditional technique) or cancellous bone and lateral cortex (modified technique) to evaluate bone strains, subsidence, and motion; femora were then loaded to failure to evaluate failure mechanical properties. RESULTS: After implantation, modified femoral prosthesis angle was 5% less than intact femora and 5.7% less than traditional implanted femora. Medial femoral bone strain was lower (P <= .05) for intact (-570 u strain) than modified (-790), but not (P = .08) traditional (-700) implanted femora. High-load implant subsidence was present but small (-0.087 mm) for the modified technique. Motion (traditional and modified) increased (P = .05) during cyclic loading (-0.17 and -0.328 mm) and failure (P = .04) (-2.121 and -3.390 mm); remaining yield and failure properties revealed no significant findings (P <= .05). CONCLUSIONS: The modified technique resulted in a smaller neck angle and minimal subsidence. Bone strain was minimally altered so stress shielding may be less compared to findings with traditional implants. Motion detected during cyclic and failure testing may lead to implant loosening in vivo. PMID- 23980641 TI - Structure of a dinuclear iron cluster-containing beta-hydroxylase active in antibiotic biosynthesis. AB - A family of dinuclear iron cluster-containing oxygenases that catalyze beta hydroxylation tailoring reactions in natural product biosynthesis by nonribosomal peptide synthetase (NRPS) systems was recently described [Makris, T. M., Chakrabarti, M., Munck, E., and Lipscomb, J. D. (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 15391-15396]. Here, the 2.17 A X-ray crystal structure of the archetypal enzyme from the family, CmlA, is reported. CmlA catalyzes beta hydroxylation of l-p-aminophenylalanine during chloramphenicol biosynthesis. The fold of the N-terminal domain of CmlA is unlike any previously reported, but the C-terminal domain has the alphabetabetaalpha fold of the metallo-beta-lactamase (MBL) superfamily. The diiron cluster bound in the C-terminal domain is coordinated by an acetate, three His residues, two Asp residues, one Glu residue, and a bridging oxo moiety. One of the Asp ligands forms an unusual monodentate bridge. No other oxygen-activating diiron enzyme utilizes this ligation or the MBL protein fold. The N-terminal domain facilitates dimerization, but using computational docking and a sequence-based structural comparison to homologues, we hypothesize that it likely serves additional roles in NRPS recognition and the regulation of O2 activation. PMID- 23980643 TI - Family function and its relationship to injury severity and psychiatric outcome in children with acquired brain injury: a systematized review. AB - AIM: The psychological and psychiatric outcome of children with acquired brain injury is influenced by many variables. A review was undertaken to clarify the contribution of family function, how it relates to injury severity, and what particular aspects of family function influence psychological outcome in this group. METHOD: A systematized review of the literature of studies published between 1970 and 2012 from OvidMedline, PsychoInfo, PsycARTICLES, and Cochrane was undertaken focusing on family function, injury severity, and psychiatric outcome. RESULTS: Thirty-six papers met the inclusion criteria. Injury severity was linked to the development of organic personality change. Family function before injury, measured by the Family Assessment Device or the Clinical Rating Scale, had a statistically significant effect on general psychological functioning in six out of eight studies. Family function had a significant effect for oppositional defiant disorder and secondary attention-deficit-hyperactivity disorder. The effects of family function may differ depending on the age of the child and the severity of the injury. Some styles of parenting moderated recovery. After injury, family function was related to the child's contemporaneous psychiatric symptoms. The level of evidence for these papers was 3 or 4 (Oxford Centre for Evidence-based Medicine criteria). INTERPRETATION: Screening for some aspects of family functioning before injury and family function during the rehabilitation phase may identify children at risk of psychiatric disorders. PMID- 23980644 TI - Introduction for symposium on engaging youth in prevention message creation: the theory and practice of active involvement interventions. PMID- 23980645 TI - Pharmacokinetic/pharmacodynamic relationship of cefquinome against Pasteurella multocida in a tissue-cage model in yellow cattle. AB - The cephalosporin antimicrobial drug cefquinome was administered to yellow cattle intravenously (i.v.) and intramuscularly (i.m.) at a dose of 1 mg/kg of body weight in a two-period crossover study. The pharmacokinetic (PK) properties of cefquinome in serum, inflamed tissue-cage fluid (exudate), and noninflamed tissue cage fluid (transudate) were studied using a tissue-cage model. The in vitro and ex vivo activities of cefquinome in serum, exudate, and transudate against a pathogenic strain of Pasteurella multocida (P. multocida) were determined. A concentration-independent antimicrobial activity of cefquinome was confirmed for levels lower than 4 * MIC. Integration of in vivo pharmacokinetic data with the in vitro MIC provided mean values for the time that drug levels remain above the MIC (T > MIC) in serum was 14.10 h after intravenous and 14.46 h after intramuscular dosing, indicating a likely high level of effectiveness in clinical infections caused by P. multocida of MIC 0.04 MUg/mL or less. These data may be used as a rational basis for setting dosing schedules, which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms. PMID- 23980646 TI - Clinical experience of esophageal perforation occurring with endoscopic submucosal dissection. AB - Esophageal perforation occurring during or after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is a rare, but serious complication. However, reports of its characteristics, including endoscopic imaging and management, have not been fully detailed. To analyze and report the clinical presentation and management of esophageal perforations occurred during or after EMR/ESD. Four hundred seventy-two esophageal neoplasms in 368 patients were treated (171 EMR; ESD 306) at Northern Yokohama Hospital from 2003 to 2012. Esophageal perforation occurred in a total of seven (1.9%) patients, all of whom were male and had undergone ESD. The etiology of perforation was: three (42.9%) intraoperative; three (42.9%) balloon dilatation for stricture prevention; one (14.2%) due to food bolus impaction. All cases were managed non-operatively based on the comprehensive assessment of clinical severity, extent of the injury, and the time interval from perforation to treatment onset. Conservative management included (i) bed rest and continuous monitoring to determine the need for operative intervention; (ii) fasting and intravenous fluid infusion/ tube feeding; and (iii) intravenous antibiotics. All defects closed spontaneously, save one case where closure was achieved by endoscopic clipping. Surgery was not required. Conservative management for esophageal perforation during advanced endoscopic resection is may be possible when there is no delay in diagnosis or treatment. Decision-making should be governed purely by multidisciplinary discussion. PMID- 23980647 TI - Release of guests from encapsulated masked hydrophobic precursors by a phototrigger. AB - Examples of release of organic acids from encapsulated p-methoxyphenacyl esters provided here demonstrate the value of a phototrigger strategy to release chemicals of interest in water from hydrophobic precursors. In this study, a photochemical beta-cleavage process centered on the p-methoxyphenacyl group is exploited to release the acid of interest from a water-soluble capsule made up of octa acid. PMID- 23980648 TI - On familiarity deficits in mild cognitive impairment: a reply to Migo and Westerberg. AB - In this brief response to Migo and Westerberg we explain why we think that their criticism of our previous research showing familiarity deficits in mild cognitive impairment patients (MCI) is not sound. More concretely, we have replicated the effect several times previously, and we justify statistically the fact that in the previous paper we had to combine two MCI samples to demonstrate a reliable familiarity deficit. We note that there are several studies showing conflicting results. However, although the basis for these discrepancies remains uncertain, a new report has replicated the presence of deficits in familiarity, and more importantly, demonstrated its correlation with structural imaging biomarkers of Alzheimer's disease. PMID- 23980649 TI - Triptans and ergot alkaloids in the acute treatment of migraine: similarities and differences. PMID- 23980650 TI - Neutrophil-endothelial interactions mediate angiopoietin-2-associated pulmonary endothelial cell dysfunction in indirect acute lung injury in mice. AB - Unresolved inflammation in the lung is thought to elicit loss of endothelial cell (EC) barrier integrity and impaired lung function. We have shown, in a mouse model of shock/sepsis, that neutrophil interactions with resident pulmonary cells appear central to the pathogenesis of indirect acute lung injury (iALI). Normally, EC growth factors angiopoietin (Ang)-1 and Ang-2 maintain vascular homeostasis through tightly regulated interaction with the kinase receptor Tie2 expressed on ECs. Although Ang-1/Tie2 has been shown to promote vessel integrity, stimulating downstream prosurvival/antiinflammatory signaling, Ang-2, released from activated ECs, is reported to promote vessel destabilization. This mechanism of regulation, together with recent clinical findings that plasma Ang-2 levels are significantly elevated in patients who develop acute respiratory distress syndrome, has focused our investigation on the contribution of Ang-2 to the development of iALI. A murine model of hemorrhagic shock-induced priming for the development of iALI after subsequent septic challenge was used in this study. Our findings show that 1) Ang-2 is elevated in our experimental model for iALI, 2) direct EC/neutrophil interactions contribute significantly to EC Ang-2 release, and 3) suppression of Ang-2 significantly decreases inflammatory lung injury, neutrophil influx, and lung and plasma IL-6 and TNF-alpha. These findings support our hypothesis and suggest that Ang-2 plays a role in the loss of pulmonary EC barrier function in the development of iALI in mice resultant from the sequential insults of hemorrhagic shock and sepsis and that this is mediated by EC interaction with activated neutrophils. PMID- 23980652 TI - Broad host range plasmids. AB - Plasmids are and will remain important cloning vehicles for biotechnology. They have also been associated with the spread of a number of diseases and therefore are a subject of environmental concern. With the advent of sequencing technologies, the database of plasmids is increasing. It will be of immense importance to identify the various bacterial hosts in which the plasmid can replicate. The present review article describes the features that confer broad host range to the plasmids, the molecular basis of plasmid host range evolution, and applications in recombinant DNA technology and environment. PMID- 23980651 TI - Ethnic differences in the clusters of menopausal symptoms. AB - Our purpose for this study was to identify clusters of midlife women by menopausal symptoms in a multiethnic sample, and to determine ethnic differences in the clusters. This was a secondary analysis of data from 501 women in a larger Internet study on menopausal symptom experiences. The data were analyzed using factor analysis, hierarchical cluster analysis, and multinominal logistic analysis. A three cluster solution was adopted (F = 575.71, p <.01). The clusters differed significantly in the country of birth and ethnicity (p <.05). Only in the low symptomatic cluster were there significant ethnic differences in menopausal symptoms. PMID- 23980653 TI - Regioselective silyl/acetate exchange of disaccharides yields advanced glycosyl donor and acceptor precursors. AB - Glycoconjugates are composed of carbohydrate building blocks linked together in a multitude of ways giving rise to diverse biological functions. Carbohydrates are especially difficult to synthetically manipulate because of the similar reactivity of their numerous and largely equivalent hydroxyl groups. Hence, methodologies for both the efficient protection and selective modification of carbohydrate alcohols are considered important synthetic tools in organic chemistry. When per-O-TMS protected mono- or disaccharides in a mixture of pyridine and acetic anhydride are treated with acetic acid, regioselective exchange of silicon for acetate protecting groups occurs. Acid concentration, thermal conditions, and microwave assistance mediate the silyl/acetate exchange reaction. Regiocontrol is achieved by limiting the equivalents of acetic acid, and microwave irradiation hastens the process. We coined the term Regioselective Silyl Exchange Technology (ReSET) to describe this process, which essentially sets the protecting groups anew. To demonstrate the scope of the reaction, the conditions were applied to lactose, melibiose, cellobiose, and trehalose. ReSET provided rapid access to a wide range of orthogonally protected disaccharides that would otherwise require multiple synthetic steps to acquire. The resulting bifunctional molecules are poised to serve as modular building blocks for more complex glycoconjugates. PMID- 23980654 TI - Overexpression of cotton GhMKK4 enhances disease susceptibility and affects abscisic acid, gibberellin and hydrogen peroxide signalling in transgenic Nicotiana benthamiana. AB - Mitogen-activated protein kinase (MAPK) cascades are involved in plant development, stress responses and hormonal signal transduction. MAPK kinases (MAPKKs), as the key nodes in these cascades, link MAPKs and MAPKK kinases (MAPKKKs). In this study, GhMKK4, a novel group C MAPKK gene from cotton (Gossypium hirsutum), was isolated and identified. Its expression can be induced by various stresses and signalling molecules. The overexpression of GhMKK4 in Nicotiana benthamiana enhanced its susceptibility to bacterial and fungal pathogens, but had no significant effects on salt or drought tolerance. Notably, the overexpressing plants showed increased sensitivity to abscisic acid (ABA) and gibberellin A3 (GA3), and ABA and gibberellin (GA) signalling were affected on infection with Ralstonia solanacearum bacteria. Furthermore, the overexpressing plants showed more reactive oxygen species (ROS) accumulation and stronger inhibition of catalase (CAT), a ROS-scavenging enzyme, than control plants after salicylic acid (SA) treatment. Interestingly, two genes encoding ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC), the key enzymes in polyamine synthesis, exhibited reduced R. solanacearum-induced expression in overexpressing plants. These findings broaden our knowledge about the functions of MAPKKs in diverse signalling pathways and the negative regulation of disease resistance in the cotton crop. PMID- 23980656 TI - The information needs and media preferences of Canadian cancer specialists regarding breast cancer treatment related arm morbidity. AB - The information needs and media preferences of Canadian cancer specialists regarding breast cancer treatment related arm morbidity. Breast cancer treatment related arm morbidity is a common but pernicious condition that is under recognised, under-diagnosed, and can result in long-term impairment and disability. Despite the prevalence of this condition, little is known about breast cancer specialists' information needs and media preferences around this issue. In-depth telephone interviews with 14 Canadian cancer specialists were conducted, and were coded and analysed using a grounded theory approach. Findings revealed that cancer specialists were open to receiving all types of information about treatment related arm morbidity, and have preferences for particular types of media formats. However, barriers that could problematise the uptake of research findings into clinical practice were also noted and included gaps in specialists' knowledge of the complex nature of treatment related lymphoedema. Hence providing specialists with summary information about arm morbidity will not suffice, and an educational campaign around this condition, including the importance of physician vigilance in regularly monitoring patients for early and latent indications of this morbidity may be necessary. PMID- 23980657 TI - H2 dissociation over NbO: the first step toward hydrogenation of Mg. AB - Niobium-based oxide nanoparticles have proven to be catalytically effective toward hydrogenation of Mg where H2 dissociation over the niobium-oxides is considered to be a crucial reaction step. However, the role of niobium oxides toward H2 dissociation still remains unclear as to what atomic configurations are responsible for the catalytic activity. H2 dissociation over different surface planes of Nb, NbO, and Nb2O5 as well as small NbO clusters is performed by using a density functional theory. The calculations reveal that H2 dissociation, adsorption energy, and the bond type between H and surfaces (clusters) depend on the atomic configurations of Nb and O. In particular, H2 adsorption on NbO(111) is enhanced by O atoms without forming O-H bond where the bond type of H and surface is found to be an electron pairing. Thus, NbO(111) could not only be a effective catalyst but also potentially prevent the formation of MgO during the hydrogenation of Mg. The results should be helpful in developing and tailoring the efficient catalyst toward H2 dissociation and hydrogenation of Mg. PMID- 23980658 TI - Postmortem distribution of 3-beta-hydroxybutyrate. AB - The concentrations of 3-beta-hydroxybutyrate (3HB) in femoral blood, urine, vitreous humor as well as pericardial and cerebrospinal fluids were retrospectively examined in a series of medico-legal autopsies, which included cases of diabetic ketoacidosis, hypothermia fatalities without ethanol in blood, bodies presenting mild decompositional changes, and sudden deaths in chronic alcoholics. Similar increases in 3HB concentrations were observed in blood, vitreous, and pericardial fluid, irrespective of the cause of death, suggesting that pericardial fluid and vitreous can both be used as alternatives to blood for postmortem 3HB determination. Urine 3HB levels were higher than blood values in most cases. Cerebrospinal fluid 3HB levels were generally lower than concentrations in blood and proved to be diagnostic of underlying metabolic disturbances only when significant increases occurred. PMID- 23980659 TI - Do you know your patient? Knowing individuals with dementia combined with evidence-based care promotes function and satisfaction in hospitalized older adults. PMID- 23980661 TI - Clinical considerations for care of older adult cancer survivors. AB - The number of cancer survivors has been steadily increasing due in part to the aging population and advancements in cancer care and treatment. Of the current 13.7 million cancer survivors in the United States, most are 65 or older. Aging changes and the presence of comorbidities add complexity to the care of cancer survivors. In addition. common long-term cancer-related symptoms and late effects of cancer treatments provide challenges to nurses and other health professionals caring for older cancer survivors. Transition from oncology care to primary or shared care requires understanding of detailed information about the specific cancer diagnosis, treatments received, and recommendations for follow-up care to prevent recurrence, recognize treatment-associated health effects, and understand strategies for health promotion. Nurses in all practice areas will care for cancer survivors and must be prepared to deliver safe and effective care. PMID- 23980663 TI - Regulation of the NADPH oxidase and associated ion fluxes during phagocytosis. AB - The production of reactive oxygen species (ROS) within immune cell phagosomes is critical for antimicrobial activity and for correct antigen processing, and influences signaling pathways that direct host responses to infection and inflammation. Because excess oxidants can cause tissue damage and oxidative stress, phagocytes must precisely control both the location and timing of NADPH oxidase activity. How differential regulation is achieved at phagosomes is not well understood. Recent studies have revealed that the PI(3)P phosphoinositide plays an important role in locally boosting phagosomal NADPH oxidase activity through its binding to the p40(phox) NADPH oxidase subunit. Furthermore, phox subunit dynamics at phagosomes may regulate the timing of the oxidative burst. Novel elements regulating catalytic core trafficking include Rab27 and SNAP-23. In addition to trafficking events, the activity of the electrogenic oxidase is also governed by ionic fluxes, which are constrained at phagosomes owing to low intraphagosomal volume and dynamic display of channels, transporters, and pumps. New insights on the interdependence of phagosomal pH and ROS have been recently elucidated, and chloride channels important for microbicidal functions, including CFTR, and CLIC family channels, have been identified. Finally, periphagosomal calcium microdomains and calcium-dependent S100A8/9 protein recruitment may help fine-tune spatiotemporal regulation of NADPH oxidase activation for an effective immune response. PMID- 23980664 TI - Withdrawal of antiepileptic drugs during presurgical video-EEG monitoring: an observational study for evaluation of current practice at a referral center for epilepsy. AB - OBJECTIVES: Withdrawal of antiepileptic drugs (AEDs) before and during video-EEG monitoring is commonly implemented to reduce time needed to register a sufficient number of seizures during presurgical evaluation. There are, however, few guidelines regarding withdrawal rate and observation time. MATERIAL AND METHODS: We performed an observational study including sixty patients admitted to the national Norwegian epilepsy centre and registered tapering of AEDs and their effect on seizure rate and possible complications. RESULTS: The mean daily seizure rate before admission to the EMU was 0.4 (range 0.02-4) increasing to 1.1 (range 0-8) at the EMU. 29 patients (48%) followed a slow tapering rate whereas 31 (52%) had an intermediate tapering rate. There was no significant difference between the patients with a daily seizure rate during LTM of more or <0.7 seizures per day, an increase of seizure frequency from habitual to during LTM of more or <3.3 or 6.9 with regard to rate of tapering (slow vs intermediate) etiology or AED monotherapy vs polytherapy. Twenty-six patients (43%) had a sufficient number of seizures registered within 3 days to conclude regarding the presurgical evaluation. Two patients received escape treatment while 25 patients did have 24 h-seizure-clusters. There was no serious event. CONCLUSIONS: Less than 50% of the patients got a sufficient number of seizures for a conclusive result within 3 days. An increase in the registration period could increase the number of successful registrations. PMID- 23980665 TI - Genetic variation underlies temperature tolerance of embryos in the sea urchin Heliocidaris erythrogramma armigera. AB - Ocean warming can alter natural selection on marine systems, and in many cases, the long-term persistence of affected populations will depend on genetic adaptation. In this study, we assess the potential for adaptation in the sea urchin Heliocidaris erythrogramma armigera, an Australian endemic, that is experiencing unprecedented increases in ocean temperatures. We used a factorial breeding design to assess the level of heritable variation in larval hatching success at two temperatures. Fertilized eggs from each full-sibling family were tested at 22 degrees C (current spawning temperature) and 25 degrees C (upper limit of predicted warming this century). Hatching success was significantly lower at higher temperatures, confirming that ocean warming is likely to exert selection on this life-history stage. Our analyses revealed significant additive genetic variance and genotype-by-environment interactions underlying hatching success. Consistent with prior work, we detected significant nonadditive (sire-by dam) variance in hatching success, but additionally found that these interactions were modified by temperature. Although these findings suggest the potential for genetic adaptation, any evolutionary responses are likely to be influenced (and possibly constrained) by complex genotype-by-environment and sire-by-dam interactions and will additionally depend on patterns of genetic covariation with other fitness traits. PMID- 23980666 TI - White blood cell count is positively associated with benign prostatic hyperplasia. AB - OBJECTIVES: To determine whether low-grade systemic inflammation is associated with prostatic enlargement/benign prostatic hyperplasia. METHODS: Prostate volume was measured by transrectal ultrasonography in 576 Japanese men. The association between prostate volume and routine clinical inflammatory markers (C-reactive protein level, white blood cell count, or the differential white cell count [neutrophils, lymphocytes, basophils, eosinophils, and monocytes]) were analyzed. Contributors to prostate volume were identified in univariate and multivariable linear regression models. RESULTS: Prostate volume was found to have a positive association with serum prostate-specific antigen level (P < 0.001), white blood cell count (P = 0.027) and absolute neutrophil count (P = 0.010). In univariate linear regression models, a large prostate volume was associated with older age, higher prostate-specific antigen, and higher white blood cell and neutrophil counts. A multivariable model adjusted for age, prostate-specific antigen, and C reactive protein showed that the white blood cell count and the neutrophil count were independently associated with prostate volume. An increased white blood cell count was also associated with higher total International Prostatic Symptom Scores (P < 0.001). CONCLUSIONS: White blood cell count seems to be associated with the degree of prostate enlargement and lower urinary tract symptoms. Chronic low-grade systemic inflammation might be involved in the etiology of benign prostatic hyperplasia. PMID- 23980667 TI - JAK2 V617F mutation and 46/1 haplotype in Chinese Budd-Chiari syndrome patients. AB - BACKGROUND AND AIM: The presence of JAK2V617F was reported to be associated with JAK2 46/1 haplotype, which was considered as an independent risk factor for Budd Chiari syndrome (BCS) in Western countries. However, little is known in China. Therefore, the aim of this study was to determine whether the 46/1 haplotype is associated with such patients. METHODS: Patients with primary BCS and controls were consecutively admitted in our study from October 2009 to December 2012. The subjects were detected for the JAK2V617F mutation by allele-specific polymerase chain reaction (AS-PCR) and the JAK2 46/1 haplotype by real-time PCR. RESULTS: The prevalence of JAK2V617F mutation was 2.37% (7/295) in BCS patients, and 46/1 haplotype was overrepresented in JAK2V617F-positive BCS patients compared with controls (P < 0.01). The risk for the JAK2V617F-positive BCS with CC genotype was elevated compared with subjects presented TT genotype (OR = 13.4, 95%CI = 2.01 89.5) and non-CC genotype (OR = 15.0, 95%CI = 2.45-91.7). CONCLUSIONS: Our study showed that the presence of 46/1 haplotype increased the risk of JAK2V617F positive BCS in China. In addition, low prevalence of JAK2V617F mutation in BCS patients suggested that myeloproliferative neoplasms (MPNs) should not be an etiological factor of BCS in China. PMID- 23980668 TI - "Yarning" as a method for community-based health research with Indigenous women: the Indigenous Women's Wellness Research Program. AB - This project explores yarning as a methodology for understanding health and wellness from an indigenous woman's perspective. Previous research exploring indigenous Australian women's perspectives have used traditional Western methodologies and have often been felt by the women themselves to be inappropriate and ineffective in gathering information and promoting discussion. This research arose from the indigenous women themselves, and resulted in the exploration of using yarning as a methodology. Yarning is a conversational process that involves the sharing of stories and the development of knowledge. It prioritizes indigenous ways of communicating, in that it is culturally prescribed, cooperative, and respectful. The authors identify different types of yarning that are relevant throughout their research, and explain two types of yarning-family yarning and cross-cultural yarning-which have not been previously identified in research literature. This project found that yarning as a research method is appropriate for community-based health research with indigenous Australian women. This may be an important finding for health professionals and researchers to consider when working and researching with indigenous women from other countries. PMID- 23980670 TI - Breast cancer in the elderly: reducing the losses. PMID- 23980669 TI - Putting some excitement into constraint-induced movement therapy. PMID- 23980671 TI - Anomalous endocrine feedback of peri-menopause in the etiology of type II ovarian cancer. PMID- 23980673 TI - Changes and challenges: a career in prostate surgery. AB - Roger Kirby speaks to Natasha Galukande, Assistant Commissioning Editor. Roger Kirby graduated in Medical Sciences from Cambridge University (Cambridge, UK) in 1972. He then trained in surgery at University of London (London, UK) before specializing in urology. Kirby is currently the director of The Prostate Centre (London, UK), which he established in 2005. Kirby is the founding editor of the journal Prostate Cancer and Prostate Diseases, in addition to being the associate editor of the British Journal of Urology International, and founding editor of Trends in Urology and Men's Health. He has written over 60 books, published over 300 papers and performed over 2000 radical prostatectomies. In 2005, Kirby was awarded the St Peter's Medal by the British Association of Urological Surgeons. Kirby has also helped to raise over L3 million as trustee and secretary of the Urological Foundation and former chair of Prostate UK. PMID- 23980674 TI - Tasquinimod: a novel drug in advanced prostate cancer. AB - Tasquinimod, an oral quinolone-3-carboxamide with anti-tumor activity in preclinical models of prostate cancer, has been tested in patients with minimally symptomatic castration-resistant prostate cancer (CRPC), showing promising inhibitory effects on the occurrence of metastasis and delayed disease progression. Although its mode of action is not fully understood, tasquinimod presumably exerts its unique anti-tumor action through inhibition of angiogenesis and immunomodulation. In clinical studies, tasquinimod demonstrated anti-tumor activity in prostate cancer in combination with a mild-to-moderate side effect profile. With single-agent tasquinimod, dose-limiting toxicity was amylase elevation without signs of pancreatitis and sinus tachycardia. The maximum tolerated dose in Phase I studies in patients with CRPC was once daily administration of 0.5-1-mg tasquinimod orally. In a Phase II trial, significant clinical activity has been demonstrated in asymptomatic or minimally symptomatic, chemotherapy-naive, metastatic CRPC (mCRPC) patients. Men were randomized to tasquinimod or placebo in a 2:1 fashion; treatment with tasquinimod resulted in significant improvement of median progression-free survival (7.6 vs 3.3 months with placebo; p = 0.0042). Based on these encouraging effects, a randomized, double-blind, placebo-controlled trial in men with minimally symptomatic mCRPC has been designed. This large Phase III trial, powered for a primary end point of progression-free survival, has now enrolled the target number of 1200 men. If the Phase II data are validated in the Phase III trial a new compound with a unique mode of action might become approved as a future therapy for minimally symptomatic mCRPC patients. PMID- 23980675 TI - Rituximab for the treatment of follicular lymphoma. AB - Rituximab is the first and most widely adopted anti-CD20 monoclonal antibody, and has dramatically improved outcomes for patients with B-cell malignancies. Rituximab is active as a single agent and when combined with chemotherapy improves both response rates and survival compared with chemotherapy alone. This approach has become standard of care in this setting. A number of Phase III studies using extended applications of rituximab have demonstrated that patients achieve a significantly longer progression-free survival, at the cost of an increase in infective complications. This has resulted in the widespread adoption of maintenance rituximab following the completion of primary therapy. Rituximab is useful in both previously untreated patients and at relapse, although a subset of patients develop disease that is rituximab resistant, which along with histologic transformation remains a significant management problem for patients with follicular lymphoma. The toxicities are modest and manageable, including infusion reactions, late-onset neutropenia, impaired humoral immunity, reactivation of hepatitis and possibly pulmonary toxicity. PMID- 23980676 TI - Best of International Stereotactic Radiosurgery Society Congress 2013: stereotactic body radiation therapy. Part I: spinal tumors. AB - The 11th biennial International Stereotactic Radiosurgery Society Congress represented another historical gathering of professionals in the field of stereotactic radiosurgery. This congress was held on 16-20 June 2013 in Toronto (ON, Canada), and the chairman was Arjun Sahgal, the co-chair was Michael Schwartz and president of the society was Jean Regis. The congress attracted 550 attendants from all over the world and over 300 abstracts were presented. Among the abstracts presented, 62 (36 oral) were pertaining to stereotactic body radiation therapy (SBRT). Exciting new findings were presented by colleagues from North America, Europe and Asia. This short conference scene (part I) provides a summary of the best abstracts on SBRT for spinal tumors presented in the congress. A separate conference scene on SBRT for nonspinal tumors (part II) also appears in this issue of Future Oncology. PMID- 23980677 TI - Best of International Stereotactic Radiosurgery Society Congress 2013: stereotactic body radiation therapy. Part II: nonspinal tumors. AB - The 11th biennial International Stereotactic Radiosurgery Society Congress represented another historical gathering of professionals in the field of stereotactic radiosurgery. This congress was held on 16-20 June 2013 in Toronto (ON, Canada), and the chairman was Arjun Sahgal, co-chair was Michael Schwartz and president of the society was Jean Regis. The congress attracted 550 attendants from all over the world and over 300 abstracts were presented. Among the abstracts presented, 62 (36 oral) were pertaining to stereotactic body radiation therapy (SBRT). Exciting new findings were presented by colleagues from North America, Europe and Asia. This short conference scene (part II) provides a summary of the best abstracts on SBRT for nonspinal tumors presented in the congress. A separate conference scene on SBRT for spinal tumors (part I) also appears in this issue of Future Oncology. PMID- 23980678 TI - Inhaled cisplatin deposition and distribution in lymph nodes in stage II lung cancer patients. AB - Lung cancer therapies during the last decade have focused on targeting the genome of cancer cells, and novel routes for administering lung cancer therapies have been investigated for decades. Aerosol therapies for several systematic diseases and systemic infections were introduced into the market a decade ago. One of the main issues of aerosol therapies has been the ability to investigate the deposition of a drug compound throughout the systematic circulation and lymph node circulation. Until now, none of the published studies have efficiently shown the deposition of a chemotherapy pharmaceutical within the lymph node tissue. In our current work we present, for the first time, with the novel CytoViva((r)) (AL, USA) technique, the deposition of cisplatin aerosol therapy in surgically resected stage II lymph nodes from lung cancer patients. Finally, we present the distribution of cisplatin in correlation with the cisplatin concentration in different lymph stations and comment on the possible mechanisms of distribution. PMID- 23980679 TI - Recent evidence on alcohol and cancer epidemiology. AB - This review presents an overview of the impact of alcohol consumption on cancer risk. Results from the 2009 International Agency for Research on Cancer monograph as well as the most recent meta-analyses and epidemiological studies are considered. Alcohol consumption is one of the most important known risk factors for human cancer and potentially one of the most avoidable factors, but it is increasing worldwide. Ethanol in alcoholic beverages is carcinogenic to humans and causes several cancers (oral cavity, pharynx, larynx, esophagus, colorectum, liver and female breast). Cumulative lifetime consumption, frequency and drinking pattern appear to play a role in risk characterization. While the role of heavy drinking has been long recognized, new evidence suggests that light consumption (up to one drink/day) is also associated with adverse effects. In addition, some genetic polymorphisms interact with alcohol metabolism and may modify its impact. PMID- 23980680 TI - Next-generation sequencing for lung cancer. AB - Lung cancer is biologically aggressive and is the leading cause of cancer-related deaths. The development of lung cancer is unique in each patient according to clinical characterizations, prognosis, response and tolerance to treatment. Traditional capillary-based single-gene sequencing by a first-generation technique (known as Sanger sequencing) has been replaced by next-generation sequencing (NGS) since it allows massive parallel sequencing with lower cost and higher throughput. The NGS approach has made remarkable advances compared with traditional methods. We expect these methodologies to comprehensively interpret the global landscape of cancer and provide more information to fulfill the needs of personalized medicine. This review covers a brief introduction and summary on various NGS technologies, applications and important findings by NGS in lung cancer advances, including further discoveries in previously known target genes (EGFR, ALK and KRAS), the identification of additional lung cancer mutations and the global coordination of cancer genome studies. PMID- 23980681 TI - Circulating tumor cells: utopia or reality? AB - Circulating tumor cells (CTCs) could be considered a sign of tumor aggressiveness, but highly sensitive and specific methods of CTC detection are necessary owing to the rarity and heterogeneity of CTCs in peripheral blood. This review summarizes recent studies on tumor biology, with particular attention to the metastatic cascade, and the molecular characterization and clinical significance of CTCs. Recent technological approaches to enrich and detect these cells and challenges of CTCs for individualized cancer treatment are also discussed. This review also provides an insight into the positive and negative features of the future potential applications of CTC detection, which sometimes remains still a 'utopia', but its actual utility remains among the fastest growing research fields in oncology. PMID- 23980682 TI - Anticancer mechanism of apigenin and the implications of GLUT-1 expression in head and neck cancers. AB - Apigenin, a natural phytoestrogen flavonoid, has potential biological effects, including antioxidative, anti-inflammatory and anticancer activities. The mechanisms of anticancer activities of apigenin are unknown. Some studies have found that apigenin inhibits GLUT-1 mRNA and protein expression in cancer cells. Thus, we hypothesized that apigenin exerts similar effects on head and neck cancers through its inhibition of GLUT-1 expression. In this article, we review the anticancer mechanism of apigenin and the implications of GLUT-1 expression in head and neck cancers. In addition, we describe the current state of knowledge about the relationship between apigenin and GLUT-1 expression in head and neck cancers. PMID- 23980684 TI - Functional and pharmacodynamic evaluation of metronomic cyclophosphamide and docetaxel regimen in castration-resistant prostate cancer. AB - AIM: The aim of our study was to investigate the association of docetaxel and metronomic cyclophosphamide (CYC) in castration-resistant prostate cancer (CRPC). MATERIALS & METHODS: CRPC xenografts were established with PC3 cells. Mice were treated with a combination of CYC (50 mg/kg/day) and docetaxel (10-30 mg/kg/week) or with docetaxel alone. Docetaxel plasma levels were analyzed in patients receiving the drug alone or combined with CYC. RESULTS: Metronomic CYC is an effective adjuvant in blocking tumor growth in vivo, with comparable efficacy and less toxic effects compared with docetaxel treatment. CYC acts by downregulating cell proliferation and inducing apoptosis thorough upregulation of p21 and inhibition of angiogenesis. Finally, CYC increases docetaxel plasma levels in patients. CONCLUSION: Metronomic CYC exerts anti-tumoral effects in an in vivo model of prostate cancer and in patients with CRPC, and also increases the bioavailability of docetaxel. These results explain the favorable toxicity and activity profiles observed in patients treated with this regimen. PMID- 23980683 TI - Tissue engineering and regeneration of lymphatic structures. AB - Tissue engineering is the process by which biological structures are recreated using a combination of molecular signals, cellular components and scaffolds. Although the perceived potential of this approach to reconstruct damaged or missing tissues is seemingly limitless, application of these ideas in vivo has been more difficult than expected. However, despite these obstacles, important advancements have been reported for a number of organ systems, including recent reports on the lymphatic system. These advancements are important since the lymphatic system plays a central role in immune responses, regulation of inflammation, lipid absorption and interstitial fluid homeostasis. Insights obtained over the past two decades have advanced our understanding of the molecular and cellular mechanisms that govern lymphatic development and function. Utilizing this knowledge has led to important advancements in lymphatic tissue engineering, which is the topic of this review. PMID- 23980685 TI - Controlling tumor invasion: bevacizumab and BMP4 for glioblastoma. AB - AIM: Bevacizumab has been reported to result in increased tumor invasion when used to treat malignant glioma. We hypothesized that BMP4 would prevent diffuse tumor infiltration induced by bevacizumab for malignant glioma in a xenograft model. METHODS: Human glioblastoma (GBM) tumor cells were implanted in the striatum of immunocompromised mice. The animals were treated with bevacizumab and BMP4. Tumor growth and invasion were measured. RESULTS: The bevacizumab-treated mice had increased survival compared with control animals (p = 0.02). BMP4 alone did not result in improved survival (p = 1.0). The bevacizumab (p = 0.006) and bevacizumab plus BMP4 (p = 0.006) groups demonstrated significantly decreased total tumor size compared with control. Tumor invasion was significantly decreased in the bevacizumab (p = 0.005), BMP4 (p = 0.04) alone and bevacizumab plus BMP4 (p = 0.002) groups compared with control. No synergistic effect between bevacizumab and BMP4 was observed. CONCLUSION: Bevacizumab treatment did not result in diffuse infiltration of human GBM in a mouse xenograft model. BMP4 did have an independent favorable effect on GBM that was not synergistic with bevacizumab treatment. PMID- 23980686 TI - Angiosarcoma associated with a Kasabach-Merritt syndrome: report of two cases treated with paclitaxel. AB - Angiosarcomas are rare, aggressive vascular malignancies of endothelial cell differentiation. Kasabach-Merritt syndrome is a rare condition defined by the association of thrombocytopenia and consumption coagulopathy with specific vascular tumors, such as tufted angioma or kaposiform hemangioendothelioma. We report here two cases of angiosarcomas complicated by a Kasabach-Merritt syndrome and their outcome after treatment with paclitaxel. PMID- 23980687 TI - Control of relapsed germ cell tumor and SLE nephritis by high-dose chemotherapy and autologous hematopoietic cell transplantation. AB - High-dose chemotherapy and hematopoietic stem cell support remains a curative treatment option for relapsed or nonresponsive germ cell tumors, and has been applied experimentally to control severe autoimmune diseases. In the present study, we report on a patient with systemic lupus erythematosus nephritis who developed a nonseminomatous germ cell tumor that relapsed after standard chemotherapy and surgery. The patient received high-dose chemotherapy supported by autologous hematopoietic cell transplantation based on its indication for relapsed germ cell tumors. Prolonged control of his relapsed germ cell tumor and systemic lupus erythematosus was attained with high-dose chemotherapy and hematopoietic stem cell support. An extensive literature review is provided alongside a detailed discussion of the aforementioned case. PMID- 23980689 TI - Human-beta-defensins-1-3 and analogs do not require proton motive force for antibacterial activity against Escherichia coli. AB - Human-beta-defensins 1-3 (HBD-1-3) and their C-terminal analogs Phd-1-3 do not show antibacterial activity against Escherichia coli in the presence of mono- and divalent cations. Activity of peptides was examined against E. coli pretreated with carbonyl cyanide m-chlorophenylhydrazone (CCCP) and salt remedial Escherichia coli ftsEX, a deletion mutant of FtsEX complex [an ATP-binding cassette (ABC) transporter protein], in the presence of Na(+), Ca(2+), and Mg(2+). Activity was observed in the presence of Na(+) and Ca(2+), although not in the presence of Mg(2+) against E. coli, when proton motive force (PMF) was dissipated by CCCP. The peptides exhibited antibacterial activity against E. coli ftsEX even in the presence of Na(+) and Ca(2+). Our results indicate that HBD-1-3 and Phd-1-3 do not require PMF for their antibacterial activity. The absence of activity against E. coli in the presence of Na(+) and Ca(2+) ions is due to not only weakened electrostatic interactions with anionic membrane components, but also involvement of electrochemical gradients. However, Mg(2+) prevents electrostatic interaction of the peptides with the outer membrane resulting in loss of activity. PMID- 23980690 TI - Minding the body: psychotherapy and cancer survival. AB - OBJECTIVES: This article reviews evidence regarding effects of psychotherapy on overall cancer survival time. Special emphasis is given to research on adverse effects of depression on cancer survival, breast cancer, and mediating psychophysiological pathways linking psychosocial support to longer survival. DESIGN: It reviews all published clinical trials addressing effects of psychotherapy on cancer survival, emphasizing depression, breast cancer, and psychophysiological evidence linking stress, depression, and support to cancer survival. METHODS: Systematic literature review and synthesis. RESULTS: Eight of 15 published trials indicate that psychotherapy enhances cancer survival time. No studies show an adverse effect of psychotherapy on cancer survival. Potential psychophysiological mechanisms linking stress to shorter survival include dysregulation of diurnal cortisol, increased pro-inflammatory cytokines, reduced natural killer cell activity, shorter telomeres and lower telomerase activity, glucocorticoid-mediated suppression of p53 and BrCA1 gene expression, and sympathetic nervous system activation of vascular endothelial growth factor. CONCLUSIONS: Stress and support affect the course of cancer progression. STATEMENT OF CONTRIBUTION: What is known? Stress and support have been thought to be related to cancer risk and progression, but evidence has been mixed. Depression is a natural co-morbid condition with cancer. It has not been clear how stress and support could physiologically affect the rate of cancer progression. Immune function was not thought to have much relevance to cancer progression. Few other physiological mechanisms linking stress to cancer progression were known. What does this paper add? There is evidence from 15 RCTs indicating that effective psychosocial support improves quantity as well as quality of life with cancer. There is evidence that chronic depression predicts poorer prognosis with cancer. Dysregulated circadian cortisol patterns predict more rapid cancer progression. Inflammatory processes affect cancer growth and progression. Sympathetic nervous system activity, telomere length, telomerase activity, and oncogene expression are affected by stress and can affect cancer growth. PMID- 23980691 TI - Synthesis of electron-deficient oxacalix[2]arene[2]triazines and their isomeric analogs from a one-pot reaction of perfluorinated dihydroxybenzenes with dichlorotriazines. AB - Efficient synthesis of tetraoxacalix[2]perfluoroarene[2]triazines and their isomeric analogs from a one-pot macrocyclic condensation reaction of methoxy- and amino-substituted dichlorotriazines with tetrafluorobenzene-1,3-, -1,4-, and -1,2 diols was developed. X-ray analysis demonstrates that they adopt drastically different 1,3-alternate conformations in the crystalline state while in solution they undergo very fast conformational changes relative to the NMR time scale. PMID- 23980692 TI - Challenges and opportunities in polymer technology applied to veterinary medicine. AB - An important frontier in the administration of therapeutic drugs to veterinary species is the use of different polymers as drug delivery platforms. The usefulness of polymers as platforms for the administration of pharmaceutical and agricultural agents has been clearly recognized in the recent decades. The chemical versatility of polymers and the wide range of developed controlled release strategies enhance the possibilities for the formulation of active molecules. In particular, the veterinary area offers opportunities for the development of novel controlled-release drug delivery technologies adapted to livestock or companion animal health needs. In some cases, it also allows to improve profitability in meat production or to meet the safety criteria related to drug residues. A number of factors affect the selection of polymers and subsequent properties of the controlled-release drug delivery system. However, their selection also dictates the release kinetics of the drug from the delivery system. Such choices are therefore crucial as they affect the success and potential of the delivery system for achieving the therapeutic goals of the veterinarian. It is the intention of this review to give an overview of the most relevant polymers, which are used or have been tested as drug delivery release rate modifiers in the veterinary field. The article highlights some recent developments focusing on their advantages and applications and analyzes the future direction of the scientific and technological advancements in this area. PMID- 23980693 TI - Randomized controlled trial of daily interruption of sedatives in critically ill children. AB - AIM: To study the feasibility of daily interruption of sedatives in critically ill children. METHODS: Prospective randomized controlled open-label trial, performed in a pediatric intensive care unit of a tertiary care teaching and referring hospital. 30 children (0-12 years) receiving mechanically ventilation for >24 h were included. In the intervention group, all sedatives were stopped daily and restarted when COMFORT-behavior score >=17. The control group received standard care. Primary end points were amounts of sedatives and number of bolus medications in the first 3 days after enrollment and number of (near) incidents. Secondary end points were duration of mechanical ventilation, length of stay in pediatric intensive care, and changes in COMFORT-behavior score. RESULTS: Midazolam and morphine use were lower in the intervention group compared with the control group (P = 0.007 and P = 0.02, respectively), whereas the number of bolus medications did not differ between groups. Two complications were recorded: one patient (intervention group) lost his intravenous line, and one patient (control group) had an unplanned extubation. Duration of mechanical ventilation was significantly shorter in the intervention group compared with the control group (median [interquartile range] of 4 [3-8] and 9 [4-10] days, respectively, P = 0.03). Length of stay in the PICU in the intervention group was significantly shorter than in the control group (median [interquartile range] of 6 [4-9] and 10 [7-15] days, respectively, P = 0.01). CONCLUSIONS: Daily interruption of sedatives in critically ill children is feasible, results in decreased use of sedation, earlier extubation, and shorter length of stay. PMID- 23980694 TI - Trypanosoma brucei (UMP synthase null mutants) are avirulent in mice, but recover virulence upon prolonged culture in vitro while retaining pyrimidine auxotrophy. AB - African trypanosomes are capable of both de novo synthesis and salvage of pyrimidines. The last two steps in de novo synthesis are catalysed by UMP synthase (UMPS) - a bifunctional enzyme comprising orotate phosphoribosyl transferase (OPRT) and orotidine monophosphate decarboxylase (OMPDC). To investigate the essentiality of pyrimidine biosynthesis in Trypanosoma brucei, we generated a umps double knockout (DKO) line by gene replacement. The DKO was unable to grow in pyrimidine-depleted medium in vitro, unless supplemented with uracil, uridine, deoxyuridine or UMP. DKO parasites were completely resistant to 5-fluoroorotate and hypersensitive to 5-fluorouracil, consistent with loss of UMPS, but remained sensitive to pyrazofurin indicating that, unlike mammalian cells, the primary target of pyrazofurin is not OMPDC. The null mutant was unable to infect mice indicating that salvage of host pyrimidines is insufficient to support growth. However, following prolonged culture in vitro, parasites regained virulence in mice despite retaining pyrimidine auxotrophy. Unlike the wild-type, both pyrimidine auxotrophs secreted substantial quantities of orotate, significantly higher in the virulent DKO line. We propose that this may be responsible for the recovery of virulence in mice, due to host metabolism converting orotate to uridine, thereby bypassing the loss of UMPS in the parasite. PMID- 23980696 TI - Clinical application and evaluation of the Bien diagnostic criteria for Rasmussen encephalitis. AB - PURPOSE: The 2005 diagnostic criteria for Rasmussen encephalitis (RE) are based on seizures, clinical deficits, electroencephalography (EEG), neuroimaging, and pathology (Brain, 128, 2005, 451). We applied these criteria to patients evaluated for RE and epilepsy surgery controls to determine the sensitivity, specificity, and positive and negative predictive values (PPVs, NPVs) using pathology as the gold standard. METHODS: We identified patients evaluated for RE based on medical records from 1993 to 2011. Fifty-two control patients with refractory epilepsy, unilateral magnetic resonance imaging (MRI) changes, and biopsies were selected from an epilepsy surgery database from matching years. Patients meeting all three of group A and/or two of three group B criteria were classified as meeting full criteria (positive). Patients not meeting full criteria were classified as negative. When available, pathology findings were re reviewed with neuropathologists, and MRI imaging was re-reviewed with a neuroradiologist. KEY FINDINGS: RE was considered in the differential diagnosis for 82 patients, of whom 35 had biopsies. Twenty patients met full criteria (positive) without another explanation, including seven for whom biopsy was required to meet criteria and one in whom another etiology was identified. Two patients met full criteria but had another explanation. Thirty-five met partial criteria (negative), of whom 14 had another etiology identified. Twenty-five met no criteria (negative). The diagnostic criteria had a sensitivity of 81% with four false negatives (criteria-negative, biopsy-positive) when compared to pathology as a gold standard. Five false positives (criteria positive, biopsy negative) had identifiable alternate diagnoses. SIGNIFICANCE: The 2005 Bien clinical diagnostic criteria for RE have reasonably high sensitivity and specificity and good clinical-pathologic correlation in most cases. We suggest modification of the criteria to allow inclusion of cases with well-described but less common features. Specifically we suggest making the diagnosis in the absence of epilepsia partialis continua (EPC) or clear progression of focal cortical deficits or MRI findings if biopsy is positive and two of the A criteria are met (B3 plus two of three A criteria). This would improve the sensitivity of the criteria. PMID- 23980695 TI - Dynamin rings: not just for fission. AB - The GTPase dynamin has captivated researchers for over two decades, even managing to establish its own research field. Dynamin's allure is partly due to its unusual biochemical properties as well as its essential role in multiple cellular processes, which include the regulation of clathrin-mediated endocytosis and of actin cytoskeleton. On the basis of the classic model, dynamin oligomerization into higher order oligomers such as rings and helices directly executes the final fission reaction in endocytosis, which results in the generation of clathrin coated vesicles. Dynamin's role in the regulation of actin cytoskeleton is mostly explained by its interactions with a number of actin-binding and -regulating proteins; however, the molecular mechanism of dynamin's action continues to elude us. Recent insights into the mechanism and role of dynamin oligomerization in the regulation of actin polymerization point to a novel role for dynamin oligomerization in the cell. PMID- 23980698 TI - CRP gene polymorphism predicts post-stroke functional outcome in Han Chinese. AB - OBJECTIVES: Stroke is a major cause of long-term disability and morbidity worldwide. C-reactive protein (CRP), an inflammatory marker, has been reported to be an independent predictor of functional outcome after ischemic stroke (IS). Because several single nucleotide polymorphisms (SNPs) at the CRP locus have been linked with elevated CRP levels, we hypothesized that CRP genetic variation might be associated with functional disability in patients after first-ever IS. METHODS: A total of 1716 patients from western China with first-ever IS were genotyped for the CRP SNPs rs1130864 and rs1800947 using the ligation detection reaction method. Functional outcome was assessed 3 months after IS using the modified Rankin Scale. Then, we tested the association of CRP SNP genotypes with stroke outcome after adjusting for non-genetic factors. RESULTS: Our data showed a significant association between the T allele of rs1130864 and poor functional outcome in IS patients. In addition, the presence of TT+CT genotypes of rs1130864 strongly predicted functional disability within the first 3 months, even after adjusting for potential confounders. CONCLUSIONS: Our study indicates that SNP rs1130864 in the CRP gene is an independent predictor of 3-month functional outcome in patients with first-onset IS in a Han Chinese population. Further studies in different ethnic groups are needed to validate our findings. PMID- 23980697 TI - Application of (1)h NMR spectroscopy-based metabolomics to sera of tuberculosis patients. AB - Nuclear magnetic resonance (NMR) spectroscopy is an ideal platform for the metabolic analysis of biofluids due to its high reproducibility, nondestructiveness, nonselectivity in metabolite detection, and the ability to simultaneously quantify multiple classes of metabolites. Tuberculosis (TB) is a chronic wasting inflammatory disease characterized by multisystem involvement, which can cause metabolic derangements in afflicted patients. In this study, we combined multivariate pattern recognition (PR) analytical techniques with (1)H NMR spectroscopy to explore the metabolic profile of sera from TB patients. A total of 77 serum samples obtained from patients with TB (n = 38) and healthy controls (n = 39) were investigated. Orthogonal partial least-squares discriminant analysis (OPLS-DA) was capable of distinguishing TB patients from controls and establishing a TB-specific metabolite profile. A total of 17 metabolites differed significantly in concentration between the two groups. Serum samples from TB patients were characterized by increased concentrations of 1 methylhistidine, acetoacetate, acetone, glutamate, glutamine, isoleucine, lactate, lysine, nicotinate, phenylalanine, pyruvate, and tyrosine, accompanied by reduced concentrations of alanine, formate, glycine, glycerolphosphocholine, and low-density lipoproteins relative to control subjects. Our study reveals the metabolic profile of sera from TB patients and indicates that NMR-based methods can distinguish TB patients from healthy controls. NMR-based metabolomics has the potential to be developed into a novel clinical tool for TB diagnosis or therapeutic monitoring and could contribute to an improved understanding of disease mechanisms. PMID- 23980699 TI - Mechanistic insights into the contribution of epithelial damage to airway remodeling. Novel therapeutic targets for asthma. AB - It has been suggested that an inherent airway epithelial repair defect is the root cause of airway remodeling in asthma. However, the relationship between airway epithelial injury and repair, airway remodeling, and airway hyperresponsiveness (AHR) has not been directly examined. We investigated the contribution of epithelial damage and repair to the development of airway remodeling and AHR using a validated naphthalene (NA)-induced murine model of airway injury. In addition, we examined the endogenous versus exogenous role of the epithelial repair peptide trefoil factor 2 (TFF2) in disease pathogenesis. A single dose of NA (200 mg/kg in 10 ml/kg body weight corn oil [CO] vehicle, intraperitoneally) was administered to mice. Control mice were treated with CO (10 ml/kg body weight, intraperitoneally). At 12, 24, 48, and 72 hours after NA or CO injection, AHR and various measures of airway remodeling were examined by invasive plethysmography and morphometric analyses, respectively. TFF2-deficient mice and intranasal treatment were used to examine the role of the epithelial repair peptide. NA treatment induced denudation and apoptosis of airway epithelial cells, goblet cell metaplasia, elevated AHR, and increased levels of endogenous TFF2. Airway epithelial changes peaked at 12 hours after NA treatment, whereas airway remodeling changes were observed from 48 hours. TFF2 was protective against epithelial damage and induced remodeling and was found to mediate organ protection via a platelet-derived growth factor-associated mechanism. Our findings directly demonstrate the contribution of epithelial damage to airway remodeling and AHR and suggest that preventing airway epithelial damage and promoting epithelial repair may have therapeutic implications for asthma treatment. PMID- 23980700 TI - Onset, risk factors, and impact of delirium in patients with traumatic spinal cord injury. AB - Delirium is a commonly reported acute care adverse event in patients with traumatic spinal cord injury (TSCI), but studies specifically investigating it in this population are lacking. The purpose of this study was to characterize the onset, risk factors, and impact of delirium in patients with TSCI. Patients discharged between 2008 and 2010 were identified from a prospective registry in an acute SCI center. Controls were matched to delirium cases based on date of discharge from acute care. Patient characteristics, risk factors, and the hospital unit (intensive care, spine step-down, spine ward) in which delirium occurred were collected retrospectively. Length of stay (LOS) was calculated and compared between cases and controls. A predictive model was built for patient characteristics and risk factors associated with delirium using logistical regression. There were 192 patients identified from the study group; 34 (17.7%) were delirium cases and 34 were selected as controls. Most delirious episodes were reported during high acuity care (76.5%). The median time interval between injury and delirium identification was 8.5 days (interquartile range=5-31). Age at injury (p<0.01) and initial motor score (p<0.05) were significantly associated with delirium. Patients with delirium had significantly greater LOS than controls (median LOS=46.9 vs. 15.3 days respectively, p<0.0001). Elderly patients who sustain a TSCI and have a low motor score on admission are at increased risk of delirium. These results could contribute to the development of a screening program to address the problem of delirium in the TSCI population. PMID- 23980701 TI - Speaking discourses and silent lips: women and gender-based portraits in sudden infant death publications. AB - AIMS AND OBJECTIVES: To reveal the prominent discourses and assigned social ordering given to women in paediatric research in Sweden concerning the subject of sudden infant death syndrome. BACKGROUND: There are no further studies in Sweden and elsewhere, regarding publishing portraits of women's social ordering in nursing research surrounding sudden infant death syndrome. DESIGN AND METHODS: The material encompassed all 55 articles/comments published by the Swedish Medical Journal 1980-2007 (7 March) as retrieved using selected keywords. The items were accessed in full text, and a discourse analytical approach was used triangulated with feminist theoretical perspectives. RESULTS: Three main discourses were identified: (1) women as bearers of guilt and accountability, (2) a social ordering where women's biology and lifestyles received great attention together with a tribute to mothers as having the principal responsibility as parent and caregiver and (3) gender-based health policy portrayals showing women/mothers in marginalised social and structural contexts or exposed to one sided disciplinary penal codes despite the Swedish welfare state having long declared gender equality in its family policies and in paediatric nursing practices. CONCLUSIONS: Although results from this study primarily relate to the Swedish contexts, they may also reflect the dual role in paediatric nursing practices in other countries, that is, (1) as being medical experts on children's health (paediatrics and nursing) and (2) as change agents with regard to childcare and practical recommendations directed to individuals (mothers, fathers, both or other caregivers of infants). RELEVANCE TO CLINICAL PRACTICE: The study highlights the needs of not merely seeing the family or the mother as ultimate and individual beneficiaries of medical/practical advice about child caring duties in infancy. Further studies are encouraged to recognise infant nursing practices, gender equality and safe parenthood in child health research and nursing practices. PMID- 23980702 TI - Host-habitat location by the parasitoid, Nasonia vitripennis Walker (Hymenoptera: Pteromalidae). AB - This study investigated the role of odorant cues used during host-habitat location by the generalist parasitoid, Nasonia vitripennis Walker. Nasonia vitripennis is a common parasitoid of Dipteran pupae found in association with decaying carrion. Behavioral assays were used to investigate the host-habitat searching behavior under different scenarios. First, we demonstrated N. vitripennis to be significantly attracted toward odorant cues associated with decaying meat. The biological activity of nine of the volatile molecules constituting the odor of decaying meat was tested on the searching behavior of parasitoid females through two complementary chemoecological approaches: electroantennography (EAG) and olfactometry bioassays. Butanoic acid and butan-1 ol elicited high olfactory responses, but no attraction was induced by these two chemicals. Behavioral assays showed that, among the VOCs tested, methyldisulfanylmethane (DMDS) was the only volatile chemical to induce attraction in N. vitripennis. PMID- 23980703 TI - Controllable superlubricity of glycerol solution via environment humidity. AB - The effect of humidity on the lubrication property of glycerol solution between steel surfaces has been investigated in this paper. A stable superlubricity with a friction coefficient about 0.006 has been found under the relative humidity between around 40% RH and 50% RH. Especially, it is noted that the lubrication state can be switched between superlubricity and nonsuperlubricity by adjusting humidity, which is attributed to the humidity-dependent hydrogen-bonding pattern in the solution. The mechanism of such superlubricity is attributed to the hydrated layer of water between the surface layers, which is formed by hydrogen bonded glycerol and water molecules and strong enough to bear load, absorbed on each side of the solid surfaces. The work has potential applications, providing a simple and environment-friendly way to accomplish controllable superlubrication between steel pairs, which are commonly used in industry. PMID- 23980704 TI - The role of muscle activation in cruciate disease. AB - Traditional investigations into the etiopathogenesis of canine cranial cruciate ligament (CCL) disease have focused primarily on the biological and mechanical insults to the CCL as a passive stabilizing structure of the stifle. However, with recent collaboration between veterinarians and physical therapists, an increased focus on the role of muscle activity and aberrant motor control mechanisms associated with anterior cruciate ligament (ACL) injuries and rehabilitation in people has been transferred and applied to dogs with CCL disease. Motor control mechanisms in both intact and cruciate-deficient human knees may have direct translation to canine patients, because the sensory and motor components are similar, despite moderate anatomic and biomechanical differences. Components of motor control, such as muscle recruitment and the coordination and amplitudes of activation are strongly influenced by afferent proprioceptive signaling from peri- and intra-articular structures, including the cruciate ligaments. In people, alterations in the timing or amplitude of muscle contractions contribute to uncoordinated movement, which can play a critical role in ACL injury, joint instability and the progression of osteoarthritis (OA). A better understanding of motor control mechanisms as they relate to canine CCL disease is vitally important in identifying modifiable risk factors and applying preventative measures, for development of improved surgical and rehabilitative treatment strategies. The purpose of this review article is to analyze the influence of altered motor control, specifically pelvic limb muscle activation, in dogs with CCL disease as evidenced by mechanisms of ACL injury and rehabilitation in people. PMID- 23980705 TI - "Drinking won't get you thinking": a content analysis of adolescent-created print alcohol counter-advertisements. AB - Involvement in creating antialcohol advertisements generates enthusiasm among adolescents; however, little is known about the messages adolescents develop for these activities. In this article, we present a content analysis of 72 print alcohol counteradvertisements created by high school (age 14-17 years old) and college (18-25 years old) students. The posters were content analyzed for poster message content, persuasion strategies, and production components, and we compared high school and college student posters. All of the posters used a slogan to highlight the main point/message of the ad and counterarguments/consequences to support the slogans. The most frequently depicted consequences were negative consequences of alcohol use, followed by negative-positive consequence comparison. Persuasion strategies were sparingly used in advertisements and included having fun/one of the gang, humor/unexpected, glamour/sex appeal, and endorsement. Finally, posters displayed a number of production techniques including depicting people, clear setting, multiple colors, different font sizes, and object placement. College and high school student constructed posters were similar on many features (e.g., posters displayed similar frequency of utilization of slogans, negative consequences, and positive negative consequence comparisons), but were different on the use of positive consequences of not using alcohol and before-after comparisons. Implications for teaching media literacy and involving adolescents and youth in developing alcohol prevention messages are discussed. PMID- 23980706 TI - Macular pigment levels do not influence C-Quant retinal straylight estimates in young Caucasians. AB - BACKGROUND: Individuals with higher than normal levels of macular pigment optical density (MPOD) are less affected by disability glare, when using glare source lights with a strong short-wavelength component. The aim of this study was to investigate whether estimates of retinal straylight from the Oculus Cataract Quantifier (C-Quant), which corresponds to disability glare, are associated with estimates of macular pigment levels in young Caucasian eyes. METHODS: Thirty seven Caucasian individuals (aged 19 to 40 years) with good visual acuity, free from ocular disease and with clear ocular media participated. Macular pigment optical density was measured at 0.5 degrees eccentricity from the foveal centre using a heterochromatic flicker photometry-based densitometer instrument from MacularMetrics. Retinal straylight was estimated using the C-Quant, a commercially available device, which uses a psychophysical compensation comparison method. RESULTS: Mean MPOD was 0.39 +/- 0.18 log units (range zero to 0.80) and was not significantly related to age (r = -0.07, p = 0.66). Mean straylight parameter (s) was 1.01 +/- 0.09 log units (range 0.86 to 1.21) and was not significantly related to age (r = -0.03, p = 0.86). Although there was a small tendency for straylight measurements to be reduced in individuals with higher levels of MPOD, there was no statistically significant relationship between retinal straylight and MPOD (r = -0.17, p = 0.30). CONCLUSION: Ocular straylight, estimated by the Oculus C-Quant, is little influenced by macular pigment optical density. As the C-Quant uses balanced (white) lights, it is suggested that the previous findings on the effect of macular pigment critically depend on the use of blue-dominant glare sources. PMID- 23980707 TI - Women's preference for traditional birth attendants and modern health care practitioners in Akpabuyo community of Cross River State, Nigeria. AB - The proportion of women who patronized traditional birth attendants (TBAs) or modern health care practitioners (MHCPs) was compared, including reasons for their choices. A comparative design was adopted to study 300 respondents selected through a multistage systematic random sampling technique. The instrument for data collection was a validated 21-item structured questionnaire. We observed that 75 (25%) patronized and 80 (27%) preferred TBAs, and 206 (69%) patronized and 220 (75%) preferred MHCPs, while 19 (6%) patronized both. The view that TBAs prayed before conducting deliveries was supported by a majority 75 (94%) of the respondents who preferred them. Factors associated with preference for TBAs should be addressed. PMID- 23980708 TI - Variability of subjective classifications of corneal topography maps from LASIK candidates. AB - PURPOSE: To evaluate the variability of subjective corneal topography map classification between different experienced examiners and the impact of changing from an absolute to a normative scale on the classifications. METHODS: Preoperative axial curvature maps using Scheimpflug imaging obtained with the Pentacam HR (Oculus Optikgerate, Wetzlar, Germany) and clinical parameters were sent to 11 corneal topography specialists for subjective classification according to the Ectasia Risk Scoring System. The study population included two groups: 11 eyes that developed ectasia after LASIK and 14 eyes that had successful and stable LASIK outcomes. Each case was first reviewed using the absolute scale masked to the patient group. After 3 months, the same cases were represented using a normative scale and reviewed again by the same examiners for new classifications masked to the patient group. RESULTS: Using the absolute scale, 17 of 25 (68%) cases had variations on the classifications from 0 to 4 for the same eye across examiners, and the overall agreement with the mode was 60%. Using the normative scale, the classifications from 11 of 25 (44%) cases varied from 0 to 4 for the same eye across examiners, and the overall agreement with the mode was 61%. Eight examiners (73%) reported statistically higher scores (P < .05) when using the normative scale. Considering all 550 topographic analyses (25 cases, 11 examiners, and two scales), the same classification from the two scales was reported for 121 case pairs (44%). CONCLUSION: There was significant inter observer variability in the subjective classifications using the same scale, and significant intra-observer variability between scales. Changing from an absolute to a normative scale increased the scores on the classifications by the same examiner, but significant inter-observer variability in the subjective interpretation of the maps still persisted. PMID- 23980709 TI - Mechanism of antimicrobial action of sodium metasilicate against Salmonella enterica serovar Typhimurium. AB - Sodium metasilicate (SMS) is an alkaline antimicrobial approved by the U.S. Department of Agriculture for use in poultry processing and ready-to-eat poultry products. The objectives of this study were to determine the effectiveness of SMS against Salmonella enterica serovar Typhimurium in suspension and to elucidate the antimicrobial mechanism of action of SMS. Salmonella Typhimurium (ATCC 14028) was exposed to 0 (positive control), 0.5%, 1%, 2% (wt/vol) SMS and 0.1 N NaOH (high pH) solutions for 1, 10, and 30 min. The viability of Salmonella Typhimurium cells treated with different SMS concentrations and high pH was determined on selective and nonselective media and by staining with fluorescent propidium iodide (PI) and SYTO9 nucleic acid stains in combination with flow cytometry. Transmission electron microscopy of Salmonella Typhimurium cells was performed to observe the changes at the cellular level following exposure to SMS and high pH treatments. Treating Salmonella Typhimurium cells with SMS (as low as 0.5%) resulted in immediate inactivation of Salmonella with no detectable survivors. The breakage in membrane integrity and loss of cell viability was observed by PI uptake by cells treated with SMS with subsequent flow cytometry. Salmonella Typhimurium cells exposed to SMS and high pH appeared wrinkled, vacuolated, and lysed with their cytoplasmic material leaking into extracellular matrix on transmission electron micrographs. The findings from this study indicate that SMS acts on the cytoplasmic membrane and causes lysis of the cells and leakage of intracellular contents. PMID- 23980710 TI - Enterobacter and Klebsiella species isolated from fresh vegetables marketed in Valencia (Spain) and their clinically relevant resistances to chemotherapeutic agents. AB - Occurrence of antibiotic-resistant pathogenic or commensal enterobacteria in marketed agricultural foodstuffs may contribute to their incorporation into the food chain and constitutes an additional food safety concern. In this work, we have determined the clinically relevant resistances to 11 common chemotherapeutic agents in Enterobacter and Klebsiella isolates from fresh vegetables from various sources (supermarkets and greengrocers' shops in Valencia, Spain). A total of 96 isolates were obtained from 160 vegetables analyzed (50% positive samples): 68 Enterobacter isolates (59 E. cloacae, two E. aerogenes, two E. cancerogenus, one E. gergoviae, and four E. sakazakii, currently Cronobacter spp.), and 28 Klebsiella isolates (19 K. oxytoca and 9 K. pneumoniae). Only seven isolates were susceptible to all agents tested, and no resistances to ceftazidime, ciprofloxacin, gentamicin, and chloramphenicol were detected. Most isolates were resistant to amoxicillin/clavulanic acid (74 [58 Enterobacter and 16 Klebsiella]) or to ampicillin (80 [55/25]). Other resistances were less frequent: nitrofurantoin (13 isolates [12/1]), tetracycline (6 [5/1]), co-trimoxazole (3 [3/0]), cefotaxime (1 [1/0]), and streptomycin (2 [1/1]). Multiresistant isolates to two (56 [41/15]), three (10 E. cloacae isolates), four (one E. cloacae and one K. pneumoniae isolate), and five (two E. cloacae isolates) chemotherapeutic agents were also detected. The presence of potential pathogens points to marketed fresh produce, which often is eaten raw, as a risk factor for consumer health. In addition, these results support the usefulness of these bacterial species as indicators of the spreading of antibiotic resistances into the environment, particularly in the food chain, and suggest their role as carriers of resistance determinants from farms to consumers, which may constitute an additional "silent" food safety concern. Therefore, there is a need to improve the hygienic quality of marketed fresh vegetables, from better methods to prevent contamination in the farms to the use of sanitizing practices at home. PMID- 23980711 TI - Catheter-free discharge on first postoperative day after bipolar transurethral resection of prostate: clinical outcomes of 100 cases. AB - OBJECTIVES: Our center has adopted a protocol for catheter-free first postoperative day discharge after bipolar transurethral resection of the prostate. We present the immediate, 1-month and 6-month outcomes of our first 100 cases following this protocol. METHODS: All bipolar transurethral resection of the prostate patients followed the protocol regardless of indications and background comorbid conditions. Bladder irrigation was stopped in the evening after transurethral resection of the prostate, and the catheter was removed at 06.00 hours. All patients were discharged on the first postoperative day. They were reviewed at 1 month and 6 months with the International Prostate Symptom Score and uroflowmetry. RESULTS: The mean age of the study population was 70.8 years. A total of 40 patients had urinary retention and were on an indwelling catheter before transurethral resection of the prostate. A total of 14 patients had other surgeries in the same setting as the transurethral resection of the prostate. The mean resection weight was 32.7 g. The mean irrigation time and catheter time were 4.2 h and 15.0 h, respectively. The improvement in terms of International Prostate Symptom Score, quality of life score, peak flow rate and post-void residual volume was comparable with those reported in the literature for bipolar transurethral resection of the prostate. Similarly, early and late complication rates also compared favorably with the literature. The perioperative cost was significantly reduced. CONCLUSIONS: Catheter-free first postoperative day discharge after bipolar transurethral resection of the prostate is safe with good clinical outcomes and cost savings. PMID- 23980712 TI - Cell patterning with mucin biopolymers. AB - The precise spatial control of cell adhesion to surfaces is an endeavor that has enabled discoveries in cell biology and new possibilities in tissue engineering. The generation of cell-repellent surfaces currently requires advanced chemistry techniques and could be simplified. Here we show that mucins, glycoproteins of high structural and chemical complexity, spontaneously adsorb on hydrophobic substrates to form coatings that prevent the surface adhesion of mammalian epithelial cells, fibroblasts, and myoblasts. These mucin coatings can be patterned with micrometer precision using a microfluidic device, and are stable enough to support myoblast differentiation over seven days. Moreover, our data indicate that the cell-repellent effect is dependent on mucin-associated glycans because their removal results in a loss of effective cell-repulsion. Last, we show that a critical surface density of mucins, which is required to achieve cell repulsion, is efficiently obtained on hydrophobic surfaces, but not on hydrophilic glass surfaces. However, this limitation can be overcome by coating glass with hydrophobic fluorosilane. We conclude that mucin biopolymers are attractive candidates to control cell adhesion on surfaces. PMID- 23980714 TI - Predation-associated divergence of male genital morphology in a livebearing fish. AB - Male genital morphology is remarkably diverse across internally fertilizing animals, a phenomenon largely attributed to sexual selection. Ecological differences across environments can alter the context of sexual selection, yet little research has addressed how this may influence the rapid, divergent evolution of male genitalia. Using the model system of Bahamas mosquitofish (Gambusia hubbsi) undergoing ecological speciation across blue holes, we used geometric morphometric methods to test (i) whether male genital shape (the small, approximately 1 mm long, distal tip of the sperm-transfer organ, the gonopodium) has diverged between populations with and without predatory fish and (ii) whether any observed divergence has a genetic basis. We additionally examined the effects of genetic relatedness and employed model selection to investigate other environmental factors (i.e. interspecific competition, adult sex ratio and resource availability) that could potentially influence genital shape via changes in sexual selection. Predation regime comprised the most important factor associated with male genital divergence in this system, although sex ratio and some aspects of resource availability had suggestive effects. We found consistent, heritable differences in male genital morphology between predation regimes: Bahamas mosquitofish coexisting with predatory fish possessed more elongate genital tips with reduced soft tissue compared with counterparts inhabiting blue holes without predatory fish. We suggest this may reflect selection for greater efficiency of sperm transfer and fertilization during rapid and often forced copulations in high-predation populations or differences in sexual conflict between predation regimes. Our study highlights the potential importance of ecological variation, particularly predation risk, in indirectly generating genital diversity. PMID- 23980713 TI - Sequential platelet-derived growth factor-simvastatin release promotes dentoalveolar regeneration. AB - OBJECTIVES: Timely augmentation of the physiological events of dentoalveolar repair is a prerequisite for the optimization of the outcome of regeneration. This study aimed to develop a treatment strategy to promote dentoalveolar regeneration by the combined delivery of the early mitogenic factor platelet derived growth factor (PDGF) and the late osteogenic differentiation factor simvastatin. MATERIALS AND METHODS: By using the coaxial electrohydrodynamic atomization technique, PDGF and simvastatin were encapsulated in a double-walled poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) (PDLLA-PLGA) microspheres in five different modes: microspheres encapsulating bovine serum albumin (BB), PDGF alone (XP), simvastatin alone (SB), PDGF-in-core and simvastatin-in-shell (PS), and simvastatin-in-core and PDGF-in-shell (SP). The microspheres were characterized using scanning electronic microscopy, and the in vitro release profile was evaluated. Microspheres were delivered to fill large osteotomy sites on rat maxillae for 14 and 28 days, and the outcome of regeneration was evaluated by microcomputed tomography and histological assessments. RESULTS: Uniform 20-MUm controlled release microspheres were successfully fabricated. Parallel PDGF simvastatin release was noted in the PS group, and the fast release of PDGF followed by the slow release of simvastatin was noted in the SP group. The promotion of osteogenesis was observed in XP, PS, and SP groups at day 14, whereas the SP group demonstrated the greatest bone fill, trabecular numbers, and thickest trabeculae. Bone bridging was evident in the PS and SP group, with significantly increased osteoblasts in the SP group, and osteoclastic cell recruitment was promoted in all bioactive molecule-treated groups. At day 28, osteogenesis was promoted in all bioactive molecule-treated groups. Initial corticalization was noted in the XP, PS, and SP groups. Osteoblasts appeared to be decreased in all groups, and significantly, a greater osteoclastic cell recruitment was noted in the SB and SP groups. CONCLUSIONS: Both PDGF and simvastatin facilitate dentoalveolar regeneration, and sequential PDGF simvastatin release (SP group) further accelerated the regeneration process through the enhancement of osteoblastogenesis and the promotion of bone maturation. PMID- 23980715 TI - Lethal interactions among vertebrate top predators: a review of concepts, assumptions and terminology. AB - Lethal interactions among large vertebrate predators have long interested researchers because of ecological and conservation issues. Research focusing on lethal interactions among vertebrate top predators has used several terms with a broad sense, and also introduced new terminology. We analysed the published literature with reference to the main underlying concepts and the use of terminology and its ecological context. The most frequently used terms in the literature were 'predation', 'intraguild predation', 'interference competition', and 'interspecific killing'. Most studies presented evidence of the killing of the victim (77%), but information regarding its consumption was not given in 48% of cases. More than half of the analysed studies (56%) had no solid information on the degree of competition between interacting species. By reviewing definitions and their underlying assumptions, we demonstrate that lethal interactions among large vertebrate predators could be designated using four terms-'predation', 'intraguild predation', 'interspecific competitive killing', and 'superpredation'-without the need to employ additional terminology that may increase confusion and misuse. For a correct framework of these lethal interactions it is critical to assess if the kill is consumed, if the victim is indeed a competitor of the killer, and if the prey is a high-order predator. However, these elements of the framework are simultaneously the most common constraints to studies of lethal interactions, since they often require a great effort to obtain. The proper use of terms and concepts is fundamental to understanding the causes behind lethal interactions and, ultimately, what is actually happening in these complex interactions. PMID- 23980716 TI - Total synthesis and detection of the bilirubin oxidation product (Z)-2-(3-ethenyl 4-methyl-5-oxo-1,5-dihydro-2H-pyrrol-2-ylidene)ethanamide (Z-BOX A). AB - The selective total synthesis of the pure Z-isomer of BOX A (8a), a product of oxidative heme degradation with significant physiological impact, was achieved in four to six steps starting from 3-bromo-4-methylfuran-2,5-dione (1). Z-BOX A forms a strong hydrogen bridge framework in the crystalline state. LC-MS techniques allow identification and characterization of isomeric forms of BOX A. PMID- 23980717 TI - Maternal mortality, birth with a health professional and distance to obstetric care in Indonesia and Bangladesh. AB - OBJECTIVE: To examine the relationship between distance to a health facility, consulting a health professional and maternal mortality. METHODS: Retrospective cohort study in Matlab, Bangladesh (1987-2005), to collect data on all pregnancies, births and deaths. In Java, Indonesia (2004-2005), an informant based approach identified maternal deaths and a population-based survey sampled women who survived birth. Logistic regression was used to examine the influence of distance to a health facility and uptake of a health professional on odds of dying. RESULTS: Maternal mortality was 320 per 100 000 births (95% CI: 290, 353) in Indonesia and 318 per 100 000 (95% CI: 272, 369) in Bangladesh. Women who lived further from health centres in both countries were less likely to have their births attended by health professionals than those who lived closer. For women who were assisted by a health professional, the odds of dying increased with increasing distance from a health centre [odds ratio per km; Indonesia: 1.07 (95% CI: 1.02-1.11), Bangladesh: 1.47 (95% CI: 1.22-1.78)]. There was no evidence for an association between distance to a health centre and maternal death for women who were not assisted by a health professional. CONCLUSIONS: Even in settings where health services are relatively close to women's homes, distance to a health facility affects maternal mortality for women giving birth with a health professional. Women may only seek professional care in an emergency and may be unable to reach timely care when living far away from a health centre. PMID- 23980718 TI - Anesthesia management with single injection paravertebral block for aorta coarctation in infant. AB - BACKGROUND: Thoracotomy causes severe pain in the postoperative period. Perioperative thoracic paravertebral block reduces pain score and may improve outcome after pediatric cardiac surgery. This prospective study was designed for the efficacy and duration of a single level, single injection ultrasound-guided thoracic paravertebral block (TPVB) for fifteen infants undergoing aortic coarctation repair. METHODS: After approval of the ethical committee and the relatives of the patients, 15 infants who had undergone thoracotomy were enrolled in the study. The patients received 0.5 ml.kg(-1) a bolus 0.25% bupivacaine with epinephrine 1 : 200 000 at T5-6 level after standard general anesthesia induction. Anesthesia depth with Index of Consciousness (IOC) and tissue oxygen saturation with cerebral (rSO2-C) and somatic thoracodorsal (rSO2-S) were monitored. Intraoperative hemodynamic and postoperative hemodynamic and pain scores were evaluated for 24 h after surgery. Face, Legs, Activity, Cry, Consolability (FLACC) score was utilized to measure postoperative pain in the intensive care unit. Rescue 0.05 mg.kg(-1) IV morphine was applied to patients in whom FLACC was >3. RESULTS: The median age of the patients was 4.5 (1-11) months, and the median intraoperative endtidal isoflurane concentration was 0.6% (0.3 0.8). The amount of remifentanil used intraoperatively was 4.5 (2.5-14) MUg.kg(-) (1) .h(-1). Intraoperative heart rate and blood pressure values significantly decreased compared with values detected at 5th, 10th, and 15th min after TPVB application, after incision prior and after cross-clamp (P < 0.01). The median time of first dose of morphine application after block was 320 (185-430) min. The median morphine consumption in 24 h was 0.16 (0.09-0.4) mg.kg(-1). The median length of postoperative intensive care unit and in-hospital stay times was 23 (1 67) h and 4 (1-10) days, respectively. CONCLUSION: We believe that TPVB, as part of a balanced anesthetic and analgesic regime, provides effective pain relief in patients undergoing aortic coarctation repair. PMID- 23980719 TI - Borrelia burgdorferi BbHtrA degrades host ECM proteins and stimulates release of inflammatory cytokines in vitro. AB - The Lyme disease spirochaete, Borrelia burgdorferi, causes damage to diverse host tissues and induces inflammation but the mechanisms of injury are poorly understood. We recently reported that a surface-exposed B. burgdorferi protease, which is expressed during human disease and is conserved within the major Lyme disease spirochaete species, degrades the extracellular matrix proteoglycan, aggrecan. Here we demonstrate that BbHtrA also degrades fibronectin and numerous proteoglycans found in skin, joints and neural tissues. BbHtrA degradation of fibronectin released known pro-inflammatory fibronectin fragments FnIII(13-14) and Fnf-29, which may amplify the inflammatory processes triggered by the presence of the bacteria. When this hypothesis was tested directly by exposing chondrocytes to BbHtrA in vitro, inflammatory cytokines (sICAM-1 and IL-6) and chemokines (CXCL1, CCL1, CCL2 and CCL5) that are hallmarks of Lyme disease were induced. These results provide the first evidence that, by utilizing BbHtrA, B. burgdorferi may actively participate in its dissemination and in the tissue damage and inflammation observed in Lyme disease. PMID- 23980720 TI - Effects of new antiepileptic drugs on circulatory markers for vascular risk in patients with newly diagnosed epilepsy. AB - Although it is well documented that long-term therapy with older antiepileptic drugs (AEDs) leads to an increase in risk for atherosclerosis, there has been only limited information regarding the vascular risk in patients who are treated with new AEDs. We therefore conducted a prospective longitudinal study to assess the potential effects of new AEDs on the circulatory markers for vascular risk in patients with newly diagnosed epilepsy. We recruited adult patients with epilepsy who began to receive monotherapy with one of the new AEDs, including levetiracetam (LEV), oxcarbazepine (OXC), and topiramate (TPM). Circulatory markers of vascular risk were measured twice before and after 6 months of AED monotherapy. A total of 109 patients completed the study (LEV, n = 40; OXC, n = 40; TPM, n = 29). Six months of monotherapy resulted in significant increases in low-density lipoprotein cholesterol (LEV, from 90.2 to 98.5 mg/dl, 9.2% increase, p = 0.025; OXC, from 96.5 to 103.2 mg/dl, 7.0% increase, p = 0.049), homocysteine (LEV, from 7.9 to 10.4 MUm, 31.6% increase, p = 0.001; OXC, from 8.7 to 11.5 MUm, 32.2% increase, p < 0.001; TPM, from 8.3 to 12.3 MUm, 48.2% increase, p < 0.001), apolipoprotein B (LEV, from 63.6 to 77.4 mg/dl, 21.7% increase; OXC, from 67.0 to 83.2 mg/dl, 24.2% increase; TPM, from 66.7 to 84.4 mg/dl, 26.5% increase; all p < 0.001), and apolipoprotein B/apolipoprotein A1 ratio (LEV, from 0.51 to 0.61, 19.6% increase; OXC, from 0.52 to 0.67, 28.8% increase; TPM, from 0.50 to 0.67, 34.0% increase; all p < 0.001). Serum apolipoprotein A1 and folate were significantly decreased in TPM (from 139.1 to 132.1 mg/dl, 5.0% decrease, p = 0.014) and OXC (from 8.1 to 6.4 ng/ml, 21.0% decrease, p = 0.046) groups, respectively. There were no significant changes in total cholesterol, triglyceride, high-density lipoprotein cholesterol, lipoprotein(a), and vitamin B12 in all three groups. Our findings suggest that treatment with some new AEDs might be associated with alterations in circulatory markers of vascular risk, which could contribute to the acceleration of atherosclerosis and increased risk of vascular diseases. PMID- 23980722 TI - Survival during long-term starvation: global proteomics analysis of Geobacter sulfurreducens under prolonged electron-acceptor limitation. AB - The bioavailability of terminal electron acceptors (TEAs) and other substrates affects the efficiency of subsurface bioremediation. While it is often argued that microorganisms exist under "feast or famine", in the laboratory most organisms are studied under "feast" conditions, whereas they typically encounter "famine" in nature. The work described here aims to understand the survival strategies of the anaerobe Geobacter sulfurreduces under TEA-starvation conditions. Cultures were starved for TEA and at various times sampled to perform global comparative proteomic analysis using iTRAQ to obtain insight into the dynamics of change in proteins/enzymes expression associated with change in nutrient availability/environmental stress. Proteins varying in abundance with a high level of statistical significance (p < 0.05) were identified to understand how cells change from midlog to (i) stationary phase and (ii) conditions of prolonged starvation (survival phase). The most highly represented and significantly up-regulated proteins in the survival phase cells are involved in energy metabolism, cell envelope, and transport and binding functional categories. The majority of the proteins were predicted to be localized in the cell membranes. These results document that changes in the outer and cytoplasmic membranes are needed for survival of Geobacter under starvation conditions. The cell shuts down anabolic processes and becomes poised, through changes in its membrane proteins, to sense nutrients in the environment, to transport nutrients into the cell, and to detect or utilize TEAs that are encountered. Under TEA limiting conditions, the cells turned from translucent white to red in color, indicating higher heme content. The increase in heme content supported proteomics results showing an increase in the number of cytochromes involved in membrane electron transport during the survival phase. The cell is also highly reduced with minimal change in energy charge (ATP to total adenine nucleotide ratio). Nonetheless, these proteomic and biochemical results indicate that even under TEA starvation cells remain poised for bioremediation. PMID- 23980721 TI - Survey of prophylactic intracameral antibiotic use in cataract surgery in an Australian context. PMID- 23980723 TI - Silencing of P-glycoprotein increases mortality in temephos-treated Aedes aegypti larvae. AB - Re-emergence of vector-borne diseases such as dengue and yellow fever, which are both transmitted by the Aedes aegypti mosquito, has been correlated with insecticide resistance. P-glycoproteins (P-gps) are ATP-dependent efflux pumps that are involved in the transport of substrates across membranes. Some of these proteins have been implicated in multidrug resistance (MDR). In this study, we identified a putative P-glycoprotein in the Ae. aegypti database based on its significantly high identity with Anopheles gambiae, Culex quinquefasciatus, Drosophila melanogaster and human P-gps. The basal ATPase activity of ATP-binding cassette transporters in larvae was significantly increased in the presence of MDR modulators (verapamil and quinidine). An eightfold increase in Ae. aegypti P gp (AaegP-gp) gene expression was detected in temephos-treated larvae as determined by quantitative PCR. To analyse the potential role of AaegP-gp in insecticide efflux, a temephos larvicide assay was performed in the presence of verapamil. The results showed an increase of 24% in temephos toxicity, which is in agreement with the efflux reversing effect. RNA interference (RNAi)-mediated silencing of the AaegP-gp gene caused a significant increase in temephos toxicity (57%). In conclusion, we have demonstrated for the first time in insects that insecticide-induced P-gp expression can be involved in the modulation of insecticide efflux. PMID- 23980724 TI - An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure. AB - OBJECTIVE: It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. DESIGN AND MEASUREMENTS: Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. SETTING: Field laboratories and clinical research facility. RESULTS: Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily 'toothbrush' regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8.5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. CONCLUSION: A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a 'toothbrush' regimen provides physiological cortisol exposure. PMID- 23980725 TI - Screening for hypopituitarism in 509 patients with traumatic brain injury or subarachnoid hemorrhage. AB - We performed a screening on patients with traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH) to determine the prevalence of post-traumatic hypopituitarism in neurorehabilitation in a cross-sectional, observational single center study. In addition, the therapeutic consequences of our screening were analyzed retrospectively. From February 2006 to August 2009, patients between 18 and 65 years (n=509) with the diagnosis of TBI (n=340) or SAH (n=169) were screened within two weeks of admittance to neurorehabilitation as clinical routine. Blood was drawn to determine fasting cortisol, free thyroxine (fT4), prolactin, testosterone or estradiol, and insulin-like growth factor I (IGF-I). Patients with abnormalities in the screening or clinical signs of hypopituitarism received further stimulation tests: growth hormone releasing hormone -L-arginine test and adrenocorticotrophic hormone (ACTH)-test (n=36); ACTH-test alone (n=26); or insulin tolerance test (n=56). In our screening of 509 patients, 28.5% showed lowered values in at least one hormone of the hypothalamus-pituitary axis and 4.5% in two or more axes. The most common disturbance was a decrease of testosterone in 40.7% of all men (in the following 13/131 men were given substitution therapy). Low fT4 was detected in 5.9% (n=3 were given substitution therapy). Low IGF-I was detected in 5.8%, low cortisol in 1.4%, and low prolactin in 0.2%; none were given substitution therapy. Further stimulation tests revealed growth hormone deficiency in 20.7% (n=19/92) and hypocortisolism in 23.7% (n=28/118). Laboratory values possibly indicating hypopituitarism (33%) were common but did not always implicate post-traumatic hypopituitarism. Laboratory values possibly indicating hypopituitarism were common in our screening but most patients were clinically not diagnosed as pituitary insufficient and did not receive hormone replacement therapy. A routine screening of all patients in neurorehabilitation without considering the time since injury, the severity of illness and therapeutic consequences seems not useful. PMID- 23980726 TI - Elevated serum levels of anti-Mullerian hormone can be introduced as a new diagnostic marker for polycystic ovary syndrome. AB - OBJECTIVE: To determine the possible role of anti-Mullerian hormone (AMH) in the diagnosis of polycystic ovary syndrome (PCOS) with a larger population of women and to evaluate its role as a new diagnostic marker. DESIGN: Cross-sectional study. SETTING: University hospital. POPULATION: A total of 570 women, with PCOS (n = 419) and without PCOS (n = 151). METHODS: Serum basal hormone; AMH, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, and thyroid stimulating hormone (TSH) levels were measured. Mean hormone levels were compared and the predictive value of serum AMH level was evaluated with the use of the receiver operating characteristic (ROC) curve analysis. RESULTS: No statistically significant differences were found between PCOS women and control groups in terms of age, body mass index and TSH levels. Differences between mean serum, FSH, LH and estradiol levels and LH/FSH ratio were found to be statistically significant (p < 0.001). Mean serum AMH level was higher in PCOS women than in controls (7.34 vs. 2.24 ng/mL, p < 0.001). The area under the ROC curve assay yielded a satisfactory result of 0.916 (95% confidence interval 0.897-0.935, p < 0.0001). The best compromise between 89.8% specificity and 80% sensitivity was obtained with a cut-off value of 3.94 ng/mL for PCOS diagnosis. CONCLUSIONS: Serum AMH measurement is very valuable in the diagnosis of PCOS women. The serum AMH level in women with hyperandrogenism or oligo-anovulation could indicate the diagnosis of PCOS when reliable ultrasonography data are not available or when typical clinical and laboratory findings are not available. The serum AMH level is a new and useful diagnostic tool in PCOS diagnosis. PMID- 23980727 TI - The effect of body fat distribution on ethnic differences in cardiometabolic risk factors of Chinese and Europeans. AB - This study aimed to examine the differences in body fat distribution and cardiometabolic risk between individuals of Chinese and European origin and the role of body fat distribution on ethnic differences in cardiometabolic risk. A total of 418 participants from the Multicultural Community Health Assessment Trial were assessed for visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAT), anthropometric variables, blood pressure, and lipid, insulin, and glucose levels. Multiple regression analyses were split by sex and adjusted for appropriate covariates in model 1a and further adjusted for VAT in model 1b or SAT in model 1c. A secondary model replaced body mass index (BMI) with waist circumference (WC). Chinese males had higher levels of triglycerides, insulin, homeostasis model assessment, and SAT than European males, as well as higher total cholesterol (TC), glucose, and VAT in the model adjusted for WC. Chinese females had higher glucose levels than European females after adjustment for either BMI or WC. When VAT was added to the models, differences in cardiometabolic risk factors remained significant but were attenuated between Chinese and European males and females; SAT did not attenuate the ethnic difference in cardiometabolic risk. These findings suggest that the higher VAT levels seen in the Chinese population do not fully account for the ethnic disparities in these risk factors. Given the observed interethnic difference in body composition, current BMI and WC cutoffs might be misleading when it comes to identifying Chinese individuals at risk for type 2 diabetes or cardiovascular disease. PMID- 23980728 TI - Characteristics of users of supplements containing vitamin D in Canada and associations between dose and 25-hydroxvitamin D. AB - Canadians using supplements containing vitamin D are more likely to have 25 hydroxyvitamin D (25(OH)D) levels consistent with the Recommended Dietary Allowance, particularly with the low UVB exposure during the winter. This study aimed to determine these users' characteristics and to examine the relationship between dosage and 25(OH)D using the 2007-2009 Canadian Health Measures Survey (n = 5604, 6-79 years of age). Logistic regression models examined the odds of supplement use within the preceding 30 days. Thirty-one percent used vitamin D supplements; 58.5% were female. In adjusted analyses, females' odds of supplement use were lower for those 12-19 years old (odds ratio (OR), 0.63; 95% CI, 0.41 0.96) and higher for those 60-79 years old (OR, 4.19; 95% CI, 2.69-6.64) and 40 59 years old (OR, 1.56; 95% CI, 1.10-2.20) compared with those 20-39 years old; their odds of supplement use were also higher for those of higher income (OR, 2.29; 95% CI, 1.26-4.16) and middle income (OR, 1.59; 95% CI, 1.03-2.46), those reporting >=1 chronic disease (OR, 1.48; 95% CI, 1.06-2.06), and those consuming milk >=1 time.day(-1) (OR, 1.35; 95% CI, 1.14-1.60). For males, increased use was associated with age 60-79 years (OR, 2.41; 95% CI, 1.54-3.77) and 6-11 years (OR, 1.77; 95% CI, 1.19-2.64) and higher income (OR, 2.12; 95% CI, 1.49-3.00) and middle income (OR, 1.55; 95% CI, 1.04-2.31). Use did not vary significantly by race, education, season, body mass index, health, or physical activity. A total of 35.7% of Canadians >50 years old took >=400 IU of vitamin D; 25(OH)D increased with increasing supplement dosage (r = 0.33) in winter, but differences between 1 399 IU and 400-999 IU were not significant. Usage and nonusage patterns are important to consider as ways of improving vitamin D intake are pursued. PMID- 23980729 TI - Upper- and lower-limb muscular fatigue during the 200-m front crawl. AB - The aim of this study was to investigate how upper- and lower-limb muscle fatigue evolves in a 200-m front crawl swimming race. Surface electromyography signals were collected from the flexor carpi radialis, biceps brachii, triceps brachii, pectoralis major, upper trapezius, tibialis anterior, biceps femoris, and rectus femoris muscles of 10 international-level swimmers; 4 underwater cameras were used for kinematic analysis. In addition, blood lactate was measured before and after the test using capillary blood samples. Swimming speed and stroke length decreased from the beginning to the end of the effort, whereas stroke frequency increased after an initial decrease to maintain speed. Concomitant with the decrease in speed, blood lactate increased to 11.12 (1.65) mmol.L(-1). The changes in stroke parameters were associated with an increase in integrated electromyography (20%-25%) and a decrease in spectral parameters (40%-60%) for all of the upper-limb muscles, indicating the reaching of submaximal fatigue. The fatigue process did not occur regularly during the 8 laps of the 200 m but was specific for each muscle and each subject. Lower-limb muscles did not present signals of fatigue, confirming their lower contribution to swimming propulsion. The test was conducted to individualize the training process to each muscle and each subject. PMID- 23980730 TI - Comparison of self-reported energy availability and metabolic hormones to assess adequacy of dietary energy intake in young elite athletes. AB - Previous intervention studies suggest that leptin, insulin, insulin-like growth factor 1 (IGF-1), and triiodthyronine (T3) are sensitive markers of inadequate energy intake in relation to exercise expenditures. Because of limitations in metabolic hormone measurements, self-reported energy availability (EA) based on food and activity records may present an alternative for characterizing energy status in young athletes. The purpose of the current study was to assess whether self-reported EA is related to leptin, insulin, IGF-1, and T3 in 352 young athletes. Sex, body composition, sport participation, and acute weight changes were considered as confounding variables. Multiple linear regression revealed that EA was negatively associated with leptin (p < 0.05) but not with insulin, IGF-1, or T3. Female athletes with low EA (<30 kcal.kg(-1) fat-free mass (FFM)) had higher leptin concentrations (5.0 +/- 4.7 ng.mL(-1)) and more body fat (18.3% +/- 5.1%) than did females with normal EA (leptin, 3.1 +/- 2.4 ng.mL(-1); body fat, 15.8% +/- 4.2%; both, p < 0.001). Athletes reporting acute weight loss (>1 kg.week(-1)) had a lower EA (18.9 +/- 7.4 kcal.kg(-1) FFM) than did weight-stable athletes (30.0 +/- 11.2 kcal.kg(-1) FFM) or athletes reporting weight gain (>1 kg; 49.7 +/- 13.1 kcal.kg(-1) FFM). IGF-1 and T3 were also reduced in athletes who lost weight (p < 0.01). This cross-sectional study reveals a lack of association between self-reported EA and metabolic hormones indicative of energy status in young athletes. Further studies are needed to investigate whether self reported EA and metabolic hormones are in better agreement when measured repeatedly. PMID- 23980731 TI - Effect of transcranial direct current stimulation on elbow flexor maximal voluntary isometric strength and endurance. AB - The effects of transcranial direct current stimulation (tDCS) on maximal voluntary isometric contraction (MVC) strength and the time to failure (TTF) in an isometric (30% MVC) muscle endurance test of the elbow flexors were investigated. Fifteen men (mean age, 27.7 +/- 8.4 years) were tested for MVC strength and TTF 2 times, separated by a 60-min rest. During the last 10 min of the rest period, 1 of 2 tDCS treatments or 1 sham intervention session was administered, in a randomized order, with 1 week between sessions. In the tDCS intervention, a 2 mA direct current was delivered for 10 min through an anode placed on the scalp, overlying the right motor cortical representation of the left arm; a cathode was secured over the right shoulder. In the sham intervention, the current was delivered for the first 30 s only. No significant differences between the first and second tDCS sessions were evident for MVC strength or TTF. For MVC strength (baseline, 66.0 +/- 11.4 Nm), postintervention measures decreased by 5.9% +/- 4.2% (p < 0.05), but no significant difference in the changes was evident between tDCS and sham sessions. TTF did not change significantly from preintervention (309.2 +/- 91.6 s) to postintervention (327.2 +/- 128.5 s), and there was no significant difference between interventions. It was concluded that the tDCS intervention did not affect muscle function, perhaps because of ceiling effects, in which the intervention does not enhance muscle function further when muscle function is already maximal. PMID- 23980732 TI - Explosive sport training and torque kinetics in children. AB - A high rate of force development (RFD) is often more important than maximal force in daily and sports activities. In children, resistance training has been shown to increase maximal force. It is unclear whether, or to what extent, can children improve RFD and force kinetics. For this study, we compared strength and force kinetics of boy gymnasts with those of untrained boys and untrained men. Eight boy gymnasts (age, 9.5 +/- 1.2 y), 20 untrained boys (age, 10.1 +/- 1.3 y), and 20 untrained men (age, 22.9 +/- 4.4 y) performed maximal, explosive, isometric elbow flexions (EF) and knee flexions (KF). Peak torque (maximal voluntary contraction (MVC)), elapsed times to 10%-100% MVC, peak rate of torque development (RTDpk), and other kinetics parameters were determined. When gymnasts were compared with untrained boys, size-normalized EF MVC was 11%-20% higher, RTDpk was 32% higher, and times to 30% and 80% MVC were 16% and 55% shorter, respectively (p < 0.05). No corresponding differences were observed in KF. Furthermore, although the normalized EF MVC was 28% lower in gymnasts than in men (p < 0.001), their torque kinetics parameters were similar. These findings highlight the specificity of gymnastics training, which markedly elevated the torque kinetics of young, prepubertal boys to adult levels, but only moderately affected peak torque. It is suggested that neurologic adaptations, such as enhanced firing and activation rates or increased type II motor-unit recruitment, as well as changes in musculotendinous stiffness, could explain these findings. PMID- 23980733 TI - Acute sodium ingestion has no effect on short-term food and water intake, subjective appetite, thirst, or glycemic response in healthy young men. AB - The high intake of dietary sodium (Na(+)) has been associated with obesity and insulin resistance, sparking the hypothesis that the consumption of salty foods affects food intake (FI) and postprandial blood glucose (BG) response. Therefore, we conducted 2 randomized repeated-measures experiments to examine the acute effects of the Na(+) content of solid food and beverage on FI, water intake (WI), subjective appetite, thirst, and BG. FI and WI were measured at ad libitum pizza test meals; appetite, thirst, and BG were measured at baseline and at regular intervals before and after meals. In the first experiment, 16 males (mean body mass index (BMI), 22.2 kg.m(-2)) consumed a low-Na(+) (71 mg) bean preload (300 kcal) with or without 740 mg or 1480 mg of added Na(+) 120 min prior to the pizza meal. Participants ate 116 kcal more at the test meal after consuming beans with 740 mg of added Na(+) than after beans with 1480 mg of added Na(+). In the second experiment, 19 males (mean BMI, 23.2 kg.m(-2)) consumed a low-Na(+) (62 mg) tomato beverage (73 kcal) with or without 500, 1000, 1500, or 2000 mg of added Na(+) 30 min prior to a pizza meal. The beverage with 2000 mg of added Na(+) led to higher WI during the pizza meal than the beverage with 500 mg of added Na(+). However, compared with the control conditions (no added Na(+)), added Na(+) treatments had no effect on dependent measures in either experiment. In conclusion, the acute intake of Na(+), in a solid or liquid form, did not affect short-term subjective ratings of appetite or thirst, ad libitum FI or WI, or BG in healthy young men. PMID- 23980734 TI - Effect of resveratrol and quercetin supplementation on redox status and inflammation after exercise. AB - Resveratrol and quercetin function as antioxidants and anti-inflammatories in vitro, but these mechanisms have been minimally examined in combination in exercising humans. The purpose of this investigation was to examine supplementation as a countermeasure against oxidative stress and inflammation in response to exercise. Fourteen athletes were randomly assigned, in a double-blind crossover design, to a resveratrol and quercetin combination (RQ) (120 mg resveratrol and 225 mg quercetin for 6 days and 240 mg resveratrol and 450 mg quercetin on day 7 just prior to exercise) or to placebo (P). There was a 1-week washout between trials. Blood was taken at baseline, pre-exercise, immediately after exercise, and 1 h after exercise. Plasma was analyzed for oxidative stress (F2-isoprostanes and protein carbonyls), antioxidant capacity (ferric-reducing ability of plasma (FRAP), Trolox equivalent antioxidant capacity (TEAC), oxygen radical absorptive capacity (ORAC)), and inflammation (cytokine interleukin (IL) 8 and C-reactive protein (CRP)). Statistical design utilized a 2 * 3 ANOVA and Student's t test. Pre-exercise values were not different from baseline for any measure. The postexercise increase in F2-isoprostanes was significantly less (p = 0.039 interaction) with RQ (68%) than with P (137%). Protein carbonyls, FRAP, ORAC, and TEAC significantly increased after exercise but were not affected by treatment. IL-8 and CRP increased significantly immediately after exercise but were not affected by treatment. These data indicate that RQ significantly reduces exercise-induced lipid peroxidation without associated changes in inflammation or plasma antioxidant status. PMID- 23980735 TI - Effect of short-duration lipid supplementation on fat oxidation during exercise and cycling performance. AB - The effect of intramyocellular lipids (IMCLs) on endurance performance with high skeletal muscle glycogen availability remains unclear. Previous work has shown that a lipid-supplemented high-carbohydrate (CHO) diet increases IMCLs while permitting normal glycogen loading. The aim of this study was to assess the effect of fat supplementation on fat oxidation (Fox) and endurance performance. Twenty-two trained male cyclists performed 2 simulated time trials (TT) in a randomized crossover design. Subjects cycled at ~53% maximal voluntary external power for 2 h and then followed 1 of 2 diets for 2.5 days: a high-CHO low-fat (HC) diet, consisting of CHO 7.4 g.kg(-1).day(-1) and fat 0.5 g.kg(-1).day(-1); or a high-CHO fat-supplemented (HCF) diet, which was a replication of the HC diet with ~240 g surplus fat (30% saturation) distributed over the last 4 meals of the diet period. On trial morning, fasting blood was sampled and Fox was measured during an incremental exercise; a ~1-h TT followed. Breath volatile compounds (VOCs) were measured at 3 time points. Mental fatigue, measured as reaction time, was evaluated during the TT. Plasma free fatty acid concentration was 50% lower after the HCF diet (p < 0.0001), and breath acetone was reduced (p < 0.05) "at rest". Fox peaked (~0.35 g.kg(-1)) at ~42% peak oxygen consumption, and was not influenced by diet. Performance was not significantly different between the HCF and HC diets (3369 +/- 46 s vs 3398 +/- 48 s; p = 0.39), nor were reaction times to the attention task and VOCs (p = NS for both). In conclusion, the short-term intake of a lipid supplement in combination with a glycogen-loading diet designed to boost intramyocellular lipids while avoiding fat adaptation did not alter substrate oxidation during exercise or 1-hour cycling performance. PMID- 23980736 TI - Is the frequency of weekly moderate-to-vigorous physical activity associated with the metabolic syndrome in Canadian adults? AB - Previous physical activity guidelines recommended that adults be active on most or all days of the week. Current guidelines recommend accumulating >=150 min/week of moderate-to-vigorous physical activity (MVPA), with no recommendation for frequency. This study examined the association between the frequency of physical activity throughout the week and the metabolic syndrome (MetS) in physically active adults. This cross-sectional study included 2324 adults aged 18-64 years from the 2007-2011 cycles of the nationally representative Canadian Health Measures Survey. MVPA was measured over 7 days using Actical accelerometers. Physically active participants (>=150 min/week of MVPA) were assigned to frequently active (>=5 days/week with >=30 min of MVPA) and infrequently active (1-4 days/week with >=30 min of MVPA) groups. Associations were examined using logistic regression controlling for age, sex, and education. The relative odds of the MetS was 4.43 (95% confidence interval: 2.26-8.69) times higher in physically inactive participants than physically active participants. Within physically active participants, the relative odds of the MetS was 1.73 (0.87-3.41) times higher in the infrequently active group than the frequently active group. However, this was not a significant difference (p = 0.11), and after adjustment for total weekly MVPA, the relative odds of the MetS in the infrequently active group was reduced to 0.85 (0.42-1.72). The frequency of physical activity throughout the week was not independently associated with the MetS among active adults. Conversely, the weekly volume of MVPA was strongly associated with the MetS. PMID- 23980737 TI - Comparative effects of single-mode vs. duration-matched concurrent exercise training on body composition, low-grade inflammation, and glucose regulation in sedentary, overweight, middle-aged men. AB - The effect of duration-matched concurrent exercise training (CET) (50% resistance (RET) and 50% endurance (EET) training) on physiological training outcomes in untrained middle-aged men remains to be elucidated. Forty-seven men (age, 48.1 +/ 6.8 years; body mass index, 30.4 +/- 4.1 kg.m(-2)) were randomized into 12-weeks of EET (40-60 min of cycling), RET (10 exercises; 3-4 sets * 8-10 repetitions), CET (50% serial completion of RET and EET), or control condition. The following were determined: intervention-based changes in fitness and strength; abdominal visceral adipose tissue (VAT), total body fat (TB-FM) and fat-free (TB-FFM) mass; plasma cytokines (C-reactive protein (CRP), tumor necrosis factor-alpha (TNFalpha) interleukin-6 (IL-6)); muscle protein content of p110alpha and glucose transporter 4 (GLUT4); mRNA expression of GLUT4, peroxisome proliferator activated receptor-gamma coactivator-1alpha-beta, cytochrome c oxidase, hexokinase II, citrate synthase; oral glucose tolerance; and estimated insulin sensitivity. CET promoted commensurate improvements of aerobic capacity and muscular strength and reduced VAT and TB-FM equivalently to EET and RET (p < 0.05), yet only RET increased TB-FFM (p < 0.05). Although TNFalpha and IL-6 were reduced after all training interventions (p < 0.05), CRP remained unchanged (p > 0.05). EET reduced area under the curve for glucose, insulin, and C-peptide, whilst CET and RET respectively reduced insulin and C-peptide, and C-peptide only (p < 0.05). Notwithstanding increased insulin sensitivity index after all training interventions (p < 0.05), no change presented for GLUT4 or p110alpha total protein, or chronic mRNA expression of the studied mitochondrial genes (p > 0.05). In middle-aged men, 12 weeks of duration-matched CET promoted commensurate changes in fitness and strength, abdominal VAT, plasma cytokines and insulin sensitivity, and an equidistant glucose tolerance response to EET and RET; despite no change of measured muscle mechanisms associative to insulin action, glucose transport, and mitochondrial function. PMID- 23980738 TI - Associations among evening snacking, screen time, weight status, and overall diet quality in young adolescents. AB - The purpose of this study was to determine the associations among evening snacking (food choices, portion sizes), afterschool-evening screen time, overall diet quality, and weight status. Participants consisted of 1008 young adolescents (secondary analyses, n = 651) from schools in Windsor-Essex, Ontario. The Web based Food Behaviour Questionnaire, including a 24-h diet recall, was used to assess eating and screen time behaviours (television and video and computer games), as well as nutrient intake; height and weight for BMI were measured using a stadiometer. Results indicated that the majority of participants (62%) consumed an evening snack that contributed approximately 11% of their daily caloric intake. Evening snacking was associated with an overall good diet quality compared with that of non-evening snackers (p < 0.001). Increased afterschool evening screen time was associated with fewer evening snack servings of vegetables and fruit (p < 0.05) and an overall increase in evening snack food portion sizes (p < 0.001). After accounting for other evening snacking factors, participants with greater than 6 h of afterschool-evening screen time were less likely to have a good overall diet quality compared with those with less than 1 h of afterschool-evening screen time. Therefore, increased screen time, because it is associated with greater evening snack portion sizes and overall poor diet quality, is of great concern regarding young adolescents' evening behaviour. PMID- 23980739 TI - [Not Available]. AB - The objective of this study was to examine the influence of Ramadan fast on appetite sensations, nutritional intakes and body weight in Malians with type 2 diabetes. Appetite sensations were assessed before Ramadan and then at the second, ninth, and sixteenth days of Ramadan (period). A total of 24 subjects recorded their appetite sensations every 2 h between 0800 and 2200 h using visual analogue scales. Daily energy intakes were estimated by a 48-h food recall (before and during Ramadan). Results showed a significant sex effect for desire to eat (p < 0.04) and a significant period effect for desire to eat and fullness (p < 0.01). Significant sex by period interactions were observed for fullness (p < 0.001), desire to eat (p < 0.01), and prospective food consumption (p < 0.03). Moreover, significant sex by period by time interactions were found for all appetite sensations (p < 0.007). Interaction effects were mainly explained by sex differences in appetite sensations before rather than during Ramadan. Although a significant body weight loss was observed in men and a significant decrease in waist circumference was found in women (p < 0.05), no significant changes in reported average daily energy intakes were observed in either men or women. According to these preliminary results, Ramadan fasting has an impact on appetite sensations that is probably not the same in men and women. PMID- 23980742 TI - Electrostatic force curves in finite-size-ion electrolytes. AB - We obtain analytical expressions for electrostatic forces between an atomic force microscope tip and a sample immersed in an electrolyte. These simple expressions relate force to tip-sample separation explicitly incorporating tip size, solvent ion size, and solvent ion concentration. If the ions are much smaller than the tip-sample gap, the force decays monotonically, a consequence of the corresponding monotonic decays of the correlation function in the Debye-Huckel context. If the ions are of size comparable to the tip-sample gap, then oscillations appear superimposed on the overall decay, a consequence of the geometric mismatch between ion cluster size and the gap size. PMID- 23980743 TI - Efficacy of endodontic applications of ozone and low-temperature atmospheric pressure plasma on root canals infected with Enterococcus faecalis. AB - This study aimed to compare the antimicrobial efficacy of low-temperature atmospheric pressure plasma (LTAPP) design and gaseous ozone delivery system with 2.5% NaOCl on Enterococcus faecalis in root canal walls and dentine tubules. The samples were divided into LTAPP (n = 12), ozone (n = 12), NaOCl (positive control, n = 12) and saline (negative control, n = 6) groups. Microbial samples were collected using paper points and dentin chips from root canals. Antimicrobial efficacy was assessed by counting the colony-forming units of Ent. faecalis before and after each irrigation protocol. Data were analysed using Kruskal-Wallis, Wilcoxon signed-rank, Friedman and Bonferroni t (Dunn's test) tests (P = 0.05). The microbial sampling with paper points showed antibacterial efficacy of NaOCl, LTAPP, ozone and saline in descending order, respectively (P < 0.05). The microbial sampling with dentin chips demonstrated a superior efficacy of LTAPP compared with NaOCl in the middle third (P < 0.05), while both had similar effects in coronal and apical thirds (P > 0.05). NaOCl and LTAPP were better than ozone at the coronal and middle parts of the root canals (P < 0.05). These findings led us to suggest that LTAPP, which has no thermal and chemical effects, may be of great aid in endodontic treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: The present study handles different perspectives on chemomechanical preparation of root canals. Ozone and low-temperature atmospheric pressure plasma (LTAPP) were investigated to determine whether they could be an alternative for NaOCl. Up to now, chemical solutions (NaOCl, chlorhexidine digluconate, etc...) have been used to disinfect the root canals. When the reported effects of LTAPP on biological and chemical decontamination were taken into consideration, a question rose whether it has antimicrobial efficacy in root canals infected with E. faecalis. According to the findings of the present study, LTAPP may constitute a promising aid in endodontics in disinfection of root canals. PMID- 23980744 TI - Increases of ferrous iron oxidation activity and arsenic stressed cell growth by overexpression of Cyc2 in Acidithiobacillus ferrooxidans ATCC19859. AB - Acidithiobacillus ferrooxidans plays an important role in bioleaching in reproducing the mineral oxidant of ferric iron (Fe(3+) ) by oxidization of ferrous iron (Fe(2+) ). The high-molecular-weight c-type cytochrome Cyc2 that is located in the external membrane is postulated as the first electron carrier in the Fe(2+) oxidation respiratory pathway of A. ferrooxidans. To increase ferrous iron oxidation activity, a recombinant plasmid pTCYC2 containing cyc2 gene under the control of Ptac promoter was constructed and transferred into A. ferrooxidans ATCC19859. The transcriptional level of cyc2 gene was increased by 2.63-fold and Cyc2 protein expression was observed in the recombinant strain compared with the control. The ferrous iron oxidation activity and the arsenic stressed cell growth of the recombinant strain were also elevated. PMID- 23980745 TI - SCORS-G stimulus characteristics of select thematic apperception test cards. AB - There has been surprisingly little research into the stimulus properties of the Thematic Apperception Test Cards (TAT; Murray, 1943). This study used the Social Cognition and Object Relations Scale-Global Rating Method (SCORS-G; Stein, Hilsenroth, Slavin-Mulford, & Pinsker, 2011 ; Westen, 1995 ) to explore the stimulus properties of select TAT cards in a clinical sample. The SCORS-G is a theoretically based and empirically validated measure of object relations that has widely been used in TAT research. A sample of 80 patients referred for psychological assessment at a large Northeastern hospital were administered the TAT (Cards 1, 2, 3BM, 4, 13MF, 12M, and 14) as part of their assessment battery. Trained raters scored the narratives using the SCORS-G. The SCORS-G ratings were analyzed to determine the nature and degree of object representation "pull" both across and within the TAT cards. The results showed that Cards 3BM and 13MF exhibited the greatest card pull for negative pathological object representations, and Card 2 displayed the highest card pull for adaptive and mature object representations. Both clinical and research related implications are discussed. PMID- 23980746 TI - Post-marketing surveillance of prescription drug safety: past, present, and future. PMID- 23980747 TI - Rethinking insurance coverage of "experimental" Applied Behavioral Analysis therapy and its usefulness in combating autism spectrum disorder. PMID- 23980748 TI - To include or to exclude? The policy question plaguing women's role in clinical trials. PMID- 23980749 TI - Magnetic resonance spectroscopy imaging-directed transrectal ultrasound biopsy increases prostate cancer detection in men with prostate-specific antigen between 4-10 ng/mL and normal digital rectal examination. AB - OBJECTIVES: To evaluate the ability of magnetic resonance spectroscopic imaging to improve prostate cancer detection rate. METHODS: A retrospective analysis was carried out of 278 men with prostate-specific antigen in the range of 4-10 ng/mL and normal digital rectal examination who underwent transrectal ultrasound-guided prostate biopsy. Outcomes were compared between men who had a standard biopsy versus those who also underwent a prebiopsy magnetic resonance spectroscopic imaging. Men with an abnormal voxel on magnetic resonance spectroscopic imaging had standard transrectal ultrasound biopsies plus biopsies directed to the abnormal voxels. RESULTS: The study group (n = 140) and control group (n = 138) were similar in baseline parameters, such as mean age, prostate size and mean prostate-specific antigen. The overall cancer detection in the magnetic resonance spectroscopic imaging positive group (24.4%) was more than double that of the control group (10.1%). On comparing the magnetic resonance spectroscopic imaging results with the transrectal ultrasound biopsy findings, magnetic resonance spectroscopic imaging had 95.6% sensitivity, 41.9% specificity, a positive predictive value of 24.4%, a negative predictive value of 98% and an accuracy of 51.4%. CONCLUSIONS: Magnetic resonance spectroscopic imaging-directed transrectal ultrasound biopsy increases the cancer detection rate compared with standard transrectal ultrasound biopsy in patients with normal digital rectal examination and elevated prostate-specific antigen in the range of 4-10 ng/mL. PMID- 23980750 TI - Chondrogenesis of mesenchymal stem cells in an osteochondral environment is mediated by the subchondral bone. AB - In articular cartilage repair, cells that will be responsible for the formation of repair tissue are often exposed to an osteochondral environment. To study cartilage repair mechanisms in vitro, we have recently developed a bovine osteochondral biopsy culture model in which cartilage defects can be simulated reproducibly. Using this model, we now aimed at studying the chondrogenic potential of human bone marrow-derived mesenchymal stem cells (hBMSCs) in an osteochondral environment. In contrast to standard in vitro chondrogenesis, it was found that supplementing transforming growth factor beta (TGFbeta) to culture medium was not required to induce chondrogenesis of hBMSCs in an osteochondral environment. hBMSC culture in defects created in osteochondral biopsies or in bone-only biopsies resulted in comparable levels of cartilage-related gene expression, whereas culture in cartilage-only biopsies did not induce chondrogenesis. Subcutaneous implantation in nude mice of osteochondral biopsies containing hBMSCs in osteochondral defects resulted in the formation of more cartilaginous tissue than hBMSCs in chondral defects. The subchondral bone secreted TGFbeta; however, the observed results could not be attributed to TGFbeta, as either capturing TGFbeta with an antibody or blocking the canonical TGFbeta signaling pathway did not result in significant changes in cartilage related gene expression of hBMSCs in the osteochondral culture model. Inhibition of BMP signaling did not prevent chondrogenesis. In conclusion, we demonstrate that chondrogenesis of hBMSCs is induced by factors secreted from the bone. We have strong indications that this is not solely mediated by members of the TGFbeta family but other, yet unknown, factors originating from the subchondral bone appeared to play a key role. PMID- 23980751 TI - The impact of stent strut porosity on reducing flow in cerebral aneurysms. AB - BACKGROUND AND PURPOSE: Flow diversion techniques are increasingly used to treat cerebral aneurysms. The optimal stent porosity to achieve aneurysm obliteration would allow clinicians to treat aneurysms more effectively. We sought to determine the optimal porosity threshold in an in vitro flow model that would lead to stagnation of flow in an aneurysm. METHODS: Using a 3-dimensional (3-D) sidewall aneurysm glass model and a 2-dimensional (2-D) cavity model, we measured the total kinetic energy (TKE) in the cavity and aneurysm using digital particle image velocimetry by adjusting for the surface area of a metal mesh across the cavity. Additionally, we assessed how a gap between the mesh and 2-D cavity impacted circulatory patterns within a cavity. RESULTS: In the 3-D aneurysm model, we noted a 90.4% reduction in TKE after placement of a stent. In the 2-D cavity model, we adjusted the porosity between 39.1% and 64.8% and noted a reduction in the TKE by 99.75% and 93.9%, respectively. When there was a gap between the mesh and entry into the cavity, unfavorable circulatory conditions occurred with the development of counterclockwise flow that had increased TKE within the cavity. CONCLUSIONS: The current model demonstrates a method to evaluate the optimal porosity threshold to achieve thrombosis of an aneurysm as a primary modality. Moreover, a gap may occur between the stent and the aneurysm that may create unfavorable circulatory conditions by increasing flow into the aneurysm. PMID- 23980752 TI - Mechanisms and ecological role of carbon transfer within coastal seascapes. AB - Worldwide, coastal systems provide some of the most productive habitats, which potentially influence a range of marine and terrestrial ecosystems through the transfer of nutrients and energy. Several reviews have examined aspects of connectivity within coastal seascapes, but the scope of those reviews has been limited to single systems or single vectors. We use the transfer of carbon to examine the processes of connectivity through multiple vectors in multiple ecosystems using four coastal seascapes as case studies. We discuss and compare the main vectors of carbon connecting different ecosystems, and then the natural and human-induced factors that influence the magnitude of effect for those vectors on recipient systems. Vectors of carbon transfer can be grouped into two main categories: detrital particulate organic carbon (POC) and its associated dissolved organic and inorganic carbon (DOC/DIC) that are transported passively; and mobile consumers that transport carbon actively. High proportions of net primary production can be exported over meters to hundreds of kilometers from seagrass beds, algal reefs and mangroves as POC, with its export dependent on wind-generated currents in the first two of these systems and tidal currents for the last. By contrast, saltmarshes export large quantities of DOC through tidal movement, while land run-off plays a critical role in the transport of terrestrial POC and DOC into temperate fjords. Nekton actively transfers carbon across ecosystem boundaries through foraging movements, ontogenetic migrations, or 'trophic relays', into and out of seagrass beds, mangroves or saltmarshes. The magnitude of these vectors is influenced by: the hydrodynamics and geomorphology of the region; the characteristics of the carbon vector, such as their particle size and buoyancy; and for nekton, the extent and frequency of migrations between ecosystems. Through a risk-assessment process, we have identified the most significant human disturbances that affect the integrity of connectivity among ecosystems. Loss of habitat, net primary production (NPP) and overfishing pose the greatest risks to carbon transfer in temperate saltmarsh and tropical estuaries, particularly through their effects on nekton abundance and movement. In comparison, habitat/NPP loss and climate change are likely to be the major risks to carbon transfer in temperate fjords and temperate open coasts through alteration in the amount of POC and/or DOC/DIC being transported. While we have highlighted the importance of these vectors in coastal seascapes, there is limited quantitative data on the effects of these vectors on recipient systems. It is only through quantifying those subsidies that we can effectively incorporate complex interactions into the management of the marine environment and its resources. PMID- 23980753 TI - A single molecular light-up sensor for quantification of Hg2+ and Ag+ in aqueous medium: high selectivity toward Hg2+ over Ag+ in a mixture. AB - A bis-heteroleptic Ru(II) complex (1) is presented that acts as a single molecular dual analyte sensor and quantifies Hg(2+) and Ag(+) by luminescence at two different wavelengths. The sensor has stronger binding to Hg(2+) than to its likely competitor Ag(+) allowing quantification of Hg(2+) in a sample with Ag(+) without a masking agent. 1 also selectively senses Ag(+) in the absence of Hg(2+) by enhancing the PL intensity at a different wavelength. PMID- 23980755 TI - Blood lead concentrations in sub-Saharan African children below 6 years: systematic review. AB - OBJECTIVE: To assess the geometric mean of blood lead levels in children aged below 6 years living in sub-Saharan Africa. METHODS: Search strategies were developed in MEDLINE, Web of Science and Google scholar system, supplemented by screening of references from included papers and review articles. Studies including children younger than 6 years residing in sub-Saharan Africa (SSA) were eligible. The studies were assessed for quality of methods for blood collection, for participants' recruitment and for quality control for lead analyses. Data were extracted and synthetised by estimating the mean weighted by sample size. RESULTS: A total of 11 148 published papers were identified with only 16 studies conducted in SSA. Only nine of them were relevant of inclusion criteria. The weighted mean of blood lead levels was 13.1 MUg/dl. Five of included studies were classified as being less likely to present selection bias, having performed venipuncture and adequate quality control for lead analyses. The weighted mean from analyses involving only these studies was 16.2 MUg/dl. Six of the included studies reported the prevalence of blood lead levels >=10 MUg/dl; levels ranged from 7.0% to 70.9%. Only one study reported the prevalence of blood lead levels >=5 MUg/dl (50%). CONCLUSIONS: The geometric mean of blood lead levels in sub Saharan African children is still elevated relative to the US children. The new standard from the Centers for Disease Control and Prevention (5 MUg/dl) implies that important efforts should be directed towards the initiation (or reinforcement) of prevention programmes and thorough research studies in sub Saharan Africa. PMID- 23980754 TI - Sphingosine kinase A is a pleiotropic and essential enzyme for Leishmania survival and virulence. AB - Sphingosine kinase is a key enzyme in sphingolipid metabolism, catalysing the conversion of sphingosine or dihydrosphingosine into sphingosine-1-phosphate or dihydrosphingosine-1-phosphate respectively. In mammals, sphingosine-1-phosphate is a powerful signalling molecule regulating cell growth, differentiation, apoptosis and immunity. Functions of sphingosine kinase or sphingosine-1 phosphate in pathogenic protozoans are virtually unknown. While most organisms possess two closely related sphingosine kinases, only one sphingosine kinase homologue (SKa) can be identified in Leishmania, which are vector-borne protozoan parasites responsible for leishmaniasis. Leishmania SKa is a large, cytoplasmic enzyme capable of phosphorylating both sphingosine and dihydrosphingosine. Remarkably, deletion of SKa leads to catastrophic defects in both the insect stage and mammalian stage of Leishmania parasites. Genetic and biochemical analyses demonstrate that proper expression of SKa is essential for Leishmania parasites to remove toxic metabolites, to survive stressful conditions, and to cause disease in mice. Therefore, SKa is a pleiotropic enzyme with vital roles throughout the life cycle of Leishmania. The essentiality of SKa and its apparent divergence from mammalian counterparts suggests that this enzyme can be selectively targeted to reduce Leishmania infection. PMID- 23980756 TI - Is it time to include point-of-care ultrasound in general surgery training? A review to stimulate discussion. AB - BACKGROUND: Point-of-care ultrasound scanning or POCUS is a focused ultrasound (US) scan, performed by non-imaging clinicians during physical examination, an invasive procedure or surgery. As this technology becomes cheaper, smaller and easier to use, its scope for use by surgeons grows, a trend that may generate a gap between use and training. Opportunities for enhanced general surgery skill sets may be reduced unless consideration is given to inclusion of POCUS in general surgery training. AIMS: To stimulate discussion regarding inclusion of POCUS in the general surgery curriculum; to resource this discussion with an overview of current trends and issues around POCUS; and to discuss concerns and controversies that may arise if POCUS was adopted into general surgery training. METHOD: A literature search was performed using PUBMED, MEDLINE, Google and Google Scholar, using the terms 'ultrasound', 'point-of-care-ultrasound', 'bedside ultrasound', 'portable ultrasound' and 'hand-held ultrasound'. Literature, references and non-literature resources found were reviewed for relevance to US education in general surgery. CONCLUSIONS: Increasingly, medical students are graduating with basic POCUS skills. Specialty-specific uses of POCUS are proliferating. Training and assessment resources are not keeping up, in accessibility or standardization. A learned surgical college led training and accreditation process would require aligned education in anatomy and US technology and collaboration with the specialist imaging community to ensure appropriate standards are clarified and met. Research is also required into how general surgery trainees can best achieve and maintain POCUS competence. PMID- 23980757 TI - Analysis of storage and structural carbohydrates in developing wheat (Triticum aestivum L.) grains using quantitative analysis and microscopy. AB - In this paper, the content of all major carbohydrates and the spatial distribution of starch, arabinoxylan and beta-glucan in developing wheat kernels (Triticum aestivum L. var. Homeros) from anthesis until maturity were studied. By combining information from microscopy and quantitative analysis, a comprehensive overview on the changes in storage and structural carbohydrates in developing grains was obtained. In the phase of cell division and expansion, grains were characterized by a rapid accumulation of water and high concentrations of the water-soluble carbohydrates fructan, sucrose, glucose and fructose. During the grain filling phase, starch, protein, beta-glucan and arabinoxylan accumulated, while during grain maturation and desiccation, only a loss of moisture took place. The comprehensive approach of this study allowed finding correlations, which are discussed within the context of grain development. Particular attention was given to the transient presence of high fructan concentrations, which was associated with the most striking compositional changes during grain development. PMID- 23980758 TI - Proteolytic assays on quantum-dot-modified paper substrates using simple optical readout platforms. AB - Paper-based assays are a promising diagnostic format for point-of-care applications, field deployment, and other low-resource settings. To date, the majority of efforts to integrate nanomaterials with paper-based assays have utilized gold nanoparticles. Here, we show that semiconductor quantum dots (QDs), in combination with Forster resonance energy transfer (FRET), are also suitable nanomaterials for developing paper-based assays. Paper fibers were chemically modified with thiol ligands to immobilize CdSeS/ZnS QDs, the QDs were self assembled with dye-labeled peptides to generate efficient FRET, and steady-state and fluorescence lifetime imaging microscopy (FLIM) were used for characterization. Peptides were selected as substrates for three different proteases and a series of kinetic assays for proteolytic activity was carried out, including multiplexed assays and pro-enzyme activation assays. Quantitative results were obtained within 5-60 min at levels as low as 1-2 nM of protease. These assays were possible using simple optical readout platforms that did not negate the low cost, ease of use, and overall accessibility advantages of paper based assays. A violet light-emitting diode (LED) excitation source and color imaging with either a digital camera, consumer webcam, or smartphone camera were sufficient for analysis on the basis of a red/green color intensity ratio. At most, a universal serial bus (USB) connection to a computer was required and the instrumentation cost orders of magnitude less than that typically utilized for in vitro bioanalyses with QDs. This work demonstrates that QDs are valuable probes for developing a new generation of paper-based diagnostics. PMID- 23980759 TI - Long-term functional outcomes and their predictors after hemispherectomy in 115 children. AB - PURPOSE: To examine the long-term functional outcomes and their predictors using a patient/family centered approach in a cohort of children who had hemispherectomy. Functional outcome measures studied were the following: ambulation ability, visual symptoms, spoken language, reading skills, and behavioral problems. METHODS: We reviewed 186 consecutive children who underwent hemispherectomy between 1997 and 2009 at our center. Preoperative clinical, electroencephalography (EEG), imaging, and surgical data were collected. One hundred twenty-five families completed a structured questionnaire to assess the functional status and seizure outcome. Prognostic predictors were examined using a multivariate regression analysis. KEY FINDINGS: At a mean follow-up of 6.05 years after hemispherectomy, 70 patients (56%) were seizure-free and 45 (36%) had seizure recurrence; 10 patients (8%) were free of their preoperative seizures but had new-onset nonepileptic spells and were excluded from further analysis. Of 115, at follow-up (mean age at follow-up 12.7 years, range 2-28 years), 96 patients (83%) walked independently, 10 (8.7%) walked with assistance, and 9 (7.8%) were unable to walk. New visual symptoms that were not present preoperatively were reported only in 28 patients (24%). Eighty patients (70%) had satisfactory spoken language skills but only 44 (42%) of the 105 children older than 6 years had satisfactory reading skills. Significant behavioral problems were reported in 30 patients (27%). Only five (6.2%) of the 81 children aged between 6 and 18 years attended mainstream school without assistance; 48 (59%) were in mainstream school with assistance and the rest were in special school for disabled or home cared. Five (21%) of the 24 patients older than 18 years of age were gainfully employed. Multivariate logistic regression analysis identified the following factors as independently associated with poor functional outcome. (1) Seizure recurrence negatively affected all functional domains--ambulation ability, spoken language and reading skills, and behavior (p < 0.05). (2) Abnormalities in the unoperated hemisphere on magnetic resonance imaging (MRI) (p < 0.05) and preexisting quadriparesis (p < 0.01) correlated with poor motor outcome. (3) Multilobar MRI abnormalities in the contralateral hemisphere (odds ratio [OR] = 13.9, p = 0.001) and young age (indeterminate preoperative language status) at hemispherectomy (OR = 11.1, p = 0.01) also correlated with poor language outcome. (4) Younger age at epilepsy onset correlated with poor reading skills (p = 0.01) but not with spoken language skills. SIGNIFICANCE: This study highlights the long-term functional status of patients after hemispherectomy. The majority of patients were ambulant independently; however, impairments in reading and spoken language were frequent. Seizure recurrence after hemispherectomy and contralateral hemisphere abnormalities on MRI were the major predictors of poor outcome in ambulation, spoken language, and reading abilities. This study will assist in presurgical counseling using simple understandable functional outcome measures and may help in planning early interventions after hemispherectomy to improve functional outcome. PMID- 23980761 TI - Stronger spatial genetic structure in recolonized areas than in refugia in the European beech. AB - Extant rear-edge populations located in former glacial refugia remain understudied despite their high conservation value. These populations should have experienced strong genetic drift due to their small size and long isolation. Moreover, the prolonged action of isolation by distance in refugial areas should result in stronger regional spatial genetic structure (SGS) than in recolonized areas, but empirical tests of this prediction are scarce. To fill this gap, we first used a set of 16 microsatellite markers to investigate the genetic structure of European beech in France in 65 populations from three refugial areas and one control recolonized (nonrefugial) area. Then, using the same approach, we reanalysed published isozyme data from 375 populations distributed across the entire species range. We found stronger genetic differentiation among populations in refugia than in recolonized areas. However, contrary to expectations, regional SGS was lower within refugia than within recolonized areas. Published studies presenting similar analyses suggest that our results could have generality across different biogeographical settings and types of organisms. Strong and prolonged genetic drift in refugial areas could have erased the signature of range expansions that is still visible in recolonized areas. Our results therefore suggest that Pleistocene population isolation has played a key role in increasing the genetic complexity of extant rear-edge populations. PMID- 23980760 TI - Mycobacterium tuberculosis bacteraemia: experience from a non-endemic urban centre. AB - The isolation of Mycobacterium tuberculosis from blood culture specimens has been associated with human immunodeficiency virus (HIV) co-infection with variable impact on tuberculosis (TB) mortality reported. The overwhelming majority of M. tuberculosis bacteraemia cases were described in developing countries. We present a nested case-control analysis of clinical, sociodemographic and behavioural risk factors in patients with positive M. tuberculosis blood cultures compared with patients with negative blood cultures from a 9-year population-based active TB surveillance study conducted in Houston, Texas. There were 42 patients with M. tuberculosis bacteraemia, 47 blood culture negative patients and 3573 patients for whom no mycobacterial blood culture was requested. HIV infection was more common in patients for whom a mycobacterial blood culture was requested (79.8% versus 15.1% p <0.001). Of the patients with M. tuberculosis bacteraemia, six were HIV negative or had no documentation of HIV status, including five with immunosuppressive conditions other than HIV. Patients with M. tuberculosis bacteraemia were more likely than patients with negative blood cultures to be deceased at diagnosis or to die while on TB therapy (50.0% versus 17.0%, p <0.01), to report men-who-have-sex-with-men behaviour (31.7% versus 13.0%, p 0.03), to have renal failure (28.6% versus 6.4%, p 0.01), and to have HIV RNA levels higher than 500 000 copies/mL (61.9% versus 17.2%, p <=0.01). Requests for mycobacterial culture of blood specimens were more common in HIV-infected individuals, and the presence of M. tuberculosis bacteraemia was associated with a significant increase in mortality. PMID- 23980762 TI - Vectored dispersal of Symbiodinium by larvae of a Caribbean gorgonian octocoral. AB - The ability of coral reefs to recover from natural and anthropogenic disturbance is difficult to predict, in part due to uncertainty regarding the dispersal capabilities and connectivity of their reef inhabitants. We developed microsatellite markers for the broadcast spawning gorgonian octocoral Eunicea (Plexaura) flexuosa (four markers) and its dinoflagellate symbiont, Symbiodinium B1 (five markers), and used them to assess genetic connectivity, specificity and directionality of gene flow among sites in Florida, Panama, Saba and the Dominican Republic. Bayesian analyses found that most E. flexuosa from the Florida reef tract, Saba and the Dominican Republic were strongly differentiated from many E. flexuosa in Panama, with the exception of five colonies from Key West that clustered with colonies from Panama. In contrast, Symbiodinium B1 was more highly structured. At least seven populations were detected that showed patterns of isolation by distance. The symbionts in the five unusual Key West colonies also clustered with symbionts from Panama, suggesting these colonies are the result of long-distance dispersal. Migration rate tests indicated a weak signal of northward immigration from the Panama population into the lower Florida Keys. As E. flexuosa clonemates only rarely associated with the same Symbiodinium B1 genotype (and vice versa), these data suggest a dynamic host-symbiont relationship in which E. flexuosa is relatively well dispersed but likely acquires Symbiodinium B1 from highly structured natal areas prior to dispersal. Once vectored by host larvae, these symbionts may then spread through the local population, and/or host colonies may acquire different local symbiont genotypes over time. PMID- 23980763 TI - Fine-scale temporal adaptation within a salmonid population: mechanism and consequences. AB - We demonstrate a clear example of local adaptation of seasonal timing of spawning and embryo development. The consequence is a population of pink salmon that is segmented into spawning groups that use the same limited habitat. We synthesize published observations with results of new analyses to demonstrate that genetic variation of these traits results in survival differentials related to that variation, and that density-dependent embryo mortality and seasonally variable juvenile mortality are a mechanism of selection. Most examples of local adaptation in natural systems depend on observed correlations between environments and fitness traits, but do not fully demonstrate local adaptation: that the trait is genetically determined, exhibits different fitness in common environments or across different environments, and its variation is mechanistically connected to fitness differences. The geographic or temporal scales of local adaptation often remain obscure. Here, we show that heritable, fine-scale differences of timing of reproductive migration in a pink salmon (Oncorhynchus gorbuscha) resulted in temporal structure that persisted several generations; the differences enable a density-dependent population to pack more spawners into limited spawning habitat, that is, enhance its fitness. A balanced trade-off of survivals results because embryos from early-migrating fish have a lower freshwater survival (harsh early physical conditions and disturbance by late spawners), but emigrant fry from late-migrating fish have lower marine survivals (timing of their vernal emergence into the estuarine environment). Such fine-scale local adaptations increase the genetic portfolio of the populations and may provide a buffer against the impacts of climate change. PMID- 23980764 TI - Population genetic data of a model symbiotic cnidarian system reveal remarkable symbiotic specificity and vectored introductions across ocean basins. AB - The Aiptasia-Symbiodinium symbiosis is a promising model for experimental studies of cnidarian-dinoflagellate associations, yet relatively little is known regarding the genetic diversity of either symbiotic partner. To address this, we collected Aiptasia from 16 localities throughout the world and examined the genetic diversity of both anemones and their endosymbionts. Based on newly developed SCAR markers, Aiptasia consisted of two genetically distinct populations: one Aiptasia lineage from Florida and a second network of Aiptasia genotypes found at other localities. These populations did not conform to the distributions of described Aiptasia species, suggesting that taxonomic re evaluation is needed in the light of molecular genetics. Associations with Symbiodinium further demonstrated the distinctions among Aiptasia populations. According to 18S RFLP, ITS2-DGGE and microsatellite flanker region sequencing, Florida anemones engaged in diverse symbioses predominantly with members of Symbiodinium Clades A and B, but also C, whereas anemones from elsewhere harboured only S. minutum within Clade B. Symbiodinium minutum apparently does not form a stable symbiosis with other hosts, which implies a highly specific symbiosis. Fine-scale differences among S. minutum populations were quantified using six microsatellite loci. Populations of S. minutum had low genotypic diversity and high clonality (R = 0.14). Furthermore, minimal population structure was observed among regions and ocean basins, due to allele and genotype sharing. The lack of genetic structure and low genotypic diversity suggest recent vectoring of Aiptasia and S. minutum across localities. This first ever molecular genetic study of a globally distributed cnidarian and its Symbiodinium assemblages reveals host-symbiont specificity and widely distributed populations in an important model system. PMID- 23980765 TI - Malaria infections reinforce competitive asymmetry between two Ficedula flycatchers in a recent contact zone. AB - Parasites may influence the outcome of interspecific competition between closely related host species through lower parasite virulence in the host with which they share the longer evolutionary history. We tested this idea by comparing the prevalence of avian malaria (Haemosporidia) lineages and their association with survival in pied and collared flycatchers (Ficedula hypoleuca and F. albicollis) breeding in a recent contact zone on the Swedish island of Oland. A nested PCR protocol amplifying haemosporidian fragments of mtDNA was used to screen the presence of malaria lineages in 1048 blood samples collected during 6 years. Competitively inferior pied flycatchers had a higher prevalence of blood parasites, including the lineages that were shared between the two flycatcher species. Multistate mark-recapture models revealed a lower survival of infected versus uninfected female pied flycatchers, while no such effects were detected in male pied flycatchers or in collared flycatchers of either sex. Our results show that a comparatively new host, the collared flycatcher, appears to be less susceptible to a local northern European malarial lineage where the collared flycatchers have recently expanded their distribution. Pied flycatchers experience strong reproductive interference from collared flycatchers, and the additional impact of species-specific blood parasite effects adds to this competitive exclusion. These results support the idea that parasites can strongly influence the outcome of interspecific competition between closely related host species, but that the invading species need not necessarily be more susceptible to local parasites. PMID- 23980766 TI - Single-photon technique for the detection of periodic extraterrestrial laser pulses. AB - To draw humankind's attention to its existence, an extraterrestrial civilization could well direct periodic laser pulses toward Earth. We developed a technique capable of detecting a quasi-periodic light signal with an average of less than one photon per pulse within a measurement time of a few tens of milliseconds in the presence of the radiation emitted by an exoplanet's host star. Each of the electronic events produced by one or more single-photon avalanche detectors is tagged with precise time-of-arrival information and stored. From this we compute a histogram displaying the frequency of event-time differences in classes with bin widths on the order of a nanosecond. The existence of periodic laser pulses manifests itself in histogram peaks regularly spaced at multiples of the-a priori unknown-pulse repetition frequency. With laser sources simulating both the pulse source and the background radiation, we tested a detection system in the laboratory at a wavelength of 850 nm. We present histograms obtained from various recorded data sequences with the number of photons per pulse, the background photons per pulse period, and the recording time as main parameters. We then simulated a periodic signal hypothetically generated on a planet orbiting a G2V type star (distance to Earth 500 light-years) and show that the technique is capable of detecting the signal even if the received pulses carry as little as one photon on average on top of the star's background light. PMID- 23980768 TI - Beware the numbers game. PMID- 23980767 TI - Effect of SPE-like proton or photon radiation on the kinetics of mouse peripheral blood cells and radiation biological effectiveness determinations. AB - Exploration missions outside low-Earth orbit are being planned; therefore, it is critical to understand the risk astronauts would be exposed to in the space environment, especially during extravehicular activities (EVAs). Reductions in white blood cell (WBC) numbers can occur as a result of exposure to solar particle event (SPE) radiation. The aim of the present study was to determine the duration of the effects on blood cell numbers from exposure to a single whole body dose of SPE-like proton radiation or photon radiation as well as to determine the radiation biological effectiveness (RBE) values at those times when radiation exposure causes blood cell numbers to experience the most critical effects when using mice as a model. Our results indicate that both types of radiation cause significant reductions in the numbers of all blood cell types at different times post-irradiation. The RBE values were not significantly different from 1.0. These results indicate that the risk estimations for astronauts from exposure of mice to SPE-like proton radiation are comparable to those previously made for doses of standard reference radiations, suggesting that countermeasures should be developed for the decreases in blood cell counts observed following the exposure of mice to SPE radiation. PMID- 23980773 TI - DH adviser recommends safer staffing. PMID- 23980776 TI - Day of national action became biggest improvement event in history of the NHS. PMID- 23980777 TI - Campaign lights the way for hospital to save L100,000. PMID- 23980781 TI - Let us not fear being radical. PMID- 23980785 TI - Compassion is the key. PMID- 23980789 TI - Commissioning health care for offenders. AB - This article sets out the background to offender health care in the UK and explains how the commissioning of services in England is changing. The roles and responsibilities of NHS England and clinical commissioning groups are explained with reference to prison health care, and other secure accommodation and community offender health. Identified risks such as poor attendance at partnership boards, and lack of capability and capacity in clinical commissioning groups may lead to less attention being given to local system delivery and less engagement with key partners. Nurse managers, working in commissioning and provider settings, need to understand the changes to achieve greater partnership working and ensure that the quality of care across pathways is maintained for offenders. PMID- 23980790 TI - 'Caring around the clock': a new approach to intentional rounding. AB - Intentional rounding is a widely debated topic and, in this article, Nottingham University Hospitals NHS Trust shares its experience and learning from implementing an innovative approach based on the process across 79 wards. The authors look at the need for education and for cultural shift to achieve the best results. The issue of intentional rounding was raised in 2012 by prime minister David Cameron, who responded to a report of failings published by the Parliamentary and Health Service Ombudsman (2011) by announcing that all nurses would be expected to do hourly rounds to improve care. The need for the process has been demonstrated further in the recommendations from the Mid Staffordshire NHS Foundation Trust Public Inquiry (Francis 2013). PMID- 23980791 TI - Are nurses expected to have information technology skills? AB - This article discusses the knowledge management skills required by nurses in the context of the government's information strategy for England and Wales, which highlights the importance of managing data in providing efficient health care. It also reports on a study that looked at whether employers' job descriptions and person specifications include the need for basic information and communication technology skills outlined in the NHS knowledge and skills framework (Agenda for Change Project Team 2004), and the degree to which these skills are regarded as important to good nursing care. PMID- 23980792 TI - Working in partnership. PMID- 23980793 TI - Altered invariant natural killer T cell subsets and its functions in patients with oral squamous cell carcinoma. AB - Invariant natural killer T (iNKT) cells are glycolipid-reactive T lymphocytes that share receptors and function with natural killer (NK) cells and reportedly play a pivotal role in various immune responses. However, iNKT cells are not well characterized in patients with oral squamous cell carcinoma (OSCC). We investigated the populations and functions of circulating iNKT (CD3(+) 6B11(+) ) cells from thirty-eight patients with OSCC and twenty-eight healthy donors by flow cytometry. Circulating iNKT cells were significantly lower (P < 0.01) in patients as compared to those in healthy controls. Further, iNKT subsets revealed a marked decrease in CD4(-) CD8(-) (double negative, DN) subset with concomitant increase in CD8(+) subset in patients as compared to healthy controls (P = 0.03 and P < 0.01, respectively), whereas CD4(+) subset was similarly distributed in both groups. The functional analysis demonstrated that residual iNKT cells from patients had impaired proliferative response to alpha-galactosylceramide (alpha GalCer)-pulsed dendritic cells (DCs) and Th2-like cytokine profile. However, in vitro activation with alpha-GalCer-pulsed DCs restores IFN-gamma expression and enhances antitumour activity to human cancer cells lines (SCC-4, KB and MCF7). It appears that the selectively enriched iNKT subsets and modulation of their function by specific ligand/agonist may be useful for cellular therapy in patients with OSCC. Further, reduced levels of iNKT cells and its DN subset may be used as potential prognostic factors for patients with OSCC. PMID- 23980794 TI - Decay of Salmonella enterica, Escherichia coli and bacteriophage MS2 on the phyllosphere and stored grains of wheat (Triticum aestivum). AB - Cereal crops grown in the biosolids-amended soil can potentially become contaminated with pathogenic micro-organisms during growth and at the time of harvesting. There is small but unquantified potential risk of transfer of enteric pathogens to humans and animals from contaminated plants and grains. This study examined decay of Escherichia coli, Salmonella enterica serovar Typhimurium and bacteriophage MS2 on the wheat phyllosphere and on stored grains. This was done to assess the health implications of cereal crops contaminated from land application of biosolids. E. coli, S. enterica and MS2 were inoculated onto the leaves, spikelets and grains of wheat. The change in the numbers of inoculated micro-organisms was determined over time to calculate the respective 90% reduction time (T90 ) in each of these environments. A rapid inactivation (T90 <1 3 days) of E. coli and S. enterica and MS2 from the plant phyllosphere was observed, particularly from the spikelets. The decay rates were influenced by micro-organism type and location on the plant phyllosphere. Decay times on the stored grains were longer (T90 9-71 days), with some observed influence of grain variety on pathogen decay times. SIGNIFICANCE AND IMPACT OF THE STUDY: Results of this study suggest that there is very limited potential of enteric pathogens survival on wheat phyllosphere and grains. Therefore, the risk of transfer of enteric pathogens from biosolids-amended soil to consumers of grain products is considered to be low. This study has important implications for the grains industry, as the results suggest that chances of preharvest contamination of grains with enteric pathogens from biosolids-amended soil are low. PMID- 23980795 TI - Mechanically robust superamphiphobic aluminum surface with nanopore-embedded microtexture. AB - A simple fabrication technique was developed for preparing a mechanically robust superamphiphobic surface on an aluminum (Al) plate. Dual geometric architectures with micro- and nanoscale structures were formed on the surface of the Al plate by a combination of simple chemical etching and anodization. This proposed methodology involves (1) fabrication of irregular microscale plateaus on the surface of the Al plate, (2) formation of nanopores, and (3) fluorination. Wettability measurements indicated that the fabricated Al surface became super repellent toward a broad range of liquids with surface tension in the range 27.5 72 mN/m. By varying the anodization time, we measured and compared the effects of morphological change on the wettability. The adhesion property and mechanical durability of the fabricated superamphiphobic Al surface were evaluated by the Scotch tape and hardness tests, respectively. The results showed that the fabricated Al surface retained mechanical robustness because the down-directed surface made by nanopores on the microtextured surface was durable enough even after high force was applied. Almost no damage of the film was observed, and the surface still exhibited superamphiphobicity after the tests. The fabricated superamphiphobic surface also remained stable after long-term storage. The simple and time-saving fabrication technique can be extended to any large-area three dimensional surface, making it potentially suitable for large-scale industrial fabrications of mechanically robust superamphiphobic surfaces. PMID- 23980796 TI - Interview with a quality leader: Dr. John Combes on boards and governance. AB - Dr. Combes is senior vice president at the American Hospital Association (AHA) and president and COO of the Center for Healthcare Governance. The Interview with Dr. John Combes on Boards and Governance provides a perspective on key changes, issues, competencies, and metrics that hospital boards must address. The role of quality professionals to be effective with boards is also described. PMID- 23980797 TI - Editorial comment to Ventral onlay buccal mucosa urethroplasty: a 10-year experience. PMID- 23980798 TI - What makes maternity teams effective and safe? Lessons from a series of research on teamwork, leadership and team training. AB - We describe lessons for safety from a synthesis of seven studies of teamwork, leadership and team training across a healthcare region. Two studies identified successes and challenges in a unit with embedded team training: a staff survey demonstrated a positive culture but a perceived need for greater senior presence; training improved actual emergency care, but wide variation in team performance remained. Analysis of multicenter simulation records showed that variation in patient safety and team efficiency correlated with their teamwork but not individual knowledge, skills or attitudes. Safe teams tended to declare the emergency earlier, hand over in a more structured way, and use closed-loop communication. Focused and directed communication was also associated with better patient-actor perception of care. Focus groups corroborated these findings, proposed that the capability and experience of the leader is more important than seniority, and identified teamwork and leadership issues that require further research. PMID- 23980799 TI - Measuring implicit gender-role orientation: the gender initial preference task. AB - Individuals prefer their name letters over nonname letters, which is known as the name-letter effect (NLE). This research aimed to examine a possible NLE for gender-role orientation (GRO) by rating letters for their gender-typicality in an initial preference task (Gender-IPT). Indeed, a clear NLE appeared: Men rated their initials as more male-typical, whereas women rated them as more female typical. The Gender-IPT showed good convergent validity with other direct and indirect (Gender Implicit Association Test) measures of GRO as well as predictive validity with sensation seeking and gender-typical everyday life behaviors. The Gender-IPT seems to be a useful and practical indirect measure to assess GRO in a short, convenient, and computer-independent way, complementing other indirect measures of GRO. PMID- 23980800 TI - Successful creation of tissue-engineered autologous auricular cartilage in an immunocompetent large animal model. AB - Tissue-engineered cartilage has historically been an attractive alternative treatment option for auricular reconstruction. However, the ability to reliably generate autologous auricular neocartilage in an immunocompetent preclinical model should first be established. The objectives of this study were to demonstrate engineered autologous auricular cartilage in the immunologically aggressive subcutaneous environment of an immunocompetent animal model, and to determine the impact of in vitro culture duration of chondrocyte-seeded constructs on the quality of neocartilage maturation in vivo. Auricular cartilage was harvested from eight adult sheep; chondrocytes were isolated, expanded in vitro, and seeded onto fibrous collagen scaffolds. Constructs were cultured in vitro for 2, 6, and 12 weeks, and then implanted autologously in sheep and in control nude mice for 6 and 12 weeks. Explanted tissue was stained with hematoxylin and eosin, safranin O, toluidine blue, collagen type II, and elastin. DNA and glycosaminoglycans (GAGs) were quantified. The quality of cartilage engineered in sheep decreased with prolonged in vitro culture time. Superior cartilage formation was demonstrated after 2 weeks of in vitro culture; the neocartilage quality improved with increased implantation time. In nude mice, neocartilage resembled native sheep auricular cartilage regardless of the in vitro culture length, with the exception of elastin expression. The DNA quantification was similar in all engineered and native cartilage (p>0.1). All cartilage engineered in sheep had significantly less GAG than native cartilage (p<0.02); significantly more GAG was observed with increased implantation time (p<0.02). In mice, the GAG content was similar to that of native cartilage and became significantly higher with increased in vitro or in vivo durations (p<0.02). Autologous auricular cartilage was successfully engineered in the subcutaneous environment of an ovine model using expanded chondrocytes seeded on a fibrous collagen scaffold after a 2-week in vitro culture period. PMID- 23980801 TI - Production of indole alkaloids by metabolic engineering of the tryptophan pathway in rice. AB - Tryptophan decarboxylase (TDC) converts tryptophan (Trp) into tryptamine, consequently increasing the metabolic flow of tryptophan derivatives into the production of secondary metabolites such as indole alkaloids. We inserted an expression cassette containing OsTDC, a putative tryptophan decarboxylase gene from rice, into an expression plasmid vector containing OASA1D, the feedback resistant anthranilate synthase alpha-subunit mutant (OASA1D). Overexpression of OASA1D has been reported to significantly increase Trp levels in rice. The co expression of OsTDC and OASA1D in rice calli led to almost complete depletion of the Trp pool and a consequent increase in the tryptamine pool. This indicates that TDC inactivity is a contributory factor for the accumulation of Trp in rice transgenics overexpressing OASA1D. Metabolic profiling of the calli expressing OsTDC and OASA1D revealed the accumulation of serotonin and serotonin-derived indole compounds (potentially pharmacoactive beta-carbolines) that have not been reported from rice. Rice calli overexpressing OASA1D:OASA1D is a novel system for the production of significant amounts of pharmacologically useful indole alkaloids in rice. PMID- 23980804 TI - Varietal differences in the flavonol content of mulberry (Morus spp.) leaves and genetic analysis of quercetin 3-(6-malonylglucoside) for component breeding. AB - The varietal differences in the flavonol glycosides rutin, isoquercitrin, kaempferol 3-(6-rhamnosylglucoside), quercetin 3-(6-malonylglucoside), astragalin, quercetin 3-(6-acetylglucoside), and kaempferol 3-(6 malonylglucoside) contained in mulberry leaves were elucidated. This information was used for breeding mulberry cultivars with a high concentration of functional components. The flavonol content, composition, and proportion in leaves varied widely. 'Kobuchizawa 1' had the highest level of total flavonols (1819 mg/100 g of dry weight), 5 times higher than that of 'Mikurasima 15' (393 mg/100 g of dry weight). Quercetin 3-(6-malonylglucoside) was the most abundant flavonol, although it was not found in all cultivars. Quercetin 3-(6-acetylglucoside) was only found in 'Keguwa'. From the quercetin 3-(6-malonylglucoside) content in crossbred offspring, malonyltransferase, an enzyme involved in quercetin 3-(6 malonylglucoside) synthesis, was acquired according to Mendelian inheritance. An offspring with a higher quercetin 3-(6-malonylglucoside) level than both parents was obtained from the crossing. This suggested that crossbreeding was effective for acquiring cultivars with a higher content of quercetin 3-(6 malonylglucoside). PMID- 23980803 TI - Ex vivo dissection increases lymph node yield in oesophagogastric cancer. AB - BACKGROUND: Retrieval and analysis of an adequate number of lymph nodes is critical for accurate staging of oesophageal and gastric cancer. Higher total node counts reported by pathologists are associated with improved survival. A prospective study was undertaken to understand the factors contributing to variability in lymph node counts after oesophagogastric cancer resections and to determine whether a novel strategy of ex vivo dissection of resected specimens into nodal stations improves node counts reported by pathologists. METHODS: The study involved 88 patients with potentially curable oesophagogastric cancer undergoing radical resection. Lymph node counts were obtained from pathology reports and analysed in relation to multiple variables including the introduction of ex vivo dissection of nodal stations in theatre. RESULTS: Higher lymph node counts were obtained with ex vivo dissection of nodal stations (median 19 versus 8, P < 0.01). Node counts also varied significantly with the reporting pathologist (median range 4 to 48, P = 0.02) which was independent of the level of experience of the pathologist (P = 0.67). Node counts were not affected by patient age (P = 0.26), gender (P = 0.50), operative approach (P = 0.50) or neoadjuvant therapy (P = 0.83). CONCLUSIONS: Specimen handling is a significant factor in determining lymph node yield following radical oesophageal and gastric cancer resections. Ex vivo dissection of resected specimens into nodal stations improves node counts without alterations to surgical techniques. Ex vivo dissection should be considered routine. PMID- 23980802 TI - A molecular switch in the efficiency of translation reinitiation controls expression of var2csa, a gene implicated in pregnancy-associated malaria. AB - Plasmodium falciparum malaria parasites export the protein PfEMP1 to the surface of infected erythrocytes, enabling them to adhere to receptors in the microvasculature and thereby avoid clearance by the spleen. The gene var2csa encodes the form of PfEMP1 that binds specifically within the placenta, causing pregnancy-associated malaria, and appears to not be expressed in the absence of a placenta. We previously described an upstream open reading frame (uORF) that is responsible for repression of translation of the downstream ORF (dORF) that encodes VAR2CSA, thus keeping the gene silent when parasites infect non-pregnant individuals. To elucidate the molecular mechanism by which this repression is overcome during pregnancy, we stably transformed parasites with reporter gene constructs designed to detect switches in the efficiency of dORF translation. We found that proper regulation of switching relies on two separate components, (i) active translation of the uORF and (ii) sequence-specific characteristics of the surrounding transcript, which together control the ability of the ribosome complex to reinitiate a second round of translation and thus express VAR2CSA. These results provide the first details of a molecular switch that allows parasites take advantage of the unique niche provided by the placenta. PMID- 23980805 TI - Immunohistochemical expression of granzyme B and perforin in discoid lupus erythematosus. AB - Discoid lupus erythematosus (DLE) is a chronic photosensitive dermatosis characterized by scarring and atrophy. Granzyme B is a serine protease found in the cytoplasmic granules of cytotoxic lymphocytes and natural killer cells. Perforin permits delivery of the cytotoxic granzymes A and B into target cells to induce apoptosis and cause target cell death. The current study investigated the expression of granzyme B and perforin in 25 cases of DLE and in 10 cases of normal skin by immunohistochemistry and correlated their expression with the clinicopathological features in the studied DLE group. Both granzyme B and perforin were expressed in DLE with absent expression in normal skin. They were parallelly expressed in DLE where granzyme B was associated with features of chronicity such as old age (p = 0.05) and long duration of the disease (p = 0.05). Perforin expression in DLE was associated with male gender (p = 0.04) and outdoor workers (p = 0.04). Finally, expression of both granzyme B and perforin in dermal lymphocytic inflammatory infiltrate in DLE may indicate the cytotoxicity of the infiltrate. The parallel expression of both molecules may refer to the cooperative relationship between them to enhance cytotoxicity. Higher expression of granzyme B than perforin may indicate the presence of other pathways for granzyme B release independent from perforin. PMID- 23980806 TI - Low prevalence but high specificity of material-specific memory impairment in epilepsy associated with hippocampal sclerosis. AB - PURPOSE: Material-specific memory impairment is used as a lateralizing tool in the evaluation of temporal lobe epilepsy. Lateralizing ability of material specific memory deficits in temporal lobe epilepsy remains controversial. METHODS: We studied memory impairment profiles of verbal and nonverbal memory deficits with eight memory subtests of four neuropsychological instruments (two verbal and two nonverbal) in 87 right-handed patients with epilepsy associated with unilateral mesial temporal sclerosis (MTS; 44 right - R, 43 left - L) and 42 controls, with an IQ >70, at least 8 years of education, and without comorbidities. KEY FINDINGS: Selective verbal memory impairment was noted in 11 of 43 or 25.6% of left MTS cases, with 82.2% specificity, whereas selective nonverbal memory impairment was noted in 11 of 42 or 26.2% of right MTS cases, with 92% specificity. Nonlateralizing profiles of memory performance were seen in the remaining 65 of 87 patients. Approximately half (46/87 or 52.9%) of the patients had intact memory function in both modalities, equally distributed between patients with right MTS (23/44) and left MTS (23/43). Global impairment of both memory types was seen in 12 of 87 or 13.8% of patients, equally distributed between the two groups (7/43 left and 5/44 right). SIGNIFICANCE: Lateralizing profiles of selective verbal and nonverbal memory deficits are highly specific for left and right MTS, although infrequently encountered in our patients. Nonlateralizing profiles predominated in this population. These findings suggest hemispheric asymmetry memory function, with complex functional interaction of the hippocampi, and possible compensatory mechanisms in the setting of a unilateral lesion. PMID- 23980807 TI - Click annulation of pseudo[2]rotaxane to [2]catenane exploiting homoditopic nitrile N-oxide. AB - A mild annulation reaction of a propargyl-terminated pseudorotaxane with a homoditopic stable nitrile N-oxide enabled the efficient synthesis of catenanes consisting of not only dibenzo-24-crown-8-ether (DB24C8) but also dibenzo-30 crown-10-ether (DB30C10) as a wheel component. A dynamic (1)H NMR study showed the highly enhanced mobility of the components of the DB30C10-based [2]catenane due to the enlarged wheel cavity. PMID- 23980808 TI - Real-world safety and effectiveness outcomes of a zotarolimus-eluting stent: final 3-year report of the RESOLUTE International study. AB - OBJECTIVES: We evaluated the safety and effectiveness of the ResoluteTM zotarolimus-eluting stent (R-ZES) in real-world clinical practice through 3 years. BACKGROUND: A randomized comparison of the R-ZES and the XIENCE VTM everolimus-eluting stent showed no difference in any outcomes through 3-year follow-up in high-volume academic centers. RESOLUTE International is a confirmatory trial designed to evaluate the R-ZES in real-world clinical practice. METHODS: RESOLUTE International is a single arm, observational trial that enrolled 2,349 patients from 88 centers with only a few inclusion and exclusion criteria. The primary end-point was the composite of cardiac death and target vessel myocardial infarction (TV-MI) at 1 year. Secondary end-points include target lesion failure (TLF), target vessel revascularization (TVR), and their components, and stent thrombosis (ST). RESULTS: At 3 years 97.2% of patients completed clinical follow-up. The mean age was 63.4 +/- 11.2 years, 77.8% were male, and 30.4% had diabetes. The average number of stents per patient was 1.6 +/- 1.0; and mean stent length was 30.9 +/- 20.5 mm. Dual antiplatelet therapy was used in 91.1% of patients at 1 year, 43.0% at 2 years, and 34.6% at 3 years. Cardiac death and TV-MI occurred in 161 patients (7.0%). There were 6 (0.3%) very late ST events for a total ST rate of 1.1% through 3 years. The rates of clinically driven target lesion revascularization (TLR), TVR, and TLF were 5.7%, 7.4%, and 11.4%, respectively. CONCLUSIONS: The safety and effectiveness of the R-ZES through 3 years in this real-world all-comer study was consistent with previously reported all-comer trials. PMID- 23980809 TI - Elucidating the fragmentation of consciousness underpins future neurosurgical research. PMID- 23980810 TI - TLR2 and TLR4 in cutaneous leishmaniasis caused by Leishmania major. AB - Cutaneous leishmaniasis (CL) is a self-healing skin disease which rarely for unknown reason(s) the lesion develops to a non-healing form. It seems that the initial contact of Leishmania parasites with the host innate immune system is an important step in the outcome of the disease. Recent studies suggested that toll like receptors (TLRs) play a role in Leishmania recognition. In this study, the level of TLR2 and TLR4 was checked in patients with healing form of lesion and compared with that of patients with non-healing form of lesion caused by Leishmania major. Gene expression of TLR2 and TLR4 in peripheral blood-derived macrophages, before and after stimulation with live L. major promastigotes, was evaluated using quantitative real-time reverse transcription PCR and flow cytometry. The results showed that the mean relative gene expression and difference membrane expression of TLR2 in macrophages of patients with healing form of lesion were significantly higher than patients with non-healing form of lesion (P < 0.0001 and P = 0.0034), respectively, and the mean relative gene expression and difference in protein expression of TLR4 in macrophages of patients with healing form of lesion were significantly higher than that of patients with non-healing form of lesion (P = 0.021 and P = 0.002), respectively. The data suggested a possible role for TLR2 and TLR4 in the outcome of CL lesion. Further studies are needed to understand more about the detail role of the immune factors in leishmaniasis. PMID- 23980811 TI - Reduction in Enteroccocus faecalis counts - a comparison between rotary and reciprocating systems. AB - AIM: To compare the chemomechanical reduction and regrowth of Enterococcus faecalis between rotary and reciprocating systems in root canal preparation. METHODOLOGY: Seventy-six single-rooted human mandibular premolars were selected and standardized to 15 mm in length. Root canals were enlarged up to a size 25 K file and irrigated with distilled water and then were infected with E. faecalis for 4 weeks. The specimens were divided into 3 groups (n = 24) for instrumentation with Mtwo, Twisted File and WaveOne. Each group was further divided into two subgroups (n = 12) according to the irrigant used: distilled water or 5.25% sodium hypochlorite (NaOCl). Before and after rotary preparation, microbiological samples were collected using three sterilized paper points, and efficacy was expressed as reduction in percentage. The proportion of grown samples for 60 days was evaluated using nonparametric Kaplan-Meier survival analysis. Differences amongst groups were tested using the log-rank test at a significance level of 0.05. RESULTS: In the main root canal, the percentage reduction in the distilled water and 5.25% NaOCl groups ranged from 95.9% to 100%, with no significant differences amongst the three systems (P > 0.05). The bacterial regrowth in NaOCl groups revealed that Mtwo had the lowest number of samples regrown at 60 days, giving statistically significant differences with respect to Twisted File (P = 0.029) and WaveOne (P = 0.005). CONCLUSIONS: Reciprocating and rotary systems resulted in similar percentage reduction in E. faecalis when using either distilled water or 5.25% NaOCl solution. Over time, the Mtwo system was more effective regarding disinfection. PMID- 23980812 TI - Ankyrin-repeat proteins from sponge symbionts modulate amoebal phagocytosis. AB - Bacteria-eukaryote symbiosis occurs in all stages of evolution, from simple amoebae to mammals, and from facultative to obligate associations. Sponges are ancient metazoans that form intimate symbiotic interactions with complex communities of bacteria. The basic nutritional requirements of the sponge are in part satisfied by the phagocytosis of bacterial food particles from the surrounding water. How bacterial symbionts, which are permanently associated with the sponge, survive in the presence of phagocytic cells is largely unknown. Here, we present the discovery of a genomic fragment from an uncultured gamma proteobacterial sponge symbiont that encodes for four proteins, whose closest known relatives are found in a sponge genome. Through recombinant approaches, we show that these four eukaryotic-like, ankyrin-repeat proteins (ARP) when expressed in Eschericha coli can modulate phagocytosis of amoebal cells and lead to accumulation of bacteria in the phagosome. Mechanistically, two ARPs appear to interfere with phagosome development in a similar way to reduced vacuole acidification, by blocking the fusion of the early phagosome with the lysosome and its digestive enzymes. Our results show that ARP from sponge symbionts can function to interfere with phagocytosis, and we postulate that this might be one mechanism by which symbionts can escape digestion in a sponge host. PMID- 23980813 TI - Renal transplant in plasma cell dyscrasias with lenalidomide treatment after autologous stem cell transplantation. AB - Plasma cell dyscrasias (PCD) are a spectrum of diseases characterized by clonal proliferation of plasma cells secreting a monoclonal immunoglobulin. Although considered an incurable disease, a combination of autologous stem cell transplant with novel therapies, including lenalidomide, has improved the overall and progression-free survival of these patients. Renal impairment is an important complication of the disease that, in some cases, progresses to end-stage renal disease. Due to the characteristics of PCD, traditionally these patients have not been candidates for renal transplantation. However, treatment improvement allows a reconsideration of this perception, especially in younger patients with good performance status and treatment response. We report two cases of patients diagnosed with PCD undergoing renal transplantation after autologous stem cell transplantation, both cases under treatment with lenalidomide. We also report their perioperative management and their outcome. PMID- 23980814 TI - International comparisons of kidney transplantation rates - seeking a road to success. PMID- 23980815 TI - Metastatic calcifications after parathyroidectomy in a dialysis patient. PMID- 23980816 TI - Paradox of rising thyroid stimulating hormone despite increasing thyroxine dose in hypothyroidism and the association with nephrotic syndrome. PMID- 23980817 TI - Association of N-terminal domain polymorphisms of the porcine glucocorticoid receptor with carcass composition and meat quality traits. AB - The glucocorticoid receptor (GR) is a ubiquitously acting transcription factor that is responsible for mediating the physiological response to stress and adaptation to environmental conditions. Genetic variation of a GR gene (NR3C1) may therefore contribute to multiple phenotypic alterations and influence relevant traits of animal production. Here, we examined effects of two non synonymous mutations of the porcine NR3C1, leading to amino acid exchanges p.Glu13Asp (c.39A>C) and p.Val19Leu (c.55G>C) in the N-terminal domain of the GR, on meat quality and carcass composition. In addition, we explored their influence on transcriptional activity of GR in vitro. A commercial crossbreed Pietrain * (German Large White * German Landrace) herd (n = 545) in which genotypes and relevant traits had been collected was used to perform the association analysis. The single nucleotide polymorphism (SNP) c.55G>C was significantly associated with conductivity and meat color scores. These effects were highly consistent considering the physiological relationship between these traits. Association analysis of SNP c.39A>C also revealed significant effects on closely connected meat quality traits. In addition, SNP c.55G>C showed association with carcass traits, mainly those related to muscle deposition. The molecular mechanism of action of both amino acid substitutions remains obscure because neither showed significant influence on transcriptional activity of GR. Our study emphasizes NR3C1 as an important candidate gene for muscle-related traits in pigs, but further work is necessary to clarify the molecular background of the identified associations. PMID- 23980818 TI - Cognitive and behavioral deficits following bilateral thalamic stroke: a longitudinal study. AB - We describe behavioral and neuropsychological outcome of a patient (N.S.), who showed a bilateral paramedian thalamic ischemic lesion, with particular reference to the longitudinal evolution of topographical disorientation (TD) and confabulations. We report clinical neuropsychological/behavioral data over a 43 month follow-up. The results show early after the stroke a severe amnesic confabulatory syndrome with dysexecutive deficits, associated with memory disorders both for visuo-spatial and verbal materials and TD both for known and new places. Behavioral disinhibition and anosognosia for cognitive deficits were also observed. All cognitive impairments have been recovered during the long-term follow-up. Bilateral paramedian thalamic infarcts often lead to severe and long lasting neurological and cognitive impairments. Only a few cases showed good recovery. Our patient represents an interesting and uncommon case of bilateral paramedian thalamic syndrome with a significant neuropsychological recovery. PMID- 23980819 TI - Underreporting of robotic surgery complications. AB - BACKGROUND: Since its Food and Drug Administration (FDA) approval, robot-assisted laparoscopic surgery has grown with expanding indications. One factor used to expand indications is device-related complications. We designed a study to evaluate device-related robotic surgery complications reported to FDA. METHODS: We searched the FDA device-related complication database, LexisNexis, and PACER (Public Access to Court Electronic Records) to identify robotic surgery-related complications over a 12-year period (January 1, 2000 to August 1, 2012). Cases from LexisNexis and PACER were cross-referenced with the FDA database to determine cases where an FDA report was inaccurate, filed late or not filed. RESULTS: A total of 245 events were reported to the FDA during the study period, including 71 deaths and 174 nonfatal injuries. Median time to report an event to the FDA was 30 days (range = 0-930 days). Eight cases were identified from the LexisNexis and PACER searches where FDA reports were improperly filed. In five of these, no report was filed with a mean follow-up of 4.1 years (range = 2.3-5.8 years). In the three cases where a report was filed, the mean time between the event and the FDA report was 20.4 months (611 days, range = 292-930 days). CONCLUSIONS: It is important that the true incidence of complications with robotic-assisted laparoscopic surgery be known to ensure continued safe innovation. PMID- 23980820 TI - Evaluation of dermoscopic algorithm for seborrhoeic keratosis: a prospective study in 412 patients. AB - BACKGROUND: Although most seborrhoeic keratoses can be easily diagnosed with dermoscopy, some lesions mimic a number of other diseases and lack typical dermoscopic criteria. Validation of the diagnostic algorithm and further understanding about dermoscopy of seborrhoeic keratosis is necessary. OBJECTIVE: To evaluate the dermoscopic criteria, define dermoscopic patterns and optimize the diagnostic algorithm of seborrhoeic keratosis in a large series of cases. PATIENTS AND METHODS: An unselected consecutive series of 416 clinically suspected seborrhoeic keratoses from 412 patients were prospectively included. All the lesions were imaged with dermoscopy, analysed for dermoscopic patterns and features. An independent blinded histopathological diagnosis as well as dermoscopic diagnosis was made for each lesion. RESULTS: A total of 416 lesions were analysed. Using histopathological diagnoses as the gold standard, the two step algorithm achieved a sensitivity of 79.1, a specificity of 78.3% (P < 0.01) and a kappa index of 0.223. An optimized algorithm that combined lack of blue grey or blue-white colour, sharp demarcation, mica-like structure and yellowish colour with the two-step algorithm demonstrated a sensitivity of 95.7%, a specificity of 78.3% (P < 0.001) and a kappa index of 0.594. Pattern analysis revealed 12 dermoscopic patterns. The elevated lesions mainly presented fissures/ridges pattern, exophytic papillary pattern, crypts pattern and mica like pattern; the flat lesions mainly presented structureless pattern and coral like pattern. CONCLUSION: Seborrhoeic keratosis may present a variety of dermoscopic patterns and features. The combination of lack of blue-grey or blue white colour, sharp demarcation, mica-like structure and yellowish colour with the two-step algorithm could improve its diagnostic accuracy. PMID- 23980821 TI - H2 reactions on palladium clusters. AB - Adsorption of an H2 molecule on Pd(N) clusters (N = 2-4, 7, 13, 19, and 55) is investigated using density functional theory with the hybrid PBE0 functional. Low energy Pd(N) isomers, taken from a large pool of candidate structures for all cluster sizes (except N = 55), are used in systematic searches for the most stable Pd(N)H2 (molecular) and Pd(N)2H (dissociative) adsorption complexes. Molecular adsorption of H2 is found to occur strictly at atop sites, with the strongest binding typically occurring at the site with the smallest coordination. Binding of dissociated H atoms occurs preferentially on 3-fold faces and on certain favorable edge sites, while binding at atop sites is unstable. Dissociative adsorption is energetically preferred to molecular adsorption for all cluster sizes. The dissociative adsorption energy decreases with cluster size, with pronounced variations due to cluster size effects for the smallest clusters. Adsorption reaction pathways are computed for cluster sizes up to N = 13. Molecular adsorption is found to be barrierless in all cases. Dissociative adsorption occurs without a barrier for the pathways studied for N = 7 and 13 and with a small barrier on the smaller clusters. Finally, lowest-energy pathways for the migration of a dissociated hydrogen atom between local minima on a cluster surface are computed for the Pd4, Pd7, and Pd13 clusters. Calculated migration barriers range from 0.05 to 0.25 eV. PMID- 23980823 TI - Self-protective strategies, violence and psychopathy: theory and a case study. AB - Although it has been proposed that attachment is a key factor in psychopathy and violence, conceptualization of its potential role remains limited. This article uses the dynamic-maturational model of attachment and adaptation (DMM; Crittenden, 2008 ) and a case study to illustrate an etiological model of psychopathy and violence. The Adult Attachment Interview (AAI; George, Kaplan, & Main, 1984 -1996), coded according to the DMM system (Crittenden & Landini, 2011 ), was used to identify the participant's self-protective attachment strategies, and to explore indexes indicating opportunities for change. To allow a more elaborated understanding of this participant's personality, AAI findings were compared and contrasted with the Rorschach method (Rorschach, 1921 /1942). The AAI indicated unresolved loss and trauma, alternation between delusionally idealizing dismissive (Type A) and menacing-paranoid entangled (Type C) strategies, possible depression, and the potential for reorganization. The Rorschach showed many similarities with the AAI findings. Implications for the understanding of psychopathy, violence, and treatment are presented. PMID- 23980824 TI - Comprehensive theory of the Deans' switch as a variable flow splitter: fluid mechanics, mass balance, and system behavior. AB - The Deans' switch is an effluent switching device based on controlling flows of carrier gas instead of mechanical valves in the analytical flow path. This technique offers high inertness and a wear-free operation. Recently new monolithic microfluidic devices have become available. In these devices the whole flow system is integrated into a small metal device with low thermal mass and leak-tight connections. In contrast to a mechanical valve-based system, a flow controlled system is more difficult to calculate. Usually the Deans' switch is used to switch one inlet to one of two outlets, by means of two auxiliary flows. However, the Deans' switch can also be used to deliver the GC effluent with a specific split ratio to both outlets. The calculation of the split ratio of the inlet flow to the two outlets is challenging because of the asymmetries of the flow resistances. This is especially the case, if one of the outlets is a vacuum device, such as a mass spectrometer, and the other an atmospheric detector, e.g. a flame ionization detector (FID) or an olfactory (sniffing) port. The capillary flows in gas chromatography are calculated with the Hagen-Poiseuille equation of the laminar, isothermal and compressible flow in circular tubes. The flow resistances in the new microfluidic devices have to be calculated with the corresponding equation for rectangular cross-section microchannels. The Hagen Poiseuille equation underestimates the flow to a vacuum outlet. A corrected equation originating from the theory of rarefied flows is presented. The calculation of pressures and flows of a Deans' switch based chromatographic system is done by the solution of mass balances. A specific challenge is the consideration of the antidiffusion resistor between the two auxiliary gas lines of the Deans' switch. A full solution for the calculation of the Deans' switch including this restrictor is presented. Results from validation measurements are in good accordance with the developed theories. A spreadsheet-based flow calculator is part of the Supporting Information. PMID- 23980822 TI - Differential response of human adipose tissue-derived mesenchymal stem cells, dermal fibroblasts, and keratinocytes to burn wound exudates: potential role of skin-specific chemokine CCL27. AB - Many cell-based regenerative medicine strategies toward tissue-engineered constructs are currently being explored. Cell-cell interactions and interactions with different biomaterials are extensively investigated, whereas very few studies address how cultured cells will interact with soluble wound-healing mediators that are present within the wound bed after transplantation. The aim of this study was to determine how adipose tissue-derived mesenchymal stem cells (ASC), dermal fibroblasts, and keratinocytes will react when they come in contact with the deep cutaneous burn wound bed. Burn wound exudates isolated from deep burn wounds were found to contain many cytokines, including chemokines and growth factors related to inflammation and wound healing. Seventeen mediators were identified by ELISA (concentration range 0.0006-9 ng/mg total protein), including the skin-specific chemokine CCL27. Burn wound exudates activated both ASC and dermal fibroblasts, but not keratinocytes, to increase secretion of CXCL1, CXCL8, CCL2, and CCL20. Notably, ASC but not fibroblasts or keratinocytes showed significant increased secretion of vascular endothelial growth factor (5-fold) and interleukin-6 (253-fold), although when the cells were incorporated in bi layered skin substitute (SS) these differences were less pronounced. A similar discrepancy between ASC and dermal fibroblast mono-cultures was observed when recombinant human-CCL27 was used instead of burn wound exudates. Although CCL27 did not stimulate the secretion of any of the wound-healing mediators by keratinocytes, these cells, in contrast to ASC or dermal fibroblasts, showed increased proliferation and migration. Taken together, these results indicate that on transplantation, keratinocytes are primarily activated to promote wound closure. In contrast, dermal fibroblasts and, in particular, ASC respond vigorously to factors present in the wound bed, leading to increased secretion of angiogenesis/granulation tissue formation factors. Our findings have implications for the choice of cell type (ASC or dermal fibroblast) to be used in regenerative medicine strategies and indicate the importance of taking into account interactions with the wound bed when developing advanced therapies for difficult to-close cutaneous wounds. PMID- 23980825 TI - Solution processed Al-doped ZnO nanoparticles/TiOx composite for highly efficient inverted organic solar cells. AB - We investigated the electrical properties of solution processed Al-doped ZnO (AZO) nanoparticles, stabilized by mixing with a TiOx complex. Thin solid films cast from the solution of AZO-TiOx (AZOTi) (Ti/Zn ~0.4 in the bulk and ~0.8 on its surface) is processable in inert environment, without a need for either ambient air exposure for hydrolysis or high temperature thermal annealing commonly applied to buffer layers of most metal-oxides. It was found that the electronic structure of AZOTi matches the electronic structure of several electron acceptor and donor materials used in organic electronic devices, such as solar cells. Inverted solar cells employing a bulk heterojunction film of poly(3 hexylthiophene) and phenyl-C61-butyric acid methyl ester, cast on an indium-tin oxide/AZOTi electrode, and capped with a tungsten oxide/aluminum back electrode, give rise to a nearly 70% fill factor and an optimized open-circuit voltage as a result of efficient hole blocking behavior of AZOTi. The resulting electron collecting/blocking capability of this material solves crucial interfacial recombination issues commonly observed at the organic/metal-oxide interface in most inverted organic bulk heterojunction solar cells. PMID- 23980827 TI - Computed tomographic anatomy of the nasal cavity, paranasal sinuses and tympanic cavity of the koala. AB - OBJECTIVE: To use cross-sectional imaging (helical computed tomography (CT)) combined with conventional anatomical dissection to define the normal anatomy of the nasal cavity and bony cavitations of the koala skull. METHODS: Helical CT scans of the heads of nine adult animals were obtained using a multislice scanner acquiring thin slices reconstructed in the transverse, sagittal and dorsal planes. Subsequent anatomical dissection permitted confirmation of correct identification and further delineation of bony and air-filled structures visible in axial and multiplanar reformatted CT images. RESULTS: The nasal cavity was relatively simple, with little scrolling of nasal conchae, but bony cavitations were complex and extensive. A rostral maxillary recess and ventral conchal, caudal maxillary, frontal and sphenoidal paranasal sinuses were identified and characterised. Extensive temporal bone cavitation was shown to be related to a large epitympanic recess. CONCLUSIONS: The detailed anatomical data provided are applicable to future functional and comparative anatomical studies, as well as providing a preliminary atlas for clinical investigation of conditions such as cryptococcal rhinosinusitis, a condition more common in the koala than in many other species. PMID- 23980828 TI - Patent Angiostrongylus mackerrasae infection in a black flying fox (Pteropus alecto). AB - BACKGROUND: A wild adult male black flying fox (Pteropus alecto) was presented unable to fly or hang strongly. RESULTS: Necropsy and histological examination revealed a severe pneumonia, with numerous Angiostrongylus mackerrasae in the pulmonary artery. The pulmonary parenchyma contained numerous eggs and rare larvae. CONCLUSION: This is the first report of patent Angiostrongylus infection in an accidental (i.e. non-Rattus) host species. It is also the first report of A. mackerrasae infection in an accidental host (including flying foxes). Worms recovered from cases of suspected angiostrongyliasis should be examined in morphological detail to ensure correct identification. PMID- 23980829 TI - Acquired proximal renal tubulopathy in dogs exposed to a common dried chicken treat: retrospective study of 108 cases (2007-2009). AB - BACKGROUND: Proximal renal tubulopathy was reported in Australian dogs with markedly increased frequency from September 2007. METHODS: Two veterinarian completed surveys were launched in response to an increased incidence of acquired proximal renal tubulopathy in dogs. The selection criterion for inclusion was glucosuria with blood glucose < 10 mmol/L. Data collected included signalment, presenting signs, history of feeding treats, results of urinalysis and blood tests, treatment and time to resolution of clinical signs. RESULTS: A total of 108 affected dogs were studied. All had been fed the same brand of dried chicken treats, made in China, for a median of 12 weeks (range, 0.3-78 weeks). Small breeds (< 10 kg) accounted for 88% of cases. Common presenting signs included polyuria/polydipsia (76%), lethargy (73%), inappetence (65%) and vomiting (54%). Common biochemical findings included euglycaemia (74%; 71/96), hypoglycaemia (23%; 22/96), acidosis (77%; 20/26), hypokalaemia (45%; 38/84), hypophosphataemia (37%; 28/75) and azotaemia (27%; 23/85). In addition to discontinuation of treats, 64 dogs received medical treatment, including intravenous fluids (52%) and oral electrolyte, amino acid or vitamin supplements. Six dogs died or were euthanased. Two dogs were necropsied. Histopathological findings consisted of proximal tubular necrosis accompanied by regeneration. Time to resolution of clinical signs in 35 survivors available for follow-up was < 2 weeks (n = 8), 2-4 weeks (n = 2), 5-7 weeks (n = 5) and 2-6 months (n = 10). CONCLUSION: Of the 108 dogs with acquired proximal renal tubulopathy contemporaneous with chicken treat consumption, most survived but many required aggressive supportive care. The treats likely contained a toxin targeting the proximal renal tubules. Diet history and urinalysis were vital for diagnosis. PMID- 23980830 TI - Companion animal veterinarians' use of clinical communication skills. AB - OBJECTIVE: To describe the communication techniques used by clients and veterinarians during companion animal visits in Australia. DESIGN: A cross sectional descriptive study. METHODS: A total of 64 veterinary consultations were audiotaped and analysed with the Roter Interaction Analysis System (RIAS); clients completed appointment level measures, including their satisfaction and perceptions of relational communication. RESULTS: Participants were 24 veterinarians and 64 clients. Statements intended to reassure clients were expressed frequently in the consultations, but in 59% of appointments empathy statements were not expressed towards either the client or the patient. In 10% of appointments, veterinarians did not used any open-ended questions. Overall client satisfaction was high and veterinarians' expressions of empathy directed to the client resulted in higher levels of client satisfaction. Clients' perceptions of relational communication were related to several veterinarian and client nonverbal scales. CONCLUSIONS: A focus on developing evidence-based clinical communication skills is expected to further enhance the veterinarian-client patient relationship and associated clinical outcomes. Particular recommendations include the development of a broader emotion-handling repertoire, increased emphasis on the use of open-ended enquiry, including assessment of the client's perspective, as well as attention to aspects of nonverbal communication. The study provides preliminary evidence for the importance of verbal expressions of empathy during the companion animal consultation. PMID- 23980831 TI - Tiger snake (Notechis scutatus) envenomation in a horse. AB - BACKGROUND: A 7-year-old Thoroughbred gelding presented with muscle fasciculation, reluctance to move, profuse sweating, tachycardia, tachypnoea and a localised, unilateral swelling on the muzzle. History and physical examination were suggestive of snake envenomation. METHODS: A sandwich ELISA for the detection of snake venom was performed on serum and urine samples. RESULT: The test performed on urine confirmed a diagnosis of tiger snake envenomation. CONCLUSION: The response to treatment with antivenom and supportive medical therapy was excellent. PMID- 23980833 TI - Encephalomyocarditis virus infection in a splenectomised calf. AB - BACKGROUND: Encephalomyocarditis (EMC) caused by EMC virus (EMCV) was diagnosed in a 5-month-old splenectomised calf, which died suddenly on an experimental farm that had a high infestation of rodents. RESULTS: At postmortem examination, the lungs were dark purple and diffusely congested. On histological examination, the calf had severe necrotising myocarditis. EMCV was isolated from the heart. The polyprotein gene of the EMCV isolate was amplified by PCR and had 85-91% identity with published EMCV sequences, including 89% identity with isolates from Queensland. On phylogenetic analysis, the polyprotein gene had highest sequence identity with South Korean EMCV strain, CBNU. CONCLUSION: This is the first report of naturally occurring EMC in cattle in Australia and the first report of naturally occurring bovine EMC from which EMCV has been isolated. PMID- 23980832 TI - Neospora caninum and reproductive wastage in extensively managed Queensland beef herds. AB - OBJECTIVE: To compare reproduction in extensively managed, tropically adapted beef cows that were either seropositive or seronegative to Neospora caninum. DESIGN: Longitudinal study of cows within management groups. METHODS: Compare pregnancy with weaning outcomes for 502 seropositive and 3255 seronegative cows in 25 management groups. RESULTS: We found N. caninum in all herds, with an average of 20% of 2640 tested animals seropositive within management group; prevalence varied between 0% and 94%. At 7 of 10 sites assessed, there was evidence of horizontal transmission of N. caninum. There was no overall difference in pregnancy rate (79% vs 75%; P > 0.05), reproductive wastage after confirmed pregnancy diagnosis (11% vs 10%; P > 0.05) or weaning rate (67% vs 68%; P > 0.05) between seronegative and seropositive cows, respectively. In one herd where a combination of risk factors for N. caninum was present, a significant reduction in pregnancy rate occurred after the 6 months mating (85% vs 69%; P < 0.05). The fetal and calf losses observed were lowest in south-east Queensland (4.3% of 117 pregnancies), highest in north-west Queensland (15.5% of 413 pregnancies) and intermediate in north-east Queensland (10.2% of 1625 pregnancies). Other infectious agents that are known to cause reproductive wastage were endemic in many herds, though none appeared to cause significant fetal or calf loss in this study. CONCLUSION: Despite a high prevalence of N. caninum, there was no apparent effect on beef cattle reproduction, but there is potential to cause reproductive wastage if known risk factors to neosporosis are in effect. PMID- 23980834 TI - Review of Australia's import policy for horses finalised. PMID- 23980835 TI - Accuracy of visual prediction of pathology of colorectal polyps: how accurate are we? AB - BACKGROUND: Small and diminutive polyps seen at colonoscopy could be left unresected because of a balance of risks between perceived low malignant potential and complications of removing the polyp. This relies on a high accuracy in prediction of the pathology of the polyp. This study was undertaken to determine if experienced endoscopists could determine the histological types of polyps found at colonoscopy. METHODS: We performed a prospective study at Christchurch Hospital from December 2010 to December 2012. Gastroenterologists and surgeons were asked to fill out a questionnaire at time of colonic polypectomy, predicting pathology of polyp excised. Data were collected on indication for colonoscopy, location, size of polyp and use of narrow band imaging. Predictive accuracy was then calculated. RESULTS: A total of 527 polyps were excised from 258 patients. Ninety-one per cent were less than 1 cm. Predictive accuracy of hyperplastic polyps was 47%. Of the 53% wrong predictions, 82% were adenomas. Predictive accuracy of adenoma was 42%, with 66% of incorrect predictions being hyperplastic polyps. Accuracy was lowest in the right colon, with only 25% of predicted hyperplastic polyps actually being hyperplastic. A patient's age, sex, polyp size and site did not affect prediction accuracy. Overall accuracy of visual prediction of pathology of all colorectal polyps was 45%. Narrow band imaging was used too infrequently to determine how useful it was. CONCLUSION: Pathology of colorectal polyps cannot be accurately predicted visually alone. All polyps visualized at colonoscopy should be excised for ex vivo histology, regardless of size, location or predicted pathology. PMID- 23980837 TI - Chronic exposure to PCBs (Aroclor 1254) exacerbates obesity-induced insulin resistance and hyperinsulinemia in mice. AB - Evidence from recent epidemiological studies has emerged implicating exposure to environmental toxicants as a novel risk factor for the development of type 2 diabetes (T2D) and the metabolic syndrome in the general population. Humans and other organisms in high trophic levels of the food chain consume persistent organic pollutants (POP) through their diet. Few experimental studies demonstrating cause and effect are available and evidence for a direct association between accumulation of POP and T2D is preliminary; however, the possibility exists that lipophilic chemicals that accumulate in fatty tissue may disrupt cellular function and metabolic homeostasis. Chronic exposure of diabetes prone C57B/6 mice to a polychlorinated biphenyl (PCB) mixture (Aroclor 1254, 36 mg/kg/wk, 20 wk) alone or in combination with high-fat diet impairs carbohydrate metabolism was compared to vehicle-treated control animals. Specifically, PBC exposure was found to produce hyperinsulinemia in both lean and diet-induced obese mice and exacerbated whole-body insulin resistance in obese mice. These changes in carbohydrate metabolism in response to Aroclor 1254 occurred without marked effect on body weight in both lean and obese mice. Our results demonstrate a causative association between PCB exposure and obesity-induced insulin resistance and hyperinsulinemia independent of body weight changes, an observation that contributes to a growing body of evidence suggesting that exposure to environmental pollutants represents a novel risk factor contributing to the diabetes epidemic. PMID- 23980836 TI - Contributions of the sigma(W) , sigma(M) and sigma(X) regulons to the lantibiotic resistome of Bacillus subtilis. AB - In Bacillus subtilis, the extracytoplasmic function (ECF) sigma factors sigma(M) , sigma(W) and sigma(X) all contribute to resistance against lantibiotics. Nisin, a model lantibiotic, has a dual mode of action: it inhibits cell wall synthesis by binding lipid II, and this complex also forms pores in the cytoplasmic membrane. These activities can be separated in a nisin hinge-region variant (N20P M21P) that binds lipid II, but no longer permeabilizes membranes. The major contribution of sigma(M) to nisin resistance is expression of ltaSa, encoding a stress-activated lipoteichoic acid synthase, and sigma(X) functions primarily by activation of the dlt operon controlling d-alanylation of teichoic acids. Together, sigma(M) and sigma(X) regulate cell envelope structure to decrease access of nisin to its lipid II target. In contrast, sigma(W) is principally involved in protection against membrane permeabilization as it provides little protection against the nisin hinge region variant. sigma(W) contributes to nisin resistance by regulation of a signal peptide peptidase (SppA), phage shock proteins (PspA and YvlC, a PspC homologue) and tellurite resistance related proteins (YceGHI). These defensive mechanisms are also effective against other lantibiotics such as mersacidin, gallidermin and subtilin and comprise an important subset of the intrinsic antibiotic resistome of B. subtilis. PMID- 23980838 TI - Toxicity of fipronil to the midge, Cricotopus lebetis Sublette. AB - Fipronil, a relatively new insecticide more recently developed than organophosphates and pyrethroids, has been detected in surface water draining from agricultural and urban-developed areas. This insecticide is primarily lost through subsurface and surface drainage from terrestrial areas where it has been applied. Invasive aquatic plants often need to be managed in these receiving water bodies to prevent loss of recreational and functional values (e.g., drainage), especially in subtropical and tropical areas. One insect of particular interest is the chironomid midge Cricotopus lebetis Sublette, which may be a useful augmentative biocontrol agent for the invasive aquatic weed Hydrilla verticillata L.f. Royale. Exposure of aquatic organisms, especially insects, to fipronil may significantly impact nontarget populations. These studies investigated the sensitivity of C. lebetis to fipronil exposures ranging from 24 to 96 h. The LC50 observed for each exposure interval was 7.26 MUg/L (24 h), 2.61 MUg/L (48 h), 1.78 MUg/L (72 h), and 1.06 MUg/L (96 h). The LC90 values observed were 47.18 MUg/L (24 h), 9.55 MUg/L (48 h), 6.45 MUg/L (72 h), and 4.81 MUg/L (96 h). Behavioral changes were seen at all fipronil concentration levels, where larvae exited the plant and exhibited abnormal behavior, such as restricted movement and lack of feeding. Results indicate that acute lethality occurred at environmentally relevant concentrations of fipronil. PMID- 23980839 TI - An analysis of workplace exposures to benzene over four decades at a petrochemical processing and manufacturing facility (1962-1999). AB - Benzene, a known carcinogen, can be generated as a by-product during the use of petroleum-based raw materials in chemical manufacturing. The aim of this study was to analyze a large data set of benzene air concentration measurements collected over nearly 40 years during routine employee exposure monitoring at a petrochemical manufacturing facility. The facility used ethane, propane, and natural gas as raw materials in the production of common commercial materials such as polyethylene, polypropylene, waxes, adhesives, alcohols, and aldehydes. In total, 3607 benzene air samples were collected at the facility from 1962 to 1999. Of these, in total 2359 long-term (>1 h) personal exposure samples for benzene were collected during routine operations at the facility between 1974 and 1999. These samples were analyzed by division, department, and job title to establish employee benzene exposures in different areas of the facility over time. Sampling data were also analyzed by key events over time, including changes in the occupational exposure limits (OELs) for benzene and key equipment process changes at the facility. Although mean benzene concentrations varied according to operation, in nearly all cases measured benzene quantities were below the OEL in place at the time for benzene (10 ppm for 1974-1986 and 1 ppm for 1987-1999). Decreases in mean benzene air concentrations were also found when data were evaluated according to 7- to 10-yr periods following key equipment process changes. Further, an evaluation of mortality rates for a retrospective employee cohort (n = 3938) demonstrated that the average personal benzene exposures at this facility (0.89 ppm for the period 1974-1986 and 0.125 ppm for the period 1987-1999) did not result in increased standardized mortality ratio (SMRs) for diseases or malignancies of the lymphatic system. The robust nature of this data set provides comprehensive exposure information that may be useful for assessing human benzene exposures at similar facilities. The data also provide a basis for comparable measured exposure levels and the potential for adverse health effects. These data may also prove beneficial for comparing relative exposure potential for production versus nonproduction operations and the relationship between area and personal breathing zone samples. PMID- 23980840 TI - Estimating lifetime risk from spot biomarker data and intraclass correlation coefficients (ICC). AB - Human biomarker measurements in tissues including blood, breath, and urine can serve as efficient surrogates for environmental monitoring because a single biological sample integrates personal exposure across all environmental media and uptake pathways. However, biomarkers represent a "snapshot" in time, and risk assessment is generally based on long-term averages. In this study, a statistical approach is proposed for estimating long-term average exposures from distributions of spot biomarker measurements using intraclass correlations based upon measurement variance components from the literature. This methodology was developed and demonstrated using a log-normally distributed data set of urinary OH-pyrene taken from our own studies. The calculations are generalized for any biomarker data set of spot measures such as those from the National Health and Nutrition Evaluation Studies (NHANES) requiring only spreadsheet calculations. A three-tiered approach depending on the availability of metadata was developed for converting any collection of spot biomarkers into an estimated distribution of individual means that can then be compared to a biologically relevant risk level. Examples from a Microsoft Excel-based spreadsheet for calculating estimates of the proportion of the population exceeding a given biomonitoring equivalent level are provided as an appendix. PMID- 23980841 TI - Stress hyperglycaemia in hospitalized patients with coronary artery disease and type 2 diabetes risk. AB - BACKGROUND: AIMS: (i) To evaluate glucometabolic status of patients without known diabetes hospitalized due to coronary artery disease (CAD), (ii) to assess markers of systemic inflammation determined during admission and to evaluate their relationship with glucometabolic status and (iii) to analyse usefulness of HbA1c determined during admission in patients with CAD to detect abnormal glucose regulation (AGR). MATERIALS & METHODS: We studied 440 patients with CAD admitted to the cardiology ward. Patients were grouped in four groups during admission according to clinical data, fasting plasma glucose and HbA1c: diabetes, HbA1c > 5.9%, stress hyperglycaemia (SH) and normal. In 199 subjects without known diabetes, an oral glucose tolerance test (OGTT) was performed 3 months after discharge, and they were reclassified according to WHO 1998 criteria. Biochemical and inflammatory markers were measured. RESULTS: The OGTT showed that 27.4% of subjects without known diabetes at admission had diabetes, 11.2% had impaired fasting glucose + impaired glucose tolerance, 33.5% impaired glucose tolerance, 3.6% impaired fasting glucose, and 24.4% normal glucose metabolism. Odds ratio for having diabetes 3 months after discharge in HbA1c > 5.9% group was 5.91 (P < 0.0001) and in SH group was 1.82 (P = 0.38). The best HbA1c cut-off point to predict AGR was 5.85%. HbA1c levels during admission were highly predictive of having AGR (AUC ROC 0.76 [95% CI 0.67-0.84]). CONCLUSION: We reported a high prevalence of AGR in subjects with CAD. Stress hyperglycaemia in patients with CAD was not associated with an increased risk of diabetes 3 months later. HbA1c in patients hospitalized with CAD was a useful tool to detect AGR. PMID- 23980843 TI - Dual selectivity: electrophile and nucleophile selective cross-coupling reactions on a single aromatic substrate. AB - The development of a high yielding, both nucleophile and electrophile selective cross-coupling reaction with aromatic rings is presented. The reaction is general with respect to functional groups. Furthermore, the products still contain a boronic ester and a bromide. These two functional groups allow them to be easy-to prepare, highly complex starting materials for further reactions, avoiding protecting group transformations. PMID- 23980842 TI - The Arabidopsis lectin receptor kinase LecRK-I.9 enhances resistance to Phytophthora infestans in Solanaceous plants. AB - Late blight caused by the plant pathogenic oomycete Phytophthora infestans is known as one of the most destructive potato diseases. Plant breeders tend to employ NB-LRR-based resistance for introducing genetically controlled late blight resistance in their breeding lines. However, P. infestans is able to rapidly escape this type of resistance, and hence, NB-LRR-based resistance in potato cultivars is often not durable. Previously, we identified a novel type of Phytophthora resistance in Arabidopsis. This resistance is mediated by the cell surface receptor LecRK-I.9, which belongs to the family of L-type lectin receptor kinases. In this study, we report that expression of the Arabidopsis LecRK-I.9 gene in potato and Nicotiana benthamiana results in significantly enhanced late blight resistance. Transcriptional profiling showed strong reduction in salicylic acid (SA)-mediated defence gene expression in LecRK-I.9 transgenic potato lines (TPLs). In contrast, transcripts of two protease inhibitor genes accumulated to extreme high levels, suggesting that LecRK-I.9-mediated late blight resistance is relying on a defence response that includes activation of protease inhibitors. These results demonstrate that the functionality of LecRK-I.9 in Phytophthora resistance is maintained after interfamily transfer to potato and N. benthamiana and suggest that this novel type of LecRK-based resistance can be exploited in breeding strategies to improve durable late blight resistance in Solanaceous crops. PMID- 23980845 TI - Chronic pruritus associated with dermatologic disease in infancy and childhood: update from an interdisciplinary group of dermatologists and pediatricians. AB - An effective treatment strategy for chronic pruritus in children with dermatologic disorders should consider the multidimensional aspects of pruritus, the unique challenges associated with treating pruritic skin disorders in the pediatric population, and evidence-based therapies with demonstrated antipruritic benefits and clinically relevant effects on patient/family quality of life (QoL). The Course of Advanced Learning for the Management of ITch (CALM-IT) Task Force is an interdisciplinary group of experts specializing in core aspects of pruritus treatment, integrating pediatrics, dermatology, psychotherapy, pruritus management, and sleep. CALM-IT recently convened to provide updated guidance on managing chronic pruritus associated with dermatologic diseases in pediatric patients, with a special focus on atopic dermatitis (AD) and chronic spontaneous urticaria (csU). This review highlights the updated concepts and best practices, which were built upon international PRACTALL consensus and modified for children and infants with AD and csU. CALM-IT supports the routine use of basic skin therapy and the escalation of topical medications, according to severity and focused on rapid itch control. Anti-inflammatory agents should be appropriate for infants and children (i.e., with an optimized therapeutic index) and have proven antipruritic properties, such as those demonstrated by methylprednisolone aceponate. New experimental findings do not support the use of non-sedating oral antihistamines as adjuvant antipruritic therapy for AD. In csU, oral H1 antihistamine use is justified, consistent with the distinct pathophysiologic mechanisms of itch underlying AD and csU. All encompassing QoL assessments should consider the burden of both patient and caregiver and should address outstanding unmet clinical needs of pediatric patients. Future research areas include integrated QoL assessments and multidisciplinary treatment programs with pediatric-targeted pruritic therapies providing rapid itch control. PMID- 23980846 TI - Black currant seed oil supplementation of mothers enhances IFN-gamma and suppresses IL-4 production in breast milk. AB - BACKGROUND: The first year of infancy is crucial for the development of atopic immune response. Inadequate early Th1 and Treg responses and increased production of Th2 cytokines are associated with atopy. Breast milk contains several immunomodulatory cytokines and other factors that might influence the maturation of the infant's immune system. We assessed the cytokines in breast milk of mother of newborn infants and their associations with black currant seed oil (BCSO) supplementation during pregnancy, mother's atopic status and the development of infant's atopic dermatitis. METHODS: Mothers and infants from an intervention study by black currant seed oil (n = 31) or olive oil as placebo (n = 30) were included in the study. Breast milk samples were collected during the first 3 months of breastfeeding. Breast milk levels of IL-4, IL-5, IL-10, IL-12, IFN gamma and TNF were measured by Luminex technology. RESULTS: BCSO intervention group had decreased level of IL-4 (p = 0.044) and elevated level of IFN-gamma (p = 0.014) in breast milk as compared to olive oil group. No significant differences were observed in IL-5, IL-10, IL-12 and TNF levels between the BCSO and olive oil groups. Mothers who had atopic dermatitis had significantly decreased levels of IL-10 (p = 0.044) in breast milk. Breast milk of the mothers of the children who developed atopic dermatitis had lower levels of IFN-gamma (p = 0.039) as compared to the breast milk of the mothers of the children without dermatitis. CONCLUSION: Dietary intervention with BCSO had immunomodulatory effects on breast milk cytokine production towards Th2 to Th1 immunodeviation. PMID- 23980847 TI - Functional textiles for atopic dermatitis: a systematic review and meta-analysis. AB - Atopic dermatitis (AD) is a relapsing inflammatory skin disease with a considerable social and economic burden. Functional textiles may have antimicrobial and antipruritic properties and have been used as complementary treatment in AD. We aimed to assess their effectiveness and safety in this setting. We carried out a systematic review of three large biomedical databases. GRADE approach was used to rate the levels of evidence and grade of recommendation. Meta-analyses of comparable studies were carried out. Thirteen studies (eight randomized controlled trials and five observational studies) met the eligibility criteria. Interventions were limited to silk (six studies), silver-coated cotton (five studies), borage oil, and ethylene vinyl alcohol (EVOH) fiber (one study each). Silver textiles were associated with improvement in SCORAD (2 of 4), fewer symptoms, a lower need for rescue medication (1 of 2), no difference in quality of life, decreased Staphyloccosus aureus colonization (2 of 3), and improvement of trans-epidermal water loss (1 of 2), with no safety concerns. Silk textile use was associated with improvement in SCORAD and symptoms (2 of 4), with no differences in quality of life or need for rescue medication. With borage oil use only skin erythema showed improvement, and with EVOH fiber, an improvement in eczema severity was reported. Recommendation for the use of functional textiles in AD treatment is weak, supported by low quality of evidence regarding effectiveness in AD symptoms and severity, with no evidence of hazardous consequences with their use. More studies with better methodology and longer follow-up are needed. PMID- 23980849 TI - Large serine recombinase domain structure and attachment site binding. AB - Large serine recombinases (LSRs) catalyze the movement of DNA elements into and out of bacterial chromosomes using site-specific recombination between short DNA "attachment sites". The LSRs that function as bacteriophage integrases carry out integration between attachment sites in the phage (attP) and in the host (attB). This process is highly directional; the reverse excision reaction between the product attL and attR sites does not occur in the absence of a phage-encoded recombination directionality factor, nor does recombination typically occur between other pairings of attachment sites. Although the mechanics of strand exchange are reasonably well understood through studies of the closely related resolvase and invertase serine recombinases, many of the fundamental aspects of the LSR reactions have until recently remained poorly understood on a structural level. In this review, we discuss the results of several years worth of biochemical and molecular genetic studies of LSRs in light of recently described structural models of LSR-DNA complexes. The focus is understanding LSR domain structure, how LSRs bind to the attP and attB attachment sites, and the differences between attP-binding and attB-binding modes. The simplicity, site selectivity and strong directionality of the LSRs has led to their use as important tools in a number of genetic engineering applications in a wide variety of organisms. Given the important potential role of LSR enzymes in genetic engineering and gene therapy, understanding the structure and DNA-binding properties of LSRs is of fundamental importance for those seeking to enhance or alter specificity and functionality in these systems. PMID- 23980848 TI - Maternal allergy is associated with surface-bound IgE on cord blood basophils. AB - BACKGROUND: The cell type(s) mediating the maternal influence on allergic disease in children remain unclear. We set out to define the relationship between maternal allergy and frequencies of cord blood (CB) basophils, and plasmacytoid dendritic cells (pDCs); to characterize surface-bound IgE and FcepsilonRI expressions on these cells; and to investigate the association between maternal and CB serum IgE levels with surface-bound IgE and FcepsilonRI expressions. METHODS: One hundred and three mother/infant dyads were recruited prenatally, and maternal allergic history was recorded. Maternal blood was collected prior to delivery, and CB was collected after birth. Flow cytometry was used to identify CB basophils and pDCs and to determine surface-bound IgE and FcepsilonRI expressions. RESULTS: Frequencies of CB basophils and pDCs were low and not related to maternal history of allergy. Percentages of CB basophils with surface bound IgE were significantly higher in infants of allergic mothers compared with infants of non-allergic mothers (median, 59.60% vs. 19.70%, p = 0.01). IgE on CB basophils correlated with CB IgE levels (r = 0.72, p < 0.0001), but not with maternal IgE levels (r = 0.26, p = 0.06). IgE on CB pDCs was low and not significantly associated with maternal or CB IgE levels. Similarly, FcepsilonRI expression by CB basophils and pDCs was not significantly associated with maternal or CB IgE levels. CONCLUSIONS: Frequencies of CB basophils and pDCs are not influenced by maternal allergy. CB basophils and pDCs have surface-bound IgE and express FcepsilonRI; however, only IgE on CB basophils appears influenced by maternal allergy. PMID- 23980850 TI - Synthesis, electrochemistry, and electrogenerated chemiluminescence of two BODIPY appended bipyridine homologues. AB - Two new 2,2'-bipyridine (bpy) derivatives containing ancillary BODIPY chromophores attached at the 5- and 5'-positions (BB3) or 6- and 6'-positions (BB4) were prepared and characterized. In this work, the basic photophysics, electrochemistry, and electrogenerated chemiluminescence (ECL) of BB3 and BB4 are compared with those previously reported for a related bpy-BODIPY derivative (BB2) (J. Phys. Chem. C 2011, 115, 17993-18001). Cyclic voltammetry revealed that BB3 and BB4 display reversible 2e(-) oxidation and reduction waves, which consist of two closely spaced (50-70 mV) 1e(-) events. This redox behavior is consistent with the frontier molecular orbitals calculated for BB3 and BB4 and indicates that the 2,2'-bipyridine spacer of each bpy-BODIPY homologue does not facilitate efficient electronic communication between the tethered indacene units. In the presence of a coreactant such as tri-n-propylamine (TPA) or benzoyl peroxide (BPO), BB3 and BB4 exhibit strong ECL and produce spectra that are very similar to their corresponding photoluminescence profiles. The ECL signal obtained under annihilation conditions, however, is significantly different and is characterized by two distinct bands. One of these bands is centered at ~570 nm and is attributed to emission via an S- or T-route. The second band occurs at longer wavelengths and is centered around ~740 nm. The shape and concentration dependence of this long-wavelength ECL signal is not indicative of emission from an excimer or aggregate, but rather it suggests that a new emissive species is formed from the bpy-BODIPY luminophores during the annihilation process. PMID- 23980863 TI - Abstracts of the 49th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology. September 9-11, 2013. Brisbane, Australia. PMID- 23980864 TI - Long-term stasis and short-term divergence in the phenotypes of microsnails on oceanic islands. AB - Phenotypic divergence is often unrelated to genotypic divergence. An extreme example is rapid phenotypic differentiation despite genetic similarity. Another extreme is morphological stasis despite substantial genetic divergence. These opposite patterns have been viewed as reflecting opposite properties of the lineages. In this study, phenotypic radiation accompanied by both rapid divergence and long-term conservatism is documented in the inferred molecular phylogeny of the micro land snails Cavernacmella (Assimineidae) on the Ogasawara Islands. The populations of Cavernacmella on the Sekimon limestone outcrop of Hahajima Island showed marked divergence in shell morphology. Within this area, one lineage diversified into types with elongated turret shells, conical shells and flat disc-like shells without substantial genetic differentiation. Additionally, a co-occurring species with these types developed a much larger shell size. Moreover, a lineage adapted to live inside caves in this area. In contrast, populations in the other areas exhibited no morphological differences despite high genetic divergence among populations. Accordingly, the phenotypic evolution of Cavernacmella in Ogasawara is characterized by a pattern of long term stasis and periodic bursts of change. This pattern suggests that even lineages with phenotypic conservatism could shift to an alternative state allowing rapid phenotypic divergence. PMID- 23980865 TI - Pharmacokinetics and absorption of the anticancer agents dasatinib and GDC-0941 under various gastric conditions in dogs--reversing the effect of elevated gastric pH with betaine HCl. AB - Changes in gastric pH can impact the dissolution and absorption of compounds presenting pH-dependent solubility. We assessed, in dogs, the effects of gastric pH-modifying agents on the oral absorption of two weakly basic anticancer drugs, dasatinib and GDC-0941. We also tested whether drug-induced hypochlorhydria could be temporarily mitigated using betaine HCl. Pretreatments with pentagastrin, famotidine, betaine HCl, or combinations of famotidine and betaine HCl were administered orally to dogs prior to drug dosing. The gastric pH was measured under each condition for up to 7 h, and the exposure of the compounds tested was calculated. The average gastric pH in fasted dogs ranged from 1.45 to 3.03. Pentagastrin or betaine HCl treatments lowered the pH and reduced its variability between dogs compared to control animals. In contrast, famotidine treatment maintained gastric pH at values close to 7 for up to 5 h, while betaine HCl transiently reduced the pH to approximately 2 in the famotidine-treated dogs. Famotidine pretreatment lowered GDC-0941 exposure by 5-fold, and decreased dasatinib measurable concentrations 30-fold, compared to the pentagastrin-treated dogs. Betaine HCl restored GDC-0941 AUC in famotidine-treated dogs to levels achieved in control animals, and increased dasatinib AUC to 1.5-fold that measured in control dogs. The results confirmed the negative impact of acid reducing agents on the absorption of weakly basic drugs. They also suggested that betaine HCl coadministration may be a viable strategy in humans treated with acid reducing agents in order to temporarily reduce gastric pH and restore drug exposure. PMID- 23980866 TI - Metabolic syndrome and gingival inflammation in Caucasian children with a family history of obesity. AB - AIM: To investigate whether metabolic syndrome (MetS) and its components are associated with gingival inflammation in children. MATERIALS AND METHODS: This is a cross-sectional analysis from the baseline visit of the QUebec Adipose and Lifestyle InvesTigation in Youth cohort, an ongoing longitudinal study investigating the natural history of obesity in children of Quebec, Canada. The analytic sample includes 448 children aged 8-10 years, 39% of whom were overweight or obese. MetS was defined according to the International Diabetes Federation recommendations. Gingival inflammation was defined by the level of gingival crevicular fluid (GCF) tumour necrosis factor alpha (TNF-alpha) and the extent of gingival bleeding. Sex-specific linear regression analyses estimated the associations between MetS and gingival inflammation, adjusting for potential confounders. RESULTS: Twenty-five children had MetS. Boys with MetS compared to those without, had a 49.5% (p-value = 0.001) higher GCF TNF-alpha level and 13.7% (p-value = 0.033) more sites with gingival bleeding. Moreover, for three of the five components of MetS - waist circumference, fasting plasma triglycerides, systolic blood pressure - an increase was associated with increased GCF TNF-alpha level in boys. No such findings were seen in girls. CONCLUSION: An association between MetS and gingival inflammation was observed as early as in childhood, and may differ by sex. PMID- 23980867 TI - Enzyme-triggered cargo release from methionine sulfoxide containing copolypeptide vesicles. AB - We have developed a facile, scalable method for preparation of enzyme-responsive copolypeptide vesicles that requires no protecting groups or expensive components. We designed amphiphilic copolypeptides containing segments of water soluble methionine sulfoxide, M(O), residues that were prepared by synthesis of a fully hydrophobic precursor diblock copolypeptide, poly(l-methionine)65-b-poly(L leucine0.5-stat-L-phenylalanine0.5)20, M65(L0.5/F0.5)20, followed by its direct oxidation in water to give the amphiphilic M(O) derivative, M(O)65(L0.5/F0.5)20. Assembly of M(O)65(L0.5/F0.5)20 in water gave vesicles with average diameters of a few micrometers that could then be extruded to nanoscale diameters. The M(O) segments in the vesicles were found to be substrates for reductase enzymes, which regenerated hydrophobic M segments and resulted in a change in supramolecular morphology that caused vesicle disruption and release of cargos. PMID- 23980868 TI - Lack of mitochondrial DNA structure in Balkan donkey is consistent with a quick spread of the species after domestication. AB - A total of 132 mtDNA sequences from 10 Balkan donkey populations were analysed to ascertain their regional genetic structure and to contribute to the knowledge of the spreading of the species after domestication. The Balkan donkey sequences were compared with those from 40 Burkina Faso donkeys as an African outgroup to account for possible local Balkan scenarios. The 172 sequences gave 62 different haplotypes (55 in Balkan donkey). Virtually all the analysed populations had haplotypes assigned to either Clade 1 or Clade 2 even though the relative proportion of Clade 1 or 2 haplotypes differed across populations. Geographical maps constructed using factors computed via principal component analysis showed that the Balkan donkey populations are not spatially structured. AMOVA confirmed a lack of genetic structure in Balkan donkey mtDNA. Balkan populations were poorly differentiated (PhiST = 0.071). Differentiation between the Balkan donkey and the African outgroup also was low. The lack of correspondence between geographical areas and maternal genetic structure is consistent with the hypothesis suggesting a very quick spread of the species after domestication. The current research illustrates the difficulties to trace routes of expansion in donkey, as the species has no geographical structure. PMID- 23980869 TI - Rapamycin reduces burn wound progression by enhancing autophagy in deep second degree burn in rats. AB - Burn wound progression is caused by many mechanisms including local tissue hypoperfusion, prolonged inflammation, free radical damage, apoptosis, and necrosis in burn wounds. Autophagy, a homeostatic process by which cells break down their own components, was found to protect against ischemic injury, inflammatory diseases, and apoptosis in some cases. We tested whether rapamycin, an autophagy inducer, could ameliorate burn wound progression and promote wound healing through autophagy enhancement. Using a previously described deep second degree burn model, we first tested the effects of rapamycin on autophagic response in burn wound tissue. Autophagy levels in wound tissue of treated rats were increased as compared with controls. Furthermore, we found that laser Doppler flowmetry values and Na/K-ATPase activities were markedly higher in the treated wounds. The content of interleukin-8, methane dicarboxylic aldehyde, and myeloperoxidase activity in the wounds of treated rats were much lower than in controls. The apoptotic rates in treated wounds were much lower than controls as determined by terminal deoxynucleotidyl transferase mediated nick end labeling assay. Finally, histomorphological analysis showed that burn wound progression in the treatment group was ameliorated. The time to wound reepithelialization was shorter in the treated wounds than controls 22.5 +/- 1.4 days vs. 24.8 +/- 1.3 days (mean +/- standard deviation, p < 0.01). PMID- 23980871 TI - Transitivity analysis: a framework for the study of social values in the context of points of view. AB - Since its inception, psychology has struggled with issues of conceptualization and operationalization of social-psychological phenomena. The study of social values and points of view has been prone to such difficulties, despite a predominant concern of qualitative distinctions in the variability of both of these phenomena across different individuals and social groups. And while interest in both traces a common origin in Rokeach's studies of narrow mindedness, the study of both phenomena has since proceeded apace. In this study, we posit a renewed reconciliation between the two that is best served through a social-psychological model of points of view in terms of the values that inspire them. We draw on critical linguistics to propose a theoretical and methodological framework that can aid a systematic study of value structures as they take different forms and meanings through particular types of points of view. In five stages of qualitative analysis, the model deconstructs utterances into distinct terms that reveal a predominant perspective-taking style that can be utilized towards the categorization of different points of view, in terms of values that imbue them and that serve to provide them with a coherent angle of constructing a particular narrative. PMID- 23980870 TI - Measurement of tanning dependence. AB - BACKGROUND: Indoor tanning has been found to be addictive. However, the most commonly used tanning dependence measures have not been well validated. OBJECTIVE: The study's purpose was to explore the psychometric characteristics of and compare the modified Cut-down, Annoyed, Guilty, Eye-opener Scale (mCAGE), modified Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition - Text Revised (mDSM-IV-TR) and Tanning Pathology Scale (TAPS) measures of tanning dependence and provide recommendations for research and practice. METHODS: This study was a cross-sectional online survey with 18- to 25-year-old female university students. The main outcome variable was tanning dependence measured by the mCAGE, mDSM-IV-TR and TAPS. RESULTS: Internal consistency of the TAPS subscales was good but was poor for the mCAGE and mDSM-IV-TR, except when their items were combined. Agreement between the mCAGE and mDSM-IV-TR was fair. Factor analysis of the TAPS confirmed the current four-factor structure. All of the tanning dependence scales were significantly correlated with one another. Likewise, most of the tanning dependence scales were significantly correlated with other measures of tanning attitudes and behaviours. However, the tolerance to tanning TAPS subscale was not significantly correlated with any measure of tanning attitudes or behaviours and had the lowest subscale internal reliability and eigenvalues. CONCLUSION: Based on the data and existing literature, we make recommendations for the continued use of tanning dependence measures. Intervention may be needed for the approximately 5% of college women who tend to be classified as tanning dependent across measures. Monitoring of individuals reporting tanning dependence symptoms is warranted. PMID- 23980872 TI - Substituent effect on the photoreduction kinetics of benzophenone. AB - The kinetics of the photoreduction of four benzophenone derivatives by isopropyl alcohol was examined in acetonitrile, namely, tetra-meta-trifluoromethyl-, di para-trifluoromethyl-, di-para-methoxy benzophenone, and, for comparison, the unsubstituted molecule itself. The basic spectroscopic (absorption and phosphorescence spectra) and photophysical (quantum yields and excited state energies) properties were established, and the key kinetic parameters were determined by the laser flash photolysis transient absorption technique. The rate coefficients of both the primary and secondary photoreduction reaction show remarkable dependence on ring substitution. This substantial effect is caused by the considerable change in the activation energy of the corresponding process. The experimental results as well as DFT quantum chemical calculations clearly indicate that these benzophenone derivatives all react as n-pi* excited ketones, and the rate as well as the activation energy of the reduction steps change parallel with the reaction enthalpies, the determining factor being the stability of the forming aromatic ketyl radicals. The secondary photoreduction of benzophenones by the aliphatic ketyl radical formed in the primary step occurs via a hydrogen bonded complex. The binding energy of the hydrogen bonded complex between the aliphatic ketyl radical reactant and a solvent molecule is a critical parameter influencing the observable rate of the secondary photoreduction. PMID- 23980873 TI - Retraction of DOI: 10.1089/thy.2012.0224. PMID- 23980874 TI - How ternary mobile phases allow tuning of analyte retention in hydrophilic interaction liquid chromatography. AB - An attractive yet hardly explored feature of hydrophilic interaction liquid chromatography (HILIC) is the tuning of analyte retention through the addition of an alcohol to the water (W)-acetonitrile (ACN) mobile phase (MP). When retention times increase sharply between 10/90 and 5/95 (v/v) W/ACN, intermediate retention values are stepwise accessible with a ternary MP of 5/90/5 (v/v/v) W/ACN/alcohol by switching from methanol to ethanol to isopropyl alcohol. We investigate the physicochemical basis of this retention tuning by molecular dynamics simulations using a model of a 9 nm silica pore between two solvent reservoirs. Our simulations show that alcohol molecules insert themselves neatly into the retentive W-rich layer at the silica surface, without disrupting the layer's structure or altering its essential properties. With the decreasing tendency of an alcohol (methanol > ethanol > isopropyl alcohol) to move toward the silica surface, the contrast between the W-rich layer and the bulk MP sharpens as the latter becomes more organic, while the W density near the silica surface remains high. Analyte retention increases with the ratio between the W mole fraction in the diffuse part of the W-rich layer and that in the bulk MP. We predict that tuning of HILIC retention is possible over a wide range through the choice of the third solvent in a W/ACN-based ternary MP, whereby the largest retention values can be expected from W-immiscible solvents that fully remain in the bulk MP. PMID- 23980875 TI - Laparoscopic stapled excision of non-parasitic splenic cysts. AB - BACKGROUND: A laparoscopic spleen preserving surgical approach is preferred for the management of symptomatic non-parasitic splenic cysts. The aim of this study was to review our experience with managing this rare presentation. METHODS: A retrospective review of all cases of splenic cysts was performed over a 10-year period (2001-2011). Demographic data, clinical history, investigations, operative details and the outcome of each case were reviewed with an emphasis on patients who underwent laparoscopic stapled cyst excision. RESULTS: Eleven cases were identified. Seven patients were managed surgically; six by laparoscopic stapled cyst excision and one by open excision of remnant splenic tissue. Laparoscopic management was successful in all six cases and radiological and clinical follow up (median: 28 months) revealed no evidence of cyst recurrence in five of six cases. One patient developed an asymptomatic, non-progressing and small recurrent anterior cyst and she continues to be observed. CONCLUSION: Laparoscopic stapled splenic cyst excision can be performed safely and is particularly effective for large superficial non-parasitic cysts. This technique allows spleen preservation with a low cyst recurrence rate. However, it may not be suitable for deeper intraparenchymal splenic cysts. Further studies are required to refine the management of specific subtypes of non-parasitic splenic cysts. PMID- 23980876 TI - Gene electrotransfer of plasmid antiangiogenic metargidin peptide (AMEP) in disseminated melanoma: safety and efficacy results of a phase I first-in-man study. AB - Antiangiogenic metargidin peptide (AMEP) is a novel anticancer agent exerting antiproliferative and antiangiogenic effects by binding to alphavbeta3 and alpha5beta1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I study investigated safety and tolerability of intratumoral plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA). In each patient, two cutaneous lesions were identified (one treated and one control). At day 1 and day 8, plasmid AMEP was injected intratumorally followed by electrotransfer. Patients were monitored weekly until day 29, and at day 64. Local efficacy was assessed at day 29 by direct measurement, and posttreatment biopsies for AMEP mRNA levels were evaluated by reverse transcriptase quantitative polymerase chain reaction. Plasmid copy number in blood and urine was determined by quantitative polymerase chain reaction. Minimal systemic toxicity was observed, including transient fever and transitory increase in C reactive protein. No related serious adverse events occurred. Plasmid AMEP was detected in plasma but not in urine. AMEP mRNA was found in three of five treated lesions and none of the control lesions. At day 29, all five treated lesions were stable in diameter, whereas four of five control lesions increased more than 20%. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe and that local transfection was obtained. PMID- 23980877 TI - The hapten-atopy hypothesis III: the potential role of airborne chemicals. AB - One explanation for the large increase in the prevalence of atopic disease in developed countries during the last 50 years is the 'hygiene hypothesis'. This proposes that a reduced exposure to pathogenic microorganisms at a key period(s) during development results in the maintenance or acquisition of an atopic phenotype. Alternatively, or additionally, we have postulated that increased exposure to chemicals generally, and to irritant/haptenic chemicals in particular, during critical windows of maternal pregnancy/early life have also contributed to changes in the prevalence of atopic disease. Having previously reviewed the potential roles of oral and cutaneous exposure to chemicals on the subsequent diagnosis of atopic disease, we here consider possible evidence of a role for exposure to airborne chemicals as a contributory factor in acquired susceptibility to atopic allergy. After controlling for known confounders, five specific maternal occupations during pregnancy have been implicated as being associated with subsequent atopic disease in the offspring. Each of these occupations is characterized by high and persistent exposure to airborne chemicals. High-level exposure to volatile organic compounds in the domestic environment, either during pregnancy or in early life, is also associated with development of childhood atopic disease. Similarly, sustained exposure to airborne chlorinated chemicals from swimming pools during childhood has been associated with the development of atopic allergy. A possible immunological basis for these associations is that exposure to certain airborne chemicals, even at low levels, can result in the delivery of 'danger' signals that, in turn, bias the immune response towards the selective induction or maintenance of preferential T helper 2-type immune responses consistent with the acquisition of allergic sensitization. PMID- 23980878 TI - Structurally conserved binding sites of hemagglutinin as targets for influenza drug and vaccine development. AB - ProBiS is a new method to identify the binding site of protein through local structural alignment against the nonredundant Protein Data Bank (PDB), which may result in unique findings compared to the energy-based, geometry-based, and sequence-based predictors. In this work, binding sites of Hemagglutinin (HA), which is an important target for drugs and vaccines in influenza treatment, have been revisited by ProBiS. For the first time, the identification of conserved binding sites by local structural alignment across all subtypes and strains of HA available in PDB is presented. ProBiS finds three distinctive conserved sites on HA's structure (named Site 1, Site 2, and Site 3). Compared to other predictors, ProBiS is the only one that accurately defines the receptor binding site (Site 1). Apart from that, Site 2, which is located slightly above the TBHQ binding site, is proposed as a potential novel conserved target for membrane fusion inhibitor. Lastly, Site 3, located around Helix A at the stem domain and recently targeted by cross-reactive antibodies, is predicted to be conserved in the latest H7N9 China 2013 strain as well. The further exploration of these three sites provides valuable insight in optimizing the influenza drug and vaccine development. PMID- 23980880 TI - Performance of serum alpha-fetoprotein levels in the diagnosis of hepatocellular carcinoma in patients with a hepatic mass. AB - OBJECTIVES: The role of serum alpha-fetoprotein (AFP) measurements in the diagnosis of hepatocellular carcinoma (HCC) remains controversial. Some guidelines have advised against the use of AFP in the diagnosis of HCC. This study was conducted to evaluate the performance of AFP in the diagnosis of HCC, and to identify the optimal cut-off value of serum AFP in the diagnosis of HCC in patients with a hepatic mass. METHODS: Patients who presented during the period from May 1997 to March 2003 with hepatic lesions, for whom paired data on serum AFP values at baseline and lesion histology were available, were reviewed. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis. RESULTS: Data for a total of 805 patients were evaluated. The mean AFP value was 26,900 ng/ml (range: 0-1,965,461 ng/ml). The histological diagnosis was HCC in 557 patients. The optimal AFP cut off value was 10 ng/ml (for sensitivity of 82.6% and specificity of 70.4%). At a cut-off level of 200 ng/ml, sensitivity, specificity, and positive and negative predictive values were 47.7%, 97.1%, 97.5% and 44.4%, respectively. The diagnostic performance of AFP remains similar in patients with chronic hepatitis B virus infection, despite a lower negative predictive value. Common aetiologies of liver lesions associated with elevated AFP include cholangiocarcinoma and neuroendocrine tumours. CONCLUSIONS: In Asian patients with suspicious liver lesions, the cut-off AFP level of 200 ng/ml is useful to achieve a diagnosis of HCC with high specificity and reasonable sensitivity. The measurement of serum AFP should not be excluded from guidelines for the diagnosis of HCC. PMID- 23980879 TI - The role of nesfatin-1 in the regulation of food intake and body weight: recent developments and future endeavors. AB - Nesfatin-1 was discovered in 2006 and introduced as a potential novel anorexigenic modulator of food intake and body weight. The past years have witnessed increasing evidence establishing nesfatin-1 as a potent physiological inhibitor of food intake and body weight and unravelled nesfatin-1's interaction with other brain transmitters to exert its food consumption inhibitory effect. As observed for other anorexigenic brain neuropeptides, nesfatin-1 is also likely to exert additional, if not pleiotropic, actions in the brain and periphery. Recent studies established the prominent expression of the nesfatin-1 precursor, nucleobindin2 (NUCB2), in the stomach and pancreas, where nesfatin-1 influences endocrine secretion. This review will highlight the current experimental state-of knowledge on the effects of NUCB2/nesfatin-1 on food intake, body weight and glucose homeostasis. Potential implications in human obesity will be discussed in relation to the evidence of changes in circulating levels of NUCB2/nesfatin-1 in disease states, the occurrence of genetic NUCB2 polymorphisms and--in contrast to several other hormones--the independence of leptin signalling known to be blunted under conditions of chronically increased body weight. PMID- 23980882 TI - Regulatory small RNAs. AB - Recent years have been marked by a burst of studies on the role of various RNAs in the regulation of gene expression. These regulatory effects act on the level of both chromatin in the nuclei and the cytoplasm during translation. The review papers of this issue are mainly dedicated to different types of small RNAs of 20 30 nucleotides. The small RNAs control diverse cellular functions including genome protection against transpositions of mobile elements of the genome. PMID- 23980883 TI - Targeting heterochromatin formation to transposable elements in Drosophila: potential roles of the piRNA system. AB - Successful heterochromatin formation is critical for genome stability in eukaryotes, both to maintain structures needed for mitosis and meiosis and to silence potentially harmful transposable elements. Conversely, inappropriate heterochromatin assembly can lead to inappropriate silencing and other deleterious effects. Hence targeting heterochromatin assembly to appropriate regions of the genome is of utmost importance. Here we focus on heterochromatin assembly in Drosophila melanogaster, the model organism in which variegation, or cell-to-cell variable gene expression resulting from heterochromatin formation, was first described. In particular, we review the potential role of transposable elements as genetic determinants of the chromatin state and examine how small RNA pathways may participate in the process of targeted heterochromatin formation. PMID- 23980881 TI - Genome-wide profiling of chromosome interactions in Plasmodium falciparum characterizes nuclear architecture and reconfigurations associated with antigenic variation. AB - Spatial relationships within the eukaryotic nucleus are essential for proper nuclear function. In Plasmodium falciparum, the repositioning of chromosomes has been implicated in the regulation of the expression of genes responsible for antigenic variation, and the formation of a single, peri-nuclear nucleolus results in the clustering of rDNA. Nevertheless, the precise spatial relationships between chromosomes remain poorly understood, because, until recently, techniques with sufficient resolution have been lacking. Here we have used chromosome conformation capture and second-generation sequencing to study changes in chromosome folding and spatial positioning that occur during switches in var gene expression. We have generated maps of chromosomal spatial affinities within the P. falciparum nucleus at 25 Kb resolution, revealing a structured nucleolus, an absence of chromosome territories, and confirming previously identified clustering of heterochromatin foci. We show that switches in var gene expression do not appear to involve interaction with a distant enhancer, but do result in local changes at the active locus. These maps reveal the folding properties of malaria chromosomes, validate known physical associations, and characterize the global landscape of spatial interactions. Collectively, our data provide critical information for a better understanding of gene expression regulation and antigenic variation in malaria parasites. PMID- 23980884 TI - piRNA clusters as a main source of small RNAs in the animal germline. AB - PIWI subfamily Argonaute proteins and small RNAs bound to them (PIWI interacting RNA, piRNA) control mobilization of transposable elements (TE) in the animal germline. piRNAs are generated by distinct genomic regions termed piRNA clusters. piRNA clusters are often extensive loci enriched in damaged fragments of TEs. New TE integration into piRNA clusters causes production of TE-specific piRNAs and repression of cognate sequences. piRNAs are thought to be generated from long single-stranded precursors encoded by piRNA clusters. Special chromatin structures might be essential to distinguish these genomic loci as a source for piRNAs. In this review, we present recent findings on the structural organization of piRNA clusters and piRNA biogenesis in Drosophila and other organisms, which are important for understanding a key epigenetic mechanism that provides defense against TE expansion. PMID- 23980885 TI - Multifunctionality of PIWI proteins in control of germline stem cell fate. AB - PIWI proteins interacting with specific type of small RNAs (piRNAs) repress transposable elements in animals. Besides, they have been shown to participate in various cellular processes: in the regulation of heterochromatin formation including telomere structures, in the control of translation and the cell cycle, and in DNA rearrangements. PIWI proteins were first identified by their roles in the self-renewal of germline stem cells. PIWI protein functions are not limited to gonadogenesis, but the role in determining the fate of stem cells is their specific feature conserved throughout the evolution of animals. Molecular mechanisms underlying these processes are far from being understood. This review focuses on the role of PIWI proteins in the control of maintenance and proliferation of germinal stem cells and its relation to the known function of PIWI in transposon repression. PMID- 23980886 TI - PIWI-interacting RNAs (piRNAs) - a mouse testis perspective. AB - Over the past decade, PIWI-interacting RNAs (piRNAs) have emerged as the most intriguing class of small RNAs. Almost every aspect of piRNA biology defies established rules of the RNA interference world while the scope of piRNA functional potential spans from transcriptional gene silencing to genome defense to transgenerational epigenetic phenomena. This review will focus on the genomic origins, biogenesis, and function of piRNAs in the mouse testis - an exceptionally robust experimental system amenable to genetic, cell-biological, molecular, and biochemical studies. Aided and frequently guided by knowledge obtained in insect, worm, and fish germ cells, mouse spermatogenesis has emerged as the primary model in understanding the role of this conserved pathway in mammals. PMID- 23980887 TI - Heterochromatin formation and transcription in relation to trans-inactivation of genes and their spatial organization in the nucleus. AB - The role of transcription in heterochromatin formation in the nuclei of eukaryotes, originally shown for the pericentromeric heterochromatin assembly in fission yeasts, has now become an accepted paradigm extended to multicellular eukaryotes. It has been shown that small RNAs involved in the RNA interference system in its broadest sense can play an important role in this multi-step process - they are recognized by complementary interactions with the newly formed nuclear transcripts and recruit protein complexes to the local genomic sites for heterochromatinization. The role of transcription as a trigger of this process at the sites of genomic repeats will be considered in this review using various examples of heterochromatin formation, with an emphasis on discussion of its role in trans-chromosomal interactions causing gene inactivation. PMID- 23980888 TI - Quantitative aspects of RNA silencing in metazoans. AB - Small regulatory RNAs (microRNAs, siRNAs, and piRNAs) exhibit several unique features that clearly distinguish them from other known gene regulators. Their genomic organization, mode of action, and proposed biological functions raise specific questions. In this review, we focus on the quantitative aspect of small regulatory RNA biology. The original nature of these small RNAs accelerated the development of novel detection techniques and improved statistical methods and promoted new concepts that may unexpectedly generalize to other gene regulators. Quantification of natural phenomena is at the core of scientific practice, and the unique challenges raised by small regulatory RNAs have prompted many creative innovations by the scientific community. PMID- 23980889 TI - Biogenesis, evolution, and functions of plant microRNAs. AB - This review focuses on the biological role of one class of plant small RNAs, ~22 nt microRNAs (miRNAs). The majority of plant miRNA targets are genes encoding the effector factors of cell signaling pathways. The regulation of their expression is necessary for both ontogenesis and rapid response of plants to biotic and abiotic stress factors. We also summarized current views on the biogenesis and evolution of plant miRNAs as well as the techniques used for their investigation. PMID- 23980890 TI - New functions of small nucleolar RNAs. AB - Small nucleolar RNAs (snoRNAs) are one of the most abundant and well-studied groups of non-coding RNAs. snoRNAs are mostly engaged in processing of rRNA. However, recent data indicate that snoRNAs are also involved in other processes including regulation of alternative splicing, translation and oxidative stress. snoRNAs are also involved in pathogenesis of some hereditary diseases and cancer. Therefore, the range of snoRNAs' functions is significantly wider than it has been assumed earlier. PMID- 23980891 TI - Identification of proteins specifically interacting with YB-1 mRNA 3' UTR and the effect of hnRNP Q on YB-1 mRNA translation. AB - In this study, proteins specifically interacting with the 3' untranslated region (UTR) of mRNA of the multifunctional Y-box-binding protein 1 (YB-1) were identified. One of these, hnRNP Q, was shown to specifically interact with the regulatory element (RE) in YB-1 mRNA 3' UTR and to inhibit translation of this mRNA. Its binding to the RE was accompanied by displacement from this element of the poly(A)-binding protein (PABP), a positive regulator of YB-1 mRNA translation, and by enhanced binding of the negative YB-1 mRNA translation regulator - YB-1 itself. PMID- 23980892 TI - Rhodopsin, Zn(2+), and retinitis pigmentosa: a short tale requiring continuation. AB - Understanding the relationship between the visual pigment rhodopsin and Zn2+ under normal conditions and in case of deficiency of the latter, as well as the realization of the role of Zn2+ in the development of the hereditary disease retinitis pigmentosa, have great theoretical and practical importance. In this mini-review, we briefly examine the basic experimental data on the role of Zn2+ in the retina and photoreceptors, binding of endogenous Zn2+ by zinc-binding sites of differing affinities in rhodopsin, the influence of the exogenous Zn2+ on various properties of rhodopsin, including its ability for phosphorylation and activation of transducin, as well as its thermal stability and regeneration. Conflicting results on the correlation between Zn2+ content in the blood serum and the development of retinitis pigmentosa in patients are demonstrated. The review also shows the success of the application of animal models of induced or hereditary retinal degeneration and discusses some of the methodological approaches and therapeutic techniques to relieve the manifestations of this disease. PMID- 23980893 TI - Destabilization of CH2 domains in intact IgG2 is accompanied by reduced ability to inhibit complement system factor C1. AB - Fc fragments (hFc) of human myeloma IgG2 proteins LOM and SIN having core hinge (Cys-Cys-Val-Glu-Cys-Pro-Pro-Cys) were first obtained by a modified proteolytic procedure. The thermostability of CH2 domains inside of standard Fc, hFc fragments, and intact IgG2 LOM and SIN was studied by fluorescence spectroscopy. It was found that CH2 domains of intact IgG2 are destabilized. The destabilization is accompanied by reduced ability of IgG2 to inhibit the activation of complement system by classical pathway. This could be due to the decrease in the affinity of CH2 domains to factor C1q. PMID- 23980894 TI - Extracellular phosphomannan as a phosphate reserve in the yeast Kuraishia capsulata. AB - We have found that extracellular phosphomannan is the main phosphate reserve in the yeast Kuraishia capsulata, in contrast to other yeast species effectively absorbing Pi. Under nitrogen starvation, K. capsulata absorbed essentially all Pi from the medium containing 240 mM glucose, 2.5 mM MgSO4, and 11 mM KH2PO4. Inorganic polyphosphate level in the cells was about 14% of the Pi absorbed. Most of the Pi (~60%) was found in the fraction of extracellular phosphomannan that can be used as a carbon and phosphorus source by this yeast in deficient media. PMID- 23980895 TI - Synthesis and properties of the 5,10,15-trimesityltruxen-5-yl radical. AB - The synthesis of a long-lived, truxene-based radical that is highly delocalized and exhibits a narrow EPR absorption is reported. The radical is stable for multiple hours in a solution exposed to air and remains for months in the solid state under inert gas. Characterization and properties are discussed. PMID- 23980897 TI - Impact of wildfires on ozone exceptional events in the Western u.s. AB - Wildfires generate substantial emissions of nitrogen oxides (NOx) and volatile organic compounds (VOCs). As such, wildfires contribute to elevated ozone (O3) in the atmosphere. However, there is a large amount of variability in the emissions of O3 precursors and the amount of O3 produced between fires. There is also significant interannual variability as seen in median O3, organic carbon and satellite derived carbon monoxide mixing ratios in the western U.S. To better understand O3 produced from wildfires, we developed a statistical model that estimates the maximum daily 8 h average (MDA8) O3 as a function of several meteorological and temporal variables for three urban areas in the western U.S.: Salt Lake City, UT; Boise, ID; and Reno, NV. The model is developed using data from June-September 2000-2012. For these three locations, the statistical model can explain 60, 52, and 27% of the variability in daily MDA8. The Statistical Model Residual (SMR) can give information on additional sources of O3 that are not explained by the usual meteorological pattern. Several possible O3 sources can explain high SMR values on any given day. We examine several cases with high SMR that are due to wildfire influence. The first case considered is for Reno in June 2008 when the MDA8 reached 82 ppbv. The wildfire influence for this episode is supported by PM concentrations, the known location of wildfires at the time and simulations with the Weather and Research Forecasting Model with Chemistry (WRF-Chem) which indicates transport to Reno from large fires burning in California. The contribution to the MDA8 in Reno from the California wildfires is estimated to be 26 ppbv, based on the SMR, and 60 ppbv, based on WRF-Chem. The WRF-Chem model also indicates an important role for peroxyacetyl nitrate (PAN) in producing O3 during transport from the California wildfires. We hypothesize that enhancements in PAN due to wildfire emissions may lead to regional enhancements in O3 during high fire years. The second case is for the Salt Lake City (SLC) region for August 2012. During this period the MDA8 reached 83 ppbv and the SMR suggests a wildfire contribution of 19 ppbv to the MDA8. The wildfire influence is supported by PM2.5 data, the known location of wildfires at the time, HYSPLIT dispersion modeling that indicates transport from fires in Idaho, and results from the CMAQ model that confirm the fire impacts. Concentrations of PM2.5 and O3 are enhanced during this period, but overall there is a poor relationship between them, which is consistent with the complexities in the secondary production of O3. A third case looks at high MDA8 in Boise, ID, during July 2012 and reaches similar conclusions. These results support the use of statistical modeling as a tool to quantify the influence from wildfires on urban O3 concentrations. PMID- 23980896 TI - Genotyping of IL-8-251 T > A yields prognostic information in patients with gastric carcinoma. AB - This study was designed to investigate the association of the IL-8-251 T > A gene polymorphism with clinicopathological features and the prognostic role of the gene polymorphism in patients with gastric adenocarcinoma. The gene polymorphism was detected by the polymerase chain reaction-restriction fragment length polymorphism method, followed by univariate and multivariate analyses to elicit its prognostic role. The frequency of IL-8-251 A/A, A/T and T/T genotypes were 11.0% (23/210), 43.8% (92/210) and 45.2% (95/210), respectively. The IL-8-251 gene polymorphism was closely correlated with depth of invasion (p = 0.007), grade of differentiation (p = 0.002) and TNM stage (p = 0.009). A/A genotype carriers showed more frequency of serosa involvement, low grade of differentiation and advanced stage of gastric carcinoma. IL-8-251 T > A gene polymorphism have no significant correlation with other clinicopathological features. The 5-year overall survival of IL-8-251 A/A genotype and T allele carriers were 30.8% and 59.2%, respectively. There is a significant discrepancy among the different genotype carriers. Multivariate analysis with the Cox regression model revealed that the IL-8-251 A/A genotype is an independent prognostic indicator (HR = 2.285, 95% Confidence Interval = 1.06-4.93, p = 0.035). We conclude that the IL-8-251 A/A genotype may indicate a poor prognosis for gastric adenocarcinoma patients. PMID- 23980898 TI - Chain flexibility and dynamics of polysaccharide hyaluronan in entangled solutions: a high frequency rheology and diffusing wave spectroscopy study. AB - We have investigated the linear viscoelastic properties of high molecular weight hyaluronan in aqueous solution using an experimental approach combining mechanical rheometry and optical microrheology. The complex shear modulus has been measured over a broad frequency range from 10(-1) to 10(7) rad/s. Chain flexibility is characterized by the persistence length lpand this parameter has been determined for the first time in the entangled regime here from high frequency modulus data. At NaHA concentrations above the entanglement concentration ce, lp is essentially independent of polymer concentration, temperature, and ionic strength. The latter is consistent with the Odijk-Skolnick Fixman theory. The scaling exponent describing the concentration dependence of the plateau modulus G0 agrees well with predictions for polymers in good solvents. The scaling exponents for the specific viscosity etasp and relaxation time TR are slightly higher than theoretically predicted for polyelectrolytes in the high salt limit, indicating, that molecular aggregation occurs at higher polymer concentrations. PMID- 23980899 TI - Multimodal assessment of optokinetic visual stimulation response in migraine with aura. AB - OBJECTIVE: This study aimed to assess activation patterns and the hemodynamic response to optokinetic stimulation in migraine with aura patients compared with controls. BACKGROUND: It has been proposed that altered visual motion processing in striate and extrastriate visual areas is present in migraine patients and might play a role in the pathophysiology of the disease. Besides activating a large visual network, optokinetic stimulation in particular has been shown to provoke symptoms associated with migraine. METHODS: In this study, we examined the response to visual stimulation in 18 migraine with aura patients compared with 18 healthy controls by using functional magnetic resonance imaging and functional transcranial Doppler, thereby assessing the activation pattern of the visual areas (V1-V5) as well as the vasomotor reactivity of the posterior cerebral artery. For stimulation, we used a vertically rotating optokinetic drum with complex colored figures. RESULTS: Group analysis of migraineurs with aura vs controls revealed different activation patterns in functional magnetic resonance imaging: attenuation of the physiological right lateralization with a significantly increased activation in the left V5 complex, the left area V3, and the right V5 complex. Analysis of the visually evoked flow response of the cerebral blood flow velocity in the posterior cerebral artery showed a larger side-difference of the offset latency (P < .05) and a reduced steepness of the decreasing slope on the left side (P < .05). CONCLUSION: Combining examinations with a good structural (functional magnetic resonance imaging) and temporal (functional transcranial Doppler) resolution is a novel approach to migraine pathophysiology. Our findings of an altered pattern of activation by optokinetic visual stimulation with hyperresponsiveness in visual areas activated by motion perception (V5 and V3) further strengthen the concept of an interictal motion processing deficit in migraine. This is complemented by the slower restitution of the visually evoked flow response after stimulus offset in migraine with aura patients. PMID- 23980900 TI - Radiofrequency catheter ablation for the treatment of idiopathic premature ventricular contractions originating from the right ventricular outflow tract: a systematic review and meta-analysis. AB - BACKGROUND: Frequent idiopathic premature ventricular contractions (PVCs) have been associated with left ventricular cardiomyopathy. Idiopathic PVCs often originate from the right ventricular outflow tract (RVOT), and radiofrequency catheter ablation (RFCA) is being used as a treatment to alleviate symptoms. A meta-analysis was performed to evaluate RFCA for the treatment of frequent idiopathic PVCs on heart function. METHODS AND RESULTS: A literature search was conducted using Medline and Embase to identify studies evaluating the effects of RFCA as treatment for PVCs originating from the RVOT. Articles were chosen if they reported the effect of RFCA on the quantity of PVCs or ventricular function. Only studies in English were included. Articles were excluded if they did not separate results for PVCs originating from areas other than the RVOT. A total of 450 articles were retrieved from electronic searches, and 14 articles were included in this systematic review. Six of these were meta-analyzed (N = 70) and showed a reduction in the total number of PVCs in 24 hours after RFCA by a mean of -30089.44 confidence interval [CI]: -31658.47, -28520.40, P < 0.00001). Left ventricular ejection fraction (LVEF) was reported in five of the 14 studies, which included 108 patients. RFCA significantly improved LVEF by a mean of 10.36 (CI: 8.75, 11.97, P < 0.00001) in patients with frequent PVCs from the RVOT. The remaining studies reported their results differently and were not included in the meta-analyses but were described separately. CONCLUSIONS: RFCA reduces the number of PVCs and improves the cardiac function in patients with idiopathic frequent PVCs originating from the RVOT. PMID- 23980901 TI - Compound clear cell sarcoma misdiagnosed as a Spitz nevus. AB - Clear cell sarcoma (CCS) typically presents as a tumor in the deep soft tissue of extremities, but when centered in the dermis it may be confused with a melanocytic nevus, primary nodular or metastatic melanoma. Compound variants of CCS, i.e. tumor cells present in both the epidermis and underlying soft tissue have not yet been described. Herein we report such a case, which initially presented as a nodule on the left wrist of a young woman at 19 years of age. The lesion was then interpreted as 'Spitz nevus, compound type'. Twelve years later the patient noticed an enlarged lymph node in the right axilla. The excised lymph node was nearly completely replaced by malignant tumor cells, which were immunoreactive for S100 protein. They resembled the tumor cells of the wrist lesion. Cytogenetic analysis of the metastatic tumor revealed a t(12;22) translocation. Fluorescence in situ hybridization confirmed Ewing's sarcoma breakpoint region 1 (EWSR1) rearrangement in 70% of the tumor cells, thereby supporting the diagnosis of metastatic CCS. Our case is of interest because it documents that CCS can involve the epidermis. This observation expands the morphological spectrum associated with this tumor. PMID- 23980902 TI - Molecular population genetics of the melanic plumage polymorphism in Arctic skuas (Stercorarius parasiticus): evidence for divergent selection on plumage colour. AB - The Arctic skua (Stercorarius parasiticus) is a classic example of an avian plumage polymorphism, with variation in melanin-based ventral plumage coloration defining pale, intermediate and dark morphs in adults of both sexes. However, despite several decades of field research, there is an incomplete understanding of how the polymorphism in ventral plumage colour is maintained and the selective forces involved. Here, we investigate selection on a locus (MC1R) that is strongly associated with plumage colour variation in Arctic skuas using patterns of nucleotide variation and comparison to neutral loci (nuclear introns and mtDNA). We find that three linked nonsynonymous mutations in MC1R, including the single mutation described previously, are associated with plumage colour in the Arctic skua. The position of nonsynonymous mutations on a MC1R haplotype network implies that divergent selection drove the initial evolution of the colour morphs. Comparisons of F(ST)s of MC1R vs. nuclear introns among five skua populations differing in proportion of dark morphs along an approximate north south cline reveal a signature of divergent selection on MC1R. In contrast, we find limited evidence for balancing selection on MC1R within populations, although the power is low. Our results provide strong evidence for both past and ongoing selection on MC1R, and, by implication, plumage colour in Arctic skuas. The results suggest that a fruitful avenue for future ecological studies will be analysis of selection on morphs in colonies at the extremes along the morph ratio cline. PMID- 23980904 TI - Is therapeutic hypothermia the real cause of fluid retention and hyponatraemia in neonates with perinatal asphyxia? PMID- 23980905 TI - Genome-wide association with delayed puberty in swine. AB - An improvement in the proportion of gilts entering the herd that farrow a litter would increase overall herd performance and profitability. A significant proportion (10-30%) of gilts that enter the herd never farrow a litter; reproductive reasons account for approximately a third of gilt removals, with anestrous and failure to conceive the most common reasons for culling. Tools to select gilts for reproductive longevity through genomics or alternative phenotypes would be of great benefit to the producer. Ninety-one gilts that failed to display behavioral estrus by 240 days (cases) and 127 pubertal littermates (controls) were genotyped with the Illumina Porcine SNP60 Beadchip. One hundred and seventy-four SNPs with the most significant associations were genotyped in an additional 86 cases and 103 controls. Twelve of these associations were significant in the final analysis. The most significant (P < 1.5 * 10(-14) ) region associated with failure to attain puberty was on chromosome 4 surrounding the NHLH2 gene. Delayed pubertal development and age at first estrus have been associated with NHLH2 in mice. Because attainment of puberty is a complex trait, identifying genes that affect pubertal age would greatly contribute to our knowledge of reproductive development as well as overall fertility. PMID- 23980906 TI - Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole induced hypochlorhydria. AB - Previous studies have demonstrated that increased gastric pH from the use of acid reducing agents, such as proton-pump inhibitors or H2-receptor antagonists, can significantly impact the absorption of weakly basic drugs that exhibit pH dependent solubility. Clinically practical strategies to mitigate this interaction have not been developed. This pilot study evaluated the extent and time course of gastric reacidification after a solid oral dosage form of anhydrous betaine HCl in healthy volunteers with pharmacologically induced hypochlorhydria. Six healthy volunteers with baseline normochlorhydria (fasting gastric pH < 4) were enrolled in this single period study. Hypochlorhydria was induced via 20 mg oral rabeprazole twice daily for four days. On the fifth day, an additional 20 mg dose of oral rabeprazole was given and gastric pH was monitored continuously using the Heidelberg pH capsule. After gastric pH > 4 was confirmed for 15 min, 1500 mg of betaine HCl was given orally with 90 mL of water and gastric pH was continuously monitored for 2 h. Betaine HCl significantly lowered gastric pH by 4.5 (+/- 0.5) units from 5.2 (+/- 0.5) to 0.6 (+/- 0.2) (P < 0.001) during the 30 min interval after administration. The onset of effect of betaine HCl was rapid, with a mean time to pH < 3 of 6.3 (+/- 4.3) min. The reacidification period was temporary with a gastric pH < 3 and < 4 lasting 73 (+/ 33) and 77 (+/- 30) min, respectively. Betaine HCl was well tolerated by all subjects. In healthy volunteers with pharmacologically induced hypochlorhydria, betaine HCl was effective at temporarily lowering gastric pH. The rapid onset and relatively short duration of gastric pH reduction gives betaine HCl the potential to aid the absorption of orally administered weakly basic drugs that exhibit pH dependent solubility when administered under hypochlorhydric conditions. PMID- 23980907 TI - Spontaneous improvement of untreated mild Graves' ophthalmopathy: Rundle's curve revisited. AB - BACKGROUND: According to Rundle's curve, Graves' ophthalmopathy (GO) worsens during an initial phase up to a peak of maximum severity, then improves and reaches a static plateau, with the activity curve preceding the severity curve by a few months. To our knowledge, no studies have tried to replicate Rundle's curve, and very few have investigated the natural history of GO. Here, we studied GO natural history retrospectively and tried to identify factors that may affect it. METHODS: A total of 65 patients with untreated GO underwent an eye assessment after a median of seven months after the appearance of GO and then after a median of 40 months. The primary endpoints were the variation of the single GO features and of the NOSPECS score, as well as the overall outcome of GO. The secondary endpoint was the influence of several variables (age, sex, smoking, GO and thyroid disease duration, thyroid treatment, thyroid status, thyroid volume, anti TSH receptor autoantibodies) on the outcome of GO. RESULTS: The majority of patients had mild, minimally active GO, and only five had a Clinical Activity Score (CAS) >3. There was a significant reduction of CAS (p<0.0001) and NOSPECS (p=0.01) between the first and last observation, with a timing pattern resembling Rundle's curve. This difference was confirmed even when patients with a CAS >3 at first observation were excluded. At the last observation, 50.8% of patients had improved, 33.8% had remained stable, and 15.4% had worsened moderately or substantially. The overall outcome of GO was not affected by any of the variables under examination. CONCLUSIONS: In confirmation of Rundle's observations, untreated GO improves spontaneously with time in the majority of patients, with an activity peak between 13 and 24 months, which may have implications in determining the proper timing of GO treatments. PMID- 23980908 TI - Trichoscopy in paediatric patients with tinea capitis: a useful method to differentiate from alopecia areata. AB - OBJECTIVES: Trichoscopy (hair and scalp dermatoscopy) facilitates the diagnosis of hair and scalp disorders. The aim of our study was to identify the trichoscopic features in diagnosis of tinea capitis (TC) and to compare these findings with alopecia areata (AA). MATERIALS AND METHODS: Our study included 15 children with TC and 10 children with AA as a control group. Affected areas of the scalp on all the cases were analysed under a magnification of 20X and 40X by a digital dermatoscope (MoleMax II). RESULTS: Broken and dystrophic hairs were found in dermatological examination of all the patients with TC. In addition, corkscrew hairs, comma hairs and black dots were observed respectively. Yellow dots, exclamation mark hairs and vellus hair were observed in patients with AA. CONCLUSIONS: Broken and dystrophic hairs, corkscrew hairs, comma hairs and black dots were observed only in patients with TC; yellow dots, exclamation mark hairs and vellus hairs were observed only in patients with alopesi areata. Further studies with larger numbers of patients are needed to determine specific trichoscopic findings of TC and to access differential diagnosis. PMID- 23980909 TI - The natural course of early-onset atopic dermatitis in Taiwan: a population-based cohort study. AB - BACKGROUND: Atopic dermatitis (AD) often manifests in early childhood and has variable disease course among individual patients. Previous studies regarding the natural course of AD have usually been of small sample size and were not based on nationwide populations. OBJECTIVES: We aimed to find out the disease duration and remission rate of children with early-onset AD (onset in the first 2 years of life) in Taiwan, and to determine whether the presence of allergic rhinitis (AR) or asthma affects the disease course. METHODS: The patients with early-onset AD in a nationally representative cohort were selected using the National Health Insurance Research Database of Taiwan and were followed from birth to 10 years of age. Kaplan-Meier survival analysis was carried out to analyse the disease duration and remission of AD. Between-group analysis using the log-rank test was carried out to analyse the influence of risk factors on the disease course. RESULTS: Of the 1404 children with early-onset AD, 19.4% had disease duration < 1 year and 48.7% had disease duration < 4 years. During the follow-up, 69.8% of the patients went into remission. Sex, onset age, presence of AR, presence of asthma and presence of respiratory atopy (either AR or asthma) did not show statistically significant influence on disease course. CONCLUSIONS: Children in Taiwan with early-onset AD had disease of variable natural course, and the median disease duration was 4.2 years. About 70% of the patients went into remission eventually. The presence of AR or asthma did not affect the disease course of AD. PMID- 23980910 TI - Changes in reported food intake in adults with type 2 diabetes in response to a nonprescriptive dietary intervention. AB - OBJECTIVES: There is a lack of published data about the food intake of patients with type 2 diabetes and the changes that they make in response to patient centred dietary advice. The present study describes the changes reported in response to a nonprescriptive dietary intervention based upon UK dietary guidelines. METHODS: Two hundred and sixty-two patients (87 women and 175 men) from the Early ACTivity in Diabetes (ACTID) trial who received the dietary intervention returned 4 days food diaries at baseline and 6 months. Nonparametric tests were used to examine changes in meal patterns, total energy intake and energy from food groups between baseline and 6 months. RESULTS: Mean (SD) number of reported meals day(-1) was 3.0 (0.3) and mean (SD) number of snacks was 1.1 (0.6) at both baseline and 6 months for men and women. Men reported decreasing energy intake by a mean (SD) of 912 (1389) KJ/day [218 (332) kcal day(-1) ] (P < 0.001) and women by 515 (1130) KJ/day [123 (270) kcal day(-1) ] (P < 0.001). Men reported reducing energy from alcoholic drinks [-234 (527) KJ day(-1) ; P < 0.001], white bread [-113 (402) KJ day(-1) ; P = 0.001], biscuits [i.e. cookies 67 (205) KJ day(-1) ; P < 0.001] and cakes [-50 (410) KJ day(-1) ; P = 0.0012]. Women reported reducing energy from mixed main meals [-134 (456) KJ day(-1) ; P = 0.036], pasta and rice [-79 (326) KJ day(-1) ; P = 0.019], high-energy drinks [ 59 (159) KJ day(-1) ; P = 0.001] and white bread [-59 (368) KJ day(-1) ; P = 0.042]. CONCLUSIONS: Men and women in the Early ACTID study reported small changes in higher-energy and lower-fibre foods and drinks in response to patient centred dietary advice. PMID- 23980911 TI - Vedolizumab for the treatment of IBD: a selective therapeutic approach targeting pathogenic a4b7 cells. AB - Inflammatory bowel diseases (IBD) are characterized by a persistent recruitment of large quantities of leucocytes from the blood to the gut mucosa. Adhesion molecules, such as integrins and their ligands, are the main players in this complex process. Leucocyte traffic control using a specific integrin inhibitors, such as natalizumab, has been plagued by severe systemic effects. The alpha4beta7 - integrin and its ligand, the MadCAM-1, have been of special interest, since they are found exclusively on the gut-homing lymphocyte subpopulations and in the intestinal mucosa respectively. It follows that inhibition of such molecules should offer gut-specific immunosuppression, without the systemic effects of aspecific integrin- antagonists. We review the role of vedolizumab, a humanized antibody against the alpha4beta7 - integrin, in both ulcerative colitis (UC) and Crohn's disease (CD). Results from clinical trials show that vedolizumab is effective in the induction and maintenance of remission in active CD and UC and has a very good safety profile. These data allow to confidently prospect that vedolizumab will be an important therapeutic option in the future of IBD treatment. PMID- 23980913 TI - Emergency department staff attitudes towards mental health consumers: a literature review and thematic content analysis. AB - Visits to the emergency department (ED) for mental health reasons account for 10 15% of all visits. Consumers of mental health ED services, however, report that they often feel sent to the back of the queue and that their mental health concerns are not taken seriously, suggesting that societal stigma has impacted their care in the ED. In this study, we systematically explore the research concerning the attitudes of ED professional staff towards those who present with issues related to mental health. Four themes emerge from the literature: consumer perspectives, whose tenor is generally one of negativity; staff-reported attitudes and influencing factors, such as age, experience, and confidence in working with mental health presentations; the environmental climate of the ED, which might not be conducive to good mental health care; and interventions that have been used to evaluate changes in attitudes. PMID- 23980912 TI - FATCAT: (an efficient) Functional and Tractographic Connectivity Analysis Toolbox. AB - We present a suite of software tools for facilitating the combination of functional magnetic resonance imaging (FMRI) and diffusion-based tractography from a network-focused point of view. The programs have been designed for investigating functionally derived gray matter networks and related structural white matter networks. The software comprises the Functional and Tractographic Connectivity Analysis Toolbox (FATCAT), now freely distributed with AFNI. This toolbox supports common file formats and has been designed to integrate as easily as possible with existing standard FMRI pipelines and diffusion software, such as AFNI, FSL, and TrackVis. The programs are efficient, run by commandline for facilitating group processing, and produce several visualizable outputs. Here, we present the programs and their underlying methods, and we also provide a test example of resting-state FMRI analysis combined with tractography. Tractography results are compared with existing methods, showing significantly reduced runtime and generally similar connectivity, but with important differences such as more circumscribed tract regions and more physiologically identifiable paths produced between several region-of-interest pairs. Currently, FATCAT uses only diffusion tensor-based tractography (one direction per voxel), but higher-order models will soon be included. PMID- 23980915 TI - Total synthesis of the tetracyclic lupin alkaloid (+)-allomatrine. AB - (+)-Allomatrine (1) has been synthesized using an imino-aldol reaction and N acyliminium cyclization as key steps. Strategically, use of the tert butylsulfinimine derivative of (E)-4-(trimethylsilyl)but-2-enal enabled the staged formation of three C-C bonds, a C-N bond, and the four stereogenic centers within the target. PMID- 23980914 TI - Variation in the heritability of body mass index based on diverse twin studies: a systematic review. AB - OBJECTIVES: Over the past three decades, twin studies have shown variation in the heritability of obesity. This study examined the difference of body mass index (BMI) heritability (BMI-H) by population characteristics, such as sex, age, time period of observation and average BMI, as well as by broad social-environmental factors as indicated by country-level gross domestic product (GDP) per capita and GDP growth rate. METHODS: Twin studies that reported BMI-H and were published in English from January 1990 to February 2011 after excluding those with disease, special occupations or combined heritability estimates for country/ethnic groups were searched in PubMed. 32 studies were identified from Finland (7), the United Kingdom (6), the United States (3), Denmark (3), China (3), Netherlands (2), South Korea (2), Sweden (2) and four from other countries. Meta-regression models with random effects were used to assess variation in BMI-H. RESULTS: Heterogeneity of BMI-H is significantly attributable to variations in age (<20, 20-55 and >=56 years), time period of observation (i.e. year of data collection), average BMI and GDP (<=$20,000, $20,001-26,000 and >$26,000). BMI-H was higher in adolescents (<20 years), in studies done in past years, and in populations with higher average BMIs or higher GDP per capita (>=$26,000) than their counterparts. Consistent lowering effects of high GDP growth rate (>median) on BMI-H were shown through stratified analyses by GDP. BMI-H was lower in countries of mid-level GDP, particularly those experiencing rapid economic growth. CONCLUSIONS: BMI-H is sensitive to age, time period of observation, average BMI, GDP and rapid economic growth. PMID- 23980916 TI - Preliminary time-course study of antiinflammatory macrophage infiltration in crush-injured skeletal muscle. AB - Muscle damage induces massive macrophage infiltration of the injury site, in which activated pro-inflammatory and anti-inflammatory phenotypes (currently classified as M1 and M2, respectively) have been documented as distinct functional populations predominant at different times after the conventional acute injury by intramuscular injection of snake venoms (cardiotoxin, notexin) or chemicals (bupivacaine hydrochloride, barium chloride). The present study employed a muscle-crush injury model that may better reflect the physiologic damage and repair processes initiated by contusing a gastrocnemius muscle in the lower hind-limb of adult mice with hemostat forceps, and examined the time-course invasion of M1 and M2 macrophages during muscle regeneration by immunocytochemistry of CD197 and CD206 marker proteins. CD197-positive M1 macrophages were observed exclusively at 1-4 days after crush followed by the alternative prevalence of CD206-positive M2 at 7 days of myogenic differentiation, characterized by increasing levels of myogenin messenger RNA expression. Preliminary PCR analysis showed that M2 may produce hepatocyte growth factor (HGF) in culture, providing additional benefit to understanding that M2 populations actively promote regenerative myogenesis (muscle fiber repair) and moto-neuritogenesis (re-attachment of motoneuron terminals onto damaged fibers) through their time-specific infiltration and release of growth factor at the injury site early in muscle regeneration. PMID- 23980917 TI - Computed tomography predictors of hepatocellular carcinoma tumour necrosis after chemoembolization. AB - BACKGROUND: Radiographical features associated with a favourable response to trans-arterial chemoembolization (TACE) are poorly defined for patients with hepatocellular carcinoma (HCC). METHODS: From 2008 to 2012, all first TACE interventions for HCC performed at the University of Alabama at Birmingham (UAB) were retrospectively reviewed. Only patients with a pre-TACE and a post-TACE computed tomography (CT) scan were included in the analyses (n = 115). HCC tumour response to TACE was quantified via the the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Univariate and multivariable analyses were constructed. RESULTS: The index HCC tumours experienced a > 90% or complete tumour necrosis in 59/115 (51%) of patients after the first TACE intervention. On univariate analysis, smaller tumour size, peripheral tumour location and arterial enhancement were associated with a > 90% or complete tumour necrosis, whereas, only smaller tumour size [odds ratio (OR) 0.62; 95% confidence interval (CI) 0.48, 0.81] and peripheral location (OR 6.91; 95% CI 1.75, 27.29) were significant on multivariable analysis. There was a trend towards improved survival in the patients that experienced a > 90% or complete tumour necrosis (P = 0.08). CONCLUSIONS: Peripherally located smaller HCC tumours are most likely to experience a > 90% or complete tumour necrosis after TACE. Surprisingly, arterial phase enhancement and portal venous-phase washout were not significantly predictive of TACE-induced tumour necrosis. The TACE response was not statistically associated with improved survival. PMID- 23980919 TI - Correlation of headache frequency and psychosocial impairment in migraine: a cross-sectional study. AB - OBJECTIVE: To investigate if a headache frequency of 15 days per month constitutes a turning point in the psychosocial impairment associated with migraine. BACKGROUND: Migraine is differentiated into episodic and chronic forms based on a headache frequency criterion (< vs >=15 headache days per month). It is presently not clear if this criterion represents a clinically and pathophysiologically meaningful turning point of the disease. METHODS: Six hundred and one migraine patients completed measures of pain-specific disability (Migraine Disability Assessment Scale, von Korff scale), health-related quality of life (Short Form-12 Health Survey), habitual well-being (Marburg questionnaire), and anxiety and depression (Hospital Anxiety and Depression Score). RESULTS: A significant increase of psychosocial impairment with the number of headache days per month was found at lower headache frequencies, but leveled off at higher headache frequencies. Visual inspection and spline interpolation suggested that the turning point was not exactly at 15 headache days per month but rather around 13.3 (confidence interval: 8.9-17.7) days. Accordingly, significant correlations between headache days and psychosocial impairment were found in the group with <=13 headache days per month (Spearman's rho = 0.25, P < .001) but not in the group with >13 headache days (rho = -0.02, n.s.). CONCLUSION: These results suggest that a meaningful turning point in psychosocial impairment associated with migraine is located around 13.3 headache days per month, somewhat below the 15-headache days criterion that by definition separates chronic from episodic migraine. However, confidence intervals surrounding the turning point were large. Further studies will be needed to more exactly localize the turning point. PMID- 23980921 TI - Solvent-driven preferential association of lignin with regions of crystalline cellulose in molecular dynamics simulation. AB - The precipitation of lignin onto cellulose after pretreatment of lignocellulosic biomass is an obstacle to economically viable cellulosic ethanol production. Here, 750 ns nonequilibrium molecular dynamics simulations are reported of a system of lignin and cellulose in aqueous solution. Lignin is found to strongly associate with itself and the cellulose. However, noncrystalline regions of cellulose are observed to have a lower tendency to associate with lignin than crystalline regions, and this is found to arise from stronger hydration of the noncrystalline chains. The results suggest that the recalcitrance of crystalline cellulose to hydrolysis arises not only from the inaccessibility of inner fibers but also due to the promotion of lignin adhesion. PMID- 23980920 TI - Exercise and sleep in community-dwelling older adults: evidence for a reciprocal relationship. AB - Exercise behaviour and sleep are both important health indicators that demonstrate significant decreases with age, and remain modifiable well into later life. The current investigation examined both the chronic and acute relationships between exercise behaviour and self-reported sleep in older adults through a secondary analysis of a clinical trial of a lifestyle intervention. Seventy-nine community-dwelling, initially sedentary, older adults (mean age = 63.58 years, SD = 8.66 years) completed daily home-based assessments of exercise behaviour and sleep using daily diary methodology. Assessments were collected weekly and continued for 18 consecutive weeks. Multilevel models revealed a small positive chronic (between-person mean-level) association between exercise and wake time after sleep onset, and a small positive acute (within-person, day-to-day) association between exercise and general sleep quality rating. The within-person exercise and general sleep quality rating relationship was found to be reciprocal (i.e. sleep quality also predicted subsequent exercise behaviour). As such, it appears exercise and sleep are dynamically related in older adults. Efforts to intervene on either sleep or exercise in late-life would be wise to take the other into account. Light exposure, temperature regulation and mood may be potential mechanisms of action through which exercise can impact sleep in older adults. PMID- 23980922 TI - The changing paradigm of air pollution monitoring. AB - The air pollution monitoring paradigm is rapidly changing due to recent advances in (1) the development of portable, lower-cost air pollution sensors reporting data in near-real time at a high-time resolution, (2) increased computational and visualization capabilities, and (3) wireless communication/infrastructure. It is possible that these advances can support traditional air quality monitoring by supplementing ambient air monitoring and enhancing compliance monitoring. Sensors are beginning to provide individuals and communities the tools needed to understand their environmental exposures with these data individual and community based strategies can be developed to reduce pollution exposure as well as understand linkages to health indicators. Each of these areas as well as corresponding challenges (e.g., quality of data) and potential opportunities associated with development and implementation of air pollution sensors are discussed. PMID- 23980923 TI - Pure hydroxyapatite phantoms for the calibration of in vivo X-ray fluorescence systems of bone lead and strontium quantification. AB - Plaster of Paris [poP, CaSO4.(1)/(2) H2O] is the standard phantom material used for the calibration of in vivo X-ray fluorescence (IVXRF)-based systems of bone metal quantification (i.e bone strontium and lead). Calibration of IVXRF systems of bone metal quantification employs the use of a coherent normalization procedure which requires the application of a coherent correction factor (CCF) to the data, calculated as the ratio of the relativistic form factors of the phantom material and bone mineral. Various issues have been raised as to the suitability of poP for the calibration of IVXRF systems of bone metal quantification which include its chemical purity and its chemical difference from bone mineral (a calcium phosphate). This work describes the preparation of a chemically pure hydroxyapatite phantom material, of known composition and stoichiometry, proposed for the purpose of calibrating IVXRF systems of bone strontium and lead quantification as a replacement for poP. The issue with contamination by the analyte was resolved by preparing pure Ca(OH)2 by hydroxide precipitation, which was found to bring strontium and lead levels to <0.7 and <0.3 MUg/g Ca, respectively. HAp phantoms were prepared from known quantities of chemically pure Ca(OH)2, CaHPO4.2H2O prepared from pure Ca(OH)2, the analyte, and a HPO4(2-) containing setting solution. The final crystal structure of the material was found to be similar to that of the bone mineral component of NIST SRM 1486 (bone meal), as determined by powder X-ray diffraction spectrometry. PMID- 23980924 TI - Shock-induced ventricular tachycardia: what is the mechanism? PMID- 23980925 TI - The effect of person-centred communication on parental stress in a NICU: a randomized clinical trial. AB - AIM: To investigate the effect of the Guided Family-Centred Care intervention, developed by the lead author, on parental stress in a neonatal intensive care unit (NICU). METHODS: Parents (n = 134) of infants born <=34 weeks gestational age were randomly assigned to a standard care group (n = 60) or intervention group (n = 74) between April 2011 and August 2012. Guided Family-Centred Care components used were as follows: scheduled nurse-parent dialogues, semi structured reflection sheets and person-centred communication. Parental stress was assessed at discharge using parent-reported outcomes on the Nurse Parent Support Tool and the Parental Stressor Scale: Neonatal Intensive Care Unit. RESULTS: The total stress scores reported by parents did not vary significantly between the intervention and standard groups, with a mean (SD) of 2.70 (0.67) versus 2.84 (0.71), respectively. However, the confidence interval included the prespecified clinical significance level. Subscale and Nurse Parent Support Tool scores did not differ between the groups. Overall, mothers reported more stress than fathers (p < 0.001). CONCLUSION: Our study was unable to demonstrate the effect of person-centred communication using the Guided Family-Centred Care intervention. It may be necessary to replicate the design to address the risk of contamination and add instruments sensitive to human interaction. PMID- 23980926 TI - Ethnic differences in oro-facial somatosensory profiles-quantitative sensory testing in Chinese and Danes. AB - Ethnic differences in pain experiences have been widely assessed in various pathological and experimental conditions. However, limited sensory modalities have been described in previous research, and the affective-motivational factors have so far been estimated to be the main mediator for the ethnic differences. This study aimed to detect the ethnic differences of oro-facial somatosensory profiles related to the sensory-discriminative dimension in healthy volunteers. The standardised quantitative sensory testing battery developed by the German Research Network on Neuropathic Pain was performed bilaterally in the infraorbital and mental regions on age- and gender-matched healthy Chinese and Danes, 29 participants each group. The influences of ethnicity, gender and test site on the somatosensory profile were evaluated by three-way anova. The ethnic disparities were also presented by Z-scores. Compared to Danes, Chinese were more sensitive to thermal detection, thermal pain, mechanical deep pain and mechanical pain rating parameters (P < 0.002) related to small fibre functions. However, the inverse results were observed for mechanical tactile modality related to large fibre function (P < 0.001) and wind-up ratio (P = 0.006). Women presented higher sensitivity compared to men. The mean Z-scores of all the parameters from Chinese group were in the normal zone created by Danish Caucasians' means and SDs. The ethnic disparities in somatosensory profile illustrated the necessity of establishing the reference data for different ethnic groups and possibly individual pain management strategies for the different ethnic groups. PMID- 23980927 TI - Design and fabrication of a new class of nano hybrid materials based on reactive polymeric molecular cages. AB - This paper describes a strategy of fabricating a new class of nano hybrid particles in terms of the "nanocages" of reactive molecular matrices/networks. The concept is to design molecular matrices functionalized with particular reactive groups, which can on-site synthesize and fix nanoparticles at the designated positions of the molecular networks. The cages of the molecular networks impose the confinement and protection to the nanoparticles so that the size and the stability of nano hybrid particles can be better controlled. To this end, polyamide network polymers (PNP) were synthesized and adopted as the reactive molecular cages for the control of silver nanoparticles formation. It follows that the silver nano hybrid particles fabricated by this method have an average diameter of 4.34 nm much smaller than any other or similar methods ie by a hyperbranched polyamide polymer (HB-PA). As per our design, the size of the silver nano hybrid particles can also be tuned by controlling the molar ratio between silver ions and the functional groups in the polymeric matrices. The silver nano hybrid particles reveal the substantially enhanced stability in aqueous solutions, which gives rise to the long stable performance of localized surface plasmon resonance. As the nano hybrid particles display long eminent nanoeffects, they exert broad implications for a wide range of applications such as biomedicine, catalysis, and optoelectronics. PMID- 23980928 TI - Experimental study of the influence of anticipated control on human thermal sensation and thermal comfort. AB - To investigate whether occupants' anticipated control of their thermal environment can influence their thermal comfort and to explain why the acceptable temperature range in naturally ventilated environments is greater than that in air-conditioned environments, a series of experiments were conducted in a climate chamber in which the thermal environment remained the same but the psychological environment varied. The results of the experiments show that the ability to control the environment can improve occupants' thermal sensation and thermal comfort. Specifically, occupants' anticipated control decreased their thermal sensation vote (TSV) by 0.4-0.5 and improved their thermal comfort vote (TCV) by 0.3-0.4 in neutral-warm environment. This improvement was due exclusively to psychological factors. In addition, having to pay the cost of cooling had no significant influence on the occupants' thermal sensation and thermal comfort in this experiment. Thus, having the ability to control the thermal environment can improve occupants' comfort even if there is a monetary cost involved. PMID- 23980929 TI - Skin rash and arthritis a simplified appraisal of less common associations. AB - Skin and joint manifestations are part of the clinical spectrum of many disorders. Well-known associations include psoriatic arthritis and arthritis associated with autoimmune connective tissue diseases. This review focuses on less common associations where skin lesions can provide easily accessible and valuable diagnostic clues, and directly lead to the specific diagnosis or limit the list of possibilities. This may also affect health care resources as diagnostic tests are often low-specific, highly expensive and poorly available. This group of diseases can be divided into two subsets, based on the presence/absence of fever, and then further classified according to elementary skin lesions (macular, urticarial, maculo-papular, vesico-bullous, pustular, petechial and nodular). In most instances joint involvement occurs as peripheral migrating polyarthritis. Erythematosus macular or urticarial rashes occur in most febrile disorders such as monogenic autoinflammatory syndromes, Schnitzler's syndrome, Still's disease and rheumatic fever and afebrile diseases as urticarial vasculitis. Pustular rash may be observed in chronic recurrent multifocal osteomyelitis (CRMO) and pyogenic arthritis with pyoderma gangrenosum and acne (PAPA) syndrome (both febrile) as well as in Behcet's disease and Synovitis, acne, pustulosis, hyperostosis and osteitis syndrome (both non-febrile). Papular lesions are typical of secondary syphilis, sarcoidosis, interstitial granulomatous dermatitis, papular petechial of cutaneous small-vessel vasculitis and nodular lesions of polyarteritis nodosa and multicentric reticulohistiocytosis all of which are afebrile. Differential diagnosis includes infections and drug reactions which may mimic several of these conditions. To biopsy the right skin lesion at the right time it is essential to obtain relevant histological information. PMID- 23980930 TI - No place to turn: nursing students' experiences of moral distress in mental health settings. AB - While researchers have documented the significant issue of moral distress among nurses, few have explored moral distress among mental health nurses. In addition, no research to date has explored nursing students' experiences of moral distress during mental health clinical rotations, despite nursing students typically reporting negative attitudes towards mental health nursing. This manuscript reports on a qualitative study involving seven Canadian baccalaureate nursing students, who reported on their experiences of moral distress during a 13-week clinical rotation on inpatient psychiatric units. Overall, nursing students reported significant moral distress related to the perceived lack of nurses talking meaningfully to patients on the unit, a hierarchical power structure for physicians, a lack of information given to patients about their psychiatric medications, and an inability of their nursing instructors to advocate for ethical change on the units. Several students made a specific connection between their moral distress and not wanting to pursue a career in mental health nursing. PMID- 23980931 TI - Formative evaluation of the dietary assessment component of Children's and Adolescents' Nutrition Assessment and Advice on the Web (CANAA-W). AB - BACKGROUND: The increased availability of computers and the efficiency and user acceptability of computer-assisted questioning have increased the attractiveness of computer-administered querying for large-scale population nutrition research during the last decade. The Young Adolescents' Nutrition Assessment on Computer (YANA-C), a computer-based 24-h dietary recall, was originally developed to collect dietary data among Belgian-Flemish adolescents. A web-based version was created to collect parentally reported dietary data of preschoolers, called Young Children's Nutrition Assessment on the Web (YCNA-W), which has been improved and adapted for use in young adolescents: Children and Adolescents' Nutrition Assessment and Advice on the Web (CANAA-W). The present study describes recent developments and the formative evaluation of the dietary assessment component. METHODS: A feasibility questionnaire was completed by 131 children [mean (SD) age: 11.3 (0.7) years] and 53 parents. Eight focus groups were held with children (n = 65) and three with parents (n = 17). RESULTS: Children (C) and parents (P) found the instrument clear (C: 97%; P: 94%), comprehensible (C: 92%; P: 100%), attractive (C: 84%; P: 85%), fun (C: 93%; P: 83%) and easy to complete (C: 91%; P: 83%). There was ample explanation (C: 95%; P: 94%); the pictures were clear (C: 97%; P: 96%); and most respondents found the food items easy to find (C: 71%, P: 85%). The results helped to refine the lay out and structure of the instrument and the list of food items included. CONCLUSIONS: Children and parents were enthusiastic. The major challenge will be to convince parents who are less interested in dietary intake and less computer literate to participate in this type of study. Children in this age group (11-12 years) should complete the instrument with assistance from an adult. PMID- 23980932 TI - Fractal patterning of nanoparticles on polymer films and their SERS capabilities. AB - We demonstrate control, via electro-hydrodynamic (EHD) induced polymer instabilities and nanoparticle mobility, of hierarchical fractal arrangements of gold nanoparticles on patterned thin polymer films. The induced changes in the film curvature enhance fractal formation for high and not for low mobility nanoparticles. The high mobility nanoparticles cluster in circular fractal networks on the rims of a hexagonally ordered array of EHD-induced polymer peaks. These arrangements exhibit plasmonic properties for surface-enhanced Raman scattering (SERS) spectroscopy. PMID- 23980933 TI - Smoking does influence disease behaviour and impacts the need for therapy in Crohn's disease in the biologic era. AB - BACKGROUND: Recently, the notion that smoking may adversely affect Crohn's disease (CD) outcomes has been challenged by the suggestion that the widespread use of immunosuppressants and anti-TNF drugs might offset the adverse effects of tobacco. AIM: To reassess the influence of tobacco smoking on disease phenotype and complications on a time-dependent analysis, taking into account the different therapeutic interventions. METHODS: We designed a retrospective cohort study of 3224 patients with Crohn's disease. The data were collected from the Spanish national inflammatory bowel disease registry (ENEIDA), including information regarding demographics, clinical characteristics, disease complications, therapeutic interventions and smoking status. Patients were classified as nonsmokers, smokers and former smokers, according to their present and past smoking habits. RESULTS: In the univariate analysis, smokers had more strictures (22.6% vs. 19.3%, P < 0.05) and less colonic involvement (7.2% vs. 10.9%, P < 0.05), and were more frequently under treatment with steroids (91.6% vs. 85.8%, P < 0.05), immunosuppressants (73.5% vs. 63.6% P < 0.05) or anti-TNF drugs (31.4% vs. 25.1%, P < 0.05) than nonsmokers. In the time-dependent multivariate analysis, smokers were found to have a significantly decreased survival free of stricturing disease (HR: 1.5, CI 95% 1.18-1.90) or perianal complications (HR: 1.50, CI 95% 1.01-1.46), and had a higher risk for requiring thiopurine therapy (HR: 1.20, CI 95% 1.05-1.30). CONCLUSION: These results suggest that, despite the widespread use of immunosuppressants and anti-TNF drugs, smokers with Crohn's disease still have a more severe disease course, with increased therapeutic requirements when compared with nonsmokers. PMID- 23980934 TI - Estimating the contribution of occupational solar ultraviolet exposure to skin cancer. AB - BACKGROUND: Exposure to solar ultraviolet (UV) radiation is the main causative factor for skin cancer. Outdoor workers are at particular risk because they spend long working hours outside, may have little shade available and are bound to take their lunch at their workplace. Despite epidemiological evidence of a doubling in risk of squamous cell carcinoma (SCC) in outdoor workers, the recognition of skin cancer as an occupational disease remains scarce. OBJECTIVES: To assess occupational solar UV doses and their contribution to skin cancer risk. METHODS: A numerical model (SimUVEx) was used to assess occupational and lunch break UV exposure, and to characterize exposure patterns and anatomical distribution. Risk of SCC was estimated from an existing epidemiological model. RESULTS: Horizontal body locations received 2.0-2.5 times more UV than vertical locations. The dose associated with having lunch outdoors every day was similar to that from doing outdoor work 1 day per week, but only half that of a seasonal worker. Outdoor work is associated with an increased risk of SCC and also with frequent acute episodes. CONCLUSIONS: Occupational solar exposure contributes greatly to overall lifetime UV dose, resulting in an excess risk of SCC. The magnitude of the estimated excess in risk supports the recognition of SCC as an occupational disease. PMID- 23980935 TI - Caregiver burden mediates between caregiver's mental health condition and elder's behavioral problems among Japanese family caregivers. AB - OBJECTIVES: In Japan, the prevalence of depression has been reported to occur among 1 in 4 family caregivers. The purpose of this study was to investigate the self-rated burden associated with mental health conditions among caregivers. METHODS: We studied 95 caregivers aged 38-87 years in a cross-sectional study. The General Health Questionnaire (GHQ-12) score of 4 or more was defined as poor mental health. RESULTS: The proportion of caregivers with poor mental health was 24%. Caregivers with a high GHQ-12 score had the number of caregiver burdens increased by 2.5-fold compared to those with a low GHQ-12 score (p = 0.001). The proportion of caregivers with a high GHQ-12 score was significantly higher with an increasing number of behavioral problems among care recipients (p = 0.003). A mediational model was used to identify the underlying mechanism of the relationship between the number of behavioral problems and poor mental health in caregivers. Consequently, we found that mental health conditions in caregivers were associated with both the number of caregiver burdens and behavioral problems among care recipients. CONCLUSIONS: It is vital to provide support not only to the caregivers but also to their elderly relatives, paying particular attention to early identification of poor mental health in caregivers so as to administer effective interventions, and to offer useful advice concerning how to deal with behavioral problems. PMID- 23980936 TI - Telehealth trends and the challenge for infrastructure. AB - BACKGROUND: As telehealth takes advantage of improved networks, there is a growing need to understand the infrastructure needs of future telehealth developments. This work aims to predict such needs based on current trends and research. MATERIALS AND METHODS: We conducted a literature review of telehealth with a focus on advanced network infrastructure. We drew inferences from our previous demonstrator projects in advanced telehealth, but the most important findings emerged from interviews with a panel of thought leaders. RESULTS: Our results show that there will be simultaneous and coupled evolution of telehealth through the space spanned by three axes: care models, clinical applications, and technology. We also consider a two-dimensional model of reach and complexity to describe future applications. Universal access to advanced networks will drive fundamental changes in healthcare deliver. The biggest change will be seen in home and mobile health care delivery, forming part of a trend toward patient centric models. Other aspects of decentralization in healthcare systems will include networks of caregivers. Besides this reach trend, the complexity trend will include integrating multiple-channel applications and seamlessly moving large datasets in real time among hospitals, other medical facilities, and homes. There is a need to provide infrastructure that does not have an upper limit on quality of service and allows telehealth to address mobility, usability, interoperability, intelligence, and adaptability in a systematic way. PMID- 23980937 TI - Telemedicine and face-to-face care for pediatric obesity. AB - The University of California Davis Medical Center (Sacramento, CA) has pioneered the use of telemedicine in its approach to childhood obesity to cover more than 20 rural clinics in California. In our study, we compared the outcomes of the Telemedicine Weight Management Clinic (TM) with those of its face-to-face (FTF) Weight Management Clinic counterpart over the last 5 years, predicting the results to be equivalent or in favor of TM. All children seen in the TM from June 2006 to June 2011 were included (n=121), and encounter notes in medical records were reviewed. For comparison, an equivalent sample of FTF patients was selected from that time frame (n=122). Data that were also abstracted from the medical record included age at first visit, gender, race, referral site, and comorbid diagnoses. Forty-two percent of TM patients compared with 52% of FTF patients received a change in diagnosis. Thirty-nine percent of TM patients received a change in diagnostic evaluation compared with 67% of patients in FTF. When comparing patients who received more than one visit with either form of consultation, the TM group demonstrated substantially more improvement than the FTF group in improving nutrition (88% versus 65%), increasing activity (76% versus 49%), and decreasing screen time (33% versus 8%). Substantially more TM patients were successful with a combined outcome of any one of the weight parameters that included weight loss, weight maintenance, or slowing of weight gain (69% TM versus 44% FTF). Our study suggests that telemedicine can serve as a feasible strategy to increase access to medical care for childhood obesity in rural communities and promote changes in lifestyle with the goal of maintaining a healthy weight. PMID- 23980938 TI - Providers' perspectives: utilizing telepsychiatry in schools. AB - BACKGROUND: The field of telepsychiatry has rapidly advanced a focus on decreasing health disparities by improving access to mental healthcare for children and adolescents. However, perfecting the quality and effectiveness of telemental healthcare is an ongoing process in the face of various documented barriers. Although consumer and provider satisfactions have been investigated in the telepsychiatry literature, perspectives of psychiatrists who consult with schools have been relatively understudied. The current study focuses on the utilization of telepsychiatry consultation to school mental health providers, by reporting on the perspectives of psychiatrists who provide consultation services. MATERIALS AND METHODS: Using quantitative and qualitative data, the psychiatrists' perspectives about their consultation experiences were examined and compared with previously obtained data from school mental health providers about their experiences with the telepsychiatry consultation. RESULTS: Results indicate positive provider experiences with telepsychiatry, including reports that students were more likely to disclose clinical information via video compared with face-to-face contact. However, concerns regarding technological difficulties, logistics, and information sharing were endorsed by some of the psychiatrists. Comparison with clinician reports revealed many similarities; however, differences were noted in regard to the psychiatrists' ability to communicate with the students and their level of preparedness for the consultations. CONCLUSIONS: Recommendations for ongoing evaluation and implementation of effective telepsychiatry consultation for schools are provided. Improvements in communication, scheduling, and addressing technological difficulties within the consultation team through training and consultation are recommended. Future directions for including student, caregiver, and other provider perspectives are also discussed. PMID- 23980939 TI - Utilization, benefits, and impact of an e-consultation service across diverse specialties and primary care providers. AB - BACKGROUND: Access to specialist advice remains a barrier for primary care providers (PCPs) and their patients. Virtual consultations have been used to expedite access. There are few studies demonstrating the utilization and impact of such services. We established a regional e-consultation service that was used across a wide range of specialty services and PCPs. MATERIALS AND METHODS: We prospectively collected all e-consultations submitted from April 1, 2011 to June 30, 2012. Utilization data collected included number of e-consultations submitted, specialist response, and time required for the specialist to complete the e-consultation. Perceived benefit to the PCPs and their patients and the impact on care delivery were determined from a close-out survey. RESULTS: Fifty nine PCPs submitted 406 e-consultations to 16 specialty services. The specialist provided an answer without requesting further information in 89% of cases, with >90% of cases taking <15 min for the specialist to complete. Seventy-five percent of cases were answered in <3 days. The service was perceived as highly beneficial to providers and patients in>90% of cases. In 43% of submitted cases a traditional referral was originally contemplated but was now avoided. CONCLUSIONS: We successfully implemented an e-consultation service across diverse PCPs and specialty services that was highly valued. Almost half of referrals submitted would have required a face-to-face consultation if the service had not been available. Thus e-consultation has tremendous potential for improving access to specialist advice in a much more timely manner than the traditional referral consultation process. PMID- 23980940 TI - Studying kids in motor vehicle crashes is tough! PMID- 23980941 TI - Copper-catalyzed asymmetric hydrogenation of aryl and heteroaryl ketones. AB - High throughput screening enabled the development of a Cu-based catalyst system for the asymmetric hydrogenation of prochiral aryl and heteroaryl ketones that operates at H2 pressures as low as 5 bar. A ligand combination of (R,S)-N-Me-3,5 xylyl-BoPhoz and tris(3,5-xylyl)phosphine provided benzylic alcohols in good yields and enantioselectivities. The electronic and steric characteristics of the ancillary triarylphosphine were important in determining both reactivity and selectivity. PMID- 23980943 TI - Social media is blurring professional boundaries. PMID- 23980942 TI - Associations between obesogenic risk factors and depression among adolescents: a systematic review. AB - Adolescence is a transitional life phase that is associated with heightened risk for two major health conditions - obesity and mental health problems. Given the established comorbidity of obesity and depression, one avenue that warrants further exploration is the association between obesogenic risk and obesity in the expression and maintenance of depressive symptoms. The aim of the current systematic review was to identify and evaluate the empirical literature reporting the relationships between obesogenic risk factors (physical activity, sedentary behaviour, diet and weight status) and depression in adolescents. A search of five databases for studies published over the last decade found 24 studies eligible for review. Relationships were found between lack of physical exercise, heightened sedentary behaviour, poor diet quality, obese or overweight and depression in adolescence. However, the finding that obesogenic risk factors are associated with poor adolescent mental health should be interpreted with caution as data typically come from non-representative samples with less than optimal study design and methodology. PMID- 23980949 TI - Nurses warned of disciplinary risk over improper Facebook postings. PMID- 23980945 TI - Poor pay prompts thousands of nurses to rethink job, survey finds. PMID- 23980954 TI - Thousands of posts cut since the coalition government took office. PMID- 23980956 TI - Quick-fix staffing at poor performing trusts. PMID- 23980959 TI - Older retirement age reveals need for a debate on workforce planning. PMID- 23980965 TI - 'Tanzania changed me'. AB - NHS clinicians who volunteer overseas contribute to developing countries' health services by providing local staff with training. The volunteers also enhance their leadership skills. Many forward-thinking NHS trusts actively support relationships with overseas organisations but barriers remain. PMID- 23980966 TI - Self-care success. AB - Nurse-led community care for substance misusers is improving the health of individuals who had previously struggled with conventional services. Health interventions tailored to accommodate chaotic lifestyles have also helped reduce clients' social isolation. PMID- 23980967 TI - A moving experience. AB - Moving patients to free up beds for new admissions exposes frail individuals to the risk of falls and delirium. Yet evidence suggests it is an increasingly common practice. This article sets out the consequences of inappropriate moves and considers some solutions. PMID- 23980968 TI - The artificial pancreas. AB - Nurse Janet Allen is a key member of a Cambridge based research team that has developed and tested the 'artificial pancreas', a technological advance that radically improves blood control in people with type 1 diabetes. PMID- 23980988 TI - Assessment and diagnosis of overactive bladder in women. AB - Overactive bladder (OAB) is a distressing problem that affects many women in the UK. Symptoms of OAB include urinary urgency with or without urgency incontinence, usually with frequency and nocturia. This article discusses the assessment of women reporting lower urinary tract symptoms, including simple tests to be performed and specialist investigations that may be required before a diagnosis of OAB can be confirmed. PMID- 23980989 TI - Viral infections of the skin: clinical features and treatment options. AB - Viral infections of the skin can cause significant distress and embarrassment for people who are affected. This article explores four specific viral infections that manifest on the skin: herpes simplex, herpes zoster, viral warts and molluscum contagiosum. It describes the presentation and appearance of the virus as it affects the skin and what can be done to minimise the spread of the virus. Management options are considered, although many of these conditions are self limiting. PMID- 23980990 TI - Use of femoral nerve blocks in adults with hip fractures. AB - Healthcare professionals will be aware of the need to improve treatment of hip fractures, with the ultimate goal of returning the individual to pre-injury health. Patients with hip fractures awaiting surgery can experience severe pain that may be difficult to relieve with traditional analgesics. Physical assessment and essential nursing care require moving the patient, which further increases pain. Nerve blocks have been administered as a form of post-operative pain relief in a variety of surgical procedures, and there is growing interest in the use of femoral nerve blocks in the pre-operative period for patients with hip fractures. This article looks at the prevalence of hip fractures and associated problems. It highlights the importance of effective management of pain and explores the use of local anaesthetics for pain relief. PMID- 23980991 TI - Acute asthma exacerbation. PMID- 23980994 TI - Community challenge. PMID- 23980992 TI - In tune with the times. AB - Radical changes to commissioning introduced by the Health and Social Care Act 2012 have created new opportunities for nurses. PMID- 23980996 TI - How to build self-confidence. PMID- 23980997 TI - Microstructured optical fibers and live cells: a water-soluble, photochromic zinc sensor. AB - A new biologically compatible Zn(II) sensor was fabricated by embedding a Zn(II) sensing spiropyran within the surface of a liposome derived from Escherichia coli lipids (LSP2). Solution-based experiments with increasing Zn(II) concentrations show improved aqueous solubility and sensitivity compared to the isolated spiropyran molecule (SP2). LSP2 is capable of sensing Zn(II) efflux from dying cells with preliminary data indicating that sensing is localized near the surface membrane of HEK 293 cells. Finally, LSP2 is suitable for development into a nanoliter-scale dip-sensor for Zn(II) using microstructured optical fiber as the sensing platform to detect Zn(II) in the range of 100 rhoM with minimal photobleaching. Existing spiropyran based sensing molecules can thus be made biologically compatible, with an ability to operate with improved sensitivity using nanoscale liquid sample volumes. This work represents the first instance where photochromic spiropyran molecules and liposomes are combined to create a new and multifunctional sensing entity for Zn(II). PMID- 23980998 TI - Confronting unknown planetary boundary threats from chemical pollution. AB - Rockstrom et al. proposed a set of planetary boundaries that delimitate a "safe operating space for humanity". One of the planetary boundaries is determined by "chemical pollution", however no clear definition was provided. Here, we propose that there is no single chemical pollution planetary boundary, but rather that many planetary boundary issues governed by chemical pollution exist. We identify three conditions that must be simultaneously met for chemical pollution to pose a planetary boundary threat. We then discuss approaches to identify chemicals that could fulfill those conditions, and outline a proactive hazard identification strategy that considers long-range transport and the reversibility of chemical pollution. PMID- 23980999 TI - Quantum dot based fluorometric detection of cancer TF-antigen. AB - Cancer is a major global health challenge that would benefit from advances in screening methods for early detection that are rapid and low cost. TF-antigen is a tumor-associated antigen displayed on cell surface proteins of a high percentage of human carcinomas. Here we present a fluorometric bioassay for TF antigen (galactose-beta-(1->3)-N-acetyl-d-galactosamine) that utilizes quantum dot (QD) technology coupled with magnetic beads for rapid detection of TF-antigen at high sensitivity (10(-7) M range). In the competitive bioassay, 4-aminophenyl beta-d-galactopyranoside (4-APG) conjugated to QDs competes with TF-antigen for binding sites on peanut agglutinin (PNA) that is immobilized on magnetic beads. The bioassay is specific and ultrasensitive in the environment of complex protein mixtures, demonstrating its potential applicability for the screening of clinical samples. PMID- 23981000 TI - Neoadjuvant therapy for downstaging of locally advanced hilar cholangiocarcinoma: a systematic review. AB - BACKGROUND: Hilar cholangiocarcinoma is a rare but highly lethal type of cancer. A minority of patients present with resectable disease. Surgery remains the only treatment modality offering a chance of long-term survival. Unresectable patients are typically offered palliative treatment. The aim of this systematic review was to summarize the evidence for neoadjuvant therapy followed by surgical resection in patients presenting with hilar cholangiocarcinoma. METHODS: Cochrane databases, Medline, PubMed and EMBASE were systematically searched to identify articles describing neoadjuvant therapy and surgical resection or re-assessment of resectability in patients with hilar cholangiocarcinoma. Included were all articles with original research. Study selection and data extraction were performed separately by two reviewers using a standardized protocol. RESULTS: From 732 articles 8 full text articles and 2 abstracts met the inclusion criteria. The 2 abstracts and 1 full text article were case reports, 3 articles were retrospective and 4 were prospective studies (2 phase I and 2 phase II studies). Photodynamic therapy, chemotherapy and radiation therapy were used in various indications in populations that included patients with hilar cholangiocarcinoma, some of which were primarily unresectable. Overall quality of articles was limited. CONCLUSION: Current evidence suggests that neoadjuvant therapy in patients with unresectable hilar cholangiocarcinoma can be performed safely and in a selected group of patients can lead to subsequent surgical R0 resection. Surgical resection of downstaged patients should be assessed in properly designed phase II studies. PMID- 23981001 TI - beta-mannosyl linkages inhibit CAWS arteritis by negatively regulating dectin-2 dependent signaling in spleen and dendritic cells. AB - AIMS: CAWS, Candida albicans water-soluble fraction, is an extracellular mannoprotein produced by C. albicans NBRC1385. It is a ligand of dectin-2, the C type lectin receptor for innate immunity, and has strong potency for induction of vasculitis in DBA/2 mice. The structure of this mannoprotein is known to be modulated by the culture conditions. To clarify the structure required for vasculitis, CAWSs were prepared in the two culture conditions with or without pH control, and biological properties were compared. METHODS: CAWSs prepared by the standard protocol and pH controlled at 7.0 were designated as CAWS and CAWS727, respectively. The antigenicity was detected by the anti-Candida mannan IgG. These chemical structures were assessed by nuclear magnetic resonance analysis and the lectin array system. The in vitro activity of CAWSs was tested by tumor necrosis factor-alpha (TNF-alpha) induction using bone marrow-derived dendritic cells and spleen cell cultures. RESULTS: The antigenicity of CAWS727 was similar to CAWS but the nuclear magnetic resonance analysis showed a higher ratio of beta mannosyl linkages were detected in CAWS727. The lectin array showed relative affinities of CAWS727 to alpha-mannosyl specific lectins were weaker than those of CAWS. CAWS induced severe vasculitis in DBA/2 mice while CAWS727 did not. CAWS significantly induced TNF-alpha but CAWS727 did slightly. In addition, CAWS induced TNF-alpha production was inhibited by mixing with CAWS727 in a concentration dependent manner. CONCLUSION: The alpha-mannosyl linkages of Candida mannan is a key molecule for the immunotoxicity. CAWS727, which conatins beta-mannosyl linkages, competitively bound to lectin receptors, and resulted in reductions in the inflammatory response. PMID- 23981002 TI - Effects of selenium on Pteridium aquilinum and urethane-induced lung carcinogenesis. AB - The results of our previous study demonstrated that ptaquiloside, the main toxic agent found in Pteridium aquilinum, suppresses natural killer (NK) cell-mediated cytotoxicity. However, the ability of ptaquiloside to suppress the cytotoxicity of NK cells was prevented by selenium supplementation. NK cells play an important role in the innate immune response and have the ability to kill tumor cells. Therefore, we hypothesized that selenium may prevent the higher susceptibility to urethane-induced lung carcinogenesis that has been observed in mice treated with P. aquilinum. The immunosuppressive effects of ptaquiloside have been associated with a higher number of urethane-induced lung nodules in mice. Hence, we assessed the effects of P. aquilinum-induced immunosuppression on urethane-induced lung carcinogenesis in C57BL/6 mice that had been supplemented with selenium. For these experiments, mice were treated with both an aqueous extract of P. aquilinum (20 g/kg/day) and selenium (1.3 mg/kg) by gavage once daily for 14 days followed by a once-weekly intraperitoneal injection of urethane (1 g/kg) for 10 weeks that was accompanied by gavage 5 days a week. Lung adenomas in mice that had been treated with P. aquilinum plus urethane occurred with a frequency that was 44% higher than that in mice that had been treated with only urethane. In mice that had been supplemented with selenium and treated with P. aquilinum plus urethane, the occurrence of lung adenomas was reduced to 26%. These results suggest that selenium prevents the immunosuppressive effects of P. aquilinum on urethane induced lung carcinogenesis. PMID- 23981003 TI - Immunotherapeutic potential of CpG oligodeoxynucleotides in veterinary species. AB - Innate immunity plays a critical role in host defense against infectious diseases by discriminating between self and infectious non-self. The recognition of infectious non-self involves germ-line encoded pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). The PAMPs are the components of pathogenic microbes which include not only the cell wall constituents but also the unmethylated 2'-deoxy-ribo-cytosine-phosphate-guanosine (CpG) motifs. These CpG motifs present within bacterial and viral DNA are recognized by toll-like receptor 9 (TLR9), and signaling by this receptor triggers a proinflammatory cytokine response which, in turn, influences both innate and adaptive immune responses. The activation of TLR9 with synthetic CpG oligodeoxynucleotides (ODNs) induces powerful Th1-like immune responses. It has been shown to provide protection against infectious diseases, allergy and cancer in laboratory animal models and some domestic animal species. With better understanding of the basic biology and immune mechanisms, it would be possible to exploit the potential of CpG motifs for animal welfare. The research developments in the area of CpG and TLR9 and the potential applications in animal health have been reviewed in this article. PMID- 23981004 TI - Gossypol suppresses mouse T lymphocytes via inhibition of NFkappaB, NFAT and AP-1 pathways. AB - Gossypol is a kind of yellow polyphenolic compounds extracted from root stem and seed of the cotton plant. In the present study, we investigated its immunosuppressive mechanism by using BALB/c mouse T lymphocytes in vitro. When mouse splenocytes was incubated with gossypol, the extract effectively suppress the overproduction of the cell stimulated by concanavalin A (ConA) in a dose manner. This inhibitive activity was mainly due to interfering Th1 and Th2 cytokines production and decreasing CD4(+) T cell populations and ratio of CD4(+)/CD8(+). Furthermore, we also showed that signal transduction via NF kappaB, NFAT and AP-1 are critical to the ConA-induced T cell activation in mice. The data revealed that gossypol could down-regulate activation of ConA-induced NF kappaB, NFAT and AP-1 signal transduction pathways in mouse T lymphocyte. These observations indicated that gossypol exhibited immunosuppressive effects by inhibition T lymphocyte activation in vitro. PMID- 23981005 TI - Chemical stability of graphene fluoride produced by exposure to XeF2. AB - Fluorination can alter the electronic properties of graphene and activate sites for subsequent chemistry. Here, we show that graphene fluorination depends on several variables, including XeF2 exposure and the choice of substrate. After fluorination, fluorine content declines by 50-80% over several days before stabilizing. While highly fluorinated samples remain insulating, mildly fluorinated samples regain some conductivity over this period. Finally, this loss does not reduce reactivity with alkylamines, suggesting that only nonvolatile fluorine participates in these reactions. PMID- 23981006 TI - Is experience on a farm an effective approach to understanding animal products and the management of dairy farming? AB - The understanding of animal products and dairy farming is important for the promotion of dairy farming. Thus, to examine the effects of farm experience on the understanding of animal products and the management of dairy farming, the interaction between students and dairy cows was investigated in groups of first year veterinary nursing students in 2011 and 2012 (n = 201). These students included 181 women and 20 men. Nine items about dairy cows were presented in a questionnaire. The survey was performed before and after praxis on the educational farm attached to the authors' university. After praxis on the farm, increases occurred in the number of positive responses to the items involving the price of milk, dairy farming and the taste of milk. For these items, a significant difference (P < 0.05) was found between the scores obtained before and after training. The results of the study suggested that farm experience is useful for improving the understanding of animal products and dairy farming. PMID- 23981007 TI - Headache as a crucial symptom in the etiology of convexal subarachnoid hemorrhage. AB - BACKGROUND: Convexal subarachnoid hemorrhage has been associated with different diseases, reversible cerebral vasoconstriction syndrome and cerebral amyloid angiopathy being the 2 main causes. OBJECTIVE: To investigate whether headache at onset is determinant in identifying the underlying etiology for convexal subarachnoid hemorrhage. METHODS: After searching in the database of our hospital, 24 patients were found with convexal subarachnoid hemorrhage in the last 10 years. The mean age of the sample was 69.5 years. We recorded data referring to demographics, symptoms and neuroimaging. RESULTS: Cerebral amyloid angiopathy patients accounted for 46% of the sample, 13% were diagnosed with reversible cerebral vasoconstriction syndrome, 16% with several other etiologies, and in 25%, the cause remained unknown. Mild headache was present only in 1 (9%) of the 11 cerebral amyloid angiopathy patients, while severe headache was the dominant feature in 86% of cases of the remaining etiologies. CONCLUSION: Headache is a key symptom allowing a presumptive etiological diagnosis of convexal subarachnoid hemorrhage. While the absence of headache suggests cerebral amyloid angiopathy as the more probable cause, severe headache obliges us to rule out other etiologies, such as reversible cerebral vasoconstriction syndrome. PMID- 23981008 TI - Impact of systemic treatment of psoriasis on inflammatory parameters and markers of comorbidities and cardiovascular risk: results of a prospective longitudinal observational study. AB - BACKGROUND: Several markers of comorbidities and cardiovascular (CV) risk are disturbed in moderate to severe psoriasis (PsO). The effect of systemic treatments of psoriasis on these markers remains poorly understood. OBJECTIVES: To study the frequency of disturbance of inflammatory parameters and markers of comorbidities and CV risk associated with moderate to severe PsO and psoriatic arthritis (PsA), and to assess their evolution under systemic treatments. METHODS: Monocentric prospective study on patients with PsO and PsA starting a systemic treatment for their psoriasis. The following markers were evaluated at baseline (M0), 3 months (M3) and 6 months (M6); weight, fasting blood glucose, blood pressure, uric acid, hepatic steatosis, smoking, lipid, metabolic and inflammatory parameters. RESULTS: Forty-three patients, 31 PsO and 12 PsA, were included. Forty completed the study. Response to treatment was good, with 71% of the population obtaining a Psoriasis Area and Severity Index (PASI) of 75. All patients had at least one comorbidity, and 45% had two or more. A statistically significant decrease was observed only for inflammatory parameters (C-reactive protein [CRP], P = 0.004) and erythrocyte sedimentation rate (ESR, P = 0.002). We did not observe any correlation between the PASI and CRP (correlation coefficient 0.128, P = 0.438) or ESR (correlation coefficient 0.294, P = 0.069) for responding patients. CONCLUSIONS: We observed a high frequency of disturbance of inflammatory parameters and markers of comorbidities and CV risk in a population with moderate to severe PsO and PsA, most of which were not detected before. A significant decrease in inflammatory parameters was noted after the introduction of systemic therapy, while other parameters remained unaffected by the treatment, except the weight that increased under biologics therapies. PMID- 23981009 TI - Patient, physician, and procedural factors influencing the use of defibrillation testing during initial implantable cardioverter defibrillator insertion: findings from the NCDR(r). AB - BACKGROUND: Advances in implantable cardioverter defibrillator (ICD) technology have resulted in more effective defibrillation, and the need for defibrillation threshold (DFT) testing has been questioned. METHODS: A total of 64,227 initial ICD implant procedures performed at 1,261 facilities (April to December 2010) in the NCDR RegistryTM were selected to identify patterns of practice related to DFT testing. Patient, physician, and procedural characteristics were compared. Independent association of DFT testing with in-hospital adverse events or mortality was also examined. RESULTS: DFT testing was performed in 71% of patients. Patients who did not undergo testing were older; more often had heart failure, lower left ventricular ejection fraction, atrial arrhythmias, and a primary prevention indication; and were more likely to receive a cardiac resynchronization therapy device. In addition, patients who did not undergo testing were less likely to be implanted in a metropolitan area and more often implanted at a teaching hospital, in New England, in the Mid-Atlantic, or in the Pacific U.S . In-hospital adverse events occurred in 2.56% of patients who underwent DFT testing compared to 3.58% who did not (P < 0.001). Death or any complication remained more likely to occur in patients who did not undergo testing (odds ratio and 95% confidence interval: 1.46 [1.33, 1.61], P < 0.001), after adjusting for baseline and procedural differences. CONCLUSIONS: DFT testing is not performed in many (29%) patients in clinical practice. Patients who did not undergo testing were more likely to have adverse events and to be older with more comorbidities, which could explain why DFT testing was avoided. Prospective randomized data are needed to determine the impact of DFT testing on outcome. PMID- 23981010 TI - Implication of ultraviolet light in the etiology of uveal melanoma: A review. AB - Uveal melanoma is the most frequent intraocular cancer and the second most common form of melanoma. It metastasizes in half of the patients and the prognostic is poor. Although ultraviolet (UV) radiation is a proven risk factor for skin melanoma, the role of UV light in the etiology of uveal melanoma is still contradictory. We have compared epidemiological and genetic evidences of the potential role of UV radiation in uveal melanoma with data on cutaneous melanoma. Even though frequently mutated genes in skin melanoma (e.g. BRAF) differ from those found in uveal melanoma (i.e. GNAQ, GNA11), their mutation pattern bears strong similarities. Furthermore, we provide new results showing that RAC1, a gene recently found harboring UV-hallmark mutation in skin melanoma, is also mutated in uveal melanoma. This article aims to review the work done in the last decades to understand the etiology of uveal melanoma and discuss new avenues, which shed some light on the potential role of UV exposure in uveal melanoma. PMID- 23981011 TI - Analysis of PAC1 receptor gene variants in Caucasian and African American infants dying of sudden infant death syndrome. AB - AIM: Stress peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), has been implicated in sudden infant death syndrome (SIDS). The aim of this exploratory study was to determine whether variants in the gene encoding the PACAP-specific receptor, PAC1, are associated with SIDS in Caucasian and African American infants. METHODS: Polymerase chain reaction and Sanger DNA sequencing was used to compare variants in the 5'-untranslated region, exons and intron-exon boundaries of the PAC1 gene in 96 SIDS cases and 96 race- and gender-matched controls. RESULTS: The intron 3 variant, A/G: rs758995 (variant 'h'), and the intron 6 variant, C/T: rs10081254 (variant 'n'), were significantly associated with SIDS in Caucasians and African Americans, respectively (p < 0.05). Also associated with SIDS were interactions between the variants rs2302475 (variant 'i') in PAC1 and rs8192597 and rs2856966 in PACAP among Caucasians (p < 0.02) and rs2267734 (variant 'q') in PAC1 and rs1893154 in PACAP among African Americans (p < 0.01). However, none of these differences survived post hoc analysis. CONCLUSION: Overall, this study does not support a strong association between variants in the PAC1 gene and SIDS; however, a number of potential associations between race-specific variants and SIDS were identified that warrant targeted investigations in future studies. PMID- 23981012 TI - A comparative study of the OsstellTM versus the Osstell MentorTM to evaluate implant stability in human cadaver mandibles. AB - The aim of this study was to assess the primary stability of dental implants by resonance frequency analysis (RFA) using the OsstellTM and Osstell MentorTM devices and to investigate the reproducibility and comparability of the results obtained with these devices. Twenty-four Straumann implants (Straumann AG, Basel, Switzerland) were placed in the anterior mandible of 12 fresh edentulous human cadaver mandibles. The implant stability quotients (ISQs) were measured with the OsstellTM and Osstell MentorTM when implants were inserted at 50% of their length and following their complete insertion. The OsstellTM device measured lower scores compared with the Osstell MentorTM. This was significant for the full position (mean difference = 9.9), t (11) = 7.4, P < 0.001 and for the halfway position (mean difference = 5.9), t (11) = 2.41, P = 0.03. In conclusion, the OsstellTM produced relatively lower ISQ scores than the Osstell MentorTM. PMID- 23981013 TI - Forest bolsters bird abundance, pest control and coffee yield. AB - Efforts to maximise crop yields are fuelling agricultural intensification, exacerbating the biodiversity crisis. Low-intensity agricultural practices, however, may not sacrifice yields if they support biodiversity-driven ecosystem services. We quantified the value native predators provide to farmers by consuming coffee's most damaging insect pest, the coffee berry borer beetle (Hypothenemus hampei). Our experiments in Costa Rica showed birds reduced infestation by ~ 50%, bats played a marginal role, and farmland forest cover increased pest removal. We identified borer-consuming bird species by assaying faeces for borer DNA and found higher borer-predator abundances on more forested plantations. Our coarse estimate is that forest patches doubled pest control over 230 km2 by providing habitat for ~ 55 000 borer-consuming birds. These pest control services prevented US$75-US$310 ha-year(-1) in damage, a benefit per plantation on par with the average annual income of a Costa Rican citizen. Retaining forest and accounting for pest control demonstrates a win-win for biodiversity and coffee farmers. PMID- 23981014 TI - Prevalence of subclinical ketosis in mainly pasture-grazed dairy cows in New Zealand in early lactation. AB - AIMS: The main aim of this study was to describe the prevalence of primary subclinical ketosis (SCK) in mainly pasture-grazed dairy cows in three dairy farming regions of New Zealand 7-12, and 35-40 days post-calving. A second aim was to investigate herd- and cow-level factors associated with the prevalence of SCK. METHODS: A cross-sectional longitudinal prevalence survey was undertaken in 1,620 dairy cows from 57 herds. A random sample of cows without disease in the prior 30 days were enrolled at one farm visit within 5 days of calving, and blood samples were collected 7 and 28 days later (7-12 and 35-40 days post-calving) for measurement of beta-hydroxy butyrate (BHBA) concentrations using an electronic cow-side meter. SCK was defined as blood BHBA concentration >=1.4 mmol/L. RESULTS: Mean cow-level prevalence of SCK varied with interval post-calving (16.8 and 3.2% at 7-12 days and 35-40 days post-calving, respectively) and age (13.0 and 13.1% of 2-year olds and >=8-year olds, respectively, compared to 7.2% of 3-4 year-old cows). Mean herd-level prevalence of SCK was 14.3 (min 0, max 60.0)% and 2.6 (min 0, max 24.4)% at 7-12 days and 35-40 days post-calving, respectively, and was greater in Southland (13.3%) than Waikato and Canterbury herds (6.9 and 4.7%, respectively). CONCLUSIONS: This is the first population-based report of the prevalence of SCK in New Zealand dairy herds and demonstrates that age and interval post-calving are important risk factors determining prevalence; and that there is wide variation in prevalence between herds. CLINICAL RELEVANCE: Subclinical ketosis may be unrecognised but common in many New Zealand dairy cows in the first 2 weeks of lactation. PMID- 23981015 TI - Neuroprotection and reduction of glial reaction by cannabidiol treatment after sciatic nerve transection in neonatal rats. AB - In neonatal rats, the transection of a peripheral nerve leads to an intense retrograde degeneration of both motor and sensory neurons. Most of the axotomy induced neuronal loss is a result of apoptotic processes. The clinical use of neurotrophic factors is difficult due to side effects and elevated costs, but other molecules might be effective and more easily obtained. Among them, some are derived from Cannabis sativa. Cannabidiol (CBD) is the major non-psychotropic component found on the surface of such plant leaves. The present study aimed to investigate the neuroprotective potential of CBD. Thus, 2-day-old Wistar rats were divided into the following experimental groups: sciatic nerve axotomy + CBD treatment (CBD group), axotomy + vehicle treatment (phosphate buffer group) and a control group (no-treatment group). The results were analysed by Nissl staining, immunohistochemistry and terminal deoxynucleotidyl transferase dUTP nick end labeling at 5 days post-lesion. Neuronal counting revealed both motor and sensory neuron rescue following treatment with CBD (15 and 30 mg/kg). Immunohistochemical analysis (obtained by synaptophysin staining) revealed 30% greater synaptic preservation within the spinal cord in the CBD-treated group. CBD administration decreased the astroglial and microglial reaction by 30 and 27%, respectively, as seen by glial fibrillary acidic protein and ionised calcium binding adaptor molecule 1 immunolabeling quantification. In line with such results, the terminal deoxynucleotidyl transferase dUTP nick end labeling reaction revealed a reduction of apoptotic cells, mostly located in the spinal cord intermediate zone, where interneurons promote sensory-motor integration. The present results show that CBD possesses neuroprotective characteristics that may, in turn, be promising for future clinical use. PMID- 23981016 TI - Autonomy versus control: finding the sweet spot. PMID- 23981017 TI - A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. AB - The impact of first-line treatment with the anti-CD 20 chimeric monoclonal antibody rituximab in patients with warm-antibody reactive autoimmune haemolytic anaemia (WAIHA) is unknown. We report the first randomized study of 64 patients with newly diagnosed WAIHA who received prednisolone and rituximab combined (N = 32) or prednisolone monotherapy (N = 32). After 12 months, a satisfactory response was observed in 75% of the patients treated with rituximab and prednisolone but in a significantly smaller proportion (36%) of those given prednisolone alone (P = 0.003). Furthermore, relapse-free survival was significantly better after the combined therapy than after prednisolone monotherapy (P = 0.02). After 36 months, about 70% of the patients were still in remission in the rituximab-prednisolone group, whereas only about 45% were still in complete or partial remission in the prednisolone group. There was no significant difference between the two groups regarding adverse reactions to the studied medications. Likewise, serious adverse events were equally distributed, and no allergic reactions to rituximab were recorded. In conclusion, our data show that using rituximab and prednisolone combined rather than prednisolone alone as first-line treatment in WAIHA increases both the rate and the duration of the response. PMID- 23981019 TI - Information needs and information-seeking behaviour analysis of primary care physicians and nurses: a literature review. AB - BACKGROUND: The increase in the adoption of electronic health records (EHR) has contributed to physicians and nurses experiencing information overload. To address the problem of information overload, an assessment of the information needs of physicians and nurses will assist in understanding what they view as useful information to make patient care more efficient. OBJECTIVE: To analyse studies that assessed the information needs and information-seeking behaviour of physicians and nurses in a primary care setting to develop a better understanding of what information to present to physicians when they making clinical decisions. METHOD: A literature review of studies was conducted with a comprehensive search in PubMed, cinahl, scopus, as well as examination of references from relevant papers and hand-searched articles to identify articles applicable to this review. RESULTS: Of the papers reviewed the most common information needs found among physicians and nurses were related to diagnoses, drug(s) and treatment/therapy. Colleagues remain a preferred information source among physicians and nurses; however, a rise in Internet usage is apparent. CONCLUSION: Physicians and nurses need access to the Internet and job-specific resources to find practitioner oriented information. In addition, effective usage of resources is important for improving patient care. PMID- 23981020 TI - Information needs of clinicians and non-clinicians in the Emergency Department: a qualitative study. AB - BACKGROUND: Identifying the information needs of Emergency Department (ED) staff and sources of information that they use can help to improve efficiency and effectiveness in the ED. As Emergency Medicine has unique characteristics, information needs of the Emergency Department (ED) staff might be different from other settings. However, few studies have investigated the information needs of ED staff and the sources of information that they use. OBJECTIVES: We aimed to investigate the information needs of ED staff and the sources of information that they used in their practice. METHODS: It was a qualitative study, in which data were collected using semi-structured interviews and 34 ED staff were interviewed in total. To analyse data, the method of framework analysis was used. RESULTS: Different types of information needs and sources of information were found in the ED. Patient information was considered the most important type of information, and verbal communication was the most frequently used source of information. CONCLUSION: The variety of information used in the ED shows task complexity in this department which might not be simply addressed by technology. Further research is needed to identify how computerised information systems can be improved to meet users' information needs in the ED. PMID- 23981021 TI - Integrating information literacy in health sciences curricula: a case study from Quebec. AB - OBJECTIVE: To portray an information literacy programme demonstrating a high level of integration in health sciences curricula and a teaching orientation aiming towards the development of lifelong learning skills. The setting is a French-speaking North American university. METHODS: The offering includes standard workshops such as MEDLINE searching and specialised sessions such as pharmaceutical patents searching. A contribution to an international teaching collaboration in Haiti where workshops had to be thoroughly adapted to the clientele is also presented. Online guides addressing information literacy topics complement the programme. RESULTS AND EVALUATION: A small team of librarians and technicians taught 276 hours of library instruction (LI) during the 2011-2012 academic year. Methods used for evaluating information skills include scoring features of literature searches and user satisfaction surveys. DISCUSSION: Privileged contacts between librarians and faculty resulting from embedded LI as well as from active participation in library committees result in a growing reputation of library services across academic departments and bring forth collaboration opportunities. Sustainability and evolution of the LI programme is warranted by frequent communication with partners in the clinical field, active involvement in academic networks and health library associations, and reflective professional strategies. PMID- 23981022 TI - An analysis of benefits and risk information on pharmaceutical web sites for the treatment of menopause. AB - BACKGROUND: As the Internet is a source of information for many health consumers, there is a need to evaluate the information about prescription drugs provided on pharmaceutical manufacturers' web sites. OBJECTIVES: Using a sample of pharmaceutical manufacturers' web sites for the treatment of menopause, the main objective of this study was to evaluate consumer-oriented information about benefits and risks of prescription drugs for the treatment of menopause provided on pharmaceutical web sites. METHODS: Pharmaceutical manufacturers' web sites for analysis were identified using a list of U.S. FDA-approved hormone therapies for the treatment of menopause. RESULTS: This study revealed substantial gaps in how benefits and risk information were presented on the web sites. Specifically, information about the benefits was prominent while risk information was incomplete and challenging to find. Further, references to the scientific literature to support claims advertised about prescription drug benefits were not provided. CONCLUSIONS: Given the lack of scientific evidence to support claims of benefits and limited disclosure about risks, more information is needed for consumers to be able to weigh the benefits and risks of these treatments for menopause. Overall, these findings provide guidance for evaluating drug information provided on pharmaceutical web sites. PMID- 23981023 TI - The role of readability in effective health communication: an experiment using a Japanese health information text on chronic suppurative otitis media. AB - OBJECTIVES: This study identifies the most significant readability factors and examines ways of improving and evaluating Japanese health information text in terms of ease of reading and understanding. METHODS: Six different Japanese texts were prepared based on an original short text written by a medical doctor for a hospital web site intended for laypersons regarding chronic suppurative otitis media. Four were revised for single readability factor (syntax, vocabulary, or text structure) and two were modified in all three factors. Using a web-based survey, 270 high school students read one of the seven texts, including the original, completed two kinds of comprehension tests, and answered questions on their impressions of the text's readability. RESULTS: Significantly higher comprehension test scores were shown in the true or false test for a mixed text that presented important information first for better text structure. They were also found in the cloze test for a text using common vocabulary and a cohesive mixed text. CONCLUSIONS: Vocabulary could be a critical single readability factor when presumably combined with better text structure. Using multiple evaluation methods can help assess comprehensive readability. The findings on improvement and evaluation methods of readability can be applied to support effective health communication. PMID- 23981024 TI - The accuracy of references in PhD theses: a case study. AB - BACKGROUND: Inaccurate references and citations cause confusion, distrust in the accuracy of a report, waste of time and unnecessary financial charges for libraries, information centres and researchers. OBJECTIVES: The aim of the study was to establish the accuracy of article references in PhD theses from the Tehran and Tabriz Universities of Medical Sciences and their compliance with the Vancouver style. METHODS: We analysed 357 article references in the Tehran and 347 in the Tabriz. Six bibliographic elements were assessed: authors' names, article title, journal title, publication year, volume and page range. Referencing errors were divided into major and minor. RESULTS: Sixty two percent of references in the Tehran and 53% of those in the Tabriz were erroneous. In total, 164 references in the Tehran and 136 in the Tabriz were complete without error. Of 357 reference articles in the Tehran, 34 (9.8%) were in complete accordance with the Vancouver style, compared with none in the Tabriz. Accuracy of referencing did not differ significantly between the two groups, but compliance with the Vancouver style was significantly better in the Tehran. CONCLUSIONS: The accuracy of referencing was not satisfactory in both groups, and students need to gain adequate instruction in appropriate referencing methods. PMID- 23981025 TI - An investigation into the move towards electronic journals: a case study of NHS libraries in Kent, Surrey and Sussex. AB - Electronic journals are so embedded into practice in academic libraries that it is easy to forget that this is not the case everywhere. In NHS libraries, for example, the staff face a particular set of issues. This article is based on Rebecca England's dissertation on this topic, completed as part of the MSc Econ course in Information and Library studies at Aberystwyth University. Rebecca is E resources Librarian at the Maidstone and Tunbridge Wells NHS Trust. She investigated the momentum towards electronic journals in NHS libraries in the Kent, Surrey and Sussex region and the potential for a regional purchasing consortium. PMID- 23981026 TI - International trends in health science librarianship: Part 7. Taking stock. AB - This article reviews the six papers published so far in this series on global trends in health science librarianship. Starting with a retrospective review of trends in the twentieth-century, the series has covered 6 different regions, with contributions from 21 countries. As this is the half-way point in the survey, it seems a useful point at which to reflect on what has emerged so far. The method of content analysis is used to identify key trends. The top five trends are explored. PMID- 23981027 TI - Learn something new in 20 minutes: Bite Size sessions to support research and teaching. AB - The School of Health and Related Research (ScHARR) at The University of Sheffield run an innovative series of informal 20-minute Bite Size sessions to help staff and students teach, research, collaborate and communicate more effectively. The sessions have two clear strands: one focused on teaching and the other on research. The remit is not to teach people how to use something in their work or study, but to let them know why they should use it and how they can employ it. By introducing participants to the possibilities and how they can apply ideas and technologies in their work and study in an enthusiastic manner, it is possible to send them away with at least the intention to explore and experiment. The evidence shows that this organic approach is working--staff and students are starting to use many of the tools that Bite Size has covered. Any kind of widespread change within organisations can be hard to deliver, but by bringing champions on your side and delivering sessions in a convenient, informal and timely manner; good practice and ideas can spread naturally. PMID- 23981028 TI - Mediator lipidomics in ophthalmology: targets for modulation in inflammation, neuroprotection and nerve regeneration. AB - Studies in the central nervous system (CNS) and retina have revealed the significance of docosahexaenoic acid (DHA), an essential omega-3, 22 carbon 6 double bond (22:6), fatty acid. DHA is necessary for various functions in the CNS, including neuronal membrane bio- and synaptogenesis in memory and vision, and it is the precursor for docosanoids and neuroprotectin D1 (NPD1; 10R,17S dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z hexaenoic acid), a DHA bio-derivative with neuroprotective properties. This review covers three targets in ophthalmology for mediator lipidomics, a subgroup within the field of metabolomics: inflammation, neuroprotection and nerve regeneration. It also discusses the role DHA, NPD1 and other lipid mediators play in these three areas. PMID- 23981029 TI - Structural change of human hair induced by mercury exposure. AB - Mercury is one of the most hazardous pollutants in the environment. In this paper, the structural change of human hair induced by mercury exposure was studied. Human hair samples were, respectively, collected from the normal Beijing area and the Hg-contaminated Wanshan area of the Guizhou Province, China. Inductively coupled plasma mass spectroscopy was used to detect the element contents. A small angle X-ray scattering technique was used to probe the structural change. Three reflections with 8.8, 6.7, and 4.5 nm spacing were compared between the normal and the Hg-contaminated hair samples. The results confirm that the 4.5 nm reflection is from the ordered fibrillar structure of glycosaminoglycan (GAG) in proteoglycan (PG) that composes the matrix around the intermediate filaments. The increase of Ca content makes the regular oriented fibrillar structure of GAG transform to a random oriented one, broadening the angular extent of the reflection with 4.5 nm spacing. However, overdose Hg makes the core proteins where the ordered fibrils of GAG are attached become coiled, which destroys the ordered arrangements of fibrillar GAG in PG, resulting in the disappearance of the reflections with 4.5 nm spacing. The disappearance of the 4.5 nm reflection can be used as a bioindicator of overdose Hg contamination to the human body. A supercoiled-coil model of hair nanoscale structure and a possible mechanism of mercury effect in human hair are proposed in this paper. PMID- 23981031 TI - A bovine myeloid antimicrobial peptide (BMAP-28) kills methicillin-resistant Staphylococcus aureus but promotes adherence of the bacteria. AB - The cathelicidin family is one of the several families of antimicrobial peptides (AMPs). A bovine myeloid antimicrobial peptide (BMAP-28) belongs to this family. Recently, the emergence of drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) has become a big problem. AMPs are expected to be leading compounds of new antibiotics against drug-resistant bacteria. In this study, we focused on the activity of BMAP-28 against bacterial cell surfaces. First, we observed morphological change of MRSA caused by BMAP-28 using a scanning probe microscope. We also studied activities of BMAP-28 against adherence of S. aureus to fibronectin, collagen type I, collagen type IV. We confirmed whether BMAP-28 can bind to lipoteichoic acid (LTA) of S. aureus. BMAP 28 was indicated as damaging the cell surface of MRSA. In a particular range of concentrations, BMAP-28 promoted adherence of S. aureus against fibronectin and collagens. It was revealed that BMAP-28 and LTA of S. aureus bound with each other. Our study showed the potential of BMAP-28 which can damage MRSA and interact with LTA of S. aureus but promote its adherence in some concentrations. This study provides new points of which to take notice when we use AMPs as medicines. PMID- 23981030 TI - Organic carbonates from natural sources. PMID- 23981032 TI - Palladium catalyzed cyclizations of oxime esters with 1,2-disubstituted alkenes: synthesis of dihydropyrroles. AB - Pd-catalyzed cyclizations of oxime esters with 1,2-dialkylated alkenes provide an entry to chiral dihydropyrroles. Substrate and catalyst controlled strategies for selective product formation (vs alternative pyrroles) are outlined. PMID- 23981033 TI - Spirolactam-based acetyl-CoA carboxylase inhibitors: toward improved metabolic stability of a chromanone lead structure. AB - Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide 21, which was advanced to preclinical development. PMID- 23981036 TI - In situ reactive compatibilization of polypropylene/ethylene-propylene-diene monomer thermoplastic vulcanizate by zinc dimethacrylate via peroxide-induced dynamic vulcanization. AB - This work demonstrates an approach of in situ reactive compatibilization between polypropylene (PP) and ethylene-propylene-diene monomer (EPDM) by using zinc dimethacrylate (ZDMA) as a compatibilizer and, simultaneously, as a very strong reinforcing agent. With the incorporation of 7phr ZDMA in the PP/EPDM (30/70, w/w) thermoplastic vulcanizate (TPV), the tensile strength, tear strength, elongation at break, and hardness of PP/EPDM/ZDMA TPV were increased from 5.3 MPa, 31.3 kN/m, 222%, and 78 up to 11.2 MPa, 64.2 kN/m, 396%, and 83, respectively. This tremendous reinforcing as well as the compatibilization effect of the ZDMA was understood by polymerization of ZDMA and ZDMA reacted with EPDM and PP during peroxide-induced dynamic vulcanization. A peculiar phase structure that rubber particles were surrounded and "bonded" by a thick transition zone that contained numerous of nanoparticles with dimensions of about 20-30 nm was observed from transmission electron microscopy. Scanning electron microscopy results confirmed that incorporation of ZDMA reduced the size of the cross-linked EPDM particles. Moreover, we found that the compatibilized TPV showed a higher tan delta peak temperature for EPDM phase and a lower tan delta peak temperature for PP phase. The suggested method for in situ reactive compatibilization of PP and EPDM offers routes to the design of new TPV-based technical products for diversified applications. PMID- 23981034 TI - Interventional treatment of a biliary stricture after adult right-lobe living donor liver transplantation with duct-to-duct anastomosis. AB - BACKGROUND: [corrected] A biliary stricture is the most common complication after living-donor liver transplantation (LDLT). The present study was performed to examine treatment methods and outcomes after treatment for a biliary stricture after LDLT. METHODS AND RESULTS: From January 2000 to December 2010, 488 patients underwent LDLT using the right lobe with duct-to-duct anastomosis at our transplantation centre. Overall biliary strictures were detected in 160 patients (32.8%), and the majority occurred within 2 years after LDLT. Biliary strictures were related to bile leakage (P < 0.001) and the urgency of the surgery (P = 0.012) in a multivariate analysis. All biliary strictures were treated with interventional modalities including an endoscopic or a percutaneous approach. Failure of interventional treatment was demonstrated in 13 patients (8.5%), among them, four (2.6%) underwent re-transplantation and nine (5.9%) died of sepsis and biliary cirrhosis during the follow-up period. A biliary stricture was not related to the survival rate (P = 0.586). CONCLUSION: The incidence of overall biliary stricture was related to bile leakage and the urgency of the surgery. All biliary strictures could be treated by interventional modalities. These approaches are effective, complementary and help to avoid the need for surgery for a biliary stricture. PMID- 23981037 TI - Investigation of the association between psoriasis and human leucocyte antigens A by means of meta-analysis. AB - BACKGROUND: The association between psoriasis and human leucocyte antigen A (HLA A) does not reach a consensus. OBJECTIVES: To clarify the association between psoriasis and HLA-A. METHODS: Predefined selection criteria were applied to all relevant case-control studies (from 1972 to 2013) in two English databases. RESULTS: Twenty-three eligible articles covering 12 227 participants were included, in which 28 alleles were reported associated with psoriasis. Our meta analysis results showed that nine alleles were susceptible, 12 were protective and seven were unassociated. Subgroup analyses were conducted in terms of race, clinical type and onset age. For unspecific psoriasis, only one strongly susceptible allele was found in Caucasian and three were in Asian; three strongly protective alleles were reported in Caucasian and only one was found in Asian. There was no common allele to both races. For psoriasis vulgaris, there was no strongly susceptible allele in Caucasian but two in Asian; two strongly protective alleles were found in Caucasian and another two were in Asian. For psoriatic arthritis, two strongly susceptible alleles and one strongly protective allele were reported in Caucasian cases. For psoriasis guttate, only one strongly protective allele was found in Caucasian. In terms of onset age, A*01, A*02, A*03, A*26 and A*30 alleles were more susceptible to type I psoriasis than to type II, and it showed a stronger association in those with family history. CONCLUSIONS: Psoriasis is associated with a number of HLA-A alleles, some are susceptible, some are protective. The association of some alleles is different in terms of different races, clinical types and onset age. PMID- 23981038 TI - Broadband sharp 90-degree bends and T-splitters in plasmonic coaxial waveguides. AB - We demonstrate numerically that sharp 90 degrees bends and T-splitters can be designed in plasmonic coaxial waveguides at deep-subwavelength scale to operate without reflection and radiation over a broad range of wavelengths, including the telecommunication wavelength of 1.55 MUm. We explain the principles of the operation using a transmission line model of the waveguide in the quasi-static limit. The compact bends and T-splitters open up a new avenue for the design of densely integrated optical circuits with minimal crosstalk. PMID- 23981039 TI - Oligodendrocyte-microglia cross-talk in the central nervous system. AB - Communication between the immune system and the central nervous system (CNS) is exemplified by cross-talk between glia and neurons shown to be essential for maintaining homeostasis. While microglia are actively modulated by neurons in the healthy brain, little is known about the cross-talk between oligodendrocytes and microglia. Oligodendrocytes, the myelin-forming cells in the CNS, are essential for the propagation of action potentials along axons, and additionally serve to support neurons by producing neurotrophic factors. In demyelinating diseases such as multiple sclerosis, oligodendrocytes are thought to be the victims. Here, we review evidence that oligodendrocytes also have strong immune functions, express a wide variety of innate immune receptors, and produce and respond to chemokines and cytokines that modulate immune responses in the CNS. We also review evidence that during stress events in the brain, oligodendrocytes can trigger a cascade of protective and regenerative responses, in addition to responses that elicit progressive neurodegeneration. Knowledge of the cross-talk between microglia and oligodendrocytes may continue to uncover novel pathways of immune regulation in the brain that could be further exploited to control neuroinflammation and degeneration. PMID- 23981041 TI - Prenatal activation of maternal TLR3 receptors by viral-mimetic poly(I:C) modifies GluN2B expression in embryos and sonic hedgehog in offspring in the absence of kynurenine pathway activation. AB - Activation of the immune system during pregnancy is believed to lead to psychiatric and neurological disorders in the offspring, but the molecular changes responsible are unknown. Polyinosinic:polycytidylic acid (poly(I:C)) is a viral-mimetic double-stranded RNA complex which activates Toll-Like-Receptor-3 and can activate the metabolism of tryptophan through the oxidative kynurenine pathway to compounds that modulate activity of glutamate receptors. The aim was to determine whether prenatal administration of poly(I:C) affects the expression of neurodevelopmental proteins in the offspring and whether such effects were mediated via the kynurenine pathway. Pregnant rats were treated with poly(I:C) during late gestation and the offspring were allowed to develop to postnatal day 21 (P21). Immunoblotting of the brains at P21 showed decreased expression of sonic hedgehog, a key protein in dopaminergic neuronal maturation. Expression of alpha-synuclein was decreased, while tyrosine hydroxylase was increased. Disrupted in Schizophrenia-1 (DISC-1) and 5-HT2C receptor levels were unaffected, as were the dependence receptors Unc5H1, Unc5H3 and Deleted in Colorectal Cancer (DCC), the inflammation-related transcription factor NFkB and the inducible oxidative enzyme cyclo-oxygenase-2 (COX-2). An examination of embryo brains 5 h after maternal poly(I:C) showed increased expression of GluN2B, with reduced doublecortin and DCC but no change in NFkB. Despite altered protein expression, there were no changes in the kynurenine pathway. The results show that maternal exposure to poly(I:C) alters the expression of proteins in the embryos and offspring which may affect the development of dopaminergic function. The oxidation of tryptophan along the kynurenine pathway is not involved in these effects. PMID- 23981040 TI - Hepatitis C virus therapy is associated with lower health care costs not only in noncirrhotic patients but also in patients with end-stage liver disease. AB - BACKGROUND: The effect of anti-viral treatment on downstream costs for hepatitis C virus (HCV)-infected patients is unknown. AIM: To evaluate follow-up costs in patients with chronic HCV, stratified by liver disease severity. METHODS: Using a US private insurance database, mean all-cause per-patient-per-month (PPPM) US (2010) medical costs were calculated for HCV-infected persons who did and did not receive anti-HCV treatment between January 2002 and August 2010. Analysis was stratified by liver disease severity [noncirrhotic disease (NCD), compensated cirrhosis (CC) or end-stage liver disease (ESLD)] defined by ICD-9 and CPT codes. RESULTS: A total of 33 309 patients were included (78% NCD, 7% CC and 15% ESLD); 4111 individuals (12%) received anti-HCV treatment during the 2-year baseline period. Mean PPPM follow-up health care costs were significantly lower among treated patients with NCD ($900 vs. $1378 in untreated patients, P < 0.001) and ESLD ($3634 vs. $5071, P < 0.001) groups but not in the CC group ($1404 vs. $1795, P < 0.071; t-test). In a multivariable model adjusted for demographic characteristics, comorbidities, index date and geographical region, incremental cost ratios for total health care costs differed significantly (P < 0.001) between treated and untreated patients in the NCD and ESLD groups but not in the CC group. From this model, mean PPPM total health care costs between treated and untreated patients were $885 and $1370 in the NCD, $1369 and $1802 in the CC, and $3547 and $5137 in the ESLD groups, respectively. CONCLUSIONS: Anti-HCV therapy was associated with lower follow-up US health care costs, and these savings were independent of baseline patient comorbidities and stage of disease. PMID- 23981042 TI - Regulation of macrophage immune responses by antipsychotic drugs. AB - Antipsychotic drugs (APDs) have been used to ease clinical psychotic symptoms. APDs have also been recently discovered to induce immune regulation. Our previous studies found that atypical APDs risperidone and clozapine could inhibit INF gamma production of human peripheral blood mononuclear cells (PBMC) and could inhibit Th1 differentiation. This study further investigates APD effects on monocyte-derived macrophages, which are the major antigen-presenting cells in PBMC. Our data suggest that adhesion, phagocytosis and reactive oxygen species production of monocytic cell lines would be inhibited by haloperidol, risperidone or clozapine. Also, that APDs inhibited the production of LPS-stimulated macrophages IL-6 and IL-8 suggests that risperidone and clozapine may inhibit inflammation. We further discovered that risperidone and clozapine could inhibit IL-12 production and increase IL-10 production of LPS-stimulated macrophages. These results indicated that risperidone and clozapine could inhibit Th1 differentiation not only by increasing INF-gamma production of PBMC but by inhibiting the release of Th1-inducing cytokines and increasing Th2-inducing cytokines of LPS-stimulated macrophages to modulate and regulate immune responses. PMID- 23981043 TI - Polyaniline/carbon nanotube sheet nanocomposites: fabrication and characterization. AB - Practical approaches are needed to take advantage of the nanometer-scale mechanical properties of carbon nanotubes (CNTs) at the macroscopic scale. This study was conducted to elucidate the salient factors that can maximize the mechanical properties of nanocomposites fabricated from commercially available CNT sheets. The CNT sheets were modified by stretching to improve CNT alignment and in situ polymerization using polyaniline (PANI), a pi-conjugated conductive polymer, as a binder. The resulting CNT nanocomposites were subsequently postprocessed by hot pressing and/or high temperature treatment to carbonize the PANI as a means to improve mechanical properties. The PANI/CNT nanocomposites demonstrated significant improvement in mechanical properties compared to pristine CNT sheets. The highest specific tensile strength of PANI/stretched CNT nanocomposite was 484 MPa/(g/cm3), which was achieved in a sample with ~42 wt % of PANI. This specimen was fabricated by in situ polymerization followed by hot pressing. The highest specific Young's modulus of 17.1 GPa/(g/cm3) was measured on a sample that was hot-pressed and carbonized. In addition, the highest DC electrical conductivity of 621 S/cm was obtained on a sample prepared by in situ polymerization of PANI on a stretched CNT sheet. PMID- 23981044 TI - Forster resonance energy transfer-based biosensing platform with ultrasmall silver nanoclusters as energy acceptors. AB - We studied the energy transfer (ET) property of ultrasmall Ag nanoclusters (Ag NCs) and exploited its biosensing application for the first time. A hybridized DNA duplex model was designed to study the energy transfer process from fluorescent energy donors to Ag NCs. By changing the DNA duplex model and the number of hybridized pairs, the separation distance between the energy donor and Ag NCs was adjusted to investigate the distance dependence and possible mechanisms involved in the ET process, which was assigned to Forster resonance energy transfer (FRET). Using Ag NCs with different photophysical properties as energy acceptors, FRET-based biosensing platforms with two different energy donors were constructed utilizing either the off-on or ratiometric fluorescence signaling. This study will provide the basis for understanding energy transfer properties of Ag NCs and bring to light the universal application of these properties in bio/chemo sensing. PMID- 23981045 TI - Lateral occlusion schemes in natural and minimally restored permanent dentition: a systematic review. AB - Clinicians commonly encounter the dilemma of which lateral occlusion schemes is most suitable for a specific patient. The aim of this review is to evaluate the prevalence of the lateral occlusion schemes that exist naturally. An electronic search was completed through PubMed (MEDLINE), Google Scholar and Cochrane Library. The search was confined to peer-reviewed studies published in English, up to April 2013. The literature search was supplemented by manual searching through the bibliography lists of the selected studies. The initial search retrieved a total of 575 studies. After applying the selection criteria, only 12 studies were suitable for inclusion. The Critical Appraisal Skills Programme (CASP) tools were utilised to appraise the quality of the studies. The prevalence of canine-guided, group function and balanced occlusions was reported. Overall, there was a clear variability between the studies. The prevalence of the lateral occlusion schemes appears to be influenced by the following factors: (i) the magnitude of excursion, (ii) an individual's age and (iii) the static occlusal relationship. During complete excursion, the canine-guided occlusion tends to be more frequently observed. After partial excursion, the most prevalent lateral occlusion schemes was group function occlusion. With ageing, the prevalence of canine-guided occlusion tends to be reduced and the prevalence of group function occlusion is increased. Dentition that is closer to Class II occlusion exhibits mainly canine-guided occlusion, while for Class III occlusion, group function occlusion is more prevalent. The studies revealed no relationship between the lateral occlusion schemes and TMD development. PMID- 23981046 TI - Biologic targets identified from dynamic 18FDG-PET and implications for image guided therapy. AB - PURPOSE: The outcome of biologic image-guided radiotherapy depends on the definition of the biologic target. The purpose of the current work was to extract hyperperfused and hypermetabolic regions from dynamic positron emission tomography (D-PET) images, to dose escalate either region and to discuss implications of such image guided strategies. METHODS: Eleven patients with soft tissue sarcomas were investigated with D-PET. The images were analyzed using a two-compartment model producing parametric maps of perfusion and metabolic rate. The two image series were segmented and exported to a treatment planning system, and biological target volumes BTVper and BTVmet (perfusion and metabolism, respectively) were generated. Dice's similarity coefficient was used to compare the two biologic targets. Intensity-modulated radiation therapy (IMRT) plans were generated for a dose painting by contours regime, where planning target volume (PTV) was planned to 60 Gy and BTV to 70 Gy. Thus, two separate plans were created for each patient with dose escalation of either BTVper or BTVmet. RESULTS: BTVper was somewhat smaller than BTVmet (209 +/- 170 cm(3) against 243 +/- 143 cm(3), respectively; population-based mean and s.d.). Dice's coefficient depended on the applied margin, and was 0.72 +/- 0.10 for a margin of 10 mm. Boosting BTVper resulted in mean dose of 69 +/- 1.0 Gy to this region, while BTVmet received 67 +/- 3.2 Gy. Boosting BTVmet gave smaller dose differences between the respective non-boost DVHs (such as D98). CONCLUSIONS: Dose escalation of one of the BTVs results in a partial dose escalation of the other BTV as well. If tumor aggressiveness is equally pronounced in hyperperfused and hypermetabolic regions, this should be taken into account in the treatment planning. PMID- 23981047 TI - Differences in supratentorial white matter diffusion after radiotherapy--new biomarker of normal brain tissue damage? AB - INTRODUCTION: Therapy-induced injury to normal brain tissue is a concern in the treatment of all types of brain tumours. The purpose of this study was to investigate if magnetic resonance diffusion tensor imaging (DTI) could serve as a potential biomarker for the assessment of radiation-induced long-term white matter injury. MATERIAL AND METHODS: DTI- and T1-weighted images of the brain were obtained in 19 former radiotherapy patients [nine men and 10 women diagnosed with astrocytoma (4), pituitary adenoma (6), meningioma (8) and craniopharyngioma (1), average age 57.8 (range 35-71) years]. Average time from radiotherapy to DTI scan was 4.6 (range 2.0-7.1) years. NordicICE software (NIC) was used to calculate apparent diffusion coefficient maps (ADC-maps). The co-registration between T1 images and ADC-maps were done using the auto function in NIC. The co registration between the T1 images and the patient dose plans were done using the auto function in the treatment planning system Eclipse from Varian. Regions of interest were drawn on the T1-weighted images in NIC based on isocurves from Eclipse. Data was analysed by t-test. Estimates are given with 95% CI. RESULTS: A mean ADC difference of 4.6(0.3;8.9)* 10(-5) mm(2)/s, p = 0.03 was found between paired white matter structures with a mean dose difference of 31.4 Gy. Comparing the ADC-values of the areas with highest dose from the paired data (dose > 33 Gy) with normal white matter (dose < 5 Gy) resulted in a mean dose difference of 44.1 Gy and a mean ADC difference of 7.87(3.15;12.60)* 10(-5) mm(2)/s, p = 0.003. Following results were obtained when looking at differences between white matter mean ADC in average dose levels from 5 to 55 Gy in steps of 10 Gy with normal white matter mean ADC: 5 Gy; 1.91(-1.76;5.58)* 10(-5) mm(2)/s, p = 0.29; 15 Gy; 5.81(1.53;10.11)* 10(-5) mm(2)/s, p = 0.01; 25 Gy; 5.80(2.43;9.18)* 10(-5) mm(2)/s, p = 0.002; 35 Gy; 5.93(2.89;8.97)* 10(-5) mm(2)/s, p = 0.0007; 45 Gy; 4.32(-0.24;8.89)* 10(-5) mm(2)/s, p = 0.06; 55 Gy; -4.04(-14.96;6.89)* 10(-5) mm(2)/s, p = 0.39. CONCLUSION: The results indicate that the structural integrity of white matter, assessed by ADC-values based on DTI, undergoes changes after radiation therapy starting as early as total dose levels between 5 and 15 Gy. PMID- 23981048 TI - Psychosocial and cardiac outcomes of yoga for ICD patients: a randomized clinical control trial. AB - BACKGROUND: Because as many as 46% of implantable cardioverter defibrillator (ICD) patients experience clinical symptoms of shock anxiety, this randomized controlled study evaluated the efficacy of adapted yoga (vs usual care) in reducing clinical psychosocial risks shown to impact morbidity and mortality in ICD recipients. METHODS: Forty-six participants were randomized to a control group or an 8-week adapted yoga group that followed a standardized protocol with weekly classes and home practice. Medical and psychosocial data were collected at baseline and follow-up, then compared and analyzed. RESULTS: Total shock anxiety decreased for the yoga group and increased for the control group, t(4.43, 36), P < 0.0001, with significant differences between these changes. Similarly, consequential anxiety decreased for the yoga group but increased for the control group t(2.86,36) P = 0.007. Compared to the control, the yoga group had greater overall self-compassion, t(-2.84,37), P = 0.007, and greater mindfulness, t( 2.10,37) P = 0.04, at the end of the study. Exploratory analyses utilizing a linear model (R(2) = 0.98) of observed device-treated ventricular (DTV) events revealed that the expected number of DTV events in the yoga group was significantly lower than in the control group (P < 0.0001). Compared to the control, the yoga group had a 32% lower risk of experiencing device-related firings at end of follow-up. CONCLUSIONS: Our study demonstrated psychosocial benefits from a program of adapted yoga (vs usual care) for ICD recipients. These data support continued research to better understand the role of complementary medicine to address ICD-specific stress in cardiac outcomes. PMID- 23981049 TI - Functional diversity of Nocardia in metabolism. AB - Bacteria affiliated in the genus Nocardia are aerobic and Gram-positive actinomycetes that are widely found in aquatic and terrestrial habitats. As occasional pathogens, several of them cause infection diseases called 'nocardiosis' affecting lungs, central nervous system, cutaneous tissues and others. In addition, members of the genus Nocardia exhibit an enormous metabolic versatility. On one side, many secondary metabolites have been isolated from members of this genus that exhibit various biological activities such as antimicrobial, antitumor, antioxidative and immunosuppressive activities. On the other side, many species are capable of degrading or converting aliphatic and aromatic toxic hydrocarbons, natural or synthetic polymers, and other widespread environmental pollutants. Because of these valuable properties and the application potential, Nocardia species have attracted much interest in academia and industry in recent years. A solid basis of genetic tools including a set of shuttle vectors and an efficient electroporation method for further genetic and metabolic engineering studies has been established to conduct efficient research. Associated with the increasing data of nocardial genome sequences, the functional diversity of Nocardia will be much faster and better understood. PMID- 23981050 TI - In reply. PMID- 23981052 TI - Differential modulation of activity related to the anticipation of monetary gains and losses across the menstrual cycle. AB - Estradiol and progesterone interact with the dopaminergic and other neurotransmitter systems that are involved in the processing of rewards. On the systems level, these hormones modulate responses to stimulants as well as neuronal activity related to the anticipation of monetary gains. As different mechanisms might underlie the processing of gains and losses, the current study aims to investigate whether neural correlates of gain and loss anticipation are differentially modulated by menstrual cycle phases. Therefore, young, naturally cycling women were examined by means of functional neuroimaging during performing a modified version of the 'Monetary Incentive Delay' task in the early follicular and in the luteal menstrual cycle phase. During the low hormone early follicular phase, the anticipation of high vs. low gains and losses was associated with activity in a largely overlapping network of brain areas. However, high hormone levels in the luteal phase affected brain activity in these areas differentially during the anticipation of high vs. low gains and losses. In particular, the orbitofrontal cortex showed a reduced sensitivity to gain magnitude, whereas the ventral striatum and the anterior cingulate showed a reduced sensitivity to loss magnitude. In summary, the high amount of progesterone and estradiol in the luteal phase decreased activity related to the anticipation of monetary gains and losses in different brain areas, suggesting that hormones modulate different processes during the anticipation of gain and loss magnitude. PMID- 23981053 TI - Best interests decisions: professional practices in health and social care. AB - This paper reports on data collected in 2011 from a national study about the operation of the best interests principle, a key feature of the Mental Capacity Act (MCA) 2005 for England and Wales. The objective was to provide a picture of current professional practices in best interests decision-making. Four contrasting sample sites were selected, in which National Health Service trusts, social care and other organisations were recruited to participate. A multimethod design was followed, including an online survey with 385 participants, followed by qualitative research through a telephone survey of 68 participants, and face to-face semi-structured interviews following up 25 best interests cases, with different perspectives on the process in 12 of those cases. The current paper reports only on the qualitative findings. The findings indicate that the MCA was successful in providing a structure for these practitioners, and that the five principles of the MCA were in general adhered to. A variety of perceived risks led to best interests processes being undertaken, and a typical scenario was for a period of hospitalisation or ill health to trigger a best interests decision process about a social care and or a life decision. The study supported previous research in finding the notion of capacity the most difficult aspect of the MCA, and it provides evidence of some specific capacity assessment practices, including problematic ones relating to 'insight'. Best interests decisions were often made by consensus, with practitioners taking on different roles within the process. Meetings played a key part, but other ways of involving people lacking capacity and significant others were also important. It was recommended that the issues highlighted in this research could be clarified further in the Code of Practice, or within risk guidance. PMID- 23981054 TI - Regulation by resveratrol of the cellular factors mediating liver damage and regeneration after acute toxic liver injury. AB - BACKGROUND AND AIM: Acute liver injury is manifested by different degree of hepatocyte necrosis and may recover via the process of hepatocyte regeneration once the injury is discontinued. Most of the liver injury is associating with inflammatory cytokines. Resveratrol (RSV) is a natural phytoalexin with powerful anti-inflammatory effects. AIM: The effects of RSV on cellular factors mediating liver damage and regeneration in acute carbon tetrachloride (CCl4 ) liver injury were investigated. RESULTS: RSV decreased alanine aminotransferase, aspartate aminotransferase, necrosis, and 4-hydroxynonenal in the CCl4 -injured liver. RSV decreased hepatocyte apoptosis by reducing caspase 8 and caspase 3 but not Bax and Bcl-xL. RSV reduced Kupffer cells recruitment, the expressions of tumor necrosis factor-alpha and interleukin-6, but not interleukin-10. RSV lowered the numbers of anti-5-bromon-2'-deoxyuridine and anti-Ki67-positive hepatocytes. Hepatic hepatocyte growth factor, c-Met and transforming growth factor-alpha expressions were reduced by RSV, while transforming growth factor-beta1 and hepatic stellate cells activation were not changed. RSV reduced the injury induced CXCL10 elevations in serum and liver in vivo. Besides, RSV inhibited CXCL10 release from CCl4 -injured hepatocytes in vitro. In contrast, recombinant CXCL10 improved the viability of CCl4 -injured hepatocytes. CONCLUSIONS: RSV therapy can be beneficial for acute toxic liver injury. RSV reduced hepatocyte apoptosis but limited hepatocyte regeneration possibly through reducing the hepatomitogenic signaling and the release of CXCL10. PMID- 23981051 TI - Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women. AB - Pharmacological response depends on multiple factors and one of them is sex gender. Data on the specific effects of sex-gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex-gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex-gender influences pharmacogenomics and pharmacogenetics. Sex related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex-gender-based approach with the aim of tailoring therapies to an individual's needs and concerns. PMID- 23981055 TI - Spatial and temporal variability of biomarkers and microbial diversity reveal metabolic and community flexibility in Streamer Biofilm Communities in the Lower Geyser Basin, Yellowstone National Park. AB - Detailed analysis of 16S rRNA and intact polar lipids (IPLs) from streamer biofilm communities (SBCs), collected from geochemically similar hot springs in the Lower Geyser Basin, Yellowstone National Park, shows good agreement and affirm that IPLs can be used as reliable markers for the microbial constituents of SBCs. Uncultured Crenarchaea are prominent in SBS, and their IPLs contain both glycosidic and mixed glyco-phospho head groups with tetraether cores, having 0-4 rings. Archaeal IPL contributions increase with increasing temperature and comprise up to one-fourth of the total IPL inventory at >84 degrees C. At elevated temperatures, bacterial IPLs contain abundant glycosidic glycerol diether lipids. Diether and diacylglycerol (DAG) lipids with aminopentanetetrol and phosphatidylinositol head groups were identified as lipids diagnostic of Aquificales, while DAG glycolipids and glyco-phospholipids containing N acetylgycosamine as head group were assigned to members of the Thermales. With decreasing temperature and concomitant changes in water chemistry, IPLs typical of phototrophic bacteria, such as mono-, diglycosyl, and sulfoquinovosyl DAG, which are specific for cyanobacteria, increase in abundance, consistent with genomic data from the same samples. Compound-specific stable carbon isotope analysis of IPL breakdown products reveals a large isotopic diversity among SBCs in different hot springs. At two of the hot springs, 'Bison Pool' and Flat Cone, lipids derived from Aquificales are enriched in (13) C relative to biomass and approach values close to dissolved inorganic carbon (DIC) (approximately 00/00), consistent with fractionation during autotrophic carbon fixation via the reversed tricarboxylic acid pathway. At a third site, Octopus Spring, the same Aquificales diagnostic lipids are 100/00 depleted relative to biomass and resemble stable carbon isotope values of dissolved organic carbon (DOC), indicative of heterotrophy. Other bacterial and archaeal lipids show a similar variance, with values resembling the DIC or DOC pool or a mixture thereof. This variance cannot be explained by hot spring chemistry or temperature alone, but instead, we argue that intermittent input of exogenous organic carbon can result in metabolic shifts of the chemotrophic communities from autotrophy to heterotrophy and vice versa. PMID- 23981056 TI - Effects of chemical amendments on the lability and speciation of metals in anaerobically digested biosolids. AB - The interaction of inorganic contaminants present in biosolids with iron, aluminum, and manganese oxy/hydroxides has been advocated as a key mechanism limiting their bioavailability. In this study, we investigated whether this is indeed the case, and further, whether it can be exploited to produce optimized biosolids products through the addition of chemical additives during sewage sludge processing. Experiments were conducted to investigate whether the addition of iron- and aluminum-based amendments (at 5 different rates) during the anaerobic digestion phase of wastewater treatment can effectively change the speciation or lability of contaminant metals (copper, zinc and cadmium) in biosolids destined for use in agriculture. The performance of the bioreactors was monitored throughout and the speciation and lability were determined in both fresh and 3-month aged biosolids using X-ray absorption spectroscopy (Cu, Zn) and isotopic dilution ((65)Cu, (65)Zn, (109)Cd). The tested amendments (FeCl3, Al2(SO4)3, and Al-rich water treatment residual) did not cause significant changes in metal speciation and were of limited use for reducing the lability of contaminant metals in good quality biosolids (suitable for use in agriculture), suggesting that high affinity binding sites were already in excess in these materials. However, the use of chemical amendments may offer advantages in terms of treatment process optimization and may also be beneficial when biosolids are used for contaminated site remediation. PMID- 23981058 TI - Increased ectopic fat cells in the longitudinal muscularis layer of the oviduct isthmus in obese Japanese Black cows. AB - In obese humans, mesenchymal stem cells differentiate to become ectopic fat cells in muscles. These ectopic fat cells inhibit the contraction of vascular smooth muscles. Stem cells have been recently identified in the human oviduct, a structure important in reproduction. We therefore investigated the number of Oil Red O (ORO)-positive cells in the oviducts of control Japanese Black cows (n = 6; body condition score [BCS], 3.0 on a 5-point scale) compared to those with diet induced obesity (n = 5; BCS, 4.0). We stained the ampulla and isthmus collected on the second day after ovulation with ORO and then counted the positive cells in each layer in 10 cross-sections of the ampulla or isthmus. The obese group (23.4 +/- 3.4 in the 10 sections) had larger numbers of ORO-positive cells in the longitudinal muscularis of the isthmus (P < 0.05) than did the control group (15.0 +/- 2.4). ORO-positive cells were also observed in all other layers of the isthmus and ampulla; however, the number of cells in these layers did not differ significantly between obese cows and controls. Whether this observed increase in ORO-positive cells in the oviducts of obese cows affects their reproduction warrants further study. PMID- 23981059 TI - Plasmon-controlled light-harvesting: design rules for biohybrid devices via multiscale modeling. AB - Photosynthesis is triggered by the absorption of light by light-harvesting (LH) pigment-protein complexes followed by excitation energy transfer to the reaction center(s). A promising strategy to achieve control on and to improve light harvesting is to complement the LH complexes with plasmonic particles. Here a recently developed QM/MM/continuum approach is used to investigate the LH process of the peridinin-chlorophyll-protein (PCP) complex on a silver island film. The simulations not only reproduce and interpret the experiments but they also suggest general rules to design novel biohybrid devices; hot-spot configurations in which the LH complex is sandwiched between couples of metal aggregates are found to produce the largest amplifications. Indications about the best distances and orientations are also reported together with illumination and emission geometries of the PCP-NP system necessary to achieve the maximum enhancement. PMID- 23981060 TI - Prognostic implications of DPP-4 inhibitor vs. sulfonylurea use on top of metformin in a real world setting - results of the 1 year follow-up of the prospective DiaRegis registry. AB - BACKGROUND: DPP-4 inhibitors (DPP4-I) have been shown to provide non-inferior glycaemic control compared with sulfonylureas (SU), but result in a reduction of body weight and a significantly lower risk of hypoglycaemia in patients with type 2 diabetes. We aimed to validate these results in a large real-world sample of patients participating in the prospective DiaRegis registry and to assess prognostic implications. METHODS: DiaRegis included 3810 patients with type 2 diabetes in which antidiabetic therapy was intensified. We defined two patient subgroups, the first receiving either a DPP4-I or SU on top of prior metformin monotherapy and the second containing patients out of subgroup 1 with unaltered treatment for 1 year. RESULTS: After enrolment 884 patients with prior metformin monotherapy received a dual combination of metformin with either DPP4-I (n = 628; 71%) or SU (n = 256; 29%). Patient characteristics, blood glucose and blood pressure control as well as comorbidity burden were virtually identical. There were neither significant differences in the change of HbA1c over the 12 months treatment period nor in the reduction of body weight, but fasting (p = 0.033) and postprandial glucose levels (p = 0.01) were significantly lower in those receiving DPP4-I. Hypoglycaemia was significantly less frequent in patients receiving DPP4-I (OR 0.32; 95% CI 0.19-0.54). Qualitative changes were robust for subgroup 2 (except of fasting plasma glucose). Patients receiving DPP4-I had significantly less stroke/transitory ischaemic attack (0.2 vs. 2.0; p < 0.05) during the 1 year follow-up, whereas other vascular events (coronary artery bypass graft, percutaneous coronary intervention) were borderline significant. CONCLUSIONS: The present results confirm prior randomised controlled trial results in patients with type 2 diabetes from real world clinical practice demonstrating that DPP4-I on top of prior metformin monotherapy result in similar HbA1c reductions within 12 months but a significant reduction in hypoglycaemia compared with sulfonylurea added to metformin. The reduction in vascular events observed has to be verified in larger cohorts. PMID- 23981061 TI - European guidelines for topical PDT part 1 JEADV 2013; 27: 536-544. PMID- 23981062 TI - Stereodivergent access to cis- and trans-3,5-disubstituted 1,4-thiazane 1-oxides by cyclization of homochiral beta-amino sulfoxides and sulfones. The preparation of isomeric ant venom alkaloids. AB - Intramolecular conjugate additions of homochiral (E)-1-alkenyl 2-aminoalkyl sulfoxides and sulfones were investigated. The relative position of the 3,5 substituents of the resulting 1,4-thiazane oxides was found to be dependent on the oxidation state of the sulfur atom, demonstrating a simple and highly stereodivergent synthetic protocol. Selected cis- and trans-3,5-disubstituted 1,4 thiazane dioxides were converted to cis- and trans-2,5-disubstituted pyrrolidines, known ant venom alkaloids. PMID- 23981063 TI - Remediating cancer via splicing modulation. AB - The identification of three distinct but structurally related classes of microbial-derived spliceosome modulators has provided an exciting opportunity for the development of mechanistically new cancer treatments. A team at UC San Diego has undertaken a SAR study on the spliceosome modulator FD-895 that focused on improving compound stability, while retaining potent antiproliferative and splicing activity. This led to the identification of a more potent and stable analog, (17S)-FD-895 (1), and a less active but extremely stable cyclopropane analog 2, which is currently undergoing preclinical evaluation. These analogs will serve as templates for next generation spliceosome modulating anticancer drugs. PMID- 23981057 TI - Classical electrostatics for biomolecular simulations. PMID- 23981064 TI - Mycobacterium tuberculosis infection of human dendritic cells decreases integrin expression, adhesion and migration to chemokines. AB - Tuberculosis (TB) remains a major global health problem accounting for millions of deaths annually. Approximately one-third of the world's population is infected with the causative agent Mycobacterium tuberculosis. The onset of an adaptive immune response to M. tuberculosis is delayed compared with other microbial infections. This delay permits bacterial growth and dissemination. The precise mechanism(s) responsible for this delay have remained obscure. T-cell activation is preceded by dendritic cell (DC) migration from infected lungs to local lymph nodes and synapsis with T cells. We hypothesized that M. tuberculosis may impede the ability of DCs to reach lymph nodes and initiate an adaptive immune response. We used primary human DCs to determine the effect of M. tuberculosis on expression of heterodimeric integrins involved in cellular adhesion and migration. We also evaluated the ability of infected DCs to adhere to and migrate through lung endothelial cells, which is necessary to reach lymph nodes. We show by flow cytometry and confocal microscopy that M. tuberculosis-infected DCs exhibit a significant reduction in surface expression of the beta(2) (CD18) integrin. Distribution of integrin beta(2) is also markedly altered in M. tuberculosis-infected DCs. A corresponding reduction in the alphaL (CD11a) and alphaM (CD11b) subunits that associate with integrin beta(2) was also observed. Consistent with reduced integrin surface expression, we show a significant reduction in adherence to lung endothelial cell monolayers and migration towards lymphatic chemokines when DCs are infected with M. tuberculosis. These findings suggest that M. tuberculosis modulates DC adhesion and migration to increase the time required to initiate an adaptive immune response. PMID- 23981065 TI - Association of IL28B polymorphism with fibrosis, liver inflammation, gender respective natural history of hepatitis C virus in Egyptian patients with genotype 4. AB - The polymorphism of interleukin 28B (IL28B) rs12979860 is associated with spontaneous and treatment-induced clearance in hepatitis C virus (HCV) genotype 4 (G4). However, there is no information on its interaction with gender, moreover its association with intrahepatic inflammation in North Africans is not studied and its association with fibrosis in North Africans (especially Egyptians) is controversial. This study aims to explore the association between the minor allele of the IL28B rs12979860 polymorphism with gender, fibrosis and necroinflammation in Egyptian G4 HCV patients. IL28B rs12979860 was genotyped in 224 individuals, including 100 healthy controls and 124 consecutive patients with chronic HCV. Results showed (1) IL28B rs12979860 minor alleles associated with susceptibity to chronic HCV mainly in men not women, (2) no association between IL28B rs12979860 with fibrosis and necroinflammation activity, (3) the IL28B rs12979860 TT genotype associated with severe fibrosis in women only and with the necroinflammation activity in men using a recessive model. In conclusion, the IL28B rs12979860 polymorphism is not associated with fibrosis and liver inflammation in Egyptian HCV G4. Nonetheless, the TT genotype of IL28B rs12979860 polymorphism affects the natural history of each gender independently. PMID- 23981066 TI - Systematic review: probiotics in the management of lower gastrointestinal symptoms in clinical practice -- an evidence-based international guide. AB - BACKGROUND: Evidence suggests that the gut microbiota play an important role in gastrointestinal problems. AIM: To give clinicians a practical reference guide on the role of specified probiotics in managing particular lower gastrointestinal symptoms/problems by means of a systematic review-based consensus. METHODS: Systematic literature searching identified randomised, placebo-controlled trials in adults; evidence for each symptom/problem was graded and statements developed (consensus process; 10-member panel). As results cannot be generalised between different probiotics, individual probiotics were identified for each statement. RESULTS: Thirty seven studies were included; mostly on irritable bowel syndrome [IBS; 19 studies; treatment responder rates: 18-80% (specific probiotics), 5-50% (placebo)] or antibiotic-associated diarrhoea (AAD; 10 studies). Statements with 100% agreement and 'high' evidence levels indicated that: (i) specific probiotics help reduce overall symptom burden and abdominal pain in some IBS patients; (ii) in patients receiving antibiotics/Helicobacter pylori eradication therapy, specified probiotics are helpful as adjuvants to prevent/reduce the duration/intensity of AAD; (iii) probiotics have favourable safety in patients in primary care. Items with 70-100% agreement and 'moderate' evidence were: (i) specific probiotics help relieve overall symptom burden in some patients with diarrhoea-predominant IBS, and reduce bloating/distension and improve bowel movement frequency/consistency in some IBS patients and (ii) with some probiotics, improved symptoms have led to improvement in quality of life. CONCLUSIONS: Specified probiotics can provide benefit in IBS and antibiotic associated diarrhoea; relatively few studies in other indications suggested benefits warranting further research. This study provides practical guidance on which probiotic to select for a specific problem. PMID- 23981068 TI - A low-cost, small volume circuit for autologous blood normothermic perfusion of rabbit organs. AB - We have designed a laboratory extracorporeal normothermic blood perfusion system for whole organs (e.g., kidney) that achieves pulsatile flow, low levels of hemolysis, and a blood priming volume of 60 mL or less. Using this uniquely designed extracorporeal circuit, we have achieved perfusion of two isolated ex vivo constructs. In the first experiment, we successfully perfused a rabbit epigastric flap based on the femoral vessels. In the second experiment, we were able to perfuse the isolated rabbit kidney for 48 h (range for all kidneys was 12 48 h) with excellent urine output, normal arterial blood gasses at 24 h, and normal ex vivo kidney histology at the conclusion of the experiments. These parameters have not been achieved before with any known or previously published laboratory extracorporeal circuits. The study has implications for prolonged organ perfusion prior to transplantation and for tissue engineering of vascularized tissues, such as by the perfusion of decellularized organs. PMID- 23981067 TI - Solvothermal synthesis of monodisperse LiFePO4 micro hollow spheres as high performance cathode material for lithium ion batteries. AB - A microspherical, hollow LiFePO4 (LFP) cathode material with polycrystal structure was simply synthesized by a solvothermal method using spherical Li3PO4 as the self-sacrificed template and FeCl2.4H2O as the Fe(2+) source. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) show that the LFP micro hollow spheres have a quite uniform size of ~1 MUm consisting of aggregated nanoparticles. The influences of solvent and Fe(2+) source on the phase and morphology of the final product were chiefly investigated, and a direct ion exchange reaction between spherical Li3PO4 templates and Fe(2+) ions was firstly proposed on the basis of the X-ray powder diffraction (XRD) transformation of the products. The LFP nanoparticles in the micro hollow spheres could finely coat a uniform carbon layer ~3.5 nm by a glucose solution impregnating-drying-sintering process. The electrochemical measurements show that the carbon coated LFP materials could exhibit high charge-discharge capacities of 158, 144, 125, 101, and even 72 mAh g(-1) at 0.1, 1, 5, 20, and 50 C, respectively. It could also maintain 80% of the initial discharge capacity after cycling for 2000 times at 20 C. PMID- 23981070 TI - In aged men, central vessel transmural pressure is reduced by brief Valsalva manoeuvre during strength exercise. AB - A brief Valsalva manoeuvre, lasting 2-3 s, performed by young healthy men during strength exercise reduces transmural pressure acting on intrathoracic arteries. In this study, we sought to verify this finding in older men. Twenty normotensive, prehypertensive and moderately hypertensive otherwise healthy men 46-69 years old performed knee extensions combined with inspiration or with brief Valsalva manoeuvre performed at 10, 20 and 40 mmHg mouth pressure. Same respiratory manoeuvres were also performed at rest. Non-invasively measured blood pressure, knee angle, respiratory airflow and mouth pressure were continuously registered. In comparison to inspiration, estimated transmural pressure acting on thoracic arteries changed slightly and insignificantly during brief Valsalva manoeuvre at 10 and 20 mmHg mouth pressure. At 40 mmHg mouth pressure, transmural pressure declined at rest (-8.8 +/- 11.4 mmHg) and during knee extension (-12.1 +/- 11.9 mmHg). This decline ensued, as peak systolic pressure increase caused by this manoeuvre, was distinctly <40 mmHg. Only a main effect of mouth pressure was revealed (P<0.001) and neither exercise nor interaction between these factors, what suggests that transmural pressure decline, depended mainly on intrathoracic pressure developed during brief Valsalva manoeuvre. Resting blood pressure did not influence the effect of brief Valsalva manoeuvre on transmural pressure. PMID- 23981071 TI - Colpoda secrete viable Listeria monocytogenes within faecal pellets. AB - Transmission electron microscopy was used to demonstrate that co-cultures of the ciliate Colpoda RR (an environmental isolate) and Colpoda MLS-5 (a food processing environment isolate) with the pathogenic Listeria monocytogenes DRDC8 resulted in secretion of faecal pellets containing intact DRDC8 cells. A green fluorescent protein expressing variant of DRDC8 was used in co-cultures to confirm that the pellet-associated bacterial cells were L. monocytogenes. Viability was confirmed by plate counts, and assay of microbial respiratory activity-proved DRDC8 cells present within faecal pellets was metabolically active. Following treatment of faecal pellets secreted by Colpoda RR and MLS-5 with gentamycin and sodium hypochlorite (NaOCl), no loss of viability of the pellet-located DRDC8 cells was observed, indicating that faecal pellet encapsulated DRDC8 cells are resistant to biocidal agents. This work suggests that Colpoda-derived faecal pellets may provide a mechanism for transmission of L. monocytogenes and other pathogenic bacteria. Furthermore, bacteria encapsulated by faecal pellets may be resistant to disinfectants and cleaning agents used in food manufacturing and preparation facilities. PMID- 23981072 TI - Surface folding-induced attraction and motion of particles in a soft elastic gel: cooperative effects of surface tension, elasticity, and gravity. AB - We report some experimental observations regarding a new type of long-range interaction between rigid particles that prevails when they are suspended in an ultrasoft elastic gel. A denser particle submerges itself to a considerable depth inside the gel and becomes elasto-buoyant by balancing its weight against the elastic force exerted by the surrounding medium. By virtue of a large elasto capillary length, the surface of the gel wraps around the particle and closes to create a line singularity connecting the particle to the free surface of the gel. A substantial amount of tensile strain is thus developed in the gel network parallel to the free surface that penetrates to a significant depth inside the gel. The field of this tensile strain is rather long-range because of a large gravito-elastic correlation length and sufficiently strong to pull two submerged particles into contact. The particles move toward each other with an effective force following an inverse linear distance law. When more monomers or dimers of the particles are released inside the gel, they orient rather freely inside the capsules where they are located and attract each other to form closely packed clusters. Eventually, these clusters themselves interact and coalesce. This is an emergent phenomenon in which gravity, capillarity, and elasticity work in tandem to create a long-range interaction. We also present the results of a related experiment, in which a particle suspended inside a thickness-graded gel moves accompanied by the continuous folding and the relaxation of the gel's surface. PMID- 23981073 TI - Hydration properties and ionic radii of actinide(III) ions in aqueous solution. AB - Ionic radii of actinide(III) cations (from U(III) to Cf(III)) in aqueous solution have been derived for the first time starting from accurate experimental determination of the ion-water distances obtained by combining extended X-ray absorption fine structure (EXAFS) results and molecular dynamics (MD) structural data. A strong analogy has been found between the lanthanide and actinide series concerning hydration properties. The existence of a contraction of the An-O distance along the series has been highlighted, while no decrease of the hydration number is evident up to Cf(III). PMID- 23981075 TI - Relationships between radial glial progenitors and 5-HT neurons in the paraventricular organ of adult zebrafish - potential effects of serotonin on adult neurogenesis. AB - In non-mammalian vertebrates, serotonin (5-HT)-producing neurons exist in the paraventricular organ (PVO), a diencephalic structure containing cerebrospinal fluid (CSF)-contacting neurons exhibiting 5-HT or dopamine (DA) immunoreactivity. Because the brain of the adult teleost is known for its neurogenic activity supported, for a large part, by radial glial progenitors, this study addresses the origin of newborn 5-HT neurons in the hypothalamus of adult zebrafish. In this species, the PVO exhibits numerous radial glial cells (RGCs) whose somata are located at a certain distance from the ventricle. To study relationships between RGCs and 5-HT CSF-contacting neurons, we performed 5-HT immunohistochemistry in transgenic tg(cyp19a1b-GFP) zebrafish in which RGCs are labelled with GFP under the control of the cyp19a1b promoter. We show that the somata of the 5-HT neurons are located closer to the ventricle than those of RGCs. RGCs extend towards the ventricle cytoplasmic processes that form a continuous barrier along the ventricular surface. In turn, 5-HT neurons contact the CSF via processes that cross this barrier through small pores. Further experiments using proliferating cell nuclear antigen or 5-bromo-2'-deoxyuridine indicate that RGCs proliferate and give birth to 5-HT neurons migrating centripetally instead of centrifugally as in other brain regions. Furthermore, treatment of adult zebrafish with tryptophan hydroxylase inhibitor causes a significant decrease in the number of proliferating cells in the PVO, but not in the mediobasal hypothalamus. These data point to the PVO as an intriguing region in which 5-HT appears to promote genesis of 5-HT neurons that accumulate along the brain ventricles and contact the CSF. PMID- 23981076 TI - Chicken or egg? Risks of misattribution of cause-effect relationships in studies of association. PMID- 23981074 TI - Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis. AB - While there have been significant advances in our understanding of the autoimmune responses and the molecular nature of the target autoantigens in primary biliary cirrhosis (PBC), unfortunately these data have yet to be translated into new therapeutic agents. We have taken advantage of a unique murine model of autoimmune cholangitis in which mice expressing a dominant negative form of transforming growth factor beta receptor II (dnTGFbetaRII), under the control of the CD4 promoter, develop an intense autoimmune cholangitis associated with serological features similar to human PBC. CD40-CD40 ligand (CD40L) is a major receptor-ligand pair that provides key signals between cells of the adaptive immune system, prompting us to determine the therapeutic potential of treating autoimmune cholangitis with anti-CD40L antibody (anti-CD40L; MR-1). Four-week-old dnTGFbetaRII mice were injected intraperitoneally with either anti-CD40L or control immunoglobulin (Ig)G at days 0, 2, 4 and 7 and then weekly until 12 or 24 weeks of age and monitored for the progress of serological and histological features of PBC, including rigorous definition of liver cellular infiltrates and cytokine production. Administration of anti-CD40L reduced liver inflammation significantly to 12 weeks of age. In addition, anti-CD40L initially lowered the levels of anti-mitochondrial autoantibodies (AMA), but these reductions were not sustained. These data indicate that anti-CD40L delays autoimmune cholangitis, but the effect wanes over time. Further dissection of the mechanisms involved, and defining the events that lead to the reduction in therapeutic effectiveness will be critical to determining whether such efforts can be applied to PBC. PMID- 23981077 TI - Understanding the cellular mechanism of recovery from freeze-thaw injury in spinach: possible role of aquaporins, heat shock proteins, dehydrin and antioxidant system. AB - Recovery from reversible freeze-thaw injury in plants is a critical component of ultimate frost survival. However, little is known about this aspect at the cellular level. To explore possible cellular mechanism(s) for post-thaw recovery (REC), we used Spinacia oleracea L. cv. Bloomsdale leaves to first determine the reversible freeze-thaw injury point. Freeze (-4.5 degrees C)-thaw-injured tissues (32% injury vs <3% in unfrozen control) fully recovered during post-thaw, as assessed by an ion leakage-based method. Our data indicate that photosystem II efficiency (Fv/Fm) was compromised in injured tissues but recovered during post thaw. Similarly, the reactive oxygen species (O2 (*-) and H2 O2 ) accumulated in injured tissues but dissipated during recovery, paralleled by the repression and restoration, respectively, of activities of antioxidant enzymes, superoxide dismutase (SOD) (EC. 1.14.1.1), and catalase (CAT) (EC.1.11.1.6) and ascorbate peroxidase (APX) (EC.1.11.1.11). Restoration of CAT and APX activities during recovery was slower than SOD, concomitant with a slower depletion of H2 O2 compared to O2 (*-) . A hypothesis was also tested that the REC is accompanied by changes in the expression of water channels [aquaporines (AQPs)] likely needed for re-absorption of thawed extracellular water. Indeed, the expression of two spinach AQPs, SoPIP2;1 and SodeltaTIP, was downregulated in injured tissues and restored during recovery. Additionally, a notion that molecular chaperones [heat shock protein of 70 kDa (HSP70s)] and putative membrane stabilizers [dehydrins (DHNs)] are recruited during recovery to restore cellular homeostasis was also tested. We noted that, after an initial repression in injured tissues, the expression of three HSP70s (cytosolic, endoplasmic reticulum and mitochondrial) and a spinach DHN (CAP85) was significantly restored during the REC. PMID- 23981078 TI - Effect of social networks and well-being on acute care needs. AB - The effect of social surroundings has been noted as an important component of the well-being of elderly people. A strong social network and strong and steady relationships are necessary for coping when illness or functional limitations occur in later life. Vulnerability can affect well-being and functioning particularly when sudden life changes occur. The objective of this study was to analyse how the determinants of social well-being affect individual acute care needs when sudden life changes occur. Empirical evidence was collected using a cross-sectional mail survey in Finland in January 2011 among individuals aged 55 79 years. The age-stratified random sample covered 3000 individuals, and the eventual response rate was 56% (1680). Complete responses were received from 1282 respondents (42.7%). The study focuses on the compactness of social networks, social disability, the stability of social relationships and the fear of loneliness as well as how these factors influence acute care needs. The measurement was based on a latent factor structure, and the key concepts were measured using two ordinal items. The results of the structural model suggest that the need for care is directly affected by social disability and the fear of loneliness. In addition, social disability is a determinant of the fear of loneliness and therefore plays an important role if sudden life changes occur. The compactness of social networks decreases social disability and partly diminishes the fear of loneliness and therefore has an indirect effect on the need for care. The stability of social relationships was influenced by the social networks and disability, but was an insignificant predictor of care needs. To conclude, social networks and well-being can decrease care needs, and supportive actions should be targeted to avoid loneliness and social isolation so that the informal network could be applied as an aspect of care-giving when acute life changes occur. PMID- 23981079 TI - Relevance of ineffective esophageal motility to secondary peristalsis in patients with gastroesophageal reflux disease. AB - BACKGROUND AND AIMS: The study aimed to investigate the hypothesis whether the presence of Ineffective esophageal motility would affect physiological characteristics of secondary peristalsis. METHODS: Secondary peristalsis was performed with slow and rapid air injections into mid-esophagus of 18 ineffective esophageal motility patients and 15 age-matched controls. Severity of ineffective esophageal motility was defined by the application of combined multichannel intraluminal impedance and manometry. RESULTS: Ineffective esophageal motility patients included 11 patients without impedance abnormality and seven patients with impedance abnormality during liquid and/or viscous swallowing. The prevalence of failed secondary peristaltic response during slow air injection was significantly greater in ineffective esophageal motility patients without impedance abnormality (3/11 [27%], P < 0.001) and with impedance abnormality (4/7 [57%], P = 0.04) than healthy subjects. The threshold volume for inducing secondary peristalsis during rapid air injection was significantly greater in ineffective esophageal motility patients with impedance abnormality (6.1 +/- 0.3 mL) than healthy subjects (4.6 +/- 0.3 mL, P < 0.05) and ineffective esophageal motility patients without impedance abnormality (4.1 +/- 0.4 mL, P < 0.05). The frequency of peristaltic response during rapid air injection was significantly lower in ineffective esophageal motility patients with impedance abnormality (40% [20-50%] than healthy subjects (90% [90-100%], P < 0.05). CONCLUSIONS: Defective activation of secondary peristalsis is present in ineffective esophageal motility patients with impedance abnormality. Our study indicates that increased ineffective esophageal motility severity associated with defective triggering of secondary peristalsis may contribute to impaired esophageal clearance in patients with gastroesophageal reflux disease. PMID- 23981080 TI - Novel facial cosmetic area 'O zone' shows unique characteristics in sebum excretion and acne lesion distribution. AB - BACKGROUND: We usually divided cosmetic facial zone into the T zone and U zone by the level of sebum secretion. Our recent studies suggested that the perioral area showed different characteristics in the aspect of acne development. OBJECTIVE: To investigate the unique characteristics of the O zone (perioral area) among the three facial areas. METHODS: A total of 102 patients clinically diagnosed as acne vulgaris were included. The acne lesions were counted from the clinical digital photographs by facial areas. The sebum level was measured using Sebumeter((r)) . Area-weighted (AW) sebum and AW density of three areas of face were calculated. Statistical analysis was performed according to age and gender. RESULTS: There were no differences in the mean AW sebum level between the gender and age groups. Male has higher AW density of acne lesions than female at the O zone. The mean AW density of acne lesions on the NT zone, U zone, and whole face showed decrease by age, but at the O zone, 21-30 years group showed the highest mean AW density of acne. LIMITATIONS: Age- and gender-matched patients do not represent the whole acne patients. CONCLUSION: We suggested that the O zone is an independent facial zone, which showed a moderate-to-high sebum secreting area, maintained the acne lesions development by age, and predominated acne lesions in the male acne patients than female acne patients. Therefore, the O zone should be separated from the usual cosmetic T zone, and NT zone should replace the old T zone. PMID- 23981081 TI - The role of vascular epithelial growth factor receptor-tyrosine kinase inhibitors in the treatment of advanced breast cancer: a meta-analysis of 12 randomized controlled trials. AB - AIM: To perform a systematic review and meta-analysis of randomized controlled trials to determine the efficacy and toxicity of approved vascular epithelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in advanced breast cancer. METHODS: A comprehensive literature search for studies published up to August 2013 was performed. The endpoints were overall survival (OS), progression free survival (PFS), overall response rate (ORR) and grade 3 or 4 adverse event (AEs). The pooled hazard ratio (HR) or relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: Twelve randomized controlled trials involved 3256 patients were ultimately identified. The intention to treatment (ITT) analysis demonstrated that VEGFR-TKI therapy significantly improved ORR (RR 1.14, 95% CI: 1.03-1.28, p = 0.016), but it did not translate into benefits in PFS (HR 0.99, 95% CI: 0.81-1.22, p = 0.93) and OS (HR 1.11, 95% CI 0.99-1.24, p = 0.084) when compared to non-VEGFR-TKI therapy. Additionally, a higher incidence of grade 3 or 4 anemia, neutropenia, thrombocytopenia, diarrhea, hand-foot syndrome and fatigue was observed in VEGFR TKI-based therapy. CONCLUSIONS: The VEGFR-TKI-based therapy offered a significant improvement in ORR in patients with advanced breast cancer but did not benefit PFS and OS. With present available data from randomized clinical trials, we were still unable to clearly set the role of VEGFR-TKIs in the treatment of metastatic breast cancer (MBC). PMID- 23981083 TI - Erectile dysfunction and asymptomatic coronary artery disease: frequently detected by computed tomography coronary angiography but not by exercise electrocardiography. AB - AIMS: Erectile dysfunction (ED) and vascular disease, in particular coronary artery disease (CAD), have the common denominator of endothelial dysfunction. ED frequently precedes a CAD event by between 2 and 5 years (average 3 years). ED also predicts an acute coronary syndrome as well as increased mortality, suggesting the rupture of an asymptomatic coronary plaque. This study compares multi-detector cardiac computed tomography (MDCT) with maximal treadmill exercising in men with ED and no coronary symptoms as a means of detecting coronary lesions. METHODS: Sixty-five men with organic ED and no cardiac symptoms were prospectively screened for CAD. All underwent maximal exercise testing and MDCT in the same 7-day period. The Sexual Health Inventory for Men questionnaire established the presence of ED. FINDINGS: The exercise ECG was borderline abnormal in three men and normal in 62. CT calcium was present in 53 (score 5 1671) and non-calcified plaque in seven. The MDCT angiogram was normal in only 5 (3.25%). CONCLUSION: Erectile dysfunction may predict CAD in the absence of cardiac symptoms. MDCT detects subclinical plaque which may be vulnerable to rupture and which is not flow limiting enough to influence the exercise ECG. The window of 2-5 years between ED and a CAD event offers an opportunity for aggressive risk factor reduction. ED should be a routine question in any risk calculator. PMID- 23981084 TI - Effect of Metal Extension of Crown in the Screw Access Channel of a Posterior Implant Abutment on the Retention of Cement Retained Prosthesis. AB - PURPOSE: Reducing the height of the implant abutment due to limited interarch space decreases the surface area for retention of cemented restorations. The purpose of this in vitro study was to see whether engaging the screw access channel with metal extension compensates for the loss of retention of posterior crowns cemented on shorter abutments. MATERIAL AND METHODS: Four identical prefabricated abutments were mounted on implant replicas embedded in acrylic resin blocks. Three of these abutments were reduced in height by 1 mm, 2 mm, and 3 mm respectively and one was left unmodified. Two sets of base metal crowns were fabricated for each abutment, one without and one with the metal extension inside the screw access channel. The crowns were cemented using Tempbond NE. The tensile forces required to separate the cemented crowns from abutments were measured using an Instron testing machine. Statistical analysis of the data was performed using a 2-way analysis of variance and Fisher's protected least significant difference at 0.05 level of significance. RESULTS: An increase of 24% to 261% in retentive forces was observed for the group having metal extension in the screw access channel. Statistically significant differences (P < .001) were found among 2 types of crowns and four heights of abutments. Generally, the retentive forces were reduced in magnitude as the abutment height was reduced. CONCLUSION: The retention of a casting cemented to posterior implant abutments is influenced by the height of the abutment and the metal extension engaging the screw access channel. The crowns made with a metal extension showed superior retention values. PMID- 23981082 TI - Genetics of platelet inhibitor treatment. AB - Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is the standard of care in patients undergoing percutaneous coronary intervention (PCI) and in patients with acute coronary syndromes (ACS) because this regimen has markedly decreased the rate of cardiovascular events. The substantial variability in pharmacodynamic response as well as the moderate antiplatelet efficacy of clopidogrel has raised major concerns, since high on-clopidogrel platelet reactivity has consistently been associated with increased risk for ischaemic events in PCI patients. Baseline demographic and clinical variables contributing to the observed variability have been identified. Besides this, research within the past decade has focused on the impact of genetic polymorphisms encoding transport systems or enzymes involved in the absorption and metabolism of these drugs. Loss-of-function polymorphisms in CYP2C19 are the strongest individual variables affecting pharmacokinetics and antiplatelet response to clopidogrel, but explain no more than 5 to 12% of the variability in adenosine diphosphate induced platelet aggregation on clopidogrel. No genetic variables contributing to clinical outcomes of patients treated with the newer P2Y12 receptor antagonists, prasugrel or ticagrelor, have been identified so far. This review aims to provide an update on the current status of genotype-based personalized therapy with clopidogrel. PMID- 23981085 TI - One-dimensional carbon-sulfur composite fibers for Na-S rechargeable batteries operating at room temperature. AB - Na-S batteries are one type of molten salt battery and have been used to support stationary energy storage systems for several decades. Despite their successful applications based on long cycle lives and low cost of raw materials, Na-S cells require high temperatures above 300 degrees C for their operations, limiting their propagation into a wide range of applications. Herein, we demonstrate that Na-S cells with solid state active materials can perform well even at room temperature when sulfur-containing carbon composites generated from a simple thermal reaction were used as sulfur positive electrodes. Furthermore, this structure turned out to be robust during repeated (de)sodiation for ~500 cycles and enabled extraordinarily high rate performance when one-dimensional morphology is adopted using scalable electrospinning processes. The current study suggests that solid-state Na-S cells with appropriate atomic configurations of sulfur active materials could cover diverse battery applications where cost of raw materials is critical. PMID- 23981087 TI - Free-amine directed arylation of biaryl-2-amines with aryl iodides by palladium catalysis. AB - A new palladium-catalyzed free-amine directed arylation of C(sp(2))-H bonds in the presence of AgOAc and TFA is described. Biaryl-2-amines react with various aryl iodides to give the corresponding mono- or diarylated products with exclusive regioselectivity. PMID- 23981086 TI - What is the origin of the arterial vascularization of the corpora cavernosa? A computer-assisted anatomic dissection study. AB - The purpose of this study was to identify the microscopic arterial vascularization of the corpora cavernosa (CC) of the penis using computer assisted anatomic dissection (CAAD), determine the contribution of the different penile arteries towards this vascularization, detail the nature of cavernospongiosum shunts, and locate the anastomoses between these different arteries. Tissue specimens were taken from five donors who donated their bodies to science. The specimens were fixed in 10% formalin and sliced into a series of five 5-MUm sections at intervals of 200 MUm. The first section was stained with hematoxylin-eosin or Masson's trichrome and the second with anti-protein S100. The cavernous artery of the penis is not the only source of arterial vascularization of the CC. In four of the five cases studied, we found two to four perforating branches arising from the dorsal arteries of the penis that join up with the cavernous artery of the penis or that are solely responsible for the vascularization of the distal third of the penis. The bulbo-urethral and urethral arteries are situated outside of the tunica albuginea of the corpus spongiosum on their lateral and dorsal sides. The anastomoses do not occur between the cavernous artery of the penis and the corpus spongiosum but between the cavernous artery of the penis and the urethral artery on the surface of the tunica albuginea. All of these arteries are accompanied by nerve branches. The CC were found to be vascularized by both cavernous and dorsal arteries of the penis. Intrapenile vascularization is organized around four arterial axes, which are anastomosed by multiple neurovascular shunts. PMID- 23981088 TI - Synthesis, resolution, and biological evaluation of atropisomeric (aR)- and (aS) 16-methyllamellarins N: unique effects of the axial chirality on the selectivity of protein kinases inhibition. AB - The total synthesis of the optically active (aR)- and (aS)-16-methyllamellarins N (3a and 3b) was achieved via resolution on HPLC chiral stationary phase. The kinase inhibitory activities of both enantiomers were evaluated on eight protein kinases relevant to cancer and neurodegenerative diseases (CDK1/cyclin B, CDK2/cyclin A, CDK5/p25, GSK-3alpha/beta, PIM1, DYRK1A, CLK3, and CK1). Isomer (aR)-3b exhibited potent but nonselective inhibition on all protein kinases except CK1, while (aS)-3a selectively inhibited only GSK-3alpha/beta, PIM1, and DYRK1A. The different inhibition profiles of (aS)-3a and (aR)-3b were elucidated by docking simulation studies. Although parental lamellarin N (2) inhibited the action of topoisomerase I, both (aS)-3a and (aR)-3b showed no inhibition of this enzyme. The phenotypic cytotoxic activities of 2, (aS)-3a, and (aR)-3b on three cancer cell lines (HeLa, SH-SY5Y, and IMR32) changed according to their topoisomerase I and protein kinase inhibitory activities. PMID- 23981089 TI - Facile and selective synthesis of oligothiophene-based sensitizer isomers: an approach toward efficient dye-sensitized solar cells. AB - Two sets of isomeric organic dyes with n-hexyl (DH and AH) or 2-ethylhexyl (DEH and AEH) groups substituted at the spacer part have been designed and straightforwardly synthesized via a facile and selective synthetic route. The structure difference between the isomers stands at the position of the incorporated alkyl chains which are introduced into the terthiophene spacer close to the donor (D) or anchor (A) side. The relationship between the isomeric structures and the optoelectronic properties are systematically investigated. It is found that, in the D series dyes, the alkyl group is much closer to the aromatic donor moiety, which brings about strong steric hindrance and therefore causes a remarkable twist in the molecular skeleton. In contrast, a more planar chemical structure and more effective pi-conjugation are realized in the A series dye isomers. Consequently, the A series isomeric dyes demonstrate bathochromically shifted absorption bands, resulting in the improved light harvesting capability and enhanced photo-generated current. However, the D series isomeric dyes with more twisted molecular skeleton have suppressed the intermolecular interactions and retarded the charge recombination more efficiently, which induces higher open-circuit photovoltage. Combining the two effects on the performance of the fabricated dye-sensitized solar cells (DSSC), the influence from the short-circuit photocurrent plays a more significant role on the power conversion efficiency (eta). As a result, isomer AEH-based DSSC with quasi-solid-state electrolyte displays the highest eta of 7.10% which remained at 98% of the initial value after continuous light soaking for 1000 h. Promisingly, a eta of 8.66% has been achieved for AEH-based DSSC with liquid electrolyte containing Co(II)/(III) redox couple. This work presents the crucial issue of molecular engineering and paves a way to design organic sensitizers for highly efficient and stable DSSCs. PMID- 23981095 TI - Systematic review: the efficacy of herbal therapy in inflammatory bowel disease. AB - BACKGROUND: Complementary and alternative medicine (CAM), particularly herbal therapy, is widely used by patients with inflammatory bowel disease (IBD) but controlled data are limited. AIM: To systematically review the literature on the efficacy of herbal therapy in the treatment of ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Publications in English and non-English literatures (MEDLINE, EMBASE, EBM Reviews, AMED, Global Health) were searched from 1947 to 2013 for controlled clinical studies of herbal therapy in IBD. Outcome measures included response and remission rates. RESULTS: Twenty-one randomised controlled trials (14 UC; 7 CD) including a total of 1484 subjects (mean age 41, 50% female) were analysed. In UC, aloe vera gel, Triticum aestivum (wheat grass juice), Andrographis paniculata extract (HMPL-004) and topical Xilei san were superior to placebo in inducing remission or response, and curcumin was superior to placebo in maintaining remission; Boswellia serrata gum resin and Plantago ovata seeds were as effective as mesalazine, whereas Oenothera biennis (evening primrose oil) had similar relapse rates as omega-3 fatty acids in the treatment of UC. In CD, Artemisia absinthium (wormwood) and Tripterygium wilfordii were superior to placebo in inducing remission, and preventing clinical recurrence of post-operative CD respectively. CONCLUSIONS: Randomised controlled trials of herbal therapy for the treatment of IBD show encouraging results but studies remain limited and heterogenous. Larger controlled studies with stricter endpoints and better-defined patient groups are required to obtain more conclusive results on the use of CAM therapies in IBD. PMID- 23981096 TI - Impact of dry weight determined by calf bioimpedance ratio on carotid stiffness and left ventricular hypertrophy in hemodialysis patients. AB - Our previous study has shown that modification of bioimpedance technique by the measurement of bioimpedance ratio in the calf (calf-BR) was a simple and practical method in assessing fluid status in hemodialysis patients. However, the consequences of periodical dry weight (DW) adjustment under the guidance of calf BR on target organ damage have not been investigated. One hundred fifteen hemodialysis patients were enrolled in this pilot trial. Patients were divided into bioimpedance group and control group according to their dialysis schedule. In the bioimpedance group, DW was routinely adjusted under the guidance of calf BR every 3 months. In the control group, the assessment of DW remained a clinical judgment. Carotid stiffness, left ventricular mass index (LVMI), and calf-BR were measured at baseline and at the 12th month in both groups. Home blood pressure (BP) was monitored monthly. Episodes of dialysis-related adverse events were recorded. No significant differences were observed in parameters between the two groups at baseline. Compared with the control group, the bioimpedance group had significantly lower values in terms of the annual averages of systolic home BP (147.4 +/- 15.3 mm Hg vs. 152.6 +/- 16.9 mm Hg, P = 0.019), carotid stiffness index beta (10.7 +/- 3.3 vs. 12.2 +/- 3.1, P = 0.003), LVMI (155.21 +/- 15.64 g/m(2) vs. 165.17 +/- 16.76 g/m(2) , P < 0.001), and the percentage of individuals with calf-BR over target range (P = 0.040) at month 12, with less annual averages of antihypertensive medications used and lower frequency of intradialytic hypotension, muscle cramps, or clotted angioaccess. Continued DW control achieved by periodical calf-BR measurement improved arterial stiffness and left ventricular hypertrophy with good tolerability in hemodialysis patients. PMID- 23981098 TI - Canine transmissible venereal tumour: a review. AB - Canine transmissible venereal tumour (CTVT) is a contagious venereal tumour of dogs, commonly observed in dogs that are in close contact with one another, or in stray and wild dogs that exhibit unrestrained sexual activity. CTVT represents a unique, naturally transmissible, contagious tumour, where the mutated tumour cell itself is the causative agent and perpetuates as a parasitic allograft in the host. Clinical history, signalment and cytological features are often obvious for establishing a diagnosis though biopsy and histological examination may be needed in atypical cases. Most cases are curable with three intravenous injections of vincristine sulphate at weekly intervals. The role of stray and wild dogs makes the disease difficult to control and necessitates sustained animal birth control in stray dogs along with prompt therapy of the affected dogs. This review captures the manifold developments in different areas embracing this fascinating tumour, including its biology, diagnosis and therapeutic alternatives. PMID- 23981099 TI - Patients' lay expertise in chronic self-care: a case study in type 1 diabetes. AB - BACKGROUND: The impact of chronic diseases in our society is growing. The idea of self-care generates understandable enthusiasm and is seen as a natural answer. It is important to develop an understanding of self-care practices that goes beyond a clinical understanding of the disease and that acknowledges everyday practicalities, and the perspective of the patient. OBJECTIVE: To shed light on some of the practicalities of everyday chronic self-care, to expose to analysis the key role of lay expertise and to stress the importance of its recognition in future chronic care practices and technology. DESIGN: Ethnomethodological investigations based on observations of a patient support group (10 months) and some shadowing sessions of everyday practices, semi-structured interviews with individuals with type 1 diabetes (n = 14) and professional caregivers (n = 7). ANALYSIS: The qualitative data analysis was inspired by grounded theory and aimed at ordering data under emerging categories and topics. RESULTS: The patient's knowledge and expertise is critical to grounding, integrating and complementing technical-medical/clinical knowledge in everyday chronic self-care. To deal with the intricacies and difficulties of everyday chronic self-care, individuals with type 1 diabetes develop different ways of knowing and dealing with the disease that need to be equally taken into account in the reorganization of care delivery, and in the design of the tools to support it. CONCLUSION: Rethinking the traditional separation between hard and soft data may be a possible first step towards rethinking the role of lay expertise in chronic care towards better supports for self-care practices and patient empowerment. PMID- 23981100 TI - The Trojan Horse of the microbiological arms race: phage-encoded toxins as a defence against eukaryotic predators. AB - Phage-encoded Shiga toxin (Stx) acts as a bacterial defence against the eukaryotic predator Tetrahymena. To function as an effective bacterial anti predator defence, Stx must kill a broad spectrum of predators. Consistent with that assertion, we show here that bacterially encoded Stx efficiently kills the bacteriovore Acanthamoeba castellanii in co-culture. We also show that, in addition to Stx, the phage-encoded exotoxin, diphtheria toxin (Dtx) expressed by Corynebacterium diphtheriae also can function as part of an anti-predator strategy; it kills Acanthamoeba in co-culture. Interestingly, only exotoxins produced by bacteria internalized by the Acanthamoeba predator are cytolethal; the presence of purified Dtx or Stx in culture medium has no effect on predator viability. This finding is consistent with our results indicating that intoxication of Acanthamoeba by these exotoxins does not require a receptor. Thus bacteria, in the disguise of a food source, function as a 'Trojan Horse', carrying genes encoding an exotoxin into target organisms. This 'Trojan Horse' mechanism of exotoxin delivery into predator cells allows intoxication of predators that lack a cell surface receptor for the particular toxin, allowing bacteria-bearing exotoxins to kill a broader spectrum of predators, increasing the fitness of the otherwise 'defenceless' prey bacteria. PMID- 23981101 TI - Mechanistic insight into the formation of acetic acid from the direct conversion of methane and carbon dioxide on zinc-modified H-ZSM-5 zeolite. AB - Methane and carbon dioxide are known greenhouse gases, and the conversion of these two C1-building blocks into useful fuels and chemicals is a subject of great importance. By solid-state NMR spectroscopy, we found that methane and carbon dioxide can be co-converted on a zinc-modified H-ZSM-5 zeolite (denoted as Zn/H-ZSM-5) to form acetic acid at a low temperature range of 523-773 K. Solid state (13)C and (1)H MAS NMR investigation indicates that the unique nature of the bifunctional Zn/H-ZSM-5 catalyst is responsible for this highly selective transformation. The zinc sites efficiently activate CH4 to form zinc methyl species (-Zn-CH3), the Zn-C bond of which is further subject to the CO2 insertion to produce surface acetate species (-Zn-OOCCH3). Moreover, the Bronsted acid sites play an important role for the final formation of acetic acid by the proton transfer to the surface acetate species. The results disclosed herein may offer the new possibility for the efficient activation and selective transformation of methane at low temperatures through the co-conversion strategy. Also, the mechanistic understanding of this process will help to the rational design of robust catalytic systems for the practical conversion of greenhouse gases into useful chemicals. PMID- 23981103 TI - Multicomponent reactions involving arynes, quinolines, and aldehydes. AB - The multicomponent reaction involving arynes, quinolines, and aldehydes leading to the diastereoselective synthesis of benzoxazino quinoline derivatives in good yields proceeding via 1,4-zwitterionic intermediates is reported. In addition, the synthetic potential of various carbonyl compounds in this reaction as well as the utility of isoquinoline as the nucleophilic trigger has been examined. PMID- 23981102 TI - Diagnosis, pathogenesis and treatment of myositis: recent advances. AB - Dermatomyositis (DM), polymyositis (PM), necrotizing myopathy (NM) and inclusion body myositis (IBM) are four distinct subtypes of idiopathic inflammatory myopathies - in short myositis. Recent studies have shed some light on the unique pathogenesis of each entity. Some of the clinical features are distinct, but muscle biopsy is indispensable for making a reliable diagnosis. The use of magnetic resonance imaging of skeletal muscles and detection of myositis-specific autoantibodies have become useful additions to our diagnostic repertoire. Only few controlled trials are available to substantiate current treatment approaches for myositis and hopes are high that novel modalities will become available within the next few years. In this review we provide an up-to-date overview of the pathogenesis and diagnostic approach of myositis. We aim to present a guide towards therapeutic and general management. PMID- 23981104 TI - Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. AB - OBJECTIVES: We investigated whether metformin can improve endothelial function and decrease inflammatory activity, and thereby decrease the risk of atherothrombotic disease. SUBJECTS AND DESIGN: A randomized, placebo-controlled trial with a follow-up period of 4.3 years set in the outpatient clinics of three nonacademic hospitals (Hoogeveen, Meppel and Coevorden Hospitals, the Netherlands). A total of 390 patients with type 2 diabetes treated with insulin were included. Either metformin 850 mg or placebo (one to three times daily) was added to insulin therapy. Urinary albumin excretion and plasma levels of von Willebrand factor (vWf), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured at baseline and after 4, 17, 30, 43 and 52 months. RESULTS: Metformin significantly reduced levels of vWF, sVCAM-1, t PA, PAI-1, CRP and sICAM-1, which, except for CRP, remained significant after adjustment for baseline differences in age, sex, smoking and severity of previous cardiovascular (CV) disease. No effects on urinary albumin excretion or sE selectin were observed. The improvements in vWf and sVCAM-1 statistically explained about 34% of the reduction in the risk of CV morbidity and mortality associated with metformin treatment in this study. CONCLUSIONS: Metformin is associated with improvement in some (vWF and sVCAM-1) but not all markers of endothelial function, which may explain why it is associated with a decreased risk of CV disease in type 2 diabetes. PMID- 23981106 TI - A pooled analysis of exenatide use and risk of acute pancreatitis. AB - OBJECTIVE: To estimate the association between exenatide BID use and acute pancreatitis across two claims-based studies. RESEARCH DESIGN AND METHODS: We pooled two cohort studies within separate commercial health insurance databases. We included initiators of exenatide BID and all other antihyperglycemic drugs without prior pancreatitis from 2005-2008. Poisson regression models provided rate ratios (RRs) and 95% confidence intervals (CIs) of the association of exenatide BID with acute pancreatitis adjusted for quintiles of propensity scores. MAIN OUTCOME MEASURES: Primary inpatient diagnoses of acute pancreatitis with correction for misclassification via a validation sub-study. RESULTS: There were 49,956 initiators of exenatide BID and 692,333 initiators of other antihyperglycemic drugs. Patients in the two studies were similar on many demographic and clinical characteristics. Exenatide BID initiators had a higher prevalence of diagnoses consistent with diabetes complications (e.g. peripheral neuropathy) and cardiovascular risk factors (e.g. hypertension). In both studies, current exenatide BID use was not associated with uncorrected outcomes of acute pancreatitis (pooled RR 1.0; CI 0.8-1.3). PPV correction resulted in a slightly higher point estimate for current use (pooled RR 1.3; CI 1.0-1.7) and past use (pooled RR 1.6; 95% CI 1.2-2.1). CONCLUSIONS: These data are consistent with little or no higher risk of acute pancreatitis associated with current exenatide BID use relative to nonuse. Although previous work identified non-causal mechanisms, an increased incidence of acute pancreatitis following cessation of treatment remains a possibility. Bias due to residual confounding or outcome misclassification may remain, and should be considered a potential explanation for these findings. PMID- 23981107 TI - Real-time, non-invasive microscopic confirmation of clinical diagnosis of bullous pemphigoid using in vivo reflectance confocal microscopy. AB - BACKGROUND: Bullous pemphigoid is an autoimmune disease affecting prevalently the elder. In vivo reflectance confocal microscopy is a non-invasive technique for real-time imaging of the skin with cellular-level resolution. No previous data has been reported about confocal microscopy of bullous pemphigoid. Aim of this preliminary study is the evaluation of the potential of in vivo reflectance confocal microscopy for real-time, microscopical confirmation of clinical bullous pemphigoid diagnosis. METHODS: A total of nine lesions from patients affected by pemphigoid underwent in vivo reflectance confocal microscopy before histological examination. RESULTS: In our preliminary study, confocal microscopy showed high grade of correspondence to histopathology. In particular, presence of sub epidermal cleft and variable amount of oedema of the upper dermis associated with inflammatory cells infiltration were seen as prevalent confocal features in the bullous lesions considered. Differently, in urticarial lesions, no specific features could be appreciated at confocal analysis beside the presence of signs of spongiosis and perivascular inflammation. CONCLUSION: Confocal microscopy seems to be useful for in vivo, microscopical confirmation of the clinical suspect of bullous pemphigoid and for biopsy site selection in urticarial lesions to obtain a more significant specimen for histopathological examination. PMID- 23981108 TI - Solid solution, phase separation, and cathodoluminescence of GaP-ZnS nanostructures. AB - Quaternary solid-solution nanowires made of GaP and ZnS have been synthesized through well-designed synthetic routines. The as-synthesized GaP-ZnS solid solution nanowires exhibit decent crystallinity with the GaP phase as the host, while a large amount of twin structural defects are observed in ZnS-rich nanowires. Cathodoluminescence studies showed that GaP-rich solid-solution nanowires have a strong visible emission centered at 600 nm and the ZnS-rich solid-solution nanowires exhibited a weak emission peak in the UV range and a broad band in the range 400-600 nm. The formation mechanism, processes, and optical emissions of GaP-ZnS solid-solution nanowires were discussed in detail. PMID- 23981105 TI - Peptic ulcer disease: one in five is related to neither Helicobacter pylori nor aspirin/NSAID intake. AB - BACKGROUND: The proportion (and even the reality) of peptic ulcer disease (PUD) not related to H. pylori or NSAID/aspirin is debated. AIM: To analyse the current epidemiological and clinical characteristics of peptic ulcer disease in French general hospitals. METHODS: Prospective multicentre study of patients with peptic ulcer disease in 32 French general hospitals over 1 year. H. pylori status was assessed by histology, and/or serology and/or C13-urea breath test. NSAID/aspirin intake (obtained by direct interview) and data about concomitant diseases were collected on the day of endoscopy. RESULTS: Nine hundred and thirty-three patients were selected during the year 2009. After exclusion of 118 patients with only erosive duodenitis, 24 with major missing data, 13 with other causes of ulcer and 65 negative for H. pylori by only one test, 713 patients were classified into four groups: 285 (40.0%) had only H. pylori infection; 133 (18.7%) only gastrotoxic drugs; 141 (19.8%) had both and 154 (21.6%) neither H. pylori infection nor gastrotoxic drug intake ('idiopathic ulcers'). Patients with idiopathic ulcers differed in many ways both from H. pylori and NSAID/aspirin groups. However, multivariate analysis identified only three independent predictors: age, French metropolitan origin and the presence of comorbidities. CONCLUSION: In a general hospital-based population in France, peptic ulcer disease appears idiopathic in a fifth of cases. PMID- 23981110 TI - Hydrolase treatments help unravel the function of intervessel pits in xylem hydraulics. AB - Intervessel pits are structures that play a key role in the efficiency and safety functions of xylem hydraulics. However, little is known about the components of the pit membrane (PM) and their role in hydraulic functions, especially in resistance to cavitation. We tested the effect of commercial chemicals including a cellulase, a hemicellulase, a pectolyase, a proteinase and DTT on xylem hydraulic properties: vulnerability to cavitation (VC) and conductance. The effects were tested on branch segments from Fagus sylvatica (where the effects on pit structure were analyzed using TEM) and Populus tremula. Cellulose hydrolysis resulted in a sharp increase in VC and a significant increase in conductance, related to complete breakdown of the PM. Pectin hydrolysis also induced a sharp increase in VC but with no effect on conductance or pit structure observable by TEM. The other treatments with hemicellulase, proteinase or DTT showed no effect. This study brings evidence that cellulose and pectins are critical components underpinning VC, and that PM components may play distinct roles in the xylem hydraulic safety and efficiency. PMID- 23981111 TI - Teaching Goldilocks to supervise: not too much, not too little, but just right. PMID- 23981112 TI - 'But I do believe you've got to accept that that's what life's about': older adults living in New Zealand talk about their experiences of loss and bereavement support. AB - This paper explores older people's views, experiences and sources of bereavement support following the death of a spouse, family member or other significant individual. Telephone interviews were conducted with 28 bereaved older adults recruited from the Brief Risk Identification Geriatric Health Tool trial participants in three geographically diverse District Health Boards in New Zealand. Analysis adhered to the principles of grounded theory and followed the National Centre for Social Research 'Framework' approach. Findings indicate that family and friends play a fundamental role supporting older bereaved adults, both emotionally and practically. Existing community-based organisations were identified as an important source of support following bereavement. Despite the emotional, financial and practical challenges associated with bereavement, the majority of participants questioned the role of, need for and value of formal bereavement support services. Instead, study participants cited a combination of being older and previous life experiences as factors that had enabled them to cope with these largely 'expected' events. Moreover, they demonstrated considerable resilience in managing the emotional and practical changes associated with loss and bereavement. This study poses a challenge to the argument that the growing secularisation of society has led to an increase in the use of professional bereavement services over more 'traditional' forms of support, such as family, friends and community and religious organisations. The paper highlights the value of adopting a public health-based approach as a way of optimising bereavement support via the use of existing community organisations previously known to older people. This is particularly important in those countries where the provision of bereavement support is limited due to resource constraints. PMID- 23981113 TI - Mechanical control of electroresistive switching. AB - Hysteretic metal-insulator transitions (MIT) mediated by ionic dynamics or ferroic phase transitions underpin emergent applications for nonvolatile memories and logic devices. The vast majority of applications and studies have explored the MIT coupled to the electric field or temperarture. Here, we argue that MIT coupled to ionic dynamics should be controlled by mechanical stimuli, the behavior we refer to as the piezochemical effect. We verify this effect experimentally and demonstrate that it allows both studying materials physics and enabling novel data storage technologies with mechanical writing and current based readout. PMID- 23981114 TI - Refractory heart failure dependent on short-term mechanical circulatory support: what next? Heart transplant or long-term ventricular assist device. AB - Chronic heart failure is a progressive and eventually fatal illness. Although the disease cannot be cured and treatment is symptom oriented, most of the patients benefit from optimum medical treatment. Patients with rapid deterioration in chronic advanced heart failure refractory to medical treatment need inotropic support and may need intra-aortic balloon pump to maintain circulatory support, which of course cannot be prolonged beyond a certain limit. The outcome of heart transplant and long-term ventricular assist device (VAD) in such patients is poor. The short-term mechanical circulatory support (MCS) offered to such patients not only provides effective circulatory support and stabilizes them hemodynamically, but also halts the ensuing or reverts the established end-organ failure. As the name suggests, the short-term MCS offers support for the short term, usually less than a month. Although some patients with acute heart failure experience recovery of myocardial function with short-term MCS support, others become dependent. These patients, stabilized and "stuck" with short-term MCS, can be "rescued" with long-term VAD or heart transplantation. Both the procedures, when done in this special situation, have their inherent advantages, disadvantages, and complications and hence need the careful consideration about the choice of the procedure. We have tried to elucidate this situation by considering the advantages and disadvantages of both options. PMID- 23981115 TI - Incidence and relative risk of hepatic toxicity in patients treated with anti angiogenic tyrosine kinase inhibitors for malignancy. AB - AIM: The aim of this study is to investigate the incidence and risk of hepatic toxicity in patients receiving tyrosine kinase inhibitors (TKIs) through a large up-to-date meta-analysis of available clinical trials. METHODS: PubMed was reviewed for phase III randomized trials with axitinib, pazopanib, sorafenib, sunitinib, regorafenib or vandetanib. The characteristics of each study and incidence of all and high grades of ALT, AST and total bilirubin increase were collected. RESULTS: A total of 3691 patients was available for meta-analysis, 1170 had metastatic renal cell carcinoma; 950 had advanced non-small cell lung carcinoma, 454 had hepatocarcinoma, 753 had metastatic colorectal cancer and 362 had metastatic soft-tissue sarcoma. The incidence of ALT, AST and bilirubin increase of any grade in patients treated with TKIs was 34.0% (95% CI 31.6, 36.3), 39.2% (95% CI 36.7, 41.6) and 21.8% (95% CI 19.9, 23.7), respectively. The incidence of the high grade increase was 5.2% (95% CI 4.2, 6.4), 5.0% (95% CI, 3.8, 6.2) and 1.7% (95% CI 1.1, 2.4), respectively. The relative risk of ALT, AST and total bilirubin increase was 1.85, 2.19 and 1.79 for any grade and 2.75, 2.39 and 1.65 for high grade, respectively. CONCLUSIONS: Hepatotoxicity is a relative common event occurring in 23-40% of patients treated with TKIs. Despite this, only 5% of patients have had high grade of toxicity. A better knowledge of this phenomenon may prevent high grade toxicity and reduce treatment discontinuation due to this adverse event. PMID- 23981116 TI - Vinorelbine rescue therapy for dogs with primary urinary bladder carcinoma. AB - The goal of this study was to evaluate the anti-tumour activity and toxicoses of vinorelbine as a palliative rescue therapy for dogs with primary urinary bladder carcinoma. Thirteen dogs refractory to prior chemotherapeutics and one dog naive to chemotherapeutic treatment were enrolled. Vinorelbine (15 mg m(-2) IV) was administered intravenously along with concurrent oral anti-inflammatory drugs, if tolerated. A median of six doses of vinorelbine (range: 1-16) was administered. Two dogs (14%) had partial responses, and eight (57%) experienced stable disease. Subjective improvement in clinical signs was noted in 11 dogs (78%). Adverse events were mild and primarily haematological in nature. Median time to progression was 93 days (range: 20-239 days). Median survival time for all dogs was 187 days; median survival for 13 pre-treated dogs was 207 days. Vinorelbine may have utility in the management of canine primary urinary bladder carcinoma and should be evaluated in a prospective study. PMID- 23981118 TI - Recent progress in understanding activity cliffs and their utility in medicinal chemistry. AB - The activity cliff concept is of high relevance for medicinal chemistry. Recent studies are discussed that have further refined our understanding of activity cliffs and suggested different ways of exploiting activity cliff information. These include alternative approaches to define and classify activity cliffs in two and three dimensions, data mining investigations to systematically detect all possible activity cliffs, the introduction of computational methods to predict activity cliffs, and studies designed to explore activity cliff progression in medicinal chemistry. The discussion of these studies is complemented with new findings revealing the frequency of activity cliff formation when different molecular representations are used and the distribution of activity cliffs across different targets. Taken together, the results have a number of implications for the practice of medicinal chemistry. PMID- 23981117 TI - Attenuation of bone morphogenetic protein signaling during amphibian limb development results in the generation of stage-specific defects. AB - The vertebrate limb is one of the most intensively studied organs in the field of developmental biology. Limb development in tetrapod vertebrates is highly conserved and dependent on the interaction of several important molecular pathways. The bone morphogenetic protein (BMP) signaling cascade is one of these pathways and has been shown to be crucial for several aspects of limb development. Here, we have used a Xenopus laevis transgenic line, in which expression of the inhibitor Noggin is under the control of the heat-shock promoter hsp70 to examine the effects of attenuation of BMP signaling at different stages of limb development. Remarkably different phenotypes were produced at different stages, illustrating the varied roles of BMP in development of the limb. Very early limb buds appeared to be refractory to the effects of BMP attenuation, developing normally in most cases. Ectopic limbs were produced by overexpression of Noggin corresponding to a brief window of limb development at about stage 49/50, as recently described by Christen et al. (2012). Attenuation of BMP signaling in stage 51 or 52 tadpoles lead to a reduction in the number of digits formed, resulting in hypodactyly or ectrodactyly, as well as occasional defects in the more proximal tibia-fibula. Finally, inhibition at stage 54 (paddle stage) led to the formation of dramatically shortened digits resulting from loss of distal phalanges. Transcriptome analysis has revealed the possibility that more Noggin-sensitive members of the BMP family could be involved in limb development than previously suspected. Our analysis demonstrates the usefulness of heat-shock-driven gene expression as an effective method for inhibiting a developmental pathway at different times during limb development. PMID- 23981119 TI - Differential endosomal pathways for radically modified peptide vectors. AB - In the current work we characterize the uptake mechanism of two NickFect family members, NF51 and NF1, related to the biological activity of transfected plasmid DNA (pDNA). Both vectors condense pDNA into small negatively charged nanoparticles that transfect HeLa cells with equally high efficacy and the delivery is mediated by SCARA3 and SCARA5 receptors. NF1 condenses DNA into less homogeneous and less stable nanoparticles than NF51. NF51/pDNA nanoparticles enter the cells via macropinocytosis, while NF1/pDNA complexes use clathrin- or caveolae-mediated endocytosis and macropinocytosis. Analysis of separated endosomal compartments uncovered lysomotropic properties of NF51 that was also proven by cotransfection with chloroquine. In summary we characterize how radical modifications in peptides, such as introducing a kink in the structure of NF51 or including extra negative charge by phospho-tyrosine substitution in NF1, resulted in equally high efficacy for gene delivery, although this efficacy is achieved by using differential transfection pathways. PMID- 23981120 TI - Does diverticular disease protect against sigmoid colon cancer? PMID- 23981121 TI - Increased whole blood viscosity associated with arterial stiffness in patients with non-alcoholic fatty liver disease. AB - BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor for increased cardiovascular disease. The brachial-ankle pulse wave velocity (baPWV) is a marker for early atherosclerotic changes. Recently, the effect of changed blood rheology on atherosclerosis has received attention. A study confirmed that whole blood viscosity (WBV) is a predictor of cardiovascular events. Therefore, this study aimed to investigate the association of WBV with baPWV in patients with NAFLD. METHODS: In this cross-sectional study, the relationship between WBV and baPWV was investigated in 2032 participants (1035 men and 997 women) with NAFLD in a general health examination. RESULTS: Different metabolic parameters were compared across WBV (3/s) quartiles. The mean values of baPWV gradually increased with WBV (3/s) quartiles. Stepwise multiple linear regression analysis revealed that WBV (3/s) is a significant determinant for increased baPWV both in men and in women (for male, beta = 0.229; P < 0.001; for female, beta = 0.672; P < 0.001). CONCLUSIONS: The findings showed that baPWV elevated as WBV (3/s) increased in NAFLD. Moreover, WBV (3/s) is independently associated with baPWV even after adjusting other cardiovascular risk factors. Early detection of abnormal WBV levels at low shear rate should warrant for early search of undetected arterial stiffness in patients with NAFLD. PMID- 23981122 TI - The relationship of urotensin II with insulin resistance and hs-CRP in patients having PCOS. AB - UrotensinII (UII), one of the most potent vasoconstrictor proteins, may be associated with insulin resistance. The objective of our research was to determine the level of UII in sera of patients with PCOS and to investigate the relationship between UII and insulin resistance in patients with PCOS. Fourty seven PCOS patients and 42 healthy women were included in the study. Serum fasting glucose, insulin, UII, free testosterone and hs-CRP levels of the patients were examined. The HOMA-IR formula was used to calculate insulin resistance. Insulin sensitivity was calculated by using the QUICKI-IS formula. The two groups did not show any a significant difference in terms of age and BMI (p > 0.05). Serum UII, hs-CRP, insulin levels and the HOMA-IR were significantly higher in the patients with PCOS (p < 0.05). In the analysis of the correlation, UII and HOMA-IR showed statistically significant, moderately strong and positive correlation(r = 044, p < 0.001). UII and QUICKI-IS showed statistically significant, moderately strong and negative correlation(r = -0.44, p < 0.001). Also, a significant and positive correlation was found between with UII and hs CRP(r = 0.51, p < 0.001). Our study data suggested that UII may have a role in the pathophysiology of insulin resistance and increased cardiovascular risk, which are commonly found in patients with PCOS. PMID- 23981123 TI - Liver transplantation for acute liver failure caused by macrophage activation syndrome. AB - Macrophage activation syndrome (MAS) is a rare, potentially fatal condition, which most frequently complicates rheumatological conditions and is often associated with liver dysfunction. In this case report of a patient with MAS, acute liver failure developed despite conventional immunosuppressive therapy. Liver transplantation resulted in rapid recovery and the patient has remained well for six years. A recent diagnosis of Adult Onset Still's Disease (AOSD) provides additional supporting evidence that the initial presentation was caused by MAS. While transplantation in the context of systemic disease remains controversial, this first reported case of successful adult liver transplantation for acute liver failure caused by MAS raises an interesting clinical dilemma. PMID- 23981124 TI - Autophagy impairment aggravates the inhibitory effects of high glucose on osteoblast viability and function. AB - Autophagy is a highly regulated homoeostatic process involved in the lysosomal degradation of damaged cell organelles and proteins. This process is considered an important pro-survival mechanism under diverse stress conditions. A diabetic milieu is known to hamper osteoblast viability and function. In the present study, we explored the putative protective role of autophagy in osteoblastic cells exposed to an HG (high glucose) medium. HG was found to increase protein oxidation and triggered autophagy by a mechanism dependent on reactive oxygen species overproduction in osteoblastic MC3T3-E1 cells. MC3T3-E1 cell survival was impaired by HG and worsened by chemical or genetic inhibition of autophagy. These findings were mimicked by H2O2-induced oxidative stress in these cells. Autophagy impairment led to both defective mitochondrial morphology and decreased bioenergetic machinery and inhibited further osteoblast differentiation in MC3T3 E1 cells upon exposure to HG. These novel findings indicate that autophagy is an essential mechanism to maintain osteoblast viability and function in an HG environment. PMID- 23981125 TI - Synthesis and photoinduced electron transfer studies of a tri(phenothiazine) subphthalocyanine-fullerene pentad. AB - A novel donor-acceptor pentad featuring subphthalocyanine and fullerene as the primary electron donor and acceptor, and three phenothiazine entities as secondary hole transferring agents, have been newly synthesized and characterized as an photosynthetic reaction center model compound. Occurrences of ultrafast photoinduced electron transfer (PET) and slower charge recombination are witnessed in the pentad from the femtosecond and nanosecond transient absorption studies. PMID- 23981126 TI - Fibroblast growth factor 19 in patients with bile acid diarrhoea: a prospective comparison of FGF19 serum assay and SeHCAT retention. AB - BACKGROUND: Bile acid diarrhoea is a common, under-diagnosed cause of chronic watery diarrhoea, responding to specific treatment with bile acid sequestrants. We previously showed patients with bile acid diarrhoea have lower median levels compared with healthy controls, of the ileal hormone fibroblast growth factor 19 (FGF19), which regulates bile acid synthesis. AIM: To measure serum FGF19 and SeHCAT retention prospectively in patients with chronic diarrhoea. METHODS: One hundred and fifty-two consecutive patients were grouped according to (75) Se homocholic acid taurine (SeHCAT) 7-day retention: normal (>15%) in 72 (47%) diarrhoea controls; <=15% in 54 (36%) with primary bile acid diarrhoea, and in 26 (17%) with secondary bile acid diarrhoea. Fasting blood was assayed for FGF19, 7alpha-hydroxy-4-cholesten-3-one (C4) and total bile acids. RESULTS: FGF19 was significantly lower in the primary bile acid diarrhoea group compared with the diarrhoea control group (median 147 vs. 225 pg/mL, P < 0.001), and also in the secondary group (P < 0.006). FGF19 and SeHCAT values were positively correlated (rs = 0.44, P < 0.001); both were inversely related to C4. Other significant relationships included SeHCAT and body mass index (BMI)(P = 0.02), and FGF19 with age (P < 0.01). The negative and positive predictive values of FGF19 <= 145 pg/mL for a SeHCAT <10% were 82% and 61%, respectively, and were generally improved in an index including BMI, age and C4. In a subset of 28 primary patients, limited data suggested that FGF19 could predict response to sequestrant therapy. CONCLUSIONS: Reduced fibroblast growth factor 19 is a feature of bile acid diarrhoea. Further studies will fully define its role in predicting the response of these patients to therapy. PMID- 23981130 TI - Molecular conformations of crystalline L-cysteine determined with vibrational cross angle measurements. AB - The molecular conformations of crystalline L-cysteine prepared in its orthorhombic form were determined by the vibrational cross angle measurements. Its major dihedral angles of chemical bonds determined by this method are consistent with the results from diffraction experiments. In addition, the relative orientations of the chemical bonds associated with the hydrogen atoms of the NH3(+) group and the thiol group are also determined. The results demonstrate that the vibrational cross angle method based on the multiple-mode approach can potentially become a structural tool for determining molecular conformations. The major challenges for the method to become a general molecular structural tool are discussed, and some approaches to address them are proposed. PMID- 23981131 TI - Comparison of hemolysis between CentriMag and RotaFlow rotary blood pumps during extracorporeal membrane oxygenation. AB - The purpose of this investigation was to compare the hemolysis levels for patients on extracorporeal membrane oxygenation (ECMO) incorporating two different rotary blood pumps (CentriMag [CMAG] and RotaFlow [RF]) in identical circuits otherwise. The difference between the two pumps is the cost. One is 20 30 times less expensive than the other. A retrospective analysis of all patients placed on ECMO from June 2008 through May 2012 was done to evaluate hemolysis. Daily plasma hemoglobin (pHb), lactate dehydrogenase (LDH), and lactate levels were collected on all patients. Values were compared between those patients who received a CMAG and those who received an RF. Patients had to be on ECMO for more than 2 days to be included in the study. Linear mixed effects models were fit to the data to assess differences over time for each continuous outcome. Forty patients were placed on ECMO incorporating CMAG, whereas 40 patients received an RF. There were no significant statistical differences between CMAG and RF groups when comparing days on support (8.7 +/- 5.0; 8.4 +/- 5.7), age (44.8 +/- 18.3; 46.1 +/- 16.0), body surface area (2.03 +/- 0.36; 1.96 +/- 0.31), gender (male: 58%, female: 42%; male: 55%, female: 45%), etiology, type of support (veno arterial [VA)]: 78%, veno-venous [VV)]: 22%; VA: 82%, VV: 18%) and pre-ECMO LDH levels (4004.0 +/- 3583.2; 3603.7 +/- 3354.1). There were also no significant differences between the CMAG and RF groups when comparing the mean values for daily pHb levels (5.7 +/- 3.6; 5.7 +/- 4.2), lactate levels (2.8 +/- 1.9; 3.0 +/- 2.1), and LDH levels (2656.3 +/- 1606.8; 2688.6 +/- 1726.1) or daily lactate, LDH, and pHb levels for the first 10 days of support. From our investigation, there is no difference between the CMAG and the RF blood pumps in regard to the creation of hemolysis during ECMO. The difference in cost of the devices does not correlate with the performance and outcomes. PMID- 23981132 TI - Job rotation and internal marketing for increased job satisfaction and organisational commitment in hospital nursing staff. AB - AIM: To develop or enhance the job satisfaction and organisational commitment of nurses by implementing job rotation and internal marketing practices. BACKGROUND: No studies in the nursing management literature have addressed the integrated relationships among job rotation, internal marketing, job satisfaction and organisational commitment. METHOD: This cross-sectional study included 266 registered nurses (response rate 81.8%) in two southern Taiwan hospitals. Software used for data analysis were SPSS 14.0 and AMOS 14.0 (structural equation modelling). RESULTS: Job rotation and internal marketing positively affect the job satisfaction and organisational commitment of nurses, and their job satisfaction positively affects their organisational commitment. CONCLUSION: Job rotation and internal marketing are effective strategies for improving nursing workforce utilisation in health-care organisations because they help to achieve the ultimate goals of increasing the job satisfaction of nurses and encouraging them to continue working in the field. This in turn limits the vicious cycle of high turnover and low morale in organisations, which wastes valuable human resources. IMPLICATIONS FOR NURSING MANAGEMENT: Job rotation and internal marketing help nursing personnel acquire knowledge, skills and insights while simultaneously improving their job satisfaction and organisational commitment. PMID- 23981133 TI - Establishing entrustment of residents and autonomy. AB - As residents, we constantly strive to independently manage our patients and develop care plans, while the role of the attending faculty varies between complete supervision and control, to allowing complete autonomy. This concept of attending physicians allowing appropriate autonomy so that residents can develop independence in their practice has been termed entrustment. Patients' and instructors' entrustment of responsibility reflects upon one's preparedness to assume professional responsibility after graduation. Over the past several months, we have been reflecting on our experiences working in the emergency department and how different faculty members entrust residents during each shift. Some experiences have been incredible as we develop our styles of practice, while others have been incredibly frustrating and soured the learning environment. As third-year residents, we studied the factors that allow faculty to foster an appropriate amount of entrustment and conducted discussions with multiple residents on this topic. We have found several themes of how this can be done well and share these ideas with a goal of improving autonomy for emergency medicine residents. PMID- 23981134 TI - Bioreduction of aryl azides during mutasynthesis of new ansamitocins. AB - Supplementing a culture of a mutant strain of Actinosynnema pretiosum that is unable to biosynthesize aminohydroxy benzoic acid (AHBA), with 3-azido-5-hydroxy benzoic acid and 3-azido-5-amino-benzoic acid, unexpectedly yielded anilino ansamitocins instead of the expected azido derivatives. This is the first example of the bioreduction of organic azides. The unique nature of these results was demonstrated when 3-azido-5-amino-benzoic acid was fed to the corresponding AHBA blocked mutant of Streptomyces hygroscopicus, the geldanamycin producer. This mutasynthetic experiment yielded the fully processed azido derivative of geldanamycin. PMID- 23981135 TI - A historical perspective on the discovery of the Kell blood group carriers. PMID- 23981136 TI - Solution processed ZnO hybrid nanocomposite with tailored work function for improved electron transport layer in organic photovoltaic devices. AB - We demonstrate improved organic photovoltaic device performance using solution processed electron transport layers of ZnO nanoparticle (NP) films containing organic additives, poly(vinylpyrrolidone) (PVP), or diethanolamine (DEA), that do not require post processing after film deposition. Inclusion of PVP or DEA decreased the ZnO work function by 0.4 eV through interfacial dipole formation. While PVP did not change the ZnO NP shape or size, DEA modified the ZnO shape from 5 nm * 15 nm nanorods to 5 nm nanoparticles. At an optimized PVP concentration of 0.7 wt %, ZnO NP:PVP electron transport layers (ETLs) improved the efficiency of inverted P3HT:PCBM devices by 37%, primarily through higher fill factor. ZnO NP:PVP and ZnO NP:DEA ETLs increased the open circuit voltage of inverted P3HT:ICBA devices by 0.07 V due to decreasing ETL work function, leading to enhanced built-in field. The relationship between ZnO nanocomposite ETL work function, donor-acceptor energy offset, and device performance is discussed. The effects of the two additives are compared. PMID- 23981137 TI - 3D reconstruction of skin pathological tissue: the understanding of microrelief pattern and dermal ridge. AB - AIM: Most studies about the structures of the human skin have been on the general histologic features of the skin. The purpose of this study was to understand the relationship between the microrelief (MR) pattern and histologic structure of the human skin, and to find the usefulness of the three-dimensional reconstruction (3DR) technique of pathological skin tissue. MATERIALS, SUBJECTS, AND METHODS: Human skin specimens were obtained from the medial forearm, abdomen, and volar aspects of the finger tips of cadavers. Two-dimensional surface-viewed images of the skin showing MR patterns were obtained using dry dermoscopy. Histologic structures of the skin were evaluated by 3D images obtained using the 3DR technique. RESULTS: MR was deeper and wider in the abdomen than in the medial side of the forearm. In the medial side of the forearm, 10.27 rete ridges were distributed in a plateau, on average. In the abdomen, about 14.37 rete ridges were distributed in a plateau. From 3DR technique, MR pattern thought to be a superordinate concept to rete ridges. CONCLUSION: The 3DR technique was useful and may allow a better understanding of the pathogenetic changes in the skin surface in aging skin. PMID- 23981138 TI - Immunolocalization of melatonin and follicle-stimulating hormone receptors in caprine ovaries and their effects during in vitro development of isolated pre antral follicles. AB - The expression of melatonin type 1 (MT1) and FSH (FSHR) receptors in caprine ovaries and the effects of these hormones on the in vitro development of isolated pre-antral follicles were evaluated. Follicles (<=200 MUm) were cultured for 12 days in alpha-MEM (control) or melatonin (100 or 1000 pg/ml) or sequential melatonin medium (100 pg/ml: from day 0 to day 6; 1000 pg/ml: from day 6 to day 12; experiment 1) and in control or sequential FSH (100 ng/ml from day 0 to day 6; 500 ng/ml from day 6 to day 12) or sequential melatonin or this latter plus sequential FSH (experiment 2). MT1 and FSHR expressions were observed in granulosa cells from secondary and antral follicles. The oocytes from primordial and primary follicles also express FSHR. Sequential melatonin increased the percentage of normal follicles and oocyte recovery compared with the control or melatonin (1000 pg/ml) at day 12. In experiment 2, all the treatments increased the normal follicles and growth compared with the control. In conclusion, this study demonstrated the presence of MT1 and FSHR in caprine ovaries. The addition of increased concentrations of melatonin (sequential medium) or FSH can be used to promote the in vitro development of caprine pre-antral follicles. PMID- 23981140 TI - Long-term outcome of the anal fistula plug for anal fistula of cryptoglandular origin. AB - AIM: This study aimed to evaluate the long-term outcome of the anal fistula plug in the treatment of anal fistula of cryptoglandular origin. METHOD: A review of all patients who had at least one anal fistula plug inserted from March 2007 to August 2008 was performed. Only anal fistulae of cryptoglandular origin were included. Success was defined as the closure of the external opening with no further purulent discharge or collection. RESULTS: Thirty anal fistula plugs were inserted in 26 patients [median age 40 (26-70) years]. Twenty-six of the fistulae were transsphincteric and three were suprasphincteric. One patient had a high intersphincteric fistula, which was the only fistula that did not have a seton inserted. The median duration between seton insertion and the plug procedure was 12 (4-28) weeks. The median length of the fistula tract was 3 (1-7.5) cm. After a median follow-up of 59 (13-97) weeks, 26 (86.7%) fistulae recurred. Of the 26 failures, the median time to failure was 8 (2-54) weeks. Subsequent surgical interventions were performed in 20 of the failures. CONCLUSION: The role of the fistula plug in the management of anal fistula of cryptoglandular origin remains debatable and warrants further evaluation. PMID- 23981142 TI - Abstracts of the 10th Asia Pacific Medical Education Conference (APMEC). Singapore. January 16-20, 2013. PMID- 23981139 TI - Physiological regulation in infants of women with a mood disorder: examining associations with maternal symptoms and stress. AB - BACKGROUND: The offspring of mothers with mood disorders may evidence increased behavioral problems as early as preschool; however, no study to date has examined psychophysiological characteristics during infancy, particularly among offspring of mothers diagnosed with bipolar disorder. Elucidating psychobiological mechanisms of risk early in development is critical to inform prevention and early intervention efforts. METHOD: This study compared physiological and behavioral responsivity in 6-month-old infants (N = 329) of mothers with lifetime histories of bipolar disorder (BD, n = 44), major depressive disorder (MDD, n = 244), or no history of Axis I disorders (CTL, n = 41). Infant respiratory sinus arrhythmia (RSA) was measured in a laboratory stressor paradigm. Measures of infant affect and behavior during mother-infant interaction, current maternal depressive symptoms, and exposure to stressful life events were examined with respect to diagnostic group and RSA. RESULTS: Groups did not differ in baseline RSA or infant affect measures. However, during the stressor task, infants of mothers with BD evidenced increases in RSA, while infants of MDD and CTL mothers evidenced decreases in RSA. Though levels of postnatal stress and current levels of maternal depressive symptoms differed among groups, neither of these factors predicted infant psychophysiological responses. CONCLUSIONS: At 6 months of age, infants of mothers with BD show differences in psychophysiological regulation. These differences cannot be accounted for by perinatal outcome, current maternal depressive symptoms, or exposure to stressful life events, and thus may reflect endophenotypic markers of psychopathological risk. PMID- 23981141 TI - Clinical features and predictors of clinical outcomes in Korean patients with Crohn's disease: a Korean association for the study of intestinal diseases multicenter study. AB - BACKGROUND AND AIM: Although differences in genetic susceptibility and the clinical features of Crohn's disease (CD) have been reported between Asian and Caucasian patients, the disease course and predictors of CD in Asians remains poorly defined. The study therefore aimed to investigate factors predictive of the clinical outcomes of patients with CD in a Korean population. METHODS: This retrospective multicenter cohort study included 728 Korean CD patients from 13 university hospitals. The first CD-related surgery or need for immunosuppressive or biological agents were regarded as the clinical outcomes of interest. RESULTS: A total of 126 (17.3%) CD patients underwent CD-related surgery, while 473 (65.0%) and 196 (26.9%) were prescribed thiopurine drugs and infliximab, respectively. Multivariate Cox regression analysis identified current (hazard ratio [HR] = 1.86; P = 0.018) and former smoking habits (HR = 1.78; P = 0.049), stricturing (HR = 2.24; P < 0.001), and penetrating disease behavior at diagnosis (HR = 3.07; P < 0.001) as independent predictors associated with the first CD related surgery. With respect to immunosuppressive and biological agents, younger age (< 40 years) (HR = 2.17; P < 0.001 and HR = 2.10; P = 0.006, respectively), ileal involvement (HR = 1.36; P = 0.035 and HR = 2.17; P = 0.006, respectively), and perianal disease (HR = 1.42; P = 0.001 and HR = 1.38; P = 0.038, respectively) at diagnosis were significant predictors for the need of these medications. CONCLUSIONS: In Korean patients with CD, stricturing, penetrating disease behavior, and smoking habits at the time of diagnosis are independent predictors for CD-related surgery. It was also identified that younger age (< 40 years), ileal involvement, and perianal disease at diagnosis are predictive of a need for immunosuppressive or biological agents. PMID- 23981145 TI - Structuring the collaboration of science and service in pursuit of a shared vision. AB - The enduring needs of our society highlight the importance of a shared vision to improve human functioning and yield better lives for families and communities. Science offers a powerful strategy for managing the inevitable uncertainty in pursuit of these goals. This article presents ideas and examples of methods that could preserve the strengths of the two major paradigms in children's mental health, evidence-based treatments and individualized care models, but that also have the potential to extend their applicability and impact. As exemplified in some of the articles throughout this issue, new models to connect science and service will likely emerge from novel consideration of better ways to structure and inform collaboration within mental health systems. We contend that the future models for effective systems will involve increased attention to (a) client and provider developmental pathways, (b) explicit frameworks for coordinating people and the knowledge and other resources they use, and (c) a balance of evidence based planning and informed adaptation. We encourage the diverse community of scientists, providers, and administrators in our field to come together to enhance our collective wisdom through consideration of and reflection on these concepts and their illustrations. PMID- 23981144 TI - Selective inhibitors of bacterial t-RNA-(N(1)G37) methyltransferase (TrmD) that demonstrate novel ordering of the lid domain. AB - The tRNA-(N(1)G37) methyltransferase (TrmD) is essential for growth and highly conserved in both Gram-positive and Gram-negative bacterial pathogens. Additionally, TrmD is very distinct from its human orthologue TRM5 and thus is a suitable target for the design of novel antibacterials. Screening of a collection of compound fragments using Haemophilus influenzae TrmD identified inhibitory, fused thieno-pyrimidones that were competitive with S-adenosylmethionine (SAM), the physiological methyl donor substrate. Guided by X-ray cocrystal structures, fragment 1 was elaborated into a nanomolar inhibitor of a broad range of Gram negative TrmD isozymes. These compounds demonstrated no activity against representative human SAM utilizing enzymes, PRMT1 and SET7/9. This is the first report of selective, nanomolar inhibitors of TrmD with demonstrated ability to order the TrmD lid in the absence of tRNA. PMID- 23981146 TI - Influenza A(H1N1)pdm09 vaccine effectiveness and other characteristics associated with hospitalization in chronic liver disease patients. AB - BACKGROUND & AIMS: To date, few studies have investigated the clinical effectiveness of influenza vaccine in chronic liver disease patients. The aim of this study was to examine the effectiveness of monovalent inactivated influenza A(H1N1)pdm09 vaccine and other characteristics associated with hospitalization in patients with chronic hepatitis C. METHODS: We conducted a hospital-based cohort study during influenza A(H1N1)pdm09 pandemic. A total of 408 patients (132 vaccinated, 276 unvaccinated) with detectable HCV-RNA were followed up with respect to any hospitalization using a weekly postal questionnaire. Reported hospitalizations were verified by medical records. RESULTS: During the epidemic period, 28 hospitalizations (6 vaccinated, 22 unvaccinated) were observed. After adjustment for potential confounders, vaccination decreased the odds ratio (OR) for hospitalization with marginal significance (OR = 0.43, 95%CI = 0.16-1.17). Besides, positive association with hospitalization was observed in patients with albumin levels <3.5 g/dl (OR = 8.40, 3.66-19.3) and steroid users (OR = 5.58, 0.98-31.7). CONCLUSIONS: Among patients with chronic hepatitis C, A(H1N1)pdm09 vaccine appeared to have a protective effect against hospitalization. Those patients with a higher risk for hospitalization should be carefully followed during the influenza season, even when vaccinated. PMID- 23981147 TI - Prevalence of problematic mobile phone use in British adolescents. AB - The problematic use of mobile phones among adolescents has not been widely studied. There are very few instruments for assessing potential technological addiction to mobile phones, or for categorizing different types of users or uses. The most widely used scale is the Mobile Phone Problem Use Scale (MPPUS), which is used to study adult populations, and has been applied in various forms in international contexts. The aims of this study were to adapt the Spanish version of this scale (MPPUSA) to British adolescents, and then to estimate the prevalence of possible problematic users. A questionnaire was administered to a sample of 1,529 secondary school pupils aged between 11 and 18 years, with 1,026 completed questionnaires being collected. The analysis showed that the factor and construct validity and reliability were comparable to those obtained in previous studies. The prevalence of problematic users among the students was 10%, and the typical problematic user tended to be an adolescent between 11 and 14 years old, studying in a public school, who considered themselves to be an expert user of this technology, who made extensive use of his/her mobile phone, and who attributed the same problem of use among their peers. These users presented notable scores in all the symptoms covered by the scale used to assess problematic use. In conclusion, the adaptation of the MPPUSA as a screening scale for British adolescents presents good sensitivity and specificity for detecting the main addictive symptoms proposed in this validated version. PMID- 23981148 TI - The effects of virtual experience on attitudes toward real brands. AB - Although the commercial availability and implementation of virtual reality interfaces has seen rapid growth in recent years, little research has been conducted on the potential for virtual reality to affect consumer behavior. One unaddressed issue is how our real world attitudes are affected when we have a virtual experience with the target of those attitudes. This study compared participant (N=60) attitudes toward car brands before and after a virtual test drive of those cars was provided. Results indicated that attitudes toward test brands changed after experience with virtual representations of those brands. Furthermore, manipulation of the quality of this experience (in this case modification of driving difficulty) was reflected in the direction of attitude change. We discuss these results in the context of the associative-propositional evaluation model. PMID- 23981149 TI - Estimation of CYP2D6*10 genotypes on citalopram disposition in Chinese subjects by population pharmacokinetic assay. AB - WHAT IS KNOWN AND OBJECTIVE: There is great interindividual variability in citalopram (CIT) pharmacokinetics. We attempted to establish a population pharmacokinetic (PPK) model of CIT in Chinese healthy subjects, to evaluate the effect of genetic polymorphism on CIT pharmacokinetics and to compare the PPK and non-compartmental (NCA) assays in the estimation of CIT bioequivalence. METHODS: Blood samples of 23 healthy subjects were collected after administration of CIT; plasma concentration of CIT was analysed using LC/MS-MS. CYP2C19 and CYP2D6*10 genotypes were determined. PPK model was established by using nonlinear mixed effect modelling (NONMEM). The model was evaluated using goodness-of-fit plots and relative error measurements. Bioequivalence of CIT was evaluated by both PPK and NCA method. RESULTS AND DISCUSSION: The estimated population absorption rate constant (ka ), clearance (CL/F) and volume of distribution (Vd/F) in Chinese healthy subjects are 0.64 L/h, 12.7 L/h and 705 L, respectively. Different CYP2C19 and CYP2D6 genotypes have impacts on CIT pharmacokinetics. There is about 5.5% decrement of CL/F for each CYP2C19*2 or CYP2D6*10 allele. The 90% confidence interval of CIT bioavailability obtained from NCA and PPK model were 96.4-105.4% and 92.5-103.4%, respectively. WHAT IS NEW AND CONCLUSION: The PPK of CIT is best characterized by a one-compartment disposition model with first-order absorption. CYP2C19 and CYP2D6 genotypes have impacts on the CL/F of CIT. Bioequivalence of CIT can be estimated by both NCA and PPK model. PMID- 23981150 TI - Correlation of P53 and granzyme B expression in oral squamous cell carcinoma with clinicopathologic findings. AB - BACKGROUND: The present study aimed to evaluate the correlation of P53 and granzyme B (GB) expression, and also the relationship between P53 expression and GB+ cell density with lymph node metastasis, histologic grade, and inflammation intensity in oral squamous cell carcinoma (OSCC). METHODS: Immunohistochemical technique with P53 and GB antibodies were performed on stored paraffin blocks from 48 patients with OSCC (with lymph node metastasis n = 24; without lymph node metastasis n = 24). The density of GB expression was quantified both in invasive front (peritumoral ) and within cancer nests (intratumoral ). RESULTS: P53 positivity was seen in 13 (54.16%) cases of the nonmetastatic group and 14 cases (58.3%) in the metastatic group. A significant correlation was seen between P53 immunoexpression and histologic grade (P = 0.047), but there was no significant correlation between P53 expression with lymph node metastasis and inflammation intensity. The density of GB+ cells in the peritumoral zone correlates with a higher intratumoral GB expression (P = 0.001) and was significantly higher in the nonmetastatic group (P = 0.029). No significant correlation between GB and P53 immunoexpression, lymph node metastasis, or inflammation intensity was seen. CONCLUSION: The present study showed that the presence of a higher density of GB+ cells infiltrating the peritumoral area may have an important role against tumoral cells, prevent lymph node metastasis, and better prognosis in OSCC patients. PMID- 23981151 TI - Clinical application of amniotic membrane as a biologic dressing in oral cavity and pharyngeal defects after tumor resection. AB - BACKGROUND: Oropharyngeal malignancies represent management challenges for the head and neck surgeons. Tumor resection and reconstruction with graft is the standard treatment. Split-thickness skin grafts are routinely used to cover the mucosal defects arising from resections. As amniotic membrane (AM) is used as a dressing substitute in burn, we decided to evaluate the efficacy of AM as a biologic wound dressing material for surgical defects of mucosa in the oropharyngeal region. METHODS: This was a single- institution prospective study which included 50 patients with primary oropharyngeal malignancy who underwent tumor resection between March 2010 and November 2011, and were up for two to 20 months after the surgical procedure. We used amniotic membrane (AM) for dressing of the defects in the oral cavity and pharynx under general anesthesia. Efficacy of this procedure was assessed by rating of the pain and granulation tissue formation with surface epithelialization at the site of graft. RESULTS: The results were evaluated in the postoperative period. Forty males (80 %) and 10 females (20%) were participated, age from 20 to 80 years with a mean age of 50 +/ 10.41 years. The patients underwent partial glossectomy, or floor of mouth resection according to tumor location. Complete adherence of AM to the wound was detected in all cases. Allergy either systemic or local was not reported in any of the cases. The membrane was very effective in 40 patients, and effective in 10 cases. CONCLUSION: Amniotic membrane (AM) can be used as a biologic dressing material for covering the mucosal defects in the oropharynx. PMID- 23981152 TI - Retinopathy of prematurity: incidence, risk factors, and outcome. AB - BACKGROUND: This study was planned to determine the rate, the predisposing factors, and the outcome of retinopathy of prematurity (ROP) in very low birth weight (VLBW) infants hospitalized in the neonatal intensive care unit (NICU) of a tertiary care hospital in Tehran. METHODS: All VLBW neonates admitted to the NICU, from April 2007 through March 2010 were enrolled. All relevant perinatal data, including the hospital course up to the time of discharge were documented. Repeated ophthalmologic examinations were done by a single ophthalmologist to observe the progression and subsequent resolution of ROP. RESULTS: Out of 414 infants undergoing ophthalmologic examination, ROP was detected in 71 infants (17.14 %); 3.4 % stage I, 8.7 % stage II, and 5.1 % stage III. ROP stages IV or V were not detected. After adjustment for different variables, the following independent risk factors were identified: VLBW (P = 0.002, OR = 4.89), multiple gestation (P = 0.001, R = 3.51), resuscitation at birth (P = 0.003, OR = 3), blood transfusion more than 45 mL/kg (P = 0.02, OR = 4.91), oxygen therapy for more than five days (P = 0.009, OR = 3.11), and age more than 10 days to regain birth weight (P = 0.008, OR = 1.06).Thirty-three patients with stages II and III ROP were treated with laser therapy, all of them improved and none progressed to blindness. CONCLUSION: Our findings identify the major risk factors for ROP; skillful management of high-risk pregnancies, prevention of preterm births, appropriate neonatal care, high index of suspicion, routine screening, and prompt treatment are crucial to prevent the development and progression of ROP. PMID- 23981153 TI - Psychiatric comorbidities in ADHD children: an Iranian study among primary school students. AB - BACKGROUND: This study was performed to determine the lifetime prevalence of psychiatric disorders concomitant with attention deficit/hyperactivity disorder (ADHD) among primary school students. METHODS: One thousand six hundred fifty eight primary school students (781 females and 877 males) were selected in a cluster random manner in 2010. The first screening was performed by the Conner's teacher rating scale revised and Teacher ADHD rating scale-IV and then the students, in whom the ADHD was diagnosed by a child and adolescent psychiatrist according to DSM-IV-TR, were evaluated by K-SADS-PL semi-structured interview to detect the psychiatric comorbidities. RESULTS: The prevalence of psychiatric comorbidities in ADHD subjects was 62.5%. Oppositional defiant disorder (29.4%), specific phobia (21.9%), and enuresis (17.5%) were the most common comorbidities. The most common comorbidities in ADHD-IA (inattentive type) (n = 29) were specific phobia (34.5%), oppositional defiant disorder (20.7%), chronic motor tic disorder (17.2%), and enuresis (17.2%). The most common comorbidities in ADHD-HI (hyperactive/impulsive type) (n = 15) were chronic motor tic disorder (33.3%), oppositional defiant disorder (26.7%), and specific phobia (26.7%). The most common comorbidities in ADHD-C (combined type) (n = 116) were oppositional defiant (31.9%), enuresis (19%), and specific phobia (18.1%). The frequency of chronic vocal tic disorder was higher in ADHD-HI compared with ADHD-C (P = 0.01). CONCLUSION: The results of this study indicated that the frequency of other psychiatric comorbidities in primary school students with ADHD is high that may affect disease course and treatment. Hence, evaluation for other comorbidities in ADHD patients should be considered. PMID- 23981154 TI - Genital warts in 250 Iranian patients and their high- risk sexual behaviors. AB - BACKGROUND AND OBJECTIVE: Genital wart is the most common sexually transmitted disease worldwide. Sexual risk factors and sexual behavior pattern may be different in various countries. In this study, we tried to evaluate demographic information and some sexual behaviors and risk factors in Iranian patients with genital warts. METHODS: In this cross-sectional study, 250 patients with anogenital warts were evaluated. They had been referred to the Sexually Transmitted Diseases Clinic of Razi Hospital. Demographic information and sexual risk factors and pattern of sexual behaviors were recorded in the questionnaires. RESULTS: One hundred twenty-five men and 125 women with genital warts were evaluated. The most common age group was 20- 30 years old; 24.8% were single; 29.6% had academic education; 35 (14%) of the patients had started sexual activity before 15 years of age; 92% reported unsafe sex; seven (2.8%) of them were HIV infected; two cases (0.8%) were homosexual; and seven cases (2.8%) were bisexual. Genital herpes simplex type 2 was the most common coincident sexually transmitted disease (6.4%). CONCLUSION: Genital wart in men may be as common as women, married and singles, and mostly involves younger people. Sexual high-risk behaviors and unsafe sex make them at risk for HIV infection. Sexual health education should be considered in high-risk groups. PMID- 23981155 TI - Elevated nitric oxide metabolites are associated with obesity in women. AB - BACKGROUND: Nitric oxide (NO) plays a role in almost every biologic system including regulation of energy balance and food intake. This study aimed at determining association between serum nitric oxide metabolite (NOx) levels and obesity in a population-based study. METHODS: In a cross-sectional study, NOx levels were measured in 3505 adult participants. Pregnant women and those with diabetes, renal dysfunction, chronic diarrhea, and hospitalization within the past three months, subjects using antihypertensive medications or aspirin, and those with missing data were excluded. Finally, 2445 subjects (1004 men and 1441 women) were included. RESULTS: Women with body mass index (BMI) > 30 kg/m2 compared to those with BMI < 25 kg/m2, had significantly higher serum NOx concentrations after multivariable adjustment (B = 5.24, P = 0.002). In addition, there was a significant trend of increasing serum NOx concentrations in categories of BMI in women. Women with a waist circumference (WC) >= 90 cm had significantly higher serum NOx concentration even after multivariate adjustment. Women with waist-to-hip ratio (WHR) >= 0.90 had significantly higher serum NOx concentration; however, the association was not significant after multivariable adjustment. None of the parameters were significantly associated with NOx in men. CONCLUSION: A positive association between BMI and WC and serum NOx concentration was found in women which might be a reflection of increased NO production. PMID- 23981156 TI - PCR-based clonality analysis in diffuse large B-cell lymphoma using BIOMED-2 primers of IgH (FR3) on formalin-fixed paraffin-embedded tissue. AB - INTRODUCTION: BIOMED-2 multiplex polymerase chain reaction (PCR) protocol is a widely accepted tool for evaluation of clonality in lymphoma diagnosis. Diffuse large B-cell lymphoma (DLBCL) is the most common non- Hodgkin,s lymphoma and displays a special challenge for PCR-based clonality analysis due to a high frequency of somatic hypermutation in rearranged immunoglobulin (Ig) domains. In this study, we evaluated detection of B- cell clonality in DLBCL by using Ig heavy chain (IgH) framework region 3 (FR3) primers in formalin- fixed paraffin- embedded (FFPE) tissue. METHOD: FFPE samples from 100 cases diagnosed as DLBCL in the period of 2005 through 2011 were assessed in this study. Clonality of IgH (FR3) was evaluated by PCR amplification method that was optimized for FFPE tissue. RESULTS: The clonal detection rate was (62.8%) with IgH (FR3) assay after modification, using filter for better DNA purification on negative cases. DNA quality in FFPE samples stored in recent five years were significantly better than older paraffin blocks (P < 0.001). Although a higher rate of clonality was observed in more recent group, it was not statistically significant. CONCLUSION: By using IgH (FR3) primers followed by one additional filter tube for better DNA purification, we could achieve a considerable rate of clonality with little adverse impact of DNA degradation. PMID- 23981157 TI - Hepatotoxicity of Dorema aucheri (Bilhar) in albino mice. AB - BACKGROUND: The geographic map of cancer prevalence differs due to environmental and dietary factors in various populations. High prevalence of a number of cancers in some regions is thought to be attributed to local dietary habits. Dorema aucheri (Bilhar) is used commonly as an herbal medicine in some regions including Iran. The aim of this study was to evaluate whether Dorema aucheri has carcinogenic effects in albino mice or not. METHODS: The Dorema aucheri leaves were extracted by Soxhlet method and were injected intraperitoneally and randomly into 28 healthy albino mice which were divided into seven groups. One was put aside as the non-injected control group. The second control group was chosen to be injected by a known carcinogen. Another group was injected by carcinogen and then, Bilhar extract. The left four groups were injected the extracts in a dose- dependent manner, increasingly in the range of 0.4 - 3.2mL/kg. Extract injections were repeated every 48- hour intervals for three times. Then, liver and serum samples were analyzed biochemically and pathologically. RESULTS: The pathologic and biochemical studies showed that the injection of plant extracts caused necrosis, inflammation of the liver tissue, cell proliferation, cholestasis, and there were significant increases in release of liver enzymes [ALP, ALT (SGPT) and AST (SGOT)] and bilirubin compared to the non-injected control group. The level of liver damage was dose dependent. CONCLUSIONS: Dorema aucheri has potential hepatotoxic capacities and possibly this may be related to the high prevalence of cancer in some regions of Iran. PMID- 23981158 TI - Transplantation of schwann cells differentiated from adipose stem cells improves functional recovery in rat spinal cord injury. AB - BACKGROUND: When the spinal cord is damaged, medical procedures are vital to prevent of improvement of the lesion. Because of poor regeneration ability of central nervous tissue, the most injuries are irreversible. One of encouraging interventions for treatment of spinal cord injury is Schwann cell transplantation. However, isolation of Schwann cell for clinical interventions is complicated approach with low cells yield and purity. Thus, easily accessed sources like Adipose mesenchymal stem cells have been taken notice. Therefore, this study was planned to assess the effect of adipose stromal cell-derived Schwann cell transplantation in functional recovery after lateral hemisection in adult rats. METHODS: After isolation, adipose stem cells were differentiated to Schwann cells. The differentiation was verified by immunocytochemistry and reverse transcription-polymerase chain reaction (RT-PCR). Then, we loaded the cells into collagen scaffolds with parallel aligned canals and transplanted into rats with 3 mm lesions at T9 - T10 level. Motor and sensory improvement were evaluated by open field locomotor scale, narrow beam, and tail flick tests for 60 days. Subsequently, conventional histology and immunohistochemistry were performed. RESULTS: In vitro results revealed that mesenchymal stem cells after differentiation gained Schwann cells morphology and markers. Schwann cell-grafted group had significantly higher locomotor and sensory scores in comparison with the control and scaffold without cell groups. Histological observations showed differentiated cells have the ability to improve axonal regeneration and remyelination. CONCLUSION: Our study proved that adipose tissue- derived Schwann cells can change the rough environment of damaged spinal cord and support axon regeneration and enhance functional recovery, and possibly be helpful for people suffering from spinal cord injuries. PMID- 23981159 TI - Mortality and injuries among Iranians in Iraq-Iran war: a systematic review. AB - BACKGROUND: The Iraq-Iran war was one of the longest conflicts in the twentieth century. The aim of our research was to review the incidence of mortality and injuries of the war. METHODS: A search strategy was designed and run in Medline, EMBASE, Scopus, and Iranian databases including Scientific Information Database (SID), IranMedex, and Magiran. Also, searching grey literature, checking references, tracking citations, hand-searching of focused journals, and websites were utilized for retrieval of related studies. All of articles which studied epidemiology of mortality or injuries of the war were included. The excluding criteria were case reports, case series, laboratory researches, and nonoriginal studies. RESULTS: Fourteen articles out of 1751 primary results were selected to be included in the study. During the war (1980 - 1988), 188,015 to 217,489 Iranians were killed (about 70 people per day). The mean age of mortality was 23 years. Six thousand four hundred twenty-seven (2.9%) of those who died during the war were females. One thousand five chemical warfare victims died between 1983 and 1994. From 1985 through 1998, 82 veterans had successful suicides too. At the end of war, we had 398, 587 veterans who needed follow- up. Among them, there were 52,000 chemical warfare victims. Between 1988 and 2003, 1400 people died and 2313 injured due to landmines and unexploded ordnances in five border provinces. CONCLUSION: The war caused a lot of mortalities and morbidities in our country. Now, 24 years after the war, many physically, mentally, and chemically injured victims have remained. We suggest other studies about indirect impacts of the war on societies, families, friends, and affiliates of the victims. PMID- 23981160 TI - Placental mesenchymal dysplasia complicated by hydrops fetalis and fetal death: a case report. AB - Placental mesenchymal dysplasia is a rare condition of the placenta and its true incidence and underlying cause has remained unknown till now due to its rarity. Its accurate diagnosis is essential, because placental mesenchymal dysplasia is usually compatible with a good fetal and maternal outcome. A precise ultrasonographic evaluation can contribute to the identification of characteristic features, particularly to discriminate it from partial hydatidiform mole, its main differential diagnosis. We report an early third trimester pathologically- diagnosed case of placental mesenchymal dysplasia. It was complicated by fetal hydrops and death. PMID- 23981161 TI - Fish bone ingestion: a case report of a unique route of extraction. AB - Foreign body ingestion is a common problem in otolaryngology. In this case report, we present a patient with fish bone ingestion with a unique route of extraction. A 50-year-old woman was presented with a complaint of odynophagia while eating fish. Rigid laryngoscopy revealed nothing except ecchymosis on the right pyriform sinus. We performed an axial neck computed tomography (CT) scan and found the fish bone at the retropharyngeal space. After three days there was a tender bulging in the neck. We extracted the fish bone thorough a small incision on the neck. We recommend the performance of CT scan in patients with suspected hypopharyngeal and esophageal sharp foreign body impaction. PMID- 23981162 TI - Mandibular metastasis from follicular thyroid carcinoma: a rare case after twelve years. AB - Metastatic tumor of the mandible is a rare lesion and differentiated carcinomas of the thyroid as the primary site of origin are even more uncommon. A case of late metastasis of follicular thyroid carcinoma (FTC) to the mandible is presented here. The metastasis arose 12 years after thyroidectomy. Although relatively rare, thyroid tumors metastasis to the mandible should be born in mind, as in rare cases this metastasis may be the only presentation of the original malignancy. PMID- 23981163 TI - Polymorphous low-grade adenocarcinoma of the larynx: a rare case report. AB - Laryngeal polymorphous low-grade adenocarcinoma is a rare malignant tumor with a predilection for intraoral sites. Polymorphous low-grade adenocarcinoma mostly occurs during the sixth to eighth decades of life with a female predilection. Although histopathologic evaluations enabled the definite diagnosis of this tumor, it might be mistaken with adenoid cystic carcinoma or mixed cellular tumor especially in situations when specimens with small sizes are available. We present a rare case of laryngeal polymorphous low-grade adenocarcinoma in a 55 year-old female patient. PMID- 23981164 TI - Identification of IVS-I (-1) (G > C) or Hb Monroe as a report on the beta-globin gene with a beta-thalassemia minor phenotype in south of Iran. AB - We described the first report of IVS-I (-1), codon 30 (G > C) or Hb Monroe in five individuals from four unrelated families in Khuzestan Province. Polymerase chain reaction (PCR) followed by sequencing of the beta-globin gene confirmed the presence of Hb Monroe in the heterozygous form which causes beta-thalassemia due to missplicing in the course of mRNA processing. This mutation has been described in individuals originated from Arabic and Behbahani origins, Ahvaz City, south of Iran. The knowledge of the beta-globin variants present in the Iranian population is essential for the molecular diagnosis and prevention of hemoglobinopathies. PMID- 23981165 TI - Photoclinic. Parry-Romberg syndrome. PMID- 23981166 TI - Cryptococcosis as an emerging systemic mycosis in dogs. AB - OBJECTIVE: To review the etiology, pathogenesis, and clinical presentations of canine cryptococcosis that are of relevance to veterinary emergency and critical care veterinarians. Diagnosis, treatment, and public health considerations of the disease will also be discussed. ETIOLOGY: Cryptococcosis is a multisystemic disease of dogs, with a predilection for the CNS, caused by encapsulated yeast species of the genus Cryptococcus. The 2 main pathogenic species are Cryptococcus neoformans and Cryptococcus gattii (previously known as C. neoformans var. gattii). Cryptococcosis is an emerging disease in North America, with C. gattii gaining prominence as a cause of serious veterinary and human disease. DIAGNOSIS: Definitive diagnosis is made by serologic (antigen) testing, culture, and identification of the organism using light microscopy. False negatives and false positives, while uncommon, can occur in dogs using commercially available antigen tests. Cytological examination demonstrates the organism in a majority of cases, although culture is more sensitive. Specific media are required to differentiate between C. neoformans and C. gattii. THERAPY: The most commonly used antifungal drugs to treat canine cryptococcosis are azole antifungals and amphotericin B. Some strains of Cryptococcus are resistant to antifungal drugs, especially fluconazole. Cautious use of glucocorticoids in critically affected dogs with CNS presentations can improve outcome. PROGNOSIS: Prognosis is variable and depends on the severity of disease, underlying host immunocompetence, and financial constraints of the owner. Altered mental status in dogs with CNS cryptococcosis is a negative prognostic indicator. PMID- 23981167 TI - Pollinator shifts between Ophrys sphegodes populations: might adaptation to different pollinators drive population divergence? AB - Local adaptation to different pollinators is considered one of the possible initial stages of ecological speciation as reproductive isolation is a by-product of the divergence in pollination systems. However, pollinator-mediated divergent selection will not necessarily result in complete reproductive isolation, because incipient speciation is often overcome by gene flow. We investigated the potential of pollinator shift in the sexually deceptive orchids Ophrys sphegodes and Ophrys exaltata and compared the levels of floral isolation vs. genetic distance among populations with contrasting predominant pollinators. We analysed floral hydrocarbons as a proxy for floral divergence between populations. Floral adoption of pollinators and their fidelity was tested using pollinator choice experiments. Interpopulation gene flow and population differentiation levels were estimated using AFLP markers. The Tyrrhenian O. sphegodes population preferentially attracted the pollinator bee Andrena bimaculata, whereas the Adriatic O. sphegodes population exclusively attracted A. nigroaenea. Significant differences in scent component proportions were identified in O. sphegodes populations that attracted different preferred pollinators. High interpopulation gene flow was detected, but populations were genetically structured at species level. The high interpopulation gene flow levels independent of preferred pollinators suggest that local adaptation to different pollinators has not (yet) generated detectable genome-wide separation. Alternatively, despite extensive gene flow, few genes underlying floral isolation remain differentiated as a consequence of divergent selection. Different pollination ecotypes in O. sphegodes might represent a local selective response imposed by temporal variation in a geographical mosaic of pollinators as a consequence of the frequent disturbance regimes typical of Ophrys habitats. PMID- 23981174 TI - Selective turn-on ammonia sensing enabled by high-temperature fluorescence in metal-organic frameworks with open metal sites. AB - We show that fluorescent molecules incorporated as ligands in rigid, porous metal organic frameworks (MOFs) maintain their fluorescence response to a much higher temperature than in molecular crystals. The remarkable high-temperature ligand based fluorescence, demonstrated here with tetraphenylethylene- and dihydroxyterephthalate-based linkers, is essential for enabling selective and rapid detection of analytes in the gas phase. Both Zn2(TCPE) (TCPE = tetrakis(4 carboxyphenyl)ethylene) and Mg(H2DHBDC) (H2DHBDC(2-) = 2,5-dihydroxybenzene-1,4 dicarboxylate) function as selective sensors for ammonia at 100 degrees C, although neither shows NH3 selectivity at room temperature. Variable-temperature diffuse-reflectance infrared spectroscopy, fluorescence spectroscopy, and X-ray crystallography are coupled with density-functional calculations to interrogate the temperature-dependent guest-framework interactions and the preferential analyte binding in each material. These results describe a heretofore unrecognized, yet potentially general property of many rigid, fluorescent MOFs and portend new applications for these materials in selective sensors, with selectivity profiles that can be tuned as a function of temperature. PMID- 23981175 TI - Measurement of esophago-gastric junction cross-sectional area and distensibility by an endolumenal functional lumen imaging probe for the diagnosis of gastro esophageal reflux disease. AB - BACKGROUND: Measurement of esophago-gastric junction (EGJ) cross-sectional area (CSA) and distensibility by an Endolumenal Functional Lumen Imaging Probe (EndoFLIP(r)) may distinguish between gastro-esophageal reflux disease (GERD) patients and healthy volunteers (HV). We aimed to assess the agreement of EndoFLIP(r) measurements with clinical and physiologic diagnosis of GERD. METHODS: Twenty-one HV and 18 patients with typical GERD symptoms were studied. After gastroscopy, EGJ CSA, and distensibility were measured by EndoFLIP(r). Forty-eight hour esophageal pH monitoring was then performed by a wireless system. The ability of EndoFLIP(r) to discriminate GERD patient and HVs was assessed. Planned secondary analysis then assessed whether EGJ CSA and distensibility were increased in individuals with pathologic acid exposure. KEY RESULTS: Healthy volunteers were younger and had lower body mass index (BMI; both p < 0.001). Pathologic acid exposure was present in 3/21 (14%) HVs and 9/18 (50%) patients (p = 0.126). At 30 mL EndoFLIP(r) bag volume, EGJ CSA was higher (p = 0.058) and EGJ distensibility was lower (p = 0.020) in HVs than patients. Secondary analysis showed that EGJ measurements were similar in participants with and without pathologic acid exposure (CSA 98 mm2 vs 107 mm2; p = 0.789, distensibility; p = 0.704). An inverse association between BMI and CSA (R2 = 0.2758, p = 0.001) and distensibility (R2 = 0.2005, p = 0.005) was present. CONCLUSIONS & INFERENCES: Endolumenal Functional Lumen Imaging Probe is not useful for GERD diagnosis because EGJ CSA and distensibility do not distinguish between HVs and GERD patients defined by clinical presentation or pH measurement. This unexpected result may be due to an important, confounding interaction of obesity. PMID- 23981176 TI - I-35W bridge collapse and response. PMID- 23981177 TI - Silver/ThioClickFerrophos complex as an effective catalyst for asymmetric conjugate addition of glycine imino ester to unsaturated malonates and alpha enones. AB - The AgOAc/ThioClickFerrophos complex effectively catalyzed the conjugate addition of glycine imino esters to arylidene and alkylidene malonates, furnishing the corresponding adducts in good yields with high enantioselectivities, in the presence or absence of an external base. The complex also catalyzed conjugate addition to alpha-enones in the presence of 1,4-diazabicyclo[2.2.2]octane with high enantioselectivity, with formation of a small amount of cycloadducts. PMID- 23981178 TI - In vitro hydrodynamic analysis of pin and cone bearing designs of the Jarvik 2000 adult ventricular assist device. AB - The Jarvik 2000 adult ventricular assist device (VAD) is a second-generation blood pump with mechanical contact bearings. The original configuration of the pump employed a pin bearing and a more recent configuration uses a cone bearing. We compare the hydrodynamic performance of the two designs under steady-state and pulsatile flow conditions in vitro. Furthermore, we employ the Intermittent Low Speed (ILS) Flowmaker Controller to demonstrate the effect on pulsatility index (PI) performance of both device configurations. We use an open-loop flow system in both steady-state and pulsatile arrangements, complete with pressure transducers and flow probes. Working fluid was a 3.6 cP blood-analog, glycerin water solution. Steady-state flow tests were carried out to determine pressure flow (H-Q) performance curves. Pulsatile tests under normotensive, hypertensive, and hypotensive conditions were executed with controller speed 3 (10710 +/- 250 rpm) at 100 beats per minute. Steady-state tests show greater capacity for pressure and flow with the cone bearing, compared with pin bearing, with best efficiency point (BEP) 68% greater for cone bearing. Pulsatile tests show the cone bearing design to yield a 20% increase in Qavg , a 17% decrease in pulsatility index (PIQ ), and a qualitative increase in pressure responsivity. The ILS mode (for both bearing designs) decreases Qavg by 68% and likewise increases PIQ by 360% and pulsatility ratio (Rpul ) by 200%. The ILS controller regularly reduces the flow, increasing pulsatility index during device operation. The Jarvik 2000 continuous-flow VAD can sustain pulsatile flow under pulsating pressure conditions. The new cone bearing design yields increased flow rates over the earlier pin bearing design. PMID- 23981179 TI - Nomenclature for red blood cell blood group alleles. PMID- 23981180 TI - Chemical library screening for WNK signalling inhibitors using fluorescence correlation spectroscopy. AB - WNKs (with-no-lysine kinases) are the causative genes of a hereditary hypertensive disease, PHAII (pseudohypoaldosteronism type II), and form a signal cascade with OSR1 (oxidative stress-responsive 1)/SPAK (STE20/SPS1-related proline/alanine-rich protein kinase) and Slc12a (solute carrier family 12) transporters. We have shown that this signal cascade regulates blood pressure by controlling vascular tone as well as renal NaCl excretion. Therefore agents that inhibit this signal cascade could be a new class of antihypertensive drugs. Since the binding of WNK to OSR1/SPAK kinases was postulated to be important for signal transduction, we sought to discover inhibitors of WNK/SPAK binding by screening chemical compounds that disrupt the binding. For this purpose, we developed a high-throughput screening method using fluorescent correlation spectroscopy. As a result of screening 17000 compounds, we discovered two novel compounds that reproducibly disrupted the binding of WNK to SPAK. Both compounds mediated dose dependent inhibition of hypotonicity-induced activation of WNK, namely the phosphorylation of SPAK and its downstream transporters NKCC1 (Na/K/Cl cotransporter 1) and NCC (NaCl cotransporter) in cultured cell lines. The two compounds could be the promising seeds of new types of antihypertensive drugs, and the method that we developed could be applied as a general screening method to identify compounds that disrupt the binding of two molecules. PMID- 23981181 TI - Neonatal liver abscesses associated with candidemia: three cases and review of literature. AB - BACKGROUND: Our aim was to identify risk factors for the development of neonatal Candida liver abscess and to find useful information to better manage this potentially fatal complication. METHODS: A computerized search was conducted using PubMed. Overall, three articles describing the history of seven infants were finally considered. The characteristics of these seven cases were analyzed together with those of three new cases that we treated in the recent past. RESULTS: All the neonates were premature. Previous antibiotic use was reported in all the cases, umbilical venous catheterization in 9/10 and total parenteral nutrition in 8/10. Candida albicans was isolated in 9/10. All the patients presented with aspecific signs of sepsis. Liver abscesses were described as "microabscesses" or "miliary abscesses" in three cases, as solitary lesion in two cases. In one case two lesions and in one four lesions were reported. Three infants died. CONCLUSIONS: Liver ultrasonography should be performed in all the neonates with signs of sepsis, especially in the presence of candidemia and/or hepatomegaly and/or significant change in liver enzymes. Umbilical venous catheter should be removed, and peripheral IV access should be used until there is documented clearance from the blood with three or more negative blood cultures. PMID- 23981182 TI - Correlation of UGT1A1 TATA-box polymorphism and jaundice in breastfed newborns early presentation of Gilbert's syndrome. AB - OBJECTIVE: The etiology of jaundice in otherwise healthy breastfed newborns that can present as early-onset exaggerated physiologic jaundice, or late breast milk jaundice (BMJ), is not yet entirely understood. This study tested the hypothesis that molecular marker for Gilbert's syndrome (GS), UGT1A1 TATA-box polymorphism, is associated with this disorders. METHODS: We have investigated the UGT1A1 polymorphism frequency and its relation to severity of hyperbilirubinemia and jaundice duration among 220 exclusively breastfed term newborns; 57 of them with non-physiologic hyperbilirubinemia (NH), and 163 with BMJ, and in 187 healthy controls. RESULTS: Significant differences in TA7/7 genotype frequency were established. The highest frequency was observed among the newborns with BMJ (42.0%), intermediate in the NH group (24.6%), while the controls had the lowest TA7/7 frequency (12.8%). Linear increase in TA7/7 frequency was observed depending on the duration of jaundice, peaking at 42.4% in newborns with the longest jaundice duration. Positive correlation between the serum bilirubin levels and the TATA-box length was established in all groups. CONCLUSION: This study provides evidence that UGT1A1 TATA-box polymorphism is an important risk factor for developing jaundice in term breastfed newborns, presented as either early non-physiologic hyperbilirubinemia or breast milk jaundice. These results further support the original Odell's idea of neonatal jaundice as an early presentation of GS. PMID- 23981183 TI - Retrospective evaluation of pregnancy outcomes in women with familial Mediterranean fever. AB - AIM: Familial Mediterranean fever (FMF) is an autosomal recessive condition characterized by periodic attacks of fever, aseptic serositis and synovitis. In this study, we investigated maternal and neonatal outcomes in pregnant patients with FMF. METHODS: This retrospective study consisted of 46 pregnant patients with FMF who attended the perinatology clinic of Dr Zekai Tahir Burak Research and Training Hospital between January 2008 and December 2012. The following clinical and demographic data were obtained by reviewing the patients' medical records: maternal age, colchicine use during pregnancy, obstetric history, pregnancy outcome and maternal and neonatal complications during the current pregnancy. RESULTS: The patients with FMF had higher rates of premature rupture of membranes (PROM) and Cesarean delivery as well as low birth weight infants; however, rates of stillbirth, gestational diabetes, preeclampsia did not differ between the groups. Preterm delivery rates were higher in the study group, but this difference did not reach statistical significance. Patients with pregnancy complications had significantly more basal proteinuria than did patients without complications. Nine patients did not receive colchicine therapy in the previous or current pregnancies. Within this subgroup, four (44.4%) of the patients had a history of two or more previous miscarriages. However, there were only three cases (8.1%) of two or more miscarriages among 37 patients who received colchicine; this difference was statistically significant CONCLUSIONS: FMF leads to higher rates of PROM, recurrent miscarriage and preterm deliveries. Colchicine treatment is safe in pregnancy and may lead to a decreased miscarriage rate. PMID- 23981184 TI - The relationship between third trimester maternal hemoglobin and birth weight/length; results from the tertiary center in Turkey. AB - OBJECTIVE: The aim of this study was to investigate the relationship between third trimester maternal hemoglobin values and fetal birth weight/length. METHODS: Retrospective study was conducted on 28600 Turkish pregnant women who delivered between January 2010 and December 2011. Hemoglobin values at third trimester, all birth weights/lengths of newborns were retrospectively analyzed. Maternal third trimester hemoglobin values and birth weights/lengths were compared and correlated. RESULTS: The high hemoglobin concentrations at third trimester were associated with high birth weight (odds ratio 1.08; 95% confidence interval 1.05-1.11; p=0.00) and significant positive correlation was determined between maternal third trimester hemoglobin and birth weights/lengths (p=0.00). Low hemoglobin was associated with low length of newborns (p=0.00). CONCLUSIONS: The low hemoglobin values at third trimester gestation were associated with low birth weight and length in Turkish women. The anemia can be a direct cause of deterioration of in utero fetal growth due to lack of oxygen flow to placental tissue or can be an indirect indicator of maternal nutrition deficit. In both circumstances this study reveals that treatment of anemia is directly correlated with better fetal outcomes. PMID- 23981185 TI - Specific formulas improve the estimation of fetal weight by ultrasound scan. AB - OBJECTIVE: To develop and evaluate local, sex specific, small for gestational age (SGA) specific, large for gestational age (LGA) specific and combined (biometry, sex and Doppler indices) formulas for ultrasound estimated fetal weight (EFW). METHOD: Low-risk singleton pregnancies that delivered within 7 days from ultrasound examination were assessed. A formula-generating group (1407 pregnancies) and a validation group (469 pregnancies) were created. Fractional regression analysis was used to develop the formulas. Systematic error, random error, fraction within the 10% of actual birth weight and Bland-Altman analysis were used. RESULTS: The local formula and the Hadlock formula with local co efficients performed better than the Hadlock formula. The SGA-specific formula, the LGA-specific formula and the combined formula had the lower systematic error (MSE: +0.0022291, -0.4226888, +0.8386222, respectively) and the narrower 95% LOA (-292.8 to +292.23, -485.6 to +461.5, -425.7 to +450.46, respectively). The SGA- and the LGA-specific formulas had higher fraction within the 10% of actual birth weight (81.5% and 84%, respectively). CONCLUSIONS: Local formulas improve the EFW calculation. The combined formula can further optimize the accuracy and precision. Application of specific formulas for the small and the large fetus had the most pronounced effect in improving fetal weight estimation. PMID- 23981186 TI - Changes in basal rates and bolus calculator settings in insulin pumps during pregnancy in women with type 1 diabetes. AB - OBJECTIVE: To explore insulin pump settings in a cohort of pregnant women with type 1 diabetes on insulin pump therapy with a bolus calculator. METHODS: Twenty seven women with type 1 diabetes on insulin pump therapy were included in this study. At 8, 12, 21, 27 and 33 weeks, insulin pump settings and HbA1c were recorded. Results were compared with 96 women with type 1 diabetes on multiple daily injection therapy. RESULTS: Throughout pregnancy, the carbohydrate-to insulin ratio decreased at all three main meals. The most pronounced decrease was observed at breakfast, where the carbohydrate-to-insulin ratio was reduced, from median 12 (range 4-20) in early pregnancy to 3 (2-10) g carbohydrate per unit insulin in late pregnancy. Basal insulin delivery increased by ~50%, i.e. from 0.8 (0.5-2.2) to 1.2 (0.6-2.5) IU/h at 5 a.m. and from 1.0 (0.6-1.5) to 1.3 (0.2 2.3) IU/h at 5 p.m. during pregnancy. HbA1c levels during pregnancy, the occurrence of severe hypoglycemia and pregnancy outcomes were similar in the two groups. CONCLUSIONS: In women with type 1 diabetes on insulin pump therapy with a bolus calculator, the carbohydrate-to-insulin ratio declined 4-fold from early to late pregnancy, whereas changes in basal insulin delivery were smaller. PMID- 23981187 TI - Identification of conservative microRNAs in Saanen dairy goat testis through deep sequencing. AB - MicroRNA (miRNA) is a kind of small non-coding RNA molecules that function as important gene expression regulators by targeting messenger RNAs for post transcriptional endonucleolytic cleavage or translational inhibition. In this study, small RNA libraries were constructed based on adult dairy goat testicular tissues and sequenced using the Illumina high-throughput sequencing technology. Blasted to miRNAs of cow and sheep in miRBase 19.0, 373 conserved miRNAs were identified in dairy goat testis and 91 novel paired-miRNAs were found. Expression of miRNAs in the dairy goat testis (miR-10b, miR-126-3p, miR-126-5p, miR-34c, miR 449b and miR-1468) was confirmed by qRT-PCR. In addition, the 128 conserved miRNAs were found by comparing the miRNA expression profiles in dairy goat testis with those in cow and mouse, which all might be involved in dairy goat testis development and meiosis. This study reveals the first miRNA profile related to the biology of testis in the dairy goat. The characterization of these miRNAs could contribute to a better understanding of the molecular mechanisms of reproductive physiology and development in the dairy goat. PMID- 23981188 TI - Dynamic insight into protein structure utilizing red edge excitation shift. AB - Proteins are considered the workhorses in the cellular machinery. They are often organized in a highly ordered conformation in the crowded cellular environment. These conformations display characteristic dynamics over a range of time scales. An emerging consensus is that protein function is critically dependent on its dynamics. The subtle interplay between structure and dynamics is a hallmark of protein organization and is essential for its function. Depending on the environmental context, proteins can adopt a range of conformations such as native, molten globule, unfolded (denatured), and misfolded states. Although protein crystallography is a well established technique, it is not always possible to characterize various protein conformations by X-ray crystallography due to transient nature of these states. Even in cases where structural characterization is possible, the information obtained lacks dynamic component, which is needed to understand protein function. In this overall scenario, approaches that reveal information on protein dynamics are much appreciated. Dynamics of confined water has interesting implications in protein folding. Interfacial hydration combines the motion of water molecules with the slow moving protein molecules. The red edge excitation shift (REES) approach becomes relevant in this context. REES is defined as the shift in the wavelength of maximum fluorescence emission toward higher wavelengths, caused by a shift in the excitation wavelength toward the red edge of absorption spectrum. REES arises due to slow rates (relative to fluorescence lifetime) of solvent relaxation (reorientation) around an excited state fluorophore in organized assemblies such as proteins. Consequently, REES depends on the environment-induced motional restriction imposed on the solvent molecules in the immediate vicinity of the fluorophore. In the case of a protein, the confined water in the protein creates a dipolar field that acts as the solvent for a fluorophore in the protein. In this Account, we focus on REES to monitor organization and dynamics of soluble and membrane proteins utilizing intrinsic protein fluorescence. We discuss here the application of REES in various conformations of proteins. While application of REES to proteins in native conformation has been in use for a long time, our work highlights the potential of this approach in case of molten globule and denatured conformations. For example, we have demonstrated the presence of residual structure, that could not be detected using other methods, by REES of denatured spectrin. Given the functional relevance of such residual structures, these results are very far reaching. We discuss here the application of REES to molten globule conformation and to the green fluorescent protein (GFP). The case of GFP is particularly interesting since the dipolar field in this case is provided by the protein matrix itself and not confined water. We envision that future applications of REES in proteins will involve generating a dynamic hydration map of the protein, which would allow us to explore protein function in terms of local dynamics and hydration. PMID- 23981189 TI - The synergistic effect of heredity and exposure to second-hand smoke on adult onset asthma. AB - RATIONALE: Identification of the subpopulation especially susceptible to the adverse effects of second-hand smoke exposure (SHS) would be useful for preventive actions and interventions. OBJECTIVES: To investigate whether asthmatic heredity indicates susceptibility to the effects of SHS on the risk of adult-onset asthma. METHODS: A population-based incident case-control study of clinically defined adult-onset asthma and randomly drawn control subjects (adults 21-63 yr old) from a geographically defined area in South Finland. After excluding current and ex-smokers there were 226 cases and 450 disease-free control subjects. MEASUREMENTS AND MAIN RESULTS: Our outcome measure was new adult-onset asthma. Parental asthma and recent SHS had a synergistic effect on the risk of asthma, the adjusted odds ratio being 1.97 (95% confidence interval, 1.12-3.45) for SHS; 2.64 (1.65-4.24) for parental asthma; and 12.69 (3.44-46.91) for their joint effect (relative excess risk due interaction, 9.08 [-0.22 to 43.18]). Synergistic effect followed a dose-dependent pattern with both recent and cumulative SHS exposures, with relative excess risk due interaction for parental asthma and over 100 SHS cigarette-years of 6.17 (0.57-19.16). CONCLUSIONS: This is the first study showing that individuals with asthmatic heredity have a considerably increased risk of adult-onset asthma when exposed to SHS. SHS exposure has dose-dependent synergism with family history of asthma, the joint effect being stronger with higher exposure levels. Avoiding SHS could be an important preventive measure for reducing the risk of adult-onset asthma among those with asthmatic heredity. Asking about family history of asthma is a useful tool for identifying these susceptible individuals in clinical and preventive settings. PMID- 23981190 TI - Biological evaluation of hyperforin and its hydrogenated analogue on bacterial growth and biofilm production. AB - Bacterial biofilms are organized communities of microorganisms, embedded in a self-produced matrix, growing on a biotic surface and resistant to many antimicrobial agents when associated with a medical device. These biofilms require the development of new strategies for the prevention and treatment of infectious disease, including the potential use of natural products. One interesting natural product example is Hypericum, a plant genus that contains species known to have antimicrobial properties. The major constituent of Hypericum perforatum is an unstable compound named hyperforin (1); for this reason it was not believed to play a significant role in the pharmacological effects. In this investigation a hydrogenated hyperforin analogue (2) was tested on several ATCC and clinical isolate strains, in their planktonic and biofilm form (Staphylococcus aureus, MRSA, and Enterococcus faecalis). Compound 2 was effective against planktonic and biofilm cultures, probably due to higher stability, showing the percentage of cells killed in the range from 45% to 52%. These results are noteworthy from the point of view of future development of these polyprenylated phloroglucinols as potential antibiotics. PMID- 23981191 TI - An observational study of cognitive function in patients with irritable bowel syndrome and inflammatory bowel disease. AB - BACKGROUND: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are associated with several risk factors for developing cognitive impairment. These include altered cytokine levels, concurrent mood disorders, and the presence of chronic pain. This observational study aimed to explore the cognitive profile of patients with these conditions. METHODS: Participants completed the Cardiff Cognitive Battery, a series of computerized neuropsychological performance tests that examine a range of cognitive function including psychomotor speed, memory, and intelligence. A progressive analysis of covariance model was used with demographic details, anxiety and depression scores entered as covariates. Fecal calprotectin levels were measured in IBD patients to determine disease activity. KEY RESULTS: In total 231 participants were recruited (150 IBD patients, 40 IBS patients, and 41 healthy controls). IBD patients had significantly lower scores on fluid (p = 0.01) and crystalline intelligence tests (p = 0.028) compared to healthy volunteers, however, this reflected differences in concurrent mood disorder and level of education. When these factors were added as covariates, there was no significant difference between the groups. Duration and activity of disease did not affect cognitive function in IBD patients. Severity of symptoms had no impact on cognition in patients with IBS. CONCLUSIONS & INFERENCES: The results of this observational study do not support the hypothesis that IBS or IBD have an intrinsic disease process that is associated with cognitive dysfunction. It is possible that concurrent mood disorders, in particular depression, may affect the cognitive performance of patients with IBD in specific tasks. PMID- 23981192 TI - Takotsubo cardiomyopathy in a jeweler following a hold-up: forensic considerations. AB - The authors present a case of takotsubo cardiomyopathy (TTC) following physical assault. In France, public prosecutor orders a medicolegal assessment after an assault for all living victims. Medicolegal assessment aims to establish a causal relation between an aggression and the injury sustained. An 80-year-old jeweler was the victim of assault, restraint and confinement during the hold-up of his jewelry store. After the event, he experienced constrictive chest pain with a sensation of oppression. Transthoracic echography showed apical and middle wall akinesis with apical ballooning pattern. In this case, the experts reasonably accepted that there was a direct, certain, and exclusive causal relation between the aggression and the cardiomyopathy. Forensic specialists should be aware of TTC because it is a frequent complication of stress situations and its incidence in forensic cases is probably underestimated. PMID- 23981193 TI - Preoperative assessment of longitudinal extension of cholangiocarcinoma with peroral video-cholangioscopy: a prospective study. AB - BACKGROUND AND AIM: Preoperative assessment of longitudinal extension of cholangiocarcinoma (CCA) is essential for making decisions concerning surgical resection and selecting operative procedures. We evaluated the accuracy of peroral video-cholangioscopy (PVCS) in diagnosing longitudinal extension of CCA. METHODS: Patients with CCA who underwent preoperative PVCS were considered for this study. We evaluated the accuracy of PVCS in diagnosing longitudinal extension of perihilar cholangiocarcinoma (PCCA) and distal extrahepatic cholangiocarcinoma (DCCA) to the secondary biliary radicles and confluence of the hepatic ducts, respectively, on the hepatic side and to the intrapancreatic common bile duct on the papillary side. Diagnostic accuracy was determined by comparing the results with those of histopathological analyses of surgical specimens. RESULTS: Forty-three consecutive patients were enrolled. The cholangioscope could not be advanced into the hepatic side in eight of the 25 patients with PCCA and in five of the 18 patients with DCCA. The accuracy of PVCS in diagnosing longitudinal extension of CCA on the hepatic and papillary sides was 82.4% and 92.0%, respectively, in patients with PCCA and 92.3% and 100%, respectively, in patients with DCCA. PVCS accurately detected longitudinal extension of CCA to the hepatic and papillary sides that was not detected previously by endoscopic retrograde cholangiography in 20.0% and 11.6% patients, respectively. CONCLUSIONS: PVCS proved useful for the preoperative assessment of longitudinal extension of CCA. Therefore, it can aid surgeons in deciding surgical resectability and selecting operative procedures. This, in turn, may impact overall patient prognosis. PMID- 23981194 TI - Panama Canal expansion illustrates need for multimodal near-source air quality assessment. PMID- 23981195 TI - Pontine control of ejaculation and female orgasm. AB - INTRODUCTION: The physiological component of ejaculation shows parallels with that of micturition, as both are essentially voiding activities. Both depend on supraspinal influences to orchestrate the characteristic pattern of activity in the pelvic organs. Unlike micturition, little is known about the supraspinal pathways involved in ejaculation and female orgasm. AIM: To identify brainstem regions activated during ejaculation and female orgasm and to compare them with those activated during micturition. METHODS: Ejaculation in men and orgasm in women were induced by manual stimulation of the penis or clitoris by the participants' partners. Positron emission tomography (PET) with correction for head movements was used to capture the pattern of brain activation at the time of sexual climax. MAIN OUTCOME MEASURES: PET scans showing areas of activation during sexual climax. RESULTS: Ejaculation in men and orgasm in women resulted in activation in a localized region within the dorsolateral pontine tegmentum on the left side and in another region in the ventrolateral pontine tegmentum on the right side. The dorsolateral pontine area was also active in women who attempted but failed to have an orgasm and in women who imitated orgasm. The ventrolateral pontine area was only activated during ejaculation and physical orgasm in women. CONCLUSION: Activation of a localized region on the left side in the dorsolateral pontine tegmentum, which we termed the pelvic organ-stimulating center, occurs during ejaculation in men and physical orgasm in women. This same region has previously been shown to be activated during micturition, but on the right side. The pelvic organ-stimulating center, via projections to the sacral parasympathetic motoneurons, controls pelvic organs involved in voiding functions. In contrast, the ventrolateral pontine area, which we term the pelvic floor-stimulating center, produces the pelvic floor contractions during ejaculation in men and physical orgasm in women via direct projections to pelvic floor motoneurons. PMID- 23981196 TI - The evaluation of leukocytes in response to the in vitro testing of ventricular assist devices. AB - Infection is a clinically relevant adverse event in patients with ventricular assist device (VAD) support. The risk of infection could be linked to a reduced immune response resulting from damage to leukocytes during VAD support. The purpose of this study was to develop an understanding of leukocyte responses during the in vitro testing of VADs by analyzing the changes to their morphology and biochemistry. The VentrAssist implantable rotary blood pump (IRBP) and RotaFlow centrifugal pump (CP) were tested in vitro under constant hemodynamic conditions. Automated hematology analysis of samples collected regularly over 25 h tests was undertaken. A new flow cytometric assay was employed to measure biochemical alteration, necrosis (7-AAD) and morphological alteration (CD45 expression) of the circulating leukocytes during the pumping process. The results of hematology analysis show the total leukocyte number and subset counts decreased over the period of in vitro tests dependent on different blood pumps. The percentage of leukocytes damaged during 6-h tests was 40.8 +/- 5.7% for the VentrAssist IRBP, 17.6 +/- 5.4% for the RotaFlow CP, and 2.7 +/- 1.8% for the static control (all n=5). Flow cytometric monitoring of CD45 expression and forward/side scatter characteristics revealed leukocytes that were fragmented into smaller pieces (microparticles). Scanning electron microscopy and imaging flow cytometry were used to confirm this. Device developers could use these robust cellular assays to gain a better understanding of leukocyte-specific VAD performance. PMID- 23981197 TI - Serum cytochrome c and m30-neoepitope of cytokeratin-18 in chronic hepatitis C. AB - BACKGROUND & AIMS: Cytochrome c (CYC) and M30-neoepitope of cytokeratin-18 (M30 CK18) are involved at different levels in apoptotic pathways. We aimed to evaluate an association between serum CYC, M30-CK18 and disease activity as well response to therapy in chronic hepatitis C (CHC). METHODS: Seventy CHC patients were enrolled in this study. Forty five of them completed pegylated interferon plus ribavirin therapy. Histopathological evaluation of hepatic inflammatory activity and fibrosis, as well as blood liver function tests, was performed. Serum concentrations of M30-CK18 and CYC were measured by ELISA. RESULTS: Median serum concentration of M30-CK18 was higher in CHC patients [283 U/L] vs. control [113 U/L] (P = 0.0003) and was associated with inflammatory activity and liver fibrosis (P < 0.001). Serum M30-CK18 positively correlated with serum activity of ALT and GGT. CYC was not detected in sera of control group, whereas in CHC, 41.43% patients had detectable CYC in serum samples [0.60 ng/ml]. Detectable baseline serum CYC had been negatively associated with sustained virological response (SVR). In patients with detectable CYC, SVR rate was 20% vs. 60% in patients with undetectable CYC (P = 0.007). CONCLUSIONS: Elevated serum M30-CK18, as an indicator of enhanced apoptosis of hepatocytes, parallels active hepatic inflammation and fibrosis but also biochemical activity in CHC; thus, it may serve as a comprehensive non-invasive marker of disease activity. On the other hand, detection of serum CYC at baseline may be negatively associated with treatment response to pegylated interferon plus ribavirin in CHC. PMID- 23981198 TI - Forecasting the absolute and relative shortage of physicians in Japan using a system dynamics model approach. AB - BACKGROUND: In Japan, a shortage of physicians, who serve a key role in healthcare provision, has been pointed out as a major medical issue. The healthcare workforce policy planner should consider future dynamic changes in physician numbers. The purpose of this study was to propose a physician supply forecasting methodology by applying system dynamics modeling to estimate future absolute and relative numbers of physicians. METHOD: We constructed a forecasting model using a system dynamics approach. Forecasting the number of physician was performed for all clinical physician and OB/GYN specialists. Moreover, we conducted evaluation of sufficiency for the number of physicians and sensitivity analysis. RESULT & CONCLUSION: As a result, it was forecast that the number of physicians would increase during 2008-2030 and the shortage would resolve at 2026 for all clinical physicians. However, the shortage would not resolve for the period covered. This suggests a need for measures for reconsidering the allocation system of new entry physicians to resolve maldistribution between medical departments, in addition, for increasing the overall number of clinical physicians. PMID- 23981200 TI - Prognostic value of hepatocyte nuclear factors 4alpha and 1alpha identified by tissue microarray in resectable hepatocellular carcinoma. AB - BACKGROUND AND AIM: This study aimed to investigate the prognostic value of expression of hepatocyte nuclear factors (HNFs) involved in hepatic gene transcription in patients undergoing curative resection for hepatocellular carcinoma (HCC). METHODS: We performed immunohistochemical analyses on microarrays of the tumors and matched adjacent tissue using antibodies against HNF1alpha, HNF1beta, HNF4alpha, and alpha-fetoprotein (AFP). We evaluated the prognostic value of biomarker expression using Cox regression and the Kaplan Meier method in a training cohort of 220 patients and conducted an independent validation in 232 patients. We also determined whether measurement of HNFs improved risk prediction beyond the use of established factors, using net reclassification improvement (NRI). RESULTS: Post-surgical recurrence and hepatic death were predicted by intratumoral HNF4alpha underexpression in both cohorts. In the training cohort they were also predicted by peritumoral HNF1alpha positivity. A pooled cohort analysis showed that these predictors were independently associated with early but not late-phase recurrence, and resultant mortality. Intratumoral expression levels of HNF4alpha were correlated with those of HNF1alpha, HNF1beta, and AFP (P < 0.05). Similarly, HNF1alpha expression in peritumoral tissue was correlated with that of other markers (P < 0.05). There was no significant correlation between expression of HNF4alpha in tumors and HNF1alpha in peritumoral tissue. Adding combinations of intratumoral HNF4alpha and peritumoral HNF1alpha to 2-year recurrence and 5-year mortality models including known clinicopathological prognostic factors significantly improved the NRI indexes (39% and 44%, respectively; P < 0.05). CONCLUSIONS: Immunohistological activation of intratumoral HNF4alpha and depletion of peritumoral HNF1alpha have prognostic significance for delayed recurrence and death after HCC resection. PMID- 23981201 TI - The neutrophil lymphocyte ratio level in patients with end-stage renal disease. PMID- 23981202 TI - Enhanced recovery and dissolution of griseofulvin nanoparticles from surfactant free nanocomposite microparticles incorporating wet-milled swellable dispersants. AB - Nanocomposite microparticles (NCMPs) incorporating drug nanoparticles and wet milled swellable dispersant particles were investigated as a surfactant-free drug delivery vehicle with the goal of enhancing the nanoparticle recovery and dissolution rate of poorly water-soluble drugs. Superdisintegrants were used as inexpensive, model, swellable dispersant particles by incorporating them into NCMP structure with or without wet-stirred media milling along with the drug. Suspensions of griseofulvin (GF, model drug) along with various dispersants produced by wet-milling were coated onto Pharmatose(r) to prepare NCMPs in a fluidized bed process. Hydroxypropyl cellulose (HPC, polymer) alone and with sodium dodecyl sulfate (SDS, surfactant) was used as base-line stabilizer/dispersant during milling. Croscarmellose sodium (CCS, superdisintegrant) and Mannitol were used as additional dispersants to prepare surfactant-free NCMPs. Nanoparticle recovery during redispersion and dissolution of the various GF-laden NCMPs were examined. Suspensions prepared by co-milling GF/HPC/CCS or milling GF/HPC/SDS were stable after 30 h of storage. After drying, due to its extensive swelling capacity, incorporation of wet-milled CCS in the NCMPs caused effective breakage of the NCMP structure and bursting of nanoparticle clusters, ultimately leading to fast recovery of the GF nanoparticles. Optimized wet co-milling and incorporation of CCS in NCMP structure led to superior dispersant performance over incorporation of unmilled CCS or physically mixed unmilled CCS with NCMPs. The enhanced redispersion correlated well with the fast GF dissolution from the NCMPs containing either CCS particles or SDS. Overall, swellable dispersant (CCS) particles, preferably in multimodal size distribution, enable a surfactant-free formulation for fast recovery/dissolution of the GF nanoparticles. PMID- 23981199 TI - Regulation of placental angiogenesis. AB - Ample interest has been evoked in using placental angiogenesis as a target for the development of diagnosis tools and potential therapeutics for pregnancy complications based on the knowledge of placental angiogenesis in normal and aberrant pregnancies. Although these goals are still far from reach, one would expect that two complementary processes should be balanced for therapeutic angiogenesis to be successful in restoring a mature and functional vascular network in the placenta in any pregnancy complication: (i) pro-angiogenic stimulation of new vessel growth and (ii) anti-angiogenic inhibition of vessel overgrowth. As the best model of physiological angiogenesis, investigations of placental angiogenesis provide critical insights not only for better understanding of normal placental endothelial biology but also for the development of diagnosis tools for pregnancy complications. Such investigations will potentially identify novel pro-angiogenic factors for therapeutic intervention for tissue damage in various obstetric complications or heart failure or anti-angiogenic factors to target on cancer or vision loss in which circulation needs to be constrained. This review summarizes the genetic and molecular aspects of normal placental angiogenesis as well as the signaling mechanisms by which the dominant angiogenic factor vascular endothelial growth factor regulates placental angiogenesis with a focus on placental endothelial cells. PMID- 23981204 TI - Observation charts with overlapping blood pressure and heart rate graphs do not yield the performance advantage that health professionals assume: an experimental study. AB - AIM: To investigate whether overlapping blood pressure and heart rate graphs improve chart-users' ability to recognize derangements in these vital signs on hospital observation charts. BACKGROUND: Many health professionals prefer blood pressure and heart rate graphs to overlap. One justification is the use of a visual cue called the 'Seagull Sign' to detect physiological abnormalities. DESIGN: A 3 * 2 * 2 mixed-design experiment, with three independent variables: participant group, graph format (separate vs. overlapping) and alerting system (integrated colour-based track-and-trigger system present vs. absent). METHODS: Over 64 experimental trials, 'Seagull-trained' nurses and novices randomly assigned to receive 'Seagull training' or remain untrained, viewed sequences of blood pressure and heart rate observations recorded on four different chart design extracts. The designs represented a crossing of the graph format and alerting system variables. For each design, eight cases contained normal data and eight contained an abnormal systolic blood pressure or heart rate observation (half of which yielded a Seagull Sign on overlapping plots). Participants (tested between January-May 2011) judged whether observations were physiologically normal or abnormal. RESULTS: Across all cases, participants from all groups responded faster and made fewer errors when blood pressure and heart rate observations were graphed separately, especially when a track-and-trigger system was present. Even for 'Seagull-trained' participants viewing 'Seagull Sign available' cases, no advantage of overlapping graphs was found. CONCLUSIONS: These findings suggest that overlapping graphs do not yield the performance advantage that many health professionals assume, either for novices or experienced nurses, even when the Seagull Sign is used. PMID- 23981203 TI - In vitro-in vivo extrapolation (IVIVE) for predicting human intestinal absorption and first-pass elimination of drugs: principles and applications. AB - Oral administration remains the preferred dosing method in clinical practice and drug development. Oral bioavailability (F) is a function of the fraction absorbed (Fabs), gastrointestinal or gut wall availability (FG), and hepatic availability (FH). Therefore, predicting intestinal absorption (Fabs) and first-pass elimination (FG and FH) from in vitro data may facilitate the selection of more orally bioavailable drug candidates in earlier stages of drug discovery and development. This review provides an overview of the determinants of intestinal absorption and first-pass elimination of drugs and focuses on the principles and applications of conventional in vitro--in vivo extrapolation (IVIVE) methods to predict Fabs, FG, and FH in humans. PMID- 23981205 TI - Always look on the bright side of life. PMID- 23981206 TI - The impact of periodontitis on oral health-related quality of life: a review of the evidence from observational studies. AB - Modern population based oral health management requires a complete understanding of the impact of disease in order to provide efficient and effective oral health care and guidance. Periodontitis is an important cause of tooth loss and has been shown to be associated with a number of systemic conditions. The impact of oral conditions and disorders on quality of life has been extensively studied. However, the impact of periodontitis on quality of life has received less attention. This review summarizes the literature on the impact of periodontitis on oral health-related quality of life (OHRQoL). Relevant publications were identified after searching the MEDLINE and EMBASE electronic databases. Screening of titles and abstracts and data extraction was conducted. Only observational studies were included in this review. Most of the reviewed studies reported a negative impact of periodontitis on OHRQoL. However, the reporting standards varied across studies. Moreover, most of the studies were conducted in developed countries. PMID- 23981207 TI - Internet information on child oral health and the first dental visit. AB - BACKGROUND: This study evaluated the available online information regarding a child's first dental visit (CFDV) and compares this with internationally recognized guidelines for the timing of CFDV. METHODS: Online information regarding CFDV was searched using the Google search engine under the Australian domain for four selected search terms and limited to the first 50 results. The websites of selected professional dental associations were also investigated for recommended CFDV timing. Guidelines recommended the CFDV from when the first tooth erupts or by the age of one year. RESULTS: Information on timing for CFDV was available on the internet and consistent with recognized guidelines for almost half of the 157 sites examined. Information on CFDV was consistent with guidelines when mentioned in professional dental association and public (government and corporate) sites. Misinformation regarding CFDV was primarily associated with dental forums and sites owned by dental professionals. The three most popular topics of additional information included oral hygiene instruction, procedures for age-one CFDV and preparing the child for the CFDV. CONCLUSIONS: Internet information regarding a child's first dental visit was generally informative but not always in agreement with the recommendations of professional dental associations. Misinformation regarding CFDV was primarily associated with dental forums and dental professional owned sites. PMID- 23981208 TI - Chemical, morphological and microhardness changes of dentine after chemomechanical caries removal. AB - BACKGROUND: This study compared the chemical, morphological and microhardness changes in carious dentine following application of NaOCl-based (Carisolv), papain-based (Papacarie) chemomechanical caries removal agents with conventional rotary method. METHODS: Thirty-two carious and eight non-carious human permanent molars were used. The carious molars were randomly distributed into four groups: Group 1 (positive control) - molars were left without caries removal; Group 2 - caries excavated with rotary method; Group 3 - caries excavated with Carisolv; Group 4 - caries excavated with Papacarie. Group 5 (negative control) consisted of eight sound molars. After caries excavation, all specimens were prepared for chemical, morphological analysis and Vickers hardness testing. RESULTS: EDX analysis showed no significant difference in Ca wt%, P wt% and Ca/P ratio among Groups 2 to 5. Vickers hardness of dentine from Groups 3 and 4 was significantly lower (p < 0.05) than for Groups 2 and 5. The use of Papacarie resulted in a dentine surface without smear layer and patent tubules, while Carisolv resulted in a dentine surface exhibiting two patterns: (1) the presence of smear layer or (2) patent tubules with partial smear layer formation. CONCLUSIONS: Papain-based (Papacarie) chemomechanical caries removal method is a reliable alternative to conventional rotary and NaOCl-based (Carisolv) caries removal. PMID- 23981209 TI - Cephalometric evaluation of mandibular advancement at different horizontal jaw positions in obstructive sleep apnoea patients: a pilot study. AB - BACKGROUND: The aim of this study was to comparatively evaluate the efficacy of the mandibular advancement device (MAD) at 50% (P2) and 75% (P3) of maximum mandibular advancement, relative to maximum intercuspation (P1) subjectively and objectively. METHODS: Eighteen subjects previously diagnosed with obstructive sleep apnoea (OSA) were selected for the study. ESS score, VAS score, soft palate angle, MP-H distance, S-H distance, a C4 -H distance, a Pu -p Pu distance and total pharyngeal area were calculated at P1, P2 and P3 positions with the help of an adjustable MAD. The results were statistically analysed. RESULTS: ESS score, VAS score, soft palate angle, MP-H distance, S-H distance and radius of curvature of airway at P2 and P3 were significantly lower compared to P1, but there was no significant difference between P2 and P3. CONCLUSIONS: The MAD produced significant improvement in objective signs and subjective symptoms at both 50% and 75% of the maximum mandibular protrusion positions at comparable comfort levels. Therefore, MAD may be given at 50% of maximum advancement in order to reduce dental or temporomandibular joint disturbances. PMID- 23981210 TI - Do school based anti-smoking campaigns delivered by oral health therapists work? AB - BACKGROUND: The dental profession has a pivotal role in cancer prevention. In Queensland, oral health therapists (OHTs) are in a unique position to provide quality smoking cessation programmes and intervention strategies to young adolescents through the school based oral health services they provide. METHODS: This study undertook a smoking cessation and prevention programme targeted to female high school students in a dental setting. An oral health therapist delivered an anti-smoking message and educated adolescents of the health-risk effects of smoking. RESULTS: A total of 1217 female students were recruited with 621 (51%) in the intervention group and 596 (49%) in the control group. There was a significant improvement in the knowledge of both systemic and oral health effects of smoking in the intervention group (p < 0.04). The results of the study demonstrated that the dental setting is an effective avenue for educating young individuals on smoking related conditions. CONCLUSIONS: A smoking cessation and prevention programme targeted to female high school students in a dental setting provides a novel means of delivering an anti-smoking message and educating adolescents of the health-risk effects of smoking. PMID- 23981211 TI - Non-carious cervical lesions: influence of morphology and load type on biomechanical behaviour of maxillary incisors. AB - BACKGROUND: The aim of this study was to measure the effect of simulating two different loads on maxillary incisors displaying eight morphological types of non carious cervical lesions, unrestored and restored with an adhesive restoration, by quantifying the stress distributions generated using finite element analysis. METHODS: Virtual models of maxillary incisors were generated using the CAD software (RhinoCeros). After composing virtual dental and supporting structures with and without non-carious cervical lesions, each model was meshed using a control mesh device (ANSYS Finite Element Analysis Software). All of the virtual models were subjected to two load types, oblique load and vertical load, to simulate occlusal forces of 100 N each. Comparisons were made between simulated teeth with non-carious cervical lesions, with and without composite resin restorations, and a simulated sound tooth. Data summarizing the stress distributions were obtained in MPa using von Mises criteria. RESULTS: Oblique loading on simulated non-carious cervical lesions resulted in greater stress concentration compared with vertical loading, and non-carious cervical lesions with acute angles displayed higher stress concentrations at the depth of the lesion. Restoring the lesions with an adhesive restoration, such as composite resin, appeared to overcome this stress concentration. CONCLUSIONS: Restoring NCCLs with adhesive restorative materials, such as a nanohybrid composite resin, appears to recover the biomechanical behaviour similar to sound teeth. PMID- 23981212 TI - Comparison of relative TLR-2 and TLR-4 expression level of disease and healthy gingival tissue of smoking and non-smoking patients and periodontally healthy control patients. AB - BACKGROUND: Toll-like receptors are a family of sensor proteins that induce the inflammatory diseases in context of microbial infection. The role of these proteins in periodontal disease and their interaction with smoking status are yet to be investigated. The aim of the present study was to evaluate the effect of smoking on gene expression of toll like receptor 2 (TLR-2) and toll-like receptor 4 (TLR-4) in patients with periodontitis. METHODS: RNAs were extracted from gingival biopsies of healthy sites (no bleeding on probing and pocket depth <=3 mm) as well as diseased sites (with bleeding on probing and pocket depth >=5 mm) of 20 smoker and 17 non-smoker subjects with chronic periodontitis. Gingival biopsies from eight periodontally healthy, never-smoker subjects served as control. Real-time PCR was carried out to evaluate the relative quantities of TLR 2 and TLR-4 mRNA concentrations. RESULTS: Regardless of smoking status, the relative expression levels of TLR-2 and TLR-4 were significantly greater (about 3 fold) at diseased sites compared to healthy sites of patients with periodontitis and healthy controls (p < 0.05). In sites with periodontitis, smoking caused an increase of about 6.5 fold in mRNA levels of TLR-4 in gingival tissue (p < 0.05). CONCLUSIONS: Although periodontitis might significantly increase TLR-2 and TLR-4 gene expression in gingival tissues, smoking habit in periodontitis subjects could selectively potentiate TLR-4 gene expression. PMID- 23981213 TI - Preservation of coronal tooth fragments prior to reattachment. AB - BACKGROUND: Reattachment of the tooth fragment is a well-accepted treatment option in dealing with crown fractures. Hydration of the fragment is an important aspect in this treatment. The present study evaluated the effect of storing fragments in different storage media prior to reattachment. METHODS: Sixty bovine incisors were randomly divided into five groups. The teeth were fractured and the fragments were dried for 48 hours and then immersed in one of the four experimental media (distilled water, milk, egg white, or 50% dextrose solution) for 2 hours. Tooth fragments in the control group were kept dry. The apical segments of the fractured teeth were stored in physiological saline. Fragments were reattached and force was applied on the labial side of the teeth at a 1 mm/min rate until failure. RESULTS: One-way ANOVA indicated that the storage medium affects bond strength (p = 0.002). Multiple comparison tests showed that the teeth preserved in the 50% dextrose solution and the egg white exhibited significantly higher bond strengths compared to the control group (p < 0.05). CONCLUSIONS: Preservation of the fractured tooth fragment in egg white or hypertonic solutions results in a higher strength of the bond between the restoration and the tooth as compared to storage in water or dried conditions. PMID- 23981214 TI - Enhanced bone formation during healing process of tooth sockets filled with demineralized human dentine matrix. AB - BACKGROUND: Orthodontic procedures are often limited by the presence of bone defects caused by trauma, periodontal diseases or surgeries, thus requiring the development of materials capable to compensate such deficiencies. Since bone morphogenetic proteins (BMPs) are indicative of bone reconstitution, this study aimed to evaluate histological and immunohistochemically the temporal location of BMP-2 and BMP-4 in osteoblasts of rat alveolar wounds filled with demineralized human dentine matrix (DHDM), used as a graft material. METHODS: After extraction of the upper second molars, the left side alveoli were filled with DHDM and the right side served as the control. The animals were euthanized after 3, 5, 10 and 14 days of surgery. After fixation, demineralization and paraffin embedding, representative samples of each group were stained with H&E and immunohistochemically evaluated. RESULTS: The data showed a statistically significant (p < 0.05) increased number of osteoblasts positively immunostained for BMP-2 and BMP-4 on the experimental side (left) at 10 days. Our results also showed that even when not degraded, dentine matrix was incorporated to new bone formation after 14 days of surgery. CONCLUSIONS: The results suggest that DHDM acts as a scaffold for osteoblast differentiation, actively yielding new bone formation, and it may represent an effective bone implant material. PMID- 23981215 TI - Correlation between the severity of periodontitis and coronary artery stenosis in a Chinese population. AB - BACKGROUND: The aim of this study was to evaluate the relationship between the severity of periodontitis and the extent and degree of coronary artery stenosis in a Chinese population. METHODS: Patients (n = 853) with coronary artery stenosis confirmed by coronary angiography were eligible to take part in the study. Only subjects that were >=60 years old, had >=50% stenosis in at least one coronary artery, and did not have diabetes or a history of smoking were included (n = 115). After periodontal examination, including bleeding index, probing depth calculus index, plaque index and periodontal attachment loss, four groups were defined based on the severity of periodontitis: no periodontitis/gingivitis (M0, n = 19); mild periodontitis (M1, n = 27); moderate periodontitis (M2, n = 31); and severe periodontitis (M3, n = 38). The extent and degree of coronary artery stenosis was obtained by calculating the Gensini score (GS). RESULTS: The GS was significantly greater in the M3 group compared with the M0 group. Multiple linear regression analysis revealed that probing depth and plaque index were significantly correlated with the GS. CONCLUSIONS: The extent and severity of coronary artery stenosis in Chinese patients >=60 years old is positively correlated with the severity of periodontitis. PMID- 23981216 TI - Application of chlorhexidine, fluoride and artificial saliva during radiotherapy: an in vitro study of microleakage in Class V restorations. AB - BACKGROUND: The aim of this study was to evaluate the effect on microleakage in Class V restorations of daily applications of artificial saliva, fluoride mouthrinses and chlorhexidine to irradiated bovine teeth. METHODS: Class V cavities were created in 60 bovine teeth. The teeth were divided randomly into two groups: the first group (n = 30) was subjected to radiotherapy until the teeth had received a total accumulated dose of 60 Gy; the second group (n = 30) was used as a control group. Both groups were divided into three subgroups (n = 10): in Group A teeth were submerged in Xeros Dentaid((r)) artificial saliva; Group B teeth were submerged in a solution of 1% amine fluoride; Group C teeth were submerged in 0.12% chlorhexidine. All treatments were applied three times a day for six weeks. Afterwards microleakage into the composite restorations was measured using MIP4 image software. RESULTS: It was seen that radiation caused increases in microleakage in composite restorations. Statistically significant differences were found in the artificial saliva group (p = 0.013) and the chlorhexidine group (p = 0.023). CONCLUSIONS: Microleakage in composite restorations was greater among radiated teeth. PMID- 23981217 TI - Dental visiting by insurance and oral health impact. AB - BACKGROUND: The aim of this study was to explore whether oral health has an influence on the association between dental insurance and dental visiting. METHODS: A random sample of adults aged 30-61 years living in Australia was drawn from the Australian Electoral Roll. Data were collected by mailed survey in 2009 2010, including age, gender, household income, dental insurance status, dental visiting and oral health impact. RESULTS: Responses were collected from n = 1096 persons (response rate = 39.1%). Dental insurance was positively associated with visiting a dentist in the last 12 months (prevalence ratio (PR) = 1.48; 95% CI: 1.31-1.67), while oral health impact was not associated with recent visiting PR = 1.01; 95% CI: 0.89-1.14). Visiting for the purpose of pain relief was less prevalent among insured participants (PR = 0.60; 95% CI: 0.44-0.81), but more prevalent among those with poor oral health (PR = 2.85; 95% CI: 2.15-3.76). It was found that oral health impact did not alter the relationship between dental insurance and visiting. CONCLUSIONS: Oral health impacts were not associated with recent dental visits, but were associated with visits for pain relief. Dental insurance was associated with a greater likelihood of recent visits and lower levels of relief of pain visits. PMID- 23981218 TI - Effect of non-surgical periodontal treatment on HbA1c: a meta-analysis of randomized controlled trials. AB - BACKGROUND: A meta-analysis of randomized clinical trials (RCTs) was conducted to evaluate whether non-surgical periodontal treatment can reduce the HbA1c% level in type 2 diabetic patients. Recent accumulation of RCTs necessitates updating of the findings of previous reviews. METHODS: A search of the literature on English publications was conducted in Cochrane CENTRAL, Medline and EMBASE (until 31 March 2012). An RCT was selected if the study population was type 2 diabetic patients (>=16 years old) diagnosed with periodontitis, and compared HbA1c% change with or without non-surgical periodontal treatment for at least three months of the study duration. Weighted mean differences for pooled data and antibiotic use strata were calculated. Heterogeneity and publication bias were explored. RESULTS: A total of 358 articles were identified but only six were suitable. Compared to the control group, the pooled analysis (n = 422) showed 0.41% (95% CI: -0.73% to -0.09%, p = 0.013) absolute difference in HbA1c% with treatment. Studies without adjunctive antibiotic had HbA1c% change of -0.64% (95% CI: -1.06% to -0.23%, p = 0.002), but we could not conclude on the effect of adjunctive antibiotic use (p = 0.734). Publication bias was significant with Egger's test (p = 0.014) but not with Begg's test (p = 0.06). CONCLUSIONS: The meta-analysis suggested that non-surgical periodontal treatment was associated with a reduction in HbA1c%. PMID- 23981219 TI - The use of virtual planning and navigation in the treatment of temporomandibular joint ankylosis. AB - Temporomandibular joint ankylosis is not common in our community but can occur as a result of severe facial trauma or significant connective tissue disorders such as rheumatoid arthritis, osteoarthritis and psoriatic arthritis, and unfortunately as a result of iatrogenic causes. Ankylosis surgery is aimed at gap arthroplasty and mobilization of the joints. However, the removal of the bony ankylosis and the production of a gap between the ramus of the mandible and the base of the skull is often difficult because of the size of the ankylosis and the anatomy on the inner aspect of the mandible. As a result of this, the author has found that surgical navigation has been useful with the removal of the ankylosis, both on the medial side of the mandible and the cranial base. Once the ankylosis has been freed and the mandible mobilized, the gap arthroplasty needs to be maintained or the release of the ankylosis will fail and the joints will re ankylose. It is important to maintain the space produced by the arthroplasty but this is difficult when autogenous materials such as temporalis muscle, dermis fat and other like materials are used. The gap ultimately closes under the influence of the masseter and medial pterygoid muscles and the ankylosis may return. This case report presents three representative patients in whom ankylosis has been released and the gap reconstructed with a total alloplastic joint replacement. All patients have had their ankylosis removed with the aid of a navigation system and all patients have been reconstructed with bilateral Biomet prosthesis. One patient has had their implant selected using virtual planning and the production of templates to help with placement of the stock implant. PMID- 23981220 TI - Oral manifestations of secondary syphilis in the elderly - a timely reminder for dentists. AB - Syphilis is a sexually transmitted infectious disease caused by Treponema pallidum. Cases of syphilis have increased in frequency and are challenging when affecting the elderly. The main causes of increased prevalence of syphilis are sexual promiscuity, lack of knowledge about the disease and decreasing use of barrier protection. Clinically, the oral manifestation of syphilis may resemble other entities, which hampers the correct diagnosis. We report a case of a 79 year-old male with weight loss and feeding difficulties. In the oral cavity there were ulcerative lesions in the hard palate and bilaterally in the buccal mucosa. The incisional biopsy revealed only a non-specific ulceration of the oral mucosa. After 20 days, the patient was re-evaluated and presented maculopapular lesions in the palmar and plantar areas. Positive serological venereal disease reference laboratory (VDRL) tests confirmed the diagnosis of secondary syphilis. The patient was treated with Benzathine penicillin G. After two weeks of treatment the oral lesion disappeared and the patient returned to normal feeding and gained weight. This case report reinforces the need to alert physicians and dentists to include sexually transmitted infections such as syphilis in the differential diagnosis of oral ulcerative lesions in elderly sexually active patients. PMID- 23981221 TI - Perioral dermatitis from high fluoride dentifrice: a case report and review of literature. AB - Perioral dermatitis is a papulopustular eruption, commonly related to the inappropriate application of topical corticosteroids with occasional reports of inhaled corticosteroids and decreased personal hygiene. We present a case of a 45 year-old female with a one-year history of perioral dermatitis related to the use of highly fluoridated toothpaste commenced to control dental caries. PMID- 23981222 TI - Hepatocellular carcinoma metastasis to the maxilla: a rare case. AB - The manifestation of metastatic malignant disease in the oral cavity can present in a number of ways and may mimic benign conditions. This case reports a rare presentation from a metastasis of a hepatocellular carcinoma that had invaded the attached gingiva of the maxilla and which on initial inspection could have been misdiagnosed as a pyogenic granuloma. With the advent of new classes of drugs to manage this disease it could be expected that this presentation may become more common. PMID- 23981223 TI - The spontaneously developing numb lower lip. AB - A case of a patient with impaired sensation in the distribution of the left mental nerve, having had no recent dental treatment, is presented. The cause proved to be a secondary tumour with the primary lesion being an adenocarcinoma of the lung in an individual who had never smoked. The radiological appearance suggested a possible dental abscess. The need for diagnostic vigilance is emphasized. PMID- 23981224 TI - Success for a novel approach to priority setting in South Australian public dental clinics. PMID- 23981227 TI - NPEBseq: nonparametric empirical bayesian-based procedure for differential expression analysis of RNA-seq data. AB - BACKGROUND: RNA-seq, a massive parallel-sequencing-based transcriptome profiling method, provides digital data in the form of aligned sequence read counts. The comparative analyses of the data require appropriate statistical methods to estimate the differential expression of transcript variants across different cell/tissue types and disease conditions. RESULTS: We developed a novel nonparametric empirical Bayesian-based approach (NPEBseq) to model the RNA-seq data. The prior distribution of the Bayesian model is empirically estimated from the data without any parametric assumption, and hence the method is "nonparametric" in nature. Based on this model, we proposed a method for detecting differentially expressed genes across different conditions. We also extended this method to detect differential usage of exons from RNA-seq data. The evaluation of NPEBseq on both simulated and publicly available RNA-seq datasets and comparison with three popular methods showed improved results for experiments with or without biological replicates. CONCLUSIONS: NPEBseq can successfully detect differential expression between different conditions not only at gene level but also at exon level from RNA-seq datasets. In addition, NPEBSeq performs significantly better than current methods and can be applied to genome-wide RNA seq datasets. Sample datasets and R package are available at http://bioinformatics.wistar.upenn.edu/NPEBseq. PMID- 23981228 TI - Room temperature dehydrogenation of ethane, propane, linear alkanes C4-C8, and some cyclic alkanes by titanium-carbon multiple bonds. AB - The transient titanium neopentylidyne, [(PNP)Ti=C(t)Bu] (A; PNP(-)=N[2-P(i)Pr2-4 methylphenyl]2(-)), dehydrogenates ethane to ethylene at room temperature over 24 h, by sequential 1,2-CH bond addition and beta-hydrogen abstraction to afford [(PNP)Ti(eta(2)-H2C?CH2)(CH2(t)Bu)] (1). Intermediate A can also dehydrogenate propane to propene, albeit not cleanly, as well as linear and volatile alkanes C4 C6 to form isolable alpha-olefin complexes of the type, [(PNP)Ti(eta(2) H2C?CHR)(CH2(t)Bu)] (R = CH3 (2), CH2CH3 (3), (n)Pr (4), and (n)Bu (5)). Complexes 1-5 can be independently prepared from [(PNP)Ti?CH(t)Bu(OTf)] and the corresponding alkylating reagents, LiCH2CHR (R = H, CH3(unstable), CH2CH3, (n)Pr, and (n)Bu). Olefin complexes 1 and 3-5 have all been characterized by a diverse array of multinuclear NMR spectroscopic experiments including (1)H-(31)P HOESY, and in the case of the alpha-olefin adducts 2-5, formation of mixtures of two diastereomers (each with their corresponding pair of enantiomers) has been unequivocally established. The latter has been spectroscopically elucidated by NMR via C-H coupled and decoupled (1)H-(13)C multiplicity edited gHSQC, (1)H (31)P HMBC, and dqfCOSY experiments. Heavier linear alkanes (C7 and C8) are also dehydrogenated by A to form [(PNP)Ti(eta(2)-H2C?CH(n)Pentyl)(CH2(t)Bu)] (6) and [(PNP)Ti(eta(2)-H2C?CH(n)Hexyl)(CH2(t)Bu)] (7), respectively, but these species are unstable but can exchange with ethylene (1 atm) to form 1 and the free alpha olefin. Complex 1 exchanges with D2C?CD2 with concomitant release of H2C?CH2. In addition, deuterium incorporation is observed in the neopentyl ligand as a result of this process. Cyclohexane and methylcyclohexane can be also dehydrogenated by transient A, and in the case of cyclohexane, ethylene (1 atm) can trap the [(PNP)Ti(CH2(t)Bu)] fragment to form 1. Dehydrogenation of the alkane is not rate determining since pentane and pentane-d12 can be dehydrogenated to 4 and 4-d12 with comparable rates (KIE = 1.1(0) at ~29 degrees C). Computational studies have been applied to understand the formation and bonding pattern of the olefin complexes. Steric repulsion was shown to play an important role in determining the relative stability of several olefin adducts and their conformers. The olefin in 1 can be liberated by use of N2O, organic azides (N3R; R = 1-adamantyl or SiMe3), ketones (O?CPh2; 2 equiv) and the diazoalkane, N2CHtolyl2. For complexes 3-7, oxidation with N2O also liberates the alpha-olefin. PMID- 23981229 TI - Inbreeding depression in an insect with maternal care: influences of family interactions, life stage and offspring sex. AB - Although inbreeding is commonly known to depress individual fitness, the severity of inbreeding depression varies considerably across species. Among the factors contributing to this variation, family interactions, life stage and sex of offspring have been proposed, but their joint influence on inbreeding depression remains poorly understood. Here, we demonstrate that these three factors jointly shape inbreeding depression in the European earwig, Forficula auricularia. Using a series of cross-breeding, split-clutch and brood size manipulation experiments conducted over two generations, we first showed that sib mating (leading to inbred offspring) did not influence the reproductive success of earwig parents. Second, the presence of tending mothers and the strength of sibling competition (i.e. brood size) did not influence the expression of inbreeding depression in the inbred offspring. By contrast, our results revealed that inbreeding dramatically depressed the reproductive success of inbred adult male offspring, but only had little effect on the reproductive success of inbred adult female offspring. Overall, this study demonstrates limited effects of family interactions on inbreeding depression in this species and emphasizes the importance of disentangling effects of sib mating early and late during development to better understand the evolution of mating systems and population dynamics. PMID- 23981230 TI - High glucose concentration up-regulates the expression of matrix metalloproteinase-9 and -13 in tendon cells. AB - BACKGROUND: Diabetes mellitus is associated with tendinopathy or tendon injuries. However, the mechanism underlying diabetic tendinopathy is unclear. The purpose of this study was to examine the effects of high glucose concentrations on the activity and expression of matrix metalloproteinases, type I collagen, and type III collagen in tendon cells. METHODS: Tendon cells from rat Achilles tendons were treated with 6 mM, 12 mM, and 25 mM glucose, and then cell proliferation was evaluated by the 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Messenger RNA (mRNA) expression of MMP-2, MMP-8, MMP-9, and MMP-13 and type I and type III collagen was assessed by quantitative real-time polymerase chain reaction (PCR). The enzymatic activity of MMP-2 and MMP-9 was measured by gelatin zymography. RESULTS: The MTT assay results showed that the glucose concentration did not affect tendon cell proliferation. The results of the real-time PCR assay revealed that the mRNA expression of MMP-9 and MMP-13 was up-regulated by treatment with 25 mM glucose, whereas the mRNA expression of type I and III collagen was not affected. Gelatin zymography showed that 25 mM glucose increased the enzymatic activity of MMP-9. CONCLUSIONS: High glucose concentration up-regulates the expression of MMP-9 and MMP-13 in tendon cells, which may account for the molecular mechanisms underlying diabetic tendinopathy. PMID- 23981232 TI - Mapping affected sites of cavernous malformation in the posterior cranial fossa. PMID- 23981231 TI - Oxytocin induced oxidative stress in lactating Bubalis bubalis (Nili Ravi). AB - BACKGROUND: Oxytocin has been reported for a wide range of adverse effects in different species of lactating animals. The present study was aimed to evaluate the adverse effects of oxytocin on biomarkers of oxidative stress in buffaloes. Lactating buffaloes (n = 40) were randomly selected from a commercial dairy farm located in the peri-urban area of district Faisalabad, Pakistan and divided into two equal groups viz. treatment and control groups, each containing 20 buffaloes. Buffaloes in treatment group were injected with oxytocin before each milking (morning and evening) for milk let down; whereas, animals in control group were milked naturally without oxytocin injection. Both the groups were assessed for oxidative stress biomarkers. RESULTS: Results showed significantly higher levels (P <= 0.05) of TOS, tHcy and ceruloplasmin oxidase activity in lactating buffaloes injected with oxytocin as compared to those of control group. On the other hand, serum levels of TAS, PON1 and arylesterase were significantly lower (P <= 0.05) in the buffaloes of treatment group. CONCLUSIONS: Oxytocin injection in lactating buffaloes resulted in elevated oxidative stress by increasing the total homocysteine and ceruloplasmin oxidase activity and decreasing enzymatic activities of antioxidant enzymes including paraoxonase-1 and arylesterase; that might render the animals to poor productive and reproductive potential. PMID- 23981233 TI - Improving forensic mental health care to Indigenous Australians: theorizing the intercultural space. AB - This paper uses the 'intercultural space' as an educational strategy to prepare nurses to work respectfully with Indigenous patients in a forensic mental health context; offers an educational approach that introduces nurses to Indigenous knowledge, beliefs and values, examines power relations in colonized countries between the dominant white cultural group and the Indigenous population and encourages nurses to critically reflect on their health care practice; and explores the intercultural space as a shared space between cultures fostering open and robust inquiry where neither culture dominates and new positions, representations and understandings can emerge. Given the disproportionately high number of Indigenous people imprisoned in colonized countries, this paper responds to research from Western Australia on the need to prepare forensic mental health nurses to deliver care to Indigenous patients with mental health disorders. The paper highlights the nexus between theory, research and education that can inform the design and implementation of programmes to help nurses navigate the complex, layered and contested 'intercultural space' and deliver culturally safe care to Indigenous patients. Nurses are encouraged to critically reflect on how beliefs and values underpinning their cultural positioning impact on health care to Indigenous patients. The paper draws on intercultural theory to offer a pedagogical framework that acknowledges the negative impacts of colonization on Indigenous health and well-being, repositions and revalues Indigenous cultures and knowledges and fosters open and robust inquiry. This approach is seen as a step towards working more effectively in the intercultural space where ultimately binary oppositions that privilege one culture over another and inhibit robust inquiry are avoided, paving the way for new, more inclusive positions, representations and understandings to emerge. While the intercultural space can be a place of struggle, tension and ambiguity, it also offers deep potential for change. PMID- 23981234 TI - Eyelash growth induced by topical prostaglandin analogues, bimatoprost, tafluprost, travoprost, and latanoprost in rabbits. AB - PURPOSE: Prostaglandin analogues (PGA) are ocular hypotensive agents used for the treatment of glaucoma. Hypertrichosis of the eyelashes has been reported in humans as a side effect. Eyelash growth was investigated with clinical trials in people using bimatoprost. Scattered reports of eyelash growth during the treatment of glaucoma with other PGA are also found in the literature. We investigated the effect of 4 different topical PGA on eyelash length. METHODS: Forty New Zealand white rabbits were divided into 4 groups and received daily topical application of bimatoprost, tafluprost, travoprost, and latanoprost in the left eye for 4 weeks. The right eye received no treatment. Eyelash length was measured in both eyes before and after treatment using a stainless steel digital caliper. RESULTS: Bimatoprost and tafluprost groups had significant increases in eyelash length. We did not observe significant eyelash growth in rabbits receiving travoprost and latanoprost after 1 month of treatment. CONCLUSIONS: Today, only bimatoprost is approved for growing eyelashes, and our research shows that tafluprost could be further explored by the cosmetic and pharmaceutical industry. Additional research using travoprost and latanoprost as agents for eyelash growth should be performed in the future using prolonged treatment periods to determine whether or not these PGA induce eyelash growth, and investigate other possible side effects. PMID- 23981236 TI - The Erectile Performance Anxiety Index: scale development and psychometric properties. AB - INTRODUCTION: Erectile dysfunction is a highly publicized and prevalent condition with marked adverse effects on men's social, emotional, and quality of life. Although several instruments have emerged for assessing erectile dysfunction and its impact on men's quality of life, none of the existing instruments provide a specific assessment of men's erectile performance anxiety. AIM: This article reports on the development and psychometric evaluation of the Erectile Performance Anxiety Index (EPAI)--a 10-item self-report scale designed to fill an important gap in the assessment of male erectile dysfunction. METHODS: A total of 207 men ranging in age from 18 to 79 took part in the study. All subjects completed an online battery consisting of the EPAI, along with measures of related sexual functioning, social anxiety, state anxiety, and depressive symptoms. A small subset of study participants (N = 42) completed the EPAI a second time for determining test-retest reliability. MAIN OUTCOME MEASURE: Test retest reliability was determined by Pearson's product-moment correlations. Internal reliability was assessed using Cronbach's alpha. Factor validity was evaluated by a maximum likelihood factor analysis with oblique rotation. Convergent and discriminant validity was assessed by comparing the strength of association between the EPAI and measures varying in their hypothesized shared variance with the construct of erectile performance anxiety. RESULTS: The EPAI demonstrated excellent internal consistency, with Cronbach's alpha = 0.93 and excellent test-retest reliability (r = 0.85) over an average period of 3.5 weeks. Results of an exploratory factor analysis revealed a one-factor solution that accounted for 63% of the total variance. Preliminary evidence supports the convergent and discriminant validity of the EPAI. CONCLUSION: Results support the use of the EPAI as a reliable, valid, and efficient instrument for the assessment of erectile performance anxiety. Potential research and clinical applications are discussed. PMID- 23981238 TI - First row transition metal(II) thiocyanate complexes, and formation of 1-, 2-, and 3-dimensional extended network structures of M(NCS)2(solvent)2 (M = Cr, Mn, Co) composition. AB - The reaction of first row transition M(II) ions with KSCN in various solvents form tetrahedral (NMe4)2[M(II)(NCS)4] (M = Fe, Co), octahedral trans M(II)(NCS)2(Sol)4 (M = Fe, V, Ni; Sol = MeCN, THF), and K4[M(II)(NCS)6] (M = V, Ni). The reaction of M(NCS)2(OCMe2)2 (M = Cr, Mn) in MeCN and [Co(NCMe)6](BF4)2 and KSCN in acetone and after diffusion of diethyl ether form M(NCS)2(Sol)2 that structurally differ as they form one-dimensional (1-D) (M = Co; Sol = THF), two dimensional (2-D) (M = Mn; Sol = MeCN), and three-dimensional (3-D) (M = Cr; Sol = MeCN) extended structures. 1-D Co(NCS)2(THF)2 has trans-THFs, while the acetonitriles have a cis geometry for 2- and 3-D M(NCS)2(NCMe)2 (M = Cr, Mn). 2-D Mn(NCS)2(NCMe)2 is best described as Mn(II)(MU(N,N)-NCS)(MU(N,S)-NCS)(NCMe)2 [= Mn2(MU(N,N)-NCS)2(MU(N,S)-NCS)2(NCMe)4] with the latter MU(N,S)-NCS providing the 2-D connectivity. In addition, the reaction of Fe(NCS)2(OCMe2)2 and 7,7,8,8 tetracyanoquino-p-dimethane (TCNQ) forms 2-D structured Fe(II)(NCS)2TCNQ. The magnetic behavior of 1-D Co(NCS)2(THF)2 can be modeled by a 1-D Fisher expression (H = -2JS(i).S(j)) with g = 2.4 and J/kB = 0.68 K (0.47 cm(-1)) and exhibit weak ferromagnetic coupling. Cr(NCS)2(NCMe)2 and Fe(II)(NCS)2TCNQ magnetically order as antiferromagnets with Tc's of 37 and 29 K, respectively, while Mn(NCS)2(NCMe)2 exhibits strong antiferromagnetic coupling. M(NCS)2(THF)4 and K4[M(NCS)6] (M = V, Ni) are paramagnets with weak coupling between the octahedral metal centers. PMID- 23981237 TI - Histopathological diagnosis of adenocarcinoma in Barrett's esophagus. AB - The present review describes the histological markers of Barrett's esophagus (BE) that make it possible to distinguish between Barrett's carcinoma (BC) and gastric carcinoma. With regard to high-grade dysplasia, the indications for endoscopic resection (ER) or major surgery for management of BC cannot be decided on the basis of biopsy histology, and the choice between them should be made according to BC invasion depth. Therefore, we recommend that the term 'well-differentiated tubular adenocarcinoma' be used rather than 'high-grade dysplasia' (intraepithelial neoplasia). High-grade dysplasia is regarded as BC in Japan and other countries such as Germany. Such lesions should not be treated by endoscopic ablation but by ER, because components of invasive carcinoma are frequently present in the mucosa and submucosa, and knowledge obtained from ER samples is needed for additional therapy. Further studies on the relationship between the incidence of nodal metastasis and mucosal depth in mucosal BC are needed to decide the indications for ER. Suchstudies should involve subserial microscopic examination of slices 2-3 mm thick. To resolve the issue of regression of high grade dysplasia, international experts in gastroenterological pathology need to conduct histopathological reviews of the first and last samples taken from such cases, as there are large differences between North American, European, and Japanese pathologists in the criteria used for histological diagnosis of dysplasia and adenocarcinoma without clear invasion, and both interobserver and intraobserver variations have been reported. Future studies will need to focus on which carcinomas are curable by ER. PMID- 23981235 TI - Optochemical control of deoxyoligonucleotide function via a nucleobase-caging approach. AB - Synthetic oligonucleotides have been extensively applied tocontrol a wide range of biological processes such as gene expression, gene repair, DNA replication, and protein activity. Based on well-established sequence design rules that typically rely on Watson-Crick base pairing interactions researchers can readily program the function of these oligonucleotides. Therefore oligonucleotides provide a flexible platform for targeting a wide range of biological molecules, including DNA, RNA, and proteins. In addition, oligonucleotides are commonly used research tools in cell biology and developmental biology. However, a lack of conditional control methods has hampered the precise spatial and temporal regulation of oligonucleotide activity, which limits the application of these reagents to investigate complex biological questions. Nature controls biological function with a high level of spatial and temporal resolution and in order to elucidate the molecular mechanisms of biological processes, researchers need tools that allow for the perturbation of these processes with Nature's precision. Light represents an excellent external regulatory element since irradiation can be easily controlled spatially and temporally. Thus, researchers have developed several different methods to conditionally control oligonucleotide activity with light. One of the most versatile strategies is optochemical regulation through the installation and removal of photolabile caging groups on oligonucleotides. To produce switches that can control nucleic acid function with light, chemists introduce caging groups into the oligomer backbone or on specific nucleobases to block oligonucleotide function until the caging groups are removed by light exposure. In this Account, we focus on the application of caged nucleobases to the photoregulation of DNA function. Using this approach, we have both activated and deactivated gene expression optochemically at the transcriptional and translational level with spatial and temporal control. Specifically, we have used caged triplex-forming oligomers and DNA decoys to regulate transcription, and we have regulated translation with light-activated antisense agents. Moreover, we also discuss strategies that can trigger DNA enzymatic activity, DNA amplification, and DNA mutagenesis by light illumination. More recently, we have developed light-activated DNA logic operations, an advance that may lay the foundation for the optochemical control of complex DNA calculations. PMID- 23981239 TI - Vesicular powder as carrier for doxycycline hydrochloride and metronidazole combination therapy. AB - In this study, vesicular proniosomal powder encapsulating doxycycline hydrochloride (DH) and metronidazole (MT) combination therapy was developed using different types of spans, cholesterol (CH) and maltodextrin as a carrier. Proniosomal powder was free flowing and spherical in shape. The surfactant structure affected the entrapment efficiency of both drugs with highest value of Sp 60 proniosomes of 45.16% and 42.64% for DH and MT, respectively. Incorporation of CH influenced vesicle stability and permeability with optimum concentration of 10 mole%. Increasing the surfactant loading from 1 mM to 3 mM resulted in a significant decrease in the amount of drugs (mg) entrapped per mM lipid (from 9.95 to 1.13 and from 8.88 to 1.22 for DH and MT, respectively). Longer chain length surfactants produced larger vesicles. Surfactant hydrophilicity affected zeta potential. Both drugs were molecularly dispersed in the proniosomal powder with no chemical interaction with other components. Proniosomal powder was stable at 2-8 degrees C for three months. PMID- 23981240 TI - High prevalence of fibromyalgia-associated symptoms in patients with hypothalamic pituitary disorders. AB - OBJECTIVES: Various complaints of patients with fibromyalgia often resemble clinical features observed in patients with hypothalamic-pituitary diseases. The aim of this study was to evaluate whether patients with hypothalamic-pituitary diseases are at increased risk for fibromyalgia syndrome (FMS). METHODS: A questionnaire for evaluating fibromyalgia-associated symptoms was sent to 121 patients with hypothalamic-pituitary disorders (HPD) (60 women, 61 men; mean age, 55.4 years; range, 21-83 years) of the endocrine outpatient clinic. 115 patients (57 women, 58 men; mean age 56.9 years; range, 21 to 82 years) with cardiovascular diseases (CD) served as controls. RESULTS: Fibromyalgia-associated symptoms regarding muscular complaints were significantly more frequent in the HPD group than in CD patients (53.7 % vs. 35.7%, p= 0.003). In particular, we found a significant higher prevalence of autonomic symptoms in the HPD group as compared to the CD group regarding several qualities (cold hands, p=0.039; flatulence, p=0.022; tiredness, p=0.017). In addition, swollen and painful finger joints were reported more often in the HPD group than in the CD group (p=0.002). Of note, no differences regarding any fibromyalgia-associated symptom were detected when patients with hypothalamic-pituitary hormone excess syndromes were compared to those with a pituitary pathology without hormonal excess. Similarly, prevalence of fibromyalgia-associated symptoms was not related to the treatment modality of pituitary disease; i.e. surgical vs. conservative or any hormonal replacement therapy. CONCLUSIONS: Our data suggest that patients with hypothalamic-pituitary disorders may be at increased risk of developing fibromyalgia-associated symptoms. PMID- 23981242 TI - Assessment of metal pollution sources by SEM/EDS analysis of solid particles in snow: a case study of Zerjav, Slovenia. AB - Solid particles in snow deposits, sampled in mining and Pb-processing area of Zerjav, Slovenia, have been investigated using scanning electron microscopy/energy-dispersive X-ray spectroscopy (SEM/EDS). Identified particles were classified as geogenic-anthropogenic, anthropogenic, and secondary weathering products. Geogenic-anthropogenic particles were represented by scarce Zn- and Pb-bearing ore minerals, originating from mine waste deposit. The most important anthropogenic metal-bearing particles in snow were Pb-, Sb- and Sn bearing oxides and sulphides. The morphology of these particles showed that they formed at temperatures above their melting points. They were most abundant in snow sampled closest to the Pb-processing plant and least abundant in snow taken farthest from the plant, thus indicating that Pb processing was their predominant source between the last snowfall and the time of sampling. SEM/EDS analysis showed that Sb and Sn contents in these anthropogenic phases were higher and more variable than in natural Pb-bearing ore minerals. The most important secondary weathering products were Pb- and Zn-containing Fe-oxy-hydroxides whose elemental composition and morphology indicated that they mostly resulted from oxidation of metal-bearing sulphides emitted from the Pb-processing plant. This study demonstrated the importance of single particle analysis using SEM/EDS for differentiation between various sources of metals in the environment. PMID- 23981241 TI - Is small-bowel capsule endoscopy effective for diagnosis of esophagogastric lesions related to portal hypertension? AB - BACKGROUND AND AIM: Effectiveness of capsule endoscopy (CE) for screening the small bowel in patients with portal hypertension (PHT) has been reported. However, few reports discuss CE detection of specific esophagogastric lesions related to PHT. Thus, we assessed whether CE is useful for detecting such lesions. METHODS: One hundred nineteen consecutive patients with PHT comprised the study group. All had undergone esophagogastroduodenoscopy (EGD) prior to CE. The diagnostic yield of CE for esophageal varices (EVs), gastric varices (GVs), and portal hypertensive gastropathy (PHG) was evaluated. In addition, diagnostic yield in relation to form, location of the varices, grade, and extent of PHG was evaluated. RESULTS: EVs were found by EGD in 71 patients. The overall diagnostic yield of CE for EVs was 72% (51/71). The diagnostic yield was significantly greater for F2/F3 EVs than for F1 EVs (87% vs 61%, P = 0.03). The diagnostic yield was significantly greater for Lm/Ls EVs than for Li EVs (85% vs 55%, P = 0.01). The diagnostic yield was significantly greater for locus superior/locus medialis EVs than for locus inferior EVs (85% vs 55%, P = 0.01). GVs were found by EGD in 29 patients. Only one case was detected by CE. PHG was found by EGD in 35 patients. The diagnostic yield of CE for PHG was 69% (24/35). There was no difference in diagnostic yield between cases of severe and mild PHG (82% vs 63%, P = 0.44). Diagnostic yield of CE for PHG in the gastric body was significantly greater than that in the fundus (100% vs 48%, P = 0.0009). CONCLUSION: CE is reliable for diagnosis of F2/F3 and/or Lm/Ls EVs and of PHG in the gastric body. PMID- 23981243 TI - The importance of histopathological diagnosis in the management of lesions presenting as peri-implantitis. AB - PURPOSE: This study is a histopathological analysis of lesions clinically diagnosed as peri-implantitis (PI). MATERIALS AND METHODS: This retrospective study included microscopic findings in 117 peri-implant biopsies from lesions presenting clinical and radiographic features of peri-implantitis. RESULTS: The study group included 117 biopsies, mean age 55.2 years; 60.9% of biopsies were from failing implants during explantation, the remaining from surviving implants. All cases showed microscopic evidence for inflammation; however, although 41% exhibited only nonspecific inflammation, 29.9% exhibited actinomyces-related inflammation, 18.8% pyogenic granuloma (PG), and 10.3% giant cell granuloma (GCG). Differences in implant failure rates between pathological diagnostic groups were not statistically significant. Lesions with simple inflammation could not be distinguished clinically or radiographically from the potentially destructive lesions. CONCLUSIONS: There were no clinical features which could distinguish PI with simple inflammation from potentially destructive lesions mimicking PI, such as GCG, PG, and actinomycosis. However, to control GCG and PG surgical procedures would be recommended, actinomycosis would indicate specific antibiotics, whereas in nonspecific inflammation, these measures may not be indicated. The results of the present study provide evidence for the importance of early microscopic examination of lesions presenting clinically as peri implantitis, a step toward more accurate diagnosis and improved treatment of PI and lesions mimicking PI. PMID- 23981244 TI - Bradykinin preconditioning affects the number of degenerated neurons and the level of antioxidant enzymes in spinal cord ischemia in rabbits. AB - Bradykinin preconditioning has been used for acquisition of tolerance after spinal cord ischemia. Rabbits were preconditioned intraperitoneally with bradykinin 48 h prior to 20 min of abdominal aorta ligation followed by 24 and 48 h of reperfusion. The activities of SOD and catalase were measured and Fluoro Jade B (FJB)-positive degenerated neurons were evaluated. The outcomes of Tarlov scoring system used to assess neurological functions showed significant improvement in bradykinin groups compared to the ischemic group. The number of FJB-positive degenerated neurons was decreased in ventral horns of both bradykinin groups. Significantly decreased activities of total SOD and mitochondrial Mn-SOD were also detected in both bradykinin groups versus ischemic group while CuZn-SOD and catalase activities were significantly decreased only in the bradykinin group after 24h of reperfusion versus ischemic group. These findings suggest that one of the possibilities of the neuroprotective effect of delayed bradykinin preconditioning against spinal cord ischemic injury could be realized by mitochondrial protection and decreased synthesis of Mn-SOD as well as by promotion of neuronal survival. PMID- 23981246 TI - Molecular iodine initiates hydroborations of alkenes with N-heterocyclic carbene boranes. AB - The hydroboration of alkenes of diverse structural types by assorted N heterocyclic carbene boranes can be accomplished by addition of 5-10% diiodine. For example, reaction of 1,3-dimethylimidazol-2-ylidene borane (diMe-Imd-BH3) with 10% I2 followed by addition of 2,3-dimethyl-2-butene provided the corresponding thexyl NHC-borane (diMe-Imd-BH2thexyl) in 75% yield. This and related monohydroboration products are stable to chromatography and storage. The scope of the new reaction is described, and the mechanism is probed by (11)B NMR experiments. PMID- 23981245 TI - Transformational leadership and safety performance among nurses: the mediating role of knowledge-related job characteristics. AB - AIMS: To report the impact of transformational leadership on two dimensions of nurses' safety performance (i.e. safety compliance and safety participation) and to study the mediating role of knowledge-related job characteristics in this relationship. BACKGROUND: Safety performance refers to the behaviours that employees exhibit to adhere to safety guidelines and to promote health and safety at their workplace. Nurses' safety performance is a major challenge for healthcare settings, urging the need to identify the key determinants and psychological mechanisms that influence it. DESIGN: A cross-sectional survey study. METHODS: The study was carried out in September 2010 in a large Belgian hospital. We used self-administered questionnaires; 152 nurses participated. The hypotheses were tested using hierarchical regression analyses. RESULTS/FINDINGS: In line with our first hypothesis, the results show that transformational leadership exerted a significant positive impact on both dimensions of nurses' safety performance. This positive relation was mediated by knowledge-related job characteristics, supporting our second hypothesis. CONCLUSION: Head nurses' transformational leadership can enhance nurses' compliance with and participation in safety. Furthermore, transformational head nurses are able to influence the perception that their nurses have about the kind and amount of knowledge in their job, which can also lead to increases in both dimensions of nurses' safety performance. This study therefore demonstrates the key impact that transformational head nurses have, both directly and indirectly, on the safety performance of their nurses. PMID- 23981247 TI - Model systems for a no-analog future: species associations and climates during the last deglaciation. AB - As the earth system moves to a novel state, model systems (experimental, observational, paleoecological) are needed to assess and improve the predictive accuracy of ecological models under environments with no contemporary analog. In recent years, we have intensively studied the no-analog plant associations and climates in eastern North America during the last deglaciation to better constrain their spatiotemporal distribution, test hypotheses about climatic and megaherbivory controls, and assess the accuracy of species- and community-level models. The formation of no-analog plant associations was asynchronous, beginning first in the south-central United States; at sites in the north-central United States, it is linked to declining megafaunal abundances. Insolation and temperature were more seasonal than present, creating climates currently nonexistent in North America, and shifting species-climate relationships for some taxa. These shifts pose a common challenge to empirical paleoclimatic reconstructions, species distribution models (SDMs), and conservation optimization models based on SDMs. Steps forward include combining recent and paleoecological data to more fully describe species' fundamental niches, employing community-level models to model shifts in species interactions under no analog climates, and assimilating paleoecological data with mechanistic ecosystem models. Accurately modeling species interactions under novel environments remains a fundamental challenge for all forms of ecological models. PMID- 23981248 TI - Hyperchloraemic metabolic acidosis induced by the iron chelator deferasirox: a case report and review of the literature. AB - WHAT IS KNOWN AND OBJECTIVE: Deferasirox is a new treatment of iron overload that is administered orally once-a-day, resulting in better acceptance in patients. Deferasirox-induced renal tubular dysfunction has been reported on very rare occasions. CASE SUMMARY: A 17-year-old adolescent with beta-thalassaemia on deferasirox 30 mg/kg daily presented with isolated hyperchloraemic metabolic acidosis (bicarbonate 12.9 mM, sodium 137 mM, chloride 111 mM, potassium 3.6 mM). Acidosis resolved after withdrawing deferasirox. Naranjo adverse drug reaction scale suggested that the likelihood that deferasirox was responsible for acidosis was probable. Eight cases of metabolic acidosis have been reported in patients treated with deferasirox. In most cases, acidosis was associated with further features of renal tubular dysfunction. WHAT IS NEW AND CONCLUSION: We describe herein a case of metabolic acidosis in the setting of treatment with the deferasirox. Our case and the literature indicate a potential risk of kidney toxicity on this agent. PMID- 23981249 TI - Cross-generational effects of temperature on flight performance, and associated life-history traits in an insect. AB - Nongenetic parental effects may affect offspring phenotype, and in species with multiple generations per year, these effects may cause life-history traits to vary over the season. We investigated the effects of parental, offspring developmental and offspring adult temperatures on a suite of life-history traits in the globally invasive agricultural pest Grapholita molesta. A low parental temperature resulted in female offspring that developed faster at low developmental temperature compared with females whose parents were reared at high temperature. Furthermore, females whose parents were reared at low temperature were heavier and more fecund and had better flight abilities than females whose parents were reared at high temperature. In addition to these cross-generational effects, females developed at low temperature had similar flight abilities at low and high ambient temperatures, whereas females developed at high temperature had poorer flight abilities at low than at high ambient temperature. Our findings demonstrate a pronounced benefit of low parental temperature on offspring performance, as well as between- and within-generation effects of acclimation to low temperature. In cooler environments, the offspring generation is expected to develop more rapidly than the parental generation and to comprise more fecund and more dispersive females. By producing phenotypes that are adaptive to the conditions inducing them as well as heritable, cross-generational plasticity can influence the evolutionary trajectory of populations. The potential for short term acclimation to low temperature may allow expanding insect populations to better cope with novel environments and may help to explain the spread and establishment of invasive species. PMID- 23981250 TI - Seasonal influenza vaccine effectiveness among children, 2010-2012. AB - BACKGROUND: The annual differences in the seasonal influenza vaccine and the circulating strains make it necessary to assess influenza vaccine effectiveness (VE) yearly. We assessed the effectiveness of the trivalent inactivated influenza vaccine for the 2010-2011 and 2011-2012 influenza seasons among children in Guangzhou, China. METHODS: We conducted a 1:2 matched case-control study based on date of birth (+/-7 days), gender, and area of residence. The influenza cases from surveillance sites in Guangzhou were laboratory-confirmed during the 2010 2012 seasons. The controls were randomly selected from children aged 6-59 months in the Children's Expanded Programmed Immunization Administrative Computerized System. The influenza vaccination information for both cases and controls was retrieved from this system. RESULTS: We analyzed the vaccination information for 1255 influenza cases and 2510 matched controls in 2 influenza seasons in Guangzhou, China. We found that the VE for vaccination during the 2010-2011 and 2011-2012 seasons of virus circulation was 73.2% (95% confidence interval (CI), 52.2-85.0%) and 52.9% (95% CI, 42.1-61.7%), respectively. The VE decreased from 68.9% (95% CI, 57.5-77.2%) in the period between January and March to 48.4% (95% CI, 33.8-59.7%) in the period between April and June. CONCLUSIONS: This post licensing study of VE found moderate protection against influenza for vaccinated children aged 6-59 months. Although the influenza vaccine strains for the 2010 2011 and the 2011-2012 seasons were the same, our study indicated that annual vaccination is recommended even for those who received the vaccine during the previous season. PMID- 23981251 TI - Eyes on new product development. PMID- 23981252 TI - The association of physical and mental health with sexual activity in older adults in a retirement community. AB - INTRODUCTION: Understanding sexual behavior is important when evaluating the health needs of older adults. Little research has addressed the effect of specific health conditions on sexual inactivity in this growing population. AIM: The study aims to assess the association of mental and physical health conditions with sexual inactivity among adults 55 and older living in The Villages, Florida. METHODS: Exposure data for 22 self-reported health conditions were assessed in relation to sexual inactivity in 22,654 participants ages 55 and older, including 1,879 participants over age 80 in a community-based cross-sectional study. Logistic regression analyses were conducted separately for men and women to evaluate the likelihood of being sexually active for each health condition. Covariates included age, race, education, income, self-reported overall health, and marital status. MAIN OUTCOME MEASURES: The odds ratio and 95% confidence intervals for sexual activity status were calculated separately for men and women. RESULTS: Fifty-five percent of men and 45% of women reported being sexually active. Significant positive correlates of sexual activity included walking at least 1-2 times per week, participating in at least two registered clubs, engaging in physical and social activities, no tobacco use, fewer medications, increased alcohol consumption, and reporting a good quality of life, psychological well-being, or social support. Sexual inactivity was significantly related to cancer, bladder/bowl problems, major surgery, poor vision, mental health conditions, and cardiovascular disease and its risk factors including diabetes, hypertension, and high cholesterol. Additional associations with sexual inactivity included hearing loss and dementia for men, and dermatologic conditions, problems with the joints, bone or back, gastrointestinal problems, alcohol misuse, chronic wound care, and gum disease in women. CONCLUSIONS: Mental and physical health conditions have very similar associations with sexual inactivity in men and women. Increased sexual activity was associated with positive physical, social, and emotional health indicators. PMID- 23981253 TI - No need for more muscle biopsies in members of the Spanish LGMD1F family. The gene has been identified at last. PMID- 23981254 TI - Topochemical cross-linking of the [Hf2N2] layers with sulfur in alpha-HfNBr. AB - alpha-HfNBr (space group Pmmn) isostructural with FeOCl consists of orthorhombic [Hf2N2] layers sandwiched by bromide layers. By the reaction with Na2S at 750 degrees C in a sealed glass tube, the alpha-type [Hf2N2] layers are topochemically cross-linked with sulfur to form alpha-Hf2N2S with a mutual shift of the layers in the ab plane by (a/2 + b/2) to crystallize in space group Immm and the lattice parameters a = 4.1422(1), b = 3.5058(1), and c = 11.4043(3) A. At a higher reaction temperature of 850 degrees C, the beta-type layered variant beta-Hf2N2S with a double honeycomb network is obtained, which adopts the La2O2S structure with space group P3m1 and the lattice parameters a = 3.5805(1) and c = 6.4063(1) A. PMID- 23981256 TI - Scientific evaluation and pricing of medical devices and associated procedures in France. AB - Medical devices are many and various, ranging from tongue spatulas to implantable or invasive devices and imaging machines; their lifetimes are short, between 18 months and 5 years, due to incessant incremental innovation; and they are operator-dependent: in general, the clinical user performs a fitting procedure (hip implant or pacemaker), a therapeutic procedure using a non-implantable invasive device (arrhythmic site ablation probe, angioplasty balloon, extension spondyloplasty system, etc.) or follow-up of an active implanted device (long term follow-up of an implanted cardiac defibrillator or of a deep brain stimulator in Parkinson's patients). A round-table held during the XXVIII(th) Giens Workshops meeting focused on the methodology of scientific evaluation of medical devices and the associated procedures with a view to their pricing and financing by the French National Health Insurance system. The working hypothesis was that the available data-set was sufficient for and compatible with scientific evaluation with clinical benefit. Post-registration studies, although contributing to the continuity of assessment, were not dealt with. Moreover, the focus was restricted to devices used in health establishments, where the association between devices and technical medical procedures is optimally representative. An update of the multiple regulatory protocols governing medical devices and procedures is provided. Issues more specifically related to procedures as such, to non-implantable devices and to innovative devices are then dealt with, and the proposals and discussion points raised at the round-table for each of these three areas are presented. PMID- 23981258 TI - How can the quality of medical data in pharmacovigilance, pharmacoepidemiology and clinical studies be guaranteed? AB - The development of medicinal products is subject to quality standards aimed at guaranteeing that database contents accurately reflect the source documents. Paradoxically, these standards hardly address the quality of the source data itself. The objective of this work was to propose recommendations to improve data quality in three fields (pharmacovigilance, pharmacoepidemiology and clinical studies). The analysis was focused on the data and on the critical stages presenting critical quality problems, for which the current guidelines are insufficiently detailed, unsuitable and/or poorly applied. Finally, recommendations have been proposed, mainly focused on the origin of the data and its transcription. PMID- 23981260 TI - Off-label prescriptions: how to identify them, frame them, announce them and monitor them in practice? AB - Following the Mediator crisis and the passage of the Health and Safety Law of December 2011, off-label prescriptions are a real concern shared by all those involved in healthcare system. Off-label, in the strictest sense of the term, is defined as all prescriptions that do not correspond to the summary of product characteristics (SPC), particularly those that fail to comply with the indications and dosage regimens defined by the marketing authorization (MA) for clear safety reasons. There are various rasons for off-label prescriptions, both conscious and unconscious. They are intended to respond to unmet medical needs, the needs of poorly studied populations or not studied at all in trials, but in relation to whom it is reasonable to extrapolate that MA would be given (common sense prescriptions) and, additionally, to urgent public health needs (such as baclofen, pregnant women, and HIV drugs). All these prescriptions would deserve to be studied for a potential MA. However, there are off-label prescriptions that need to be restricted or even penalized in the case of compassionate prescriptions or unjustified prescriptions or prescriptions not based on any scientific grounds. Off-label prescriptions are not easy to track down because if the prescriber has to write "off-label" on his prescription, then clearly, in practice, he will only do so in exceptional cases. Neither the pharmacists who dispense the drug nor the Social Security that reimburses it, have access to the diagnosis (or targeted indication). Thus, in order to identify the off-label prescription, we must be able to cross reference the available databases (such as pharmacovigilance database, medicalized information system program [programme de medicalisation des systemes d'information, PMSI], hospital drug formularies, general sample of beneficiaries [echantillon generaliste de beneficiaires, EGB] or national inter-regional Health Insurance Information System [systeme national d'informations inter-regions d'Assurance maladie, SNIIRAM], sales data, and data from market surveys). The shared computerized patient file may resolve this problem. The temporary use recommendation (TUR) proposed by the Drug Safety Law will only partially deal with this problem for recently marketed molecules. This temporary and exceptional mechanism will authorize a recognized off-label prescription, which may be reimbursed and monitored for 3 years. These TURs will only concern a small portion of "off-label" drugs having yet a positive risk/benefit ratio (conditional MA) but this is far from matching with majority of off-label prescriptions. As such, and in order to improve the use of drugs, it is important to propose a control system for all "off-label" prescriptions with a dedicated committee: the "off-label" committee which would determine the frame of the "off-label" prescriptions. PMID- 23981262 TI - Pharmacoepidemiology studies: what levels of evidence and how can they be reached? AB - In pharmacoepidemiology studies, the nature of the research question will dictate the choice of methodological approach and the conditions for optimizing the level of evidence. Thus, to document the treated population and the modes of use of a new drug in real-life prescribing conditions, a descriptive approach through cross-sectional or longitudinal studies conducted on databases, or else ad-hoc studies, will be preferred. On the other hand, evaluation of the real-life "effectiveness" of a new drug will be based on cohort, case-control or scientific modeling, depending on the drug and the disease of interest. For questions involving drug risks and safety, it is the adverse effects profile that will guide the choice of study design, both for identification of the effect (signal) and assessment of causation. In all cases, in the post-marketing authorization (MA) setting, the evidence acquired in pre-MA studies serves as the basis for generating hypotheses. Whatever the research question and the method chosen to address it, the potential biases and their impact on the results need to be identified. In certain cases, a combination of several complementary approaches may prove preferable to a single study. PMID- 23981264 TI - Medico-economic evaluation of health products in the context of the Social Security Financing Act for 2012. AB - The participants in round table 6 of the Giens Workshops 2012 drafted recommendations based on the collective interpretation of important elements of the decree concerning the medico-economic evaluation of health products published a few days earlier (02 October 2012). The medico-economic evaluation (MEE), becomes an additional determinant for fixing the prices of health products by the Health products economic committee (Comite economique des produits de sante, CEPS) via the hierarchisation of treatment strategies, and thus modifies the market access conditions. Limiting the analysis to medicinal products and medical devices for which a major, important or moderate improvement in the medical service rendered (ASMR) or of the expected service (ASA) has been requested and presenting a significant budget impact on the Social Security expenses, excludes health products with ASMR or ASA with a lower level requested which often create complex price fixing problems and often have a major budget impact. This latter concept remains to be defined in detail. The MEE envisaged for the first registration must include the need to confirm or refute the initial hypotheses especially concerning the actual position in the therapeutic strategy at the time of renewal of the registration. For the first registration, the conventional reference to European prices guaranteeing a minimum price to innovative medicinal products, the medico-economic models submitted by the industry to the French Drug Authority (Haute autorite de sante, HAS) must be used to guide the compilation of new data to be requested at the time of the registration renewal and to negotiate the level of the discounts in the framework of a price-volume agreement, if applicable. The MEE will allow comparing the result of the analysis to the model hypothesis at the time of the renewal of the registration, which may contribute to the renegotiation (either up or down) of the price of health goods. The costs related to obtaining new data must be controlled. In order for the MEE to allow confirming the relationship between the price requested and the benefit expected, the group privileges the definition of reference values with an indicative and non-normative value, likely to evolve with time rather than a threshold. Concerning the evaluation procedure: the time to market access must not be lengthened; while the possibility of regular meetings between the industry and the HAS is recommended to avoid methodological divergences. A transitory period should allow the implementation of the entire evaluation procedure which must also take into account the specificities of health products registered before the 3 October 2013. PMID- 23981267 TI - FIB-SEM: an additional technique for investigating internal structure of pollen walls. AB - Pollen grain morphology has been widely used in the classification of the Acanthaceae, where external pollen wall features have proved useful in determining relationships between taxa. Although detailed information has been accumulated using light microscopy, transmission electron microscopy and scanning electron microscopy (SEM) techniques, internal pollen wall features lack investigation and the techniques are cumbersome. A new technique involving precise cross sectioning or slicing of pollen grains at a selected position for examining wall ultrastructure, using a focused ion beam-scanning electron microscope (FIB-SEM), has been explored and promising results have been obtained. The FIB-SEM offers a good technique for reliable, high resolution, three dimensional (3D) viewing of the internal structure of the pollen grain wall. PMID- 23981266 TI - [Use of the PMSI for the detection of adverse drug reactions]. AB - AIM: To evaluate the performance of a query on international classification of diseases 10(th) version (ICD10) codes in the database of the programme for the medicalisation of information systems (programme de medicalisation des systemes d'information, PMSI) to identify serious adverse drug reactions (ADR). METHODS: The query concerned hospital stays of patients discharged from the French University Hospital of Rennes in 2009. All the hospitalization summaries including a selected ICD10 code were analysed to validate ADR. RESULTS: Out of 383 cases, 142 cases were validated (37.1%). Performance of some ICD10 codes was particularly interesting, above 40% (T88.6, L27.0, J70.4, G62.0 and N14.1) and 79.5% of the ADR were detected by these five codes. During the study period, 98 ADR of the same type were spontaneously reported by physicians, 22 of which were common with the ICD10 query. CONCLUSIONS: The use of PMSI can be a tool for signal detection of serious ADR, in addition to spontaneous reporting. PMID- 23981268 TI - Microalgae-based biodiesel: a multicriteria analysis of the production process using realistic scenarios. AB - Microalgae-based biodiesel has several benefits over other resources such as less land use, potential cultivation in non-fertile locations, faster growth and especially a high lipid-to-biodiesel yield. Nevertheless, the environmental and economic behavior for high scale production depends on several variables that must be addressed in the scale-up procedure. In this sense, rigorous modeling and multicriteria evaluation are performed in order to achieve optimal topology for third generation biodiesel production. Different scenarios and the most promising technologies tested at pilot scale are assessed. Besides, the sensitivity analysis allows the detection of key operating variables and assumptions that have a direct effect on the lipid content. The deviation of these variables may lead to an erroneous estimation of the scale-up performance of the technology reviewed in the microalgae-based biodiesel process. The modeling and evaluation of different scenarios of the harvesting, oil extraction and transesterification help to identify greener and cheaper alternatives. PMID- 23981269 TI - Nitrogen conservation and acidity control during food wastes composting through struvite formation. AB - One of the main problems of food waste composting is the intensive acidification due to initial rapid fermentation that retards decomposition efficiency. Lime addition overcame this problem, but resulted in significant loss of nitrogen as ammonia that reduces the nutrient contents of composts. Therefore, this study investigated the feasibility of struvite formation as a strategy to control pH and reduce nitrogen loss during food waste composting. MgO and K2HPO4 were added to food waste in different molar ratios (P1, 1:1; P2, 1:2), and composted in 20-L composters. Results indicate that K2HPO4 buffered the pH in treatment P2 besides supplementing phosphate into the compost. In P2, organic decomposition reached 64% while the formation of struvite effectively reduced the nitrogen loss from 40.8% to 23.3% during composting. However, electrical conductivity of the compost increased due to the addition of Mg and P salts that requires further investigation to improve this technology. PMID- 23981270 TI - Effect of macro- and micro-nutrient limitation on superoxide dismutase activities and carotenoid levels in microalga Dunaliella salina CCAP 19/18. AB - The aim of this study was to assess the effects of sixteen stress conditions on total carotenoid production and the response of antioxidative enzyme superoxide dismutase (SOD) in microalga Dunaliella salina. Of the stress conditions tested, high-light illumination (240 MUmol photons m(-2) s(-1)) in combination with nitrogen depletion were the conditions associated with maximum carotenoid production and which induced Fe-SOD and retained the specific Mn-SOD isoform. Removal of the micronutrients manganese (Mn), Zinc (Zn) and Iron (Fe) as well as nitrogen from the medium enhanced carotenoid production on day 5, while the removal of nitrogen and Mn from the growth medium drastically affected carotenoid production at all time-points. The differential response of SODs influences the levels of carotenoid biosynthesis as chronic molecular defence strategies of D. salina. PMID- 23981272 TI - Learning new vocabulary during childhood: effects of semantic training on lexical consolidation and integration. AB - Research suggests that word learning is an extended process, with offline consolidation crucial for the strengthening of new lexical representations and their integration with existing lexical knowledge (as measured by engagement in lexical competition). This supports a dual memory systems account, in which new information is initially sparsely encoded separately from existing knowledge and integrated with long-term memory over time. However, previous studies of this type exploited unnatural learning contexts, involving fictitious words in the absence of word meaning. In this study, 5- to 9-year-old children learned real science words (e.g., hippocampus) with or without semantic information. Children in both groups were slower to detect pauses in familiar competitor words (e.g., hippopotamus) relative to control words 24h after training but not immediately, confirming that offline consolidation is required before new words are integrated with the lexicon and engage in lexical competition. Children recalled more new words 24h after training than immediately (with similar improvements shown for the recall and recognition of new word meanings); however, children who were exposed to the meanings during training showed further improvements in recall after 1 week and outperformed children who were not exposed to meanings. These findings support the dual memory systems account of vocabulary acquisition and suggest that the association of a new phonological form with semantic information is critical for the development of stable lexical representations. PMID- 23981271 TI - A cytotoxic protein (BF-CT1) purified from Bungarus fasciatus venom acts through apoptosis, modulation of PI3K/AKT, MAPKinase pathway and cell cycle regulation. AB - BF-CT1, a 13 kDa protein isolated from Bungarus fasciatus snake venom through CM cellulose ion exchange chromatography at 0.02 M NaCl salt gradient showed cytotoxicity in in vitro and in vivo experimental models. In in vivo Ehrlich ascites carcinoma (EAC) induced BALB/c mice model, BF-CT1 treatment reduced EAC cell count significantly through apoptotic cell death pathway as evidenced by FACS analysis, increased caspase 3, 9 activity and altered pro, antiapoptotic protein expression. BF-CT1 treatment caused cell shrinkage, chromatin condensation and induced apoptosis through increased caspase 3, caspase 9 activity, PARP cleavage and down regulation of heat shock proteins in U937 leukemic cell line. Cytosolic cytochrome C production was increased after BF-CT1 treatment upon U937 cell line. BF-CT1 treated U937 cell showed cell cycle arrest at sub G1 phase through cyclin D and CDK down regulation with up regulation of p15 and p16. It also down regulated PI3K/AKT pathway and MAPkinase pathway and promoted apoptosis and regulated cell proliferation in U937 cells. BF-CT1 prevented angiogenesis in in vitro U937 cell line through decreased VEGF and TGF beta1 production. PMID- 23981273 TI - The power of print: children's trust in unexpected printed suggestions. AB - How do children evaluate the veracity of printed text? We examined children's handling of unexpected suggestions conveyed via print versus orally. In Experiment 1 (N=131), 3- to 6-year-olds witnessed a speaker either read aloud an unexpected but not completely implausible printed label (e.g., fish for a bird like animal with some fish features) or speak the label without accompanying text. Pre-readers accepted labels in both conditions. Early readers often rejected spoken labels yet accepted them in the print condition, and in Experiment 2 (N=55) 3- to 6-year-olds continued to apply them even after the print was obscured. Early readers accept printed testimony that they reject if only spoken, and the influence of text endures even when it is no longer visible. PMID- 23981274 TI - Modified implant surface with slower and less initial biofilm formation. AB - BACKGROUND: Peri-implant mucositis and peri-implantitis are a raising issue in dental implantology. Peri-implant infections are mainly caused by the formation of biofilm. Different surface textures exhibit various conditions for biofilm formation resulting in several speed of maturation and development. MATERIALS AND METHODS: On three different titanium implant surfaces, machined-surface (M), sandblasted large grit, and acid-etched surface (SLA) and machined-modified acid etched surface (mod MA) initial biofilms were collected. Plaque formation was investigated by erythrosine staining and energy-dispersive X-ray spectroscopy (EDX). For testing the biocompatibility of these plaque-settled surfaces, autoclaved specimens were settled with human gingival fibroblasts, and cell viability was tested. RESULTS: The mean initial plaque surface was detected in the following descending order: M > SLA > mod MA. The differences between these groups were significant. The highest cell viability was detected in the M groups, whereas mod MA and SLA showed comparable results. The results of initial biofilm formation were proved by EDX. CONCLUSIONS: Within the limitations of this study, conclusion can be made that mod MA surface shows significant slower initial biofilm formation which could be an advantage in initial transgingival healing process and also an easement for oral hygiene of patients because maturation of plaque is retarded, and immature biofilms are easier to remove. PMID- 23981275 TI - Acute thrombosis of bioprosthetic mitral valve. AB - We report a case of acute thrombosis of bioprosthetic mitral valve in a 59 year old Korean female, who underwent a mitral valve replacement with a 25 mm Carpentier - Edwards PERIMOUNT Plus bioprosthesis (Edwards Lifesciences, Inc.; Irvine, CA, USA) and a mini-Maze procedure for correction of mitral stenosis (MS) and atrial fibrillation (AF). On the 10th postoperative day, the patient began to complain of increasing dyspnea and general malaise. Her symptoms worsened and developed into pulmonary edema. Echocardiography revealed a mean diastolic pressure gradient (MDPG) of 10 mmHg across the mitral valve and pressure-half time (PHT) of 166 msec. Due to progressive decompensated heart failure, the patient underwent a repeat sternotomy to replace the bioprosthetic mitral valve. Intraoperatively, we found a thrombosis around the bioprosthetic mitral valve. We excised the bioprosthetic mitral valve and replaced it with a 27 mm ATS mechanical valve (ATS medical, Inc.; Minneapolis, MN, USA). We experienced a rare case that required an early reoperation for a thrombosis of the bioprosthetic valve. PMID- 23981276 TI - Fossil ginkgophyte seedlings from the Triassic of France resemble modern Ginkgo biloba. AB - BACKGROUND: Fossil evidence of ginkgophyte ontogeny is exceedingly rare. Early development in the extant Ginkgo biloba is characterized by a series of distinct ontogenetic stages. Fossils providing insights into the early ontogeny of ancient ginkgophytes may be significant in assessing the degree of relatedness between fossil ginkgophytes and G. biloba. RESULTS: An assemblage of seedlings from the early Middle Triassic of France is assigned to the ginkgophytes based on leaf morphology. The specimens represent an ontogenetic sequence consisting of four stages: (I) formation of the cotyledons in the seed and germination; (II) development of primary leaves and taproot; (III) thickening of the taproot and appearance of secondary roots; and (IV) development of the first differentiated leaves and absence of the seed remnants. CONCLUSIONS: The fossil seedlings provide a rare opportunity to examine the early ontogeny of a Triassic ginkgophyte. Germination and seedling development in the fossil are nearly identical to that of the extant gymnosperm G. biloba. We hypothesize that the fossil may be closely related biologically to G. biloba, and that certain developmental processes in seedling development were in place by the Middle Triassic. PMID- 23981278 TI - Insertion of zerovalent nickel into the N-N bond of N-heterocyclic-carbene activated N2O. AB - Metal-mediated cleavage of the N-N bond is a rarely observed phenomenon in the chemistry of nitrous oxide (N2O). We demonstrate that, upon activation of N2O with N-heterocyclic carbenes, zerovalent nickel is able to insert into the N-N bond to give nitrosyl complexes. PMID- 23981279 TI - Expert recommendations on the application of interferon for chronic hepatitis B. AB - To help the clinicians correctly and scientifically apply interferon for the treatment of chronic hepatitis B, more than 40 experts majored in infectious and liver diseases updated the 'Expert recommendations on the treatment of chronic hepatitis B with interferon (2007)' following a systematic literature review, summary of clinical experiences and thorough consultation and discussion. The updated expert recommendations primarily included fundamental new knowledge of the use of interferon and individualized interferon therapy. Specifically, we provided recommendations for implementing optimized therapeutic regimens based on quantitative changes in hepatitis B surface antigen and hepatitis B virus DNA levels 24 weeks after interferon therapy. The updated expert recommendations provided itemized details and supplement for the Guidelines for the Prevention and Treatment of Chronic Hepatitis B and they also offer a basis for individualized therapy of chronic hepatitis B with interferon. PMID- 23981280 TI - New insights in the pathogenesis and therapy of idiopathic recurrent pericarditis in children. AB - Pericarditis has several different causes, however, in about 70% of paediatric patients, a specific aetiology cannot be detected and the pericarditis is considered idiopathic. Recurrences may occur in up to 15-30% of cases. The pathogenesis of recurrent disease is controversial. Infectious, autoimmune and autoinflammatory pathways have been proposed as mechanisms involved in recurrences. Therapeutic strategies are not standardised, non-steroidal anti inflammatory drugs at high dosages being the mainstay of therapy with the possible addition of low dose colchicine to prevent recurrences. Biological agents are considered a possible new therapeutic frontiers in the care of idiopathic recurrent pericarditis. PMID- 23981277 TI - Effects of prenatal cocaine exposure on child behavior and growth at 10 years of age. AB - We examined physical growth and behavioral outcomes in 226 10-year-old children who were participants in a longitudinal study of prenatal cocaine exposure (PCE), while controlling for other factors that affect development. During the first trimester, 42% of the women used cocaine, with use declining across pregnancy. At the 10-year follow-up, the caregivers were 37years old, had 12.8years of education, and 50% were African American. First trimester cocaine exposure predicted decreased weight, height, and head circumference at 10years. First trimester cocaine use also predicted maternal ratings of less sociability on the EAS Temperament Survey and more withdrawn behavior problems on the Child Behavior Checklist, more anxious/depressed behaviors on the Teacher Report Form, and more self-reported depressive symptoms on the Children's Depression Inventory. In addition, exposure to violence mediated the effect of PCE on child and teacher reports of depressive symptoms, but not of maternal reports of sociability and withdrawn behaviors. These behaviors may be precursors of later psychiatric problems. PMID- 23981281 TI - Ssanghwa-tang, an oriental herbal cocktail, exerts anti-melanogenic activity by suppression of the p38 MAPK and PKA signaling pathways in B16F10 cells. AB - BACKGROUND: Ssanghwa-tang (SHT) is a widely used medication for the treatment of fatigue, pain, inflammation, hypothermia, erectile dysfunction, cancer, and osteoporosis in Asia, however, role of SHT on the melanin synthesis has not been checked previously. Thus, the present study was designed to determine the effect of SHT on alpha-melanocyte stimulating hormone (alpha-MSH)-induced melanogensis and its mechanisms of action in murine B16F10 melanoma cells. METHOD: Cellular melanin content and tyrosinase activity in murine B16F10 melanoma cells were determined after alpha-MSH stimulation with or without pre-treatment of SHT at the concentration of 250 and 500 MUg/ml. Expression level of tyrosinase, tyrosinase-related protein 1 (TRP-1), TRP-2, microphthalmia-associated transcription factor (MITF), and activation of c-AMP-dependent protein kinase (PKA), c-AMP-related element binding protein (CREB), and mitogen-activated protein kinases (MAPKs) were examined by Western blot analysis. RESULTS: SHT significantly inhibited alpha-MSH-induced melanin synthesis and tyrosinase activity, and also decreased alpha-MSH-induced expression of MITF, tyrosinase, and TRP-1. In addition, SHT remarkably suppressed tyrosinase, CRE, and MITF luciferase reporter activity in a resting state as well as in alpha-MSH stimulating condition. Phosphorylation of p38 MAPK by alpha-MSH stimulation was efficiently blocked by SHT pre-treatment. Moreover, SHT as an herbal cocktail showed synergistic anti-melanogenic effect compared with that of each single constituent herb. CONCLUSION: SHT efficiently inhibited c-AMP-induced melanin synthesis in B16F10 cells via suppression of PKA and p38 MAPK signaling pathways and subsequently decreased the level of CREB phosphorylation, MITF, and melanogenic enzymes. These results indicate that SHT may be useful as herbal medicine for treating hyperpigmentation and cosmetics as a skin-whitening agent. PMID- 23981282 TI - Genetic variation and gains in resistance of strawberry to Colletotrichum gloeosporioides. AB - Anthracnose crown rot is an important disease of strawberry primarily caused by Colletotrichum gloeosporioides in Florida and North Carolina. Information on the magnitude of additive and nonadditive genetic variation is required to define breeding strategies and to estimate potential genetic gains. However, little is known about the genetic control of resistance and its utility in breeding. Our objectives were to obtain estimates of heritabilities and of components of genetic variances, genotype-environment interactions, and gains for resistance, and to examine the effects of locations and transplant types on the estimates. An incomplete diallel mating design generated 42 full-sib families, which were propagated in plugs from seed (seedling tests) and as bare-root runner plants (clonal tests) of different genotypes of the same families. Both seedlings and clones were inoculated with C. gloeosporioides under field conditions in North Carolina and Florida during the 2010-11 season. Narrow-sense heritability (h(2)) and broad-sense heritability (H(2)) for both clones and seedlings were higher at the North Carolina location (h(2) = 0.34 to 0.62 and H(2) = 0.46 to 0.85) than at the Florida location (h(2) = 0.16 to 0.22 and H(2) = 0.37 to 0.46). Likewise, the seedling tests showed higher genetic control than the clonal tests at both locations. Estimates of dominance variance were approximately one-third of the additive variance at North Carolina and were even larger at Florida. Epistasis was negative at both locations and assumed zero for heritability (H(2)) calculations. Genotype-environment interactions were different by transplant type, suggesting rank changes across locations. 'Pelican' was the most resistant parent at both locations, followed by 'NCH09-68' at the NC location and 'Winter Dawn' at the Florida location. Selection and deployment of the most resistant clone within each of the five best families is estimated to produce average genetic gains of 53.0 and 73.7% at the North Carolina and Florida locations, respectively. PMID- 23981283 TI - Adaptive responses by mouse fetus to a maternal HLE diet by downregulating SREBP1: a microarray- and bio-analytic-based study. AB - Maternal diet has long been recognized as a significant factor affecting offspring development and health, but the target genes affected by a maternal high-lipid diet are currently unknown. In this study, the gene expression profile of neonatal mouse liver was analyzed using gene chips to identify genes with significant up- or downregulated expression levels due to maternal high-fat diet during gestation. Real-time PCR and Western blotting were used to measure key genes selected using microarray. Serum lipid, glucose, and insulin levels in adult offspring from dams fed with chow or a high-lipid diet were measured using commercial kits. Results indicate that the expression of genes involved in cholesterol and fatty acid synthesis were significantly inhibited, while the expression of genes involved in glycolysis were significantly decreased by maternal high-lipid diet during gestation. SREBP1 might be the key gene regulating genes involved in fatty acid, glucose, and cholesterol metabolism in response to a maternal high-fat diet. PMID- 23981285 TI - Palliative 5-fluorouracil and cisplatin chemotherapy in recurrent metastatic sebaceous carcinoma: Case report and literature review. AB - Sebaceous carcinoma is a rare malignant tumor of the skin. Although this tumor is not completely understood due to its rarity and the paucity of published reports, it is known to be an aggressive tumor with a high incidence in Asia. Sebaceous carcinomas occur preferentially in the periocular region and require attention not to miss the associated Muir-Torre syndrome. In the case of localized disease, a wide local excision with clear margin followed by adjuvant radiation therapy is usually considered the standard treatment strategy but there is no agreed treatment strategy or standard chemotherapeutic regimen for recurrent metastatic sebaceous carcinoma. We report here two cases of recurrent metastatic sebaceous carcinoma patients who responded to 5-fluorouracil and cisplatin combination chemotherapy, and review the literature. We suggest that 5-fluorouracil-cisplatin can be considered a feasible and effective treatment modality for recurrent sebaceous carcinoma. PMID- 23981284 TI - Validation of analytical methods in compliance with good manufacturing practice: a practical approach. AB - BACKGROUND: The quality and safety of cell therapy products must be maintained throughout their production and quality control cycle, ensuring their final use in the patient. We validated the Lymulus Amebocyte Lysate (LAL) test and immunophenotype according to International Conference on Harmonization Q2 Guidelines and the EU Pharmacopoeia, considering accuracy, precision, repeatability, linearity and range. METHODS: For the endotoxin test we used a kinetic chromogenic LAL test. As this is a limit test for the control of impurities, in compliance with International Conference on Harmonization Q2 Guidelines and the EU Pharmacopoeia, we evaluated the specificity and detection limit.For the immunophenotype test, an identity test, we evaluated specificity through the Fluorescence Minus One method and we repeated all experiments thrice to verify precision. The immunophenotype validation required a performance qualification of the flow cytometer using two types of standard beads which have to be used daily to check cytometer reproducibly set up. The results were compared together.Collected data were statistically analyzed calculating mean, standard deviation and coefficient of variation percentage (CV%). RESULTS: The LAL test is repeatable and specific. The spike recovery value of each sample was between 0.25 EU/ml and 1 EU/ml with a CV% < 10%. The correlation coefficient (>= 0.980) and CV% (< 10%) of the standard curve tested in duplicate showed the test's linearity and a minimum detectable concentration value of 0.005 EU/ml.The immunophenotype method performed thrice on our cell therapy products is specific and repeatable as showed by CV% inter -experiment < 10%. CONCLUSIONS: Our data demonstrated that validated analytical procedures are suitable as quality controls for the batch release of cell therapy products.Our paper could offer an important contribution for the scientific community in the field of CTPs, above all to small Cell Factories such as ours, where it is not always possible to have CFR21 compliant software. PMID- 23981287 TI - Dark-field imaging of thin specimens with a forescatter electron detector at low accelerating voltage. AB - A forescatter electron detector (FSED) was used to acquire dark-field micrographs (DF-FSED) on thin specimens with a scanning electron microscope. The collection angles were adjusted with the detector distance from the beam axis, which is similar to the camera length of the scanning transmission electron microscope annular DF detectors. The DF-FSED imaging resolution was calculated with SMART-J on an aluminum alloy and carbon nanotubes (CNTs) decorated with platinum nanoparticles. The resolution was three to six times worse than with bright-field imaging. Measurements of nanometer-size objects showed a similar feature size in DF-FSED imaging despite a signal-to-noise ratio 12 times smaller. Monte Carlo simulations were used to predict the variation of the contrast of a CNT/Fe/Pt system as a function of the collection angles. It was constant for very high collection angles (>450 mrad) and confirmed experimentally. The reverse contrast between carbon black particles and the smallest titanium dioxide (TiO2) nanoparticles was predicted by Monte Carlo simulations and observed in the DF FSED micrograph of a battery electrode coating. However, segmentation of the micrograph was not able to isolate the TiO2 nanoparticle phase because of the close contrast of small TiO2 nanoparticles compared to the C black particles. PMID- 23981286 TI - Gene Ontology annotation of sequence-specific DNA binding transcription factors: setting the stage for a large-scale curation effort. AB - Transcription factors control which information in a genome becomes transcribed to produce RNAs that function in the biological systems of cells and organisms. Reliable and comprehensive information about transcription factors is invaluable for large-scale network-based studies. However, existing transcription factor knowledge bases are still lacking in well-documented functional information. Here, we provide guidelines for a curation strategy, which constitutes a robust framework for using the controlled vocabularies defined by the Gene Ontology Consortium to annotate specific DNA binding transcription factors (DbTFs) based on experimental evidence reported in literature. Our standardized protocol and workflow for annotating specific DNA binding RNA polymerase II transcription factors is designed to document high-quality and decisive evidence from valid experimental methods. Within a collaborative biocuration effort involving the user community, we are now in the process of exhaustively annotating the full repertoire of human, mouse and rat proteins that qualify as DbTFs in as much as they are experimentally documented in the biomedical literature today. The completion of this task will significantly enrich Gene Ontology-based information resources for the research community. Database URL: www.tfcheckpoint.org. PMID- 23981265 TI - National observatory on the therapeutic management in ambulatory care patients aged 65 and over, with type 2 diabetes, chronic pain or atrial fibrillation. AB - The primary objective of the S.AGES cohort is to describe the real-life therapeutic care of elderly patients. Patients and methods. This is a prospective observational cohort study of 3 700 non-institutionalized patients over the age of 65 years with either type 2 diabetes mellitus (T2DM), chronic pain or atrial fibrillation (AF) recruited by French general practitioners (GPs). Follow-up is planned for 3 years. Baseline characteristics. In the chronic pain sub-cohort, 33% of patients are treated with only grade 1 analgesics, 29% with grade 2 analgesics and 3% with grade 3 analgesics, and 22% have no pain treatment. In the T2DM sub-cohort, 61% of patients have well-controlled diabetes (Hb1c<7%) and 18% are treated with insulin. In the AF sub-cohort, 65% of patients have a CHADS2 score greater than 2, 77% are treated with oral anticoagulants, 17% with platelet inhibitors, 40% with antiarrhythmic drugs and 56% with rate slowing medications. Conclusion. The S.AGES cohort presents a unique opportunity to clarify the real life therapeutic management of ambulatory elderly subjects and will help to identify the factors associated with the occurrence of major clinical events. PMID- 23981288 TI - Surface analysis of titanium biological modification with glow discharge. AB - BACKGROUND: Glow discharge plasma (GDP) technology has been used to graft various proteins to the titanium surface, including albumin, type I collagen, but without fibronectin. PURPOSE: The aim of this study was to evaluate and analyze the physical properties of fibronectin-grafted titanium surfaces after GDP treatment. MATERIALS AND METHODS: Grade II titanium discs after cleaning and autoclaving were considered as original specimens, thus divided into four groups. The groups were different upon two treatments (GDP only and fibronectin grafting after GDP) and two storage temperature (4 degrees C and 25 degrees C). The implant surface morphology was characterized by scanning electron microscopy (SEM), roughness measurement, and wettability evaluation. The concentration relationship of fibronectin was by fluorescein isothiocyanate (FITC) labeling. RESULTS: SEM images showed that regular planar texture revealed on the surface of GDP-treated group, and irregular-folding protein was found on the fibronectin-grafted discs. Fibronectin-grafted groups had higher hydrophilicity and greater surface roughness than GDP-treated specimens. The storage temperature did not make obvious difference on the surface topography, wettability, and roughness. The number of fibronectin dots on the titanium surface labeling by FITC had positive relationship with the concentration of fibronectin solution used. CONCLUSIONS: Biologically modified titanium surface is more hydrophilic and rougher than GDP treated ones. GDP treatment combined with fibronectin grafting increased the surface hydrophilicity and surface roughness of titanium discs, which may attribute to the affinity of cell adhesion, migration, proliferation, and differentiation. PMID- 23981289 TI - Phenotypic characteristics of early Wolfram syndrome. AB - BACKGROUND: Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. METHODS: Eighteen subjects (ages 5.9-25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. RESULTS: Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 +/- 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 +/- 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. CONCLUSIONS: WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression. PMID- 23981291 TI - Clinical outcomes and direct costings of endoluminal clipping compared to surgery in the management of iatrogenic colonic perforation. AB - OBJECTIVE: To compare the outcomes and costs of endoluminal clipping and surgery in the management of iatrogenic colonic perforation. METHODS: A retrospective, single-center, clinical and economic analysis of outcomes and costings between endoluminal clipping and surgery in consecutive cases of iatrogenic colonic perforations was conducted. RESULTS: In total, 7136 colonoscopies performed over a 6-year period were complicated by 12 (0.17%) perforations. Seven cases were treated by endoscopic clipping (with a success rate of 71.4%) and five with immediate surgery. Both groups of patients had similar clinical and individual characteristics. Patients who were treated with endoscopic clipping had a shorter period of hospitalization (median 9 vs 13 days) compared to surgery, but this was not statistically significant. Compared to patients who had immediate surgery, the median direct health-care costs for all procedures (US$ 115.10 vs US$ 1479.50, P = 0.012) and investigations (US$ 124.60 vs US$ 512.90, P = 0.048) during inpatient stay were lower for the endoscopic clipping group. There was a trend towards a lower overall inpatient median cost for patients managed with endoscopic clipping compared to surgery (US$ 1481.70 vs US$ 3281.90, P = 0.073). CONCLUSION: Endoluminal clipping may be more cost-effective than surgery in the management of iatrogenic colonic perforations. PMID- 23981295 TI - Raven's matrices and working memory: a dual-task approach. AB - Raven's Matrices Test was developed as a "pure" measure of Spearman's concept of general intelligence, g. Subsequent research has attempted to specify the processes underpinning performance, some relating it to the concept of working memory and proposing a crucial role for the central executive, with the nature of other components currently unclear. Up to this point, virtually all work has been based on correlational analysis of number of correct solutions, sometimes related to possible strategies. We explore the application to this problem of the concurrent task methodology used widely in developing the concept of multicomponent working memory. Participants attempted to solve problems from the matrices under baseline conditions, or accompanied by backward counting or verbal repetition tasks, assumed to disrupt the central executive and phonological loop components of working memory, respectively. As in other uses of this method, number of items correct showed little effect, while solution time measures gave very clear evidence of an important role for the central executive, but no evidence for phonological loop involvement. We conclude that this and related concurrent task techniques hold considerable promise for the analysis of Raven's matrices and potentially for other established psychometric tests. PMID- 23981292 TI - Using electronic technology to improve clinical care - results from a before after cluster trial to evaluate assessment and classification of sick children according to Integrated Management of Childhood Illness (IMCI) protocol in Tanzania. AB - BACKGROUND: Poor adherence to the Integrated Management of Childhood Illness (IMCI) protocol reduces the potential impact on under-five morbidity and mortality. Electronic technology could improve adherence; however there are few studies demonstrating the benefits of such technology in a resource-poor settings. This study estimates the impact of electronic technology on adherence to the IMCI protocols as compared to the current paper-based protocols in Tanzania. METHODS: In four districts in Tanzania, 18 clinics were randomly selected for inclusion. At each site, observers documented critical parts of the clinical assessment of children aged 2 months to 5 years. The first set of observations occurred during examination of children using paper-based IMCI (pIMCI) and the next set of observations occurred during examination using the electronic IMCI (eIMCI). Children were re-examined by an IMCI expert and the diagnoses were compared. A total of 1221 children (671 paper, 550 electronic) were observed. RESULTS: For all ten critical IMCI items included in both systems, adherence to the protocol was greater for eIMCI than for pIMCI. The proportion assessed under pIMCI ranged from 61% to 98% compared to 92% to 100% under eIMCI (p < 0.05 for each of the ten assessment items). CONCLUSIONS: Use of electronic systems improved the completeness of assessment of children with acute illness in Tanzania. With the before-after nature of the design, potential for temporal confounding is the primary limitation. However, the data collection for both phases occurred over a short period (one month) and so temporal confounding was expected to be minimal. The results suggest that the use of electronic IMCI protocols can improve the completeness and consistency of clinical assessments and future studies will examine the long-term health and health systems impact of eIMCI. PMID- 23981290 TI - The role of retinoic acid in hepatic lipid homeostasis defined by genomic binding and transcriptome profiling. AB - BACKGROUND: The eyes and skin are obvious retinoid target organs. Vitamin A deficiency causes night blindness and retinoids are widely used to treat acne and psoriasis. However, more than 90% of total body retinol is stored in liver stellate cells. In addition, hepatocytes produce the largest amount of retinol binding protein and cellular retinoic acid binding protein to mobilize retinol from the hepatic storage pool and deliver retinol to its receptors, respectively. Furthermore, hepatocytes express the highest amount of retinoid x receptor alpha (RXRalpha) among all the cell types. Surprisingly, the function of endogenous retinoids in the liver has received very little attention. RESULTS: Based on the data generated from chromatin immunoprecipitation followed by sequencing, the global DNA binding of transcription factors including retinoid x receptor alpha (RXRalpha) along with its partners i.e. retinoic acid receptor alpha (RARalpha), pregnane x receptor (PXR), liver x receptor (LXR), farnesoid x receptor (FXR), and peroxisome proliferator-activated receptor alpha (PPARalpha) has been established. Based on the binding, functional annotation illustrated the role of those receptors in regulating hepatic lipid homeostasis. To correlate the DNA binding data with gene expression data, the expression patterns of 576 genes that regulate lipid homeostasis were studied in wild type and liver RXRalpha-null mice treated with and without RA. The data showed that RA treatment and RXRalpha deficiency had opposite effects in regulating lipid homeostasis. A subset of genes (114), which could clearly differentiate the effect of ligand treatment and receptor deficiency, were selected for further functional analysis. The expression data suggested that RA treatment could produce unsaturated fatty acids and induce triglyceride breakdown, bile acid secretion, lipolysis, and retinoids elimination. In contrast, RXRalpha deficiency might induce the synthesis of saturated fatty acids, triglyceride, cholesterol, bile acids, and retinoids. In addition, DNA binding data indicated extensive cross-talk among RARalpha, PXR, LXR, FXR, and PPARalpha in regulating those RA/RXRalpha-dependent gene expression levels. Moreover, RA reduced serum cholesterol, triglyceride, and bile acid levels in mice. CONCLUSIONS: We have characterized the role of hepatic RA for the first time. Hepatic RA mediated through RXRalpha and its partners regulates lipid homeostasis. PMID- 23981294 TI - Ten-year review of Danish children with chronic non-bacterial osteitis. AB - OBJECTIVES: To compare clinical characteristics of children with chronic non infectious osteomyelitis (CNO) with either mono- or multifocal bone lesions, and to report potential advantages of using whole-body MRI. METHODS: A retrospective evaluation of 31 children (19 girls, 12 boys) diagnosed with CNO between 2001 and 2011. CNO was diagnosed as mono-, or multifocal inflammatory bone lesions (osteomyelitis, osteitis, osteosclerosis), duration of complaints more than 6 weeks and exclusion of infection and malignancy. Clinical and radiological data were registered. The definition of mono- or multifocality was based on the description of imaging results. RESULTS: Mean age at disease onset was 10.3 +/- 2.6 years. Mean duration of active disease was 44.4 +/- 25.6 months. Twenty-two (71.0%) had two or more bone lesions and 9 (29.0%) had one lesion. Of those with multifocal lesions six were initially detected as monofocal. The most frequent location of the bone lesions was in the metaphysis of the lower extremities. MRI/CT discovered most lesions compared to x-ray and scintigraphy. MRI was performed in 93.5% of which 25.8 % had a whole-body-MRI. Whole-body MRI revealed disclosure of several silent lesions. Extra-osseous involvement occurred in 64.5%. In the multifocal group 22.7 % had psoriasis and 13.6 % had pustulosis palmoplantaris but neither was seen in the monofocal group. All were treated with NSAIDs; 54.8% corticosteroids, 29.1 % methotrexate, 9.7 % pamidronate and 3.2 % infliximab. CONCLUSIONS: Monofocal CNO had comparable clinical and radiological characteristics to multifocal disease. We conclude that whole-body MRI is a relevant screening instrument for the diagnosis of CNO. PMID- 23981296 TI - Three-dimensional chemical mapping by EFTEM-TomoJ including improvement of SNR by PCA and ART reconstruction of volume by noise suppression. AB - Electron tomography is becoming one of the most used methods for structural analysis at nanometric scale in biological and materials sciences. Combined with chemical mapping, it provides qualitative and semiquantitative information on the distribution of chemical elements on a given sample. Due to the current difficulties in obtaining three-dimensional (3D) maps by energy-filtered transmission electron microscopy (EFTEM), the use of 3D chemical mapping has not been widely adopted by the electron microscopy community. The lack of specialized software further complicates the issue, especially in the case of data with a low signal-to-noise ratio (SNR). Moreover, data interpretation is rendered difficult by the absence of efficient segmentation tools. Thus, specialized software for the computation of 3D maps by EFTEM needs to include optimized methods for image series alignment, algorithms to improve SNR, different background subtraction models, and methods to facilitate map segmentation. Here we present a software package (EFTEM-TomoJ, which can be downloaded from http://u759.curie.fr/fr/download/softwares/EFTEM-TomoJ), specifically dedicated to computation of EFTEM 3D chemical maps including noise filtering by image reconstitution based on multivariate statistical analysis. We also present an algorithm named BgART (for background removing algebraic reconstruction technique) allowing the discrimination between background and signal and improving the reconstructed volume in an iterative way. PMID- 23981297 TI - Schizosaccharomyces pombe grows exponentially during the division cycle with no rate change points. AB - Length measurements during the division cycle of 86 individual Schizosaccharomyces pombe cells demonstrate that length grows exponentially with no change in the growth rate and no rate change point (RCP) observed for any cell. These results support the proposal that length extension, or cell growth, is exponential during the division cycle. The finding of exponential growth during the cell cycle is significant because these results challenge and contradict the current, consensus, widely believed, and widely accepted view that growth of S. pombe during the division cycle is complex with ranges of linear growth changing at proposed RCPs. Biochemical synthetic patterns support and explain the observed exponential cell growth. Exponential growth of S. pombe is consistent with, and supports, the central tenets of the continuum model. PMID- 23981298 TI - Improved developmental ability of porcine oocytes grown in nude mice after fusion with cytoplasmic fragments prepared by centrifugation: a model for utilization of primordial oocytes. AB - Primordial oocytes are a potential resource for medical and zoological application, but those of large animals have not yet been reported to show efficient embryonic development. In the present study, we established a pig model for production of blastocysts from primordial oocytes that had been grafted into nude mice and matured in vitro, in combination with fusion of cytoplasmic fragments. Neonatal porcine ovaries in which most follicles are at the primordial stage were minced and grafted into nude mice (Crlj:CD1-Foxn1(nu)). About 60 days after detection of vaginal opening, the mice were given 62.5 U/mL porcine FSH for 2 weeks by infusion to enhance follicular development. Developmentally competent oocytes collected from porcine ovaries (conventional oocytes) were matured in vitro and subjected to serial centrifugation to prepare cytoplasmic fragments without a metaphase plate (cytoplasts). Three cytoplasts were fused by electrostimulation to an oocyte retrieved from a host mouse (xenogeneic oocyte) and matured in vitro. Then these fused oocytes were fertilized and subsequently cultured in vitro. No blastocysts were generated from xenogeneic oocytes without fusion of cytoplasm. When xenogeneic oocytes had been fused with three cytoplasts, the blastocyst rate increased significantly to 14.3%, comparable to that for untreated conventional oocytes (20.0%). The numbers of cells in blastocysts for these fused oocytes (37.2 cells/blastocyst) were not significantly different from those for conventional oocytes (25.4 cells/blastocyst). Our findings show that it is possible to use primordial oocytes of large mammals in combination with xenografting of ovarian tissue and also ooplasmic fusion. PMID- 23981299 TI - Maternal dietary intake alters organ mass and endocrine and metabolic profiles in pregnant ewe lambs. AB - To determine the impacts of Se supply and maternal dietary intake on ewe organ mass and endocrine and metabolic changes throughout gestation, pregnant first parity ewes (n=77) were allocated to 6 treatments in a 2*3 factorial array. Factors included Se [adequate Se (ASe; 9.5MUg/kg BW) vs. high Se (HSe; 81.8MUg/kg BW)] initiated at breeding and dietary intake [60% (RES), 100% (CON), or 140% (EXC) of requirements] initiated on d 50 of gestation. Ewes were individually fed and blood samples from the jugular vein were obtained approximately every 14 d from d 50 until parturition. Maternal Se supply did not impact endocrine or metabolic status. There was a nutritional intake by day interaction for NEFA, blood urea nitrogen (BUN), insulin, triiodothyronine (T3), thyroxine (T4), progesterone (P4), and estradiol-17beta (E2). As expected, with increased maternal intake, NEFA concentrations were reduced. During the last weeks of gestation, BUN and insulin were elevated in EXC compared with RES ewes. Although the pattern of T3 and T4 differed throughout gestation within a treatment group, as maternal intake increased, circulating T3 and T4 were increased. For P4 and E2, as maternal dietary intake increased, there was a reduction in the steroid concentrations in jugular blood. There was only a main effect of maternal nutrition (P<0.001) for cortisol concentrations with EXC ewes having greater concentrations than RES and CON ewes, which did not differ. Although Se is known to influence thyroid hormone metabolism, supranutritional levels during pregnancy did not alter circulating T3 and T4 concentrations. Alterations in maternal endocrine status may have influenced placental transport of nutrients to the developing fetus, which we have shown previously is affected by maternal dietary Se and intake. In addition, the alterations in mammary gland weight that we observed may explain the impact of maternal nutrition on mammary gland function and colostrum production, thereby further impairing growth of developing neonates. PMID- 23981300 TI - Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers. AB - BACKGROUND: The patient-derived xenograft (PDX) model is likely to reflect human tumor biology more accurately than cultured cell lines because human tumors are implanted directly into animals; maintained in an in vivo, three-dimensional environment; and never cultured on plastic. PDX models of head and neck squamous cell carcinoma (HNSCC) have been developed previously but were not well characterized at the molecular level. HNSCC is a deadly and disfiguring disease for which better systemic therapy is desperately needed. The development of new therapies and the understanding of HNSCC biology both depend upon clinically relevant animal models. We developed and characterized the patient-derived xenograft (PDX) model because it is likely to recapitulate human tumor biology. METHODS: We transplanted 30 primary tumors directly into mice. The histology and stromal components were analyzed by immunohistochemistry. Gene expression analysis was conducted on patient tumors and on PDXs and cell lines derived from one PDX and from independent, human tumors. RESULTS: Five of 30 (17%) transplanted tumors could be serially passaged. Engraftment was more frequent among HNSCC with poor differentiation and nodal disease. The tumors maintained the histologic characteristics of the parent tumor, although human stromal components were lost upon engraftment. The degree of difference in gene expression between the PDX and its parent tumor varied widely but was stable up to the tenth generation in one PDX. For genes whose expression differed between parent tumors and cell lines in culture, the PDX expression pattern was very similar to that of the parent tumor. There were also significant expression differences between the human tumors that subsequently grew in mice and those that did not, suggesting that this model enriches for cancers with distinct biological features. The PDX model was used successfully to test targeted drugs in vivo. CONCLUSION: The PDX model for HNSCC is feasible, recapitulates the histology of the original tumor, and generates stable gene expression patterns. Gene expression patterns and histology suggested that the PDX more closely recapitulated the parental tumor than did cells in culture. Thus, the PDX is a robust model in which to evaluate tumor biology and novel therapeutics. PMID- 23981301 TI - Combining docking site and phosphosite predictions to find new substrates: identification of smoothelin-like-2 (SMTNL2) as a c-Jun N-terminal kinase (JNK) substrate. AB - Specific docking interactions between mitogen-activated protein kinases (MAPKs), their regulators, and their downstream substrates, are crucial for efficient and accurate signal transmission. To identify novel substrates of the c-Jun N terminal kinase (JNK) family of MAPKs, we searched the human genome for proteins that contained (1), a predicted JNK-docking site (D-site); and (2), a cluster of putative JNK target phosphosites located close to the D-site. Here we describe a novel JNK substrate that emerged from this analysis, the functionally uncharacterized protein smoothelin-like 2 (SMTNL2). SMTNL2 protein bound with high-affinity to multiple MAPKs including JNK1-3 and ERK2; furthermore, the identity of conserved amino acids in the predicted docking site (residues 180 193) was necessary for this high-affinity binding. In addition, purified full length SMTNL2 protein was phosphorylated by JNK1-3 in vitro, and this required the integrity of the D-site. Using mass spectrometry and mutagenesis, we identified four D-site-dependent phosphoacceptor sites in close proximity to the docking site, at S217, S241, T236 and T239. A short peptide comprised of the SMTNL2 D-site inhibited JNK-mediated phosphorylation of the ATF2 transcription factor, showing that SMTNL2 can compete with other substrates for JNK binding. Moreover, when transfected into HEK293 cells, SMTNL2 was phosphorylated by endogenous JNK in a D-site dependent manner, on the same residues identified in vitro. SMTNL2 protein was expressed in many mammalian tissues, with a notably high expression in skeletal muscle. Consistent with the hypothesis that SMTNL2 has a function in skeletal muscle, SMTNL2 protein expression was strongly induced during the transition from myoblasts to myotubes in differentiating C2C12 cells. PMID- 23981303 TI - Symposium on the J wave patterns and a J wave syndrome. PMID- 23981304 TI - The genetics of the J wave patterns. PMID- 23981302 TI - NFkappaB-mediated cyclin D1 expression by microRNA-21 influences renal cancer cell proliferation. AB - MicroRNAs regulate post-transcriptomic landscape in many tumors including renal cell carcinoma. We have recently shown significantly increased expression of miR 21 in renal tumors and that this miRNA contributes to the proliferation of renal cancer cells in culture. However, the mechanism by which miR-21 regulates renal cancer cell proliferation is poorly understood. Addiction to constitutive NFkappaB activity is hallmark of many cancers including renal cancer. Using miR 21 Sponge in renal cancer cells to block endogenous function of miR-21, we show inhibition of phosphorylation of p65 subunit of NFkappaB, IKKbeta and IkappaB, which results in attenuation of NFkappaB transcriptional activity. Subtle reduction in the tumor suppressor PTEN has been linked to various malignancies. We showed previously that miR-21 targeted PTEN in renal cancer cells. Inhibition of PTEN by siRNAs restored miR-21 Sponge-induced suppression of phosphorylation of p65, IKKbeta, IkappaB and NFkappaB transcriptional activity along with reversal of miR-21 Sponge-reduced phosphorylation of Akt. Expression of constitutively active Akt protected against miR-21 Sponge- and PTEN-mediated decrease in p65/IKKbeta/IkappaB phosphorylation and NFkappaB transcriptional activity. Furthermore, IKKbeta and p65 were required for miR-21-induced renal cancer cell proliferation. Interestingly, miR-21 controlled the expression of cyclin D1 through NFkappaB-dependent transcription. Finally, we demonstrate that miR-21-regulated renal cancer cell proliferation is mediated by cyclin D1 and CDK4. Together, our results establish a molecular order of a phosphatase-kinase couple involving PTEN/Akt/IKKbeta and NFkappaB-dependent cyclin D1 expression for renal carcinoma cell proliferation by increased miR-21 levels. PMID- 23981305 TI - Concomitant ECG findings and J wave patterns. PMID- 23981306 TI - The Stanford/PAVA data collection form for coding J waves on routine screening 10second ECGs. AB - The study of J waves and slurs and their association with cardiovascular death is clouded by the lack of a standardized coding or classification methodology. Over the past three years of studying these ECG patterns, we have evolved a Data Entry Form that is designed to resolve some of the key issues. These issues include the effect of other ECG findings, whether the QRS-ST junction occurs before or after the J waves, if contiguous leads are required and rules to distinguish J waves from fragmented QRS complexes. This form is now being used to code the ECGs of 44,000 VA patients and the follow up is being extended to 15years to resolve these issues. PMID- 23981307 TI - Prevalence of early repolarisation/J wave patterns in the normal population. PMID- 23981308 TI - J wave patterns and ST elevation in women. PMID- 23981309 TI - The prevalence and clinical significance of J wave patterns in athletes. PMID- 23981310 TI - The J wave patterns and risk of sudden cardiac death in patients with coronary artery disease. PMID- 23981311 TI - Dynamic electrocardiographic recordings in patients with idiopathic ventricular fibrillation. PMID- 23981312 TI - Sudden cardiac death associated with J wave elevation in the inferolateral leads: insights from a multicenter registry. PMID- 23981314 TI - The histamine H1 receptor and recollection-based discrimination in a temporal order memory task in the mouse. AB - The histaminergic system in the central nervous system is involved in a variety of physiological, pathological and behavioral processes. There is now substantial evidence for an important role of histaminergic neurotransmission in learning and memory related processes. The histamine H1 receptor (H1R) is the most abundant histamine receptor in the mammalian brain. We have recently demonstrated that the genetic inactivation of the H1R in mice impairs episodic-like memory, defined as the ability to remember previous experiences with respect to their content and their temporal and spatial context. The ability to encode and retrieve the temporal order of unique events, that is its temporal context, is a core feature of episodic memory. Here we asked whether episodic-like memory deficits of H1R-KO mice are possibly due to changes in the processing, encoding or maintenance of temporal or sequence information which is critical for episodic-like memory formation. H1R-KO mice were tested in the temporal object memory (TOM) task with different inter-trial intervals (ITIs). H1R-KO mice showed impaired TOM when being tested under both, short and longer ITIs. Another aim of the study was to determine whether temporal order discrimination is based on either familiarity or recollection-based memory processes. The performance of wild type (WT) animals in the TOM task suggests that they used recollection-like discrimination strategies. PMID- 23981313 TI - Phospholipase C-beta in immune cells. AB - Great progress has recently been made in structural and functional research of phospholipase C (PLC)-beta. We now understand how PLC-beta isoforms (beta1-beta4) are activated by GTP-bound Galphaq downstream of G protein-coupled receptors. Numerous studies indicate that PLC-betas participate in the differentiation and activation of immune cells that control both the innate and adaptive immune systems. The PLC-beta3 isoform also interplays with tyrosine kinase-based signaling pathways, to inhibit Stat5 activation by recruiting the protein tyrosine phosphatase SHP-1, with which PLC-beta3 and Stat5 form a multi-molecular signaling platform, named SPS complex. The SPS complex has important regulatory roles in tumorigenesis and immune cell activation. PMID- 23981315 TI - A newly isolated Bacillus licheniformis strain thermophilically produces 2,3 butanediol, a platform and fuel bio-chemical. AB - BACKGROUND: 2,3-Butanediol (2,3-BD), a platform and fuel bio-chemical, can be efficiently produced by Klebsiella pneumonia, K. oxytoca, and Serratia marcescens. However, these strains are opportunistic pathogens and not favorable for industrial application. Although some generally regarded as safe (GRAS) microorganisms have been isolated in recent years, there is still a demand for safe 2,3-BD producing strains with high productivity and yield under thermophilic fermentation. RESULTS: Bacillus licheniformis strain 10-1-A was newly isolated for 2,3-BD production. The optimum temperature and medium pH were 50 degrees C and pH 7.0 for 2,3-BD production by strain 10-1-A. The medium composition was optimized through Plackett-Burman design and response surface methodology techniques. With a two-stage agitation speed control strategy, 115.7 g/L of 2,3 BD was obtained from glucose by fed-batch fermentation in a 5-L bioreactor with a high productivity (2.4 g/L.h) and yield (94% of its theoretical value). The 2,3 BD produced by strain 10-1-A comprises (2R,3R)-2,3-BD and meso-2,3-BD with a ratio of nearly 1:1. The bdh and gdh genes encoding meso-2,3-butanediol dehydrogenase (meso-BDH) and glycerol dehydrogenase (GDH) of strain 10-1-A were expressed in Escherichia coli and the proteins were purified. meso-2,3-BD and (2R,3R)-2,3-BD were transformed from racemic acetoin by meso-BDH and GDH with NADH, respectively. CONCLUSIONS: Compared with the reported GRAS 2,3-BD producers, B. licheniformis 10-1-A could thermophilically produce 2,3-BD with a high concentration, productivity and yield. Thus, the newly isolated GRAS strain 10-1-A might be a promising strain for industrial production of 2,3-BD. Two key enzymes for meso-2,3-BD and (2R,3R)-2,3-BD production were purified and further studied, and this might be helpful to understand the mechanism for 2,3-BD stereoisomers forming in B. licheniformis. PMID- 23981316 TI - Nondestructive method for quantifying thallium dopant concentrations in CsI:Tl crystals. AB - We report a quantitative method for using X-ray fluorescence (XRF) to nondestructively measure the true content of Tl dopant in CsI:Tl scintillator crystals. The instrument is the handheld LeadTracerTM, originally developed at RMD Instruments for measuring Pb concentration in electronic components. We describe both the measurement technique and specific findings on how changes in crystal size and growth parameters affect Tl concentration. This method is also applicable to numerous other activator ions important to scintillators, such as Ce(3+) and Eu(2+). PMID- 23981318 TI - The role of measurement in establishing evidence. AB - Measurement outcomes are frequently used as evidence in favor of or against medical and surgical interventions, health policies, and system designs. Indeed, in the medical and health services research literature, outcomes are the currency of policy debate and decision making. Yet in the philosophy of science and philosophy of medicine, the measures used in evidence-based medicine (EBM) are rarely discussed. Rather, the focus here is almost exclusively on study design and hierarchies of evidence. This concentration on the methodology of study design has meant that for practical purposes the measures used in randomized controlled trials, observational studies, audits, and so forth, appear as a "black box." Yet as I argue in the first part of this article, an engagement with measurement can improve our understanding of EBM and the quality of our evidence. In the second part of the article, I develop such an engagement with one aspect of measurement, namely, the validity of patient-reported outcome measures. Here, I illustrate some of the complexity that is required to improve the validity of these measures and hence the validity of our study outcomes, that is, evidence. The concentration in philosophy of science on study design over measurement methodology perhaps reveals the interest that many philosophers of medicine have in causation, but there is more to the production of high-quality scientific evidence than securing the causal inference. PMID- 23981319 TI - Treatment of refractory irritable bowel syndrome with visceral osteopathy: short term and long-term results of a randomized trial. AB - OBJECTIVE: In light of the low efficiency of available drugs in treating irritable bowel syndrome (IBS), there has been a growing interest in its alternative therapies. The aim of this study was to evaluate the effectiveness of visceral osteopathy for IBS. METHODS: In total, 31 consecutive refractory IBS patients were prospectively included in a randomized, crossover placebo controlled study. Qualitative evaluation of depression and four symptoms including constipation, diarrhea, abdominal distension and abdominal pain before and after each phase of the study were conducted using visual analog scales, measures of rectal sensitivity and colonic transit time. One year after the study, the assessment of symptoms was performed again in all patients. RESULTS: Visceral osteopathy was associated with a significant amelioration of self reported diarrhea, abdominal distension and abdominal pain, while constipation did not change significantly after this therapy. It was also associated with decreased rectal sensitivity, presenting as an increase in threshold volume, constant sensation volume and maximum tolerable volume (P < 0.001). However, no significant evolution of rectal sensitivity was observed when patients underwent placebo manipulations. Modifications of depression and total or segmental colonic transit time were not observed. One year after the end of this trial, symptom scores of diarrhea, abdominal distension and abdominal pain were significantly lower than those at enrollment (P < 0.05). CONCLUSION: This study suggests that visceral osteopathy improves short-term and long-term abdominal distension and pain, and also decreases rectal sensitivity in IBS patients. PMID- 23981317 TI - Genes involved in thoracic exoskeleton formation during the pupal-to-adult molt in a social insect model, Apis mellifera. AB - BACKGROUND: The insect exoskeleton provides shape, waterproofing, and locomotion via attached somatic muscles. The exoskeleton is renewed during molting, a process regulated by ecdysteroid hormones. The holometabolous pupa transforms into an adult during the imaginal molt, when the epidermis synthe3sizes the definitive exoskeleton that then differentiates progressively. An important issue in insect development concerns how the exoskeletal regions are constructed to provide their morphological, physiological and mechanical functions. We used whole-genome oligonucleotide microarrays to screen for genes involved in exoskeletal formation in the honeybee thoracic dorsum. Our analysis included three sampling times during the pupal-to-adult molt, i.e., before, during and after the ecdysteroid-induced apolysis that triggers synthesis of the adult exoskeleton. RESULTS: Gene ontology annotation based on orthologous relationships with Drosophila melanogaster genes placed the honeybee differentially expressed genes (DEGs) into distinct categories of Biological Process and Molecular Function, depending on developmental time, revealing the functional elements required for adult exoskeleton formation. Of the 1,253 unique DEGs, 547 were upregulated in the thoracic dorsum after apolysis, suggesting induction by the ecdysteroid pulse. The upregulated gene set included 20 of the 47 cuticular protein (CP) genes that were previously identified in the honeybee genome, and three novel putative CP genes that do not belong to a known CP family. In situ hybridization showed that two of the novel genes were abundantly expressed in the epidermis during adult exoskeleton formation, strongly implicating them as genuine CP genes. Conserved sequence motifs identified the CP genes as members of the CPR, Tweedle, Apidermin, CPF, CPLCP1 and Analogous-to-Peritrophins families. Furthermore, 28 of the 36 muscle-related DEGs were upregulated during the de novo formation of striated fibers attached to the exoskeleton. A search for cis regulatory motifs in the 5'-untranslated region of the DEGs revealed potential binding sites for known transcription factors. Construction of a regulatory network showed that various upregulated CP- and muscle-related genes (15 and 21 genes, respectively) share common elements, suggesting co-regulation during thoracic exoskeleton formation. CONCLUSIONS: These findings help reveal molecular aspects of rigid thoracic exoskeleton formation during the ecdysteroid coordinated pupal-to-adult molt in the honeybee. PMID- 23981321 TI - Effects of a word-learning training on children with cochlear implants. AB - Preschool children with hearing loss who use cochlear implants demonstrate vocabulary delays when compared to their peers without hearing loss. These delays may be a result of deficient word-learning abilities; children with cochlear implants perform more poorly on rapid word-learning tasks than children with normal hearing. This study explored the malleability of rapid word learning of preschoolers with cochlear implants by evaluating the effects of a word-learning training on rapid word learning. A single-subject, multiple probe design across participants measured the impact of the training on children's rapid word learning performance. Participants included 5 preschool children with cochlear implants who had an expressive lexicon of less than 150 words. An investigator guided children to identify, repeat, and learn about unknown sets of words in 2 weekly sessions across 10 weeks. The probe measure, a rapid word-learning task with a different set of words than those taught during training, was collected in the baseline, training, and maintenance conditions. All participants improved their receptive rapid word-learning performance in the training condition. The functional relation indicates that the receptive rapid word-learning performance of children with cochlear implants is malleable. PMID- 23981320 TI - Protection of the heart by treatment with a divalent-copper-selective chelator reveals a novel mechanism underlying cardiomyopathy in diabetic rats. AB - BACKGROUND: Intracellular calcium (Ca2+) coordinates the cardiac contraction cycle and is dysregulated in diabetic cardiomyopathy. Treatment with triethylenetetramine (TETA), a divalent-copper-selective chelator, improves cardiac structure and function in patients and rats with diabetic cardiomyopathy, but the molecular basis of this action is uncertain. Here, we used TETA to probe potential linkages between left-ventricular (LV) copper and Ca2+ homeostasis, and cardiac function and structure in diabetic cardiomyopathy. METHODS: We treated streptozotocin-diabetic rats with a TETA-dosage known to ameliorate LV hypertrophy in patients with diabetic cardiomyopathy. Drug treatment was begun either one (preventative protocol) or eight (restorative protocol) weeks after diabetes induction and continued thereafter for seven or eight weeks, respectively. Total copper content of the LV wall was determined, and simultaneous measurements of intracellular calcium concentrations and isometric contraction were made in LV trabeculae isolated from control, diabetic and TETA treated diabetic rats. RESULTS: Total myocardial copper levels became deficient in untreated diabetes but were normalized by TETA-treatment. Cardiac contractility was markedly depressed by diabetes but TETA prevented this effect. Neither diabetes nor TETA exerted significant effects on peak or resting [Ca2+](i). However, diabetic rats showed extensive cardiac remodelling and decreased myofibrillar calcium sensitivity, consistent with observed increases in phosphorylation of troponin I, whereas these changes were all prevented by TETA. CONCLUSIONS: Diabetes causes cardiomyopathy through a copper-mediated mechanism that incorporates myocardial copper deficiency, whereas TETA treatment prevents this response and maintains the integrity of cardiac structure and myofibrillar calcium sensitivity. Altered calcium homeostasis may not be the primary defect in diabetic cardiomyopathy. Rather, a newly-described copper-mediated mechanism may cause this disease. PMID- 23981322 TI - Fibromyalgia: a daring new look. PMID- 23981323 TI - Antifungal activity of dental resins containing amphotericin B-conjugated nanoparticles. AB - OBJECTIVES: To evaluate the antifungal activity, biocompatibility and mechanical properties of dental resins containing silica nanoparticles functionalized with amphotericin B (SNP-DexOxAmB) against five species of Candida. METHODS: Dental resin composites (Spectrum, Dentsply DeTrey, GmbH, Germany) having 2% (w/w) of SNP-DexOxAmB (SNPs of 5 and 80nm, denoted as SNP5 and SNP80) were aged for 10, 20 and 30 days at 37 degrees C, in phosphate buffer saline buffer pH 7.4 (PBS). At different time, the antifungal activity was evaluated by a direct contact assay against 1*10(4)cells of Candida. The biocompatibility of the resins was tested against human fibroblasts, endothelial cells and red blood cells. RESULTS: Dental resins containing SNP5-DexOxAmB have high (1*10(4)cells killed in 5h by ~70mg of dental resin composite containing 2% (w/w) of SNP-DexOxAmB) and durable (for at least 1 month) antifungal activity against five strains of Candida. The incorporation of the nanoparticles (NPs) had no significant change in the mechanical properties of the resin, specifically the flexural strength and modulus. Our results further show that the antifungal activity is mainly mediated by direct contact and not by leaching of NPs from the resin. Resins incorporating SNP5-DexOxAmB have longer-term antifungal activity than SNP80-DexOxAmB. The antimicrobial activity of resins with SNP5-DexOxAmB persists after 4 cycles of re use and it is superior to the activity obtained for dental resins containing silver NPs. In addition, dental resins incorporating SNP5-DexOxAmB are non cytotoxic against human skin fibroblasts and human umbilical vein endothelial cells, and non-hemolytic against human red blood cells. SIGNIFICANCE: The incorporation of SNP5-DexOxAmB in dental resins resulted in a non-cytotoxic composite with high and durable antifungal activity. PMID- 23981324 TI - The future, prayers, and lies. PMID- 23981325 TI - Editor's note. PMID- 23981326 TI - Molecular cloning and expression analysis of a dorsal homologue from Eriocheir sinensis. AB - Dorsal as a crucial component of Toll signaling pathway, played important roles in induction and regulation of innate immune responses. In this study, we cloned a NF-kappaB-like transcription factor Dorsal from Eriocheir sinensis and designated it as EsDorsal. The full-length cDNA of EsDorsal was 2493 bp with a 2022-bp open reading frame (ORF) encoding a 673-amino acid protein. This protein contained a 171-residue conserved Rel homology domain (RHD) and a 102-residue Ig like, plexins and transcription factors domain (IPT). By phylogenetic analysis, EsDorsal was clustered into one group together with other invertebrate Dorsals or NF-kappaBs, and then clustered with vertebrate NF-kappaBs. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis results showed that (a) EsDorsal had higher expression level in immune organs; (b) EsDorsal differentially induced after injection of lipopolysaccharides (LPS), peptidoglycan (PG) or zymosan (GLU). Importantly, EsDorsal was more responsive to LPS than GLU and PG. Collectively, EsDorsal was differentially inducibility in response to various PAMPs, suggesting its involvement in a specific innate immune regulation in E. sinensis. PMID- 23981327 TI - Innate immune responses of salmonid fish to viral infections. AB - Viruses are the most serious pathogenic threat to the production of the main aquacultured salmonid species the rainbow trout Oncorhynchus mykiss and the Atlantic salmon Salmo salar. The viral diseases Infectious Pancreatic Necrosis (IPN), Pancreatic Disease (PD), Infectious Haemorrhagic Necrosis (IHN), Viral Haemorrhagic Septicaemia (VHS), and Infectious Salmon Anaemia (ISA) cause massive economic losses to the global salmonid aquaculture industry every year. To date, no solution exists to treat livestock affected by a viral disease and only a small number of efficient vaccines are available to prevent infection. As a consequence, understanding the host immune response against viruses in these fish species is critical to develop prophylactic and preventive control measures. The innate immune response represents an important part of the host defence mechanism preventing viral replication after infection. It is a fast acting response designed to inhibit virus propagation immediately within the host, allowing for the adaptive specific immunity to develop. It has cellular and humoral components which act in synergy. This review will cover inflammation responses, the cell types involved, apoptosis, antimicrobial peptides. Particular attention will be given to the type I interferon system as the major player in the innate antiviral defence mechanism of salmonids. Viral evasion strategies will also be discussed. PMID- 23981328 TI - Ligand specificities of Toll-like receptors in fish: indications from infection studies. AB - Toll like receptors (TLRs) are present in many different fish families from several different orders, including cyprinid, salmonid, perciform, pleuronectiform and gadiform representatives, with at least some conserved properties among these species. However, low conservation of the leucine-rich repeat ectodomain hinders predictions of ligand specificities of fish TLRs based on sequence information only. We review the presence of a TLR genes, and changes in their gene expression profiles as result of infection, in the context of different fish orders and fish families. The application of RT-qPCR and availability of increasing numbers of fish genomes has led to numerous gene expression studies, including studies on TLR gene expression, providing the most complete dataset to date. Induced changes of gene expression may provide (in)direct evidence for the involvement of a particular TLR in the reaction to a pathogen. Especially when findings are consistent across different studies on the same fish species or consistent across different fish species, up-regulation of TLR gene expression could be a first indication of functional relevance. We discuss TLR1, TLR2, TLR4, TLR5 and TLR9 as presumed sensors of bacterial ligands and discuss as presumed sensors of viral ligands TLR3 and TLR22, TLR7 and TLR8. More functional studies are needed before conclusions on ligands specific to (groups of) fish TLRs can be drawn, certainly true for studies on non-mammalian TLRs. Future studies on the conservation of function of accessory molecules, in conjunction with TLR molecules, may bring new insight into the function of fish TLRs. PMID- 23981329 TI - Biology and host response to Cyprinid herpesvirus 3 infection in common carp. AB - Viruses from the family Alloherpesviridae form an aquatic clade of herpesviruses infecting fish and amphibia. Diseases caused by these herpesviruses are of increasing importance because of the high morbidity and mortality associated with the infection, and the difficulties in diagnosing latently infected carriers. Cyprinid herpesvirus 3 (CyHV-3) induces a severe disease and mortality in common carp and thus greatly affects carp aquaculture and trade. This review summarises advancements in the understanding of the infection process and the current knowledge on immune responses of carp to CyHV-3. A focus is laid on host genetics and immunity responsible for resistance/survival from the disease and on the viral mechanisms accountable for evasion of carp immune responses. As current knowledge of immune responses to CyHV-3 is still limited, perspectives for future studies are outlined. Analysing CyHV-3 fish-host interactions will be useful and thought-provoking for a basic understanding of fish immune responses. PMID- 23981330 TI - Individualizing treatment and choice of medication in lichen planus: a step by step approach. AB - Although lichen planus is one of the most common dermatological entities, very few reviews on its management exist in the literature. Standard therapeutic approaches include various topical treatments (including topical corticosteroids, calcineurin inhibitors, vitamin D analogs) and phototherapy modalities, as well as systemic corticosteroids and systemic retinoids. While localized skin lesions are easily managed with standard modalities, generalized forms and in particular involvement of hair follicles, nails and mucosa, as well as eyes are often challenging. This review proposes an evidence-based and differential therapeutic regime, taking into account many new emerging systemic therapies to help clinicians optimize treatment according to the type, extent and severity of the disease. An individual therapeutic ladder has been developed for each location, starting with standard modalities and ranking alternative systemic treatments (mainly methotrexate and hydroxychloroquine, as well as cyclosporine, azathioprine and mycophenolate mofetil) according to efficacy, evidence level and side-effect profile. PMID- 23981331 TI - Non-labeled monitoring of targeted liposome interactions with a model receptor surface: effect of flow rate and water content. AB - In this study, we present a novel in vitro approach that utilizes two surface sensitive and label-free techniques, i.e. surface plasmon resonance (SPR) and quartz crystal microbalance (QCM), to study the interfacial events during liposome-target surface interactions. The flow channels of SPR and QCM devices were first synchronized via hydrodynamic modeling. Biotin-streptavidin was used as a model pair and self-assembled monolayers (SAMs) were utilized as model surfaces for targeted liposome-surface interaction studies. The interactions between biotin-liposomes and the streptavidin-biotin-SAM surfaces were investigated under controlled shear flows using the synchronized SPR and QCM devices. The response of the liposome interaction was monitored as a function of the flow rate. The affinity and the amount of bound liposome indicated that the increased flow rate improved the binding of the targeted liposomes to the model membrane surfaces. The combined use of the synchronized SPR and QCM devices for nanoparticle interaction studies clearly demonstrates the effect of the flow rate (or the shear stress) on the liposome binding. Our results suggest that the binding of liposomes to the model membranes is flow rate and shear stress regulated. Thus, the flow rate (or the shear stress), which is usually neglected, should be taken into account during the development and optimization of targeted liposome formulations. In addition, the water content within the liposome layer (including the water inside the liposomes and the water between the liposomes) had a significant influence on the visco-elasticity and the binding kinetics to the SAM surfaces. PMID- 23981332 TI - Quantitative assessment of the switchability of generic products. AB - Generics are usually considered to exhibit comparable in vivo properties in terms of efficacy and safety and for this reason are intended to be interchangeable with the reference product. The aim of this study is to provide a quantitative picture of the switchability problem between two generics and to introduce the concept of conditional probability of bioequivalence (BE) acceptance. Monte Carlo simulations were performed to examine all possible relationships between the tested products. Four types of percent BE acceptances are defined and evaluated: (a) %BA1, when generic T1 is compared to the R product, (b) %BA2, in cases of comparison of generic T2 with the R product, (c) %BA21, when generic T2 is compared to another generic T1, and finally (d) %BA21C which is the conditional probability of percent bioequivalence acceptance of generic T2versus another generic T1 given that both T1 and T2 are declared bioequivalent to the same R formulation. The simulations were expanded to study concomitantly the performance of T1 and T2 when compared to the same R formulation. In each case, the 2 * 2 cross-over design was used and evaluation of BE was based on the classic BE limits (0.80-1.25) and the stricter BE limits (0.90-1.11) for narrow therapeutic index (NTI) drugs. A number of 24 and 48 subjects were assumed to participate in the simulated trials, while the coefficient of variation for the within-subject variability (CVw) was 20% and 40%. A number 40,000 BE trials were simulated under each condition. The T1/R and T2/R ratios ranged from 0.80 to 1.25 using a step of 0.05. Even though two generics (T1 and T2) can be declared bioequivalent to the same R product, this does not ensure that they are always mutually bioequivalent. On the contrary, two generic products which differ substantially from the R product can still have a high probability to be truly interchangeable. The two generics (T1 and T2) can be switched from one to another when the T1/R and T2/R ratios are close to the same value, the CVw of the drug is low, and each BE study of T1-R and T2-R was conducted using a relatively large number of subjects. In the same context, two generic NTI drugs which differ more than 10% from the R product can still be declared bioequivalent to one another depending on the relative T1/R and T2/R ratios. Switchability between generics assessed at the 0.90-1.11 interval is safer, but not always ensured. PMID- 23981333 TI - New gene delivery system based on oligochitosan and solid lipid nanoparticles: 'in vitro' and 'in vivo' evaluation. AB - In the present work, we evaluated the potential utility for gene delivery of three oligochitosans (OligoCh) that differs in the M(n) (OligoChA: 6.1 kDa, OligoChB: 11.5 kDa, and OligoChC: 13.7 kDa), with deacetylation degree of 85%. OligoCh were complexed directly with the pCMS-EGFP plasmid to form OligoCh-DNA carriers. Taking into account the features and benefits of both Ch and SLNs, we also combined the OligoCh with SLNs. The three OligoCh presented a great ability to condense and protect the DNA. The OligoCh of highest M(n) (OligoChC) complexed with SLNs at a OligoChC:DNA:SLN ratio 2.5:1:5 induced the highest transfection level in HEK-293 cells at day 3; being transfection 2-fold higher at day 7. After the intravenous administration to mice, OligoChC-DNA and OligoChC-DNA-SLN vectors were able to induce the expression of EGFP in the spleen, lung and liver, which was maintained for at least 7 days. In spite of the difference in the "in vitro" transfection levels between both vectors, no difference was detected in transfection after "in vivo" administration. Moreover, the OligoChC improved the "in vivo" transfection efficacy of the DNA-SLN vector. This work shows the potential utility of the combination of SLNs and OligoCh for the development of new non-viral vectors for gene therapy. PMID- 23981334 TI - [11C]befloxatone brain kinetics is not influenced by Bcrp function at the blood brain barrier: a PET study using Bcrp TGEM knockout rats. AB - Knockout (KO) animals are useful tools with which to assess the interplay between P-glycoprotein (P-gp; Abcb1) and the breast cancer resistance protein (Bcrp, Abcg2), two major ABC-transporters expressed at the blood-brain barrier (BBB). However, one major drawback of such deficient models is the possible involvement of compensation between transporters. In the present study, P-gp and Bcrp distribution in the brain as well as P-gp expression levels at the BBB were compared between the Bcrp TGEM KO rat model and the wild-type (WT) strain. Therefore, we used confocal microscopy of brain slices and western blot analysis of the isolated brain microvessels forming the BBB. This deficient rat model was used to assess the influence of Bcrp on the brain and peripheral kinetics of its substrate [(11)C]befloxatone using positron emission tomography (PET). The influence of additional P-gp inhibition was tested using elacridar (GF120918) 2 mg/kg in Bcrp KO rats. The distribution pattern of P-gp in the brain as well as P gp expression levels at the BBB was similar in Bcrp-deficient and WT rats. Brain and peripheral kinetics of [(11)C]befloxatone were not influenced by the lack of Bcrp. Neither was the brain uptake of [(11)C]befloxatone in Bcrp-deficient rats influenced by the inhibition of P-gp. In conclusion, the Bcrp-deficient rat strain, in which we detected no compensatory mechanism or modification of P-gp expression as compared to WT rats, is a suitable model to study Bcrp function separately from that of P-gp at the BBB. However, although selectively transported by BCRP in vitro, our results suggest that [(11)C]befloxatone PET imaging might not be biased by impaired function of this transporter in vivo. PMID- 23981335 TI - Comparison of fenofibrate-mesoporous silica drug-loading processes for enhanced drug delivery. AB - Loading a poorly water-soluble drug onto a high surface area carrier such as mesoporous silica (SBA-15) can increase the drug's dissolution rate and oral bioavailability. The loading method can influence subsequent drug properties including solid state structure and release rate. The objective of this research was to compare several loading processes in terms of drug distribution throughout the mesoporous silica matrix, drug solid state form and drug release properties. A model poorly water-soluble drug fenofibrate was loaded onto SBA-15 using; (i) physical mixing, (ii) melt, (iii) solvent impregnation, (iv) liquid CO2 and (v) supercritical CO2 methods. Physical mixing resulted in heterogeneous drug loading, with no evidence of drug in the mesopores and the retention of the drug in its crystalline state. The other loading processes yielded more homogeneous drug-loading; the drug was deposited into the mesopores of the SBA-15 and was non crystalline. All the processing methods resulted in enhanced drug release compared to the unprocessed drug with the impregnation, liquid and SC-CO2 producing the greatest increase at t=30 min. PMID- 23981336 TI - Pure insulin highly respirable powders for inhalation. AB - The aim of the present research was to investigate the possibility to obtain by spray drying an insulin pulmonary powder respirable and stable at room temperature without the use of excipients. Several insulin spray-dried powders were prepared with or without the addition of excipients (mannitol, bovine serum albumin, aspartic acid) from water dispersions or from acidic aqueous solutions. Each formulation was characterized using laser diffraction, scanning electron microscopy and in vitro aerosol performance with a Turbospin DPI device. Stability was assessed by the quantification of impurities with a molecular mass greater than that of insulin (HMWP) and related proteins (A21+ORP). Insulin powders prepared without excipients from an acid solution showed a shrivelled, raisin-like shape of non-aggregated microparticles and a high respirability (FPF>65%). The optimal result with respect to respirability and stability was reached when the pH of the insulin acetic acid solution to spray dry was adjusted at pH 3.6 with ammonium hydroxide. The median volume diameter of the obtained powder was 4.04 MUm, insulin content 95%, emitted dose of 89.5%, MMAD 1.79 MUm and fine particle fraction of 83.6%. This powder was stable at room temperature over a period of eighteen months with respect to the content of A21+ORP. As far as the HMWP content was concerned, the powder complied with the specification limits for a period of five months. The insulin acetic powder opens up the possibility of a more effective pulmonary therapy less dependent on refrigerated storage. PMID- 23981337 TI - Enhanced intestinal absorption of etoposide by self-microemulsifying drug delivery systems: roles of P-glycoprotein and cytochrome P450 3A inhibition. AB - Etoposide is recognized as a dual P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) substrate drug with poor water-solubility. To improve its solubility and bioavailability, three novel self-microemulsifying drug delivery systems (SMEDDS) contained the known P-gp and CYP3A inhibitory surfactants, Cremophor RH40, Cremophor EL, or Polysorbate 80, were prepared. This work aims to evaluate the enhanced intestinal absorption of etoposide SMEDDS as well as to explore the roles of P-gp and CYP3A inhibition in the absorption process. Etoposide SMEDDS were orally administered to rats for in vivo bioavailability investigation. In situ single-pass intestinal perfusion with mesenteric vein cannulation was employed to study the drug permeability and intestinal metabolism. In vitro Caco 2 cell models were applied to study the effects of P-gp and CYP3A inhibition by SMEDDS on the cellular accumulation of etoposide. It was found that the bioavailability and in situ intestinal absorption were significantly enhanced by SMEDDS with the order of Polysorbate 80-based SMEDDS>Cremophor EL-based SMEDDS>Cremophor RH40-based SMEDDS. In addition, there was a dramatically high linear correlation between the AUC0-t values and the apparent permeability coefficient values based on the appearance of the drug in mesenteric vein blood. Cellular uptake studies demonstrated that P-gp inhibition by SMEDDS played an important role in etoposide uptake. Moreover, etoposide metabolism was demonstrated to be dramatically inhibited by the three kinds of SMEDDS. These finding may assist in the improvement of the intestinal absorption of P-gp and/or CYP3A substrate drugs. PMID- 23981338 TI - Enhancement effect of P-gp inhibitors on the intestinal absorption and antiproliferative activity of bestatin. AB - Bestatin is an immunomodulator with antitumor activity. This study was performed to investigate the effect of P-gp on the intestinal absorption and antiproliferative activity of bestatin. Our results showed that P-gp inhibitors significantly increased rat intestinal absorption of bestatin in vivo and in vitro. The net efflux ratio of bestatin was 2.2 across mock-/MDR1-MDCK cell monolayers and was decreased by P-gp inhibitors, indicating bestatin was a substrate of P-gp. Furthermore, the IC50 values of bestatin on U937 and K562 cells were decreased dramatically and the intracellular concentrations of bestatin were increased by incubation of cells with verapamil or Cyclosporin A. K562/ADR cells exhibited a higher IC50 value and a lower intracellular level of bestatin. The bestatin level in K562/ADR cells was partially restored by incubation with doxorubicin. However, P-gp and APN mRNA levels were not changed by bestatin. These results suggested that the intestinal absorption and accumulation in cancer cells for bestatin were limited by P-gp-mediated efflux. Additional attention should be paid to the alternative exposure of bestatin when bestatin was coadministered with drugs as P-gp substrates in clinic. PMID- 23981339 TI - Reproducibility of cine displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance for measuring left ventricular strains, torsion, and synchrony in mice. AB - BACKGROUND: Advanced measures of cardiac function are increasingly important to clinical assessment due to their superior diagnostic and predictive capabilities. Cine DENSE cardiovascular magnetic resonance (CMR) is ideal for quantifying advanced measures of cardiac function based on its high spatial resolution and streamlined post-processing. While many studies have utilized cine DENSE in both humans and small-animal models, the inter-test and inter-observer reproducibility for quantification of advanced cardiac function in mice has not been evaluated. This represents a critical knowledge gap for both understanding the capabilities of this technique and for the design of future experiments. We hypothesized that cine DENSE CMR would show excellent inter-test and inter-observer reproducibility for advanced measures of left ventricular (LV) function in mice. METHODS: Five normal mice (C57BL/6) and four mice with depressed cardiac function (diet-induced obesity) were imaged twice, two days apart, on a 7T ClinScan MR system. Images were acquired with 15-20 frames per cardiac cycle in three short-axis (basal, mid, apical) and two long-axis orientations (4-chamber and 2-chamber). LV strain, twist, torsion, and measures of synchrony were quantified. Images from both days were analyzed by one observer to quantify inter-test reproducibility, while inter observer reproducibility was assessed by a second observer's analysis of day-1 images. The coefficient of variation (CoV) was used to quantify reproducibility. RESULTS: LV strains and torsion were highly reproducible on both inter-observer and inter-test bases with CoVs <= 15%, and inter-observer reproducibility was generally better than inter-test reproducibility. However, end-systolic twist angles showed much higher variance, likely due to the sensitivity of slice location within the sharp longitudinal gradient in twist angle. Measures of synchrony including the circumferential (CURE) and radial (RURE) uniformity of strain indices, showed excellent reproducibility with CoVs of 1% and 3%, respectively. Finally, peak measures (e.g., strains) were generally more reproducible than the corresponding rates of change (e.g., strain rate). CONCLUSIONS: Cine DENSE CMR is a highly reproducible technique for quantification of advanced measures of left ventricular cardiac function in mice including strains, torsion and measures of synchrony. However, myocardial twist angles are not reproducible and future studies should instead report torsion. PMID- 23981340 TI - The hURAT1 rs559946 polymorphism and the incidence of gout in Han Chinese men. AB - OBJECTIVES: Our previous study identified rs559946, a human urate transporter 1 (hURAT1) single nucleotide polymorphism (SNP), as being significantly associated with risk of primary hyperuricaemia (HUA) in a Han Chinese population. In the current study we aimed to identify the genetic effects of rs559946 on gout susceptibility in Han Chinese men. METHOD: A total of 335 patients with gout and 376 healthy controls were recruited for a case-control association study. To examine the functional effect of rs559946, we performed luciferase reporter assays and an electrophoretic mobility shift assay (EMSA). RESULTS: rs559946 was found to be significantly associated with gout susceptibility (p = 0.004), with T allele carriers showing a decreased risk of gout [odds ratio (OR) 0.70, 95% confidence interval (CI) 0.55-0.89]. Multiple linear regression analysis identified a significant association between rs559946 genotypes and tophi. Luciferase reporter assays show increased transcriptional activity of the hURAT1 promoter with the C allele of rs559946. EMSA detected binding of nuclear proteins to both the T and C alleles, although increased binding was observed with the T allele. Cold competition assays suggest that rs559946 may bind within a glucocorticoid receptor (GR) binding motif. CONCLUSIONS: Our study suggests that the rs559946 polymorphism is associated with increased HUA risk and may also contribute to gout development in Han Chinese men. The T to C substitution within rs559946 increased the transcriptional activity, and potentially increases gout susceptibility. PMID- 23981341 TI - Propagation of dynamic nuclear polarization across the xenon cluster boundaries: elucidation of the spin-diffusion bottleneck. AB - Earlier Dynamic Nuclear Polarization (DNP) experiments with frozen xenon/1 propanol/trityl mixtures have demonstrated spontaneous formation of pure xenon clusters above 120 K, enabling spectrally-resolved real-time measurements of (129)Xe nuclear magnetization in the clusters and in the surrounding radical-rich matrix. A spin-diffusion bottleneck was postulated to explain the peculiar time evolution of (129)Xe signals in the clusters as well as the apparent discontinuity of (129)Xe polarization across the cluster boundaries. A self contained ab initio model of nuclear spin diffusion in heterogeneous systems is developed here, incorporating the intrinsic T1 relaxation towards the temperature dependent equilibrium polarization and the spin-diffusion coefficients based on the measured NMR line widths and the known atomic densities in each compartment. This simple model provides the physical basis for the observed spin-diffusion bottleneck and is in a good quantitative agreement with the earlier measurements. A simultaneous fit of the model to the time-dependent NMR data at two different DNP frequencies provides excellent estimates of the cluster size, the intrinsic sample temperature, and (129)Xe T1 constants. The model was also applied to the NMR data acquired during relaxation towards the thermal equilibrium after the microwaves were turned off, to estimate T1 relaxation time constants inside and outside the clusters. Fitting the model to the data during and after DNP provides consistent estimates of the cluster size. PMID- 23981342 TI - Additive relationship between serum fibroblast growth factor 21 level and coronary artery disease. AB - BACKGROUND: Expression and activity of the fibroblast growth factor (FGF) 21 hormone-like protein are associated with development of several metabolic disorders. This study was designed to investigate whether serum FGF21 level was also associated with the metabolic syndrome-related cardiovascular disease, atherosclerosis, and its clinical features in a Chinese cohort. METHODS: Two hundred-and-fifty-three subjects visiting the Cardiology Department (Sixth People's Hospital affiliated to Shanghai JiaoTong University) were examined by coronary arteriography (to diagnose coronary artery disease (CAD)) and hepatic ultrasonography (to diagnose non-alcoholic fatty liver disease (NAFLD)). Serum FGF21 level was measured by enzyme-linked immunosorbent assay and analyzed for correlation to subject and clinical characteristics. The independent factors of CAD were determined by multivariate logistic regression analysis. RESULTS: Subjects with NAFLD showed significantly higher serum FGF21 than those without NAFLD (388.0 pg/mL (253.0-655.4) vs. 273.3 pg/mL (164.9-383.7), P < 0.01). Subjects with CAD showed significantly higher serum FGF21, regardless of NAFLD diagnosis (P < 0.05). Serum FGF21 level significantly elevated with the increasing number of metabolic disorders (P for trend < 0.01). After adjustment of age, sex, and BMI, FGF21 was positively correlated with total cholesterol (P < 0.05) and triglyceride (P < 0.01). FGF21 was identified as an independent factor of CAD (odds ratio = 2.984, 95% confidence interval: 1.014-8.786, P < 0.05). CONCLUSIONS: Increased level of serum FGF21 is associated with NAFLD, metabolic disorders and CAD. PMID- 23981343 TI - First report in South America of companion animal colonization by the USA1100 clone of community-acquired meticillin-resistant Staphylococcus aureus (ST30) and by the European clone of methicillin-resistant Staphylococcus pseudintermedius (ST71). AB - BACKGROUND: Methicillin-resistant staphylococci can colonize and cause diseases in companion animals. Unfortunately, few molecular studies have been carried out in Brazil and other countries with the aim of characterizing these isolates. Consequently, little is known about the potential role of companion animals in transmitting these resistant bacteria to humans. In this work we searched for mecA gene among Staphylococcus isolates obtained from nasal microbiota of 130 healthy dogs and cats attended in a veterinary clinic located in the west region of Rio de Janeiro. The isolates recovered were identified to the species level and characterized using molecular tools. RESULTS: A community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) isolate related to USA1100 (Southwest Pacific clone) and susceptible to all non-beta-lactams was detected in a cat (1.7%, 1/60). Another coagulase-positive isolate harboring mecA was recovered from a dog (1.4%, 1/70) and identified as Staphylococcus pseudintermedius (MRSP) related to the European clone (ST71). The two isolates of Staphylococcus conhii subsp. urealyticus (1.4%, 1/70 dogs and 1.7%, 1/60 cats), similarly to the MRSP isolate, also presented high-level multiresistance. The majority of the methicillin-resistant coagulase-negative staphylococci recovered were Staphylococcus saprophyticus (5.7%, 4/70 dogs and 6.7%, 4/60 cats) and all clustered into the same PFGE type. CONCLUSIONS: This work demonstrates that mecA harboring Staphylococcus isolates are common members of the nasal microbiota of the healthy companion animals studied (9.2%, 12/130 animals), including some high level multiresistant isolates of S. pseudintermedius and S. conhii subsp. urealyticus. The detection, for the first time in South America, of USA1100 related CA-MRSA and of ST71 MRSP (European clone), colonizing companion animals, is of concern. Both S. pseudintermedius and S. aureus are important agents of infections for animals. The USA1100 CA-MRSA is a causative of severe and disseminated diseases in healthy children and adults. Additionally, MRSP is a nosocomial pathogen in veterinarian settings. It had already been demonstrated that the virulent ST71 MRSP is geographically spread over Europe and USA, with potential for zoonotic infections. PMID- 23981346 TI - Contrast loading: power output and rest interval effects on neuromuscular performance. AB - PURPOSE: This study examined the effect of rest interval after the execution of a jump-squat set with varied external mechanical-power outputs on repeated-jump (RJ) height, mechanical power, and electromyographic (EMG) activity. METHODS: Twelve male volleyball players executed 6 RJs before and 1, 3, 5, 7, and 10 min after the execution of 6 repetitions of jump squats with a load: maximized mechanical-power output (Pmax), 70% of Pmax, 130% of Pmax, and control, without extra load. RESULTS: RJ height did not change (P = .44) after the jump squats, mechanical power was higher (P = .02) 5 min after the 130%Pmax protocol, and EMG activity was higher (P = .001) after all exercise protocols compared with control. Irrespective of the time point, however, when the highest RJ set for each individual was analyzed, height, mechanical power, and EMG activity were higher (P = .001-.04) after all loading protocols compared with control, with no differences observed (P = .53-.72) among loads. CONCLUSIONS: Rest duration for a contrast-training session should be individually determined regardless of the load and mechanical-power output used to activate the neuromuscular system. The load that maximizes external mechanical-power output compared with a heavier or a lighter load, using the jump-squat exercise, is not more effective for increasing jumping performance afterward. PMID- 23981345 TI - The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold. AB - BACKGROUND: Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound's mechanism of action. RESULTS: Dual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX2R) occupancies in the range of 65 to 80%. In rats, the time course of OX2R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes. CONCLUSION: The higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses. PMID- 23981347 TI - High sensitivity and specificity of a new functional flow cytometry assay for clinically significant heparin-induced thrombocytopenia antibodies. AB - INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition, in which the anticoagulant heparin, platelet factor 4 (PF4), and platelet-activating antibodies form complexes with prothrombotic properties. Laboratory tests to support clinical diagnosis are subdivided into functional, platelet activation assays, which lack standardization, or immunological assays, which have moderate specificity toward HIT. In this study, clinical performance of HITAlert, a novel in vitro diagnostic (IVD) registered platelet activation assay, was tested in a large cohort of HIT-suspected patients and compared with immunological assays. METHODS: From 346 HIT-suspected patients (single center), clinical data including 4T pretest probability results, citrated platelet-poor plasmas, and sera were collected, allowing direct comparison of clinical observations with HITAlert results. HITAlert performance was compared with PF4 IgG ELISA (246 patients, three centers) and PF4 PaGIA (298 patients, single center). RESULTS: HITAlert showed high sensitivity (88.2%) and specificity (99.1%) when compared with clinical diagnosis. Agreement of HITAlert with PF4 ELISA- and PF4 PaGIA-positive patients is low (52.7 and 23.2%, respectively), while agreement with PF4 IgG ELISA- and PF4 PaGIA-negative patients is very high (98.1 and 99.1%, respectively). CONCLUSION: HITAlert performance is excellent when compared with clinical HIT diagnosis, making it a suitable assay for rapid testing of platelet activation due to anticoagulant therapy. PMID- 23981348 TI - The utility of diffusion tensor imaging tractography for post-operative evaluation of a patient with hemispherotomy performed for intractable epilepsy. AB - Hemispherotomy is an effective treatment for patients with severe epilepsy caused by hemispheric abnormalities such as hemimegalencephaly or other dysplastic malformations. Here, we report a 5-year-old boy who experienced right-side hemiconvulsion due to left hemispheric cortical dysplasia. He presented with mild right hemiparesis that had been present since seizure onset. Ictal electroencephalogram obtained during the hemiconvulsion showed localized epileptic discharges in the left hemisphere. He underwent a left peri-insular hemispherotomy. Three months after surgery, clonic convulsions returned in the left leg and EEG-video monitoring showed localized epileptic discharges in the frontal region. Magnetic resonance images showed that the genu of corpus callosum was unsectioned and diffusion tensor imaging tractography confirmed the presence of callosal fibers in the genu of the corpus callosum. Clonic convulsion disappeared after additional section of the corpus callosum. Further studies are warranted to determine the utility of diffusion tensor imaging tractography on the assessment of subcortical fibers following disconnective epilepsy surgery. PMID- 23981349 TI - Compound heterozygosity in GPR56 with bilateral frontoparietal polymicrogyria. AB - Polymicrogyria is caused by a diverse etiology, one of which is gene mutation. At present, only one gene (GPR56) is known to cause polymicrogyria, which leads to a distinctive phenotype termed bilateral frontoparietal polymicrogyria (BFPP). BFPP is an autosomal recessive inherited human brain malformation with abnormal cortical lamination. Here, we identified compound heterozygous GPR56 mutations in a patient with BFPP. The proband was a Japanese female born from non consanguineous parents. She presented with mental retardation, developmental motor delay, epilepsy exhibiting the feature of Lennox-Gastaut syndrome, exotropia, bilateral polymicrogyria with a relatively spared perisylvian region, bilateral patchy-white-matter MRI signal changes, and hypoplastic pontine basis. GPR56 sequence analysis revealed a c.107G>A substitution leading to a p.S36N, and a c.113G>A leading to a p.R38Q. Although affected individuals with compound heterozygosity in GPR56 have not been previously described, we presume that compound heterozygosity of these two mutations in a ligand binding domain within the extracellular N-terminus of protein could result in BFPP. In addition, we observed unusually less involvement of perisylvian cortex for polymicrogyria, and Lennox-Gastaut syndrome for epilepsy, which are likely common features in patients with BFPP caused by GPR56 mutations. PMID- 23981350 TI - Inferring nucleosome positions with their histone mark annotation from ChIP data. AB - MOTIVATION: The nucleosome is the basic repeating unit of chromatin. It contains two copies each of the four core histones H2A, H2B, H3 and H4 and about 147 bp of DNA. The residues of the histone proteins are subject to numerous post translational modifications, such as methylation or acetylation. Chromatin immunoprecipitiation followed by sequencing (ChIP-seq) is a technique that provides genome-wide occupancy data of these modified histone proteins, and it requires appropriate computational methods. RESULTS: We present NucHunter, an algorithm that uses the data from ChIP-seq experiments directed against many histone modifications to infer positioned nucleosomes. NucHunter annotates each of these nucleosomes with the intensities of the histone modifications. We demonstrate that these annotations can be used to infer nucleosomal states with distinct correlations to underlying genomic features and chromatin-related processes, such as transcriptional start sites, enhancers, elongation by RNA polymerase II and chromatin-mediated repression. Thus, NucHunter is a versatile tool that can be used to predict positioned nucleosomes from a panel of histone modification ChIP-seq experiments and infer distinct histone modification patterns associated to different chromatin states. AVAILABILITY: The software is available at http://epigen.molgen.mpg.de/nuchunter/. PMID- 23981352 TI - Effects of triclabendazole on secretion of danofloxacin and moxidectin into the milk of sheep: role of triclabendazole metabolites as inhibitors of the ruminant ABCG2 transporter. AB - ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP) mediates drug-drug interactions that affect the secretion of drugs into milk. The aims of this study were: (1) to determine whether the major plasma metabolites of the flukicide triclabendazole (TCBZ), triclabendazole sulfoxide (TCBZSO) and triclabendazole sulfone (TCBZSO2), inhibit ovine and bovine ABCG2 and its Y581S variant in vitro, and (2) to examine whether coadministration of TCBZ with the ABCG2 substrates danofloxacin (a fluoroquinolone) and moxidectin (a milbemycin) affects the secretion of these drugs into the milk of sheep. TCBZSO and TCBZSO2 inhibited ruminant ABCG2 in vitro by reversing the reduced mitoxantrone accumulation and reducing basal to apical transport of nitrofurantoin in cells transduced with bovine variants (S581 and Y581) and the ovine variant of ABCG2. Coadministration of TCBZ with moxidectin or danofloxacin to sheep resulted in significantly reduced levels of moxidectin, but not danofloxacin, in the milk of TCBZ-treated sheep compared to sheep administered moxidectin or danofloxacin alone. The milk area under concentration time curve (AUC 0-48 h) was 2.99+/-1.41 MUg h/mL in the group treated with TCBZ and moxidectin, and 7.75+/-3.58 MUg h/mL in the group treated with moxidectin alone. The AUC (0-48 h) milk/plasma ratio was 37% lower in the group treated with TCBZ and moxidectin (7.34+/-1.51) than in the group treated with moxidectin alone (11.68+/-3.61). TCBZ metabolites appear to inhibit ruminant ABCG2 and affect the secretion of ABCG2 substrates into milk of sheep. PMID- 23981351 TI - A combined omics study on activated macrophages--enhanced role of STATs in apoptosis, immunity and lipid metabolism. AB - BACKGROUND: Macrophage activation by lipopolysaccharide and adenosine triphosphate (ATP) has been studied extensively because this model system mimics the physiological context of bacterial infection and subsequent inflammatory responses. Previous studies on macrophages elucidated the biological roles of caspase-1 in post-translational activation of interleukin-1beta and interleukin 18 in inflammation and apoptosis. However, the results from these studies focused only on a small number of factors. To better understand the host response, we have performed a high-throughput study of Kdo2-lipid A (KLA)-primed macrophages stimulated with ATP. RESULTS: The study suggests that treating mouse bone marrow derived macrophages with KLA and ATP produces 'synergistic' effects that are not seen with treatment of KLA or ATP alone. The synergistic regulation of genes related to immunity, apoptosis and lipid metabolism is observed in a time dependent manner. The synergistic effects are produced by nuclear factor kappa light-chain-enhancer of activated B cells (NF-kB) and activator protein (AP)-1 through regulation of their target cytokines. The synergistically regulated cytokines then activate signal transducer and activator of transcription (STAT) factors that result in enhanced immunity, apoptosis and lipid metabolism; STAT1 enhances immunity by promoting anti-microbial factors; and STAT3 contributes to downregulation of cell cycle and upregulation of apoptosis. STAT1 and STAT3 also regulate glycerolipid and eicosanoid metabolism, respectively. Further, western blot analysis for STAT1 and STAT3 showed that the changes in transcriptomic levels were consistent with their proteomic levels. In summary, this study shows the synergistic interaction between the toll-like receptor and purinergic receptor signaling during macrophage activation on bacterial infection. AVAILABILITY: Time-course data of transcriptomics and lipidomics can be queried or downloaded from http://www.lipidmaps.org. CONTACT: shankar@ucsd.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23981353 TI - Uterine fluid from bitches with mating-induced endometritis reduces the attachment of spermatozoa to the uterine epithelium. AB - Persistence of free fluid in the uterine lumen of bitches with endometrial hyperplasia appears to be diagnostic for mating-induced endometritis and is associated with reduced chances of pregnancy. This study investigated the possibility that reduced fertility might be associated with an effect of uterine fluid on sperm. Uterine lavage fluid was collected pre- and post-insemination from normal bitches without ultrasonographically-detectable luminal fluid (n=4), and previously non-pregnant bitches with endometrial hyperplasia and luminal fluid (n=4). Concentrations of polymorphonuclear neutrophils (PMNs) were measured and the effect of the fluid on the attachment of spermatozoa to the uterine epithelium was studied using medium (M) 199 as a control. To elucidate whether any effect was accounted for by the presence of PMNs, attachment was also measured in M199 with PMNs added at the concentration found in lavage fluid. Pre insemination lavage fluid from both groups contained low concentrations of PMNs which increased post-insemination; the increase was larger for bitches with uterine fluid. Compared with M199 controls, lavage fluid reduced the attachment of spermatozoa; fluid from bitches with endometrial hyperplasia and uterine fluid had a greater effect than normal bitches, and post-insemination fluid had a greater effect than pre-insemination fluid. Spermatozoal attachment was reduced by a similar magnitude for M199 with added PMNs, although post-insemination fluid from bitches with endometrial hyperplasia reduced attachment more than M199 with added PMNs. Poor fertility in bitches with uterine luminal fluid might be partially associated with impaired attachment of spermatozoa to uterine epithelium, mediated principally, but not solely, by PMN influx into the uterine lumen. PMID- 23981354 TI - Effects of surface molecular chirality on adhesion and differentiation of stem cells. AB - Chirality is one of the most fascinating and ubiquitous cues in nature, especially in life. The effects of chiral surfaces on stem cells have, however, not yet been revealed. Herein we examined the molecular chirality effect on stem cell behaviors. Self assembly monolayers of L- or D-cysteine (Cys) were formed on a glass surface coated with gold. Mesenchymal stem cells (MSCs) derived from bone marrow of rats exhibited more adhering preference and thus less cell spreading on the L surface than on the d one at the confluent condition. More protein adsorption was observed on the L surface after immersed in cell culture medium with fetal bovine serum. After osteogenic and adipogenic co-induction at the confluent condition, a larger proportion of cells became osteoblasts on the d surface, while the adipogenic fraction on the L surface was found to be higher than on the D surface. In order to interpret how this chirality effect worked, we fabricated Cys microislands of two sizes on the non-fouling poly(ethylene glycol) hydrogel to pre-define the spreading areas of single cells. Then the differentiation extents did not exhibit a significant difference between L and D surfaces under a given area of microislands, yet very significant differences of osteogenesis and adipogenesis were found between different areas. So, the molecular chirality influenced stem cells, probably via favored adsorption of natural proteins on the L surface, which led to more cell adhesion; and the larger cell spreading area with higher cell tension in turn favored osteogenesis rather than adipogenesis. As a result, this study reveals the molecular chirality on material surfaces as an indirect regulator of stem cells. PMID- 23981355 TI - Site-specific PEGylation of a mutated-cysteine residue and its effect on tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising antitumor agent that specifically induces apoptosis in broad-spectrum tumor cell lines, meanwhile leaving normal cells unaffected. Unfortunately, the clinical development of TRAIL was hampered, and could be attributed to its instability, bioavailability or poor delivery. Although N-terminal specific PEGylation provides a means to improve the pharmacokinetic and stability of TRAIL, it took a bit longer time to accomplish the PEGylation process than expected. We therefore designed another PEGylation approach, mutated Cys-SH site specific PEGylation, to conjugate methoxypoly(ethylene glycol) maleimide (mPEG MAL) with TRAIL (95-281) mutant N109C. Asn-109 was chosen as the PEGylated site for it is a potential N-linked glycosylation site. It was shown that ~90% TRAIL mutant N109C could be PEGylated by mPEG-MAL within 40 min. And mPEG(MAL)-N109C was revealed to possess superior in vitro stability and antitumor activity than N terminal specifically PEGylated TRAIL (114-281) (mPEG(ALD)-TRAIL(114-281)). What's more, mPEG(MAL)-N109C exhibited more therapeutic potentials than mPEG(ALD) TRAIL(114-281) in tumor xenograft model, benefitting from better drug delivery and bioavailability. These results have demonstrated mutated Cys-SH specific PEGylation is an alternative to site-specifically PEGylate TRAIL efficiently and effectively other than N-terminal specific PEGylation. PMID- 23981356 TI - Repair of rabbit segmental femoral defects by using a combination of tetrapod shaped calcium phosphate granules and basic fibroblast growth factor-binding ion complex gel. AB - The effect of tetrapod-shaped alpha tricalcium phosphate granules (TB) as a scaffold combined with basic fibroblast growth factor (bFGF)-binding ion complex gel (f-IC gel) on neovascularization and bone regeneration was evaluated in segmental femoral defects of rabbits. The defects were stabilized using a plate with a polypropylene mesh cage (PMC) containing one of the following: PMC alone (PMC group), TB (TB group), TB and bFGF (TB/f group), TB and IC gel (TB/IC group), or TB and f-IC gel (TB/f-IC group). Four rabbits from each group were euthanized at 2 and 4 weeks after surgery. Histomorphometry showed that the number of vessels and the volume of new bone in the TB/f-IC group were significantly higher than those in the other groups at all time points. There were no differences in the extent of neovascularization and new bone formation between the TB and TB/f groups. These findings suggest that the combination of TB and f-IC gel facilitated both neovascularization and new bone formation in segmental femoral defects of rabbits. This combination may be of considerable use for treating segmental long bone defects. PMID- 23981357 TI - How functional connectivity between emotion regulation structures can be disrupted: preliminary evidence from adolescents with moderate to severe traumatic brain injury. AB - Outcome of moderate to severe traumatic brain injury (TBI) includes impaired emotion regulation. Emotion regulation has been associated with amygdala and rostral anterior cingulate (rACC). However, functional connectivity between the two structures after injury has not been reported. A preliminary examination of functional connectivity of rACC and right amygdala was conducted in adolescents 2 to 3 years after moderate to severe TBI and in typically developing (TD)control adolescents, with the hypothesis that the TBI adolescents would demonstrate altered functional connectivity in the two regions. Functional connectivity was determined by correlating fluctuations in the blood oxygen level dependent(BOLD) signal of the rACC and right amygdala with that of other brain regions. In the TBI adolescents, the rACC was found to be significantly less functionally connected to medial prefrontal cortices and to right temporal regions near the amygdala (height threshold T = 2.5, cluster level p < .05, FDR corrected), while the right amygdala showed a trend in reduced functional connectivity with the rACC (height threshold T = 2.5, cluster level p = .06, FDR corrected). Data suggest disrupted functional connectivity in emotion regulation regions. Limitations include small sample sizes. Studies with larger sample sizes are necessary to characterize the persistent neural damage resulting from moderate to severe TBI during development. PMID- 23981360 TI - Reagents for developmental regulation of Hedgehog signaling. AB - We have examined a number of reagents for their ability to modulate activity of the Hh signaling pathway during embryonic development of Xenopus. In particular we have focused on regulation of events occurring during tailbud stages and later. Two inducible protein reagents based on the Gli1 and Gli3 transcription factors were generated and the activity of these proteins was compared to the Hh signaling pathway inhibitor, cyclopamine, and the activators, Smoothened agonist (SAG) and purmorphamine (PMA). Effectiveness of reagents was assayed using both molecular biological techniques and biological readouts. We found that the small molecule modulators of the Hh pathway were highly specific and effective and produced results generally superior to the more conventional protein reagents for examination of later stage developmental processes. PMID- 23981361 TI - Identification and RNA binding characterization of plant virus RNA silencing suppressor proteins. AB - Suppression is a common mechanism employed by viruses to evade the antiviral effects of the host's RNA silencing pathway. The activity of suppression has commonly been localized to gene products in the virus, but the variety of mechanisms used in suppression by these viral proteins spans nearly the complete biochemical pathway of RNA silencing in the host. This review describes the agrofiltration assay and a slightly modified version of the agro-infiltration assay called co-infiltration, which are common methods used to observe RNA silencing and identify viral silencing suppressor proteins in plants, respectively. In addition, this review will provide an overview of two methods, electrophoretic mobility shift assay and fluorescence polarization, used to assess the binding of a suppressor protein to siRNA which has been shown to be a general mechanism to suppress RNA silencing by plant viruses. PMID- 23981362 TI - A versatile tool for the analysis of neuronal survival. AB - To understand the principles that govern mechanisms of neuronal survival or death it is necessary to systematically model these processes. Methods involving overexpression or knockdown of a gene of interest using non-viral transfection of primary neurons can easily be adapted to study cell death pathways in primary neurons. However, common biochemical approaches to measure cell death are insufficient to measure neuronal viability in these systems. To investigate the functional role of genes in cultured neurons, we therefore established a cell based assay using a cotransfection/cocultivation approach in primary cortical neurons from mouse or rat. Using this method, it is possible to use well established cell culture models of neuronal damage, and to analyze cell survival in genetically different neurons on a single-cell basis following apoptotic stimuli under identical conditions. The duration of the entire protocol is 10 days. Finally, the method may be applicable to a wide range of damage models, primary cells, and cell lines as well as it can be used for high content screening (HCS) studies and downstream image cytometry. PMID- 23981363 TI - Drug survival of the first course of anti-TNF agents in patients with rheumatoid arthritis and seronegative spondyloarthritis: analysis from the MonitorNet database. AB - OBJECTIVES: To compare drug survival of different anti-TNF drugs (infliximab, INF, etanercept, ETA, and adalimumab, ADA) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) by analysing data collected from an Italian multicenter observational cohort study. METHODS: All patients with RA or SpA registered in the MonitorNet database who started their first course of anti-TNF therapy were included. Overall drug survival was measured, along with specific reasons of discontinuation (inefficacy or adverse events). A first set of analyses using RA as reference category assessed the relationship between diagnosis and drug survival. A second set of analyses stratified by diagnosis (RA and SpA) used INF as reference drug. Adjustment for confounders was performed. The results are presented as adjusted hazard ratios (adjHR) and 95% confidence intervals (95%CI). RESULTS: 2640 RA patients and 1220 SpA patients with a median follow-up of 17 months (IQR 7.2-33.4) were included in the analyses. Patients with a diagnosis of SpA showed a lower risk of drug discontinuation with an adjHR (95%CI) of 0.81 (0.73, 0.90). In SpA, the subset of patients with ankylosing spondylitis (AS) showed the best survival on treatment. In RA, both ETA and ADA showed a significantly lower probability of withdrawal when compared to INF [adjHR (95%CI) 0.46 (0.38, 0.56) and 0.68 (0.57, 0.81), respectively]. Similar results were found in SpA. CONCLUSIONS: Drug survival for SpA is longer than that in RA mainly due to the AS subgroup. In both RA and SpA, ETA and ADA showed a better retention on treatment when compared to INF. PMID- 23981364 TI - Interaction of nonsteroidal anti-inflammatory drugs with membranes: in vitro assessment and relevance for their biological actions. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world due to their anti-inflammatory, analgesic and antipyretic properties. Nevertheless, the consumption of these drugs is still associated with the occurrence of a wide spectrum of adverse effects. Regarding the major role of membranes in cellular events, the hypothesis that the biological actions of NSAIDs may be related to their effect at the membrane level has triggered the in vitro assessment of NSAIDs-membrane interactions. The use of membrane mimetic models, cell cultures, a wide range of experimental techniques and molecular dynamics simulations has been providing significant information about drugs partition and location within membranes and also about their effect on diverse membrane properties. These studies have indeed been providing evidences that the effect of NSAIDs at membrane level may be an additional mechanism of action and toxicity of NSAIDs. In fact, the pharmacokinetic properties of NSAIDs are closely related to the ability of these drugs to interact and overcome biological membranes. Moreover, the therapeutic actions of NSAIDs may also result from the indirect inhibition of cyclooxygenase due to the disturbing effect of NSAIDs on membrane properties. Furthermore, increasing evidences suggest that the disordering effects of these drugs on membranes may be in the basis of the NSAIDs induced toxicity in diverse organ systems. Overall, the study of NSAIDs-membrane interactions has proved to be not only important for the better understanding of their pharmacological actions, but also for the rational development of new approaches to overcome NSAIDs adverse effects. PMID- 23981366 TI - Physical properties of fish gelatin-based bio-nanocomposite films incorporated with ZnO nanorods. AB - Well-dispersed fish gelatin-based nanocomposites were prepared by adding ZnO nanorods (NRs) as fillers to aqueous gelatin. The effects of ZnO NR fillers on the mechanical, optical, and electrical properties of fish gelatin bio nanocomposite films were investigated. Results showed an increase in Young's modulus and tensile strength of 42% and 25% for nanocomposites incorporated with 5% ZnO NRs, respectively, compared with unfilled gelatin-based films. UV transmission decreased to zero with the addition of a small amount of ZnO NRs in the biopolymer matrix. X-ray diffraction showed an increase in the intensity of the crystal facets of (10i1) and (0002) with the addition of ZnO NRs in the biocomposite matrix. The surface topography of the fish gelatin films indicated an increase in surface roughness with increasing ZnO NR concentrations. The conductivity of the films also significantly increased with the addition of ZnO NRs. These results indicated that bio-nanocomposites based on ZnO NRs had great potentials for applications in packaging technology, food preservation, and UV shielding systems. PMID- 23981367 TI - Autophagy, senescence, and arterial inflammation: relationship to arterial health and longevity. PMID- 23981365 TI - Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma. AB - Malignant gliomas are the most common adult brain cancers. In spite of aggressive treatment, recurrence occurs in the great majority of patients and is invariably fatal. Polyunsaturated fatty acids are abundant in brain, particularly omega-6 arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA). Although the levels of omega-6 and omega-3 polyunsaturated fatty acids are tightly regulated in brain, the omega-6:omega-3 ratio is dramatically increased in malignant glioma, suggesting deregulation of fundamental lipid homeostasis in brain tumor tissue. The migratory properties of malignant glioma cells can be modified by altering the ratio of AA:DHA in growth medium, with increased migration observed in AA rich medium. This fatty acid-dependent effect on cell migration is dependent on expression of the brain fatty acid binding protein (FABP7) previously shown to bind DHA and AA. Increased levels of enzymes involved in eicosanoid production in FABP7-positive malignant glioma cells suggest that FABP7 is an important modulator of AA metabolism. We provide evidence that increased production of eicosanoids in FABP7-positive malignant glioma growing in an AA-rich environment contributes to tumor infiltration in the brain. We discuss pathways and molecules that may underlie FABP7/AA-mediated promotion of cell migration and FABP7/DHA mediated inhibition of cell migration in malignant glioma. PMID- 23981368 TI - Acupuncture in asthmatic children: a prospective, randomized, controlled clinical trial of efficacy. AB - BACKGROUND: The incidence of asthma and asthmatic bronchitis (hereafter asthma) in Danish preschool children is estimated to be 10%-20%. Few well-controlled studies have been published on acupuncture and asthma, and no researchers have focused on asthma in preschool children. OBJECTIVE: The study's primary objective was to investigate the efficacy of acupuncture for treating asthma in children aged 6 mo-6 y. DESIGN: This study was a prospective, randomized, controlled clinical trial. SETTING: The study was conducted in two acupuncture clinics in Denmark. PARTICIPANTS: The research team randomly selected preschool children with medically diagnosed asthma and assigned them 1:1 to an intervention or control group. INTERVENTION: The intervention group received 10 acupuncture treatments over 3 mo. The control group received no placebo treatment. PRIMARY OUTCOME MEASURES: Efficacy was evaluated using asthma diaries. A Wilcoxon rank sum test was used for the analyses of longitudinal intragroup changes and paired differences between groups. Using a two-sided, 5% significance level and a power of 90%, a sample size of 100 patients/group was necessary. RESULTS: The research team randomly selected 122 children, with 52 children (26 intervention, 26 controls) being available for evaluation at 12 mo. Symptom scores and medication use were not different between the groups at 8 mo after completion of acupuncture. Significant reductions were observed in subjective asthma symptoms and in use of inhaled steroids (IHS) and beta(2) agonists in both groups at 3 mo. Compared with the control group, the reduction in asthma symptoms (P = .0376) and use of IHS (P = .0005) was significantly larger in the intervention group. CONCLUSION: Although the effect was not sustained beyond the treatment period, the study demonstrated that acupuncture had an effect on asthma in preschool children for the duration of the treatment course as assessed by subjective parameters and use of medication. PMID- 23981369 TI - Acupuncture for chronic fatigue syndrome: a randomized, sham-controlled trial with single-blinded design. AB - CONTEXT: Given that the etiology of chronic fatigue syndrome (CFS) is believed to be multidimensional, interventions generally have been nonspecific and typically produce only mild to moderate effects. In medical practice, treatment for CFS remains largely symptomatic. Preliminary evidence of the efficacy of acupuncture for CFS is available, but the field has lacked high-quality trials. OBJECTIVE: The research team conducted the study to determine the efficacy of acupuncture for CFS. DESIGN: A two-arm, randomized, controlled, singleblinded design was adopted. SETTING: The study took place in a teaching laboratory at the School of Chinese Medicine at the University of Hong Kong, Hong Kong, China. PARTICIPANTS: Recruited through press publicity in Hong Kong, 127 individuals--40 men and 87 women--participated in the study. Intervention Through careful implementation of sham acupuncture in the control group (CG), the study blinded all participants with regard to their experimental or control status. The treatment regime was 2 sessions/wk for 4 consecutive wk. OUTCOME MEASURES: Measures of fatigue (Chalder's Fatigue Scale), health-related quality of life (SF-12), and general mental health (GH Q-12) were taken at baseline and upon completion of treatment. RESULTS: Ninety-nine participants completed the interventions, with 50 and 49 participants in the experimental group (EG) and CG respectively. Repeated measures ANOVA revealed a significant decrease in physical (F(1,93) = 4.327; P = .040) and mental fatigue (F(1,96) = 10.451; P = .002) and improvement in the physical component score of SF-12 (F(1,93) = 4.774; P = .031). Considerable effects with Cohen's d were observed in the sham-control group: 0.92, 0.78, and 0.38 for the three scores, respectively. These positive effects could have included some therapeutic effects due to pressure on the acupuncture points from the sham needles in addition to normal placebo effects. The EG showed moderate net effect sizes with Cohen's d: 0.52, 0.63, and 0.54 for the three outcome measures, respectively. CONCLUSION: Despite considerable positive effects for the CG, the EG demonstrated significant net-effect sizes at a moderate magnitude in physical and mental fatigue and in the physical component of health-related quality of life. The impacts on general mental health outcomes appeared to be smaller. PMID- 23981370 TI - Auricular acupuncture for drug dependence: an open-label randomized investigation on clinical outcomes, health-related quality of life, and patient acceptability. AB - CONTEXT: Substance abuse has been prevalent in Malaysia for many years and currently represents one of the main concerns to its society. The limitations of conventional therapies have resulted in efforts to explore the potentia of complementary therapies in the management of drug addiction. The evidence for auricular acupuncture (AA) as a potential complementary therapy for drug addiction is still limited and inconclusive. OBJECTIVE: The study intended (1) to compare the clinical outcomes of methadone maintenance treatment (MMT) alone and MMT plus AA (MMT+AA) with regard to the daily methadone dose, number of cigarettes smoked/wk, relapse rates, and withdrawal symptoms; (2) to evaluate health-related quality of life (HR QoL) pre- and postintervention; and (3) to determine participants' acceptance of AA therapy. DESIGN: The research team designed this study to be prospective, longitudinal, open-labeled, and randomized, with one intervention group (AA group) and one control group. SETTING: The settings were three MMT centers in Terengganu, Malaysia: (1) the Methadone Maintenance Treatment (MMT) Center, Hospital Sultanah Nur Zahirah; (2) the MMT Center, Marang Health Clinic; and (3) the MMT Center, Seberang Takir Health Clinic. PARTICIPANTS: Participants were individuals who were enrolled in the three MMT programs. INTERVENTION: After randomization, the intervention group received MMT+AA while the control group received MMT only. Participants in the AA group underwent concurrent AA sessions for 8 wk. OUTCOME MEASURES: All outcomes were evaluated using questionnaires that the research team developed and WHOQOL BREF. Data were analysed employing descriptive and nonparametric statistics (SPSS v16). RESULTS: A total of 97, eligible, male patients consented to participation (MMT = 42; MMT+AA = 55; median age = 36.0 y; Malay ethnicity = 97.9%). After screening for dropouts, the data from only 69 participants were considered for postintervention analysis (MMT = 40; MMT+AA = 29). At preintervention, participants differed significantly by HR QoL profile and the frequency of withdrawal symptoms (better for MMT participants). Postintervention, all groups reported significantly reduced numbers of cigarettes smoked and a reduced methadone dose (P < .05), whereas no significant difference was detected for other parameters. No difference for relapse rate was detected between the groups. On separate group analysis, only the number of cigarettes was significantly lower for MMT+AA participants, whereas apart from methadone dose, all other parameters had significantly improved over time in the MMT+AA cohort. The additional AA therapy also demonstrated favorable acceptance and tolerable side effects. CONCLUSION: Findings implied that AA could be beneficial as an adjunct to MMT in managing addiction, but the effectiveness of AA still requires further extensive investigation. PMID- 23981371 TI - Effect of hydration on whole blood viscosity in firefighters. AB - CONTEXT: Cardiovascular disease (CVD) is the leading cause of on-duty death among firefighters, totaling 45% of on-duty fatalities. Heat stress and fluid losses can result in decreases in cardiac output of firefighters, despite sustained tachycardia and maximally elevated heart rate during emergencies. Measurements of whole blood viscosity (WBV) may serve as an independent biomarker of the hydration and dehydration states of on-duty firefighters. OBJECTIVE: The current pilot study investigates the effects of a strenuous firefighting simulation and subsequent rehydration on WBV and other biological metrics in nine healthy, nonsmoking firefighters to (1) determine whether dehydration and rehydration result in detectable changes in WBV and (2) compare WBV with the results from a range of conventional medical tests. DESIGN: The research team designed a single center, unblinded pilot study. SETTING: Fire Training Division, 1900 Lind Ave SW, Renton, WA, 98057. PARTICIPANTS: Participants were 9 healthy, nonsmoking firefighters who were volunteers. OUTCOME MEASURE(S): Vital signs, traditional medical blood tests, and WBV were measured for each firefighter (1) at baseline, (2) after exercise but before rehydration with alkaline water, and (3) postexercise and after rehydration. Hematocrit (HCT), hemoglobin (Hb), and WBV increased after exercise and before rehydration. RESULTS: Dehydration during the mock fire drill resulted in elevated WBV at both low- and high-shear rates. HCT and Hb increased due to dehydration and hemoconcentration. Hb and HCT returned to baseline values after exercise and rehydration, and while WBV improved, baseline values were not restored. After exercise but before rehydration, WBV changes were significantly larger than HCT and Hb changes, suggesting the profound influence of hydration states on WBV. CONCLUSIONS: WBV measurements were better determinants of hydration states than HCT or Hb and should be performed to monitor the cardiovascular health of at-risk firefighters. PMID- 23981372 TI - Jorge Flechas, MD: the potential of oxytocin, nitric oxide, and iodine. PMID- 23981373 TI - Gestational exposure to cadmium alters crucial offspring rat brain enzyme activities: the role of cadmium-free lactation. AB - The present study aimed to shed more light on the effects of gestational (in utero) exposure to cadmium (Cd) on crucial brain enzyme activities of Wistar rat offspring, as well as to assess the potential protective/restorative role that a Cd-free lactation might have on these effects. In contrast to earlier findings of ours regarding the pattern of effects that adult-onset exposure to Cd has on brain AChE, Na(+),K(+)- and Mg(2+)-ATPase activities, as well as in contrast to similar experimental approaches implementing the sacrificing mode of anaesthesia, in utero exposure to Cd-chloride results in increased AChE and Na(+),K(+)-ATPase activities in the newborn rat brain homogenates that were ameliorated through a Cd-free lactation (as assessed in the brain of 21-day-old offspring). Mg(2+) ATPase activity was not found to be significantly modified under the examined experimental conditions. These findings could provide the basis for a further evaluation of the herein discussed neurotoxic effects of in utero exposure to Cd, in a brain region-specific manner. PMID- 23981374 TI - Ethanolic extract of Boswellia ovalifoliolata bark and leaf attenuates doxorubicin-induced cardiotoxicity in mice. AB - The aim of the study was to investigate the potential protective effect of ethanolic extract of Boswellia ovalifoliolata (BO) bark and leaf against doxorubicin (DOX)-induced cardiotoxicity in mice. Ethanolic extracts of BO bark (400 mg/kg) and leaves (250 mg/kg) were given orally to mice for 9 consecutive days and DOX (15 mg/kg; i.p.) was administered on the seventh day. Extract protected against DOX-induced ECG changes. It significantly inhibited DOX provoked glutathione depletion and accumulation of malondialdehyde. The decrease in antioxidant enzyme activities of catalase, superoxide dismutase, glutathione peroxidase in cardiac tissue were significantly (p<0.05) mitigated after treatment with BO bark and leaf extracts. Pretreatment with BO significantly (p<0.05) restored the levels of DOX-induced rise of SGPT, SGOT, serum lactate dehydrogenase and creatine kinase-MB levels. These findings suggest that ethanolic extract of BO has protective effects against DOX-induced cardiotoxicity. PMID- 23981375 TI - Tanshinone I protects mice from aristolochic acid I-induced kidney injury by induction of CYP1A. AB - Hepatic CYP1A especially CYP1A2 plays an important role in the reduction of aristolochic acid I (AAI) nephrotoxicity. In this study, we investigated the effects of tanshinone I, a strong inducer of Cyp1a, on the nephrotoxicity induced by AAI. Histopathology and blood biochemistry assays showed that tanshinone I could reduce AAI-induced acute kidney injury. Pharmacokinetics analysis revealed that tanshinone I markedly decreased AUC of AAI in plasma and the content of AAI in both liver and kidney, indicating the enhancement of AAI metabolism. Real-time PCR and Western blot analysis confirmed that tanshinone I effectively increased the mRNA and protein levels of hepatic CYP1A1 and CYP1A2 in vivo. Luciferase assay showed that tanshinone I strongly increased the transcriptional activity of CYP1A1 and CYP1A2 in the similar extent. In summary, our data suggested that tanshinone I facilitated the metabolism of AAI and prevented AAI-induced kidney injury by induction of hepatic CYP1A 1/2 in vivo. PMID- 23981376 TI - Evaluation of lead levels in biological samples of mentally retarded children in different stages using advanced extraction method. AB - In present study the lead (Pb) levels has been assessed by analyzing the scalp hair and blood samples of mentally retarded/intellectual disabled (MR/ID) children of both genders, age ranged 3-8 years. For comparative purpose, healthy age matched children were also selected. The cloud point extraction of Pb from digested biological samples was carried out by complexed with ammonium pyrrolidinedithiocarbamate. The complexed analyte was subsequently isolated from the aqueous matrix in the micelles of a non-ionic surfactant (Triton X-114). Dilution of the surfactant-rich phase with acidified ethanol was performed after phase separation, and the Pb content was measured by flame atomic absorption spectrometer. Factors affecting the cloud point extraction were evaluated and optimized. The proposed procedure allowed the determination of lead in certified standard and real samples with detection limits of 0.834MUgL(-) and enhancement factor 55. The results were compared with those of healthy children have same age, socioeconomic status and residential areas. PMID- 23981377 TI - Ethyl acetate fraction of Garcina epunctata induces apoptosis in human promyelocytic cells (HL-60) through the ROS generation and G0/G1 cell cycle arrest: a bioassay-guided approach. AB - Number of deaths due to cancer diseases is increasing in the world. There is an urgent need to develop alternative therapeutic measures against the disease. Our study reports the cytotoxicity activity of Garcina epunctata (gutifferae) in human promyelocytic leukemia cells (HL-60) and prostate cancer cells (PC-3) was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Changes in mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and morphological changes associated with apoptosis were examined by flow cytometry and Hoescht staining respectively. The results of in vitro antiproliferative screening of fractions and extract from G. epunctata indicated that three fractions inhibited the viability of PC-3 cells with IC50 varied from 50 to 88 MU/ml while two fractions inhibited the proliferation of HL-60 cells with IC50 range between 47.5 and 12 MUg/ml. Among the entire fraction tested, Hex EtOAc (75:25) showed cytotoxic effects on the two cell lines and EtOAc fraction was most active only HL-60 cells (12 MUg/ml). Treatment of HL-60 cells with G. epunctata (20, 50, 100 MUg/ml) for 24 h led to a significant dose-dependent increase in the percentage of cells in sub-G1 phase by analysis of the content of DNA in cells, and a number of apoptotic bodies containing nuclear fragments were observed in cells treated with 100 MUg/ml. The EtOAc fraction of G. epunctata treatment significantly arrested HL-60 cells at the G0/G1 phase (p<0.05) and ROS was significantly elevated as well as the loss of membrane mitochondrial potential in a concentration dependant manner. The results demonstrated that the EtOAc fraction of G. epunctata inhibited the proliferation of HL-60 cells, leading to cell cycle arrest and programmed cell death, which was confirmed to occur through the mitochondrial pathway. PMID- 23981378 TI - Wuchereria bancrofti transmission pattern in southern Mali prior to and following the institution of mass drug administration. AB - BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the goal of stopping transmission of lymphatic filariasis (LF) through yearly mass drug administration (MDA). Although preliminary surveys of the human population in Mali suggested that Wuchereria bancrofti infection was highly endemic in the Sikasso district, baseline entomological data were required to confirm high levels of transmission prior to the selection of villages in this region for a study of the impact of MDA on transmission of LF by anopheline vectors. METHODS: W. bancrofti transmission was assessed in 2001 (pre-MDA) and 2002 (post-MDA) in the Central District of Sikasso in southern Mali by dissection of Anopheles mosquitoes caught using the human landing catch (HLC) method. The relative frequencies and molecular forms of An. gambiae complex were determined. RESULTS: The majority (86%) of the anopheline vectors captured were identified as An. gambiae complex, and these accounted for >90% of the entomological inoculation rate (EIR) during both years of the study. There was a dramatic decrease in the number of An. gambiae complex mosquitoes captured and in the An. gambiae complex infectivity rates following MDA, accounting for the observed decrease in EIR in 2002 (from 12.55 to 3.79 infective bites per person during the transmission season). An. funestus complex mosquitoes were responsible for a low level of transmission, which was similar during both years of the study (1.2 infective bites per person during the transmission season in 2001 and 1.03 in 2002). CONCLUSIONS: Based on the entomological data from this study, the district of Sikasso was confirmed as an area of high W. bancrofti transmission. This led to the selection of this area for a multi-national study on the effects of MDA on LF transmission by anopheline vectors. Comparison of vector transmission parameters prior to and immediately following the first round of MDA demonstrated a significant decrease in overall transmission. Importantly, the dramatic variability in EIR over the transmission season suggests that the efficacy of MDA can be maximized by delivering drug at the beginning of the rainy season (just prior to the peak of transmission). PMID- 23981380 TI - Cytochrome P450 2C19*2 polymorphism in patients with stable coronary heart disease and risk for secondary cardiovascular disease events: results of a long term follow-up study in routine clinical care. AB - BACKGROUND: CYP2C19*2 polymorphism is related to metabolizer phenotypes resulting in reduced effectiveness in converting the antiplatelet drug clopidogrel to active drug. An association of the genotype itself with adverse outcomes is discussed. We investigated the prognostic value of carriage of the CYP2C19*2 allele in a high risk group of patients with prevalent coronary heart disease (CHD) at baseline during long-term follow-up under conditions of routine clinical care. METHODS: In n=1050 patients with stable CHD at baseline genotyping of CYP2C19 allele *2 (rs4244285; 681G>A) was performed. The Cox-proportional hazards model was employed to investigate the association of CYPC19*2 allele status with cardiovascular disease (CVD) events during eight year follow-up. The analysis was also performed in patients who did not take clopidogrel or ticlopidin. RESULTS: Only the very few patients homozygous for a loss-of-function variant of CYP2C19, allele *2 (2.6%), had a statistically significantly higher incidence rate for secondary CVD events during long-term follow-up than wild-type carriers (50.8 versus 21.5 per 1000 patients years; rate for heterozygous carries 17.2 per 1000 patient years). The hazard ratio after adjustment for covariates compared to the wild-type carriers was 2.59 (95% confidence interval (CI) 1.27-5.28) and 0.80 (95% CI 0.52-1.23) for homozygous and heterozygous allele carriers, respectively. CONCLUSIONS: In this medium-size group of patients with stable CHD homozygous carriers of the loss-of-function allele CYP2C19*2 were at increased risk for subsequent CVD events during 8 year follow-up independent of other risk factors. As only few patients carried the homozygous loss-of-function variant and we found overall no evidence for improved clinical utility, a benefit of genotyping in this patient population seems unlikely. PMID- 23981381 TI - Expression, purification and characterization of a feruloyl esterase A from Aspergillus flavus. AB - Feruloyl esterases are key enzymes involved in the complete hydrolysis of hemicellulose. In the present study, the encoding sequence of putative feruloyl esterase A (AfFaeA) was cloned from genomic DNA from Aspergillus flavus and expressed in Pichia pastoris. The purified recombinant AfFaeA had apparent relative molecular mass of about 40,000 and had an optimum pH of 6.0, although it was stable at pH values ranging from 4.5 to 8.0. The optimum temperature for AfFaeA was 58 degrees C. AfFaeA had hydrolytic activity toward methyl caffeate, methyl p-coumarate, methyl ferulate and methyl sinapate. Substrate specificity profiling of AfFaeA demostrated it is a type-A feruloyl esterase. The good performance of AfFaeA to release ferulic acid from steam exploded corn stalk in concert with Geobacillus stearothermophilus xylanase mutant indicated it is a promising biocatalyst for biomass degradation. PMID- 23981379 TI - Association between fruits and vegetables intake and frequency of breakfast and snacks consumption: a cross-sectional study. AB - BACKGROUND: There are very few studies on the frequency of breakfast and snack consumption and its relation to fruit and vegetable intake. This study aims to fill that gap by exploring the relation between irregular breakfast habits and snack consumption and fruit and vegetable intake in Tuscan adolescents. Separate analyses were conducted with an emphasis on the potentially modifying factors of sex and age. METHODS: Data was obtained from the 2010 Tuscan sample of the Health Behaviour in School-aged Children (HBSC) study. The HBSC study is a cross sectional survey of 11-, 13- and 15-year-old students (n = 3291), selected from a random sample of schools. Multivariate logistic regression was used for analyzing the food-frequency questionnaire. RESULTS: A significant relation was found between low fruit and vegetable intake and irregular breakfast habits. Similarly, low fruit intake was associated with irregular snack consumption, whereas vegetable intake did not prove to be directly related to irregular snack consumption. Different patterns emerged when gender and age were considered as modifying factors in the analyses. A statistically significant relation emerged only among female students for irregular breakfast habits and fruit and vegetable intake. Generally, older female participants with irregular breakfast habits demonstrated a higher risk of low fruit and vegetable intake. Age pattern varied between genders, and between fruit and vegetable consumption. CONCLUSIONS: Results suggest that for those adolescents who have an irregular consumption of breakfast and snacks, fruit intake occurs with a lower frequency. Lower vegetable consumption was associated with irregular breakfast consumption. Gender and age were shown to be moderators and this indicated the importance of analyzing fruit and vegetable intake and meal types separately. This study also confirmed that health-promotion campaigns that aim to promote regular meal consumption and consumption of fruits and vegetables need to take into account gender and age differences in designing promotional strategies. Future research should identify evidence-based interventions to facilitate the achievement of the Italian guidelines for a healthy diet for fruit, vegetables and meals intake. PMID- 23981382 TI - Adhesion of ZAP-70+ chronic lymphocytic leukemia cells to stromal cells is enhanced by cytokines and blocked by inhibitors of the PI3-kinase pathway. AB - CLL cell survival and proliferation is enhanced through direct contact with supporting cells present in lymphoid tissues. PI3Ks are critical signal transduction enzymes controlling B cell survival and activation. PI3K inhibitors have entered clinical trials and show promising therapeutic activity; however, it is unclear whether PI3K inhibitor drugs differentially affect ZAP-70 positive versus negative CLL cells or target specific microenvironmental interactions. Here we provide evidence that CD40L+IL-4, IL-8 or IL-6 enhance adhesion to stromal cells, with IL-6 showing a selective effect on ZAP-70 positive cells. Stimulatory effects of IL-8 or IL-6 are fully reversed by PI3K inhibition, while the effects of CD40L+IL-4 are partially reversed. While CD40L+IL-4 is the only stimulation increasing CLL cell survival for all patient groups, IL-6 protects ZAP-70 positive cells from cell death induced by PI3K inhibition. Altogether, our results indicate that targeting the PI3K pathway can reverse protective CLL microenvironment interactions in both ZAP-70 positive and negative CLL despite their differences in cytokine responsiveness. PMID- 23981383 TI - Factors affecting match performance in professional Australian football. AB - OBJECTIVES: To determine the physical activity measures and skill-performance characteristics that contribute to coaches' perception of performance and player performance rank in professional Australian Football (AF). DESIGN: Prospective, longitudinal. METHODS: Physical activity profiles were assessed via microtechnology (GPS and accelerometer) from 40 professional AF players from the same team during 15 Australian Football League games. Skill-performance measure and player-rank scores (Champion Data Rank) were provided by a commercial statistical provider. The physical-performance variables, skill involvements, and individual player performance scores were expressed relative to playing time for each quarter. A stepwise multiple regression was used to examine the contribution of physical activity and skill involvements to coaches' perception of performance and player rank in AF. RESULTS: Stepwise multiple-regression analysis revealed that 42.2% of the variance in coaches' perception of a player's performance could be explained by the skill-performance characteristics (player rank/min, effective kicks/min, pressure points/min, handballs/min, and running bounces/ min), with a small contribution from physical activity measures (accelerations/min) (adjusted R2 = .422, F6,282 = 36.054, P < .001). Multiple regression also revealed that 66.4% of the adjusted variance in player rank could be explained by total disposals/min, effective kicks/min, pressure points/min, kick clangers/min, marks/min, speed (m/min), and peak speed (adjusted R2 = .664, F7,281 = 82.289, P < .001). Increased physical activity throughout a match (speed [m/min] beta - 0.097 and peak speed beta - 0.116) negatively affects player rank in AF. CONCLUSIONS: Skill performance rather than increased physical activity is more important to coaches' perception of performance and player rank in professional AF. PMID- 23981384 TI - Conventional magnetic resonance imaging in the differentiation between high and low-grade brain tumours in paediatric patients. AB - OBJECTIVE: It has been described that hyperintensity in diffusion-weighted imaging (DWI) correlates with high-grade tumours, and high signal-intensity in T2 weighted (T2w) images identifies low-grade tumours. We aimed to investigate the potential of routine conventional MRI sequences, such as DWI and T2-w, to pre operatively distinguish between low-grade and high-grade brain tumours in paediatric patients. MATERIAL AND METHODS: Two raters, blinded to the histological diagnosis, rated the aspect and signal intensity of MR images (T2w and DWI) from 37 children with newly diagnosed brain tumours. Histological diagnoses included 18 low-grade and 19 high-grade brain tumours. RESULTS: The inter-rater agreement was 81-95%. High-grade tumours were never hypointense on DWI and low-grade tumours were usually hyperintense on T2w. Specificity was 100% for low-grade tumours and 90% for high-grade tumours. About 95% of the high-grade tumours and about 70% of the low-grade tumours were correctly diagnosed. CONCLUSION: The combination of general morphological aspect of the tumours and signals on T2-w and DWI yield a high accuracy of pre-operative differentiation between low-grade and high-grade paediatric tumours. PMID- 23981385 TI - Skin cancer surveillance and malignancies of the skin in a community-dwelling cohort of patients with newly diagnosed chronic lymphocytic leukemia. AB - PURPOSE: Assess compliance with skin cancer screening guidelines in a community dwelling cohort of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and evaluate the clinical utility of such screening. METHODS: We identified patients diagnosed at Mayo Clinic with CLL between January 1, 2004, and June 1, 2012, who resided within 30 miles of Mayo Clinic. We evaluated adherence to skin cancer screening and identified the prevalence of skin malignancies during follow up. Medical records were reviewed to document skin cancer screening and diagnosis of a skin malignancy. RESULTS: Collectively, 113 individuals who met criteria were diagnosed with CLL during the study interval. Forty-one patients (36%) had a whole body skin examination by either a dermatologist or primary care provider documented within 6 months of diagnosis; of these; nine (8% of overall cohort; 22% of examined patients) had a skin malignancy identified. Fifteen additional skin malignancies were diagnosed during follow-up. There were a total of 24 skin malignancies (21% of cohort) diagnosed, including basal cell carcinoma (n = 10), squamous cell carcinoma (n = 11), sebaceous carcinomas (n = 2), and melanoma (n = 1). CONCLUSION: We documented a low compliance with guidelines to screen for skin malignancy in a community-dwelling cohort of patients with newly diagnosed CLL. Standardized and systems-based approaches are likely to increase compliance with skin cancer screening guidelines in patients with CLL. PMID- 23981386 TI - Cochrane review summary: Pharmacological interventions for promoting smoking cessation during pregnancy. PMID- 23981387 TI - SAPC hot topic: is it a dangerous idea to make physiotherapists the gatekeepers of frontline primary care for all patients with musculoskeletal problems? PMID- 23981388 TI - The thalamus in cirrhotic patients with and without hepatic encephalopathy: a volumetric MRI study. AB - BACKGROUND & AIMS: The thalamus is a major relay and filter station in the central neural system. Some previous studies have suggested that the thalamus maybe implicated in the pathogenesis of hepatic encephalopathy. The aim of our study was to investigate changing thalamic volumes in cirrhotic patients with and without hepatic encephalopathy. METHODS: Neuropsychological tests and structural MR scanning were performed on 24 cirrhotic patients, 23 cirrhotic patients with minimal hepatic encephalopathy, 24 cirrhotic patients during their first episode of overt hepatic encephalopathy, and 33 healthy controls. Voxel-based morphometry analysis was performed to detect gray matter morphological changes. The thalamus and whole brain volume were extrapolated. A receiver operating characteristic curve analysis of thalamic volumes was used to discriminate patients with minimal hepatic encephalopathy from those with hepatic cirrhosis. RESULTS: Thalamic volume increased in a stepwise manner in patients with progressively worse stages of hepatic encephalopathy compared to healthy subjects. Additionally, a comparison of gray matter morphometry between patients with Child-Pugh grades A, B, or C and controls revealed a progression in thalamic volumes in parallel with the degree of liver failure. Moreover, thalamic volume was significantly correlated with the number connection test A time and digit-symbol test score in cirrhotic patients with minimal hepatic encephalopathy (r=0.659, P=0.001; r= 0.577, P=0.004; respectively). The area under the receiver operating characteristic curve was 0.827 (P=0.001). CONCLUSIONS: A significantly increased thalamic volume may be provide an objective imaging measure for predicting seizures due to minimal hepatic encephalopathy in cirrhotic patients. PMID- 23981389 TI - Electronic structures and optical properties for Ag-N-codoped ZnO nanotubes. AB - The structural and electronic/optical properties of pure and Ag-N-codoped (8,0) ZnO nanotubes have been studied using first-principles calculations in the framework of the local spin density approximation. The configurations for Zn atoms replaced by Ag atoms are p-type semiconductor materials, and the bandgap increases when N atoms are doped into ZnO nanotube configurations. The optical studies based on dielectric function and reflectivity indicate that new transition peaks in the visible light range are observed, which can be ascribed to the Ag and N doping. Furthermore, there is a red shift observed with the increase of N concentration. PMID- 23981390 TI - Plasma membrane protein ubiquitylation and degradation as determinants of positional growth in plants. AB - Being sessile organisms, plants evolved an unparalleled plasticity in their post embryonic development, allowing them to adapt and fine-tune their vital parameters to an ever-changing environment. Crosstalk between plants and their environment requires tight regulation of information exchange at the plasma membrane (PM). Plasma membrane proteins mediate such communication, by sensing variations in nutrient availability, external cues as well as by controlled solute transport across the membrane border. Localization and steady-state levels are essential for PM protein function and ongoing research identified cis- and trans-acting determinants, involved in control of plant PM protein localization and turnover. In this overview, we summarize recent progress in our understanding of plant PM protein sorting and degradation via ubiquitylation, a post translational and reversible modification of proteins. We highlight characterized components of the machinery involved in sorting of ubiquitylated PM proteins and discuss consequences of protein ubiquitylation on fate of selected PM proteins. Specifically, we focus on the role of ubiquitylation and PM protein degradation in the regulation of polar auxin transport (PAT). We combine this regulatory circuit with further aspects of PM protein sorting control, to address the interplay of events that might control PAT and polarized growth in higher plants. PMID- 23981391 TI - Measurement of circulating endothelial cells to support the diagnosis of veno occlusive disease after hematopoietic stem cell transplantation. PMID- 23981392 TI - Arbidol inhibits viral entry by interfering with clathrin-dependent trafficking. AB - Arbidol (ARB) is a broad-spectrum antiviral displaying activity against a number of enveloped and non-enveloped viruses. It was described as a viral entry inhibitor and shown to interact at the molecular level with lipid membranes and viral fusion glycoproteins to impede viral entry and fusion. However its mechanism of action at the cellular level remains unknown. Here, by using live cell confocal imaging and the hepatitis C virus as a model virus, we show that ARB affects clathrin-mediated endocytosis by impeding dynamin-2-induced membrane scission. Moreover it induces the intracellular accumulation of clathrin-coated structures where viral particles are trapped. Collectively, our results shed light on the mechanistic aspects of ARB antiviral activity and suggest that ARB could prevent cell infection by viruses that enter through clathrin-mediated endocytosis. PMID- 23981393 TI - Safety cases for medical devices and health information technology: involving health-care organisations in the assurance of safety. AB - In the United Kingdom, there are more than 9000 reports of adverse events involving medical devices annually. The regulatory processes in Europe and in the United States have been challenged as to their ability to protect patients effectively from unreasonable risk and harm. Two of the major shortcomings of current practice include the lack of transparency in the safety certification process and the lack of involvement of service providers. We reviewed recent international standardisation activities in this area, and we reviewed regulatory practices in other safety-critical industries. The review showed that the use of safety cases is an accepted practice in UK safety-critical industries, but at present, there is little awareness of this concept in health care. Safety cases have the potential to provide greater transparency and confidence in safety certification and to act as a communication tool between manufacturers, service providers, regulators and patients. PMID- 23981394 TI - Factors shaping effective utilization of health information technology in urban safety-net clinics. AB - Urban safety-net clinics are considered prime targets for the adoption of health information technology innovations; however, little is known about their utilization in such safety-net settings. Current scholarship provides limited guidance on the implementation of health information technology into safety-net settings as it typically assumes that adopting institutions have sufficient basic resources. This study addresses this gap by exploring the unique challenges urban resource-poor safety-net clinics must consider when adopting and utilizing health information technology. In-depth interviews (N = 15) were used with key stakeholders (clinic chief executive officers, medical directors, nursing directors, chief financial officers, and information technology directors) from staff at four clinics to explore (a) nonhealth information technology-related clinic needs, (b) how health information technology may provide solutions, and (c) perceptions of and experiences with health information technology. Participants identified several challenges, some of which appear amenable to health information technology solutions. Also identified were requirements for effective utilization of health information technology including physical infrastructural improvements, funding for equipment/training, creation of user groups to share health information technology knowledge/experiences, and specially tailored electronic billing guidelines. We found that despite the potential benefit that can be derived from health information technologies, the unplanned and uninformed introduction of these tools into these settings might actually create more problems than are solved. From these data, we were able to identify a set of factors that should be considered when integrating health information technology into the existing workflows of low-resourced urban safety net clinics in order to maximize their utilization and enhance the quality of health care in such settings. PMID- 23981395 TI - Making sense of personal health information: challenges for information visualization. AB - This article presents a systematic review of the literature on information visualization for making sense of personal health information. Based on this review, five application themes were identified: treatment planning, examination of patients' medical records, representation of pedigrees and family history, communication and shared decision making, and life management and health monitoring. While there are recognized design challenges associated with each of these themes, such as how best to represent data visually and integrate qualitative and quantitative information, other challenges and opportunities have received little attention to date. In this article, we highlight, in particular, the opportunities for supporting people in better understanding their own illnesses and making sense of their health conditions in order to manage them more effectively. PMID- 23981396 TI - 'Trying to find information is like hating yourself every day': the collision of electronic information systems in transition with patients in transition. AB - The consequences of parallel paper and electronic medical records (EMR) and their impact on informational continuity are examined. An interdisciplinary team conducted a multi-site, ethnographic field study and retrospective documentation review from January 2010 to December 2010. Three case studies from the sample of older patients with hip fractures who were transitioning across care settings were selected for examination. Analysis of data from interviews with care providers in each setting, field observation notes, and reviews of medical records yielded two themes. First, the lack of interoperability between electronic information systems has complicated, not eased providers' ability to communicate with others. Second, rather than transforming the system, digital records have sustained health care's 'culture of documentation'. While some information is more accessible and communications streamlined, parallel paper and electronic systems have added to front line providers' burden, not lessened it. Implementation of truly interoperable electronic health information systems need to be expedited to improve care continuity for patients with complex health-care needs, such as older patients with hip fractures. PMID- 23981397 TI - "I miss the care even though I know it's just a machine": an explorative study of the relationship between an Internet-based smoking cessation intervention and its participants. AB - This study aimed to investigate how users perceive the different elements of an internet based smoking cessation intervention and to see if the program meet needs and expectations of people in a smoking cessation process. Nine semi structured interviews were conducted in February 2010. Participants were recruited via the homepage of the smoking cessation program Dit Digitale Stopprogram (Your Digital Quit Program) operated by the Danish Cancer Society. The main result was that participants established a relationship to the program which influenced their smoking cessation process. Participants perceived the program as caring and found it supportive. However, the program also created feelings of frustration, disappointment and anger. Some participants in the last phase of cessation experienced text messages from the program as smoking cues. The study concluded that individual interpretations of the different elements in an Internet-based smoking cessation intervention can have both positive and negative impact on the smoking cessation process of participants. PMID- 23981398 TI - Introducing new tools for assessment of parent- and child-reported outcomes in paediatric rheumatology practice: a work in progress. AB - It is increasingly recognised that regular assessment of parent- and child reported outcomes (PCROs) in routine paediatric rheumatology practice may help to increase the quality of care of children with rheumatic diseases. However, most of the instruments available for assessment of PCROs have remained essentially research tools and are not routinely administered in most centres. Recently, new multidimensional questionnaires for paediatric rheumatic diseases have been devised. These tools have been specifically designed for regular administration in a busy clinical setting and have the advantage over other clinical measures of incorporating all main PCROs in a single instrument. This review describes briefly the multidimensional questionnaires developed for the assessment of PCROs in children with juvenile idiopathic arthritis, juvenile dermatomyositis, and juvenile systemic lupus erythematosus and discusses the rationale underlying their creation. Furthermore, it illustrates the methodology and benefits related to the use of multidimensional questionnaires in the collection of standardised quantitative data. PMID- 23981399 TI - Fluoride: what are the facts? PMID- 23981400 TI - Effect of acupressure on patients in Turkey receiving hemodialysis treatment for uremic pruritus. AB - CONTEXT: Pruritus develops for various reasons at any stage of treatment for the majority of patients receiving hemodialysis (HD) due to end-stage renal failure (ESRF). Today, many nonpharmacological treatment methods, including acupressure, are used to relieve the discomfort experienced by patients due to pruritus. Acupressure has been proven to reduce the intensity of pruritus when it is used alone or in combination with pharmacologic methods. OBJECTIVE: This study was conducted to determine the effect of acupressure on pruritus in patients receiving hemodialysis treatment. DESIGN: This study was a nonrandomized, controlled trial. SETTING: The study occurred at four hemodialysis centers in Turkey. PARTICIPANTS: Seventy-eight patients, 38 in the intervention group (IG) and 40 in the control group (CG), met the inclusion criteria and completed the study. INTERVENTION: The IG received acupressure that was applied using a transcutaneous electrical nerve stimulation (TENS) acupressure apparatus, and the control group (CG) received no acupressure. The study used the SP6, ST36, SP10, and LI11 acupuncture points, with acupressure occurring three times/wk for 6 wks for a total of 18 sessions. OUTCOME MEASURES: The study's data were collected using a patient identification form, a visual analogue scale (VAS), and a pruritus score. RESULTS: It was found that IG participants' mean VAS and pruritus scores significantly decreased at wk 6 (P < .001), as compared to the CG, and that the decrease showed a stable trend in wks 12 and 18 (P > .05). The IG was observed to use less medication than the CG throughout the study (P < .001). CONCLUSION: It was concluded that acupressure provided to hemodialysis patients was effective in reducing pruritus. The research team suggests that the use of acupressure should be expanded by informing HD patients and nurses working in HD units about the benefits of acupressure. PMID- 23981401 TI - Triglyceride accumulation: inhibitory effects of tangzhiqing formula. AB - CONTEXT: The tangzhiqing formula (TZQ-F) is a traditional antidiabetic prescription that includes red peony root, mulberry leaf, lotus leaf, danshen root, and hawthorn leaf. The research team's previous study showed that the TZQ-F had beneficial effects on abnormal glucose and lipid metabolism. OBJECTIVE: This study was aimed at investigating TZQ-F's mechanism of lipid metabolism to evaluate its inhibitory effect on triglyceride (TG) accumulation. DESIGN: This study included both an in vivo and an in vitro component. For the in vivo study, C57BL/6 mice were used as the normal control group, and KK-A(y) mice were divided into five groups: (1) model control group, (2) positive control group (10 mg/kg/d rosiglitazone), (3) 500 mg/kg/d TZQ-F treated KK-A(y) mice, (4) 200 mg/kg/d TZQ-F treated KK-A(y) mice, and (5) 100 mg/kg/d TZQ-F treated KK-A(y) mice. For the in vitro study, 3T3-L1 cells were divided into the following: (A) red peony total saponins, (B) danshen total polyphenols, (C) lotus leaf total flavonoids, (D) lotus leaf total alkaloids, (E) mulberry leaf total flavonoids, (F) mulberry leaf total alkaloids, (G) mulberry leaf polysaccharide, and (H) hawthorn leaf total flavonoids, and (I) tangzhiqing formula, including a normal group (NG) and a model control group (CG). SETTING: This study occurred at Tianjin University of Traditional Chinese Medicine (TUTCM), Tianjin, China. INTERVENTION: TZQ-F, suspended either in a 5% acacia solution and a vehicle (5% acacia solution) were given orally to the KK-A(y) mice once/d (16:00-17:00) for 4 wk. OUTCOME MEASURES: RT-PCR and a Western blot analysis were used to detect gene and protein expression respectively. RESULTS: The in vivo study showed that TZQ-F significantly reduced body weight without changing food intake in KK-A(y) mice and significantly decreased the levels of serum glucose (GLU), triglycerides (TG), and free fatty acids (FFA). TZQ-F significantly increased expression of AMP activated protein kinase (AMPK) and phosphorylation of AMPK in the liver and muscle tissues of the KK-A(y) mice. TZQ-F significantly decreased expression of acetyl-CoA carboxylase (ACC), fatty-acid synthase (FAS), hormone-sensitive lipase (HSL), and tumor necrosis factor-alpha (TNF-alpha) in the liver and muscles. It also significantly decreased expression of sterol regulatory element binding protein-1c (SREBP-1c) while it significantly increased expression of glucose transporter type 4 (GLUT-4). The in vitro study showed that TZQ-F significantly suppressed the accumulation of TG and FFA in mature adipocytes and similarly increased expression of AMPK and peroxisome proliferator-activated receptors alpha (PPAR-alpha) and phosphorylation of AMPK, while it decreased expression of ACC, FAS, HSL, and SREBP-1c. CONCLUSIONS: The findings partly clarified the inhibitory effects of TZQ-F on TG accumulation related to the AMPK signaling pathway. PMID- 23981402 TI - Self-reported use of complementary and alternative medicine therapies in a reflexology randomized clinical trial. AB - BACKGROUND: According to the National Center for Complementary and Alternative Medicine (NCCAM), about one-third of American cancer patients have used complementary and alternative medicine (CAM). OBJECTIVE: The objective of this secondary analysis was an assessment of the use of other CAM by women with advanced breast cancer who were undergoing chemotherapy and who participated in a randomized clinical trial (RCT) studying the safety and efficacy of reflexology. For this secondary analysis, the research team hypothesized an increased CAM use due to exposure to the reflexology trial. METHODS/DESIGN: For this secondary analysis, the team conducted telephone interviews at baseline, wk 5, and wk 11 to assess the use of 23 common CAM therapies. SETTING: The study took place at 14 medical oncology clinics across the Midwestern United States. PARTICIPANTS: Participants included women with advanced breast cancer who were undergoing chemotherapy and/or hormonal therapy. INTERVENTION: In the study related to this secondary analysis, the research team randomly assigned the women to one of three primary groups: (1) reflexology; (2) lay foot manipulation (LFM); and (3) control. In addition, the research team used two test groups to establish the study's protocol: (1) test reflexology and (2) test LFM. For this secondary analysis, the research team considered the two reflexology groups (test and intervention) and the two LFM groups (test and intervention) to be the active groups, comparing their use of CAM to the control group's use at the selected time points. PRIMARY OUTCOME MEASURES: The research team used a linear, mixed effects model to analyze the number of therapies used at the three time points. The team performed t tests to compare therapy use at baseline for those women who completed the study vs those who dropped out. The team used the CAM-use instrument. RESULTS: In total, 385 women participated. The research team found no differences in CAM use for the active groups vs the control group over time or in those women who stayed in the study vs those who dropped out. The team found an increase in CAM use at wk 5 compared to baseline, followed by a decrease at wk 11; however, the time trends were the same in the active groups and the control group CONCLUSIONS: In women with advanced breast cancer, researchers can rely upon one assessment of CAM use during an RCT of a CAM therapy. PMID- 23981403 TI - The effect of a homeopathic complex on psychophysiological onset insomnia in males: a randomized pilot study. AB - CONTEXT: Psychophysiological onset insomnia (PI) is defined as sleeplessness exceeding 30 min due to learned, sleep-preventing behaviors and hyperarousal at bedtime. This common condition significantly impacts sufferers' health, occupational performance, and interpersonal relationships. Conventional treatment with hypnotics has many shortcomings. Homeopathic medication may present an alternative treatment for this condition. OBJECTIVE: The study intended to determine the effect of a homeopathic complex on PI. DESIGN: The research team designed a randomized, double-blind, placebo-controlled, 4-wk pilot study, using matched pairs. SETTING: The study took place at the Homeopathy Health Clinic at the University of Johannesburg in Johannesburg, South Africa. PARTICIPANTS: Forty six males aged between 18 and 40 y with chronic PI were recruited; 28 completed the study- placebo group (n = 14) and experimental group (n = 14). INTERVENTIONS: The homeopathic complex was made in 20% alcohol. The placebo consisted of the unmedicated vehicle only. OUTCOME MEASURES: The study used the Pre-sleep Arousal Scale (PSAS) and the Sleep Diary (SD), which assessed sleep-onset latency. RESULTS: The experimental group showed a statistically significant improvement in presleep arousal as well as sleep onset latency over the 4 wks of the study. The Wilcoxon signed-rank test revealed that the improvement occurred gradually. Intergroup analysis showed through both the PSAS and the SD that the experimental group had outperformed the placebo group by day 28 of the study. CONCLUSION: Findings suggest that daily use of the homeopathic complex does have an effect over a 4-wk period on physiological and cognitive arousal at bedtime as well as on sleep onset latency in PI sufferers. Further research on the use of this complex for PI is warranted before any definitive conclusions can be drawn. PMID- 23981404 TI - Treating generalized anxiety disorder using complementary and alternative medicine. AB - CONTEXT: The high comorbidity rate of generalized anxiety disorders (GADs) with other diagnoses-such as panic disorder, depression, alcohol abuse, posttraumatic stress disorder, insomnia, and obsessive compulsive disorder- make it one of the most common diagnoses found in primary care, with women predominantly affected. It is estimated that 5.4%-7.6% of primary care visits are associated with GAD and in addition to impairments in mental health there is additional impairment in pain, function, and activities of daily life, accelerating the need to reconsider the medical management of this disorder and move from the traditional medical model to a more holistic approach, focusing on self-care. OBJECTIVE: The study intended to investigate the effectiveness of a pilot program that used multiple complementary and alternative medicine (CAM) therapies, focusing on self-care behaviors for treatment of GAD. DESIGN: The study used a quasi-experimental, pretestposttest design to evaluate the benefits of the multitherapy program for one group of individuals with GAD. SETTING: The study occurred at a military treatment facility in the Pacific Northwest. PARTICIPANTS: Participants were a convenience sample of volunteers seeking treatment at the military treatment facility. The study enrolled participants (N = 37) if they had a documented history of GAD or met screening criteria for GAD using the GAD-7. INTERVENTIONS: Participants received acupuncture treatments once/wk for 6 wks and engaged in yogic breathing exercises, self- and/or partner-assisted massage therapy using scented oils, episodic journaling, nutrition counseling, and exercise. OUTCOME MEASURES: The primary outcome of interest was the reduction in anxiety as measured by the anxiety subscale on the Depression Anxiety Stress Scale-21 (DASS 21), which assesses three negative affective states: (1) depression (DASS-D), (2) anxiety (DASS-A), and (3) stress (DASS-S). The research team also measured preand post-GAD-7 scores since it used them as a screening criterion for enrollment. In addition, the team assessed participants' levels of pain on a Likert scale. RESULTS: Of the originally enrolled participants, 68% completed the program (n = 25). The study found significant reductions in anxiety pre- and posttest using GAD-7 and identified overall and individual subscale reductions on the DASS-21. While not specifically targeted for treatment, secondary exploratory outcomes included reductions in use of anxiolytic medication and in the pain scale. The study considered the burden of use of multiple therapies upon participants; however, participation in the study's therapies was high. CONCLUSION: The findings in this pilot study suggest multimodal interventions focusing on self care behaviors may be feasible for patients seeking therapies that are adjunct or alternative to conventional treatments. The study also suggested that this type of patient will participate in multitherapy options, and it offers support for expanding the conceptualization of and treatment for GAD by integrating CAM into existing cognitive-behavioral models. PMID- 23981405 TI - Ronald Rothenberg, MD: preventive and regenerative medicine and the power of optimization. PMID- 23981406 TI - Safety evaluation and therapeutic efficacy of Habb-e-Asgand, a commonly used antirheumatic polyherbal Unani formulation. AB - CONTEXT: Rheumatoid arthritis (RA) is a chronic autoimmune disorder. Habb-e Asgand (HEA) is a polyherbal, Unani formulation widely used in the treatment of RA. Traditional systems of medicine or plant-based drugs are an attractive alternative treatment because of their professed efficacy in curing the disease. Medicinal herbs and herbal formulations are generally considered to be safer than the conventional drugs for RA. Unani drugs are known not to produce toxic effects and are presumed to be nontoxic. However, no objective, verifiable data exists to support the claims of nontoxicity and efficacy. OBJECTIVES: The present study was designed to evaluate the safety and therapeutic efficacy of HEA in Wistar rats. SETTING: The study took place at the University College of Medical Sciences and GTB Hospital, University of Delhi, Dilshad Garden, Delhi, India. DESIGN: Oral toxicity studies--one acute (14 d) and one long-term (90 d)--were carried out using three doses of HEA--57.5, 115, and 230 mg/kg body weight (BWT)--in both male and female rats. The research team also carried out a study on antirheumatic activity. The team induced arthritis in three groups of male rats using collagen type II (CII), and for 20 d, one group was treated once weekly with saline; a second group was treated once weekly with methotrexate (MTX) at 0.25 mg/kg BWT IP; and a third group was treated daily with HEA at 115 mg/kg BWT orally. A control group received saline but was not induced with RA. OUTCOME MEASURES: Rheumatoid factor (RF); anticyclic citrullinated peptide (a-CCP) antibody; antinuclear antibody (ANA); and C-reactive protein (CRP) were measured. RESULTS: The acute and long-term, oral toxicity studies showed that HEA administration did not produce any overt toxicity or mortality and that it was safe at all dose levels tested. No major alterations were observed in hematology, serum biochemistry, necropsy, and histopathology at the therapeutic equivalent dose (ie, 115 mg/kg BWT). HEA administration for 20 d in arthritis-induced rats significantly reduced the levels of autoantibodies and CRP, and the results were comparable with those of MTX, the standard, disease-modifying antirheumatic drug (DMARD). CONCLUSION: The study's results provided evidence that HEA is not toxic at the therapeutic dose. The antiarthritic activity of HEA may be due to its disease-modifying activities, thus supporting the traditional use of this formulation for treatment of RA. PMID- 23981407 TI - A pilot study of S-adenosylmethionine in treatment of functional abdominal pain in children. AB - CONTEXT: Functional abdominal pain (FAP) is one of the most common functional gastrointestinal disorders (FGIDs) in children. Currently, medical practitioners widely use tricyclic antidepressants to treat FAP. Those antidepressants, however, have been associated with an increased risk of suicidal ideation, and the accompanying side effects often limit the benefits. S-adenosylmethionine (SAM e) is a dietary supplement that has efficacy as an antidepressant and as a treatment for chronic pain. OBJECTIVE: The research team hypothesized that during SAM-e exposure (1) participants' pain reports would significantly improve over time, (2) participants' reported quality of life would significantly improve over time, and (3) toxicity measures (liver-function tests and mania and depression scales) would not change significantly. DESIGN: The research team performed an open-label, doseescalation trial of oral SAM-e among children with FAP. Participants came to the research facility for measurements at baseline and after 2 wk, 1 mo, and 2 mo. The research team monitored participants for potential toxicities (liver toxicity, mania, and depression) throughout the trial. SETTING: The trial was conducted at the University of California, San Diego. PARTICIPANTS: The research team recruited children and adolescents with FAP via advertisement at several community general pediatric clinics and at the research team's subspecialty pediatric gastrointestinal clinic at a tertiary care center. The eight resulting participants were children with a median and mean age of 14 y. INTERVENTION: To treat persistent abdominal pain, all participants received SAM-e at an initial dose of 200 mg/d, with escalation to a maximum dose of 1400 mg/d over the period of 2 mo. OUTCOME MEASURES: The primary outcomes were the participants' self-reports of pain and quality of life. The research team used the multidimensional measure for recurrent abdominal pain (MM-RAP), Wong-Baker FACES Pain Rating Scale, and the PedsQL for those measurements. The team used repeated measures analyses to analyze the data. RESULTS: Six participants completed the study. The research team demonstrated an improvement in self-pain reports over the 2-mo follow-up period (P = .004). The median dose of SAM-e that participants took at the 2-mo follow-up period was 1400 mg (interquartile range: 950-1400 mg) daily. Liver function tests and assessments for mania and depression did not change over the study period. CONCLUSIONS: Oral SAM-e demonstrates promise in reducing abdominal pain among children with FAP, with minimal toxicity. The research team needs to conduct larger, placebo-controlled trials to support its initial findings. PMID- 23981408 TI - Iyengar yoga and the use of props for pediatric chronic pain: a case study. AB - Iyengar yoga uses postures and props to support the body so that practitioners can engage in poses that would otherwise be more difficult. This type of yoga may be useful in treating children and adolescents who have chronic pain and disability. In this case study, the authors discuss a 14-y-old girl who had two surgeries for gastro-esophageal reflux disease (GERD) and who had continued chest and abdominal pain, as well as vomiting, difficulty eating, weight loss, and anxiety. Having significantly impaired functioning, she was unable to attend school, sleep, socialize, or eat, and she had become wheelchair-bound. Despite evaluations and treatments by specialists over an extended period of time, her symptoms had not improved. This case history describes how the authors used a 4 mo treatment of Iyengar yoga to help the adolescent resume activities and re engage with her environment. The authors intend this report to stimulate scientific study of this form of treatment for children and adolescents with chronic pain. PMID- 23981409 TI - Optimization of magnetic flux density for fast MREIT conductivity imaging using multi-echo interleaved partial fourier acquisitions. AB - BACKGROUND: Magnetic resonance electrical impedance tomography (MREIT) has been introduced as a non-invasive method for visualizing the internal conductivity and/or current density of an electrically conductive object by externally injected currents. The injected current through a pair of surface electrodes induces a magnetic flux density distribution inside the imaging object, which results in additional magnetic flux density. To measure the magnetic flux density signal in MREIT, the phase difference approach in an interleaved encoding scheme cancels out the systematic artifacts accumulated in phase signals and also reduces the random noise effect by doubling the measured magnetic flux density signal. For practical applications of in vivo MREIT, it is essential to reduce the scan duration maintaining spatial-resolution and sufficient contrast. In this paper, we optimize the magnetic flux density by using a fast gradient multi-echo MR pulse sequence. To recover the one component of magnetic flux density Bz, we use a coupled partial Fourier acquisitions in the interleaved sense. METHODS: To prove the proposed algorithm, we performed numerical simulations using a two dimensional finite-element model. For a real experiment, we designed a phantom filled with a calibrated saline solution and located a rubber balloon inside the phantom. The rubber balloon was inflated by injecting the same saline solution during the MREIT imaging. We used the multi-echo fast low angle shot (FLASH) MR pulse sequence for MRI scan, which allows the reduction of measuring time without a substantial loss in image quality. RESULTS: Under the assumption of a priori phase artifact map from a reference scan, we rigorously investigated the convergence ratio of the proposed method, which was closely related with the number of measured phase encode set and the frequency range of the background field inhomogeneity. In the phantom experiment with a partial Fourier acquisition, the total scan time was less than 6 seconds to measure the magnetic flux density Bz data with 128*128 spacial matrix size, where it required 10.24 seconds to fill the complete k-space region. CONCLUSION: Numerical simulation and experimental results demonstrated that the proposed method reduces the scanning time and provides the recovered Bz data comparable to what we obtained by measuring complete k-space data. PMID- 23981410 TI - Growth, structure and spectral studies of a novel mixed crystal potassium zinc manganese sulphate. AB - Mixed crystals of K2Zn0.84 Mn0.16(SO4)2.6H2O were grown from an equimolar aqueous solution of Tutton's salt, K2 Zn(SO4)2.6H2O and MnSO4 by slow evaporation solution growth technique. The crystal composition as determined by single crystal XRD analysis reveals the co-existence of zinc and manganese in the mixed crystal. The surface morphological changes are observed by scanning electron microscopy. Small variations in cell parameter values, slight shifts in characteristic vibrational patterns in FT-IR and reduction in intensities observed in XRD confirm the crystal stress as a result of formation of mixed crystal. High resolution XRD diffraction estimates the crystalline perfection of the mixed crystal with predominantly vacancy type of defects. It belongs to P21/c space group with cell parameter values, a=6.1530 A, b=12.2230 A, c=9.0430 A, alpha=beta=nu=90 degrees , V=657.56 A(3), Z=4. High transmittance in the visible region is observed. PMID- 23981411 TI - Ion imprinted polymeric nanoparticles for selective separation and sensitive determination of zinc ions in different matrices. AB - Preparation of Zn(2+) ion-imprinted polymer (Zn-IIP) nanoparticles is presented in this report. The Zn-IIP nanoparticles are prepared by dissolving stoichiometric amounts of zinc nitrate and selected chelating ligand, 3,5,7,20,40 pentahydroxyflavone, in 15 mL ethanol-acetonitrile (2:1; v/v) mixture as a porogen solvent in the presence of ethylene glycol-dimethacrylate (EGDMA) as cross-linking, methacrylic acid (MAA) as functional monomer, and 2,2 azobisisobutyronitrile (AIBN) as initiator. After polymerization, Cavities in the polymer particles corresponding to the Zn(2+) ions were created by leaching the polymer in HCl aqueous solution. The synthesized IIPs were characterized by scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, fluorescence spectroscopy and thermal analysis techniques. Also, the pH range for rebinding of Zn(2+) ion on the IIP and equilibrium binding time were optimized, using flame atomic absorption spectrometry. In selectivity study, it was found that imprinting results increased affinity of the material toward Zn(2+) ion over other competitor metal ions with the same charge and close ionic radius. The prepared IIPs were repeatedly used and regenerated for six times without any significant decrease in polymer binding affinities. Finally, the prepared sorbent was successfully applied to the selective recognition and determination of zinc ion in different real samples. PMID- 23981412 TI - Non-invasive investigation on a VI century purple codex from Brescia, Italy. AB - Purple codices are among the most relevant and prestigious book productions of Late Antique and Medieval age. They usually contained texts from Holy Writings written with golden or silver inks on parchment dyed in a purple hue. According to the tradition, the colour of parchment was obtained by the well renowned Tyrian purple dye. From the material point of view, however, very little is known about the compounds actually used in the manufacture of these manuscripts. Presently, the information available is limited to the ancient art treatises, with very few diagnostic evidences supporting them and, moreover, none confirming the presence of Tyrian purple. It is more than apparent, then, the need to have at disposal larger and more complete information at the concern, in order to verify what came to us from the literary tradition only. In this study, preliminary results are presented from non-invasive investigation on a VI century purple codex, the so-called CodexBrixianus, held in the Biblioteca Civica Queriniana at Brescia (Italy). Analyses were carried out with XRF spectrometry, UV-visible diffuse reflectance spectrophotometry, molecular spectrofluorimetry and optical microscopy. The results suggest the hypothesis that Tyrian purple had been used as a minor component mixed with other less precious dyes such as folium or orchil. PMID- 23981413 TI - Quantum mechanical and spectroscopic (FT-IR, 13C, 1H NMR and UV) investigations of potent antiepileptic drug 1-(4-chloro-phenyl)-3-phenyl-succinimide. AB - This study represents an integrated approach towards understanding the vibrational, electronic, NMR, and structural aspects, and reactivity of 1-(4 chloro-phenyl)-3-phenyl-succinimide (CPPS). A detailed interpretation of the FT IR, UV and NMR spectra were reported. The equilibrium geometry, bonding features, and harmonic vibrational frequencies have been investigated with the help of density functional theory (DFT) B3LYP method using 6-31G(d,p) and 6-311++G(d,p) basis set. The scaled theoretical wavenumber showed very good agreement with the experimental values. The (1)H and (13)C nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the Gauge-Invariant Atomic Orbital (GIAO) method. Stability of the molecule, arising from hyperconjugative interactions and charge delocalization, has been analyzed using Natural Bond Orbital (NBO) analysis. The results show that ED in the sigma(*) and pi(*) antibonding orbitals and second order delocalization energies E(2) confirm the occurrence of intramolecular charge transfer (ICT) within the molecule. UV-Vis spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies, were calculated by Time-Dependent DFT (TD-DFT) approach. To estimate chemical reactivity of the molecule, the molecular electrostatic potential (MEP) surface map is calculated for the optimized geometry of the molecule. PMID- 23981415 TI - Pressure-tuning micro-Raman spectra of artists' pigments: alpha- and beta-copper phthalocyanine polymorphs. AB - The two polymorphs of copper phthalocyanine, alpha- and beta-CuPc, have been examined by micro-Raman spectroscopy at pressures approaching 5.0 GPa. The metastable alpha-polymorph does not exhibit any structural changes, while the more thermodynamically stable beta-polymorph does exhibit a reversible phase transition at 2.0 GPa. The pressure dependences (dnu/dP) for a selected number of vibrational modes are reported. Two regions of the Raman spectra, 800-900 cm(-1) and 1100-1200 cm(-1), are sensitive to pressure such that they can be used as indicators of the polymorphic form. PMID- 23981414 TI - The organotin coordination polymer [(n-Bu3Sn)4Fe(CN)6H2O] as effective catalyst towards the oxidative degradation of methylene blue. AB - The structure of the supramolecular coordination polymer SCP 1; [(n Bu3Sn)4Fe(CN)6H2O] consists of octahedral [Fe(CN)6](4-) building blocks which are connected by the TBPY-5 configured n-Bu3Sn(CN..)2 fragments creating 3D-network structure. Fenton and photo-Fenton oxidative discoloration of Methylene Blue (MB) has been investigated by hydrogen peroxide catalyzed with the SCP 1. The reaction exhibited pseudo first-order kinetics with respect to each of MB and H2O2. The irradiation of the reaction with UV-light enhanced the rate of MB mineralization, Kobs=0.76 h(-1). Mineralization of MB was investigated by FT-IR spectra. Disodium salt of terephthalic acid photoluminescence probing technology was carried out to identify the reactive oxygen species. The different parameters that affect MB degradation rate were evaluated. Moreover, the efficiency of recycled the SCP 1 and the mechanism of degradation of MB dye were investigated. PMID- 23981416 TI - Novel mixed ligand complexes of bioactive Schiff base (E)-4-(phenyl (phenylimino) methyl) benzene-1,3-diol and 2-aminophenol/2-aminobenzoic acid: synthesis, spectral characterization, antimicrobial and nuclease studies. AB - A novel bidentate Schiff base ligand has been synthesized using 2,4 dihydroxybenzophenone and aniline. Its mixed ligand complexes of MAB type [M=Mn(II), Co(II), Ni(II), Cu(II) and Zn(II); HA=Schiff base and B=2 aminophenol/2-aminobenzoic acid] have been synthesized and characterized on the basis of spectral data UV-Vis, IR, (1)H NMR, FAB-Mass, EPR, SEM and magnetic studies. All the complexes were soluble in DMF and DMSO. Elemental analysis and molar conductance values indicate that the complexes are non-electrolytes. HA binds with M(II) ions through azomethine and deprotonated phenolic group and B binds through the primary amine group and deprotonated phenolic/carboxylic groups. Using FAB-Mass the cleavage pattern of the ligand (HA) has been established. All the complexes adopt octahedral geometry around the metal ions. It has been confirmed with the help of UV-Vis, IR, (1)H NMR and FAB-Mass spectral data. DNA binding activities of the complexes 1d and 2d are studied by UV-Vis spectroscopy and cleavage studies of Schiff base ligand and its complexes 1d and 2d have been by agarose gel electrophoresis method. In vitro biological activities of the free ligand (HA) and their metal complexes (1a-1e and 2a-2e) were screened against few bacteria, Escherichia coli, Staphylococcus saphyphiticus, Staphylococcus aureus, Pseudomonas aeruginosa and fungi Aspergillus niger, Enterobacter species, Candida albicans by well diffusion technique. PMID- 23981417 TI - Reduced and oxidised scytonemin: theoretical protocol for Raman spectroscopic identification of potential key biomolecules for astrobiology. AB - Scytonemin is an important UV-radiation protective biomolecule synthesised by extremophilic cyanobacteria in stressed terrestrial environments. Scytonemin and its reduced form have been both isolated experimentally and the Raman spectrum for scytonemin has been assigned and characterised experimentally both in extracts and in living extremophilic cyanobacterial colonies. Scytonemin is recognised as a key biomarker molecule for terrestrial organisms in stressed environments. We propose a new, theoretically plausible structure for oxidised scytonemin which has not been mentioned in the literature hitherto. DFT calculations for scytonemin, reduced scytonemin and the new structure modelled and proposed for oxidised scytonemin are reported along with their Raman spectroscopic data and lambdamax UV-absorption data obtained theoretically. Comparison of the vibrational spectroscopic assignments allows the three forms of scytonemin to be detected and identified and assist not only in the clarification of the major features in the experimentally observed Raman spectral data for the parent scytonemin but also support a protocol proposed for their analytical discrimination. The results of this study provide a basis for the search for molecules of this type in future astrobiological missions of exploration and the search for extinct and extant life terrestrially. PMID- 23981418 TI - Quantum chemical characterization of N-(2-hydroxybenzylidene)acetohydrazide (HBAH): a detailed vibrational and NLO analysis. AB - The molecular modeling of N-(2-hydroxybenzylidene)acetohydrazide (HBAH) was carried out using B3LYP, CAMB3LYP and PBE1PBE levels of density functional theory (DFT). The molecular structure of HBAH was solved by means of IR, NMR and UV-vis spectroscopies. In order to find the stable conformers, conformational analysis was performed based on B3LYP level. A detailed vibrational analysis was made on the basis of potential energy distribution (PED). HOMO and LUMO energies were calculated, and the obtained energies displayed that charge transfer occurs in HBAH. NLO analysis indicated that HBAH can be used as an effective NLO material. NBO analysis also proved that charge transfer, conjugative interactions and intramolecular hydrogen bonding interactions occur through HBAH. Additionally, major contributions from molecular orbitals to the electronic transitions were investigated theoretically. PMID- 23981421 TI - Flexor tendon repair rehabilitation protocols: a systematic review. AB - PURPOSE: To systematically review various flexor tendon rehabilitation protocols and to contrast those using early passive versus early active range of motion. METHODS: We searched PubMed and Cochrane Library databases to identify articles involving flexor tendon injury, repair, and rehabilitation protocols. All zones of injury were included. Articles were classified based on the protocol used during early rehabilitation. We analyzed clinical outcomes, focusing on incidence of tendon rupture and postoperative functional range of motion. We also analyzed the chronological incidence of published tendon rupture with respect to the protocol used. RESULTS: We identified 170 articles, and 34 met our criteria, with evidence ranging from level I to level IV. Early passive motion, including both Duran and Kleinert type protocols, results included 57 ruptures (4%) and 149 fingers (9%) with decreased range of motion of 1598 tendon repairs. Early active motion results included 75 ruptures (5%) and 80 fingers (6%) with decreased range of motion of 1412 tendon repairs. Early passive range of motion protocols had a statistically significantly decreased risk for tendon rupture but an increased risk for postoperative decreased range of motion compared to early active motion protocols. When analyzing published articles chronologically, we found a statistically significant trend that overall (passive and active rehabilitation) rupture rates have decreased over time. CONCLUSIONS: Analyzing all flexor tendon zones and literature of all levels of evidence, our data show a higher risk of complication involving decreased postoperative digit range of motion in the passive protocols and a higher risk of rupture in early active motion protocols. However, modern improvements in surgical technique, materials, and rehabilitation may now allow for early active motion rehabilitation that can provide better postoperative motion while maintaining low rupture rates. PMID- 23981423 TI - Southern California Society for Surgery of the Hand (SCSSH) award for the Journal of Hand Surgery 2012 article of the year. PMID- 23981419 TI - Spectroscopic studies of micelle-enhanced ligand exchange of gallium (III)/4-(2 pyridylazo) resorcinol complex by calf thymus DNA. AB - The effect of cationic micelles of cetyltrimethylammonium bromide (CTAB) on the interaction of gallium (III) with 4-(2-pyridylazo) resorcinol (PAR) under varying conditions has been studied spectrophotometrically. At pH 6.0, CTAB (0.05% w/v) markedly enhanced the absorption intensity of gallium (III)-PAR complex. Furthermore, the introduction of CTAB provided unique selectivity for the ligand exchange of Ga(III)-PAR by calf thymus dsDNA over calf thymus ssDNA. This phenomenon offers a novel spectrophotometric sensing strategy for direct detection of dsDNA. PMID- 23981424 TI - Paul R. Manske 2012 award for the best upper extremity congenital research manuscript. PMID- 23981425 TI - Response to "Scaphoid waist nonunion with humpback deformity treated without structural bone graft". PMID- 23981426 TI - Letter regarding "Heterotopic ossification following distal radius fractures in a patient with Parkinson disease treated with levodopa-carbidopa". PMID- 23981427 TI - In reply. PMID- 23981428 TI - In reply. PMID- 23981429 TI - Malignant giant cell tumor of the tendon sheath. PMID- 23981430 TI - In reply. PMID- 23981431 TI - Use of alternative childhood immunization schedules in King County, Washington, USA. AB - OBJECTIVE: To determine the percentage of parents in King County, Washington using an alternative childhood immunization schedule (ACIS) and the type of ACIS used. PATIENT AND METHODS: We distributed self-administered surveys to parents at 5 practices regarding the immunization schedule they planned to use or were using. Parents who selected an ACIS were asked to describe its main characteristics and information source. RESULTS: We received 517 surveys and included 502 in analysis. The percentage of parents using an ACIS was 9.4% (95% CI: 7%, 12.2%). Only 6% described their ACIS as the Dr. Sears Schedule, although the book in which it is featured was the most frequently cited ACIS information source (29%). There was a significant association between ACIS use and non Hispanic white parents and parents of children 12-23 months old. CONCLUSION(S): A minority of King County parents use an ACIS. The Dr. Sears Schedule does not predominate. PMID- 23981432 TI - Obstacles to ideal anti-HIV antibody-dependent cellular cytotoxicity responses. AB - A safe and effective vaccine against HIV is a global health priority. Large-scale phase III clinical vaccine trials based on neutralizing antibodies and cytotoxic T-lymphocytes have failed to provide protection, highlighting the lack of understanding of basic immune correlates of protection against HIV. The partial success of the RV144 vaccine trial, however, sparked an intense research effort to identify and describe the protective potential of non-neutralizing antibodies. Correlates of protection analyses have identified antibodies that induced antibody-dependent cellular cytotoxicity (ADCC) as potentially important. Despite the attractiveness of utilizing ADCC antibodies for HIV vaccine design, it is important to note that effective ADCC responses are contingent on many factors. As discussed in this review, these factors are important considerations for determining the feasibility of designing an optimal ADCC antibody-inducing vaccine construct. Important determinants of ADCC responses include characteristics of the antibody, such as isotype and subclass, antigen specificity, titer, durability and glycosylation of the constant region. Second, ADCC immune responses are highly contingent on the natural killer (NK) cell effectors. This review will describe the current state of knowledge regarding the ontogeny of NK cells, highlighting the continuous "education" they undergo that determines their functional potential upon stimulation. Other important NK cell factors, such as constant region receptor polymorphisms, cellular exhaustion, and the effects of the cytokine milieu on cellular function, will also be covered. Finally, an exciting, but yet untested, role for NK cell-mediated ADCC lies in its potential ability to eliminate latently infected cells, which harbor the viral reservoir. The review will address the potential of a two-pronged attack, where latently infected cells are induced to express HIV antigens and then eliminated by NK cells via an ADCC mechanism, with the goal of inducing a cure. PMID- 23981433 TI - Socio-demographic and behavioral determinants of hepatitis B vaccination and infection in pregnant women on Mayotte Island, Indian Ocean. AB - BACKGROUND: Socio-demographic and behavioral determinants of Hepatitis B virus (HBV) vaccination and infection among pregnant women (PW) of Mayotte Island (Indian Ocean) are not well understood. METHODS: Six hundred and seventy-one pregnant women presenting to public antenatal clinics on Mayotte Island were included between September 15, 2008 and September 27, 2009. Socio-demographics, sexual risk behavior characteristics, and data for HBV biomarkers were collected. Logistic regression was undertaken to study determinants of HBV vaccination and factors associated with the risk of HBV infection were assessed using a survival method adapted to interval-censored data. Due to missing data for HBV biomarkers, data were analyzed using multiple imputation (MI). RESULTS: Past or recent HBV infection was observed for 35.5% (95% confidence interval (CI): 30.4-40.8) of PW and 18.6% (95% CI: 14.7-23.2) had evidence of HBV vaccination. PW with unemployed and education qualification (adjusted odds ratio (aOR) 2.65, 95% CI 1.52-4.60) and student status (aOR 4.79, 95% CI 1.63-4.07) were better vaccinated against HBV, compared to those without employment and education. Being born on Comoros was associated with a 63% reduction in HBV vaccination (aOR 0.37, 95% CI 0.21 0.65), compared to be born in Mayotte/France. Women with a history of sexually transmitted infections in the last 5 years had an increased risk of HBV infection (adjusted hazard ratio (aHR) 3.10, 95% CI: 1.13-8.50), whereas those who sometimes used condoms had a 60% reduced risk (aHR=0.40, 95% CI: 0.23-0.69). CONCLUSIONS: Socio-demographic factors were identified for HBV vaccination, while behavioral factors were observed for HBV infection. These results could help to determine priorities for intervention. PMID- 23981434 TI - Coexistence of internal carotid artery stenosis with intracranial aneurysm. AB - BACKGROUND: Studies have hypothesized that alterations in haemodynamics and rheological properties in the main vessels like the main stem of the carotid artery or the internal carotid arteries are responsible for the formation of cerebral aneurysms. AIMS: The objectives of the current analyses were to collate data that have examined the occurrence of cerebral aneurysm with coexisting internal carotid artery stenosis. METHODS: Data sources were collated from detailed PubMed search obtained from 1990 till current. Published literature that deals with the epidemiologic properties as well as prevalence was scanned for data extraction. Publications that reported coexistence of internal carotid artery stenosis with intracranial aneurysm, detected by any modality of imaging, was included in the current study. Spearman's correlation analyses were used to obtain significant information of coexistence of an intracranial aneurysm with an extracranial internal carotid artery stenosis. RESULTS: The frequency of concurrent extracranial internal carotid artery stenosis and an unruptured cerebral artery aneurysm is not known exactly, but has been estimated to be approximately 4%. The major limitations of the current analyses actually can be retrospectively traced to the lack of detailed analyses in this important area of investigation. CONCLUSIONS: Although low in absolute occurrence, there is a significant correlation of the existence of an intracranial aneurysm with carotid artery stenosis. Thus, if peripheral stenosis is detected by any imaging modality including carotid Ultrasonography scan, we recommend digital subtraction intracranial angiography to detect any potential aneurysm and define its radiologic morphology. PMID- 23981435 TI - Effect of the silencing of the Ehcp112 gene on the in vitro virulence of Entamoeba histolytica. AB - BACKGROUND: Entamoeba histolytica is an intestinal protozoan parasite that causes amoebiasis in humans, affecting up to 50 million people worldwide each year and causing 40,000 to 100,000 deaths annually. EhCP112 is a cysteine proteinase of E. histolytica able to disrupt cell monolayers and digest extracellular matrix proteins, it is secreted by trophozoites and it can be active in a wide range of temperature and pH. These characteristics have encouraged the use of EhCP112 in the design and production of possible vaccines against amoebiasis, obtaining promising results. Nevertheless, we have no conclusive information about the role of EhCP112 in the E. histolytica pathogenesis. METHODS: A set of three specific siRNA sequences were used to silence the Ehcp112 gene via the soaking system. Silencing was evaluated by Western blot using an antibody against the EhCP112 recombinant protein. Finally, we analyzed the protease activity, the phagocytosis rate and the ability to destroy MDCK cells of the EhCP112-silenced trophozoites. RESULTS: The highest silencing effect on EhCP112 was detected at 16 h of treatment; time enough to perform the in vitro virulence assays, which showed that EhCP112 silencing produces a significant reduction in cytolysis and phagocytosis of target cells, indicating the participation of this proteinase in these events. CONCLUSIONS: EhCP112 is involved in the in vitro virulence of E. histolytica. PMID- 23981436 TI - Community interaction and child maltreatment. AB - The way in which parents interact with their environment may have implications for their likelihood of abuse and neglect. This study examines the parent environment relationship through community involvement and perception, using social disorganization theory. We hypothesize mothers who participate in their communities and have positive perceptions of them may be less likely to maltreat their children because of the potential protective capacity of neighborhood supports. Using information from the 5 year Fragile Families and Child Wellbeing Study (n=2991), the mother's self-reported acts of psychological and physical maltreatment and neglect are measured. A mother's community involvement index is the number of community activities a mother was involved in, and community perception is measured by two five-item Likert scales assessing perception of community collective efficacy. We analyze the relationship between community variables and each of mother's maltreatment behaviors as well as the interaction between community factors using a series of nested logistic regressions. Higher levels of community involvement are associated with lower levels of psychological aggression. More positive perception of community social control is associated with lower levels of physical assault. A moderation effect of community perception suggests that a mother's perception of her community changes the relationship between community involvement and psychological child abuse. The results provide important policy and empirical implications to build positive and supportive communities as a protective factor in child maltreatment. Getting parents involved in their communities can improve the environment in which children and families develop, and decrease the likelihood that maltreatment will occur. PMID- 23981437 TI - Incorporating spatial dependence into Bayesian multiple testing of statistical parametric maps in functional neuroimaging. AB - The analysis of functional neuroimaging data often involves the simultaneous testing for activation at thousands of voxels, leading to a massive multiple testing problem. This is true whether the data analyzed are time courses observed at each voxel or a collection of summary statistics such as statistical parametric maps (SPMs). It is known that classical multiplicity corrections become strongly conservative in the presence of a massive number of tests. Some more popular approaches for thresholding imaging data, such as the Benjamini Hochberg step-up procedure for false discovery rate control, tend to lose precision or power when the assumption of independence of the data does not hold. Bayesian approaches to large scale simultaneous inference also often rely on the assumption of independence. We introduce a spatial dependence structure into a Bayesian testing model for the analysis of SPMs. By using SPMs rather than the voxel time courses, much of the computational burden of Bayesian analysis is mitigated. Increased power is demonstrated by using the dependence model to draw inference on a real dataset collected in a fMRI study of cognitive control. The model also is shown to lead to improved identification of neural activation patterns known to be associated with eye movement tasks. PMID- 23981438 TI - Personalized foot orthoses with embedded temperature sensing: Proof of concept and relationship with activity. AB - Plantar foot surface temperature has been identified as a clinically relevant physiological variable. Embedding sensors in foot orthoses (FOs) may allow long term monitoring of these temperatures, with compliance via the detection of periods of activity being a potential clinical utilization. This study aimed to test novel designs for FOs with embedded sensing that were produced via additive manufacturing and determine if foot temperature measurements could be used to detect periods of increased activity. FOs with embedded temperature sensors were developed and tested in 10 healthy participants over four day wear periods. Activity monitoring was used to estimate energy expenditure during testing. A threshold-based algorithm was developed to identify time periods of high activity from foot temperature data. Group differences in estimated energy expenditure between time periods below and above the threshold were significant in both the training and validation sets (p<0.001). Significant differences were also seen at individual participant level (p<0.001 in all cases). These results demonstrate the feasibility of using FOs with embedded sensing to monitor plantar surface foot temperatures during normal daily activities and for extended periods and show that periods of increased activity can be identified using foot temperature data. PMID- 23981439 TI - Measurement of the vibration of the middle ear ossicles with removed eardrum: a method for quantification of ossicular fixation. AB - Chronic inflammation of the middle ear is a common disease in which the mobility of the middle ear ossicles may be reduced; resulting in hearing impairment. Knowledge of the degree of ossicular mobility is useful in helping a surgeon determine how to proceed with treatment. In advanced cases, mobility can be assessed by manually pressing on the ossicles, but in less advanced cases manual assessment can provide limited useful information. Ossicular vibration can be measured with a laser vibrometer, but only the manubrium of the malleus is optically visible without removing the eardrum. Since the eardrum is the means by which acoustic energy is translated into the mechanical motion of the ossicles, removing it renders any subsequent measurements of ossicular motion meaningless. We therefore devised a technique in which the ossicles are vibrated magnetically. After measuring the response of the umbo to acoustic stimulation, we removed the eardrum and attached a small magnet to the manubrium. An electromagnetic excitation coil was then used to vibrate the magnet, and the signal to the coil was adjusted until the vibration of the ossicles matches that achieved acoustically. In this paper we explain the method and describe some test measurements on a vinyl membrane, and some preliminary results obtained on a fresh-frozen human temporal bone before and after artificial fixation of the ossicles. PMID- 23981440 TI - Risk factors among people surviving out-of-hospital cardiac arrest and their thoughts about what lifestyle means to them: a mixed methods study. AB - BACKGROUND: The known risk factors for coronary heart disease among people prior suffering an out-of-hospital cardiac arrest with validated myocardial infarction aetiology and their thoughts about what lifestyle means to them after surviving have rarely been described. Therefore the aim of the study was to describe risk factors and lifestyle among survivors. METHODS: An explanatory mixed methods design was used. All people registered in the Northern Sweden MONICA myocardial registry between the year 1989 to 2007 who survived out-of-hospital cardiac arrest with validated myocardial infarction aetiology and were alive at the 28th day after the onset of symptoms (n = 71) were included in the quantitative analysis. Thirteen of them participated in interviews conducted in 2011 and analysed via a qualitative manifest content analysis. RESULTS: About 60% of the people had no history of ischemic heart disease before the out-of-hospital cardiac arrest, but 20% had three cardiovascular risk factors (i.e., hypertension, diabetes mellitus, total cholesterol of more or equal 5 mmol/l or taking lipid lowering medication, and current smoker). Three categories (i.e., significance of lifestyle, modifying the lifestyle to the new life situation and a changed view on life) and seven sub-categories emerged from the qualitative analysis. CONCLUSIONS: For many people out-of-hospital cardiac arrest was the first symptom of coronary heart disease. Interview participants were well informed about their cardiovascular risk factors and the benefits of risk factor treatment. In spite of that, some chose to ignore this knowledge to some extent and preferred to live a "good life", where risk factor treatment played a minor part. The importance of the support of family members in terms of feeling happy and having fun was highlighted by the interview participants and expressed as being the meaning of lifestyle. Perhaps the person with illness together with health care workers should focus more on the meaningful and joyful things in life and try to adopt healthy behaviours linked to these things. PMID- 23981441 TI - Association between health-related quality of life, physical fitness, and physical activity in older adults recently discharged from hospital. AB - The purpose of this study was to determine the relationship among health-related quality of life (HRQOL), physical fitness, and physical activity in older patients after recent discharge from hospital. One hundred fifteen independent living older adults (ages 70-92 years) were included. HRQOL (Medical Outcomes Study 36-item Short Form Health Survey), physical activity (Physical Activity Scale for the Elderly), and physical fitness (Senior Fitness Test) were measured 2-4 weeks after discharge. Higher levels of physical activity and physical fitness were correlated with higher self-reported HRQOL. Although cause and effect cannot be determined from this study, the results suggest that a particular focus on the value of physical activity and physical fitness while in hospital and when discharged from hospital may be important to encourage patients to actively preserve independence and HRQOL. It may be especially important to target those with lower levels of physical activity, poorer physical fitness, and multiple comorbidities. PMID- 23981443 TI - Alcohol and other drug use at school leavers' celebrations. AB - BACKGROUND: A significant proportion of adolescents who attend celebratory events often engage in substantial alcohol and other drug use. We examined patterns, influences and impacts of drug consumption at an end of schooling life celebration. METHODS: Seventeen- to 18-year-old Australians who intended to attend (n = 541) and who attended the celebration (n = 405), respectively, completed pre- and post-event surveys. RESULTS: Males consumed 18.44 and females 13.24 Australian standard drinks on an average day during the school leavers' event. Compared with their last social event, there was greater alcohol (P < 0.0005) and ecstasy use (P < 0.046 for Day 1 and P < 0.008 on Day 3). However, the number of drinks consumed per hour appeared to be similar across contexts. Most (87%) experienced at least one negative outcome attributed to alcohol and other drug use. Safety strategies were frequently used and appeared to be protective against some of the most common harms (hangover, vomiting, black out and unprotected sex). CONCLUSIONS: The use of alcohol and other drugs at this celebratory event appears to be reflective of the greater than usual number of drinking hours that are available to participants. The use of safety strategies can be successful in mitigating some of the most common drug-related harms. PMID- 23981444 TI - Energy transfer from luminescent centers to Er3+ in erbium-doped silicon-rich oxide films. AB - The energy transfer mechanism between luminescent centers (LCs) and Er3+ in erbium-doped silicon-rich oxide (SROEr) films prepared by electron beam evaporation is investigated. Intense photoluminescence of the LCs (weak oxygen bonds, neutral oxygen vacancies, and Si=O states) within the active matrixes is obtained. Fast energy transfer from Si=O states to Er3+ takes advantage in the SROEr film and enhances the light emission from Er3+. The introduction of Si nanoclusters, which induces the Si=O states and facilitates the photon absorption of the Si=O states, is essential to obtain intense photoluminescence from both Si=O states and Er3+. PMID- 23981442 TI - Stress-response pathways are altered in the hippocampus of chronic alcoholics. AB - The chronic high-level alcohol consumption seen in alcoholism leads to dramatic effects on the hippocampus, including decreased white matter, loss of oligodendrocytes and other glial cells, and inhibition of neurogenesis. Examining gene expression in post mortem hippocampal tissue from 20 alcoholics and 19 controls allowed us to detect differentially expressed genes that may play a role in the risk for alcoholism or whose expression is modified by chronic consumption of alcohol. We identified 639 named genes whose expression significantly differed between alcoholics and controls at a False Discovery Rate (FDR) <= 0.20; 52% of these genes differed by at least 1.2-fold. Differentially expressed genes included the glucocorticoid receptor and the related gene FK506 binding protein 5 (FKBP5), UDP glycosyltransferase 8 (UGT8), urea transporter (SLC14A1), zinc transporter (SLC39A10), Interleukin 1 receptor type 1 (IL1R1), thioredoxin interacting protein (TXNIP), and many metallothioneins. Pathways related to inflammation, hypoxia, and stress showed activation, and pathways that play roles in neurogenesis and myelination showed decreases. The cortisol pathway dysregulation and increased inflammation identified here are seen in other stress related conditions such as depression and post-traumatic stress disorder and most likely play a role in addiction. Many of the detrimental effects on the hippocampus appear to be mediated through NF-kappaB signaling. Twenty-four of the differentially regulated genes were previously identified by genome-wide association studies of alcohol use disorders; this raises the potential interest of genes not normally associated with alcoholism, such as suppression of tumorigenicity 18 (ST18), BCL2-associated athanogene 3 (BAG3), and von Willebrand factor (VWF). PMID- 23981445 TI - Gestational hypertension in atrial natriuretic peptide knockout mice and the developmental origins of salt-sensitivity and cardiac hypertrophy. AB - OBJECTIVE: To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring. METHODS: Female mice lacking atrial natriuretic peptide (ANP-/-) were used as a model of gestational hypertension. Heterozygous ANP+/- offspring was bred from crossing either ANP+/+ females with ANP-/- males yielding ANP+/-(WT) offspring, or from ANP-/- females with ANP+/+ males yielding ANP+/-(KO) offspring. Maternal BP during pregnancy was measured using radiotelemetry. At 14weeks of age, offspring BP, gene and protein expression were measured in the kidney with real-time quantitative PCR, receptor binding assay and ELISA. RESULTS: ANP+/-(KO) offspring exhibited normal BP at 14weeks of age, but displayed significant CH (P<0.001) as compared to ANP+/-(WT) offspring. ANP+/-(KO) offspring exhibited significantly increased gene expression of natriuretic peptide receptor A (NPR-A) (P<0.001) and radioligand binding studies demonstrated significantly reduced NPR-C binding (P=0.01) in the kidney. Treatment with high salt diet increased BP (P<0.01) and caused LV hypertrophy (P<0.001) and interstitial myocardial fibrosis only in ANP+/-(WT) and not ANP+/-(KO) offspring, suggesting gestational hypertension programs the offspring to show resistance to salt-induced hypertension and LV remodeling. Our data demonstrate that altered maternal environments can determine the salt-sensitive phenotype of offspring. PMID- 23981451 TI - The evaluation of children with prolonged cough accompanied by American College of Chest Physicians guidelines. AB - INTRODUCTION: In children, coughs lasting longer than 4 weeks are considered to be chronic, with etiological factors varying widely. OBJECTIVE: This study included children with chronic cough who were followed for 1 year. All cases were evaluated with the guidance of the American College of Chest Physicians (ACCP), and etiological factors were analyzed. METHODS: The study included 270 children between the ages of 2 months and 14 years. Their presenting symptoms, physical examination findings and laboratory data were recorded. All patients underwent laboratory tests including direct chest X-ray and spirometric measurements. Several patients required additional advanced examinations such as a sweat test, determination of immunoglobulin levels and bronchoscopy. Patients were reevaluated according to ACCP recommendations, and etiological factors were investigated. RESULTS: The total of 270 patients were included in the study included 43.3% (n=153) females with a mean age of 6.5 +/- 2.3 years (7 months to 17 years). After a 1-year follow-up of patients, we determined that the most common etiologic factors were asthma (27%), asthma-like syndrome (15.5%) and gastroesophageal reflux (10%). Other etiological factors included upper airway cough syndrome and protracted bronchitis, respectively. CONCLUSION: The use of a standardized clinical approach such as the ACCP increases the possibility for fast and accurate diagnosis during the treatment of children with chronic cough, and the use of these guidelines should be required. PMID- 23981452 TI - Acute bacterial meningitis: current review and treatment update. AB - Bacterial meningitis is an infection of the meninges that can be infected by bacteria, virus, or fungus. The classic triad of bacterial meningitis consists of fever, neck stiffness, and altered mental status; headache is also another common symptom. Interventions for bacterial meningitis include prompt diagnosis, and initiation of antimicrobial therapy to optimize bacterial kill and decrease inflammatory response in the subarachnoid space. Nursing management consists of effective delivery of antibiotic therapy, fluid management, and supportive care. PMID- 23981446 TI - The transporter-opsin-G protein-coupled receptor (TOG) superfamily. AB - Visual rhodopsins are recognized members of the large and diverse family of G protein-coupled receptors (GPCRs), but their evolutionary origin and relationships to other proteins are not known. In a previous paper [Shlykov MA, Zheng WH, Chen JS & Saier MH Jr (2012) Biochim Biophys Acta 1818, 703-717], we characterized the 4-toluene sulfonate uptake permease (TSUP) family of transmembrane proteins, and showed that these 7-transmembrane segment (TMS) or 8 TMS proteins arose by intragenic duplication of a gene encoding a 4-TMS protein, sometimes followed by loss of a terminal TMS. In this study, we show that the TSUP, GPCR and microbial rhodopsin families are related to each other and to six other currently recognized transport protein families. We designate this superfamily the transporter/opsin/G protein-coupled receptor (TOG) superfamily. Despite their 8-TMS origins, the members of most constituent families exhibit 7 TMS topologies that are well conserved, and these arose by loss of either the N terminal TMS (more frequent) or the C-terminal TMS (less frequent), depending on the family. Phylogenetic analyses revealed familial relationships within the superfamily and protein relationships within each of the nine families. The results of the statistical analyses leading to the conclusion of homology were confirmed using hidden Markov models, Pfam and 3D superimpositions. Proteins functioning by dissimilar mechanisms (channels, primary active transporters, secondary active transporters, group translocators and receptors) are interspersed on a phylogenetic tree of the TOG superfamily, suggesting that changes in the transport and energy-coupling mechanisms occurred multiple times during evolution of this superfamily. PMID- 23981453 TI - Viral meningitis and encephalitis. AB - Meningitis is an inflammation of the meninges, whereas encephalitis is inflammation of the parenchymal brain tissue. The single distinguishing element between the 2 diagnoses is the altered state of consciousness, focal deficits, and seizures found in encephalitis. Consequently meningoencephalitis is a term used when both findings are present in the patient. Viral meningitis is not necessarily reported as it is often underdiagnosed, whereas encephalitis cases are on the increase in various areas of North America. Improved imaging and viral diagnostics, as well as enhanced neurocritical care management, have improved patient outcomes to date. PMID- 23981454 TI - Brain abscess. AB - A brain abscess is defined as a localized collection of pus within the parenchyma of the brain or meninges. Brain abscesses are a complication of ear, sinus, and/or dental infections. Although they may occur in many brain locations, the most common sites are frontal and temporal lobes. Modern neuroimaging and laboratory analysis have led to prompt diagnosis and have decreased the mortality rates from brain abscess. Critical care nurses have a vital role in performing accurate neurologic assessments, timely administration of antibiotics, and management of fever. PMID- 23981455 TI - Spinal epidural abscess. AB - Spinal epidural abscess is a rare bacterial infection located within the spinal canal. Early diagnosis and rapid treatment are important because of its potential to cause rapidly progressive spinal cord compression and irreversible paralysis. A staphylococcus bacterial infection is the cause in most cases. Treatment includes antibiotics and possible surgical drainage of the abscess. A favorable neurologic outcome correlates with the severity and duration of neurologic deficits before surgery and the timeliness of the chosen intervention. It is important for the critical care nurse to monitor the patient's neurologic status and provide appropriate interventions. PMID- 23981456 TI - Ventriculitis of the central nervous system. AB - An infection of the ventricular system of the brain is referred to as ventriculitis. The signs and symptoms of ventriculitis include the triad of altered mental status, fever, and headache, as seen in the patient with meningitis. Identifying the organism responsible is important in determining the cause and in planning a treatment strategy. Nurses have a pivotal role in the early identification and management of the patient with ventriculitis. PMID- 23981457 TI - Central nervous system infections. PMID- 23981458 TI - Scarring following steroid tendon sheath injections for tenosynovitis in children with juvenile idiopathic arthritis: a single-centre experience. PMID- 23981460 TI - Cholesterol and cardiovascular disorders. PMID- 23981461 TI - Diagnosing cardiovascular disease from the perspective of the brain and inflammation. AB - Numerous lifestyle, emotional, and biological factors have been identified as risk factors for heart disease. These include socioeconomic status, early childhood and intimate partner abuse, disruption of sleep patterns, lack of exercise, and unhealthy food choices. Genetic and epigenetic factors are also critical components of the equation. A common denominator that links directly or indirectly all of these factors is inflammation. In some instances, the production of inflammatory molecules may precipitate the illness, while in others they may be produced in response to the underlying cause. Regardless of whether through direct or indirect means, inflammation contributes to the gradual loss of cellular energy substrates, which culminates in impaired diastolic performance. For that reason, to refer to a failure of the cardiovascular system as heart or cardiovascular disease lessens the potentially important contribution of a myriad of other factors. This article begins with the premise that impaired cardiac functioning is more than a heart disorder. An argument will be made that impaired cardiac functioning can also be an economic, behavioral, and/or emotional disorder, which subsequently gives rise to a metabolic failure. Therefore, a multi-systems approach should be taken to identify prior to the onset of damage biological and non-biological predictors of impending heart disease. PMID- 23981462 TI - How I do it: the patient who asks about lifestyle choices to prevent heart disease. PMID- 23981463 TI - Appropriate clinical use of statins: a discussion of the evidence, scope, benefits, and risk. PMID- 23981464 TI - The role of omega-3 polyunsaturated fatty acids in cardiovascular health. AB - Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) play an important role in both primary and secondary prevention of cardiovascular diseases (CVDs). Clinicians should strongly consider therapy with omega-3 PUFAs for individuals at risk for CVD and with known CVD, particularly individuals who are at increased risk for sudden cardiac death. The amount of omega-3 PUFA in erythrocyte membranes, which is the omega-3 index, could prove to be a modifiable risk factor for CVD. This review outlines potential mechanisms of action, the omega-3 index, results of clinical and prevention trials, and recommendations for omega-3 PUFA therapy in CVD. The majority of epidemiologic and controlled interventional studies have demonstrated that marine- and plant-derived omega-3 PUFAs have beneficial effects on CVD. The omega-3 index may prove to be a valuable tool for assessing an individual's need for increased omega-3 PUFAs through diet or supplementation. PMID- 23981465 TI - The role of nutrition, nutraceuticals, vitamins, antioxidants, and minerals in the prevention and treatment of hypertension. AB - Macronutrient and micronutrient deficiencies are very common in the general population and may be even more common in patients with hypertension and cardiovascular disease due to genetic or environmental causes and prescription drug use. These deficiencies will have an enormous impact on present and future cardiovascular health and outcomes, such as hypertension, myocardial infarction, stroke and renal disease, and on overall health costs. The diagnosis and treatment of these nutrient deficiencies can reduce blood pressure; improve vascular health, endothelial dysfunction, and vascular biology; and decrease cardiovascular events. Vascular biology assumes a pivotal role in the initiation and perpetuation of hypertension and target organ damage (TOD). Endothelial activation, oxidative stress, inflammation, autoimmune vascular dysfunction, and vascular smooth-muscle dysfunction are initial events in hypertension. Nutrient gene interactions determine a broad array of phenotypic consequences, such as vascular problems and hypertension. In addition to other lifestyle modifications, optimal nutrition, nutraceutical supplements, vitamins, antioxidants, minerals, weight loss, exercise, smoking cessation, and moderate restriction of alcohol and caffeine can prevent and control hypertension in many patients. An integrative approach combining these lifestyle suggestions with the correct pharmacologic treatment will best achieve new goals for blood pressure levels, reduce cardiovascular risk factors, improve vascular biology and vascular health, reduce cardiovascular TOD, and reduce health care expenditures. In this article, the expanded scientific role for nutraceutical supplements in the treatment of essential hypertension will be discussed. It is the purpose of this article to review only the hypertension clinical trials that have evaluated the clinical use and efficacy of nutrition, weight loss, exercise, and nutritional supplements, vitamins, minerals, and antioxidants. PMID- 23981467 TI - Differences in retinoid levels and metabolism among gastropod lineages: imposex susceptible gastropods lack the ability to store retinoids in the form of retinyl esters. AB - The presence of a complex retinoid system was long believed to be a chordate/vertebrate novelty. However, recent findings indicate otherwise since the gastropod mollusk Osilinus lineatus was found to have the capacity to store retinoids in the form of retinyl esters (REs), a key feature to maintain a homeostatic control of retinoid levels. Here, we investigated whether such a complex retinoid system is widely distributed among gastropod lineages. Additionally, since one of the most spectacular examples of endocrine disruption in the wild, the masculinization of female gastropods (imposex) by the retinoid X receptor (RXR) agonist, tributyltin (TBT), has been linked with perturbed retinoid signaling, we also investigated if retinoid storage mechanisms in the form of retinyl esters were present in imposex-susceptible gastropods. Initially, we determined the presence of both polar (active retinoic acid isomers) and nonpolar retinoids (retinol, REs) in selected gastropod species: the limpet Patella depressa and the imposex-susceptible whelks Nucella lapillus and Nassarius reticulatus. Although all species presented active retinoid forms, N. lapillus and N. reticulatus were shown to lack nonpolar retinoids. The absence of REs, which are the common retinoid storage form found in vertebrates and in O. lineatus suggest that those species are unable to use them to maintain a homeostatic control of their retinoid levels. In order to further clarify the retinoid metabolic pathways in imposex-susceptible gastropods, a retinoid exposure study was carried out with N. lapillus. The results demonstrate that although N. lapillus is able to metabolize several retinoid precursors, it lacks the capacity to store retinoids as REs. Whether the lack of retinoid storage mechanisms in the form of REs in imposex-susceptible gastropods plays an important role in the susceptibility to RXR agonists warrants additional studies. PMID- 23981466 TI - Identification of key structural elements for neuronal calcium sensor-1 function in the regulation of the temperature-dependency of locomotion in C. elegans. AB - BACKGROUND: Intracellular Ca2+ regulates many aspects of neuronal function through Ca2+ binding to EF hand-containing Ca2+ sensors that in turn bind target proteins to regulate their function. Amongst the sensors are the neuronal calcium sensor (NCS) family of proteins that are involved in multiple neuronal signalling pathways. Each NCS protein has specific and overlapping targets and physiological functions and specificity is likely to be determined by structural features within the proteins. Common to the NCS proteins is the exposure of a hydrophobic groove, allowing target binding in the Ca2+-loaded form. Structural analysis of NCS protein complexes with target peptides has indicated common and distinct aspects of target protein interaction. Two key differences between NCS proteins are the size of the hydrophobic groove that is exposed for interaction and the role of their non-conserved C-terminal tails. RESULTS: We characterised the role of NCS-1 in a temperature-dependent locomotion assay in C. elegans and identified a distinct phenotype in the ncs-1 null in which the worms do not show reduced locomotion at actually elevated temperature. Using rescue of this phenotype we showed that NCS-1 functions in AIY neurons. Structure/function analysis introducing single or double mutations within the hydrophobic groove based on information from characterised target complexes established that both N- and C terminal pockets of the groove are functionally important and that deletion of the C-terminal tail of NCS-1 did not impair its ability to rescue. CONCLUSIONS: The current work has allowed physiological assessment of suggestions from structural studies on the key structural features that underlie the interaction of NCS-1 with its target proteins. The results are consistent with the notion that full length of the hydrophobic groove is required for the regulatory interactions underlying NCS-1 function whereas the C-terminal tail of NCS-1 is not essential. This has allowed discrimination between two potential modes of interaction of NCS-1 with its targets. PMID- 23981469 TI - A Calibration-Free, Noncontact, Disposable Liquid Dispensing Cartridge Featuring an Online Process Control. AB - We present a noncontact liquid dispenser that uses a disposable cartridge for the calibration-free dosage of diverse biochemical reagents from the nanoliter to the microliter range. The dispensing system combines the advantages of a positive displacement syringe pump (responsible for defining the aliquot's volume with high accuracy) with a highly dynamic noncontact dispenser (providing kinetic energy to detach the liquid from the tip). The disposable, noncontact dispensing cartridge system renders elaborate washing procedures of tips obsolete. A noncontact sensor monitors the dispensing process to enable an online process control. To further increase confidence and reliability for particularly critical biomedical applications, an optional closed-loop control prevents malfunctions. The dispensing performance was characterized experimentally in the range of 0.25 to 10.0 uL using liquids of different rheological properties (viscosity 1.03 16.98 mPas, surface tension 30.49-70.83 mN/m) without adjusting or calibrating the actuation parameters. The precision ranged between a coefficient of variation of 0.5% and 5.3%, and the accuracy was below +/-10%. The presented technology has the potential to contribute significantly to the improvement of biochemical liquid handling for laboratory automation in terms of usability, miniaturization, cost reduction, and safety. PMID- 23981468 TI - The effect of primary organic particles on emergency hospital admissions among the elderly in 3 US cities. AB - BACKGROUND: Fine particle (PM2.5) pollution related to combustion sources has been linked to a variety of adverse health outcomes. Although poorly understood, it is possible that organic carbon (OC) species, particularly those from combustion-related sources, may be partially responsible for the observed toxicity of PM2.5. The toxicity of the OC species may be related to their chemical structures; however, few studies have examined the association of OC species with health impacts. METHODS: We categorized 58 primary organic compounds by their chemical properties into 5 groups: n-alkanes, hopanes, cyclohexanes, PAHs and isoalkanes. We examined their impacts on the rate of daily emergency hospital admissions among Medicare recipients in Atlanta, GA and Birmingham, AL (2006-2009), and Dallas, TX (2006-2007). We analyzed data in two stages; we applied a case-crossover analysis to simultaneously estimate effects of individual OC species on cause-specific hospital admissions. In the second stage we estimated the OC chemical group-specific effects, using a multivariate weighted regression. RESULTS: Exposures to cyclohexanes of six days and longer were significantly and consistently associated with increased rate of hospital admissions for CVD (3.40%, 95%CI = (0.64, 6.24%) for 7-d exposure). Similar increases were found for hospitalizations for ischemic heart disease and myocardial infarction. For respiratory related hospital admissions, associations with OC groups were less consistent, although exposure to iso-/anteiso-alkanes was associated with increased respiratory-related hospitalizations. CONCLUSIONS: Results suggest that week-long exposures to traffic-related, primary organic species are associated with increased rate of total and cause-specific CVD emergency hospital admissions. Associations were significant for cyclohexanes, but not hopanes, suggesting that chemical properties likely play an important role in primary OC toxicity. PMID- 23981470 TI - Association between neutrophil-lymphocyte ratio and impaired myocardial perfusion in patients with known or suspected coronary disease. AB - OBJECTIVE: To determine whether an elevated neutrophil-lymphocyte ratio (NLR) is associated with chronically impaired myocardial perfusion in patients with known or suspected coronary disease. BACKGROUND: Elevated NLRs are positively associated with cardiac events, anatomic coronary disease, and myocardial infarct size. However, no study has evaluated the association between NLR and chronically impaired myocardial perfusion. METHODS: This study included 683 patients undergoing cardiac positron emission tomography (PET) with a calculable NLR within 90 days of PET. The primary outcome was myocardial perfusion defect size measured in percent of left ventricular mass (%LV60). RESULTS: NLR was independently associated with %LV60 when analyzed as both a continuous and binary outcome (p < 0.001). Individuals with NLR above the 90th percentile had a 5-fold increased likelihood of significant perfusion defects compared to individuals with NLR between the 10th and 25th percentiles (Odds ratio = 4.7, p < 0.001). CONCLUSION: An elevated NLR demonstrated strong associations with myocardial perfusion. PMID- 23981471 TI - The effects of personal resources and coping strategies on depression and anxiety in patients with chronic obstructive pulmonary disease. AB - OBJECTIVES: Little is known about how personal resources and coping strategies influence depression and anxiety in patients with COPD. The purpose of this study was to examine the effect of personal resources on the coping strategies and psychological responses and the mediating role of coping strategies on the relationship of personal resources to depression and anxiety in patients with COPD using a path model. METHODS: This was a cross-sectional correlational study. The participants were 209 patients diagnosed with COPD in South Korea. Personal resources were defined as knowledge of COPD, self-efficacy, and social support. Coping includes both problem-oriented and affect-oriented coping strategies. RESULTS: Higher levels of knowledge of the disease were associated with fewer depressive symptoms; and this relationship was partially mediated by problem oriented coping strategies. Higher levels of self-efficacy were related to less depression and anxiety. Patients with more perceived social support experienced fewer depressive symptoms through the use of problem-oriented coping strategies. CONCLUSIONS: Our findings suggest that problem-oriented coping strategies may explain the mechanism of how knowledge of the disease and social support influence depressive symptoms for patients with COPD. Further interventions focusing on modifiable factors, including personal resources and problem-oriented coping strategies, are warranted to improve psychological outcomes for patients with COPD. PMID- 23981472 TI - What surgeons should tell patients with oesophago-gastric cancer: a cross sectional study of information needs. AB - BACKGROUND: Evidence shows that patients with cancer have many information needs, but specific requirements of patients undergoing surgery for oesophago-gastric (OG) cancer have not been well explored. This study surveyed information needs of patients with OG cancer and explored associations between patient characteristics and information needs. PATIENTS: A validated questionnaire assessing the importance of information about i) the nature, process and prognosis of the cancer, ii) tests, iii) treatments, and iv) physical and psychosocial outcomes (quality of life information) was completed by patients before and after OG cancer treatment. Items responses were transformed to a 0-100 score and linear regression explored associations between clinical and socio-demographic patient characteristics and patient information needs. RESULTS: Questionnaires from 136 respondents were received (response rate 60%, 25% pre-operative, 77% men, mean age 66). Most types of information were rated as important, with information about prognosis and quality of life issues being scored as highly important by over 112 (82%) patients. Linear regression showed that women rated information relating to treatment and psychosocial effects as more important than men (p < 0.038), but no other associations were identified. CONCLUSIONS: Most patients with OG cancer want detailed information, especially information about prognosis and quality of life. It is recommended that surgeons provide this for patients alongside information that the surgeon considers important. PMID- 23981473 TI - Physiological adaptations to prolonged fasting in the overwintering striped skunk (Mephitis mephitis). AB - Wintertime physiology of captive striped skunks (Mephitis mephitis) in response to cold ambient temperature (Ta) and fasting was investigated with body temperature (Tb) and activity recordings and analyses of hematology, plasma biochemistry and tissue fatty acids (FA). After 105 days of food deprivation, the skunks were in phase II of fasting indicated by the elevated plasma nonesterified FA and glycerol but no accumulation of nitrogen end products. Shorter-chain saturated and monounsaturated FA together with C18-20 n-3 polyunsaturated FA were preferentially mobilized. Individual amino acids responded to fasting in a complex manner, while essential and nonessential amino acid sums remained stable. Increases in hemoglobin and hematocrit suggested dehydration. The activity levels were lower in mid-January-early March, and the activity bouts were mostly displayed between 17:00-23:00 h. Daily torpor was observed in two females with 29 and 46 bouts. The deepest torpor (Tb<31 degrees C) occurred between dawn and early afternoon and lasted for 3.3 +/- 0.18 h. The average minimum Tb was 29.2 +/ 0.15 degrees C and the lowest recorded Tb was 25.8 degrees C. There was significant relation between the average 24-h Tb and Ta. Increases in wintertime Ta, as predicted by climate change scenarios, could influence torpor patterns in the species. PMID- 23981474 TI - Recruitment for a clinical trial of chronic disease self-management for older adults with multimorbidity: a successful approach within general practice. AB - BACKGROUND: A robust research base is required in General Practice. The research output for General Practice is much less than those of other clinical disciplines. A major impediment to more research in this sector is difficulty with recruitment. Much of the research in this area focuses on barriers to effective recruitment and many projects have great difficulty with this process. This paper seeks to describe a systematic approach to recruitment for a randomized controlled trial that allowed the study team to recruit a substantial number of subjects from General Practice over a brief time period. METHODS: A systematic approach to recruitment in this setting based on prior literature and the experience of the investigator team was incorporated into the design and implementation of the study. Five strategies were used to facilitate this process. These included designing the study to minimize the impact of the research on the day-to-day operations of the clinics, engagement of general practitioners in the research, making the research attractive to subjects, minimizing attrition and ensuring recruitment was a major focus of the management of the study. Outcomes of the recruitment process were measured as the proportion of practices that agreed to participate, the proportion of potentially eligible subjects who consented to take part in the trial and the attrition rate of subjects. Qualitative interviews with a subset of successfully recruited participants were done to determine why they chose to participate in the study; data were analyzed using thematic analysis. RESULTS: Five out of the six general practices contacted agreed to take part in the study. Thirty-eight per cent of the 1663 subjects who received a letter of invitation contacted the university study personnel regarding their interest in the project. Recruitment of the required number of eligible participants (n = 256) was accomplished in seven months. Thematic analysis of interviews with 30 participants regarding key factors in their study participation identified a personalised letter of endorsement from their general practitioner, expectation of personal benefit and altruism as important factors in their decision to participate. CONCLUSION: Recruitment can be successfully achieved in General Practice through design of the research project to facilitate recruitment, minimize the impact on general practice operations and ensure special care in enrolling and maintaining subjects in the project. PMID- 23981475 TI - Endovascular treatment for acute ischemic stroke in octogenarians compared with younger patients: a meta-analysis. AB - BACKGROUND: Little is known about the safety and efficacy of endovascular therapy for acute ischemic stroke in octogenarians. AIM: We performed a systematic review and meta-analysis of published studies comparing outcomes of octogenarians and younger patients after endovascular treatment for acute ischemic stroke. METHODS: A computerized search of the medical literature from 1990 to 2012 was performed to identify comparative studies of endovascular treatment of ischemic stroke patients 80 years or older and younger patients. Data on clinical outcomes, mortality, symptomatic intracerebral hemorrhage, and recanalization were abstracted. RESULTS: Data from eight studies with 2729 patients were included in the final analysis. Good functional outcome defined as modified Rankin score 2 or less within 90 days was more common in younger patients compared with octogenarians [odds ratio 2.694; 95% confidence interval 1.941-3.740, P < 0.001). Symptomatic hemorrhage and death were significantly more come in patients 80 years or older (odds ratio 1.604; 95% confidence interval 1.013-2.540, P = 0.04 and odds ratio 3.695; 95% confidence interval 2.517-5.424, P < 0.001, respectively). Successful recanalization defined as Thrombolysis in Myocardial Infarction (TIMI) 2-3 was seen less frequently in older patients; however, this did not reach statistical significance (odds ratio 0.814; 95% confidence interval 0.522-1.269, P = 0.364). CONCLUSION: Formal meta-analysis showed that octogenarians are less likely to achieve functional independence and have higher rates of mortality and intracerebral hemorrhage following endovascular treatment for ischemic stroke compared with younger patients. Decisions regarding endovascular treatment of elderly patients should be individualized until randomized controlled trials are available. PMID- 23981476 TI - The MSHA pilus of Vibrio parahaemolyticus has lectin functionality and enables TTSS-mediated pathogenicity. AB - Vibrio parahaemolyticus is a seafood-borne pathogen which causes acute inflammatory gastroenteritis--a process which is mediated by the translocation of type three secretion system effector proteins. The molecular interactions governing colonization of the intestinal epithelium by this pathogen remain poorly understood. The mannose-sensitive haemagglutinin (MSHA) pilus was identified in this study as a significant factor in bacterial-host cell adherence and subsequent pathogenesis towards Caco-2 human intestinal epithelial cells. Deletion of essential components of the MSHA pilus resulted in a 60% decrease in adherence and a similar reduction in bacterial uptake by human intestinal cells. The diminished adherence of MSHA mutants correlated with significant decreases in V. parahaemolyticus-induced Caco-2 cell lysis, cell rounding and IL-8 secretion. Glycan array comparison between the V. parahaemolyticus wild type and MSHA deficient mutants identified lectin functionality for the MSHA pilus with specificity towards the fucosylated blood group oligosaccharide antigens Lewis A and X and blood groups A and B. The MSHA pilus also exhibited high affinity for the structurally related asialo-GM1 ganglioside, lacto-N-fucopentaose I and lacto N-difucohexaose I. We hypothesize that these glycans act as receptors for the MSHA pilus in the gastrointestinal tract, thereby facilitating efficient colonization of the intestinal epithelium by V. parahaemolyticus. PMID- 23981477 TI - Yeast cell assay with a surface plasma resonance sensor at multiple penetration depths. AB - We demonstrated a novel yeast cell assay using a multiple depth surface plasmon resonance platform, which has three detection depths. In the study we first identified the minimal and maximum number of cells required for detection and then used the platform to conduct a drug potency study. The study showed that the rank order of potency for 3 drugs could be clearly determined and was the same regardless of the penetration depth used for the measurement. The rank order made sense based on their respective mechanism of action. However the data quality of the inhibition curve was best when measured at the 1500 nm depth. The dose dependent response was noticeable even after only 15 min treatment, which is much earlier than those from traditional methods. By comparing the response units obtained at 3 different penetration depths in various yeast cell assays, we have confirmed that simultaneously monitoring from multiple penetration depths likely offers advantages to better detect robust signals from yeast cells, which proves difficult with other optical sensors with a short penetration depth of < 300 nm. The assay could be broadly applicable to other rigid and spherical cell types for biology studies and for antibiotic discovery. PMID- 23981478 TI - Learning to run from narrative foreclosure: one woman's story of aging and physical activity. AB - In this article, the authors construct a story of one woman's (Justine's) experience of learning to run within the context of a beginners group. Building on existing scholarship on narrative, aging, and physical activity, this work is part of a larger ethnographic project examining subjective accounts of the physically active aging body across the life course. Concerned with often simplistically linear problems of representation, the authors present a messy text that represents the complex and fluid nature of Justine's embodied tale. The aim is to show the intersection of biographical (storied) identity with health behavior choices and to interrogate the process of challenging narrative foreclosure. By using the emerging genre of messy text as a creative analytic practice, the authors avoid prompting a single, closed, convergent reading of Justine's story. Instead, they provoke interpretation within the reader as witness and expand the ways in which research on aging and physical activity has been represented. PMID- 23981479 TI - What is the most dangerous snake? AB - Letter to Editor of Journal of Venomous Animals and Toxins. PMID- 23981481 TI - PPARgamma forms a bridge between DNA methylation and histone acetylation at the C/EBPalpha gene promoter to regulate the balance between osteogenesis and adipogenesis of bone marrow stromal cells. AB - The balance between osteogenesis and adipogenesis of bone marrow stromal cells is impaired in many human diseases. Knowledge of how to fine-tune this balance is of medical importance. CCAAT/enhancer binding protein alpha (C/EBPalpha) has been shown to regulate the balance between osteogenesis and adipogenesis of C3H10T1/2 cells, with epigenetic modifications of the C/EBPalpha promoter playing an important role. The present study aimed to elucidate the underlying molecular mechanisms. The results showed that peroxisome proliferator-activated receptor gamma (PPARgamma) binds the -1286 bp/-1065 bp region of the C/EBPalpha promoter to activate C/EBPalpha expression during osteogenesis and adipogenesis of C3H10T1/2 cells. DNA hypermethylation in the -1286 bp/-1065 bp region, observed at the terminal stage of osteogenesis, prevented PPARgamma binding, and then histone deacetylase 1 (HDAC1) occupied this region to reduce the level of histone acetylation. We regulated the balance between osteogenesis and adipogenesis of mouse bone marrow stromal cells through modulation of DNA methylation and histone acetylation status. In addition, in bone marrow stromal cells from the glucocorticoid-induced osteoporosis (GIO) mouse, hypomethylation of CpG sites, higher binding of PPARgamma, acetylated histones 3 and 4, and reduced binding of HDAC1 in the -1286 bp/-1065 bp region of C/EBPalpha promoter were observed, compared with normal mice. This study provides a deeper insight into the molecular mechanisms underlying the balance between osteogenesis and adipogenesis regulated by C/EBPalpha in synergy with PPARgamma, and suggests a molecular model for how DNA methylation and histone acetylation are linked by PPARgamma to regulate differentiation of bone marrow stromal cells. PMID- 23981480 TI - Correlation between insulin resistance and serum ghrelin in non-diabetic ankylosing spondylitis patients undergoing anti-TNF-alpha therapy. AB - OBJECTIVES: To evaluate whether anti-TNF-alpha therapy (infliximab) administration alters circulating levels of ghrelin, an anti-inflammatory gastric peptide. We also assessed possible associations of circulating ghrelin concentrations with CRP and ESR levels, metabolic syndrome, demographic characteristics and other adipokines in ankylosing spondylitis (AS) patients. METHODS: We studied 30 consecutive non-diabetic AS patients, without history of cardiovascular (CV) events, on periodical treatment with infliximab. Serum ghrelin levels were determined immediately prior to and after an infliximab infusion. Correlations of ghrelin serum levels with disease activity, systemic inflammation and metabolic syndrome were assessed. Potential changes in ghrelin concentration following an infusion of infliximab were analysed. RESULTS: We observed a negative correlation between ghrelin concentration and insulin resistance (HOMA-IR immediately before infliximab infusion- at time 0 and at the end of infliximab infusion- at time 120') (r=-0.496; p=0.01 at time 0; r=-0.393; p=0.047 at time 120', respectively). We also found a positive correlation with insulin sensitivity (QUICKI) (r=0.415; p=0.035 at time 0; r=0.465; p=0.017 at time 120'). A correlation was found between ghrelin and resistin prior to infliximab infusion (r=0.429; p=0.046), and a negative correlation between serum ghrelin levels at time 0 and triglycerides (r=-0.416; p=0.035). No differences in ghrelin levels according to specific clinical features of the disease were seen. A single infliximab infusion led to mild but not significant increase in ghrelin serum concentration. CONCLUSIONS: In AS patients undergoing periodical treatment with anti-TNF-alpha monoclonal antibody-infliximab a link between insulin resistance and serum ghrelin concentration was observed. PMID- 23981482 TI - Indication criteria for cataract extraction and gender differences in waiting time. AB - PURPOSE: The purpose of this study was to investigate national indication criteria tool for cataract extraction (NIKE), a clinical tool for establishing levels of indications for cataract surgery, in relation to gender differences in waiting times for cataract extraction (CE). METHODS: Data were collected by The Swedish National Cataract Register (NCR). Eye clinics report to NCR voluntarily and on regular basis (98% coverage). Comparisons regarding gender difference in waiting times were performed between NIKE-categorized and non-NIKE-categorized patients, as well as between different indication groups within the NIKE-system. All calculations were performed in spss version 20. Multivariate analyses were carried out using logistic regression, and single variable analyses were carried out by Student's t-test or chi square as appropriate. RESULTS: Gender, age, visual acuity and NIKE-categorization were associated with waiting time. Female patients had a longer waiting time to CE than male, both within and outside the NIKE-system. Gender difference in waiting time was somewhat larger among patients who had not been categorized by NIKE. In the non-NIKE-categorized group, women waited 0.20 months longer than men. In the group which was NIKE-categorized, women waited 0.18 months longer than men. CONCLUSIONS: It is reasonable to assume that prioritizing patients by means of NIKE helps to reduce the gender differences in waiting time. Gender differences in waiting time have decreased as NIKE was introduced and there may be a variety of explanations for this. However, with the chosen study design, we could not distinguish between effects related to NIKE and those due to other factors which occurred during the study period. PMID- 23981484 TI - Endonuclease-containing Penelope retrotransposons in the bdelloid rotifer Adineta vaga exhibit unusual structural features and play a role in expansion of host gene families. AB - BACKGROUND: Penelope-like elements (PLEs) are an enigmatic group of retroelements sharing a common ancestor with telomerase reverse transcriptases. In our previous studies, we identified endonuclease-deficient PLEs that are associated with telomeres in bdelloid rotifers, small freshwater invertebrates best known for their long-term asexuality and high foreign DNA content. Completion of the high quality draft genome sequence of the bdelloid rotifer Adineta vaga provides us with the opportunity to examine its genomic transposable element (TE) content, as well as TE impact on genome function and evolution. RESULTS: We performed an exhaustive search of the A. vaga genome assembly, aimed at identification of canonical PLEs combining both the reverse transcriptase (RT) and the GIY-YIG endonuclease (EN) domains. We find that the RT/EN-containing Penelope families co exist in the A. vaga genome with the EN-deficient RT-containing Athena retroelements. Canonical PLEs are present at very low copy numbers, often as a single-copy, and there is no evidence that they might preferentially co-mobilize EN-deficient PLEs. We also find that Penelope elements can participate in expansion of A. vaga multigene families via trans-action of their enzymatic machinery, as evidenced by identification of intron-containing host genes framed by the Penelope terminal repeats and characteristic target-site duplications generated upon insertion. In addition, we find that Penelope open reading frames (ORFs) in several families have incorporated long stretches of coding sequence several hundred amino acids (aa) in length that are highly enriched in asparagine residues, a phenomenon not observed in other retrotransposons. CONCLUSIONS: Our results show that, despite their low abundance and low transcriptional activity in the A. vaga genome, endonuclease-containing Penelope elements can participate in expansion of host multigene families. We conclude that the terminal repeats represent the cis-acting sequences required for mobilization of the intervening region in trans by the Penelope-encoded enzymatic activities. We also hypothesize that the unusual capture of long N-rich segments by the Penelope ORF occurs as a consequence of peculiarities of its replication mechanism. These findings emphasize the unconventional nature of Penelope retrotransposons, which, in contrast to all other retrotransposon types, are capable of dispersing intron containing genes, thereby questioning the validity of traditional estimates of gene retrocopies in PLE-containing eukaryotic genomes. PMID- 23981483 TI - Separation and purification of water-soluble iridoid glucosides by high speed counter-current chromatography combined with macroporous resin column separation. AB - Four iridoid glucosides, shanzhiside methyl ester, phloyoside II, chlorotuberside, and penstemonoside, were isolated and purified from an herbal medicinal plant for the first time by high-speed counter-current chromatography (HSCCC) using a two-phase solvent system composed of ethyl acetate-n-butanol water (5:14:12, v/v/v). A total of 37mg of shanzhiside methyl ester, 29mg of phloyoside II, 27mg of chlorotuberside, and 21mg of penstemonoside with the purity of 99.2%, 98.5%, 97.3%, and 99.3%, respectively, were obtained in one-step separation within 4h from 150mg of crude extract. To the best of our knowledge, this is the first report of separation and purification of iridoid glucosides from natural sources by HSCCC. The chemical structures of all the four compounds were identified by ESI-MS, (1)H NMR, and (13)C NMR. PMID- 23981485 TI - An especial skill in elite wheelchair basketball players. AB - We aimed to investigate whether an especial skill is present in elite wheelchair basketball players when taking twenty shots with a regular basketball from five different distances (11 ft, 13 ft, 17 ft, & 19 ft) from the basket including the free throw line (15 ft). Twelve elite male basketball players participated. The results showed that as distance increased shot accuracy decreased in line with force by variability predictions for the 11 ft, 13 ft, 17 ft, & 19 ft distances. However, shot performance at the free throw line where players are more familiar with practicing free throw shots did not follow this trend. A linear regression line was drawn to predict performance at the free throw line based on nearer (11 ft & 13 ft) and farer (17 ft & 19 ft) distances to the basket, this was then compared to actual performance. A significant difference between actual and predicted scores was found (p<.05) supporting the presence of an especial skill. Significant positive correlations were found for the 11 ft and 17 ft distance, age, years of playing, and accumulated practice hours with performance at the 15 ft line (p<.05). These correlations imply the operation of generalization in the especial skill. This observation received support from applying a model in which shot accuracy as a function of distance was approximated by two regression lines. PMID- 23981486 TI - Sit-to-stand movement in children: a longitudinal study based on kinematics data. AB - Although the ability to stand from a seated posture is relevant for clinical practice, there are few studies investigating the process of acquisition and refinement of the motor components involved in sit-to-stand movement (STS) in children. Therefore, this longitudinal study aims to describe kinematic characteristics of the STS movement in children from 12 to 18 months, and also to investigate the relationship between changes in STS movement and childrens' daily life mobility. Ten healthy children were evaluated at 12,13,14,15 and 18 months of age. A motion analysis system was used to measure total duration of STS movement and angular movements of each joint, and frequencies of successful and unsupported STS were obtained. The Pediatric Evaluation of Disability Inventory was used to assess childrens' daily-life mobility. Results showed that children tend to increase the frequency of successful trials over the months by reducing the total duration and decreasing peak ankle dorsiflexion and trunk flexion during STS. Children also started to stand up from chair with decreased trunk flexion angle among ages. At the end of the STS, we observed decreases in trunk flexion and knee flexion over age. Furthermore, kinematic characteristics that reflect improvements in STS movement are related to better performance of functional skills and decreased level of assistance provided by the caregiver in daily-life mobility of younger children. However, the strength of these associations decreases from 14 months of age onwards. PMID- 23981487 TI - A network meta-analysis of the efficacy of opioid analgesics for the management of breakthrough cancer pain episodes. AB - CONTEXT: With many medications available for the management of breakthrough cancer pain (BTCP), physicians may require additional guidance in selecting an appropriate medication to suit an individual patient's needs. OBJECTIVES: To identify all the evidence and assess the relative clinical value of currently approved BTCP medications. METHODS: Following a systematic literature search (2007-2010), the results of 10 randomized controlled trials investigating the effects of BTCP medications (intranasal fentanyl spray [INFS], fentanyl pectin nasal spray, fentanyl sublingual tablets, fentanyl buccal soluble film, fentanyl buccal tablets, oral transmucosal fentanyl citrate, and morphine sulfate immediate release) were synthesized using a network meta-analysis. The main outcome was pain intensity difference (PID) relative to placebo up to 60 minutes after the intake of medication. RESULTS: INFS, fentanyl pectin nasal spray, fentanyl buccal tablet, and oral transmucosal fentanyl citrate showed greater PIDs relative to placebo than other BTCP medications 15 minutes after intake. All other medications showed greater PIDs relative to placebo at 30 minutes, except morphine sulfate immediate release, which did not show efficacy over placebo until 45 minutes. Only INFS produced clinically meaningful pain relief (absolute PID >=2) at 15 minutes. CONCLUSION: From current evidence, although all BTCP medications provided pain relief within the time frames assessed, transmucosal fentanyl medications achieved a greater level of pain relief in a shorter time frame than placebo or oral morphine. PMID- 23981488 TI - How and why did a regional palliative care program lead to changes in a region? A qualitative analysis of the Japan OPTIM study. AB - CONTEXT: Improving palliative care is one of the major issues throughout the world. OBJECTIVES: The primary aim of this study was to explore how and why a regional palliative care program led to changes in a region. METHODS: As part of a nationwide mixed-methods study of a regional palliative care program, a qualitative study was performed with 101 health care professionals involved in the implementation of the program. In-depth interviews were done, focusing on perceived changes and the perceived reasons for the changes. We used thematic analyses. RESULTS: Seven themes were identified as follows: 1) improved communication and cooperation among regional health care professionals; 2) increased confidence in the system to care for cancer patients at home; 3) improved knowledge/skills, practice, and perception of palliative care; 4) contribution to self-growth; 5) wide variability in perceived changes in the knowledge and perception of patients, family members, and the general public; 6) wide variability in the perceived regionwide effects of the project; and 7) unresolved issues. Participants emphasized improved communication and cooperation among regional health care professionals and stated a variety of ways of how communication and cooperation influenced daily practice. The main reasons for changes included regionwide interdisciplinary conferences and informal interactions at a variety of meetings. CONCLUSION: This study advances understanding of how the regional palliative care program created a change in the region. The findings are useful for developing a conceptual framework and identifying key interventions to improve regional palliative care for clinicians, researchers, and policy makers. PMID- 23981489 TI - Drug delivery to the central nervous system by polymeric nanoparticles: what do we know? AB - Nanoparticles enable the delivery of a great variety of drugs including anticancer drugs, analgesics, anti-Alzheimer's drugs, cardiovascular drugs, protease inhibitors, and several macromolecules into the brain after intravenous injection of animals. The mechanism of the nanoparticle-mediated drug transport across the BBB appears to be receptor-mediated endocytosis followed by transcytosis into the brain or by drug release within the endothelial cells. Modification of the nanoparticle surface with covalently attached targeting ligands or by coating with certain surfactants that lead to the adsorption of specific plasma proteins after injection is necessary for this receptor-mediated uptake. A very critical and important requirement for nanoparticulate brain delivery is that the employed nanoparticles are biocompatible and, moreover, rapidly biodegradable, i.e. over a time frame of a few days. In addition to enabling drug delivery to the brain, nanoparticles, as with doxorubicin, may importantly reduce the drug's toxicity and adverse effects due to an alteration of the body distribution. Because of the possibility to treat severe CNS diseases such as brain tumours and to even transport proteins and other macromolecules across the blood-brain barrier, this technology holds great promise for a non invasive therapy of these diseases. PMID- 23981490 TI - Science and policy on endocrine disrupters must not be mixed: a reply to a "common sense" intervention by toxicology journal editors. AB - The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU. PMID- 23981491 TI - Advancements in office-based anesthesia in oral and maxillofacial surgery. PMID- 23981492 TI - An office-based approach to the diagnosis and management of osteonecrosis. PMID- 23981493 TI - Extraction socket grafting and buccal wall regeneration with recombinant human bone morphogenetic protein-2 and acellular collagen sponge. PMID- 23981494 TI - Office-based management of dental alveolar trauma. PMID- 23981495 TI - Evidence-based surgical-orthodontic management of impacted teeth. PMID- 23981496 TI - Office-based procedures for unusual impactions. PMID- 23981497 TI - Coronectomy: indications, outcomes, and description of technique. PMID- 23981498 TI - Office placement of skeletal anchorage devices. PMID- 23981499 TI - Surgical uprighting of second molars. PMID- 23981500 TI - Office procedures for the oral and maxillofacial surgeon. PMID- 23981501 TI - Certified athletic trainers' perspectives on rehabilitation adherence in collegiate athletic training settings. AB - CONTEXT: Adherence to sport-injury rehabilitation protocols may be pivotal in ensuring successful rehabilitation and return-to-play outcomes. OBJECTIVES: To investigate athletic trainers' perspectives related to the degree to which rehabilitation adherence is an issue in collegiate athletic training settings, gain insight from certified athletic trainers regarding the factors contributing to rehabilitation nonadherence (underadherence and overadherence), and ascertain views on the most effective means for promoting adherence. DESIGN: Cross sectional, mixed methods. SETTING: Collegiate athletic training in the United States. PARTICIPANTS: Certified athletic trainers (n = 479; 234 male, 245 female). MAIN OUTCOME MEASURES: Online survey consisting of 3 questions regarding rehabilitation adherence, each followed by an open-ended comments section. Descriptive statistics were calculated for quantitative items; hierarchical content analyses were conducted for qualitative items. RESULTS: Most (98.3%) participants reported poor rehabilitation adherence to be a problem (1.7% = no problem, 29.2% = minor problem, 49.7% = problem, 19.4% = major problem), while most (98.96%) participants reported that they had athletes who exhibited poor rehabilitation adherence (1% = never, 71.4% = occasionally, 22.5% = often, 5% = always). In addition, the majority (97.91%) of participants reported that overadherence (eg, doing too much, failing to comply with activity restrictions, etc) was at least an occasional occurrence (2.1% = never, 69.3% = occasionally, 26.3% = often, 1.9% = always). Hierarchical content analyses regarding the constructs of poor adherence and overadherence revealed 4 major themes: the motivation to adhere, the development of good athletic trainer-athlete rapport and effective communication, athletic trainers' perception of the coaches' role in fostering adherence, and the influence of injury- or individual- (eg, injury severity, sport type, gender) specific characteristics on rehabilitation adherence. CONCLUSIONS: These results suggest that participants believe that underadherence (and to a lesser extent overadherence) is a frequent occurrence in collegiate athletic training settings. Strategies for enhancing rehabilitation adherence rates and preventing overadherence may therefore be important for optimizing rehabilitation outcomes. PMID- 23981502 TI - Living Machines 2012: the First International Conference on Biomimetic and Biohybrid Systems. PMID- 23981503 TI - Influence of physical contact on neuromuscular fatigue and markers of muscle damage following small-sided games. AB - OBJECTIVES: Physical contact is frequent in rugby league competition and is thought to be a major contributor to the fatigue and creatine kinase (CK) response, although direct evidence is lacking. The aim of this study was to investigate the influence that physical contact had on the fatigue and CK response to small-sided games. DESIGN: Cross-over, counter-balanced study. METHODS: Twenty-three junior elite rugby league players were divided into two groups. Group one played a contact game on day 1 before playing a non-contact game 72 h later; group two played the games in reverse order. The rules were identical for each game, with the only difference being a 10s contact bout every 50s during the contact game. Upper and lower body neuromuscular fatigue and blood concentrations of CK were assessed immediately before, immediately after, and 12 and 24h after the games. During each game, players wore global positioning system units to provide information on movements. RESULTS: CK increased after both games, peaking immediately following the non-contact game; CK was still rising 24h following the contact game. The difference between the two conditions was practically meaningful at this point (likelihood=likely, 82%; ES=0.86). There were moderate to large reductions in upper body power following the contact game (ES=-0.74 to -1.86), and no reductions following the non-contact game. CONCLUSIONS: This study indicates that large increases in blood CK and upper body fatigue result from physical contact. Training sessions involving physical contact should be performed well in advance of scheduled games. PMID- 23981504 TI - A topical microemulsion for the prevention of allergic rhinitis symptoms: results of a randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial (Nares study). AB - BACKGROUND: Since barrier protection measures to avoid contact with allergens are being increasingly developed, we assessed the clinical efficacy and tolerability of a topical nasal microemulsion made of glycerol esters in patients with allergic rhinitis. METHODS: Randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial in which adult patients with allergic rhinitis or rhinoconjunctivitis due to sensitization to birch, grass or olive tree pollens received treatment with topical microemulsion or placebo during the pollen seasons. Efficacy variables included scores in the mini-RQLQ questionnaire, number and severity of nasal, ocular and lung signs and symptoms, need for symptomatic medications and patients' satisfaction with treatment. Adverse events were also recorded. RESULTS: Demographic characteristics were homogeneous between groups and mini-RQLQ scores did not differ significantly at baseline (visit 1). From symptoms recorded in the diary cards, the ME group showed statistically significant better scores for nasal congestion (0.72 vs. 1.01; p = 0.017) and mean total nasal symptoms (0.7 vs. 0.9; p = 0.045). At visit 2 (pollen season), lower values were observed in the mini-RQLQ in the ME group, although there were no statistically significant differences between groups in both full analysis set (FAS) and patients completing treatment (PPS) populations. The results obtained in the nasal symptoms domain of the mini-RQLQ at visit 2 showed the highest difference (-0.43; 95% CI: -0.88 to 0.02) for the ME group in the FAS population. The topical microemulsion was safe and well tolerated and no major discomforts were observed. Satisfaction rating with the treatment was similar between the groups. CONCLUSIONS: The topical application of the microemulsion is a feasible and safe therapy in the prevention of allergic symptoms, particularly nasal congestion. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01478425. PMID- 23981505 TI - Stroke in rural coastal Ecuador: a community-based survey. AB - Stroke will be South America's next epidemic. Therefore, information on stroke particularities in the region will help to overcome its impact burden. We evaluated prevalence, pattern of sub-types, and pathogenic mechanisms underlying stroke in Atahualpa, a village representative of rural coastal Ecuador. In a three-phase epidemiologic study, suspected cases were detected by a door-to-door survey (Phase I). Then, neurologists evaluated suspected cases and randomly selected negative persons (Phase II), and confirmed patients underwent complementary exams (Phase III). We found 20 stroke patients (mean age 70 years, 60% men) among 642 persons aged >=40 years. Stroke prevalence was 31.150/00 that increased with age. Most patients had sub-cortical infarctions associated with leukoaraiosis or microbleeds. Hypertensive arteriolopathy was the most likely mechanism underlying strokes (55% patients). Intracranial arterial lesions were found in 47% cases. Extracranial atherosclerotic lesions or cardiac sources of emboli were not found in any case. Comparison of our findings with a previous survey performed in the same village showed an alarming increase in stroke prevalence (from 14.080/00 in 2003 to 31.150/00 in 2012, P = 0.03). PMID- 23981506 TI - The rapid detection of Cryptosporidium and Giardia species in clinical stools using the Quik Chek immunoassay. AB - Diagnostic testing in the United Kingdom for Cryptosporidium and Giardia species is routinely performed by microscopy. In this study, two hundred stool samples from human clinical cases were examined for the presence of these two parasites comparing microscopy with an antigen immunoassay, Quik Chek (Techlab, Inc.). The Quik Chek assay was shown to have a sensitivity and specificity for Cryptosporidium detection of 87.6% and 98.9% respectively and for Giardia detection, 93.3% and 99.4% respectively. The high correlation with microscopy data provides evidence to support implementation of this rapid test within diagnostic microbiology laboratories. PMID- 23981507 TI - Effects of a general practice guided web-based weight reduction program--results of a cluster-randomized controlled trial. AB - BACKGROUND: Preliminary findings suggest that web-based interventions may be effective in achieving significant weight loss and weight loss maintenance. To date only few findings within primary care patients and especially the involvement of general practitioners are available. The aim of this trial was to examine the short-term effectiveness of a web-based coaching program in combination with an accompanied telephone counselling regarding weight reduction in a primary care setting. METHODS: The study was a cluster-randomized trial with an observation period of 12 weeks. Individuals recruited by general practitioners randomized to the intervention group participated in a web-based coaching program based on education, motivation, exercise guidance, daily SMS reminding, weekly feedback through internet and active monitoring by general practitioners. Participants in the control group received usual care and advice from their practitioner without the web-based coaching program. The main outcome was weight change between admission and after 12 weeks. RESULTS: 186 participants (109 intervention group, 77 control group) were recruited into study. For 76 participants from the intervention group and 72 participants from the control group weight measurements were available both at baseline and 12 weeks. Weight decreased on average by 4.2 kg in the intervention group and 1.7 kg in the control group (mean group difference 2.5 kg; 95%CI 1,1; 3,8; p < 0.001). Reductions for waist circumference and BMI were also significantly larger within intervention. CONCLUSION: Findings of the present trial suggest that the tested web-based coaching program for weight loss is effective in short-term. Further RCTs are desirable in order to confirm present findings in larger populations and to investigate long-term outcomes. TRIAL REGISTRATION: German Register for Clinical Trials: DRKS00003067. PMID- 23981508 TI - Biochemical and structural characterization of a novel bacterial manganese dependent hydroxynitrile lyase. AB - Hydroxynitrile lyases (HNLs), which catalyse the decomposition of cyanohydrins, are found mainly in plants. In vitro, they are able to catalyse the synthesis of enantiopure cyanohydrins, which are versatile building blocks in the chemical industry. Recently, HNLs have also been discovered in bacteria. Here, we report on the detailed biochemical and structural characterization of a hydroxynitrile lyase from Granulicella tundricola (GtHNL), which was successfully heterologously expressed in Escherichia coli. The crystal structure was solved at a crystallographic resolution of 2.5 A and exhibits a cupin fold. As GtHNL does not show any sequence or structural similarity to any other HNL and does not contain conserved motifs typical of HNLs, cupins represent a new class of HNLs. GtHNL is metal-dependent, as confirmed by inductively coupled plasma/optical emission spectroscopy, and in the crystal structure, manganese is bound to three histidine and one glutamine residue. GtHNL displayed a specific activity of 1.74 U.mg(-1) at pH 6 with (R)-mandelonitrile, and synthesized (R)-mandelonitrile with 90% enantiomeric excess at 80% conversion using 0.5 m benzaldehyde in a biphasic reaction system with methyl tertiary butyl ether. PMID- 23981509 TI - Usefulness of complement activation products in Chinese patients with systemic lupus erythematosus. AB - OBJECTIVES: To evaluate the roles of complement activation products C3d and C4d binding to lymphocytes in the diagnosis of systemic lupus erythematosus (SLE) in a Chinese cohort of patients. METHODS: 96 patients with SLE, 44 patients with other autoimmune disease and 40 healthy control individuals were enrolled in this study. The levels of C3d and C4d binding to peripheral CD4+ T and CD19+ B lymphocyts (designated as T-C3d, T-C4d, B-C3d, B-C4d ) was assessed by flow cytometry. The diagnostic values of these biomarkers were determined by receiver operator characteristic analysis. RESULTS: The levels of T-C3d, T-C4d, B-C3d, B C4d were significantly higher in SLE patients than patients with other disease and healthy controls (p<0.01). As diagnostic tools, T-C4d and B-C4d were 61.1% sensitive/94.3% specific and 63.9% sensitive/94.3% specific in differentiating SLE patients from patients with other disease and healthy controls, respectively. T-C4d and B-C4d were significantly associated with SLE disease activity as measured by the SLE disease activity index (SLEDAI) (p<0.001), low serum C3 (p<0.001), low serum C4 (p=0.006), anti-dsDNA (IIF) (p=0.001), and anti-dsDNA (ELISA) (p=0.001). CONCLUSIONS: Complement activation products C3d and C4d binding to lymphocytes can reflect the disease activity of SLE and can be used as biomarkers for SLE. PMID- 23981510 TI - Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study. AB - BACKGROUND: The profile of cognitive and behavioral variation observed in individuals with fragile X syndrome (FXS), the most common known cause of inherited intellectual impairment, suggests aberrant functioning of specific brain systems. Research investigating animal models of FXS, characterized by limited or lack of fragile X mental retardation protein, (FMRP), has linked brain dysfunction to deficits in the cholinergic and glutamatergic systems. Thus, we sought to examine in vivo levels of neurometabolites related to cholinergic and glutamatergic functioning in males and females with FXS. METHODS: The study participants included 18 adolescents and young adults with FXS, and a comparison group of 18 individuals without FXS matched for age, sex and general intellectual functioning. Proton magnetic resonance spectroscopy (MRS) was used to assess neurometabolite levels in the caudate nucleus, a region known to be greatly enlarged and involved in abnormal brain circuitry in individuals with FXS. A general linear model framework was used to compare group differences in metabolite concentration. RESULTS: We observed a decrease in choline (P = 0.027) and in glutamate + glutamine (P = 0.032) in the caudate nucleus of individuals with FXS, relative to individuals in the comparison group. CONCLUSIONS: This study provides evidence of metabolite differences in the caudate nucleus, a brain region of potential importance to our understanding of the neural deficits underlying FXS. These metabolic differences may be related to aberrant receptor signaling seen in animal models. Furthermore, identification of the specific neurometabolites involved in FXS dysfunction could provide critical biomarkers for the design and efficacy tracking of disease-specific pharmacological treatments. PMID- 23981512 TI - Outcomes of manual extracapsular versus phacoemulsification cataract extraction by beginner resident surgeons. AB - PURPOSE: To evaluate the safety and efficacy of phacoemulsification cataract extraction and manual extracapsular cataract extraction (ECCE) performed by beginning resident surgeons. SETTING: Dallas Veterans Affairs Medical Center, Dallas, Texas, USA. DESIGN: Retrospective cohort study. METHODS: A review was performed of each resident's series of initial cataract surgery procedures as a late first-year or second-year resident. Data were collected for cases performed over almost a 6-year period during which initially the first primary surgeon cases were ECCE and later, the first primary surgeon cases were phacoemulsification. For each case, the following data were gathered: technique of cataract extraction, laterality, resident, vitreous loss or dropped nucleus, placement of posterior chamber intraocular lens (IOL), and need for reoperation within 90 days of surgery. RESULTS: Complications occurred in 6 (2.5%) of 244 cases in which phacoemulsification was performed by a beginner resident primary surgeon and in 7 (4.1%) of 172 cases in which ECCE was used (P=.40). Posterior chamber IOLs were placed in all but 2 phacoemulsification cases and 4 ECCE cases (P=.24). Moreover, 3 cases in the phacoemulsification group and 1 case in the ECCE group required a reoperation within 90 days (P=.65). CONCLUSION: Phacoemulsification cataract extraction can be taught safely and effectively to residents with no cataract surgery experience as a primary surgeon. PMID- 23981511 TI - Electrocortical changes associated with minocycline treatment in fragile X syndrome. AB - Minocycline normalizes synaptic connections and behavior in the knockout mouse model of fragile X syndrome (FXS). Human-targeted treatment trials with minocycline have shown benefits in behavioral measures and parent reports. Event related potentials (ERPs) may provide a sensitive method of monitoring treatment response and changes in coordinated brain activity. Measurement of electrocortical changes due to minocycline was done in a double-blind, placebo controlled crossover treatment trial in children with FXS. Children with FXS (Meanage 10.5 years) were randomized to minocycline or placebo treatment for 3 months then changed to the other treatment for 3 months. The minocycline dosage ranged from 25-100 mg daily, based on weight. Twelve individuals with FXS (eight male, four female) completed ERP studies using a passive auditory oddball paradigm. Current source density (CSD) and ERP analysis at baseline showed high amplitude, long-latency components over temporal regions. After 3 months of treatment with minocycline, the temporal N1 and P2 amplitudes were significantly reduced compared with placebo. There was a significant amplitude increase of the central P2 component on minocycline. Electrocortical habituation to auditory stimuli improved with minocycline treatment. Our study demonstrated improvements of the ERP in children with FXS treated with minocycline, and the potential feasibility and sensitivity of ERPs as a cognitive biomarker in FXS treatment trials. PMID- 23981513 TI - Retinal nerve fibre layer thickness measured by Spectralis spectral-domain optical coherence tomography: The Beijing Eye Study. AB - PURPOSE: The aim of this study was to measure retinal nerve fibre layer thickness (RNFLT) and its associated factors in a population-based setting. METHODS: The population-based Beijing Eye Study 2011 included 3468 individuals. The study participants underwent spectral-domain optical coherence tomography (Spectralis((r)) ; Spectralis OCT)-assisted measurement of the RNFLT. For this study, exclusion criteria were glaucoma, pseudoexfoliation, best-corrected visual acuity of >0.5 logMAR, macular diseases, previous ocular surgery and known neurological diseases. The only inclusion criterion was an age of 50+ years. RESULTS: The inclusion criteria were fulfilled by 2548 participants. Mean RNFLT was 102 +/- 11 MUm. RNFLT was significantly (p < 0.001) thicker in the temporal inferior sector (153 +/- 21 MUm) than in the temporal superior sector (138 +/- 21 MUm), nasal inferior sector (118 +/- 24 MUm), nasal superior sector (106 +/- 21 MUm), temporal sector (76 +/- 13 MUm) and nasal sector (73 +/- 15 MUm). The mean intereye difference in RNFLT was 4.4 +/- 6.0 MUm. In multivariate analysis, thicker RNFLT was associated with younger age (p < 0.001), female gender (p < 0.001), urban region (p = 0.003), larger optic disc size (p < 0.001), larger neuroretinal rim area (p < 0.001), hyperopic refractive error (p < 0.001), larger beta zone of parapapillary atrophy (p = 0.008) and thicker subfoveal choroidal thickness (p = 0.02). RNFLT decreased by about 0.2 MUm (0.2%) per year of life and by 1 MUm (1%) per dioptre of myopia. CONCLUSION: Mean RNFLT (measured by Spectralis((r)) OCT; 102 +/- 11 MUm) was associated with younger age, female gender, urban region of habitation, larger optic disc, larger rim, hyperopic refractive error, larger parapapillary beta zone and thicker subfoveal choroidal thickness. Independent of age and refractive error, the RNFL was thickest temporal inferiorly and thinnest temporally and nasally. PMID- 23981514 TI - Transparency and translation of science in a modern world. AB - The co-Editors-in-Chief of Environmental Health respond to an unusual initiative taken by editors of 14 toxicology journals to influence pending decisions by the European Commission to establish a framework for regulating chemicals that pose a hazard to normal function of the endocrine system. This initiative is also the subject of this Commentary in this journal by authors who recently reviewed the subject and who point out inaccuracies in the toxicology editors' critique. The dispute is about potential public policy development, rather than on science translation and research opportunities and priorities. The toxicology journal editors recommend that chemicals be examined in depth one by one, ignoring modern achievements in biomedical research that would allow new understanding of the effects of classes of toxic substances in complex biological systems. Concerns about policy positions framed as scientific ones are especially important in a time with shrinking public support for biomedical research affects priorities. In such a setting, conflict of interest declarations are important, especially in research publications that address issues of public concern and where financial and other interests may play a role. Science relies on trust, and reasonable disclosure of financial or other potential conflicts is therefore essential. This need has been emphasized by recent discoveries of hidden financial conflicts in publications in toxicology journals, thus misleading readers and the public about the safety of particular industrial products. The transparency provided by Environmental Health includes open access and open peer review, with reader access to reviews, including the identity of reviewers and their statements on possible conflicts of interest. However, the editors of the 14 toxicology journals did not provide any information on potential conflicts of interest, an oversight that needs to be corrected. PMID- 23981515 TI - Identification of stable cytotoxic factors in the gas phase extract of cigarette smoke and pharmacological characterization of their cytotoxicity. AB - Smoking is a major risk factor for atherosclerotic vascular diseases, but the mechanism for its genesis is unknown. We have recently shown that the gas phase of cigarette smoke (nicotine- and tar-free cigarette smoke extract; CSE) likely to reach the systemic circulation contains stable substances which cause cytotoxicity like plasma membrane damage and cell death in cultured cells, and also that the plasma membrane damage is caused through sequential activation of protein kinase C (PKC) and NADPH oxidase (NOX) and the resulting generation of reactive oxygen species (PKC/NOX-dependent mechanism), whereas cell death is caused through PKC/NOX-dependent and -independent mechanisms. To identify these stable substances, the CSE was prepared by passing the main-stream smoke of 10 cigarettes through a Cambridge glass fiber filter, trapping of the smoke in a vessel cooled at -80 degrees C, and subsequent dissolution in 10ml of water. The CSE was fractionated into nine fractions using reversed-phase HPLC, and each fraction was screened for cytotoxicity in cultured cells, using propidium iodide uptake assay for cell membrane damage and MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] reduction assay for cell viability. The cytotoxicity was positive in two of the nine fractions (Fr2 and Fr5). After extraction of the active fractions into dichloromethane, GC/MS analysis identified 2-cyclopenten-1-one (CPO) in Fr5 but none in Fr2. After derivatization of the active fractions with O-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine hydrochloride, GC/MS analysis identified acrolein, acetone and propionaldehyde in Fr2, and methyl vinyl ketone (MVK) in Fr5. After 4-h incubation, authentic acrolein and MVK induced concentration-dependent cytotoxicity with EC50 values of 75.9+/-8.2 and 47.0+/-8.0MUM (mean+/-SEM; n=3), respectively, whereas acetone, propionaldehyde and CPO were without effect. However, after 24-h incubation, CPO induced concentration-dependent cytotoxicity with an EC50 value of 264.0+/-16.9MUM (n=3). The concentrations of acrolein, MVK and CPO in the CSE were 3368+/-334, 2429+/-123 and 392.9+/-31.8MUM (n=4), respectively, which were higher than the cytotoxic concentrations. The cytotoxicity of acrolein and MVK consisted of plasma membrane damage and decreased cell viability: the plasma membrane damage was totally prevented by treatment with an inhibitor of PKC or NOX, whereas the decreased cell viability was only partially prevented by these inhibitors. The cytotoxicity of CPO consisted only of decreased cell viability, which was totally resistant to these inhibitors. These results show that acrolein and MVK are responsible for the acute cytotoxicity of the CSE through PKC/NOX-dependent and -independent mechanisms, whereas CPO is responsible for the delayed cytotoxicity of the CSE through a PKC/NOX-independent mechanism. PMID- 23981516 TI - The impact of lean production on musculoskeletal and psychosocial risks: an examination of sociotechnical trends over 20 years. AB - This paper provides an extensive review of studies carried out in lean production environments in the last 20 years. It aims to identify the effects of lean production (negative or positive) on occupational health and related risk factors. Thirty-six studies of lean effects were accepted from the literature search and sorted by sector and type of outcome. Lean production was found to have a negative effect on health and risk factors; the most negative outcomes being found in the earliest studies in the automotive industry. However, examples of mixed and positive effects were also found in the literature. The strongest correlations of lean production with stress were found for characteristics found in Just-In-Time production that related to reduced cycle time and reduction of resources. Increased musculoskeletal risk symptoms were related to increases of work pace and lack of recovery time also found in Just-In-Time systems. An interaction model is developed to propose a pathway from lean production characteristics to musculoskeletal and psychosocial risk factors and also positive outcomes. An examination is also made of the changing focus of studies investigating the consequences of lean production over a 20-year period. Theories about the effects of lean production have evolved from a conceptualization that it is an inherently harmful management system, to a view that it can have mixed effects depending on the management style of the organization and the specific way it is implemented. PMID- 23981517 TI - True-slime-mould-inspired hydrostatically coupled oscillator system exhibiting versatile behaviours. AB - Behavioural diversity is an indispensable attribute of living systems, which makes them intrinsically adaptive and responsive to the demands of a dynamically changing environment. In contrast, conventional engineering approaches struggle to suppress behavioural diversity in artificial systems to reach optimal performance in given environments for desired tasks. The goals of this research include understanding the essential mechanism that endows living systems with behavioural diversity and implementing the mechanism in robots to exhibit adaptive behaviours. For this purpose, we have focused on an amoeba-like unicellular organism: the plasmodium of true slime mould. Despite the absence of a central nervous system, the plasmodium exhibits versatile spatiotemporal oscillatory patterns and switches spontaneously among these patterns. By exploiting this behavioural diversity, it is able to exhibit adaptive behaviour according to the situation encountered. Inspired by this organism, we built a real physical robot using hydrostatically coupled oscillators that produce versatile oscillatory patterns and spontaneous transitions among the patterns. The experimental results show that exploiting physical hydrostatic interplay-the physical dynamics of the robot-allows simple phase oscillators to promote versatile behaviours. The results can contribute to an understanding of how a living system generates versatile and adaptive behaviours with physical interplays among body parts. PMID- 23981519 TI - Development of a core-stability model: a delphi approach. AB - CONTEXT: Despite widespread acceptance, there is currently no consensus on the definition, components, and the specific techniques most appropriate to measure and quantify core stability. OBJECTIVE: To develop a comprehensive core-stability model addressing its definition, components, and assessment techniques. DESIGN: Delphi technique. SETTING: University laboratory. PARTICIPANTS: 15 content experts from United States and Canada, representing a variety of disciplines. MAIN OUTCOME MEASURE: The authors distributed an open-ended questionnaire pertaining to a core-stability definition, components, and assessment techniques specific to each expert. They collected data over 2 rounds of telephone interviews. They concluded data collection once a consensus was achieved that equated with 51% agreement among respondents. RESULTS: The authors developed a working definition of core stability as the ability to achieve and sustain control of the trunk region at rest and during precise movement. Eighty-three percent of the experts considered the definition satisfactory. Therefore, the definition was accepted. Furthermore, the experts agreed that muscles (14/15 = 93.3%) and neuromuscular control (8/12 = 66.7%) were components of core stability. Assessment techniques were identified and inconsistencies were highlighted; however, no consensus was established. CONCLUSIONS: A consensus core stability definition was created and 2 components were identified. However, of the initial definitions provided by the experts, no 2 were identical, which revealed the inconsistencies among experts and the importance of this study. Nonetheless, the goal of obtaining a consensus definition was obtained. Although a consensus for the assessment techniques of core stability could not be reached, it was a beneficial starting point to identify the inconsistencies that were discovered among the content experts. PMID- 23981518 TI - Magnesium, vitamin D status and mortality: results from US National Health and Nutrition Examination Survey (NHANES) 2001 to 2006 and NHANES III. AB - BACKGROUND: Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between serum 25(OH)D and risk of mortality may be modified by magnesium intake level. METHODS: We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III cohort were determined by using probabilistic linkage with the National Death Index (NDI). RESULTS: High intake of total, dietary or supplemental magnesium was independently associated with significantly reduced risks of vitamin D deficiency and insufficiency respectively. Intake of magnesium significantly interacted with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency. Additionally, the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin D insufficiency. Furthermore, the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median. CONCLUSIONS: Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with vitamin D intake may contribute to vitamin D status. The associations between serum 25(OH)D and risk of mortality may be modified by the intake level of magnesium. Future studies, including cohort studies and clinical trials, are necessary to confirm the findings. PMID- 23981520 TI - Personalized management: inoperable gastrointestinal stromal tumors. AB - Historically, patients with inoperable gastrointestinal stromal tumors (GISTs) had a very poor prognosis because of the highly resistant nature of these tumors to conventional chemotherapy. The rational and progressive development of tyrosine kinase inhibitors (TKIs) since the initial proof-of-concept studies with imatinib mesylate in the late 1990s, all designed to exploit key pathways that lead to GISTs being so oncogenically addicted, have revolutionized the treatment of GIST. Median overall survival has improved from less than a year to at least 5 years in patients with advanced or metastatic disease. Imatinib remains the standard first-line treatment in advanced GIST; however, resistance to imatinib and subsequent other TKIs inevitably develops in most but not all patients. As much as efforts will continue to identify new drugs for patients with disease that becomes refractory to these agents, there has also been a need to focus on optimizing the use of currently available therapies by using a combination of molecular tools to stratify patients more effectively, pharmacodynamic markers and pharmacokinetic modeling to maximize these agents' activity in individual patients, and reappraising the role of surgery in the management of patients with metastatic disease. These all form part of a modern, multidisciplinary approach to the management of GIST patients. PMID- 23981521 TI - Efficacy and safety of medical therapy for low bone mineral density in patients with inflammatory bowel disease: a meta-analysis and systematic review. AB - BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) are at risk for osteoporosis and fracture. However, the efficacy of medical treatments for osteoporosis in increasing bone mineral density (BMD) in patients with IBD has not been well characterized. METHODS: We conducted a meta-analysis and systematic review of controlled trials to evaluate the efficacy and safety of medical therapies used for low BMD in patients with IBD (Crohn's disease, ulcerative colitis, or indeterminate colitis). We searched MEDLINE, EMBASE, Google scholar, the University Hospital Medical Information Network (UMIN) Clinical Trials Registry, and Cochrane Central Register of Controlled Trials for studies that assessed the efficacy of medical treatment for low BMD in patients with IBD. We also manually searched abstracts from scientific meetings and bibliographies of identified articles for additional references. The primary outcome assessed was changes in BMD at the lumbar spine. We also collected data on hip BMD, numbers of new fractures, and adverse effects. Data were pooled by using random-effects models and by mixed-effects analysis for primary aims, when subgroup analysis by individual drug was possible. RESULTS: We analyzed data from 19 randomized controlled studies; 2 used calcium and vitamin D as therapies, 13 used bisphosphonates, 4 used fluoride, 1 used calcitonin, and 1 used low-impact exercise. The pooled effect of bisphosphonates was greater than that of controls in increasing BMD at the lumbar spine (standard difference in means, 0.51; 95% confidence interval, 0.29-0.72) and hip (standard difference in means, 0.26; 95% confidence interval, 0.04-0.49) with comparable tolerability, and the risk of vertebral fractures was reduced. Fluoride increased lumbar spine BMD, but its ability to reduce risk of fracture was unclear. There was no evidence that the other interventions increased BMD. CONCLUSIONS: On the basis of a meta-analysis, bisphosphonate is effective and well tolerated for the treatment of low BMD in patients with IBD and reduces the risk of vertebral fractures. There are insufficient data to support the efficacy of calcium and vitamin D, fluoride, calcitonin, or low-impact exercise. However, the small number of randomized controlled trials limited our meta-analysis. PMID- 23981522 TI - 17beta-Oestradiol Protects Primary-Cultured Rat Cortical Neurons from Ketamine Induced Apoptosis by Activating PI3K/Akt/Bcl-2 Signalling. AB - Numerous studies in rodents have indicated that exposure to ketamine during the period when synaptogenesis is highly active induces neurodegeneration. Thus, there is a growing need to develop strategies to prevent ketamine-induced brain injury in the developing brain. Oestradiol is a neuroactive steroid that prevents neuronal cell death in different experimental models by activating cell survival signals and inhibiting apoptotic signals. The main goal of this study was to investigate the neuroprotective effects of 17beta-oestradiol against ketamine induced apoptotic neurodegeneration in primary-cultured cortical neurons. The data revealed that 17beta-oestradiol (0.1 MUM) in combination with ketamine (100 MUM) increased cell viability in the MTT assay and reduced the number of apoptotic cells detected by TUNEL and Hoechst 33258 staining. To elucidate a possible mechanism by which 17beta-oestradiol exerts its neuroprotective effect, we investigated the PI3K pathway using an inhibitor of PI3K, LY294002. The protective effects of 17beta-oestradiol were abrogated by LY294002. Furthermore, we found that 17beta-oestradiol not only induced phosphorylation of the PI3K substrate Akt, but also increased the expression of Bcl-2, which down-regulated ketamine-induced caspase-3 activity and inhibited neuronal apoptosis. These data demonstrate that 17beta-oestradiol exerts a neuroprotective effect against ketamine-induced neuronal apoptosis by activating the PI3K/Akt/Bcl-2 signalling pathway. Therefore, 17beta-oestradiol appears to be a promising agent in preventing or reversing ketamine's toxic effects on neurons at an early developmental stage. PMID- 23981523 TI - Effect of haemodynamic changes on epithelium-related intestinal injury in off pump coronary surgery. AB - OBJECTIVES: Intestinal injury is thought to play a central role in the occurrence of multiorgan dysfunction after on-pump coronary surgery. Clinical benefits of off-pump revascularisation remain, however, controversial. MATERIAL AND METHODS: Hepatic enzymes and plasmatic IL-6, IL-8 and intestinal-type fatty acid binding protein (I-FABP) were determined in 20 patients (age 65-75) undergoing either on pump (n = 10) or off-pump (n = 10) coronary surgery. Haemodynamic and biochemical parameters, catecholamine and volume therapy were monitored. RESULTS: Central venous pressure (CVP) was significantly higher in the off-pump group during and 12h after operation (9.5 +/- 1.35 vs. 6.21 +/- 0.63 mmH2O, p = 0.012). Higher GGT and GLDH levels occurred in the off-pump group and correlated with the elevated I FABP levels at 24h (935.8 +/- 83.7 vs. 370.4 +/- 67.7 pg/mL, p<0.001). CVP correlated with I-FABP peak values (Pearson's coefficient 0.852). IL-6 and IL-8 were released to a lower extent in the off-pump group compared to on pump (p<0.05) at 24h (139.3 +/- 27.7 vs. 279.4 +/- 56.2 and 15.3 +/- 7.4 vs. 38.5 +/- 13.8 pg/mL) and at 72 h post-operatively (4.5 +/- 2.1 vs. 30.1 +/- 12.1 and 7.8 +/- 1.2 vs. 17.1 +/- 5.2 pg/mL). CONCLUSIONS: While inflammatory activation is reduced with CPB avoidance, elevated CVP during off-pump surgery is followed by temporary postoperative enterocyte damage that may threaten the normal function of the gastrointestinal system and lead - in certain groups of high risk patients -to irrecoverable injury. PMID- 23981524 TI - Pain and pruritus in cutaneous lupus: their association with dermatologic quality of life and disease activity. AB - OBJECTIVES: To evaluate the association of pain and pruritus with Dermatologic Quality of Life (QoL) and cutaneous disease activity in patients with 1) specific cutaneous lupus erythematosus (CLE) lesions, 2) non-specific CLE lesions and 3) both types of CLE lesions. METHODS: We evaluated 42 consecutive SLE patients with at least one active lesion attributed to lupus. Pain and pruritus were evaluated using a visual analogue scale, dermatologic QoL with the DLQI, clinical activity with the CLASI score and systemic activity with the SLEDAI-2K. RESULTS: The patients were predominantly females, mean age 34.2+/-11.2 years and median SLE duration of 7 years. Sixteen patients (38%) had specific lesions, 12 (28.5%) non specific lesions and 14 patients (33%) both lesions. Patients with both lesions had the highest CLASI activity scores (median 17) (p<0.0001), all the cases of severe activity (p=0.002) and higher (worst) DLQI scores (median 11.5, p=0.04). The overall median pain score was 5 (0-9). Patients with non-specific or the combination of both CLE lesions had more pain (p<0.008). Pain correlated with the DLQI (tau=0.38, p=0.001) and the CLASI activity score (tau=0.47, p=0.002). Pain was more intense in vasculitis and bullous lesions followed by oral ulcers. Pruritus score did not differ among groups (median 6) and did not correlate with the DLQI or the CLASI activity score. CONCLUSIONS: We identified pain as a factor that correlated with dermatologic QoL and cutaneous activity. In this sense, this feature needs to be considered as part of the treatment targets in lupus. PMID- 23981525 TI - Ischemic stroke in patients with cancer: is it different from usual strokes? AB - BACKGROUND: It remains unclear whether the characteristics of ischemic stroke in patients with cancer (ISC) differ from usual ischemic strokes (non-ISC). Although a small number of studies have been conducted to characterize ISC, the status of cancer has rarely been considered seriously. AIMS: We aimed to investigate the features of ISC according to the status of cancer, and compare their characteristics with those of non-ISC. METHODS: We assessed and classified 204 ISC patients into two groups: 104 with active (ISC-active) and 100 with inactive (ISC-inactive) cancer. For each ISC patient, two age- and gender-matched ischemic stroke patients without history of cancer were selected as non-ISC control subjects. We compared the clinical/laboratory data, stroke mechanisms, and diffusion weighted imaging (DWI) lesion patterns between ISC-active and non-ISC patients, and between ISC-inactive and non-ISC patients. RESULTS: ISC-active patients demonstrated higher C-reactive protein (CRP) and D-dimer, more frequent cryptogenic stroke and patterns of multiple DWI lesions (in bilateral anterior or in anterior and posterior circulations), and less prevalent conventional risk factors than non-ISC patients, while ISC-inactive patients revealed no such marked differences. Among ISC-active patients, both elevated CRP and D-dimer levels were associated with cryptogenic mechanism and multiple lesion patterns. Furthermore, ISC-active patients with cryptogenic strokes tended to have multiple lesion patterns and metastasis. CONCLUSIONS: ISC-active, but not ISC-inactive, is distinct in terms of risk factors, stroke mechanisms, and lesion patterns. Chronic inflammation and an activated coagulation system may contribute to the pathogenic mechanism of strokes, the extent of each depending on the activity and severity of cancer. PMID- 23981526 TI - Posterior reversible encephalopathy syndrome (PRES) in an HIV-1 infected patient with disseminated varicella zoster virus: a case report. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is an uncommon pathology characterized by the acute onset of headache, vomiting, altered consciousness, seizures and focal neurological deficits. It was initially described in the setting of hypertension, uremia and immunosuppression. In the last decade there have been emerging reports of PRES in patients with advanced human immunodeficiency virus (HIV)-infection in the presence of hypertension, dialysis, hypercalcaemia and two opportunistic infections: blastomycosis and tuberculosis (TB). CASE PRESENTATION: Here we present the case of a 54 year old male being treated for disseminated varicella zoster virus (VZV) and vasculopathy in the setting of HIV infection who acutely deteriorated to the point of requiring intubation. His clinicoradiological diagnosis was of PRES and he subsequently improved within 72 h with supportive management. Serial neuroimaging correlated with the clinical findings. The pathogenesis of PRES is poorly understood but is thought to stem from vasogenic oedema either as a result of loss of endothelial integrity and transudate of fluid across the blood-brain barrier, or secondary to vasospasm resulting in tissue oedema in the absence of infarction. How HIV infection impacts on this model is unclear. It is possible the HIV infection causes endothelial dysfunction and disruption of the blood brain barrier that may be further exacerbated by infections in the central nervous system. CONCLUSION: The phenomenon of PRES in advanced HIV is an important clinical entity for both physicians and critical care doctors to recognize firstly given its potential mortality but also because of its favourable prognosis and reversibility with supportive care and treatment of underlying causes. PMID- 23981528 TI - A paired comparison of intracameral mydriatics in refractive lens exchange surgery. AB - PURPOSE: To compare the efficacy and intra-operative safety of intracameral mydriatics to topical mydriatics in patients undergoing refractive lens exchange (RLE) surgery. METHODS: In a randomized intra-individually comparing study performed at Koskelas Eye Clinic, Lulea, and Department of Clinical Sciences/Ophthalmology, Umea University Hospital, Umea, Sweden, 56 patients undergoing same-day bilateral RLE were included. Pupils were randomly dilated with topical mydriatics in one eye and intracameral mydriatics in the fellow eye. Pupil sizes were recorded intra-operatively throughout the procedures. Perceived pain/discomfort and glare were assessed immediately postoperatively using a visual analogue scale from 0 to 10. RESULTS: Topical mydriatics and intracameral mydriatics both give satisfactory pupil dilation in routine RLE. However, there was noticeable iris billowing in 17 eyes dilated with topical mydriatics but only one eye with intracameral mydriatics (p < 0.001). Pupils were initially slightly larger in the topical mydriatics group but contracted during surgery. There was no perceived difference with regards to glare, pain or discomfort between the treatments. The surgeon graded intracameral mydriatics eyes as easier to operate on. CONCLUSION: Both topical mydriatics and intracameral mydriatics give satisfactory mydriasis for RLE, but pupil constriction and iris billowing are more pronounced with topical mydriatics. PMID- 23981527 TI - Doppler flowmetry as a tool of predictive, preventive and personalised dentistry. AB - Periodontal lesions are considered a major problem in the global burden of oral diseases due to their high frequency and negative impact on quality of life. Periodontal inflammation is accomplished by a breakdown of microcirculatory function. Early detection of gingival microvessel dysfunction helps diagnose and prevent the progression of initial periodontal pathology. Doppler flowmetry is a useful tool in the diagnosis, monitoring, prognosis and management of periodontal patients which allows access not only of gingival blood flow but also of pulpal microcirculation. Doppler flowmeters might help to realise the ultimate target of predictive, preventive and personalised periodontology tailored with respect to the particular patient. This article highlights the main working principles of laser Doppler flowmeters and the ultrasonic Doppler flowmeters. The advances in blood flow measurement by ultrasonic flowmetry are discussed. PMID- 23981529 TI - Synthesis and antiproliferative evaluation of novel benzoimidazole-contained oxazole-bridged analogs of combretastatin A-4. AB - A series of novel oxazole-bridged analogs of combretastatin A-4 bearing a benzo[d]-imidazole as B ring were synthesized and evaluated for antiproliferative activities against five human cancer cell lines. Among all the synthesized compounds, the N-unsubstituted benzoimidazole analog 5 and the analogs 6b, 7a and 7b with a small hydrophobic group on nitrogen atom of benzoimidazole ring were identified as the most potent inhibitors of tumor cell growth with IC50 values at nanomolar levels (5, IC50=8.4 nM, HT29; 6b, 7a, 7b, IC50=9.6 nM, 3.8 nM, 3.0 nM, A549). In a murine H22 tumor xenograft model, compound 5 exhibited significant antitumor activity. The binding mode of compound 5 in the colchicine binding site of tubulin was probed. PMID- 23981530 TI - The carbonate analogues of 5'-halogenated resiniferatoxin as TRPV1 ligands. AB - A series of carbonate analogues of 5'-halogenated RTX have been investigated in order to examine the effect of the carbonate group as a linker and the role of halogens in the reversal of activity from agonism to antagonism for rat and human TRPV1 heterologously expressed in Chinese hamster ovary cells. The carbonate analogues showed similar activities to the corresponding RTX derivatives in rat TRPV1 but lower potency in human TRPV1. 5-Halogenation converted the agonists to partial agonists or full antagonists and the extent of antagonism reflected the order of I>Br>Cl>F, with a somewhat greater extent of antagonism for the derivatives of the 4-amino RTX surrogates compared to the corresponding derivatives of RTX itself. The carbonate analogues of I-RTX (60) and 5-bromo-4 amino-RTX (66) were potent and full antagonists with Ki(ant)=2.23 and 2.46 nM, respectively, for rat TRPV1, which were ca. 5-fold more potent than I-RTX (2) under our conditions. The conformational analysis of the I-RTX-carbonate (60) indicated that its bent conformation was similar to that of I-RTX, consistent with compound 60 and I-RTX showing comparable potent antagonism. PMID- 23981531 TI - DNA binding and cytotoxicity of copper (II) imidazole terpyridine complexes: role of oxyanion, hydrogen bonding and pi-pi interaction. AB - Mononuclear complexes [Cu(Itpy)X(H2O)]X (Itpy--imidazole terpyridine, X--NO3 1 and X--ClO4 2) have been synthesized and characterized. Single crystal X-ray diffraction of complex 1 shows distorted octahedral geometry around the copper (II) ion. Presence of multiple hydrogen bonding network in the molecule results in anti-parallel stacking of the molecule. Both the complexes show dual mode of binding to DNA. Both the complexes have been found to bring about DNA cleavage in the presence of H2O2 and show potent cytotoxicity towards lung carcinoma cell line. The ability of the two complexes to induce apoptosis has been investigated by using combination of nuclear stains. FACS analysis shows that both the complexes bring about cell cycle arrest at 2.5 MUM concentration. PMID- 23981532 TI - Substituted 2-hydroxy-N-(arylalkyl)benzamides induce apoptosis in cancer cell lines. AB - Variously substituted 2-hydroxy-N-(arylalkyl)benzamides were prepared and screened for antiproliferative and cytotoxic activity in cancer cell lines in vitro. Five compounds, out of 33 showed single-digit micromolar IC50 values against several human cancer cell lines. One of the most potent compounds N-((R) 1-(4-chlorophenylcarbamoyl)-2-phenylethyl)-5-chloro-2-hydroxybenzamide (6k) reduced proliferation and induced apoptosis in the melanoma cell line G361 in a dose-dependent manner, as shown by decrease in 5-bromo-2'-deoxyuridine incorporation and increase in several apoptotic markers, including subdiploid population increase, activation of caspases and site-specific poly-(ADP ribose)polymerase (PARP) cleavage. PMID- 23981533 TI - Numerical Surrogates for Human Observers in Myocardial Motion Evaluation From SPECT Images. AB - In medical imaging, the gold standard for image-quality assessment is a task based approach in which one evaluates human observer performance for a given diagnostic task (e.g., detection of a myocardial perfusion or motion defect). To facilitate practical task-based image-quality assessment, model observers are needed as approximate surrogates for human observers. In cardiac-gated SPECT imaging, diagnosis relies on evaluation of the myocardial motion as well as perfusion. Model observers for the perfusion-defect detection task have been studied previously, but little effort has been devoted toward development of a model observer for cardiac-motion defect detection. In this work, we describe two model observers for predicting human observer performance in detection of cardiac motion defects. Both proposed methods rely on motion features extracted using previously reported deformable mesh model for myocardium motion estimation. The first method is based on a Hotelling linear discriminant that is similar in concept to that used commonly for perfusion-defect detection. In the second method, based on relevance vector machines (RVM) for regression, we compute average human observer performance by first directly predicting individual human observer scores, and then using multi reader receiver operating characteristic analysis. Our results suggest that the proposed RVM model observer can predict human observer performance accurately, while the new Hotelling motion-defect detector is somewhat less effective. PMID- 23981534 TI - Contextual action recognition and target localization with an active allocation of attention on a humanoid robot. AB - Exploratory gaze movements are fundamental for gathering the most relevant information regarding the partner during social interactions. Inspired by the cognitive mechanisms underlying human social behaviour, we have designed and implemented a system for a dynamic attention allocation which is able to actively control gaze movements during a visual action recognition task exploiting its own action execution predictions. Our humanoid robot is able, during the observation of a partner's reaching movement, to contextually estimate the goal position of the partner's hand and the location in space of the candidate targets. This is done while actively gazing around the environment, with the purpose of optimizing the gathering of information relevant for the task. Experimental results on a simulated environment show that active gaze control, based on the internal simulation of actions, provides a relevant advantage with respect to other action perception approaches, both in terms of estimation precision and of time required to recognize an action. Moreover, our model reproduces and extends some experimental results on human attention during an action perception. PMID- 23981535 TI - Origin, lineage and function of cerebellar glia. AB - The glial cells of the cerebellum, and particularly astrocytes and oligodendrocytes, are characterized by a remarkable phenotypic variety, in which highly peculiar morphological features are associated with specific functional features, unique among the glial cells of the entire CNS. Here, we provide a critical report about the present knowledge of the development of cerebellar glia, including lineage relationships between cerebellar neurons, astrocytes and oligodendrocytes, the origins and the genesis of the repertoire of glial types, and the processes underlying their acquisition of mature morphological and functional traits. In parallel, we describe and discuss some fundamental roles played by specific categories of glial cells during cerebellar development. In particular, we propose that Bergmann glia exerts a crucial scaffolding activity that, together with the organizing function of Purkinje cells, is necessary to achieve the normal pattern of foliation and layering of the cerebellar cortex. Moreover, we discuss some of the functional tasks of cerebellar astrocytes and oligodendrocytes that are distinctive of cerebellar glia throughout the CNS. Notably, we report about the regulation of synaptic signalling in the molecular and granular layer mediated by Bergmann glia and parenchymal astrocytes, and the functional interaction between oligodendrocyte precursor cells and neurons. On the whole, this review provides an extensive overview of the available literature and some novel insights about the origin and differentiation of the variety of cerebellar glial cells and their function in the developing and mature cerebellum. PMID- 23981536 TI - Which outcome measures should be utilized to determine readiness to play after ACL reconstruction? AB - CLINICAL SCENARIO: Anterior cruciate ligament (ACL) injuries are associated with a lengthy recovery time, decreased performance, and an increased rate of reinjury. To improve performance of the injured knee, affected athletes often undergo surgical reconstruction and rehabilitation. Determining when an athlete is ready to safely return to play (RTP), however, can be challenging for clinicians. Although various outcome measures have been recommended, their ability to predict a safe RTP is questionable. FOCUSED CLINICAL QUESTION: Which outcome measures should be used to determine readiness to return to play after ACL reconstruction? PMID- 23981537 TI - Metabolic features of the cell danger response. AB - The cell danger response (CDR) is the evolutionarily conserved metabolic response that protects cells and hosts from harm. It is triggered by encounters with chemical, physical, or biological threats that exceed the cellular capacity for homeostasis. The resulting metabolic mismatch between available resources and functional capacity produces a cascade of changes in cellular electron flow, oxygen consumption, redox, membrane fluidity, lipid dynamics, bioenergetics, carbon and sulfur resource allocation, protein folding and aggregation, vitamin availability, metal homeostasis, indole, pterin, 1-carbon and polyamine metabolism, and polymer formation. The first wave of danger signals consists of the release of metabolic intermediates like ATP and ADP, Krebs cycle intermediates, oxygen, and reactive oxygen species (ROS), and is sustained by purinergic signaling. After the danger has been eliminated or neutralized, a choreographed sequence of anti-inflammatory and regenerative pathways is activated to reverse the CDR and to heal. When the CDR persists abnormally, whole body metabolism and the gut microbiome are disturbed, the collective performance of multiple organ systems is impaired, behavior is changed, and chronic disease results. Metabolic memory of past stress encounters is stored in the form of altered mitochondrial and cellular macromolecule content, resulting in an increase in functional reserve capacity through a process known as mitocellular hormesis. The systemic form of the CDR, and its magnified form, the purinergic life-threat response (PLTR), are under direct control by ancient pathways in the brain that are ultimately coordinated by centers in the brainstem. Chemosensory integration of whole body metabolism occurs in the brainstem and is a prerequisite for normal brain, motor, vestibular, sensory, social, and speech development. An understanding of the CDR permits us to reframe old concepts of pathogenesis for a broad array of chronic, developmental, autoimmune, and degenerative disorders. These disorders include autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), asthma, atopy, gluten and many other food and chemical sensitivity syndromes, emphysema, Tourette's syndrome, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), epilepsy, suicidal ideation, organ transplant biology, diabetes, kidney, liver, and heart disease, cancer, Alzheimer and Parkinson disease, and autoimmune disorders like lupus, rheumatoid arthritis, multiple sclerosis, and primary sclerosing cholangitis. PMID- 23981538 TI - A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways. AB - BACKGROUND: Changing perspectives on the natural history of celiac disease (CD), new serology and genetic tests, and amended histological criteria for diagnosis cast doubt on past prevalence estimates for CD. We set out to establish a more accurate prevalence estimate for CD using a novel serogenetic approach. METHODS: The human leukocyte antigen (HLA)-DQ genotype was determined in 356 patients with 'biopsy-confirmed' CD, and in two age-stratified, randomly selected community cohorts of 1,390 women and 1,158 men. Sera were screened for CD-specific serology. RESULTS: Only five 'biopsy-confirmed' patients with CD did not possess the susceptibility alleles HLA-DQ2.5, DQ8, or DQ2.2, and four of these were misdiagnoses. HLA-DQ2.5, DQ8, or DQ2.2 was present in 56% of all women and men in the community cohorts. Transglutaminase (TG)-2 IgA and composite TG2/deamidated gliadin peptide (DGP) IgA/IgG were abnormal in 4.6% and 5.6%, respectively, of the community women and 6.9% and 6.9%, respectively, of the community men, but in the screen-positive group, only 71% and 75%, respectively, of women and 65% and 63%, respectively, of men possessed HLA-DQ2.5, DQ8, or DQ2.2. Medical review was possible for 41% of seropositive women and 50% of seropositive men, and led to biopsy-confirmed CD in 10 women (0.7%) and 6 men (0.5%), but based on relative risk for HLA-DQ2.5, DQ8, or DQ2.2 in all TG2 IgA or TG2/DGP IgA/IgG screen positive subjects, CD affected 1.3% or 1.9%, respectively, of females and 1.3% or 1.2%, respectively, of men. Serogenetic data from these community cohorts indicated that testing screen positives for HLA-DQ, or carrying out HLA-DQ and further serology, could have reduced unnecessary gastroscopies due to false positive serology by at least 40% and by over 70%, respectively. CONCLUSIONS: Screening with TG2 IgA serology and requiring biopsy confirmation caused the community prevalence of CD to be substantially underestimated. Testing for HLA-DQ genes and confirmatory serology could reduce the numbers of unnecessary gastroscopies. PMID- 23981539 TI - Human platelet lysate stimulates high-passage and senescent human multipotent mesenchymal stromal cell growth and rejuvenation in vitro. AB - BACKGROUND AIMS: Multipotent mesenchymal stromal cells (MSCs) are clinically useful because of their immunomodulatory and regenerative properties, but MSC therapies are limited by the loss of self-renewal and cell plasticity associated with ex vivo expansion culture and, on transplantation, increased immunogenicity from xenogen exposure during culture. Recently, pooled human platelet lysate (hPL) has been used as a culture supplement to promote MSC growth; however, the effects of hPL on MSCs after fetal bovine serum (FBS) exposure remain unknown. METHODS: MSCs were cultured in medium containing FBS or hPL for up to 16 passages, and cell size, doubling time and immunophenotype were determined. MSC senescence was assessed by means of a fluorometric assay for endogenous beta galactosidase expression. MSCs cultured with FBS for different numbers of passages were switched to hPL conditions to evaluate the ability of hPL to "rescue" the proliferative capacity of MSCs. RESULTS: hPL culture resulted in more rapid cell proliferation at earlier passages (passage 5 or earlier) than remove FBS; by day 4, hPL (5%) yielded an MSC doubling time of 1.28 days compared with 1.52 days in 16% FBS. MSCs cultured first in FBS and switched to hPL proliferated more and demonstrated less beta-galactosidase production and smaller cell sizes than remove MSCs continuously propagated in FBS. CONCLUSIONS: hPL enables rapid expansion of MSCs without adversely affecting immunophenotype. hPL culture of aged and senescent MSCs demonstrated cellular rejuvenation, reflected by decreased doubling time and smaller cell size. These results suggest that expansion of MSCs in hPL after FBS exposure can enhance cell phenotype and proliferative capacity. PMID- 23981540 TI - Chronic kidney disease of uncertain aetiology: prevalence and causative factors in a developing country. AB - BACKGROUND: This study describes chronic kidney disease of uncertain aetiology (CKDu), which cannot be attributed to diabetes, hypertension or other known aetiologies, that has emerged in the North Central region of Sri Lanka. METHODS: A cross-sectional study was conducted, to determine the prevalence of and risk factors for CKDu. Arsenic, cadmium, lead, selenium, pesticides and other elements were analysed in biological samples from individuals with CKDu and compared with age- and sex-matched controls in the endemic and non-endemic areas. Food, water, soil and agrochemicals from both areas were analysed for heavy metals. RESULTS: The age-standardised prevalence of CKDu was 12.9% (95% confidence interval [CI] = 11.5% to 14.4%) in males and 16.9% (95% CI = 15.5% to 18.3%) in females. Severe stages of CKDu were more frequent in males (stage 3: males versus females = 23.2% versus 7.4%; stage 4: males versus females = 22.0% versus 7.3%; P < 0.001). The risk was increased in individuals aged >39 years and those who farmed (chena cultivation) (OR [odds ratio] = 1.926, 95% CI = 1.561 to 2.376 and OR = 1.195, 95% CI = 1.007 to 1.418 respectively, P < 0.05). The risk was reduced in individuals who were male or who engaged in paddy cultivation (OR = 0.745, 95% CI = 0.562 to 0.988 and OR = 0.732, 95% CI = 0.542 to 0.988 respectively, P < 0.05). The mean concentration of cadmium in urine was significantly higher in those with CKDu (1.039 MUg/g) compared with controls in the endemic and non-endemic areas (0.646 MUg/g, P < 0.001 and 0.345 MUg/g, P < 0.05) respectively. Urine cadmium sensitivity and specificity were 70% and 68.3% respectively (area under the receiver operating characteristic curve = 0.682, 95% CI = 0.61 to 0.75, cut-off value >=0.397 MUg/g). A significant dose-effect relationship was seen between urine cadmium concentration and CKDu stage (P < 0.05). Urine cadmium and arsenic concentrations in individuals with CKDu were at levels known to cause kidney damage. Food items from the endemic area contained cadmium and lead above reference levels. Serum selenium was <90 MUg/l in 63% of those with CKDu and pesticides residues were above reference levels in 31.6% of those with CKDu. CONCLUSIONS: These results indicate chronic exposure of people in the endemic area to low levels of cadmium through the food chain and also to pesticides. Significantly higher urinary excretion of cadmium in individuals with CKDu, and the dose-effect relationship between urine cadmium concentration and CKDu stages suggest that cadmium exposure is a risk factor for the pathogensis of CKDu. Deficiency of selenium and genetic susceptibility seen in individuals with CKDu suggest that they may be predisposing factors for the development of CKDu. PMID- 23981541 TI - Intravenous thrombolysis for acute ischemic stroke occurring during hospitalization for transient ischemic attack. AB - BACKGROUND: There are limited data regarding the use of intravenous thrombolysis in patients who experienced acute ischemic symptoms during their hospitalization for prior transient ischemic attack. AIM: We sought to prospectively evaluate the safety and efficacy of intravenous thrombolysis for the treatment of acute ischemic stroke occurring during hospitalization for transient ischemic attack in an international, multicenter study. METHODS: Consecutive patients with acute ischemic stroke that occurred during hospitalization for prior transient ischemic attack were treated with intravenous thrombolysis in five tertiary-care stroke centers. Early arterial recanalization was determined by transcranial Doppler at the end of recombinant tissue plasminogen activator infusion using previously validated criteria. Symptomatic intracranial hemorrhage complicating intravenous thrombolysis was evaluated using the National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study definition. Functional independence at three-months was defined as Modified Rankin Scale score of 0-2. RESULTS: Systemic recombinant tissue plasminogen activator infusion (median onset-to-treatment time 70 mins, interquartile range 50-150) was given in 25 consecutive patients (mean age 66 +/- 10 years) who developed acute ischemic stroke symptoms (median National Institutes of Health Stroke Scale score 10 points; interquartile range 8-14) during hospitalization for prior transient ischemic attack (median ABCD(2) score 5 points; median time-to-symptom recurrence 24 h, interquartile range 24-48). No symptomatic intracranial hemorrhage (0%; 95% confidence interval 0-12%) was documented. Early complete recanalization occurred in 64% of patients (95% confidence interval 44-80%), and 84% (95% confidence interval 65-94%) achieved three-month functional independence. The rate of three month functional independence was higher in patients treated with intravenous tissue plasminogen activator within 90 mins from symptom onset compared with those with onset-to-treatment time>90 mins (81% vs. 33%; P = 0.031). CONCLUSIONS: Intravenous thrombolysis for symptoms of acute ischemic stroke occurring after hospitalization for transient ischemic attack appears to be safe. These pilot data support resetting the clock if new symptoms recur shortly after transient ischemic attack. PMID- 23981542 TI - Resveratrol attenuates the release of inflammatory cytokines from human bronchial smooth muscle cells exposed to lipoteichoic acid in chronic obstructive pulmonary disease. AB - During bacterial infections, pathogen-associated molecular patterns (PAMPs) induce cytokine/chemokine release in immunoactive cells. This increases corticosteroid-resistant airway inflammation in chronic obstructive pulmonary disease (COPD) and leads to exacerbations. Anti-inflammatory therapies other than corticosteroids are required and resveratrol is currently under discussion. Resveratrol is an activator of sirtuins, which are class III histone deacetylases (HDACs). We suggested that human airway smooth muscle cells (HASMCs) release COPD associated cytokines/chemokines in response to lipoteichoic acid (LTA), a major PAMP of gram-positive bacteria and that resveratrol is superior to the corticosteroid dexamethasone in suppressing these cytokines/chemokines. Cultivated HASMCs of patients with COPD were pre-incubated with resveratrol or dexamethasone before stimulation with LTA. CCL2, GM-CSF, IL-6 and IL-8 were analysed in culture supernatants by enzyme-linked immunosorbent assay. Drug effects were investigated in the absence and presence of trichostatin A (TSA), an inhibitor of class I/II HDACs, and EX527, an inhibitor of the sirtuin SIRT1. LTA induced robust cytokine/chemokine release. Resveratrol was superior to dexamethasone in reducing CCL-2, IL-6 and IL-8 in LTA-exposed HASMCs of patients with COPD. Both drugs were equally effective in reducing GM-CSF. Resveratrol effects were partially reversed by EX527 but not by TSA. Dexamethasone effects were partially reversed by TSA but not by EX527. We conclude that HASMCs contribute to the increase in airway inflammation in COPD exacerbations caused by gram-positive bacterial infections. Our data suggest resveratrol as an alternative anti-inflammatory therapy in infection-induced COPD exacerbations. Resveratrol and corticosteroids suppress cytokine/chemokine expression through activation of SIRT1 or interaction with class I/II HDACs, respectively, in HASMCs. PMID- 23981543 TI - Neural network based diagonal decoupling control of powered wheelchair systems. AB - This paper proposes an advanced diagonal decoupling control method for powered wheelchair systems. This control method is based on a combination of the systematic diagonalization technique and the neural network control design. As such, this control method reduces coupling effects on a multivariable system, leading to independent control design procedures. Using an obtained dynamic model, the problem of the plant's Jacobian calculation is eliminated in a neural network control design. The effectiveness of the proposed control method is verified in a real-time implementation on a powered wheelchair system. The obtained results confirm that robustness and desired performance of the overall system are guaranteed, even under parameter uncertainty effects. PMID- 23981544 TI - Comparison of Mono-, Bi-, and Tripolar Configurations for Stimulation and Recording With an Interfascicular Interface. AB - Previous studies have indicated that electrodes placed between fascicles can provide nerve recruitment with high topological selectivity if the areas of interest in the nerve are separated with passive elements. In this study, we investigated if this separation of fascicles also can provide topologically selective nerve recordings and compared the performance of mono-, bi-, and tripolar configurations for stimulation and recording with an intra-neural interface. The interface was implanted in the sciatic nerve of 10 rabbits and achieved a median selectivity of S=0.98-0.99 for all stimulation configurations, while recording selectivity configurations was in the range of S=0.70-0.80 with the monopolar configuration providing the lowest and the average reference configuration the highest recording selectivity. Interfascicular electrodes could provide an interesting addition to the bulk of peripheral nerve interfaces available for neural prosthetic devices. The separation of the nerve into chambers by the passive elements of the electrode could ensure a higher selectivity than comparable cuff electrodes and the intra-neural location could provide an option of targeting mainly central fascicles. Further studies are, however, still required to develop biocompatible electrodes and test their stability and safety in chronic experiments. PMID- 23981545 TI - Salmonella mycotic thoracoabdominal aortic aneurysm associated with chronic lymphocytic leukemia. AB - Non-typhoidal Salmonella infections typically cause self-limiting gastroenteritis. However, extraintestinal focal infections, including mycotic aneurysms of the aorta, can also occur. We present the case of a 71-year-old man with chronic lymphocytic leukemia (CLL) and a large type V thoracoabdominal mycotic aneurysm infected with Salmonella enteritidis, complicated by thoracolumbar spondylodiscitis, paravertebral collections, and epidural abscess. This is the first report of Salmonella aortitis in the setting of CLL, and the unusual extent of local infective invasion seen here with Salmonella enteritidis infection raises a suspicion of CLL-related immunosuppression as a direct predisposing factor. This case illustrates the need to consider the possibility of an immune defect, even in CLL patients with normal leukocyte counts. The underlying mechanisms are unclear, but are likely to involve defects in cell mediated immunity, thought to be of particular importance in invasive infections with intracellular pathogens such as Salmonella spp. PMID- 23981546 TI - Challenges in implementing The Institute of Medicine systematic review standards. AB - In 2011, The Institute of Medicine (IOM) identified a set of methodological standards to improve the validity, trustworthiness, and usefulness of systematic reviews. These standards, based on a mix of theoretical principles, empiric evidence, and commonly considered best practices, set a high bar for authors of systematic reviews.Based on over 15 years of experience conducting systematic reviews, the Agency for Healthcare Research and Quality Evidence-based Practice Center (EPC) program has examined the EPC's adherence and agreement with the IOM standards. Even such a large program, with infrastructure and resource support, found challenges in implementing all of the IOM standards. We summarize some of the challenges in implementing the IOM standards as a whole and suggest some considerations for individual or smaller research groups needing to prioritize which standards to adhere to, yet still achieve the highest quality and utility possible for their systematic reviews. PMID- 23981547 TI - Changes in geographic variation in the uptake of cervical cancer screening in Taiwan: possible effects of "leadership style factor"? AB - OBJECTIVES: Wennberg proposed the "practice style factor" to explain the large variations in the use of medical care. As a corollary, we propose the "leadership style factor" of the director of the city/county bureau of public health to explain changes in geographic variation in the uptake of cervical cancer screening. METHODS: We first calculated the triennial Pap smear rates for women aged 30-69 years from 1997 through 2010 for each city/county in Taiwan and the rate difference and rate ratio between the highest and the lowest city/county to illustrate the geographic variation in the uptake of cervical cancer screening. We then created an expert panel to conduct a hypothesis generation process to examine the possible effects of "leadership style factors" in explaining the changes. RESULTS: The Pap smear rate in Taiwan as a whole was 35% in 1997 and increased to 56% in 2001, and was then stable until 2010 (55%). In 2002, the geographic variation in the Pap smear rate was the smallest, ranging from 49% in Penghu County to 63% in I-lan County, with a rate ratio of 1.28. Unfortunately, the rate ratio increased to 1.49 in 2010, the rate being lowest in Penghu County (42%) and highest in Tainan City (63%). We identified four cities/counties with unique patterns of change in Pap smear rates, which were highly associated with the leadership style of the director of the city/county bureau of public health. CONCLUSIONS: Despite the launch of an organized cancer screening program in Taiwan, geographic variation in the uptake of cervical cancer screening still exists and has increased during the past decade. The "leadership style factor" of the director of the city/county bureau of public health might play a plausible role in explaining the pattern of change in geographic variation in the use of cervical cancer screening in Taiwan. PMID- 23981548 TI - Relationship between ambient fine particles and ventricular repolarization changes and heart rate variability of elderly people with heart disease in Beijing, China. AB - OBJECTIVE: To explore the effects of particulate matters less than 2.5 MUm in aerodynamic diameter (PM2.5) on heart repolarization/depolarization and heart rate variability (HRV). METHODS: We conducted a panel study for elderly subjects with heart disease in Beijing from 2007 to 2008. PM2.5 was measured at a fixed station for 20 h continuously each day while electrocardiogram (ECG) indexes of 42 subjects were also recorded repeatedly. Meteorological data was obtained from the China Meteorological Data Sharing Service System. A mixed linear regression model was used to estimate the associations between PM2.5 and the ECG indexes. The model was adjusted for age, body mass index, sex, day of the week and meteorology. RESULTS: Significant adverse effects of PM2.5 on ECG indexes reflecting HRV were observed statistically and the strongest effect of PM2.5 on HRV was on lag 1 day in our study. However, there were no associations between PM2.5 and ECG indexes reflecting heart repolarization/depolarization. Additionally, the effects of PM2.5 on subjects with hypertension were larger than on the subjects without hypertension. CONCLUSION: This study showed ambient PM2.5 could affect cardiac autonomic function of the elderly people with heart disease, and subjects with hypertension appeared to be more susceptive to the autonomic dysfunction induced by PM2.5. PMID- 23981549 TI - Application of statistical distribution of PM10 concentration in air quality management in 5 representative cities of China. AB - OBJECTIVE: To estimate the frequency of daily average PM10 concentrations exceeding the air quality standard (AQS) and the reduction of particulate matter emission to meet the AQS from the statistical properties (probability density functions) of air pollutant concentration. METHODS: The daily PM10 average concentration in Beijing, Shanghai, Guangzhou, Wuhan, and Xi'an was measured from 1 January 2004 to 31 December 2008. The PM10 concentration distribution was simulated by using the lognormal, Weibull and Gamma distributions and the best statistical distribution of PM10 concentration in the 5 cities was detected using to the maximum likelihood method. RESULTS: The daily PM10 average concentration in the 5 cities was fitted using the lognormal distribution. The exceeding duration was predicted, and the estimated PM10 emission source reductions in the 5 cities need to be 56.58%, 93.40%, 80.17%, 82.40%, and 79.80%, respectively to meet the AQS. CONCLUSION: Air pollutant concentration can be predicted by using the PM10 concentration distribution, which can be further applied in air quality management and related policy making. PMID- 23981550 TI - Impact of heat wave in 2005 on mortality in Guangzhou, China. AB - OBJECTIVE: To assess the impact of the heat wave in 2005 on mortality among the residents in Guangzhou and to identify susceptible subpopulations in Guangzhou, China. METHODS: The data of daily number of deaths and meteorological measures from 2003 to 2006 in Guangzhou were used in this study. Heat wave was defined as ?7 consecutive days with daily maximum temperature above 35.0 degrees C and daily mean temperature above the 97th percentile during the study period. The excess deaths and rate ratio (RR) of mortality in the case period compared with the reference period in the same summer were calculated. RESULTS: During the study period, only one heat wave in 2005 was identified and the total number of excess deaths was 145 with an average of 12 deaths per day. The effect of the heat wave on non-accidental mortality (RR=1.23, 95% CI: 1.11-1.37) was found with statistically significant difference. Also, greater effects were observed for cardiovascular mortality (RR=1.34, 95% CI: 1.13-1.59) and respiratory mortality (RR=1.31, 95% CI: 1.02-1.69). Females, the elderly and people with lower socioeconomic status were at significantly higher risk of heat wave-associated mortality. CONCLUSION: The 2005 heat wave had a substantial impact on mortality among the residents in Guangzhou, particularly among some susceptible subpopulations. The findings from the present study may provide scientific evidences to develop relevant public health policies and prevention measures aimed at reduction of preventable mortality from heat waves. PMID- 23981551 TI - Evaluation of the protein requirement in Chinese young adults using the indicator amino acid oxidation technique. AB - OBJECTIVE: To accurately calculate the protein requirements in Chinese young adults using the indicator amino acid oxidation technique. METHODS: Nine women and ten men received a restricted daily level of protein intake (0.75, 0.82, 0.89, 0.97, and 1.05 g/kg), along with L-[1-13C]-leucine. Subjects' protein requirement was determined by a biphasic linear regression crossover analysis of F13CO2 data. In doing so, a breakpoint at the minimal rate of appearance of 13CO2 expiration specific to each level of dietary protein was identified. This trial was registered with the Chinese clinical trial registry as ChiCTR-ONC-11001407. RESULTS: The Estimated Average Requirement (EAR) and the Recommended Nutrient Intake (RNI) of protein for healthy Chinese young adults were determined to be 0.87 and 0.98 g/(kg*d), respectively, based on the indicator amino acid oxidation technique. CONCLUSION: The EAR and RNI of mixed protein are 5% and 16% that are lower than the current proposed EAR and RNI (0.92 and 1.16 g/(kg*d), respectively), as determined by the nitrogen balance method. The respective EAR and RNI recommendations of 0.87 and 0.98 g/(kg*d) of mixed protein are estimated to be reasonable and suitable for Chinese young adults. PMID- 23981552 TI - Immunotoxicological evaluation of wheat genetically modified with TaDREB4 gene on BALB/c mice. AB - OBJECTIVE: To evaluate the immunotoxicological effects of genetically modified wheat with TaDREB4 gene in female BALB/c mice. METHODS: Female mice weighing 18 22 g were divided into five groups (10 mice/group), which were set as negative control group, common wheat group, parental wheat group, genetically modified wheat group and cyclophosphamide positive control group, respectively. Mice in negative control group and positive control group were fed with AIN93G diet, mice in common wheat group, non-genetically modified parental wheat group and genetically modified wheat group were fed with feedstuffs added corresponding wheat (the proportion is 76%) for 30 days, then body weight, absolute and relative weight of spleen and thymus, white blood cell count, histological examination of immune organ, peripheral blood lymphocytes phenotyping, serum cytokine, serum immunoglobulin, antibody plaque-forming cell, serum half hemolysis value, mitogen-induced splenocyte proliferation, delayed-type hypersensitivity reaction and phagocytic activities of phagocytes were detected. RESULTS: No immunotoxicological effects related to the consumption of the genetically modified wheat were observed in BALB/c mice when compared with parental wheat group, common wheat group and negative control group. CONCLUSION: From the immunotoxicological point of view, results from this study demonstrate that genetically modified wheat with TaDREB4 gene is as safe as the parental wheat. PMID- 23981553 TI - Short-term effects of air pollution on mortality in a heavily polluted Chinese city. PMID- 23981554 TI - Effect of different calcium supplements on bone metabolism in rats. PMID- 23981555 TI - A subchronic toxicity study on Lactobacillus fermentum GM 090 in rat. PMID- 23981556 TI - Effect of hypertonic versus isotonic saline resuscitation on heme oxygenase-1 expression in visceral organs following hemorrhagic shock in rats. AB - To compare the early effects of hypertonic and isotonic saline resuscitation on heme oxygenase-1 (HO-1) expression in organs of rats with hemorrhagic shock. Rats were randomly divided into hypertonic saline resuscitation (HTS), normal saline resuscitation (NS) and sham groups. HO-1 mRNA, protein expression and apoptosis were evaluated in organs. In the HTS group, significant difference was noted in HO-1 protein in small intestinal mucosa and liver compared with the NS and sham groups, and in HO-1 mRNA in liver and kidney compared with the sham group. The apoptosis of small intestinal mucosa, liver, heart, and lung was significantly lower in the HTS group than that in the NS group. In this study, small volume resuscitation with HTS can efficiently up-regulate the expression level of HO-1 in small intestinal mucosa and liver, which may be one of the mechanisms alleviating organ damage. PMID- 23981557 TI - Lack of association between genetic polymorphisms affecting autonomic activity and coronary artery spasm. PMID- 23981559 TI - Characteristics of callers accessing the tobacco cessation quitline in mainland China. PMID- 23981558 TI - Safety observation study on haemophilus influenza type B conjugate vaccines injected at different sites in Chinese infants. AB - In the present study, the safety of Haemophilus influenza type b conjugate vaccines inoculated in the upper arm deltoid and vastus lateralis muscle was evaluated. 680 infants aged 2-5 months and 6-12 months were selected to be the research subjects in whom the Hib conjugate vaccines were inoculated by injection in the upper arm deltoid and vastus lateralis muscle, respectively. The safety analysis indicated that there were no statistic differences in the incidence rates of adverse reactions when the Hib conjugate vaccines were inoculated at different sites. So we concluded that the safety of inoculation injection of Hib conjugate vaccines in vastus lateralis muscle was the same as that inoculated in the upper arm deltoid. PMID- 23981560 TI - Equity study in health workforce on tuberculosis control in China: a nationwide evaluation. PMID- 23981561 TI - Efficient worm-like locomotion: slip and control of soft-bodied peristaltic robots. AB - In this work, we present a dynamic simulation of an earthworm-like robot moving in a pipe with radially symmetric Coulomb friction contact. Under these conditions, peristaltic locomotion is efficient if slip is minimized. We characterize ways to reduce slip-related losses in a constant-radius pipe. Using these principles, we can design controllers that can navigate pipes even with a narrowing in radius. We propose a stable heteroclinic channel controller that takes advantage of contact force feedback on each segment. In an example narrowing pipe, this controller loses 40% less energy to slip compared to the best-fit sine wave controller. The peristaltic locomotion with feedback also has greater speed and more consistent forward progress PMID- 23981562 TI - Real-time posture reconstruction for Microsoft Kinect. AB - The recent advancement of motion recognition using Microsoft Kinect stimulates many new ideas in motion capture and virtual reality applications. Utilizing a pattern recognition algorithm, Kinect can determine the positions of different body parts from the user. However, due to the use of a single-depth camera, recognition accuracy drops significantly when the parts are occluded. This hugely limits the usability of applications that involve interaction with external objects, such as sport training or exercising systems. The problem becomes more critical when Kinect incorrectly perceives body parts. This is because applications have limited information about the recognition correctness, and using those parts to synthesize body postures would result in serious visual artifacts. In this paper, we propose a new method to reconstruct valid movement from incomplete and noisy postures captured by Kinect. We first design a set of measurements that objectively evaluates the degree of reliability on each tracked body part. By incorporating the reliability estimation into a motion database query during run time, we obtain a set of similar postures that are kinematically valid. These postures are used to construct a latent space, which is known as the natural posture space in our system, with local principle component analysis. We finally apply frame-based optimization in the space to synthesize a new posture that closely resembles the true user posture while satisfying kinematic constraints. Experimental results show that our method can significantly improve the quality of the recognized posture under severely occluded environments, such as a person exercising with a basketball or moving in a small room. PMID- 23981563 TI - Natural and artificial radionuclide activity concentrations in surface sediments of Izmit Bay, Turkey. AB - Surface sediments from the north-eastern coast of the Marmara Sea, Turkey's most industrialized coastal region, were enriched with radioisotopes from the Chernobyl explosion in 1986. Caesium-137 in these sediments is also thought to originate from one former paper mill located nearby that used wood contaminated by Chernobyl explosion-originated (137)Cs for paper production. The average activity concentration of the (137)Cs was 21 Bq kg(-1), while naturally occurring radioisotopes, i.e. (40)K, (226)Ra, and (228)Ra, were 568, 18 and 24 Bq kg(-1), respectively, in surface sediments. The natural radionuclide activities reached their highest levels near petrochemical, phosphate and fertilizer processing facilities. Average (137)Cs activities were generally up to ten times higher than in Middle Eastern marine sediments and lower than those in Northern European sediments. PMID- 23981564 TI - Short and long term bystander effect induction by fathead minnows (Pimephales promelas, Rafinesque, 1820) injected with environmentally relevant whole body doses of 226Ra. AB - Bystander effect induction by fathead minnows injected with environmentally relevant doses of (226)Ra was investigated. Twenty four h and 6 months after injection with a single dose of 21, 210 or 2100 MUBq, fin tissue samples emitted a pro-apoptotic signal, which reduced the clonogenic survival of an apoptosis sensitive reporter cell line. Twenty four h and 10 weeks after injection explants from non-injected bystander fish, swum with the injected fish, also emitted a pro apoptotic signal. However 6 months after injection the bystander fish to 21 and 210 MUBq injected fish emitted an anti-apoptotic signal. This demonstrates that extremely low dose irradiation can have effects outside of the irradiated fish. This has implications for population and ecosystem responses to contamination. PMID- 23981566 TI - Participation in clinical supervision (PACS): an evaluation of student nurse clinical supervision facilitated by mental health service users. AB - This paper discusses an innovative learning approach in which people having experience of mental health services facilitated humanistic clinical supervision with groups of student nurses in the classroom. A four-day course of preparation for the role of supervisor is described and the results of subsequent clinical supervision sessions are analysed. Seven service users who had previous experience of teaching students in the classroom and fifty students on a Diploma/BSc in mental health nursing course participated in the project, which was evaluated through focus groups. The results indicated that the service user supervisors appreciated the skills they had gained on the course and felt that they were more appropriate than lecturers to facilitate clinical supervision sessions. Some students expressed initial uncertainty about the appropriateness of service users as supervisors but as changes to the pedagogical process of supervision were made and the supervisors gained more experience and confidence, students expressed greater satisfaction. The authors conclude that clinical supervision facilitated by service users who have preparation and continual support can add considerable value to the learning experience of student nurses. PMID- 23981565 TI - Therapeutic time window and dose dependence of xenon delivered via echogenic liposomes for neuroprotection in stroke. AB - AIMS: Neurologic impairment following ischemic injury complicates the quality of life for stroke survivors. Xenon (Xe) has favorable neuroprotective properties to modify stroke. Xe delivery is hampered by a lack of suitable administration strategies. We have developed Xe-containing echogenic liposomes (Xe-ELIP) for systemic Xe delivery. We investigated the time window for Xe-ELIP therapeutic effect and the most efficacious dose for neuroprotection. Molecular mechanisms for Xe neuroprotection were investigated. METHODS: Xenon-containing echogenic liposomes were created by a previously developed pressurization-freezing method. Following right middle cerebral artery occlusion (2 h), animals were treated with Xe-ELIP at 2, 3, or 5 h to determine time window of therapeutic effect. The neuroprotectant dosage for optimal effect was evaluated 3 h after stroke onset. Expression of brain-derived neurotrophic factor (BDNF), protein kinase B (Akt), and mitogen-activated protein kinases (MAPK) was determined. RESULTS: Xenon containing echogenic liposomes administration for up to 5 h after stroke onset reduced infract size. Treatment groups given 7 and 14 mg/kg of Xe-ELIP reduced infarct size. Behavioral outcomes corresponded to changes in infarct volume. Xe ELIP treatment reduced ischemic neuronal cell death via activation of both MAPK and Akt. Elevated BDNF expression was shown following Xe-ELIP delivery. CONCLUSION: This study demonstrates the therapeutic efficacy of Xe-ELIP administered within 5 h after stroke onset with an optimal dosage range of 7-14 mg/kg for maximal neuroprotection. PMID- 23981567 TI - Lower-extremity muscle activity during aquatic and land treadmill running at the same speeds. AB - CONTEXT: Muscle activation during aquatic treadmill (ATM) running has not been examined, despite similar investigations for other modes of aquatic locomotion and increased interest in ATM running. OBJECTIVES: The objectives of this study were to compare normalized (percentage of maximal voluntary contraction; %MVC), absolute duration (aDUR), and total (tACT) lower-extremity muscle activity during land treadmill (TM) and ATM running at the same speeds. DESIGN: Exploratory, quasi-experimental, crossover design. SETTING: Athletic training facility. PARTICIPANTS: 12 healthy recreational runners (age = 25.8 +/- 5 y, height = 178.4 +/- 8.2 cm, mass = 71.5 +/- 11.5 kg, running experience = 8.2 +/- 5.3 y) volunteered for participation. INTERVENTION: All participants performed TM and ATM running at 174.4, 201.2, and 228.0 m/min while surface electromyographic data were collected from the vastus medialis, rectus femoris, gastrocnemius, tibialis anterior, and biceps femoris. MAIN OUTCOME MEASURES: For each muscle, a 2 * 3 repeated-measures ANOVA was used to analyze the main effects and environment speed interaction (P <= .05) of each dependent variable: %MVC, aDUR, and tACT. RESULTS: Compared with TM, ATM elicited significantly reduced %MVC (-44.0%) but increased aDUR (+213.1%) and tACT (+41.9%) in the vastus medialis, increased %MVC (+48.7%) and aDUR (+128.1%) in the rectus femoris during swing phase, reduced %MVC (-26.9%) and tACT (-40.1%) in the gastrocnemius, increased aDUR (+33.1%) and tACT (+35.7%) in the tibialis anterior, and increased aDUR (+41.3%) and tACT (+29.2%) in the biceps femoris. At faster running speeds, there were significant increases in tibialis anterior %MVC (+8.6-15.2%) and tACT (+12.7-17.0%) and rectus femoris %MVC (12.1-26.6%; swing phase). CONCLUSION: No significant environment-speed interaction effects suggested that observed muscle-activity differences between ATM and TM were due to environmental variation, ie, buoyancy (presumed to decrease %MVC) and drag forces (presumed to increase aDUR and tACT) in the water. PMID- 23981568 TI - Fractalkine (CX3CL1) enhances hippocampal N-methyl-D-aspartate receptor (NMDAR) function via D-serine and adenosine receptor type A2 (A2AR) activity. AB - BACKGROUND: N-Methyl-D-aspartate receptors (NMDARs) play fundamental roles in basic brain functions such as excitatory neurotransmission and learning and memory processes. Their function is largely regulated by factors released by glial cells, including the coagonist d-serine. We investigated whether the activation of microglial CX3CR1 induces the release of factors that modulate NMDAR functions. METHODS: We recorded the NMDAR component of the field excitatory postsynaptic potentials (NMDA-fEPSPs) elicited in the CA1 stratum radiatum of mouse hippocampal slices by Shaffer collateral stimulation and evaluated D-serine content in the extracellular medium of glial primary cultures by mass spectrometry analysis. RESULTS: We demonstrated that CX3CL1 increases NMDA-fEPSPs by a mechanism involving the activity of the adenosine receptor type A2 (A2AR) and the release of the NMDAR coagonist D-serine. Specifically (1) the selective A2AR blocker 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4 triazolo[1,5-c]pyrimidine (SCH58261) and the genetic ablation of A2AR prevent CX3CL1 action while the A2AR agonist 5-(6-amino-2-(phenethylthio)-9H-purin-9-yl) N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide (VT7) mimics CX3CL1 effect, and (2) the selective blocking of the NMDAR glycine (and D-serine) site by 5,7 dicholorokynurenic acid (DCKA), the enzymatic degradation of D-serine by D-amino acid oxidase (DAAO) and the saturation of the coagonist site by D-serine, all block the CX3CL1 effect. In addition, mass spectrometry analysis demonstrates that stimulation of microglia and astrocytes with CX3CL1 or VT7 increases D serine release in the extracellular medium. CONCLUSIONS: CX3CL1 transiently potentiates NMDAR function though mechanisms involving A2AR activity and the release of D-serine. PMID- 23981570 TI - Aroma exposure time and aroma concentration in relation to satiation. AB - The present study investigated the effect of aroma exposure time and aroma concentration on ad libitum intake and subjective satiation. In a within-subject study, thirty-eight unrestrained, healthy female participants (age: 18-39 years; BMI: 18.5-26.0 kg/m2) were asked to consume tomato soup during lunchtime, until they felt comfortably full. Every 30 s, the participants consumed 10 g of a bland soup base while tomato soup aroma was delivered separately through the nose via a retronasal tube that was attached to an olfactometer. This gave the impression of consuming real tomato soup. For each sip, the aroma varied in exposure time (3 and 18 s) and concentration (5 * ), resulting in four different test conditions. Ad libitum food intake and appetite profile parameters were measured. A 9% lower food intake was observed when the participants were exposed to the condition with 18 s exposure time and a high concentration than when exposed to the other three conditions. These results indicate that changing the retronasal aroma release by aroma concentration and aroma exposure time affects food intake. PMID- 23981569 TI - Caesarean delivery and subsequent pregnancy interval: a systematic review and meta-analysis. AB - BACKGROUND: Caesarean delivery has increased worldwide, however, the effects on fertility are largely unknown. This systematic review aims to compare subsequent sub-fertility (time to next pregnancy or birth) among women with a Caesarean delivery to women with a vaginal delivery. METHODS: Systematic review of the literature including seven databases: CINAHL; the Cochrane Library; Embase; Medline; PubMed; SCOPUS and Web of Knowledge (1945 - October 2012), using detailed search-strategies and reference list cross-checking. Cohort, case control and cross-sectional studies were included. Two assessors reviewed titles, abstracts, and full articles using standardised data abstraction forms and assessed study quality. RESULTS: 11 articles were eligible for inclusion in the systematic review, of these five articles which adjusted for confounders were combined in a meta-analysis, totalling 750,407 women using fixed-effect models. Previous Caesarean delivery was associated with an increased risk of sub fertility [pooled odds ratio (OR) 0.90; 95% CI 0.86, 0.93]. Subgroup analyses by parity [primiparous women: OR 0.91; 95% CI 0.87, 0.96; not limited to primiparous women: OR 0.81; 95% CI 0.73, 0.90]; by publication date (pre-2000: OR 0.80, 95% CI 0.68, 0.94; post-2000: OR 0.90, 95% CI 0.86, 0.94); by length of follow-up (<10 years: OR 0.81, 95% CI 0.73, 0.90; >10 years: OR 0.91, 95% CI 0.87, 0.96); by indication for mode of delivery (specified: 0.92, 95% CI 0.88, 0.97; not specified: OR 0.81, 95% CI 0.73, 0.90); by cohort size (<35,000: OR 0.79, 95% CI 0.67, 0.92; >35,000: OR 0.90, 95% CI 0.87, 0.95), by definition of sub-fertility used divided into (birth interval [BI]: OR 0.89, 95% CI 0.84, 0.94; inter pregnancy interval [IPI]: OR 0.91, 95% CI 0.85, 0.97; and categorical measures: OR 0.81, 95% CI 0.73, 0.90); continuous measures: OR 0.91, 95% CI 0.87, 0.96) were performed. Results of the six studies not included in the meta-analysis (which did not adjust for confounders) are presented individually. CONCLUSIONS: The meta-analysis shows an increased waiting time to next pregnancy and risk of sub-fertility among women with a previous Caesarean delivery. However, included studies are limited by poor epidemiological methods such as variations in the definition of time to next pregnancy, lack of confounding adjustment, or details of the indication for Caesarean delivery. Further research of a more robust methodological quality to better explore any underlying causes of sub-fertility and maternal intent to delay childbearing is warranted. PMID- 23981571 TI - The contribution of housing renovation to children's blood lead levels: a cohort study. AB - BACKGROUND: Routine renovation of older housing is a risk factor for childhood lead poisoning, but the contribution to children's blood lead levels is poorly defined for children with lower exposure levels. METHODS: We examined a prospective cohort of 276 children followed from 6 to 24 months of age. We conducted surveys of renovation activities and residential lead hazards and obtained blood lead level (B-Pb) every six months. We analyzed B-Pb in a repeated measures design using a mixed effects linear model. RESULTS: Parent reported interior renovation ranged from 11 to 25% of housing units at the four, 6-month periods. In multivariable analysis, children whose housing underwent interior renovation had a 12% higher mean B-Pb by two years of age compared with children whose housing units were not renovated (p < 0.01). The time between renovation and the child blood lead sample was associated with higher B-Pb (p-value for trend <0.01); compared to children in non-renovated housing, children whose housing units underwent renovation in the prior month had a 17% higher mean B-Pb at two years of age, whereas children whose housing renovation occurred in the prior 2-6 months had an 8% higher mean B-Pb. We also found an association between higher paint lead loading, measured using an X-ray fluorescence (XRF) based paint lead index, and child B-Pb (p = 0.02); for every 10 mg/cm2 increase in paint lead loading index there was a 7.5% higher mean childhood B-Pb. CONCLUSIONS: In an analysis of data collected before the recent changes to Environmental Protection Agency's Lead, Renovation, Repair and Painting Rule, routine interior housing renovation was associated with a modest increase in children's B-Pb. These results are important for the provision of clinical advice, for housing and public health professionals, and for policymakers. PMID- 23981572 TI - Helicobacter pylori-induced gastric inflammation and gastric cancer. AB - Helicobacter pylori (H. pylori) infect over half of the world's population. The prevalence of H. pylori infection and the predominant genotype of H. pylori virulence factors vary considerably across different geographical regions. H. pylori could uniquely persist for decades in the harsh stomach environment, where it damages the gastric mucosa and changes the pattern of gastric hormone release, thereby affects gastric physiology. By utilizing various virulence factors, H. pylori targets different cellular proteins to modulate the host inflammatory response and initiate multiple "hits" on the gastric mucosa, resulting in chronic gastritis and peptic ulceration. Among the long-term consequences of H. pylori infection is gastric malignancies, particularly gastric cancer (GC) and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. As such, H. pylori has been recognized as a class I carcinogen by the International Agency for Research on Cancer. Despite a close causal link between H. pylori infection and the development of gastric malignancies, the precise mechanisms involved in this process are still obscure. Studies over the past two decades have revealed that H. pylori exert oncogenic effects on gastric mucosa through a complex interaction between bacterial factors, host factors, and environmental factors. Numerous signaling pathways can be activated by H. pylori. In this review, we aim to elaborate on the recent developments in the pathophysiological mechanisms of H. pylori-induced gastric inflammation and gastric cancer. PMID- 23981573 TI - Chronic pancreatitis: a path to pancreatic cancer. AB - Chronic pancreatitis predisposes to pancreatic cancer development and both diseases share a common etiology. A central role has been proposed for the digestive enzyme-secreting acinar cell that can undergo ductal metaplasia in the inflammatory environment of pancreatitis. This metaplastic change is now a recognised precursor of pancreatic cancer. Inflammatory molecules also foster tumour growth through autocrine and paracrine effects in the epithelium and the stroma. These insights have raised new opportunities such as the manipulation of inflammation as a preventive and/or therapeutic strategy for pancreatic cancer. Finally, we address the need for an in-depth study of the pancreatic acinar cells. PMID- 23981574 TI - Chronic inflammation and gallbladder cancer. AB - Gallbladder cancer (GBC) is the most common biliary tract malignancy with an extremely poor prognosis. Epidemiological data have demonstrated that chronic inflammation resulting from infection of gallbladder or gallstones predispose individuals to GBC. Recent studies have begun to elucidate molecular mechanisms underlying the development of GBC in the setting of chronic inflammation. It is possible that persistently local inflammatory reactions may contribute to the development and progression of GBC through inducing genetic alterations, and subsequent promoting survival and proliferation of mutated sells, inhibiting apoptosis, stimulating angiogenesis and metastasis. This article reviews the current understanding of the involvement of chronic inflammation in gallbladder tumorigenesis. PMID- 23981575 TI - MiR-215 modulates gastric cancer cell proliferation by targeting RB1. AB - Growing evidence indicates that miRNAs play critical roles in tumorigenesis and cancer progression. Here, we report that miR-215 is significantly up-regulated in gastric cancer tissues from either gastrectomy or gastroscopy. Receiver Operator Characteristic (ROC) curve analysis indicated that miR-215 may be a candidate biomarker for gastric cancer diagnosis. Inhibition of miR-215 significantly suppressed gastric cancer cell proliferation possibly via G1 arrest. Further analyses indicated that miR-215 was able to target retinoblastoma tumor suppressor gene 1 (RB1) through its 3'-UTR in gastric cancer cells. These data suggest that frequently up-regulated miR-215 in gastric cancer may influence cell proliferation by targeting RB1. PMID- 23981576 TI - Hepatitis B virus-induced hepatocellular carcinoma. AB - Many factors are considered to contribute to hepatitis B virus (HBV) associated hepatocellular carcinoma (HCC), including products of HBV, HBV integration and mutation, and host susceptibility. HBV X protein (HBx) can interfere with several signal pathways that associated with cell proliferation and apoptosis, and the impact of HBx C-terminal truncation in the development of HCC has been implicated. Recent studies by advanced sequencing technologies have revealed recurrent HBV DNA integration sites in hepatoma cells and susceptible genes/SNPs play an important role in the pathogenesis of liver cancer. Epigenetic changes, immune and inflammatory factors are also important contributing factors for liver cancer. This mini-review provides an overview on the recent development of HBV induced HCC. PMID- 23981577 TI - Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: suppressing effects of EGCG on the development of liver lesions. AB - Non-alcoholic steatohepatitis (NASH), which involves hepatic inflammation and fibrosis, is associated with liver carcinogenesis. The activation of the renin angiotensin system (RAS), which plays a key role in blood pressure regulation, promotes hepatic fibrogenesis. In this study, we investigated the effects of (-) epigallocatechin-3-gallate (EGCG), a major component of green tea catechins, on the development of glutathione S-transferase placental form (GST-P)-positive (GST P(+)) foci, a hepatic preneoplastic lesion, in SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP ZF) obese and hypertensive rats. Male 7-week-old SHRSP-ZF rats and control non obese and normotensive WKY rats were fed a high fat diet and received intraperitoneal injections of carbon tetrachloride twice a week for 8weeks. The rats were also provided tap water containing 0.1% EGCG during the experiment. SHRSP-ZF rats presented with obesity, insulin resistance, dyslipidemia, an imbalance of adipokines in the serum, and hepatic steatosis. The development of GST-P(+) foci and liver fibrosis was markedly accelerated in SHRSP-ZF rats compared to that in control rats. Additionally, in SHRSP-ZF rats, RAS was activated and inflammation and oxidative stress were induced. Administration of EGCG, however, inhibited the development of hepatic premalignant lesions by improving liver fibrosis, inhibiting RAS activation, and attenuating inflammation and oxidative stress in SHRSP-ZF rats. In conclusion, obese and hypertensive SHRSP-ZF rats treated with a high fat diet and carbon tetrachloride displayed the histopathological and pathophysiological characteristics of NASH and developed GST-P(+) foci hepatic premalignant lesions, suggesting the model might be useful for the evaluation of NASH-related liver tumorigenesis. EGCG might also be able to prevent NASH-related liver fibrosis and tumorigenesis. PMID- 23981580 TI - Gastrointestinal cancers: influence of gut microbiota, probiotics and prebiotics. AB - Cancers of the gastrointestinal (GI) tract continue to represent a major health problem, despite progress in therapy. Gut microbiota is a key element related to the genesis of GI cancers, countless papers addressing this burning issue across the world. We provide an updated knowledge of the involvement of gut microbiota in GI tumorigenesis, including its underlying mechanisms. We present also a comprehensive review of the evidence from animal and clinical studies using probiotics and/or prebiotics in the prevention and/or therapy of GI tumours, of GI cancer therapy-related toxicity and of post-operative complications. We summarize the anticarcinogenic mechanisms of these biotherapeutics from in vitro, animal and clinical interventions. More research is required to reveal the interactions of microflora with genetic, epigenetic and immunologic factors, diet and age, before any firm conclusion be drawn. Well-designed, randomized, double blind, placebo-controlled human studies using probiotics and/or prebiotics, with adequate follow-up are necessary in order to formulate directions for prevention and therapy. PMID- 23981579 TI - Inflammation and gastrointestinal cancer: an overview. AB - Gastrointestinal cancers collectively rank as the most lethal cancers worldwide, and are strongly linked with chronic inflammation. Despite advances over the last decade into our understanding of the etiology of these malignancies, both from a host perspective and with respect to environmental factors, current treatment strategies comprising surgery, chemotherapy and/or radiotherapy are still associated with unacceptably poor patient survival rates. Accordingly, there is a pressing need to identify new molecular targets which can underpin the development of next-generation treatment strategies to improve patient outcomes, and serve as biomarkers for early disease detection. In this review we provide an updated discussion on the identity of such candidate molecules, with a focus on innate immune system regulators within the gastrointestinal mucosal epithelium which promote inflammation and tumorigenesis. PMID- 23981578 TI - Two co-existing germline mutations P53 V157D and PMS2 R20Q promote tumorigenesis in a familial cancer syndrome. AB - Germline mutations are responsible for familial cancer syndromes which account for approximately 5-10% of all types of cancers. These mutations mainly occur at tumor suppressor genes or genome stability genes, such as DNA repair genes. Here we have identified a cancer predisposition family, in which eight members were inflicted with a wide spectrum of cancer including one diagnosed with lung cancer at 22years old. Sequencing analysis of tumor samples as well as histologically normal specimens identified two germline mutations co-existing in the familial cancer syndrome, the mutation of tumor suppressor gene P53 V157D and mismatch repair gene PMS2 R20Q. We further demonstrate that P53 V157D and/or PMS2 R20Q mutant promotes lung cancer cell proliferation. These two mutants are capable of promoting colony formation in soft agar as well as tumor formation in transgenic drosophila system. Collectively, these data have uncovered the important role of co-existing germline P53 and PMS2 mutations in the familial cancer syndrome development. PMID- 23981581 TI - MicroRNA let-7c inhibits migration and invasion of human non-small cell lung cancer by targeting ITGB3 and MAP4K3. AB - MicroRNAs play an important regulatory role in carcinogenesis and cancer metastasis. Different members of let-7 family have been reported to be decreased in human lung tumors. However, the effect of specific let-7 member on metastasis of NSCLC remains undefined. Our current study detected the expression of let-7 members in 94 cases of NSCLC and a significant association was noticed between low levels of let-7c expression and metastasis, venous invasion, advanced TNM stages and poor survival of NSCLC patients. Consistently, ectopic expression of let-7c in relatively highly metastatic cells remarkably suppressed their migration and invasion. Inhibition of let-7c in cells with relatively low metastatic potential promoted their motility and invasion. We then analyzed the potential targets of let-7c and found that ITGB3 and MAP4K3 were directly repressed by let-7c. Upon restoring the expression of ITGB3 and MAP4K3, the effects of let-7c on tumor metastasis were partially reversed, and more importantly, the expression levels of ITGB3 and MAP4K3 were inversely correlated with let-7c in 64 NSCLC tissues. Collectively, our results suggest that let-7c, by degrading ITGB3 and MAP4K3, prevents NSCLC metastasis. PMID- 23981582 TI - Initial physical grades and cognitive stages after acute stroke: who receives comprehensive rehabilitation services? AB - OBJECTIVES: To study the degree to which initial physical grades and cognitive stages of independence assessed by physical medicine and rehabilitation (PM&R) staff early after hospitalization for acute stroke relate to the decision to either provide rehabilitation in consultation or admission to a specialized rehabilitation unit (SRU) for comprehensive, high-intensity, multidisciplinary rehabilitation. DESIGN: An observational study. SETTING: Early rehabilitation assessment by PM&R staff during patients' acute hospitalization for stroke in 112 Veterans Affairs facilities. PATIENTS: The sample included 8,783 veterans who were assessed by PM&R staff. METHODS: Shortly after hospital admission, functional status was determined according to 7 physical grades and 7 cognitive stages of increasing independence. Patients' physical grades and cognitive stages ranged at initial PM&R assessment from the lowest and most dependent "I" through intermediate "II, III, IV, V, or VI," and ended with the highest at total independence "VII." To assess the statistically independent effects of physical grade and cognitive stage, a multivariable generalized estimating equation was applied to account for within Veterans Affairs facilities correlation and to adjust for demographics, stroke type, comorbidities, clinical events before PM&R assessment, and facility-related factors. MAIN OUTCOME MEASUREMENTS: The decision to admit patients to an SRU for comprehensive rehabilitation. RESULTS: Only 11.2% of those patients assessed after stroke were admitted to an SRU after the acute management phase. After statistical adjustment, patients at the lowest physical grade (I) of independence had a 9-fold increased odds of admission to an SRU compared with those at the highest combined physical grades VI/VII (adjusted odds ratio 9.15, 95% confidence interval 4.31-19.39). In contrast, patients at intermediate cognitive stages of independence were the most likely to be admitted to an SRU. The presence of an SRU within the treating Veterans Affairs facility was strongly related to admission. CONCLUSIONS: Patients' physical grades and cognitive stages assessed early after stroke are strong determinants of referral for comprehensive rehabilitation. PMID- 23981583 TI - Identification of bacteria in enrichment cultures of sulfate reducers in the Cariaco Basin water column employing Denaturing Gradient Gel Electrophoresis of 16S ribosomal RNA gene fragments. AB - BACKGROUND: The Cariaco Basin is characterized by pronounced and predictable vertical layering of microbial communities dominated by reduced sulfur species at and below the redox transition zone. Marine water samples were collected in May, 2005 and 2006, at the sampling stations A (10 degrees 30' N, 64 degrees 40' W), B (10 degrees 40' N, 64 degrees 45' W) and D (10 degrees 43'N, 64 degrees 32'W) from different depths, including surface, redox interface, and anoxic zones. In order to enrich for sulfate reducing bacteria (SRB), water samples were inoculated into anaerobic media amended with lactate or acetate as carbon source. To analyze the composition of enrichment cultures, we performed DNA extraction, PCR-DGGE, and sequencing of selected bands. RESULTS: DGGE results indicate that many bacterial genera were present that are associated with the sulfur cycle, including Desulfovibrio spp., as well as heterotrophs belonging to Vibrio, Enterobacter, Shewanella, Fusobacterium, Marinifilum, Mariniliabilia, and Spirochaeta. These bacterial populations are related to sulfur coupling and carbon cycles in an environment of variable redox conditions and oxygen availability. CONCLUSIONS: In our studies, we found an association of SRB-like Desulfovibrio with Vibrio species and other genera that have a previously defined relevant role in sulfur transformation and coupling of carbon and sulfur cycles in an environment where there are variable redox conditions and oxygen availability. This study provides new information about microbial species that were culturable on media for SRB at anaerobic conditions at several locations and water depths in the Cariaco Basin. PMID- 23981584 TI - Growth of the flat bones of the membranous neurocranium: a computational model. AB - This article assumes two stages in the formation of the bones in the calvaria, the first one takes into account the formation of the primary centers of ossification. This step counts on the differentiation from mesenchymal cells into osteoblasts. A molecular mechanism is used based on a system of reaction diffusion between two antagonistic molecules, which are BMP2 and Noggin. To this effect we used equations whose behavior allows finding Turing patterns that determine the location of the primary centers. In the second step of the model we used a molecule that is expressed by osteoblasts, called Dxl5 and that is expressed from the osteoblasts of each flat bone. This molecule allows bone growth through its borders through cell differentiation adjacent to each bone of the skull. The model has been implemented numerically using the finite element method. The results allow us to observe a good approximation of the formation of flat bones of the membranous skull as well as the formation of fontanelles and sutures. PMID- 23981585 TI - Evaluation of different distortion correction methods and interpolation techniques for an automated classification of celiac disease. AB - Due to the optics used in endoscopes, a typical degradation observed in endoscopic images are barrel-type distortions. In this work we investigate the impact of methods used to correct such distortions in images on the classification accuracy in the context of automated celiac disease classification. For this purpose we compare various different distortion correction methods and apply them to endoscopic images, which are subsequently classified. Since the interpolation used in such methods is also assumed to have an influence on the resulting classification accuracies, we also investigate different interpolation methods and their impact on the classification performance. In order to be able to make solid statements about the benefit of distortion correction we use various different feature extraction methods used to obtain features for the classification. Our experiments show that it is not possible to make a clear statement about the usefulness of distortion correction methods in the context of an automated diagnosis of celiac disease. This is mainly due to the fact that an eventual benefit of distortion correction highly depends on the feature extraction method used for the classification. PMID- 23981586 TI - N-terminal pro-brain natriuretic peptide shows diagnostic accuracy for detecting atrial fibrillation in cryptogenic stroke patients. AB - BACKGROUND: Diagnosing paroxysmal atrial fibrillation in patients with stroke can be difficult. We aimed to determine if N-terminal pro-brain natriuretic peptide can help identify paroxysmal atrial fibrillation in cryptogenic stroke. METHODS AND RESULTS: Among 264 ischemic stroke patients, serum levels of N-terminal pro brain natriuretic peptide were measured within 72 h of stroke onset. In cryptogenic stroke patients, 24-h Holter monitoring was used to look for paroxysmal atrial fibrillation within the first week and also three- and six months after admission. First, patients with a defined etiology were used to construct a receiver operating characteristic curve for the diagnosis of atrial fibrillation. From this curve, the sensitivity and specificity of preestablished cutoff points for the diagnosis of atrial fibrillation were calculated. A logistic regression was performed to assess the independent relationship of the logarithm of N-terminal pro-brain natriuretic peptide levels with atrial fibrillation. The cutoff points were then evaluated in patients with cryptogenic stroke. RESULTS: One hundred eighty-four patients had a specific stroke etiology. Fifty-five patients had atrial fibrillation. Using multivariate analysis, the logarithm of N-terminal pro-brain natriuretic peptide levels was independently associated with atrial fibrillation. The area under the receiver operating characteristic curve of N-terminal pro-brain natriuretic peptide for the diagnosis of atrial fibrillation was 0.91 (95% confidence interval 0.87-0.95). The cutoff point of 265.5 pg/ml had a sensitivity of 100% and specificity of 70.5% for the diagnosis of atrial fibrillation. The cutoff point of 912 pg/ml had a sensitivity of 81.8% and a specificity of 87.5%. Eighty patients had a cryptogenic stroke. In 17, paroxysmal atrial fibrillation was found during follow up. In these patients, the area under the curve for the diagnosis of paroxysmal atrial fibrillation was 0.83. The cutoff point of 265.5 had a sensitivity of 88.2% and a specificity of 61.9%. The cutoff point of 912 pg/ml had a sensitivity of 47.1% and a specificity of 88.9%. CONCLUSION: N-terminal pro-brain natriuretic peptide has good accuracy in predicting the presence of paroxysmal atrial fibrillation in patients with cryptogenic stroke and can help to identify these patients. PMID- 23981587 TI - Opercular myoclonic-anarthric status epilepticus due to glutamic acid decarboxylase antibody-associated encephalitis. AB - We report a patient who was diagnosed with opercular myoclonic-anarthric status epilepticus and found to have glutamic acid decarboxylase antibody (GADA) associated encephalitis, a previously unrecognised aetiology of this condition. The patient was a 23-year-old female admitted for investigation of focal myoclonic status epilepticus in the right side of the face and glossopharyngeal area. Intravenous corticosteroid was administered and improvement was observed in seizure activity and overall general health. A video sequence of opercular myoclonia is included. Due to the presence of inflammatory elements based on brain MRI and CSF studies, a decision to investigate autoimmune encephalitis was undertaken. Anti-GAD65 radioimmunoassay was markedly positive. This case study highlights the need for awareness of the clinical presentation of GADA-associated encephalitis. [Published with video sequences]. PMID- 23981588 TI - Editor's commentary. PMID- 23981589 TI - PEEP titration: new horizons. PMID- 23981590 TI - Respiratory support in patients with amyotrophic lateral sclerosis. PMID- 23981591 TI - Assessment of humidification performance: still no easy method! PMID- 23981592 TI - CPAP in cystic fibrosis: is it time to surrender yet? PMID- 23981593 TI - The authors respond to: CPAP in cystic fibrosis: is it time to surrender yet? PMID- 23981594 TI - Identification of novel PTPRQ phosphatase inhibitors based on the virtual screening with docking simulations. AB - Protein tyrosine phosphatase receptor type Q (PTPRQ) is an unusual PTP that has intrinsic dephosphorylating activity for various phosphatidyl inositides instead of phospho-tyrosine substrates. Although PTPRQ was known to be involved in the pathogenesis of obesity, no small-molecule inhibitor has been reported so far. Here we report six novel PTPRQ inhibitors identified with computer-aided drug design protocol involving the virtual screening with docking simulations and enzyme inhibition assay. These inhibitors exhibit moderate potencies against PTPRQ with the associated IC50 values ranging from 29 to 86 MUM. Because the newly discovered inhibitors were also computationally screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further development by structure-activity relationship studies to optimize the antiobestic activities. Structural features relevant to the stabilization of the inhibitors in the active site of PTPRQ are addressed in detail. PMID- 23981595 TI - Development of anti-inflammatory drugs - the research and development process. AB - The research and development process for novel drugs to treat inflammatory diseases is described, and several current issues and debates relevant to this are raised: the decline in productivity, attrition, challenges and trends in developing anti-inflammatory drugs, the poor clinical predictivity of experimental models of inflammatory diseases, heterogeneity within inflammatory diseases, 'improving on the Beatles' in treating inflammation, and the relationships between big pharma and biotechs. The pharmaceutical research and development community is responding to these challenges in multiple ways which it is hoped will lead to the discovery and development of a new generation of anti inflammatory medicines. PMID- 23981596 TI - Moderate hypothermia inhibits brain inflammation and attenuates stroke-induced immunodepression in rats. AB - AIMS: Stroke causes both brain inflammation and immunodepression. Mild-to moderate hypothermia is known to attenuate brain inflammation, but its role in stroke-induced immunodepression (SIID) of the peripheral immune system remains unknown. This study investigated the effects in rats of moderate intra-ischemic hypothermia on SIID and brain inflammation. METHODS: Stroke was induced in rats by permanent distal middle cerebral artery occlusion combined with transient bilateral common carotid artery occlusion, while body temperature was reduced to 30 degrees C. Real-time PCR, flow cytometry, in vitro T-cell proliferation assays, in vivo delayed-type hypersensitivity (DTH) reaction and confocal microscopy were used to study SIID and brain inflammation. RESULTS: Brief intra ischemic hypothermia helped maintain certain leukocytes in the peripheral blood and spleen and enhanced T-cell proliferation in vitro and delayed-type hypersensitivity in vivo, suggesting that hypothermia reduces SIID. In contrast, in the brain, brief intra-Ischemic hypothermia inhibited mRNA expression of anti inflammatory cytokine IL-10 and proinflammatory mediators INF-gamma, TNF-alpha, IL-2, IL-1beta and MIP-2. Brief intra-Ischemic hypothermia also attenuated the infiltration of lymphocytes, neutrophils (MPO(+) cells) and macrophages (CD68(+) cells) into the ischemic brain, suggesting that hypothermia inhibited brain inflammation. CONCLUSIONS: Brief intra-ischemic hypothermia attenuated SIID and protected against acute brain inflammation. PMID- 23981597 TI - Neurologic complications of HIV infection: highlights from the 2013 Conference on Retroviruses and Opportunistic Infections. AB - Thirty years into the HIV epidemic, the management and investigation of neurologic complications of HIV disease have evolved from a struggle to understand and treat inexorable disorders to an optimistic effort to address more subtle but often complex conditions in patients surviving long-term with a chronic disease. Although severe forms of HIV encephalitis and HIV-associated dementia, myelopathy, opportunistic infections, and neuropathy are still frequently encountered entities where access to HIV treatment is limited, in settings with sufficient resources, they are predominantly seen in those who present late to care or are unable to maintain consistent antiretroviral adherence. In 2013, practitioners, patients, and investigators can realistically aim for an outstanding quality of life for those living with HIV infection and seek to reduce morbidity associated with milder forms of HIV-associated neurocognitive disorder (HAND). Neurologic presentations at the 20th Conference on Retroviruses and Opportunistic Infections (CROI) reflected this now well established paradigm shift, focusing on treatment strategies to optimize neurologic and cognitive function, the pathogenesis of HAND in the current era, imaging biomarkers of HAND, the confluence of HIV infection and aging, and characterization of central nervous system HIV reservoirs of infection. PMID- 23981598 TI - Treatment as prevention: toward an AIDS-free generation. AB - In British Columbia, Canada, intensive efforts have been made to implement and maintain a treatment-as-prevention strategy among the HIV-infected population. Acceleration of antiretroviral therapy coverage has resulted in a substantial increase in the median CD4+ cell count at which treatment is initiated and a dramatic decline in community plasma HIV RNA levels. This has resulted in a reduction in diagnoses of new cases of HIV infection, including among injection drug users. Proportions of individuals with viral suppression have steadily increased and the expansion of antiretroviral therapy coverage has not been associated with increased levels of HIV resistance. Further, adoption of routine HIV testing in acute care settings has been very well accepted and has captured new cases at a rate of 5 per 1000 tests outside of high-risk populations, offering an additional strategy for identifying and linking at least some individuals with undiagnosed HIV infection to care. Deriving optimal individual and social health outcomes in HIV infection requires improvement in every element of the cascade of care. This article summarizes a presentation by Julio S. G. Montaner, MD, at the IAS-USA continuing education program held in San Francisco, California, in March 2013. PMID- 23981599 TI - Challenges in the management of osteoporosis and vitamin D deficiency in HIV infection. AB - Until 2013, the National Osteoporosis Foundation guidelines did not include HIV infection and highly active antiretroviral therapy as osteoporosis risk factors that should trigger dual-energy x-ray absorptiometry (DEXA) screening for low bone mineral density (BMD) in older adults, but numerous data indicate that individuals with HIV infection are at early and increased risk for osteoporosis and fracture. For this reason, experts support the use of DEXA screening for HIV infected postmenopausal women and men older than 50 years. Factors contributing to increased risk of low BMD in individuals with HIV infection include inflammation, effects of antiretroviral therapy, and numerous patient risk factors, including vitamin D deficiency. Workup for low BMD should include assessment for fracture risk and secondary causes of low BMD, including vitamin D deficiency, hyperparathyroidism, subclinical hyperthyroidism, hypogonadism, and phosphate wasting. Bisphosphonates are the preferred treatment to prevent fracture in low BMD but are not appropriate for treating osteomalacia, which is characterized by vitamin D deficiency and phosphate wasting. This article summarizes a presentation by Todd T. Brown, MD, PhD, at the IAS-USA continuing education program held in Atlanta, Georgia, in April 2013. PMID- 23981600 TI - HIV, aging, and cognition: emerging issues. AB - The prevalence of HIV-associated neurocognitive disorder has not changed from the pre- to the potent antiretroviral therapy era, remaining at approximately 50%. In research settings, mild neurocognitive disorder (MND) and so-called asymptomatic neurocognitive impairment (ANI) are now more common than HIV-associated dementia. The diagnosis of ANI is misleading because functional deficits, when tested in a laboratory, and degree of neuropsychologic testing abnormalities are often comparable in patients with ANI and those with symptomatic MND. Age-related comorbidities increase the risk of cognitive impairment in HIV infection. In a cohort of patients aged 60 years or older with excellent antiretroviral therapy adherence, correlates to cognitive impairment were apolipoprotein (Apo) E4 genotype and a novel measure of the effectiveness of antiretroviral drugs in monocytes, the monocyte efficacy (ME) score, with trend associations for diabetes and nadir CD4+ cell count. Management of impairment includes ensuring that patients are on and adhere to antiretroviral therapy and addressing comorbidities. Switching from effective and well-tolerated antiretroviral therapy for patients with mild cognitive impairment is not routinely recommended, but this must still be addressed on a case-by-case basis. This article summarizes a presentation by Victor G. Valcour, MD, at the IAS-USA continuing education program held in Atlanta, Georgia, in April 2013. PMID- 23981601 TI - Current status of laparoscopic surgery for gastric cancer. PMID- 23981602 TI - Change of CMTM7 expression, a potential tumor suppressor, is associated with poor clinical outcome in human non-small cell lung cancer. AB - BACKGROUND: CKLF-like MARVEL transmembrane domain-containing 7 (CMTM7) located at 3p22.3, is a frequent deletion site and a tumor suppressor gene (TSG) locus in many cancer, which suggests CMTM7 may be a potential TSG. The aim of this study was to investigate the correlations of CMTM7 expression and survival rate in patients with non-smallcell lung cancer (NSCLC). METHODS: Surgical specimens of 180 cases with pathologically confirmed NSCLC were grouped into 18 tissue microarray slides. CMTM7 expression in these specimens were detected by immunohistochemistry staining and representative cases were confirmed by Western blotting. Univariate and multivariate analyses were performed to identify the association of CMTM7 expression with pathological features and survival of patients with NSCLC. RESULTS: A total of 78.9% of the 180 patients had variations of CMTM7 protein expression, either up-regulated or down-regulated. Univariate analysis showed that the patients' survival rate after surgery was highly correlated with CMTM7 expression (P = 0.0091). In addition, prognostic factors were examined by multivariate Cox regression analysis, and results suggested that CMTM7 expression was a unique prognostic factor in NSCLC survival. CONCLUSIONS: The CMTM7 expression may be related to survival of patients with NSCLC and a unique prognostic factor. CMTM7 may play an important role in NSCLC development. PMID- 23981603 TI - BRAF(V600E) mutation is not a positive predictor for distant metastasis in sporadic papillary thyroid carcinoma. AB - BACKGROUND: BRAF(V600E) mutation is correlated with local aggressive clinicopathological features in papillary thyroid carcinoma; yet the relationship between this genetic variation and distant papillary thyroid carcinoma metastasis was unclear. This study aimed to investigate whether BRAF(V600E) is predictive for distant metastasis in the Chinese population. METHODS: One hundred and seven patients with papillary thyroid carcinoma were enrolled in this study, including 43 patients with distant metastasis and 64 patients without. Quantitative real time polymerase chain reaction was used to detect BRAF(V600E) mutation, while immunohistochemistry was performed to detect vascular endothelial growth factor (VEGF) expression. The associations between distant metastasis and BRAF(V600E) mutation, and VEGF expression as well as local clinicopathological factors were determined. RESULTS: A total of 28.6% of the patients in the distant metastasis group harbored BRAF(V600E) mutation, which was significantly lower than in the without distant metastasis group (68.8%, P < 0.001). BRAF(V600E) mutation was negatively correlated with positive VEGF expression (P = 0.001). Furthermore, 52.2% of the patients with distant metastasis exhibited VEGF expression, compared with 25.0% of those without. Higher levels of VEGF expression were also observed in the distant metastasis group. Tumor size, extra-thyroid invasion, and BRAF(V600E) mutation were independent predictors for distant metastasis according to multivariate analysis (odds ratios were 2.8, 12.4, and 0.3; 95% CI 1.483 5.334, and 2.950-52.407, 0.100-0.890; P = 0.002, 0.001, and 0.030, respectively). BRAF(V600E) mutation was negatively correlated with distant metastasis in adult subgroup analysis (P = 0.005) but was not an independent parameter. CONCLUSIONS: BRAF(V600E) mutation is predictive for distant metastasis in papillary thyroid carcinoma but not positively. VEGF may be involved in the pathogenesis of distant metastasis. PMID- 23981604 TI - Tracking in vivo migration and distribution of antigen-specific cytotoxic T lymphocytes by 5,6-carboxyfluorescein diacetate succinimidyl ester staining during cancer immunotherapy. AB - BACKGROUND: Killing of targeted tumors during adoptive cell transfer therapy is associated with cytotoxic T lymphocyte (CTL) numbers, immunophenotype, tumor specificity, and in vivo residence time, migration, and distribution. Therefore, tracing in vivo persistence, migration, and distribution of CTLs is important for cancer immunotherapy. METHODS: Optimal staining concentration for CTL proliferation was determined by cell counting kit-8 (CCK-8) assay and killing efficiencies of CTLs or carboxyfluorescein diacetate succinimidyl ester (CFSE) labeled melanoma antigen-specific cytotoxic T lymphocytes (CFSE-CTLs) for malignant melanoma cells in vitro were compared. Additionally, CFSE-CTLs were intravenously transfused to mice receiving B16 melanoma, and their residence time, migration, and distribution in vivo were observed by measuring fluorescence intensities of CFSE-CTLs per gram of tissue (%FI/g) in various tissues and analyzing tumor/non-tumor (T/NT) values. Anti-tumor effects of transferred CTLs and correlation between %FI/g and D-value of tumor size were analyzed. RESULTS: Five-micromolar CFSE was optimal for labeling CTLs with minimal cytotoxicity. No significant difference occurred between CTLs and CFSE-CTLs for tumor cell killing (P = 0.849) or interleukin-2 (P = 0.318) and interferon-gamma (P = 0.201) levels. Distribution of CTLs in vivo varied with time. A negative correlation between %FI/g in tumors and D-value of tumor sizes by Spearman correlation analysis was observed. CTLs were recruited to and killed tumors from 6 hours to 3 days after cell infusion. CTLs were observed up to three weeks later in the tumor, liver, kidneys, and spleen; this was related to the abundant blood supply or the nature of immune organs. CONCLUSIONS: CCK-8 assay is a novel method to select optimal CFSE staining concentrations. Fluorescence intensity of transferred CTLs reflects their killing efficiency of tumors. CFSE fluorescent markers can trace in vivo CTL persistence, migration, and distribution because of its stability, long half life, and low toxicity. PMID- 23981605 TI - Treatment outcomes of occult breast carcinoma and prognostic analyses. AB - BACKGROUND: The surgical management of occult breast cancer is controversial. We compared the outcomes of different treatments of occult breast cancer and evaluated the potential prognostic factors for overall survival and recurrence. METHODS: We retrospectively reviewed 77 patients who presented to our hospital from 1968 to 2011 with a diagnosis of occult breast cancer. Patients were divided into three groups: 42 patients (63%) were treated with modified radical mastectomy+axillary lymph node dissection (ALND), 16 patients (24%) were treated with ALND + postoperative radiotherapy, and 9 patients (13%) with only ALND. Survival analyses were undertaken to compare the efficacy of these three treatments. RESULTS: Of the 77 patients with occult breast cancer, 2 patients were lost to follow-up and 8 patients refused surgical treatment: 67 patients (90.4%) were included in this analysis. The median follow-up was 62.2 (0.6-328.0) months. Kaplan-Meier analyses showed no significant difference in overall survival and recurrence-free survival between the three groups (P = 0.494 and 0.397, respectively). The prevalence of local recurrence was 11.9% for the mastectomy + ALND, 18.8% for ALND + radiotherapy, and 11.1% for ALND-only groups, and those for distant recurrence were 2.4%, 12.5%, and 11.1%, respectively. Compared with progesterone receptor-negative subjects, progesterone receptor positive patients had better overall survival and lower recurrence rates (P = 0.057 and 0.062, respectively). CONCLUSIONS: There was no significant difference in outcomes between mastectomy and breast-preserving surgery. Expression of the progesterone receptor should be taken into account when evaluating the prognosis of occult breast cancer. PMID- 23981606 TI - Tamoxifen-resistant breast cancer cells possess cancer stem-like cell properties. AB - BACKGROUND: Cancer stem cells (CSCs) are the cause of cancer recurrence because they are resistant to conventional therapy and contribute to cancer growth and metastasis. Endocrinotherapy is the most common breast cancer therapy and acquired tamoxifen (TAM) resistance is the main reason for endocrinotherapy failure during such therapy. Although acquired resistance to endocrine treatment has been extensively studied, the underlying mechanisms are unclear. We hypothesized that breast CSCs played an important role in TAM-induced resistance during breast cancer therapy. Therefore, we investigated the biological characteristics of TAM-resistant (TAM-R) breast cancer cells. METHODS: Mammosphere formation and tumorigenicity of wild-type (WT) and TAM-R MCF7 cells were tested by a mammosphere assay and mouse tumor xenografts respectively. Stem cell markers (SOX-2, OCT-4, and CD133) and epithelial-mesenchymal transition (EMT) markers were tested by quantitative real-time (qRT)-PCR. Morphological observation was performed to characterize EMT. RESULTS: After induction of TAM resistance, TAM-R MCF7 cells exhibited increased proliferation in the presence of TAM compared to that of WT MCF7 cells (P < 0.05), indicating enhanced TAM resistance of TAM-R MCF7 cells compared to that of WT MCF7 cells. TAM-R MCF7 cells showed enhanced mammosphere formation and tumorigenicity in nude mice compared to that of WT MCF7 cells (P < 0.01), demonstrating the elevated CSC properties of TAM-R MCF7 cells. Consistently, qRT-PCR revealed that TAM-R MCF7 cells expressed increased mRNA levels of stem cell markers including SOX-2, OCT 4, and CD133, compared to those of WT MCF7 cells (P < 0.05). Morphologically, TAM R MCF7 cells showed a fibroblastic phenotype, but WT MCF7 cells were epithelial like. After induction of TAM resistance, qRT-PCR indicated that MCF7 cells expressed increased mRNA levels of Snail, vimentin, and N-cadherin and decreased levels of E-cadherin, which are considered as EMT characteristics (P < 0.05). CONCLUSION: TAM-R MCF7 cells possess CSC characteristics and may be responsible for TAM resistance during breast cancer therapy. PMID- 23981607 TI - Clinical significance of costimulatory molecule B7-H3 expression on CD3(+) T cells in colorectal carcinoma. AB - BACKGROUND: B7-H3 has been widely studied in the context of tumor progression in recent years, and behaves as a tumor cell marker in a variety of tumors including colorectal carcinoma. The mechanism of B7-H3 in tumor progression is complicated and not clear yet. Studies have revealed that B7 family molecules are expressed on infiltrated lymphocytes as well as tumor cells in tumor microenvironment, which indicates that different expression pattern may lead to different clinical outcomes. METHODS: The expression of B7-H3 was detected in tissues of 98 colorectal carcinoma patients by using immunohistochemistry. Then the expression of B7-H3 on CD3(+) T lymphocytes isolated from fresh cancer tissues of 12 colorectal carcinoma patients was analyzed by flow cytometry assay. The relationship between the expression of B7-H3 on CD3(+) T lymphocytes and patients' clinical pathological parameters was demonstrated with statistical analysis. RESULTS: Patients with more CD3(+) T cell infiltration survived much longer than patients with less CD3(+) T cell infiltration (P < 0.05); B7-H3 was highly expressed by infiltrating CD3(+) T lymphocytes in colorectal carcinoma tissues. The expression of B7-H3 was found to be significantly related with lymph node metastasis status (P < 0.05), but not with the patient's gender, age, tumor size, differentiation degree, depth of tumor invasion, Dukes' stage, distant metastasis and whether or not mucinous adenocarcinoma was present (P > 0.05). Moreover, the survival time of patients with low expression of B7-H3 was obviously longer than those of high B7-H3 expression patients, but the seven-year survival rate showed no difference between the high and low B7-H3 expression patients (P > 0.05). CONCLUSION: The negative costimulatory molecule B7-H3 on infiltrating CD3(+) T lymphocytes in colorectal carcinoma bears importance in the clinical pathological progress and prognosis of colorectal carcinoma. PMID- 23981608 TI - Inactivation of Smad4 is a prognostic factor in intrahepatic cholangiocarcinoma. AB - BACKGROUND: Smad4 is found mutated in many cancers. It acts as a tumor suppressor in the regulation of TGF-beta signaling pathway. The objective of this work was to study the expression of Smad4 in intrahepatic cholangiocarcinoma (ICC) and its relationship with the biological behavior and prognosis of the disease. METHODS: Forty-nine paraffin-embedded ICC specimens and nine normal liver tissues were analyzed by immunohistochemical methods using Smad4 monoclonal antibodies. The expression of Smad4 was compared with the clinical pathological characteristics of the patients. RESULTS: The expression of Smad4 was 100% positive in normal liver tissues, which was higher than that in the ICC (44.9%). Negative labeling of the Smad4 protein was found in 26.1% (6/23) of well-differentiated ICCs and 61.5% (16/26) of poorly to moderately differentiated ICCs, and 34.3% (12/35) and 71.4% (10/14) showed negative Smad4 labeling (P = 0.018) of ICC at pathological Tumor Node Metastasis (pTNM) stage I-II and pTNM stage III-IV separately. Furthermore, 72% (8/11) of lymph node metastatic ICCs and 73.3% (11/15) of intrahepatic metastatic ICCs showed negative labeling of the Smad4 protein. The loss of Smad4 expression in those metastatic ICCs was significantly more severe compared with non-metastatic ICCs (P = 0.000). CONCLUSIONS: The expression of Smad4 was associated with the histological grade, clinical stage, and metastasis of ICC (P < 0.05). The detection of Smad4 may be helpful in determining the degree of malignancy and prognosis of ICC. PMID- 23981609 TI - Tumor biomarkers: help or mislead in the diagnosis of xanthogranulomatous cholecystitis?-analysis of serum CA 19-9, carcinoembryonic antigen, and CA 12-5. AB - BACKGROUND: Xanthogranulomatous cholecystitis (XGC) is a rare type of gallbladder inflammation. Unlike other cholecystitis, it can be easily misdiagnosed as gallbladder cancer based on radiological images. In response to misdiagnosis, extended surgical treatments are inappropriately given to patients, which is not beneficial to their health and/or recovery. In this study, we set out to determine whether tumor biomarkers can help to avoid misdiagnosis in patients with XGC. METHODS: Between January 2005 and January 2012, a total of 37 preoperative patients at Sir Run Run Shaw Hospital were suspicious of having gallbladder cancer and was pathologically confirmed to be XGC after surgical operations. Before operations, all patients received a tumor biomarker test to verify diagnosis, which included serum CA 19-9, carcinoembryonic antigen (CEA), and CA 12-5. RESULTS: A measured amount (54.05%) of cases (20 in 37) had at least one elevation over the thresholds of CA 19-9 (37 IU/L), CEA (5 ng/ml), and CA 12 5 (35 IU/L), which increased the suspicion of malignancy and consequently enhanced the difficulty to make right diagnosis of XGC as benign. 45.95% of cases (17 in 37) had an elevation in CA 19-9. 2.70% of cases (one in 37) had an elevation in CEA and 24.32% of cases (nine in 37) had an elevation in CA 12-5. Analysis with Fisher's exact test discovered that the presence of common bile duct stone was a contributor to elevations of CA19-9 in patients with XGC. However, even in cases without common bile duct stones, 42.86% of patients (nine in 21) had elevations of at least one tumor biomarker. Among them, 26.09% of patients (six in 21) had elevations of CA 19-9, with the maximum of 536.29 IU/L. CONCLUSIONS: The elevations of tumor biomarkers in XGC were frequent, suggesting their inabilities to clarify the disease's nature, especially when there was a suspicion of gallbladder cancer. Intraoperative frozen pathology of gallbladder might be a possible solution. However, it is against the en bloc surgical principle and has the potential to cause tumor cell spreading. More research should be conducted, such as the discovery of a novel biomarker, so that XGC can less likely be misdiagnosed as malignancy until the final pathological judgment. PMID- 23981610 TI - Health related quality of life among patients with chronic graft-versus-host disease in China. AB - BACKGROUND: Chronic graft-versus-host disease (GVHD), the commonest long-term complication after allogeneic hematopoietic stem cell transplantation (HSCT), has a negative impact on patients' health related quality of life (HRQoL). This study was designed to investigate the HRQoL in patients with chronic GVHD in China. METHODS: Two hundred and sixty-four patients with chronic GVHD who were >= 24 months post-HSCT and had been in continuous complete remission since HSCT were enrolled in this retrospective study. HRQoL was evaluated using an SF-36 questionnaire. Multivariate analysis was used to identify the factors that affect HRQoL in patients with chronic GVHD. RESULTS: HRQoL in patients categorized as having mild and moderate chronic GVHD was significantly better than in those in the severe category. In the moderate chronic GVHD category, markedly poorer HRQoL was observed in patients with both multiple organ involvement and more severe organ impairment than in those without these factors. According to multivariate analysis, chronic GVHD severity had the greatest significant negative impact on patients' HRQoL; whereas being female was associated with a negative impact on psychological health. CONCLUSION: Chronic GVHD severity strongly correlates with negative impacts on patients' HRQoL. PMID- 23981611 TI - Subchondral bone grafting reduces degenerative change of knee joint in patients of giant cell tumor of bone. AB - BACKGROUND: Giant cell tumors (GCTs) most commonly occur around the knee. The most beneficial procedure for this disease has been extensive curettage with reconstruction. However, since many GCTs may compromise the subchondral bone, surgery can further jeopardize the articular cartilage and result in secondary osteoarthritis. In this study, we aimed to determine the factors associated with the development of degenerative arthritis and the effect of bone grafting on the prevention of secondary osteoarthritis. METHODS: We retrospectively analyzed 76 patients with GCT around the knee. The mean age at first diagnosis was 31.1 years. Surgical treatments included extensive curettage and cementation with or without bone grafting in the subchondral bone. Patient follow-up was a median duration of 35 months, ranging from 18 to 113 months. RESULTS: The local recurrence rate was 5.3% (4/76). Secondary degenerative changes occurred in 30.3% (23/76) of the patients. Less than 10 mm of the residual thickness of the remaining subchondral bone was correlated with secondary degenerative changes in 57 patients (P < 0.001). Of these 57 patients, 56.5% (13/23) treated with bone cement reconstruction alone developed secondary degenerative changes; following bone grafting, the rate decreased to 29.4% (10/34), with a statistically significant difference (P = 0.041). CONCLUSIONS: GCT patients with less residual thickness of the subchondral bone are more likely to develop degenerative arthritis after curettage. Bone grafting in the subchondral bone area is recommended when the residual thickness of the subchondral bone is less than 10 mm. PMID- 23981612 TI - Heme oxygenase-1 promotes Caco-2 cell proliferation and migration by targeting CTNND1. AB - BACKGROUND: Heme oxygenase-1 (HO-1) can be induced by inflammatory cytokines, oxidation, ischemia, hypoxia, and endotoxins. As a "graft survival protective gene," HO-1 is a hot spot in organ transplantation research. However, the role of HO-1 gene expression in the function of human colon adenocarcinoma cell line (Caco-2) cells has not been reported previously. METHODS: The role of HO-1 in the proliferation and migration of Caco-2 cells was analyzed using a stable HO-1 expression plasmid. We constructed a recombinant adeno-associated virus plasmid containing the HO-1 gene, heme oxygenase 1 (HMOX1), which was transfected into Caco-2 intestinal cells. We identified a number of target genes by global microarray analysis combined with real-time polymerase chain reaction (PCR) and chromatin immunoprecipitation assay. RESULTS: Our results showed that significant HO-1 upregulation was demonstrated in the Caco-2 cells after HO-1 transfection. Restoration of HO-1 expression promoted proliferation and invasion in vitro. The CTNND1 gene, a member of the armadillo protein family, was identified as a direct HO-1 target gene. CONCLUSION: Overexpression of HO-1 promotes Caco-2 cell proliferation and migration by targeting the CTNND1 gene. PMID- 23981614 TI - Totally laparoscopic bypass surgery for aortoiliac occlusive disease in China. AB - BACKGROUND: Totally laparoscopic aortic surgery is still in its infancy in China. One of the factors preventing adoption of this technique is its steep learning curve. The objective of this study was to evaluate the feasibility and safety of laparoscopic surgery for aortoiliac occlusive disease (AIOD). METHODS: From November 2008 to November 2012, 12 patients were treated for severe AIOD with a totally laparoscopic bypass surgery at our university hospital. The demographic data, operative data, postoperative recovery data, morbidity and mortality were analyzed and compared with those of conventional open approach. RESULTS: Twelve totally laparoscopic aortic surgery procedures, including two iliofemoral bypasses (IFB), three unilateral aortofemoral bypasses (UAFB), and seven aortobifemoral bypasses (ABFB), were performed. Conversion to open procedures was required in three patients. The mean operation time was 518 (range, 325-840) minutes, mean blood loss was 962 (range, 400-2500) ml, and mean aortic anastomosis time was 75 (range, 40-150) minutes. Compared with conventional open approach for aortofemoral bypasses performed concomitantly during this period, laparoscopic patients required fewer narcotics and a shorter in-hospital stay and earlier recovery. Postoperative complications developed in four patients, including a single patient with transient left hydronephrosis, ischemic colonic fistula and pneumonia, residual aortic stenosis proximal to the anastomotic site, and asymptomatic partial left renal infarction. All patients recovered and were discharged on postoperative Days 7-14 except one patient that died of respiratory failure on Day 46. All grafts were patent with follow-up imaging performed by Duplex examination, with a mean follow-up time of 10.7 (range, 2-61) months. CONCLUSION: Totally laparoscopic bypass surgery is a feasible and safe procedure for AIOD, but attention needs to be paid to improve laparoscopic skills of vascular surgery in order to minimize morbidity during the learning curve of this advanced procedure. PMID- 23981613 TI - Evaluation on the efficacy and safety of domestic bivalirudin during percutaneous coronary intervention. AB - BACKGROUND: Bivalirudin was widely used as an anticoagulant during coronary interventional procedure in western countries. However, it was not available in China before this clinical trial was designed. This randomized, single-blind and multicenter clinical trial aimed to evaluate the efficacy and the safety of domestic bivalirudin during percutaneous coronary intervention (PCI). METHODS: A randomized, single-blind, multicenter trial was designed. Elective PCI candidates in five centers were randomized into a bivalirudin group and a heparin group, which were treated with domestic bivalirudin and non-fractional heparin during the PCI procedure. The efficacy was evaluated by comparing the activated coagulation time (ACT), the procedural success rate (residual stenosis < 20% in target lesions without any coronary artery related adverse events within 24 hours after PCI), and the survival rate without major adverse cardiac events at 30 days after PCI between the two groups. Safety was evaluated by the major/minor bleeding rate. RESULTS: A total of 218 elective PCI patients were randomized into a bivalirudin group (n = 110) and heparin group (n = 108). Except for two patients needing additional dosing in the heparin group, the ACT values of all other patients in both groups were longer than 225 seconds at 5 minutes after the first intravenous bolus. Procedural success rates were respectively 100.0% and 98.2% in the bivalirudin group and heparin group (P > 0.05). Survival rates without major adverse cardiac events at 30 days after PCI were 100.0% in the bivalirudin group and 98.2% in the heparin group (P > 0.05). Mild bleeding rates were 0.9% and 6.9% (P < 0.05) at 24 hours, and 1.9% and 8.8% (P < 0.05) at 30 days after PCI in the bivalirudin group and heparin group respectively. There was one severe gastrointestinal bleeding case in the heparin group. CONCLUSIONS: Domestic bivalirudin is an effective and safe anticoagulant during elective PCI procedures. The efficacy is not inferior to heparin, but the safety is superior to heparin. PMID- 23981615 TI - Neovascularization in the carotid atherosclerotic plaque is not associated with inflammatory cell aggregation. AB - BACKGROUND: Monocytes and macrophages in atherosclerotic plaque lead to plaque instability. The aim of the study was to determine if plaque neovascularization led to inflammation. METHODS: Patients were consecutively enrolled if their carotid intimal media thickness was > 2 mm, as revealed by duplex ultrasound. The patients then underwent dynamic contrast enhanced magnetic resonance imaging (DCE MRI) and fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography combined with computed tomography (PET CT). A target to background ratio (TBR) of >= 1.25 or < 1.25 served as the cutoff point for the presence and absence of inflammation, respectively. RESULTS: Twenty-six patients underwent bilateral carotid DCE MRI and 24 patients also underwent PET CT. One hundred and fifty-five plaques were evaluated by both DCE MRI and PET CT. There was no significant difference in plaque morphology between the TBR >= 1.25 (n = 61) and TBR < 1.25 (n = 94) groups. No significant differences were found in plasma volume and transfer constant between the TBR >= 1.25 and TBR < 1.25 groups. CONCLUSION: Our study did not find a significant correlation between plaque neovascularization and the aggregation of inflammatory cells. PMID- 23981616 TI - Randomized comparison of intracoronary tirofiban versus urokinase as an adjunct to primary percutaneous coronary intervention in patients with acute ST-elevation myocardial infarction: results of the ICTUS-AMI trial. AB - BACKGROUND: No randomized trial has been performed to compare the efficacy of an intracoronary bolus of tirofiban versus urokinase during primary percutaneous coronary intervention (PCI). We investigated whether the effects of adjunctive therapy with an intracoronary bolus of urokinase was noninferior to the effects of an intracoronary bolus of tirofiban in patients with ST-elevation myocardial infarction (STEMI) undergoing PCI. METHODS: A total of 490 patients with acute STEMI undergoing primary PCI were randomized to an intracoronary bolus of tirofiban (10 ug/kg; n = 247) or urokinase (250 kU/20 ml; n = 243). Serum levels of P-selectin, von Willebrand factor (vWF), CD40 ligand (CD40L), and serum amyloid A (SAA) in the coronary sinus were measured before and after intracoronary drug administration. The primary endpoint was the rate of complete ( >= 70%) ST-segment resolution (STR) at 90 minutes after intervention, and the noninferiority margin was set to 15%. RESULTS: In the intention-to-treat analysis, complete STR was achieved in 54.4% of patients treated with an intracoronary bolus of urokinase and in 60.6% of those treated with an intracoronary bolus of tirofiban (adjusted difference: -7.0%; 95% confidence interval: -15.7% to 1.8%). The corrected TIMI frame count of the infarct-related artery was lower, left ventricular ejection fraction was higher, and the 6-month major adverse cardiac event-free survival tended to be better in the intracoronary tirofiban group. An intracoronary bolus of tirofiban resulted in lower levels of P-selectin, vWF, CD40L, and SAA in the coronary sinus compared with an intracoronary bolus of urokinase after primary PCI (P < 0.05). CONCLUSIONS: An intracoronary bolus of urokinase as an adjunct to primary PCI for acute STEMI is not equally effective to an intracoronary bolus of tirofiban with respect to improvement in myocardial reperfusion assessed by STR. This may be caused by less reduction in coronary circulatory platelet activation and inflammation. PMID- 23981617 TI - Relationships between use of statins and arterial stiffness in normotensive and hypertensive patients with coronary artery disease. AB - BACKGROUND: Statins improve arterial stiffness in patients with coronary artery disease (CAD). Hypertension is a predominant contributor of arterial stiffening. However, the influence of hypertension on the effect of statins for improving arterial stiffness in CAD patients has seldom been investigated. Therefore, in this study, we investigated the relationships between statin use and arterial stiffness in normotensive and hypertensive CAD patients. METHODS: Brachial-ankle pulse wave velocity (ba-PWV) was measured in 437 patients, including 220 hypertensive CAD patients (121 used statins, 99 did not) and 217 normotensive CAD patients (105 used statins, 112 did not). The normotensive and hypertensive CAD patients were matched according to age, sex, and body mass index (BMI). RESULTS: In the normotensive and hypertensive CAD patients, lipid profiles were significantly improved in the statin group compared with the non-statin group. No significant differences in the administered statins (i.e., atorvastatin, simvastatin, rosuvastatin, and pravastatin) and statin therapy duration were found between normotensive and hypertensive CAD patients (all P > 0.05). No significant correlation of ba-PWV and statin therapy duration was found in all CAD patients, normotensive CAD patients, or hypertensive CAD patients (all P > 0.05). ba-PWV in the statin group was significantly lower than that in the non statin group in normotensive CAD patients ((1331.68 +/- 167.52) cm/s vs. (1468.61 +/- 244.54) cm/s, P = 0.002) but not in hypertensive CAD patients (P > 0.05). In multiple linear regression analyses, statin therapy was significantly associated with ba-PWV after adjusting for confounding variables in normotensive CAD patients (P = 0.018) but not in hypertensive CAD patients (P > 0.05). CONCLUSIONS: Statins may significantly improve arterial stiffness in CAD patients, and hypertension may probably influence the effectiveness of statin therapy in improving arterial stiffness in this population. Further studies are required to investigate the effect of statins on arterial stiffness in normotensive and hypertensive CAD patients. PMID- 23981618 TI - A novel deletion-frameshift mutation in the S1 region of HERG gene in a Chinese family with long QT syndrome. AB - BACKGROUND: The congenital Long QT syndrome (LQTS) is a hereditary cardiac channelopathy that is characterized by a prolonged QT interval, syncope, ventricular arrhythmias, and sudden death. The chromosome 7-linked type 2 congenital LQTS (LQT2) is caused by gene mutations in the human ether-a-go-go related gene (HERG). METHODS: A Chinese family diagnosed with LQTS were screened for KCNQ1, HERG and SCN5A, using polymerase chain reaction (PCR), direct sequencing, and clong sequencing. We also investigated the mRNA expression of the HERG gene. RESULTS: We identified a novel I414fs + 98X mutation in the HERG gene. The deletion mutation of 14-bp in the first transmembrane segment (S1) introduced premature termination codons (PTCs) at the end of exon 6. This mutation would result in a serious phenotype if the truncated proteins co-assembled with normal subunit to form the defective channels. But only the proband was symptomatic. CONCLUSIONS: We found that the mRNA level of the HERG gene was significantly lower in I414fs + 98X carriers than in noncarriers. We found a novel I414fs + 98X mutation. The mRNA level supports that NMD mechanism might regulate the novel mutation. PMID- 23981619 TI - Relationship between uric acid and arterial stiffness in the elderly with metabolic syndrome components. AB - BACKGROUND: High uric acid (UA) levels and metabolic syndrome (MS) are risk factors for atherosclerotic diseases. Brachial-ankle pulse wave velocity (baPWV) is a valid and reproducible measurement by which to assess arterial stiffness and a surrogate marker of atherosclerosis. However, little is known about the relationship between them, especially in elderly Chinese with MS components who are at high risk for atherosclerotic diseases. METHODS: One thousand and twenty Chinese subjects (159 women) older than 60 years of age (mean age (70.6 +/- 5.7) years) with at least one MS component underwent routine laboratory tests, and baPWV measurements were analyzed. RESULTS: Participants were divided into four groups by MS components. The mean age did not significantly differ among the MS component groups. We found that not only the diagnostic factors (blood pressure, body mass index (BMI), lipids, glucose) of MS but also baPWV, UA, insulin, homeostasis model of assessment for insulin resistence index (HOMAIR) levels increased, and high density lipoprotein (HDL)-C decreased with an increased number of MS components (test for trend P < 0.05). The association between UA and baPWV was observed after adjustment for gender, age, blood pressure, BMI, serum creatinine and high density lipoprotein, and insulin resistance (r = 0.186, P < 0.0001). There were increases in the odds ratios for the association between the number of components of MS, UA and baPWV, even after adjustment for traditional risk factors. However, after adjustment for insulin or HOMA-IR, there were no significant differences in the multivariate odds ratios among the number of MS components for UA. CONCLUSIONS: The UA level is positively associated with baPWV and MS, but the association between UA and MS is dependent on insulin resistance. Furthermore, baPWV is independently associated with MS in our study population. PMID- 23981620 TI - Mutation detection of type II hair cortex keratin gene KRT86 in a Chinese Han family with congenital monilethrix. AB - BACKGROUND: Monilethrix is an autosomal dominant hair disorder characterized clinically by alopecia and follicular papules. In this study, we collected a Han monilethrix family to detect the mutations in patients and investigated the correlation between the genotype and phenotype of monilethrix. METHODS: In this study, we identified a Chinese family with monilethrix through light microscopic and scanning electron microscopic (SEM) examination. Genomic DNA from peripheral blood samples was prepared. DNA samples from controls and monilethrix patients were subject to polymerase chain reaction (PCR) amplification. Two pairs of primers were used to amplify the seventh exon of KRT86. Mutation screening of the PCR products was detected using direct sequencing. RESULTS: Light microscopic examination showed a regular alternate enlargement and narrow area. SEM examination showed that part of the cuticle of the nodules shed and disappeared gradually in the narrow area with granular protrusions on the surface similar to the erosion-like structure. Parallel longitudinal ridge and groovepattern appeared, and the ridges varied in width, like dead wood. A heterozygous transversion mutation c.1204G > A (p.E402K) in the seventh exon of KRT86 was identified in both patients. CONCLUSIONS: The mutation of extron 7 of KRT86 identified plays a major role in the pathogenesis of this pedigree with monilethrix, and is a mutation hot spot of KRT86. Further research is needed to explore the relationship between the phenotype and the mutation of the type II hair keratin gene KRT86 of monilethrix. PMID- 23981621 TI - Towards prenatal biomonitoring in Nanjing, China: lead and cadmium levels in the duration of pregnancy. AB - BACKGROUND: Prenatal lead and cadmium exposure will not only influence the mother' organ systems, but also will provide an environment that may influence the fetus and neonate in a harmful way.In the present study, we detected the blood lead levels (BLLS) and cadmium levels for the duration of pregnancy and 6 12 weeks after delivery and to analyze the influencing factors of BLLs in healthy pregnant women. METHODS: A cohort study survey was carried out. We recruited 174 healthy pregnant women without pregnancy or obstetric complications or abnormal pregnancy outcomes as the gravida group, and 120 healthy non-pregnant women as the control group. RESULTS: The lead concentrations in the three pregnancy trimesters and in the postpartum period were: (5.98 +/- 2.43), (5.54 +/- 2.01), (5.59 +/- 1.97), and (6.76 +/- 1.74) ug/dl; and (6.75 +/- 2.13) ug/dl in the control group. The cadmium concentrations in the three pregnancy trimesters and postpartum period were 1.61 +/- 0.45, 1.63 +/- 0.46, 1.64 +/- 0.49, and 1.67 +/- 0.57. We found that the BLLs in the gravida group were lower than in the control group during all three trimesters. Occupations, supplement nutritional elements (dietary supplements and nutritional (food) elements), and the time of house painting could affect BLLs in pregnant women. Lead-related occupations, using cosmetics, and living in a house painted more recently than one year previously are risk factors of high BLLs among pregnant women, while calcium, iron, zinc, and milk supplements are protective factors. CONCLUSIONS: These findings may help people, especially pregnant women, to reduce lead exposure via supplements of calcium, iron, zinc, and milk or avoiding contacting risk factors. PMID- 23981622 TI - Preliminary molecular analysis of bacterial composition in periapical lesions with primary endodontic infections of deciduous teeth. AB - BACKGROUND: The bacterial composition of periapical lesions in deciduous teeth has not been well documented. This study was designed to explore the bacterial compositions, especially the dominant bacteria in periapical lesions using 16S rRNA sequencing. METHODS: Tissue samples were collected from 11 periapical lesions in deciduous teeth with primary endodontic infections. DNA was extracted from each sample and analyzed using 16S rRNA cloning and sequencing for the identification of bacteria. RESULTS: All DNA samples were positive for 16S rRNA gene PCR. One hundred and fifty-one phylotypes from 810 clones were identified to eight phyla, and each sample contained an average of 25.9 phylotypes. In addition, 59 phylotypes were detected in more than two samples, and Fusobacterium (F.) nucleatum (8/11), Dialister (D.) invisus (8/11), Campylobacter (C.) gracilis (7/11), Escherichia (E.) coli DH1 (6/11), Aggregatibacter (A.) segnis (6/11), and Streptococcus (S.) mitis (6/11) were the most prevalent species. Furthermore, 45 as-yet-uncultivated phylotypes were also identified. CONCLUSIONS: Chronic periapical lesions in deciduous teeth contained polymicrobial infections. F. nucleatum, D. invisus, C. gracilis, E. coli DH1, A. segnis, and S. mitis were the most prevalent species detected by 16S rRNA sequencing. PMID- 23981623 TI - Comparison study of two diagnostic and grading systems for conjunctivochalasis. AB - BACKGROUND: Different diagnostic and grading systems of conjunctivochalasis have resulted in apparent disparity between the prevalence rates of recent population based studies. This study aimed to investigate the disparity between 4-level system cited from Meller and Tseng in 1998 (abbreviated here as Meller's system) and 5-level system modified from Meller's system cited from Zhang and associates (abbreviated here as Zhang's system) regarding the diagnosis and the patients' preferences for the treatment of conjunctivochalasis in the general population. METHODS: A total of 546 senile residents living in the Guiyangyuan community of Shanghai, China, participated in the study. The diagnostic criteria for conjunctivochalasis were based on two diagnostic grading systems: Meller's system and Zhang's system, which was modified from Meller's system. The participants' preference regarding medical treatment for conjunctivochalasis was determined according to the response to a question. One year later, a follow-up interview determines whether the patient had undergone surgery for conjunctivochalasis. RESULTS: With Meller's system, 398 participants were confirmed as having conjunctivochalasis, and the prevalence rate was 72.89%. According to Zhang's system, only 213 participants were diagnosed as having conjunctivochalasis, and the prevalence rate was 39.01%. A total of 109 eyes underwent medical treatment or surgery for conjunctivochalasis in the following year, including eight eyes that were diagnosed as grade II and 101 eyes that were diagnosed as grade III according to Meller's system and five eyes that were diagnosed as grade I, 55 eyes that were diagnosed as grade II, 31 eyes that were diagnosed as grade III, and 18 eyes that were diagnosed as grade IV according to Zhang' system. CONCLUSION: Diagnoses of conjunctivochalasis using Zhang's system are more consistent with patient requests and the medical treatment strategies used than diagnoses made using Meller's system. PMID- 23981624 TI - Diagnostic accuracy of fiberoptic ductoscopy plus in vivo iodine staining for intraductal proliferative lesions. AB - BACKGROUND: Iodine staining during endoscopy has been successfully used to detect early carcinomatous and precancerous lesions in the esophagus, cervix, and oral cavity. The objective of this study was to determine the diagnostic accuracy of fiberoptic ductoscopy (FDS) plus in vivo iodine staining for intraductal proliferative lesions of the breast. METHODS: We performed periodic acid-Schiff (PAS) and in vitro iodine staining on 52 and 64 specimens of benign mammary hyperplasia, respectively, and 57 and 53 specimens of ductal carcinoma in situ (DCIS), respectively. Next, FDS was performed on 177 recurrent nipple discharge patients who were randomly divided into two groups. One group was iodine-staining group in which 92 patients were randomly selected to undergo iodine staining during FDS, and the remaining 85 were assigned to the control group. Biopsy specimens of suspicious lesions were obtained and subjected to histopathological examination. RESULTS: Following PAS staining, benign mammary hyperplasia lesions were positively stained, while negligible PAS positivity was observed in the DCIS lesions (P < 0.05). Following in vitro iodine staining, benign mammary hyperplasia specimens appeared dark brown, whereas DCIS samples appeared significantly lighter or unstained. Compared with the pathological examination results, FDS with iodine staining showed an agreement rate in the diagnosis of ductal intraepithelial neoplasia (DIN), sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and Youden index of 97.82%, 98.83%, 83.33%, 5.93, 0.014, and 0.8216, respectively; the corresponding values for FDS without iodine staining were 88.24%, 89.16%, 50.00%, 1.78, 0.217, and 0.3916, respectively. CONCLUSION: FDS with iodine staining was superior to conventional FDS for the diagnosis of DIN and is valuable for breast cancer prevention. PMID- 23981625 TI - In vitro cartilage production using an extracellular matrix-derived scaffold and bone marrow-derived mesenchymal stem cells. AB - BACKGROUND: Cartilage repair is a challenging research area because of the limited healing capacity of adult articular cartilage. We had previously developed a natural, human cartilage extracellular matrix (ECM)-derived scaffold for in vivo cartilage tissue engineering in nude mice. However, before these scaffolds can be used in clinical applications in vivo, the in vitro effects should be further explored. METHODS: We produced cartilage in vitro using a natural cartilage ECM-derived scaffold. The scaffolds were fabricated by combining a decellularization procedure with a freeze-drying technique and were characterized by scanning electron microscopy (SEM), micro-computed tomography (micro-CT), histological staining, cytotoxicity assay, biochemical and biomechanical analysis. After being chondrogenically induced, the induction results of BMSCs were analyzed by histology and Immunohisto-chemistry. The attachment and viability assessment of the cells on scaffolds were analyzed using SEM and LIVE/DEAD staining. Cell-scaffold constructs cultured in vitro for 1 week and 3 weeks were analyzed using histological and immunohistochemical methods. RESULTS: SEM and micro-CT revealed a 3-D interconnected porous structure. The majority of the cartilage ECM was found in the scaffold following the removal of cellular debris, and stained positive for safranin O and collagen II. Viability staining indicated no cytotoxic effects of the scaffold. Biochemical analysis showed that collagen content was (708.2-44.7) ug/mg, with GAG (254.7 +/- 25.9) ug/mg. Mechanical testing showed the compression moduli (E) were (1.226 +/- 0.288) and (0.052 +/- 0.007) MPa in dry and wet conditions, respectively. Isolated canine bone marrow-derived stem cells (BMSCs) were induced down a chondrogenic pathway, labeled with PKH26, and seeded onto the scaffold. Immunofluorescent staining of the cell-scaffold constructs indicated that chondrocyte-like cells were derived from seeded BMSCs and excreted ECM. The cell scaffold constructs contained pink, smooth and translucent cartilage-like tissue after 3 weeks of culture. We observed evenly distributed cartilage ECM proteoglycans and collagen type II around seeded BMSCs on the surface and inside the pores throughout the scaffold. CONCLUSION: This study suggests that a cartilage ECM scaffold holds much promise for in vitro cartilage tissue engineering. PMID- 23981626 TI - Chemoradiotherapy followed by surgery could improve the efficacy of treatments in patients with resectable esophageal carcinoma. AB - BACKGROUND: The effectiveness of chemoradiotherapy followed by surgery (CRTS) in patients with resectable esophageal carcinoma remains controversial. We performed a systematic review of the literature with meta-analysis. METHODS: Electronic databases were used to identify published studies between January 1992 and April 2012. Pooled relative risk (RR) with 95% confidence interval (95% CI) was utilized to estimate the strength of the association between CRTS and surgery alone (SA) survival of the resectable esophageal carcinoma patients. Heterogeneity and publication bias were also assessed in the present study. RESULTS: The final analysis of 2755 resectable esophageal carcinoma cases from 21 randomized controlled trials (RCTs) are presented. Compared to the SA group, the 1, 3- and 5-year survival rates were significantly higher in the CRTS group (all P < 0.05); the 3- and 5-year survival rates for the Eastern patients, Western patients, patients undergoing concurrent chemoradiotherapy, patients with squamous cell carcinoma, patients undergoing High-dose radiotherapy (>= 40 Gy), and patients given either "cisplatin + Fluorouracil" or "cisplatin + paclitaxel" chemotherapy were significantly higher in the CRTS group (all P < 0.05). There were no statistical significances in the 3- and 5-year survival rates for patients undergoing sequential chemoradiotherapy or patients with adenocarcinoma between the two groups (all P > 0.05). Compared to the RCTS group, the surgery rate in the SA group was higher (P < 0.05), while the CRTS group had significantly higher radical resection rate, R0 resection rate and lower postoperative local recurrence rate (all P < 0.05). The differences in postoperative complication incidence, post-operative distant metastasis and postoperative mortality rate were not statistically significant between the two groups (all P > 0.05). CONCLUSION: CRTS can significantly improve the survival and surgical conditions of patients with resectable esophageal carcinoma. PMID- 23981627 TI - Rabeprazole 10 mg versus 20 mg in preventing relapse of gastroesophageal reflux disease: a meta-analysis. AB - BACKGROUND: Several randomized controlled trials (RCTs) have compared endoscopic and symptomatic relapses in patients with erosive gastroesophageal reflux disease (GERD). We have summarized current evidence for rabeprazole 10 or 20 mg once daily for GERD maintenance treatment over 1 or 5 years. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched, through August 2012, for eligible RCTs of adults with erosive GERD. The efficacies of rabeprazole 10 and 20 mg/d were compared. RESULTS: The search identified 288 citations, and five RCTs containing 1480 patients were considered eligible. Heartburn relapse rates did not differ significantly between patients treated with rabeprazole 10 and 20 mg/d for 1 year (relative risk (RR) = 1.29; 95% confidence interval (CI): 0.97-1.72), but differed in patients treated for 5 years (RR = 1.274; 95% CI: 1.005-1.615). Endoscopic relapse rates differed significantly between rabeprazole 10 and 20 mg/d for 1 year (RR = 1.92; 95% CI: 1.21-3.06), for 5 years (RR = 1.667; 95% CI: 1.073-2.589), and in combined 1- and 5-year maintenance trials (RR = 1.785; 95% CI: 1.298-2.456). CONCLUSION: Rabeprazole 20 mg/d was superior to rabeprazole 10 mg/d in preventing endoscopic relapse of erosive GERD, but that the two dosages were equivalent in symptomatic relief over 1 year. PMID- 23981628 TI - Uncoupling protein and nonalcoholic fatty liver disease. AB - OBJECTIVE: To review the current advances on the role of uncoupling protein (UCP) in the pathogenesis and progress of nonalcoholic fatty liver disease (NAFLD). DATA SOURCES: A comprehensive search of the PubMed literature without restriction on the publication date was carried out using keywords such as UCP and NAFLD. STUDY SELECTION: Articles containing information related to NAFLD and UCP were selected and carefully analyzed. RESULTS: The typical concepts, up-to-date findings, and existing controversies of UCP2 in NAFLD were summarized. Besides, the effect of a novel subtype of UCP (hepatocellular down regulated mitochondrial carrier protein, HDMCP) in NAFLD was also analyzed. Finally, the concept that any mitochondrial inner membrane carrier protein may have, more or less, the uncoupling ability was reinforced. CONCLUSIONS: Considering the importance of NAFLD in clinics and UCP in energy metabolism, we believe that this review may raise research enthusiasm on the effect of UCP in NAFLD and provide a novel mechanism and therapeutic target for NAFLD. PMID- 23981629 TI - Neuropsychiatric disorders and cognitive dysfunction in patients with Cushing's disease. AB - OBJECTIVE: To review the main neuropsychiatric disorders and cognitive deficits in patients with Cushing's disease (CD) and the associated pathophysiological mechanisms underlying CD. These mechanistic details may provide recommendations for preventing or treating the cognitive impairments and mood disorders in patients with CD. DATA SOURCES: Data were obtained from papers on psychiatric and cognitive complications in CD published in English within the last 20 years. To perform the PubMed literature search, the following keywords were input: cushing's disease, cognitive, hippocampal, or glucocorticoids. STUDY SELECTION: Studies were selected if they contained data relevant to the topic addressed in the particular section. Because of the limited length of this article, we have frequently referenced recent reviews that contain a comprehensive amalgamation of literature rather than the actual source papers. RESULTS: Patients with active CD not only suffer from many characteristic clinical features, but also show some neuropsychiatric disorders and cognitive impairments. Among the psychiatric manifestations, the common ones are emotional instability, depressive disorder, anxious symptoms, impulsivity, and cognitive impairment. Irreversible effects of previous glucocorticoid (GC) excess on the central nervous system, such as hippocampal and the basal ganglia, is the most reasonable reason. Excess secretion of cortisol brings much structural and functional changes in hippocampal, such as changes in neurogenesis and morphology, signaling pathway, gene expression, and glutamate accumulation. Hippocampal volume loss can be found in most patients with CD, and decreased glucose utilization caused by GCs may lead to brain atrophy, neurogenesis impairment, inhibition of long-term potentiation, and decreased neurotrophic factors; these may also explain the mechanisms of GC-induced brain atrophy and hippocampal changes. CONCLUSIONS: Brain atrophy and hippocampal changes caused by excess secretion of cortisol are thought to play a significant pathophysiological role in the etiology of changes in cognitive function and psychiatric disturbances. The exact mechanisms by which GCs induce hippocampal volume loss are not very clear till now. So, further investigations into the mechanisms by which GCs affect the brain and the effective coping strategy are essential. PMID- 23981630 TI - Effect of ventricular leads position on the clinic outcome of cardiac resynchronization therapy. AB - The RV lead position, either RVA or RVHS appears to make no difference in the response to CRT but the LV lead placement play a vital role.9,30 The latest activated regions of LV or areas without transmural myocardial scar for an optimal CRT are preferred. Currently, data demonstrate that no significant difference of clinical outcomes in posterior, anterior, and lateral LV lead position was found, while the ideal pacing site of the LV should be avoided in the apex position as suggested in COMPANION trial and MADIT-CRT trial. And dual site LV CRT, which is a new technique, is also still in progress and we are looking forward to getting more updates from that. PMID- 23981631 TI - Current concept in first metatarsophalangeal joint replacement. PMID- 23981632 TI - Progress of mother-to-child transmission of HIV programs in China: successes, challenges and way forward. PMID- 23981633 TI - Smoking is a risk factor for venous thromboembolism. PMID- 23981634 TI - Surgical technique of video endoscopic inguinal lymphadenectomy via a hypogastric subcutaneous approach. PMID- 23981635 TI - Endovascular treatment of acute proximal deep venous thrombosis secondary to iliac vein compression syndrome: a novel technique for thrombus removal. PMID- 23981636 TI - Two closely neighboring hepatocellular carcinomas mimicking intrahepatic metastasis are confirmed as double primary tumors by the loss of heterozygosity analysis of microsatellites. PMID- 23981637 TI - Red cell distribution width itself without other inflammatory markers may not accurately provide information about severity of coronary artery disease. PMID- 23981638 TI - Two cases of aggressive angiomyxoma of vulva. PMID- 23981639 TI - Congenital absence of right pulmonary artery associated with left patent ductus arteriosus and aortic coarctation. PMID- 23981640 TI - Disseminated herpes zoster in immunocompetent patients not due to varicella zoster virus gene mutation. PMID- 23981642 TI - Rapidly destructive arthrosis of the hip joint. PMID- 23981641 TI - Regional lymphomatoid papulosis successfully controlled by interferon alpha-2b and nitrogen mustard solution. PMID- 23981643 TI - In vitro expression of gelatinases in reconstructed melanoma model composited MV3 cells. PMID- 23981644 TI - ST-11 clonal complex serogroup C Neisseria Meningitidis strain in China. PMID- 23981645 TI - Low-dose oral cyclophosphamide therapy is effective for condylomata acuminata. PMID- 23981646 TI - Scimitar syndrome in an adult with atrial septal defect and severe pulmonary hypertension. PMID- 23981647 TI - Intracranial plasmacytomas mimicking epidural hematoma and revealed by brain hernia. PMID- 23981648 TI - Estimating the toxicity of ambient fine aerosols using freshwater rotifer Brachionus calyciflorus (Rotifera: Monogononta). AB - The toxicity of atmospheric fine particulate matter (PM2.5) in Atlanta is assessed using freshwater rotifers (Brachionus calyciflorus). The PM-laden quartz filters were extracted in both water and methanol. Aerosol extracts were passed through a C-18 column to separate the PM components into hydrophobic and hydrophilic fractions. Toxicity data reported in the units of LC50 (concentration that kills 50% of the test population in 24 h) shows that ambient particles are toxic to the rotifers with LC50 values ranging from 5 to 400 MUg of PM. The methanol extract of the aerosols was substantially more toxic (8 +/- 6 times) to the rotifers compared to the water extracts. A sizeable fraction (>70%) of toxicity was found to be associated with the hydrophobic fraction of PM. However, none of the bulk aerosol species was strongly correlated with the LC50 values suggesting a complicated mechanism of toxicity probably involving synergistic interactions of various PM components. PMID- 23981650 TI - A bio-inspired study on tidal energy extraction with flexible flapping wings. AB - Previous research on the flexible structure of flapping wings has shown an improved propulsion performance in comparison to rigid wings. However, not much is known about this function in terms of power efficiency modification for flapping wing energy devices. In order to study the role of the flexible wing deformation in the hydrodynamics of flapping wing energy devices, we computationally model the two-dimensional flexible single and twin flapping wings in operation under the energy extraction conditions with a large Reynolds number of 106. The flexible motion for the present study is predetermined based on a priori structural result which is different from a passive flexibility solution. Four different models are investigated with additional potential local distortions near the leading and trailing edges. Our simulation results show that the flexible structure of a wing is beneficial to enhance power efficiency by increasing the peaks of lift force over a flapping cycle, and tuning the phase shift between force and velocity to a favourable trend. Moreover, the impact of wing flexibility on efficiency is more profound at a low nominal effective angle of attack (AoA). At a typical flapping frequency f * = 0.15 and nominal effective AoA of 10 degrees , a flexible integrated wing generates 7.68% higher efficiency than a rigid wing. An even higher increase, around six times that of a rigid wing, is achievable if the nominal effective AoA is reduced to zero degrees at feathering condition. This is very attractive for a semi-actuated flapping energy system, where energy input is needed to activate the pitching motion. The results from our dual-wing study found that a parallel twin-wing device can produce more power compared to a single wing due to the strong flow interaction between the two wings. PMID- 23981649 TI - EURO-WABB: an EU rare diseases registry for Wolfram syndrome, Alstrom syndrome and Bardet-Biedl syndrome. AB - BACKGROUND: Wolfram, Alstrom and Bardet-Biedl (WABB) syndromes are rare diseases with overlapping features of multiple sensory and metabolic impairments, including diabetes mellitus, which have caused diagnostic confusion. There are as yet no specific treatments available, little or no access to well characterized cohorts of patients, and limited information on the natural history of the diseases. We aim to establish a Europe-wide registry for these diseases to inform patient care and research. METHODS: EURO-WABB is an international multicenter large-scale observational study capturing longitudinal clinical and outcome data for patients with WABB diagnoses. Three hundred participants will be recruited over 3 years from different sites throughout Europe. Comprehensive clinical, genetic and patient experience data will be collated into an anonymized disease registry. Data collection will be web-based, and forms part of the project's Virtual Research and Information Environment (VRIE). Participants who haven't undergone genetic diagnostic testing for their condition will be able to do so via the project. CONCLUSIONS: The registry data will be used to increase the understanding of the natural history of WABB diseases, to serve as an evidence base for clinical management, and to aid the identification of opportunities for intervention to stop or delay the progress of the disease. The detailed clinical characterisation will allow inclusion of patients into studies of novel treatment interventions, including targeted interventions in small scale open label studies; and enrolment into multi-national clinical trials. The registry will also support wider access to genetic testing, and encourage international collaborations for patient benefit. PMID- 23981651 TI - Histone acetyltransferase PCAF up-regulated cell apoptosis in hepatocellular carcinoma via acetylating histone H4 and inactivating AKT signaling. AB - BACKGROUND: PCAF is an important intrinsic histone acetyltransferases. This study tried to establish the effect of PCAF on HCC cell apoptosis. METHOD: Both in vitro and in vivo experiments including IHC, DAPI staining, caspase 3/7 activity assay, BrdU assay, MTT assay, western immunoblotting and co-immunoprecipitation were used here. RESULTS: PCAF was found to be expressed at the low level in most of HCC cell lines. PCAF overexpression induced cell apoptosis and growth arrest with increased Histone H4 acetylation and inactivation of AKT signaling in Huh7 and HepG2 cells. The opposite results were obtained by silencing PCAF in Hep3B cells. The co-immunoprecipitation assay confirmed that PCAF protein was bound with histone H4 protein in the nucleus of Hep3B cells. Finally, the in vivo experiment confirmed the findings mentioned-above. CONCLUSION: These data identified PCAF promotes cell apoptosis and functions as a HCC repressor through acetylating histone H4 and inactivating AKT signaling. PMID- 23981652 TI - Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic hematopoietic stem cell transplantation for acute leukemia patients: a single center experience. AB - Due to the high transplant related morbidity and mortality (TRM), relatively younger acute leukemia patients that have a good performance status and no comorbidity are eligible for myeloablative conditioning (MAC) followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). The outcomes of 84 consecutive adult patients with ALL (n=38) or AML (n=46) who underwent allo HSCT from their HLA-identical siblings were evaluated retrospectively. The median age at transplantation was 34 (17-58 years) for the whole patient population. Of these, 24 patients received a MAC and 60 patients received a fludarabine-based reduced intensity conditioning regimen (RIC). After a median follow-up of 32 months (range, 1-119), for the entire group, the 3-year estimated overall survival (OS) was 57.5% and the disease-free survival (DFS) was 51.5%. The OS for ALL and AML patients were 53.9% vs 62.1%: and DFS were 50.5% and 53.4%, respectively. The 3-year estimated OS for RIC and MAC patients were 63.2% and 41.7%; and DFS were 57.1% and 34.7%, respectively. In ALL patients, conditioning regimens (RIC vs MAC) led to similar OS and DFS; however, in AML patients both OS (70.1% vs 21.4%) and DFS (59.3% vs 42.9%) were found to be higher in RIC patients compared to MAC recipients. Overall, the TRM at day 100 was 1.7% and has increased up to 5.1% at 1st year. In multivariate analysis, the diagnosis (p=0.03) and RIC regimen (p=0.027) were the prognostic variables for prolonged OS in all patients; and RIC regimen (p=0.031) was the only prognostic factor for prolonged OS in AML patients. The first complete remission (CR1) was correlated with a prolonged DFS as an independent variable for all patients (p=0.09). Eleven of the RIC patients (18.3%) and 6 of the MAC patients (25%) developed acute graft versus-host disease (GvHD). Seventeen of the RIC patients (33.3%) and 4 of the MAC patients (16.7%) developed chronic GvHD. In conclusion, RIC conditioning regimens may provide a longer OS and DFS, especially in patients with AML who are in first CR, not eligible for MAC conditioning. PMID- 23981653 TI - Challenges in lymphoma diagnosis in HIV positive patients in the South African setting. AB - An increase in high grade B-cell lymphomas has been noted in HIV infection. Sub Saharan Africa is the epicentre of the epidemic and in Gauteng, South Africa >90% of patients with high grade lymphoma tested positive for HIV infection. The diagnosis of lymphoma may be challenging in HIV because of reactive conditions which mimic lymphomas, the atypical clinical presentation and the atypical histological findings. The WHO classification divides lymphomas into discrete categories. Despite this, tumours in HIV positive patients commonly show atypical morphological, immunophenotypic, molecular and cytogenetic features, making exact classification difficult. This has lead to an increase in the diagnosis of the highly aggressive B-cell lymphoma, unclassifiable with features intermediate between DLBCL and BL. It appears likely that HIV-associated lymphomas represent a continuum of disease. PMID- 23981654 TI - Cohesin in development and disease. AB - Cohesin is a ring-shaped complex, conserved from yeast to human, that was named for its ability to mediate sister chromatid cohesion. This function is essential for chromosome segregation in both mitosis and meiosis, and also for DNA repair. In addition, more recent studies have shown that cohesin influences gene expression during development through mechanisms that likely involve DNA looping and interactions with several transcriptional regulators. Here, we provide an overview of how cohesin functions, highlighting its role both in development and in disease. PMID- 23981655 TI - Molecular causes of aneuploidy in mammalian eggs. AB - Mammalian oocytes are particularly error prone in segregating their chromosomes during their two meiotic divisions. This results in the creation of an embryo that has inherited the wrong number of chromosomes: it is aneuploid. The incidence of aneuploidy rises significantly with maternal age and so there is much interest in understanding this association and the underlying causes of aneuploidy. The spindle assembly checkpoint, a surveillance mechanism that operates in all cells to prevent chromosome mis-segregation, and the cohesive ties that hold those chromosomes together, have thus both been the subject of intensive investigation in oocytes. It is possible that a lowered sensitivity of the spindle assembly checkpoint to certain types of chromosome attachment error may endow oocytes with an innate susceptibility to aneuploidy, which is made worse by an age-related loss in the factors that hold the chromosomes together. PMID- 23981657 TI - Headaches in a 15-year-old: Is unruptured aneurysm an incidental finding...or not? PMID- 23981656 TI - Female-biased dimorphism underlies a female-specific role for post-embryonic Ilp7 neurons in Drosophila fertility. AB - In Drosophila melanogaster, much of our understanding of sexually dimorphic neuronal development and function comes from the study of male behavior, leaving female behavior less well understood. Here, we identify a post-embryonic population of Insulin-like peptide 7 (Ilp7)-expressing neurons in the posterior ventral nerve cord that innervate the reproductive tracts and exhibit a female bias in their function. They form two distinct dorsal and ventral subsets in females, but only a single dorsal subset in males, signifying a rare example of a female-specific neuronal subset. Female post-embryonic Ilp7 neurons are glutamatergic motoneurons innervating the oviduct and are required for female fertility. In males, they are serotonergic/glutamatergic neuromodulatory neurons innervating the seminal vesicle but are not required for male fertility. In both sexes, these neurons express the sex-differentially spliced fruitless-P1 transcript but not doublesex. The male fruitless-P1 isoform (fruM) was necessary and sufficient for serotonin expression in the shared dorsal Ilp7 subset, but although it was necessary for eliminating female-specific Ilp7 neurons in males, it was not sufficient for their elimination in females. By contrast, sex-specific RNA-splicing by female-specific transformer is necessary for female-type Ilp7 neurons in females and is sufficient for their induction in males. Thus, the emergence of female-biased post-embryonic Ilp7 neurons is mediated in a subset specific manner by a tra- and fru-dependent mechanism in the shared dorsal subset, and a tra-dependent, fru-independent mechanism in the female-specific subset. These studies provide an important counterpoint to studies of the development and function of male-biased neuronal dimorphism in Drosophila. PMID- 23981660 TI - BMP9 and COX-2 form an important regulatory loop in BMP9-induced osteogenic differentiation of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) can self-renew and differentiate into osteogenic, chondrogenic, adipogenic and myogenic lineages. It's reported that bone morphogenetic protein 9 (BMP9) is one of the most potent osteogenic BMPs to initiate the commitment of MSCs to osteoblast lineage. Cyclooxygenase-2 (COX-2) is critical for bone fracture healing and osteogenic differentiation in MSCs. However, the relationship between COX-2 and BMP9 in osteogenesis remains unknown. Herein, we investigate the role of COX-2 in BMP9-induced osteogenesis in MSCs. We demonstrate that COX-2 is up-regulated as a target of BMP9 in MSCs. Both COX-2 inhibitor (NS-398) and COX-2 knockdown siRNAs can effectively decrease alkaline phosphatase (ALP) activities induced by BMP9 in MSCs. NS-398 also down-regulates BMP9-induced expression of osteopontin and osteocalcin, so does the matrix mineralization. The in vivo studies indicate that knockdown of COX-2 attenuates BMP9-induced ectopic bone formation. In perinatal limb culture assay, NS-398 is shown to reduce the hypertropic chondrocyte zone and ossification induced by BMP9. Mechanistically, knockdown of COX-2 significantly inhibits the BMP9 up regulated expression of Runx2 and Dlx-5 in MSCs, which can be rescued by exogenous expression of COX-2. Furthermore, knockdown of COX-2 apparently reduces BMP9 induced BMPR-Smad reporter activity, the phosphorylation of Smad1/5/8, and the expression of Smad6 and Smad7 in MSCs. NS-398 blocks the expression of BMP9 mediated by BMP9 recombinant adenovirus. Taken together, our findings suggest that COX-2 plays an important role in BMP9 induced osteogenic differentiation in MSCs; BMP9 and COX-2 may form an important regulatory loop to orchestrate the osteogenic differentiation in MSCs. PMID- 23981658 TI - Structural patterns of the proximal femur in relation to age and hip fracture risk in women. AB - Fractures of the proximal femur are the most devastating outcome of osteoporosis. It is generally understood that age-related changes in hip structure confer increased risk, but there have been few explicit comparisons of such changes in healthy subjects to those with hip fracture. In this study, we used quantitative computed tomography and tensor-based morphometry (TBM) to identify three dimensional internal structural patterns of the proximal femur associated with age and with incident hip fracture. A population-based cohort of 349 women representing a broad age range (21-97years) was included in this study, along with a cohort of 222 older women (mean age 79+/-7years) with (n=74) and without (n=148) incident hip fracture. Images were spatially normalized to a standardized space, and age- and fracture-specific morphometric features were identified based on statistical maps of shape features described as local changes of bone volume. Morphometric features were visualized as maps of local contractions and expansions, and significance was displayed as Student's t-test statistical maps. Significant age-related changes included local expansions of regions low in volumetric bone mineral density (vBMD) and local contractions of regions high in vBMD. Some significant fracture-related features resembled an accentuated aging process, including local expansion of the superior aspect of the trabecular bone compartment in the femoral neck, with contraction of the adjoining cortical bone. However, other features were observed only in the comparison of hip fracture subjects with age-matched controls including focal contractions of the cortical bone at the superior aspect of the femoral neck, the lateral cortical bone just inferior to the greater trochanter, and the anterior intertrochanteric region. Results of this study support the idea that the spatial distribution of morphometric features is relevant to age-related changes in bone and independent to fracture risk. In women, the identification by TBM of fracture-specific morphometric alterations of the proximal femur, in conjunction with vBMD and clinical risk factors, may improve hip fracture prediction. PMID- 23981659 TI - Effect of glucocorticoid treatment on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover. AB - The aim of this study was to analyse the effect of glucocorticoid therapy (GCCT) on Wnt signalling antagonists (sclerostin and Dkk-1) and their relationship with bone turnover. 25 patients (8 M/17 F, aged 48+/-19yrs) recently initiating GCCT (>=7.5mg/day, <=6months) were prospectively included. Bone turnover markers (bone formation: P1NP, osteocalcin [OC], bone ALP; bone resorption: sCTx) and Wnt antagonists (serum sclerostin and Dkk-1) were assessed in all patients (short term and 12months after initiating GCCT). Bone mineral density (BMD) was performed to assess osteoporosis. The results were compared with 60 healthy controls. At short-term patients on GCCT showed a significant decrease in bone formation markers versus controls (P1NP: 19+/-9 vs. 43+/-16ng/mL, p<0.001; OC: 7.4+/-2.4 vs. 18.4+/-5.2ng/mL, p=0.001) and in Dkk-1 levels (24.5+/-20.1 vs. 36.8+/-13.7pmol/L, p=0.008) with similar sclerostin values (41.8+/-21.8 vs. 42.1+/-13.9pmol/L, p=0.950). Sclerostin correlated positively with GCCT doses (r=0.449, p=0.024) and lumbar BMD (r=0.424, p=0.035), and negatively with bone ALP (r=-0.398, p=0.049). A progressive decrease in Dkk-1 levels was observed at 12months, (19.1+/-14.9, p=0.001), whereas sclerostin increased compared to controls (48.9+/-11.6, p=0.045). In conclusion, the effect of GCCT on the serum levels of the Wnt signalling parameters differs depending on the antagonist evaluated. Whereas sclerostin values increased and showed a relationship with the dose and bone AP, Dkk-1 levels decreased throughout the study suggesting a counter-regulatory mechanism of this factor thereby reducing the deleterious effect of GCCT in the bone. PMID- 23981661 TI - Urban forests as hubs for novel zoonosis: blood meal analysis, seasonal variation in Culicoides (Diptera: Ceratopogonidae) vectors, and avian haemosporidians. AB - Culicoides vectors can transmit a diverse array of parasites and are globally distributed. We studied feeding preferences and seasonal variation of Culicoides (Diptera: Ceratopogonidae) vectors in an urban forest of Germany to determine whether humans living nearby are readily exposed to vector-borne parasites from wild animals. We used a fragment of the mtDNA COI gene to identify hosts from blood meals. We amplified a fragment of the mtDNA cyt b to detect haemosporidian infections in Culicoides abdomens and thoraxes. We detected a total of 22 Culicoides species. Fifty-eight blood meals (84%) were from humans, 10 from birds, and one from livestock. We found Culicoides kibunensis (considered ornithophilic) with 29 human blood meals. Host generalist Culicoides festivipennis and Culicoides obsoletus had 14 human blood meals. Culicoides clastrieri and Culicoides semimaculatus fed on birds; previously humans were their only known host. Six thoraxes and three abdomens were infected with either Haemoproteus pallidulus or Haemoproteus parabelopolskyi. There were changes in Culicoides community structure across months. Culicoides pictipennis was the dominant species during spring, C. kibunensis and C. clastrieri were dominant during summer, and C. obsoletus was dominant by early autumn. All dominant species were generalists feeding on birds, livestock and humans. Our results indicate that humans can serve as a blood source for dominant Culicoides species instead of the normal wild animal hosts in urban areas. PMID- 23981662 TI - Development of feeding systems and strategies of supplementation to enhance rumen fermentation and ruminant production in the tropics. AB - The availability of local feed resources in various seasons can contribute as essential sources of carbohydrate and protein which significantly impact rumen fermentation and the subsequent productivity of the ruminant. Recent developments, based on enriching protein in cassava chips, have yielded yeast fermented cassava chip protein (YEFECAP) providing up to 47.5% crude protein (CP), which can be used to replace soybean meal. The use of fodder trees has been developed through the process of pelleting; Leucaena leucocephala leaf pellets (LLP), mulberry leaf pellets (MUP) and mangosteen peel and/or garlic pellets, can be used as good sources of protein to supplement ruminant feeding. Apart from producing volatile fatty acids and microbial proteins, greenhouse gases such as methane are also produced in the rumen. Several methods have been used to reduce rumen methane. However, among many approaches, nutritional manipulation using feed formulation and feeding management, especially the use of plant extracts or plants containing secondary compounds (condensed tannins and saponins) and plant oils, has been reported. This approach could help todecrease rumen protozoa and methanogens and thus mitigate the production of methane. At present, more research concerning this burning issue - the role of livestock in global warming warrants undertaking further research with regard to economic viability and practical feasibility. PMID- 23981663 TI - Effects of repeated 5-HT6 receptor stimulation on BDNF gene expression and cell survival. AB - In support of the neurotrophic hypothesis of depression chronic antidepressant drug treatment increases brain-derived neurotrophic factor (bdnf) gene expression and neurogenesis. Regarding 5-HT active drugs, the 5-HT receptor behind these effects remains unidentified. Here we report the effect of repeated 5-HT6 receptor stimulation on bdnf expression and cell survival. The previously reported acute stimulatory action of the selective 5-HT6 agonist LY-586713 on hippocampal bdnf expression was still present following sub-chronic (4 days), but not chronic (14 days), treatment. The effect on 5-HT6-mediated cell survival was also dependent on a similar length of treatment. Hence, our study found no support for a primary effect of 5-HT6 receptors in the mediation of chronic antidepressant drug-induced up-regulation of bdnf expression or neurogenesis. PMID- 23981664 TI - The beta4 nicotinic receptor subunit modulates the chronic antidepressant effect mediated by bupropion. AB - The objective of the current study is to investigate the role of the nicotinic receptor beta4 subunit in the antidepressant activity of bupropion. Wild-type (beta4+/+) and knockout (beta4-/-) mice were intraperitoneally administered with normal saline (control) or bupropion (40mg/kg) daily for the first two weeks. Forced swim tests were performed on day 1 to determine the acute effect of bupropion at 0, 15, 30, 45, or 60min after the injection, and after two weeks of daily treatment to determine the chronic effects. To examine the remnant effects of bupropion after withdrawal, forced swim tests were performed one and two weeks after the last day of treatment with bupropion. Our results indicate that: (1) the acute treatment with bupropion increases the swimming time (i.e., antidepressant effect) in beta4+/+ and beta4-/- mice from both genders, (2) the antidepressant effect after the chronic treatment is seen only in female beta4+/+ mice, and (3) the residual antidepressant effect of bupropion persists only in male beta4+/+ mice after one week withdrawal. We conclude that the beta4 subunit plays a modulatory role in the chronic antidepressant effect mediated by bupropion, and that its effect is gender-specific. PMID- 23981665 TI - The long-term efficacy and safety of levetiracetam in a tertiary epilepsy centre. AB - AIM: To evaluate the long-term efficacy and safety of levetiracetam based on a large population of patients in a tertiary epilepsy centre. METHODS: All patients who received levetiracetam at the Seoul National University Hospital between January 2007 and March 2009 were evaluated. Patients who underwent brain surgery for seizure control or who had associated progressive disease were excluded from this study. The electronic medical records of these patients were reviewed retrospectively. RESULTS: A total of 568 patients were recruited, including 124 patients with generalised epilepsy. The mean duration of the follow-up period was 29.3 months. The seizure-free rate was 33.6% and was higher in patients with generalised epilepsy (51.6%) than patients with localisation-related epilepsy (28.6%). There was a strong correlation between initial response and dose-up response in 351 patients with increased dosage during the follow-up period. A total of 486 adverse events developed in 316 patients. The most common adverse event (24.3%) was irritability, which was associated with a high rate of drug discontinuation. Previous history of mood disorder was the only factor related to the development of irritability in patients using this medication. CONCLUSION: Levetiracetam was effective and safe as monotherapy and add-on therapy for partial and generalised epilepsy. The initial response to levetiracetam may provide useful information for predicting the response to increased dose of levetiracetam. However, the use of this medication was associated with a rate of irritability that was higher than expected in patients with a history of mood disorders. PMID- 23981666 TI - Physicians' attitude toward female genital plastic surgery: a multinational survey. AB - INTRODUCTION: The demand for female genital plastic surgery (FGPS) has increased over the last few decades. Yet, to date, there are no objective explicit measurements to define "abnormal" appearance of genital organs. Using the results of this study, we aimed to produce a statement of the European Society for Sexual Medicine (ESSM) on FGPS practice. AIMS: To evaluate the prevalence of demand for FGPS and to explore the attitudes of sexual medicine specialists toward indications for FGPS. METHODS: Attendees of the 2012 Annual Congress of the ESSM in Amsterdam, the Netherlands, were asked to participate in a survey during the congress. MAIN OUTCOME MEASURE: A 25-item self-report, closed-question questionnaire subdivided into three sections: sociodemographic data, professional background, and personal attitudes toward FGPS. RESULTS: Overall, a total of 360 physicians (mean age 48 years; range 23-72) from different medical disciplines completed the survey. There were diverse responses among participants regarding the definition of abnormal labial appearance and the techniques for labial reduction they perform. Overall, 65% responded that FGPS is frequently or occasionally demanded by the patients they treat. Likewise, most physicians (63%) reported that they never perform FGPS. Conversely, only 14% reported that they either frequently or occasionally perform FGPS. Almost one-third of participants believe that FGPS (labial surgery) improves sexual function. Fifty-two percent of participants answered that they believe that self image is the main reason for women to ask for labial surgery. CONCLUSIONS: Self-image was regarded as the main factor in the demand for FGPS. Many practitioners in the field of sexual medicine recommend that women be referred for consultation with a psychiatrist or psychologist before undergoing FGPS. PMID- 23981667 TI - Intravenous thrombolysis for acute ischemic stroke in the 3- to 4.5-hour window- the Malabar experience. AB - BACKGROUND: Intravenous thrombolysis for acute ischemic stroke with recombinant tissue plasminogen activator has been shown to be beneficial up to 4.5-hours of symptom onset. AIMS: The study aims to review our experience with thrombolysis with recombinant tissue plasminogen activator in the 3- to 4.5-hours window in acute ischemic stroke. SETTINGS AND DESIGN: Prospective observational study of patients with acute ischemic stroke thombolysed between 3- and 4.5-hours after onset from July 2009 to October 2012 at a tertiary-care center in the Malabar region of South India. MATERIALS AND METHODS: The dose of recombinant tissue plasminogen activator used was 50 mg in all patients. Inclusion and exclusion criteria were similar to European Co-operative Acute Stroke Study-3 criteria, with the exceptions that we did not use an age cutoff of 80 years and did not restrict thrombolysis for previous stroke with diabetes or elevated blood glucose levels. STATISTICAL ANALYSIS USED: Good outcome was defined as a three-month modified Rankin Score of 2 or less. The chi-square test was used to compare the outcome among various sub-types of ischemic stroke. The age, blood glucose, National Institute of Health Stroke Scale Score, and time to thrombolysis were compared between groups with the nonparametric Mann-Whitney U-test. RESULTS: Thirty-one patients (median age 65 years, range 44-85, and median National Institute of Health Stroke Scale Score 10, range 5-22) were thrombolysed in the 3 to 4.5-hours window after stroke onset during the study period. In the first 24 h, 16 patients (52%) improved in National Institute of Health Stroke Scale Score by 4 or more points while three worsened by 4 or more points. At the three-month follow up, 15 patients (48%) were functionally independent (modified Rankin Score <= 2). None had symptomatic intracerebral hemorrhage. There was no significant difference in outcome between the various ischemic stroke sub-types. The baseline age, National Institute of Health Stroke Scale Score, blood glucose, and onset to treatment time did not differ significantly between the groups with good and poor outcome. CONCLUSION: Our initial experience confirms that thrombolysis for ischemic stroke in the extended window is safe and beneficial. PMID- 23981668 TI - A new motif in the N-terminal of acetylcholinesterase triggers amyloid-beta aggregation and deposition. AB - BACKGROUND AND PURPOSE: As a molecular chaperone, acetylcholinesterase (AChE; EC 3.1.1.7) plays a critical role in the pathogenesis of Alzheimer's disease (AD). The peripheral anionic site (PAS) of AChE has been indicated as the amyloid-beta (Abeta) binding domain. The goal of this study was to determine other motifs in AChE involved in Abeta aggregation and deposition. METHODS AND RESULTS: The beta hairpin in monomeric Abeta is the key motif of nucleation-dependent Abeta self aggregation. As AChE could induce Abeta aggregation and deposition, we searched AChE for beta-hairpin structures. In A11-specific dot blot assay, AChE was detected by an oligomer-specific antibody A11, implying the existence of beta hairpin structures in AChE as beta-hairpin was the core motif of oligomers. A molecular superimposing approach further revealed that the N-terminal region, from Glu7 to Ile20, in AChE (AChE 7-20) was similar to the beta-hairpin domain in Abeta. The results of further dot blot assays, thioflavin T fluorescence assays, and electron microscopy imaging experiments, indicated that the N-terminal synthetic peptide AChE7-20 had nearly the same ability as AChE with regard to triggering Abeta aggregation and deposition. CONCLUSIONS: AChE 7-20, a beta hairpin region in AChE, might be a new motif in AChE capable of triggering Abeta aggregation and deposition. This finding will be helpful to design new and more effective Abeta aggregation inhibitors for AD treatment. PMID- 23981669 TI - The PROBIT approach in estimating the prevalence of wasting: revisiting bias and precision. AB - BACKGROUND: The PROBIT methodology was presented in the 1995 World Health Organization Technical Report on Anthropometry as an alternative to the standard prevalence based method of measuring malnutrition in children. Theoretically the PROBIT method will always give a smaller standard error than the standard prevalence method in measuring malnutrition. A recent article by Dale et al. assessed the PROBIT method for measuring global acute malnutrition measure and found that the method was biased and the precision was superior only for sample sizes less than 150 when compared to the standard method. In a manner similar to Dale, our study further investigated the bias and precision of the PROBIT method for different sample sizes using simulated populations. RESULTS: The PROBIT method showed bias for each of the ten simulated populations, but the direction and magnitude of the average bias was changed depending on the simulated population. For a given simulated population, the average bias was relatively constant for all sample sizes drawn. The 95% half-width confidence interval was lower for the PROBIT method than the standard prevalence method regardless of the sample size or simulated population. The absolute difference in the confidence limits showed the most gains for the PROBIT method for the smaller samples sizes, but the ratio of confidence intervals was relatively constant across all sample sizes. CONCLUSIONS: The PROBIT method will provide gains in precision regardless of the sample size, but the method may be biased. The direction and magnitude of the bias depends on the population it is drawn from. PMID- 23981670 TI - Determinants of complementary feeding practices among Nepalese children aged 6-23 months: findings from Demographic and Health Survey 2011. AB - BACKGROUND: The adoption of inappropriate feeding practices is one of the reasons for under nutrition in Nepal and elsewhere. The objective of this study was to describe the rate of and identify the factors associated with providing the World Health Organization (WHO) recommended infant feeding practices of minimum dietary diversity, minimum meal frequency and minimum acceptable diet in Nepal amongst young children between 6-23 months in 2011. METHODS: Data from Nepal Demographic and Health Survey (NDHS) 2011 was used. Prevalence of minimum dietary diversity, minimum meal frequency and minimum acceptable diet was obtained by using descriptive statistics. A Chi-square test (chi2) followed by multiple logistic regression analyses were used to determine the adjusted effect of potential factors on the outcome variables. RESULTS: Of the 698 children aged 6-23 months; while 535 (76.6%) received the minimum meal frequency, only 212 (30.4%) children received the minimum dietary diversity, and 185 (26.5%) received an acceptable diet. Children of older mothers (>35 years); educated mothers and fathers; and mothers from all the development regions except the Mid-western region were more likely to have been provided with the recommended dietary diversity. Children of mothers who had attended >=4 antenatal visits and who lived in the Eastern region were more likely to provide their child with the recommended meal frequency. Children of mothers, who attended >= 4 antenatal visits, were educated and whose fathers had at least a secondary education were more likely to meet the recommended acceptable diet standards. CONCLUSION: Young children aged less than two years in Nepal are at risk for not meeting the WHO recommended infant feeding standards given that only about one in three children were provided with the recommended dietary diversity and acceptable diet. This finding suggests that the majority of children are at risk of under nutrition. An appropriate mix of health education and food supplements could be a feasible option for Nepal to improve the number of children who meet the recommended infant feeding guidelines, reduce under nutrition and improve the survival rates of young children. PMID- 23981671 TI - Triphenyltin chloride induces spindle microtubule depolymerisation and inhibits meiotic maturation in mouse oocytes. AB - Meiosis produces haploid gametes for sexual reproduction. Triphenyltin chloride (TPTCL) is a highly bioaccumulated and toxic environmental oestrogen; however, its effect on oocyte meiosis remains unknown. We examined the effect of TPTCL on mouse oocyte meiotic maturation in vitro and in vivo. In vitro, TPTCL inhibited germinal vesicle breakdown (GVBD) and first polar body extrusion (PBE) in a dose dependent manner. The spindle microtubules completely disassembled and the chromosomes condensed after oocytes were exposed to 5 or 10MUgmL(-1) TPTCL. gamma Tubulin protein was abnormally localised near chromosomes rather than on the spindle poles. In vivo, mice received TPTCL by oral gavage for 10 days. The general condition of the mice deteriorated and the ovary coefficient was reduced (P<0.05). The number of secondary and mature ovarian follicles was significantly reduced by 10mgkg(-1) TPTCL (P<0.05). GVBD decreased in a non-significant, dose dependent manner (P>0.05). PBE was inhibited with 10mgkg(-1) TPTCL (P<0.05). The spindles of in vitro and in vivo metaphase II oocytes were disassembled with 10mgkg(-1) TPTCL. These results suggest that TPTCL seriously affects meiotic maturation by disturbing cell-cycle progression, disturbing the microtubule cytoskeleton and inhibiting follicle development in mouse oocytes. PMID- 23981673 TI - The role of MAP kinases in the induction of iNOS expression in neutrophils exposed to NDMA: the involvement transcription factors. AB - PURPOSE: The role of MAP kinases in the activation of AP-1 (c-Jun, c-Fos) and NF kappaB p65 engaged in the regulation of iNOS expression in human neutrophils (PMNs) exposed to N-nitrosodimethylamine (NDMA) was analyzed in the study. MATERIAL AND METHODS: The study included a group of 20 healthy individuals. Isolated human PMN were incubated in the presence of NDMA. Selective MAP kinases inhibitors were used. The expression of proteins in the cytoplasmic and nuclear fractions was assessed using Western blot method. RESULTS: The results show that NDMA intensifies iNOS, c-Jun, NF-kappaB p65 and IkappaB-alpha expression in the analyzed PMNs. The blocking of the p38 pathway led to lower iNOS expression, and higher expression of c-Jun and c-Fos in the cytoplasmic fraction, and also lower c-Jun expression in the nuclear fraction of PMNs exposed to NDMA. A decrease in iNOS expression in the cytoplasmic fraction, and also c-Jun in both fractions of the examined cells, was observed as a result of JNK pathway inhibition. The blocking of the ERK5 pathway led to higher iNOS, c-Jun and c-Fos expression in the cytoplasmic fraction, and higher c-Jun expression in the nuclear fraction of PMNs exposed to NDMA. The study also demonstrated that blocking of the p38 and JNK pathways resulted in higher expression of NF-kappaB p65 and IkappaB-alpha in the cytoplasmic fraction and their lower expression in the nuclear fraction of these cells. CONCLUSION: Our data indicate the role of MAP kinases p38 and JNK in the activation of c-Jun and NF-kappaB p65 transcription factors engaged in the regulation of iNOS expression in human neutrophils exposed to NDMA. However ERK5 kinase is not involved in the regulation of iNOS and NO production by those cells. PMID- 23981674 TI - Cross-talk between integrin receptor and insulin-like growth factor receptor in regulation of collagen biosynthesis in cultured fibroblasts. AB - PURPOSE: Cellular processes are regulated by signals generated by adhesion receptors and growth factor receptors. IGFbinding protein 1 (IGFBP-1) is a molecule which may affect the both signaling pathways through inactivation of IGF I (ligand for IGF-IR) and binding to RGD region of integrin receptors. Whether this phenomenon is important in communication between insulin-like growth factor receptor (IGF-IR) and beta1-integrin receptor in regulation of prolidase activity and collagen biosynthesis is the aim of this study. MATERIAL AND METHOD: We studied the effects of IGFBP-1, IGF-I, thrombin (integrin activator), echistatin (disintegrin), phosphatidylinositol 3-kinase inhibitor (LY-294002) and ERK 1/2 inhibitors (PD98059 and UO126) on prolidase activity, collagen biosynthesis and expression of proteins participating in pathways generated by these receptors. RESULTS: Stimulation of beta1-integrin and IGF-I receptors by standard ligands was proved to up-regulate collagen synthesis in cultured fibroblasts. IGFBP-1, similarly as echistatin and studied inhibitors, contributed to down-regulation of ERK1/2, Akt, mTOR expression and up-regulation of NFkappaB. It was accompanied by parallel decrease in prolidase activity and collagen biosynthesis. CONCLUSION: The data suggest that "cross talk" between IGF-I receptor and integrin receptor may play important role in regulation of prolidase activity and collagen biosynthesis. PMID- 23981675 TI - Kinetic study of brilliant green adsorption from aqueous solution onto white rice husk ash. AB - The present research was focused on the study of adsorption kinetics of brilliant green (BG) onto white rice husk ash from aqueous solutions. The research was performed in the temperature interval 290-320 K in 10 degrees steps and in the concentration range of 3-100 mg L(-1). Batch studies were conducted in order to determine the optimal adsorbent dose, and the time required to reach the adsorption equilibrium at each temperature. The effect of the initial concentration of brilliant green was studied (pH not adjusted), as well as the effect of temperature. The maximum adsorption capacity of the WRHA for BG at 320 K was determined to be 85.56 mg g(-1). The adsorption kinetic data were analyzed employing several kinetic models: pseudo-first-order equation, pseudo-second order equation, Elovichequation, Banghman's equation, Diffusion-chemisorption model, and Boyd kinetic expression. It was established that the adsorption process obeyed the pseudo-second-order kinetic model. Based on the rate constants obtained by this kinetic model using Arrhenius and Eyring equations, the activation parameters were determined, namely the activation energy (50.04 kJ mol(-1)), the change of entropy (-318.31 J mol(-1) K(-1)), enthalpy (-47.50 kJ mol(-1)), and Gibbs free energy (range 44.81-54.36 kJ mol(-1)) for the formation of activated complex from the reagents. PMID- 23981672 TI - Sildenafil ameliorates biomarkers of genotoxicity in an experimental model of spontaneous atherosclerosis. AB - BACKGROUND: It is well known that enhanced production of reactive oxygen species (ROS) leads to oxidative stress observed in atherosclerosis and that ROS can also cause damage in cellular macromolecules, including DNA. Considering previous report that sildenafil, an inhibitor of phosphodiesterase 5 (PDE5), has antioxidant effects, in the present study we evaluated the effect of this drug on genotoxicity of blood mononuclear cells (MNC) and liver cells from atherosclerotic apolipoprotein E knockout mice (apoE(-/-)). METHODS: ROS production in MNC was evaluated by flow cytometry with the fluorescent dye dihydroethidium (DHE), a method that has been used to quantify the production of superoxide anion, and DNA damage was evaluated in both MNC and liver cells using the alkaline comet assay. Sildenafil-administered apoE(-/-) mice were compared with strain-matched mice administered with vehicle and with C57BL/6 wild-type (WT) mice. RESULTS: MNC from apoE(-/-) vehicle exhibited a 2-fold increase in production of superoxide anion in comparison with WT. In contrast, sildenafil administered apoE(-/-) mice showed superoxide anion levels similar to those observed in WT mice. Similarly, MNC and liver cells from apoE(-/-) vehicle mice showed a 4-fold and 2-fold augmented DNA fragmentation compared with WT, respectively, and sildenafil-administered apoE(-/-) mice exhibited minimal DNA damage in those cells similar to WT mice. CONCLUSIONS: ApoE(-/-) mice chronically administered with sildenafil exhibited reduced levels of superoxide anion in MNC and less DNA fragmentation in MNC and liver cells, which are biomarkers of genotoxicity. Therefore, sildenafil may offer a new perspective to the use of PDE5 inhibitors to protect against DNA damage, in cells involved in the inflammatory and dyslipidemic processes that accompany atherosclerosis. PMID- 23981676 TI - Designing robust alumina nanowires-on-nanopores structures: superhydrophobic surfaces with slippery or sticky water adhesion. AB - Hierarchical alumina surfaces with different morphologies were fabricated by a simple one-step anodization method. These alumina films were fabricated by a new raw material: silica gel plate (aluminum foil with a low purity of 97.17%). The modulation of anodizing time enabled the formation of nanowires-on-nanopores hybrid nanostructures having controllable nanowires topographies through a self assembly process. The resultant structures were demonstrated to be able to achieve superhydrophobicity without any hydrophobic coating layer. More interestingly, it is found that the as-prepared superhydrophobic alumina surfaces exhibited high contrast water adhesion. Hierarchical alumina film with nanowire bunches-on-nanopores (WBOP) morphology presents extremely slippery property which can obtain a sliding angle (SA) as low as 1 degrees , nanowire pyramids-on nanopores (WPOP) structure shows strongly sticky water adhesion with the adhesive ability to support 15 MUL inverted water droplet at most. The obtained superhydrophobic alumina surfaces show remarkable mechanical durability even treated by crimping or pressing without impact on the water-repellent performance. Moreover, the created surfaces also show excellent resistivity to ice water, boiling water, high temperature, organic solvent and oil contamination, which could expand their usefulness and efficacy in harsh conditions. PMID- 23981677 TI - Adsorption of Cd(II) and Pb(II) by a novel EGTA-modified chitosan material: kinetics and isotherms. AB - In this study, a novel adsorbent was synthesized by functionalizing chitosan with ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) ligands. The adsorption capability of EGTA-modified chitosan was investigated by the removal of Cd(II) and Pb(II) from aqueous solutions. The adsorption and regeneration studies were performed by batch techniques. The effects of pH, contact time, and initial metal concentration were studied. Metal uptake by EGTA chitosan was 0.74 mmol g(-1) for Cd(II) and 0.50 mmol g(-1) for Pb(II). The adsorption mechanism, that the adsorbent formed octahedral chelate structures with bivalent metal ions, was proposed tentatively based on the experimental results of FTIR and the theoretically calculated data of point charges. The kinetics of Cd(II) and Pb(II) on EGTA-chitosan complied with the pseudo-second order model and the adsorption rate was also influenced by intra-particle diffusion. BiLangmuir isotherm model was well fitted to the experimental data of one-component adsorption suggesting the surface heterogeneity of the novel adsorbent. The extended form of the BiLangmuir model was tested for the modeling of two-component adsorption equilibrium of Cd(II) and Pb(II) on EGTA-chitosan. In the two-component solution, both competitive adsorption and positive synergy of chelation between metal ions occurred and the novel adsorbent showed higher affinity toward Cd(II). PMID- 23981678 TI - Phenol degradation by TiO2 photocatalysts combined with different pulsed discharge systems. AB - Films of TiO2 nanotubes distributed over the inner surface of a discharge reactor cylinder (CTD) or adhered to a stainless steel electrode surface (PTD) in a discharge reactor were compared with a single-discharge (SD) system to investigate their efficiencies in phenol degradation. Morphology studies indicated that the TiO2 film was destroyed in the PTD system, but that there was no change in the CTD system after discharge. X-ray diffraction results revealed that the anatase phase of the original sample was preserved in the CTD system, but that an anatase-to-rutile phase transformation occurred in the PTD system after discharge. The highest efficiencies of phenol degradation and total organic carbon (TOC) mineralization were observed in the CTD system, and there was no decrease in phenol degradation efficiency upon reuse of a TiO2 film, indicating high catalysis activity and stability of the TiO2 photocatalysts in the combined treatment. TiO2 photocatalysts favored the formation of hydrogen peroxide and disfavored the formation of ozone. A greater degree of oxidation of intermediates and higher energy efficiency in phenol oxidation were observed with the TiO2 plasma systems, especially in the CTD system, compared to those with the SD system. PMID- 23981679 TI - Utility of tissue expansion in pediatric phallic reconstruction: a 10-year experience. AB - OBJECTIVE: Boys with complex penile anomalies often undergo multiple operations, leaving a paucity of unscarred skin for further reconstructive procedures. Our objective was to evaluate the ability of tissue expansion to provide local skin for successful phallic reconstruction. MATERIALS AND METHODS: Eighty boys (mean age of 11.9 years) with hypospadias (n = 42) or epispadias (n = 38) formed the study cohort. All patients had undergone at least one failed reconstructive operation. Indications for tissue expansion included scarcity of penile skin with urethral stenosis, urethrocutaneous fistula, chordee, and/or residual defect. One or two expanders were placed under the skin of the penile shaft and removed at the time of reconstruction. RESULTS: Average time between expander placement and reconstruction was 10.9 weeks. Mean follow-up time was 25.3 months. Complications during expansion occurred in 33 patients (41.3%). Twenty-two patients (27.5%) had at least one expander removed prematurely and 46.9% were replaced. Expansion yielded adequate tissue for reconstruction in 76 patients (95.0%). Successful outcomes were achieved in 39 patients after initial reconstruction and 25 patients after further intervention, yielding an overall success rate of 80.0%. CONCLUSION: Tissue expansion is a useful tool with an acceptable rate of complications for phallic reconstruction in patients who have failed prior surgical reconstruction. PMID- 23981680 TI - Pediatric urolithiasis in a non-endemic country: a single center experience from The Netherlands. AB - OBJECTIVE: To provide insight in causative factors of pediatric urolithiasis in The Netherlands, a non-endemic country. PATIENTS AND METHODS: Data from 71 children with urolithiasis and stone analyses between 1996 and 2010 in the Radboud University Nijmegen Medical Centre were studied retrospectively. Patients (48 boys, 23 girls, ratio 2.1:1) were aged 0.5-18.3 years (mean 8.8, SD 5.6). All stone analyses were performed with FTIR spectroscopy. RESULTS: Of the 49 patients with metabolic analysis, 78% showed one (n = 15) or more (n = 23) metabolic abnormalities. Forty-seven percent had hypercalciuria (n = 23), 31% had hyperoxaluria (n = 15), 29% hypocitraturia (n = 14), 10% hyperuricosuria (n = 5), 10% cystinuria (n = 5), and 6% had hypomagnesiuria (n = 3). Sixty-one percent of the stones were composed of calcium phosphate, calcium oxalate, or a combination of those. Twenty-six percent consisted of pure or mixed magnesium ammonium phosphate, 8.3% pure or mixed urate, and 8.3% cystine. CONCLUSION: Children with urolithiasis in The Netherlands show stone composition similar to other Western European countries. However, a high percentage of metabolic abnormalities (78%) was found, indicating the need for extensive evaluation of pediatric urolithiasis to find underlying causes and thereby prevent stone recurrences. A close collaboration between a pediatric nephrologist and urologist is mandatory for optimal surgical and medical treatment. PMID- 23981681 TI - Effect of maternal chronic intermittent hypoxia during gestation on offspring growth in the rat. AB - OBJECTIVE: Obstructive sleep apnea, a breathing disorder caused by the repetitive collapse of the upper airway during sleep, results in a state of chronic intermittent hypoxia (CIH). Although the etiology and consequences of CIH are extensively investigated in the adult, the developmental ramifications of this disease process are unknown. DESIGN: This study was done to investigate the effect of CIH during gestation on offspring development. Pregnant female Spraque Dawley rats were exposed to daily CIH throughout the gestational period. RESULTS: Postnatal day-1 offspring from CIH mothers were asymmetrically growth restricted, with decreased body weights and elevated brain-weight:liver-weight ratios. Furthermore, CIH newborns had elevated heart- and brain-weight:body weight ratios, and decreased liver-weight:body weight ratios. By adulthood, body weights of growth restricted offspring were significantly greater, as were the liver weight:body weight ratios. CIH offspring also had greater body fat deposition, were hyperglycemic and had elevated plasma levels of insulin during development into adults. CONCLUSION: These data suggest that alteration of the maternal intrauterine environment by gestational CIH effects the long-term development of the offspring and increases the risk of the offspring to metabolic diseases in adulthood. PMID- 23981683 TI - Prevalence of rheumatologist-diagnosed psoriatic arthritis in patients with psoriasis in European/North American dermatology clinics. AB - BACKGROUND: Prompt identification and treatment of psoriatic arthritis (PsA) in patients with psoriasis is critical to reducing the risk of joint damage, disability, and comorbidities. OBJECTIVE: We sought to estimate PsA prevalence in patients with plaque psoriasis in 34 dermatology centers in 7 European and North American countries. METHODS: Consecutive patients were evaluated by dermatologists for plaque psoriasis and subsequently by rheumatologists for PsA. PsA prevalence was estimated primarily based on rheumatologists' assessment of medical history, physical examination, and laboratory tests. RESULTS: Of 949 patients evaluated, 285 (30%) had PsA (95% confidence interval 27-33) based on rheumatologists' assessment. PsA diagnosis changed in 1.2% of patients when diagnostic laboratory tests were added to medical history and physical examination. Of 285 patients given the diagnosis of PsA, 117 (41%) had not been previously given the diagnosis. LIMITATIONS: Bias may have been introduced by lack of standardized diagnostic criteria and unbalanced recruitment based on country populations. CONCLUSIONS: In this study, almost a third of patients with psoriasis seen in dermatology centers had PsA as determined by rheumatologists. More than a third of patients with PsA had not been previously given the diagnosis. Clinical evaluation alone is often sufficient basis for PsA diagnosis, but laboratory test results may be helpful in some patients. PMID- 23981684 TI - A three-stage method for the 3D reconstruction of the tracheobronchial tree from CT scans. AB - This paper proposes a method for segmenting the airways from CT scans of the chest to obtain a 3D model that can be used in the virtual bronchoscopy for the exploration and the planning of paths to the lesions. The method is composed of 3 stages: a gross segmentation that reconstructs the main airway tree using adaptive region growing, a finer segmentation that identifies any potential airway region based on a 2D process that enhances bronchi walls using local information, and a final process to connect any isolated bronchus to the main airways using a morphologic reconstruction process and a path planning technique. The paper includes two examples for the evaluation and discussion of the proposal. PMID- 23981685 TI - Synthesis of some novel 4-arylidene pyrazoles as potential antimicrobial agents. AB - BACKGROUND: Pyrazole and pyrazolone motifs are well known for their wide range of biological activities such as antimicrobial, anti-inflammatory, and antitumor activities. The incorporation of more than one pharmacophore in a single scaffold is a well known approach for the development of more potent drugs. In the present investigation, a series of differently substituted 4-arylidene pyrazole derivatives bearing pyrazole and pyrazolone pharmacophores in a single scaffold was synthesized. RESULTS: The synthesis of novel 4-arylidene pyrazole compounds is achieved through Knovenagel condensation between 1,3-diaryl-4-formylpyrazoles and 3-methyl-1-phenyl-1H-pyrazol-5-(4H)-ones in good yields. All compounds were evaluated for their in vitro antimicrobial activity. CONCLUSIONS: A series of 4 arylidene pyrazole derivatives was evaluated for their in vitro antimicrobial activity against two Gram-positive (Bacillus subtilis and Staphylococcus aureus) and two Gram-negative bacteria (Pseudomonas fluorescens and Escherichia coli), as well as two pathogenic fungal strains (Candida albicans and Saccharomyces cerevisiae). The majority of the compounds displayed excellent antimicrobial profile against the Gram-positive (B. subtilis and S. aureus), and some of them are even more potent than the reference drug ciprofloxacin. PMID- 23981686 TI - Extremely preterm birth and adolescent mental health in a geographical cohort born in the 1990s. AB - BACKGROUND: Preterm birth confers risk for poor outcome, including mental health problems. Survival of extremely preterm (EP; <28 weeks' gestation) or extremely low birthweight (ELBW; <1000 g) infants increased in the 1990s but psychiatric outcomes in older adolescents born preterm since 1990 are not well documented. This study aimed to characterize mental health and personality traits in a prospective geographical cohort of adolescents born EP/ELBW in Victoria, Australia in 1991 and 1992. METHOD: At age 18 years, 215 EP/ELBW and 157 normal birthweight (>2499 g) control adolescents completed the Structured Clinical Interview for DSM-IV Disorders, Axis 1 Non-Patient version (SCID-I/NP), the Children's Interview for Psychiatric Syndromes (ChIPS) attention deficit hyperactivity disorder (ADHD) module, and questionnaires assessing recent depression and anxiety symptoms and personality traits. RESULTS: ADHD prevalence was significantly elevated in EP/ELBW adolescents compared with controls [15% v. 7%; odds ratio (OR) 2.67, 95% confidence interval (CI) 1.08-6.58]. Aside from ADHD, however, EP/ELBW and control adolescents reported very similar outcomes, with other lifetime diagnoses identified in 23% of EP/ELBW and 21% of controls. These were predominantly mood and anxiety disorders (21% EP/ELBW, 20% controls). The groups did not differ in recent depression or anxiety symptoms assessed using questionnaires, and personality traits were also similar. CONCLUSIONS: ADHD was more prevalent in EP/ELBW adolescents than controls, which is consistent with some, but not all, reports on preterm survivors born before the 1990s, and younger preterm children born in the 1990s. The high rates of anxiety and mood disorders were similar in both groups, and comparable with population-based estimates. PMID- 23981682 TI - Pruritus in patients treated with targeted cancer therapies: systematic review and meta-analysis. AB - BACKGROUND: Pruritus has been anecdotally described in association with targeted cancer therapies. The risk of pruritus has not been systematically ascertained. OBJECTIVE: A systematic review and meta-analysis of the literature was conducted for axitinib, cetuximab, dasatinib, erlotinib, everolimus, gefitinib, imatinib, ipilimumab, lapatinib, nilotinib, panitumumab, pazopanib, rituximab, sorafenib, temsirolimus, tositumomab, vandetanib, and vemurafenib. METHODS: Databases from PubMed, Web of Science (January 1998 through July 2012), and American Society of Clinical Oncology abstracts (2004 through 2012) were searched. Incidence and relative risk of pruritus were calculated using random- or fixed-effects model. RESULTS: The incidences of all-grade and high-grade pruritus were 17.4% (95% confidence interval 16.0%-19.0%) and 1.4% (95% confidence interval 1.2%-1.6%), respectively. There was an increased risk of all-grade pruritus (relative risk 2.90 [95% confidence interval 1.76-4.77, P < .001]) and variation among different drugs (P < .001). LIMITATIONS: The reporting of pruritus may vary, resulting from concomitant medications, comorbidities, and underlying malignancies. We found a higher incidence of pruritus in patients with solid tumors, concordant with those targeted therapies with the highest pruritus incidences. CONCLUSION: There is a significant risk of developing pruritus in patients receiving targeted therapies. To prevent suboptimal dosing and decreased quality of life, patients should be counseled and treated against this untoward symptom. PMID- 23981687 TI - A common reference-based indirect comparison meta-analysis of intravenous valproate versus intravenous phenobarbitone for convulsive status epilepticus. AB - OBJECTIVE: To compare intravenous valproate (IV-VPA) with intravenous phenobarbitone (IV-PB) in the treatment of established generalised convulsive status epilepticus (GCSE). Efficacy and safety were estimated using a common reference based indirect comparison meta-analysis (CRBMA) methodology. METHODS: Randomised controlled trials (RCTs) investigating the use of IV-VPA or IV-PB versus intravenous phenytoin (IV-PHT) for GCSE were identified by a systematic search of the literature. A random effects model was used to estimate Mantel Haenszel odds ratios (ORs) for efficacy and safety of IV-VPA or IV-PB versus IV PHT in a standard meta-analysis. Adjusted indirect comparisons were then made between VPA and PB using the obtained results. RESULTS: CRBMA showed that VPA does not lead to significantly higher seizure cessation (OR 1.00; 95% CI: 0.36 2.76) compared to PB, although it exhibits fewer adverse effects (OR 0.17; 95% CI: 0.04-0.71). Results of this CRBMA are consistent with results of a recently published head-to-head comparison of IV-VPA and IV-PB. CONCLUSION: There is insufficient evidence to demonstrate superiority of IV-VPA over IV-PB for the treatment of GCSE in terms of efficacy. Some direct and indirect comparisons suggest that VPA has a better safety profile than PB. However, the limited numbers of underpowered RCTs included in this meta-analysis are not sufficient to justify a change in clinical practice. More rigorous and appropriately powered RCTs are therefore required to definitively determine the efficacy and tolerability of VPA for the treatment of GCSE. PMID- 23981688 TI - Modulation of Dcytb (Cybrd 1) expression and function by iron, dehydroascorbate and Hif-2alpha in cultured cells. AB - BACKGROUND: Duodenal cytochrome b (Dcytb) is a mammalian plasma ferric reductase enzyme that catalyses the reduction of ferric to ferrous ion in the process of iron absorption. The current study investigates the relationship between Dcytb, iron, dehydroascorbate (DHA) and Hif-2alpha in cultured cell lines. METHODS: Dcytb and Hif-2alpha protein expression was analysed by Western blot technique while gene regulation was determined by quantitative PCR. Functional analyses were carried out by ferric reductase and (59)Fe uptake assays. RESULTS: Iron and dehydroascorbic acid treatment of cells inhibited Dcytb mRNA and protein expression. Desferrioxamine also enhanced Dcytb mRNA level after cells were treated overnight. Dcytb knockdown in HuTu cells resulted in reduced mRNA expression and lowered reductase activity. Preloading cells with DHA (to enhance intracellular ascorbate levels) did not stimulate reductase activity fully in Dcytb-silenced cells, implying a Dcytb-dependence of ascorbate-mediated ferrireduction. Moreover, Hif-2alpha knockdown in HuTu cells led to a reduction in reductase activity and iron uptake. CONCLUSIONS: Taken together, this study shows the functional regulation of Dcytb reductase activity by DHA and Hif 2alpha. GENERAL SIGNIFICANCE: Dcytb is a plasma membrane protein that accepts electrons intracellularly from DHA/ascorbic acid for ferrireduction at the apical surface of cultured cells and enterocytes. PMID- 23981689 TI - Change in plasma levels of amino acid neurotransmitters and its correlation with clinical heterogeneity in early Parkinson's disease patients. AB - BACKGROUND: The correlation between plasma amino acid (AA) neurotransmitters and clinical heterogeneity in early patients with Parkinson's disease (PD) is still poorly understood. AIMS: To examine the plasma levels of AA neurotransmitters in early patients with PD and to evaluate their correlation with PD subtypes. METHODS: Based on the predominant symptoms, fifty-one patients with PD were enrolled and divided into four subgroups: (1) akinetic-rigid type (ART), (2) tremor-dominant type (TDT), (3) postural instability/gait difficulty type (PIGD), and (4) mixed type (MT). Plasma levels of AA were measured by HPLC-RF, and their potential diagnostic practicality and their association with PD subtypes were evaluated by the receiver operating characteristic (ROC) and correlation analysis, respectively. RESULTS: Patients with PD exhibited markedly lower levels of Asp, Glu, Tau, L-ser, and lower values of Glu/GABA ratio than healthy controls. The ROC analysis revealed their high sensitivity (77.1-87.5%) and specificity (58.8-88.2%). Furthermore, the glutamic acid (Glu), gamma aminobutyric acid (GABA) level in the PIGD subtype was increased as compared with other subtypes and was negatively correlated with the ART/PIGD ratio. CONCLUSION: The decrease in plasma Asp, Glu, Tau, L-ser levels, and the value of Glu/GABA ratio may be helpful for early PD diagnosis. The elevated GABA level may be the biochemical basis for the specific symptoms of PIGD PD. PMID- 23981690 TI - Expression of aquaporins in prostate and seminal vesicles of diabetic rats. AB - INTRODUCTION: Aquaporins (AQPs) are membrane proteins that facilitate the movement of water and many small solutes across biological membranes. Seminal fluid is primarily produced by prostate and seminal vesicles, and its production may potentially be mediated by many mechanisms related to transudation of fluid. Epidemiological data suggest that semen volume in diabetic men is significantly less than in nondiabetic men. AIM: To investigate the change in volume of secretions of the prostate and seminal vesicles in diabetic rats and its association with the expression of AQPs 1-4. METHODS: Twenty male Sprague Dawley rats were randomly divided among 4- and 6-week diabetic groups and 4- and 6-week control groups. Prostate and seminal vesicle secretions were collected and measured, and levels of expression of AQPs 1-4 were determined by immunohistochemical study and Western blot. MAIN OUTCOME MEASURES: The levels of expression of AQPs 1-4 were determined in the prostate and seminal vesicles of diabetic rats by Western blot and immunohistochemical study. RESULTS: Plasma glucose was significantly higher in diabetic model groups than in controls (P < 0.05). The weights of secretions of the prostate and seminal vesicles were significantly lower in diabetic model groups (P < 0.05). The levels of expression of AQPs 1 and 4 in seminal vesicles were significantly lower in diabetic model groups (P < 0.05). There was no difference in the level of expression of AQP3 in seminal vesicles among the groups. The levels of expression of AQPs 1, 3, and 4 in prostate were significantly lower in diabetic model groups (P < 0.05). AQP2 was not detectable in the prostate or seminal vesicles of any of the groups. CONCLUSIONS: Decreased weight of prostate secretions in diabetic rats may be partly due to decreased levels of AQPs 1, 3, and 4 in prostatic tissue. Decreased weight of seminal vesicle secretions in diabetic rats may be partly due to decreased levels of AQP1 and AQP4 in seminal vesicles. There is no relationship between the expression of AQPs 1-4 and the duration of disease. PMID- 23981691 TI - ProAlgaZyme subfraction improves the lipoprotein profile of hypercholesterolemic hamsters, while inhibiting production of betaine, carnitine, and choline metabolites. AB - BACKGROUND: Previously, we reported that ProAlgaZyme (PAZ) and its biologically active fraction improved plasma lipids in hypercholesterolemic hamsters, by significantly increasing the high density lipoprotein cholesterol (HDL-C) while reducing non-HDL cholesterol and the ratio of total cholesterol/HDL-C. Moreover, hepatic mRNA expression of genes involved in HDL/reverse cholesterol transport were significantly increased, while cholesteryl ester transfer protein (CETP) expression was partially inhibited. In the current study, we investigated the therapeutic efficacy of the biologically active fraction of PAZ (BaP) on the plasma lipid and plasma metabolomic profiles in diet induced hypercholesterolemic hamsters. METHODS: Fifty male Golden Syrian hamsters were fed a high fat diet for 4 weeks prior to randomization into 6 groups, based on the number of days they received subsequent treatment. Thus animals in T0, T3, T7, T10, T14, and T21 groups received BaP for 0, 3, 7, 10, 14, and 21 days, respectively, as their drinking fluid. Plasma lipids were assayed enzymatically, while real-time reverse transcriptase polymerase chain reaction (RT-PCR) provided the transcription levels of the Apolipoprotein (Apo) A1 gene. The plasma metabolomic profile was determined using 1H nuclear magnetic resonance (NMR) spectroscopy in conjunction with multivariate analysis. RESULTS: Plasma HDL-C was significantly increased in T3 (P < 0.05) and T21 (P < 0.001), while non-HDL cholesterol was significantly reduced in T3, T7, T10 (P < 0.001) and T14, T21 (P < 0.01). Moreover, the ratio of total cholesterol/HDL-C was significantly lower in all BaP treated groups (P < 0.001) as compared with T0. Quantitative RT-PCR showed an increase in Apo A1 expression in T10 (3-fold) and T21 (6-fold) groups. NMR data followed by multivariate analysis showed a clear separation between T0 and T21 groups, indicating a difference in their metabolomic profiles. Plasma concentrations of metabolites associated with a risk for atherosclerosis and cardiovascular disease, including choline, phosphocholine, glycerol-phosphocholine, betaine and carnitine metabolites were significantly lower in the T21 group. CONCLUSION: Treatment with BaP significantly improved the plasma lipid profile by increasing HDL-C and lowering non-HDL cholesterol. In addition, BaP potentially improved the plasma metabolomic profile by reducing the concentration of key metabolites associated with risk for atherosclerosis and cardiovascular disease. PMID- 23981692 TI - The spot sign and tranexamic acid on preventing ICH growth--AUStralasia Trial (STOP-AUST): protocol of a phase II randomized, placebo-controlled, double-blind, multicenter trial. AB - RATIONALE: No evidence-based acute therapies exist for intracerebral hemorrhage. Intracerebral hemorrhage growth is an important determinant of patient outcome. Tranexamic acid is known to reduce hemorrhage in other conditions. AIM: The study aims to test the hypothesis that intracerebral hemorrhage patients selected with computed tomography angiography contrast extravasation 'spot sign' will have lower rates of hematoma growth when treated with intravenous tranexamic acid within 4.5-hours of stroke onset compared with placebo. DESIGN: The Spot sign and Tranexamic acid On Preventing ICH growth--AUStralasia Trial is a multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled, investigator initiated, academic Phase II trial. Intracerebral hemorrhage patients fulfilling clinical criteria (e.g. Glasgow Coma Scale >7, intracerebral hemorrhage volume <70 ml, no identified secondary cause of intracerebral hemorrhage, no thrombotic events within the previous 12 months, no planned surgery) and demonstrating contrast extravasation on computed tomography angiography will receive either intravenous tranexamic acid 1 g 10-min bolus followed by 1 g eight-hour infusion or placebo. A second computed tomography will be performed at 24 +/- 3 hours to evaluate intracerebral hemorrhage growth and patients followed up for three months. STUDY OUTCOMES: The primary outcome measure is presence of intracerebral hemorrhage growth by 24 +/- 3 hours, defined as either >33% or >6 ml increase from baseline, and will be adjusted for baseline intracerebral hemorrhage volume. Secondary outcome measures include growth as a continuous measure, thromboembolic events, and the three-month modified Rankin Scale score. DISCUSSION: This is the first trial to evaluate the efficacy of tranexamic acid in intracerebral hemorrhage patients selected based on an imaging biomarker of high likelihood of hematoma growth. The trial is registered as NCT01702636. PMID- 23981694 TI - Human immunodeficiency virus and the acquired immune deficiency syndrome. PMID- 23981695 TI - Clinical Management and Review of Sjogren's Syndrome. PMID- 23981693 TI - The proteome of the calcified layer organic matrix of turkey (Meleagris gallopavo) eggshell. AB - BACKGROUND: Chicken eggshell mineralization is a prominent model for biomineralization not only because of its importance for avian reproduction but also because of the commercial interest associated with eggshell quality. An analysis and comparison of the protein constituents of eggshells of several species would contribute to a better understanding of the shell mineralization process. The recent publication of the turkey genome sequence now provides a basis for the in-depth analysis of the turkey eggshell proteome. RESULTS: Proteomic analysis of turkey acid-soluble and acid-insoluble organic eggshell matrix yielded 697 identified proteins/protein groups. However, intensity-based absolute quantification (iBAQ) results indicated that the 47 most abundant identified proteins already constituted 95% of the total turkey eggshell matrix proteome. Forty-four of these proteins were also identified in chicken eggshell matrix previously. Despite these similarities there were important and unexpected differences. While ovocleidin-116 and ovocalyxin-36 were major proteins constituting approximately 37% of the identified proteome, other members of the group of so-called eggshell-specific proteins were not identified. Thus ovocalyxin-21 and ovocalyxin-32 were missing among matrix proteins. Conversely, major turkey eggshell proteins were not detected in chicken, such as the bone protein periostin, the mammalian counterpart of which is involved in many aspects of bone metabolism and which represented 10-11% of the total identified proteome. CONCLUSIONS: Even members of the same avian family show important differences in eggshell matrix composition and more studies on the proteome and the transcriptome level will be necessary to identify a common toolkit of eggshell mineralization and to work out species differences among functional eggshell protein sets and their role in eggshell production. PMID- 23981696 TI - Compounding with Beta-1,3-d-glucan. PMID- 23981697 TI - Psoriasis. PMID- 23981698 TI - Probiotics and their effect on leaky gut syndrome and associated diseases. PMID- 23981699 TI - Immune System Disorders: What's New and Interesting in Print and On-Line. PMID- 23981701 TI - The basics of compounding: compounding suppositories, part 2-extemporaneous preparation. PMID- 23981700 TI - Transdermal nifedipine for wound healing: case reports. PMID- 23981702 TI - Providing care for diabetic veterinary patients. PMID- 23981703 TI - Stability of hydrocortisone sodium succinate after reconstitution in 0.9% sodium chloride injection and storage in polypropylene syringes for pediatric use. AB - The stabilty of hydrocortisone sodium succinate (10 mg/mL) in 0.9% sodium chloride injection has been studied at 25 deg C and 5 deg C in polypropylene syringes by means of a stabililty-indicating high-performance liquid chromatography assay method. The concentration of the drug was directly related to the peak height, and the percent relative standard deviation based on 5 injections was 1.2. Benzyl alcohol, which was added as a preservative, did not interfere with the assay procedure. Two products of decomposition separated from the intact drug. At 25 deg C, the loss in potency was less than 10% after 7 days of storage. At 5 deg C, it was less than 3% when stored for 21 days. The pH value of the injection decreased from 7.2 to 6.3 when stored at 25 deg C for 21 days and from 7.2 to 7.0 when stored at 5 deg C for 21 days. The drug did not adsorb onto the syringes, and the physical appearance of the injection did not change. PMID- 23981704 TI - Stability of Lisinopril Syrup (2 mg/mL) Extemporaneously Compounded from Tablets. AB - The stability of lisinopril syrup (2 mg/mL) extemporaneously compounded from tablets was investigated. Zestril tablets (Lot CSC201, Zeneca Pharmaceuticals, Wilmington, Del) were crushed, dissolved in water, filtered, and diluted with syrup NF to a final nominal concentration of 2 mg/mL. The solution was then equally divided among amber-colored prescription bottles and was stored at 5 deg C and 23 deg C. During the 30-day study period, samples were extracted by means of a water:methanol mix, and the concentration of lisinopril was determined by a stability-indicating high-performance liquid chromatography assay procedure. Stability was also determined by pH measurements annd visual inspection for color or clarity change. Over the 30-day study period, the percentage of the inital lisinopril concentration remained between 99.42% +/- 0.19% and 95.68% +/- 1.5% for the 5 deg C samples and 98.83% +/- 0.46% and 96.48% +/- 0.62% for the 23 deg C samples. PMID- 23981705 TI - Pharmaceutical profile of vitamin C tablets and capsules. AB - This study examines the pharmaceutical profile of 3 brands of immediate-release vitamin C tablets (500 mg) available commercially in North Carolina and 3 batches of vitamin C capsules (500 mg) extemporaneously prepared in our laboratory. Several pharmaceutical tests were performed on 3 bottles from 3 different brands of immediate-release vitamin C tablets that were purchased from local stores. The brands were compared with respect to thickness, weight variation, hardness, dissolution, disintegration time, and content uniformity tests. The results showed differences among the brands in thickness, weight variation, hardness, and disintegration time. Bottles from 2 of the brands showed a significant difference in some of their test profiles. Weight variation, dissolution, and content uniformity were determiined for the prepared capsules. The average weight of the capsules from the 3 batches was similar and was slightly below 700 mg. The content of ascorbic acid in the capsules ranged form 95.4% to 113.5% of the labeled amount, with an overall average of 107.5% for the 3 batches. Dissolution tests on the capsules revealed that the release of vitamin C was complete within a 1-hour period, which is similar to that seen with the commercial tablets. These results make it advisable for pharmacists, when counseling patients, to have this variability among commercial brands of vitamin C in mind. PMID- 23981706 TI - The impact of hazelnuts in land-use changes on soil carbon and in situ soil respiration dynamics. AB - Our study assessed the impact of hazelnuts (Coryllus avellena L.) in land-use conversion from forest (F) to agricultural land (AL) on various attributes of soil respiration dynamics, such as soil elemental carbon (C%) content, microbial respiration, bulk density, soil pH, electrical conductivity, and seasonal variations. We developed soil C% models to compare soil C% between F and AL soils. Four field trips were conducted in the winter and summer of 2008 and the spring and fall of 2009 in the Karasu region of Turkey. During each trip, 42 sites were visited F (n = 21) and AL (n = 21). Our results showed that hazelnuts plantations in AL could reduce elemental C% by 27% (winter 2008), 16% (summer 2008), 41% (spring 2009), and 22% (fall 2009) in the four seasons studied when compared to F soils. In situ soil respiration was also reduced by 31% (spring 2008), 67% (fall 2008), 88% (spring 2009), and 79% (fall 2009) in AL soils over F soils. The percent of organic matter of AL soils was declined by 36% (winter 2008), 23% (summer 2008), 34% (spring 2009), and 26% (fall 2009) in comparison to F soils. Significant reductions in the correlation between C%-percent clay and C% electrical conductivity were also recorded for AL soils over F soils. Furthermore, AL soils showed higher bulk density (7.4% and 7%) when compared to F soils. We also found that in situ soil respiration had significant seasonal correlations (p < 0.05) with soil pH (0.537), soil temperature, and percent clay (-0.486) in F soils (summer 2008, spring 2009). Additionally, we found that seasonal variations of four sampling seasons had a moderate impact on in situ respiration and that the differences were statistically significant, except for the winter-summer and spring-fall seasonal pairs. Linear regression C models showed significant differences for F and AL soils. PMID- 23981707 TI - Bioremediation of copper-containing wastewater by sulfate reducing bacteria coupled with iron. AB - In order to treat copper-containing wastewater effectively using sulfate reducing bacteria (SRB), iron (Fe(0)) was added to enhance the activity of SRB. The SRB system and the SRB + Fe(0) system were operated under continuous operation. The sulfate reduction efficiency of the SRB + Fe(0) system was twice as much as that of the SRB system with the sulfate loading rate at 125 mg L(-1) h(-1). The effect of COD/SO4(2-) on sulfate reduction indicates an enhanced activity of SRB by adding Fe(0). 99% of total sulfate was deducted in both systems at pH 4.0-7.0, and temperature slightly influenced the removal of sulfate in the SRB + Fe(0) system. In the copper-containing wastewater treatment, the SRB + Fe(0) system shows a better performance since sulfate removal in this system was higher than the SRB system, and the removal ratio of Cu(2+) was held above 95% in SRB + Fe(0) system at all influent Cu(2+) concentrations. PMID- 23981708 TI - Oxychlorine species suppress postsurgical adhesions in rats. AB - BACKGROUND: Surgically induced adhesions complicate up to 100% of abdominal surgeries. Food and Drug Administration-approved treatments are generally not only less effective than desired but they also have major contraindications. Oxychlorine species, including chlorine dioxide (ClO2), suppress scar formation in infected wounds without affecting keratinocytes while reducing fibroblast proliferation. The aim of the present study was to evaluate the effect of oxychlorine solutions containing ClO2 on adhesion formation. METHODS: Male Wistar rats were subjected to Buckenmaier model of surgical adhesions and treated with either oxychlorine solutions containing ClO2 (40-150 ppm) or isotonic saline solution. To increase the severity of adhesions, peritonitis was produced by intraperitoneal administration of a diluted nonlethal dose of feces (50 mg/kg). Wound strength of the healed wound was measured to evaluate the effects of oxychlorine solutions. In addition, an oxychlorine solution of lesser efficacy (at 100 ppm) was compared with three available anti-adhesion materials. RESULTS: Reproducibility of the model was validated in 26 rats. Oxychlorine solutions containing ClO2 (40-110 ppm) significantly reduced postsurgical adhesion formation without affecting the strength of the healed wound. Higher concentrations (120 and 150 ppm) had no effect. Fecal peritonitis significantly increased, and solutions with ClO2 at 110 ppm significantly reduced adhesion formation. The effect of the oxychlorine solution was significantly greater than that of Interceed, Guardix, Seprafilm, and isotonic saline solution. CONCLUSIONS: ClO2-containing oxychlorine solutions could be an innovative strategy for the suppression of surgical adhesion formation, with the additional advantage of contributing antiseptic properties. PMID- 23981709 TI - Celastrol protects kidney against ischemia-reperfusion-induced injury in rats. AB - BACKGROUND: Ischemia-reperfusion (IR) causes various damages in renal tissues, which is exacerbated by hypoxia-induced excessive inflammation and deteriorates the prognosis of patients after kidney surgery. Celastrol is a potent inflammation inhibitor that has little toxicity. In this report, we investigated whether celastrol protects against IR-induced renal injury in rats. MATERIALS AND METHODS: Renal IR injury was induced by occlusion of the bilateral renal pedicles for 45 min followed by reperfusion for 6 h. Celastrol or vehicle solution was intraperitoneally injected 30 min before renal ischemia, respectively. Renal histology, function, and pro-inflammatory cytokines and mediators were assessed. The effect of celastrol on nuclear translocation of nuclear factor kappa B (NF kappaB) was also measured. RESULTS: Celastrol significantly suppressed elevation of the renal function markers and the lipid peroxidation level, alleviated renal tubular damage, and decreased the levels of tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemotactic protein-1 (MCP-1) messenger RNA in kidney caused by IR. Moreover, celastrol prevented IR-induced expression of pro inflammatory mediators, which was associated with suppression of nuclear translocation of NF-kappaB subunit p65. CONCLUSIONS: Celastrol ameliorated the acute kidney injury caused by IR, which was associated with inhibiting local NF kappaB activation and inflammation. Our findings suggest that celastrol could be useful for preventing IR-induced renal injury. PMID- 23981710 TI - Study protocol: cluster randomised controlled trial to assess the clinical and cost effectiveness of a staff training intervention in inpatient mental health rehabilitation units in increasing service users' engagement in activities. AB - BACKGROUND: This study focuses on people with complex and severe mental health problems who require inpatient rehabilitation. The majority have a diagnosis of schizophrenia whose recovery has been delayed due to non-response to first-line treatments, cognitive impairment, negative symptoms and co-existing problems such as substance misuse. These problems contribute to major impairments in social and everyday functioning necessitating lengthy admissions and high support needs on discharge to the community. Engagement in structured activities reduces negative symptoms of psychosis and may lead to improvement in function, but no trials have been conducted to test the efficacy of interventions that aim to achieve this. METHODS/DESIGN: This study aims to investigate the clinical and cost effectiveness of a staff training intervention to increase service users' engagement in activities. This is a single-blind, two-arm cluster randomised controlled trial involving 40 inpatient mental health rehabilitation units across England. Units are randomised on an equal basis to receive either standard care or a "hands-on", manualised staff training programme comprising three distinct phases (predisposing, enabling and reinforcing) delivered by a small team of psychiatrists, occupational therapists, service users and activity workers. The primary outcome is service user engagement in activities 12 months after randomisation, assessed using a standardised measure. Secondary outcomes include social functioning and costs and cost-effectiveness of care. DISCUSSION: The study will provide much needed evidence for a practical staff training intervention that has potential to improve service user functioning, reducing the need for hospital treatment and supporting successful community discharge. The trial is registered with Current Controlled Trials (Ref ISRCTN25898179). PMID- 23981711 TI - EFNEP's impact on the quality of life of its participants and educators. AB - OBJECTIVE: Determine whether the Expanded Food and Nutrition Education Program (EFNEP) affects the quality of life (QOL) of its participants and educators. DESIGN: Longitudinal, where QOL was measured 3 times for participants (pre, post, 3-month delayed post) and educators (before and 6 and 12 months after training). SETTING: Participants' and educators' QOL was measured in Colorado, Kansas, Missouri, and Nebraska. Georgia and Texas measured educators; Minnesota and Virginia measured participants. PARTICIPANTS: English speaking EFNEP participants and educators. MAIN OUTCOME MEASURES: The investigators used the QOL Profile to measure QOL in 3 domains: Being (who one is), Belonging (connection with social and physical environment), and Becoming (achieving personal goals). ANALYSIS: Chi square and t tests compared group demographics; repeated-measures ANOVA detected changes over time; ANCOVA examined the influence of demographic variables. RESULTS: Both groups had QOL Profile scores above 1.5, which is considered acceptable. Participants improved from pre to post in the Being domains including Overall Being (least square means [standard error of the mean], 3.1 [0.2] to 4.1 [0.3]), and in Social Belonging (3.5 [0.3] to 3.8 [0.3]); most improvements were sustained at 3 months. Educators improved in the Belonging domains, and a number of scores continued to improve at 1 year after training, for example, Social Belonging (4.2 [0.5], 5.0 [0.5], and 5.8 [0.6]); and Community Belonging (3.5 [0.5], 3.8 [0.5], and 4.7 [0.5]) at the 3 time points, respectively. CONCLUSIONS AND IMPLICATIONS: EFNEP improved the QOL of participants, primarily in the Being domain, and of educators, primarily in the Belonging domain. The QOL profile has the potential to broaden the assessment of EFNEP impacts. PMID- 23981712 TI - On the subject of rigor in the study of amyloid beta-protein assembly. AB - According to Thomas Kuhn, the success of 'normal science,' the science we all practice on a daily basis, depends on the adherence to, and practice of, a paradigm accepted by the scientific community. When great scientific upheavals occur, they involve the rejection of the current paradigm in favor of a new paradigm that better integrates the facts available and better predicts the behavior of a particular scientific system. In the field of Alzheimer's disease, a recent example of such a paradigm shift has been the apparent rejection of the 'amyloid cascade hypothesis,' promulgated by Hardy and Higgins in 1992 to explain the etiology of Alzheimer's disease, in favor of what has been referred to as the 'oligomer cascade hypothesis'. This paradigm shift has been breathtaking in its rapidity, its pervasiveness in the Alzheimer's disease field, and its adoption in an increasing number of other fields, including those of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and the prionoses. However, these facts do not mean, a priori, that the experiments extant, and any re interpretation of them, should be accepted by rote as support for the new paradigm. In the discussion that follows, I consider the foundational studies leading to the oligomer cascade hypothesis and evaluate the current state of the paradigm. I argue here that, more often than not, insufficient rigor has been applied in studies upon which this new paradigm has been based. Confusion, rather than clarity, has resulted. If the field is to make progress forward using as its paradigmatic basis amyloid beta-protein oligomerization, then an epistemological re-evaluation of the amyloid beta-protein oligomer system is required. PMID- 23981713 TI - Long-lasting hyperpolarization underlies seizure reduction by low frequency deep brain electrical stimulation. AB - Mesial temporal lobe epilepsy (MTLE) is a common medically refractory neurological disease. Deep brain electrical stimulation (DBS) of grey matter has been used for MTLE with limited success. However, stimulation of a white matter tract connecting the hippocampi, the ventral hippocampal commissure (VHC), with low frequencies that simulate interictal discharges has shown promising results, with seizure reduction greater than 98% in bilateral hippocampi during stimulation and greater than 50% seizure reduction in bilateral hippocampi after treatment. A major hurdle to the implementation and optimization of this treatment is that the mechanisms of seizure reduction by low frequency electrical stimulation (LFS) are not known. The goal of this study is to understand how commissural fibre tract stimulation reduces bilateral hippocampal epileptic activity in an in vitro slice preparation containing bilateral hippocampi connected by the VHC. It is our hypothesis that electrical stimuli induce hyperpolarization lasting hundreds of milliseconds following each pulse which reduces spontaneous epileptic activity during each inter-stimulus interval (ISI). Stimulus-induced long-lasting-hyperpolarization (LLH) can be mediated by GABA(B) inhibitory post-synaptic potentials (IPSPs) or slow after-hyperpolarization (sAHP). To test the role of LLH in effective bilateral seizure reduction by fibre tract stimulation, we measured stimulus-induced hyperpolarization during LFS of the VHC using electrophysiology techniques. Antagonism of the GABA(B) IPSP and/or sAHP diminished stimulus-induced hyperpolarization concurrently with LFS efficacy (greater than 50% reduction). Blocking both the GABA(B) IPSP and sAHP simultaneously eliminated the effect of electrical stimulation on seizure reduction entirely. These data show that LFS of the VHC is an effective protocol for bilateral hippocampal seizure reduction and that its efficacy relies on the induction of long-lasting hyperpolarization mediated through GABA(B) IPSPs and sAHP. Based on this study, optimization of the timing of LFS and LFS-induced-LLH may lead to improved outcomes from DBS treatments for human epilepsy. PMID- 23981714 TI - Activity-dependent downregulation of D-type K+ channel subunit Kv1.2 in rat hippocampal CA3 pyramidal neurons. AB - The intrinsic excitability of neurons plays a critical role in the encoding of memory at Hebbian synapses and in the coupling of synaptic inputs to spike generation. It has not been studied whether somatic firing at a physiologically relevant frequency can induce intrinsic plasticity in hippocampal CA3 pyramidal cells (CA3-PCs). Here, we show that a conditioning train of 20 action potentials (APs) at 10 Hz causes a persistent reduction in the input conductance and an acceleration of the AP onset time in CA3-PCs, but not in CA1-PCs. Induction of such long-term potentiation of intrinsic excitability (LTP-IE) was accompanied by a reduction in the D-type K(+) current, and was abolished by the inhibition of endocytosis or protein tyrosine kinase (PTK). Consistently, the CA3-PCs from Kv1.2 knock-out mice displayed no LTP-IE with the same conditioning. Furthermore, the induction of LTP-IE depended on the back-propagating APs (bAPs) and intact distal apical dendrites. These results indicate that LTP-IE is mediated by the internalization of Kv1.2 channels from the distal regions of apical dendrites, which is triggered by bAP-induced dendritic Ca(2+) signalling and the consequent activation of PTK. PMID- 23981715 TI - Teleost fish models in membrane transport research: the PEPT1(SLC15A1) H+ oligopeptide transporter as a case study. AB - Human genes for passive, ion-coupled transporters and exchangers are included in the so-called solute carrier (SLC) gene series, to date consisting of 52 families and 398 genes. Teleost fish genes for SLC proteins have also been described in the last two decades, and catalogued in preliminary SLC-like form in 50 families and at least 338 genes after systematic GenBank database mining (December 2010 March 2011). When the kinetic properties of the expressed proteins are studied in detail, teleost fish SLC transporters always reveal extraordinary 'molecular diversity' with respect to the mammalian counterparts, which reflects peculiar adaptation of the protein to the physiology of the species and/or to the environment where the species lives. In the case of the H+ -oligopeptide transporter PEPT1(SLC15A1), comparative analysis of diverse teleost fish orthologs has shown that the protein may exhibit very eccentric properties in terms of pH dependence (e.g., the adaptation of zebrafish PEPT1 to alkaline pH), temperature dependence (e.g., the adaptation of icefish PEPT1 to sub-zero temperatures) and/or substrate specificity (e.g., the species-specificity of PEPT1 for the uptake of l-lysine-containing peptides). The revelation of such peculiarities is providing new contributions to the discussion on PEPT1 in both basic (e.g., molecular structure-function analyses) and applied research (e.g., optimizing diets to enhance growth of commercially valuable fish). PMID- 23981716 TI - Three-dimensional organization of local excitatory and inhibitory inputs to neurons in laminae III-IV of the spinal dorsal horn. AB - Laser scanning photostimulation was used to map the distribution of the synaptic input zones (sites that give local synaptic inputs) for dorsal horn laminae III IV neurons, in parasagittal and transverse slices of the rat lumbar spinal cord, and examine how these inputs differed for neurons of different morphologies. All neurons received local excitatory and inhibitory synaptic inputs from within laminae III-IV, while a subset of neurons also received excitatory input from the superficial laminae, especially lamina IIi, as well as the II/III border region. Two anatomical properties were found to be predictive of the dorsoventral position of a neuron's input zone relative to its soma: (1) both excitatory and inhibitory input zones were more dorsal for neurons with longer dorsal dendrites, and (2) excitatory, but not inhibitory, input zones were more dorsal (relative to the soma) for more ventral neurons, with the transition between the dorsal input zones of laminae III-IV neurons and the ventral input zones of lamina II neurons occurring at the II/III border. The observed morphophysiological correlations support the idea that interlaminar connectivity is mediated via translaminar dendritic extensions and that, more generally, local connectivity within the dorsal horn is governed by rules relating the position of a neuron's soma and dendrites to the position of the local presynaptic neurons from which it receives inputs, which are specific to the axis and direction (dorsal vs. ventral), whether the input is excitatory or inhibitory, and the laminar position of the postsynaptic neuron. PMID- 23981717 TI - Intravital Forster resonance energy transfer imaging reveals elevated [Ca2+]i and enhanced sympathetic tone in femoral arteries of angiotensin II-infused hypertensive biosensor mice. AB - Artery narrowing in hypertension can only result from structural remodelling of the artery, or increased smooth muscle contraction. The latter may occur with, or without, increases in [Ca(2+)]i. Here, we sought to measure, in living hypertensive mice, possible changes in artery dimensions and/or [Ca(2+)]i, and to determine some of the mechanisms involved. Ca(2+)/calmodulin biosensor (Forster resonance energy transfer-based) mice were made hypertensive by s.c. infusion of angiotensin II (Ang II, 400 ng kg(-1) min(-1), 2-3 weeks). Intravital fluorescence microscopy was used to determine [Ca(2+)]i and outer diameter of surgically exposed, intact femoral artery (FA) of anaesthetized mice. Active contractile FA 'tone' was calculated from the basal-state diameter and the passive (i.e. Ca(2+)-free) diameter (PD). Compared to saline control, FAs of Ang II-infused mice had (1) ~21% higher active tone and (2) ~78 nm higher smooth muscle [Ca(2+)]i, but (3) the same PDs. The local Ang II receptor (AT1R) blocker losartan had negligible effect on tone or [Ca(2+)]i in control FAs, but reduced the basal tone by ~9% in Ang II FAs. Both i.v. hexamethonium and locally applied prazosin abolished the difference in FA tone and [Ca(2+)]i, suggesting a dominant role of sympathetic nerve activity (SNA). Changes in diameter and [Ca(2+)]i in response to locally applied phenylephrine, Ang II, arginine vasopressin, elevated [K(+)]o and acetylcholine were not altered. In summary, FAs of living Ang II hypertensive mice have higher [Ca(2+)]i, and are more constricted, due, primarily, to elevated SNA and some increased arterial AT1R activation. Evidence of altered artery reactivity or remodeling was not found. PMID- 23981718 TI - Comparison of Ca2+ transients and [Ca2+]i in the dendrites and boutons of non fast-spiking GABAergic hippocampal interneurons using two-photon laser microscopy and high- and low-affinity dyes. AB - Using two-photon laser microscopy, high- and low-affinity dyes and patch clamp electrophysiology, we successfully measured somatic stimulation-evoked Ca(2+) transients simultaneously in the dendrites and axonal boutons of the same non fast-spiking GABAergic interneurons in acute slice preparations obtained from hippocampal area CA1. The advantage of the acute preparation is that both neuronal connections and anatomy are maintained. Calculated as unperturbed values, the amplitudes of Ca(2+) transients and changes in [Ca(2+)]i in response to somatic single or burst stimulation were much higher in boutons (428 nM/AP) than in dendrites (49 nM/AP), leading to the conclusion that the much greater influx of Ca(2+) observed in terminals might be due to a higher density of N-type voltage-sensitive Ca(2+) channels compared to the L-type channels present in dendrites. Whereas the decay of Ca(2+) transients recorded in dendrites was primarily mono-exponential, the decay in boutons was bi-exponential, as indicated by an initial fast phase, followed by a much slower reduction in fluorescence intensity. The extrusion of Ca(2+) was much faster in boutons than in dendrites. To avoid saturation effects and the flawed conversion of fluorescence measures of [Ca(2+)]i, we assessed the limits of [Ca(2+)] measurements (which ranged between 6 and 82% of the applied dye saturation) when high- and low-affinity dyes were applied at different concentrations. When two APs were delivered at a high frequency (>3 Hz) of stimulation, the low-affinity indicators OGB-6F (KD = 3.0 MUM) and OGB-5N (KD = 20 MUM) were able to accurately reflect the changes in DeltaF/F produced by the consecutive APs. There was no difference in the endogenous buffer capacity (kappaE), which can shape Ca(2+) signals, calculated in dendrites (kappaE = 354) or boutons (kappaE = 458). PMID- 23981721 TI - Expression pattern of STAT5A gene during early bovine embryogenesis. AB - Growth hormone (GH) plays an important role in early embryo development. It has been shown to activate multiple pathways, the most comprehensively studied being the STAT/JAK (Signal transducers and activators of transcription/Janus kinase) pathway. The objective of the present study was to investigate STAT5A gene expression during early bovine embryogenesis. Real-time polymerase chain reaction (RT-PCR) was used to measure the abundance of STAT5A transcripts. The mRNA was present at all stages of preimplantation bovine embryos investigated. The most abundant STAT5A expression occurred at the 2-cell stage. Expression was markedly reduced between the 4-cell and 8-cell stages, coinciding with the known time of embryo genome activation and loss of maternal mRNAs. This finding suggests that the embryonic STAT5A gene is primarily activated by maternal gene products. PMID- 23981719 TI - Influence of spiking activity on cortical local field potentials. AB - The intra-cortical local field potential (LFP) reflects a variety of electrophysiological processes including synaptic inputs to neurons and their spiking activity. It is still a common assumption that removing high frequencies, often above 300 Hz, is sufficient to exclude spiking activity from LFP activity prior to analysis. Conclusions based on such supposedly spike-free LFPs can result in false interpretations of neurophysiological processes and erroneous correlations between LFPs and behaviour or spiking activity. Such findings might simply arise from spike contamination rather than from genuine changes in synaptic input activity. Although the subject of recent studies, the extent of LFP contamination by spikes is unclear, and the fundamental problem remains. Using spikes recorded in the motor cortex of the awake monkey, we investigated how different factors, including spike amplitude, duration and firing rate, together with the noise statistic, can determine the extent to which spikes contaminate intra-cortical LFPs. We demonstrate that such contamination is realistic for LFPs with a frequency down to ~10 Hz. For LFP activity below ~10 Hz, such as movement-related potential, contamination is theoretically possible but unlikely in real situations. Importantly, LFP frequencies up to the (high-) gamma band can remain unaffected. This study shows that spike-LFP crosstalk in intra-cortical recordings should be assessed for each individual dataset to ensure that conclusions based on LFP analysis are valid. To this end, we introduce a method to detect and to visualise spike contamination, and provide a systematic guide to assess spike contamination of intra-cortical LFPs. PMID- 23981720 TI - Tracking pulmonary gas exchange by breathing control during exercise: role of muscle blood flow. AB - Populations of group III and IV muscle afferent fibres located in the adventitia of the small vessels appear to respond to the level of venular distension and to recruitment of the vascular bed within the skeletal muscles. The CNS could thus be informed on the level of muscle hyperaemia when the metabolic rate varies. As a result, the magnitude and kinetics of the change in peripheral gas exchange - which translates into pulmonary gas exchange - can be sensed. We present the view that the respiratory control system uses these sources of information of vascular origin, among the numerous inputs produced by exercise, as a marker of the metabolic strain imposed on the circulatory and the ventilatory systems, resulting in an apparent matching between pulmonary gas exchange and alveolar ventilation. PMID- 23981722 TI - The clinical outcome of adjuvant therapy with black seed oil on intractable paediatric seizures: a pilot study. AB - AIM: To evaluate the effect of black seed oil, as add-on treatment to antiepileptic drugs (AEDs), on seizure frequency and severity as well as oxidative stress in intractable epilepsy patients. METHODS: A prospective, randomised, single-blinded, controlled, crossover pilot study. Five healthy children were included as controls. Thirty intractable epileptic children were randomly assigned to either Group I or II. Group I received placebo for four weeks, followed by a two-week washout period, and subsequently black seed oil for four weeks. Group II received the same intervention but in the reverse order. All patients received AEDs throughout the study period. Prior to allocation, all patients underwent a neurological assessment and evaluation of oxidative stress markers; total antioxidant capacity (TAC) and malondialehyde (MDA). Patients were assessed at Weeks 4 and 10 for oxidative stress markers and seizure frequency and severity. RESULTS: At baseline, both groups (I, II) had significantly lower serum TAC levels relative to healthy controls (p=0.007), while MDA levels were unchanged. After the 4-week period of black seed oil administration, there was no significant difference between the two groups with regards to seizure frequency, severity, or oxidative stress markers (TAC and MDA; p>0.05). Eight patients had >50% reduction in seizure frequency/severity after black seed oil versus placebo. CONCLUSION: Children with intractable epilepsy show evidence of oxidative stress. Administration of 40-80 mg/kg/day of black seed oil as add-on therapy did not alter either oxidative stress markers or seizure frequency or severity in intractable epileptic patients. PMID- 23981723 TI - Independent living with Duchenne muscular dystrophy and home mechanical ventilation in areas of Japan with insufficient national welfare services. AB - In Japan, there is no national 24-hour home care system for people with severe impairments. Despite this fact, a small number of people with Duchenne muscular dystrophy on home mechanical ventilation pursue independent living. Therefore, our aim was to better understand the process by which these individuals arrived at this goal for independence (i.e., choosing to live at home in Japan instead of in special sanatoriums that provide sufficient support and care). Twenty-one participants were interviewed in 2011 and 2013. The interviews were recorded, transcribed, and analysed following a grounded theory approach. These individuals placed particular emphasis on their personal choice regarding where and how they live as well as on whom they depend. Therefore, the core element underlying participants' goals for independent living was self-reliant independency. To improve their social inclusion, the strategies used by the participants to retain their autonomy in an underdeveloped Japanese welfare system by establishing relationships with people in their communities can prevent them from experiencing social isolation. This could serve as an example to their counterparts in other countries. PMID- 23981725 TI - Long-term maintenance of limbal epithelial progenitor cells using rho kinase inhibitor and keratinocyte growth factor. AB - Corneal epithelial stem cells are located in the limbus, the junction between the cornea and the conjunctiva. A limbal epithelium model in vitro would be useful for the study of epithelial stem cells, as well as improving the quality of cultivated epithelial sheets for the treatment of limbal stem cell deficiency. In this study, we succeeded in constructing a limbal epithelium-like structure that could be maintained for at least 5 months in vitro. We modified conventional medium by replacing epidermal growth factor with keratinocyte growth factor (KGF) and adding Y-27632, a rho kinase inhibitor. Using this medium, epithelial cells freshly isolated from human limbus were cocultured with human mesenchymal stem cell-derived feeder cells. Cells formed a stratified layer without air exposure, and both basal and suprabasal layers maintained their unique morphologies for up to 5 months. Basal layers expressed the progenitor marker p63 uniformly and K15 heterogeneously. Expressions of PAX6, K3, and K12 indicated that cell sheets underwent normal differentiation in the corneal epithelium lineage. Although medium was changed daily after day 7, cell debris was observed every day, suggesting that cell sheets underwent turnover. Furthermore, secondary colonies were observed from cells dissociated from 1-month and 3-month cultured sheets. In conclusion, human limbal epithelial cell sheet cultures with KGF and Y-27632 maintained stratification, high expression of both stem/progenitor markers and differentiation markers, and colony-forming cells long-term. This protocol may be useful as an in vitro limbal epithelial model for basic studies. PMID- 23981724 TI - Immunosuppressants affect human neural stem cells in vitro but not in an in vivo model of spinal cord injury. AB - Clinical immunosuppression protocols use calcineurin inhibitors, such as cyclosporine A (CsA) or tacrolimus (FK506), or mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus (rapamycin). These compounds alter immunophilin ligand signaling pathways, which are known to interact downstream with mediators for human neural stem cell (hNSC) differentiation and proliferation, suggesting that immunosuppressants may directly alter hNSC properties. We investigated whether immunosuppressants can exert direct effects on the differentiation, proliferation, survival, and migration of human central nervous system-derived stem cells propagated as neurospheres (hCNS-SCns) in vitro and in an in vivo model of spinal cord injury. We identified unique, immunosuppressant-dependent effects on hCNS-SCns differentiation and proliferation in vitro. All immunosuppressants tested increased neuronal differentiation, and CsA and rapamycin inhibited proliferation in vitro. No immunosuppressant-mediated effects on hCNS-SCns survival or migration in vitro were detected. These data suggested that immunosuppressant administration could alter hCNS-SCns properties in vivo. We tested this hypothesis by administering immunosuppressants to constitutively immunodeficient spinal cord injured mice and assessed survival, proliferation, differentiation, and migration of hCNS-SCns after 14 weeks. In parallel, we administered immunosuppressants to immunocompetent spinal cord injury (SCI) mice and also evaluated hCNS-SCns engraftment and fate. We identified no effect of immunosuppressants on the overall hCNS-SCns fate profile in either xenotransplantation model. Despite a lower level of human cell engraftment in immunocompetent SCI mice, functional locomotor recovery was observed in animals receiving hCNS-SCns transplantation with no evidence of allodynia. These data suggest that local cues in the microenvironment could exert a stronger influence on hCNS-SCns than circulating levels of immunosuppressants; however, differences between human and rodent metabolism/pharmokinetics and xenograft versus allograft paradigms could be determining factors. PMID- 23981726 TI - Administration of murine stromal vascular fraction ameliorates chronic experimental autoimmune encephalomyelitis. AB - Administration of adipose-derived stromal/stem cells (ASCs) represents a promising therapeutic approach for autoimmune diseases since they have been shown to have immunomodulatory properties. The uncultured, nonexpanded counterpart of ASCs, the stromal vascular fraction (SVF), is composed of a heterogeneous mixture of cells. Although administration of ex vivo culture-expanded ASCs has been used to study immunomodulatory mechanisms in multiple models of autoimmune diseases, less is known about SVF-based therapy. The ability of murine SVF cells to treat myelin oligodendrocyte glycoprotein35-55-induced experimental autoimmune encephalitis (EAE) was compared with that of culture-expanded ASCs in C57Bl/6J mice. A total of 1 * 10(6) SVF cells or ASCs were administered intraperitoneally concomitantly with the induction of disease. The data indicate that intraperitoneal administration of ASCs significantly ameliorated the severity of disease course. They also demonstrate, for the first time, that the SVF effectively inhibited disease severity and was statistically more effective than ASCs. Both cell therapies also demonstrated a reduction in tissue damage, a decrease in inflammatory infiltrates, and a reduction in sera levels of interferon-gamma and interleukin-12. Based on these data, SVF cells effectively inhibited EAE disease progression more than culture-expanded ASCs. PMID- 23981728 TI - MDMA assisted psychotherapy found to have a large effect for chronic post traumatic stress disorder. PMID- 23981729 TI - Molecular dynamics study of the proposed proton transport pathways in [FeFe] hydrogenase. AB - Possible proton transport pathways in Clostridium pasteurianum (CpI) [FeFe] hydrogenase were investigated with molecular dynamics simulations. This study was undertaken to evaluate the functional pathway and provide insight into the hydrogen bonding features defining an active proton transport pathway. Three pathways were evaluated, two of which consist of water wires and one of predominantly amino acid residues. Our simulations suggest that protons are not transported through water wires. Instead, the five-residue motif (Glu282, Ser319, Glu279, H2O, Cys299) was found to be the likely pathway, consistent with previously made experimental observations. The pathway was found to have a persistent hydrogen bonded core (residues Cys299 to Ser319), with less persistent hydrogen bonds at the ends of the pathway for both H2 release and H2 uptake. Single site mutations of the four residues have been shown experimentally to deactivate the enzyme. The theoretical evaluation of these mutations demonstrates redistribution of the hydrogen bonds in the pathway, resulting in enzyme deactivation. Finally, coupling between the protein dynamics near the proton transport pathway and the redox partner binding regions was also found as a function of H2 uptake and H2 release states, which may be indicative of a correlation between proton and electron movement within the enzyme. PMID- 23981731 TI - "Natural" isomolecular hormone replacement: an evidence-based medicine approach. PMID- 23981727 TI - Dissection of the human multipotent adult progenitor cell secretome by proteomic analysis. AB - Multipotent adult progenitor cells (MAPCs) are adult adherent stromal stem cells currently being assessed in acute graft versus host disease clinical trials with demonstrated immunomodulatory capabilities and the potential to ameliorate detrimental autoimmune and inflammation-related processes. Our previous studies documented that MAPCs secrete factors that play a role in regulating T-cell activity. Here we expand our studies using a proteomics approach to characterize and quantify MAPC secretome components secreted over 72 hours in vitro under steady-state conditions and in the presence of the inflammatory triggers interferon-gamma and lipopolysaccharide, or a tolerogenic CD74 ligand, RTL1000. MAPCs differentially responded to each of the tested stimuli, secreting molecules that regulate the biological activity of the extracellular matrix (ECM), including proteins that make up the ECM itself, proteins that regulate its construction/deconstruction, and proteins that serve to attach and detach growth factors from ECM components for redistribution upon appropriate stimulation. MAPCs secreted a wide array of proteases, some detectable in their zymogen forms. MAPCs also secreted protease inhibitors that would regulate protease activity. MAPCs secreted chemokines and cytokines that could provide molecular guidance cues to various cell types, including neutrophils, macrophages, and T cells. In addition, MAPCs secreted factors involved in maintenance of a homeostatic environment, regulating such diverse programs as innate immunity, angiogenesis/angiostasis, targeted delivery of growth factors, and the matrix metalloprotease cascade. PMID- 23981732 TI - Using serum hormone analysis to develop hormone replacement therapy regimens-part 1. PMID- 23981730 TI - Health related quality of life and mental distress after PCI: restoring a state of equilibrium. AB - BACKGROUND: Patient self reported measures for Health Related Quality of Life (HRQOL) and mental distress are frequently used to evaluate outcome of therapeutic strategies in cardiac patients.Our study aims to describe changes in HRQOL and mental distress after percutaneous coronary intervention (PCI) focusing on temporal pattern of change and interdependences between both outcome measures. METHOD: 163 PCI patients recruited at 7 cardiovascular care units in Austria answered MacNew Health Related Quality of Life and Hospital Anxiety and Depression Scale (HADS) questionnaires during hospital stay after intervention and at 1, 6, 12 and 24 months. RESULTS: Improvement of MacNew HRQOL was found up to 6 month after PCI. Mental distress declined during the first month of the follow-up period. MacNew HRQOL is negatively correlated to mental distress. The relationship could be well described by a linear regression with MacNew HRQOL as dependent and HADS Total score as independent variable. The explained variance (R2) of the regression equation increases drastically from 45% at the baseline to a level between 67% and 77% in the follow up. CONCLUSION: Our data suggest that the regression equation describing the relation between MacNew HRQOL and HADS Total score six month after PCI defines a state of equilibrium: In absence of actual symptoms of coronary artery disease (CAD) both measures reflect the general health status and the general attitude underlying the self-assessment of health. At the baseline this equilibrium is imbalanced because the symptoms of CAD have a more pronounced impact on the disease specific MacNew HRQOL measure than on the non-disease specific HADS measure for mental distress. In order to use the MacNew questionnaire as a monitoring and/or prognostic tool it seems promising to refer to the state of equilibrium to define expectancy values for successful treatment. PMID- 23981734 TI - Compounded testosterone gels: a guide for clinicians and pharmacists. PMID- 23981733 TI - Testosterone deficiency in men: new treatments for andropause. PMID- 23981735 TI - Managing zinc deficiency in an office setting. PMID- 23981736 TI - Fentanyl troche protocol. PMID- 23981738 TI - Estrogen use in dogs: indications and complications. PMID- 23981737 TI - Basics of compounding: inhalation preparations. PMID- 23981739 TI - Compatibility and stability of linezolid injection admixed with gentamicin sulfate and tobramycin sulfate. AB - The purpose of this study was to evaluate the physical compatibility and chemical stability of linezolid 200 mg/100mL admixed with gentamicin sulfate 80 mg and tobramycin sulfate 80 mg over 7 days at 4 deg C and 23 deg C. The test samples were prepared by adding the required amount of the aminoglycoside antibiotic to bags of linezolid injection 200mg/100mL. Physical and chemical stability based on drug concentrations initially and after 1, 3, 5, and 7 days of storage at 4 deg C ad 23 deg C were evaluated. The linezolid-aminoglycoside admixtures were clear when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. The admixtures remained colorless throughout the study. High-performance liquid chromatography analysis indicated little or no loss of linezolid in any sample stored at either temperature throughtout the study. Gentamicin sulfate and tobramycin sulfate in the linezolid admixtures at 4 deg C remained stable for 7 days, but at 23 deg C gentamicin sulfate was stable for 5 days and tobramycin sulfate was stable for only 1 day before aminoglycoside losses exceeded 10%. Admixtures of linezolid 200mg/100mL with gentamicin sulfate 80 mg and tobramycin sulfate 80 mg were physically compatible and chemically stable for at least 7 days when stored at 4 deg C and for 5 days or 1 day, repectively, at 23 deg C. PMID- 23981740 TI - Stability of nafcillin sodium after reconstitution in 0.9% sodium chloride injeciton and storage in polypropylene syringes for pediatric use. AB - The stability of nafcillin sodium (10 mg/mL) in 0.9% sodium chloride injection has been studied at 25 deg C and 5 deg C in polypropylene syringes by means of a stablilty-indicating high-performance liquid chromatograph assay method. The concentrations of the drug were directly related to peak heights and the percent relative standard deviation based on 5 injections was 1.2. The sodium citrate (added as a buffering agent in the powder) did not interfere with the assay procedure. The product(s) of decomposition separated from the intact drug. At 25 deg C, the loss in potency was less than 2% after 7 days of storage, and at 5 deg C it was also less than 2% when stored for 44 days. The pH values of the injections were between 6.2 to 7.0 throughout this study, except after 14 days of storage at room temperature (potency, 82.3%; pH,5.3). The drug did not adsorb to the syringes, and the physical appearance of the injection did not change. Nafcillin sodium was considered stable for at least 7 days at 25 deg C and 44 days at 5 deg C. PMID- 23981741 TI - Stability of levothyroxine sodium injection in polypropylene syringes. AB - A stability-indicating high-performance liquid chromatography assay method was used to study the stability of levothyroxine sodium injection (100 micrograms/mL) in 0.9% sodium chloride injection after being stored at 5 deg C in polypropylene syringes. The method developed is accurate and precise and has a percent relative standard deviation of 1.3 based on 5 readings. The concentrations of the drug were directly related to the peak heights. The drug in the injection did not adsorb onto the polypropylene syringes. After 7 days of storage at 5 deg C, the injection was clear, the pH value had not changed, and there was no loss in the potency of levothyroxine sodium. The manufacturer's recommendation that the injection be used immediately after reconstitution is very conservative. PMID- 23981742 TI - Fibromyalgia or pseudo fibromyalgia? - we have to get it right. PMID- 23981743 TI - Th17 Cells in Immunopathogenesis and treatment of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by the sequestration of various leukocyte subpopulations within both the developing pannus and synovial space. The chronic nature of this disease results in inflammation of multiple joints, with subsequent destruction of the joint cartilage and erosion of bone. Identification of T helper (Th)17 cells led to breaking the dichotomy of the Th1/Th2 axis in immunopathogenesis of autoimmune diseases such as RA, and its experimental model, collagen-induced arthritis (CIA). Th17 cells produce cytokines, including interleukin (IL)-17, IL-6, IL-21, IL-22 and tumor necrosis factor (TNF)-alpha, with pro-inflammatory effects, which appear to have a role in immunopathogenesis of RA. Regarding the wide ranging production of pro-inflammatory cytokines and chemokines by Th17 cells, it is expected that Th17 cell could be a potent pathogenic factor in disease immunopathophysiology. Thus the identification of effector mechanisms used by Th17 cells in induction of disease lesions may open new prospects for designing a new therapeutic strategy for treatment of RA. PMID- 23981744 TI - HLA-B*5801: utility and cost-effectiveness in the Asia-Pacific Region. AB - Gout is a common condition which is mainly treated with the hypo-uricemic agent, allopurinol. Although allopurinol is generally a well-tolerated drug, there is a small risk of developing potentially fatal complications, such as allopurinol hypersensitivity syndrome. Recent advances in pharmacogenomics have made possible the identification of genes which confer susceptibility to specific drugs. A recent multi-national case-control study has reported allopurinol as the most common drug associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. Several studies have established a strong association between the human leukocyte antigen (HLA)-B*5801 gene and development of Stevens-Johnson syndrome and toxic epidermal necrolysis. The allele frequency of HLA-B*5801 is highest in the South East Asian population.Since other hypo-uricemic agents are available, patients may wish to have HLA-B*5801 testing before being started on allopurinol. As the test for HLA-B*5801 is expensive, time-consuming and only available in selected laboratories, there is a need to evaluate the utility and cost-effectiveness of this test in our region. PMID- 23981745 TI - National survey of knowledge, attitude and practice of fibromyalgia among rheumatologists in China. AB - AIM: Fibromyalgia (FM) is a chronic disorder characterized by widespread musculoskeletal pain and fatigue. It is a less frequently diagnosed disease in China, thus Chinese rheumatologists may have lower awareness of FM compared with colleagues in Western countries. The aim of this study is to investigate the perceptions of FM in Chinese rheumatologists and analyze their therapeutic approach in clinical practice. METHOD: An anonymous questionnaire survey was conducted among a nationwide sample of Chinese rheumatologists at the 15th National Rheumatology Conference in 2010. The 20-question survey included questions regarding background, work experience, perceptions of diagnosis and behaviors of treatment related to FM. Continuing medical education (CME) information was also collected in the survey. RESULTS: Seven hundred and seven rheumatologists responded to the questionnaire, a response rate of 60%. Less than one-fifth of the respondents were experienced in dealing with FM. Although most of the respondents regarded FM as a distinct pathological entity, nearly 30% of Chinese rheumatologists believed that FM was only a psychological disorder. The respondents recognized some of the FM-related symptoms, but had limited knowledge on the diagnostic criteria. Eighty percent of the respondents declared they had difficulties in treating FM patients. However, nearly all (90.8%) respondents believed that the prognosis of FM patients was usually benign. Our data also showed that most Chinese rheumatologists were eager for CME on FM. CONCLUSION: The awareness and perception of FM are still low among Chinese rheumatologists. CME on FM is needed for improving the quality of health care in China. PMID- 23981746 TI - A systematic review of ultrasonography as an outcome measure of skin involvement in systemic sclerosis. AB - The modified Rodnan skin score is widely accepted as a validated tool to assess skin involvement in systemic sclerosis, which is a hallmark of this heterogeneous disease. Ultrasonography is increasingly being utilized in the study of other rheumatic diseases. The utility of ultrasonography to measure skin thickness in systemic sclerosis has been explored since three decades ago. The aim of this review was to examine the validity of ultrasonography as an outcome measure of skin involvement in systemic sclerosis. Original articles in English, published before December 2010, pertaining to the use of B mode ultrasound assessing skin involvement in systemic sclerosis were reviewed. Data were extracted with a focus on criterion and construct validity, reproducibility and responsiveness to change. Seventeen papers were analyzed. Skin thickness was most commonly studied, although skin echogenicity has also been examined. There was heterogeneity with regards to subjects, definitions used and sites imaged. Although there was limited information regarding reliability, when reported, the results showed excellent reproducibility. There was also a lack of construct and criterion validity and evidence for sensitivity to change. Ultrasound has potential as an outcome measure in systemic sclerosis. However, more work needs to be done in order to prove that it is a feasible outcome measure with proven validity. PMID- 23981747 TI - Disease patterns of rheumatology outpatients seen in a tertiary hospital serving a multi-ethnic, urban Asian population in Singapore. AB - AIMS: To describe the spectrum of diseases seen in an outpatient setting in the Singapore General Hospital, the largest tertiary referral centre in Singapore. METHODS: In this cross-sectional study, medical records of patients scheduled for an appointment at the rheumatology specialist outpatient clinics over a 4-month period (10 August 2010-31 December 2010) were reviewed. Primary diagnoses documented by the attending physician at the latest visit were recorded. RESULTS: Among 4180 patients (29.5% male; mean [SD] age: 53.5 [15.1] years; 77.0% Chinese, 8.0% Malay, 8.8% Indian and 6.2% others), the spectrum of diseases seen was as follows [disease - definite n (%), probable n (%)]: Arthritis: rheumatoid arthritis - 958 (22.9%), 68 (1.6%); osteoarthritis - 452 (10.8%), 39 (0.9%); crystal arthritis - 417 (10.0%), 18 (0.4%); spondyloarthritis - 227 (5.4%), 61 (1.5%); psoriatic arthritis - 158 (3.8%), 9 (0.2%); other inflammatory arthritis 153 (3.7%), 94 (2.2%); Connective tissues diseases: systemic lupus erythematosus - 412 (9.9%), 26 (0.6%); vasculitis - 105 (2.5%), 22 (0.5%); Sjogren's syndrome - 81 (1.9%), 32 (0.8%); overlap syndromes - 73 (1.8%); scleroderma - 50 (1.2%), 4 (0.1%); undifferentiated connective tissue diseases - 45 (1.1%), 106 (2.5%); myositis - 41 (1.0%), 12 (0.3%); antiphospholipid syndrome - 22 (0.5%), 7 (0.2%); polymyalgia rheumatica - 16 (0.4%); Others: soft tissue rheumatism - 155 (3.7%); osteoporosis - 61 (1.5%); other non-rheumatologic conditions - 189 (4.5%); other rheumatologic conditions - 67 (1.6%). CONCLUSION: Rheumatoid arthritis, osteoarthritis and crystal arthritis were the three most common rheumatological diseases seen in a tertiary referral centre serving a multi-ethnic urban Asian population in Singapore. PMID- 23981748 TI - Interferon-gamma release assays versus tuberculin skin testing in patients with rheumatoid arthritis. AB - OBJECTIVE: The aim of this study was to analyze the results of interferon-gamma release assays (IGRAs) and tuberculin skin tests (TST) performed to detect latent tuberculosis infection (LTBI) in patients with rheumatoid arthritis (RA). METHODS: Interferon-gamma release assays and TST test results were summarized and systematically reviewed. RESULTS: Four hundred and five RA patients and 339 controls that underwent IGRA and/or TST were identified in seven studies. Five studies were case-control studies and two were cross-sectional studies. Among RA patients, the IGRA positivity rate was 31.6% (89/282; range 11.4%-44.6%), and the TST positivity rate was 23.0% (78/339; range from 14.60% to 45%). Concordance rates ranged from 40% to 76% and discordance rates from 24% to 29.7%. Agreement between IGRAs and TST in RA was poor (69.6%, k = 0.33, 95% CI 0.188-0.478). The IGRA positivity rate was 31.0% in RA and 40.0% in controls, which was not significant (relative risk [RR] 0.802, 95% CI 0.629-1.023, P = 0.075). The TST positivity rate was 24.7% in RA and 50.5% in controls, and this difference was not significant (RR 0.680, 95% CI 0.331-1.339, P = 0.295). CONCLUSIONS: Positivity rates of IGRA and TST were 31.6 and 23.0%, respectively, in RA patients. Agreement between IGRA and TST results in RA was poor. Our data suggest that both IGRA and TST are needed to detect LTBI in RA. PMID- 23981749 TI - Patterns of angiotensin converting enzyme insertion/deletion gene polymorphism among an Egyptian cohort of patients with rheumatoid arthritis. AB - AIM: This case control study was designed to determine the patterns of angiotensin converting enzyme insertion/deletion (ACE I/D) gene polymorphism in rheumatoid arthritis (RA) patients and healthy controls. METHODS: The study population was divided into two groups: the study group included 66 RA patients diagnosed according to the American College of Rheumatology (ACR) classification criteria for RA, and the control group included 66 healthy adults who were age and sex-matched to the RA group. All RA patients were assessed by Disease Activity Score (DAS28), ACR Classification of Global Functional Disability Status and Sharp's score as outcome measures. Gene investigations for ACE I/D polymorphism were performed by polymerase chain reaction (PCR) in both groups. RESULTS: The ACE I/D polymorphism was the (D/D) genotype in 60.6% (n = 40) of RA patients, the (I/D) genotype in 31.8% (n = 21) and the (I/I) genotype in 7.6% (n = 5). The frequency of (D) carriage was significantly higher in the RA cases than in the control group (76.5% vs. 53.8%, respectively, P = 0.0002). ACE D allele carriers were at higher risk of RA, 2.8 times higher than (I) carriers and those who had the homozygote (DD) genotype had 5.6 times the possibility of having RA. No correlations were observed between the homozygote (DD) genotype and disease activity or severity in RA patients. CONCLUSIONS: Our study suggests that high frequency of the ACE D allele contributes to the heritability of RA susceptibility compared to other ACE alleles. On the other hand, no association was detected between ACE I/D polymorphism and the severity of RA. PMID- 23981750 TI - Remission in rheumatoid arthritis by different criteria does not converge over the inflammatory markers. AB - OBJECTIVE: Remission is an ideal target in the management of rheumatoid arthritis (RA). We compared American College of Rheumatology (ACR) 1981 preliminary definition of remission, European League Against Rheumatism (EULAR) disease activity score of 28 joints - C-reactive protein (DAS28 (3)-CRP) and DAS28 (3) ESR (erythrocyte sedimentation rate) and newer ACR/EULAR remission criteria from 2011. We assessed the agreement between these definitions using kappa statistics in a real-time clinical scenario. MATERIALS AND METHODS: This is a cross sectional study in which 460 patients' charts were reviewed. Their data on tender and swollen joint counts, visual analogue scale of patient global assessment (Pt GA), ESR and CRP were retrieved. One hundred patients who fulfilled one of the remission criteria and had all the required five variables were selected and they were categorized into remission using all the four definitions. RESULTS: Only one case out of 100 fulfilled all four remission criteria. Among 100 cases: ACR 1981 classified six in remission; ACR/EULAR 2011, eight; DAS28 (3)-ESR, 24; and DAS28 (3)-CRP classified 100 patients in remission. A substantial number of patients continued to have features suggesting persisting active inflammation, despite being categorized into remission. A major portion of disagreement was in ESR and CRP. The value spread of all clinical parameters such as swollen joint count, tender joint count and Pt GA had no significant difference in the patients classified as being in remission. CONCLUSION: The DAS28 (3)-CRP overestimated remission compared to all other criteria. Disagreement was more in laboratory inflammatory parameters. A uniform definition of remission is needed. PMID- 23981751 TI - Low body mass index is associated with impaired quality of life in patients with rheumatoid arthritis. AB - AIM: To investigate the relationship between quality of life (QOL) and rheumatoid chachesia, malnutrition in patients with rheumatoid arthritis (RA). METHODS: EuroQol Group 5-Dimension Self-Report Questionnaire (EQ5D) and Japanese Health Assessment Questionnaire (JHAQ) scores, body mass index (BMI), arm muscle area (AMA) and clinical indicators were measured in 385 RA patients. One-way analysis of variance for obtained data was conducted among three groups: 131 with low BMI (< 20), 163 with moderate (20-25) and 91 with high BMI (>=25). Then multiple regression analyses for JHAQ and EQ5D scores with nutritional and clinical indicators as independent variables were performed. RESULTS: EQ5D and JHAQ scores were significantly lower and higher, respectively, in the low BMI group than those in the moderate BMI group. Clinical indicators including doses of corticosteroid were similar among the three groups except for disease duration. Disease activity score (DAS) 28, disease duration, C-reactive protein and AMA were significant variables in the regression model for EQ5D. CONCLUSION: Low BMI deteriorates the QOL of RA patients. Muscle protein loss apparently leads to a reduction in BMI and QOL. PMID- 23981752 TI - Expression, localization and clinical application of exogenous Smith proteins D1 in gene transfected HEp-2 cells. AB - AIM: To establish an improved substrate for an indirect immunofluorescence test (IIF) to detect anti-Sm antibody. METHODS: Full-length Smith protein D1(Sm-D1) complementary DNA was obtained from human larynx carcinoma cell line HEp-2 by reverse transcription - polymerase chain reaction (RT-PCR) and cloned into the mammalian expression vector pEGFP-C1. The recombinant plasmid pEGFP-Sm-D1 was transfected into HEp-2 cells. The expression, localization and antigenicity of fusion proteins of green fluorescent protein (GFP) in transfected cells were confirmed by means of immunoblotting (IBT), confocal fluorescence microscopy and IIF analysis. Transfected HEp-2 cells were analyzed with reference serum and compared with untransfected HEp-2 cells by IIF. RESULTS: Stable expression of the Sm-D1-GFP was maintained for more than ten generations. This Sm-D1-GFP showed the antigenicity of Sm-D1 with a characteristic phenotype in IIF.Six of 12 serum specimens from systemic lupus erythematosus contained both 29/28 and 13.5 kDa proteins and showed characteristic immunofluorescent patterns. The same phenomenon appeared in 3/6 serum samples which contained 29/28 kDa proteins only. Sera from 10 healthy donors did not react with HEp-Sm-D1 or HEp-2 at 1:80 attenuant degrees. No alteration in expression, localization and morphology was observed when HEp-Sm-D1 or HEp-2 interacted with the reference sera which could react with Ro/SSA, La/SSB, beta2GP1, centromere, histone, and Scl-70 antibodies in routine IIF tests. CONCLUSION: As a new kind of substrate of IIF, HEp-Sm-D1 can be used to detect anti-Sm antibodies. Transfected HEp-2 cells keep the immunofluorescent property of HEp-2 cells in immunofluorescence anti-nuclear antibody (IFANA) test and could potentially be used as substrate for routine IFANA detection. PMID- 23981753 TI - Up regulation of serum tumor necrosis factor-related apoptosis inducing ligand in juvenile-onset systemic lupus erythematosus: relations with disease activity, antibodies to double -stranded DNA, nephritis and neutropenia. AB - OBJECTIVES: Apoptosis is induced by binding of death receptor ligands, members of the tumor necrosis factor (TNF) superfamily, to their cognate receptors. It is suggested that TNF-related apoptosis inducing ligand (TRAIL) is involved in pathogenesis of juvenile-onset systemic lupus erythematosus (JSLE). This study aimed to assess TRAIL concentrations in sera of JSLE children and to determine their potential relationship with disease activity, anti-double-stranded DNA (anti-dsDNA) levels, neutropenia and renal involvement. METHODS: Circulating levels of TRAIL were measured by enzyme-linked immunosorbent assay (ELISA) in serum samples obtained from 40 JSLE patients (20 with active and 20 with inactive disease) and 20 controls. RESULTS: The mean (SEM) serum TRAIL concentration in JSLE was 1750.7 (440.2) pg/mL. Serum TRAIL concentrations in patients were higher than those in controls (P < 0.01). Serum TRAIL concentrations for children with inactive disease (1854.8 [485.4] pg/mL) and those with activity (1646.6 [390.6] pg/mL) were statistically comparable. JSLE children with positive anti-dsDNA antibodies had significantly higher TRAIL levels (mean = 1846 [456] vs. 1455 [325] pg/mL; P < 0.05). Serum TRAIL concentrations were significantly higher in classes III and IV nephritis compared to classes I and II nephritis (1970 [512] vs. 1330 [331] pg/mL; P < 0.01). Serum TRAIL concentrations in patients with neutropenia were higher than those without neutropenia (1805 [505] vs. 1516 [400] pg/mL; P = 0.042) and in controls (P = 0.024). CONCLUSIONS: Our data indicate that an increased level of TRAIL is a feature of JSLE that correlates with disease activity, anti-dsDNA titers neutropenia and lupus nephritis. PMID- 23981754 TI - Peripheral arterial disease in patients with systemic lupus erythematosus: a prospective controlled study. AB - AIM: The aim of our study was to: (i) map out the presence of peripheral vascular disease in a sample of systemic lupus erythematosus (SLE) patients; and (ii) correlate our findings with disease characteristics, activity indices, traditional risk factors of atherosclerosis and thrombotic variables. METHODS: The study population comprised 120 SLE patients and 100 controls. Clinical data were collected for patients and controls with stress on clinical issues of SLE patients, including British Isles Lupus Assessment Group index score, anti-double stranded DNA titer C3 and C4 levels, and treatment taken, mainly steroids. Measurements of thrombotic variables were performed. Non-invasive arterial assessment was performed, including carotid duplex scanning and measurement of carotid artery intima-media thickness (IMT) and peripheral arterial assessment and measurement of ankle-brachial pressure index (ABPI). RESULTS: The mean age of SLE patients was 32 years and mean disease duration was 8 years. There were no statistically significant differences in the traditional vascular risk factors measured between SLE patients and controls. There were significantly higher plasma levels of thrombotic variables in SLE patients. The average IMT was statistically significantly greater in SLE patients compared to controls. Thirty SLE patients (25%) had an ABPI < 1.0 compared with six controls (6%), which was statistically significant. CONCLUSION: This study showed an increased prevalence of peripheral arterial disease in SLE patients as shown by the higher carotid artery IMT and lower ABPI in such patients compared with controls. Multiple risk factors are likely to be involved in such findings. PMID- 23981755 TI - Role of anti-annexin A5 in pathogenesis of hypercoagulable state in patients with antiphospholipid syndrome. AB - AIM: Despite several attempts made during the last decade, the exact pathogenesis of exceedingly high thrombotic events and bad obstetric outcome in antiphospholipid syndrome (APS) remains elusive. Anti-annexin A5 (aANX IgG) is thought to have a role in pathophysiology of APS. We studied role of aANX IgG in the pathogenesis of hypercoagulable state in APS patients. METHODS: We estimated levels of aANX IgG in 112 patients with APS (86 primary and 26 secondary). We also estimated aANX IgG levels in 40 age- and sex-matched healthy controls, 10 patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) each, without any history of thrombosis or pregnancy morbidity, 10 patients of non-APS thrombosis and 10 patients of pregnancy loss without APS. RESULTS: Only three healthy controls, two SLE (P = 0.239), one RA patient (P = 0.794), three non-APS thrombosis patients (P = 0.086) and two patients with pregnancy loss without APS (P = 0.258) had marginally elevated values, whereas 53 primary APS (P < 0.001) and 16 secondary APS (P < 0.001) were positive. We also compared aANX IgG levels in different groups. Mean +/- standard errors of the mean of healthy controls was 3.77 +/- 0.49, in SLE patients it was 4.88 +/- 1.17 (P = 1.000), in RA patients it was 4.67 +/- 0.97 (P = 1.000), in non-APS thrombosis it was 7.93 +/- 0.88 (P = 0.488) and in pregnancy loss without APS it was 6.80 +/- 0.93 (P = 0.789). However, it was significantly elevated in primary APS (12.87 +/- 1.07, P < 0.001), secondary APS (11.98 +/- 1.41, P = 0.001) and total APS patients (12.68 +/- 0.88, P < 0.001). CONCLUSION: From the above observations it appears that aANX IgG plays a significant role in producing a hypercoagulable state in primary and secondary APS. PMID- 23981756 TI - Incidence and prevalence of idiopathic inflammatory myopathies in South Australia: a 30-year epidemiologic study of histology-proven cases. AB - AIM: To describe the epidemiology of biopsy-proven idiopathic inflammatory myopathies (IIM) in South Australia (SA). METHODS: Cases of IIM were ascertained by review of all muscle biopsy reports from the Neuropathology Laboratory, Hanson Institute (wherein all adult muscle biopsies in SA are reported) from 1980 to 2009. Clinical correlation of these patients by review of medical records was undertaken. SA population denominator numbers were obtained from the Australian Bureau of Statistics. RESULTS: Three hundred and fifty-two biopsy-proven cases of IIM were identified between 1980 and 2009. The overall annual incidence of IIM appeared to be rising with a mean incidence of eight cases per million population (95% CI: 7.2-8.9). This corresponded with an increasing annual incidence of inclusion body myositis (IBM) (prevalence of 50.5 cases per million population in 2009, 95% CI: 40.2-62.7). A female preponderance was noted in both dermatomyositis (DM) (F : M = 2.75 : 1.00) and polymyositis (PM) (F : M = 1.55 : 1.00) but gender distribution was almost equal in IBM (F : M = 1.1 : 1.0). Mean age at diagnosis for IBM (67.5 years) was higher than for DM (55.1 years) and PM (59.0 years). A higher proportion of DM patients reported living in urban dwellings and DM patients tended to be predominantly professionals. CONCLUSIONS: In SA there is an increasing incidence of IBM and the prevalence is one of the highest reported to date. This may reflect an increase in the number of biopsies performed, improved histological techniques or a genuine increase in incidence. PMID- 23981757 TI - Anti-carbonic anhydrase III autoantibodies in vasculitis syndrome. AB - AIM: To identify autoantibodies useful in the diagnosis of primary vasculitides. METHODS: The presence of antibodies against proteins in the lysate of mouse blood vessels was examined by two-dimensional electrophoresis followed by Western blotting for the pooled serum sample from patients with various forms of vasculitis: polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), Wegener's granulomatosis (WG) and Takayasu's arteritis (TA). Autoantigenicity in patients with vasculitides was examined by Western blotting and enzyme-linked immunosorbent assay (ELISA). Clinicopathological correlations between the positivity of the autoantibodies and clinical status of patients with the vasculitis were examined. RESULTS: The autoantigen detected in the lysate of pooled sera from patients with vasculitides was identified by mass spectrometry as carbonic anhydrase III (CAIII). ELISA showed significantly higher prevalence of anti-CAIII antibodies in MPA patients (MPA, 11/23 [47.8%]; healthy controls, 2/32 [6.3%]; P < 0.001). Further, anti-CAIII antibody-positive MPA patients had higher vasculitis activity scores compared to anti-CAIII antibody-negative patients, and a weak and not significant negative correlation was observed between anti-CAIII antibody levels and myeloperoxidase - anti-nuclear cytoplasmic antibody (MPO-ANCA) levels. No significant differences were found in anti-CAIII autoantibody levels between MPA and the other primary vasculitides. CONCLUSION: We found significantly high prevalence of anti-CAIII antibody levels in sera from MPA patients. Although the number of samples available in this study is small and anti-CAIII autoantibodies display weak specificity for MPA, anti-CAIII antibodies may be useful for diagnosing MPA in patients who have no ANCA, as well as for assessing disease activity. PMID- 23981758 TI - MEFV gene mutations in Henoch-Schonlein purpura. AB - AIM: Coexistence of familial Mediterranean fever (FMF) with various systemic vasculitides, including Henoch-Schonlein purpura (HSP) and other inflammatory disorders has been reported and the MEFV gene has been suggested to play an important role in the pathogenesis of this association. In the present study, the mutation rate of the MEFV gene in HSP and its association with the clinical course of the disease were evaluated. METHOD: The study group comprised 68 children (36 boys and 32 girls) diagnosed as having HSP. The spectrum and degree of organ involvement and the levels of serum C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were documented for each patient. Allele specific PCR using oligonucleotide probes which include 12 MEFV mutations (E148Q, P369S, F479L, M680I [G/C], M680I [G/A], I692del, M694V, M694I, K695R, V726A, A744S, R761H) were used for mutation analysis. RESULTS: Of the 68 patients studied, 50 (74%) showed no mutation, while 18 (26%) had MEFV mutation. Mutation analysis of the whole group revealed that 15 (22%) patients were heterozygous for one of the screened MEFV mutations, while three (4.5%) patients were compound heterozygous for two of the studied mutations, and one (1.5%) patient was homozygous for E148Q/E148Q mutations. Gastrointestinal and joint involvement, and edema were more frequently observed in patients with MEFV mutations, while ESR and CRP levels were significantly higher (P < 0.05) in patients with MEFV mutations. CONCLUSION: MEFV mutations, especially, E148Q and M694V, mutations might be associated with HSP and may affect clinical presentation and laboratory findings in HSP patients. PMID- 23981759 TI - The use of temporal artery ultrasound in the diagnosis of giant cell arteritis in routine practice. AB - AIM: The exact diagnostic role of temporal artery ultrasound (TAU) remains unclear. The aim of this study was to determine the sensitivity and specificity of a positive halo sign in patients undergoing TAU in a clinical setting, and to perform a review of existing evidence. METHOD: Patients who had undergone TAU at a single centre in Australia were included in the study. The presence or absence of a halo sign and whether it was unilateral or bilateral was determined retrospectively from radiology reports. Pathology results were used to determine which patients underwent a temporal artery biopsy and if the biopsy was positive or negative. A case note review was performed to determine presenting clinical features and if a clinical diagnosis of giant cell arteritis was made. The sensitivity, specificity and likelihood ratios of TAU compared to both biopsy and clinical diagnosis were calculated. RESULTS: Fifty patients were identified as having had a TAU (28% male, mean age 69). When compared to biopsy-proven cases, the sensitivity of a halo sign was 40%, specificity 81%, positive likelihood ratio 2.1 and negative likelihood ratio 0.7. When compared to clinical diagnosis, the sensitivity was 42%, specificity 94%, positive likelihood ratio 7.1 and negative likelihood 0.6. CONCLUSIONS: Sensitivity and specificity results were comparable to the literature. A halo sign may preclude the need for biopsy in cases of high clinical suspicion and contraindications to surgery. Biopsy remains necessary in most cases, irrespective of whether a halo sign is present. PMID- 23981761 TI - An unusual cause of visual loss in a patient with giant cell arteritis. PMID- 23981762 TI - A case of unusual association of Gaucher's disease with spinal tuberculosis. PMID- 23981763 TI - Mycobacterial tenosynovitis of the hand in a patient with systemic lupus erythematosus. PMID- 23981764 TI - Ramsay Hunt syndrome associated with tocilizumab therapy in rheumatoid arthritis: a case report. PMID- 23981765 TI - Reversal of chronic refractory tophaceous gout with erosions with pegloticase. PMID- 23981766 TI - Myelodysplastic syndrome presenting as sarcoidosis. PMID- 23981767 TI - Two cases of familial Mediterranean fever associated with sarcoidosis (Lofgren's syndrome) and rheumatoid arthritis. PMID- 23981768 TI - Socioeconomic disparities in stroke case fatality--Observations from Riks-Stroke, the Swedish stroke register. AB - BACKGROUND: Low socioeconomic status (low education and income level) has been found to be associated with increased stroke mortality. However, findings from previous studies on the association between socioeconomic status and case fatality (survival) after stroke have been inconsistent. AIMS: The study aims to explore the association between socio-economic status and survival after stroke using Riks-Stroke, the Swedish Stroke Register, with emphasis on changes in survival (in)equality with time after stroke. METHODS: All 76 hospitals in Sweden admitting acute stroke patients participate in Riks-Stroke. Riks-Stroke data on 18- to 74-year-old patients with onset of first stroke during the years 2001-2009 were combined with data from other official Swedish registers. Case fatality was analyzed by socioeconomic status (education, income, country of birth, and cohabitation) and other patient characteristics. RESULTS: Of the 62,497 patients in the study, a total of 6094 (9.8%) died within the first year after stroke. Low income, primary school education, and living alone were independently associated with higher case fatality after the acute phase. Differences related to income and cohabitation were present already early, at 8-28 days after stroke, with the gaps expanding thereafter. The association between education and case fatality was not present until 29 days to one-year after stroke. Dissimilarities in secondary preventative medications prescribed on discharge from hospital had only a minor impact on these differences. CONCLUSIONS: Socioeconomic status had only a limited effect on acute phase case fatality, indicating minor disparities in acute stroke treatment. The survival inequality, present already in the subacute phase, increased markedly over time since the stroke event. The socioeconomic differences could not be explained by differences in secondary prevention at discharge from hospital. Large socioeconomic differences in long-term survival after stroke may exist also in a country with limited income inequity. PMID- 23981769 TI - Body imaging and sexual behavior in lean women with polycystic ovary syndrome. AB - INTRODUCTION: In women with polycystic ovary syndrome (PCOS), changes in body appearance may influence the feminine identity of the patients with possible consequent depression and sexual dysfunction. AIM: The study aims to examine the differences in mood, perceived body image, sexual behavior, and clitoral vascularization between lean PCOS patients and healthy eumenorrheic controls. METHODS: Thirty-three lean PCOS women (Group I) and 22 healthy nonhirsute volunteers (Group II) were submitted, on day 3-5 of the cycle, to ultrasonographic (US) and Doppler analyses, to clinical, hormonal, and biochemical evaluations, and to psychometric tests. MAIN OUTCOMES MEASURES: Main outcome measures are Ferriman-Gallwey score (FG), clitoral volume, clitoral artery Pulsatility Index, the two-factor Italian McCoy female questionnaire (MFSQ), the Stunkard Figure Rating Scale (FRS), and the Beck Depression Inventory (BDI) questionnaire. RESULTS: The FG score and the androgens resulted, as expected, more elevated in PCOS patients than in controls. However, the US assessment of the clitoral body volume and the resistances registered at the level of the dorsal clitoral artery did not show any difference between Group I and Group II patients. Moreover, the two-factor Italian MFSQ, the FRS, and the BDI were similar in both groups. CONCLUSIONS: It seems that in lean PCOS women, the moderate hirsutism and hyperandrogenism do not have any important influence on body image and self-esteem and, as a consequence, on sexual function. PMID- 23981770 TI - Organic matter humification in vermifiltration process for domestic sewage sludge treatment by excitation-emission matrix fluorescence and Fourier transform infrared spectroscopy. AB - Performance of a conventional biofilter (BF) and two vermifilters (VFs, different heights) containing earthworms was investigated for domestic sewage sludge (DWS) treatment. Humic-acid like (HAL) fraction isolated from the influent sludge (IS) and effluent sludge of BF (ESBF) and VFs (ESVFs) were determined the elemental and functional composition, and structural characteristics using various analytical approaches. Results showed that performance of DWS treatment in the VFs was preferable to that in the BF. With respect to IS-HAL and ESBF-HAL, ESVFs HAL had low C, H and N contents and C/O ratio, and high O, carboxyl and phenolic OH group contents, and C/N, C/H and E4/E6 ratios, and large molecular weight. The excitation-emission (Ex/Em) matrix spectra revealed that an additional peak was found at Ex/Em wavelength pairs of 345/435 nm in ESVFs-HAL. Further, Fourier transform infrared spectra showed that vermifiltration led to the loss of aliphatic materials and carbohydrates, and the enrichment of carbonyl and phenolic OH groups in HAL fractions. Additionally, the increase in VF height seemed to accelerate humification degree of organic matter in the effluent sludge. In summary, vermifiltration is alternate technology for transformation of organic matter into humic substances, and thus improves quality of DWS as soil organic fertilizer. PMID- 23981771 TI - Human resistin in chemotherapy-induced heart failure in humanized male mice and in women treated for breast cancer. AB - Resistin is a circulating mediator of insulin resistance mainly expressed in human monocytes and responsive to inflammatory stimuli. Recent clinical studies have connected elevated resistin levels with the development and severity of heart failure. To further our understanding of the role of human resistin in heart failure, we studied a humanized mouse model lacking murine resistin but transgenic for the human Retn gene (Hum-Retn mice), which exhibits basal and inflammation-stimulated resistin levels similar to humans. Specifically, we explored whether resistin underlies acute anthracycline-induced cardiotoxicity. Remarkably, doxorubicin (25mg/kg ip) led to a 4-fold induction of serum resistin levels in Hum-Retn mice. Moreover, doxorubicin-induced cardiotoxicity was greater in the Hum-Retn mice than in littermate controls not expressing human resistin (Retn(-/-)). Hum-Retn mice showed increased cardiac mRNA levels of inflammatory and cell adhesion genes compared with Retn(-/-) mice. Macrophages, but not cardiomyocytes, from Hum-Retn mice treated with doxorubicin in vitro showed dramatic induction of hRetn (human resistin) mRNA and protein expression. We also examined resistin levels in anthracycline-treated breast cancer patients with and without cardiotoxicity. Intriguingly, serum resistin levels in women undergoing anthracycline-containing chemotherapy increased significantly at 3 months and remained elevated at 6 months in those with subsequent cardiotoxicity. Further, elevation in resistin correlated with decline in ejection fraction in these women. These results suggest that elevated resistin is a biomarker of anthracycline-induced cardiotoxicity and may contribute in the development of heart failure via its direct effects on macrophages. These results further implicate resistin as a link between inflammation, metabolism, and heart disease. PMID- 23981773 TI - Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial. AB - BACKGROUND: There is increasing evidence linking vitamin D deficiency to both susceptibility to, and severity of, multiple sclerosis (MS). Patients with the clinically isolated syndrome represent the initial presentation of a demyelinating disorder, and those with asymptomatic lesions on magnetic resonance imaging (MRI) are at risk of progression to clinically definite MS. The aims of this study are to examine the immunologic effects of vitamin D in both healthy individuals and in patients with clinically isolated syndrome, and in the latter group the effects on disease progression assessed by MRI and clinical measures. METHODS/DESIGN: This is a single-center double-blind randomized placebo controlled clinical trial. The primary endpoint is the immunologic effects of two doses of vitamin D compared with placebo over 24 weeks in both healthy control participants and patients presenting with the clinically isolated syndrome. Healthy control participants (n = 39) and patients with clinically isolated syndrome (n = 45) will be randomized to one of three arms, namely 1) vitamin D 5,000 IU daily, 2) vitamin D 10,000 IU daily, or 3) placebo, and followed up for 24 weeks. In both patients and healthy control participants, the primary outcome will be immunologic measures of the frequency of CD4 T-cell subsets and cytokine responses in peripheral blood mononuclear cells, assessed at baseline, and after 16 and 24 weeks of treatment. Secondary endpoints, in the patients with clinically isolated syndrome, will be relapse activity, and the number of new T2 lesions and gadolinium-enhancing lesions assessed by MRI in the two vitamin D treated groups compared with the placebo-treated group over the 24 weeks of the study. TRIAL REGISTRATION: EU Clinical Trials Register: EudraCT: 2012-000635-68. ClinicalTrials.gov identifier: NCT01728922. PMID- 23981772 TI - The heparin-binding domains of IGFBP-2 mediate its inhibitory effect on preadipocyte differentiation and fat development in male mice. AB - IGF-binding protein (IGFBP)-2 overexpression confers resistance to high-fat feeding and inhibits the differentiation of preadipocytes in vitro. However, whether administration of IGFBP-2 can regulate adipogenesis in vivo and the domains that mediate this response have not been defined. IGFBP-2 contains 2 heparin-binding domains (HBD), which are localized in the linker region (HBD1) and C-terminal region (HBD2) of IGFBP-2. To determine the relative importance of these domains, we used synthetic peptides as well as mutagenesis. Both HBD1 and HBD2 peptides inhibited preadipocyte differentiation, but the HBD2 peptide was more effective. Selective substitution of charged residues in the HBD1 or HBD2 regions attenuated the ability of the full-length protein to inhibit cell differentiation, but the HBD2 mutant had the greatest reduction. To determine their activities in vivo, pegylated forms of each peptide were administered to IGFBP-2(-/-) mice for 12 weeks. Magnetic resonance imaging scanning showed that only the HBD2 peptide significantly reduced (48 +/- 9%, P < .05) gain in total fat mass. Both inguinal (32 +/- 7%, P < .01) and visceral fat (44 +/- 7%, P < .01) were significantly decreased by HBD2 whereas HBD1 reduced only visceral fat accumulation (24 +/- 5%, P < .05). The HBD2 peptide was more effective peptide in reducing triglyceride content and serum adiponectin, but only the HBD2 peptide increased serum leptin. These findings demonstrate that the HBD2 domain of IGFBP 2 is the primary region that accounts for its ability to inhibit adipogenesis and that a peptide encompassing this region has activity that is comparable with native IGFBP-2. PMID- 23981775 TI - Multiple polymorphisms within the PLCE1 are associated with esophageal cancer via promoting the gene expression in a Chinese Kazakh population. AB - Although recent genome-wide association studies of esophageal squamous cell carcinoma (ESCC) identified a susceptibility locus in phospholipase C epsilon 1 (PLCE1) in Chinese Han populations, few studies further confirmed these findings in pure Kazakh population in which there are higher incidence and mortality of ESCC. Here, we investigated the potential associations between 19 SNPs of PLCE1 and susceptibility to ESCC in 222 cases and 326 controls from a pure ethnic population of Kazakh. Real-time PCR and immunohistochemistry were performed to detect the PLCE1 expression levels and evaluate their association with PLCE1 polymorphism. We found that only 4 SNPs (rs753724, rs11187842, rs2274223, and rs12263737) with moderate linkage disequilibrium (LD) confer significantly increased risk of ESCC, with the ORs ranging from 1.43 to 2.04, and there was a risk allele dose-dependent increase in ESCC risk (P-trend=0.043). Especially, the risk effects of rs2274223 were more evident in poor differentiation and advanced clinical stages of Kazakh ESCC. Additionally, the significantly lowest PLCE1 mRNA expression was found in the KYSE-150 cell line having no risk alleles compared with other three cell lines having risk alleles, and the normal tissues of both homozygous mutant type of PLCE1 rs12263737 and rs2274223 had a higher PLCE1 staining score than that of homozygous wild type. Our findings suggested that genetic variants in PLCE1 might serve as candidate markers for Kazakh ESCC susceptibility, and these LD variants might influence ESCC risk individually and jointly by promoting the messenger RNA and protein expression of the gene. PMID- 23981776 TI - In-silico analysis of simple and imperfect microsatellites in diverse tobamovirus genomes. AB - An in-silico analysis of simple sequence repeats (SSRs) in 30 species of tobamoviruses was done. SSRs (mono to hexa) were present with variant frequency across species. Compound microsatellites, primarily of variant motifs accounted for up to 11.43% of the SSRs. Motif duplications were observed for A, T, AT, and ACA repeats. (AG)-(TC) was the most prevalent SSR-couple. SSRs were differentially localized in the coding region with ~54% on the 128 kDa protein while 20.37% was exclusive to 186 kDa protein. Characterization of such variations is important for elucidating the origin, sequence variations, and structure of these widely used, but incompletely understood sequences. PMID- 23981777 TI - Breast radiotherapy and heart disease - where are we now? PMID- 23981774 TI - Characterization of two pathogenic mutations in cystathionine beta-synthase: different intracellular locations for wild-type and mutant proteins. AB - Cystathionine beta-synthase (CBS) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the condensation of homocysteine with serine to generate cystathionine. Homocystinuria is an autosomal recessive disorder commonly caused by a deficiency of CBS activity. Here, we characterized a novel CBS mutation (c.260C>A (p.T87N)) and a previously reported variant (c.700G>A (p.D234N)) found in Venezuelan homocystinuric patients, one nonresponsive and one responsive to vitamin B6. Both mutant proteins were expressed in vitro in prokaryotic and eukaryotic cells, finding lower soluble expression in HEK-293 cells (19% T87N and 23% D234N) compared to wild-type CBS. Residual activities obtained for the mutant proteins were 3.5% T87N and 43% D234N. Gel exclusion chromatography demonstrated a tendency of the T87N mutant to aggregate while the distribution of the D234N mutant was similar to wild-type enzyme. Using immunofluorescence microscopy, an unexpected difference in intracellular localization was observed between the wild type and mutant proteins. While the T87N mutant exhibited a punctate appearance, the wild-type protein was homogeneously distributed inside the cell. Interestingly, the D234N protein showed both distributions. This study demonstrates that the pathogenic CBS mutations generate unstable proteins that are unable (T87N) or partially unable (D234N) to assemble into a functional enzyme, implying that these mutations might be responsible for the homocystinuria phenotype. PMID- 23981778 TI - Is it me or is it hot in here? A plea for more research into hot flushes. PMID- 23981779 TI - The effect of heat waves on ambulance attendances in Brisbane, Australia. AB - Introduction Heat waves have significant impacts on mortality and morbidity. However, little is known regarding effects on pre-admission health outcomes such as ambulance attendances, particularly in subtropical regions. Problem This study investigated both main temperature effects and the added effects of heat waves on ambulance attendances in Brisbane, a subtropical city in Australia. METHODS: Daily data relating to 783,935 ambulance attendances, along with data on meteorological variables and air pollutants, were collected for the period 2000 2007. Ambient temperature (main) effects were assessed using a distributed lag nonlinear approach that accounted for delayed effects of temperature, while added heat wave effects were incorporated separately using a local heat wave definition. Effect estimates were obtained for total, cardiovascular and respiratory attendances, and different age groups. RESULTS: Main effects of temperature were found for total attendances, which increased by 50.6% (95% CI, 32.3%-71.4%) for a 9.5 degrees C increase above a reference temperature of 29 degrees C. An added heat wave effect on total attendances was observed (18.8%; 95% CI, 6.5%-32.5%). Significant effects were found for both respiratory and cardiovascular attendances, particularly for those aged 65 and above. CONCLUSION: Ambulance attendances can be significantly impacted by sustained periods of high temperatures, and are a valid source of early detection of the effects of extreme temperatures on the population. The planning of ambulance services may need to be adapted as a consequence of increasing numbers of heat waves in the future. Ambulance attendance data also should be utilized in the development of heat warning systems and climate change adaptation strategies. PMID- 23981780 TI - Use of eXIA 160 XL for contrast studies in micro-computed tomography: experimental observations. AB - The purpose of this study was to evaluate the time course of contrast enhancement of spleen, liver, and blood using eXIA 160 XL in healthy mice. eXIA 160 XL was intravenously injected in C57bl/6 mice (n = 12) at a dose of 0.1 mL/20 g (16 mg iodine [I]/20 g) (n = 6) or 0.2 mL/20 g (32 mg I/20 g) (n = 6). The distribution was analyzed by repeated micro-computed tomographic scans up to 48 hours after contrast administration. Images were analyzed using Amide software. Regions of interest were drawn in the spleen, liver, and left ventricle. Contrast enhancement was measured and expressed as a function of time. Peak contrast enhancement of the spleen was reached at 30 minutes, and peak contrast enhancement of the liver occurred 45 minutes after 16 mg I/20 g. Given that this contrast was found to be rather low in the spleen in comparison with former eXIA 160 products, experiments were done at a higher dose. However, the 32 mg I/20 g dose was lethal for mice. Enhancement inside the heart lasts for 1 hour. Administration of eXIA 160 XL results in long-lasting blood pool contrast with higher contrast enhancement in heart and liver in comparison with eXIA 160; however, the administered dose should be limited to 16 mg I/20 g. PMID- 23981781 TI - In vivo demonstration of cancer molecular imaging with ultrasound radiation force and buried-ligand microbubbles. AB - In designing targeted contrast agent materials for imaging, the need to present a targeting ligand for recognition and binding by the target is counterbalanced by the need to minimize interactions with plasma components and to avoid recognition by the immune system. We have previously reported on a microbubble imaging probe for ultrasound molecular imaging that uses a buried-ligand surface architecture to minimize unwanted interactions and immunogenicity. Here we examine for the first time the utility of this approach for in vivo molecular imaging. In accordance with previous results, we showed a threefold increase in circulation persistence through the tumor of a fibrosarcoma model in comparison with controls. The buried-ligand microbubbles were then activated for targeted adhesion through the application of noninvasive ultrasound radiation forces applied specifically to the tumor region. Using a clinical ultrasound scanner, microbubbles were activated, imaged, and silenced. The results showed visually conspicuous images of tumor neovasculature and a twofold increase in ultrasound radiation force enhancement of acoustic contrast intensity for buried-ligand microbubbles, whereas no such increase was found for exposed-ligand microbubbles. We therefore conclude that the use of acoustically active buried-ligand microbubbles for ultrasound molecular imaging bridges the demand for low immunogenicity with the necessity of maintaining targeting efficacy and imaging conspicuity in vivo. PMID- 23981782 TI - Age-dependent small-animal internal radiation dosimetry. AB - Rats at various ages were observed to present with different radiosensitivity and bioavailability for radiotracers commonly used in preclinical research. We evaluated the effect of age-induced changes in body weight on radiation dose calculations. A series of rat models at different age periods were constructed based on the realistic four-dimensional digital rat whole-body (ROBY) computational model. Particle transport was simulated using the MCNPX Monte Carlo code. Absorbed fractions (AFs) and specific absorbed fraction (SAFs) of monoenergetic photons/electrons and S values of eight positron-emitting radionuclides were calculated. The SAFs and S values for most source-target pairs were inversely correlated with body weight. Differences between F-18 S values for most source-target pairs were between -1.5% and -2%/10 g difference in body weight for different computational models. For specific radiotracers, the radiation dose to organs presents a negative correlation with rat body weight. The SAFs for monoenergetic photons/electrons and S values for common positron emitting radionuclides can be exploited in the assessment of radiation dose delivered to rats at different ages and weights. The absorbed dose to organs is significantly higher in the low-weight young rat model than in the adult model, which would result in steep secondary effects and might be a noteworthy issue in laboratory animal internal dosimetry. PMID- 23981783 TI - Micro-positron emission tomography/contrast-enhanced computed tomography imaging of orthotopic pancreatic tumor-bearing mice using the alphavbeta3 integrin tracer 64Cu-labeled cyclam-RAFT-c(-RGDfK-)4. AB - The purpose of this study was to develop a clinically relevant orthotopic xenotransplantation model of pancreatic cancer and to perform a preclinical evaluation of a new positron emission tomography (PET) imaging probe, 64Cu labeled cyclam-RAFT-c(-RGDfK-)4 peptide (64Cu-RAFT-RGD), using this model. Varying degrees of alphavbeta3 integrin expression in several human pancreatic cancer cell lines were examined by flow cytometry and Western blotting. The cell line BxPC-3, which is stably transfected with a red fluorescence protein (RFP), was used for surgical orthotopic implantation. Orthotopic xenograft was established in the pancreas of recipient nude mice. An in vivo probe biodistribution and receptor blocking study, preclinical PET imaging coregistered with contrast-enhanced computed tomography (CECT) comparing 64Cu-RAFT-RGD and 18F fluoro-2-deoxy-d-glucose (18F-FDG) accumulation in tumor, postimaging autoradiography, and histologic and immunohistochemical examinations were done. Biodistribution evaluation with a blocking study confirmed that efficient binding of probe to tumor is highly alphavbeta3 integrin specific. 64Cu-RAFT-RGD PET combined with CECT provided for precise and easy detection of cancer lesions. Autoradiography, histologic, and immunohistochemical examinations confirmed the accumulation of 64Cu-RAFT-RGD in tumor versus nontumor tissues. In comparative PET studies, 64Cu-RAFT-RGD accumulation provided better tumor contrast to background than 18F-FDG. Our results suggest that 64Cu-RAFT-RGD PET imaging is potentially applicable for the diagnosis of alphavbeta3 integrin-expressing pancreatic tumors. PMID- 23981784 TI - Monitoring of radiochemotherapy in patients with glioblastoma using O-(2 18Fluoroethyl)-L-tyrosine positron emission tomography: is dynamic imaging helpful? AB - Monitoring of radiochemotherapy (RCX) in patients with glioblastoma is difficult because unspecific alterations in magnetic resonance imaging with contrast enhancement can mimic tumor progression. Changes in tumor to brain ratios (TBRs) in positron emission tomography (PET) using O-(2-18fluoroethyl)-l-tyrosine (18F FET) after RCX with temozolomide of patients with glioblastoma have been shown to be valuable parameters to predict survival. The kinetic behavior of 18F-FET in the tumors is another promising parameter to analyze tumor metabolism. In this study, we investigated the predictive value of dynamic 18F-FET PET during RCX of glioblastoma. Time-activity curves (TACs) of 18F-FET uptake of 25 patients with glioblastoma were evaluated after surgery (FET-1), early (7-10 days) after completion of RCX (FET-2), and 6 to 8 weeks later (FET-3). Changes in the time to peak (TTP) and the slope of the TAC (10-50 minutes postinjection) were analyzed and related to survival. Changes in kinetic parameters of 18F-FET uptake after RCX showed no relationship with survival time. In contrast, the high predictive value of changes of TBR to predict survival was confirmed. We conclude that dynamic 18F-FET PET does not provide additional prognostic information during RCX. Static 18F-FET PET imaging (20-40 minutes postinjection) appears to be sufficient for this purpose and reduces costs. PMID- 23981785 TI - Shear forces from flow are responsible for a distinct statistical signature of adherent microbubbles in large vessels. AB - Real-time ultrasound-based targeted molecular imaging in large blood vessels holds promise for early detection and diagnosis of stroke risk by identifying early markers for atherosclerosis prior to plaque formation. Singular spectrum based targeted molecular (SiSTM) imaging is a recently proposed method that uses changes in statistical dimensionality-quantified by a normalized singular spectrum area (NSSA)-to image receptor-ligand-bound adherent microbubbles. However, the precise physical mechanism responsible for the distinct statistical signature was previously unknown. In this study, in vitro flow phantom experiments were performed to elucidate the physical mechanism in large blood vessel environments. In the absence of flow, an increase in the NSSA of adherent microbubbles with respect to tissue was not observed with increased microbubble concentration or pulse length (p > .23; n = 5) but was observed with increased flow rate (p < .01; n = 10). When observing the dynamics of the adherent microbubble statistics, a good correlation was observed between the NSSA and the derivative of image intensity (R2 > .97). In addition, a monotonic relationship between the NSSA and decorrelation was demonstrated. These findings confirm the hypothesis that the statistical signature of adherent microbubbles is derived from frame-to-frame decorrelation, which is induced by flow shear forces. PMID- 23981786 TI - Prevalence of alcohol use before and during pregnancy and predictors of drinking during pregnancy: a cross sectional study in Sweden. AB - BACKGROUND: There is a paucity of research on predictors for drinking during pregnancy among women in Sweden and reported prevalence rates differ considerably between studies conducted at different antenatal care centres. Since this knowledge is relevant for preventive work the aim of this study was to investigate these issues using a multicenter approach. METHODS: The study was conducted at 30 antenatal care centers across Sweden from November 2009 to December 2010. All women in pregnancy week 18 or more with a scheduled visit were asked to participate in the study. The questionnaire included questions on sociodemographic data, alcohol consumption prior to and during the pregnancy, tobacco use before and during pregnancy, and social support. RESULTS: Questionnaires from 1594 women were included in the study. A majority, 84%, of the women reported alcohol consumption the year prior to pregnancy; about 14% were categorized as having hazardous consumption, here defined as a weekly consumption of > 9 standard drinks containing 12 grams of pure alcohol or drinking more than 4 standard drinks at the same occasion. Approximately 6% of the women consumed alcohol at least once after pregnancy recognition, of which 92% never drank more than 1 standard drink at a time. Of the women who were hazardous drinkers before pregnancy, 19% reduced their alcohol consumption when planning their pregnancy compared with 33% of the women with moderate alcohol consumption prior to pregnancy. Factors predicting alcohol consumption during pregnancy were older age, living in a large city, using tobacco during pregnancy, lower score for social support, stronger alcohol habit before pregnancy and higher score for social drinking motives. CONCLUSIONS: The prevalence of drinking during pregnancy is relatively low in Sweden. However, 84% of the women report drinking in the year preceding pregnancy and most of these women continue to drink until pregnancy recognition, which means that they might have consumed alcohol in early pregnancy. Six factors were found to predict alcohol consumption during pregnancy. These factors should be addressed in the work to prevent alcohol-exposed pregnancies. PMID- 23981787 TI - Sox4, EMT programs, and the metastatic progression of breast cancers: mastering the masters of EMT. AB - Epithelial-mesenchymal transition (EMT) programs require the expression of a variety of so-called master regulators of EMT, including members of the Snail, Zeb, and Twist transcription factor families. Teleologically, the requirement for such a diverse group of 'master regulators' seems evolutionarily cumbersome, and emerging evidence indicates that these transcription factors do in fact mediate unique and specialized functions, suggesting the existence of higher-order 'masters' that truly direct and coordinate EMT programs. Accordingly, Tiwari and colleagues recently delineated an elegant pathway wherein transforming growth factor-beta stimulates Sox4 expression, which induces that of the histone methyltransferase, Ezh2, thereby reprogramming the epigenome to elicit EMT programs and metastasis of breast cancers. This viewpoint highlights Sox4 as a 'new' master of EMT programs and metastatic breast cancer. PMID- 23981788 TI - Health care and personal care needs among residents in nursing homes, group homes, and congregate housing in Japan: why does transition occur, and where can the frail elderly establish a permanent residence? AB - OBJECTIVES: Japan has had high rates of transition to nursing homes from other long term care facilities. It has been hypothesized that care transitions occur because a resident's condition deteriorates. The aim of the present study was to compare the health care and personal care needs of residents in nursing homes, group homes, and congregate housing in Japan. DESIGN: The present study was conducted using a cross-sectional study design. SETTING/SUBJECTS: The present study included 70,519 elderly individuals from 5 types of residential facilities: care medical facilities (heavy medical care; n = 17,358), geriatric intermediate care facilities (rehabilitation aimed toward a discharge to home; n = 26,136), special nursing homes (permanent residence; n = 20,564), group homes (group living, n = 1454), and fee-based homes for the elderly (congregate housing; n = 5007). MEASUREMENTS: The managing director at each facility provided information on the residents' health care and personal care needs, including activities of daily living (ADLs), level of required care, level of cognitive impairment, current disease treatment, and medical procedures. RESULTS: A multinomial logistic regression analysis demonstrated a significantly lower rate of medical procedures among the residents in special nursing homes compared with those in care medical facilities, geriatric intermediate care facilities, group homes, and fee-based homes for the elderly. The residents of special nursing homes also indicated a significantly lower level of required care than those in care medical facilities. CONCLUSION: The results of our study suggest that care transitions occur because of unavailable permanent residence option for people who suffer with medical deterioration. The national government should modify residential facilities by reorganizing several types of residential facilities into nursing homes that provide a place of permanent residence. PMID- 23981789 TI - Letter of response to Dr Aronow. PMID- 23981790 TI - Treatment of hypertension in the elderly. PMID- 23981791 TI - Microbial community functional structure in response to antibiotics in pharmaceutical wastewater treatment systems. AB - It is widely demonstrated that antibiotics in the environment affect microbial community structure. However, direct evidence regarding the impacts of antibiotics on microbial functional structures in wastewater treatment systems is limited. Herein, a high-throughput functional gene array (GeoChip 3.0) in combination with quantitative PCR and clone libraries were used to evaluate the microbial functional structures in two biological wastewater treatment systems, which treat antibiotic production wastewater mainly containing oxytetracycline. Despite the bacteriostatic effects of antibiotics, the GeoChip detected almost all key functional gene categories, including carbon cycling, nitrogen cycling, etc., suggesting that these microbial communities were functionally diverse. Totally 749 carbon-degrading genes belonging to 40 groups (24 from bacteria and 16 from fungi) were detected. The abundance of several fungal carbon-degrading genes (e.g., glyoxal oxidase (glx), lignin peroxidase or ligninase (lip), manganese peroxidase (mnp), endochitinase, exoglucanase_genes) was significantly correlated with antibiotic concentrations (Mantel test; P < 0.05), showing that the fungal functional genes have been enhanced by the presence of antibiotics. However, from the fact that the majority of carbon-degrading genes were derived from bacteria and diverse antibiotic resistance genes were detected in bacteria, it was assumed that many bacteria could survive in the environment by acquiring antibiotic resistance and may have maintained the position as a main player in nutrient removal. Variance partitioning analysis showed that antibiotics could explain 24.4% of variations in microbial functional structure of the treatment systems. This study provides insights into the impacts of antibiotics on microbial functional structure of a unique system receiving antibiotic production wastewater, and reveals the potential importance of the cooperation between fungi and bacteria with antibiotic resistance in maintaining the stability and performance of the systems. PMID- 23981792 TI - Pediatric compounding: coloring outside the lines. PMID- 23981793 TI - Stability issues for compounding extemporaneously prepared oral formulations for pediatric patients. PMID- 23981794 TI - Flavoring: compounding a treat. PMID- 23981795 TI - Autism in children. PMID- 23981797 TI - Topical therapy for localized hyperhidrosis. PMID- 23981796 TI - Methylphenidate-placebo: a trial for attention deficit disorders. PMID- 23981798 TI - The basics of compounding: powders and granules. PMID- 23981799 TI - Using serum hormone analysis to develop hormone replacement therapy regimens- part 2. PMID- 23981800 TI - Rhodococcus equi pneumonia in foals. PMID- 23981801 TI - Compatibility screening of hextend during simulated y-site administration with other drugs. AB - The physical compatibility of Hextend (6% hetastarch in lactated electrolyte injection, Abbott Laboratories, Abbott Park, Illinois) with 100 selected other drugs during simulated Y-site injection was evaluated by means of visual observation, turbidity measurement, and electronic particle content assessment when appropriate. Five-milliliter samples of Hextend injection were combined with 5 mL of 100 other test drugs that included anti-infectives, analgesics, antihistamines, diuretics, steroids, and other supportive care drugs undilted or diluted in 5% dextrose injection (or if necessary to avoid incompatibility of the secondary drug with the diluent, 0.9% sodium chloride injection). Visual examinations were performed with the unaided eye in normal diffuse fluorescent light and by means of a Tyndall beam (a high-intensity monodirectional light beam) to enhance visualization of small particles and low-level turbidity. The turbidity of each sample was measured as well. The particle content of samples with no visible incompatibility was measured. Evaluation of the samples was performed initially and at 1 and 4 hours after preparation. Ninety-seven of the 100 test drugs were compatible with Hextend injection during the 4-hour observation period. However, amphotericin B and diazepam resulted in precipitation, and sodium bicarbonate resulted in microcrystalline precipitation. Hextend injection should not be administered simultaneously with those incompatible drugs. Other drugs previously reported to be incompatible with 6% hetastarch in 0.9% sodium chloride injection were not found to be incompatible with Hextend. PMID- 23981802 TI - Stability of ethacrynate sodium after reconstitution in 0.9% sodium chloride injection and storage in polypropylene syringes for pediatric use. AB - The stability of ethacrynate sodium (1 mg/mL) in 0.9% sodium chloride injection has been studied at 25 deg C and 5 deg C in polypropylene syringes by using a stability-indicating high-performance liquid chromatography assay method. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation based on 5 injections was 1.6. Mannitol, which is added as an excipient in the injection, did not interfere with the assay procedure. Two products of decomposition separated from the intact drug. At 25 deg C, there was no loss in potency after 14 days of storage or at 5 deg C after 22 days of storage. the pH value (6.5) of the injection remained constant throughout the study period. The drug was not adsorbed onto the syringes and the physical appearance of the injection did not change. PMID- 23981803 TI - Stability of acyclovir sodium after reconstitution in 0.9% sodium chloride inection and storage in polypropylene syringes for pediatric use. AB - The stability of acyclovir sodium (10 mg/mL) in 0.9% sodium chloride injection has been studied at 25 deg C and 5 deg C in polypropylene syringes by means of a stability-indicating high-performance liquid chromatography (HPLC) assay method. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation (RSD) based on 5 injections was 1.0. At 25 deg C, there was no loss in potency after 30 days of storage, and at 5 deg C, the drug had begun to precipitate within 5 days. Therefore, the stability could not be investigated. The pH values of the injections were between 10.4 and 10.7. The drug was not adsorbed onto the syringes, and the physical appearance of the injection did not change. PMID- 23981804 TI - Suffolk Show 2011: prehospital medical coverage in a mass-gathering event. AB - INTRODUCTION: Despite their popularity and unique characteristics, county shows, also known as agricultural fairs, are amongst the least-studied mass-gathering events. Suffolk Show is one of the biggest such events in the UK, attracting tens of thousands of people annually over a 2-day period. In addition to trade stands and livestock displays, the 2011 show included top international show jumping and other sport activities. Problem Due to the range of activities and large number of attendees of different ages and medical backgrounds, combined with a lack of objective data about medical contacts made during these events, medical officers and local emergency services find planning an appropriate level of medical coverage for county shows particularly challenging. This study involved analyzing the characteristics of medical contacts during a major county show and assessing the level of medical coverage provided. METHODS: Data collected from St John Ambulance (SJA) and British Red Cross standard medical records of all contacts on the show ground over the two days were analyzed in terms of demographics, presenting complaints, medical history, and discharge destination. The Event Safety Guide by the Health and Safety Executive (HSE) was the agreed standard for the level of medical coverage. RESULTS: More than 90,000 people visited the show, with a total of 180 medical contacts recorded. Patient presentation rate (per 1,000 attendees) was 2.0 and the transport to hospital rate (per 1,000 attendees) was 0.1. Of the 112 cases handled by SJA, 74 (66%) were women and 49 (44%) were 18-64 years of age. Wounds, lacerations and abrasions made up 26 (23.2%) of all presentations to SJA, followed by foot and lower limb blisters at 20 (17.8%). Hypertension was the most common medical history in presentations to SJA (11 cases, 10%), followed by asthma in 7 (6%). CONCLUSION: The majority of presentations were due to minor injuries or ailments. An understanding of the event characteristics, demographics, and nature of medical contacts will provide organizers, medical officers, and local emergency services with information about the level of coverage and resources required. This data can further help advance knowledge of mass-gathering medicine across the various types of events. PMID- 23981805 TI - Role of P-glycoprotein in the efflux of raltegravir from human intestinal cells and CD4+ T-cells as an interaction target for anti-HIV agents. AB - Cellular efflux and uptake transports of several anti-HIV agents are mediated by plasma membrane-localized solute transporters. However, transporters involved in raltegravir disposition have not been fully characterized. Here, we performed in vitro studies to identify transporters mediating transcellular transport of raltegravir. Transepithelial raltegravir transport was examined using porcine kidney epithelial cell line (LLC-PK1) and LLC-PK1 cells stably transfected with P glycoprotein (also known as Multiple drug resistance 1) (L-MDR1). Transepithelial transport of raltegravir in Caco-2 cell monolayers, and intracellular accumulation of raltegravir in the MT-2 and MT-4 (CD4+ T-) cells were measured in the presence or absence of anti-HIV agents. The uptake of raltegravir was investigated in HEK-293 cells expressing each of several solute carrier family transporters. The apical-to-basal raltegravir transport was significantly decreased in L-MDR1 as compared to that in LLC-PK1 monolayers. In HEK-293 cells expressing breast cancer resistance protein (BCRP), raltegravir accumulation was lower than that in the mock-transfected cells. In Caco-2 cells, protease inhibitors including nelfinavir, ritonavir and lopinavir enhanced the apical-to basal transport of raltegravir. By contrast, reverse transcriptase inhibitors such as zidovudine, efavirenz, and nevirapine, had no effect on raltegravir transport. The cellular accumulation of raltegravir in MT-2 cells, which express P-glycoprotein, was significantly increased in the presence of protease inhibitors. By contrast, protease inhibitors only marginally increased the accumulation of raltegravir in MT-4 cells, in which P-glycoprotein is not expressed. The present findings suggest that raltegravir is a substrate of both P glycoprotein and BCRP. Protease inhibitors increase the absorptive transport of raltegravir in Caco-2 cells, and the cellular accumulation in T-cells, at least in part, by P-glycoprotein-mediated interaction. PMID- 23981806 TI - Identification of a new membrane-permeable inhibitor against inositol-1,4,5 trisphosphate-3-kinase A. AB - Ectopic expression of the neuron-specific inositol-1,4,5-trisphosphate-3-kinase A (ITPKA) in lung cancer cells increases their metastatic potential because the protein exhibits two actin regulating activities; it bundles actin filaments and regulates inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals by phosphorylating InsP3. Thus, in order to inhibit the metastasis-promoting activity of ITPKA, both its actin bundling and its InsP3kinase activity has to be blocked. In this study, we performed a high throughput screen in order to identify specific and membrane-permeable substances against the InsP3kinase activity. Among 341,44 small molecules, 237 compounds (0.7%) were identified as potential InsP3kinase inhibitors. After determination of IC50-values, the three compounds with highest specificity and highest hydrophobicity (EPPC-3, BAMB-4, MEPTT-3) were further characterized. Only BAMB-4 was nearly completely taken up by H1299 cells and remained stable after cellular uptake, thus exhibiting a robust stability and a high membrane permeability. Determination of the inhibitor type revealed that BAMB-4 belongs to the group of mixed type inhibitors. Taken together, for the first time we identified a highly membrane-permeable inhibitor against the InsP3kinase activity of ITPKA providing the possibility to partly inhibit the metastasis-promoting effect of ITPKA in lung tumor cells. PMID- 23981807 TI - High-frequency oscillatory ventilation with tracheal gas insufflation: the rescue strategy for brain-lung interaction. AB - The occurrence of moderate to severe acute respiratory distress syndrome due to traumatic brain injury is not uncommon and is associated with an extremely high incidence of morbidity and mortality. Owing to the complex interaction between the lung and brain, protective ventilation for the lung with lower tidal volume and higher positive end-expiratory pressure with or without mild hypercapnia might be harmful for the brain, and maintaining normocapnia or mild hypocapnia by increasing tidal volume or respiratory rate (or both) with lower positive end expiratory pressure levels for protecting the brain might lead to ventilator induced lung injury. Balancing the end-point between lungs and brain becomes a challenging issue, and non-conventional modes of mechanical ventilation might play a role in the more difficult clinical cases. In this commentary, the authors discuss the rationale, based on the physiologic principle of targeting both vital organs, of applying high-frequency oscillation and tracheal gas insufflation in acute respiratory distress syndrome patients with traumatic brain injury. PMID- 23981808 TI - End of the barbexaclone era: an experience of treatment withdrawal. AB - Barbexaclone is a salt compound of phenobarbital and propylhexedrine (a drug with indirect sympathomimetic properties). Due to the presence of the psychostimulating agent, propylhexedrine, this drug has less of a sedative effect and is well tolerated, compared to phenobarbital. Barbexaclone was widely used in Turkey until 2009 when its production ended, however, it gave rise to an epidemic for which we were not prepared. Since then, no standardised management protocol has been developed and each patient has been evaluated individually, thereby creating tailor-made solutions based on the extent of each patient's supply of remaining drug (from a few tablets to a stock which might last for six months). The rate of seizure freedom was 37.7% under barbexaclone treatment and dropped to 32.2% in the follow-up period after discontinuation of the drug. In the majority of cases, a new antiepileptic drug was added and this was commonly levetiracetam, a more expensive drug. In this article, we share our experiences of a general problem: the withdrawal of an antiepileptic drug from the market. Although there was prior notification regarding barbexaclone withdrawal, it was not possible to contact all patients since such a database is not available in Turkey. Although no conclusions regarding the efficacy of the drug or comparison of efficacy with other antiepileptic drugs is provided, it is nonetheless noteworthy to share these experiences since some patients had lost seizure control for reasons that could not be explained. PMID- 23981809 TI - Boundary violations, gender and the nature of nursing work. AB - Complaints against nurses can be made on several grounds and orders, including removal from the registry of nurses, can be made as a result of these complaints. Boundary violations generally relate to complaints around criminal charges, unsatisfactory professional conduct or professional misconduct or a lack of good character. This article explores the spectrum of boundary violations in the nurse patient relationship by reviewing disciplinary cases from the New South Wales Nurses and Midwives Tribunal and Professional Standards Committees. The complaints spanned a spectrum of behaviours, from minor infringements such as inappropriate compliments to intimate touching and sexual intercourse. Furthermore, the majority of respondents were men, although men comprise a minority of the nursing profession. This phenomenon is discussed in terms of gender stereotyping and nursing work. In addition, the possibility that improved supervision may have gone some way to preventing the violations is explored. PMID- 23981810 TI - Expression of hyaluronan (hyaluronic acid) in the developing laminar architecture of the human fetal brain. AB - Hyaluronan (also called hyaluronic acid or HA) plays a key role in the morphogenesis of the brain, but little is known about its expression in the human fetal neocortex. Using immunohistochemical methods, we assayed the expression of HA, glial fibrillary acidic protein, vimentin, nestin, and proliferating cell nuclear antigen in paraffin-embedded histologic sections of 8 mid-term fetuses (estimated gestational age, 12-16 weeks; crown-rump length, 75-120mm). At 12-13 weeks, HA was expressed strongly along the membranes of many cells in the cortical plate and the layer 1 or marginal zone, but showed weak, spotty expression in a fiber-rich layer adjacent to the cortical plate, called the cortical stratified transitional field-1 (STF-1 or a primitive form of the subplate). At 15-16 weeks, HA was expressed in the layer 1 and in the early subplate or presubplate, but less strongly in cells of the possible STF-5 near the subventricular zone. However, the positive observation in STF-5 was probably a result of individual difference in development. The developing cortical plate seemed to produce HA in the presubplate to harbor axonal plexus of various afferent systems, while Cajal-Retzius cells were likely to accumulate HA in the layer 1. The HA-rich zones, those sandwiched the cortical plate, might avoid further migration of cortical cells. PMID- 23981811 TI - Canadian adolescent perceptions and knowledge about the social determinants of health: an observational study of Kingston, Ontario youth. AB - BACKGROUND: Upstream social determinants of health (SDH) have become widely acknowledged as lying at the root of poor health outcomes in Canada and globally. The Commission on the Social Determinants of Health maintains that educating the public about the SDH is a key step towards population health equity. Little is known about adolescent perceptions of the determinants of health. Curriculum in Ontario is lacking in SDH content, placing a much greater emphasis on individual, lifestyle behaviors, such as diet, physical activity, and safe sex practices. Identifying a gap in SDH knowledge within the adolescent population is required to advocate for health curriculum revision to include SDH material. METHODS: Student sociodemographic information was obtained through a self-administered questionnaire. Concept mapping exercises were used to determine students' knowledge of the determinants of health and the SDH. Knowledge was approximated by the relative number of SDH concepts present in student maps. Poisson regression analysis was used to determine correlations between sociodemographic characteristics and SDH knowledge. RESULTS: Concept maps indicated that students attributed their health primarily to physical determinants versus social determinants; 44% of maps contained no SDH content. Statistical analyses indicated that students' SDH knowledge varied by their relative socioeconomic status (SES). CONCLUSIONS: Findings suggest that 1) there is an SDH knowledge gap in the adolescent population, and 2) an inequity in adolescent SDH knowledge exists across socio-economic factors. Current Ontario health curriculum requires revision to include SDH material, which will require greater communication and collaboration from both educational institutions and health agencies in Canada. PMID- 23981812 TI - Attention to natural auditory signals. AB - The challenge of understanding how the brain processes natural signals is compounded by the fact that such signals are often tied closely to specific natural behaviors and natural environments. This added complexity is especially true for auditory communication signals that can carry information at multiple hierarchical levels, and often occur in the context of other competing communication signals. Selective attention provides a mechanism to focus processing resources on specific components of auditory signals, and simultaneously suppress responses to unwanted signals or noise. Although selective auditory attention has been well-studied behaviorally, very little is known about how selective auditory attention shapes the processing on natural auditory signals, and how the mechanisms of auditory attention are implemented in single neurons or neural circuits. Here we review the role of selective attention in modulating auditory responses to complex natural stimuli in humans. We then suggest how the current understanding can be applied to the study of selective auditory attention in the context natural signal processing at the level of single neurons and populations in animal models amenable to invasive neuroscience techniques. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives". PMID- 23981813 TI - Validation of the Korean version of the European Organization for Research and Treatment of Cancer brain cancer module (EORTC QLQ-BN20) in patients with brain tumors. AB - BACKGROUND: The European Organization for Research and Treatment of Cancer Quality of Life Brain Cancer Module has been translated into Korean, but to date, its reliability and validity have been evaluated in a pilot study alone. The European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire is, overall, a valid instrument to assess the health-related quality of life in Korean cancer patients, although its reliability and validity have not yet been evaluated in patients with brain tumors. This study aimed at evaluating the psychometric properties of these instruments in patients with brain tumors. FINDINGS: The 2 instruments were used for 307 Korean patients with brain tumors. Multi-trait scaling confirmed the scale structure of the instruments with good item convergent and discriminant validity. The reliability was acceptable for all scales except for cognitive functioning and nausea and vomiting. The instruments could be used to distinguish between clinically distinct groups of patients. CONCLUSIONS: The study findings indicate that the instruments are valid and suitable for the assessment of the health-related quality of life in patients with brain tumors as well as in those with primary brain cancer. PMID- 23981814 TI - Combination of inositol and alpha lipoic acid in metabolic syndrome-affected women: a randomized placebo-controlled trial. AB - BACKGROUND: Inositol has been reported to improve insulin sensitivity since it works as a second messenger achieving insulin-like effects on metabolic enzymes. The aim of this study was to evaluate the inositol and alpha lipoic acid combination effectiveness on metabolic syndrome features in postmenopausal women at risk of breast cancer. METHODS: A six-month prospective, randomized placebo controlled trial was carried out on a total of 155 postmenopausal women affected by metabolic syndrome at risk of breast cancer, the INOSIDEX trial. All women were asked to follow a low-calorie diet and were assigned randomly to daily consumption of a combination of inositol and alpha lipoic acid (77 pts) or placebo (78 pts) for six months. Primary outcomes we wanted to achieve were both reduction of more than 20% of the HOMA-IR index and of triglycerides serum levels. Secondary outcomes expected were both the improvement of high-density lipoprotein cholesterol levels and the reduction of anthropometric features such as body mass index and waist-hip ratio. RESULTS: A significant HOMA-IR reduction of more than 20% was evidenced in 66.7% (P <0.0001) of patients, associated with a serum insulin level decrease in 89.3% (P <0.0000). A decrease in triglycerides was evidenced in 43.2% of patients consuming the supplement (P <0.0001). An increase in HDL cholesterol (48.6%) was found in the group consuming inositol with respect to the placebo group. A reduction in waist circumference and waist hip ratio was found in the treated group with respect to the placebo group. CONCLUSIONS: Inositol combined with alpha lipoic acid can be used as a dietary supplement in insulin-resistant patients in order to increase their insulin sensitiveness. Daily consumption of inositol combined with alpha lipoic acid has a significant bearing on metabolic syndrome. As metabolic syndrome is considered a modifiable risk factor of breast tumorigenesis, further studies are required to assess whether inositol combined with alpha lipoic acid can be administered as a dietary supplement in breast cancer primary prevention. TRIAL REGISTRATION: Current Controlled Trial ISRCTN74096908. PMID- 23981816 TI - Incidence of acute care adverse events and long-term health-related quality of life in patients with TSCI. AB - BACKGROUND CONTEXT: Adverse events (AEs) with significant resultant morbidity are common during the acute hospital care of patients with traumatic spinal cord injury (TSCI). The Rick Hansen SCI Registry (RHSCIR) collects Canada-wide data on patients with TSCI, such as sociodemographic, injury, diagnosis, intervention, and health outcome details. These data contribute to an evidence base for informing best practice and improving SCI care. As the RHSCIR captures data on patients from prehospital to community phases of care, it is an invaluable resource for providing information on health outcomes resulting from TSCI, including outcomes related to AEs. PURPOSE: To determine the incidence and types of AEs occurring in patients with TSCI during acute care and the impact on length of stay (LOS) and health-related quality of life (HRQOL). STUDY DESIGN/SETTING: Prospective cohort study at an academic quaternary referral center. PATIENT SAMPLE: Patients with TSCI discharged from our institution between 2008 and 2010 were identified using the RHSCIR. The RHSCIR includes patients admitted to one of the participating centers across Canada, who have been clinically diagnosed with an acute TSCI or classified as AIS A, B, C, D, or cauda equina. OUTCOME MEASURES: Acute-phase LOS and HRQOL were assessed for impact resulting from the number and type of AEs experienced. Health-related quality of life was determined using the short-form 36 (SF-36) physical and mental component summary scores and functional independence measure. METHODS: Data related to patients' injury, diagnoses, hospital admission, and SF-36 scores were obtained from the local RHSCIR. Data on intra-, pre-, and postoperative AEs were collected prospectively using the Spine Adverse Events Severity System data collection system, documenting all AEs experienced by each patient. Multivariate analyses were performed to determine whether patient and injury characteristics were associated with the number and type of AEs experienced and whether these were associated with LOS and HRQOL determined on follow-up. RESULTS: One hundred seventy-one patients with TSCI were included, 81.3% were men and mean age at injury was 47.2+/-20.3 years. Adverse events occurred in 77.2% of patients, 14.6% experienced an intraoperative and 73.7% experienced a pre/postoperative event. The most frequent pre/postoperative AEs were urinary tract infections (UTIs) (32.2%), pneumonias (32.8%), neuropathic pain (15.2%), decubitus ulcers (14.6%), and delirium (18.7%). Length of stay was significantly affected by decubitus ulcers, delirium, pneumonias, and UTIs (p<.01), increasing 1.7 (UTIs) to 2.2 (decubitus ulcers) times compared with patients without the specific AEs. Health-related quality of life was not affected by acute care AEs but rather those identified at 1-year follow-up. CONCLUSIONS: This prospective study found that more than 77% of patients with TSCI sustain an AE during acute hospital care, significantly higher than previously reported. We demonstrate the utility of a dedicated AE collection system and the effect of these events on health status. PMID- 23981815 TI - Sexual quality of life after hormonal and surgical treatment, including phalloplasty, in men with micropenis: a review. AB - INTRODUCTION: The term micropenis encompasses a range of congenital and acquired conditions that result in an abnormally short penis. Small penis size may persist into adulthood, becoming a major cause of dissatisfaction. AIM: To review the literature pertaining to the effects of hormonal and surgical treatment on psychosexual functioning and quality of life (QoL) in individuals with micropenis who were raised male. MAIN OUTCOME MEASURES: Long-term psychosexual and QoL outcomes after hormonal and surgical treatment, including phalloplasty. METHODS: PubMed search for relevant publications (1955-2012) on the role of hormonal and surgical treatment in sexual QoL in adult men with micropenis. RESULTS: Multiple variations in the etiology of micropenis make it difficult to draw firm conclusions that fit all of the patients within this disparate population. However, the literature review supports the conclusions that (i) male gender assignment is preferable for most 46,XY infants with congenital micropenis because of the likelihood of male gender development and genitosexual function; (ii) small penis size persisting into adulthood and dissatisfaction with genital appearance jeopardize sexual QoL; (iii) there is no known intervention, apart from phalloplasty, to guarantee that the penis will become normal in size; (iv) early data suggest that the phalloplasty technique considered the gold standard for gender reassignment in the transgender population can also be transferred to 46,XY patients with micropenis; (v) psychological support should be an integral part of management in order to alleviate the distress and impairment of QoL experienced by these individuals. CONCLUSIONS: Further publication of series with large numbers and longer follow-up is needed. Specific outcome kits should be designed to measure more precisely patients' degrees of satisfaction with cosmetic, anatomical, and functional variables. Only if health-care professionals fully appreciate the impact of this condition can optimal care be provided. PMID- 23981817 TI - Effect of vertebroplasty on the compressive strength of vertebral bodies. AB - BACKGROUND CONTEXT: Percutaneous vertebroplasty has been used successfully for many years in the treatment of painful compressive vertebral fractures due to osteoporosis. PURPOSE: To compare the effect of vertebroplasty on the compressive strength of unfractured vertebral bodies. STUDY DESIGN: Biomechanical study on cadaveric thoracic vertebrae. METHODS: Forty vertebral bodies from four cadaveric thoracic spines were used for this experiment. Before testing, each thoracic spine was submitted to bone density testing and radiographic evaluation to rule out any obvious fractures. Under image intensification, 6 mL of a mixture of polymethylmethacrylate (PMMA) with barium (8 g of barium/40 g of PMMA) was injected into every other vertebral body of each spine specimen. After vertebroplasty, all soft tissues were dissected from the spine, and the vertebral bodies were separated and potted for mechanical testing. Testing to failure was performed using a combination of axial compression and anterior flexion moments. Two pneumatic cylinders applied anterior and posterior loads at a distance ratio of 4:3 relative to the anterior vertebral body wall, whereas two additional cylinders applied lateral loads, each at a constant rate of 200 N/s. RESULTS: The average failure loads for nonvertebroplasty specimens was 6724.02 +/- 3291.70 N, whereas the specimens injected with PMMA failed at an average compressive force of 5770.50 +/- 2133.72 N. No statistically significant difference in failure loads could be detected between intact specimens and those that had undergone vertebroplasty. CONCLUSIONS: Under these specific loading conditions, no significant increase in compressive strength of the vertebral bodies could be documented. This suggests that some caution should be applied to the concept of "prophylactic" vertebroplasty in patients at risk for fracture. PMID- 23981819 TI - Negative pressure wound therapy (NPWT) for spinal wounds: a systematic review. AB - BACKGROUND CONTEXT: The management of postoperative spinal wound complication remains a challenge, with surgical site infection (SSI) incidence rates ranging from 0.4% to 20% after spinal surgery. Negative pressure wound therapy (NPWT) has been highlighted as an intervention that may stimulate healing and prevent SSI. However, the wound healing mechanism by NPWT and its effectiveness in spinal wounds still remain unclear. PURPOSE: To systematically search, critically appraise, and summarize randomized controlled trials (RCTs) and non-RCTs assessing the effectiveness of NPWT in patients with a spinal wound. STUDY DESIGN: Systematic review. METHODS: A systematic review based on search strategies recommended by the Cochrane Back and Wounds Review Groups was undertaken using Cochrane Library, MEDLINE, EMBASE, and CINAHL databases. Any publications between 1950 and 2011 were included. Funding to undertake the review was received from the University of Huddersfield Collaborative Venture Fund ($4,820) and KCI Medical ($4,820). RESULTS: Ten retrospective studies and four case studies of patients with spinal wound complication were included in this systematic review. No RCTs were found. Only one study described more than 50 patients. Generally, a pressure of -125 mm Hg was used in adults. Duration of NPWT in situ ranged from 3 to 186 days. Wound healing was assessed every 2 to 3 days and generally completed between 7 days and 16 months. Negative pressure wound therapy is contraindicated in the presence of active cerebrospinal fluid leak, metastatic or neoplastic disease in the wound or in patients with an allergy to the NPWT dressing and in those with a bleeding diathesis. CONCLUSIONS: Published reports are limited to small retrospective and case studies, with no reports of NPWT being used as a prophylactic treatment. Larger prospective RCTs of NPWT are needed to support the current evidence that it is effective in treating spinal wound complications. In addition, future studies should investigate its use as a prophylactic treatment to prevent infection and report data relating to safety and health economics. PMID- 23981818 TI - Rectal perforation after AxiaLIF instrumentation: case report and review of the literature. AB - BACKGROUND CONTEXT: Bowel perforation is an uncommon complication of posterior spinal surgery. The AxiaLIF transsacral instrumentation system has been used for the treatment of L5-S1 spondylolisthesis and degenerative disc disease since its introduction in 2005 as a potentially less invasive alternative to traditional anterior or posterior interbody fusion. PURPOSE: In this article, we report a case of a rectal perforation as a complication of placement of the AxiaLIF instrumentation system that was successfully treated without the removal of the device. STUDY DESIGN: Case report. METHODS: The patient presented with progressive back pain and sepsis 3 weeks after an L5-S1 fusion done with the AxiaLIF technique at an outside facility. The patient was managed with antibiotic therapy and a diverting ileostomy, without the removal of the AxiaLIF device. RESULTS: Over the next year, she had symptoms indicative of nonunion of the operated level and breakdown at the adjacent level, which were confirmed with imaging. She underwent revision posterior spinal fusion without the removal of the AxiaLIF device. Eighteen months after the AxiaLIF device was placed, the patient continued to demonstrate no signs of infection recurrence. CONCLUSIONS: Delayed presentation of rectal perforation with a subsequent anaerobic sepsis is a potential complication of the presacral approach to the L5-S1 disc space. Recognition and treatment with fecal diversion and long-term intravenous antibiotics is an alternative to device removal and sacral reconstruction. PMID- 23981821 TI - Continuous real-time in vivo measurement of cerebral nitric oxide supports theoretical predictions of an irreversible switching in cerebral ROS after sufficient exposure to external toxins. AB - BACKGROUND: Mathematical models of the interactions between alphasynuclein (alphaS) and reactive oxygen species (ROS) predict a systematic and irreversible switching to damagingly high levels of ROS after sufficient exposure to risk factors associated with Parkinson's disease (PD). OBJECTIVES: We tested this prediction by continuously monitoring real-time changes in neurochemical levels over periods of several days in animals exposed to a toxin known to cause Parkinsonian symptoms. METHODS: Nitric oxide (NO) sensors were implanted in the brains of freely moving rats and the NO levels continuously recorded while the animals were exposed to paraquat (PQ) injections of various amounts and frequencies. RESULTS: Long-term, real-time measurement of NO in a cohort of animals showed systematic switching in levels when PQ injections of sufficient size and frequency were administered. The experimental observations of changes in NO imply a corresponding switching in endogenous ROS levels and support theoretical predictions of an irreversible change to damagingly high levels of endogenous ROS when PD risks are sufficiently large. CONCLUSIONS: Our current results only consider one form of PD risk, however, we are sufficiently confident in them to conclude that: (i) continuous long-term measurement of neurochemical dynamics provide a novel way to measure the temporal change and system dynamics which determine Parkinsonian damage, and (ii) the bistable feedback switching predicted by mathematical modelling seems to exist and that a deeper analysis of its characteristics would provide a way of understanding the pathogenic mechanisms that initiate Parkinsonian cell damage. PMID- 23981820 TI - Mild diabetes is not a contraindication for surgical decompression in cervical spondylotic myelopathy: results of the AOSpine North America multicenter prospective study (CSM). AB - BACKGROUND CONTEXT: Cervical spondylotic myelopathy (CSM) is a chronic spinal cord disease and can lead to progressive or stepwise neurologic decline. Several factors may influence this process, including extent of spinal cord compression, duration of symptoms, and medical comorbidities. Diabetes is a systemic disease that can impact multiple organ systems, including the central and peripheral nervous systems. There has been little information regarding the effect of diabetes on patients with coexistent CSM. PURPOSE: To provide empirical data regarding the effect of diabetes on treatment outcomes in patients who underwent surgical decompression for coexistent CSM. STUDY DESIGN/SETTING: Large prospective multicenter cohort study of patients with and without diabetes who underwent decompressive surgery for CSM. PATIENT SAMPLE: Two hundred thirty-six patients without and 42 patients with diabetes were enrolled. Of these, 37 were mild cases and five were moderate cases. Four required insulin. There were no severe cases associated with end-organ damage. OUTCOME MEASURES: Self-report measures include Neck Disability Index and version 2 of 36-Item Short Form Health Survey (SF-36v2), and functional measures include modified Japanese Orthopedic Association (mJOA) score and Nurick grade. METHODS: We compared presurgery symptoms and treatment outcomes between patients with and without diabetes using univariate and multivariate models, adjusting for demographics and comorbidities. RESULTS: Diabetic patients were older, less likely to smoke, and more likely to be on social security disability insurance. Patients with diabetes presented with a worse Nurick grade, but there were no differences in mJOA and SF-36v2 at presentation. Overall, there was a significant improvement in all outcome parameters at 12 and 24 months. There was no difference in the level of improvement between the patients with and without diabetes, except in the SF-36v2 Physical Functioning, in which diabetic patients experienced significantly less improvement. There were no differences in surgical complication rates between diabetic patients and nondiabetic patients. CONCLUSIONS: Except for a worse Nurick grade, diabetes does not seem to affect severity of symptoms at presentation for surgery. More importantly, with the exception of the SF-36v2 Physical Functioning scores, outcomes of surgical treatment are similar in patients with diabetes and without diabetes. Surgical decompression is effective and should be offered to patients with diabetes who have symptomatic CSM and are appropriate surgical candidates. PMID- 23981822 TI - New perspectives in nuclear neurology for the evaluation of Parkinson's disease. AB - The pathophysiology of Parkinson's disease (PD) has not yet been completely elucidated. However, during the past few years, significant progress has been made in understanding the intra- and extracellular mechanisms by which proteins such as alpha-synuclein and neuroinflammatory molecules may display impaired function and/or expression in PD. Recent developments in imaging techniques based on positron emission tomography (PET) and single photon emission computed tomography (SPECT) now allow the non-invasive tracking of such molecular targets of known relevance to PD in vivo. This article summarizes recent PET and SPECT studies of new radiopharmaceuticals and discusses their potential role and perspectives for use in the fields of new drug development and early diagnosis for PD, as well to aid in differential diagnosis and monitoring of the progression of PD. PMID- 23981823 TI - Evolutionary Dynamics of a Highly Pathogenic Type 2 Porcine Reproductive and Respiratory Syndrome Virus: Analyses of Envelope Protein-Coding Genes. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has long been an economically devastating swine viral disease. The recent emergence of a highly pathogenic type 2 PRRSV with high mobility and mortality in China, spreading in Vietnam, Laos, and Thailand has placed neighbouring countries at risk. This study applied a codon-based extension of the Bayesian relaxed clock model and the fixed effects maximum-likelihood method to investigate and compare the evolutionary dynamics of type 2 PRRSV for all of known structural envelope protein-coding genes. By comparing the highly pathogenic type 2 PRRSV clade against the typical type 2 PRRSV clade, this study demonstrated that the highly pathogenic clade evolved at high rates in all of the known structural genes but did not display rapid evolutionary dynamics compared with typical type 2 PRRSV. In contrast, the ORF3, ORF5 and ORF6 genes of the highly pathogenic clade evolved in a qualitatively different manner from the genes of the typical clade. At the population level, several codons of the sequence elements that were involved in viral neutralization, as well as codons that were associated with in vitro attenuation/over-attenuation, were predicted to be selected differentially between the typical clade and the highly pathogenic clade. The results of this study suggest that the multigenic factors of the envelope protein-coding genes contribute to diversifying the biological properties (virulence, antigenicity, etc.) of the highly pathogenic clade compared with the typical clade of type 2 PRRSV. PMID- 23981825 TI - Drugs banned for use in food animals: an explanation. PMID- 23981824 TI - Personalized management of atrial fibrillation: Proceedings from the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association consensus conference. AB - The management of atrial fibrillation (AF) has seen marked changes in past years, with the introduction of new oral anticoagulants, new antiarrhythmic drugs, and the emergence of catheter ablation as a common intervention for rhythm control. Furthermore, new technologies enhance our ability to detect AF. Most clinical management decisions in AF patients can be based on validated parameters that encompass type of presentation, clinical factors, electrocardiogram analysis, and cardiac imaging. Despite these advances, patients with AF are still at increased risk for death, stroke, heart failure, and hospitalizations. During the fourth Atrial Fibrillation competence NETwork/European Heart Rhythm Association (AFNET/EHRA) consensus conference, we identified the following opportunities to personalize management of AF in a better manner with a view to improve outcomes by integrating atrial morphology and damage, brain imaging, information on genetic predisposition, systemic or local inflammation, and markers for cardiac strain. Each of these promising avenues requires validation in the context of existing risk factors in patients. More importantly, a new taxonomy of AF may be needed based on the pathophysiological type of AF to allow personalized management of AF to come to full fruition. Continued translational research efforts are needed to personalize management of this prevalent disease in a better manner. All the efforts are expected to improve the management of patients with AF based on personalized therapy. PMID- 23981826 TI - The use of psychoactive agents in veterinary medicine. PMID- 23981827 TI - To Benzoate or Not To Benzoate: Cats are the Question. PMID- 23981828 TI - Feline ophthalmic disease: feline herpesvirus and systematic hypertension. PMID- 23981830 TI - Regulatory issues for the use of bulk drugs in veterinary compounding. PMID- 23981829 TI - Evaluating transdermal medication forms for veterinary patients, part 1. PMID- 23981831 TI - A simplified guide to veterinary compounding. PMID- 23981832 TI - Equipment for large-volume aseptic veterinary compounding. PMID- 23981833 TI - Compounded injectables for veterinary use. PMID- 23981834 TI - The basics of compounding: emulsions, part 1. PMID- 23981835 TI - Infertility care and the role of the compounding pharmacist. PMID- 23981836 TI - Consolidation of pharmacy compounding services: an alternative to outsourcing. PMID- 23981837 TI - Chemical stability of methylprednisolone sodium succinate after reconstitution in 0.9% sodium chloride injection and storage in polypropylene syringes. AB - The chemical stability of methylprednisolone sodium succinate (10 mg/mL) in 0.9% sodium chloride injection has been studied at 25 deg C and 5 deg C in polypropylene syringes by means of a stability-indicating high-performance liquid chromatography assay method. The concentrations of the drug were directly related to the peak height, and the percent relative standard deviation based on five injections was 1.2. Benzyl alcohol, which is added as a preservative, did not interfere with the assay. Two products of decomposition separated from the intact drug. At 25 deg C, the loss of potency was less than 10% after 4 days of storage. At 5 deg C, the loss of potency was less than 5% when the injection was stored for 21 days. After 17 days of storage at 25 deg C, the pH value of the injection decreased from 7.2 to 6.5, and there was no change in the pH value when the injection was stored for 21 days at 5 deg C. The drug did not adsorb onto the syringes, and the physical appearance of the injection did not change. PMID- 23981838 TI - Stability and dissolution of lozenge and emulsion formulations of metronidazole benzoate. AB - Chicken flavored glycerinated gelatin candy-based lozenges and oil-in-water emulsions of metronidazole benzoate were prepared for veterinary use. The stability and dissolution of the lozenges and emulsions were investigated via a high-pressure (performance) liquid chromatography (HPLC) assay. The separation and quantitation of metronidazole benzoate were achieved on a Phenomenex IB-SIL 5 C8 column (250 x 4.6 mm,id) at ambient temperature, with a 55:45 v/v pH 7.0 phosphate buffer-acetonitrile mobile phase at a flow rate of 1.0 mL/min. Tinidazole was used as the internal standard. A sample of metronidazole benzoate form the lozenge and emulsion was prepared for assay by dissolving one lozenge or 1g of the emulsion in 50:50 v/v methanol-water solution, and that sample was filtered through a 0.2 micrometer membrane filter before assay. The chromatogram was monitored with ultraviolet detection at 230 nm. The HPLC separation of metronidazole benzoate was achieved in less than 10 minutes; sensitivity was in the rage of 10 ng/mL. This method can be used to separate metronidazole and benzoic acid, which are degradation products of metronidazole benzoate, and demonstrated linearity for metronidazole benzoate in the range of 0.01 to 100 micrograms/mL. Accuracy and precision were less than 1.0% and less than 0.54%, repectively. The limit of quantitation was 10 ng/mL, and the limit of detection was 0.01 ng/mL, based on a signal-to-noise ratio of 3 and a 20 microliter injection. The recoveries of metronidazole benzoate from the lozenge and emulsion were 98% +/- 4% and 99% +/- 2%, respectively. Stability testing of the new formulations was performed at ambient temperature and at 4 deg C. Dissolution testing used the USP paddle method at 37 deg C and 100 rpm in simulated gastric fluid without pepsin. Both formulations were stable at ambient temperature and at 4 deg C. Metronidazole benzoate is completely released from the lozenge and emulsion formulations based on dissolution T50% values of 4.2 and 24 minutes and T90% values of 12.8 and 83 minutes, repectively. PMID- 23981839 TI - The response of Populus spp. to cadmium stress: chemical, morphological and proteomics study. AB - Poplar (Populus) species are seen as candidates for removing heavy metal contamination from polluted soil. A bottom-up multidisciplinary approach was utilized to compare the performances of clones 58-861 and Poli (Populus nigra) and A4A, a Populus nigra * Populus deltoides hybrid to Cd toxicity. Qualitative and quantitative differences in their tolerance to Cd exposure and the uptake, accumulation and translocation of Cd were noted following the hydroponic exposure of rooted cuttings to 20 MUM CdSO4 for either 48 h or 14 d. Cadmium was less toxic for the hybrid clone A4A as compared to Poli and 58-861. Cd uptake and root to shoot translocation were determined by AAS, and its compartmentation was analyzed using SEM/EDX. A comparative proteomic approach was utilized to identify changes in proteins expression according to dose and time of exposure. Toxicity to Cd mainly influenced proteins related to general defense, stress response and carbohydrate metabolism. PMID- 23981840 TI - Comparison of rescue and relief activities within 72 hours of the atomic bombings in Hiroshima and Nagasaki. AB - PURPOSE: To clarify the factors and reasons for the differences in the outcomes of rescue and relief efforts in Hiroshima and Nagasaki, mainly focusing on the numbers of rescue/relief staffs and casualties in the period within 72 hours of the atomic bombings in August 1945. METHODS: By retrieving the data and information from the records and reports concerning the disasters in the two cities, together with other publications as to the damages by the atomic bombings and subsequent rescue-relief activities, and restoration activities. RESULTS AND CONCLUSIONS: It seems that there was less damage in Nagasaki, where a stronger atomic bomb was used than in Hiroshima. There were crucial geographic factors that led to the different effects in terms of the numbers of victims; however, systematic organization and mobilization of rescue and relief staffs, maintenance of functional transportation, and advanced medical knowledge and public warning with regard to disaster all may have contributed to a lower death toll and increase in survivors in Nagasaki. PMID- 23981842 TI - Heterogeneity of manufacturers' declarations for lipemia interference--an urgent call for standardization. AB - INTRODUCTION: Due to the budget limitations, laboratories mostly rely on the manufacturers' information about the influence of interfering substances on laboratory results. However, some manufacturers do not follow the recommended procedures for testing interferences (CLSI standard) and there is a great variability in the presentation of data regarding lipemia interference. MATERIALS AND METHODS: We aimed to verify the manufacturers' specifications for lipemia interference for clinical chemistry reagents provided by Beckman Coulter, Roche and Siemens. Bias was determined using the Intralipid(r) simulated lipemic samples. Furthermore, we aimed to compare obtained data with the manufacturers' claims and desirable specification for imprecision derived from biological variation. RESULTS: i) Manufacturers' declarations were not confirmed for all three manufacturers; ii) the magnitude and direction of the effect of lipemia on laboratory results differ substantially between the three tested analytical systems; and iii) manufacturers are using arbitrary limits in declaring the expected effect of interference on laboratory results. CONCLUSIONS: There is an urgent need to standardize the way manufacturers test and report their data on the lipemia interference. We propose that, instead of arbitrary limits, manufacturers use evidence based quality specifications for assessing the allowable biases. Moreover, laboratories should be aware of the possible lack of replicability of manufacturers' declarations. PMID- 23981841 TI - Analytical characterization and clinical evaluation of an enzyme-linked immunosorbent assay for measurement of afamin in human plasma. AB - BACKGROUND: Comparative proteomics has recently identified afamin, the newest member of the albumin gene family, as a potential biomarker for ovarian cancer. The aim of this study was the analytical and clinical evaluation of a sandwich enzyme-linked immunosorbent assay for the determination of afamin in human plasma. METHODS: We evaluated precision, linearity, and detection limit of the assay, analyte stability and biological variability, determined reference values and quantified afamin concentrations in various diseases. RESULTS: Within-run and total coefficients of variation were <10%. The method was linear across the tested measurement range. Detection limit was 7 mg/L for the assay. The analyte was stable for 24 h at room temperature, for 48 h at 4 degrees C, and for at least one year at -20 degrees C and -80 degrees C. The reference change value for healthy individuals was 24%. Age- and sex-independent reference values in healthy blood donors were 45-99 mg/L (median 68 mg/L). In the clinical assay evaluation afamin plasma concentrations were modestly decreased in patients with heart failure. Patients with pneumonia or sepsis exhibited markedly decreased afamin plasma concentrations. However, patients with chronic renal disease or chronic obstructive pulmonary disease showed no difference in afamin plasma concentrations as compared to healthy individuals. Correlation analyses revealed an inverse association between afamin and inflammatory biomarkers. CONCLUSIONS: The afamin assay meets quality specifications for laboratory medicine. The results of the clinical assay evaluation revealed novel insights with respect to afamin as a potential negative acute phase protein and should encourage further studies. PMID- 23981843 TI - Performance specifications of common chemistry analytes on the AU series of chemistry analyzers for miscellaneous body fluids. AB - BACKGROUND: Body fluids are frequently submitted to the clinical laboratory. Standard chemistry analyzers are generally not FDA approved for body fluid analysis and regulatory authorities require individual laboratories to validate their performance characteristics. METHODS: Precision, linearity, accuracy, and sample stability were assessed for 10 different chemistry analytes using ascites, pleural, peritoneal dialysate, and synovial fluids on the Beckman Coulter (BC) AU5431. The effect of altered protein concentration and pH was investigated. Chemistry results from the AU5431 were compared with results from the BC AU5832 and the BC AU680. Additionally, 22 paired serum/pleural fluids were evaluated for their biochemical ability to distinguish a transudate from an exudate. RESULTS: Precision for each assay and body fluid type had a CV <14.5%. Recovery for the various analytes in all fluid types was 94.9-112%. CAP survey samples were within one SDI of the peer group. Sample pH, but not protein concentration, affected chemistry results. Inter-instrument comparison of results using the AU5431, AU5800, and AU680 was excellent. A combinatorial approach for discriminating between transudates and exudates had a sensitivity and specificity of 94% and 50%, respectively. CONCLUSIONS: Body fluid samples with pH values within the acceptable range can be analyzed on the BC AU instruments. PMID- 23981844 TI - Characterization of municipal solid waste temporary storage sites: risks posed to surrounding areas as a consequence of fire incidents. AB - In this study temporary storage sites of municipal solid waste were characterized based on their potential social, health and environmental impacts as a consequence of spontaneous fires, by employing Boolean as well as weighted-linear combination approaches in connection with various fuzzy set functions of population density around the storage sites. Sweden was used as the case study and data from 105 storage sites were analysed; of these, 38 were identified to be posing high risk for downwind residing population. Furthermore, during the past 10years, the fire frequency and the average population residing within a radius of 1, 2, and 3km were found to be comparatively higher for storage sites owned by private companies than for those owned by municipalities. The study provided first-cut information of poorly sited temporary storage sites and can help in formalizing the comprehensive risk analysis in the future. PMID- 23981845 TI - Determinants of multidrug-resistant tuberculosis in patients who underwent first line treatment in Addis Ababa: a case control study. AB - BACKGROUND: Worldwide, there were 650,000 multidrug-resistant tuberculosis (MDR TB) cases in 2010, and in 2008 the World Health Organization estimated that 150,000 deaths occurred annually due to MDR-TB. Ethiopia is 15th among the 27 MDR TB high-burden countries. This study identifies factors associated with the occurrence of MDR-TB in patients who underwent first-line TB treatment in Addis Ababa City. METHODS: A case control study was conducted at St. Peter Hospital and five health centers in Addis Ababa from 1 November 2011 to February 30, 2012. Cases were MDR-TB patients who were confirmed with culture and drug susceptibility testing and were in treatment at St. Peter Hospital during the study period. Controls were patients who were on first-line anti-TB treatment and were registered as cured or having completed treatment in the period 9 April 2009 28 February 2010, in five health centers of Addis Ababa City. Accordingly, 134 cases and an equal number of controls were included in this study. A structured interview questionnaire was used to assess factors that could potentially be associated with the occurrence of MDR-TB. RESULTS: Factors that were significantly associated with MDR-TB: drug side effects during first-line treatment (adjusted odds ratio (AOR): 4.5, 95% CI; 1.9 - 10.5); treatment not directly observed by a health worker (AOR = 11.7, 95% CI; 4-34.3); interruption of treatment of at least a day (AOR = 13.1, 95% CI 3.0-56.6); duration of treatment between 2 and 7 months (AOR = 14.8, 95% CI 2.3-96.4); and retreatment with the Category II regimen (P = 0.000). In the current study, HIV infection was not significantly associated with the occurrence of MDR-TB. CONCLUSIONS: Patients who were not in strict DOTS programs and did not adhere to first-line TB treatment and patients who experienced side effects during first-line treatment and Category II retreatment were at significantly increased risk of developing MDR-TB. The DOTS program should, therefore, be strengthened to increase patient adherence. Drug-susceptibility testing is also highly recommended for all Category I treatment regimen failures before those patients begin the Category II regimen. PMID- 23981846 TI - NMR metabolomics for identification of adenosine A1 receptor binding compounds from Boesenbergia rotunda rhizomes extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Boesenbergia rotunda Linn. (Zingiberaceae) is traditionally used in many Asian countries as medicine for stomach pain and discomfort, viral and bacterial infection, inflammation, and as diuretic agent. AIM OF THE STUDY: The study aimed to identify adenosine A1 receptor binding compounds from Boesenbergia rotunda rhizome extract by using comprehensive extraction coupled to the NMR metabolomics method. MATERIALS AND METHODS: Dried and powdered Boesenbergia rotunda rhizomes were extracted with the comprehensive extraction method to obtain several fractions with different polarity. Each fraction was divided into two: for NMR analysis and for adenosine A1 receptor binding test. Orthogonal projection to the least square analysis (OPLS) was used to study the correlation between metabolites profile and adenosine A1 receptor binding activity of the plant extracts. Based on Y-related coefficient and variable of important (VIP) value, signals in active area of OPLS loading plot were studied and the respective compounds were then elucidated RESULTS AND DISCUSSIONS: Based on OPLS Y-related coefficient plot and variable of importance value plot, several characteristic signals were found to positively correlate to the binding activity. By using 1D and 2D NMR spectra of one of the most active fraction, pinocembrine and hydroxy-panduratin were identified as the possible active compounds. Two signals from ring C of pinocembrine flavanone skeleton with negative coefficient correlations possibly overlapped with those of non-active methoxylated flavanones which were also presence in the extract. NMR based metabolomics applied in this study was able to quickly identify bioactive compounds from plant extract without necessity to purify them. Further confirmation by isolating pinocembrine and hydroxy-panduratin and testing their adenosine A1 receptor binding activity to chemically validate the method are required. CONCLUSION: Two flavonoid derivatives, pinocembrine and hydroxy panduratin, have been elucidated as possible active compounds bind to adenosine A1 receptor. Flavonoid was reported to be one of natural antagonist ligand for adenosine A1 receptor while antagonistic activity to the receptor is known to associate with diuretic activity. Thus, the result of this research supports the traditional use of Boesenbergia rotunda rhizome extract as diuretic agent. PMID- 23981847 TI - Guarana: revisiting a highly caffeinated plant from the Amazon. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Guarana (Paullinia cupana Kunth var. sorbilis (Mart.) Ducke) has been traditionally consumed by indigenous communities of the Amazon region. It is valued mainly for its stimulant property because of its high content of caffeine, which can be up to 6% in the seeds. AIM OF THE REVIEW: The purpose of this review is to revisit this typically Brazilian plant, addressing economic considerations, the chemical makeup of the seeds and pharmacological properties so far investigated. RESULTS: Guarana is primarily produced in the Brazilian states of Amazonas and Bahia, and approximately 70% of the production is used by the industry of soft and energy drinks. The other 30% becomes guarana powder for direct consumption in capsules or dilution in water, or it serves as a raw material for the pharmaceutical and cosmetics industries. In addition to its stimulant property, guarana has other therapeutic properties, which have aroused the interest of the scientific community. CONCLUSION: This review shows that other guarana properties may be explored and how scarce are the studies regarding agronomic, plant pathology, physiology and breeding. So far, caffeine has been the main reason to study guarana and still will lead the researches because the demand for this alkaloid by food and pharmaceutical industry, and a strongly growing market related with beauty products. However, guarana has other components and there is great interest in studies designed to elucidate the effects of guarana's bioactive components and their potential pharmacological applications. Significant part of the guarana production in Brazil still comes from Indians tribes in the Amazon State, and any improvement in this plant, in any aspect, may propitiate a positive economic impact in their lives. PMID- 23981848 TI - A method for the design and development of medical or health care information websites to optimize search engine results page rankings on Google. AB - BACKGROUND: The Internet is a widely used source of information for patients searching for medical/health care information. While many studies have assessed existing medical/health care information on the Internet, relatively few have examined methods for design and delivery of such websites, particularly those aimed at the general public. OBJECTIVE: This study describes a method of evaluating material for new medical/health care websites, or for assessing those already in existence, which is correlated with higher rankings on Google's Search Engine Results Pages (SERPs). METHODS: A website quality assessment (WQA) tool was developed using criteria related to the quality of the information to be contained in the website in addition to an assessment of the readability of the text. This was retrospectively applied to assess existing websites that provide information about generic medicines. The reproducibility of the WQA tool and its predictive validity were assessed in this study. RESULTS: The WQA tool demonstrated very high reproducibility (intraclass correlation coefficient=0.95) between 2 independent users. A moderate to strong correlation was found between WQA scores and rankings on Google SERPs. Analogous correlations were seen between rankings and readability of websites as determined by Flesch Reading Ease and Flesch-Kincaid Grade Level scores. CONCLUSIONS: The use of the WQA tool developed in this study is recommended as part of the design phase of a medical or health care information provision website, along with assessment of readability of the material to be used. This may ensure that the website performs better on Google searches. The tool can also be used retrospectively to make improvements to existing websites, thus, potentially enabling better Google search result positions without incurring the costs associated with Search Engine Optimization (SEO) professionals or paid promotion. PMID- 23981849 TI - Prognostic scoring system for locoregional control among the patients with nasopharyngeal carcinoma treated by intensity-modulated radiotherapy. AB - The prognostic value of T category for locoregional control in patients with nasopharyngeal carcinoma (NPC) has decreased with the extensive use of intensity modulated radiotherapy (IMRT). We aimed to develop a prognostic scoring system (PSS) that incorporated tumor extension and clinical characteristics for locoregional control in NPC patients treated with IMRT. The magnetic resonance imaging scans and medical records of 717 patients with nonmetastatic NPC treated with IMRT at Sun Yat-sen University Cancer Center between January 2003 and January 2008 were reviewed. Age, pathologic classification, primary tumor extension, primary gross tumor volume (GTV-p), T and N categories, and baseline lactate dehydrogenase (LDH) level were analyzed. Hierarchical cluster analysis as well as univariate and multivariate analyses were used to develop the PSS. Independent prognostic factors for locoregional relapse included N2-3 stage, GTV p >=26.8 mL, and involvement of one or more structures within cluster 3. We calculated a risk score derived from the regression coefficient of each factor and classified patients into four groups: low risk (score 0), intermediate risk (score >0 and <=1), high risk (score >1 and <=2), and extremely high risk (score >2). The 5-year locoregional control rates for these groups were 97.4%, 93.6%, 85.2%, and 78.6%, respectively (P < 0.001). We have developed a PSS that can help identify NPC patients who are at high risk for locoregional relapse and can guide individualized treatments for NPC patients. PMID- 23981850 TI - Re-challenge chemotherapy with gemcitabine plus carboplatin in patients with non small cell lung cancer. AB - Despite recent improvements to current therapies and the emergence of novel agents to manage advanced non-small cell lung cancer (NSCLC), the patients' overall survival remains poor. Re-challenging with first-line chemotherapy upon relapse is common in the management of small cell lung cancer but is not well reported for advanced NSCLC. NSCLC relapse has been attributed to acquired drug resistance, but the repopulation of sensitive clones may also play a role, in which case re-challenge may be appropriate. Here, we report the results of re challenge with gemcitabine plus carboplatin in 22 patients from a single institution who had previously received gemcitabine plus platinum in the first line setting and had either partial response or a progression-free interval of longer than 6 months. In this retrospective study, the charts of patients who underwent second-line chemotherapy for NSCLC in our cancer center between January 2005 and April 2010 were reviewed. All the patients who received a combination of gemcitabine and carboplatin for re-challenge were included in the study. These patients were offered second-line treatment on confirmation of clear radiological disease progression. The overall response rate was 15% and disease control rate was 75%. The median survival time was 10.4 months, with 46% of patients alive at 1 year. These results suggest that re-challenge chemotherapy should be considered in selected patients with radiological partial response or a progression-free survival of longer than 6 months to the initial therapy. PMID- 23981851 TI - Correlation analysis of preoperative serum alpha-fetoprotein (AFP) level and prognosis of hepatocellular carcinoma (HCC) after hepatectomy. AB - BACKGROUND: To investigate the prediction value of preoperative serum alpha fetoprotein (AFP) level for the prognosis of hepatocellular carcinoma (HCC), by comparing pathological characteristics, recurrence rate and survival rate after hepatectomy. METHODS: 108 cases of HCC patients who received liver resection in our hospital from 2005 to 2011 were enrolled in this study. According to preoperative serum AFP level, the patients were divided into AFP <= 20 ng/mL group, AFP 20 to 400 ng/mL group and AFP > 400 ng/mL group, and the clinicopathological and cytopathological features were compared. All the patients were followed up for 24 months, the postoperative recurrence rates and survival rates were compared and analyzed, and the risk factors for HCC postoperative survival rate were studied by multifactor regression analysis. RESULTS: Of the 108 cases of HCC patients, there were 42 cases in AFP <=20 ng/mL group, 28 cases in AFP 20-400 ng/mL group and 39 cases in AFP > 400 ng/mL group. It was shown that cell differentiation degrees (chi2 = 20.198, P = 0.000) and microvascular invasion rates (chi2 = 20.358, P = 0.000) were significantly different among the three groups. The AFP <= 20 ng/mL group showed higher cell differentiation degrees and significantly lower microvascular invasion rates compared to the other groups (P < 0.05). The follow-up data showed that postoperative 2-year recurrence rate (chi2 = 6.164, P = 0.046), 18-month survival rate (chi2 = 7.647, P = 0.022) and 24-month survival rate (chi2 = 6.725, P = 0.035) of the three groups were significantly different, and we found that the AFP <= 20 ng/mL group had lower postoperative 2-year recurrence rate, and higher 18-month survival rate and 24-month survival rate than the other two groups (P <0.05). Multiple logistic regression analysis indicated that tumor diameter (>= 5 cm) and preoperative serum AFP level (> 400 ng/mL) were closely correlated with HCC postoperative survival rate (P <0.05). CONCLUSIONS: It is shown that preoperative serum AFP level has considerable predictive value for the malignant feature and prognosis of HCC. It is suggested that HCC patients with no contraindication of operation and serum AFP <= 20 ng/mL can benefit most from primary treatment of hepatectomy. While HCC patients with serum AFP higher than 20 ng/mL need comprehensive therapy besides surgical resection and close follow up. PMID- 23981852 TI - Sleep Spindles: Where They Come From, What They Do. AB - Sleep spindles are extensively studied electroencephalographic rhythms that recur periodically during non-rapid eye movement sleep and that are associated with rhythmic discharges of neurons throughout the thalamocortical system. Their occurrence thus constrains many aspects of the communication between thalamus and cortex, ranging from sensory transmission, to cortical plasticity and learning, to development and disease. I review these functional aspects in conjunction with novel findings on the cellular and molecular makeup of spindle-pacemaking circuits. A highlight in the search of roles for sleep spindles is the repeated finding that spindles correlate with memory consolidation in humans and animals. By illustrating that spindles are at the forefront understanding on how the brain might benefit from sleep rhythms, I hope to stimulate further experimentation. PMID- 23981853 TI - Providing for women's pleasure in the next generation of condoms. PMID- 23981854 TI - Diagnosis of allergic rhinitis: inter-rater reliability and predictive value of nasal endoscopic examination: a prospective observational study. AB - OBJECTIVE: To determine the inter-rater reliability of nasal endoscopic findings and the feasibility of diagnosis of allergic rhinitis based solely on symptoms and nasal endoscopy. DESIGN: Prospective observational study. SETTING: University Teaching hospital. PARTICIPANTS: One hundred and eight patients were referred from the allergy clinic included in the study. MAIN OUTCOME MEASURES: Predictive value of symptoms and nasal endoscopic examination to diagnose allergic rhinitis and inter-rater reliability of the examination were evaluated. RESULTS: Logistic regression analysis of patient symptoms and nasal examination findings revealed no significant predictive power for any of the symptoms or examination findings. The Fleiss kappa coefficient of the three raters was calculated. Inter-rater variability among the three physicians demonstrated that mucosal oedema (kappa = 0,48, P < 0.001), polypoid degeneration of the inferior turbinate tail (kappa = 0.48, P = 0.01), nasal polyps (kappa = 0.96, P < 0.001) and nasal septal deviation (kappa = 0.65, P = 0.01) showed significant inter-rater agreement. A low kappa coefficient (0.29) was found, and the inter-rater variability among physicians in interpreting the characteristics of nasal secretions was significant (P = 0.04). The inter-rater variability among the three physicians suggested that turbinate hypertrophy (kappa = 0.31) and turbinate colour (kappa = 0.38) showed no significant inter-rater agreement. CONCLUSIONS: Patient symptoms and nasal endoscopy findings do not provide reliable diagnosis of allergic rhinitis. Turbinate colour and hypertrophy are believed to be related to allergic rhinitis; however, these were subject to marked inter-rater variability in this study. PMID- 23981855 TI - Synthesis and X-ray crystallographic investigation of N-(alpha-D arabinopyranosyl)alkanamides as N-glycoprotein linkage region analogs. AB - N-Glycoprotein linkage region constituents namely 2-deoxy-2-acetamido-beta-D glucopyranose (GlcNAc) and asparagine (Asn) are conserved among all eukaryotes. Earlier crystallographic studies on the linkage region conformation revealed that among all the models and analogs of the N-glycoprotein linkage region, XylbetaNHAc showed maximum deviation in the phiN value as compared to the value reported for the model compound, GlcNAcbetaNHAc. In order to understand the effect of another pentopyranose, viz., arabinose, on the N-glycosidic torsion angles and molecular assembly, three arabinopyranosyl alkanamides were synthesized and their X-ray crystal structures elucidated. A comparative analysis of the N-glycosidic torsion, phiN of the three analogs revealed the greater rotational freedom around the C1-N1 bond as compared to the GlcNAc derivatives. Molecular assembly of propionamido and chloroacetamido derivatives is characterized by the presence of anti-parallel bilayers of the molecules. This unique molecular assembly is hitherto unknown in all other models and analogs of N-glycoprotein linkage region. This study reveals that N-glycosidic torsions are influenced by the glycan as well as molecular packing. PMID- 23981856 TI - Identification of the common antigenic determinant shared by Streptococcus pneumoniae serotypes 33A, 35A, and 20 capsular polysaccharides. AB - In order to better understand cross-reactions of serogroup 33 polysaccharides and the typing sera, the structure of pneumococcal capsular polysaccharide serotype 33A was elucidated. Serotype 33A has been shown to have an identical polysaccharide backbone as that of serotype 33F, with two additional sites of O acetylation at C5, and C6 of the 3-beta-Galf residue in serotype 33A. This finding is consistent with the presence of an additional functional acetyltransferase gene (wcjE) in the cps biosynthetic locus of serotype 33A compared to 33F. The identical polysaccharide backbone with at least one common O acetylation site (C2 of 5-beta-Galf) shared by serotype 33A and 33F polysaccharides is proposed to be the epitope recognized by typing serum 33b. In addition, a 5,6-di-O-acetylated ->3)-beta-d-Galf5,6Ac-(1->3)-beta-d-Glcp-(1-> disaccharide unit, a common structural motif present in serotypes 33A, 20, and 35A polysaccharides, is proposed to be the antigenic determinant recognized by typing serum 20b. PMID- 23981857 TI - A comparison of traditional food and health strategies among Taiwanese and Chinese immigrants in Atlanta, Georgia, USA. AB - BACKGROUND: Ethnobotanical studies on the use of plants amongst migrant populations are of great relevance to public health. Traditional health strategies, which incorporate plants as medicines, foods, or both - can play an important role in individual well-being. However, at the same time, migrant populations' traditional knowledge of such practices may be under a state of greater threat of decline due to factors such as limited access to the plant materials and physical isolation from the homeland, which serves as the primary living reservoir for this knowledge. METHODS: In this study, we conducted a medical ethnobotanical survey focusing on a comparison of local medicinal food and health strategies with members of two Asian immigrant populations in metro Atlanta: Chinese and Taiwanese. Snowball sampling techniques were employed to recruit 83 study participants, 57 of which were included in the final analysis. Semi-structured interview techniques were used to question participants about their beliefs and usage of the yin yang system, usage of Chinese herbs and medicinal foods, preference and usage of Eastern and Western medicines, and gardening for medicinal foods. RESULTS AND CONCLUSION: Comparison of the two groups demonstrated a remarkable difference in health strategies concerning medicinal plant use, including statistically significant differences in beliefs concerning yin and yang, uses of Eastern versus Western medicine, and gardening for medicinal foods. Domestic health strategies in the form of medicinal foods play an important role in local health practices, especially among the Taiwanese participants. The collective desire for the use of both Eastern and Western medicine by both groups highlights the important role that cultural competency training will play in preparing allopathic health practitioners to serve increasingly diverse patient populations in the US. PMID- 23981858 TI - Shifting the focus of one's attention mediates improvement in cognitive therapy for social anxiety disorder. AB - BACKGROUND: Cognitive therapy is an effective treatment for social anxiety disorder but little is known about the mechanisms by which the treatment achieves its effects. AIMS: This study investigated the potential role of self-focused attention and social phobia related negative automatic thoughts as mediators of clinical improvement. METHOD: Twenty-nine patients with social phobia received individual cognitive therapy (ICT) in a randomized controlled trial. Weekly process and outcome measures were analysed using multilevel mediation models. RESULTS: Change from self-focused to externally focused attention mediated improvements in social anxiety one week later. In contrast, change in frequency of, or belief in, negative social phobia related negative automatic thoughts did not predict social anxiety one week later. CONCLUSIONS: Change in self-focused attention mediate therapeutic improvement in ICT. Therapists should therefore target self-focused attention. PMID- 23981859 TI - Adjunctive steroid in HIV-negative patients with severe Pneumocystis pneumonia. AB - BACKGROUND: High-dose steroid therapy has been proven effective in AIDS-related Pneumocystis pneumonia (PCP) but not in non-AIDS-related cases. We evaluated the effects on survival of steroids in HIV-negative patients with PCP. METHODS: Retrospective study patients admitted to the ICU with hypoxemic PCP. We compared patients receiving HDS (>=1 mg/Kg/day prednisone equivalent), low-dose steroids (LDS group, <1 mg/Kg/day prednisone equivalent), and no steroids (NS group). Variables independently associated with ICU mortality were identified. RESULTS: 139 HIV-negative patients with PCP were included. Median age was 48 [40-60] years. The main underlying conditions were hematological malignancies (n=55, 39.6%), cancer (n=11, 7.9%), and solid organ transplantation (n=73, 52.2%). ICU mortality was 26% (36 deaths). The HDS group had 72 (51.8%) patients, the LDS group 35 (25%) patients, and the NS group 32 (23%) patients. Independent predictors of ICU mortality were SAPS II at ICU admission (odds ratio [OR], 1.04/point; [95%CI], 1.01-1.08, P=0.01), non-hematological disease (OR, 4.06; [95%CI], 1.19-13.09, P=0.03), vasopressor use (OR, 20.31; 95%CI, 6.45-63.9, P<0.001), and HDS (OR, 9.33; 95%CI, 1.97-44.3, P=0.02). HDS was not associated with the rate of ICU-acquired infections. CONCLUSIONS: HDS were associated with increased mortality in HIV-negative patients with PCP via a mechanism independent from an increased risk of infection. PMID- 23981863 TI - Evolution of life history and behavior in Hominidae: towards phylogenetic reconstruction of the chimpanzee-human last common ancestor. AB - The origin of the fundamental behavioral differences between humans and our closest living relatives is one of the central issues of evolutionary anthropology. The prominent, chimpanzee-based referential model of early hominin behavior has recently been challenged on the basis of broad multispecies comparisons and newly discovered fossil evidence. Here, we argue that while behavioral data on extant great apes are extremely relevant for reconstruction of ancestral behaviors, these behaviors should be reconstructed trait by trait using formal phylogenetic methods. Using the widely accepted hominoid phylogenetic tree, we perform a series of character optimization analyses using 65 selected life-history and behavioral characters for all extant hominid species. This analysis allows us to reconstruct the character states of the last common ancestors of Hominoidea, Hominidae, and the chimpanzee-human last common ancestor. Our analyses demonstrate that many fundamental behavioral and life history attributes of hominids (including humans) are evidently ancient and likely inherited from the common ancestor of all hominids. However, numerous behaviors present in extant great apes represent their own terminal autapomorphies (both uniquely derived and homoplastic). Any evolutionary model that uses a single extant species to explain behavioral evolution of early hominins is therefore of limited use. In contrast, phylogenetic reconstruction of ancestral states is able to provide a detailed suite of behavioral, ecological and life-history characters for each hypothetical ancestor. The living great apes therefore play an important role for the confident identification of the traits found in the chimpanzee-human last common ancestor, some of which are likely to represent behaviors of the fossil hominins. PMID- 23981864 TI - Supplementation of sperm cryopreservation media with cell permeable superoxide dismutase mimetic agent (MnTE) improves goat blastocyst formation. AB - The aim of this study was to assess whether a cell permeable superoxide dismutase agent such as MnTE, can further improve the quality of frozen/thawed semen sample using a commercially optimized sperm cryopreservation media (Bioxcell). Bioxcell was supplemented with different concentration of MnTE. Sperm membrane integrity, motility, viability and acrosomal status were assessed after freezing. Optimized concentration of MnTE was defined and used to assess fertilization and developmental potential. 0.1 MUM MnTE significantly improved membrane integrity while 0.01 MUM MnTE significantly improved acrosomal integrity post thawing. Addition of 0.01 MUM MnTE also improved blastocyst formation rate. Supplementation of commercially optimized cryopreservation media with MnTE further improves the quality of goat frozen semen sample and may have important consequence of future embryo development. This effect may be attributed to cell permeable behavior of this antioxidant which may protect sperm genome from ROS induced DNA damage. PMID- 23981865 TI - Diaphragmatic dysfunction in the intensive care unit: caught in the cross-fire between sepsis and mechanical ventilation. AB - Accumulating evidence indicates that diaphragmatic weakness is common and frequently severe in mechanically ventilated patients. Supinski and Callahan now report that infection is a major risk factor for diaphragmatic weakness in this patient population. Importantly, they show that patients with the greatest levels of diaphragmatic dysfunction have a much poorer prognosis in terms of more prolonged ventilation as well as higher mortality. Mechanical ventilation itself has also been found to induce diaphragmatic weakness along with cellular changes resembling those found in sepsis. Future studies should be directed at understanding the interaction between sepsis and mechanical ventilation, and to developing therapeutic approaches that target their common cellular pathways implicated in diaphragmatic weakness. PMID- 23981866 TI - Water shortages and extreme events: a call for research. AB - Water shortages as a result of extreme weather events, such as flooding and severe cold, have the potential to affect significant numbers of people. Therefore, the need to build robust, coordinated plans based on scientific evidence is crucial. The literature review outlined in this short communication was conducted as part of a joint Drinking Water Inspectorate and Health Protection Agency (now Public Health England) report which aimed to review the scientific evidence base on extreme events, water shortages and the resulting health impacts. A systematic literature review was undertaken to identify published literature from both peer-reviewed and grey literature sources. The retrieved literature was then assessed using the Scottish Intercollegiate Guidelines Network quality assessment. The authors found very few scientific studies. However, a great deal of valuable grey literature was retrieved and used by the research team. In total, six main themes of importance that were identified by the review and discussed included health impacts, water quantity and quality, alternative supplies, vulnerable groups, communication with those affected and the emergency response. The authors conclude that more research needs to be conducted on health impacts and extreme events water shortages in order to build the future knowledge base and development of resilience. PMID- 23981867 TI - Eliminating false positives in a qPCR assay for the detection of the uidA gene in Escherichia coli. AB - Due to contaminant Escherichia coli DNA present in recombinant Taq polymerase reagents, it is not possible to reliably detect low levels of E. coli in samples using the quantitative polymerase chain reaction (qPCR) assay. Native Taq polymerase was successfully used in this study to detect five uidA gene copies (5 fg of genomic DNA) of the uidA gene. PMID- 23981869 TI - Distinguishing human and possum faeces using PCR markers. AB - Specificity testing of two published polymerase chain reaction (PCR) markers for the detection of human faecal pollution, revealed 100% false-positive rates to brush-tailed possum faeces (n = 10), but low false-positive rates against other potential pollution sources. Cross-reaction with possums could be a problem with other human-specific markers; therefore, a possum PCR marker was developed for use in conjunction with human PCR markers. The possum PCR marker was based on Bacteroidales 16S ribosomal ribonucleic acid sequences, and was tested on 233 individual faecal samples from 11 other animal species. Sensitivity of the possum marker in possum faeces (n = 36) was high at 83.3%. Cross-reactivity of the possum marker was limited to black swan (7/20 samples), human (2/48 samples) and rabbit (1/10) faecal samples, all at marker concentrations at least four orders of magnitude lower than possum faeces. The possum marker was not detected in human sewage or the faeces of other animal species. Specificity of the possum PCR marker, therefore, was high at 95.7%. To exclude the possibility that only possum pollution is being detected, additional testing by other faecal source tracking methods is required where the water sample is positive for both human and possum markers. PMID- 23981868 TI - Antibiotic-resistance and virulence genes in Enterococcus isolated from tropical recreational waters. AB - The prevalence of enterococci harboring tetracycline- and vancomycin-resistance genes, as well as the enterococcal surface protein (esp) has mostly been determined in clinical settings, but their prevalence in tropical recreational waters remains largely unknown. The present study determined the prevalence of tetM (tetracycline-resistance), vanA and vanB (vancomycin-resistance) in the bacterial and viral fractions, enterococci and their induced phages isolated from tropical recreational marine and fresh waters, dry and wet sands. Since lysogenic phages can act as vectors for antibiotic-resistance and virulence factors, the prevalence of the mentioned genes, as well as that of an integrase-encoding gene (int) specific for Enterococcus faecalis phages was determined. Up to 60 and 54% of the bacterial fractions and enterococci, respectively, harbored at least one of the tested genes suggesting that bacteria in tropical environments may be reservoirs of antibiotic-resistance and virulence genes. int was detected in the viral fractions and in one Enterococcus isolate after induction. This study presents the opportunity to determine if the presence of bacteria harboring antibiotic-resistance and virulence genes in tropical recreational waters represents a threat to public health. PMID- 23981870 TI - Development of a quaternized chitosan with enhanced antibacterial efficacy. AB - The antibacterial activity of a water-soluble chitosan derivative prepared by chemical modification to quaternary ammonium compound N,N,N-trimethylchitosan (TC) was investigated against four selected waterborne pathogens: Aeromonas hydrophila ATCC 35654, Yersinia enterocolitica ATCC 9610, Listeria monocytogenes ATCC 19111 and Escherichia coli O157:H7 ATCC 32150. An inactivation of 4 log CFU/ml of all waterborne pathogens was noted for the quaternized chitosan as compared with chitosan over a short contact time (30 min) and low dosage (4.5 ppm) at ambient temperature. A marked increase in glucose level, protein content and lactate dehydrogenase (LDH) activity was observed concurrently in the cell supernatant to be a major bactericidal mechanism. The results suggest that the TC derivative may be a promising commercial substitute for acid-soluble chitosan for rapid and effective disinfection of water. PMID- 23981871 TI - Inactivation of Ascaris eggs in water using hydrogen peroxide and a Fenton type nanocatalyst (FeOx/C) synthesized by a novel hybrid production process. AB - Inactivation tests of Ascaris eggs (Ae) were performed using hydrogen peroxide and a Fenton type nanocatalyst supported on activated carbon (AC) (FeOx/C). Blank inactivation tests were also carried out using H2O2 and H2O2/AC as oxidation systems. The FeOx/C nanocatalyst was synthesized through a novel hybrid method developed in this work. The method is based on the incipient impregnation technique, using isopropyl alcohol as dissolvent and chelating agent of the iron salt and the ultrasonic method. The supported nanocatalyst contained 2.61% w/w of total iron and the support 0.2% w/w. Transmission electron microscopy (TEM) energy dispersive spectrometer (EDS) images permitted verification of the presence of finely dispersed FeOx nanoparticles, with sizes ranging from 19 to 63 nm. SEM-EDS analysis and TEM images also showed good dispersion of iron oxide nanoparticles, most probably maghemite; gamma-Fe2O3, able to produce hydroperoxyl radical as reported in the literature. The FeOx/C nanocatalyst-H2O2 system showed an average Ae inactivation efficiency of 4.46% Ae/mg H2O2. This value is significantly higher than the result obtained using the support-H2O2 system and H2O2 alone and it is also better than data reported for the classical Fenton process (homogeneous phase) with or without UV light. PMID- 23981872 TI - Short-term microbial release during rain events from on-site sewers and cattle in a surface water source. AB - The protection of drinking water from pathogens such as Cryptosporidium and Giardia requires an understanding of the short-term microbial release from faecal contamination sources in the catchment. Flow-weighted samples were collected during two rainfall events in a stream draining an area with on-site sewers and during two rainfall events in surface runoff from a bovine cattle pasture. Samples were analysed for human (BacH) and ruminant (BacR) Bacteroidales genetic markers through quantitative polymerase chain reaction (qPCR) and for sorbitol fermenting bifidobacteria through culturing as a complement to traditional faecal indicator bacteria, somatic coliphages and the parasitic protozoa Cryptosporidium spp. and Giardia spp. analysed by standard methods. Significant positive correlations were observed between BacH, Escherichia coli, intestinal enterococci, sulphite-reducing Clostridia, turbidity, conductivity and UV254 in the stream contaminated by on-site sewers. For the cattle pasture, no correlation was found between any of the genetic markers and the other parameters. Although parasitic protozoa were not detected, the analysis for genetic markers provided baseline data on the short-term faecal contamination due to these potential sources of parasites. Background levels of BacH and BacR makers in soil emphasise the need to including soil reference samples in qPCR-based analyses for Bacteroidales genetic markers. PMID- 23981873 TI - Comparative study of disinfectants for use in low-cost gravity driven household water purifiers. AB - Point-of-use (POU) gravity-driven household water purifiers have been proven to be a simple, low-cost and effective intervention for reducing the impact of waterborne diseases in developing countries. The goal of this study was to compare commonly used water disinfectants for their feasibility of adoption in low-cost POU water purifiers. The potency of each candidate disinfectant was evaluated by conducting a batch disinfection study for estimating the concentration of disinfectant needed to inactivate a given concentration of the bacterial strain Escherichia coli ATCC 11229. Based on the concentration of disinfectant required, the size, weight and cost of a model purifier employing that disinfectant were estimated. Model purifiers based on different disinfectants were compared and disinfectants which resulted in the most safe, compact and inexpensive purifiers were identified. Purifiers based on bromine, tincture iodine, calcium hypochlorite and sodium dichloroisocyanurate were found to be most efficient, cost effective and compact with replacement parts costing US$3.60-6.00 for every 3,000 L of water purified and are thus expected to present the most attractive value proposition to end users. PMID- 23981874 TI - Effects of salinity on photoreactivation of Escherichia coli after UV disinfection. AB - The effects of sodium chloride on photoreactivation of Escherichia coli were examined, assuming the discharge of ultraviolet (UV)-treated wastewater to water environment at different salinities. Suspensions of E. coli were first exposed to a low-pressure UV lamp in phosphate buffer to achieve 3 log inactivation, followed by an exposure to fluorescent light in NaCl solutions at the concentration of 1.0, 1.4, 1.9, 2.4 and 2.9 weight/volume %. When photoreactivation was completed in 3 h, survival ratio was recovered about 2 log in 1.0, 1.4, and 1.9% NaCl solutions, which was equivalent to the recovery observed in phosphate-buffered solution. Meanwhile, the recovery was suppressed to 0.8 log and -0.2 log in 2.4 and 2.9% NaCl solutions, respectively, which was significantly less than the recovery in phosphate buffer according to the t-test (p < 0.05). An endonuclease sensitive site assay demonstrated that the suppressed photoreactivation in 2.9% NaCl solution was due to the failure at repairing UV induced pyrimidine dimers in the genome. In conclusion, photoreactivation of E. coli was significantly suppressed in NaCl solution at 2.4% or higher but not affected in NaCl solution at 1.9% or lower. This implies that photoreactivation of E. coli may potentially occur in brackish and coastal areas where salinity is rather low. PMID- 23981875 TI - Optimal pH in chlorinated swimming pools - balancing formation of by-products. AB - In order to identify the optimal pH range for chlorinated swimming pools, the formation of trihalomethanes, haloacetonitriles and trichloramine was investigated in the pH-range 6.5-7.5 in batch experiments. An artificial body fluid analogue was used to simulate bather load as the precursor for by-products. The chlorine-to-precursor ratio used in the batch experiments influenced the amounts of by-products formed, but regardless of the ratio the same trends in the effect of pH were observed. Trihalomethane formation was reduced by decreasing pH, but haloacetonitrile and trichloramine formation increased. To evaluate the significance of the increase and decrease of the investigated organic by-products at the different pH values, the genotoxicity was calculated based on literature values. The calculated genotoxicity was approximately at the same level in the pH range 6.8-7.5 and increased when pH was 6.7 or lower. An optimal pH range for by products formation in swimming pools was identified at pH 7.0-7.2. In the wider pH range (pH 6.8-7.5), the effect on by-product formation was negligible. Swimming pools should never be maintained at lower pH than 6.8 since formation of both haloacetonitriles and trichloramine increase significantly below this value. PMID- 23981876 TI - Quantification of human norovirus GII, human adenovirus, and fecal indicator organisms in wastewater used for irrigation in Accra, Ghana. AB - Quantitative microbial risk assessment (QMRA) is frequently used to estimate health risks associated with wastewater irrigation and requires pathogen concentration estimates as inputs. However, human pathogens, such as viruses, are rarely quantified in water samples, and simple relationships between fecal indicator bacteria and pathogen concentrations are used instead. To provide data that can be used to refine QMRA models of wastewater-fed agriculture in Accra, stream, drain, and waste stabilization pond waters used for irrigation were sampled and analyzed for concentrations of fecal indicator microorganisms (human specific Bacteroidales, Escherichia coli, enterococci, thermotolerant coliform, and somatic and F+ coliphages) and two human viruses (adenovirus and norovirus genogroup II). E. coli concentrations in all samples exceeded limits suggested by the World Health Organization, and human-specific Bacteroidales was found in all but one sample, suggesting human fecal contamination. Human viruses were detected in 16 out of 20 samples, were quantified in 12, and contained 2-3 orders of magnitude more norovirus than predicted by norovirus to E. coli concentration ratios assumed in recent publications employing indicator-based QMRA. As wastewater irrigation can be beneficial for farmers and municipalities, these results should not discourage water reuse in agriculture, but provide motivation and targets for wastewater treatment before use on farms. PMID- 23981877 TI - Water quality perceptions and willingness to pay for clean water in peri-urban Cambodian communities. AB - This paper studies household demand for improved water quality in peri-urban Cambodia, with particular attention paid to the influence of water quality on willingness to pay (WTP). Utilizing data from 915 household surveys, we analyze responses to a contingent valuation scenario using multivariate logit regression techniques that account for subjective perceptions of water quality. We estimate a mean household WTP for improved water quality of US$3 (roughly 1.2% of mean income) per month for households in this sample. We also find that the majority of households believe that their in-house water after storage, handling, and treatment is safe to drink. Furthermore, beliefs about existing levels of water quality have a significant impact on WTP for improved water quality. However, while perceptions of quality (and thus WTP) are highly related to taste preferences, actual water quality is relatively uncorrelated with water quality perceptions. These findings suggest that interventions aiming to increase the adoption of water treatment should account for underlying perceptions of water quality. PMID- 23981878 TI - Improving service delivery of water, sanitation, and hygiene in primary schools: a cluster-randomized trial in western Kenya. AB - Water, sanitation, and hygiene (WASH) programs in schools have been shown to improve health and reduce absence. In resource-poor settings, barriers such as inadequate budgets, lack of oversight, and competing priorities limit effective and sustained WASH service delivery in schools. We employed a cluster-randomized trial to examine if schools could improve WASH conditions within existing administrative structures. Seventy schools were divided into a control group and three intervention groups. All intervention schools received a budget for purchasing WASH-related items. One group received no further intervention. A second group received additional funding for hiring a WASH attendant and making repairs to WASH infrastructure, and a third group was given guides for student and community monitoring of conditions. Intervention schools made significant improvements in provision of soap and handwashing water, treated drinking water, and clean latrines compared with controls. Teachers reported benefits of monitoring, repairs, and a WASH attendant, but quantitative data of WASH conditions did not determine whether expanded interventions out-performed our budget-only intervention. Providing schools with budgets for WASH operational costs improved access to necessary supplies, but did not ensure consistent service delivery to students. Further work is needed to clarify how schools can provide WASH services daily. PMID- 23981879 TI - Perceptions of bottled water consumers in three Brazilian municipalities. AB - This study presents perceptions of consumers of bottled water in their households in three Brazilian municipalities. Data from interviews were analyzed using the Discourse Collective Subject method. Interviewees spent, on average, the equivalent of 40% of their water bill for the public water supply on the purchase of bottled water. The decision about water consumption in the household was predominantly made by women. Interviewees were particularly concerned with health risks and expressed a strong preference for the safety and organoleptic qualities of bottled water, particularly in cases where the tap water supply did not fully meet the regulated water quality standards. Interviewees were largely unaware of the origin, type, storage, and social and environmental impacts of bottled water. Results highlight the importance of water education efforts among the general population and the key role of women in the processes related to drinking water. The need for gender-specific interventions and the empowerment of women on water issues is noted. Results also strongly support the relevance of ensuring the provision of safe drinking water, from the source to the consumption point, with the trust of consumers. PMID- 23981880 TI - Potable water scarcity: options and issues in the coastal areas of Bangladesh. AB - In the coastal areas of Bangladesh, scarcity of drinking water is acute as freshwater aquifers are not available at suitable depths and surface water is highly saline. Households are mainly dependent on rainwater harvesting, pond sand filters and pond water for drinking purposes. Thus, individuals in these areas often suffer from waterborne diseases. In this paper, water consumption behaviour in two southwestern coastal districts of Bangladesh has been investigated. The data for this study were collected through a survey conducted on 750 rural households in 39 villages of the study area. The sample was selected using a random sampling technique. Households' choice of water source is complex and seasonally dependent. Water sourcing patterns, households' preference of water sourcing options and economic feasibility of options suggest that a combination of household and community-based options could be suitable for year-round water supply. Distance and time required for water collection were found to be difficult for water collection from community-based options. Both household and community-based options need regular maintenance. In addition to installation of water supply facilities, it is necessary to make the residents aware of proper operation and maintenance of the facilities. PMID- 23981881 TI - Mechanisms of post-supply contamination of drinking water in Bagamoyo, Tanzania. AB - Access to household water connections remains low in sub-Saharan Africa, representing a public health concern. Previous studies have shown water stored in the home to be more contaminated than water at the source; however, the mechanisms of post-supply contamination remain unclear. Using water quality measurements and structured observations of households in Bagamoyo, Tanzania, this study elucidates the causal mechanisms of the microbial contamination of drinking water after collection from a communal water source. The study identifies statistically significant loadings of fecal indicator bacteria (FIB) occurring immediately after filling the storage container at the source and after extraction of the water from the container in the home. Statistically significant loadings of FIB also occur with various water extraction methods, including decanting from the container and use of a cup or ladle. Additionally, pathogenic genes of Escherichia coli were detected in stored drinking water but not in the source from which it was collected, highlighting the potential health risks of post-supply contamination. The results of the study confirm that storage containers and extraction utensils introduce microbial contamination into stored drinking water, and suggest that further research is needed to identify methods of water extraction that prevent microbial contamination of drinking water. PMID- 23981882 TI - Microbial quality and bacteria pathogens in private wells used for drinking water in northeastern Ohio. AB - In agricultural intensive areas, drinking contaminated water from private wells is considered an important cause of acute gastroenteric illnesses (AGI), particularly among high-risk populations. In the summer of 2009, the microbial water quality of 180 randomly selected private wells in two northeastern Ohio counties, a region with a high concentration of dairy farms, was assessed. Forty five percent (82/180) of water samples were contaminated with total coliforms. Generic Escherichia coli were present in 9% (16/180) of samples. Using real-time polymerase chain reaction, E. coli O157:H7 was identified in 4% (7/180) of specimens. Campylobacter spp. DNA could not be amplified from 70 of the samples tested for this organism. The frequency of generic E. coli contamination varied among townships (P < 0.001). Well structure (i.e. age and depth) or other common measures of pollution potential (depth of water, hydrology, topography, net recharge soil media) was not correlated with coliforms and E. coli contamination. Importantly, the presence of the pathogen E. coli O157:H7 was not associated with the presence of fecal indicators in the water samples: Only one of the seven E. coli O157-positive samples was also positive for generic E. coli. Appropriate risk management and communication processes are needed to reduce the potential waterborne disease outbreaks in agricultural intensive areas. PMID- 23981883 TI - PCR amplification and DNA sequence of mcyA gene: the distribution profile of a toxigenic Microcystis aeruginosa in the Hartbeespoort Dam, South Africa. AB - Using new polymerase chain reaction (PCR) primers, a once known to be under transcribed microcystin synthetase A (mcyA) gene from the only known toxigenic cyanobacterium Microcystis aeruginosa dominating the Hartbeespoort Dam was consistently amplified from genomic DNA extracted from a set of algal and cell free water samples collected across this dam. In addition to this, five more mcy genes (mcyBCDEG) were also amplified during this study. The resultant mcyA PCR products (518 bp) were purified and sequenced and gave nucleotide sequence segments of 408 bp sizes. The obtained sequence was aligned to the published mcyA gene sequence available online on the NCBI database and resulted in 100% similarity to a 408 bp mcyA gene sequence segment of M. aeruginosa UWOCC RID-1. Furthermore, it was found that the above sequence segment (408 bp) spans from a common base in M. aeruginosa PCC 7806 and M. aeruginosa PCC 7820 from 141 to 548 bp in the N-methyl transferase (NMT) region signifying their closer relatedness to M. aeruginosa UWOCC strains. This study has for the first time amplified mcyA gene consistently from both intracellular and extracellular DNA extracts obtained from algal and cell free water samples, respectively. Sequence data and the amplified mcy genes showed that M. aeruginosa is widely distributed and dominant in this dam. PMID- 23981884 TI - Assessment of water and seafood microbiology quality in a mangrove region in Vitoria, Brazil. AB - Mangroves are vital part of the local economy for some communities in the region of Vitoria, Brazil. Oysters, mussels, and crabs, which are naturally abundant in the mangroves, are harvested and largely consumed in restaurants and by the population. In recent years, unusually high rates of annual gastroenteritis cases have been reported in the region suggesting an association between the consumption of contaminated shellfish and the development of gastrointestinal diseases. The objective of this study was to evaluate water samples and mussels collected in the mangrove region using bacterial indicator Escherichia coli and enteric viruses (adenovirus, rotavirus, and norovirus). Our results showed that the region of study is impacted by a continuous discharge of domestic sewage. Although E. coli was detected at low densities in water samples, mussels were shown to be 400 times more contaminated throughout the period of the study. Adenovirus and rotavirus genomes were detected by nested-polymerase chain reaction respectively in 76 and 88% of water samples and 100% of mussel samples. Norovirus was found in 4.8% of water samples and was not detected in the mussels. The screening of bivalves for the presence of health-significant enteric viruses can help in the prevention of outbreaks among shellfish consumers and contribute to improvement of the estuarine environment. PMID- 23981885 TI - Formulations for success in compounding, part 1. PMID- 23981886 TI - Capsule-weighing and trituration calculations. PMID- 23981887 TI - Irrigation with piperacillin for the treatment of bladder infection: a case study. PMID- 23981888 TI - The basics of compounding emulsions, part 2. PMID- 23981889 TI - Evaluating transdermal medication forms for veterinary patients. PMID- 23981890 TI - The role of natural progesterone in natural hormone replacement therapy. PMID- 23981891 TI - Pharmacy cleanroom project management considerations: an experience-based perspective. PMID- 23981892 TI - Stability of piperacillin sodium after reconstitution in 0.9% sodium chloride injection and storage in polypropylene syringes for pediatric use. AB - A stability-indicating high-performance liquid chromatography (HPLC) assay method was used to study the stability of piperacillin sodium (40 mg/mL) in 0.9% sodium chloride injection at 25 deg C and 5 deg C in polypropylene syringes. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation (RSD) based on five injections was 0.8. Three products of decomposition separated from the intact drug. At 25 deg C, the loss in potency was less than 10% after 5 days of storage, and at 5 deg C, it was less than 2% when stored for 28 days. The pH value of the injection decreassed from 5.3 to 4.4 when stored for 28 days at 5 deg C. The drug was not adsorbed onto the syringes, and the physical appearance of the injection did not change. PMID- 23981893 TI - Stability of oral liquid dosage forms of ethacrynic Acid. AB - The stability of ethacrynic acid (2.5 mg/mL) in oral liquid dosage forms was investigated. Tablets in 0.05 M phosphate buffer (available commercially) in water were used to prepare the dosage forms. The effects of mannitol and sugar on the stability of ethacrynic acid were negligible. There was no change in the physical appearance of the oral liquid dosage forms or pH values during the study. There was, however, a new peak in the chromatogram from the products(s) of decomposition. An oral liquid dosage form of ethacrynic acid containing 0.05 M phosphate buffer and 10% mannitol was stable for 24 days when stored at 5 deg C and for only 3 days when stored at 25 deg C. PMID- 23981894 TI - Preparation and evaluation of sustained drug release from pluronic polyol rectal suppositories. AB - Suppository dosage forms offer several advantages in drug delivery and can be compounded in a pharmacy setting for the needs of the individual patient. In this study, we have examined the use of Pluronic polyols in the development of sustained-release rectal suppository formulations. Solid and liquid Pluronic poyols (Pluronic L61, F68, L101, and F108) were combined in a weight ratio ranging from 80:20 (solid to liquid) to 70:30 to prepare the bases. The release behavior of a model drug, riboflavin, from the suppositories wee evaluated by means of the United Stated Pharmacopeia Basket Dissolution Method. When compared with the control Polybase suppository, which released 50% of the drug (t50) in about 7.23 minutes, Pluronic F68/L61 suppositories at an 80:20 weight ratio exhibited a t50 of 86.5 minutes (1.44 hours). Riboflavin release from suppositories made with Pluronic F108/L101 was even further delayed. The t50 of riboflavin from Pluronic F108/L101 suppositories at an 80:20 weight ratio, for instance, was 274.4 minutes (4.6 hours). The results of this study show that by choosing specific combinations of Pluronic polyols and weight ratios, compounding pharmacists can prepare sustained-release suppository formulations that can deliver drugs within minutes to hours. This flexibility of compounding sustained release suppositories is beneficial, especially for the management of chronic pain in cancer patients. PMID- 23981895 TI - Comparison of ultrasonography and magnetic resonance imaging for the assessment of clinically defined knee enthesitis in spondyloarthritis. AB - OBJECTIVES: Ultrasonography (US) and magnetic resonance imaging (MRI) are increasingly used imaging techniques for visualising entheses, however few studies have made a direct comparison of each. This study aimed to compare each technique for the detection of enthesitis in patients with spondyloarthritis (SpA) related knee swelling in order to make a lesion by lesion comparison. METHODS: Consecutive SpA patients with knee synovitis were recruited: each had clinical assessment for enthesitis at 8 sites in the involved knee joint followed by US and MRI examinations. Inflammatory and structural changes at tendon and ligament insertions were scored and a lesion by lesion comparison was made. RESULTS: 21 patients were recruited. Clinically defined involved knee joint enthesitis was evident in 18 of 21 (86%) patients in 61 of 168 (36%) evaluated sites. Clinical enthesitis was associated with more hypoechogenicity (16 vs. 4%, p=0.007) and thickening (16 vs. 6%, p=0.03) by US compared to non-tender sites. Considering all MRI findings only increased signal in the surrounding tissues was higher at tender sites (41 vs. 20%, p=0.01) and the insertions points themselves showed little abnormality. The positive agreements between individual lesions by both methods was very low (10-26%) with low kappa values (0.06-0.18) with no correlations between the MRI and US scores (r2= 0.059). CONCLUSIONS: The difficulty in procuring 'gold standard' histological validation is synovial joints makes the assessment of enthesitis using clinical and current imaging protocols of limited utility for diagnostic purposes. PMID- 23981896 TI - The impact of eating quickly on anthropometric variables among schoolgirls: a prospective cohort study in Japan. AB - BACKGROUND: Because most studies about the relationship between eating quickly and overweight/obesity have been cross-sectional, it is necessary to investigate prospectively the influence of eating quickly on anthropometric variables in order to examine the causal relationship. The aim of the present study was to investigate the impact of eating quickly on anthropometric variables among schoolgirls in a prospective cohort study. METHODS: We investigated 427 non overweight/obese schoolgirls from fourth grade (aged 9 or 10 years) in Ina-town, Japan from 2004 to 2006. Physical examinations and a questionnaire survey were conducted in fourth grade and 3 years later (in seventh grade). Height, weight, percent body fat (%BF) and waist circumference (WC) were measured in physical examinations, and information on eating speed was collected in a questionnaire survey. RESULTS: The differences in anthropometric variables (body mass index, %BF, WC and waist-to-height ratio) between fourth and seventh grade were significantly greater in girls who continued to eat quickly from fourth to seventh grade than in those who did not continue to eat quickly during this 3 year period. In contrast, these differences were not statistically significant in girls who ate quickly in fourth grade but not in seventh grade compared with those who did not continue to eat quickly during the 3-year period. CONCLUSION: Eating quickly was associated with excess gains in anthropometric variables. The present study also suggested that stopping a habit of eating quickly prevents these excess gains in non-overweight/obese girls, which could contribute to the prevention of childhood overweight and obesity. PMID- 23981897 TI - Synthesis and biological analysis of benzazol-2-yl piperazine sulfonamides as 11beta-hydroxysteroid dehydrogenase 1 inhibitors. AB - In the last decade the inhibition of the enzyme 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1) emerged as a promising new strategy to treat diabetes and several metabolic syndrome phenotypes. Using a molecular modeling approach and classical bioisosteric studies, we discovered a new class of 11beta HSD1 inhibitors bearing an arylsulfonylpiperazine scaffold. Optimization of the initial lead resulted in compound 11 that selectively inhibits 11beta-HSD1 (IC50=0.7 MUM). PMID- 23981898 TI - Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides. AB - Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Abeta following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d. PMID- 23981899 TI - A high-yield route to synthesize the P-glycoprotein radioligand [11C]N-desmethyl loperamide and its parent radioligand [11C]loperamide. AB - N-Desmethyl-loperamide and loperamide were synthesized from alpha,alpha-diphenyl gamma-butyrolactone and 4-(4-chlorophenyl)-4-hydroxypiperidine in five and four steps with 8% and 16% overall yield, respectively. The amide precursor was synthesized from 4-bromo-2,2-diphenylbutyronitrile and 4-(4-chlorophenyl)-4 hydroxypiperidine in 2 steps with 21-57% overall yield. [(11)C]N-Desmethyl loperamide and [(11)C]loperamide were prepared from their corresponding amide precursor and N-desmethyl-loperamide with [(11)C]CH3OTf through N [(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 20-30% and 10-15% radiochemical yields, respectively, based on [(11)C]CO2 and decay corrected to end of bombardment (EOB), with 370-740 GBq/MUmol specific activity at EOB. PMID- 23981900 TI - Functional consequence of syndesmotic malreduction. PMID- 23981901 TI - Are bilateral femoral fractures no longer a marker for death? AB - OBJECTIVES: To determine whether previously reported high mortality rates associated with bilateral femoral fractures have decreased over time. DESIGN: Retrospective review. SETTING: Urban academic trauma center. PATIENTS: STUDY GROUP: 54 adults with bilateral femoral fractures treated at our center from 2000 to 2006. The 108 fractures were initially treated with external fixation (11%), reamed antegrade nailing (23%), and reamed retrograde nailing (67%). Unilateral control group: 461 patients with unilateral femoral fractures treated at our center from 2002 to 2005. INTERVENTION: Univariate analysis compared our results with those of a published historical control group from the same center approximately 15 years ago (study period, 1984-1990). MAIN OUTCOME MEASUREMENTS: Mortality rates. RESULTS: We noted marked differences between the current mortality rate associated with bilateral femoral fractures and that of the historical control group. The mortality rate decreased over time at our center for both bilateral (26%-7%, P = 0.002) and unilateral (12%-2%, P = 0.0001) fractures. Mortality rates were still significantly higher (P = 0.037) for bilateral (7%) than for unilateral (2%) fractures. CONCLUSIONS: Mortality rates and Injury Severity Scores were reduced for bilateral and unilateral femoral fractures compared with data reported 15 years ago from the same center. The improved outcome might be related in part to changes in resuscitation, triage, intensive care, and orthopaedic management of the patients. However, considering that the Injury Severity Score also significantly decreased, the improvement might have occurred because of changes in injury patterns, perhaps secondary to improved safety features in motor vehicles. LEVEL OF EVIDENCE: Prognostic level III. See instructions for authors for a complete description of levels of evidence. PMID- 23981902 TI - Impact of breast cancer surgery on angiogenesis circulating biomarkers: a prospective longitudinal study. AB - BACKGROUND: Debate about the potential effects that surgery might have on cancer cells dormancy and angiogenesis prompted us to investigate the impact of breast surgery on circulating angiogenesis modulating gene transcripts and proteins. METHODS: Blood samples from 10 female patients diagnosed with breast cancer and 6 with fibroadenoma were collected before surgery and post-operatively on days 3 and 7 (breast cancer patients only). A set of 84 angiogenesis-associated transcripts were assessed using quantitative PCR arrays, and circulating protein levels (vascular endothelial growth factor A (VEGFA), IL8 and fibroblast growth factor 2 (FGF2) were measured using ELISA in the same samples. The results were investigated against clinicopathological data and patient outcome. RESULTS: Plasma levels of VEGFA and IL8 after surgery were significantly elevated in the breast cancer group compared to the control group (P = 0.038 and P = 0.021, respectively). In the cohort of breast cancer patients, VEGFA increased on day 3 (P = 0.038) and declined on day 7 (P= 0.017), while IL8 did not change on day 3 but showed a significant decline on day 7 (P = 0.02). FGF2 levels did not change significantly over time. Regarding gene transcripts, we detected upregulation of a significant number of angiogenesis-specific genes in patients with breast cancer versus controls: sphingosine kinase 1(SPHK1), epidermal growth factor (EGF), vascular endothelial growth factor C (VEGFC), neuropilin 1 (NRP1), fibroblast growth factor (FGF1), laminin alpha 5 (LAMA5), collagen type IV alpha 3 (COL4A3), IL8, ephrin B2 (EFNB2), ephrin A3 (EFNA3), tyrosine endothelial kinase (TEK), integrin beta 3 (ITGB3), AKT1, thrombospondin 1 (THBS1), chemokine (C-C motif) ligand 11 (CCL11) and TIMP metallopeptidase inhibitor 3 (TIMP3). Surgery induced an altered expression in several keygenes in breast cancer patients. We identified an upregulation of COL4A3 and downregulation of chemokine (C-X-C motif) ligand 9 (CXCL9), EGF, FGF1, Kinase insert domain receptor (KDR), Placental growth factor (PGF), TIMP3 and VEGFC. CONCLUSION: Breast cancer patients have a different expression profile of circulating angiogenesis biomarkers compared to patients with fibroadenoma. Moreover, mastectomy promotes a transient increase of VEGFA and a shift in the expression patterns of a broad panel of angiogenesis-related circulating gene transcripts. PMID- 23981903 TI - Interleukin-6 -174G/C gene polymorphism affects muscle damage response to acute eccentric resistance exercise in elderly obese women. AB - The IL-6 gene polymorphism has been associated with disease prevalence and different physiological responses to exercise. Eccentric resistance exercise (ERE) is considered a nonpharmacological tool to prevent the chronic degenerative profile associated with aging and obesity. Consequently, the aim of the present study was to investigate the influence of IL-6 -174G/C polymorphism on acute interleukin-6 (IL-6) and creatine kinase (CK) temporal response to ERE in elderly obese women. Ninety women completed seven sets of ten repetitions (eccentric only) of an acute ERE session at 110% of the ten repetitions maximum (10RM). IL-6 genotypes displayed no difference at baseline. ERE induced changes in CK concentration over time occurred only in the GG group, F(2.619, 136.173)=5.199, p=0.003, with CK activity increased from 106.8+/-6.9 U/l pre-intervention to 122.7+/-11.2 U/l at 24 h and 131.9+/-14.4 U/l at 48 h post-exercise. IL-6 concentration in the GG group was lower than the CC/CG group only at 0 h post exercise (3.78+/-0.58 pg/ml versus 6.51+/-1.91 pg/ml, p=0.030). Only the GG genotype group had higher CK activity 24-48 h following ERE and greater CK integral values, while IL-6 activity over 48 h was higher in the CC/CG genotype group. In conclusion, IL-6 genotype affects CK and IL-6 in response to ERE. It is of interest that the ERE protocol induced an elevation in CK, indicating possible muscle damage without exacerbating IL-6 and CK for the GG genotype. PMID- 23981904 TI - Effect of calcium beta-hydroxy-beta-methylbutyrate (CaHMB) with and without resistance training in men and women 65+yrs: a randomized, double-blind pilot trial. AB - BACKGROUND: Evidence suggests CaHMB may impact muscle mass and/or strength in older adults, yet no long-term studies have compared its effectiveness in sedentary and resistance training conditions. The purpose of this study was to evaluate the effects of 24 weeks of CaHMB supplementation and resistance training (3 d wk(-1)) or CaHMB supplementation only in >=65 yr old adults. METHODS: This double-blinded, placebo-controlled, trial occurred in two phases under ad libitum conditions. Phase I consisted of two non-exercise groups: (a) placebo and (b) 3 g CaHMB consumed twice daily. Phase II consisted of two resistance exercise groups: (a) placebo and resistance exercise and (b) 3 g CaHMB consumed twice daily and resistance exercise (RE). Strength and functionality were assessed in both phases with isokinetic leg extension and flexion at 60 degrees .s(-1) and 180 degrees .s(-1) (LE60, LF60, LE180, LF180), hand grip strength (HG) and get-up-and-go (GUG). Dual X-Ray Absorptiometry (DXA) was used to measure arm, leg, and total body lean mass (LM) as well as total fat mass (FM). Muscle Quality was measured for arm (MQ(HG)=HG/arm LM) and Leg (MQ60=LE60/leg LM) (MQ180=LE180/leg LM). RESULTS: At 24 weeks of Phase I, change in LE60 (+8.8%) and MQ180 (+20.8%) for CaHMB was significantly (p<0.05) greater than that for placebo group. Additionally, only CaHMB showed significant (p<0.05) improvements in total LM (2.2%), leg LM (2.1%), and LE180 (+17.3%), though no treatment effect was observed. Phase II demonstrated that RE significantly improved total LM (4.3%), LE60 (22.8%), LE180 (21.4%), HG (9.8%), and GUG (10.2%) with no difference between treatment groups. At week 24, only CaHMB group significantly improved FM (-3.8%) and MQHG (7.3%); however there was no treatment main effect for these variables. CONCLUSION: CaHMB improved strength and MQ without RE. Further, RE is an effective intervention for improving all measures of body composition and functionality. PMID- 23981905 TI - Enhancing retention of an Internet-based cohort study of men who have sex with men (MSM) via text messaging: randomized controlled trial. AB - BACKGROUND: Black and Hispanic men who have sex with men (MSM) are disproportionately affected by HIV in the United States. The Internet is a promising vehicle for delivery of HIV prevention interventions to these men, but retention of MSM of color in longitudinal Internet-based studies has been problematic. Text message follow-up may enhance retention in these studies. OBJECTIVE: To compare retention in a 12-month prospective Internet-based study of HIV-negative MSM randomized to receive bimonthly follow-up surveys either through an Internet browser online or through text messages. METHODS: Internet-using MSM were recruited through banner advertisements on social networking and Internet dating sites. White, black, and Hispanic men who were >=18, completed an online baseline survey, and returned an at-home HIV test kit, which tested HIV negative, were eligible. Men were randomized to receive follow-up surveys every 2 months on the Internet or by text message for 12 months (unblinded). We used time-to-event methods to compare the rate of loss-to-follow-up (defined as non-response to a follow-up survey after multiple systematically-delivered contact attempts) in the 2 follow-up groups, overall and by race/ethnicity. Results are reported as hazard ratios (HR) and 95% confidence intervals (CI) of the rate of loss-to-follow-up for men randomized to text message follow-up compared to online follow-up. RESULTS: Of 1489 eligible and consenting men who started the online baseline survey, 895 (60%) completed the survey and were sent an at-home HIV test kit. Of these, 710 of the 895 (79%) returned the at-home HIV test kit, tested HIV negative, and were followed prospectively. The study cohort comprised 66% white men (470/710), 15% (106/710) black men, and 19% (134/710) Hispanic men. At 12 months, 77% (282/366) of men randomized to online follow-up were retained in the study, compared to 70% (241/344) men randomized to text message follow-up (HR=1.30, 95% CI 0.97-1.73). The rate of loss-to-follow-up was non-significantly higher in the text message arm compared to the online arm for both white (HR=1.43, 95% CI 0.97-1.73) and Hispanic men (HR=1.71, 95% CI 0.91-3.23); however, loss-to-follow-up among black men was non-significantly lower among those who received text message follow-up compared to online follow-up (HR=0.78, 95% CI 0.41-1.50). In the online arm, black men were significantly more likely to be lost to follow-up compared to white men (HR=2.25, 95% CI 1.36-3.71), but this was not the case in the text message arm (HR=1.23, 95% CI 0.70-2.16). CONCLUSIONS: We retained >70% of MSM enrolled in an online study for 12 months; thus, engaging men in online studies for a sufficient time to assess sustained outcomes is possible. Text message follow-up of an online cohort of MSM is feasible, and may result in higher retention among black MSM. PMID- 23981906 TI - Environmental barriers, person-environment fit and mortality among community dwelling very old people. AB - BACKGROUND: Environmental barriers are associated with disability-related outcomes in older people but little is known of the effect of environmental barriers on mortality. The aim of this study was to examine whether objectively measured barriers in the outdoor, entrance and indoor environments are associated with mortality among community-dwelling 80- to 89-year-old single-living people. METHODS: This longitudinal study is based on a sample of 397 people who were single-living in ordinary housing in Sweden. Participants were interviewed during 2002-2003, and 393 were followed up for mortality until May 15, 2012.Environmental barriers and functional limitations were assessed with the Housing Enabler instrument, which is intended for objective assessments of Person Environment (P-E) fit problems in housing and the immediate outdoor environment. Mortality data were gathered from the public national register. Cox regression models were used for the analyses. RESULTS: A total of 264 (67%) participants died during follow-up. Functional limitations increased mortality risk. Among the specific environmental barriers that generate the most P-E fit problems, lack of handrails in stairs at entrances was associated with the highest mortality risk (adjusted RR 1.55, 95% CI 1.14-2.10), whereas the total number of environmental barriers at entrances and outdoors was not associated with mortality. A higher number of environmental barriers indoors showed a slight protective effect against mortality even after adjustment for functional limitations (RR 0.98, 95% CI 0.96-1.00). CONCLUSION: Specific environmental problems may increase mortality risk among very-old single-living people. However, the association may be confounded by individuals' health status which is difficult to fully control for. Further studies are called for. PMID- 23981907 TI - A balanced iterative random forest for gene selection from microarray data. AB - BACKGROUND: The wealth of gene expression values being generated by high throughput microarray technologies leads to complex high dimensional datasets. Moreover, many cohorts have the problem of imbalanced classes where the number of patients belonging to each class is not the same. With this kind of dataset, biologists need to identify a small number of informative genes that can be used as biomarkers for a disease. RESULTS: This paper introduces a Balanced Iterative Random Forest (BIRF) algorithm to select the most relevant genes for a disease from imbalanced high-throughput gene expression microarray data. Balanced iterative random forest is applied on four cancer microarray datasets: a childhood leukaemia dataset, which represents the main target of this paper, collected from The Children's Hospital at Westmead, NCI 60, a Colon dataset and a Lung cancer dataset. The results obtained by BIRF are compared to those of Support Vector Machine-Recursive Feature Elimination (SVM-RFE), Multi-class SVM RFE (MSVM-RFE), Random Forest (RF) and Naive Bayes (NB) classifiers. The results of the BIRF approach outperform these state-of-the-art methods, especially in the case of imbalanced datasets. Experiments on the childhood leukaemia dataset show that a 7% ~ 12% better accuracy is achieved by BIRF over MSVM-RFE with the ability to predict patients in the minor class. The informative biomarkers selected by the BIRF algorithm were validated by repeating training experiments three times to see whether they are globally informative, or just selected by chance. The results show that 64% of the top genes consistently appear in the three lists, and the top 20 genes remain near the top in the other three lists. CONCLUSION: The designed BIRF algorithm is an appropriate choice to select genes from imbalanced high-throughput gene expression microarray data. BIRF outperforms the state-of-the-art methods, especially the ability to handle the class imbalanced data. Moreover, the analysis of the selected genes also provides a way to distinguish between the predictive genes and those that only appear to be predictive. PMID- 23981909 TI - Activating the microscale edge effect in a hierarchical surface for frosting suppression and defrosting promotion. AB - Despite extensive progress, current icephobic materials are limited by the breakdown of their icephobicity in the condensation frosting environment. In particular, the frost formation over the entire surface is inevitable as a result of undesired inter-droplet freezing wave propagation initiated by the sample edges. Moreover, the frost formation directly results in an increased frost adhesion, posing severe challenges for the subsequent defrosting process. Here, we report a hierarchical surface which allows for interdroplet freezing wave propagation suppression and efficient frost removal. The enhanced performances are mainly owing to the activation of the microscale edge effect in the hierarchical surface, which increases the energy barrier for ice bridging as well as engendering the liquid lubrication during the defrosting process. We believe the concept of harnessing the surface morphology to achieve superior performances in two opposite phase transition processes might shed new light on the development of novel materials for various applications. PMID- 23981911 TI - Use and knowledge of Cactaceae in Northeastern Brazil. AB - BACKGROUND: This study aimed to record the use, and knowledge that residents from Sao Francisco community (Paraiba, Brazil) have regarding the Cactaceae. METHODS: Semi-structured interviews were carried out with 118 informants; 50 men and 68 women. The cacti cited in this study were organised into use categories and use values were calculated. Differences in the values applied to species and use categories by men and women were compared via a G test (Williams). RESULTS: The nine species identified were: Cereus jamacaru DC., Melocactus bahiensis (Brtitton & Rose) Luetzelb., Nopalea cochenillifera (L.) Salm-Dyck., Opuntia ficus indica (L.) Mill, Opuntia stricta (Haw.) Haw., Pilosocereus gounellei (F.A.C. Weber) Byles & Rowley, Pilosocereus pachycladus F. Ritter, Tacinga inamoena (K. Schum) N.P. Taylor & Stuppy, Tacinga palmadora (Britton & Rose) N.P. Taylor & Stuppy. In total, 1,129 use citations were recorded, divided into 11 categories. The use value categories with the highest scores were forage (0.42), food (0.30) and construction (building) (0.25). P. pachycladus showed the greatest use value, versatility and number of plant parts used. CONCLUSION: The survey showed that the Cactaceae is extremely important for several uses and categories attributed to different species. Apart from contributing to the ethnobotanical knowledge of the Cactaceae, another important focus of this study was to reinforce the necessity for further studies that record the traditional knowledge about this plant family, which has been lost in younger generations. PMID- 23981910 TI - Brugia pahangi: immunization with early L3 ES alters parasite migration, and reduces microfilaremia and lymphatic lesion formation in gerbils (Meriones unguiculatus). AB - Previous studies have shown that intradermally (ID) injected Brugia pahangi L3 s migrate through various tissues and into the lymphatics of gerbils in a distinct pattern. Excretory/secretory products (ES) produced at the time of invasion of B. pahangi are likely to be important in this early migration phase of the parasite life cycle in their rodent host. Hence, early L3 ES was collected from 24h in vitro cultures of B. pahangi L3 larvae and used in immunization experiments to investigate the effect of immunity to early L3 ES on worm migration, survival and development of B. pahangi. Immunization of gerbils with ES in RIBI adjuvant produced antibodies to numerous ES proteins eliciting a strong humoral response to ES and indirect fluorescent antibody (IFA) assay using anti-ES serum recognized the ES proteins on the surface of B. pahangi L3 larvae. Following ES immunization, gerbils were challenged either ID or intraperitoneally (IP) with 100 L3 s of B. pahangi and euthanized at 3 or 106 days post inoculation (DPI). Immunization with early ES slowed the migration of ID inoculated L3 at 3 DPI and significantly altered the locations of adult worms at 106 DPI. Immunization did not induce protection in any treatment group. However, immunized animals had significantly fewer microfilariae per female worm suggesting the antigens in ES are important in microfilariae development or survival in the host. The number of lymphatic granulomas was also significantly reduced in ES immunized animals. It is important to note that microfilariae serve as a nidus in these granulomas. Our results shows immunization with early Brugia malayi L3 ES alters the worm migration, affects circulating microfilarial numbers and reduces lymphatic granulomas associated with B. pahangi infection in gerbils. PMID- 23981913 TI - Theoretical exploration of Tennessee community pharmacists' perceptions regarding opioid pain reliever abuse communication. AB - BACKGROUND: Community pharmacists are a key intervention point in efforts to prevent and mitigate the impact of prescription drug abuse and misuse (PDA/M); yet pharmacists' perceptions regarding PDA/M have been explored only briefly in the literature. OBJECTIVES: 1) To explore Tennessee community pharmacists' perceptions regarding opioid pain reliever (OPR) prescribing, dispensing and abuse; 2) to explore community pharmacists' self-efficacy beliefs regarding PDA/M specific communication; and 3) to evaluate perceived barriers to engaging patients in PDA/M-specific communication. METHODS: A 55-item survey instrument was developed using the Theory of Planned Behavior (TpB) as a theoretical framework. Questionnaires were mailed to a stratified sample of 2000 licensed Tennessee pharmacists using the Tailored Design Method of survey administration during October and November, 2012. RESULTS: A response rate of 40% was obtained. A majority of pharmacists (87.5%) perceived OPR abuse to be a problem in their practice settings. On average, a little more than half (53%) of prescriptions issued for OPRs were estimated to be for patients with one or more legitimate medical reasons justifying the medication(s). A small fraction of pharmacists (13%) reported having addiction treatment facility information in their practice settings, and only a small percent reported strong self-efficacy beliefs regarding PDA/M patient communication. Job-related time constraints were perceived as the primary barrier to engaging in PDA/M communication. CONCLUSIONS: Community pharmacists in Tennessee are aware of PDA/M by patients receiving opioid prescriptions and value their role in communicating with these patients but indicate their ability to do so effectively is hindered by a lack of confidence, training, and time. Further research to identify and test methods for facilitating PDA/M communication by pharmacists is indicated. PMID- 23981912 TI - How youth-friendly are pharmacies in New Zealand? Surveying aspects of accessibility and the pharmacy environment using a youth participatory approach. AB - BACKGROUND: The international youth population has significant unmet health needs, and there have been many calls to increase youth health care access. Community pharmacies may be able to help address these needs, but very little research has investigated this area and it is not known whether the current community pharmacy setting is acceptable or appropriate for youth. OBJECTIVES: 1) To obtain information on physical factors which could affect young people's use of community pharmacies in New Zealand, including accessibility, opening times and the physical youth-friendliness of the pharmacy environment. 2) To involve and utilize young people in the research process, in order to understand their needs and interpretation of survey data. METHODS: This study applied a cross sectional survey design, informed by a sequential youth participatory approach. A questionnaire was developed in consultation with a youth advisory group (YAG). Questionnaires distributed to pharmacists at 500 randomly selected pharmacies nationwide between May and September 2011 collected information on whether the pharmacy met selected youth-friendly criteria. These included physical aspects of youth-friendliness, such as opening times and the pharmacy environment. The YAG also provided a youth perspective in the interpretation of the results. RESULTS: Three mail shots achieved a response rate of 50.5%. Most respondents reported the pharmacy to be accessible by public transport and many had extended opening hours. Although most pharmacies met some youth-friendly criteria with regards to the pharmacy environment (e.g. having a private consultation area), more specific criteria (such as displaying youth health information) were usually not met. Interpretive feedback from the YAG highlighted areas for improvement. CONCLUSIONS: Pharmacies show potential as youth-friendly health care access points and most already meet some youth-friendly criteria. Areas identified for improvement will require a greater youth focus from the profession, and should be undertaken in consultation with young people. We recommend the use of youth participation approaches in future pharmacy practice research into youth health services. PMID- 23981915 TI - Quality Assurance for Sterile Products. PMID- 23981916 TI - Sterile compounding with barrier isolation technology. PMID- 23981914 TI - Modeling the effects of light and temperature on algae growth: state of the art and critical assessment for productivity prediction during outdoor cultivation. AB - The ability to model algal productivity under transient conditions of light intensity and temperature is critical for assessing the profitability and sustainability of full-scale algae cultivation outdoors. However, a review of over 40 modeling approaches reveals that most of the models hitherto described in the literature have not been validated under conditions relevant to outdoor cultivation. With respect to light intensity, we therefore categorized and assessed these models based on their theoretical ability to account for the light gradients and short light cycles experienced in well-mixed dense outdoor cultures. Type I models were defined as models predicting the rate of photosynthesis of the entire culture as a function of the incident or average light intensity reaching the culture. Type II models were defined as models computing productivity as the sum of local productivities within the cultivation broth (based on the light intensity locally experienced by individual cells) without consideration of short light cycles. Type III models were then defined as models considering the impacts of both light gradients and short light cycles. Whereas Type I models are easy to implement, they are theoretically not applicable to outdoor systems outside the range of experimental conditions used for their development. By contrast, Type III models offer significant refinement but the complexity of the inputs needed currently restricts their practical application. We therefore propose that Type II models currently offer the best compromise between accuracy and practicability for full scale engineering application. With respect to temperature, we defined as "coupled" and "uncoupled" models the approaches which account and do not account for the potential interdependence of light and temperature on the rate of photosynthesis, respectively. Due to the high number of coefficients of coupled models and the associated risk of overfitting, the recommended approach is uncoupled models. Most of models do not include the modeling of endogenous respiration and the modeling of light and temperature acclimation in spite of their potential effect on productivity. PMID- 23981917 TI - Bacterial endotoxins and pyrogens. PMID- 23981918 TI - Antineoplastic agents. PMID- 23981919 TI - Evaluating transdermal medication forms for veterinary patients, part 3: methimazole. PMID- 23981920 TI - Formulations for success,part 2. PMID- 23981921 TI - Basics of compounding: suspensions. PMID- 23981922 TI - Incompatibilities of lansoprazole injection with other drugs during simulated y site coadministration. AB - The physical compatibility of lansoprazole injection with selected other drugs during simulated Y-site coadministration was evaluated by means of visual observation, turbidity measurement, and particle content assessment. Five milliliter samples of lansoprazole 0.55 mg/mL in 0.9% sodium chloride injection were conbined with 5 mL of 112 other drugs including antineoplastics, analgesics, antiinfectives, and supportive-care drugs undiluted or diluted in 0.9% sodium chloride injection or 5 % dextrose injection for amphotericin B. Visual examinations were performed with the unaided eye in fluorescent light and by means of a Tyndall beam (a high-intesity, monodirectional light beam) to enhance the visualization of small particles and low-level trubidity. The turbidity of each sample was measured as well. Particle sizing and counting were performed on selected samples. Evaluation of the samples was performed initially and at 1 and 4 hours after preparation. Of the drugs tested, 92 were incompatible with lansoprazole 0.55 mg/mL in 0.9% sodium chloride injection during the 4-hour observation period. Gross precipitation or color changes visible in normal diffuse room light with the unaided eye occurred with 45 drugs. Phenomena not visible with the unaided eye, such as microprecipitation and /or increases in measured turbidity, occurred with 47 drugs. Only 20 drugs were found to be compatible for at least 4 hours. The measured turbidity of the lansoprazole control solutions and the compatible test samples, remained essentially unchanged throughout the study. In addition, the compatible samples exhibited no color change or substantial change in particle size and content throughout the observation period. In conbination with lansoprazole, only 20 drugs were considered to be physically compatible. Ninety-two drugs exhibited frank precipitation, microparticulate formation, color changes, or unacceptable increases of measured turbidity within 4 hours and should not be simultaneously coadministered with lansoprazole. PMID- 23981923 TI - A New High-performance Liquid Chromatographic Method for Fludarabine and Fludarabine Phosphate Compounded in Liposomes. AB - A simple and reproducible high-pressure liquid chromatography (HPLC) method was developed to measure simultaneously the concentrations of both fludarabine and liposome-compounded fludarabine in plasma. In this method, hypoxanthine 9-B-D arabinofuranoside was used as an internal standard. Fludarabine, fludarabine phosphate, and hypoxanthine 9-B-D arabinofuranoside were extracted from plasma and were separated by means of isocratic elution from a C18 reversed-phase column. The mobile phase consisted of 5% (v/v) methanol in 10mM ammonium phosphate solution. The pH of the mobile phase was adjusted to 2.2 with 85% phosphoric acid. The detection wavelength was 260 nm, and the retention times for fludarabine, fludarabine phosphate, and hypoxanthine 9-B-D arabinofuranoside were 48, 27, and 12 minutes, respectively. The recovery efficiencies varied depending on the amount spiked; however, they were 89% and 58% for 10 micrograms/mL of fludarabine and fludarabine phosphate, respectively. The limits of quantification for fludarabine and fludarabine phosphate were 0.03 micrograms/mL and 0.5 micrograms/mL, respectively. The assay was reproducible, and the within-day coefficients of variation (n=4) were less than 6.9% and less than 8.7% for fludarabine and fludarabine phosphate, respectively. The between day variabilities (n=4) were less than 6.3% and less then 6.4% for fludarabine and fludarabine phophate, respecitvley. The assays were linear within the range of 0.025 to 10 micrograms/mL (r squared = 0.999) for fludarabine and 0.5 to 10 micrograms/mL (r squared = 0.999) for fludarabine phosphate. PMID- 23981924 TI - Compatibility and stability of potassium chloride and magnesium sulfate in 0.9% sodium chloride injection and 5% dextrose injeciton solutions. AB - The compatibility and stability of 80 mmol/L potassium chloride and 16 mmol/L magnesium sulfate in 0.9% sodium chloride injection and in 5% dextrose injection solutions at 22 deg C have been studied by means of a Beckman Clinical Chemistry Analyzer Synchron CX5 Delta. The infusions were stable for 24 hours at 22 deg C. The results from both diluents showed an average of +/-5% fluctuations in concentration. None of the samples appeared to form visible precipitation or to change in color or clarity. PMID- 23981925 TI - Immunogenicity of anti-tumour necrosis factor drugs in rheumatic diseases. AB - Despite the significant advantages in clinical practice associated with TNF inhibitors, a loss of response over time is sometimes observed, in some cases possibly due to immunogenicity, i.e. the development of antibodies direct against the drug. This review evaluates the immunogenicity of different anti-TNF agents, and discusses its effects on efficacy and safety. Available evidence indicates that all anti-TNF drugs may induce an immune response. However, the variation in the occurrence of anti-drug antibodies, as well as the variation in the impact of antibodies on the efficacy and safety, can be explained by drug conformation itself, use of concomitant immunosuppressants and differences in dosing regimen and route of administration. The association between the development of anti-drug antibodies and low drug serum concentrations is clinically relevant since it is likely related to low response. Strict monitoring of neutralising antibodies might be useful for tailoring therapeutic strategy. There is no evidence of cross reactivity among different drugs: immunogenicity (the development of specific anti-drug antibodies to one TNF inhibitor) does not seem to affect the effectiveness of another anti-TNF agents; therefore, switching to another drug of the same class might be effective in patients who have developed anti-drug antibodies to a TNF inhibitor. PMID- 23981927 TI - Identification of forty-five gene-derived polymorphic microsatellite loci for the sea cucumber, Apostichopus japonicus. PMID- 23981926 TI - Does Navigation Improve Accuracy of Placement of Pedicle Screws in Single-level Lumbar Degenerative Spondylolisthesis?: A Comparison Between Free-hand and Three dimensional O-Arm Navigation Techniques. AB - STUDY DESIGN: This was a prospective, nonrandomized study. OBJECTIVES: To assess the accuracy of O-arm navigation-based pedicle screw insertion in lumbar degenerative spondylolisthesis and to compare it with free-hand pedicle screw insertion technique in matched population. SUMMARY OF BACKGROUND DATA: O-arm navigation is latest in navigation technology that can provide real-time intraoperative images in 3 dimensions while placing the pedicle screws to improve intraoperative pedicle screw accuracy. Degenerative lumbar spondylolisthesis is a locally unstable pathology and placement of pedicle screws can cause increased rotation and translation of the vertebral body. However, is this motion detected by the tracker placed across the unstable segment, is a matter of debate. Inability to detect these positional changes can lead to pedicle perforation while inserting screws using navigation. No study has evaluated the role of O-arm navigation in this patient population. MATERIALS AND METHODS: The study population was divided into 2 groups with 19 patients each, one comprising patients who underwent O-arm navigation-based pedicle screw insertion (group 1) and the other comprising patients who underwent free-hand pedicle screw insertion technique (group 2). A total of 152 pedicle screws were implanted in 38 patients for 1-level instrumented fusion for degenerative lumbar spondylolisthesis. Intraoperative 3-dimensional computed tomography scans using the O-arm were obtained for all patients after insertion of pedicle screws. The images were reviewed intraoperatively and postoperatively for the analysis of pedicle breaches. Assessments in either of the group included (i) accuracy of placement of screws; (ii) the rate and direction of perforation; and (iii) the number of segments the perforated screw was away from the navigation tracker. RESULTS: Mean age of patients in group 1 (O-arm navigation-assisted) was 60 years (SD 11.25; range, 37-73 y), whereas in group 2 (free-hand pedicle screw) was 62 years (SD 18.07; range, 36-90 y). Overall anatomic perforation rate was 12.5% (19/152). Individually, group 1 had 14.47% (11/76) of perforations in comparison with 10.53% (8/76) observed in group 2. The difference was not statistically significant. The lateral margin was the most common site of perforation in both group 1 (64%, 7/11) and group 2 (62.5%, 5/8). Functional perforation rate for the series was 3.3% (5/152), with group 1 having 2.63% (2/76) and group 2 having 3.95% (3/76). The rate of perforation (PR) was significantly higher statistically when the tracker was placed 3 or more [PR 37.5% (6/16)] spinal segments away from instrumented segment compared with when it was placed 1 (0%) or 2 [PR 13.89% (5/36)] spinal segments away. Overall, 11 screws (11/152, 7.24%) had grade 2 perforations and had to be revised. No neurological complications were observed in the series. CONCLUSIONS: O-arm navigation does not provide any significant advantage over conventional free-hand pedicle screw insertion technique in patients with single-level degenerative spondylolisthesis. The accuracy is dependent on the distance of the tracker from the level of instrumentation. Lateral perforations are more common because of instability at the instrumented level leading to translation and rotation of the vertebral body while placing pedicle screws leading to preferential lateral trajectory. These lateral perforations could not be prevented by using navigation. However, no significant complications were noted in either technique. PMID- 23981928 TI - Rapid detection of RB1 recurrent mutations in retinoblastoma by ARMS-PCR. PMID- 23981929 TI - Evaluation of genetic diversity of Portuguese Pinus sylvestris L. populations based on molecular data and inferences about the future use of this germplasm. PMID- 23981930 TI - Suiformes conservation: a study case of strategies for DNA utilization. PMID- 23981931 TI - Two novel SNPs in the coding region of bovine VDR gene and their associations with growth traits. PMID- 23981932 TI - Isolation and characterization of twenty-one polymorphic microsatellite loci from Schizothorax o'connori and cross-species amplification. PMID- 23981933 TI - Eleven novel polymorphic microsatellite loci in the ornate spiny lobster Panulirus ornatus (Decapoda: Palinuridae). PMID- 23981934 TI - Development of twenty microsatellite loci from the Tibetan ground tit (Parus humilis). PMID- 23981935 TI - Isolation and characterization of ten microsatellite loci from Korean Astragalus mongholicus (Fabaceae). PMID- 23981936 TI - Isolation and characterization of twelve new polymorphic microsatellite markers in the miiuy croaker (Miichthys miiuy) genome. PMID- 23981937 TI - Polymorphic microsatellite markers in Taxus chinensis var. mairei (Taxaceae). PMID- 23981939 TI - N-substituted 8-aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes as sigma receptor ligands with potential neuroprotective effects. AB - Several libraries of similarly N-substituted 8 aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (9), N-methyl-8 aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes (14), and N-methyl-11 aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecan-8-ones (13) were synthesised and screened against a panel of CNS targets in order to develop structure affinity relationships for cage-modified trishomocubane sigma receptor ligands based on the N-substituted 4 azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (8) scaffold. In general, compared to the corresponding 4 azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols, compounds of type 9 were potent sigma receptor ligands with low levels of subtype selectivity, while the corresponding N-methyl-8 aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes showed reduced affinity but greater selectivity for sigma2 receptors. The N-methyl-11 aminopentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecan-8-ones demonstrated the poorest sigma receptor affinities, suggesting that 4 azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ols interact with sigma receptors in the bridged hemiaminal form rather than as the non transannular, aminoketone tautomers. Several compounds of type 8, 9, and 14 were assessed for their ability to inhibit nitric oxide release in vitro, and demonstrated comparable or greater efficacy than 4-phenyl-1-(4 phenylbutyl)piperidine (PPBP), an established neuroprotective sigma ligand with NOS inhibitory activity. PMID- 23981940 TI - NMR study into the mechanism of recognition of the degree of polymerization by oligo/polysialic acid antibodies. AB - Oligo/polysialic acids consisting of consecutive alpha(2,8)-linkages on gangliosides and glycoproteins play a role in cell adhesion and differentiation events in a manner that is dependent on the degree of polymerization (DP). Anti oligo/polysialic acid antibodies often have DP-dependent antigenic specificity, and such unique antibodies are often used in biological studies for the detection and differentiation of oligo/polysialic acids. However, molecular mechanisms remain unclear. We here use NMR techniques to analyze the binding epitopes of the anti-oligo/polysialic acid monoclonal antibodies (mAb) A2B5 and 12E3. The mAb A2B5, which has a preference for trisialic acid, recognizes sialic acid residues at the non-reducing terminus and those in nascent units. On the other hand, mAb 12E3, which prefers oligo/polysialic acids of more than six sugar units, recognizes inner sialic acid residues. In both structural complexes, the interresidue transferred NOE correlations are significantly different from those arising from analogs of the free states, indicating that the bound and free sugar conformations are distinct. The ability of the two mAbs to distinguish the chain lengths comes from different binding epitopes and possibly from the conformational differences in the oligo/polysialic acids. Information on the recognition modes is needed for the structural design of immunoreactive antigens for the development of high-affinity anti-polysialic acid antibodies and of related vaccines against pathogenic, polysialic acid-coated bacteria. PMID- 23981941 TI - [The intestinal microbiota and human disease]. AB - Advances in sequencing technology and the development of metagenomics have opened up new ways to investigate the microorganisms inhabiting the human gut. The intestinal microbiota confer protection against pathogens, contribute to the maturation of the immune system, and regulate host metabolism. The composition of gut microbiota in early life is influenced by mode of birth, diet, and antibiotics. Decreased biodiversity and alterations in the composition of the intestinal microbiota have been observed in many diseases including obesity, neonatal necrotizing enterocolitis, inflammatory bowel disease, and recurrent Clostridium difficile infection. Therapeutic options for the diseases linked to imbalance in the microbiota include modifying the gut microbiota through diet, probiotics, and fecal transplants. PMID- 23981942 TI - [Endoscopic characteristics of upper gastrointestinal mesenchymal tumors originating from muscularis mucosa or muscularis propria]. AB - BACKGROUND/AIMS: Subepithelial tumors are occasionally found during upper gastrointestinal endoscopy. The purpose of this study was to evaluate endoscopic characteristics of mesenchymal tumors originating from muscularis mucosa or muscularis propria. METHODS: A total of 307 mesenchymal tumors of the upper gastrointestinal tract were diagnosed between March 2006 and February 2012 at Yeouido St. Mary's Hospital (Seoul, Korea). Data on endoscopic and endoscopic ultrasonographic findings were collected and analyzed by retrospectively reviewing the medical records. RESULTS: The mean size of the mesenchymal tumors originating from muscularis mucosa was significantly smaller than those originating from muscularis propria (10.5+/-6.9 mm vs. 14.3+/-13.9 mm, p=0.035). The most common locations of the mesenchymal tumors originating from muscularis mucosa and muscularis propria were esophagus (69.1%) and body of the stomach (43.3%), respectively (p<0.001). Rolling sign was more commonly observed with mesenchymal tumors originating from muscularis mucosa (80.4%, p=0.001), and cushion sign was more frequently absent with those originating from muscularis propria (72.4%, p<0.001). Internal echo was homogenous in 89.7% and 81.9% of mesenchymal tumors originating from muscularis mucosa and muscularis propria, respectively (p=0.092). CONCLUSIONS: The size, location, and movability of mesenchymal tumors originating from muscularis mucosa were different from those of mesenchymal tumor originating from muscularis propria.propria. PMID- 23981943 TI - [A prospective study of factors influencing on the clinical characteristics of colonic diverticulosis]. AB - BACKGROUND/AIMS: The prevalence of colonic diverticulosis in Korea is increasing in conjunction with the adoption of western dietary pattern, extension of lifespan, and advances in diagnostic modalities. The clinical characteristics of colonic diverticulosis seem to be gradually becoming similar to those of Western societies. Therefore, factors associated with the clinical characteristics of colonic diverticulosis in Korea were investigated. METHODS: The data of 200 patients diagnosed with colonic diverticulosis using colonoscopy between May 2010 and April 2012 at Inje University Seoul Paik Hospital (Seoul, Korea) were prospectively collected. Clinical parameters acquired through a questionnaire include age, body mass index, waist circumference, exercise, diet, smoking, drinking habits, etc. Correlation between these factors and the clinical features of diverticulosis were analyzed. RESULTS: Mean age of the patients was 54.9+/ 11.9 (range 17-79) years and male to female ratio was 2.2:1. Most diverticula were located on the right side of the colon (83%) and the mean number of diverticulum was 4.07+/-3.9. Factor associated with the location of diverticulum on the left side was age (p=0.001). There was a positive correlation between the waist circumference and the number of diverticulum (partial correlation coefficient r'=0.143, p=0.047). Diverticulitis occurred more frequently in younger patients than in older patients (p=0.002). CONCLUSIONS: Colonic diverticulosis in older patients is found more frequently on the left colon, and the number of diverticulosis is associated with central obesity. PMID- 23981944 TI - [Prevalence and risk factors of colorectal adenoma in 14,932 koreans undergoing screening colonoscopy]. AB - BACKGROUND/AIMS: Current international guidelines recommend colorectal cancer screening for average-risk people over 50 years of age. Accordingly, we aimed to estimate the prevalence of colorectal neoplasms in all age groups and evaluate associated risk factors. METHODS: Data of 14,932 subjects who underwent colonoscopy from July 2006 to January 2012 at Health Promotion Center, Gangnam Severance Hospital (Seoul, Korea) as part of a health check-up were reviewed retrospectively. RESULTS: The overall prevalence of colorectal neoplasms and adenoma were 34.6% and 25.3%, respectively. Colorectal adenoma was found in 3.2%, 13.0%, 21.7%, 33.8%, 44.0%, 50.5%, and 54.2% of subjects under 30 years, 30-39 years, 40-49 years, 50-59 years, 60-69 years, 70-79 years, and over 80 years of age (trend p<0.0001). Independent predictors of colorectal adenoma included male gender (OR 2.38, 95% CI 2.084-2.718), positive occult blood (2.266, 1.761-2.917), positive serology of Helicobacter pylori (1.253, 1.114-1.409) and hypertriglyceremia (1.267, 1.065-1.508). Compared to the 30-39 years of age reference group, the ORs for each age group were 0.195 (under 30 years), 1.634 (40-49 years), 2.954 (50-59 years), 5.159 (60-69 years), 5.640 (70-79 years), 11.020 (over 80 years), while the 95% CIs were 0.071-0.536 (under 30 years), 1.340-1.992 (40-49 years), 2.421-3.604 (50-59 years), 4.109-6.476 (60-69 years), 3.822-8.322 (70-79 years), and 2.809-42.234 (over 80 years). CONCLUSIONS: Colorectal adenoma prevalence increased proportionally with age. Only subjects under the age of 30 years had a definitely lower prevalence of colorectal adenoma. Male gender, positive occult blood, positive serology of H. pylori, and hypertriglyceremia were associated risk factors of colorectal adenoma. PMID- 23981945 TI - [How should azathioprine be dosed in Crohn's disease? a novel strategy of maximum dose-titration based on the lower limit of leukocyte count and tolerability]. AB - BACKGROUND/AIMS: Although general guidelines have suggested weight-based dosing of azathioprine (AZA, 2.5 mg/kg/day) for Crohn's disease (CD), a substantial number of patients develop bone marrow suppression. The aim of this study was to evaluate the maximum dose of AZA not based on weight but titrated according to the lower limit of leukocyte count for maintaining remission in patients with CD. METHODS: Among a total of seventy-eight patients with CD, who had been followed up at Kosin University Gospel Hospital (Busan, Korea) from 2010 to 2011, those treated with the maximum dose of AZA meeting both drug-tolerability and leukocytes count of more than 4,000/mm3 for steroid-free maintaining remission were enrolled. The titrated maximum AZA dose and its relationship with weight were evaluated. RESULTS: A total of 42 patients (male, 32 patients; mean age, 31 years) were enrolled. The maximum dose of AZA was 49.1 mg/day. The dose per weight was 0.87 mg/kg/day and negatively correlated with body weight (g=-0.51, p=0.01) and BMI (g=-0.33, p=0.034). AZA dose per weight in the below 40 years old group was significantly higher than that in the above 40 years old group (p=0.039). CONCLUSIONS: Dose decision of AZA based only on weight could put the patients to inappropriately low or high dose resulting in need of additional therapy or serious side effect, respectively. Therefore, the maximum dose titration based on the lower limit of leukocyte count and tolerability is a novel and a valuable strategy in deciding the dose of thiopurines. PMID- 23981946 TI - Primary mucosa-associated lymphoid tissue lymphoma of the esophagus, manifesting as a submucosal tumor. AB - We report a case of primary mucosa-associated lymphoid tissue (MALT) lymphoma in the esophagus that manifested as a large submucosal tumor (SMT). Primary esophageal lymphoma is very rare, occurring in less than 1% of all patients with gastrointestinal lymphoma. Only a few cases of MALT lymphoma in the esophagus have been reported in the English literature. A 53-year-old man was referred to Dongguk University Ilsan Hospital (Goyang, Korea) in July 2012 for further evaluation and treatment of an esophageal SMT. Endoscopy showed a cylindrically elongated submucosal mass with normal overlying mucosa in the mid esophagus, 25 30 cm from the incisor teeth. He underwent surgery to confirm the diagnosis. Pathologic findings showed diffuse small atypical lymphoid cells which were stained with Bcl-2, CD20, but not with CD3, CD5, CD23, Bcl-6, or cyclin D1. These cells showed a positive monoclonal band for immunoglobulin heavy chain gene rearrangement. Based on the pathological, immunohistochemical, and molecular biological features, the esophageal mass was diagnosed as extranodal marginal zone B-cell lymphoma of the MALT type. PMID- 23981947 TI - Submucosal tumor-like early-stage mucinous gastric carcinoma: a case study. AB - Mucinous gastric carcinoma (MGC) is an unusual histologic subtype, and early detection of MGC is very rare. Early-stage MGC appears as an elevated lesion resembling a submucosal tumor (SMT) due to abundant mucin pools in the submucosa or mucosa. We report a rare case of SMT-like early-stage MGC. Tumor type was predicted preoperatively based on characteristic endoscopic findings, in which an SMT-like mass was observed at the gastric fundus. The tumor was covered by nearly normal mucosa, but with an opening allowing for the passage of copious mucus discharge. A total gastrectomy with Roux-en-Y esophagojejunostomy was subsequently performed. Histopathology of the tumor revealed early-stage (lamina propria) mucinous adenocarcinoma. PMID- 23981948 TI - [A case of spindle cell carcinoma of the stomach presenting with hematochezia and weight loss due to fistulous tract formation with colon]. AB - Spindle cell carcinoma (SpCC) is a rare tumor consisting of spindle cells which express cytokeratin. Despite recent advances in immunohistochemical and genetic studies, precise histogenesis of SpCC is still controversial and this tumor had been referred to with a wide range of names (in the past): carcinosarcoma, pseudosarcoma, sarcomatoid carcinoma, pseudosarcomatous carcinoma, and collision tumor. Recently, the authors experienced an extremely rare case of SpCC arising from the stomach. A 64-year-old male presented with unintended weight loss and hematochezia. Endoscopic examination revealed a fistulous tract between the stomach and the transverse colon which was made by direct invasion of SpCC of the stomach to the colon. Histologically, the tumor was positive for both vimentin and cytokeratin but negative for CD117, CD34, actin, and desmin. Herein, we report a case of SpCC arising from the stomach that formed a fistulous tract with the colon which was diagnosed during evaluation of hematochezia and weight loss. PMID- 23981949 TI - Transformation of Castleman's disease into follicular dendritic cell sarcoma, presenting as an asymptomatic intra-abdominal mass. AB - Follicular dendritic cell (FDC) sarcoma is an extremely rare malignant neoplasm arising from FDCs. The exact origin of FDCs remains unclear; both a hematopoietic lineage origin and a stromal cell derivation have been proposed. Proliferation of FDCs can lead to benign reactive lesions or generate neoplastic conditions. The lesions are most commonly found in lymph nodes and usually involve the head and neck area. Castleman's disease is a rare non-neoplasitic lymphoproliferative disorder. Rare cases of hyaline-vascular Castleman's disease have been associated with FDC sarcoma, but a clonal relationship has not been convincingly demonstrated. A pathway toward tumor evolution, beginning with hyperplasia and dysplasia of FDCs, has been proposed. Despite this known association between Castleman's disease and FDC sarcoma, there have only been few reported cases of sarcoma arising as a complication of pre-existing Castleman's disease, especially in abdominal lesions. We describe here a 51-year-old female with an FDC sarcoma arising from unicentric, hyaline-vascular type Castleman's disease in an intra abdominal mass. Pathologically, the lesion showed a series of changes during the process of transformation from Castleman's disease to FDC sarcoma. (Korean J Gastroenterol 2013;62:131-134). PMID- 23981950 TI - Fecal estrogen, progestagen and glucocorticoid metabolites during the estrous cycle and pregnancy in the giant anteater (Myrmecophaga tridactyla): evidence for delayed implantation. AB - BACKGROUND: Declining numbers of wild giant anteaters highlight the importance of sustainable captive populations. Unfortunately, captive reproductive management is limited by the lack of external physical indicators of female reproductive status and the aggressive behavior of males. We examined the endocrinology of the estrous cycle and pregnancy, and whether delayed implantation is a gestational strategy for giant anteaters as described for other xenarthrans. METHODS: Feces were collected from seven captive females 3-5 times weekly and mating was recorded. Concentrations of estrogen (estrone-glucuronide, E1, and estradiol 17beta, E2), progestagen (20-oxo-progestagens, P4), and glucocorticoid (GC) metabolites were examined in fecal extracts by enzyme immunoassay. RESULTS: Estrous cycles for nulliparous females (6 cycles, n = 2) compared to the multiparous female (6 cycles, n = 1) were shorter (47.3 +/- 4.3 days versus 62.5 +/- 2.6 days) with relatively lower luteal phase concentrations of P4 (49.4 +/- 2.9 ng/g versus 136.8 +/- 1.8 ng/g). The four remaining females had unclear ovarian activity: two females exhibited apparent luteal activity but unclear fluctuations in estrogens, while the other two females had parallel fecal P4 and estrogens concentrations. Pregnancy ranged 171-183 days with females returning to estrus post-partum as early as 60 days (n = 3, 1.8-4 years of age at mating). Delayed implantation was indicated by a biphasic elevation in fecal P4 metabolites: the initial 4-fold increase occurred for 81-105 days and was followed by a 26-fold secondary rise in P4 metabolites lasting 66-94 days prior to parturition. Fecal GC was correlated with fecal estrogens and greatest during estrus, late pregnancy, and six days prior to parturition (estrous cycle GC, 14.4 62.8 ng/g; pregnancy GC, 13.6-232.7 ng/g). CONCLUSIONS: Estrous cycles of giant anteaters occurred year-round, but were shorter and more intermittent in younger nulliparous animals compared to a multiparous female. A pronounced elevation in fecal P4, estrogen, and GC occurred during late gestation after an initial post mating delay providing evidence for delayed implantation. Adrenocorticoid activity indicated impending parturition. Differences in estrous cycle characteristics with age and the protracted but variable gestation length must be considered to improve reproductive success and neonatal survival in giant anteaters. PMID- 23981951 TI - Peer clustering of exercise and eating behaviours among young adults in Sweden: a cross-sectional study of egocentric network data. AB - BACKGROUND: Research suggests that the growing prevalence of obesity may be related to the influence of the health behaviours of peers. We look at clustering of exercise and eating behaviours amongst a previously unstudied group, young adults in Sweden. Previous research has mainly been conducted in the United States and Britain, countries that have relatively high rates of obesity. METHODS: Using ego-alter dyads from the egocentric network data as the unit of analysis, we conduct logistic regressions to investigate the association between ego and alter exercise and eating behaviours. RESULTS: Respondents have a significantly greater probability of engaging in regular exercise and eating healthily if a nominated peer also does so. Furthermore, the degree to which this behavior is shared is modulated by the strength of the relationship between the two individuals, with a greater probability of engaging in these behaviours observed when the relationship with the nominated peer is strong relative to when the relationship is weak. However, we find that ego-alter homogeneity in terms of gender and migration status was not associated with a significantly greater probability of behaving in a similar manner to a nominated peer. Furthermore, the status of the nominated peer as a relative or not did not impact the probability that the ego would engage in similar health behaviours to that alter. CONCLUSIONS: We observe strong associations between ego and alter health behaviours for young adults, consistent with previous research. Although we cannot draw causal inferences, these results suggest that the health behaviours of an individual's peers may play a role in shaping their own health behaviours. PMID- 23981953 TI - Swallow preservation exercises during chemoradiation therapy maintains swallow function. AB - OBJECTIVE: To evaluate a swallow preservation protocol (SPP) in which patients received swallow therapy before, during, and after radiation treatment and its efficacy in maintaining swallowing function in head and neck cancer patients. DESIGN: Case series with chart review. SETTING: Tertiary care academic medical center. SUBJECTS AND METHODS: Eighty-five patients who received radiation (RT) or chemoradiation (CRT) participated in the SPP from 2007 to 2012. Subjects were divided into 2 groups: compliant and noncompliant with SPP. At each SPP visit, the diet of each patient was recorded as regular (chewable), puree, liquid, or gastrostomy tube (G-tube) dependent, along with their compliance with the swallow exercises. Patients were stratified by age, gender, tumor stage, type of treatment, radiation dose, diet change, dysguesia, odynophagia, pain, and stenosis. Statistical analysis was performed comparing the 2 compliance groups in regards to swallowing-related outcomes at 1 month after completion of therapy. RESULTS: Fifty-seven patients were compliant and 28 were noncompliant with SPP during treatment. The compliant group had a higher percentage of patients tolerating a regular diet (54.4% vs 21.4%, P = .008), a lower G-tube dependence (22.8% vs 53.6%, P = .008), and a higher rate of maintaining or improving their diet (54.4% vs 25.0%, P = .025) compared to noncompliant patients. CONCLUSION: A swallow preservation protocol appears to help maintain or improve swallow function in head and neck cancer patients undergoing RT or CRT. Patients who are able to comply with swallow exercises are less likely to worsen their diet, receive a G-tube, or develop stenosis. PMID- 23981952 TI - Long-term biopersistence of tangled oxidized carbon nanotubes inside and outside macrophages in rat subcutaneous tissue. AB - Because of their mechanical strength, chemical stability, and low molecular weight, carbon nanotubes (CNTs) are attractive biological implant materials. Biomaterials are typically implanted into subcutaneous tissue or bone; however, the long-term biopersistence of CNTs in these tissues is unknown. Here, tangled oxidized multi-walled CNTs (t-ox-MWCNTs) were implanted into rat subcutaneous tissues and structural changes in the t-ox-MWCNTs located inside and outside of macrophages were studied for 2 years post-implantation. The majority of the large agglomerates were present in the intercellular space, maintained a layered structure, and did not undergo degradation. By contrast, small agglomerates were found inside macrophages, where they were gradually degraded in lysosomes. None of the rats displayed symptoms of cancer or severe inflammatory reactions such as necrosis. These results indicate that t-ox-MWCNTs have high biopersistence and do not evoke adverse events in rat subcutaneous tissue in vivo, demonstrating their potential utility as implantable biomaterials. PMID- 23981954 TI - Sitting time and cardiometabolic risk in US adults: associations by sex, race, socioeconomic status and activity level. AB - BACKGROUND: Sitting time is associated with adverse health outcomes including chronic disease and premature mortality. However, it is not known if the association of sitting time with cardiometabolic risk factors varies across sociodemographic or health factors. METHODS: The sample included 4560 adults (>=20 years) who participated in the cross-sectional 2007-2010 US National Health and Nutrition Examination Survey. Participants self-reported typical daily sitting time. Weight, height, blood pressure, and fasting triglycerides, high density lipoprotein-cholesterol (HDL-C), glucose and insulin were measured. Homeostatic model assessment-insulin resistance (HOMA-IR) and beta cell function (HOMA-%B) were calculated. A subsample of 3727 participants underwent an oral glucose tolerance test to obtain 2 h postload glucose levels. Population-weighted linear regression analysis was used to examine the association between sitting time and each cardiometabolic risk factor, stratified by sex, race, socioeconomic status and activity level. Analyses were controlled for demographics, socioeconomic status, survey cycle, personal and family medical history, diet and physical activity. RESULTS: Sitting time was significantly associated with adverse levels of waist circumference, body mass index, triglycerides, HDL-C, insulin, HOMA-IR, HOMA-%B and 2 h postload glucose, but not with blood pressure or glucose level. In stratified analyses, sitting time was most consistently related to cardiometabolic risk factors among low and middle socioeconomic groups and for those who reported no weekly physical activity, but there were few differences between sex or race groups. CONCLUSIONS: Self-reported sitting time was associated with adverse cardiometabolic risk factors consistently across sex and race groups in a representative US sample, independent of other risk factors. Excessive sitting warrants a public health concern. PMID- 23981955 TI - Experimental induction of social instability during early breeding does not alter testosterone levels in male black redstarts, a socially monogamous songbird. AB - Testosterone plays an important role in territorial behavior of many male vertebrates and the Challenge Hypothesis has been suggested to explain differences in testosterone concentrations between males. For socially monogamous birds, the challenge hypothesis predicts that testosterone should increase during male-male interactions. To test this, simulated territorial intrusion (STI) experiments have been conducted, but only about a third of all bird species investigated so far show the expected increase in testosterone. Previous studies have shown that male black redstarts (Phoenicurus ochruros) do not increase testosterone during STIs or short-term male-male challenges. The aim of this study was to evaluate whether black redstarts modulate testosterone in an experimentally induced longer-term unstable social situation. We created social instability by removing males from their territories and compared the behavior and testosterone concentrations of replacement males and neighbors with those of control areas. Testosterone levels did not differ among replacement males, neighbors and control males. Injections with GnRH resulted in elevation of testosterone in all groups, suggesting that all males were capable of increasing testosterone. We found no difference in the behavioral response to STIs between control and replacement males. Furthermore, there was no difference in testosterone levels between replacement males that had expanded their territory and new-coming males. In combination with prior work these data suggest that testosterone is not modulated by male-male interactions in black redstarts and that testosterone plays only a minor role in territorial behavior. We suggest that territorial behavior in species that are territorial throughout most of their annual life-cycle may be decoupled from testosterone. PMID- 23981956 TI - Theoretical framework of population genetics with somatic mutations taken into account: application to copy number variations in humans. AB - Traditionally, population genetics focuses on the dynamics of frequencies of alleles acquired by mutations on germ-lines, because only such mutations are heritable. Typical genotyping experiments, however, use DNA from some somatic tissues such as blood, which harbors somatic mutations at the current generation in addition to germ-line mutations accumulated since the most recent common ancestor of the sample. This common practice may sometimes cause erroneous interpretations of polymorphism data, unless we properly understand the role of somatic mutations in population genetics. We here introduce a very basic theoretical framework of population genetics with somatic mutations taken into account. It is easy to imagine that somatic mutations at the current generation simply add individual-specific variations, as errors in mutation detection do. Our theory quantifies this increment under various conditions. We find that the major contribution of somatic mutations plus errors is to very rare variants, particularly to singletons. The relative contribution is markedly large when mutations are deleterious. Because negative selection also increases rare variants, it is important to distinguish the roles of these mutually confounding factors when we interpret the data, even after correcting for demography. We apply this theory to human copy number variations (CNVs), for which the composite effect of somatic mutations and errors may not be negligible. Using genome-wide CNV data, we demonstrate how the joint action of the two factors, selection and somatic mutations plus errors, shapes the observed pattern of polymorphism. PMID- 23981959 TI - Comparative study of the mutant prevention concentrations of vancomycin alone and in combination with levofloxacin, rifampicin and fosfomycin against methicillin resistant Staphylococcus epidermidis. AB - No mutant-prevention concentration (MPC) with methicillin-resistant Staphylococcus epidermidis (MRSE) has been reported. The study aimed to evaluate the propensity of vancomycin individually and in combination to prevent MRSE from mutation. A total of 10 MRSE clinical isolates were included in the study. Susceptibility testing demonstrated that the susceptibility rates to vancomycin, rifampicin, levofloxacin and fosfomycin were 100, 100, 50 and 90%, respectively. The fractional inhibition concentration indices (FICI) for vancomycin combined with rifampicin, levofloxacin or fosfomycin were >=1.5 but <=2, >=1.5 but <=2, and >0.5 but <=1.5, respectively, implying indifferent interactivity. The MPC with susceptible strains was determined to be the lowest antibiotic concentration inhibiting visible growth among 10(10) CFU on four agar plates (9 cm in diameter) after a 72-h incubation at 37 degrees C. The MPCs were 16~32, >64, >=64 and 4~16 MUg ml(-1) for vancomycin, rifampicin, fosfomycin and levofloxacin, respectively. The vancomycin MPCs of combinations with fosfomycin (32 MUg ml(-1)), levofloxacin (2 MUg ml(-1)) and rifampicin (2 or 4 MUg ml(-1)) were 1~4, 16~32 and 16~32 MUg ml(-1), respectively. Against mutants selected by vancomycin, rifampicin, levofloxacin and fosfomycin individually, antibiotics had standard MICs of 2~4 MUg ml(-1) for vancomycin, >64 MUg ml(-1) for rifampicin, 4~8 MUg ml(-1) for levofloxacin and ?64 MUg ml(-1) for fosfomycin. Thus single-step mutation can lead to resistance of MRSE to rifampicin, levofloxacin and fosfomycin, rather than non-susceptibility to vancomycin. Vancomycin-fosfomycin combination might be a superior alternative to vancomycin in blocking the growth of MRSE mutants, especially for high-organism-burden infections. PMID- 23981960 TI - Simple and rapid characterization of mycolic acids from Dietzia strains by using MALDI spiral-TOFMS with ultra high mass-resolving power. AB - Mycolic acids have been used as important chemotaxonomic markers. In this study, a newly developed matrix-assisted laser desorption/ionization time-of-flight mass spectrometer with a spiral ion trajectory (MALDI spiral-TOFMS) was applied to the characterization of mycolic acids of three type strains of validated species belonging to the genus Dietzia (D. papillomatosis 105045(T), D. kunjamensis NBRC 105042(T) and D. timorensis NBRC 104184(T)), by analysis of total fatty acid methyl ester fractions. In addition, owing to the high mass-resolving power of MALDI spiral-TOFMS, adjacent peaks (0.036 Da mass differences) were successfully separated, and weak peaks corresponding to oxygenated mycolic acids were detected. For all samples, the distributions of carbon-chain lengths were mainly in the range of C30-C42 and the average number of carbon-chain lengths was about 37, which agreed reasonably well with reported results for the genus Dietzia. The number of double bonds and/or cyclopropane rings was 0-2. Relative peak intensities of each mycolic acid methyl ester were used to compare the mycolic acids of the three strains. The mycolic acids of D. papillomatosis and D. kunjamensis were characterized by a high content of mycolic acids with 0-1 double bond or cyclopropane ring and an almost equal content of mycolic acids with odd- and even-numbered carbon-chain lengths. In contrast, mycolic acids of D. timorensis were characterized by a high content of mycolic acids with 1-2 double bonds and/or cyclopropane rings with an even-numbered carbon-chain length. By using MALDI spiral-TOFMS, mycolic acids from three type strains of the genus Dietzia were characterized easily and rapidly. PMID- 23981957 TI - The genomics of incompatibility factors and sex determination in hybridizing species of Cottus (Pisces). AB - Cottus rhenanus and Cottus perifretum have formed hybrid lineages and narrow hybrid zones that can be best explained through the action of natural selection. However, the underlying selective forces as well as their genomic targets are not well understood. This study identifies genomic regions in the parental species that cause hybrid incompatibilities and tests whether these manifest in a sex specific manner to learn about processes that affect natural hybridization in Cottus. Interspecific F2 crosses were analyzed for 255 markers for genetic mapping and to detect transmission distortion as a sign for genetic incompatibilities. The Cottus map consists of 24 linkage groups with a total length of 1575.4 cM. A male heterogametic (XY) sex determination region was found on different linkage groups in the two parental species. Genetic incompatibilities were incomplete, varied among individuals and populations and were not associated with the heterogametic sex. The variance between populations and individuals makes it unlikely that there are species-specific incompatibility loci that could affect the gene pool of natural hybrids in a simple and predictable way. Conserved synteny with sequenced fish genomes permits to genetically study the Cottus genome through the transfer of genomic information from the model fish species. Homology relationships of candidate genomic regions in Cottus indicate that sex determination is not based on the same genomic regions found in other fish species. This suggests a fast evolutionary turnover of the genetic basis of sex determination that, together with the small size of the heterogametic regions, may contribute to the absence of fitness effects related to the Haldane's rule. PMID- 23981961 TI - Two new pentanorlanostane metabolites from a soil fungus Curvularia borreriae strain HS-FG-237. PMID- 23981962 TI - Indanostatin, a new neuroprotective compound from Streptomyces sp. PMID- 23981963 TI - In vitro effects of tigecycline in combination with colistin (polymyxin E) and sulbactam against multidrug-resistant Acinetobacter baumannii. AB - The lack of active antimicrobial agents against multidrug-resistant (MDR) Acinetobacter baumannii has posed great threat to the public health. Combination therapies with antibiotics owning different antimicrobial mechanisms have been proposed as good options for treating MDR A. baumannii infections. This study was aimed to investigate the in vitro effects of tigecycline in combination with colistin and sulbactam against MDR A. baumannii. A total of 70 strains from two hospitals in China were examined in the study. The checkerboard method was used for determining synergistic activity of different antibiotic combinations. Tigecycline/colistin combination displayed synergistic and partial synergistic activity in 24.3% of the isolates, whereas the tigecycline/sulbactam combination showed synergistic and partial synergistic activity in 64.3% of the isolates. Neither of the combinations showed antagonism in this study. In addition, for evaluating the ability of combinations on resistance prevention, mutant prevention concentrations (MPCs) of tigecycline, colistin, sulbactam alone and tigecycline in combination with colistin and sulbactam were studied against MDR A. baumannii. Compared with tigecycline used alone, combination therapies could achieve lower MPCs of tigecycline. However, when the MPCs of dual-drug therapy were in conjunction with clinical pharmacokinetic profiles, combinations may not strictly curb the occurrence of resistance at current dosage regimen. In summary, this study suggested that combination therapy was a good option for treating MDR A. baumannii infections. But the finding that combination with these drugs at current dosage regimen may not prevent emergence of resistance warranted further studies on dosage of combined antibiotics required for achieving resistance prevention. PMID- 23981964 TI - Prenatal diagnosis and molecular cytogenetic characterization of a de novo pure distal 9p deletion and literature review. AB - We present rapid aneuploidy diagnosis of distal 9p deletion by array comparative genomic hybridization using uncultured amniocytes in a pregnancy associated with an abnormal maternal serum screening result and intrauterine growth restriction (IUGR) in the fetus. We review the literature of prenatal diagnosis of distal 9p deletion, and add abnormal maternal serum biochemistry and fetal IUGR in the distinctive prenatal findings in pregnancy with fetal distal 9p deletion. We discuss the consequence of haploinsufficiency of DOCK8, KANK1, VLDLR and DMRT1 in this case. PMID- 23981965 TI - Conserved domains and SINE diversity during animal evolution. AB - Eukaryotic genomes harbour a number of mobile genetic elements (MGEs); moving from one genomic location to another, they are known to impact on the host genome. Short interspersed elements (SINEs) are well-represented, non-autonomous retroelements and they are likely the most diversified MGEs. In some instances, sequence domains conserved across unrelated SINEs have been identified; remarkably, one of these, called Nin, has been conserved since the Radiata Bilateria splitting. Here we report on two new domains: Inv, derived from Nin, identified in insects and in deuterostomes, and Pln, restricted to polyneopteran insects. The identification of Inv and Pln sequences allowed us to retrieve new SINEs, two in insects and one in a hemichordate. The diverse structural combination of the different domains in different SINE families, during metazoan evolution, offers a clearer view of SINE diversity and their frequent de novo emergence through module exchange, possibly underlying the high evolutionary success of SINEs. PMID- 23981967 TI - Natural hormone replacement therapy: what it is and what consumers really want. PMID- 23981966 TI - Phase 2 study of pemetrexed plus carboplatin, or pemetrexed plus cisplatin with concurrent radiation therapy followed by pemetrexed consolidation in patients with favorable-prognosis inoperable stage IIIA/B non-small-cell lung cancer. AB - INTRODUCTION: There is no consensus chemotherapy regimen with concurrent radiotherapy (RT) for inoperable stage IIIA/B non-small-cell lung cancer. This trial evaluated pemetrexed with carboplatin (PCb) or cisplatin (PC) with concurrent RT followed by consolidation pemetrexed. METHODS: In this open-label, noncomparative phase II trial, patients with inoperable stage IIIA/B non-small cell lung cancer (initially all histologies, later restricted to nonsquamous) were randomized (1:1) to PCb or PC with concurrent RT (64-68 Gy over days 1-45). Consolidation pemetrexed monotherapy was administered every 21 days for three cycles. Primary endpoint was 2-year overall survival (OS) rate. RESULTS: From June 2007 to November 2009, 98 patients were enrolled (PCb: 46; PC: 52). The 2 year OS rate was PCb: 45.4% (95% confidence interval [CI], 29.5-60.0%); PC: 58.4% (95% CI, 42.6-71.3%), and in nonsquamous patients was PCb: 48.0% (95% CI, 29.0 64.8%); PC: 55.8% (95% CI, 38.0-70.3%). Median time to disease progression was PCb: 8.8 months (95% CI, 6.0-12.6 months); PC: 13.1 months (95% CI, 8.3-not evaluable [NE]). Median OS (months) was PCb: 18.7 (95% CI, 12.9-NE); PC: 27.0 (95% CI, 23.2-NE). The objective response rates (ORRs) were PCb: 52.2%; PC: 46.2%. Grade 4 treatment-related toxicities (% PCb/% PC) were: anemia, 0/1.9; neutropenia, 6.5/3.8; thrombocytopenia, 4.3/1.9; and esophagitis, 0/1.9. Most patients completed scheduled chemotherapy and RT during induction and consolidation phases. No drug-related deaths were reported during chemoradiotherapy. CONCLUSIONS: Because of study design, efficacy comparisons cannot be made. However, both combinations with concurrent RT were active and well tolerated. PMID- 23981968 TI - Hormone replacement therapy: part 1 - the evolution of hormone treatment. PMID- 23981969 TI - Bioidentical hormones in the treatment of osteoporosis. PMID- 23981970 TI - The value of hormone assessment. PMID- 23981971 TI - Estrogen replacement: a review of current literature. PMID- 23981972 TI - Treating andropause: prohormones and hormone metabolic modifiers. PMID- 23981973 TI - Bioidentical topical progesterone: a survey of patients. PMID- 23981974 TI - Minimizing the risk of cholesterol-lowering therapy. PMID- 23981975 TI - The basics of compounding: tablets and pills. PMID- 23981976 TI - Compounding containment devices: buyer be aware. PMID- 23981977 TI - Stability of Ephedrine Sulfate at Ambient Temperature and 4 deg C in Polypropylene Syringes. AB - The stability of 5 mg/mL ephedrine sulfate in 0.9% sodium chloride in 10-mL polypropylene syringes stored at ambient temperature and at 4 deg C for up to 60 days was investigated. Concentration levels of ephedrine sulfate were determined by means of a high-performance liquid chromatography stability-indicating assay at 0, 1, 4, 7, 14, 30, 45 and 60 days after preparation of the syringes. Benzyl alcohol, which was added as a preservative, did not interfere with the assay. The injections in polypropylene syringes were stable for up to 60 days at both ambient temperature and at 4 deg C. The pH of the ephedrine sulfate injections did not change appreciably in a particular direction during the 60-day study period. These data support the stability of ephedrine sulfate under the storage conditions investigated in this study. PMID- 23981978 TI - Assessment of the stability of teicoplanin in intravenous infusions. AB - The advance preparation of intravenous solutions of teicoplanin, which is often used in antibiotic infusions for hospitalized patients, may be advantageous. The objective of this study was to investigate the stability of teicoplanin stored at 4 deg C in polyvinyl chloride bags to determine whether such solutions could be safely stored without deterioration. Five bags containing 0.4g teicoplanin per 100 mL of 5 % dextrose injection were studied for 1 month by means of high performance liquid chromatography, visual inspection, and pH measurement. The color of teicoplanin diluted in dextrose became slightly yellow, and the pH values of the preparations decreased significantly during the period of the study without affecting the chromatographic parameters. The teicoplanin solution was stable for 6 days at 4 deg C as a result of the shortest shelf life of 90% residual potency of the five major glycopeptide components. Despite the color and pH variations, the teicoplanin infusion remained chemically stable when stored up to 6 days at 4 deg C in polyvinyl chloride bags. Thus the infusion could be prepared in advance by a centralized intravenous admixture service for use within the limits described. PMID- 23981979 TI - Release of morphine sulfate from compounded slow-release capsules: the effect of formulation on release. AB - Morphine sulfate is often used to treat severe pain. Pharmacists have been requested to compound morphine sulfate sustained-release capsules in dosages that are not available commercially. However, there has been considerable controversy about the advisability of that practice. This study determined the release of six formulations of 300 mg morphine sulfate sustained-release capsules by means of a United States Pharmacopeia (USP) type III dissolution apparatus. The formulation suggested by a reputable compounding consulting company released almost half the morphine in the first hour of a time-release test and did not adequately sustain the release of the remainder. With increases in the level of hydroxypropyl methylcellulose (Methocel), the release was prolonged and the amount of drug released during the first hour was reduced. One formulation of encapsulated compressed pellets showed that the release could be sustained significantly beyond that of the original formulation. In addition, the increased agitation that occurs in the gastointestinal tract when the medication is taken after a meal reduced the period of sustained release and slightly increased the amount of morphine released during the first hour after administration. In conclusion, the original formula of morphine sulfate sustained-release capsules (Formula A) is probably not adequate for most applications. The formulations with a greater percentage of Methocel are preferred. In addition, the pelleted formulation was superior; however, it may not be feasible to use this labor-intensive approach to compound capsules. PMID- 23981980 TI - Physical activity levels across adult life and grip strength in early old age: updating findings from a British birth cohort. AB - INTRODUCTION: observational studies do not always find positive associations between physical activity and muscle strength despite intervention studies consistently showing that exercise improves strength in older adults. In previous analyses of the MRC National Survey of Health and Development (NSHD), the 1946 British birth cohort, there was no evidence of an association between leisure time physical activity (LTPA) across adulthood and grip strength at age 53. This study tested the hypothesis that cumulative benefits of LTPA across mid-life on grip strength will have emerged by age 60-64. METHODS: data from the MRC NSHD were used to investigate the associations between LTPA at ages 36, 43, 53 and 60 64 and grip strength at 60-64. Linear regression models were constructed to examine the effect of activity at each age separately and as a cumulative score, including adjustment for potential confounders and testing of life course hypotheses. RESULTS: there were complete longitudinal data available for 1,645 participants. There was evidence of a cumulative effect of LTPA across mid-life on grip strength at 60-64. Compared with the third of participants who reported the least LTPA participation across the four time points, those in the top third had on average 2.11 kg (95% CI: 0.88, 3.35) stronger grip after adjustments. CONCLUSIONS: increased levels of LTPA across mid-life were associated with stronger grip at age 60-64, in both men and women. As these associations have emerged since age 53, it suggests that LTPA across adulthood may prevent decline in grip strength in early old age. PMID- 23981981 TI - Reduction-degradable PEG-b-PAA-b-PEG triblock copolymer micelles incorporated with MTX for cancer chemotherapy. AB - Reduction-breakable core-shell type polymeric micelles from reduction-degradable amphiphilic polyethylene glycol-b-polyamide amine-b-polyethylene glycol triblock copolymers (PEG-b-PAA-b-PEG) were prepared as new drug carriers of methotrexate (MTX) for cancer chemotherapy. The PEG-b-PAA-b-PEG copolymers were synthesized in a simple one-step process under mild condition through Michael addition. Spherical micelles with diameters ranging from 65 to 123nm were successfully fabricated from the copolymers. These micelles could effectively encapsulate the anti-cancer drug MTX in the core with drug loading content around 13%. The incorporation of MTX resulted in a little size increase but did not influence the morphology of micelles. The drug was hardly released from the micelles in normal condition without DDT as the reductant, but fast released up to 100% within 24h when the structure of micelle core was broken in the presence of DTT, thus provided a potential tool for tumor targeting delivery of MTX using the higher concentration of reductant in tumor tissues. The proliferation inhibition experiments demonstrate that MTX-encapsulated micelles show significant cytotoxicity to KB, HepG2 and 4T1 tumor cells, especiallythe 4T1 cells. PMID- 23981982 TI - Attributes and barriers to care of pelvic pain in university women. AB - STUDY OBJECTIVE: To describe rates of pelvic pain in university women ages 18 and older and to explore the barriers to adequate health care for pelvic pain in this population. DESIGN: A cross-sectional study (Canadian Task Force classification II-2). SETTING: University of Florida, Gainesville, FL. PATIENTS: A total of 2000 female students at the University of Florida were randomly selected for participation. INTERVENTIONS: The 2000 sample members were sent a questionnaire to be completed online. MEASUREMENTS AND MAIN RESULTS: The online questionnaire was hosted through the REDCap electronic data capture tool hosted at the University of Florida. This questionnaire included demographic items, general health and health behavior questions, measures to assess different types of pelvic pain (e.g., dysmenorrheal; dyspareunia; urinary, bowel, and vulvar pain), items regarding barriers to care for pelvic pain problems, and quality of life measures. Data were exported to SAS software (SAS Institute Inc., Cary, NC) for analysis. Of the 2000 subjects who received the questionnaire invitation, 390 filled out the questionnaire, yielding a response rate of 19.5%. Respondents' ages ranged from 18 to 62 with a mean of 23 years. A total of 72.8% of respondents reported experiencing pelvic pain over the past 12 months. Dysmenorrhea was reported by nearly 80% of participants, over one third of participants noted deep dyspareunia, and a significant proportion of participants reported symptoms related to bowel movements. Vulvar symptoms, including superficial dyspareunia, were reported by 21.5% of participants. Most participants with pelvic pain (78.8%) have not received any diagnosis for their pain, whereas 73.6% reported not yet having visited a doctor. Significant barriers to receiving adequate medical care were reported, including difficulty with insurance coverage and physicians' lack of time and knowledge or interest in chronic pelvic pain conditions. CONCLUSION: Pelvic pain in younger women is a critical public health issue experienced by a significant portion of the population. Significant awareness deficits and barriers to care exist. Careful study of the barriers to receiving adequate medical care reported by these women will allow researchers to describe how best to improve care for these syndromes. PMID- 23981984 TI - Identification of a known GJB6 mutation in an autosomal dominant inherited Chinese family with hidrotic ectodermal dysplasia. AB - OBJECTIVE: Mutation in the gap junction beta 6 (GJB6) gene has been reported to be associated with an autosomal dominant disorder hidrotic ectodermal dysplasia (HED), characterized by congenital nail clubbing, alopecia and palmoplantar keratoderma. The aim of this study is to investigate relationship between genetic mutation in GJB6 and HED in an affected Chinese family. METHODS: We selected a Chinese HED family consisting of a total of 17 individuals including 8 HED patients (5 males and 3 females). The whole coding region of GJB6 was amplified by polymerase chain reaction and sequenced. RESULTS: Sequence analysis identified a heterozygous missense mutation c.31G>A (p.G11R) in GJB6 gene of affected individuals, but not in healthy individuals. CONCLUSION: A c.31G>A (p.G11R) missense mutation in GJB6 gene is the genotypic characteristic for HED in Chinese population. PMID- 23981983 TI - Recurrent connections form a phase-locking neuronal tuner for frequency-dependent selective communication. AB - The brain requires task-dependent interregional coherence of information flow in the anatomically connected neural network. However, it is still unclear how a neuronal group can flexibly select its communication target. In this study, we revealed a hidden routing mechanism on the basis of recurrent connections. Our simulation results based on the spike response model show that recurrent connections between excitatory and inhibitory neurons modulate the resonant frequency of a local neuronal group, and that this modulation enables a neuronal group to receive selective information by filtering a preferred frequency component. We also found that the recurrent connection facilitates the successful routing of any necessary information flow between neuronal groups through frequency-dependent resonance of synchronized oscillations. Taken together, these results suggest that recurrent connections act as a phase-locking neuronal tuner which determines the resonant frequency of a local group and thereby controls the preferential routing of incoming signals. PMID- 23981985 TI - Effect of UGT2B7 genetic variants on serum valproic acid concentration. AB - OBJECTIVE: To investigate the effect of UGT2B7 A268G and UGT2B7 G211T genetic polymorphism on serum drug concentration of valproic acid (VPA). METHODS: Genetic polymorphisms of UGT2B7 A268G and UGT2B7 G211T were tested in 248 epileptic patients by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Data including basic information, epilepsy type, times and doses of drug, treatment response and liver and kidney functions were collected. Statistical analysis was performed by SPSS 13.0 through multivariate linear regression, one-way ANOVA, chi(2) test, and paired T-test. RESULTS: Based on multivariate linear regression, there was no significant difference between gender, age, or body mass index and VPA, but concentration-to-dose ratios (CDRs) were positively correlated with VPA. The genetic polymorphisms of UGT2B7 A268G and UGT2B7 G211T were consistent with Hardy-Weinberg equilibrium. UGT2B7-268A > G allele frequency distribution A was 30.05%, and G was 69.95%. Variance analysis showed that serum drug concentration was significantly different in the genotype of AA, AG, or GG (F=5.477, P=0.005). Further analysis of paired T test showed that AA type was significantly different from GG type (P=0.048), and that serum concentration of AA type was much higher than that of GG type, while no significant difference between AA type and AG type, GG type and AG type. UGT2B7 G211T allele frequency distribution G was 77.24%, and T was 22.58%. There was no significant difference in standardized serum concentration among genotypes of GG, GT, and TT. CONCLUSION: This study reveals UGT2B7 A268G genetic polymorphism distribution in Chinese epilepsy population. UGT2B7 A268G plays an important role in VPA's metabolism, and has certain effect on VPA's serum concentration. Epilepsy patient with this genotype should be adjusted the dose of VPA to make a therapeutic effect. PMID- 23981986 TI - [Effects of Jianpi Qinghua Recipe on angiotensin II/NADPH oxidase pathway in 5/6 nephrectomized rats]. AB - OBJECTIVE: To study the effect of Jianpi Qinghua Recipe ( JPQHR) on angiotensin II/NADPH oxidase pathway in 5/6 nephrectomized rat renal failure model and the underlying mechanisms. METHODS: The animals were divided into 4 groups: the sham operated group, the renal failure group, the JPQHR-treated group and the losartan treated group. After 60-days therapy, serum nitrogen and creatinine were measured. The expression of angiotensin II type 1 receptor (AT1) protein and the expression of p47phox mRNA in renal tissue was determined. SOD and MDA were also examined. RESULTS: Compared with the sham-operated group, the levels of SCr and serum BUN and the AT1 protein and p47phox mRNA expression in the renal failure group were significantly increased. The activities of SOD in renal tissue from the renal failure group was significantly down-regulated while MDA was up regulated (P<0.05). Compared with the renal failure group, the levels of SCr and serum BUN and the AT1 protein and p47phox mRNA expression in both JPQHR-treated group and losartan-treated group were significantly decreased. The activities of SOD in renal tissue from JPQHR-treated group and losartan-treated group were significantly up-regulated whereas the content of MDA were down-regulated (P<0.05). Compared with the losartan-treated group, the activities of SOD in renal tissue from the JPQHR-treated group was obviously increased (P<0.05), the decrease in AT1 protein and p47phox mRNA was more evident but not statistically different (P>0.05). The level of SCr and serum BUN and the content of MDA were also not statistically different (P>0.05). CONCLUSION: Through decrease the expression of angiotensin II and NADPH oxidase, JPQHR can reduce the oxidative stress in chronic renal failure and delay the renal fibrosis progression. PMID- 23981987 TI - [Effects of intravenous transplantation of human umbilical cord blood mononuclear cells combined compound Danshen dripping pills on the microenvironment and apoptosis in the myocardium of the rabbits with acute myocardial infarction]. AB - OBJECTIVE: To explore the effects of compound Danshen dripping pills (CDDP) and CDDP combined with transplantation of human umbilical cord blood cells (HUMNCs) on the inflammatory response, oxidative stress, myocardial cell apoptosis and cardiac function, and also to investigate the possible mechanisms of the combined therapy in the acute myocardial infarction (AMI). METHODS: Rabbit model of AMI successfully established by ligation of the left anterior coronary artery (LAD). Forty rabbits were randomly divided into 4 groups (n=10 per group): a control group, injected with 0.5 mL of saline in 24 h after AMI and then gavaged with 5 mL of saline daily; a CDDP group, injected with saline 0.5 mL after AMI and then gavaged with CDDP (270 mg/d) daily; a transplantation group, injected with 0.5 mL of saline contained 3 * 10(7) HUCBMCs [labeled with green fluorescent protein (GFP)] and then gavaged with 5 mL of saline daily; a combined group, injected with 0.5 mL of saline contained 3 * 10(7) HUCBMCs (labeled with GFP) and then gavaged with CDDP (270 mg/d) daily. Cardiac function index such as left ventricular fractional shorting (LVFS) and ejection fraction(LVEF) were measured by echocardiography; the pathological changes were observed by HE staining and the white blood cells in the myocardium were determined by light microscopy. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in myocardium were detected by nitrotetrazolium blue chloride (NBT) and thiobarbituric acid colorimetric measurement respectively. The number of transplanted cells in the myocardium was examined by GFP positive cells counted with fluorescence microscopy. RESULTS: 1) Compared with the control group (at 1 or 4 week), LVEF and LVFS were significant improved in the CDDP group, the transplantation group and the combined groups (all P<0.05), the improvement degree of cardiac function in the combined group was the most significance. There was no significant difference between the CDDP group and the transplantation group. 2) Compared with the control group (at 1 or 4 week), the number of white blood cell, myocardial cell apoptosis ratio were decreased significantly in the CDDP group, the transplantation group and the combined groups (all P<0.05), this decrease in the combined group was the most significance, and there was no significant difference between the CDDP group and the transplantation group. 3) Compared with control (at 4 week), the SOD activity was increased significantly, and MDA content in myocardium was decreased in the CDDP group, this change in the combined group was the most significance. 4) GFP-positive cells were found to be present in the peri-myocardial infarction area in the transplantation group and the combined group at 1, 4 weeks post-transplantation. The number of the GFP positive cells in the combined group was more than that in the transplantation group (P<0.05). CONCLUSION: The intravenous transplantation of HUMNCs combined with the CDDP in the treatment of rabbits with AMI could increase the survival rate of transplanted cells and inhibit the myocardial cell apoptosis, therefore improve the heart function. The possible mechanism of the combined treatment may be involved in the inhibition of the inflammatory response and oxidative stress in the myocardium following AMI. PMID- 23981988 TI - [DNA methylation status of miR-126 and its host gene EGFL7 in CD4+ T cells from patients with systemic lupus erythematosus]. AB - OBJECTIVE: To explore the mechanisms by which DNA methylation regulates miR-126 and its host gene EGFL7 in CD4+ T cells from patients with systemic lupus erythematosus (SLE). METHODS: We analyzed the expression and the DNA methylation status within promoter region of EGFL7 and miR-126 by real-time qPCR and bisulfite genomic sequencing analysis. RESULTS: miR-126 and EGFL7 mRNA expression was upregulated in CD4+ T cells from SLE compared with that from healthy controls (P<0.01). EGFL7 mRNA level was positively correlated with miR-126 expression in CD4+ T cells from SLE (r=0.538, P=0.015). The average methylation level of EGFL7 promoter in CD4+ T cells from SLE was lower than that from healthy controls (P<0.05). CONCLUSION: The upregulation of miR-126 and its host gene EGFL7 expression in CD4+ T cells from SLE is associated with the hypomethylation of the EGFL7 promoter. PMID- 23981989 TI - [miR-126 inhibits colon cancer proliferation and invasion through targeting IRS1, SLC7A5 and TOM1 gene]. AB - OBJECTIVE: To explore the expression pattern and function of miR-126 in human colon cancer and the underlying mechanisms. METHODS: The expression pattern of miR-126 in high-density human colon cancer tissue microarray was analyzed by in situ hybridization. Further more, the biological function of miR-126 in colon cancer in vitro was investigated by establishing a stable miR-126 over-expression cell lines. RESULT: The expression of miR-126 was lower in the tumor tissue, especially in metastasis tissue. The down-regulation of miR-126 was more obvious in the patients who displayed bad prognosis (P=0.025). Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. MiR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer. CONCLUSION: MiR-126 was able to inhibit the development of colon cancer and its level was closely related with the prognosis of patients with colon cancer. The potential target genes for miR-126 might include IRS1, SLC7A5 and TOM1. Therefore, miR-126 might be a therapeutic target for colon cancer diagnosis and treatment. PMID- 23981990 TI - [Gene polymorphisms of CYP3A5 and MDR-1 in Hans renal transplant recipients in Hunan Province]. AB - OBJECTIVE: To identify the polymorphisms of cytochrome P450 3A5 gene (CYP3A5) and multidrug resistance gene 1 (MDR-1) and their distributions in Hans renal transplant recipients in Hunan province, we analyzed the difference of the gene polymorphisms and distributions between Hunan province and 11 other provinces of China. METHODS: We collected 598 Hans renal transplant recipients who had operation or follow-up examination in 3rd Xiangya Hospital from Hunan province. We examined the gene polymorphisms of CYP3A5 and MDR-1 and compared their distributions with the data from 11 other provinces of China by chi-square test. RESULTS: There were CYP3A5*1/*1 genotype in 58 cases (9.7%), CYP3A5*1/*3 genotype in 251 cases (42.0%), CYP3A5*3/*3 genotype in 289 cases (48.3%); MDR-1 3435CC genotype in 238 cases (39.8%), MDR-1 3435CT genotype in 263 cases (44.0%), MDR-1 3435TT genotype in 97 cases (16.2%). Frequency of CYP3A5*1/*1 and *1/*3 genotypes of Hunan province was higher than the that from the 11 other provinces of China and the frequency of mutator *3 was lower. Frequency of MDR-1 3435CC and 3435CT genotypes of Hunan province was higher and the frequency of mutator T was lower than that from the 11 other provinces of China. CONCLUSIONS: There were significant difference in gene polymorphisms and distributions of CYP3A5 and MDR 1 between Hunan province and the 11 other provinces of China. It may be a guideline for us to use calcineurin inhibitor drugs in the early stage after renal transplantation. PMID- 23981991 TI - [Optimization of diagnosis indicator selection and inspection plan by 3.0T MRI in breast cancer]. AB - OBJECTIVE: To optimize 3.0T MRI diagnosis indicator in breast cancer and to select the best MRI scan program. METHODS: Totally 45 patients with breast cancers were collected, and another 35 patients with benign breast tumor served as the control group. All patients underwent 3.0T MRI, including T1- weighted imaging (T1WI), fat suppression of the T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), 1H magnetic resonance spectroscopy (1H-MRS) and dynamic contrast enhanced (DCE) sequence. With operation pathology results as the gold standard in the diagnosis of breast diseases, the pathological results of benign and malignant served as dependent variables, and the diagnostic indicators of MRI were taken as independent variables. We put all the indicators of MRI examination under Logistic regression analysis, established the Logistic model, and optimized the diagnosis indicators of MRI examination to further improve MRI scan of breast cancer. RESULTS: By Logistic regression analysis, some indicators were selected in the equation, including the edge feature of the tumor, the time-signal intensity curve (TIC) type and the apparent diffusion coefficient (ADC) value when b=500 s/mm2. The regression equation was Logit (P)=-21.936+20.478X6+3.267X7+ 21.488X3. CONCLUSION: Valuable indicators in the diagnosis of breast cancer are the edge feature of the tumor, the TIC type and the ADC value when b=500 s/mm2. Combining conventional MRI scan, DWI and dynamic enhanced MRI is a better examination program, while MRS is the complementary program when diagnosis is difficult. PMID- 23981992 TI - [Histomorphological analyse of accelerating the fibrocartilage layer repair of patella-patellar tendon junction in rabbits by low intensity pulsed ultrasound stimulation]. AB - OBJECTIVE: To analyse the effect of low intensity pulsed ultrasound stimulation (LIPUS) on accelerating the fibrocartilage layer repair of patella-patellar tendon junction. METHODS: A total of 60 mature female New Zealand white rabbits undergoing standard partial patellectomy were divided into 2 groups randomly. The control group was given comfort treatment and the treatment group was given LIPUS treatment starting from day 3 to the end of week 6 postoperatively. The scheduled time points of animal euthanization would be at week 6, week 12 and week 18 postoperatively. The patella-patellar tendon (PPT) complex would be harvested and cut into sections after decalcification for H&E staining, Safranine o/fast green staining. The thickness and gray value of fibrocartilage layer were analyzed by SANO Microscope Partner image analyzer. RESULTS: At week 6, week 12 and week 18 postoperatively, the fibrocartilage layer in the treatment group was significantly thicker than that in the control group (P<0.01), and the gray value of fibrocartilage layer was significantly smaller than that in the control group (P<0.01). CONCLUSION: LIPUS helps to accelerate the fibrocartilage layer repair of patella-patellar tendon junction in rabbit models. PMID- 23981993 TI - [En bloc excision and reconstruction of the defect with pasteurized autograft for femoral primary malignant bone tumor in children]. AB - OBJECTIVE: To evaluate the efficacy of femoral primary malignant bone tumors treated by limb salvage, with wide en bloc excision and reconstruction of the defect with recycled pasteurized autograft. METHODS: From January 2008 to January 2011, 11 patients (7 males, 4 females), aged (11.0+/-2.5) years suffering from femoral primary malignant bone tumors were treated with en bloc excision and reconstruction of the defect with recycled pasteurized autograft. Ten patients were histopathologically diagnosed with high-grade osteosarcoma, and 1 with Ewing's sarcoma.According to the Enneking staging system, all patients were in Stage IIb. RESULTS: All patients were followed-up for 24-65(42+/-20) months and all showed bony union at the last follow-up. The length of tumor bone resection was (17.5+/-3.2) cm, the operation time was (180+/-35) min, the intraoperative blood loss was (1200+/-250) mL, and drainage volume was (650+/-125) mL. Local skin necrosis occurred in 1 patient (9.1%), which was resolved by debridement. Nonunion occurred in 3 patients (27.3%), who were treated by secondary iliac crest cancellous bone grafting.Pulmonary metastasis occurred in 1 patient (9.1%) who died 35 months post-operatively. According to the function assessment by the Enneking system, 5 patients had excellent results, 4 had good results, 1 fair and 1 poor results, with a satisfaction rate of 81.2%. CONCLUSION: A pasteurized autograft can be an easily accessible and economical alternative for children's malignant bone tumor of femurs. PMID- 23981994 TI - [Comparison of Cyberwand dual probe lithotriptor and Swiss lithoclast master in ultrasonically guided percutaneous nephrolithotomy for renal staghorn calculi]. AB - OBJECTIVE: To evaluate and compare the efficiency and safety of Cyberwand dual probe lithotriptor and Swiss lithoclast master in percutaneous nephrolithotomy for renal staghorn calculi. METHODS: A total of 138 patients with renal staghorn calculi were divided randomly into a Cyberwand dual probe lithotripter group (Group A, n=71) and a Swiss lithoclast master group(Group B, n=67). The data for operative time, blood loss volume, one-stage calculus clearance rate, hospitalization time, cost of hospitalization and complication in the two groups were collected and compared. RESULTS: The renal access was established successfully and the one-stage percutaneous nephrolithotomy (PCNL) was performed in the 2 groups. There was no significant difference in the size of stones, the age of patients and the complications between the 2 groups before the operations. Intraoperative gravel time in the Group A was significantly shorter than that in the Group B (77.14+/-21.39 vs 84.25+/-20.62, P=0.049). There was no significant difference in the one-staged stone clearance rate, blood loss volume in the operation between the 2 groups. The one-staged stone clearance rate in the 2 groups were 67.6% (48/71) and 70.1% (47/67) respectively, with no significant difference (P=0.854). CONCLUSION: Two lithotrities were safe and efficient for renal staghorn calculi. But comparing with Swiss lithoclast master, Cyberwand dual probe lithotriptor is more efficient and convenient. PMID- 23981995 TI - [Research progress of postoperative atrial fibrillation]. AB - Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery, which leads to hemodynamics disorder, prolongs hospitalization and increases mortality. The underlying mechanisms behind POAF are associated with cardiomyocyte injury, sympathetic activation and inflammation. The prediction of POAF is based on correlated index from pre-, intra- and post surgery. POAF can be treated by rhythm and heart rate control as well as and antithrombotic therapy. PMID- 23981996 TI - Knowledge of blood sugar control standard brings the higher attainment rate of HbA1c. AB - OBJECTIVE: To analyze the important controllable factors which affect the glycemic control of diabetes. METHODS: A cross-sectional study was carried out to examine the role of relevant characteristics in glycemic control by a sampling investigation of 430 diabetic patients in Hunan, China. A questionnaire was designed for personal interviews to collect data. Univariate regression analysis and multiple linear regression analysis were used to evaluate the effects of various factors on glycated hemoglobin A1c (HbA1c) control. RESULTS: The level of HbA1c in 430 patients was (8.7+/-2.6)%, and the value in 34% patients among them was <= 7.0%. Base on univariate regression analysis some factors were associated with good HbA1c control, including age, diabetic education, self monitoring of blood glucose, knowledge of blood sugar control standard, living environment, and self-owned glucometer. However, the upgraded treatment was associated with poor control. Based on multiple linear regression analysis, the first four factors mentioned above were protective factors for HbA1c while upgraded treatment was risk factor for HbA1c. CONCLUSION: Knowledge of blood sugar control standard, diabetic education and self monitoring of blood glucose are important controllable factors for better glycemic control of diabetes. PMID- 23981997 TI - [Effects of age on left ventricular twist-displacement loop assessed by velocity vector imaging]. AB - OBJECTIVE: To assess effect of age on the characteristic of left ventricular (LV) twist-displacement loop in health volunteers by velocity vector imaging (VVI) and to provide a new method for LV function evaluation in clinic. METHODS: After obtaining basal and apical LV short-axis images in 98 healthy volunteers (18-75 years old) by 2-dimensional echocardiography, we use VVI software to analysis LV twist motion and radial displacement at each plane off-line. The peak LV twist (Ptw), the peak untwist velocity (PutwV), the proportion of untwist in isovolumetric relaxation period (Iutw%) and LV radial displacement (Dis) were measured and calculated. Then we constructed LV twist-displacement loop and compared the characteristic of them among different groups. RESULTS: Ptw increased gradually with the increase in age. The biggest PutwV was in the group of 30-60 years old. Iutw% increased gradually before 60 years old, then decreased after that. Dis was not obviously different among the three groups. The characteristic of LV twist-displacement loop was like the configuration of 8. There was a linear relation between twist and displacement during systole, and the slope increased gradually with the increase in age. During early diastole, the relatively small radial expanding displacement displayed with untwisting, resulting in a much steeper twist-displacement relationship curve occurred in each group, which was getting smooth gradually when the radial expanding displacement increased during mid to late diastole. CONCLUSIONS: VVI can be used to effectively and noninvasively assess LV twist-displacement loop with change in age and provide important information for LV function. The effect of age must take into account when evaluate the LV function by the twist-displacement loop. PMID- 23981998 TI - [Role of stress in myocardial protection of ischemic preconditioning]. AB - OBJECTIVE: To determine the role of stress in myocardial protection of ischemic preconditioning (IPC). METHODS: Thirty rabbits were randomly divided into an IPC group, an etomidate (Etom) group, an ischemic/reperfusion (IR) group, a methylprednisolone (MP) group and a sham group. The ratio of infarction size versus risk area (infarct/risk) was calculated. The elevations of the serum creatine kinase (CK) activity and cardiac troponin I (cTnI) concentrations as well as the serum cortisol concentrations were measured. RESULTS: The percentages of infarct/risk in the IPC group, the MP group, the IR group, and the Etom group were (5.86+/-2.81)%, (11.28+/-3.62)%, (26.79+/-4.53)%, and (18.19+/-3.72)%, respectively. The elevations of the serum CK activity in the IPC group, the MP group, the IR group, and the Etom group were (255+/-89), (314+/-160), (855+/ 371), and (768+/-404) U/L, respectively. The elevations of serum cTnI concentrations in the IPC group, the MP group, the IR group, and the Etom group were (3.6+/-0.6),(6.1+/-2.2), (8.1+/-3.6), and (6.4+/-1.6) MUg/L, respectively. Those indicators among the groups were significantly different (P<0.05). Cortisol reaction was markedly diminished in the Etom group. CONCLUSION: A blunted cortisol reaction can markedly reduce the benefit of IPC while methylprednisolone shows cardioprotective effects, suggesting that stress might be involved in the myocardial protection of IPC. PMID- 23981999 TI - [Effect of blood glucose fluctuation and the sustained high blood glucose on renal pathological change and collagen IV expression in diabetic rats]. AB - OBJECTIVE: To observe the effect of blood glucose fluctuation and the sustained high blood glucose on renal pathological change and collagen IV (Col IV) expression in diabetic rats. METHODS: The 60 male Sprague-Dawley (SD) rats were randomly assigned into a normal control group (NC) and a model group (DM). The rats in the normal control group were fed with normal diet, while the rats in the model group were fed with high-sucrose-high-fat diet for 6 weeks. After that,streptozocin (STZ, 30 mg/kg) was injected to induce diabetic model. The model group was then randomly divided into 2 subgroups: a sustained high blood glucose group and a fluctuation blood glucose group (animals in the latter group were subcutaneously injected with insulin twice daily). Rats were sacrificed after 3 months and kidney tissues were dissected for HE and PAS staining, Col IV immunohistochemistry and Western blot. RESULTS: Compared with the normal control group, the renal glomeruli and capillary basal membrane in the diabetic rats was getting larger and thicker, respectively; the capsular space and ground substance was extended and increased, respectively; the volume of renal tubule, kidney hypertrophy index, glomeruler sclerosis index and Col IV content were all increased in the diabetic rats (P<0.01). Compared with the sustained high blood glucose group, the above mentioned pathological changes were more serious in the blood glucose fluctuation group. CONCLUSION: The capillary basal membrane of kidney in diabetic rats is thicker and the ground substance is increased. The degree of glomeruler sclerosis is more serious in the blood glucose fluctuation group compared with the sustained high blood glucose group, which is confirmed by the increased level of Col IV. PMID- 23982000 TI - [Non-thoracoscopic and thoracoscopic modified Nuss procedure for correction of pectus excavatum]. AB - OBJECTIVE: To summarize the curative effect, safety and experience of non thoracoscopic modified Nuss procedure for correction of pectus excavatum (PE). METHODS: From January 2007 to December 2011, 267 cases of PE patients were selected in our hospital. Among them 85 were treated by thoracoscopic minimally invasive modified Nuss Procedure and 182 by non-thoracoscopic procedure. The operation time, blood loss during operation, length of postoperative hospital stay and effect of treatment were compared retrospectively. RESULTS: All the 267 patients finished the repair procedure smoothly. The non-thoracoscopic group had advantage in terms of operative time (22.5 min vs 35.1 min, P<0.05). As for the blood loss during operation, length of postoperative hospital stay and effect of treatment, there was no significant difference among the 2 groups (P>0.05). There were no deaths. CONCLUSION: Non-thoracoscopic minimally invasive modified Nuss procedure is as safe and effective as thoracoscopic Nuss procedure. With advantages of simplified operation procedure and shorter operation time, it is easier in practice. PMID- 23982001 TI - [Advances in study on the therapy for limited-stage small cell lung cancer]. AB - Small cell lung cancer (SCLC) are divided into limited and extensive stage diseases. Limited-stage SCLC (LS-SCLC) is confined to the ipsilateral hemithorax and within a single radiotherapy region, 30%-40% of patients with SCLC are limited stage. The median ranges of survival for patients with LS-SCLC is from 15 to 20 months. Approximately 20%-40% of patients with LS-SCLC can survive for two years. According to the guidelines, patients with LS-SCLC should be treated with combined concurrent chemoradiotherapy and patients with LS-SCLC achieving a complete remission or patient with stage I disease who have had resection should be offered prophylactic cranial irradiation (PCI). Whereas in SCLC, targeted therapies is still in the early stage and few clinical trial data is available to support its effect. PMID- 23982002 TI - Professor Elio Lugaresi's contributions to neurology and sleep disorders. AB - The authors present a brief historical review of the most important contributions by Professor Elio Lugaresi, of the University of Bologna, Italy, to neurology and sleep disorders. PMID- 23982003 TI - The cost of medication and the cost of treatment are not the same thing for multiple sclerosis. PMID- 23982004 TI - Wilson's disease. PMID- 23982005 TI - Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene. AB - OBJECTIVE: Wilson's disease (WD) is an inborn error of metabolism caused by abnormalities of the copper-transporting protein encoding gene ATP7B. In this study, we examined ATP7B for mutations in a group of patients living in southern Brazil. METHODS: 36 WD subjects were studied and classified according to their clinical and epidemiological data. In 23 subjects the ATP7B gene was analyzed. RESULTS: Fourteen distinct mutations were detected in at least one of the alleles. The c.3207C>A substitution at exon 14 was the most common mutation (allelic frequency=37.1%) followed by the c.3402delC at exon 15 (allelic frequency=11.4%). The mutations c.2018-2030del13 at exon 7 and c.4093InsT at exon 20 are being reported for the first time. CONCLUSION: The c.3207C>A substitution at exon 14, was the most common mutation, with an allelic frequency of 37.1%. This mutation is the most common mutation described in Europe. PMID- 23982006 TI - Patients with autosomal dominant spinocerebellar ataxia have more risk of falls, important balance impairment, and decreased ability to function. AB - OBJECTIVES: To assess balance and ability to function in patients with spinocerebellar ataxia. METHODS: A total of 44 patients with different spinocerebellar ataxia types 1, 2, 3, and 6 were evaluated using the Tinetti balance and gait assessment and the functional independence measure. The scale for the assessment and rating of ataxia and the international cooperative ataxia rating scale were used to evaluate disease severity. RESULTS: Most patients showed significant risk of falls. The balance scores were significantly different in spinocerebellar ataxia types. A significant positive correlation between balance and disease severity was found. CONCLUSION: Patients with spinocerebellar ataxia have important balance impairment and risk of falls that influence the ability to function such as self-care, transfers, and locomotion. Furthermore, the more severe ataxia is, the more compromised are postural balance, risk of falls, and ability to function. PMID- 23982007 TI - Antiparasitic antibodies occur with similar frequency in patients with clinically established multiple sclerosis with or without oligoclonal bands in the cerebrospinal fluid. AB - The "hygiene hypothesis" postulates an inverse relationship between the prevalence of parasitic infections and the frequency of multiple sclerosis (MS). OBJECTIVE: It was to study whether antibodies against parasites could be demonstrated more frequently in blood serum from MS patients with oligoclonal bands (OCB) than from MS patients without OCB. METHODS: We studied serum samples from 164 patients who had previously been analyzed to investigate OCB. Parasitic antibodies were studied through unidimensional electrophoresis of proteins on polyacrylamide gel against Taenia antigens, searching for antiparasitic specific low molecular weight antibodies and also for antiparasitic nonspecific high molecular weight antibodies. RESULTS: Two of the 103 patients with no evidence of OCB had antibodies of low molecular weight and 59 of them had antibodies of high molecular weight. Of the 61 patients with evidence of OCB, one showed antibodies of low molecular weight and 16 showed antibodies of high molecular weight. CONCLUSION: Antiparasitic antibodies are detected with similar frequency in MS patients with OCB and in MS patients without OCB. PMID- 23982008 TI - Medication withdrawal may be an option for a select group of patients in relapsing-remitting multiple sclerosis. AB - This article describes the clinical and radiological evolution of a stable group of patients with relapsing-remitting multiple sclerosis that had their disease modifying therapy (DMT) withdrawn. Forty patients, which had made continuous use of one immunomodulator and had remained free of disease for at least 5 years, had their DMT withdrawn and were observed from 13 to 86 months. Out of the followed patients, 4 (10%) patients presented with new attacks. In addition to these patients, 2 (5%) patients had new lesions revealed by magnetic resonance imaging that did not correspond to clinical attacks. Despite these results, the difficult decision to withdraw medication requires careful analysis. Withdrawal, however, should not be viewed as simply the suspension of treatment because these patients should be evaluated periodically, and the immunomodulators should be readily reintroduced if new attacks occur. Nonetheless, medication withdrawal is an option for a select group of patients. PMID- 23982009 TI - Walking execution is not affected by divided attention in patients with multiple sclerosis with no disability, but there is a motor planning impairment. AB - PURPOSE: We analysed the cognitive influence on walking in multiple sclerosis (MS) patients, in the absence of clinical disability. METHOD: A case-control study was conducted with 12 MS patients with no disability and 12 matched healthy controls. Subjects were referred for completion a timed walk test of 10 m and a 3D-kinematic analysis. Participants were instructed to walk at a comfortable speed in a dual-task (arithmetic task) condition, and motor planning was measured by mental chronometry. RESULTS: Scores of walking speed and cadence showed no statistically significant differences between the groups in the three conditions. The dual-task condition showed an increase in the double support duration in both groups. Motor imagery analysis showed statistically significant differences between real and imagined walking in patients. CONCLUSION: MS patients with no disability did not show any influence of divided attention on walking execution. However, motor planning was overestimated as compared with real walking. PMID- 23982010 TI - Nullity of GSTT1/GSTM1 related to pesticides is associated with Parkinson's disease. AB - Genetic and environmental factors affect the pathogenesis of Parkinson's disease (PD). Genetic variants of the enzyme glutathione S-transferases (GST) may be related to the disease. This study aimed to evaluate the influence of genetic variants of GST (GSTT1/GSTM1) and their association with the exposure to environmental toxins in PD patients. We studied 254 patients with PD and 169 controls. The GSTM1/GSTT1 variants were analyzed by polymerase chain reaction. We applied the Fisher's exact test and the chi2 test for statistical analysis (p<0.05). The present and absence for GSTT1 and GSTM1 were similar in patients and controls. The null for GSTT1 and GSTM1 (0/0) and exposure to pesticides prevailed in patients (18%) compared to controls (13%, p=0.014). This study suggests the association between PD and previous exposure to pesticides, whose effect may be enhanced in combination with null for GSTT1/GSTM1. PMID- 23982011 TI - Fatigue in patients with epilepsy and its association with depression and sleep quality. AB - OBJECTIVE: It was to evaluate the relationships between fatigue and excessive daytime sleepiness, sleep quality, depression and anxiety. METHODS: This was a cross-sectional study on 98 unselected adult patients with epilepsy (PWE) at a tertiary center. It used clinical-sociodemographic characteristics, fatigue measured by the SF-36 vitality subscale (VsSF-36) and the Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index and Beck Depression and Anxiety Inventories. RESULTS: We observed that our patients presented vitality or fatigue similar to drivers with chronic headaches evaluated in the same city. Fatigue was related to depression, anxiety and sleep quality, but not to daytime sleepiness. A multiple linear regression analysis was conducted and we observed that fatigue was independently correlated with depression and quality of sleep. However, no significant difference was observed regarding seizure frequency or number of antiepileptic drugs. CONCLUSION: Fatigue needs to be studied more in PWE, and its risk factors need to be controlled, along with sleep quality and psychiatric disorders. PMID- 23982012 TI - Autonomic evaluation of hepatitis C virus infected patients. AB - There are few studies reporting the association between hepatitis C virus (HCV) infection and disautonomia. We have evaluated the autonomic cardiovascular function in 12 patients with sensory small-fiber polyneuropathy infected by HCV. The mean age was 49 +/- 13 years old. The mean infection time was 9.6 years in six (50%) patients. Thermal and pinprick hypoesthesia was observed in distal legs in all patients. Autonomic symptoms were referred by eight (66.7%) patients. Among patients with abnormal autonomic cardiovascular test, five (41.7%) showed abnormal results in two or more tests. Valsalva maneuver was abnormal in seven (58.3%) patients. We can consider that there is an association of both parasympathetic and sympathetic efferent cardiovascular dysfunction in this group of patients. PMID- 23982013 TI - Hematoma volumes of spontaneous intracerebral hemorrhage: the ellipse (ABC/2) method yielded volumes smaller than those measured using the planimetric method. AB - OBJECTIVE: To compare two different methods for measuring intracerebral hemorrhage (ICH) volume: the ellipse volume (called ABC/2), and the software aided planimetric. METHODS: Four observers evaluated 20 brain computed tomography (CT) scans with spontaneous ICH. Each professional measured the volume using the ABC/2 and the planimetric methods. The average volumes were obtained, and the intra- and inter-rater variability was determined. RESULTS: There is an absolute 2.24 cm3 average difference between both methodologies. Volumes yielded by the ABC/2 method were as much as 14.9% smaller than by the planimetric one. An intra observer variability rate of 0.46% was found for the planimetric method and 0.18% for the ABC/2. The inter-observer rates were 1.69 and 1.11% respectively. CONCLUSIONS: Both methods are reproducible. The ABC/2 yielded hemorrhage volumes as much as 14.9% smaller than those measured using the planimetric methodology. PMID- 23982014 TI - Endoscopic third ventriculostomy is a safe and effective procedure for the treatment of Blake's pouch cyst. AB - OBJECTIVE: Blake's pouch cyst (BPC) is a midline cystic malformation of the posterior fossa, within Dandy-Walker's complex (DWC), often associated with hydrocephalus. Endoscopic third ventriculostomy (ETV) has been an alternative to conventional methods for BPC treatment. This study aimed at reporting our experience with ETV in a series of patients with BPC. METHODS: Of 33 patients diagnosed with midline posterior fossa cyst, 26 met the protocol criteria for DWC, and eight subjects with BPC were selected (aged one month to two years old). All cases were treated with ETV. RESULTS: Five patients were male; and three were prenatally diagnosed. They had hydrocephalus and motor deficiencies. Motor assessment at a five-year follow-up yielded normal findings. All patients improved, and only one had residual cognitive dysfunction, despite overall neurological improvement. There were no complications. CONCLUSIONS: ETV was a safe and effective procedure, reducing risks and morbidity associated with open surgery and shunt-related problems. PMID- 23982015 TI - There is much to be learnt about the costs of multiple sclerosis in Latin America. AB - METHOD: A systematic review of the literature from 1990 to 2011 was conducted. Outcome measures included: mean cost of disease modifying therapies (DMTs), mean cost of treatment of relapses and mean cost of disease by stage stratification measured by the expanded disability status scale (EDSS). RESULTS: Seven studies from three countries (Brazil, Argentina and Colombia) were included. In 2004, in Argentina, the mean cost of DMT treatment was reported to be USD 35,000 per patient treated. In Brazil, the total MS expenditure of DMTs rose from USD 14,011,700 in 2006 to USD 122,575,000 in 2009. Patient costs ranged between USD 10,543 (EDSS 8-9.5) and USD 25,713 (EDSS 3-5.5). Indirect costs markedly increased for the EDSS 8-9.5 patients. CONCLUSION: Further research assessing the economic burden of MS in LA is warranted. PMID- 23982016 TI - Neuromyelitis optica with very late onset. PMID- 23982017 TI - Historical sketches of the beginnings of the academic "Mental and Nervous Diseases" in Brazil, and European influences. AB - We present the common milestones of the neurology and psychiatry in Brazil, but, previously, they were summarized in the European matrix. The main psychiatric and neurological historical interceptions may be recognized by the terms neurology, psychiatry, alienism, neurosis and insanity; its organogenesis or socio- and psychogenetic basis; and its proximity or distance from internal medicine. PMID- 23982018 TI - Image findings of Vogt-Koyanagi-Harada. PMID- 23982019 TI - Delayed hemichorea syndrome associated with nonketotic hyperglycemia. PMID- 23982020 TI - Should all patients with transient ischemic attacks be admitted to a hospital in Brazil? PMID- 23982021 TI - Eighteen years of experience with Acinetobacter baumannii in a tertiary care hospital. AB - OBJECTIVE: To characterize the descriptive and molecular epidemiology of Acinetobacter baumannii in our hospital. DESIGN: Longitudinal analysis of electronic microbiology laboratory records and isolates. SETTING: A 1,500 bed public teaching hospital in the Miami area. PATIENTS: Consecutive patients with A. baumannii from January 1994 to December 2011. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: : Data on all A. baumannii isolates were clustered at the patient level, and the first isolate per single patient was determined. Yearly trends were analyzed based on carbapenem susceptibilities and originating units for all first isolates and first blood isolates per unique patient. Additionally, carbapenem nonsusceptible isolates frozen in the microbiology laboratory since 1998 were retrieved and evaluated using polymerase chain reaction and randomly amplified polymorphic DNA techniques. A total of 9,334 A. baumannii isolates were detected, of which 4,484 isolates (48%) were identified as first positive isolates per unique patient. Most of the burden of disease was located in the ICUs (odds ratio, 2.64 [95% CI, 2.17-3.22]; p < 0.0001) and in the adult wards (odds ratio, 3.867 [95% CI, 2.71-5.52]; p < 0.0001). Respiratory specimens constituted the most frequent source (49%; odds ratio, 1.619 [95% CI, 1.391 1.884]; p < 0.0001). Of the 4,484 first isolates, 846 isolates (18.9%) were carbapenem nonsusceptible and 3,638 isolates (81.1%) were carbapenem susceptible. Over the years, the number of carbapenem nonsusceptible isolates increased, whereas the number of carbapenem susceptible decreased (p < 0.0001). The trauma ICU had the highest burden of carbapenem nonsusceptible first isolates (205 of 846; 24.2%). Seven clones were discovered among 144 carbapenem nonsusceptible isolates; one of these clones was found from 1999 to 2005. OXA-23 and OXA-40 were identified in 96 and 13 isolates, respectively. One isolate harbored a novel CTX M-115 enzyme. CONCLUSIONS: This constitutes the largest experience with A. baumannii reported to date from a single center. Half of all isolates were respiratory specimens and were from adult ICUs, especially trauma. Even though this was a polyclonal process, a single clone was identified in the hospital through a 6-year span. PMID- 23982022 TI - The role of potentially preventable hospital exposures in the development of acute respiratory distress syndrome: a population-based study. AB - OBJECTIVE: Acute respiratory distress syndrome is a common complication of critical illness, with high mortality and limited treatment options. Preliminary studies suggest that potentially preventable hospital exposures contribute to acute respiratory distress syndrome development. We aimed to determine the association between specific hospital exposures and the rate of acute respiratory distress syndrome development among at-risk patients. DESIGN: Population-based, nested, Matched case-control study. PATIENTS: Consecutive adults who developed acute respiratory distress syndrome from January 2001 through December 2010 during their hospital stay (cases) were matched to similar-risk patients without acute respiratory distress syndrome (controls). They were matched for 6 baseline characteristics. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Trained investigators blinded to outcome of interest reviewed medical records for evidence of specific exposures, including medical and surgical adverse events, inadequate empirical antimicrobial treatment, hospital-acquired aspiration, injurious mechanical ventilation, transfusion, and fluid and medication administration. Conditional logistic regression was used to calculate the risk associated with individual exposures. During the 10-year period, 414 patients with hospital-acquired acute respiratory distress syndrome were identified and matched to 414 at-risk, acute respiratory distress syndrome-free controls. Adverse events were highly associated with acute respiratory distress syndrome development (odds ratio, 6.2; 95% CI, 4.0-9.7), as were inadequate antimicrobial therapy, mechanical ventilation with injurious tidal volumes, hospital-acquired aspiration, and volume of blood products transfused and fluids administered. Exposure to antiplatelet agents during the at-risk period was associated with a decreased risk of acute respiratory distress syndrome. Rate of adverse hospital exposures and prevalence of acute respiratory distress syndrome decreased during the study period. CONCLUSIONS: Prevention of adverse hospital exposures in at risk patients may limit the development of acute respiratory distress syndrome. PMID- 23982023 TI - Intraoperative risk factors associated with postoperative pressure ulcers in critically ill patients: a retrospective observational study. AB - OBJECTIVE: The risk for pressure ulcers is rarely identified in the perioperative period, and the influence of this period on risk factors has not been as rigorously studied as the postoperative period. We hypothesized that intraoperative risk factors exist, which increase the likelihood of a postoperative new-onset pressure ulcer. DESIGN: A retrospective observational study. SETTING: A large midwestern U.S. quaternary care institution. PATIENTS: A total of 2,695 adult surgical patients underwent operative procedures and received care in one of three ICUs using an electronic documentation application. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was hospital-acquired pressure ulcer categorized as stages II, III, and IV; deep tissue injury; or unstageable. Univariate analyses comparing patients with and without the outcome of pressure ulcers were conducted for each preoperative characteristic or comorbidity. Patients were matched using the logit of the propensity score based solely on their preoperative comorbidities. Adjusted associations between development of pressure ulcers and intraoperative characteristics were determined in the postmatch cohort. We identified seven independent preoperative patients' characteristics and comorbidities in our adult surgical patient sample: American Society of Anesthesiologists risk classification 4 or 5, underweight body mass index, noncardiac surgery, history of congestive heart failure, renal disease, existing airway present prior to arrival in the operating room, and age. The only significant association in the matched dataset accounting for patient preoperative variability is the use of intraoperative blood products. CONCLUSION: Postoperative pressure ulcers developed in 10.7% of critically ill patients in our study. Only intraoperative use of blood products, not operative case length, hypotension, or vasopressor use, was associated with postoperative pressure ulcer development on adjusted analysis. PMID- 23982024 TI - The use of higher platelet: RBC transfusion ratio in the acute phase of trauma resuscitation: a systematic review. AB - OBJECTIVE: With the recognition of early coagulopathy, trauma resuscitation has shifted toward liberal platelet transfusions. The overall benefit of this strategy remains controversial. Our objective was to compare the effects of a liberal use of platelet (higher platelet:RBC ratios) with a conservative approach (lower ratios) in trauma resuscitation. DATA SOURCES: We systematically searched Medline, Embase, Web of Science, Biosis, Cochrane Central, and Scopus. STUDY SELECTION: Two independent reviewers selected randomized controlled trials and observational studies comparing two or more platelet:RBC ratios in trauma resuscitation. We excluded studies investigating the use of whole blood or hemostatic products. DATA EXTRACTION: Two independent reviewers extracted data and assessed the risk of bias. Primary outcomes were early (in ICU or within 30 d) and late (in hospital or after 30 d) mortality. Secondary outcomes were multiple organ failure, lung injury, and sepsis. DATA SYNTHESIS: From 6,123 citations, no randomized controlled trials were identified. We included seven observational studies (4,230 patients) addressing confounders through multivariable regression or propensity scores. Heterogeneity of studies precluded meta-analysis. Among the five studies including exclusively patients requiring massive transfusions, four observed a lower mortality with higher ratios. Two studies considering nonmassively bleeding patients observed no benefit of using higher ratios. Two studies evaluated the implementation of a massive transfusion protocol; only one study observed a decrease in mortality with higher ratios. Of the two studies at low risk of survival bias, one study observed a survival benefit. Three studies assessed secondary outcomes. One study observed an increase in multiple organ failure with higher ratios, whereas no study demonstrated an increased risk in lung injury or sepsis. CONCLUSIONS: There is insufficient evidence to strongly support the use of a precise platelet:RBC ratio for trauma resuscitation, especially in nonmassively bleeding patients. Randomized controlled trials evaluating both the safety and efficacy of liberal platelet transfusions are warranted. PMID- 23982025 TI - Bundle of measures for external cerebral ventricular drainage-associated ventriculitis. AB - OBJECTIVE: To assess the prevalence and outcome of external cerebral ventricular drainage-associated ventriculitis in neurocritical patients before and after the implementation of a bundle of external cerebral ventricular drainage-associated ventriculitis control measures. DESIGN: Clinical prospective case series. SETTING: University Hospital of Larissa, Greece. PATIENTS: Consecutive patients were recruited from the ICU of the hospital. Patient inclusion criteria included presence of external ventricular drainage and ICU stay more than 48 hours. INTERVENTION: The bundle of external cerebral ventricular drainage-associated ventriculitis control measures included 1) reeducation of ICU personnel on issues of infection control related to external cerebral ventricular drainage, 2) meticulous intraventricular catheter handling, 3) cerebrospinal fluid sampling only when clinically necessary, and 4) routine replacement of the drainage catheter on the seventh drainage day if the catheter was still necessary. The bundle was applied after an initial period (preintervention) where standard policy for external cerebral ventricular drainage-associated ventriculitis was established. MEASUREMENTS: External cerebral ventricular drainage-associated ventriculitis prevalence, external cerebral ventricular drainage-associated ventriculitis events per 1,000 drainage days (drain-associated infection rate), length of ICU stay, Glasgow Outcome Scale at 6 months, and risk factors for external cerebral ventricular drainage-associated ventriculitis. MAIN RESULTS: Eighty-two patients entered the study in the preintervention period and 57 patients during the intervention period. During the preintervention and intervention period, external cerebral ventricular drainage-associated ventriculitis prevalence was 28% and 10.5% (p = 0.02) and drain-associated infection rate was 18 and 7.1, respectively (p = 0.0001); mean (95% CI) length of ICU stay in patients who presented external cerebral ventricular drainage associated ventriculitis was 44.4 days (36.4-52.4 d), whereas mean (95% CI) length of ICU stay in patients who did not was 20 days (16.9-23.2 d) (p < 0.001). Furthermore, the length of ICU stay was associated with length of drainage (p = 0.0001). Therefore, the presence of external cerebral ventricular drainage associated ventriculitis and the length of drainage were the only variables associated with a prolonged ICU stay. Unfavorable outcome in Glasgow Outcome Scale at 6 months was not associated with the presence of external cerebral ventricular drainage-associated ventriculitis (p = 0.5). No significant differences were found when Glasgow Outcome Scale was analyzed according to the two study periods. CONCLUSIONS: The implementation of a bundle of measures for external cerebral ventricular drainage-associated ventriculitis control was associated with significantly decreased postintervention prevalence of the infection. PMID- 23982026 TI - Effects of propofol on patient-ventilator synchrony and interaction during pressure support ventilation and neurally adjusted ventilatory assist. AB - OBJECTIVES: Evaluating the physiologic effects of varying depths of propofol sedation on patient-ventilator interaction and synchrony during pressure support ventilation and neurally adjusted ventilatory assist. DESIGN: Prospective crossover randomized controlled trial. SETTING: University hospital ICU. PATIENTS: Fourteen intubated patients mechanically ventilated for acute respiratory failure. INTERVENTIONS: Six 25-minute trials randomly performed applying both pressure support ventilation and neurally adjusted ventilatory assist during wakefulness and with two doses of propofol, administered by Target Control Infusion, determining light (1.26 +/- 0.35 MUg/mL) and deep (2.52 +/- 0.71 MUg/mL) sedation, as defined by the bispectral index and Ramsay Sedation Scale. MEASUREMENTS AND MAIN RESULTS: We measured electrical activity of the diaphragm to assess neural drive and calculated its integral over time during 1 minute (?electrical activity of the diaphragm/min) to estimate diaphragm energy expenditure (effort), arterial blood gases, airway pressure, tidal volume and its coefficient of variation, respiratory rate, neural timing components, and calculated the ineffective triggering index. Increasing the depth of sedation did not cause significant modifications of respiratory timing, while determined a progressive significant decrease in neural drive (with both modes) and effort (in pressure support ventilation only). In pressure support ventilation, the difference in ineffective triggering index between wakefulness and light sedation was negligible (from 5.9% to 7.6%, p = 0.97); with deep sedation, however, ineffective triggering index increased up to 21.8% (p < 0.0001, compared to both wakefulness and light sedation). With neurally adjusted ventilatory assist, ineffective triggering index fell to 0%, regardless of the depth of sedation. With both modes, deep sedation caused a significant increase in PaCO2, which resulted, however, from different breathing patterns and patient-ventilator interactions. CONCLUSIONS: In pressure support ventilation, deep propofol sedation increased asynchronies, while light sedation did not. Propofol reduced the respiratory drive, while breathing timing was not significantly affected. Gas exchange and breathing pattern were also influenced by propofol infusion to an extent that varied with the depth of sedation and the mode of ventilation. PMID- 23982027 TI - External validation of the Emergency Trauma Score for early prediction of mortality in trauma patients. AB - OBJECTIVES: The Emergency Trauma Score has been developed for early estimation of mortality risk in adult trauma patients with an Injury Severity Score of 16 or higher. Emergency Trauma Score combines four early predictors available at the trauma resuscitation room: age, Glasgow Coma Scale, base excess, and prothrombin time. Our goal was to validate the Emergency Trauma Score in two large external cohorts. As the Injury Severity Score is not accurately known at the time patients present at the resuscitation room, we evaluated the performance of Emergency Trauma Score in all trauma patients. DESIGN: External validation study using data from two prospectively collected trauma registries. SETTING: Two academic level 1 trauma centers. PATIENTS: Adult patients admitted to the hospital after treatment at the trauma resuscitation room. INTERVENTION: Calibration and discrimination of the original Emergency Trauma Score were assessed within each cohort separately. MEASUREMENT AND MAIN RESULTS: A total of 4,418 consecutive patients were evaluated. Discrimination was good in both validation cohorts, with areas under the receiver-operating curve curves that were even higher (0.94 and 0.92, respectively) than that in the original cohort (0.83). Predicted mortality was systematically too high compared with actual mortality in patients with low-to-medium expected risk (< 25%). Calibration improved in the lower expected risk range after exclusion of patients with Injury Severity Score less than 16. CONCLUSIONS: The Emergency Trauma Score model performs well in discriminating between trauma patients who will survive and who will not. If applied to all trauma patients, predicted mortality risks are too high in the low-risk category. PMID- 23982028 TI - Association of low serum 25-hydroxyvitamin D levels and sepsis in the critically ill. AB - OBJECTIVE: We hypothesized that deficiency in 25-hydroxyvitamin D prior to hospital admission would be associated with sepsis in the critically ill. DESIGN: Two-center observational study of patients treated in medical and surgical ICUs. SETTING: Two hundred nine medical and surgical intensive care beds in two teaching hospitals in Boston, MA. PATIENTS: Three thousand three hundred eighty six patients, 18 years old or older, in whom 25-hydroxyvitamin D was measured prior to hospitalization between 1998 and 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: : Preadmission 25-hydroxyvitamin D was categorized as deficiency in 25-hydroxyvitamin D (<= 15 ng/mL), insufficiency (15-30 ng/mL), and sufficiency (>= 30 ng/mL). The primary outcome was sepsis as defined by International Classification of Diseases, 9th Edition, Clinical Modification and validated by the 2001 Society of Critical Care Medicine/European Society of Intensive Care Medicine, American College of Chest Physicians, American Thoracic Society, and Surgical Infection Society international sepsis definitions conference guidelines. Logistic regression examined the presence of sepsis 3 days prior to critical care initiation to 7 days after critical care initiation. Adjusted odds ratios were estimated by multivariable logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive for the risk of sepsis. In the full cohort, 25-hydroxyvitamin D deficiency is a significant predictor for the risk of International Classification of Diseases, 9th Edition, Clinical Modification-defined sepsis following multivariable adjustment, including age, gender, race, type (surgical vs medical), and Deyo-Charlson index (adjusted odds ratio, 1.51 [95% CI, 1.17-1.94]; p = 0.001) relative to patients with 25 hydroxyvitamin D sufficiency. In a subset of cohort patients enriched for those with International Classification of Diseases, 9th Edition, Clinical Modification diagnosed sepsis (n = 444), preadmission 25-hydroxyvitamin D deficiency is a significant predictor for the risk of conference guideline-defined sepsis following multivariable adjustment, including age, gender, race, type (surgical vs medical), and Acute Physiology and Chronic Health Evaluation II (adjusted odds ratio, 2.05 [95% CI, 1.19-3.52]; p = 0.009) relative to patients with 25 hydroxyvitamin D sufficiency. Furthermore, in cohort patients with International Classification of Diseases, 9th Edition, Clinical Modification-defined sepsis (n = 568), the multivariable adjusted risk of 90-day mortality was 1.6-fold higher in those with preadmission 25-hydroxyvitamin D values in the insufficient and deficient range, compared with those with preadmission vitamin D sufficiency (adjusted odds ratio, 1.63 [95% CI, 1.11-2.39]; p = 0.01). CONCLUSION: 25 hydroxyvitamin D deficiency prior to hospital admission is a significant predictor of sepsis in the critically ill. Additionally, patients with sepsis who are not vitamin D sufficient have an increased risk of mortality following critical care initiation. PMID- 23982029 TI - Treatment with neuromuscular blocking agents and the risk of in-hospital mortality among mechanically ventilated patients with severe sepsis. AB - OBJECTIVES: Recent trials suggest that treatment with neuromuscular blocking agents may improve survival in patients requiring mechanical ventilation for acute respiratory distress syndrome. We examined the association between receipt of a neuromuscular blocking agent and in-hospital mortality among mechanically ventilated patients with severe sepsis. DESIGN: A pharmacoepidemiologic cohort study of patients with sepsis and a respiratory infection who had been admitted to intensive care and placed on mechanical ventilation within the first 2 days of hospitalization. We used propensity score matching and instrumental variable methods to compare the outcomes of patients treated with neuromuscular blocking agents within the first 2 hospital days to those who were not. Sensitivity analysis was used to model the effects of a hypothetical unmeasured confounder. SETTING: Three hundred thirty-nine U.S. hospitals that participated in the Premier Perspective database between 2004 and 2006. PATIENTS: Seven thousand eight hundred sixty-four patients met inclusion criteria, including 1,818 (23%) who were treated with a neuromuscular blocking agent by hospital day 2. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients who received neuromuscular blocking agents were younger (mean age, 62 vs 68), more likely to be treated with vasopressors (69% vs 65%) and had a lower in-hospital mortality rate (31.9% vs 38.3%, p < 0.001). In 3,518 patients matched on the propensity for treatment, receipt of a neuromuscular blocking agent was associated with a reduced risk of in-hospital mortality (risk ratio, 0.88; 95% CI, 0.80, 0.96). An analysis using the hospital neuromuscular blocking agent-prescribing rate as an instrumental variable found receipt of a neuromuscular blocking agent associated with a 4.3% (95% CI, -11.5%, 1.5%) reduction in in-hospital mortality. CONCLUSIONS: Among mechanically ventilated patients with severe sepsis and respiratory infection, early treatment with a neuromuscular blocking agent is associated with lower in-hospital mortality. PMID- 23982030 TI - Frequency, risk factors, and outcomes of early unplanned readmissions to PICUs. AB - OBJECTIVES: To determine the rate of unplanned PICU readmissions, examine the characteristics of index admissions associated with readmission, and compare outcomes of readmissions versus index admissions. DESIGN: Retrospective cohort analysis. SETTING: Ninety North American PICUs that participated in the Virtual Pediatric Intensive Care Unit Systems. PATIENTS: One hundred five thousand four hundred thirty-seven admissions between July 2009 and March 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unplanned PICU readmission within 48 hours of index discharge was the primary outcome. Summary statistics, bivariate analyses, and mixed-effects logistic regression model with random effects for each hospital were performed.There were 1,161 readmissions (1.2%). The readmission rate varied among PICUs (0-3.3%), and acute respiratory (56%), infectious (35%), neurological (28%), and cardiovascular (20%) diagnoses were often present on readmission. Readmission risk increased in patients with two or more complex chronic conditions (adjusted odds ratio, 1.72; p < 0.001), unscheduled index admission (adjusted odds ratio, 1.37; p < 0.001), and transfer to an intermediate unit (adjusted odds ratio, 1.29; p = 0.004, compared with ward). Trauma patients had a decreased risk of readmission (adjusted odds ratio, 0.67; p = 0.003). Gender, race, insurance, age more than 6 months, perioperative status, and nighttime transfer were not associated with readmission. Compared with index admissions, readmissions had longer median PICU length of stay (3.1 vs 1.7 d, p < 0.001) and higher mortality (4% vs 2.5%, p = 0.002). CONCLUSIONS: Unplanned PICU readmissions were relatively uncommon, but were associated with worse outcomes. Several patient and admission characteristics were associated with readmission. These data help identify high-risk patient groups and inform risk-adjustment for standardized readmission rates. PMID- 23982031 TI - Independent external validation of the status epilepticus severity score. AB - OBJECTIVES: A clinical scoring system for patients with status epilepticus was developed for predicting outcome, planning the level of monitoring needed, and guiding treatment. The aim was to confirm the external validity and transportability of the Status Epilepticus Severity Score prediction functions for outcome in adult patients with status epilepticus. DESIGN: Observational cohort study. SETTING: Tertiary academic medical care center. PATIENTS: Consecutive adult ICU patients with status epilepticus. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: History of seizures, age, seizure type, and level of consciousness were determined at status epilepticus onset, in order to calculate the Status Epilepticus Severity Score. The main outcome measure was the ability to accurately predict the outcome of status epilepticus by measures of discrimination and calibration. Among 171 status epilepticus patients with a mean age of 64.1 years (+/- 16.3), mortality was 18%. The receiver operating characteristic curve for prediction of death by the Status Epilepticus Severity Score had an area under the curve of 0.744 with an optimal cutoff point greater than or equal to 4. Hosmer-Lemeshow statistics revealed good calibration of the Status Epilepticus Severity Score (chi-square goodness-of-fit test = 1.39; p = 0.845). CONCLUSIONS: This study is the first independent external validation of the predictive accuracy of the Status Epilepticus Severity Score and its transportability to ICU patients with status epilepticus. Measures of discrimination and calibration indicated that Status Epilepticus Severity Score performed reasonably well on our cohort of ICU patients with status epilepticus. However, the specific optimal cutoff point for survival versus death in our cohort was different than proposed. PMID- 23982032 TI - Enhanced protein-energy provision via the enteral route feeding protocol in critically ill patients: results of a cluster randomized trial. AB - OBJECTIVES: To determine the effect of the enhanced protein-energy provision via the enteral route feeding protocol, combined with a nursing educational intervention on nutritional intake, compared to usual care. DESIGN: Prospective, cluster randomized trial. SETTING: Eighteen ICUs from United States and Canada with low baseline nutritional adequacy. PATIENTS: One thousand fifty-nine mechanically ventilated, critically ill patients. INTERVENTIONS: A novel feeding protocol combined with a nursing educational intervention. MEASUREMENTS AND MAIN RESULTS: The two primary efficacy outcomes were the proportion of the protein and energy prescriptions received by study patients via the enteral route over the first 12 days in the ICU. Safety outcomes were the prevalence of vomiting, witnessed aspiration, and ICU-acquired pneumonia. The proportion of prescribed protein and energy delivered by enteral nutrition was greater in the intervention sites compared to the control sites. Adjusted absolute mean difference between groups in the protein and energy increases were 14% (95% CI, 5-23%; p = 0.005) and 12% (95% CI, 5-20%; p = 0.004), respectively. The intervention sites had a similar improvement in protein and calories when appropriate parenteral nutrition was added to enteral sources. Use of the enhanced protein-energy provision via the enteral route feeding protocol was associated with a decrease in the average time from ICU admission to start of enteral nutrition compared to the control group (40.7-29.7 hr vs 33.6-35.2 hr, p = 0.10). Complication rates were no different between the two groups. CONCLUSIONS: In ICUs with low baseline nutritional adequacy, use of the enhanced protein-energy provision via the enteral route feeding protocol is safe and results in modest but statistically significant increases in protein and calorie intake. PMID- 23982033 TI - Incidence and outcomes associated with early heart failure pharmacotherapy in patients with ongoing cardiogenic shock. AB - OBJECTIVES: Guidelines recommend beta-blockers and renin-angiotensin-aldosterone system blockers to improve long-term survival in hemodynamically stable myocardial infarction patients with a reduced left ventricular ejection fraction. The prevalence and outcomes associated with beta and renin-angiotensin aldosterone system blocker therapy in patients with ongoing cardiogenic shock is unknown. DESIGN: Secondary analysis of a randomized controlled trial. SETTING: In patients with cardiogenic shock lasting more than 24 hours enrolled in Tilarginine Acetate Injection in a Randomized International Study in Unstable Myocardial Infarction Patients With Cardiogenic Shock, we compared 30-day mortality in patients who received beta or renin-angiotensin-aldosterone system blockers (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or aldosterone antagonists) within 24 hours of randomization with those who did not. INTERVENTIONS: None. PATIENTS: The final study population included 240 patients. A total of 66 patients (27.5%) had either beta blocker or renin angiotensin-aldosterone system blocker administered within the first 24 hours after the diagnosis of cardiogenic shock. beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone antagonists were prescribed in 18.8%, 10.6%, and 5.0% of patients, respectively. MEASUREMENTS AND MAIN RESULTS: The observed 30-day mortality among patients was higher in patients who received beta or renin-angiotensin-aldosterone system blockers prior to cardiogenic shock resolution (27.3% vs 16.9%; adjusted hazard ratio, 2.36; 95% CI, 1.06-5.23; p = 0.035). Compared with patients not given beta or renin angiotensin-aldosterone system blockers, the 30-day mortality was higher among patients treated only with beta-blockers (33.3% vs 16.9%, p = 0.017) but not among those only treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (18.2% vs 16.9%, p = 1.000). CONCLUSIONS: The administration of beta or renin-angiotensin-aldosterone system blockers is common in North America and Europe in patients with myocardial infarction and cardiogenic shock prior to cardiogenic shock resolution. This therapeutic practice was independently associated with higher 30-day mortality, although a statistically significant difference was only observed in the subgroup of patients administered beta-blockers. PMID- 23982034 TI - Localization of sodium channel subtypes in mouse ventricular myocytes using quantitative immunocytochemistry. AB - Voltage-gated sodium channels are responsible for the rising phase of the action potential in cardiac muscle. Previously, both TTX-sensitive neuronal sodium channels (NaV1.1, NaV1.2, NaV1.3, NaV1.4 and NaV1.6) and the TTX-resistant cardiac sodium channel (NaV1.5) have been detected in cardiac myocytes, but relative levels of protein expression of the isoforms were not determined. Using a quantitative approach, we analyzed z-series of confocal microscopy images from individual mouse myocytes stained with either anti-NaV1.1, anti-NaV1.2, anti NaV1.3, anti-NaV1.4, anti-NaV1.5, or anti-NaV1.6 antibodies and calculated the relative intensity of staining for these sodium channel isoforms. Our results indicate that the TTX-sensitive channels represented approximately 23% of the total channels, whereas the TTX-resistant NaV1.5 channel represented 77% of the total channel staining in mouse ventricular myocytes. These ratios are consistent with previous electrophysiological studies in mouse ventricular myocytes. NaV1.5 was located at the cell surface, with high density at the intercalated disc, but was absent from the transverse (t)-tubular system, suggesting that these channels support surface conduction and inter-myocyte transmission. Low-level cell surface staining of NaV1.4 and NaV1.6 channels suggest a minor role in surface excitation and conduction. Conversely, NaV1.1 and NaV1.3 channels are localized to the t tubules and are likely to support t-tubular transmission of the action potential to the myocyte interior. This quantitative immunocytochemical approach for assessing sodium channel density and localization provides a more precise view of the relative importance and possible roles of these individual sodium channel protein isoforms in mouse ventricular myocytes and may be applicable to other species and cardiac tissue types. PMID- 23982036 TI - Nanotechnology: the ultimate alchemy. PMID- 23982035 TI - Barrier Isolators: A New, High-tech Option for the Preparation of Sterile Admixtures. PMID- 23982037 TI - Future Trends in High-technology Pharmacy Compounding. PMID- 23982039 TI - Basics of compounding: parenteral preparations. PMID- 23982038 TI - Topical secretin for the treatment of autism. PMID- 23982040 TI - Hormone replacement therapy: part 2-estrogen defined. PMID- 23982041 TI - The science behind hormone replacement therapy, part ! PMID- 23982042 TI - New perspectives on vancomycin use in home care, part 1. PMID- 23982043 TI - Cross-contamination in Porcelain Mortars. AB - Porcelain mortars and pestles are frequently used to comminute drug substances on a small scale and (in some cases) in the production of liquid and semisolid suspensions. Although it is generally accepted that removal of a drug substance from a rough surface by rinsing may be difficult and may lead to cross contamination, no hard data support that theory. In this study, the amount of salicylic acid remaining on a porcelain mortar after different washing procedures was quantified and compared with the amount remaining on a plastic mortar. Drug residues in the "mg" range on the porcelain mortars made common rinsing procedures appear inappropriate, but no traces of drug were detected on plastic mortars. In addition, the quality of suspension ointments with respect to particle size and homogeneity produced by the two types of mortars was compared. Porcelain and plastic mortars appeared equally suitable for use in the production of semisolid suspensions. PMID- 23982044 TI - Stability of an oral liquid dosage form of glycopyrrolate prepared from tablets. AB - A stability-indicating assay method has been developed to quantify glycopyrrolate in an oral liquid dosage form. The developed method is accurate and precise and has a percent relative standard deviation of 1.8 based on 5 injections. The deomposition product and the excipients present in the dosage form did not interfere with the assay procedure. An oral liquid dosage form (0.5 mg/mL in water) that was prepared using 1-mg commercially available tablets was stable for 25 days (loss in potency, 8.2%). During that time, the pH value of the dosage form decreased from 6.8 to 6.6. PMID- 23982045 TI - Stability of pentobarbital sodium after reconstitution in 0.9% sodium chloride injection and repackaging in glass and polypropylene syringes. AB - The stability of pentobarbital sodium (10 mg/mL) in 0.9% sodium chloride injection and pentobarbital sodium (50 mg/mL) after repackaging in glass and polypropylene syringes has been studied at 25 deg C by means of a stability indicating high-performance liquid chromatography assay method. The concentrations of the drug were directly related to peak heights, and the percent relative standard deviation based on 5 injections was 1.7. The pH value of the sample, which was prepared by diluting the injection (50 mg/mL) to 10 mg/mL with 0.9% sodium chloride injection, decreased from 9.2 to 8.2. At this pH, the free base began to crystallize out in less than 24 hours. After the undiluted commercial injection was repackaged in glass or polypropylene syringes, there was no significant loss of potency after 31 days of storage at 25 deg C. The pH value of the injection remained constant at 9.2.The pentobarbital sodium in injection appears to be very stable, because the loss in potency was only about 6.2% after it was boiled in water for 1.5 hours. PMID- 23982047 TI - Human exposure to aluminium. AB - Human activities have circumvented the efficient geochemical cycling of aluminium within the lithosphere and therewith opened a door, which was previously only ajar, onto the biotic cycle to instigate and promote the accumulation of aluminium in biota and especially humans. Neither these relatively recent activities nor the entry of aluminium into the living cycle are showing any signs of abating and it is thus now imperative that we understand as fully as possible how humans are exposed to aluminium and the future consequences of a burgeoning exposure and body burden. The aluminium age is upon us and there is now an urgent need to understand how to live safely and effectively with aluminium. PMID- 23982048 TI - PET imaging of serotoninergic neurotransmission with [(11)C]DASB and [(18)F]altanserin after focal cerebral ischemia in rats. AB - The use of selective serotonin reuptake inhibitors has shown functional improvement after stroke. Despite this, the role of serotoninergic neurotransmission after cerebral ischemia evolution and its involvement in functional recovery processes are still largely unknown. For this purpose, we performed in parallel in vivo magnetic resonance imaging and positron emission tomography (PET) with [(11)C]DASB and [(18)F]altanserin at 1, 3, 7, 14, 21, and 28 days after middle cerebral artery occlusion (MCAO) in rats. In the ischemic territory, PET with [(11)C]DASB and [(18)F]altanserin showed a dramatic decline in serotonin transporter (SERT) and 5-HT2A binding potential in the cortex and striatum after cerebral ischemia. Interestingly, a slight increase in [(11)C]DASB binding was observed from days 7 to 21 followed by the uppermost binding at day 28 in the ipsilateral midbrain. In contrast, no changes were observed in the contralateral hemisphere by using both radiotracers. Likewise, both functional and behavior testing showed major impaired outcome at day 1 after ischemia onset followed by a recovery of the sensorimotor function and dexterity from day 21 to day 28 after cerebral ischemia. Taken together, these results might evidence that SERT changes in the midbrain could have a key role in the functional recovery process after cerebral ischemia. PMID- 23982049 TI - NOX2 deficiency ameliorates cerebral injury through reduction of complexin II mediated glutamate excitotoxicity in experimental stroke. AB - Although NADPH oxidase (NOX)-mediated oxidative stress is considered one of the major mechanisms triggering the pathogenic actions of ischemic stroke and very recent studies have indicated that NADPH oxidase is a major source of reactive oxygen species (ROS) production controlling glutamate release, how neuronal NADPH oxidase activation is coupled to glutamate release is not well understood. Therefore, in this study, we used an in vivo transient middle cerebral artery occlusion model and in vitro primary cell cultures to test whether complexins, the regulators of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes necessary for vesicle fusion, are associated with NOX2 derived ROS and contribute to glutamate-mediated excitotoxicity in ischemic stroke. In this study, we first identified the upregulation of complexin II in the ischemic brain and evaluated its potential role in ischemic stroke showing that gene silencing of complexin II ameliorated cerebral injury as evidenced by reduced infarction volume, neurological deficit, and neuron necrosis accompanied by decreased glutamate levels, consistent with the results from NOX2(-/-) mice with ischemic stroke. We further demonstrated that complexin II expression was mediated by NOX2 in primary cultured neurons subjected to oxygen-glucose deprivation (OGD) and contributed to OGD-induced glutamate release and neuron necrosis via SNARE signaling. Taken together, these findings for the first time provide evidence that complexin II is a central target molecule that links NADPH oxidase-derived ROS to glutamate-mediated neuronal excitotoxicity in ischemic stroke. PMID- 23982053 TI - Tactile feedback display with spatial and temporal resolutions. AB - We report the electronic recording of the touch contact and pressure using an active matrix pressure sensor array made of transparent zinc oxide thin-film transistors and tactile feedback display using an array of diaphragm actuators made of an interpenetrating polymer elastomer network. Digital replay, editing and manipulation of the recorded touch events were demonstrated with both spatial and temporal resolutions. Analog reproduction of the force is also shown possible using the polymer actuators, despite of the high driving voltage. The ability to record, store, edit, and replay touch information adds an additional dimension to digital technologies and extends the capabilities of modern information exchange with the potential to revolutionize physical learning, social networking, e commerce, robotics, gaming, medical and military applications. PMID- 23982054 TI - Sjogren Syndrome-Associated Small Fiber Neuropathy: Characterization From a Prospective Series of 40 Cases. AB - We conducted the current study to analyze the clinical, immunologic, and neurophysiologic features of primary Sjogren syndrome (pSS)-associated sensory small fiber neuropathies (SFNs). Forty consecutive pSS patients with SFN were included. SFN was defined by the presence of suggestive sensory painful symptoms with normal nerve conduction studies and abnormal neurophysiologic tests for small nerve fibers or a low intraepidermal nerve fiber density at skin biopsy. Included patients were compared to 100 pSS patients without peripheral neuropathy.SFN patients were mainly female (92.5%). Age at pSS diagnosis was 55.3 +/- 13.1 years, and at SFN diagnosis, 58.9 +/- 11.8 years, with a median time to SFN diagnosis after symptom onset of 3.4 years. Clinical symptoms included burning pains (90%), numbness (87.5%), tingling (82.5%), pins and needles (72.5%), electric discharges (70%), and allodynia (55%). Dysautonomia included vasomotor symptoms (66%) and hyperhidrosis (47%). Abnormal neurophysiologic tests included laser evoked potentials (97.5%), thermal quantitative sensory testing (67.5%), and sympathetic skin reflex (40%). A skin biopsy revealed low intraepidermal nerve fiber density in 76% of the 17 tested patients.Compared to the 100 pSS patients without peripheral neuropathy, the 40 pSS-SFN patients were older at pSS diagnosis (55.3 +/- 13.1 vs. 49.5 +/- 14.9 yr; p = 0.03), and more often had xerostomia (97.5% vs. 81%; p = 0.01) and arthralgia (82.5% vs. 65.0%; p = 0.04). Immunologically, they were characterized by a lower prevalence of serum B-cell activation markers, that is, antinuclear antibodies (65% vs. 85%; p = 0.01), anti-SSA (42.5% vs. 71%; p = 0.002), and anti-SSB (17.5% vs. 39%; p = 0.017); rheumatoid factor (32.5% vs. 66%; p = 0.0005); and hypergammaglobulinemia (35% vs. 62%; p = 0.005).In conclusion, we report the main features of SFN in patients with pSS, the first such study to our knowledge. Our results show that patients with pSS-associated SFN are characterized by an older age at pSS diagnosis and a distinctive immunologic profile hallmarked by a lower frequency of serum B-cell activation markers. PMID- 23982055 TI - Glucocorticoid Therapy and the Risk of Infection in Patients With Newly Diagnosed Autoimmune Disease. AB - Glucocorticoid (GC) therapy is associated with the risk of life-threatening adverse events in patients with autoimmune disease. To determine accurately the incidence and predictors of GC-related adverse events during initial GC treatment, we conducted a cohort study. Patients with autoimmune disease who were initially treated with GCs in Japan National Hospital Organization (NHO) hospitals were enrolled. Cox proportional hazard regression was used to determine the independent risks for GC-related serious adverse events and mortality. Survival was analyzed according to the Kaplan-Meier method and was assessed with the log-rank test.The 604 patients had a total follow-up of 1105.8 person-years (mean, 1.9 year per patient). One hundred thirty-six patients had at least 1 infection with objective confirmation, and 71 patients had serious infections. Twenty-two cardiovascular events, 55 cases of diabetes, 30 fractures, 23 steroid psychosis events, and 4 avascular bone necrosis events occurred during the follow up period. The incidence of serious infections was 114.8 (95% confidence interval, 95.7-136.6) per 1000 person-years. After adjustment for covariates, the following independent risk factors for serious infection were found: elderly age (hazard ratio [HR], 1.25/10-yr age increment; p = 0.016), presence of interstitial lung disease (HR, 2.01; p = 0.011), high-dose GC use (>=29.9 mg/d) (HR, 1.71; p = 0.047), and low performance status (Karnofsky score, HR, 0.98/1 score increment; p = 0.002). During the follow-up period, 73 patients died, 35 of whom died of infection. Similarly, elderly age, the presence of interstitial lung disease, and high-dose GC use were found to be significant independent risk factors for mortality. The incidence of serious and life-threatening infection was higher in patients with autoimmune disease who were initially treated with GCs. Although the primary diseases are important confounding factors, elderly age, male sex, the presence of interstitial lung diseases, high-dose GCs, and low performance status were shown to be risk factors for serious infection and mortality. PMID- 23982056 TI - Impact of Cryoglobulinemic Syndrome on the Outcome of Chronic Hepatitis C Virus Infection: A 15-Year Prospective Study. AB - We evaluated the influence of cryoglobulinemic syndrome (CS) on the outcome of chronic hepatitis C virus (HCV) infection in a 15-year prospective study. We assessed a cohort of 950 chronically HCV-infected patients, collected from the beginning of 1990 to the end of 2010. All patients had received a liver histologic diagnosis. Mixed cryoglobulinemia (MC) was determined in 246 patients (25.8%), of whom 184 also had CS. They were assessed every 3 months for 15 years, at least; 141 patients with CS and 601 without MC completed the study.No spontaneous clearance of cryoglobulins was noted. Type II to type III spontaneous switching was ascertained in 1.6% (0.08%/yr) patients. The estimated progression rate of liver fibrosis was lower in CS(+) than in MC(-) patients (p < 0.05). The 15-year cumulative probability of developing cirrhosis and/or hepatocellular carcinoma was higher in MC(-) than in CS(+) patients (24.9% vs. 14.2%, p < 0.005 and 20.3% vs. 7.5%, p = 0.003, respectively). Renal insufficiency, neurologic impairment, or B-cell non-Hodgkin lymphoma were significantly more frequent in CS(+) than in MC(-) patients (32.6% vs. 3%, p < 0.0001; 31.2% vs. 4.8%, p < 0.0001; and 15% vs. 7.1%, p = 0.003, respectively). However, in spite of different morbidity features and causes of death, the 15-year survival rate was similar in the 2 groups (70.2% vs. 71.7%). Antiviral therapy had an undisputable impact on patient outcome.This 15-year prospective cohort study shows that, although CS has no influence on the overall survival of HCV-infected patients, it significantly modifies the natural history of chronically HCV-infected patients. PMID- 23982057 TI - Severe Measles Infection: The Spectrum of Disease in 36 Critically Ill Adult Patients. AB - France has recently witnessed a nationwide outbreak of measles. Data on severe forms of measles in adults are lacking. We sought to describe the epidemiologic, clinical, treatment, and prognostic aspects of the disease in adult patients who required admission to an intensive care unit (ICU). We performed a retrospective analysis of a cohort of 36 adults admitted to a total of 64 ICUs throughout France for complications of measles from January 1, 2009, to December 31, 2011. All cases of measles were confirmed by serologic testing and/or reverse transcription polymerase chain reaction.The cohort consisted of 21 male and 15 female patients, with a median age of 29.2 years (25th-75th interquartile range [IQR], 27.2-34.2 yr) and a median Simplified Acute Physiology Score (SAPS II) of 13 (IQR, 9-18). Among the 26 patients whose measles vaccination status was documented, none had received 2 injections. One patient had developed measles during childhood. Underlying comorbid conditions included chronic respiratory disease in 9 patients, immunosuppression in 7 patients, and obesity in 3 patients, while measles affected 5 pregnant women.Respiratory complications induced by measles infection led to ICU admission in 32 cases, and measles related neurologic complications led to ICU admission in 2 cases. Two patients were admitted due to concurrent respiratory and neurologic complications.Bacterial superinfection of measles-related airway infection was suspected in 28 patients and was documented in 8. Four cases of community acquired pneumonia, 6 cases of ventilator-associated pneumonia, 1 case of tracheobronchitis, and 2 cases of sinusitis were microbiologically substantiated.Of 11 patients who required mechanical ventilation, 9 developed acute respiratory distress syndrome (ARDS). Among the patients with ARDS, extraalveolar air leak complications occurred in 4 cases. Five patients died, all of whom were severely immunocompromised.On follow-up, 1 patient had severe chronic respiratory failure related to lung fibrosis, and 2 patients had mild lower limb paraparesis along with bladder dysfunction, both of which were ascribable to measles-induced encephalitis and myelitis. Among the 5 pregnant patients, the course of measles infection was uneventful, albeit 1 patient underwent emergent cesarean delivery because of fetal growth restriction.Measles is a disease with protean and potentially deceptive clinical manifestations, especially in the immunocompromised patient. Measles-associated pneumonitis and its complications, and less commonly postinfectious encephalomyelitis, are the main source of morbidity and mortality. In contrast with the usually benign course of the disease in immunocompetent patients, measles occurring in immunocompromised patients gives rise to lethal complications including ARDS, with or without bacterial superinfection. Other patients potentially at high risk for severe measles are young adults and pregnant women. Measles pneumonitis may predispose to air leak disease in patients using mechanical ventilation. To date, vaccination remains the most potent tool to control measles infection. PMID- 23982058 TI - The Spectrum of FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia: New Insights Based on a Survey of 44 Cases. AB - Imatinib is the treatment of choice for FIP1L1/PDGFRA (F/P)-associated chronic eosinophilic leukemia (F/P CEL), but its optimal dosing, duration, and possibility of discontinuation are still a matter of debate. A retrospective multicenter study was conducted with 44 F/P CEL patients identified in the French Eosinophil Network and treated with imatinib. The most frequently involved systems were skin (57%), spleen (52%), and lung (45%), and eosinophilic heart disease was observed in 15 patients (34%). Complete hematologic response (CHR) was obtained in all patients, and complete molecular response (CMR) in 95% of patients (average initial imatinib dose, 165 mg/d). For 29 patients the imatinib dose was tapered with a maintenance dose of 58 mg/d (+/-34 mg/d), allowing sustained CHR and CMR. None of the patients developed resistance during a median follow-up of 52.3 months (range, 1.4-97.4 mo). Imatinib was stopped in 11 patients; 6 of the patients subsequently relapsed, but 5 remained in persistent CHR or CMR (range, 9-88 mo). These results confirm that an initial low-dose regimen of imatinib (100 mg/d) followed by a lower maintenance dose can be efficient for obtaining long-term CHR and CMR. Our data also suggest that imatinib can be stopped in some patients without molecular relapse. PMID- 23982059 TI - Prevalence of infarct and villous clumps, and the expression of alpha-smooth muscle actin in the placental basal plate in severe preeclampsia. AB - The present study was conducted to investigate the prevalence of multifocal infarcts and multifocal villous clumps, as well as the expression of alpha-smooth muscle actin (alpha-SMA) in the basal plate of the placenta. Multifocal infarcts and/or multifocal villous clumps were more frequently observed in early onset severe preeclampsia (EOSPE; n=20) compared with the early control (n=18), late onset severe preeclampsia (LOSPE; n=20) and late control (n=20) groups. Infarct in transitional and late stages was significantly more frequent compared with that in the early stage in EOSPE. In LOSPE, the infarct in the early stage was significantly increased compared with transitional and late stages. The expression of alpha-SMA mRNA and protein was determined by RT-PCR and western blotting, respectively, and increased progressively in late, transitional and early infarct, and positively correlated with the number of smooth muscle cells of villous vessels and myofibroblasts of villous stroma studied by immunohistochemistry. These results indicated that multifocal infarct and multifocal villous clumps may affect the blood flow through the basal plate, not only by directly blocking vessels, but also by indirectly making the vessels extruded by contraction of cells stained by alpha-SMA. In addition, foci in the early stage may be more important in affecting the contractility of the placental basal plate. PMID- 23982060 TI - Competitive migration behaviors of multiple ions and their impacts on ion exchange resin packed microbial desalination cell. AB - Mixed ion-exchange resins packed microbial desalination cell (R-MDC) could stabilize the internal resistance, however, the impacts of multiple ions on R-MDC performance was unclear. This study investigated the desalination performance, multiple ions migration behaviors and their impacts on R-MDCs fed with salt solution containing multiple anions and cations. Results showed that R-MDC removed multiple anions better than multiple cations with desalination efficiency of 99% (effluent conductivity <0.05 ms/cm) at hydraulic retention time of 50 h. Competitive migration order was SO4(2-)>NO3(-)>Cl(-) for anions and Ca(2+)~Mg(2+)>NH4(+)>Na(+) for cations, jointly affected by both their molar conductivity and exchange selectivity on resins. After long-term operation, the existence of higher concentration Ca(2+) and Mg(2+) caused the electric conductivity of mixed resins decrease and scaling on the surface of cation exchange membrane adjoined with cathode chamber, suggesting that R-MDC would be more suitable for desalination of water with lower hardness. PMID- 23982062 TI - Evaluation of nutrient removal efficiency and microbial enzyme activity in a baffled subsurface-flow constructed wetland system. AB - In this study, the enzyme activities and their relationships to domestic wastewater purification are investigated in four different types of subsurface flow constructed wetlands (CWs), namely the traditional horizontal subsurface flow, horizontal baffled subsurface-flow, vertical baffled subsurface-flow, and composite baffled subsurface-flow CWs. Results showed that the urease activity in the composite baffled subsurface-flow CW was significantly higher than in the other three CWs, while the phosphatase activity in the vertical baffled subsurface-flow CW were higher than in the other three CWs. There were significant and very significant correlations between the activities of urease and the removal rates of TN and NH4(+)-N for the horizontal baffled flow, horizontal subsurface flow, and composite baffled subsurface flow CWs. This study suggests that the activity of urease in the root zones of those three CWs is an important indicator for N purification from wastewaters. PMID- 23982061 TI - Inhibitory effects of soluble algae products (SAP) released by Scenedesmus sp. LX1 on its growth and lipid production. AB - Soluble algal products (SAP) accumulated in culture medium via water reuse may affect the growth of microalga during the cultivation. Scenedesmus sp. LX1, a freshwater microalga, was used in this study to investigate the effect of SAP on growth and lipid production of microalga. Under the SAP concentrations of 6.4 25.8 mg L(-1), maximum algal density (K) and maximum growth rate (Rmax) of Scenedesmus sp. LX1 were decreased by 50-80% and 35-70% compared with the control group, respectively. The effect of SAP on lipid accumulation of Scenedesmus sp. LX1 was non-significant. According to hydrophilic-hydrophobic and acid-base properties, SAP was fractionized into six fractions. All of the fractions could inhibit the growth of Scenedesmus sp. LX1. Organic bases (HIB, HOB) and hydrophilic acids (HIA) showed the strongest inhibition. HIA could also decrease the lipid content of Scenedesmus sp. LX1 by 59.2%. As the inhibitory effect, SAP should be seriously treated before water reuse. PMID- 23982063 TI - Salinity manipulation as an effective method for enhanced starch production in the marine microalga Tetraselmis subcordiformis. AB - Microalgal starch is considered a promising feedstock for bioethanol production. The biomass and starch accumulation in the marine microalga Tetraselmis subcordiformis were characterized under different salinities in response to nitrogen repletion (+N) or depletion (-N) at high irradiance (HI) or low irradiance (LI). Under favorable nutritional conditions (HI+N), biomass accumulation was seldom affected under 20% normal salinity, though starch accumulation were somewhat reduced. Increased salinity impaired overall biomass and starch accumulation, though it led to a temporary starch accumulation at initial cultivation phase. Under nitrogen deprivation, decreased salinity strengthened biomass and starch accumulation regardless of irradiance. The highest starch content of 58.2% dry weight and starch productivity of 0.62 g L( 1) d(-1) were obtained under HI-N with 20% normal salinity. Decreased salinity combined with -N generated moderate stress to facilitate starch accumulation. Salinity manipulation can be effectively applied for enhanced starch production in marine microalgae. PMID- 23982064 TI - Biomechanical analysis using infrared thermography of a traditional metal plate versus a carbon fibre/epoxy plate for Vancouver B1 femur fractures. AB - Traditional high-stiffness metal plates for Vancouver B1 femur shaft fractures below the tip of a hip implant can cause stress shielding, bone resorption, and implant loosening. This is the first study to compare the biomechanics of a traditional metal plate versus a low-stiffness carbon fibre/epoxy composite plate for this injury. A total hip replacement was implanted in two previously validated intact artificial femurs. Femurs were fitted with either a metal or composite plate and had a 5 mm fracture gap created to simulate a Vancouver B1 shaft fracture. Femurs were cyclically loaded using 5 Hz at 7 degrees of adduction with an average axial load of 800 N (range = 400-1200 N). Overall mechanical stiffnesses and femur and plate thermographic stresses were obtained. Femur/metal plate stiffness (698 N/mm) was only 12% higher than femur/composite plate stiffness (625 N/mm). The femur with the composite plate had 22.7% higher combined average stress compared to the femur with the metal plate, having specific differences of 29.5% (anterior view), 33.9% (posterior view), 1.0% (medial view), and 26.4% (lateral view). The composite plate itself had an average 21.1% reduction in stress compared to the metal plate. The composite plate reduced stress shielding, yet provided adequate stiffness. PMID- 23982065 TI - Effect of hydration on the frequency-dependent viscoelastic properties of articular cartilage. AB - The aim of this study was to determine the effect of tissue hydration on the frequency-dependant viscoelastic properties of articular cartilage. Such changes were determined at frequencies associated with normal (1-10 Hz) and impulsive/traumatic (90 Hz) heel-strike times. Cartilage on bone samples, obtained from bovine humeral heads, was tested when hypo-hydrated and hyper hydrated using dynamic mechanical analysis. Dynamic mechanical analysis was performed at a range of frequencies between 1 and 90 Hz. Hypo-hydration increased the stiffness of cartilage as compared to hyper-hydrated cartilage; this increase was greater at higher frequencies. The storage modulus and stiffness increased in hypo-hydrated cartilage as compared to hyper-hydrated cartilage. However, the loss modulus and stiffness increased when cartilage was hypo-hydrated as compared to hyper-hydrated, but these increases were not frequency dependent. An impulsive heel-strike time may result in a greater increase of stiffness in hypo-hydrated cartilage, compared with hyper-hydrated cartilage. However, the ratio of storage to loss stiffness was greater for hyper-hydrated cartilage, thereby, reducing the tissue's ability to dissipate energy and increasing the likelihood of cartilage rupture. PMID- 23982066 TI - Advantages of using volar vein repair in finger replantations. AB - Providing adequate venous outflow is essential in finger replantation surgeries. For a successful result, the quality and quantity of venous repairs should be adequate to drain arterial inflow. The digital dorsal venous plexus is a reliable source of material for venous repairs. Classically, volar digital veins have been used only when no other alternative was available. However, repairing volar veins to augment venous outflow has a number of technical advantages and gives a greater chance of survival. Increasing the repaired vein:artery ratio also increases the success of replantation. The volar skin, covering the volar vein, is less likely to be avulsed during injury and is also less likely to turn necrotic, than dorsal skin, after the replantation surgery. Primary repair of dorsal veins can be difficult due to tightness ensuing from arthrodesis of the underlying joint in flexion. In multiple finger replantations, repairing the volar veins after arterial repair and continuing to do so for each finger in the same way without changing the position of the hand and surgeon save time. In amputations with tissue loss, the size discrepancy is less for volar veins than for dorsal veins. We present the results of 366 finger replantations after volar vein repairs. PMID- 23982067 TI - The superficial circumflex iliac artery perforator flap in intra-oral reconstruction. AB - INTRODUCTION: The superficial circumflex iliac artery perforator (SCIP) flap is a modification of the groin flap using perforators of the superficial circumflex iliac artery (SCIA). It has mainly been used in lower-limb reconstruction with no descriptions in the literature of its use in intra-oral soft-tissue head and neck reconstruction. This article reports the initial Newcastle experience. METHODS: Data were gathered prospectively for the first five head and neck patients with SCIP flap reconstruction. All patients had a speech and swallowing assessment as part of their post-operative follow-up. RESULTS: An SCIP flap was used following the resection for four intra-oral squamous cell carcinomas (SCCs) and one pharyngeal SCC. There was no flap compromise and excellent functional outcome at 6 months. The donor-site morbidity was minimal with direct closure achieved in each case leaving a scar easily concealed in the groin crease. CONCLUSIONS: Overall, the results at both the primary and donor sites in our first five cases have been aesthetically and functionally excellent. The flap pedicle easily reached the common recipient vessels in the neck. The vessels can be of smaller calibre but well within the scope of the microsurgeon. The SCIP flap appears to offer a thin, pliable, reliable flap with an excellent donor site. PMID- 23982068 TI - Yersinia pestis subverts the dermal neutrophil response in a mouse model of bubonic plague. AB - The majority of human Yersinia pestis infections result from introduction of bacteria into the skin by the bite of an infected flea. Once in the dermis, Y. pestis can evade the host's innate immune response and subsequently disseminate to the draining lymph node (dLN). There, the pathogen replicates to large numbers, causing the pathognomonic bubo of bubonic plague. In this study, several cytometric and microscopic techniques were used to characterize the early host response to intradermal (i.d.) Y. pestis infection. Mice were infected i.d. with fully virulent or attenuated strains of dsRed-expressing Y. pestis, and tissues were analyzed by flow cytometry. By 4 h postinfection, there were large numbers of neutrophils in the infected dermis and the majority of cell-associated bacteria were associated with neutrophils. We observed a significant effect of the virulence plasmid (pCD1) on bacterial survival and neutrophil activation in the dermis. Intravital microscopy of i.d. Y. pestis infection revealed dynamic interactions between recruited neutrophils and bacteria. In contrast, very few bacteria interacted with dendritic cells (DCs), indicating that this cell type may not play a major role early in Y. pestis infection. Experiments using neutrophil depletion and a CCR7 knockout mouse suggest that dissemination of Y. pestis from the dermis to the dLN is not dependent on neutrophils or DCs. Taken together, the results of this study show a very rapid, robust neutrophil response to Y. pestis in the dermis and that the virulence plasmid pCD1 is important for the evasion of this response. IMPORTANCE: Yersinia pestis remains a public health concern today because of sporadic plague outbreaks that occur throughout the world and the potential for its illegitimate use as a bioterrorism weapon. Since bubonic plague pathogenesis is initiated by the introduction of Y. pestis into the skin, we sought to characterize the response of the host's innate immune cells to bacteria early after intradermal infection. We found that neutrophils, innate immune cells that engulf and destroy microbes, are rapidly recruited to the injection site, irrespective of strain virulence, indicating that Y. pestis is unable to subvert neutrophil recruitment to the site of infection. However, we saw a decreased activation of neutrophils that were associated with Y. pestis strains harboring the pCD1 plasmid, which is essential for virulence. These findings indicate a role for pCD1-encoded factors in suppressing the activation/stimulation of these cells in vivo. PMID- 23982069 TI - Vibrio cholerae ToxR downregulates virulence factor production in response to cyclo(Phe-Pro). AB - Vibrio cholerae is an aquatic organism that causes the severe acute diarrheal disease cholera. The ability of V. cholerae to cause disease is dependent upon the production of two critical virulence determinants, cholera toxin (CT) and the toxin-coregulated pilus (TCP). The expression of the genes that encode for CT and TCP production is under the control of a hierarchical regulatory system called the ToxR regulon, which functions to activate virulence gene expression in response to in vivo stimuli. Cyclic dipeptides have been found to be produced by numerous bacteria, yet their biological function remains unknown. V. cholerae has been shown to produce cyclo(Phe-Pro). Previous studies in our laboratory demonstrated that cyclo(Phe-Pro) inhibited V. cholerae virulence factor production. For this study, we report on the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We have demonstrated that exogenous cyclo(Phe-Pro) activated the expression of leuO, a LysR-family regulator that had not been previously associated with V. cholerae virulence. Increased leuO expression repressed aphA transcription, which resulted in downregulation of the ToxR regulon and attenuated CT and TCP production. The cyclo(Phe-Pro)-dependent induction of leuO expression was found to be dependent upon the virulence regulator ToxR. Cyclo(Phe-Pro) did not affect toxR transcription or ToxR protein levels but appeared to enhance the ToxR-dependent transcription of leuO. These results have identified leuO as a new component of the ToxR regulon and demonstrate for the first time that ToxR is capable of downregulating virulence gene expression in response to an environmental cue. IMPORTANCE: The ToxR regulon has been a focus of cholera research for more than three decades. During this time, a model has emerged wherein ToxR functions to activate the expression of Vibrio cholerae virulence factors upon host entry. V. cholerae and other enteric bacteria produce cyclo(Phe-Pro), a cyclic dipeptide that we identified as an inhibitor of V. cholerae virulence factor production. This finding suggested that cyclo(Phe-Pro) was a negative effector of virulence factor production and represented a molecule that could potentially be exploited for therapeutic development. In this work, we investigated the mechanism by which cyclo(Phe-Pro) inhibited virulence factor production. We found that cyclo(Phe-Pro) signaled through ToxR to activate the expression of leuO, a new virulence regulator that functioned to repress virulence factor production. Our results have identified a new arm of the ToxR regulon and suggest that ToxR may play a broader role in pathogenesis than previously known. PMID- 23982070 TI - Clathrin- and Arp2/3-independent endocytosis in the fungal pathogen Candida albicans. AB - Clathrin-mediated endocytosis (CME) is conserved among eukaryotes and has been extensively analyzed at a molecular level. Here, we present an analysis of CME in the human fungal pathogen Candida albicans that shows the same modular structure as those in other fungi and mammalian cells. Intriguingly, C. albicans is perfectly viable in the absence of Arp2/3, an essential component of CME in other systems. In C. albicans, Arp2/3 function remains essential for CME as all 15 proteins tested that participate in CME, including clathrin, lose their characteristic dynamics observed in wild-type (WT) cells. However, since arp2/3 cells are still able to endocytose lipids and fluid-phase markers, but not the Ste2 and Mup1 plasma membrane proteins, there must be an alternate clathrin independent pathway we term Arp2/3-independent endocytosis (AIE). Characterization of AIE shows that endocytosis in arp2 mutants relies on actin cables and other Arp2/3-independent actin structures, as inhibition of actin functions prevented cargo uptake in arp2/3 mutants. Transmission electron microscopy (TEM) showed that arp2/3 mutants still formed invaginating tubules, cell structures whose proper functions are believed to heavily rely on Arp2/3. Finally, Prk1 and Sjl2, two proteins involved in patch disassembly during CME, were not correctly localized to sites of endocytosis in arp2 mutants, implying a role of Arp2/3 in CME patch disassembly. Overall, C. albicans contains an alternative endocytic pathway (AIE) that relies on actin cable function to permit clathrin-independent endocytosis (CIE) and provides a system to further explore alternate endocytic routes that likely exist in fungal species. IMPORTANCE: There is a well-established process of endocytosis that is generally used by eukaryotic cells termed clathrin-mediated endocytosis (CME). Although the details are somewhat different between lower and higher eukaryotes, CME appears to be the dominant endocytic process in all eukaryotes. While fungi such as Saccharomyces cerevisiae have proven excellent models for dissecting the molecular details of endocytosis, loss of CME is so detrimental that it has been difficult to study alternate pathways functioning in its absence. Although the fungal pathogen Candida albicans has a CME pathway that functions similarly to that of S. cerevisiae, inactivation of this pathway does not compromise growth of yeast-form C. albicans. In these cells, lipids and fluid-phase molecules are still endocytosed in an actin-dependent manner, but membrane proteins are not. Thus, C. albicans provides a powerful model for the analysis of CME-independent endocytosis in lower eukaryotes. PMID- 23982071 TI - The molecular mechanisms of allosteric mutations impairing MepR repressor function in multidrug-resistant strains of Staphylococcus aureus. AB - Overexpression of the Staphylococcus aureus multidrug efflux pump MepA confers resistance to a wide variety of antimicrobials. mepA expression is controlled by MarR family member MepR, which represses mepA and autorepresses its own production. Mutations in mepR are a primary cause of mepA overexpression in clinical isolates of multidrug-resistant S. aureus. Here, we report crystal structures of three multidrug-resistant MepR variants, which contain the single amino-acid substitution A103V, F27L, or Q18P, and wild-type MepR in its DNA-bound conformation. Although each mutation impairs MepR function by decreasing its DNA binding affinity, none is located in the DNA binding domain. Rather, all are found in the linker region connecting the dimerization and DNA binding domains. Specifically, the A103V substitution impinges on F27, which resolves potential steric clashes via displacement of the DNA binding winged-helix-turn-helix motifs that lead to a 27-fold reduction in DNA binding affinity. The F27L substitution forces F104 into an alternative rotamer, which kinks helix 5, thereby interfering with the positioning of the DNA binding domains and decreasing mepR operator affinity by 35-fold. The Q18P mutation affects the MepR structure and function most significantly by either creating kinks in the middle of helix 1 or completely unfolding its C terminus. In addition, helix 5 of Q18P is either bent or completely dissected into two smaller helices. Consequently, DNA binding is diminished by 2,000-fold. Our structural studies reveal heretofore-unobserved allosteric mechanisms that affect repressor function of a MarR family member and result in multidrug-resistant Staphylococcus aureus. IMPORTANCE: Staphylococcus aureus is a major health threat to immunocompromised patients. S. aureus multidrug-resistant variants that overexpress the multidrug efflux pump mepA emerge frequently due to point mutations in MarR family member MepR, the mepA transcription repressor. Significantly, the majority of MepR mutations identified in these S. aureus clinical isolates are found not in the DNA binding domain but rather in a linker region, connecting the dimerization and DNA binding domains. The location of these mutants underscores the critical importance of a properly functioning allosteric mechanism that regulates MepR function. Understanding the dysregulation of such allosteric MepR mutants underlies this study. The high resolution structures of three such allosteric MepR mutants reveal unpredictable conformational consequences, all of which preclude cognate DNA binding, while biochemical studies emphasize their debilitating effects on DNA binding affinity. Hence, mutations in the linker region of MepR and their structural consequences are key generators of multidrug-resistant Staphylococcus aureus. PMID- 23982072 TI - Redox and light control the heme-sensing activity of AppA. AB - The DNA binding activity of the photosystem-specific repressor PpsR is known to be repressed by the antirepressor AppA. AppA contains a blue-light-absorbing BLUF domain and a heme-binding SCHIC domain that controls the interaction of AppA with PpsR in response to light and heme availability. In this study, we have solved the structure of the SCHIC domain and identified the histidine residue that is critical for heme binding. We also demonstrate that dark-adapted AppA binds heme better than light-excited AppA does and that heme bound to the SCHIC domain significantly reduces the length of the BLUF photocycle. We further show that heme binding to the SCHIC domain is affected by the redox state of a disulfide bridge located in the Cys-rich carboxyl-terminal region. These results demonstrate that light, redox, and heme are integrated inputs that control AppA's ability to disrupt the DNA binding activity of PpsR. IMPORTANCE: Photosynthetic bacteria must coordinate synthesis of the tetrapyrroles cobalamin, heme, and bacteriochlorophyll, as overproduction of the latter two is toxic to cells. A key regulator controlling tetrapyrrole biosynthesis is PpsR, and the activity of PpsR is controlled by the heme-binding and light-regulated antirepressor AppA. We show that AppA binds heme only under dark conditions and that heme binding significantly affects the length of the AppA photocycle. Since AppA interacts with PpsR only in the dark, bound heme thus stimulates the antirepressor activity of PpsR. This causes the redirection of tetrapyrrole biosynthesis away from heme into the bacteriochlorophyll branch. PMID- 23982073 TI - Genome and transcriptome adaptation accompanying emergence of the definitive type 2 host-restricted Salmonella enterica serovar Typhimurium pathovar. AB - Salmonella enterica serovar Typhimurium definitive type 2 (DT2) is host restricted to Columba livia (rock or feral pigeon) but is also closely related to S. Typhimurium isolates that circulate in livestock and cause a zoonosis characterized by gastroenteritis in humans. DT2 isolates formed a distinct phylogenetic cluster within S. Typhimurium based on whole-genome-sequence polymorphisms. Comparative genome analysis of DT2 94-213 and S. Typhimurium SL1344, DT104, and D23580 identified few differences in gene content with the exception of variations within prophages. However, DT2 94-213 harbored 22 pseudogenes that were intact in other closely related S. Typhimurium strains. We report a novel in silico approach to identify single amino acid substitutions in proteins that have a high probability of a functional impact. One polymorphism identified using this method, a single-residue deletion in the Tar protein, abrogated chemotaxis to aspartate in vitro. DT2 94-213 also exhibited an altered transcriptional profile in response to culture at 42 degrees C compared to that of SL1344. Such differentially regulated genes included a number involved in flagellum biosynthesis and motility. IMPORTANCE Whereas Salmonella enterica serovar Typhimurium can infect a wide range of animal species, some variants within this serovar exhibit a more limited host range and altered disease potential. Phylogenetic analysis based on whole-genome sequences can identify lineages associated with specific virulence traits, including host adaptation. This study represents one of the first to link pathogen-specific genetic signatures, including coding capacity, genome degradation, and transcriptional responses to host adaptation within a Salmonella serovar. We performed comparative genome analysis of reference and pigeon-adapted definitive type 2 (DT2) S. Typhimurium isolates alongside phenotypic and transcriptome analyses, to identify genetic signatures linked to host adaptation within the DT2 lineage. PMID- 23982076 TI - The labeling debate in the United States. AB - The mandatory labeling of genetically modified (GM) food has become the predominant policy issue concerning biotechnology in the United States. The controversy over GM labeling is being debated at several different levels and branches of government. At the federal level, the Food and Drug Administration, which has primary jurisdiction over food safety and labeling, has steadfastly refused to require labeling of GM foods since 1992 based on its conclusion that GM foods as a category present no unique or higher risks than other foods. Proposed legislation has been repeatedly introduced in the US. Congress over the years to mandate GM labeling, but has made very little progress. With federal labeling requirements apparently stalled, the main activity has switched to the state level, where numerous individual states are considering mandatory GM labeling, either through legislation or proposition. The debate over GM labeling, at both the federal and state levels, has focused on five issues: (1) public opinion; (2) the legality of labeling requirements; (3) the risks and benefits of GM foods; (4) the costs and burdens of GM labeling; and (5) consumer choice. While the pro-labeling forces argue that all of these factors weigh in favor of mandatory GM labeling, a more careful evaluation of the evidence finds that all five factors weigh decisively against mandatory GM labeling requirements. PMID- 23982075 TI - Role of protein A in the evasion of host adaptive immune responses by Staphylococcus aureus. AB - Heritable defects in human B cell/antibody development are not associated with increased susceptibility to Staphylococcus aureus infection. Protein A (SpA), a surface molecule of S. aureus, binds the Fcgamma domain of immunoglobulin (Ig) and cross-links the Fab domain of VH3-type B cell receptors (IgM). Here we generated S. aureus spa variants harboring amino acid substitutions at four key residues in each of the five Ig-binding domains of SpA. Wild-type S. aureus required SpA binding to Ig to resist phagocytosis and SpA-mediated B cell receptor cross-linking to block antibody development in mice. The spaKKAA mutant, which cannot bind Ig or IgM, was phagocytosed and elicited B cell responses to key virulence antigens that protected animals against lethal S. aureus challenge. The immune evasive attributes of S. aureus SpA were abolished in uMT mice lacking mature B cells and antibodies. Thus, while wild-type S. aureus escapes host immune surveillance, the spaKKAA variant elicits adaptive responses that protect against recurrent infection. IMPORTANCE: Staphylococcus aureus causes recurrent skin and bloodstream infections without eliciting immunity. Heritable defects in neutrophil and T cell function, but not B cell or antibody development, are associated with increased incidence of S. aureus infection, and efforts to develop antibody-based S. aureus vaccines have thus far been unsuccessful. We show here that the Fcgamma and VH3-type Fab binding activities of staphylococcal protein A (SpA) are essential for S. aureus escape from host immune surveillance in mice. The virulence attributes of SpA in mice required mature B cells and immunoglobulin. These results suggest that antibodies and B cells play a key role in the pathogenesis of staphylococcal infections and provide insights into the development of a vaccine against S. aureus. PMID- 23982074 TI - Fc gamma receptor 3A polymorphism and risk for HIV-associated cryptococcal disease. AB - Cryptococcus neoformans is one of the most common causes of fungal disease in HIV infected persons, but not all of those who are infected develop cryptococcal disease (CD). Although CD4(+) T cell deficiency is a risk factor for HIV associated CD, polymorphisms of phagocytic Fc gamma receptors (FCGRs) have been linked to CD risk in HIV-uninfected persons. To investigate associations between FCGR2A 131 H/R and FCGR3A 158 F/V polymorphisms and CD risk in HIV-infected persons, we performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS): 55 who were HIV infected and developed CD and a matched control group of 54 who were HIV infected and 55 who were HIV uninfected. Using additive and allelic statistical models for analysis, the high-affinity FCGR3A 158V allele was significantly associated with CD status after adjusting for race/ethnicity (odds ratio [OR], 2.1; P = 0.005), as was the FCGR3A 158 VV homozygous genotype after adjusting for race/ethnicity, rate of CD4(+) T cell decline, and nadir CD4(+) T cell count (OR, 21; P = 0.005). No associations between CD and FCGR2A 131 H/R polymorphism were identified. In binding studies, human IgG (hIgG)-C. neoformans complexes exhibited more binding to CHO-K1 cells expressing FCGR3A 158V than to those expressing FCGR3A 158F, and in cytotoxicity assays, natural killer (NK) cells expressing FCGR3A 158V induced more C. neoformans-infected monocyte cytotoxicity than those expressing FCGR3A 158F. Together, these results show an association between the FCGR3A 158V allele and risk for HIV-associated CD and suggest that this polymorphism could promote C. neoformans pathogenesis via increased binding of C. neoformans immune complexes, resulting in increased phagocyte cargo and/or immune activation. IMPORTANCE: HIV-associated CD4(+) T cell deficiency is a sine qua non for HIV associated cryptococcal disease (CD), but not all patients with CD4(+) T cell deficiency develop CD despite serological evidence of previous infection. At present, there are no biomarkers that predict HIV-associated CD risk. The goal of our study was to understand whether Fc gamma receptor (FCGR) polymorphisms that have been shown to portend CD risk in HIV-uninfected people are associated with CD risk in HIV-infected people. Such biomarkers could identify those who would benefit most from targeted prophylaxis and/or earlier treatment, particularly in sub-Saharan Africa, where there are nearly a million cases of HIV-associated CD annually. A biomarker of risk could also identify potential candidates for immunization, should there be a vaccine for Cryptococcus neoformans. PMID- 23982077 TI - Continuous separation of particles in a PDMS microfluidic channel via travelling surface acoustic waves (TSAW). AB - We demonstrate a simple and efficient device for the continuous label-free separation of microparticles using travelling surface acoustic waves (TSAW). A focusing interdigitated unidirectional transducer released high frequency (133.3 MHz) TSAW normal to the fluid flow direction to segregate 3 MUm particles from 10 MUm particles with a separation efficiency of 100%. The TSAW based separator does not necessitate a tight alignment of the PDMS microchannel with the transducer. PMID- 23982078 TI - Increased parietal activity after training of interference control. AB - Recent studies suggest that computerized cognitive training leads to improved performance in related but untrained tasks (i.e. transfer effects). However, most study designs prevent disentangling which of the task components are necessary for transfer. In the current study, we examined whether training on two variants of the adaptive dual n-back task would affect untrained task performance and the corresponding electrophysiological event-related potentials (ERPs). Forty three healthy young adults were trained for three weeks with a high or low interference training variant of the dual n-back task, or they were assigned to a passive control group. While n-back training with high interference led to partial improvements in the Attention Network Test (ANT), we did not find transfer to measures of working memory and fluid intelligence. ERP analysis in the n-back task and the ANT indicated overlapping processes in the P3 time range. Moreover, in the ANT, we detected increased parietal activity for the interference training group alone. In contrast, we did not find electrophysiological differences between the low interference training and the control group. These findings suggest that training on an interference control task leads to higher electrophysiological activity in the parietal cortex, which may be related to improvements in processing speed, attentional control, or both. PMID- 23982079 TI - Clinical nuggets and pearls: chronic neuropathic pain and opioid tolerance. PMID- 23982080 TI - Compounding with controlled substances. PMID- 23982081 TI - The problem of drug diversion. PMID- 23982083 TI - Compounding for Diseases of the Oral Cavity: A Discussion with Stu Sommerville, RPh. PMID- 23982082 TI - Providing Analgesia and Curtailing Drug Diversion: A Pharmacist's Perspective. PMID- 23982084 TI - Creating a productivity measurement tool for a home infusion pharmacy. PMID- 23982085 TI - Basics of compounding: biotechnologic preparations. PMID- 23982086 TI - A review of bioidentical hormone replacement therapy. PMID- 23982087 TI - New perspectives on vancomycin use in home care, part 2: delivery systems. PMID- 23982088 TI - Physical and Chemical Stability of Morphine Sulfate 5mg/mL and 50mg/mL Packaged in Plastic Syringes. AB - The objective of this study was to evaluate the physical and chemical stability of morphine sulfate in concentrations of 5 mg/mL in 0.9% sodium chloride injection and 50 mg/mL in both 0.9% sodium chloride injection and in sterile water for injection packaged in plastic syringes. Test samples of morphine sulfate 5-mg/mL and 50-mg/mL solutions were packaged as 20 mL of drug solution in 30-mL plastic syringes, sealed with plastic tip caps, and stored at 4 deg C and 23 deg C for 60 days. Test samples were also stored at -20 deg C and 37 deg C (temperature extremes that might be encountered during shipping) for 2 days. Evaluations of physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by means of visual observation in normal room light as well as with a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stabililty of the drug was evaluated by using a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. All samples of morphine sulfate 5-mg/mL solutions stored at 4 deg C, 23 deg C, and 37 deg C and the 50-mg/mL solutions stored at 23 deg C and 37 deg C remained free of precipitation throughout the study. In those solutions, little or no change in measured particulate burden or haze level was found, However, the solutions of morphine sulfate 50 mg/mL in 0.9% sodium chloride injection and in sterile water for injection exhibited an obvious precipitate within 2 to 4 days of storage at 4 deg C. Warming the solution to redissolve the visible precipitate left a substantial microparticulate content of up to 29,000 microparticulates/mL. When both morphine sulfate concentrations were frozen, precipitation was also noted. Upon thawing, the solutions yielded substantial measured microparticulate quantities of more than 20,000 microparticulates/mL in the 5-mg/mL concentration and more than 52,000 microparticulates/mL in the 50 mg/mL concentration. In addition, morphine sulfate 50mg/mL in both diluents exhibited a slight yellow discoloration after 30 days of storage at 23 deg C. Little or no loss of morphine sulfate occurred in any of the samples at any storage temperature throughout the study. Analysis of the samples after redissolving the visible precipitate in the low-temperature samples demonstrated that the morphine sulfate remained intact. Morphine concentrations were found to be 95% or greater over 60 days when stored at both 4 deg C and 23 deg C. In addition, morphine concentrations were greater than 97% when stored at -20 deg C, and they were 98% or greater when stored at 37 deg C after 2 days. However. exposure to low temperatures may result in precipitation, including microparticulate content that does not fully redissolve upon warming. PMID- 23982089 TI - Physical and chemical stability of low and high concentrations of morphine sulfate with clonidine hydrochloride packaged in plastic syringes. AB - The objective of this study was to evaluate the physical and chemical stability of morphine sulfate 5 mg/mL with clonidine hydrochloride 0.25 mg/mL in 0.9% sodium chloride injection and morphine sulfate 50 mg/mL with clonidine hydrochloride 4 mg/mL in sterile water for injection when packaged in plastic syringes. Test samples of morphine sulfate 5-mg/mL with clonidine hydrochloride 0.25-mg/mL and morphine sulfate 50-mg/mL with clonidine hydrochloride 4-mg/mL solutions were packaged as 20 mL of drug solution in 30-mL plastic syringes, sealed with plastic tip caps, and stored at 4 deg C and 23 deg C for 60 days. Test samples were also stored at -20 deg C and 37 deg C (temperature extremes that might be encountered during shiping) for 2 days. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by means of visual observation in normal room light and with a high-intensity monodirectional light beam. In addition turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by means of a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. All samples of morphine sulfate 5-mg/mL with clonidine hydrochloride 0.25mg/mL solutions stored at 4 deg C, 23 deg C, and 37 deg C and the morphine sulfate 50-mg/mL with clonidine HCl 4 mg/mL solrtions stored at 23 deg C and 37 deg C remained free of precipitation throughout the study. Little or no change in measured particulate burden and haze level were found in those solutions. However, morphine sulfate 50 mg/ml with clonidine HCl 4 mg/mL stored at 4 deg C exhibited an obvious precipitate within 2 to 4 days. Warming the solution to redissolve the precipitate left a substantial microparticulate content that was measured to be more than 33,000 microparticulates/mL. Upon freezing, both high- and low- concentration samples precipitated and yielded substantial measured microparticulate quantities up to 35,000 microparticulates/mL in the low-concentration combination and 50,000 microparticulates/mL in the high-concentration combination. In addition, as with morphine sulfate 50 mg/mL alone, the high-concentration combination exhibited a slight yellow discoloration after 30 days of storage at 23 deg C. Little or no loss of morphine sulfate and clonidine hydrochloride occurred in any of the samples at any storage temperature throughout the study. Morphine concentrations were found to be about 98% or greater, and clonidine hydrochloride concentrations were about 97% or greater throughout the study period under each storage condition. Morphine sulfate solutions at concentrations ranging from 5 to 50 mg/mL combined with clonidine hydrochloride ranging from 0.25 to 4 mg/mL can be packaged in plastic syringes, stored and shipped with little or no loss of drug. However, freezing should be avoided. PMID- 23982090 TI - Physical and chemical stability of low and high concentrations of morphine sulfate with bupivacaine hydrochloride packaged in plastic syringes. AB - The objective of this study was to evaluate the physical and chemical stability of morphine sulfate 5 mg/mL with bupivacaine hydrochloride 2.5 mg/mL in 0.9% sodium chloride injection and morphine sulfate 50 mg/mL with bupivacaine hydrochloride 25 mg/mL in sterile water for injection packaged in plastic syringes. Test samples of morphine sulfate 5-mg/mL with bupicvacaine hydrochloride 2.5-mg/mL and morphine sulfate 50-mg/mL with bupivacaine hydrochloride 25-mg/mL solutions were packaged as 20 mL of drug solution in 30-mL plastic syringes, sealed with plastic tip caps, and stored at 4 deg C and 23 deg C for 60 days. Test samples were also stored at -20 deg C and 37 deg C (temperature extremes that might be encountered during shipping) for 2 days. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by means of visual observation under normal room light and with a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated with a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. All test samples remained free of visible precipitation throughout the study. The inclusion of the bupivacaine hydrochloride prevented the precipitation of morphine sulfate that occurs at a lower storage temperature. For solutions stored at 4 deg C, 23 deg C, and 37 deg C, little or no change in measured particulate burden and haze level were found. However, samples stored frozen at 20 deg C exhibited a substantial microparticulate content upon thawing that was measured to be nearly 12,000 microparticulates/mL. Most samples were clear and colorless throughout the study. However, morphine sulfate 50 mg/mL exhibited a slight yellow discoloration after 7 days of storage at 23 deg C. Little or no loss of morphine sulfate and bupivacaine hydrochloride occurred in any of the samples at any storage temperature throughout the study. Morphine concentrations were found to be about 97% or greater, and bupivacaine hydrochloride concentrations were about 95% or greater throughout the study period under each storage condition. Morphine sulfate solutions at concentrations ranging from 5 mg/mL to 50 mg/mL combined with bupivacaine hydrochloride 2.5 mg/mL to 25 mg/mL can be packaged in plastic syringes stored, and shipped with little or no loss of drug. However, freezing should be avoided. PMID- 23982091 TI - Physical and Chemical Stability of Hydromorphone Hydrochloride 1.5 and 80 mg/mL Packaged in Plastic Syringes. AB - The objective of this study was to evaluate the physical and chemical stability of hydromorphone hydrochloride in concentrations of 1.5 and 80 mg/mL in 0.9% sodium chloride injection packaged in plastic syringes. Test samples of hydromorphone hydrochloride 1.5- and 80-mg/mL solutions were packaged as 20 mL of drug solution in 30-mL plastic syringes, sealed with plastic tip caps, and stored at 4 deg C and 23 deg C for 60 days and at -20 deg C and 37 deg C (temperature extremes that might be encounterd during shipping) for 2 days. Evaluations for physical and chemical stability were performed initially and throughout the storage periods. Physical stability was assessed by means of visual observation in normal room light with a high-intensity monodirectional light beam. In addition, turbidity and particle content were measured electronically. The chemical stability of the drug was evaluated by means of a stability-indicating high-performance liquid chromatographic (HPLC) analytical technique. All samples of hydromorphone hydrochloride remained free of visible precipitation throughout the study. Those solutions stored at 4 deg C, 23 deg C, or 37 deg C exhibited little or no change in measured particulate burden and haze level. Freezing the solution resulted in an increase in microparticulate content that did not redissolve when the solution was warmed at room temperature. Little or no loss of hydromorphone hydrochloride occurred in any of the samples at any storage temperature throughout the study. Hydromorphone hydrochloride concentrations were found to be 95% or greater over 60 days at both 4 deg C and 23 deg C; concentrations were greater than 97% at both -20 deg C and 37 deg C after 2 days. Hydromorphone hydrochloride solutions at concentrations ranging from 1.5 to 80 mg/mL in 0.9% sodium chloride injection can be packaged in plastic syringes, stored, and shipped with little or no loss of drug. Freezing should be avoided. PMID- 23982093 TI - The discovery of chagas disease (1908-1909): great successes and certain misunderstandings and challenges. PMID- 23982094 TI - Prevalence and clinical features of celiac disease in patients with hepatitis B virus infection in Southern Brazil. AB - INTRODUCTION: Celiac disease is an autoimmune disorder that involves gluten intolerance and can be triggered by environmental factors including hepatitis B virus (HBV) infection. This study aimed to describe the prevalence of celiac disease in individuals with HBV infection and to describe the clinical and laboratory characteristics of celiac disease associated with HBV. METHODS: This cross-sectional study included 50 hepatitis B patients tested for IgA anti endomysial antibodies (EMAs) and tissue anti-transglutaminase (TTG) between August 2011 and September 2012. RESULTS: Fifty patients were included with a mean age of 46.0 +/- 12.6 (46.0) years; 46% were female and 13% were HBeAg+. Six patients had positive serology for celiac disease, four were EMA+, and five were TTG+. When individuals with positive serology for celiac disease were compared to those with negative serology, they demonstrated a higher prevalence of abdominal pain (100% vs. 33.3%, p = 0.008), lower median creatinine (0.7 mg/dL vs. 0.9 mg/dL, p = 0.007) and lower mean albumin (3.6 +/- 0.4 g/L vs. 3.9 +/- 0.3g/L, p = 0.022). All individuals with positive serology for celiac disease underwent upper digestive endoscopy, and three of the patients exhibited a macroscopic pattern suggestive of celiac disease. Histologically, five patients demonstrated an intra epithelial lymphocytic infiltrate level > 30%, and four patients showed villous atrophy associated with crypt hyperplasia on duodenal biopsy. CONCLUSIONS: An increased prevalence of celiac disease was observed among hepatitis B patients. These patients were symptomatic and had significant laboratory abnormalities. These results indicate that active screening for celiac disease among HBV infected adults is warranted. PMID- 23982095 TI - Positive serology for viral hepatitis and donor self-exclusion in Southern Brazil. AB - INTRODUCTION: Despite the great advances in serological testing for transfusion transmitted infections, the selection of blood donors by blood bank operators remains the only way to avoid transmission within the testing window period. Part of this selection is the self-exclusion form, on which the donors can exclude their blood from donation without any explanation. This study assessed the clinical and epidemiological characteristics related to positivity for viral hepatitis and to the use of the confidential self-exclusion (CSE) form. METHODS: This transversal study analyzed the data collected from blood donors' files in a hospital in Southern Brazil. Univariate and multivariate analyses identified the clinical and epidemiological variables related to positive serologies of viral hepatitis and to whether the donor was self-excluded. RESULTS: Of the 3,180 donors included in this study, 0.1% tested positive for HBsAg, 2.1% for anti-HBc, and 0.9% for anti-HCV. When the 93 donors with positive serologies for viral hepatitis were compared with those who were negative, a greater proportion of the positive serology group was found to have had a history of blood transfusions (OR=4.908; 95%CI=1.628 - 14.799; p<0.01), had repeatedly donated (OR=2.147; 95%CI=1.236 - 3.729; p<0.01), and used the CSE form for self-exclusion (OR=7.139; 95%CI=2.045 - 24.923; p<0.01). No variables were independently associated with self-exclusion. CONCLUSIONS: A history of blood transfusion, repeated donations, and self-exclusion are factors that should be considered during viral hepatitis screenings in blood banks. PMID- 23982096 TI - Bioactivity of plant extracts on the larval and pupal stages of Aedes aegypti (Diptera, Culicidea). AB - INTRODUCTION: Aedes aegypti is responsible for the transmission of the dengue and yellow fever viruses. This study evaluated the effects of extracts from Cnidosculos phyllacanthus, Ricinus communis, and Coutarea hexandra on the developmental periods of A.aegypti larvae and pupae. Crude extracts of C. phyllacanthus and C. hexandra and oil from R. communis and C. phyllacanthus were used. METHODS: Bioassays of the larvicidal and pupicidal effects of these products at different concentrations and times of exposure were evaluated. The lethal and sublethal effects were determined using different concentrations in larvicidal tests. Mortality data were evaluated by Probit analysis to determine the LC50 and LC90 values. RESULTS: The vegetable oils from C. phyllacanthus and R. communis demonstrated greater efficiency for larval control with an LC50=0.28ul/mL and an LC90=1.48ul/mL and LC50=0.029ul/mL and a LC90=0.26ul/mL, respectively. In pupal tests toxic effects for all insects were verified after exposure to the products at significant LC50 and LC90 values for 24 and 48h. The effects of sublethal concentrations of C. phyllacanthus (oil) were more effective on the insects. CONCLUSIONS: The vegetables oils from C. phyllacanthus and R. communis demonstrated greater potential from the control of different developmental periods in the life cycle of this insect. PMID- 23982097 TI - Molecular and biological characterization of Trypanosoma cruzi strains isolated from children from Jequitinhonha Valley, State of Minas Gerais, Brazil. AB - INTRODUCTION: The biological diversity of Trypanosoma cruzi strains plays an important role in the clinical and epidemiological features of Chagas disease. METHODS: Eight T. cruzi strains isolated from children living in a Chagas disease vector-controlled area of Jequitinhonha Valley, State of Minas Gerais, Brazil, were genetically and biologically characterized. RESULTS: The characterizations demonstrated that all of the strains belonged to T. cruzi II, and showed high infectivity and a variable mean maximum peak of parasitemia. Six strains displayed low parasitemia, and two displayed moderate parasitemia. Later peaks of parasitemia and a predominance of intermediate and large trypomastigotes in all T. cruzi strains were observed. The mean pre-patent period was relatively short (4.2 +/- 0.25 to 13.7 +/- 3.08 days), whereas the patent period ranged from 3.3 +/- 1.08 to 34.5 +/- 3.52 days. Mortality was observed only in animals infected with strain 806 (62.5%). Histopathological analysis of the heart showed that strains 501 and 806 caused inflammation, but fibrosis was observed only in animals infected with strain 806. CONCLUSIONS: The results indicate the presence of an association between the biological behavior in mice and the genetic characteristics of the parasites. The study also confirmed general data from Brazil where T. cruzi II lineage is the most prevalent in the domiciliary cycle and generally has low virulence, with some strains capable of inducing inflammatory processes and fibrosis. PMID- 23982098 TI - Rapid detection and differentiation of mycobacterial species using a multiplex PCR system. AB - INTRODUCTION: The early diagnosis of mycobacterial infections is a critical step for initiating treatment and curing the patient. Molecular analytical methods have led to considerable improvements in the speed and accuracy of mycobacteria detection. METHODS: The purpose of this study was to evaluate a multiplex polymerase chain reaction system using mycobacterial strains as an auxiliary tool in the differential diagnosis of tuberculosis and diseases caused by nontuberculous mycobacteria (NTM) RESULTS: Forty mycobacterial strains isolated from pulmonary and extrapulmonary origin specimens from 37 patients diagnosed with tuberculosis were processed. Using phenotypic and biochemical characteristics of the 40 mycobacteria isolated in LJ medium, 57.5% (n=23) were characterized as the Mycobacterium tuberculosis complex (MTBC) and 20% (n=8) as nontuberculous mycobacteria (NTM), with 22.5% (n=9) of the results being inconclusive. When the results of the phenotypic and biochemical tests in 30 strains of mycobacteria were compared with the results of the multiplex PCR, there was 100% concordance in the identification of the MTBC and NTM species, respectively. A total of 32.5% (n=13) of the samples in multiplex PCR exhibited a molecular pattern consistent with NTM, thus disagreeing with the final diagnosis from the attending physician. CONCLUSIONS: Multiplex PCR can be used as a differential method for determining TB infections caused by NTM a valuable tool in reducing the time necessary to make clinical diagnoses and begin treatment. It is also useful for identifying species that were previously not identifiable using conventional biochemical and phenotypic techniques. PMID- 23982099 TI - Histoplasmosis in immunocompetent individuals living in an endemic area in the Brazilian Southeast. AB - INTRODUCTION: The distribution of infection by Histoplasma capsulatum in Brazil is heterogeneous, and the number of cases affecting immunocompetent individuals is relatively small. This study reports the epidemiological and clinical data regarding histoplasmosis in non-immunosuppressed individuals. METHODS: The study included only the immunocompetent patients with histoplasmosis who were diagnosed between 1970 and 2012 at a university hospital located in Ribeirao Preto, State of Sao Paulo, Brazil. Clinical and epidemiological data were collected retrospectively from the patient records. RESULTS: Of the 123 patients analyzed, 95 had an active disease that manifested in the different clinical forms of histoplasmosis. Men were the predominant gender, and most patients resided in the Northeast of the State of Sao Paulo and in the nearby municipalities of the State of Minas Gerais. The risk factors for acquiring histoplasmosis and prolonged contact in a rural environment were recorded in 43.9% and 82.9% of cases, respectively. Smoking, alcoholism, and comorbidity rates were high among the patients with the chronic pulmonary and subacute/chronic disseminated forms of histoplasmosis. Many patients achieved clinical cure spontaneously, but 58.9% required antifungals; the disease lethality rate was 5.3%. CONCLUSIONS: Immunocompetent individuals manifested the diverse clinical forms of histoplasmosis over a period of 4 decades, revealing an additional endemic area of this fungal disease in the Brazilian Southeast. PMID- 23982100 TI - Treatment and education reduce the severity of schistosomiasis periportal fibrosis. AB - INTRODUCTION: This study evaluates the factors associated with the development of severe periportal fibrosis in patients with Schistosoma mansoni. METHODS: A cross sectional study was conducted from April to December 2012 involving 178 patients infected with S. mansoni who were treated in the Hospital das Clinicas of Pernambuco, Brazil. Information regarding risk factors was obtained using a questionnaire. Based on the patients' epidemiological history, clinical examination, and upper abdomen ultrasound evaluation, patients were divided into 2 groups: 137 with evidence of severe periportal fibrosis and 41 patients without fibrosis or with mild or moderate periportal fibrosis. Univariate and multivariate analyses were conducted using EpiInfo software version 3.5.5. RESULTS: Illiterate individuals (30.1%) and patients who had more frequent contact with contaminated water in towns in the Zona da Mata of Pernambuco (33.2%) were at greater risk for severe periportal fibrosis. Based on multivariate analysis, it was determined that an education level of up to 11 years of study and specific prior treatment for schistosomiasis were preventive factors for severe periportal fibrosis. CONCLUSIONS: The prevailing sites of the severe forms of periportal fibrosis are still within the Zona da Mata of Pernambuco, although there has been an expansion to urban areas and the state coast. Specific treatment and an increased level of education were identified as protective factors, indicating the need for implementing social, sanitary, and health education interventions aimed at schistosomiasis to combat the risk factors for this major public health problem. PMID- 23982101 TI - Phenotypic detection of metallo-beta-lactamases in Pseudomonas aeruginosa and Acinetobacter baumannii isolated from hospitalized patients in Sao Luis, State of Maranhao, Brazil. AB - INTRODUCTION: Acquired metallo-beta-lactamases (MbetaL) are emerging determinants of resistance in Pseudomonas aeruginosa and Acinetobacter baumannii. The objectives of this study were to phenotypically detect MbetaL in imipenem resistant P. aeruginosa and A. baumannii, to investigate the association between MbetaL-positive strains and hospitals, and to compare the resistance profiles of MbetaL-producing and non-MbetaL-producing strains. METHODS: The approximation disk and combined disk assay methods were used in this study. RESULTS: A total of 18 (38.3%) P. aeruginosa isolates and 1 (5.6%) A. baumannii isolate tested positive for the presence of MbetaL. CONCLUSIONS: These results demonstrate the need for strict surveillance and for the adoption of preventive measures to reduce the spread of infection and potential outbreaks of disease caused by MbetaL-producing microorganisms. PMID- 23982102 TI - First report of yellow fever virus in non-human primates in the State of Parana, Brazil. AB - Sylvatic yellow fever is a zoonosis associated mainly with wild animals, especially those in the genus Alouatta, that act as the source of infection. Once infected, these animals pass the disease on to humans by way of an infected mosquito belonging to the genera Aedes, Haemagogus, or Sabethes. The present study is the first report of a case of yellow fever in non-human primates (NHP) in the State of Parana, Brazil. After the case was diagnosed, several prophylactic measures were adopted to prevent outbreaks of the disease in humans. PMID- 23982103 TI - Possible artemisinin-based combination therapy-resistant malaria in Nigeria: a report of three cases. AB - Artemisinin-based combination therapy-resistant malaria is rare in Sub-Saharan Africa. The World Health Organization identifies monitoring and surveillance using day-3 parasitaemia post-treatment as the standard test for identifying suspected artemisinin resistance. We report three cases of early treatment failure due to possible artemisinin-based combination therapy-resistant Plasmodium falciparum malaria. All cases showed adequate clinical and parasitological responses to quinine. This study reveals a need to re-evaluate the quality and efficacy of artemisinin-based combination therapy agents in Nigeria and Sub-Saharan Africa. PMID- 23982104 TI - Gas-forming pyogenic liver abscess. PMID- 23982105 TI - Biomarker in Helicobacter pylori infection: the standoff condition? PMID- 23982106 TI - Virality prediction and community structure in social networks. AB - How does network structure affect diffusion? Recent studies suggest that the answer depends on the type of contagion. Complex contagions, unlike infectious diseases (simple contagions), are affected by social reinforcement and homophily. Hence, the spread within highly clustered communities is enhanced, while diffusion across communities is hampered. A common hypothesis is that memes and behaviors are complex contagions. We show that, while most memes indeed spread like complex contagions, a few viral memes spread across many communities, like diseases. We demonstrate that the future popularity of a meme can be predicted by quantifying its early spreading pattern in terms of community concentration. The more communities a meme permeates, the more viral it is. We present a practical method to translate data about community structure into predictive knowledge about what information will spread widely. This connection contributes to our understanding in computational social science, social media analytics, and marketing applications. PMID- 23982107 TI - Bioappearance and pharmacokinetics of bioactives upon coffee consumption. AB - Habitual consumption of medium amounts of coffee over the whole life-span is hypothesized to reduce the risk to develop diabetes type 2 (DM2) and Alzheimer's disease (AD). To identify putative bioactive coffee-derived metabolites, first, pooled urine from coffee drinkers and non-coffee drinkers were screened by UPLC HDMS. After statistical data analysis, trigonelline, dimethylxanthines and monomethylxanthines, and ferulic acid conjugates were identified as the major metabolites found after coffee consumption. For quantitative analysis of these markers in body fluids, targeted methods based on stable-isotope dilution and UPLC-MS/MS were developed and applied to plasma samples from a coffee intervention study (n = 13 volunteers) who consumed a single cup of caffeinated coffee brew after a 10-day washout period. Chlorogenic acid-derived metabolites were found to be separated into two groups showing different pharmacokinetic properties. The first group comprised, e.g., ferulic acid and feruloyl sulfate and showed early appearance in the plasma (~1 h). The second group contained particularly chlorogenic acid metabolites formed by the intestinal microflora, appearing late and persisting in the plasma (>6 h). Trigonelline appeared early but persisted with calculated half-life times ~5 h. The plasma levels of caffeine metabolites significantly and progressively increased 2-4 h after coffee consumption and did not reach c max within the time frame of the study. The pharmacokinetic profiles suggest that particularly trigonelline, caffeine, its metabolites, as well as late appearing dihydroferulic acid, feruloylglycine and dihydroferulic acid sulfate formed from chlorogenic acid by the intestinal microflora accumulate in the plasma due to their long half-life times during habitual consumption of several cups of coffee distributed over the day. Since some of these metabolites have been reported to show antioxidant effects in vivo, antioxidant-response-element activating potential, and neuroprotective properties, respectively, some of these key metabolites might account for the inflammation- and DM2/AD risk reducing effects reported for habitual life time consumption of coffee. PMID- 23982108 TI - The use of digital technology in the class and laboratory. PMID- 23982109 TI - Hot flashes and sleep: curious or spurious link? PMID- 23982110 TI - Fatty acid synthase expression is strongly related to menopause in early-stage breast cancer patients. AB - OBJECTIVE: Overexpression of fatty acid synthase (FASN), the enzyme involved in the de novo synthesis of fatty acids, has been reported in several human carcinomas, including breast cancer, and has been related to poor prognosis. Our aim was to analyze the association of FASN tumor tissue expression with clinicopathological and anthropometrical features in early-stage breast cancer patients. METHODS: We prospectively studied 53 women with early-stage breast cancer who were treated with surgical operation and postoperative chemotherapy. RESULTS: Menopause status and age were strongly associated with higher levels of FASN tumor expression (P < 0.005 and P = 0.038, respectively). Body mass index and pathological stage were also related to FASN tumor expression. CONCLUSIONS: Our findings suggest that FASN could be a potential therapeutic target in postmenopausal breast cancer patients. However, further studies are needed. PMID- 23982111 TI - Use and discontinued use of menopausal hormone therapy by healthy women in Norway: the Hordaland Women's Cohort study. AB - OBJECTIVE: This work aims to study the use of hormone therapy (HT) in a representative cohort of Norwegian women during the menopausal transition, to identify predictors of HT use, and to describe the reappearance of symptoms in former HT users. METHODS: In 1997, 2,229 women in Hordaland County, aged 40 to 44 years, were selected randomly from a national health survey and followed up with seven postal questionnaires in 1999-2010. Data from 2,002 women (90%) were eligible for analysis. Summary statistics and multiple logistic regression analysis were used. We studied the reappearance of symptoms after HT discontinuation using a subcohort based on their propensity scores for HT use. RESULTS: The 2-year incidence of new HT users dropped from 8.2% (95% CI, 7.0-9.5) in 2002 to 4.3% (95% CI, 3.4-5.2) in 2004 and remained stable despite an increasing prevalence of symptoms in the cohort. Self-rated health was stable during the period. The mean duration of HT use was 4.5 years (95% CI, 4.0-5.0). The odds of HT use were higher among women with daily hot flushes than among those who never or rarely experienced them (odds ratio, 3.2; 95% CI, 2.3-4.4). After HT cessation, hot flushes returned and corresponded to those in untreated controls. CONCLUSIONS: The 2-year incidence of HT users decreased almost 50% after 2002. Increasing symptoms and decreasing incidence of HT use did not influence self-rated health. Hot flushes were the strongest predictor of HT use. Symptoms reappeared in most women after HT cessation. PMID- 23982112 TI - Hypertensive pregnancy, menopausal symptoms, and heart disease: a motley crew of characters. PMID- 23982113 TI - Efficacy of omega-3 for vasomotor symptoms treatment: a randomized controlled trial. AB - OBJECTIVE: This study aims to determine the efficacy and tolerability of omega-3 fatty acids in reducing vasomotor symptoms (VMS) frequency and bother in perimenopausal and postmenopausal women. METHODS: This study was a 12-week, three by-two factorial, randomized controlled trial. Eligible women were randomized to a double-blind comparison of omega-3 (n = 177) or placebo (n = 178) capsules, and simultaneously to yoga (n = 107), aerobic exercise (n = 106), or their usual physical activity (n = 142). Participants received 1.8 g of omega-3 daily for 12 weeks. Each capsule contained ethyl eicosapentaenoic acid (425 mg), docosahexaenoic acid (100 mg), and other omega-3s (90 mg). Primary outcomes were VMS frequency and bother. Secondary outcomes included sleep quality (Pittsburgh Sleep Quality Index), insomnia symptoms (Insomnia Severity Index), depressive symptoms (Physician's Health Questionnaire-8), and anxiety (Generalized Anxiety Disorder-7). RESULTS: The mean baseline frequency of VMS per day was 7.6 (95% CI, 7.0 to 8.2). After 12 weeks, the reduction in VMS frequency with omega-3 (-2.5; 95% CI, -3.0 to -1.9) did not differ significantly from that with placebo (-2.7; 95% CI, -3.3 to -2.2), with a relative difference of 0.3 fewer hot flashes per day (95% CI, -0.5 to 1.0; P = 0.28). Changes in VMS bother at 12 weeks were also similar between groups, with no relative difference on a four-point scale (95% CI, -0.1 to 0.2; P = 0.36). Omega-3s compared with placebo showed no improvement in self-reported sleep or mood (P > 0.09 for all comparisons). CONCLUSIONS: Among healthy, sedentary perimenopausal and postmenopausal women, a 12-week treatment with omega-3 does not improve VMS frequency, VMS bother, sleep, or mood compared with placebo. PMID- 23982114 TI - The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. AB - The organic cation transporter 3 (OCT3) is a widely expressed transporter for endogenous and exogenous organic cations. Of particular interest is OCT3 expression and function in the brain, where it plays a role in serotonin clearance and influences mood and behavior. Protein kinase signaling mediates rapid modulation of cerebral processes, but little is known about acute regulation of OCT3 by protein kinases. Therefore, we cloned mouse OCT3 (mOCT3) and generated a human embryonic kidney cell line stably expressing the transporter to study transport characteristics, acute regulation by protein kinases, and interaction with psychotropic drugs. Uptake measurement was performed using the fluorescent cation 4-(4-(dimethylamino)styryl)-N methylpyridinium iodide (ASP(+), 1 MUM) as a substrate. The translational value of these findings was determined by comparing results obtained with cloned mouse and human OCT3. mOCT3-mediated transport is membrane potential dependent and pH independent. ASP(+) uptake by mOCT3 and human OCT3 (hOCT3) was efficiently inhibited by 1-methyl-4-phenylpyridinium, tetrapentylammonium (TPA(+)), corticosterone, serotonin, and histamine and by the drugs ketamine, fluoxetine, and diazepam. The half maximal inhibitory concentrations of mOCT3 and hOCT3 for TPA(+), serotonin, diazepam, and ketamine are significantly different. Diazepam is a non-transported inhibitor. Furthermore, the activities of mOCT3 and hOCT3 are acutely regulated by the p56 (lck) tyrosine kinase by decreasing their V max. Studies with freshly isolated renal proximal tubules from mOCT1/2(-/-) mice, in which mOCT3 is the only OCT present, confirmed this regulation pathway. Only the activity of hOCT3 is regulated by calmodulin. These findings suggest that even though many transport properties of mOCT3 and hOCT3 are similar, there are also species-specific aspects of OCT3 function. PMID- 23982115 TI - Transpedicular vertebral body augmentation reinforced with pedicle screw fixation in fresh traumatic A2 and A3 lumbar fractures: comparison between two devices and two bone cements. AB - This retrospective study compares efficacy and safety of balloon kyphoplasty (BK) with calcium phosphate (Group A) versus KIVA implant with PMMA (Group B) reinforced with three vertebrae pedicle screw constructs for A2 and A3 single fresh non-osteoporotic lumbar (L1-L4) fractures in 38 consecutive age- and diagnosis-matched patient populations. Extracanal leakage of both low-viscosity PMMA and calcium phosphate (CP) as well as the following roentgenographic parameters: segmental kyphosis (SKA), anterior (AVBHr) and posterior (PVBHr) vertebral body height ratio, spinal canal encroachment (SCE) clearance, and functional outcome measures: VAS and SF-36, were recorded and compared between the two groups. All patients in both groups were followed for a minimum 26 (Group A) and 25 (Group B) months. Extracanal CP and PMMA leakage was observed in four (18 %) and three (15 %) vertebrae/patients of group A and B, respectively. Hybrid fixation improved AVBHr, SKA, SCE, but PVBHr only in group B. VAS and SF-36 improved postoperatively in the patients of both groups. Short-segment construct with the novel KIVA implant restored better than BK-fractured lumbar vertebral body, but this had no impact in functional outcome. Since there was no leakage difference between PMMA and calcium phosphate and no short-term adverse related to PMMA use were observed, we advice the use of PMMA in fresh traumatic lumbar fractures. PMID- 23982116 TI - Possibility of the hamatum carpometacarpal joint as a new joint donor site for interphalangeal joint restoration. AB - OBJECTIVE: This research investigates the anatomic basis for the repair and reconstruction of hand joints using transposition of the carpometacarpal (CMC) joint of the hamatum. METHODS: The morphology and structure of the CMC joints of the hamatum and the base joints of the middle phalanx were observed on 22 freshly frozen wrist specimens at Shanghai 6th People's Hospital Research Institute of Microsurgery. The volar dorsal dia, radioulnar dia, depth of concave, and area of the joints were measured. Data were obtained through statistical analysis, and the resemblance of joints was compared in terms of morphology, structure, area, length, and diameter. RESULTS: The radioulnar dia of the CMC joints of the hamatum (13.54 +/- 1.15 mm) did not exhibit any evident differences in the middle phalanx of the forefinger, middle finger, and ring finger, and in the distal phalanx of the thumb. The volar dorsal dia of the CMC joints of the hamatum (10.71 +/- 0.93 mm) exhibited an evident difference in the middle phalanx of the ring finger. In all fingers, the depth of the ulnar and radial concave of the CMC joints of the hamatum (1.30 +/- 0.08 and 0.95 +/- 0.05 mm, respectively) and the area of the CMC joints of the hamatum (139.89 +/- 5.44 mm(2)) showed an evident difference. CONCLUSION: The CMC joint of the hamatum could be considered a new and viable joint donor site that could be used to repair and reconstruct the base joints of the middle phalanx. PMID- 23982117 TI - Open reduction and bi-columnar internal fixation of intra-articular distal humerus fractures through a combined medial and lateral approach. AB - PURPOSE: The aim of this retrospective study was to investigate the suitability of bi-columnar internal fixation through a combined medial and lateral approach for the treatment of intra-articular distal humerus fractures. METHODS: Nineteen cases of intra-articular distal humerus fractures were treated with open reduction and bi-columnar internal fixation through a combined medial and lateral approach. The reduction in the articular surface and functional recovery of the affected elbows was assessed at an average follow-up of 15.8 +/- 7.9 (7-43) months. RESULTS: The gap in the main articular fragments was less than 1 mm in 16 cases, while a gap of more than 1 mm and less than 2 mm was identified in 2 cases and of 3.7 mm in one case. All the fractures were united. At the latest follow up, the mean flexion-extension of the elbows was 113.4 degrees +/- 20.7 degrees , while the pronation-supination of the forearms was 158.3 degrees +/- 8.5 degrees , and the mean Mayo Elbow Performance Index was 93.7 +/- 9.1 points, leading to 13 excellent outcomes, and 6 with good results. CONCLUSIONS: Intra articular fractures of the distal humerus can be effectively treated by open reduction and internal fixation through a combined medial and lateral approach at the elbow. PMID- 23982118 TI - Phase I clinical and pharmacokinetic/pharmacogenetic study of a triplet regimen of S-1/irinotecan/oxaliplatin in patients with metastatic colorectal or gastric cancer. AB - PURPOSE: We conducted a phase I study of S-1 combined with irinotecan and oxaliplatin (TIROX) to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety, pharmacokinetics, pharmacogenetics, and preliminary efficacy in patients with metastatic colorectal cancer (MCRC) or metastatic gastric cancer (MGC). METHODS: Patients received escalating doses of S 1 (30-40 mg/m2 b.i.d.) orally on days 1-14, an escalating dose of intravenous irinotecan (120-150 mg/m2) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m2) on day 1 every 3 weeks. RESULTS: Twenty-three patients (10 MCRC, 13 MGC; 13 chemonaive, 10 previously treated for metastatic disease) were treated across six dose levels. Because only one patient experienced a dose-limiting toxicity of grade 3 anorexia at the highest dose level (S-1 40 mg/m2 b.i.d., irinotecan 150 mg/m2, and oxaliplatin 85 mg/m2) (n = 8), the MTD was not obtained, and this level was established as the RD. With a median of 10 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (43 %), diarrhea (13 %), and nausea (13 %). In 22 efficacy-evaluable patients, the objective tumor response rate was 59.1 % (75 % for both MCRC and MGC in the first line setting) and the disease control rate was 100 %. The exploratory pharmacokinetic/pharmacogenetic study showed that CYP2A6 variants (*4, *7, *9) are associated with a lower metabolic ratio of S-1 (exposure ratio of 5 fluorouracil to tegafur). CONCLUSIONS: The new triplet TIROX regimen has shown promising antitumor activity and a favorable toxicity profile in patients with MCRC and MGC. PMID- 23982119 TI - Automatic segmentation of pulmonary fissures in computed tomography images using 3D surface features. AB - Pulmonary interlobar fissures are important anatomic structures in human lungs and are useful in locating and classifying lung abnormalities. Automatic segmentation of fissures is a difficult task because of their low contrast and large variability. We developed a fully automatic training-free approach for fissure segmentation based on the local bending degree (LBD) and the maximum bending index (MBI). The LBD is determined by the angle between the eigenvectors of two Hessian matrices for a pair of adjacent voxels. It is used to construct a constraint to extract the candidate surfaces in three-dimensional (3D) space. The MBI is a measure to discriminate cylindrical surfaces from planar surfaces in 3D space. Our approach for segmenting fissures consists of five steps, including lung segmentation, plane-like structure enhancement, surface extraction with LBD, initial fissure identification with MBI, and fissure extension based on local plane fitting. When applying our approach to 15 chest computed tomography (CT) scans, the mean values of the positive predictive value, the sensitivity, the root-mean square (RMS) distance, and the maximal RMS are 91 %, 88 %, 1.01 +/- 0.99 mm, and 11.56 mm, respectively, which suggests that our algorithm can efficiently segment fissures in chest CT scans. PMID- 23982120 TI - Incident ischemic heart disease and recent occupational exposure to particulate matter in an aluminum cohort. AB - Fine particulate matter (PM(2.5)) in air pollution, primarily from combustion sources, is recognized as an important risk factor for cardiovascular events but studies of workplace PM(2.5) exposure are rare. We conducted a prospective study of exposure to PM(2.5) and incidence of ischemic heart disease (IHD) in a cohort of 11,966 US aluminum workers. Incident IHD was identified from medical claims data from 1998 to 2008. Quantitative metrics were developed for recent exposure (within the last year) and cumulative exposure; however, we emphasize recent exposure in the absence of interpretable work histories before follow-up. IHD was modestly associated with recent PM(2.5) overall. In analysis restricted to recent exposures estimated with the highest confidence, the hazard ratio (HR) increased to 1.78 (95% CI: 1.02, 3.11) in the second quartile and remained elevated. When the analysis was stratified by work process, the HR rose monotonically to 1.5 in both smelter and fabrication facilities, though exposure was almost an order of magnitude higher in smelters. The differential exposure-response may be due to differences in exposure composition or healthy worker survivor effect. These results are consistent with the air pollution and cigarette smoke literature; recent exposure to PM(2.5) in the workplace appears to increase the risk of IHD incidence. PMID- 23982122 TI - Associations between summertime ambient pollutants and respiratory morbidity in New York City: comparison of results using ambient concentrations versus predicted exposures. AB - Epidemiological analyses of air quality often estimate human exposure from ambient monitoring data, potentially leading to exposure misclassification and subsequent bias in estimated health risks. To investigate this, we conducted a case-crossover study of summertime ambient ozone and fine particulate matter (PM(2.5)) levels and daily respiratory hospitalizations in New York City during 2001-2005. Comparisons were made between associations estimated using two pollutant exposure metrics: observed concentrations and predicted exposures from the EPA's Stochastic Human Exposure and Dose Simulation (SHEDS) model. Small, positive associations between interquartile range mean ozone concentrations and hospitalizations were observed and were strongest for 0-day lags (hazard ratio (HR)=1.013, 95% confidence interval (CI): 0.998, 1.029) and 3-day lags (HR=1.006, 95% CI: 0.991, 1.021); applying mean predicted ozone exposures yielded similar results. PM(2.5) was also associated with admissions, strongest at 2- and 4-day lags, with few differences between exposure metrics. Subgroup analyses support recognized sociodemographic differences in concentration-related hospitalization risk, whereas few inter-stratum variations were observed in relation to SHEDS exposures. Predicted exposures for these spatially homogenous pollutants were similar across sociodemographic strata, therefore SHEDS predictions coupled with the case-crossover design may have masked observable heterogeneity in risks. However, significant effect modification was found for subjects in the top exposure-to-concentration ratio tertiles, suggesting risks may increase as a consequence of infiltration or greater exposure to outdoor air. PMID- 23982121 TI - Cardiovascular impacts and micro-environmental exposure factors associated with continuous personal PM2.5 monitoring. AB - The US Environmental Protection Agency's (US EPA) Detroit Exposure and Aerosol Research Study (DEARS) has provided extensive data on human exposures to a wide variety of air pollutants and their impact on human health. Previous analyses in the DEARS revealed select cardiovascular (CV) health outcomes such as increase in heart rate (HR) associated with hourly based continuous personal fine particulate matter (PM2.5) exposures in this adult, non-smoking cohort. Examination of time activity diary (TAD), follow-up questionnaire (FQ) and the continuous PM2.5 personal monitoring data provided the means to more fully examine the impact of discreet human activity patterns on personal PM2.5 exposures and changes in CV outcomes. A total of 329 343 min-based PM2.5 personal measurements involving 50 participants indicated that ~75% of these total events resulted in exposures <35 MUg/m(3). Cooking and car-related events accounted for nearly 10% of the hourly activities that were identified with observed peaks in personal PM2.5 exposures. In-residence cooking often resulted in some of the highest incidents of 1 min exposures (33.5-17.6 MUg/m(3)), with average peaks for such events in excess of 209 MUg/m(3). PM2.5 exposure data from hourly based personal exposure activities (for example,, cooking, cleaning and household products) were compared with daily CV data from the DEARS subject population. A total of 1300 hourly based lag risk estimates associated with changes in brachial artery diameter and flow-mediated dilatation (BAD and FMD, respectively), among others, were defined for this cohort. Findings indicate that environmental tobacco smoke (ETS) exposures resulted in significant HR changes between 3 and 7 h following the event, and exposure to smells resulted in increases in BAD on the order of 0.2-0.7 mm/MUg/m(3). Results demonstrate that personal exposures may be associated with several biological responses, sometimes varying in degree and direction in relation to the extent of the exposure. PMID- 23982123 TI - Chlorogenic acid induced apoptosis and inhibition of proliferation in human acute promyelocytic leukemia HL-60 cells. AB - Chlorogenic acid (CA), is found in high abundance in the leaves of a number of plants and has antibacterial, antiphlogistic, antimutagenic, antioxidant and other biological activities. It reportedly possesses antitumor activity via the induction of apoptosis in chronic myelogenous leukemia (CML) cell lines, including U937 and K562 cells. However, the effects of CA on human acute promyelocytic leukemia (APL) HL-60 cells remains unknown. In the current study, the ability of CA to cause G0/G1 cycle arrest and induce apoptosis in the treatment of human APL HL-60 cells was investigated. Following 5 days treatment with 1, 5 and 10 uM CA, cell viability and the effects of CA on the growth of HL 60 cells were investigated using a growth curve constructed using trypan blue staining. Induction of apoptosis and inhibition of cell proliferation were estimated using Wright's-Giemsa staining, Hoechst 33342 and propidium iodide (PI) staining, DNA ladder analysis and flow cytometry, following 48 h cell treatment with various doses of CA. The results indicated that the growth of HL-60 cells reached a plateau phase at 72 h and the proliferation inhibition rate of HL-60 cells in CA-treated groups was significantly higher compared with the control, in a time- and dose-dependent manner. However, the level of apoptosis of HL-60 cells treated with CA markedly increased and formed more apoptotic bodies compared with the cells with no drug treatment, according to the Wright's-Giemsa staining, Hoechst 33342 and PI staining, respectively. Using DNA ladder analysis and flow cytometry it was shown that a significant characteristic DNA ladder was observed when treated with CA. CA was capable of arresting cell cycle at G0/G1 phase. Apoptosis of HL-60 cells treated with CA for 48 h was promoted significantly in a dose-dependent manner, as well as the inhibition of proliferation. The observations revealed that CA inhibits proliferation and induces preprophase apoptosis of HL-60 cells. Thus, the concentration of 10 uM may be the optimal dose for treatment human acute promyelocytic leukemia. PMID- 23982124 TI - A severe prenatal presentation of Cat Eye Syndrome. PMID- 23982125 TI - [Intensive care management of critically ill adults with congenital heart disease]. AB - Due to improvements in cardiac surgery and perioperative care the number of adults with congenital heart disease is continuously growing. The perioperative and intensive care management of these patients is a challenge due to the variety of pathologies and surgical options as well as the complex pathophysiology. Many patients develop organ dysfunction with time and many require multiple cardiac operations as well as non-cardiac interventions during adulthood. While these patients are best treated in dedicated tertiary centers that provide a multidisciplinary expertise, basic knowledge of this population is important for everyone involved in acute medical care. This review will discuss some general aspects of adults with congenital heart disease such as pulmonary hypertension, Eisenmenger syndrome, cyanosis, pregnancy and perioperative care, with a special focus on the management of critically ill patients. PMID- 23982128 TI - Compounding for Skin Care: An Interview with John Hollis, RPh. PMID- 23982126 TI - Immunotherapeutic efficacy of recombinant Mycobacterium smegmatis expressing Ag85B-ESAT6 fusion protein against persistent tuberculosis infection in mice. AB - The application of immunotherapy in combination with chemotherapy is considered an effective treatment strategy against persistent Mycobacterium tuberculosis (Mtb) infection. In this study, we constructed a novel recombinant Mycobacterium smegmatis (rMS) strain that expresses Ag85B and ESAT6 fusion protein (AE-rMS). Immunization of C57BL/6 mice with AE-rMS generated mainly Th1-type immune responses by strongly stimulating IFN-gamma- and IL-2-producing splenocytes and increasing antigen-specific cytotoxic T lymphocyte (CTL) activity. To test the immunotherapeutic efficacy of AE-rMS, a persistent tuberculosis infection (PTBI) model was established via tail-vein injection of C57BL/6 mice with 1*10(4) colony forming units (CFU) of Mtb strain H37Rv in combination with concurrent chemotherapy drugs isoniazid (INH) and pyrazinamide (PZA). PTBI mice immunized with AE-rMS showed high levels of IFN-gamma secreted by splenocytes and decreased bacteria loads in lung. Treatment with only the anti-tuberculosis (anti-TB) drugs RFP and INH (RI), decreased bacteria loads to low levels, with the Th1-type immune response further attenuated. Moreover, AE-rMS, when combined with RI treatment, further reduced the bacteria load as well as the pathological tissue damage in lung. Together, these results demonstrated the essential roles of AE rMS-induced Th1-type responses, providing an effective treatment strategy by combining AE-rMS and RI for persistent TB. PMID- 23982127 TI - Towards real-time image deconvolution: application to confocal and STED microscopy. AB - Although deconvolution can improve the quality of any type of microscope, the high computational time required has so far limited its massive spreading. Here we demonstrate the ability of the scaled-gradient-projection (SGP) method to provide accelerated versions of the most used algorithms in microscopy. To achieve further increases in efficiency, we also consider implementations on graphic processing units (GPUs). We test the proposed algorithms both on synthetic and real data of confocal and STED microscopy. Combining the SGP method with the GPU implementation we achieve a speed-up factor from about a factor 25 to 690 (with respect the conventional algorithm). The excellent results obtained on STED microscopy images demonstrate the synergy between super-resolution techniques and image-deconvolution. Further, the real-time processing allows conserving one of the most important property of STED microscopy, i.e the ability to provide fast sub-diffraction resolution recordings. PMID- 23982129 TI - Mary kay inc: compounding in a cosmetics megacorporation. PMID- 23982130 TI - Options in wound care. PMID- 23982131 TI - Basics of compounding: cosmetics for special populations and using cosmetics as vehicles. PMID- 23982132 TI - Tablet cutting. PMID- 23982133 TI - A review of parenteral admixtures requiring select containers and administration sets. PMID- 23982134 TI - Medications discontinued in the United States. PMID- 23982135 TI - Veterinary compounding for ferrets. PMID- 23982136 TI - Sterilization of talc for use in pleurodesis. PMID- 23982137 TI - A review of bioidentical hormone replacement therapy, part 3. PMID- 23982138 TI - Stability of Gentamicin Sulfate and Tobramycin Sulfate in AutoDose Infusion System Bags. AB - The objective of this study was to evaluate the physical and chemical stability of gentamicin sulfate 85mg/100mL and tobramycin sulfate 95mg/100mL, each of which was admixed in 0.9% sodium chloride injection and packaged in AutoDose Infusion System bags. Triplicate test samples were prepared by admixing the necessary amounts of the aminoglycoside antibiotics with a portion of 0.9% sodium chloride injection and bringing the admixture of each drug to a final volume of 100mL with additional 0.9% sodium chloride injection. The test solutions were packaged in ethylene vinyl acetate (EVA) plastic containers (AutoDose bags) designed for use in the AutoDose Infusion System. Samples were stored protected from light and were evaluated at appropriate intervals for up to 7 days at 23 deg C and up to 30 days at 4 deg C. Physical stability was assessed by means of a multistep evaluation procedure that included both turbidimetric and particulate measurement, as well as visual inspection. Chemical stability was assessed initially and at appropriate intervals during the study periods with stability indicating high-performance liquid chromatographic (HPLC) analytical techniques based on the determination of drug concentrations. The aminoglycoside admixtures were clear and colorless when viewed in normal fluorescent room light and with a Tyndall beam. Measured turbidity and particulate content were low and exhibited little change. HPLC analysis indicated that both gentamicin sulfate and tobramycin sulfate remained stable for 30 days at 4 deg C and for 7 days at 23 deg C. Both gentamicin sulfate and tobramycin sulfate exhibited physical and chemical stability that were consistent with previous studies of those drugs. The AutoDose Infusion System bags did not adversely affect the physical and chemical stability of those aminoglycoside anitbiotics. PMID- 23982139 TI - Stability of 4-aminopyridine and 3,4-diaminopyridine oral capsules. AB - The objective of this study was to evaluate the chemical stability of 4 aminopyridine 5-mg capsules and 3,4-diaminopyridine 5-mg capsules under a variety of storage conditions. Each of the two drug preparations was extemporaneously prepared in hard gelatin capsules; lactose and micronized silica gel were used as excipients. Samples were stored under three conditions: refigeration at 4 deg C and protected from light for 6 months, protected from light at room temperature that ranged from 22 deg C to 24 deg C for 6 months, and at a temperature of 37 deg C and protected from light for 1 month. Once each month, visual inspection of the capsules and their powder contents was performed to identify observable changes (color, texture, etc) and the weight of the capsule content was measured individually. Chemical stability was assessed initially and at monthly intervals by means of a stability-indicating high-pressure liquid chromatography (HPLC) analytical technique based on the determination of drug content. No visible changes were observed in any of the samples under any of the storage conditions. The hard gelatin capsules remained clear and colorless, and the content of the capsules remained an off-white powder when viewed under normal fluorescent room light. Capsule content weight did not change during the study. Both 4 aminopyridine and 3,4-diaminopyridine exhibited excellent chemical stability under all study conditions. Little or no loss of drug content occurred in either product under refrigeration, at room temperature, and even at the elevated temperature of 37 deg C. The oral 5-mg capsules of 4-aminopyridine and 3,4 diaminopyridine did not undergo decomposition or other adverse changes within 6 months at refrigerated room temperature or within 1 month of storage at 37 deg C. PMID- 23982140 TI - Platinum drugs and neurotoxicity: effects on intracellular calcium homeostasis. AB - [Pt(O,O'-acac)(gamma-acac)(DMS)] (PtAcacDMS) is a new platinum compound showing low reactivity with nucleobases and specific reactivity with sulfur ligands intracellularly. It induces apoptosis in breast cancer cells, but appears to be less neurotoxic to the developing cerebellum than cisplatin (cisPt). The aim of this study was to assess the neurotoxicity of platinum compounds on calcium homeostasis in the dentate gyrus and Cornu Ammonis regions of the hippocampal formation during rat postnatal development. Two intracellular calcium homeostasis systems were taken for measurement, calbindin, a calcium buffer protein, and a plasma membrane calcium ATPase (PMCA1). The platinum compounds showed different effects on these markers in the two areas. One day after injection (PD11), cisPt decreased calbindin immunoreactivity and PMCA1 labeling in both regions; at PD17, the downregulation of PMCA1 persisted. Instead, PtAcacDMS produced varying effects on calbindin immunoreactivity in the two regions at PD11 and PD17; but in all cases, the changes incurred in calbindin immunoreactivity were counterbalanced by changes produced in PMCA1 expression. In conclusion, PtAcacDMS seems to affect calcium homeostasis in the central nervous system differently than cisPt. Both the platinum compounds act early to alter the calbindin buffering system. However, the most important difference between cisPt and PtAcacDMS is that, in vivo, the latter acts early to stimulate calcium efflux from nerve cells as reflected by its effect on PMCA1. The rapid onset of an activated calcium pump appears to be essential to cope with the excessive intracellular calcium concentration stemming from the downregulation of calbindin which could damage neuron function and morphology. PMID- 23982141 TI - Advances and critical concerns with the microfluidic enrichments of circulating tumor cells. AB - Over the past two decades, circulating tumor cells (CTCs) have been widely recognized for their importance in clinical trials. While most enrichment methods for these cells have been conducted through the batch process due to their rarity in blood and the need for large sample volumes, the batch process leads to unavoidable cell loss. Given the heterogenetic features of CTCs, this cell loss may limit the validity of research that relies on the isolation of CTCs; such research includes cancer prognosis, diagnosis of minimal residual diseases, assessment of tumor sensitivity to anticancer drugs, and the personalization of anticancer therapies. Recent advances in microfluidic approaches have made it possible to enrich CTCs with a small degree of cell loss. In this review, we highlight several microfluidic-based positive and negative enrichment methods that are the subject of considerable research interest (e.g. EpCAM-dependent assay and EpCAM-independent assay) and suggest a microfluidic-based single cell analysis platform for the down-stream analysis of CTCs. We also discuss critical concerns and future directions for research. PMID- 23982142 TI - IGF-1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH-stimulated goiter. AB - Although thyroid-stimulating hormone (TSH) is known to be a major regulator of thyroid hormone biosynthesis and thyroid growth, insulin-like growth factor 1 (IGF-1) is required for mediating thyrocyte growth in concert with TSH in vitro. We generated mice with thyrocyte-selective ablation of IGF-1 receptor (TIGF1RKO) to explore the role of IGF-1 receptor signaling on thyroid function and growth. In 5-wk-old TIGF1RKO mice, serum thyroxine (T4) concentrations were decreased by 30% in concert with a 43% down-regulation of the monocarboxylate transporter 8 (MCT8), which is involved in T4 secretion. Despite a 3.5-fold increase in circulating concentrations of TSH, thyroid architecture and size were normal. Furthermore, thyrocyte area was increased by 40% in WT thyroids after 10 d TSH injection, but this effect was absent in TSH-injected TIGF1RKO mice. WT mice treated with methimazole and sodium perchlorate for 2 or 6 wk exhibited pronounced goiter development (2.0 and 5.4-fold, respectively), but in TIGF1RKO mice, goiter development was completely abrogated. These data reveal an essential role for IGF-1 receptor signaling in the regulation of thyroid function and TSH stimulated goitrogenesis. PMID- 23982143 TI - Regulation of UHRF1 by miR-146a/b modulates gastric cancer invasion and metastasis. AB - Epigenetic changes play significant roles in the development of cancer. UHRF1, as an epigenetic regulator, has been shown to be overexpressed and to coordinate tumor suppressor gene silencing in several cancers. However, the role and underlying mechanism of UHRF1 in gastric cancer (GC) progression remain largely unknown. In this study, we investigated the expression and function of UHRF1 in GC metastasis and explored its upstream regulatory mechanisms at the microRNA level. UHRF1 was overexpressed in GC tissues, especially in metastatic ones, and a high level of UHRF1 expression predicted poor survival. The down-regulation of UHRF1 suppressed GC invasion and metastasis in vitro and in vivo. We identified and verified miR-146a and miR-146b as direct upstream regulators of UHRF1. Furthermore, the restoration of miR-146a/b dramatically reduced the expression of UHRF1 through the direct targeting of its 3'-UTR, and this effect in turn reactivated the slit homologue 3 (Slit3), cadherin 4 (CDH4), and runt-related transcription factor 3 (RUNX3) genes via promoter demethylation. Finally, analyses of miR-146a/b and UHRF1 levels in human GC tissues revealed that miR 146a/b correlated inversely with UHRF1 expression. These findings describe a new mechanism for the regulation of UHRF1 and aberrant DNA hypermethylation in GC. The newly identified miR-146a/b/UHRF1 axis provides insight into the GC metastasis process, and targeting this novel axis represents a therapeutic approach to blocking GC metastasis. PMID- 23982144 TI - Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury. AB - We investigated how complement activation promotes tissue injury and organ dysfunction during acute inflammation. Three models of acute lung injury (ALI) induced by LPS, IgG immune complexes, or C5a were used in C57BL/6 mice, all models requiring availability of both C5a receptors (C5aR and C5L2) for full development of ALI. Ligation of C5aR and C5L2 with C5a triggered the appearance of histones (H3 and H4) in bronchoalveolar lavage fluid (BALF). BALF from humans with ALI contained H4 histone. Histones were absent in control BALF from healthy volunteers. In mice with ALI, in vivo neutralization of H4 with IgG antibody reduced the intensity of ALI. Neutrophil depletion in mice with ALI markedly reduced H4 presence in BALF and was highly protective. The direct lung damaging effects of extracellular histones were demonstrated by airway administration of histones into mice and rats (Sprague-Dawley), which resulted in ALI that was C5a receptor-independent, and associated with intense inflammation, PMN accumulation, damage/destruction of alveolar epithelial cells, together with release into lung of cytokines/chemokines. High-resolution magnetic resonance imaging demonstrated lung damage, edema and consolidation in histone-injured lungs. These studies confirm the destructive C5a-dependent effects in lung linked to appearance of extracellular histones. PMID- 23982146 TI - Mitochondrial dysfunction and calcium deregulation by the RanBP9-cofilin pathway. AB - Mitochondrial dysfunction and synaptic damage are important features of Alzheimer's disease (AD) associated with amyloid beta (Abeta) and tau. We reported previously that the scaffolding protein RanBP9, which is overall increased in brains of patients with AD and in mutant APP transgenic mice, simultaneously promotes Abeta generation and focal adhesion disruption by accelerating the endocytosis of APP and beta1-integrin, respectively. Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates Abeta-induced neurotoxicity. Here we show in primary hippocampal neurons that RanBP9 potentiates Abeta-induced reactive oxygen species (ROS) overproduction, apoptosis, and calcium deregulation. Analyses of calcium-handling measures demonstrate that RanBP9 selectively delays the clearance of cytosolic Ca(2+) mediated by the mitochondrial calcium uniporter through a process involving the translocation of cofilin into mitochondria and oxidative mechanisms. Further, RanBP9 retards the anterograde axonal transport of mitochondria in primary neurons and decreases synaptic mitochondrial activity in brain. These data indicate that RanBP9, cofilin, and Abeta mimic and potentiate each other to produce mitochondrial dysfunction, ROS overproduction, and calcium deregulation, which leads to neurodegenerative changes reminiscent of those seen in AD. PMID- 23982145 TI - The CB1 receptor mediates the peripheral effects of ghrelin on AMPK activity but not on growth hormone release. AB - This study aimed to investigate whether the growth hormone release and metabolic effects of ghrelin on AMPK activity of peripheral tissues are mediated by cannabinoid receptor type 1 (CB1) and the central nervous system. CB1-knockout (KO) and/or wild-type mice were injected peripherally or intracerebroventricularly with ghrelin and CB1 antagonist rimonabant to study tissue AMPK activity and gene expression (transcription factors SREBP1c, transmembrane protein FAS, enzyme PEPCK, and protein HSL). Growth hormone levels were studied both in vivo and in vitro. Peripherally administered ghrelin in liver, heart, and adipose tissue AMPK activity cannot be observed in CB1-KO or CB1 antagonist-treated mice. Intracerebroventricular ghrelin treatment can influence peripheral AMPK activity. This effect is abolished in CB1-KO mice and by intracerebroventricular rimonabant treatment, suggesting that central CB1 receptors also participate in the signaling pathway that mediates the effects of ghrelin on peripheral tissues. Interestingly, in vivo or in vitro growth hormone release is intact in response to ghrelin in CB1-KO animals. Our data suggest that the metabolic effects of ghrelin on AMPK in peripheral tissues are abolished by the lack of functional CB1 receptor via direct peripheral effect and partially through the central nervous system, thus supporting the existence of a possible ghrelin-cannabinoid-CB1-AMPK pathway. PMID- 23982147 TI - Experimental sepsis-induced mitochondrial biogenesis is dependent on autophagy, TLR4, and TLR9 signaling in liver. AB - Organ injury in sepsis is initially characterized by dysfunction without cell death and structural damage, and thus with the ability to recover organ function. Adaptive metabolic responses to sepsis can prevent bioenergetic failure and death. These studies were aimed at investigating the influence of sepsis on mitochondrial homeostasis, focusing on removal of dysfunctional mitochondria and restitution of a healthy mitochondrial population. These data demonstrate decreased hepatic oxidative phosphorylation by 31 +/- 11% following murine cecal ligation and puncture (CLP) at 8 h and 34 +/- 9% following LPS treatment in vitro at 12 h (P<0.05). In addition, there was a loss of mitochondrial membrane potential. Mitochondrial density and number initially decreased (relative area per micrograph of 64+/-10% at baseline vs. 39+/-13% at 8 h following LPS; P<0.05) and was associated with an increase in autophagy and mitophagy. CLP-induced markers of mitochondrial biogenesis and mitochondrial number and density recovered over time. Furthermore, these data suggest that mitochondrial biogenesis was dependent on an autophagy and mitochondrial DNA/Toll-like receptor 9 (TLR9) signaling pathway. These results suggest that hepatocyte survival and maintenance of function in sepsis is dependent on a mitochondrial homeostasis pathway marked by mitophagy and biogenesis. PMID- 23982149 TI - Reduced dimensionality (4,3)D-hnCOCANH experiment: an efficient backbone assignment tool for NMR studies of proteins. AB - Sequence specific resonance assignment of proteins forms the basis for variety of structural and functional proteomics studies by NMR. In this context, an efficient standalone method for rapid assignment of backbone ((1)H, (15)N, (13)C(alpha) and (13)C') resonances of proteins has been presented here. Compared to currently available strategies used for the purpose, the method employs only a single reduced dimensionality experiment--(4,3)D-hnCOCANH and exploits the linear combinations of backbone ((13)C(alpha) and (13)C') chemical shifts to achieve a dispersion relatively better compared to those of individual chemical shifts (see the text). The resulted increased dispersion of peaks--which is different in sum (CA + CO) and difference (CA - CO) frequency regions--greatly facilitates the analysis of the spectrum by resolving the problems (associated with routine assignment strategies) arising because of degenerate amide (15)N and backbone (13)C chemical shifts. Further, the spectrum provides direct distinction between intra- and inter-residue correlations because of their opposite peak signs. The other beneficial feature of the spectrum is that it provides: (a) multiple unidirectional sequential (i->i + 1) (15)N and (13)C correlations and (b) facile identification of certain specific triplet sequences which serve as check points for mapping the stretches of sequentially connected HSQC cross peaks on to the primary sequence for assigning the resonances sequence specifically. On top of all this, the F2-F3 planes of the spectrum corresponding to sum (CA + CO) and difference (CA - CO) chemical shifts enable rapid and unambiguous identification of sequential HSQC peaks through matching their coordinates in these two planes (see the text). Overall, the experiment presented here will serve as an important backbone assignment tool for variety of structural and functional proteomics and drug discovery research programs by NMR involving well behaved small folded proteins (MW < 15 kDa) or a range of intrinsically disordered proteins. PMID- 23982150 TI - PDB@: an offline toolkit for exploration and analysis of PDB files. AB - Protein Data Bank (PDB) is a freely accessible archive of the 3-D structural data of biological molecules. Structure based studies offers a unique vantage point in inferring the properties of a protein molecule from structural data. This is too big a task to be done manually. Moreover, there is no single tool, software or server that comprehensively analyses all structure-based properties. The objective of the present work is to develop an offline computational toolkit, PDB@ containing in-built algorithms that help categorizing the structural properties of a protein molecule. The user has the facility to view and edit the PDB file to his need. Some features of the present work are unique in itself and others are an improvement over existing tools. Also, the representation of protein properties in both graphical and textual formats helps in predicting all the necessary details of a protein molecule on a single platform. PMID- 23982148 TI - Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. AB - OBJECTIVE: Childhood maltreatment increases risk for psychopathology. For some highly prevalent disorders (major depression, substance abuse, anxiety disorders, and posttraumatic stress disorder) a substantial subset of individuals have a history of maltreatment and a substantial subset do not. The authors examined the evidence to assess whether those with a history of maltreatment represent a clinically and biologically distinct subtype. METHOD: The authors reviewed the literature on maltreatment as a risk factor for these disorders and on the clinical differences between individuals with and without a history of maltreatment who share the same diagnoses. Neurobiological findings in maltreated individuals were reviewed and compared with findings reported for these disorders. RESULTS: Maltreated individuals with depressive, anxiety, and substance use disorders have an earlier age at onset, greater symptom severity, more comorbidity, a greater risk for suicide, and poorer treatment response than nonmaltreated individuals with the same diagnoses. Imaging findings associated with these disorders, such as reduced hippocampal volume and amygdala hyperreactivity, are more consistently observed in maltreated individuals and may represent a maltreatment-related risk factor. Maltreated individuals also differ from others as a result of epigenetic modifications and genetic polymorphisms that interact with experience to increase risk for psychopathology. CONCLUSIONS: Phenotypic expression of psychopathology may be strongly influenced by exposure to maltreatment, leading to a constellation of ecophenotypes. While these ecophenotypes fit within conventional diagnostic boundaries, they likely represent distinct subtypes. Recognition of this distinction may be essential in determining the biological bases of these disorders. Treatment guidelines and algorithms may be enhanced if maltreated and nonmaltreated individuals with the same diagnostic labels are differentiated. PMID- 23982151 TI - Derailed by diversity? Purpose buffers the relationship between ethnic composition on trains and passenger negative mood. AB - Many individuals feel socially isolated and distressed in ethnically diverse settings. Purpose in life may buffer this form of distress by fostering one's sense of having a meaningful direction, which may also be of significance to others. In two experience-sampling studies with ethnically diverse participants, we examined associations between the ethnic composition of urban trains and passenger distress, and tested purpose as a moderator of these relationships. Study 1 showed that participants of all ethnic backgrounds reported greater negative mood when the percentage of ethnic out-group members aboard their train increased. However, individual differences in purpose significantly attenuated this effect. Study 2 replicated and extended these findings experimentally by showing that relative to a control condition, briefly writing about purpose prior to boarding trains also diminished the impact of ethnic composition on negative mood. The discussion addresses strategies for promoting positive adjustment in our increasingly diverse society. PMID- 23982152 TI - What drives priming effects in the affect misattribution procedure? AB - The affect misattribution procedure (AMP) is one of the most promising implicit measures to date, showing high reliability and large effect sizes. The current research tested three potential sources of priming effects in the AMP: affective feelings, semantic concepts, and prepotent motor responses. Ruling out prepotent motor responses as a driving force, priming effects on evaluative and semantic target responses occurred regardless of whether the key assignment in the task was fixed or random. Moreover, priming effects emerged for affect-eliciting primes in the absence of semantic knowledge about the primes. Finally, priming effects were independent of the order in which primes and targets were presented, suggesting that AMP effects are driven by misattribution rather than biased perceptions of the targets. Taken together, these results support accounts that attribute priming effects in the AMP to a general misattribution mechanism that can operate on either affective feelings or semantic concepts. PMID- 23982153 TI - Green synthesis of carbon dots with down- and up-conversion fluorescent properties for sensitive detection of hypochlorite with a dual-readout assay. AB - High quality carbon dots (C-dots) with down- and up-conversion fluorescence have been synthesized through low-temperature carbonization using sweet pepper as the carbon source. The C-dots with a quantum yield (QY) of 19.3% exhibit superior photophysical properties, for example, narrow and symmetric emission spectra, large stock shifts, resistance to photobleaching, and excitation-dependent fluorescence behavior. The excellent C-dots serve as useful fluorescent probes for hypochlorite (ClO(-)) detection by both down- and up-conversion fluorescence. Two consecutive linear ranges allow a wide determination of ClO(-) concentrations with a low detection limit of 0.05 MUmol L(-1) and 0.06 MUmol L(-1) (S/N = 3) for down- and up-conversion fluorescence measurements, respectively. The proposed detection method is advantageous because it is simple, sensitive, dual-signalling model and low-cost and has potential extensive applications in environmental and biological assays. PMID- 23982154 TI - Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets. AB - Moderate low-carbohydrate/high-fat (LC-HF) diets are widely used to induce weight loss in overweight subjects, whereas extreme ketogenic LC-HF diets are used to treat neurological disorders like pediatric epilepsy. Usage of LC-HF diets for improvement of glucose metabolism is highly controversial; some studies suggest that LC-HF diets ameliorate glucose tolerance, whereas other investigations could not identify positive effects of these diets or reported impaired insulin sensitivity. Here, we investigate the effects of LC-HF diets on glucose and insulin metabolism in a well-characterized animal model. Male rats were fed isoenergetic or hypocaloric amounts of standard control diet, a high-protein "Atkins-style" LC-HF diet, or a low-protein, ketogenic, LC-HF diet. Both LC-HF diets induced lower fasting glucose and insulin levels associated with lower pancreatic beta-cell volumes. However, dynamic challenge tests (oral and intraperitoneal glucose tolerance tests, insulin-tolerance tests, and hyperinsulinemic euglycemic clamps) revealed that LC-HF pair-fed rats exhibited impaired glucose tolerance and impaired hepatic and peripheral tissue insulin sensitivity, the latter potentially being mediated by elevated intramyocellular lipids. Adjusting visceral fat mass in LC-HF groups to that of controls by reducing the intake of LC-HF diets to 80% of the pair-fed groups did not prevent glucose intolerance. Taken together, these data show that lack of dietary carbohydrates leads to glucose intolerance and insulin resistance in rats despite causing a reduction in fasting glucose and insulin concentrations. Our results argue against a beneficial effect of LC-HF diets on glucose and insulin metabolism, at least under physiological conditions. Therefore, use of LC-HF diets for weight loss or other therapeutic purposes should be balanced against potentially harmful metabolic side effects. PMID- 23982155 TI - Mitochondrial and performance adaptations to exercise training in mice lacking skeletal muscle LKB1. AB - LKB1 and its downstream targets of the AMP-activated protein kinase family are important regulators of many aspects of skeletal muscle cell function, including control of mitochondrial content and capillarity. LKB1 deficiency in skeletal and cardiac muscle (mLKB1-KO) greatly impairs exercise capacity. However, cardiac dysfunction in that genetic model prevents a clear assessment of the role of skeletal muscle LKB1 in the observed effects. Our purposes here were to determine whether skeletal muscle-specific knockout of LKB1 (skmLKB1-KO) decreases exercise capacity and mitochondrial protein content, impairs accretion of mitochondrial proteins after exercise training, and attenuates improvement in running performance after exercise training. We found that treadmill and voluntary wheel running capacity was reduced in skmLKB1-KO vs. control (CON) mice. Citrate synthase activity, succinate dehydrogenase activity, and pyruvate dehydrogenase kinase content were lower in KO vs. CON muscles. Three weeks of treadmill training resulted in significantly increased treadmill running performance in both CON and skmLKB1-KO mice. Citrate synthase activity increased significantly with training in both genotypes, but protein content and activity for components of the mitochondrial electron transport chain increased only in CON mice. Capillarity and VEGF protein was lower in skmLKB1-KO vs. CON muscles, but VEGF increased with training only in skmLKB1-KO. Three hours after an acute bout of muscle contractions, PGC-1alpha, cytochrome c, and VEGF gene expression all increased in CON but not skmLKB1-KO muscles. Our findings indicate that skeletal muscle LKB1 is required for accretion of some mitochondrial proteins but not for early exercise capacity improvements with exercise training. PMID- 23982156 TI - The insulin receptor plays an important role in secretory differentiation in the mammary gland. AB - Insulin is known to be an important regulator of milk secretion in the lactating mammary gland. Here we examine the role of insulin signaling in mammary development in pregnancy using a mouse with a floxed insulin receptor (IR) crossed with a mouse expressing Cre specifically in the mammary gland. In the mammary glands of these IR(fl/fl) Cre(+) mice, expression of IR is significantly diminished throughout development. Glands from these mice had 50% fewer alveoli at midpregnancy; casein and lipid droplets were diminished by 60 and 75%, respectively, indicating a role for IR both in alveolar development and differentiation. In an acinar preparation from mammary epithelial cells (MEC) isolated from pregnant mice, insulin stimulated lumen formation, mammary cell size, acinar size, acinar casein content, and the formation of lipid droplets with a Km of ~1.7 nM. IGF-I and IGF-II had no effect at concentrations below 50 nM, and a function blocking antibody to the IGF type 1 receptor did not alter the response to insulin. We conclude that insulin interacting with IR is essential for mammary differentiation during murine pregnancy. Using array analysis, we then examined the expression of genes up- or downregulated >1.5-fold in the IR(fl/fl) Cre(+) MECs, finding significant downregulation of differentiation specific genes and upregulation of cell cycle and extracellular matrix genes. We conclude that insulin fosters differentiation and may inhibit cell proliferation in the mammary gland of the midpregnant mouse. PMID- 23982157 TI - Intracellular lipid content is a key intrinsic determinant for hepatocyte viability and metabolic and inflammatory states in mice. AB - The liver is an essential metabolic organ. In addition to metabolizing glucose and lipids, hepatocytes also secrete various cytokines that modulate both hepatocyte metabolism and liver inflammation. Hepatocyte injury and death and liver inflammation are the major contributors to liver diseases, including nonalcoholic steatohepatitis (NASH). Anatomic locations have a profound effect on hepatocyte metabolism, and liver zonation describes the metabolic heterogeneity of hepatocytes along the portovenous axis. However, it is unclear whether hepatocyte heterogeneity is affected by intrinsic factors and whether dietary fat, a risk factor for NASH, has distinct detrimental effects on different hepatocyte subpopulations. Here, we showed that mouse livers contained both high lipid and low-lipid subpopulations of hepatocytes. The high-lipid subpopulation was more susceptible to injury and apoptosis and produced more proinflamatrory cytokines after treatment with endotoxin and saturated fatty acids. Dietary fat consumption further increased fatty acid uptake, intracellular lipid levels, hepatocyte injury and death, and the expression of proinflammatory cytokines in the high-lipid subpopulation. In contrast, dietary fat slightly increased lipid levels, cell death, and expression of proinflammatory cytokines in the low-lipid subpopulation. The low-lipid subpopulation produced more glucose. Fat consumption further activated the gluconeogenic program in the low-lipid, but not the high lipid, subpopulations. These data suggest that intracellular lipid content is a key intrinsic determinant for hepatocyte heterogeneity of metabolic, inflammatory, and survival states. PMID- 23982158 TI - alpha-Cells are dispensable in postnatal morphogenesis and maturation of mouse pancreatic islets. AB - Glucagon-producing alpha-cells are the second-most abundant cell type in the islet. Whereas alpha-cells make up less than 20% of the cells in a mature mouse islet, they occupy a much larger proportion of the pancreatic endocrine cell population during the early postnatal period, the time when morphological and functional maturation occurs to form adult islets. To determine whether alpha cells have a role in postnatal islet development, a diphtheria toxin-mediated alpha-cell ablation mouse model was established. Rapid and persistent depletion of alpha-cells was achieved by daily injection of the toxin for 2 wk starting at postnatal day 1 (P1). Total pancreatic glucagon content in the alpha-cell-ablated mice was undetectable at P14 and still less than 0.3% of that of the control mice at 4 mo of age. Histological analyses revealed that formation of spherical islets occurred normally, and the islet size distribution was not changed despite the near-total lack of alpha-cells. Furthermore, there were no differences in expression of beta-cell maturation marker proteins, including urocortin 3 and glucose transporter 2, in the alpha-cell-ablated islets at P14. Mice lacking alpha-cells grew normally and appeared healthy. Both glucose and insulin tolerance tests demonstrated that the alpha-cell-ablated mice had normal glucose homeostasis. These results indicate that alpha-cells do not play a critical role in postnatal islet morphogenesis or functional maturation of beta-cells. PMID- 23982159 TI - Altered subcutaneous abdominal adipose tissue lipid synthesis in obese, insulin resistant humans. AB - The purpose of this study was to evaluate the variability of subcutaneous abdominal adipose tissue (AT) dynamics in obese subjects with a wide range of insulin sensitivity (IS) and the correlation between these two metabolic measures. Ten obese (BMI 30-40 kg/m2) nondiabetic subjects with (n = 6) and without (n = 4) the metabolic syndrome were studied following a 12-wk 2H2O labeling period. Subcutaneous abdominal AT biopsies were collected. Deuterium incorporation into triglyceride (TG)-glycerol and TG-palmitate were measured by gas chromatography-mass spectrometry for the calculation of fractional TG synthesis (fTG) and fractional de novo lipogenesis (fDNL). Muscle IS and insulin mediated nonesterified fatty acid (NEFA) suppression (a measure for adipose IS) indexes were derived from the oral glucose tolerance test (OGTT). The ability of subcutaneous abdominal AT to synthesize lipids varied significantly in obese subjects (fTG range 7-28%, fDNL range 1.1-4.6%) with significantly lower values (>35% reduction) for both parameters in obese with the metabolic syndrome. fTG correlated positively with muscle IS (r = 0.64, P = 0.04) and inversely with NEFA suppression during the OGTT (r = -0.69, P = 0.03). These results demonstrate a large variability in subcutaneous abdominal AT lipid turnover in obesity. Moreover, a reduced capacity for subcutaneous abdominal AT fat storage is associated with muscle and adipose tissue insulin resistance as well as with the metabolic syndrome, thus identifying a form of obesity at heightened risk for type 2 diabetes and cardiovascular disease. PMID- 23982160 TI - An electron paramagnetic resonance method for measuring the affinity of a spin labeled analog of cholesterol for phospholipids. AB - Cholesterol (chol)-lipid interactions are thought to play an intrinsic role in determining lateral organization within cellular membranes. Steric compatibility of the rigid steroid moiety for ordered saturated chains contributes to the high affinity that holds chol and sphingomyelin together in lipid rafts whereas, conversely, poor affinity of the sterol for highly disordered polyunsaturated fatty acids (PUFAs) is hypothesized to drive the formation of PUFA-containing phospholipid domains depleted in chol. Here, we describe a novel method using electron paramagnetic resonance (EPR) to measure the relative affinity of chol for different phospholipids. We monitor the partitioning of 3beta-doxyl-5alpha cholestane (chlstn), a spin-labeled analog of chol, between large unilamellar vesicles (LUVs) and cyclodextrin (mbetaCD) through analysis of EPR spectra. Because the shape of the EPR spectrum for chlstn is sensitive to the very different tumbling rates of the two environments, the ratio of the population of chlstn in LUVs and mbetaCD can be determined directly from spectra. Partition coefficients (K(B)(A)) between lipids derived from our results for chlstn agree with values obtained for chol and confirm that decreased affinity for the sterol accompanies increasing acyl chain unsaturation. The virtue of this EPR method is that it provides a measure of chol binding that is quick, employs a commercially available probe and avoids the necessity for physical separation of LUVs and mbetaCD. PMID- 23982161 TI - Host-centric proteomics of stool: a novel strategy focused on intestinal responses to the gut microbiota. AB - The diverse community of microbes that inhabits the human bowel is vitally important to human health. Host-expressed proteins are essential for maintaining this mutualistic relationship and serve as reporters on the status of host microbiota interaction. Therefore, unbiased and sensitive methods focused on host proteome characterization are needed. Herein we describe a novel method for applying shotgun proteomics to the analysis of feces, focusing on the secreted host proteome. We have conducted the most complete analysis of the extracellular mouse gut proteome to date by employing a gnotobiotic mouse model. Using mice colonized with defined microbial communities of increasing complexity or a complete human microbiota ('humanized'), we show that the complexity of the host stool proteome mirrors the complexity of microbiota composition. We further show that host responses exhibit signatures specific to the different colonization states. We demonstrate feasibility of this approach in human stool samples and provide evidence for a "core" stool proteome as well as personalized host response features. Our method provides a new avenue for noninvasive monitoring of host-microbiota interaction dynamics via host-produced proteins in stool. PMID- 23982163 TI - Polyaminoborane main chain scission using N-heterocyclic carbenes; formation of donor-stabilised monomeric aminoboranes. AB - The reaction of N-heterocyclic carbenes with polyaminoboranes [MeNH-BH2]n or [NH2 BH2]n at 20 degrees C led to depolymerisation and the formation of labile, monomeric aminoborane-NHC adducts, RNH-BH2-NHC (R = Me or H); a similar NHC adduct of Ph2N=BCl2 was characterized by single crystal X-ray diffraction. PMID- 23982162 TI - Grading breast cancer tissues using molecular portraits. AB - Tumor progression and prognosis in breast cancer patients are difficult to assess using current clinical and laboratory parameters, where a pathological grading is indicative of tumor aggressiveness. This grading is based on assessments of nuclear grade, tubule formation, and mitotic rate. We report here the first protein signatures associated with histological grades of breast cancer, determined using a novel affinity proteomics approach. We profiled 52 breast cancer tissue samples by combining nine antibodies and label-free LC-MS/MS, which generated detailed quantified proteomic maps representing 1,388 proteins. The results showed that we could define in-depth molecular portraits of histologically graded breast cancer tumors. Consequently, a 49-plex candidate tissue protein signature was defined that discriminated between histological grades 1, 2, and 3 of breast cancer tumors with high accuracy. Highly biologically relevant proteins were identified, and the differentially expressed proteins indicated further support for the current hypothesis regarding remodeling of the tumor microenvironment during tumor progression. The protein signature was corroborated using meta-analysis of transcriptional profiling data from an independent patient cohort. In addition, the potential for using the markers to estimate the likelihood of long-term metastasis-free survival was also indicated. Taken together, these molecular portraits could pave the way for improved classification and prognostication of breast cancer. PMID- 23982164 TI - Effects of L-DOPA on striatal iodine-123-FP-CIT binding and behavioral parameters in the rat. AB - PURPOSE: The effect of clinical L-3,4-dihydroxyphenylalanine (L-DOPA) doses on the binding of [121I]N-Omega-fluoropropyl-2beta-carbomethoxy-3beta-(4 iodophenyl)nortropane (121[I]FP-CIT) to the rat dopamine transporter (DAT) was investigated using small animal single-photon emission computed tomography. MATERIALS AND METHODS: DAT binding was measured at baseline, after challenge with the aromatic L-amino acid decarboxylase inhibitor benserazide, and after challenge with either 5 or 10 mg/kg L-DOPA plus benserazide. For baseline and challenges, striatal equilibrium ratios (V3'') were computed as an estimation of the binding potential. Moreover, striatal V3'' values were correlated with parameters of motor and exploratory behavior. RESULTS: V3'' differed significantly between baseline and either dose of L-DOPA/benserazide. Moreover, V3'' differed significantly between L-DOPA treatment groups. After 5 mg/kg L DOPA/benserazide, DAT binding was inversely correlated with sitting duration (1-5 min) and sitting frequency (10-15 min). After 10 mg/kg L-DOPA/benserazide, an inverse correlation was found between DAT binding and sitting duration (1-30 min), whereas DAT binding and duration of ambulatory activity (1-30 min) as well as head and shoulder motility (10-15 min) exhibited a positive correlation. CONCLUSION: Challenge with 5 and 10 mg/kg L-DOPA/benserazide led to mean reductions in DAT binding by 34 and 20%, respectively. Results indicate a biphasic response with a higher effect on DAT after the lower dose of L-DOPA. The reduction in DAT binding may be interpreted in terms of competition between [123I]FP-CIT and endogenous dopamine. Moreover, there is preliminary evidence of an association between striatal DAT and motor and exploratory parameters. PMID- 23982165 TI - Monophosphoryl lipid A induces bone marrow precursor cells to differentiate into myeloid-derived suppressor cells. AB - Myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs) are important in the immune response. In vitro, DCs are derived from myeloid precursors by stimulation with granulocyte macrophage colony-stimulating factor and interleukin 4. Previous studies demonstrated that lipopolysaccharide (LPS) in combination with interferon-gamma inhibited DC development but enhanced MDSC functions. Monophosphoryl lipid A (MPL), derived from LPS, is a unique immunomodulatory Toll like receptor 4 agonist. In the present study, MPL was used to disturb DC differentiation from myeloid precursors and it was observed that prolonged stimulation with MPL led to the accumulation of MDSCs in vitro and in vivo. In conclusion, it was demonstrated that stimulation by MPL from the beginning of cell differentiation disturbed the development of DCs and led to the accumulation of MDSCs. PMID- 23982167 TI - Reply to the comment of Drs Goldman and Vollmer. PMID- 23982166 TI - Transduction of fetal mice with a feline lentiviral vector induces liver tumors which exhibit an E2F activation signature. AB - Lentiviral vectors are widely used in basic research and clinical applications for gene transfer and long-term expression; however, safety issues have not yet been completely resolved. In this study, we characterized hepatocarcinomas that developed in mice 1 year after in utero administration of a feline-derived lentiviral vector. Mapped viral integration sites differed among tumors and did not coincide with the regions of chromosomal aberrations. Furthermore, gene expression profiling revealed that no known cancer-associated genes were deregulated in the vicinity of viral integrations. Nevertheless, five of the six tumors exhibited highly significant upregulation of E2F target genes, of which a majority are associated with oncogenesis, DNA damage response, and chromosomal instability. We further show in vivo and in vitro that E2F activation occurs early on following transduction of both fetal mice and cultured human hepatocytes. On the basis of the similarities in E2F target gene expression patterns among tumors and the lack of evidence implicating insertional mutagenesis, we propose that transduction of fetal mice with a feline lentiviral vector induces E2F-mediated major cellular processes that drive hepatocytes toward uncontrolled proliferation culminating in tumorigenesis. PMID- 23982168 TI - Incidence and review of sessile serrated polyp reporting in a district general hospital in the UK. AB - The aim of this 4-year audit was to establish whether sessile serrated polyps/adenomas (SSP/A) were diagnosed in a district general hospital in the UK. The study also explored whether SSP/A in the right colon were misdiagnosed as hyperplastic polyps. A retrospective search of the computer records from 2009 to 2012 inclusive for all lesions diagnosed and coded as SSP/A and/or hyperplastic polyps proximal to the splenic flexure was undertaken. All slides were reviewed and a diagnosis of SSP/A made using the criteria recently suggested by the American College of Gastroenterology. Over the study period, no cases of SSP/A were made. On review of all hyperplastic polyps proximal to the splenic flexure, 13/31 in 2009, 17/40 in 2010, 19/48 in 2011 and 16/48 in 2012 were re-classified as SSP/A. The most likely reason for the under-diagnosis of SSP/A is lack of awareness of the lesion both clinically and by pathologists. Adequate biopsies and deeper sections are important to help make the diagnosis of SSP/A. This study shows that SSP/A are reasonably frequently encountered in non-specialist practice settings and that both clinicians and pathologist in this setting need to be aware of its existence. PMID- 23982169 TI - Prognostic role of tumor volume for radiotherapy outcome in patient with T2 laryngeal cancer. AB - BACKGROUND AND PURPOSE: Tumor volume (TV) is recognized as a prognostic factor of treatment outcome for head and neck tumors but is not routinely included in the treatment decision-making process. The purpose of the study was to define its prognostic role for patients with T2 laryngeal cancer. MATERIAL AND METHODS: TV of 160 patients who underwent RT between 2002 and 2006 for T2 laryngeal squamous cell carcinoma were reviewed. The tumor was located in the glottis and epiglottis in 82 (51%) and 78 (49%) patients, respectively. TV was manually contoured on pretreatment, planning, contrast-enhanced CT scans and the volumetric measurement (cm3) was calculated by the volume algorithm. RESULTS: The median TV value was 2.01 cm3 (range 0.15-21.68 cm3). The median TV was significantly lower in patients with glottic tumors (p<0.0001), N0 (p<0.001), or well histopatologically differentiated tumors (p=0.01). A significant correlation between TV, hemoglobin concentration (p<0.01), and total dose (TD; p<0.001) was observed. On univariate analyses, TV influenced local control (LC; p=0.02) and overall survival (OS, p<0.001). On multivariate analysis, both age (HR 1.038, p=0.03) and TV (HR=1.075, p=0.01) remained significantly related to LC and OS (age: HR 1.038, p=0.005; TV: HR 1.097, p=0.0001). CONCLUSION: Large TV worsen prognosis of patients with T2 laryngeal cancer. A large TV is more common for supraglottic, poorly differentiated tumors and may suggest higher risk of nodal spread. The routine estimation of TV prior to therapy may be essential in order to select the best treatment option for patients with T2 laryngeal cancer. PMID- 23982170 TI - Using the Internet-based upload blood glucose monitoring and therapy management system in patients with type 1 diabetes. AB - The aim of this study is to assess the impact of the internet-based upload blood glucose monitoring and therapy management system (Carelink((r))) in patients with type 1 diabetes. Diabetic patients treated with pump infusion for >=3 months were prospectively randomized to use the CareLink((r)) with (4 months) and without (4 months) diabetes-team initiated contact (n = 36, intervention group) or to continue standard care for 4 months and then transfer to the CareLink((r)) without diabetes-team initiated contact (n = 34, control group). In the first 4 months, treatment was adjusted monthly by the same team in both groups. Main outcome measures were HbA1c level and scores on the Diabetes Treatment Satisfaction and Diabetes Quality of Life Questionnaires. Patients who submitted <3 times during each 4-month segment were considered noncompliant. Mean patient age was 14.02 +/- 5.33 years; mean diabetes duration, 6.4 +/- 4.7 years; median duration of pump treatment, 2.5 years. After 4 months, mean HbA1c level decreased from 8.75 +/- 0.84 to 8.45 +/- 0.90% in the intervention group (p = 0.013) and from 8.65 +/- 0.57 to 8.37 +/- 0.73% in the control group (p = 0.054). Within the intervention group, the difference in the change in HbA1c levels between compliant and noncompliant patients was significant (8.17 +/- 0.81 vs. 8.99 +/- 0.85%, p = 0.017). Only in the compliant subgroup was the decrease from baseline significant (p = 0.006). Similar findings were noted in the control group at 8 months (p < 0.05 and p = 0.018, respectively). There were no significant changes in questionnaire scores at 4 or 8 months in either group. Use of the CareLink((r)) system is associated with significantly improved glycemic control in compliant patients, with no apparent effect on patient satisfaction or quality of life. PMID- 23982171 TI - Hydroa vacciniforme-like lymphoma: a chronic EBV+ lymphoproliferative disorder with risk to develop a systemic lymphoma. AB - Hydroa vacciniforme-like lymphoma (HVLL) is an Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disorder of childhood that occurs mainly in Central and South America and Asia. We present the clinicopathological features of 20 Mexican children with HVLL with a median age of 8 years at diagnosis (range, 1 15). All patients presented with skin lesions involving sun-exposed areas, but not exclusively. Fever, lymphadenopathy, and hepatosplenomegaly were often observed. Most patients were treated with immunomodulators and/or immunosuppressive agents, resulting in temporary remission. For 13 patients follow-up was available for a median of 3 years (range, 1 month-13 years). Three patients with long follow-up (9-13 years) are alive with disease. Four patients died, 2 after developing systemic lymphoma. Histologically, the skin showed a predominantly angiocentric and periadnexal Epstein-Barr early RNA+ lymphoid infiltrate with variable atypia and subcutaneous involvement. Fifteen patients showed a T-cell phenotype (12, alphabeta; 2, gammadelta; 1, silent phenotype) and monoclonal T-cell receptor-gamma rearrangements, whereas 6 exhibited a natural killer (NK)-cell phenotype. Four patients had hypersensitivity to mosquito bites. One patient showed both phenotypes. HVLL is an EBV-associated lymphoproliferative disorder of alphabeta-, gammadelta-, or NK-cell phenotype with a broad clinical spectrum, usually prolonged clinical course, and risk for progression to systemic disease. PMID- 23982172 TI - Axl, a prognostic and therapeutic target in acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow stroma. AB - Acute myeloid leukemia (AML) represents a clonal disease of hematopoietic progenitors characterized by acquired heterogenous genetic changes that alter normal mechanisms of proliferation, self-renewal, and differentiation.(1) Although 40% to 45% of patients younger than 65 years of age can be cured with current therapies, only 10% of older patients reach long-term survival.(1) Because only very few novel AML drugs were approved in the past 2 decades, there is an urgent need to identify novel targets and therapeutic strategies to treat underserved AML patients. We report here that Axl, a member of the Tyro3, Axl, Mer receptor tyrosine kinase family,(2-4) represents an independent prognostic marker and therapeutic target in AML. AML cells induce expression and secretion of the Axl ligand growth arrest-specific gene 6 (Gas6) by bone marrow-derived stromal cells (BMDSCs). Gas6 in turn mediates proliferation, survival, and chemoresistance of Axl-expressing AML cells. This Gas6-Axl paracrine axis between AML cells and BMDSCs establishes a chemoprotective tumor cell niche that can be abrogated by Axl-targeting approaches. Axl inhibition is active in FLT3-mutated and FLT3 wild-type AML, improves clinically relevant end points, and its efficacy depends on presence of Gas6 and Axl. Axl inhibition alone or in combination with chemotherapy might represent a novel therapeutic avenue for AML. PMID- 23982173 TI - Polycomb repressive complex 2 (PRC2) suppresses EMU-myc lymphoma. AB - Deregulation of polycomb group complexes polycomb repressive complex 1 (PRC1) and 2 (PRC2) is associated with human cancers. Although inactivating mutations in PRC2-encoding genes EZH2, EED, and SUZ12 are present in T-cell acute lymphoblastic leukemia and in myeloid malignancies, gain-of-function mutations in EZH2 are frequently observed in B-cell lymphoma, implying disease-dependent effects of individual mutations. We show that, in contrast to PRC1, PRC2 is a tumor suppressor in Eu-myc lymphomagenesis, because disease onset was accelerated by heterozygosity for Suz12 or by short hairpin RNA-mediated knockdown of Suz12 or Ezh2. Accelerated lymphomagenesis was associated with increased accumulation of B-lymphoid cells in the absence of effects on apoptosis or cell cycling. However, Suz12-deficient B-lymphoid progenitors exhibit enhanced serial clonogenicity. Thus, PRC2 normally restricts the self-renewal of B-lymphoid progenitors, the disruption of which contributes to lymphomagenesis. This finding provides new insight regarding the functional contribution of mutations in PRC2 in a range of leukemias. PMID- 23982174 TI - Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality. AB - HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36 3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death. PMID- 23982176 TI - Human VKORC1 mutations cause variable degrees of 4-hydroxycoumarin resistance and affect putative warfarin binding interfaces. AB - Since the discovery of warfarin-sensitive vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1), 26 human VKORC1 (hVKORC1) missense mutations have been associated with oral anticoagulant resistance (OACR). Assessment of warfarin resistance using the "classical" dithiothreitol-driven vitamin K 2,3-epoxide reductase (VKOR) assay has not reflected clinical resistance phenotypes for most mutations. Here, we present half maximal inhibitory concentrations (IC50) results for 21 further hVKORC1 mutations obtained using a recently validated cell-based assay (J Thromb Haemost 11(5):872). In contrast to results from the dithiothreitol-driven VKOR assay, all mutations exhibited basal VKOR activity and warfarin IC50 values that correspond well to patient OACR phenotypes. Thus, the present assay is useful for functional investigations of VKORC1 and oral anticoagulant inhibition of the vitamin K cycle. Additionally, we modeled hVKORC1 on the previously solved structure of a homologous bacterial enzyme and performed in silico docking of warfarin on this model. We identified one binding site delineated by 3 putative binding interfaces. These interfaces comprise linear sequences of the endoplasmic reticulum-lumenal loop (Ser52-Phe55) and the first (Leu22-Lys30) and fourth (Phe131-Thr137) transmembrane helices. All known OACR associated hVKORC1 mutations are located in or around these putative interfaces, supporting our model. PMID- 23982175 TI - A novel role for factor VIII and thrombin/PAR1 in regulating hematopoiesis and its interplay with the bone structure. AB - Analysis of hematopoietic stem cells (HSCs) in factor VIII knockout (FVIIIKO) mice revealed a novel regulatory role for the coagulation cascade in hematopoiesis. Thus, HSCs in FVIIIKO mice had reduced proportions of CD34(low) cells within Lin(-)Sca(+)Kit(+) progenitors, and exhibited reduced long-term repopulating capacity as well as hyper granulocyte-colony-stimulating factor (G CSF)-induced mobilization. This disregulation of HSCs is likely caused by reduced levels of thrombin, and is associated with altered protease-activated receptor 1 (PAR1) signaling, as PAR1 KO mice also exhibited enhanced G-CSF-induced mobilization. Analysis of reciprocal bone marrow (BM) chimera (FVIIIKO BM into wild-type recipients and vice versa) and the detection of PAR1 expression on stromal elements indicates that this phenotype is likely controlled by stromal elements. Micro-computed tomography analysis of distal tibia metaphyses also revealed for the first time a major impact of the FVIII/thrombin/PAR1 axis on the dynamic bone structure, showing reduced bone:tissue volume ratio and trabecular number in FVIIIKO and PAR1KO mice. Taken together, these results show a critical and novel role for the coagulation cascade, mediated in part by thrombin-PAR1 interaction, and regulates HSC maintenance and a reciprocal interplay between HSCs and the dynamic bone structure. PMID- 23982177 TI - MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program. AB - MDM2 is a key negative regulator of the tumor suppressor p53, however, the prognostic significance of MDM2 overexpression in diffuse large B-cell lymphoma (DLBCL) has not been defined convincingly. In a p53 genetically-defined large cohort of de novo DLBCL patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, we assessed MDM2 and p53 expression by immunohistochemistry (n = 478), MDM2 gene amplification by fluorescence in situ hybridization (n = 364), and a single nucleotide polymorphism in the MDM2 promoter, SNP309, by SNP genotyping assay (n = 108). Our results show that MDM2 overexpression, unlike p53 overexpression, is not a significant prognostic factor in overall DLBCL. Both MDM2 and p53 overexpression do not predict for an adverse clinical outcome in patients with wild-type p53 but predicts for significantly poorer survival in patients with mutated p53. Variable p53 activities may ultimately determine the survival differences, as suggested by the gene expression profiling analysis. MDM2 amplification was observed in 3 of 364 (0.8%) patients with high MDM2 expression. The presence of SNP309 did not correlate with MDM2 expression and survival. This study indicates that evaluation of MDM2 and p53 expression correlating with TP53 genetic status is essential to assess their prognostic significance and is important for designing therapeutic strategies that target the MDM2-p53 interaction. PMID- 23982178 TI - Aryl hydrocarbon receptor and experimental autoimmune arthritis. AB - Aryl hydrocarbon receptor (Ahr) is thought to be a crucial factor that regulates immune responses. Many Ahr-mediated immune regulatory mechanisms have been discovered, which will likely enhance our understanding of the molecular pathogenesis of autoimmune inflammation including rheumatoid arthritis (RA). RA is a systemic inflammatory disease that affects approximately 1 % of the population and is characterized by chronic inflammation of the synovium and subsequent joint destruction. Recent findings showed that Ahr plays critical roles in the development of Th17 cells, which are key effector T cells in a variety of human autoimmune diseases including RA. Consistent with these findings, our previous study demonstrated that Ahr in T cells is important for the development of collagen-induced arthritis, a widely used murine model of human RA, possibly via the induction of Th17 cells. In addition, Ahr is an attractive molecule because tobacco smoke is a well-known environmental risk factor for RA development and Ahr agonists, such as 2,3,7,8-tetrachlorodibenzo-p dioxin, 3-methyl cholanthrene, and benzo[a]pyrene, are major toxic components in cigarettes. This review summarizes recent findings on Ahr functions in immune cells in the context of RA pathogenesis during stimulation with smoking-derived ligands. We also discuss the potential link between Ahr and novel factors, such as microRNAs, in the development of RA, thereby providing further mechanistic insight into this autoimmune disorder. PMID- 23982180 TI - The impact of ongoing national terror on the community of hospital nurses in Israel. AB - The main goal of this study was to explore the connections between the exposure of nurses in Israel to national terror and the levels of distress experienced due to ongoing terror attacks. The data were collected from 214 nurses from various parts of Israel who work in three types of heath services (mainly hospital departments) and provide help to victims of terror. The nurses reported very high levels of burnout, high levels of stress and medium-to high levels of intrusive memories. Levels of exposure were associated with burnout, intrusive memories and level of stress. More professional attention should be given to hospital nurses who provide care for trauma patients. PMID- 23982181 TI - Porous carbon nanoparticle networks with tunable absorbability. AB - Porous carbon materials with high specific surface areas and superhydrophobicity have attracted much research interest due to their potential application in the areas of water filtration, water/oil separation, and oil-spill cleanup. Most reported superhydrophobic porous carbon materials are fabricated by complex processes involving the use of catalysts and high temperatures but with low throughput. Here, we present a facile single-step method for fabricating porous carbon nanoparticle (CNP) networks with selective absorbability for water and oils via the glow discharge of hydrocarbon plasma without a catalyst at room temperature. Porous CNP networks were grown by the continuous deposition of CNPs at a relatively high deposition pressure. By varying the fluorine content, the porous CNP networks exhibited tunable repellence against liquids with various degrees of surface tension. These porous CNP networks could be applied for the separation of not only water/oil mixtures but also mixtures of liquids with different surface tension levels. PMID- 23982179 TI - Contrasting demographic histories of the neighboring bonobo and chimpanzee. AB - The Pleistocene epoch was a period of dramatic climate change that had profound impacts on the population sizes of many animal species. How these species were shaped by past events is often unclear, hindering our understanding of the population dynamics resulting in present day populations. We analyzed complete mitochondrial genomes representing all four recognized chimpanzee subspecies and the bonobo to infer the recent demographic history and used simulations to exclude a confounding effect of population structure. Our genus-wide Bayesian coalescent-based analysis revealed surprisingly dissimilar demographic histories of the chimpanzee subspecies and the bonobo, despite their overlapping habitat requirements. Whereas the central and eastern chimpanzee subspecies were inferred to have expanded tenfold between around 50,000 and 80,000 years ago and today, the population size of the neighboring bonobo remained constant. The changes in population size are likely linked to changes in habitat area due to climate oscillations during the late Pleistocene. Furthermore, the timing of population expansion for the rainforest-adapted chimpanzee is concurrent with the expansion of the savanna-adapted human, which could suggest a common response to changed climate conditions around 50,000-80,000 years ago. PMID- 23982183 TI - Detection of real-time dynamics of drug-target interactions by ultralong nanowalls. AB - Detecting drug-target interactions in real-time is a powerful approach for drug discovery and analytics. We show here for the first time the ultra fast electrical real-time detection and quantification of antibiotics using a novel biohybrid nanosensor. The biomolecular sensing is performed on ultralong (mm range) high aspect ratio nanowall (50 nm width) surfaces functionalized with operator DNA tetO which is specifically bound by the sensor protein TetR. This sensor protein is released from the operator DNA in a dose dependent manner by exposing the device functionalized with this bound DNA-protein complex to tetracycline antibiotics. As a result, the electrical conductance is accordingly modulated by these surface net charge changes. The switching mechanism of sensor proteins attached at the functionalized surfaces and releasing them again by antibiotics is demonstrated. With the here presented device the detection limit is below the limits of prevailing detection methods. Moreover, the study is extended to detect antibiotic residues in spiked organic milk from cows far below the maximum residual level of the European Union. In spiked milk samples a detection limit for tetracycline concentrations in the 100 fM level was achieved. The nanowall devices are fabricated by atomic layer deposition-based spacer lithography on full wafer scale which is a simple approach capable for mass production. PMID- 23982182 TI - Laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy as revisional procedure after adjustable gastric band--a systematic review. AB - The adjustable gastric band (L)AGB gained popularity as a weight loss procedure. However, long-term results are disappointing; many patients need revision to laparoscopic Roux-en-Y gastric bypass (LRYGB) or sleeve gastrectomy (LSG). The purpose of this study was to assess morbidity, mortality, and results of these two revisional procedures. Fifteen LRYGB studies with a total of 588 patients and eight LSG studies with 286 patients were included. The reason for revision was insufficient weight loss or weight regain in 62.2 and 63.9% in LRYGB and LSG patients. Short-term complications occurred in 8.5 and 15.7% and long-term complications in 8.9 and 2.5%. Reoperation was performed in 6.5 and 3.5%. Revision to LRYGB or LSG after (L)AGB is feasible and relatively safe. Complication rate is higher than in primary procedures. PMID- 23982184 TI - Loss of P53 facilitates invasion and metastasis of prostate cancer cells. AB - Prostate cancer is a lethal cancer for the invasion and metastasis in its earlier period. P53 is a tumor suppressor gene which plays a critical role on safeguarding the integrity of genome. However, loss of P53 facilitates or inhibits the invasion and metastasis of tumor is still suspended. In this study, we are going to explain whether loss of P53 affect the invasion and metastasis of prostate cancer cells. To explore whether loss of P53 influences the invasion and metastasis ability of prostate cancer cells, we first compared the invasion ability of si-P53 treated cells and control cells by wound healing, transwell assay, and adhesion assay. We next tested the activity of MMP-2, MMP-9, and MMP 14 by western blot and gelatin zymography. Moreover, we employed WB and IF to identify the EMT containing E-cad, N-cad, vimentin, etc. We also examined the expression of cortactin, cytoskeleton, and paxillin by immunofluorescence, and tested the expression of ERK and JNK by WB. Finally, we applied WB to detect the expression of FAK, Src, and the phosphorylation of them to elucidate the mechanism of si-P53 influencing invasion and metastasis. According to the inhibition rate of si-P53, we choose the optimized volume of si-P53. With the volume, we compare the invasion and metastasis ability of Du145 and si-P53 treated cells. We find si-P53 promotes the invasion and metastasis in prostate cancer cells, increases the expression and activity of MMP-2/9 and MMP-14. Also, si-P53 promotes EMT and cytoskeleton rearrangement. Further analyses explain that this effect is associated with FAK-Src signaling pathway. Loss of P53 promotes the invasion and metastasis ability of prostate cancer cells and the mechanism is correlated with FAK-Src signaling pathway. P53 is involved in the context of invasion and metastasis. PMID- 23982185 TI - Does previous failed ESWL have a negative impact of on the outcome of ureterorenoscopy? A matched pair analysis. AB - This study aims to evaluate the outcome of ureteroscopy/ureterorenoscopy (URS) as a salvage procedure for stones resistant to extracorporeal shock wave lithotripsy (ESWL). Between January 2009 and January 2012, 313 patients with upper tract lithiasis were treated by URS. Among them, 87 (27.8 %) had undergone URS after prior ESWL failed to achieve stone clearance (Salvage group). These patients were matched with a group of patients who underwent URS as first-line modality (Primary group). Stone-free rates and adjuvant procedures represented the primary points for comparison. Secondary points for comparison included complications, procedure duration, total laser energy used and length of hospitalization. Matching was possible in all cases. Stone clearance rates were 73.6 and 82.8 % for the Salvage and Primary group, respectively. The difference in stone clearance rates between the two groups was not statistically significant (p = 0.186). A total of 11 patients (12.6 %) in the Primary group and 18 patients (20.7 %) in the Salvage group underwent an adjuvant procedure (p = 0.154). No statistically significant differences were noted in terms of complications, procedure duration and length of hospitalization. In the Primary group, the laser energy used for stone fragmentation was higher (p = 0.043). The rate of ureteric stenting at the end of the procedure was higher for the Salvage group (p = 0.030). Previous failed ESWL is not a predictor for unfavorable outcome of URS. Salvage URS is associated, however, with an increased need for ureteric stenting at the end of the procedure. PMID- 23982186 TI - Neural correlates of emotional distractibility in bipolar disorder patients, unaffected relatives, and individuals with hypomanic personality. AB - OBJECTIVE: Neuropsychological deficits and emotion dysregulation are present in symptomatic and euthymic patients with bipolar disorder. However, there is little evidence on how cognitive functioning is influenced by emotion, what the neural correlates of emotional distraction effects are, and whether such deficits are a consequence or a precursor of the disorder. The authors used functional MRI (fMRI) to investigate these questions. METHOD: fMRI was used first to localize the neural network specific to a certain cognitive task (mental arithmetic) and then to test the effect of emotional distractors on this network. Euthymic patients with bipolar I disorder (N=22), two populations at high risk for developing the disorder (unaffected first-degree relatives of individuals with bipolar disorder [N=17]), and healthy participants with hypomanic personality traits [N=22]) were tested, along with three age-, gender-, and education-matched healthy comparison groups (N=22, N=17, N=24, respectively). RESULTS: There were no differences in performance or activation in the task network for mental arithmetic. However, while all participants exhibited slower responses when emotional distractors were present, this response slowing was greatly enlarged in bipolar patients. Similarly, task-related activation was generally increased under emotional distraction; however, bipolar patients exhibited a further increase in right parietal activation that correlated positively with the response slowing effect. CONCLUSIONS: The results suggest that emotional dysregulation leads to exacerbated neuropsychological deficits in bipolar patients, as evidenced by behavioral slowing and task-related hyperactivation. The lack of such a deficit in high-risk populations suggests that it occurs only after disease onset, rather than representing a vulnerability marker. PMID- 23982187 TI - Current world literature. Genetics and epidemiology. PMID- 23982190 TI - Improved Performance of Anti-miRNA Oligonucleotides Using a Novel Non-Nucleotide Modifier. AB - Anti-microRNA oligonucleotides (AMOs) are steric blocking antisense reagents that inhibit microRNA (miRNA) function by hybridizing and repressing the activity of a mature miRNA. First generation AMOs employed 2'-O-Methyl RNA nucleotides (2'OMe) with phosphorothioate (PS) internucleotide linkages positioned at both ends to block exonuclease attack. Second generation AMOs improved potency through the use of chemical modifications that increase binding affinity to the target, such as locked nucleic acid (LNA) residues. However, this strategy can reduce specificity as high binding affinity compounds can bind to and suppress function of related sequences even if one or more mismatches are present. Further, unnatural modified nucleic acid residues can have toxic side effects. In the present study, a variety of non-nucleotide modifiers were screened for utility in steric blocking antisense applications. A novel compound, N,N-diethyl-4-(4-nitronaphthalen-1 ylazo)-phenylamine ("ZEN"), was discovered that increased binding affinity and blocked exonuclease degradation when placed at or near each end of a single stranded oligonucleotide. This new modification was combined with the 2'OMe RNA backbone to make ZEN-AMOs. The new ZEN-AMOs have high potency and can effectively inhibit miRNA function in vitro at low nanomolar concentrations, show high specificity, and have low toxicity in cell culture.Molecular Therapy-Nucleic Acids (2013) 2, e117; doi:10.1038/mtna.2013.46; published online 27 August 2013. PMID- 23982189 TI - Association of polymorphisms in natural killer cell-related genes with preterm birth. AB - Inflammation is implicated in preterm birth, but genetic studies of inflammatory genes have yielded inconsistent results. Maternal DNA from 1,646 participants in the Pregnancy, Infection, and Nutrition Cohort, enrolled in Orange and Wake counties, North Carolina (1995-2005), were genotyped for 432 tag single nucleotide polymorphisms (SNPs) in 30 candidate genes. Gene-level and SNP associations were modeled within strata of genetic ancestry. Six genes were associated with preterm birth among European Americans: interleukin 12A (IL12A); colony-stimulating factor 2 (CSF2); interferon gamma receptor 2 (IFNGR2); killer cell immunoglobulin-like receptor, three domain, long cytoplasmic tail, 2 (KIR3DL2); interleukin 4 (IL4); and interleukin 13 (IL13). Of these, relatively strong single-SNP associations were seen in IFNGR2 and KIR3DL2. Among the 4 genes related to natural killer cell function, 2 (IL12A and CSF2) were consistently associated with reduced risk of prematurity for both European and African Americans. SNPs tagging a locus control region for IL4 and IL13 were associated with an increased risk of spontaneous preterm birth for European Americans (rs3091307; risk ratio = 1.9; 95% confidence interval: 1.4, 2.5). Although gene level associations were detected only in European Americans, single-SNP associations among European and African Americans were often similar in direction, though estimated with less precision among African Americans. In conclusion, we identified novel associations between variants in the natural killer cell immune pathway and prematurity in this biracial US population. PMID- 23982191 TI - Carboxylation of thin graphitic sheets is faster than that of carbon nanohorns. AB - Globular aggregates of carbon nanohorns (CNHs) often contain graphite-like thin sheets (GLSs), and providing different functions to CNHs and GLSs would expand the possible applications of the CNH-GLS aggregates. We show that the GLS edges can be carboxylated selectively by immersing the aggregates in an aqueous solution of H2O2 at room temperature for 1 hour. The presence of carboxyl groups was confirmed by temperature-programmed desorption mass spectroscopy measurements, and their amounts were evaluated using thermogravimetric analysis. The preferential carboxylation of GLSs at their edges was evidenced, after the carboxyl groups were reacted with Pt-ammine complexes, by electron microscopic observation of the Pt atoms at the GLS edges. Since few holes in CNH walls were opened by the short-period H2O2 treatment, there was little carboxylation of CNHs. PMID- 23982192 TI - Regulation of plasminogen activator activity and expression by cyclic mechanical stress in rat mandibular condylar chondrocytes. AB - To investigate the mechanism of cartilage degradation induced by overloading in the temporomandibular joint (TMJ), the effect of cyclic mechanical compressive stress on the activity of plasminogen activator (PA) and the expression of the predominant components of the PA system were analyzed in cultured mandibular condylar chondrocytes (MCCs) in rats. MCCs were exposed to cyclic mechanical compressive stress (2000, 4000 and 6000 u strain) at 0.5 Hz by a four-point bending system. The activity of PA was determined by hydrolysis of the chromogenic substrate H-D-Val-Leu-Lys-pNA (S-2251). The mRNA and protein expression levels of urokinase-type PA (uPA), tissue-type PA (tPA), uPA receptor (uPAR) and PA inhibitor 1 (PAI-1) were detected by qPCR and western blot analysis, respectively. Cyclic mechanical stress at 4000 and 6000 u strain induced the expression of uPA, tPA and uPAR, and increased the activity of PA. Furthermore, cyclic mechanical stress at 6000 u strain also inhibited the expression of PAI-1. Analysis of pericellular proteolytic activity demonstrated that PA functioned as the active enzyme in excessive mechanical stress responsiveness (e.g., 4000 and 6000 u strain) largely via uPAR, not PAI-1. Cyclic mechanical stress at 2000 u strain induced the expression of tPA and PAI-1; however, it did not change the activity of PA. These results suggested that the mechanical induction of uPA, tPA and uPAR upregulated PA activity, which may provide a proteolytic environment of extracellular matrix components and subsequently contribute to the cartilage degradation in TMJ osteoarthritis. PMID- 23982194 TI - Cardiac calcified amorphous tumor stuck in the aortic valve that mimicked a chameleon's tongue: report of a case. AB - A calcified amorphous tumor (CAT) is a rare intracardiac mass that carries a risk of embolism. We herein present the case of a club-shaped CAT that originated from the calcified mitral annulus. Echocardiography indicated a pendular motion of the mass and repeated entrapment by a stenotic aortic valve that was sustained for several beats, mimicking a chameleon's tongue. An emergency operation was performed because of the risk of embolism, as well as potential progression of cardiac failure due to worsening aortic valve stenosis. The histological findings were consistent with the diagnosis of a CAT. This report describes a case of an intracardiac tumor that showed unique motion like a chameleon's tongue. PMID- 23982193 TI - Non-cirrhotic portal-systemic encephalopathy caused by enlargement of a splenorenal shunt after pancreaticoduodenectomy for locally advanced duodenal cancer: report of a case. AB - We report a case of portal-systemic encephalopathy occurring secondary to a splenorenal shunt, 2 years after a pancreaticoduodenectomy for locally advanced duodenal carcinoma. A 55-year-old woman was brought to our hospital with a decreased level of consciousness. Laboratory testing revealed an elevated serum ammonia level (221 MUg/dl) and normal liver function. Retrospective review of a series of contrast-enhanced computed tomography scans of the abdomen identified a splenorenal shunt, which had gradually enlarged over the past 2 years (Fig. 1). The decreased level of consciousness was thought to be due to portal-systemic encephalopathy secondary to the splenorenal shunt. We performed balloon-occluded retrograde transvenous obliteration to occlude the splenorenal shunt, following which her serum ammonia level returned to normal (28 MUg/dl) and an alert level of consciousness was maintained. PMID- 23982195 TI - Spirometric and radiological evaluation of the remnant lung long after major pulmonary resection: can compensatory phenomena be recognized in clinical cases? AB - PURPOSES: The purpose of this study was to investigate the compensatory phenomena after lung resection in clinical cases by evaluating the spirometric and radiological parameters. METHODS: Forty patients undergoing lobectomy for stage IA lung cancer were divided into the following groups: (A) patients with <10 (n = 20) and (B) patients with >=10 resected subsegments (n = 20). Comparisons were made of the predicted and observed postoperative values of spirometry and radiological parameters, such as lung volumetry and the "estimated lung weight". Predicted values were based on the number of resected subsegments. The postoperative time to re-evaluation was at least 1 year for both groups. RESULTS: The predicted postoperative values of spirometry underestimated the actual values, and the differences were more significant in group B (forced vital capacity, p = 0.006, forced expiratory volume in 1 s, p = 0.011). Focusing on the remnant lungs on the surgical side, group B had significantly larger % postoperative lung volumes (161 +/- 6.0 %) and % estimated lung weight (124 +/- 5.4 %) than did group A (114 +/- 3.8%, p < 0.0001; 89.5 +/- 4.4%, p < 0.0001, respectively). CONCLUSIONS: Major lung resection in clinical cases causes a compensatory restoration of the pulmonary function and tissue. PMID- 23982196 TI - [Second victim : Critical incident stress management in clinical medicine]. AB - BACKGROUND: Critical incidents in clinical medicine can have far-reaching consequences on patient health. In cases of severe medical errors they can seriously harm the patient or even lead to death. The involvement in such an event can result in a stress reaction, a so-called acute posttraumatic stress disorder in the healthcare provider, the so-called second victim of an adverse event. Psychological distress may not only have a long lasting impact on quality of life of the physician or caregiver involved but it may also affect the ability to provide safe patient care in the aftermath of adverse events. METHODS: A literature review was performed to obtain information on care giver responses to medical errors and to determine possible supportive strategies to mitigate negative consequences of an adverse event on the second victim. An internet search and a search in Medline/Pubmed for scientific studies were conducted using the key words "second victim, "medical error", "critical incident stress management" (CISM) and "critical incident stress reporting system" (CIRS). Sources from academic medical societies and public institutions which offer crisis management programs where analyzed. The data were sorted by main categories and relevance for hospitals. Analysis was carried out using descriptive measures. RESULTS: In disaster medicine and aviation navigation services the implementation of a CISM program is an efficient intervention to help staff to recover after a traumatic event and to return to normal functioning and behavior. Several other concepts for a clinical crisis management plan were identified. CONCLUSIONS: The integration of CISM and CISM-related programs in a clinical setting may provide efficient support in an acute crisis and may help the caregiver to deal effectively with future error events and employee safety. PMID- 23982197 TI - [Second victim : Deliberations on dealing with treatment complications]. PMID- 23982198 TI - Evidence that pericytes regulate aquaporin-4 polarization in mouse cortical astrocytes. AB - Aquaporin-4 (AQP4) water channels are concentrated in astrocytic endfoot membranes at the brain-blood and brain-cerebrospinal fluid interfaces. The mechanisms underpinning the polarized distribution of AQP4 are poorly understood. Here we tested the hypothesis that pericytes regulate AQP4 anchoring to perivascular astrocytic endfoot membranes. AQP4 immunofluorescence of brain sections obtained from novel transgenic double reporter mice expressing enhanced green fluorescent protein (eGFP) in astrocytes and Discoma Red (DsRed) in pericytes revealed strong AQP4 signal in astrocytic processes adjacent to pericytes. Quantitative immunogold analysis of C57BL/6 mice showed that the AQP4 expression was higher in endfoot membranes abutting pericytes than in those facing endothelial cells. Similar findings were made for alpha-syntrophin, a member of the dystrophin-associated protein complex (DAPC). The enrichment of alpha-syntrophin in membranes ensheathing pericytes persisted after Aqp4 gene deletion. Our data support the concept that pericytes regulate AQP4 polarization. PMID- 23982199 TI - Morin inhibits sortase A and subsequent biofilm formation in Streptococcus mutans. AB - Streptococcus mutans (S. mutans) is the main etiological agent of dental caries, and adheres to the tooth surface through the sortase A (SrtA)-mediated cell wall anchored protein Pac. Inhibition of SrtA activity results in a marked reduction in the adhesion potential of S. mutans, and the frequency of dental caries. Morin is a natural plant extract that was previously reported to inhibit Staphylococcus aureus SrtA activity. Here, we demonstrate that morin has an inhibitory effect against S. mutans UA159 SrtA, with an IC50 of 27.2 +/- 2.6 MUM. Western blotting demonstrated that 30 MUM morin induced the partial release of the Pac protein into the supernatant. The biofilm mass of S. mutans was reduced in the presence of 30 MUM morin, which was not caused by a decrease in S. mutans viability. These results indicate that morin might be important as a new agent to prevent caries. PMID- 23982200 TI - Effect of different carbon sources on decolourisation of an industrial textile dye under alkaline-saline conditions. AB - White-rot fungal strains of Trametes versicolor and Phanerochaete chrysosporium were selected to study the decolourisation of the textile dye, Reactive Black 5, under alkaline-saline conditions. Free and immobilised T. versicolor cells showed 100 % decolourisation in the growth medium supplemented with 15 g l(-1) NaCl, pH 9.5 at 30 degrees C in liquid batch culture. Continuous culture experiments were performed in a fixed-bed reactor using free and immobilised T. versicolor cells and allowed 85-100 % dye decolourisation. The immobilisation conditions for the biomass and the additional supply of carbon sources improved the decolourisation performance during a long-term trial of 40 days. Lignin peroxidase, laccase and glyoxal oxidase activities were detected during the experiments. The laccase activity varied depending on carbon source utilized and glycerol-enhanced laccase activity compared to sucrose during extended growth. PMID- 23982201 TI - Functional characterization of the agtABCD and agtSR operons for 4-aminobutyrate and 5-aminovalerate uptake and regulation in Pseudomonas aeruginosa PAO1. AB - Growth of Pseudomonas aeruginosa on diamines cadaverine, putrescine, and diaminopropane requires the gamma-glutamylation pathway to convert these diamines into delta-aminovalerate (AMV), gamma-aminobutyrate (GABA), and beta-alanine. From DNA microarrays experiments the agtABCD operon (PA0603-0606) encoding components for an ABC transporter system was found inducible by exogenous AMV, GABA, and beta-alanine, but not by diamines. Induction of the agtABCD operon was abolished in the mutants of upstream agtS (PA0600) or agtR (PA0601) genes encoding the membrane-anchored sensor and the response regulator of a two component regulatory system, respectively. Growth phenotype analysis supports the physiological functions of these agt genes on utilization of AMV and GABA. Through measurements of beta-galactosidase activities from an agtA::lacZ fusion, the requirement of a functional AgtS in control of the induction effect by exogenous AMV and GABA was further substantiated. The recombinant hexa-hisidine tagged agtR was constructed and purified to demonstrate its specific interactions with the agtA promoter region by electrophoretic mobility shift assays. In summary, this study establishes the functions of agtSR and agtABCD operons in AMV and GABA uptake, and provides a potential linkage between AMV/GABA metabolism and polymicrobial infection through the recently reported function of agtR in sensing of peptidoglycan shed by gram-positive bacteria (Korgaonkar et al., Proc Natl Acad Sci USA 110:1059-1064, 2013). PMID- 23982202 TI - Characterization of Vibrio cholerae bacteriophages isolated from the environmental waters of the Lake Victoria region of Kenya. AB - Over the last decade, cholera outbreaks have become common in some parts of Kenya. The most recent cholera outbreak occurred in Coastal and Lake Victoria region during January 2009 and May 2010, where a total of 11,769 cases and 274 deaths were reported by the Ministry of Public Health and Sanitation. The objective of this study is to isolate Vibrio cholerae bacteriophages from the environmental waters of the Lake Victoria region of Kenya with potential for use as a biocontrol for cholera outbreaks. Water samples from wells, ponds, sewage effluent, boreholes, rivers, and lakes of the Lake Victoria region of Kenya were enriched for 48 h at 37 degrees C in broth containing a an environmental strain of V. cholerae. Bacteriophages were isolated from 5 out of the 42 environmental water samples taken. Isolated phages produced tiny, round, and clear plaques suggesting that these phages were lytic to V. cholerae. Transmission electron microscope examination revealed that all the nine phages belonged to the family Myoviridae, with typical icosahedral heads, long contractile tails, and fibers. Head had an average diameter of 88.3 nm and tail of length and width 84.9 and 16.1 nm, respectively. Vibriophages isolated from the Lake Victoria region of Kenya have been characterized and the isolated phages may have a potential to be used as antibacterial agents to control pathogenic V. cholerae bacteria in water reservoirs. PMID- 23982203 TI - Nutrient regulation of immunity: O-GlcNAcylation regulates stimulus-specific NF kappaB-dependent transcription. AB - Nutrients regulate gene transcription by the dynamic cycling of O-linked N acetylglucosamine (O-GlcNAc) on proteins that constitute the transcriptional machinery. A study shows that O-GlcNAcylation of the nuclear factor kappaB (NF kappaB) subunit c-Rel is required for its binding to the promoters of some, but not all, key T cell receptor-dependent genes; however, O-GlcNAcylation is dispensable for the binding of c-Rel to the promoters of tumor necrosis factor alpha-dependent genes. This study not only illustrates how specific stimuli that act on the same transcription factor can elicit the expression of particular sets of genes, it also suggests a possible mechanism for autoimmunity in diabetes. PMID- 23982204 TI - Activation of the Cl- channel ANO1 by localized calcium signals in nociceptive sensory neurons requires coupling with the IP3 receptor. AB - We report that anoctamin 1 (ANO1; also known as TMEM16A) Ca(2+)-activated Cl(-) channels in small neurons from dorsal root ganglia are preferentially activated by particular pools of intracellular Ca(2+). These ANO1 channels can be selectively activated by the G protein-coupled receptor (GPCR)-induced release of Ca(2+) from intracellular stores but not by Ca(2+) influx through voltage-gated Ca(2+) channels. This ability to discriminate between Ca(2+) pools was achieved by the tethering of ANO1-containing plasma membrane domains, which also contained GPCRs such as bradykinin receptor 2 and protease-activated receptor 2, to juxtamembrane regions of the endoplasmic reticulum. Interaction of the carboxyl terminus and the first intracellular loop of ANO1 with IP3R1 (inositol 1,4,5 trisphosphate receptor 1) contributed to the tethering. Disruption of membrane microdomains blocked the ANO1 and IP3R1 interaction and resulted in the loss of coupling between GPCR signaling and ANO1. The junctional signaling complex enabled ANO1-mediated excitation in response to specific Ca(2+)signals rather than to global changes in intracellular Ca(2+). PMID- 23982205 TI - Maternal hyperglycemia activates an ASK1-FoxO3a-caspase 8 pathway that leads to embryonic neural tube defects. AB - Neural tube defects result from failure to completely close neural tubes during development. Maternal diabetes is a substantial risk factor for neural tube defects, and available evidence suggests that the mechanism that links hyperglycemia to neural tube defects involves oxidative stress and apoptosis. We demonstrated that maternal hyperglycemia correlated with activation of the apoptosis signal-regulating kinase 1 (ASK1) in the developing neural tube, and Ask1 gene deletion was associated with reduced neuroepithelial cell apoptosis and development of neural tube defects. ASK1 activation stimulated the activity of the transcription factor FoxO3a, which increased the abundance of the apoptosis promoting adaptor protein TRADD, leading to activation of caspase 8. Hyperglycemia-induced apoptosis and the development of neural tube defects were reduced with genetic ablation of either FoxO3a or Casp8 or inhibition of ASK1 by thioredoxin. Examination of human neural tissues affected by neural tube defects revealed increased activation or abundance of ASK1, FoxO3a, TRADD, and caspase 8. Thus, activation of an ASK1-FoxO3a-TRADD-caspase 8 pathway participates in the development of neural tube defects, which could be prevented by inhibiting intermediates in this cascade. PMID- 23982206 TI - Activation of the transcriptional function of the NF-kappaB protein c-Rel by O GlcNAc glycosylation. AB - The transcription factor nuclear factor kappaB (NF-kappaB) rapidly reprograms gene expression in response to various stimuli, and its activity is regulated by several posttranslational modifications, including phosphorylation, methylation, and acetylation. The addition of O-linked beta-N-acetylglucosamine (a process known as O-GlcNAcylation) is an abundant posttranslational modification that is enhanced in conditions such as hyperglycemia and cellular stress. We report that the NF-kappaB subunit c-Rel is modified and activated by O-GlcNAcylation. We identified serine 350 as the site of O-GlcNAcylation, which was required for the DNA binding and transactivation functions of c-Rel. Blocking the O-GlcNAcylation of this residue abrogated c-Rel-mediated expression of the cytokine-encoding genes IL2, IFNG, and CSF2 in response to T cell receptor (TCR) activation, whereas increasing the extent of O-GlcNAcylation of cellular proteins enhanced the expression of these genes. TCR- or tumor necrosis factor (TNF)-induced expression of other NF-kappaB target genes, such as NFKBIA (which encodes IkappaBalpha) and TNFAIP3 (which encodes A20), occurred independently of the O GlcNAcylation of c-Rel. Our findings suggest a stimulus-specific role for hyperglycemia-induced O-GlcNAcylation of c-Rel in promoting T cell-mediated autoimmunity in conditions such as type 1 diabetes by enhancing the production of T helper cell cytokines. PMID- 23982207 TI - Activation loop dynamics determine the different catalytic efficiencies of B cell and T cell-specific tec kinases. AB - Itk (interleukin-2-inducible T cell kinase) and Btk (Bruton's tyrosine kinase) are nonreceptor tyrosine kinases of the Tec family that signal downstream of the T cell receptor (TCR) and B cell receptor (BCR), respectively. Despite their high sequence similarity and related signaling roles, Btk is a substantially more active kinase than Itk. We showed that substitution of 6 of the 619 amino acid residues of Itk with the corresponding residues of Btk (and vice versa) was sufficient to completely switch the activities of Itk and Btk. The substitutions responsible for the swap in activity are all localized to the activation segment of the kinase domain. Nuclear magnetic resonance and hydrogen-deuterium exchange mass spectrometry analyses revealed that Itk and Btk had distinct protein dynamics in this region, which could explain the differences in catalytic efficiency between these kinases. Introducing Itk with enhanced activity into T cells led to enhanced and prolonged TCR signaling compared to that in cells with wild-type Itk. These findings imply that evolutionary pressures have led to Tec kinases having distinct enzymatic properties, depending on the cellular context. We suggest that the weaker catalytic activities of T cell-specific kinases serve to regulate cellular activation and prevent aberrant immune responses. PMID- 23982208 TI - Efficacy of bispectral index monitoring during balanced propofol sedation for colonoscopy: a prospective, randomized controlled trial. AB - BACKGROUND AND AIMS: Appropriate use of propofol is necessary, and objective monitoring of sedation with propofol may be helpful. Studies on the efficacy of bispectral index (BIS) monitoring in deep sedation have been conducted, but its efficacy in colonoscopy with moderate sedation is unknown. In this study, the efficacy of BIS monitoring during colonoscopy with moderate level sedation via balanced propofol sedation was investigated. METHODS: To determine the cut-off value of BIS before the test, an optimal BIS value was determined. Patients who were scheduled to undergo outpatient colonoscopy were prospectively randomized to either a BIS or control group. Finally, a total of 115 patients were selected for this study. The satisfaction level, the complication, and the dosage of the administered propofol were compared. RESULTS: The BIS values and the modified observer's assessment of alertness/sedation scores (MOAA/S) were positively correlated (r=0.66 and p<0.001). The optimal cut-off value of BIS for maintaining moderate sedation was 81, and the area under the ROC curve was 0.88 (95% CI 0.82 0.93), indicating high prediction accuracy. However, there was no difference between the BIS group and the control group in levels of satisfaction of either patients or endoscopists. In addition, there was no difference in the complication and the required dose of propofol between both groups. CONCLUSIONS: BIS and clinical sedation scores, MOAA/S scores, showed a high level of correlation. However, no significant efficacy was observed in the BIS group who underwent outpatient colonoscopy. PMID- 23982209 TI - Safety analysis of a hemostatic powder in a porcine model of acute severe gastric bleeding. AB - BACKGROUND: Non-variceal upper gastrointestinal (UGI) bleeding is a common condition that requires prompt lifesaving therapy and traditional endoscopic treatments require high technical proficiency to perform. AIMS: This study was conducted to identify any local or systemic histopathologic effects of a hemostatic powder in a porcine model of active, severe, non-variceal UGI hemorrhage. METHODS: This prospective, non-blinded animal study was performed in accordance with Good Laboratory Practice and Animal Care and Use Guidelines. Six animals underwent gastrotomy and creation of a looped vascular bundle, which was placed into the stomach lumen. The transplanted vascular bundle was punctured with an endoscopic needle-knife to create Forrest grade Ia or Ib bleeding. The hemostatic powder was then applied until hemostasis was achieved. RESULTS: Initial hemostasis was achieved in all animals. Results of pre- and post treatment coagulation studies were similar. All animals survived at least 9 days post-procedure. The hemostatic powder was not found in any local, regional, or systemic tissues. Gross and histologic analysis of systemic organs showed no infarct, particulate, or embolic effects. No gross or microscopic necropsy findings were treatment-related. CONCLUSIONS: The hemostatic powder achieved initial hemostasis (even in animals with spurting arterial bleeding) with no bowel obstruction or unintended luminal effects, no local or regional particulate effects, no systemic embolic effects, and no systemic coagulopathic effects. PMID- 23982210 TI - Quantification of phospholipids classes in human milk. AB - Phospholipids are integral constituents of the milk fat globule membranes and they play a central role in infants' immune and inflammatory responses. A methodology employing liquid chromatography coupled with evaporative light scattering detector has been optimized and validated to quantify the major phospholipids classes in human milk. Phospholipids were extracted using chloroform and methanol and separated on C18 column. Repeatability, intermediate reproducibility, and recovery values were calculated and a large sample set of human milk analyzed. In human milk, phospholipid classes were quantified at concentrations of 0.6 mg/100 g for phosphatidylinositol; 4.2 mg/100 g for phosphatidylethanolamine, 0.4 mg/100 g for phosphatidylserine, 2.8 mg/100 g for phosphatidylcholine, and 4.6 mg/100 g for sphingomyelin. Their relative standard deviation of repeatability and intermediate reproducibility values ranging between 0.8 and 13.4 % and between 2.4 and 25.7 %, respectively. The recovery values ranged between 67 and 112 %. Finally, the validated method was used to quantify phospholipid classes in human milk collected from 50 volunteers 4 weeks postpartum providing absolute content of these lipids in a relatively large cohort. The average content of total phospholipids was 23.8 mg/100 g that corresponds to an estimated mean intake of 140 mg phospholipids/day in a 4-week old infant when exclusively breast-fed. PMID- 23982211 TI - What healthcare reform means for rural America. PMID- 23982212 TI - Combination of pharmacophore hypothesis, genetic function approximation model, and molecular docking to identify novel inhibitors of S6K1. AB - S6K1 has emerged as a potential target for the treatment for obesity, type II diabetes and cancer diseases. Discovery of S6K1 inhibitors has thus attracted much attention in recent years. In this investigation, a hybrid virtual screening method that involves pharmacophore hypothesis, genetic function approximation (GFA) model, and molecular docking technology has been used to discover S6K1 inhibitors especially with novel scaffolds. The common feature pharmacophore hypothesis and GFA regression model of S6K1 inhibitors were first developed and applied in a virtual screen of the Specs database for retrieving S6K1 inhibitors. Then, the molecular docking method was carried out to re-filter these screened compounds. Finally, 60 compounds with promising S6K1 inhibitory activity were carefully selected and have been handed over to the other group to complete the follow-up compound synthesis (or purchase) and activity test. PMID- 23982213 TI - Four discriminant models for detecting keratoconus pattern using Zernike coefficients of corneal aberrations. AB - PURPOSE: We compared the ability of four discriminant models to detect keratoconus (KC) using Zernike coefficients of corneal aberrations. METHODS: We studied 51 eyes with KC, 46 with KC suspect, 50 after laser in situ keratomileusis, and 65 normal eyes. Four statistical discriminant analyses-linear discriminant analysis, k-nearest neighbor algorithm, Mahalanobis distance method, and neural network method-were performed using Zernike coefficients of corneal aberrations obtained by a Placido-based topographer. The detection scheme was constructed using a training set of data from one half of the randomly selected study participants, and performance was evaluated by a validation set in the other half. RESULTS: Performance of the four models was different when <12 explanatory variables were included. Performance using the 2nd- to 4th-order Zernike terms did not differ significantly among models; average accuracy was 79 %. CONCLUSIONS: Determining explanatory variables of Zernike expansion coefficients of the corneal topography in discriminant models may contribute to improving accuracy of KC detection over the discriminant model, as appropriate selection of explanatory variables gave similar results despite different discriminant models. PMID- 23982214 TI - Comparison of macular ganglion cell complex thickness to total retinal thickness ratio between Hungarian and Japanese eyes. AB - PURPOSE: To compare macular ganglion cell complex (GCC) thickness to total retinal thickness (G/T) ratio and the potential influence of race, age, macular outer retinal (OR) thickness, refractive error, intraocular pressure (IOP), mean deviation (MD) and disc area on GCC thickness between healthy European Caucasian and Japanese subjects. METHODS: GCC, OR and total retinal thickness were measured with the RTVue-100 Fourier-domain optical coherence tomograph (OCT) in one eye of 102 healthy subjects (52 Hungarian and 50 Japanese) 24-80 years of age. The chi (2) test, analysis of covariance and multiple regression analysis were used. RESULTS: There was no significant difference in average, superior and inferior GCC thickness and G/T ratio between the two ethnic groups (P > 0.05 for all comparisons). In the Japanese eyes, a significant positive relationship between GCC thickness and OR thickness was found (P < 0.001). This was not seen in the Hungarian eyes (P = 0.07). No significant relationship between GCC thickness and age, refractive error, IOP, MD or disc area was found for either group. CONCLUSIONS: GCC thickness and G/T ratio do not differ between healthy Hungarian and Japanese eyes. In contrast, the difference found for the relationship of GCC and OR between Japanese and Hungarian eyes suggests that in the macular retina there are ethnically related differences that need to be considered when any new macular OCT parameter is proposed for the diagnosis of glaucoma. PMID- 23982215 TI - Tpl2 kinase impacts tumor growth and metastasis of clear cell renal cell carcinoma. AB - Due to the innate high metastatic ability of renal cell carcinoma (RCC), many patients with RCC experience local or systemic relapses after surgical resection. A deeper understanding of the molecular pathogenesis underlying advanced RCC is essential for novel innovative therapeutics. Tumor progression locus 2 (Tpl2), upregulated in various tumor types, has been reported to be associated with oncogenesis and metastatic progression via activation of the MAPK signaling pathway. Herein, the relevance of Tpl2 in tumor growth and metastasis of RCC is explored. Inspection of The Cancer Genome Atlas (TCGA) indicated that Tpl2 overexpression was significantly related to the presence of metastases and poor outcome in clear cell RCC (ccRCC), which is the most aggressive subtype of RCC. Moreover, expression of Tpl2 and CXCR4 showed a positive correlation in ccRCC patients. Depletion of Tpl2 by RNAi or activity by a Tpl2 kinase inhibitor in human ccRCC cells remarkably suppressed MAPK pathways and impaired in vitro cell proliferation, clonogenicity, anoikis resistance, migration, and invasion capabilities. Similarly, orthotopic xenograft growth and lung metastasis were significantly inhibited by Tpl2 silencing. Furthermore, Tpl2 knockdown reduced CXCL12-directed chemotaxis and chemoinvasion accompanied with impaired downstream signaling, indicating potential involvement of Tpl2 in CXCR4-mediated metastasis. Taken together, these data indicate that Tpl2 kinase is associated with and contributes to disease progression of ccRCC. IMPLICATIONS: Tpl2 kinase activity has prognostic and therapeutic targeting potential in aggressive clear cell renal cell carcinoma. PMID- 23982217 TI - DNA damage-inducible gene, reprimo functions as a tumor suppressor and is suppressed by promoter methylation in gastric cancer. AB - In several types of human cancer, the gene expression of Reprimo, a highly glycosylated protein, is frequently silenced via methylation of its promoter. The aim of this study was to characterize the epigenetic inactivation of Reprimo and its biologic function and clinical relevance in gastric cancer. The correlation between Reprimo methylation and clinical relevance was assessed in 83 primary human gastric cancer tissues. The effects of Reprimo expression were also examined using in vitro and in vivo assays. Reprimo methylation was cancer specific and frequently observed. In two gastric cancer cell lines without Reprimo methylation, we observed faint or weak Reprimo expression under normal conditions and high expression under DNA-damaging conditions. In four gastric cancer cell lines with Reprimo methylation, however, Reprimo expression remained faint even under DNA-damaging conditions, with expression being restored in combination with agents that induce demethylation. Enforced Reprimo expression robustly inhibited cell proliferation and anchorage-independent colony formation and enhanced DNA damage-induced apoptosis. Inverse effects were observed via siRNA-mediated knockdown of endogenous Reprimo. Reprimo expression inhibited tumorigenesis in vivo. Reprimo methylation was also associated with a poor response in patients with gastric cancer treated with chemotherapy (P1/4 0.028), and a poor prognosis in patients with advanced gastric cancer (P1/4 0.03). In conclusion, Reprimo expression is normally induced in response to DNA damage, acting as a novel tumor suppressor in gastric cancer. However, Reprimo methylation abrogates its expression and effects. The clinical assessment of Reprimo promoter methylation may serve not only as a predictive marker for chemotherapy, but also as a marker for tumor aggressiveness. PMID- 23982216 TI - The twist box domain is required for Twist1-induced prostate cancer metastasis. AB - Twist1, a basic helix-loop-helix transcription factor, plays a key role during development and is a master regulator of the epithelial-mesenchymal transition (EMT) that promotes cancer metastasis. Structure-function relationships of Twist1 to cancer-related phenotypes are underappreciated, so we studied the requirement of the conserved Twist box domain for metastatic phenotypes in prostate cancer. Evidence suggests that Twist1 is overexpressed in clinical specimens and correlated with aggressive/metastatic disease. Therefore, we examined a transactivation mutant, Twist1-F191G, in prostate cancer cells using in vitro assays, which mimic various stages of metastasis. Twist1 overexpression led to elevated cytoskeletal stiffness and cell traction forces at the migratory edge of cells based on biophysical single-cell measurements. Twist1 conferred additional cellular properties associated with cancer cell metastasis including increased migration, invasion, anoikis resistance, and anchorage-independent growth. The Twist box mutant was defective for these Twist1 phenotypes in vitro. Importantly, we observed a high frequency of Twist1-induced metastatic lung tumors and extrathoracic metastases in vivo using the experimental lung metastasis assay. The Twist box was required for prostate cancer cells to colonize metastatic lung lesions and extrathoracic metastases. Comparative genomic profiling revealed transcriptional programs directed by the Twist box that were associated with cancer progression, such as Hoxa9. Mechanistically, Twist1 bound to the Hoxa9 promoter and positively regulated Hoxa9 expression in prostate cancer cells. Finally, Hoxa9 was important for Twist1-induced cellular phenotypes associated with metastasis. These data suggest that the Twist box domain is required for Twist1 transcriptional programs and prostate cancer metastasis. IMPLICATIONS: Targeting the Twist box domain of Twist1 may effectively limit prostate cancer metastatic potential. PMID- 23982218 TI - Coordination chemistry may explain pharmacokinetics and clinical response of vanadyl sulfate in type 2 diabetic patients. AB - Vanadium, abbreviated V, is an early transition metal that readily forms coordination complexes with a variety of biological products such as proteins, metabolites, membranes and other structures. The formation of coordination complexes stabilizes metal ions, which in turn impacts the biodistribution of the metal. To understand the biodistribution of V, V in oxidation state iv in the form of vanadyl sulfate (25, 50, 100 mg V daily) was given orally for 6 weeks to 16 persons with type 2 diabetes. Elemental V was determined using Graphite Furnas Atomic Absorption Spectrometry against known concentrations of V in serum, blood or urine. Peak serum V levels were 15.4 +/- 6.5, 81.7 +/- 40 and 319 +/- 268 ng ml(-1) respectively, and mean peak serum V was positively correlated with dose administered (r = 0.992, p = 0.079), although large inter-individual variability was found. Total serum V concentration distribution fit a one compartment open model with a first order rate constant for excretion with mean half times of 4.7 +/- 1.6 days and 4.6 +/- 2.5 days for the 50 and 100 mg V dose groups respectively. At steady state, 24 hour urinary V output was 0.18 +/- 0.24 and 0.97 +/- 0.84 mg in the 50 and 100 mg V groups respectively, consistent with absorption of 1 percent or less of the administered dose. Peak V in blood and serum were positively correlated (r = 0.971, p < 0.0005). The serum to blood V ratio for the patients receiving 100 mg V was 1.7 +/- 0.45. Regression analysis showed that glycohemoglobin was a negative predictor of the natural log(ln) peak serum V (R(2) = 0.40, p = 0.009) and a positive predictor of the euglycemic hyperinsulinemic clamp results at high insulin values (R(2) = 0.39, p = 0.010). Insulin sensitivity measured by euglycemic-hyperinsulinemic clamp was not significantly correlated with ln peak serum V. Globulin and glycohemoglobin levels taken together were negative predictors of fasting blood glucose (R(2) = 0.49, p = 0.013). Although V accumulation in serum was dose-dependent, no correlation between total serum V concentration and the insulin-like response was found in this first attempt to correlate anti-diabetic activity with total serum V. This study suggests that V pools other than total serum V are likely related to the insulin-like effect of this metal. These results, obtained in diabetic patients, document the need for consideration of the coordination chemistry of metabolites and proteins with vanadium in anti-diabetic vanadium complexes. PMID- 23982219 TI - Maternal understanding of infective endocarditis after hospitalization: assessing the knowledge of mothers of children with congenital heart disease and the practical implications. AB - This study aimed to examine the knowledge of mothers of children with congenital heart disease as well as the association of cardiological factors and maternal characteristics with maternal understanding. Mothers of 135 children (<=2 years old) were interviewed to assess maternal knowledge of infective endocarditis (IE) using the Hannover Inventory of Parental Knowledge of Congenital Heart Disease. Two subscales, endocarditis and risk factors, were used. Cardiological data as well as maternal characteristics were collected. Two-thirds of the mothers achieved only low scores, answering 0-20 % of the questions correctly (endocarditis = 64.4 %; risk factors = 71.1 %). Mothers with higher education recalled the correct definition of IE (P = 0.001) and the importance of dental hygiene (P = 0.004) more often. Mothers with only one child were more likely to know the most typical symptom (P = 0.007). The severity of the heart disease and the requirement of endocarditis prophylaxis did not influence maternal understanding. Yet, mothers assessing the heart disease as severe showed better knowledge (typical symptom P = 0.021; importance of dental hygiene P = 0.007). If mothers learned the diagnosis before their child's birth, they remembered relevant information more often. Mothers receiving information by the medical staff and from the Internet showed better knowledge (definition P = 0.014; importance of dental hygiene P = 0.001). Due to low levels of knowledge, more efforts must be put into the education of mothers. Educational programs should take maternal characteristics into account, providing written material and thereby keeping the instruction of lower-educated persons in mind. Furthermore, education should be focused on mothers of children requiring IE prophylaxis. PMID- 23982220 TI - Echocardiography assessment of the aorta in children with chronic kidney disease. PMID- 23982221 TI - Fatal varicella due to the vaccine-strain varicella-zoster virus. AB - We describe a death in a 15-mo-old girl who developed a varicella-like rash 20 d after varicella vaccination that lasted for 2 mo despite acyclovir treatment. The rash was confirmed to be due to vaccine-strain varicella-zoster virus (VZV). This is the first case of fatal varicella due to vaccine-strain VZV reported from the United States. The patient developed severe respiratory complications that worsened with each new crop of varicella lesions; vaccine-strain VZV was detected in the bronchial lavage specimen. Sepsis and multi-organ failure led to death. The patient did not have a previously diagnosed primary immune deficiency, but her failure to thrive and repeated hospitalizations early in life (starting at 5 mo) for presumed infections and respiratory compromise treated with corticosteroids were suggestive of a primary or acquired immune deficiency. Providers should monitor for adverse reactions after varicella vaccination. If severe adverse events develop, acyclovir should be administered as soon as possible. The possibility of acyclovir resistance and use of foscarnet should be considered if lesions do not improve after 10 d of treatment (or if they become atypical [e.g., verrucous]). Experience with use of varicella vaccine indicates that the vaccine has an excellent safety profile and that serious adverse events are very rare and mostly described in immunocompromised patients. The benefit of vaccination in preventing severe disease and mortality outweigh the low risk of severe events occurring after vaccination. PMID- 23982222 TI - Determination of chlorinated hydrocarbons in water using highly sensitive mid infrared sensor technology. AB - Chlorinated aliphatic hydrocarbons and chlorinated aromatic hydrocarbons (CHCs) are toxic and carcinogenic contaminants commonly found in environmental samples, and efficient online detection of these contaminants is still challenging at the present stage. Here, we report an advanced Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR) sensor for in-situ and simultaneous detection of multiple CHCs, including monochlorobenzene, 1,2 dichlorobenzene, 1,3-dichlorobenzene, trichloroethylene, perchloroethylene, and chloroform. The polycrystalline silver halide sensor fiber had a unique integrated planar-cylindric geometry, and was coated with an ethylene/propylene copolymer membrane to act as a solid phase extractor, which greatly amplified the analytical signal and contributed to a higher detection sensitivity compared to the previously reported sensors. This system exhibited a high detection sensitivity towards the CHCs mixture at a wide concentration range of 5~700 ppb. The FTIR-ATR sensor described in this study has a high potential to be utilized as a trace-sensitive on-line device for water contamination monitoring. PMID- 23982224 TI - The evolution of spin distribution in the photoexcited triplet state of ethyne elaborated porphyrins. AB - Ethyne elaboration of a (porphinato)Zn(II) (PZn) chromophoric core renders fine control over the zero-field splitting (ZFS) parameters of the lowest energy photoexcited triplet state (T1), resulting in the ability to manipulate the spin distribution and establish highly symmetrical coincident optical and magnetic principal axes. PMID- 23982223 TI - Whole-genome sequencing reveals untapped genetic potential in Africa's indigenous cereal crop sorghum. AB - Sorghum is a food and feed cereal crop adapted to heat and drought and a staple for 500 million of the world's poorest people. Its small diploid genome and phenotypic diversity make it an ideal C4 grass model as a complement to C3 rice. Here we present high coverage (16-45 * ) resequenced genomes of 44 sorghum lines representing the primary gene pool and spanning dimensions of geographic origin, end-use and taxonomic group. We also report the first resequenced genome of S. propinquum, identifying 8 M high-quality SNPs, 1.9 M indels and specific gene loss and gain events in S. bicolor. We observe strong racial structure and a complex domestication history involving at least two distinct domestication events. These assembled genomes enable the leveraging of existing cereal functional genomics data against the novel diversity available in sorghum, providing an unmatched resource for the genetic improvement of sorghum and other grass species. PMID- 23982225 TI - Neural substrates of treatment response to cognitive-behavioral therapy in panic disorder with agoraphobia. AB - OBJECTIVE: Although exposure-based cognitive-behavioral therapy (CBT) is an effective treatment option for panic disorder with agoraphobia, the neural substrates of treatment response remain unknown. Evidence suggests that panic disorder with agoraphobia is characterized by dysfunctional safety signal processing. Using fear conditioning as a neurofunctional probe, the authors investigated neural baseline characteristics and neuroplastic changes after CBT that were associated with treatment outcome in patients with panic disorder with agoraphobia. METHOD: Neural correlates of fear conditioning and extinction were measured using functional MRI before and after a manualized CBT program focusing on behavioral exposure in 49 medication-free patients with a primary diagnosis of panic disorder with agoraphobia. Treatment response was defined as a reduction exceeding 50% in Hamilton Anxiety Rating Scale scores. RESULTS: At baseline, nonresponders exhibited enhanced activation in the right pregenual anterior cingulate cortex, the hippocampus, and the amygdala in response to a safety signal. While this activation pattern partly resolved in nonresponders after CBT, successful treatment was characterized by increased right hippocampal activation when processing stimulus contingencies. Treatment response was associated with an inhibitory functional coupling between the anterior cingulate cortex and the amygdala that did not change over time. CONCLUSIONS: This study identified brain activation patterns associated with treatment response in patients with panic disorder with agoraphobia. Altered safety signal processing and anterior cingulate cortex-amygdala coupling may indicate individual differences among these patients that determine the effectiveness of exposure-based CBT and associated neuroplastic changes. Findings point to brain networks by which successful CBT in this patient population is mediated. PMID- 23982227 TI - "Surgical failure in patient with cervical fracture and ankylosing spondylitis treated with teriparatide to try to augment consolidation ". PMID- 23982226 TI - CpG oligodeoxynucleotide induces bone marrow precursor cells into myeloid-derived suppressor cells. AB - Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) perform a number of functions in different immunological settings. In standard in vitro experiments, DCs are produced from mouse bone marrow (BM) cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Our previous study demonstrated that BM precursor cells could differentiate into MDSCs when co-cultured with poly (I:C). In the present study, BM precursor cells cultured in GM-CSF and IL-4 were treated with CpG oligodeoxynucleotide (CpG ODN). We observed that Gr1+CD11b+ cells exhibiting MDSC functions accumulated in the co culture system. A similar phenomenon was also observed in Listeria monocytogenes infected mice. In conclusion, we demonstrated that prolonged CpG ODN stimulation could inhibit the development of DCs and induce the differentiation of BM precursor cells into MDSCs. PMID- 23982228 TI - Risk of seizure and its clinical implication in the patients with cerebral metastasis from lung cancer. AB - BACKGROUND: The prevalence, risk factors, and clinical implication of seizure development were investigated in patients with metastatic brain tumors. METHODS: Medical records and radiological findings were analyzed retrospectively in 258 patients with brain metastasis from lung cancer who underwent Gamma Knife radiosurgery (GKS) between January 2008 and December 2009. RESULTS: During the follow-up period 32 patients (12.4 %) experienced seizure episodes. Coexistence of leptomeningeal seeding was a significant risk factor related to development of seizure (p < 0.001). Prophylactic use of anticonvulsants was not correlated with reduction of seizure incidence (p = 0.818). Continued use of anticonvulsants was necessary in nine of the 258 patients (3.5 %) because of recurrent seizures. Imaging studies performed immediately after seizure attacks in the patients with known metastatic brain lesions revealed tumor progression or complications related to treatment in 35 of 42 episodes of seizure (77.8 %). CONCLUSIONS: Patients with metastatic lesions have a substantial risk of developing seizure. Seizure in known metastatic brain tumor patients are usually related to disease progression or complications of treatment. Follow-up imaging should be considered for each seizure episode and adequate multimodal treatment needs to be added to antiepileptic medication. PMID- 23982229 TI - The value of immediate postoperative MR imaging following endoscopic endonasal pituitary surgery. AB - BACKGROUND: Although the value of early MR imaging has been justified for microscopic transphenoidal surgery, there is no literature evaluating immediate postoperative MR imaging following endoscopic endonasal resection of pituitary adenomas. We hypothesized that MRI of the pituitary gland performed on the first postoperative day is just as effective at detecting residual disease and/or reconstruction materials as the MRI at 3 months following surgery. METHODS: We retrospectively evaluated 102 consecutive patients who underwent endoscopic endonasal surgery for presumed pituitary adenomas. Sixty-four patients met the inclusion criteria with immediate and 3 months MR imaging. Imaging was evaluated by two sets of observers. The following parameters were assessed: enhancement pattern of the pituitary gland, pituitary stalk, nodular enhancement (residual tumor) or linear enhancement (non-tumoral) and residual reconstruction/packing materials. RESULTS: Gross total resection of the tumors with no cavernous sinus involvement was achieved in 49 out of 52 (94%) patients. Eleven out of 12 remaining patients with cavernous sinus invasion had residual cavernous sinus component visible on both immediate and 3 month MR imaging. The pituitary gland, position of stalk, and nasoseptal flap could be identified on both post-operative MRIs in all patients. The sensitivity and specificity for residual tumor detection on immediate MRI was 100% and 97.9%, respectively. The kappa index evaluating interobserver agreement for identification of residual tumor and packing/reconstruction material on immediate MR was 0.83 and 0.72 indicating near perfect and substantial agreement, respectively. CONCLUSION: Immediate MR imaging performed following endoscopic endonasal resection of pituitary lesions provides accurate and reliable information regarding the presence of residual tumor compared to reconstruction and packing materials. PMID- 23982230 TI - A surgical technique to expand the operative corridor for supracerebellar infratentorial approaches: technical note. AB - BACKGROUND: The supracerebellar infratentorial approach is a commonly used route in neurosurgery. It provides a narrow and deep corridor to the dorsal midbrain and pineal region. The authors describe a surgical technique to expand the operative corridor and the surgeon's working angles during this approach. METHODS: Thirteen cases of patients who underwent resection of their lesions using this extended approach were reviewed. During their suboccipital craniotomy, additional bone over the transverse sinus (paramedian approach) and the confluence of the sinuses (midline approach) were removed. Two sutures (tentorial stay sutures) were anchored to the tentorium anterior to the transverse sinus and tension was applied. A video narrated by the senior author describes the details of technique. RESULTS: This additional bone removal and tentorial stay sutures led to gentle elevation of the tentorium and partial mobilization of the dural venous sinuses superiorly. This technique enhanced operative viewing through improved illumination and expanded working angles for microsurgical instruments while minimizing the need for fixed retractors and extensive cerebellar retraction. All patients underwent satisfactory removal of their lesions. No patient suffered from any related complication. CONCLUSION: The use of stay sutures anchored on the tentorium is a simple and effective technique that expands the surgical corridor during supracerebellar infratentorial approaches. PMID- 23982231 TI - Current trends in translational research in leptospirosis. AB - PURPOSE OF REVIEW: In the past years, the importance of studying leptospirosis in a translational context has become more evident. This review addresses recent findings in the study of leptospirosis infection, focusing on those applicable to public health, or that will affect management and diagnosis of cases of leptospirosis. RECENT FINDINGS: We review here recent findings regarding translational aspects of leptospirosis research. Briefly, PCR or a combination of serology and PCR seem to have a higher sensitivity than the current gold standard (microagglutination test). More clinical trials are needed to determine the best treatment for mild and severe leptospirosis. Dendritic cells and gammadelta T cells seem to have an important role in the immune response to leptospirosis. Environmental assessment is emerging as a very useful tool. SUMMARY: In order to understand leptospirosis, multiple aspects need to be considered, including host, pathogen and environment. In this review, we will address newer diagnostics, current advances in immunology and treatment and the growing role of environmental assessment. PMID- 23982232 TI - New findings in the pathogenesis of leprosy and implications for the management of leprosy. AB - PURPOSE OF REVIEW: This review focuses on recent work in leprosy pathogenesis. New research of both innate and adaptive immune responses to Mycobacterium leprae is described. The proposition that Mycobacterium lepromatosis is a new species causing leprosy is discussed. RECENT FINDINGS: Modulation of the lipid metabolism and reprogramming of adult Schwann cells have both been suggested as mechanisms used by M. leprae to disseminate the disease. New markers associated with localized, disseminated disease or the occurrences of leprosy reactions include the human interferons, CD163, microRNA-21, NOD2, galectin-3 and toll-like receptor 4. The role of keratinocytes instead of macrophages is underlined in the pathogenesis of leprosy. Adaptive immunity reports focus on the role of T regulatory cells and cytokines secreted by T helper cells in leprosy. Finally, a newly identified species named M. lepromatosis has been detected in patients with leprosy and severe erythema nodosum leprosum. SUMMARY: Novel biological pathways have been identified to be associated with the clinical phenotype of leprosy or the occurrence of leprosy reactions. Future work should include larger numbers of clinical samples from across the leprosy spectrum in order to give new insights in the pathogenesis and management of the disease. PMID- 23982233 TI - The whole parasite, pre-erythrocytic stage approach to malaria vaccine development: a review. AB - PURPOSE OF REVIEW: The whole sporozoite (SPZ) vaccine platform provides the only established approach for inducing high-level sustained protective immunity in humans against malaria. We introduce this platform, highlight literature published since 2011, and discuss the challenges of further development. RECENT FINDINGS: There are three major approaches to development of a whole parasite vaccine to prevent malaria infection using the SPZ platform: radiation-attenuated sporozoites (irrSPZ), chemoprophylaxis with infectious sporozoites (CPS), and genetically attenuated parasites (GAPs). In all three, SPZ are administered to the vaccinee. All three protect animals against infection when administered by injection with a needle and syringe, and irrSPZ and CPS protect against Plasmodium falciparum malaria in humans when P. falciparum SPZ (PfSPZ) are administered by mosquito bite. Metabolically active, nonreplicating (radiation attenuated) aseptic, purified, cryopreserved PfSPZ (PfSPZ Vaccine), and infectious, aseptic, purified, cryopreserved PfSPZ administered with chemoprophylaxis (PfSPZ-CVac approach) administered by needle and syringe have entered clinical trials. Preliminary data indicate that the PfSPZ Vaccine is safe, well tolerated and highly protective when administered intravenously. SUMMARY: With proof-of-concept now established for high-grade protection induced by parenteral administration of a whole sporozoite vaccine, pathways for further development are currently being defined. Demonstration of high-level, durable, cross-strain P. falciparum protection would set the stage for licensure of a vaccine that could lead to dramatic reductions in malaria morbidity and mortality, and eventually elimination of this ancient scourge. PMID- 23982234 TI - Intra-abdominal fungal infections. AB - PURPOSE OF REVIEW: The clinical spectrum of intra-abdominal fungal infections has not been systematically analyzed in the literature. RECENT FINDINGS: Even though intra-abdominal fungal infections have been recognized with increasing frequency in the recent years, most clinical experience is limited to case reports or uncontrolled case series. These infections are more common than clinically recognized disease. The clinical presentation varies broadly depending on the organism and host's immune status, but it is frequently severe, difficult to treat, and associated with significant morbimortality. Predisposing factors, clinical characteristics, and advances in the management are discussed. SUMMARY: Intra-abdominal fungal infections are increasingly important in clinical practice. Early recognition and a combined treatment approach, usually consisting of surgical intervention and systemic antifungal therapy, are required for improved outcomes. PMID- 23982235 TI - Recent insights into Clostridium difficile pathogenesis. AB - PURPOSE OF REVIEW: Clostridium difficile infection (CDI) is the leading cause of antibiotic-associated diarrhea and pseudomembranous colitis in the healthcare setting. An emerging consensus suggests that CDI is caused by pathogenic toxin production, gut microbial dysbiosis and altered host inflammatory responses. The aim of this review is to summarize and highlight recent advances focused on CDI pathogenic mechanisms. RECENT FINDINGS: Potential paradigm shifts relating to the mechanisms of toxin action and inhibition have recently been reported, with new insights into spore germination and surface protein function also gaining traction. Multiomic analysis of microbiome dysbiosis has identified important CDI associated microbial community shifts that may form the basis of future targeted bacteriotherapy, and functional metabolite biomarkers that require further characterization. Classical innate and adaptive immunity against CDI is rapidly being delineated, with novel innate S-nitrosylation signals also being identified. SUMMARY: Studies in patients and animal disease models are shedding new light on the critical roles of the microbiota, metabolome and host responses in primary and recurrent CDI. An improved understanding of the CDI disease pathogenesis will provide the basis for developing new therapies for treating disease and preventing recurrence. PMID- 23982236 TI - Clostridium difficile: biological therapies. AB - PURPOSE OF REVIEW: Biological therapies for Clostridium difficile infection (CDI) include probiotics and faecal microbiota transplant (FMT). There is significant interest in their use in treating refractory/recurrent CDI. This review summarizes the latest evidence for these approaches. RECENT FINDINGS: The small number of randomized controlled trials (RCTs) using probiotics in CDI have produced variable results; the most recent showed no benefit in preventing disease. However, several meta-analyses published in the last year have suggested benefit in their use, but these conclusions are limited by the poor quality of many of the primary studies, and lack of standardization of the probiotic administered. In contrast, FMT appears highly effective for the treatment of CDI. In the only published RCT, the cure rate was 81%, which is close to the rate shown by meta-analyses of previous case series. The use of artificially produced bacterial mixtures in place of faecal samples is now under investigation. SUMMARY: Biological therapies for CDI, especially FMT, will continue to attract attention. Further, large-scale RCTs are required to identify which patients are most likely to benefit from these therapies in the future. PMID- 23982237 TI - New developments in chemotherapeutic options for Clostridium difficile colitis. AB - PURPOSE OF REVIEW: Clostridium difficile infections (CDIs) are of increasing concern in healthcare due to increasing incidence as well as suboptimal response to standard therapies. This review focuses on current updates in chemotherapeutic treatment options for primary CDI as well as for relapse. RECENT FINDINGS: Metronidazole and vancomycin remain the standard therapy for mild and severe CDI, respectively. Fidaxomicin was approved for use in CDI by the US Food and Drug Administration in 2011 and new studies have shown a decreased rate of recurrence as compared with vancomycin as well as potential promise for use as a chaser. Rifaximin may be useful in salvage therapy for recurrent CDI as well as for a chaser. Tigecycline, teicoplanin, doxycycline, linezolid, nitazoxanide, amixicile, LFF571, and CB-183 315 have in-vitro activity and are under different stages of study. Monoclonal antitoxin antibodies for prevention of relapse of CDI are currently under evaluation in a phase 3 clinical trial. SUMMARY: A variety of promising new treatment options for Clostridium difficile are under development, although further studies are necessary to determine the efficacy of these newer treatments for cure and preventing disease relapse. PMID- 23982238 TI - Hepatitis E. AB - PURPOSE OF REVIEW: Hepatitis E has been regarded as a disease of the developing world, where it causes large waterborne outbreaks and sporadic cases of hepatitis. Recent research has shown this received wisdom to be mistaken. RECENT FINDINGS: Recent studies have shown that authochtonous (locally acquired) hepatitis E does occur in developed countries, is caused by hepatitis E virus (HEV) genotypes 3 and 4, and is zoonotic with pigs as the primary host. Most infections are clinically inapparent. However, acute symptomatic hepatitis E has a predilection for middle-aged and elderly men, with an excess mortality in patients with underlying chronic liver disease. Chronic infection occurs in the immunosuppressed with rapidly progressive cirrhosis if untreated, the treatment of choice being ribavirin monotherapy for 3 months. Hepatitis E has a range of extra-hepatic manifestations, including a spectrum of neurological syndromes. HEV can be transmitted by blood transfusion and has recently been found in donated blood in a number of countries. SUMMARY: The diagnosis should be considered in any patient with a raised alanine aminotranferase, irrespective of age or travel history. The safety of blood products needs to be fully assessed, as a matter of priority, as blood donors are not currently screened for HEV. PMID- 23982239 TI - Cystoisospora and cyclospora. AB - PURPOSE OF REVIEW: The present review focuses on recent epidemiological and diagnostic advances in cystoisosporiasis and cyclosporiasis. RECENT FINDINGS: Continuous outbreaks of these parasites occur worldwide. Sporadic cases in the United States are travel acquired, but also domestically acquired. New molecular diagnostic methods allow for accurate early diagnosis in humans, and might potentially decrease the burden of disease by detecting these parasites in vehicles of transmission. SUMMARY: Better understanding of the epidemiology of Cyclospora cayetanensis and to a less extent to Cystoisospora belli has been gained recently. However, several gaps still remain in knowledge on the transmission and on mechanisms of persistent infection in immunosuppressed patients and prevention. New molecular methods might help in filling these gaps and in controlling transmission. PMID- 23982240 TI - Current world literature. PMID- 23982242 TI - Facilitation of voluntary goal-directed action by reward cues. AB - Reward-associated cues are known to influence motivation to approach both natural and man-made rewards, such as food and drugs. However, the mechanisms underlying these effects are not well understood. To model these processes in the laboratory with humans, we developed an appetitive Pavlovian-instrumental transfer procedure with a chocolate reward. We used a single unconstrained response that led to an actual rather than symbolic reward to assess the strength of reward motivation. Presentation of a chocolate-paired cue, but not an unpaired cue, markedly enhanced instrumental responding over a 30-s period. The same pattern was observed with 10-s and 30-s cues, showing that close cue-reward contiguity is not necessary for facilitation of reward-directed action. The results confirm that reward-related cues can instigate voluntary action to obtain that reward. The effectiveness of long-duration cues suggests that in clinical settings, attention should be directed to both proximal and distal cues for reward. PMID- 23982243 TI - Just post it: the lesson from two cases of fabricated data detected by statistics alone. AB - I argue that requiring authors to post the raw data supporting their published results has the benefit, among many others, of making fraud much less likely to go undetected. I illustrate this point by describing two cases of suspected fraud I identified exclusively through statistical analysis of reported means and standard deviations. Analyses of the raw data behind these published results provided invaluable confirmation of the initial suspicions, ruling out benign explanations (e.g., reporting errors, unusual distributions), identifying additional signs of fabrication, and also ruling out one of the suspected fraud's explanations for his anomalous results. If journals, granting agencies, universities, or other entities overseeing research promoted or required data posting, it seems inevitable that fraud would be reduced. PMID- 23982244 TI - Fear of holes. AB - Phobias are usually described as irrational and persistent fears of certain objects or situations, and causes of such fears are difficult to identify. We describe an unusual but common phobia (trypophobia), hitherto unreported in the scientific literature, in which sufferers are averse to images of holes. We performed a spectral analysis on a variety of images that induce trypophobia and found that the stimuli had a spectral composition typically associated with uncomfortable visual images, namely, high-contrast energy at midrange spatial frequencies. Critically, we found that a range of potentially dangerous animals also possess this spectral characteristic. We argue that although sufferers are not conscious of the association, the phobia arises in part because the inducing stimuli share basic visual characteristics with dangerous organisms, characteristics that are low level and easily computed, and therefore facilitate a rapid nonconscious response. PMID- 23982245 TI - Female genital mutilation: a hidden epidemic (statement from the European Academy of Paediatrics). AB - Female genital mutilation or female circumcision is frequently performed worldwide. It is estimated by the World Health Organisation that worldwide, 100 140 million girls and women currently have to live with the consequences of female genital mutilation. The article argues that the tradition is one of the causes, while another four possible reasons for undergoing such cruel mutilation of young girls exist. Today, there exists a classification of at least four different ways of such mutilation which has no health benefits, and it harms girls and women in many ways. Long-term consequences like recurrent urinary tract infections, dysmenorrhea, sexual problems, infertility and complications both for the mother and infant at delivery are mentioned. Female genital mutilation is a violation of the fundamental human rights, as well as a savage breach of the integrity and personality. CONCLUSION: The European Academy of Paediatrics advises its members to initiate appropriate counselling for parents and female adolescents regarding the risk of female genital mutilation and strongly condemns female genital mutilation and councils its members not to perform such procedures. PMID- 23982246 TI - Familial male-limited precocious puberty in neurofibromatosis type I. AB - Precocious puberty in patients with neurofibromatosis type 1 (NF-1) is predominantly central in origin, with intracranial pathologies like optic glioma. We describe one patient with NF-1 who presented with precocious puberty with the eventual diagnosis of familial male-limited precocious puberty and share the potential pitfalls. He presented at 7 years of age with growth spurt and pubertal genitalia development with enlarged testicular volume of 7 mL, but LHRH stimulation test revealed blunted luteinizing hormone and follicle-stimulating hormone peak suggestive of a peripheral cause, contrary to the expectation due to the background of NF-1. Testosterone level was elevated with bone age advancement by 2 years. Genetic analysis revealed a previously reported heterozygous missense mutation of the luteinizing hormone/choriogonadotropin receptor gene Ala572Val. His father was also heterozygous for the same mutation but was apparently asymptomatic and not short. CONCLUSION: Our report illustrates two potential pitfalls in the clinical evaluation of patients with familial male-limited precocious puberty (FMPP). Firstly, patients with FMPP will have mild to moderately enlarged testes and should not be wrongly diagnosed as central precocious puberty without the gonadotropin-releasing hormone stimulation test. Secondly, family members with the same mutation may have different phenotypic severities, where some male carriers may have subtle features. PMID- 23982247 TI - Renal tubular dysfunction in patients with molecular defects of the insulin receptor gene. PMID- 23982248 TI - Phase I clinical trial of lenalidomide in combination with temsirolimus in patients with advanced cancer. AB - BACKGROUND: Lenalidomide, an immunomodulatory and anti-angiogenic drug, and temsirolimus, an mTOR inhibitor, have synergistic anti-cancer effects in preclinical models. We conducted a phase I study of the combination in patients with advanced cancers. PATIENTS AND METHODS: A "3 + 3" study design was used. During the escalation phase, lenalidomide (orally, days 1-21) and temsirolimus (intravenously, once a week) were given at the following respective doses: level 1 (10 mg, 15 mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle = 28 days). The maximum tolerated dose, dose-limiting toxicity, and response were assessed. RESULTS: Forty-three patients were treated (median age: 58 years (range, 21-80); male/female: 26/17). The most common diagnoses were colorectal cancer (N = 5), sarcoma (N = 5), neuroendocrine carcinoma (N = 4) and adenoid cystic carcinoma (N = 4). Overall, 121 cycles (median: 2) were administered. No dose-limiting toxicities were observed. The maximum tested dose (dose level 4) was used in the expansion phase. Grade 3-4 treatment-related hematologic toxicities (all reversible) were seen in 19 (72%) patients and included neutropenia (N = 12), thrombocytopenia (N = 6), and infection (N = 1). Grade 3 hyperglycemia and Grade 3 hypertriglyceridemia were noted in 21% and 20% of patients, respectively. Of 43 patients, 30 (70%) received prophylactic anticoagulation. There were no thrombotic events. Response was evaluable in 40 patients: one (2.5%) patient had a partial response and 19 (48%) had stable disease (SD), with SD >= 6 months in 6 (15%) patients. Tumor types with SD >= 6 months were soft tissue sarcoma (2/5; 40%), adenoid cystic carcinoma (1/4; 25%), parotid adenocarcinoma (1/2; 50%), adrenocortical carcinoma (1/3; 33%), and neuroendocrine carcinoma (1/4; 25%). The median progression-free survival duration was 2.2 months (95% CI, 1.5-2.9), and the median overall survival duration was 7.8 months (95% CI, 5.1-10.6). CONCLUSIONS: Lenalidomide and temsirolimus combination therapy was well tolerated and associated with clinical benefit in patients with soft tissue sarcoma, adenoid cystic carcinoma, neuroendocrine carcinoma, parotid carcinoma, and adrenocortical carcinoma. PMID- 23982249 TI - Safety of epidural analgesia in the perioperative care of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: The perioperative coagulopathy, hemodynamic instability, and infectious complications that may occur during cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has raised concerns about the safety of epidural analgesia in patients undergoing such procedures. METHODS: We conducted a retrospective review of the perioperative anesthetic management of 215 adult patients who had undergone CRS with HIPEC with epidural analgesia. We reviewed epidural-related complications and analyzed the effect of early initiation of continuous epidural analgesia on estimated blood loss, intraoperative fluid administration, blood transfusion and vasopressor requirements, time to extubation, and length of stay. RESULTS: No epidural hematomas or abscesses were reported. Two patients (0.9 %) had delays in epidural removal because of thrombocytopenia, and two had epidural-site erythema (0.9 %). The majority of postoperative epidural-related hypotensive episodes were successfully treated with fluid boluses. Early initiation of epidural analgesic infusions (before HIPEC) was associated with significantly less surgical blood loss and fluid requirements (P = 0.005 and 0.02, respectively). Pre-HIPEC initiation of epidural infusions was not associated with a statistically significant difference in the following: volume of blood transfused, intraoperative vasopressors use, time to extubation, and length of hospital stay. CONCLUSIONS: With close hematologic monitoring and particular attention to sterility, epidural analgesia can be safely provided to patients undergoing CRS with HIPEC. Early initiation of continuous epidural infusions during surgery could lead to decreased blood loss and less intraoperative fluid administration. Prospective randomized studies are required to further investigate these potential benefits. PMID- 23982250 TI - Hypoxia in melanoma: using optical spectroscopy and EF5 to assess tumor oxygenation before and during regional chemotherapy for melanoma. AB - BACKGROUND: There is increasing evidence that tumor hypoxia plays a significant role in the chemoresistance of melanoma, but to our knowledge, real-time tumor oxygenation during isolated limb infusion (ILI) has not been studied. We sought to demonstrate the feasibility of measuring real-time alterations in tissue oxygenation. METHODS: Consecutive patients with histologically confirmed in transit melanoma were enrolled onto a prospective single-arm pilot study and administered the hypoxia marker drug EF5. All patients were treated with ILI. Optical spectroscopy readings were obtained at three locations: two discrete target lesions and one normal skin control. Measurements were taken at 11 predefined time points during ILI. RESULTS: A total of six patients were enrolled onto this pilot study. Intratumor and normal skin optical spectroscopy readings were found to have discrete inflection points throughout the duration of therapy, corresponding with established time points. Baseline hypoxia as measured by both optical spectroscopy and EF5 immunofluorescence was variable, but on the basis of optical spectra, tumors appeared to become more hypoxic compared to normal skin after tourniquet application. The optical hypoxia signature was variable between patients while hemoglobin absorption increased. CONCLUSIONS: To our knowledge, this is the first use of real-time optical spectroscopy to evaluate oxygenation and perfusion within melanoma lesions during regional chemotherapy. We report our development of this new noninvasive means of assessing tumor vascular function, which has the potential to be a powerful tool for noninvasive examination of the melanoma tumor microenvironment. PMID- 23982251 TI - Efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in the management of malignant ascites. AB - BACKGROUND: In peritoneal surface disease, accumulation of malignant ascites represents a difficult problem to treat, with adverse impact on quality of life. The role of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in controlling malignant ascites is not well defined. METHODS: A retrospective analysis of a prospectively maintained database of 1,000 procedures was performed. Type of malignancy, resolution of ascites, duration and agent of chemoperfusion, performance status, resection status, morbidity, mortality, and survival were reviewed. RESULTS: Ascites was found in 299 patients (310 procedures) either before or during exploration. A total of 142 (46 %) procedures were performed for appendiceal primary disease, 53 (17 %) colorectal, 20 (6 %) gastric, 45 (15 %) mesothelioma, and 26 (8 %) ovarian. A total of 288 (93 %) patients had resolution of ascites by 3 months' follow-up. In patients with ascites, complete cytoreduction was obtained in 15 versus 59 % when ascites was not present (p < 0.001). In the group of patients who had their ascites controlled, 243 of 288 (84 %) had resection with residual macroscopic disease (R2 status). Twenty-two patients (7 %) had persistent ascites at 3 months' follow-up, 19 (86 %) of whom had an R2 resection. Univariate analysis revealed that type of primary disease, resection status, duration or agent of chemoperfusion, and performance status did not predict failure. CONCLUSIONS: CRS-HIPEC is effective in controlling ascites in 93 % of patients with malignant ascites, even when a complete cytoreduction is not feasible. Ascites is predictive of incomplete cytoreduction and worse overall survival. Although complete cytoreduction remains the goal of this procedure, HIPEC can provide palliative value in selected patients with malignant ascites. PMID- 23982252 TI - Down-regulation of stromal caveolin-1 expression in esophageal squamous cell carcinoma: a potent predictor of lymph node metastases, early tumor recurrence, and poor prognosis. AB - BACKGROUND: Recent studies have identified loss of stromal caveolin-1 (Cav-1) expression as a new prognostic histological characteristic in various types of human cancers. However, the clinical and pathological significance of stromal Cav 1 expression in esophageal squamous cell carcinoma (ESCC) remains largely unknown. We examined Cav-1 expression in both tumor and stromal cells in ESCC tissue by immunohistochemical analysis to evaluate its clinicopathological significance and prognostic value. METHODS: A total of 110 patients with ESCC who underwent surgical resection were included in this study. The expression of Cav-1 in both tumor and stromal cells in esophageal tumor tissues was examined immunohistochemically. RESULTS: Cav-1 expression was found in the cytoplasm of both tumor and stromal cells. Tumor Cav-1 overexpression was observed in 37.3 % tumors, which correlated to deeper tumor invasion (p = 0.038). Down-regulation of stromal Cav-1 expression was observed in 40.9 % tumors. The stromal Cav-1 down regulation group had more lymph node metastases and more locoregional recurrences than those with higher expression (p = 0.020 and p = 0.002, respectively). In addition, down-regulation of stromal Cav-1 expression was associated with shorter disease-free survival (p < 0.001) and overall survival (p < 0.001). Multivariate analysis revealed that down-regulation of stromal Cav-1 expression was an independent prognostic factor for both disease-free survival (p = 0.028) and overall survival (p = 0.007). CONCLUSIONS: Down-regulation of stromal Cav-1 expression in ESCC had high malignant potential. It predicts high-risk of lymph node metastases and locoregional recurrence, and it could be a powerful prognostic marker for patients with ESCC. PMID- 23982253 TI - Allogeneic blood transfusion does not affect outcome after curative resection for advanced cholangiocarcinoma. AB - PURPOSE: To assess the impact of perioperative blood transfusion on overall and disease-free survival in patients undergoing curative resection for cholangiocarcinoma. METHODS: In a single-center study, 128 patients undergoing curative resection for cholangiocarcinoma between 2001 and 2010 were assessed. The median follow-up period was 19 months. Transfused and nontransfused patients were compared by Cox regression and propensity score analyses. RESULTS: Overall, 38 patients (29.7 %) received blood transfusions. The patient characteristics were highly biased with respect to receiving transfusions (propensity score 0.69 +/- 0.22 vs. 0.11 +/- 0.16, p < 0.001). In the unadjusted analysis, blood transfusion was associated with a 105 % increased risk of mortality [hazard ratio (HR) 2.05, 95 % CI 1.19-3.51, p = 0.010]. In the multivariate (HR 1.14, 95 % CI 0.52-2.48, p = 0.745) and the propensity score-adjusted Cox regression (HR 1.02, 95 % CI 0.39-2.62, p = 0.974), blood transfusion had no influence on overall survival. Similarly, in the propensity score-adjusted Cox regression (HR 0.62, 95 % CI 0.24-1.58, p = 0.295), no relevant effect of blood transfusion on disease free survival was observed. CONCLUSIONS: To our knowledge, this is the first propensity score-based analysis providing compelling evidence that the worse oncological outcome after curative resection for advanced cholangiocarcinoma in patients receiving perioperative blood transfusions is caused by the clinical circumstances requiring the transfusions, not by the blood transfusions themselves. PMID- 23982254 TI - Elevated preoperative neutrophil-to-lymphocyte ratio as a predictor of survival after gastroenterostomy in patients with advanced pancreatic adenocarcinoma. AB - BACKGROUND: There is increasing evidence that the presence of an ongoing systemic inflammatory response, especially a high preoperative neutrophil-to-lymphocyte ratio (NLR), is associated with a poor outcome for a variety of common solid tumors. However, few studies have investigated the clinical value of the NLR in patients undergoing gastroenterostomy for advanced pancreatic cancer. METHODS: A total of 83 patients who had symptoms of gastric outlet obstruction due to advanced pancreatic cancer and underwent gastroenterostomy were analyzed. The prognostic significance of the NLR was analyzed. The relationship between the NLR value and postoperative outcome was also evaluated. RESULTS: The median survival time was 9.4 months in patients with an NLR of <4, whereas it was 3.4 months in patients with an NLR of >=4 (P < 0.001). The multivariate analysis revealed that an NLR of >=4, the presence of liver metastases, daily pain, and lack of postoperative chemotherapy were significant prognostic factors. A higher NLR was associated with postoperative morbidity; 13 % of patients with an NLR of <4 and 36 % of those with an NLR of >=4 (P = 0.012) developed morbidities. With regard to quality of life, 96 % of patients with an NLR of <4 and 36 % of patients with an NLR of >=4 had adequate oral intake of solid food without any support with intravenous nutrition for at least 1 month after surgery (P < 0.001). CONCLUSIONS: The preoperative NLR offers important prognostic information for patients who have gastric outlet obstruction due to advanced pancreatic adenocarcinoma. PMID- 23982256 TI - Total skin-sparing mastectomy in BRCA mutation carriers. AB - BACKGROUND: Total skin-sparing mastectomy (TSSM) with preservation of the nipple areolar complex skin has become increasingly accepted as an oncologically safe procedure. Oncologic outcomes after TSSM in BRCA mutation carriers have not been well-studied. METHODS: We identified 53 BRCA-positive patients who underwent bilateral TSSM for prophylactic (26 patients) or therapeutic indications (27 patients) from 2001 to 2011. Cases were age-matched (for prophylactic cases) or age- and stage-matched (for therapeutic cases) with non-BRCA-positive patients. Outcomes included tumor involvement of resected nipple tissue, the development of new breast cancers in patients who underwent risk-reducing TSSM, and local regional recurrence in patients who underwent therapeutic TSSM. RESULTS: Outcomes from 212 TSSM procedures in 53 cases and 53 controls were analyzed. In patients undergoing TSSM for prophylactic indications, in situ cancer was found in one (1.9 %) nipple specimen in BRCA-positive patients versus two specimens (3.8 %) in the non-BRCA-positive cohort (p = 1). At a mean follow-up of 51 months, no new cancers developed in either cohort. In patients undergoing TSSM for therapeutic indications, in situ or invasive cancer was found in zero of the nipple specimens in BRCA-positive patients versus two specimens (3.7 %) in the non-BRCA-positive cohort (p = 0.49). At a mean follow-up of 37 months, there were no local-regional recurrences in the BRCA-positive cohort and 1 (3.7 %) in the non-BRCA-positive cohort. CONCLUSIONS: TSSM is an oncologically safe procedure in BRCA-positive patients. In patients undergoing TSSM as a risk-reducing strategy, 4-year follow up demonstrates no increased risk of developing new breast cancers; longer-term follow-up is ongoing. PMID- 23982255 TI - Video-assisted thoracoscopic surgical thymectomy to treat early thymoma: a comparison with the conventional transsternal approach. AB - BACKGROUND: For thymoma, the feasibility of resection via video-assisted thoracoscopic surgery (VATS) remains controversial. The objective of our study was to compare the outcomes of VATS and transsternal thymectomy in order to evaluate the efficacy of the VATS method for treatment of early stage thymoma. METHODS: This study is a retrospective study of 120 patients who underwent thymectomy of early stage thymoma (Masaoka stage I and II) in a single medical center from 1991 to 2010. Of these patients, 76 patients underwent VATS thymectomy (VATS group) and 44 patients underwent the conventional transsternal approach (sternotomy group). We applied the Kaplan-Meier method to estimate overall survival (OS), recurrence-free survival (RFS), and time to tumor recurrence (TTR) of these two groups. RESULTS: The mean follow-up time was 61.9 months in the VATS group and 69.7 months in the sternotomy group. There was no surgery-related mortality or major complication. The VATS group had smaller specimen size (p < 0.05) and tumor size (p < 0.01), shorter length of stay (LOS) in the hospital (p < 0.01), and shorter duration of chest tube drainage (p < 0.05) than the sternotomy group. There were no significant differences between the two groups for OS, RFS, and TTR. CONCLUSIONS: In early stage thymoma, VATS thymectomy associated with shorter hospital LOS and shorter duration of pleural drainage compared with the conventional transsternal approach. Otherwise, the two approaches had similar oncologic outcomes during the mean 60-month follow-up period. PMID- 23982257 TI - Valproic acid sensitizes TRAIL-resistant anaplastic thyroid carcinoma cells to apoptotic cell death. AB - BACKGROUND: Anaplastic thyroid carcinoma (ATC) is an aggressive human tumor associated with a median survival of 2-6 months. TRAIL, as a ligand of death receptors, is known to induce apoptotic cell death in several cancer cells. However, TRAIL treatment alone is not effective against TRAIL-resistant cancer cells. This study was designed to investigate whether valproic acid (VPA) enhances apoptotic cell death of TRAIL-resistant ATC cells and to identify the mechanism of cell death of ATC cells by combination treatment with VPA and TRAIL. METHODS: To evaluate the cytotoxic effect of TRAIL and/or VPA on ATC cells, we used the MTT assay. The effects of VPA and TRAIL on apoptosis were assessed using FACS analysis (Annexin-V/PI stain) and Western blotting. RESULTS: The combination of VPA with TRAIL significantly induced apoptotic cell death compared with 8505C and ARO cells treated with TRAIL alone. The protein levels of cleaved caspase-8, 3, and PARP were increased in VPA and TRAIL co-treated ARO cells. The combination induced the activation of JNK and the phosphorylation of FADD and c-Jun but not p38. However, pretreatment with caspase inhibitors reduced the expression of cleaved caspase-8, -3, and PARP in co-treated ARO cells. SP600125 remarkably reduced the expression of cleaved caspase-8, -3, and PARP and the phosphorylation of FADD and c-Jun, as well as apoptotic cell death. CONCLUSIONS: VPA sensitized TRAIL-resistant ATC cells to apoptotic cell death through involvement of the JNK pathway. Thus, the combination of VPA and TRAIL may be a promising therapy for ATC. PMID- 23982258 TI - A cost-minimization analysis comparing total thyroidectomy alone and total thyroidectomy with prophylactic central neck dissection in clinically nodal negative papillary thyroid carcinoma. AB - BACKGROUND: Total thyroidectomy (TT) with prophylactic central neck dissection (pCND) remains controversial for clinically nodal-negative (cN0) papillary thyroid carcinoma (PTC), and the issue of cost rarely has been examined. We evaluated whether pCND at the time of TT is more cost-saving than TT alone in the medium- to long-term. METHODS: For a hypothetical group of 50-year-old females with a 1.5-cm cN0 PTC, a decision-tree model using TreeAge Software was developed to simulate outcomes and compare the 20-year accumulative direct cost between TT alone and TT+pCND strategies. Baseline values and ranges were determined from a systematic review of the literature. Sensitivity analyses were conducted to test model strength. Cost estimate of surgical procedures, complications, and radioiodine (RAI) ablation was based on government gazette. RESULTS: The cost accrued per patient for the primary operation under TT alone and TT+pCND strategies were USD 6,702.81 and USD 10,062.35, respectively, whereas the cost for the reoperative procedure were USD 12,981.40 and USD 12,509.09, respectively. The 20-year accumulative cost for TT alone and TT+pCND strategies were USD 19,888.36 and USD 22,760.86, respectively. The incremental cost per patient was USD 2,872.50. In the univariate and bivariate sensitivity analyses, no change in conclusion was seen by varying the rates of complications, annualized locoregional recurrences and RAI, or by extending the model to 50 years. CONCLUSIONS: From a pure economic institution's perspective, TT+pCND is more expensive in the medium- and long-term and seems less justified compared with TT alone for cN0 PTC. PMID- 23982259 TI - Investigation of deregulated genes of Notch signaling pathway in human T cell acute lymphoblastic leukemia cell lines and clinical samples. AB - In diagnostic research challenges, quantitative real-time PCR (QPCR) has been widely utilized in gene expression analysis because of its sensitivity, accuracy, reproducibility, and most importantly, quantitativeness. Real-time PCR base kits are wildly applicable in cancer signaling pathways, especially in cancer investigations. T-cell acute lymphoblastic leukemia (T-ALL) is a type of leukemia that is more common in older children and teenagers. Deregulation of the Notch signaling pathway promotes proliferation and inhibits apoptosis of the lymphoblastic T cells. The aim of this study was to investigate the effect of Notch signaling activation on the expression of target genes using real-time QPCR and further use this method in clinical examination after validation. Two T-ALL cell lines, Jurkat and Molt-4, were used as models for activation of the Notch signaling via over-expression of the Notch1 intracellular domain. Expression analysis was performed for six downstream target genes (NCSTN, APH1, PSEN1, ADAM17, NOTCH1 and C-MYC) which play critical roles in the Notch signaling pathway. The results showed significant difference in the expression of target genes in the deregulated Notch signaling pathway. These results were also verified in 12 clinical samples bearing over-expression of the Notch signaling pathway. Identification of such downstream Notch target genes, which have not been studied inclusively, provides insights into the mechanisms of the Notch function in T cell leukemia, and may help identify novel diagnoses and therapeutic targets in acute lymphoblastic leukemia. PMID- 23982260 TI - A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy. AB - Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules. PMID- 23982261 TI - A cellular automaton model examining the effects of oxygen, hydrogen ions and lactate on early tumour growth. AB - Some tumours are known to exhibit an extracellular pH that is more acidic than the intracellular, creating a 'reversed pH gradient' across the cell membrane and this has been shown to affect their invasive and metastatic potential. Tumour hypoxia also plays an important role in tumour development and has been directly linked to both tumour morphology and aggressiveness. In this paper, we present a hybrid mathematical model of intracellular pH regulation that examines the effect of oxygen and pH on tumour growth and morphology. In particular, we investigate the impact of pH regulatory mechanisms on the cellular pH gradient and tumour morphology. Analysis of the model shows that: low activity of the Na+/H+ exchanger or a high rate of anaerobic glycolysis can give rise to a "fingering" tumour morphology; and a high activity of the lactate/H+ symporter can result in a reversed transmembrane pH gradient across a large portion of the tumour mass. Also, the reversed pH gradient is spatially heterogeneous within the tumour, with a normal pH gradient observed within an intermediate growth layer within the spheroid. We also include a fractal dimension analysis of the simulated tumour contours, in which we compare the fractal dimensions of the simulated tumour surfaces with those found experimentally via photomicrographs. PMID- 23982262 TI - Measuring the overall genetic component of nevirapine pharmacokinetics and the role of selected polymorphisms: towards addressing the missing heritability in pharmacogenetic phenotypes? AB - OBJECTIVE: Nevirapine is an important component of highly active antiretroviral therapy used in the treatment of HIV infection. There is a considerable variation in the pharmacokinetics of nevirapine and this variation can impact the efficacy and toxicity of nevirapine. Although some of this variation can be attributed to environmental factors, the degree to which heritability influences nevirapine pharmacokinetics is unknown. This study aims to estimate how much variation in nevirapine pharmacokinetics is due to genetic factors and to investigate the contribution of selected polymorphisms to this variability. METHODS: Two doses of immediate-release nevirapine were administered to European (n=11) and African American (n=6) participants recruited from the Research in Access to Care in the Homeless cohort. A repeated drug administration method was then used to determine the relative genetic contribution (r(GC)) to variability in nevirapine AUC(0-6 h). Nevirapine plasma levels were quantified using LC/MS/MS. Patients were also genotyped for selected polymorphisms in candidate genes that may influence nevirapine pharmacokinetics. RESULTS: A significant r(GC) for nevirapine AUC(0-6 h) was found in Europeans (P=0.02) and African Americans (P=0.01). A trend toward higher nevirapine AUC(0-6 h) for the CYP2B6 516TT (rs3745274; Q172H) genotype was observed in European Americans (P=0.19). CONCLUSION: This study demonstrates that there is a significant genetic component to variability in nevirapine pharmacokinetics. Although genetic variants such as CYP2B6 polymorphisms attributed to some of this variation, these data suggest that there may be additional genetic factors that influence nevirapine pharmacokinetics. PMID- 23982263 TI - Imaging atherosclerosis and risk of plaque rupture. AB - Atherosclerosis imaging strategies can delineate characteristics of plaques at risk of rupture and thrombosis. Structural plaque imaging identifies high-risk plaque features, including lipid pools, thin fibrous caps, and intraplaque hemorrhage. New molecular imaging techniques complement structural imaging approaches by illuminating important features of plaque biology, with a prominent focus on detecting inflammation as a high-risk phenotype. As we unravel the molecular and structural characteristics underlying thrombosis-prone plaques, there is significant promise for eventual early identification and prediction of atherosclerotic plaque complications before they occur. Here we focus on recent imaging insights into high-risk arterial plaques, the etiologic agent of acute myocardial infarction, stroke, and sudden cardiac death. PMID- 23982265 TI - Yolk sac tumour: a rare cause of raised serum alpha-foetoprotein in a young child with a large liver mass. AB - BACKGROUND: Primary yolk sac tumour of the liver is extremely rare, and when it occurs in a young child it can be confused with hepatoblastoma. OBJECTIVE: To present a retrospective case series of primary hepatic yolk sac tumour from two institutions to highlight the imaging features. MATERIALS AND METHODS: We conducted a retrospective review of pathological and imaging findings in biopsy proven pure primary yolk sac tumour of the liver. RESULTS: A total of three children (15 months to 6 years) presented between 2006 and 2012 with primary hepatic yolk sac tumour. Two children presented with acute abdomen after minor trauma caused by tumour rupture and haemoperitoneum. We identified five additional paediatric cases of pure hepatic yolk sac tumour with descriptions of imaging findings in the literature. In seven of these eight children, central necrosis was seen on cross-sectional imaging. CONCLUSION: Primary yolk sac tumour should be considered as an alternative diagnosis to hepatoblastoma in a young child with a large liver mass and significantly raised serum alpha-foetoprotein, but in view of the nonspecific imaging features histological examination is essential for diagnosis. Although there are no specific imaging findings of primary yolk sac tumour, presence of cystic or necrotic areas and a tendency for tumour rupture are suggestive features. PMID- 23982264 TI - Multiple adipose depots increase cardiovascular risk via local and systemic effects. AB - Adipose tissue modifies the development of cardiovascular disease in a complex manner: obesity is a major risk factor, especially when accompanied by a central fat distribution. For that reason the characteristics of visceral adipose tissue have attracted most of the research interest thus far, and measurement of waist circumference is now recommended for everyday clinical practice. However, the direct, causative role of visceral fat in cardiometabolic disease remains to be established. Epidemiological and clinical studies show that accumulation of fat subcutaneously, in the gluteofemoral area, is protective against cardiovascular disease, but the exact molecular mechanisms remain unclear. In the last few years, imaging has allowed the study of smaller fat depots that may interact locally with important tissues: epicardial fat with the myocardium, perivascular fat with the vessel wall and the developing atherosclerotic plaque, and renal sinus fat with the renal artery. Unraveling the heterogeneous fat distribution and metabolic phenotypes in human obesity will facilitate optimal assessment of cardiovascular risk in overweight and obese individuals. PMID- 23982266 TI - Soluble form of receptor for advanced glycation end-products (sRAGE): do sRAGE ligands or anti-sRAGE auto-antibodies interfere with sRAGE quantification? AB - BACKGROUND: The soluble form of the receptor for advanced glycation end-products (sRAGE) has been studied in various diseases. It is not clear why sRAGE levels vary between studies, with controversial results. What also remains to be determined is whether receptor for advanced glycation end-products (RAGE) ligands could affect sRAGE assessment by epitope masking. Recently described anti-sRAGE autoantibodies may play an interfering role. The aim of this study was therefore to investigate the influence of RAGE ligands and anti-sRAGE autoantibodies on sRAGE quantification. METHODS: The RAGE ligands carboxymethyllysine (CML; AGEs with a high affinity for RAGE), S100 proteins, high-mobility group protein B1 (HMGB1) and beta-amyloid peptide (abeta) were tested by enzyme-linked immunosorbent assay (ELISA) with recombinant sRAGE (rHu-sRAGE) or serum from healthy controls. Using ELISA, anti-sRAGE autoantibodies (IgGs) were identified in haemodialysis (HD) patients, then purified and incubated with rHu-sRAGE or serum to investigate their effects on sRAGE levels. RESULTS: RAGE ligands, either alone at three different concentrations (CML was also tested at different glycation levels) or a mixture of all these ligands, did not affect sRAGE levels when incubated with rHu-sRAGE or control serum. Compared with healthy controls, HD patients had higher levels of sRAGE (P < 0.001) and anti-sRAGE IgGs (P < 0.05). However, incubation of rHu-sRAGE with purified IgGs from HD patients had no effect on sRAGE quantification. CONCLUSIONS: RAGE ligands or anti-sRAGE autoantibodies did not interfere with sRAGE quantification. Further studies are required to elucidate the variability in sRAGE levels reported in the literature and to define the potential of sRAGE for use as a reliable biomarker. PMID- 23982267 TI - Biogeography and biodiscovery hotspots of macroalgal marine natural products. AB - This review covers the literature published for marine natural products isolated from macroalgae and addresses the taxonomic details of source organisms, the chemical types of isolated compounds and the location of sampling sites. The emphasis of this review is on the identification of the most bioprospected taxa and regions, as well as on how these trends have shifted over time. PMID- 23982268 TI - Use of domesticated pigs by Mesolithic hunter-gatherers in northwestern Europe. AB - Mesolithic populations throughout Europe used diverse resource exploitation strategies that focused heavily on collecting and hunting wild prey. Between 5500 and 4200 cal BC, agriculturalists migrated into northwestern Europe bringing a suite of Neolithic technologies including domesticated animals. Here we investigate to what extent Mesolithic Ertebolle communities in northern Germany had access to domestic pigs, possibly through contact with neighbouring Neolithic agricultural groups. We employ a multidisciplinary approach, applying sequencing of ancient mitochondrial and nuclear DNA (coat colour-coding gene MC1R) as well as traditional and geometric morphometric (molar size and shape) analyses in Sus specimens from 17 Neolithic and Ertebolle sites. Our data from 63 ancient pig specimens show that Ertebolle hunter-gatherers acquired domestic pigs of varying size and coat colour that had both Near Eastern and European mitochondrial DNA ancestry. Our results also reveal that domestic pigs were present in the region ~500 years earlier than previously demonstrated. PMID- 23982269 TI - Dosimetric comparison between intensity-modulated radiotherapy and standard wedged tangential technique for whole-breast radiotherapy in Asian women with relatively small breast volumes. AB - We sought to investigate whether intensity-modulated radiotherapy (IMRT) has a dosimetric advantage compared to the standard wedged tangential technique (SWT) for whole-breast radiotherapy (WBRT) in Asian women with relatively small breast volume. Computed tomography images of 25 Asian patients with early-stage breast cancer (right 15, left 10) used for WBRT planning were examined. After contouring the target volumes and bilateral lungs and, for left-side treatment, the heart, 4 plans were made for each patient: namely, SWT, tangential-field IMRT (T-IMRT), 3 field IMRT (3F-IMRT), and 4-field IMRT (4F-IMRT). The prescribed dose was 5000 cGy. The median planning target volume (PTV) for WBRT was 552.6 cc (range 288.8 1518.4 cc). Compared to SWT, (1) T-IMRT achieved significant improvement for dose homogeneity in the PTV (p < 0.001) and the dose received by 2% (D2) of the PTV (p < 0.001). T-IMRT also reduced the bilateral lung mean dose (p < 0.001) and the ipsilateral lung volume which received more than 20 Gy (V20) (p = 0.01). (2) 3F IMRT resulted in a significant increase in the mean dose to the ipsilateral lung (p < 0.001) and to the contralateral lung (p < 0.001). (3) 4F-IMRT also resulted in a significant increase in the mean dose to the ipsilateral lung (p < 0.001) and to the contralateral lung (p < 0.001). Tangential-field IMRT provided an improved dose distribution compared with SWT for WBRT in Asian women with a relatively small breast volume. PMID- 23982270 TI - Sources of HPV vaccine hesitancy in parents. AB - Despite strong national recommendations to vaccinate adolescents against the human papillomavirus (HPV), only 14% of teenage girls completed all 3 doses in 2010. Parental hesitancy may be one of the strongest reasons behind this low uptake rate. This review investigates sources of parental hesitancy including parental concerns associated with vaccinations in general, parental knowledge as a basis of HPV vaccine hesitancy, social qualms parents may have with regards to the HPV vaccine, and parental attitudes toward allowing their sons to be vaccinated against HPV. By better understanding these sources of hesitancy, we can focus research efforts towards addressing them in an attempt to improve HPV vaccine uptake. PMID- 23982271 TI - Perfect imaging, epsilon-near zero phenomena and waveguiding in the scope of nonlocal effects. AB - Plasmons in metals can oscillate on a sub-wavelength length scale and this large k response constitutes an inherent prerequisite for fascinating effects such as perfect imaging and intriguing wave phenomena associated with the epsilon-near zero (ENZ) regime. While there is no upper cut-off within the local-response approximation (LRA) of the plasma polarization, nonlocal dynamics suppress response beyond omega/v(F), where v(F) is the Fermi velocity of the electron gas. Nonlocal response has previously been found to pose limitations to field enhancement phenomena. Accounting for nonlocal hydrodynamic response, we show that perfect imaging is surprisingly only marginally affected by nonlocal properties of a metal slab, even for a deep subwavelength case and an extremely thin film. Similarly, for the ENZ response we find no indications of nonlocal response jeopardizing the basic behaviors anticipated from the LRA. Finally, our study of waveguiding of gap plasmons even shows a positive nonlocal influence on the propagation length. PMID- 23982272 TI - Multiple sclerosis is primarily a neurodegenerative disease. AB - The precise pathogenesis of multiple sclerosis is unknown. The assumption of a primary immunopathogenesis of the disease is seriously flawed and has failed to deliver an effective therapy for most patients. The progressive degeneration of grey and white matter is integral to the natural history of the disease and is reflected in the atrophy of brain and spinal cord. Demyelination is an essential component of this primary neurodegenerative process rather than the target of a systemic immune response. The primary pathology of multiple sclerosis is a process of neurodegeneration based on the integrity of the blood-brain barrier. Primary progressive multiple sclerosis is the prototype neurodegenerative disease, and the relapsing-remitting form in younger population represents the modifying effect of steroids (vitamin D, sex and stress hormones) on metabolic functions of the central nervous system. PMID- 23982273 TI - Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. AB - OBJECTIVE: Patients with borderline personality disorder are characterized by emotional hyperarousal with increased stress levels, anger proneness, and hostile, impulsive behaviors. They tend to ascribe anger to ambiguous facial expressions and exhibit enhanced and prolonged reactions in response to threatening social cues, associated with enhanced and prolonged amygdala responses. Because the intranasal administration of the neuropeptide oxytocin has been shown to improve facial recognition and to shift attention away from negative social information, the authors investigated whether borderline patients would benefit from oxytocin administration. METHOD: In a randomized placebo controlled double-blind group design, 40 nonmedicated, adult female patients with a current DSM-IV diagnosis of borderline personality disorder (two patients were excluded based on hormonal analyses) and 41 healthy women, matched on age, education, and IQ, took part in an emotion classification task 45 minutes after intranasal administration of 26 IU of oxytocin or placebo. Dependent variables were latencies and number or initial reflexive eye movements measured by eye tracking, manual response latencies, and blood-oxygen-level-dependent responses of the amygdala to angry and fearful compared with happy facial expressions. RESULTS: Borderline patients exhibited more and faster initial fixation changes to the eyes of angry faces combined with increased amygdala activation in response to angry faces compared with the control group. These abnormal behavioral and neural patterns were normalized after oxytocin administration. CONCLUSIONS: Borderline patients exhibit a hypersensitivity to social threat in early, reflexive stages of information processing. Oxytocin may decrease social threat hypersensitivity and thus reduce anger and aggressive behavior in borderline personality disorder or other psychiatric disorders with enhanced threat-driven reactive aggression. PMID- 23982275 TI - Ghrelin inhibits ovarian epithelial carcinoma cell proliferation in vitro. AB - The only orexigenic peptide, ghrelin, which is primarily produced by the gastrointestinal tract, has been implicated in malignant cell proliferation and invasion. Ghrelin is a natural ligand of the growth hormone secretagogue receptor 1a (GHSR1a). However, the role of ghrelin in ovarian epithelial carcinoma remains unknown since the expression of GHSR1a in ovary is not confirmed. The aim of the present study was to assess expression of ghrelin and its receptor in human ovarian epithelial carcinoma and to examine the effect of ghrelin on carcinoma cell proliferation. Frozen sections of ovarian samples and the human ovarian epithelial carcinoma cell line, HO-8910, were used to characterize the expression of ghrelin/GHSR1a axis and the effect of ghrelin on proliferation. We found that ghrelin and GHSR1a are expressed in ovarian epithelial carcinoma in vivo and in vitro. Ghrelin inhibits the proliferation and growth of HO-8910 cells by G1 phase arrest, and this inhibition may be abolished by the ghrelin receptor antagonist D Lys-3-GH-releasing peptide-6 and ghrelin neutralizing antibody. Ghrelin enhances HO-8910 cell apoptosis and autophagy. The activation of mammalian target of rapamycin (mTOR) signaling pathway blocks the effects of ghrelin-induced autophagy and apoptosis, therefore reverses the inhibition of HO-8910 cell proliferation induced by ghrelin. In conclusion, the present study demonstrates that ghrelin inhibits the proliferation of human HO-8910 ovarian epithelial carcinoma cells by inducing apoptosis and autophagy via the mTOR signaling pathway. This study provides a novel regulatory signaling pathway of ghrelin regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy. PMID- 23982274 TI - A modified TNM-7 staging system to better predict the survival in patients with hepatocellular carcinoma after hepatectomy. AB - OBJECTIVE: To evaluate the accuracy of the 7th edition of the American Joint Committee on Cancer staging system (TNM-7) for patients undergoing hepatectomy for hepatocellular carcinoma (HCC) and to propose a modified TNM system for better prediction of survival. METHODS: Clinico-pathological data for 1,313 patients who underwent hepatectomy as initial treatment for HCC between 2000 and 2008 were retrieved from a prospective database. Overall survival (OS) and disease-free survival (DFS) were analyzed to evaluate the predictive value. RESULTS: The 1-, 3-, 5-year OS and DFS of 1,313 patients were 79.2, 55.4, 45.5 %, and 52.6, 36.1, 31.8 %, respectively. Multivariate analysis revealed that major vascular invasion was the most important prognostic factor for both OS and DFS, along with tumour number and size. Patients with pT1 and pT2 disease had significantly better OS and DFS than those with pT3 disease (P < 0.001). There was no significant difference between pT3a and pT4 (P = 0.552) but patients with pT3b disease had a worse OS and DFS than those with pT4 disease (P = 0.006 and P < 0.001, respectively). A modified TNM system within the existing framework was proposed to combine the current pT3a and pT4 together as the new pT3 and to change pT3b to the new pT4. Analysis showed that this modified system had a better prognostic power than either TNM-6 or TNM-7. CONCLUSION: TNM-7 would seem to be inaccurate for staging advanced HCC. The modified system can improve both the prognostic accuracy and the hazard discrimination of disease to be consistent among subgroups of HCC. PMID- 23982276 TI - Mercury bioaccumulation and the population dynamics of Mesopodopsis slabberi (Crustacea: Mysidacea) along a mercury contamination gradient. AB - The mercury bioaccumulation and population dynamics of the mysid Mesopodopsis slabberi was assessed along a mercury gradient in Ria de Aveiro (Portugal). M. slabberi is one of the most important mysid species in European temperate coastal shallow waters playing a key ecological role. Nevertheless, no references were found concerning the possible consequences of the Hg on the trophodynamics of these coastal ecosystems. M. slabberi showed a clear bioaccumulation along the Hg gradient and through life, with mature females reaching the highest concentrations. In terms of population structure, higher densities and biomasses of M. slabberi were assessed in the most contaminated areas contrarily to the least polluted areas. Despite the mercury accumulation in its tissues no strong negative effects on the structure and population dynamics of the species were observed. However, mysids might be important in the transfer of metals from the sediments and zooplankton to higher trophic levels such as fishes, most of them with commercial interest. PMID- 23982278 TI - Investigation of lysine side chain interactions of interleukin-8 with heparin and other glycosaminoglycans studied by a methylation-NMR approach. AB - Although the interaction between interleukin-8 (IL-8) and glycosaminoglycans (GAGs) is crucial for the mediation of inflammatory effects, little is known about the site specificity of this interaction. Therefore, we studied complexes of IL-8 and heparin (HEP) as well as other GAGs in a multidisciplinary approach, involving site-directed mutagenesis, mass spectrometry, fluorescence and solution NMR spectroscopy as well as computer modeling. The interaction between GAG and IL 8 is largely driven by the amine groups of the lysine and the guanidinium groups of arginine side chains. However, due to fast exchange with the solvent, it is typically not possible to detect NMR signals of those groups. Here, we applied reductive (13)C-methylation of the lysine side chains providing sensitive NMR probes for monitoring directly the sites of GAG interaction in (1)H-(13)C correlation experiments. We focused on the lysine side chains K25, K28, K59, K69 and K72 of IL-8 (1-77), which were reported to be involved in the binding to GAGs. The NMR signals of these residues were assigned in (1)H-(13)C HSQC spectra through the help of site-directed mutagenesis. NMR and fluorescence titration experiments in combination with molecular docking and molecular dynamics simulations were applied to investigate the involvement of each lysine in the binding with HEP and various GAG hexasaccharides. We identified K25, K69 and K72 to be the most relevant binding anchors of IL-8(1-77) for the analyzed GAGs. PMID- 23982279 TI - Heterogeneous susceptibility of valve endothelial cells to mesenchymal transformation in response to TNFalpha. AB - Lack of understanding of the early mechanisms of aortic valve stenosis and calcification hinders the development of diagnostic and therapeutic intervention strategies. Inflammation is a known component of early aortic valve disease and can induce mesenchymal transformation in a subset of aortic valve endothelial cells. Here we present a three-dimensional culture system that allows transforming and non-transforming cells to be independently isolated and analyzed. We have used the system to identify and characterize the dynamic invasion and phenotypic transition of two distinct subsets of endothelial cells: those that invade and transform under TNFalpha treatment, and those that resist mesenchymal transformation and remain endothelial. We determine that non transformed cells maintain control levels of endothelial genes VE-cadherin and eNOS, while transformed cells lose these endothelial characteristics and upregulate alpha-smooth muscle actin. Both subsets of cells have an inflammatory phenotype marked by increased ICAM-1, but transformed cells have increased MMP-9, Notch1, TGF-beta, and BMP-4, while non-transformed cells do not. Transformed cells also have distinct effects on alignment of collagen fibers as they invade the hydrogel system, which is not found in control endothelial or interstitial valve cells. Understanding the role of transforming and non-transforming endothelial cells in valve disease will provide an important pathological link between early inflammation and later stages of disease. Discovery of the molecular signature of transformation-resistant endothelial cells could inform development of treatment strategies that promote survival of the valve endothelium. PMID- 23982281 TI - Citizen science as seen by scientists: Methodological, epistemological and ethical dimensions. AB - Citizen science as a way of communicating science and doing public engagement has over the past decade become the focus of considerable hopes and expectations. It can be seen as a win-win situation, where scientists get help from the public and the participants get a public engagement experience that involves them in real and meaningful scientific research. In this paper we present the results of a series of qualitative interviews with scientists who participated in the 'OPAL' portfolio of citizen science projects that has been running in England since 2007: What were their experiences of participating in citizen science? We highlight two particular sets of issues that our participants have voiced, methodological/epistemological and ethical issues. While we share the general enthusiasm over citizen science, we hope that the research in this paper opens up more debate over the potential pitfalls of citizen science as seen by the scientists themselves. PMID- 23982280 TI - Can molecular imaging enable personalized diagnostics? An example using magnetomotive photoacoustic imaging. AB - The advantages of photoacoustic (PA) imaging, including low cost, non-ionizing operation, and sub-mm spatial resolution at centimeters depth, make it a promising modality to probe nanoparticle-targeted abnormalities in real time at cellular and molecular levels. However, detecting rare cell types in a heterogeneous background with strong optical scattering and absorption remains a big challenge. For example, differentiating circulating tumor cells in vivo (typically fewer than 10 cells/mL for an active tumor) among billions of erythrocytes in the blood is nearly impossible. In this paper, a newly developed technique, magnetomotive photoacoustic (mmPA) imaging, which can greatly increase the sensitivity and specificity of sensing targeted cells or molecular interactions, is reviewed. Its primary advantage is suppression of background signals through magnetic enrichment/manipulation with simultaneous PA detection of magnetic contrast agent targeted objects. Results from phantom and in vitro studies demonstrate the capability of mmPA imaging to differentiate regions targeted with magnetic nanoparticles from the background, and to trap and sensitively detect targeted cells at a concentration of a single cell per milliliter in a flow system mimicking a human peripheral artery. This technique provides an example of the ways in which molecular imaging can potentially enable robust molecular diagnosis and treatment, and accelerate the translation of molecular medicine into the clinic. PMID- 23982282 TI - Association between corticotropin-releasing hormone receptor 1 and 2 (CRHR1 and CRHR2) gene polymorphisms and personality traits. AB - Previous studies have reported that the hypothalamic-pituitary-adrenal axis is involved with personality traits. We examined the association between corticotropin-releasing hormone receptor (CRHR) genes and personality traits. We investigated the 12 single-nucleotide polymorphisms of intron CRHR (six in CRHR1 and six in CRHR2, respectively) in 218 healthy volunteers using TaqMan PCR assays. Personality traits were assessed using the Revised NEO-Personality Inventory, the Temperament and Character Inventory, and the State-Trait Anxiety Inventory. No significant associations were observed between CRHR1 and CRHR2 expression and personality traits. These results fail to provide support for an association of CRHR1 and CRHR2 with personality traits in a Japanese adult population. PMID- 23982283 TI - Replication of a ROBO2 polymorphism associated with conduct problems but not psychopathic tendencies in children. AB - The co-occurrence of conduct problems (CPs) and high callous-unemotional (CU) traits specifies risk for adult psychopathy and is under a high genetic influence. A previous genome-wide pooled DNA study of 7-year olds identified a set of candidate single-nucleotide polymorphisms (SNPs) that might differentiate high CP+CU children from healthy children. We attempted to replicate an identified subset of these SNP-psychopathy associations. In a case-control design, 210 clinically referred children were partitioned into Comparison, High CP+Low CU, and High CP+CU groups and genotyped. One SNP, rs13064369, differentiated the groups but was associated with high CP, regardless of the level of CU traits, that is, the rare and heterozygote variants CC and CT were significantly more frequent in both CP groups compared with Comparisons but did not differ from each other. We replicated the finding that a polymorphism associated with the ROBO2 gene, which is involved in neurodevelopment, confers risk for the common emotionally reactive, impulsive aspects of conduct disorder, independent of concurrent risk for psychopathy. PMID- 23982285 TI - Extensive deep dermatophytosis cause by Trichophyton rubrum in a patient with liver cirrhosis and chronic renal failure. AB - Dermatophytes are the main pathogen of superficial skin fungal infections. On rare occasions, they can cause deep and extensive infections, especially in immunocompromised hosts. We reported a 48-year-old patient with liver cirrhosis and chronic renal failure who developed an extensive deep dermatophytosis with possible hematogenous dissemination. Skin histopathology showed extensive involvement of hair follicles and dermis by fungal elements. The pathogen was cultured from both skin biopsy specimen and central venous line. It was identified as Trichophyton rubrum by morphology and further conformed by sequencing of internal transcribed spacers of ribosomal DNA. The patient died quickly before the identification was available. PMID- 23982284 TI - Siderophore production by pathogenic mucorales and uptake of deferoxamine B. AB - Clinical reports have established that mucormycosis, mainly caused by Rhizopus spp., frequently occurs in patients treated with deferoxamine B (DFO, Desferal((r))) which is misappropriated by these fungi. Siderophore production by twenty mucoralean isolates was therefore investigated using a commercial iron depleted culture medium. Siderophore production was detected for most of the isolates. Our experiments confirmed that feroxamine B (iron chelate of DFO) promoted in vitro growth of Rhizopus arrhizus. Electrophoretic analysis of somatic extracts revealed iron-regulated proteins of 60 and 32 kDa which were lacking in iron-depleted culture conditions. Using a fluorescent derivative of deferoxamine B, we showed by fluorescence microscopy the entry of the siderophore within the fungal cells, thus suggesting a shuttle mechanism encompassing the uptake of the entire siderophore-ion complex into the cell. This useful tool renders possible a better understanding of iron metabolism in Mucorales which could lead to the development of new diagnostic method or new antifungal therapy using siderophores as imaging contrast agents or active drug vectors. PMID- 23982286 TI - Chronic paracoccidioidomycosis of the intestine as single organ involvement points to an alternative pathogenesis of the mycosis. AB - Current knowledge on the natural history of paracoccidioidomycosis states that the chronic form of the disease results from reactivation of quiescent foci established years or decades before during the primary lung infection. Once reactivated, the fungi can disseminate to virtually any organ or system. We present herein two chronic paracoccidioidomycosis patients with a single organ involvement that points to an alternative pathogenesis of the mycosis. These patients suggest that the chronic form may also arise from reactivation of foci not confined to the lungs, due to the early dissemination of yeast cells during the primary infection. PMID- 23982287 TI - Dual-energy CT perfusion and angiography in chronic thromboembolic pulmonary hypertension: diagnostic accuracy and concordance with radionuclide scintigraphy. AB - OBJECTIVES: To evaluate the diagnostic accuracy of dual-energy computed tomography (DECT) perfusion and angiography versus ventilation/perfusion (V/Q) scintigraphy in chronic thromboembolic pulmonary hypertension (CTEPH), and to assess the per-segment concordance rate of DECT and scintigraphy. METHODS: Forty consecutive patients with proven pulmonary hypertension underwent V/Q scintigraphy and DECT perfusion and angiography. Each imaging technique was assessed for the location of segmental defects. Diagnosis of CTEPH was established when at least one segmental perfusion defect was detected by scintigraphy. Diagnostic accuracy of DECT perfusion and angiography was assessed and compared with scintigraphy. In CTEPH patients, the per-segment concordance between scintigraphy and DECT perfusion/angiography was calculated. RESULTS: Fourteen patients were diagnosed with CTEPH and 26 with other aetiologies. DECT perfusion and angiography correctly identified all CTEPH patients with sensitivity/specificity values of 1/0.92 and 1/0.93, respectively. At a segmental level, DECT perfusion showed moderate agreement (kappa = 0.44) with scintigraphy. Agreement between CT angiography and scintigraphy ranged from fair (kappa = 0.31) to slight (kappa = 0.09) depending on whether completely or partially occlusive patterns were considered, respectively. CONCLUSIONS: Both DECT perfusion and angiography show satisfactory performance for the diagnosis of CTEPH. DECT perfusion is more accurate than angiography at identifying the segmental location of abnormalities. KEY POINTS: * Chronic thromboembolic pulmonary hypertension (CTEPH) is potentially treatable by surgery. * Dual-energy computed tomography (DECT) allows angiography and perfusion using a single acquisition. * Both DECT perfusion and angiography showed satisfactory diagnostic performance in CTEPH. * DECT perfusion was more accurate than angiography in identifying segmental abnormalities. PMID- 23982288 TI - Diffusion tensor imaging and tractography to evaluate sacral nerve root abnormalities in endometriosis-related pain: a pilot study. AB - OBJECTIVE: To prospectively evaluate microstructural abnormalities in sacral nerve roots in women affected by chronic pelvic pain associated with endometriosis. METHODS: We enrolled 30 women with an ultrasound diagnosis of endometriosis and moderate-severe chronic pelvic pain; 10 age-matched healthy women comprised the control group. All subjects underwent 3 T magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI); the sacral roots were reconstructed by post-processing the DTI data with dedicated software. Mean fractional anisotropy (FA) values in the S1, S2 and S3 roots were quantified. Analysis of FA values was performed by two radiologists in order to evaluate the interobserver agreement. RESULTS: The sacral nerve roots in healthy subjects were clearly visualised. Most of the patients with endometriosis displayed abnormalities of S1, S2 and S3 bilaterally at tractography, including an irregular and disorganised appearance. FA values in the S1, S2 and S3 roots were significantly lower in patients than in controls (P < 0.0001, <0.05 and <0.02, respectively) for both observers. No significant difference was found between observers. CONCLUSION: DTI with tractography is a non-invasive means of detecting changes in the microarchitecture of the sacral nerve roots. It can qualitatively and quantitatively reveal sacral root abnormalities in patients with endometriosis-associated pain. KEY POINTS: * MRI is increasingly used for endometriosis and chronic pelvic pain (CPP). * Magnetic resonance tractography can demonstrate microarchitectural abnormalities in sacral nerve roots. * Tractography shows altered microstructure of sacral roots affected by endometriosis and CPP. * S1-S3 fractional anisotropy values are lower in endometriosis than in healthy women. * Sacral nerve root alteration may explain the nature of endometriosis-related CPP. PMID- 23982289 TI - Dynamic contrast-enhanced and ultra-high-resolution breast MRI at 7.0 Tesla. AB - OBJECTIVE: To assess the feasibility of 7-T contrast-enhanced breast MRI in patients with suspicious masses. METHODS: Twenty patients with 23 suspicious breast masses on conventional imaging (mean size 13 mm, range 5-27 mm) were examined at 7 T. The MRI protocol included a dynamic series with injection of 0.1 mmol/kg gadobutrol (seven consecutive 3D T1-weighted gradient echo sequences, resolution 1 * 1 * 2 mm(3), temporal resolution 63 s) and ultra-high-resolution imaging (T1-weighted 3D gradient echo sequence, resolution 0.45 * 0.57 * 0.45 mm(3)). Two observers (R1 and R2) independently judged the examinations on image quality and classified lesions according to BI-RADS. The added value of ultra high-resolution imaging was assessed. RESULTS: The image quality was deemed excellent in 1 and 0, good in 10 and 12, sufficient in 8 and 8, and insufficient in 1 and 0 for R1 and R2 respectively. Twenty of the 23 lesions were identified at 7-T MRI by both observers. All histopathologically proven malignant lesions (n = 19) were identified and classified as BI-RADS-MRI 4 or 5. Ultra-high-resolution imaging increased reader confidence in 88 % (R1) and 59 % (R2) of acquisitions. CONCLUSION: The study shows the feasibility of dynamic contrast-enhanced 7-T breast MRI, where all malignant mass lesions were identified by two observers. KEY POINTS: * Magnetic resonance imaging is important in the evaluation of breast cancer. * Recently, 7-T MRI has become available. * The 7-T dynamic contrast enhanced breast MRI is feasible in patients. * The 7-T breast examinations are amenable to evaluation according to BI-RADS. PMID- 23982290 TI - The impact of bilateral salpingo-oophorectomy on breast MRI background parenchymal enhancement and fibroglandular tissue. AB - OBJECTIVE: The objective of this study was to evaluate the effect of bilateral salpingo-oophorectomy (BSO) on background parenchymal enhancement (BPE) and the amount of fibroglandular tissue (FGT) seen on breast MRI. METHODS: Retrospective review identified 21 BRCA mutation carriers who underwent breast MRI before and after elective BSO. After exclusion of patients placed on postoperative hormone replacement therapy, there were 18 eligible patients. Blinded to surgical status, three independent readers used categorical scales to rate BPE (minimal, mild, moderate, marked) and the amount of FGT (fatty, scattered, heterogeneously dense, dense) on pre- and post-BSO MRI examinations. The sign test was used to assess for changes in the categorical ratings of BPE and FGT. RESULTS: Significant proportions of women demonstrated decreases in BPE and in the amount of FGT following oophorectomy (P = 0.004 and 0.02, respectively.) BPE decreases were larger and seen earlier than FGT changes. There was no significant relationship between age/body mass index and changes in BPE and FGT. CONCLUSIONS: BPE and the amount of FGT seen on breast MRI are significantly decreased by oophorectomy; BPE decreases to a greater extent and earlier than FGT. KEY POINTS: * Background parenchymal enhancement significantly decreases at breast MRI following oophorectomy. * Fibroglandular tissue significantly decreases on breast MRI following oophorectomy. * Decrease in background parenchymal enhancement is greater than in fibroglandular tissue. * Decrease in background parenchymal enhancement occurs earlier than in fibroglandular tissue. PMID- 23982293 TI - Euthanasia and aiding suicide to remain criminal acts in Canada. PMID- 23982291 TI - Risk of colorectal cancer after initiation of orlistat: matched cohort study. AB - OBJECTIVE: To examine the risk of colorectal cancer after orlistat initiation in the UK population. DESIGN: Retrospective matched cohort study. SETTING: Data from the UK Clinical Practice Research Datalink from September 1998 to December 2008. PARTICIPANTS: 33,625 adults aged 18 years or over who started treatment with orlistat; each orlistat initiator was matched to up to five non-initiators (n=160,347) on age, sex, body mass index, and calendar time. MAIN OUTCOME MEASURES: Associations between orlistat initiation and the risk of colorectal cancer, assessed by calculating hazard ratios with propensity score adjusted Cox proportional hazard models. RESULTS: Of 193,972 patients with a median age of 47 (interquartile range 37-57) years, 77% were women and approximately 90% were obese (body mass index >= 30). Orlistat initiators were more likely to have a previous history of diabetes or hypertension and to receive prescriptions for anti-diabetes drugs, statins, and aspirin compared with non-initiators. In the intention to treat analysis, 57 colorectal cancer events were identified among orlistat initiators and 246 among non-initiators, with median follow-up times of 2.96 and 2.86 years, respectively. The calculated incidence rate of colorectal cancer per 100,000 person years was 53 (95% confidence interval 41 to 69) for orlistat initiators and 50 (44 to 57) for non-initiators. Orlistat initiation was not associated with a higher risk of colorectal cancer (adjusted hazard ratio 1.11, 95% confidence interval 0.84 to 1.47). Findings were robust in the as treated analyses and in patients who were aged 50 years or over, were morbidly obese, or had a history of diabetes. CONCLUSIONS: This study found no evidence of an increased risk of colorectal cancer after the initiation of orlistat. It is limited by the relatively short follow-up time, and the possibility of adverse effects of long term orlistat use on risk of colorectal cancer cannot be excluded. PMID- 23982294 TI - Link between antihyperglycemic drugs and cancer is unproved, US endocrinologists say. PMID- 23982295 TI - Reduction of aqueous CrVI using nanoscale zero-valent iron dispersed by high energy electron beam irradiation. AB - High energy electron beam (HEEB) irradiation was used to disperse nanoscale zero valent iron (NZVI) for reduction of CrVI to CrIII in aqueous solution. Pore size distribution, scanning electron microscopy and X-ray diffraction characterizations demonstrated that HEEB irradiation could effectively increase the dispersion of NZVI resulting in more active reduction sites of Crvi on NZVI. Batch reduction experiments indicated that the reductive capacity of HEEB irradiation-modified NZVI (IMNZVI) was significantly improved, as the reductive efficiency reached 99.79% under the optimal conditions (electron beam dose of 30 kGy at 10 MeV, pH 2.0 and 313 K) compared with that of raw NZVI (72.14%). Additionally, the NZVI was stable for at least two months after irradiation. The modification mechanism of NZVI by HEEB irradiation was investigated and the results indicated that charge and thermal effects might play key roles in dispersing the NZVI particles. PMID- 23982296 TI - [Surgical frontal lecture. Still important for teaching students?]. AB - In times of manifold digital learning resources open to public access lectures in surgery still play a major role in medical training. It is a platform for discussion with the medical teacher and provides the opportunity to create a vivid learning experience by showing live operations via video streaming and inviting patients to the lectures. When then change in paradigm is achieved from pure knowledge transfer to cross-linkage of knowledge, the surgical lecture will be a major future keystone in medical education, where the lecturer can reach the students with his own passion for the field of expertise and get them interested in surgery. PMID- 23982297 TI - [Ectopic parathyroid adenomas]. PMID- 23982298 TI - The brain in overdrive: a new look at borderline and related disorders. AB - Borderline personality disorder (BPD) has been recognized as heterogeneous, etiologically, stemming from many combinations of genetic and environmental factors BPD never occurs alone: it is always accompanied by traits of other personality disorders and by various symptom-conditions, especially mood disorders. The controversy about linkage between BPD and bipolar disorder could not be resolved when the debate relied only on clinical description. Some twin studies suggested modest overlap between BPD and bipolar disorder. Current neuroimaging research points to similarities in brain changes among several conditions characterized by emotional over-reactivity to stress: bipolar disorder, certain cases of BPD and attention-deficit hyperactivity (ADHD). These include alterations in the limbic system (e.g., amygdala and hippocampus) and neocortex (especially the prefrontal cortex). An important subset of BPD exists in which brain changes are essentially identical with those of bipolar disorder. Relevant brain-change findings and treatment implications are summarized in this article. PMID- 23982299 TI - Dimorphisms of the proteasome subunit beta type 8 gene (PSMB8) of ectothermic tetrapods originated in multiple independent evolutionary events. AB - The proteasome subunit beta type 8 gene (PSMB8) encodes one of the beta subunits of the immunoproteasome responsible for the generation of peptides presented by major histocompatibility complex class I molecules. Dimorphic alleles of the PSMB8 gene, termed A and F types, based on the deduced 31st amino acid residue of the mature protein have been reported from various vertebrates. Phylogenetic analysis revealed the presence of dichotomous ancient lineages, one comprising the F-type PSMB8 of basal ray-finned fishes, and the other comprising the A-type PSMB8 of these animals and both the F- and A-type PSMB8 of Xenopus and acanthopterygians, indicating that evolutionary history of the PSMB8 dimorphism was not straightforward. We analyzed the PSMB8 gene of five reptile and one amphibian species and found both the A and F types from all six. Phylogenetic analysis indicated that the PSMB8 F type was apparently regenerated from the PSMB8 A type at least five times independently during tetrapod evolution. Genomic typing of wild individuals of geckos and newts indicated that the frequencies of the A- and F-type alleles are not highly biased in these species. Phylogenetic analysis of each exon of the reptile PSMB8 gene suggested interallelic sequence homogenization as a possible evolutionary mechanism for the apparent recurrent regeneration of PSMB8 dimorphism in tetrapods. An extremely strong balancing selection acting on PSMB8 dimorphism was implicated in an unprecedented pattern of allele evolution. PMID- 23982300 TI - A comprehensive multiscale framework for simulating optogenetics in the heart. AB - Optogenetics has emerged as an alternative method for electrical control of the heart, where illumination is used to elicit a bioelectric response in tissue modified to express photosensitive proteins (opsins). This technology promises to enable evocation of spatiotemporally precise responses in targeted cells or tissues, thus creating new possibilities for safe and effective therapeutic approaches to ameliorate cardiac function. Here we present a comprehensive framework for multiscale modelling of cardiac optogenetics, allowing both mechanistic examination of optical control and exploration of potential therapeutic applications. The framework incorporates accurate representations of opsin channel kinetics and delivery modes, spatial distribution of photosensitive cells, and tissue illumination constraints, making possible the prediction of emergent behaviour resulting from interactions at sub-organ scales. We apply this framework to explore how optogenetic delivery characteristics determine energy requirements for optical stimulation and to identify cardiac structures that are potential pacemaking targets with low optical excitation thresholds. PMID- 23982301 TI - Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. AB - OBJECTIVE: Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. METHOD: This was a two site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. CONCLUSIONS: Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice. PMID- 23982302 TI - Effect of heavy metals (Cu, Pb, and As) on the ultrastructure of Sargassum pallidum in Daya Bay, China. AB - Concentrations of Cu, Pb, and As were determined in seawater, surface sediment, Sargassum pallidum collected from the Daya Bay, China. The influence of metal contamination on the marine alga was investigated at chemical and ultrastructural level. Mean concentrations of Cu (19.44 mg kg(-1)) and Pb (33.99 mg kg(-1)) were found to be high in sediment, whereas concentration of As (122.29 mg kg(-1)) in S. pallidum was higher than that in water and sediment. The ultrastructure of S. pallidum cells was anomalous and aberrant. Energy-dispersive x-ray spectroscopic analysis revealed that the nanometal particles in the form of comparatively high electron density substance diffused in the cell structures constituted by Cu, Pb, As, etc. There is a remarkable similarity or correspondence in the anomalous elements between the geochemistry and the botanic cell, and the heavy metals have potential hazardous effect on the ocean ecology system in Daya Bay. PMID- 23982304 TI - Association between teaching and support skills and subjective effectiveness of nutritional guidance of registered dietitians at hospitals in a Japanese prefecture. AB - OBJECTIVE: The aim of this study is to clarify the association between teaching and support skills and the subjective effectiveness of nutritional guidance of registered dietitians working at hospitals. METHODS: We carried out a questionnaire survey of registered dietitians at hospitals in a Japanese prefecture. The utilization of nutritional teaching skills in nutritional guidance was investigated using a self-produced 36-item questionnaire that was designed to be mainly used for diabetic patients in 4 settings: first guidance, first assessment, contemplation stage, and preparation stage. The support skills were evaluated by Kikuchi's Scale of Social Skills: 18 items. The subjective effectiveness of nutritional guidance was defined by the behavioral change of the patients after nutritional guidance as evaluated by a registered dietitian. RESULTS: There were 75 respondents (response rate 46.6 %). Among the teaching skills, basic skills in an interview were often used, but some related to coaching skills were not in common use in nutritional guidance. Based on the results of principal component analysis, we created a scale for scoring the utilization of nutritional teaching skills in each setting. Multiple linear regression analysis illustrated that high subjective effectiveness of nutritional guidance was associated with high score of teaching skills in the preparation stage setting and high score of support skills. CONCLUSIONS: These results show that, in addition to frequent use of nutritional teaching skills, improvement of support skills is also necessary to enhance the effectiveness of nutritional guidance. PMID- 23982303 TI - The future for genetic studies in reproduction. AB - Genetic factors contribute to risk of many common diseases affecting reproduction and fertility. In recent years, methods for genome-wide association studies (GWAS) have revolutionized gene discovery for common traits and diseases. Results of GWAS are documented in the Catalog of Published Genome-Wide Association Studies at the National Human Genome Research Institute and report over 70 publications for 32 traits and diseases associated with reproduction. These include endometriosis, uterine fibroids, age at menarche and age at menopause. Results that pass appropriate stringent levels of significance are generally well replicated in independent studies. Examples of genetic variation affecting twinning rate, infertility, endometriosis and age at menarche demonstrate that the spectrum of disease-related variants for reproductive traits is similar to most other common diseases. GWAS 'hits' provide novel insights into biological pathways and the translational value of these studies lies in discovery of novel gene targets for biomarkers, drug development and greater understanding of environmental factors contributing to disease risk. Results also show that genetic data can help define sub-types of disease and co-morbidity with other traits and diseases. To date, many studies on reproductive traits have used relatively small samples. Future genetic marker studies in large samples with detailed phenotypic and clinical information will yield new insights into disease risk, disease classification and co-morbidity for many diseases associated with reproduction and infertility. PMID- 23982306 TI - MitomiRs, chloromiRs and modelling of the microRNA inhibition. AB - MicroRNAs are non-coding parts of nuclear and mitochondrial genomes, preventing the weakest part of the genetic regulatory networks from being expressed and preventing the appearance of a too many attractors in these networks. They have also a great influence on the chromatin clock, which ensures the updating of the genetic regulatory networks. The post-transcriptional inhibitory activity by the microRNAs, which is partly unspecific, is due firstly to their possibly direct negative action during translation by hybridizing tRNAs, especially those inside the mitochondrion, hence slowing mitochondrial respiration, and secondly to their action on a large number of putative m-RNA targets like those involved in immunetworks; We show that the circuits in the core of the interaction graphs are responsible for the small number of dedicated attractors that correspond to genetically controlled functions, partly due to a general filtering by the microRNAs. We analyze this influence as well as their impact on important functions like the control by the p53 network over the apoptosis/proliferation system and the homeostasis of the energy metabolism. In this last case, we show the role of two kinds of microRNAs, both involved in the control of the mitochondrial genome: (1) nuclear microRNAs, called mitoMirs, inhibiting mitochondrial genes and (2) putative mitochondrial microRNAs inhibiting the tRNAs functioning. PMID- 23982305 TI - Association of smoking with intraocular pressure in middle-aged and older Japanese residents. AB - OBJECTIVES: To clarify whether smoking was associated with elevated intraocular pressure (IOP) and to evaluate the interrelationship among IOP, blood viscosity, and smoking. METHODS: This cross-sectional study analyzed health examination data obtained between 2001 and 2004 from 1113 individuals (829 men and 284 women), ranging in age from 28 to 79 years, who had not undergone any ocular surgery or medical treatment for hypertension, ocular hypertension, and glaucoma. RESULTS: Multiple-regression analysis showed that systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI), and number of cigarettes smoked per day had a significantly positive association with IOP in men (P < 0.05). In women also, SBP, DBP, and BMI were positively related to IOP (P < 0.05). On the contrary, age had a significant negative association with IOP in both sexes (P < 0.01). Analysis of covariance and multiple logistic regression analyses showed that the adjusted mean IOP and the multivariate odds ratios for IOP increased with increasing cigarette consumption in men (P for trend = 0.01 and 0.06, respectively). Analysis of covariance found that smoking was significantly associated with both high IOP and high hematocrit in men (P for trend <0.05); however, the adjusted mean IOP values were higher in smokers than in nonsmokers, regardless of the hematocrit level. CONCLUSIONS: The results of this study suggested that the IOP level may be substantially affected by smoking habit in middle-aged and older Japanese men. PMID- 23982307 TI - APSLAP: an adaptive boosting technique for predicting subcellular localization of apoptosis protein. AB - Apoptotic proteins play key roles in understanding the mechanism of programmed cell death. Knowledge about the subcellular localization of apoptotic protein is constructive in understanding the mechanism of programmed cell death, determining the functional characterization of the protein, screening candidates in drug design, and selecting protein for relevant studies. It is also proclaimed that the information required for determining the subcellular localization of protein resides in their corresponding amino acid sequence. In this work, a new biological feature, class pattern frequency of physiochemical descriptor, was effectively used in accordance with the amino acid composition, protein similarity measure, CTD (composition, translation, and distribution) of physiochemical descriptors, and sequence similarity to predict the subcellular localization of apoptosis protein. AdaBoost with the weak learner as Random Forest was designed for the five modules and prediction is made based on the weighted voting system. Bench mark dataset of 317 apoptosis proteins were subjected to prediction by our system and the accuracy was found to be 100.0 and 92.4 %, and 90.1 % for self-consistency test, jack-knife test, and tenfold cross validation test respectively, which is 0.9 % higher than that of other existing methods. Beside this, the independent data (N151 and ZW98) set prediction resulted in the accuracy of 90.7 and 87.7 %, respectively. These results show that the protein feature represented by a combined feature vector along with AdaBoost algorithm holds well in effective prediction of subcellular localization of apoptosis proteins. The user friendly web interface "APSLAP" has been constructed, which is freely available at http://apslap.bicpu.edu.in and it is anticipated that this tool will play a significant role in determining the specific role of apoptosis proteins with reliability. PMID- 23982308 TI - Characterization of the carbohydrate components of Taenia solium oncosphere proteins and their role in the antigenicity. AB - This study examines the carbohydrate composition of Taenia solium whole oncosphere antigens (WOAs), in order to improve the understanding of the antigenicity of the T. solium. Better knowledge of oncosphere antigens is crucial to accurately diagnose previous exposure to T. solium eggs and thus predict the development of neurocysticercosis. A set of seven lectins conjugates with wide carbohydrate specificity were used on parasite fixations and somatic extracts. Lectin fluorescence revealed that D-mannose, D-glucose, D-galactose and N-acetyl D-galactosamine residues were the most abundant constituents of carbohydrate chains on the surface of T. solium oncosphere. Lectin blotting showed that posttranslational modification with N-glycosylation was abundant while little evidence of O-linked carbohydrates was observed. Chemical oxidation and enzymatic deglycosylation in situ were performed to investigate the immunoreactivity of the carbohydrate moieties. Linearizing or removing the carbohydrate moieties from the protein backbones did not diminish the immunoreactivity of these antigens, suggesting that a substantial part of the host immune response against T. solium oncosphere is directed against the peptide epitopes on the parasite antigens. Finally, using carbohydrate probes, we demonstrated for the first time that the presence of several lectins on the surface of the oncosphere was specific to carbohydrates found in intestinal mucus, suggesting a possible role in initial attachment of the parasite to host cells. PMID- 23982309 TI - Chromosomal inversions among insecticide-resistant strains of Anopheles stephensi Liston, a malaria mosquito. AB - Polytene chromosomes were prepared from the ovarian nurse cells of semi-gravid females of ten insecticide-resistant strains of Anopheles stephensi. Altogether, 16 heterozygous paracentric inversions, namely b/+ (11D-16C) in alphamethrin; i/+ (14B-18A) and h/+ (27B-28A) in DDT; j/+ (14A-16B) in chlorpyrifos; k/+ (11D-16B) in cyfluthrin; l/+ (11A-16C) in deltamethrin; m/+ (14B-15C) and e/+ (32A-33B) in bifenthrin; n/+ (12D-14B), f/+ (33A-36A) and g/+ (33C-34A) in propoxur; o/+ (11A 12D), h/+ (37A-37C) and i/+ (31C-32C) in temephos; d/+ (33D-35C) in carbofuran and a/+ (41C-43B) in neem strains, were reported. No inversions were observed in X chromosome so far. The frequency of inversions in different insecticides was found to be highest in the 2R arm, followed by the 3R arm. Such inversions were not reported in the corresponding susceptible strains or in the parental stocks. PMID- 23982310 TI - Vector movement underlies avian malaria at upper elevation in Hawaii: implications for transmission of human malaria. AB - With climate warming, malaria in humans and birds at upper elevations is an emerging infectious disease because development of the parasite in the mosquito vector and vector life history are both temperature dependent. An enhanced mosquito-movement model from climate warming predicts increased transmission of malaria at upper elevation sites that are too cool for parasite development in the mosquito vector. We evaluate this model with avian malaria (Plasmodium relictum) at 1,900-m elevation on the Island of Hawaii, with air temperatures too low for sporogony in the vector (Culex quinquefasciatus). On a well-defined site over a 14-year period, 10 of 14 species of native and introduced birds became infected, several epizootics occurred, and the increase in prevalence was driven more by resident species than by mobile species that could have acquired their infections at lower elevations. Greater movement of infectious mosquitoes from lower elevations now permits avian malaria to spread at 1,900 m in Hawaii, in advance of climate warming at that elevation. The increase in malaria at upper elevations due to dispersal of infectious mosquitoes is a real alternative to temperature for the increased incidence of human malaria in tropical highlands. PMID- 23982312 TI - Facile and green synthesis of palladium nanoparticles-graphene-carbon nanotube material with high catalytic activity. AB - We report a facile and green method to synthesize a new type of catalyst by coating Pd nanoparticles (NPs) on reduced graphene oxide (rGO)-carbon nanotube (CNT) nanocomposite. An rGO-CNT nanocomposite with three-dimensional microstructures was obtained by hydrothermal treatment of an aqueous dispersion of graphene oxide (GO) and CNTs. After the rGO-CNT composites have been dipped in K2PdCl4 solution, the spontaneous redox reaction between the GO-CNT and PdCl4(2-) led to the formation of nanohybrid materials consisting rGO-CNT decorated with 4 nm Pd NPs, which exhibited excellent and stable catalytic activity: the reduction of 4-nitrophenol to 4-aminophenol using NaBH4 as a catalyst was completed in only 20 s at room temperature, even when the Pd content of the catalyst was 1.12 wt%. This method does not require rigorous conditions or toxic agents and thus is a rapid, efficient, and green approach to the fabrication of highly active catalysts. PMID- 23982313 TI - Precisely designed layered silicate as an effective and highly selective CO2 adsorbent. AB - A layered silicate co-modified with amino and octadecyl groups exhibited efficient and very selective adsorption for CO2 over N2 and H2O at ambient pressure and temperature. PMID- 23982311 TI - Two different lineages of bedbug (Cimex lectularius) reflected in host specificity. AB - Co-speciation between host-parasite species is generally thought to result in mirror-image congruent phylogenies. For the last several centuries, many bat species have been turning synanthropic, especially those that are hosted by bedbugs in Europe. There is evidence of only limited gene flow from the population of people to the population of bats. This study was focused on comparison of survival, development, and the reproduction rate based on cross feeding experiments. In our research, we used two bedbugs groups of Cimex lectularius-bat- and human-associated and respectively as specific/non-specific host bat and commercial human blood. Both lineages show different behavior according to their host preferences. During the bat blood experiment, we found significant differences between both human- and bat-associated bedbugs (Log rank test fourth chi(2) = 9.93, p > 0.05; fifth chi(2) = 11.33, p < 0.05), while no differences occurred with the human blood experiment between the survival levels. In molting, differences between both groups were significant particularly in the case of the bat blood experiment (fourth chi(2) = 5.91, p < 0.05). In the case of the bat blood experiment, we found a higher probability of molting in bat associated groups than in human-associated groups. In the case of the human blood experiment, molting probability was stable in both specific and non-specific, showing similar pattern in both cases for all stages. Our results indicate an occurrence of two ecotypes within the one species C. lectularius. These findings support earlier data about morphological and mitochondrial DNA differences. The differentiation of both lineages fits the concept of specific host choice. PMID- 23982315 TI - The cathelicidin-BF Lys16 mutant Cbf-K16 selectively inhibits non-small cell lung cancer proliferation in vitro. AB - The 30-amino acid antimicrobial peptide Cbf-K16 is a cathelicidin-BF (BF-30) Lys16 mutant derived from the snake venom of Bungarus fasciatus. Our previous study found that BF-30 selectively inhibited the proliferation of the metastatic melanoma cell line B16F10 in vitro and in vivo, but had a negligible effect on human lung cells. In the present study, it was demonstrated for the first time that Cbf-K16 selectively inhibits the proliferation of lung carcinoma cells in vitro, with low toxicity to normal cells. The half-maximal inhibitory concentrations (IC50) of Cbf-K16 against H460 human non-small cell lung carcinoma cells and mouse Lewis lung cancer cells were only 16.5 and 10.5 uM, respectively, which were much less compared to that of BF-30 (45 and 40.3 uM). Data using a transmission electron microscope (TEM) assay showed that, at 20 and 40 uM, Cbf K16 induced the rupture of the cytoplasmic membrane, which was consistent with data obtained from lactate dehydrogenase (LDH) release assays. The LDH release increased from 17.8 to 52.9% as the duration and dosage of Cbf-K16 increased. Annexin V-fluorescein and propidium iodide staining assays indicated that there were no obvious apoptotic effects at the different dosages and times tested. In H460 cells, the rate of genomic DNA binding increased from 51.9 to 86.8% as the concentration of Cbf-K16 increased from 5 to 10 uM. These data indicate that Cbf K16 selectively inhibits the proliferation of lung carcinoma cells via cytoplasmic membrane permeabilization and DNA binding, rather than apoptosis. Although Cbf-K16 displayed significant cytotoxic activity (40 uM) against tumor cells, in splenocytes no significant inhibitory effect was observed and hemolysis was only 5.6%. These results suggest that Cbf-K16 is a low-toxicity anti-lung cancer drug candidate. PMID- 23982316 TI - Association between increased epicardial adipose tissue volume and coronary plaque composition. AB - To assess the relationship between epicardial adipose tissue volume (EATV) and plaque vulnerability in significant coronary stenosis using a 40-MHz intravascular ultrasound (IVUS) imaging system (iMap-IVUS), we analyzed 130 consecutive patients with coronary stenosis who underwent dual-source computed tomography (CT) and cardiac catheterization. Culprit lesions were imaged by iMap IVUS before stenting. The iMAP-IVUS system classified coronary plaque components as fibrous, lipid, necrotic, or calcified tissue, based on the radiofrequency spectrum. Epicardial adipose tissue was measured as the tissue ranging from -190 to -30 Hounsfield units. EATV, calculated as the sum of the fat areas on short axis images, was 85.0 +/- 34.0 cm(3). There was a positive correlation between EATV and the percentage of necrotic plaque tissue (R (2) = 0.34, P < 0.01), while there was a negative correlation between EATV and the percentage of fibrous tissue (R (2) = 0.24, P < 0.01). Multivariate analysis revealed that an increased low-density lipoprotein cholesterol level (beta = 0.15, P = 0.03) and EATV (beta = 0.14, P = 0.02) were independently associated with the percentage of necrotic plaque tissue. An increase in EATV was associated with the development of coronary atherosclerosis and, potentially, with the most dangerous type of plaque. PMID- 23982317 TI - Intravascular ultrasound morphology of culprit lesions and clinical demographics in patients with acute coronary syndrome in relation to low-density lipoprotein cholesterol levels at onset. AB - Despite current standards of care aimed at achieving targets for low-density lipoprotein cholesterol (LDL-C), many patients remain at high residual risk of cardiovascular events. We sought to assess the LDL-C-dependent differences in culprit intravascular ultrasound (IVUS) morphologies and clinical characteristics in patients with acute coronary syndrome (ACS). Eighty-six consecutive ACS patients whose culprit lesions imaged by preintervention IVUS were divided into two groups based on the fasting LDL-C level on admission: a low-LDL-C group (LDL C <2.6 mmol/l, n = 45) and a high-LDL-C group (LDL-C >=2.6 mmol/l, n = 41). Patients with stable angina with LDL-C <2.6 mmol/l (n = 30) were also enrolled as an age- and gender-matched control. The low-LDL-C ACS group was significantly older (72 +/- 12 vs 64 +/- 14 years, P = 0.007) and more diabetic (47 % vs 15 %, P = 0.001). Importantly, IVUS morphologies were comparable between low- and high LDL-C ACS groups (all P not significant), whereas culprit plaque was more hypoechoic and less calcified in the low-LDL-C ACS group than in the low-LDL-C stable angina group. Furthermore, compared with the low-LDL-C ACS nondiabetic group, the low-LDL-C ACS diabetic group was more obese, more triglyceride rich (1.3 +/- 0.6 vs 0.9 +/- 0.4 mmol/l, P = 0.003), and more endothelially injured, but no different for the culprit IVUS morphologies. In multivariate analysis, diabetes was independently associated with a low LDL-C level on admission in patients with ACS. There was no relationship between the LDL-C level at onset and culprit-plaque IVUS morphologies in ACS patients, although culprit plaque in the low-LDL-C ACS group was more vulnerable than in the low-LDL-C stable angina group. In patients with low-LDL-C levels, diabetes with atherogenic dyslipidemia might be the key residual risk. PMID- 23982318 TI - Histone deacetylase inhibitor suppresses virus-induced proinflammatory responses and type 1 diabetes. AB - Microbial infections are hypothesized to play a key role in the mechanism leading to type 1 diabetes (T1D). We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced islet destruction to better understand how virus infection triggers T1D. Inoculation of the LEW1.WR1 rat with KRV results in systemic inflammation followed by insulitis and islet destruction 2-4 weeks post-infection. In this study, we evaluated the effect of treatment with the anti-inflammatory histone deacetylase inhibitor (HDACi) ITF-2357 on KRV-induced immunity and disease progression. Administering LEW1.WR1 rats with KRV plus ITF-2357 on 14 consecutive days beginning on the day of infection protected animals from islet infiltration and T1D. ITF-2357 reversed KRV-induced T and B cell accumulation in the spleen or pancreatic lymph nodes on day 5 following infection. Moreover, ITF-2357 reduced the expression level of KRV-induced p40 subunit of IL-12/IL-23 in spleen cells in vitro and in the peripheral blood in vivo. ITF-2357 suppressed the KRV-induced expression of transcripts for IRF-7 in the rat INS-1 beta cell line. ITF-2357 increased the virus-induced IL-6 gene expression in the spleen, but did not alter the ability of LEW1.WR1 rats to develop normal KRV-specific humoral and cellular immune responses and clear the virus from the pancreatic lymph nodes, spleen, and serum. Finally, ITF-2357 reversed virus-induced modulation of bacterial communities in the intestine early following infection. The data suggest that targeting innate immune pathways with inhibitors of HDAC might represent an efficient therapeutic strategy for preventing T1D. KEY MESSAGE: Microbial infections have been implicated in triggering type 1 diabetes in humans and animal models. The LEW1.WR1 rat develops inflammation and T1D following infection with Kilham rat virus. The histone deacetylase inhibitor ITF-2357 suppresses virus-induced inflammation and prevents diabetes. ITF-2357 prevents T1D without altering virus-specific adaptive immunity or virus clearance. ITF-2357 therapy may be an efficient approach to prevent T1D in genetically susceptible individuals. PMID- 23982319 TI - Neuregulin1beta1 antagonizes apoptosis via ErbB4-dependent activation of PI3 kinase/Akt in APP/PS1 transgenic mice. AB - Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid protein (Abeta) and extensive neuronal cell death. Apoptosis plays a crucial role in loss of neurons in AD. Neuregulin1 (NRG1) has been found to protect neurons from oxygen glucose deprivation induced apoptosis and hypoxia ischemia induced apoptosis. However, the relationship between NRG1 and apoptosis related protein expression in AD and its mechanism remain uncertain. The present study explores the effects of NRG1 on Abeta-induced apoptosis in AD. In this study, extracellular domain of NRG1beta1 (NRG1beta1-ECD) promoted the expression of p ErbB4 receptor, p-Akt and increased the level of Bcl-2 both in APP/PS1 transgenic mice and in vitro. In primary culture of neurons, the level of Bcl-2 protein decreased significantly after Abeta treatment. These changes were inhibited by pretreatment of neurons with NRG1beta1-ECD. A specific inhibitor of PI3 kinase/Akt pathway, wortmannin, significantly abrogated the effects of NRG1beta1 ECD on p-Akt and Bcl-2 levels. Furthermore, the expression of PI3-kinase/Akt by NRG1beta1-ECD was ErbB4-dependent. Our data demonstrated that NRG1beta1-ECD might serve as an obvious neuroprotection in AD, and the possible protective mechanism occurs most likely via ErbB4-dependent activation of PI3-kinase/Akt pathway. PMID- 23982321 TI - Trends in pediatric imaging: ultrasound. AB - For the last three decades, two-dimensional (2D) echocardiography and Doppler echocardiography have been the primary imaging modalities for the diagnosis and management of heart disease in infants, children, and adolescents. These methods are non-invasive, highly sensitive, and cost-effective, and widely available, making them very useful in clinical work. During this period, the anatomic and hemodynamic abnormalities associated with different congenital and acquired pediatric heart diseases have been well outlined by echocardiography. Recent advances in computer technology, signal processing, and transducer design have allowed the capabilities of pediatric echocardiography to be expanded beyond qualitative 2D imaging and blood flow Doppler analysis. New modalities such as three-dimensional echocardiography, tissue Doppler imaging and speckle tracking echocardiography have been used to evaluate parameters such as ventricular volume, myocardial velocity, regional strain, and strain rate, providing new insight into cardiovascular morphology and ventricular systolic and diastolic function. Accordingly, a comprehensive and sophisticated quantification of ventricular function is now part of most echocardiography protocols. Use of measurements adjusted for body size and age is common practice today. These developments have further strengthened the position of echocardiography in pediatric cardiology. PMID- 23982320 TI - Harpagophytum procumbens prevents oxidative stress and loss of cell viability in vitro. AB - Harpagophytum procumbens, popularly known as devil's claw, is a plant commonly used in the treatment of diseases of inflammatory origin. The anti-inflammatory effects of H. procumbens have been studied; however, the mechanism of action is not elucidated. It is known that excess of reactive oxygen and nitrogen species may contribute to increasing tissue damage due to inflammation. In the present study, we examined the effects of H. procumbens infusion, crude extract and fractions on lipid peroxidation (brain homogenates) induced by different pro oxidants (Fe(2+) or sodium nitroprusside) and the effects of ethyl acetate fraction (rich in phenolic compounds) on antioxidant defenses (catalase activity and thiol levels) and cell damage (brain cortical slices) induced by different pro-oxidants. All tested extracts of H. procumbens inhibited lipid peroxidation in a concentration-dependent manner. Furthermore, the ethyl acetate fraction had the highest antioxidant effects either by decreasing lipid peroxidation and cellular damage or restoring thiols levels and catalase activity. Taken together, our results showed that H. procumbens acts either by preventing oxidative stress or loss of cell viability. Thus, the previously reported anti-inflammatory effect of H. procumbens could also be attributed to its antioxidant activity. PMID- 23982322 TI - Diffusion-weighted MRI and optimal b-value for characterization of liver lesions. AB - BACKGROUND: Diffusion-weighted imaging (DWI) is commonly used to distinguish between benign and malignant liver lesions. However, different b-values are recommended. PURPOSE: To determine the most suitable b-value in DWI for differentiation of benign and malignant liver lesions. MATERIAL AND METHODS: A total of 124 lesions in 89 consecutive patients (43 men, 46 women; age, mean +/- standard deviation, 58 +/- 14 years) with a pathological or radiological diagnosis of malignant or benign focal liver lesions after magnetic resonance imaging (MRI) were included in this study. Routine abdominal MRI and DWI were performed using seven b-values (0, 50, 200, 400, 600, 800, 1000 s/mm(2)). Lesions were analyzed for benignity/malignity using apparent diffusion coefficient (ADC) values with 10 b-value combinations and by measuring the lesion/normal parenchyma ADC ratio. RESULTS: Mean ADC values were significantly different between malignant and benign lesions for all b-value combinations (P=0.000). The best b value combination was 0 and 800 (Az=0.935). Using lower b-values such as 0 and 50 together with higher b-values >= 600 s/mm(2) was beneficial (Az=0.928 and 0.927). Mean ADC values were approximately 13% (1-15%) higher in total when b=0 and b=50 s/mm(2) were included in multiple b-value combinations. CONCLUSION: In DWI, we recommend the use of b-values of 0 and 800 s/mm(2) as two b-values, or b=0, 50, 600, 800, and 1000 s/mm(2) as multiple b-values for distinguishing between benign and malignant liver lesions. Mean ADC value is 13% higher in total by additional use of b=0 and b=50 s/mm(2) in multiple b-value combinations. PMID- 23982323 TI - Laser-induced rotation and cooling of a trapped microgyroscope in vacuum. AB - Quantum state preparation of mesoscopic objects is a powerful playground for the elucidation of many physical principles. The field of cavity optomechanics aims to create these states through laser cooling and by minimizing state decoherence. Here we demonstrate simultaneous optical trapping and rotation of a birefringent microparticle in vacuum using a circularly polarized trapping laser beam--a microgyroscope. We show stable rotation rates up to 5 MHz. Coupling between the rotational and translational degrees of freedom of the trapped microgyroscope leads to the observation of positional stabilization in effect cooling the particle to 40 K. We attribute this cooling to the interaction between the gyroscopic directional stabilization and the optical trapping field. PMID- 23982324 TI - Ketamine for treatment-resistant depression: ready or not for clinical use? PMID- 23982325 TI - The type of adjuvant strongly influences the T-cell response during nanoparticle based immunization. AB - Potent vaccines require the ability to effectively induce immune responses. Especially for the control of infectious diseases with intracellular pathogens, like viruses or bacteria, potent T-cell responses are indispensable. Several delivery systems such as nanoparticles have been considered to boost the immunogenicity of pathogen derived peptides or subunits for the induction of potent T-cell responses. Since they can be further functionalized with immunostimulants, like Toll-like receptor (TLR) agonists, they improve the response by enhanced activation of the innate immune system. Currently, TLR agonists like unmethylated CpG oligonucleotides and the synthetic dsRNA derivate polyriboinosinic acid-polyribocytidylic acid (poly[I:C]) are widely used as vaccine adjuvants. CpG and poly(I:C) trigger different TLRs and therefore show differential signal transduction. Recently, we established biodegradable calcium phosphate (CaP) nanoparticles as potent T cell inducing vaccination vehicles. In this commentary we discuss the role of CpG and poly(I:C) for the effective induction of virus-specific T cells during immunization with CaP nanoparticles. The presented results underline the importance of the right formulation of vaccines for specific immunization purpose. PMID- 23982326 TI - Data fabrication and falsification and empiricist philosophy of science. AB - Scientists have rules pertaining to data fabrication and falsification that are enforced with significant punishments, such as loss of funding, termination of employment, or imprisonment. These rules pertain to data that describe observable and unobservable entities. In this commentary I argue that scientists would not adopt rules that impose harsh penalties on researchers for data fabrication or falsification unless they believed that an aim of scientific research is to develop true theories and hypotheses about entities that exist, including unobservable ones. This argument presents a challenge for constructive empiricists, such as van Fraassen. Constructive empiricists need to be able to explain why rules pertaining to data fabrication and falsification do not threaten their philosophy of science. PMID- 23982328 TI - Cytokinin-producing, plant growth-promoting rhizobacteria that confer resistance to drought stress in Platycladus orientalis container seedlings. AB - One of the proposed mechanisms through which plant growth-promoting rhizobacteria (PGPR) enhance plant growth is the production of plant growth regulators, especially cytokinin. However, little information is available regarding cytokinin-producing PGPR inoculation on growth and water stress consistence of forest container seedlings under drought condition. This study determined the effects of Bacillus subtilis on hormone concentration, drought resistance, and plant growth under water-stressed conditions. Although no significant difference was observed under well-watered conditions, leaves of inoculated Platycladus orientalis (oriental thuja) seedlings under drought stress had higher relative water content and leaf water potential compared with those of noninoculated ones. Regardless of water supply levels, the root exudates, namely sugars, amino acids and organic acids, significantly increased because of B. subtilis inoculation. Water stress reduced shoot cytokinins by 39.14 %. However, inoculation decreased this deficit to only 10.22 %. The elevated levels of cytokinins in P. orientalis shoot were associated with higher concentration of abscisic acid (ABA). Stomatal conductance was significantly increased by B. subtilis inoculation in well watered seedlings. However, the promoting effect of cytokinins on stomatal conductance was hampered, possibly by the combined action of elevated cytokinins and ABA. B. subtilis inoculation increased the shoot dry weight of well-watered and drought seedlings by 34.85 and 19.23 %, as well as the root by 15.445 and 13.99 %, respectively. Consequently, the root/shoot ratio significantly decreased, indicative of the greater benefits of PGPR on shoot growth than root. Thus, inoculation of cytokinin-producing PGPR in container seedlings can alleviate the drought stress and interfere with the suppression of shoot growth, showing a real potential to perform as a drought stress inhibitor in arid environments. PMID- 23982327 TI - Monitoring of the bacterial and fungal biodiversity and dynamics during Massa Medicata Fermentata fermentation. AB - The microbial community dynamics play an important role during Massa Medicata Fermentata (MMF) fermentation. In this study, bacterial and fungal communities were investigated based on the culture-dependent method and polymerase chain reaction-denaturing gradient gel electrophoresis analysis. Meanwhile the dynamic changes of digestive enzyme activities were also examined. Plating results showed that MMF fermentation comprised two stages: pre-fermentation stage (0-4 days) was dominated by bacterial community and post-fermentation stage (5-9 days) was dominated by fungal community. The amount of bacteria reached the highest copy number 1.2 * 10(10) CFU/g at day 2, but the fungi counts reached 6.3 * 10(5) CFU/g at day 9. A total of 170 isolates were closely related to genera Enterobacter, Klebsiella, Acinetobacter, Pseudomonas, Mucor, Saccharomyces, Rhodotorula, and Amylomyces. DGGE analysis showed a clear reduction of bacterial and fungal diversity during fermentation, and the dominant microbes belonged to genera Enterobacter, Pediococcus, Pseudomonas, Mucor, and Saccharomyces. Digestive enzyme assay showed filter paper activity; the activities of amylase, carboxymethyl cellulase, and lipase reached a peak at day 4; and the protease activity constantly increased until the end of the fermentation. In this study, we carried out a detailed and comprehensive analysis of microbial communities as well as four digestive enzymes' activities during MMF fermentation process. The monitoring of bacterial and fungal biodiversity and dynamics during MMF fermentation has significant potential for controlling the fermentation process. PMID- 23982329 TI - A new method for the determination of critical polyethylene glycol concentration for selective precipitation of DNA fragments. AB - Separation strategies based on size-selective precipitation of DNA fragments with polyethylene glycol (PEG) have been used for achieving desired DNA interval in automated sample preparation for next-generation sequencing. By varying PEG concentration, DNA fragments of different sizes can be precipitated onto surfaces of carboxyl-coated paramagnetic particles selectively, and therefore, the desired DNA interval can be obtained. However, one of the crucial points in this approach is to determine the critical PEG concentration for DNA fragment of a certain size. The aim of this work was to develop a convenient and reliable method for accurately determining the critical PEG concentration. In our method, at a fixed concentration of sodium chloride (NaCl), recovered DNA samples obtained with different PEG concentrations were directly quantified, and their concentrations as a function of the PEG concentration were fitted by the logistic function. The critical PEG value was easily and accurately determined from the fitted logistic function. The repeatability and stability of the critical PEG value were assessed, showing an excellent reliability of the method. Based on this method, critical PEG values of different-size DNA fragments were determined at different NaCl concentrations. The effectiveness of the method was also demonstrated by selective precipitation of DNA fragments. PMID- 23982330 TI - Diagnostic and therapeutic strategy and the most efficient prognostic factors of breast malignant fibrous histiocytoma. AB - We analyzed the clinicopathological features of 9 breast malignant fibrous histiocytoma (MFH) patients. Immunohistochemistry was used to make both diagnosis and differential diagnosis, and to identify prognostic factors. All tumors lacked epithelial markers but expressed mesenchymal markers, suggesting a mesenchymal origin. Of the five cases expressing Ki-67, two of three patients with axillary lymph node involvement died between 6-8 months, and two died at 17 and 26 months after diagnosis. The two remaining cases, with low Ki-67 expression, had no recurrent or metastatic disease at 145 months after diagnosis. Previous studies have shown that surgery is the primary treatment of choice, but no clear benefit from adjuvant chemotherapy was observed. We demonstrate that axillary lymph node involvement and high expression of Ki-67 are associated with poorer prognosis. A literature review indicates surgery remains the first choice for MFH, but benefits from adjuvant chemotherapy remain unclear. PMID- 23982334 TI - Effects of sex and season in haematological parameters and cellular composition of spleen and head kidney of pejerrey (Odontesthes bonariensis). AB - Phylogenetic diversity in fish determines high interspecific variability in morphology as well as in physiological parameters. Moreover, several haematological variables and the organ composition of haemolymphopoietic sites may vary according to sex or season. The aim of this study was to establish the haematological parameters and the cellular composition of haemolymphopoietic organs in Odontesthes bonariensis, a commercially valuable fish species in Argentina, and also to determine gender or seasonal variations. Haematocrit exhibited the highest value in summer, while haemoglobin concentration was greater in summer and autumn. Erythrocyte count was higher in spring than autumn and winter, but did not differ with summer. The increase in these variables in seasons with higher water temperatures might be a compensatory mechanism to compensate the lower level of oxygen in the environment. Leucocyte formula and blast haemolymphopoietic cells in spleen and head kidney also showed annual variations since cells related to specific immune response, i.e., lymphocytes and thrombocytes, decrease in winter, whereas cells of the non-specific immune pathways, such as granulocyte, rise. The elevation of a particular type of circulating leucocyte was preceded by an increase in values of its precursor in blood in the previous season. Both, spleen and head kidney were active in haemolymphopoiesis, although with some differences in their activity during different seasons. Males showed higher values of circulating lymphoblasts and granulocytes than females, whereas females exhibited higher values of thrombocytes. This study corroborates the high interspecific variations in haematological parameters in fish that underlines the needing of basic studies in order to assess fish health status in new promising species for aquaculture. PMID- 23982332 TI - Periodicity in tumor vasculature targeting kinetics of ligand-functionalized nanoparticles studied by dynamic contrast enhanced magnetic resonance imaging and intravital microscopy. AB - In the past two decades advances in the development of targeted nanoparticles have facilitated their application as molecular imaging agents and targeted drug delivery vehicles. Nanoparticle-enhanced molecular imaging of the angiogenic tumor vasculature has been of particular interest. Not only because angiogenesis plays an important role in various pathologies, but also since endothelial cell surface receptors are directly accessible for relatively large circulating nanoparticles. Typically, nanoparticle targeting towards these receptors is studied by analyzing the contrast distribution on tumor images acquired before and at set time points after administration. Although several exciting proof-of concept studies demonstrated qualitative assessment of relative target concentration and distribution, these studies did not provide quantitative information on the nanoparticle targeting kinetics. These kinetics will not only depend on nanoparticle characteristics, but also on receptor binding and recycling. In this study, we monitored the in vivo targeting kinetics of alphavbeta3-integrin specific nanoparticles with intravital microscopy and dynamic contrast enhanced magnetic resonance imaging, and using compartment modeling we were able to quantify nanoparticle targeting rates. As such, this approach can facilitate optimization of targeted nanoparticle design and it holds promise for providing more quantitative information on in vivo receptor levels. Interestingly, we also observed a periodicity in the accumulation kinetics of alphavbeta3-integrin targeted nanoparticles and hypothesize that this periodicity is caused by receptor binding, internalization and recycling dynamics. Taken together, this demonstrates that our experimental approach provides new insights in in vivo nanoparticle targeting, which may proof useful for vascular targeting in general. PMID- 23982333 TI - Thermosensitive mPEG-b-PA-g-PNIPAM comb block copolymer micelles: effect of hydrophilic chain length and camptothecin release behavior. AB - PURPOSE: Block copolymer micelles are extensively used as drug controlled release carriers, showing promising application prospects. The comb or brush copolymers are especially of great interest, whose densely-grafted side chains may be important for tuning the physicochemical properties and conformation in selective solvents, even in vitro drug release. The purpose of this work was to synthesize novel block copolymer combs via atom transfer radical polymerization, to evaluate its physicochemical features in solution, to improve drug release behavior and to enhance the bioavailablity, and to decrease cytotoxicity. METHODS: The physicochemical properties of the copolymer micelles were examined by modulating the composition and the molecular weights of the building blocks. A dialysis method was used to load hydrophobic camptothecin (CPT), and the CPT release and stability were detected by UV-vis spectroscopy and high-performance liquid chromatography, and the cytotoxicity was evaluated by MTT assays. RESULTS: The copolymers could self-assemble into well-defined spherical core-shell micelle aggregates in aqueous solution, and showed thermo-induced micellization behavior, and the critical micelle concentration was 2.96-27.64 mg L(-1). The micelles were narrow-size-distribution, with hydrodynamic diameters about 128-193 nm, depending on the chain length of methoxy polyethylene glycol (mPEG) blocks and poly(N isopropylacrylamide) (PNIPAM) graft chains or/and compositional ratios of mPEG to PNIPAM. The copolymer micelles could stably and effectively load CPT but avoid toxicity and side-effects, and exhibited thermo-dependent controlled and targeted drug release behavior. CONCLUSIONS: The copolymer micelles were safe, stable and effective, and could potentially be employed as CPT controlled release carriers. PMID- 23982335 TI - Manipulating the oxygen reduction activity of platinum shells with shape controlled palladium nanocrystal cores. AB - The oxygen reduction reaction (ORR) activities of Pt shells were found to have a strong dependence on the surface structure by depositing them on Pd nanocrystals with different shapes. PMID- 23982337 TI - RNA interference suppression of Nogo-66 receptor prevents Nogo-66-mediated inhibition of invasion and adhesion and simultaneously increases cell apoptosis in C6 cells. AB - Gliomas are the most common primary tumors of the central nervous system (CNS). Nogo-66 is an extracellular domain of Nogo-A, which can block axon regeneration in the CNS after trauma. Some studies have indicated that Nogo-A and its receptor (NgR) are expressed in tumor tissues; however, their roles in tumors are still unknown. We report the impact of Nogo-66 and NgR on the proliferation, apoptosis, adhesion and invasion of C6 glioma cells. Short hairpin RNA (shRNA)-triggered RNA interference was used to inhibit NgR expression in C6 cells. Then, an in vitro cell adhesion assay was performed to assess the effect of NgR downregulation on the adhesion ability of C6 cells. In addition, a chamber assay and a cell scratch assay were conducted to test invasion ability. The spontaneous apoptosis of C6 cells was examined by flow cytometry, western blotting and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. NgR downregulation resulted in a significant increase of C6 adhesion and invasion activity in the presence of Nogo-66, markedly inhibited proliferation and induced spontaneous apoptosis. In conclusion, knockdown of NgR enhanced invasion and adhesion but increased cell apoptosis in C6 cells, suggesting that Nogo-66/NgR might have complex effects on glioma cells. PMID- 23982336 TI - Mass spectrometry-based targeted proteomics as a tool to elucidate the expression and function of intestinal drug transporters. AB - Intestinal transporter proteins affect the oral bioavailability of many drugs in a significant manner. In order to estimate or predict their impact on oral drug absorption, data on their intestinal expression levels are needed. So far, predominantly mRNA expression data are available which are not necessarily correlated with the respective protein content. All available protein data were assessed by immunoblotting techniques such as Western blotting which both possess a number of limitations for reliable protein quantification. In contrast to this, mass spectrometry-based targeted proteomics may represent a promising alternative method to provide comprehensive protein expression data. In this review, we will summarize so far available intestinal mRNA and protein expression data for relevant human multidrug transporters. Moreover, recently observed mass spectrometry-based targeted proteomic data will be presented and discussed with respect to potential functional consequences. Associated to this, we will provide a short tutorial how to set up these methods and emphasize critical aspects in method development. Finally, potential limitations and pitfalls of this emerging technique will be discussed. From our perspective, LC-MS/MS-based targeted proteomics represents a valuable new method to comprehensively analyse the intestinal expression of transporter proteins. The resulting expression data are expected to improve our understanding about the intestinal processing of drugs. PMID- 23982338 TI - Histologic findings predictive of a diagnosis of de novo autoimmune hepatitis after liver transplantation in adults. AB - BACKGROUND: Autoimmune hepatitis (AIH) after liver transplantation has been defined histologically as a "hepatitic" pattern of injury, characterized by lymphoplasmacytic inflammation with necroinflammatory activity (NIA), comparable with findings seen in native livers. This definition, however, is difficult to apply in practice because specific histologic criteria are not clearly delineated. This study aimed to determine which histologic features correlated best with clinical and serologic features of dAIH. METHODS: Index liver biopsies from patients with autoimmune-like hepatitis transplanted for non-AIH in two centers (n=35 and 20) were reviewed. Histologic features were correlated with the clinical diagnosis of AIH based on a retrospective review of clinical and serologic data, including therapeutic response. RESULTS: A clinical diagnosis of AIH was retrospectively assigned to 24 of 35 (68%) and 18 of 20 (90%) patients, respectively (P=0.10). In multivariate analysis, centrilobular NIA and centrilobular plasma cell (PC) ratio of 30% to 50% were independently discriminating for a clinical diagnosis of AIH (P=0.04 and 0.05, respectively). The best level of predictability (99.6%) was mathematically achieved when severe centrilobular NIA and centrilobular PC ratio of 30% to 50% were both present. CONCLUSION: A histologic pattern of centrilobular injury including increased NIA and increased PC infiltration correlates with measurements of autoimmunity in liver recipients. It could be used to segregate cases for further study and introduced into the AIH scoring systems when applied in the context of liver transplantation. PMID- 23982339 TI - Pretransplantation erythropoiesis-stimulating agent hyporesponsiveness is associated with increased kidney allograft failure and mortality. AB - BACKGROUND: Poor response to erythropoiesis-stimulating agents (ESA) is associated with morbidity and mortality among dialysis patients. It is unclear whether the risk associated with poor ESA response during dialysis extends beyond kidney transplantation. We examined pretransplantation ESA response and its effect on allograft failure and mortality. METHODS: The cohort included all adult Medicare recipients from the U.S. Renal Data System who had received a kidney transplant during years 2000 to 2007 and had at least 6 months of hemodialysis immediately before transplantation. ESA hyporesponsiveness was primarily defined as a monthly ESA dose of 75,000 units or higher and hematocrit 33% or less for at least 3 consecutive months in the pretransplantation period. Crude and adjusted Cox proportional hazards models and Kaplan-Meier methods were used to estimate the effect of ESA hyporesponsiveness on allograft failure and all-cause mortality. RESULTS: The study group consisted of 36,450 patients; 1004 exhibited hyporesponsiveness. The adjusted hazard ratios (95% confidence interval) for allograft failure and mortality after transplantation were 1.23 (1.10-1.42) and 1.61 (1.43-1.81), respectively, supporting that poor ESA response during hemodialysis is associated with adverse posttransplantation outcomes. CONCLUSIONS: ESA hyporesponsiveness may be useful in identifying potential allograft recipients who are at high risk for subsequent morbidity and mortality and may benefit from more intensive pretransplantation and posttransplantation monitoring. PMID- 23982340 TI - OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. AB - BACKGROUND: The once-daily (QD), prolonged-release formulation of tacrolimus has been shown to improve adherence versus twice-daily (BD) tacrolimus. Treatment nonadherence in transplant recipients has been associated with poor graft outcomes. METHODS: This open-label, parallel-group study randomized adults with end-stage renal disease undergoing primary kidney transplantation or retransplantation to an initial dose of tacrolimus BD 0.2 mg/kg per day (Arm 1; n=309), QD 0.2 mg/kg per day (Arm 2; n=302), QD 0.3 mg/kg per day (Arm 3; n=304) all with mycophenolate mofetil and corticosteroids (tapered) over 24 weeks, or tacrolimus QD 0.2 mg/kg per day with mycophenolate mofetil, basiliximab, and corticosteroids given only perioperatively (Arm 4; n=283). The primary composite endpoint (efficacy failure; per protocol set) was defined as graft loss, biopsy confirmed acute rejection, or graft dysfunction at week 24. Graft dysfunction was defined as estimated glomerular filtration rate Modification of Diet in Renal Disease-4 formula of less than 40 mL/min/1.73 m(2). The prespecified noninferiority margin was 12.5%. RESULTS: The per protocol set included 976 patients: 237, 263, 246, and 230 patients in Arms 1 to 4, respectively. Noninferiority of the composite endpoint was demonstrated for Arm 2 versus Arm 1; Kaplan-Meier estimates of efficacy failure were 42.2% and 40.6%, respectively (difference, -1.6%; 95% confidence interval [CI], -12.2% to 9.0%). Noninferiority to Arm 1 was not confirmed for Arm 3 (difference, -3.5%; 95% CI, -13.6% to 6.6%) or Arm 4 (difference, -7.1%; 95% CI, -16.1% to 1.9%). Graft dysfunction (estimated glomerular filtration rate <40 mL/min/1.73 m(2)) was the main determinant of composite-endpoint efficacy failure across all arms. CONCLUSIONS: In patients representative of the European kidney transplant population, tacrolimus QD-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day tacrolimus BD. PMID- 23982341 TI - Predictors and consequences of fatigue in prevalent kidney transplant recipients. AB - BACKGROUND: Fatigue has been underinvestigated in stable kidney transplant recipients (KTRs). The objectives of this study were to investigate the nature, severity, prevalence, and clinical awareness of fatigue in medically stable KTRs, examine the impact of fatigue on quality of life (QoL), and explore the underlying causes of posttransplantation fatigue. METHODS: This single-center cross-sectional study enrolled 106 stable KTRs. Multi-dimensional Fatigue Inventory-20 was used to measure five fatigue dimensions: General Fatigue, Physical Fatigue, Reduced Activity, Reduced Motivation, and Mental Fatigue. Clinical awareness of fatigue was determined by reviewing medical records. QoL was assessed by Medical Outcomes Study Short Form-36 Questionnaire. Demographic, clinical, psychosocial, and behavioral parameters were evaluated as fatigue predictors. RESULTS: Fatigue was found in 59% of KTRs. Only 13% had this symptom documented in medical records. Fatigue in KTRs was in the same range as chronically unwell patients, with Physical Fatigue, Reduced Activity, and Reduced Motivation approached levels observed in chronic fatigue syndrome. All fatigue dimensions significantly and inversely correlated with QoL (P<0.001 for all associations). Demographic predictors were male, older age, and non-Caucasian ethnicity (P<=0.05 for all associations). Clinical predictors included elevated highly sensitive C-reactive protein (inflammation), decreased estimated glomerular filtration rate (graft dysfunction), and reduced lean tissue index (P<=0.05 for all associations). Psychosocial and behavioral predictors were inferior sleep quality, anxiety, and depression (P<0.01 for all associations). CONCLUSIONS: Fatigue is common and pervasive in clinically stable KTRs. It is strongly associated with reduced QoL. This study identified modifiable fatigue predictors and sets the scene for future interventional studies. PMID- 23982342 TI - Exploratory use of cardiovascular magnetic resonance imaging in liver transplantation: a one-stop shop for preoperative cardiohepatic evaluation. AB - BACKGROUND: Preoperative cardiovascular risk stratification in orthotopic liver transplantation candidates has proven challenging due to limitations of current noninvasive modalities. Additionally, the preoperative workup is logistically cumbersome and expensive given the need for separate cardiac, vascular, and abdominal imaging. We evaluated the feasibility of a "one-stop shop" in a magnetic resonance suite, performing assessment of cardiac structure, function, and viability, along with simultaneous evaluation of thoracoabdominal vasculature and liver anatomy. METHODS: In this pilot study, patients underwent steady-state free precession sequences and stress cardiac magnetic resonance (CMR), thoracoabdominal magnetic resonance angiography, and abdominal magnetic resonance imaging (MRI) on a standard MRI scanner. Pharmacologic stress was performed using regadenoson, adenosine, or dobutamine. Viability was assessed using late gadolinium enhancement. RESULTS: Over 2 years, 51 of 77 liver transplant candidates (mean age, 56 years; 35% female; mean Model for End-stage Liver Disease score, 10.8; range, 6-40) underwent MRI. All referred patients completed standard dynamic CMR, 98% completed stress CMR, 82% completed late gadolinium enhancement for viability, 94% completed liver MRI, and 88% completed magnetic resonance angiography. The mean duration of the entire study was 72 min, and 45 patients were able to complete the entire examination. Among all 51 patients, 4 required follow-up coronary angiography (3 for evidence of ischemia on perfusion CMR and 1 for postoperative ischemia), and none had flow-limiting coronary disease. Nine proceeded to orthotopic liver transplantation (mean 74 days to transplantation after MRI). There were six ascertained mortalities in the nontransplant group and one death in the transplanted group. Explant pathology confirmed 100% detection/exclusion of hepatocellular carcinoma. No complications during CMR examination were encountered. CONCLUSIONS: In this proof-of-concept study, it appears feasible to perform a comprehensive, efficient, and safe preoperative liver transplant imaging in a CMR suite-a one-stop shop, even in seriously ill patients. PMID- 23982343 TI - The missing "link": an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation. AB - Proteoglycan (PG) synthesis begins with the sequential addition of a "linker chain", made up of four sugar residues, to a specific region of a core protein. Defects in the enzymes catalyzing steps two to four of the linker chain synthesis have been shown to cause autosomal recessive human phenotypes while no mutation has yet been reported in humans for the xylosyltransferases 1 and 2 (XT1 and XT2), the initiating enzymes in the linker chain formation. Here, we present a consanguineous Turkish family with two affected individuals presenting with short stature, distinct facial features, alterations of fat distribution, and moderate intellectual disability. X-rays showed only mild skeletal changes in the form of a short femoral neck, stocky and plump long bones and thickened ribs. Using a combination of whole-exome sequencing (WES), determination of homozygous stretches by WES variants, and classical linkage analysis, we identified the homozygous missense mutation c.C1441T in XYLT1, encoding XT1, within a large homozygous stretch on chromosome 16p13.12-p12.1. The mutation co-segregated with the phenotype in the family, is not found in over 13,000 alleles in the exome variant server and is predicted to change a highly conserved arginine at position 481 (p.R481W) located in the putative catalytical domain. Immunostaining of primary patient fibroblasts showed a loss of predominance of Golgi localization in mutant cells. Moreover, western blot analysis of decorin in cell culture supernatant demonstrated glycosylation differences between patient and control cells. Our data provide evidence that functional alterations of XT1 cause an autosomal recessive short stature syndrome associated with intellectual disability. PMID- 23982344 TI - Gold complexes inhibit the aggregation of prion neuropeptides. AB - Prion diseases are characterized by conformational conversion of prion protein from a normal cellular form to an abnormal scrapie isoform (PrP(Sc)). PrP106-126 is a prion neuropeptide and an accepted model used to study the characteristics of PrP(Sc) because such a model has biological and physiochemical properties similar to those of PrP(Sc). Some metal complexes have a strong binding affinity for PrP106-126 and a good inhibitory effect against amyloid fibril formation. However, the effects of the metal ligand configuration on peptide binding and aggregation are not well known. To investigate interaction and peptide aggregation between prion neuropeptides and two gold complexes with different ligand configurations ([Au(bpy)Cl2]PF6 and [Au(dien)Cl]Cl2, where bpy is 2,2' bipyridine and dien is diethylenetriamine), six prion peptides with either a His111-mutated or a Met109/112-mutated residue were used in this study. The selection of the mutant was based on the corresponding neuropeptide from other species. The results showed that the aromatic gold complex [Au(bpy)Cl2]PF6 exhibits better binding affinity and a better inhibitory effect against peptide aggregation than the tridentate complex [Au(dien)Cl]Cl2. For the sequence specific PrP106-126 and its mutants, His111 plays the most important role in peptide aggregation and binding affinity. Furthermore, Met112 has a greater effect on the binding affinity than Met109. Compared with the mutated short 14 amino acid peptides, the hydrophobic region of PrP106-126 contributes to both binding affinity and self-aggregation behavior. This work will help to understand and develop potential metallodrugs against amyloid disorder. PMID- 23982345 TI - Identification and characterization of an unusual metallo-beta-lactamase from Serratia proteamaculans. AB - Metallo-beta-lactamases (MBLs) are a family of metalloenzymes that are capable of hydrolyzing beta-lactam antibiotics and are an important means by which bacterial pathogens use to inactivate antibiotics. A database search of the available amino acid sequences from Serratia proteamaculans indicates the presence of an unusual MBL. A full length amino acid sequence alignment indicates overall homology to B3 type MBLs, but also suggests considerable variations in the active site, notably among residues that are relevant to metal ion binding. Steady-state kinetic measurements further indicate functional differences and identify two relevant pK a values for catalysis (3.8 for the enzyme-substrate complex and 7.8 for the free enzyme) and a preference for penams with modest reactivity towards some cephalosporins. An analysis of the metal ion content indicates the presence of only one zinc ion per active site in the resting enzyme. In contrast, kinetic data suggest that the enzyme may operate as a binuclear enzyme, and it is thus proposed that a catalytically active di-Zn(2+) center is formed only once the substrate is present. PMID- 23982346 TI - Janus nanogels of PEGylated Taxol and PLGA-PEG-PLGA copolymer for cancer therapy. AB - Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. PMID- 23982347 TI - Trinuclear zinc complexes for biologically relevant MU3-oxoanion binding and carbon dioxide fixation. AB - Tremendous efforts have been made to model multinuclear zinc enzymes. Despite such efforts, it remains a challenge to design single molecules that stabilize MU3-oxoanion-bridged trinuclear zinc cores as analogues of enzymatic active sites. The conversion of carbon dioxide to carbonates is a biological process mediated by carbonic anhydrases and a natural process for large-scale carbon dioxide fixation. Here we report a trinuclear zinc scaffold for capturing biologically relevant MU3-oxoanions, such as phosphate and carbonate, and its ability to catalytically convert carbon dioxide to carbonates. Structurally characterized {Zn3(MU3-PO4)} and {Zn3(MU3-CO3)} cores are observed in solution by nuclear magnetic resonance and high-resolution mass spectrometry. The activity of the MU3-carbonate unit can be sterically controlled, which makes the carbon dioxide fixation cycle feasible. Our results suggest that this trinuclear zinc scaffold catalytically converts carbon dioxide to carbonates under mild conditions and provides a good model for studying oxoanion-bridged zinc cores in solution. PMID- 23982353 TI - A garden in Nassau: Winslow Homer. PMID- 23982354 TI - Infectious disease experts offer laboratory testing guide. PMID- 23982355 TI - FDA might consider restrictions on menthol cigarettes. PMID- 23982356 TI - FDA: Acetaminophen may trigger serious skin problems. PMID- 23982363 TI - Revealing the incidentalome when targeting the tumor genome. PMID- 23982364 TI - A piece of my mind. The road back to the bedside. PMID- 23982365 TI - Laparoscopic cholecystectomy, intraoperative cholangiograms, and common duct injuries. PMID- 23982366 TI - Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. AB - IMPORTANCE: The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations. OBJECTIVE: To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics. DESIGN, SETTING, AND PATIENTS: Single center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012). INTERVENTIONS: In the study's first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]). RESULTS: In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events. CONCLUSION AND RELEVANCE: In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, respectively. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01441180. PMID- 23982367 TI - Association between cholecystectomy with vs without intraoperative cholangiography and risk of common duct injury. AB - IMPORTANCE: Significant controversy exists regarding routine intraoperative cholangiography in preventing common duct injury during cholecystectomy. OBJECTIVE: To investigate the association between intraoperative cholangiography use during cholecystectomy and common duct injury. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of all Texas Medicare claims data from 2000 through 2009. We identified Medicare beneficiaries 66 years or older who underwent inpatient or outpatient cholecystectomy for biliary colic or biliary dyskinesia, acute cholecystitis, or chronic cholecystitis. We compared results from multilevel logistic regression models to the instrumental variable analyses. INTERVENTIONS: Intraoperative cholangiography use during cholecystectomy was determined at the level of the patients (yes/no), hospitals (percentage intraoperative cholangiography use for all cholecystectomies at the hospital), and surgeons (percentage use for all cholecystectomies performed by the surgeon). Percentage of use at the hospital and percentage of use by surgeon were the instrumental variables. MAIN OUTCOMES AND MEASURES: Patients with claims for common duct repair operations within 1 year of cholecystectomy were considered as having major common duct injury. RESULTS: Of 92,932 patients undergoing cholecystectomy, 37,533 (40.4%) underwent concurrent intraoperative cholangiography and 280 (0.30%) had a common duct injury. The common duct injury rate was 0.21% among patients with intraoperative cholangiography and 0.36% among patients without it. In a logistic regression model controlling for patient, surgeon, and hospital characteristics, the odds of common duct injury for cholecystectomies performed without intraoperative cholangiography were increased compared with those performed with it (OR, 1.79 [95% CI, 1.35-2.36]; P < .001). When confounding was controlled with instrumental variable analysis, the association between cholecystectomy performed without intraoperative cholangiography and duct injury was no longer significant (OR, 1.26 [95% CI, 0.81 1.96]; P = .31). CONCLUSIONS AND RELEVANCE: When confounders were controlled with instrumental variable analysis, there was no statistically significant association between intraoperative cholangiography and common duct injury. Intraoperative cholangiography is not effective as a preventive strategy against common duct injury during cholecystectomy. PMID- 23982369 TI - Changes in health care spending and quality for Medicare beneficiaries associated with a commercial ACO contract. AB - IMPORTANCE: In a multipayer system, new payment incentives implemented by one insurer for an accountable care organization (ACO) may also affect spending and quality of care for another insurer's enrollees served by the ACO. Such spillover effects reflect the extent of organizational efforts to reform care delivery and can contribute to the net impact of ACOs. OBJECTIVE: We examined whether the Blue Cross Blue Shield (BCBS) of Massachusetts' Alternative Quality Contract (AQC), an early commercial ACO initiative associated with reduced spending and improved quality for BCBS enrollees, was also associated with changes in spending and quality for Medicare beneficiaries, who were not covered by the AQC. DESIGN, SETTING, AND PARTICIPANTS: Quasi-experimental comparisons from 2007-2010 of elderly fee-for-service Medicare beneficiaries in Massachusetts (1,761,325 person years) served by 11 provider organizations entering the AQC in 2009 or 2010 (intervention group) vs beneficiaries served by other providers (control group). Using a difference-in-differences approach, we estimated changes in spending and quality for the intervention group in the first and second years of exposure to the AQC relative to concurrent changes for the control group. Regression and propensity score methods were used to adjust for differences in sociodemographic and clinical characteristics. MAIN OUTCOMES AND MEASURES: The primary outcome was total quarterly medical spending per beneficiary. Secondary outcomes included spending by setting and type of service, 5 process measures of quality, potentially avoidable hospitalizations, and 30-day readmissions. RESULTS: Before entering the AQC, total quarterly spending per beneficiary for the intervention group was $150 (95% CI, $25-$274) higher than for the control group and increased at a similar rate. In year 2 of the intervention group's exposure to the AQC, this difference was reduced to $51 (95% CI, -$109 to $210; P = .53), constituting a significant differential change of -$99 (95% CI, -$183 to -$16; P = .02) or a 3.4% savings relative to an expected quarterly mean of $2895. Savings in year 1 were not significant (differential change, -$34; 95% CI, -$83 to $16; P = .18). Year 2 savings derived largely from lower spending on outpatient care (differential change, -$73; 95% CI, -$97 to -$50; P < .001), particularly for beneficiaries with 5 or more conditions, and included significant differential changes in spending on procedures, imaging, and tests. Annual rates of low density lipoprotein cholesterol testing differentially improved for beneficiaries with diabetes in the intervention group by 3.1 percentage points (95% CI, 1.4-4.8 percentage points; P < .001) and for those with cardiovascular disease by 2.5 percentage points (95% CI, 1.1-4.0 percentage points; P < .001), but performance on other quality measures did not differentially change. CONCLUSIONS AND RELEVANCE: The AQC was associated with lower spending for Medicare beneficiaries but not with consistently improved quality. Savings among Medicare beneficiaries and previously demonstrated savings among BCBS enrollees varied similarly across settings, services, and time, suggesting that organizational responses were associated with broad changes in patient care. PMID- 23982370 TI - Does this patient with shoulder pain have rotator cuff disease?: The Rational Clinical Examination systematic review. AB - IMPORTANCE: Rotator cuff disease (RCD) is the most common cause of shoulder pain seen by physicians. OBJECTIVE: To perform a meta-analysis to identify the most accurate clinical examination findings for RCD. DATA SOURCES: Structured search in MEDLINE, EMBASE, and CINAHL from their inception through May 2013. STUDY SELECTION: For inclusion, a study must have met the following criteria: (1) description of history taking, physical examination, or clinical tests concerning RCD; (2) detailing of sensitivity and specificity; (3) use of a reference standard with diagnostic criteria prespecified; (4) presentation of original data, or original data could be obtained from the authors; and (5) publication in a language mastered by one of the authors (Danish, Dutch, English, French, German, Norwegian, Spanish, Swedish). MAIN OUTCOMES AND MEASURES: Likelihood ratios (LRs) of symptoms and signs of RCD or of a tear, compared with an acceptable reference standard; quality scores assigned using the Rational Clinical Examination score and bias evaluated with the Quality Assessment of Diagnostic Accuracy Studies tool. RESULTS: Twenty-eight studies assessed the examination of referred patients by specialists. Only 5 studies reached Rational Clinical Examination quality scores of level 1-2. The studies with quality scores of level 1-2 included 30 to 203 shoulders with the prevalence of RCD ranging from 33% to 81%. Among pain provocation tests, a positive painful arc test result was the only finding with a positive LR greater than 2.0 for RCD (3.7 [95% CI, 1.9 7.0]), and a normal painful arc test result had the lowest negative LR (0.36 [95% CI, 0.23-0.54]). Among strength tests, a positive external rotation lag test (LR, 7.2 [95% CI, 1.7-31]) and internal rotation lag test (LR, 5.6 [95% CI, 2.6-12]) were the most accurate findings for full-thickness tears. A positive drop arm test result (LR, 3.3 [95% CI, 1.0-11]) might help identify patients with RCD. A normal internal rotation lag test result was most accurate for identifying patients without a full-thickness tear (LR, 0.04 [95% CI, 0.0-0.58]). CONCLUSIONS AND RELEVANCE: Because specialists performed all the clinical maneuvers for RCD in each of the included studies with no finding evaluated in more than 3 studies, the generalizability of the results to a nonreferred population is unknown. A positive painful arc test result and a positive external rotation resistance test result were the most accurate findings for detecting RCD, whereas the presence of a positive lag test (external or internal rotation) result was most accurate for diagnosis of a full-thickness rotator cuff tear. PMID- 23982368 TI - Association between a genetic variant related to glutamic acid metabolism and coronary heart disease in individuals with type 2 diabetes. AB - IMPORTANCE: Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals. OBJECTIVE: To identify genetic determinants of CHD that are specific to patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS: We studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses' Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001 2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1517 CHD cases and 2671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 nondiabetic CHD cases and 1637 nondiabetic CHD-negative controls from the Nurses' Health Study and Health Professionals Follow-up Study cohorts. Exposures included 2,543,016 common genetic variants occurring throughout the genome. MAIN OUTCOMES AND MEASURES: Coronary heart disease--defined as fatal or nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. RESULTS: A variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabetic participants, with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95% CI, 1.22-1.51]; P = 2 * 10( 8)). No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95% CI, 0.87-1.13]; P = .89), consistent with a significant gene * diabetes interaction on CHD risk (P = 2 * 10(-4)). Compared with protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate ammonia ligase (GLUL) gene in human endothelial cells (P = .0048). A decreased ratio between plasma levels of gamma-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029). CONCLUSION AND RELEVANCE: A single-nucleotide polymorphism (rs10911021) was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes and was functionally related to glutamic acid metabolism, suggesting a mechanistic link. PMID- 23982371 TI - Acute abdominal pain and abnormal CT findings. PMID- 23982372 TI - Gastroenteritis hospitalizations in older children and adults in the United States before and after implementation of infant rotavirus vaccination. PMID- 23982373 TI - Vitamin D supplementation during first 12 months of life. PMID- 23982374 TI - Vitamin D supplementation during first 12 months of life--reply. PMID- 23982375 TI - Reductions in funding for medical research. PMID- 23982376 TI - Reductions in funding for medical research. PMID- 23982377 TI - Reductions in funding for medical research. PMID- 23982378 TI - Autism and Lyme disease. PMID- 23982379 TI - Reductions in funding for medical research--reply. PMID- 23982381 TI - Autism and Lyme disease--reply. PMID- 23982383 TI - The Fourth of July in 1913. PMID- 23982384 TI - JAMA patient page. Tamoxifen update. PMID- 23982385 TI - Impact of cow's milk allergy on enterocolitis associated with Hirschsprung's disease. AB - PURPOSE: To investigate the impact of cow's milk allergy (CMA) on infants with Hirschsprung's disease (HD). METHODS: Twenty-four patients, who developed gastrointestinal symptoms before the age of 60 days and underwent surgery for HD in the period between January 2003 and December 2012, were enrolled in this study. They were divided into two groups based on CMA-related findings: stimulation index of lymphocyte stimulation test >300 % and the presence of eosinophilic infiltration in the resected colon. Ten patients were determined specimen as not having CMA (Group A), because they did not satisfy any of the criteria. The remaining 14 were determined as having possible CMA (Group B), because they satisfied either or both findings. Patient background characteristics, pre- and postoperative clinical history, and laboratory data were compared between Groups A and B. RESULTS: Pre- and postoperative enterocolitis did not occur in Group A patients. Postoperative enterocolitis was more frequent in Group B than in Group A (p = 0.04). Other clinical and laboratory data did not show significant difference between the two groups. CONCLUSION: CMA is a possible risk factor for postoperative enterocolitis in patients with HD. PMID- 23982386 TI - External stabilization for severe tracheobronchomalacia using separated ring reinforced ePTFE grafts is effective and safe on a long-term basis. AB - PURPOSE: Tracheobronchomalacia is a respiratory disorder that results from abnormal cartilage development. Since 2003, we have performed external stabilization for severe tracheobronchomalacia using separated ring-reinforced expanded polytetrafluoroethylene (ePTFE) grafts. The aim of this study was to analyze the short- and long-term outcomes of our procedure. METHODS: We reviewed the charts of patients who underwent external tracheobronchial stabilization from January 2003 through December 2012. Separated ring-reinforced ePTFE grafts were fixed to the anterior and posterior lesions of malacia independently, with confirmation of a well-opened lumen by bronchoscopy. RESULTS: Five children with severe tracheobronchomalacia underwent six operations. The median follow-up period was 43 months (range 11-109 months). There was no operative mortality associated with the procedure. One patient required removal of a section of the graft owing to the development of bronchial granulation tissue at the site of fixation. All patients showed improved respiratory function, and tracheal growth was confirmed by follow-up computed tomography. CONCLUSIONS: External stabilization with separated ring-reinforced ePTFE grafts for severe tracheobronchomalacia is effective, less invasive than alternatives and preserves the growth potential of the affected airway segment. PMID- 23982387 TI - Impact of the histological type on the prognosis of patients with prenatally diagnosed sacrococcygeal teratomas: the results of a nationwide Japanese survey. AB - PURPOSE: To identify the impact of the histological diagnosis on the prognosis of prenatally diagnosed sacrococcygeal teratoma (SCT), we analyzed the data obtained during prenatal surveillance and assessed the postnatal outcomes in a large cohort of fetuses with SCT in Japan. METHODS: A nationwide retrospective cohort study was conducted among 97 fetuses prenatally diagnosed with SCT between 2000 and 2009. Of these, 84 had a histological diagnosis. In addition, we conducted a second surveillance program of the prognosis of 72 patients who were reported to be alive at the initial surveillance conducted 2 years previously. RESULTS: The tumors comprised 51 (61 %) mature teratomas, 33 (39 %) immature teratomas and 0 (0 %) malignant teratomas. Immature teratomas were also associated with a significantly higher mortality rate (immature teratomas: 8/31, mature teratomas: 2/48). Late recurrence was observed in six of 72 cases (8.3 %). Among these six cases, recurrence with a malignant component was observed in four patients. All six patients were successfully treated. CONCLUSIONS: Mature teratoma was the most common histological type observed in this study. The patients with immature teratomas exhibited an increased risk of mortality. Late recurrence was observed in 8.3 % of the cases. PMID- 23982388 TI - Expression of Sproutys and SPREDs is decreased during lung branching morphogenesis in nitrofen-induced pulmonary hypoplasia. AB - PURPOSE: Pulmonary hypoplasia (PH) is a life-threatening condition associated with congenital diaphragmatic hernia (CDH), characterized by defective lung development. Sproutys and Sprouty-related proteins (SPREDs) play a key role in lung branching morphogenesis through modification of epithelial-mesenchymal interactions. During the pseudoglandular stage, Sproutys are highly expressed in distal airway epithelium, while SPREDs within the surrounding mesenchyme. Sprouty2/4 knockouts show severe defects in branching morphogenesis with reduced number of distal airways. SPRED-1 and SPRED-2 are strongly expressed in regions of new airway formation, highlighting their important function in branching pattern. We hypothesized that expression of Sprouty2, Sprouty4, SPRED-1 and SPRED 2 is decreased during lung branching morphogenesis in nitrofen-induced PH. METHODS: Timed-pregnant rats received either nitrofen or vehicle on E9.5. On E15.5 (n = 16), fetal lungs were micro-dissected and divided into controls and PH, while on E18.5 (n = 24) groups were: control, PH without CDH [CDH(-)], and PH with CDH [CDH(+)]. Pulmonary gene expression levels of Sprouty2, Sprouty4, SPRED 1 and SPRED-2 were analyzed by qRT-PCR. Immunohistochemistry was performed to evaluate protein expression/distribution. RESULTS: On E18.5, relative mRNA expression levels of Sprouty2, Sprouty4, SPRED-1 and SPRED-2 were significantly decreased in CDH(-) and CDH(+) groups compared to controls (P < 0.05). Immunoreactivity of Sprouty2, Sprouty4, SPRED-1 and SPRED-2 was markedly diminished on E18.5 in nitrofen-induced PH. CONCLUSION: Decreased expression of Sproutys and SPREDs during the terminal pseudoglandular stage may disrupt lung branching morphogenesis by interfering with epithelial-mesenchymal interactions contributing to PH. PMID- 23982389 TI - Non-transplant surgery for short bowel syndrome. AB - The goal of any treatment programme for short bowel syndrome SBS is to achieve nutritional enteral autonomy. This must begin with conservation of as much bowel as possible from the time of first presentation. Frequent causes of the short bowel syndrome are intestinal atresia, necrotizing enterocolitis, midgut volvulus, extended intestinal aganglionosis, 'vanished gut' often associated with gastroschisis and occasionally catastrophic trauma. Atresia is more amenable to successful surgery than other causes, except when associated with gastroschisis. Intrinsic dysmotility has a poor prognosis. Intestinal lengthening procedures are only indicated if there is sufficient bowel dilatation. Extended intestinal aganglionosis is rarely amenable to any form of non-transplant surgery. Options available are to conserve bowel, close stomas early (use all available bowel to the maximum or even re-feed stoma effluent into the distal unused bowel), release adhesions causing obstruction, resect strictures, taper or excise localized dilatations and finally address dilated bowel with lengthening and tailoring operations. These procedures aim to improve effective peristalsis, thereby reducing bacterial overgrowth and improving nutrient contact with enteral mucosa to maximize absorption and intestinal adaptation. The Bianchi longitudinal splicing operation and the serial transverse enteroplasty operations have stood the test of time in providing considerable improvement in enteral nutritional autonomy in around 60% of cases. In SBS without dilatation attempts at 'mechanically' delaying transit (nipple valves, reversed bowel segments, colon interposition) have had inconsistent outcomes. Growing neomucosa and lengthening bowel by longitudinal stretch are still experimental. PMID- 23982390 TI - Impact of pediatric intestinal transplantation on intestinal failure in Japan: findings based on the Japanese intestinal transplant registry. AB - INTRODUCTION: We assessed the impact of intestinal transplantation on Japanese pediatric patients with intestinal failure with data from the Japanese intestinal transplant registry. METHODS: Standardized forms were sent to all known intestinal transplantation programs, requesting information on transplants performed between 1996 and June 30, 2012. Patients younger than 18 years were analyzed. Patient and graft survival estimates were obtained using the Kaplan Meier method. RESULTS: Of the 14 intestinal transplants, 4 were deceased and 10 were living donor transplants. The primary indications were: short gut syndrome (n = 7), intestinal functional disorder (n = 6), and re-transplantation (n = 1). The overall 1- and 5-year patient survival rates were 77 and 57%, respectively. In transplants performed after 2006 (n = 6), the one-year patient survival rate was 83%, and the 5-year survival rate was 83%. Graft one- and 5-year survival rates were 83 and 83%, respectively. The living-related transplant survival rate was 80% at 1 year and 68% at 2 years, compared to 67 and 67% for cadaveric transplant recipients. There were no statistically significant differences in patient (p = 0.88) and graft (p = 0.76) survival rates between living donor and cadaveric transplant recipients. All current survivors discontinued PN. CONCLUSION: Intestinal transplantation has become an effective therapy for patients with intestinal failure who cannot tolerate PN. PMID- 23982391 TI - Redo surgery for biliary atresia. AB - The Kasai redo surgery is important for treating biliary atresia. In the era of liver transplantation (LTx), pediatric surgeons must accurately select patients for redo surgery and ensure that potential LTx can be performed later. Although optimal timing for redo varies among cases, appropriate timing is essential. We reviewed the significance, optimal timing, operative procedures, and indications of Kasai redo surgery. Between 1989 and 2011, 2,630 patients were registered in the Japanese Biliary Atresia Registry (JBAR), and the data collected from JBAR regarding Kasai redo surgery were analyzed. Patients were divided into two groups, Group 1 (1989-1999, n = 1,423) and Group 2 (2000-2011, n = 1,207). The redo incidence significantly reduced in Group 2. Although no significant difference was found in the native liver jaundice-free survival rates between the two groups, the overall survival rate at initial registry was significantly higher in Group 2. This may be because of the limited number of patients selected for redo and increased availability of early LTx. Patients who achieved sufficient bile drainage following the initial Kasai surgery but developed sudden bile flow cessation were the best candidates for Kasai redo surgery; it should be performed only once for this subset. PMID- 23982392 TI - Management of blunt pancreatic trauma in children. AB - Blunt trauma to the abdomen accounts for the majority of abdominal injuries in children. Pancreatic injury is the fourth most common solid organ injury, following injuries to the spleen, liver and kidneys. The most common complications are the formation of pancreatic fistulae, pancreatitis and the development of pancreatic pseudocysts, which usually present several weeks after injury. The nonoperative management of minor pancreatic injury is well accepted; however, the treatment of more serious pancreatic injuries with capsular, ductal or parenchymal disruption in pediatric patients remains controversial. Based on the data presented in this literature review, although children with pancreatic injuries (without ductal disruption) do not appear to suffer increased morbidity following conservative management, patients with ductal disruption may benefit from operative intervention. PMID- 23982393 TI - Extraskeletal Ewing sarcoma in children and adolescents: impact of narrow but negative surgical margin. AB - PURPOSE: The aim of the study was to determine the impact of negative but close resection margins on local recurrence in children with extraskeletal Ewing sarcoma (EES). METHOD: We reviewed records of 32 patients with EES treated between March 2005 and March 2013. All patients except one underwent surgical excision either upfront or after induction chemotherapy. Patients with viable tumor and negative surgical margins, which were categorized as less than or greater than 1 cm, were selected. Local control and survival analysis were performed for patients in both the groups. RESULTS: The 5-year event-free and overall survival rates of entire cohort is 68 and 77 %, respectively. Surgical margins were negative in 23/26 (90.3 %) patients. There were no local recurrences in any of the patients with margins of less than 1 cm. Only one patient with a margin greater than 1 cm had a local recurrence along with distant metastases. A tumor-free margin of more than 1 cm did not affect overall or event-free survival (p = NS). CONCLUSION: Optimal local control is feasible in children with EES regardless of the quantitative extent of negative margins. Achieving a three dimensional tumor-free margin should be the goal of surgical resection. PMID- 23982394 TI - Risk factors for posterior shoulder instability in young athletes. AB - BACKGROUND: While posterior glenohumeral instability is becoming increasingly common among young athletes, little is known of the risk factors for injury. PURPOSE: To determine the modifiable and nonmodifiable risk factors for posterior shoulder instability in a high-risk cohort. STUDY DESIGN: Case-control study (prognosis); Level of evidence, 2. METHODS: A prospective cohort study in which 714 young athletes were followed from June 2006 through May 2010 was conducted. Baseline testing included a subjective history of instability, instability testing by a sports medicine fellowship-trained orthopaedic surgeon, range of motion, strength measurement with a handheld dynamometer, and bilateral noncontrast magnetic resonance imaging of the shoulder. A musculoskeletal radiologist measured glenoid version, height, depth, rotator interval (RI) height, RI width, RI area, and RI index. Participants were followed to document all acute posterior shoulder instability events during the 4-year follow-up period. The time to the posterior shoulder instability event during the follow-up period was the primary outcome of interest. Univariate and multivariable Cox proportional hazards regression models were used to analyze the data. RESULTS: Complete data on 714 participants were obtained. During the 4-year surveillance period, 46 shoulders sustained documented glenohumeral instability events, of which only 7 were posterior in direction. The baseline factors that were associated with subsequent posterior instability during follow-up were increased glenoid retroversion (P < .0001), increased external rotation strength in adduction (P = .029) and at 45 degrees of abduction (P = .015), and increased internal rotation strength in adduction (P = .038). CONCLUSION: This is the largest known prospective study to follow healthy participants in the development of posterior shoulder instability. Posterior instability represents 10% of all instability events. The most significant risk factor was increased glenoid retroversion. While increased internal/external strength was also associated with subsequent instability, it is unclear whether these strength differences are causative or reactive to the difference in glenoid anatomy. This work confirms that increased glenoid retroversion is a significant prospective risk factor for posterior instability. PMID- 23982395 TI - Revision osteochondral allograft transplantations: do they work? AB - BACKGROUND: Primary fresh osteochondral allograft transplantation is a useful treatment option for osteochondral lesions in the knee. Clinical failure of primary osteochondral allograft transplantation may require further surgery, including revision osteochondral allograft transplantation. PURPOSE: To evaluate outcomes of patients who have undergone revision osteochondral allograft transplantation of the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: This series included 33 patients (33 knees) who underwent revision osteochondral allograft transplantation between 1983 and 2012, were at least 2 years out from surgery, and had a minimum 2-year follow-up. Clinical evaluations included the International Knee Documentation Committee pain, function, and total scores; Knee Society function score; and modified Merle d'Aubigne and Postel scale. Failure of the revision allograft was defined as conversion to partial or total knee arthroplasty. RESULTS: The mean follow-up after revision osteochondral allograft transplantation was 10 years, with 75% of patients having more than 5 years' follow-up. Thirteen patients (39%) had failed results after revision osteochondral allograft transplantation, with a mean time to failure of 5.5 years. The remaining 20 patients (61%) had surviving revision allografts, with a mean graft survival of 10 years. Mean pain and function scores at the last follow up were improved. Survivorship of the revision allograft was 61% at 10 years. CONCLUSION: Revision osteochondral allograft transplantation of the knee demonstrated acceptable clinical outcomes, although they were inferior to primary allograft transplantation procedures. Revision osteochondral allograft transplantation may be considered an option for patients with a failed primary osteochondral allograft. PMID- 23982396 TI - Arthroscopic suture anchor repair of the lateral ligament ankle complex: a cadaveric study. AB - BACKGROUND: Operative treatment of mechanical ankle instability is indicated for patients with multiple sprains and continued episodes of instability. Open repair of the lateral ankle ligaments involves exposure of the attenuated ligaments and advancement back to their anatomic insertions on the fibula using bone tunnels or suture implants. HYPOTHESIS: Open and arthroscopic fixation are equal in strength to failure for anatomic Brostrom repair. STUDY DESIGN: Controlled laboratory study. METHODS: Seven matched pairs of human cadaveric ankle specimens were randomized into 2 groups of anatomic Brostrom repair: open or arthroscopic. The calcaneofibular ligament and anterior talofibular ligament were excised from their origin on the fibula. In the open repair group, 2 suture anchors were used to reattach the ligaments to their anatomic origins. In the arthroscopic repair group, identical suture anchors were used for repair via an arthroscopic technique. The ligaments were cyclically loaded 20 times and then tested to failure. Torque to failure, degrees to failure, initial stiffness, and working stiffness were measured. A matched-pair analysis was performed. Power analysis of 0.8 demonstrated that 7 pairs needed to show a difference of 30%, with a 15% standard error at a significance level of alpha = .05. RESULTS: There was no difference in the degrees to failure, torque to failure, or stiffness for the repaired ligament complex. Nine of 14 specimens failed at the suture anchor. CONCLUSION: There is no statistical difference in strength or stiffness of a traditional open repair as compared with an arthroscopic anatomic repair of the lateral ligaments of the ankle. CLINICAL RELEVANCE: An arthroscopic technique can be considered for lateral ligament stabilization in patients with mild to moderate mechanical instability. PMID- 23982397 TI - Biomechanical properties of suture anchor repair compared with transosseous sutures in patellar tendon ruptures: a cadaveric study. AB - BACKGROUND: Ruptures of the patellar tendon are debilitating injuries requiring surgical repair. Reliable data about the most appropriate suture technique and suture material are missing. The standard procedure consists of refixing the tendon with sutures in transpatellar tunnels, sometimes combined with augmentation. HYPOTHESIS: Suture anchors provide at least equal results concerning gap formation during cyclic loading and ultimate failure load compared with transosseous suture repair. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 30 human cadaveric patellar tendons underwent tenotomy followed by repair with 5.5-mm titanium suture anchors, 5.5-mm resorbable hydroxyapatite suture anchors, or transpatellar suture tunnels with No. 2 Ultrabraid and the Krackow whipstitch technique. Biomechanical analysis included pretensioning the constructs at 20 N for 30 seconds and then cyclic loading of 250 cycles between 20 and 100 N at 1 Hz in a servohydraulic testing machine with measurement of elongation. After this, ultimate failure load and failure mode analysis was performed. RESULTS: Compared with transosseous sutures, tendon repairs with suture anchors yielded significantly less gap formation during cyclic loading (P < .05) and resisted significantly higher ultimate failure loads (P < .05). Common failure mode was pullout of the eyelet within the suture anchor in the hydroxyapatite anchor group and rupture of the suture in the titanium anchor group and-at lower load to failure-in the transosseous group. CONCLUSION: Patellar tendon repair with suture anchors yields significantly better biomechanical results than repair with the commonly applied transosseous sutures. CLINICAL RELEVANCE: These findings may be of relevance for future clinical treatment of patellar tendon ruptures. Randomized controlled clinical trials comparing suture anchors to transosseous suture repair are desirable. PMID- 23982398 TI - The effect of pelvic tilt on radiographic markers of acetabular coverage. AB - BACKGROUND: Radiographic indices of acetabular coverage are crucial to objectively characterize femoroacetabular impingement and plan bony decompression. It is established that changes in pelvic inclination result in alterations of acetabular crossover; however, it is unclear what influence this has on other measures of acetabular anatomy. HYPOTHESIS: The objective of the present study was to determine if, and to what degree, a variation in pelvic tilt alters 4 measures of acetabular anatomy: the angle of Sharp, Tonnis angle, percentage of acetabular crossover, and lateral center edge angle (LCEA). The hypothesis was that pelvic tilt would significantly alter all measures of acetabular coverage. STUDY DESIGN: Descriptive laboratory study. METHODS: Fluoroscopic images of 8 adult hemipelvises were obtained at 7 positions of rotation in the sagittal plane to investigate the change of each measurement in response to pelvic orientation. Two reviewers obtained measurements from each image at 2 separate time points. RESULTS: Each increment of pelvic inclination resulted in increased measures of acetabular coverage for all measurements, whereas each increment of decreased pelvic inclination resulted in decreased measures of acetabular coverage for all measurements. Significant differences in the measured LCEA, acetabular crossover, and Tonnis angle were identified at each increment of tilt as compared with neutral radiographs. No significant differences could be identified for the angle of Sharp. CONCLUSION: Pelvic tilt significantly alters the measures of LCEA, crossover, and Tonnis angle in this cadaveric study. Pelvic inclination results in increased measures of acetabular coverage, whereas decreasing inclination decreases each measure. CLINICAL RELEVANCE: Given the known individual and positional pelvic tilt variability, standing anteroposterior pelvic radiographs may provide a more physiological representation of acetabular coverage in the young adult population. PMID- 23982399 TI - Location of the femoral tunnel aperture in single-bundle anterior cruciate ligament reconstruction: comparison of the transtibial, anteromedial portal, and outside-in techniques. AB - BACKGROUND: Previous 3-dimensional computed tomography (3D CT) studies of knees after anterior cruciate ligament (ACL) reconstruction have compared femoral tunnel positions obtained using the transtibial and anteromedial drilling techniques. This study used postoperative in vivo 3D CT analysis to compare the locations of the femoral tunnel aperture among 3 drilling techniques used in ACL reconstruction: transtibial, anteromedial portal, and outside-in. HYPOTHESIS: The use of the transtibial drilling technique might result in a less anatomically accurate femoral tunnel placement than the anteromedial portal and outside-in techniques. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Immediate postoperative in vivo 3D CT was used to assess the location of the femoral tunnel aperture in 153 patients who underwent single-bundle ACL reconstruction using the transtibial (n = 42), anteromedial portal (n = 73), or outside-in (n = 38) techniques. Femoral tunnel positions were measured by an anatomic coordinate axis method in the low-to-high and deep-to-shallow directions of the distal femur at 90 degrees of knee flexion. RESULTS: The low-to-high femoral tunnel positions were significantly higher in the transtibial group than in the anteromedial portal (P < .001) and outside-in (P < .001) groups. There were no differences among the 3 groups in the deep-to-shallow femoral tunnel positions (P = .773). CONCLUSION: The transtibial technique of anatomic reconstruction resulted in more highly positioned femoral tunnels in the low-to-high direction than did the anteromedial portal and outside-in techniques. However, no significant differences in the femoral tunnel location were observed in the deep-to-shallow direction. PMID- 23982400 TI - Femoroacetabular impingement in athletes: current concepts. AB - Hip disorders are increasingly recognized as a cause of dysfunction and disability among athletes. Femoroacetabular impingement (FAI) is a common source of hip problems. While FAI may sometimes be present as an incidental asymptomatic finding, substantial secondary joint damage may occur. This problem is often observed in young adult, and even adolescent, athletes. FAI morphology results in a breakdown of the labrum and articular surfaces from forces generated during sporting activities that would otherwise be well tolerated by a normal joint. A description of the pathomechanics is included. Detection of pathological FAI is important to minimize its harmful effects. The history, examination findings, and pertinent imaging studies are detailed. Nonoperative measures, including training modifications and pelvic stabilization exercises, may be of some benefit in modulating symptoms. When secondary joint damage has occurred, surgical intervention is usually necessary. While most can be managed with arthroscopic techniques, open and mini-open methods are discussed as well. With proper recognition and treatment, most athletes can expect to return to sports, although the long-term implications of high-level activities must still be considered. These results are summarized. PMID- 23982401 TI - Return to athletic activity after plate fixation of displaced midshaft clavicle fractures. AB - BACKGROUND: Recent data support primary plate fixation of displaced midshaft clavicle fractures. The safety and efficacy of this practice have not been well documented in athletes. HYPOTHESIS: Plate fixation of clavicle fractures in athletes is a safe and effective procedure, resulting in a reliable and timely return to play. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 29 patients with displaced midshaft clavicle fractures from athletic activity were treated with plate fixation between January 1, 2003 and December 31, 2008, including 1 patient treated for each clavicle for separate injuries. All 29 patients were contacted for follow-up. At a mean follow-up of 21 months, patients completed a questionnaire focused on the time to return to athletics and treatment course. Patients also completed the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) questionnaire. Radiographs were reviewed to identify fracture comminution, displacement, shortening, and angulation; radiographic union time; and malunion. RESULTS: All of the patients (30/30 cases) returned to sports after open reduction internal fixation of their fracture. The mean time to return to play was 83 days with a range of 13 to 277 days. Seven (23%) of the cases returned to athletics at <=6 weeks after surgery, and a total of 20 patients (67%) returned at <=12 weeks after surgery. All patients (100%) were satisfied with their treatment. The QuickDASH scores revealed almost perfect recovery (mean score, 0.8 of 100). Four minor complications were identified. No patient had a refracture, plate fracture, loss of fixation, nonunion, malunion, or deep wound infection. CONCLUSION: Plate fixation of displaced clavicle fractures in athletes is a safe procedure, resulting in a high satisfaction rating and minimal disability to the upper extremity. An early return (<6 weeks) to sports is possible after this treatment; however, the time to return is highly variable. PMID- 23982402 TI - Computed tomography analysis of the femoral tunnel position and aperture shape of transportal and outside-in ACL reconstruction: do different anatomic reconstruction techniques create similar femoral tunnels? AB - BACKGROUND: The desire to perform independent femoral drilling in anterior cruciate ligament (ACL) reconstruction has prompted interest in both the transportal (TP) and outside-in (OI) techniques. However, there have been no in vivo studies on the differences in femoral aperture shape between the 2 techniques. PURPOSE: To evaluate the femoral tunnel aperture shape and femoral tunnel position between ACL reconstruction using the TP and OI techniques. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 80 patients were randomized to undergo double-bundle ACL reconstruction using either the TP (n = 40) or OI (n = 40) technique. The femoral tunnel aperture shape (height/width ratio), aperture axis angle (angle between the aperture axis and femoral shaft axis), and femoral tunnel position were assessed by computed tomography. RESULTS: The mean height/width ratio of the anteromedial (AM) femoral tunnels in the TP group (1.35 +/- 0.16) was significantly more ellipsoidal than that in the OI group (1.22 +/- 0.16) (P = .008). There was no difference between the 2 groups in the posterolateral (PL) tunnels (TP, 1.32 +/- 0.23; OI, 1.35 +/- 0.29; P = .99). The mean aperture axis angle of the PL femoral tunnels in the OI group was significantly more perpendicular to the femoral shaft axis and had a more variable range than that in the TP group (P = .007). The mean PL femoral tunnel position in the OI group was significantly shallower and a little higher than that in the TP group (P = .006). CONCLUSION: The TP technique revealed a more ellipsoidal AM femoral tunnel aperture than the OI technique. The mean PL femoral tunnel position in the OI group was significantly shallower than that in the TP group, with a more variable and more perpendicular aperture axis angle to the femoral shaft axis. CLINICAL RELEVANCE: The TP technique might be more advantageous than the OI technique in terms of graft coverage, with a more ellipsoidal AM femoral tunnel and more horizontal and consistent PL aperture axis angle. In addition, it may be useful to consider the shallower PL femoral tunnel positions created with the OI technique. PMID- 23982403 TI - Another look: is there a flaw to current hip septic arthritis diagnostic algorithms? AB - BACKGROUND: Septic arthritis is an emergency. In 1999 Kocher et al. identified four clinical criteria to distinguish hip septic arthritis from transient synovitis in children (nonweightbearing, erythrocyte sedimentation rate >= 40 mm/L, white blood cell count > 12 * 10(9)/L, temperature > 38.5 degrees C). Subsequent authors evaluating the same criteria produced conflicting results. This calls into question the use of such diagnostic algorithms. The reasons for the differences remain unclear. QUESTIONS/PURPOSES: To what degree do studies, evaluating the predictive ability of diagnostic algorithms for septic arthritis, differ with regard to their results? Why do these differences exist? Is there a flaw in the statistical handling of the data? METHODS: Using PubMed, original studies evaluating the clinical criteria for distinguishing hip septic arthritis and transient synovitis in children were identified. Clinical and statistical methods were examined. RESULTS: Six studies evaluated the clinical criteria. Two found all four criteria able to distinguish septic arthritis from transient synovitis. There was significant variation between the studies in the risk engendered by the presence of each criteria. The differences were the result of the fact that in all cases, sample sizes were too small and in three cases, there were too few episodes of septic arthritis for a reliable predictive algorithm to be produced. CONCLUSIONS: Differing results between studies appear as a result of sample size and insufficient cases of septic arthritis in some cohorts. Transferable and reliable results can be achieved if sufficiently large samples with an adequate number of cases of septic arthritis are recruited. PMID- 23982404 TI - CORR Insights (r): Coronal limb alignment and indications for high tibial osteotomy in patients undergoing revision ACL reconstruction. PMID- 23982405 TI - A patient-derived Constant-Murley score is comparable to a clinician-derived score. AB - BACKGROUND: Although there are many advantages to patient-based assessment for musculoskeletal conditions, one common problem is that many of these assessments are perceived to be subjective. To overcome this limitation for patient-based shoulder evaluation, we developed a modified Constant-Murley score that allows patients to complete subjective and objective sections of the score. QUESTIONS/PURPOSES: The purpose of our study was to assess the reliability of the new patient-based Constant-Murley score questionnaire by comparing composite scores and subscores obtained with those obtained using the standard physician based Constant-Murley questionnaire in the same group of patients. METHODS: Between August and October 2000, all patients having shoulder surgery in our institute were invited to participate in this study; 58 of 61 (95%) opted to do so and completed the patient-based questionnaire at preoperative and postoperative assessments. The clinician-based Constant-Murley score was performed by a clinician who was blinded to the corresponding patient-based questionnaire. Patients underwent various procedures ranging from manipulation under anesthesia and arthroscopic procedures to reverse shoulder arthroplasty. RESULTS: The mean patient-based and the clinician-based Constant-Murley scores were 47 (SD = 19.5; range, 4-90; N = 108) and 48 (SD = 19.9; range, 4-90; N = 108) points respectively. The mean difference was -1.3 (SD = 3; range, -11 to 8; N = 108) points. The new patient-based Constant-Murley score questionnaire reproduced the patient-based method and had substantial to almost perfect agreement with it for the composite score and various subgroups. CONCLUSIONS: These results suggest that a patient-based questionnaire can be used interchangeably with or in place of a clinician-based Constant-Murley score. These results apply to subjective and objective items of the Constant-Murley score. PMID- 23982407 TI - Reply to the Letter to the editor: Staphylococcus aureus screening and decolonization in orthopaedic surgery and reduction of surgical site infections. PMID- 23982406 TI - Causes, risk factors, and trends in failures after TKA in Korea over the past 5 years: a multicenter study. AB - BACKGROUND: Failure after total knee arthroplasty (TKA) may be related to emerging technologies, surgical techniques, and changing patient demographics. Over the past decade, TKA use in Korea has increased substantially, and demographic trends have diverged from those of Western countries, but failure mechanisms in Korea have not been well studied. QUESTIONS/PURPOSES: We determined the causes of failure after TKA, the risk factors for failure, and the trends in revision TKAs in Korea over the last 5 years. METHODS: We retrospectively reviewed 634 revision TKAs and 20,234 primary TKAs performed at 19 institutes affiliated with the Kleos Korea Research Group from 2008 to 2012. We recorded the causes of failure after TKA using 11 complications from the standardized complication list of The Knee Society, patient demographics, information on index and revision of TKAs, and indications for index TKA. The influences of patient demographics and indications for index TKA on the risk of TKA failure were evaluated using multivariate regression analysis. The trends in revision procedures and demographic features of the patients undergoing revision TKA over the last 5 years were assessed. RESULTS: The most common cumulative cause of TKA failure was infection (38%) followed by loosening (33%), wear (13%), instability (7%), and stiffness (3%). However, the incidence of infections has declined over the past 5 years, whereas that of loosening has increased and exceeds that of infection in the more recent 3 years. Young age (odds ratio [OR] per 10 years of age increase, 0.41; 95% confidence interval [CI], 0.37-0.49) and male sex (OR, 1.88; 95% CI, 1.42-2.49) were associated with an increased risk of failure. The percentage of revision TKAs in all primary and revision TKAs remained at approximately 3%, but the annual numbers of revision TKAs in the more recent 3 years increased from that of 2008 by more than 23%. CONCLUSIONS: Despite a recent remarkable increase in TKA use and differences in demographic features, the causes and risk factors for failures in Korea were similar to those of Western countries. Infection was the most common cause of failure, but loosening has emerged as the most common cause in more recent years, which would prompt us to scrutinize the cause and solution to reduce it. PMID- 23982409 TI - CORR Insights (r): Trabecular metal in total knee arthroplasty associated with higher knee scores: a randomized controlled trial. PMID- 23982408 TI - The detrimental effects of systemic Ibuprofen delivery on tendon healing are time dependent. AB - BACKGROUND: Current clinical treatment after tendon repairs often includes prescribing NSAIDs to limit pain and inflammation. The negative influence of NSAIDs on bone repair is well documented, but their effects on tendon healing are less clear. While NSAIDs may be detrimental to early tendon healing, some evidence suggests that they may improve healing if administered later in the repair process. QUESTIONS/PURPOSES: We asked whether the biomechanical and histologic effects of systemic ibuprofen administration on tendon healing are influenced by either immediate or delayed drug administration. METHODS: After bilateral supraspinatus detachment and repair surgeries, rats were divided into groups and given ibuprofen orally for either Days 0 to 7 (early) or Days 8 to 14 (delayed) after surgery; a control group did not receive ibuprofen. Healing was evaluated at 1, 2, and 4 weeks postsurgery through biomechanical testing and histologic assessment. RESULTS: Biomechanical evaluation resulted in decreased stiffness and modulus at 4 weeks postsurgery for early ibuprofen delivery (mean +/- SD [95% CI]: 10.8 +/- 6.4 N/mm [6.7-14.8] and 8.9 +/- 5.9 MPa [5.4-12.3]) when compared to control repair (20.4 +/- 8.6 N/mm [16.3-24.5] and 15.7 +/- 7.5 MPa [12.3-19.2]) (p = 0.003 and 0.013); however, there were no differences between the delayed ibuprofen group (18.1 +/- 7.4 N/mm [14.2-22.1] and 11.5 +/- 5.6 MPa [8.2-14.9]) and the control group. Histology confirmed mechanical results with reduced fiber reorganization over time in the early ibuprofen group. CONCLUSIONS: Early administration of ibuprofen in the postoperative period was detrimental to tendon healing, while delayed administration did not affect tendon healing. CLINICAL RELEVANCE: Historically, clinicians have often prescribed ibuprofen after tendon repair, but this study suggests that the timing of ibuprofen administration is critical to adequate tendon healing. This research necessitates future clinical studies investigating the use of ibuprofen for pain control after rotator cuff repair and other tendon injuries. PMID- 23982410 TI - Retained bullet removal in civilian pelvis and extremity gunshot injuries: a systematic review. AB - BACKGROUND: Although gunshot injuries are relatively common, there is little consensus about whether retained bullets or bullet fragments should be removed routinely or only in selected circumstances. QUESTIONS/PURPOSES: We performed a systematic review of the literature to answer the following questions: (1) Is bullet and/or bullet fragment removal from gunshot injuries to the pelvis or extremities routinely indicated? And, if not, (2) what are the selected indications for removal of bullets and/or bullet fragments? METHODS: A search of the English-language literature on the topic of gunshot injury and bullet removal was performed using the National Library of Medicine and MEDLINE((r)) and supplemented by hand searching of bibliographies of included references. Studies were included if they provided clinical data on one or both of our study questions; included studies were evaluated using the levels of evidence rubric. Most studies on the subject were expert opinion (Level V evidence), and these were excluded; one Level III study and seven Level IV studies were included. RESULTS: No studies provided a rationale for routine bullet removal in all cases. The studies identified bullet fragment removal as indicated acutely for those located within a joint, the palm, or the sole. Chronic infection, persistent pain at the bullet site, and lead intoxication were reported as late indications for bullet removal. CONCLUSIONS: The evidence base for making clinical recommendations on the topic of bullet and bullet fragment removal after gunshot injury is weak. Level I and II evidence is needed to determine the indications for bullet removal after gunshot injury. PMID- 23982411 TI - CORR Insights (r): The value of valgus stress radiographs in the workup for medial unicompartmental arthritis. PMID- 23982412 TI - [SK2 guidelines for assessment of mental and psychosomatic diseases: A statement]. PMID- 23982414 TI - MRSA and C difficile deaths continue to fall in England and Wales. PMID- 23982413 TI - Identification of FDA-approved drugs targeting breast cancer stem cells along with biomarkers of sensitivity. AB - Recently developed genomics-based tools are allowing repositioning of Food and Drug Administration (FDA)-approved drugs as cancer treatments, which were employed to identify drugs that target cancer stem cells (CSCs) of breast cancer. Gene expression datasets of CSCs from six studies were subjected to connectivity map to identify drugs that may ameliorate gene expression patterns unique to CSCs. All-trans retinoic acid (ATRA) was negatively connected with gene expression in CSCs. ATRA reduced mammosphere-forming ability of a subset of breast cancer cells, which correlated with induction of apoptosis, reduced expression of SOX2 but elevated expression of its antagonist CDX2. SOX2/CDX2 ratio had prognostic relevance in CSC-enriched breast cancers. K-ras mutant breast cancer cell line enriched for CSCs was resistant to ATRA, which was reversed by MAP kinase inhibitors. Thus, ATRA alone or in combination can be tested for efficacy using SOX2, CDX2, and K-ras mutation/MAPK activation status as biomarkers of response. PMID- 23982415 TI - NHS consultant who was sacked for seeing private patients while sick wins appeal. PMID- 23982416 TI - A model of sensitivity and resistance to histone deacetylase inhibitors in diffuse large B cell lymphoma: Role of cyclin-dependent kinase inhibitors. AB - Diffuse large B cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma. While the initial treatment strategy is highly effective, relapse occurs in 40% of cases. Histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs but their single agent efficacy against relapsed DLBCL has been variable, ranging from few complete/partial responses to some stable disease. However, most patients showed no response to HDACi monotherapy for unknown reasons. Here we show that sensitivity and resistance to the hydroxamate HDACi, PXD101, can be modeled in DLBCL cell lines. Sensitivity is characterized by G 2/M arrest and apoptosis and resistance by reversible G 1 growth arrest. These responses to PXD101 are independent of several negative prognostic indicators such as DLBCL subtype, BCL2 and MYC co-expression, and p53 mutation, suggesting that HDACi might be used effectively against highly aggressive DLBCL tumors if they are combined with other therapeutics that overcome HDACi resistance. Our investigation of mechanisms underlying HDACi resistance showed that cyclin-dependent kinase inhibitors (CKIs), p21 and p27, are upregulated by PXD101 in a sustained fashion in resistant cell lines concomitant with decreased activity of the cyclin E/cdk2 complex and decreased Rb phosphorylation. PXD101 treatment results in increased association of CKI with the cyclin E/cdk2 complex in resistant cell lines but not in a sensitive line, indicating that the CKIs play a key role in G 1 arrest. The results suggest several treatment strategies that might increase the efficacy of HDACi against aggressive DLBCL. PMID- 23982417 TI - Differential rRNA genes expression in bread wheat and its inheritance. AB - The expression of the ribosomal RNA (rRNA) genes from rye, located within the nucleolus organizer regions (NORs), is repressed by cytosine methylation in wheat x rye hybrids and in triticale, as consequence of nucleolar dominance. Our previous study revealed that bread wheat cultivars with a maximum number of four Ag-NORs presented high level of rDNA cytosine methylation when compared to others with a maximum of six Ag-NORs. In order to evaluate the inheritance of the Ag NORs number and NOR methylation patterns, we produced F1 hybrids between bread wheat cultivars with four Ag-NORs and bread wheat cultivars with six Ag-NORs (in the direct and reciprocal senses). The F2 progenies of these F1 hybrids were also evaluated for the NOR number and methylation patterns. Parent bread wheat cultivars with a maximum of four Ag-NORs after treated with 5-azacytidine evidenced a maximum of six Ag-NORs per metaphase cell and a maximum of six nucleoli per interphase nucleus, confirming that the expression of the rRNA genes in bread wheat is related to cytosine methylation. Most of the F1 hybrids showed a maximum number of four or six Ag-NORs, similarly to that of the female parent suggesting a non-mendelian inheritance, while other hybrids presented four or six Ag-NORs in both senses of the cross. The F1 NOR methylation patterns showed some fragments common to their parents but also novel fragments suggesting genomic and/or chromosome rearrangements after hybridization. Despite the different NOR patterns among the parents, an invariable NOR pattern was found among the F1 plants suggesting a tendency to stability, which was also transmitted to the F2. The F2 progenies showed plants with a maximum of four, five and/or six Ag-NORs. The ratio of plants with four, five and/or six Ag-NORs per F2 progeny was variable and did not follow any specific mendelian proportion. These results allowed us to suggest that the inheritance of the number of Ag-NORs by the F1 and F2 plants did not follow any mendelian inheritance and were not correlated to NOR methylation patterns in contrast to what was verified for their parents. PMID- 23982418 TI - The podocin mutation R229Q and early recurrence (within the first year) of glomerular disease after renal transplantation. AB - BACKGROUND: Podocin is a key protein involved in the pathogenesis of steroid resistant nephrotic syndrome and/or focal segmental glomerulosclerosis (FSGS) and is characterized by a high rate of early recurrence after renal transplantation (RTx) in children and adults. MATERIAL AND METHODS: We studied 206 RTx adult recipients: 187 with a diagnosis of glomerular nephropathy, GN (biopsy-proven in 149, clinical in 38), plus 19 with unknown diagnosis as original kidney disease (OKD), the NPHS2 gene polymorphism, G755A, and correlated with the presence of early recurrence of OKD within the first year (proteinuria over 1 g/day and graft biopsy proven). RESULTS: The A allele podocin gene mutation frequency was 3.4% (14/412) overall - 7.1% (4/56) in FSGS as expected, but surprisingly 5.7% (6/106) in IgA nephropathy. Fifty recipients (24.3%) developed proteinuria >1 g/d, with 12 recipients demonstrating early clinico-pathological recurrence by 1 year (5.8%) with 5/28 in FSGS, 2/53 in IgAN, 2/14 in membranoproliferative GN (with 1 graft loss within the first year), 1/19 in crescentic GN, 1/19 in unknown disease, and 1/38 in clinical GN. Only 2 recurrent patients (both with FSGS) had the R229Q podocin mutation (16.7%). CONCLUSIONS: The podocin mutation R229Q may play a role in the pathogenesis of FSGS and in early recurrence after transplantation, but does not allow accurate prediction of recurrence or the associated potential for prevention. PMID- 23982420 TI - Rodent models of psychiatric disorders--practical considerations. PMID- 23982419 TI - Women pharmacy consumers' experiences with weight loss treatment across Victoria, Australia. AB - BACKGROUND: Given the role of pharmacy in weight management is increasing, anecdotally weight loss treatments are consumed by more women than men, and there are some causes of overweight and obesity specific to women, it is important that pharmacists provide evidence-based services that consider women's needs as a basis for a future population based approach. OBJECTIVES: To determine what weight management options are preferred by women pharmacy consumers, how they feel about pharmacists providing advice in this area, and what they desire in a weight management program. METHODS: A random sample of women pharmacy consumers were asked to complete a questionnaire in randomly selected pharmacies across Victoria. Questionnaires were self-completed or with assistance from the researcher. Logistic regression analysis was used to determine any significant associations between demographic characteristics and previous weight loss attempts, pharmacy specific outcomes and what women want in their ideal weight management program. SETTING: Community pharmacies across Victoria, Australia. MAIN OUTCOME MEASURE: The views and opinions of women pharmacy consumers across Victoria regarding pharmacy involvement in weight management and currently available weight management products and/or programs. RESULTS: The response rate was high: 86 % (395/460). Approximately 48 % (153/319) of women were in the overweight, obese or severely obese body mass index category (BMI). 71.1 % (281/395) of women had attempted to lose weight in the past. Women in the overweight BMI category were 2.6 times more likely to have attempted to lose weight (95 % CI 1.4, 4.9), and women in the obese BMI category were 10.6 times more likely to have attempted to lose weight (95 % CI 4.1, 27.7) compared to the women with a BMI <25 kg/m(2). Approximately 80 % (230/281) of women felt comfortable receiving advice from pharmacists with 42 % (117/281) wanting a pharmacist in their ideal weight management program and 42 % (118/281) wanting their program to be delivered in a pharmacy. CONCLUSIONS: Women pharmacy consumers used a range of weight management approaches and had mainly positive views about the involvement of pharmacists in their ideal weight management program. PMID- 23982422 TI - Nonthermal atmospheric argon plasma jet effects on Escherichia coli biomacromolecules. AB - Nonthermal atmospheric plasma jet, a promising technology based on ionized gas at low temperatures, can be applied for disinfection of contaminated surfaces. In this study, Escherichia coli cells and their macromolecules were exposed to the nonthermal atmospheric argon plasma jet for different time durations. Total protein, genomic DNA, and malondialdehyde (MDA) levels of E. coli were assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining; agarose gel electrophoresis; and measurement of absorbance at 534 nm, respectively. After exposure, the spectroscopic results of liquid samples indicated that the survival reduction of E. coli can reach to 100 % in an exposure time of 600 s. Moreover, inactivation zones of E. coli, DNA degradation, and MDA levels were significantly increased. Additionally, banding patterns of total protein were changed and amino acid concentrations increased following ninhydrin test. The experimental results suggest that the nonthermal plasma could serve as an effective instrument for both sterilizing E. coli and degrading macromolecules from the surface of the objects being sterilized. PMID- 23982423 TI - Adenovirus-mediated IL-24 expression enhances the chemosensitivity of multidrug resistantgastric cancer cells to cisplatin. AB - Chemotherapy is one of the commonly used strategies in gastric cancer, especially for unresectable patients, but it becomes insensitive to repeated administration of even the most effective chemotherapeutic agents, such as cisplatin. Given this, there is an urgent need for developing chemosensitizers to overcome acquired resistance to chemotherapeutic agents. Interleukin-24 (IL-24), a cytokine-tumor suppressor, shows broad-spectrum and tumor-specific antitumor properties, and studies have demonstrated that IL-24 could conspicuously restore the chemosensitivity of MDR cancer cells. Herein, we developed a human MDR gastric cancer cell subline, SGC7901/CDDP, by repeated selection of resistant clones of parental sensitive cells, and further investigated the chemosensitizing effects and the underlying mechanisms of adenovirus-mediated IL-24 (Ad-IL-24) gene therapy plus CDDP for the human MDR gastric cancer cells SGC7901/CDDP in vitro and in vivo. The results demonstrated that the expression of IL-24 mRNA and protein was profoundly downregulated in SGC7901/CDDP cells by RT-PCR and western blot analysis. In addition, the cell viability assay showed that the IC50 of SGC7901/CDDP cells to CDDP, 5-FU, ADM and MTX was significantly enhanced compared to parental sensitive SGC7901 cells. Ad-IL-24-induced IL-24 overexpression decreased the IC50 of the above agents (not MTX), induced G2/M cell cycle arrest, and Ad-IL-24 plus CDDP elicited significant apoptosis and tumor suppression of SGC7901/CDDP cells in vitro and SGC7901/CDDP cell xenograft tumors in vivo, respectively. Moreover, our results demonstrated that the mechanisms of Ad-IL-24 elicited chemosensitizing effects were closely associated with a substantial upregulation of Bax and downregulation of P-gp and Bcl-2 in SGC7901/CDDP cells in vitro and SGC7901/CDDP xenograft tissues in vivo. Thus, this study indicates that overexpression of IL-24 gene can significantly promote chemosensitivity in MDR phenotype SGC7901/CDDP gastric cancer cells. PMID- 23982421 TI - Do more MRI findings imply worse disability or more intense low back pain? A cross-sectional study of candidates for lumbar disc prosthesis. AB - OBJECTIVE: To examine whether combined magnetic resonance imaging (MRI) findings are related to the degree of disability and low back pain (LBP) in candidates for lumbar disc prosthesis surgery. MATERIALS AND METHODS: This cross-sectional study included 170 disc prosthesis candidates (mean age 41 years; 88 women) with chronic non-radicular LBP and localized disc degeneration. Experienced radiologists rated Modic changes and disc findings at L4-S1 on pre-treatment MRIs. An MRI total score (0-10) for findings at L4/L5 plus L5/S1 was calculated for Modic type I and/or II changes, a posterior high intensity zone (HIZ) in the disc, dark/black nucleus pulposus signal, and >=40 % disc height decrease. We analyzed the relationship of the MRI total score to the Oswestry Disability Index (ODI) (n = 170) and LBP intensity scores (0-100 visual analogue scale, n = 165) using multiple linear regression and adjusting for age, gender, body mass index, smoking, and anxiety/depression. RESULTS: The MRI total score was not related to ODI (regression coefficient 0.12, p = 0.79) or LBP intensity (regression coefficient 0.64, p = 0.37). When individual MRI findings were analyzed, patients with HIZ at L5/S1 had slightly lower ODI scores (4.7 points, p = 0.02). In post hoc analyses, results remained unchanged after adding facet arthropathy to the MRI total score and adjusting also for physical workload and physical leisure time activity. CONCLUSIONS: The combined MRI findings were not related to the degree of disability or the intensity of LBP. These degenerative MRI findings cannot explain variation in pre-treatment disability and pain in patients with chronic LBP accepted for disc prosthesis surgery. PMID- 23982424 TI - Chronic hepatitis C as a risk factor for colorectal adenoma. AB - INTRODUCTION: Over the last decade, epidemiologic studies have determined a relationship between chronic hepatitis C (CHC) and malignancies other than hepatocellular carcinoma (HCC), particularly in gastrointestinal malignancies. This study aims to evaluate the incidence of colorectal adenomas and advanced neoplasia in CHC patients compared to the general population and to evaluate whether CHC infection is an independent risk factor for colorectal adenomas and advanced neoplasia. METHODS: This is a retrospective, case-control study. CHC patients who underwent screening colonoscopy between September 2006 and September 2010 were compared to randomly selected non-hepatitis C controls undergoing screening colonoscopy during the same period. Multivariate analysis was performed taking into account the known risk factors for colorectal adenoma. RESULTS: Two hundred thirty-three CHC patients and 466 controls that underwent screening colonoscopy were included in the study. CHC patients were younger and more likely to be male, smoker and have HIV infection compared to the control group (p < 0.05). CHC group had a significantly higher number of patients with adenomas (adenoma detection rate of 37.8 vs. 30.3 %; p = 0.04) and hyperplastic polyps (p = 0.01) detected on screening colonoscopy. The total number of adenomas detected was also higher in the CHC group; however, this was not statistically significant (0.69 vs. 0.58 per patient; p > 0.05). CHC patients were twice more likely to have advanced neoplasia detected compared to non-hepatitis C patients (odds ratio 2.04, 95 % confidence interval = 1.20-3.49; p = 0.03). CHC group was also more likely to have adenomas of >=6 mm (p = 0.005) and macroadenomas of >=1 cm (p = 0.02). LIMITATIONS: Limitations include the single-center, retrospective design of the study. CONCLUSIONS: Our study is the first to demonstrate a significantly higher rate of adenomas, advanced neoplasia, and hyperplastic polyps in CHC patients compared to the general population. On multivariate analysis, CHC infection was found to be an independent risk factor for colorectal adenoma, particularly advanced neoplasia. Larger prospective studies are needed to strengthen our findings which may have implications for colorectal cancer screening. PMID- 23982426 TI - Enhanced recovery after elective colorectal resection outside a strict fast-track protocol. A single centre experience. AB - INTRODUCTION: Optimising the management of hospitalised patients is a major concern. In colorectal surgery, the concept of enhanced recovery has been popularised by means of "fast-track" protocols, aiming at patient's discharge on the second postoperative day. Nevertheless, a strict fast-track protocol has several limitations. It is very demanding for the patient and therefore applicable only to a limited number of patients. AIM: In order to optimise, in every aspect, the postoperative recovery of each patient undergoing an elective colorectal resection inside our institution, we set up a "soft" enhanced recovery programme. MATERIAL-METHODS: A retrospective analysis was conducted in 92 patients evaluating the respective impact of protocol application throughout the duration of the hospital stay. RESULTS: When all the required measures of our protocol were correctly implemented, the median discharge day was postoperative day 3 (range 3-5 days). On the contrary, when deviations occurred, they resulted in longer hospital stay (p < 0.001). Patients operated by laparoscopy were discharged earlier than patients operated by laparotomy (p < 0.001). The use of nasogastric tube and postoperative drainage prolonged significantly the length of stay (p = 0.001 and p < 0.001 respectively). When the urinary catheter was not removed or oral feeding not resumed on postoperative day 1, the patients were discharged later (p < 0.001). CONCLUSIONS: There are substantial possibilities of optimising the recovery process after an elective colorectal resection, outside a strict fast-track protocol. PMID- 23982425 TI - Is complete mesocolic excision with central vascular ligation safe and effective in the surgical treatment of right-sided colon cancers? A prospective study. AB - PURPOSE: Complete mesocolic excision (CME) with central vascular ligation (CVL) has been proposed for treatment of colon cancers based on the same principles as total mesorectal excision. Impressive outcomes have been reported, however, direct comparisons with the classic procedure are lacking. METHODS: Forty-five consecutive patients operated on in the last 5 years with CME and CVL right hemicolectomy entered the study. Fifty-eight right-sided colon cancer patients operated in the previous 5 years with classic approach constituted the control group. Intra- and postoperative course assessed the safety of the procedure. Primary end-points for oncological adequacy were recurrence and survival rate. RESULTS: All operations were successful with no increase in postoperative complications (p = 0.85). Number of harvested nodes and length of vascular ligation were shown to be significantly better in the CME group (p < 0.01). A higher number of tumor deposits were harvested thus allowing chemotherapy in newly upstaged patients. Locoregional recurrences were never experienced in CME patients (p = 0.03). The risk of cancer-related death was reduced by over one half in all CME patients, and even by three quarters in node-positive tumors. The classic operation was significantly associated with poor outcome (p < 0.01). CONCLUSION: This study shows that CME with CVL is a safe and effective surgical approach for right colon cancer, thus confirming the previously reported oncological adequacy. The procedure was shown to significantly decrease local recurrences and to improve the survival rate, particularly in node-positive patients. Urgent diffusion of this technique is warranted. PMID- 23982427 TI - Hollow flower micelles from a diblock copolymer. AB - A poly(2-vinylpyridine)-block-poly(2-(4-vinylphenyl)pyridine) (P2VP106-b-PVPPy95) coil-coil diblock copolymer forms hollow flower micelles in a mixed solvent of methanol and water (95/5, v/v) in a one step process. The geometry and composition of the micelles allow formation of a Pt-Au bimetallic dendritic nanocatalyst with a Pt leaf at room temperature. PMID- 23982428 TI - Molecular plasmonics for nanoscale spectroscopy. AB - Surface- and tip-enhanced Raman and LSPR spectroscopies have developed over the past 15 years as unique tools for uncovering the properties of single particles and single molecules that are unobservable in ensemble measurements. Measurements of individual events provide insight into the distribution of molecular properties that are averaged over in ensemble experiments. Raman and LSPR spectroscopy can provide detailed information on the identity of molecular species and changes in the local environment, respectively. In this review a detailed discussion is presented on single-molecule and single-particle Raman and LSPR spectroscopy focusing on the major developments in the fields and applications of the techniques. PMID- 23982429 TI - Eosinophilic granulomatosis with polyangiitis presenting as acute sciatic nerve neuropathy resembling lumbar disease. PMID- 23982431 TI - From genome mining to phenotypic microarrays: Planctomycetes as source for novel bioactive molecules. AB - Most members of the phylum Planctomycetes share many unusual traits that are unique for bacteria, since they divide independent of FtsZ through asymmetric budding, possess a complex life cycle and comprise a compartmentalized cell plan. Besides their complex cell biological features Planctomycetes are environmentally important and play major roles in global matter fluxes. Such features have been successfully employed in biotechnological applications such as the anaerobic oxidation of ammonium in wastewater treatment plants or the utilization of enzymes for biotechnological processes. However, little is known about planctomycetal secondary metabolites. This is surprising as Planctomycetes have several key features in common with known producers of small bioactive molecules such as Streptomycetes or Myxobacteria: a complex life style and large genome sizes. Planctomycetal genomes with an average size of 6.9 MB appear as tempting targets for drug discovery approaches. To enable the hunt for bioactive molecules from Planctomycetes, we performed a comprehensive genome mining approach employing the antiSMASH secondary metabolite identification pipeline and found 102 candidate genes or clusters within the analyzed 13 genomes. However, as most genes and operons related to secondary metabolite production are exclusively expressed under certain environmental conditions, we optimized Phenotype MicroArray protocols for Rhodopirellula baltica and Planctomyces limnophilus to allow high throughput screening of putative stimulating carbon sources. Our results point towards a previously postulated relationship of Planctomycetes with algae or plants, which secrete compounds that might serve as trigger to stimulate the secondary metabolite production in Planctomycetes. Thus, this study provides the necessary starting point to explore planctomycetal small molecules for drug development. PMID- 23982430 TI - Diversity and dynamics of fungal endophytes in leaves, stems and roots of Stellera chamaejasme L. in northwestern China. AB - This study was conducted to explore fungal endophyte communities inhabiting a toxic weed (Stellera chamaejasme L.) from meadows of northwestern China. The effects of plant tissue and growth stage on endophyte assemblages were characterized. Endophytes were recovered from 50 % of the samples, with a total of 714 isolates. 41 operational taxonomical units (OTUs) were identified, consisting of 40 OTUs belonging primarily to Ascomycota and 1 OTU belonging to Basidiomycota. Pleosporales and Hypocreales were the orders contributing the most species to the endophytic assemblages. The total colonization frequency and species richness of endophytic fungi were higher in roots than in leaves and stems. In addition, for the plant tissues, the structure of fungal communities differed significantly by growth stages of leaf emergence and dormancy; for the plant growth stages, the structure of fungal communities differed significantly by plant tissues. This study demonstrates that S. chamaejasme serves as a reservoir for a wide variety of fungal endophytes that can be isolated from various plant tissues. PMID- 23982432 TI - Electronically stabilized nanowire growth. AB - Metallic nanowires show unique physical properties owing to their one-dimensional nature. Many of these unique properties are intimately related to electron electron interactions, which have a much more prominent role in one dimension than in two or three dimensions. Here we report the direct visualization of quantum size effects responsible for preferred lengths of self-assembled metallic iridium nanowires grown on a germanium (001) surface. The nanowire length distribution shows a strong preference for nanowire lengths that are an integer multiple of 4.8 nm. Spatially resolved scanning tunneling spectroscopic measurements reveal the presence of electron standing waves patterns in the nanowires. These standing waves are caused by conduction electrons, that is the electrons near the Fermi level, which are scattered at the ends of the nanowire. PMID- 23982435 TI - The development of adolescent generalized anxiety and depressive symptoms in the context of adolescent mood variability and parent-adolescent negative interactions. AB - This study explored the influence of adolescent mood variability on the symptom development of generalized anxiety and depression in the context of parent adolescent negative interactions. Participants were 456 adolescents (55.7 % male) from a community sample, who were followed from age 13 to 16 years. During 4 annual assessments, adolescents reported on their generalized anxiety and depressive symptoms, and both parents and adolescents on levels of negative interactions with each other. Within each study year, adolescents rated their daily mood states during 5 consecutive days for 3 times per year (total of 9 weeks). The absolute differences between mood states on consecutive days were summed to construct a mood variability score. Results showed that high levels of adolescent mood variability predicted increases in generalized anxiety and depressive symptoms across the studied period. No influence of negative interactions on anxiety and depression development was found, but positive predictive links from mood variability to negative interactions at age 14 and 15 appeared. The study underscores the role of adolescent mood variability in the development of symptoms of generalized anxiety and depression during adolescence, but found little evidence for an influence of parent-adolescent negative interactions on internalizing problem development. PMID- 23982434 TI - Maternal expectancy versus objective measures of child skill: evidence for absence of positive bias in mothers' expectations of children with internalizing disorders. AB - Parents of anxious children are thought to be more attuned to threat, which might translate into less positive bias in parental report of child coping and ability, unlike parents of non-anxious children. Maternal expectancy bias was examined in a sample of 43 clinically anxious (51 % female), 30 clinically anxious/depressed (50 % female), and 44 non-clinical control children (46 % female), 8-14 years of age. When compared to an objective observer's ratings of the children, mothers of non-clinical children demonstrated a positive bias (i.e., over-rated their children's performance) for both ratings of expected speech performance in absolute terms and relative to peers. Mothers in the clinical groups did not exhibit this positive expectancy bias. Moreover, mothers of clinical children reported lower expectations in absolute terms and relative to peers than mothers of non-clinical children. The data suggest that mothers of clinical children held accurate expectations for child performance when compared to the gold standard of an objective observer. PMID- 23982433 TI - Prevalence of PIK3CA mutations and the SNP rs17849079 in Arab breast cancer patients. AB - Carcinomas initiate and progress due to genetic and epigenetic alterations in epithelial cells. However, recently, these alterations have also been reported in stromal fibroblasts. The gain-of-function mutations in the PI3K p110 catalytic subunit (PIK3CA) have been identified in many cancers with a current global incidence of 26% (18-40%) in breast carcinomas. We analyzed the mutational frequency of PIK3CA of three hotspots (exons 1, 9, and 20) in 81 primary invasive breast cancers (BC) and 25 cultured breast cancer-associated fibroblast (CAF) samples by Sanger sequencing in Arab breast cancer patients. Associations between the incidence of any PIK3CA mutation and several clinicopathologic characteristics were assessed using chi-square tests for categorical or t test for continuous variables. Furthermore, survival curves were estimated using the Kaplan-Meier method with the log rank test to evaluate the significance of their differences. We identified a total of 21 PIK3CA missense mutations with a frequency of 25.9%. The majority of the mutations, 17 out of 21 (81%), were in exon 20 (p.His1047Arg, p.His1047Lys, p.Thr1025Ala, p.Gly1049Arg, p.Asp1056Asn) while the remainder, 4 out of 21 (19%) were in exon 9 (p.Glu545Lys). PIK3CA mutations were significantly associated with lower grade and hormone receptor positivity. Although there was a favorable trend in overall survival for patients whose tumor harbored PIK3CA mutations, the difference was not statistically significant (P = 0.10). However, we did not detect any somatic mutations in CAFs. Furthermore, we have shown a high prevalence (8.2-fold) of a silent variant (SNP, rs17849079) in the Arab breast cancer population compared with disease-free individuals. PMID- 23982436 TI - The outcome and cost-effectiveness of nurse-led care in people with rheumatoid arthritis: a multicentre randomised controlled trial. AB - OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of nurse-led care (NLC) for people with rheumatoid arthritis (RA). METHODS: In a multicentre pragmatic randomised controlled trial, the assessment of clinical effects followed a non-inferiority design, while patient satisfaction and cost assessments followed a superiority design. Participants were 181 adults with RA randomly assigned to either NLC or rheumatologist-led care (RLC), both arms carrying out their normal practice. The primary outcome was the disease activity score (DAS28) assessed at baseline, weeks 13, 26, 39 and 52; the non-inferiority margin being DAS28 change of 0.6. Mean differences between the groups were estimated controlling for covariates following per-protocol (PP) and intention-to treat (ITT) strategies. The economic evaluation (NHS and healthcare perspectives) estimated cost relative to change in DAS28 and quality-adjusted life-years (QALY) derived from EQ5D. RESULTS: Demographics and baseline characteristics of patients under NLC (n=91) were comparable to those under RLC (n=90). Overall baseline adjusted difference in DAS28 mean change (95% CI) for RLC minus NLC was -0.31 ( 0.63 to 0.02) for PP and -0.15 (-0.45 to 0.14) for ITT analyses. Mean difference in healthcare cost (RLC minus NLC) was L710 (-L352, L1773) and -L128 (-L1263, L1006) for PP and ITT analyses, respectively. NLC was more cost-effective with respect to cost and DAS28, but not in relation to QALY utility scores. In all secondary outcomes, significance was met for non-inferiority of NLC. NLC had higher 'general satisfaction' scores than RLC in week 26. CONCLUSIONS: The results provide robust evidence to support non-inferiority of NLC in the management of RA. TRIAL REGISTRATION: ISRCTN29803766. PMID- 23982437 TI - Predictive value of ERCC1 and RRM1 gene single-nucleotide polymorphisms for first line platinum- and gemcitabine-based chemotherapy in non-small cell lung cancer patients. AB - Platinum-based chemotherapy with third generation drugs (such as gemcitabine) is an efficacious regimen of first-line treatment of patients with advanced, unresectable non-small cell lung cancer (NSCLC), without activating EGFR mutations. Mechanism of action of cytostatics are distortions in the DNA. ERCC1 and RRM1 are key proteins involved in the repair of DNA, thus, they may be responsible for the ineffectiveness of therapy. We investigated whether ERCC1 (19007C>T) and RRM1 (-37C>A) polymorphisms impact response to chemotherapy and survival in 62 patients with NSCLC treated with platinum and gemcitabine. Single nucleotide polymorphisms (SNPs) were assessed using a PCR-RFLP method in DNA isolated from PBLs. There were no statistically significant relationships between ERCC1 genotypes and response to therapy (p=0.581, chi2=1.09) as well as patient overall survival (OS). Carriers of the RRM1 AC genotype showed disease progression significantly more frequently (p=0.019, chi2=5.473) compared to carriers of the AA or CC genotypes. Carriers of the ERCC1/RRM1TT/CC genotype combination showed disease control significantly more frequently (p=0.047, chi2=3.95) compared to carriers of other genotype combinations. Patients with AA or CC genotypes of RRM1 showed significantly higher progression-free survival probability (p=0.0001, HR=0.39, 95% CI, 0.22-0.70) and OS probability (p=0.0104, HR=0.39, 95% CI, 0.18-0.82) compared to those with the AC genotype. In Cox regression model, poor performance status (p=0.0016, HR=4.78, 95% CI, 1.82 12.56), AC genotype of RRM1 gene (p=0.0414, HR=2.47, 95% CI, 1.04-5.87), lack of prior surgical treatment (p=0.0425, HR=4.71, 95% CI, 1.06-20.92) and lack of subsequent lines of treatment (p=0.0127, HR=3.23, 95% CI, 1.29-8.11) were significantly associated with shortening of patient survival. The analysis of RRM1 (-37C>A) more than ERCC1 (19007C>T) polymorphism may be a promising tool in the qualification of NSCLC patients for chemotherapy containing platinum compounds and gemcitabine. PMID- 23982438 TI - [Patient education of elderly with mobility impairments : Conception and evaluation of needs during and after release from a geriatric clinic setting]. AB - BACKGROUND: Patient education can contribute to obtaining and maintaining mobility in elderly with mobility impairments. The aim of this study was to evaluate counseling, training, and information needs in elderly patients with mobility impairments before, during, and after a hospital stay in a geriatric clinic. METHODS: A prospective longitudinal study was conducted. Needs were assessed at admission (t1), after 2 weeks (t2), at discharge (t3), after 3 months (t4), and after 6 months (t5). Data were analyzed using descriptive statistics. RESULTS: At almost all time points, there was a need of counseling and information. Counseling needs mainly comprised the themes assistive advices, fall prevention, professional nursing care, other services, nutrition, and pain management. Information needs comprised the themes fall prevention, professional nursing care, other services, assistive devices, nutrition, and modification of living space. There was a need of training mainly at admission and at discharge. Training needs comprised approach to assistive devices and mobility facilitation. CONCLUSION: Training should include activities related to mobility, while counseling and information should comprise all areas of life. PMID- 23982439 TI - Playfulness over the lifespan and its relation to happiness: results from an online survey. AB - BACKGROUND: Playfulness is an understudied topic in adults and particularly among the elderly. There is no large study to date on age-related changes in playfulness across the lifespan, nor have relations with different indicators of well-being been investigated in much detail as yet. PARTICIPANTS AND METHODS: In total, 4100 adults completed online self-ratings on their playfulness, happiness and Seligman's three orientations to happiness (a pleasurable, engaged and meaningfully fulfilled life). RESULTS: In a cross-sectional design, playfulness was stable across the lifespan; variations in the mean scores were relatively small (half a standard deviation). Yet participants <40 years yielded the comparatively lowest scores. There were no gender differences. Playfulness was best predicted by the scale assessing a pleasurable life and was positively related to happiness. CONCLUSION: Playfulness seems to be of relevance in all age groups and displays robust relations with different indicators of well-being. PMID- 23982440 TI - Cellular senescence in normal and premature lung aging. AB - The incidence of chronic respiratory diseases (e.g., chronic obstructive pulmonary disease, COPD) and interstitial lung diseases (e.g., pneumonia and lung fibrosis) increases with age. In addition to immune senescence, the accumulation of senescent cells directly in lung tissue might play a critical role in the increased prevalence of these pulmonary diseases. In the last couple of years, detailed studies have identified the presence of senescent cells in the aging lung and in diseased lungs of patients with COPD and lung fibrosis. Cellular senescence has been shown for epithelial cells of bronchi and alveoli as well as mesenchymal and vascular cells. Known risk factors for pulmonary diseases (cigarette smoke, air pollutions, bacterial infections, etc.) were identified in experimental studies as being possible mediators in the development of cellular senescence. The present findings indicate the importance of cellular senescence in normal lung aging and in premature aging of the lung in patients with COPD, lung fibrosis, and probably other respiratory diseases. PMID- 23982441 TI - A comparison of measurements of sodium, potassium, haemoglobin and creatinine between an Emergency Department-based point-of-care machine and the hospital laboratory. AB - Blood gas analysers provide electrolyte and metabolic data. In the author's institution, these values were not used clinically because of the risk of inaccuracy. To discover whether this approach was warranted, we compared values from our Radiometer point-of-care (POC) analyser and the laboratory. A total of 207 patients from an urban Emergency Department received venepuncture for sodium, potassium, creatinine and haemoglobin. Two samples were drawn; one analysed in the laboratory, the other on the POC machine. The results were: sodium: n=182, mean difference (MD) (lab-POC) 3.36, 95% limits of agreement (LOA) 0.18-6.54; potassium: n=171, MD 0.46, 95% LOA -0.12 to 1.03; creatinine: n=183, MD 1.6, 95% LOA -16.2 to 18.7; haemoglobin: n=191, MD -0.29, 95% LOA -1.71 to 1.12. Thus, sodium and potassium showed negative bias on the Radiometer compared with the laboratory. Creatinine and haemoglobin agreed well. We advocate the clinical use of POC values when taken in clinical context. PMID- 23982442 TI - A "wrap-and-wrest" mechanism of fluorescence quenching of CdSe/ZnS quantum dots by surfactant molecules. AB - We identified a mechanism of fluorescence quenching of CdSe/ZnS quantum dots (QDs) coated with two organic layers, octadecylamine and an amphiphilic polymer containing COOH groups, by nonionic polyoxyethylene-based (C12En) surfactants. The surfactant molecules by themselves do not affect the fluorescence of the QDs. For the quenching to occur, "wrapping" of the QDs by a bilayer of the surfactant molecules is necessary. The formation of the bilayer causes an irreversible detachment ("wresting") of the ligand molecules, accompanied by the creation of quenching sites on the QD surface. Due to its two-stage nature, we refer to the quenching mechanism as the "wrap-and-wrest" mechanism. The adsorption of the surfactant on the QD surface is a relatively slow process, occurring within minutes or hours. Such long quenching times allowed monitoring surfactant adsorption progress in real time. The fluorescence signal decays exponentially, and the decay time is inversely proportional to the surfactant concentration in solution. PMID- 23982443 TI - High-level beta1-integrin expression in a subpopulation of highly tumorigenic oral cancer cells. AB - OBJECTIVES: The beta1 integrin (CD29) is a putative marker for cancerous epithelial stem cells. Cancer stem cells are essential to drive tumor growth, recurrence, and metastasis. We investigated the role of beta1-integrin expression in the development of malignant phenotypes of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Immunostaining was used to analyze the expression levels of beta1 integrins in different types of cell colonies and tumor spheres. The results of cell viability and migration assays with and without siRNA knockdown of beta1-integrin expression were compared. Cells expressing beta1 integrins were evaluated for their tumorigenicity in mice. The expression of beta1 integrins in human specimens of oral cancers at different clinical stages was semiquantified based on immunohistochemical staining of the beta1-integrin protein. RESULTS: The expression level of beta1 integrins in Meng-1 oral epidermoid carcinoma cells (OECM-1) cells was significantly higher in holoclonal colonies and tumor spheres compared to control cells. The knockdown of beta1 integrin expression in OECM-1 cells reduced cell proliferation, migration, and tumor sphere formation. Beta-1 integrin (+) cells were more tumorigenic in the mouse xenograft model than beta1 integrin (-) cells. In the human specimens, the expression level of the beta1-integrin protein positively correlated with the clinical stage. CONCLUSION: The expression of beta1 integrin in OECM-1 cells is involved in the development of malignant phenotypes of OSCC. CLINICAL RELEVANCE: Inhibitors for beta1-integrin signaling may be suitable to become target-specific therapies for OSCC. PMID- 23982444 TI - Effect of pulverized natural bone mineral on regeneration of three-wall intrabony defects. A preclinical study. AB - AIMS: The objective of this study is to evaluate the effects of a paste-like bone substitute material with easy handling properties and improved mechanical stability on periodontal regeneration of intrabony defects in dogs. MATERIALS AND METHODS: Mandibular and maxillary first and third premolars were extracted, and three-wall intrabony defects were created on second and fourth premolars. After a healing period of 3 months, acute type defects were filled with a paste-like formulation of deproteinized bovine bone mineral (DBBM) (particle size, 0.125 0.25 mm) in a collagenous carrier matrix (T1), pulverized DBBM (particle size, 0.125-0.25 mm) without the carrier (T2), or Bio-Oss(r) granules (particle size, 0.25-1.00 mm) as control (C). All defects were covered with a Bio-Gide(r) membrane. The dogs were sacrificed after 12 weeks, and the specimens were analyzed histologically and histometrically. RESULTS: Postoperative healing of all defects was uneventful, and no histological signs of inflammation were observed in the augmented and gingival regions. New cementum, new periodontal ligament, and new bone were observed in all three groups. The mean vertical bone gain was 3.26 mm (T1), 3.60 mm (T2), and 3.81 mm (C). That of new cementum was 2.25 mm (T1), 3.88 mm (T2), and 3.53 mm (C). The differences did not reach statistical significance. The DBBM particles were both incorporated in new bone and embedded in immature bone marrow. CONCLUSIONS: The results of this preclinical study showed that the 0.125-0.25-mm DBBM particles in a powder or paste formulation resulted in periodontal regeneration comparable to the commercially available DBBM. Osteoconductivity, in particular, was not affected by DBBM size or paste formulation. CLINICAL RELEVANCE: The improved handling properties of the paste-like bone substitute consisting of small DBBM particles embedded in a collagen-based carrier hold promise for clinical applications. PMID- 23982445 TI - Calcium fructoborate helps control inflammation associated with diminished bone health. AB - Inflammation has been identified as a possible contributory factor to disruption of the normal bone remodeling process, a process essential to healthy bone mineral density. Several large population-based clinical studies have specifically shown that levels of C-reactive protein, an immune recognition protein that is a sensitive marker of inflammation, are inversely and independently associated with total bone mineral density. The evidence suggests that control of C-reactive protein levels may contribute to bone health by protecting against inflammation's disruption of the equilibrium between bone resorption and bone deposition. Calcium fructoborate, a patented complex of calcium, fructose, and boron found naturally in fresh and dried fruits, vegetables and herbs, and wine, is a sugar-borate ester. A growing body of peer reviewed, published clinical research indicates that the calcium fructoborate significantly reduces serum levels of the C-reactive protein in humans, suggesting that this unique plant-mineral complex may contribute to bone health by controlling the inflammation associated with loss of bone mineral density. PMID- 23982446 TI - The Top3beta way to untangle RNA. PMID- 23982447 TI - TMEM16C cuts pain no SLACK. PMID- 23982448 TI - A finely tuned cortical amplifier. PMID- 23982449 TI - 10,000 hours to perfection. PMID- 23982450 TI - Whole slurry fermentation of maleic acid-pretreated oil palm empty fruit bunches for ethanol production not necessitating a detoxification process. AB - The yield of ethanol from oil palm empty fruit bunches (EFB) was increased on exploiting maleic acid pretreatment combined with fermentation of the pretreated whole slurry. The optimized conditions for pretreatment were to expose EFB to a high temperature (190 degrees C) with 1 % (w/v) maleic acid for a short time duration (3 min ramping to the set temperature with no holding) in a microwave digester. An enzymatic digestibility of 60.9 % (based on theoretical glucose yield) was exhibited using pretreated and washed EFB after 48 h of hydrolysis. Simultaneous saccharification and fermentation (SSF) of the whole slurry of pretreated EFB for 48 h resulted in 61.3 % theoretical yield of ethanol based on the initial amount of glucan in untreated EFB. These results indicate that maleic acid is a suitable catalyst not requiring detoxification steps for whole slurry fermentation of EFB for ethanol production, thus improving the process economics. Also, the whole slurry fermentation can significantly increase the biomass utilization by converting sugar from both solid and liquid phases of the pretreated slurry. PMID- 23982451 TI - Evolution of (18)FDG pituitary uptake after medical control of acromegaly. PMID- 23982452 TI - Molecular and Merrifield supported chiral diamines for enantioselective addition of ZnR2 (R = Me, Et) to ketones. AB - Chiral 1,2-ethylenediamines have been previously reported as active catalysts in the enantioselective addition reactions of ZnR2 to either methyl- or trifluoromethyl-ketones. Subtle changes in the molecular structure of different catalysts are described herein and lead to a dramatic effect in their catalytic activity. From these findings, we demonstrate the selective reactivity of the ligands used in the addition of ZnR2 (R = Me, Et) to methyl- and trifluoromethyl ketones offering an enantioselective access either to chiral non-fluorinated alcohols or to chiral fluorinated tertiary alcohols. Considering the importance of the chiral trifluoromethyl carbinol fragment in several biologically active compounds, we have extended the scope of the addition reaction of ZnEt2 to several trifluoromethylketones catalyzed by (R,R)-1,2-diphenylethylenediamine derivatives. This work explores a homogeneous approach that provides excellent yields and very high ee and the use of a heterogenized tail-tied ligand affording moderate ee, high yields and allowing an easier handling and recycling. PMID- 23982453 TI - Hybrid CT angiography and quantitative 15O-water PET for assessment of coronary artery disease: comparison with quantitative coronary angiography. AB - PURPOSE: CT angiography (CTA) can rule out significant stenoses with a very high reliability, whereas its ability to confirm significant stenoses is suboptimal. In contrast, measurements of myocardial blood flow (MBF) provide information on the haemodynamic consequences of stenoses. Therefore, a combination of the two might improve diagnostic accuracy. We conducted a head-to-head comparison of CTA, measurement of MBF by (15)O-water PET, and hybrid PET/CTA for the detection of significant coronary artery stenoses. METHODS: The study group comprised 44 outpatients scheduled for invasive coronary angiography (ICA) with an intermediate pretest likelihood of coronary artery disease. The patients underwent 64-slice CTA and baseline and hyperaemic PET before ICA with quantitative coronary angiography analysis. RESULTS: On a per-patient basis, the negative predictive values (NPV; 95% confidence intervals in parentheses) were 88 % (64 - 97%) for CTA, 90% (71 - 97%) for PET and 92% (74 - 98%) for PET/CTA, and the positive predictive values (PPV) were 71% (53 - 85%) for CTA, 87% (68 - 95%) for PET and 100% (84 - 100%) for PET/CTA. Similarly, on a per-vessel basis the NPVs (which were generally high) were 97% (94 - 100%) for CTA, 95 % (90 - 99%) for PET and 97% (95 - 100%) for PET/CTA, and the PPVs (which were lower, but higher with PET/CTA) were 53% (39 - 66%) for CTA, 53 % (40 - 66%) for PET and 85 % (73 - 97%) for PET/CTA. In six patients, CTA analysis was hampered by the presence of severe calcifications. However, with the addition of the PET data, all six patients were correctly categorized. CONCLUSION: Cardiac quantitative hybrid PET/CTA imaging has better diagnostic accuracy than CTA alone and PET alone. CTA has a suboptimal PPV, suggesting that hybrid PET/CTA imaging should be used to assess the significance of coronary stenoses diagnosed by CTA. PMID- 23982454 TI - Absolute myocardial flow quantification with (82)Rb PET/CT: comparison of different software packages and methods. AB - PURPOSE: In clinical cardiac (82)Rb PET, globally impaired coronary flow reserve (CFR) is a relevant marker for predicting short-term cardiovascular events. However, there are limited data on the impact of different software and methods for estimation of myocardial blood flow (MBF) and CFR. Our objective was to compare quantitative results obtained from previously validated software tools. METHODS: We retrospectively analyzed cardiac (82)Rb PET/CT data from 25 subjects (group 1, 62 +/- 11 years) with low-to-intermediate probability of coronary artery disease (CAD) and 26 patients (group 2, 57 +/- 10 years; P=0.07) with known CAD. Resting and vasodilator-stress MBF and CFR were derived using three software applications: (1) Corridor4DM (4DM) based on factor analysis (FA) and kinetic modeling, (2) 4DM based on region-of-interest (ROI) and kinetic modeling, (3) MunichHeart (MH), which uses a simplified ROI-based retention model approach, and (4) FlowQuant (FQ) based on ROI and compartmental modeling with constant distribution volume. RESULTS: Resting and stress MBF values (in milliliters per minute per gram) derived using the different methods were significantly different: using 4DM-FA, 4DM-ROI, FQ, and MH resting MBF values were 1.47 +/- 0.59, 1.16 +/- 0.51, 0.91 +/- 0.39, and 0.90 +/- 0.44, respectively (P<0.001), and stress MBF values were 3.05 +/- 1.66, 2.26 +/- 1.01, 1.90 +/- 0.82, and 1.83 +/- 0.81, respectively (P<0.001). However, there were no statistically significant differences among the CFR values (2.15 +/- 1.08, 2.05 +/- 0.83, 2.23 +/- 0.89, and 2.21 +/- 0.90, respectively; P=0.17). Regional MBF and CFR according to vascular territories showed similar results. Linear correlation coefficient for global CFR varied between 0.71 (MH vs. 4DM-ROI) and 0.90 (FQ vs. 4DM-ROI). Using a cut-off value of 2.0 for abnormal CFR, the agreement among the software programs ranged between 76 % (MH vs. FQ) and 90 % (FQ vs. 4DM-ROI). Interobserver agreement was in general excellent with all software packages. CONCLUSION: Quantitative assessment of resting and stress MBF with (82)Rb PET is dependent on the software and methods used, whereas CFR appears to be more comparable. Follow-up and treatment assessment should be done with the same software and method. PMID- 23982455 TI - Effects of oral nicorandil therapy on sympathetic nerve activity and cardiac events in patients with chronic heart failure: subanalysis of our previous report using propensity score matching. AB - PURPOSE: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, improves cardiac sympathetic nerve activity (CSNA) in patients with ischaemic heart disease. However, the long-term effects on both CSNA, as evaluated by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, and prognosis have not been determined in patients with chronic heart failure (CHF). METHODS: This study was a subanalysis of our previous results that serial (123)I-MIBG scintigraphic studies are the most useful prognostic indicator in CHF patients. The study group comprised 208 patients with CHF (left ventricular ejection fraction <45 %) but no cardiac events for at least 5 months identified on the basis of a history of decompensated acute heart failure requiring hospitalization. These patients underwent (123)I-MIBG scintigraphy and echocardiography just before leaving the hospital and again 6 months later. We selected 170 patients and used propensity propensity score matching to compare patients who received oral nicorandil (85 patients) and those who did not (85 patients). The patients were followed up for a median of 5.03 years, with the primary and secondary study end-points defined as the occurrence of a fatal cardiac event and a major adverse cardiac event (MACE), respectively. RESULTS: After treatment, the extent of changes in (123)I-MIBG scintigraphic and echocardiographic parameters in the nicorandil group were more favourable than in those not receiving nicorandil. Of the 170 patients, a fatal cardiac event occurred in 42, and a MACE in 68 during the study. Multivariate Cox regression analyses revealed that no nicorandil treatment was a significant predictor of both cardiac death and MACE in our patients with CHF. On Kaplan-Meier analysis, the rates of freedom from cardiac death or from MACE in the nicorandil group were significantly higher than in those not receiving nicorandil (all p<0.05). CONCLUSION: Long-term nicorandil treatment improves CSNA and left ventricular parameters in patients with CHF. Furthermore, this agent is potentially effective for reducing the incidence of cardiac events in patients with CHF. PMID- 23982456 TI - 131I treatment for thyroid cancer and risk of developing primary hyperparathyroidism: a cohort study. AB - PURPOSE: To evaluate the association between (131)I therapy for thyroid cancer and risk of developing primary hyperparathyroidism. METHODS: This was a nationwide population-based cohort study of patients with thyroid cancer diagnosed during the period 1997-2008. The data were obtained from the Taiwan National Health Insurance Research dataset. The cumulative (131)I dose in each patient was calculated. Hazard ratios (HRs) were calculated using a proportional hazards model to estimate the effect of (131)I therapy on the risk of developing primary hyperparathyroidism in the cohort. RESULTS: A total of 8,946 patients with thyroid cancer were eligible for the final analysis. Among these patients, 8 developed primary hyperparathyroidism during the follow-up period that represented 38,248 person-years giving an incidence rate of 20.9 per 10(5) person years. (131)I was used in the treatment of 6,153 patients (68.8%) with a median cumulative dose of 3.7 GBq. The adjusted HRs were 0.21 (95% CI 0.02-1.86) and 0.46 (95% CI 0.10-2.10) for those receiving a cumulative (131)I dose of 0.1-3.6 GBq and >=3.7 GBq, respectively, compared to no therapy. The risk of developing primary hyperparathyroidism did not increase with increasing (131)I dose (test for trend p = 0.51). No interaction was found between (131)I dose and age (p = 0.94) or (131)I dose and sex (p = 0.99). CONCLUSION: (131)I treatment for thyroid cancer did not increase risk of primary hyperparathyroidism during a 10-year follow-up in this study population. Further research with a longer follow-up period is needed to assess late adverse effects beyond 10 years. PMID- 23982457 TI - Plumbagin induces the apoptosis of human tongue carcinoma cells through the mitochondria-mediated pathway. AB - BACKGROUND: Plumbagin, a quinonoid constituent isolated from the root of Plumbago zeylanica L., has been proven to possess anti-tumor activity both in vitro and in vivo. However, its anti-tumor properties for human tongue carcinoma have not been reported. This study aimed to investigate the inhibitory effect and the underlying mechanism of plumbagin on the growth of human tongue carcinoma cells. MATERIAL AND METHODS: Cell proliferation ability was detected by EdU incorporation assay and colony formation assay. Cell-cycle distribution was determined by flow cytometric analysis using propidium iodide (PI) staining. Cellular apoptosis was then evaluated by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Western blotting was applied to assay the expression of Bax and Bcl-2. RESULTS: Plumbagin inhibited the growth and proliferation of Tca8113 cells in vitro in a concentration- and time-dependent manner. The cell cycles of plumbagin-treated Tca8113 cells were arrested at the G2/M phase. Cells treated with plumbagin presented the characteristic morphological changes of apoptosis. The ratio of Bax/Bcl-2 was raised by plumbagin in a concentration-dependent manner. CONCLUSIONS: These results indicate that plumbagin induces the apoptosis of Tca8113 cells through mitochondria-mediated pathway. PMID- 23982458 TI - A comparison of two coaching approaches to enhance implementation of a recovery oriented service model. AB - Moving to recovery-oriented service provision in mental health may entail retraining existing staff, as well as training new staff. This represents a substantial burden on organisations, particularly since transfer of training into practice is often poor. Follow-up supervision and/or coaching have been found to improve the implementation and sustainment of new approaches. We compared the effect of two coaching conditions, skills-based and transformational coaching, on the implementation of a recovery-oriented model following training. Training followed by coaching led to significant sustained improvements in the quality of care planning in accordance with the new model over the 12-month study period. No interaction effect was observed between the two conditions. However, post hoc analyses suggest that transformational coaching warrants further exploration. The results support the provision of supervision in the form of coaching in the implementation of a recovery-oriented service model, and suggest the need to better elucidate the mechanisms within different coaching approaches that might contribute to improved care. PMID- 23982460 TI - Contradictory discourses of health promotion and disease prevention in the educational curriculum of Norwegian public health nursing: a critical discourse analysis. AB - AIMS: Health care is under constant change creating new and demanding tasks for public health nurses. The curriculum for public health nursing students is controlled by governmental directives that decide the structure and content of their education. This paper analyses manifest and latent discourses in the curriculum, in order to reveal underlying governmental principles for how public health nurses should promote health and prevent diseases. METHODS: A critical discourse analysis of the Norwegian public health nursing curriculum was conducted. RESULTS: The study indicates i) 'a competing biomedical and social scientific knowledge-discourse', with biomedical knowledge dominating the content of the curriculum; ii) 'a paternalistic meta-discourse', referring to an underlying paternalistic ideology despite a clear focus on user participation; and iii) 'a hegemonic individual discourse'. Even though the curriculum stipulates that public health nurses should work at both an individual and a societal level, there is very little population focus in the text. CONCLUSIONS: Recent political documents concerning public health nursing focus more on health promotion, however, this is not sufficiently explicit in the curriculum. The lack of emphasis on social scientific knowledge, and the blurred empowerment and population perspective in the curriculum, can lead to less emphasis on health promotion work in public health nursing education and practice. The curriculum should be revised in order to meet the recent governmental expectations. PMID- 23982459 TI - Understanding the interactions between bacteria in the human gut through metabolic modeling. AB - The human gut microbiome plays an influential role in maintaining human health, and it is a potential target for prevention and treatment of disease. Genome scale metabolic models (GEMs) can provide an increased understanding of the mechanisms behind the effects of diet, the genotype-phenotype relationship and microbial robustness. Here we reconstructed GEMs for three key species, (Bacteroides thetaiotamicron, Eubacterium rectale and Methanobrevibacter smithii) as relevant representatives of three main phyla in the human gut (Bacteroidetes, Firmicutes and Euryarchaeota). We simulated the interactions between these three bacteria in different combinations of gut ecosystems and compared the predictions with the experimental results obtained from colonization of germ free mice. Furthermore, we used our GEMs for analyzing the contribution of each species to the overall metabolism of the gut microbiota based on transcriptome data and demonstrated that these models can be used as a scaffold for understanding bacterial interactions in the gut. PMID- 23982461 TI - The communicative and critical health literacy scale--Swedish version. AB - BACKGROUND: Health literacy (HL) is an important determinant for health and a valuable health indicator within public health. As such, it is a significant outcome variable of health promotion efforts. Valid and reliable instruments are needed to evaluate health promotion interventions and to assess levels of HL in a population. One of the few measurements of communicative and critical HL is the Japanese Communicative and Critical Health Literacy scale (C & C HL scale). To make it possible to use this instrument in Sweden, the C & C HL scale was translated into Swedish and different aspects of validity, including test-retest reliability, of the translated version were tested. METHODS: After translation and back-translation, The Swedish C & C HL scale was tested for content validity and test-retest reliability. Data were collected from a committee consisting of public health experts and bilingual people, and from a test group of 35 persons. RESULTS: The Swedish C & C HL scale was understandable and showed evidence of content validity. The test-retest confirmed that it was stable over time, percentage agreements for the items ranging from 66% to 89% (M = 74%). CONCLUSIONS: The Swedish C & C HL scale is equivalent to the Japanese C & C HL scale in terms of language and content. The items cover the major aspects of communicative and critical HL and are understandable and stable over time, i.e., reliable. PMID- 23982462 TI - Accuracy of death certificates of cardiovascular disease in a community intervention in Sweden. AB - AIM: The aim was to investigate the possibility to evaluate the mortality pattern in a community intervention programme against cardiovascular disease by official death certificates. METHODS: For all deceased in the intervention area (Norsjo), the accuracy of the official death certificates were compared with matched controls in the rest of Vasterbotten. The official causes of death were compared with new certificates, based on the last clinical record, issued by three of the authors, and coded by one of the authors, all four accordingly blinded. RESULTS: The degree of agreement between the official underlying causes of death in "cardiovascular disease" (CVD) and the re-evaluated certificates was not found to differ between Norsjo and the rest of Vasterbotten. The agreement was 87% and 88% at chapter level, respectively, but only 55% and 55% at 4-digit level, respectively. The reclassification resulted in a 1% decrease of "cardiovascular deaths" in both Norsjo and the rest of Vasterbotten. CONCLUSIONS: The disagreements in the reclassification of cause of death were equal but large in both directions. The official death certificates should be used with caution to evaluate CVD in small community intervention programmes, and restricted to the chapter level and total populations. PMID- 23982463 TI - The Symptom Checklist-core depression (SCL-CD6) scale: psychometric properties of a brief six item scale for the assessment of depression. AB - AIMS: Major depressive disorders are common, with substantial impact on individuals/society. Brief scales for depression severity, based on a small number of characteristics all of which are necessary for diagnosis, have been recommended in self-reported versions for clinical work or research when aiming to quickly and accurately measure depression. We have examined psychometric properties of a brief 6-item version of the Symptom Checklist (SCL), the Symptom Checklist core depression scale (SCL-CD6) and aimed to identify a cut-point for epidemiological research. METHODS: The psychometric evaluation of the SCL-CD6 was mainly performed by a Mokken analysis of unidimensionality in a random sample of 1476 residents in the Stockholm County, aged 18-64 years. The standardization of SCL-CD6 was based on ROC analysis, using the Major Depression Inventory as index of validity. Predictive validity was subsequently assessed using register data on hospital admissions and purchases of prescribed medications linked to a sample of 5985 participants in the Swedish Longitudinal Occupational Survey of Health (SLOSH). RESULTS: The SCL-CD6 obtained a coefficient of homogeneity of 0.70 by Mokken analysis, which indicates high unidimensionality and a meaningful dimensional measure of depression severity. By ROC we identified a score of 17 or higher (total range 0-24) as the best cut-point for major depression (sensitivity 0.68, specificity 0.98) which predicted subsequent purchases of antidepressants as well as hospitalisations with a depressive episode. CONCLUSIONS: The SCL-CD6 was found a valid depression scale with higher unidimensionality than longer epidemiological instruments and thus particularly suitable for assessment in larger population surveys. PMID- 23982464 TI - [Two-stage urethral reconstruction with buccal mucosa for hypospadias cripples : Long-term results]. AB - So-called hypospadias cripples are a challenging group of patients who present with multiple previous repair operations with unsatisfactory functional and cosmetic results. Attempts at renewed correction can be carried out with various techniques and different materials and staged repair with buccal mucosa according to Bracka has shown good results. PMID- 23982465 TI - Thyroid cancer: zealous imaging has increased detection and treatment of low risk tumours. PMID- 23982466 TI - Association between CAG repeat polymorphisms and the risk of prostate cancer: a meta-analysis by race, study design and the number of (CAG)n repeat polymorphisms. AB - Although a number of studies have been conducted on the association between prostate cancer and CAG repeat polymorphisms of the androgen receptor gene, this association remains elusive and controversial. In this meta-analysis, we aimed to evaluate the effects of (CAG)n repeat genetic polymorphisms on the incidence of prostate cancer, particularly as regards race, study design and the number of (CAG)n repeats. To collect articles published on the association between CAG repeats and prostate cancer, publications were identified from the National Center for Biotechnology Information (NCBI) database of epidemiological studies published up to October 2011; our identification of publications was not limited by a language barrier. The following search keywords were used: prostate cancer risk, CAG repeat polymorphism, androgen receptor gene and human. Stata version 10 was used for the meta-analysis and the publication bias was measured through the Begg's test and Egger's test. This meta-analysis included 47 studies with 13,346 cases and 15,172 control or non-cases and consisted of 31 reports based on Caucasians, ten on Asians, one on Hispanics and four on combined ethnic groups. The carriers of a shorter CAG repeat sequence had an increased risk of prostate cancer (OR 1.21, 95% CI 1.10-1.34 for all subjects; OR 1.21, 95% CI 1.10-1.34 for prospective studies; OR 1.32, 95% CI 1.15-1.51 for retrospective studies) regardless of the exact length of the CAG repeat, compared with carriers of a longer repeat sequence. In terms of race, the risk of carrying a shorter CAG repeat sequence was 1.10- and 1.83-fold higher than that of a longer repeat sequence in Caucasians and Asians, respectively. For the specific number of CAG repeat polymorphisms, carriers of <22 repeats were observed to have a higher risk of prostate cancer (OR 1.16, 95% CI 1.04-1.29) compared with carriers with >= 22 CAG repeat polymorphisms, particularly for Asians (OR 2.06, 95% CI 1.00-4.24). This meta-analysis suggests that a shorter CAG repeat polymorphism may increase the risk of prostate cancer compared with the longer CAG repeat; in particular, the effect of shorter CAG repeats on the increased risk of prostate cancer was predominantly observed in Caucasians and Asians. PMID- 23982467 TI - Drug-coated balloons for treatment of coronary artery disease: updated recommendations from a consensus group. AB - AIMS: Drug-coated balloon catheters (DCB) are a new clinical treatment modality for coronary and peripheral artery disease. The goal of the consensus group is to develop recommendations for the clinical use of DCB based on randomized clinical trials and the best available clinical evidence. The present paper gives an update on the recommendations against the background of a variety of new data published since the first paper was presented. METHODS AND RESULTS: The general concept of our recommendations for the coronary use of DCB includes the preparation of the lesion to facilitate drug delivery and to estimate the need for stent implantation, especially after relevant dissections. Lesion preparation includes conventional angioplasty. In more complex lesions, additional treatments and imaging or functional measurements are helpful. In case of no flow-limiting dissection and an acceptable but not stent-like primary result, DCB use without additional stent implantation may be considered. The proposed advantages of the DCB only concept over a direct stent approach include reduced restenosis rates in indications where DES show limited efficacy, the reduction of DAPT especially in patients with contraindications for prolonged DAPT, and the option of leaving no foreign object behind resulting in vascular restoration with potentially plaque regression instead of neo-atherosclerosis. CONCLUSIONS: DCB allow for local drug delivery in endovascular therapy leaving no permanent implant behind. PMID- 23982468 TI - Effects of trimetazidine in patients with acute myocardial infarction: data from the Korean Acute Myocardial Infarction Registry. AB - BACKGROUND: Excess myocardial fatty acid oxidation can cause a range of deleterious myocardial effects. Trimetazidine (TMZ) is a clinically effective antianginal agent that selectively inhibits long-chain 3-ketoacyl CoA thiolase, reducing fatty acid oxidation and stimulating glucose oxidation. The role of TMZ in acute myocardial infarction (AMI), however, remains unclear. Our retrospective analysis explores the effect on clinical outcomes of adding TMZ to standard treatment in patients with AMI. METHODS: All 13,733 AMI patients registered in the Korean Acute Myocardial Infarction Registry from 2005 to 2008 were retrospectively enrolled. Patients were divided into two groups: those treated with TMZ during their in-hospital management period and those who were not. Primary endpoints were all-cause death combined in-hospital and 12-month death and major adverse cardiac events (MACE), which included all-cause death, recurrent myocardial infarction (MI), repeated percutaneous coronary intervention (PCI) for target lesion revascularization (TLR), and coronary artery bypass graft. Propensity-matched patients were analyzed using an adjusted Cox proportional hazards model. RESULTS: Baseline clinical and angiographic characteristics in the TMZ and no-TMZ groups were generally similar, with the exceptions of pre-PCI thrombolysis in myocardial infarction flow grade, stent type, and stent length. Over 12 months, the relative risk of all-cause death fell by 59 % (event rate 2.3 vs. 6.4 %; hazard ratio 0.41, 95 % CI 0.18-0.97, P = 0.042) and the relative risk of MACE fell by 76 % (event rate 2.3 vs. 9.5 %; hazard ratio 0.24, 95 % CI 0.10-0.56, P = 0.001) in the TMZ group compared with those in the no-TMZ group. CONCLUSIONS: Trimetazidine appeared to improve clinical outcomes in AMI patients by significantly reducing all-cause mortality and MACE over 12 months. PMID- 23982470 TI - BTG1 inhibits breast cancer cell growth through induction of cell cycle arrest and apoptosis. AB - BTG1, which belongs to the BTG/Tob family, regulates cell cycle progression in a variety of cell types and appears to play roles in inhibiting proliferation, promoting apoptosis and stimulating cellular differentiation in multiple cell types. However, it remains unclear whether BTG1 is a breast cancer suppressor gene, and the role of BTG1 in breast cancer cell growth has not yet been determined. In the present study, we observed that BTG1 was weakly expressed in human breast tumors and in breast cancer cells (MCF-7 and MDA-MB-231). In addition, we investigated the potential effects of BTG1 on breast cancer cell proliferation, cell cycle distribution and apoptosis after stable transfection with the BTG1 expression vector. We found that overexpression of BTG1 inhibited cell proliferation, induced G0/G1 cell cycle arrest and promoted apoptosis. Further investigation indicated that overexpression of BTG1 was involved in the inhibition of the expression of cell cycle-related proteins, cyclin B1 and cyclin D1, and pro-apoptotic factors, Bax and caspase-3, and was also involved in the promotion of anti-apoptotic factor Bcl-2. In vivo, animal experiments showed that tumors overexpressing BTG1 displayed a slower growth rate than the control xenografts. TUNEL end staining assay revealed that BTG1 induced tumor necrosis and apoptosis. Taken together, our data revealed that, in breast cancer cells, BTG1 inhibits cell growth through induction of cell cycle arrest and apoptosis. These results indicate that BTG1 may be used as a novel therapeutic target for human breast cancer treatment. PMID- 23982469 TI - Low glucose utilization and neurodegenerative changes caused by sodium fluoride exposure in rat's developmental brain. AB - Fluorine, a toxic and reactive element, is widely prevalent throughout the environment and can induce toxicity when absorbed into the body. This study was to explore the possible mechanisms of developmental neurotoxicity in rats treated with different levels of sodium fluoride (NaF). The rats' intelligence, as well as changes in neuronal morphology, glucose absorption, and functional gene expression within the brain were determined using the Morris water maze test, transmission electron microscopy, small-animal magnetic resonance imaging and Positron emission tomography and computed tomography, and Western blotting techniques. We found that NaF treatment-impaired learning and memory in these rats. Furthermore, NaF caused neuronal degeneration, decreased brain glucose utilization, decreased the protein expression of glucose transporter 1 and glial fibrillary acidic protein, and increased levels of brain-derived neurotrophic factor in the rat brains. The developmental neurotoxicity of fluoride may be closely associated with low glucose utilization and neurodegenerative changes. PMID- 23982471 TI - Entire thickness profiles of the epithelium and contact lens in vivo imaged with high-speed and high-resolution optical coherence tomography. AB - PURPOSE: To test the feasibility of measuring the entire thickness profiles of the epithelium and contact lens (CL) in vivo, using high-speed and high resolution spectral-domain optical coherence tomography (SD-OCT). METHODS: A custom-built, long scan depth SD-OCT was developed based on a complementary metal oxide semiconductor (CMOS) camera, and the axial resolution was approximately 5.1 MUm in tissue. Five eyes of five subjects were imaged twice across the horizontal meridian before and while wearing one CL. Semiautomatic measurement was done to yield the entire thickness profiles of the epithelium, total cornea, and CL after correcting for optical distortion. RESULTS: The full width and depth of the epithelium, ocular surface, and CL were clearly visualized. The epithelial thickness at the center was 51.9+/-3.5 MUm; it remained at this thickness across the central 7 mm diameter and then increased at both temporal and nasal peripheries. The CL profile showed the thinnest point at the center with thickness of 100.3+/-4.9 MUm. The thickness increased toward the midperiphery and then decreased at the edge. CONCLUSIONS: This pilot study demonstrated the feasibility of using high-speed CMOS-based OCT to evaluate the entire thickness profiles of the epithelium and CL in vivo. Further development will be needed to extend the scanning from 2D to 3D with a robust automatic image processing ability. PMID- 23982472 TI - Ocular surface infections in northeastern state of malaysia: a 10-year review of bacterial isolates and antimicrobial susceptibility. AB - OBJECTIVE: Ocular surface infections that include infections of conjunctiva, adnexa, and cornea have the potential risk of causing blindness within a given population. Empirical antibiotic therapy is usually initiated based on epidemiological data of common causative agents. Thus, the aims of this study were to determine the bacterial agents and their susceptibility patterns of isolates from ocular surface specimens in our hospital. METHODS: This is a retrospective analysis and records of bacterial isolates from ocular surface specimens in Hospital Universiti Sains Malaysia from January 2001 to December 2010 were examined. Specimens were processed according to standard laboratory procedures. Antimicrobial susceptibility testing was conducted based on Clinical and Laboratory Standards Institute recommendations. Only single, nonrepetitive isolates were included in the analysis. RESULTS: A total of 1,267 isolates were obtained during the study period, which comprised Staphylococcus aureus (n = 299, 23.6%), Pseudomonas aeruginosa (n = 194, 15.3%), Streptococcus pneumoniae (n = 108, 8.5%), Haemophilus influenzae (n = 100, 7.9%), Haemophilus parainfluenzae (n = 84, 6.6%), and Enterobacter spp. (n = 81, 6.4%). Fungi contributed to 4.4% of the total isolates. The antimicrobial susceptibility testing demonstrated that gram-positive bacteria were generally resistant to gentamicin (19%-57%), whereas gram-negative bacteria were resistant to chloramphenicol (27%-58%). CONCLUSIONS: Based on the above results, knowledge of the initial Gram stain findings is imperative before the commencement of empirical antibiotic therapy. Therefore, a simple Gram staining for all eye specimens is highly recommended. PMID- 23982473 TI - A novel one-pot route for large-scale preparation of highly photoluminescent carbon quantum dots powders. AB - A simple one-pot microwave-assisted approach has been established for the large scale preparation of carbon quantum dots (CDs) with excellent water solubility and photoluminescence. The properties and mechanism were demonstrated. Moreover, the CDs have been applied to the detection of tetracycline hydrochloride. PMID- 23982474 TI - The effects of climate and aero allergens changes in allergic rhinoconjunctivitis and allergic asthma patients in Mediterranean region between 2011 and 2012. PMID- 23982475 TI - Theoretical studies on the structure, thermochemical and detonation properties of amino and nitroso substituted 1,2,4-triazol-5-one-N-oxides. AB - DFT calculations at the B3LYP/aug-cc-pVDZ level have been carried out to explore the structure, stability, electron density, heat of formation, detonation velocity and detonation pressure of substituted amino- and nitroso-1,2,4-triazol 5-one-N-oxides. Heats of formation of substituted triazol-5-one-N-oxides have been computed at the B3LYP/aug-cc-pVDZ level via isodesmic reaction procedure. Materials Studio 4.1 package was used to predict the crystal density of model compounds. Kamlet-Jacob equations were used to calculate detonation properties based on the calculated heat of explosion and crystal density. The designed compounds 4, 6, 7 and 8 have shown higher performance compared with those of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane and octanitrocubane. Atoms-in-molecule (AIM) analyses have also been carried out to understand the nature of intramolecular interactions in the designed molecules. PMID- 23982476 TI - Computational insight into novel molecular recognition mechanism of different bioactive GAs and the Arabidopsis receptor GID1A. AB - Gibberellin (GA) is an essential plant hormone and plays a significant role during the growth and development of the higher plants. The molecular recognition mode between GA and receptor Arabidopsis thaliana GIBBERELLIN INSENSITIVE DWARF1 A (AtGID1A) was investigated by molecular docking and dynamics simulations to clarify the selective perceived mechanism of different bioactive GA molecules to AtGID1A. The 6-COOH group of GA, especially its beta configuration, was found to be an indispensable pharmacophore group for GA recognition and binding to AtGID1A. Not only does a strong salt bridge interaction between the 6beta-COOH group of GA and Arg244 of AtGID1A play a very important role in the GA recognition of the receptor, but also an indirect water bridge interaction between the pharmacophore group 6beta-COOH of GA and the residue Tyr322 of AtGID1A is essential for the GA binding to the receptor. The site-directed residues mutant modeling study on the receptor-binding pocket confirmed that the mutations of Arg244 and Tyr322 decreased the GA binding activity due to the disappearances of the salt bridge and the hydrogen bond interaction. The 3beta-OH group of GA was well known to be necessary for the GA bioactivity due to its forming a unique hydrogen bond with Tyr127 of AtGID1A. In addition, the hydrophobic interaction between GA and AtGID1A was considered a necessary factor to lock the GA active conformation and stabilize the GA-GID1A complex structure. The novel molecular recognition mode will be beneficial in elucidating the GA regulation function on the growth and development of the higher plants. PMID- 23982477 TI - Adiponectin inhibits neutrophil apoptosis via activation of AMP kinase, PKB and ERK 1/2 MAP kinase. AB - Neutrophils are abundant, short-lived leukocytes that play a key role in the immune defense against microbial infections. These cells die by apoptosis following activation and uptake of microbes and will also enter apoptosis spontaneously at the end of their lifespan if they do not encounter a pathogen. Adiponectin exerts anti-inflammatory effects on neutrophil antimicrobial functions, but whether this abundant adipokine influences neutrophil apoptosis is unknown. Here we report that adiponectin in the physiological range (1-10 MUg/ml) reduced apoptosis in resting neutrophils, decreasing caspase-3 cleavage and maintaining Mcl-1 expression by stabilizing this anti-apoptotic protein. We show that adiponectin induced phosphorylation of AMP-activated kinase (AMPK), protein kinase B (PKB), extracellular signal-regulated kinase (ERK 1/2) and p38 mitogen activated protein kinase (MAPK). Pharmacological inhibition of AMPK, PKB and ERK 1/2 ablated the pro-survival effects of adiponectin and treatment of neutrophils with an AMPK specific activator (AICAR) and AMPK inhibitor (compound C) respectively decreased and increased apoptosis. Finally, activation of AMPK by AICAR or adiponectin also decreased ceramide accumulation in the neutrophil cell membrane, a process involved in the early stages of spontaneous apoptosis, giving another possible mechanism downstream of AMPK activation for the inhibition of neutrophil apoptosis. PMID- 23982478 TI - Intramyocardial injection of autologous bone marrow-derived ex vivo expanded mesenchymal stem cells in acute myocardial infarction patients is feasible and safe up to 5 years of follow-up. AB - In experimental studies, mesenchymal stem cell (MSC) transplantation in acute myocardial infarction (AMI) models has been associated with enhanced neovascularization and myogenesis. Clinical data however, are scarce. Therefore, the present study evaluates the safety and feasibility of intramyocardial MSC injection in nine patients, shortly after AMI during short-term and 5-year follow up. Periprocedural safety analysis demonstrated one transient ischemic attack. No other adverse events related to MSC treatment were observed during 5-year follow up. Clinical events were compared to a nonrandomized control group comprising 45 matched controls. A 5-year event-free survival after MSC-treatment was comparable to controls (89 vs. 91 %, P = 0.87). Echocardiographic imaging for evaluation of left ventricular function demonstrated improvements up to 5 years after MSC treatment. These findings were not significantly different when compared to controls. The present safety and feasibility study suggest that intramyocardial injection of MSC in patients shortly after AMI is feasible and safe up to 5-year follow-up. PMID- 23982479 TI - Enzyme-responsive supramolecular nanovalves crafted by mesoporous silica nanoparticles and choline-sulfonatocalix[4]arene [2]pseudorotaxanes for controlled cargo release. AB - Mesoporous silica nanoparticles (MSNs) have been surface-functionalized with choline moieties encircled by sulfonatocalix[4]arenes. Two enzyme cleavable sites are incorporated in the stalks for specific enzymes to regulate the release of loaded cargos from MSNs. These gated materials show a clear enzymatic response and proven orthogonality. PMID- 23982480 TI - Photocatalytic H2 generation based on noble-metal-free binuclear cobalt complexes using visible-light. AB - Two new binuclear cobalt complexes, namely {[Co(dmgH)(dmgH2)]2L1} (I) and {[Co(dmgH)(dmgH2)]2L2} (II) (dmgH = dimethylglyoximate monoanion; dmgH2 = dimethylglyoxime, L1 = 1,3-bis(4-pyridyl)propane), L2 = 1,3-bis(imidazol-1 ylmethyl)benzene), have been synthesized by the self-assembly of [Co(dmgH)(dmgH2)] and L1 or L2, respectively. An efficient photocatalytic system was constructed by combining a noble-metal-free cobalt complex as the catalyst with Eosin Y dye (EY(2-)) as the photosensitizer to give an efficient H2 generating system under visible-light irradiation (lambda > 420 nm) using triethanolamine (TEOA) as a sacrificial electron donor. The maximum amount of H2 generated was 1013 TON for I and 1134 TON for II over a 2 h irradiation period (lambda > 420 nm) under the conditions of pH 8.0, 5% TEOA (v/v), an EY(2-) concentration of 4.0 * 10(-4) M and a catalyst concentration of 4.0 * 10(-4) M in the mixed solvent system of CH3CN-H2O (3 : 1, v/v). In addition, the mechanism of H2 generation in the photolysis system was briefly discussed. PMID- 23982481 TI - Combined X-ray and neutron diffraction study of vacancies and disorder in the dimorphic clathrate Ba8Ga16Sn30 of type I and VIII. AB - We report detailed structural investigations of the dimorphic clathrate Ba8Ga16Sn30 that crystallizes in both type I and VIII clathrate structures. Single crystals of type I and VIII have been examined using single crystal X-ray and Laue neutron diffraction in the temperature range T = 10 K-500 K. The utilization of both X-ray and neutron diffraction gives a unique ability to reveal the occurrence of minute vacancy occupancies in the host structure. The vacancies are shown to be located on the 6c (type I) and 24g (type VIII) framework sites. Largest vacancy densities are observed for type I p-Ba8Ga16Sn30, 1.3(4)%, and type VIII n-Ba8Ga16Sn30, 0.7(2)%. The relation between guest atom disorder and occurrence of glasslike thermal conductivity in intermetallic clathrates was also investigated. In type VIII Ba8Ga16Sn30 neither n-type (crystalline thermal conductivity) nor p-type (glasslike thermal conductivity) showed any significant disorder of the guest atoms; they do however show anharmonic motion. The glasslike thermal conductivity of p-type Ba8Ga16Sn30 is interpretable as a result of higher effective mass of p-type charge-carriers affecting phonon scattering. In type I Ba8Ga16Sn30 guest atoms are highly disordered for both carrier types and samples of both charge carrier types have glasslike thermal conductivity. PMID- 23982482 TI - Mammalian cortical bone in tension is non-Haversian. AB - Cortical bone, found in the central part of long bones like femur, is known to adapt to local mechanical stresses. This adaptation has been linked exclusively with Haversian remodelling involving bone resorption and formation of secondary osteons. Compared to primary/plexiform bone, the Haversian bone has lower stiffness, fatigue strength and fracture toughness, raising the question why nature prefers an adaptation that is detrimental to bone's primary function of bearing mechanical stresses. Here, we show that in the goat femur, Haversian remodelling occurs only at locations of high compressive stresses. At locations corresponding to high tensile stresses, we observe a microstructure that is non Haversian. Compared with primary/plexiform bone, this microstructure's mineralisation is significantly higher with a distinctly different spatial pattern. Thus, the Haversian structure is an adaptation only to high compressive stresses rendering its inferior tensile properties irrelevant as the regions with high tensile stresses have a non-Haversian, apparently primary microstructure. PMID- 23982483 TI - A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model. AB - Adoptive cell transfer (ACT) using ex vivo-expanded anti-tumor T cells such as tumor-infiltrated lymphocytes or genetically engineered T cells potently eradicates established tumors. However, these two approaches possess obvious limitations. Therefore, we established a novel methodology using total tumor RNA (ttRNA) to prime dendritic cells (DC) as a platform for the ex vivo generation of anti-tumor T cells. We evaluated the antigen-specific expansion and recognition of T cells generated by the ttRNA-DC-T platform, and directly modulated the differentiation status of these ex vivo-expanded T cells with a cytokine cocktail. Furthermore, we evaluated the persistence and in vivo anti-tumor efficacy of these T cells through murine xenograft and syngeneic tumor models. During ex vivo culture, IL-2 preferentially expanded CD4 subset, while IL-7 enabled homeostatic proliferation from the original precursors. T cells tended to lose CD62L during ex vivo culture using IL-2; however, IL-12 could maintain high levels of CD62L by increasing expression on effector T cells (Tem). In addition, we validated that OVA RNA-DC only selectively expanded T cells in an antigen specific manner. A cytokine cocktail excluding the use of IL-2 greatly increased CD62Lhigh T cells which specifically recognized tumor cells, engrafted better in a xenograft model and exhibited superior anti-tumor activities in a syngeneic intracranial model. ACT using the ex vivo ttRNA-DC-T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers. PMID- 23982484 TI - Lenalidomide overcomes suppression of human natural killer cell anti-tumor functions by neuroblastoma microenvironment-associated IL-6 and TGFbeta1. AB - BACKGROUND: Treatment for children with high-risk neuroblastoma with anti disialoganglioside mAb ch14.18, IL-2, and GM-CSF plus 13-cis-retinoic acid after myeloablative chemotherapy improves survival, but 40 % of patients still relapse during or after this therapy. The microenvironment of high-risk neuroblastoma tumors includes macrophages, IL-6, and TGFbeta1. We hypothesized that this microenvironment suppresses anti-tumor functions of natural killer (NK) cells and that lenalidomide, an immune-modulating drug, could overcome suppression. METHODS: Purified NK cells were cultured with IL-2, neuroblastoma/monocyte conditioned culture medium (CM), IL-6, TGFbeta1, and lenalidomide in various combinations and then characterized using cytotoxicity (direct and antibody dependent cell-mediated cytotoxicity), cytokine, flow cytometry, and Western blotting assays. Anti-tumor activity of NK cells with lenalidomide, ch14.18, or both was evaluated with a xenograft model of neuroblastoma. RESULTS: CM from neuroblastoma/monocyte co-cultures contains IL-6 and TGFbeta1 that suppress IL-2 activation of NK cell cytotoxicity and IFNgamma secretion. IL-6 and TGFbeta1 activate the STAT3 and SMAD2/3 pathways in NK cells and suppress IL-2 induction of cytotoxicity, granzymes A and B release, perforin expression, and IFNgamma secretion. Lenalidomide blocks IL-6 and TGFbeta1 activation of these signaling pathways and inhibits their suppression of NK cells. Neuroblastoma cells in NOD/SCID mice exhibit activated STAT3 and SMAD2/3 pathways. Their growth is most effectively inhibited by co-injected peripheral blood mononuclear cells (PBMC) containing NK cells when mice are treated with both ch14.18 and lenalidomide. CONCLUSION: Immunotherapy with anti-tumor cell antibodies may be improved by lenalidomide, which enhances activation of NK cells and inhibits their suppression by IL-6 and TGFbeta1. PMID- 23982485 TI - Myeloid-derived suppressor cell function is reduced by Withaferin A, a potent and abundant component of Withania somnifera root extract. AB - Myeloid cells play a crucial role in tumor progression. The most common tumor infiltrating myeloid cells are myeloid-derived suppressor cells (MDSC) and tumor associated macrophages (TAMs). These cells promote tumor growth by their inherent immune suppressive activity which is enhanced by their cross-talk. The root extract of the plant Withania somnifera (Ashwagandha) (WRE) has been reported to reduce tumor growth. HPLC analysis identified Withaferin A (WA) as the most abundant constituent of WRE and led us to determine whether the anti-tumor effects of WRE and WA involve modulating MDSC and TAM activity. A prominent effect of MDSC is their production of IL-10 which increases upon cross-talk with macrophages, thus polarizing immunity to a pro-tumor type 2 phenotype. In vitro treatment with WA decreased MDSC production of IL-10 and prevented additional MDSC production of IL-10 generated by MDSC-macrophage cross-talk. Macrophage secretion of IL-6 and TNFalpha, cytokines that increase MDSC accumulation and function, was also reduced by in vitro treatment with WA. Much of the T-cell suppressive activity of MDSC is due to MDSC production of reactive oxygen species (ROS), and WA significantly reduced MDSC production of ROS through a STAT3 dependent mechanism. In vivo treatment of tumor-bearing mice with WA decreased tumor weight, reduced the quantity of granulocytic MDSC, and reduced the ability of MDSC to suppress antigen-driven activation of CD4+ and CD8+ T cells. Thus, adjunctive treatment with WA reduced myeloid cell-mediated immune suppression, polarized immunity toward a tumor-rejecting type 1 phenotype, and may facilitate the development of anti-tumor immunity. PMID- 23982486 TI - Evaluating the effectiveness of an intervention program to influence attitudes of students towards peers with disabilities. AB - In this study we examine the effectiveness of an intervention program to influence attitudes of elementary school students towards peers with intellectual, physical and severe physical and intellectual disabilities. A quasi experimental longitudinal study was designed with an experimental group and a control group, both comprising two rural schools. An intervention program was developed for kindergarten (n(experimental) = 22, n(control) = 31) and elementary school students without disabilities (n(experimental) = 91, n(control) = 127) (age range 4-12 years old). This intervention consisted of a 3 weeks education project comprising six lessons about disabilities. The Acceptance Scale for Kindergarten-revised and the Attitude Survey to Inclusive Education were used to measure attitudes at three moments: prior to the start of the intervention, after the intervention and 1 year later. The outcomes of the multilevel analysis showed positive, immediate effects on attitudes of kindergarten students, but limited effects on elementary school students' attitudes. PMID- 23982487 TI - Language and verbal memory in individuals with a history of autism spectrum disorders who have achieved optimal outcomes. AB - Some individuals who lose their autism spectrum disorder diagnosis may continue to display subtle weaknesses in language. We examined language and verbal memory in 44 individuals with high-functioning autism (HFA), 34 individuals with "optimal outcomes" (OO) and 34 individuals with typical development (TD). The OO group scored in the average range or above on all measures and showed few differences from the TD group. The HFA group performed within the average range but showed significantly lower mean performance than the other groups on multiple language measures, even when controlling for verbal IQ. Results also indicate that OO individuals show strong language abilities in all areas tested, but that their language may show greater reliance on verbal memory. PMID- 23982488 TI - Brief report: social skills, internalizing and externalizing symptoms, and respiratory sinus arrhythmia in autism. AB - Theoretical and empirical models describe respiratory sinus arrhythmia (RSA) as a peripheral biomarker of emotion regulation and social competence. Recent findings also link RSA to individual differences in social functioning within autism spectrum disorder (ASD). However, associations between RSA and symptoms of internalizing/externalizing psychopathology in ASD have not been explored. We assessed RSA, social functioning, and internalizing/externalizing symptoms among boys with and without ASD. Compared with controls, participants with ASD evidenced reduced parasympathetic cardiac control, which correlated with social behavior. Symptoms were associated with deficiencies in RSA, over-and-above the contribution of social functioning. These findings yield a more nuanced understanding of parasympathetic function in ASD, and suggest a role for integrative intervention strategies that address socioemotional difficulties. PMID- 23982489 TI - Cardioprotective effects of exenatide against oxidative stress-induced injury. AB - Myocardial ischemia/reperfusion (MI/R) leads to oxidative stress, which may in turn lead to myocardial injury. In the present study, we investigated the effects of exenatide, a glucagon-like peptide-1 (GLP-1) analogue, on oxidative stress induced injury in vitro and in vivo. In in vitro experiments, H9c2 cells were incubated with exenatide to determine the direct cytoprotective effects of exenatide following exposure to hydrogen peroxide (H2O2). Pre-treatment with exenatide (1 nM), prior to H2O2 exposure, increased cell viability and inhibited H2O2-induced reactive oxygen species (ROS) production. Exenatide also decreased the levels of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the cultured supernatants, as well as those of malondialdehyde (MDA) in the H9c2 cells and increased the total superoxide dismutase (T-SOD) levels in the H9c2 cells. In in vivo experiments, an animal model of MI/R was induced by coronary occlusion. Pre-treatment with exenatide (10 ug/kg/day) protected the rat hearts from MI/R-induced injury by decreasing the levels of LDH and CK-MB in plasma, increasing the levels of catalase, T-SOD and glutathione peroxidase (GSH-Px) in the heart and decreasing the MDA levels in the rats with MI/R-induced injury. Exenatide also reduced the infarct size and enhanced cardiac function in the rats with MI/R-induced injury. Moreover, pre-treatment with exenatide inhibited cardiomyocyte apoptosis, increased Aktserine473 and Badserine136 phosphorylation and decreased cleaved caspase-3 expression in vitro and in vivo; however, these effects were attenuated by the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Our results suggest that exenatide exerts significant cardioprotective effects against oxidative stress-induced injury in vitro and in vivo. The mechanisms involved may be attributed to the scavenging of oxidative stress products, such as ROS, the increase in the concentrations of antioxidant defense enzymes and the inhibition of cardiomyocyte apoptosis. The anti-apoptotic effects of exenatide were, at least in part, associated with the activation of the PI3K/Akt signaling pathway. PMID- 23982490 TI - Senescence-associated protein p400 is a prognostic marker in renal cell carcinoma. AB - Mutations of the von Hippel-Lindau (VHL) tumor suppressor gene cause hereditary and sporadic renal cell carcinomas (RCCs). The best characterized function of VHL protein is suppression of the alpha subunit of hypoxia inducible factor (HIF). Additional VHL functions have been reported, including induction of senescence upon loss of VHL mediated by downregulation of the chromatin remodeling factor p400. Induction of senescence either by oncogene activation or inactivation of tumor suppressors is considered a critical feature of mammalian cells by which to suppress tumorigenesis. In the present study, we investigated the relationship between the expression of p400 and patient survival following RCC diagnosis taking advantage of a large and well-documented series of RCC patients with long term follow-up information. The expression of p400 was measured by immunohistochemistry using a tissue microarray containing tumor tissue samples from 868 RCC patients. Chi-squared tests, Kaplan-Meier curves, Cox regression models and Spearman's rank correlation estimates were used to investigate the possible relationship between p400 expression and Ki-67 proliferative index, clinical and pathological characteristics and patient survival. Complete loss of p400 expression was detected in 64% of all tumor specimens, and decreased p400 expression was associated with advanced tumor stage, higher grade of malignancy and regional lymph node metastasis. Among well-differentiated RCCs, high proliferation (Ki-67 index>10) was found in 12% of carcinomas with an increased p400 expression, compared to 5% of RCCs with decreased p400 expression. Multiple Cox regression indicated that patients with low proliferative tumors and increased p400 expression had a 60% lower cancer-specific mortality risk compared to those affected by low proliferative RCCs with decreased p400 expression. In summary, patients affected by highly proliferative tumors with decreased p400 expression exhibit a poor prognosis by multiple Cox regression. Our data suggest that the highly proliferative, decreased-p400 subgroup of RCCs represents tumors that are characterized by a loss of the tumor-suppressive mechanism of senescence. PMID- 23982493 TI - What you might hear in the waiting room. PMID- 23982491 TI - Stanniocalcin1 is a key mediator of amyloidogenic light chain induced cardiotoxicity. AB - Immunoglobulin light chain (LC) amyloidosis (AL) results from overproduction of circulating amyloidogenic LC proteins and subsequent amyloid fibril deposition in organs. Mortality in AL amyloidosis patients is highly associated with a rapidly progressive AL cardiomyopathy, marked by profound impairment of diastolic and systolic cardiac function and significant early mortality. While myocardial fibril deposition contributes to the severe diastolic dysfunction seen in AL cardiomyopathy patients, the degree of fibril deposition has not been found to correlate with prognosis. Previously, we and others showed a direct cardiotoxic effect of amyloidogenic LC proteins (AL-LC), which may contribute to the pathophysiology and mortality observed in AL cardiomyopathy patients. However, the mechanisms underlying AL-LC related cardiotoxicity remain unknown. Mammalian stanniocalcin1 (STC1) is associated with a number of cellular processes including oxidative stress and cell death. Herein, we find that STC1 expression is elevated in cardiac tissue from AL cardiomyopathy patients, and is induced in isolated cardiomyocytes in response to AL-LC, but not non-amyloidogenic LC. STC1 overexpression in vitro recapitulates the pathophysiology of AL-LC mediated cardiotoxicity, with increased ROS production, contractile dysfunction and cell death. Overexpression of STC1 in vivo results in significant cardiac dysfunction and cell death. Genetic silencing of STC1 prevents AL-LC induced cardiotoxicity in cardiomyocytes and protects against AL-LC induced cell death and early mortality in zebrafish. The cardiotoxic effects of STC1 appears to be mediated via mitochondrial dysfunction as indicated by loss of mitochondrial membrane potential, ROS production and increased mitochondrial calcium levels. Collectively, this work identifies STC1 as a critical determinant of AL-LC cardiotoxicity. PMID- 23982492 TI - Nociceptive-induced myocardial remote conditioning is mediated by neuronal gamma protein kinase C. AB - Deciphering the remote conditioning molecular mechanism may provide targets to develop therapeutics that can broaden the clinical application. To further investigate this, we tested whether two protein kinase C (PKC) isozymes, the ubiquitously expressed epsilon PKC (epsilonPKC) and the neuronal-specific gamma PKC (gammaPKC), mediate nociceptive-induced remote myocardial conditioning. Male Sprague-Dawley rats were used for both in vivo and ex vivo myocardial ischemia reperfusion protocols. For the in vivo studies, using a surgical abdominal incision for comparison, applying only to the abdomen either bradykinin or the epsilonPKC activator (psiepsilonRACK) reduced myocardial infarct size (45 +/- 1, 44 +/- 2 %, respectively, vs. incision: 43 +/- 2 %, and control: 63 +/- 2 %, P < 0.001). Western blot showed only epsilonPKC, and not gammaPKC, is highly expressed in the myocardium. However, applying a selective gammaPKC inhibitor (gammaV5-3) to the abdominal skin blocked remote protection by any of these strategies. Using an ex vivo isolated heart model without an intact nervous system, only selective epsilonPKC activation, unlike a selective classical PKC isozyme activator (activating alpha, beta, betaII, and gamma), reduced myocardial injury. Importantly, the classical PKC isozyme activator given to the abdomen in vivo (with an intact nervous system including gammaPKC) during myocardial ischemia reduced infarct size as effectively as an abdominal incision or psiepsilonRACK (45 +/- 1 vs. 45 +/- 2 and 47 +/- 1 %, respectively). The classical PKC activator-induced protection was also blocked by spinal cord surgical transection. These findings identified potential remote conditioning mimetics, with these strategies effective even during myocardial ischemia. A novel mechanism of nociceptive-induced remote conditioning, involving gammaPKC, was also identified. PMID- 23982494 TI - Concerns about academic publishing on YouTube. PMID- 23982495 TI - Concerns about publishing on YouTube. PMID- 23982496 TI - In reply. PMID- 23982497 TI - Doctors of podiatric medicine could help ease the physician shortage. PMID- 23982498 TI - In reply. PMID- 23982499 TI - An economic argument for investment in physician resilience. PMID- 23982500 TI - In reply. PMID- 23982501 TI - Compassion: necessary but not sufficient. PMID- 23982502 TI - In reply. PMID- 23982503 TI - Peripheral vascular ultrasound examinations are important in ultrasound training for medical students. PMID- 23982504 TI - In reply. PMID- 23982506 TI - A case in HIV ethics: a medical student's perspective. PMID- 23982507 TI - Oh, Mrs. Muramoto. PMID- 23982508 TI - Medicine and the arts. Not the story by Jessica Bloom, Samuel Neher, and Peter Park. Commentary. PMID- 23982511 TI - AM last page: master's degree in health professions education programs. PMID- 23982512 TI - Serum levels of 25-hydroxyvitamin D are associated with cognitive impairment in type 2 diabetic adults. AB - Hypovitaminosis D is highly prevalent in type 2 diabetes. The aim of this study is to determine the serum levels of 25-hydroxyvitamin D [25(OH)D] in type 2 diabetic patients with and without mild cognitive impairment (MCI), and examine the relationship of 25(OH)D and MCI with other clinical factors. One hundred and sixty-five diabetic patients were enrolled in this study. Among whom, 95 patients were considered as MCI [Montreal Cognitive Assessment score (MoCA) < 26] and the other 70 as no MCI (MoCA >= 26). Subjects were assessed clinically. Diabetic patients with MCI had a longer duration of DM, fewer years of education, elevated fasting blood glucose (FBG), resistant index (RI) of carotid, and lower levels of 25(OH)D {[17.35 (13.02-25.92) vs 28.00 (19.67-34.30)] ng/ml, P < 0.001}. The MoCA score was positively correlated with log10[25(OH)D], education year, and inversely correlated with duration of DM, history of hypertension, intima-media thickness (IMT), FBG, max-RI, and min-RI. Log10[25(OH)D] was positively correlated with MoCA score, and inversely correlated with IMT, in multivariate regression analysis adjusted for age, sex, and education year, 25(OH)D (beta = 0.210, P = 0.003), history of hypertension (beta = -0.191, P = 0.007), IMT (beta = -0.194, P = 0.007), and FBG (beta = -0.157, P = 0.026) independently predicted MoCA score. In conclusion, our results suggest that levels of serum 25(OH)D are inversely associated with the cognitive impairment in diabetic patients. Vitamin D may be a potential protective factor for cognitive impairment in patients with type 2 diabetes. PMID- 23982513 TI - Proteins that contain a functional Z-DNA-binding domain localize to cytoplasmic stress granules. AB - Long double-stranded RNA may undergo hyper-editing by adenosine deaminases that act on RNA (ADARs), where up to 50% of adenosine residues may be converted to inosine. However, although numerous RNAs may undergo hyper-editing, the role for inosine-containing hyper-edited double-stranded RNA in cells is poorly understood. Nevertheless, editing plays a critical role in mammalian cells, as highlighted by the analysis of ADAR-null mutants. In particular, the long form of ADAR1 (ADAR1(p150)) is essential for viability. Moreover, a number of studies have implicated ADAR1(p150) in various stress pathways. We have previously shown that ADAR1(p150) localized to cytoplasmic stress granules in HeLa cells following either oxidative or interferon-induced stress. Here, we show that the Z-DNA binding domain (Zalpha(ADAR1)) exclusively found in ADAR1(p150) is required for its localization to stress granules. Moreover, we show that fusion of Zalpha(ADAR1) to either green fluorescent protein (GFP) or polypyrimidine binding protein 4 (PTB4) also results in their localization to stress granules. We additionally show that the Zalpha domain from other Z-DNA-binding proteins (ZBP1, E3L) is likewise sufficient for localization to stress granules. Finally, we show that Z-RNA or Z-DNA binding is important for stress granule localization. We have thus identified a novel role for Z-DNA-binding domains in mammalian cells. PMID- 23982514 TI - Wobble decoding by the Escherichia coli selenocysteine insertion machinery. AB - Selenoprotein expression in Escherichia coli redefines specific single UGA codons from translational termination to selenocysteine (Sec) insertion. This process requires the presence of a Sec Insertion Sequence (SECIS) in the mRNA, which forms a secondary structure that binds a unique Sec-specific elongation factor that catalyzes Sec insertion at the predefined UGA instead of release factor 2 mediated termination. During overproduction of recombinant selenoproteins, this process nonetheless typically results in expression of UGA-truncated products together with the production of recombinant selenoproteins. Here, we found that premature termination can be fully avoided through a SECIS-dependent Sec-mediated suppression of UGG, thereby yielding either tryptophan or Sec insertion without detectable premature truncation. The yield of recombinant selenoprotein produced with this method approached that obtained with a classical UGA codon for Sec insertion. Sec-mediated suppression of UGG thus provides a novel method for selenoprotein production, as here demonstrated with rat thioredoxin reductase. The results also reveal that the E. coli selenoprotein synthesis machinery has the inherent capability to promote wobble decoding. PMID- 23982515 TI - Catalytic mechanism of alpha-phosphate attack in dUTPase is revealed by X-ray crystallographic snapshots of distinct intermediates, 31P-NMR spectroscopy and reaction path modelling. AB - Enzymatic synthesis and hydrolysis of nucleoside phosphate compounds play a key role in various biological pathways, like signal transduction, DNA synthesis and metabolism. Although these processes have been studied extensively, numerous key issues regarding the chemical pathway and atomic movements remain open for many enzymatic reactions. Here, using the Mason-Pfizer monkey retrovirus dUTPase, we study the dUTPase-catalyzed hydrolysis of dUTP, an incorrect DNA building block, to elaborate the mechanistic details at high resolution. Combining mass spectrometry analysis of the dUTPase-catalyzed reaction carried out in and quantum mechanics/molecular mechanics (QM/MM) simulation, we show that the nucleophilic attack occurs at the alpha-phosphate site. Phosphorus-31 NMR spectroscopy ((31)P-NMR) analysis confirms the site of attack and shows the capability of dUTPase to cleave the dUTP analogue alpha,beta-imido-dUTP, containing the imido linkage usually regarded to be non-hydrolyzable. We present numerous X-ray crystal structures of distinct dUTPase and nucleoside phosphate complexes, which report on the progress of the chemical reaction along the reaction coordinate. The presently used combination of diverse structural methods reveals details of the nucleophilic attack and identifies a novel enzyme-product complex structure. PMID- 23982516 TI - A winged helix domain in human MUS81 binds DNA and modulates the endonuclease activity of MUS81 complexes. AB - The MUS81-EME1 endonuclease maintains metazoan genomic integrity by cleaving branched DNA structures that arise during the resolution of recombination intermediates. In humans, MUS81 also forms a poorly characterized complex with EME2. Here, we identify and determine the structure of a winged helix (WH) domain from human MUS81, which binds DNA. WH domain mutations greatly reduce binding of the isolated domain to DNA and impact on incision activity of MUS81-EME1/EME2 complexes. Deletion of the WH domain reduces the endonuclease activity of both MUS81-EME1 and MUS81-EME2 complexes, and incisions made by MUS81-EME2 are made closer to the junction on substrates containing a downstream duplex, such as fork structures and nicked Holliday junctions. WH domain mutation or deletion in Schizosaccharomyces pombe phenocopies the DNA-damage sensitivity of strains deleted for mus81. Our results indicate an important role for the WH domain in both yeast and human MUS81 complexes. PMID- 23982517 TI - Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I. AB - Mitochondrial topoisomerase I is a genetically distinct mitochondria-dedicated enzyme with a crucial but so far unknown role in the homeostasis of mitochondrial DNA metabolism. Here, we present data suggesting a negative regulatory function in mitochondrial transcription or transcript stability. Deficiency or depletion of mitochondrial topoisomerase I increased mitochondrial transcripts, whereas overexpression lowered mitochondrial transcripts, depleted respiratory complexes I, III and IV, decreased cell respiration and raised superoxide levels. Acute depletion of mitochondrial topoisomerase I triggered neither a nuclear mito biogenic stress response nor compensatory topoisomerase IIbeta upregulation, suggesting the concomitant increase in mitochondrial transcripts was due to release of a local inhibitory effect. Mitochondrial topoisomerase I was co immunoprecipitated with mitochondrial RNA polymerase. It selectively accumulated and rapidly exchanged at a subset of nucleoids distinguished by the presence of newly synthesized RNA and/or mitochondrial RNA polymerase. The inactive Y559F mutant behaved similarly without affecting mitochondrial transcripts. In conclusion, mitochondrial topoisomerase I dampens mitochondrial transcription and thereby alters respiratory capacity. The mechanism involves selective association of the active enzyme with transcriptionally active nucleoids and a direct interaction with mitochondrial RNA polymerase. The inhibitory role of topoisomerase I in mitochondrial transcription is strikingly different from the stimulatory role of topoisomerase I in nuclear transcription. PMID- 23982518 TI - Two- and three-input TALE-based AND logic computation in embryonic stem cells. AB - Biological computing circuits can enhance our ability to control cellular functions and have potential applications in tissue engineering and medical treatments. Transcriptional activator-like effectors (TALEs) represent attractive components of synthetic gene regulatory circuits, as they can be designed de novo to target a given DNA sequence. We here demonstrate that TALEs can perform Boolean logic computation in mammalian cells. Using a split-intein protein splicing strategy, we show that a functional TALE can be reconstituted from two inactive parts, thus generating two-input AND logic computation. We further demonstrate three-piece intein splicing in mammalian cells and use it to perform three-input AND computation. Using methods for random as well as targeted insertion of these relatively large genetic circuits, we show that TALE-based logic circuits are functional when integrated into the genome of mouse embryonic stem cells. Comparing construct variants in the same genomic context, we modulated the strength of the TALE-responsive promoter to improve the output of these circuits. Our work establishes split TALEs as a tool for building logic computation with the potential of controlling expression of endogenous genes or transgenes in response to a combination of cellular signals. PMID- 23982519 TI - Resourcefulness training for grandmothers raising grandchildren: establishing fidelity. AB - Over one million American grandmothers raise grandchildren, and many experience stress that adversely affects their mental health. Teaching resourcefulness skills can minimize this stress. However, before testing effectiveness of resourcefulness training (RT), its fidelity must be established. This pilot intervention trial examined the fidelity of two methods of RT: expressive writing (journaling) and verbal disclosure (voice recording) using a quasi-experimental design with random assignment of 80 grandmothers to RT-expressive writing, RT verbal disclosure, or expressive writing or verbal disclosure alone. Quantitative data (Resourcefulness Scale) and qualitative data (journals, recordings) were collected. Grandmothers with RT showed greater resourcefulness over time than those without RT, with similar effects for RT-expressive writing and RT-verbal disclosure. Evidence for the use of RT skills was found in journals and recordings. The findings provide support for RT intervention fidelity and support moving forward to test RT effectiveness in reducing grandmothers' stress and promoting their mental health. PMID- 23982520 TI - Unusual cause for smoldering dysphagia. Lymphocytic esophagitis. PMID- 23982521 TI - Factors associated with the length of remission of psoriasis vulgaris. AB - BACKGROUND: Cardiovascular risk factors are found with significantly high frequency in psoriatic patients. Periods of remission and reactivation of lesions are common in psoriasis. OBJECTIVE: Considering the association of chronic inflammation with the atherogenic process, we aimed to search for a possible relationship between the lipid profile, adipokine levels and body mass index (BMI) at the end of a successful treatment for psoriasis, and the length of remission of psoriasis. METHODS: Forty-three patients were clinically and analytically studied after a successful treatment [as shown by Psoriasis Area and Severity Index (PASI)]--nine treated with topical agents, 17 with narrow-band UV light B (NB-UVB) and 17 with psoralen plus UVA-and were followed to record the length of remission. RESULTS: The length of psoriasis remission correlated negatively and significantly with cholesterol levels, which correlated significantly and positively with C-reactive protein (CRP). In multiple linear regression analysis, cholesterol, CRP, PASI and BMI were associated with the length of remission. Patients with cholesterol levels <200 mg/dL (n = 13) presented a significantly longer remission, lower BMI and triglycerides values, and a trend towards lower PASI and CRP values than those with high cholesterol (n = 30). Considering patients according to the treatment used, cholesterol was also associated with length of remission, especially for patients treated with NB-UVB and topical therapy. CONCLUSION: Psoriasis patients with the highest cholesterol levels presented higher BMIs, triglycerides levels and shorter remission periods. Our data suggest that the identification of potentially treatable conditions, such as dyslipidaemia and obesity, and their adequate treatment may benefit psoriasis patients by increasing the length of remission of the disease. PMID- 23982522 TI - Breast cancer: BEATRICE bevacizumab trial--every cloud has a silver lining. PMID- 23982525 TI - Innovation: Tumour board--introducing real time to oncology management. PMID- 23982526 TI - Serum calcium level among normal pregnant and pre-eclamptic women in a sub urban area of Bangladesh. AB - Pre-eclampsia along with its complications seems to be one of the major causes of maternal morbidity and mortality. Despite numerous studies, the etiology of pre eclampsia has not yet been fully elucidated. The present study prospectively determines and evaluate whether maternal serum levels of calcium has any association with pre-eclampsia. It was a cross sectional study carried out in the department of Biochemistry, Mymensingh Medical College from July 2009 to June 2010. A total of 76 subjects were selected with the duration of pregnancy from 28th wks to term. Among them 42 were normal pregnant women and 32 were pre eclamptic, admitted in the department of obstetrics and gynaecology Mymensingh Medical College Hospital. The mean+/-SD serum calcium of normal pregnant women and that of the pre-eclamptic were 7.62+/-0.24 and 7.32+/-0.28mg/dl respectively. There was significant (p<0.001) decrease in serum calcium in subject with pre eclampsia in comparison to that of the normal pregnancy. So, level of calcium may be significantly decreased in pre-eclampsia. PMID- 23982524 TI - The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. AB - Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-alpha2b, pegylated-interferon-alpha2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted. PMID- 23982527 TI - Morphometric study of thyroid angle in different age and sex in Bangladeshi cadaver. AB - This cross sectional descriptive study was to measure the thyroid angle and to establish the difference between sexes of different age groups in Bangladeshi cadaver. A total 60 human larynges were collected by purposive sampling from October 2008 to March 2009. Among them 45(male 23 and female 22) were collected from Bangladeshi cadavers (9 to 60 years) at the autopsy laboratory of Department of Forensic Medicine and 15 (male 6 and female 9) from stillborn infants of viable age (28 to 40 weeks of gestation) from Gynaecology and Obstetrics Department of Mymensingh Medical College, Mymensingh. The thyroid angle was measured and significant differences of the dimensions between different age and sex groups were observed. In the present study observed findings was compared with those of other researchers. The mean+/-SD thyroid angle was found as 65.00+/ 11.65 degree in age Group A (28 to 40 weeks of gestation), 73.69+/-6.56 degree in age Group B (9 to 16 years) and 77.76+/-7.76 degree in age Group C (17 to 60 years). The mean thyroid angle was higher in female (83.1667+/-5.78220 degree) than that in male (73.9412+/-7.09460 degree) and statistically moderately significant in Group C, where t = 3.853 and p = 0.001. In statistical analysis, differences between age and sex groups were calculated by using Students (unpaired) 't' test. The present study revealed that the value was significantly greater in adult female than male and the value increased with age. PMID- 23982523 TI - Molecular targets on the horizon for kidney and urothelial cancer. AB - As whole-genome sequencing technology rapidly advances, the insights gained from deciphering cancer genomes are shifting the paradigm in the diagnosis and treatment of cancer with the promise of individualized treatment for each patient. Information gained in this way is extensive for certain cancers, but fairly limited in renal cell carcinomas and urothelial carcinoma. Mutations in multiple, potentially druggable genes have been identified in urothelial carcinomas; however, the association between molecular alterations and clinical outcome has not yet been robustly demonstrated. Data in this area are emerging in renal cell carcinoma, leading to the development of targeted agents that have improved overall survival. Unfortunately, these treatments rarely yield complete responses, are not curative, and development of resistance ensues. This Review will focus on the biology of non-hormonally driven urological cancers. We discuss how approaches using whole-genome sequencing can facilitate the discovery of biomarkers of drug sensitivity in both renal cell carcinomas and urothelial carcinomas. For renal cell carcinomas, we will describe how genomic and epigenomic mining has uncovered novel genes and pathways involved in tumorigenesis, tumour classification and mechanisms of resistance in the various subsets of this disease and the potential for exploiting these discoveries in the clinic. PMID- 23982528 TI - Serum calcium level among smear positive pulmonary tuberculosis patients in Bangladesh. AB - This case control study was carried out in the Department of Biochemistry, Mymensingh Medical College, Bangladesh in cooperation with the Outpatient Department and Medicine Units of Mymensingh Medical College Hospital, Fulbaria Upazilla Health Complex, Mymensingh and some DOTS centers of BRAC, a non government organization during the period of July 2006 to June 2007. The aim of the study was to explore the status of serum calcium level in smear positive Bangladeshi pulmonary tuberculosis patients. A total of 120 people of different age groups were included in this study. Subjects were divided into two groups - Group I (Control; n=60) apparently healthy people selected matching by age, sex and socioeconomic status with the cases and Group II (Case; n=60) people with smear positive pulmonary tuberculosis. Serum calcium was estimated by colorimetric principle. Serum calcium was adjusted by serum albumin concentration. Statistical analysis was done by using SPSS windows package. Among the groups, mean+/-SD of adjusted serum calcium in Group II (2.41+/-0.15mmol/L) was significantly higher (p<0.001) than that in Group I (1.85+/-0.11mmol/L). It is evident from the study that serum calcium level significantly increases in smear positive Bangladeshi pulmonary tuberculosis patients. PMID- 23982529 TI - Labor outcome of primigravidae in Mymensingh Medical College Hospital. AB - This cross sectional study was done in the department of Obstetrics and Gynae, Mymensingh Medical College Hospital, during the period 1st January to 30th June 2000 to evaluate the labor outcome in primigrvidae women. Total 1250 cases were delivered in this period. Among all 500(40%) were primigravidae. All the primigravidae were included and labor was monitored and managed by close observation. Condition of the baby was determined by applying APGAR (Appearance, Pulse, Grimace, Activity and Respiration) score. Maximum (66.6%) of patients were belonged to 21-29 years age group. Only few 28.2% had regular antenatal check-up. Risk factors were present in 32% cases. Common risk factors were PET (Pre eclamptic toxemia) and eclampsia. Mode of deliveries were normal vaginal delivery (NVD) in (51.6%) cases, Lower Uterine Caesarean section (LUCS) in 43.8% cases, Ventouse in 2.8% cases, Forceps in 9(1.8%) cases and craniotomy was required in 2(0.4%) cases. Complications during labor were prolonged labor, postpartum hemorrhage, obstructed labor and perineal tear. PET was common (29.62%) in age group 30-36 years and eclampsia was more common (15%) in age group 16-20 years. NVD were more (55.85%) in 21-29 years group than other age group. The duration of labor pain was short in the age group of 21-29 years and was prolonged in the age group 30-36 years. Maternal mortality was 1.6% (8) cases. Causes of death were septic shock, renal failure and Cerebrovascullar accident. Morbidities after delivery were hypertension, wound infection, puerperal psychosis, acute renal failure, vesicovaginal fistula, hypertensive retinopathy, chronic ill health and retention of urine. Among 500 cases 92.6% were live born and 7.4% were still born. Among total cases 81.6% babies were healthy, 6.8% were asphyxiated, 71.2% had normal birth weight 21.4% had low birth weight, 18% were premature and 7.4% were IUGR. This study shows the safest and easiest delivery age group of primigravidae is between 21-29 years. Maternal mortality and early neonatal death are still holding high rate. PMID- 23982530 TI - Peak expiratory flow rate of normal school going children in Mymensingh municipality. AB - This cross sectional study was conducted to measure the PEFR values of normal school going children of Mymensingh, Bangladesh. Peak expiatory flow rate (PEFR) is a lung function test which is easily measurable and reproducible but the base line values of PEFR have not been studied in large scale among Bangladeshi children. In Mymensingh municipality out of 79 schools 4 schools were selected purposively. A total of 984 (499 boys and 485 girls, nearly equal in ratio) normal children (6-15 years), were selected randomly by using lottery technic in classroom. To obtain peak expiratory flow rate (PEFR) mini Wright peak flow meter was used. The highest of three readings was taken as the correct value. Anthropometric parameters including body weight and height were recorded by bathroom scale and stadiometer respectively and body surface area was calculated. According to age interval (10 months) in boys and girls the mean difference of PEFR values showed that among age categories of 6, 7 & 8 years had no significant (p were <0.18, <0.73 and <0.70 accordingly) and all other age categories the mean difference of PEFR between boys and girls had significant (p<0.01). The correlation coefficient (r values) and the level of significance between different anthropometric parameters and PEFR in case of boys and girls were significant (p<0.001). Correlation of height (boys r=0.961 & girls r=0.954) with PEFR was the highest in comparison to other anthropometric parameters (age, sex and body weight). Boys had significantly higher values of PEFR than the girls at any height. PMID- 23982531 TI - Sexual and urinary outcome after surgical treatment for low rectal cancer. AB - Carcinoma involving the lower part of the rectum is now successfully managed by sphincter saving surgery with less morbidity and uneventful recovery. This study was designed to observe the sexual and urinary dysfunction in both sexes of the patients suffering from cancer of the lower third of the rectum managed by surgical intervention with preservation of sphincter. A comparative study was carried out on 54 patients with low rectal cancer who underwent ultra-low anterior resection in the department of surgery, Bangabandhu Sheikh Mujib Medical University, Dhaka from January, 2009 to December, 2010. Patients were divided into two groups depending on the tumor distance from anal verge. Thirty one (57%) patients were in Group A (Experimental) where tumor distance was 5cm from anal verge and upper 1cm of anal sphincter was sacrificed during surgical intervention. Twenty three (43%) patients were in Group B (Control) where tumor distance was 6cm from anal verge and whole length (4cm) of anal sphincter was preserved during surgical intervention. The mean+/-SD age of the patients was 45.96+/-14.41 years. During surgery, ultra low anterior resection was performed to remove the tumor in all patients and for anastomosis double stapling technique was performed in 52(96%) patients and hand sewn technique was performed in 2(4%) patients irrespective of tumor distance from anal verge. Covering ileostomy was fashioned in all but one patient. During post-operative follow up Sexual activity in both groups of male patients (Potency, P=0.17; ejaculation; satisfaction and loss of libido, P=0.15) and in female patients (Satisfaction and loss of libido, P=0.15) was not significantly hampered following surgery. Urinary function was assessed by incontinence, increased frequency (P=0.54) and retention (n=0) which were not impaired significantly following surgery. Sexual and urinary function was not significantly impaired in both sexes after low rectal cancer surgery. Sphincter saving surgery can be performed in a very low rectal cancer with preservation of anal sphincter. PMID- 23982532 TI - Traumatic gut injury: a study of 100 cases in Mymensingh Medical College Hospital. AB - This study was done to find out the mode of presentations, management options and the factors which dictate the out-come of the patients with traumatic gut injury. It has been carried out in the department of Surgery, Mymensingh Medical College Hospital in 100 patients with traumatic gut injury from January 2009 to December 2010. Most of the patients were within 21-30 years (47%) and male patients were the predominant group (90%). In this study penetrating injury was more common (57%) than non-penetrating (43%) injury as a cause of gut injury. Stab (64.91%) was the main mechanism of penetrating abdominal trauma; while road traffic (58.14%) was the main mechanism of non-penetrating abdominal trauma. Diagnosis was made on clinical presentation, physical examination and some investigations. Abdominal pain (98%) was the chief complain and chief sign was abdominal tenderness (98%) and absent bowel sound (91%). Small gut injury was present in 71% patients, 20% patients had large gut injury and 9% had both gut injury. In small gut, jejunum (49.29%) was the most vulnerable portion and right sided colon (55%) was the most affected portion in large gut trauma. Spectrum of injury in small gut included single perforation (63%), multiple perforations (23%), laceration (11%) and devascularization (3%) injury. Primary repair in 60.87%, resection & anastomosis in 27.54% and resection anastomosis with proximal diversion in 11.59% patients were done in small gut injury. Injuries in the large gut were classified into three categories according to Flint Colon Injury Severity Scoring. Highest incidence was in Grade I (60%) category, second in Grade II (35%) and Grade III (5%) was the third one. Simple primary repair in 40%, primary repair or resection anastomosis with proximal diversion in 30%, loop ileostomy in 20% and Hartman's procedure in 10% were done in patients of large gut injury. Resection anastomosis with proximal diversion was performed in patients of both small and large gut injury. Outcome of management was quiet acceptable with 47% of patients having uneventful recovery. Delayed presentation, delayed definitive management, haemodynamically unstable patient, site and number of injuries in the gut were the crucial factor for the overall 44% morbidities of this series. Morbidity rate was 9%. More than half of the patients (56.04%) discharged from the hospital within 10 days. Only a few patients could be followed up for a few months after surgery, who reported to have a satisfactory outcome with no morbidity. PMID- 23982533 TI - Body iron status among acute myocardial infarction patients. AB - This case control cross sectional study was carried out in the department of Biochemistry, Mymensingh Medical College in collaboration with Cardiology department of Mymensingh Medical College Hospital, Mymensingh during the period of July 2004 to June 2005. The aim of the study was to explore the status of body iron among acute myocardial infarction (AMI) patients in Bangladesh as a means to monitor the possibility of management of these patients. A total of 100 subjects were selected and were grouped as Group I (50 healthy Control subjects) and Group II (50 subjects of AMI Cases). Serum iron, total iron binding capacity (TIBC) & transferrin saturation were estimated from each sample. Statistical analysis was done by using SPSS windows package. Among the groups, mean+/-SD of Group I serum iron, TIBC & transferrin saturation were 71.84+/-9.10, 336.66+/-35.39 & 21.73+/ 4.88 respectively and of Group II serum iron, TIBC & transferrin saturation were 137.55+/-18.22, 267.99+/-34.97 & 52.40+/-11.74 respectively. By comparing Group I with Group II highly significant difference were found in case of serum iron (p<0.001), TIBC (p<0.001) and transferrin saturation (p<0.001). It is evident from the study that body iron (serum iron, TIBC & transferrin saturation) level significantly increases among acute myocardial infarction patients in Bangladesh. PMID- 23982534 TI - Detection of TEM, SHV and CTX-M in Mymensingh region in Bangladesh. AB - The development of antibiotic resistance in bacteria following introduction of antimicrobial agents has emerged as an important medical problem everywhere in the world including Bangladesh. Extended spectrum beta-lactamases (ESBLs) are rapidly evolving group of beta-lactamase enzymes produced by the Gram negative bacteria. This study was undertaken to characterize ESBL producing gram negative bacilli from urine, skin wound (pus and wound infection). A total of 300 gram negative bacilli were screened for resistance to third generation Cephalosporins (3GCs) by disc diffusion test. The ESBL status was confirmed by double disc diffusion test (DDDT), minimum inhibitory concentration (MIC) by agar dilution method as recommended by Clinical Laboratory Standard Institute 2010 (CLSI) and multiplex PCR for TEM, SHV and CTX-M, CTX-M-3, CTX-M-14 genes. The present study revealed a higher occurrence of multi drugs resistant ESBLs production among gram negative isolates where Klebsiella spp. were the leading bacteria 36/45 (80%), followed by Proteus spp. 40/55 (72.7%), Esch. coli 105/156 (67.3%) and others 25/35 (71.4 %). Rate of TEM, SHV and CTX-M genes present in study population were 50.46%, 18.69% and 46.72% respectively. Among the CTX-M positive genes CTX-M-3 and CTX-M-14 were 78.0% (39/50) and 80.0% (40/50) respectively. Results indicate that routine ESBL detection should be made mandatory and irrational use of third generation cephalosporins must be discouraged to reduce multi drugs resistance bacteria, to increase patients' compliance and to make an antibiotic policy. PMID- 23982535 TI - Haemodynamic and end tidal CO2 changes during laparoscopic cholecystectomy under general anaesthesia. AB - A prospective observational study was done on 50 patients to investigate the haemodynamic and end tidal CO2 (EtCO2) changes in healthy patients without cardiopulmonary pathology during elective laparoscopic cholecystectomy in head up position under standard protocol of general anaesthesia. During surgery, intra abdominal pressure was maintained at 15 mmHg by a CO2 insufflator and minute ventilation was controlled with a constant tidal volume and fixed respiratory rate. Haemodynamic parameters, EtCO2, SpO2 and ECG were recorded before and after induction and positioning of the patients and at 5 minutes interval for the first 30 minutes, then 10 minutes interval for the rest of the period. Highly significant increase (p<0.001) in pulse rate, systolic, diastolic and mean arterial pressure occurred at 30 minutes after insufflations and positioning of the patient. A very highly significant (p<0.001) increase in EtCO2 from the base line was at 40 minutes after insufflations and positioning of the patients. There was no change in SpO2 and ECG. This study supports the significant physiological changes in terms of haemodynamic and EtCO2 during laparoscopic cholecystectomy and recommends the meticulous monitoring of these parameters during the surgery and balance the benefit of laparoscopy against the intra operative risk. PMID- 23982536 TI - Laparoscopic findings of subfertile women attended in a tertiary level care centre. AB - This retrospective study was done in the Obstetrics and Gynaecology Department of Bangladesh Medical College hospital during the period of July 2003 to June 2004 in the women suffering from primary and secondary subfertility, who underwent laparoscopy. The aim of this study was to see the laparoscopic findings of internal genitalia and other pelvic structures in subfertile women. The study group comprises 55 cases of which 67.37% of primary and 32.73% were of secondary subfertility. Both the ovaries were normal looking in 41.81% cases. Endometriosis was present in 5.45% of both the ovaries. Corpus luteum was seen in 20% cases on right ovary and in 27.27% cases on left ovary. Laparoscopy shows normal looking fallopian tube in 65.45% cases in right side and 61.81% cases in the left side. Right sided tubal block was in 5.46% and 9.10 % in the left side. Both the tubes were patent in 81.6% cases. PMID- 23982537 TI - Comparative efficacy of subcutaneous versus oral methotrexate in active rheumatoid arthritis. AB - This prospective study was conducted in rheumatology clinic under the department of medicine of Bangabandhu Sheikh Mujib Medical University from December 2004 to December 2005 to asses the efficacy, safety and compliance of subcutaneous methotrexate (MTX) in active rheumatoid arthritis (RA) patients. A total of 92 active rheumatoid arthritis patients according to American College of Rheumatology (ACR) criteria were recruited for the trial for six months. Among them 46 cases belonged to injectable MTX group and 46 cases belonged to oral MTX group. Mean+/-SD age of patients was 45.54+/-12.42 vs. 44.63+/-13.99 years in subcutaneous group and oral group respectively. In the subcutaneous group 41 were female and 5 male; in the oral group 34 were female and 12 male. Mean duration of the disease was 49.74 months in subcutaneous group and 49 months in oral group. RA test was positive in 35 cases in both groups whereas Rose Waaler test was positive in 19 patients in subcutaneous group and 14 patients in oral group. At 24 week, response rate of ACR 20 was significantly higher in subcutaneous MTX than oral MTX group (93% vs. 80%, p=0.02). Similarly ACR 50 response was significantly higher in subcutaneous MTX than in oral group (89% vs. 72%, p=0.03). ACR 70 response was not significantly higher in SCMTX group then oral group (11% vs. 9 %, p=0.72). Adverse effects were relatively less in subcutaneous MTX and most common side effects were nausea (37% vs. 63%), vomiting (11% vs. 30%), dyspepsia (29% vs. 48%), dizziness (4l% vs. 52%) and alopecia (72% vs. 85%). The results of the study demonstrated that subcutaneous MTX was significantly more effective than oral MTX at the same dosage in active Rheumatoid arthritis patients with no increase in side effects. PMID- 23982538 TI - Immediate outcome of chronic total occlusion opening in post-angioplasty patients. AB - The study sought to compare procedural outcomes for patients undergoing percutaneous coronary intervention (PCI) of a chronic total coronary artery occlusion (CTO) with a matched non-CTO cohort. Percutaneous coronary intervention of a CTO is a common occurrence, and the outcome for patients with successful PCI of a CTO has not been clearly defined. Between November 2006 and December 2010, a total of 2,000 consecutive patients consecutively underwent PCI for a CTO. Utilizing propensity scoring methods, a matched non-CTO cohort of 2,000 patients was identified and compared to the CTO group. The cohorts were stratified as successful and failed procedures in United Hospital Limited Dhaka. The in hospital major adverse cardiac event (MACE) rate was 3.8% in the CTO cohort. Technical success has improved over the last 10 years (overall 74.4%, slope 1.0%/year, p=0.02, R2=49.9%) as did procedural success (overall 69.9%, slope 1.2%/year, p=0.02, R2=51.5%) without a concomitant increase in in-hospital MACE rates (slope 0.1%/year, p=0.7). There was a distinct advantage for successful CTO treatment compared with failed CTO treatment (73.5% vs. 65.1%, p=0.001). The CTO versus non-CTO survival was the same (71.2% vs. 71.4%, p=0.9). Diabetics in the CTO cohort had a lower survival compared with non-diabetics (58.3% vs. 74.3%, p=0.0001). These data represent outcome of PCI for a CTO. The 10-year survival rates for matched non-CTO and the CTO cohorts were similar. Success rates have continued to improve without an accompanying increase in MACE rates. A successfully revascularized CTO confers a significant survival advantage compared with failed revascularization. PMID- 23982539 TI - Etiological pattern of demented patients attending in a tertiary hospital. AB - This is a cross sectional study where 125 demented patients were enrolled who attended in neurology department of Bangabandhu Sheikh Mujib Medical University (BSMMU) Hospital. The purpose of the study was to find out the etiology of dementia. Dementia was diagnosed by the criteria indicated by Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV and confirmed by Mini Mental State Examination (MMSE) score. Diagnosis of specific type of dementia was made on the basis of established criteria. The most common etiological factor was post stroke dementia (PSDE) (36%) followed by Alzheimer's disease (AD) (14.4%), multi infarct dementia (MID) (8%), Mixed AD and PSDE (6.4%), vitamin B12 deficiency (4.8%) etc. Vascular dementia is the most common etiological factor. Next to this is the Alzheimer disease. This study will provide baseline information regarding the types of dementia occurring in Bangladeshi population and will be the basis of planning health program and data for future research. PMID- 23982540 TI - The management of cubitus varus using Ilizarov method. AB - Cubitus varus is the most common complications of supracondylar fractures. Various combinations of osteotomy and fixation have been described to correct the deformity but each is associated with significant complications. In this study, we used distraction osteogenesis and Ilizarov frame fixation to treat 12 elbows with cubitus varus. The mean time to follow up was 24 months (10-38) and the mean time to frame removed was 14.5 weeks (10-22). The mean carrying angle was corrected from -19.8 degrees (-10 degrees -32 degrees ) to 6.2 degrees (2 degrees -12 degrees ). In patients with cubitus varus was from 35.5 degrees (22 degrees 45 degrees ). There were 11 excellent and one good result. PMID- 23982541 TI - Blood level of lead in women with unexplained infertility. AB - Toxic effect of lead on human reproductive system is a recent concern. Various studies suggest that lead has adverse effect on the reproductive system of both sexes. The present cross-sectional case-control study was done to investigate the blood lead level in women with unexplained infertility. The study was conducted in the Department of Obstetrics and Gynecology and Department of Biochemistry, Bangabandhu Sheikh Mujib Medical University (BSMMU), Bangladesh from July 2008 - June 2009. A total of 50 women with unexplained infertility (case) ranging from 18-40 years were consecutively included in the study. An equal number of apparently healthy fertile women (control) were included as control. None of the cases and controls was diabetic. Of the infertile women over half (54%) of the patients had primary infertility and 46% secondary infertility. The mean blood level of lead was significantly higher in case group than that in control group (130.0+/-45.2 vs. 78.3+/-36.4MUg/L, (p<0.001). Correlation between blood lead level and FSH revealed that the two variables had a significantly linear relationship (r=0.213, p=0.033). The correlation coefficient shows that 21% of the variations in FSH can be explained by blood level of lead. Infertile women with absence of the apparent causes of infertility including absence of their male-partner infertility may have unusually high level of lead which could be attributed to infertility. PMID- 23982542 TI - Risk factors of acute coronary syndrome among Bangladeshi people. AB - Two hundred consecutive patients of acute coronary syndrome aged 30-80 years (inclusive) admitted to the coronary care unit of National institute of Cardiovascular Diseases, Dhaka, were prospectively recruited as cases. Two hundred controls were prospectively selected either from individuals attending in the Shaheed Suhrawardy Medical College Hospital, admitted for elective surgery or in medicine ward for conditions that were unlikely to confound a comparative analysis. The Cases had significantly lower yearly incomes than controls, and significantly higher number of cases is occupied as sedentary worker. Smoking was an important risk factor. About 70% of cases and 45% of controls smoked previously cigarettes. Consumption of non smoke tobacco is another risk factor. The high risk of IHD in developing countries attributed to low consumption of fruit and vegetables, and in our study regular consumption of fruits (taking fruit at least 4 days a week) shows 20.5% cases and 33% of controls (OR 0.524, 95%CI 0.333-0.823) and p value was 0.005. Around 23.5% of the cases were diabetic compared with 4.5% of controls. We found 5% cases and 1.5% controls having known dyslipidemia. Although the body-mass index of cases was 24.68+/-3.06 Kg/M2 and controls 20.54+/-4.37 Kg/M2. The WHR was also significantly greater in cases 0.98+/-0.05M vs. controls 0.93+/-0.102M (p<0.001). About 31% of cases and 2% of controls had past history of myocardial infarction. The most predictive independent variables were previous smoking (p<0.001), WHR (p<0.001), history of hypertension (p<0.001), and income (p<0.001). Smoking and WHR were associated with the highest risks. The variables revealed to be significantly associated with acute coronary syndrome by bivariate analyses were all entered into the model directly. Eleven variables entered into the model. Of them Age, occupation, family income (yearly), fruit consumption, known hypertension, known DM, known dyslipidemia, previous MI, previous smoking, BMI and Waist and hip ratio were found to be the independent predictors of acute coronary syndrome. The study found that smoking tobacco, diabetes mellitus, hypertension, visceral obesity and less fruit intake are the important factors of acute coronary syndrome in Bangladesh. PMID- 23982543 TI - Maternal & fetal outcome of eclamptic patients admitted in obstetrics & gynaecology department of secondary care hospital in Bangladesh. AB - This cross sectional observational study was done in Department of Obs & Gynae, General Hospital Tangail, to find out the maternal and fetal outcome of eclamptic admitted patient in secondary care hospital in Bangladesh. Study period was Jan 2008 to Dec 2008. Sample size was 100. During this period total 4727 patients were admitted among them 124(2.62%) were eclamptic patients. From that 124 patients 100 cases were randomly included. Among all patients 80% had age <25 years and 62% were primigravidae. Maximum (75%) patients had antepartum eclampsia. Postpartum and intrapartum eclampsia were 18% and 7% accordingly. Among all patients, 45% had primary education and 36% were illiterate. Most of the patients (73%) were from below average class family. Fifty two percent (52%) patients had >37 weeks completed pregnancy. Maximum patients (91%) had no or infrequent antenatal check-up. All the patients had convulsion before admission and 85% were unconscious. Among total patients 55% were delivered by lower uterine caesarian section and 45% were delivered by vaginal route. Maximum 74(74%) patients could not reached hospital within 4 hours of first convulsion. Time interval between the first convulsion and delivery was <12 hours in 72% cases. In 98(98%) cases magnesium sulphate (MgSO4) and in 2% of cases diazepam was used as anticonvulsant. Complications of eclampsia were found in 30% cases. Complications were pulmonary edema, PPH, CVA, HELLP syndrome, obstetric shock, DIC, acute renal failure. Among all 9(9%) patients were expired. Causes of maternal death were pulmonary edema, heart failure, CVA, HELLP syndrome. Maternal morbidities after delivery were observed in 53% cases. Recorded morbidities were infection, CVA and hypertension. Among 100 cases 87 were live born and 13 were still born. Out of 87 live born babies 50 were needed admission. Among admitted neonates 11 were died in the first week. Causes of early neonatal death were perinatal asphyxia, septicemia and prematurity. Among 100 deliveries 66% had low birth weight (LBW). Among 11 neonatal death, 9(81%) had low birth weight. In this study we observe maternal mortality, still born, early neonatal death and perinatal mortality rates are still high. So, this study implicates to improve the existing management of eclampsia. PMID- 23982544 TI - Evaluation of foot ulcers in diabetic patients. AB - This is a prospective observational study of 50 cases of diabetic foot ulcer conducted from June 2010 to May 2011 in the Department of Surgery of Shaheed Ziaur Rahman Medical College Hospital and the Diabetic Hospital, Bogra. This study revealed that diabetic foot ulcers are not uncommon complication in our country. The purpose of the study was to undergo a thorough evaluation of diabetic foot ulcers for better management as well as better outcome of patients. The maximum age group of this study was 41-50 years; mean+/-SD age was 55+/-15 years and male to female ratio was 1.4:1. This study showed that diabetic foot ulcers were more common in low-socio-economic group, among smokers, among poor glycemic controlled group and long duration of diabetics. In this series, 92% patients had peripheral neuropathy, 22% had foot deformity and 70% patients had vascular insufficiency in the foot and legs. In this series, 68% patients presented early diabetic complication i.e. 44% patients belonged to grade '0' and 24% patients belonged to Grade 1, which were suitable for safety of the limb or reducing major amputation if treated properly. PMID- 23982545 TI - Relationship between physical work load and lumbar disc herniation. AB - Lumbar disc herniation (LDH) is a disabling problem. This retrospective case control study was done to evaluate the possible relevance of physical work load with Lumbar Disc Herniation. We have performed this study in the Spinal Surgery Unit of Department of Orthopaedic Surgery at BSMMU, Dhaka from July 2007 to June 2010 where 200 cases with Lumbar Disc Herniation and 200 control subjects matched by age, gender and area of residence were taken and analyzed. Chi-square test was computed for sex, area of residence, type of physical work and effort at work, whereas Odds ratio was computed for physical work load, stress at work and daily working period. The highest odds ratio (OR) was with the physical work load (OR: 03.48, CI: 01.84-06.59), hard work (OR: 03.14, CI: 01.74-05.65) and working period of >8 hours (OR: 01.34, CI: 0.75-02.38). Odds ratio for heavy load carrying at work was 03.48 and less job satisfaction or stress at work was 02.45. There was a statistically significant positive association between cumulative exposure of physical work load and lumbar disc herniation indicating an increased occurrence of herniation in heavy physical work load and occupation requiring harder efforts. PMID- 23982546 TI - Protective ileostomy in low anterior resection for rectal cancer -- can it be avoided? AB - The necessity of a protective ileostomy in patients subjected to low anterior resection for rectal cancer has been discussed controversially. This prospective observational study was carried out to see the outcome of low anterior resection without a covering ileostomy. Forty patients underwent low anterior resection for primary rectal carcinoma in mid and distal rectum without any covering ileostomy from January 2007 and June 2010 in the department of Surgery of Bangabandhu Sheikh Mujib Medical University and two other private hospitals in Dhaka city. The primary objective of the study was to demonstrate clinical anastomotic leak rate, reoperation rate and morbidity and mortality related to leak. Thirty two male and eight female patients underwent low anterior resection for primary rectal carcinoma. Median age was 53 years (range 23-67). Majority of the tumors were located within 10cm from anal verge and most of the cases were in Duke's stage B and C. One male patient (overall 2.5%) developed clinical anastomotic leakage, but responded well to conservative treatment. There was no 30 days mortality. Covering ileostomy can be avoided in selected patients with low anterior resection for primary carcinoma in mid and distal rectum. PMID- 23982547 TI - Prevalence and risk factors of chronic obstructive pulmonary disease (COPD) in Dhaka city population. AB - This prospective, cross-sectional population based survey was carried out in the Respiratory wing, Department of Medicine, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh to see the prevalence and risk factors of chronic obstructive pulmonary disease (COPD) among Dhaka City Population in Bangladesh. The total sample size was 900 at the age of 35 years or above. Spirometry was performed according to ATS criteria. Data related to smoking history, respiratory symptoms, co-morbidities, physical examination findings, spirometry values and other investigation reports were noted in the questionnaire. The mean age was 45.26+/-10.08 (Mean+/-SD); of them, male 76.9% and female 23.1%. Among them, smoker was 481 with a smoking duration of 10 pack year 27.8% and non smoker were 419. Spirometric screening yielded diagnosis of COPD in 11.4% (103/900). Using operational severity criteria adopted from Global Initiative for Obstructive Lung Disease (GOLD) mild, moderate, severe and very severe COPD were found in 42.7%, 27.2%, 20.4% and 9.7% respectively. The hall mark symptom of COPD exertional dyspnea was seen in 10.4%, non-specific symptoms like cough and sputum were found in 40% and 19% respectively. Physical sign like vesicular breath sound with prolonged expiration and ronchi were found in 6.1% and 4.1% respectively. In this study, age (Mean+/-SD in years) (57.34+/-11.74), Sex (Male: Female = 4:1), low BMI (Mean+/-SD) (21.56+/-3.83), Smoker 56(20.2%) and low Socio-economic condition 54(13.6%) found to be risk factor of COPD. Regression analysis revealed that age (p<0.001), sex (p<0.001), smoking duration (p<0.001) and low socioeconomic condition (p<0.05) as independent risk factors for COPD. PMID- 23982548 TI - Serum zinc and magnesium level in newly diagnosed type-2 diabetic subjects. AB - This cross sectional study aimed to determine serum levels of zinc and magnesium in 80 newly diagnosed type 2 diabetic (Group I) and 80 healthy non-diabetic subjects (Group II). Diabetic patients without any complications were studied. It was carried out in the Department of Biochemistry, Mymensingh Medical College in cooperation with the out patient Department of Endocrinology of Mymensingh Medical College, Bangabandhu Sheikh Mujib Medical University and BIRDEM Hospital, Dhaka during the period from July 2008 to June 2009. A total of 160 subjects aged 55-65 years were enrolled for this study. Of them 80 were newly diagnosed type 2 diabetic (Group I) and 80 were apparently healthy non-diabetic (Group II) subjects. For both case and control, persons having no current medication, intercurrent illness, macro or microvascular complications and history of renal failure were selected. Atomic Absorption Spectrophotometer (AAS) was used to estimate the serum levels of zinc and magnesium. The Plasma zinc (72.07+/ 6.84MUg/dl) and magnesium (1.86+/-0.17mg/dl) significantly decreased in type 2 diabetic patients when compared with control (76.59+/-6.10MUg/dl, 1.99+/ 0.17mg/dl). It is concluded that type 2 diabetes mellitus can result in changes in zinc and magnesium levels. As the present study sample was small so it is difficult to draw any definite conclusion. However, the estimation and supplementation of both zinc and magnesium may be suggested in those cases. PMID- 23982549 TI - Histomorphological patterns of lupus nephritis with evaluation of WHO 1982 and ISN/RPS 2003 classifications. AB - WHO classifications and newly introduced ISN/RPS classification are in use to identify the different morphological patterns of lupus nephritis. This study was carried out to learn in details the spectrum of histomorphology in lupus nephritis according to both WHO and ISN/RPS classifications. A total of 58 patients with histological diagnosis of lupus nephritis were included in the study. Renal biopsy samples were evaluated both by light microscopy and immunofluorescence microscopy. Diffuse lupus nephritis was the most frequent histological class diagnosed (90%) along with common occurrence of hyaline thrombi, wire loop lesions, fibrinoid necrosis and crescents. No case of minimal glomerular lesion or advanced sclerosing lesion was found. The ISN/RPS classification was found to be more convenient to follow with its classes and definitions of diagnostic terms. PMID- 23982550 TI - Serum uric acid: an early indicator of oxidative stress in beta thalassemia population. AB - Iron induced alteration in the redox balance is a major complication in the beta thalassemia major patients receiving regular blood transfusion. Variable degrees of association between uric acid level with the free iron and its storage form ferritin in thalassemic patients are suggested to play a significant role in this alteration by an unclear mechanism. In the present study, we made an effort to analyze the association of serum uric acid with oxidative stress and to evaluate the predictive value of serum iron, serum ferritin and serum uric acid level on oxidative stress induced lipid peroxidation in beta thalassemic patients. For this we assayed these parameters in 61 patients of beta thalassemia major and 51 age and sex matched controls of a rural area of West Bengal. Serum TBARS, serum Uric acid, serum Ferritin and serum Iron levels were significantly higher in the patient group (p<0.001 for all of them). Significant correlations existed between serum levels of TBARS, Uric acid, Ferritin and Iron levels in the patient group whereas only serum TBARS levels showed significant correlation with serum iron level in the control group. Regression analysis revealed that uric acid levels have a better predictive value (beta=0.3, p=0.001) than serum ferritin value (beta=0.013, p=0.871) for indicating TBARS production. PMID- 23982551 TI - Congenital stenosis in the descending colon causing intestinal obstruction in a one and half years male child. AB - A one and half years male child presented with constipation with severe colicky abdominal pain, bilious vomiting & abdominal distension. He had history of recurrent bouts of constipation followed by gastroenteritis since birth for which he had taken symptomatic treatment & sometimes remained symptom free but he had no other significant history or associated condition. In laboratory investigations, barium enema study of large gut result simulates to Hirschsprung's disease but suction rectal biopsy revealed normal rectal tissue texture. So, consideration of diagnostic tools along with patient's general condition decision was taken for diagnostic laparotomy & peroperatively the child was diagnosed as a case of intestinal obstruction due to congenital colonic stenosis in the descending colon. After resection of stenotic segment and end to end anastomosis, histopathologycal examination of resected stenosed colon was done & it was finally proved as congenital stenosis in the descending colon. The post operative period of the patient was uneventful and he was discharged on 7th postoperative day & followed up upto 6 months. He had been found alright without any complain. Here we tried to high light that the congenital colonic stenosis as a rare, but might be a possible cause of partial/complete intestinal obstruction from newborn to older children in any part of the colon & that should kept in mind for avoiding diagnostic dilemma & proper management of patient. PMID- 23982552 TI - A case of swallowed surprising foreign bodies in a young psychotic man. AB - Here we present a case of a young psychotic man who presented with chronic abdominal pain without clear history of foreign body (FB) ingestion. On examination patient was euphoric in mood, mildly anaemic & dehydrated from repeated vomiting. Abdomen was tender and rigid in epigastrium with no visible or palpable swelling. Routine hematology and biochemistry being normal, visible & echognic FBs were found on plain x-ray abdomen (AP & Lateral views) & USG abdomen. The case was revealed by plain x-ray and ultrasonography of abdomen. Since the foreign bodies swallowed were elongated, sharp edged or pointed and potentially injurious, no attempt was made to get them out by upper GI endoscopy. Their nature was revealed at formal laparotomy and gastrotomy. The patient recovered uneventfully. He was sent for psychiatric follow up. PMID- 23982553 TI - Thelazia callipaeda infestation in Bangladesh: a case report. AB - A 5 years old girl was admitted to Ophthalmology department of Mymensingh Medical College Hospital, Mymensingh with excessive watering, redness and movement of something in her right eye for last 2 months. She had unaided visual acuity- 6/6, matted eye lashes and mucoid discharge in right eye. Follicles were present on the fornices and lower palpebral conjunctiva of the same eye. On eversion of the right upper lid there were silicon tube like coiled moving structures seen at the lateral part of the upper fornics. Six nematodes were seen in the upper fornics around the duct of lacrimal glands. After removing the nematodes, one specimen was sent to parasitology department of Bangladesh Agriculture University for species identification. They reported that sending specimen is an adult "Thelazia Callipaeda". By the present study, the presence of human ocular T. callipaeda infestation is second reported case in Bangladesh. Ophthalmologists should be aware about parasitic infestation of conjunctiva. PMID- 23982554 TI - Hepatocellular carcinoma metastasis to the tip of the coracoid process. AB - Hepatocellular carcinoma (HCC) is the commonest and the most frequent primary malignant tumour of the liver. Chronic hepatitis B is the most common cause of HCC. Metastatic HCC has an aggressive course and a poor outcome. Common sites of hematogenous metastasis are lungs, bones & adrenal glands. Involvement of vertebra, pelvis, rib & skull is reported but coracoid process of scapula is an extremely rare site of metastasis. Thus we are going to present an unusual site of metastasis of HCC to the tip of the coracoid process of left scapula which was presented as a nodular swelling over the lateral aspect of left shoulder. On examination viral marker revealed HBsAg positive & negative negative hepatitis C virus (HCV). Ultrasonography of abdomen revealed large, well defined, heterogenous mass measuring 12*7.5 cm in the left lobe of liver. Chest radiograph showed a small radio opaque shadow on the tip of the coracoid process of left scapula. Fine needle aspiration cytology (FNAC) was done from the nodule & cytological examination showed malignant hepatocytes & traversing endothelial cells resembling hepatocellular carcinoma. PMID- 23982555 TI - An unusual foreign body in the urinary bladder. AB - In the urinary tract, foreign body is most commonly found in the urinary bladder. Most foreign bodies in the lower urinary tract are self-inserted via urethra as a result of exotic impulses, psychiatric illness, sexual curiosity, or sexual practice while intoxicated. Various types of foreign bodies have been reported such as wire, screw, fish, thermometer, or animal such as snake. Here we report a case of 22 years men who gave the history of self insertion of a large saline set both ends are cut. Diagnosis can be made by proper history taking, clinical examination, and relevant investigation. The treatment of foreign bodies is determined by their size, location, shape, and mobility. In most cases endoscopic management is appropriate but sometimes open procedure is required. Our case with an unusual foreign body admitted in general hospital Jamalpur for better management and subsequently foreign body was removed by suprapubic cystostomy. PMID- 23982556 TI - Hypertriglyceridemia associated with eruptive xanthomas and lipemia retinalis in newly diagnosed diabetes mellitus. AB - Severe hypertriglyceridemia can cause the deposit of lipids in the dermis (eruptive xanthomas) and in the retina (lipemia retinalis). Lipemia retinalis and eruptive xanthoma are occasionally seen in patients with diabetes mellitus and are thought to be due to abnormalities in the serum lipid fractions. Here a 15 year's old girl presented with typical symptoms of diabetes with skin lesions over hands and feet. On examination skin lesions were non-tender yellow papules with creamy-colored centers on extensor surfaces of the arms, hands and feet. Ophthalmoscopic examination showed creamy white retinal vessels with a faded pinkish white retinal back ground both in the periphery and posterior pole of the retina. Laboratory findings showed a grossly lipemic serum with markedly elevated serum levels of triglycerides 8869mg/dl cholesterol 498mg/dl. Her fasting blood glucose was 20.8mmol/l, 2 hours after breakfast was 50.5mmol/l and HbA1c was 14.6%. Eruptive xanthomas and lipaemia retinalis can occur in primary and secondary hyperlipoproteinemias, therefore a careful personal and family history as well as laboratory investigations is recommended in order to detect an underlying cause. PMID- 23982557 TI - Hypersensitivity reaction to all drugs of category-1 anti-tuberculosis regime in an adult tuberculosis patient. AB - Adverse drug reaction to tuberculous chemotherapy is not an uncommon problem. Usually it occurs to single drug and can be treated easily with minimal intervention. We follow WHO recommended guideline for National Tuberculosis Control Programs to treat these adverse reactions. Here we found an adult who has been suffering left sided pleural tuberculosis developed anaphylactic reaction to first dose of category-1 anti-TB regime. Later on it was found that he could not even tolerate smaller challenging doses of isoniazide, Ethambutol, Rifampicin and Pyrazinamide separately. It became very difficult to choose an alternate regime for this patient. Lastly a regime with levofloxacin, streptomycin and clarithromycin was give to treat him and patient was recovered with this regime successfully. This experience will help in management of unusual drug reactions to anti-tuberculosis drugs. PMID- 23982558 TI - Successful pregnancy outcome with coexisting primary epithelial ovarian carcinoma. AB - Maternal epithelial ovarian cancer (EOC) is rare. EOC is reported to occur in 1:12,000 to 1:50,000 pregnancies. We report a case of Stage IA epithelial ovarian cancer detected in the first trimester managed by laparotomy at 13 weeks followed by left sided salpingo-oophorectomy and infra-colic omentectomy. Histopathology revealed papillary mucinous cystadenocarcinoma (well differentiated with negative peritoneal cytology for malignancy). Chemotherapy was not warranted due to early stage disease and she had an uneventful gestation ending in vaginal delivery of a 2.5 kilogram male baby at term. During the period of follow up she developed no clinical or biochemical evidence of tumour recurrence or relapse. PMID- 23982559 TI - Pregnancy outcome in a case of non-obstructive hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a relatively common genetic disorder (1:500) inherited as an autosomal dominant trait. It is caused by mutations in any one of 10 genes encoding protein components of cardiac sarcomere. Some theoretically calculated risks exist when patients with HCM become pregnant. The physiologic increase of cardiac output and increased stroke volume may be impaired due to the non-compliant ventricular walls. In the first trimester, the physiologic hypervolemia of pregnancy to some extent counteracts the natural decrease in peripheral vascular resistance which would have otherwise provoked an obstruction gradientin systolic flow. As pregnancy advances, the vena caval compression may decrease venous return causing cardiac compromise, whereas the stress of labour may precipitate arrhythmia. We report our experience of a pregnancy with co existant non-obstructive hypertrophic cardiomyopathy and nodal bradycardia ultimately resulting in pre-term delivery, neonatal death and maternal death in puerperium from overt cardiac failure after a relatively uneventful gestation. PMID- 23982560 TI - Acute renal failure following wasp sting. AB - Wasp stings can result in multi system involvement ranging from intravascular hemolysis, rhabdomyolysis, acute renal failure cardiac involvement, hepatic dysfunction and occasionally thrombocytopenia and coagulopathy. We report here a case of eight year old boy presented with history of wasp sting followed by scanty micturation, generalized swelling and respiratory distress. After admission renal replacement therapy along with oral Prednisolone was started as serum creatinine level was gradually increasing. Kidney biopsy reveled Acute Interstitial Nephritis (AIN). Diagnosis was made of acute renal failure due to AIN following wasp stings. PMID- 23982561 TI - HIV-associated nephropathy (HIVAN): a short review of different authors. AB - Human immunodeficiency virus associated nephropathy (HIVAN) is clinically and morphologically a distinctive type of renal parenchymal disorder. It is presented in an HIV-seropositive individual by proteinuria and progressive renal insufficiency, usually without oedema or hypertension. Renal biopsy most commonly reveals a collapsing form of focal segmental glomerulosclerosis with marked proliferation of glomerular podocytes and tubular microcystic dilatation. These characteristic changes are attributed to incorporation of DNA and mRNA of human immunodeficiency virus type 1 into the renal parenchymal cells. Newly introduced highly active anti-retroviral therapy (HAART) has significantly reduced the incidence of HIVAN in the recent years. The HAART has been found to retard and revert the progression of renal insufficiency towards end-stage renal disease, and to increase survival of the patient. Therefore a renal biopsy should be performed in all suspected patients for definitive diagnosis of HIVAN and better patient management. PMID- 23982562 TI - Portopulmonary hypertension. AB - Pulmonary involvement is common in patients with portal hypertension and can manifest in diverse manners. Changes in pulmonary arterial resistance, manifesting either as the hepatopulmonary syndrome or portopulmonary hypertension (POPH), have been increasingly recognized in these patients in recent years. The prognosis in patients with liver disease who also suffer from significant POPH is considered to be poor. Higher degree of pulmonary artery pressure (PAP) may preclude a patient from liver transplant as mortality in these patients is high. This review summarizes the clinicopathologic features, diagnostic criteria, as well as the latest concepts in the pathogenesis and management of POPH, which is defined as is a form of pulmonary arterial hypertension (PAH) associated with portal hypertension with or without underlying chronic liver disease. PMID- 23982563 TI - Health-care utilization in Dutch systemic sclerosis patients. AB - This study aims to examine healthcare utilization and its determinants among patients with systemic sclerosis (SSc). A cross-sectional survey among all patients with SSc visiting an outpatient clinic of an academic hospital in the Netherlands was done. Assessments included sociodemographic characteristics and a survey on healthcare utilization including a registration of contacts with healthcare services since onset of disease, contacts, and number of visits with healthcare services over the last 12 months. A total healthcare utilization score of all visits over the last 12 months was computed and classified as high and low care utilization according to the median. In addition, the Short Form-36 and the Scleroderma Health Assessment Questionnaire (SHAQ) were administered. Logistic regression analysis was used to determine the relationship between high and low healthcare utilization as dependent variable and sociodemographic and disease characteristics as independent variables. Sixty-four patients returned the questionnaires. Over the last 12 months, 83% of the patients had had contact with one or more physicians. On average, patients reported 3.9 visits (SD, 2.9) to a rheumatologist and 6.9 visits (SD, 9.3) to other medical specialists over the last 12 months. The median total health-care utilization was six visits over the last 12 months. Multivariate regression showed that a higher SHAQ score was significantly associated with higher health-care utilization. Patients with SSc visited a considerable number of various health-care providers. Patients with more functional disability were using more healthcare. PMID- 23982565 TI - Social factors associated with readiness for sexual activity in adolescents: a population-based cohort study. AB - Various factors are associated with sexual activity in adolescence and it is important to identify those that promote healthy and adaptive romantic and sexual development. The objectives of this study were to describe rates of early sexual intercourse (before 16 years) and sexual readiness in adolescence and to assess the extent to which these were social patterned. We prospectively studied nearly 5,000 15-year-olds from the Avon Longitudinal Study of Parents and Children, a UK birth cohort. Between 2006 and 2008, female and male participants answered a computer assisted interview about romantic and sexual behaviors in the last year. Predictors of sexual intercourse and readiness for sexual intercourse were examined across a range of sociodemographic measures. Overall, 17.7% (95% CI 16.7%, 18.9%) of participants reported having had sexual intercourse in the last year, with more girls than boys reporting sexual experience (risk ratio 1.30, 95% CI 1.15, 1.47). Of these, one-third of both male and female were classed as unready because they were unwilling, lacking in autonomy, felt regret or had not used contraception. There was strong evidence of social patterning for sexual activity with higher rates for young people from poorer homes, with lower social class, and with younger, less educated mothers. In contrast, among 860 young people who had had sexual intercourse, there was no clear evidence of associations between social factors and sexual readiness. The lack of social patterning in sexual readiness supports the provision of comprehensive education to develop life skills for adolescents across all social groups. PMID- 23982564 TI - Intra-articular methylprednisolone acetate injection at the knee joint and the hypothalamic-pituitary-adrenal axis: a randomized controlled study. AB - The objective of this study was to evaluate the effect of intra-articular corticosteroid injection (IACI) of methylprednisolone acetate (MPA) on the hypothalamic-pituitary-adrenal (HPA) axis in patients with osteoarthritis of the knee. Patients with symptomatic osteoarthritis of the knee who failed to respond to nonsteroidal anti-inflammatory medications and physical therapy were randomized between group 1 and group 2. Group 1 patients had an IACI of 80 mg of MPA at the knee joint and group 2 patients had an intra-articular injection (IAI) of 6 ml (60 mg) of sodium hyaluronate (control group). Immediately prior to the IAI and on weeks 1, 2, 3, 4, and 8 following IAI, patients from both groups underwent a low-dose (1 MUg) adrenocorticotropin hormone (ACTH) stimulation test. Demographic, clinical, laboratory, and radiologic variables were documented in all patients. Both criteria of <7 MUg/dl increase in the serum cortisol level and absolute levels of <18 MUg/dl 30 min following the ACTH stimulation test were used to define secondary adrenal insufficiency (SAI). Twenty patients were randomized in each group. In group 1, 25 % of patients had SAI vs. none in group 2 (p = 0.0471). The earliest SAI was observed at week 2, and latest SAI was observed at week 4. SAI was observed at one time point, two consecutive time points, or two separate time points in the same patient. There was no correlation between SAI and any of the demographic, clinical, or laboratory variables. An IACI of 80 mg MPA at the knee joint induced a transient SAI in 25 % of the patients, an effect that was observed between week 2 and week 4 following the IACI. PMID- 23982566 TI - HIV infection and sexual behaviors among non-commercial men who have sex with men at different venues. AB - The prevalence of HIV infection among men who have sex with men (MSM) has increased rapidly in China. Previous studies suggested that some venue-specific characteristics could significantly affect MSM's sexual behaviors that were related to HIV transmission. Thus, to compare the HIV infection rates and related risky sexual behaviors among MSM at different venues, we conducted a cross sectional study with time-location sampling in Shenzhen, China. Among the 801 MSM recruited in the study, 7.0 % (n = 56) were found to be HIV positive, with 0.9 % of MSM at bars (BMSM), 3.5 % of MSM at suburban recreational centers (RMSM), 8.1 % of MSM at saunas (SMSM), 9.3 % of MSM at parks (PMSM), and 10.1 % of MSM at dorm-based venues (DMSM). HIV infection was significantly more prevalent in MSM in dorm-based venues, parks, and saunas than in other venues. Compared to MSM in other venues, BMSM were more likely to be single, drug and alcohol users, but less likely to be HIV and syphilis positive. More PMSM reported having unprotected anal intercourse with other men while more SMSM reported having multiple male sex partners and more RMSM had a low level of HIV-related knowledge. The results indicated that MSM frequenting different venues were inconsistent with regards to demographic characteristics, HIV and syphilis infection rates, and risky sexual behaviors. Greater efforts are needed to develop intervention strategies that target specific venues and risky behaviors. PMID- 23982567 TI - Sexual healing: daily diary investigation of the benefits of intimate and pleasurable sexual activity in socially anxious adults. AB - A growing literature attests to deficits in social and romantic life quality in people with elevated social anxiety, but no research to date has explored how intense intimate encounters influence social anxiety symptoms. This study investigated whether the presence and quality of sexual activity on a given day predicted less social anxiety and negative cognitions on a subsequent day. We also explored whether the benefits of sexual activity would be stronger for more socially anxious individuals. Over 21 days, 172 undergraduate students described the presence and quality of sexual activity, social anxiety symptoms, and use of social comparisons on the day in question. Time-lagged analyses determined that being sexually active on one day was related to less social anxiety symptoms and the generation of fewer negative social comparisons the next day. Furthermore, more intense experiences of pleasure and connectedness during sex predicted greater reductions in social anxiety the next day for people high in trait social anxiety, compared to those low in trait social anxiety. These results were similar regardless of whether sex occurred in the context of romantic relationships or on weekdays versus weekends. The results suggest that sexual activity, particularly when pleasurable and intimate, may mitigate some of the social anxiety and negative comparisons frequently experienced by people with high trait social anxiety. PMID- 23982568 TI - Perceptions of HPV, genital warts, and penile/anal cancer and high-risk sexual behaviors among men who have sex with men in Hong Kong. AB - The prevalence of HIV and HPV is high among men who have sex with men (MSM) in China. It is unclear whether cognitive and affective responses related to HPV and HPV-related diseases are negatively associated with HIV-related risk behaviors among MSM. This cross-sectional study interviewed 449 adult Chinese MSM in Hong Kong. The prevalence of unprotected anal intercourse (UAI) and having had anal sex with more than one man in the last 6 months (multiple male sex partnerships) was 39.0 and 71.3 %, respectively. After adjusting for four significant background variables (education level, cohabitation with a man, exposure to HIV prevention materials, and HIV voluntary counseling and testing), variables negatively associated with UAI and/or multiple male sex partnerships included (1) correct HPV-related knowledge (AOR = 0.48-0.66), (2) perceived susceptibility (AOR = 0.32-0.55) and perceived severity (AOR = 0.12-0.60) related to HPV and HPV related diseases, and (3) fear towards contracting genital warts and penile/anal cancer (AOR = 0.40-0.55). Perceived high chance of contracting HPV was positively associated with multiple partnerships (AOR = 4.74). It is possible to reduce HIV related risk behaviors by increasing levels of knowledge, cognitions, and fear related to HPV and related diseases. It is important to integrate prevention of HIV with prevention of sexually transmitted infections. Such interventions are warranted. PMID- 23982569 TI - Lifetime abstention of sexual intercourse and health in middle-aged and older adults: results from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. AB - This study aimed to examine the association of lifetime abstention of sexual intercourse with lifetime Axis I and II psychiatric disorders, attempted suicide, past-year Axis I psychiatric disorder, past-year medical condition, past-year obesity, health-related quality of life, and health service use in middle-aged and older adults in the United States. Face-to-face interviews were conducted in the 2004-2005 Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. Analyses were performed for the subsample aged 40 years and older (males = 14,427; female = 19,860). Lifetime abstinence from sexual intercourse, sociodemographic variables, prevalence of lifetime Axis I and II DSM-IV psychiatric disorders, schizophrenia, and attempted suicide, past-year Axis I psychiatric disorders, 14 medical conditions, obesity, health-related quality of life, and health service use were obtained. The prevalence of lifetime abstinence from sexual intercourse was 0.90 % (0.88 % for males; 1.00 % for females). The adjusted risks of any lifetime and past-year Axis I disorder, any lifetime and past-year substance-use disorders, lifetime alcohol-use disorder, lifetime and past-year alcohol-abuse disorder, lifetime nicotine dependence, lifetime drug-use disorder, and lifetime drug-abuse disorder were significantly lower for who abstained from sexual intercourse than for those who did not. However, those who abstained from sexual intercourse were more likely to have a diagnosis of obesity and lifetime avoidant and dependent personality disorders. The unadjusted risk of dysthymic disorder was also significantly greater for those who abstained from sexual intercourse. Results indicate that the effect of lifetime absence of sexual intercourse on psychiatric disorders is mixed. PMID- 23982570 TI - Gold nanoparticles and fluorescently-labelled DNA as a platform for biological sensing. AB - In the past decade gold nanoparticle-nucleic acid conjugates became progressively important for biomedical applications. Fluorophores attached to nucleic acid-gold nanoparticle conjugates have opened up a new era of biological sensing. The most promising advancement in this field was the invention of the so-called 'nano flare' systems. These systems are capable of detecting specific endocellular targets such as mRNAs, microRNAs or small molecules in real time. In this minireview, we discuss the current progress in the field of DNA-nanoparticles as sensors, their properties, stability, cellular uptake and cytotoxicity. PMID- 23982571 TI - Informed consent. PMID- 23982572 TI - The role of smooth muscle cells in the pathophysiology of pelvic organ prolapse. AB - Pelvic organ prolapse (POP) is a prevalent and disabling condition. The pathophysiology of prolapse is multifactorial, and no single mechanism adequately explains all aspects of its development. The pathophysiology of POP is complex and incompletely understood. Smooth muscle (SM), an integral part of the vaginal wall and endopelvic structures that support the pelvic viscera, has also been implicated in the pathophysiology of POP. In this article, we review the role of smooth muscle cells (SMC) in the pathophysiology of POP, also addressing the anatomy of SM in pelvic floor, morphometric analysis, biomechanical properties, and potential mechanisms. PMID- 23982573 TI - Outcomes of a comprehensive nonsurgical approach to pelvic floor rehabilitation for urinary symptoms, defecatory dysfunction, and pelvic pain. AB - OBJECTIVE: The authors' intent was to determine the clinical efficacy of comprehensive pelvic floor rehabilitation among women with symptoms of pelvic floor dysfunction (PFD). METHODS: We performed a retrospective analysis of women referred to an academic female pelvic medicine and reconstructive surgery practice for PFD. Data were gathered from the records of 778 women referred for pelvic floor therapy for urinary, bowel, pelvic pain, and sexual symptoms over the course of 4 years. RESULTS: Patients who completed at least 5 therapy sessions reported a mean symptom improvement of 80% in each of the 3 main categories analyzed, namely, urinary incontinence, defecatory dysfunction, and pelvic pain. CONCLUSIONS: Comprehensive, nonoperative management of PFD including pelvic floor muscle training, biofeedback, electrogalvanic stimulation, constipation management, behavioral modification, incontinence devices, and pharmacotherapy including vaginal estrogen is effective in the treatment of women with PFD. PMID- 23982574 TI - Robotic virtual reality simulation plus standard robotic orientation versus standard robotic orientation alone: a randomized controlled trial. AB - OBJECTIVE: The objective of this study was to compare the effect of virtual reality simulation training plus robotic orientation versus robotic orientation alone on performance of surgical tasks using an inanimate model. METHODS: Surgical resident physicians were enrolled in this assessor-blinded randomized controlled trial. Residents were randomized to receive either (1) robotic virtual reality simulation training plus standard robotic orientation or (2) standard robotic orientation alone. Performance of surgical tasks was assessed at baseline and after the intervention. Nine of 33 modules from the da Vinci Skills Simulator were chosen. Experts in robotic surgery evaluated each resident's videotaped performance of the inanimate model using the Global Rating Scale (GRS) and Objective Structured Assessment of Technical Skills-modified for robotic-assisted surgery (rOSATS). RESULTS: Nine resident physicians were enrolled in the simulation group and 9 in the control group. As a whole, participants improved their total time, time to incision, and suture time from baseline to repeat testing on the inanimate model (P = 0.001, 0.003, <0.001, respectively). Both groups improved their GRS and rOSATS scores significantly (both P < 0.001); however, the GRS overall pass rate was higher in the simulation group compared with the control group (89% vs 44%, P = 0.066). CONCLUSIONS: Standard robotic orientation and/or robotic virtual reality simulation improve surgical skills on an inanimate model, although this may be a function of the initial "practice" on the inanimate model and repeat testing of a known task. However, robotic virtual reality simulation training increases GRS pass rates consistent with improved robotic technical skills learned in a virtual reality environment. PMID- 23982575 TI - Impact of physical therapy on quality of life and function after vaginal reconstructive surgery. AB - OBJECTIVES: Although pelvic floor physical therapy (PFPT) can be beneficial for complaints after vaginal reconstructive surgery, it is not routinely offered to all patients. We sought to evaluate the role of perioperative PFPT in improving quality of life and function after prolapse repairs. METHODS: This randomized controlled trial compared PFPT to standard care after vaginal reconstructive surgery. The intervention group received PFPT 2 weeks preoperatively and 2, 4, 6, 8, and 12 weeks postoperatively, as well as a physician assessment. Control subjects underwent a physician's assessment alone at the same time points postoperatively. Both groups completed pelvic organ prolapse quantification examinations, intravaginal electromyography (EMG), voiding diaries, and validated questionnaires at baseline and 12 weeks. The primary outcome was change in the World Health Organization Quality of Life-BREF scale after surgery. RESULTS: Forty-nine women completed the study: 24 women in the PFPT group and 25 women in the control group. At 12 weeks, condition-specific questionnaires improved for the entire sample, confirming effectiveness of surgery. Nevertheless, no significant differences were noted between the groups despite therapy with PFPT. However, intravaginal EMG measures were notably affected by the intervention. The PFPT group showed significantly lower averages across all measurements of rest, indicating positive impact on muscle function. Pearson correlations revealed associations with better scores on the World Health Organization Quality of Life BREF physical domain and greater EMG relaxation, supporting effects from PFPT on quality of life. CONCLUSIONS: Pelvic symptoms improved in all subjects after vaginal reconstructive surgery. Whereas PFPT did not result in detectable subjective differences in this short-term study, superior muscular function suggested benefit from the intervention. PMID- 23982576 TI - Apical descent in the office and the operating room: the effect of prolapse size. AB - OBJECTIVES: The support of the uterine cervix with Valsalva or cough assessed in the clinic and the support of the uterine cervix with traction in the operating room often differs. The objectives of this study were to test the null hypothesis that the difference between preoperative and intraoperative values of pelvic organ prolapse quantification (POP-Q) point C is not related to prolapse size and to determine if other factors exist that predict this difference. METHODS: This is a retrospective review of women who had a vaginal hysterectomy in the Female Pelvic Medicine and Reconstructive Surgery division between 2005 and 2011 and had preoperative and intraoperative POP-Q point C recorded. A difference of 5 cm was established by a panel of urogynecologists as clinically significant. Student t tests and chi analyses were used and a logistic regression performed. RESULTS: There were 206 subjects included. The mean difference in point C between the 2 clinical settings was 3.5 cm. A difference of 5 cm or greater was present in 33%. The mean difference in point C was larger for women with lesser stages of prolapse (stage 1, 5.8 cm; stage 2, 3.0 cm; stage 3/4, 1.4 cm; P<0.001). A difference of 5 cm or greater in point C was more often present in women with lesser stages of prolapse: 70.3% of women with stage 1 prolapse, 9.3% of women with stage 2 prolapse, and 8.5% of women with stage 3 prolapse (P<0.001). CONCLUSIONS: We reject our null hypothesis. A difference of 5 cm or greater between POP-Q point C in the clinic and the POP-Q point C in the operating room occurred more frequently in women with lesser stages of prolapse. PMID- 23982577 TI - Defining patients' knowledge and perceptions of vaginal mesh surgery. AB - OBJECTIVE: Given recent government investigations and media coverage of the controversy regarding mesh surgery, we sought to define patients' knowledge and perceptions of vaginal mesh surgery. STUDY DESIGN: An anonymous survey was distributed to a convenience sample of new patients at urogynecology and female urology clinics at a single medical center during April to June 2012. The survey assessed patients' demographics, information sources, and beliefs and concerns regarding mesh surgery. The Fisher's exact test was used to identify predictors of patients' beliefs regarding mesh. Logistic and linear regressions were used to identify predictors of aversion to surgery and higher concern regarding future surgery. RESULTS: One hundred sixty-four women completed the survey; 62.2% (102/164) indicated knowledge of mesh surgery for prolapse and/or incontinence and were included in subsequent analyses. The mean +/- SD age was 58.0 +/- 12.5 years, and 24.5% reported prior mesh surgery. The most common information source was television commercials (57.8%); only 23.5% of the women reported receiving information from a medical professional. Participants indicated the following regarding vaginal mesh: class-action lawsuit in progress (55/102 [54.0%]), causes pain (47/102 [47.1%]), possibility of rejection (35/102 [34.3%]), can cause bleeding and become exposed vaginally (30/102 [29.4%]), and should be removed owing to recall (28/102 [27.5%]). Of these women, 22.1% (19/86) indicated they would not consider mesh surgery. On multivariable logistic regression, level of concern, information from friends/family, and knowledge of class-action lawsuit predicted aversion to mesh surgery. CONCLUSION: Nearly two thirds of new patients had knowledge of vaginal mesh surgery. We identified considerable misinformation and aversion to future mesh surgery among these women. PMID- 23982578 TI - Botulinum toxin type A (BOTOX) for refractory myofascial pelvic pain. AB - OBJECTIVE: To assess intralevator botulinum toxin type A (Botox) injections for refractory myofascial pelvic pain with short tight pelvic floor. METHODS: Retrospective cohort study of all women with intralevator Botox injection (100 300 Units) from 2005 through 2010 for refractory myofascial pelvic pain. Primary outcomes were self-reported pain on palpation and symptom improvement. Secondary outcomes included postinjection complications and a second injection. Pain was assessed during digital palpation of the pelvic floor muscles using a scale of 0 to 10, with 10 being the worst possible pain. Follow-up occurred at less than 6 weeks after injection and again at 6 weeks or more. Data are presented as median (interquartile range) or proportion. RESULTS: Thirty-one patients met eligibility criteria; 2 patients were lostto follow-up and excluded. The median age was 55.0 years (38.0-62.0 years). Before Botox injection, the median pain score was 9.5 (8.0-10.0). Twenty-nine patients (93.5%) returned for the first follow-up visit; 79.3% reported improvement in pain, whereas 20.7% reported no improvement. The median pain with levator palpation was significantly lower than before injection (P<0.0001). Eighteen women (58.0%) had a second follow-up visit with a median pain score that remained lower than before injection (P<0.0001). Fifteen (51.7%) women elected to have a second Botox injection; the median time to the second injection was 4.0 months (3.0-7.0 months). Three (10.3%) women developed de novo urinary retention, 2 patients (6.9%) reported fecal incontinence, and 3 patients (10.3%) reported constipation and/or rectal pain; all adverse effects resolved spontaneously. CONCLUSIONS: Intralevator injection of Botox demonstrates effectiveness in women with refractory myofascial pelvic pain with few self limiting adverse effects. PMID- 23982579 TI - Readability of common health-related quality-of-life instruments in female pelvic medicine. AB - OBJECTIVES: The average American adult reads below the eighth-grade level. To determine whether self-reported health-related quality-of-life questionnaires used for pelvic floor disorders are appropriate for American women, we measured reading levels of questionnaires for urinary incontinence (UI), pelvic organ prolapse (POP), and fecal incontinence (FI). METHODS: An online literature search identified questionnaires addressing UI, POP, and FI. Readability was assessed using Flesch-Kincaid reading level and ease formulas. Flesch-Kincaid grade level indicates the average grade one is expected to completely and lucidly comprehend the written text. Flesch-Kincaid reading ease score, from 0 to 100, indicates how easy the written text can be read. RESULTS: Questionnaires were categorized by UI, POP, FI, and combined pelvic floor symptoms. The median Flesch-Kincaid reading level was 7.2, 10.1, 7.6, and 9.7, for UI, POP, FI, and combined pelvic floor symptoms, respectively. Reading levels varied greatly between questionnaires, with only 54% of questionnaires written below the eighth-grade level. CONCLUSIONS: We identified significant variation in reading levels among the questionnaires and found the 2 most commonly used questionnaires per survey in 2008 at Society of Urodynamics and Female Pelvic Medicine and Urogenital Reconstruction were above the recommended eighth-grade reading level. As specialty societies focus on standardizing questionnaires for research, reading levels should be considered so they are generalizable to larger populations of women with pelvic floor disorders. PMID- 23982580 TI - Rectal mesh erosion after robotic sacrocolpopexy. AB - We report an unusual case of rectal mesh erosion presenting 16 months after robotic sacrocolpopexy. The patient initially underwent a robotic sacrocolpopexy, lysis of adhesions, midurethral sling, and posterior colporrhaphy for symptomatic grade 2 pelvic organ prolapse and urodynamic stress incontinence. Her postoperative recovery was uneventful. Sixteen months later, an anterior 2 * 2-cm rectal mesh erosion was noted on the colonoscopy performed when she presented with hematochezia. PMID- 23982581 TI - Erosion of pelvicol used in sacrocolpopexy. AB - INTRODUCTION: Biologic graft materials are used more frequently in pelvic reconstructive surgeries. We describe here the complete process of removal of such a biologic graft in the office. CASE: We report a case of a 69-year-old woman with pig dermal graft erosion 1 year after placement. The patient presented with complaints of vaginal discharge. Upon examination, the graft material was seen eroding through the vaginal apex. The pig tissue was removed whole and intact in the office without complications. CONCLUSION: Transvaginal removal of pig tissue in the office relieved the patient's symptoms. PMID- 23982582 TI - Surgically shortened vagina lengthened by laparoscopic Davydov procedure. AB - BACKGROUND: The laparoscopic Davydov procedure is a neovagina surgical technique most commonly used in patients with vaginal agenesis. We present a unique case of vaginal length restoration using this procedure in a patient with vaginal shortening after multiple vaginal surgeries. CASE: A 62-year-old patient presented to our office after multiple vaginal surgeries with symptoms suggestive of cystocele, rectocele, vaginal vault prolapse, and dyspareunia. Excessive vaginal shortening and a painful vaginal apex were also noted upon initial examination. A laparoscopic Davydov procedure was performed to lengthen the vagina and to eliminate the apical pain. CONCLUSION: The laparoscopic Davydov procedure is a surgical option for patients with surgically shortened vaginas and dyspareunia. PMID- 23982583 TI - Unique complication of a Shirodkar cerclage: remote formation of a vesicocervical fistula in a patient with the history of cervical cerclage placement: a case report and literature review. AB - BACKGROUND: Cervical cerclage placement is an accepted treatment for cervical insufficiency and recurrent second-trimester pregnancy loss. The most commonly described complications of cerclage include rupture of fetal membranes, intra amniotic infection, endometritis, and peripartum bleeding. We present a unique case of a vesicocervical fistula formation remote from cerclage placement. CASE: A vesicocervical fistula was diagnosed in a 51-year-old patient who presented with a chief complaint of vaginal bleeding. The fistula was found on cystoscopic examination after the extrusion, from the cervix, of Mersilene tape from a Shirodkar cerclage placed 13 years earlier for management of cervical insufficiency. CONCLUSION: Although the presented condition was managed conservatively, one should discuss remote formation of urogenital fistulae as a rare complication of cervical cerclage at the time of informed consent. PMID- 23982584 TI - Mesh extrusion through the internal cervical os: an unusual complication following laparoscopic sacrocervicopexy. AB - Mesh extrusion or exposure is a known complication of procedures using synthetic mesh for vaginal vault and pelvic organ suspension. Preservation of the uterine cervix is thought to be protective against such complications, as the well vascularized in situ cervix provides an added barrier between the mesh and the colpotomy incision, limiting potential exposure to the vaginal flora. We describe a case of a 55-year-old multipara, who presented with vaginal discharge following a supracervical hysterectomy with sacrocervicopexy and was found to have a delayed mesh extrusion though the endocervical os. PMID- 23982585 TI - Labial fusion causing recurrent cyst formation and a novel approach to surgical management. AB - BACKGROUND: Labial fusion may occur as a result of lichen sclerosus, lichen planus, genital mutilation, obstetric laceration, and atrophic vaginitis. Koebner phenomenon, or reformation of scar tissue over the clitoris after trauma to the involved tissue, may confound attempts at surgical management. CASE: A 22-year old nulligravid patient presented with labia minora fusion that had been present since childhood. Her most bothersome symptoms were the recurrence of periclitoral pseudocysts with pain and discharge after spontaneous or needle drainage. Her symptoms and examination findings persisted despite a prolonged course of topical clobetasol, and she desired surgical intervention. A silastic vessel loop was placed through the tract between her clitoris and fused overlying labia. The ends of the vessel loop were brought together and tied in a fashion similar to cutting setons used to manage complex anal fistulae. Over the subsequent weeks, additional ties were used to sequentially tighten the loop and gradually divide the fused labia, ultimately exposing the patient's normal clitoris, which was uninjured by the procedure. Topical clobetasol was used throughout the process to prevent reagglutination of the labia. CONCLUSIONS: Our experience suggests that adaptation of a cutting seton may be used effectively in the surgical management of labial fusion to allow for gradual division of the skin bridge while minimizing the risk of recurrence of agglutination. PMID- 23982586 TI - Ligand modified nanoparticles increases cell uptake, alters endocytosis and elevates glioma distribution and internalization. AB - Nanoparticles (NPs) were widely used in drugs/probes delivery for improved disease diagnosis and/or treatment. Targeted delivery to cancer cells is a highly attractive application of NPs. However, few studies have been performed on the targeting mechanisms of these ligand-modified delivery systems. Additional studies are needed to understand the transport of nanoparticles in the cancer site, the interactions between nanoparticles and cancer cells, the intracellular trafficking of nanoparticles within the cancer cells and the subcellular destiny and potential toxicity. Interleukin 13 (IL-13) peptide can specifically bind IL 13Ralpha2, a receptor that is highly expressed on glioma cells but is expressed at low levels on other normal cells. It was shown that the nanoparticels modification with the IL-13 peptide could improve glioma treatment by selectively increasing cellular uptake, facilitating cell internalization, altering the uptake pathway and increasing glioma localization. PMID- 23982587 TI - Mechanism, decomposition pathway and new evidence for self-healing of manganese oxides as efficient water oxidizing catalysts: new insights. AB - The electrochemical water-oxidation reaction usually requires a catalyst to reduce the overpotential and Earth-abundant catalysts, like MnO2, are attracting much attention. Here we use chemometric analysis, EPR and UV-Vis spectroscopies to track Mn(II) and MnO4(-) byproducts to the reaction of a MnO2 film in the presence of cerium(IV) ammonium nitrate. Permanganate ion is involved in at least two key reactions: it may oxidize water to O2 or can combine with Mn(II) to remake MnO2 solid. We propose mechanisms for water oxidation and present a self healing process for this reaction. PMID- 23982588 TI - Golgi cell activity during eyeblink conditioning in decerebrate ferrets. AB - Golgi cells have a central position in the cerebellar cortical network and are indirectly connected to Purkinje cells, which are important for the acquisition of learned responses in classical conditioning. In order to clarify the role of Golgi cells in classical conditioning, we made extracellular Golgi cell recordings during different stages of conditioning, using four different conditional stimuli. Our results show that forelimb and superior colliculus stimulation, but not mossy fiber stimulation, evokes a short latency increase in Golgi cell firing. These results suggest that Golgi cells are involved in modulating input to the cerebellar cortex. There were however no differences in Golgi cell activity between naive and trained animals, which suggests that Golgi cells are not intimately involved in the plastic changes that occur during classical conditioning. The absence of long latency effects of the conditional stimulus also questions whether Golgi cells contribute to the generation of a temporal code in the granule cells. PMID- 23982589 TI - Effects of attention and perceptual uncertainty on cerebellar activity during visual motion perception. AB - Recent clinical and neuroimaging studies have revealed that the human cerebellum plays a role in visual motion perception, but the nature of its contribution to this function is not understood. Some reports suggest that the cerebellum might facilitate motion perception by aiding attentive tracking of visual objects. Others have identified a particular role for the cerebellum in discriminating motion signals in perceptually uncertain conditions. Here, we used functional magnetic resonance imaging to determine the degree to which cerebellar involvement in visual motion perception can be explained by a role in sustained attentive tracking of moving stimuli in contrast to a role in visual motion discrimination. While holding the visual displays constant, we manipulated attention by having participants attend covertly to a field of random-dot motion or a colored spot at fixation. Perceptual uncertainty was manipulated by varying the percentage of signal dots contained within the random-dot arrays. We found that attention to motion under high perceptual uncertainty was associated with strong activity in left cerebellar lobules VI and VII. By contrast, attending to motion under low perceptual uncertainty did not cause differential activation in the cerebellum. We found no evidence to support the suggestion that the cerebellum is involved in simple attentive tracking of salient moving objects. Instead, our results indicate that specific subregions of the cerebellum are involved in facilitating the detection and discrimination of task-relevant moving objects under conditions of high perceptual uncertainty. We conclude that the cerebellum aids motion perception under conditions of high perceptual demand. PMID- 23982590 TI - Assisted reproduction counseling in women aged 40 and above: a cohort study. AB - PURPOSE: Fertility treatment in women aged >=40 year old remains difficult and controversial. All available studies in older women report results of one specific method of ART, i.e. IUI, IVF/ICSI or oocyte donation, and success rates are always published per attempt but never per patient. Randomized studies are not available because of the obvious heterogeneity in patient populations and treatment options. This prospective observational study aimed at analyzing the outcome in a consecutive cohort of patients above 40 undergoing various methods of ART. METHODS: A total number of 909 women older than 40 attended our fertility centre during a 3 years period. A flowchart showing the consecutive ART treatments with their respective outcome was constructed. Any delivery after 22 weeks gestation (or 500 g.) was taken as primary endpoint. Crude cumulative delivery rates (CDRs) and binomial exact 95 % confidence limits (95 % CLs) were calculated for each group of interest. RESULTS: ART treatment could be proposed to 737 patients (81 %) and eventually 585 patients (64 %) started ART treatment: 111 patients started IUI, 439 patients started IVF/ICSI and 35 patients started oocyte donation as a primary approach ART. Ten patients got pregnant spontaneously and delivered before starting any treatment. In the 909 patients consulting for infertility, 111 deliveries were achieved after ART, i.e. a crude CDR of 12.2 % (95 % CL 10.1 % to 14.5 %). CONCLUSION: Only 10 % of patients aged 40 and above could achieve delivery of their genetically-own child, while 1 % conceived spontaneously. More than one third of patients consulting never started any treatment for different reasons, i.e. anticipated poor prognosis, financial restrictions, illness or spontaneous pregnancy. PMID- 23982591 TI - Optimizing the allocation of resources for genomic selection in one breeding cycle. AB - KEY MESSAGE: We developed a universally applicable planning tool for optimizing the allocation of resources for one cycle of genomic selection in a biparental population. The framework combines selection theory with constraint numerical optimization and considers genotype * environment interactions. Genomic selection (GS) is increasingly implemented in plant breeding programs to increase selection gain but little is known how to optimally allocate the resources under a given budget. We investigated this problem with model calculations by combining quantitative genetic selection theory with constraint numerical optimization. We assumed one selection cycle where both the training and prediction sets comprised double haploid (DH) lines from the same biparental population. Grain yield for testcrosses of maize DH lines was used as a model trait but all parameters can be adjusted in a freely available software implementation. An extension of the expected selection accuracy given by Daetwyler et al. (2008) was developed to correctly balance between the number of environments for phenotyping the training set and its population size in the presence of genotype * environment interactions. Under small budget, genotyping costs mainly determine whether GS is superior over phenotypic selection. With increasing budget, flexibility in resource allocation increases greatly but selection gain leveled off quickly requiring balancing the number of populations with the budget spent for each population. The use of an index combining phenotypic and GS predicted values in the training set was especially beneficial under limited resources and large genotype * environment interactions. Once a sufficiently high selection accuracy is achieved in the prediction set, further selection gain can be achieved most efficiently by massively expanding its size. Thus, with increasing budget, reducing the costs for producing a DH line becomes increasingly crucial for successfully exploiting the benefits of GS. PMID- 23982593 TI - Reply: the early pathological process in sporadic Alzheimer's disease. PMID- 23982594 TI - An RNA modification with remarkable resistance to RNase A. AB - A 3'-deoxy-3'-C-methylenephosphonate modified diribonucleotide is highly resistant to degradation by spleen phosphodiesterase and not cleaved at all by snake venom phosphodiesterase. The most remarkable finding is that, despite the fact that both the vicinal 2-hydroxy nucleophile and the 5'-oxyanion leaving group are intact, the 3'-methylenephosponate RNA modification is also highly resistant towards the action of RNase A. PMID- 23982592 TI - Selfing for the design of genomic selection experiments in biparental plant populations. AB - Self-fertilization (selfing) is commonly used for population development in plant breeding, and it is well established that selfing increases genetic variance between lines, thus increasing response to phenotypic selection. Furthermore, numerous studies have explored how selfing can be deployed to maximal benefit in the context of traditional plant breeding programs (Cornish in Heredity 65:201 211,1990a, Heredity 65:213-220,1990b; Liu et al. in Theor Appl Genet 109:370-376, 2004; Pooni and Jinks in Heredity 54:255-260, 1985). However, the impact of selfing on response to genomic selection has not been explored. In the current study we examined how selfing impacts the two key aspects of genomic selection GEBV prediction (training) and selection response. We reach the following conclusions: (1) On average, selfing increases genomic selection gains by more than 70 %. (2) The gains in genomic selection response attributable to selfing hold over a wide range population sizes (100-500), heritabilities (0.2-0.8), and selection intensities (0.01-0.1). However, the benefits of selfing are dramatically reduced as the number of QTLs drops below 20. (3) The major cause of the improved response to genomic selection with selfing is through an increase in the occurrence of superior genotypes and not through improved GEBV predictions. While performance of the training population improves with selfing (especially with low heritability and small population sizes), the magnitude of these improvements is relatively small compared with improvements observed in the selection population. To illustrate the value of these insights, we propose a practical genomic selection scheme that substantially shortens the number of generations required to fully capture the benefits of selfing. Specifically, we provide simulation evidence that indicates the proposed scheme matches or exceeds the selection gains observed in advanced populations (i.e. F 8 and doubled haploid) across a broad range of heritability and QTL models. Without sacrificing selection gains, we also predict that fully inbred candidates for potential commercialization can be identified as early as the F 4 generation. PMID- 23982595 TI - Glyoxalase 1 as a candidate for indicating the metastatic potential of SN12C human renal cell carcinoma cell clones. AB - Three clones with differential metastatic potential were established from the parental SN12C human renal cell carcinoma (HRCC). We previously reported that in the two high metastatic SN12C clones, two isoforms of ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) showed decreased expression by using two dimensional electrophoresis (2-DE) covering a pH range (pH 3.0-10.0) followed by liquid chromatography-tandem mass spectrometry. However, in the case of the low metastatic clone, the spot volume for UCH-L1 was almost the same as for the parental SN12C. In the present study, we found one protein spot which was correlated with the metastatic potential of SN12C clones by using 2-DE over a narrow pH range (pH 4.0-7.0). The protein glyoxalase 1 (GLO1) appeared to be directly proportional to the metastatic potential of the SN12C clones. GLO1 was the only protein which consistently varied according to the metastatic potentials of SN12C clones. GLO1 was increased in high metastatic cell lines by western blot analysis. These findings suggest that GLO1 is associated with the metastatic potential of SN12C HRCC clones. We expanded our experimental range to include clones of scirrhous gastric cancer cell lines (OCUM-2M, OCUM-2D and OCUM-2MLN) and similar results were obtained, thereby further strengthening our original findings. PMID- 23982596 TI - Diffusion tensor and volumetric magnetic resonance imaging using an MR-compatible hand-induced robotic device suggests training-induced neuroplasticity in patients with chronic stroke. AB - Stroke is the third leading cause of mortality and a frequent cause of long-term adult impairment. Improved strategies to enhance motor function in individuals with chronic disability from stroke are thus required. Post-stroke therapy may improve rehabilitation and reduce long-term disability; however, objective methods for evaluating the specific impact of rehabilitation are rare. Brain imaging studies on patients with chronic stroke have shown evidence for reorganization of areas showing functional plasticity after a stroke. In this study, we hypothesized that brain mapping using a novel magnetic resonance (MR) compatible hand device in conjunction with state-of-the-art magnetic resonance imaging (MRI) can serve as a novel biomarker for brain plasticity induced by rehabilitative motor training in patients with chronic stroke. This hypothesis is based on the premises that robotic devices, by stimulating brain plasticity, can assist in restoring movement compromised by stroke-induced pathological changes in the brain and that these changes can then be monitored by advanced MRI. We serially examined 15 healthy controls and 4 patients with chronic stroke. We employed a combination of diffusion tensor imaging (DTI) and volumetric MRI using a 3-tesla (3T) MRI system using a 12-channel Siemens Tim coil and a novel MR compatible hand-induced robotic device. DTI data revealed that the number of fibers and the average tract length significantly increased after 8 weeks of hand training by 110% and 64%, respectively (p<0.001). New corticospinal tract (CST) fibers projecting progressively closer to the motor cortex appeared during training. Volumetric data analysis showed a statistically significant increase in the cortical thickness of the ventral postcentral gyrus areas of patients after training relative to pre-training cortical thickness (p<0.001). We suggest that rehabilitation is possible for a longer period of time after stroke than previously thought, showing that structural plasticity is possible even after 6 months due to retained neuroplasticity. Our study is an example of personalized medicine using advanced neuroimaging methods in conjunction with robotics in the molecular medicine era. PMID- 23982598 TI - Pertuzumab: a review of its use for first-line combination treatment of HER2 positive metastatic breast cancer. AB - Pertuzumab (Perjeta(r)) is a humanized anti-HER2 monoclonal antibody that binds to the extracellular dimerization subdomain of the HER2 receptor and reduces HER2 intracellular signalling by preventing HER2 from forming heterodimers with other HER receptors. Inhibition of HER2 signalling results in a reduction of tumour cell proliferation, invasiveness and survival. Pertuzumab and trastuzumab bind to different sites on the HER2 receptor and have complementary antitumour activities; they act synergistically in inhibiting the growth of HER2 overexpressing breast cancer cell lines in vitro. The efficacy of intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) in combination with trastuzumab plus docetaxel in the first-line treatment of HER2-positive metastatic breast cancer was demonstrated in the randomized, double-blind, placebo-controlled, multinational, phase III CLEOPATRA trial. Pertuzumab in combination with trastuzumab and docetaxel significantly increased independently assessed median progression-free survival (primary endpoint), objective response rate and overall survival compared with placebo in combination with trastuzumab and docetaxel. Pertuzumab had an acceptable tolerability profile when added to trastuzumab and docetaxel in the pivotal CLEOPATRA trial. Thus, pertuzumab is a valuable addition to the growing list of anti-HER2 targeted therapies for breast cancer. PMID- 23982597 TI - Value of transcranial Doppler, perfusion-CT and neurological evaluation to forecast secondary ischemia after aneurysmal SAH. AB - INTRODUCTION: This study was conducted to prospectively evaluate the diagnostic value of detailed neurological evaluation, transcranial Doppler sonography (TCD) and Perfusion-CT (PCT) to predict delayed vasospasm (DV) and delayed cerebral infarction (DCI) within the following 3 days in patients with aneurysmal subarachnoid hemorrhage (SAH). METHODS: A total of 61 patients with aneurysmal SAH were included in the study. All patients were amenable for neurological evaluation throughout the critical phase to develop secondary ischemia after SAH. The neurological status was assessed three times a day according to a detailed examination protocol. Mean flow velocities (MFV) in intracranial vessel trunks were measured daily by TCD. Native CT and PCT were routinely acquired at 3-day intervals and, in addition, whenever it was thought to be of diagnostic relevance. The predictive values of abnormal PCT and accelerations in TCD (MFV > 140 cm/s) to detect angiographic DV and DCI within the following 2 days were calculated and compared to the predictive value of delayed ischemic neurological deficits (DIND). RESULTS: The accuracy of TCD and PCT to predict DV or DCI was 0.65 and 0.63, respectively. In comparison, DIND predicted DV or DCI with an accuracy of 0.96. Pathological PCT findings had a higher sensitivity (0.93) and negative predictive value (0.98) than TCD (0.81 and 0.96). CONCLUSION: Neurological assessment at close intervals is the most accurate parameter to detect DV and DCI in the following 3 days. However, DIND may not be reversible. The routine acquisition of PCT in addition to daily TCD examinations seems reasonable, particularly in patients who are not amenable to a detailed neurological examination since it has a higher sensitivity and negative predictive value than TCD and leaves a lower number of undetected cases of vasospasm and infarction. PMID- 23982599 TI - Afatinib: first global approval. AB - Afatinib, an irreversible inhibitor of the ErbB family of tyrosine kinases, is under development with Boehringer Ingelheim for the once-daily, oral treatment of cancer. Afatinib downregulates ErbB signalling by covalently binding to epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, irreversibly inhibiting tyrosine kinase autophosphorylation. It also inhibits transphosphorylation of HER3. Oral afatinib (GilotrifTM) has been approved in the US for the first-line treatment of patients with metastatic non small-cell lung cancer (NSCLC) who have tumours with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test. Afatinib has also been approved in Taiwan for the first-line treatment of patients with EGFR mutation-positive NSCLC. In addition, the European Medicines Agency's Committee for Medicinal Products for Human Use has recommended the approval of afatinib (Giotrif(r)) for the treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations who are EGFR tyrosine kinase inhibitor naive. Afatinib is also under regulatory review in Canada, Japan and other Asian countries. This article summarizes the milestones in the development of afatinib, leading to this first approval in patients with metastatic NSCLC. PMID- 23982600 TI - The relationship between lymphocyte subsets and clinico-pathological determinants of survival in patients with primary operable invasive ductal breast cancer. AB - BACKGROUND: The importance of lymphocyte subtypes in determining outcome in primary operable ductal invasive breast cancer remains unclear. The aim of present study was to examine the relationship between tumour lymphocyte subsets infiltrate and standard clinico-pathological factors and survival in patients with primary operable invasive ductal breast cancer. METHODS: The analysis of the inflammatory cell infiltrate, including lymphocyte subtypes, was undertaken using immunohistochemical techniques and visual quantitative and semi-quantitative techniques in 338 patients with ductal breast cancer. RESULTS: The majority (91%) of patients had high grade inflammatory cell infiltrate. The median follow-up of the survivors was 164 months. During this period, 65 died of their cancer. On univariate analysis, tumour inflammatory cell infiltrate, macrophages infiltrate (P<0.05), lymphocytic infiltrate (P<0.001) and CD8+ T-lymphocytic infiltrate (P<0.01) were associated with improved cancer-specific survival, whereas neutrophil (P<0.05) and CD138+ B-lymphocytic infiltrate (P<0.001) were associated with poorer cancer-specific survival. On multivariate analysis, tumour lymphocytic infiltrate (P<0.001), macrophage infiltrate (P<0.05), CD8+ T lymphocytic infiltrate (P<0.01) and CD138+ B-lymphocytic infiltrate (P<0.001) were independently associated with cancer survival. When the significant inflammatory cell types were included with tumour-based factors in multivariate analysis only tumour size (Hazard ratios (HR): 2.55, 95% confidence interval (CI): 1.53-4.27, P<0.001), Ki-67 index (HR: 2.08, 95% CI: 1.08-4.00, P<0.05), lymphovascular invasion (HR: 4.40, 95% CI: 2.07-9.35, P<0.001), macrophage infiltrate (HR: 0.49, 95% CI: 0.33-0.73, P<0.001), lymphocytic infiltrate (HR: 0.11, 95% CI: 0.05-0.23, P<0.001), CD8+ T-lymphocytic infiltrate (HR: 0.57, 95% CI: 0.38-0.87, P<0.001) and CD138+ B-lymphocytic infiltrate (HR: 2.86, 95% CI: 1.79-4.56, P<0.001) were independently associated with cancer survival. CONCLUSION: The majority of patients with invasive ductal breast cancer had high grade inflammatory cell infiltrate. In these patients, inflammatory cells including macrophage and lymphocytic infiltrate, and subsets CD8+ T-lymphocytic infiltrate and CD138+ B-lymphocytic infiltrate had superior prognostic value, compared with hormone status and lymph node involvement in patients with primary operable invasive ductal breast cancer. PMID- 23982601 TI - Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder. AB - BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients. METHODS: We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models. RESULTS: With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients. CONCLUSION: The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design. PMID- 23982602 TI - HCC-ART score, a simple, highly sensitive and specific test for early diagnosis of hepatocellular carcinoma: a large-scale, multicentre study. AB - BACKGROUND: A simple scoring system is needed to discriminate HCC from patients with chronic liver diseases (CLD). The simplest score would be one that requires only variables that can be documented simply from routine laboratory tests without the need for sophisticated tests. METHODS: Data from the estimation group (1351 patients) and the validation group (2208 patients) were retrospectively analysed. Liver fibrosis-negative control and liver cirrhosis were compared with HCC. Area under ROC curve (AUC) were used to develop HCC-alpha-fetoprotein routine test (HCC-ART). RESULTS: Hepatocellular carcinoma-AFP-routine test showed diagnostic accuracy for liver cirrhosis vs HCC with ROC curves of 0.99%, sensitivity of 97%, and specificity of 96% in the estimation, and 0.95%, 90%, and 83%, respectively, in the validation. Sensitivity (97%) and specificity (100%) were obtained to discriminate HCC from liver fibrosis. Area under curve for AFP at 400 U l(-1) was 0.70, sensitivity was 41%, and specificity was 99% in the estimation, and 0.77%, 54%, and 99%, respectively, in the validation. The AUC for HCC-ART in HCC with single tumour, absent vascular invasion, size <2 cm and CLIP score (0-1) were 0.95, 0.93, 0.86, 0.87, respectively, compared with 0.72, 0.71, 0.71, 0.50, respectively, for AFP. CONCLUSION: Hepatocellular carcinoma-AFP routine test could increase the accuracy of HCC screening and surveillances and could be used worldwide without extra efforts. PMID- 23982603 TI - Review of processing and analysis methods for DNA methylation array data. AB - The promise of epigenome-wide association studies and cancer-specific somatic DNA methylation changes in improving our understanding of cancer, coupled with the decreasing cost and increasing coverage of DNA methylation microarrays, has brought about a surge in the use of these technologies. Here, we aim to provide both a review of issues encountered in the processing and analysis of array-based DNA methylation data and a summary of the advantages of recent approaches proposed for handling those issues, focusing on approaches publicly available in open-source environments such as R and Bioconductor. We hope that the processing tools and analysis flowchart described herein will facilitate researchers to effectively use these powerful DNA methylation array-based platforms, thereby advancing our understanding of human health and disease. PMID- 23982604 TI - TNFAIP8 as a predictor of metastasis and a novel prognostic biomarker in patients with epithelial ovarian cancer. AB - BACKGROUND: Tumour necrosis factor-alpha-induced protein 8 (TNFAIP8) has been recently documented in various malignancies, but its role in epithelial ovarian cancer (EOC) remains unknown. METHODS: Tumour necrosis factor-alpha-induced protein 8 expression was determined by real-time reverse transcription PCR and western blot analysis. Tumour tissues, consisting of serous, mucinous, endometrioid and clear cell histotypes, from 202 EOC patients (International Federation of Gynecologists and Obstetricians I-IV) who underwent primary cytoreduction were collected. Then, we examined the immunohistochemical expression of TNFAIP8 and evaluated its clinical significances. RESULTS: Tumour necrosis factor-alpha-induced protein 8 overexpression was significantly associated with high histologic grade (P=0.005), large residual tumour size (P=0.014), recurrence (P=0.024) and response to chemotherapy (P<0.001). Multivariate analysis showed that TNFAIP8 overexpression was independently correlated with the presence of lymph node (odds ratio (OR): 4.129; 95% confidence interval (CI): 1.491-11.435; P=0.006) and intraperitoneal metastasis (OR: 2.209; 95% CI: 1.174-4.156; P=0.014). Moreover, results revealed that the status of TNFAIP8 expression was an independently prognostic factor for both cancer-specific survival (hazard ratio (HR): 1.852; 95% CI: 1.322-2.594; P<0.001) and disease-free survival (HR: 1.724; 95% CI: 1.235-2.407; P=0.001) in patients with EOC. CONCLUSION: The present data provide evidence that TNFAIP8 predicts EOC metastasis and poor survival, highlighting its potential function as a therapeutic target for EOCs. PMID- 23982605 TI - Existing models, but not neutrophil-to-lymphocyte ratio, are prognostic in malignant mesothelioma. AB - BACKGROUND: Recent studies proposed neutrophil-to-lymphocyte ratio (NLR) as a prognostic biomarker in malignant pleural mesothelioma (MPM). We examined baseline prognostic variables including NLR and the EORTC and CALGB models as predictors of overall survival (OS) in MPM. METHODS: In this retrospective study, 274 consecutive eligible, newly presenting patients with MPM were included. Of these, 159 received chemotherapy, 10 had tri-modality therapy, 2 underwent surgery only and 103 received supportive care alone. Univariate analyses and multivariate Cox models were calculated for OS. RESULTS: In univariate analysis, poor prognostic factors were: age >=65 years, nonepithelioid histology, stage III IV, poor performance status (PS), weight loss, chest pain, low haemoglobin and high platelet count. A baseline NLR>= 5 did not predict worse OS (hazard ratio (HR) 1.25; P=0.122). On multivariate analysis, age, histology, PS, weight loss, chest pain and platelet count remained significant. The EORTC and CALGB prognostic groups were validated as predictive for OS (HR 1.62; P<0.001 and HR 1.65; P<0.001, respectively). CONCLUSION: Our findings validate standard prognostic variables and the existing EORTC and CALGB models, but not NLR, at initial diagnosis of MPM. In guiding patient management at diagnosis, it is important to consider multiple baseline variables that jointly predict survival. PMID- 23982606 TI - Evaluation of vegetables in Tsukuba for contamination with radioactive materials from the accident at Fukushima Daiichi nuclear power plant. AB - A large amount of radioactive material was released into the atmosphere after the accident of the Fukushima Daiichi Nuclear Power Plant following the Tohoku earthquake on 11 March 2011, and traces of these materials were detected in Tsukuba. Because radioactive materials can adhere to vegetables, the authors made a qualitative evaluation of vegetables in Tsukuba, estimated internal exposure dose based on quantitative measurement results, and investigated several decontamination methods. Qualitative analysis of vegetable contamination was done by autoradiography. Quantitative analysis was done using a high-purity germanium detector. To assess decontamination, two methods were tested: one with running water and the other with boiling water. In addition, boiled soup stock was measured. In the qualitative evaluation by autoradiography, radioactive materials were not uniformly distributed but adhered to vegetables in clumps and hot spots. In the quantitative evaluation to measure contamination of outer and inner leaves of sanchu lettuce, it was observed that the concentration of I was 8,031.35 +/- 764.79 Bq kg in the outer leaves and 115.28 +/- 20.63 Bq kg in the inner leaves. In addition, the concentration of Cs was 1,371.93 +/- 366.45 Bq kg in the outer leaves and 9.68 +/- 15.03 Bq kg in the inner leaves. This suggests that one can greatly reduce internal exposure dose by removing the outer leaves if one has to eat vegetables just after a nuclear accident. In the decontamination assessment, a decontamination efficiency of up to 70% was achieved by boiling vegetables for 20 min. PMID- 23982607 TI - Investigation of photon shielding property changes in curing high density concrete. AB - High density concrete is usually used for radiation shielding around radiotherapy treatment rooms. Because the concrete is specified differently at the design, construction, and verification stages, the relationship between the intended performance and the actual performance of the shielding material might not be entirely clear. In this study, cylindrical samples of high density shielding concrete were taken as each section of a new radiotherapy bunker was poured. The shielding performance of each sample [measured by beam attenuation and tenth value layers (TVL)] was evaluated for 15 MV and 6 MV x-ray beams and for the 1.25 MeV monoenergetic gamma beam from a Co source. Transmission curves to 3 TVL were mapped for a representative sample. The samples were also imaged and analyzed using Co Cone Beam Computed Tomography (CoCBCT). Results indicate no significant change in the TVL of high density concrete samples as they cure. The minor fluctuations in shielding properties observed are explained by the heterogeneous structure of the samples as indicated in the CoCBCT images. PMID- 23982608 TI - Long lived gamma emitting radionuclides in incense. AB - A study of long-lived gamma emitters in incense was performed. The incense samples originated from seven different countries, and the investigated radionuclides were Ra, Ra, and K. Gamma spectroscopy revealed the presence of all three investigated radionuclides in all samples. Interestingly, the activity concentrations revealed a clear bimodal distribution that distinguished samples that were natural incense from others that were processed incense. The activity concentrations in the latter group were found to be one order of magnitude greater than in the former group. Consequently, the estimated annual effective dose from the latter group was one order of magnitude higher than that of the former group. Nonetheless, the doses from both groups were found to be some three orders of magnitude less than the average worldwide exposure to inhaled natural radionuclides. This finding suggests the radiological safety of incense for the investigated radionuclides. PMID- 23982609 TI - Realistic approach to estimate lens doses and cataract radiation risk in cardiology when personal dosimeters have not been regularly used. AB - Interventional fluoroscopic guided cardiac procedures lead to radiation exposure to the lenses of the eyes of cardiologists, which over time may be associated with an increased risk of cataracts. This study derives radiation doses to the lens of the eye in cardiac catheterization laboratories from measurements of individual procedures to allow for estimates of such doses for those cases when personal dosimeters have not been used regularly. Using active electronic dosimeters at the C-arm (at 95 cm from the isocenter), scatter radiation doses have been measured for cardiac procedures and estimated radiation doses to the lenses of the cardiologists for different groups of procedures (diagnostic, PTCAs, and valvular). Correlation factors with kerma area product included in the patient dose reports have been derived. The mean, median, and third quartile scatter dose values per procedure at the C-arm for 1,969 procedures were 0.99, 0.78 and 1.25 mSv, respectively; for coronary angiography, 0.51, 0.45, and 0.61 mSv, respectively; for PTCAs, 1.29, 1.07, and 1.56 mSv; and for valvular procedures, 1.64, 1.45, and 2.66 mSv, respectively. For all the procedures, the ratio between the scatter dose at the C-arm and the kerma area product resulted in between 10.3-11.3 MUSv Gy cm. The experimental results of this study allow for realistic estimations of the dose to the lenses of the eyes from the workload of the cardiologists and from the level of use of radiation protection tools when personal dosimeters have not been regularly used. PMID- 23982610 TI - Daily radionuclide ingestion and internal radiation doses in Aomori prefecture, Japan. AB - To assess internal annual dose in the general public in Aomori Prefecture, Japan, 80 duplicate cooked diet samples, equivalent to the food consumed over a 400-d period by one person, were collected from 100 volunteers in Aomori City and the village of Rokkasho during 2006-2010 and were analyzed for 11 radionuclides. To obtain average rates of ingestion of radionuclides, the volunteers were selected from among office, fisheries, agricultural, and livestock farm workers. Committed effective doses from ingestion of the diet over a 1-y period were calculated from the analytical results and from International Commission on Radiological Protection dose coefficients; for 40K, an internal effective dose rate from the literature was used. Fisheries workers had significantly higher combined internal annual dose than the other workers, possibly because of high rates of ingestion of marine products known to have high 210Po concentrations. The average internal dose rate, weighted by the numbers of households in each worker group in Aomori Prefecture, was estimated at 0.47 mSv y-1. Polonium-210 contributed 49% of this value. The sum of committed effective dose rates for 210Po, 210Pb, 228Ra, and 14C and the effective dose rate of 40K accounted for approximately 99% of the average internal dose rate. PMID- 23982611 TI - Development of serum copper-based biological dosimetry in whole body gamma irradiation of mice. AB - A new biological dosimeter based on serum copper has been developed. Serum copper in mice subjected to a 60Co source at a dose rate of 0.5 Gy min-1 was detected using the bis(cyclohexanone) oxaldihydrazone colorimetric method. The dose range was from 0.5-7 Gy. The results demonstrate that serum copper decreases with increasing dose. A linear dose response is obtained. The detection limit based on serum copper is the same as that with the lower limit of dose assessment; i.e., about 1 Gy. The decrease in serum copper continues until the 28th day after gamma radiation. The absorbed doses in mice assessed using the linear curve are close to "blind" doses of 4 and 6 Gy. Therefore, serum copper is a quick, simple, and accurate biomarker for early assessment of radiation exposure of mice in the range of 0.5-7 Gy. PMID- 23982612 TI - Radioactive seed localization with 125I for nonpalpable lesions prior to breast lumpectomy and/or excisional biopsy: methodology, safety, and experience of initial year. AB - The use of radioactive seed localization (RSL) as an alternative to wire localizations (WL) for nonpalpable breast lesions is rapidly gaining acceptance because of its advantages for both the patient and the surgical staff. This paper examines the initial experience with over 1,200 patients seen at a comprehensive cancer center. Radiation safety procedures for radiology, surgery, and pathology were implemented, and radioactive material inventory control was maintained using an intranet-based program. Surgical probes allowed for discrimination between 125I seed photon energies from 99mTc administered for sentinel node testing. A total of 1,127 patients (median age of 57.2 y) underwent RSL procedures with 1,223 seeds implanted. Implanted seed depth ranged from 10.3-107.8 mm. The median length of time from RSL implant to surgical excision was 2 d. The median 125I activity at time of implant was 3.1 MBq (1.9 to 4.6). The median dose rate from patients with a single seed was 9.5 uSv h-1 and 0.5 uSv h-1 at contact and 1 m, respectively. The maximum contact dose rate was 187 uSv h-1 from a superficially placed seed. RSL performed greater than 1 d before surgery is a viable alternative to WL, allowing flexibility in scheduling, minimizing day of surgery procedures, and improving workflow in breast imaging and surgery. RSL has been shown to be a safe and effective procedure for preoperative localization under mammographic and ultrasound guidance, which can be managed with the use of customized radiation protection controls. PMID- 23982613 TI - Biodosimetry of restoration workers for the Tokyo Electric Power Company (TEPCO) Fukushima Daiichi nuclear power station accident. AB - The biological dose of nuclear workers engaged in emergency response tasks at Tokyo Electric Power Company (TEPCO) Fukushima Daiichi Nuclear Power Station was estimated in the present study. As the national core center for radiation emergency medical preparedness in Japan, the National Institute of Radiological Sciences (NIRS) received all individuals who were suspected of being overexposed to acute radiation. In the course of health examinations at NIRS, biological dosimetry was performed by the dicentric chromosome assay (DCA). Twelve individuals were examined from 21 March-1 July 2011. The results indicated that the estimated exposure doses for all individuals were lower than 300 mGy, with the mean value of about 101 mGy. These results by DCA were in accordance with those obtained by physical dosimetry based on personal dosimeter recording assessment. The results corroborate the fact that no acute radiation syndrome was observed among the workers examined. PMID- 23982614 TI - The effect of X-ray scattering by water in the irradiation of cell cultures for the dosimetric characterization of a new prototype of IORT (Intra-Operative Radiation Therapy) device: Monte Carlo simulation and experimental validation. AB - The electron beam emitted backward by plasma focus devices is being considered as a radiation source for Intra-Operative Radiation Therapy (IORT) applications. Radiobiological investigations have been conducted to assess the potential of this new prototype of IORT device. A standard x-ray beam, ISO-H60, was used for comparison, irradiating cell cultures in a holder filled with an aqueous solution. The influence of scattering by the culture water and by the walls of the holder was investigated to determine their influence on the dose delivered to the cell culture. MCNPX simulations were run and experimental measurements conducted. The effect of scattering by the holder was found to be negligible; scattering by the culture water was determined to give an increase in dose of the order of 10%. PMID- 23982615 TI - Measurement of internal radiation exposure among decontamination workers in villages near the crippled Fukushima Daiichi Nuclear Power Plant. AB - Decontamination workers may face a high risk of exposure to internal irradiation through inhalation during decontamination activities; there is, however, little previous research on the levels of internal contamination during decontamination procedures. The authors reviewed the medical records, including whole body counter measurements, of decontamination workers in villages near the crippled Fukushima Daiichi Nuclear Power Plant to assess their levels of internal radiation exposure. In total, 83 decontamination workers were enrolled in this study. They were regularly engaged in decontamination activities in highly contaminated areas where surface 137Cs deposition density was over 100 kBq m-2. The present study showed low levels of internal exposure among the decontamination workers near the Fukushima Daiichi nuclear plant. The cesium burdens of all the decontamination workers were below detection limits. They had reported no acute health problems. The resuspension of radioactive materials may cause minimal internal contamination during decontamination activities. PMID- 23982616 TI - Calixarene cleansing formulation for uranium skin contamination. AB - An oil-in-water cleansing emulsion containing calixarene molecule, an actinide specific chelating agent, was formulated in order to improve the decontamination of uranium from the skin. Commonly commercialized cosmetic ingredients such as surfactants, mineral oil, or viscosifying agents were used in preparing the calixarene emulsion. The formulation was characterized in terms of size and apparent viscosity measurements and then was tested for its ability to limit uranyl ion permeation through excoriated pig-ear skin explants in 24-h penetration studies. Calixarene emulsion effectiveness was compared with two other reference treatments consisting of DTPA and EHBP solutions. Application of calixarene emulsion induced the highest decontamination effect with an 87% decrease in uranium diffusion flux. By contrast, EHBP and DTPA solutions only allowed a 50% and 55% reduction of uranium permeation, respectively, and had the same effect as a simple dilution of the contamination by pure water. Uranium diffusion decrease was attributed to uranyl ion-specific chelation by calixarene within the formulation, since no significant effect was obtained after application of the same emulsion without calixarene. Thus, calixarene cleansing emulsion could be considered as a promising treatment in case of accidental contamination of the skin by highly diffusible uranium compounds. PMID- 23982620 TI - Visual discrimination of rotated 3D objects in Malawi cichlids (Pseudotropheus sp.): a first indication for form constancy in fishes. AB - Fish move in a three-dimensional environment in which it is important to discriminate between stimuli varying in colour, size, and shape. It is also advantageous to be able to recognize the same structures or individuals when presented from different angles, such as back to front or front to side. This study assessed visual discrimination abilities of rotated three-dimensional objects in eight individuals of Pseudotropheus sp. using various plastic animal models. All models were displayed in two choice experiments. After successful training, fish were presented in a range of transfer tests with objects rotated in the same plane and in space by 45 degrees and 90 degrees to the side or to the front. In one experiment, models were additionally rotated by 180 degrees , i.e., shown back to front. Fish showed quick associative learning and with only one exception successfully solved and finished all experimental tasks. These results provide first evidence for form constancy in this species and in fish in general. Furthermore, Pseudotropheus seemed to be able to categorize stimuli; a range of turtle and frog models were recognized independently of colour and minor shape variations. Form constancy and categorization abilities may be important for behaviours such as foraging, recognition of predators, and conspecifics as well as for orienting within habitats or territories. PMID- 23982621 TI - Familiarity-connected or stress-based contagious yawning in domestic dogs (Canis familiaris)? Some additional data. AB - The present short note aimed at further exploring data from a recent study showing socially modulated auditory contagious yawning in domestic dogs (Canis familiaris). Two independent observers further extended the analysis of all video recordings made in the previous study and coded both the number of yawns performed by the dogs and the frequencies or durations of stress-related behaviors exhibited throughout the presentation of familiar and unfamiliar yawns. By showing no significant difference between conditions in the frequencies or durations of the coded behaviors, nor any association between the number of yawns and the frequencies or durations of stress-related behaviors, results raised doubt on the stress-induced yawn hypothesis, thus supporting social modulation. The exact mechanism underlying contagious yawning, however, needs further research. PMID- 23982624 TI - Gene regulation: Bookmarking gets cohesin. PMID- 23982622 TI - Specialised use of working memory by Portia africana, a spider-eating salticid. AB - Using expectancy-violation methods, we investigated the role of working memory in the predatory strategy of Portia africana, a salticid spider from Kenya that preys by preference on other spiders. One of this predator's tactics is to launch opportunistic leaping attacks on to other spiders in their webs. Focussing on this particular tactic, our experiments began with a test spider on a ramp facing a lure (dead prey spider mounted on a cork disc) that could be reached by leaping. After the test spider faced the lure for 30 s, we blocked the test spider's view of the lure by lowering an opaque shutter before the spider leapt. When the shutter was raised 90 s later, either the same lure came into view again (control) or a different lure came into view (experimental: different prey type in same orientation or same prey type in different orientation). We recorded attack frequency (number of test spiders that leapt at the lure) and attack latency (time elapsing between shutter being raised and spiders initiating a leap). Attack latencies in control trials were not significantly different from attack latencies in experimental trials, regardless of whether it was prey type or prey orientation that changed in the experimental trials. However, compared with test spiders in the no-change control trials, significantly fewer test spiders leapt when prey type changed. There was no significant effect on attack frequency when prey orientation changed. These findings suggest that this predator represents prey type independently of prey orientation. PMID- 23982625 TI - Cancer genomics: Signature analysis suggests cancer origins. PMID- 23982626 TI - Catalyst activity or stability: the dilemma in Pd-catalyzed polyketone synthesis. AB - A series of Pd-complexes containing nonsymmetrical bis(aryl-imino)acenaphthene (Ar-BIAN) ligands, characterized by substituents on the meta positions of the aryl rings, have been synthesized, characterized and applied in CO/vinyl arene copolymerization reactions. Crystal structures of two neutral Pd-complexes have been solved allowing comparison of the bonding properties of the ligand. Kinetic and mechanistic investigations on these complexes have been performed. The kinetic investigations indicate that in general ligands with electron-withdrawing substituents give more active, but less stable, catalytic systems, although steric effects also play a role. The good performance observed with nonsymmetrical ligands is at least in part due to a compromise between catalyst activity and lifetime, leading to a higher overall productivity with respect to catalysts based on their symmetrical counterparts. Additionally, careful analysis of the reaction profiles provided information on the catalyst deactivation pathway. The latter begins with the reduction of a Pd(II) Ar-BIAN complex to the corresponding Pd(0) species, a reaction that can be reverted by the action of benzoquinone. Then the ligand is lost, a process that appears to be facilitated by the contemporary coordination of an olefin or a CO molecule. The so formed Pd(0) complex immediately reacts with another molecule of the initial Pd(II) complex to give a Pd(I) dimeric species that irreversibly evolves to metallic palladium. Mechanistic investigations performed on the complex with a nonsymmetrical Ar-BIAN probe evidence that the detected intermediates are characterized by the Pd-C bond trans to the Pd-N bond of the aryl ring bearing electron-withdrawing substituents. In addition, the intermediate resulting from the insertion of 4-methylstyrene into the Pd-acyl bond is a five-member palladacycle and not the open-chain eta(3)-allylic species observed for complexes with Ar-BIANs substituted in ortho position. PMID- 23982627 TI - Peripheral and central nervous system inhibition of 11beta-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384. AB - ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens >=2 mg daily maintained peripheral HSD-1 inhibition >=88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition >=81%. No CNS formation of D3 cortisol (the mass labeled product of HSD-1) was detected following ABT-384 >=2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets. PMID- 23982629 TI - Assessment of reward responsiveness in the response bias probabilistic reward task in rats: implications for cross-species translational research. AB - Mood disorders, such as major depressive disorder, are characterized by abnormal reward responsiveness. The Response Bias Probabilistic Reward Task (hereafter referred to as probabilistic reward task (PRT)) quantifies reward responsiveness in human subjects, and an equivalent animal assessment is needed to facilitate preclinical translational research. Thus, the goals of the present studies were to develop, validate and characterize a rat analog of the PRT. Adult male Wistar and Long-Evans rats were trained in operant testing chambers to discriminate between two tone stimuli that varied in duration (0.5 and 2 s). During a subsequent test session consisting of 100 trials, the two tones were made ambiguous (0.9 and 1.6 s) and correct identification of one tone was reinforced with a food pellet three times more frequently than the other tone. In subsequent experiments, Wistar rats were administered either a low dose of the dopamine D2/D3 receptor agonist pramipexole (0.1 mg kg(-1), subcutaneous) or the psychostimulant amphetamine (0.5 mg kg(-1), intraperitoneal) before the test session. Similar to human subjects, both rat strains developed a response bias toward the more frequently reinforced stimulus, reflecting robust reward responsiveness. Mirroring prior findings in humans, a low dose of pramipexole blunted response bias. Moreover, in rats, amphetamine potentiated response bias. These results indicate that in rats, reward responsiveness can be quantified and bidirectionally modulated by pharmacological manipulations that alter striatal dopamine transmission. Thus, this new procedure in rats, which is conceptually and procedurally analogous to the one used in humans, provides a reverse translational platform to investigate abnormal reward responsiveness across species. PMID- 23982630 TI - Willingness to pay and quality of life in patients with atopic dermatitis. AB - Atopic dermatitis (AD) is a frequent and burdensome disease. The objectives of this study were (1) to assess the willingness to pay (WTP) and quality of life (Qol) in AD patients and (2) to compare the results with data on other chronic skin diseases. To collect data, a non-interventional, cross-sectional nationwide postal survey on adult patients with clinically diagnosed AD was performed; socio demographic data, clinical features/symptoms, WTP and QoL were recorded. WTP was assessed in three different approaches, including relative and absolute figures. Data from n = 384 AD patients (mean age 42.0, range 18-92, 69.8 % female) were analyzed. WTP for complete healing was on median 1,000 (average 11,884) and exceeded WTP in rosacea (median 500) but not in vitiligo (median 3,000). Mean Dermatology Life Quality Index (DLQI) was 8.5 (vitiligo 7.0; psoriasis 6.7; rosacea 4.3) and correlated with pruritus, xerosis and disturbed sleep. WTP and DLQI correlated only marginally (r s = 0.134, p = 0.01). In conclusion, AD patients show high WTP and markedly reduced QoL compared to other chronic skin diseases. PMID- 23982631 TI - Effects of interleukin (IL)-6 gene polymorphisms on recurrent aphthous stomatitis. AB - Recurrent aphthous stomatitis (RAS) is a common disease with oral ulceration in which cytokines are thought to play an important role. High levels of interleukin (IL)-6, a pro-inflammatory cytokine have been detected in the circulation of ulcer tissue. The purpose of the present study was to investigate if the IL-6 gene polymorphisms are associated with RAS or clinical characteristics of RAS in a cohort of Turkish population. 184 RAS patients and 150 healthy controls were included in the study. The genotypes of IL-6 gene -572G>C and -174G>C polymorphisms were determined using polymerase chain reaction based restriction fragment length polymorphism analysis. The genotype frequencies of -572G>C polymorphism showed statistically significant differences between RAS patients and controls (p = 0.01). Frequencies of GG + GC genotypes and G allele of -572G>C polymorphism were found higher in RAS patients (p = 0.0001, OR 10.8, 95 % CI 2.79 70.5; p = 0.0008, OR 2.06, 95 % CI 1.35-3.17, respectively). The genotype frequencies of -174G>C polymorphism also showed statistically significant differences between RAS patients and controls (p < 0.0001). Frequencies of GG genotype and G allele of -174G>C polymorphism were found higher in RAS patients (p < 0.0001, OR 4.87, 95 % CI 3.06-7.85; p < 0.0001, OR 3.82, 95 % CI 2.64-5.59, respectively). GG-GG combined genotype and G-G haplotype of -174G>C to -572G>C loci were also significantly higher in RAS patients (p < 0.0001 and p = 1.5 * 10( 8), respectively). After stratifying clinical and demographical characteristics of RAS patients according to IL-6 gene polymorphisms, an association was observed between family history of RAS and -174G>C polymorphism (p = 0.011). Susceptibility effects of both IL-6 gene -572G>C and -174G>C polymorphisms for RAS were observed. Further studies are necessary to prove the association of IL-6 gene polymorphisms with RAS. PMID- 23982628 TI - Traumatic stress reactivity promotes excessive alcohol drinking and alters the balance of prefrontal cortex-amygdala activity. AB - Post-traumatic stress disorder (PTSD) and alcoholism are highly comorbid in humans and have partially overlapping symptomatic profiles. The aim of these studies was to examine the effects of traumatic stress (and stress reactivity) on alcohol-related behaviors and neuronal activation patterns. Male Wistar rats were trained to respond for alcohol, were exposed to predator odor (bobcat urine) paired with context and were tested for short- and long-term avoidance of the predator odor-paired context, alcohol self-administration and compulsivity of alcohol responding. Rats were re-exposed to the odor-paired context for western blot analysis of ERK phosphorylation in subregions of the medial prefrontal cortex (mPFC) and the amygdala. Rats that avoided the predator-paired chamber (Avoiders) exhibited persistent avoidance up to 6 weeks post conditioning. Avoiders exhibited increases in operant alcohol responding over weeks, as well as more compulsive-like responding for alcohol adulterated with quinine. Following re-exposure to the predator odor-paired context, Avoiders and Non-Avoiders exhibited unique patterns of neuronal activation in subregions of the mPFC and the amygdala, which were correlated with changes in avoidance and alcohol drinking. Furthermore, activity of upstream regions was differentially predictive of downstream regional activity in the Avoiders versus Non-Avoiders. An animal model for assessing the effect of traumatic stress on alcohol drinking reveals individual differences in neuronal activation patterns associated with re exposure to traumatic stress-related stimuli, and may provide insight into the neural mechanisms underlying excessive alcohol consumption in humans with PTSD. PMID- 23982632 TI - How a diversity-oriented approach has inspired a new hypothesis for the gabosine biosynthetic pathway. A new synthesis of (+)-gabosine C. AB - A new synthesis of (+)-gabosine C has been accomplished as part of a general diversity-oriented approach that also delivered the previously unknown (-)-4-epi gabosine C. The identification of the unexpected intermediate (+)-8, together with the isolation of ketones 9 and 10 in previous investigations, prompted us to formulate a new hypothesis for the biosynthesis of gabosines, based on a keto enol equilibrium cascade pathway starting from 2-epi-5-epi-valiolone, along which the necessary precursors for all the different types of gabosines are generated. PMID- 23982633 TI - Polychlorinated biphenyls in sea birds from Ascension Island, South Atlantic Ocean. PMID- 23982634 TI - Effect of occult hepatitis B virus infection on the early-onset of hepatocellular carcinoma in patients with hepatitis C virus infection. AB - Although overt hepatitis B virus (HBV) infection promotes the onset of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-infected patients, the effect of occult HBV infection remains unclear. The aim of this study was to investigate the effect of occult HBV infection on the early-onset of HCC in HCV infected patients. A total of 173 HCC patients with HCV infection were enrolled and classified into 2 groups according to the median age of HCC onset: the early onset group (n=91; 61.1+/-5.6 years) and the late-onset group (n=82; 73.8+/-3.7 years). Independent factors associated with the early-onset of HCC were assessed by multivariate analysis. In the overall analysis, independent risk factors for the early-onset of HCC were the white blood cell count and alanine aminotransferase level, but not the presence of HBV DNA. In a stratification analysis according to albumin levels of >=3.5 g/dl, the presence of HBV DNA was a significant independent risk factor for the early-onset of HCC (OR 145.18, 95% CI 1.38-15296.61, P=0.036), whereas the presence of antibodies against hepatitis B core antigen was not found to be a risk factor. The presence of HBV DNA was not a risk factor for the early-onset of HCC in the overall analysis. However, its presence was an independent factor for the early-onset of HCC in HCV-infected patients with an albumin level of >=3.5 g/dl. Thus, occult HBV infection may accelerate hepatocarcino-genesis in HCV-infected patients with relatively low carcinogenic potential. PMID- 23982635 TI - Semitendinosus tendon regeneration after anterior cruciate ligament reconstruction: can we use it twice? AB - PURPOSE: It has been demonstrated that the semitendinosus tendon can regenerate after being harvested in its whole length and thickness for anterior cruciate ligament (ACL) reconstruction. Ultrasound studies and guided biopsies of the regenerated tendon have shown compatibility and resembling features of the normal tendon. The question is if this neo-tendon is biologically and functionally adequate for re-use? METHODS: Two randomised groups of 150 volunteers were followed up for two years after harvesting the semitendinosus only (25) or the semitendinosus and gracilis tendons (25) in ACL reconstruction. The patients were followed up with clinical and ultrasound examinations, biopsies and histological tests. Surgical exploration was done in three patients for macroscopic verification. The injected arteries of four lower limbs were dissected and the tendon's arterial supplies were examined. RESULTS: Seventy-two percent of the cases showed regeneration of the semitendinosus tendons. The neotendons were inserted mostly below the knee joint (83.3%) where they had fused with the gracilis tendon, and above the joint (60%) when the gracilis was harvested as well. The isokinetic strength of the hamstrings and quadriceps was not significantly diminished on the operated side. A macroscopic and histological analysis of the regenerated tendons demonstrates close resemblance to normal anatomy, with focal areas of fibrosis. In one patient the regenerated tendon was used for medial patellofemoral ligament reconstruction. CONCLUSION: The semitendinosus muscle can recover and the tendon has great potential to regenerate after harvesting for ACL reconstruction. Our data suggest that the regenerated tendons could be used for iterative ligament reconstruction. PMID- 23982636 TI - Do we really need closed-suction drainage in total hip arthroplasty? A meta analysis. AB - PURPOSE: The clinical use of closed-suction drainage, which aims to reduce postoperative wound haematomas and infection, is common. This study was performed to determine whether closed-suction drainage is safe and effective in promoting wound healing and reducing blood loss and other complications compared with no drainage in total hip arthroplasty. METHODS: The literature search was based on PubMed, the Cochrane Library, MEDLINE, and EMBASE. The data were evaluated using the generic evaluation tool designed by the Cochrane Bone, Joint and Muscle Trauma Group, and then analysed using RevMan 5.0. Twenty randomised controlled trials involving 3,186 patients were included in our analysis. RESULTS: The results of our meta-analysis indicate that closed-suction drainage reduces the requirement for dressing reinforcement, but increases the rate of homologous blood transfusion. No significant difference was observed in the incidence of infection, blood loss, changes in haemoglobin and haematocrit, functional assessment, or other complications when the drainage group was compared with the no-drainage group. CONCLUSIONS: Our results of the comparison between closed suction drainage and no drainage in THA have indicated that the routine use of closed-suction drainage for elective total hip arthroplasty may be of more harm than benefit. PMID- 23982637 TI - Predictors of early mortality after hip fracture surgery. AB - PURPOSE: The aim of this study was to examine causes and potential risk factors for 30-day mortality after hip fracture surgery (HFS) at a high-volume tertiary care hospital. METHODS: We retrospectively reviewed 467 patients who underwent HFS at our institution. Multivariate analysis was undertaken to identify potential predictors of early mortality. RESULTS: The 30-day mortality rate was 7.5% (35/467). The most common causes of death were pneumonia (37.1%, 13/35), acute coronary syndrome (31.4%, 11/35) and sepsis (14.3%, 5/35). Surgery after 48 hours of admission had a significantly higher 30-day mortality rate (11 % versus 4%, p = 0.006). There was a significant difference in age (p = 0.034), admission source (p < 0.001), preoperative haemoglobin (p < 0.001), walking ability (p = 0.004), number of comorbidities (p = 0.004) and pre-existing dementia (p = 0.01), cardiac disease (p < 0.001), chronic obstructive pulmonary disorder (COPD) (p = 0.036) and renal failure (p = 0.007) between the 30-day mortality group and the rest of the cohort. Surgical delay greater than 48 hours, admission source and pre-existing cardiac disease were identified as the strongest predictors of 30 day mortality. CONCLUSION: Surgical delay is an important but avoidable determinant of early mortality after HFS. Respiratory and cardiac function needs to be optimised postoperatively with early intervention in patients with signs of cardiovascular compromise or infection. PMID- 23982638 TI - Press-fit cementless acetabular fixation with and without screws. AB - PURPOSE: Cementless acetabular fixation for total hip arthroplasty (THA) is widely used. The question of using screws for a better primary and secondary acetabular fixation has been discussed in the literature in recent years. The aim of this meta-analysis was to compare fixation of acetabular cups with and without screws in total hip arthroplasty. METHODS: Electronic databases Embase, PubMed and Cochrane Library were used to search for randomised controlled trials reported through May 2013 of cementless acetabular fixation for THA with and without screws. Two independent reviewers assessed the trials for eligibility and quality. All related data matching our standards were abstracted for meta analysis by RevMan 5.0. Evaluation criteria included revisions, migration and osteolysis. RESULTS: A total of 1,130 THAs enrolled into five trials were included in this meta-analysis. All studies compared fixation of acetabular cups with and without screws, and our pooled data showed no statistical significance between the two surgical methods in revision, migration and osteolysis. CONCLUSION: There is no significant difference between cementless acetabular fixation for THA with and without screws in revisions, migration or osteolysis. PMID- 23982639 TI - Treatment principles for osteochondral lesions in foot and ankle. AB - Osteochondral lesion of the talus (OLT) is a broad term used to describe an injury or abnormality of the talar articular cartilage and adjacent bone. A variety of terms have been used to refer to this clinical entity, including osteochondritis dissecans (OCD), osteochondral fracture and osteochondral defect. Whether OLT is a precursor to more generalised arthrosis of the ankle remains unclear, but the condition is often symptomatic enough to warrant treatment. In more than one third of cases, conservative treatment is unsuccessful, and surgery is indicated. There is a wide variety of treatment strategies for osteochondral defects of the ankle, with new techniques that have substantially increased over the last decade. The common treatment strategies of symptomatic osteochondral lesions include nonsurgical treatment, with rest, cast immobilisation and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Surgical options are lesion excision, excision and curettage, excision combined with curettage and microfracturing, filling the defect with autogenous cancellous bone graft, antegrade (transmalleolar) drilling, retrograde drilling, fixation and techniques such as osteochondral transplantation [osteochondral autograft transfer system (OATS)] and autologous chondrocyte implantation (ACI). Furthermore, smaller lesions are symptomatic and when left untreated, OCDs can progress; current treatment strategies have not solved this problem. The target of these treatment strategies is to relieve symptoms and improve function. Publications on the efficacy of these treatment strategies vary. In most cases, several treatment options are viable, and the choice of treatment is based on defect type and size and preferences of the treating clinician. PMID- 23982640 TI - Update in foot and ankle surgery. PMID- 23982641 TI - Laparoscopic treatment for adhesive small bowel obstruction: is it the gold standard in children too? PMID- 23982642 TI - Laparoscopic splenectomy: a surgeon's experience of 302 patients with analysis of postoperative complications. AB - BACKGROUND: This study aimed to evaluate the operative and clinical outcomes in a series of 302 consecutive laparoscopic splenectomies and to analyze the risk factors of postoperative complications. METHODS: The study retrospectively reviewed 302 consecutive patients who underwent laparoscopic splenectomy. The patients were classified into three disease groups: benign spleen-related disease (group 1, n = 196), malignant spleen-related disease (group 2, n = 42), and portal hypertension (group 3, n = 64). The three groups were compared in terms of perioperative data. Postoperative complications were classified into three complication groups according to the Clavien-Dindo Classification of Surgical Complications and Severity: no complication, mild complications, and severe complications. Multivariate logistic regression was used to analyze the independent risk factors of postoperative complications. RESULTS: The patients in group 1 were younger and had a higher body mass index, a lower American Society of Anesthesiology (ASA) score, and a smaller spleen than the patients in groups 2 and 3. Fewer patients in group 1 required hand-port assistance than in the other two groups. Group 1 had shorter operative times, required fewer transfusions, presented a lower incidence of complications, and had shorter postoperative stays than groups 2 and 3. In the analysis of complications, high ASA score was an independent risk factor for the occurrence of complications. Both high ASA score and larger spleen size were independent risk factors for the occurrence of severe complications. Compared with total laparoscopic splenectomy, the data including the hand-assisted cases showed a reduction in odds ratio for both the occurrence of complications and the occurrence of severe complications. CONCLUSIONS: The treatment of malignant spleen-related disease and portal hypertension with laparoscopic splenectomy is more challenging than the treatment of benign disease. High ASA score is an independent risk factor for the occurrence of complications, whereas high ASA score and larger spleen size are both independent risk factors for the occurrence of severe complications. The appropriate introduction of the hand-assisted technique may facilitate the laparoscopic procedure and reduce postoperative complications. PMID- 23982643 TI - Feasibility of the laparoscopic appendicitis score. PMID- 23982644 TI - Transrectal robotic natural orifice translumenal endoscopic surgery (NOTES) applied to intestinal anastomosis in a porcine intestine model. AB - BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES) is a minimally invasive operation using devices such as flexible endoscopes and linear or circular staplers. Nevertheless, hand-sewn anastomosis in NOTES remains challenging. This study aimed to investigate the feasibility of transrectal robotic NOTES requiring intracorporeal small intestinal anastomosis and closure of the rectal anterior wall incision in a relevant human model. METHODS: The authors developed a flexible rectal proctoscope with a diameter of 43 mm for transrectal robotic NOTES. Small intestinal anastomosis was performed in a porcine intestinal transrectal NOTES model using two robotic arms and a camera inserted through the proctoscope and a rectal anterior wall incision. The quality of transrectal small intestinal anastomosis using the da Vinci surgical system (transrectal robotic NOTES group) was compared with that of transabdominal anastomosis using the da Vinci surgical system (transabdominal robot-assisted surgery group) and transrectal anastomosis using traditional transanal endoscopic microsurgery (TEM) instruments (TEM NOTES group). The quality of transrectal rectal anterior wall suturing in the transrectal robotic NOTES group was compared with that of the TEM NOTES group and the open surgical instruments group (open group). RESULTS: Robotic intracorporeal suturing was performed successfully in the porcine intestine model. During small intestinal anastomosis, burst pressure in the transrectal robotic NOTES group (67.7 +/- 29.3 mmHg) was similar to that in the transabdominal robot-assisted surgery group (73.3 +/- 18.2 mmHg) but significantly higher than in the TEM NOTES group (20.3 +/- 24.0 mmHg; p < 0.01). During rectal anterior wall suturing, the burst pressure did not differ significantly between the transrectal robotic NOTES group (149.9 +/- 81.1 mmHg) and the open group (195.0 +/- 60.5 mmHg). CONCLUSIONS: The preliminary safety and efficacy of transrectal robotic NOTES was established. Further studies are required to determine the practical feasibility of this procedure. PMID- 23982645 TI - Bariatric surgery rapidly improves mitochondrial respiration in morbidly obese patients. AB - BACKGROUND: Obesity and its attendant comorbidities are an emerging epidemic. Chronic metabolic inflammation (metainflammation) is thought to precipitate obesity-associated morbidities; however, its mechanistic progression is poorly understood. Moreover, although interventions such as diet, exercise, and bariatric surgery can control body weight, their effects on metainflammation are also poorly understood. Recently, metainflammation and the pathobiology of obesity have been linked to mitochondrial dysfunction. Herein we examined the effects of bariatric surgery on mitochondrial respiration as an index of resolving metainflammation in morbidly obese patients. METHODS: This institutional review board-approved study involved morbidly obese patients (body mass index > 35 kg/m(2)) undergoing sleeve gastrectomy or Roux-en-Y gastric bypass. Mitochondrial respiration was assessed in peripheral blood monocytes and in skeletal muscle samples before surgery and at 12 weeks after surgery. Patient biometrics, homeostasis model assessment-estimated insulin resistance (HOMA-IR) score, C-reactive protein, and lipid profile were analyzed. RESULTS: Twenty patients were enrolled and showed an average percent excess body weight loss of 30.3% weight loss at 12 weeks after surgery. Average HOMA-IR score decreased from 3.0 to 1.2 in insulin-resistant patients. C-reactive protein, an index of metainflammation, showed a modest decrease. Lipid profile remained stable. Intriguingly, mitochondrial basal and maximal respiration rates in peripheral blood monocytes increased after surgery. Basal rates of skeletal muscle mitochondrial respiration were unchanged, but the maximal respiration rate trended toward an increase after surgery. CONCLUSIONS: Cellular and tissue mitochondrial respiration increased in a morbidly obese patient cohort after laparoscopic bariatric surgery. These changes were consistent in patients with postsurgical weight loss. Importantly, no significant changes or improvements occurred in canonical indices used to assess recovery after bariatric surgery over this short time course. Thus, increased mitochondrial respiration may represent a novel biomarker of early improvement and positive outcome after surgery in morbidly obese patients. PMID- 23982646 TI - Thoracoscopic hepatectomy for malignant liver tumor. AB - BACKGROUND: Anatomical position of the liver poses a difficulty in approaching the lesions using a laparoscopic approach. METHODS: The patient was a 79-year-old man with a surgical history of laparoscopic sigmoidectomy for colon cancer and posterior segmentectomy of the liver for metastatic liver tumor. On admission, he presented with another liver tumor (diameter, 1.5 cm) in the dome of segment VIII. Because of the high possibility of severe adhesion around the liver and difficulty of approaching the lesion from the abdomen, we selected the transthoracic approach rather than the abdominal approach; the patient consented to this procedure. The patient was placed in the left-lateral position under general anesthesia with single-lung ventilation. We placed three trocars into the right thoracic space. The intrathoracic space was observed using a flexible-tip rigid scope (Olympus, Tokyo, Japan). The tumor was detected by inserting a flexible laparoscopic ultrasound probe (Hitachi Aloka, Ltd., Tokyo, Japan) through the diaphragm; the diaphragm was dissected immediately above the tumor using a harmonic scalpel (Ethicon Endo-Surgery, Inc., Cornelia, GA). The liver surface was precoagulated using a low-voltage monopolar coagulator with a ball shaped tip (Amco Inc., Tokyo, Japan) with the electrosurgical unit VIO300D (Erbe Elektromedizin, Tuebingen, Germany). The parenchyma was first sealed using BiClamp LAP forceps (Erbe Elektromedizin) and divided using the harmonic scalpel. The specimen was extracted using a retrieval bag. After complete hemostasis was achieved, the diaphragm was closed by continuous suturing. RESULTS: The operation lasted for 310 min and estimated blood loss was 10 mL. The patient was discharged on postoperative day 4. CONCLUSIONS: Although the duration of TH was long because of the narrow thoracic cavity space, TH was performed without any problems. As a rule, we should select TH for lesions located in the dorsal segment VII/VIII, with severe adhesion around the liver. PMID- 23982647 TI - Long-term effectiveness of cholecystectomy and endoscopic sphincterotomy in the management of gallstone pancreatitis. AB - BACKGROUND: Gallstone pancreatitis (GSP) is a common condition, accounting for 30 40 % of all pancreatitis cases. All GSP patients should undergo definitive treatment to prevent further attacks. This study aimed to investigate the long term outcome after definitive treatment in England by cholecystectomy, endoscopic sphincterotomy (ES), or both. METHODS: Hospital episode statistics data were used to identify patients admitted for the first time with GSP between January and December 2005. These patients were followed for 18 months to identify those who underwent definitive treatment. Treatment groups then were followed until December 2010 to identify readmissions with a further GSP attack as an emergency or admissions with complications of gallstone disease. RESULTS: 5,079 patients admitted with a first bout of GSP between January and December 2005. The in hospital mortality rate was 7.8 %. Of those who survived the initial attack, 2,511 went on to have a cholecystectomy, 419 had an ES alone, and 496 had ES followed by cholecystectomy. Recurrent pancreatitis after definitive treatment was more common among patients treated with ES (6.7 %) than among those treated with cholecystectomy (4.4 %) or ES followed by cholecystectomy (1.2 %) (p < 0.05). Admissions with other complications attributable to gallstones in patients treated with ES alone were similar to those seen in patients who had received no definitive treatment (12.2 vs. 9.4 %). CONCLUSIONS: Cholecystectomy offers better protection than ES against further bouts of pancreatitis in patients with GSP, but ES is an acceptable alternative. Interval cholecystectomy in patients treated initially with ES was the most effective method of preventing further pancreatitis, and the patients who underwent treatment by ES alone remained at risk of readmission with gallstone-related problems. Patients who have undergone ES and are fit for surgery should have a cholecystectomy. PMID- 23982648 TI - The laparoscopic mini-gastric bypass: the Italian experience: outcomes from 974 consecutive cases in a multicenter review. AB - BACKGROUND: Due to the failure of the "old Mason loop," the mini-gastric bypass (MGB) has been viewed with skepticism. During the past 12 years, a growing number of authors from around the world have continued to report excellent short- and long-term results with MGB. METHODS: One university center, three regional hospitals, and two private hospitals participated in this study. From July 2006 to December 2012, 475 men (48.8 %) and 499 women (51.2 %) underwent 974 laparoscopic MGBs. The mean age of these patients was 39.4, and their preoperative body mass index was 48 +/- 4.58 kg/m(2). Type 2 diabetes mellitus (T2DM) affected 224 (22.9 %) of the 974 patients, whereas 291 of the 974 patients (29.8 %) presented with hypertension. The preoperative gastrointestinal status was explored in all the patients through esophagogastroduodenoscopia. The major end points of the study were definitions of both MGB safety and efficacy in the long term as well as the endoscopic changes in symptomatic patients eventually produced by surgery. RESULTS: The rate of conversion to open surgery was 1.2 % (12/974), and the mortality rate was 0.2 % (2/974). The perioperative morbidity rate was 5.5 % (54/974), with 20 (2 %) of the 974 patients requiring an early surgical revision. The mean hospital length of stay was 4.0 +/- 1.7 days. At this writing, 818 patients are being followed up. Late complications have affected 74 (9 %) of the 818 patients. The majority of these complications (66/74, 89.1 %) have occurred within 1 year after surgery. Bile reflux gastritis was symptomatic, with endoscopic findings reported for 8 (0.9 %) and acid peptic ulcers for 14 (1.7 %) of the 818 patients. A late revision surgery was required for 7 (0.8 %) of the 818 patients. No patient required revision surgery due to biliary gastritis. At 60 months, the percentage of excess weight loss was 77 +/- 5.1 %, the T2DM remission was 84.4 %, and the resolution of hypertension was 87.5 %. CONCLUSIONS: Despite initial skepticism, this study, together with many other large-scale, long-term similar studies from around the world (e.g., Taiwan, United States, France, Spain, India, Lebanon) demonstrated the MGB to be a short, simple, low-risk, effective, and durable bariatric procedure. PMID- 23982650 TI - Safety of single-incision cholecystectomy. PMID- 23982649 TI - The feasibility of delivering a duodenal-jejunal bypass liner (EndoBarrier) endoscopically with patients under conscious sedation. AB - BACKGROUND: The endoscopically placed duodenal-jejunal bypass liner (DJBL) or EndoBarrier gastrointestinal liner has been designed for the treatment of type 2 diabetes mellitus and simultaneous achievement of weight loss by obese patients. This study was performed to determine the safety, efficacy, and feasibility of delivering the DJBL with the patient under conscious sedation (CS). The primary end points of the study were safety and complications. The secondary end points were delivery time (min), amount of propofol (mg) used, and the total hospital stay (h). METHODS: This prospective study compared placement of the DJBL with the patient under propofol sedation and placement with the patient under general anesthesia (GA). The study included 56 patients, with 28 patients in each group. RESULTS: Both groups were comparable in terms of age, gender, and body mass index. All the devices were placed successfully, and no complications occurred in either group. Comparison of the CS group with the GA group respectively showed a mean total operation time of 29 versus 56 min, a mean propofol use of 170 versus 258 mg, and a mean hospital stay of 11 versus 22 h. CONCLUSION: Delivery of the DJBL to patients under CS is feasible, safe, and efficient in terms of time and cost. Because of possible complications during the procedure, the authors recommend placement of the DJBL with the patient under CS in proximity to the operating room. PMID- 23982651 TI - Reply to: doi: 10.1007/s00464-013-3111-4: TEM or TAMIS: what is the future of transanal endoscopic surgery? PMID- 23982652 TI - Performing simple and safe dunking pancreaticojejunostomy using mattress sutures in pure laparoscopic pancreaticoduodenectomy. AB - BACKGROUND: Although recent technological developments and improved endoscopic procedures have further spread the application of laparoscopic pancreatic resection, laparoscopic pancreaticoduodenectomy still presents major technical difficulties, such as when performing pancreatic-enteric anastomosis. METHODS: Laparoscopic dunking pancreaticojejunostomy using mattress sutures was performed in 15 consecutive patients with a soft pancreas and a nondilated pancreatic duct between October 2011 and December 2012. RESULTS: According to the International Study Group on Pancreatic Fistula criteria, 3 patients developed PF (grade A), whereas the remaining 12 patients did not. CONCLUSIONS: Dunking pancreaticojejunostomy using mattress sutures is considered to be a feasible and safe method for performing pure laparoscopic pancreaticoduodenectomy. PMID- 23982653 TI - Effects of the closing speed of stapler jaws on bovine pancreases. AB - BACKGROUND: The division of the pancreatic parenchyma using a stapler is important in pancreatic surgery, especially for laparoscopic surgery. However, this procedure has not yet been standardized. METHODS: We analyzed the effects of the closing speed of stapler jaws using bovine pancreases for each method. Furthermore, we assigned 10 min to the slow compression method, 5 min to the medium-fast compression method, and 30 s to the rapid compression (RC) method. The time allotted to holding (3 min) and dividing (30 s) was equal under each testing situation. RESULTS: We found that the RC method showed a high-pressure tolerance compared with the other two groups (rapid, 126 +/- 49.0 mmHg; medium fast, 55.5 +/- 25.8 mmHg; slow, 45.0 +/- 15.7 mmHg; p < 0.01), although the histological findings of the cut end were similar. The histological findings of the pancreatic capsule and parenchyma after the compression by staple jaws without firing also were similar. CONCLUSIONS: RC may provide an advantage as measured by pressure tolerance. A small series of distal pancreatectomy with a stapler that compares the speed of different stapler jaw closing times is required to prove the feasibility of these results after the confirmation of the advantages of the RC method under various settings. PMID- 23982654 TI - Predicting who will fail early discharge after laparoscopic colorectal surgery with an established enhanced recovery pathway. AB - BACKGROUND: Despite using laparoscopy and enhanced recovery pathways (ERP), some patients are not ready for early discharge. The goal of this study was to identify predictors for patients who might fail early discharge, so that any defined factors might be addressed and optimized. METHODS: A prospectively maintained database was reviewed for major elective laparoscopic colorectal surgical procedures. Cases were divided into day of discharge groups: <= 3 days and >4 days. All followed a standardized ERP. Demographic and clinical data were compared using Student's paired t tests or Fisher's exact test, with p value < 0.05 statistically significant. Regression analysis was performed to identify significant variables. RESULTS: There were 275 <= 3 days patients and 273 >4 days patients. There were significant differences between groups in body mass index (p = 0.0123), comorbidities (p = 0.0062), ASA class (p = 0.0014), operation time (p < 0.001), postoperative complications (p < 0.001), and 30-day reoperation rate (p = 0.0004). There were no significant differences for intraoperative complications (p = 0.724), readmissions (p = 0.187), or mortality rate (p = 1.00). Significantly more patients were discharged directly home in the <= 3-days cohort. Using logistic regression, every hour of operating time increased the risk of length of stay >4 days by 2.35 %. CONCLUSIONS: Elective colorectal surgery patients with longer operation times and more comorbidities are more likely to fail early discharge. These patients should have different expectations of the ERP, as an expected 1- to 3-day stay may not be achievable. By identifying patients at risk for failing early discharge, resources and postoperative support can be better allocated and patients better informed about likely recovery. PMID- 23982655 TI - A hybrid method of laparoscopic-assisted open liver resection through a short upper midline laparotomy can be applied for all types of hepatectomies. AB - BACKGROUND: Although hepatectomy procedures should be designed to provide both curability and safety, minimal invasiveness also should be pursued. METHODS: We analyzed the data related to our method for laparoscopy-assisted open resections (hybrid method) through a short upper midline incision for various types of hepatectomies. Of 215 hepatectomies performed at Nagasaki University Hospital between November 2009 and June 2012, 102 hepatectomies were performed using hybrid methods. RESULTS: A hybrid method was applicable for right trisectionectomy in 1, right hemihepatectomy in 32, left hemihepatectomy in 29, right posterior sectionectomy in 7, right anterior sectionectomy in 1, left lateral sectionectomy in 2, and segmentectomy in 7 patients, and for a minor liver resection in 35 patients (12 combined resections). The median duration of surgery was 366.5 min (range 149-709) min, and the median duration of the laparoscopic procedure was 32 min (range 18-77) min. The median blood loss was 645 g (range 50-5,370) g. Twelve patients (12 %) developed postoperative complications, including bile leakage in three patients, wound infections in two patients, ileus in two patients, and portal venous thrombus, persistent hyperbilirubinemia, incisional hernia, local liver infarction each in one patient. There were no perioperative deaths. CONCLUSIONS: Our method of hybrid hepatectomy through a short upper midline incision is considered to be applicable for all types of hepatectomy and is a reasonable approach with no abdominal muscle disruption, which provides safe management of the hepatic vein and parenchymal resection even for patients with bilobular disease. PMID- 23982656 TI - Reduced leaching of the herbicide MCPA after bioaugmentation with a formulated and stored Sphingobium sp. AB - The use of pesticides on sandy soils and on many non-agricultural areas entails a potentially high risk of water contamination. This study examined leaching of the herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA) after bioaugmentation in sand with differently formulated and stored Sphingobium sp. T51 and at different soil moisture contents. Dry formulations of Sphingobium sp. T51 were achieved by either freeze drying or fluidised bed drying, with high initial cell viability of 67-85 %. Storage stability of T51 cells was related to formulation excipient/carrier and storage conditions. Bacterial viability in the fluidised bed-dried formulations stored at 25 degrees C under non-vacuum conditions was poor, with losses of at least 97 % within a month. The freeze-dried formulations could be stored substantially longer, with cell survival rates of 50 %, after 6 months of storage at the same temperature under partial vacuum. Formulated and long-term stored Sphingobium cells maintained their MCPA degradation efficacy and reduced MCPA leaching as efficiently as freshly cultivated cells, by at least 73 % when equal amounts of viable cells were used. The importance of soil moisture for practical field bioaugmentation techniques is discussed. PMID- 23982657 TI - Subclinical atherosclerosis and markers of immune activation in HIV-infected children and adolescents: the CaroVIH Study. AB - BACKGROUND: HIV-infected adults display increased cardiovascular disease, probably driven by inflammation and immune activation. These relationships have not been addressed in vertically HIV-infected children and adolescents, a population at very high risk for long-term non-AIDS complications. METHODS: Carotid intima media thickness (IMT) was measured in a cohort of HIV-infected children and adolescents and healthy controls. C-reactive protein and markers of immune activation (CD38+HLA-DR+) and immune senescence (CD28-CD57+) were determined. RESULTS: One hundred fifty HIV-infected patients and 150 controls were included, 64.8% female. IMT was thicker in HIV-infected patients (0.434 mm +/- 0.025 vs. 0.424 mm +/- 0.018, P < 0.001). After adjustment by age, sex, body mass index, and smoking status, HIV infection was independently associated with thicker IMT (odds ratio, 2.28; 95% confidence interval: 1.25 to 4.13; P = 0.007). Among HIV-related variables, a low CD4 nadir was related to an increased IMT. Although HIV-infected subjects presented higher frequencies of activated CD4+ and CD8+ T cells (P = 0.002 and P = 0.087, respectively), no relation was found between IMT and inflammation, immune activation, or senescence. CONCLUSIONS: Structural changes of the vasculature present early in vertically HIV-infected subjects as well as immune activation and senescence. These patients should be carefully monitored for the prompt detection and early treatment of cardiovascular disease. PMID- 23982658 TI - Performance of 3 rapid tests for discrimination between HIV-1 and HIV-2 in Guinea Bissau, West Africa. AB - As HIV-2 is intrinsically resistant to nonnucleoside reverse transcriptase inhibitors, it is mandatory to discriminate between HIV types before initiating antiretroviral treatment. Guinea-Bissau has the world's highest prevalence of HIV 2 and HIV-1/HIV-2 dually infected individuals. We evaluated 3 rapid tests for discrimination between HIV-1, HIV-2, and dual infections among 219 patients from Guinea-Bissau by comparing with the gold standard (INNO-LIA). Genie III HIV-1/HIV 2 was the best performer with regard to discriminatory capacity (agreement 91.8%), followed by Immunoflow HIV1-HIV2 (agreement 90.9%) and SD Bioline HIV-1/2 3.0 (agreement 84.5%). Our results underscore the need for evaluation of tests in relevant populations before implementation. PMID- 23982659 TI - Pulse wave velocity as index of arterial stiffness in HIV-infected patients compared with a healthy population. AB - BACKGROUND: Chronic HIV infection leads to premature atherosclerosis. Arterial stiffness is considered a subclinical marker of cardiovascular disease. METHODS: Pulse wave velocity (PWV) was determined in 254 individuals (174 HIV-infected patients and 80 healthy controls, 2:1 matched by age and gender) to compare the prevalence of arterial stiffness and to identify associated factors. PWV was determined using noninvasive automated device (Complior). Factors associated with impaired PWV were assessed among cardiovascular risk factors, HIV infection parameters, and laboratory data. Logistic regression analyses were performed to determine differences between groups and factors associated to arterial stiffness. RESULTS: Overall, 81.4% of participants were male, median age was 46.54 [interquartile range (IQR): 41-52] years. Higher percentages of HIV infected subjects showed dyslipemia (P = 0.012) and smoking habit (P = 0.002). The median time from HIV diagnosis was 13 (IQR: 6-18) years and the median time on antiretroviral therapy was 11 (IQR: 5-15) years. Nearly, all patients were virologically suppressed (89.7%) at the time of PWV. Arterial stiffness in the global population was 20.5%, 18.9% in HIV-infected group, and 23.8% in controls (P = 0.405). High diastolic blood pressure and high levels of triglycerides at time of PWV were associated with increased PWV (P = 0.009 and P = 0.023, respectively). CONCLUSIONS: Virologically suppressed HIV-infected patients showed similar arterial elasticity to non-HIV-infected patients. HIV-related conditions were not associated with arterial stiffness, probably because of the good immunologic and virological status of this group. However, high diastolic pressure at the time of PWV and high levels of triglycerides were associated risk factors. PMID- 23982661 TI - ACSM4 polymorphisms are associated with rapid AIDS progression in HIV-infected patients. AB - : Our aim was to explore the association among ACSM4 and PECI polymorphisms and AIDS progression in 454 HIV-infected patients never treated with antiretroviral drugs (146 long-term nonprogressors, 228 moderate progressors, and 80 rapid progressors). For ACSM4 polymorphisms, rs7137120 AA/AG and rs7961991 CC/CT genotypes had higher odds of having a rapid AIDS progression [odds ratio (OR) = 3.21; 95% of confidence interval (95% CI) = 1.26 to 8.16; P = 0.014 and OR = 3.60; 95% CI = 1.38 to 9.36; P = 0.009, respectively]. Additionally, the ACSM4 haplotype integrated for both rs7961991 A and rs7137120 C alleles had higher odds of having a rapid AIDS progression (OR = 2.85; 95% CI = 1.28 to 6.25; P = 0.010). For PECI polymorphisms, no significant associations were found. In conclusion, ACSM4 polymorphisms might play a significant role in AIDS progression. PMID- 23982660 TI - Early sex work initiation independently elevates odds of HIV infection and police arrest among adult sex workers in a Canadian setting. AB - OBJECTIVES: To explore factors associated with early sex work initiation and model the independent effect of early initiation on HIV infection and prostitution arrests among adult sex workers (SWs). DESIGN: Baseline data (2010 2011) were drawn from a cohort of SWs who exchanged sex for money within the last month and were recruited through time location sampling in Vancouver, Canada. Analyses were restricted to adults >=18 years old. METHODS: SWs completed a questionnaire and HIV/sexually transmitted infection testing. Using multivariate logistic regression, we identified associations with early sex work initiation (<18 years old) and constructed confounder models examining the independent effect of early initiation on HIV and prostitution arrests among adult SWs. RESULTS: Of 508 SWs, 193 (38.0%) reported early sex work initiation, with 78.53% primarily street-involved SWs and 21.46% off-street SWs. HIV prevalence was 11.22%, which was 19.69% among early initiates. Early initiates were more likely to be Canadian born [adjusted odds ratio (AOR): 6.8, 95% confidence interval (CI): 2.42 to 19.02], inject drugs (AOR: 1.6, 95% CI: 1.0 to 2.5), and to have worked for a manager (AOR: 2.22, 95% CI: 1.3 to 3.6) or been coerced into sex work (AOR: 2.3, 95% CI: 1.14 to 4.44). Early initiation retained an independent effect on increased risk of HIV infection (AOR: 2.5, 95% CI: 1.3 to 3.2) and prostitution arrests (AOR: 2.0, 95% CI: 1.3 to 3.2). CONCLUSIONS: Adolescent sex work initiation is concentrated among marginalized, drug, and street-involved SWs. Early initiation holds an independent increased effect on HIV infection and criminalization of adult SWs. Findings suggest the need for evidence-based approaches to reduce harm among adult and youth SWs. PMID- 23982662 TI - Linkage, engagement, and viral suppression rates among HIV-infected persons receiving care at medical case management programs in Washington, DC. AB - BACKGROUND: The District of Columbia Department of Health funds facilities to provide HIV medical case management (MCM), inclusive of linkage, engagement in care, and treatment adherence support. The objective of this analysis was to identify the differences in the clinical outcomes among HIV-infected persons receiving care at MCM-funded facilities compared with those in nonfunded facilities. METHODS: Newly diagnosed and prevalent HIV-infected persons were identified from the District of Columbia Department of Health surveillance system. Clinical outcomes of interest were linkage, retention in care, and viral suppression. Bivariate analyses and random effects logistic regression were used to examine the differences in demographics and clinical outcomes of persons receiving care at MCM-funded and nonfunded facilities. RESULTS: Among 5631 prevalent cases, 56.7% received care at MCM-funded facilities of which 76.2% were retained in care, and 70.6% achieved viral suppression. Those receiving care in MCM-funded facilities were significantly more likely to be retained in care [adjusted odds ratio (aOR) 4.13; 95% confidence interval (CI): 1.93 to 8.85] and as likely (aOR 1.06; 95% CI: 0.68 to 1.62) to be virally suppressed than persons receiving care in nonfunded facilities. Among 789 newly diagnosed persons, those diagnosed in MCM-funded facilities were not significantly more likely to be linked to care within 3 months (aOR 0.50; 95% CI: 0.21 to 1.18) than those diagnosed in nonfunded facilities. DISCUSSION: This study provides evidence that MCM may be beneficial to HIV-infected persons in DC by improving retention in care. Further identification of the specific services providing the most benefit to clients is needed, including a better understanding of the complex relationship between retention and viral suppression. PMID- 23982664 TI - A novel approach for the one-pot preparation of alpha-ketoamides by anodic oxidation. AB - The direct oxidative synthesis of alpha-ketoamides via anodic oxidation was developed by using dioxygen as a reactant under mild conditions. This methodology has a broad substrate scope (aromatic amines, aliphatic amines and ammonium acetate) and opens up an interesting and attractive avenue for the synthesis of alpha-ketoamide derivatives. PMID- 23982663 TI - NIH support of Centers for AIDS Research and Department of Health Collaborative Public Health Research: advancing CDC's Enhanced Comprehensive HIV Prevention Planning project. AB - The contributions reported in this supplemental issue highlight the relevance of NIH-funded CEWG research to health department-supported HIV prevention and care activities in the 9 US cities with the highest numbers of AIDS cases. The project findings have the potential to enhance ongoing HIV treatment and care services and to advance the wider scientific agenda. The HIV testing to care continuum, while providing a framework to help track progress on national goals, also can reflect the heterogeneities of local epidemics. The collaborative research that is highlighted in this issue not only reflects a locally driven research agenda but also demonstrates research methods, data collection tools, and collaborative processes that could be encouraged across jurisdictions. Projects such as these, capitalizing on the integrated efforts of NIH, CDC, DOH, and academic institutions, have the potential to contribute to improvements in the HIV care continuum in these communities, bringing us closer to realizing the HIV prevention and treatment goals of the NHAS. PMID- 23982665 TI - Paper-based analytical devices for point-of-care infectious disease testing. AB - Paper-based devices provide an alternative technology for simple, low-cost, portable, and disposable or recyclable diagnostic tools for many applications, including clinical diagnosis, food quality control, and environmental monitoring. The present review focuses on new paper-based tests for point-of-care (POC) infectious disease testing. This review provides a brief presentation of the fabrication techniques and the main sample preparation procedures. Recent immunological and molecular testing formats based on new paper-based solutions which go beyond conventional lateral flow formats are also added. Emphasis is placed on how paper systems could be used for detecting whole and viable bacteria associated to infectious diseases. Paper has recently become attractive, since it is a ubiquitous and extremely cheap material. It is easy to store, easy to use, and is compatible with many (bio)chemical and (bio)medical applications. Paper absorbs and transports liquids by capillary force without additional mechanical assistance. Hence, paper-based analytical devices are promising and possibly game changing, even if they still suffer from limitations, including accuracy and sensitivity. It is anticipated that, in the near future, with advances in fabrication procedures and associated analytical techniques, there will be a continuous flow of innovative paper-based diagnostics kits. PMID- 23982666 TI - Is there a relationship between cribriform plate dimensions and septal deviation angle? AB - The aim of this retrospective study was to investigate the relationship between cribriform plate (CP) dimensions and septal deviation degree. Coronal paranasal CT scans of 99 patients were reviewed. We measured depth and width of cribriform plate on both sides and compared with septal deviation side and septal deviation degree. Deviation angles were 6.85 +/- 1.47 degrees for right deviations; and 7.11 +/- 1.63 degrees for the left deviations. The mean depth of CP was 5.08 +/- 1.57 mm at the right side and 5.06 +/- 1.59 mm at the left side; and the mean width of CP was found 4.71 +/- 1.36 mm at the right side and 4.56 +/- 1.51 mm at the left side. When CP dimensions were evaluated according to the septal deviation side, mean width of CP was 4.69 +/- 1.36 mm at ipsilateral side (deviated side); and 4.58 +/- 1.51 mm at the contralateral side. The mean depth of CP was 4.9 +/- 1.56 mm at the ipsilateral side (deviated side); and 5.22 +/- 1.58 mm at the contralateral side. The CP depth at the contralateral side was significantly higher than that of the ipsilateral side (deviated side). In right SD, ipsilateral and contralateral CP depth increased. As deviation angle increased, ipsilateral and contralateral CP width, right and left CP width increased. Ipsilateral and contralateral CP width; and additionally ipsilateral and contralateral CP depth increased together. In other words, right and left CP width; and CP depth increased simultaneously. It is well known that the higher incidence of intracranial penetration is on the side where the position of the ethmoid roof (ER) is lower. The presence of septal deviation, the possibility of the deeper CP at the contralateral side should be taken into consideration to avoid iatrogenic injury. PMID- 23982667 TI - Surgical management of elongated styloid process: intraoral or transcervical? AB - The purpose of this study is to compare the results of surgical approaches in management of elongated styloid process. Eight patients with Eagle's syndrome due to elongated styloid process were included in this study. All necessary preoperative diagnostic work-ups were done and four of them were operated transorally and four were operated extraorally. Preoperative and postoperative symptoms and postoperative patient satisfaction were investigated. No early or late postoperative complications were encountered in transoral group. One of the patients who was operated transcervically experienced a transient weakness in the marginal mandibular branch of facial nerve which resolved spontaneously within 2 weeks. Complete remission of symptoms was achieved in seven patients at the final follow-up, only one of the patients, who was operated intraorally, had partial remission. Only one of the patients who had unilateral excision of elongated styloid process transcervically complained about the permanent scar. Transoral approach is a safe surgical alternative achieving adequate treatment. The advantages of intraoral approach include less surgical travma, less surgical time and lack of servical scar, with similar outcomes when compared with transcervical approach. PMID- 23982668 TI - Parapharyngeal abscess is frequently associated with concomitant peritonsillar abscess. AB - To characterize patients with parapharyngeal abscess admitted to a Danish tertiary care centre and evaluate our management. This is a retrospective chart review. All records of patients with parapharyngeal abscess admitted to the Ear Nose-Throat Department at Aarhus University Hospital, Denmark, from January 2001 through December 2011 were reviewed. In total, 63 patients (41 males), aged 4-89 years (median, 45 years) were included in the study. The mean annual incidence of parapharyngeal abscess was 0.9 cases/100,000 population. Thirty-three (52%) patients had concomitant peritonsillar abscess. In two patients the parapharyngeal abscess was accompanied by necrotizing fasciitis. The most frequent surgical approach used was intrapharyngeal incision in combination with tonsillectomy. The most commonly used antibiotic regimen was benzylpenicillin plus metronidazole. Seven (13%) patients returned to the operating theatre due to post-tonsillectomy haemorrhage or insufficient abscess drainage. Tonsillectomy and internal incision of the abscess in combination with a narrow-spectrum intravenous penicillin and metronidazole is a safe and efficient approach for managing parapharyngeal abscesses. This approach, however, carries a relatively high complication rate, requiring close surveillance in the early post-operative period. This is especially true for parapharyngeal abscess patients without peritonsillar abscess. In our series, these patients were more ill, more likely to experience complications, require intensive care, intubation, and tracheotomy, than parapharyngeal abscess patients with concurrent peritonsillar abscess. The frequent co-existence of parapharyngeal abscess and peritonsillar abscess favours careful consideration of addition of tonsillectomy to intrapharyngeal incision. PMID- 23982669 TI - Risk factors for internal carotid artery injury in adults during simple nasopharyngeal surgeries. AB - The purpose of this study attempted to analyze the potential risk factors for internal carotid artery injury during simple nasopharyngeal surgeries with or without an endoscopic aid. One hundred and seventy magnetic resonance imaging scans (340 halves) of the brain were retrospectively reviewed and studied. Anatomic variations of carotid arteries were classified, and various distances from the internal carotid arteries to the nasopharyngeal subsites were directly measured on the scans. The mean distances between the internal carotid arteries and nasopharyngeal subsites were significantly shortened in patients with nasopharyngeal internal carotid artery aberrancy, female gender, and lower body weight. The distance to the posterior nasopharyngeal wall was also shortened with age. However, the severity of nasopharyngeal carotid artery variations (kinking and coiling) did not reflect the shortening of mean distances to nasopharyngeal subsites. In conclusion, from multiple linear regression analysis, we found that the risk of an internal carotid artery injury during simple nasopharyngeal surgeries with or without an endoscopic aid is greatest in adult patients with nasopharyngeal carotid artery aberrancy, followed by female gender, lower body weight, and increasing age. PMID- 23982670 TI - Characterization of age-related changes in sacculocolic response parameters assessed by cervical vestibular evoked myogenic potentials. AB - Age-related changes have been documented in anatomical studies on peripheral as well as central vestibular systems. Similar changes have also been observed for saccular responses evaluated through Cervical vestibular evoked myogenic potential (cVEMP) after the age of 60 years. Nevertheless, most of these studies have either made use of small sample sizes, considered inappropriate for normative studies of such kind, or incorporated wider age groups which might have confounded the conclusions. In order to overcome the above shortcomings, the present study aimed at evaluating the effect of age on cVEMP using larger sample size and distributing the participants to smaller age group divisions. A cross sectional design was employed to record cVEMPs from 280 healthy volunteers in the age range of 10-85 years who were distributed to seven age groups (10-20, 20-30, 30-40, 40-50, 50-60, 60-70 and above 70 years). The latency, amplitude, inter aural asymmetry ratio, and threshold were compared using one-way analysis of variance, whereas the response rate was calculated in terms of percentage of ears in which the responses were identifiable. The results revealed a steady decline in response rate and amplitude with advancing age beyond 5th decade (50-60 years). In addition, the latency of P13 and N23 was prolonged, while the thresholds worsened with increasing age also after 50 years. Hence, age-matched norms have to be considered while interpreting the results of cVEMP, especially in individuals above 50 years of age. PMID- 23982671 TI - Sandwich grafting technique for endoscopic endonasal repair of cerebrospinal fluid rhinorrhoea. AB - The surgical management of cerebrospinal fluid (CSF) rhinorrhoea has changed significantly after the introduction of functional endoscopic sinus surgery. The clear anatomical exposure of the roof of the nasal and paranasal sinus cavities by the endoscope offers the surgeon a golden chance to identify the area of CSF leak, and thus enables one to adequately plan the management. The aim of this work is to evaluate the use of facia lata sandwich graft technique for endoscopic endonasal repair of CSF rhinorrhoea. Forty patients with CSF rhinorrhoea were treated endoscopically using 2 layers of facia lata (underlay and onlay) interposed with a layer of septal cartilage or conchal bone in-between (sandwich technique) for repair. Fifty-five percent of cases were regarded as spontaneous CSF leaks with no obvious cause, 30% following head injury and 15% were iatrogenic. The ethmoidal roof was the commonest location of CSF leak (60%) followed in frequency by the cribriform plate and the sphenoid sinus (20% each). Follow-up period was 12-24 months. We have achieved a 95% success rate in managing CSF leaks in our 40 patients in the first attempt repair and 100% success rate after second attempt repair. Endoscopic endonasal repair of CSF leaks is quite safe and effective procedure with high success rate and avoid the morbidity associated with craniotomy. Using the three-layer, sandwich-grafting technique of facia lata further adds more security to the sealing of CSF and augments the results of repair. PMID- 23982672 TI - Identification and Genotyping of Human Sapoviruses Collected from Sewage Water in Naples and Palermo, Italy, in 2011. AB - Human sapoviruses were identified in 15 (12.4 %) of 121 inlet sewage samples collected from wastewater treatment plants in Naples and Palermo, Italy, in 2011. All strains, except one GI.1, were genotyped as GI.2 by sequencing a capsid gene fragment. This is the first detection of sapovirus in wastewaters in Italy. PMID- 23982674 TI - Efficacy of higher dose 13.3 mg/24 h rivastigmine patch on instrumental activities of daily living in patients with mild-to-moderate Alzheimer's disease. AB - BACKGROUND: Stabilizing/reducing decline in the ability to perform activities of daily living (ADLs) is important in management of Alzheimer's disease (AD). METHODS: Post hoc analysis of OPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer's disease (OPTIMA), a double-blind trial comparing 13.3 and 9.5 mg/24 h rivastigmine patch in patients with AD demonstrating functional and cognitive decline with 9.5 mg/24 h patch. Efficacy on Alzheimer's disease Cooperative Study instrumental ADL (ADCS-IADL) items, higher level function (HLF), and autonomy factors was assessed. RESULTS: The ADCS-IADL, HLF, and autonomy factors favored 13.3 mg/24 h patch at all time points, reaching significance from weeks 16 to 48, 24 to 48, and 32 to 48, respectively. Higher dose patch demonstrated significantly greater efficacy on 10 of 17 ADCS-IADL items at 1 or more time points (P < .05 vs 9.5 mg/24 h patch). More adverse events were observed with higher dose patch; study discontinuations were similar between the doses. CONCLUSIONS: Greater efficacy of 13.3 versus 9.5 mg/24 h patch on ADL, including autonomy and HLF factors, supports this additional dosing option to prolong patients' independence. PMID- 23982677 TI - The prognostic value of miRNA146a in follicular thyroid carcinoma. PMID- 23982676 TI - Antiangiogenic therapy improves the antitumor effect of adoptive cell immunotherapy by normalizing tumor vasculature. AB - Abnormal tumor vasculature and subsequent tumor hypoxia contribute to immune tolerance of tumor cells by impeding the homing of cytotoxic T cells into tumor parenchyma and inhibiting their antitumor efficacy. These obstacles might explain why the promising approach of adoptive cell immunotherapy does not exert significant antitumor activity. Hypoxia contributes to immune suppression by activating hypoxia-inducible factor (HIF-1) and the vascular endothelial growth factor pathway, which plays a determining role in promoting tumor cell growth and survival. Tumor hypoxia creates an immunosuppressive microenvironment via the accumulation and subsequent polarization of inflammatory cells toward immune suppression phenotypes, such as myeloid-derived suppressor cells, tumor associated macrophages, and dendritic cells. Antiangiogenic therapy could normalize tumor vasculature and decrease hypoxic tumor area and thus may be an effective modality to potentiate immunotherapy. Adoptive cell immunotherapy alone is not efficient enough to decrease tumor growth as its antitumor effect is inhibited by the immunosuppressive hypoxic tumor microenvironment. This review describes that combination of antiangiogenic therapy with adoptive cell immunotherapy can exert synergistic antitumor effect, which will contribute to improve strategies for future anticancer therapies. PMID- 23982678 TI - Mediterranean diet and metabolic syndrome: an updated systematic review. AB - The metabolic syndrome is a health condition characterized by abdominal obesity, dyslipidemia, elevated blood pressure and impaired glucose tolerance, with increasing prevalence. Adherence to the Mediterranean diet seems to exert beneficial effects regarding the metabolic syndrome prevalence and progression. Thus, we performed an updated systematic review of studies which have evaluated the effect of the Mediterranean dietary pattern on the metabolic syndrome. This was a systematic review of epidemiological observational studies and clinical trials. English language publications in the databases PubMed, Embase, Scopus, until May 31, 2013, were included in this review. New evidence from prospective cohort studies, cross-sectional studies and clinical trials supports the beneficial role of adherence to the Mediterranean dietary pattern regarding metabolic syndrome presence and progression. Considering the magnitude of metabolic syndrome, efforts should be made to encourage adoption of this pattern in Mediterranean countries and similar dietary pattern in countries where metabolic syndrome is prevalent. PMID- 23982679 TI - Volatiles from intact and Lygus-damaged Erigeron annuus (L.) Pers. are highly attractive to ovipositing Lygus and its parasitoid Peristenus relictus Ruthe. AB - Trap cropping and biological control can provide a sustainable means of controlling insect pests. Insects in the genus Lygus (Hemiptera: Miridae) are major pests on cotton and horticultural crops throughout the United States, and pesticide resistance within Lygus populations necessitates more sustainable long term management techniques. Here, we explore behavioral responses of Lygus bugs (L. rubrosignatus Knight) and an introduced parasitoid, Peristenus relictus (Hymenoptera: Braconidae), to a common field edge plant, Erigeron annuus, which has the potential to serve as a trap host. Erigeron annuus is attractive to Lygus in the field, with Lygus preferentially moving to Erigeron patches compared to more abundant cotton plants. To determine the role of odor cues in mediating this attraction, we collected volatiles from E. annuus with and without Lygus damage, and then tested the attractiveness of these volatiles vs. those of cotton to Lygus females and female P. relictus wasps using Y-tube and wind tunnel bioassays. We found that undamaged E. annuus emits high concentrations of a complex volatile blend (60+ compounds), with novel compounds induced and constitutive compounds up-regulated in response to damage. Additionally, both female Lygus bugs and female P. relictus wasps are highly attracted to E. annuus volatiles over those of cotton in almost every combination of damage treatments. Our results suggest that Erigeron annuus would be an effective trap plant to control Lygus in cotton, since it is highly attractive to both the pest and its natural enemy. PMID- 23982681 TI - Infection: Rice yields new oral therapy for rotavirus infection. PMID- 23982682 TI - Therapy: Probiotics do not reduce antibiotic-associated or Clostridium difficile diarrhoea in older hospitalized patients. PMID- 23982683 TI - The '-omics' revolution and oesophageal adenocarcinoma. AB - Oesophageal adenocarcinoma (OAC) is the eighth most common cancer type worldwide with a dismal 5-year survival. Barrett oesophagus, the replacement of the normal squamous epithelia with glandular cells, is the first step in the pathway towards OAC. Although most patients with OAC present de novo, the presence of the easily detectable OAC precursor lesion, Barrett oesophagus, enables the possibility of early detection of high-risk patients who are more likely to progress. Currently, identification of high-risk patients depends on histopathological assessment of dysplasia with no regards to molecular pathogenesis. In the future, screening and risk stratification initiatives for Barrett oesophagus that incorporate molecular profiles might permit improved early diagnosis and intervention strategies with the possibility of preventing OAC. For the majority of patients presenting de novo at an advanced stage, combining so-called -omics datasets with current clinical staging algorithms might enable OACs to be better classified according to distinct molecular programmes, thereby leading to better targeted treatment strategies as well as cancer monitoring regimes. This Review discusses how the latest advances in -omics technologies have improved our understanding of the development and biology of OAC, and how this development might alter patient management in the future. PMID- 23982684 TI - Bile acid receptors as targets for drug development. AB - The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications. PMID- 23982685 TI - Liver: Caffeine is a potent stimulator of autophagy to reduce hepatic lipid content--a coffee for NAFLD? PMID- 23982686 TI - A one-pot coupling-addition-cyclocondensation sequence (CACS) to 2-substituted 3 acylpyrroles initiated by a copper-free alkynylation. AB - A novel three-component synthesis of 2-substituted 3-acylpyrroles can be initiated by a copper-free Pd-catalyzed alkynylation in a one-pot fashion. The reaction sequence proceeds under mild reaction conditions and in moderate to good yields with a broad scope of diversity. PMID- 23982687 TI - Inhibition of angiopoietin 2 attenuates lumen formation of tumour-associated vessels in vivo. AB - Anti-angiogenic therapy, inhibition of a co-operative process with vascular endothelial cells and pericytes could be an effective strategy to treat malignant tumours. Apart from vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang2) is a promising target of anti-angiogenic therapy. Although inhibition of Ang2 has been shown to decrease tumour size in preclinical and phase I trials, its mechanisms of action remain largely unknown. To elucidate the mechanisms of Ang2 inhibition, we have focused on differentiation of the vessels as well as on growth of the vessels, especially in vivo. L1-10, a selective Ang2 inhibitor was used. The in vitro effects of Ang2 inhibition or addition of Ang2 using HUVECs were also examined. Growth and differentiation of tumour-associated vessels were investigated in xenografts derived from a colon cancer treated by L1-10. Effects of VEGF inhibition were also examined to discriminate Ang2-specific action on the tumour-associated vessels. In vitro studies showed that VEGF enhanced proliferation and tube formation of HUVECs, and caused a significant increase in Rac1 and CDC42 expression when cultured in the collagen matrix gel, whereas neither Ang2 nor L1-10 affected in vitro behaviour of HUVECs or levels of the proteins. In vivo, on the other hand, we found that Ang2 inhibition with treatment of L1-10 dose-dependently decreased tumour growth. Furthermore, we found that L1-10 treatment extends the tumour-associated vessels whilst it suppressed a sound lumen formation. Histological analysis on xenografts suggests that Ang2 inhibition could have disturbed in vivo vascular differentiation. Our data provide a novel aspect that Ang2 may play an essential role in in vivo vascular differentiation, thus supporting a rationale for Ang2-targeted therapy against colon cancer. PMID- 23982688 TI - Describing the profile of patients on concurrent rifampin and warfarin therapy in western Kenya: a case series. AB - BACKGROUND: Rifampicin's ability to induce hepatic enzymes is responsible for causing a clinically significant drug interaction with warfarin. Little data exists to guide clinicians on managing this interaction, especially in Sub Saharan Africa where many patients are exposed to this combination due to a higher burden of tuberculosis. OBJECTIVE: The objective of the case series is to provide insight to practicing clinicians of the unique dynamics of this drug interaction in resource-constrained settings. The case series will provide details on commonly encountered scenarios and the dosage adjustments required to maintain a therapeutic INR. METHODS: A retrospective chart review was conducted of patients attending the Moi Teaching and Referral Hospital anticoagulation clinic in Eldoret, Kenya. Patients were included if they had a history of concurrent rifampicin and warfarin therapy and a minimum follow up of 2 months. Descriptive statistics were used to explain the demographic characteristics, time to therapeutic INR and average weekly warfarin dose. The inference on proportions test was conducted to compare the time in the therapeutic range (TTR) for patients on concurrent rifampicin to the rest of the patients not receiving rifampicin in the clinic. RESULTS: Of the 350 patient charts evaluated, 10 met the inclusion criteria. The median percentage increase of the weekly warfarin dose from baseline was 15.7%. For the patients in this analysis, the median TTR was 47%. DISCUSSION: Patients on concurrent therapy should be rigorously monitored with regular INR checks and warfarin dosage adjustments. Empiric dosage adjustments of warfarin should be avoided but patient characteristics can aid in understanding the alterations seen in INR. PMID- 23982690 TI - Clinical utility gene card for: progressive familial intrahepatic cholestasis type 1. PMID- 23982689 TI - Clinical utility gene card for: progressive familial intrahepatic cholestasis type 2. PMID- 23982691 TI - Clinical utility gene card for: von Hippel-Lindau (VHL). PMID- 23982692 TI - A novel locus for episodic ataxia:UBR4 the likely candidate. AB - Episodic ataxias (EAs) are rare neurological channelopathies that are characterized by spells of imbalance and a lack of co-ordination. There are seven clinically recognized EAs and multiple isolated cases. Five disease-causing genes have been identified to date. We describe a novel form of autosomal dominant EA in a large three-generation Irish family. This form of EA presents in early childhood with periods of unsteadiness generalized weakness and slurred speech during an attack, which may be triggered by physical tiredness or stress. Linkage analysis undertaken in 13 related individuals identified a single disease locus (1p36.13-p34.3) with a LOD score of 3.29. Exome sequencing was performed. Following data analysis, which included presence/absence within the linkage peak, two candidate variants were identified. These are located in the HSPG2 and UBR4 genes. UBR4 is an ubiquitin ligase protein that is known to interact with calmodulin, a Ca(2+) protein, in the cytoplasm. It also co-localizes with ITPR1 a calcium release channel that is a major determinant of mammal co-ordination. Although UBR4 is not an ion channel gene, the potential for disrupted Ca(2+) control within neuronal cells highlights its potential for a role in this form of EA. PMID- 23982693 TI - [Non-fusion techniques for treatment of pediatric scoliosis]. AB - The primary goal of treatment in children with early onset scoliosis (EOS) is to control the deformity and to allow spinal and chest wall growth to continue and improve pulmonary function. In skeletally immature children spondylodesis leads to fusion of the instrumented segments with associated nonsymmetrical growth and pulmonary insufficiency. Non-fusion, techniques such as growing rods, vertical expandable prosthetic titanium rib(r) (VEPTR) and staples have evolved over the past years. Each technique has its different spectrum of indications which the surgeon has to follow accurately to prevent the patient from developing complications. A new trend started by using magnetically controlled growing rods to avoid the need for anesthesia and open surgery during adaptive growth. The intention of this article is to give the reader a synopsis about the three most important non-fusion techniques based on own experience and the current literature. PMID- 23982694 TI - Role of N-Acetylcysteine to Prevent Contrast-Induced Nephropathy: A Meta analysis. AB - It is unclear whether N-acetylcysteine is useful in preventing contrast-induced nephropathy in patients undergoing coronary angiography. Because of different inclusion and exclusion criteria and different definitions of studied parameters, various studies have reported different outcomes. A systematic search was done using PubMed, Ovid, and the Cochrane library, and studies were pooled after strict inclusion and exclusion criteria. Separate analysis was conducted for all endpoints including only studies that used an N-acetylcysteine (NAC) dose of 600 mg, and another separate analysis was conducted for all endpoints including only studies that used oral route NAC to study how the dose and route of administration of NAC affect the outcomes. The results of the pooled analysis significantly favored the use of NAC to prevent contrast-induced nephropathy in patients undergoing coronary angiography but failed to show any significant benefit in terms of creatinine levels preangiography and postangiography, need for dialysis, and all-cause mortality. The effects of route and dose of NAC did not show any significant difference except in respect to incidence of postcatheterization nephropathy. This study shows that NAC may not have any impact on clinical outcomes after peripheral or coronary artery catheterization and that dose and route do not seem to have any effect on these outcomes. PMID- 23982695 TI - An Open-Label Randomized Crossover Trial of Lyophilized Black Raspberries on Postprandial Inflammation in Older Overweight Males: A Pilot Study. AB - This study was a 14-day, outpatient, open-label randomized crossover trial of lyophilized black raspberries (BRBs) in older overweight or obese males to determine whether BRB consumption affects postprandial inflammation associated with consumption of a high-fat high-calorie (HFHC) meal. Ten study participants consumed 45 g/d of lyophilized BRBs for 4 days, followed by a HFHC breakfast plus BRBs on day 6 or consumed the HFHC breakfast on day 6 without previous consumption of BRBs and then crossed over to the other treatment after a 2-day washout period. Blood samples were obtained before and 1, 2, 4, 8, and 12 hours after consumption of the HFHC breakfast. The primary study outcomes were changes in area under the concentration-time curve (AUC) for interleukin-6 (IL-6), C reactive protein (CRP), and tumor necrosis factor-alpha (TNF-alpha). The secondary outcomes were safety and tolerability of lyophilized BRB powder. The chronology and values of measured serum concentrations for IL-6, TNF-alpha, and CRP were consistent with those described previously by other investigators. The AUC of serum IL-6 was lowered significantly (P = 0.03, n = 10) with BRB consumption (34.3 +/- 7.6 pg.mL-1.h-1 compared with 42.4 +/- 17.9 pg.mL-1.h-1 for consumption of the HFHC meal alone). However, no significant differences (change in AUC) were calculated for serum CRP and TNF-alpha. The findings of this pilot study suggest that consumption of lyophilized BRBs may attenuate postprandial inflammation in overweight or obese males consuming a HFHC meal. Further investigation of BRBs is warranted to better elucidate their inflammomodulatory potential. PMID- 23982696 TI - Excessive long-term platelet inhibition with prasugrel or ticagrelor and risk of infection: another hidden danger? PMID- 23982697 TI - Drug Dose Adjustment in Dialysis Patients Admitted in Clinics Other Than Internal Medicine. AB - Many drugs that are administered during hospitalization are metabolized or excreted through kidneys, consequently require dosage adjustment. We aimed to investigate inappropriate prescription of drugs requiring renal dose adjustment (RDA) in various surgical and medical inpatient clinics. We retrospectively determined dialysis patients hospitalized between January 2007 and December 2010. Inpatient clinics, including cardiology, pulmonary medicine, neurology, infectious diseases (medical clinics) and cardiovascular surgery, orthopedics, general surgery, obstetrics and gynecology, and neurosurgery (surgical clinics), were screened via electronic database. Total and RDA medications were determined. RDA drugs correctly adjusted to creatinine clearance were labeled as RDA-A (appropriate), otherwise as RDA-I (inappropriate). Renal doses of RDA medications were based on the "American College of Physicians Drug Prescribing in Renal Failure, fifth Edition." Two hundred seventeen hospitalization records of 172 dialysis patients (92 men and 80 women) were included in the analysis. Mean age of patients was 59.4 +/- 14.6 years, and the mean hospitalization duration was 8.5 +/- 7.8 days. In total, 247 (84.3%, percentage in drugs requiring dose adjustment) and 175 (46.2%) drugs have been inadequately dosed in surgical and medical clinics, respectively. The percentage of patients to whom at least 1 RDA I drug was ordered was 92% and 91.4% for surgical and medical clinics, respectively (P > 0.05). Nephrology consultation numbers were 8 (7.1%) in surgical and 32 (30.4%) in medical clinics. The most common RDA-I drugs were aspirin and famotidine. A significant portion of RDA drugs was ordered inappropriately both in surgical and medical clinics. Nephrology consultation rate was very low. Measures to increase physician awareness are required to improve results. PMID- 23982698 TI - Ventilatory function and intra-abdominal pressure in patients who underwent abdominoplasty with plication of the external oblique aponeurosis. AB - BACKGROUND: After correction of rectus diastasis there is a change in the values obtained by spirometry in the first few postoperative days. In specific cases, a plication of the external oblique aponeurosis in addition to plication of the anterior rectus sheath is indicated. Therefore, the aim of this study was to evaluate ventilatory function and intra-abdominal pressure (IAP) in patients who underwent abdominoplasty with the plication of the anterior rectus sheath, associated with an "L-shaped" plication of the external oblique aponeurosis. METHODS: Eighteen female patients, classified as Nahas type III or B, were selected. Spirometry was performed preoperatively and on the 2nd, 7th, and 15th days after surgery. Intraoperatively, the IAP was measured at five points in the surgical procedure: (1) before skin incision, (2) after the plication of the rectus abdominis muscle, (3) after the L-plication of the aponeurosis of the external oblique, (4) after skin closure, and (5) after the use of a compressive garment. RESULTS: There was a significant reduction in spirometry values after surgery. There was no correlation between body mass index (BMI), pain, the increase of IAP, and the width of diastasis and changes in spirometry (p <= 0.05) in any of the postoperative evaluations. CONCLUSION: Spirometric parameters change on the 2nd and 7th postoperative days and tend to normalize on the 15th day. Postoperative pain, BMI, and increased IAP are not related to these changes. The use of compressive garments increases the IAP. PMID- 23982700 TI - Zinc and myocardial ischemia/reperfusion injury. AB - As an important trace element, zinc is required for the normal cellular structure and function, and impairment of zinc homeostasis is associated with a variety of health problems including cardiovascular disease. Zinc homeostasis is regulated through zinc transporters, zinc binding molecules, and zinc sensors. Zinc also plays a critical role in cellular signaling. Studies have documented that zinc homeostasis is impaired by ischemia/reperfusion in the heart and zinc dyshomeostasis may play a role in the pathogenesis of myocardial ischemia/reperfusion injury. Both exogenous and endogenously released zinc may play an important role in cardioprotection against ischemia/reperfusion injury. The goal of this review is to summarize the current understanding of the roles of zinc homeostasis and zinc signaling in myocardial ischemia/reperfusion injury. PMID- 23982701 TI - Overexpression of heparanase in ovarian cancer and its clinical significance. AB - It has been reported that heparanase (HPSE) is overexpressed in ovarian cancer and is associated with tumor invasion and metastasis. However, a systematic study on the contribution of HPSE to tumor metastasis is rarely reported. In this study, based on the measurement of HPSE serum concentration, the expression of HPSE at both the mRNA and protein levels in tumors and its effects on the biological behaviors of cancer cells, we elucidated the role of HPSE in tumor invasion and metastasis in ovarian cancer and concluded that either the expression of HPSE in cancer and/or the serum concentration of HPSE may be a useful biomarker for the evaluation of surgery effects and prognosis prediction. PMID- 23982702 TI - Efficacy of multi-detector computerized tomography scan, endoscopic ultrasound, and laparoscopy for predicting tumor resectability in pancreatic adenocarcinoma. AB - BACKGROUND: Definitive treatment for pancreatic adenocarcinoma is surgical resection. Endoscopic ultrasound (EUS), multi-detector computerized tomography scan (MDCT), and laparoscopy are current preoperative methods for assessing the resectability in this malignancy. This study compared the efficacy of these methods in predicting the resectability of pancreatic adenocarcinoma. METHODOLOGY: One hundred and fifty-seven patients considered for resection of pancreatic adenocarcinoma in two centers in Iran were evaluated. All of the patients were evaluated by MDCT and/or EUS; ones that had resectable tumor in imaging were assessed by laparoscopy/laparotomy. Patients undergoing pancreaticoduodenectomy were followed for 2 years. RESULTS: The majority (67%) were male. The mean age was 66 years. The lesion was situated in the head of pancreas in 127 cases (81%). Tumor resectability rate according to the MDCT scan/EUS, laparoscopy, and laparotomy was 6%, 5%, and 3%, respectively. Only 3% of the pancreatic adenocarcinoma cases were resectable at the time of diagnosis. Fifty percent of patients predicted to have resectable tumor according to MDCT/EUS and 37.5% of cases that had resectable disease in laparoscopy were found to have unresectable lesions at laparotomy and or postsurgical follow up. CONCLUSIONS: Prognosis continues to be dismal for pancreatic adenocarcinoma, and better methods to assess tumor resectability are needed. PMID- 23982703 TI - Torus hyperplasia of pyloric antrum. PMID- 23982704 TI - Porcelain gallbladder. PMID- 23982705 TI - Use of FDG/PET CT to diagnose malignancy as the cause of mucocele of the appendix. AB - Mucocele of the appendix is an uncommon condition characterized by luminal distension and accumulation of a mucoid material. Occasionally, it can be caused due to malignancy like cystadenocarcinoma, and the preoperative diagnosis of which is very rare. We report a case of a 64-year-old lady presenting with intermittent abdominal pain diagnosed on ultrasonography as a mucocele where preoperative (18)F-flurodeoxyglucose positron emission tomography/computerized tomography (FDG PET/CT) findings raised a strong suspicion of malignancy. FDG PET/CT findings brought about a change in therapeutic plan, and the patient was considered for a more extensive surgical resection. The final histopathology revealed cystadenocarcinoma as the cause of appendicular mucocele, a finding hitherto undescribed on FDG PET/CT. PMID- 23982706 TI - The clinician engagement and education session: modernizing "academic detailing". PMID- 23982707 TI - Eculizumab long-term therapy for pediatric renal transplant in aHUS with CFH/CFHR1 hybrid gene. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulation of the complement system. Outcomes of kidney transplantation are poor owing to aHUS recurrence and loss of graft. Patients carrying CFH mutations or CFH/CFHR1 hybrid genes present a very high risk of recurrence despite preventive plasmapheresis. Evaluation of recent data suggests that prophylactic eculizumab pretransplant might be the preferred therapy if available. CASE-DIAGNOSIS/TREATMENT: We report 3-year follow-up data in a 9-year-old boy with aHUS and successful renal transplant treated with prophylactic eculizumab without recurrence. He presented with aHUS at age 3, irreversible renal failure and uncontrolled severe hypertension with concentric left ventricular hypertrophy, recurrent acute pulmonary edema, and congestive heart failure despite five hypotensive agents and bilateral nephrectomy. Complement analysis demonstrated the presence of a CFH/CFHR1 hybrid gene inherited from his mother and a SNP risk CFH haplotype inherited from his father. Kidney transplant was performed with prophylactic eculizumab and subsequent fortnightly administration. Three years post-transplant, graft function remains stable (serum creatinine 0.9 mg/dl), hypertension is controlled, no left ventricular hypertrophy, no opportunistic infections, and negative clinical chemistry parameters for hemolysis. CONCLUSION: Eculizumab is a safe and effective therapy for preventing TMA recurrence and provides long-term graft function in aHUS with the CFH/CFHR1 hybrid gene. PMID- 23982708 TI - The prospective pediatric continuous renal replacement therapy (ppCRRT) registry: a critical appraisal. AB - Continuous renal replacement therapy (CRRT), which provides gradual, predictable clearance and fluid removal, is commonly used to manage acute kidney injury (AKI) and fluid overload in critically ill children. The Prospective Pediatric CRRT (ppCRRT) Registry, founded in 2001 and comprising 13 pediatric centers in the United States, represents the largest cohort of children receiving CRRT to date. Data from the ppCRRT has been used to describe pediatric CRRT demographics and epidemiology, improve technical aspects of CRRT provision for children, and identify novel or underappreciated risk factors affecting survival. Whereas the registry has successfully answered many questions, a number of questions remain unanswered and new ones have arisen. This article describes the ppCRRT Registry, including its major findings, the lessons learned, and the limitations inherent in its design. Additionally, using the registry as a framework, areas of future study are identified and potential methodologies examined. PMID- 23982709 TI - Acute kidney injury following Russell's viper bite in the pediatric population: a 6-year experience. AB - BACKGROUND: Snake bite continues to be an important public health problem in tropical countries, and Russell's viper is common in south-Asian countries such as India, Sri Lanka, and Myanmar. CASE-DIAGNOSIS/TREATMENT: Russell's viper envenomation can cause acute kidney injury (AKI) by various mechanisms. Few studies address AKI following Russell's viper bite in the pediatric population. CONCLUSIONS: In this study, we report our center's 6-year experience of such pediatric patients and identify the poor prognostic factors. PMID- 23982710 TI - Safety and efficacy of transcranial direct current stimulation in acute experimental ischemic stroke. AB - BACKGROUND AND PURPOSE: Transcranial direct current stimulation is emerging as a promising tool for the treatment of several neurological conditions, including cerebral ischemia. The therapeutic role of this noninvasive treatment is, however, limited to chronic phases of stroke. We thus ought to investigate whether different stimulation protocols could also be beneficial in the acute phase of experimental brain ischemia. METHODS: The influence of both cathodal and anodal transcranial direct current stimulation in modifying brain metabolism of healthy mice was first tested by nuclear magnetic resonance spectroscopy. Then, mice undergoing transient proximal middle cerebral artery occlusion were randomized and treated acutely with anodal, cathodal, or sham transcranial direct current stimulation. Brain metabolism, functional outcomes, and ischemic lesion volume, as well as the inflammatory reaction and blood brain barrier functionality, were analyzed. RESULTS: Cathodal stimulation was able, if applied in the acute phase of stroke, to preserve cortical neurons from the ischemic damage, to reduce inflammation, and to promote a better clinical recovery compared with sham and anodal treatments. This finding was attributable to the significant decrease of cortical glutamate, as indicated by nuclear magnetic resonance spectroscopy. Conversely, anodal stimulation induced an increase in the postischemic lesion volume and augmented blood brain barrier derangement. CONCLUSIONS: Our data indicate that transcranial direct current stimulation exerts a measurable neuroprotective effect in the acute phase of stroke. However, its timing and polarity should be carefully identified on the base of the pathophysiological context to avoid potential harmful side effects. PMID- 23982711 TI - Atrial fibrillation, stroke risk, and warfarin therapy revisited: a population based study. AB - BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is a major risk factor for ischemic stroke. This study aims to update the knowledge about AF and associated stroke risk and benefits of anticoagulation. METHODS: We extracted data from the hospital, specialized outpatient, and primary healthcare and drug registries in a Swedish region with 1.56 million residents. We identified all individuals who had received an AF diagnosis during the previous 5 years; all stroke events during 2010; and patients with AF aged >=50 years who had received warfarin during 2009. RESULTS: AF had been diagnosed in 38 446 subjects who were alive at the beginning of 2010 (prevalence of 3.2% in the adult [>=20 years] population); ~46% received warfarin therapy. In 2010, there were 4565 ischemic stroke events and 861 intracranial hemorrhages. AF had been diagnosed in 38% of ischemic events (>=50% among those aged >=80 years) and in 23% of intracranial hemorrhages. An AF diagnosis was often lacking in hospital discharge records after stroke events. Warfarin therapy was associated with an odds ratio of 0.50 (confidence interval, 0.43-0.57) for ischemic stroke and, despite an increased risk of intracranial hemorrhage, an odds ratio of 0.57 (confidence interval, 0.50-0.64) for the overall risk for stroke. CONCLUSIONS: AF is more common than present guidelines suggest. The attributable risk of AF for ischemic stroke increases with age and is close to that of hypertension in individuals aged >=80 years. Because a majority of patients with AF with increased risk for stroke had not received anticoagulation therapy, there is a large potential for improvement. PMID- 23982712 TI - Sex differences in the use of early do-not-resuscitate orders after intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Studies show that women are more likely to receive do-not resuscitate (DNR) orders after acute medical illnesses than men. However, the sex differences in the use of DNR orders after acute intracerebral hemorrhage (ICH) have not been described. METHODS: We conducted a retrospective study of consecutive patients hospitalized for acute ICH at a tertiary stroke center between 2006 and 2010. Unadjusted and multivariable logistic regression analyses were performed to test for associations between female sex and early (<24 hours of presentation) DNR orders. RESULTS: A total of 372 consecutive ICH patients without preexisting DNR orders were studied. Overall, 82 (22%) patients had early DNR orders after being hospitalized with ICH. In the fully adjusted model, early DNR orders were more likely in women (odds ratio, 3.18; 95% confidence interval, 1.51-6.70), higher age (odds ratio, 1.09 per year; 95% confidence interval, 1.05 1.12), larger ICH volume (odds ratio, 1.01 per cm(3); 95% confidence interval, 1.01-1.02), and lower initial GCS score (odds ratio, 0.76 per point; 95% confidence interval, 0.69-0.84). Early DNR orders were less likely when the patients were transferred from another hospital (odds ratio, 0.28, 95% confidence interval, 0.11-0.76). CONCLUSIONS: Women are more likely to receive early DNR orders after ICH than men. Further prospective studies are needed to determine factors contributing to the sex variation in the use of early DNR order after ICH. PMID- 23982713 TI - Critical pressure for arterial wall rupture in major human cerebral arteries. AB - BACKGROUND AND PURPOSE: Intracranial bleeding is linked to hemodynamic stress factors, such as hypertension. However, there are no studies that tested the breaking pressure of normal large cerebral arteries in humans. METHODS: The brains of 10 cadavers (age, 47+/-14 years; 9 men) were harvested within 48 hours postmortem for 31 segments of the main intracranial arteries. After careful microsurgical preparation, the vessels were pressurized with saline and observed until they ruptured. RESULTS: Vessel diameters averaged 2.6+/-0.3 mm (range, 1.2 4.3 mm). The average rupture pressure was 2.21+/-0.59 atm (range, 1.13-4.3 atm) and decreased with age at -0.025 atm/y (R2=40%; P<0.0002). The maximum diameter distention at rupture was 30+/-9% (13%-52%), which also decreased with age ( 0.5%/y; R2=78%; P<0.00001). Neither the rupture pressure nor the maximum distention showed significant dependence on the resting vessel diameter. No significant dependencies were found on the vessel origin, vascular configuration, direction of the rupture, or the presence of minor coexisting pathology. CONCLUSIONS: Human cerebral arterial wall breaks only at extremely high intravascular pressures, exceeding several times the highest observed systolic blood pressure, even accounting for age trends. Systolic hypertension alone may not be sufficient to cause intracranial hemorrhage, and there may be additional contributing factors. PMID- 23982714 TI - Antiplatelet loading improves behavioral outcome in a rabbit model of stroke. AB - BACKGROUND AND PURPOSE: No approved acute therapy exists for thousands of patients with ischemic stroke who present ineligible for thrombolytics. The purpose of this proof-of-concept study was to evaluate the efficacy of acute antiplatelet loading on stroke outcome in the rabbit small clot embolic model. METHODS: Sixty male New Zealand white rabbits were embolized via small clots into the middle cerebral artery. Two hours later, animals were treated with (1) aspirin (5 mg/kg; n=20); (2) usual dual antiplatelet loading (aspirin 10 mg/kg+clopidogrel 10 mg/kg; n=20); or (3) high-dose dual antiplatelet loading (aspirin 10 mg/kg+clopidogrel 30 mg/kg; n=20). The coprimary outcomes were as follows: (1) platelet inhibition and (2) behavioral outcome as measured by the P50 (milligrams of clot that leads to neurological dysfunction in 50% of animals in a group). RESULTS: There was a significant difference in 3-hour arachidonic acid and ADP (P<0.011); 6-hour collagen and ADP (P<0.01, P<0.01); and 24-hour collagen, arachidonic acid, and ADP (P=0.02, P<0.01, P<0.01) platelet inhibition. The behavioral outcome was significantly better in the usual dual antiplatelet loading versus aspirin group (P=0.02). CONCLUSIONS: This study suggests that usual dual antiplatelet loading is clinically beneficial in a validated model of acute stroke. Study of usual dual antiplatelet loading in acute stroke is warranted to provide treatment to stroke victims ineligible for current therapies. PMID- 23982715 TI - Surgery for intracerebral hemorrhage: moving forward or making circles? PMID- 23982716 TI - Modelling the efficiency of local versus central provision of intravenous thrombolysis after acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Prehospital redirection of stroke patients to a regional center is used as a strategy to maximize the provision of intravenous thrombolysis. We developed a model to quantify the benefit of redirection away from local services that were already providing thrombolysis. METHODS: A microsimulation using hospital and ambulance data from consecutive emergency admissions to 10 local acute stroke units estimated the effect of redirection to 2 regional neuroscience centers. Modeled outcomes reflected additional journey time and accuracy of stroke identification in the prehospital phase, and the relative efficiency of patient selection and door-needle time for each local site compared with the nearest regional neuroscience center. RESULTS: Thrombolysis was received by 223/1884 emergency admissions. Based on observed site performance, 68 additional patients would have been treated after theoretical redirection of 1269 true positive cases and 363 stroke mimics to the neuroscience center. Over 5 years redirection of this cohort generated 12.6 quality-adjusted life years at a marginal cost of L6730 ($10,320, ?8347). The average additional cost of a quality adjusted life year gain was L534 ($819, ?673). CONCLUSIONS: Under these specific circumstances, redirection would have improved outcomes from thrombolysis at little additional cost. PMID- 23982717 TI - Ambulatory blood pressure in patients with lacunar stroke: association with total MRI burden of cerebral small vessel disease. AB - BACKGROUND AND PURPOSE: Asymptomatic lacunar infarcts, white matter lesions, cerebral microbleeds, and enlarged perivascular spaces are MRI markers of cerebral small vessel disease (cSVD). Higher blood pressure (BP) levels are associated with the presence of these markers separately, but the association with the total burden of cSVD on brain MRI, expressed by the simultaneous presence of multiple markers of cSVD (a compound score), has not been investigated. METHODS: We performed 24-hour ambulatory BP monitoring in 122 patients with first-ever lacunar stroke. On brain MRI, we scored the presence of each marker of cSVD. One point was awarded for the presence of each marker, producing a score between 0 and 4. Associations with BP levels were tested with ordinal regression analyses. RESULTS: Eighteen (15%) patients had no markers of cSVD, and 6 (5%) patients had 4 markers. Most patients (45; 37%) had 2 different markers. After correction for age and sex, higher 24-hour, day, and night systolic (24-hour odds ratio, 1.25; 95% confidence interval, 1.02-1.52 per 10 mm Hg) and diastolic (24-hour odds ratio, 1.32; 95% confidence interval, 1.12-1.56 per 5 mm Hg) BP were all significantly associated with an increasing total burden of cSVD. CONCLUSIONS: We found a positive association of ambulatory BP levels with total burden of cSVD on brain MRI. With increasing BP levels, there is a piling up of damage in the brain. We suggest that further cSVD studies also consider viewing the total burden in addition to each of the MRI markers separately. PMID- 23982719 TI - Pulsed LLLT improves tendon healing in rats: a biochemical, organizational, and functional evaluation. AB - In the last decades, the tendon injuries have increased substantially. Previous results suggested that low-level laser treatment (LLLT) promotes synthesis of extracellular matrix and improves the functional properties of the tendon. The aim of this study was to evaluate the effects of different protocols of LLLT on partially tenotomized tendons. Adult male rats were divided into the following: G1-intact, G2-injured, G3-injured + LLLT (4 J/cm(2) continuous), G4-injured + LLLT (4 J/cm(2) at 20 Hz). G2, G3, and G4 were euthanized 8 days after injury. G5 injured, G6-injured + LLLT (4 J/cm(2) continuous), and G7-injured + LLL (4 J/cm(2) at 20 Hz until the seventh day and 2 kHz from 8 to 14 days). G5, G6, and G7 were euthanized on the 15th day. Glycosaminoglycan (GAG) level was quantified by dimethylmethylene blue method and analyzed on agarose gel. Toluidine blue (TB) stain was used to observe metachromasy. CatWalk system was used to evaluate gait recovery. Collagen organization was analyzed by polarization microscopy. The GAG level increased in all transected groups, except G5. In G6 and G7, there was a significant increase in GAG in relation to G5. In G3 and G4, the presence of dermatan sulfate band was more prominent than G2. TB stains showed intense metachromasy in the treated groups. Birefringence analysis showed improvement in collagen organization in G7. The gait was significantly improved in G7. In conclusion, pulsed LLLT leads to increased organization of collagen bundles and improved gait recovery. PMID- 23982720 TI - Shear bond strength and ultrastructural interface analysis of different adhesive systems to Er:YAG laser-prepared dentin. AB - The aim of this study was to evaluate the shear bond strength (SBS) of a microhybrid composite resin bonded with three different adhesive systems to Er:YAG laser- (EL) or bur-prepared dentin surfaces and to analyze the quality and ultrastructure of the adhesive-dentin interfaces by scanning electron microscopy (SEM). The specimens prepared for SBS test and SEM analysis were randomly assigned to eight groups (G1-G8): G1, EL (Fidelis PlusIII, Fotona) + Clearfil S3 Bond (C3S); G2, EL + AdperSE Plus (SE); G3, EL + laser etch + Adper Single Bond2 (SB2); G4, EL + acid etch + SB2; G5, EL + SB2 (no etching); G6, bur + acid etch + SB2; G7, bur + S3; G8, bur + SE. Laser was used in very short pulse mode at a setting of 200 mJ/20 Hz for dentin preparation and at 80 mJ/10 Hz for dentin etching. Bond strength test: 3.5 * 2.0 mm cylindrical molds were placed onto adhesives and filled with the composites. After 24 h in distilled water, SBS was tested at a crosshead speed of 0.5 mm/min. SEM analysis: The dentin-adhesive interfaces were evaluated for the ultrastructure of hybrid layer. Data of SBS (MPa) were statistically analyzed by ANOVA and Tukey HSD. ER:YAG laser-prepared dentin has demonstrated significantly more SBS (p < 0.01) for SE when compared to bur-prepared dentin. No significancies (p > 0.05) in SBS have been determined between the total-etch adhesive applied groups with regard to etching types. SEM analysis revealed that hybrid layers obtained in Er:YAG laser-irradiated dentin exhibited more irregular and non-homogeneous pattern than the conventionally prepared dentin. In conclusion, SE Bond demonstrated superior results in Er:YAG laser-ablated dentin compared to bur-prepared dentin. PMID- 23982718 TI - Low cardiorespiratory fitness in African Americans: a health disparity risk factor? AB - Low cardiorespiratory fitness (CRF) is a well-established risk factor for all cause and cardiovascular disease mortality. African Americans have higher rates of cardiovascular disease compared with their Caucasian counterparts. However, the extent to which lower CRF levels contribute to the excess risk in African Americans has not been fully explored. The purpose of this review is to: (i) explore the literature evaluating the relationship between CRF and mortality specifically in African American populations; and (ii) critically evaluate the studies which have compared CRF between African American and Caucasians in epidemiological studies and clinical trials. We have further discussed several potential mechanisms that may contribute to the observation of lower CRF levels in African American compared with Caucasian adults, including potential racial differences in physical activity levels, muscle fiber type distribution, and hemoglobin levels. If lower CRF is generally present in African Americans compared with Caucasians, and is of a clinically meaningful difference, this may represent an important public health concern. PMID- 23982722 TI - Hybrid chalcogenide nanoparticles: 2D-WS2 nanocrystals inside nested WS2 fullerenes. AB - The MOCVD assisted formation of nested WS2 inorganic fullerenes (IF-WS2) was performed by enhancing surface diffusion with iodine, and fullerene growth was monitored by taking TEM snapshots of intermediate products. The internal structure of the core-shell nanoparticles was studied using scanning electron microscopy (SEM) after cross-cutting with a focused ion beam (FIB). Lamellar reaction intermediates were found occluded in the fullerene particles. In contrast to carbon fullerenes, layered metal chalcogenides prefer the formation of planar, plate-like structures where the dangling bonds at the edges are stabilized by excess S atoms. The effects of the reaction and annealing temperatures on the composition and morphology of the final product were investigated, and the strength of the WS2 shell was measured by intermittent contact-mode AFM. The encapsulated lamellar structures inside the hollow spheres may lead to enhanced tribological activities. PMID- 23982721 TI - Modulating effect of low level-laser therapy on fibrosis in the repair process of the tibialis anterior muscle in rats. AB - The treatment of muscle injuries is a common practice at rehabilitation centers. Low-level laser therapy (LLLT) has demonstrated positive effects regarding the modulation of the inflammatory response, the enhancement of the tissue repair process and the prevention of fibrosis. The aim of the present study was to evaluate the effects of LLLT on morphological aspects of muscle tissue, collagen remodeling and activity of matrix metalloproteinase 2 (MMP-2) in rat skeletal muscle following acute injury. Wistar rats were divided into five groups: (1) control group (n = 10), (2) sham group (n = 10), (3) LLLT group (n = 30), (4) non treated injury group (n = 30) and (5) injury + LLLT group (n = 30). Cryoinjury was performed on the belly of the tibialis anterior (TA) muscle. LLLT was performed daily with an AlGaAs laser (780 nm; beam spot of 0.04 cm(2), output power of 40 mW, power density of 1 W/cm(2), energy density of 10 J/cm(2) and 10-s exposure time). Animals were euthanized at 1, 3 and 7 days. The TA muscles were removed and weighed. Morphological aspects were evaluated using H & E staining. The amount and distribution of collagen fibers were evaluated by picrosirius staining. Characterization and activity of MMP-2 were evaluated by zymography and Western blot techniques, respectively. The results revealed that LLLT induced a reduction in inflammatory infiltrate and myonecrosis after 1 day, an increase in the number of blood vessels after 3 and 7 days as well as an increase in the number of immature muscle fibers and MMP-2 gelatinase activity after 7 days. In conclusion, LLLT has a positive effect on the inflammatory process, MMP2 activity and collagen organization and distribution in the repair process of rat skeletal muscle. PMID- 23982723 TI - Modelling dynamics of plasmid-gene mediated antimicrobial resistance in enteric bacteria using stochastic differential equations. AB - The ubiquitous commensal bacteria harbour genes of antimicrobial resistance (AMR), often on conjugative plasmids. Antimicrobial use in food animals subjects their enteric commensals to antimicrobial pressure. A fraction of enteric Escherichia coli in cattle exhibit plasmid-gene mediated AMR to a third generation cephalosporin ceftiofur. We adapted stochastic differential equations with diffusion approximation (a compartmental stochastic mathematical model) to research the sources and roles of stochasticity in the resistance dynamics, both during parenteral antimicrobial therapy and in its absence. The results demonstrated that demographic stochasticity among enteric E. coli in the occurrence of relevant events was important for the AMR dynamics only when bacterial numbers were depressed during therapy. However, stochasticity in the parameters of enteric E. coli ecology, whether externally or intrinsically driven, contributed to a wider distribution of the resistant E. coli fraction, both during therapy and in its absence, with stochasticities in individual parameters interacting in their contribution. PMID- 23982724 TI - The role of CCNH Val270Ala (rs2230641) and other nucleotide excision repair polymorphisms in individual susceptibility to well-differentiated thyroid cancer. AB - Well-differentiated thyroid cancer (DTC) is the most common form of thyroid cancer (TC); however, with the exception of radiation exposure, its etiology remains largely unknown. Several single nucleotide polymorphisms (SNPs) have previously been implicated in DTC risk. Nucleotide excision repair (NER) polymorphisms, despite having been associated with cancer risk at other locations, have received little attention in the context of thyroid carcinogenesis. In order to evaluate the role of NER pathway SNPs in DTC susceptibility, we performed a case-control study in 106 Caucasian Portuguese DTC patients and 212 matched controls. rs2230641 (CCNH), rs2972388 (CDK7), rs1805329 (RAD23B), rs3212986 (ERCC1), rs1800067 (ERCC4), rs17655, rs2227869 (ERCC5), rs4253211 and rs2228529 (ERCC6) were genotyped using TaqMan(r) methodology, while conventional PCR-RFLP was employed for rs2228000 and rs2228001 (XPC). When considering all DTC cases, only rs2230641 (CCNH) was associated with DTC risk; a consistent increase in overall DTC risk was observed for both the heterozygous genotype (OR=1.89, 95% CI=1.14-3.14) and the variant allele carriers (OR=1.79, 95% CI=1.09-2.93). Histological stratification analysis confirmed an identical effect on follicular TC (OR=2.72, 95% CI=1.19-6.22, for heterozygous; OR=2.44, 95% CI=1.07-5.55, for variant allele carriers). Considering papillary TC, the rs2228001 (XPC) variant genotype was associated with increased risk (OR=2.33, 95% CI=1.05-5.16), while a protective effect was observed for rs2227869 (ERCC5) (OR=0.26, 95% CI=0.08-0.90, for heterozygous; OR=0.25, 95% CI=0.07-0.86, for variant allele carriers). No further significant results were observed. Our results suggest that NER polymorphisms such as rs2230641 (CCNH) and, possibly, rs2227869 (ERCC5) and rs2228001 (XPC), may influence DTC susceptibility. However, larger studies are required to confirm these results. PMID- 23982726 TI - Triage: what can we do to improve our practice? PMID- 23982727 TI - How objective is the observed mortality following critical care? PMID- 23982728 TI - Are preoperative oral care bundles needed to prevent postoperative pneumonia? PMID- 23982729 TI - Sedation level and the prevalence of delirium. PMID- 23982730 TI - Correspondence to: can optimal drug dosing during ECMO improve outcomes? PMID- 23982731 TI - A liaison between intrinsic and extrinsic regulators of pluripotency. PMID- 23982732 TI - Blm10 facilitates nuclear import of proteasome core particles. AB - Short-lived proteins are degraded by proteasome complexes, which contain a proteolytic core particle (CP) but differ in the number of regulatory particles (RPs) and activators. A recently described member of conserved proteasome activators is Blm10. Blm10 contains 32 HEAT-like modules and is structurally related to the nuclear import receptor importin/karyopherin beta. In proliferating yeast, RP-CP assemblies are primarily nuclear and promote cell division. During quiescence, RP-CP assemblies dissociate and CP and RP are sequestered into motile cytosolic proteasome storage granuli (PSG). Here, we show that CP sequestration into PSG depends on Blm10, whereas RP sequestration into PSG is independent of Blm10. PSG rapidly clear upon the resumption of cell proliferation and proteasomes are relocated into the nucleus. Thereby, Blm10 facilitates nuclear import of CP. Blm10-bound CP serves as an import receptor cargo complex, as Blm10 mediates the interaction with FG-rich nucleoporins and is dissociated from the CP by Ran-GTP. Thus, Blm10 represents the first CP-dedicated nuclear import receptor in yeast. PMID- 23982734 TI - Desymmetrization of trehalose via regioselective DIBAL reductive ring opening of benzylidene and substituted benzylidene acetals. AB - Trehalose dibenzylidene and substituted dibenzylidene acetals were reductively opened either at O6 or O4 in a regioselective manner by using a DIBAL stock solution prepared in toluene or dichloromethane, respectively, to achieve desymmetrization of the trehalose core. The method was applied to synthesize various biologically important unsymmetrically substituted trehalose glycoconjugates, including a mycobacterial trisaccharide, a 4-epi-trehalosamine analog and a maradolipid. PMID- 23982733 TI - IQGAP1 is a novel phosphatidylinositol 4,5 bisphosphate effector in regulation of directional cell migration. AB - Phosphatidylinositol 4,5 bisphosphate (PIP2) is a key lipid messenger for regulation of cell migration. PIP2 modulates many effectors, but the specificity of PIP2 signalling can be defined by interactions of PIP2-generating enzymes with PIP2 effectors. Here, we show that type Igamma phosphatidylinositol 4-phosphate 5 kinase (PIPKIgamma) interacts with the cytoskeleton regulator, IQGAP1, and modulates IQGAP1 function in migration. We reveal that PIPKIgamma is required for IQGAP1 recruitment to the leading edge membrane in response to integrin or growth factor receptor activation. Moreover, IQGAP1 is a PIP2 effector that directly binds PIP2 through a polybasic motif and PIP2 binding activates IQGAP1, facilitating actin polymerization. IQGAP1 mutants that lack PIPKIgamma or PIP2 binding lose the ability to control directional cell migration. Collectively, these data reveal a synergy between PIPKIgamma and IQGAP1 in the control of cell migration. PMID- 23982735 TI - Synthesis, characterization, DNA binding studies, photocleavage, cytotoxicity and docking studies of ruthenium(II) light switch complexes. AB - A new ligand 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2yl)phenylboronic acid and its (IPPBA) three ruthenium(II) complexes [Ru(phen)2(IPPBA)](ClO4)2 (1), [Ru(bpy)2(IPPBA)](ClO4)2 (2) and [Ru(dmb)2(IPPBA)](ClO4)2 (3) have been synthesized and characterized by elemental analysis, UV/VIS, IR, (1)H-NMR,(13)C NMR and mass spectra. The binding behaviors of the three complexes to calf thymus DNA were investigated by absorption spectra, emission spectroscopy, viscosity measurements, thermal denaturation and photoactivated cleavage. The DNA-binding constants for complexes 1, 2 and 3 have been determined to be 7.9 * 10(5) M(-1), 6.7 * 10(5) M(-1) and 2.9 * 10(5) M(-1). The results suggest that these complexes bound to double-stranded DNA in an intercalation mode. Upon irradiation at 365 nm, three ruthenium complexes were found to promote the cleavage of plasmid pBR322 DNA from super coiled form I to nicked form II. Further in the presence of Co(2+), the emission of DNA-Ru(IotaIota) complexes can be quenched. And when EDTA was added, the emission was recovered. The experimental results show that all three complexes exhibited the "on-off-on" properties of molecular "light switch". The highest Cytotoxicity potential of the complex1 was observed on the Human alveolar adenocarcinoma (A549) cell line. Good agreement was generally found between the spectroscopic techniques and molecular docked model which provides further evidence of groove binding. PMID- 23982736 TI - Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. AB - The induction of senescence for cancer treatment has provoked considerable interest recently. Metformin, a first-line drug for diabetes mellitus type 2, appears to be associated with a lower risk and improved outcomes in hepatocellular carcinoma (HCC). The mechanism involved in function of metformin in HCC is poorly understood. We show that low doses of metformin induced hepatoma cell senescence characterized by accumulation of senescence-associated beta galactosidase activity (SA-beta-gal) and the senescence marker Dec1, whereas the higher doses initiated apoptotic cell death. Metformin-induced senescence was accompanied by enhanced phosphorylation levels of AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC). The expression of acetylated p53 at Lys382 (Ac-p53) and p21 was also increased, while phosphorylation of p53 at Ser15 (p-p53), p53, p16 and pRB was rarely altered after metformin treatment. Moreover, inhibition of AMPK decreased p-AMPK, p-ACC, Ac-p53 and p21 expression, diminished SA-beta-gal staining and restored hepatoma cell proliferation. In addition, p53 siRNA transfection attenuated metformin induced SA-beta-gal staining. Intriguingly, co-expression of SIRT1 and p53 dramatically reduced the levels of Ac-p53, however, low doses of metformin treatment partially reversed the effect of SIRT1 on p53 acetylation and elevated SA-beta-gal activity. These observations indicate that activation of the AMPK pathway promotes senescence in hepatoma cells exposed to low concentrations of metformin in a p53-dependent manner. Further, low doses of metformin may have the potential to be used as an adjuvant to HCC therapy. PMID- 23982737 TI - Toward consensus-based actions that balance invasive plant management and conservation of at-risk fauna. AB - Limiting the spread of invasive plants has become a high priority among natural resource managers. Yet in some regions, invasive plants are providing important habitat components to native animals that are at risk of local or regional extirpation. In these situations, removing invasive plants may decrease short term survival of the at-risk taxa. At the same time, there may be a reluctance to expand invaded habitats to benefit at-risk species because such actions may increase the distribution of invasive plants. Such a dilemma can result in "management paralysis," where no action is taken either to reduce invasive plants or to expand habitats for at-risk species. A pragmatic solution to this dilemma may be to develop an approach that considers site-specific circumstances. We constructed a "discussion tree" as a means of initiating conversations among various stakeholders involved with managing habitats in the northeastern USA to benefit several at-risk taxa, including New England cottontails (Sylvilagus transitionalis). Major components of this approach include recognition that expanding some invaded habitats may be essential to prevent extirpation of at risk species, and the effective control of invasive plants is dependent on knowledge of the status of invasives on managed lands and within the surrounding landscape. By acknowledging that management of invasive plants is a complex issue without a single solution, we may be successful in limiting their spread while still addressing critical habitat needs. PMID- 23982738 TI - Inhibition of SIRT6 in prostate cancer reduces cell viability and increases sensitivity to chemotherapeutics. AB - SIRT6 is an important histone modifying protein that regulates DNA repair, telomere maintenance, energy metabolism, and target gene expression. Recently SIRT6 has been identified as a tumor suppressor and is down-regulated in certain cancer types, but not in other cancers. From deposited gene profiling studies we found that SIRT6 was overexpressed in prostate tumors, compared with normal or paratumor prostate tissues. Tissue micro-array studies confirmed the higher levels of SIRT6 in both prostate tumor tissues and prostate cancer cells than in their normal counterparts. Knockdown of SIRT6 in human prostate cancer cells led to sub-G1 phase arrest of cell cycle, increased apoptosis, elevated DNA damage level and decrease in BCL2 gene expression. Moreover, SIRT6-deficiency reduced cell viability and enhanced chemotherapeutics sensitivity. Taken together, this study provides the first evidence of SIRT6 overexpression in human prostate cancer, and SIRT6 regulation could be exploited for prostate cancer therapy. PMID- 23982739 TI - Genome-wide association studies on prostate cancer: the end or the beginning? AB - Prostate cancer (PCa) is the second most frequently diagnosed malignancy in men. Genome-wide association studies (GWAS) has been highly successful in discovering susceptibility loci for prostate cancer. Currently, more than twenty GWAS have identified more than fifty common variants associated with susceptibility with PCa. Yet with the increase in loci, voices from the scientific society are calling for more. In this review, we summarize current findings, discuss the common problems troubling current studies and shed light upon possible breakthroughs in the future. GWAS is the beginning of something wonderful. Although we are quite near the end of the beginning, post-GWAS studies are just taking off and future studies are needed extensively. It is believed that in the future GWAS information will be helpful to build a comprehensive system intergraded with PCa prevention, diagnosis, molecular classification, personalized therapy. PMID- 23982741 TI - Structural biology study of human TNF receptor associated factor 4 TRAF domain. AB - TRAF4 is a unique member of TRAF family, which is essential for innate immune response, nervous system and other systems. In addition to be an adaptor protein, TRAF4 was identified as a regulator protein in recent studies. We have determined the crystal structure of TRAF domain of TRAF4 (residues 292-466) at 2.60 A resolution by X-ray crystallography method. The trimericly assembled TRAF4 resembles a mushroom shape, containing a super helical "stalk" which is made of three right-handed intertwined alpha helixes and a C-terminal "cap", which is divided at residue L302 as a boundary. Similar to other TRAFs, both intermolecular hydrophobic interaction in super helical "stalk" and hydrogen bonds in "cap" regions contribute directly to the formation of TRAF4 trimer. However, differing from other TRAFs, there is an additional flexible loop (residues 421-426), which contains a previously identified phosphorylated site S426 exposing on the surface. This S426 was reported to be phosphorylated by IKKalpha which is the pre-requisite for TRAF4-NOD2 complex formation and thus to inhibit NOD2-induced NF-kappaB activation. Therefore, the crystal structure of TRAF4-TRAF is valuable for understanding its molecular basis for its special function and provides structural information for further studies. PMID- 23982742 TI - Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes. AB - With defined culture protocol, human embryonic stem cells (hESCs) are able to generate cardiomyocytes in vitro, therefore providing a great model for human heart development, and holding great potential for cardiac disease therapies. In this study, we successfully generated a highly pure population of human cardiomyocytes (hCMs) (>95% cTnT+) from hESC line, which enabled us to identify and characterize an hCM-specific signature, at both the gene expression and DNA methylation levels. Gene functional association network and gene-disease network analyses of these hCM-enriched genes provide new insights into the mechanisms of hCM transcriptional regulation, and stand as an informative and rich resource for investigating cardiac gene functions and disease mechanisms. Moreover, we show that cardiac-structural genes and cardiac-transcription factors have distinct epigenetic mechanisms to regulate their gene expression, providing a better understanding of how the epigenetic machinery coordinates to regulate gene expression in different cell types. PMID- 23982740 TI - The evolving landscape in the therapy of acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of myeloid precursors arrested in their maturation, creating a diverse disease entity with a wide range of responses to historically standard treatment approaches. While significant progress has been made in characterizing and individualizing the disease at diagnosis to optimally inform those affected, progress in treatment to reduce relapse and induce remission has been limited thus far. In addition to a brief summary of the factors that shape prognostication at diagnosis, this review attempts to expand on the current therapies under investigation that have shown promise in treating AML, including hypomethylating agents, gemtuzumab ozogamicin, FLT3 tyrosine kinase inhibitors, antisense oligonucleotides, and other novel therapies, including aurora kinases, mTOR and PI3 kinase inhibitors, PIM kinase inhibitors, HDAC inhibitors, and IDH targeted therapies. With these, and undoubtedly many others in the future, it is the hope that by combining more accurate prognostication with more effective therapies, patients will begin to have a different, and more complete, outlook on their disease that allows for safer and more successful treatment strategies. PMID- 23982743 TI - Osmotin-expressing transgenic tea plants have improved stress tolerance and are of higher quality. AB - Drought is a major stress that affects the yield and quality of tea, a widely consumed beverage crop grown in more than 20 countries of the world. Therefore, osmotin gene-expressing transgenic tea plants produced using earlier optimized conditions were evaluated for their tolerance of drought stress and their quality. Improved tolerance of polyethylene glycol-induced water stress and faster recovery from stress were evident in transgenic lines compared with the normal phenotype. Significant improvements in growth under in-vitro conditions were also observed. Besides enhanced reactive oxygen species-scavenging enzyme activity, the transgenic lines contained significantly higher levels of flavan-3 ols and caffeine, key compounds that govern quality and commercial yield of the beverage. The selected transgenic lines have the potential to meet the demands of the tea industry for stress-tolerant plants with higher yield and quality. These traits of the transgenic lines can be effectively maintained for generations because tea is commercially cultivated through vegetative propagation only. PMID- 23982744 TI - Myoloid-related protein 8, an endogenous ligand of Toll-like receptor 4, is involved in epileptogenesis of mesial temporal lobe epilepsy via activation of the nuclear factor-kappaB pathway in astrocytes. AB - The role of Toll-like receptor 4 (TLR4) in the activation of innate immunity has been extensively studied in the past several years. Here, we are the first to report that myeloid-related protein 8 (MRP8), an endogenous TLR4 ligand, is involved in the epileptogenesis of mesial temporal lobe epilepsy (MTLE). We find that the expression of MRP8, TLR4, and interleukin 1-beta (IL-1beta) was upregulated in a MTLE model during both acute and chronic disease stages. We next investigated the possible roles played by astrocytes, which have been shown to be the major source of IL-1beta during epilepsy. Stimulation via MRP8 led to the induction of IL-1beta in astrocytes in vitro, accompanied by the activation of Nuclear Factor-kappaB, while knockdown of TLR4 or inhibition of NF-kappaB in astrocytes prevented this IL-1beta induction. Thus, MRP8 may potentiate the perpetuation of MTLE by activating the NF-kappaB pathway in astrocytes, and could be a new target for anticonvulsant therapies. PMID- 23982745 TI - Rat cerebellar slice cultures exposed to bilirubin evidence reactive gliosis, excitotoxicity and impaired myelinogenesis that is prevented by AMPA and TNF alpha inhibitors. AB - The cerebellum is one of the most affected brain regions in the course of bilirubin-induced neurological dysfunction. We recently demonstrated that unconjugated bilirubin (UCB) reduces oligodendrocyte progenitor cell (OPC) survival and impairs oligodendrocyte (OL) differentiation and myelination in co cultures of dorsal root ganglia neurons and OL. Here, we used organotypic cerebellar slice cultures, which replicate many aspects of the in vivo system, to dissect myelination defects by UCB in the presence of neuroimmune-related glial cells. Our results demonstrate that treatment of cerebellar slices with UCB reduces the number of myelinated fibres and myelin basic protein mRNA expression. Interestingly, UCB addition to slices increased the percentage of OPC and decreased mature OL content, whereas it decreased Olig1 and increased Olig2 mRNA expression. These UCB effects were associated with enhanced gliosis, revealed by an increased burden of both microglia and astrocytes. Additionally, UCB treatment led to a marked increase of tumor necrosis factor (TNF)-alpha and glutamate release, in parallel with a decrease of interleukin (IL)-6. No changes were observed relatively to IL-1beta and S100B secretion. Curiously, both alpha-amino 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist and TNF alpha antibody partially prevented the myelination defects that followed UCB exposure. These data point to a detrimental role of UCB in OL maturation and myelination together with astrocytosis, microgliosis, and both inflammatory and excitotoxic responses, which collectively may account for myelin deficits following moderate to severe neonatal jaundice. PMID- 23982747 TI - CD33 in Alzheimer's disease. AB - The amyloid-beta peptide (Abeta) cascade hypothesis posits that Abeta accumulation is the fundamental initiator of Alzheimer's disease (AD), and mounting evidence suggests that impaired Abeta clearance rather than its overproduction is the major pathogenic event for AD. Recent genetic studies have identified cluster of differentiation 33 (CD33) as a strong genetic locus linked to AD. As a type I transmembrane protein, CD33 belongs to the sialic acid-binding immunoglobulin-like lectins, mediating the cell-cell interaction and inhibiting normal functions of immune cells. In the brain, CD33 is mainly expressed on microglial cells. The level of CD33 was found to be increased in the AD brain, which positively correlated with amyloid plaque burden and disease severity. More importantly, CD33 led to the impairment of microglia-mediated clearance of Abeta, which resulted in the formation of amyloid plaques in the brain. In this article, we review the recent epidemiological findings of CD33 that related with AD and discuss the levels and pathogenic roles of CD33 in this disease. Based on the contributing effects of CD33 in AD pathogenesis, targeting CD33 may provide new opportunities for AD therapeutic strategies. PMID- 23982748 TI - Therapeutic effect of transplanted human Wharton's jelly stem cell-derived oligodendrocyte progenitor cells (hWJ-MSC-derived OPCs) in an animal model of multiple sclerosis. AB - Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). A potential new therapeutic approach for MS is cell transplantation which may promote remyelination. We transplanted human Wharton's jelly stem cell-derived oligodendrocyte progenitor cells (hWJ-MSC-derived OPCs) into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE), the animal model of MS. We studied the effect of the transplanted OPCs on the functional and pathological manifestations of the disease. Transplanted hWJ-MSC-derived OPCs significantly reduced the clinical signs of EAE. Histological examinations showed that remyelination was significantly increased after transplantation. These results suggest that hWJ-MSC derived OPCs promote the regeneration of myelin sheaths in the brain. PMID- 23982749 TI - In vivo targeting of activated leukocytes by a beta2-integrin binding peptide. AB - BACKGROUND: In immunopathological conditions, clinical diagnosis is commonly made on the basis of patient symptoms, measurement of blood leukocyte levels or proinflammatory biomarkers, non-specific radiological findings and, regarding infection, microbiological analysis. Nevertheless, frequently the exact spatial location of inflammation or even infection cannot be reliably identified, despite the use of up-to-date clinical, laboratory and imaging techniques. For this reason, new tools are warranted for use in advanced diagnosis and therapy targeting in patients. OBJECTIVE: The peptide CPCFLLGCC (LLG), known to bind activated beta2-integrins in vitro, was fused with green fluorescent protein (GFP) to test the ability of LLG fusions to target and bind activated leukocytes in vivo. METHODS: A murine skin scratch inflammation model was chosen for the convenient non-surgical detection of GFP. RESULTS: The murine skin lesion inflammation model demonstrated in vivo targeting of LLG-GFP to sites of inflammation. Targeting by LLG-GFP fusion construct depends on the ability of the LLG-moiety to bind activated leukocytes. Control construct unable to bind beta2 integrins appeared biologically inert. CONCLUSION: The data support the possibility of using this fluorescently labeled peptide as a tool for both the detection of and targeting to inflammatory sites characterized by robust leukocyte activation. PMID- 23982750 TI - Serum miR-200c is a novel prognostic and metastasis-predictive biomarker in patients with colorectal cancer. AB - OBJECTIVE: To evaluate the ability of epithelial-to-mesenchymal transition related microRNAs (miRNAs) as serum biomarkers for prognosis and prediction of metastasis in patients with colorectal cancer (CRC). BACKGROUND: Epithelial-to mesenchymal transition-related miRNAs drive CRC progression and metastasis. However, their potential as serum biomarkers in CRC has not been studied. METHODS: This was a 3-phase study using 446 colorectal specimens. In the first phase, we selected candidate miRNAs associated with metastasis by analyzing the expression of 4 miR-200 family members (miR-200b, -200c, -141, and -429) in serum samples from 12 patients with stage I and IV CRC. The second phase involved independent validation of candidate miRNAs in serum from 182 patients with CRC and 24 controls. Finally, we analyzed expression in matched 156 tumor tissues from 182 patients with CRC and an independent set of 20 matched primary CRC and corresponding liver metastases to identify the source of circulating miRNAs. RESULTS: After initial screening, miR-200c was selected as the candidate serum miRNA best associated with metastasis. Validation analysis revealed that serum miR-200c levels were significantly higher in stage IV than in stage I-III CRCs. High serum miR-200c demonstrated a significant positive correlation with lymph node metastasis, distant metastasis, and prognosis (P = 0.0026, P = 0.0023, and P = 0.0064, respectively). More importantly, serum miR-200c was an independent predictor for lymph node metastasis (odds ratio: 4.81, 95% confidence interval: 1.98-11.7, P = 0.0005) and tumor recurrence (hazard ratio: 4.51, 95% confidence interval: 1.56-13.01, P = 0.005) and emerged as an independent prognostic marker for CRC (hazard ratio: 2.67, 95% confidence interval: 1.28-5.67, P = 0.01). CONCLUSIONS: Serum miR-200c has strong potential to serve as a noninvasive biomarker for CRC prognosis and predicting metastasis. PMID- 23982751 TI - DNA double-strand breaks: linking gene expression to chromosome morphology and mobility. AB - Ionizing radiation can lead to DNA double-strand breaks (DSBs) which belong to the most dangerous forms of damage to the DNA. Cells possess elaborate repair mechanisms and react in a complex manner to the emergence of DSBs. Experiments have shown that gene expression levels in irradiated cells are changed, and thousands of radiation-responsive genes have been identified. On the other hand, recent studies have shown that gene expression is tightly connected to the three dimensional organization of the genome. In this work, we analyzed the chromatin organization in the cell nuclei before and after exposure to ionizing radiation with an expression-dependent folding model. Our results indicate that the alteration of the chromosome organization on the scale of a complete chromosome is rather limited despite the expression level change of a large number of genes. We further modelled breaks within sub-compartments of the model chromosomes and showed that entropic changes caused by a break lead to increased mobility of the break sites and help to locate break ends further to the periphery of the sub compartments. We conclude that the changes in the chromatin structure after irradiation are limited to local scales and demonstrate the importance of entropy for the behaviour of break ends. PMID- 23982752 TI - Reactivation of X chromosome upon reprogramming leads to changes in the replication pattern and 5hmC accumulation. AB - Once set, the inactive status of the X chromosome in female somatic cells is preserved throughout subsequent cell divisions. The inactive status of the X chromosome is characterized by many features, including late replication. In contrast to induced pluripotent stem cells (iPSCs) in mice, the X chromosome in human female iPSCs usually remains inactive after reprogramming of somatic cells to the pluripotent state, although recent studies point to the possibility of reactivation of the X chromosome. Here, we demonstrated that, during reprogramming, the inactive X chromosome switches from late to synchronous replication, with restoration of the transcription of previously silenced genes. This process is accompanied by accumulation of a new epigenetic mark or intermediate of the DNA demethylation pathway, 5-hydroxymethylcytosine (5hmC), on the activated X chromosome. Our results indicate that the active status of the X chromosome is better confirmed by early replication and the reappearance of 5hmC, rather than by appearance of histone marks of active chromatin, removal of histone marks of inactive chromatin, or an absence of XIST coating. PMID- 23982746 TI - Receptor tyrosine kinase (RTK) signalling in the control of neural stem and progenitor cell (NSPC) development. AB - Important developmental responses are elicited in neural stem and progenitor cells (NSPC) by activation of the receptor tyrosine kinases (RTK), including the fibroblast growth factor receptors, epidermal growth factor receptor, platelet derived growth factor receptors and insulin-like growth factor receptor (IGF1R). Signalling through these RTK is necessary and sufficient for driving a number of developmental processes in the central nervous system. Within each of the four RTK families discussed here, receptors are activated by sets of ligands that do not cross-activate receptors of the other three families, and therefore, their activation can be independently regulated by ligand availability. These RTK pathways converge on a conserved core of signalling molecules, but differences between the receptors in utilisation of signalling molecules and molecular adaptors for intracellular signal propagation become increasingly apparent. Intracellular inhibitors of RTK signalling are widely involved in the regulation of developmental signalling in NSPC and often determine developmental outcomes of RTK activation. In addition, cellular responses of NSPC to the activation of a given RTK may be significantly modulated by signal strength. Cellular propensity to respond also plays a role in developmental outcomes of RTK signalling. In combination, these mechanisms regulate the balance between NSPC maintenance and differentiation during development and in adulthood. Attribution of particular developmental responses of NSPC to specific pathways of RTK signalling becomes increasingly elucidated. Co-activation of several RTK in developing NSPC is common, and analysis of co-operation between their signalling pathways may advance knowledge of RTK role in NSPC development. PMID- 23982753 TI - Long-term incubation with mifepristone (MLTI) increases the spine density in developing Purkinje cells: new insights into progesterone receptor mechanisms. AB - Cerebellar Purkinje cells (PC) physiologically reveal an age-dependent expression of progesterone with high endogenous concentrations during the neonatal period. Even if progesterone has been previously shown to induce spinogenesis, dendritogenesis and synaptogenesis in immature PC, data about the effects of progesterone on mature PC are missing, even though they could be of significant therapeutic interest. The current study demonstrates for the first time a progesterone effect, depending on the developmental age of PC. Comparable with the physiological course of the progesterone concentration, experimental treatment with progesterone for 24 h achieves the highest effects on the dendritic tree during the early neonate, inducing an highly significant increase in dendritic length, spine number and spine area, while spine density in mature PC could not be further stimulated by progesterone incubation. Observed progesterone effects are certainly mediated by classical progesterone receptors, as spine area and number were comparable to controls when progesterone incubation was combined with mifepristone (incubation for 24 h), an antagonist of progesterone receptors A and B (PR-A/PR-B). In contrast, an increase in the spine number and area of both immature and mature PC was detected when slice cultures were incubated with mifepristone for more than 72 h (mifepristone long-time incubation, MLTI). By including time-lapse microscopy, electron microscopic techniques, PCR, western blot, and MALDI IMS receptor analysis, as well as specific antagonists like trilostane and AG 205, we were able to detect the underlying mechanism of this diverging mifepristone effect. Thus, our results provide new insights into the function and signaling mechanisms of the recently described progesterone receptor membrane component 1 (PGRMC1) in PC. It is highly suitable that progesterone does not just induce effects by the well-known genomic mechanisms of the classical progesterone receptors but also acts through PGRMC1 mediated non-genomic mechanisms. Thus, our results provide first proofs for a previously discussed progesterone-dependent induction of neurosteroidogenesis in PC by interaction with PGRMC1. But while genomic progesterone effects mediated through classical PR-A and PR-B seem to be restricted to the neonatal period of PC, PGRMC1 also transmits signals by non-genomic mechanisms like regulation of the neurosteroidogenesis in mature PC. Thus, PGRMC1 might be an interesting target for future clinical studies and therapeutic interventions. PMID- 23982754 TI - Celiac disease patient IgA antibodies induce endothelial adhesion and cell polarization defects via extracellular transglutaminase 2. AB - We have recently found that celiac disease patient serum-derived autoantibodies targeted against transglutaminase 2 interfere with several steps of angiogenesis, including endothelial sprouting and migration, though the mechanism involved remained to be fully characterized. This study now investigated the processes underlying the antiangiogenic effects exerted by celiac disease patient antibodies on endothelial cells, with particular regard to the adhesion, migration, and polarization signaling pathway. We observed that celiac IgA reduced endothelial cell numbers by affecting adhesion without increasing apoptosis. Endothelial cells in the presence of celiac IgA showed weak attachment, a high susceptibility to detach from fibronectin, and a disorganized extracellular matrix due to a reduction of protein cross-links. Furthermore, celiac patient IgA led to secretion of active transglutaminase 2 from endothelial cells into the culture supernatants. Additionally, cell surface transglutaminase 2 mediated integrin clustering in the presence of celiac IgA was coupled to augmented expression of beta1-integrin. We also observed that celiac patient IgA treated endothelial cells had migratory defects and a less polarized phenotype when compared to control groups, and this was associated with the RhoA signaling pathway. These biological effects mediated by celiac IgA on endothelial cells were partially influenced but not completely abolished by R281, an irreversible extracellular transglutaminase 2 enzymatic activity inhibitor. Taken together, our results imply that celiac patient IgA antibodies disturb the extracellular protein cross-linking function of transglutaminase 2, thus altering cell extracellular matrix interactions and thereby affecting endothelial cell adhesion, polarization, and motility. PMID- 23982755 TI - The anti-tumor drug bleomycin preferentially cleaves at the transcription start sites of actively transcribed genes in human cells. AB - The genome-wide pattern of DNA cleavage at transcription start sites (TSSs) for the anti-tumor drug bleomycin was examined in human HeLa cells using next generation DNA sequencing. It was found that actively transcribed genes were preferentially cleaved compared with non-transcribed genes. The 143,600 identified human TSSs were split into non-transcribed genes (82,596) and transcribed genes (61,004) for HeLa cells. These transcribed genes were further split into quintiles of 12,201 genes comprising the top 20, 20-40, 40-60, 60-80, and 80-100 % of expressed genes. The bleomycin cleavage pattern at highly transcribed gene TSSs was greatly enhanced compared with purified DNA and non transcribed gene TSSs. The top 20 and 20-40 % quintiles had a very similar enhanced cleavage pattern, the 40-60 % quintile was intermediate, while the 60-80 and 80-100 % quintiles were close to the non-transcribed and purified DNA profiles. The pattern of bleomycin enhanced cleavage had peaks that were approximately 200 bp apart, and this indicated that bleomycin was identifying the presence of phased nucleosomes at TSSs. Hence bleomycin can be utilized to detect chromatin structures that are present at actively transcribed genes. In this study, for the first time, the pattern of DNA damage by a clinically utilized cancer chemotherapeutic agent was performed on a human genome-wide scale at the nucleotide level. PMID- 23982757 TI - Deciphering the global organization of clustering in real complex networks. AB - We uncover the global organization of clustering in real complex networks. To this end, we ask whether triangles in real networks organize as in maximally random graphs with given degree and clustering distributions, or as in maximally ordered graph models where triangles are forced into modules. The answer comes by way of exploring m-core landscapes, where the m-core is defined, akin to the k core, as the maximal subgraph with edges participating in at least m triangles. This property defines a set of nested subgraphs that, contrarily to k-cores, is able to distinguish between hierarchical and modular architectures. We find that the clustering organization in real networks is neither completely random nor ordered although, surprisingly, it is more random than modular. This supports the idea that the structure of real networks may in fact be the outcome of self organized processes based on local optimization rules, in contrast to global optimization principles. PMID- 23982756 TI - Cytokine functions of TIMP-1. AB - The tissue inhibitors of metalloproteinases (TIMPs) are well recognized for their role in extracellular matrix remodeling by controlling the activity of matrix metalloproteinases (MMPs). Independent of MMP inhibition, TIMPs act as signaling molecules with cytokine-like activities thereby influencing various biological processes including cell growth, apoptosis, differentiation, angiogenesis, and oncogenesis. Recent studies on TIMP-1's cytokine functions have identified complex regulatory networks involving a specific surface receptor and subsequent signaling pathways including miRNA-mediated posttranscriptional regulation of gene expression that ultimately control the fate and behavior of the cells. The present review summarizes the current knowledge on TIMP-1 as a cytokine modulator of cell functions, outlines recent progress in defining molecular pathways that transmit TIMP-1 signals from the cell periphery into the nucleus, and discusses TIMP-1's role as a cytokine in the pathophysiology of cancer and other human diseases. PMID- 23982758 TI - Biomechanical analysis of the tibial tray design in TKA: comparison between modular and offset tibial trays. AB - PURPOSE: The aim of this work was to develop a computational biomechanical study to compare the performance of tibial trays with different offsets for a total knee arthroplasty. The goal was to investigate whether the offset tibial tray shifts the bone stress distribution, influencing the clinical outcome. METHODS: Three geometric models were developed for the intact tibia bone: one considering a standard tibia case and the other two reproducing tibias with a medial or a lateral offset of the metaphysis. Appropriate prosthetic components were assembled in the bone for the aforementioned cases. The finite element method was used to obtain the mechanical stress distribution for the models, and the stress shielding effect due to the prosthesis was analysed. RESULTS: The obtained results revealed that the offset cases are subjected to higher stresses than the standard case. These values can be two times superior to the ones verified in a standard case. The stress shielding effect was confirmed along all the analysed paths, except near the stem's end in some areas. CONCLUSION: The higher stresses registered can originate lower clinical outcomes in the offset cases. These findings can be an important beginning to understand whether better bone stress distribution could be achieved in deformity correction with associated osteotomies instead of offsetting. PMID- 23982759 TI - Intra-articular remodelling of hamstring tendon grafts after anterior cruciate ligament reconstruction. AB - PURPOSE: A summary is provided on the existing knowledge about the specific healing phases of the intra-articular hamstring tendon graft used for ACL reconstruction. Differences between human and animal in vivo studies are explained, and implications for the postoperative time period are laid out. METHODS: A systematic review of the existing literature was performed on the topic of tendon remodelling of hamstring grafts in ACL reconstruction using Medline database. Publications between 1982 and 2012 were included. Special focus was directed on in vivo human and animal studies analysing intra-articular free tendon graft remodelling. RESULTS: Animal and human in vitro and vivo researches have demonstrated three characteristic stages of graft healing after ACL reconstruction: an early graft healing phase with central graft necrosis and hypocellularity and no detectable revascularization of the graft tissue, followed by a phase of proliferation, the time of most intensive remodelling and revascularization and finally, a ligamentization phase with characteristic restructuring of the graft towards the properties of the intact ACL. However, a full restoration of either the biological or biomechanical properties of the intact ACL is not achieved. CONCLUSION: Significant knowledge on human cruciate ligament remodelling has been added in the understanding of the processes during the course of graft healing. Most importantly, the remodelling process in humans is prolonged compared to animal studies. While today's rehabilitation protocols are often extrapolated from findings of animal in vivo healing studies, current findings of human in vivo healing studies might require new post-operative regimens following hamstring ACL reconstruction. PMID- 23982762 TI - Elusive 2-aminofuran Diels-Alder substrates for a straightforward synthesis of polysubstituted anilines. AB - The first multicomponent coupling of isocyanides, alpha,beta-unsaturated carbonylic compounds and dienophiles, based on the trapping of unstable intermediate 2-aminofurans, is described. This novel tandem [4 + 1]-[4 + 2] cycloaddition is efficiently catalysed by yttrium triflate and constitutes an operationally simple and highly convergent approach to a variety of polysubstituted anilines. Moreover, this methodology permits the use of tert butylisocyanide as a convertible isocyanide to yield directly N-unprotected anilines in the same pot. PMID- 23982761 TI - Deletion of the transforming growth factor beta receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. AB - OBJECTIVE: While transforming growth factor beta (TGFbeta) signaling plays a critical role in chondrocyte metabolism, the TGFbeta signaling pathways and target genes involved in cartilage homeostasis and the development of osteoarthritis (OA) remain unclear. Using an in vitro cell culture method and an in vivo mouse genetic approach, we undertook this study to investigate TGFbeta signaling in chondrocytes and to determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFbeta signaling. METHODS: TGFbeta receptor type II (TGFbetaRII)-conditional knockout (KO) (TGFbetaRII(Col2ER)) mice were generated by breeding TGFbetaRII(flox/flox) mice with Col2-CreER-transgenic mice. Histologic, histomorphometric, and gene expression analyses were performed. In vitro TGFbeta signaling studies were performed using chondrogenic rat chondrosarcoma cells. To determine whether Mmp13 and Adamts5 are critical downstream target genes of TGFbeta signaling, TGFbetaRII/matrix metalloproteinase 13 (MMP-13)- and TGFbetaRII/ADAMTS-5-double-KO mice were generated and analyzed. RESULTS: Inhibition of TGFbeta signaling (deletion of the Tgfbr2 gene in chondrocytes) resulted in up-regulation of Runx2, Mmp13, and Adamts5 expression in articular cartilage tissue and progressive OA development in TGFbetaRII(Col2ER) mice. Deletion of the Mmp13 or Adamts5 gene significantly ameliorated the OA-like phenotype induced by the loss of TGFbeta signaling. Treatment of TGFbetaRII(Col2ER) mice with an MMP-13 inhibitor also slowed OA progression. CONCLUSION: Mmp13 and Adamts5 are critical downstream target genes involved in the TGFbeta signaling pathway during the development of OA. PMID- 23982763 TI - Does a diagnosis of myelogenous leukemia require 20% marrow myeloblasts, and does <5% marrow myeloblasts represent a remission? The history and ambiguity of arbitrary diagnostic boundaries in the understanding of myelodysplasia. PMID- 23982764 TI - Abnormal hypermethylation of promoter region downregulates chemokine CXC ligand 14 expression in gastric cancer. AB - CXCL14, a new member of the CXC subfamily of chemokines, is differentially expressed in several types of tumors. The expression of CXCL14 and its clinical significance in gastric cancer are unclear to date. In this study, the expression of CXCL14 was detected by quantitative PCR and immunohistochemistry assay. DNA methylation was analyzed by bisulfite sequencing PCR. Student's t-test and Kruskal-Wallis H test were used to evaluate the differences of the CXCL14 expression between the groups. Kaplan-Meier survival curve and Cox regression model were used to evaluate the clinical significance of CXCL14 expression in gastric cancer. Data indicated that the levels of CXCL14 mRNA declined (P<0.001) in gastric carcinoma tissues compared to the paired normal tissues. Immunohistochemical analysis also showed the decrease of CXCL14 protein in the tumor tissue (P<0.001). Analysis of CpG islands methylation in CXCL14 promoter region and first exon area indicated that the abnormal hypermethylation of promoter region in tumor tissue is one of the mechanisms causing the reduction. When gastric cancer cells were demethylated with 5-Aza-2'-deoxycytidine, CXCL14 expression was restored. Downregulation of CXCL14 was associated with the depth of penetration (P<0.001) and positively correlated with prognosis in stage III/IV (P=0.046). In conclusion, it is possible that CXCL14 is involved in the development and progression of gastric cancer. Hypermethylation in the promoter is one of the reasons that CXCL14 has lower expression in gastric adenocarcinoma tissues. The level of CXCL14 expression may be a valuable adjuvant parameter in predicting the prognosis of gastric cancer patients and, thus, a potential therapeutic target. PMID- 23982766 TI - A randomised single-blind study to improve health-related quality of life by treating anaemia of chronic kidney disease with Aranesp(r) (darbepoetin alfa) in older people: STIMULATE. AB - BACKGROUND: The prevalence of chronic kidney disease (CKD) increases with age, and the risk of significant anaemia increases as renal function declines. The objectives of this study were to assess the effect of darbepoetin alfa administration on health-related quality of life (HRQOL) through treatment for anaemia in older patients with CKD. METHODS: In this multicentre, randomised, placebo-controlled trial, older patients (aged >= 70 years) with CKD (Stages 3-5, predialysis) and haemoglobin (Hb) < 11.0 g/dL were randomised to darbepoetin alfa (n = 28) or placebo (n = 23). HRQOL was measured using a number of instruments including Short Form-36 (SF-36) and Functional Assessment of Cancer Therapy Anaemia (FACT-An). RESULTS: The primary endpoint, mean SF-36 Vitality Score at Week 24, was comparable between the darbepoetin alfa (51.4 [95 % CI 48.0, 54.9]) and placebo (46.7 [40.9, 52.5]) groups. Darbepoetin alfa-treated patients experienced statistically significant improvements in some SF-36 and FACT-An Subscale Scores. Mean Hb was higher with darbepoetin alfa (12.5 [12.1, 12.9] g/dL) than with placebo (10.5 [10.1, 11.0] g/dL). The safety profiles were comparable between the treatment groups. The study was limited by only 20 % of the planned patient recruitment being achieved. CONCLUSIONS: Darbepoetin alfa increased Hb and, within study limitations, suggested that improvements in some HRQOL domains in older CKD patients with anaemia may be achieved with more physiological haemoglobin. PMID- 23982767 TI - Urinary brain-derived neurotrophic factor: a potential biomarker for objective diagnosis of overactive bladder. AB - PURPOSE: To investigate the diagnostic performance of urinary brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) as potential biomarkers for overactive bladder (OAB). METHODS: Ninety women diagnosed with OAB and 45 normal controls without OAB were enrolled. Urine samples were collected from all subjects. Urinary BDNF and NGF levels were measured using enzyme-linked immunosorbent assays. Results normalized by urinary creatinine (Cr) levels were compared between OAB groups and controls. Symptom severity was assessed using overactive bladder symptom score. RESULTS: Urinary BDNF and NGF levels were elevated in OAB groups but not in controls. Mean (SD) baseline BDNF and NGF levels normalized by Cr levels were significantly higher in OAB subjects than in controls (20.609 +/- 23.932 vs. 1.779 +/- 0.729, p < 0.01) and (0.258 +/- 0.264 vs. 0.081 +/- 0.028, p < 0.01), respectively. Urinary BDNF/Cr levels were 80-fold higher than NGF/Cr levels in OAB subjects. Receiver operating characteristic curves for assessing urinary BDNF/Cr levels in OAB groups showed sensitivity and specificity of 93.33 and 88.89 %, respectively. Urinary BDNF levels were associated with OAB symptom severity. CONCLUSIONS: Urinary BDNF/Cr levels are elevated in women with OAB and are significantly associated with symptom severity. No elevation of BDNF is found in women without OAB. BDNF analysis has better sensitivity than NGF in detecting OAB in subjects without other lower urinary tract disorders. Results of the present study suggest a potential role for BDNF as an objective biomarker for OAB diagnosis. PMID- 23982768 TI - Surgical recurrence after primary ileocolic resection for Crohn's disease. AB - BACKGROUND: The current study was conducted to assess long-term outcomes after primary ileocolic resection for Crohn's disease (CD) and to identify factors associated with surgical relapse in the era of immunosuppressive medications. METHODS: Data were collected retrospectively on 116 consecutive patients, who underwent primary ileocolic resection for CD at a tertiary referral center between 1997 and 2006. Medical records were reviewed, and the use of immunomodulators was noted. The cumulative probability for a second operation due to recurrent CD was described by Kaplan-Meier curves. RESULTS: Ten patients (8.6 %) developed surgical recurrence after a mean follow-up period of 8.1 (+/-2.6) years. The percentage of patients not requiring further surgery was 96.5% and 88.0 % at 5 and 10 years, respectively. An urgent indication for surgery was significantly associated with the necessity of repeated intestinal resection (hazard ratio 5.6, 95 % confidence interval 1.2-27.0, p = 0.0145). In addition, postoperative exposure to azathioprine/6-mercaptopurine for more than 3 months decreased the probability of surgical recurrence significantly (hazard ratio 2.5, 95 % confidence interval 0.6-9.9, p = 0.0349). CONCLUSIONS: In contrast to previous studies, we observed a significant low surgical recurrence rate after primary ileocolic resection. Additionally, maintenance treatment with azathioprine/6-mercaptopurine after surgery may reduce the necessity for repeat surgical intervention. PMID- 23982769 TI - Autologous fat grafting in the treatment of a rectourethroperineal fistula. PMID- 23982770 TI - The Parental Cancer Questionnaire: scale structure, reliability, and validity. AB - PURPOSE: This study aims to determine the principal component structure of the Parental Cancer Questionnaire (PCQ) in a sample of adult children whose parents had cancer and to illustrate the validity and reliability of subscales. METHOD: The PCQ was administered to 311 adult children of parents with cancer along with the Posttraumatic Growth Inventory, Carer's Assessment of Difficulties Scale, Carer's Assessment of Satisfactions Scale, Reaction to Diagnosis of Cancer Questionnaire, and the Grief Diagnostic Instrument. RESULTS: Exploratory Principal Components Analysis identified three dimensions of the parental cancer experience (explaining 51 % of the variance amongst scale items). The components were parental cancer benefits (e.g. 'I became closer to my sick parent during his/her cancer.'), emotional experiences (e.g. 'I was devastated by my parent's cancer.'), and caregiver strain (e.g. 'I feel/felt there was nobody to assist or support me in caring for my parent.'). Convergent and discriminant validity were demonstrated by meaningful correlations with other related measures (ranging from 0.14 to 0.68), and strong internal reliability was shown with Cronbach alpha between 0.87 and 0.91. CONCLUSIONS: The PCQ has a clear three-component structure and demonstrates good reliability. The measure has excellent face, content, convergent, and discriminant validity, indicating a structure suitable for use in future research. The measure appears to be a useful measure of the experience of parental cancer for adult children. PMID- 23982771 TI - Support needs of Chinese immigrant cancer patients. AB - PURPOSE: To enable better psychosocial, informational, and practical support of Chinese patients with cancer, this study was conducted to identify the specific support needs of Chinese immigrant cancer patients. METHODS: The Cancer Portal Project at Memorial Sloan-Kettering Cancer Center's Center for Immigrant Health and Cancer Disparities is a patient navigation program that assists underserved and minority cancer patients in obtaining social and economic assistance at ten New York City cancer clinics. This need assessment was conducted as part of the Portal Project. Sixty-four questions were added to the existing Portal Intake Form about the needs and preferences for Chinese-language support and survivorship services. Descriptive analysis was performed, as well as an exploratory principal component's factor analysis to determine if there were any patterns in the services and programs in which patients were interested. RESULTS: Ninety-six patients were approached for participation; 59 agreed to participate. Eighty-eight percent of participants were born in China. Ninety-seven percent preferred to speak Mandarin, Cantonese, or Fujianese in the healthcare setting. When asked about general interest in support programs, 53 % of the participants were "very interested," 27 % were "maybe interested," and 17 % were "not interested." Programs in which more participants were "very interested" included those that would provide information about obtaining financial assistance (79 %) and social assistance (74 %), information on treatment options (67 %), help in coping with the burden of illness on the family (65 %), and information about general healthcare (63 %). The factor analysis resulted in the identification of five factors: social/financial/treatment and care issues, nutrition and exercise/networking/general health care, coping with fear and stress, herbs and dietary supplements, and acupuncture and acupressure. CONCLUSION: In this study, 80 % of the participants expressed interest in programs tailored for Chinese cancer patients. The most frequently preferred topics for potential services were information-based. Findings provide a foundation for future research and the development of culturally and linguistically targeted support programs and interventions for this unique population. PMID- 23982773 TI - Situation analysis and issues in management of biomedical waste in select small health care facilities in a ward under Bruhat Bengaluru Mahanagara Palike, Bangalore, India. AB - Smaller health care facilities especially clinics though believed to generate lesser quantum/categories of medical waste, the number of clinics/small health care settings are considerable. The movement to manage biomedical waste in a safe and scientific manner has gathered momentum among the medium and large hospitals in Bangalore, but there has been a little understanding and focus on the smaller health care facilities/clinics in this aspect. It is important to gather evidence regarding the current situation of bio-medical waste (BMW) management and issues in smaller health care settings, so as to expand the safe management to all points of generation in Bangalore and will also help to plan relevant interventional strategies for the same. Hence an exploratory study was conducted to assess the current situation and issues in management of BMW among small health care facilities (sHCF). This cross sectional study was conducted in T. Dasarahalli (ward number 15) under Bruhat Bengaluru Mahanagar Palike (BBMP) of Bangalore. Data was collected from a convenient sample of 35 nursing homes (<50 beds) and clinics in December 2011. The results of this study indicate that 3 (20 %) of nursing homes had a Policy for Health Care Waste Management, though committees for Infection control and Hospital waste management were absent. Recording system like injury and waste management registers were non-existent. In our study the Common Bio-medical Waste Treatment Facility operator collected waste from 28 (80 %) of the sHCF. Segregation at the point of generation was present in 22 (62.9 %) of the sHCF. Segregation process was compliant as per BMW rules 1998 among 5 (16.1 %) of the sHCF. 18 sHCF workers were vaccinated with hepatitis B and tetanus. Deficiencies were observed in areas of containment, sharps management and disinfection. It was observed that though the quantum and category of waste generated was limited there exist deficiencies which warrant initiation of system development measures including capacity building. PMID- 23982772 TI - Colorectal cancer screening among Korean Americans: a systematic review. AB - The incidence of colorectal cancer (CRC) among Korean Americans (KAs) has increased in recent years, even as the rate in nearly ever other population group in the United States has decreased. Reversing this trend will require improving screening rates, but a variety of sociocultural factors may inhibit this goal. We conducted a systematic review of the published literature on cancer screening among KAs, and identified thirteen eligible studies that examined CRC screening. KAs have CRC screening rates that are significantly lower than the national average. Only about one in four KAs ages 50 and older reports having ever had a fecal ocult blood test (FOBT) and only about 40 % have ever had a sigmoidoscopy or colonoscopy. KA adults are also significantly less likely than the general US population to say they have heard of FOBT, sigmoidoscopy, or colonoscopy. In the KA population, screening rates are higher among adults with higher socioeconomic status, greater acculturation to the United States, more cancer knowledge, more social support, and better access to healthcare services. Improving cultural and financial access to health education and healthcare services may increase CRC screening among KAs and reduce the incidence of the disease. PMID- 23982774 TI - Proteomic analysis of the differences in orbital protein expression in thyroid orbitopathy. AB - BACKGROUND: Thyroid orbitopathy (TO) is a multi-system inflammatory disease characterized by orbital congestion, ocular surface disorders, restrictive myopathy, and skin lesions. The molecular and cellular processes of pathogenic formation of TO orbital fat tissues are not fully understood. In this study, a comparative proteomic analysis was conducted to investigate the importance of some differential proteins of orbital fat tissues in TO. METHODS: The differential proteins were analyzed by comparing the two-dimensional gel electrophoresis (2-DE) maps of the orbital fat tissues of TO with those of normal orbital fat tissues. The 2-DE results were further verified by Western blot and immunohistochemistry. RESULTS: Fifteen up-regulated and two down-regulated proteins in TO orbital fat tissues in comparison with the control were exhibited by 2-DE maps. The over-expressed proteins including guanine nucleotide-binding protein, isocitrate dehydrogenase (IDH), annexin A2, heat shock protein 60 (HSP 60), calreticulin (CALR), protein disulfide-isomerase A3 (PDIA3), spectrin, superoxide dismutase (SOD), and transitional endoplasmic reticulum ATPase (TER ATPase) may contribute to increased thyroid-stimulating hormone receptor (TSHR) expression and cell proliferation. The proteomic data of specific proteins are consistent with those determined by Western blot and immunohistochemistry. CONCLUSIONS: Comparison of orbital fat proteins from thyroid orbitopathy with age matched controls shows significant differences in the proteome, and up regulations of the specific proteins in orbital fat tissues from TO are associated with biochemical mechanisms or capacities against endoplasmic reticulum stress, mitochondria dysfunction, and cell proliferation as well as apoptosis in TO orbital fat tissues. PMID- 23982775 TI - Unilateral intravitreal dexamethazone implant for bilateral retinitis pigmentosa related macular edema. PMID- 23982776 TI - Prognostic impact of positive surgical margins after resection of colorectal cancer liver metastases: reappraisal in the era of modern chemotherapy. AB - BACKGROUND: The purpose of the present study was to assess the prognostic impact of positive surgical margins (R1) after liver resection (LR) of colorectal liver metastases (CRLM) in the era of modern chemotherapy regimens. R1 resection is a negative prognostic factor after LR of CRLM. The significance of R1 margins in the era of effective chemotherapy is unknown. METHODS: From January 2000 to December 2009, 215 patients (177 men: 62 %; median age 60 years; range 30-84 years) underwent LR of CRLM. The LR was considered R1 (margin <1 mm) in 49 patients (23 %) and R0 in 166 patients (77 %). Overall, 108 (50 %) patients received preoperative chemotherapy and 156 (72 %) patients received postoperative chemotherapy. RESULTS: With a median follow-up of 36 months (range 1-141 months), the 5-year overall survival (OS) rate (47 vs 40 %; p = 0.05) and the disease-free survival (DFS) rate (36 vs 23 %; p = 0.006) were significantly lower in the R1 group. Recurrence developed in 152 patients (71 %) and the rate of recurrence was significantly higher (84 vs 67 %; p = 0.02) in the R1 group. On multivariate analysis, N+ status of the colorectal primary tumor (p = 0.008), presence of radiologically occult disease (p = 0.04), and R1 resection (p = 0.03) were independent adverse predictors of OS. The N+ status of the primary tumor (p = 0.003) and R1 resection (p = 0.02) were independent adverse predictors of DFS. On multivariate analysis use of postoperative chemotherapy was the only independent predictor of improved DFS (p = 0.02) in the R1 group. CONCLUSIONS: A positive resection margin remains a significant poor prognostic factor after LR of CRLM in the era of modern chemotherapy. Postoperative chemotherapy reduces recurrence rates after R1 resection of CRLM. PMID- 23982777 TI - Hepatic artery reconstruction in living donor liver transplantation: risk factor analysis of complication and a role of MDCT scan for detecting anastomotic stricture. AB - BACKGROUND: In partial liver transplantation, reconstruction of the hepatic artery is technically highly demanding and the incidence of arterial complications is high. We attempted to identify the risk factors for anastomotic complications after hepatic artery reconstruction and examined the role of multidetector-row computed tomography (MDCT) in the evaluation of the reconstructed hepatic artery in liver transplant recipients. METHODS: A total of 109 adult-to-adult living donor liver transplantations (LDLT) were performed at our institute between 1999 and July 2011. Hepatic artery reconstruction was performed under a surgical microscope (MS group, n = 84), until we began to adopt surgical loupes (4.5*) for arterial reconstructions in all cases after January 2009 (SL group, n = 25). A dynamic MDCT study was prospectively carried out on postoperative days 7, 14, and 28, and at postoperative month 3, 6, and 12 after April 2005 (n = 60). RESULTS: There were no cases of hepatic artery thrombosis and six cases (5.5 %) of interventional radiology-confirmed hepatic artery stenosis (HAS). Risk factor analysis for HAS showed that ABO-incompatible LDLT was associated with HAS. Use of surgical loupes provided superior results as compared to anastomosis under a surgical microscope, and it also provided the advantage of reduced operative time. The MDCT procedure was useful for detecting HAS; however, the false positive rate was relatively high until 3 months after the LDLT (100 % sensitivity and 72.8 % specificity at 3 months). CONCLUSIONS: Hepatic arterial anastomosis using surgical loupes tended to be time-saving and to yield similar or better results than traditional microscope-anastomosis. The use of MDCT aided the diagnosis of HAS, although the substantial false positive rate should be borne in mind in clinical practice. PMID- 23982778 TI - Outcomes of asymptomatic anastomotic leaks found on routine postoperative water soluble enema following anterior resection for cancer. AB - BACKGROUND: The incidence and consequence of an anastomotic leak associated with low anterior resection for cancer mandates covering stoma in most cases. A water soluble enema is often performed to assess anastomotic integrity prior to stoma reversal. The functional outcome following reversal in patients with occult radiologically detected leaks is poorly defined. The goal of the present study was to determine the functional outcome in patients with a radiologically detected anastomotic leak who subsequently underwent stoma reversal. METHODS: This case control study used patients with and without radiologically detected occult anastomotic leak having undergone reversal of covering stomata. The study group was matched with controls for age, gender, procedure, tumor stage, and adjuvant/neoadjuvant therapy. Validated fecal incontinence quality of life (FIQL), Cleveland Clinic Fecal Incontinence Score (CCFIS), and the Memorial Sloan Kettering Cancer Center (MSKCC) Bowel Function Index (BFI) were used. Patient satisfaction, medication use, and ancillary procedures prior to closure were also recorded. RESULTS: Thirteen patients with radiologically detected occult anastomotic leaks and 13 matched controls were identified from a prospectively maintained database. The FIQL, CCFIS, and MSKCC BFI scores were significantly reduced in those with occult leaks. The mean number of radiological and surgical interventions was significantly greater in the patients with occult leaks. Antidiarrheal and bulking agent use, as well as patient satisfaction, were the same for both groups. Only one patient in the occult leak group would not undergo stoma reversal again. CONCLUSIONS: Reversal of a defunctioning ileostomy in the presence of an occult radiological leak can be associated with poorer functional outcomes, but patient satisfaction is undiminished. PMID- 23982779 TI - How useful are perioperative biochemical parameters in predicting the duration of calcium and/or vitamin D supplementation after total thyroidectomy? AB - BACKGROUND: Oral calcium and calcitriol are often prescribed after total thyroidectomy to avoid biochemical and/or symptomatic hypocalcemia. We aimed to identify independent perioperative factors that correlated with the duration of calcium and/or calcitriol supplementation after total thyroidectomy. METHODS: Of 271 eligible patients, 48 (17.7 %) required calcium and/or calcitriol supplements on discharge. Patients were gradually weaned from the supplementation by one surgeon according to a biweekly algorithm based on serum calcium (Ca). Duration of supplementation was calculated from the date of operation to the date of ceasing all supplementation without biochemical hypocalcemia (i.e., serum adjusted Ca >= 8.44 mg/dL). The Cox regression analysis was performed to identify independent perioperative factors for duration of supplementation. The best cut off value for these independent factors was determined by the receiver characteristic curve. RESULTS: In the multivariate analysis, parathyroid hormone (PTH) at skin closure (PTH-SC) (RR 1.742, 95 % CI 1.080-2.810) and on postoperative day 1 adjusted Ca (Ca-D1) (RR 77.526, 95 % CI 3.600-1669.57) were the only two independent determinants for shorter duration before ceasing all supplementation. The best cut-off values in predicting supplementation >= 6 months for PTH-SC and Ca-D1 were 7.08 pg/mL (sensitivity = 100 %, specificity = 60.5 %, PPV = 40.0 % and NPV = 100 %) and 7.88 mg/dL (sensitivity = 90.0 %, specificity = 55.3 %, PPV = 34.6 % and NPV = 95.5 %), respectively. CONCLUSIONS: Both PTH-SC and Ca-D1 were independently associated with the duration of supplementation after total thyroidectomy. Almost all patients with PTH-SC >= 7.08 pg/mL or Ca-D1 >= 7.88 mg/dL did not require supplementation >= 6 months whereas about one third of patients with PTH-SC <7.08 pg/mL or Ca-D1 <7.88 mg/dL required supplementation >= 6 months. PMID- 23982780 TI - Study on the use of T-tube for patients with persistent duodenal fistula: is it useful? AB - BACKGROUND: The commonest surgical treatment used for peptic ulcer perforation is omental patching. If, however, the perforation leaks, it rarely heals by itself due to persistence of duodenal fistula (DF). We present our experience with a T tube placed into the DF for better outcome of the patients. METHODS: All patients in our hospital with DF following failure of surgery for duodenal perforation were included in this study. After identification of the perforation, a size 16 French T-tube was put in place. The patients were analyzed on basis of duration of hospital stay, complications related to the T-tube and overall complications, start of oral feeds, and follow-up. RESULTS: In this 3-year study, ten patients with DF were admitted. The mean age was 50 years. The T-tube was kept in place within the fistula for 20.5 days. The mean duration to start oral feeds was 8.8 days. The mean duration of hospital stay was 23.2 days, and the mean follow-up period was 6.3 months. The complications observed in the postoperative period were fever in four patients, wound dehiscence in four patients, and peritoneal collection in two patients, all of which were managed easily. There was no peritubal leakage and no failure of surgery as regards placement of a T-tube. There were no deaths in this study. CONCLUSIONS: Placement of a T-tube into a DF appears to be very effective procedure for managing this complication of surgical repair of a perforated peptic ulcer with an omental patch. The technique appears to be simple and rewarding. Further use of this method by other workers will substantiate our efforts. PMID- 23982781 TI - Airtight tracheocutaneostomy after window resection of the trachea for invasive papillary thyroid carcinoma: experience of 109 cases. AB - BACKGROUND: There are some tracheal surgeries for invasive papillary thyroid carcinoma (PTC) requiring tracheal resection. We create an airtight tracheocutaneostomy (TCS) by suturing the tracheal hole to the skin when window resection of the trachea is required. Here, we present the outcomes of PTC patients who underwent surgery with airtight TCS. METHODS: We enrolled 109 patients (18 males and 91 females) who underwent initial surgery for PTC and TCS after partial window resection of the trachea between 1987 and 2010. The average patient age was 61 and the average follow-up was 99 months. The TCS was closed using a local skin flap 3-6 months after surgery in 78 patients, and it closed spontaneously in 13 patients. The TCS of the remaining 18 patients was not closed for various reasons, such as a poor general condition, permanent bilateral vocal cord paralysis, and loss to follow-up. RESULTS: None of the 109 patients showed any serious complications of TCS. Minor wound infection, partial skin necrosis, granulation, and air leakage were observed in 12 (11 %), 2 (2 %), 7 (6 %), and 4 (4 %) patients, respectively. Infection was more likely to occur in patients whose cricoid cartilage was resected (p = 0.0456). Although macroscopically curative surgery was performed for all patients, 38 patients (35 %) had a suspiciously positive margin in the resected tracheal mucosa. Five margin positive (13 %) and five margin-negative (7 %) patients showed excision site recurrence, but the margin status did not directly affect the prognosis. External beam radiation therapy (EBRT) (50-60 Gy) was administered to nine patients, none of whom showed excision site recurrence, although eight were microscopically margin-positive. Among various clinicopathological features, tumor size > 4 cm and age >= 60 years were significant (p = 0.0281) and marginal (p = 0.0771) predictors of excision site recurrence on univariate analysis. On multivariate analysis, age >= 60 years (p = 0.0484) and tumor size > 4 cm (p = 0.0763) were independent and marginal predictors of excision site recurrence, respectively. To date, 14 and 17 patients have shown lymph node and distant recurrence, respectively, and nine have died of PTC. CONCLUSIONS: Tracheocutaneostomy is a safe surgical technique after partial window resection of the trachea, although we have to be careful of infection when resecting the cricoid cartilage. Large tumor size and old age are risk factors for excision site recurrence. EBRT may be useful to prevent excision site recurrence, especially in patients with a suspected positive margin. PMID- 23982782 TI - Hypothyroidism after hemithyroidectomy. AB - BACKGROUND: The risk of hypothyroidism after hemithyroidectomy is variable, and most estimates come from single institutional studies. The purpose of the present study was to determine the incidence of hypothyroidism at the population level, and to evaluate predictive factors for hypothyroidism after hemithyroidectomy. METHODS: This retrospective study identified euthyroid patients who underwent hemithyroidectomy between 2000 and 2010 for benign disease in Kaiser Permanente Southern California regional hospitals. The incidence of hypothyroidism [thyroid stimulating hormone (TSH) levels >4 MUIU/ml] was analyzed. The independent effect of age-quartile, gender, race, thyroiditis, and preoperative TSH level on the development of hypothyroidism was evaluated. RESULTS: Of 1,240 euthyroid patients identified, 417 (34 %) developed hypothyroidism, and 314 (25 % of total group) needed levothyroxine. Hypothyroidism was more common in age-quartile 2 (32 %), age-quartile 3 (37 %), and age-quartile 4 (42 %) than in age-quartile 1 (25 %) [adjusted odds ratio (OR) = 1.87; 95 % confidence interval (CI) 1.27-2.76, p = 0.002; age-quartile 4 compared to age-quartile 1]. Hypothyroidism was more frequent with increasing preoperative TSH levels 36, 72, and 92 % in patients with TSH levels of 1.0-2, 2.01-3, and 3.01-4 MUIU/ml, respectively, compared to 17 % in those with TSH levels <1 MUIU/ml [adjusted OR = 45.1; 95 % CI 13.5-151, p < 0.0001; 3.01-4 MUIU/ml compared to <1 MUIU/ml]. Thyroiditis was also an independent predictor of hypothyroidism. CONCLUSIONS: About one third of euthyroid patients who undergo hemithyroidectomy develop hypothyroidism. The most significant predictor is the preoperative TSH level, with an approximate doubling of risk for each 1 unit of TSH increase over 1 MUIU/ml. Our categorical scale is simple and allows for easy recall when counseling patients preoperatively. PMID- 23982783 TI - The prognostic relevance of psammoma bodies and ultrasonographic intratumoral calcifications in papillary thyroid carcinoma. PMID- 23982784 TI - Effective implementation of "surprise and startle" scenarios in surgical training. PMID- 23982785 TI - Study on the use of T-tube for patients with persistent duodenal fistula: is it useful? PMID- 23982786 TI - Confronting the global burden of surgical disease: the research tools for the job. PMID- 23982787 TI - Effects of stimulation of autophagy on the urinary excretion of biomarkers of the oxidative status. AB - Autophagy, a health-promoting lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles including 8-OHdG-rich mitochondria, is under investigation as a target for prevention and/or treatment of several human diseases and decelerating aging. Stimulation of autophagy was shown to rescue older liver cells from accumulation of 8-OHdG-rich mitochondria and to increase urinary 8-OHdG levels. Urinary 8 hydroxy-2'-deoxyguanosine (8-OHdG) is a recently recommended biomarker for monitoring oxidative status over time. In order to rule out the possibility that the in vivo stimulation of autophagy may cause an increase in the oxidative status, in this study we compared the effects of the stimulation of autophagy by two different procedures (the administration of antilipolytic drug and everolimus, an mTOR inhibitor in clinical use) on the urinary levels of 8-OHdG and 15-isoprostane F2t, another well-known biomarker of the oxidative status. Results show that both procedures increased the urinary 8-OHdG levels without any change in urinary 15-isoprostane F2t; this increase in urinary 8-OHdG levels after the antilipolytic drug was fully suppressed by the simultaneous injection of glucose to make rats transiently incompetent for the endocrine stimulation of autophagy. Conclusions are that the in vivo stimulation of autophagy does not affect the oxidative status and that the increasing effect on urinary 8-OHdG may be secondary to an increased degradation of previously accumulated 8-OHdG-rich (mt)DNA. The authors are aware that findings may open the way to a safe, easy, highly desirable non-invasive test for successful in vivo activation of autophagy after pharmacological stimulation. PMID- 23982788 TI - Trauma-associated tinnitus. AB - BACKGROUND: Up to 53% of individuals suffering from traumatic brain injuries develop tinnitus. OBJECTIVE: To review the current literature on trauma associated tinnitus in order to provide orientation for the clinical management of patients with trauma-associated tinnitus. MATERIALS: A systematic literature search has been conducted in PubMed database applying the search terms posttraumatic tinnitus and trauma-associated tinnitus. Results have been complemented by related studies, book chapters, and the authors' clinical experience. RESULTS: Not only mechanical, pressure-related, or noise-related head traumata but also neck injuries and emotional trauma can cause tinnitus. Exact diagnosis is essential. Disorders such as ossicular chain disruption, traumatic eardrum perforation, or perilymphatic fistula can be surgically treated. It should also be considered that pulsatile tinnitus can be a sign of life threatening disorders such as carotid cavernous fistulas, arteriovenous malformations, and carotid dissections. Also, posttraumatic stress disorder should be taken into consideration as a potential contributing factor. CONCLUSIONS: There is an evident mismatch between the high incidence of trauma associated tinnitus and scarce literature on the topic. A consistent and-at best standardized assessment of tinnitus- and hearing-related sequelae of trauma is recommended both for the improvement of clinical care and for a deeper understanding of the various pathophysiological mechanisms of trauma-associated tinnitus. PMID- 23982789 TI - Affect recognition in traumatic brain injury: responses to unimodal and multimodal media. AB - OBJECTIVES: To compare affect recognition by people with and without traumatic brain injury (TBI) for (1) unimodal and context-enriched multimodal media; (2) positive (happy) and negative emotions; and (3) neutral multimodal stimuli. PARTICIPANTS: A total of 60 people with moderate to severe TBI and 60 matched controls. MEASURES: (1) facial affect, (2) vocal affect, and (3) multimodal affect. RESULTS: Compared with controls, people with TBI scored significantly lower on both unimodal measures but not on the multimodal measure. Within- group comparisons for people with TBI revealed that they were better at recognizing affect from multimodal than unimodal stimuli. As a group, participants with TBI who were categorized as having impaired facial/vocal affect recognition were less accurate at recognizing all emotions, including happy, than unimpaired participants. Neutral stimuli were more poorly identified by participants with TBI than by those with controls. CONCLUSION: Context-enriched multimodal stimuli may enhance affect recognition for people with TBI. People with TBI who have impaired affect recognition may have problems identifying both positive (happy) and negative expressions. Furthermore, people with TBI may perceive affect when there is none. PMID- 23982790 TI - Preliminary examination of the impact of traumatic brain injury and posttraumatic stress disorder on self-regulated learning and academic achievement among military service members enrolled in postsecondary education. AB - OBJECTIVE: Delineate the effects of self-reported traumatic brain injury (TBI) or posttraumatic stress disorder (PTSD) on self-regulated learning and academic achievement for university-enrolled military Service members. PARTICIPANTS: Students (N = 192) from 8 regionally diverse universities, representing an estimated 6% of Service members enrolled across schools. SETTING: Public universities that are members of the Servicemember Opportunity College consortium. DESIGN: Cross-sectional study evaluating the relationships between self-reported TBI, PTSD, and self-regulated learning variables and their contribution to academic achievement. MAIN MEASURES: Self-report of military service; symptoms of TBI and PTSD; self-regulation strategies including effort, time/environment regulation, and academic self-efficacy; and grade point average (GPA). RESULTS: There was no effect of self-reported TBI or PTSD on GPA, effort regulation, or time/environment regulation strategies; however, participants with TBI or PTSD reported significantly lower academic self-efficacy. Multiple regression analysis revealed self-efficacy was the strongest predictor of GPA among all participants, followed by military rank. CONCLUSION: The sample consisted of high achieving students responsive to a university administrator, which raises the possibility of sampling bias. Because of the low recruitment rate for this study and lack of published research on this subject, replicating the results is necessary before drawing generalizable conclusions about the population. PMID- 23982791 TI - Building statewide infrastructure for effective educational services for students with TBI: promising practices and recommendations. AB - OBJECTIVE: To identify promising practices in educational service delivery. METHODS: Consensus-building process with a multidisciplinary group of researchers, policy makers, and state Department of Education personnel. RESULTS: This white paper presents the group's consensus on the essential components of a statewide educational infrastructure to support students with traumatic brain injury across the spectrum of injury severity: (a) identification, screening, and assessment practices; (b) systematic communication between medical and educational systems; (c) tracking of child's progress over time; and (d) professional development for school personnel. The white paper also presents key outcomes for measuring success and provides recommendations both for policy change and for furthering research in childhood brain injury. PMID- 23982792 TI - A comparison of concussive symptoms reported by parents for preschool versus school-aged children. AB - OBJECTIVE: To compare parental report of symptoms of concussion for children with superficial head injury versus children with a diagnosis of a mild traumatic brain injury (mTBI). SETTING: Urban hospital emergency department. PARTICIPANTS: Parents of 159 children aged 2 to 12 years who presented with an injury to the head. PROCEDURE: Parents were contacted within 1 week of injury and assigned into 3 groups according to their child's age and medical diagnosis (group 1, parents of 2- to 5-year-olds with mTBI (n = 39); group 2, parents of 6- to 12-year-olds with mTBI (n = 41); and group 3, parents of 2- to 12-year-olds with superficial injury to the head (n = 35). RESULTS: Symptoms of concussion were reported in all groups; however, significantly fewer symptoms were reported for children with superficial injuries to the head than for children with mTBI (M = 2.51 vs M = 6.91; P < .001). For mTBI, parents of younger children reported significantly fewer symptoms than parents of older children (M = 5.23 vs M = 8.51; P < .001). CONCLUSIONS: A careful approach needs to be taken when evaluating the severity of mTBI for preschool children. Failure to do so may result in misidentification and subsequent lack of management. PMID- 23982794 TI - Clinical image: Linear branching depigmentation of the leg. PMID- 23982796 TI - Preclinical studies on tumor-specific fluorescent targeting agents: the need for a gold standard of tumor localization. PMID- 23982795 TI - Comparison of three dimeric 18F-AlF-NOTA-RGD tracers. AB - PURPOSE: RGD peptide-based radiotracers are well established as integrin alphavbeta3 imaging probes to evaluate tumor angiogenesis or tissue remodeling after ischemia or infarction. In order to optimize the labeling process and pharmacokinetics of the imaging probes, we synthesized three dimeric RGD peptides with or without PEGylation and performed in vivo screening. PROCEDURES: Radiolabeling was achieved through the reaction of F-18 aluminum-fluoride complex with the cyclic chelator, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). Three imaging probes were synthesized as (18)F-AlF-NOTA-E[c(RGDfK)]2, (18)F-AlF NOTA-PEG4-E[c(RGDfK)]2, and (18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2. The receptor binding affinity was determined by competitive cell binding assay, and the stability was evaluated by mouse serum incubation. Tumor uptake and whole body distribution of the three tracers were compared through direct tissue sampling and PET quantification of U87MG tumor-bearing mice. RESULTS: All three compounds remained intact after 120 min incubation with mouse serum. They all had a rapid and relatively high tracer uptake in U87MG tumors with good target-to-background ratios. Compared with the other two tracers, (18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2 had the highest tumor uptake and the lowest accumulation in the liver. The integrin receptor specificity was confirmed by co-injection of unlabeled dimeric RGD peptide. CONCLUSION: The rapid one-step radiolabeling strategy by the complexation of (18)F-aluminum fluoride with NOTA-peptide conjugates was successfully applied to synthesize three dimeric RGD peptides. Among the three probes developed, (18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2 with relatively low liver uptake and high tumor accumulation appears to be a promising candidate for further translational research. PMID- 23982797 TI - Alfred Russel Wallace (1823-1913): the forgotten co-founder of the Neo-Darwinian theory of biological evolution. AB - The British naturalist Alfred Russel Wallace (1823-1913), who had to leave school aged 14 and never attended university, did extensive fieldwork, first in the Amazon River basin (1848-1852) and then in Southeast Asia (1854-1862). Based on this experience, and after reading the corresponding scientific literature, Wallace postulated that species were not created, but are modified descendants of pre-existing varieties (Sarawak Law paper, 1855). Evolution is brought about by a struggle for existence via natural selection, which results in the adaptation of those individuals in variable populations who survive and reproduce (Ternate essay, 1858). In his monograph Darwinism (1889), and in subsequent publications, Wallace extended the contents of Darwin's Origin of Species (1859) into the Neo Darwinian theory of biological evolution, with reference to the work of August Weismann (1834-1914). Wallace also became the (co)-founder of biogeography, biodiversity research, astrobiology and evolutionary anthropology. Moreover, he envisioned what was later called the anthropocene (i.e., the age of human environmental destructiveness). However, since Wallace believed in atheistic spiritualism and mixed up scientific facts and supernatural speculations in some of his writings, he remains a controversial figure in the history of biology. PMID- 23982798 TI - Metabolic scaling theory in plant biology and the three oxygen paradoxa of aerobic life. AB - Alfred Russell Wallace was a field naturalist with a strong interest in general physiology. In this vein, he wrote that oxygen (O2), produced by green plants, is "the food of protoplasm, without which it cannot continue to live". Here we summarize current models relating body size to respiration rates (in the context of the metabolic scaling theory) and show that oxygen-uptake activities, measured at 21 vol.% O2, correlate closely with growth patterns at the level of specific organs within the same plant. Thus, whole plant respiration can change ontogenetically, corresponding to alterations in the volume fractions of different tissues. Then, we describe the evolution of cyanobacterial photosynthesis during the Paleoarchean, which changed the world forever. By slowly converting what was once a reducing atmosphere to an oxidizing one, microbes capable of O2-producing photosynthesis modified the chemical nature and distribution of the element iron (Fe), slowly drove some of the most ancient prokaryotes to extinction, created the ozone (O3) layer that subsequently shielded the first terrestrial plants and animals from harmful UV radiation, but also made it possible for Earth's forest to burn, sometimes with catastrophic consequences. Yet another paradox is that the most abundant protein (i.e., the enzyme Rubisco, Ribulose-1,5-biphosphate carboxylase/oxygenase) has a greater affinity for oxygen than for carbon dioxide (CO2), even though its function is to bind with the latter rather than the former. We evaluate this second "oxygen paradox" within the context of photorespiratory carbon loss and crop yield reduction in C3 vs. C4 plants (rye vs. maize). Finally, we analyze the occurrence of reactive oxygen species (ROS) as destructive by-products of cellular metabolism, and discuss the three "O2-paradoxa" with reference to A. R. Wallace's speculations on "design in nature". PMID- 23982799 TI - Use of pharmacologic agents for the primary prevention of osteoporosis among older women with low bone mass. AB - We examined the use of pharmacologic agents for the primary prevention of osteoporosis among older women with osteopenia. We found that these individuals were not managed in concordance with the National Osteoporosis Foundation (NOF) guidelines and that self-perceived osteoporosis risk and lower bone density were strongly associated with receipt of treatment. INTRODUCTION: Although osteoporosis medications are used for the primary prevention of osteoporosis among persons with low bone mass (osteopenia), their use may be discordant with clinical practice guidelines. METHODS: We studied women 55 years and older participating in the Global Longitudinal Study of Osteoporosis in Women (GLOW). Eligible participants had a dual energy x-ray absorptiometry (DXA) test performed at the University of Alabama at Birmingham hospital and had an osteopenia diagnosis based on their DXA test results. Participants' demographics, fracture risk factors, and exposure to osteoporosis medications were determined from the GLOW survey. We examined the proportions of women managed in concordance with the National Osteoporosis Foundation 2008 guidelines, and we assessed factors independently associated with osteoporosis treatment decisions. Women with a prior spine or hip fracture were excluded. RESULTS: Among 597 eligible women from GLOW, the mean age +/- standard deviation (SD) was 70 +/- 7 years. Among all subjects, 309 (52%) were treated in concordance with the NOF 2008 guidelines. Greater self-perceived osteoporosis risk and lower bone mineral density were significantly and consistently associated with receipt of osteoporosis treatment, both for those considered appropriate and for those considered inappropriate for treatment based on the NOF guidelines. CONCLUSIONS: We found significant discordance between NOF 2008 guidelines and pharmacologic management of women with osteopenia. A person's self-perceived osteoporosis risk and bone mineral density were most strongly associated with receipt of osteoporosis medication use among women with low bone mass. PMID- 23982800 TI - A parallel group double-blind RCT of vitamin D3 assessing physical function: is the biochemical response to treatment affected by overweight and obesity? AB - Vitamin D may affect skeletal muscle function. In a double-blind, randomised, placebo-controlled trial, we found that vitamin D3 supplementation (400 or 1,000 I.U. vs. placebo daily for 1 year with bimonthly study visits) does not improve grip strength or reduce falls. INTRODUCTION: This study aimed to test the supplementation effects of vitamin D3 on physical function and examine associations between overweight/obesity and the biochemical response to treatment. METHODS: In a parallel group double-blind RCT, healthy postmenopausal women from North East Scotland (latitude-57 degrees N) aged 60-70 years (body mass index (BMI), 18-45 kg/m(2)) were assigned (computer randomisation) to daily vitamin D3 (400 I.U. (n = 102)/1,000 I.U. (n = 101)) or matching placebo (n = 102) (97, 96 and 100 participants analysed for outcomes, respectively) from identical coded containers for 1 year. Grip strength (primary outcome), falls, diet, physical activity and ultraviolet B radiation exposure were measured bimonthly, as were serum 25(OH)D, adjusted calcium (ACa) and phosphate. Fat/lean mass (dual energy X-ray absorptiometry), anthropometry, 1,25-dihydroxyvitamin D and parathyroid hormone were measured at baseline and 12 months. Participants and researchers were blinded throughout intervention and analysis. RESULTS: Treatment had no effect on grip strength (mean change (SD)/year = -0.5 (2.5), -0.9 (2.7) and -0.4 (3.3) kg force for 400/1,000 I.U. vitamin D3 and placebo groups, respectively (P = .10, ANOVA)) or falls (P = .65, chi-squared test). Biochemical responses were similar across BMI categories (<25.25-29.99, >=30 kg/m(2)) with the exception of a small change at 12-months in serum ACa in overweight compared to non-overweight participants (P = .01, ANOVA; 1,000 I.U. group). In the placebo group, 25(OH)D peak concentration change (winter to summer) was negatively associated with weight (r = -.268), BMI (r = -.198), total (r = -.278) and trunk fat mass (r = -.251), with total and trunk fat mass predictive of winter to summer 25(OH)D change (P = .01/.004 respectively, linear regression). CONCLUSION: We found no evidence of an improvement in physical function following vitamin D3 supplementation for 1 year. PMID- 23982801 TI - Age-period-cohort effects in the incidence of hip fractures: political and economic events are coincident with changes in risk. AB - An age-period cohort model was fitted to analyse time effects on hip fracture incidence rates by sex (Portugal, 2000-2008). Rates increased exponentially with age (age effect). Incidence rates decreased after 2004 for women and were random for men (period effect). New but comprehensive fluctuations in risk were coincident with major political/economic changes (cohort effect). INTRODUCTION: Healthcare improvements have allowed prevention but have also increased life expectancy, resulting in more people being at risk. Our aim was to analyse the separate effects of age, period and cohort on incidence rates by sex in Portugal, 2000-2008. METHODS: From the National Hospital Discharge Register, we selected admissions (aged >= 49 years) with hip fractures (ICD9-CM, codes 820.x) caused by low/moderate trauma (falls from standing height or less), readmissions and bone cancer cases. We calculated person-years at risk using population data from Statistics Portugal. To identify period and cohort effects for all ages, we used an age-period-cohort model (1-year intervals) followed by generalised additive models with a negative binomial distribution of the observed incidence rates of hip fractures. RESULTS: There were 77,083 hospital admissions (77.4 % women). Incidence rates increased exponentially with age for both sexes (age effect). Incidence rates fell after 2004 for women and were random for men (period effect). There was a general cohort effect similar in both sexes; risk of hip fracture altered from an increasing trend for those born before 1930 to a decreasing trend following that year. Risk alterations (not statistically significant) coincident with major political and economic change in the history of Portugal were observed around birth cohorts 1920 (stable-increasing), 1940 (decreasing-increasing) and 1950 (increasing-decreasing only among women). CONCLUSIONS: Hip fracture risk was higher for those born during major economically/politically unstable periods. Although bone quality reflects lifetime exposure, conditions at birth may determine future risk for hip fractures. PMID- 23982802 TI - Greater seasonal cycling of 25-hydroxyvitamin D is associated with increased parathyroid hormone and bone resorption. AB - SUMMARY: This analysis assessed whether seasonal change in 25-hydroxyvitamin D concentration was associated with bone resorption, as evidenced by serum parathyroid hormone and C-terminal telopeptide concentrations. The main finding was that increased seasonal fluctuation in 25-hydroxyvitamin D was associated with increased levels of parathyroid hormone and C-terminal telopeptide. INTRODUCTION: It is established that adequate 25-hydroxyvitamin D (25(OH)D, vitamin D) concentration is required for healthy bone mineralisation. It is unknown whether seasonal fluctuations in 25(OH)D also impact on bone health. If large seasonal fluctuations in 25(OH)D were associated with increased bone resorption, this would suggest a detriment to bone health. Therefore, this analysis assessed whether there is an association between seasonal variation in 25(OH)D and bone resorption. METHODS: The participants were (n = 279) Caucasian and (n = 88) South Asian women (mean (+/-SD); age 48.2 years (14.4)) who participated in the longitudinal Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England study (2006-2007). The main outcomes were serum 25(OH)D, serum parathyroid hormone (sPTH) and serum C-terminal telopeptide of collagen (sCTX), sampled once per season for each participant. RESULTS: Non-linear mixed modelling showed the (amplitude/mesor) ratio for seasonal change in log 25(OH)D to be predictive of log sPTH (estimate = 0.057, 95 % CI (0.051, 0.063), p < 0.0001). Therefore, individuals with a higher seasonal change in log 25(OH)D, adjusted for overall log 25(OH)D concentration, showed increased levels of log sPTH. There was a corresponding significant ability to predict the range of seasonal change in log 25(OH)D through the level of sCTX. Here, the corresponding parameter statistics were estimate = 0.528, 95 % CI (0.418, 0.638) and p <= 0.0001. CONCLUSIONS: These findings suggest a possible detriment to bone health via increased levels of sPTH and sCTX in individuals with a larger seasonal change in 25(OH)D concentration. Further larger cohort studies are required to further investigate these preliminary findings. PMID- 23982803 TI - Production and repair of implant-induced microdamage in the cortical bone of goats after long-term estrogen deficiency. AB - SUMMARY: By using an ovariectomized goat model, we found that estrogen depletion decreases bone quality and makes it susceptible to screw-induced mechanical microdamage. Both diffuse microdamage and linear cracks accumulated up to 3 weeks after screw implantation, and the microdamage was repaired gradually after 4-8 months. INTRODUCTION: The aim of this study was to observe the effect of long term estrogen deficiency on the creation and repair of microdamage in cortical bone adjacent to bone screw. METHODS: Cortical bone screws were placed in the tibial diaphyses 28 months after ovariectomy (OVX) or sham operation (Sham-Op) in female goats. The goats were euthanized at 0 day, 21 days, 4 months, and 8 months after screw implantation. Microdamage morphology and repair were examined in peri screw bone using histomorphometric method, and the nanomechanical properties of peri-screw bone were examined with nanoindentation testing. RESULTS: Tibiae from ovariectomized goats in which screws had been placed had significantly higher levels of diffuse microdamage and significantly more linear cracks than those from sham goats, and the diffuse microdamage was more obvious than linear cracks in the region adjacent to the implant. Both diffuse microdamage and linear cracks accumulated up to day 21 and then gradually repaired at 4 and 8 months after surgery. The trend for bone remodeling in each group was consistent with changes in the level of microdamage. Nanoindentation testing showed that both elastic modulus and hardness in peri-screw bone were significantly decreased in OVX group compared to Sham-Op group. The hardness and elastic modulus also showed a downward trend up to 4 months after screw implantation and then exhibited some recovery after 8 months. CONCLUSIONS: Estrogen depletion decreases bone quality and makes it vulnerable to screw-induced mechanical damage, which may compromise the initial stability of an orthopedic implant. PMID- 23982805 TI - Electronic collimation and radiation protection in paediatric digital radiography: revival of the silver lining. AB - In digital radiography we are now able to electronically collimate images after acquisition. This may seem convenient in paediatric imaging, but we have to be aware that electronic collimation has two major downsides. Electronic collimation implicates that the original field size should have been smaller and the child has been exposed to unnecessary radiation. Also, by use of electronic collimation, potentially important information may be lost. The "silver lining", denoting the X-ray beam collimation, can serve as a useful radiation protection instrument to check for proper field size and detect unnecessary exposure. Furthermore, the silver lining confirms all exposed anatomy is shown in the final image, and thus may also serve as a quality assurance instrument as the patient has the right to all acquired information. Teaching Points * The ability to electronically collimate an image after acquisition may serve to enhance contrast in the region of interest. * The ability to electronically collimate an image after acquisition carries the risk of overexposure. * The ability to electronically collimate an image after acquisition carries the risk of losing important information. * The silver lining can serve as a quality control instrument for proper collimation. * The patient has the right to all information obtained during an X-ray examination. PMID- 23982804 TI - Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites. AB - Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus-induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine-activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus-loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand-off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNgamma, IL-12, IFNalpha and TNFalpha) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune-mediated tumor cell killing. PMID- 23982806 TI - Recent developments in transition metal carbides and nitrides as hydrogen evolution electrocatalysts. AB - The production of hydrogen by the electrolysis of water, a sustainable and greenhouse-gas-free source, requires an efficient and abundant electrocatalyst that minimizes energy consumption. Interest in transition metal carbides and nitrides has been aroused by their promising properties that make them potential substitutes for Pt-group metals as catalysts for the hydrogen evolution reaction. In this review, we discuss systematically the recent progress in the development of group IV-VI metal carbides and nitrides toward the hydrogen evolution reaction. Some strategies for designing such catalysts and improving their efficiency and reliability, including nanostructuring, optimizing hydrogen binding energy, interaction with the supporting material, and exploiting hybrid structures, are highlighted. We conclude with an outlook on the challenges in designing future HER electrocatalysts. PMID- 23982808 TI - Capsosiphon fulvescens glycoprotein inhibits AGS gastric cancer cell proliferation by downregulating Wnt-1 signaling. AB - Previously, we examined various apoptosis pathways in the AGS gastric cancer cell line using Capsosiphon fulvescens glycoprotein (Cf-GP). In this study, we focused on the downregulation of the Wnt-1 signaling pathway and cell cycle arrest. Upregulation of the Wnt signaling pathway has been observed in various cancer cells. The Wnt signal ligand acts in both canonical and non-canonical pathways. Among them, Wnt-1 was dependent on the canonical pathway. Here, we show inhibition of Wnt-1 signaling, beta-catenin and transcription factors in AGS cells via Cf-GP. First, we examined the Frizzled receptor and Wnt-1 signal related proteins including Axin, LRP, beta-catenin, APC and GSK-3beta. In addition, the expression levels of transcription factors Tcf/LEF were determined by western blot analysis and RT-PCR. Based on the data, we confirmed downregulation of the Wnt-1 signaling pathway by Cf-GP. Also, we determined the expression levels of cell cycle-related proteins cyclin D and c-myc, and looked for cell cycle arrest by cell cycle test analysis. We found that AGS cells arrested in the G0/G1 phase by Cf-GP. These results provide a mechanism of AGS cell inhibition through the downregulation of Wnt-1 signaling by Cf-GP. PMID- 23982809 TI - Membranoproliferative glomerulonephritis: the times they are a-changin'. PMID- 23982810 TI - Vascular endothelial growth factor receptor 1 signaling facilitates gastric ulcer healing and angiogenesis through the upregulation of epidermal growth factor expression on VEGFR1+CXCR4 + cells recruited from bone marrow. AB - BACKGROUND: Angiogenesis is essential for gastric ulcer healing. Recent results suggest that vascular endothelial growth factor receptor 1 (VEGFR1), which binds to VEGF, promotes angiogenesis. In the present study, we investigated the role of VEGFR1 signaling in gastric ulcer healing and angiogenesis. METHODS: Gastric ulcers were induced by serosal application of 100 % acetic acid in wild-type (WT) and tyrosine kinase-deficient VEGFR1 mice (VEGFR1 TK(-/-)). Bone marrow transplantation into irradiated WT mice was carried out using bone marrow cells isolated from WT and VEGFR1 TK(-/-) mice. RESULTS: Ulcer healing was delayed in VEGFR1 TK(-/-) mice compared to WT mice and this was accompanied by decreased angiogenesis, as evidenced by reduced mRNA levels of CD31 and decreased microvessel density. Recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) was suppressed and epidermal growth factor (EGF) expression in ulcer granulation tissue was attenuated. Treatment of WT mice with neutralizing antibodies against VEGF or CXCR4 also delayed ulcer healing. In WT mice transplanted with bone marrow cells from VEGFR1 TK(-/-) mice, ulcer healing and angiogenesis were suppressed, and this was associated with reduced recruitment of bone marrow cells to ulcer granulation tissue. VEGFR1 TK(-/-) bone marrow chimeras also exhibited downregulation of EGF expression on CXCR4(+)VEGFR1(+) cells recruited from the bone marrow into ulcer lesions. CONCLUSION: VEGFR1-mediated signaling plays a critical role in gastric ulcer healing and angiogenesis through enhanced EGF expression on VEGFR1(+)CXCR4(+) cells recruited from the bone marrow into ulcer granulation tissue. PMID- 23982813 TI - Poetry for the uninitiated: Dannie Abse's "X-Ray" in an undergraduate medicine and literature class. AB - I recently taught an upper-division Honors class in Medicine and Literature with students ranging from a pre-physician's assistant student and nursing student to English, French, History, and Technical Writing majors. The common thread connecting these students initially was their self-described fear of and helplessness with poetry. However, as the semester drew to a close, their class discussion and journals revealed not only increased comfort with poetry but also a preference for it. The information and insight they got from poetry, they said, were the reason they took a medical humanities course in the first place and commented that the poetry we read provoked more substantial "medicine and literature" discussions than prose. Poetry provides a good starting place to analyze complex human relationships, and the focus on language and form levels the intellectual playing field: students are all unfamiliar with how to do it and are learning a new skill together. This could be accomplished, of course, with a literary short story, but for the diverse population of students in this class, the brevity of poetry made it all the more appealing. PMID- 23982811 TI - Peroxisomes in dental tissues of the mouse. AB - Patients with mild forms of peroxisomal biogenesis disorders show facial dysmorphism and exhibit dentition problems accompanied by enamel hypoplasia. However, no information is available on the role of peroxisomes in dental and paradontal tissues. Therefore, we studied the distribution of these organelles, their protein composition and the expression of corresponding genes during dental development and in mature decalcified teeth in mice. Perfusion-fixed heads of mice of different developmental stages (E13.5 to adult) were cut in sagittal direction into two halves and embedded in paraffin for serial sectioning and subsequent peroxidase-based immunohistochemistry or double-immunofluorescence preparations. Frozen, unfixed heads of newborn mice were used for cryosectioning and subsequent laser-assisted microdissection of ameloblasts and odontoblasts, RNA isolation and RT-PCR analysis. Our results revealed the presence of peroxisomes already in the bud stage of dental development. An increase in peroxisome abundance was noted during differentiation of ameloblasts and odontoblasts with the highest number of organelles in Tomes' processes of mature ameloblasts. A strong heterogeneity of peroxisomal enzyme content developed within differentiated dental cell types. A drastic down-regulation of catalase in maturing ameloblasts was noted in contrast to high levels of lipid metabolizing enzymes in peroxisomes of these cells. As known from the literature, differentiated ameloblasts are more prone to oxidative damage which could be explained by the low catalase levels inside of this cell type. PMID- 23982812 TI - A compelling practice: empowering future leaders in the medical humanities. AB - Medical students and faculty explore the medical humanities for diverse reasons: as a medium for self-reflection, a means to cultivate professionalism and humanism, and a way to gain an appreciation for the broader contexts in which illness and health occur. One important area for development is increasing the exposure of learners and clinicians of various levels of training to the medical humanities and to role models in the field. Student-led programs in the medical humanities at the American Medical Student Association (AMSA) address these needs by offering unique opportunities for learning and sharing experiences. AMSA programs connect physicians-in-training using technology to create virtual communication and learning opportunities. These include monthly book discussion webinars, the Writers' Institute and the Medical Humanities Scholars Program (MHSP). PMID- 23982815 TI - Trimethoxybenzene- and trimethylbenzene-based compounds bearing imidazole, indole and pyrrole groups as recognition units: synthesis and evaluation of the binding properties towards carbohydrates. AB - The aim of the study was to evaluate the potential of trimethoxybenzene- and trimethylbenzene-based compounds bearing imidazole or indole groups as recognition sites in the complexation of carbohydrates. Representatives of these compounds were prepared and their binding properties toward selected carbohydrates evaluated. The results of the binding studies were compared with those obtained for the prepared pyrrole bearing analogues and for the previously described triethylbenzene-based receptors. PMID- 23982816 TI - Ertapenem versus standard triple antibiotic therapy for the treatment of perforated appendicitis in pediatric patients: a prospective randomized trial. AB - BACKGROUND: The primary objective of this study was to compare triple therapy with ertapenem treatments in pediatric patients with perforated appendicitis, especially in terms of postoperative infectious complications. The secondary objective of this study was to assess the relative impact of therapy with ertapenem and triple antibiotic regimen on the emergence of resistant bacteria in bowel flora in the patients. MATERIALS AND METHODS: Children aged 3 months to 17 years with perforated appendicitis were randomized 1:1 to receive ertapenem or triple therapy. Serial rectal cultures were obtained from participants enrolled in the study, allowing assessment of the relative impact of therapy with ertapenem and triple therapy on bowel colonization by resistant bacteria. RESULTS: In this study, 107 patients were included. No difference existed in time to full oral intake and regular diet, the length of antibiotic therapy, the length of the postoperative hospitalization, or the length of hospital stay between the two groups. Patients in the triple-therapy group were more likely to suffer from a postoperative infectious complication than those in the ertapenem group (6/54 vs. 2/53, p > 0.05). Bowel colonization with resistant organisms at the end of therapy in the triple-therapy group was significantly different than in the ertapenem group (35.2 vs. 11.3%, p < 0.05). CONCLUSIONS: Bowel colonization with resistant bacteria was less likely to occur after ertapenem treatment than triple therapy. The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and/or multidosed antibiotic regimens for the empiric treatment of perforated appendicitis in children. PMID- 23982817 TI - Failed Nissen fundoplication in children: causes and management. AB - INTRODUCTION: Nissen fundoplication (NF) is the gold standard procedure for the treatment of gastroesophageal reflux (GER) in children. However, it fails in a significant proportion of patients. The purpose of this study was to identify preoperative predictors of failure and to examine the results of reoperations. PATIENTS AND METHODS: The charts of patients who underwent NF at our institution between 1992 and 2011 were retrospectively reviewed. Surgery was indicated in patients with symptomatic GER in whom medical treatment failed, particularly, in cases of esophageal atresia (EA), congenital diaphragmatic hernia (CDH), and neurologic impairment (NI). Chi-square comparisons and logistic regression were used to test comorbidities, previous abdominal surgery, surgical technique, gastrostomy, pyloromyotomy or pyloroplasty, age, weight, and surgical complications as possible predictors of NF failure. RESULTS: A total of 360 children (217 male and 143 female) underwent NF. Comorbidities were NI (n = 100, 27.8%), EA (n = 50, 13.9%), CDH (n = 22, 6.1%), and abdominal wall defects (AWD) (n = 6, 1.7%). A total of 35 patients (9.7%) had esophageal stenosis. Age at surgery was 3.06 years (0.04-20.7 years) and weight was 12 kg (2-77 kg). NF was open in 196 patients (54.4%) and laparoscopic in 164 patients (45.6%) (with 9 conversions). Follow-up was 6.7 years (0.01-18.7 years). A total of 42 patients (11, 7%) had postoperative complications (10 wound infection, 9 dumping syndrome, 8 gastrostomy related complications, 7 intestinal obstruction, 5 evisceration, 2 chylothorax, and 1 pneumothorax). Reflux recurred in 42 patients (11.7%) and 35 patients (9.7%) underwent redo NF 1.01 years (0.02-8.4 years) after the initial surgery. A total of nine patients (2.5%) required further interventions (five another redo NF, three esophageal replacements, and one esophago-gastric disconnection). A total of 29 patients (8.1%) died during the follow-up (25 because of their baseline disease, 3 in the postoperative period, and 1 because of pulmonary aspiration 3 years after surgery). EA (31.6% failure) and CDH (46.7% failure) were the only comorbidities predictive of NF failure (p < 0.05). CONCLUSIONS: Failure of NF is particularly frequent in patients previously operated upon for EA or CDH and can be predicted preoperatively. However, the benefits of the operation may outweigh this risk. Redo NF is indicated if symptoms of GER recur, but the proportion of failure is even higher. In subsequent failures, other options like esophageal replacement or esophagogastric dissociation should also be considered. PMID- 23982818 TI - Increased incidence of hypertrophic pyloric stenosis in esophageal atresia patients. AB - INTRODUCTION: Around half of patients with esophageal atresia (EA) have additional congenital anomalies. Hypertrophic pyloric stenosis (HPS) in these patients is less known, with only 36 cases reported in the past literature. This retrospective study aimed to establish the incidence and clinical presentation of EA patients in combination with HPS in our hospital. MATERIALS AND METHODS: A retrospective study was based on the medical histories from all patients with EA who underwent surgical repair in our hospital from 1988 through 2012. RESULTS: Of 267 patients with EA, 20 also developed HPS (7.5%). The latter group showed male predominance, 90 versus 60% in the EA without HPS group. The first symptoms of HPS were mostly vomiting and/or feeding intolerance (n = 19). The diagnosis was mostly delayed, with a median of 6 days (range, 1-21 days). CONCLUSIONS: This is the first report on the high incidence of HPS in a large series of EA patients. The incidence found is 30 times higher than that in the normal population. HPS should be considered when patients show recurrent or persisting vomiting and feeding intolerance after surgery. The reason for the higher incidence should be further investigated. PMID- 23982819 TI - Tissue engineering of skin for wound coverage. AB - Over the past few decades, important milestones have been reached in the field of skin tissue engineering, bringing the ultimate goal of fabricating an autologous dermoepidermal skin substitute with all its cellular components and skin appendages closer to reality. Yet, scientific progress alone is not enough, clinical demands must be addressed and commercial interests need to be fulfilled. This review gives an overview of commercially available skin substitutes for skin replacement therapies and an insight into the recent development of an autologous full-thickness skin substitute that can readily be transplanted in large quantities onto the patient. PMID- 23982820 TI - Management of avulsion injuries. AB - The optimal management sequence to treat avulsion injuries in children is particularly difficult because of the following problems: (1) Assessment of these rare but frequently massive injuries can be very difficult and treacherous, as the extent of the injury is often underestimated and treatment therefore considered inappropriate; (2) Avulsion injuries have a high risk of infection: lesions are always contaminated due to the mechanism of injury (mostly vehicle accidents) and subsequent long-term hospitalization adds an additional risk for nosocomial infections; (3) Children with avulsion injuries have an increased risk to develop functional deficits: although the body grows, scars and reconstructed tissues may not adapt sufficiently and this may lead to serious constraints. Because of these problems, avulsion injuries may lead to a high morbidity and even mortality, especially if the injury is mismanaged. Reviewing the most recent data regarding the management of avulsion injuries yields the following key points: (1) A scoring system may help to assess the primary dimension of the defect; (2) Innovative techniques such as the use of a Vacuum Assisted Closure system may lower the risk of infection; (3) Choosing a comprehensive, reconstructive approach taking the growth of the child into consideration, may reduce the development of serious functional deficits and improve cosmetic outcome. PMID- 23982821 TI - Syntheses, crystal structures and thermal properties of six coordination polymers based on 2-(p-methylphenyl)-imidazole dicarboxylate. AB - Through solvothermal reactions of 2-(p-methylphenyl)-1H-imidazole-4,5 dicarboxylic acid (p-MePhH3IDC) with transition-metal ions, six coordination polymers [Pb2(p-MePhHIDC)(p-MePhH2IDC)2(phen)2]n (phen = 1,10-phenanthroline) (), [Pb(p-MePhH2IDC)2]n (), [Cd3(p-MePhHIDC)2(p-MePhH2IDC)2(H2O)2]n (), {[Cd(p MePhHIDC)(H2O)]4.H2O}n (), {[Cd2(p-MePhHIDC)2(4,4'-bipy)].4H2O}n (4,4'-bipy = 4,4'-bipyridine) () and [Mn3(p-MePhHIDC)2(p-MePhH2IDC)2(4,4'-bipy)]n () have been synthesized successfully. X-ray single-crystal analyses show that polymers have rich structural chemistry ranging from one-dimensional (), two-dimensional () to three-dimensional polymers (, , and ). In these polymers, the p-MePhH3IDC ligand shows flexible coordination modes tuned by different synthetical conditions, including the addition of coligands, temperature, pH value and so on. Furthermore, the polymers have been investigated by solid-state ultraviolet spectra and thermogravimetric analyses. PMID- 23982822 TI - Ammonia in the atmosphere: a review on emission sources, atmospheric chemistry and deposition on terrestrial bodies. AB - Gaseous ammonia (NH3) is the most abundant alkaline gas in the atmosphere. In addition, it is a major component of total reactive nitrogen. The largest source of NH3 emissions is agriculture, including animal husbandry and NH3-based fertilizer applications. Other sources of NH3 include industrial processes, vehicular emissions and volatilization from soils and oceans. Recent studies have indicated that NH3 emissions have been increasing over the last few decades on a global scale. This is a concern because NH3 plays a significant role in the formation of atmospheric particulate matter, visibility degradation and atmospheric deposition of nitrogen to sensitive ecosystems. Thus, the increase in NH3 emissions negatively influences environmental and public health as well as climate change. For these reasons, it is important to have a clear understanding of the sources, deposition and atmospheric behaviour of NH3. Over the last two decades, a number of research papers have addressed pertinent issues related to NH3 emissions into the atmosphere at global, regional and local scales. This review article integrates the knowledge available on atmospheric NH3 from the literature in a systematic manner, describes the environmental implications of unabated NH3 emissions and provides a scientific basis for developing effective control strategies for NH3. PMID- 23982823 TI - Particle size distribution of n-alkanes and polycyclic aromatic hydrocarbons (PAHS) in urban and industrial aerosol of Algiers, Algeria. AB - The distribution of ambient air n-alkanes and polycyclic aromatic hydrocarbons (PAHs) associated to particles with aerodynamic diameters lesser than 10 MUm (PM(10)) into six fractions (five stages and a backup filter) was studied for the first time in Algeria. Investigation took place during September of 2007 at an urban and industrial site of Algiers. Size-resolved samples (<0.49, 0.49-0.95, 0.95-1.5, 1.5-3.0, 3.0-7.2, and 7.2-10 MUm) were concurrently collected at the two sampling sites using five-stage high-volume cascade impactors. Most of n alkanes (~72 %) and PAHs (~90 %) were associated with fine particles <= 1.5 MUm in both urban and industrial atmosphere. In both cases, the n-alkane contents exhibited bimodal or weakly bimodal distribution peaking at the 0.95-1.5-MUm size range within the fine mode and at 7.3-10 MUm in the coarse mode. Low molecular weight PAHs displayed bimodal patterns peaking at 0.49-0.95 and 7.3-10 MUm, while high molecular weight PAHs exhibited mono-modal distribution with maximum in the <0.49-MUm fraction. While the mass mean diameter of total n-alkanes in the urban and industrial sites was 0.70 and 0.84 MUm, respectively, it did not exceed 0.49 MUm for PAHs. Carbon preference index (~1.1), wax% (10.1-12.8), and the diagnostic ratios for PAHs all revealed that vehicular emission was the major source of these organic compounds in PM(10) during the study periods and that the contribution of epicuticular waxes emitted by terrestrial plants was minor. According to benzo[a]pyrene-equivalent carcinogenic power rates, ca. 90 % of overall PAH toxicity across PM(10) was found in particles <= 0.95 MUm in diameter which could induce adverse health effects to the population living in these areas. PMID- 23982824 TI - A Visual Basic simulation software tool for performance analysis of a membrane based advanced water treatment plant. AB - A Visual Basic simulation software (WATTPPA) has been developed to analyse the performance of an advanced wastewater treatment plant. This user-friendly and menu-driven software is based on the dynamic mathematical model for an industrial wastewater treatment scheme that integrates chemical, biological and membrane based unit operations. The software-predicted results corroborate very well with the experimental findings as indicated in the overall correlation coefficient of the order of 0.99. The software permits pre-analysis and manipulation of input data, helps in optimization and exhibits performance of an integrated plant visually on a graphical platform. It allows quick performance analysis of the whole system as well as the individual units. The software first of its kind in its domain and in the well-known Microsoft Excel environment is likely to be very useful in successful design, optimization and operation of an advanced hybrid treatment plant for hazardous wastewater. PMID- 23982825 TI - Chest X-ray screening for lung cancer: overdiagnosis, endpoints, and randomized population trials. AB - Publication of the National Lung Screening Trial (NLST) generated excitement by concluding that CT screening reduces lung cancer mortality when compared to chest X-ray (CXR) screening. In contrast, CXR screening has long been considered to be ineffective. This is because randomized population trials (RPTs) have failed to demonstrate significant mortality reductions in populations randomized to CXR screening. While these studies demonstrate that CXR screening is associated with significant survival advantages, these advantages have been widely interpreted as spurious, due to the inference that CXR screening leads to substantial lung cancer overdiagnosis. Indeed, the reality of the overdiagnosis hypothesis is the only alternative to the conclusion that CXR screening was effective in these trials and that survival more accurately reflected the benefit of CXR screening than mortality. Mortality comparisons would be biased if randomization fails to create comparison groups with an equal probability of mortality from the target cancer. The objective of this manuscript is to review existing RPTs on CXR screening for lung cancer, and to analyze which endpoint most accurately reflects screening efficacy. We conclude that the evidence supports that CXR screening is superior to no screening, and the magnitude of overdiagnosis is minimal in the context of CXR screening. PMID- 23982826 TI - The effect of ultrasound on the expression of CNTF gene, a possible cause of ultrasound influence on the rate of injured peripheral nerve regeneration. AB - In this article we evaluate the effects of ultrasound radiation and its causes on the rate of injured peripheral nerve regeneration by crushing the sciatic nerve of rats with hemostatic forceps. The rats were divided into three test and one control groups. The test groups were radiated using three different types of ultrasound parameters while the control group just received sham expose. The amount of nerve regeneration was measured via functional test by extracting sciatic functional index from rats paw prints. The results showed that one of the test group parameters had the best functional results compared to other groups. Obtaining this outcome, the investigations continued by 50 rats with crushed sciatic nerve. These rats again divided into two test and control groups while for the test group the best parameters were assigned. In different time intervals compound muscle action potential wave was recorded from five rats of each group. Then their sciatic nerves were extracted to measure the amount of ciliary neurotropic factor gene expression by real time polymerase chain reaction. Crush injury sets the sciatic functional index to about -90 and compound muscle action potential to 6.8 mV in both control and test groups. After the period of treatment with ultrasound, the sciatic functional index reached the value of -25 in control group and -10 in test group and compound muscle action potential value reached 11 in control and 18 in test group. The results of electrophysiological tests confirmed the results of functional tests. At the end of the second, third and fourth weeks, the outcomes of real time polymerase chain reaction showed that the expression of ciliary neurotropic factor gene in test group was higher than control group as well as the amount in test group was approximately 11, 2 and 6 times higher than test group in corresponding weeks. Hence we can conclude that increase in the expression of ciliary neurotropic factor gene, as a nerve growth factor, following ultrasound radiation, can be considered as the reason of the effect of ultrasound on the rate of injured nerve regeneration. PMID- 23982827 TI - A novel human Fab antibody for Trop2 inhibits breast cancer growth in vitro and in vivo. AB - Human trophoblastic cell surface antigen 2 (Trop2) has been suggested as an oncogene, which is associated with the different types of tumors. In this study, a human Fab antibody against Trop2 extracellular domain was isolated from phage library by phage display technology, and characterized by ELISA, FACS, fluorescence staining and Western blotting analysis. MTT, apoptosis assay and wound healing assay were employed to evaluate the inhibitory effects of Trop2 Fab on breast cancer cell growth in vitro, while tumor-xenograft model was employed to evaluate the inhibitory effects on breast cancer growth in vivo. The results showed that Trop2 Fab inhibited the proliferation, induced the apoptosis and suspended the migration of MDA-MB-231 cells in a dose dependent manner. The expression caspase-3 was activated, and the expression of Bcl-2 was reduced while that of Bax was elevated in MDA-MB-231 cells by treating with Trop2 Fab. In addition, Trop2 Fab inhibited the growth of breast cancer xenografts and the expression of Bcl-2 was reduced while that of Bax was elevated in xenografts. Trop2 Fab, which was isolated successfully in this research, is a promising therapeutic agent for the treatment of Trop2 expressing breast cancer. PMID- 23982828 TI - Tiny hair tuft: a clue for occipital cephalocele. AB - Recurrent meningitis is a rare problem and can be due to alterations in immune system, or craniospinal defect. Any clue either in patient's history or physical examination would be helpful for avoiding unnecessary and tiring tests. Here we present the case of a child with recurrent bacterial meningitis who had an unnoticed hair tuft on the occipital region. The final diagnosis was occipital cephalocele with a rare presentation of a tiny tuft of hair. PMID- 23982829 TI - Yield of screening for TB and HIV among children failing to thrive in Botswana. AB - BACKGROUND: Failure to thrive (FTT) is a sign of tuberculosis (TB) and human immunodeficiency virus (HIV) infection. We assessed TB and HIV prevalence in children with FTT at one clinic in Botswana. METHODS: In July 2010, we screened all children attending a 'Well Child' clinic for FTT. Children with FTT were referred to a paediatrician who: (i) assessed causes of FTT, (ii) evaluated for HIV and TB and (iii) reviewed the patient chart for evaluations for TB and HIV. RESULTS: Of 919 children screened, 176 (19%) had FTT. One hundred eighteen (67%) children saw a paediatrician, and of these, 95 (81%) completed the TB evaluation. TB was newly diagnosed in 6 of 95 (6%). At review, HIV status was known in 23 of 118 (19%). Ninety-five had an unknown HIV status. Forty-five (47%) tested for HIV; all tested HIV-negative. CONCLUSION: TB and HIV screening among children with FTT diagnosed TB in 6% of cases completing an evaluation, but no new HIV infections. PMID- 23982832 TI - Chronic spontaneous right coronary artery dissection. PMID- 23982833 TI - Intracavitary cardiac hydatid cysts with a high risk of thromboemboli. Invasive nature of cardiac echinococcosis. AB - Hydatid cysts are a serious health problem in many countries that raise farm animals, and they usually involve the liver and lungs. Although cardiac involvement is a rare manifestation of hydatid cyst disease, its early diagnosis and surgical management are crucial. Patients with cardiac hydatidosis may develop acute life-threatening complications secondary to their invasion of surrounding cardiac structures, such as cyst rupture together with systemic and pulmonary dissemination. Therefore, surgical excision is the definitive method of treatment for cardiac hydatid cysts in order to prevent these potential life threatening complications, even for asymptomatic patients. Herein, we report the case of a 36-year-old man who initially presented with pleuritic chest pain, hemoptysis, and dyspnea. This was followed by the revelation of multiple cardiopericardial hydatid cysts which were discovered via transesophageal echocardiography and multislice computed tomography. In this case, there was a higher risk of cyst rupture and thromboembolism during systemic and pulmonary circulation due to the invasive nature of the cysts which were located in the left atrium as well as between the pulmonary artery and aorta. The patient successfully underwent the removal of the multiple cardiac cysts under cardiopulmonary bypass by taking into account their relationship with the surrounding cardiac structures and the potential risk of local, systemic, and pulmonary dissemination. A pathological evaluation of the surgical specimens confirmed the diagnosis of cardiac echinococcosis and the aggressive nature of the cardiopericardial hydatid cysts by demonstrating their myocardial invasion. PMID- 23982834 TI - Pericardial cyst. PMID- 23982837 TI - Seven-year incidence of age-related cataracts among an elderly Chinese population in Shihpai, Taiwan: The Shihpai Eye Study. AB - PURPOSE: To report the 7-year incidence of age-related cataracts in a metropolitan Chinese elderly population. METHODS: The Shihpai Eye Study 2006 included 460 (55.8%) of 1361 participants in the 1999 baseline survey for a follow-up eye examination. Cataract was graded by one ophthalmologist using the Lens Opacities Classification System III. RESULTS: The 7-year incidence of pure nuclear opacity was 18.5% (95% confidence interval [CI]: 12.7%-24.3%)]; 34.7% (95% CI: 27.6%-41.8%) for cortical opacity; and 0.6% (95% CI: 0%-1.8%) for posterior subcapsular opacity. On the other hand, 11.6% (95% CI: 6.8%-16.4%) participants developed both nuclear and cortical opacity, 3.5% (95% CI: 0.8% 6.2%) nuclear and posterior subcapsular opacity; and 1.7% (95% CI: 0%-3.6%) cortical and posterior subcapsular opacity. A total of 3.5% (95% CI: 0.8%-6.2%) of participants developed all three types of cataract. Nuclear cataract was significantly associated with current smoking (P = 0.04; relative risk [RR]: 2.05; 95% CI: 1.05-3.99). Males were almost half as likely (P = 0.04; RR: 0.57; 95% CI: 0.34-0.97) to develop cortical opacity, whereas participants with a history of diabetes were approximately twice as likely to develop cortical opacity (P = 0.05; RR 2.43; 95% CI: 1.02-5.81). A higher level of education (P = 0.03; RR: 0.40; 95% CI: 0.18-0.91) and a higher body mass index (P = 0.02; RR: 0.28; 95% CI: 0.10-0.79) was protective of posterior subcapsular cataract. CONCLUSIONS: This study indicated a high incidence of cortical opacities and lower incidence of nuclear opacities compared with Caucasians. Posterior subcapsular opacity incidence and cataract surgery rate were comparable. PMID- 23982838 TI - Laser capture microdissection-directed profiling of glycolytic and mTOR pathways in areas of selectively ablated Muller cells in the murine retina. AB - PURPOSE: We have reported previously down-regulation of key metabolic pathways, the glycolytic and mTOR pathways, from a global retinal microarray analysis after selective Muller cell ablation in a novel transgenic model. The purpose of the present study was to examine changes in expression of key molecules of glycolytic and mTOR pathways specifically in patches of Muller cell loss. METHODS: Eyes were enucleated 1 and 3 months after induced Muller cell ablation, directly embedded in optimal cutting temperature medium, and snap frozen in liquid nitrogen. Laser capture microdissection (LCM) was conducted to dissect patches of Muller cell loss for quantitative RT-PCR (qRT-PCR) analysis of key genes of the glycolytic (glyceraldehyde-3-phosphate dehydrogenase, enolase 1 and 2, lactate dehydrogenase A and B) and mTOR pathways (insulin-like growth factor receptor 1, phosphatidylinositide-3-kinase, Akt1, and regulatory-associated protein of mTOR). Protein validations were performed by immunohistochemistry. RESULTS: The LCM directed qRT-PCR analysis of Muller cell ablated specimens demonstrated reduced transcription of genes involved in the glycolytic and mTOR metabolic pathways. Of the proteins we chose to study, only enolase 1 was expressed by Muller cells. Other glycolytic and mTOR pathway proteins were expressed by photoreceptor inner and outer segments, which were lost in patches of Muller cell ablation. CONCLUSIONS: We found suppression of genes encoding various glycolytic and mTOR pathway-associated enzymes in areas of Muller cell loss. This appeared mainly to be due to loss of photoreceptor inner and outer segments. The consequences of metabolic derangement caused by Muller cell ablation warrant further investigation. PMID- 23982836 TI - Carotid and popliteal artery intima-media thickness in patients with poor oral hygiene and the association with acute-phase reactants. AB - PURPOSE: The aim of this study was to evaluate whether poor oral hygiene is associated with carotid and popliteal arterial intima-media thickness, which is one of the predictors of future progression of sub-clinical atherosclerosis, and highsensitivity C-reactive protein (hsCRP) and fibrinogen levels. METHODS: A specialised dentist checked the patients and selected 550 patients during periodontal examinations, according to their oral hygiene. The patients had no history of atherosclerotic disease. Carotid and popliteal artery B-mode ultrasonographic examinations and hsCRP and fibrinogen levels were analysed at baseline and after a mean of 6.2 months. The patients were scored on the DMFT index for the number of decayed (D), missing (M), and filled (F) teeth (T). We also used the Silness-Loe plaque index (SLI) to evaluate oral hygiene and dental plaque. The patients were divided into two groups using the DMFT and SLI criteria. Group I had a DMFT index score from 0 to 3 and SLI index score of 0 or 1. Group II had a DMFT index score from 4 to 28 and SLI index score of 2 or 3. RESULTS: A significant association was observed between dental status, oral hygiene, carotid and popliteal artery intima-media thickness and hsCRP level. Patients with increasing DMFT and SLI scores correlated with increasing carotid artery intima-media thickness. CONCLUSIONS: The results clearly showed that chronic poor oral hygiene and tooth loss are related to sub-clinical atherosclerotic changes in the carotid arteries and may be indicative of future progression of atherosclerosis. PMID- 23982840 TI - Enhancing performance while avoiding damage: a contribution of macular pigment. AB - PURPOSE: To compare action spectra for visual discomfort in the fovea and the parafovea and to determine the effect of macular pigment (MP). METHODS: Visual discomfort thresholds to lights from 440 to 600 nm were obtained for six young (<35 y), visually normal subjects with a wide range of MP densities (0.10-0.71 at 30' eccentricity). Foveal and parafoveal conditions were assessed. Discomfort thresholds were also obtained for xenon-white light (partially absorbed by MP), and a broadband yellow (outside the absorption band of MP). MP was measured psychophysically using heterochromatic flicker photometry (HFP). RESULTS: For the parafovea, discomfort sensitivity (1/threshold) increased sharply with decreasing wavelength for all subjects. Commensurate with a subject's MP level, MP significantly reduced visual discomfort to short wavelengths (including xenon white light) for central viewing. CONCLUSIONS: MP simultaneously reduces visual discomfort and protects from light damage at short wavelengths. As a result, MP increases the range of safe and comfortable light levels. Because higher light levels enable improved visual sensitivity for fine detail, these findings indicate that the spectral absorption properties and spatial distribution of MP combine to protect the retina while enhancing visual performance. The action spectrum for visual discomfort closely matches the risk for acute light damage to the retinal pigment epithelium, and it is consistent with a major influence from the intrinsically photosensitive retinal ganglion cells containing melanopsin. We suggest that MP interacts with nonimage-forming retinal input to achieve the dual outcomes of visual discomfort reduction and protection from light damage. PMID- 23982839 TI - ABCA4 gene screening by next-generation sequencing in a British cohort. AB - PURPOSE: We applied a recently reported next-generation sequencing (NGS) strategy for screening the ABCA4 gene in a British cohort with ABCA4-associated disease and report novel mutations. METHODS: We identified 79 patients with a clinical diagnosis of ABCA4-associated disease who had a single variant identified by the ABCA4 microarray. Comprehensive phenotypic data were obtained, and the NGS strategy was applied to identify the second allele by means of sequencing the entire coding region and adjacent intronic sequences of the ABCA4 gene. Identified variants were confirmed by Sanger sequencing and assessed for pathogenicity by in silico analysis. RESULTS: Of the 42 variants detected by prescreening with the microarray, in silico analysis suggested that 34, found in 66 subjects, were disease-causing and 8, found in 13 subjects, were benign variants. We detected 42 variants by NGS, of which 39 were classified as disease causing. Of these 39 variants, 31 were novel, including 16 missense, 7 splice site-altering, 4 nonsense, 1 in-frame deletion, and 3 frameshift variants. Two or more disease-causing variants were confirmed in 37 (47%) of 79 patients, one disease-causing variant in 36 (46%) subjects, and no disease-causing variant in 6 (7%) individuals. CONCLUSIONS: Application of the NGS platform for ABCA4 screening enabled detection of the second disease-associated allele in approximately half of the patients in a British cohort where one mutation had been detected with the arrayed primer extension (APEX) array. The time- and cost efficient NGS strategy is useful in screening large cohorts, which will be increasingly valuable with the advent of ABCA4-directed therapies. PMID- 23982841 TI - Stimulus-induced changes of reflectivity detected by optical coherence tomography in macaque retina. AB - PURPOSE: To investigate the properties and origin of retinal intrinsic signals by functional optical coherence tomography (fOCT) in macaque retinas. METHODS: We modified a spectral domain OCT system to be able to give short-duration flashes or continuous light stimulation to the retina of three adult macaque monkeys (Macaca mulatta) under general anesthesia. Changes in the intensities of the OCT signals following the stimulus were determined. RESULTS: Stimulus-evoked decreases or increases in the OCT signals were observed in the photoreceptor inner segment ellipsoids and outer segments, respectively. Experiments with focal and colored stimuli confirmed that these fOCT signals originated from the photoreceptors. No diffuse changes in the OCT signals were detected in the inner retinal layers; however, there were slow changes in small discrete areas where the retinal vessels were located. The polarity of the fOCT signals in the inner retinal layer was dependent on each activated region, and one of the possible sources of the reflectance changes was the light-scattering changes of the retinal vessels. CONCLUSIONS: The fOCT signals in the macaque retina consist of at least three components: light-scattering changes from the photoreceptor inner segment ellipsoids, light-scattering changes from the outer segments, and slow light-scattering changes from the blood vessels in the inner retina. This technique has the potential of mapping local neuronal activity three dimensionally and may help in the diagnosis of retinal disorders of different retinal origins. PMID- 23982842 TI - Complement factor C3a alters proteasome function in human RPE cells and in an animal model of age-related RPE degeneration. AB - PURPOSE: Complement activation plays an unequivocal role in the pathogenesis of age-related macular degeneration (AMD). More recent evidence suggests an additional role in AMD for the ubiquitin proteasome pathway (UPP), a protein degradation nanomachinery present in all types of eukaryotic cells. The purpose of this study was to elaborate on these findings and investigate whether the complement system directly contributes to derangements in the UPP through the activated complement components C3a and C5a. METHODS: In the retinal pigment epithelial cells (RPE) of monocyte chemoattractant protein-1-deficient CCL2(-/-) mice, a mouse model that may serve as a model for age-related atrophic degeneration of the RPE, proteasome function was investigated by immunohistochemistry of household (beta5) and immuno (beta5i) subunit expression. Subsequently, proteasome overall activity was determined using the BodipyFl Ahx3L3VS probe in primary-cultured human retinal pigment epithelial cells (HRPE) cells that were exposed to different stimuli including C3a and C5a, using confocal laser scanning microscopy and flow cytometry. Gene expression and protein levels of proteasome subunits alpha7, PA28alpha, beta5, and beta5i were also studied in RPE cells after exposure to IFN-gamma, C3a, and C5a by real-time PCR and Western blotting. RESULTS: Retinal pigment epithelial cells of CCL2(-/-) mice showed immunoproteasome upregulation. C3a, but not C5a supplementation, induced a decreased proteasome overall activity in HRPE cells, whereas mRNA and protein levels of household proteasome and immunoproteasome subunits were unaffected. CONCLUSIONS: In HRPE cells, C3a induces decreased proteasome-mediated proteolytic activity, whereas in a mouse model of age-related RPE atrophy, the immunoproteasome was upregulated, indicating a possible role for complement driven posttranslational alterations in proteasome activity in the cascade of pathologic events that result in AMD. PMID- 23982843 TI - Patient-related and system-related barriers to glaucoma follow-up in a county hospital population. AB - PURPOSE: To identify the barriers to glaucoma follow-up and to assess how ethnicity influences the effect of such barriers among patients in a county hospital population. METHODS: This cross-sectional study included 152 patients, 76 with poor clinic follow-up and 76 with good clinic follow-up, who were recruited at the San Francisco General Hospital glaucoma clinic as part of a case control study. All subjects were required to be established patients with glaucoma initially seen and diagnosed in the clinic at least 1 year before enrollment. An oral questionnaire pertaining to the barriers to follow-up for glaucoma, as well as patient ethnicity, was administered to all participating subjects. The main outcome measure was the prevalence of significant barriers to follow-up, both overall and stratified by ethnicity. RESULTS: The most prevalent barriers to follow-up included long clinic waiting times (75%), appointment scheduling difficulties (38%), the effect of other medical or physical comorbidities (29%), and difficulties related to medical interpretation (23%). While several barriers were cited as being important across different ethnicities, Latinos and Asian-Pacific Islanders were particularly affected by difficulties related to medical interpretation (P = 0.0001) and long waiting times in the clinic (P = 0.048). CONCLUSIONS: Understanding patient-reported barriers to glaucoma follow-up and their variation based on ethnicity may give providers insight as to why patients do not adhere to follow-up recommendations. Strategies to improve follow-up may include reduced clinic wait times, simplified appointment scheduling, and provision of appropriate education and counseling regardless of the patient's native language and ethnicity. PMID- 23982844 TI - Comparison of macular choroidal thickness among patients older than age 65 with early atrophic age-related macular degeneration and normals. AB - PURPOSE: To compare macular choroidal thickness between patients older than 65 years with early atrophic age-related macular degeneration (AMD) and normals. METHODS: This was a consecutive, cross-sectional observational study. Enhanced depth imaging spectral-domain optical coherence tomography using horizontal raster scanning at 12 locations throughout the macula was performed in one eye of consecutive patients presenting with large soft drusen alone, drusen with additional features of early AMD, or a normal fundus. Choroidal thickness was measured at 7 points for each raster scan in the central 3 mm of the macula (total 84 points per eye). In addition, a single subfoveolar measurement was obtained for each eye. RESULTS: One hundred fifty eyes of 150 patients were included. There was no significant difference between mean refractive error for each diagnosis category via one-way ANOVA (P = 0.451). Mean macular choroidal thickness (CT) was 235 +/- 49 MUm (range, 125-334 MUm; median 222 MUm) for normals, 161 +/- 39 MUm (range, 89-260 MUm; median = 158 MUm) for the drusen group, and 115 +/- 40 MUm (range, 22-256 MUm; median = 112 MUm) for patients with AMD. Mean macular CT was significantly different via one-way ANOVA among all diagnosis categories (P < 0.001). CONCLUSIONS: The presence of features of early AMD without geographic atrophy and/or soft drusen alone is associated with decreased mean macular CT in vivo compared to that in patients with no chorioretinal pathology. Using enhanced depth imaging, measurement of a single subfoveolar choroidal thickness is highly correlated to mean central macular CT. PMID- 23982845 TI - Vitreous levels of active ocriplasmin following intravitreal injection: results of an ascending exposure trial. AB - PURPOSE: To characterize the levels of active ocriplasmin over a period of ascending time points (range, 5 minutes to 7 days) from intravitreal injection of a 125-MUg dose to sampling. METHODS: During this 7-week controlled, open-label, phase 2 study, a single intravitreal (125 MUg) dose of ocriplasmin was injected into the midvitreous of one eye of each of 34 patients prior to their scheduled primary pars plana vitrectomy. Patients were allocated to vitreous sampling at the beginning of the surgery, which occurred 5 to 30 minutes, 31 to 60 minutes, 2 to 4 hours, 24 +/- 2 hours, or 7 +/- 1 days after ocriplasmin injection, or to the control group, who received no ocriplasmin injection. RESULTS: With increasing time from ocriplasmin injection to vitreous sampling, mean active ocriplasmin concentration decreased. While at 5 to 30 minutes postinjection, mean active ocriplasmin concentration was 11,597.7 ng/mL, within 31 to 60 minutes from injection the mean active ocriplasmin concentration had reduced to 8108.7 ng/mL; and by 24 hours after injection, half of the patients (2/4) had active ocriplasmin concentrations below the lower limit of quantification (LLQ; <272.4 ng/mL), as did all samples from the day 7 and control groups. No ocular serious adverse events (SAEs) were reported in patients who received ocriplasmin, while three ocular SAEs occurred in the study eye of one patient in the control group (1/38; 2.6%). CONCLUSIONS: Active ocriplasmin concentrations in vitreous samples decreased with increasing time from injection to sample, with enzyme levels in all of the patients in the day 7 group being comparable to those in the control group. (ClinicalTrials.gov number, NCT01159665.). PMID- 23982846 TI - Horizontal saccade dynamics after childhood monocular enucleation. AB - PURPOSE: We investigated the effects of monocularity on oculomotor control by examining the characteristics of the horizontal saccades of people with one eye, and comparing them to those of a group of age-matched controls who viewed the stimuli monocularly and binocularly. METHODS: Participants were tested in a no gap, no-overlap saccadic task using a video-based remote eye tracker. One group consisted of unilaterally eye enucleated participants (N = 15; mean age, 31.27 years), the other of age-matched people with normal binocular vision (N = 18; mean age, 30.17 years). RESULTS: The horizontal saccade dynamics of enucleated people are similar to those of people with normal binocularity when they view monocularly and, with the exception of latency, when they view binocularly. The data show that the monocular saccades of control and enucleated observers have longer latencies than the binocular saccades of the control group, the saccades of the enucleated observers are as accurate as those of the controls viewing monocularly or binocularly, smaller saccades are more accurate than the larger ones, and abducting saccades are faster than adducting saccades. CONCLUSIONS: Our data suggest that the true monocularity produced by early enucleation does not result in slower visual processing in the afferent (sensory) pathway, or in deficits in the efferent (motor) pathways of the saccadic system. Possible mechanisms to account for the effects of monocular vision on saccades are discussed. PMID- 23982847 TI - Influence of freezing stress on morphological alteration and biofilm formation by Listeria monocytogenes: relationship with cell surface hydrophobicity and membrane fluidity. AB - The morphological changes and adhesive property of three Listeria monocytogenes strains submitted to freezing stress (-20 degrees C) were studied. The atomic force micrographs showed a reduction in the cell size and an evolution to coccoid shape. The phenotypic slime production of L. monocytogenes and the expression of the adhesive gene were investigated before and after 10 months of incubation in salmon at -20 degrees . Our results showed that after ten months, stressed stains become more adherent and able to produce slime. In addition, we noted that this pathogen presents same physiological changes to adapt to starvation conditions. The cellular fatty acids composition of adhered and floating cells of three L. monocytogenes strains was taken into consideration. The stressed strains presented different chain lengths and therefore an increase in the hydrophobicity level. Moreover, we noted that the adhesive property of L. monocytogenes strains affects the Benzalkonium chloride bacterial sensitivity which increased after biofilm formation. PMID- 23982848 TI - Vector strength after Goldberg, Brown, and von Mises: biological and mathematical perspectives. AB - The vector strength, a number between 0 and 1, is a classical notion in biology. It was first used in neurobiology by Goldberg and Brown (J Neurophys 31:639-656, 1969) but dates back at least to von Mises (Phys Z 19:490-500, 1918). It is widely used as a means to measure the periodicity or lack of periodicity of a neuronal response to an outside periodic signal. Here, we provide a self contained and simple treatment of a closely related notion, the synchrony vector, a complex number with the vector strength as its absolute value and with a definite phase that one can directly relate to a biophysical delay. The present analysis is essentially geometrical and based on convexity. As such it does two things. First, it maps a sequence of points, events such as spike times on the time axis, onto the unit circle in the complex plane so that for a perfectly periodic repetition, a single point on the unit circle appears. Second, events hardly ever occur periodically, so that we need a criterion of how to extract periodicity out of a set of real numbers. It is here where convex geometry comes in, and a geometrically intuitive picture results. We also quantify how the events cluster around a period as the vector strength goes to 1. A typical example from the auditory system is used to illustrate the general considerations. Furthermore, von Mises' seminal contribution to the notion of vector strength is explained in detail. Finally, we generalize the synchrony vector to a function of angular frequency, not fixed on the input frequency at hand and indicate its potential as a "resonating" vector strength. PMID- 23982849 TI - Resonating vector strength: what happens when we vary the "probing" frequency while keeping the spike times fixed. AB - The synchrony vector, whose length stands for the vector strength (VS), is a means to quantify the amount of periodicity in a neuronal response to a given periodic signal, say, the stimulus. One usually chooses the input angular frequency and evaluates the synchrony vector as a weighted sum of exponentials taken at given experimental spike times of the neuronal response in combination with the driving input frequency. Given the experimental spike times, we replace the stimulus frequency by a variable probing frequency, study the synchrony vector in dependence upon this probing frequency, i.e., as a function of the frequency as a real variable, and exhibit both mathematically and experimentally a resonance behavior once the variable frequency is in the neighborhood of the stimulus frequency. Furthermore, a "resonating" VS is shown to be quite useful since one need not know the external frequency but can simply stick to the given spike times and analyze the ensuing resonance as the frequency varies, for example, to determine at the same time a "best" frequency and the corresponding VS. Finally, it is straightforward to determine the corresponding phase originating from, say, a delay as well. PMID- 23982850 TI - Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia pain. AB - OBJECTIVE: There is vast evidence to support the presence of brain aberrations in patients with fibromyalgia (FM), and it is possible that central plasticity is critical for the transition from acute to chronic pain. The aim of the present study was to investigate the relationship between brain structure and function in patients with FM. METHODS: Functional connectivity of the brain during application of intermittent pressure-pain stimuli and measures of brain structure were compared between 26 patients with FM and 13 age- and sex-matched healthy controls. Magnetic resonance imaging (MRI) was performed to obtain high resolution anatomic images and functional MRI scans of the brain, which were used for measurements of pain-evoked brain activity. RESULTS: FM patients displayed a distinct overlap between decreased cortical thickness, decreased brain volumes, and decreased functional regional coherence in the rostral anterior cingulate cortex. The morphometric changes were more pronounced with longer exposure to FM pain. In addition, there was evidence of an association between structural and functional changes in the mesolimbic areas of the brain and the severity of comorbid depression symptoms in FM patients. CONCLUSION: The combined integration of structural and functional measures allowed for a unique characterization of the impact of FM pain on the brain. These data may lead to the identification of early structural and functional brain alterations in response to pain, which could be used to develop markers for predicting the development of FM and other pain disorders. PMID- 23982851 TI - Association of BRCA1 germline mutations in young onset triple-negative breast cancer (TNBC). AB - BACKGROUND: BRCA1-associated breast cancers have been associated to a triple negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. PATIENTS AND METHODS: From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. RESULTS: Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. CONCLUSION: Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1. PMID- 23982852 TI - SEOM clinical guidelines for the treatment of nasopharyngeal carcinoma 2013. AB - Nasopharyngeal carcinoma cases are not frequently encountered in our environment. Local stages are treated with radiotherapy. For advanced local stages, the association of chemotherapy with radiotherapy improves the rates of survival. In the case of metastatic disease stages, treatment requires platinum-based chemotherapy and patients may achieve a long survival time. PMID- 23982853 TI - SEOM clinical guidelines for the treatment of head and neck cancer (HNC) 2013. AB - Head and neck cancer represents 5 % of oncologic cases in adults. Early stage treatments are local with surgery and/or radiotherapy. For locally advanced stages, treatment requires radiotherapy combined with platinum-based drugs or cetuximab. Induction chemotherapy should be considered for selected cases. In the case of metastatic disease, adjuvant or palliative treatment is based on platinum agents and cetuximab. PMID- 23982854 TI - Return to work following breast cancer treatment: the employers' side. AB - PURPOSE: Research on employers' experiences with return to work (RTW) of employees with breast cancer is lacking. Employers seem to be the key people to create good working conditions. Our aim is to explore how Belgian employers experience their role and responsibility in RTW of employees with breast cancer. METHODS: Using a qualitative design (Grounded Theory) 17 employers from the public (7), private (5) and non-profit (5) sector, directly involved in the RTW process, were interviewed. The analysis was based on the Qualitative Analysis Guide of Leuven (QUAGOL) with constant data comparison and interactive team dialogue as important guiding characteristics. RESULTS: RTW of employees with breast cancer is experienced by employers as an intangible process that is difficult to manage. This was expressed in (1) concern, referring to the employer's personal and emotional involvement, (2) uncertainty about the course of illness and the guidance needed by the employee and (3) specific dilemmas in the RTW process (when does one infringe on employee privacy; employee vs. organization interest; employers' personal vs. professional role). The degree to which this was experienced related to variety in organizational, employer, and employee factors. CONCLUSIONS: The findings of this study confirm the importance of the employer's involvement in RTW of employees with breast cancer and contribute to a better understanding of its complexity. The employers did their best to grasp the intangibility of the RTW process. Further research is needed to refine these findings and to discover the specific needs of employers regarding supporting RTW of breast cancer patients. PMID- 23982855 TI - Effect of nitrous oxide inhalation on pain after propofol and rocuronium injection. AB - PURPOSE: This prospective, double-blind, placebo-controlled study was designed to determine the efficacy of nitrous oxide (N(2)O) in alleviating the pain that followed sequential injection of propofol and rocuronium. METHODS: A total of 205 adult patients (age, 18-68 years) received one of the following combinations: NaCl and 100 % O(2) (group C); 0.5 mg/kg lidocaine and 100 % O(2) (group L); NaCl and a mixture of 67 % N(2)O/O(2) (group N); or 0.5 mg/kg lidocaine and a mixture of 67 % N(2)O/O(2) (group LN). Vein occlusion was released after 1 min, and 5 ml propofol was injected over 10 s. Pain was evaluated on a visually enlarged, laminated, numeric rating (0-10) scale. The remainder of the induction dose of propofol (with a 3-ml bolus of normal saline and 0.6 mg/kg rocuronium) was then injected. The response to the rocuronium injection was assessed with a four-point scale (0-3). RESULTS: The incidence and severity of pain from the propofol injection in groups L, N, and LN were significantly lower than those in group C (P < 0.001). Frequency and intensity of the withdrawal response were significantly less in groups N and LN than in groups C and L (no response, P < 0.001; severe response, P < 0.001). CONCLUSIONS: Pretreatment with inhaled N(2)O can reduce the pain associated with propofol and rocuronium injection. Moreover, N(2)O (with or without lidocaine) is more effective than lidocaine alone in reducing rocuronium-related withdrawal reactions associated with sequential injection of propofol and rocuronium. PMID- 23982857 TI - Ultrasound-guided subcutaneous cervical plexus block for carotid endarterectomy in a patient with chronic obstructive pulmonary disease. PMID- 23982856 TI - Cerebral dysfunction after coronary artery bypass surgery. AB - Cerebral dysfunction after cardiac surgery remains a devastating complication and is growing in importance with our aging populations. Neurological complications following cardiac surgery can be classified broadly as stroke, encephalopathy (including delirium), or postoperative cognitive dysfunction (POCD). These etiologies are caused primary by cerebral emboli, hypoperfusion, or inflammation that has largely been attributed to the use of cardiopulmonary bypass. Preventative operative strategies, such as off-pump coronary artery bypass grafting (CABG), can potentially reduce the incidence of postoperative neurological complications by avoiding manipulation of the ascending aorta. Although off-pump CABG is associated with reduced risk of stroke, there are no convincing differences in POCD between off-pump and on-pump CABG. Recently, the focus of postoperative neurological research has shifted from managing cardiopulmonary bypass to patient-related factors. Identifying changes in brains of aged individuals undergoing cardiac surgery may improve strategies for preventing cerebral dysfunction. Advanced age is associated with more undiagnosed cerebrovascular disease and is a major risk factor for stroke and POCD following cardiac surgery. Preoperative cerebrovascular evaluation and adaptation of surgical strategies will provide preventative approaches for cerebral dysfunction after CABG. This review focuses on recent findings of the relationship between perioperative stress and underlying fragility of the brain in cardiac surgical patients. PMID- 23982858 TI - Comparison of donor-site morbidity and satisfaction between anterolateral thigh and parascapular free flaps in the same patient. AB - The purpose of this study was to compare donor-site morbidity after anterolateral thigh (ALT) and parascapular (PS) free flap harvest in the same patient. A total of 13 patients were included in this study. Because of initial flap loss, each patient received ALT as well as PS free flap transplantation. A total of 10 patients were available for follow-up. The average follow-up time was 44.5 months. Besides physical examination, range of motion and scar dimensions were assessed to objectify donor-site deficiencies. The subjective donor-site morbidity was assessed by the patients using a self-report questionnaire. In addition, patients were requested to state their donor-site preference. ALT donor site revealed more sensitivity deficiencies compared with the PS harvest site (8 vs. 4). The latter provoked less functional impairments (1 vs. 2). Scar dimensions were larger at PS harvest site (25.8 * 4.3 cm vs. 23.3 * 3.6 cm). Patients' satisfaction was in favor of the PS donor site (1.9 vs. 2.7). Among the 10 patients, 7 patients preferred the PS and 3 patients preferred the ALT donor site. Comparison of donor-site morbidities in the same patient reveals a valuable tool to diminish individual bias. Despite the low number of cases, we were able to demonstrate the superiority of PS compared with ALT donor sites.The Level of Evidence of the study is III. PMID- 23982859 TI - Arm regeneration in two species of cuttlefish Sepia officinalis and Sepia pharaonis. AB - To provide quantitative information on arm regeneration in cuttlefish, the regenerating arms of two cuttlefish species, Sepia officinalis and Sepia pharaonis, were observed at regular intervals after surgical amputation. The third right arm of each individual was amputated to ~10-20 % starting length. Arm length, suction cup number, presence of chromatophores, and behavioral measures were collected every 2-3 days over a 39-day period and compared to the contralateral control arm. By day 39, the regenerating arm reached a mean 95.5 +/ 0.3 % of the control for S. officinalis and 94.9 +/- 1.3 % for S. pharaonis. The process of regeneration was divided into five separate stages based on macroscopic morphological events: Stage I (days 0-3 was marked by a frayed leading edge; Stage II (days 4-15) by a smooth hemispherical leading edge; Stage III (days 16-20) by the appearance of a growth bud; Stage IV (days 21-24) by the emergence of an elongated tip; and Stage V (days 25-39) by a tapering of the elongated tip matching the other intact arms. Behavioral deficiencies in swimming, body postures during social communication, and food manipulation were observed immediately after arm amputation and throughout Stages I and II, returning to normal by Stage III. New chromatophores and suction cups in the regenerating arm were observed as early as Stage II and by Stage IV suction cup number equaled that of control arms. New chromatophores were used in the generation of complex body patterns by Stage V. These results show that both species of cuttlefish are capable of fully regenerating lost arms, that the regeneration process is predictable and consistent within and across species, and provide the first quantified data on the rate of arm lengthening and suction cup addition during regeneration. PMID- 23982860 TI - Association of bone morphogenetic protein 6 with exocrine gland dysfunction in patients with Sjogren's syndrome and in mice. AB - OBJECTIVE: Primary Sjogren's syndrome (SS) is characterized by autoimmune activation and loss of function in secretory epithelia. The present study was undertaken to investigate and characterize changes in the epithelia associated with the loss of gland function in primary SS. METHODS: To identify changes in epithelial gene expression, custom microarrays were probed with complementary RNA (cRNA) isolated from minor salivary glands (MSGs) of female patients with primary SS who had low focus scores and low salivary flow rates, and the results were compared with those obtained using cRNA from the MSGs of sex-matched healthy volunteers. The effect of bone morphogenetic protein 6 (BMP-6) on salivary gland function was tested using adeno-associated virus-mediated gene transfer to the salivary glands of C57BL/6 mice. RESULTS: A significant increase in expression of BMP-6 was observed in RNA isolated from SS patients compared with healthy volunteers. Overexpression of BMP-6 locally in the salivary or lacrimal glands of mice resulted in the loss of fluid secretion as well as changes in the connective tissue of the salivary gland. Assessment of the fluid movement in either isolated acinar cells from mice overexpressing BMP-6 or a human salivary gland cell line cultured with BMP-6 revealed a loss in volume regulation in these cells. Lymphocytic infiltration in the submandibular gland of BMP-6 vector-treated mice was increased. No significant changes in the production of proinflammatory cytokines or autoantibodies associated with SS (anti-Ro/SSA and anti-La/SSB) were found after BMP-6 overexpression. CONCLUSION: In addition to identifying BMP-6 expression in association with xerostomia and xerophthalmia in primary SS, the present results suggest that BMP-6-induced salivary and lacrimal gland dysfunction in primary SS is independent of the autoantibodies and immune activation associated with the disease. PMID- 23982861 TI - Effective inhibition of nasopharyngeal carcinoma in vitro and in vivo by targeting glycolysis with oxamate. AB - Elevated aerobic glycolysis in cancer cells (Warburg effect) has been observed in many tumor types including nasopharyngeal carcinoma (NPC), which can often be detected clinically using FDG-PET. However, the role of glycolysis in supporting the growth of NPC cells and its therapeutic implications still remain to be investigated. In the present study, we showed that the LDH inhibitor oxamate significantly suppressed NPC cell proliferation in vitro and tumor growth in vivo, yet exhibited minimum toxicity to normal nasopharyngeal epithelial cells in vitro and was well tolerated in mice. Moreover, oxamate exhibited cytotoxic effect in NPC cells under hypoxia. Mechanistic study showed that oxamate significantly inhibited LDH activity, leading to a substantial decrease in glucose uptake and lactate production. Combination of oxamate with a mitochondrial respiratory complex I inhibitor resulted in a significant depletion of cellular ATP and a synergistic killing of cancer cells. Our results suggest that inhibition of glycolysis by oxamate is an effective therapeutic strategy for treatment of NPC and that combination of this compound with mitochondrial targeted agents may improve the therapeutic activity. PMID- 23982862 TI - Two-dimensional liquid chromatography for direct chiral separations: a review. AB - Separation of enantiomers remains a challenge owing to their identical physical and chemical properties in an achiral environment, and research on specialized separation techniques such as multidimensional achiral-chiral liquid chromatography continues to resolve individual enantiomers in complex samples. Recent advances in application of multidimensional liquid chromatography applied to chiral analysis are reviewed. For this reason, benefits of achiral-chiral coupling are shown, with emphasis in applications on biological and pharmaceutical fields as well as pesticide analysis. A description of standard instrumental setup in both heart-cut and comprehensive multidimensional liquid chromatography is shown. The most broadly used chiral stationary phases for multidimensional liquid chromatography are summarized. An extensive overview of different interface designs applied to complex samples is presented. PMID- 23982863 TI - How can survival processing improve memory encoding? AB - We investigated the psychological mechanism of survival processing advantage from the perspective of false memory in two experiments. Using a DRM paradigm in combination with analysis based on signal detection theory, we were able to separately examine participants' utilization of verbatim representation and gist representation. Specifically, in Experiment 1, participants rated semantically related words in a survival scenario for a survival condition but rated pleasantness of words in the same DRM lists for a non-survival control condition. The results showed that participants demonstrated more gist processing in the survival condition than in the pleasantness condition; however, the degree of item-specific processing in the two encoding conditions did not significantly differ. In Experiment 2, the control task was changed to a category rating task, in which participants were asked to make category ratings of words in the category lists. We found that the survival condition involved more item-specific processing than did the category condition, but we found no significant difference between the two encoding conditions at the level of gist processing. Overall, our study demonstrates that survival processing can simultaneously promote gist and item-specific representations. When the control tasks only promoted either item-specific representation or gist representation, memory advantages of survival processing occurred. PMID- 23982864 TI - Transfer RNA: a dancer between charging and mis-charging for protein biosynthesis. AB - Transfer RNA plays a fundamental role in the protein biosynthesis as an adaptor molecule by functioning as a biological link between the genetic nucleotide sequence in the mRNA and the amino acid sequence in the protein. To perform its role in protein biosynthesis, it has to be accurately recognized by aminoacyl tRNA synthetases (aaRSs) to generate aminoacyl-tRNAs (aa-tRNAs). The correct pairing between an amino acid with its cognate tRNA is crucial for translational quality control. Production and utilization of mis-charged tRNAs are usually detrimental for all the species, resulting in cellular dysfunctions. Correct aa tRNAs formation is collectively controlled by aaRSs with distinct mechanisms and/or other trans-factors. However, in very limited instances, mis-charged tRNAs are intermediate for specific pathways or essential components for the translational machinery. Here, from the point of accuracy in tRNA charging, we review our understanding about the mechanism ensuring correct aa-tRNA generation. In addition, some unique mis-charged tRNA species necessary for the organism are also briefly described. PMID- 23982865 TI - Non-coding RNA annotation: deciphering the second genetic code. PMID- 23982866 TI - Less invasive palliative surgery for spinal metastases. AB - BACKGROUND: There may be patients with spinal metastasis for whom neither vertebroplasty/kyphoplasty nor open surgery is appropriate. Percutaneous pedicle screw fixation (PPSF) may fill the gap between techniques. OBJECTIVES: To assess the outcome of the PPSF and radiotherapy/chemotherapy. METHODS: PPSF was performed for 16 patients (mean age, 57 +/- 12 years) with pathologic fractures, Tomita score >= 5, 3-6 months of life expectancy, minimal epidural tumor extension and a Nurick grade better than 3. PPSF was performed under general anesthesia. Collapsed vertebra(e) was restored during assembly of contoured rod. Vertebroplasty was then performed for 14 patients at the restored vertebra(e). The Eastern Cooperative Oncology Group (ECOG) performance status grade was 2 in seven patients and 3 in nine. The numerical rating pain score (NRS) was 8.2 +/- 1.8. The follow-up was 261 +/- 193 days. RESULTS: All patients walked home at postoperative day 4-7. Radiotherapy and chemotherapy was performed for 8 and 10 patients, respectively. ECOG was improved or stationary in 13/16 (81%) at 1-month and improved in 6/6 of alive patients at the last follow-up. NRS was 3.8 +/- 2.0. The median ambulation and survival times were 207 and 222 days. CONCLUSION: Using a multidisciplinary approach, quality of life can be improved for fragile patients with spinal metastasis. PMID- 23982868 TI - Abstracts of CIRSE (Cardiovascular and Interventional Radiological Society of Europe) 2013. September 14-18, 2013. Barcelona, Spain. PMID- 23982867 TI - Elevated preoperative C-reactive protein levels are a risk factor for the development of postoperative infectious complications following elective colorectal surgery. AB - PURPOSE: The present study was designed to evaluate the relationship between the preoperative C-reactive protein levels and the incidence of postoperative infectious complications in patients undergoing colorectal surgery. METHODS: This study was a retrospective cohort study of a consecutive series of 464 patients who underwent elective colorectal resection between April 2010 and March 2012. We evaluated the patients' preoperative conditions, including the preoperative C reactive protein levels, surgical content, and incidence of postoperative infectious complications. RESULTS: Postoperative infectious complications occurred in 133 patients (28.7 %). In the univariate analysis, male gender, rectal surgery, open surgery, elevated preoperative white blood cell counts, elevated preoperative C-reactive protein levels, extended operative times, large amounts of blood loss during surgery, and ostomy formation were found to be significantly associated with the incidence of postoperative infectious complications. In the multivariate analysis, elevated preoperative C-reactive protein levels (OR per mg/dl = 1.17, 95 % CI = 1.02-1.37, P = 0.02) and large amounts of blood loss during surgery (OR per 100 g = 1.13, 95 % CI = 1.06-1.23, P < 0.01) were found to be independently associated with the incidence of postoperative infectious complications. CONCLUSIONS: This study provides evidence of an association between the preoperative C-reactive protein level and the incidence of postoperative infectious complications following colorectal surgery, which should be further confirmed in prospective and appropriately designed studies. PMID- 23982869 TI - Changes in technique and efficiency after high-intensity exercise in cross country skiers. AB - This study investigated changes in technique and efficiency after high-intensity exercise to exhaustion in elite cross-country skiers. Twelve elite male skiers completed 4 min submaximal exercise before and after a high-intensity incremental test to exhaustion with the G3 skating technique on a 5% inclined roller-ski treadmill. Kinematics and kinetics were monitored by instrumented roller skis, work rate was calculated as power against roller friction and gravity, aerobic metabolic cost was determined from gas exchange, and blood lactate values indicated the anaerobic contribution. Gross efficiency was the work rate divided by aerobic metabolic rate. A recovery period of 10 min between the incremental test and the posttest was included to allow the metabolic values to return to baseline. Changes in neuromuscular fatigue in upper and lower limbs before and after the incremental test were indicated by peak power in concentric bench press and squat-jump height. From pretest to posttest, cycle length decreased and cycle rate increased by approximately 5% (P < 0.001), whereas the amount of ski forces did not change significantly. Oxygen uptake increased by 4%, and gross efficiency decreased from 15.5% +/- 0.7% to 15.2% +/- 0.5% from pretest to posttest (both P < .02). Correspondingly, blood lactate concentration increased from 2.4 +/- 1.0 to 6.2 +/- 2.5 mmol/L (P < .001). Bench-press and squat-jump performance remained unaltered. Elite cross-country skiers demonstrated a less efficient technique and shorter cycle length during submaximal roller-ski skating after high-intensity exercise. However, there were no changes in ski forces or peak power in the upper and lower limbs that could explain these differences. PMID- 23982870 TI - Age class influence on the yield of edible fungi in a managed Mediterranean forest. AB - Lack of information and difficulty in predicting wild edible sporocarp yields is blocking its integration in forest management. In the Mediterranean area, this nontimber forest product has increased its market value, consumption demand, and interest over the last decade. In this work, sampling year and stand age effects are analyzed in order to advance knowledge of edible fungi community structure, dynamics, and production. Weekly autumnal sporocarp monitoring was performed from 1997 to 2011 in a Pinus pinaster managed forest in central Spain. After applying a random stand age-stratified survey, 21 plots of 150 m(2) have been set with three per stand age class. The forest age classes have been defined as follows: 0 10 years, mixture of parent and regenerated trees, 11-20, 21-40, 41-60, 61-90, and over 90 years. A total of 153 species belonging to 56 genera were recorded, 55 of which are edible. The production of edible sporocarps was 19.8 kg ha(-1), representing 31 % of total production. Sporocarp production presents a sharp interannual variability with autumns 62 times more productive than others. The most abundant edible species in terms of fresh weight per hectare has been Lactarius deliciosus with 7.0 kg ha(-1). Edible fungi yields registered a significant decline in 10 years following regenerative cutting. The presence of parent trees significantly increases production with regard to the first class. The highest production of edible species occurs in the middle age, 41-60 years, and in the following classes, a decrease is produced. L. deliciosus production registered differences with age, manifesting in a high yield in young stands (11 20 years) and significant recovery in woodlands near to the cutting. PMID- 23982872 TI - Association of rs2233678 and rs2233679 polymorphisms in the PIN1 gene with cancer risk: a meta-analysis. AB - To data, epidemiological studies have assessed the association between peptidyl propyl-cis/trans isomerase 1 (PIN1) gene polymorphisms and cancer risk, including breast cancer, hepatocellular carcinoma, lung cancer, esophageal cancer, head and neck squamous cell carcinoma, and laryngeal squamous cell cancer. However, the results of these studies remain controversial. We aimed to examine the associations between two SNPs (rs2233678 and rs2233679) of PIN1 gene and cancer risk by conducting a meta-analysis of case-control studies. A total of seven publications were included in this meta-analysis for both rs2233678 and rs2233679. Overall, rs2233678 polymorphism was found to be associated with decreased cancer risk in four genetic models (C-allele vs. G-allele: odd ratio (OR) = 0.73, 95% confidence interval (CI): 0.60-0.88; CC vs. GG: OR = 0.55, 95% CI: 0.36-0.84; CC+CG vs. GG: OR = 0.72, 95% CI 0.58-0.90; CC vs. CG+GG: OR = 0.58, 95% CI 0.38-0.89). However, the rs2233679 polymorphism of PIN1 gene did not appear to have an influence on caner susceptibility. In the subgroup analysis by cancer type, we observed that the PIN1 rs2233678 polymorphism was significantly associated with decreased breast cancer risk (C-allele vs. G-allele: OR = 0.73, 95% CI: 0.60-0.89; CC+CG vs. GG: OR = 0.71, 95% CI 0.57-0.89). Further subgroup analyses showed that the PIN1 rs2233678 polymorphism was associated with decreased cancer risk among Asian people (C-allele vs. G-allele: OR = 0.63, 95% CI: 0.51-0.79; CC vs. GG: OR = 0.44, 95% CI: 0.25-0.80; CC+CG vs. GG: OR = 0.63, 95% CI 0.50-0.79; CC vs. CG+GG: OR = 0.47, 95% CI 0.26-0.86). In conclusion, PIN1 rs2233678 polymorphism might be a potential biomarker for cancer risk among Asians, especially for breast cancer. Further large and well-designed studies are needed to confirm this conclusion. PMID- 23982873 TI - Ethnicity modifies the association between functional microRNA polymorphisms and breast cancer risk: a HuGE meta-analysis. AB - Common functional polymorphisms in the promoter region of microRNAs (miRNAs), based on multiple lines of evidence, might participate in transcriptional regulation and other biological processes, which interact to increase the risk of developing breast cancer. Since 2005, many studies have investigated the association between breast cancer risk and common single nucleotide polymorphisms (SNPs) in miRNAs. However, the findings of several meta-analyses are inconclusive or ambiguous. The aim of this Human Genome Epidemiology meta-analysis was to determine more precisely the relationship between common miRNA polymorphisms and breast cancer risk. Twelve case-control studies with a total of 7,170 breast cancer patients and 8,783 healthy controls were included. Eight SNPs in miRNA genes were examined. When all eligible studies were pooled in the meta-analysis, the miR-196a-2 rs11614913*T, miR-499 rs3746444*T, and miR-605 rs2043556*A alleles predicted a decreased risk of breast cancer among Asians, while not Caucasians. In addition, the miR-27a rs895919*C allele might be a protective factor for breast cancer among Caucasians. However, for the miR-146a rs2910164 (G>C), miR 149 rs2292832 (G>T), miR-373 rs12983273 (C>T), and miR-423 rs6505162 (C>A) polymorphisms, we failed to find any significant association with the risk of breast cancer in any genetic model. In conclusion, the current meta-analysis supports that the miR-196a-2 rs11614913*T, miR-499 rs3746444*T, miR-605 rs2043556*A, and miR-27a rs895919*C alleles might be protective factors for breast cancer. PMID- 23982874 TI - Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells--an in vitro and in silico study. AB - Targeting breast cancer stem cells (BCSCs) offers a promising strategy for breast cancer treatment. We examined the plant alkaloid ellipticine for its efficacy to inhibit the expression of aldehyde dehydrogenase 1 class A1 (ALDH1A1)-positive BCSCs by in vitro and in silico methods. At 3 mM concentration, ellipticine decreased the expression of ALDH1A1-positive BCSCs by 62% (p = 0.073) in the MCF7 cell line and by 53% (p = 0.024) in the SUM159 cell line compared to vehicle treated cultures. Ellipticine significantly reduced the formation of mammospheres, whereas paclitaxel enhanced mammosphere formation in both the treated cell lines. Interestingly, when treated with a combination of ellipticine and paclitaxel, the percentage of ALDH1A1-positive BCSCs dropped by several fold in vitro. A homology model of Homo sapiens ALDH1A1 was built using the crystal structure of NAD-bound sheep liver class I aldehyde dehydrogenase [PDB ID: 1BXS] as a template. Molecular simulation and docking studies revealed that the amino acids Asn-117 and Asn-121, Glu-249, Cys-302, and Gln-350, present in the active site of human ALDH1A1, played a vital role in interacting with the drug. The present study suggests that ellipticine reduces the proliferation and self renewal ability of ALDH1A1-positive BCSCs and can be used in combination with a cytotoxic drug like paclitaxel for potential targeting of BCSCs. PMID- 23982875 TI - Overexpression of MACC1 protein and its clinical implications in patients with glioma. AB - Metastasis associated in colon cancer 1 (MACC1) has been regarded as a novel potential therapeutic target for multiple cancers. However, the impact of MACC1 in glioma remains unclear. The aim of this study was to analyze the correlation of MACC1 expression with the clinicopathological features of glioma. MACC1 mRNA and protein expression levels in human glioma tissues were detected by quantitative real-time polymerase chain reaction and immunohistochemistry assays, respectively. MACC1 mRNA and protein expression were both significantly higher in glioma tissues than in corresponding noncancerous brain tissues (both P < 0.001). In addition, statistical analysis suggested that high MACC1 expression was significantly correlated with advanced pathological grade (P = 0.004) and that patients with high expression of MACC1 protein exhibited a poorer prognosis than those with low MACC1 expression. Furthermore, Cox multivariate analysis showed that MACC1 overexpression was an independent prognostic factor for predicting the overall survival of glioma patients. In conclusion, expression of MACC1 in glioma could be adopted as a candidate biomarker for the diagnosis of clinical stage and for assessing prognosis, indicating for the first time that MACC1 may play an important role in the tumor development and progression in glioma. MACC1 might be considered as a novel therapeutic target against this cancer. PMID- 23982877 TI - Association of XRCC5 VNTR polymorphism with the development of chronic myeloid leukemia. AB - Double-strand breaks (DSBs) inducing agents influence the fidelity of DNA repair in both normal cells and leukemic cells, causing major genomic instability. In eukaryotic cells, non-homologous end joining pathway (NHEJ) is the major mechanism for DSB repair. Human X-ray repair cross-complementing 5 (XRCC5) gene encodes for the protein KU86, an important component of NHEJ pathway. Variable number of tandem repeats (VNTR) polymorphism (rs 6147172) in the promoter region of XRCC5 gene was shown to have effect on gene expression and was found to be associated with the development of several cancers. We analyzed VNTR polymorphism of XRCC5 gene in 461 chronic myeloid leukemia (CML) cases and 408 controls by polymerase chain reaction. Our results showed that frequency of 0R/0R genotype was significantly elevated in CML cases compared to that of controls (p = 0.05). Significant difference in the genotype distribution was observed between cases and controls (p = 0.02). The risk of CML development was found to be elevated for individuals carrying lower repeats (1R p = 0.03; 0R p = 0.007). Elevated 0R/0R genotype frequency was found to be significantly associated with early age at onset (<= 30 years) and slightly elevated in chronic phase and poor hematologic response to imatinib mesylate. The influence of zero repeat on enhanced expression of XRCC5 might confer risk to error-prone repair leading to genomic instability and CML. Hence, the VNTR polymorphism in the promoter region of XRCC5 gene could serve as an important prognostic marker in CML development. PMID- 23982876 TI - Vascular endothelial growth factor (VEGF) -2578C/A and -460C/T gene polymorphisms and lung cancer risk: a meta-analysis involving 11 case-control studies. AB - The aim of this meta-analysis is to generate large-scale evidence on whether common vascular endothelial growth factor (VEGF) gene polymorphisms (-2578C/A [dbSNP: rs699947] and -460C/T [dbSNP: rs833061]) are associated with lung cancer. A literature search of PubMed, Embase, Web of Science, Cochrane Library, and CBM databases was conducted to identify all eligible studies published before May 3, 2013. Crude odds ratios (ORs) with their corresponding confidence intervals (95% CIs) were used to evaluate the strength of the association. Eleven case-control studies were included with a total of 3,861 lung cancer cases and 3,676 controls in this meta-analysis. For the VEGF -2578C/A polymorphism, the combined results showed that there exist highly significant risk factors for individuals carrying the A allele resulting in lung cancer, and the magnitude of this effect was similar in smoker patients and squamous cell carcinoma (SCC) patients. Unlike the situation with the -2578C/A polymorphism, the VEGF -460C/T polymorphism is not associated with the risk of lung cancer in neither Asians nor Caucasians. However, when stratified according to smoking status and histological types of lung cancer, we found that the T allele (-460C/T) was associated with decreased lung cancer risk among nonsmoker patients and SCC patients. Our findings showed that the -2578C/A polymorphism may increase lung cancer risk, especially in smoker patients and SCC patients, whereas the -460C/T polymorphism may decrease lung cancer risk, especially in nonsmoker patients and SCC patients. PMID- 23982878 TI - Association of TGF-beta1 -509C/T polymorphisms with breast cancer risk: evidence from an updated meta-analysis. AB - Epidemiological studies have evaluated the association between transforming growth factor-beta1 (TGF-beta1) -509C/T polymorphisms and breast cancer risk. However, the results remain conflicting rather than conclusive. The aim of this study was to comprehensively clarify the association between TGF-beta1 -509C/T polymorphisms and breast cancer risk. All relevant studies were searched in the electronic databases. The potential sources of heterogeneity were detected with the chi-square-based Q test. The strength of associations between TGF-beta1 509C/T polymorphisms and breast cancer risk was measured by odds ratio (OR) and 95 % confidence intervals (CI). Publication bias was tested by Begg's test and Egger's test. A total of 10 studies including 10,913 cases and 14,187 controls were included in the meta-analysis. Overall, there was no evidence of significant association of TGF-beta1 -509C/T polymorphisms with breast cancer risk (TT vs. CC [OR = 0.97, 95 % CI = 0.83-1.14]; CT vs. CC [OR = 1.05, 95 % CI = 0.90-1.22]; TT + CT vs. CC [OR = 0.99, 95 % CI = 0.91-1.08]; T allele vs. C allele [OR = 0.99, 95 % CI = 0.93-1.06]). Similar results were also found in the subgroup analyses by ethnicity and source of control. When stratified by estrogen receptor (ER) status, TT genotype and T allele were associated with a decreased ER-positive breast cancer risk (OR = 0.66, 95 % CI = 0.49-0.90 and OR = 0.85, 95 % CI = 0.75 0.96, respectively). The present meta-analysis results suggest that TGF-beta1 509C/T variants may not contribute to the risk of breast cancer overall. However, T allele may be a potential protective factor for developing ER-positive breast cancer. Well-designed studies with larger sample size were required to verify our findings further. PMID- 23982879 TI - Association of RASSF1A promoter methylation with gastric cancer risk: a meta analysis. AB - Ras-association domain family 1A (RASSF1A), a candidate tumor suppressor gene, is frequently silenced and inactivated by hypermethylation of its promoter region in several human tumors. However, the association between RASSF1A promoter methylation and gastric cancer risk remains conflicting. The aim of this study was to assess the association of RASSF1A promoter methylation with gastric cancer risk by a comprehensive meta-analysis. Relevant studies were identified by searches of PubMed and Web of Science databases with no restrictions. Combined odds ratio (OR) and 95 % confidence interval (CI) were used to assess the strength of the association between RASSF1A promoter methylation and gastric cancer risk. A chi-square-based Q test and sensitivity analyses were performed to test the between-study heterogeneity and the contributions of single studies to the final results, respectively. Funnel plots were carried out to evaluate publication bias. Overall, a significant association was observed between RASSF1A promoter methylation and gastric cancer risk (OR, 12.67; 95 % CI, 8.12-19.78; p < 0.001) with no between-study heterogeneity. Subgroup analyses further revealed that gastric cancer risk was increased for individuals carrying the methylated RASSF1A compared with those with unmethylated RASSF1A. In addition, no publication bias was detected in the overall and subgroup analyses. This study identified a strong association between RASSF1A promoter methylation and risk of gastric cancer and highlighted a promising potential for RASSF1A promoter methylation in gastric cancer risk prediction. PMID- 23982881 TI - Novel sesquiterpenoid glycosides and sesquiterpenes from the roots of Illicium henryi. AB - Seven new sesquiterpenoid glycosides, consisting of one thapsan-type (1), two capnellane-type (2 and 3), four floridanolide sesquiterpene glycosides (4-7), and one new azulene-type sesquiterpene (8), along with six known sesquiterpenes (9 14) were isolated from the roots of Illicium henryi. The structures of 1-8 were elucidated by extensive spectroscopic analyses and chemical methods. The absolute configurations of 1, 2, and 8 were determined based on Rh2(OCOCF3)4-induced CD, Mo2(OAc)4-induced CD data, and calculated electronic circular dichroism (ECD), respectively. Compound 1 was found to exhibit weak neurotoxicant activity. PMID- 23982880 TI - Comprehensive assessment of the association between DNA repair gene XRCC3 rs861539 C/T polymorphism and lung cancer risk. AB - A few case-control studies were performed to assess the association between X-ray repair cross-complementing group 3 (XRCC3) rs861539 C/T polymorphism and lung cancer susceptibility, but no consistent finding was reported. In the present study, we performed a meta-analysis of 14 case-control studies with a total of 7,869 lung cancer cases and 10,778 controls to provide a comprehensive assessment of the association between XRCC3 rs861539 C/T polymorphism and lung cancer risk. Pooled odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CIs) were calculated to assess the strength of the association. Overall, there was no significant association between XRCC3 rs861539 C/T polymorphism and lung cancer risk under all genetic models [OR (95 % CI) for T versus C, 1.00 (0.89-1.13), P = 0.99; OR (95 % CI) for TT versus CC, 1.07 (0.81-1.41), P = 0.62; OR (95 % CI) for TT/CT versus CC, 0.95 (0.84-1.07), P = 0.39; OR (95 % CI) for TT versus CT/CC, 1.10 (0.86-1.39), P = 0.62]. In the subgroup analyses of both Asians and Caucasians, there was still no significant association between XRCC3 rs861539 C/T polymorphism and lung cancer risk under all genetic models (All P values were more than 0.05). However, there was an obvious association between XRCC3 rs861539 C/T polymorphism and decreased risk of lung cancer in the subgroup analysis of the mixed population (All P values were less than 0.05). In addition, there was some risk of publication bias in the meta-analysis, and there was obvious discrepancy in the findings between studies with large sample size and studies with small sample size in the meta-analysis. The meta-analysis indicates that the association between XRCC3 rs861539 C/T polymorphism and lung cancer risk is still uncertain owing to the obvious discrepancy in the findings between studies with large sample size and studies with small sample size. More studies with large sample size are needed to further assess the association. PMID- 23982882 TI - Towards cancer cell-specific phototoxic organometallic rhenium(I) complexes. AB - Over the recent years, several Re(I) organometallic compounds have been shown to be toxic to various cancer cell lines. However, these compounds lacked sufficient selectivity towards cancer tissues to be used as novel chemotherapeutic agents. In this study, we probe the potential of two known N,N-bis(quinolinoyl) Re(I) tricarbonyl complex derivatives, namely Re(I) tricarbonyl [N,N-bis(quinolin-2 ylmethyl)amino]-4-butane-1-amine (Re-NH2) and Re(I) tricarbonyl [N,N-bis(quinolin 2-ylmethyl)amino]-5-valeric acid (Re-COOH), as photodynamic therapy (PDT) photosensitizers. Re-NH2 and Re-COOH proved to be excellent singlet oxygen generators in a lipophilic environment with quantum yields of about 75%. Furthermore, we envisaged to improve the selectivity of Re-COOH via conjugation to two types of peptides, namely a nuclear localization signal (NLS) and a derivative of the neuropeptide bombesin, to form Re-NLS and Re-Bombesin, respectively. Fluorescent microscopy on cervical cancer cells (HeLa) showed that the conjugation of Re-COOH to NLS significantly enhanced the compound's accumulation into the cell nucleus and more specifically into its nucleoli. Importantly, in view of PDT applications, the cytotoxicity of the Re complexes and their bioconjugates increased significantly upon light irradiation. In particular, Re-Bombesin was found to be at least 20-fold more toxic after light irradiation. DNA photo-cleavage studies demonstrated that all compounds damaged DNA via singlet oxygen and, to a minor extent, superoxide production. PMID- 23982883 TI - XPF protein levels determine sensitivity of malignant melanoma cells to oxaliplatin chemotherapy: suitability as a biomarker for patient selection. AB - As the options for systemic treatment of malignant melanoma (MM) increase, the need to develop biomarkers to identify patients who might benefit from cytotoxic chemotherapy becomes more apparent. In preclinical models, oxaliplatin has activity in cisplatin-resistant cells. In this study, we have shown that oxaliplatin forms interstrand crosslinks (ICLs) in cellular DNA and that loss of the heterodimeric structure-specific endonuclease XPF-ERCC1 causes hypersensitivity to oxaliplatin in mammalian cells. XPF deficiency resulted in late S-phase arrest and persistence of double-strand breaks following oxaliplatin treatment. In a panel of 12 MM cell lines, oxaliplatin sensitivity correlated with XPF and ERCC1 protein levels. The knockdown of ERCC1 and XPF protein levels by RNA interference increased sensitivity of cancer cells to oxaliplatin; overexpression of exogenous ERCC1 significantly decreased drug sensitivity. Following immunohistochemical optimization, XPF protein levels were quantified in MM tissue samples from 183 patients, showing variation in expression and no correlation with prognosis. In 57 patients with MM treated with cisplatin or carboplatin, XPF protein levels did not predict the likelihood of clinical response. We propose that oxaliplatin should not be discarded as a potential treatment for MM on the basis of the limited activity of cisplatin in unselected patients. Moreover, we show that XPF-ERCC1 protein levels are a key determinant of the sensitivity of melanoma cells to oxaliplatin in vitro. Immunohistochemical detection of XPF appears suitable for development as a tissue biomarker for potentially selecting patients for oxaliplatin treatment in a prospective clinical trial. PMID- 23982884 TI - Letrozole combined with gonadotropin-releasing hormone analog for metastatic male breast cancer. AB - The role of aromatase inhibitors combined with gonadotropin-releasing hormone analog in metastatic male breast cancer patients remains unknown. In this retrospective study we evaluated the activity of letrozole combined with a gonadotropin-releasing hormone analog as a first- or second-line therapy for metastatic male breast cancer patients. 19 men entered the study. We did not observe any grade 3 or 4 adverse events. 2 patients (10.5 %) had complete response, 7 patients (36.8 %) experienced a partial response, 7 patients (36.8 %) had stable disease lasting >= 6 months, and 3 patients (15.8 %) had progressive disease. Overall, the disease control rate was 84.2 %. Median progression-free survival was 12.5 months (95 % CI 8.2-16.9), median overall survival was 35.8 months (95 % CI 24.4-49.2), 1- and 2-year survival rates were 89.5 and 67 %, respectively. Interestingly, 3 out of 4 patients treated with the combination following disease progression while on aromatase inhibitor monotherapy confirmed or improved the best overall response observed in the first-line setting. The combination of letrozole and gonadotropin-releasing hormone analog is effective and safe in hormone-receptor positive, metastatic male breast cancer patients. PMID- 23982885 TI - Preparation and characterization of hydrophilic composites AA/EPMA loaded with hydroxyapatite. AB - Copolymeric composites of acrylamide (AA) and 2,3-epoxypropyl methacrylate (EPMA) with hydroxyapatite (HA) load were studied. Swelling studies reports an anomalous or non-Fickian behavior following a good fitting to a pseudo second order mathematical treatment (alpha = 0.05, p < 0.0001). The composites showed a strong dependence on pH, related with the variations in the swelling behavior. The addition of load induces a diminution of swelling capacity and an increase of diametric tensile strength (DTS) ranging between 20 and 90 kPa. The calorimetric experiments showed two steps at 78 degrees C and 255 degrees C assigned to water loss and samples Tg. The drug control released was adjusted to a two-term equation obtaining a diffusion coefficient around 10(-5) cm(2) /s. The samples showed a significant bioactivity in vitro and it was certified by SEM, EDS and surface area calculus. PMID- 23982886 TI - Lipopolysaccharide increases the incidence of collagen-induced arthritis in mice through induction of protease HTRA-1 expression. AB - OBJECTIVE: The protease HTRA-1 is closely associated with rheumatoid arthritis (RA). The molecular mechanisms that control HTRA-1 expression are currently unknown. This study was undertaken to determine the regulatory role of Toll-like receptors (TLRs) on HTRA-1 expression in mice with collagen-induced arthritis (CIA) and in synovial cells from RA patients. METHODS: HTRA-1 messenger RNA and protein production in mouse fibroblasts, mouse macrophages, and freshly isolated RA patient synovial cells treated with TLR ligands were detected by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Arthritis incidence and severity were determined using clinical scores and histopathologic analysis. Involvement of HTRA-1 in lipopolysaccharide (LPS) increased arthritis incidence and severity in mice was determined using anti-HTRA 1 monoclonal antibody. The signal pathways involved in HTRA-1 expression were accessed by specific inhibitors, RNA interference, dual-luciferase reporter, and chromatin immunoprecipitation methods. RESULTS: LPS and tenascin-C, but not the other TLR ligands tested, strongly induced HTRA-1 expression. LPS significantly increased HTRA-1 expression in the joint tissue as well as arthritis incidence and severity in mice with CIA. Blocking HTRA-1 by antibody significantly decreased LPS-promoted CIA severity. Inhibiting NF-kappaB significantly decreased LPS-induced HTRA-1 expression in mouse and human cells. Dual-luciferase reporter assay and ChIP analysis showed that p65 directly binds to HTRA-1 promoter (amino acid 347). CONCLUSION: Our findings indicate that TLR-4 activation increases HTRA 1 expression through the NF-kappaB pathway in fibroblasts and macrophages. HTRA-1 expression is involved in the enhancing effects of LPS on CIA. This study offers new insights into the regulation of HTRA-1 expression via LPS/TLR-4 and the role of HTRA-1 in RA pathogenesis. PMID- 23982887 TI - Development and validation of an LCMS method to determine the pharmacokinetic profiles of caffeic acid phenethyl amide and caffeic acid phenethyl ester in male Sprague-Dawley rats. AB - A validated LCMS method was developed for the quantitative determination of caffeic acid phenethyl amide (CAPA) and caffeic acid phenethyl ester (CAPE) from rat plasma. Separation was achieved using a reverse-phase C12 HPLC column (150 * 2.00 mm, 4 um) with gradient elution running water (A) and acetonitrile (B). Mass spectrometry was performed with electrospray ionization in negative mode. This method was used to determine the pharmacokinetic profiles of CAPA and CAPE in male Sprague-Dawley rats following intravenous bolus administration of 5, 10 and 20 mg/kg of CAPA and 20 mg/kg of CAPE. The pharmacokinetic analysis suggests the lack of dose proportionality in the dose range of 5-20 mg/kg of CAPA. Total clearance values for CAPA ranged from 45 to 156 mL/min and decreased with increasing dose of CAPA. The volume of distribution for CAPA ranged from 17,750 to 52,420 mL, decreasing with increasing dose. The elimination half-life for CAPA ranged from 243.1 to 295.8 min and no statistically significant differences were observed between dose groups in the range of 5-20 mg/kg (p > 0.05). The elimination half-life for CAPE was found to be 92.26 min. PMID- 23982888 TI - Chronic kidney disease and the risk of incident gout among middle-aged men: a seven-year prospective observational study. AB - OBJECTIVE: The kidney is the major organ that facilitates excretion of urate in humans. Surprisingly, few studies have assessed whether a reduced glomerular filtration rate (GFR) and/or kidney damage is associated with a higher incidence of gout, and this study was undertaken to address this question. METHODS: Data from a 7-year followup of patients enrolled in the Multiple Risk Factor Intervention Trial, a primary prevention trial for cardiovascular disease among 12,866 men ages 35-57 years, were used for the present investigation. Presence of gout was determined by the study physicians from the original trial. Chronic kidney disease was defined using criteria similar to those proposed by the National Kidney Foundation. The Cox proportional hazards regression model was used to assess the association between gout and chronic kidney disease, after accounting for the effects of potential confounders. RESULTS: Overall, there were 722 cases of physician- diagnosed incident gout over 76,602 person-years of followup. The standardized incidence ratio of gout among those with chronic kidney disease was 1,217 (95% confidence interval [95% CI] 1,191-1,244). The adjusted hazard ratio (HR) among those with chronic kidney disease was 1.61 (95% CI 1.60-1.61). Each standard deviation decline in the estimated GFR was associated with an HR of 1.43 (95% CI 1.35-1.51). Including the serum urate level, as well as the urate-chronic kidney disease interaction term, as variables in the second analysis did not attenuate the HR. Proteinuria and hematuria, two markers of kidney damage, were associated with an elevated risk of gout independent of the estimated GFR. CONCLUSION: Chronic kidney disease manifesting as reduced glomerular function or as presence of blood or protein in the urine increases the risk of incident gout. PMID- 23982889 TI - Cadmium and cellular signaling cascades: interactions between cell death and survival pathways. AB - Cellular stress elicited by the toxic metal Cd(2+) does not coerce the cell into committing to die from the onset. Rather, detoxification and adaptive processes are triggered concurrently, allowing survival until normal function is restored. With high Cd(2+), death pathways predominate. However, if sublethal stress levels affect cells for prolonged periods, as in chronic low Cd(2+) exposure, adaptive and survival mechanisms may deregulate, such that tumorigenesis ensues. Hence, death and malignancy are the two ends of a continuum of cellular responses to Cd(2+), determined by magnitude and duration of Cd(2+) stress. Signaling cascades are the key factors affecting cellular reactions to Cd(2+). This review critically surveys recent literature to outline major features of death and survival signaling pathways as well as their activation, interactions and cross talk in cells exposed to Cd(2+). Under physiological conditions, receptor activation generates 2nd messengers, which are short-lived and act specifically on effectors through their spatial and temporal dynamics to transiently alter effector activity. Cd(2+) recruits physiological 2nd messenger systems, in particular Ca(2+) and reactive oxygen species (ROS), which control key Ca(2+)- and redox-sensitive molecular switches dictating cell function and fate. Severe ROS/Ca(2+) signals activate cell death effectors (ceramides, ASK1-JNK/p38, calpains, caspases) and/or cause irreversible damage to vital organelles, such as mitochondria and endoplasmic reticulum (ER), whereas low localized ROS/Ca(2+) levels act as 2nd messengers promoting cellular adaptation and survival through signal transduction (ERK1/2, PI3K/Akt-PKB) and transcriptional regulators (Ref1 Nrf2, NF-kappaB, Wnt, AP-1, bestrophin-3). Other cellular proteins and processes targeted by ROS/Ca(2+) (metallothioneins, Bcl-2 proteins, ubiquitin-proteasome system, ER stress-associated unfolded protein response, autophagy, cell cycle) can evoke death or survival. Hence, temporary or permanent disruptions of ROS/Ca(2+) induced by Cd(2+) play a crucial role in eliciting, modulating and linking downstream cell death and adaptive and survival signaling cascades. PMID- 23982890 TI - The isoflavone irilone contributes to the estrogenic potential of dietary supplements containing red clover. AB - A recent intervention study demonstrated the occurrence of irilone as second most abundant isoflavone next to daidzein in human plasma after consumption of a red clover-based dietary supplement (RCDS) containing predominately formononetin ? biochanin A > irilone (12 % of these isoflavones). To elucidate the relevance of this finding, in the present study (1) the representativeness of the isoflavone composition of the RCDS and (2) the estrogenic activity of irilone were investigated. Thus, major isoflavones were quantified in eight commercially available RCDS. Furthermore, the estrogenic activities of irilone and other isoflavones were determined by marker gene expression in Ishikawa and cell proliferation in MCF-7 cells. Irilone amounted to 1.8-10.9 mg/g capsule content and 5-18 % of the three major isoflavones, respectively, demonstrating the general occurrence of irilone in RCDS. Moreover, irilone significantly induced the activity of alkaline phosphatase (AlP) as well as AlP, progesterone receptor, and androgen receptor mRNA levels in Ishikawa cells. Furthermore, irilone significantly induced MCF-7 cell proliferation. Neither 17beta-estradiol (E2) induced AlP activity nor E2-induced MCF-7 cell proliferation was affected by irilone. ICI182,780 antagonized IRI-induced effects on both AlP activity and cell proliferation, suggesting an estrogen receptor agonistic mode of action. Taking into account the estrogenic activity of red clover isoflavones (formononetin, biochanin A, prunetin, glycitein) and their biotransformation products (daidzein, genistein, ethylphenol) as well as published plasma levels of isoflavones after consumption of RCDS, irilone could contribute approximately 50 % of the E2 equivalents estimated for daidzein. PMID- 23982891 TI - The effect of connectives on the selection of arguments: implicit consequentiality bias for the connective "but". AB - Recent studies about the implicit causality of inter-personal verbs showed a symmetric implicit consequentiality bias for psychological verbs. This symmetry is less clear for action verbs because the verbs assigning the implicit cause to the object argument (e.g. "Peter protected John because he was in danger.") tend to assign the implicit consequence to the same argument (e.g. "Peter protected John so he was not hurt."). We replicated this result by comparing continuations of inter-personal events followed by a causal connective "because" or a consequence connective "so". Moreover, we found similar results when the consequence connective was replaced by a contrastive connective "but". This result was confirmed in a second experiment where we measured the time required to imagine a consistent continuation for a fragment finishing with "but s/he ...". The results were consistent with a contrastive connective introducing a denial of a consequence of the previous event. The results were consistent with a model suggesting that thematic roles and connectives can predict preferred co reference relations. PMID- 23982892 TI - Berberine acts as a natural inhibitor of Wnt/beta-catenin signaling- identification of more active 13-arylalkyl derivatives. AB - Aberrant activation of the canonical Wnt/beta-catenin signaling pathway has been reported for numerous tumors of different origins. In most cases, mutations in components of the Wnt signaling pathway or in beta-catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/beta-catenin signaling is of specific therapeutic interest. Herein, we investigated the plant-derived isoquinoline alkaloid berberine, which has been reported to have anticancer activity, and synthetic 13-arylalkyl derivatives thereof for their effects on Wnt/beta-catenin signaling. Berberine did not show major effects on viability of HEK-293 embryonic kidney and HCT116 colon carcinoma cells and was not toxic in concentrations up to 20 uM. Berberine inhibited beta-catenin transcriptional activity and attenuated anchorage-independent growth. As a result of berberine treatment, cellular levels of active beta-catenin were reduced concomitant with an increase in the expression of E-cadherin. However, in unstimulated cells, the effects on beta-catenin levels were low. A screen of synthetic 13-arylalkyl berberine derivatives identified compounds exhibiting activities superior to those of the naturally occurring parent substance with more than 100-fold lower EC50 values for Wnt-repression. Thus, berberine and its synthetic derivatives represent potential therapeutic agents to inhibit Wnt/beta-catenin signaling in tumorigenesis. PMID- 23982893 TI - Evaluating the arcuate fasciculus with combined diffusion-weighted MRI tractography and electrocorticography. AB - The conventional model of language-related brain structure describing the arcuate fasciculus as a key white matter tract providing a direct connection between Wernicke's region and Broca's area has been called into question. Specifically, the inferior precentral gyrus, possessing both primary motor (Brodmann Area [BA] 4) and premotor cortex (BA 6), has been identified as a potential alternative termination. The authors initially localized cortical sites involved in language using measurement of event-related gamma-activity on electrocorticography (ECoG). The authors then determined whether language-related sites of the temporal lobe were connected, via white matter structures, to the inferior frontal gyrus more tightly than to the precentral gyrus. The authors found that language-related sites of the temporal lobe were far more likely to be directly connected to the inferior precentral gyrus through the arcuate fasciculus. Furthermore, tractography was a significant predictor of frontal language-related ECoG findings. Analysis of an interaction between anatomy and tractography in this model revealed tractrography to have the highest predictive value for language related ECoG findings of the precentral gyrus. This study failed to support the conventional model of language-related brain structure. More feasible models should include the inferior precentral gyrus as a termination of the arcuate fasciculus. The exact functional significance of direct connectivity between temporal language-related sites and the precentral gyrus requires further study. PMID- 23982895 TI - Structural glance into a novel anti-staphylococcal peptide. AB - Novel antimicrobial peptides are valuable molecules for developing anti-infective drugs to counteract the contemporary spread of microbial drug-resistance. Here we focus on a novel peptide (RKWVWWRNR-NH2) derived from the fragment 107-115 of the human lysozyme that displays a 20-fold increase in anti-staphylococcal activity. The conformational analysis of this peptide and its interaction with model lipidic phases-as assayed by circular dichroism and fluorescence spectroscopy show a noteworthy spectral change, which might be related to its anti staphylococcal activity. The secondary structure of peptide [K(108)W(111)] 107 115 hLz was dramatically affected through a single substitution at position 111 (Ala by Trp). Therefore, this conformational change might improve the interaction of the novel peptide with the bacterial plasma membrane. These results highlight the role of peptide secondary structure and the distribution of polar/nonpolar residues for the effective interaction of this peptide with the bacterial plasma membrane, a key step for triggering its lethal effect. This knowledge may contribute to the rational design of a new generation of antimicrobial peptides with increased efficacy developed from natural sources by simple screening tools. PMID- 23982894 TI - Medial olivocochlear-induced transient-evoked otoacoustic emission amplitude shifts in individual subjects. AB - Activation of the medial olivocochlear reflex (MOCR) can be assessed indirectly using transient-evoked otoacoustic emissions (TEOAEs). The change in TEOAE amplitudes when the MOCR is activated (medial olivocochlear (MOC) shift) has most often been quantified as the mean value in groups of subjects. The usefulness of MOC shift measurements may be increased by the ability to quantify significant shifts in individuals. This study used statistical resampling to quantify significant MOC shifts in 16 subjects. TEOAEs were obtained using transient stimuli containing energy from 1 to 10 kHz. A nonlinear paradigm was used to extract TEOAEs. Transient stimuli were presented at 30 dB sensation level (SL) with suppressor stimuli presented 12 dB higher. Contralateral white noise, used to activate the MOCR, was presented at 30 dB SL and was interleaved on and off in 30-s intervals during a 7-min recording period. Confounding factors of middle ear muscle reflex and slow amplitude drifts were accounted for. TEOAEs were analyzed in 11 1/3-octave frequency bands. The statistical significance of each individual MOC shift was determined using a bootstrap procedure. The minimum detectable MOC shifts ranged from 0.10 to 3.25 dB and were highly dependent on signal-to-noise ratio at each frequency. Subjects exhibited a wide range of magnitudes of significant MOC shifts in the 1.0-3.2-kHz region (median = 1.94 dB, range = 0.34 6.51 dB). There was considerable overlap between the magnitudes of significant and nonsignificant shifts. While most subjects had significant MOC shifts in one or more frequency bands below 4 kHz, few had significant shifts in all of these bands. Above 4 kHz, few significant shifts were seen, but this may have been due to lower signal-to-noise ratios. The specific frequency bands containing significant shifts were variable across individuals. Further work is needed to determine the clinical usefulness of examining MOC shifts in individuals. PMID- 23982896 TI - Potentiating toxicological interaction of single-walled carbon nanotubes with dissolved metals. AB - The present study explored the ecotoxicology of single-walled carbon nanotubes (SWCNTs) and their likely interaction with dissolved metals, with a focus on the effect of in vivo exposure in marine mussels. Any nano-scale effects were negated by the tendency of uncoated SWCNTs to agglomerate in water, particularly with high ionic strength as is the case in estuarine and full-strength seawater. However, SWCNTs, in combination with natural organic matter, remained suspended in seawater for long enough to become available to filter-feeding mussels, leading to their concentration on and increased contact with gill epithelia during exposure. For the first time, the authors describe a potentiating toxicological effect, expressed as DNA strand breaks obtained using the comet assay, on divalent metals afforded by negatively charged SWCNT agglomerates in seawater at concentrations as low as 5 ug L-1. This is supported by the observation that SWCNTs alone were only toxic at concentrations >=100 ug L-1 and that the SWCNT-induced DNA damage was correlated with oxidative stress only in the absence of metals. If these laboratory experiments are confirmed in the natural environment, the present results will have implications for the understanding of the role of carbon nanotubes in environmental metal dynamics, toxicology, and consequently, regulatory requirements. PMID- 23982897 TI - Reply: To PMID 23780828. PMID- 23982899 TI - Abstracts of the Environmental Mutagen Society 44th Annual Meeting. September 21 25, 2013. Monterey, California, USA. PMID- 23982898 TI - Punishing and cardiovascular effects of intravenous histamine in rats: pharmacological selectivity. AB - Although drugs may serve as reinforcers or punishers of operant behavior, the punishing function has received much less experimental attention than the reinforcing function. A sensitive method for studying drug-induced punishment is to assess choice for a punished response over an unpunished response. In these experiments, rats chose between pressing one lever and receiving a sucrose pellet or pressing another lever and receiving a sucrose pellet plus an intravenous injection of histamine. When sucrose was delivered equally frequently for either the punished or the unpunished response, rats selected the unpunished lever consistently, but decreases in the punished response did not differ as a function of intravenous histamine dose (0.1-1 mg/kg/inj). Changing the procedure so that sucrose was delivered on the unpunished lever with p = .5 increased the rats' responding on the punished lever with saline injections. In addition, the same range of histamine doses produced a much larger range of responses on the punished lever that was dose dependent. Using these procedures to assess the receptors mediating histamine's effects, the histamine H1 -receptor antagonists, pyrilamine and ketotifen, antagonized the punishing effect of histamine, but the histamine H2 -receptor antagonist ranitidine did not. However, ranitidine pretreatments reduced histamine-induced heart-rate increases to a greater extent than did the histamine H1 -receptor antagonists when administered at the same doses examined under conditions of histamine punishment. Overall, the present findings extend the general hypothesis that activation of histamine H1 -receptors mediates the punishing effects of histamine. They also introduce methods for rapidly assessing pharmacological mechanisms underlying drug-induced punishment. PMID- 23982900 TI - Circumportal pancreas: a clinicoradiological and embryological review. AB - Circumportal pancreas is a congenital fusion anomaly of the pancreas where the pancreatic tissue from the uncinate process, anomalously encases the portal vein and/or the superior mesenteric vein. Depending upon the level of the pancreatic annulus the variant can be classified into three subtypes-suprasplenic, infrasplenic or mixed; and each subtype exhibits either an anteportal or retroportal main pancreatic duct. Limited literature is available on this intriguing anomaly primarily because of its relatively low prevalence in humans (published prevalence rates vary from 0.2 to 2.5 %), probable lack of awareness among medical professionals and its generally symptomless course. In an attempt to appraise the embryological basis, clinicoradiological manifestations and potential surgical implications of circumportal pancreas, literature published in English was searched using PubMed and information collated so as to provide up-to date information on this relatively understudied entity. The anomaly by itself remains innocuous but its preoperative recognition in those undergoing pancreatic resection bears decisive influence on planning and selecting apposite surgical resection planes as inadvertent duct injury can lead to pancreatic fistula. PMID- 23982901 TI - Anti-CD73 therapy impairs tumor angiogenesis. AB - CD73 is an ecto-nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti-tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti-CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor-derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro angiogeneic effects of CD73 relied on both enzymatic and non-enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment. PMID- 23982902 TI - The role and development of sprinting speed in soccer. AB - The overall objective of this review was to investigate the role and development of sprinting speed in soccer. Time-motion analyses show that short sprints occur frequently during soccer games. Straight sprinting is the most frequent action before goals, both for the scoring and assisting player. Straight-line sprinting velocity (both acceleration and maximal sprinting speed), certain agility skills, and repeated-sprint ability are shown to distinguish groups from different performance levels. Professional players have become faster over time, indicating that sprinting skills are becoming more and more important in modern soccer. In research literature, the majority of soccer-related training interventions have provided positive effects on sprinting capabilities, leading to the assumption that all kinds of training can be performed with success. However, most successful intervention studies are time consuming and challenging to incorporate into the overall soccer training program. Even though the principle of specificity is clearly present, several questions remain regarding the optimal training methods within the larger context of the team-sport setting. Considering time-efficiency effects, soccer players may benefit more by performing sprint training regimens similar to the progression model used in strength training and by world-leading athletics practitioners, compared with the majority of guidelines that traditionally have been presented in research literature. PMID- 23982903 TI - The O-C2 angle established at occipito-cervical fusion dictates the patient's destiny in terms of postoperative dyspnea and/or dysphagia. AB - PURPOSE: We have revealed that the cause of postoperative dyspnea and/or dysphagia after occipito-cervical (O-C) fusion is mechanical stenosis of the oropharyngeal space and the O-C2 alignment, rather than total or subaxial alignment, is the key to the development of dyspnea and/or dysphagia. The purpose of this study was to confirm the impact of occipito-C2 angle (O-C2A) on the oropharyngeal space and to investigate the chronological impact of a fixed O-C2A on the oropharyngeal space and dyspnea and/or dysphagia after O-C fusion. MATERIALS AND METHODS: We reviewed 13 patients who had undergone O-C2 fusion, while retaining subaxial segmental motion (OC2 group) and 20 who had subaxial fusion without O-C2 fusion (SA group). The O-C2A, C2-C6 angle and the narrowest oropharyngeal airway space were measured on lateral dynamic X-rays preoperatively, when dynamic X-rays were taken for the first time postoperatively, and at the final follow-up. We also recorded the current dyspnea and/or dysphagia status at the final follow-up of patients who presented with it immediately after the O-C2 fusion. RESULTS: There was no significant difference in the mean preoperative values of the O-C2A (13.0 +/- 7.5 in group OC2 and 20.1 +/- 10.5 in group SA, Unpaired t test, P = 0.051) and the narrowest oropharyngeal airway space (17.8 +/- 6.0 in group OC2 and 14.9 +/- 3.9 in group SA, Unpaired t test, P = 0.105). In the OC2 group, the narrowest oropharyngeal airway space changed according to the cervical position preoperatively, but became constant postoperatively. In contrast, in the SA group, the narrowest oropharyngeal airway space changed according to the cervical position at any time point. Three patients who presented with dyspnea and/or dysphagia immediately after O-C2 fusion had not resolved completely at the final follow-up. The narrowest oropharyngeal airway space and postoperative dyspnea and/or dysphagia did not change with time once the O-C2A had been established at O-C fusion. CONCLUSIONS: The O-C2A established at O-C fusion dictates the patient's destiny in terms of postoperative dyspnea and/or dysphagia. Surgeons should pay maximal attention when establishing the O-C2A during surgery, because their careless decision for the O-C2A may cause persistent dysphagia or a life-threatening consequence. We recommend that the O-C2A in O-C fusion should be kept at least at more than the preoperative O-C2A in the neutral position. PMID- 23982904 TI - Backache and infection. PMID- 23982905 TI - Spinal cord cross-sectional area during flexion and extension in the patients with cervical ossification of posterior longitudinal ligament. AB - PURPOSE: The pathomechanism of cervical myelopathy due to cervical ossification of posterior longitudinal ligament (C-OPLL) remains unclear. No previous literature has quantified the influence of dynamic factors on cervical myelopathy due to C-OPLL. The purpose was to investigate the influence of dynamic factors on the spinal column in the patients with C-OPLL using CT scan after myelography (MCT). METHODS: The study included 41 patients with cervical myelopathy due to C OPLL. An MCT was done during neck flexion and extension, and spinal cord cross sectional areas (SCCSA) were measured at each disc level between C2/3 and C7/T1. Ossification morphology at each segment was divided into three groups, connection department, coating part, and non-connection department of OPLL group. Dynamic changes of SCCSA in each group of ossification morphology were calculated. The relationship between clinical results and SCCSA at the narrowest level was investigated. RESULTS: MCT showed SCCSA changes during neck extension; 7.4 +/- 5.1 mm(2) in the connection department, 5.8 +/- 6.0 mm(2) in the coating part, and 6.7 +/- 6.4 mm(2) in the non-connection department of OPLL group. There difference was not statistically significant. There was a weak correlation between the JOA score and SCCSA at the narrowest level (R = 0.49). There was no significant correlation between the recovery rate of JOA score and SCCSA at the narrowest level (R = 0.37). CONCLUSION: Dynamic factors are seen both in cervical myelopathy patients with the continuous type of OPLL and others. Deterioration of myelopathy could be induced by motion effects even in the connection department of OPLL. PMID- 23982906 TI - Measurement properties of the German Michigan Hand Outcomes Questionnaire in patients with trapeziometacarpal osteoarthritis. AB - OBJECTIVE: To investigate the reliability, validity, and responsiveness of the Michigan Hand Outcomes Questionnaire (MHQ) in patients with trapeziometacarpal (TMC) joint osteoarthritis (OA). METHODS: In this prospective observational study, patients diagnosed with TMC joint OA who received either conservative or surgical treatment were included. At baseline and at 1 year following the beginning of treatment, we measured key pinch strength and the patients filled out the MHQ, the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, and the Short Form 12 health survey. Patients also completed these questionnaires 2-11 days after the last study visit. In order to analyze the measurement properties of the MHQ, we calculated test-retest reliability (intraclass correlation coefficient [ICC]), internal consistency (Cronbach's alpha for the 6 subscales), construct validity (Pearson's correlation coefficient [r]), responsiveness (effect sizes), and the minimum important change (MIC). RESULTS: We included 177 patients, of whom 109 were scheduled for surgery. The mean +/- SD MHQ total score for surgical patients increased from 48 +/- 14 at baseline to 75 +/- 18 at 1 year (P <= 0.001). In contrast, no treatment effect was observed in the conservative group (P = 0.74). The MHQ total score showed excellent test retest reliability (ICC 0.95) and correlated strongly with the DASH (r = -0.77). Internal consistency of the MHQ subscales ranged between 0.77 and 0.89. A large effect size of 1.7 was found for the surgical patients, with an MIC of 17 points. CONCLUSION: The MHQ demonstrated good reliability, validity, and responsiveness in patients with TMC joint OA and can be recommended as a suitable assessment instrument in this population. PMID- 23982907 TI - Rare bleeding disorders: genetic, laboratory, clinical, and molecular aspects. Preface. PMID- 23982908 TI - Bone remodelling in the natural acetabulum is influenced by muscle force-induced bone stress. AB - A modelling framework using the international Physiome Project is presented for evaluating the role of muscles on acetabular stress patterns in the natural hip. The novel developments include the following: (i) an efficient method for model generation with validation; (ii) the inclusion of electromyography-estimated muscle forces from gait; and (iii) the role that muscles play in the hip stress pattern. The 3D finite element hip model includes anatomically based muscle area attachments, material properties derived from Hounsfield units and validation against an Instron compression test. The primary outcome from this study is that hip loading applied as anatomically accurate muscle forces redistributes the stress pattern and reduces peak stress throughout the pelvis and within the acetabulum compared with applying the same net hip force without muscles through the femur. Muscle forces also increased stress where large muscles have small insertion sites. This has implications for the hip where bone stress and strain are key excitation variables used to initiate bone remodelling based on the strain-based bone remodelling theory. Inclusion of muscle forces reduces the predicted sites and degree of remodelling. The secondary outcome is that the key muscles that influenced remodelling in the acetabulum were the rectus femoris, adductor magnus and iliacus. PMID- 23982909 TI - Lung cancer risk from radon in Ontario, Canada: how many lung cancers can we prevent? AB - PURPOSE: To calculate the burden of lung cancer illness due to radon for all thirty-six health units in Ontario and determine the number of radon-attributable lung cancer deaths that could be prevented. METHODS: We calculated the population attributable risk percent, excess life-time risk ratio, life-years lost, the number of lung cancer deaths due to radon, and the number of deaths that could be prevented if all homes above various cut-points were effectively reduced to background levels. RESULTS: It is estimated that 13.6 % (95 % CI 11.0, 16.7) of lung cancer deaths in Ontario are attributable to radon, corresponding to 847 (95 % CI 686, 1,039) lung cancer deaths each year, approximately 84 % of these in ever-smokers. If all homes above 200 Bq/m(3), the current Canadian guideline, were remediated to background levels, it is estimated that 91 lung cancer deaths could be prevented each year, 233 if remediation was performed at 100 Bq/m(3). There was important variation across health units. CONCLUSIONS: Radon is an important contributor to lung cancer deaths in Ontario. A large portion of radon attributable lung cancer deaths are from exposures below the current Canadian guideline, suggesting interventions that install effective radon-preventive measures into buildings at build may be a good alternative population prevention strategy to testing and remediation. For some health units, testing and remediation may also prevent a portion of radon-related lung cancer deaths. Regional attributable risk estimates can help with local public health resource allocation and decision making. PMID- 23982910 TI - Bioanalysis of tolvaptan, a novel AVP-V2 receptor antagonist in human plasma by a novel LC-ESI-MS/MS method: a pharmacokinetic application in healthy South Indian male subjects. AB - A simple, rapid and sensitive liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) assay method is proposed for the determination of tolvaptan in human plasma samples using tolvaptan d7 as internal standard (IS). Analyte and the IS were extracted from 100 MUL of human plasma via simple liquid-liquid extraction. The chromatographic separation was achieved on a C18 column using a mixture of methanol and 0.1% formic acid buffer (80:20, v/v) as the mobile phase at a flow rate of 1.0 mL/min. The calibration curve obtained was linear (r(2) >= 0.99) over the concentration range of 0.05-501 ng/mL. Method validation was performed as per US Food and Drug Administration guidelines and the results met the acceptance criteria. The intra-day and inter-day precision (coefficient of variation) and accuracy results in three validation batches across five concentration levels were well within the acceptance limits. A run time of 2.0 min for each sample made it possible to analyze more samples in a short time, thus increasing the productivity. The proposed method was successfully applied to a pharmacokinetic study of 15 mg and 60 mg tolvaptan tablet formulation in healthy South Indian male subjects under fasting condition. PMID- 23982911 TI - Polymeric scaffold aided stem cell therapeutics for cardiac muscle repair and regeneration. AB - The constantly expanding repository of novel polymers and stem cells has opened up new vistas in the field of cardiac tissue engineering. Successful regeneration of the complex cardiac tissue mainly centres on the appropriate scaffold material with topographical features that mimic the native environment. The integration of stem cells on these scaffolds is expected to enhance the regeneration potential. This review elaborates on the interplay of these vital factors in achieving the functional cardiac tissue. The recent advances in polymers, nanocomposites, and stem cells from different sources are highlighted. Special emphasis is laid on the clinical trials involving stem cells and the state-of-the-art materials to obtain a balanced perspective on the translational potential of this strategy. PMID- 23982912 TI - Cytogenetic characterization of HB2 epithelial cells from the human breast. AB - HB2 is a cell line originated by subcloning of MTSV1-7 mammary luminal epithelial cells isolated from human milk and immortalization via introduction of the gene encoding simian virus 40 (SV40) large T antigen. Despite its wide utilization as non-neoplastic counterpart in assays aimed to elucidating various biochemical and genetical aspects of normal and tumoral breast cells, to our knowledge no literature data have so far appeared concerning the chromosomal characterization of the HB2 cells. Here, we report the cytogenetic characterization of the karyotype of HB2 cells, which puts in evidence the occurrence of changes in chromosomal number and structure and the presence of unidentified chromosomal markers in variable amount. Our results do not detract from the utility of HB2 cells in illustrating fundamental aspects of breast cell biology, but rather interject a note of caution into generalizing results obtained with this cell line to other non-immortalized epithelial cell populations from the human breast. Therefore, this work represents a useful resource for all who want to perform appropriate and focused future studies on this cell line and proposes precise indications for a knowledgeable use of HB2 cells. PMID- 23982913 TI - Establishment and characterization of a primary and a metastatic melanoma cell line from Grey horses. AB - The Grey horse phenotype, caused by a 4.6 kb duplication in Syntaxin 17, is strongly associated with high incidence of melanoma. In contrast to most human melanomas with an early onset of metastasis, the Grey horse melanomas have an extended period of benign growth, after which 50% or more eventually undergo progression and may metastasize. In efforts to define changes occurring during Grey horse melanoma progression, we established an in vitro model comprised of two cell lines, HoMel-L1 and HoMel-A1, representing a primary and a metastatic stage of the melanoma, respectively. The cell lines were examined for their growth and morphological characteristics, in vitro and in vivo oncogenic potential, chromosome numbers, and expression of melanocytic antigens and tumor suppressors. Both cell lines exhibited malignant characteristics; however, the metastatic HoMel-A1 showed a more aggressive phenotype characterized by higher proliferation rates, invasiveness, and a stronger tumorigenic potential both in vitro and in vivo. HoMel-A1 displayed a near-haploid karyotype, whereas HoMel-L1 was near-diploid. The cell lines expressed melanocytic lineage markers such as TYR, TRP1, MITF, PMEL, ASIP, MC1R, POMC, and KIT. The tumor suppressor p53 was strongly expressed in both cell lines, while the tumor suppressors p16 and PTEN were absent in HoMel-A1, potentially implicating significance of these pathways in the melanoma progression. This in vitro model system will not only aid in understanding of the Grey horse melanoma pathogenesis, but also in unraveling the steps during melanoma progression in general as well as being an invaluable tool for development of new therapeutic strategies. PMID- 23982914 TI - Establishment of an in vitro culture system for intestinal epithelial cells from Pheretima aspergillum (E. Perrier). PMID- 23982915 TI - Developmental potency of pre-implant parthenogenetic goat embryos: effect of activation protocols and culture media. AB - The developmental potency of pre-implant parthenogentic goat embryos were compared under two chemical activation protocols in three different culture media groups. The in vitro matured oocytes were chemically activated by two protocols viz. P1 (CB-CHX-6DMAP) and P2 (Ca-CHX-6DMAP). The activated oocytes under both the protocols were developed in three culture media, viz. modified synthetic oviductal fluid (mSOF), research vitro cleave medium (RVCL), and RVCL-Blast. While comparing the developmental potential of activated oocytes, it was observed that the oocytes activated under P2 protocol pooled over three culture media group producing significantly higher mean cleavage rate (43.2+/-0.9 vs 40.6+/ 1.5), blastocyst development (16.4+/-1.1 vs 12.6+/-0.8), and blastomere count (120.7+/-4.7 vs 113.2+/-4.1) as compared to P1 protocol. The comparison of effect of culture media pooled over protocol groups revealed that the mean cleavage rate observed under RVCL-Blast (44.8+/-1.3) and RVCL (45.3+/-0.5) were significantly higher (P<=0.01) than mSOF (35.8+/-1.2). However, the mean blastocyst development observed under RVCL-Blast group (18.8+/-3.2) was significantly higher than RVCL (14.0+/-0.8) and mSOF (10.8+/-0.4). Similarly, the mean blastomere count under RVCL-Blast group (136.0+/-3.7) was significantly higher (P<=0.01) than RVCL (114.7+/-1.0) and mSOF (100.2+/-0.5) groups. The semiquantitative RT PCR analysis showed the expression of pro-apoptotic caspase 3 gene in P1 and anti-apoptotic Mcl-1 gene in P2. This study concludes that the activation protocol P2 and embryo cultured under RVCL-Blast group were optimum for chemical activation and culture medium, respectively. PMID- 23982916 TI - Fisetin attenuates hydrogen peroxide-induced cell damage by scavenging reactive oxygen species and activating protective functions of cellular glutathione system. AB - Hydrogen peroxide (H2O2) can induce cell damage by generating reactive oxygen species (ROS), resulting in DNA damage and cell death. The aim of this study is to elucidate the protective effects of fisetin (3,7,3',4',-tetrahydroxy flavone) against H2O2-induced cell damage. Fisetin reduced the level of superoxide anion, hydroxyl radical in cell free system, and intracellular ROS generated by H2O2. Moreover, fisetin protected against H2O2-induced membrane lipid peroxidation, cellular DNA damage, and protein carbonylation, which are the primary cellular outcomes of H2O2 treatment. Furthermore, fisetin increased the level of reduced glutathione (GSH) and expression of glutamate-cysteine ligase catalytic subunit, which is decreased by H2O2. Conversely, a GSH inhibitor abolished the cytoprotective effect of fisetin against H2O2-induced cells damage. Taken together, our results suggest that fisetin protects against H2O2-induced cell damage by inhibiting ROS generation, thereby maintaining the protective role of the cellular GSH system. PMID- 23982917 TI - Polyunsaturated fatty acid metabolism in enterocyte models: T84 cell line vs. Caco-2 cell line. AB - Human colon carcinoma cell lines such as Caco-2 cells, model of mature enterocytes and T84 cells, model of crypt cells are useful to study interactions between nutrient processing and metabolic functions at intestinal level. Our study aimed at comparing the ability of Caco-2 and T84 cells (1) to incorporate dietary polyunsaturated fatty acids (PUFA), (2) to process them and (3) to sort them into neutral lipids (NL), free fatty acids (FFA) and phospholipids (PL). Caco-2 and T84 cells were exposed to a 7-day long supplementation with PUFA. The amounts of fatty acids accumulated and incorporated into the NL, FFA or PL fractions were higher in Caco-2 than in T84 cells. Caco-2 cells were able to significantly elongate C18 PUFA and C20 PUFA of both n-3 and n-6 families. In contrast, T84 cells were unable to elongate the n-6 fatty acids whereas elongation of n-3 fatty acids was detectable but marginal. Similarly, a Delta6 desaturase activity was observed in Caco-2 but not in T84 cells. In T84 cells, each exogenous fatty acid was predominantly accumulated in the PL fraction. In Caco-2 cells, C20 fatty acids and C18:2n-6 was preferentially accumulated in the PL fraction, while C22 PUFA and C18:3n-3 was preferentially accumulated in the NL fraction. Overall, this study has shown that Caco-2 and T84 cells, as models of intestinal mucosal cells, present large differences in PUFA accumulation capacity, specific elongase and desaturase activities and distribution pattern of exogenous PUFA and of their metabolites in the lipid classes. PMID- 23982918 TI - Sex-specific extent and severity of white matter damage in multiple sclerosis: implications for cognitive decline. AB - Cognitive dysfunction is common in multiple sclerosis (MS). However, the relationship between white matter (WM) damage and cognition remains insufficiently clear. This study investigates the extent and severity of WM diffusion abnormalities in MS patients and relations with cognition. Diffusion tensor imaging scans were obtained in 131 MS patients (88 women, 6 years postdiagnosis) and 49 age-matched controls (29 women). Patient groups were equal in terms of disease duration, disability, and WM lesion volume. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were compared between groups. Post hoc analyses calculated the spatial extent and severity of diffusion abnormalities to relate these to cognitive performance. In controls, 31% of WM voxels showed higher FA in men; therefore, all patient analyses were within-sex. The extent of diffusion changes was higher in male patients than in female patients for all parameters (FA: 24% in women, 53% in men), as was the severity of changes (FA: Z = -0.18 in women, Z = -0.41 in men). Especially the extent of FA abnormalities was strongly related to cognitive performance in all patients (r = -0.42, P < 0.0001). Regionally, thalamic decreases in FA were especially correlated with cognitive performance. Cognitively impaired patients showed greater extent and severity on all diffusion parameters compared to cognitively preserved patients. The WM of male patients was both more extensively and also more severely affected than that of female patients. The extent of WM FA changes, especially in the thalamus, was associated with cognitive performance in this cohort of early MS patients. PMID- 23982919 TI - Backbone 1H, 15N, and 13C and side chain 13Cbeta NMR chemical shift assignment of murine interleukin-10. AB - Almost complete assignment of backbone (1)H, (13)C, (15)N and side chain (13)Cbeta resonances for the immune-regulatory cytokine IL-10 is reported. The protein was overexpressed in Escherichia coli and was refolded from inclusion bodies. The point mutation C149Y was introduced to suppress incorrect disulfide bond formation and to improve protein refolding. PMID- 23982920 TI - Experimental analysis of the transverse mechanical behaviour of annulus fibrosus tissue. AB - Uniaxial tensile and relaxation tests were carried out on annulus fibrosus samples carved out in the circumferential direction. Images were shot perpendicularly to the loading direction. Digital image correlation techniques accurately measured the evolution of full displacement fields in both transverse directions: plane of fibres and plane of lamellae. In the fibre plane, strains were governed by the reorientation of fibres along the loading direction. This implies strong transverse shrinkage with quasi-linear behaviour. Conversely, a wide range of behaviour was observed in the lamella plane: from shrinkage to swelling. Strong nonlinear evolutions were generally obtained. The strain field in the lamella plane generally presented a central strip section with more pronounced swelling. Our physical interpretation relies on the porous nature of annulus tissue and its anisotropic stiffness. Indeed, the liquid over-pressure generated inside the sample by the strong shrinkage in the fibre plane discharges in the perpendicular direction since rigidity is lower in the lamella plane. Regarding the strain field measured in the lamella plane, this interpretation agrees with (a) symmetric strain distribution with respect to the longitudinal axis of samples, (b) the reversal in behaviour from shrinkage to swelling and (c) the decrease in strain during relaxation tests associated with outward flows. The variety of transverse behaviours observed experimentally could result from uncertainties regarding the initial reference state of tissue samples. Since the mechanical behaviour is highly nonlinear, experimental results underline that a slight uncertainty concerning the pre-stress applied to samples can lead to wide variability in the mechanical properties identified. PMID- 23982921 TI - Development of racial-ethnic identity among First Nation children. AB - Elements of racial-ethnic identity, often found among adolescents from racial ethnic minority groups, have their origins in middle childhood and pre adolescence. The present study explored the developmental trajectory of some of those components among Native Canadian children living on relatively remote First Nation communities. Children and young adolescents (N = 414,209 female) between the ages of 6-11 completed measures assessing their level of racial-ethnic identity, concrete operational thought, implicit and explicit self-esteem, implicit and explicit in-group attitudes, and the importance of their racial ethnic identity each year for 5 years. Consistent with predictions from cognitive developmental theory, trajectory modeling revealed significant increases over time in explicit and implicit in-group attitudes, level of concrete operational thought and the importance of children's racial-ethnic identity. However, level of racial-ethnic identity remained unchanged over time. The results are discussed in terms of cognitive-developmental theory, and the influence of living in a racially homogeneous environment on the development of racial-ethnic identity among minority group children. Studies are also suggested for future research. PMID- 23982923 TI - Pregnancy and Behcet's disease: comment on the article by Noel et al. PMID- 23982924 TI - Stabilization of duplex DNA and RNA by dangling ends studied by free energy simulations. AB - Single unpaired nucleotides at the end of double-stranded nucleic acids, termed dangling ends, can contribute to duplex stability. Umbrella sampling free energy simulations of dangling cytosine and guanine nucleotides at the end of duplex and single stranded RNA and DNA molecules have been used to investigate the molecular origin of dangling end effects. In unrestraint simulations, the dangling end nucleotides stayed close to placements observed in experimental structures. Calculated free energy contributions associated with the presence of dangling nucleotides were in reasonable agreement with experiment predicting the general trend of a more stabilizing effect of purine vs. pyrimidine dangling ends. In addition, the calculations indicate a more significant stabilizing effect of dangling ends at the 5'-end vs. 3'-end in case of DNA and the opposite trend in case of RNA. Both electrostatic and van der Waals interactions contribute to the duplex stabilizing effect of dangling end nucleotides. The free energy simulation scheme could also be used to design dangling end nucleotides that result in enhanced duplex stabilization. PMID- 23982922 TI - Is the rodent maternal separation model a valid and effective model for studies on the early-life impact on ethanol consumption? AB - RATIONALE: Early-life events can cause long-term neurobiological and behavioural changes with a resultant effect upon reward and addiction processes that enhance risk to develop alcohol use disorders. Maternal separation (MS) is used to study the mediating mechanisms of early-life influences in rodents. In MS studies, the pups are exposed to maternal absence during the first postnatal weeks. The outcome of MS experiments exhibits considerable variation and questions have been raised about the validity of MS models. OBJECTIVES: This short review aims to provide information about experimental conditions that are important to consider when assessing the impact of early-life environment on voluntary ethanol consumption. RESULTS: The results from currently used MS protocols are not uniform. However, studies consistently show that longer separations of intact litters predispose for higher ethanol consumption and/or preference in adult male rats as compared to shorter periods of MS. Studies using individual pup MS paradigms, other controls, low ethanol concentrations, adult females or examining adolescent consumption reported no differences or inconsistent results. CONCLUSIONS: There is no "a rodent MS model", there are several models and they generate different results. The compiled literature shows that MS is a model of choice for analysis of early-life effects on voluntary ethanol consumption but there are examples of MS paradigms that are not suitable. These studies emphasize the importance to carefully designed MS experiments to supply the optimal conditions to definitely test the research hypothesis and to be particulate in the interpretation of the outcome. PMID- 23982925 TI - Ecotoxicity of climbazole, a fungicide contained in antidandruff shampoo. AB - Emerging pollutants such as personal care products can reach the environment via effluents from wastewater treatment plants (WWTPs) and digested sludge. Only recently, the antidandruff agent and antimycotic climbazole was detected for the first time in a WWTP effluent with concentrations up to 0.5 ug/L. Climbazole acts as a C14-demethylase inhibitor (DMI) fungicide and thus has a high efficacy against fungi, but knowledge of its potential environmental impact is lacking. Therefore, the aim of the present study was to characterize climbazole's ecotoxicity by conducting standard biotests with organisms representing different trophic levels from the aquatic as well as the terrestrial ecosystems. It was found that the toxicity of climbazole is mostly similar to that of other DMI fungicides, whereas it proved to be particularly toxic to primary producers. The lowest median effective concentrations (EC50s) were determined for Lemna minor, at 0.013 mg/L (biomass yield), and Avena sativa, at 18.5 mg/kg soil dry weight (shoot biomass). Reduction of frond size in water lentils and shoot length in higher plants suggested an additional plant growth-retarding mode of action of climbazole. In addition, it was demonstrated here that for an ionizable compound such as climbazole, the soil pH can have a considerable influence on phytotoxicity. PMID- 23982926 TI - The social sciences, philosophy, and the cultural turn in the 1930s USDA. AB - One of the more unusual attempts by the American state to mobilize academic expertise unfolded in the late 1930s, when the United States Department of Agriculture (USDA) hired scholars in the "culture and personality" fields and philosophy to aid its efforts to promote economic, social, and cultural change in the countryside. USDA progressives also reached out to disciplinary scholars in other ways as they sought to institute a deliberative mode of planning in local communities and to remake the curricula of the land-grant colleges in support of that project. These USDA initiatives and scholars' responses reveal that scientific knowledge was mobilized in the 1930s not just for the instrumental purpose of regulating economic behavior but also to explain and legitimate federal programs and to inform ambitious projects for cultural change. At the USDA, as at many other sites between the wars, scientific thinkers turned to the social sciences and philosophy in order to understand and then change the public mind. PMID- 23982927 TI - Impact of cell cycle delay on micronucleus frequency in TK6 cells. AB - Previous studies with TK6 cells have shown that extending the recovery period after pulse treatment allows for greater micronucleus expression for some compounds. This study explores the role of cell cycle delay in micronucleus expression after pulse treatment with three model genotoxins [mitomycin C, etoposide (ETOP), vinblastine]. Cells were treated for 4 hr and allowed to recover for 36 hr with samples removed at various time points during the recovery period and analyzed for cell cycle distribution, apoptosis and micronucleus frequency. Our results show that mitomycin C causes cell cycle delay for 20 hr after pulse treatment and cell cycle perturbation is no longer evident after 36 hr of recovery. The micronucleus frequency of cells sampled at 36 hr is doubled when compared with cells sampled at 20 hr after mitomycin C removal. When cells were treated with indirect acting genotoxins (ETOP, vinblastine), cell cycle perturbation was not observed at the 20 hr time point. Micronucleus frequency after treatment with either ETOP or vinblastine did not differ between the 20 hr and the 36 hr time point. All three compounds induced similar levels of apoptosis ranging from 4.5 to 5.6% with maximum induction occurring at the 36-hr time point. We conclude that TK6 cells exhibit extended cell cycle arrest after exposure to MMC and can go on to express micronuclei, after overcoming cell cycle arrest. PMID- 23982928 TI - Causes and clinical significance of prolonged activated partial thromboplastin times in thalassaemia major. PMID- 23982930 TI - Long-Range Correlations and Complex Regulation of Pacing in Long-Distance Road Racing. AB - Purpose: To analyse time domain, spectral and fractal properties of speed regulation during half-marathon racing. Methods: In twenty-one male experienced runners high-resolution data on speed (V), stride frequency (SF) and stride length (SL) were assessed during half-marathon competition (21098 m). Performance times, time and frequency domain variability, spectral scaling exponent (beta) and fractal dimension (FD) of V, SF and SL were analysed. Results: V of 3.65+/ 0.41 m.s-1, SF of 1.41+/-0.05 Hz and SL of 2.58+/-0.25 m occurred with higher (p<0.05) individual variability in V and SL compared to SF. Beta and FD were always in between 1.04 and 1.88 and 1.56 to 1.99, respectively. Beta and FD differed (p<0.05) in SF and SL compared to V and were correlated in V and SL (r=0.91, p<0.05). Spectral peaks of V, SF and SL occurred at wavelengths in between 3 to 35 min, and those of V and SL were interrelated (r=0.56, p<0.05). Mean SF and mean SL were significantly correlated with performance (r=0.59 and r=0.95, p<0.05). SL accounted for 84+/-6 % and SF for 16+/-6 % of speed variability, respectively. Conclusions: The observed non-random fluctuations in V, SF and SL correspond to non-stationary fractional Brownian motion with inherent long-range correlations. This indicates a similar complex regulation process in experienced runners that is primarily mediated via SL. PMID- 23982929 TI - Germline variation in NCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer. AB - Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (OR = 2.43, 95% CI = 1.73-3.39; p < 0.0001). NCF4 is part of the NAPDH complex, a key factor in biochemical pathways and the innate immune response. While not definitive, our analyses suggest that the variant allele does not affect expression of NCF4, but rather modulates activity of the NADPH complex. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer. PMID- 23982931 TI - Controlled microstructuring of janus particles based on a multifunctional poly(ethylene glycol). AB - A novel water insoluble, multifunctional poly(ethylene glycol), poly(hydrazide ethylene glycol-co-benzyl glycidyl ether) (P(HZ-co-BnGE)), is synthesized via thiol-ene click reaction of poly(allyl glycidyl ether-co-benzyl glycidyl ether) (P(AGE-co-BnGE)). The base polymer P(AGE-co-BnGE) is previously prepared by anionic ring-opening copolymerization of the corresponding monomers. To demonstrate utility, bicompartmental microspheres and microcylinders containing P(HZ-co-BnGE) in one of the compartments are prepared via electrohydrodynamic (EHD) co-jetting. Next, spatially controlled surface reactivity toward sugars is demonstrated by selective binding of 2alpha-mannobiose to the P(HZ-co-BnGE) compartment only, as confirmed by a carbohydrate-lectin-binding assay. These sugar-reactive hydrazide-presenting microparticles have potential applications for glyco-targeted drug delivery. PMID- 23982933 TI - Nucleophilic addition of nitrogen to aryl cations: mimicking Titan chemistry. AB - The reactivity of aryl cations toward molecular nitrogen is studied systematically in an ion trap mass spectrometer at 10(2) Pascal of nitrogen, the pressure of the Titan main haze layer. Nucleophilic addition of dinitrogen occurs and the nature of aryl group has a significant influence on the reactivity, through inductive effects and by changing the ground state spin multiplicity. The products of nitrogen activation, aryldiazonium ions, react with typical nitriles, aromatic amines, and alkynes (compounds that are relevant as possible Titan atmosphere constituents) to form covalently bonded heterocyclic products. Theoretical calculations at the level [DFT(B3LYP)/6-311++G(d,p)] indicate that the N2 addition reaction is exothermic for the singlet aryl cations but endothermic for their triplet spin isomers. The -OH and -NH2 substituted aryl ions are calculated to have triplet ground states, which is consistent with their decreased nitrogen addition reactivity. The energy needed for the generation of the aryl cations from their protonated precursors (ca. 340 kJ/mol starting with protonated aniline) is far less than that required to directly activate the nitrogen triple bond (the lowest energy excited state of N2 lies ca. 600 kJ/mol above the ground state). The formation of aza-aromatics via arene ionization and subsequent reactions provide a conceivable route to the genesis of nitrogen containing organic molecules in the interstellar medium and Titan haze layers. PMID- 23982932 TI - Electron capture dissociation of divalent metal-adducted sulfated N-glycans released from bovine thyroid stimulating hormone. AB - Sulfated N-glycans released from bovine thyroid stimulating hormone (bTSH) were ionized with the divalent metal cations Ca(2+), Mg(2+), and Co by electrospray ionization (ESI). These metal-adducted species were subjected to infrared multiphoton dissociation (IRMPD) and electron capture dissociation (ECD) and the corresponding fragmentation patterns were compared. IRMPD generated extensive glycosidic and cross-ring cleavages, but most product ions suffered from sulfonate loss. Internal fragments were also observed, which complicated the spectra. ECD provided complementary structural information compared with IRMPD, and all observed product ions retained the sulfonate group, allowing sulfonate localization. To our knowledge, this work represents the first application of ECD towards metal-adducted sulfated N-glycans released from a glycoprotein. Due to the ability of IRMPD and ECD to provide complementary structural information, the combination of the two strategies is a promising and valuable tool for glycan structural characterization. The influence of different metal ions was also examined. Calcium adducts appeared to be the most promising species because of high sensitivity and ability to provide extensive structural information. PMID- 23982934 TI - Flash desorption/mass spectrometry for the analysis of less- and nonvolatile samples using a linearly driven heated metal filament. AB - In this paper, the important issue of the desorption of less- and nonvolatile compounds with minimal sample decomposition in ambient mass spectrometry is approached using ambient flash desorption mass spectrometry. The preheated stainless steel filament was driven down and up along the vertical axis in 0.3 s. At the lowest position, it touched the surface of the sample with an invasion depth of 0.1 mm in 50 ms (flash heating) and was removed from the surface (fast cooling). The heating rate corresponds to ~10(4) degrees C/s at the filament temperature of 500 degrees C. The desorbed gaseous molecules were ionized by using a dielectric barrier discharge ion source, and the produced ions were detected by a time-of-flight (TOF) mass spectrometer. Less-volatile samples, such as pharmaceutical tablets, narcotics, explosives, and C60 gave molecular and protonated molecule ions as major ions with thermal decomposition minimally suppressed. For synthetic polymers (PMMA, PLA, and PS), the mass spectra reflected their backbone structures because of the suppression of the sequential thermal decompositions of the primary products. The present technique appears to be suitable for high-throughput qualitative analyses of many types of solid samples in the range from a few ng to 10 MUg with minimal sample consumption. Some contribution from tribodesorption in addition to thermal desorption was suggested for the desorption processes. Figure ? PMID- 23982935 TI - Evidence for sequence scrambling in collision-induced dissociation of y-type fragment ions. AB - Sequence scrambling from y-type fragment ions has not been previously reported. In a study designed to probe structural variations among b-type fragment ions, it was noted that y fragment ions might also yield sequence-scrambled ions. In this study, we examined the possibility and extent of sequence-scrambled fragment ion generation from collision-induced dissociation (CID) of y-type ions from four peptides (all containing basic residues near the C-terminus) including: AAAAHAA NH2 (where "A" denotes carbon thirteen ((13)C1) isotope on the alanine carbonyl group), des-acetylated-alpha-melanocyte (SYSMEHFRWGKPV-NH2), angiotensin II antipeptide (EGVYVHPV), and glu-fibrinopeptide b (EGVNDNEEGFFSAR). We investigated fragmentation patterns of 32 y-type fragment ions, including y fragment ions with different charge states (+1 to +3) and sizes (3 to 12 amino acids). Sequence-scrambled fragment ions were observed from ~50 % (16 out of 32) of the studied y-type ions. However, observed sequence-scrambled ions had low relative intensities from ~0.1 % to a maximum of ~12 %. We present and discuss potential mechanisms for generation of sequence-scrambled fragment ions. To the best of our knowledge, results on y fragment dissociation presented here provide the first experimental evidence for generation of sequence-scrambled fragments from CID of y ions through intermediate cyclic "b-type" ions. PMID- 23982936 TI - Interleaved Distance-of-Flight Mass Spectrometry: A Simple Method to Improve the Instrument Duty Factor. AB - Distance-of-flight mass spectrometry (DOFMS) is a velocity-based, spatially dispersive MS technique in which ions are detected simultaneously along the plane of a spatially selective detector. In DOFMS, ions fly though the instrument and mass separate over a set period of time. The single flight time at which all ions are measured defines the specific m/z values that are detectable; the range of m/z values is dictated by the length of the spatially selective detector. However, because each packet of ions is detected at a single flight time, multiple groups of ions can fly through the instrument concurrently and be detected at a single detector. In this way, DOFMS experiments can be interleaved to perform several mass separation experiments within a single DOF repetition period. Interleaved operation allows the orthogonal acceleration region to be operated at a repetition rate higher than the reciprocal of the flight time, which improves the duty factor of the technique. In this paper, we consider the fundamental parameters of interleaved DOFMS and report first results. PMID- 23982937 TI - [Prediction of pre-eclampsia: claim, reality and clinical consequences]. PMID- 23982938 TI - [Midwives and smoking--attitudes, smoking status and counselling competence in the course of training]. AB - Tobacco consumption is a major public health threat. Midwives can contribute to the reduction of tobacco use among pregnant women and young families. It can be assumed that personal smoking behaviour and knowledge of harmful effects influences counselling activities. The aim of this study was to assess smoking status, nicotine dependency and the will to change of midwifery students in german-speaking countries. Broad data on this population is not available so far. In 2010, a self-administered questionnaire survey was conducted among Austrian, German and Swiss midwifery schools. Sociodemographic characteristics, smoking habits, personal attitudes towards smoking, knowledge of cessation strategies, perceived self-efficacy and competence to counsel pregnant women regarding their smoking habits of midwifery trainees were examined. 1 126 students and 38 teaching midwives answered this questionnaire (RR=61.8%). 22.7% are daily or occasional smokers. 6.8% have to be considered as medium and heavy smokers. 98.1% consider cessation counselling for pregnant and breast-feeding women as a midwife's task, while 76.5% feel competent enough to do so. 75.5% rate cessation counselling through midwives as effective stop-smoking procedures compared to blurry knowledge on related health risks and effective stop-smoking strategies. The self-reported smoking prevalence is considerably lower than in previous studies and other populations. Knowledge of harmful effects and of effective treatment options needs improvement. Counselling competence needs to be included in a broader way in midwifery curricula. PMID- 23982939 TI - Do we need cephalic spread of spinal anaesthesia for caesarean section? A different approach to CSE-EVE for reducing hypotension. AB - Spinal anaesthesia is the most preferred anaesthetic technique for elective as well as for unplanned Caesarean sections. Spinal-induced hypotension remains the most important side effect with a reported incidence between 20% and 100%. It can cause -maternal discomfort (nausea and vomiting) and impaired utero-placental perfusion. The present study was designed to examine the influence of epidural volume effect on the spread and duration of low-dose hyperbaric levobupivacaine. The aim of this study was to evaluate the influence of epidural restriction (injection of saline) on the distribution of anaesthesia as well as the incidence of hypotension during the spinal anaesthesia.After the approval by the ethics committee, 60 full-term parturient women (ASA I or II) with uncomplicated pregnancies were prospectively randomized into 2 groups: the SA group (single shot spinal anaesthesia) included 37 patients and the CSE-EVR group (combined spinal-epidural anaesthesia) included 39 patients in whom we induced the restriction of the spinal space by epidural volume compression. The blocks were performed at the L2/3 or L3/4 level in a sitting position, in the CSE-EVR group using the needle-through-needle technique. The initial dose for CSE-EVR was exactly half of the SA dose (0.5 mg per 10 cm height of hyperbaric levobupivacaine and 20 microg fentanyl). After spinal injection, an epidural catheter was located in the CSE-EVR and a volume of 20 mL saline solution injected. After injection, the women were turned supine with a left uterine displacement. Surgery was allowed when a sensory block at or above the T8 dermatome was established. We evaluated the height of the block by the pinprick method and the motor block by the Bromage scale, 10 min after spinal injection, during the operation time and at the end of surgery. Haemodynamic monitoring (NIBP, HR) was assessed every 2 min until the childbirth, then every 5 min during operative time. Anaesthetic efficacy was evaluated for breakthrough pain by visual analogue pain score (VAPS), Apgar score at birth, umbilical artery pH, and epinephrine consumption.The level of anaesthesia 10 min after the induction was significantly higher in the spinal group (SA) than in the CSE-EVR T5 (T4-T7) vs. T7 (T6-T8) group.The SA group experienced complete motor block during the time of anaesthesia, while the CSE-EVR group demonstrated significantly faster motor recovery. The incidence of hypotension and ephedrine supplementation was significantly lower in the CSE-EVR group (19 vs. 35 patients) than in the SA group (p<0.05).The neonatal outcome and umbilical artery pH were higher in the CSE-EVR group. Both groups were comparable in demographic data, VAS scores, preloading and infusion volume, atropine or ephedrine use, and adverse effects such as nausea or skin pruritus.We demonstrated a possible restriction of the spread of spinal anaesthesia by using epidural volume restriction with 20 mL saline as part of a combined spinal epidural technique. The study shows that CSE with EVR using only 50% of the levobupivacaine dose provided adequate anaesthesia for elective Caesarean delivery, as well as better maternal haemodynamic stability. PMID- 23982940 TI - Prenatal immunomodulation treatment in neonatal myasthenia gravis. AB - Neonatal mysthenia gravis (NMG) is a rare cause of arthrogryposis multiplex congenita (AMC) due to diaplacental transfer of maternal acetylcholine receptors (AChR) antibodies. 2 cases of severe NMG complicated by chronic lung disease and pulmonary arterial hypertension are reported. With respect to the severe course of the index patient, prenatal diagnosis and immunomodulation treatment were offered during the 2nd pregnancy. The combination of prenatal immunoadsorption (IA) therapy, administration of intravenous immunoglobulin (IVIG) and prednisolone failed. Failure may be partly explained by immaturity of the infant. However, considering the successful treatment of fetal/neonatal alloimmune thrombocytopenia (AIT) reported in literature, a treatment approach with IVIG doses up to 1-2 g/kg per week plus prednisone/prednisolone at a higher dose up to 1 mg/kg/d might be more effective. PMID- 23982941 TI - [Unexpected respiratory distress in the delivery room--a rare differential diagnosis for the obstetrician and neonatologist]. AB - We present the case of a female infant born prematurely at 34 weeks of gestation. Prenatally a midsized ventricular septal defect was diagnosed. Due to marked respiratory distress intubation was attempted but failed, since the tube could not be placed beyond the glottis. Oxygenation could be improved by nasopharyngeal bag ventilation. The clinical course as well as radiographic imaging was suggestive for a complete tracheal agenesis with broncho-oesophageal fistula which was confirmed at autopsy. Tracheal agenesis (TA) is a rare differential diagnosis of postnatal respiratory distress and the obstetrician or neonatologist will regularly be surprised by this malformation. Partial or complete absence of the trachea without associated malformations will be rarely diagnosed antenatally. In the case of the absence of an oesophageal fistula to the remaining airway a congenital high airway obstruction syndrome (CHAOS) ensues, leading to enlarged hyperechogenic lungs, dilated and fluid-filled trachea and bronchi and an absent tracheal flow during foetal breathing. Aetiology of TA is unknown, therapeutic options are limited thus making TA a usually fatal disorder. PMID- 23982942 TI - Response rates of three modes of survey administration and survey preferences of rheumatoid arthritis patients. AB - OBJECTIVE: To compare survey response rates and preferences for 3 modes of survey administration in rheumatoid arthritis (RA) patients. METHODS: Adult RA patients were identified from Kaiser Permanente Southern California's electronic medical records. One hundred patients each were randomly assigned to telephone, mail with followup letter, and mail with followup telephone call as modes of survey administration. Respondents completed a 7-page survey (in English or Spanish) that included the Health Assessment Questionnaire disability index and pain scale, EuroQol 5-dimensions, and generic questions on preferences and sociodemographics. Response rates were based on the number of completed surveys received from the total number of patients contacted (n = 295; 5 were ineligible). RESULTS: The mean +/- SD age of the cohort was 61 +/- 12.3 years, with the majority being women (141 [85%] of 166). Of the 3 modes of survey administration, telephone (63 [64%] of 99) had the highest response rate, followed by mail with followup telephone call (55 [56%] of 98) and mail with followup letter (48 [49%] of 98). When asked about preference over administration mode, 57% (95 of 166) preferred to complete the survey by mail, followed by telephone (27 [16%] of 166) and internet (17 [10%] of 166). CONCLUSION: When asked about their choice of survey administration mode for reporting their health status, the majority of RA patients in this study had a strong preference for a mail survey as compared to a telephone interview. However, the response rate in the telephone administration mode of survey was the highest between the 3 modes of administration that were compared. Future studies in RA can achieve better response using telephone over mail-in surveys. PMID- 23982943 TI - Development and application of FRAX in the management of osteoporosis in Ireland. AB - SUMMARY: The Irish Fracture Risk Assessment (FRAX) tool is the first fracture prediction model that has been calibrated using national hip fracture incidence data and Irish mortality rates. The Irish FRAX tool can be used to identify intervention thresholds for Ireland based on the fracture probability equivalent to that of a woman with a prior fracture. OBJECTIVES: The objective of the study is to describe the 10-year probability of osteoporotic fracture in men and women in Ireland by using the Irish version of the FRAX tool and to develop FRAX-based intervention thresholds. METHODS: The FRAX model for Ireland was constructed from the age- and sex-stratified hip fracture incidence rates from 2008 to 2010. For other major osteoporotic fractures, incidence rates were imputed, using age- and sex-specific Swedish ratios for hip to osteoporotic fracture risks. Lifetime fracture probabilities and 10-year probabilities of a major osteoporotic fracture were calculated in women to determine potential intervention thresholds. RESULTS: Based on the incidence of hip fracture and mortality, the average lifetime probability of hip fracture from the age of 50 years was 7.8% in men and 18.2% in women from Ireland. Probability-based intervention threshold derived from BMD T scores were problematic. When a BMD T-score<=-2.5 standard deviations (SD) was used as an intervention threshold, the increase in risk associated with the BMD threshold decreased progressively with age such that, at the age of 80 years or more, a T-score of -2.5 SD was protective. The 10-year probability of a major osteoporotic fracture by age, equivalent to that of women with a previous fracture, rose with age, from 3.0% at the age of 40 years to 30% at the age of 90 years, and identified women at increased risk at all ages. CONCLUSION: The Irish FRAX tool is the first fracture prediction model that has been calibrated using national hip fracture incidence data and Irish mortality rates. PMID- 23982945 TI - Simulation of nanoparticle transport in airways using Petrov-Galerkin finite element methods. AB - The transport and deposition properties of nanoparticles with a range of aerodynamic diameters ( 1 nm <= d <= 150 nm) were studied for the human airways. A finite element code was developed that solved both the Navier-Stokes and advection-diffusion equations monolithically. When modeling nanoparticle transport in the airways, the finite element method becomes unstable, and, in order resolve this issue, various stabilization methods were considered in terms of accuracy and computational cost. The stabilization methods considered here include the streamline upwind, streamline upwind Petrov-Galerkin, and Galerkin least squares approaches. In order to compare the various stabilization approaches, the approximate solution from each stabilization approach was compared to the analytical Graetz solution, which is a model for monodispersed, dilute particle transport in a straight cylinder. The optimal stabilization method, especially with regard to accuracy, was found to be the Galerkin least squares approach for the Graetz problem when the Peclet number was larger than 10(4). In the human airways geometry, the Galerkin least squares stabilization approach once more provided the most accurate approximate solution for particles with an aerodynamic diameter of 10 nm or larger, but mesh size had a much greater effect on accuracy than the choice of stabilization method. The choice of stabilization method had a greater impact than mesh size for particles with an aerodynamic diameter 10 nm or smaller, but the most accurate stabilization method was streamline upwind Petrov-Galerkin in these cases. PMID- 23982944 TI - Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation. AB - Increased CCL2 expression in prostate cancer (PCa) cells enhanced metastasis via macrophage recruitment. However, its linkage to androgen receptor (AR)-mediated PCa progression remains unclear. Here, we identified a previously unrecognized regulation: targeting AR with siRNA in PCa cells increased macrophage recruitment via CCL2 up-regulation, which might then result in enhancing PCa invasiveness. Molecular mechanism dissection revealed that targeting PCa AR with siRNA promoted PCa cell migration/invasion via CCL2-dependent STAT3 activation and epithelial mesenchymal transition (EMT) pathways. Importantly, pharmacologic interruption of the CCL2/CCR2-STAT3 axis suppressed EMT and PCa cell migration, providing a new mechanism linking CCL2 and EMT. Simultaneously targeting PCa AR with siRNA and the CCL2/CCR2-STAT3 axis resulted in better suppression of PCa growth and metastasis in a xenograft PCa mouse model. Human PCa tissue microarray analysis suggests that increased CCL2 expression may be potentially associated with poor prognosis of PCa patients. Together, these results may provide a novel therapeutic approach to better battle PCa progression and metastasis at the castration resistant stage via the combination of targeting AR with siRNA and anti-CCL2/CCR2-STAT3 signalling. PMID- 23982946 TI - Contextual control of audiovisual integration in low-level sensory cortices. AB - Potential sources of multisensory influences on low-level sensory cortices include direct projections from sensory cortices of different modalities, as well as more indirect feedback inputs from higher order multisensory cortical regions. These multiple architectures may be functionally complementary, but the exact roles and inter-relationships of the circuits are unknown. Using a fully balanced context manipulation, we tested the hypotheses that: (1) feedforward and lateral pathways subserve speed functions, such as detecting peripheral stimuli. Multisensory integration effects in this context are predicted in peripheral fields of low-level sensory cortices. (2) Slower feedback pathways underpin accuracy functions, such as object discrimination. Integration effects in this context are predicted in higher-order association cortices and central/foveal fields of low-level sensory cortex. We used functional magnetic resonance imaging to compare the effects of central versus peripheral stimulation on audiovisual integration, while varying speed and accuracy requirements for behavioral responses. We found that interactions of task demands and stimulus eccentricity in low-level sensory cortices are more complex than would be predicted by a simple dichotomy such as our hypothesized peripheral/speed and foveal/accuracy functions. Additionally, our findings point to individual differences in integration that may be related to skills and strategy. Overall, our findings suggest that instead of using fixed, specialized pathways, the exact circuits and mechanisms that are used for low-level multisensory integration are much more flexible and contingent upon both individual and contextual factors than previously assumed. PMID- 23982948 TI - Phototropin 2 is involved in blue light-induced anthocyanin accumulation in Fragaria x ananassa fruits. AB - Anthocyanins are widespread, essential secondary metabolites in higher plants during color development in certain flowers and fruits. In strawberries, anthocyanins are also key contributors to fruit antioxidant capacity and nutritional value. However, the effects of different light qualities on anthocyanin accumulation in strawberry (Fragaria x ananassa, cv. Sachinoka) fruits remain elusive. In the present study, we showed the most efficient increase in anthocyanin content occurred by blue light irradiation. Light sensing at the molecular level was investigated by isolation of two phototropin (FaPHOT1 and FaPHOT2), two cryptochrome (FaCRY1 and FaCRY2), and two phytochrome (FaPHYA and FaPHYB) homologs. Expression analysis revealed only FaPHOT2 transcripts markedly increased depending on fruit developmental stage, and a corresponding increase in anthocyanin content was detected. FaPHOT2 knockdown resulted in decreased anthocyanin content; however, overexpression increased anthocyanin content. These findings suggested blue light induced anthocyanin accumulation, and FaPHOT2 may play a role in sensing blue light, and mediating anthocyanin biosynthesis in strawberry fruits. This is the first report to find a relationship between visible light sensing, and color development in strawberry fruits. PMID- 23982949 TI - Massive accumulation of 11C-Pittsburg compound B in the occipital lobes of a patient with early-onset dementia accompanied by muscle weakness and hypertonicity. AB - A 44-year-old woman underwent 11C-Pittsburg compound B (11C-PiB), 18F fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), 99mTc-ethyl-cysteinate-dimer single photon emission computed tomography, and magnetic resonance imaging after presenting with progressive dementia, muscle weakness, and hypertonicity. Some of her family members had died of muscle weakness with early-onset dementia of unknown etiology. Neurological and psychological examinations revealed moderate dementia in general fields and muscle weakness in her upper limbs. 11C-PiB PET/CT revealed abnormal accumulations of amyloid in the bilateral occipital lobes, while physiological uptakes of 11C-PiB in areas that normally show high uptake, such as white matter, appeared relatively decreased. Meanwhile, cerebrospinal fluid (CSF) amyloid-beta was decreased, and CSF total and phosphorylated tau proteins were increased. This case may be representative of a new category of amyloid deposition disease characterized by early-onset dementia, muscle weakness, and hypertonicity, or at least, a new uptake pattern of PiB in variant AD. PMID- 23982950 TI - Memory dysfunction in primary Sjogren's syndrome is associated with anti-NR2 antibodies. AB - OBJECTIVE: Our understanding of the etiology and pathogenesis of neuropsychiatric involvement in primary Sjogren's syndrome (SS) is incomplete. In systemic lupus erythematosus, it has been reported that antibodies directed against N-methyl-D aspartate receptor subtype NR2 (anti-NR2) interfere with memory and learning function, as well as mood. This has not been investigated in primary SS; however, the present study was undertaken to advance our understanding of neuropsychiatric involvement in this disease. METHODS: Sixty-six patients with primary SS and 66 age- and sex-matched healthy control subjects underwent clinical examination and neuropsychological evaluation. Anti-NR2 antibodies were measured in serum and cerebrospinal fluid. Hippocampus volume was estimated using software extensions to SPM5. RESULTS: Patients with primary SS had smaller hippocampi than healthy subjects (mean +/- SD 8.15 +/- 0.98 cm(3) versus 8.49 +/- 0.88 cm(3); P = 0.01). In patients with primary SS, anti-NR2 antibodies in cerebrospinal fluid were associated with a worse performance in 8 of 10 memory and learning tests, and anti-NR2 antibodies in serum were associated with a worse performance in 6 of those same tests. In addition, a higher proportion of patients with depression than patients without depression had serum anti-NR2 antibody levels above the cutoff value. CONCLUSION: Results of this study indicate that anti-NR2 antibodies may represent one of the pathogenetic mechanisms for cognitive disturbances and mood disorders in patients with primary SS. PMID- 23982951 TI - Effect of substituting arginine and lysine with alanine on antimicrobial activity and the mechanism of action of a cationic dodecapeptide (CL(14-25)), a partial sequence of cyanate lyase from rice. AB - The antimicrobial activity of analogs obtained by substituting arginine and lysine in CL(14-25), a cationic alpha-helical dodecapeptide, with alanine against Porphyromonas gingivalis, a periodontal pathogen, varied significantly depending on the number and position of cationic amino acids. The alanine-substituted analogs had no hemolytic activity, even at a concentration of 1 mM. The antimicrobial activities of CL(K20A) and CL(K20A, K25A) were 3.8-fold and 9.1 fold higher, respectively, than that of CL(14-25). The antimicrobial activity of CL(R15A) was slightly lower than that of CL(14-25), suggesting that arginine at position 15 is not essential but is important for the antimicrobial activity. The experiments in which the alanine-substituted analogs bearing the replacement of arginine at position 24 and/or lysine at position 25 were used showed that arginine at position 24 was crucial for the antimicrobial activity whenever lysine at position 25 was substituted with alanine. Helical wheel projections of the alanine-substituted analogs indicate that the hydrophobicity in the vicinity of leucine at position 16 and alanines at positions 18 and/or 21 increased by substituting lysine at positions 20 and 25 with alanine, respectively. The degrees of diSC3 -5 release from P. gingivalis cells and disruption of GUVs induced by the alanine-substituted analogs with different positive charges were not closely related to their antimicrobial activities. The enhanced antimicrobial activities of the alanine-substituted analogs appear to be mainly attributable to the changes in properties such as hydrophobicity and amphipathic propensity due to alanine substitution and not to their extents of positive charge (cationicity). PMID- 23982952 TI - Alone again: John Zubek and the troubled history of sensory deprivation research. AB - In the 1950s, sensory deprivation research emerged as an influential new field for behavioral science researchers, supported by the intelligence community. Within a few years, deprivation research had become ubiquitous; images of sensory deprivation were invoked to explain a wide range of phenomena, from religious revelations to the very structure of psychoanalysis. Yet within a decade and a half, this field of research became implicated in cases of torture and abuse. This article examines the history of University of Manitoba psychologist John Zubek, who remained one of the final researchers still conducting sensory deprivation research in the 1970s. It raises questions on how might it be possible to successfully and cautiously perform controversial research. PMID- 23982953 TI - Changes in cellular energy allocation in Enchytraeus albidus when exposed to dimethoate, atrazine, and carbendazim. AB - Cellular energy allocation (CEA) is a methodology developed to evaluate the effects of toxic stress on the metabolic balance of organisms. It consists of the integration of the energy reserves available (Ea; total carbohydrate, protein and lipid content) and energy consumption (Ec) estimated by measuring electron transport system (ETS) activity. The main goal of the present study was to evaluate the effects on the energy budget of the soil invertebrate Enchytraeus albidus (Oligochaeta) after exposure to dimethoate, atrazine, and carbendazim (by testing the reproduction 10% effective concentration, 20% effective concentration, 50% effective concentration and 90% effective concentration) over periods of time from 0 d to 2 d, 4 d, and 8 d. Significant changes in energy reserves were observed with all pesticides, together with effects on energy consumption. Carbohydrates were the first energy source to be used, and clear depletions occurred with all pesticides. Energy consumption increased generally over longer exposures and with higher concentrations of the pesticides. Although clear changes were seen in the individual energy reserve budgets and on Ec, CEA was only significantly reduced with atrazine exposures longer than 4 d. The nearly absent effects on CEA at concentrations known to affect reproduction indicate that the reduction in reproduction is not likely to be caused by a reduction in the total energy budget during the first 8 d of exposure. The present study showed the importance of complementing CEA interpretation with the individual Ea and Ec parameters, in particular if these show opposite balances. The Ea and Ec results were in good agreement with gene transcription results from a parallel study, hence suggesting translation and showing the advantage of combining various effect levels to advance the understanding of mechanisms. PMID- 23982954 TI - 15-LO/15-HETE mediated vascular adventitia fibrosis via p38 MAPK-dependent TGF beta. AB - 15-Lipoxygenase/15-hydroxyeicosatetraenoic acid (15-LO/15-HETE) is known to modulate pulmonary vascular medial hypertrophy and intimal endothelial cells migration and angiogenesis after hypoxia. However, it is unclear whether 15-HETE affects the adventitia of the pulmonary arterial wall. We performed immunohistochemistry, adventitia fibrosis, pulmonary artery fibroblasts phenotype and extracellular matrix (ECM) deposition to determine the role of 15-HETE in hypoxia-induced pulmonary vascular adventitia remodeling. Our studies showed that O2 deprivation induced adventitia hypertrophy of pulmonary arteries with ECM accumulation in both humans with pulmonary arterial hypertension and hypoxic rats. Hypoxia induced 15-LO expression in adventitia. With the inhibitor, NDGA depressed the hypoxia induced ECM deposition and 15-LO production in hypoxic rats. Hypoxia up-regulated the expression of alpha-SMA, type-Ia collagen and fibronectin in cultured fibroblasts, which seemed to be due to the increased 15 LO/15-HETE. Exogenous 15-HETE mediated the ECM and phenotypic alterations of the fibroblasts as well. The 15-LO/15-HETE induced adventitia fibrosis and fibroblasts phenotypic alterations depended on signaling of the transforming growth factor-beta1 (TGF-beta1)/Smad2/3 pathway. P38 mitogen-activated protein kinase (p38 MAPKs) was likely to mediate 15-LO induced TGF-beta1 and Smad2/3 activation after hypoxia. The results suggest that adventitia fibrosis is an important event in the hypoxia induced pulmonary arterial remodeling, which relies on 15-LO/15-HETE induced p38 MAPK-dependent TGF-beta1/Smad2/3 intracellular signaling systems. PMID- 23982955 TI - Design, synthesis, and application of stimulus-sensing biohybrid hydrogels. AB - A key feature of any living system is the ability to sense and react to the environmental stimuli. The biochemical characterization of the underlying biological sensors combined with advances in polymer chemistry has enabled the development of stimulus-sensitive biohybrid materials that translate most diverse chemical and biological input into a precise change in material properties. In this review article, we first describe synthesis strategies of how biological and chemical polymers can functionally be interconnected. We then provide a comprehensive overview of how the different properties of biological sensor molecules such as competitive target binding and allosteric modulation can be harnessed to develop responsive materials with applications in tissue engineering and drug delivery. PMID- 23982956 TI - New genetic model for predicting phenotype traits in sports. AB - PURPOSE: The aim of the current study was to construct a genetic model with a new algorithm for predicting athletic-performance variability based on genetic variations. METHODS: The influence of 6 polymorphisms (ACE, ACTN-3, BDKRB2, VDR ApaI, VDR-BsmI, and VDR-FokI) on vertical jump was studied in top-level male Italian soccer players (n = 90). First, the authors calculated the traditional total genotype score and then determined the total weighting genotype score (TWGS), which accounts for the proportion of significant phenotypic variance predicted by the polymorphisms. Genomic DNA was extracted from saliva samples using a standard protocol. Genotyping was performed using polymerase chain reaction (PCR). RESULTS: The results obtained from the new genetic model (TWGS) showed that only 3 polymorphisms entered the regression equation (ACTN-3, ACE, and BDKRB2), and these polymorphisms explained 17.68-24.24% of the vertical-jump variance. With the weighting given to each polymorphism, it may be possible to identify a polygenic profile that more accurately explains, at least in part, the individual variance of athletic-performance traits. CONCLUSIONS: This model may be used to create individualized training programs based on a player's genetic predispositions, as well as to identify athletes who need an adapted training routine to account for individual susceptibility to injury. PMID- 23982957 TI - Impaired neurogenesis and neurite outgrowth in an HIV-gp120 transgenic model is reversed by exercise via BDNF production and Cdk5 regulation. AB - Human immunodeficiency virus (HIV) infection-associated neurocognitive disorders is accompanied with brain atrophy. In these patients, impairment of adult neurogenesis and neurite outgrowth in the hippocampus may contribute to cognitive dysfunction. Although running exercises can enhance neurogenesis and normalize neurite outgrowth, the underlying molecular mechanisms are not well understood. The HIV envelope protein, gp120, has been shown to impair neurogenesis. Using a gp120 transgenic mouse model, we demonstrate that exercise stimulated neural progenitor cell (NPC) proliferation in the hippocampal dentate gyrus and increased the survival rate and generation of newborn cells. However, sustained exercise activity was necessary as the effects were reversed by detraining. Exercise also normalized dendritic outgrowth of neurons. Furthermore, it increased the expression of hippocampal brain-derived neurotrophic factor (BDNF) and normalized hyperactivation of cyclin-dependent kinase 5 (Cdk5). Hyperactivated Cdk5 or gp120 treatment led to aberrant neurite outgrowth and BDNF treatment normalized the neurite outgrowth in NPC cultures. These results suggest that sustained exercise has trophic activity on the neuronal lineage which is mediated by Cdk5 modulation of the BDNF pathway. PMID- 23982959 TI - Quality of life and health care use in patients with arthralgias without synovitis compared with patients diagnosed with early rheumatoid arthritis: data from an early arthritis cohort. AB - OBJECTIVE: To compare the burden of disease and its development over time in patients referred to an early arthritis cohort who were diagnosed either as having arthralgias without synovitis or as having rheumatoid arthritis (RA). METHODS: Patients diagnosed as having arthralgias without synovitis or RA were selected from the Rotterdam Early Arthritis Cohort. Data on clinical and psychological characteristics, demographics, pain scores (Rheumatoid Arthritis Disease Activity Index), functional ability (Health Assessment Questionnaire), health-related quality of life (HRQOL; Short Form 36), fatigue (visual analog scale and Fatigue Assessment Scale), and health care utilization (HCU) were collected at baseline and at 6 and 12 months of followup. The burden of disease measures (pain, functional ability, fatigue, and HRQOL) and HCU levels were plotted over time for both groups. A Poisson regression model for repeated data was used to identify determinants of HCU for both groups. RESULTS: At baseline, 330 patients with arthralgias without synovitis (nonsynovitis [NS] group) and 244 RA patients (RA group) were included. Overall, the burden of disease measures and HCU levels were very similar between groups. Both groups showed improvement over time with respect to pain scores, functional ability, HRQOL, and HCU levels. Independent predictors of high HCU were identified as more pain, worse physical health, and external locus of control in the NS group and as shorter duration of symptoms, low chance locus of control, and worse physical functioning in the RA group. CONCLUSION: Despite the absence of an inflammatory diagnosis, patients with arthralgias without synovitis experienced a similar burden of disease compared with RA patients. PMID- 23982958 TI - YWHAE/14-3-3epsilon: a potential novel genetic risk factor and CSF biomarker for HIV neurocognitive impairment. AB - YWHAE (14-3-3epsilon) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated neurocognitive disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3* more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5* less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for neurocognitive status in HIV-seropositive women. PMID- 23982960 TI - Shoulder pain in the community: an examination of associative factors using a longitudinal cohort study. AB - OBJECTIVE: To determine factors that are predictive of incident, recurrent, or resolved shoulder pain in a community-based sample from the general population. METHODS: This study used data from the North West Adelaide Health Study, a cohort study located in the northwestern suburbs of Adelaide, South Australia. Data were obtained between 2004 and 2006 and between 2008 and 2010, with time between measurements ranging from 2-6 years (median 4 years), using a computer-assisted telephone interview, a clinical assessment, and a self-completed questionnaire. Multivariate logistic regression was used to examine the factors associated with shoulder pain. RESULTS: Overall, 14.6% (95% confidence interval [95% CI] 12.7 16.7) of 2,337 eligible participants reported that they had developed (or had incident) shoulder pain between 2 time points of the cohort study, 8.8% (95% CI 7.5-10.3) reported recurrent shoulder pain, and 8.7% (95% CI 7.0-10.6) had resolved shoulder pain. Incident shoulder pain was significantly associated with physically heavier occupational activities and pain in other joints after adjustment for age, sex, and body mass index. Recurrent shoulder pain was also associated with pain in other joints, but also with depressive symptoms, smoking, and decreased shoulder range of movement. Resolved shoulder pain was associated with being female, other areas of pain, and decreased shoulder range of movement, but higher grip strength. CONCLUSION: Different factors were associated with incident, recurrent, or resolved shoulder pain in a longitudinal cohort study. Consideration of all of these factors may assist in the prevention and management of shoulder pain and the possible identification of those at risk of long-term shoulder problems. PMID- 23982961 TI - Triple negative breast cancer initiating cell subsets differ in functional and molecular characteristics and in gamma-secretase inhibitor drug responses. AB - Increasing evidence suggests that stem-like cells mediate cancer therapy resistance and metastasis. Breast tumour-initiating stem cells (T-ISC) are known to be enriched in CD44(+) CD24(neg/low) cells. Here, we identify two T-ISC subsets within this population in triple negative breast cancer (TNBC) lines and dissociated primary breast cancer cultures: CD44(+) CD24(low+) subpopulation generates CD44(+) CD24(neg) progeny with reduced sphere formation and tumourigenicity. CD44(+) CD24(low+) populations contain subsets of ALDH1(+) and ESA(+) cells, yield more frequent spheres and/or T-ISC in limiting dilution assays, preferentially express metastatic gene signatures and show greater motility, invasion and, in the MDA-MB-231 model, metastatic potential. CD44(+) CD24(low+) but not CD44(+) CD24(neg) express activated Notch1 intracellular domain (N1-ICD) and Notch target genes. We show N1-ICD transactivates SOX2 to increase sphere formation, ALDH1+ and CD44(+) CD24(low+) cells. Gamma secretase inhibitors (GSI) reduced sphere formation and xenograft growth from CD44(+) CD24(low+) cells, but CD44(+) CD24(neg) were resistant. While GSI hold promise for targeting T-ISC, stem cell heterogeneity as observed herein, could limit GSI efficacy. These data suggest a breast T-ISC hierarchy in which distinct pathways drive developmentally related subpopulations with different anti-cancer drug responsiveness. PMID- 23982963 TI - Local synovial engagement of angiogenic TIE-2 is associated with the development of persistent erosive rheumatoid arthritis in patients with early arthritis. AB - OBJECTIVE: To examine the role of vascular endothelial growth factor (VEGF) and angiopoietin signaling in the diagnosis and disease outcome of patients with early arthritis. METHODS: Fifty patients with early arthritis (disease duration <1 year) who had not been treated with disease-modifying antirheumatic drugs (DMARDs) were monitored prospectively and were classified at baseline and after 2 years as having undifferentiated arthritis (UA), rheumatoid arthritis (RA), or spondyloarthritis (SpA). All patients underwent arthroscopic synovial biopsy at baseline. Synovial expression of VEGF, VEGF receptor, angiopoietin 1 (Ang-1), Ang 2, TIE-2, and activated p-TIE-2 was evaluated by immunohistochemistry. Serum levels of VEGF, Ang-1, and Ang-2 were measured by enzyme-linked immunosorbent assay. Secreted products of macrophages stimulated with Ang-1 and Ang-2 were measured using a multiplex system. RESULTS: Expression of Ang-1 was comparable between the patients with RA at baseline and patients with UA who fulfilled the criteria for RA over time (UA/RA), and it was significantly higher in patients with RA (P < 0.05) or UA/RA (P < 0.005) than in patients with SpA. TIE-2 and p TIE-2 were more highly expressed in patients with RA (P < 0.005) or UA/RA (P < 0.05) than in patients with SpA. Ang-1 significantly enhanced the tumor necrosis factor-dependent macrophage production of cytokines and chemokines that are known to be elevated in the synovial fluid of patients with early RA. In RA, relative TIE-2 activation predicted the development of erosive disease (R(2) = 0.35, P < 0.05). CONCLUSION: Local engagement of synovial TIE-2 is observed during the earliest phases of RA, suggesting that TIE-2 signaling may contribute to disease development and progression or may indicate an attempt to protect against these processes. Early therapeutic targeting of TIE-2 signaling may be useful in improving outcome in arthritis. PMID- 23982962 TI - Reliability of neuroanatomical measurements in a multisite longitudinal study of youth at risk for psychosis. AB - Multisite longitudinal neuroimaging designs are used to identify differential brain structural change associated with onset or progression of disease. The reliability of neuroanatomical measurements over time and across sites is a crucial aspect of power in such studies. Prior work has found that while within site reliabilities of neuroanatomical measurements are excellent, between-site reliability is generally more modest. Factors that may increase between-site reliability include standardization of scanner platform and sequence parameters and correction for between-scanner variations in gradient nonlinearities. Factors that may improve both between- and within-site reliability include use of registration algorithms that account for individual differences in cortical patterning and shape. In this study 8 healthy volunteers were scanned twice on successive days at 8 sites participating in the North American Prodrome Longitudinal Study (NAPLS). All sites employed 3 Tesla scanners and standardized acquisition parameters. Site accounted for 2 to 30% of the total variance in neuroanatomical measurements. However, site-related variations were trivial (<1%) among sites using the same scanner model and 12-channel coil or when correcting for between-scanner differences in gradient nonlinearity and scaling. Adjusting for individual differences in sulcal-gyral geometries yielded measurements with greater reliabilities than those obtained using an automated approach. Neuroimaging can be performed across multiple sites at the same level of reliability as at a single site, achieving within- and between-site reliabilities of 0.95 or greater for gray matter density in the majority of voxels in the prefrontal and temporal cortical surfaces as well as for the volumes of most subcortical structures. PMID- 23982968 TI - Controlled growth of large-area high-performance small-molecule organic single crystalline transistors by slot-die coating using a mixed solvent system. AB - A slot-die coating technique is used for the crystal alignment of triisopropylsilylethynyl (TIPS)-pentacene in solution-processed field-effect transistors (FETs). The film thickness, uniformity, and crystal growth behavior are well controlled by tuning the coating parameters and by using a mixed solvent system (toluene/anisole). An average saturation regime FET mobility of 1.8 cm(2) V(-1) s(-1) is achieved under ambient conditions. PMID- 23982970 TI - Pathogenesis of graft-versus-host disease: innate immunity amplifying acute alloimmune responses. AB - In addition to reduced-intensity conditioning, which has expanded the eligibility for hematopoietic cell transplantation (HCT) to older patients, increased availability of alternative donors, including HLA-mismatched unrelated donors, has increased access to allogeneic HCT for more patients. However, acute graft versus-host disease (GVHD) remains a lethal complication, even in HLA-matched donor-recipient pairs. The pathophysiology of GVHD depends on aspects of adaptive immunity and interactions between donor T-cells and host dendritic cells (DCs). Recent work has revealed that the role of other immune cells and endothelial cells and components of the innate immune response are also important. Tissue damage caused by the conditioning regimen leads to the release of exogenous and endogenous "danger signals". Exogenous danger signals called pathogen-associated molecular patterns and endogenous noninfectious molecules known as damage associated molecular patterns (DAMPs) are responsible for initiating or amplifying acute GVHD by enhancing DC maturation and alloreactive T-cell responses. A significant association of innate immune receptor polymorphisms with outcomes, including GVHD severity, was observed in patients receiving allogeneic HCT. Understanding of the role of innate immunity in acute GVHD might offer new therapeutic approaches. PMID- 23982972 TI - From random coil polymers to helical structures induced by carbon nanotubes and supramolecular interactions. AB - A simple method is reported for the preparation of double-helical structures through a series of achiral random and block copolymers poly(styrene-co-4 vinylbenzyl triazolylmethyl methylthymine) (PS-co-PVBT) with various T units on the side chains through click reactions of poly(styrene-co-4-vinylbenzyl azide) (PS-co-PVBN(3)) with propargyl thymine (PT) and also the synthesis of the A appended pyrene derivative (A-Py) through click chemistry. This double-helical structure is observed from achiral random-coil polystyrene (PS) main chains, stabilized through the combination of multiple A-T hydrogen bonds, and pi-pi stacking between pyrene units and single-walled carbon nanotubes (SWCNTs). PMID- 23982971 TI - Subclavian transectional stent fracture and migration to the aortic carrefour: a case description of retrieval by snare system. AB - Percutaneous transluminal angioplasty with or without stent has become the treatment of choice for stenotic lesion in subclavian arteries. However, there is a growing concern following many reports of stent fractures, a serious complication of endovascular therapy. We report for the first time a case of delayed left subclavian stent fracture with transection of the protruding ostial part and migration into the aortic carrefour that was retrieved by a snare device. PMID- 23982969 TI - Structural organization and function of mouse photoreceptor ribbon synapses involve the immunoglobulin protein synaptic cell adhesion molecule 1. AB - Adhesive interactions in the retina instruct the developmental specification of inner retinal layers. However, potential roles of adhesion in the development and function of photoreceptor synapses remain incompletely understood. This contrasts with our understanding of synapse development in the CNS, which can be guided by select adhesion molecules such as the Synaptic Cell Adhesion Molecule 1 (SynCAM 1/CADM1/nectin-like 2 protein). This immunoglobulin superfamily protein modulates the development and plasticity of classical excitatory synapses. We show here by immunoelectron microscopy and immunoblotting that SynCAM 1 is expressed on mouse rod photoreceptors and their terminals in the outer nuclear and plexiform layers in a developmentally regulated manner. Expression of SynCAM 1 on rods is low in early postnatal stages (P3-P7) but increases after eye opening (P14). In support of functional roles in the photoreceptors, electroretinogram recordings demonstrate impaired responses to light stimulation in SynCAM 1 knockout (KO) mice. In addition, the structural integrity of synapses in the OPL requires SynCAM 1. Quantitative ultrastructural analysis of SynCAM 1 KO retina measured fewer fully assembled, triadic rod ribbon synapses. Furthermore, rod synapse ribbons are shortened in KO mice, and protein levels of Ribeye, a major structural component of ribbons, are reduced in SynCAM 1 KO retina. Together, our results implicate SynCAM 1 in the synaptic organization of the rod visual pathway and provide evidence for novel roles of synaptic adhesion in the structural and functional integrity of ribbon synapses. PMID- 23982973 TI - How to produce personality neuroscience research with high statistical power and low additional cost. AB - Personality neuroscience involves examining relations between cognitive or behavioral variability and neural variables like brain structure and function. Such studies have uncovered a number of fascinating associations but require large samples, which are expensive to collect. Here, we propose a system that capitalizes on neuroimaging data commonly collected for separate purposes and combines it with new behavioral data to test novel hypotheses. Specifically, we suggest that groups of researchers compile a database of structural (i.e., anatomical) and resting-state functional scans produced for other task-based investigations and pair these data with contact information for the participants who contributed the data. This contact information can then be used to collect additional cognitive, behavioral, or individual-difference data that are then reassociated with the neuroimaging data for analysis. This would allow for novel hypotheses regarding brain-behavior relations to be tested on the basis of large sample sizes (with adequate statistical power) for low additional cost. This idea can be implemented at small scales at single institutions, among a group of collaborating researchers, or perhaps even within a single lab. It can also be implemented at a large scale across institutions, although doing so would entail a number of additional complications. PMID- 23982974 TI - Utility of musculoskeletal ultrasound in a Department of Defense rheumatology practice: a four-year retrospective experience. AB - OBJECTIVE: To analyze the utility of musculoskeletal ultrasound (MSUS) in a rheumatology department and characterize relevant clinical trends. METHODS: Electronic medical records of all patients (n = 503) requiring MSUS in our department from January 2007 to December 2011 were reviewed. Rheumatologists performed MSUS using MyLab 25 or MyLab 70 systems. Clinical data were collected, including age, sex, symptoms, joint(s) examined, MSUS findings, procedures, further radiologic studies, and additional specialty consults. Results were tabulated from 717 total MSUS encounters and each was categorized as a completed encounter or an incomplete encounter. All magnetic resonance imaging (MRI) reports that followed MSUS were examined for concurrence. Cumulative numbers of MSUS examinations and MRIs were totaled. The Medicare global national average cost for MRIs and potential savings were calculated. RESULTS: A total of 789 joint sites were examined by MSUS. There were 84 US-guided procedures. Overall, 158 specialty consults were generated. After MSUS, 55 additional radiologic studies were ordered. There were 613 (85.5%) primary completed MSUS encounters and 104 cases (14.5%) requiring further imaging studies or an orthopedic consultation. There was an increased use of MSUS and a concurrent decreased use of MRI in our department over 4 consecutive years. We calculated the total potential savings from our rheumatology service to the Department of Defense as approximately $27,937.80 to $38,047.20 over 4 years. CONCLUSION: MSUS has a positive impact in a rheumatology practice. MSUS augments the clinical examination, influences diagnosis and management, decreases reliance on other imaging modalities, and reduces health care costs. PMID- 23982975 TI - Swollen to tender joint count ratio: a novel combination of routine measures to assess pain and treatment response in rheumatoid arthritis. PMID- 23982978 TI - Role of Fms-like tyrosine kinase 3 ligand as a potential biologic marker of lymphoma in primary Sjogren's syndrome. AB - OBJECTIVE: Patients with primary Sjogren's syndrome (SS) are at greater risk of developing lymphoma. This study was undertaken to evaluate whether the Fms-like tyrosine kinase 3 ligand (Flt-3L) might be associated with lymphoma in primary SS. METHODS: Serum levels of Flt-3L were measured in 369 patients with primary SS from the French Assessment of Systemic Signs and Evolution of Sjogren's Syndrome study cohort and in 10 patients with primary SS at the time of lymphoma diagnosis in an Italian cohort. Associations between increased levels of Flt-3L and a history of lymphoma, history of previously diagnosed criteria related to a high risk of lymphoma, and greater extent of disease activity were evaluated. RESULTS: Among patients with primary SS, higher levels of Flt-3L were significantly associated with a history of lymphoma (P = 0.0001). Previous markers for risk of lymphoma development, such as presence of purpura, low levels of C4, presence of lymphocytopenia, low levels of IgM, high levels of beta2 -microglobulin, and a higher primary SS disease activity score, were all associated with higher levels of Flt-3L. The levels of Flt-3L were also increased in serum obtained from patients with primary SS at the time of lymphoma diagnosis. Furthermore, the Flt 3L levels were elevated in the serum of 6 patients up to 94 months (mean 46 months) prior to the diagnosis of lymphoma. Receiver operating characteristic curve analysis showed that an Flt-3L level of 175 pg/ml was the ideal cutoff value for demonstrating an association with lymphoma (specificity 97.5%, sensitivity 44%, negative predictive value 97%). CONCLUSION: Flt-3L is associated with lymphoma in primary SS, and constitutes a good biologic marker. Higher levels of this cytokine are present several years before the diagnosis of lymphoma, and may be useful as a predictive marker of lymphoproliferative disorders in primary SS. PMID- 23982977 TI - Size tuning of Ag-decorated TiO2 nanotube arrays for improved bactericidal capacity of orthopedic implants. AB - Surface modification of orthopedic implants using titanium dioxide nanotubes and silver nanoparticles (SNs) is a promising approach to prevent bacteria adhesion, biofilm formation, and implant infection. Herein, we utilized a straightforward and all-solution process to prepare silver-decorated TiO2 nanotube arrays with surface density of 10(3) to 10(4) per um(2). With controlling the synthesis conditions, hexagonal closed-packed nanotubes with opening diameter of 30-100 nm that are decorated with SNs with varying sizes (12-40 nm) were prepared. Various analytical techniques were utilized to characterize the size, morphology, distribution, valance state, surface roughness, and composition of the prepared antibacterial films. The bactericidal capacity of the films were studied on Escherichia coli (E. coli) by drop-test method and correlated with the size and percentage of Ag as well as the surface density of TiO2 nanotube arrays. Synergetic effect of TiO2 nanotubes and SNs on the antibacterial activity of the composite films is shown. The bactericidal capacity is found to depend on the size characteristics of the Ag-TiO2 coating. The highest antibacterial activity is obtained for TiO2 nanotubes with opening diameter of about 100 nm and SNs with an average size of 20 nm. MTT assay using osteoblast MG63 cells was performed to examine the cell viability. We suggest that release rate of the silver ions is an important factor controlling the antibacterial activity. Additionally, the size dependency of the bactericidal capacity implies that electrical coupling between silver and TiO2 nanotubes and improved hydrophobicity of the coating might influence the bacterial behavior of the hybrid nanostructures. PMID- 23982976 TI - Discovery of novel potent DeltaF508-CFTR correctors that target the nucleotide binding domain. AB - The deletion of Phe508 (DeltaF508) in the first nucleotide binding domain (NBD1) of CFTR is the most common mutation associated with cystic fibrosis. The DeltaF508-CFTR mutant is recognized as improperly folded and targeted for proteasomal degradation. Based on molecular dynamics simulation results, we hypothesized that interaction between DeltaF508-NBD1 and housekeeping proteins prevents DeltaF508-CFTR delivery to the plasma membrane. Based on this assumption we applied structure-based virtual screening to identify new low-molecular-weight compounds that should bind to DeltaF508-NBD1 and act as protein-protein interaction inhibitors. Using different functional assays for CFTR activity, we demonstrated that in silico-selected compounds induced functional expression of DeltaF508-CFTR in transfected HeLa cells, human bronchial CF cells in primary culture, and in the nasal epithelium of homozygous DeltaF508-CFTR mice. The proposed compounds disrupt keratin8-DeltaF508-CFTR interaction in DeltaF508-CFTR HeLa cells. Structural analysis of DeltaF508-NBD1 in the presence of these compounds suggests their binding to NBD1. We conclude that our strategy leads to the discovery of new compounds that are among the most potent correctors of DeltaF508-CFTR trafficking defect known to date. PMID- 23982979 TI - Altered resting-state connectivity in Huntington's disease. AB - Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Using resting-state fMRI (rs-fMRI) we investigated the functional integrity of resting state networks (RSN) in HD. 17 HD and 19 matched control participants were examined at a 3 Tesla MR scanner. After controlling for structural degeneration by means of voxel-based morphometry, task-free rs-fMRI data were analyzed using Independent Component Analysis (ICA) and a dual-regression approach in the context of genetic and clinical parameters. Further, we evaluated HD-related differences in interregional connectivity between networks. RSN analysis showed a significant increase in intrinsic functional connectivity in the HD sample compared with controls, including the thalamus, striatum, prefrontal, premotor, and parietal maps. A subset of the Default Mode Network (DMN) was also affected. In the HD cohort, motor impairment correlated with higher network connectivity in mainly motor and parietal cortices. Deteriorating total functional capacity was additionally associated with higher connectivity in the striatum, thalamus, insular and frontal areas. This pattern of increased activity in intrinsic functional networks might suggest a reduced ability of intra-network differentiation with clinical disease progression in HD. Finally, results showed reduced long-range connectivity between parietal ICA components in HD compared to controls, indicating impaired functional coupling between interregional networks in HD. Our data demonstrates that functional connectivity is profoundly altered in HD, both within and between RSN. Rs-fMRI analysis may provide additional valuable insights into neuronal dysfunctions beyond HD-related structural degeneration and disruptions of functional circuits in HD. PMID- 23982980 TI - Prospective analysis of ventral hernia repair using the VentralightTM ST hernia patch. AB - The aim of the current prospective study was to show the results of a new type of medium-weight monofilament polypropylene mesh covered with a hydrogel barrier on the visceral side. Between July 2011 and April 2013 prospectively collected data on 30 consecutive patients who underwent abdominal wall hernia repair using a medium-weight mesh covered with carboxymethylcellulose-sodiumhyaluronate coating (VentralightTM ST mesh, Davol Inc, Subsidary of C. R. Bard, Inc. Warwick, RI) were analyzed. Out of these patients, those who had a follow-up of at least 12 months were selected. Short- and long-term outcomes were described. Meanwhile, registration continues up to completion of a series with 100 included patients. A total of 17 patients were selected (men/women ratio 11/6). Median follow-up was 12 months (range 12-21). Mean hernia diameter was 7 cm x 5 cm (craniocaudal x laterolateral) (range 1.5 x 1.5 to 20 x 15). Mean length of hospital stay was 6.1 days. Postoperative Visual Analogue Scale (VAS) at last follow-up was significantly lower than the preoperative VAS (P = 0.017) There were no intraoperative complications. Four patients (23%) developed minor complications. Two patients had mild discomfort, another two patients developed a seroma. No recurrences were observed. This intermediate study shows good results using a biofilm coated mesh and confirm the positive results obtained in the Sasse clinical trial. PMID- 23982981 TI - Upconversion-nanophosphor-based functional nanocomposites. AB - Upconversion nanophosphors have the ability to generate visible or near-infrared (NIR) emissions under continuous-wave NIR excitation. Utilizing this special photoluminescent properties, upconversion nanophosphors can be used as key components in complex nanocomposites for a wide range of applications. This review summarizes the basic concept, fabrication strategy, and typical application of upconversion-nanophosphor-based functional nanocomposites. The motivation to design these structures comes from the potential applications in detection, multi-modality bioimaging, and NIR light-induced therapy, as well as the tuning of the upconversion luminescence emissions. This review will give a brief summary of this rapidly developing field, and provide guidance to design and to fabricate new nanocomposites based on upconversion nanophosphors. PMID- 23982983 TI - Cryptogenic left main thrombosis: successful mechanical clot retrieval with a self-expanding trapping device. AB - We present the case of a 52-year-old male with ST-segment elevation myocardial infarction due to a spontaneous large left main thrombosis, without any angiographic evidence for coronary artery disease. After multiple unsuccessful attempts of thrombaspiration the large clot was mechanically retrieved by a flow restoration device that was primarily made for intracranial interventions. Intravascular ultrasound revealed marginal lumen narrowing after the intervention, but the final coronary angiogram showed a patent left main and there was no relevant stenosis remaining. PMID- 23982982 TI - Electron tomography on gamma-aminobutyric acid-ergic synapses reveals a discontinuous postsynaptic network of filaments. AB - The regulation of synaptic strength at gamma-aminobutyric acid (GABA)-ergic synapses is dependent on the dynamic capture, retention, and modulation of GABA A type receptors by cytoplasmic proteins at GABAergic postsynaptic sites. How these proteins are oriented and organized in the postsynaptic cytoplasm is not yet established. To better understand these structures and gain further insight into the mechanisms by which they regulate receptor populations at postsynaptic sites, we utilized electron tomography to examine GABAergic synapses in dissociated rat hippocampal cultures. GABAergic synapses were identified and selected for tomography by using a set of criteria derived from the structure of immunogold labeled GABAergic synapses. Tomography revealed a complex postsynaptic network composed of filaments that extend ~ 100 nm into the cytoplasm from the postsynaptic membrane. The distribution of these postsynaptic filaments was strikingly similar to that of the immunogold label for gephyrin. Filaments were interconnected through uniform patterns of contact, forming complexes composed of 2-12 filaments each. Complexes did not link to form an integrated, continuous scaffold, suggesting that GABAergic postsynaptic specializations are less rigidly organized than glutamatergic postsynaptic densities. PMID- 23982984 TI - Influence of nanoparticle-embedded polymeric surfaces on cellular adhesion, proliferation, and differentiation. AB - The development of functional substrates to direct cellular organization is important for biomedical applications such as regenerative medicine and biorobotics. In this study, we prepared freestanding polymeric ultrathin films (nanofilms) consisting of poly(lactic acid) (PLA) and magnetic nanoparticles (MNPs), and evaluated the effects of their surface properties on the organization of cardiac-like rat myoblasts (H9c2). We changed surface properties of the PLA nanofilms (i.e., roughness and wettability) as a function of MNPs concentration. We found that the incorporation of MNPs into the nanofilms enhanced both proliferation and adhesion of H9c2 cells. Through the morphological assessment of the differentiated H9c2 cells, we also found that the presence of MNPs significantly increased the fusion index and the surface area of myotubes. In conclusion, the embedding of MNPs is a simple method to tailor the physicochemical properties of the polymeric nanofilms, yet it is an effective approach to enhance the cellular morphogenesis in the field of cardiac tissue engineering for regenerative medicine and biorobotics applications. PMID- 23982985 TI - Behavioral momentum and resurgence: Effects of time in extinction and repeated resurgence tests. AB - Resurgence is an increase in a previously extinguished operant response that occurs if an alternative reinforcement introduced during extinction is removed. Shahan and Sweeney (2011) developed a quantitative model of resurgence based on behavioral momentum theory that captures existing data well and predicts that resurgence should decrease as time in extinction and exposure to the alternative reinforcement increases. Two experiments tested this prediction. The data from Experiment 1 suggested that without a return to baseline, resurgence decreases with increased exposure to alternative reinforcement and to extinction of the target response. Experiment 2 tested the predictions of the model across two conditions, one with constant alternative reinforcement for five sessions, and the other with alternative reinforcement removed three times. In both conditions, the alternative reinforcement was removed for the final test session. Experiment 2 again demonstrated a decrease in relapse across repeated resurgence tests. Furthermore, comparably little resurgence was observed at the same time point in extinction in the final test, despite dissimilar previous exposures to alternative reinforcement removal. The quantitative model provided a good description of the observed data in both experiments. More broadly, these data suggest that increased exposure to extinction may be a successful strategy to reduce resurgence. The relationship between these data and existing tests of the effect of time in extinction on resurgence is discussed. PMID- 23982986 TI - Is swollen to tender joint count ratio a new and useful clinical marker for biologic drug response in rheumatoid arthritis? Results from a Swedish cohort. AB - OBJECTIVE: To study the impact of swollen to tender joint count ratio (STR) and other baseline characteristics on treatment response to a first course of anti tumor necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) patients. METHODS: Patients with RA initiating their first course of anti-TNF treatment were included in a structured clinical followup protocol. Based on pragmatic thresholds and plausibility, patients were categorized as having low (STR <0.5), moderate (0.5 <= STR <= 1.0), or high (STR >1.0) joint count ratios. The data were collected and followed during the period of March 1999 through December 2010. RESULTS: A total of 2,507 patients were included in the study (median age 56 years, 78% women). Of these patients, 344 (14%) had a low STR, 1,180 (47%) had a moderate STR, and 983 (39%) had a high STR. According to these STR thresholds, 23% of patients (95% confidence interval [95% CI] 18-29%) with low, 39% (95% CI 35-43%) with moderate, and 40% (95% CI 36-44%) with high STR achieved the American College of Rheumatology criteria for 50% improvement (ACR50) response at 6 months after initiation. Correlation tests showed that STR was associated with ACR50 response independent of both swollen and tender joint counts. Logistic regression analysis consistently showed that moderate STR, high STR, not using prednisolone, high baseline Disease Activity Score in 28 joints, and low baseline Health Assessment Questionnaire scores were significantly associated with favorable ACR50 response with odds ratios of 1.93 (P < 0.01), 2.82 (P < 0.01), 0.65 (P < 0.01), 1.49 (P < 0.01), and 0.47 (P < 0.01), respectively. CONCLUSION: STR is a new and feasible predictor of treatment response in RA. RA patients with a moderate to high STR have a 2- to 3-fold increased likelihood of responding according to ACR50 criteria. PMID- 23982987 TI - Diabetes and "defective" genes in the twentieth-century United States. AB - In the decades following the discovery of insulin, eugenicists grew concerned that more diabetics would survive into their reproductive years and contribute "defective" genes to the gene pool. Insulin thus came to be seen as both a blessing for the individual and a problem for the future of humankind. Nevertheless, diabetics in the United States were neither prevented nor discouraged from reproducing. I argue that this stemmed from the widespread belief that diabetes was a disease primarily of middle-class whites, who possessed positive traits that outweighed their particular genetic defect. Historians of eugenics have demonstrated convincingly that race and class stereotypes made some populations more vulnerable to coercive eugenic practices. The case of diabetes demonstrates that race and class stereotypes could also confer protection. In the end, possession of a defective gene mattered less than the perception of one's contribution to society. PMID- 23982988 TI - Is the severity of knee osteoarthritis on magnetic resonance imaging associated with outcome of exercise therapy? AB - OBJECTIVE: To evaluate associations between severity of knee osteoarthritis (OA) on magnetic resonance imaging (MRI) and treatment outcomes in knee OA patients treated with exercise therapy in an exploratory study. METHODS: Ninety-five participants with knee OA in a 12-week exercise program had obtained 3.0T MRI scans of the knee joint prior to treatment. MRI data were systematically assessed for OA severity of multiple features (cartilage integrity, bone marrow lesions, osteophyte formation, effusion/synovitis, and meniscal abnormalities) according to the Boston Leeds Osteoarthritis Knee Score method. Regression analyses were performed to analyze associations between OA severity on MRI (for the tibiofemoral and patellofemoral [PF] compartments) and outcome of exercise therapy, i.e., changes in activity limitations (Western Ontario and McMaster Universities Osteoarthritis Index physical function; primary outcome), pain and upper leg muscle strength, and treatment response (Outcome Measures in Rheumatology/Osteoarthritis Research Society International criteria). RESULTS: Improvements of 24%, 34%, and 21% on average in activity limitations, pain, and muscle strength, respectively, after 12-week exercise therapy were found (P < 0.001). Severity of abnormalities in PF cartilage integrity was significantly associated with fewer improvements in both activity limitations (P = 0.01) and muscle strength (P = 0.04). Severity of PF osteophyte formation was significantly associated with fewer improvements in muscle strength (P < 0.01). All other features on MRI were not associated with treatment outcome. CONCLUSION: Effectiveness of exercise therapy seems to be independent of OA severity on MRI, except for abnormalities in cartilage integrity and osteophyte formation, both in the PF compartment. Our study suggests that all grades of OA severity on MRI can benefit from professionally supervised exercise therapy, although the effects might be reduced in patients with advanced PF OA. PMID- 23982989 TI - Improving antenatal risk assessment in women exposed to high risks. AB - Antenatal substance use and related psychosocial risk factors are known to increase the likelihood of child protection involvement; less is known about the predictive nature of maternal reflective functioning (RF) in this population. This preliminary study assessed psychosocial and psychological risk factors for a group of substance dependent women exposed to high risks in pregnancy, and their impact on child protection involvement. Pregnant women on opiate substitution treatment (n = 11) and a comparison group (n = 15) were recruited during their third trimester to complete measures of RF (Pregnancy Interview), childhood trauma, mental health and psychosocial assessments. At postnatal follow-up, RF was reassessed (Parent Development Interview - Revised Short Version) and mother infant dyads were videotaped to assess emotional availability (EA). Child protection services were contacted to determine if any concerns had been raised for infant safety. Significant between-group differences were observed for demographics, psychosocial factors, trauma and mental health symptoms. Unexpectedly, no significant differences were found for RF or EA between groups. Eight women in the 'exposed to high risks' group became involved with child protection services. Reflective functioning was not significantly associated with psychosocial risk factors, and therefore did not mediate the outcome of child protection involvement. Women 'exposed to high risks' were equally able to generate a model of their own and their infants' mental states and should not be seen within a deficit perspective. Further research is required to better understand the range of risk factors that predict child protection involvement in high risk groups. PMID- 23982990 TI - Stressful life experiences and mental health problems among unaccompanied asylum seeking children. AB - Unaccompanied asylum-seeking children aged 10-16 years (N = 93, M = 13.8, SD = 1.4, 81% boys) were assessed 6 months after arrival in Norway (SD = 5 months). Participants originated from 14 countries (63% Asia; 36% Africa). Severe life events (SLE) and psychological symptoms were measured by self-report. Participants reported a mean of 5.5 SLE (SD = 2.4), the most prevalent being death of a close person (68%), witnessing violence (63%), and war (62%). Some 54% scored above clinical cutoff on posttraumatic stress symptoms, 30% on anxiety symptoms, 20% on depressive symptoms, and 7% on externalizing symptoms. Number of SLE was associated with posttraumatic stress disorder symptoms (r =.50, p < .001), depression (r =.27, p = .020), and anxiety symptoms(r =. 34, p = .003), but not externalizing symptoms (r =.02, p = .874). None of the symptom variables were associated with age or gender. Results indicate that many unaccompanied asylum-seeking children have experienced not only war-related traumas but several other severe life adversities as well. It may thus be helpful to conduct early assessments on this group of children to assess their need for treatment or other psychosocial interventions. PMID- 23982991 TI - Cognitive-behavioral treatment of a second-generation child of Pakistani descent: ethnocultural and clinical considerations. AB - Ethnocultural variables in cognitive behavioral therapy (CBT) are gaining an increasing amount of attention. This is a welcome development since cultural responsiveness is a core element in ethical and effective CBT practice. However, the literature is sparse and generally silent regarding CBT with children of Pakistani descent. Accordingly, this case based article attempts to close the knowledge gap by reviewing the extant literature pertaining to the role of religion, help seeking behavior, and emotional expression in Pakistani families. The literature review is followed by a case discussion of an 11 year old second generation Pakistani male living in the United Kingdom who is struggling with posttraumatic stress disorder (PTSD). The case presentation highlights the importance of culturally informed case conceptualization and individually tailored interventions. The case illustrates the way cognitive behavioral psychotherapy balanced empirically based procedures with a sensitive appreciation of cultural context. PMID- 23982992 TI - An efficient method for the synthesis of phenacyl ester-protected dipeptides using neutral alumina-supported sodium carbonate 'Na2 CO3 /n-Al2 O3 '. AB - In the synthesis of dipeptides (Boc-AA(1)-AA(2)-OPac: AA(1) and AA(2) represent amino acids) protected by phenacyl (Pac) ester, amines and solid bases as the base for the conversion of the trifluoroacetic acid (TFA) salt of the amino component (TFA.H-AA(2)-OPac) into the corresponding free amino component (H-AA(2) OPac) were examined. The synthesis of a dipeptide (Boc-Ala-Gly-OPac) using amines for the conversion afforded an unsatisfactory yield with by-products. On the other hand, the use of neutral alumina-supported Na(2) CO(3) (Na(2)CO(3) /n Al(2)O(3)) as a solid base for the conversion provided the dipeptide in a quantitative yield without by-products. The application of Na(2)CO(3) /n-Al2 O3 to the synthesis of some dipeptides protected by Pac ester gave the desired peptides in excellent yields. PMID- 23982994 TI - Need glucose to sprout: local metabolic control of angiogenesis. PMID- 23982995 TI - How to limit radial artery spasm during percutaneous coronary interventions: The spasmolytic agents to avoid spasm during transradial percutaneous coronary interventions (SPASM3) study. AB - AIMS: To compare the efficacy of three vasodilators in preventing radial artery spasm (RAS) in patients undergoing transradial percutaneous coronary interventions (PCI). METHODS AND RESULTS: 731 patients were randomized to receive diltiazem 5 mg, verapamil 2.5 mg, or isosorbide dinitrate (ISDN) 1 mg before coronary intervention. RAS occurred in 20.1% in the whole population and was significantly reduced by verapamil and ISDN compared to diltiazem (16.2, 17.2, and 26.6%, respectively; P < 0.006). There was also a trend towards less severe pain (more than 8 on a numerical scale from 0 [no pain] to 10 [maximal pain]), and less severe RAS (complete catheter blockage or severe pain), among patients treated by verapamil compared to ISDN and diltiazem (1.3% vs. 2.8% vs. 2.9%, P = 0.43 and 5.1% vs. 6.2% vs. 9.5%, respectively, P = 0.13). No difference was found between the three vasodilators in terms of crossover or safety events. Female gender, failure at first attempt to access the radial artery, emergency procedures, and the use of diltiazem were independent predictors of RAS. CONCLUSION: Verapamil and ISDN considerably reduce the incidence of RAS compared to diltiazem during transradial PCI. PMID- 23982996 TI - The peroxisome proliferator-activated receptor gamma agonist pioglitazone preserves bone microarchitecture in experimental arthritis by reducing the interleukin-17-dependent osteoclastogenic pathway. AB - OBJECTIVE: To investigate the effect of pioglitazone on inflammation-induced bone loss and changes in bone microarchitecture in rats with adjuvant-induced arthritis (AIA), focusing on the contribution of interleukin-17 (IL-17) and the balance of RANKL and osteoprotegerin (OPG). METHODS: Male Lewis rats sensitized with Freund's complete adjuvant were treated orally for 21 days with 30 mg/kg/day of pioglitazone or vehicle. Arthritis severity was evaluated by clinical and histologic examination. Bone mineral density (BMD) was assessed by dual x-ray absorptiometry. The therapeutic effect of pioglitazone on changes of the bone architecture was determined by micro-computed tomography (micro-CT). Levels of RANKL, OPG, and IL-17 were determined by serum immunoassay and by synovial tissue immunohistochemistry. Messenger RNA for IL-17 and retinoic acid receptor-related orphan nuclear receptor gammat (RORgammat) was evaluated by quantitative reverse transcription-polymerase chain reaction and IL-17 promoter activity by gene reporter assay. RESULTS: Micro-CT analysis revealed that pioglitazone treatment reduced arthritis severity and bone erosion scores and increased BMD in comparison to vehicle treatment. Cortical bone thickness was preserved, although the major beneficial effect of pioglitazone was on indices of the trabeculae, especially trabecular separation. Pioglitazone reduced the ratio of RANKL to OPG, in both the serum and the inflamed synovium. Circulating levels of IL-17 were significantly reduced by pioglitazone treatment, as were the percentages of IL-17 positive cells, mainly polymorphonuclear cells, in the inflamed synovium. Induction of IL-17 was strictly dependent on the binding of RORgammat to IL-17 promoter, and lentiviral overexpression of peroxisome proliferator-activated receptor gamma (PPARgamma) reduced the expression of RORgammat. CONCLUSION: Pioglitazone decreased the level of inflammatory bone destruction and protected the bone microarchitecture in rats with AIA by controlling the circulating and local expression of IL-17, with a subsequent decrease in the RANKL-to-OPG ratio. Along with the inhibition of RORgammat expression after PPARgamma overexpression, these findings provide evidence of the major contribution of reduced IL-17/RANKL dependent osteoclastogenesis. PMID- 23982993 TI - Expanding the scope of site-specific recombinases for genetic and metabolic engineering. AB - Site-specific recombinases are tremendously valuable tools for basic research and genetic engineering. By promoting high-fidelity DNA modifications, site-specific recombination systems have empowered researchers with unprecedented control over diverse biological functions, enabling countless insights into cellular structure and function. The rigid target specificities of many sites-specific recombinases, however, have limited their adoption in fields that require highly flexible recognition abilities. As a result, intense effort has been directed toward altering the properties of site-specific recombination systems by protein engineering. Here, we review key developments in the rational design and directed molecular evolution of site-specific recombinases, highlighting the numerous applications of these enzymes across diverse fields of study. PMID- 23982997 TI - Autologous serum eye drops for dry eye. AB - BACKGROUND: =Theoretically, autologous serum eye drops (AS) have a potential advantage over traditional therapies based on the assumption that ASserve not only as a lacrimal substitute to provide lubrication, but also contain other biochemical components mimicking natural tears more closely. The application of AS in dry eye treatment has gained popularity as a second-line therapy in the treatment of dry eye.Published studies on the subject indicate that autologous serum could be an effective treatment for dry eye. OBJECTIVES: To evaluate the efficacy and safety of AS compared to artificial tears for treating dry eye. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 3),Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE,(January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences(LILACS) (January 1982 to April 2013), themetaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov(www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We also searched the Science Citation Index Expanded database (September 2013) and reference lists of included studies. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 April 2013. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which AS was compared to artificial tears in the treatment of dry eye in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all titles and abstracts and assessed full-text articles of potentially eligible trials. Two review authors extracted data and assessed the methodological quality and characteristics of the included trials.We contacted investigators for missing data. For both primary and secondary outcomes, we reported mean differences with corresponding 95% confidence intervals(CIs) for continuous outcomes. MAIN RESULTS: We identified four eligible RCTs in which AS was compared with artificial tear treatment or saline in individuals (n = 72 participants)with dry eye of various etiologies (Sjogren's syndrome-related dry eye, non-Sjogren's syndrome dry eye and postoperative dry eye induced by laser-assisted in situ keratomileusis (LASIK)). The quality of the evidence provided by these trials was variable. A majority of the risk of bias domains were judged to have an unclear risk of bias in two trials owing to insufficient reporting of trial characteristics.One trial was considered to have a low risk of bias for most domains while another was considered to have a high risk of bias for most domains. Incomplete outcome reporting and heterogeneity in the participant populations and follow-up periods prevented the inclusion of these trials in a summary meta-analysis. For the primary outcome, improvement in participant-reported symptoms at one month, one trial (12 participants) showed no difference in participant-reported symptoms between 20% AS and artificial tears. Based on the results of two trials in 32 participants, 20% AS may provide some improvement in participant-reported symptoms compared to traditional artificial tears after two weeks of treatment. One trial also showed positive results with a mean difference in tear breakup time (TBUT) of 2.00 seconds (95% CI 0.99 to 3.01 seconds) between 20% AS and artificial tears after two weeks, which were not similar to findings from the other trials. Based on all other objective clinical assessments included in this review, AS was not associated with improvements in aqueous tear production measured by Schirmer's test (two trials, 33 participants), ocular surface condition with fluorescein (four trials, 72 participants) or Rose Bengal staining (three trials, 60 participants), and epithelial metaplasia by impression cytology compared to artificial tears (one trial, 12 participants). Data on adverse effects were not reported by three of the included studies. In one study, there were no serious adverse events reported with the collection of and treatment with AS. AUTHORS' CONCLUSIONS: Overall there was inconsistency in the possible benefits of AS in improving participant reported symptoms and TBUT and lack of effect based on other objective clinical measures. Well-planned, large, high-quality RCTs are warranted, in different severities of dry eye and using standardized questionnaires to measure participant-reported outcomes and objective clinical tests as well as objective biomarkers to assess the benefit of AS therapy for dry eye. PMID- 23982999 TI - The targeting nanothin polyelectrolyte shells in system with immobilized bacterial cells for antitumor factor production. AB - Development of anticancer treatment strategies is ongoing considering still inadequate efficiency of existing anticancer therapeutics. Moreover, the lack of therapeutic agents selectivity against the tumor cells requires further investigations into novel anticancer strategies. The use of pathogenic microorganisms producing an oncolytic agent may be an approach for apoptotic therapy in cancer treatment. The purpose of this study was to investigate the targeting efficiency of Bacillus subtilis bacterial cells coated with modified polyelectrolyte shells applied to protect the bacterial cells from potential host immune response as well as to enhance the tumor-targeting efficiency. The shells were modified with transferrin to increase affinity toward the target tumor cells. The impact of bacterial cells coated with unmodified or modified nanothin shells on human leukemia cells was evaluated in vitro. It was observed that the bacterial cells coated with modified shells with incorporated transferrin exhibited stronger lethal impact on leukemia cells as compared to bacterial cells with unmodified shell coating. Applied modified membrane conformation allowing for functioning of encapsulated microorganisms may find potential use in local antitumor treatment purposes. PMID- 23982998 TI - Tonotopic organization of vertical cells in the dorsal cochlear nucleus of the CBA/J mouse. AB - The systematic and topographic representation of frequency is a first principle of organization throughout the auditory system. The dorsal cochlear nucleus (DCN) receives direct tonotopic projections from the auditory nerve (AN) as well as secondary and descending projections from other sources. Among the recipients of AN input in the DCN are vertical cells (also called tuberculoventral cells), glycinergic interneurons thought to provide on- or near-best-frequency feed forward inhibition to principal cells in the DCN and various cells in the anteroventral cochlear nucleus (AVCN). Differing lines of physiological and anatomical evidence suggest that vertical cells and their projections are organized with respect to frequency, but this has not been conclusively demonstrated in the intact mammalian brain. To address this issue, we retrogradely labeled vertical cells via physiologically targeted injections in the AVCN of the CBA/J mouse. Results from multiple cases were merged with a normalized 3D template of the cochlear nucleus (Muniak et al. [2013] J. Comp. Neurol. 521:1510-1532) to demonstrate quantitatively that the arrangement of vertical cells is tonotopic and aligned to the innervation pattern of the AN. These results suggest that vertical cells are well positioned for providing immediate, frequency-specific inhibition onto cells of the DCN and AVCN to facilitate spectral processing. PMID- 23983000 TI - Performance of the assessment of quality of life measure in people with hip and knee joint disease and implications for research and clinical use. AB - OBJECTIVE: To comprehensively evaluate the performance of the Assessment of Quality of Life (AQoL) instrument for measuring health-related quality of life (HRQOL) in people with hip and knee joint disease (arthritis or osteoarthritis). METHODS: Data from 237 individuals were available for analysis from a national cross-sectional, population-based study of hip and knee joint disease in Australia. AQoL-4D data were evaluated using Rasch analysis. A range of measurement properties was explored, including model and item fit, threshold ordering, differential item functioning, and targeting. RESULTS: Good overall fit of the AQoL with the Rasch model was demonstrated across a range of tests, supporting internal validity. Only 1 item (relating to hearing) showed evidence of misfit. Most AQoL items showed logical sequencing of response option categories, with threshold disordering evident for only 2 of the 12 items (items 4 and 9). Minor issues with potential clinical and research implications include limited options for reporting pain and some evidence of measurement bias between demographic subgroups (including age and sex). Participants' HRQOL was generally better than that represented by the AQoL items (mean +/- SD for person abilities 2.15 +/- 1.39, mean +/- SD for item difficulties 0.00 +/- 0.67), indicating ceiling effects that could impact the instrument's ability to detect HRQOL improvement in population-based studies. CONCLUSION: The AQoL is a competent tool for assessing HRQOL in people with hip and knee joint disease, although researchers and clinicians should consider the caveats identified when selecting appropriate HRQOL measures for future outcome assessment involving this patient group. PMID- 23983001 TI - Barriers to optimal disease control for rheumatoid arthritis patients with moderate and high disease activity. AB - OBJECTIVE: To evaluate barriers that prevent rheumatoid arthritis (RA) patients from achieving Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) scores within the current recommended levels for low disease activity (LDA) or clinical remission (DAS28-ESR score <3.2). METHODS: Using an electronic medical record program, clinical data for RA patients treated in Optimising Patient Outcomes in Australian Rheumatology clinics, with a recorded DAS28-ESR score, were collected at one point in time. The data included demographics, medications, disease measures, and the rheumatologist's opinion of the main barriers preventing improvement to the recommended DAS28 score. RESULTS: Of the 4,037 patients with a recorded DAS28-ESR score, 304 patients (7.5%) had high disease activity (HDA) and 1,211 patients (30%) had moderate disease activity (MDA). For 584 HDA or MDA patients, the barriers to disease control (BTCs) were recorded by the rheumatologist when there was no adjustment to disease-modifying antirheumatic drug (DMARD) therapy. The recorded BTCs were irreversible joint damage (19.7%), patient-driven preference (14.7%), noninflammatory musculoskeletal pain (9.2%), insufficient time to assess the effect of recently initiated DMARDs (9.2%), safety concerns (7.5%), comorbidities (6.5%), resistant disease (6.3%), and other less common reasons. These patients received DMARDs (97.4%), including biologic agents (34.1%), methotrexate (74.8%), and oral corticosteroids (41.8%). CONCLUSION: This study identified clinical situations in which rheumatologists elected to continue RA patients with MDA or HDA on DMARD therapy without adjustment to achieve clinical remission or an LDA target of a DAS28-ESR score <3.2. PMID- 23983002 TI - V-shaped organic semiconductors with solution processability, high mobility, and high thermal durability. AB - V-shaped organic semiconductors have been designed and synthesized via a large scale applicable synthetic route. Solution-crystallized films based on such molecules have demonstrated high-performance transistor properties with maximum mobilities of up to 9.5 cm(2) V(-1) s(-1) as well as pronounced thermal durability of up to 150 degrees C inherent in the V-shaped cores. PMID- 23983003 TI - Abstracts of the Thirty-Sixth Meeting of the American Society of Primatologists. June 19-22, 2013. San Juan, Puerto Rico. PMID- 23983004 TI - Improving staff reports of falls in assisted living. AB - This study examined falls data reported by staff to (a) describe characteristics of falls in this population and (b) analyze the quality and utility of the data available from incident reports (IRs) to improve fall prevention. Data from 34 incident reports were analyzed. Descriptive and frequency analyses were conducted to describe fall characteristics, use of assistive devices, high-risk medication use, and prevalence of omitted data on IRs. Thirty-four falls occurred among 15 residents (age, M = 84 years). More than half resulted in injury. Significant omissions of data were noted in the IRs, which may have limited full analysis of fall events and the ability to communicate about health outcomes of these events and the prevention of subsequent falls. This study provides data about falls in assisted living and recommendations for enhanced data collection to support the monitoring of falls risk and the prevention of future falls. PMID- 23983005 TI - Unmasking the information encoded as structural motifs of viral RNA genomes: a potential antiviral target. AB - RNA viruses show enormous capacity to evolve and adapt to new cellular and molecular contexts, a consequence of mutations arising from errors made by viral RNA-dependent RNA polymerase during replication. Sequence variation must occur, however, without compromising functions essential for the completion of the viral cycle. RNA viruses are safeguarded in this respect by their genome carrying conserved information that does not code only for proteins but also for the formation of structurally conserved RNA domains that directly perform these critical functions. Functional RNA domains can interact with other regions of the viral genome and/or proteins to direct viral translation, replication and encapsidation. They are therefore potential targets for novel therapeutic strategies. This review summarises our knowledge of the functional RNA domains of human RNA viruses and examines the achievements made in the design of antiviral compounds that interfere with their folding and therefore their function. PMID- 23983006 TI - Formation of truncated peptide by-products via sequence-specific formyl group transfer from Trp(For) residues to Nalpha in the course of Boc-SPPS. AB - (N(In))-Formyl protective group of tryptophan has been introduced as a base/nucleophile-labile protective group. It has long been known that a free Nalpha-amino group of the peptide can serve as a nucleophile: an irreversible formyl N(In) -> NH(2) transfer is consistently observed when deformylation is performed last on an otherwise deprotected peptide that possesses free Nalpha amino group. Obviously, this particular side reaction should be expected any time free amino group is exposed to Trp(For), but, at the best of our knowledge, has never been reported in the course of Boc-SPPS. In the present communication, we describe a set of appropriately designed model experiments that permitted to detect the title side reaction both in solution and in solid-phase reactions. We observed intermolecular formyl group transfer with a model compound, Trp(For) NH(2). Importantly, we also observed this migration on solid support with the rate roughly estimated to be up to 1% of residues per minute. We also observed that the formyl-group transfer reaction occurred in a sequence-dependent manner and was suppressed to a non-detectable level using 'in situ neutralization' technique. Because this side reaction is sequence dependent, there might be situations when the rate of the formation of Nalpha -formyl termination by products is significant. In other cases, the Nalpha -For truncated by-products would not contaminate the final peptide significantly but still could be a source of microheterogeneity. PMID- 23983007 TI - Automated, spatio-temporally controlled cell microprinting with polymeric aqueous biphasic system. AB - Cell printing is a promising approach to create organized constructs for tissue engineering applications. We present an automated cell printing microtechnology based on the use of an aqueous two-phase system (ATPS) interfaced with a three axis motorized system. Cells suspended in the denser aqueous dextran (DEX) phase are loaded into printing tips, which are placed onto the cartridge of the motorized system. Using a computer interface, tips are lowered in the vicinity of a biological surface maintained in the immersion, aqueous polyethylene glycol (PEG) phase to perform a horizontal motion, autonomously dispense their contents onto the surface, and retracted out of the PEG phase. The motorized ATPS technology allows precise spatial and temporal control of the printing process and supports printing fully viable cells. We conduct a systematic study and show that the resolution of ATPS-mediated cellular patterns depends on several factors including the dimensions of the printing tips, lateral speed of tips during horizontal motion, and the loaded volume of the DEX phase in the tips. The finest resolution is ~300 um obtained with a tip diameter of 200 um at a printing tip speed of 16.5 mm/s. Higher speeds result in unstable DEX patterns that break into drops due to capillary instability, and thus are avoided. We also test a number of printing substrates and find that in addition to a cell monolayer, decellularized matrices can serve as a substrate for cell printing with ATPS. Using the principles from the characterization studies, we create duplex prints of cells to demonstrate the potential of this approach for spatio-temporally controlled cell placement. The ATPS printing microtechnology will be a step forward toward developing well-organized, three-dimensional tissue constructs. PMID- 23983009 TI - Targeting protein-protein interactions to rescue Deltaf508-cftr: a novel corrector approach to treat cystic fibrosis. PMID- 23983008 TI - Value of isolated IgA anti-beta2 -glycoprotein I positivity in the diagnosis of the antiphospholipid syndrome. AB - OBJECTIVE: To examine the prevalence of isolated IgA anti-beta2 -glycoprotein I (anti-beta2 GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of beta2 GPI, with clinical manifestations of the antiphospholipid syndrome (APS) in 3 patient groups and to evaluate the pathogenicity of IgA anti-beta2 GPI in a mouse model of thrombosis. METHODS: Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n = 558), patients with SLE from the Hopkins Lupus Cohort (n = 215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n = 5,098) were evaluated. IgA anti-beta2 GPI titers and binding to domain IV/V of beta2 GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti-beta2 GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity. RESULTS: A total of 198 patients were found to be positive for IgA anti-beta2 GPI isotype, and 57 patients were positive exclusively for IgA anti-beta2 GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-beta2 GPI-positive serum samples reacted with domain IV/V of anti-beta2 GPI, and 77% of those had clinical features of APS. Isolated IgA anti-beta2 GPI positivity was associated with an increased risk of arterial thrombosis (P < 0.001), venous thrombosis (P = 0.015), and all thrombosis (P < 0.001). The association between isolated IgA anti-beta2 GPI and arterial thrombosis (P = 0.0003) and all thrombosis (P = 0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-beta2 GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls. CONCLUSION: Isolated IgA anti-beta2 GPI-positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid tests are negative and APS is suspected is recommended. IgA anti-beta2 GPI antibodies directed to domain IV/V of beta2 GPI represent an important subgroup of clinically relevant antiphospholipids. PMID- 23983010 TI - Efficacy and safety of renal denervation in elderly patients with resistant hypertension. AB - BACKGROUND: Catheter-based renal sympathetic denervation (RD) causes significant blood pressure (BP) reductions in patients with resistant hypertension (rHTN). However, hypertensive elderly patients reportedly have a lower sympathetic tone than younger patients and a BP lowering effect of RD in this population has not yet been demonstrated. The purpose of this study was to assess the efficacy and safety of RD in elderly patients. METHODS: We reviewed all consecutive patients aged >= 75 years (mean: 78 years) with rHTN treated with RD. Twenty-four patients were included in this prospective study. Office and ambulatory BPs were assessed at baseline and 6-months follow-up. Primary endpoint was the change in office systolic BP at 6 months. RESULTS: Baseline mean office BP was 173/86 +/- 21/13 mm Hg. Baseline 24-hr mean ambulatory BP, available in 22 patients, was 158/80 +/- 20/13 mm Hg. Baseline creatinine was 1.0 +/- 0.18 mg/dl and mean number of antihypertensive agents at baseline 4.3 +/- 1.4. No device- or procedure-related adverse events occurred. At 6-months follow-up, the mean office BP decreased by 19/11 +/- 29/16 mm Hg (P < 0.01 compared to baseline). Mean systolic 24 hr ambulatory BP, available in 17 patients, decreased by 9/5 +/- 13/13 mm Hg. Antihypertensive medications could be reduced in nine patients. Furthermore, renal function was not impaired. CONCLUSION: According to our findings, a similar magnitude of BP reduction as reported in previous trials can be expected in elderly patients. Elderly patients with rHTN should not be excluded from renal denervation. PMID- 23983011 TI - Opioids compared to placebo or other treatments for chronic low-back pain. AB - BACKGROUND: The use of opioids in the long-term management of chronic low-back pain (CLBP) has increased dramatically. Despite this trend, the benefits and risks of these medications remain unclear. This review is an update of a Cochrane review first published in 2007. OBJECTIVES: To determine the efficacy of opioids in adults with CLBP. SEARCH METHODS: We electronically searched the Cochrane Back Review Group's Specialized Register, CENTRAL, CINAHL and PsycINFO, MEDLINE, and EMBASE from January 2006 to October 2012. We checked the reference lists of these trials and other relevant systematic reviews for potential trials for inclusion. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that assessed the use of opioids (as monotherapy or in combination with other therapies) in adults with CLBP that were at least four weeks in duration. We included trials that compared non-injectable opioids to placebo or other treatments. We excluded trials that compared different opioids only. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data onto a pre designed form. We pooled results using Review Manager (RevMan) 5.2. We reported on pain and function outcomes using standardized mean difference (SMD) or risk ratios with 95% confidence intervals (95% CI). We used absolute risk difference (RD) with 95% CI to report adverse effects. MAIN RESULTS: We included 15 trials (5540 participants). Tramadol was examined in five trials (1378 participants); it was found to be better than placebo for pain (SMD -0.55, 95% CI -0.66 to -0.44; low quality evidence) and function (SMD -0.18, 95% CI -0.29 to -0.07; moderate quality evidence). Transdermal buprenorphine (two trials, 653 participants) may make little difference for pain (SMD -2.47, 95%CI -2.69 to -2.25; very low quality evidence), but no difference compared to placebo for function (SMD -0.14, 95%CI -0.53 to 0.25; very low quality evidence). Strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol), examined in six trials (1887 participants), were better than placebo for pain (SMD -0.43, 95%CI -0.52 to -0.33; moderate quality evidence) and function (SMD -0.26, 95% CI -0.37 to -0.15; moderate quality evidence). One trial (1583 participants) demonstrated that tramadol may make little difference compared to celecoxib (RR 0.82, 95% CI 0.76 to 0.90; very low quality evidence) for pain relief. Two trials (272 participants) found no difference between opioids and antidepressants for either pain (SMD 0.21, 95% CI -0.03 to 0.45; very low quality evidence), or function (SMD -0.11, 95% -0.63 to 0.42; very low quality evidence). The included trials in this review had high drop-out rates, were of short duration, and had limited interpretability of functional improvement. They did not report any serious adverse effects, risks (addiction or overdose), or complications (sleep apnea, opioid-induced hyperalgesia, hypogonadism). In general, the effect sizes were medium for pain and small for function. AUTHORS' CONCLUSIONS: There is some evidence (very low to moderate quality) for short-term efficacy (for both pain and function) of opioids to treat CLBP compared to placebo. The very few trials that compared opioids to non-steroidal anti-inflammatory drugs (NSAIDs) or antidepressants did not show any differences regarding pain and function. The initiation of a trial of opioids for long-term management should be done with extreme caution, especially after a comprehensive assessment of potential risks. There are no placebo-RCTs supporting the effectiveness and safety of long-term opioid therapy for treatment of CLBP. PMID- 23983012 TI - Analysis of buprenorphine in whole blood using liquid chromatography-tandem mass spectrometry. AB - With buprenorphine use on the rise it has become more important than ever for the forensic laboratory to be capable of analyzing for it. Described is the approach used by the Georgia Bureau of Investigation for the screening and confirmation of buprenorphine in whole blood by liquid chromatography-tandem mass spectrometry (LC-MS-MS), along with case reviews for the first 2 months of method implementation. Screening by LC-MS-MS is capable of identifying buprenorphine cases at concentrations as low as 1-2 ug/L. Confirmatory testing is performed on both indicatively screened samples and cases where buprenorphine is specifically requested. Confirmatory analysis by LC-MS-MS has a limit of detection and limit of quantitation of 0.75 ug/L with estimated uncertainties of 7.2% at 1 ug/L, 3.5% at 10 ug/L and 4.8% at 20 ug/L based on a 95% confidence interval, with the highest percent coefficient of variation being 3.7% for the 1 ug/L level. Since its implementation, the laboratory has reported out nine cases for buprenorphine. Seven of those cases were detected by the initial screen and two were identified by a specific request for buprenorphine. The cases' average concentration was 4.25 ug/L with a mode of 3.1 ug/L. PMID- 23983013 TI - Quantification of several acidic drugs in equine serum using LC-MS-MS. AB - The use of nonsteroidal antiinflammatory drugs in racehorses is allowed under most jurisdictions. Furosemide is administered to treat exercise-induced pulmonary hemorrhage. To help distinguish between therapeutic and illegal uses, racing regulatory bodies have set thresholds in serum for several drugs. The method for the simultaneous detection and quantification of furosemide, flunixin, ketoprofen, phenylbutazone and oxyphenbutazone using 500 uL of serum, and liquid extraction using diethyl ether : hexanes : dichloromethane followed by liquid chromatography tandem mass spectrometry quantitation, was developed and validated. Method validation included inter- and intraday precision and accuracy. Method validation also included bench-top, freeze-thaw, processed and long-term storage stability testing. For all stability testing, the compounds showed a breakdown of <15%. Inter- and intraday precision for all compounds was found to be within the acceptance interval of +/-15% [+/-20% at the lower limit of quantitation (LLOQ)]. Accuracy data for all compounds were within the acceptance interval of +/-15% (+/-20% at the LLOQ). Uncertainty was calculated using the simplified Guide to the Expression of Uncertainty in Measurement approach and was <30% for all drugs at 95% confidence level. The method was found to be both robust and accurate for all tested drugs. PMID- 23983015 TI - A phenotypic comparison of osteoblast cell lines versus human primary osteoblasts for biomaterials testing. AB - Immortalized cell lines are used more frequently in basic and applied biology research than primary bone-derived cells because of their ease of access and repeatability of results in experiments. It is clear that these cell models do not fully resemble the behavior of primary osteoblast cells. Although the differences will affect the results of biomaterials testing, they are not clearly defined. Here, we focused on comparing proliferation and maturation potential of three osteoblast cell lines, SaOs2, MG-63, and MC3T3-E1 with primary human osteoblast (HOb) cells to assess their suitability as in vitro models for biomaterials testing. We report similarities in cell proliferation and mineralization between primary cells and MC3T3-E1. Both, SaOs2 and MG-63 cells demonstrated a higher proliferation rate than HOb cells. In addition, SaOs2, but not MG-63, cells demonstrated similar ALP activity, mineralization potential and gene regulation to HOb's. Our results demonstrate that despite SaOs-2, MG63, and MC3T3 cells being popular choices for emulating osteoblast behavior, none can be considered appropriate replacements for HOb's. Nevertheless, these cell lines all demonstrated some distinct similarities with HOb's, thus when applied in the correct context are a valuable in vitro pilot model of osteoblast functionality, but should not be used to replace primary cell studies. PMID- 23983014 TI - Expression of m1-type muscarinic acetylcholine receptors by parvalbumin immunoreactive neurons in the primary visual cortex: a comparative study of rat, guinea pig, ferret, macaque, and human. AB - Cholinergic neuromodulation is a candidate mechanism for aspects of arousal and attention in mammals. We have reported previously that cholinergic modulation in the primary visual cortex (V1) of the macaque monkey is strongly targeted toward GABAergic interneurons, and in particular that the vast majority of parvalbumin immunoreactive (PV) neurons in macaque V1 express the m1-type (pirenzepine sensitive, Gq-coupled) muscarinic ACh receptor (m1AChR). In contrast, previous physiological data indicates that PV neurons in rats rarely express pirenzepine sensitive muscarinic AChRs. To examine further this apparent species difference in the cholinergic effectors for the primary visual cortex, we have conducted a comparative study of the expression of m1AChRs by PV neurons in V1 of rats, guinea pigs, ferrets, macaques, and humans. We visualize PV- and mAChR immunoreactive somata by dual-immunofluorescence confocal microscopy and find that the species differences are profound; the vast majority (>75%) of PV-ir neurons in macaques, humans, and guinea pigs express m1AChRs. In contrast, in rats only ~25% of the PV population is immunoreactive for m1AChRs. Our data reveal that while they do so much less frequently than in primates, PV neurons in rats do express Gq-coupled muscarinic AChRs, which appear to have gone undetected in the previous in vitro studies. Data such as these are critical in determining the species that represent adequate models for the capacity of the cholinergic system to modulate inhibition in the primate cortex. PMID- 23983016 TI - Primary antiphospholipid syndrome-associated diffuse alveolar hemorrhage. AB - OBJECTIVE: Diffuse alveolar hemorrhage (DAH) is an uncommon complication of primary antiphospholipid syndrome (APS). We aimed to describe the clinical characteristics, treatment, and outcomes of primary APS-associated DAH in a single center. METHODS: We conducted a retrospective review of all adults with primary APS-associated DAH evaluated at Mayo Clinic over a 15-year period. DAH was defined as bilateral pulmonary infiltrates and bronchoalveolar lavage (BAL) fluid documenting progressively bloody returns and/or the presence of >20% hemosiderin-laden macrophages. Patients with other causes of DAH were excluded. RESULTS: Eighteen patients were identified (median age 43 years). Capillaritis was present in surgical lung biopsy samples of 3 patients. BAL differential cell counts revealed predominantly neutrophils. All patients were treated initially with glucocorticoids. Cyclophosphamide (CYC) was used in 8 patients; complete remission was achieved in 3 patients treated with CYC alone and in 1 patient receiving combination therapy with rituximab (RTX). RTX was used in 9 patients; 2 patients achieved remission with RTX alone, whereas 3 patients required combination therapy with CYC or mycophenolate mofetil (MMF). No patient achieved complete remission while receiving single therapy with MMF, azathioprine, or plasma exchange. Intravenous gamma globulin therapy was administered in 5 patients; no patient achieved control of the disease. Six patients died, all because of complications related to uncontrolled DAH or its therapy. CONCLUSION: We present the largest case series of primary APS-associated DAH reported in the literature. DAH carries a very poor prognosis and therapeutic options are limited. Immunosuppression with either CYC or RTX is associated with the highest likelihood of remission induction and should be considered early. PMID- 23983018 TI - Longitudinal predictors of dieting and disordered eating among young adults in the U.S. AB - OBJECTIVE: To assess longitudinal associations between cognitive and behavioral characteristics in adolescence and dieting and eating pathology in young adulthood. METHOD: Data from the National Longitudinal Study of Adolescent Health and multivariate logistic regressions were used to examine the unique and cumulative effects of adolescent behavior and cognition on four weight-related health indicators in young adulthood: dieting, extreme weight loss behaviors (EWLB), binge eating, and eating disorder (ED) diagnosis (N = 14,322). RESULTS: Early dieting, depression, and body image distortion (BID) prospectively predicted dieting or EWLB at Wave 3. In addition, early depression and dieting were associated with binge eating in young adulthood, and early BID was associated with ED diagnosis. Gender differences were observed. In the prospective models, the effect of depression on the onset of EWLB was stronger for women than men; while association between early depression and ED diagnosis was significantly stronger for men than women. Findings supported a cumulative risk effect. Among women, each additional correlate was associated with greater odds of eating pathology in young adulthood; among men, each additional correlate was associated with greater odds of ever reporting ED diagnosis. Overall prevalence of dieting and eating pathology among young adults was higher among women than men and increased over time for both sexes. DISCUSSION: Early weight control behavior and cognition affect long term eating patterns and are salient for both young adult men and women. Transition to young adulthood is a critical period for assessing and preventing weight and eating-related health problems. PMID- 23983017 TI - Clinical characteristics of children with juvenile dermatomyositis: the Childhood Arthritis and Rheumatology Research Alliance Registry. AB - OBJECTIVE: To investigate aspects of juvenile dermatomyositis (DM), including disease characteristics and treatment, through a national multicenter registry. METHODS: Subjects meeting the modified Bohan and Peter criteria for definite juvenile DM were analyzed from the cross-sectional Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry between 2010 and 2012 from 55 US pediatric rheumatology centers. Demographics, disease characteristics, diagnostic assessments, and medication exposure data were collected at enrollment. RESULTS: A total of 384 subjects met the criteria for analysis. At enrollment, the median Childhood Myositis Assessment Scale score was 51 (interquartile range [IQR] 46 52), the median Childhood Health Assessment Questionnaire score was 0 (IQR 0 0.5), and the median physician and subject global assessment scores were 1 (IQR 0 2) and 1 (IQR 0-3), respectively, out of a maximum of 10. Of the diagnostic assessments, magnetic resonance imaging was more likely than electromyography or muscle biopsy to show abnormalities. A total of 329 subjects had >=2 diagnostic studies performed, and >34% of these subjects reported >=1 negative study. Ninety five percent had been treated with corticosteroids and 92% with methotrexate, suggesting that these medications were almost universally prescribed for juvenile DM in the US. CONCLUSION: In 2 years, the ongoing CARRA Registry has collected clinical data on 384 children with juvenile DM and has the potential to become one of the largest juvenile DM cohorts in the world. More research is needed about prognostic factors in juvenile DM, and differences in therapy based on manifestations of disease need to be explored by practitioners. This registry provides the infrastructure needed to advance clinical and translational research and represents a major step toward improving outcomes of children with juvenile DM. PMID- 23983020 TI - Effects of NCMS on access to care and financial protection in China. AB - The introduction of the New Cooperative Medical Scheme (NCMS) in rural China has been the most rapid and dramatic extension of health insurance coverage in the developing world in this millennium. The literature to date has mainly used the uneven rollout of NCMS across counties as a way of identifying its effects on access to care and financial protection. This study exploits the cross-county variation in NCMS generosity in 2006 and 2008 in the Ningxia and Shandong provinces to estimate the effect of coverage generosity on utilization and financial protection. Our results confirm earlier findings of NCMS being effective in increasing access to care but not in increasing financial protection. In addition, we find NCMS enrollees to be sensitive to the price incentives set in the NCMS design when choosing their provider and providers to respond by increasing prices and/or providing more expensive care. PMID- 23983019 TI - Biochemical and physical signal gradients in hydrogels to control stem cell behavior. AB - Three-dimensional (3D) gradients of biochemical and physical signals in macroscale degradable hydrogels are engineered that can regulate photoencapsulated human mesenchymal stem cell (hMSC) behavior. This simple, cytocompatible, and versatile gradient system may be a valuable tool for researchers in biomaterials science to control stem cell fate in 3D and guide tissue regeneration. PMID- 23983021 TI - Anti-tumor necrosis factor alpha targets protein kinase B/c-Akt-induced resistance of effector cells to suppression in juvenile idiopathic arthritis. AB - OBJECTIVE: To determine whether therapeutic strategies that block interleukin-6 (IL-6) or tumor necrosis factor alpha (TNFalpha) can improve the responsiveness of Teff cells to suppression in patients with juvenile idiopathic arthritis (JIA). METHODS: Synovial fluid mononuclear cells (SFMCs) from the inflamed joints of patients with JIA were cultured in the presence of etanercept or anti-IL-6 in vitro, and protein kinase B (PKB)/c-Akt activation and responsiveness to suppression were measured. In addition, the in vivo effects of TNFalpha blockade were investigated using peripheral blood mononuclear cells obtained from patients before and after the start of etanercept therapy. RESULTS: In vitro treatment of SFMCs with anti-IL-6 led to improved Treg cell-mediated suppression of cell proliferation in some but not all patients. Blocking TNFalpha with etanercept, however, clearly enhanced suppression, especially that of CD8+ T cells. In the presence of etanercept, PKB/c-Akt activation of Teff cells was reduced, and cells became more susceptible to transforming growth factor beta-mediated suppression, indicating that anti-TNFalpha directly targets resistant Teff cells. CONCLUSION: This study is the first to show that anti-TNFalpha targets the resistance of Teff cells to suppression, resulting in improved regulation of inflammatory effector cells. PMID- 23983022 TI - Pediatric health care provider perceptions of weight loss surgery in adolescents. AB - This study explored pediatric health care providers' obesity treatment practices and perceptions about adolescent weight loss surgery (WLS). Surveys were e-mailed to pediatric listservs. After descriptive analyses, correlations, chi-squares, and one-way analyses of variance compared responses by provider characteristics. Surveys were completed by 109 providers. Almost half do not routinely measure body mass index. Providers typically counsel patients about lifestyle change, with limited perceived benefit; <10% have ever referred patients for WLS, citing cost (20%), risk (49%), or "not indicated in pediatrics" (17%) as reasons. However, when presented with patient scenarios of different ages and comorbidities, likeliness to refer for WLS increased substantially. Surgeons, younger providers and those with fewer years of experience were more likely to refer for WLS (P < .05). Despite expert consensus recommendations supporting WLS as part of a comprehensive obesity treatment plan, significant pediatric provider resistance to refer obese adolescents remains. Improved referral and management practices are needed. PMID- 23983023 TI - Dynamic model-based analysis of furfural and HMF detoxification by pure and mixed batch cultures of S. cerevisiae and S. stipitis. AB - Inhibitory compounds that result from biomass hydrolysis are an obstacle to the efficient production of second-generation biofuels. Fermentative microorganisms can reduce compounds such as furfural and 5-hydroxymethyl furfural (HMF), but detoxification is accompanied by reduced growth rates and ethanol yields. In this study, we assess the effects of these furan aldehydes on pure and mixed yeast cultures consisting of a respiratory deficient mutant of Saccharomyces cerevisiae and wild-type Scheffersomyces stipitis using dynamic flux balance analysis. Uptake kinetics and stoichiometric equations for the intracellular reduction reactions associated with each inhibitor were added to genome-scale metabolic reconstructions of the two yeasts. Further modification of the S. cerevisiae metabolic network was necessary to satisfactorily predict the amount of acetate synthesized during HMF reduction. Inhibitory terms that captured the adverse effects of the furan aldehydes and their corresponding alcohols on cell growth and ethanol production were added to attain qualitative agreement with batch experiments conducted for model development and validation. When the two yeasts were co-cultured in the presence of the furan aldehydes, inoculums that reduced the synthesis of highly toxic acetate produced by S. cerevisiae yielded the highest ethanol productivities. The model described here can be used to generate optimal fermentation strategies for the simultaneous detoxification and fermentation of lignocellulosic hydrolysates by S. cerevisiae and/or S. stipitis. PMID- 23983024 TI - Distinguishing between pain intensity and pain resolution: using acute post surgical pain trajectories to predict chronic post-surgical pain. AB - BACKGROUND: High intensity of acute post-surgical pain is one of the strongest predictors for chronic post-surgical pain (CPSP). We investigated the predictive power of acute post-surgical pain trajectories and the interplay of pain trajectories and diverse psychosocial risk factors in the development of CPSP. METHODS: Data from 199 patients were examined using latent growth curve analysis by means of structural equation modelling. This analytical approach was used to explicitly test the mediating role of acute pain trajectories within the association between preoperative psychosocial vulnerability factors and CPSP. RESULTS: Both initial pain intensity and pain resolution during the first five post-operative days independently contributed to the prediction of CPSP 6 months after surgery. In terms of vulnerability, anxiety and depression had clear but opposing effects on post-operative pain trajectories. Whereas depressive patients exhibited impaired pain resolution, patients with high anxiety showed better rates of pain resolution after surgery. Both effects on acute pain resolution extended to chronic pain 6 months after surgery. CONCLUSIONS: In this study, we demonstrated that going beyond conventional one-time measurements of acute pain by modelling pain trajectories may substantially enhance research on pain chronification in two ways: First, pain trajectories bear great potential to improve the prediction of CPSP. Second, they represent a meaningful link between psychosocial vulnerability and CPSP because they can be used to uncover mechanisms by which psychosocial vulnerability unfolds. The reported findings suggest that the incidence of CPSP may be reduced by optimizing post-operative pain monitoring. PMID- 23983025 TI - Brain. Editorial. PMID- 23983026 TI - Dementia: from muddled diagnoses to treatable mechanisms. PMID- 23983027 TI - Inflammation in Alzheimer's disease: insights from immunotherapy. PMID- 23983028 TI - Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study. AB - Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer's disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged >=85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-beta and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, cerebral amyoloid angiopathy, and alpha-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28-5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-beta accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88-7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12-12.79) for more severe medial temporal atrophy and 4.69 (1.14-19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or alpha-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged >=85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed to determine the impact of homocysteine-lowering treatments on dementia-related pathology. PMID- 23983029 TI - Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. AB - Chronic pain conditions are associated with abnormalities in brain structure and function. Moreover, some studies indicate that brain activity related to the subjective perception of chronic pain may be distinct from activity for acute pain. However, the latter are based on observations from cross-sectional studies. How brain activity reorganizes with transition from acute to chronic pain has remained unexplored. Here we study this transition by examining brain activity for rating fluctuations of back pain magnitude. First we compared back pain related brain activity between subjects who have had the condition for ~2 months with no prior history of back pain for 1 year (early, acute/subacute back pain group, n = 94), to subjects who have lived with back pain for >10 years (chronic back pain group, n = 59). In a subset of subacute back pain patients, we followed brain activity for back pain longitudinally over a 1-year period, and compared brain activity between those who recover (recovered acute/sub-acute back pain group, n = 19) and those in which the back pain persists (persistent acute/sub acute back pain group, n = 20; based on a 20% decrease in intensity of back pain in 1 year). We report results in relation to meta-analytic probabilistic maps related to the terms pain, emotion, and reward (each map is based on >200 brain imaging studies, derived from neurosynth.org). We observed that brain activity for back pain in the early, acute/subacute back pain group is limited to regions involved in acute pain, whereas in the chronic back pain group, activity is confined to emotion-related circuitry. Reward circuitry was equally represented in both groups. In the recovered acute/subacute back pain group, brain activity diminished in time, whereas in the persistent acute/subacute back pain group, activity diminished in acute pain regions, increased in emotion-related circuitry, and remained unchanged in reward circuitry. The results demonstrate that brain representation for a constant percept, back pain, can undergo large scale shifts in brain activity with the transition to chronic pain. These observations challenge long-standing theoretical concepts regarding brain and mind relationships, as well as provide important novel insights regarding definitions and mechanisms of chronic pain. PMID- 23983030 TI - The role of human ventral visual cortex in motion perception. AB - Visual motion perception is fundamental to many aspects of visual perception. Visual motion perception has long been associated with the dorsal (parietal) pathway and the involvement of the ventral 'form' (temporal) visual pathway has not been considered critical for normal motion perception. Here, we evaluated this view by examining whether circumscribed damage to ventral visual cortex impaired motion perception. The perception of motion in basic, non-form tasks (motion coherence and motion detection) and complex structure-from-motion, for a wide range of motion speeds, all centrally displayed, was assessed in five patients with a circumscribed lesion to either the right or left ventral visual pathway. Patients with a right, but not with a left, ventral visual lesion displayed widespread impairments in central motion perception even for non-form motion, for both slow and for fast speeds, and this held true independent of the integrity of areas MT/V5, V3A or parietal regions. In contrast with the traditional view in which only the dorsal visual stream is critical for motion perception, these novel findings implicate a more distributed circuit in which the integrity of the right ventral visual pathway is also necessary even for the perception of non-form motion. PMID- 23983031 TI - Atypical basic movement kinematics in autism spectrum conditions. AB - Individuals with autism spectrum conditions have difficulties in understanding and responding appropriately to others. Additionally, they demonstrate impaired perception of biological motion and problems with motor control. Here we investigated whether individuals with autism move with an atypical kinematic profile, which might help to explain perceptual and motor impairments, and in principle may contribute to some of their higher level social problems. We recorded trajectory, velocity, acceleration and jerk while adult participants with autism and a matched control group conducted horizontal sinusoidal arm movements. Additionally, participants with autism took part in a biological motion perception task in which they classified observed movements as 'natural' or 'unnatural'. Results show that individuals with autism moved with atypical kinematics; they did not minimize jerk to the same extent as the matched typical control group, and moved with greater acceleration and velocity. The degree to which kinematics were atypical was correlated with a bias towards perceiving biological motion as 'unnatural' and with the severity of autism symptoms as measured by the Autism Diagnostic Observation Schedule. We suggest that fundamental differences in movement kinematics in autism might help to explain their problems with motor control. Additionally, developmental experience of their own atypical kinematic profiles may lead to disrupted perception of others' actions. PMID- 23983032 TI - Decorin prevents the development of juvenile communicating hydrocephalus. AB - In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-beta has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-beta antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-beta/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-beta1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-beta-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus. PMID- 23983034 TI - Epidemiology in multiple sclerosis: a pilgrim's progress. AB - There was more neurology taught under Harold G. Wolff at Cornell University Medical College in New York than perhaps anywhere else in the country when I attended from 1948 to 1952. I took my residency at the Veterans Administration Hospital in the Bronx, New York, a teaching hospital of Cornell, with Wolff as my Director of Training. While a resident, we thought we had found a treatment for multiple sclerosis. To test our conclusion, the first Class 1 treatment trial ever conducted for multiple sclerosis was performed. This showed no effect, but the participants began investigating multiple sclerosis among the 16 million persons at prime age for symptom onset who had served in the military in World War II. This led me to study its epidemiology worldwide, beginning with a detailed review of all published population-based estimates of frequency. Among these were nationwide surveys from Sweden, Denmark, Switzerland and later Norway and Finland, which showed in each country a concentration of the significantly high regions into contiguous areas forming a single 'focus' in each land, maximal in Denmark under the age of 15 years. The primary locus of high frequency multiple sclerosis seemed to be in the south-central inland lake region of Sweden, with spread to its contiguous neighbours. These concentrations in time and space indicated that multiple sclerosis was a disease probably acquired in early adolescence. Migration studies supported this: moves from high to low showed retention of birthplace risk only for those aged >15 years, whereas opposite moves indicated susceptibility limited to some 11-45 year olds. Epidemics of multiple sclerosis would suggest the disease is not only acquired but also infectious. If an infectious origin were true, transmission would have to occur before clinical onset, and would have to involve a much greater number of subjects than clinically involved. I believe there have been epidemics in Iceland, Shetland-Orkney and the Faroe Islands. On the Faroes there were no cases of multiple sclerosis among native-born resident Faroese from 1900 until 1943, when the first of 21 cases had clinical onset, heralding a type 1 epidemic with peak incidence rates >10 per 100,000 for 1945-46. British troops who occupied the islands from April 1940 to September 1945 we believe brought a widespread (because of the scatter of Faroese cases), asymptomatic (because they were healthy troops), persistent infection we called the primary multiple sclerosis affection that involved a large proportion of Faroese, with clinical multiple sclerosis ensuing in a very small proportion. Primary multiple sclerosis affection itself may have been manifest there as a newly introduced cause of acute infectious gastroenteritis and is possibly the underlying cause of multiple sclerosis in general. PMID- 23983036 TI - Removal of Impella(r) 2.5 while maintaining vascular access: a solution to a vascular quandary. AB - Cardiogenic shock (CS) in the setting of acute myocardial infarction is associated with high in-hospital mortality rates. Society guidelines provide a Class Ib recommendation for the use of hemodynamic support devices in patients with CS following ST-elevation myocardial infarction. Exchanging of hemodynamic support devices is often complicated by inability to maintain percutaneous vascular access upon device removal in the setting of anticoagulation. This report highlights one potential solution to the dilemma of maintaining vascular access following removal of an Impella(r) 2.5 mechanical support device to allow safe transition to a TandemHeart system in a patient with refractory CS. PMID- 23983033 TI - Inhibition of angiogenesis by beta-galactosylceramidase deficiency in globoid cell leukodystrophy. AB - Globoid cell leukodystrophy (Krabbe disease) is a neurological disorder of infants caused by genetic deficiency of the lysosomal enzyme beta galactosylceramidase leading to accumulation of the neurotoxic metabolite 1-beta d-galactosylsphingosine (psychosine) in the central nervous system. Angiogenesis plays a pivotal role in the physiology and pathology of the brain. Here, we demonstrate that psychosine has anti-angiogenic properties by causing the disassembling of endothelial cell actin structures at micromolar concentrations as found in the brain of patients with globoid cell leukodystrophy. Accordingly, significant alterations of microvascular endothelium were observed in the post natal brain of twitcher mice, an authentic model of globoid cell leukodystrophy. Also, twitcher endothelium showed a progressively reduced capacity to respond to pro-angiogenic factors, defect that was corrected after transduction with a lentiviral vector harbouring the murine beta-galactosylceramidase complementary DNA. Finally, RNA interference-mediated beta-galactosylceramidase gene silencing causes psychosine accumulation in human endothelial cells and hampers their mitogenic and motogenic response to vascular endothelial growth factor. Accordingly, significant alterations were observed in human microvasculature from brain biopsy of a globoid cell leukodystrophy case. Together these data demonstrate that beta-galactosylceramidase deficiency induces significant alterations in endothelial neovascular responses that may contribute to central nervous system and systemic damages that occur in globoid cell leukodystrophy. PMID- 23983038 TI - Brain-derived neurotrophic factor: mRNA expression and protein distribution in the brain of the teleost Nothobranchius furzeri. AB - BDNF (brain-derived neurotrophic factor) is a member of the neurotrophin family and it is implicated in regulating brain development and function. The BDNF gene organization and coding sequence are conserved in all vertebrates. The present survey was conducted in a teleost fish, Nothobranchius furzeri, because it is an emerging model of aging studies due to its short lifespan and shows the high rate of adult neurogenesis typical of anamniotes. The present survey reports: 1) the identification and characterization of the cDNA fragment encoding BDNF protein, and 2) the localization of BDNF in the whole brain. BDNF mRNA expression was assessed by in situ hybridization, by employing an antisense RNA probe; BDNF protein was detected by employing a sensitive immunohistochemical technique, along with highly specific affinity-purified antibodies to BDNF. Both BDNF mRNA and protein were detected in neurons and glial cells of all regions of the brain of N. furzeri. Interestingly, BDNF was localized also in brain areas involved in adult neurogenic activities, suggesting a specific role for this neurotrophic factor in controlling cell proliferation. These results provide baseline information for future studies concerning BDNF involvement in the aging processes of the teleost brain. PMID- 23983040 TI - Where there's smoking, there's fire: the effects of smoking policies on the incidence of fires in the USA. AB - Fires and burns are among the leading causes of unintentional death in the USA. Most of these deaths occur in residences, and cigarettes are a primary cause. In this paper, I explore the relationship between smoking, cigarette policies, and fires. As smoking rates decline, there are fewer opportunities for fires; however, the magnitude of any reduction is in question. Using a state-level panel, I find that increases in cigarette prices are associated with fewer residential fires and deaths. However, laws regulating indoor smoking are associated with more fires; in particular, restaurant and bar smoking bans are associated with an increase in fires at eating and drinking establishments. This increase is important given the growing popularity of smoking bans in the USA and around the world. As workplaces, schools, and businesses ban smoking and remove ashtrays, smokers who continue to smoke are left without safe options for disposal of cigarettes, leading to more opportunities for fires to start. PMID- 23983039 TI - Phase III study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis. AB - OBJECTIVE: To evaluate the efficacious noninferiority of subcutaneous tocilizumab injection (TCZ-SC) monotherapy to intravenous TCZ infusion (TCZ-IV) monotherapy in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to synthetic and/or biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: This study had a double-blind, parallel-group, double-dummy, comparative phase III design. Patients were randomized to receive TCZ-SC 162 mg every 2 weeks or TCZ-IV 8 mg/kg every 4 weeks; no DMARDs were allowed during the study. The primary end point was to evaluate the noninferiority of TCZ-SC to TCZ-IV regarding the American College of Rheumatology criteria for 20% improvement in disease activity (ACR20) response rates at week 24 using an 18% noninferiority margin. Additional efficacy, safety, pharmacokinetic, and immunogenicity parameters were assessed. RESULTS: At week 24, ACR20 response was achieved in 79.2% (95% confidence interval [95% CI] 72.9, 85.5) of the TCZ-SC group and in 88.5% (95% CI 83.4, 93.5) of the TCZ-IV group; the weighted difference was -9.4% (95% CI -17.6, -1.2), confirming the noninferiority of TCZ-SC to TCZ-IV. Remission rates of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and the Clinical Disease Activity Index at week 24 were 49.7% and 16.4% in the TCZ-SC group and 62.2% and 23.1% in the TCZ-IV group, respectively. Serum trough TCZ concentrations were similar between the groups over time. Incidences of all adverse events and serious adverse events were 89.0% and 7.5% in the TCZ-SC group and 90.8% and 5.8% in the TCZ-IV group, respectively. Anti-TCZ antibodies were detected in 3.5% of the TCZ-SC group; no serious hypersensitivity was reported in these patients. CONCLUSION: TCZ-SC monotherapy demonstrated comparable efficacy and safety to TCZ-IV monotherapy. TCZ-SC could provide additional treatment options for patients with RA. PMID- 23983041 TI - Venous thromboembolism prevention guidelines for medical inpatients: mind the (implementation) gap. AB - BACKGROUND: Hospital-associated nonsurgical venous thromboembolism (VTE) is an important problem addressed by new guidelines from the American College of Physicians (ACP) and American College of Chest Physicians (AT9). METHODS: Narrative review and critique. RESULTS: Both guidelines discount asymptomatic VTE outcomes and caution against overprophylaxis, but have different methodologies and estimates of risk/benefit. Guideline complexity and lack of consensus on VTE risk assessment contribute to an implementation gap. Methods to estimate prophylaxis benefit have significant limitations because major trials included mostly screening-detected events. AT9 relies on a single Italian cohort study to conclude that those with a Padua score >=4 have a very high VTE risk, whereas patients with a score <4 (60% of patients) have a very small risk. However, the cohort population has less comorbidity than US inpatients, and over 1% of patients with a score of 3 suffered pulmonary emboli. The ACP guideline does not endorse any risk-assessment model. AT9 includes the Padua model and Caprini point based system for nonsurgical inpatients and surgical inpatients, respectively, but there is no evidence they are more effective than simpler risk-assessment models. CONCLUSIONS: New VTE prevention guidelines provide varied guidance on important issues including risk assessment. If Padua is used, a threshold of 3, as well as 4, should be considered. Simpler VTE risk-assessment models may be superior to complicated point-based models in environments without sophisticated clinical decision support. PMID- 23983042 TI - Haloperidol dose for the acute phase of schizophrenia. AB - BACKGROUND: Haloperidol is a benchmark, accessible antipsychotic drug against which the effects of newer treatments are gauged. OBJECTIVES: To determine the best range of doses for haloperidol for the treatment of people acutely ill with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (February 2010), which is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. SELECTION CRITERIA: We selected studies if they involved people being treated for acute schizophrenia, randomised to two or more dose ranges of non-depot haloperidol, and if they reported clinically meaningful outcomes. DATA COLLECTION AND ANALYSIS: For this update, we inspected all citations and independently re-inspected a sample of citations in order to ensure reliable selection. We resolved any disagreement by discussion, and where doubt remained, we acquired the full-text article for further inspection. We then ordered papers, and reliably re-inspected and quality assessed the full reports, and extracted data. For homogeneous dichotomous data, we calculated the risk ratio (RR) with 95% confidence intervals (CI) on an intention-to-treat (ITT) basis. We assumed that people who left the study early or were lost to follow-up had a negative outcome. We calculated mean differences (MD) for continuous outcomes that reported ITT, last observation carried forward (LOCF) data. We excluded data if loss to follow-up was greater than 50%. MAIN RESULTS: We included 19 trials with 19 different randomised dose comparisons. No studies reported data on relapse rates or quality of life and only one compared low dose (> 1.5 to 3 mg/day) haloperidol to higher dose ranges. Using standard lower dose (> 3 to 7.5 mg/day) did not result in loss of efficacy (no clinically important improvement in global state, versus standard higher dose (> 7.5 to 15 mg/day, n = 48, 1 RCT, RR 1.09, 95% CI 0.7 to 1.8, very-low-quality evidence); versus high dose (> 15 to 35 mg/day, n = 81, 2 RCTs, RR 0.95, 95% CI 0.8 to 1.2, very-low quality evidence). Doses of haloperidol in the range of > 3 to 7.5 mg/day had a lower rate of development of clinically significant extrapyramidal adverse effects than higher doses (clinically significant extrapyramidal adverse effects, versus standard higher dose, n = 64, 2 RCTs, RR 0.12, 95% CI 0.01 to 2.1, very low-quality evidence); versus high dose, n = 144, 3 RCTs, RR 0.59, 95% CI 0.5 to 0.8, very-low-quality evidence; versus very high dose (> 35 mg/day, n = 86, 2 RCTs, RR 0.70, 95% CI 0.5 to 1.1, very-low-quality evidence). None of the other comparisons between dose ranges yielded statistically significant differences, but several, particularly with lower dose ranges, were underpowered to detect clinically meaningful differences. AUTHORS' CONCLUSIONS: Noresults were conclusive and all were based on small, short studies of limited quality. However, it would be understandable if clinicians were cautious in prescribing doses in excess of 7.5 mg/day of haloperidol to a person with uncomplicated acute schizophrenia, and if people with schizophrenia were equally reticent to take greater doses. Further research is needed regarding the efficacy and tolerability of the lower dose ranges, especially > 1.5 to 3 mg/day. PMID- 23983043 TI - Eating disorders in a large clinical sample of men and women with personality disorders. AB - OBJECTIVE: We assessed and compared the prevalence of anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS) across six Axis II groups (borderline, obsessive-compulsive, avoidant, dependent, paranoid, and personality disorder NOS) and patients with major depressive disorder (MDD) without personality disorders (PD). METHOD: The sample included 3,266 consecutive and first admissions to 16 different treatment units in the Norwegian Network of Psychotherapeutic Day Hospitals between 1993 and 2009. All patients were interviewed with the SCID-II for DSM-III-R (prior to 1996) or DSM IV (from 1996) and the MINI for Axis I disorders in accordance with the LEAD (longitudinal, expert, all-data) standard. RESULTS: The prevalence of any ED in the PD sample was approximately 17% for women and 3% for men. A lower rate of ED (5%) was found for patients with MDD without PD. A significantly higher proportion of patients with borderline personality disorder were diagnosed with BN or EDNOS. The rate of AN was significantly elevated in female patients with obsessive-compulsive personality disorder. Men demonstrated significantly less diagnostic co-occurrence and no significant differential variation across PD groups or MDD. DISCUSSION: Data which included a psychiatric comparison group showed less co-occurrence and non-significant variation across PD groups for men, but demonstrated a meaningful and specific pattern of comorbidity between ED and PD for women. There was an elevated risk of ED among female patients with PD, most pronounced for borderline. An almost five-fold higher rate of AN was found among women with obsessive-compulsive PD. PMID- 23983044 TI - Relationship between metabolic syndrome and carotid intima-media thickness: cross sectional comparison between psoriasis and psoriatic arthritis. AB - OBJECTIVE: To determine the differences in carotid intima-media thickness (CIMT) between patients with psoriatic diseases with and without metabolic syndrome. METHODS: Eligible patients from the Cardiometabolic Outcome Measures in Psoriatic Arthritis Study database, which is comprised of both psoriasis and psoriatic arthritis (PsA) patients enrolled at 2 academic medical centers, were included. Detailed cardiovascular (CV) risk factors, including metabolic syndrome profiles, medication use, disease activity, and CIMT, were examined. RESULTS: A total of 343 patients with psoriatic disease were evaluated (42.28% with psoriasis and 57.72% with PsA). PsA patients were significantly older, with longer disease duration and higher blood pressure, body mass index, and C-reactive protein (CRP) level. PsA patients took more disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and underwent more CV procedures. There were no differences in prior CV events, family history of CV risk, and Framingham/Adult Treatment Panel III Risk Score. PsA patients had a higher risk of metabolic syndrome (univariate odds ratio [OR] 1.78 [95% confidence interval (95% CI) 1.08-2.95], P = 0.025). Even after adjusting for age, CRP level, and diastolic blood pressure, PsA patients not taking DMARDs were twice as likely to have metabolic syndrome compared to psoriasis patients (adjusted OR 2.09 [95% CI 0.78-5.59], P = 0.049). PsA patients with metabolic syndrome had the thickest CIMT compared to any other group (P < 0.001). CONCLUSION: PsA patients had an increased prevalence of metabolic syndrome with significantly greater CIMT measurements compared to patients with psoriasis. Furthermore, PsA patients with metabolic syndrome had the greatest CIMT measurements compared to PsA patients without metabolic syndrome and psoriasis patients with or without metabolic syndrome. Incremental increases in inflammatory pathways in PsA may contribute to a higher CV risk as compared to psoriasis patients. PMID- 23983045 TI - Enhanced mechanical properties of graphene/copper nanocomposites using a molecular-level mixing process. AB - RGO flakes are homogeneously dispersed in a Cu matrix through a molecular-level mixing process. This novel fabrication process prevents the agglomeration of the RGO and enhances adhesion between the RGO and the Cu. The yield strength of the 2.5 vol% RGO/Cu nanocomposite is 1.8 times higher than that of pure Cu. The strengthening mechanism of the RGO is investigated by a double cantilever beam test using the graphene/Cu model structure. PMID- 23983046 TI - Sulforaphane represses matrix-degrading proteases and protects cartilage from destruction in vitro and in vivo. AB - OBJECTIVE: Sulforaphane (SFN) has been reported to regulate signaling pathways relevant to chronic diseases. The aim of this study was to investigate the impact of SFN treatment on signaling pathways in chondrocytes and to determine whether sulforaphane could block cartilage destruction in osteoarthritis. METHODS: Gene expression, histone acetylation, and signaling of the transcription factors NF-E2 related factor 2 (Nrf2) and NF-kappaB were examined in vitro. The bovine nasal cartilage explant model and the destabilization of the medial meniscus (DMM) model of osteoarthritis in the mouse were used to assess chondroprotection at the tissue and whole-animal levels. RESULTS: SFN inhibited cytokine-induced metalloproteinase expression in primary human articular chondrocytes and in fibroblast-like synovial cells. SFN acted independently of Nrf2 and histone deacetylase activity to regulate metalloproteinase expression in human articular chondrocytes but did mediate prolonged activation of JNK and p38 MAPK. SFN attenuated NF-kappaB signaling at least through inhibition of DNA binding in human articular chondrocytes, with decreased expression of several NF-kappaB dependent genes. Compared with cytokines alone, SFN (10 MUM) abrogated cytokine induced destruction of bovine nasal cartilage at both the proteoglycan and collagen breakdown levels. An SFN-rich diet (3 MUmoles/day SFN versus control chow) decreased the arthritis score in the DMM model of osteoarthritis in the mouse, with a concurrent block of early DMM-induced gene expression changes. CONCLUSION: SFN inhibits the expression of key metalloproteinases implicated in osteoarthritis, independently of Nrf2, and blocks inflammation at the level of NF kappaB to protect against cartilage destruction in vitro and in vivo. PMID- 23983047 TI - A 2-stage ovarian cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies early-stage incident cancers and demonstrates high positive predictive value. AB - BACKGROUND: A 2-stage ovarian cancer screening strategy was evaluated that incorporates change of carbohydrate antigen 125 (CA125) levels over time and age to estimate risk of ovarian cancer. Women with high-risk scores were referred for transvaginal ultrasound (TVS). METHODS: A single-arm, prospective study of postmenopausal women was conducted. Participants underwent an annual CA125 blood test. Based on the Risk of Ovarian Cancer Algorithm (ROCA) result, women were triaged to next annual CA125 test (low risk), repeat CA125 test in 3 months (intermediate risk), or TVS and referral to a gynecologic oncologist (high risk). RESULTS: A total of 4051 women participated over 11 years. The average annual rate of referral to a CA125 test in 3 months was 5.8%, and the average annual referral rate to TVS and review by a gynecologic oncologist was 0.9%. Ten women underwent surgery on the basis of TVS, with 4 invasive ovarian cancers (1 with stage IA disease, 2 with stage IC disease, and 1 with stage IIB disease), 2 ovarian tumors of low malignant potential (both stage IA), 1 endometrial cancer (stage I), and 3 benign ovarian tumors, providing a positive predictive value of 40% (95% confidence interval = 12.2%, 73.8%) for detecting invasive ovarian cancer. The specificity was 99.9% (95% confidence interval = 99.7%, 100%). All 4 women with invasive ovarian cancer were enrolled in the study for at least 3 years with low-risk annual CA125 test values prior to rising CA125 levels. CONCLUSIONS: ROCA followed by TVS demonstrated excellent specificity and positive predictive value in a population of US women at average risk for ovarian cancer. PMID- 23983049 TI - Structural elaboration of a natural product: identification of 3,3' diindolylmethane aminophosphonate and urea derivatives as potent anticancer agents. AB - An approach involving rational structural elaboration of the biologically active natural product diindolylmethane (DIM) with the incorporation of aminophosphonate and urea moieties toward the discovery of potent anticancer agents was considered. A four-step approach for the synthesis of DIM aminophosphonate and urea derivatives was established. These novel compounds showed potent anticancer activities in two representative kidney and colon cancer cell lines, low toxicity to normal cells, higher potency than the parent natural product DIM and etoposide, and potent inhibition of cancer cell migration. Biophysical and immunological studies, including DAPI nuclear staining, western blot analysis with apoptotic protein markers, flow cytometry, immunocytochemistry, and comet assays of the two most potent compounds revealed good efficacies in apoptosis and DNA damage. It was found that down-regulation of nuclear factor kappaB (NF-kappaB p65) could be an important mode of action in apoptosis, and the two most potent derivatives were found to be more potent than parent compound DIM in the down regulation of NF-kappaB. Our results show the importance of structural elaboration of DIM by rational incorporation of aminophosphonate and urea moieties to produce potent anticancer agents; they also suggest that this approach using other structurally simple bioactive natural products as scaffolds holds promise for future drug discovery and development. PMID- 23983050 TI - Statistical efficiency cannot save a study without a meaningful hypothesis. PMID- 23983048 TI - Anatomy of hierarchy: feedforward and feedback pathways in macaque visual cortex. AB - The laminar location of the cell bodies and terminals of interareal connections determines the hierarchical structural organization of the cortex and has been intensively studied. However, we still have only a rudimentary understanding of the connectional principles of feedforward (FF) and feedback (FB) pathways. Quantitative analysis of retrograde tracers was used to extend the notion that the laminar distribution of neurons interconnecting visual areas provides an index of hierarchical distance (percentage of supragranular labeled neurons [SLN]). We show that: 1) SLN values constrain models of cortical hierarchy, revealing previously unsuspected areal relations; 2) SLN reflects the operation of a combinatorial distance rule acting differentially on sets of connections between areas; 3) Supragranular layers contain highly segregated bottom-up and top-down streams, both of which exhibit point-to-point connectivity. This contrasts with the infragranular layers, which contain diffuse bottom-up and top down streams; 4) Cell filling of the parent neurons of FF and FB pathways provides further evidence of compartmentalization; 5) FF pathways have higher weights, cross fewer hierarchical levels, and are less numerous than FB pathways. Taken together, the present results suggest that cortical hierarchies are built from supra- and infragranular counterstreams. This compartmentalized dual counterstream organization allows point-to-point connectivity in both bottom-up and top-down directions. PMID- 23983051 TI - Reply to dr Salander. PMID- 23983053 TI - Superhydrophobic polymer multilayers that promote the extended, long-term release of embedded water-soluble agents. AB - Polymer multilayers that exhibit surface and bulk superhydrophobicity are demonstrated to promote long-term release of water-soluble agents (for ca.1 year) when submerged in water. The extremely nonwetting nature of these materials prevents rapid influx of water, addressing a key limitation inherent to polyelectrolytebased multilayers that release imbedded agents quickly. Our results provide new and potentially general principles for the design of surface coatings in the context of controlled release. PMID- 23983054 TI - Influence of soil pH on the toxicity of zinc oxide nanoparticles to the terrestrial isopod Porcellionides pruinosus. AB - The effects of soil pH on the toxicity of ZnO nanoparticles (NPs) to the terrestrial isopod Porcellionides pruinosus were evaluated. Isopods were exposed to a natural soil amended with CaCO3 to reach 3 different pH(CaCl2) levels (4.5, 6.2, and 7.3) and to standard LUFA 2.2 soil (pH 5.5) spiked with ZnO NPs (30 nm), non-nano ZnO (200 nm), and ionic Zn as ZnCl2. Toxicity was expressed based on total Zn concentration in soil, as well as total Zn and free Zn2+ ion concentrations in porewater. Compared with ZnO-spiked soils, the ZnCl2-spiked soils had lower pH and higher porewater Ca2+ and Zn levels. Isopod survival did not differ between Zn forms and soils, but survival was higher for isopods exposed to ZnO NPs at pH 4.5. Median effect concentrations (EC50s) for biomass change showed similar trends for all Zn forms in all soils, with higher values at intermediate pH. Median lethal concentration (LC50) and EC50 values based on porewater Zn or free Zn ion concentrations were much lower for ZnO than for ionic zinc. Zn body concentrations increased in a dose-related manner, but no effect of soil pH was found. It is suggested not only that dissolved or free Zn in porewater contributed to uptake and toxicity, but also that oral uptake (i.e., ingestion of soil particles) could be an important additional route of exposure. PMID- 23983055 TI - Green biocides, a promising technology: current and future applications to industry and industrial processes. AB - The study of biofilms has skyrocketed in recent years due to increased awareness of the pervasiveness and impact of biofilms. It costs the USA literally billions of dollars every year in energy losses, equipment damage, product contamination and medical infections. But biofilms also offer huge potential for cleaning up hazardous waste sites, filtering municipal and industrial water and wastewater, and forming biobarriers to protect soil and groundwater from contamination. The complexity of biofilm activity and behavior requires research contributions from many disciplines such as biochemistry, engineering, mathematics and microbiology. The aim of this review is to provide a comprehensive analysis of emerging novel antimicrobial techniques, including those using myriad organic and inorganic products as well as genetic engineering techniques, the use of coordination complex molecules, composite materials and antimicrobial peptides and the use of lasers as such or their modified use in combination treatments. This review also addresses advanced and recent modifications, including methodological changes, and biocide efficacy enhancing strategies. This review will provide future planners of biofilm control technologies with a broad understanding and perspective on the use of biocides in the field of green developments for a sustainable future. PMID- 23983057 TI - Agreement among musculoskeletal pediatric specialists in the assessment of radiographic joint damage in juvenile idiopathic arthritis. AB - OBJECTIVE: To evaluate agreement among musculoskeletal pediatric specialists in assessing radiographic joint damage in juvenile idiopathic arthritis (JIA). METHODS: Two pediatric rheumatologists, 2 pediatric radiologists, and 2 pediatric orthopedic surgeons evaluated independently 60 radiographs of both wrists and hands of children with polyarticular-course JIA. Films were scored using an adapted and simplified version of the Larsen score, ranging from 0-5. Study radiographs were selected from 568 films used in a previous study aimed to validate an adapted pediatric version of the Sharp/van der Heijde (SHS) score. To enable comparison of specialists' scores with the adapted SHS score, the 60 radiographs were divided into 6 classes of severity of damage based on quintiles of the adapted SHS score. Agreement was evaluated in terms of absolute agreement and through weighted kappa statistics. RESULTS: The pediatric radiologists tended to assign lower scores and to provide more frequently scores of 0 than did the other specialists. Weighted kappa for the 3 pairs of specialists ranged from 0.67 0.69, indicating substantial agreement. Absolute agreement ranged from 51.3 55.7%, depending on the pair of specialists examined. Both absolute and weighted kappa concordance between specialists' scores and the adapted SHS score were poorer for the pediatric radiologist than for the other specialists. CONCLUSION: We observed fair agreement in the assessment of radiographic damage among pediatric specialists involved in the care of children with JIA. The radiologists tended to be more reserved than the rheumatologists and orthopedic surgeons in labeling radiographs as damaged or in considering changes as important. PMID- 23983056 TI - Cumulative traumas and risk thresholds: 12-month PTSD in the World Mental Health (WMH) surveys. AB - BACKGROUND: Clinical research suggests that posttraumatic stress disorder (PTSD) patients exposed to multiple traumatic events (TEs) rather than a single TE have increased morbidity and dysfunction. Although epidemiological surveys in the United States and Europe also document high rates of multiple TE exposure, no population-based cross-national data have examined this issue. METHODS: Data were analyzed from 20 population surveys in the World Health Organization World Mental Health Survey Initiative (n = 51,295 aged 18+). The Composite International Diagnostic Interview (3.0) assessed 12-month PTSD and other common DSM-IV disorders. Respondents with 12-month PTSD were assessed for single versus multiple TEs implicated in their symptoms. Associations were examined with age of onset (AOO), functional impairment, comorbidity, and PTSD symptom counts. RESULTS: 19.8% of respondents with 12-month PTSD reported that their symptoms were associated with multiple TEs. Cases who associated their PTSD with four or more TEs had greater functional impairment, an earlier AOO, longer duration, higher comorbidity with mood and anxiety disorders, elevated hyperarousal symptoms, higher proportional exposures to partner physical abuse and other types of physical assault, and lower proportional exposure to unexpected death of a loved one than cases with fewer associated TEs. CONCLUSIONS: A risk threshold was observed in this large-scale cross-national database wherein cases who associated their PTSD with four or more TEs presented a more "complex" clinical picture with substantially greater functional impairment and greater morbidity than other cases of PTSD. PTSD cases associated with four or more TEs may merit specific and targeted intervention strategies. PMID- 23983058 TI - Clinical images: Bronchial stenosis in granulomatosis with polyangiitis (Wegener's). PMID- 23983059 TI - Increased intracellular oxygen radical production in neutrophils during febrile episodes of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. AB - OBJECTIVE: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is an autoinflammatory disease of unknown etiology that primarily affects preschool-aged children. PFAPA syndrome is characterized by recurrent attacks of fever and symptoms of inflammation consistent with the disease acronym. Since autoinflammatory diseases are, by definition, mediated by cells of the innate immune system, the aim of this study was to evaluate the functional features of neutrophils, the most abundant innate immune cell in the circulation, in children with PFAPA syndrome. METHODS: Blood polymorphonuclear leukocytes (PMNs), obtained from patients with PFAPA syndrome during both febrile and asymptomatic, afebrile phases of the disease, as well as from healthy children (afebrile controls) and children with fever and abdominal pain (febrile controls), were analyzed for 3 key neutrophil characteristics: 1) apoptosis (measured by annexin V/7-aminoactinomycin D staining), 2) production of reactive oxygen species (ROS) (measured by luminol/isoluminol-amplified chemiluminescence), and 3) priming status (measured as responsiveness to galectin 3 and up-regulation of CD11b). RESULTS: Compared to PMNs obtained from patients with PFAPA syndrome during an afebrile interval and those from febrile controls, PMNs obtained from patients during a PFAPA syndrome flare produced elevated levels of intracellular NADPH oxidase-derived ROS, had significantly diminished rates of spontaneous apoptosis, and displayed signatures of priming. In contrast, PMNs from afebrile patients with PFAPA syndrome had a significantly elevated rate of spontaneous apoptosis compared to PMNs from afebrile controls. CONCLUSION: These findings demonstrate that 3 key aspects of neutrophil innate immune function, namely, apoptosis, priming, and generation of an intracellular oxidative burst, are altered, most prominently during febrile attacks, in children with PFAPA syndrome. PMID- 23983060 TI - Heat treatment of egg white controls allergic symptoms and induces oral tolerance to ovalbumin in a murine model of food allergy. AB - SCOPE: Heated foods often present low allergenicity, and have recently been used in specific oral immunotherapy for food allergies. However, the influence of heating on tolerogenicity of food allergens is not well elucidated. Here, we investigated biochemical, allergenic, and tolerogenic properties of heated egg white (EW) using a murine model of food allergy. METHODS AND RESULTS: Raw EWs were treated at 80 degrees C for 15 min (80EW, mild heating condition), 100 degrees C for 5 min (100EW, cooking condition), or 121 degrees C for 40 min (121EW, retort pouch condition), and freeze-dried. A transgenic OVA23-3 mice model expressing T-cell receptor specific for ovalbumin (OVA, a major EW allergen) induced Th2 cells and IgE production, and presented intestinal inflammation when fed untreated EW diet. 80EW-fed mice presented only moderate inflammation but high Th2 responses. 100EW-fed mice did not present inflammation but induced tolerance as seen in reduced T-cell responses and IgE levels. 100EW demonstrated higher digestive stability and slower absorption in intestine, compared with untreated EW and 80EW. 121EW was strongly aggregated, was not absorbed well, and developed Th1 responses without tolerance induction. CONCLUSION: OVA in EW treated only under a particular heat condition (e.g. 100 degrees C for 5 min) lost allergenicity, but possessed tolerogenicity. PMID- 23983062 TI - Selenium accumulation and speciation in biofortified chickpea (Cicer arietinum L.) under Mediterranean conditions. AB - BACKGROUND: Millions of people have Se-deficient diets and Se-biofortified crops could prevent such deficiency. The aim of the present study was to evaluate the potential of chickpea for use in Se fertilization programs in order to increase available Se. Two foliar Se fertilizers (sodium selenate and sodium selenite) at four rates (0, 10, 20, 40 g ha(-1)) were tested in the 2010/2011 and 2011/2012 growing seasons in a field experiment conducted under semiarid Mediterranean conditions. RESULTS: Sodium selenate was much more effectively taken by plants than sodium selenite, and there was a strong and linear relationship between total Se content and Se rate for both. For each gram of Se fertilizer, applied either as sodium selenate or sodium selenite, the increases of total Se concentration in grain were 126 and 87, and 25 and 19 ug Se kg(-1) dry weight, in 2010/2011 and 2011/2012, respectively. Se was found to be incorporated into chickpea grains mainly (>70%) as selenomethionine. CONCLUSION: Se-enriched chickpeas would be a good candidate for inclusion in biofortification programs under semiarid Mediterranean conditions and for promotion as a 'functional food'. PMID- 23983061 TI - Gain of 1q is associated with inferior event-free and overall survival in patients with favorable histology Wilms tumor: a report from the Children's Oncology Group. AB - BACKGROUND: Wilms tumor is the most common childhood renal tumor. Although the majority of patients with favorable histology Wilms tumor (FHWT) have good outcomes, some patients still experience disease recurrence and death from disease. The goal of the current study was to determine whether tumor-specific chromosome 1q gain is associated with event-free survival (EFS) and overall survival (OS) in patients with FHWT. METHODS: Unilateral FHWT samples were obtained from patients enrolled on National Wilms Tumor Study-4 and Pediatric Oncology Group Wilms Biology Study (POG 9046). 1q gain, 1p loss, and 16q loss were determined using multiplex ligation-dependent probe amplification. RESULTS: The 8-year EFS rate was 87% (95% confidence interval [95% CI], 82%-91%) for the entire cohort of 212 patients. Tumors from 58 of 212 patients (27%) displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The 8 year EFS rate was 76% (95% CI, 63%-85%) for patients with 1q gain and 93% (95% CI, 87%-96%) for those lacking 1q gain (P = .0024). The 8-year OS rate was 89% (95% CI, 78%-95%) for those with 1q gain and 98% (95% CI, 94%-99%) for those lacking 1q gain (P = .0075). Gain of 1q was not found to correlate with disease stage (P = .16). After stratification for stage of disease, 1q gain was associated with a significantly increased risk of disease recurrence (risk ratio estimate: 2.72; P = .0089). CONCLUSIONS: Gain of 1q may provide a valuable prognostic marker with which to stratify therapy for patients with FHWT. A confirmatory study is necessary before this biomarker is incorporated into the risk stratification schema of future therapeutic studies. PMID- 23983063 TI - Effects of salinity acclimation on the endocrine disruption and acute toxicity of bifenthrin in freshwater and euryhaline strains of Oncorhynchus mykiss. AB - The pyrethroid insecticide bifenthrin is frequently detected at ng/L concentrations in tributaries of the San Francisco Bay Delta. The estuary is also experiencing increasing salinity through climate change and water redirection. To evaluate the impacts of hypersaline conditions on bifenthrin toxicity in anadromous salmonids of the San Francisco Bay Delta (CA, USA), a 14-d laboratory exposure was performed using 2 strains of Oncorhynchus mykiss (rainbow trout and steelhead) acclimated to freshwater and to 8 g/L and 17 g/L salinity. The fish were then exposed to nominal concentrations of 0 ug/L, 0.1 ug/L, and 1.5 ug/L bifenthrin. Rainbow trout exhibited significant mortality following exposure to 1.5 ug/L (1.07 +/- 0.35 ug/L measured) bifenthrin in freshwater. Elevated levels of Na+ /K+ adenosine triphosphatase alpha1A mRNA subunit expression was observed in the gill of rainbow trout acclimated to hypersaline conditions relative to freshwater animals. No significant difference was noted in Na+ /K+ adenosine triphosphatase subunit levels in brains of either strain in freshwater or hypersaline conditions. Likewise, significant differences were not observed in plasma vitellogenin or steroid hormone concentrations in either strain whether maintained in freshwater or saltwater. Saltwater acclimation significantly reduced nicotinamide adenine dinucleotide phosphate-catalyzed biotransformation of bifenthrin in liver microsomes of rainbow trout but not of steelhead. The present study showed that, relative to steelhead, rainbow trout have different responses to bifenthrin acute toxicity as well as different rates of hepatic bifenthrin biotransformation and regulation of Na+ /K+ adenosine triphosphatase subunits in gills. These data indicate that significant differences exist between the strains and that animal life history may have important effects on the susceptibility of each strain to environmental contaminants. PMID- 23983064 TI - Twice daily versus once nightly dosing of pregabalin for fibromyalgia: a double blind randomized clinical trial of efficacy and safety. AB - OBJECTIVE: To compare the efficacy, discontinuation rates, and safety of once nightly versus twice daily dosing of pregabalin in a community-based trial. METHODS: This multicenter, double-blind, 8-week randomized clinical trial compared the effects of 300-mg daily doses of pregabalin given either twice daily or once nightly for the treatment of fibromyalgia in 177 patients. The primary outcome was the comparison of end point mean pain scores derived from a daily diary. RESULTS: Both twice daily (88 patients randomized) and once nightly (89 patients) pregabalin significantly reduced the average severity of pain experienced by patients (P < 0.001 for both). Treatment-emergent adverse events were reported by significantly more patients in the twice daily group than those in the once nightly group (P = 0.023). There were no significant differences between the groups for the frequencies of individual adverse events (P > 0.05 for all). There was no significant difference in adverse events or efficacy in patients taking both pregabalin and a selective serotonin and norepinephrine reuptake inhibitor or selective serotonin uptake inhibitor. CONCLUSION: While a nightly dosing schedule of pregabalin has been used by clinicians hoping to improve treatment, this study showed no significant difference (either beneficial or detrimental) between either treatment option. While there was a decrease in total patient-reported adverse events in the once nightly arm, the lack of specificity in relation to a particular adverse event suggested no real difference in adverse events. PMID- 23983065 TI - Long-term clinical outcomes following drug-eluting stent implantation for unprotected distal trifurcation left main disease: the Milan-New Tokyo (MITO) registry. AB - BACKGROUND: Unprotected distal left main trifurcation (ULMT) lesion represents a challenge for interventional cardiologists with the potential for peri-procedural complications and adverse events at follow-up especially when the main branch and the side branches are concomitantly diseased. METHODS: A retrospective cohort analysis was performed on consecutive patients with ULMT stenosis who electively underwent percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation in order to assess the technical feasibility and long-term outcomes according to the disease distribution in the trifurcation branches (true vs. non true ULMT). Primary endpoint of the study was a composite of major adverse cardiovascular events (MACE) defined as cardiac-death, myocardial infarction (MI), and target lesion revascularization (TLR) during follow-up. RESULTS: Eighty four patients underwent PCI with DES for ULMT disease during the study period (40 true trifurcation and 44 non-true trifurcation). Angiographic and procedural success were obtained in 94% and 92.8% of cases. At 3-years follow-up, the occurrence of MACE was significantly higher in patients with true ULMT than in those with non-true ULMT (HR 2.801 [confidence interval; CI 1.164-7.896], P = 0.025) due to a higher TLR rate (HR 3.032 [CI 1.164-7.896], P = 0.023). No episodes of late and very late definite/probable stent thrombosis (ST) occurred. On multivariable analysis, a true-ULMT lesion was the only independent predictor of MACE (HR 2.344 [C.I. 1.006-5.461], P = 0.049). CONCLUSIONS: PCI with DES for ULMT stenosis is feasible with a high procedural success rate and no definite/probable ST reported at follow-up. A true trifurcation lesion is associated with enhanced risk of MACE mainly driven by TLR. PMID- 23983066 TI - Is the therapeutic alliance overvalued in the treatment of eating disorders? AB - In this article, we make the case for a systematic program of research into the causal relationship between the therapeutic alliance and outcomes of psychological treatments for the eating disorders. To make that case, we need to begin by considering the validity of existing assumptions about that alliance outcome relationship. We will then suggest what research is needed to allow clinicians to structure their work to best effect (e.g., should therapists focus on establishing a strong alliance even if it means not applying more therapy specific techniques, or should they stress the application of those techniques even when the working alliance might seem likely to be weakened as a result). Although the authors have a background in cognitive-behavioral therapy (CBT), our aim is to suggest a research base that applies to a variety of psychotherapies, allowing for common or different conclusions about the alliance-outcome relationship, depending on what the proposed research indicates. PMID- 23983068 TI - Modulation of multifunctional N,O,P ligands for enantioselective copper-catalyzed conjugate addition of diethylzinc and trapping of the zinc enolate. AB - In this work, we have successfully synthesized a new family of chiral Schiff base phosphine ligands derived from chiral binaphthol (BINOL) and chiral primary amine. The controllable synthesis of a novel hexadentate and tetradentate N,O,P ligand that contains both axial and sp3-central chirality from axial BINOL and sp3-central primary amine led to the establishment of an efficient multifunctional N,O,P ligand for copper-catalyzed conjugate addition of an organozinc reagent. In the asymmetric conjugate reaction of organozinc reagents to enones, the polymer-like bimetallic multinuclear Cu-Zn complex constructed in situ was found to be substrate-selective and a highly excellent catalyst for diethylzinc reagents in terms of enantioselectivity (up to >99 % ee). More importantly, the chirality matching between different chiral sources, C2-axial binaphthol and sp3-central chiral phosphine, was crucial to the enantioselective induction in this reaction. The experimental results indicated that our chiral ligand (R,S,S)-L1- and (R,S)-L4-based bimetallic complex catalyst system exhibited the highest catalytic performance to date in terms of enantioselectivity and conversion even in the presence of 0.005 mol % of catalyst (S/C = 20 000, turnover number (TON) = 17,600). We also studied the tandem silylation or acylation of enantiomerically enriched zinc enolates that formed in situ from copper-L4-complex-catalyzed conjugate addition, which resulted in the high-yield synthesis of chiral silyl enol ethers and enoacetates, respectively. Furthermore, the specialized structure of the present multifunctional N,O,P ligand L1 or L4, and the corresponding mechanistic study of the copper catalyst system were investigated by 31P NMR spectroscopy, circular dichroism (CD), and UV/Vis absorption. PMID- 23983070 TI - Exercise-induced ischemic preconditioning detected by sequential exercise stress tests: a meta-analysis. AB - Exercise-induced ischemic preconditioning (IPC) can be assessed with the second exercise stress test during sequential testing. Exercise-induced IPC is defined as the time to 1 mm ST segment depression (STD), the rate-pressure product (RPP) at 1 mm STD, the maximal ST depression and the rate-pressure product at peak exercise. The purpose of this meta-analysis is to validate the parameters used to assess exercise-induced IPC in the scientific community. A literature search was performed using electronic database. The main key words were limited to human studies, which were (a) ischemic preconditioning, (b) warm-up phenomenon, and (c) exercise. Meta-analyses were performed on the study-specific mean difference between the clinical measures obtained in the two consecutive stress tests (second minus first test score). Random effect models were fitted with inverse variance weighting to provide greater weight to studies with larger sample size and more precise estimates. The search resulted in 309 articles of which 34 were included after revision (1053 patients). Results are: (a) time to 1 mm ST segment depression increased by 91 s (95% confidence interval (CI): 75-108), p < 0.001; (b) peak ST depression decreased by -0.38 mm (95% CI: -0.66 to -0.10), p < 0.01; and (c) rate-pressure product at 1 mm STD increased by 1.80 * 10(3)mmHg (95% CI: 1.0-2.0), p < 0.001. This is the first meta-analysis to set clinical parameters to assess the benefit of exercise-induced ischemic preconditioning in sequential stress testing. The results of this first meta-analysis on the sequential stress test confirm what is presented in the literature by independent studies on exercise-induced ischemic preconditioning. From now on, the results could be used in further research to set standardized parameters to assess the phenomenon. PMID- 23983071 TI - Increased frequency and costs of ambulatory medical care utilization prior to the diagnosis of rheumatoid arthritis: a national population-based study. AB - OBJECTIVE: To investigate the frequency and costs associated with ambulatory medical care utilization over an 8-year period in patients prior to the diagnosis of rheumatoid arthritis (RA). METHODS: We used Taiwan's National Health Insurance Research Database to identify 691 newly diagnosed RA cases between 2005 and 2010. We selected 1,382 controls without RA, frequency matched by sex, age, and the catastrophic illness certificate application year of the cases. The frequency and costs of ambulatory medical care utilization between the RA patients and controls were compared using the 2-sample Kolmogorov-Smirnov test. RESULTS: The median frequency of ambulatory medical care utilization was significantly higher in RA patients compared with controls (29 versus 13; P < 0.001) in the year before diagnosis. The differences remained significant throughout all 8 annual periods before diagnosis. Similarly, the inflation-adjusted costs of ambulatory medical care utilization in RA patients increased annually over the study period, from a median of $212 eight years preceding diagnosis to $798 one year preceding diagnosis. Frequency of ambulatory medical care utilization due to diseases of the musculoskeletal system and connective tissue (P < 0.001), acute respiratory infections (P < 0.001), diseases of the upper respiratory tract (P = 0.01), and diseases of the upper gastrointestinal tract (P = 0.04) were higher among RA patients in the 2-year period preceding diagnosis. CONCLUSION: We found increased frequency and costs of ambulatory care utilization among RA patients in Taiwan preceding diagnosis of RA. PMID- 23983072 TI - Versatile post-functionalization of polyoxometalate platforms by using an unprecedented range of palladium-catalyzed coupling reactions. AB - Handy POMs: Several palladium-catalyzed coupling reactions have been applied to polyoxometalate post-functionalization. The feasibility of each reaction with one model substrate was investigated and each set of synthetic conditions was optimized to obtain full conversions and high purity hybrid compounds. PMID- 23983069 TI - Protracted maturation of forebrain afferent connections of the ventral tegmental area in the rat. AB - The mesocorticolimbic dopamine system has long attracted the interest of researchers concerned with the unique gamut of behavioral and mental health vulnerabilities associated with adolescence. Accordingly, the development of the mesocorticolimbic system has been studied extensively, but almost exclusively with regard to dopaminergic output, particularly in the nucleus accumbens and medial prefrontal cortex. To the contrary, the ontogeny of inputs to the ventral tegmental area (VTA), the source of mesocorticolimbic dopamine, has been neglected. This is not a trivial oversight, as the activity of VTA neurons, which reflects their capacity to transmit information about salient events, is sensitively modulated by inputs. Here, we assessed the development of VTA afferent connections using the beta subunit of cholera toxin (Ctbeta) as a retrograde axonal tracer in adolescent (postnatal day 39) and early adult (8-9 week-old) rats. After intra-VTA injections of Ctbeta, adolescent and early adult animals exhibited qualitatively similar distributions of retrogradely labeled neurons in the sense that VTA-projecting neurons were present at all of the same rostrocaudal levels in all of the same structures in both age groups. However, quantitation of retrogradely labeled neurons revealed that adolescent brains, compared with early adult brains, had significantly fewer VTA-projecting neurons preferentially within an interconnected network of cortical and striatopallidal forebrain structures. These findings provide a novel perspective on the development of the mesocorticolimbic dopamine system and may have important implications for age-dependent specificity in the function of this system, particularly with regard to adolescent impulsivity and mental health vulnerabilities. PMID- 23983073 TI - A regulatory variant in CCR6 is associated with susceptibility to antitopoisomerase-positive systemic sclerosis. AB - OBJECTIVE: Recognition of the well-known pleiotropism of autoimmune genes supports the concept of a shared pathogenesis across autoimmune diseases such as rheumatoid arthritis (RA) and systemic sclerosis (SSc). Studies have reproducibly demonstrated an association between susceptibility to RA and polymorphisms of the CCR6 gene, a surface marker for Th17 cells, and the causal variant was recently identified. The present study was thus undertaken to investigate whether CCR6 polymorphisms could also be associated with susceptibility to SSc. METHODS: Twelve tag single-nucleotide polymorphisms (SNPs) of CCR6, including the known RA associated SNP rs3093023, were genotyped in a total of 2,411 SSc patients and 7,084 healthy individuals from 3 European populations (France, Italy, and Germany). Meta-analyses of the data were performed to assess whether an association exists between CCR6 polymorphisms and susceptibility to SSc or its main subtypes. Direct sequencing of DNA was performed to ascertain whether the functional dinucleotide polymorphism of CCR6 previously identified in RA (CCR6DNP) was also present in SSc. RESULTS: Combined analyses revealed an association between the rs10946216 SNP and SSc susceptibility (odds ratio [OR] 1.13, 95% confidence interval [95% CI] 1.05-1.21, adjusted P [P(adj)] = 0.026). The rs3093023 A allele and rs10946216 T allele were in high linkage disequilibrium, and both were found to confer disease susceptibility in the antitopoisomerase-positive subset of SSc patients (OR 1.27, 95% CI 1.13-1.42, P(adj) = 1.5 * 10(-3) and OR 1.32, 95% CI 1.17-1.48, P(adj) = 9.0 * 10(-5), respectively, relative to healthy controls). Direct sequencing of the DNA of 78 individuals supported the hypothesis that the regulatory dinucleotide CCR6DNP could be the causal variant in SSc. CONCLUSION: The results of this study establish CCR6 as a new susceptibility factor for antitopoisomerase-positive SSc, as demonstrated in 3 European Caucasian populations, confirming the notion that SSc and RA could conceivably share autoimmune risk alleles. The results also suggest a potential role of the interleukin-17 pathway in SSc. PMID- 23983074 TI - Fibrosis caused by loss of PTEN expression in mouse fibroblasts is crucially dependent on CCN2. AB - OBJECTIVE: Protein phosphatase and tensin homolog (PTEN) expression is reduced in dermal fibroblasts isolated from patients with diffuse cutaneous systemic sclerosis, a fibrotic autoimmune disease. In support of this finding, deletion of the PTEN gene in the dermal fibroblasts of mice has been shown to result in skin fibrosis and in vivo overexpression of connective tissue growth factor (CTGF; CCN2), a proadhesive matricellular protein; however, whether CCN2 is required for the fibrosis caused by loss of PTEN is unclear. This study was undertaken to investigate the role of CCN2 in fibrosis caused by reduced PTEN expression. METHODS: We generated conditional knockout mice in which PTEN was deleted in fibroblasts, either alone or in combination with CCN2. Skin samples were collected for histologic examination, immunohistochemical analysis, and collagen assay. RESULTS: Loss of CCN2 resulted in resistance to the increases in collagen production and myofibroblast recruitment that are caused by loss of PTEN. CCN2 deficiency did not impair Akt phosphorylation or the increases in the intensity of proliferating cell nuclear antigen staining that were caused by loss of PTEN. CONCLUSION: These data are consistent with the notion that CCN2 is required for particular aspects of the fibroproliferative response; therapeutic strategies blocking CCN2 may be of clinical benefit in combating fibrotic disease. PMID- 23983075 TI - Identification of thaumatin-like protein and aspartyl protease as new major allergens in lettuce (Lactuca sativa). AB - SCOPE: Today, about 2-8% of the population of Western countries exhibits some type of food allergy whose impact ranges from localized symptoms confined to the oral mucosa to severe anaphylactic reactions. Consumed worldwide, lettuce is a Compositae family vegetable that can elicit allergic reactions. To date, however, only one lipid transfer protein has been described in allergic reaction to lettuce. The aim of this study was to identify potential new allergens involved in lettuce allergy. METHODS AND RESULTS: Sera from 42 Spanish lettuce-allergic patients were obtained from patients recruited at the outpatient clinic. IgE binding proteins were detected by SDS-PAGE and immunoblotting. Molecular characterization of IgE-binding bands was performed by MS. Thaumatin was purified using the Agilent 3100 OFFGEL system. The IgE-binding bands recognized in the sera of more than 50% of patients were identified as lipid transfer protein (9 kDa), a thaumatin-like protein (26 kDa), and an aspartyl protease (35 and 45 kDa). ELISA inhibition studies were performed to confirm the IgE reactivity of the purified allergen. CONCLUSION: Two new major lettuce allergens-a thaumatin like protein and an aspartyl protease-have been identified and characterized. These allergens may be used to improve both diagnosis and treatment of lettuce allergic patients. PMID- 23983077 TI - Influence of preheating on antioxidant activity of the water extract from black soybean and color and sensory properties of black soybean decoction. AB - BACKGROUND: Our previous study indicated that black soybean (BS) tea (BST) made from preheated BS showed a significant protective effect against CCl4 -induced liver damage in Sprague Dawley rats due to BS's antioxidant activity. In this study, we investigated three different preheating methods on the antioxidant activity of water extract from BS (WBS) (Glycine max (L.) Merrill), as well as on the color and sensory properties of BST. RESULTS: WBS baked at 130 degrees C for 5 min showed high total phenol, flavonoid and anthocyanin contents among three preheating methods, as well as high DPPH radical-scavenging activity, ferrous ion chelating ability and reducing power. BST baked at 130 degrees C for 5 min had higher polyphenol oxidase activity and L*, a* and b* values but lower peroxidase activity then BST made from unheated BS. Sensory evaluation indicated that BST made from baked BS produced better aroma and flavor than the tea made from unheated BS or a commercial preheated BS. CONCLUSION: An appropriate preheating process improved the amount of extractable antioxidant and the antioxidant activity in WBS. BST baked at 130 degrees C for 5 min had good flavor properties, as well as high amount of antioxidant. PMID- 23983078 TI - Anopheles arabiensis egg treatment with dieldrin for sex separation leaves residues in male adult mosquitoes that can bioaccumulate in goldfish (Carassius auratus auratus). AB - The sterile insect technique (SIT) is a biological control tactic that is used as a component of area-wide integrated pest management (AW-IPM) programs. The SIT can only be applied against disease-transmitting mosquitoes when only sterile male mosquitoes are released, and the blood-sucking and potentially disease transmitting females are eliminated from the production line. For Anopheles arabiensis, a potent vector of malaria, a genetic sexing strain was developed whereby females can be eliminated by treating the eggs or larvae with the insecticide dieldrin. To evaluate the presence of dieldrin residues in male mosquitoes designated for SIT releases, a simple, sensitive, and accurate gas chromatography-electron capture detector (GC-ECD) method was developed. In addition, bioaccumulation and food chain transfer of these residues to fish after feeding with treated mosquitoes was demonstrated. The overall recovery from method validation studies was 77.3 +/- 2.2% (mean +/- relative standard deviation [RSD]) for the mosquitoes, and 99.1 +/- 4.4% (mean +/- RSD) for the fish. The average dieldrin concentration found in adult male An. arabiensis was 28.1 +/- 2.9 ug/kg (mean +/- standard deviation [SD]). A range of 23.9 +/- 1.1 ug/kg to 73.9 +/- 5.2 ug/kg (mean +/- SD) of dieldrin was found in the fish samples. These findings indicate the need to reassess the environmental and health implications of control operations with a SIT component against An. arabiensis that involves using persistent organochlorines in the sexing process. PMID- 23983080 TI - Reply to subgroup analysis comment on amiodarone and the risk of cancer. PMID- 23983079 TI - Comorbidity of common mental disorders with cancer and their treatment gap: findings from the World Mental Health Surveys. AB - OBJECTIVE: This study aimed to study the comorbidity of common mental disorders (CMDs) and cancer, and the mental health treatment gap among community residents with active cancer, cancer survivors and cancer-free respondents in 13 high income and 11 low-middle-income countries. METHODS: Data were derived from the World Mental Health Surveys (N = 66,387; n = 357 active cancer, n = 1373 cancer survivors, n = 64,657 cancer-free respondents). The World Health Organization/Composite International Diagnostic Interview was used in all surveys to estimate CMDs prevalence rates. Respondents were also asked about mental health service utilization in the preceding 12 months. Cancer status was ascertained by self-report of physician's diagnosis. RESULTS: Twelve-month prevalence rates of CMDs were higher among active cancer (18.4%, SE = 2.1) than cancer-free respondents (13.3%, SE = 0.2) adjusted for sociodemographic confounders and other lifetime chronic conditions (adjusted odds ratio (AOR) = 1.44, 95% CI 1.05-1.97). CMD rates among cancer survivors (14.6%, SE = 0.9) compared with cancer-free respondents did not differ significantly (AOR = 0.95, 95% CI 0.82-1.11). Similar patterns characterized high-income and low-middle income countries. Of respondents with active cancer who had CMD in the preceding 12 months, 59% sought services for mental health problems (SE = 5.3). The pattern of service utilization among people with CMDs by cancer status (highest among persons with active cancer, lower among survivors and lowest among cancer-free respondents) was similar in high-income (64.0%, SE = 6.0; 41.2%, SE = 3.0; 35.6%, SE = 0.6) and low-middle-income countries (46.4%, SE = 11.0; 22.5%, SE = 9.1; 17.4%, SE = 0.7). CONCLUSIONS: Community respondents with active cancer have higher CMD rates and high treatment gap. Comprehensive cancer care should consider both factors. PMID- 23983081 TI - Improvement in health-related quality of life for children with juvenile idiopathic arthritis after start of treatment with etanercept. AB - OBJECTIVE: Improvement in health-related quality of life (HRQOL) is an important therapy goal in the treatment of patients with juvenile idiopathic arthritis (JIA). We investigated the 12-month course of HRQOL in patients with JIA after the start of therapy with etanercept and identified its determining factors. METHODS: Children with JIA were enrolled in the BiKer (Biologics in Pediatric Rheumatology) registry at the start of etanercept treatment. Children were prospectively followed in the first year of treatment and completed the Pediatric Quality of Life Inventory (PedsQL) at each occasion. The change in HRQOL was investigated by random-effect regression models. The time-varying variables pain and inactive disease were used for predicting the change in HRQOL. Inactive disease was defined by the Wallace et al criteria and pain was assessed on a visual analog scale (range 0-100). RESULTS: The children (n = 61) had a mean age of 10.6 years and a mean disease duration of 3.4 years at the start of etanercept. The mean PedsQL total score was 75. The PedsQL total score increased at a rate of 2.8 units per month (P < 0.001) in the first 6 months of treatment, up to a level of 89.7. A low HRQOL score was significantly highly associated with the number of tender joints, functional restrictions, pain, disease activity, and the existence of a comorbid condition at baseline. Inactive disease and reduced pain predicted better HRQOL under etanercept treatment. CONCLUSION: HRQOL was dramatically improved in children who started etanercept treatment. Inactive disease and lower pain were important predictors for improvement of HRQOL over time. PMID- 23983083 TI - Synthesis and characterization of diphenyl quinoline and bromine-activated diphenyl quinoline organic phosphors. AB - A diphenyl quinoline (DPQ)-conjugated derivative and bromine-activated DPQ (Br DPQ) were synthesized in an inert gas atmosphere at 140 degrees C using Friedlander condensation. The compounds showed blue emission under a UV source. The structures were characterized by X-ray diffraction and Fourier transform infrared spectroscopy. The photoluminescence properties of the compounds were analysed using excitation and emission spectra. The synthesized organic phosphors shows bright emission in the blue region, with peaks at 445 and 453 nm, respectively, for DPQ and Br-DPQ in the powder form. The physical and photoluminescence properties of these organic compounds reveal promising blue emitters for high-efficiency organic light-emitting diodes. PMID- 23983082 TI - NURTURE: development and pilot testing of a novel parenting intervention for mothers with histories of an eating disorder. AB - OBJECTIVE: To describe the treatment development and pilot testing of a group parenting intervention, NURTURE (Networking, Uniting, and Reaching out To Upgrade Relationships and Eating), for mothers with histories of eating disorders. METHOD: Based on focus group findings, extant research, and expert opinion, NURTURE was designed to be delivered weekly over 16 (1.5 h) sessions via an interactive web conferencing forum. It comprises four modules: (1) laying the foundation, (2) general parenting skills, (3) eating and feeding, and (4) breaking the cycle of risk. Pilot testing was conducted with three groups of 3-6 mothers (N = 13) who had children ages 0-3 years to determine feasibility (e.g., retention), acceptability (e.g., feedback questionnaire responses), and preliminary efficacy. Maternal satisfaction with NURTURE and changes in mother child feeding relationship measures, maternal feeding style, maternal self efficacy, and maternal psychopathology (eating disorder, depression, and anxiety symptoms) across three time points (baseline, post-treatment, 6-month follow-up) were examined. All outcomes were exploratory. RESULTS: The intervention was well tolerated with a 100% retention rate. Feedback from mothers was generally positive and indicated that the groups provided an engaging, supportive experience to participants. We observed changes suggestive of improvement in self reported maternal self-efficacy and competence with parenting. There were no notable changes in measures of maternal feeding style or psychopathology. DISCUSSION: NURTURE is a feasible, acceptable, and potentially valuable intervention for mothers with eating disorder histories. Results of this pilot will inform a larger randomized-controlled intervention to determine efficacy and impact on child outcomes. PMID- 23983084 TI - Isotope dilution assay in peptide quantification: the challenge of microheterogeneity of internal standard. AB - Isotope dilution analysis allows quantitation of elements and different compounds in complex mixtures. The quantitation is based on a known amount of reference material (internal standard, IS) added to a sample that makes the result critically dependent on the value assigned to the standard. In the case of peptides, IS concentration is determined by nitrogen and amino acid analysis while purity is normally assessed by methods such as chromatography or electrophoresis that might not be able to detect many possible amino acid modifications, either naturally occurring or chemically induced. Microheterogeneity of the IS, if it is not accounted for when assigning a reference value to the standard, results in highly overestimated values in target analyte quantitation. In this viewpoint article, we illustrate the problem of internal standard microheterogeneity by analyzing synthetic human C-peptide labeled analogs. PMID- 23983085 TI - Nano-architectural alterations in mucus layer fecal colonocytes in field carcinogenesis: potential for screening. AB - Current fecal tests (occult blood, methylation, DNA mutations) target minute amounts of tumor products among a large amount of fecal material and thus have suboptimal performance. Our group has focused on exploiting field carcinogenesis as a modality to amplify the neoplastic signal. Specifically, we have shown that endoscopically normal rectal brushings have striking nano-architectural alterations which are detectable using a novel optical technique, partial wave spectroscopic microscopy (PWS). We therefore wished to translate this approach to a fecal assay. We examined mucus layer fecal colonocytes (MLFC) at preneoplastic and neoplastic time points (confirmed with rat colonoscopy) in the azoxymethane (AOM)-treated rat model and conducted PWS analysis to derive the nano architectural parameter, disorder strength (Ld). We confirmed these results with studies in a genetic model (the Pirc rat). We showed that MLFC appeared microscopically normal, consistent with field carcinogenesis. Ld was elevated at an early time point (5 weeks post-AOM injection, effect size = 0.40, P = 0.024) and plateaued before adenoma formation (10 weeks post-AOM, effect size = 0.66, P = 0.001), with no dramatic increase once tumors developed. We replicated these data in the preneoplastic Pirc rat with an effect size in the MLFC that replicated the rectal brushings (increase vs. age-matched controls of 62% vs. 74%, respectively). We provide the first demonstration of a biophotonics approach to fecal assay. Furthermore, targeting the nano-architectural changes of field carcinogenesis rather than the detection of tumor products may provide a novel paradigm for colorectal cancer screening. PMID- 23983086 TI - Anti-genotoxic potential of bilirubin in vivo: damage to DNA in hyperbilirubinemic human and animal models. AB - The bile pigment bilirubin is a known antioxidant and is associated with protection from cancer and cardiovascular disease (CVD) when present in too strong concentrations. Unconjugated bilirubin (UCB) might also possess anti genotoxic potential by preventing oxidative damage to DNA. Moderately elevated bilirubin levels are found in individuals with Gilbert syndrome and more severe in the hyperbilirubinemic Gunn rat model. This study was therefore aimed to assess the levels of oxidative damage to DNA in Gilbert syndrome subjects and Gunn rats compared to matched controls. Seventy-six individuals (age- and sex matched) were allocated into Gilbert syndrome (UCB >=17.1 MUmol/L; n = 38) or control groups (UCB < 17.1 MUmol/L; n = 38). In addition, 40 Gunn rats were used to support the results of the human trial. Single-cell gel electrophoresis (SCGE) assay measuring standard conditions (strand breaks, apurinic/apyrimidinic sites) and formamidopyrimidine glycosylase (FPG)-sensitive sites was conducted in human peripheral blood mononuclear cells (PBMC) and rat PBMCs, colon, and hepatocytes. Furthermore, urinary 8-oxo-2'-deoxyguanosine (8oxodGuo, DNA oxidation) and 8-oxo guanosine (8oxoGuo, RNA oxidation) were measured in humans. The Gilbert syndrome and Gunn rat groups had significantly higher UCB levels (P < 0.001) than the corresponding controls. No further differences in damage to DNA or RNA were detected between the two groups, except higher strand breaks (PBMCs) in Gunn rats when compared with controls. However, when demographic effects were analyzed, lower 8oxodGuo concentrations were detected in the human group with a BMI >=25 kg/m(2) (1.70 +/- 0.67 vs. 1.38 +/- 0.43 nmol/mmol creatinine, P < 0.05), although this group showed lower UCB levels than normal weight subjects. This study suggests that the disease preventative effect of UCB is unrelated to DNA oxidation/strand breaks in human and animal models of hyperbilirubinaemia. PMID- 23983087 TI - Risk factors for non-initiation of the human papillomavirus vaccine among adolescent survivors of childhood cancer. AB - Effective vaccination is now available to prevent human papillomavirus (HPV), the most common sexually transmitted infection and cause of cervical cancer. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and identify factors associated with HPV vaccine initiation and completion. Mothers of daughters of ages 9 to 17 years with/without a history of childhood cancer (n = 235, Mage = 13.2 years, SD = 2.69; n = 70, Mage = 13.3 years, SD = 2.47, respectively) completed surveys querying HPV vaccination initiation and completion along with sociodemographic, medical, HPV knowledge and communication, and health belief factors, which may relate to vaccination outcomes. Multivariate logistic regression was used to identify factors that associate with HPV vaccination initiation and completion. Among cancer survivors, 32.6% initiated and 17.9% completed the three-dose vaccine series, whereas 34.3% and 20.0% of controls initiated and completed, respectively. Univariate analyses indicated no differences between cancer/no cancer groups on considered risk factors. Among all participants, multivariate logistic regression analyses found vaccine initiation associated with older age of daughter and physician recommendation, whereas increased perceived barriers associated with a decreased likelihood of initiation (all P < 0.05). Among those having initiated, risk factors for noncompletion included being non-White, increased perceived severity of HPV, and increased perceived barriers to vaccination (all P < 0.05). A minority of adolescents surviving childhood cancer has completed vaccination despite their increased risk for HPV-related complication. These results inform the prioritization of strategies to be included in vaccine promotion efforts. PMID- 23983089 TI - Reversible pore size control of elastic microporous material by mechanical force. AB - Nanoporous materials, such as zeolites, activated carbons, and metal-organic frameworks (MOFs), are peculiar platforms in which a variety of guest molecules are stored, reacted, and/or separated. The size of the nanopores is essential to realize advanced functions. In this work, we demonstrate a very simple but innovative method for the control of nanopore size, that is, reversible and continuous control by mechanical force loaded to soft nanoporous materials. The elastic properties of several microporous materials, including zeolites, zeolite templated carbon (ZTC), activated carbon, and MOFs (e.g., ZIF-8), are examined and it is found that ZTC is a material that is suitable for the aforementioned idea thanks to its extraordinary soft properties compared to the others. The original pore size of ZTC (1.2 nm) can be contracted to 0.85 nm by using a relatively weak loading force of 135 MPa, whereas the other microporous materials barely contracted. To demonstrate the change in the physical properties induced by such artificial deformation, in situ gas adsorption measurements were performed on ZTC with and without loading mechanical force, by using CO2, CH4, and H2, as adsorbates. Upon the contraction by loading 69 or 135 MPa, CO2 adsorption amount is increased, due to the deepening of the physisorption potential well inside the micropores, as proved by the increase of the heat of adsorption. Moreover, the adsorption amount is completely restored to the original one after releasing the mechanical force, indicating the fully reversible contraction/recovery of the ZTC framework against mechanical force. The experimental results are theoretically supported by a simulation using Grand Canonical Monte Carlo method. The similar adsorption enhancement is observed also on CH4, whereas H2 is found as an exception due to the weak interaction potential. PMID- 23983090 TI - Transcutaneous electrical nerve stimulation as an adjunct to education and exercise for knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To determine the additional effects of transcutaneous electrical nerve stimulation (TENS) for knee osteoarthritis (OA) when combined with a group education and exercise program (knee group). METHODS: The study was a randomized, sham-controlled clinical trial. Patients referred for physiotherapy with suspected knee OA (confirmed using the American College of Rheumatology clinical criteria) were invited. Exclusion criteria included comorbidities preventing exercise, previous TENS experience, and TENS contraindications. Prospective sample size calculations required 67 participants in each trial arm. A total of 224 participants (mean age 61 years, 37% men) were randomized to 3 arms: TENS and knee group (n = 73), sham TENS and knee group (n = 74), and knee group (n = 77). All patients entered an evidence-based 6-week group education and exercise program (knee group). Active TENS produced a "strong but comfortable" paraesthesia within the painful area and was used as much as needed during the 6 week period. Sham TENS used dummy devices with no electrical output. Blinded assessment took place at baseline and 3, 6, 12, and 24 weeks. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function subscale at 6 weeks. Secondary outcomes included WOMAC pain, stiffness, and total scores; extensor muscle torque; global assessment of change; exercise adherence; and exercise self-efficacy. Data analysis was by intent to treat. RESULTS: All outcomes improved over time (P < 0.05), but there were no differences between trial arms (P > 0.05). All improvements were maintained at 24 week followup. CONCLUSION: There were no additional benefits of TENS, failing to support its use as a treatment adjunct within this context. PMID- 23983091 TI - Home-based exercise program and fall-risk reduction in older adults with multiple sclerosis: phase 1 randomized controlled trial. AB - OBJECTIVE: To determine the feasibility, safety, and efficacy of a home-based exercise intervention targeting fall risk in older adults with multiple sclerosis. DESIGN: A randomized controlled pilot trial. SETTING: A home-based exercise program. INTERVENTION: Participants were randomly allocated to either a home-based exercise intervention group (n = 13) or a waiting list control group (n = 14). The exercise group completed exercises targeting lower muscle strength and balance three times a week for 12 weeks. The control group continued normal activity. MEASURES: Fall risk (Physiological Profile Assessment scores), balance (Berg Balance Scale), and walking testing prior to and immediately following the 12-week intervention. Each outcome measure was placed in an analysis of covariance with group as the between-subject factor and baseline values as the covariate. Effect sizes were calculated. RESULTS: Twelve participants from the control group and ten from the exercise group completed the study. There were no related adverse events. Fall risk was found to decrease in the exercise group following the intervention (1.1 SD 1.0 vs. 0.6 SD 0.6) while there was an increase in fall risk in the control group (1.9 SD 1.5 vs. 2.2 SD 1.9). Effect sizes for most outcomes were large (eta(2) > 0.15). CONCLUSIONS: Home-based exercise was found to be feasible, safe, and effective for reducing physiological fall risk in older adults with multiple sclerosis. Our findings support the implementation of a larger trial to reduce fall risk in persons with multiple sclerosis. PMID- 23983092 TI - Distinctive population of Gfap-expressing neural progenitors arising around the dentate notch migrate and form the granule cell layer in the developing hippocampus. AB - In the adult hippocampus, granule cells continue to be generated from astrocyte like progenitors expressing glial fibrillary acidic protein (GFAP) that differ from embryonic neocortical progenitors. However, during the embryonic period, dentate granule neurons and neocortical pyramidal neurons are derived from the ventricular zone (VZ) of the pallium. Our question is when do GFAP+ progenitors of granule neurons appear in the developing hippocampus during the embryonic period, and how do they form the granule cell layer. The present analysis using Gfap-GFP transgenic mice shows that the GFP+ distinct cell population first appears in the VZ of the medial pallium at the dorsal edge of the fimbria on embryonic day 13.5. During the perinatal period, they form a migratory stream from the VZ to the developing dentate gyrus, and establish the germinal zones in the migratory stream, and the marginal and hilar regions in the developing dentate gyrus. GFP+ cells in these regions were positive for Sox2 and Ki67, but negative for BLBP. GFP+ cells with Neurogenin2 expression were largely distributed in the VZ, whereas GFP+ cells with Tbr2 and NeuroD expressions were seen in the migratory stream and developing dentate gyrus. Prox1-expressing GFP+ cells were restricted to the developing dentate gyrus. These results suggest that distinctive Gfap-expressing progenitors arising around the dentate notch form germinal regions in the migratory stream and the developing dentate gyrus where they differentiate into granule neurons, indicating that distinct astrocyte-like neural progenitors continue to generate granule neurons, from the beginning of dentate development and throughout life. J. Comp. Neurol. 522:261-283, 2014. (c) 2013 Wiley Periodicals, Inc. PMID- 23983088 TI - Genome-wide association study of dermatomyositis reveals genetic overlap with other autoimmune disorders. AB - OBJECTIVE: To identify new genetic associations with juvenile and adult dermatomyositis (DM). METHODS: We performed a genome-wide association study (GWAS) of adult and juvenile DM patients of European ancestry (n = 1,178) and controls (n = 4,724). To assess genetic overlap with other autoimmune disorders, we examined whether 141 single-nucleotide polymorphisms (SNPs) outside the major histocompatibility complex (MHC) locus, and previously associated with autoimmune diseases, predispose to DM. RESULTS: Compared to controls, patients with DM had a strong signal in the MHC region consisting of GWAS-level significance (P < 5 * 10(-8)) at 80 genotyped SNPs. An analysis of 141 non-MHC SNPs previously associated with autoimmune diseases showed that 3 SNPs linked with 3 genes were associated with DM, with a false discovery rate (FDR) of <0.05. These genes were phospholipase C-like 1 (PLCL1; rs6738825, FDR = 0.00089), B lymphoid tyrosine kinase (BLK; rs2736340, FDR = 0.0031), and chemokine (C-C motif) ligand 21 (CCL21; rs951005, FDR = 0.0076). None of these genes was previously reported to be associated with DM. CONCLUSION: Our findings confirm the MHC as the major genetic region associated with DM and indicate that DM shares non-MHC genetic features with other autoimmune diseases, suggesting the presence of additional novel risk loci. This first identification of autoimmune disease genetic predispositions shared with DM may lead to enhanced understanding of pathogenesis and novel diagnostic and therapeutic approaches. PMID- 23983093 TI - The preventive role of breadfruit against inflammation-associated epithelial carcinogenesis in mice. AB - Artocarpus communis has been identified as a rich source of flavonoids and has been gaining attention for its potential chemopreventive abilities. In this study, methanol extracts from the fruit of A. communis (MEFA) and leaf of A. communis (MELA) were prepared, and their effects on inflammation-associated skin tumorigenesis were assessed using mouse models, including 12-O tetradecanoylphorbol-13-acetate (TPA) induced cutaneous inflammation as well as 7,12-dimethylbenz[alpha]anthracene (DMBA) initiated and TPA-promoted skin tumorigenesis. According to the results, both MEFA and MELA decreased the intensity of leukocyte infiltration in mouse dorsal skin and cutaneous edema induced by TPA, which appeared to be mediated by inhibition of proinflammatory genes (inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-6) and proinflammatory mediators (TNF alpha, IL-1beta, and Prostaglandin E2 ). In addition, topical application with MEFA or MELA effectively attenuated tumor incidence, multiplicity, volume, malignancy as well as angiogenesis of TPA-stimulated skin tumor promotion in DMBA initiated mice. Notably, immunohistochemical stain showed that MEFA and MELA attenuated COX-2 expression of both skin and tumor tissues in different animal tests, which may be closely related to the suppression of nuclear factor kappa B/activator protein signaling networks. These findings first demonstrate that flavonoid-rich A. communis may exert potent anti-inflammatory activity through modulation of COX-2 in TPA-activated skin and tumor tissues. PMID- 23983094 TI - Biophysical studies of the amyloid beta-peptide: interactions with metal ions and small molecules. AB - Alzheimer's disease is the most common of the protein misfolding ("amyloid") diseases. The deposits in the brains of afflicted patients contain as a major fraction an aggregated insoluble form of the so-called amyloid beta-peptides (Abeta peptides): fragments of the amyloid precursor protein of 39-43 residues in length. This review focuses on biophysical studies of the Abeta peptides: that is, of the aggregation pathways and intermediates observed during aggregation, of the molecular structures observed along these pathways, and of the interactions of Abeta with Cu and Zn ions and with small molecules that modify the aggregation pathways. Particular emphasis is placed on studies based on high-resolution and solid-state NMR methods. Theoretical studies relating to the interactions are also included. An emerging picture is that of Abeta peptides in aqueous solution undergoing hydrophobic collapse together with identical partners. There then follows a relatively slow process leading to more ordered secondary and tertiary (quaternary) structures in the growing aggregates. These aggregates eventually assemble into elongated fibrils visible by electron microscopy. Small molecules or metal ions that interfere with the aggregation processes give rise to a variety of aggregation products that may be studied in vitro and considered in relation to observations in cell cultures or in vivo. Although the heterogeneous nature of the processes makes detailed structural studies difficult, knowledge and understanding of the underlying physical chemistry might provide a basis for future therapeutic strategies against the disease. A final part of the review deals with the interactions that may occur between the Abeta peptides and the prion protein, where the latter is involved in other protein misfolding diseases. PMID- 23983095 TI - Preworkshop knowledge of musculoskeletal anatomy of rheumatology fellows and rheumatologists of seven North, Central, and South American countries. AB - OBJECTIVE: To report the baseline knowledge of clinical anatomy of rheumatology fellows and rheumatologists from Argentina, Chile, Ecuador, El Salvador, Mexico, the US, and Uruguay. METHODS: The invitation to attend a workshop in clinical anatomy was an open call by national rheumatology societies in 4 countries or by invitation from teaching program directors in 3 countries. Prior to the workshop, a practical test of anatomic structures commonly involved in rheumatic diseases was administered. The test consisted of the demonstration of these structures or their function in the participant's or instructor's body. At one site, a postworkshop practical test was administered immediately after the workshop. RESULTS: There were 170 participants (84 rheumatology fellows, 61 rheumatologists, and 25 nonrheumatologists). The overall mean +/- SD number of correct answers was 46.6% +/- 19.9% and ranged from 32.5-67.0% by country. Rheumatology fellows scored significantly higher than nonrheumatologists. Questions related to anatomy of the hand scored the lowest of the regions surveyed. CONCLUSION: Rheumatology fellows and rheumatologists showed a deficit in knowledge of musculoskeletal anatomy that is of central importance in rheumatologic assessment and diagnosis. This gap may hinder accurate and cost effective rheumatologic diagnosis, particularly in the area of regional pain syndromes. Presently, widespread use of musculoskeletal ultrasound (MSUS) by rheumatologists may be premature, since a key component of expert-level MSUS is the integration of an accurate knowledge of anatomy with the views obtained with the ultrasound probe. PMID- 23983096 TI - Psychodynamic interventions in cancer care I: psychometric results of a randomized controlled trial. AB - OBJECTIVE: This study aimed to assess the effectiveness of psychodynamic interventions in cancer care. METHODS: Between 2006 and 2009, each consecutive outpatient of the Oncology Center of the University Hospital of Lausanne was invited to participate in a trial evaluating the effects of psychological support. Accepting patients were randomly assigned to an immediate intervention or a delayed intervention [4-month waiting list]. Patients who declined support were asked to participate in an observational group [OG]. Socio-demographic and medical data, anxiety, and depression [HADS], psychological distress [SCL-90], alexithymia [TAS] and quality of life [EORTC] were recorded at baseline, and at 1, 4, 8, and 12-months follow-up. RESULTS: Of the 1973 approached patients, 1057 were excluded, 530 refused, and 386 were included with 196 of them participating in the OG. Of the patients in the intervention group [IG] [N = 190], 94 were randomized to the immediate intervention and 96 to the delayed intervention group (dIG). IG patients were younger, predominantly female, and had more psychological symptoms compared with those in the OG. Although patients of the IG and OG showed significant improvement in quality of life from baseline to 12-months follow-up, other outcomes [anxiety, depression, psychological distress, and alexithymia] remained unchanged. CONCLUSIONS: The intervention was not effective with regards to psychometric outcome. The results have to be interpreted in light of the study design [untargeted intervention], the low levels of psychiatric symptoms, dropout of symptomatic patients, and the high prevalence of alexithymia. PMID- 23983098 TI - Amiodarone and the risk of cancer: a nationwide population-based study. PMID- 23983097 TI - Physicochemical and biochemical characterization of transgenic papaya modified for protection against Papaya ringspot virus. AB - BACKGROUND: Papaya, a nutritious tropical fruit, is consumed both in its fresh form and as a processed product worldwide. Major quality indices which include firmness, acidity, pH, colour and size, are cultivar dependent. Transgenic papayas engineered for resistance to Papaya ringspot virus were evaluated over the ripening period to address physicochemical quality attributes and food safety concerns. RESULTS: With the exception of one transgenic line, no significant differences (P > 0.05) were observed in firmness, acidity and pH. Lightness (L*) and redness (a*) of the pulps of non-transgenic and transgenic papaya were similar but varied over the ripening period (P < 0.05). Fruit mass, though non uniform (P < 0.05) for some lines, was within the range reported for similar papaya cultivars, as were shape indices of female fruits. Transgene proteins, CP and NPTII, were not detected in fruit pulp at the table-ready stage. CONCLUSION: The findings suggest that transformation did not produce any major unintended alterations in the physicochemical attributes of the transgenic papayas. Transgene proteins in the edible fruit pulp were low or undetectable. PMID- 23983099 TI - Effects of 17alpha-ethynylestradiol, fluoxetine, and the mixture on life history traits and population growth rates in a freshwater gastropod. AB - Pharmaceutical and personal care products (PPCPs), some of which have endocrine disrupting effects at environmentally relevant concentrations, have been detected in many surface waters. The authors evaluated the effects of 2 common endocrine disrupting PPCPs on the life history traits of the snail, Physa pomilia, using a life table response experiment with snails raised in environmentally relevant concentrations of 17alpha-ethynylestradiol (EE2), fluoxetine, or their mixture. Exposure to fluoxetine or the mixture reduced snail reproduction, but EE2 did not. Generally, individual life history traits were affected minimally by the PPCPs, but when integrated using a demographic model, all 3 chemical exposure scenarios decreased population growth rates, with the EE2 and fluoxetine mixture causing the most adverse effects. Overall, the results provide additional insight into the effects of PPCPs on freshwater invertebrates and point to the importance of testing simultaneous exposures to multiple PPCPs. In addition, using a demographic model to integrate individual endpoints provided insights into effects that were not apparent from individual life history traits alone and suggest at least a potential for adverse ecological effects under realistic environmental exposures concentrations. PMID- 23983100 TI - Metabolic inflexibility during submaximal aerobic exercise is associated with glucose intolerance in obese older adults. AB - OBJECTIVE: People with type 2 diabetes have reduced cardiorespiratory fitness and metabolic impairments that are linked to obesity and often occur prior to the development of type 2 diabetes. We hypothesized that obese, older adults with impaired glucose tolerance (IGT) have lower ability to shift from fat to carbohydrate oxidation when transitioning from rest to submaximal exercise than normal glucose tolerant (NGT) controls. DESIGN AND METHODS: Glucose tolerance, body composition, and substrate oxidation (measured by RER:respiratory exchange ratio) during submaximal exercise (50% and 60% VO2max ) and insulin infusion (3 hour hyperinsulinemic-euglycemic clamp) were assessed in 23 sedentary, overweight obese, older men and women. RESULTS: Obese subjects with NGT (n = 13) and IGT (n = 10) had similar resting RER, but during submaximal exercise those with IGT had a lower RER and less transition to carbohydrate oxidation than the NGT group (P < 0.05). The IGT group also oxidized less carbohydrate during insulin infusion than NGT (P < 0.05). RER at each exercise intensity independently correlated with 120 minute postprandial glucose (r = -0.54 to -0.58, P < 0.05), but not with body composition, VO2max , or RER during insulin infusion. CONCLUSIONS: Obese, older adults have metabolic inflexibility during exercise that is associated with the degree of glucose intolerance independent of age and body composition. PMID- 23983101 TI - 9G4+ autoantibodies are an important source of apoptotic cell reactivity associated with high levels of disease activity in systemic lupus erythematosus. AB - OBJECTIVE: To determine the prevalence of anti-apoptotic cell (anti-AC) antibodies with the 9G4 idiotype (9G4+) and the relationship between this and other known 9G4+ specificities and disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Serum samples from 60 SLE patients and 40 healthy donors were incubated with apoptotic Jurkat cells and assayed by flow cytometry for the binding of 9G4+ antibodies. The samples were also tested for 9G4+ reactivity against naive B cells and total IgG and IgM anti-AC antibody reactivity. RESULTS: The 9G4+ antibodies bound late ACs in sera from a majority of the SLE patients (60%) but in sera from only 2 healthy control subjects. Among samples with global IgM or IgG anti-AC antibodies, those with 9G4+ anti-AC antibodies predominated. Patients with high levels of 9G4+ anti-AC antibodies were more likely to have active disease. This was the case even in patients with IgG anti-AC antibodies or anti-double-stranded DNA antibodies. Patients with lupus nephritis were also more likely to have 9G4+ anti-AC antibodies. While 9G4+ reactivity to ACs often coincided with anti-B cell reactivity, some samples had distinct anti-AC or anti-B cell reactivity. CONCLUSION: The 9G4+ antibody represents a major species of anti-AC antibody in SLE serum, and this autoreactivity is associated with disease activity. The anti-AC reactivity of 9G4+ antibodies can be separated from the germline VH4-34-encoded anti-B cell autoreactivity. Our results indicate that ACs are an important antigenic source in SLE that positively selects B cells with intrinsic autoreactivity against other self antigens. This selection of 9G4+ B cells by ACs may represent an important step in disease progression. PMID- 23983102 TI - Decarboxylative palladium(II)-catalyzed synthesis of aryl amidines from aryl carboxylic acids: development and mechanistic investigation. AB - A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)-catalysis in a one-step microwave protocol using [Pd(O2 CCF3 )2 ], 6-methyl-2,2'-bipyridyl and trifluoroacetic acid (TFA) in N-methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron-rich ortho-substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI-MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI-MS study, support the suggested mechanism. Furthermore, a scale-out (scale up) was performed with a non-resonant microwave continuous-flow system, achieving a maximum throughput of 11 mmol h(-1) by using a glass reactor with an inner diameter of 3 mm at a flow rate of 1 mL min(-1) . PMID- 23983103 TI - CIP2A modulates cell-cycle progression in human cancer cells by regulating the stability and activity of Plk1. AB - Abnormal cell-cycle control can lead to aberrant cell proliferation and cancer. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) is an inhibitor of protein phosphatase 2A (PP2A) that stabilizes c-Myc. However, the precise role of CIP2A in cell division is not understood. Herein, we show that CIP2A is required for mitotic progression by regulating the polo-like kinase (Plk1). With mitotic entry, CIP2A translocated from the cytoplasm to the nucleus, where it was enriched at spindle poles. CIP2A depletion delayed mitotic progression, resulting in mitotic abnormalities independent of PP2A activity. Unexpectedly, CIP2A interacted directly with the polo-box domain of Plk1 during mitosis. This interaction was required to maintain Plk1 stability by blocking APC/C-Cdh1-dependent proteolysis, thereby enhancing the kinase activity of Plk1 during mitosis. We observed strong correlation and in vivo interactions between these two proteins in multiple human cancer specimens. Overall, our results established a novel function for CIP2A in facilitating the stability and activity of the pivotal mitotic kinase Plk1 in cell-cycle progression and tumor development. PMID- 23983106 TI - Exploring chemical diversity of alpha-pyrone antibiotics: molecular basis of myxopyronin biosynthesis. AB - Myxopyronins and corallopyronins are structurally related alpha-pyrone antibiotics from myxobacteria. They are thought to represent a highly promising compound class for the development of broad-spectrum antibacterial therapeutic agents, because of their ability to inhibit RNA polymerase through interaction with the "switch region", a recently identified novel drug target. Here we describe the identification and characterization of the myxopyronin biosynthetic pathway from Myxococcus fulvus Mx f50. A detailed comparison with the recently identified corallopyronin biosynthetic pathway revealed the genetic and biochemical basis, thus explaining the observed structural differences between the two natural product families. Directed mutagenesis procedures for M. fulvus Mx f50 were developed to enable functional studies and pathway modifications. Our work provided new insights into myxopyronin biosynthesis and led to the production of a novel and unexpected myxopyronin derivative. PMID- 23983105 TI - Complementary and alternative medicine use in African Americans with rheumatoid arthritis. AB - OBJECTIVE: Racial/ethnic differences with regard to complementary and alternative medicine (CAM) use have been reported in the US. However, specific details of CAM use by African Americans with rheumatoid arthritis (RA) are lacking. METHODS: Data were collected from African Americans with RA enrolled in a multicenter registry regarding the use of CAM, including food supplements, topical applications, activities, and alternative care providers. Factors associated with CAM use by sex and disease duration were assessed using t-test, Wilcoxon's rank sum test, chi-square test, and logistic regression analyses. RESULTS: Of the 855 participants, 85% were women and mean age at enrollment was 54 years. Overall, ever using any of the CAM treatments, activities, and providers was 95%, 98%, and 51%, respectively (median of 3 for number of treatments, median of 5 for activities, and median of 1 for providers). Those with longer disease duration (>2 years) were significantly more likely (odds ratio >=2.0, P < 0.05) to use raisins soaked in vodka/gin, to take fish oils, or to drink alcoholic beverages for RA treatment than those with early disease. As compared to men, women were significantly (P < 0.05) more likely to pray/attend church, write in a journal, and use biofeedback, but were less likely to smoke tobacco or topically apply household oils for treatment of RA. CONCLUSION: CAM use was highly prevalent in this cohort, even in individuals with early disease. Health care providers need to be aware of CAM use as some treatments may potentially have interactions with conventional medicines. This could be important within this cohort of African Americans, where racial disparities are known to affect access to conventional care. PMID- 23983107 TI - Abstracts of the Society for Clinical Trials Annual Meeting. Boston, Massachusetts, USA. May 19-22, 2013. PMID- 23983104 TI - Organization of sensory input to the nociceptive-specific cutaneous trunk muscle reflex in rat, an effective experimental system for examining nociception and plasticity. AB - Detailed characterization of neural circuitries furthers our understanding of how nervous systems perform specific functions and allows the use of those systems to test hypotheses. We have characterized the sensory input to the cutaneous trunk muscle (CTM; also cutaneus trunci [rat] or cutaneus maximus [mouse]) reflex (CTMR), which manifests as a puckering of the dorsal thoracolumbar skin and is selectively driven by noxious stimuli. CTM electromyography and neurogram recordings in naive rats revealed that CTMR responses were elicited by natural stimuli and electrical stimulation of all segments from C4 to L6, a much greater extent of segmental drive to the CTMR than previously described. Stimulation of some subcutaneous paraspinal tissue can also elicit this reflex. Using a selective neurotoxin, we also demonstrate differential drive of the CTMR by trkA expressing and nonexpressing small-diameter afferents. These observations highlight aspects of the organization of the CTMR system that make it attractive for studies of nociception and anesthesiology and plasticity of primary afferents, motoneurons, and the propriospinal system. We use the CTMR system to demonstrate qualitatively and quantitatively that experimental pharmacological treatments can be compared with controls applied either to the contralateral side or to another segment, with the remaining segments providing controls for systemic or other treatment effects. These data indicate the potential for using the CTMR system as both an invasive and a noninvasive quantitative assessment tool providing improved statistical power and reduced animal use. PMID- 23983108 TI - Layer thinning and etching of mechanically exfoliated MoS2 nanosheets by thermal annealing in air. AB - A simple thermal annealing method for layer thinning and etching of mechanically exfoliated MoS2 nanosheets in air is reported. Using this method, single-layer (1L) MoS2 nanosheets are achieved after the thinning of MoS2 nanosheets from double-layer (2L) to quadri-layer (4L) at 330 degrees C. The as-prepared 1L MoS2 nanosheet shows comparable optical and electrical properties with the mechanically exfoliated, pristine one. In addition, for the first time, the MoS2 mesh with high-density of triangular pits is also fabricated at 330 degrees C, which might arise from the anisotropic etching of the active MoS2 edge sites. As a result of thermal annealing in air, the thinning of MoS2 nanosheet is possible due to its oxidation to form MoO3 . Importantly, the MoO3 fragments on the top of thinned MoS2 layer induces the hole injection, resulting in the p-type channel in fabricated field-effect transistors. PMID- 23983109 TI - Impact of delayed implant and DIEP flap breast reconstruction on body image and sexual satisfaction: a prospective follow-up study. AB - OBJECTIVE: Prospective studies regarding the psychosexual impact after different types of breast reconstruction (BR) are scarce. The impact of either implant or deep inferior epigastric artery perforator (DIEP) flap BR on body image and sexual relationship satisfaction was investigated in time. METHODS: At baseline, 98 women opting for delayed implant or DIEP flap BR after mastectomy for breast cancer completed a survey. The majority was followed up at 6 months (96%) and 20 months (86%) postoperatively. Questionnaires included the body image scale, Dutch Relationship Questionnaire, Short Form - 36 Health Survey and the Impact of Event Scale. RESULTS: Mixed modeling analyses indicated that preoperative body image improved significantly after 20 months (p < 0.001), and there was no statistically significant difference between the two types of BR. A better body image was related to a better general mental health (p = 0.02), less cancer distress (p < 0.001) and a higher partner relationship satisfaction (p < 0.001). Sexual relationship satisfaction also increased after 20 months (p = 0.01), and it was positively related to higher partner relationship satisfaction but negatively affected by hormonal therapy. CONCLUSIONS: Body image and sexual relationship satisfaction significantly improved after BR, and this was not related to the BR type. Psychosexual consequences from previous cancer treatment may interfere. Lower general mental health, higher cancer distress, less partner relationship satisfaction or receiving hormonal therapy can negatively affect body image or sexual relationship satisfaction. PMID- 23983110 TI - Increased lipid oxidation during exercise in obese pubertal girls: a QUALITY study. AB - OBJECTIVE: This study explores differences in LO rates between pre-pubertal and pubertal girls of three body weight status groups. METHODS: The sample included 39 pre-pubertal girls [12 normal-weight (NW), 12 overweight (OW), and 15 obese (OB)] and 37 pubertal girls [16 NW, 10 OW, and 11 OB]. Following a rest period, the girls performed a graded maximal cycling test. The %LO contribution was computed at each stage. RESULTS: The %LO contribution did not differ between NW, OW, or OB pre-pubertal girls at each exercise stage. In contrast, pubertal OB girls showed a statistically significantly higher %LO contribution at 25, 50, and 75 W stages compared with OW and NW as well as with OB pre-pubertal girls. CONCLUSIONS: Our results demonstrate that entering puberty is a period associated with differentiation in substrate selection in obese girls. A higher %LO contribution may help girls to solicit more fat while performing submaximal exercise. PMID- 23983111 TI - In defence of logarithmic transformations. PMID- 23983112 TI - Comments on 'Log transformation: application and interpretation in biomedical research'. PMID- 23983113 TI - Log transformation in biomedical research: (mis)use for covariates. PMID- 23983114 TI - Response to comments on 'Log transformation: application and interpretation in biomedical research'. PMID- 23983115 TI - Antileishmanial activity of the essential oil from Bixa orellana. AB - Leishmaniasis is a neglected tropical disease caused by Leishmania protozoa. There is currently no vaccine against leishmaniasis, and chemotherapy remains the only effective control. However, conventional drugs are toxic, expensive, and require long periods of treatment, and resistance to clinical chemotherapeutic agents is emerging. Recent research on plants has shown a successful approach to obtain new antileishmanial alternatives. Herein, the in vitro and in vivo effects of the essential oil from Bixa orellana seeds against Leishmania amazonensis were evaluated. A total of 73 compounds were detected by gas chromatography-mass spectrometry analysis, of which ishwarane (18.6%) and geranylgeraniol (9.1%) were the major components. The oil showed activity against intracellular amastigote form (IC50 = 8.5 ug/mL), while the cytotoxic concentration was sevenfold higher for the host cells. The ability of Bixa oil to control disease progression of established cutaneous leishmaniasis in BALB/c mice was demonstrated, after a treatment with 30 mg/kg by intraperitoneal administration over 14 days. The present study reports for the first time the antileishmanial potentialities of the essential oil from B. orellana. PMID- 23983116 TI - Improving sediment-quality guidelines for nickel: development and application of predictive bioavailability models to assess chronic toxicity of nickel in freshwater sediments. AB - Within the framework of European Union chemical legislations an extensive data set on the chronic toxicity of sediment nickel has been generated. In the initial phase of testing, tests were conducted with 8 taxa of benthic invertebrates in 2 nickel-spiked sediments, including 1 reasonable worst-case sediment with low concentrations of acid-volatile sulfide (AVS) and total organic carbon. The following species were tested: amphipods (Hyalella azteca, Gammarus pseudolimnaeus), mayflies (Hexagenia sp.), oligochaetes (Tubifex tubifex, Lumbriculus variegatus), mussels (Lampsilis siliquoidea), and midges (Chironomus dilutus, Chironomus riparius). In the second phase, tests were conducted with the most sensitive species in 6 additional spiked sediments, thus generating chronic toxicity data for a total of 8 nickel-spiked sediments. A species sensitivity distribution was elaborated based on 10% effective concentrations yielding a threshold value of 94 mg Ni/kg dry weight under reasonable worst-case conditions. Data from all sediments were used to model predictive bioavailability relationships between chronic toxicity thresholds (20% effective concentrations) and AVS and Fe, and these models were used to derive site-specific sediment quality criteria. Normalization of toxicity values reduced the intersediment variability in toxicity values significantly for the amphipod species Hyalella azteca and G. pseudolimnaeus, but these relationships were less clearly defined for the mayfly Hexagenia sp. Application of the models to prevailing local conditions resulted in threshold values ranging from 126 mg to 281 mg Ni/kg dry weight, based on the AVS model, and 143 mg to 265 mg Ni/kg dry weight, based on the Fe model. PMID- 23983117 TI - Effect of ensiling treatment on secondary compounds and amino acid profile of tropical forage legumes, and implications for their pig feeding potential. AB - BACKGROUND: Smallholders in the tropics depend on local protein supplements to balance pig diets. Thus, various tropical forage legumes are a potential feeding option. Ensiling allows converting forages into a ready-to-feed-out choice, but the lactic acid fermentation may influence various (anti)nutritional components. The purpose of this study was to evaluate the effects of sucrose (SU) and a tropical Lactobacillus plantarum strain (LAB) as ensiling treatments (control, SU, LAB, LAB + SU) on the potential nutrient availability of 10 forage legume species. RESULTS: Ensiling commonly reduced antinutritional compounds such as tannins (by 49-84%) and trypsin inhibitory activity (by 74-78%), as well as oxalic acid (by 51-100%). An improved potential absorbability of protein and minerals for pigs is thus inferred. There was no major loss in total amino acids. In general, the species effect was stronger than the treatment effect. A clear effect of the treatments SU, LAB and LAB + SU over all 10 forage species was only observed for oxalic acid, single amino acids and trypsin inhibitory activity. CONCLUSION: Ensiling is a viable option to enhance nutrient utilization of tropical forages for pigs. Species-specific treatment of forage legumes is recommended. PMID- 23983118 TI - Progressing toward, and recovering from, knee replacement surgery: a five-year cohort study. AB - OBJECTIVE: To determine the trajectories of preoperative worsening and postoperative recovery for both the index knee and the contralateral knee of patients undergoing knee replacement surgery. METHODS: Of the 4,796 subjects in the Osteoarthritis Initiative cohort study database, we examined 5-year data from 177 patients who underwent isolated unilateral knee replacement surgery and no other joint replacement surgery. Patient-reported outcomes captured domains defined by the International Classification of Functioning, Disability, and Health. Domains of knee structure and function, activity limitation, and participation restriction were examined using growth-curve modeling over 5-year periods prior to and following surgery. RESULTS: Preoperative worsening of the index knee was substantial in all domains of knee impairment, activity limitation, and societal participation. Pain intensity worsened only slightly from 5 years to 2.5 years prior to surgery, but worsened by ~2 points (0-10-point scale) during the 2.5 years prior to surgery. Trajectories of improvement following surgery varied depending on the outcome measure. The contralateral knee also changed over time, such that by ~2 years following surgery, pain was worse and by 3 years, activity limitation was worse in the contralateral knee as compared to the index knee. CONCLUSION: Patients who elect to undergo knee replacement surgery demonstrate perioperative trajectories of change that influence most health domains for both the index knee and the contralateral knee. After a period of no change, escalation of pain and worsening functioning in the index knee begins ~2.5 years prior to surgery, which may be a key trigger for surgery. PMID- 23983119 TI - Epidemiology of primary Sjogren's syndrome in a French multiracial/multiethnic area. AB - OBJECTIVE: To describe the epidemiology of primary Sjogren's syndrome (SS) in a multiracial/multiethnic population. METHODS: A cross-sectional study with 5 case retrieval sources identified adults with primary SS living in the Greater Paris area (population 1,172,482 adults) in 2007. Diagnoses were verified by the American-European Consensus Group (AECG) criteria and study-specific enlarged criteria based on the presence of >=3 of 4 AECG items among subjective oral or ocular dryness, anti-SSA/SSB positivity, and positive minor salivary gland biopsy results. Prevalence estimates were standardized to those for the world population and a 5-source capture-recapture analysis (CRA) was used. Racial/ethnic differences in primary SS features were evaluated. RESULTS: In all, 133 subjects met the AECG criteria and 203 met the enlarged criteria. The 2007 prevalence of primary SS was 1.02 cases per 10,000 adults (95% confidence interval [95% CI] 0.85-1.22) for the AECG criteria and 1.52 cases per 10,000 adults (95% CI 1.30 1.76) for the enlarged criteria. The CRA indicated completeness of case findings of ~90%. Compared to subjects with European backgrounds, those with non-European backgrounds had 2.1-2.3 times higher primary SS prevalence and were younger (P < 0.0001) and were more likely to have polyclonal hypergammaglobulinemia (P < 0.0001) and anti-SSA/SSB antibodies (P = 0.0005 and P < 0.0001 for the AECG and enlarged criteria, respectively). CONCLUSION: The figure of 1.02-1.52 cases per 10,000 adults we found and estimates from the few other population-based census surveys support that the prevalence of diagnosed primary SS is between 1 and 9 cases per 10,000 (0.01-0.09%) [corrected] in the general population. Non-European race/ethnicity may be associated with increased primary SS risk and a distinct disease profile. PMID- 23983120 TI - Transient exposure of pulmonary surfactant to hyaluronan promotes structural and compositional transformations into a highly active state. AB - Pulmonary surfactant is a lipid-protein complex that lowers surface tension at the respiratory air-liquid interface, stabilizing the lungs against physical forces tending to collapse alveoli. Dysfunction of surfactant is associated with respiratory pathologies such as acute respiratory distress syndrome or meconium aspiration syndrome where naturally occurring surfactant-inhibitory agents such as serum, meconium, or cholesterol reach the lung. We analyzed the effect of hyaluronan (HA) on the structure and surface behavior of pulmonary surfactant to understand the mechanism for HA-promoted surfactant protection in the presence of inhibitory agents. In particular, we found that HA affects structural properties such as the aggregation state of surfactant membranes and the size, distribution, and order/packing of phase-segregated lipid domains. These effects do not require a direct interaction between surfactant complexes and HA and are accompanied by a compositional reorganization of large surfactant complexes that become enriched with saturated phospholipid species. HA-exposed surfactant reaches very high efficiency in terms of rapid and spontaneous adsorption of surfactant phospholipids at the air-liquid interface and shows significantly improved resistance to inactivation by serum or cholesterol. We propose that physical effects pertaining to the formation of a meshwork of interpenetrating HA polymer chains are responsible for the changes in surfactant structure and composition that enhance surfactant function and, thus, resistance to inactivation. The higher resistance of HA-exposed surfactant to inactivation persists even after removal of the polymer, suggesting that transient exposure of surfactant to polymers like HA could be a promising strategy for the production of more efficient therapeutic surfactant preparations. PMID- 23983121 TI - Common gating of both CLC transporter subunits underlies voltage-dependent activation of the 2Cl-/1H+ exchanger ClC-7/Ostm1. AB - CLC anion transporters form dimers that function either as Cl(-) channels or as electrogenic Cl(-)/H(+) exchangers. CLC channels display two different types of "gates," "protopore" gates that open and close the two pores of a CLC dimer independently of each other and common gates that act on both pores simultaneously. ClC-7/Ostm1 is a lysosomal 2Cl(-)/1H(+) exchanger that is slowly activated by depolarization. This gating process is drastically accelerated by many CLCN7 mutations underlying human osteopetrosis. Making use of some of these mutants, we now investigate whether slow voltage activation of plasma membrane targeted ClC-7/Ostm1 involves protopore or common gates. Voltage activation of wild-type ClC-7 subunits was accelerated by co-expressing an excess of ClC-7 subunits carrying an accelerating mutation together with a point mutation rendering these subunits transport-deficient. Conversely, voltage activation of a fast ClC-7 mutant could be slowed by co-expressing an excess of a transport deficient mutant. These effects did not depend on whether the accelerating mutation localized to the transmembrane part or to cytoplasmic cystathionine-beta synthase (CBS) domains of ClC-7. Combining accelerating mutations in the same subunit did not speed up gating further. No currents were observed when ClC-7 was truncated after the last intramembrane helix. Currents and slow gating were restored when the C terminus was co-expressed by itself or fused to the C terminus of the beta-subunit Ostm1. We conclude that common gating underlies the slow voltage activation of ClC-7. It depends on the CBS domain-containing C terminus that does not require covalent binding to the membrane domain of ClC-7. PMID- 23983122 TI - Remodeling of membrane lipids in iron-starved Chlamydomonas. AB - Chlamydomonas reinhardtii cells exposed to abiotic stresses (e.g. nitrogen, zinc, or phosphorus deficiency) accumulate triacylglycerols (TAG), which are stored in lipid droplets. Here, we report that iron starvation leads to formation of lipid droplets and accumulation of TAGs. This occurs between 12 and 24 h after the switch to iron-starvation medium. C. reinhardtii cells deprived of iron have more saturated fatty acid (FA), possibly due to the loss of function of FA desaturases, which are iron-requiring enzymes with diiron centers. The abundance of a plastid acyl-ACP desaturase (FAB2) is decreased to the same degree as ferredoxin. Ferredoxin is a substrate of the desaturases and has been previously shown to be a major target of the iron deficiency response. The increase in saturated FA (C16:0 and C18:0) is concomitant with the decrease in unsaturated FA (C16:4, C18:3, or C18:4). This change was gradual for diacylglyceryl-N,N,N trimethylhomoserine (DGTS) and digalactosyldiacylglycerol (DGDG), whereas the monogalactosyldiacylglycerol (MGDG) FA profile remained stable during the first 12 h, whereas MGDG levels were decreasing over the same period of time. These changes were detectable after only 2 h of iron starvation. On the other hand, DGTS and DGDG contents gradually decreased until a minimum was reached after 24 48 h. RNA-Seq analysis of iron-starved C. reinhardtii cells revealed notable changes in many transcripts coding for enzymes involved in FA metabolism. The mRNA abundances of genes coding for components involved in TAG accumulation (diacylglycerol acyltransferases or major lipid droplet protein) were increased. A more dramatic increase at the transcript level has been observed for many lipases, suggesting that major remodeling of lipid membranes occurs during iron starvation in C. reinhardtii. PMID- 23983124 TI - A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition. AB - A nonsense mutation in cereblon (CRBN) causes autosomal recessive nonsyndromic mental retardation. Cereblon is a substrate receptor for the Cullin-RING E3 ligase complex and couples the ubiquitin ligase to specific ubiquitination targets. The CRBN nonsense mutation (R419X) results in a protein lacking 24 amino acids at its C terminus. Although this mutation has been linked to mild mental retardation, the mechanism by which the mutation affects CRBN function is unknown. Here, we used biochemical and mass spectrometric approaches to explore the function of this mutant. We show that the protein retains its ability to assemble into a Cullin-RING E3 ligase complex and catalyzes the ubiquitination of CRBN-target proteins. However, we find that this mutant exhibits markedly increased levels of autoubiquitination and is more readily degraded by the proteasome than the wild type protein. We also show that the level of the mutant protein can be restored by a treatment of cells with a clinically utilized proteasome inhibitor, suggesting that this agent may be useful for the treatment of mental retardation associated with the CRBN R419X mutation. These data demonstrate that enhanced autoubiquitination and degradation account for the defect in CRBN activity that leads to mental retardation. PMID- 23983123 TI - Truncated hemoglobin, HbN, is post-translationally modified in Mycobacterium tuberculosis and modulates host-pathogen interactions during intracellular infection. AB - Mycobacterium tuberculosis (Mtb) is a phenomenally successful human pathogen having evolved mechanisms that allow it to survive within the hazardous environment of macrophages and establish long term, persistent infection in the host against the control of cell-mediated immunity. One such mechanism is mediated by the truncated hemoglobin, HbN, of Mtb that displays a potent O2 dependent nitric oxide dioxygenase activity and protects its host from the toxicity of macrophage-generated nitric oxide (NO). Here we demonstrate for the first time that HbN is post-translationally modified by glycosylation in Mtb and remains localized on the cell membrane and the cell wall. The glycan linkage in the HbN was identified as mannose. The elevated expression of HbN in Mtb and M. smegmatis facilitated their entry within the macrophages as compared with isogenic control cells, and mutation in the glycan linkage of HbN disrupted this effect. Additionally, HbN-expressing cells exhibited higher survival within the THP-1 and mouse peritoneal macrophages, simultaneously increasing the intracellular level of proinflammatory cytokines IL-6 and TNF-alpha and suppressing the expression of co-stimulatory surface markers CD80 and CD86. These results, thus, suggest the involvement of HbN in modulating the host-pathogen interactions and immune system of the host apart from protecting the bacilli from nitrosative stress inside the activated macrophages, consequently driving cells toward increased infectivity and intracellular survival. PMID- 23983125 TI - Direct cytosolic delivery of polar cargo to cells by spontaneous membrane translocating peptides. AB - Direct cellular entry of potentially useful polar compounds into cells is prevented by the hydrophobic barrier of the membrane. Toward circumventing this barrier, we used high throughput screening to identify a family of peptides that carry membrane-impermeant cargos across synthetic membranes. Here we characterize the plasma membrane translocation of these peptides with polar cargos under a variety of conditions. The spontaneous membrane-translocating peptides (SMTPs) delivered the zwitterionic, membrane-impermeant dye tetramethylrhodamine (TAMRA) into cells even when the conditions were not permissive for endocytosis. They also delivered the larger, anionic membrane-impermeant dye Alexa Fluor 546 but did not deliver a quantum dot nanoparticle. Under all conditions, the SMTP-cargo filled the cytoplasm with a diffuse, non-punctate fluorescence that was partially excluded from the nucleus. D-amino acid peptides behaved identically in vitro, ruling out proteolysis as an important factor in the diffuse cellular distribution. Thus, cytosolic delivery of SMTP-cargo conjugates is dominated by direct membrane translocation. This is in sharp contrast to Arg9-TAMRA, a representative highly cationic, cell-penetrating peptide, which entered cells only when endocytosis was permitted. Arg9-TAMRA triggered large scale endocytosis and did not appreciably escape the endosomal compartments in the 1-h timescales we studied. When injected into mice, SMTP-TAMRA conjugates were found in many tissues even after 2 h. Unconjugated TAMRA was rapidly cleared and did not become systemically distributed. SMTPs are a platform that could improve delivery of many polar compounds to cells, in the laboratory or in the clinic, including those that would otherwise be rejected as drugs because they are membrane impermeant. PMID- 23983126 TI - The natural compound cantharidin induces cancer cell death through inhibition of heat shock protein 70 (HSP70) and Bcl-2-associated athanogene domain 3 (BAG3) expression by blocking heat shock factor 1 (HSF1) binding to promoters. AB - Heat shock factor 1 (HSF1) enhances the survival of cancer cells under various stresses. The knock-out of HSF1 impairs cancer formation and progression, suggesting that HSF1 is a promising therapeutic target. To identify inhibitors of HSF1 activity, we performed cell-based screening with a library of marketed and experimental drugs and identified cantharidin as an HSF1 inhibitor. Cantharidin is a potent antitumor agent from traditional Chinese medicine. Cantharidin inhibited heat shock-induced luciferase activity with an IC50 of 4.2 MUm. In contrast, cantharidin did not inhibit NF-kappaB luciferase reporter activity, demonstrating that cantharidin is not a general transcription inhibitor. When the HCT-116 colorectal cancer cells were exposed to heat shock in the presence of cantharidin, the induction of HSF1 downstream target proteins, such as HSP70 and BAG3 (Bcl-2-associated athanogene domain 3), was suppressed. HSP70 and its co chaperone BAG3 have been reported to protect cells from apoptosis by stabilizing anti-apoptotic Bcl-2 family proteins. As expected, treating HCT-116 cancer cells with cantharidin significantly decreased the amounts of BCL-2, BCL-xL, and MCL-1 protein and induced apoptotic cell death. Chromatin immunoprecipitation analysis showed that cantharidin inhibited the binding of HSF1 to the HSP70 promoter and subsequently blocked HSF1-dependent p-TEFb recruitment. Therefore, the p-TEFb dependent phosphorylation of the C-terminal domain of RNA polymerase II was blocked, arresting transcription at the elongation step. Protein phosphatase 2A inhibition with PP2CA siRNA or okadaic acid did not block HSF1 activity, suggesting that cantharidin inhibits HSF1 in a protein phosphatase 2A-independent manner. We show for the first time that cantharidin inhibits HSF1 transcriptional activity. PMID- 23983127 TI - Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase kinase 3beta-beta catenin-mediated lung cancer metastasis. AB - We demonstrate that loss of succinate dehydrogenase 5 (SDH5) expression initiates epithelial-mesenchymal transition (EMT), which is visualized by the repression of E-cadherin and up-regulation of vimentin in lung cancer cell lines and clinical lung cancer specimens. In SDH5 knock-out mice, lung epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human lung xenograft-mouse model, we observed that knocking down endogenous SDH5 in human carcinoma cells leads to the development of multiple lymph node metastases. Moreover, our data indicate that SDH5 functions as a critical protein in regulating EMT by modulating the glycogen synthase kinase (GSK)-3beta-beta catenin signaling pathway. These results reveal a critical role for SDH5 in EMT and suggest that SDH5 may be a prognostic biomarker and potential therapeutic target for lung cancer metastasis. PMID- 23983128 TI - Selection of a nucleopolyhedrovirus isolate from Helicoverpa armigera as the basis for a biological insecticide. AB - BACKGROUND: The cotton bollworm, Helicoverpa armigera, is an insect that causes damage in a wide range of crops in Spain. Seven isolates of H. armigera single nucleopolyhedrovirus (HearSNPV) from the Iberian Peninsula were subjected to molecular and biological characterization and compared with a Chinese genotype (HearSNPV-G4). RESULTS: The estimated sizes of the Iberian genomes varied between 116.2 and 132.4 kb, compared to 131.4 kb of the HearSNPV-G4 reference genome. Phylogenetic analysis based on the lef-8, lef-9 and polh genes revealed that the Iberian strains were more closely related to one another than to other HearSNPV isolates. Occlusion body (OB) concentration-mortality responses (LC50 values) did not differ significantly among Iberian isolates when tested against a Helicoverpa armigera colony from Oxford (UK). Despite being the fastest killing isolate, HearSNPV-SP1 was as productive as isolates with lower virulence, with an average yield of 3.1 * 10(9) OBs larva(-1) . OBs of HearSNPV-SP1 and HearSNPV-G4 were similarly pathogenic against a recently established colony from southern Spain, although HearSNPV-SP1 was faster killing than HearSNPV-G4 against a range of instars. CONCLUSION: The insecticidal properties of HearSNPV-SP1 mean that this strain is likely to prove useful as the basis for a biological insecticide for control of Helicoverpa armigera in Spain. PMID- 23983129 TI - Fluorescence imaging enabled biodegradable photostable polymeric micelles. AB - Amphiphilic biodegradable photoluminescent polymers (ABPLPs) composed of a biodegradable fluorescent polymer and methoxy poly (ethyleneglycol) demonstrate intrinsic bright, tunable, and stable fluorescence emission. ABPLP micelles elicit minor cellular toxicity and can be used for cell and tissue imaging both in vitro and in vivo. PMID- 23983130 TI - Improving children's obesity-related health care quality: process outcomes of a cluster-randomized controlled trial. AB - OBJECTIVE: To examine the extent to which an intervention using electronic decision support delivered to pediatricians at the point-of-care of obese children, with or without direct-to-parent outreach, improved health care quality measures for child obesity. DESIGN AND METHODS: Process outcomes from a three arm, cluster-randomized trial from 14 pediatric practices in Massachusetts were reported. Participants were 549 children aged 6-12 years with body mass index (BMI) >= 95th percentile. In five practices (Intervention-1), pediatricians receive electronic decision support at the point-of-care. In five other practices (Intervention-2), pediatricians receive point-of-care decision support and parents receive information about their child's prior BMI before their scheduled visit. Four practices receive usual care. The main outcomes were Healthcare Effectiveness Data and Information Set (HEDIS) performance measures for child obesity: documentation of BMI percentile and use of counseling codes for nutrition or physical activity. RESULTS: Compared to the usual care condition, participants in Intervention-2, but not Intervention-1, had substantially higher odds of use of HEDIS codes for BMI percentile documentation (adjusted OR: 3.97; 95% CI: 1.92, 8.23) and higher prevalence of use of HEDIS codes for counseling for nutrition or physical activity (adjusted predicted prevalence 20.3% [95% CI 8.5, 41.2] for Intervention -2 vs. 0.0% [0.0, 2.0] for usual care). CONCLUSION: An intervention that included both decision support for clinicians and outreach to parents resulted in improved health care quality measures for child obesity. PMID- 23983131 TI - Predicting changes in posttraumatic growth and subjective well-being among breast cancer survivors: the role of social support and stress. AB - OBJECTIVE: Social support is theoretically expected to be positively associated with posttraumatic growth (PTG) and subjective well-being, and stress is expected to be positively associated with PTG and negatively associated with subjective well-being among breast cancer (BC) survivors. However, empirical evidence is mixed, predominantly cross-sectional, and few studies have examined the unique effects of these predictors on positive changes in psychological experiences post cancer diagnosis and systemic treatment. This study examined both general and BC specific social support and stress as predictors of change in PTG and subjective well-being among BC survivors. METHODS: Women (N = 173, Mage = 55.40, SD = 10.99) who had recently finished treatment completed demographic and treatment measures at baseline (T1); general and cancer-specific social support and stress, PTG and subjective well-being at 3 months (T2); and PTG and subjective well-being again at 6 months (T3). Longitudinal predictors of change in PTG and subjective well-being were examined using hierarchical multiple regression. RESULTS: The BC specific social support (beta = .12) and stress (cancer worry; beta = .10) predicted increasing levels of PTG. Improvements in subjective well-being were predicted by higher levels of general social support (beta = .21) and lower levels of general stress (beta = -.59). CONCLUSIONS: There are distinct predictors of change in PTG and subjective well-being among BC survivors, supporting the distinction between the trauma-specific process of PTG and well being. PMID- 23983132 TI - Young people at risk of psychosis: their subjective experiences of monitoring and cognitive behaviour therapy in the early detection and intervention evaluation 2 trial. AB - OBJECTIVES: To explore participants' experiences of 'enhanced monitoring' and cognitive behaviour therapy (CBT) within a randomized controlled trial evaluating early detection and prevention of psychosis ('early detection and intervention evaluation [EDIE] 2'). DESIGN: Semi-structured qualitative interviews were conducted with a sample of participants at the end of their involvement with the trial. METHODS: Ten young people were interviewed; six males and four females, with a mean age of 27.5. Nine participants identified themselves as White British and one Black British. All participants had received 'enhanced monitoring' during the trial, and 8 of 10 also received CBT. Interviews were transcribed verbatim and analysed using thematic analysis to identify central themes within and among participants' accounts. RESULTS: Three super-ordinate thematic areas were identified: 'a chance to talk', monitoring-specific themes, and CBT-specific themes. The central theme ('a chance to talk') was drawn from across all participants' accounts and represents the most consistently valued attribute of participants' experiences of the EDIE 2 trial. Sub-themes of this topic were identified as follows: interpersonal engagement, informality and normalization, and 'opening up'. Sub-themes related to monitoring include the following: clarity and reassurance, 'a therapeutic process', and challenges. CBT experience was most consistently conceptualized as 'rethinking things', and two additional CBT specific sub-themes were identified: hard work and moving forward. CONCLUSIONS: Our findings suggest that for young people at risk of psychosis, a normalizing psychosocially oriented assessment and monitoring process may have benefits for many, while CBT may help to reduce the negative impact of unusual psychological experiences for both the short- and long term. PRACTITIONER POINTS: Young people considered at risk of psychosis highly value normalizing, collaborative, and flexible approaches when engaging with research or clinical staff. All of our participants highlighted the primary value of their engagement with staff members as having a 'chance to talk' about their experiences and difficulties. CBT seems to be widely acceptable among 'at-risk' participants, though further research is required to establish the 'key ingredients' of effective CBT for 'at-risk' individuals. Valued CBT-related outcomes highlighted by participants included improved psychosocial understanding of their difficulties, improved coping ability, and greater optimism for the future. PMID- 23983133 TI - Antihyperalgesic and antiedematous activities of bisabolol-oxides-rich matricaria oil in a rat model of inflammation. AB - From the dried flower heads of Matricaria recutita L., essential oil was isolated by hydrodistillation, and in the obtained blue oil, alpha-bisabolol oxide A (21.5%), alpha-bisabolol oxide B (25.5%) and (Z)-spiroether (cis-en-yn spiroether) (10.3%) were identified as the main compounds, by gas chromatography (GC) and GC-mass spectrometry analyses. The antihyperalgesic effects of this oil were examined in a rat model of inflammation induced by carrageenan, through a modified 'paw-pressure' test. Antiedematous effects were examined in a rat model of inflammation induced by carrageenan, dextran and histamine, through plethysmometry. Matricaria oil (25, 50 and 100 mg/kg, p.o.) exhibited a significant dose-dependent reduction of hyperalgesia and edema induced by carrageenan in both prophylactic and therapeutic treatment schemes. It was more efficacious in the prophylactic treatment scheme, and the corresponding median effective dose (ED50 ) +/- standard error of the mean (SEM) values were 49.8 +/- 6.0 and 42.4 +/- 0.2 mg/kg for antihyperalgesic and antiedematous effects, respectively. Prophylactic treatments with matricaria oil (25, 50 and 100 mg/kg, p.o.) caused a significant dose-dependent antiedematous effect in dextran-induced edema with lower efficacy than in the carrageenan model. In a dose of 100 mg/kg, p.o., matricaria oil caused a slight reduction of histamine-induced edema. These results suggest that bisabolol-oxide-rich matricaria oil may be effective against pain and edema present in various inflammatory conditions, which supports matricaria traditional uses. PMID- 23983134 TI - Low- versus high-dose rituximab for rheumatoid arthritis: a systematic review and meta-analysis. AB - OBJECTIVE: The approved dose of rituximab (RTX) for rheumatoid arthritis (RA) is 2 * 1,000 mg infusions given 2 weeks apart. There is contradictory evidence regarding the effectiveness of a lower-dose regimen (2 * 500 mg) of RTX. Our aim was to compare the efficacy and safety of low- and high-dose RTX and to test the noninferiority of the low-dose regimen. METHODS: A systematic literature review searching for randomized controlled trials (RCTs) and cohort studies comparing low- and high-dose RTX for RA was conducted using the Embase, PubMed, Cochrane Library, and Web of Science databases. The primary end points were the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70 responses and the Disease Activity Score in 28 joints (DAS28) at 24 and 48 weeks. The secondary end points were patient-reported outcomes (PROs; Health Assessment Questionnaire, Short Form 36, and Functional Assessment of Chronic Illness Therapy-Fatigue scores) and adverse events. Noninferiority of low-dose RTX was tested using different approaches, one of which was based on the fixed margin method. RESULTS: In total, 6 RCTs and 2 cohort studies were identified. Four RCTs were included in the meta-analysis of efficacy outcomes, which showed no significant differences in the primary outcomes between low- and high-dose RTX. Noninferiority criteria of low-dose RTX were met for the ACR20, ACR50, DAS28, and PROs (at 24 and 48 weeks). Serious adverse events did not differ significantly. The results of 2 additional RCTs and a meta-analysis of 2 cohort studies corroborated the results of the meta-analysis of RCTs. CONCLUSION: Low-dose RTX has similar effectiveness and met noninferiority criteria for most primary outcomes. Considering the lower cost, it should be the standard RTX regimen for RA. PMID- 23983135 TI - Dietary heme iron and the risk of colorectal cancer with specific mutations in KRAS and APC. AB - Red meat intake has been linked to increased colorectal cancer (CRC) risk. Although the underlying mechanisms remain unclear, experimental studies suggest a role for dietary heme iron. Because heme iron was shown to promote specific mutations, it would be insightful to link heme iron data to CRC with mutations in key genes in an observational, population-based study. We investigated the association between dietary heme iron intake and risk of CRC with mutations in APC (adenomatous polyposis coli) and KRAS (Kirsten ras) and P53 overexpression in the Netherlands Cohort Study. After 7.3 years of follow-up, excluding the first 2.3 years due to incomplete coverage of the pathology registry and to avoid preclinical disease, adjusted hazard ratios (including adjustment for total meat) and 95% confidence intervals were calculated, using 4026 subcohort members (aged 55-69 years at baseline), 435 colon and 140 rectal cancer patients. When comparing the highest with the lowest tertile of intake, heme iron intake was associated with an increased risk of CRC harboring activating mutations in KRAS (hazard ratio = 1.71, 95% confidence interval: 1.15-2.57; P for trend = 0.03) and CRC without truncating mutations in APC (hazard ratio = 1.79, 95% confidence interval: 1.23-2.60; P for trend = 0.003). We observed a positive association between heme iron intake and the risk of CRC with activating G>A mutations in KRAS (P for trend = 0.01) and overall G>A mutations in APC (P for trend = 0.005). No associations were found with CRC harboring G>T mutations in KRAS/APC. Heme iron intake was positively associated with the risk of P53 overexpressed tumors but not with tumors without P53 overexpression (Pheterogeneity = 0.12). Heme iron intake was associated with an increased risk of colorectal tumors harboring G>A transitions in KRAS and APC and overexpression of P53. These novel findings suggest that alkylating rather than oxidative DNA-damaging mechanisms are involved in heme-induced colorectal carcinogenesis. PMID- 23983137 TI - Novel uroflow stop test at time of catheter removal is a strong predictor of early urinary continence recovery following robotic-assisted radical prostatectomy: a pilot study. AB - AIM: To study whether the ability to completely stop urinary flow during voiding at time of catheter removal, measured objectively using uroflowmetry, can predict early recovery of urine continence following robotic-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: In this pilot study, 108 patients with a minimum of 2 years follow-up, operated by a single surgeon (AEH) were subjected to an uroflowmetry at the time of urethral catheter removal following RARP. Normal Saline (150 ml) was instilled intravesically prior to catheter removal and patients were instructed to attempt to stop urine flow during voiding in uroflowmeter. Two groups were studied, group one with positive Stop Test (n = 80) and group two with negative Stop Test (n = 28). Covariates included age, BMI, IPSS score, PSA, tumor stage, prostate volume, nerve sparing status, and estimated blood loss. RESULTS: Basic characteristics were not statistically different between both groups. Early continence recovery was significantly higher in group one. Pad-free continence rates in group one and two at 1, 3, 6, 12, 18, and 24 months were 62% vs. 7% (P < 0.001), 85% vs. 28% (P < 0.001), 93% vs. 67% (P 0.001), 93% vs. 82% (P 0.079), 97% vs. 82% (P 0.006), and 97% vs. 85% (P 0.023), respectively. Uroflow Stop Test was the only independent predictor of early urine continence recovery on univariate and multivariate regression analysis [OR 2.87 (95%CI 1.34-4.38, P = < 0.001)]. CONCLUSION: Novel use of uroflowmetry at time of urethral catheter removal is a simple, non-invasive study with independent ability to predict early continence recovery following RARP. PMID- 23983138 TI - Identification of an alternative knockdown resistance (kdr)-like mutation, M918L, and a novel mutation, V1010A, in the Thrips tabaci voltage-gated sodium channel gene. AB - BACKGROUND: Knockdown resistance (kdr) has been identified as a main mechanism against pyrethroid insecticides in many arthropod pests including in the onion thrips, Thrips tabaci. To characterize and identify pyrethroid-resistance in onion thrips in Washington state, we conducted insecticide bioassays and sequenced a region of the voltage gated sodium channel gene from several different T. tabaci populations. RESULTS: Field collected Thrips tabaci were found to have large variations in resistance to the pyrethroid insecticide lambda cyhalothrin. We identified two single nucleotide substitutions in our analysis of a partial sequence of the T. tabaci voltage-gated sodium channel gene. One mutation resulted in the non-synonymous substitution of methionine with leucine (M918L), which is well known to be responsible for super knockdown resistance in some pest species. Another non-synonymous substitution, a valine (GTT) to alanine (GCT) replacement at amino acid 1010 (V1010A) was identified in our study and was associated with lambda-cyhalothrin resistance. CONCLUSION: We have characterized a known kdr mutation and identified a novel mutation in the voltage-gated sodium channel gene of Thrips tabaci associated with resistance to lambda-cyhalothrin. This gene region and these mutations are expected to be useful in the development of a diagnostic test to detect kdr resistance in many onion thrips populations. PMID- 23983139 TI - Gastric pre-processing is an important determinant of the ability of medium-chain lipid solution formulations to enhance oral bioavailability in rats. AB - The contribution of dispersion and digestion in the stomach to the bioavailability of poorly water-soluble drugs administered in lipid-based formulations was assessed by comparison of intraduodenal (ID) and peroral (p.o.) administration using cinnarizine (CZ) as a model drug. Differences in the dispersion and digestion in the gastric and intestinal compartments for medium chain triacylglycerides (MCT) and long-chain triacylglycerides (LCT) were observed, leading to differences in the oral bioavailability of CZ. Bypassing gastric processing using ID administration of lipid solution formulations decreased drug bioavailability regardless of lipid type. Overall, bioavailability from LCT formulations was higher than MCT regardless of route of administration, consistent with past data after p.o. administration and previously reported descriptions of increases in drug precipitation after administration of medium chain lipid formulations. The larger differences between bioavailability after both p.o. and ID administration for MCT compared with LCT formulations suggest that passage through the stomach is more critical for MCT formulations, and that gastric digestion may be more critical for MCT than LCT formulations. For MCT based formulations, efficient dispersion and partial digestion in the stomach may be required to allow rapid transfer to intestinal-mixed micelles and absorption in the upper small intestine prior to drug precipitation. PMID- 23983140 TI - Rapid prototyping of concave microwells for the formation of 3D multicellular cancer aggregates for drug screening. AB - Microwell technology has revolutionized many aspects of in vitro cellular studies from 2D traditional cultures to 3D in vivo-like functional assays. However, existing lithography-based approaches are often costly and time-consuming. This study presents a rapid, low-cost prototyping method of CO2 laser ablation of a conventional untreated culture dish to create concave microwells used for generating multicellular aggregates, which can be readily available for general laboratories. Polymethylmethacrylate (PMMA), polydimethylsiloxane (PDMS), and polystyrene (PS) microwells are investigated, and each produces distinctive microwell features. Among these three materials, PS cell culture dishes produce the optimal surface smoothness and roundness. A549 lung cancer cells are grown to form cancer aggregates of controllable size from ~40 to ~80 MUm in PS microwells. Functional assays of spheroids are performed to study migration on 2D substrates and in 3D hydrogel conditions as a step towards recapitulating the dissemination of cancer cells. Preclinical anti-cancer drug screening is investigated and reveals considerable differences between 2D and 3D conditions, indicating the importance of assay type as well as the utility of the present approach. PMID- 23983141 TI - Tumor necrosis factor alpha inhibition in radiographic and nonradiographic axial spondyloarthritis: results from a large observational cohort. AB - OBJECTIVE: To evaluate the baseline characteristics of patients with radiographic axial spondyloarthritis (SpA; ankylosing spondylitis [AS]) and patients with nonradiographic axial SpA, to investigate determinants of anti-tumor necrosis factor (anti-TNF) agent prescription on the background of a nonrestrictive reimbursement policy, and to assess the response to TNF inhibition. METHODS: We compared the characteristics of radiographic axial SpA and nonradiographic axial SpA in 1,070 patients from the Swiss Clinical Quality Management (SCQM) Cohort who fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA. By taking advantage of the situation that patients who are eligible for anti-TNF treatment are preferentially enrolled in the SCQM Cohort for patients with AS/axial SpA, we explored parameters leading to the initiation of anti-TNF treatment in single and multiple regression models and assessed treatment responses. RESULTS: We confirmed a similar burden of disease (as determined by self-reported disease activity, impaired function, and quality of life) in patients with nonradiographic axial SpA (n = 232) and those with radiographic axial SpA (n = 838). Patients with radiographic axial SpA had higher median levels of acute-phase reactants and higher median AS Disease Activity Scores (ASDAS; 3.2 versus 3.0). Anti-TNF treatment was initiated in 363 patients with radiographic axial SpA and 102 patients with nonradiographic axial SpA, preferentially in those with sacroiliitis on magnetic resonance imaging, peripheral arthritis, a higher C-reactive protein (CRP) level, a higher ASDAS, and a higher Bath Ankylosing Spondylitis Disease Activity Index level. The ASAS criteria for 40% improvement responses at 1 year were higher in patients with radiographic axial SpA compared with those with nonradiographic axial SpA (48.1% versus 29.6%; odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.12-4.46, P = 0.02). The difference was smaller in the subgroups of patients with elevated baseline CRP levels (51.6% in patients with radiographic axial SpA versus 38.5% in those with nonradiographic axial SpA; OR 1.7, 95% CI 0.68-4.48, P = 0.29). CONCLUSION: The indications for treatment with anti-TNF agents were comparable for patients with radiographic axial SpA and those with nonradiographic axial SpA. With the exception of patients with elevated CRP levels at baseline, higher rates of response to TNF inhibition were achieved in the group of patients with radiographic axial SpA than in the group with nonradiographic axial SpA. PMID- 23983142 TI - Sensorimotor development in neonatal progesterone receptor knockout mice. AB - Early exposure to steroid hormones can permanently and dramatically alter neural development. This is best understood in the organizational effects of hormones during development of brain regions involved in reproductive behaviors or neuroendocrine function. However, recent evidence strongly suggests that steroid hormones play a vital role in shaping brain regions involved in cognitive behavior such as the cerebral cortex. The most abundantly expressed steroid hormone receptor in the developing rodent cortex is the progesterone receptor (PR). In the rat, PR is initially expressed in the developmentally-critical subplate at E18, and subsequently in laminas V and II/III through the first three postnatal weeks (Quadros et al. [2007] J Comp Neurol 504:42-56; Lopez & Wagner [2009]: J Comp Neurol 512:124-139), coinciding with significant periods of dendritic maturation, the arrival of afferents and synaptogenesis. In the present study, we investigated PR expression in the neonatal mouse somatosensory cortex. Additionally, to investigate the potential role of PR in developing cortex, we examined sensorimotor function in the first two postnatal weeks in PR knockout mice and their wildtype (WT) and heterozygous (HZ) counterparts. While the three genotypes were similar in most regards, PRKO and HZ mice lost the rooting reflex 2-3 days earlier than WT mice. These studies represent the first developmental behavioral assessment of PRKO mice and suggest PR expression may play an important role in the maturation of cortical connectivity and sensorimotor integration. PMID- 23983143 TI - Study on discrimination of white tea and albino tea based on near-infrared spectroscopy and chemometrics. AB - BACKGROUND: White tea and albino tea have their own nutritional characteristics, but from the appearance they are quite similar to each other. It is not easy to distinguish them with existing analytical tools or by visual inspection. The current study proposed a rapid method to discriminate them based on near-infrared (NIR) spectroscopy associated with supervised pattern recognition methods. RESULTS: For this purpose, discriminant partial least-squares (DPLS) and discriminant analysis (DA) were employed to build classification models on the basis of a reduced subset of wavenumbers and different pretreatment methods. A completely independent validation set was also used to test the model performance. The results of the DA model showed that with the SNV Karl Norris derivative spectral pre-treatment samples from the two different origins could be 100% correctly discriminated. Similarly, for the DPLS model, the best classification results were obtained with the multiplicative scattering correction (MSC) + first derivative spectral pre-treatments; the accuracy of identification was 98.48% for the calibration set and 100% for the validation set. CONCLUSION: The overall results demonstrated that NIR spectroscopy with pattern recognition could be successfully applied to discriminate white tea and albino tea quickly and non-destructively without the need for various analytical determinations. PMID- 23983144 TI - Determinants of health-related quality of life in children newly diagnosed with juvenile idiopathic arthritis. AB - OBJECTIVE: To examine the degree to which nonmedical factors explain additional variance in parent proxy report and child self-report of health-related quality of life (HRQOL) among newly diagnosed children with juvenile idiopathic arthritis (JIA) after accounting for medical factors. METHODS: Parents (of children ages 2 16 years; n = 230) and patients (ages >5 years; n = 180) diagnosed within the previous 6 months completed surveys to assess medical (clinical parameters and functional status) and nonmedical (self-efficacy, coping, barriers to adherence, social support, parental distress, and access to care) factors and HRQOL (Pediatric Quality of Life Inventory Generic Core Scales). Physician-rated global assessment of disease activity, active joint count, and select laboratory variables (rheumatoid factor, antinuclear antibodies, and erythrocyte sedimentation rate) were recorded. RESULTS: Nonmedical factors, including self efficacy, coping with pain, barriers to adherence, social support, and parental distress, explained additional variance in HRQOL total, physical functioning, and psychosocial functioning scales (R(2) increases of 6%, 1%, and 13% for parent proxy report and 16%, 7%, and 30% for self-report, respectively). Parental distress was uniquely associated with parent proxy-report HRQOL, while child self efficacy and social support were uniquely associated with self-report HRQOL. CONCLUSION: Nonmedical factors are associated with HRQOL in newly diagnosed patients with JIA after accounting for medical variables, particularly for psychosocial functioning. PMID- 23983145 TI - Functional analysis of a large set of BRCA2 exon 7 variants highlights the predictive value of hexamer scores in detecting alterations of exonic splicing regulatory elements. AB - Exonic variants can alter pre-mRNA splicing either by changing splice sites or by modifying splicing regulatory elements. Often these effects are difficult to predict and are only detected by performing RNA analyses. Here, we analyzed, in a minigene assay, 26 variants identified in the exon 7 of BRCA2, a cancer predisposition gene. Our results revealed eight new exon skipping mutations in this exon: one directly altering the 5' splice site and seven affecting potential regulatory elements. This brings the number of splicing regulatory mutations detected in BRCA2 exon 7 to a total of 11, a remarkably high number considering the total number of variants reported in this exon (n = 36), all tested in our minigene assay. We then exploited this large set of splicing data to test the predictive value of splicing regulator hexamers' scores recently established by Ke et al. (). Comparisons of hexamer-based predictions with our experimental data revealed high sensitivity in detecting variants that increased exon skipping, an important feature for prescreening variants before RNA analysis. In conclusion, hexamer scores represent a promising tool for predicting the biological consequences of exonic variants and may have important applications for the interpretation of variants detected by high-throughput sequencing. PMID- 23983146 TI - Neferine, an alkaloid from lotus seed embryo, inhibits human lung cancer cell growth by MAPK activation and cell cycle arrest. AB - Neferine is the major bisbenzylisoquinoline alkaloid isolated from the seed embryo of a traditional medicinal plant Nelumbo nucifera (Lotus). Epidemiological studies have revealed the therapeutic potential of lotus seed embryo. Although several mechanisms have been proposed, a clear anticancer action mechanism of neferine on lung cancer cells is still not known. Lung cancer is the most common cause of cancer death in the world, and the patients with advanced stage of nonsmall lung cancer require adjunct chemotherapy after surgical resection for the eradication of cancer cells. In this study, the effects of neferine were evaluated and characterized in A549 cells. Neferine induced apoptosis in a dose dependent manner with the hypergeneration of reactive oxygen species, activation of MAPKs, lipid peroxidation, depletion of cellular antioxidant pool, loss of mitochondrial membrane potential, and intracellular calcium accumulation. Furthermore, neferine treatment leads to the inhibition of nuclear factor kappaB and Bcl2, upregulation of Bax and Bad, release of cytochrome C, activation of caspase cascade, and DNA fragmentation. In addition, neferine could induce p53 and its effector protein p21 and downregulation of cell cycle regulatory protein cyclin D1 thereby inducing G1 cell cycle arrest. These results suggest a novel function of neferine as an apoptosis inducer in lung cancer cells. PMID- 23983147 TI - The effect of proximal tibial corrective osteotomy on menisci, tibia and tarsal bones: a finite element model study of tibia vara. AB - BACKGROUND: Proximal tibial open wedge osteotomy (PTO) is a corrective operation used in the surgery of lower extremities and is applied to patients with varus deformities for sufficient correction. The aim of the study was to evaluate whether the PTO can achieve decreased stress-bearing on the tibia and tarsal bones in addition to correcting the mechanical axis of the lower limb in patients with tibia vara. METHODS: Three-dimensional (3D) solid modelling of the lower extremity was carried out using computed tomography (CT) and magnetic resonance (MR)-containing images of all of the bony elements and non-bony structures. PTO was applied to the obtained deformed model in the computer environment and the correction was carried out. RESULTS: Stress distributions in menisci, tibia and tarsal bones were calculated. With respect to loading on the tarsal bones, the maximum equivalent stresses on all bones decreased except for the navicula in the PTO-simulated model in the current study. CONCLUSION: These results clearly indicate that PTO can achieve decreased stresses on the tarsal bones in patients with tibia vara. PMID- 23983148 TI - Outcomes of elderly de novo acute myeloid leukemia treated by a risk-adapted approach based on age, comorbidity, and performance status. AB - Several criteria to define fitness for induction chemotherapy in elderly acute myeloid leukemia (AML) have been proposed; however, no studies have reported outcomes according to the application of a risk-adapted approach. We treated 256 consecutive patients with elderly AML (>=60 years) with a risk-adapted approach based on age, comorbidity score (CS), and performance status (ECOG). Eighty-five low-risk patients (age <= 65 years and ECOG 0-1 with CS < 2), 86 intermediate risk patients (age > 65 years or ECOG = 2 with CS < 2), and 85 high-risk patients (ECOG > 2 or CS >= 2) were treated with induction chemotherapies, including standard intensive regimens, abbreviated-scheduled regimens, and modified low dose cytarabine with oral etoposide (mLDAC), respectively. Overall response rates (ORR; complete response and complete response with incomplete recovery) for these three groups were 71.8%, 60.5%, and 41.2%, respectively, without a significant difference in early death rate (17.6%, 25.6%, 23.5%, P = 0.415). Among three abbreviated-scheduled regimens, a gemtuzumab ozogamicin (GO)-containing regimen (n = 43) showed a similar ORR rate (72.1%) to the intensive regimen. After achieving remission, 142 patients went on postremission treatments, including reduced-intensity allogeneic transplantation (RIC, n = 41), standard consolidation (n = 71), and repeated mLDAC (n = 30) according to donor availability, age, ECOG, and CS. Multivariate analyses revealed that not only RIC, but also repeated mLDAC, resulted in significantly superior survival outcomes to standard consolidation independent of age, ECOG, and CS. Clinical benefits of mLDAC for high-risk patients and abbreviated induction with GO for intermediate-risk patients should be confirmed with further studies. Our results also suggest that RIC should be actively considered in elderly AML as a postremission treatment. PMID- 23983150 TI - Microstructure of calcium stearate matrix pellets: a function of the drying process. AB - Drying is a common pharmaceutical process, whose potential to modify the final drug and/or dosage form properties is often underestimated. In the present study, pellets consisting of the matrix former calcium stearate (CaSt) incorporating the active pharmaceutical ingredient ibuprofen were prepared via wet extrusion and spheronization. Subsequent drying was performed by either desiccation, fluid-bed drying, or lyophilization, and the final pellets were compared with respect to their microstructure. To minimize the effect of solute ibuprofen molecules on the shrinking behavior of the CaSt, low ibuprofen loadings were used, as ibuprofen is soluble in the granulation liquid. Pellet porosity and specific surface area increased during desiccation, fluid-bed drying, and lyophilization. The inlet-air temperature during fluid-bed drying affected the specific surface area, which increased at lower inlet-air temperatures rather than the pellet porosity. The in vitro dissolution profiles were found to be a nonlinear function of the specific surface area. Overall, the microstructure, including porosity, pore size, and specific surface area, of CaSt pellets was a strong function of the drying conditions. PMID- 23983149 TI - Repeat post-op voiding trials: an inconvenient correlate with success. AB - AIMS: This study examined the association between the need for a repeat voiding trial after midurethral sling (MUS) surgery and 1-year success rates. METHODS: We conducted this secondary analysis of the participants in the Urinary Incontinence Treatment Network trial of midurethral sling (TOMUS) study which compared retropubic versus transobturator MUS. A standard voiding trial was attempted on all subjects. The "repeat voiding trial" group included subjects discharged with catheterization. All others were considered "self voiding." Success rates between the groups at 1-year were compared, followed by multivariate analyses controlling for previously reported clinical predictors of success. RESULTS: Most women (76%) were self-voiding, while 24% required a repeat voiding trial. The objective success rate at 1-year was 85.8% in the repeat voiding trial group and 75.3% in the self-voiding group (P = 0.01). Subjective success rate at 1-year was 61.0% in the repeat voiding trial group and 55.1% in the self-voiding group (P = 0.23). Women in the repeat voiding trial group continued to demonstrate greater objective success than the self-voiding group in multivariate analysis that controlled for previous incontinence surgery, pad weight, urethral mobility, urge score, and type of MUS (P = 0.04, OR 1.82, 95% CI 1.03-3.22). CONCLUSIONS: Women who require a repeat voiding trial following MUS surgery have greater objective success at 1-year postoperatively when compared to those who are self-voiding at the time of discharge. These results may help reassure women who require catheterization after MUS surgery that their outcome is not compromised by this immediate transient post-operative result. PMID- 23983151 TI - Underivatized amylose and cellulose as new stationary phases for hydrophilic interaction chromatography. AB - Two polysaccharide stationary phases have been newly suggested for application in hydrophilic interaction chromatography (HILIC). Both columns (amylose-silica, 250 * 4.6 mm, 5 MUm and cellulose-silica, 250 * 4.6 mm, 5 MUm) demonstrated a satisfactory retention of polar compounds. The influence of the mobile-phase composition (acetonitrile content, pH, salt concentration) on the retention was in agreement with the HILIC concept. The phases showed a very similar behavior, typical efficiency of about 50,000 plates/m, cellulose retained test compounds somewhat more strongly. Under the experimental conditions, electrostatic (non HILIC-type) interactions due to the dissociation of silanol groups on the silica surface did not influence the retention, noticeably. The applicability of polysaccharide stationary phases for the chromatography of polar compounds was proven by the separation of mixtures of sugars (fructose, glucose, saccharose, maltose, trehalose) or vitamins (nicotinamide, pyridoxine, riboflavin, thiamine, nicotinic acid, ascorbic acid). PMID- 23983152 TI - Self-assembled vehicle construction via boronic acid coupling and host-guest interaction for serum-tolerant DNA transport and pH-responsive drug delivery. AB - By exploiting boronic acid coupling and host-guest chemistry, a pH-responsive drug/gene co-delivery nanoplatform is designed for cancer treatments with the excellently serum-tolerant transfection activity and the capability to load and release hydrophobic drugs in an acidity-accelerated manner. Via boronate linkage, gamma-CD is allowed to spontaneously attach onto phenylboronic-acid-modified oligoethylenimine (PEI1.8K-PB2.9 ) at neutral condition. The formed vehicle/DNA nanoformulation is thus surrounded densely by gamma-CD moieties to biomimic the carbohydrate-rich cell surface, providing a novel approach to overcome serum susceptible drawbacks frequently associated with synthetic gene carriers. PEI1.8K PB2.9 -gamma-CD conjugates demonstrate significantly improved cell biocompatibility and transfection activity over PEI1.8K-PB2.9 . Noticeably, serum associated inhibition effect is negligible for PEI1.8K-PB2.9 -gamma-CD-mediated transfection whereas marked transfection reduction occurs for PEI25K and PEI1.8K PB2.9 upon serum exposure. Consequently, PEI1.8K-PB2.9 -gamma-CDs afford much higher transfection efficiency, that is, 25-fold higher luciferase expression over PEI25K in presence of 30% serum. An anticancer drug of doxorubicin (DOX) is shown to be readily accommodated into the nanoformulation via host-guest chemistry and intracellularly co-delivered together with plasmid DNA. Due to the acidity-labile feature of boronate linkage, DOX/gamma-CD inclusion complexes would be mostly detached from the nanoformulation triggered by acidity, leading to faster drug release. Furthermore, drug inclusion does not alter the serum compatible transfection efficiency of PEI1.8K-PB2.9 -gamma-CD. PMID- 23983153 TI - Association of genetic variants in the IL4 and IL4R genes with the severity of joint damage in rheumatoid arthritis: a study in seven cohorts. AB - OBJECTIVE: The progression of joint destruction in rheumatoid arthritis (RA) is determined by genetic factors. Changes in IL4 and IL4R genes have been associated with RA severity, but this finding has not been replicated. This study was undertaken to investigate the association between IL4- and IL4R-tagging single nucleotide polymorphisms (SNPs) and the progression rate of joint damage in RA in a multicohort candidate gene study. METHODS: IL4- and IL4R-tagging SNPs (n = 8 and 39, respectively) were genotyped in 600 RA patients for whom 2,846 sets of radiographs of the hands and feet were obtained during 7 years of followup. Subsequently, SNPs significantly associated with the progression of joint damage were genotyped and studied in relation to 3,415 radiographs of 1,953 RA patients; these included data sets from Groningen (The Netherlands), Lund (Sweden), Sheffield (UK), the North American Rheumatoid Arthritis Consortium (US), Wichita (US), and the National Data Bank (US). The relative increase in progression rate per year in the presence of a genotype was determined in each cohort. An inverse variance weighting meta-analysis was performed on the 6 data sets that together formed the replication phase. RESULTS: In the discovery phase, none of the IL4 SNPs and 7 of the IL4R SNPs were significantly associated with the joint damage progression rate. In the replication phase, 2 SNPs in the IL4R gene were significantly associated with the joint damage progression rate (rs1805011 [P = 0.02] and rs1119132 [P = 0.001]). CONCLUSION: Genetic variants in IL4R were identified, and their association with the progression rate of joint damage in RA was independently replicated. PMID- 23983154 TI - Triploid and diploid Atlantic salmon show similar susceptibility to infection with salmon lice Lepeophtheirus salmonis. AB - BACKGROUND: Sea lice infection is the most expensive disease factor for Atlantic salmon sea-cage farming. For triploid salmon to be accepted as a commercial possibility, investigation of susceptibility of triploid salmon to sea lice infection is a fundamental milestone. The susceptibility of diploid and triploid salmon to infection with Lepeophtheirus salmonis was examined in a tank trial in Scotland, a tank trial in Norway and a cage trial in Scotland. RESULTS: Following a single infection challenge, results indicated a significant correlation between fish size and the number of attached sea lice. Triploid fish were larger than diploids at the smolt stage. In the tank trials, no difference was found between infection levels on diploids and triploids after a single infection challenge. The tank trial in Scotland continued with a second infection challenge of the same fish, which also showed no infection differences between ploidies. A borderline correlation between first infection and re-infection intensity was found for PIT-tagged diploid salmon examined after each challenge. No significant difference in louse infection between diploid and triploid salmon (~2 kg) was found in the cage trial undertaken under commercial conditions. CONCLUSION: This study concludes that triploid Atlantic salmon are not more susceptible to sea louse infection than diploid fish. PMID- 23983155 TI - Filipino gout: a review. PMID- 23983156 TI - Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase II oncology clinical trials. AB - BACKGROUND: In oncology, the treatment paradigm is shifting toward personalized medicine, where the goal is to match patients to the treatments most likely to deliver benefit. Treatment effects in various subpopulations may provide some information about treatment effects in other subpopulations. PURPOSE: We compare different approaches to Phase II trial design where a new treatment is being investigated in several groups of patients. We compare considering each group in an independent trial to a single trial with hierarchical modeling of the patient groups. METHODS: We assume four patient groups with different background response rates and simulate operating characteristics of three trial designs, Simon's Optimal Two-Stage design, a Bayesian adaptive design with frequent interim analyses, and a Bayesian adaptive design with frequent interim analyses and hierarchical modeling across patient groups. RESULTS: Simon's designs are based on 10% Type I and Type II error rates. The independent Bayesian designs are tuned to have similar error rates, but may have a slightly smaller mean sample size due to more frequent interim analyses. Under the null, the mean sample size is 2-4 patients smaller. A hierarchical model across patient groups can provide additional power and a further reduction in mean sample size. Under the null, the addition of the hierarchical model decreases the mean sample size an additional 4 7 patients in each group. Under the alternative hypothesis, power is increased to at least 98% in all groups. LIMITATIONS: Hierarchical borrowing can make finding a single group in which the treatment is promising, if there is only one, more difficult. In a scenario where the treatment is uninteresting in all but one group, power for that one group is reduced to 65%. When the drug appears promising in some groups and not in others, there is potential for borrowing to inflate the Type I error rate. CONCLUSIONS: The Bayesian hierarchical design is more likely to correctly conclude efficacy or futility than the other two designs in many scenarios. The Bayesian hierarchical design is a strong design for addressing possibly differential effects in different groups. PMID- 23983158 TI - Statistical issues in the validation of prognostic, predictive, and surrogate biomarkers. AB - BACKGROUND: Biomarkers have many distinct purposes, and depending on their intended use, the validation process varies substantially. PURPOSE: The goal of this article is to provide an introduction to the topic of biomarkers, and then to discuss three specific types of biomarkers, namely, prognostic, predictive, and surrogate. RESULTS: A principle challenge for biomarker validation from a statistical perspective is the issue of multiplicity. In general, the solution to this multiplicity challenge is well known to statisticians: pre-specification and replication. Critical requirements for prognostic marker validation include uniform treatment, complete follow-up, unbiased case selection, and complete ascertainment of the many possible confounders that exist in the context of an observational sample. In the case of predictive biomarker validation, observational data are clearly inadequate and randomized controlled trials are mandatory. Within the context of randomization, strategies for predictive marker validation can be grouped into two categories: retrospective versus prospective validation. The critical validation criteria for a surrogate endpoint is to ensure that if a trial uses a surrogate endpoint, the trial will result in the same inferences as if the trial had observed the true endpoint. The field of surrogate endpoint validation has now moved to the multi-trial or meta-analytic setting as the preferred method. CONCLUSIONS: Biomarkers are a highly active research area. For all biomarker developmental and validation studies, the importance of fundamental statistical concepts remains the following: pre specification of hypotheses, randomization, and replication. Further statistical methodology research in this area is clearly needed as we move forward. PMID- 23983157 TI - Reconnecting with urban youth enrolled in a randomized controlled trial and overdue for a 12-month follow-up survey. AB - BACKGROUND: Retention of study participants in randomized controlled trials (RCTs) is crucial to study validity. PURPOSE: We analyzed the results of four retention strategies used to reconnect with urban teens enrolled in a school based RCT and overdue for a 12-month follow-up survey. METHODS: Traditional retention strategies used to reconnect with teens categorized as 'unable to contact' were weekly redials of nonworking telephone numbers and mailings to the student's home. Nontraditional retention strategies were obtaining assistance from school administration and performing outreach on Facebook. RESULTS: Of the 422 students enrolled, 125 (29.5%) were overdue for a 12-month follow-up survey, but had no working telephone number (unable to contact). We made 196 attempts to contact these 125 students, of which 82 attempts (41.8%) were successful in 'reconnecting' with the student. Using 'mailed reminder letters' as the referent category, odds ratios (95% confidence intervals) for the association between the strategy used and reconnecting were 4.60 (1.8-11.8), 1.94 (1.01-3.73), and 2.91 (0.58-14.50), respectively, for telephone number redials, Facebook outreach, and school administration assistance. Of the 422 students, 380 (90%) ultimately completed the 12-month follow-up survey. LIMITATIONS: Retention strategies were not applied hierarchically or systematically. We were unable to determine student preference for a particular strategy. Findings are likely only applicable to similar study populations. CONCLUSION: A mix of traditional retention strategies and more contemporary methods was effective in reconnecting with urban teenagers enrolled in a school-based RCT and in controlling attrition during the 12-month follow-up survey period. PMID- 23983159 TI - Analytical and clinical evaluation of biomarkers assays: when are biomarkers ready for prime time? AB - BACKGROUND: Biomarker assays can be evaluated for analytical performance (ability of assay to measure the biomarker quantity) and clinical performance (ability of assay result to inform of the clinical condition of interest). Additionally, a biomarker assay is said to have clinical utility if it ultimately improves patient outcomes when used as intended. PURPOSE: This article reviews analytical and clinical performance studies of biomarker assay tests and also some designs of clinical utility studies. RESULTS: Appropriate design and statistical analysis of analytical and clinical evaluation studies depend on the intended clinical use of the test. Some key aspects to valid performance studies include using subjects who are independent of those used to develop the test, masking users of the test to any other available test or reference results, and including in the primary statistical analysis subjects with unavailable results in an intention-to diagnose analysis. Ingenuity in study design and analysis may be required for efficient and unbiased estimation of performance. LIMITATIONS: Performance studies need to be carefully planned as they can be prone to many sources of bias. Analytical inaccuracy can hamper the clinical performance of biomarkers. CONCLUSIONS: As biomedical research and technology advance, challenges in study design and statistical analysis will continue to emerge for analytical and clinical performance studies of biomarker assays. Although not emphasized in some circles, the analytical performance of a biomarker assay is important to characterize. Analytical performance studies have many study design and statistical analysis challenges that deserve further attention. PMID- 23983160 TI - Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study. AB - BACKGROUND: Randomized clinical trials, particularly for comparative effectiveness research (CER), are frequently criticized for being overly restrictive or untimely for health-care decision making. PURPOSE: Our prospectively designed REsearch in ADAptive methods for Pragmatic Trials (RE ADAPT) study is a 'proof of concept' to stimulate investment in Bayesian adaptive designs for future CER trials. METHODS: We will assess whether Bayesian adaptive designs offer potential efficiencies in CER by simulating a re-execution of the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study using actual data from ALLHAT. RESULTS: We prospectively define seven alternate designs consisting of various combinations of arm dropping, adaptive randomization, and early stopping and describe how these designs will be compared to the original ALLHAT design. We identify the one particular design that would have been executed, which incorporates early stopping and information based adaptive randomization. LIMITATIONS: While the simulation realistically emulates patient enrollment, interim analyses, and adaptive changes to design, it cannot incorporate key features like the involvement of data monitoring committee in making decisions about adaptive changes. CONCLUSION: This article describes our analytic approach for RE-ADAPT. The next stage of the project is to conduct the re-execution analyses using the seven prespecified designs and the original ALLHAT data. PMID- 23983161 TI - Rapid on-site evaluation for endoscopic ultrasound-guided fine-needle biopsy of the pancreas decreases the incidence of repeat biopsy procedures. AB - BACKGROUND: Rapid on-site evaluation (ROSE) for endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy of the pancreas provides immediate feedback regarding cellular adequacy to aid in obtaining a definitive diagnosis and has the potential to avoid repeat procedures. The objective of the current study was to measure the impact of ROSE service on the incidence of repeat EUS FNA biopsy procedures. METHODS: Over a consecutive 3-year period, the pathology database at Washington University Medical Center was searched for patients with both an initial and subsequent EUS FNA biopsy demonstrating a solid lesion of the pancreas. These were divided temporally between the time before and after the introduction of ROSE service. Reports were reviewed and results were recorded. RESULTS: A total of 379 patients underwent ROSE service and 377 patients did not. The percentage of repeat non-ROSE EUS FNA cases was 5.8% and the percentage of repeat ROSE EUS FNA cases was 2.9%. The use of the ROSE service was found to decrease the number of repeat procedures by approximately 50% (P = .024). For those patients who underwent a repeat EUS-FNA procedure, the ROSE service provided a higher rate of definitive diagnosis among patients undergoing repeat procedures (67%) versus the non-ROSE cohort (27%). CONCLUSIONS: The use of ROSE for EUS-FNA biopsy of the pancreas was found to result in fewer patients undergoing repeat procedures. Patients who required a repeat procedure with the use of ROSE had a higher percentage of definitive diagnostic categorization on the repeat biopsy. Initial use of ROSE for EUS-FNA of solid pancreatic lesions was found to decrease the number of patients who required a repeat procedure. PMID- 23983162 TI - The occurrence of autophagic cell death in the tegument of rabbits pre-infested with Rhipicephalus sanguineus and exposed to selamectin (active principle of acaricide Pfizer Revolution(r)). AB - Ticks of Rhipicephalus sanguineus species have great medical and veterinary importance for being a vector of various diseases. In an attempt to minimize their action on the host, people have resorted to chemical control by using various acaricides, such as selamectin. Although previous studies have demonstrated its toxic action in domestic animals, no studies focused on the detection of cell death when exposed to selamectin. For this reason, the technique for detecting autophagic cell death was used in order to demonstrate the responses of rabbits' skin tissues pre-infested with R. sanguineus and exposed to different concentrations of selamectin. The obtained results when exposed to 100 and 80% concentrations of selamectin showed a strong mark of acid phosphatase on the cells of the connective tissue of the dermis and hair follicles, whereas the ones exposed to the 50% concentration had a weak mark on the cells of the connective tissue of the dermis and moderate staining in hair follicles. It became clear that, when used at high concentrations (100 and 80%), selamectin is capable to induce a large scale occurrence of the autophagic cell death process. On the other hand, the concentration of 50% causes minor morphophysiological changes in the skin of rabbit hosts when evaluated the cell death process. Therefore, the data confirms that selamectin is a powerful dose dependent toxic agent causes increased activity of the enzyme acid phosphatase. PMID- 23983164 TI - Management of reproduction and pregnancy complications in maternal obesity: which role for dietary polyphenols? AB - Obesity is a global and dramatic public health problem; maternal obesity represents one of the main risk factors of infertility and pregnancy complications as it is associated with adverse maternal and offspring outcomes. In the last few years, adipose tissue dysfunction associated with altered adipocytokine secretion has been suggested to play a critical role in all the phases of reproductive process. Obesity is a nutrition-related disorder. In this regard, dietary intervention strategies, such as high intake of fruit and vegetables, have shown significant effects in both preserving health and counteracting obesity-associated diseases. Evidence has been provided that polyphenols, important constituents of plant-derived food, can influence developmental program of oocyte and embryo, as well as pregnancy progression by modulating several cellular pathways. This review will examine the controversial results so far obtained on adipocytokine involvement in fertility impairment and pregnancy complications. Furthermore, the different effects exerted by polyphenols on oocyte, embryo, and pregnancy development will be also taken in account. PMID- 23983163 TI - Glucose and lipid homeostasis in adult rat is impaired by early-life exposure to perfluorooctane sulfonate. AB - Perfluorooctane sulfonate (PFOS), which belongs to the degradation product of many perfluorinated compounds, is on the list of persistent organic pollutants (POPs) and is currently detected in both wildlife and humans. The consequence of gestational and lactational exposure to PFOS on prediabetes effect in offspring was investigated in rats in the present study. Maternal rats were treated with vehicle, 0.5 mg/kg/day or 1.5 mg/kg/day PFOS respectively from gestation day 0 to postnatal day 21. The glucose and lipid metabolism effects were investigated on the offspring in adulthood. The gestational and lactational exposure to PFOS led to low body weight from birth to weaning, and evoked signs of a prediabetic state, with elevated fasting serum insulin and leptin level, impaired glucose tolerance, though the fasting serum glucose and glycosylated serum protein level were normal. Abnormal lipid homeostasis was also observed by the phenomenon of hepatic steatosis and increased gonadal fat pad weight. However, the circulating serum level of fasting triglyceride and cholesterol level were no different from controls. Our results suggested that developmental exposure to PFOS may contribute to glucose and lipid metabolic disorder in adulthood. PMID- 23983165 TI - Leveraging systems biology approaches in clinical pharmacology. AB - Computational modeling has been adopted in all aspects of drug research and development, from the early phases of target identification and drug discovery to the late-stage clinical trials. The different questions addressed during each stage of drug R&D has led to the emergence of different modeling methodologies. In the research phase, systems biology couples experimental data with elaborate computational modeling techniques to capture lifecycle and effector cellular functions (e.g. metabolism, signaling, transcription regulation, protein synthesis and interaction) and integrates them in quantitative models. These models are subsequently used in various ways, i.e. to identify new targets, generate testable hypotheses, gain insights on the drug's mode of action (MOA), translate preclinical findings, and assess the potential of clinical drug efficacy and toxicity. In the development phase, pharmacokinetic/pharmacodynamic (PK/PD) modeling is the established way to determine safe and efficacious doses for testing at increasingly larger, and more pertinent to the target indication, cohorts of subjects. First, the relationship between drug input and its concentration in plasma is established. Second, the relationship between this concentration and desired or undesired PD responses is ascertained. Recognizing that the interface of systems biology with PK/PD will facilitate drug development, systems pharmacology came into existence, combining methods from PK/PD modeling and systems engineering explicitly to account for the implicated mechanisms of the target system in the study of drug-target interactions. Herein, a number of popular system biology methodologies are discussed, which could be leveraged within a systems pharmacology framework to address major issues in drug development. PMID- 23983166 TI - The combination of lenalidomide and dexamethasone reduces bone resorption in responding patients with relapsed/refractory multiple myeloma but has no effect on bone formation: final results on 205 patients of the Greek myeloma study group. AB - The combination of lenalidomide plus dexamethasone (RD) is very effective for patients with relapsed/ refractory myeloma. However, the effect of RD on bone metabolism has not been previously evaluated in these patients. To address this issue, we initially performed a retrospective study in 106 consecutive patients with relapsed or refractory myeloma who received RD. We measured the following bone indices on Cycle 1/Day 1 and then on Cycles 3 and 6/Day 28: dickkopf-1 (Dkk 1), sRANKL, osteoprotegerin (OPG), bone resorption markers (C-telopeptide of collagen type-I, CTX and TRACP-5b) and bone formation markers (bone-specific alkaline phosphatase-bALP and osteocalcin). RD produced a reduction of CTX only in responders, with no effect on bone formation. To validate these results, we then evaluated prospectively 99 patients who received either RD (n550) or VRD (bortezomib + RD, n549). RD reduced CTX, mainly in responders but showed no effect on bone formation, confirming the result of the retrospective study. However, the addition of bortezomib to RD (VRD arm) reduced Dkk-1, sRANKL/OPG, and CTX, while it increased bALP and OC after six cycles of therapy. These changes were irrespective of treatment response, which was similar between treatment arms. No skeletal-related events were observed in the VRD arm while two, nonresponding patients treated with RD developed a vertebral fracture. We conclude that RD reduces bone resorption only in responding patients with relapsed/refractory myeloma but has no effect on bone formation. Combination with bortezomib, which enhances bone formation, seems to be preferred for the management of myeloma patients with osteolytic disease. PMID- 23983167 TI - Methionine pretreatment enhances the effects of valproate on axial development in a CD1 mouse model. AB - BACKGROUND: The present study was performed to evaluate the effect of methionine (Met) pretreatment on valproate (VPA) axial defects, induced in CD1 mice by a single intraperitoneal (i.p.) injection of 400 mg/kg VPA on E8 dams. This VPA dosage regimen has been in the past related to a specific pathogenic pathway cascade: (1) VPA in utero exposure, (2) H4 histone hyperacetylation (hAC) at the level of somites, (3) expression of pro-apoptotic factors in somite tissues, (4) apoptosis of somite cells, and (5) axial defects in embryos (abnormal or fused somites) and fetuses (fusions, duplications, respecifications of vertebrae, and/or ribs). METHODS: On the basis of literature suggestion, E8 CD1 mice were i.p. injected with 70 mg/kg Met 30 min before the i.p. injection with 400 mg/kg VPA. Some females were sacrificed, 1 or 3 hr after the VPA injection, embryos explanted, and used to evaluate the H4 histone hAC. The remaining females were sacrificed at term (E18) and fetuses processed for external and skeletal examination. RESULTS: The pretreatment with Met worsened the axial skeletal malformative picture in fetuses (we observed a larger number of affected segment per fetus in respect to the groups treated with VPA alone). In embryos, Met pretreatment increased the H4 hAC index and shifted the timing of the H4 hAC peak. CONCLUSIONS: Our data suggest that Met pretreatment enhances the effects of VPA in deregulating the epigenetic control of gene expression in somites, and by consequence, induces more extended dysmorphogenic effects along the axial axis. PMID- 23983168 TI - Development of a doxazosin and finasteride transdermal system for combination therapy of benign prostatic hyperplasia. AB - The treatment of benign prostatic hyperplasia can be accomplished by the use of different drugs including, doxazosin, an alpha-1 adrenergic antagonist, and finasteride (FIN), a 5-alpha reductase inhibitor. Traditionally, treatments using these drugs have been administered as either a mono or combination therapy by the oral route. A transdermal delivery system optimized for doxazosin and FIN combination therapy would provide increased patient adherence and facilitate dose adjustment. Doxazosin base (DB) was prepared from doxazosin mesylate and characterized together with FIN, by X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). The permeation enhancers, azone and lauric acid, and the gelling agents, hydroxypropyl cellulose (HPC) and Poloxamer 407 (P407), were evaluated to determine their ability to promote in vitro permeation of drugs through the pig ear epidermis. Successful preparation of DB was confirmed by evaluating the XRD, DSC, and NMR patterns and in vitro studies revealed that 3% (w/w) azone was the best permeation enhancer. When P407 gel was compared with HPC gel, it showed reduced lag time and promoted higher permeation of both drugs. This may be because of the interactions of the former with the stratum corneum, which disorganizes the lipid structure and consequently promotes higher drug permeation. PMID- 23983170 TI - Chitin microneedles for an easy-to-use tuberculosis skin test. AB - An easy-to-use tuberculosis skin test is developed with chitin microneedles that deliver purified protein derivative at the correct skin depth and result in a positive test in BCG-immunized guinea pigs. PMID- 23983171 TI - Meta-analysis of hypercoagulability genetic polymorphisms in Perthes disease. AB - Perthes disease is an osteonecrosis of the femoral epiphysis with unclear etiology. This study aimed to systematically review the association between genetic determinants of hypercoagulability (Factor V Leiden, prothrombin II, and methylenetetrahydrofolate reductase; MTHFR) and Perthes disease. PubMed and Scopus searched from inception to January 2012, data extraction and quality assessment were performed. The odds ratio (OR) for the allele effect was pooled, and heterogeneity and publication bias were assessed. Twelve case-control studies met inclusion criteria and had sufficient data for extraction. There were 824 cases and 2,033 controls with a mean age range of 6.1-14.7 years. The prevalence of the minor allele in controls was 0.015 (95% confidence interval (CI): 0.008, 0.023), 0.012 (95% CI: 0.008, 0.017), and 0.105 (95% CI: 0.044, 0.167) for factor V Leiden, prothrombin II, and MTHFR, respectively. The factor V Leiden allele increased the risk of Perthes with a pooled OR of 3.10 (95% CI: 1.68, 5.72), while prothrombin II and MTHFR had non-significantly pooled OR 1.48 (95% CI: 0.71, 3.08), and 0.97 (95% CI: 0.72, 1.30), respectively. The factor V Leiden mutation is significantly related to Perthes disease, and its screening in at risk children might be useful in the future. PMID- 23983172 TI - Graphene as an efficient sorbent for the SPE of organochlorine pesticides in water samples coupled with GC-MS. AB - The determination of organochlorine pesticides in water samples, which are harmful to humans, is very important for environmental risk assessment. Based on the excellent adsorption properties of graphene, an SPE coupled with GC-MS method for the monitoring of organochlorines (four hexachlorcyclohexanes and four dichlorodiphenyltrichloroethanes) was developed. Owing to the hydrophobic interaction and pi-pi stacking interaction between the analytes and graphene, the analytes quantitatively adsorbed onto the graphene-based SPE cartridge were eluted by ethyl acetate for analysis. Several parameters influencing the analytical performance, such as the kind of elution, sample volume, reusability of the cartridge, have been investigated in detail. Under the optimal conditions, detection of limits of 1.95-9.38 ng/L, recoveries of 83.9-107.3% at two spiked concentration levels (0.1 and 10 ng/mL) and RSDs in the range of 2.9-7.4% for real water samples were obtained for all the analytes. This work reveals the great potential of graphene in sample preparation procedures. PMID- 23983173 TI - Utility of the ultrasound examination of the hand and wrist joints in the management of established rheumatoid arthritis. AB - OBJECTIVE: To investigate the usefulness of point-of-care hand and wrist joint ultrasound (US) examination in patients with established rheumatoid arthritis (RA). METHODS: Fifty-one RA patients were evaluated using clinical disease activity measures and gray-scale and power Doppler (PD) US. Agreement between US and clinical findings and its impact on physicians' confidence and clinical decision were assessed. RESULTS: Agreement between intraarticular PD signal and joint swelling (JS) was moderate (82%; kappa = 0.44). Agreement between PD signal and joint tenderness to palpation (TTP) was fair (75%; kappa = 0.24). The greatest agreement between PD signal and clinical findings was seen in the 5th metacarpophalangeal (MCP) joint (96% JS, 88% TTP) and the poorest agreement was seen in the wrist (69% JS, 65% TTP) and 2nd (75% JS, 72% TTP) and 3rd (82% JS, 72% TTP) MCP joints. The presence of PD signal in nonswollen and/or nontender joints accounted for most of the disagreement in the wrists, while the opposite was true for the 2nd/3rd MCP joints. Agreement between sonographic synovial thickening and clinical findings was poor. Total sonographic synovial hypertrophy or PD score correlated significantly with physician-recorded, but not patient recorded, clinical outcomes. US increased both physicians' confidence in their clinical decision (P < 0.0005, irrespective of Clinical Disease Activity Index score) and patients' confidence in physicians' medical decisions (88.4% of the cases). US modified biologic agent and/or disease-modifying antirheumatic drug (DMARD) use in 7 individual cases, but it did not affect the overall treatment plan (P > 0.15) or DMARD (P < 0.062) or biologic agent (P > 1.0) use in this group of RA patients. CONCLUSION: PD examination of the wrist and 2nd/3rd MCP joints might be feasible and clinically meaningful in evaluation of disease activity in patients with established RA. US examination of the hand/wrist joints in RA increases physicians' confidence in their clinical decision and can help to individualize DMARD and biologic agent use. PMID- 23983174 TI - Small orangiophilic squamous-like cells: an underrecognized and useful morphological feature for the diagnosis of malignant mesothelioma in pleural effusion cytology. AB - BACKGROUND: The cytological diagnosis of malignant mesothelioma (MM) on serous effusion is challenging due to significant morphologic overlap with reactive mesothelial cells and adenocarcinoma. One of the morphologic features of MM in effusion cytology, small orangiophilic squamous-like cells (SOSLC), has received little attention. To the best of the authors' knowledge, the current study is the first to assess the sensitivity and specificity of SOSLC in serous effusion specimens from histology-proven MM cases along with those of reactive mesothelial and adenocarcinoma cases. METHODS: A total of 130 cases of pleural (86 cases) and peritoneal (44 cases) effusion cytology cases (30 with histology-proven MM, 41 with adenocarcinoma, and 59 with reactive mesothelial cells) were studied. The presence or absence of SOSLC was recorded in each case. RESULTS: The cytological diagnoses of the 30 histology-proven MM cases included 1) atypical mesothelial cells, favor reactive (4 cases); 2) atypical mesothelial cells, suspicious for or cannot exclude mesothelioma (18 cases); and 3) positive for MM (8 cases). SOSLC were found in 10 of the 30 MM effusion cases (33.3%), 1 of the 41 adenocarcinoma cases (2.4%), and 5 of the 59 reactive mesothelial cell cases (8.5%). SOSLC were more likely to be present in MM effusions compared with either adenocarcinoma (P<.0001) or reactive mesothelial cell (P<.02) effusions. All 10 cases of MM with SOSLC were from pleural fluids. One case of peritoneal serous adenocarcinoma had SOSLC and 5 cases of reactive mesothelial cells in peritoneal fluid were found to have SOSLC. CONCLUSIONS: Although not sensitive, the presence of SOSLC is quite specific for MM in pleural fluid cytology specimens. Finding this morphological feature in pleural fluid should alert the pathologist to a possible diagnosis of MM. PMID- 23983175 TI - Are young people hospitalised with psychosis interested in psychological therapy? AB - OBJECTIVES: Psychotic clients may be difficult to engage in psychological therapy, and many potential participants decline to participate in controlled trials of cognitive behavioural therapy. The aim of this study was to investigate psychotic patients' perspectives regarding therapy. DESIGN: The design was qualitative and used thematic analysis to investigate emerging themes. Methods A total of 46 inpatients with psychosis were interviewed about their views on therapy. Interview summaries were submitted to thematic analysis. RESULTS: A total of 41% of participants were rated as interested, 36% were rated as not interested and 23% appeared ambivalent, or their interest in therapy was unable to be assessed. Themes related to interest in therapy included the desire to build skills, to address (usually non-psychotic) symptoms and for a therapeutic relationship. Themes related to not wanting therapy included a denial of psychological problems, distrust in the healthcare system and psychologists and low perceived efficacy in therapy. CONCLUSIONS: A large minority of psychotic patients may be interested in therapy, although mostly not to address psychotic symptoms. Future research on pre-treatment approaches to disconfirm negative perceptions and increase interest in therapy is warranted. KEY PRACTITIONER MESSAGE: The reasons why some patients with psychosis are not interested in receiving psychological therapy may relate to past negative experiences with psychologists, negative perceptions of psychologists as a group and low perceived efficacy of therapy. These barriers may be addressed through interactions with psychotic patients during an admission to a hospital that disconfirms these perceptions and provides a positive alternative experience with a psychologist. Patients who are hospitalized with psychosis may be interested in receiving psychological therapy; however, the reason for this likely will not be to address psychotic symptoms. Rather, the therapist should be willing to work with the patient on a range of other presenting problems. If a patient has a lack of insight into their psychotic symptoms, this does not always negate them from perceiving other psychological problems for which they may desire support in addressing. Thus, therapists should be encouraged to approach all psychotic patients on a ward, even when there is an apparent lack of awareness of their psychotic symptoms. The themes related to patients' perspectives were generated from psychologists' summaries of interviews with patients and not directly from verbatim transcripts. Although this meant that the reasons given for participants being interested or not interested in therapy were interpreted by the psychologist, efforts were made to relate the exact reasons provided by the participants. Eighteen (29%) of the potential participants were not interviewed, usually as a result of their being discharged or transferred prior to arrangement of an interview. This meant we were unable to capture the views of these patients. Discharge prior to being seen by a psychologist is a barrier to engaging a patient in therapy and preventing them falling through the gaps of service provision. PMID- 23983176 TI - Do we need continuous glucose monitoring in type 2 diabetes? AB - Self-monitoring of blood glucose (SMBG) is recommended as a core component of diabetic patient's management but it can provide only intermittent snapshots of blood glucose levels missing often hyperglycaemic or hypoglycaemic excursions. Similarly HbA1c alone is unable to provide detailed diagnostic information and it has several limitations. In the modern diabetes monitoring, Continuous Glucose Monitoring (CGM) could be considered as a third pillar, since it provides information on day-to-day change of blood glucose levels and helps achieving treatment targets without increasing the risk of hypoglycaemia. Therefore the use of CGM may reduce glucose variability, improving glycaemic control and decreasing long-term diabetes complications. In fact the availability of continuous glucose data for patients with low and high glucose alerts may impact quality of life with short- and long-term effectiveness. Moreover CGM can be used as a powerful motivational device to change type 2 diabetic patients' lifestyle and to improve their quality of life. Although the studies on the economic feasibility to use CGM as an educational tool must be carried out, we suggest that it can be used as a powerful motivational device to change patients' lifestyle and to improve glycaemic control in type 2 diabetes (T2D). This article is protected by copyright. All rights reserved. PMID- 23983177 TI - Efficacy and safety of IV ferumoxytol for adults with iron deficiency anemia previously unresponsive to or unable to tolerate oral iron. AB - Although oral iron is the initial treatment approach for iron deficiency anemia (IDA), some patients fail to respond to or cannot tolerate oral iron. This double blind safety and efficacy study of the intravenous (IV) iron, ferumoxytol, randomized patients with a history of unsatisfactory oral iron therapy, or in whom oral iron could not be used, to ferumoxytol (n = 609) or placebo (n = 203). The proportion of patients achieving the primary endpoint (hemoglobin increase >=2.0 g/dL at Week 5) was 81.1% with ferumoxytol versus 5.5% with placebo (P < 0.0001). The mean increase in hemoglobin from Baseline to Week 5, a secondary endpoint (also the alternative preplanned primary efficacy endpoint for other health authorities), was 2.7 versus 0.1 g/dL (P < 0.0001). Achievement of a hemoglobin >=12 g/dL, time to a hemoglobin increase >=2.0 g/dL, and improvement in the Functional Assessment of Chronic Illness Therapy Fatigue score also significantly favored ferumoxytol over placebo at Week 5 (P < 0.0001). Ferumoxytol treatment-emergent adverse events were mainly mild to moderate. Ferumoxytol was effective and well tolerated in patients with IDA of any underlying cause in whom oral iron was ineffective or could not be used. This trial was registered at www.clinicaltrials.gov as #NCT01114139. PMID- 23983178 TI - Proteomics and PUGNAcity will overcome questioning of insulin resistance induction by nonselective inhibition of O-GlcNAcase. AB - PTMs are the ultimate elements that perfect the existence and the activity of proteins. Owing to PTM, not less than 500 millions biological activities arise from approximately 20 000 protein-coding genes in human. Hundreds of PTM were characterized in living beings among which is a large variety of glycosylations. Many compounds have been developed to tentatively block each kind of glycosylation so as to study their biological functions but due to their complexity, many off-target effects were reported. Insulin resistance exemplifies this problem. Several independent groups described that inhibiting the removal of O-GlcNAc moieties using O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N phenylcarbamate (PUGNAc), a nonselective inhibitor of the nuclear and cytoplasmic O-GlcNAcase, induced insulin resistance both in vivo and ex vivo. The development of potent and highly selective O-GlcNAcase inhibitors called into question that elevated O-GlcNAcylation levels are responsible for insulin resistance; these compounds not recapitulating the insulin-desensitizing effect of PUGNAc. To tackle this intriguing problem, a South Korean group recently combined ATP affinity chromatography and gel-assisted digestion to identify proteins, differentially expressed upon treatment of 3T3-L1 adipocytes with PUGNAc, involved in protein turnover and insulin signaling. PMID- 23983179 TI - Omega-3 polyunsaturated fatty acids and proanthocyanidins improve postprandial metabolic flexibility in rat. AB - Postprandial lipemia influences the development of atherosclerosis, which itself constitutes a risk factor for the development of cardiovascular diseases. The introduction of bioactive compounds may prevent these deleterious effects. Proanthocyanidins are potent antioxidants that have hypolipidemic properties, while omega-3 polyunsaturated fatty acids (omega3 PUFAs) stimulate fatty acid oxidation and gene expression programs, controlling mitochondrial functions. In this study, we investigated the effects of acute treatment of omega3 PUFAs and proanthocyanidins on the metabolic flexibility and lipid handling profiles in the skeletal muscle and adipose tissue of rats that were raised on diets, high in saturated fatty acids. For this, oil rich in docosahexaenoic (DHA-OR), grape seed proanthocyanidins extract (GSPE), or both substances (GSPE + DHA-OR) were administered with an overload of lard oil to healthy Wistar rats. Our results indicate that the addition of DHA-OR to lard oil increases insulin sensitivity and redirects fatty acids toward skeletal muscle, thereby activating fatty acid oxidation. We also observed an improvement in adipose mitochondrial functionality and uncoupling. In contrast, GSPE lowers lipidemia, prevents muscle reactive oxygen species (ROS) production and damage, furthermore, activates mitochondrial biogenesis and lipogenesis in adipose tissue. The addition of GSPE+DHA-OR to lard resulted in nearly all the effects of DHA-OR and GSPE administered individually, but the combined administration resulted in a more attenuated profile. PMID- 23983180 TI - Development of bioactive porous alpha-TCP/HAp beads for bone tissue engineering. AB - Porous beads of bioactive ceramics such as hydroxyapatite (HAp) and tribasic calcium phosphate (TCP) are considered a promising scaffold for cultivating bone cells. To realize this, alpha-TCP/HAp functionally graded porous beads are fabricated with two main purposes: to maintain the function of the scaffold with sufficient strength up to the growth of new bone, and is absorbed completely after the growth. HAp is a bioactive material that has both high strength and strong tissue-adhesive properties, but is not readily absorbed by the human body. On the contrary, alpha-TCP is highly bioabsorbable, resulting in a scaffold that is absorbed before it is completely replaced by bone. In this study, we produced porous, bead-shaped carriers as scaffolds for osteoblast culture. To control the solubility in vivo, the fabricated beads contained alpha-TCP at the center and HAp at the surface. Cell adaptability of these beads for bone tissue engineering was confirmed in vitro. It was found that alpha-TCP/HAp bead carriers exhibit low toxicity in the initial stages of cell seeding and cell adhesion. The presence of HAp in the composite bead form effectively increased ALP activity. In conclusion, it is suggested that these newly developed alpha-TCP/HAp beads are a promising tool for bone tissue engineering. PMID- 23983182 TI - Selective reactivation of human herpesvirus 6 in patients with autoimmune connective tissue diseases. AB - Viral infections have been associated with autoimmune connective tissue diseases. To evaluate whether active infection by Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus (HHV)-6, -7, -8, as well as parvovirus B19 (B19V) occur in patients with autoimmune connective tissue diseases, viral DNA loads were assessed in paired samples of serum and peripheral blood mononuclear cells (PBMCs) of 115 patients affected by different disorders, including systemic sclerosis, systemic, and discoid lupus erythematosus, rheumatoid arthritis, and dermatomyositis. Two additional groups, patients affected by inflammatory diseases (n=51) and healthy subjects (n=58) were studied as controls. The titers of anti-HHV-6 and anti-EBV antibodies were also evaluated. Cell-free HHV-6 serum viremia was detected in a significantly higher proportion of connective tissue diseases patients compared to controls (P<0.0002); a significant association between HHV-6 reactivation and the active disease state was found only for lupus erythematosus (P=0.021). By contrast, the rate of cell-free EBV viremia was similar in patients and controls groups. Cell-free CMV, HHV-8, and B19V viremia was not detected in any subject. Anti-HHV-6 and anti-EBV early antigen IgG titers were both significantly higher in autoimmune diseases patients as compared to healthy controls, although they were not associated with the presence of viremia. EBV, HHV-6, -7 prevalence and viral load in PBMCs of patients with connective tissue diseases and controls were similar. These data suggest that HHV-6 may act as a pathogenic factor predisposing patients to the development of autoimmune connective tissue diseases or, conversely, that these disorders may predispose patients to HHV-6 reactivation. PMID- 23983181 TI - Reduced replication capacity of influenza A(H1N1)pdm09 virus during the 2010-2011 winter season in Tottori, Japan. AB - A novel swine-origin influenza A(H1N1)pdm09 virus has been circulating in humans since March-April, 2009. The 2009-2010 epidemic involved predominantly a single subtype of A(H1N1)pdm09 (at 96%, 46/48) in the sentinel sites of this study. However, A(H1N1)pdm09 started to circulate together with other type/subtype (49%, 33/68) at the first peak in the next epidemic season in 2010-2011: A(H1N1)pdm09/A(H3N2) (9%, 6/68), A(H1N1)pdm09/B (35%, 24/68), and A(H1N1)pdm09/A(H3N2)/B (4%, 3/68). Single infection of A(H1N1)pdm09 became a rare event (8%, 5/65) at the second peak of the same season in 2010-2011 compared with that at the first peak (50%, 34/68). Concurrently with this decline, single infections of others, A(H3N2) or B, became evident (6%, 4/65; 14%, 9/65, respectively). Triple infections were more common (29%, 19/65) at the second peak than at the first peak (4%). The A(H1N1)pdm09 detected in 2010-2011 produced less virus upon 72 hr of incubation in vitro after the inoculations at 10(4) and 3,300 copies/ml (2.3 * 10(9) and 2.3 * 10(9) copies/ml on average) than that in 2009 2010 (3.7 * 10(9) and 1.3 * 10(10) copies/ml on average; P<0.05 by ANOVA test), respectively. As described above, the replication capacity of A(H1N1)pdm09 seems to have deteriorated in the 2010-2011 season presumably due to substantial herd immunity and allowed the existence of other type/subtype. These results suggest that assessment of replication capacity is indispensable for analysis of influenza epidemics. PMID- 23983184 TI - Perilous potential: the chance to save lives, or lose them, through low dose computed tomography screening for lung cancer. PMID- 23983183 TI - Kinetics of the neutralizing antibody response to respiratory syncytial virus infections in a birth cohort. AB - The kinetics of respiratory syncytial virus (RSV) neutralizing antibodies following birth, primary and secondary infections are poorly defined. The aims of the study were to measure and compare neutralizing antibody responses at different time points in a birth cohort followed-up over three RSV epidemics. Rural Kenyan children, recruited at birth between 2002 and 2003, were monitored for RSV infection over three epidemic seasons. Cord and 3-monthly sera, and acute and convalescent sera following RSV infection, were assayed in 28 children by plaque reduction neutralization test (PRNT). Relative to the neutralizing antibody titers of pre-exposure control sera (1.8 log10 PRNT), antibody titers following primary infection were (i) no different in sera collected between 0 and 0.4 months post-infection (1.9 log10 PRNT, P=0.146), (ii) higher in sera collected between 0.5 and 0.9 (2.8 log10 PRNT, P<0.0001), 1.0-1.9 (2.5 log10 PRNT, P<0.0001), and 2.0-2.9 (2.3 log10 PRNT, P<0.001) months post-infection, and (iii) no different in sera collected at between 3.0 and 3.9 months post-infection (2.0 log10 PRNT, P=0.052). The early serum neutralizing response to secondary infection (3.02 log10 PRNT) was significantly greater than the early primary response (1.9 log10 PRNT, P<0.0001). Variation in population-level virus transmission corresponded with changes in the mean cohort-level neutralizing titers. It is concluded that following primary RSV infection the neutralizing antibody response declines to pre-infection levels rapidly (~3 months) which may facilitate repeat infection. The kinetics of the aggregate levels of acquired antibody reflect seasonal RSV occurrence, age, and infection history. PMID- 23983185 TI - MRI-visual order-disorder micellar nanostructures for smart cancer theranostics. AB - The development of MRI-visual order-disorder structures for cancer nanomedicine explores a pH-triggered mechanism for theragnosis of tumor hallmark functions. Superparamagnetic iron oxide nanoparticles (SPIONs) stabilized with amphiphilic poly(styrene)-b-poly(acrylic acid)-doxorubicin with folic acid (FA) surfacing are employed as a multi-functional approach to specifically target, diagnose, and deliver drugs via a single nanoscopic platform for cancer therapy. The functional aspects of the micellar nanocomposite is investigated in vitro using human breast SkBr3 and colon cancer HCT116 cell lines for the delivery, release, localization, and anticancer activity of the drug. For the first time, concentration-dependent T2 -weighted MRI contrast for a monolayer of clustered cancer cells is shown. The pH tunable order-disorder transition of the core-shell structure induces the relative changes in MRI contrast. The outcomes elucidate the potential of this material for smart cancer theranostics by delivering non-invasive real-time diagnosis, targeted therapy, and monitoring the course and response of the action before, during, and after the treatment regimen. PMID- 23983186 TI - Prolonged expansion of human nucleus pulposus cells expressing human telomerase reverse transcriptase mediated by lentiviral vector. AB - Human degenerative disc disease (DDD) is characterized by progressive loss of human nucleus pulposus (HNP) cells and extracellular matrix, in which the massive deposition are secreted by HNP cells. Cell therapy to supplement HNP cells to degenerated discs has been thought to be a promising strategy to treat DDD. However, obtaining a large quality of fully functional HNP cells has been severely hampered by limited proliferation capacity of HNP cells in vitro. Previous studies have used lipofectamine or recombinant adeno-associated viral (rAAV) vectors to deliver human telomerase reverse transcriptase (hTERT) into ovine or HNP cells to prolong the activity of nucleus pulposus cells with limited success. Here we developed a lentiviral vector bearing both hTERT and a gene encoding green fluorescence protein (L-hTERT/EGFP). This vector efficiently mediated both hTERT and EGFP into freshly isolated HNP cells. The expressions of both transgenes in L-hTERT/EGFP transduced HNP cells were detected up to day 210 post viral infection, which was twice as long as rAAV vector did. Furthermore, we observed restored telomerase activity, maintained telomere length, delayed cell senescence, and increased cell proliferation rate in those L-hTERT/EGFP transduced HNP cells. Our study suggests that lentiviral vector might be a useful gene delivery vehicle for HNP cell therapy to treat DDD. PMID- 23983187 TI - Meeting physical activity guidelines and the risk of incident knee osteoarthritis: a population-based prospective cohort study. AB - OBJECTIVE: Knee osteoarthritis (OA) is a leading cause of disability and joint pain. Although other risk factors of knee OA have been identified, how physical activity affects incident knee OA remains unclear. METHODS: Using data from the first (1999-2004) and second (2005-2010) followup periods of the Johnston County Osteoarthritis Project study, we tested the association between meeting physical activity guidelines and incident knee outcomes among 1,522 adults ages >=45 years. The median followup time was 6.5 years (range 4.0-10.2 years). Physical activity at baseline (moderate-equivalent physical activity minutes/week) was calculated using the Minnesota Leisure Time Physical Activity questionnaire. Incident knee radiographic OA (ROA) was defined as the development of Kellgren/Lawrence grade >=2 in a knee at followup. Incident knee symptomatic ROA (sROA) was defined as the development of ROA and symptoms in at least 1 knee at followup. Weibull regression modeling was used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for interval-censored data. RESULTS: In multivariable models, meeting the 2008 Department of Health and Human Services (HHS) physical activity guidelines (>=150 minutes/week) was not significantly associated with ROA (HR 1.20 [95% CI 0.92-1.56]) or sROA (HR 1.24 [95% CI 0.87 1.76]). Adults in the highest level (>=300 minutes/week) of physical activity had a higher risk of knee ROA and sROA compared with inactive (0 to <10 minutes/week) participants; however, these associations were not statistically significant (HR 1.62 [95% CI 0.97-2.68] and HR 1.42 [95% CI 0.76-2.65], respectively). CONCLUSION: Meeting the HHS physical activity guidelines was not associated with incident knee ROA or sROA in a cohort of middle-aged and older adults. PMID- 23983188 TI - Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy. AB - BACKGROUND: Adenosine monophosphate-activated protein kinase (AMPK) is stimulated in embryos during diabetic pregnancy by maternal hyperglycaemia-induced embryo oxidative stress. Stimulation of AMPK disrupts embryo gene expression and causes neural tube defects. Metformin, which may be taken during early pregnancy, has been reported to stimulate AMPK activity. Thus, the benefits of improved glycaemic control could be offset by stimulated embryo AMPK activity. Here, we investigated whether metformin can stimulate AMPK activity in mouse embryos and can adversely affect embryo gene expression and neural tube defects. METHODS: Pregnant nondiabetic mice were administered metformin beginning on the first day of pregnancy. Activation of maternal and embryo AMPK [phospho-AMPK alpha (Thr172) relative to total AMPK], expression of Pax3, a gene required for neural tube closure, and neural tube defects were studied. Mouse embryonic stem cells were used as a cell culture model of embryonic neuroepithelium to study metformin effects on AMPK and Pax3 expression. RESULTS: Metformin had no effect on AMPK in embryos or maternal skeletal muscle but increased activated AMPK in maternal liver. Metformin did not inhibit Pax3 expression or increase neural tube defects. However, metformin increased activated AMPK and inhibited Pax3 expression by mouse embryonic stem cells. Mate1/Slc47a1 and Oct3/Slc22a, which encode metformin transporters, were expressed at barely detectable levels by embryos. CONCLUSIONS: Although metformin can have effects associated with diabetic embryopathy in vitro, the lack of effects on mouse embryos in vivo may be due to lack of metformin transporters and indicates that the benefits of metformin on glycaemic control are not counteracted by stimulation of embryo AMPK activity and consequent embryopathy. PMID- 23983190 TI - Cytocompatibility assessment of chemical surface treatments for phosphate glass to improve adhesion between glass and polyester. AB - Fully resorbable phosphate glass fiber reinforced polymer composites have shown real potential for replacing some of the existing metallic bone fracture fixation devices. However, some of these composites have not provided suitable mechanical strength profiles over the required healing period for bone. Typically, it has been seen that these composites can lose up to 50% or more of their strength within the first week of degradation. Functionalizing the glass surface to promote polymer adhesion or to introduce hydrophobicity at the glass surface could potentially introduce control over the mechanical properties of the composite and their retention. In this study eight chemical agents namely, Glycerol 2-phosphate disodium salt; 3-phosphonopropionic acid; 3 aminopropyltriethoxy silane; etidronic acid; hexamethylene diisocyanate; sorbitol/sodium ended PLA oligomers and amino phosphonic acid, were selected to functionalise the bulk phosphate glass surface. Selected chemical agents had one functional group (-OH or O C N) to react with the glass and another functionality (either -OH, NH2, or Na) to react with the polymer matrix and/or produce hydrophobicity at the fiber surface. Bulk phosphate glass surface-treated with the above agents were assessed for the cytotoxicity of degradation products cell material interaction in short- and long-term direct cytocompatibility studies. Results obtained from these cytocompatibility studies (using human osteosarcoma (MG63) and primary human osteoblast cell lines) revealed no cytotoxicity from the degradation products and a response comparable to controls in terms of cell functions (attachment, viability, metabolic activity, proliferation, and differentiation) and morphology. PMID- 23983189 TI - Characterization of multiple myeloma vesicles by label-free relative quantitation. AB - Multiple myeloma (MM) is a hematological malignancy caused by a microenviromentally aided persistence of plasma cells in the bone marrow. The role that extracellular vesicles (EVs), microvesicles and exosomes, released by MM cells have in cell-to-cell communication and signaling in the bone marrow is currently unknown. This paper describes the proteomic content of EVs derived from MM.1S and U266 MM cell lines. First, we compared the protein identifications between the vesicles and cellular lysates of each cell line finding a large overlap in protein identifications. Next, we applied label-free spectral count quantitation to determine proteins with differential abundance between the groups. Finally, we used bioinformatics to categorize proteins with significantly different abundances into functional groups. The results illustrate the first use of label-free spectral counting applied to determine relative protein abundances in EVs. PMID- 23983191 TI - Enhanced suppressive capacity of tumor-infiltrating myeloid-derived suppressor cells compared with their peripheral counterparts. AB - Although the main site of action for myeloid-derived suppressor cells (MDSCs) is most likely the tumor microenvironment, so far the study of these cells has been largely restricted to spleen-derived MDSCs. In this study, we compared the suppressive capacity of splenic and tumor-derived MDSCs in different subcutaneous mouse tumor models. We investigated which suppressive mechanisms were involved. Finally, we investigated whether MDSCs and regulatory T cells (Treg ) cooperate in the suppression of T-cell responses. In all models, splenic granulocytic MDSCs (grMDSC) strongly suppress CD4(+) T-cell proliferation while the suppressive effect on CD8(+) T cells is less pronounced. Splenic monocytic MDSCs (moMDSC) have a lower suppressive capacity, compared to grMDSC, on both CD4(+) and CD8(+) T-cell proliferation. Both grMDSC and moMDSC isolated from the tumor have a much stronger suppressive activity compared to MDSCs isolated from the spleen of tumor bearing mice, associated with a higher NO2 (-) production by the tumor-derived moMDSC and arginase activity for both subsets. The expression of CD80 is also elevated on tumor-derived grMDSC compared with their peripheral counterparts. Direct contact with tumor cells is required for the upregulation of CD80 and CD80(+) MDSCs are more suppressive than CD80(-) MDSCs. Coculture of Treg and MDSCs leads to a stronger suppression of CD8(+) T-cell proliferation compared to the suppression observed by Treg or MDSCs alone. Thus, we showed that tumor infiltrating MDSCs possess a stronger suppressive capacity than their peripheral counterparts and that various suppressive mechanisms account for this difference. PMID- 23983192 TI - Evidence for increasing usage of low-grade squamous intraepithelial lesion, cannot exclude high-grade squamous intraepithelial lesion (LSIL-H) Pap test interpretations. AB - BACKGROUND: Pap test (PT) interpretations of low-grade squamous intraepithelial lesion (LSIL), cannot exclude high-grade squamous intraepithelial lesion (HSIL), or LSIL-H, are used in many laboratories; however monitoring its usage for quality assurance purposes is understudied. METHODS: PTs from 2005 to 2010 were collected, and yearly frequencies of LSIL, HSIL, LSIL-H, and atypical squamous cells, cannot exclude HSIL (ASC-H) as a function of total PTs and total squamous intraepithelial lesions (SILs) were calculated. Two-year risk of cervical intraepithelial neoplasia 2 (CIN2) or worse (CIN2+) and CIN 3 or worse (CIN3+) was calculated. RESULTS: A total of 352,220 PTs were identified including 17,301 abnormal PTs. LSIL-H usage increased from 2005 to 2010 (from 0.28% of total PTs in 2005 to 0.61% in 2010, P < .01; from 5.8% of total SILs in 2005 to 12% in 2010, P < .001). HSIL usage decreased significantly from 2005 to 2010 (from 0.7% of total PTs in 2005 to 0.48% in 2010, P = .048; from 14.5% of total SILs in 2005 to 9.5% in 2010, P < .01). Usage of LSIL and ASC-H did not change. Two-year risk of CIN2+ and CIN3+ for HSIL increased significantly from 2005 to 2010 (P < .01). Two-year risk of CIN2+ and CIN3+ for LSIL-H did not change significantly from 2005 to 2010. CONCLUSIONS: The frequency of LSIL-H interpretations is significantly increasing at our institution, with a significant decrease in HSIL interpretations over the same period. Two-year risk of CIN2+ and CIN3+ for HSIL increased significantly as usage of LSIL-H increased and that of HSIL decreased. Laboratories using LSIL-H may benefit from monitoring its frequency to ensure its appropriate use. Cancer (Cancer Cytopathol) 2014;122:123-7. (c) 2013 American Cancer Society. PMID- 23983193 TI - Different tocopherol isoforms vary in capacity to scavenge free radicals, prevent inflammatory response, and induce apoptosis in both adult- and fetal-derived intestinal epithelial cells. AB - Gamma-tocopherol (gamma-Toc) and delta-Toc are two vitamin E isoforms for which biological activities are not well established, yet these isoforms are present in many different sources of vegetable oils and, therefore, contribute significantly to the total dietary intake of vitamin E. Infant formula also contains relatively high amounts of gamma-Toc and delta-Toc, compared with that found in human milk. The efficacy of gamma-Toc and delta-Toc to modulate cellular events that include oxidative stress, inflammatory response, and apoptosis-mediated cytotoxicity, relative to alpha-Toc, was determined using differentiated Caco-2 and primary FHs 74 Int cells intestinal epithelial cell lines. Antioxidant capacity of Toc isoforms followed the order of delta-Toc > gamma-Toc > alpha-Toc against peroxyl radical-induced membrane oxidation in both Caco-2 and FHs 74 Int cells, respectively. The different Toc-isoforms suppressed inflammatory response in interferon (IFN) gamma/phorbol myristate acetate (PMA)-induced Caco-2 adult derived intestinal epithelial cells, but exacerbated both IL8 and PGE2 secretion in fetal-derived FHs 74 Int intestinal epithelial cells. Lastly, Toc exhibited an isoform-dependent apoptosis-mediated cytotoxicity, whereby delta-Toc elicited the greatest apoptosis followed by gamma-Toc, whereas alpha-Toc was not cytotoxic. Cellular uptake of non-alpha-Toc isoforms were greater (P < 0.05) than that observed for alpha-Toc in both intestinal epithelial cell lines which in part explains the superior bioactive function observed for both gamma-Toc and delta Toc, compared with alpha-Toc. We conclude that the non-alpha-Toc isoforms of vitamin E have distinct roles that influence oxidative stress and inflammatory responses in both adult and fetal-derived intestinal epithelial cell lines. PMID- 23983194 TI - Surface functionalized thiol-ene waveguides for fluorescence biosensing in microfluidic devices. AB - Thiol-ene polymers possess physical, optical, and chemical characteristics that make them ideal substrates for the fabrication of optofluidic devices. In this work, thiol-ene polymers are used to simultaneously create microfluidic channels and optical waveguides in one simple moulding step. The reactive functional groups present at the surface of the thiol-ene polymer are subsequently used for the rapid, one step, site-specific functionalization of the waveguide with biological recognition molecules. It was found that while the bulk properties and chemical surface properties of thiol-ene materials vary considerably with variations in stoichiometric composition, their optical properties remain mostly unchanged with an average refractive index value of 1.566 +/- 0.008 for thiol-ene substrates encompassing a range from 150% excess ene to 90% excess thiol. Microfluidic chips featuring thiol-ene waveguides were fabricated from 40% excess thiol thiol-ene to ensure the presence of thiol functional groups at the surface of the waveguide. Biotin alkyne was photografted at specific locations using a photomask, directly at the interface between the microfluidic channel and the thiol-ene waveguide prior to conjugation with fluorescently labeled streptavidin. Fluorescence excitation was achieved by launching light through the thiol-ene waveguide, revealing bright fluorescent patterns along the channel/waveguide interface. PMID- 23983195 TI - Peptide amphiphile nanoparticles enhance the immune response against a CpG adjuvanted influenza antigen. AB - Cationic peptide amphiphile nanoparticles are employed for co-delivery of immune modulator CpG and antigen. This results in better targeting to the antigen presenting cells and eliciting strong Th1 response, which is effective against the intracellular pathogens. PMID- 23983196 TI - Patient characteristics as predictors of clinical outcome of distraction in treatment of severe ankle osteoarthritis. AB - Osteoarthritis (OA) is a slowly progressive joint disease. Joint distraction can be a treatment of choice in case of severe OA. Prediction of failure will facilitate implementation of joint distraction in clinical practice. Patients with severe ankle OA, who underwent joint distraction were included. Survival analysis was performed over 12 years (n = 25 after 12 years). Regression analyses were used to predict failures and clinical benefit at 2 years after joint distraction (n = 111). Survival analysis showed that 44% of the patients failed, 17% within 2 years and 37% within 5 years after joint distraction (n = 48 after 5 years). Survival analysis in subgroups showed that the percentage failure was only different in women (30% after 2 years) versus men (after 11 years still no 30% failure). In the multivariate analyses female gender was predictive for failure 2 years after joint distraction. Gender and functional disability at baseline predicted more pain. Functional disability and pain at baseline were associated with more functional disability. Joint distraction shows a long-term clinical beneficial outcome. However, failure rate is considerable over the years. Female patients have a higher chance of failure during follow-up. Unfortunately, not all potential predictors could be investigated and other clinically significant predictors were not found. PMID- 23983197 TI - Unilateral once daily milking locally induces differential gene expression in both mammary tissue and milk epithelial cells revealing mammary remodeling. AB - Once daily milking reduces milk yield, but the underlying mechanisms are not yet fully understood. Local regulation due to milk stasis in the tissue may contribute to this effect, but such mechanisms have not yet been fully described. To challenge this hypothesis, one udder half of six Holstein dairy cows was milked once a day (ODM), and the other twice a day (TDM). On the 8th day of unilateral ODM, mammary epithelial cells (MEC) were purified from the milk using immunomagnetic separation. Mammary biopsies were harvested from both udder halves. The differences in transcript profiles between biopsies from ODM and TDM udder halves were analyzed by a 22k bovine oligonucleotide array, revealing 490 transcripts that were differentially expressed. The principal category of upregulated transcripts concerned mechanisms involved in cell proliferation and death. We further confirmed remodeling of the mammary tissue by immunohistochemistry, which showed less cell proliferation and more apoptosis in ODM udder halves. Gene expression analyzed by RT-qPCR in MEC purified from milk and mammary biopsies showed a common downregulation of six transcripts (ABCG2, FABP3, NUCB2, RNASE1 and 5, and SLC34A2) but also some discrepancies. First, none of the upregulated transcripts in biopsies varied in milk-purified MEC. Second, only milk-purified MEC showed significant LALBA downregulation, which suggests therefore that they correspond to a mammary epithelial cell subpopulation. Our results, obtained after unilateral milking, suggest that cell remodeling during ODM is due to a local effect, which may be triggered by milk accumulation. PMID- 23983198 TI - Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. AB - OBJECTIVE: To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc) associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US. METHODS: The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure >25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg without significant interstitial lung disease) were included in these analyses. RESULTS: In total, 131 SSc patients with incident PAH were followed for a mean +/- SD of 2.0 +/- 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1- 8.4), male sex (HR 3.9, 95% CI 1.1-13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8 -22.8), and diffusing capacity for carbon monoxide (DLCO) <39% predicted (HR 4.2, 95% CI 1.3-13.8) were significant predictors of mortality. CONCLUSION: This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLCO and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients. PMID- 23983199 TI - ATP-binding cassette transporters and cholesterol translocation. AB - Cholesterol, a major component of mammalian cell membranes, plays important structural and functional roles. However, accumulation of excessive cholesterol is toxic to cells. Aberrant cholesterol trafficking and accumulation is the molecular basis for many diseases, such as atherosclerotic cardiovascular disease and Tangier's disease. Accumulation of excessive cholesterol is also believed to contribute to the early onset of Alzheimer's disease. Thus, cellular cholesterol homeostasis is tightly regulated by uptake, de novo synthesis, and efflux. Any surplus of cholesterol must either be stored in the cytosol in the form of esters or released from the cell. Recently, several ATP-binding cassette (ABC) transporters, such as ABCA1, ABCG1, ABCG5, and ABCG8 have been shown to play important roles in the regulation of cellular cholesterol homeostasis by mediating cholesterol efflux. Mutations in ABC transporters are associated with several human diseases. In this review, we discuss the physiological roles of ABC transporters and the underlying mechanisms by which they mediate cholesterol translocation. PMID- 23983201 TI - Encapsulated dental-derived mesenchymal stem cells in an injectable and biodegradable scaffold for applications in bone tissue engineering. AB - Bone grafts are currently the major family of treatment options in modern reconstructive dentistry. As an alternative, stem cell-scaffold constructs seem to hold promise for bone tissue engineering. However, the feasibility of encapsulating dental-derived mesenchymal stem cells in scaffold biomaterials such as alginate hydrogel remains to be tested. The objectives of this study were, therefore, to: (1) develop an injectable scaffold based on oxidized alginate microbeads encapsulating periodontal ligament stem cells (PDLSCs) and gingival mesenchymal stem cells (GMSCs); and (2) investigate the cell viability and osteogenic differentiation of the stem cells in the microbeads both in vitro and in vivo. Microbeads with diameters of 1 +/- 0.1 mm were fabricated with 2 * 10(6) stem cells/mL of alginate. Microbeads containing PDLSCs, GMSCs, and human bone marrow mesenchymal stem cells as a positive control were implanted subcutaneously and ectopic bone formation was analyzed by micro CT and histological analysis at 8-weeks postimplantation. The encapsulated stem cells remained viable after 4 weeks of culturing in osteo-differentiating induction medium. Scanning electron microscopy and X-ray diffraction results confirmed that apatitic mineral was deposited by the stem cells. In vivo, ectopic mineralization was observed inside and around the implanted microbeads containing the immobilized stem cells. These findings demonstrate for the first time that immobilization of PDLSCs and GMSCs in alginate microbeads provides a promising strategy for bone tissue engineering. PMID- 23983202 TI - Action observers implicitly expect actors to act goal-coherently, even if they do not: an fMRI study. AB - Actions observed in everyday life normally consist of one person performing sequences of goal-directed actions. The present fMRI study tested the hypotheses that observers are influenced by the actor's identity, even when this information is task-irrelevant, and that this information shapes their expectation on subsequent actions of the same actor. Participants watched short video clips of action steps that either pertained to a common action with an overarching goal or not, and were performed by either one or by varying actors (2 * 2 design). Independent of goal coherence, actor coherence elicited activation in dorsolateral and ventromedial frontal cortex, together pointing to a spontaneous attempt to integrate all actions performed by one actor. Interestingly, watching an actor performing unrelated actions elicited additional activation in left inferior frontal gyrus, suggesting a search in semantic memory in an attempt to construct an overarching goal that can reconcile the disparate action steps with a coherent intention. Post-experimental surveys indicate that these processes occur mostly unconsciously. Findings strongly suggest a spontaneous expectation bias toward actor-related episodes in action observers, and hence to the immense impact of actor information on action observation. PMID- 23983204 TI - Spin-component-scaled double hybrids: An extensive search for the best fifth-rung functionals blending DFT and perturbation theory. AB - Following up on an earlier preliminary communication (Kozuch and Martin, Phys. Chem. Chem. Phys. 2011, 13, 20104), we report here in detail on an extensive search for the most accurate spin-component-scaled double hybrid functionals [of which conventional double hybrids (DHs) are a special case]. Such fifth-rung functionals approach the performance of composite ab initio methods such as G3 theory at a fraction of their computational cost, and with analytical derivatives available. In this article, we provide a critical analysis of the variables and components that maximize the accuracy of DHs. These include the selection of the exchange and correlation functionals, the coefficients of each component [density functional theory (DFT), exact exchange, and perturbative correlation in both the same spin and opposite spin terms], and the addition of an ad-hoc dispersion correction; we have termed these parametrizations "DSD-DFT" (Dispersion corrected, Spin-component scaled, Double-hybrid DFT). Somewhat surprisingly, the quality of DSD-DFT is only mildly dependent on the underlying DFT exchange and correlation components, with even DSD-LDA yielding respectable performance. Simple, nonempirical GGAs appear to work best, whereas meta-GGAs offer no advantage (with the notable exception of B95c). The best correlation components appear to be, in that order, B95c, P86, and PBEc, while essentially any good GGA exchange yields nearly identical results. On further validation with a wider variety of thermochemical, weak interaction, kinetic, and spectroscopic benchmarks, we find that the best functionals are, roughly in that order, DSD PBEhB95, DSD-PBEP86, DSD-PBEPW91, and DSD-PBEPBE. In addition, DSD-PBEP86 and DSD PBEPBE can be used without source code modifications in a wider variety of electronic structure codes. Sample job decks for several commonly used such codes are supplied as electronic Supporting Information. PMID- 23983203 TI - Interaction of finger representations in the cortex of individuals with autism: a functional window into cortical inhibition. AB - An established neural biomarker of autism spectrum disorder (ASD) has the potential to provide novel biological and pharmacological targets for treatment. Lower level of inhibition in brain circuits is a leading biomarker candidate. A physiological investigation of the functional levels of inhibition in the cortex of individuals with autism can provide a strong test of the hypothesis. The amplitude of cortical response to the stimulation of adjacent fingers is controlled by the level of cortical inhibition and provides just such a test. Using magnetoencephalography, we recorded the response of the somatosensory cortex to the passive tactile stimulation of the thumb (D1), and index finger (D2), and to the simultaneous stimulation of both fingers combined (D1,D2) of the dominant (right) hand of young subjects with and without autism. For each participant, we measured the response to the stimulation of both fingers combined (D1,D2) relative to the post hoc sum of the responses to the stimulation of each finger alone (D1+D2) in multiple different ways and linearly regressed the ASD and neurotypical (NT) groups' responses. The resulting slopes were then compared: Smaller slope values imply attenuated response to paired finger stimulation, and enhanced levels of inhibition. The short-latency M40 and mid-latency M80 response slopes of the group with autism obtained in different ways were either significantly smaller, or statistically indistinguishable from NT. The result does not support reduced inhibition in the somatosensory cortex of individuals with autism, contrary to the seminal hypothesis of reduced inhibition. Implications are discussed including refinements of current theory. PMID- 23983205 TI - Nanostructured hollow tubes based on chitosan and alginate multilayers. AB - The design and production of structures with nanometer-sized polymer films based on layer-by-layer (LbL) are of particular interest for tissue engineering since they allow the precise control of physical and biochemical cues of implantable devices. In this work, a method is developed for the preparation of nanostructured hollow multilayers tubes combining LbL and template leaching. The aim is to produce hollow tubes based on polyelectrolyte multilayer films with tuned physical-chemical properties and study their effects on cell behavior. The final tubular structures are characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), microscopy, swelling, and mechanical tests, including dynamic mechanical analysis (DMA) in physiological simulated conditions. It is found that more robust films could be produced upon chemical cross-linking with genipin. In particular, the mechanical properties confirms the viscoelastic properties and a storage and young modulus about two times higher. The water uptake decreases from about 390% to 110% after the cross linking. The biological performance is assessed in terms of cell adhesion, viability, and proliferation. The results obtained with the cross-linked tubes demonstrate that these are more suitable structures for cell adhesion and spreading. The results suggest the potential of these structures to boost the development of innovative tubular structures for tissue engineering approaches. PMID- 23983206 TI - Lifetime risk of total knee replacement and temporal trends in incidence by health care setting, socioeconomic status, and geographic location. AB - OBJECTIVE: To estimate the lifetime risk of total knee replacement (TKR) and examine temporal trends in TKR incidence in the state of Victoria, Australia. METHODS: We performed a retrospective analysis of a population-based longitudinal cohort of patients (ages >=40 years) who received a primary TKR in Victoria from 1999-2008. Hospital separations and life tables were used to estimate lifetime risk. Temporal changes in TKR incidence were examined according to health care setting (public versus private), socioeconomic status (SES), and geographic location (regional versus metropolitan). RESULTS: There were 43,570 incidents of primary TKRs identified over the study period. In 2008, the lifetime risk of surgery was 10.4% (95% confidence interval [95% CI] 10.13-10.64%) for men and 11.9% (95% CI 11.63-12.13%) for women. TKRs increased steadily over the study period in private hospitals (overall increase of 90%) with a smaller growth in procedure numbers for public hospitals (overall increase of 40%). From 2002-2003 onward, the low SES tertile showed a lower incidence of TKR compared to the middle and high SES groups, with incidence rates of 1.09 (95% CI 1.04-1.15), 1.22 (95% CI 1.17-1.28), and 1.20 (95% CI 1.16-1.25) per 1,000 population, respectively (based on 2007-2008 figures). Increased numbers of TKRs were also found to be occurring among people residing in regional areas of Victoria (from 1.12 [95% CI 1.04-1.31] to 1.84 [95% CI 1.72-2.02] per 1,000 population). CONCLUSION: Increases in lifetime risk of TKR were evident. Although improved access to TKR for those living in regional areas was observed, sustained disparities relating to health care setting and SES warrant further investigation. PMID- 23983207 TI - Transport barriers and strategies of antitumor nanocarriers delivery system. AB - Nanocarriers with unique characteristics have attracted great attentions in tumor treatment, but therapeutic efficacy of drugs is limited by the nonuniform delivery of nanocarriers to tumor by three progresses blood circulation system, tumor vessels and tumor interstitium. The total number of nanocarriers usually was reduced dramatically into tumor, because nanocarriers in blood vessels always can be cleared by RES system or accumulated in kidney and liver. Abnormal vessels are almost uneven allocation on tumor surface and cannot contribute to deliver nanocarriers to all the region of tumors, especially the interior of tumors. In addition, nanocarriers will be retained in perivascular space of tumor under high interstitial fluid pressure (IFP) and heterogeneous structure of tumor matrix. In this article, we reviewed the structure of nanocarriers and the barriers in tumor microenvironment influencing delivery of nanocarriers. With the aim of transport over these barriers to increase the delivery efficiency of nanocarriers, two strategies tumor microenvironment normalization and nanocarriers optimization were proposed and designed. PMID- 23983208 TI - Electron density deformations provide new insights into the spectral shift of rhodopsins. AB - Spectral shifts of rhodopsin, which are related to variations of the electron distribution in 11-cis-retinal, are investigated here using the method of deformed atoms in molecules. We found that systems carrying the M207R and S186W mutations display large perturbations of the pi-conjugated system with respect to wild-type rhodopsins. These changes agree with the predicted behavior of the bond length alternation (BLA) and the blue shifts of vertical excitation energies of these systems. The effect of the planarity of the central and Schiff-base regions of retinal chain on the electronic structure of the chromophore is also investigated. By establishing nonlinear polynomial relations between BLA, chain distortions, and vertical excitation energies, we are also able to provide a semiquantitative approach for the understanding of the mechanisms regulating spectral shifts in rhodopsin and its mutants. PMID- 23983209 TI - Mal, more than a bridge to MyD88. AB - The family of type 1 transmembrane proteins known as Toll-like receptors (TLRs) provide early immune system recognition and response to infection. In order to transmit their signal to the nucleus and initiate activation of pro-inflammatory and anti-microbial genes, TLRs must initiate a cytoplasmic signalling cascade, which is alternately controlled by 6 known signalling adaptors. These signaling adaptors are crucial for activating the correct immune response to any given TLR / pathogen interaction. This review will focus on one of those adaptors, MyD88 adaptor-like (Mal), also known as TIRAP. Mal is critical for signalling by the best studied of the TLRs, the Gram negative bacterial lipopolysaccharide (LPS) sensor, TLR4. Mal's role in TLR2 signalling in response to activation of the bacterial lipopeptide receptor, TLR2, is more contentious. Mal is a component of the so-called 'MyD88-dependent pathway' in TLR4 signalling. Recent advances in our understanding of the signalling pathways downstream of Mal highlight MyD88 indpendent roles, thus positioning Mal as multifunctional and integral for the molecular control of bacterial infections as well as inflammatory diseases. Here we describe the sequence of molecular events involved in the signalling pathways controlled by Mal, and the importance of Mal in driving host protection against a variety of bacteria, with specific attention to the evidence for Mal's role in TLR2 signalling, recent structural findings that have altered our understanding of Mal signalling, and evidence that single nucleotide polymorphisms (SNPs) of Mal are responsible for variations in population level resistance and susceptibility to bacterial infection. PMID- 23983211 TI - Frequency of radiographic damage and progression in individual joints in children with juvenile idiopathic arthritis. AB - OBJECTIVE: To evaluate the presence and progression of radiographic joint damage, as assessed with the adapted Sharp/van der Heijde score (SHS), in individual joints in the hand and wrist in patients with juvenile idiopathic arthritis (JIA) and to compare progression of damage among different JIA categories. METHODS: A total of 372 radiographs of both wrists and hands obtained at first observation and at last followup visit (after 1-10 years) in 186 children with polyarticular course JIA were evaluated. All radiographs were scored using the adapted SHS by 2 independent readers. Radiographic assessment included evaluation of joint space narrowing (JSN) and erosions on baseline and last followup radiographs and of progression of radiographic changes from baseline to last followup radiographs. RESULTS: Both JSN and erosions occurred in all adapted SHS areas. Overall, radiographic damage and progression were more common in the wrist and less common in metacarpophalangeal (MCP) joints. The hamate and capitate areas appeared particularly vulnerable to cartilage loss. Erosions were identified most frequently in the hamate and capitate bones as well as in the second and third metacarpal bases. Patients with extended oligoarthritis were distinctly less susceptible to JSN in hand joints, whereas patients with polyarthritis showed a greater tendency to developing erosions in hand joints. CONCLUSION: Radiographic joint damage and progression in our patients with JIA were seen most commonly in the wrist and less commonly in MCP joints. The frequency and localization of structural abnormalities differed markedly across disease categories. PMID- 23983210 TI - A brief account of nanoparticle contrast agents for photoacoustic imaging. AB - Photoacoustic imaging (PAI) is a hybrid, nonionizing modality offering excellent spatial resolution, deep penetration, and high soft tissue contrast. In PAI, signal is generated based on the absorption of laser-generated optical energy by endogenous tissues or exogenous contrast agents leading to acoustic emissions detected by an ultrasound transducer. Research in this area over the years has shown that PAI has the ability to provide both physiological and molecular imaging, which can be viewed alone or used in a hybrid modality fashion to extend the anatomic and hemodynamic sensitivities of clinical ultrasound. PAI may be performed using inherent contrast afforded by light absorbing molecules such as hemoglobin, myoglobin, and melanin or exogenous small molecule contrast agent such as near infrared dyes and porphyrins. However, this review summarizes the potential of exogenous nanoparticle-based agents for PAI applications including contrast based on gold particles, carbon nanotubes, and encapsulated copper compounds. PMID- 23983212 TI - Safety and pharmacokinetics of intravenous zanamivir treatment in hospitalized adults with influenza: an open-label, multicenter, single-arm, phase II study. AB - BACKGROUND: Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza. METHODS: Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed. RESULTS: One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1-11) a median of 4.5 days (range, 1-7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment. CONCLUSIONS: Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir. CLINICAL TRIALS REGISTRATION: NCT01014988. PMID- 23983213 TI - New virulence determinants contribute to the enhanced immune response and reduced virulence of an influenza A virus A/PR8/34 variant. AB - The identification of amino acid motifs responsible for increased virulence and/or transmission of influenza viruses is of enormous importance to predict pathogenicity of upcoming influenza strains. We phenotypically and genotypically compared 2 variants of influenza virus A/PR/8/34 with different passage histories. The analysis revealed differences in virulence due to an altered type I interferon (IFN) induction, as evidenced by experiments using IFNAR(-/-) mice. Interestingly, these differences were not due to altered functions of the well known viral IFN antagonists NS1 or PB1-F2. Using reassortant viruses, we showed that differences in the polymerase proteins and nucleoprotein determined the altered virulence. In particular, changes in PB1 and PA contributed to an altered host type I IFN response, indicating IFN antagonistic properties of these proteins. Thus, PB1 and PA appear to harbor previously unknown virulence markers, which may prove helpful in assessing the risk potential of emerging influenza viruses. PMID- 23983214 TI - Overlapping roles for toxins in Clostridium difficile infection. PMID- 23983215 TI - High rate of cytomegalovirus drug resistance among patients receiving preemptive antiviral treatment after haploidentical stem cell transplantation. AB - We examined the rate, clinical impact, and risk factors of cytomegalovirus (CMV) drug resistance in 561 patients who underwent 616 hematopoietic stem cell transplantations (HSCTs) over 5 years. Drug resistance was exclusively identified in haploidentical (haplo)-HSCT recipients receiving preemptive therapy, among whom the rate was 14.5%. Resistance appeared after prolonged treatment (median, 70 days), was associated with higher preceding viral load (P < .001), and was the strongest predictor for disease by multivariate analysis. The high rate of drug resistance as interlinked with severe disease in haplo-HSCT recipients suggests the potential advantage of prophylactic over preemptive treatment in high-risk patients and highlights the need for better-tolerable anti-CMV drugs. PMID- 23983216 TI - Insulin resistance and bone strength: findings from the study of midlife in the United States. AB - Although several studies have noted increased fracture risk in individuals with type 2 diabetes mellitus (T2DM), the pathophysiologic mechanisms underlying this association are not known. We hypothesize that insulin resistance (the key pathology in T2DM) negatively influences bone remodeling and leads to reduced bone strength. Data for this study came from 717 participants in the Biomarker Project of the Midlife in the United States Study (MIDUS II). The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting morning blood glucose and insulin levels. Projected 2D (areal) bone mineral density (BMD) was measured in the lumbar spine and left hip using dual-energy X ray absorptiometry (DXA). Femoral neck axis length and width were measured from the hip DXA scans, and combined with BMD and body weight and height to create composite indices of femoral neck strength relative to load in three different failure modes: compression, bending, and impact. We used multiple linear regressions to examine the relationship between HOMA-IR and bone strength, adjusted for age, gender, race/ethnicity, menopausal transition stage (in women), and study site. Greater HOMA-IR was associated with lower values of all three composite indices of femoral neck strength relative to load, but was not associated with BMD in the femoral neck. Every doubling of HOMA-IR was associated with a 0.34 to 0.40 SD decrement in the strength indices (p<0.001). On their own, higher levels of fasting insulin (but not of glucose) were independently associated with lower bone strength. Our study confirms that greater insulin resistance is related to lower femoral neck strength relative to load. Further, we note that hyperinsulinemia, rather than hyperglycemia, underlies this relationship. Although cross-sectional associations do not prove causality, our findings do suggest that insulin resistance and in particular, hyperinsulinemia, may negatively affect bone strength relative to load. PMID- 23983218 TI - EphA4 receptor is a novel negative regulator of osteoclast activity. AB - Of the ephrin (Eph) receptors, mature osteoclasts express predominantly EphA4. This study sought to determine if EphA4 has a regulatory role in osteoclasts. Treatment of RAW/C4 cells with Epha4 small interfering RNAs (siRNAs) increased average size, Ctsk mRNA expression level, and bone resorption activity of the derived osteoclast-like cells. Activation of the EphA4 signaling in osteoclast precursors with EfnA4-fc chimeric protein reduced cell size and resorption activity of the derived osteoclasts. Homozygous Epha4 null mice had substantially less trabecular bone in femur and vertebra compared to wild-type controls. The bone loss was due to a decrease in trabecular number and an increase in trabecular spacing, but not to an increase in osteoclast-lined bone surface or an increase in the number of osteoclasts on bone surface. Dynamic histomorphometry and serum biomarker analyses indicate that bone formation in Epha4 null mice was reduced slightly but not significantly. Osteoclasts of Epha4 null mice were also larger, expressed higher levels of Mmp3 and Mmp9 mRNAs, and exhibited greater bone resorption activity than wild-type osteoclasts in vitro. Deficient Epha4 expression had no effects on the total number of osteoclast formed in response to receptor activator of NF-kappaB ligand nor on apoptosis of osteoclasts in vitro. It also did not affect the protein-tyrosine phosphorylation status of its ligands, EfnB2, EfnA2, and EfnA4, in osteoclasts. Deficient Epha4 expression in Epha4 null osteoclasts activated the beta3 -integrin signaling through reduced phosphorylation of the tyr-747 residue, which led to increased binding of the stimulatory talin and reduced binding of the inhibitory Dok1 to beta3 -integrin. This in turn activated Vav3 and the bone resorption activity of osteoclasts. In conclusion, we demonstrate for the first time that EphA4 is a potent negative regulator of osteoclastic activity, mediated in part through increased Dok1 binding to beta3 -integrin via an increase in EphA4-dependent tyr-747 phosphorylation. PMID- 23983219 TI - Trafficking of proteins through plastid stromules. AB - Stromules are thin projections from plastids that are generally longer and more abundant on non-green plastids than on chloroplasts. Occasionally stromules can be observed to connect two plastid bodies with one another. However, photobleaching of GFP-labeled plastids and stromules in 2000 demonstrated that plastids do not form a network like the endoplasmic reticulum, resulting in the proposal that stromules have major functions other than transfer of material from one plastid to another. The absence of a network was confirmed in 2012 with the use of a photoconvertible fluorescent protein, but the prior observations of movement of proteins between plastids were challenged. We review published evidence and provide new experiments that demonstrate trafficking of fluorescent protein between plastids as well as movement of proteins within stromules that emanate from a single plastid and discuss the possible function of stromules. PMID- 23983220 TI - Structure/function analysis of a type iii polyketide synthase in the brown alga Ectocarpus siliculosus reveals a biochemical pathway in phlorotannin monomer biosynthesis. AB - Brown algal phlorotannins are structural analogs of condensed tannins in terrestrial plants and, like plant phenols, they have numerous biological functions. Despite their importance in brown algae, phlorotannin biosynthetic pathways have been poorly characterized at the molecular level. We found that a predicted type III polyketide synthase in the genome of the brown alga Ectocarpus siliculosus, PKS1, catalyzes a major step in the biosynthetic pathway of phlorotannins (i.e., the synthesis of phloroglucinol monomers from malonyl-CoA). The crystal structure of PKS1 at 2.85-A resolution provided a good quality electron density map showing a modified Cys residue, likely connected to a long chain acyl group. An additional pocket not found in other known type III PKSs contains a reaction product that might correspond to a phloroglucinol precursor. In vivo, we also found a positive correlation between the phloroglucinol content and the PKS III gene expression level in cells of a strain of Ectocarpus adapted to freshwater during its reacclimation to seawater. The evolution of the type III PKS gene family in Stramenopiles suggests a lateral gene transfer event from an actinobacterium. PMID- 23983222 TI - Fluorescent protein flow within stromules. PMID- 23983217 TI - Current knowledge on cannabinoids in oral fluid. AB - Oral fluid (OF) is a new biological matrix for clinical and forensic drug testing, offering non-invasive and directly observable sample collection reducing adulteration potential, ease of multiple sample collections, lower biohazard risk during collection, recent exposure identification, and stronger correlation with blood than urine concentrations. Because cannabinoids are usually the most prevalent analytes in illicit drug testing, application of OF drug testing requires sufficient scientific data to support sensitive and specific OF cannabinoid detection. This review presents current knowledge of OF cannabinoids, evaluating pharmacokinetic properties, detection windows, and correlation with other biological matrices and impairment from field applications and controlled drug administration studies. In addition, onsite screening technologies, confirmatory analytical methods, drug stability, and effects of sample collection procedure, adulterants, and passive environmental exposure are reviewed. Delta-9 tetrahydrocannabinol OF concentrations could be >1000 ug/L shortly after smoking, whereas minor cannabinoids are detected at 10-fold and metabolites at 1000-fold lower concentrations. OF research over the past decade demonstrated that appropriate interpretation of test results requires a comprehensive understanding of distinct elimination profiles and detection windows for different cannabinoids, which are influenced by administration route, dose, and drug use history. Thus, each drug testing program should establish cut-off criteria, collection/analysis procedures, and storage conditions tailored to its purposes. Building a scientific basis for OF testing is ongoing, with continuing OF cannabinoids research on passive environmental exposure, drug use history, donor physiological conditions, and oral cavity metabolism needed to better understand mechanisms of cannabinoid OF disposition and expand OF drug testing applicability. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23983223 TI - The clinical utility of microarray technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature. AB - The clinical utility of microarray technologies when used in the context of prenatal diagnosis lies in the technology's ability to detect submicroscopic copy number changes that are associated with clinically significant outcomes. We have carried out a systematic review of the literature to calculate the utility of prenatal microarrays in the presence of a normal conventional karyotype. Amongst 12,362 cases in studies that recruited cases from all prenatal ascertainment groups, 295/12,362 (2.4%) overall were reported to have copy number changes with associated clinical significance (pCNC), 201/3090 (6.5%) when ascertained with an abnormal ultrasound, 50/5108 (1.0%) when ascertained because of increased maternal age and 44/4164 (1.1%) for all other ascertainment groups (e.g. parental anxiety and abnormal serum screening result). When additional prenatal microarray studies are included in which ascertainment was restricted to fetuses with abnormal ultrasound scans, 262/3730 (7.0%) were reported to have pCNCs. PMID- 23983221 TI - The Tarenaya hassleriana genome provides insight into reproductive trait and genome evolution of crucifers. AB - The Brassicaceae, including Arabidopsis thaliana and Brassica crops, is unmatched among plants in its wealth of genomic and functional molecular data and has long served as a model for understanding gene, genome, and trait evolution. However, genome information from a phylogenetic outgroup that is essential for inferring directionality of evolutionary change has been lacking. We therefore sequenced the genome of the spider flower (Tarenaya hassleriana) from the Brassicaceae sister family, the Cleomaceae. By comparative analysis of the two lineages, we show that genome evolution following ancient polyploidy and gene duplication events affect reproductively important traits. We found an ancient genome triplication in Tarenaya (Th-alpha) that is independent of the Brassicaceae specific duplication (At-alpha) and nested Brassica (Br-alpha) triplication. To showcase the potential of sister lineage genome analysis, we investigated the state of floral developmental genes and show Brassica retains twice as many floral MADS (for minichromosome maintenance1, AGAMOUS, DEFICIENS and serum response factor) genes as Tarenaya that likely contribute to morphological diversity in Brassica. We also performed synteny analysis of gene families that confer self-incompatibility in Brassicaceae and found that the critical serine receptor kinase receptor gene is derived from a lineage-specific tandem duplication. The T. hassleriana genome will facilitate future research toward elucidating the evolutionary history of Brassicaceae genomes. PMID- 23983224 TI - High hip fracture risk in men with severe aortic calcification: MrOS study. AB - A significant link between cardiovascular disease and osteoporosis is established in postmenopausal women, but data for men are scarce. We tested the hypothesis that greater severity of abdominal aortic calcification (AAC) was associated with an increased risk of nonspine fracture in 5994 men aged >= 65 years. AAC was assessed on 5400 baseline lateral thoracolumbar radiographs using a validated visual semiquantitative score. Total hip bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Incident nonspine fractures were centrally adjudicated. After adjustment for age, body mass index (BMI), total hip BMD, fall history, prior fracture, smoking status, comorbidities, race, and clinical center, the risk of nonspine fracture (n=805) was increased among men with higher AAC (hazard ratio [HR] quartile 4 [Q4] [AAC score >= 9] versus quartile 1 [Q1] [0-1], 1.36; 96% confidence interval [CI], 1.10-1.68). This association was due to an increased risk of hip fracture (n=178) among men with higher AAC (HR Q4 versus Q1, 2.33; 95% CI, 1.41-3.87). By contrast, the association between AAC and the risk of nonspine, nonhip fracture was weaker and not significant (HR Q4 versus Q1, 1.22; 95% CI, 0.96-1.55). The findings regarding higher AAC and increased risk of fracture were not altered in additional analyses accounting for degree of trauma, estimated glomerular filtration rate, presence of lumbar vertebral fractures (which may bias AAC assessment), preexisting cardiovascular disease, ankle brachial index, or competing risk of death. Thus, in this large cohort of elderly men, greater AAC was independently associated with an increased risk of hip fracture, but not with other nonspine fractures. These findings suggest that AAC assessment may be a useful method for identification of older men at high risk of hip fracture. PMID- 23983227 TI - In this issue: increasing impact of integrative cancer therapies. PMID- 23983225 TI - Dendritic cell-derived thrombospondin-1 is critical for the generation of the ocular surface Th17 response to desiccating stress. AB - TSP-1 is a physiologic activator of TGF-beta, a critical induction factor for Th17-mediated immunity. The purpose of this study was to investigate the role of TSP-1 in the induction of the Th17 ocular surface response to DS. TSP-1KO and WT mice were subjected to DS5 and DS10), and parameters of ocular surface disease, including corneal barrier function, conjunctival CD4(+) T cell infiltration, and GC density, were evaluated. TSP-1KO mice subjected to DS had less corneal barrier disruption, reduced loss of PAS+ GC, and decreased CD4(+) T cell infiltration in the conjunctiva. In contrast to WT, TSP-1KO mice failed to up-regulate MMP-3 and MMP-9 mRNA transcripts in the cornea and IL-17A mRNA transcripts in the conjunctiva. RAG-1KO recipients of adoptively transferred CD4(+) T cells isolated from TSP-1KO mice subjected to DS5 showed milder dry-eye phenotype and less conjunctival inflammation than recipients of CD4(+) T cells from DS5 WT control. Reconstitution of TSP-1KO mice with WT DCs prior to DS reversed the resistance of the TSP-1KO to DS-induced immunopathology. In conclusion, DC-derived TSP-1 is critical for generating the Th17 ocular surface response to DS. PMID- 23983226 TI - Prostaglandin E2 imprints a long-lasting effect on dendritic cell progenitors in the bone marrow. AB - Dendritic cells (DCs) that differentiate in vitro from the bone marrow (BM) of mice with prostaglandin E2 (PGE2)-associated inflammation of the skin, airways, or peritoneal cavity poorly initiate immune responses. To remove in vitro differentiation and allow BM-derived DCs to seed the periphery under steady-state conditions, as well as study the molecule proposed responsible, chimeric mice were engrafted for >16 wk with BM cells from mice exposed to PGE2. Serial PGE2 chimeric mice were established with BM cells from the primary chimeric mice. Immune responses in the airways and skin of the PGE2-chimeric mice and serial PGE2-chimeric mice were significantly attenuated. After inflammatory challenges by intranasal LPS, topical fluorescein isothiocyanate, and intraperitoneal alum, DCs, macrophages, and neutrophils trafficked poorly in PGE2-chimeric mice and serial PGE2-chimeric mice. Injection of BM-differentiated DCs from nonchimeric mice restored the reduced immune responses of PGE2-chimeric mice. DCs from BM of 16-wk-engrafted PGE2-chimeric and serial PGE2-chimeric mice resembled cells differentiated from BM exposed to PGE2 for only 3 d, demonstrating the long lasting effect of PGE2 on DC progenitors. PGE2 attenuates systemic immune responses by modulating myeloid cell progenitors in the BM such that BM-derived, terminally differentiated myeloid cells have poor trafficking ability to sites of need. PMID- 23983228 TI - Eugenol production in achenes and receptacles of strawberry fruits is catalyzed by synthases exhibiting distinct kinetics. AB - Eugenol is a volatile that serves as an attractant for pollinators of flowers, acts as a defense compound in various plant tissues, and contributes to the aroma of fruits. Its production in a cultivated species such as strawberry (Fragaria * ananassa), therefore, is important for the viability and quality of the fruit. We have identified and functionally characterized three strawberry complementary DNAs (cDNAs) that encode proteins with high identity to eugenol synthases from several plant species. Based on a sequence comparison with the wild relative Fragaria vesca, two of these cDNAs, FaEGS1a and FaEGS1b, most likely correspond to transcripts derived from allelic gene variants, whereas the third cDNA, FaEGS2, corresponds to a different gene. Using coniferyl acetate as a substrate, FaEGS1a and FaEGS1b catalyze the in vitro formation of eugenol, while FaEGS2 catalyzes the formation of eugenol and also of isoeugenol with a lower catalytic efficiency. The expression of these genes is markedly higher in the fruit than in other tissues of the plant, with FaEGS1a and FaEGS1b mostly expressed in the green achenes, whereas FaEGS2 expression is almost restricted to the red receptacles. These expression patterns correlate with the eugenol content, which is highest in the achene at the green stage and in the receptacle at the red stage. The transient expression of the corresponding cDNAs in strawberry fruit and the subsequent volatile analyses confirm FaEGSs as genuine eugenol synthases in planta. These results provide new insights into the diversity of phenylpropene synthases in plants. PMID- 23983229 TI - The alkylphenols 4-nonylphenol, 4-tert-octylphenol and 4-tert-butylphenol aggravate atopic dermatitis-like skin lesions in NC/Nga mice. AB - Phthalate esters in plastics act as adjuvants for immunoglobulin production, which aggravates allergic disease. However, the effects of alkylphenols (used as plasticizers and surfactants) on atopic dermatitis have not been studied in detail. Therefore, the goal of the present study was to investigate the effects of the alkylphenols 4-nonylphenol (NP), 4-tert-octylphenol (OP) and 4-tert butylphenol (BP) in a murine model of atopic dermatitis. NC/Nga mice were intraperitoneally administered NP, OP or BP and were subcutaneously injected with mite allergen in one ear to induce atopic dermatitis-like skin lesions (ADSLs). The condition of the skin was observed, and the levels of immunoglobulin in serum and inflammatory cytokines in lesions were determined. NP exacerbated mite allergen-induced ADSLs according to dose. OP and BP also significantly exacerbated skin lesions but not as a function of dose. Alkylphenols tended to increase the levels of IgE and antigen-specific IgG1 in serum. Further, the treatment of the alkylphenols increased the expression in lesions of inflammatory cytokines, interleukin-4 and monocyte chemotactic protein-3. Thymic stromal lymphopoietin levels increased according to ADSL severity. In contrast, the levels of the T-helper 1 cytokines (interleukin-18 and interferon-gamma) decreased. NP, OP or BP may enhance T-helper 2-type immune responses in NC/Nga mice, which aggravates mite allergen-induced ADSLs. Therefore, the uptake of very low levels of alkylphenols may contribute to the increase in the incidence of atopic dermatitis. PMID- 23983230 TI - Subjective stressors moderate effectiveness of a multi-component, multi-site intervention on caregiver depression and burden. AB - OBJECTIVES: The present study assessed whether caregiving contextual factors moderated outcomes of a caregiver intervention. METHODS: Extant data from the Resources for Enhancing Alzheimer's Caregiver Health (REACH) II study, a randomized-control trial of a multi-component, multi-site intervention for dementia caregivers was utilized. 498 caregivers {83.1% women; mean [standard deviation (SD)] age = 60.3 (13.1)}, and their care recipients [58.6% women, mean (SD) age = 78.5 (9.6)] were randomly assigned to intervention or control group. Multiple regression was used to regress Center for Epidemiological Studies of Depression Scale (CES-D) and Zarit burden scores on the interaction between group membership and various factors reflecting the caregiving context. RESULTS: Lower follow-up CES-D scores in the intervention group were found only for those: in the fourth quartile of baseline CES-D (beta = -0.13, p = 0.05; overall interaction p = 0.009), with high Revised Memory and Behavior Problems Checklist (RMBPC) stress (beta = -0.16, p = 0.03) and with a home health aide (beta = 0.29, p = 0.009). Diminished burden was found in the intervention group only for the following: those in the fourth quartile of baseline burden (beta = -0.16, p = 0.01), and in the fourth quartile (beta = -0.16, p = 0.05) of Mini Mental State Examination, and with high RMBPC stress (beta = -0.18, p = 0.008), with a trend for diminished burden among those with a paid homemaker (beta = -0.19, p = 0.075). CONCLUSION: Results suggest greater intervention efficacy among caregivers experiencing subjective stress. PMID- 23983231 TI - A high-throughput assay to identify modifiers of premature chromosome condensation. AB - Premature chromosome condensation (PCC) is a consequence of early mitotic entry, where mitosis begins before completion of DNA replication. Previously we have identified mutations in MCPH1, a DNA damage response and potential tumor suppressor gene, as a cause of primary microcephaly and PCC. Here we describe a high-throughput assay to identify modifiers of PCC. Reverse transfection of control siRNA followed by a forward transfection of MCPH1 small interfering RNA (siRNA) was performed to induce PCC. Condensin II subunits CAPG2 and CAPH2 were validated as PCC modifiers and therefore positive controls. Cell nuclei were detected by DAPI staining using an Operetta imaging system. PCC and nuclei number were determined using Columbus analysis software. Two batches of nine plates were used to determine assay efficacy. Each plate contained four negative (nontargeting) and eight positive control siRNAs. Mean % PCC was 12.35% (n = 72) for negative controls and 4.25% (n = 144) for positive controls. Overall false positive and false-negative rates were 0% (n = 72) and 2.1% (n = 144), respectively. This assay is currently being used to screen a human druggable genome siRNA library to identify novel therapeutic targets for cancer treatment. The assay can also be used to identify novel compounds and genes that induce PCC. PMID- 23983232 TI - A phenotypic screening approach in cord blood-derived mast cells to identify anti inflammatory compounds. AB - Mast cells are unique hematopoietic cells that are richly distributed in the skin and mucosal surfaces of the respiratory and gastrointestinal tract. They play a key role in allergic inflammation by releasing a cocktail of granular constituents, including histamine, serine proteases, and various eicosanoids and cytokines. As such, a number of drugs target either inhibition of mast cell degranulation or the products of degranulation. To identify potential novel drugs and mechanisms in mast cell biology, assays were developed to identify inhibitors of mast cell degranulation and activation in a phenotypic screen. Due to the challenges associated with obtaining primary mast cells, cord blood-derived mononuclear cells were reproducibly differentiated to mast cells and assays developed to monitor tryptase release and prostaglandin D2 generation. The tryptase assay was particularly sensitive, requiring only 500 cells per data point, which permitted a set of approximately 12,000 compounds to be screened robustly and cost-effectively. Active compounds were tested for concomitant inhibition of prostaglandin D2 generation. This study demonstrates the robustness and effectiveness of this approach in the identification of potential novel compounds and mechanisms targeting mast cell-driven inflammation, to enable innovative drug discovery efforts to be prosecuted. PMID- 23983233 TI - A phenotypic compound screening assay for lysosomal storage diseases. AB - The lysosome is a vital cellular organelle that primarily functions as a recycling center for breaking down unwanted macromolecules through a series of hydrolases. Functional deficiencies in lysosomal proteins due to genetic mutations have been found in more than 50 lysosomal storage diseases that exhibit characteristic lipid/macromolecule accumulation and enlarged lysosomes. Recently, the lysosome has emerged as a new therapeutic target for drug development for the treatment of lysosomal storage diseases. However, a suitable assay for compound screening against the diseased lysosomes is currently unavailable. We have developed a Lysotracker staining assay that measures the enlarged lysosomes in patient-derived cells using both fluorescence intensity readout and fluorescence microscopic measurement. This phenotypic assay has been tested in patient cells obtained from several lysosomal storage diseases and validated using a known compound, methyl-beta-cyclodextrin, in primary fibroblast cells derived from Niemann Pick C disease patients. The results demonstrate that the Lysotracker assay can be used in compound screening for the identification of lead compounds that are capable of reducing enlarged lysosomes for drug development. PMID- 23983234 TI - The contribution of mechanistic understanding to phenotypic screening for first in-class medicines. AB - The level of mechanistic understanding required for drug discovery is a central feature of most strategies. However, an understanding of mechanism is not required for regulatory approval. This paradox is particularly relevant to the role of phenotypic assays in drug discovery. A recent analysis revealed that phenotypic drug discovery strategies were more successful for first-in-class medicines, whereas target-based molecular strategies were more successful for followers (Nat. Rev. Drug Discov. 2011, 10, 507-519). The rationale for the success of phenotypic screening was the unbiased identification of the molecular mechanism of action. In this follow-up analysis, the format and mechanistic information used to establish the phenotypic assays that led to the first-in class small-molecule new molecular entities approved by the U.S. Food and Drug Administration between 1999 and 2008 were analyzed and compared with those approved in 2012. Not surprisingly, some level of mechanistic understanding was used to select the assay formats and chemicals screened. It is concluded that mechanism takes on different connotations depending on context and perspective and that a target need not always be the exclusive definition of mechanism. PMID- 23983235 TI - Screening juvenile justice-involved females for sexually transmitted infection: a pilot intervention for urban females in community supervision. AB - Little is known about Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) rates in community-supervised juvenile justice-involved (CSJJI) females, or how to best provide screening for sexually transmitted infections in this population. A pilot intervention allowed case managers to offer optional CT/GC screening to CSJJI females during mandated visits. Anonymous satisfaction surveys and discussion groups assessed intervention acceptability. Case managers met with 514 CSJJI females; 102 (20%) agreed to screening and 117 tests were completed. Among those screened, 21 (18%) had CT and 3 (3%) had GC. Intervention feedback from case managers and clients was positive, but there were barriers to recruitment. Lessons learned from this case manager-facilitated intervention may increase the acceptability and effectiveness of future screening methods in this setting. PMID- 23983237 TI - Temporal stability of serum concentrations of cytokines and soluble receptors measured across two years in low-risk HIV-seronegative men. AB - BACKGROUND: Prospective cohort studies often quantify serum immune biomarkers at a single time point to determine risk of cancer and other chronic diseases that develop years later. Estimates of the within-person temporal stability of serum markers partly assess the utility of single biomarker measurements and may have important implications for the design of prospective studies of chronic disease risk. METHODS: Using archived sera collected from 200 HIV-seronegative men at three visits spaced over approximately 2 years, concentrations of 14 biomarkers (ApoA1, sCD14, sgp130, sIL-6R, sIL-2Ralpha, sTNFR2, BAFF/BLyS, CXCL13, IFN-gamma, interleukin [IL]-1beta, IL-6, IL-8, IL-10, and TNF-alpha) were measured in a single laboratory. Age- and ethnicity-adjusted intraclass correlation coefficients (ICC) were calculated for each biomarker, and mixed linear regression models were used to examine the influence of age, ethnicity, season, and study site on biomarker concentrations. RESULTS: Across all three study visits, most biomarkers had ICC values indicating fair to excellent within-person stability. ApoA1 (ICC = 0.88) and TNF-alpha (ICC = 0.87) showed the greatest stability; the ICC for IL-8 (ICC = 0.33) was remarkably less stable. The ICCs were similar when calculated between pairs of consecutive visits. The covariables did not influence biomarker levels or their temporal stability. All biomarkers showed moderate to strong pairwise correlations across visits. CONCLUSIONS: Serum concentrations of most evaluated immune biomarkers displayed acceptable to excellent within-person temporal reliability over a 2-year period. Further investigation may be required to clarify the stability of IL-8. IMPACT: These findings lend support to using these serologic immune biomarkers in prospective studies investigating associations with chronic diseases. PMID- 23983238 TI - Viral hepatitis markers in liver tissue in relation to serostatus in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) incidence is increasing in the United States. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of HCC. Hepatitis infection in patients with HCC is generally diagnosed by serology, which is not always consistent with the presence of HBV and HCV in the liver. The relationship of liver viral status to serostatus in hepatocarcinogenesis is not fully understood. METHODS: HBV and HCV were evaluated in formalin-fixed, paraffin embedded liver tissue specimens in a retrospective study of 61 U.S. HCC cases of known serologic status. HBV DNA and HCV RNA were detected by PCR, reverse transcription PCR (RT-PCR), and pyrosequencing, and HBsAg and HBcAg were evaluated by immunohistochemistry. RESULTS: Viral markers were detected in the liver tissue of 25 of 61 (41%) HCC cases. Tissue viral and serologic status were discordant in 27 (44%) cases, including those with apparent "occult" infection. Specifically, HBV DNA was detected in tissue of 4 of 39 (10%) serum HBsAg (-) cases, including 1 anti-HCV(+) case; and HCV RNA was detected in tissue of 3 of 42 (7%) anti-HCV seronegative cases, including two with serologic evidence of HBV. CONCLUSIONS: Viral hepatitis, including HBV-HCV coinfection, may be unrecognized in up to 17% of patients with HCC when based on serology alone. Further research is needed to understand the clinical significance of viral makers in liver tissue of patients with HCC in the absence of serologic indices. IMPACT: The contribution of HBV and HCV to the increasing incidence of HCC in the United States may be underestimated. PMID- 23983239 TI - Protein expression of PTEN, insulin-like growth factor I receptor (IGF-IR), and lethal prostate cancer: a prospective study. AB - BACKGROUND: Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality and the potential effect modification by IGF-IR, a direct activator of the phosphoinositide-3-kinase (PI3K) pathway. METHODS: Protein expression in tumor was evaluated using tumor tissues obtained from 805 participants of the Physicians' Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression and its interaction with IGF-IR, in relation to lethal prostate cancer (cancer specific death or distant metastases). RESULTS: Low PTEN expression was associated with an increased risk of lethal prostate cancer [HR, 1.7; 95% confidence interval (CI), 0.98-3.2; Ptrend = 0.04]. The association was attenuated after adjustment for Gleason grade, tumor stage, and prostate-specific antigen (PSA) at diagnosis. A significant negative interaction between PTEN and IGF-IR was found (Pinteraction = 0.03). Either reduction in PTEN or increase in IGF-IR expression was sufficient to worsen prognosis. Models including PTEN and IGF-IR expression offer additional predicting power to prostate cancer survival, compared to those only including demographic and clinical factors. CONCLUSIONS: Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF-IR expression remains at normal level. IMPACT: PTEN and IGF-IR expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer. PMID- 23983242 TI - Simultaneous determination of 10 nucleosides and nucleobases in Antrodia camphorata using QTRAP LC-MS/MS. AB - A liquid chromatography-triple-quadrupole linear ion trap mass spectrometry (LC QTrap-MS) analysis has been developed for the identification and quantification of 10 nucleosides and nucleobases in extracts of Antrodia camphorata. The method was successfully used to qualitatively identify for six nucleosides namely, cytidine, uridine, inosine, guanosine, thymidine, adenosine and four nucleobases namely, uracil, guanine, xanthine, adenine in A. camphorata. Under optimized chromatographic conditions, good separation for 10 target compounds were obtained on an Agilent HC-C18(2) column (4.6 * 250 mm, 5 MUm) eluted by a mobile phase of 5 mM ammonium acetate solution-methanol at a flow rate of 0.5 mL/min. Data acquisition was carried out in multiple reaction monitoring transition mode. Additional identification and confirmation of target compounds were performed using the enhanced product ion modus of the linear ion trap. It was the first report about simultaneous analysis of nucleosides and nucleobases in A. camphorata using this method. These results demonstrated that the QTRAP LC-MS/MS was a useful tool for quality evaluation of some medicinal plant products by using nucleosides and nucleobases as chemical markers. This method might also be utilized for the investigation of edible plant materials and agricultural products containing nucleosides and nucleobases. PMID- 23983241 TI - Associations between dietary acrylamide intake and plasma sex hormone levels. AB - BACKGROUND: The rodent carcinogen acrylamide was discovered in 2002 in commonly consumed foods. Epidemiologic studies have observed positive associations between acrylamide intake and endometrial, ovarian, and breast cancer risks, which suggest that acrylamide may have sex-hormonal effects. METHODS: We cross sectionally investigated the relationship between acrylamide intake and plasma levels of sex hormones and sex hormone-binding globulin (SHBG) among 687 postmenopausal and 1,300 premenopausal controls from nested case-control studies within the Nurses' Health Studies. RESULTS: There were no associations between acrylamide and sex hormones or SHBG among premenopausal women overall or among never-smokers. Among normal-weight premenopausal women, acrylamide intake was statistically significantly positively associated with luteal total and free estradiol levels. Among postmenopausal women overall and among never-smokers, acrylamide was borderline statistically significantly associated with lower estrone sulfate levels but not with other estrogens, androgens, prolactin, or SHBG. Among normal-weight women, (borderline) statistically significant inverse associations were noted for estrone, free estradiol, estrone sulfate, DHEA, and prolactin, whereas statistically significant positive associations for testosterone and androstenedione were observed among overweight women. CONCLUSIONS: Overall, this study did not show conclusive associations between acrylamide intake and sex hormones that would lend unequivocal biologic plausibility to the observed increased risks of endometrial, ovarian, and breast cancer. The association between acrylamide and sex hormones may differ by menopausal and overweight status. We recommend other studies investigate the relationship between acrylamide and sex hormones in women, specifically using acrylamide biomarkers. IMPACT: The present study showed some interesting associations between acrylamide intake and sex hormones that urgently need confirmation. PMID- 23983243 TI - Stability-indicating HPLC method for arteether and application to nanoparticles of arteether. AB - A simple, precise, isocratic, reverse-phase high-performance liquid chromatography method was developed for the rapid determination of arteether using an Agilent RP C18, 4.6 * 150 mm, 5 MUm XDB column. The runtime was 9 min. The effect of flow rate, injection volume and mobile phase composition on resolution was investigated. The analytical procedures of the method were validated with respect to precision, accuracy and linearity according to the International Conference on Harmonization guidelines. The limit of detection and the limit of quantitation were 3.3 and 10.0 MUg/mL, respectively. Linearity range was from 10.00 to 500 MUg/mL. Further, the proposed method was found to be reproducible and convenient for stability-indicating analysis of arteether as a bulk drug and from nanoparticulate formulation. PMID- 23983240 TI - Genetic predictors of circulating 25-hydroxyvitamin d and risk of colorectal cancer. AB - BACKGROUND: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D. METHODS: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and associated confidence intervals for SNPs individually, SNPs simultaneously, and for a vitamin D additive genetic risk score (GRS). RESULTS: We did not observe a statistically significant association between the 25(OH)D-associated SNPs and colorectal cancer marginally, conditionally, or as a GRS, or for colon or rectal cancer separately. CONCLUSIONS: Our findings do not support an association between SNPs associated with circulating 25(OH)D and risk of colorectal cancer. Additional work is warranted to investigate the complex relationship between 25(OH)D and colorectal cancer risk. IMPACT: There was no association observed between genetic markers of circulating 25(OH)D and colorectal cancer. These genetic markers account for a small proportion of the variance in 25(OH)D. PMID- 23983244 TI - Breadth of anti-merozoite antibody responses is associated with the genetic diversity of asymptomatic Plasmodium falciparum infections and protection against clinical malaria. AB - BACKGROUND: Elucidating the mechanisms of naturally acquired immunity to Plasmodium falciparum infections would be highly valuable for malaria vaccine development. Asymptomatic multiclonal infections have been shown to predict protection from clinical malaria in a transmission-dependent manner, but the mechanisms underlying this are unclear. We assessed the breadth of antibody responses to several vaccine candidate merozoite antigens in relation to the infecting parasite population and clinical immunity. METHODS: In a cohort study in Tanzania, 320 children aged 1-16 years who were asymptomatic at baseline were included. We genotyped P. falciparum infections by targeting the msp2 gene using polymerase chain reaction and capillary electrophoresis and measured antibodies to 7 merozoite antigens using a multiplex assay. We assessed the correlation between the number of clones and the breadth of the antibody response, and examined their effects on the risk of malaria during 40 weeks of follow-up using age-adjusted multivariate regression models. RESULTS: The antibody breadth was positively correlated with the number of clones (RR [risk ratio], 1.63; 95% confidence interval [CI], 1.32-2.02). Multiclonal infections were associated with a nonsignificant reduction in the risk of malaria in the absence of antibodies (RR, 0.83; 95% CI, .29-2.34). The breadth of the antibody response was significantly associated with a reduced risk of malaria in the absence of infections (RR, 0.25; 95% CI, .09-.66). In combination, these factors were associated with a lower risk of malaria than they were individually (RR, 0.14; 95% CI, .04-.48). CONCLUSIONS: These data suggest that malaria vaccines mimicking naturally acquired immunity should ideally induce antibody responses that can be boosted by natural infections. PMID- 23983245 TI - Evaluation and reduction of asymptomatic cerebral embolism in ablation of atrial fibrillation, but high prevalence of chronic silent infarction: results of the evaluation of reduction of asymptomatic cerebral embolism trial. AB - BACKGROUND: This prospective, multicenter study sought to evaluate the incidence of asymptomatic cerebral emboli (ACE) during ablation of atrial fibrillation (AF) using a multielectrode radiofrequency (MER) system when specific procedural changes were applied. METHODS AND RESULTS: Sixty subjects (age 60+/-10 years; 87% paroxysmal; CHADS2 score, 0.6+/-0.7) undergoing AF ablation with a circular MER catheter were studied. Three procedural changes were specified: (1) ablation was performed under therapeutic vitamin K antagonist and heparin to maintain activated clotting time>350 seconds; (2) submerged loading of the catheter into the introducer before sheath insertion to minimize air ingress; and (3) either the distal or proximal electrode of the circular MER catheter was deactivated to prevent inadvertent bipolar radiofrequency interaction. MRI was performed <7 days preablation and 2 days postablation. Subjects with new cerebral findings after ablation underwent repeat MRI after 1 month. An acute ACE lesion was defined by a new hyperintensity on diffusion-weighted and fluid-attenuated inversion recovery cerebral MRI sequences. Neurological function was evaluated at baseline, postablation, and 1 month. All target pulmonary veins were isolated. In 60% (36/60) of patients, pre-existing cerebral lesions were seen on the preprocedure MRI (8 lesions per subject; interquartile range, 3-22). New postprocedural ACE occurred in only 1/60 patients (incidence, 1.7%; 95% confidence interval, 0.04 8.9), which was no longer visible on MRI after 1 month. CONCLUSIONS: Applying procedural changes to MER ablation significantly reduces the ACE incidence to 1.7%, which is on the low end of reported ACE rates of any technology. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; Identifier: NCT01520532. PMID- 23983246 TI - Prevalence, characteristics, mapping, and catheter ablation of potential rotors in nonparoxysmal atrial fibrillation. AB - BACKGROUND: Identification of critical atrial substrates in patients with nonparoxysmal atrial fibrillation (AF) failing to respond to pulmonary vein isolation is important. This study investigated the signal characteristics, substrate nature, and ablation results of rotors during AF. METHODS AND RESULTS: In total, 53 patients (age=55+/-8), 31 with persistent AF and 22 with long lasting AF, underwent pulmonary vein isolation and substrate modification of complex fractionated atrial electrograms. Small-radius-reentrant rotors were identified from signal analyses of the dominant frequency and fractionation interval and nonlinear analyses (newly developed, beat-to-beat nonlinear measurement of the repetitiveness of the electrogram morphology>6 seconds). In 15% of the patients, activation maps demonstrated occurrences of rotor-like small radius reentrant circuits (n=9; 1.1 per patient; cycle length=110+/-21 ms; diameter=11+/-6 mm) with fibrillation occurring outside these areas. Rotors were identified by conventional point-by-point mapping and signal analyses and were subsequently eradicated by catheter ablation in these patients. Persistent AF for <1 year, a smaller left atrial size, substrates with higher mean voltages and shorter total activation durations predicted a higher incidence of rotors (all P<0.05). In the multivariable model, areas of reentrant circuits exhibited a higher dominant frequency, kurtosis, and higher degree of a beat-to-beat electrogram similarity than areas without or outside the rotors (all P<0.05). CONCLUSIONS: Rotor-like re-entry with fibrillatory conduction was found in a limited number of patients with nonparoxysmal AF after pulmonary vein isolation. Those areas were characterized by rapid repetitive activity with a high degree of electrogram similarity. PMID- 23983247 TI - Discrete prepotential as an indicator of successful ablation in patients with coronary cusp ventricular arrhythmia. AB - BACKGROUND: Although coronary cusp (CC) ventricular arrhythmia (VA) can be treated by catheter ablation, reliable indicators of successful ablation sites have not been fully identified. METHODS AND RESULTS: This study comprised 392 patients undergoing radiofrequency catheter ablation for outflow tract-VA at 3 institutions from January 2007 to August 2012. The successful ablation site was on the left CC or right CC in 35 (8.9%) of the 392 patients. In 9 (26%) of these 35 patients, a discrete prepotential was recognized, 5 of whom had left CC-VAs and 4 of whom had right CC-VAs. Radiofrequency catheter ablation was successful at the site of the prepotential in all 9 of these patients. The duration of the isoelectric line between the end of the discrete prepotential and the onset of the ventricular electrogram was 27+/-13 ms. The time from onset of the discrete prepotential at the successful ablation site on the CC to the QRS onset (activation time) was 69+/-20 ms (range, 50-98 ms). Pace mapping was graded as excellent at the successful ablation site in only 1 patient. No discrete prepotential was recorded in any successful right outflow tract-VA ablation case in this study. CONCLUSIONS: A discrete prepotential was seen in 9 (26%) of 35 patients with CC-VA. In left and right CC-VA, the site of a discrete prepotential with >=50 ms activation time may indicate a successful ablation site. PMID- 23983248 TI - Extracellular matrix turnover biomarkers predict long-term left ventricular remodeling after myocardial infarction: insights from the REVE-2 study. AB - BACKGROUND: Extracellular matrix turnover plays a key role in wound repair after myocardial infarction (MI). The aim of the study was to evaluate whether biomarkers of myocardial fibrosis measurements 1 month after MI may predict left ventricular (LV) remodeling. METHODS AND RESULTS: This prospective multicenter study included 246 patients with a first anterior Q-wave MI. Echocardiographic studies were performed at hospital discharge and 12 months after MI. Brain natriuretic peptide as well as biomarkers of myocardial fibrosis (type 1 collagen telopeptide, aminoterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen) were measured 1 month after MI in 218 patients. In multivariate analysis, aminoterminal propeptide of type III procollagen/type 1 collagen telopeptide ratio <=1 (odds ratio [95% confidence interval], 1.86 [1.02-3.39]; P=0.043) 1 month after MI and brain natriuretic peptide >100 pg/mL (2.35 [1.28-4.31]; P=0.006) were associated with a pejorative LV remodeling, whereas LV ejection fraction at discharge (per 5% increment; 0.78 [0.65-0.94]; P=0.01) was independently associated with lower rates of detrimental LV remodeling at 12 months. Patients with high brain natriuretic peptide and aminoterminal propeptide of type III procollagen/type 1 collagen telopeptide ratio <=1, measured 1 month after MI, had the highest risk of developing a primary composite event (cardiovascular death or hospitalization for worsening heart failure; 14 events per 216 patients; P=0.0001) during a 3-year follow-up. CONCLUSIONS: Myocardial fibrosis turnover after MI is associated with LV remodeling. Low aminoterminal propeptide of type III procollagen/type 1 collagen telopeptide ratio (<=1) at 1 month is predictive, in addition to brain natriuretic peptide and LV ejection fraction, of detrimental LV remodeling as well as cardiovascular deaths and hospitalizations for heart failure. PMID- 23983249 TI - Depressing mitochondria-reticulum interactions protects cardiomyocytes from lethal hypoxia-reoxygenation injury. AB - BACKGROUND: Under physiological conditions, Ca(2+) transfer from the endoplasmic reticulum (ER) to mitochondria might occur at least in part at contact points between the 2 organelles and involves the VDAC1/Grp75/IP3R1 complex. Accumulation of Ca(2+) into the mitochondrial matrix may activate the mitochondrial chaperone cyclophilin D (CypD) and trigger permeability transition pore opening, whose role in ischemia/reperfusion injury is well recognized. We questioned here whether the transfer of Ca(2+) from ER to mitochondria might play a role in cardiomyocyte death after hypoxia-reoxygenation. METHODS AND RESULTS: We report that CypD interacts with the VDAC1/Grp75/IP3R1 complex in cardiomyocytes. Genetic or pharmacological inhibition of CypD in both H9c2 cardiomyoblasts and adult cardiomyocytes decreased the Ca(2+) transfer from ER to mitochondria through IP3R under normoxic conditions. During hypoxia-reoxygenation, the interaction between CypD and the IP3R1 Ca(2+) channeling complex increased concomitantly with mitochondrial Ca(2+) content. Inhibition of either CypD, IP3R1, or Grp75 decreased protein interaction within the complex, attenuated mitochondrial Ca(2+) overload, and protected cells from hypoxia-reoxygenation. Genetic or pharmacological inhibition of CypD provided a similar effect in adult mice cardiomyocytes. Disruption of ER-mitochondria interaction via the downregulation of Mfn2 similarly reduced the interaction between CypD and the IP3R1 complex and protected against hypoxia-reoxygenation injury. CONCLUSIONS: Our data (1) point to a new role of CypD at the ER-mitochondria interface and (2) suggest that decreasing ER-mitochondria interaction at reperfusion can protect cardiomyocytes against lethal reperfusion injury through the reduction of mitochondrial Ca(2+) overload via the CypD/VDAC1/Grp75/IP3R1 complex. PMID- 23983251 TI - Inositol 1,4,5-trisphosphate receptors: "exciting" players in cardiac excitation contraction coupling? PMID- 23983250 TI - Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. AB - BACKGROUND: Little is known about the function of inositol 1,4,5-trisphosphate receptors (IP3Rs) in the adult heart experimentally. Moreover, whether these Ca(2+) release channels are present and play a critical role in human cardiomyocytes remains to be defined. IP3Rs may be activated after Galphaq protein-coupled receptor stimulation, affecting Ca(2+) cycling, enhancing myocyte performance, and potentially favoring an increase in the incidence of arrhythmias. METHODS AND RESULTS: IP3R function was determined in human left ventricular myocytes, and this analysis was integrated with assays in mouse myocytes to identify the mechanisms by which IP3Rs influence the electric and mechanical properties of the myocardium. We report that IP3Rs are expressed and operative in human left ventricular myocytes. After Galphaq-protein-coupled receptor activation, Ca(2+) mobilized from the sarcoplasmic reticulum via IP3Rs contributes to the decrease in resting membrane potential, prolongation of the action potential, and occurrence of early afterdepolarizations. Ca(2+) transient amplitude and cell shortening are enhanced, and extrasystolic and dysregulated Ca(2+) elevations and contractions become apparent. These alterations in the electromechanical behavior of human cardiomyocytes are coupled with increased isometric twitch of the myocardium and arrhythmic events, suggesting that Galphaq protein-coupled receptor activation provides inotropic reserve, which is hampered by electric instability and contractile abnormalities. Additionally, our findings support the notion that increases in Ca(2+) load by IP3Rs promote Ca(2+) extrusion by forward-mode Na(+)/Ca(2+) exchange, an important mechanism of arrhythmic events. CONCLUSIONS: The Galphaq-protein/coupled receptor/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias. PMID- 23983252 TI - Dispatcher-assisted cardiopulmonary resuscitation: time to identify cardiac arrest and deliver chest compression instructions. AB - BACKGROUND: Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR), in which 9-1-1 dispatchers provide CPR instructions over the telephone, has been shown to nearly double the rate of bystander CPR. We sought to identify factors that hampered the identification of cardiac arrest by 9-1-1 dispatchers and prevented or delayed the provision of dispatcher-assisted CPR chest compressions. METHODS AND RESULTS: We reviewed dispatch recordings for 476 out-of-hospital cardiac arrests occurring between January 1, 2011, and December 31, 2011. We found that the dispatcher correctly identified cardiac arrest in 80% of reviewed cases and 92% of cases in which they were able to assess patient consciousness and breathing. The median time to recognition of the arrest was 75 seconds. Chest compressions following dispatcher-assisted CPR instructions occurred in 62% of cases when the dispatcher had the opportunity to asses for consciousness and breathing and bystander CPR was not already started. The median time to first dispatcher-assisted CPR chest compression was 176 seconds. CONCLUSIONS: Dispatchers are able to accurately diagnose cardiac arrest over the telephone, but recognition is likely not possible in all circumstances. In some cases, recognition of cardiac arrest may be improved through training in the detection of agonal respirations. Delays in the delivery of dispatcher-assisted CPR chest compressions are common and are attributable to a mixture of dispatcher behavior and factors beyond the control of the dispatcher. Performance standards for the successful and quick recognition of cardiac arrest and delivery of first chest compressions should be adopted as metrics against which emergency medical services systems can measure their performance. PMID- 23983253 TI - Performance goals for dispatcher-assisted cardiopulmonary resuscitation. PMID- 23983254 TI - REM (risk of endometrial malignancy): a proposal for a new scoring system to evaluate risk of endometrial malignancy. AB - PURPOSE: It is often difficult to distinguish a benign endometrial disease from a malignancy and tools to help the physician are needed to triage patients into high and low risk of endometrial cancer. The purpose of this study was to obtain a predictive model to assess the risk of endometrial malignancy (REM) in women with ultrasound endometrial abnormalities. EXPERIMENTAL DESIGN: Women, between ages 45 to 80 years, diagnosed through ultrasound with endometrial abnormalities and scheduled to have surgery were enrolled on a prospective study at the Department of Gynaecologic Oncology of Campus Bio-Medico, University of Rome. Preoperative clinical, ultrasound and laboratory characteristics were taken into account. Logistic regression algorithm was used to categorize patients into low- and high-risk groups for endometrial cancer. RESULTS: A total of 675 patients were considered for the analysis: 88 with endometrial cancer and 587 with benign endometrial disease. We divided the patients into two groups: training set (TS) and verification set (VS). Preoperative age, symptom, HE4 levels, and ultrasound endometrial thickness were found statistically significant, and were included into a multivariate logistic regression model to determine the probability to have endometrial cancer. In the TS, REM reported 93.3% sensitivity and 97.1% specificity [positive predictive value (PPV), 0.83; negative predictive value (NPV), 0.98; AUC, 0.957; 95% confidence interval (CI), 0.908-0.984]. In the VS, REM reported 89.3% sensitivity and 95.4% specificity (PPV, 0.73; NPV, 0.98; AUC, 0.919; 95% CI, 0.829-0.970). CONCLUSIONS: Our data support the use of REM to triage patients into low- and high-risk groups for endometrial cancer, even if an external validation of the model is needed. PMID- 23983255 TI - A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. AB - PURPOSE: This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP 870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA). EXPERIMENTAL DESIGN: Twenty-two patients with chemotherapy-naive advanced PDA were treated with 1,000 mg/m(2) gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle. RESULTS: CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = -0.929; P = 0.007). CONCLUSIONS: CP-870,893 in combination with gemcitabine was well tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted. PMID- 23983256 TI - Association of TP53 mutational status and gender with survival after adjuvant treatment for stage III colon cancer: results of CALGB 89803. AB - PURPOSE: The TP53 tumor suppressor is frequently mutated in colon cancer, but the influence of such mutations on survival remains controversial. We investigated whether mutations in the DNA-binding domain of TP53 are associated with survival in stage III colon cancer. EXPERIMENTAL DESIGN: The impact of TP53 genotype was prospectively evaluated in Cancer and Leukemia Group B 89803, a trial that randomized stage III colon cancer patients to receive adjuvant 5 fluorouracil/leucovorin (5FU/LV) or 5FU/LV with irinotecan (IFL). RESULTS: TP53 mutations were identified in 274 of 607 cases. The presence of any TP53 mutation did not predict disease-free survival (DFS) or overall survival with either adjuvant regimen when men and women were considered together or as separate groups. However, outcome differences among women became apparent when tumor TP53 genotype was stratified as wild-type versus zinc- or non-zinc-binding mutations in the TP53 DNA-binding domain. DFS at 5 years was 0.59, 0.52, and 0.78 for women with TP53 wild-type tumors, and tumors with zinc- or non-zinc-binding mutations, respectively. Survival at 5 years for these same women was 0.72, 0.59, and 0.90, respectively. No differences in survival by TP53 genotype were observed in men. CONCLUSIONS: The presence of any TP53 mutation within the DNA-binding domain did not predict survival in stage III colon cancer. However, TP53 genotype was predictive of survival in women following adjuvant therapy. Future colon cancer therapeutic trials, with inclusion of correlative molecular markers, should be designed to permit evaluation of survival and/or response to treatment in women separately from men. PMID- 23983257 TI - Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. AB - PURPOSE: Monoclonal antibodies (mAb) that block programmed death (PD)-1 or cytotoxic T lymphocyte antigen (CTLA-4) receptors have been associated with durable clinical responses against a variety of cancer types and hold great potential as novel cancer therapeutics. Recent evidence suggest that targeted blockade of multiple immunosuppressive pathways can induce synergistic antitumor responses. EXPERIMENTAL DESIGN: In this study, we investigated whether targeted blockade of CD73, an ectonucleotidase that catabolizes the hydrolysis of extracellular adenosine monophosphate (AMP) to adenosine, can enhance the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs against transplanted and chemically induced mouse tumors. RESULTS: Anti-CD73 mAb significantly enhanced the activity of both anti-CTLA-4 and anti-PD-1 mAbs against MC38-OVA (colon) and RM-1 (prostate) subcutaneous tumors, and established metastatic 4T1.2 breast cancer. Anti-CD73 mAb also significantly enhanced the activity of anti-PD-1 mAb against 3-methylcholanthrene (MCA)-induced fibrosarcomas. Gene-targeted mice revealed that single-agent therapies and combinatorial treatments were dependent on host IFN-gamma and CD8(+) T cells, but independent of perforin. Interestingly, anti-CD73 mAb preferentially synergized with anti-PD-1 mAb. We investigated the effect of extracellular adenosine on tumor-infiltrating T cells and showed that activation of A2A adenosine receptor enhances PD-1 expression, but not CTLA-4 expression, on tumor-specific CD8+ T cells and CD4+ Foxp3+ T regulatory cells. CONCLUSIONS: Taken together, our study revealed that targeted blockade of CD73 can enhance the therapeutic activity of anti-PD-1 and anti-CTLA-4 mAbs and may thus potentiate therapeutic strategies targeting immune checkpoint inhibitors in general. PMID- 23983258 TI - Preclinical efficacy of the anti-hepatocyte growth factor antibody ficlatuzumab in a mouse brain orthotopic glioma model evaluated by bioluminescence, PET, and MRI. AB - PURPOSE: Ficlatuzumab is a novel therapeutic agent targeting the hepatocyte growth factor (HGF)/c-MET pathway. We summarize extensive preclinical work using this agent in a mouse brain orthotopic model of glioblastoma. EXPERIMENTAL DESIGN: Sequential experiments were done using eight- to nine-week-old nude mice injected with 3 * 10(5) U87 MG (glioblastoma) cells into the brain. Evaluation of ficlatuzumab dose response for this brain tumor model and comparison of its response to ficlatuzumab and to temozolamide were conducted first. Subsequently, various small-animal imaging modalities, including bioluminescence imaging (BLI), positron emission tomography (PET), and MRI, were used with a U87 MG-Luc 2 stable cell line, with and without the use of ficlatuzumab, to evaluate the ability to noninvasively assess tumor growth and response to therapy. ANOVA was conducted to evaluate for significant differences in the response. RESULTS: There was a survival benefit with ficlatuzumab alone or in combination with temozolamide. BLI was more sensitive than PET in detecting tumor cells. Fluoro-D-thymidine (FLT) PET provided a better signal-to-background ratio than 2[(18)F]fluoro-2-deoxy-d glucose (FDG) PET. In addition, both BLI and FLT PET showed significant changes over time in the control group as well as with response to therapy. MRI does not disclose any time-dependent change. Also, the MRI results showed a temporal delay in comparison to the BLI and FLT PET findings, showing similar results one drug cycle later. CONCLUSIONS: Targeting the HGF/c-MET pathway with the novel agent ficlatuzumab appears promising for the treatment of glioblastoma. Various clinically applicable imaging modalities including FLT, PET, and MRI provide reliable ways of assessing tumor growth and response to therapy. Given the clinical applicability of these findings, future studies on patients with glioblastoma may be appropriate. PMID- 23983259 TI - Phase I pharmacokinetic and pharmacodynamic study of the first-in-class spliceosome inhibitor E7107 in patients with advanced solid tumors. AB - PURPOSE: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule. EXPERIMENTAL DESIGN: Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6 to 4.5 mg/m(2) were explored. RESULTS: Forty patients [24M/16F, median age 61 years (45-79)] were enrolled. At 4.5 mg/m(2), dose-limiting toxicity (DLT) consisted of grade 3 diarrhea, nausea, and vomiting and grade 4 diarrhea, respectively, in two patients. At 4.0 mg/m(2), DLT (grade 3 nausea, vomiting, and abdominal cramps) was observed in one patient. Frequently occurring side effects were mainly gastrointestinal. After drug discontinuation at 4.0 mg/m(2), one patient experienced reversible grade 4 blurred vision. The maximum tolerated dose (MTD) is 4.0 mg/m(2). No complete or partial responses during treatment were observed; one patient at 4.0 mg/m(2) had a confirmed partial response after drug discontinuation. Pharmacokinetic analysis revealed a large volume of distribution, high systemic clearance, and a plasma elimination half-life of 5.3 to 15.1 hours. Overall drug exposure increased in a dose dependent manner. At the MTD, mRNA levels of selected target genes monitored in peripheral blood mononuclear cells showed a reversible 15- to 25-fold decrease, whereas unspliced pre-mRNA levels of DNAJB1 and EIF4A1 showed a reversible 10- to 25-fold increase. CONCLUSION: The MTD for E7107 using this schedule is 4.0 mg/m(2). Pharmacokinetics is dose-dependent and reproducible within patients. Pharmacodynamic analysis revealed dose-dependent reversible inhibition of pre mRNA processing of target genes, confirming proof-of-principle activity of E7107. PMID- 23983260 TI - In pursuit of dark matter. PMID- 23983262 TI - Polo-like kinase 2 regulates selective autophagic alpha-synuclein clearance and suppresses its toxicity in vivo. AB - An increase in alpha-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering alpha-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances alpha-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of alpha-synuclein requires both phosphorylation at S129 and PLK2/alpha-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human alpha synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by alpha-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and alpha-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of alpha-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies. PMID- 23983263 TI - Inhibition of SMG-8, a subunit of SMG-1 kinase, ameliorates nonsense-mediated mRNA decay-exacerbated mutant phenotypes without cytotoxicity. AB - Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance mechanism that eliminates aberrant mRNAs containing premature termination codons (PTCs). NMD inhibits the production of aberrant proteins that still retain, at least in part, wild-type function as well as dominant-negative peptides. Therefore, the selective inhibition of NMD has the potential to ameliorate NMD-exacerbated mutant phenotypes. However, we do not have sufficient knowledge of how to effectively suppress NMD with minimum cytotoxic effects. In this study, we aimed to identify NMD-related factors that can be targeted to efficiently inhibit NMD without causing significant cytotoxicity to restore the levels of truncated but partially functional proteins. We evaluated the knockdown of 15 NMD components in Ullrich congenital muscular dystrophy fibroblasts, which have a homozygous frameshift mutation causing a PTC in the collagen type VI alpha 2 gene. Of the 15 NMD factors tested, knockdown of SMG-8 produced the best effect for restoring defective mRNA and protein levels without affecting cell growth, cell-cycle progression, or endoplasmic reticulum stress. The efficacy of SMG-8 knockdown to improve the mutant phenotype was confirmed using another cell line, from a cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy patient who carries a PTC-containing mutation in HtrA serine peptidase 1. Our results suggest that SMG-8 is an appropriate target for inhibiting NMD to improve NMD-exacerbated mutant phenotypes. NMD inhibition by knockdown of SMG-8 may also be useful to induce synergy in combining the use of read-through drugs for patients with nonsense mutation-associated diseases. PMID- 23983264 TI - Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism. AB - Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism. PMID- 23983265 TI - Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis. AB - Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women associated with the metastasis of tuberin-null cells with hyperactive mammalian target of rapamycin complex 1 (mTORC1) activity. Clinical trials with the mTORC1 inhibitor rapamycin have revealed partial efficacy but are not curative. Pregnancy appears to exacerbate LAM, suggesting that estrogen (E2) may play a role in the unique features of LAM. Using a LAM patient-derived cell line (bearing biallelic Tuberin inactivation), we demonstrate that E2 stimulates a robust and biphasic activation of ERK2 and transcription of the late response-gene Fra1 associated with epithelial-to-mesenchymal transition. In a carefully orchestrated collaboration, activated mTORC1/S6K1 signaling enhances the efficiency of Fra1 translation of Fra1 mRNA transcribed by the E2-ERK2 pathway, through the phosphorylation of the S6K1-dependent eukaryotic translation initiation factor 4B. Our results indicate that targeting the E2-ERK pathway in combination with the mTORC1 pathway may be an effective combination therapy for LAM. PMID- 23983266 TI - Recovery of a top predator mediates negative eutrophic effects on seagrass. AB - A fundamental goal of the study of ecology is to determine the drivers of habitat forming vegetation, with much emphasis given to the relative importance to vegetation of "bottom-up" forces such as the role of nutrients and "top-down" forces such as the influence of herbivores and their predators. For coastal vegetation (e.g., kelp, seagrass, marsh, and mangroves) it has been well demonstrated that alterations to bottom-up forcing can cause major disturbances leading to loss of dominant vegetation. One such process is anthropogenic nutrient loading, which can lead to major changes in the abundance and species composition of primary producers, ultimately affecting important ecosystem services. In contrast, much less is known about the relative importance of apex predators on coastal vegetated ecosystems because most top predator populations have been depleted or lost completely. Here we provide evidence that an unusual four-level trophic cascade applies in one such system, whereby a top predator mitigates the bottom-up influences of nutrient loading. In a study of seagrass beds in an estuarine ecosystem exposed to extreme nutrient loading, we use a combination of a 50-y time series analysis, spatial comparisons, and mesocosm and field experiments to demonstrate that sea otters (Enhydra lutris) promote the growth and expansion of eelgrass (Zostera marina) through a trophic cascade, counteracting the negative effects of agriculturally induced nutrient loading. Our results add to a small but growing body of literature illustrating that significant interactions between bottom-up and top-down forces occur, in this case with consequences for the conservation of valued ecosystem services provided by seagrass. PMID- 23983267 TI - Are monarch butterflies true navigators? The jury is still out. PMID- 23983268 TI - An unusual case of anomalous origin of the right coronary artery and hepatic focal nodular hyperplasia. AB - Anomalous origin of the right coronary artery (ARCA) and focal nodular hyperplasia (FNH) are frequently reported in association with congenital heart abnormalities but not with each other. We propose that both conditions may share common origins in a maladative hyperplastic response to differential vascular flow due to developmental arterial malformations or aberrant Notch signalling during simultaneous gut and cardiac vasculorigenesis. PMID- 23983269 TI - Effect of volume-oriented versus flow-oriented incentive spirometry on chest wall volumes, inspiratory muscle activity, and thoracoabdominal synchrony in the elderly. AB - BACKGROUND: Aging causes physiological and functional changes that impair pulmonary function. Incentive spirometry is widely used for lung expansion, but the effects of volume-oriented incentive spirometry (VIS) versus flow-oriented incentive spirometry (FIS) on chest wall volumes, inspiratory muscle activity, and thoracoabdominal synchrony in the elderly are poorly understood. We compared VIS and FIS in elderly subjects and healthy adult subjects. METHODS: Sixteen elderly subjects (9 women, mean +/- SD age 70.6 +/- 3.9 y, mean +/- SD body mass index 23.8 +/- 2.5 kg/m(2)) and 16 healthy adults (8 women, mean +/- age 25.9 +/- 4.3 y, mean +/- body mass index 23.6 +/- 2.4 kg/m(2)) performed quiet breathing, VIS, and FIS in randomized sequence. Chest wall kinematics (via optoelectronic plethysmography) and inspiratory muscle activity (via surface electromyography) were assessed simultaneously. Synchrony between the superior thorax and abdominal motion was calculated (phase angle). RESULTS: In the elderly subjects both types of incentive spirometry increased chest wall volumes similarly, whereas in the healthy adult subjects VIS increased the chest wall volume more than did FIS. FIS and VIS triggered similar lower thoracoabdominal synchrony in the elderly subjects, whereas in the healthy adults FIS induced lower synchrony than did VIS. FIS required more muscle activity in the elderly subjects to create an increase in chest wall volume. CONCLUSIONS: Incentive spirometry performance is influenced by age, and the differences between elderly and healthy adults response should be considered in clinical practice. PMID- 23983270 TI - Is a nasopharyngeal tube effective as interface to provide bi-level noninvasive ventilation? AB - BACKGROUND: The nasopharyngeal tube (NT) is a potential interface for noninvasive ventilation (NIV) available in all health care centers. The aim of the study was to describe our experience in the use of the NT for bi-level NIV in infants and its effectiveness. METHODS: Prospective observational study from January 2007 to December 2010, including all patients <= 6 months old admitted to the pediatric ICU (PICU) and treated with NIV with two levels of pressure using the NT. Clinical data collected before starting NIV, and at 2, 8, 12 and 24 h, were analyzed following NIV initiation: first-line or initial NIV (i-NIV), elective postextubation NIV (e-NIV), and rescue postextubation NIV (r-NIV). The need for intubation was considered to be NIV failure. RESULTS: One hundred fifty-one episodes of NIV were included in the study, with 65% of patients having bronchiolitis. e-NIV was most frequently used (48%) (i-NIV 44%, r-NIV 8%), and the failure rate, 27% in total, was highest in the i-NIV group (37%) (e-NIV 18%, r-NIV 25%). Case patients with successful outcomes had shorter PICU stays (8.5 vs. 13 d, P = .001) and hospital stays (17 vs. 23 d, P = .03) stays. The NT needed to be changed for another interface in only 5 case patients, few complications (4 of 151 patients) were observed, and mortality (2 of 151 patients) was unrelated to NIV. CONCLUSIONS: Use of the NT showed 73% effectiveness, with few complications. The effectiveness was higher in e-NIV than i-NIV. PMID- 23983271 TI - Measuring gait speed in the out-patient clinic: methodology and feasibility. AB - BACKGROUND: Gait speed is a simple physical function measure associated with key outcomes in the elderly population. Gait speed measurements may improve clinical care in patients with COPD. However, there is a knowledge gap about the reliability and variability of gait speed testing protocols in COPD. We evaluated established techniques of measuring gait speed in patients with COPD and assessed feasibility of implementing gait speed as a routine vital sign in an out-patient clinic. METHODS: The usual 4-meter gait speed (4MGS) ("walk at a comfortable/natural pace"), maximal 4MGS ("walk as fast as you can safely"), usual 10-meter gait speed (10MGS), and maximal 10MGS of subjects with stable COPD were measured. Walks were measured using a stopwatch and automated timing system. For the feasibility/implementation phase, patients from the entire spectrum of respiratory diseases completed acceptability surveys, and clinical assistants administered gait speed measurements using an automated timing system. Time to train and to administer the test and acceptability by the staff were evaluated. RESULTS: Seventy subjects enrolled; 60% were men, and the mean age +/- SD was 69 +/- 10 years. All methods showed excellent test-retest reliability (intraclass correlation coefficient of 0.95-0.97). The difference between the two timing systems did not exceed the suggested minimal clinically important difference of 0.1 m/s for the usual pace instructions but did exceed 0.1 m/s for maximal pace walks. The difference between 4MGS and 10MGS was 0.13 +/- 0.10 m/s. FEASIBILITY: Most subjects reported that gait speed measurement prior to clinic appointment was very acceptable (66%) or acceptable (33%). Time added to clinic visit measuring 4MGS was 95 +/- 20 seconds, and clinical assistants reported gait speed measurements as very acceptable (60%), acceptable (30%), and somewhat acceptable (10%). CONCLUSIONS: Gait speed is a reliable measure in COPD, regardless of instructed pace, distance, or timing mechanism; however, adhering to one protocol is suggested. 4MGS was easily implemented into clinical practice with high acceptability by patients and clinic staff. PMID- 23983272 TI - Exercise training in patients with chronic respiratory failure due to kyphoscoliosis: a randomized controlled trial. AB - BACKGROUND: Research has provided evidence for the safety, feasibility, and efficacy of exercise training in patients with COPD. However, little is known about the impact of exercise training in patients with chronic respiratory failure due to kyphoscoliosis. We evaluated the effect of an exercise training program on exercise capacity, muscle strength, dyspnea, and quality-of-life indices in subjects with chronic respiratory failure due to kyphoscoliosis. METHODS: The 34 subjects were clinically stable, had been receiving nighttime home mechanical ventilation for >= 6 months, and were randomly assigned to the exercise group (n = 17) or the control group (n = 17). The exercise group conducted cycle and strength training on 3 non-consecutive days per week for 12 weeks. We measured pulmonary function, exercise capacity, peripheral muscle strength, dyspnea scores, and quality of life. RESULTS: Statistical analysis was carried out on the data from 16 subjects in the exercise group and in 11 subjects in the control group. Three of the lung-function parameters in the exercise group significantly changed: PaCO2 (P = .04), inspiratory pressure (P = .03), and expiratory pressure (P = .04); and endurance time (P = .002) and shuttle walk distance (P = .001) increased significantly. The exercise group had significantly greater improvements in peripheral muscle strength, dyspnea, and quality of life. CONCLUSIONS: In patients with chronic respiratory failure due to kyphoscoliosis, exercise training improved exercise capacity, peripheral muscle strength, dyspnea, and quality of life. (Deutschen Register Klinischer Studien DRKS00000443). PMID- 23983273 TI - Chronic Pseudomonas aeruginosa infection and respiratory muscle impairment in cystic fibrosis. AB - BACKGROUND: Chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) is associated with increased morbidity. Chronic infection can cause limb and respiratory muscle compromise. Respiratory muscle function can be assessed via maximal inspiratory pressure (PImax), maximal expiratory pressure (PEmax), and the pressure-time index of the respiratory muscles (PTImus). We studied the effect of chronic P. aeruginosa infection on respiratory muscle function in patients with CF. METHODS: This cross-sectional study assessed PImax, PEmax, PTImus, FEV1, FVC, maximum expiratory flow during the middle half of the FVC maneuver, body mass index, and upper arm muscle area in 122 subjects with CF, in 4 subgroups matched for age and sex at different stages of P. aeruginosa infection, according to the Leeds criteria. We compared respiratory muscle function in the subgroups according to P. aeruginosa infection state. RESULTS: Median PImax was significantly lower in CF subjects with chronic P. aeruginosa infection (PImax = 62 cm H2O), compared to subjects who were never infected (PImax = 86 cm H2O, P = .02), free of infection (PImax = 74 cm H2O, P = .01), or intermittently infected (PImax = 72 cm H2O, P = .02). Median PTImus was significantly increased in CF subjects with chronic P. aeruginosa infection (PTImus = .142), compared to subjects who were free of infection (PTImus = .102, P = .006). Median upper-arm muscle area was significantly lower in CF subjects with chronic P. aeruginosa infection (upper-arm muscle area = 2,219 mm(2)), compared to subjects who were never infected (2,754 mm(2), P = .03), free of infection (2,678 mm(2), P = .01), or intermittently infected (2,603 mm(2), P = .04). Multivariate logistic regression revealed P. aeruginosa state of infection as a significant determinant of PTImus (P = .03) independently of sex, upper-arm muscle area, and FEV1. CONCLUSIONS: CF subjects with chronic P. aeruginosa infection exhibited impaired respiratory muscle function and decreased inspiratory muscle strength, and chronic P. aeruginosa infection independently impacts respiratory muscle function in subjects with CF. PMID- 23983274 TI - Tobramycin inhalation powder in cystic fibrosis patients: response by age group. AB - BACKGROUND: Tobramycin powder for inhalation (TIP) is a drug-device combination designed to reduce treatment time and improve ease of use compared with tobramycin inhalation solution (TIS) in cystic fibrosis (CF) patients. However, the ability of patients to use dry powder inhalers, and the efficacy of the treatments, may vary by age. METHODS: The "Establish a New Gold Standard for Efficacy and Safety With Tobramycin in Cystic Fibrosis" (EAGER) trial was a randomized, 24-week, multicenter, open-label, parallel-group study designed to evaluate the safety of TIP versus TIS in 553 subjects, ages >= 6 years, with CF and P. aeruginosa infection. The main efficacy end point was percent-of-predicted FEV1 at week 20 (end of third cycle of treatment). A post hoc analysis was undertaken in 517 subjects who took >= 1 dose of study medication, to evaluate the relative efficacy and safety of TIP and TIS by age group: >= 6 to < 13 y (children, n = 46); >= 13 to < 20 y (adolescents, n = 114); and >= 20 y (adults, n = 357). RESULTS: Improvements in percent-of-predicted FEV1 from baseline to end of cycle 3 were greatest in the children for both TIP and TIS. The treatment differences (TIP - TIS) were 4.7% (85% CI -1.2 to 10.6), 3.7% (85% CI -0.1 to 7.5), and -0.8% (85% CI -3.1 to 1.5) in children, adolescents, and adults, respectively. Sputum P. aeruginosa density decreased from baseline with both treatments, with comparable treatment differences across the age groups after 3 cycles: children -0.93 (85% CI -2.4 to 0.5), adolescents -0.17 (85% CI -1.2 to 0.8), and adults -0.89 (85% CI -1.3 to -0.4). Overall, subject satisfaction scores were greater in all subjects with TIP, irrespective of age group. With the exception of cough and dysphonia, the safety profile of TIP was comparable to TIS, irrespective of age. CONCLUSIONS: TIP is comparable to TIS in efficacy outcomes and safety profile but had greater patient satisfaction in all the age groups. PMID- 23983275 TI - Persistent-mode high-temperature superconductor shim coils: A design concept and experimental results of a prototype Z1 high-temperature superconductor shim. AB - Design, fabrication, and test results of a type persistent-mode high-temperature superconductor (HTS) shim coil are presented. A prototype Z1 rectangle-loop shim, cut from 46-mm wide Y-Ba-Cu-O tape manufactured by AMSC, was fabricated and tested at 77 K. The HTS shim, much thinner than the conventional NbTi shim, is placed inside the main magnet and immune to its diamagnetic wall effects. Combined with the >12-T and >10-K operation capability, the HTS shim offers a versatile design option for nuclear magnetic resonance (NMR) magnets, liquid helium-free as well as conventional, and is particularly attractive in the next generation NMR magnets. PMID- 23983276 TI - Detection of foreign body using fast thermoacoustic tomography with a multielement linear transducer array. AB - Current imaging modalities face challenges in clinical applications due to limitations in resolution or contrast. Microwave-induced thermoacoustic imaging may provide a complementary modality for medical imaging, particularly for detecting foreign objects due to their different absorption of electromagnetic radiation at specific frequencies. A thermoacoustic tomography system with a multielement linear transducer array was developed and used to detect foreign objects in tissue. Radiography and thermoacoustic images of objects with different electromagnetic properties, including glass, sand, and iron, were compared. The authors' results demonstrate that thermoacoustic imaging has the potential to become a fast method for surgical localization of occult foreign objects. PMID- 23983277 TI - Safety first, safety at early age: The quagmire of neurotoxicity in paediatric anaesthesia. PMID- 23983279 TI - A simple method for evaluation of the uptake of isoflurane and its comparison with the square root of time model. AB - BACKGROUND: The square root of time (SqRT) model had been used to predict the uptake of volatile agents. METHODS: We studied the rate of uptake of isoflurane in 10 patients using liquid isoflurane infusion through syringe pump into the closed circuit. The infusion rates were titrated to maintain a constant end tidal concentration of isoflurane of 1.5%. The predicted uptake values were also calculated from the square root principle and compared with the derived uptake. RESULTS: The observed rate of uptake was higher than predicted from the Lowe and Ernst equation (P<0.001). There exists considerable inter-individual variability in uptake pharmacokinetics and it showed statistically significant correlation with ideal body weight, body weight (P<0.01), body surface area, and body weight3/4 from 30 min of start of isoflurane infusion (P<0.05). CONCLUSION: SqRT model is inaccurate in predicting isoflurane uptake and underestimates it during closed circuit anaesthesia. PMID- 23983278 TI - Perioperative ischaemia-induced liver injury and protection strategies: An expanding horizon for anaesthesiologists. AB - Liver resection is an effective modality of treatment in patients with primary liver tumour, metastases from colorectal cancers and selected benign hepatic diseases. Its aim is to resect the grossly visible tumour with clear margins and to ensure that the remnant liver mass has sufficient function which is adequate for survival. With the advent of better preoperative imaging, surgical techniques and perioperative management, there is an improvement in the outcome with decreased mortality. This decline in postoperative mortality after hepatic resection has encouraged surgeons for more radical liver resections, leaving behind smaller liver remnants in a bid to achieve curative surgeries. But despite advances in diagnostic, imaging and surgical techniques, postoperative liver dysfunction of varied severity including death due to liver failure is still a serious problem in such patients. Different surgical and non-surgical techniques like reducing perioperative blood loss and consequent decreased transfusions, vascular occlusion techniques (intermittent portal triad clamping and ischaemic preconditioning), administration of pharmacological agents (dextrose, intraoperative use of methylprednisolone, trimetazidine, ulinastatin and lignocaine) and inhaled anaesthetic agents (sevoflurane) and opioids (remifentanil) have demonstrated the potential benefit and minimised the adverse effects of surgery. In this article, the authors reviewed the surgical and non surgical measures that could be adopted to minimise the risk of postoperative liver failure following liver surgeries with special emphasis on ischaemic and pharmacological preconditioning which can be easily adapted clinically. PMID- 23983280 TI - Effect of previous scorpion bite(s) on the action of intrathecal bupivacaine: A case control study. AB - BACKGROUND: During the routine practice in the institution, it was observed that there were persistent incidents of inadequate/failed spinal anaesthesia in patients with a history of single or multiple scorpion bite/s. To test any possible correlation between scorpion bite and the altered response to spinal anaesthesia, a case control study was conducted involving patients with a history of scorpion bite/s and without such a history. METHODS: Randomly selected 70 (n=70) patients of either sex and age range of 18-80 years, were divided into two equal groups, giving past history of one or multiple scorpion bites and giving no such a history. The anaesthetic management was identical inclusive of subarachnoid block with 3.5 ml. 0.5% bupivacaine heavy. The onsets of sensory, motor and peaks of sensory and motor blocks were observed with the pin-prick method and Bromage scale. After waiting for 20 min, if the block was inadequate, then balanced general anaesthesia was administered. The analysis of the data and application of various statistical tests was carried out using Chi-square test, percentages, independent sample t-test and paired t-test. RESULTS: Demographically both groups were comparable. In scorpion bite group, the time of onsets of both sensory and motor blocks and time for the peak of sensory and motor blocks were significantly prolonged, 4 patients had failed/inadequate sensory block and 5 patients had failed/inadequate motor block while all the patients in non-bite group had adequate intra-operative block. CONCLUSION: We conclude that there appears to be a direct correlation between the histories of old, single or multiple scorpion bites and development of resistance to effect of local anaesthetics administered intra-thecally. PMID- 23983281 TI - Organ retrieval and banking in brain dead trauma patients: Our experience at level-1 trauma centre and current views. AB - BACKGROUND: Organ retrieval from brain dead patients is getting an increased attention as the waiting list for organ recipients far exceeds the organ donor pool. In our country, despite a large population the number of brain dead donors undergoing organ donation is very less (2% in our study). AIMS: The present study was undertaken to address issues related to organ donation and share our experience for the same. METHODS: A retrospective case record analysis of over 5 years from September 2007 to August 2012 was performed and the patients fulfilling brain death criterion as per Transplantation of Human Organs and Tissue (Amendment) Act were included. Patient demographics (age, sex), mode of injury, time from injury to the diagnosis of brain death, time from diagnosis of brain death to organ retrieval and complications were analysed. STATISTICS ANALYSIS: Student's t test was used for parametric data and Chi square was used for categorical data. RESULTS: Out of 205 patients who were identified as brain dead, only 10 patients became potential organ donors. CONCLUSION: Aggressive donor management, increasing public awareness about the concept of organ donation, good communication between clinician and the family members and a well trained team of transplant coordinators can help in improving the number of organ donations. PMID- 23983283 TI - Anaesthesia for laparoscopic kidney transplantation: Influence of Trendelenburg position and CO2 pneumoperitoneum on cardiovascular, respiratory and renal function. AB - BACKGROUND: Laparoscopic donor nephrectomy is a routine practice since 1995. Until now, the recipient has always undergone open surgery for transplantation. In our institute, laparoscopic kidney transplantation (LKT) started in 2010. To facilitate this surgery, the patient must be in steep Trendelenburg position for a long duration. Hence, we decided to study the effect of CO2 pnuemoperitoneum and Trendelenburg position in chronic renal failure (CRF) patients undergoing LKT. METHODS: A total of 20 adult CRF patients having mean age of 31.7+/-10.36 years and body mass index 19.65+/-3.41 kg/m(2) without significant coronary artery disease were selected for the procedure. Cardiovascular parameters heart rate (HR), mean arterial pressure (MAP), Central venous pressure (CVP) and respiratory parameters (ETCO2, peak airway pressure) were noted at the time of induction, after induction, 15 min after creation of pnuemoperitoneum, 30 min after Trendelenburg position, 15 min after decompression of pnuemoperitonuem and after extubation. Arterial blood gas analysis was carried out after induction, 15 min after creation of pnuemoperitoneum, 30 min after Trendelenburg position and 15 min after clamp release. Total duration of surgery, anastomosis time, time for the establishment of urine output and total urine output were noted. Serum creatinine on the 1(st) and 7(th) post-operative day were recorded. RESULTS: Significant increase in HR was observed after creation of CO2 pneumoperitoneum and just before extubation. Significant increase in the MAP and CVP was noted after creation of pneumoperitoneum and after giving Trendelenburg position. No significant rise in the ETCO2 and PaCO2 was observed. Significant increase in the base deficit was observed after the clamp release, but none of the patients required correction. CONCLUSION: LKT performed in steep Trendelenburg position with CO2 pneumoperitoneum significantly influenced cardiovascular and respiratory homeostasis; however, measured parameters remained within clinically acceptable range without affecting early function of the transplanted kidney. PMID- 23983282 TI - Comparative evaluation of gum-elastic bougie and introducer tool as aids in positioning of ProSeal laryngeal mask airway in patients with simulated restricted neck mobility. AB - BACKGROUND: The ProSeal laryngeal mask airway (PLMA) is a unique laryngeal mask with a modified cuff to improve seal and a channel to facilitate gastric tube placement. This is a better device in difficult airway situations compared to classic laryngeal mask airway. This prompted us to study the ease of insertion and positioning of PLMA in patients with simulated restricted neck mobility while using gum elastic bougie (GEB) group or introducer tool (group IT) to aid insertion. METHODS: Sixty ASA I or II patients, aged between 18 years and 60 years, undergoing minor non-head and neck surgeries in the supine position were studied. A rigid neck collar was used to simulate restricted neck mobility in all patients. After anaesthetising the patients with a standard protocol, the PLMA was inserted using either of the technique using the tongue depressor to open the mouth. The ease of insertion, positioning, haemodynamic responses to insertion and other complications related to the procedure were noted. RESULTS: Regarding demographic variables, both groups were similar. The mean time taken for insertion of PLMA in group GEB was 67.80 s as compared to 46.79 s in group IT (P<0.05). Patients of group GEB had better positioning assessed by an intubating fiberscope with less end tidal carbon-di-oxide (ETCO2) values. Systolic and diastolic blood pressures were similar. The incidence of sore throat, dysphagia, and dysphonia were higher in IT group in the 12 h, but similar in 24 h. CONCLUSION: Guided insertion technique with GEB took a longer time, but had a better positioning and lower ETCO2 values when compared to IT technique. PMID- 23983284 TI - Comparison of classic laryngeal mask airway with Ambu laryngeal mask for tracheal tube exchange: A prospective randomized controlled study. AB - BACKGROUND AND AIM: Exchanging endotracheal tube (ETT) with classic laryngeal mask airwayTM (CLMATM) prior to emergence from anaesthesia is a safe technique to prevent the coughing and haemodynamic changes during extubation. We had compared CLMATM and AMBU laryngeal maskTM (ALMTM) during ETT/laryngeal mask (LM) for haemodynamic changes and other parameters. METHODS: A total of 100 American Society of Anesthesiologist Grade I and II adult female patients undergoing elective laparoscopic cholecystectomy under general anaesthesia were selected and randomly divided into two groups of 50 patients each. In Group I, CLMATM and in Group II, ALMTM was placed prior to tracheal extubation. Haemodynamic parameters were recorded during ETT/LM exchange. Glottic view was seen through the LM using flexible fibrescope. Coughing/bucking during removal of LM, ease of placement and post-operative sore throat for both groups were graded and recorded. STATISTICAL ANALYSIS: Data within the groups was analysed using paired t-test while between the groups was analysed using unpaired t-test. Chi-square test was used to analyse grades of glottic view, coughing, and post-operative sore throat. RESULTS: In Group I, there was a significant rise in systolic blood pressure and heart rate in contrast to insignificant rise in Group II. Glottis view was significantly better in Group II. Incidence of coughing, ease of placement and post-operative sore throat was identical between both groups. CONCLUSION: ALMTM is superior to CLMATM for exchange of ETT before extubation due to greater haemodynamic stability during exchange phase and is better positioned. PMID- 23983285 TI - Effect of supplementation of low dose intravenous dexmedetomidine on characteristics of spinal anaesthesia with hyperbaric bupivacaine. AB - AIMS: Intravenous (IV) dexmedetomidine with excellent sedative properties has been shown to reduce analgesic requirements during general anaesthesia. A study was conducted to assess the effects of IV dexmedetomidine on sensory, motor, haemodynamic parameters and sedation during subarachnoid block (SAB). METHODS: A total of 50 patients undergoing infraumbilical and lower limb surgeries under SAB were selected. Group D received IV dexmedetomidine 0.5 mcg/kg bolus over 10 min prior to SAB, followed by an infusion of 0.5 mcg/kg/h for the duration of the surgery. Group C received similar volume of normal saline infusion. Time for the onset of sensory and motor blockade, cephalad level of analgesia and duration of analgesia were noted. Sedation scores using Ramsay Sedation Score (RSS) and haemodynamic parameters were assessed. RESULTS: Demographic parameters, duration and type of surgery were comparable. Onset of sensory block was 66+/-44.14 s in Group D compared with 129.6+/-102.4 s in Group C. The time for two segment regression was 111.52+/-30.9 min in Group D and 53.6+/-18.22 min in Group C and duration of analgesia was 222.8+/-123.4 min in Group D and 138.36+/-21.62 min in Group C. The duration of motor blockade was prolonged in Group D compared with Group C. There was clinically and statistically significant decrease in heart rate and blood pressures in Group D. The mean intraoperative RSS was higher in Group D. CONCLUSION: Administration of IV dexmedetomidine during SAB hastens the onset of sensory block and prolongs the duration of sensory and motor block with satisfactory arousable sedation. PMID- 23983286 TI - A prospective randomised trial to compare the efficacy of povidone-iodine 10% and chlorhexidine 2% for skin disinfection. AB - CONTEXT: Infectious complications of invasive procedures affect patient outcomes adversely. Choice of antiseptic solution at the time of insertion is one of the major factors affecting their incidence. AIMS: This study was undertaken to compare efficacy of chlorhexidine 2% and povidone iodine 10% for skin disinfection prior to placement of epidural and central venous catheters (CVCs). SETTINGS AND DESIGN: A prospective randomised trial in the operating rooms of a tertiary referral cancer centre. METHODS: Sixty consecutive adult patients undergoing elective oncosurgery requiring placement of epidural and CVCs were enrolled. Paired skin swabs were collected before and after application of the antiseptic solution. The samples were incubated in McConkey's media and blood agar at 35 degrees C for up to 24 h. Any bacterial growth was graded as: <10 colonies - poor growth, 10-50 colonies - moderate growth and >50 colonies as heavy growth. Data on demographics and antibiotic prophylaxis and costs was collected for all patients. STATISTICAL ANALYSIS: Student's t-test and Mann Whitney tests were used to analyse data, P<0.05 was considered significant. RESULTS: Demographics and antibiotic prophylaxis use was similar in both groups. Before application of antiseptic solution, a variety of micro-organisms were grown from most patients with growth ranging from none-heavy. No organism was grown after application of either antiseptic solution from any patient. CONCLUSIONS: We found no differences between 2% chlorhexidine and 10% povidone iodine for skin disinfection in regard to costs, efficacy or side-effects. PMID- 23983287 TI - Role of the Truview EVO2 laryngoscope in the airway management of elective surgical patients: A comparison with the Macintosh laryngoscope. AB - BACKGROUND: The Truview EVO2(C) laryngoscope (TL) is a recently introduced optical device designed to provide an unmagnified anterior image of the glottic opening and allow indirect laryngoscopy. AIM: This study is designed to determine whether the TL is a better alternative to the Macintosh laryngoscope (ML) for routine endotracheal intubations in patients with usual airway characteristics. METHODS: We compared the Truview EVO2(C) and MLs in 140 elective surgical patients requiring general anaesthesia and intubation in a prospective crossover fashion. The two blades were compared in terms of Cormack and Lehane grades, time required for intubation, anaesthetists' assessment of ease of intubation, intubation difficulty score, attempts at intubation, success rate, soft tissue damage and arterial oxygen saturation during laryngoscopy. The Student t test and Chi-square test were used to determine the statistical significance of parametric data and categorical data, respectively. RESULTS: The Truview EVO2(C) blade provided a better laryngoscopic view than the Macintosh blade as suggested by improved Cormack and Lehane grades (in 48 patients), but required a longer time for intubation than the Macintosh blade (34.1 vs. 22.4 s), i.e., an improved view at the cost of longer mean intubation time. In spite of lower intubation difficulty scores, Truview EVO2(C) was considered as difficult to use on subjective assessment by the anaesthesiologist when compared with Macintosh. There was no difference observed between the two groups in attempts at intubation, success rate, soft tissue damage and arterial oxygen saturation during laryngoscopy. CONCLUSION: We opine that although Truview provides a better laryngoscopic view than Macintosh in difficult cases, it does not have an extra benefit over Macintosh otherwise, further indicating the need for more experience with the use of a Truview laryngoscope. PMID- 23983288 TI - Kounis syndrome resulting from anaphylaxis to diclofenac. AB - "Kounis syndrome" refers to acute coronary syndromes of varying degree (myocardial ischaemia to infarction) induced by mast cell activation as a result of allergic and anaphylactic reactions. ST-segment elevated myocardial infarction is a rare complication that can occur even in patients with normal coronary arteries due to anaphylactic reactions. We present a case that developed acute myocardial infarction following a diclofenac sodium-induced anaphylaxis. The patient did not have any previous coronary artery disease, but there was a temporal relationship with development of the anaphylactic reaction due to diclofenac sodium and the cardiac event. The patient was managed conservatively and the recovery was uneventful. PMID- 23983289 TI - Laryngeal dislocation after ventral fusion of the cervical spine. AB - We report on a 70-year-old patient who underwent ventral fusion of the cervical spine (C3/4 and C4/5) for spinal canal stenosis performed by the neurosurgery department. The patient suffered an exceedingly rare complication of the surgery laryngeal dislocation. Had the deformed laryngeal structures been overlooked and the patient extubated as usual after surgery, reintubation would have been impossible due to the associated swelling, which might have had disastrous consequences. Leftward dislocation of the larynx became apparent post operatively, but prior to extubation. Extubation was therefore postponed and a subsequent computed tomography (CT) scan revealed entrapment of laryngeal structures within the osteosynthesis. A trial of repositioning using microlaryngoscopy performed by otolaryngology (ears, nose and throat) specialists failed, making open surgical revision necessary. At surgery, the entrapped laryngeal tissue was successfully mobilised. Laryngeal oedema developed despite prompt repositioning; thus, necessitating tracheotomy and long-term ventilation. Laryngeal dislocation may be an unusual cause of post-operative neck swelling after anterior cervical spine surgery and should be considered in the differential diagnosis if surgical site haematoma and other causes have been ruled out. Imaging studies including CT of the neck may be needed before extubation to confirm the suspicion and should be promptly obtained to facilitate specific treatment. PMID- 23983290 TI - Dexmedetomidine overdosage: An unusual presentation. AB - We present a case of dexmedetomidine toxicity in a 3-year-old child. The case report describes the features and outlines the treatment strategy adopted. The child presented with bradypnoea, bradycardia, hypotension, deep hypnosis and miosis. He was successfully managed with oxygen, saline boluses and adrenaline infusion. He became haemodynamically stable with adrenaline infusion. He started responding to painful stimuli in 3 h and became oriented in 7 h. Dexmedetomidine, a selective alpha2 adrenoceptor agonist, is claimed to have a wide safety margin. This case report highlights the fact that dexmedetomidine administered in a toxic dose may be life-threatening may present with miosis and adrenaline infusion may be a useful supportive treatment. PMID- 23983291 TI - Anaesthetic management of a neonate with Kasabach-Merritt syndrome. AB - Kasabach-Merritt syndrome is characterised by giant haemangioma, thrombocytopenia and coagulopathy. Triggering of disseminated intravascular coagulation along with the need for massive blood transfusion is the major intraoperative complication. A 1-month-old boy was scheduled for excision and split skin grafting of a giant haemangioma over the left thigh. Investigations revealed severe anaemia with thrombocytopenia that was uncorrected despite multiple blood transfusions. Other treatment modalities were also unsuccessful and the neonate was taken up for excision of the haemangioma in order to correct the consumptive coagulopathy. Standard anaesthesia was administered and all appropriate measures to reduce blood loss were instituted. Massive blood transfusion was required but the intraoperative and post-operative period was uneventful and followed by a significant improvement in the haemoglobin and platelet counts in the post operative period. PMID- 23983292 TI - Anaesthetic management of previously non-diagnosed phaeochromocytoma: Clinical vigilance, the ultimate saviour of anaesthesiologist. AB - A 39-year-old male, post nephrectomy and adrenalectomy (right), was planned for adrenalectomy (left) and radiofrequency ablation of left renal mass. Clinical evaluation indicated a possibility of phaeochromocytoma, whereas biochemical parameters were found to be within normal limits. Intraoperatively, massive fluctuations in haemodynamic parameters were noticed while the tumour was being handled. Patient was stabilised with inotropes, vasopressors, fluids and careful titration of anaesthetic agents. Preoperatively diagnosed coronary disease could have complicated anaesthetic care. Optimum and modern anaesthetic care leads to safe execution of surgery. PMID- 23983294 TI - Fibrodysplasia of maxilla: A difficult airway. PMID- 23983293 TI - Ultra fast-tracking versus a conventional strategy in valve replacement surgery. PMID- 23983295 TI - Anaesthetic management of an unrecognized cerebral arteriovenous malformation bleed in a 45-day old baby. PMID- 23983297 TI - Aphonia following tracheal intubation: An unanticipated post-operative complication. PMID- 23983296 TI - Anaesthesia with and without dexmedetomidine for a child with multiple congenital anomalies posted for bilateral cataract extraction. PMID- 23983298 TI - Ethylene diamine tetra aceticacid pseudothrombocytopenia: A must to know entity for Anaesthesiologists. PMID- 23983299 TI - New airway devices in paediatric anesthesia. PMID- 23983300 TI - The painful rib syndrome. PMID- 23983301 TI - A case of a difficult airway due to large sublingual dermoid in a rural medical college. PMID- 23983302 TI - Anaesthesia for thymectomy: Use of ketamine-dexmedetomidine without muscle relaxant. PMID- 23983303 TI - A rare case of necrotising fasciitis after spinal anaesthesia. PMID- 23983304 TI - Epidural catheter kinking over the scapular margins. PMID- 23983305 TI - Airway oedema during shoulder arthroscopy: How we played it safe! PMID- 23983306 TI - Unintentional arterial cannulation during cephalic vein cannulation. PMID- 23983307 TI - Extubation difficulty after transphenoidal pituitary surgery in an acromegalic patient. PMID- 23983308 TI - A case of suspected malignant hyperthermia. PMID- 23983309 TI - Clinical causality assessment for adverse drug reactions. PMID- 23983310 TI - Milky urine: A real cause of concern. PMID- 23983311 TI - Free radicals and cardiac anaesthesia. PMID- 23983313 TI - Effects of traditional Chinese medicine Wei-Wei-Kang-Granule on the expression of EGFR and NF-KB in chronic atrophic gastritis rats. AB - Wei-Wei-Kang-Granule(WWKG) is a traditional Chinese medicine (TCM) preparation for the treatment of chronic atrophic gastritis (CAG). We examined the pathologic change and the effects of Wei-Wei-Kang-Granule (WWKG) on the expression of EGFR (epiderminal growth factor receptors) and NF-kB (nuclear transcription factor KappaB) in rats with chronic atrophic gastritis (CAG), and evaluated the possible mechanisms. Ninety rats were randomly divided into control group and four experimental groups. CAG rat models were induced by repeated stimulating experiments in the experimental groups. After modeled rats were intragastrically injected (i.g.) with WWKG at 6000mg/kg (large dose WWKG group), WWKG at 3000mg/kg (small dose WWKG group), San-Jiu-Wei-Tai-Granule(SJWTG) at 1600mg/kg(SJWTG group), and normal saline(0.9%)at 20ml/kg (model group and control group), respectively, once a day for 30 days. After 30 days, all rats were sacrificed and samples were taken from the sinus ventriculi and body of stomach. The gastric specimens were prepared for microscopic view with hematoxylin and eosin (H-E). The immunohistochemistry method was used to observe the expression of protein of EGFR and NF-kB in gastric tissue. The data were analyzed in pre-and post treatment by computer image automatic analysis system. Immunohistochemistry detection showed that the average optical density of EGFR and NF-kB in antrum was lower in large and small dose WWKG groups than the model group (P<0.01). CAG in rats was related with the damage of barrier in gastric mucosa and the misbalance of cell proliferation and apoptosis. One of the mechanisms is perhaps to reduce the expressing of EGFR and NF-Kb in gastric mucosa. PMID- 23983314 TI - Trichilia monadelpha bark extracts inhibit carrageenan-induced foot-oedema in the 7-day old chick and the oedema associated with adjuvant-induced arthritis in rats. AB - Trichilia monadelpha (Thonn) JJ De Wilde (Meliaceae) bark extract is used in African traditional medicine for the management of various disease conditions including inflammatory disorders such as arthritis. The present study was undertaken to evaluate the anti-inflammatory properties of aqueous (TWE), alcoholic (TAE) and petroleum ether extract (TPEE) of T. monadelpha using the 7 day old chick-carrageenan footpad oedema (acute inflammation) and the adjuvant induced arthritis model in rats (chronic inflammation). TWE and TPEE significantly inhibited the chick-carrageenan footpad oedema with maximal inhibitions of 57.79+/-3.92 and 63.83+/-12 respectively, but TAE did not. The reference anti-inflammatory drugs (diclofenac and dexamethasone) inhibited the chick-carrageenan-induced footpad oedema, with maximal inhibitions of 64.92+/ 2.03 and 71.85+/-15.34 respectively. Furthermore, all the extracts and the reference anti-inflammatory agents (diclofenac, dexamethasone, methotrexate) inhibited the inflammatory oedema associated with adjuvant arthritis with maximal inhibitions of 64.41+/-5.56, 57.04+/-8.57, 62.18+/-2.56%, for TWE, TAE and TPEE respectively and 80.28+/-5.79, 85.75+/-2.96, 74.68+/-3.03% for diclofenac, dexamethasone and methotrexate respectively. Phytochemical screening of the plant bark confirmed the presence of a large array of plant constituents such as alkaloids, glycosides, flavonoids, saponins, steroids, tannins and terpenoids, all of which may be potential sources of phyto-antiinflammatory agents. In conclusion, our work suggests that T. monadelpha is a potential source of antiinflammatory agents. PMID- 23983315 TI - The novel antihyperglycaemic action of Hunteria umbellata seed fractions mediated via intestinal glucose uptake inhibition. AB - The present study evaluated the antihyperglycaemic effect and mechanism of action of fractions of the aqueous seed extract of Hunteria umbellata (K. Schum.) Hallier f. (HU) in normal and alloxan-induced hyperglycaemic rats. HU was partitioned in chloroform, acetyl acetate and butan-1-ol to give chloroform fraction (HU c), ethyl acetate fraction (HU e), butanol fraction (HU b) and the "residue" (HU m), respectively. 200 mg/kg of each of these fraction dissolved in 5% Tween 20 in distilled water was investigated for its acute oral hypoglycaemic effects in normal rats over 6 hours while its repeated dose antihyperglycaemic effect was evaluated in alloxan-induced hyperglycaemic rats over 5 days. In addition, 50 mg/kg of the crude alkaloid fraction (HU Af) extracted from HU was evaluated for its possible antihyperglycaemic activity in alloxaninduced hyperglycaemic rats using oral glucose tolerance test (OGTT) over 6 hours. Using the solvent system, distilled water-butanol-ammonium hydroxide (2:15:1, v/v/v), HU b was chromatographed and stained with Dragendorff's reagent for confirmatory qualitative analysis for alkaloids. Results showed that oral pre-treatment with 200 mg/kg of HU e, HU b and HU m resulted in a significant (p<0.05, p<0.001) time dependent hypoglycaemic effect, with the butan-1-ol fraction HU causing the most significant (p<0.001) hypoglycaemic effect. In the alloxan-induced hyperglycaemic rats, repeated oral treatment with 200 mg/kg of same HU fractions for 5 days resulted in significant (p<0.05) decreases in the fasting blood glucose concentrations with the most significant (p<0.01) antihyperglycaemic effect also recorded for HU b. Similarly, oral pretreatment with 50 mg/kg of HU Af significantly (p<0.05, p<0.01 and p<0.001) attenuated an increase in the post absorptive glucose concentration at 1(st) - 6(th) h in the alloxan-induced hyperglycaemic OGTT model. In addition, alkaloid was present in most of the separated spots on the TLC plate. In conclusion, results of this study showed that HU contains a relative high amount of alkaloids which could have accounted for the antihyperglycaemic action of HU that was mediated via intestinal glucose uptake inhibition. PMID- 23983317 TI - Advances in the analytical methods for determining the antioxidant properties of honey: a review. AB - Free radicals and reactive oxygen species (ROS) have been implicated in contributing to the processes of aging and disease. In an effort to combat free radical activity, scientists are studying the effects of increasing individuals' antioxidant levels through diet and dietary supplements. Honey appears to act as an antioxidant in more ways than one. In the body, honey can mop up free radicals and contribute to better health. Various antioxidant activity methods have been used to measure and compare the antioxidant activity of honey. In recent years, DPPH (Diphenyl-1-picrylhydrazyl), FRAP (Ferric Reducing Antioxidant Power), ORAC (The Oxygen Radical Absorbance Capacity), ABTS [2, 2-azinobis (3ehtylbenzothiazoline-6-sulfonic acid) diamonium salt], TEAC [6-hydroxy-2, 5, 7, 8-tetramethylchroman-2-carboxylic acid (Trolox)-equivalent antioxidant capacity] assays have been used to evaluate antioxidant activity of honey. The antioxidant activity of honey is also measured by ascorbic acid content and different enzyme assays like Catalase (CAT), Glutathione Peroxidase (GPO), Superoxide Dismutase (SOD). Among the different methods available, methods that have been validated, standardized and widely reported are recommended. PMID- 23983316 TI - Analgesic and antipyretic activities of Drymaria cordata (Linn.) Willd (Caryophyllaceae) extract. AB - Drymaria cordata (Linn.) Willd (Caryophyllaceae) is an herbaceous plant widely used in traditional African medicine (TAM) for the treatment of diverse ailments including painful and febrile conditions. This study was conducted to investigate the analgesic and antipyretic properties of the whole plant extract of D. cordata. The acetic acid-induced writhing, formalin, and tail clip tests were used to evaluate analgesic activity while the 2,4-dinitrophenol (DNP)-, d amphetamine-, and yeast-induced hyperthermia tests were used to investigate antipyretic activity in rodents. D. cordata (100, 200, and 400 mg kg(-1), p.o) produced significant (p<0.05) analgesic activity in the mouse writhing, formalin (second phase), and tail clip tests. The effects of D. cordata were generally comparable to those of acetylsalicylic acid (ASA, 100 mg kg(-1), p.o) and morphine (2 mg kg(-1), s.c). Also, D. cordata produced significant (p<0.05) dose dependent inhibition of temperature elevation in the 2,4-DNP and yeast-induced hyperthermia models with peak effects produced at the dose of 400 mg kg(-1). The effect at this dose was comparable to that of ASA in the two models. In the d amphetamine method, D. cordata produced significant (p<0.05) dose- and time dependent reduction of temperature elevation with peak effect produced at the dose of 200 mg kg(-1). The effect of the extract at this dose was greater than that of ASA. The results obtained in this study demonstrate that the aqueous whole plant extract of Drymaria cordata possesses analgesic and antipyretic properties mediated through peripheral and central mechanisms. PMID- 23983318 TI - A novel non-toxic xylene substitute (SBO) for histology. AB - Xylene has been generally used as a clearing and deparaffinizing agent in histology. Because of the potential toxic and flammable nature of xylene, its substitutes have been introduced into some laboratories. In this study, we introduced a novel, non-toxic xylene substitute (SBO), which was generated through a mixture of 86% of white oil No.2 and 14% of N-heptane. SBO had a high boiling point (188 degrees C) and flash point (144 degrees C) coupled with a scentless and decreased volatility. To compare the effectiveness of SBO and xylene in histology, a wide range of tissue samples from rats and human beings were processed in parallel in SBO and xylene, subjected to various staining procedures. Similar to the xylene-processed paraffin blocks, the SBO-processed counterparts were easy to section without any evidence of cell shrinkage. Assessment of the SBO-treated sections stained with hematoxylin-eosin revealed a good maintenance of cell morphology and structure, and a clear definition of the cytoplasm and the nucleus. Moreover, comparable good results were achieved between the SBO- and xylene-processed tissues in other histochemical and immunohistochemical stainings. Six-month clinical applications at one department of pathology supported the potentials of SBO as a xylene substitute. In conclusion, we suggest that SBO is a safe and efficient substitute of xylene and may probably replace xylene without losing valuable diagnostic information. PMID- 23983319 TI - In-vitro propagation and antimycotic potential of extracts and essential oil of roots of Aristolochia bracteolata Linn. (Aristolochiaceae). AB - In spite of the therapeutic importance of Aristolochia bracteolata Linn. in Nigerian ethnomedicine, it is largely collected from the wild. Owing to the acclaimed potency of the plant and the difficulty in treating candidiasis, the anticandidal activity and in vitro propagation of the plant were investigated. Phytochemical screening and preparation of extracts of the roots were done using standard procedures. Clinical isolates of Candida albicans were screened against extracts and essential oil of Aristolochia bracteolata root using agar-well diffusion method. Minimum Inhibitory Concentration (MIC) of the ethanol extract was determined using broth dilution method. The nodal cuttings of A. bracteolata were cultured on Murashige and Skoog (MS) basal media. A. bracteolata contained alkaloids, saponins and cardenolides. The water extract was inactive on all isolates. The ethanol extract (500 mg/ml) and essential oil (undiluted) exhibited anticandidal activity on 9 out of 10 isolates at 10(1) - 10(6) cfu/ml inoculums concentration. Green growth and callus formation were observed in explants cultured on MS basal media after 30 days. A. bracteolata could be a source of anticandidal phytomedicine and the in vitro propagation confirmed its sustainability as anticandidal agent. PMID- 23983320 TI - Flavonoids from Sudanese Albizia zygia (Leguminosae, subfamily Mimosoideae), a plant with antimalarial potency. AB - Three flavonoids were isolated for the first time from the Sudanese medicinal plants Albizia zygia. Compounds 1-3 were identified by interpretation of ESI mass data, (1)H, (13)C and 2D NMR as well as by comparison with published data as 4',7 dihydroxyflavanone (1) 3',4',7-trihydroxyflavone (2), 3-O-methylfisetin (3',4',7 trihydroxy-3-methoxyflavone, 3). All flavonoids were tested against Plasmodium falciparum, and only compound 2 showed high antimalarial activity (IC50 0.078 ug/ml). PMID- 23983321 TI - Recommendations for the development of regulatory guidelines for registration of traditional medicines in South Africa. AB - The regulation and registration of traditional medicines (TM) continues to present challenges to many countries regardless of the fact that an increased number of the population utilises TM for their health care needs. There have been improvements in the legal and policy framework of South Africa based on the WHO guidelines. However, there are currently no guidelines or framework for the registration of TM in South Africa. This article reviews literature and existing guidelines of specific countries and regions and makes recommendations for South African guidelines. PMID- 23983322 TI - The influence of phytotherapy on prolactin level in macroprolactinoma patients. AB - The study aims at demonstrating the efficiency of phytotherapy in regulation of prolactin levels in patients diagnosed with pituitary macroprolactinoma. The study made use of workup outcomes submitted by treating healthcare facilities where the patients were first diagnosed with macroprolactinomas based on diagnostic imaging (MRI and/or CT), laboratory workup, and hormone status estimation. The data in reference served as the baseline for a comparative follow up of phytotherapeutic efficiency in terms of comparison of medical data obtained prior to phytotherapy and those submitted following herbal remedy use. The study displays the results of a five-year follow-up of macroprolactinoma patients undergoing phytotherapy. In well-responding patients, the benefit of phytotherapy in terms of prolactin level putdown can be seen 3-5 months following the phytotherapy commencement. A special attention should be paid to the favourable results obtained with patients who chose to resort to phytotherapy only. The primary outcome measure used to monitor the efficiency of the administered phytotherapy was prolactin level determined prior to, during the course of, and following phytotherapy. Implementation of phytotherapy to the effect of prolactin level regulation in patients diagnosed with macroprolactinoma, represents a completely novel therapeutic approach. The majority of the diseased resorted to phytotherapy once they were left out of any other therapeutic option offered by their treating healthcare facilities. This fact gives a substantial rise to the significance of the results presented herein and justifies the role of phytotherapy in macroprolactinoma-induced hyperprolactinaemia treatment. PMID- 23983323 TI - Effects of Sutherlandia frutescens extracts on normal T-lymphocytes in vitro. AB - Sutherlandia frutescens (SF), a popular traditional medicinal plant found in various parts of southern Africa, is used for treatment or management of HIV/AIDS and other diseases including cancer. However, its toxicity profile has not been fully established. The aims of this study were to examine the effects of 70% ethanol (SFE) and deionised water (SFW) extracts on normal isolated human T cells. An experimental study on normal human lymphocytes treated with doses SF extract doses ranging from 0.25 to 2.5 mg/ml. Untreated, vehicle-treated (Ethanol) and camptothecin (CPT) treated normal T cells were used as controls. Induction of cell death, changes in intracellular ATP, caspase-3/-7 activity and nuclear changes were analysed using flow cytometry, luminometry and nuclear staining (Hoechst) respectively. The highest concentration (2.5 mg/ml) of SFE extract induced significant necrosis (95%), depletion of ATP (76%), and inhibition of caspase-3/-7 activity (11%) following a 24 hour incubation period (p< 0.001). The 2.5 mg/ml concentration of SFW showed the same trend but were less effective (necrosis- 26%, ATP- 91%, & caspase-3/-7- 15%). These effects showed a time-dependence over 48 hours of incubation, with high doses of SFE extracts eliminating viable cells by necrosis, depleting ATP levels and decreasing caspase-3/-7 activity (p< 0.001). The activity of SFE extract was independent of ethanol. The SFW extract dilutions were less toxic than the SFE extracts. Significant DNA fragmentation as demonstrated by Hoechst staining was also seen over 48-hour incubation for high doses of both types of SF extracts. These results showed that although high concentrations of SF extracts can be toxic to normal T cells in vitro, SFW fractions were relatively safe for use. PMID- 23983324 TI - Ethnomedical study and iron content of some medicinal herbs used in traditional medicine in Cote d'Ivoire for the treatment of anaemia. AB - Medicinal plants have been a source of succour in the control of many diseases in developing countries and anaemia is no exception. In this study, ethnomedical survey was carried out for recording medicinal plants used in Northern and South Eastern Cote d'Ivoire against anaemia. Also iron content was determined for some of the recorded plants using phenanthroline method. Thirty (30) medicinal plants, covering 28 genera and 22 families were recorded. These plants were used to prepare 30 receipts for the treatment of anaemia and aggravating factors such as malaria and gastro-intestinal helminthes. Eleven (11) of these medicinal plants showed presence of iron in various quantities. The most promising were Tectona grandis, Amaranthus spinosus and Stylosanthes erecta which contained the highest iron contents viz; 266.6, 236.6 and 206.6 mg/100 g respectively. They were followed by Hoslundia opposita, Imperata cylindrica, Cajanus cajan, Thalia geniculata and Milicia excelsa. These results lend credence to the traditional use of these plants in Cote d'Ivoire's ethnomedicine for the treatment of anaemia. PMID- 23983325 TI - Bioactive diterpenes and sesquiterpenes from the rhizomes of wild ginger (Siphonochilus aethiopicus (Schweinf) B.L Burtt). AB - Wild ginger (Siphonochilus aethiopicus (Schweinf) B.L Burtt) is used in traditional medicines in the West and South of Africa. In the present study, the crude hexane extract of wild ginger was evaluated for in vitro bioactivity. The components isolated from the plant for the first time are: epi-curzerenone, furanodienone (sesquiterpenes), 8(17),12E-labdadiene-15,16-dial, 15-hydroxy 8(17),12E-labdadiene-16-al and 16-oxo-8(17),12E-labdadiene-15-oic acid (labdanes). Cytotoxicity determinations using five cell lines: SH-SY5Y (human, Caucasian, bone marrow, neuroblastoma), Jurkat (human, peripheral blood, leukaemia T cell), L929 (mouse, CH3/connective tissue, areolar and adipose tumour cells), Hep G2 (human, Caucasian, hepatocellular carcinoma) and Hs 27 (normal, human, foreskin cells) were carried out. Anti-trypanosomal activity against Trypanosoma brucei brucei (S427) blood stream forms and anti-bacterial activity against Mycobacterium aurum (CIP .104482) were also investigated. Activity against M. aurum was moderate and at 100ug/ml, the crude extract together with the labdanes showed specific cytotoxicity, indicating anti-cancer potency. Anti trypanosomal activity was observed in the crude extract which increased with the pure components: 8(17),12E-labdadiene-15,16-dial (MIC = 5.3 uM) and the sesquiterpenoids (MIC = 6.9 uM) as compared to suramin activity (MIC = 10 uM). This anti-trypanosomal activity which is being reported for the first time indicates possible usage against sleeping sickness and nagana in cattle. PMID- 23983326 TI - Traditional and alternative therapy for mental illness in Jamaica: patients' conceptions and practitioners' attitudes. AB - The aim of this study was to investigate traditional and alternative therapy for mental illness in Jamaica: patients' conceptions and practitioners' attitudes. The sample included 60 psychiatric patients selected from Ward 21 at the University of the West Indies, Kingston as well as Princess Margaret outpatient clinic, and 30 Afro-centric psychiatric nurses, psychiatrist and clinical psychologists from Kingston and St. Thomas, Jamaica. Patients were interviewed with the Short Explanatory Model Interview (SEMI) and practitioners completed a self administered questionnaire on attitudes towards traditional and alternative medicine. Results indicate that among psychiatric patients more than a third expressed the belief that the overall cause of their mental illness was as a result of supernatural factors. In general, the majority of patients felt that their perception of their problems did not concur with the western practitioner, which in turn caused distress for these patients. In case for those who also sought traditional medicine, they were more inclined to feel pleased about their interaction and the treatment they received. Results from western trained practitioners found that although they acknowledged that traditional medicine plays a major role in the treatment of mental illness among psychiatric patients the treatment was not advantageous. For the most part when all three traditional approaches were examined alternative medicine seemed more favourable than traditional healing and traditional herbal treatment. There is a need to develop models of collaboration that promote a workable relationship between the two healing systems in treating mental illness. PMID- 23983327 TI - Effect of purificatory measures through cow's urine and milk on strychnine and brucine content of Kupeelu (Strychnos nuxvomica Linn.) seeds. AB - Strychnos nux vomica Linn.(Loganaceae) commonly known as Nux vomica (Kupeelu), is a poisonous plant and its seeds are used widely in Ayurvedic system of medicine since time immemorial. Ayurveda advocates that nux vomica seeds are to be administered in therapeutics only after going through certain purificatory measures (Shodhana). There are more than six media: cow's urine (Go mutra), cow's milk (Go dugdha), cow's ghee (Go ghrita), Kanji (thin gruel), castor oil (Eranda taila) and fresh ginger juice (Ardraka swarasa) etc., which have been reported in different classical texts of Ayurveda for proper processing of nux vomica seeds. In this study, an attempt has been made to purify the seeds by using three different methods as described in ancient treatise by using cow's urine and cow's milk as media alone and together. This study revealed that all the methods studied reduced the toxicity of strychnine and brucine contents in comparison to the raw seeds as determined by HPTLC. Out of these three methods maximum reduction in strychnine and brucine contents was found when the seeds were purified by keeping them in cow's urine for seven days followed by boiling in cow's milk for three hrs. PMID- 23983328 TI - Antiulcerogenic effects and possible mechanism of action of Quassia amara (L. Simaroubaceae) extract and its bioactive principles in rats. AB - The effects of Quassia amara extract (Q. amara) and its bioactive principles quassin and 2-methoxycanthin-6-one on gastric ulceration were studied in albino rats. Q. amara (200-800 mg/kg p.o.; 5-20 mg/kg i.p) and 2-methoxycanthin-6-one (12.5, 25.0 and 50.0 mg/kg p.o; 1, 2 and 4 mg/kg i.p) but not quassin (12.5, 25.0 and 50 mg/kg p.o; 1, 2 and 4 mg/kg i.p) significantly inhibited gastric ulceration induced by indomethacin (40mg/kg). Administration of Q. amara (800 mg/kg p.o and 20 mg/kg i.p) and 2-methoxycanthin-6-one (12.5 mg/kg p.o; 4 mg/kg i.p) caused between 77%-85% cytoprotection against indomethacin (40 mg/kg, i.p) - induced gastric ulceration. Quassin did not cause any significant change in indomethacin-induced gastric ulceration. The inhibition of gastric ulceration produced by Q. amara and 2-methoxycanthin-6 one was accompanied by significant dose-dependent decreases (P< 0.01) in total gastric acidity. To investigate the probable mechanism of action, the individual effects of the extract and its principles alone and in combination with histamine (1 mg/kg) or cimetidine (0.12 mg/kg) on gastric acid secretion in situ were studied. Q. amara (20 mg/kg) and 2 methoxycanthin-6-one (4 mg/kg) but not quassin significantly (P< 0.01) inhibited the basal and histamine-induced gastric acid secretion. Inhibition of gastric acid secretion by Q. amara and 2-methoxycanthin-6-one was accentuated by cimetidine. The results suggest that Q. amara and its bioactive principle, 2 methoxycanthin-6-one possess antiulcer activity probably acting via histamine H2 receptor. This could be a potential source of potent and effective antiulcer agents. PMID- 23983329 TI - Adjuvant effects of Sijunzi decoction in chickens orally vaccinated with attenuated Newcastle-disease vaccine. AB - Many Chinese Herbal medicines (CHMs) and their components have been reported to enhance immunity. In this study, the capacity for the Chinese herbal medicine, oral administration Sijunzi Decoction (SJZD) in stimulating Newcastle disease virus(NDV) immunity in chickens was examined. Serum was sampled on days 20, 30, 40, 50 and 60 and tissues were collected on days 20, 40 and 60, respectively. The immune responses were determined by means of hemagglutination inhibition test, immunohistochemistry examination and semi-quantitative RT-PCR. The results showed that SJZD could increase the antibody titers and the area coefficient of IgA secreting cells, promote the expression of IL-2 mRNA in the whole immune period and IFN-gamma mRNA was increased in the initial stage. The SJZD used was safe with no adverse effects on chicken weight or survival, providing evidence for the use of SJZD as an oral adjuvant. PMID- 23983330 TI - The effect of pumpkin (Cucurbita pepo L) seeds and L-arginine supplementation on serum lipid concentrations in atherogenic rats. AB - The present study aimed to examine the effect of pumpkin (Cucurbita pepo L.) seeds supplementation on atherogenic diet-induced atherosclerosis. Rat were divided into two main groups , normal control and atherogenic control rats , each group composed of three subgroups one of them supplemented with 2% arginine in drinking water and the other supplemented with pumpkin seeds in diet at a concentration equivalent to 2% arginine. Supplementation continued for 37 days. Atherogenic rats supplemented with pumpkin seeds showed a significant decrease (p<0.001) in their serum concentrations of total cholesterol and LDL - C as they dropped from 4.89 mmol / L to 2.55 mmol /L and from 3.33 mmol / L to 0.70 mmol / L respectively. Serum concentrations of HDL-C were also significantly elevated in the same group. Although, atherogenic rats supplemented with 2% arginine showed significant increase in serum concentration of HDL-C, no significant changes were observed in their serum concentrations of total cholesterol and LDL-C. Our results showed that treatment of atherogenic rats with pumpkin seeds significantly decreased serum concentrations of TC and LDL-C. Our findings suggest that pumpkin seeds supplementation has a protective effect against atherogenic rats and this protective effect was not attributed to the high arginine concentrations in pumpkin seeds. PMID- 23983331 TI - Anti-inflammatory and antioxidant effects of an ethanolic extract of the aerial parts of Hilleria latifolia (Lam.) H. Walt. (Phytolaccaceae). AB - Various parts of the perennial herb Hilleria latifolia (Lam.) H. Walt. (Family: Phytolaccaceae) are used in Ghanaian traditional medicine for the treatment of several inflammatory-related disorders. The present study examined the anti inflammatory effect of an ethanolic extract of the aerial parts of Hilleria latifolia (HLE) in acute and chronic inflammation models. Since free radicals and reactive oxygen species are implicated in inflammatory diseases, the antioxidant potential of HLE was also investigated in in vitro experimental models. HLE (10 300 mg kg(-1), p.o.), either preemptively or curatively, significantly inhibited carrageenan-induced foot oedema in 7-day old chicks. Similarly, the NSAID diclofenac (10-100 mg kg(-1), i.p.) and the steroidal anti-inflammatory agent dexamethasone (0.3-3 mg kg(-1), i.p.) dose-dependently reduced the oedema in both pre-emptive and curative treatments. In the Freund's adjuvant induced-arthritis model in rats, HLE as well as the positive controls, dexamethasone and methotrexate, showed significant anti-arthritic properties when applied to established adjuvant arthritis. HLE (10-300 mg kg(-1), p.o.) significantly reduced oedema in the ipsilateral paw of rats but failed to prevent systemic arthritic spread. The DMARD methotrexate (0.1-1 mg kg(-1), i.p.) and dexamethasone (0.3-3 mg kg(-1), i.p.) reduced significantly the total polyarthritic oedema as well as the spread of the arthritis from the ipsilateral to the contralateral paws of the treated animals. The extract (0.03-1.00 mg ml( 1)) exhibited Fe(3+) reducing activity, scavenged DPPH and prevented lipid peroxidation. These findings suggest that the extract exerts in vivo anti inflammatory activity after oral administration and also has antioxidant properties which may contribute to its activity. PMID- 23983332 TI - Traditional use of plants against snakebite in Indian subcontinent: a review of the recent literature. AB - Snakebite has been a major cause of mortality across the tropical countries including Indian subcontinent. The present review deals with the enormous amount of ethnobotanical work performed in the last few years involving use of different plants against snakebite in Indian subcontinent (India, Bangladesh, Pakistan and Nepal). From a variety of literature sources the data has been compiled mentioning the plants, parts used, dosage, mode of administration, name of the ethnic communities, geographical locations etc. depending on the availability of information. PMID- 23983333 TI - Meta-analysis: therapeutic effect of transcatheter arterial chemoembolization combined with compound kushen injection in hepatocellular carcinoma. AB - Compound Kushen Injection (CKI) is Sophora Flavescens and Heterosmilacis Japonicae extract. Meta-analysis confirmed that CKI plus transcatheter arterial chemoembolization (TACE) is more superior to TACE alone for unresectable hepatocellular carcinoma (UHCC) patients. PMID- 23983334 TI - Influence of honey-roasting on the main pharmacological activities and the water soluble active glycosides of licorice. AB - In traditional Chinese medicine (TCM), licorice is usually processed with honey and traditionally used in decoction form. However, the influence of honey roasting on the main pharmacological activities and the water-soluble active constituents of licorice has not been reported. The aim of the present study is to determine whether honey-roasting can modify the main pharmacological activities and the active constituents of licorice. According to licorice clinical application and processing method, the mainly related pharmacological activities of crude licorice, processed licorice and refined honey, such as enhancing immune function, relieving cough, eliminating phlegm and detoxication, were compared. The results showed that honey-roasting obviously reinforced the licorice activity of enhancing Pi-deficiency mice's immune function, and significantly weaken the licorice activity of relieving cough, removing phlegm and detoxication. However, honey didn't show the significant activity of relieving cough, removing phlegm and detoxication. The influence of honey roasting on the chemical compositions in licorice slice and licorice decoction was investigated by using HPLC. The results showed that the content and the decocting quantity of mainly 5 active glycosides in licorice, i.e. liquiritin apioside, liquiritin, licuraside, isoliquiritin and glycyrrhizin, obviously changed after processing; glycyrrhizin and liquiritin obviously decomposed during honey-roasting. In conclusion, honey-roasting obviously modified the main pharmacological activities and the water-soluble compositions of licorice. The modification was not cause by honey only. This finding may shed some light on understanding the differences in the therapeutic values of crude and processed licorice. PMID- 23983335 TI - Effect of the aqueous extract of Justicia insularis T. Anders (Acanthaceae) on ovarian folliculogenesis and fertility of female rats. AB - Justicia insularis T. Anders (Acanthaceae) is a medicinal plant whose leaves and those of three other plants are mixed for the preparation of a concoction used to improve fertility and to reduce labour pains in women of the Western Region of Cameroon. Previous studies have demonstrated the inducing potential on ovarian folliculogenesis and steroidogenesis of the aqueous extract of the leaf mixture (ADHJ) of four medicinal plants (Aloe buettneri, Dicliptera verticillata, Hibiscus macranthus and Justicia insularis) among which the later represented the highest proportion. This study was aimed at evaluating the ovarian inducing potential of J. insularis in immature female rats. Various doses of the aqueous extract of J. insularis were daily and orally given, for 20 days, to immature female rats distributed into four experimental groups of twenty animals each. At the end of the experimental period some biochemical and physiological parameters of ovarian function were assayed. The administration of the aqueous extract of Justicia insularis significantly induced an early vaginal opening in all treated groups (P < 0.001) as well as an increase (at doses of 50 or 100 mg/kg) in the number of hemorrhagic points, Corpus luteum, implantation sites, ovarian weight, uterine and ovarian proteins. Ovarian cholesterol level (P < 0.05) significantly decreased in animals treated with the lowest dose (12.5 mg/kg). The evaluation of the toxicological effects of the extract on pregnancy showed that it significantly increased pre- and post-implantation losses, resorption index and decreased the rate of nidation as well as litter's weight. These results suggest that the aqueous extract of Justicia insularis induces ovarian folliculogenesis thus justifying its high proportion in the leaf mixture of ADHJ. PMID- 23983336 TI - Anti-diabetic activities of the methanol leaf extracts of Hymenocardia acida (tul.) in alloxan-induced diabetic rats. AB - The effect of methanolic extract of Hymenocardia acida leaves on diabetes and associated lipidemia were investigated on experimentally-induced diabetic rats. The extract did not demonstrate any acutely toxic effect in rats within the dose range (250 mg/kg - 2000 mg/kg) employed in the study; hence it was well tolerated by the rats. In all experiments, the anti-diabetic effects were dose-dependent and comparable to that of glibenclamide (2 mg/kg) standard. At a dose of 500 mg/kg, lipid profile markers such as the serum total cholesterol (TC) levels, LDL C, triglycerides and HDL-C were significantly lower (p <0.05) than those of both the treated and untreated controls. PMID- 23983337 TI - Qidantongmai protects endothelial cells against hypoxia-induced damage through regulating the serum VEGF-a level. AB - Qidantongmai (QDTM) is a Traditional Chinese Medicine (TCM) preparation that has long been used in folk medicine for the treatment of cardiovascular diseases. However, the underlying mechanisms are poorly understood. The present study was designed to determine the effects of QDTM on endothelial cells under hypoxic conditions both in vitro and in vivo. Primary human umbilical vein endothelial cells (HUVECs) were isolated, pretreated with QDTM medicated serum or saline control, and then cultured under hypoxia (2% oxygen) for 24 h. Sprague-Dawley rats were administered 1 ml/100 g of QDTM or saline twice a day for 4 days and treated with hypoxia (6 hours/day, discontinuous hypoxia, 360 mm Hg). QDTM not only protected HUVECs from hypoxia-induced damage by significantly retaining cell viability (P < 0.05) and decreasing apoptosis (P < 0.05) in vitro, but also protected liver endothelial cells from hypoxia-induced damage in vivo. Moreover, QDTM increased the serum VEGF-A level (P < 0.05) in rats treated with hypoxia for 7 days but suppressed the upregulation of serum VEGF-A in rats treated with hypoxia for 14 days. QDTM is a potent preparation that can protect endothelial cells against hypoxia-induced damage. The ability of QDTM to modulate the serum VEGF-A level may play an important role in its effects on endothelial cells. PMID- 23983338 TI - Antioxidant and anti-fatigue activities of flavonoids from Puerariae radix. AB - This study evaluated the antioxidant and anti-fatigue activities of flavonoids from Puerariae radix (FPR). In vitro antioxidant activities of FPR were investigated through hydroxyl and superoxide radical scavenging activities. In vivo anti-fatigue activity of FPR was investigated through loaded swimming exercise of mice. Results showed that FPR had not only in vitro antioxidant activities, but also an in vivo anti-fatigue activity in mice. FPR possessed superoxide and hydroxyl radical scavenging activity in in vitro experimental studies. In vivo experimental studies, FPR could evidently extend exhaustive swimming time of mice, inhibit the increase of blood lactic acid (BLA), decrease serum urea nitrogen (BUN) and malondialdehyde (MDA) contents, promote increases in the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) of mice after swimming. The results provided an important basis for developing the FPR as a novel antioxidant and anti-fatigue compound. PMID- 23983339 TI - Spasmolytic effects of aqueous extract of mixture from Aframomumum melegueta (K Schum) - Citrus aurantifolia (Christm and Panzer) on isolated trachea from rat. AB - The spasmolytic properties of the aqueous extract of Aframomum melegueta (K Schum) and Citrus aurantifolia (Christm and Panzer) (AMCA) mixture were tested on isolated rat trachea. Inhibition of the contraction was observed the in presence of the AMCA (EC 50 = 1.80 +/- 0.48 mg/mL) after a pre contraction of the trachea by acetylcholine (10-5 M). With propranolol (10-6 M), the spasmolytic activity of the mixture was inhibited and the concentration-response curve shifted to the right. The EC50 value was then 2.60 +/- 0.41 mg/mL. AMCA also inhibited contraction induced by KCl (4.10-2 M) with EC50 value = 1.86 +/- 0.65 mg/mL. These results clearly show the relaxing effect of the aqueous extract on the isolated rat trachea. This effect involved some beta-adrenergic receptor inhibition. PMID- 23983340 TI - Protective effects of two constituents of Chinese herbs on spinal motor neurons from embryonic rats with hypoxia injury. AB - Neuroprotective agents are becoming significant tools in the repair of central nervous system injuries. In this study, we determined whether ginkgolides (Gin, extract of GinkgoBiloba) and Acanthopanax senticosus saponins (ASS, flavonoids extracted from Acanthopanax herbal preparations) have protective effects on rat spinal cords exposed to anoxia and we explored the mechanisms that underlie the protective effects. Spinal motor neurons (SMNs) from rat spinal cords were obtained and divided into five groups with 10 wells in each group. In control group, SMNs suffered no injury under normal oxygen; in hypoxia- inducible (HI) group, SMNs suffered injury from hypoxia; in Gin group, 37.5ug/ml Gin were used before 24 hrs of hypoxia; in ASS group, 50ug/ml ASS were used before 24 hrs of hypoxia;in glial cell-lined derived neurotrophic factor (GDNF) group, 0.1ug/ml GDNF were used before 24 hrs of hypoxia. Changes in morphology, neuron viability, and lactate dehydrogenase (LDH) release were observed. In addition, the expression of HIF-1alpha induced by hypoxia was measured. The neuronal viability in the Gin, ASS, and GDNF pretreated groups was higher than that in the HI group (P<0.05). The viability in the Gin group was better than that in the ASS group (P<0.05), but there was no significant difference between the ASS and GDNF groups (P>0.05). The quantity of LDH released in the three pretreated groups was lower than that in the HI group (P<0.05). The expression of HIF-1alpha in the HI group was greater than that in the control group (P<0.05), and the expression in the three pretreated groups was greater than that in the HI and the control groups (P<0.05). Our results indicate that Gin and ASS which was not as effective as Gin, but its effects were similar to those of GNDF could all enhance the viability of SMNs and have protective effects on hypoxic neurons. PMID- 23983341 TI - Antidiarrhoeal activity of an ethanol extract of the stem bark of Piliostigma reticulatum (Caesalpiniaceae) in rats. AB - Piliostigma reticulatum (Caesalpiniaceae) is used in Africa as a traditional medicine for the treatment of many diseases, such as malaria, tuberculosis and diarrhoea. We investigated the antidiarrhoeal properties of a crude ethanol extract from the stem bark of Piliostigma reticulatum (EEPR) in Wistar albino rats to substantiate its traditional use and to determine its phytochemical constituents. The antidiarrhoeal activity of the plant extract was evaluated in a castor oil-induced diarrhoea model in rats and compared with loperamide. The effect of the extract on gastrointestinal motility was also determined by the oral administration of charcoal meal and castor oil-induced intestinal fluid accumulation (enteropooling). EEPR showed remarkable dose-dependent antidiarrhoeal activity evidenced by a reduction of defecation frequency and change in consistency. Extracts at 250, 500 and 1000 mg/kg body weight significantly reduced diarrhoeal faeces. EEPR also significantly inhibited gastrointestinal motility and castor oil-induced enteropooling at 500 and 1000 mg/kg, similar to the inhibition obtained in control rats treated by atropine. Phytochemical screening revealed the presence of tannins, flavonoids, polyphenols and reducing sugars in the stem bark of P. reticulatum. No mortality or visible signs of general weakness were observed in the rats following administration of the crude extract in doses up to 6000 mg/kg body weight in an acute toxicity study. Our results show that the stem bark of P. reticulatum possesses antidiarrhoeal activity and strongly suggest that its use in traditional medicine practice could be justified. PMID- 23983342 TI - Anti-inflammatory activity of crude saponin extracts from five Nigerian medicinal plants. AB - Crude saponin extracts of five medicinal plants used in the treatment of inflammatory diseases like rheumatoid arthritis, gout and haemorrhoids were screened for anti-inflammatory activity using carrageenan-induced rat paw oedema test. These plants were the whole plant of Schwenkia americana Linn (WSA), the rhizomes of Asparagus africanus Lam (RAA), the leaves of Dichrostachys cinerea Linn (LDC), the stem bark of Ficus iteophylla Miq (BFI) and the leaves of Indigofera pulchra Willd (LIP). A modify traditional method of crude saponins extraction was used to give the following percentage yields: WSA-2.74%, RAA 3.59%, LDC-1.62%, BFI-0.81% and LIP-1.57% respectively. Thin-layer chromatography was used to identify the type of saponins present in the extracts. The acute toxicity study of the crude saponin extracts in mice gave the following intraperitoneal LD50: WSA-471.2mg/kg, RAA- 1264.9mg/kg, LDC-1264.9 mg/kg, BFI 118.3mg/kg and LIP-1264.9 mg/kg respectively. The anti-inflammatory study of the extracts showed statistically significant (P<0.05) decreases in the rat paw oedema as compared to the control. The percentage inhibitions of the extracts after four hours were as follow: WSA-61%, RAA-55%, LDC-72%, BFI-66% and LIP-40% respectively. These values were found to be comparable to that of ketoprofen-63%. The study showed that the anti-inflammatory properties attributable to these plants may be due to their saponins contents. PMID- 23983343 TI - Mitochondria as pharmacological targets: the discovery of novel anti-obesity mitochondrial uncouplers from Africa's medicinal plants. AB - Obesity results from prolonged positive imbalance between energy in take and expenditure. When food intake chronically exceeds the body's energy need, an efficient metabolism results in the storage of the excess energy as fat. Mitochondria are the main centre for energy production in eukaryotic cells. Mitochondrial proton cycling is responsible for a significant proportion of basal or standard metabolic rate, therefore, further uncoupling of mitochondria may be a good way to increase energy expenditure and hence represent a good pharmacological target for the treatment of obesity. This implies that, any chemical agent or photochemical compound that further uncouples the mitochondria in vivo without having any effect on mitochondria activity could be a potential target in finding treatment for obesity. In the past, uncoupling by 2, 4 dinitrophenol has been used this way with notable success. This paper discusses the mitochondria as targets in the discovery of potential plant natural anti obesity products from Africa's rich rainforests. PMID- 23983344 TI - Acute toxicity and vascular properties of seed of Parkia biglobosa (JACQ) R. Br Gift (Mimosaceae) on rat aorta. AB - The authors report here the results of study on Parkia biglobosa seeds used in Burkina Faso for arterial hypertension treatment. Investigations were done on acute toxicity and vascular properties of fermented and roasted seeds. Acute toxicity test using mice, revealed by the intraperitoneal route a lethal dose 50 (LD50) of 1800 mg/kg and 1600 mg/kg of body weight for aqueous extract from roasted and fermented seeds respectively. According to the scale of Hodge and Sterner and that of the World Health Organization, such drugs would be classified lightly toxic. Oral administration (up to 3000 mg/kg) did not induce any death of animal. For the vascular properties, the effects of these products were tested on the aorta isolated from rats. The cumulative administration of extract from roasted and fermented seeds (0.1-10 mg/mL) in an organ bath induced a concentration-dependent relaxation of the aorta pre contracted by phenylephrine, with or without functional endothelium. The extracts (10 mg/mL) inhibited for 100% the contraction induced by phenylephrine. The EC50 values in presence and absence of endothelium were respectively of 5.37 +/- 0.12 and 4.19 +/- 1.02 mg/mL for fermented seeds; for roasted seeds these values were respectively, 5.39 +/- 1.12 and 5.93 +/- 0.95 mg/mL. Nevertheless, low concentration of roasted seeds (1 4 mg/mL) induced endothelium-dependent relaxation and this effect was inhibited by indomethacin (10-5M), and not by L-NAME (310-4M). These experimental results revealed a vasorelaxant effect of P. biglobosa seeds. P. biglobosa seems to act directly on the smooth muscle and via endothelium involving the generation of vasodilatating prostaglandins. This vasodilator effect would be in favor of an anti hypertensive property of P. biglobosa seeds. PMID- 23983345 TI - Chinese herbal medicine: a safe alternative therapy for urinary tract infection in patients with renal insufficiency. AB - We have used reduced doses of Chinese herbs for estimation of urinary tract infections (UTIs) patients with stable impairment of renal function. A total of 33 adult female patients with moderately impaired renal function and symptomatic UTIs were included in this study. Urine cultures were carried out. Patients were monitored clinically and with various laboratory tests. Chinese herbal concoction divided by milligrams of creatinine per 100 ml were orally administrated for ten days. Three patients were excluded from final analysis. Most of the patients responded symptomatically to treatment. Chinese herbs eradicated the primary pathogen in 68.7% of the patients at the day 10 of treatment. Two patients relapsed (one had abbreviated courses of therapy) 6 to 8 days posttreatment. Organisms which recurred included Escherichia coli and Pseudomonas aeruginosa. Bacterial reinfections occurred 5 to 8 days posttreatment in four patients. Adverse reactions observed among the 30 patients were rare. Nausea (6.67%) and mild elevation of hepatic enzymes (3.33%) were probably drug related. Nausea disappeared when the therapy ended. Elevated hepatic enzymes resumed at the 2 week follow-up. Two patients demonstrated slight increases in serum creatinine on day 10 of treatment. One patient had a 12.5% elevation over baseline and the other had a 13.0% elevation. Serum creatinine values had improved in these two patients at 4-week follow-up. Chinese herbal medicine was effective and safe in the treatment of UTIs with renal insufficiency. PMID- 23983346 TI - Anti-inflammatory, antioxidant, and selective antibacterial effects of Euadenia eminens root bark. AB - Euadenia eminens Hook f. (Capparaceae) has traditional uses in the management of conjunctivitis, iritis, ophthalmia, tuberculosis, otalgia and rectal prolapse. The fruit pulp is also eaten as an aphrodisiac. In this paper, we report on the anti-inflammatory, antioxidant and antibacterial effects of its roots. A 70 % ethanol extract was tested for anti-inflammatory effect using the carrageenan induced oedema in chicks. Free radical scavenging, total antioxidant and total phenol content were assessed spectrophotometrically. The extract was tested for antibacterial activity using the agar well diffusion method and micro dilution assays. The 70% ethanol extract gave a maximal inhibition of oedema by 74.18 % at 30 mg/kg. The total antioxidant capacity expressed in terms of ascorbic acid was 0.609 mg/g dry weight. The total phenol in terms of tannic acid was 7.25 mg/g dry weight. The extract also demonstrated free radical scavenging activity yielding IC50 value of 1.175 mg/mL. The root extract however, showed selective antibacterial activity, inhibiting growth of two microorganisms; Bacillus subtilis and Bacillus thurigiensis. The MICs were 500 and 1000 ug/mL respectively. These results may account in part for the ethnopharmacological use of the plant. PMID- 23983347 TI - The influence of phytotherapy on macroprolactinoma size. AB - The study aims at demonstrating the efficiency of phytotherapy in macroprolactinoma downsizing. The comparison of phytotherapeutic (PT) efficiency leant on medical records submitted by the patients prior to the PT launch, indicating the diagnosis established based on the outcome of the nuclear magnetic resonance imaging (NMRI) and/or computed tomography (CT) of the affected site and bringing the results of field-of-vision examination and hormonal status determination. The insight into the documentation in reference provided the information on tumour size and prolactin levels. The data in reference were compared against medical records submitted following phytotherapy completion. This study brings the results of a five-year investigation into the influence of phytotherapy on the size of macroprolactinomas. In patients responsive to this kind of treatment, tumour regression was witnessed within 6 months of herbal remedy use. A substantial tumour downsizing was accompanied by vision restitution;namely, in a number of cases, sight impairments are the first indicators of tumour presence. The basic parameters used for phytotherapeutic efficiency estimation and follow-up were the size of the tumour and the state of the field-of-vision, established both prior to and following phytotherapy. The results of the study presented herein unequivocally demonstrated the efficiency of phytotherapy in macroprolactinoma tumour mass downsizing, providing therefore solid grounds for the implementation of phytotherapy as a novel treatment modality of this tumour cluster. PMID- 23983348 TI - Antihyperglycemic activities of leaves of three edible fruit plants (Averrhoa carambola, Ficus hispida and Syzygium samarangense) of Bangladesh. AB - Averrhoa carambola L. (Oxalidaceae), Ficus hispida L.f. (Moraceae), and Syzygium samarangense (Blume) Merr. & L.M. Perry (Myrtaceae) are three common plants in Bangladesh, the fruits of which are edible. The leaves and fruits of A. carambola and F. hispida are used by folk medicinal practitioners for treatment of diabetes, while the leaves of S. samarangense are used for treatment of cold, itches, and waist pain. Since scientific studies are absent on the antihyperglycemic effects of the leaves of the three plants, it was the objective of the present study to evaluate the antihyperglycemic potential of methanolic extract of leaves of the plants in oral glucose tolerance tests carried out with glucose-loaded mice. The extracts at different doses were administered one hour prior to glucose administration and blood glucose level was measured after two hours of glucose administration (p.o.) using glucose oxidase method. Significant oral hypoglycemic activity was found with the extracts of leaves of all three plants tested. The fall in serum glucose levels were dose-dependent for every individual plant, being highest at the highest dose tested of 400 mg extract per kg body weight. At this dose, the extracts of A. carambola, F. hispida, and S. samarangense caused, respectively, 34.1, 22.7, and 59.3% reductions in serum glucose levels when compared to control animals. The standard antihyperglycemic drug, glibenclamide, caused a 57.3% reduction in serum glucose levels versus control. Among the three plants evaluated, the methanolic extract of leaves of S. samarangense proved to be the most potent in demonstrating antihyperglycemic effects. The result validates the folk medicinal uses of A. carambola and F. hispida in the treatment of diabetes, and indicates that the leaves of S. samarangense can also possibly be used for amelioration of diabetes-induced hyperglycemia. PMID- 23983349 TI - In vitro testing of African traditional medicines for cytotoxic, immune modulatory and anti-HIV activities. AB - African Traditional Medicines (ATMs) serve as a major source of primary healthcare for African people. The reasons for their use range from easy access, affordability, beliefs in traditional systems and long term safety. ATMs have been used to treat individuals infected with HIV and therefore need scientific validation; a view supported by Traditional Health Practitioners (THPs). This study aimed to evaluate the in vitro cytotoxicity, immune modulatory and anti-HIV activities of traditional multiple herbal preparations from local THPs. Ugambu, Ihashi, Product Nene, Product Blue, SPNa and SDKc ATM were supplied by local THPs. Changes in adenosine triphosphate (ATP) & glutathione (GSH) over 24 hours were measured using luminometry. Changes in 12 cytokines were assayed using an ELISA-based absorbance assay. Protective effects against HIV killing of MT-4 cells were tested using the XTT assay and antiviral activity was measured using an HIV-1 viral load assay. Cyclosporine and AZT were used as positive controls. Ugambu, Ihashi, Product Nene and SDKc induced a dose dependent toxicity on treated PBMCs by reducing ATP and GSH at high doses (p< 0.001). These medicinal preparations, along with SPNa, showed immunomodulatory activity by significantly (p< 0.001) changing the secretion of pro-inflammatory cytokines. Product Blue stimulated the levels of ATP and GSH in treated PBMCs at all doses however this product did not show any immunomodulatory activity on cytokine secretion when compared to control cells. Ugambu, Ihashi, Product Nene showed promising anti-HIV activity relative to AZT (p< 0.01). This study has shown that some of these traditional medicinal preparations have at least one or all the properties of immunostimulation, immunomodulation or antiretroviral effects. The mechanism of action of the shown activities should further be investigated. PMID- 23983350 TI - A model for the incorporation of the traditional healers into the national health care delivery system of South Africa. AB - In South Africa the patient uses both the traditional healers and biomedical personnel's services out of need for the best healing therapy to fulfil his/ her health needs. Failure of one to yield the expected results leads to the use of the other. This shunting back and forth prompted the researcher to undertake research and formulated a model demonstrating how the traditional healers can be incorporated into the National Health Care Delivery System of South Africa. The research used both qualitative and theory generating designs to attain the set objective. Firstly, a qualitative research design used semi-structured interviews to investigate the perceptions and attitudes of biomedical personnel, traditional healers, patients and policy makers, regarding the process of incorporation. A non-probable purposive voluntary sample was used, selection was done according to a set criteria. Data was analysed and the results of phase one as well as initial literature review were used to construct a conceptual framework for the model. Secondly, a theory generating design was employed using the three phases of Dickoff, James and Wiedenbach (1968:435) to formulate a model which was systematically, logically and consistently conceptualized. In evaluation of this model a predetermined criteria was used. The results showed that the constructed model demonstrated the government formulating policy to legalize traditional healing and affording the traditional healers legal authority to be official partners to the biomedical personnel and avail the quality health care services that fulfils the patients health needs using the primary health care approach. PMID- 23983351 TI - Nutritional content and a phase-I safety clinical trial of a herbal-nutritional supplement (IMUNITI) with putative immune-modulating properties. AB - The relationship between HIV and AIDS and poor nutrition has been well established. Poor nutrition hastens the progression of HIV infection to AIDS. The rising pandemic of HIV and AIDS and high toxicity associated with anti-retroviral use are major factors that have compelled research to explore traditional herbal medicines as potential alternatives or supplements to anti-retroviral agents. A Phase I clinical trial was conducted on IMUNITI Wellness Pack, a herbal product with putative immune-modulating properties. The product is a combination of 7 herbal preparations, minerals, vitamins, and a specially formulated soya-maize meal porridge and a bottle of water purifier. The aim was to evaluate the safety and tolerability of IMUNITI, with a purpose of developing it for use in HIV infected patients. The phase I study was conducted at the MRC clinic in Botha's hill and the study lasted 5 weeks from date of participant dosing. The study was a randomised blinded placebo-controlled phase I clinical trial conducted on 48 healthy males. The participants were randomly divided into 4 groups of 12. The 3 groups received different escalating doses of IMUNITI while the forth group received placebo tablets. Participants consumed IMUNITI daily for a period of 5 weeks. Assessments were done at baseline, week 1 and week 5 to determine the safety parameters in all participants. In this study, IMUNITI did not show any safety concerns. In all study participants, there were no significant changes above the upper limit of the reference ranges of the laboratory tests for full blood count, INR, renal and biochemical safety parameters. IMUNITI was well tolerated. Furthermore, the nutritional content analysis of IMUNITI showed that it is a high kilojoule, high protein content product which contains a mixture of sugars, vitamins, traces of calcium, phosphorus and minerals. PMID- 23983352 TI - Perspectives of traditional health practitioners on the use of microbicides for the prevention of HIV. AB - In many South African communities, Traditional Health Practitioners (THPs) are significant participants within a plural health care system. For several years, it has been argued that this role, especially in the context of HIV/AIDS, has not been fully optimised and THPs continue to operate outside the formal biomedical sector, where the latter forms the central means by which public health campaigns are delivered and implemented. In our previous research, we have shown that this separation of the biomedical and traditional sectors perpetuates a low level of understanding of HIV by THPs with adverse consequences for patients and the overall health care system. In this study we investigated whether biomedical/traditional division could be transformed through the involvement of THPs in the distribution of barrier microbicides; the latter are presently under investigation as a means of preventing HIV infection. We concluded that THPs could provide a willing and effective distribution network for the gel-based microbicides; given the large number of THPs and their patients, such a distribution strategy would ensure that microbicides are accessible and adopted relatively quickly within the target communities of the HIV prevention campaigns. PMID- 23983353 TI - Evaluation of traditional medicines I: identification of PHELA using different chromatographic techniques. AB - PHELA is a herbal mixture of four African traditional medicinal plants that has been used for decades in wasting conditions and is now being developed by the Medical Research Council (MRC) as an immune booster for patients with compromised immune system. A chromatographic fingerprint of PHELA was needed for quality control purposes. Here, a comprehensive method for fingerprinting of PHELA using different chromatographic techniques is described. It involved extraction of the PHELA by either acidic or a simple 'salting-out' method, followed by Thin Layer Chromatography (TLC) analysis and/or preparative Column Chromatography (CC). The products were thereafter analyzed by High Performance Liquid Chromatography with UV-detector (HPLC-UV), HPLC with fluorescence-detector (HPLC-FL) and Gas Chromatography with a Mass Selective Detector spectrometer (GC-MSD). The fingerprints were successfully used to differentiate PHELA from another common herbal product made from Hypericum perforatum (St. John's Wort), thereby illustrating its high potential for use in fingerprinting of PHELA and in differentiating it from other herbal medicines. By validating the different chromatographic techniques on the standardized extraction methods, this approach will enable wide application in quality control of PHELA using acceptable procedures, thereby promoting effective monitoring of the finished product in all countries where it will be used. PMID- 23983354 TI - The immunomodulatory effects of Sutherlandia frutescens extracts in human normal peripheral blood mononuclear cells. AB - Sutherlandia frutescens (SF) is one of the medicinal plants used as an immune booster in the treatment of chronic ailments such as HIV/AIDS and cancer. Limited data suggest that its efficacy is based on its regulatory effect on cytokines, the critical components of the immune response. In this study, we investigated the in vitro immunomodulatory effects of SF extracts on normal human peripheral blood mononuclear cells (PBMCs). An ELISA-based assay was used to assess the levels of expression of 12 cytokines in treated cells. An adenosine triphosphate (ATP) assay was used to assess cell viability in relation to cytokine secretion. SF ethanol extracts induced changes in cytokine secretion relative to the dose of the extract. Generally cytokine expression and secretion was low in concentration because were not stimulated with any endotoxin. The high SFE dose (2.5 mg/ml) significantly (p<0.001) decreased some cytokines including TNF-alpha and IL 1beta. Low doses of this extract (0.5 mg/ml) did not change TNF-alpha and IL 1beta secretion from the baseline (untreated cells). Changes in cytokine secretion of SFE treated cells tracked changes in ATP levels (cell viability). The SFW extract-induced changes in cytokine secretion were independent of cell viability. TNF-alpha was decreased (p<0.001) by the high dose of SFW extract while IL 1beta and IFNgamma were increased (p<0.01) by the same dose. High doses decreased cell viability which was reflected in cytokine secretion. It is evident, from these results, that SF extracts can modulate cytokine secretion in unstimulated normal PBMCs in vitro. Further studies in animal models are recommended to advance understanding of this immunomodulatory activity. PMID- 23983355 TI - Evaluation of traditional medicines III: the mechanism of immune modulation by PHELA. AB - PHELA is a herbal traditional medicine that is under development for use as an immune booster in immune compromised individuals. Therefore, the aim of this study was to determine PHELA's mechanism of action by observing for changes in cytokine profiles. Four groups of Sprague Dawley rats (n = 8) were treated daily and separately with normal-saline, cyclosporine-A, PHELA-only and PHELA+ cyclosporine-A. Thereafter, 4 animals from each group were sacrificed after 7 and 14 days of treatment. Serum Th1 cytokines (IL-2, IFN-gamma and TNF-alpha) and Th2 cytokines (IL-4 and IL-10) were measured by ELISA. The concentrations of Th1 cytokines in the PHELA-only treated group were similar to the control group on days 7 and 14. However, the Th1 cytokines were higher in the PHELA+cyclosporine-A treated group compared to cyclosporine-A group, and cyclosporine-A concentrations were similar in both groups. These results show that PHELA did not stimulate Th1 cytokines of a normal immune system but stimulated them when the immune system was suppressed by cyclosporine-A. In conclusion, PHELA is an immune-stimulant to a compromised immune system. PMID- 23983356 TI - Traditional complementary and alternative medicine: knowledge, attitudes and practices of health care workers in HIV and AIDS clinics in Durban hospitals. AB - Traditional complementary and alternative medicine (TCAM) has been reported to be commonly used among individuals with HIV and AIDS disease. However a lack of communication between health care workers (HCWs) and patients as well as between HCWs and TCAM practitioners has been identified as one of the challenges that may adversely affect treatment of HIV and AIDS patients. With improved and sustained communication HCWs, patients and TCAM practitioners would be able to make informed decisions with regards to best treatment practices based on the knowledge of what is safe, effective and what is not. In order to establish a baseline understanding of the current status of interaction and communication between HCWs and TCAM profession in Durban, South Africa, the purpose of the study was to investigate the knowledge, attitudes and practices of HCWs in the HIV and AIDS clinics towards TCAM professions. Data was collected by means of anonymous self-administered questionnaire which was distributed to HCWs in the HIV and AIDS clinics. Out of 161 HCWs in the HIV and AIDS clinics 81 HCWs returned the questionnaires resulting in 50% response rate. The results showed that participants did not possess a basic knowledge of TCAM. Out of 81 participants 23 (28%) scored zero in a true or false knowledge assessment question. PMID- 23983357 TI - Evaluation of traditional medicines II: the use of metabolite peak-kinetics to monitor PHELA in rat plasma. AB - PHELA is a herbal mixture of four African traditional medicinal plants that is under development by the Medical Research Council (MRC) for use as an immune stimulant in immune compromised individuals. Before major in vivo investigations could be conducted, there was a need to establish a plasma marker for concentration monitoring of PHELA. Chromatographic separation was achieved using a C18 RP column (250 mm * 4.6 mm * 5 um), 70% acetonitrile in water and fluorescent detection. Three groups of rats (n=5) were administered with PHELA (15.4 mg/kg) and one rat from each group was sacrificed at 1, 2, 4, 6 and 8 hours. Surprisingly, on the HPLC analysis, none of the marker peaks of spiked plasma were detectable in the plasma of treated animals. Instead, a new peak was observed at 9.2 minutes, which implied that it was a metabolite of PHELA. Using peak area per unit plasma volume (PK-area/L), the relevant pharmacokinetic parameters were derived. The metabolite's half-life was 3.47+/-0.35 hours and reached maximum concentration at 4.67 +/- 1.15 hrs. It was estimated that with once daily dosing of PHELA, the concentration at steady state (Css) would be 47.52 +/- 5.94 PK-area/L with no drug accumulation (Acc index =.009 +/- 0.004). In conclusion, the use of peak area per unit volume to derive pharmacokinetics of unknown compounds (Peak-kinetics) and to confirm ingestion of PHELA were demonstrated with a hope that they may appeal to those experiencing similar problems with monitoring of herbal products of which little is known. PMID- 23983359 TI - The anti-inflammatory and anti-nociceptive activities of Patrinia villosa and its mechanism on the proinflammatory cytokines of rats with pelvic inflammation. AB - This study explores the anti-inflammatory and anti-nociceptive activities of Patrinia villosa, a Chinese medicinal plant, and to explore its effects on the proinflammatory cytokines of the rats with pelvic inflammation model. The animals were randomly divided into Patrinia villosa group (PV group), dexamethasone group (DEX group), and model-control group (CON group) to perform an ear edema test, a carrageenin-induced paw edema test, a cotton pellet-induced granuloma formation test, and an acetic acid-induced writhing test. The model rats with pelvic inflammation were established, and the serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) in each group was detected with the Enzyme-Linked ImmunoSorbent Assay (ELISA). The results of the ear edema test, carrageenin-induced paw edema test, cotton pellet-induced granuloma formation test, and acetic acid-induced writhing test all showed that Patrinia villosa had strong anti-inflammatory and anti-nociceptive effects. In the experiment using model rats with pelvic inflammation, we found that the serum levels of IL-6, IL-8 and TNF-alpha in PV and DEX group were all significantly lower than those of the CON group, and the serum levels of IL-6 and IL-8 in PV group were significantly lower than those of the DEX group. Patrinia villosa, with its strong anti-inflammatory and anti-nociceptive activities, can be used to treat pelvic inflammation and to relieve the associated pain. PMID- 23983360 TI - Extracts of Salvia miltiorrhiza Bunge on the cytokines of rat endometriosis models. AB - Endometriosis is a common mysterious and fascinating gynaecological condition with diverse clinical manifestations, highly variable and unpredictable clinical course with decreased quality of life. Clinically, Salvia miltiorrhiza Bunge (SMB, Chinese Danshen) has been applied to treat endometriosis and get satisfactory results. The present study was aimed to explore the effects of the extracts of SMB (ESMB) on the serum levels of cancer antigen 125 (CA-125) and the levels of interleukin (IL)-13, IL-18 and tumor necrosis factor-alpha (TNF-alpha) in the peritoneal fluids of rat endometriosis models. Three extraction methods for SMB were compared, which are the sample extracted with conventional method, the sample extracted with espresso coffee machine and the commercial condensed powder of natural products. We determined tanshinone IIA, salvianolic acid B and danshensu in the ESMB of different extraction methods. Forty female Sprague Dawley (SD) rats were randomly divided into ESMB group, Danazol (positive control) group, model group and the sham-operation group (Sham group). After all the treatment ended, the serum levels of CA125 and the levels of IL-13, IL-18 and TNF-alpha in the peritoneal fluids of rat endometriosis models were measured using enzyme-linked immune-sorbent assay (ELISA) as directed by the manufacturer. The extraction efficiency of the ESMB samples extracted with coffee machine ranged from 600um to 710um was the highest. The serum levels of CA-125 and the levels of IL-18 and TNF-alpha in the peritoneal fluids of ESMB group, Danazol group and Sham group were significantly lower than those of the Model group (P<0.05). The serum levels of CA-125 and the levels of IL-18 and TNF-alpha in the peritoneal fluids of Danazol group and ESMB group were significantly higher than those of Sham group, respectively (P<0.05), and no marked difference existed between them (P>0.05). The levels of IL-13 in the peritoneal fluids of ESMB group, Danazol group and Sham group were significantly higher than those of the Model group (P<0.05). The levels of IL-13 in the peritoneal fluids of ESMB group and Danazol group were significantly lower than those of Sham group (P<0.05), and there was no marked difference between ESMB group and Sham group (P>0.05). ESMB shows promises in treating endometriosis by markedly decreasing the serum levels of CA-125 and the levels of IL-18 and TNF-alpha in the peritoneal fluids and significantly increasing the levels of IL-13 in the peritoneal fluids. PMID- 23983361 TI - Use of traditional veterinary medicine in Nhema communal area of the Midlands province, Zimbabwe. AB - This study documents the use of ethno-veterinary medicine to treat livestock in Nhema communal area in the Midlands province of Zimbabwe. This study employed oral interviews and detailed discussions with 69 smallholder farmers and 3 traditional healers. The local people use 23 plant species belonging to 16 families as ethno-veterinary remedies. Two plant families were particularly frequent in usage: Fabaceae and Solanaceae, while the most utilized plant species were Aloe chabaudii (UV = 0.69), Aloe greatheadii (UV = 0.65), Adenium multiflorum (UV = 0.63), Vernonia amygdalina (UV = 0.61), Nicotiana tabacum (UV = 56), Solanum lycopersicum (UV = 55), Capsicum annum (UV = 53) and Pouzolzia hypoleuca (UV = 51). Fourteen animal conditions were identified in the surveyed area. The major and most common animal diseases were tick-borne diseases, eye problems, retained afterbirth, fleas, lice and diarrhoea. The majority of ethno veterinary remedies (78%) were collected from the wild, with respondents mostly using herbs (11 species, 48%), followed by 6 trees (26%), 4 shrubs (17%), and 2 climbers (9%). The most frequently used plant parts were leaves (51%), followed by bark (16%), roots (13%) and fruits (10%). These remedies were mostly administered as decoctions or infusions of single plants. These plants were used not only as alternatives to conventional veterinary drugs but also because in certain diseases they were thought to be more efficacious. In view of many and widespread uses of wild plants as ethnoveterinary remedies, further research into their pharmacological activities may prove worthwhile. PMID- 23983362 TI - Antimicrobial activity of Carpolobia lutea extracts and fractions. AB - Carpolobia lutea (G. Don) (Polygalaceae) is a tropical medicinal plant putative in traditional medicines against gonorrhea, gingivitis, infertility, antiulcer and malaria. The present study evaluated the antimicrobial, antifungal and antihelicobacter effects of extracts C. lutea leaf, stem and root. The extracts were examined using the disc-diffusion and Microplates of 96 wells containing Muller-Hinton methods against some bacterial strains: Eschericia coli (ATCC 25922), E. coli (ATCC10418), Pseudomonas aeruginosa (ATCC 27853), Staphylococcus aureus (ATCC 25923), Staphyllococus aureus (ATCC 6571), Enterococcus faecalis (ATCC 29212) and Bacillus subtilis (NCTC 8853) and four clinical isolates: one fungi (Candida albican) and three bacteria (Salmonella, Sheigella and staphylococcus aureus). The Gram-positive bacteria: Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 29212), Bacillus subtilis (ATCC 19659) and the Gram-negative bacteria: Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Candida albicans (ATCC 18804) and Helicobacter pylori (ATCC 43504). Some of these extracts were found to be active against some tested strains but activity against H. pylori was >1000mg/ml and good fungistatic activity against C. albican. The MIC against C. albican is in the order n-HF > CHF > ETF= EAF.The order of potency of fraction was the ethanol root > n-HF leaf > ethanol fraction stem > chloroform fraction leaf = ethyl acetate fraction leaf. Polyphenols were demonstrated in ethanol fraction, ethyl acetate fraction, crude ethyl acetate extract and ethanol extract, respectively. These polyphenols isolated may partly explain and support the use of C. lutea for the treatment of infectious diseases in traditional Ibibio medicine of Nigeria. PMID- 23983363 TI - Histological changes in male accessory reproductive organs in rats exposed to cigarette smoke and the protective effect of honey supplementation. AB - The effect of cigarette smoke (CS) on histology of male accessory reproductive organs and the possible protective effect of honey supplementation in rats were investigated in this study. Rats received distilled water, honey, CS exposure or honey plus CS exposure. Honey (1.2 g/kg body weight/day) was administered by gavage and CS exposure (3 times per day) was done in a chamber for 13 weeks. CS exposure significantly increased relative weight of epididymis and ventral prostate. There were also significantly increased number of clear cells and epithelial height of cauda epididymis as well as severe interstitial oedema and decreased epithelial height of prostate gland. However, with the supplementation of honey, these histological changes were significantly reversed suggesting the protective effect of honey against the toxic effect of CS on male accessory reproductive organs in rats. PMID- 23983364 TI - Anti-fertility effects of different fractions of Anethum graveolens L. extracts on female rats. AB - Our previous studies showed the effects of aqueous and ethanol extracts of Anethum graveolens L. (dill) on female infertility. In the present study we investigated whether different fractions of this herb extract can cause infertility in rats. Female rats were divided into the control groups, the groups receiving either a low (0.5 g/kg)) or a high dose (5g/kg) of water, N-butanol, chloroform and ether fractions of the aqueous plant extract, and the groups receiving either a low (0.045 g/kg) or a high dose (0.45 g/kg) of the same fractions of ethanol extract. The mentioned doses were gavaged in 1mL for 10 days. Vaginal smears were prepared daily. Estradiol and progesterone levels were measured. The left oviduct and ovary were removed, their tissue subsequently being prepared in form of histology slides and stained using haematoxylin-eosin and Masson's trichrome. Female rats assigned to each group were mated with males; after that, crown-rump lengths and weights of newborn rats were measured. Results showed that each fraction produced some changes such as hormonal level reduction (chloroform fraction), diestrus phase prolongation and infertility (water fraction), and increase in pregnancy duration (chloroform and ether fractions). We concluded that each fraction comprises only some of the mentioned components and therefore recommended the usage of crude extract, especially the aqueous one, in case infertility aims to be induced. PMID- 23983365 TI - Antioxidant properties and inhibitory effect of ethanolic extract of Struchium sparganophora (Ewuro Odo) leaf on alpha--amylase and alpha--glucosidase activities. AB - Recent studies have shown that vegetables consumption could lower the risk of diabetes mellitus. Therefore, this study sought to investigate the inhibitory effect of Struchium sparganophora (Ewuro Odo) leaf on key enzyme linked to type-2 diabetes (alpha-amylase and alpha-glucosidase) as well as assessing the effect of blanching (a commonly practiced food processing technique) of this leafy vegetable on these key enzymes. Fresh leaves of Struchium sparganophora were blanched in hot water for 10 minutes, and the 70% ethanolic extracts of the fresh and blanched vegetables were prepared and used for subsequent analysis. The antioxidant properties and interaction of the extracts on alpha - amylase and alpha - glucosidase activities was determined in vitro. The result revealed that Struchium sparganophora leaf scavenged DPPH free radical and also inhibited alpha -amylase and alpha - glucosidase activities in a dose dependent manner (0.05 -0.2 mg/ml). However, blanching of this leafy vegetables caused a significant (P<0.05) increase in the antioxidant properties as typified by the DPPH radical scavenging ability and reducing property but decrease their ability to inhibit alpha - amylase and alpha - glucosidase activities. This antioxidant properties and enzyme inhibition could be part of the mechanism by which green leafy vegetables exert their anti-diabetic properties. However, blanching of the vegetable could reduce their ability to inhibit both alpha - amylase and alpha - glucosidase activity, but enhance their antioxidant properties in vitro. PMID- 23983366 TI - Medicinal plants and formulations used by the Soren clan of the Santal tribe in Rajshahi district, Bangladesh for treatment of various ailments. AB - The Santals form the largest tribal community in northern Bangladesh reside primarily in Rajshahi and Rangpur Divisions, where they live in the districts of Rajshahi, Rangpur, Thakurgaon, Dinajpur, and Panchagarh. Although they are fast losing their traditional medicinal practices, they still have their own medicinal practitioners who rely mostly on medicinal plants for treatment of a variety of ailments. The traditional medicinal practices vary quite extensively between the twelve clans of the Santals. The objective of the present study was to conduct an ethnomedicinal survey amongst the Soren clan of the Santal community residing in two villages of Tanor Santal Para in Rajshahi district to collect information on their use of medicinal plants. Interviews were conducted of the two existing Santal traditional medicinal practitioners of the Soren clan with the help of a semi-structured questionnaire and using the guided field-walk method. Plant specimens as pointed out by the practitioners were collected and pressed on the field and identification completed at the Bangladesh National Herbarium. Information on 53 medicinal plants distributed into 32 families was obtained in this survey. Ailments treated by these plants included skin disorders, respiratory tract disorders, gastro-intestinal disorders, sexual dysfunctions, sexually transmitted diseases, diabetes, helminthiasis, pain, urinary problems, filariasis, leprosy, tuberculosis, epilepsy, snake bite, enlarged heart, and paralysis. The medicinal plants used by the Santals merit further scientific studies for some of their formulations are used to treat diseases like diabetes, paralysis, enlarged heart, tuberculosis, and filariasis for which modern medicine has no known cure or medicines have developed resistant vectors. PMID- 23983367 TI - A biochemical and histopathologic study showing protection and treatment of gentamicin-induced nephrotoxicity in rabbits using vitamin C. AB - Gentamicin and vitamin C have been proposed as nephrotoxic and antioxidant, respectively. This study involved biochemical and histopathologic investigation showing protection and treatment of gentamicin-induced nephrotoxicity in rabbits using vitamin C for 26 days hypothesizing that whether vitamin C would inhibit or decrease the raised serum urea and creatinine levels. This study was conducted on 25 healthy male albino rabbits (average weight 1.5+/-0.2 kg), classified into 5 groups: group A, B, C, D and E for nephrocurative (study-I) and nephroprotective (study-II) studies. Control group of rabbits (group A) received only the vehicle of gentamicin ampoule. In study-I, gentamicin sulphate (GS 80 mg/kg, i.m.) was administered to group B and C rabbits for ten days, then group C rabbits received vitamin C 250 mg/Kg for remaining 16 days. Group D and E received GS 80 mg/kg and GS 80 mg/kg i.m.-vitamin C 250 mg/kg orally, respectively during whole period (26 days) of study-II. After 26 days, various biochemical parameters, i.e. serum creatinine, blood urea nitrogen (BUN), and serum antioxidant activity, and histopathologic investigations were made. Nephrotoxicity was observed in rabbit groups B, C and D as evident from significant (p<0.05) high levels of serum creatinine and BUN and low serum antioxidant levels as compared to the levels of control group. Decrease in the levels of serum creatinine and BUN along with the increase in serum antioxidant activity was observed after vitamin C treatment in group C. While, renal-protective role of vitamin C was seen in group E as compared to the control. In conclusion, Gentamicin induced nephrotoxicity can be attenuated or treated using vitamin C. PMID- 23983368 TI - Survey and scientific evaluation of medicinal plants used by the Pahan and Teli tribal communities of Natore district, Bangladesh. AB - The Pahans and the Telis are two of the smallest indigenous communities in Bangladesh. The Pahans, numbering about 14,000 people are widely scattered in several northern districts of the country, while the Telis are such a small community that nothing has been reported on their numbers and lifestyle. Both tribes are on the verge of disappearance. One each of the Pahan and the Teli community was located after much search in two adjoining villages of Natore district, Bangladesh. Since the tribes were found to still depend on their traditional medicinal practitioners for treatment of ailments, it was the objective of the present study to document their traditional usage of medicinal plants and to evaluate such plants against modern research-based pharmacological activity studies on these plants. Interviews were conducted of the practitioners of the Pahan and Teli community of Natore district with the help of a semi structured questionnaire and using the guided field-walk method. Plant specimens as pointed out by the practitioners were collected and pressed on the field and identification completed at the Bangladesh National Herbarium. The Pahan tribal practitioners used 13 plants distributed into 9 families for treatment of 14 different ailments. The Teli tribal practitioner used 15 plants divided into 14 families for treatment of 17 different ailments. Eight out of the thirteen plants used by the Pahan tribal practitioner (61.5%) had reported relevant pharmacological activities in the scientific literature, while six out of the fifteen plants used by the Teli tribal practitioners (40%) had such relevant pharmacological activities in accordance with their usage. The medicinal plants used by the Pahans and Telis warrant further scientific studies toward discovery of lead compounds and efficacious drugs and the documentation and protection of the traditional medical knowledge held by these tribes. PMID- 23983369 TI - Effect of Allium cepa and Allium sativum on some immunological cells in rats. AB - Extracts of some spices have been reported to play a contributory role in enhancing immune function. We evaluated and compared the effect(s) of single and combined oral administration of fresh aqueous onion (Allium cepa) and garlic (Allium sativum) extracts at different concentrations on some immunological determinants in rats. CD4 cells of the rats were estimated using Partec flow cytometric technique, while total and differential white blood cell (WBC) counts were estimated using the Sysmsex(r) automated haematology analyzing technique. Our findings revealed that, CD4 and total WBC counts were significantly increased (P<=0.05) in a dose-dependent manner in both onion (250mg/Kg/d: 349+/-11cell/ul and 2.75+/-0.15X103cell/l; 500mg/Kg/d: 389+/-10cells/ul and 3.05+/-0.05 X103cell/l; 750mg/Kg/d: 600+/-11cell/ul and 3.25+/-0.05X103cells/l) and garlic (250mg/Kg/d: 410+/-10cell/ul and 2.85+/-0.15X103cell/l; 500mg/Kg/d: 494+/ 32cells/ul and 3.30+/-0.10 X103cell/l; 750mg/Kg/d: 684+/-11cell/ul and 3.55+/ 0.05X103cells/l) treated rats when compared to the zero control (200+/-11cells/ul and 1.55+/-0.05X103cells/l, respectively). Extract of garlic at 750mg/Kg/d had significantly increased the CD4 cells and total white cell count when compared to other concentrations (P<=0.05). However, no significant effect was observed on these parameters when extracts were combined (250mg/Kg/d: 252+/-21cell/ul and 1.80+/-0.10X103cells/l; 500mg/Kg/d: 315+/-21cells/ul and 2.10+/-0.10X103cells/l; 750mg/Kg/d: 368+/-10cells/ul and 2.35+/-0.05X103cells/l, respectively), the differential WBC count showed a significant increase in the proportion of cell types (lymphocytes, neutophils and monocytes) (P<=0.05). The results from this study revealed the immune boosting capabilities of Allium cepa and Allium sativum, but underscored their synergistic activities. PMID- 23983371 TI - Antimicrobial potentials of silver colloidal (nanorods) on clinical isolates in Bayelsa state, Nigeria. AB - Antimicrobial resistance in developing countries has long been an issue of major concern. Nanotechnology has become an eye opener for the intervention on multiple drug resistance organisms. In this study we investigated the antimicrobial potentials of Silver Nitrate (nanorods) solution used in managing infectious diseases, the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of the product against microbial isolates were determined using standard microbiological techniques. The mean MIC and MBC of silver nitrate solution on fungi (0.16 ug/ml and 0.29 ug/ml respectively) was significantly lower than that of Gram positive organisms (2.35ug/ml and 2.62ug/ml) and Gram negative organisms (2.05 ug/ml and 2.10 ug/ml). Of all the Gram positive organisms, Staphylococcus spp recorded the lowest mean MIC and MBC while in the Gram negative organisms group, E. coli isolates showed the lowest mean MIC and MBC of the silver nitrate solution, though not significantly different from the other isolates. In conclusion, results from this study revealed that Silver Nitrate(nanorods) may have be broad spectrum in activity, but with higher antifungal potentials. PMID- 23983370 TI - Medicinal plants used for treatment of diabetes by the Marakh sect of the Garo tribe living in Mymensingh district, Bangladesh. AB - Diabetes mellitus is an endocrinological disorder arising from insulin deficiency or due to ineffectiveness of the insulin produced by the body. This results in high blood glucose and with time, to neurological, cardiovascular, retinal and renal complications. It is a debilitating disease and affects the population of every country of the world. Around 200 million people of the world suffer from this disease and this figure is projected to rise to 300 million in the coming years. The disease cannot be cured with allopathic medicine as the drugs used do not restore normal glucose homeostasis and moreover have side-effects. On the other hand, traditional medicinal practitioners of various countries claim to cure diabetes or at least alleviate the major symptoms and progression of this disease through administration of medicinal plants. The Garos are an indigenous community of Bangladesh, who still follow their traditional medicinal practices. Their traditional medicinal formulations contain a number of plants, which they claim to be active antidiabetic agents. Since observation of indigenous practices have led to discovery of many modern drugs, it was the objective of the present study to conduct a survey among the Marakh sect of the Garos residing in Mymensingh district of Bangladesh to find out the medicinal plants that they use for treatment of diabetes. It was found that the tribal practitioners of the Marakh sect of the Garos use twelve medicinal plants for treatment of diabetes. These plants were Lannea coromandelica, Alstonia scholaris, Catharanthus roseus, Enhydra fluctuans, Terminalia chebula, Coccinia grandis, Momordica charantia, Cuscuta reflexa, Phyllanthus emblica, Syzygium aqueum, Drynaria quercifolia, and Clerodendrum viscosum. A review of the scientific literature demonstrated that almost all the plants used by the Garo tribal practitioners have reported antidiabetic and/or antioxidant properties and have enormous potential for possible development of new and efficacious antidiabetic drugs. PMID- 23983372 TI - Antiviral and immune stimulant activities of glycyrrhizin against duck hepatitis virus. AB - This study was conducted to investigate the effect of glycyrrhizin as an immune stimulant against duck hepatitis virus (DHV). In vitro study was carried out to determine cytotoxic and antiviral effects of glycyrrhizin in VERO cells. In vivo study was performed on 40 one-day-old White Pekin ducklings. -and the birds weres divided into 4 groups: control, glycyrrhizin treated, vaccinated with live attenuated DHV vaccine and glycyrrhizin treated and vaccinated; to investigate the changes in immunity and challenge test. Blood samples were collected from each duckling for evaluation of cellular and humeral immunity. The in vitro results revealed that glycyrrhizin had antiviral and no toxic effects till 106 dilutions. Higher antibody titer was observed from the 5th week till the end of experiment in glycyrrhizin and vaccinated group. Treatment with glycyrrhizin alone or with DHV vaccine demonstrated a pronounced lymphocytic proliferation response after 4 days post-inoculation till the end of experiment, while vaccinated group revealed a pronounced proliferation response after 24 days post inoculation. Treatment with glycyrrhizin alone or combination with DHV vaccine revealed good immune stimulant and antiviral effect against DHV. PMID- 23983373 TI - Histological changes in the heart and the proximal aorta in experimental diabetic rats fed with Piper sarmentsoum. AB - Cardiovascular complications are one of the major causes of death in diabetes mellitus. Piper sarmentosum (P.s) is an herb that possesses antihyperglycaemic effects. The main aim of the study was to observe the histological changes in the heart and the proximal aorta of streptozotocin-induced diabetic rats following P.s administration. Twenty-four male Sprague-Dawley rats (n=24) were equally randomized into four groups: control group supplemented with normal saline (C); control group supplemented with P.s (CTx) ; diabetic group supplemented with normal saline (D) and, diabetic group supplemented with P.s (DTx). Diabetes was induced by STZ (50mg/kg body weight) intramuscularly. P.s extract (0.125g/kg) was administered orally for 28 days, following four weeks of STZ induction. The cardiac and aortic tissues were collected and processed under different stains: Haematoxylin and Eosin (H & E), Verhoeff-Van Gieson (VVG), Masson's Trichome (MT) and Periodic Acid- Schiff (PAS). There were abnormal cardiomyocytes nuclei, disarray of myofibres and increase in connective tissue deposits in cardiac tissues of the diabetic untreated group. The thickness of tunica media and ratio of tunica intima to media were found to be significantly increased in the aorta of diabetic untreated group (P < 0.05) compared to the control group. There were degenerative changes in the proximal aorta in diabetic untreated groups. All the histological damages of cardiac and aortic tissues were found to be lesser in the diabetic treated groups. Supplementation with P.s extract prevented the oxidative damage arising from diabetes mellitus, and reduced its complications. PMID- 23983374 TI - Xiao-Chai-Hu Tang in treating model mice with D-galactosamine-induced liver injury. AB - This study explored the effects of a classical Chinese medicine formula- Xiao Chai-Hu Tang(XCHT) on the model mice with D-galactosamine -induced liver injury. Sixty male imprinting control region (ICR) mice were used in the present study, and they were separated randomly into 6 groups: a normal control group (Group A, n=10), a model control (Group B, n=10), a positive control (Group C, n=10), a low dose of XCHT group (Group D, n=10), a medium dose of XCHT group (Group E, n=10), and a high dose of XCHT group (Group F, n=10). ELISA was used to detect the IL-6 and TNF-alpha levels in the serum. Real-time PCR was performed to assess the expression of FasmRNA, Fas-LmRNA, Bcl-2mRNA of the liver tissues. Western blotting was used to detect the Bax protein expression of the liver tissues. The serum IL-6 and TNF-alpha levels of Group B were significantly higher than the other groups (P<0.05). The expression of Fas mRNA, Fas-LmRNA, and Bax protein of the liver tissues of Group B were significantly higher than those of the other groups (P<0.05). The expression of Bcl-2 mRNA of the liver tissues of Group B was significantly lower than other groups (P<0.05). Both of XCHT and biphenyl dicarboxylate significantly decreased the serum IL-6 and TNF-alpha levels and FasmRNA, FasLmRNA, Bax protein expression and increased the Bcl-2 mRNA expression of the liver tissues of model mice (P<0.05). It may be through decreasing the serum IL-6 and TNF-alpha levels and FasmRNA, FasLmRNA, Bax protein expression and increasing the Bcl-2 mRNA expression of the liver tissues that XCHT significantly relieved the D-galactosamine -induced liver injury. PMID- 23983376 TI - Flavonoid compounds identified in Alchemilla L. species collected in the north eastern Black Sea region of Turkey. AB - This study identified flavonoid glycosides in species of the genus Alchemilla, A. procerrima, A. stricta, A. hirtipedicellata and A. sericata. A. procerrima is an endemic species for Turkey. After detailed investigation, flavonoid compounds of the species were identified for the first time. In this study, flavonoid compounds were determined by using two different chromatography techniques, TLC and HPLC. The following flavonoid compounds were identified from the Alchemilla species studied. They are as follows: orientin (luteolin-8-C-glucoside) Rf: 0,70, vitexin (apigenin-8-C-glucoside) Rf: 0,77 as flavone-C-glycoside, rutin (quercetin-3-O-rutinoside) Rf: 0,44, hyperoside (quercetin-3-O-galactoside) Rf: 0,65, isoquercetin (quercetin-3-O-glucopyranoside) Rf: 0,72, quercitrin (quercetin-3-O-rhamnoside) Rf: 0,84 as flavonol-O-glycoside. Three more folavonoids with Rf values of Rf1=0,36, Rf2=0,54 and Rf3=0,68 were also identified for the first time in this study. Rutin (quercetin-3-O-rutinoside) and the flavonoid glycoside, shown as Rf2 were found in all species. Quercitrin and isoquercetin were determined in all analysed species but A. procerrima. Hyperoside was identified in all species except for A. stricta. Vitexin was determined only in A.stricta. Orientin was determined in A. procerrima and A. stricta, but could not be determined in A. sericata and A. hirtpedicellata. Unknown flavonoid with Rf1 and Rf3 were determined outside of A. sericata. Description of these compounds in Turkish Alchemilla plants for the first time should be viewed as a discovery of an important chemosystematic feature. PMID- 23983375 TI - Efficacy of royal jelly on methotrexate-induced systemic oxidative stress and damage to small intestine in rats. AB - The aim of this present study is to investigate the mucositis caused by methotrexate (MTX), as well as whether the application of royal jelly (RJ) has a protective effect on oxidative stress. This present study included six groups each consisted of 12 Wistar rats. Distilled water (po: peroral) was given to the 1st group as placebo for 10 days and MTX (20 mg/kg, intraperitoneal: ip) on the 7th day. The 2nd group received RJ (50mg/kg, po) for 10 days and normal saline (NS) instead of MTX. RJ (50mg/kg) was given to the 3rd group for 10 days and MTX on the 7th day. The 4th group received RJ (100 mg/kg, po) for 10 days and NS was given intraperitoneally. RJ (100mg/kg) was given to the 5th group for 10 days and a single dose of MTX. Distilled water was given to the 6th (control) group for 10 days and intraperitoneal NS on the 7th day. Malondialdehyde (MDA), glutathione peroxidase and superoxide dismutase were analyzed in blood samples on the 11th day. Morphological and histopathological changes were examined in the intestinal tissue samples. Villus length and mucosal thickness, as well as the villus length/crypt ratio, were significantly decreased with MTX administration, and the semi-quantitative histological evaluation (SQHE) score was measured high (p<0.001). In addition, a decrease in the antioxidant parameters and an increase in the MDA levels were identified. The villus length and SQHE were significantly different in the groups receiving RJ (p<0.001) as compared to the MTX group. Although RJ addition had no effect on the decreased mucosal thickness and villus/crypt ratio in MTX groups, it caused an improvement in the antioxidant levels and a remarkable decrease in MDA levels. Adding RJ has a decreasing effect on the MTX-induced intestinal damage and it has a suppressive effect on MTX induced oxidative stress by means of increasing antioxidant enzyme activity and decreasing lipid peroxidation. PMID- 23983377 TI - Radical scavenging activity of selected medicinal plants from Limpopo province of South Africa. AB - Plants collected from Limpopo province of South Africa were investigated for their antioxidative potential using the DPPH radical scavenging assay. Acetone extracts of Flueggea virosa had the highest antioxidant activity with an IC50 value of 30 ug/ml, closely matching the ascorbic acid with an IC50 value of 25 ug/ml. The lowest antioxidant readings were observed with extracts of Rhynchosia venulosa (root extract) and Ficus ingens (leaf extract). Acetone extract of Bridelia virosa leaves had the highest phenolic content (156 mg GAE/g extract), while the lowest content was recorded for R. venulosa root extract and leaf extract of F. ingens (8.3 and 17.7 mg GAE/g extract, respectively). There was a linear correlation between antioxidant activity and total phenolic content. Extracts with high phenolic content had low IC50 values, while extracts with low phenolic concentrations had high IC50 values. PMID- 23983378 TI - Discovery of potent, orally active compounds of tyrosine kinase and serine/threonine-protein kinase inhibitor with anti-tumor activity in preclinical assays. AB - Traditional medicines have become the most productive source of leads for drugs development, particularly as anti-cancer agents. Various screening approaches are being applied. Sorafenib, a multikinase inhibitor, is used to treat primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer. A small library of compounds analogous to sorafenib were designed and screened for the treatment of liver cancer. Multiple members of the family in an assay panel of tyrosine kinase family and serine/threonine-protein kinase family, including VEGFR, Abl, Aurora A, p 38, Lck, Src, PDGFR, Flt3, c-RAF, c-KIT, MEK(MAPKK) were selected to test these compounds. Analysis of the selectivity patterns for these compounds shows specificity for many kinase families. IC50 were measured for the selected compounds. Multiple compounds have very similar kinase inhibition profiles of VEGFR, Flt3, FGFR to that of sorafenib. The IC50 of c-RAF of BB1 is lower than sorafenib. The IC50 of c-RAF of BB3-12 is higher than that of sorafenib. For Flt3, IC50 of BB1-4 is less than sorafenib. The IC50 value of KDR of BB1-10 is less than sorafenib. especially against c-RAF, PDGFR, c-KIT, KDR compared to sorafenib. These compounds are potent Raf1 and Flt4 kinase inhibitors. PMID- 23983379 TI - Qualitative content analysis of complementary topical therapies used to manage diabetic foot in Jordan. AB - In order to alleviate diabetic foot problems, patients sometimes seek complementary therapies outside the professional context. This paper describes the use of complementary remedies as a topical treatment for diabetic foot ulcers among Jordanians. Qualitative content analysis was used to analyse written responses of 68 patients with diabetes who have used complementary therapies to treat diabetic foot problems. These 68 persons represented a subgroup of the study population surveyed using a questionnaire, to the effect of investigating diabetic foot treatments provided in Jordan. Informants were recruited from eight healthcare facilities established in the southern part of Jordan plus from one hospital established in the Jordanian capital. The study was approved by the Boards of Ethics of the participating healthcare facilities. Content analysis yielded the category "Complementary Therapies Used", which included a range of household items (olive oil, sesame oil, honey, and vinegar), and also some indigenous Jordanian herbs (Wormwood, Myrrh, Caper, and Henna among others). The remedies were used either as a monotherapy or as mixtures, to the common goal of treating diabetic foot problems. Other interventions like Al-cowy were also sought from traditional healers. Educational campaigns are required to increase the awareness of patients and their families on possible hazards of unwise complementary therapy use. The decisions on the use of such therapies should be made in agreement with the attending healthcare professionals. PMID- 23983380 TI - Acupuncture in treating hepatic fibrosis: a review with recommendation for future studies. AB - Hepatic fibrosis, as a major medical problem, is characterized with significant morbidity and mortality. Acupuncture has potential advantages in treating hepatic fibrosis as acupuncture functions well to reduce Qi and Blood stagnation, resolve stasis and enhance body immunity, which are important factors in treating hepatic fibrosis. The aim of this review was to appraise the current limited evidence of acupuncture in treating hepatic fibrosis from both animal experiments and clinical trials by using both Chinese and western databases and to provide recommendations for future studies. PMID- 23983381 TI - Antimicrobial activity of the solvent fractions from Bulbine natalensis Tuber. AB - Bulbine natalensis Baker has been acclaimed to be used as an antimicrobial agent in the folklore medicine of South Africa without scientific evidence to substantiate or refute this claim. In view of this, the in vitro antimicrobial activity of solvent fractions (ethanol, ethyl acetate, n-butanol and water) from Bulbine natalensis Tuber against 4 Gram positive and 12 Gram negative bacteria as well as 3 fungal species were investigated using agar dilution. The ethanolic extract, n-butanol and ethyl acetate fractions inhibited 75, 87.5 and 100% respectively of the bacterial species in this study. The ethanolic, n-butanol and ethyl acetate fractions produced growth inhibition at MIC range of 1-10, 3-10 as well as 1 and 5 mg/ml respectively whereas the water fraction did not inhibit the growth of any of the bacterial species. Again, it was only the ethyl acetate fraction that inhibited the growth of Shigelli flexneri, Staphyloccus aureus and Escherichia coli. The ethanolic, ethyl acetate and n-butanolic fractions dose dependently inhibited the growth of Aspergillus niger and A. flavus whereas the water fraction produced 100% growth inhibition of the Aspergillus species at all the doses investigated. In contrast, no growth inhibition was produced on Candida albicans. The growth inhibition produced by the solvent fractions of B. natalensis Tuber in this study thus justifies the acclaimed use of the plant as an antimicrobial agent. The ethyl acetate fraction was the most potent. PMID- 23983382 TI - Evaluation of acute and subacute oral toxicity of the ethanol extract from Antidesma acidum Retz. AB - Toxicity tests of 95% ethanol extract of the root of Antidesma acidum were studied in male and female rats. The oral acute toxicity test at 5,000 mg/kg revealed that the ethanol extract did not produce toxic effects on signs, general behavious, mortality and gross appearance of internal organs of rats. Furthermore, the oral sub-acute toxicity test at the dose of 1,000 mg/kg/day displayed no significant changes in body and internal organs' weights, normal hematological and clinical blood chemistry values. Histological examination also showed normal architecture of all internal organs. In conclusion, the ethanol extract of Antidesma acidum did not produce any toxicity in oral acute and suba cute toxicity studies. PMID- 23983383 TI - Prevalence and predictors of traditional medicine utilization among persons living with AIDS (PLWA) on antiretroviral (ARV) and prophylaxis treatment in both rural and urban areas in South Africa. AB - Previous studies have reported that majority of antiretroviral (ARV) treatment naive patients use traditional medicine (TM). Given that TM use is ubiquitous in South Africa especially for chronic conditions, there is a potential for ARV non adherence and serious drug interactions among patients with HIV/AIDs who use TM. The motivating factors for TM use in HIV/AIDS patients on ARV and prophylaxis treatment have not been well defined in South Africa. This study aimed to investigate the prevalence, facilitators, predictors, and types of TM used among persons living with HIV/AIDS on antiretroviral treatment. The study was a cross sectional survey which involved 100 participants enrolled at ARV clinics in two South African provinces. Univariate and bivariate analyses were performed to assess the relationships between variables and potential predictors of TM. Sixteen percent of participants on ARV reported TM use. Seventy-nine percent used TM prior to a diagnosis of HIV. Participants were more likely to use TM if they were from a rural province, female, older, unmarried, employed, had limited education, or were HIV-positive for less than five years. TM users reported utilizing herbal or medicinal mixtures that were claimed to heal all conditions. This study provides insights into the treatment modalities selected by patients with HIV/AIDS in South Africa who are receiving ARV. This study revealed that less than 20% of participants co-used TM and ARV. However, close to 80% of participants utilize TM before contracting HIV, which is in keeping with approximate estimates by the WHO. PMID- 23983384 TI - Anti-inflammatory and anti-ulcerogenic activities of Chantaleela recipe. AB - Chantaleela recipe is indicated for relieving fever in Thai traditional folk medicine. In the present study, Chantaleela recipe was investigated for anti inflammatory, analgesic, antipyretic and anti-ulcerogenic activities. In preliminary investigation Chantaleela recipe was found to exert an inhibitory activity on the acute phase of inflammation as seen in ethyl phenylpropiolate induced ear edema as well as in carrageenan-induced hind paw edema in rats. The results suggest that the anti-inflammatory activity of Chantaleela recipe may be due to an inhibition via cyclooxygenase pathway. In the analgesic test, Chantaleela recipe showed a significant analgesic activity in both the early and late phases of formalin test, but exerted the most pronounced effect in the late phase. The analgesic activity of Chantaleela recipe may act via mechanism at peripheral and partly central nervous system. In antipyretic test, Chantaleela recipe significantly decreased rectal temperature of brewer's yeast-induced hyperthermia rats, probably by inhibiting synthesis and/or release of prostaglandin E2 in the hypothalamus. Therefore, the key mechanism of anti inflammatory, analgesic, and antipyretic activity of the Chantaleela recipe likely involves the inhibition of the synthesis and/or release of inflammatory or pain mediators, especially prostaglandins. The oral administration of the Chantaleela recipe reduced ulcer formation in acute gastric ulcer models (EtOH/HCl-, indomethacin-, and stress-induced gastric lesions). In contrast, this recipe did not reduce the secretory rate, total acidity, and increase pH in rat stomach. These results indicated that Chantaleela seem to possess anti ulcerogenic effect. This activity may be due to the increase of gastric mucosal resistance or potentiation of defensive factors and/or the decrease of aggressive factors but did not associate the anti-secretory activity. Moreover, the high oral doses treated did not cause acute toxicity in rats and the long term oral administration did not produce gastric and ileum lesions. PMID- 23983385 TI - Why HIV positive patients on antiretroviral treatment and/or cotrimoxazole prophylaxis use traditional medicine: perceptions of health workers, traditional healers and patients: a study in two provinces of South Africa. AB - The study explored the perceptions, knowledge and attitudes of patients, health workers and traditional healers about the use of traditional medicine and Anti Retroviral Therapy (ART). The study explored the perceptions, knowledge and attitudes of patients, health workers and traditional healers about the use of traditional medicine and Anti Retroviral Therapy (ART), using an exploratory qualitative design in two provinces of South Africa: an urban township health facility in the Western Cape, and a rural district hospital in KwaZulu-Natal (KZN) with antennal HIV rate of 32% and 28%'respectively. In-depth interviews were conducted with 14 participants: six HIV patients on ART and using Traditional Medicine(TM), two doctors, two nurses and four traditional healers. Two focus group discussions -one at each site - were held with community health workers who work with HIV-positive patients (Western Cape [5] and in KZN [4]). Patient said to have used Traditional Healing Practices (THP) before they were diagnosed with HIV, and some who have been diagnosed with HIV continue using TM in conjunction with ART and/or Cotrimoxazole prophylaxis. Patients preferred not to disclose THP to health professionals because of lack of support and understanding. Patients utilize THP because of family expectations, privacy and confidentiality, especially when they have not disclosed their HIV status. Healthcare professionals had strong negative opinions about THP, especially for HIV-positive patients. Traditional healers supported the patient's rationale for THP use. This study revealed a need to better understand factors involved in patients' choosing to use THP concurrently with ART. PMID- 23983386 TI - Aromatherapy as an adjuvant treatment in cancer care--a descriptive systematic review. AB - Claims of benefits of aromatherapy for cancer patients include reduced anxiety levels and relief of emotional stress, pain, muscular tension and fatigue. The objective of this paper is to provide an updated descriptive, systematic review of evidence from pre-clinical and clinical trials assessing the benefits and safety of aromatherapy for cancer patients. Literature databases such as Medline (via Ovid), the Cochrane database of systematic reviews, Cochrane Central were searched from their inception until October 2010. Only studies on cancer cells or cancer patients were included. There is no long lasting effect of aromatherapy massage, while short term improvements were reported for general well being, anxiety and depression up to 8 weeks after treatment. The reviewed studies indicate short-term effects of aromatherapy on depression, anxiety and overall wellbeing. Specifically, some clinical trials found an increase in patient identified symptom relief, psychological wellbeing and improved sleep. Furthermore, some found a short-term improvement (up to 2 weeks after treatment) in anxiety and depression scores and better pain control. Although essential oils have generally shown minimal adverse effects, potential risks include ingesting large amounts (intentional misuse); local skin irritation, especially with prolonged skin contact; allergic contact dermatitis; and phototoxicity from reaction to sunlight (some oils). Repeated topical administration of lavender and tea tree oil was associated with reversible prepubertal gynecomastia. PMID- 23983387 TI - Anti-diarrheal activity and toxicity of Learng Pid Samud recipe. AB - Learng Pid Samud (LPS) recipe is a traditional remedy in Thai folk medicine to ease the common diarrhea. The anti-diarrheal potential of LPS recipe was herein examined in vitro using a guinea-pig ileum model. The LPS exerted an inhibitory effect on acetylcholine-induced smooth muscle contraction in the guinea pig ileum. Significantly, not only did the LPS reduce the total amount of feces in the induced diarrhea rats, but also the intestinal transit in the charcoal meal test. A single oral administration with the recipe at 5,000 mg/kg did not cause acute toxicity and the daily oral administration (1,000, 2,000 and 4,000 mg/kg) for 90 days in rats did not produce any toxic signs and symptoms. In conclusion, the Learng Pid Samud recipe remedy is evidently safe and effective for the anti diarrheal treatment which supports its therapeutic uses in the alternative medicine. PMID- 23983388 TI - Garcinia kola seeds: is the aqueous extract a true aphrodisiac in male Wistar rats? AB - The age long acclaimed aphrodisiac potentials of Garcinia kola seeds in some parts of Western Nigeria has not been substantiated with scientific evidence. In this study, we have decided to evaluate the effect of aqueous seed extract of G. kola at the doses of 25, 50 and 100 mg/kg body weight on sexual behaviour of male rats. Male rats weighing 215.00 +/- 18.58 g were randomized completely into four groups (A-D) of six animals each. Animals in group A received, orally, 0.5 ml of distilled water only while those in groups B, C and D received same volume containing 25, 50 and 100 mg/kg body weight of the seed extract respectively. Frequencies of mount (MF), intromission (IF), genital toilet (GTF) and ejaculation (EF) as well as latencies of mount (ML), intromission (IL) and ejaculation (EL) were evaluated following the pairing of male rats (1:1) with non oestrous female rats. The parameters were monitored for the first (15-30 min), second (75-90 min) and third (180195 min) observatory periods. The levels of testosterone, luteinizing (LH) and follicle stimulating hormones (FSH) were also determined. Phytochemical screening of the extract revealed the presence of saponins (2.78%), cardiac glycosides (0.26%), cardenolides and dienolides (0.24%), flavonoids (1.28%) and steroids (1.14%). The 25 and 100 mg/kg body weight increased (P<0.05) the MF whereas the ML was decreased by all the doses of the extract. MF and ML were not altered during the second observatory period whereas the 50 mg/kg body weight increased these parameters during the third observatory period. Other sexual behaviour parameters as well as serum testosterone, FSH and LH were not significantly altered throughout the observatory periods. Overall, the results revealed that G. kola seeds did not have sex enhancing potential as claimed. Therefore, the acclaimed pro sexual effect of Garcinia kola seeds is scientifically untrue. This study has refuted the claim that one of the rationales for consuming the seeds by the aged population of Nigeria is to enhance sexual invigoration in males. PMID- 23983389 TI - Medicinal plants used by the Mandais--a little known tribe of Bangladesh. AB - The Mandais are a little known tribe of Bangladesh inhabiting the north central regions, particularly Tangail district of Bangladesh. Their population has been estimated to be less than 10,000 people. Although the tribe has for the most part assimilated with the mainstream Bengali-speaking population, they to some extent still retain their original tribal customs, including their traditional medicinal practices. Since this practice is also on the verge of disappearance, the objective of the present study was to conduct an ethnomedicinal survey among Mandai tribal practitioners to document their use of medicinal plants for treatment of various ailments. Four traditional practitioners were found in the exclusive Mandai-inhabited village of Chokchokia in Tangail district. Information was collected from the practitioners with the help of a semi-structured questionnaire and guided field-walk method. It was observed that the four traditional practitioners used a total of 31 plants distributed into 23 families for treatment. The various ailments treated included diabetes, low semen density, jaundice, gastrointestinal tract disorders (stomach ache, indigestion, dysentery, and diarrhea), leucorrhea, pain (rheumatic pain, joint pain), skin disorders, respiratory tract disorders (coughs, mucus, and allergy), debility, fever, and helminthiasis. From the number of plants used (seven), it appeared that gastrointestinal tract disorders formed the most common ailment among the Mandai community, possibly brought about by the low income status of the people coupled with unhygienic conditions of living. PMID- 23983390 TI - Effects of 3 topical plant extracts on wound healing in beef cattle. AB - Eleven heifers of the Puruna cattle breed were used to evaluate wound healing by second intention. An experimental wound excision model in bovines was created by means of a skin punch of diameter 2cm. The animals were topically treated for 17 days with a saline control or decoctions of Schinus terebinthifolius Raddi (Aroeira mansa), Tabebuia avellanedae Lorentz ex Griseb (Ipe Roxo), and Casearia sylvestris Sw.(Guacatonga) mixed with carboxymethyl cellulose. Centripetal retraction, clinical, and histological aspects of the wounds were observed until complete healing. Decoctions of T. avellanedae and S. terebinthifolius, but not C. sylvestris, had a beneficial effect on wound healing by second intention. PMID- 23983391 TI - Effects of Chinese herbal recipes on immunity in immunosuppressive mice. AB - The Chinese herbal formula consisting of Astragalus membranaceus, Epimedium brevicornum, Paeoniae Alba Radix and Radix Ophiopogonis in proper proportions were adopted in order to investigate the immunoenhancing properties of the herbal formula. Fifty ICR mice were randomly divided into 5 groups (NS- NS+Hy-L+Hy-M+Hy H+Hy ). The mice in hydrocortisone (Hy) groups were injected with hydrocortisone i.p. to induce the immunosuppressive condition. The mice in group NS were administered with normal saline as controls. The mice in groups NS+Hy-L+Hy-M+Hy H+Hy were administered with normal saline, low, moderate and high dose of the herbal prescription respectively by gavage for 6 days. The level of serum hemolysin, the function of antibody function cell-AFC-and CD4+/CD8+ T cell ratio were measured at the end of experiments. The results showed that the level of serum hemolysin, the function of AFC and CD4+/CD8+ T cell ratio in L+Hy-M+Hy-H+Hy groups increased significantly compared with those in NS or NS+Hy groups. These results indicate that Chinese herbal medicine prescription can enhance humoral immunity and cellular immune function of the immunosuppressive mouse. PMID- 23983392 TI - The effects of crude aqueous and alcohol extracts of Aloe vera on growth and abdominal viscera of suckling rats. AB - The gastrointestinal tract of neonates is sensitive to dietary manipulations. When nursing mothers use Aloe vera, their babies are at risk of indirect exposure to Aloe vera via breast feeding or directly as health supplements. The effects of orally administered extracts of Aloe vera in unweaned rats were investigated. Six day old Sprague-Dawley rats were gavaged with aqueous or alcohol extracts of Aloe vera (low dose 50mg. kg-1 or high dose 500mg. kg-1) daily for eight days. All data were expressed as mean +/- SD and analyzed by one way ANOVA. Pups receiving high doses of either extract had a significantly higher body mass gain than the group receiving lower dose (p < 0.05). Tibial length was significantly increased in the high dose aqueous extract group (15-26%). The differences in growth could not be attributed to circulating insulin-like growth factor-1 as the levels were not significantly different. The caecum was significantly enlarged in the rats that received the high doses of both extracts. Although, there was no significant difference in the non-fasting plasma concentration of glucose and triglycerides, the hepatic lipid and glycogen content were significantly higher (p < 0.001) for the high dose aqueous extract group. The plasma alanine transaminase was not affected by the treatments, however the high doses of the extracts significantly increased plasma alkaline phosphatase activity. Short term administration of Aloe vera extracts resulted in growth promotion, enhanced hepatic storage of metabolic substrates, increased ALP possibly in relation to bone growth and caused hypertrophy of the caecum of neonatal rats. These effects need to be explored further to enhance animal production and health. PMID- 23983393 TI - Lactogenic activity of rats stimulated by Gunnera perpensa L. (Gunneraceae) from South Africa. AB - Gunnera perpensa L. (Gunneraceae) is a medicinal plant used by Zulu traditional healers to stimulate milk production. The effect of an aqueous extract of the rhizome of the plant on milk production in rats was investigated. Female lactating rats that received oral doses of the extract of G.perpensa significantly (p<0.05) produced more milk than controls. The plant extract did not however, significantly influence the levels of prolactin, growth hormone, progesterone, cortisol, ALT, AST and albumin in the blood. The mammary glands of rats treated with the extract showed lobuloalveolar development. The extract (0.8 ug/ml) was also found to stimulate the contraction of the uterus and inhibit (23%) acetylcholinesterase activity. The cytotoxicity of the extract (LC50) to two human cell lines (HEK293 and HepG2) was 279.43 ug/ml and 222.33ug/ml, respectively. It is inferred that the plant extract exerts its activity on milk production and secretion by stimulating lobuloalveolar cell development and the contraction of myoepithelial cells in the alveoli. It is concluded that Gunnera perpensa contains constituents with lactogenic activity that apparently contribute to its effectiveness in folk medicine. PMID- 23983394 TI - Ethanolic extract of Aconiti Brachypodi Radix attenuates nociceptive pain probably via inhibition of voltage-dependent Na+ channel. AB - Aconiti Brachypodi Radix, belonging to the genus of Aconitum (Family Ranunculaceae), are used clinically as anti-rheumatic, anti-inflammatory and anti nociceptive in traditional medicine of China. However, its mechanism and influence on nociceptive threshold are unknown and need further investigation. The analgesic effects of ethanolic extract of Aconiti Brachypodi Radix (EABR) were thus studied in vivo and in vitro. Three pain models in mice were used to assess the effect of EABR on nociceptive threshold. In vitro study was conducted to clarify the modulation of the extract on the tetrodotoxin-sensitive (TTX-S) sodium currents in rat's dorsal root ganglion (DRG) neurons using whole-cell patch clamp technique. The results showed that EABR (5-20 mg/kg, i.g.) could produce dose-dependent analgesic effect on hot-plate tests as well as writhing response induced by acetic acid. In addition, administration of 2.5-10 mg/kg EABR (i.g.) caused significant decrease in pain responses in the first and second phases of formalin test without altering the PGE2 production in the hind paw of the mice. Moreover, EABR (10 ug/ml -1 mg/ml) could suppress TTX-S voltage-gated sodium currents in a dose-dependent way, indicating the underlying electrophysiological mechanism of the analgesic effect of the folk plant medicine. Collectively, our results indicated that EABR has analgesic property in three pain models and useful influence on TTX-S sodium currents in DRG neurons, suggesting that the interference with pain messages caused by the modulation of EABR on TTX-S sodium currents in DRG neurones may explain some of its analgesic effect. PMID- 23983395 TI - Preliminary evaluation of the wound healing effect of Vitex doniana sweet (Verbenaceae) in mice. AB - Vitex doniana is traditionally used in Togo to treat various diseases including wounds. The aim of this work was to evaluate the efficiency of Vitex doniana on cutaneous wound healing. Wounds were induced in ICR mice divided into four groups as following: Group I received carbopol 974P NF empty gel, Groups II and III were treated topically with carbopol gel containing 2.5% and 5% of Vitex doniana extract. Group IV received Betadine(r) 10% as standard drug. The efficacy of treatment was evaluated by planimetry and histological analysis. We secondary used the gel containing Vitex doniana at 2.5% and the pure extract at 10 mg/ml on the model of ear edema induced by xylene. Skin toxicity test was performed with the gel containing Vitex doniana at 5% and the pure extract at 30 mg/ml. Vitex doniana at 5% and 2.5% provided better wound contraction (91.14% and 86.38%) at day 12 post-excision when compared to control (51.15%). The results of histological evaluation supported the outcome of excision wound model. Moreover Vitex doniana inhibited significantly edema induced by xylene when compared to control (p< 0.05). In skin toxicity test, no abnormal symptoms were developed over 14 day-time period. Vitex doniana inhibits the topical inflammation and accelerate cutaneous wound repair. PMID- 23983396 TI - Phytomedicine versus gonorrhoea: the Bapedi experience. AB - Records regarding the phytomedicine employed by the Bapedi are almost non existent. This is the first study of herbal remedies used by Bapedi traditional healers to treat gonorrhoea, of concern as it is a danger to reproductive health. A semi-structured questionnaire, centred on sexual health, was administered to 30 traditional healers in 15 local municipalities across the three districts of Limpopo Province during 2009/10. The questionnaire focussed on the use of plants for medicine as well their application in reproductive health management. This investigation found that the Bapedi employed no less than 18 different plant species, sometimes as multiple-plant extracts, but more often as single-plant extracts. The single most used species was Catharanthus roseus, which accounted for 60% of all reported cases, followed by Aloe marlothii subsp. marlothii (13.3%). Both these species occur abundantly throughout the province and are currently not threatened. This is the first record for the use of Callilepis salicifolia, Jatropha zeyheri and Cotyledon orbiculata to treat gonorrhoea by people of any culture. PMID- 23983397 TI - Development and evaluation of a novel four-electrode device system for monitoring skin impedance. AB - Qi, meridians, and acupoints are important issues in Chinese medicine. One of the theories claims that acupuncture points and meridians have unique electrical properties. The associations between acupuncture points or meridians and special electrical properties are still under debate. In the current study, we introduced and explained a device for this kind of research and evaluated the reliability of this device as well as effects of pressure, cleaning the skin by alcohol and exfoliation on electrical skin measurements. Fifteen subjects (10 female, 5 male) were recruited to participate in the study. An impedance meter based on the four electrode technique was designed and fabricated specifically for this study. The effects of pressure, cleaning of the skin by alcohol, and exfoliation on electrical skin impedance were evaluated separately. The device repeatability was also evaluated 30 times in a 30 minutes period. Scale weight up to 200 grams, cleaning the skin with alcohol, and exfoliation didn't affect the performance of this device. The device performance didn't change significantly during the 30 minutes measurement either. The new system we evaluated can be a reliable tool for researches on electrical skin impedance in acupuncture, as its performance is fairly stable even in the presence of various confounding factors such as various pressures on the probe, cleaning the skin with alcohol and exfoliation. PMID- 23983398 TI - Acute toxicity of Opuntia ficus indica and Pistacia lentiscus seed oils in mice. AB - Opuntia ficus indica and Pistacia lentiscus L. seeds are used in traditional medicine. The objective of this study was to investigate the toxicity of the fixed oil of Opuntia ficus indica and Pistacia lentiscus L. seeds in mice through determination of LD50 values, and also the physicochemical characteristics of the fixed oil of these oils. The acute toxicity of their fixed oil were also investigated in mice using the method of Kabba and Berhens. The fixed oil of Pistacia lentiscus and Opuntia ficus indica seeds were extracted and analyzed for its chemical and physical properties such as acid value, free fatty acid percentage (% FFA), iodine index, and saponification value as well as refractive index and density. LD50 values obtained by single doses, orally and intraperitoneally administered in mice, were respectively 43 +/- 0,8 ;[40.7- 45.4 ] ml/kg body wt. p.o. and 2.72 +/- 0,1 ;[2.52-2.92] ml/kg body wt. i.p. for Opuntia ficus indica ; and 37 +/- 1 ;[34.4 - 39.8 ] ml/kg body wt. p.o. and 2.52 +/- 0,2 ;[2.22 - 2.81 ] ml/kg body wt. i.p. for Pistacia lentiscus respectively. The yields of seed oil were respectively calculated as 20.25% and 10.41%. The acid and free fatty acid values indicated that the oil has a low acidity. PMID- 23983400 TI - Cardiovascular inflammation. PMID- 23983401 TI - Angiogenesis and its therapeutic opportunities. AB - Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by "on-off switch signals" between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia) and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies). Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases. PMID- 23983403 TI - Are onconeural antibodies a clinical phenomenology in paraneoplastic limbic encephalitis? AB - Paraneoplastic neurological syndromes (PNSs) occur in patients with cancer and can cause clinical symptoms and signs of dysfunction of the nervous system that are not due to a local effect of the tumor or its metastases. Most of these clinical syndromes in adults are associated with lung cancer, especially small cell lung cancer (SCLC), lymphoma, and gynecological tumors. The finding of highly specific antibodies directed against onconeural antigens has revolutionized the diagnosis and promoted the understanding of these syndromes and led to the current hypothesis of an autoimmune pathophysiology. Accumulating data strongly suggested direct pathogenicity of these antibodies. The field of PNS has expanded rapidly in the past few years with the discovery of limbic encephalitis associated with glutamic acid decarboxylase (GAD) 65, the voltage (VGKC-gated potassium channel) complex, the methyl (N-NMDA-D-aspartate), alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and gamma aminobutyric acid (GABA) (B) receptors, and so forth. Despite this, the clinical spectrum of these diseases has not yet been fully investigated. The clinical importance of these conditions lies in their frequent response to immunotherapies and, less commonly, their association with distinctive tumors. This review provides an overview on the pathogenesis and diagnosis of PNS, with emphasis on the role of antibodies in limbic encephalitis. PMID- 23983402 TI - MicroRNAs as novel regulators of neuroinflammation. AB - MicroRNAs are relatively recently discovered class of small noncoding RNAs, which function as important regulators of gene expression. They fine-tune protein expression either by translational inhibition or mRNA degradation. MicroRNAs act as regulators of diverse cellular processes, such as cell differentiation, proliferation, and apoptosis. Their defective biogenesis or function has been identified in various pathological conditions, like inflammation, neurodegeneration, or autoimmunity. Multiple sclerosis is one of the predominated debilitating neurological diseases affecting mainly young adults. It is a multifactorial disorder of as yet unknown aetiology. As far, it is suggested that interplay between genetic and environmental factors is responsible for MS pathogenesis. The role of microRNAs in this pathology is now extensively studied. Here, we want to review the current knowledge of microRNAs role in multiple sclerosis. PMID- 23983405 TI - Inflammation in disease: mechanism and therapies. PMID- 23983404 TI - Off-label uses of anti-TNF therapy in three frequent disorders: Behcet's disease, sarcoidosis, and noninfectious uveitis. AB - Tumoral necrosis factor alpha plays a central role in both the inflammatory response and that of the immune system. Thus, its blockade with the so-called anti-TNF agents (infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab) has turned into the most important tool in the management of a variety of disorders, such as rheumatoid arthritis, spondyloarthropatties, inflammatory bowel disease, and psoriasis. Nonetheless, theoretically, some other autoimmune disorders may benefit from these agents. Our aim is to review these off-label uses of anti-TNF blockers in three common conditions: Behcet's disease, sarcoidosis, and noninfectious uveitis. Due to the insufficient number of adequate clinical trials and consequently to their lower prevalence compared to other immune disorders, this review is mainly based on case reports and case series. PMID- 23983408 TI - Critical economics of life and death: Intense + Expensive care = Intensive care? PMID- 23983407 TI - Assessment of renal function in the critically ill - Shall we look beyond predictive equations? PMID- 23983409 TI - Can calculated central venous saturation be used as a reliable tool to guide therapy in patients with shock? PMID- 23983410 TI - Assessment of accuracy of Cockcroft-Gault and MDRD formulae in critically ill Indian patients. AB - BACKGROUND: Cockroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulae have not been validated in critically ill Indian patients. We sought to quantify the discrepancy, if any, in Glomerular Filteration Rate (GFR) estimated by CG and MDRD formulae with 24 hrs urine Creatinine Clearance (Cr Cl). MATERIALS AND METHODS: Prospective cohort study in 50 adult patients in a mixed medical surgical intensive care unit. INCLUSION CRITERIA: Intensive Therapy Unit (ITU) stay >48 hrs and indwelling urinary catheter. EXCLUSION CRITERIA: Age <18 years, pregnancy, dialysis, urine output <400 ml/day and patients receiving ranitidine, cefoxitin, trimethoprim or diuretics. We estimated Creatinine Clearance by CG and MDRD formula and measured GFR by 24 hrs urine creatinine clearance. Bland Altman plot was used to find the difference between the paired observations. The association between the methods was measured by the product moment correlation coefficient. RESULT: The mean GFR as calculated by Creatinine Clearance was 79.76 ml/min/1.73 m(2) [95% Confidence Interval (CI) 65.79 to 93.72], that by CG formula was 90.05 ml/min/1.73 m(2) [95% CI: 74.50 to 105.60], by MDRD was 85.92 ml/min/1.73 m(2) [95% CI: 71.25 to 100.59]. The Bias and Precision between CG and Cr Cl were -4.5 and 140.24 respectively, between MDRD and Cr Cl was -6.1 and 122.52. The Correlation coefficient of CG formula as a measure of GFR was 0.65 (P < 0.0001), that of MDRD was 0.70 (P < 0.0001). CONCLUSION: We conclude that CG and MDRD formulae have a strong correlation with measured GFR but are not a reliable measure and overestimate GFR in critically ill Indian patients. PMID- 23983411 TI - Economic analysis of costs associated with a Respiratory Intensive Care Unit in a tertiary care teaching hospital in Northern India. AB - BACKGROUND: There is a paucity of cost analytical studies from resource constrained developing countries defining intensive care costs and their containment. OBJECTIVE: Economic analysis of costs in a Respiratory Intensive Care Unit (RICU) of a tertiary care teaching hospital in northern India. MATERIALS AND METHODS: A prospective study was conducted in 74 patients admitted in the RICU. Costs were segregated into fixed and variable costs. Total and categorized costs averaged per day and costs incurred on the first day of the RICU stay were calculated. Correlation of the costs was performed with the length of stay, length of mechanical ventilation, survival, and therapeutic intervention scoring system-28 (TISS-28). RESULTS: The total cost per day was Indian rupees (INR) 10,364 (US $ 222). 46.4% of the total cost was borne by hospital and rest by patients. The mean cost represented 36.8% of the total cost and 69.8% of the variable cost. Expenditure on personnel salary constituted 37% of the total costs and 86% of the fixed cost. Length of stay in RICU was significantly higher in nonsurvivors (14.73 +/- 13.6 days) vs. survivors (8.3 +/- 7.8 days) (P < 0.05). The TISS-28 score points in survivors was 30.6 vs. nonsurvivors 69.2 per nurse (P < 0.05) correlating strongly with the total cost (r = 0.91). CONCLUSION: Although considerably less expensive than in economically developed countries, intensive care in India remains expensive relative to the cost of living. The cost block methodology provides a framework for cost estimation, aids resource allocation and allows international comparisons of economic models. PMID- 23983406 TI - Low-density lipoprotein modified by myeloperoxidase in inflammatory pathways and clinical studies. AB - Oxidation of low-density lipoprotein (LDL) has a key role in atherogenesis. Among the different models of oxidation that have been studied, the one using myeloperoxidase (MPO) is thought to be more physiopathologically relevant. Apolipoprotein B-100 is the unique protein of LDL and is the major target of MPO. Furthermore, MPO rapidly adsorbs at the surface of LDL, promoting oxidation of amino acid residues and formation of oxidized lipoproteins that are commonly named Mox-LDL. The latter is not recognized by the LDL receptor and is accumulated by macrophages. In the context of atherogenesis, Mox-LDL accumulates in macrophages leading to foam cell formation. Furthermore, Mox-LDL seems to have specific effects and triggers inflammation. Indeed, those oxidized lipoproteins activate endothelial cells and monocytes/macrophages and induce proinflammatory molecules such as TNF alpha and IL-8. Mox-LDL may also inhibit fibrinolysis mediated via endothelial cells and consecutively increase the risk of thrombus formation. Finally, Mox-LDL has been involved in the physiopathology of several diseases linked to atherosclerosis such as kidney failure and consequent hemodialysis therapy, erectile dysfunction, and sleep restriction. All these issues show that the investigations of MPO-dependent LDL oxidation are of importance to better understand the inflammatory context of atherosclerosis. PMID- 23983412 TI - Comparison of central venous saturation by standard ABG machine versus co oximeter: Is 18 carat as good as the 24 carat gold standard? AB - AIMS: Aggressive therapy aimed at desired end-points of Early Goal Directed Therapy (EGDT) is the cornerstone of septic shock management. A key endpoint that improves outcomes is achieving central venous saturation (ScvO2) >70%. The gold standard to measure ScvO2 is by a co-oximeter (co-ox). SETTINGS AND DESIGN: This prospective, observational study from a multidisciplinary pediatric intensive care unit (PICU) was conducted to assess the validity of ScvO2 levels by standard ABG (stand ABG) machine in comparison with co-ox in conditions that shifted the oxygen dissociation curve (ODC) to the right or left in sick children and controls. MATERIALS AND METHODS: Data from paired samples was tested for correlation coefficient for pH, paCO2, paO2, and ScvO2. Tests for correlation (Pearson's coefficient) and agreement (Bland-Altman analysis) were performed on ScvO2 values obtained in various subgroups. Sensitivity and specificity for ScvO2 values determined by standard ABG machine versus co-ox were calculated in reference to EGDT endpoints. RESULTS: A total of 141 paired samples were collected from 82 children. Despite a statistically significant difference in the pH and ScvO2, there was good linear correlation between these parameters. Limits of agreement between ScvO2 measured by standard ABG machine and co-ox by Bland Altman gave 2.3% bias with 95% CI of -24.2% to 19.5%. Sensitivity and specificity of standard ABG machine in detecting low ScvO2 in shock was 84.21% and 93.18% respectively, while it was false positive in 4 samples. CONCLUSIONS: The less expensive standard ABG machine showed satisfactory correlation with gold standard co-ox over a range of patient conditions; however, the wide range for agreement was of concern and it performed particularly poorly in anemic patients. PMID- 23983413 TI - Profile of micro-organisms in intensive care unit of a level-1 trauma centre: A retrospective study. AB - BACKGROUND: Patients with trauma usually require highly specialized care in ICU and many times their recovery is complicated by infections. Aim of this study was to determine the profile of pathogens and their impact on outcome among these patients. MATERIALS AND METHODS: The clinical records of 101 consecutive patients who were admitted for more than 48-hrs in ICU during Jun-Dec 2007 were analyzed. RESULTS: Total of 953 samples from blood, urine, BAL or pus/collection were subjected to cultures. From 276 samples, 299 organisms were isolated. Among pathogens Candida Spp. [89 (29%)] were the most common, followed by Acinetobacter Spp. [69 (23%)], Pseudomonas Spp. [63 (21%)], Klebsiella Spp. [31 (10%)], coagulase negative Staphylococcus aureus [16 (5%)], E coli [12 (4%)], Enterobacter Spp. [7 (2%)], S aureus [6 (2%)], Enterococcus Spp. [5 (2%)], Citrobacter Spp. [2 (0.6%)], S maltophila [1 (0.3%)] and Providentia Spp. [1 (0.3%)]. For gram negative pathogens drug-resistance rates were as follows: Fluoroquinolones, 76%; 3(rd) generation cephalosporins, 74%; aminoglycosides, 66%; beta-lactams/beta-lactamase inhibitors combinations, 64%; and carbapenems, 50%. Among these 27% of pathogens were resistant to all 5 classes of drugs. 58% of Staphylococcus aureus were methicillin-resistant whereas 85% of coagulase negative Staphylococcus were methicillin resistant. The mortality was higher among patients in whom pathogens were isolated [Odd's Ratio (OR) 0.185; 95% confidence interval (CI) 0.049-0.640; P = 0.002]. CONCLUSIONS: Isolation of multi drug resistant pathogens is common among trauma patients admitted in ICU and is associated with increased mortality and could impact on the consumption of hospital resources. The importance of high rate of fungal isolation needs to be studied among these patients. PMID- 23983414 TI - Serum cystatin C is a poor biomarker for diagnosing acute kidney injury in critically-ill children. AB - BACKGROUND: Accurate diagnosis of acute kidney injury (AKI) is problematic especially in critically-ill patients in whom renal function is in an unsteady state. AIM: Our aim was to evaluate the role of serum (S.) cystatin C as an early biomarker of AKI in critically-ill children. SUBJECTS AND METHODS: S. creatinine and S. cystatin C were measured in 32 critically-ill children who were at risk for developing AKI. AKI was defined by both: Risk,-injury,-failure,-loss, and endstage renal disease (RIFLE) classification and glomerular filtration rate (GFR) <80 ml/min/1.73 m(2). GFR was estimated by both Schwartz formula and S. cystatin C-based equation. RESULTS: S. cystatin C was not statistically higher in AKI patients compared with non-AKI by RIFLE classification (median 1.48 mg/l vs. 1.16 mg/l, P = 0.1) while S. creatinine was significantly higher (median 0.8 mg/dl vs. 0.4 mg/dl, P = 0.001). On estimating GFR by the two equations we found, a lag between rise of S. cystatin C and creatinine denoted by lower GFR by Schwartz formula in four patients, on other hand, six patients had elevated S. cystatin C with low GFR despite normal creatinine and GFR, denoting poor concordance between the two equations and the two markers. The ability of S. creatinine in predicting AKI was superior to S. cystatin with area under the curve (AUC) 0.95 with sensitivity and specificity (100% and 84.6%, respectively) using the RIFLE classification. The same findings were found when using Schwartz formula. CONCLUSION: S. cystatin C is a poor biomarker for diagnosing AKI in critically-ill children. PMID- 23983415 TI - Management of post-intubation tracheal membrane ruptures: A practical approach. AB - Tracheal rupture is an infrequent, severe complication of endotracheal intubation, which can be difficult to diagnose. Post-intubation tracheal rupture (PiTR) is distinct from non-iatrogenic causes of tracheobronchial trauma and often requires different treatment. The increasing adoption of pre-hospital emergency services increases the likelihood of such complications from emergency intubations. Effective management strategies for PiTR outside specialist cardiothoracic units are possible. Two cases of severe PiTR, successfully managed non-operatively on a general medical-surgical intensive care unit, illustrate a modified approach to current standards. The evidence base for PiTR is reviewed and a pragmatic management algorithm presented. PMID- 23983416 TI - An innovative nasal continuous positive airway pressure assembly. AB - Continuous positive airway pressure is required by patients of obstructive sleep apnea to prevent any obstruction of airways. This requires CPAP machines which are costly, have electrical dependence and are not readily available. The nasal CPAP assembly devised by us overcomes most of these limitations and can be made from easily available materials. PMID- 23983417 TI - Hyperammonemic coma in a post-partum patient with undiagnosed urea cycle defect. AB - Urea cycle disorders (UCD) are common during neonatal period, and it is rarely reported in adults. We are reporting a patient presenting with post-partum neuropsychiatric symptoms rapidly progressing to coma. Markedly raised serum ammonia level on presentation with an initial normal magnetic resonance imaging (MRI) of brain and normal liver function tests led to the suspicion of UCD, which was confirmed on the basis of urine orotic acid and elevated serum amino acid levels. We had to resort to hemodialysis to correct the hyperammonemic coma, which was unresponsive to conventional anti-ammonia measures. She exhibited remarkable improvement with a progressive decline in serum ammonia with repeated hemodialysis and made a full recovery. Timely diagnosis and early institution of hemodialysis in the setting of a poor neurological status maybe considered a suitable treatment option. PMID- 23983418 TI - Hypertensive encephalopathy following snake bite in a child: A diagnostic dilemma. AB - Children in rural India are a vulnerable group for snake bites. Improper elicitation of history and atypical presentations could lead to misdiagnosis and delay in treatment. We are reporting the case of an 8-year-old male child who presented with convulsions, unconsciousness and hypertension who was initially managed as a case of hypertensive encephalopathy showing no sign of improvement even after 20 hs. The history when reviewed suggested neurotoxic snake bite although the patient did not have any classical local findings. Anti-snake venom administration was followed by prompt recovery. We therefore suggest that snake bite should be considered in patients from rural background presenting with hypertension, convulsion and unconsciousness, even in the absence of classical features of snake bite. PMID- 23983419 TI - Two cases of asystolic cardiac arrests managed with therapeutic hypothermia. AB - Poor neurological outcome is a common sequel of prolonged cardiac arrest. Although Therapeutic Hypothermia (TH) for neuroprotection has been a subject for research for over Half a century, its use has been limited because of many controversies and lack of clear guidelines. However for over two decades there has been a revival of interest in mild therapeutic hypothermia (32-34 degrees C) for neuroprotection. However its use after primary asystolic cardiac arrest has been questioned. Herein presenting two cases of prolonged asystolic arrest (39 minutes and 25 minutes); where therapeutic hypothermia was successfully used in following prolonged cardio pulmonary resuscitation. On patients who were in deep coma after resuscitation, TH was applied for 24 hours as per institutional protocol with full neurological recovery in both the cases. Therapeutic hypothermia might have a potential role in even in non-shockable arrests and should be considered in every successful cardiopulmonary resuscitation with poor neurological status. PMID- 23983420 TI - Two unusual complications of neuroleptic malignant syndrome. AB - Neuroleptic malignant syndrome (NMS) is a rare but well described complication of the administration of antipsychotic agents. Compartment syndrome, with increased pressures within the confined space of fascial sheaths leading to compression damage of the contained tissue, similarly is well described. Brachial plexus injuries caused by patient malposition are also very rare but a few cases have been reported. We report a case where these three complications occurred together. This was attributable to the patient developing NMS whilst asleep in the prone position overnight. PMID- 23983421 TI - Status epilepticus: An association with pyrethroid poisoning. AB - This report describes a 35 year old male who presented with seizures after consuming 4-5 bottles of "ALL-OUT" a commercial composition of pyrethroid used as insecticides. Our case report supports authors reporting an association of pyrethroid poisoning with status epilepticus. PMID- 23983422 TI - Trendelenberg position in subclavian vein cannulation in patients with pleural effusion: A necessary evil? PMID- 23983423 TI - Bile duct cyst in adults: interventional treatment, resection, or transplantation? AB - Cystic dilatations of the bile ducts may be found along the extrahepatic biliary tree, within the liver, or in both of these locations simultaneously. Presentation in adults is often associated with complications. The therapeutic possibilities have changed considerably over the last few decades. If possible, complete resection of the cyst(s) can cure the symptoms and avoid the risk of malignancy. According to the type of bile duct cyst, surgical procedures include the Roux-en-Y hepaticojejunostomy and variable types of hepatic resection. However, the diffuse forms of Todani type V cysts (Caroli disease and Caroli syndrome) in particular remain a therapeutic problem, and liver transplantation has become an important option. The mainstay of interventional treatment for Todani type III bile duct cysts is via endoscopic retrograde cholangiopancreatography. The diagnostic term "bile duct cyst" comprises quite different pathological and clinical entities. Interventional therapy, hepatic resection, and liver transplantation all have their place in the treatment of this heterogeneous disease group. They should not be seen as competitive treatment modalities, but as complementary options. Each patient should receive individualized treatment after all of the clinical findings have been considered by an interdisciplinary team. PMID- 23983424 TI - MicroRNAs and liver cancer associated with iron overload: therapeutic targets unravelled. AB - Primary liver cancer is a global disease that is on the increase. Hepatocellular carcinoma (HCC) accounts for most primary liver cancers and has a notably low survival rate, largely attributable to late diagnosis, resistance to treatment, tumour recurrence and metastasis. MicroRNAs (miRNAs/miRs) are regulatory RNAs that modulate protein synthesis. miRNAs are involved in several biological and pathological processes including the development and progression of HCC. Given the poor outcomes with current HCC treatments, miRNAs represent an important new target for therapeutic intervention. Several studies have demonstrated their role in HCC development and progression. While many risk factors underlie the development of HCC, one process commonly altered is iron homeostasis. Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised. Aberrant miRNA expression in hepatic fibrosis and injury response have been reported, as have dysregulated miRNA expression patterns affecting cell cycle progression, evasion of apoptosis, invasion and metastasis. In 2009, miR-26a delivery was shown to prevent HCC progression, highlighting its therapeutic potential. Several studies have since investigated the clinical potential of other miRNAs with one drug, Miravirsen, currently in phase II clinical trials. miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy. Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years, yielding improved HCC survival rates and patient outcomes. PMID- 23983425 TI - Risk factors for local recurrence following neoadjuvant chemoradiotherapy for rectal cancers. AB - Local recurrence (LR) has an adverse impact on rectal cancer treatment. Neoadjuvant chemoradiotherapy (nCRT) is increasingly administered to patients with progressive cancers to improve the prognosis. However, LR still remains a problem and its pattern can alter. Correspondingly, new risk factors have emerged in the context of nCRT in addition to the traditional risk factors in patients receiving non-neoadjuvant therapies. These risk factors are decisive when reviewing treatment options. This review aims to elucidate the distinctive risk factors related to LR of rectal cancers in patients receiving nCRT and to clarify their clinical significance. A search was conducted on PubMed to identify original studies investigating patients with rectal cancer receiving nCRT. Outcomes of interest, especially potential risk factors for LR in patients with nCRT, were then analyzed. The clinical importance of these risk factors is discussed. Remnant cancer cells, lymph-nodes and tumor response were found to be major risk factors. Remnant cancer cells decide the status of resection margins. Local excision following nCRT is promising in ypT0-1N0M0 cases. Dissection of lateral lymph nodes should be considered in advanced low-lying cancers. Although better tumor response resulted in a relatively lower recurrence rate, the evidence available is insufficient to justify a non-operative approach in clinical complete responders to nCRT. LR cannot be totally avoided by current multidisciplinary approaches. The related risk factors resulting from nCRT should be considered when making decisions regarding treatment selection. PMID- 23983427 TI - Human platelets inhibit liver fibrosis in severe combined immunodeficiency mice. AB - AIM: To investigate the role of human platelets in liver fibrosis. METHODS: Severe combined immunodeficiency (SCID) mice were administered CCl4 and either phosphate-buffered saline (PBS group) or human platelet transfusions (hPLT group). Concentrations of hepatocyte growth factor (HGF), matrix metallopeptidases (MMP)-9, and transforming growth factor-beta (TGF-beta) in the liver tissue were compared between the PBS and the hPLT groups by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The effects of a human platelet transfusion on liver fibrosis included the fibrotic area, hydroxyproline content, and alpha-smooth muscle actin (alpha-SMA) expression, which were evaluated by picrosirius red staining, ELISA, and immunohistochemical staining using an anti mouse alpha-SMA antibody, respectively. Phosphorylations of mesenchymal epithelial transition factor (Met) and SMAD3, downstream signals of HGF and TGF beta, were compared between the two groups by Western blotting and were quantified using densitometry. Hepatocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Furthermore, the accumulation of human platelets in the liver 2 h after platelet transfusion was compared between normal and fibrotic livers by immunohistochemical staining using an anti-human CD41 antibody. RESULTS: The fibrotic area and hydroxyproline content in the liver were both significantly lower in the hPLT group when compared to the PBS group (fibrotic area, 1.7% +/- 0.6% vs 2.5% +/- 0.6%, P = 0.03; hydroxyproline content, 121 +/- 26 ng/g liver vs 156 +/- 47 ng/g liver, P = 0.04). There was less alpha-smooth muscle actin staining in the hPLT group than in the PBS group (0.5% +/- 0.1% vs 0.8% +/- 0.3%, P = 0.02). Hepatic expression levels of mouse HGF and MMP-9 were significantly higher in the hPLT group than in the PBS group (HGF, 109 +/- 13 ng/g liver vs 88 +/- 22 ng/g liver, P = 0.03; MMP 9, 113% +/- 7%/GAPDH vs 92% +/- 11%/GAPDH, P = 0.04). In contrast, the concentration of mouse TGF-beta in the liver tissue was significantly lower in the hPLT group than in the PBS group (22 +/- 5 ng/g liver vs 39 +/- 6 ng/g liver, P = 0.02). Phosphorylation of Met was more prevalent in the hPLT group than in the PBS group (37% +/- 4%/GAPDH vs 20% +/- 8%/GAPDH, P = 0.03). Phosphorylation of SMAD3 was weaker in the hPLT group than in the PBS group (60% +/- 12%/GAPDH vs 84% +/- 12%/GAPDH, P = 0.1), although this difference was not significant. Furthermore, a lower rate of hepatocyte apoptosis was observed in the hPLT group than in the PBS group (5.9% +/- 1.7% vs 2.9% +/- 2.1%, P = 0.02). Significant human platelet accumulation was observed in the fibrotic liver tissues, whereas few platelets accumulated in the normal liver. CONCLUSION: Human platelets inhibit liver fibrosis in SCID mice. Increased concentration of HGF in the liver suppresses hepatic stellate cell activation, induces MMPs, and inhibits hepatocyte apoptosis. PMID- 23983428 TI - Human development index is associated with mortality-to-incidence ratios of gastrointestinal cancers. AB - AIM: To identify the role of human development in the incidence and mortality rates of gastrointestinal cancers worldwide. METHODS: The age-standardized incidence and mortality rates for gastrointestinal cancers, including cancers of the esophagus, stomach, pancreas, liver, gallbladder, and colorectum, were obtained from the GLOBOCAN 2008 database and United States Cancer Statistics (USCS) report. The human development index (HDI) data were calculated according to the 2011 Human Development Report. We estimated the mortality-to-incidence ratios (MIRs) at the regional and national levels, and explored the association of the MIR with development levels as measured by the HDI using a modified "drug dose to inhibition response" model. Furthermore, countries were divided into four groups according to the HDI distribution, and the MIRs of the four HDI groups were compared by one-way ANOVA followed by the Tukey-Kramer post-hoc test. State specific MIRs in the United States were predicted from the estimated HDI using the fitted non-linear model, and were compared with the actual MIRs calculated from data in the USCS report. RESULTS: The worldwide incidence and mortality rates of gastrointestinal cancers were as high as 39.4 and 54.9 cases per 100000 individuals, respectively. Linear and non-linear regression analyses revealed an inverse correlation between the MIR of gastrointestinal cancers and the HDI at the regional and national levels (beta < 0; P = 0.0028 for regional level and < 0.0001 for national level, ANOVA). The MIR differed significantly among the four HDI areas (very high HDI, 0.620 +/- 0.033; high HDI, 0.807 +/- 0.018; medium HDI, 0.857 +/- 0.021; low HDI, 0.953 +/- 0.011; P < 0.001, one-way ANOVA). Prediction of the MIRs for individual United States states using best-fitted non-linear models showed little deviation from the actual MIRs in the United States. Except for 28 data points (9.93% of 282), the actual MIRs of all gastrointestinal cancers were mostly located in the prediction intervals via the best-fit non linear regression models. CONCLUSION: The inverse correlation between HDI and MIR demonstrates that more developed areas have a relatively efficacious healthcare system, resulting in low MIRs, and HDI can be used to estimate the MIR. PMID- 23983426 TI - DNA methylation in inflammatory bowel disease and beyond. AB - Inflammatory bowel disease (IBD) is a consequence of the complex, dysregulated interplay between genetic predisposition, environmental factors, and microbial composition in the intestine. Despite a great advancement in identifying host susceptibility genes using genome-wide association studies (GWAS), the majority of IBD cases are still underrepresented. The immediate challenge in post-GWAS era is to identify other causative genetic factors of IBD. DNA methylation has received increasing attention for its mechanistical role in IBD pathogenesis. This stable, yet dynamic DNA modification, can directly affect gene expression that have important implications in IBD development. The alterations in DNA methylation associated with IBD are likely to outset as early as embryogenesis all the way until old-age. In this review, we will discuss the recent advancement in understanding how DNA methylation alterations can contribute to the development of IBD. PMID- 23983429 TI - Sessile serrated adenomas in the proximal colon are likely to be flat, large and occur in smokers. AB - AIM: To examine the epidemiology and the morphology of the proximal sessile serrated adenomas (SSAs). METHODS: We conducted a retrospective study to identify patients with SSAs using a university-based hospital pathology database query from January 2007 to April 2011. Data collected included: age, gender, ethnicity, body mass index, diabetes, smoking, family history of colorectal cancer, aspirin, and statin use. We collected data on morphology of SSAs including site (proximal or distal), size, and endoscopic appearance (flat or protuberant). We also compared proximal SSAs to proximal tubular adenomas detected during same time period. RESULTS: One hundred and twenty patients with SSAs were identified: 61% were distal and 39% were proximal SSAs. Proximal SSAs were more likely to be flat than distal (100% vs 78% respectively; P = 0.0001). Proximal SSAs were more likely to occur in smokers (OR = 2.63; 95%CI: 1.17-5.90; P = 0.02) and in patients with family history of colorectal cancer (OR = 4.72; 95%CI: 1.43-15.55; P = 0.01) compared to distal. Proximal SSAs were statistically more likely to be >= 6 mm in size (OR = 2.94; P = 0.008), and also more likely to be large (>= 1 cm) (OR = 4.55; P = 0.0005) compared to the distal lesions. Smokers were more likely to have proximal (P = 0.02), flat (P = 0.01) and large (P = 0.007) SSAs compared to non-smokers. Compared to proximal tubular adenomas, proximal SSAs were more likely to be large and occur in smokers. CONCLUSION: Proximal SSAs which accounted for two-fifths of all SSAs were more likely to present as flat lesions, larger SSAs, and were more likely to occur in smokers and in patients with family history of colorectal cancer. Our data has implications for colorectal cancer screening. PMID- 23983430 TI - Long-term leukocyte natural alpha-interferon and ribavirin treatment in hepatitis C virus recurrence after liver transplantation. AB - AIM: To evaluate the effect of long-term treatment with leukocyte natural alpha interferon (ln-alpha-IFN) plus ribavirin (RBV). METHODS: Forty-six patients with hepatitis C virus (HCV) recurrence received 3 MU three times a week of ln-alpha IFN plus RBV for 1 mo; then, patients with good tolerability (n = 30) were switched to daily IFN administration, while the remaining were treated with the same schedule. Patients have been treated for 12 mo after viral clearance while non-responders (NR) entered in the long-term treatment group. Liver biopsies were planned at baseline, 1 year after sustained virological response (SVR) and at 36 mo after start of therapy in NR. MedCalc software package was used for statistical analysis. RESULTS: About 16.7% of genotype 1-4 and 70% of genotype 2 3 patients achieved SVR. Nine patients withdrew therapy because of non-tolerance or non-compliance. A significant improvement in serum biochemistry and histological activity was observed in all SVR patients and long-term treated; 100% of patients with SVR achieved a histological response (fibrosis stabilization or improvement) with a significant reduction in mean staging value (from 2.1 to 1.0; P = 0.0031); histological response was observed in 84% of long term treated patients compared to 57% of drop-out. Six patients died during the entire study period (follow-up 40.6 +/- 7.7 mo); of them, 5 presented with severe HCV recurrence on enrollment. Diabetes (OR = 0.38, 95%CI: 0.08-0.59, P = 0.01), leukopenia (OR = 0.54, 95%CI: 0.03-0.57, P = 0.03) and severe HCV recurrence (OR = 0.51, 95%CI: 0.25-0.69, P = 0.0003) were variables associated to survival. Long term treatment was well tolerated; no patients developed rejection or autoimmune disease. CONCLUSION: Long-term treatment improves histology in SVR patients and slows disease progression also in NR, leading to a reduction in liver decompensation, graft failure and liver-related death. PMID- 23983431 TI - Somatic molecular changes and histo-pathological features of colorectal cancer in Tunisia. AB - AIM: To determine correlations between family history, clinical features and mutational status of genes involved in the progression of colorectal cancer (CRC). METHODS: Histo-pathological features and molecular changes [KRAS, BRAF and CTNNB1 genes mutations, microsatellite instability (MSI) phenotype, expression of mismatch repair (MMR) and mucin (MUC) 5AC proteins, mutation and expression analysis of TP53, MLH1 promoter hypermethylation analysis] were examined in a series of 51 unselected Tunisian CRC patients, 10 of them had a proven or probable hereditary disease, on the track of new tumoral markers for CRC susceptibility in Tunisian patients. RESULTS: As expected, MSI and MMR expression loss were associated to the presence of familial CRC (75% vs 9%, P < 0.001). However, no significant associations have been detected between personal or familial cancer history and KRAS (codons 12 and 13) or TP53 (exons 4-9) alterations. A significant inverse relationship has been observed between the presence of MSI and TP53 accumulation (10.0% vs 48.8%, P = 0.0335) in CRC tumors, suggesting different molecular pathways to CRC that in turn may reflect different environmental exposures. Interestingly, MUC5AC expression was significantly associated to the presence of MSI (46.7% vs 8.3%, P = 0.0039), MMR expression loss (46.7% vs 8.3%, P = 0.0039) and the presence of familial CRC (63% vs 23%, P = 0.039). CONCLUSION: These findings suggest that MUC5AC expression analysis may be useful in the screening of Tunisian patients with high risk of CRC. PMID- 23983432 TI - Investigation of genome instability in patients with non-alcoholic steatohepatitis. AB - AIM: To evaluate the occurrence of micronucleus (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) in the mitogen-stimulated lymphocytes of patients with non-alcoholic steatohepatitis (NASH). METHODS: The study was performed in 25 (9 females, 16 males) patients newly diagnosed with NASH, and 25 healthy subjects of similar ages and genders were used as a control group. None of the controls was known to be receiving any drugs for medical or other reasons or using alcohol. Hepatosteatosis was further excluded by abdominal ultrasound imaging in the control group. The numbers of MN, NPBs and NBUDs scored in binucleated (BN) cells were obtained from the mitogen-stimulated lymphocytes of patients and control subjects. Statistical comparisons of the numbers of BN cells with MN, NPBs and NBUDs and ages between the patients with NASH and control subjects were performed. RESULTS: The mean ages of the patients and the control group were 41.92 +/- 13.33 and 41.80 +/- 13.09 years (P > 0.05), respectively. The values of the mean body mass index (BMI), HOMA-IR, hemoglobin, creatinin, aspartate aminotransferase, alanine aminotransferase, triglyceride, high density lipoprotein, and low density lipoprotein were 31.19 +/- 4.62 kg/m(2) vs 25.07 +/- 4.14 kg/m(2), 6.71 +/- 4.68 vs 1.40 +/- 0.53, 14.73 +/- 1.49 g/dL vs 14.64 +/- 1.30 g/dL, 0.74 +/- 0.15 mg/dL vs 0.80 +/- 0.13 mg/dL, 56.08 +/- 29.11 U/L vs 16.88 +/- 3.33 U/L, 92.2 +/- 41.43 U/L vs 15.88 +/- 5.88 U/L, 219.21 +/- 141.68 mg/dL vs 102.56 +/- 57.98 mg/dL, 16.37 +/- 9.65 mg/dL vs 48.72 +/- 15.31 mg/dL, and 136.75 +/- 30.14 mg/dL vs 114.63 +/- 34.13 mg/dL in the patients and control groups, respectively. The total numbers and frequencies of BN cells with MN, NPBs and NBUDs, which were scored using the CBMN cytome assay on PHA-stimulated lymphocytes, were evaluated in the patients with NASH and control group. We found significantly higher numbers of MN, NPBs and NBUDs in the BN cells of patients with NASH than in those of the control subjects (21.60 +/- 9.32 vs 6.88 +/- 3.91; 29.28 +/- 13.31 vs 7.84 +/- 3.96; 15.60 +/- 5.55 vs 4.20 +/- 1.63, respectively, P < 0.0001). CONCLUSION: The increased numbers of MN, NPBs and NBUDs observed in the lymphocytes obtained from patients with NASH may reflect genomic instability. PMID- 23983433 TI - High level of preoperative carbohydrate antigen 19-9 is a poor survival predictor in gastric cancer. AB - AIM: To assess the clinical significance and the prognostic value of preoperative serum carbohydrate antigen 19-9 (CA 19-9) level in gastric cancer. METHODS: Between January 2005 and December 2006, 1960 patients underwent surgery for histologically confirmed gastric cancer. Of these, 163 patients had elevated serum levels of CA 19-9 preoperatively, and 1628 patients had normal serum levels of CA 19-9 preoperatively. For this study, 325 patients were selected from the group of 1628 patients by age, sex, and cancer stage to serve as controls. Statistically significant differences in survival rates were calculated using the log-rank test. A P value less than 0.05 was considered statistically significant and was determined using SAS software. RESULTS: The baseline characteristics showed some differences between the two groups with regard to histology. Overall survival (OS) in the elevated and non-elevated group was 37.90 and 68.67 mo, respectively (P < 0.001). N stage (P = 0.001) was a significant predictor of disease-free survival by multivariate analysis. Also, N stage (P < 0.001), and the presence of peritoneal metastasis (P < 0.001) remained independent factors in predicting OS by multivariate analysis. Additionally, preoperative serum CA 19-9 levels were significantly associated with OS in univariate (P = 0.009) and multivariate (P = 0.021) analyses. CONCLUSION: Serum CA 19-9 can be considered an independent prognostic factor in predicting OS in patients anticipating surgery for gastric cancer. PMID- 23983434 TI - Can trans-anal reinforcing sutures after double stapling in lower anterior resection reduce the need for a temporary diverting ostomy? AB - AIM: To evaluate trans-anal reinforcing sutures in low anterior resection using the double-stapled anastomosis technique for primary rectal cancers performed at a single institution. METHODS: The data of patients who received trans-anal reinforcing sutures were compared with those of patients who did not receive them after low anterior resection. Patients who underwent laparoscopic low anterior resection and the double-stapled anastomosis technique for primary rectal cancer between January 2008 and December 2011 were included in this study. Patients with no anastomosis, a hand-sewn anastomosis, high anterior resection, or preoperative chemoradiation were excluded. The primary outcomes measured were the incidence of postoperative anastomotic complications and placement of a diverting ileostomy. RESULTS: Among 110 patients, the rate of placement of a diverting ileostomy was significantly lower in the suture group (SG) compared with the non-suture control group (CG) [SG, n = 6 (12.8%); CG, n = 19 (30.2%), P = 0.031]. No significant difference was observed in the rate of anastomotic leakage [SG, n = 3 (6.4%); CG, n = 5 (7.9%)]. CONCLUSION: Trans-anal reinforcing sutures may reduce the need for diverting ileostomy. A randomized prospective study with a larger population should be performed in the future to demonstrate the efficacy of trans-anal reinforcing sutures. PMID- 23983435 TI - HEF-19-induced relaxation of colonic smooth muscles and the underlying mechanisms. AB - AIM: To investigate the relaxant effect of chromane HEF-19 on colonic smooth muscles isolated from rabbits, and the underlying mechanisms. METHODS: The relaxant effect and action mechanisms of HEF-19 were investigated using descending colon smooth muscle of the rabbits. Preparations 1 cm long were mounted in 15-mL tissue baths containing Tyrode's solution, maintained at 37 +/- 0.5 degrees C and aerated with a mixture of 5% CO2 in oxygen (Carbogen). The tension and amplitude of the smooth muscle strips were recorded after adding HEF 19 (10(-6), 10(-5) and 10(-4) mol/L). After cumulative administration of four antispasmodic agents, including acetylcholine chloride (Ach) (10(-4) mol/L), histamine (10(-4) mol/L), high-K(+) (60 mmol/L) and BaCl2 (8.2 mmol/L), HEF-19 (3 * 10(-7)-3 * 10(-4) mol/L) was added to investigate the relaxant effect of HEF 19. CaCl2 (10(-4)-2.5 * 10(-3) mol/L) was added cumulatively to the smooth muscle preparations pretreated with and without HEF-19 (1 * 10(-6) or 3 * 10(-6) mol/L) and verapamil (1 * 10(-7) mol/L) to study the mechanisms involved. Finally, phasic contraction was induced with ACh (15 * 10(-6) mol/L), and CaCl2 (4 * 10( 3) mol/L) was added to the smooth muscle preparations pretreated with and without HEF-19 (3 * 10(-6) mol/L or 1 * 10(-5) mol/L) and verapamil (1 * 10(-7) mol/L) in calcium-free medium to further study the underlying mechanisms. RESULTS: HEF-19 (1 * 10(-6), 1 * 10(-5) and 1 * 10(-4) mol/L) suppressed spontaneous contraction of rabbit colonic smooth muscles. HEF-19 (3 * 10(-7)-3 * 10(-4) mol/L) relaxed in a concentration-dependent manner colonic smooth muscle preparations pre contracted with BaCl2, high-K(+) solution, Ach or histamine with respective EC50 values of 5.15 +/- 0.05, 5.12 +/- 0.08, 5.58 +/- 0.16 and 5.25 +/- 0.24, thus showing a spasmolytic activity. HEF-19 (1 * 10(-6) mol/L and 3 * 10(-6) mol/L) shifted the concentration-response curves of CaCl2 to the right and depressed the maximum response to CaCl2. The two components contracted by Ach were attenuated with HEF-19 (3 * 10(-6) mol/L or 10(-5) mol/L) in calcium-free medium. CONCLUSION: HEF-19 inhibited rabbit colonic smooth muscle contraction, probably through inhibiting opening of voltage-dependent Ca(2+) channels. HEF-19 reduced inflow and intracellular release of Ca(2+) ions. PMID- 23983436 TI - Prevalence of hepatitis C infection among intravenous drug users in Shanghai. AB - AIM: To characterize the prevalence of hepatitis C virus (HCV) infection among Chinese intravenous drug users (IDUs). METHODS: A total of 432 adult IDUs (95 women and 337 men) in Shanghai were included in the study. The third-generation Elecsys Anti-HCV assay (Roche Diagnostics GmbH, Sandhofer Strasse 116, D-68305, Mannheim, Germany) was used to screen for antibodies against HCV. The RIBA strip, a supplemental anti-HCV test with high specificity, was performed on all of the samples that tested positive during the initial screening. All of the anti-HCV positive samples were analyzed with a Cobas TaqMan 48 Analyzer (Roche Diagnostics) for direct detection of HCV RNA. All of the HCV RNA-positive samples were sequenced for genotype determination. RESULTS: The preliminary screening identified 262 (60.6%) subjects who were seropositive for HCV. Of the 62 females and 200 males seropositive subjects, 16 (16.7%) and 65 (19.3%), respectively, were confirmed by RIBA, yielding an overall HCV seropositive rate of 18.8%. Four female (6.5%) and 14 male (7.0%) subjects tested positive for HCV RNA, indicating an active infection rate of 4.2% for the entire study population. The 18 HCV RNA positive serum samples were genotyped. Seven individuals were genotype 1b, and four were genotype 1a. One individual each was infected with genotypes 2a, 2b and 3a. Four subjects were co-infected with multiple strains: two with genotypes 1a and 2a, and two with genotypes 1b and 2a. The active infection rate among HCV seropositive individuals was 22.2%, which was significantly lower than most estimates. CONCLUSION: The prevalence of HCV is relatively low among IDUs in Shanghai, with a spontaneous recovery rate much higher than previous estimates. PMID- 23983437 TI - Effects of Fufang Biejia Ruangan pills on hepatic fibrosis in vivo and in vitro. AB - AIM: To explore the protective effect and the relevant mechanisms of Fufang Biejia Ruangan Pills (FFBJRGP) on hepatic fibrosis in vivo and in vitro. METHODS: Hepatic fibrosis was induced by carbon tetrachloride composite factors. Adult Wistar rats were randomly divided into four groups: normal control group; hepatic fibrosis model group; FFBJRGP-treated group at a daily dose of 0.55 g/kg; and colchicine-treated group at a daily dose of 0.1 g/kg. The effects of FFBJRGP on liver function, serum levels of hyaluronic acid (HA), type IV collagen (CIV), type III procollagen (PC III), laminin (LN), histopathology, and expression of transforming growth factor (TGF-beta1) and Smad3 in hepatic fibrosis were evaluated in vivo. The effects of FFBJRGP on survival rate, hydroxyproline content and cell cycle distribution were further detected in vitro. RESULTS: Compared with the hepatic fibrosis model group, rats treated with FFBJRGP showed a reduction in hepatic collagen deposition and improvement in hepatic lesions. Compared with those of the model group, the activities of alanine aminotransferase (62.0 +/- 23.7 U/L) and aspartate aminotransferase (98.8 +/- 40.0 U/L) in the FFBJRGP-treated group were decreased (50.02 +/- 3.7 U/L and 57.2 +/- 30.0 U/L, respectively, P < 0.01). Compared with those in the model group, the levels of PCIII (35.73 +/- 17.90 MUg/mL), HA (563.82 +/- 335.54 ng/mL), LN (89.57 +/- 7.59 ng/mL) and CIV (29.20 +/- 6.17 ng/mL) were decreased to 30.18 +/- 9.41, 456.18 +/- 410.83, 85.46 +/- 7.51 and 28.02 +/- 9.45 ng/mL, respectively. Reverse-transcriptase polymerase chain reaction and Western blotting also revealed that expression of TGF-beta1 and Smad3 were down-regulated in vivo. Cell proliferation was inhibited, the level of hydroxyproline was decreased compared with the control group (P < 0.01), and the cell cycle was redistributed when exposed to FFBJRGP in vitro. CONCLUSION: FFBJRGP inhibits hepatic fibrosis in vivo and in vitro, which is probably associated with downregulation of fibrogenic signal transduction of the TGF-beta-Smad pathway. PMID- 23983438 TI - Prevalence and features of fatty liver detected by physical examination in Guangzhou. AB - AIM: To investigate the prevalence of fatty liver discovered upon physical examination of Chinese patients and determine the associated clinical characteristics. METHODS: A total of 3433 consecutive patients who received physical examinations at the Huangpu Division of the First Affiliated Hospital at Sun Yat-sen University in Guangzhou, China from June 2010 to December 2010 were retrospectively enrolled in the study. Results of biochemical tests, abdominal ultrasound, electrocardiography, and chest X-ray were collected. The diagnosis of fatty liver was made if a patient met any two of the three following ultrasonic criteria: (1) liver and kidney echo discrepancy and presence of an increased liver echogenicity (bright); (2) unclear intrahepatic duct structure; and (3) liver far field echo decay. RESULTS: The study population consisted of 2201 males and 1232 females, with a mean age of 37.4 +/- 12.8 years. When all 3433 patients were considered, the overall prevalence of hyperlipidemia was 38.1%, of fatty liver was 26.0%, of increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels was 11.9%, of gallstone was 11.4%, of hyperglycemia was 7.3%, of hypertension was 7.1%, and of hyperuricemia was 6.2%. Of the 2605 patients who completed the abdominal ultrasonography exam, 677 (26.0%) were diagnosed with fatty liver and the prevalence was higher in males (32.5% vs females: 15.3%, P < 0.001). The overall prevalence of fatty liver increased with age, with the peak prevalence (39.5%) found in the 60 to 70-year-old age group. Among patients between the ages of 18 to 50-year-old, the prevalence of fatty liver was significantly higher in males (20.2% vs females: 8.7%, P < 0.001); the difference in prevalence between the two sexes in patients > 50-year-old did not reach statistical significance. Only 430 of the patients diagnosed with fatty liver had complete information; among those, increased ALT and/or AST levels were detected in only 30%, with all disturbances being mild or moderate. In these 430 patients, the overall prevalence of hypertriglyceridemia was 31.4%, of mixed type hyperlipidemia was 20.9%, of hypercholesterolemia was 12.3%, of hyperglycemia was 17.6%, of hypertension was 16.0%, of hyperuricemia was 15.3%, and of gallstone was 14.4%. Again, the prevalences of hypertriglyceridemia and hyperuricemia were higher in males (hypertriglyceridemia, 36.0% vs females: 12.0%, P < 0.05; hyperuricemia, 17.3% vs females: 7.2%, P < 0.05); in contrast, however, the prevalences of mixed type hyperlipidemia and hypercholesterolemia was higher in females (mixed type hyperlipidemia, 18.7% vs females: 30.1%, P < 0.05, hypercholesterolemia, 9.5% vs females: 24.1%, P < 0.05). Finally, comparison of the fatty liver group to the non-fatty liver group showed that prevalences of hyperlipidemia, hyperglycemia, hypertension, and hyperuricemia were higher in the former (all P < 0.01). CONCLUSION: A high prevalence of fatty liver is detected upon physical examination in Guangzhou, and the primary associated clinical findings are hyperlipidemia, hyperglycemia, hypertension, and hyperuricemia. PMID- 23983439 TI - Clonality analysis of neuroendocrine cells in gastric adenocarcinoma. AB - AIM: To achieve a better understanding of the origination of neuroendocrine (NE) cells in gastric adenocarcinoma. METHODS: In this study, 120 cases of gastric adenocarcinoma were obtained. First, frozen section-immunohistochemistrical samples were selected from a large quantity of neuroendocrine cells. Second, laser capture microdissection was used to get target cells from gastric adenocarcinoma and whole genome amplification was applied to get a large quantity of DNA for further study. Third, genome-wide microsatellite abnormalities [microsatellite instability (MSI), loss of heterozygosity (LOH)] and p53 mutation were detected by polymerase chain reaction (PCR)-single-strand conformation polymer- phism-silver staining and PCR-sequencing in order to identify the clonality of NE cells. RESULTS: The total incidence rate of MSI was 27.4%, while LOH was 17.9%. Ten cases had a highest concordance for the two types of cells. The other samples had similar microsatellite changes, except for cases 7 and 10. Concordant p53 mutations exhibited in sample 4, 14, 21 and 27, and there were different mutations between two kinds of cells in case 7. In case 17, mutation took place only in adenocarcinoma cells. p53 mutation was closely related with degree of differentiation, tumor-node-metastasis stage, vessel invasion and lymph node metastasis. In brief, NE and adenocarcinoma cells showed the same MSI, LOH or p53 mutation in most cases (27/30). In the other three cases, different MSI, LOH or p53 mutation occurred. CONCLUSION: NE and the gastric adenocarcinoma cells may mainly derive from the same stem cells, but the remaining cases showing different origin needs further investigation. PMID- 23983440 TI - Efficacy profiles for different concentrations of Lactobacillus acidophilus in experimental colitis. AB - AIM: To determine the efficacy profiles of different concentrations of Lactobacillus acidophilus (L. acidophilus) for treating colitis using an experimental murine model. METHODS: Colitis was established in 64 BALB/c mice by adding 5% dextran sodium sulfate (DSS) to the drinking water and allowing ad libitum access for 7 d. The mice were then randomly divided into the following control and experimental model groups (n = 8 each; day 0): untreated model control; negative-treatment model control (administered gavage of 1 mL/10 g normal saline); experimental-treatment models C4-C8 (administered gavage of 10(4), 10(5), 10(6), 10(7), or 10(8) CFU/10 g L. acidophilus, respectively); positive-treatment model control (administration of the anti-inflammatory agent prednisone acetate at 45 MUg/10 g). Eight mice given regular water (no DSS) and no subsequent treatments served as the normal control group. Body weight, fecal traits, and presence of fecal occult blood were assessed daily. All animals were sacrificed on post-treatment day 7 to measure colonic length, perform histological scoring, and quantify the major bacteria in the proximal and distal colon. Intergroup differences were determined by one-way ANOVA and post-hoc Student-Newman-Keuls comparison. RESULTS: All treatments (L. acidophilus and prednisone acetate) protected against colitis-induced weight loss (P < 0.05 vs model and normal control groups). The extent of colitis-induced colonic shortening was significantly reduced by all treatments (prednisone acetate > C4 > C5 > C7 > C8 > C6; P < 0.05 vs untreated model group), and the C6 group showed colonic length similar to that of the normal control group (P > 0.05). The C6 group also had the lowest disease activity index scores among the model groups. The bacterial profiles in the proximal colon were similar between all of the experimental-treatment model groups (all P > 0.05). In contrast, the bacterial profile in the distal colon of the C6 group showed the distinctive features (P < 0.05 vs all other experimental-treatment model groups) of Lactobacillus sp. and Bifidobacterium sp. being the most abundant bacteria and Staphylococcus aureus being the least abundant bacteria. CONCLUSION: The most therapeutically efficacious concentration of L. acidophilus (10(6) CFU/10 g) may exert its effects by modulating the bacterial profile in the distal colon. PMID- 23983441 TI - Gastrointestinal symptoms and associated factors in Chinese patients with functional dyspepsia. AB - AIM: To study the evolution of gastrointestinal symptoms and associated factors in Chinese patients with functional dyspepsia (FD). METHODS: From June 2008 to November 2009, a total of 1049 patients with FD (65.3% female, mean age 42.80 +/- 11.64 years) who visited the departments of gastroenterology in Wuhan, Beijing, Shanghai, Guangzhou, and Xi'an, China were referred for this study. All of the patients fulfilled the Rome III criteria for FD. Baseline demographic data, dyspepsia symptoms, anxiety, depression, sleep disorder, and drug treatment were assessed using self-report questionnaires. Patients completed questionnaires at baseline and after 1, 3, 6 and 12 mo follow-up. Comparison of dyspepsia symptoms between baseline and after follow-up was explored using multivariate analysis of variance of repeated measuring. Multiple linear regression was done to examine factors associated with outcome, both longitudinally and horizontally. RESULTS: Nine hundred and forty-three patients (89.9% of the original population) completed all four follow-ups. The average duration of follow-up was 12.24 +/- 0.59 mo. During 1-year follow-up, the mean dyspeptic symptom score (DSS) in FD patients showed a significant gradually reduced trend (P < 0.001), and similar differences were found for all individual symptoms (P < 0.001). Multiple linear regression analysis showed that sex (P < 0.001), anxiety (P = 0.018), sleep disorder at 1-year follow-up (P = 0.019), weight loss (P < 0.001), consulting a physician (P < 0.001), and prokinetic use during 1-year follow-up (P = 0.035) were horizontally associated with DSS at 1-year follow-up. No relationship was found longitudinally between DSS at 1-year follow-up and patient characteristics at baseline. CONCLUSION: Female sex, anxiety, and sleep disorder, weight loss, consulting a physician and prokinetic use during 1-year follow-up were associated with outcome of FD. PMID- 23983442 TI - Systematic review and meta-analysis of laparoscopy-assisted and open total gastrectomy for gastric cancer. AB - AIM: To evaluate the safety and efficacy of laparoscopy-assisted total gastrectomy (LATG) and open total gastrectomy (OTG) for gastric cancer. METHODS: A comprehensive search of PubMed, Cochrane Library, Web of Science and BIOSIS Previews was performed to identify studies that compared LATG and OTG. The following factors were checked: operating time, blood loss, harvested lymph nodes, flatus time, hospital stay, mortality and morbidity. Data synthesis and statistical analysis were carried out using RevMan 5.1 software. RESULTS: Nine studies with 1221 participants were included (436 LATG and 785 OTG). Compared to OTG, LATG involved a longer operating time [weighted mean difference (WMD) = 57.68 min, 95%CI: 30.48-84.88; P < 0.001]; less blood loss [standard mean difference (SMD) = -1.71; 95%CI: -2.48 - -0.49; P < 0.001]; earlier time to flatus (WMD= -0.76 d; 95%CI: -1.22 - -0.30; P < 0.001); shorter hospital stay (WMD = -2.67 d; 95%CI: -3.96 - -1.38, P < 0.001); and a decrease in medical complications (RR = 0.41, 95%CI: 0.19-0.90, P = 0.03). The number of harvested lymph nodes, mortality, surgical complications, cancer recurrence rate and long term survival rate of patients undergoing LATG were similar to those in patients undergoing OTG. CONCLUSION: Despite a longer operation, LATG can be performed safely in experienced surgical centers with a shorter hospital stay and fewer complications than open surgery. PMID- 23983443 TI - Noninfectious interstitial lung disease during infliximab therapy: case report and literature review. AB - Pulmonary abnormalities are not frequently encountered in patients with inflammatory bowel diseases. However, lung toxicity can be induced by conventional medications used to maintain remission, and similar evidence is also emerging for biologics. We present the case of a young woman affected by colonic Crohn's disease who was treated with oral mesalamine and became steroid-dependent and refractory to azathioprine and adalimumab. She was referred to our clinic with a severe relapse and was treated with infliximab, an anti-tumor necrosis factor alpha (TNF-alpha) antibody, to induce remission. After an initial benefit, with decreases in bowel movements, rectal bleeding and C-reactive protein levels, she experienced shortness of breath after the 5(th) infusion. Noninfectious interstitial lung disease was diagnosed. Both mesalamine and infliximab were discontinued, and steroids were introduced with slow but progressive improvement of symptoms, radiology and functional tests. This represents a rare case of interstitial lung disease associated with infliximab therapy and the effect of drug withdrawal on these lung alterations. Given the increasing use of anti-TNF alpha therapies and the increasing reports of pulmonary abnormalities in patients with inflammatory bowel diseases, this case underlines the importance of a careful evaluation of respiratory symptoms in patients undergoing infliximab therapy. PMID- 23983444 TI - Hepatotoxicity associated with glucosamine and chondroitin sulfate in patients with chronic liver disease. AB - Glucosamine and chondroitin sulfate are molecules involved in the formation of articular cartilage and are frequently used for symptom relief in patients with arthrosis. These molecules are well tolerated with scarce secondary effects. Very few cases of possible hepatotoxicity due to these substances have been described. The aim of this paper is to report the frequency of presumed glucosamine hepatotoxicity in patients with liver disease. A questionnaire was given to 151 consecutive patients with chronic liver disease of different etiology (mean age 59 years, 56.9% women) attended in an outpatient clinic with the aim of evaluating the frequency of consumption of these drugs and determine whether their use coincided with a worsening in liver function test results. Twenty-three patients (15.2%) recognized having taken products containing glucosamine or chondroitin sulfate previously or at the time of the questionnaire. Review of the clinical records and liver function tests identified 2 patients presenting an elevation in aminotransferase values temporarily associated with glucosamine treatment; one of the cases simultaneously presented a skin rash attributed to the drug. Review of these two patients and the cases described in the literature suggest toxicity of glucosamine and chondroitin sulfate. The clinical spectrum is variable, and the mechanism of toxicity is not clear but may involve reactions of hypersensitivity. The consumption of products containing glucosamine and/or chondroitin sulfate is frequent among patients with chronic liver diseases and should be taken into account on the appearance of alterations in liver function tests not explained by the underlying disease. PMID- 23983445 TI - A case of rapidly progressing leiomyosarcoma combined with squamous cell carcinoma in the esophagus. AB - Esophageal leiomyosarcoma is a rare tumor that accounts for less than 1% of all malignant esophageal tumors. Esophageal leiomyosarcoma combined with squamous cell carcinoma is even rarer than solitary leiomyosarcoma. We experienced a case of leiomyosarcoma combined with squamous cell carcinoma that progressed very rapidly. PMID- 23983446 TI - Intestinal Behcet's disease appearing during treatment with adalimumab in a patient with ankylosing spondylitis. AB - Behcet's disease (BD) is a chronic inflammatory disease affecting multiple organ systems, such as the skin, joints, blood vessels, central nervous system, and gastrointestinal tract. Intestinal BD is characterized by intestinal ulcerations and gastrointestinal symptoms. The medical treatment of intestinal BD includes corticosteroids and immunosupressants. There have been several reports of tumor necrosis factor-alpha (TNF-alpha) blockers being successful in treatment of refractory intestinal BD. Here, we report on a patient who was diagnosed with intestinal BD despite treatment with the fully humanized TNF-alpha blocker (adalimumab) for underlying ankylosing spondylitis. This patient achieved clinical remission and complete mucosal healing through the addition of a steroid and azathioprine to the adalimumab regimen. PMID- 23983447 TI - Favorable effect of modest alcohol consumption to fatty liver disease. AB - We previously reported that modest alcohol consumption was significantly inversely associated with fatty liver disease. Feng et al pointed out a discrepancy of statistical significance between our current larger scale cohort and a previous cohort. However, the prevalence of non-alcoholic fatty liver disease was higher in non or minimal drinkers than those in light drinkers in both cohorts. They also argue that some potential co-factors such as soft drink consumption and genetic variations should be discussed. PMID- 23983448 TI - Narrow band imaging with magnification endoscopy for celiac disease: results from a prospective, single-center study. AB - In celiac disease (CD), the intestinal lesions can be patchy and partial villous atrophy may elude detection at standard endoscopy (SE). Narrow Band Imaging (NBI) system in combination with a magnifying endoscope (ME) is a simple tool able to obtain targeted biopsy specimens. The aim of the study was to assess the correlation between NBI-ME and histology in CD diagnosis and to compare diagnostic accuracy between NBI-ME and SE in detecting villous abnormalities in CD. Forty-four consecutive patients with suspected CD undergoing upper gastrointestinal endoscopy have been prospectively evaluated. Utilizing both SE and NBI-ME, observed surface patterns were compared with histological results obtained from biopsy specimens using the k-Cohen agreement coefficient. NBI-ME identified partial villous atrophy in 12 patients in whom SE was normal, with sensitivity, specificity, and accuracy of 100%, 92.6%, and 95%, respectively. The overall agreement between NBI-ME and histology was significantly higher when compared with SE and histology (kappa score: 0.90 versus 0.46; P = 0.001) in diagnosing CD. NBI-ME could help identify partial mucosal atrophy in the routine endoscopic practice, potentially reducing the need for blind biopsies. NBI-ME was superior to SE and can reliably predict in vivo the villous changes of CD. PMID- 23983449 TI - A Thomson-type mass and energy spectrometer for characterizing ion energy distributions in a coaxial plasma gun operating in a gas-puff mode. AB - Measurements of ion energy distribution are performed in the accelerated plasma of a coaxial electromagnetic plasma gun operating in a gas-puff mode at relatively low discharge energy (900 J) and discharge potential (4 kV). The measurements are made using a Thomson-type mass and energy spectrometer with a gated microchannel plate and phosphor screen as the ion sensor. The parabolic ion trajectories are captured from the sensor screen with an intensified charge coupled detector camera. The spectrometer was designed and calibrated using the Geant4 toolkit, accounting for the effects on the ion trajectories of spatial non uniformities in the spectrometer magnetic and electric fields. Results for hydrogen gas puffs indicate the existence of a class of accelerated protons with energies well above the coaxial discharge potential (up to 24 keV). The Thomson analyzer confirms the presence of impurities of copper and iron, also of relatively high energies, which are likely erosion or sputter products from plasma-electrode interactions. PMID- 23983450 TI - The Innovation Deficit in Urban Water: The Need for an Integrated Perspective on Institutions, Organizations, and Technology. AB - Interaction between institutional change and technological change poses important constraints on transitions of urban water systems to a state that can meet future needs. Research on urban water and other technology-dependent systems provides insights that are valuable to technology researchers interested in assuring that their efforts will have an impact. In the context of research on institutional change, innovation is the development, application, diffusion, and utilization of new knowledge and technology. This definition is intentionally inclusive: technological innovation will play a key role in reinvention of urban water systems, but is only part of what is necessary. Innovation usually depends on context, such that major changes to infrastructure include not only the technological inventions that drive greater efficiencies and physical transformations of water treatment and delivery systems, but also the political, cultural, social, and economic factors that hinder and enable such changes. On the basis of past and present changes in urban water systems, institutional innovation will be of similar importance to technological innovation in urban water reinvention. To solve current urban water infrastructure challenges, technology-focused researchers need to recognize the intertwined nature of technologies and institutions and the social systems that control change. PMID- 23983452 TI - Influence of sclerotomy use on vitreous incarceration in an experimental model of vitrectomized eye. AB - PURPOSE: To evaluate the influence of sclerotomy use during vitrectomy (vitreous cutter, illumination probe, or infusion-line entrance) on postoperative vitreous incarceration using an experimental model of vitrectomized eye. MATERIALS AND METHODS: Experimental, randomized, and observer-masked study in which 23-gauge transconjunctival sutureless vitrectomy was performed in cadaveric pig eyes. Postoperative incisional vitreous entrapment was evaluated by direct visualization. No vitreous incarceration was classified as grade 0 (G0), thin vitreous entrapment was classified as grade 1 (G1), and thick vitreous strands as grade 2 (G2). RESULTS: A total of 46 eyes were included. Vitreous incarceration was detected in 91.3% (43.5% G1, 47.8% G2) of the sclerotomies used by the vitreous cutter probe, 95.7% (45.7% G1, 50% G2) of the illumination-pipe entrances, and 93.5% (45.7% G1, 47.8% G2) of the infusion-line incisions. No statistical differences were found when comparing incisional vitreous incarceration after vitrectomy according to sclerotomy use. CONCLUSION: Different manipulation of the sclerotomies, depending on their use, does not seem to influence postvitrectomy vitreous entrapment in our experimental model. PMID- 23983453 TI - Retinal vein occlusion during flare of multicentric Castleman's disease. AB - We report a case of successive bilateral retinal vein occlusion in a human immunodeficiency virus (HIV)-positive male with multicentric Castleman's disease treated successfully with a single injection of intravitreal bevacizumab. Castleman's disease should be a differential diagnosis of occlusive retinovascular disease and, occasionally, ocular manifestation can lead to systemic diagnosis. PMID- 23983451 TI - Unit Process Wetlands for Removal of Trace Organic Contaminants and Pathogens from Municipal Wastewater Effluents. AB - Treatment wetlands have become an attractive option for the removal of nutrients from municipal wastewater effluents due to their low energy requirements and operational costs, as well as the ancillary benefits they provide, including creating aesthetically appealing spaces and wildlife habitats. Treatment wetlands also hold promise as a means of removing other wastewater-derived contaminants, such as trace organic contaminants and pathogens. However, concerns about variations in treatment efficacy of these pollutants, coupled with an incomplete mechanistic understanding of their removal in wetlands, hinder the widespread adoption of constructed wetlands for these two classes of contaminants. A better understanding is needed so that wetlands as a unit process can be designed for their removal, with individual wetland cells optimized for the removal of specific contaminants, and connected in series or integrated with other engineered or natural treatment processes. In this article, removal mechanisms of trace organic contaminants and pathogens are reviewed, including sorption and sedimentation, biotransformation and predation, photolysis and photoinactivation, and remaining knowledge gaps are identified. In addition, suggestions are provided for how these treatment mechanisms can be enhanced in commonly employed unit process wetland cells or how they might be harnessed in novel unit process cells. It is hoped that application of the unit process concept to a wider range of contaminants will lead to more widespread application of wetland treatment trains as components of urban water infrastructure in the United States and around the globe. PMID- 23983454 TI - Cross-reactivity of human monoclonal antibodies generated with peripheral blood lymphocytes from dengue patients with Japanese encephalitis virus. AB - BACKGROUND: Hybridomas that produce human monoclonal antibodies (HuMAbs) against Dengue virus (DV) had been prepared previously using peripheral blood lymphocytes from patients with DV during the acute and convalescent phases of a secondary infection. Anti-DV envelope glycoprotein (E) 99 clones, anti-DV premembrane protein (prM) 8 clones, and anti-DV nonstructural protein 1 (NS1) 4 clones were derived from four acute-phase patients, and anti-DV E 2 clones, anti-DV prM 2 clones, and anti-DV NS1 8 clones were derived from five convalescent-phase patients. METHODS AND RESULTS: In the present study, we examined whether these clones cross-reacted with Japanese encephalitis virus (JEV), which belongs to the same virus family. Forty-six of the above-described 99 (46/99) anti-E, 0/8 anti prM, and 2/4 anti-NS1 HuMAbs from acute-phase, and 0/2 anti-E, 0/2 anti-prM, and 5/8 anti-NS1 HuMAbs from convalescent-phase showed neutralizing activity against JEV. Thus, most of the anti-E and anti-NS1 (but not the anti-prM) antibodies cross-reacted with JEV and neutralized this virus. Interestingly, 3/46 anti-E HuMAbs derived from acute-phase patients and 3/5 anti-NS1 HuMAbs from convalescent-phase patients showed particularly high neutralizing activity against JEV. Consequently, the HuMAbs showing neutralization against JEV mostly consisted of two populations: one was HuMAbs recognizing DV E and showing neutralization activity against all four DV serotypes (complex-type) and the other was HuMAbs recognizing DV NS1 and showing subcomplex-type cross-reaction with DV. CONCLUSION: Anti-DV E from acute phase (46/99) and anti-DV NS1 (7/12) indicate neutralizing activity against JEV. In particular, three of 46 anti-DV E clones from acute phase and three of five anti-NS1 clones from convalescent phase showed strong neutralizing activity against JEV. PMID- 23983455 TI - Glyphosate and AMPA inhibit cancer cell growth through inhibiting intracellular glycine synthesis. AB - Glycine is a nonessential amino acid that is reversibly converted from serine intracellularly by serine hydroxymethyltransferase. Glyphosate and its degradation product, aminomethylphosphonic acid (AMPA), are analogs to glycine, thus they may inhibit serine hydroxymethyltransferase to decrease intracellular glycine synthesis. In this study, we found that glyphosate and AMPA inhibited cell growth in eight human cancer cell lines but not in two immortalized human normal prostatic epithelial cell lines. AMPA arrested C4-2B and PC-3 cancer cells in the G1/G0 phase and inhibited entry into the S phase of the cell cycle. AMPA also promoted apoptosis in C4-2B and PC-3 cancer cell lines. AMPA upregulated p53 and p21 protein levels as well as procaspase 9 protein levels in C4-2B cells, whereas it downregulated cyclin D3 protein levels. AMPA also activated caspase 3 and induced cleavage of poly (adenosine diphosphate [ADP]-ribose) polymerase. This study provides the first evidence that glyphosate and AMPA can inhibit proliferation and promote apoptosis of cancer cells but not normal cells, suggesting that they have potentials to be developed into a new anticancer therapy. PMID- 23983456 TI - Synthesis and evaluation of mutual azo prodrug of 5-aminosalicylic acid linked to 2-phenylbenzoxazole-2-yl-5-acetic acid in ulcerative colitis. AB - In this study, the syntheses of 4-aminophenylbenzoxazol-2-yl-5-acetic acid, (an analogue of a known nonsteroidal anti-inflammatory drug [NSAID]) and 5-[4 (benzoxazol-2-yl-5-acetic acid)phenylazo]-2-hydroxybenzoic acid (a novel mutual azo prodrug of 5-aminosalicylic acid [5-ASA]) are reported. The structures of the synthesized compounds were confirmed using infrared (IR), hydrogen-1 nuclear magnetic resonance (1H NMR), and mass spectrometry (MS) spectroscopy. Incubation of the azo compound with rat cecal contents demonstrated the susceptibility of the prepared azo prodrug to bacterial azoreductase enzyme. The azo compound and the 4-aminophenylbenzoxazol-2-yl-5-acetic acid were evaluated for inflammatory bowel diseases, in trinitrobenzenesulfonic acid (TNB)-induced colitis in rats. The synthesized diazo compound and the 4-aminophenylbenzoxazol-2-yl-5-acetic acid were found to be as effective as 5-aminosalicylic acid for ulcerative colitis. The results of this work suggest that the 4-aminophenylbenzoxazol-2-yl-5-acetic acid may represent a new lead for treatment of ulcerative colitis. PMID- 23983458 TI - Erratum: User assessment of Norditropin NordiFlex(r), a new prefilled growth hormone pen: a Phase IV multicenter prospective study [Corrigendum]. AB - [This corrects the article on p. 455 in vol. 7, PMID: 23737664.]. PMID- 23983457 TI - Impact of a pharmaceutical care program on clinical evolution and antiretroviral treatment adherence: a 5-year study. AB - BACKGROUND: Antiretroviral treatments (ART) form the basis of adequate clinical control in human immunodeficiency virus-infected patients, and adherence plays a primary role in the grade and duration of the antiviral response. The objectives of this study are: (1) to determine the impact of the implementation of a pharmaceutical care program on improvement of ART adherence and on the immunovirological response of the patients; and (2) to detect possible correlations between different adherence evaluation measurements. METHODS: A 60 month long retrospective study was conducted. Adherence measures used were: therapeutic drug monitoring, a simplified medication adherence questionnaire, and antiretroviral dispensation records (DR). The number of interviews and interventions related to adherence made for each patient in yearly periods was related to the changes in the adherence variable (measured with DR) in these same yearly periods. The dates when the laboratory tests were drawn were grouped according to proximity with the study assessment periods (February-May, 2005 2010). RESULTS: A total of 528 patients were included in the study. A significant relationship was observed between the simplified medication adherence questionnaire and DR over the 60-month study period (P < 0.01). Improvement was observed in the mean adherence level (P < 0.001), and there was a considerable decrease in the percentage of patients with CD4+ lymphocytes less than 200 cells/mm(3) (P < 0.001). A relationship was found between the number of patients with optimum adherence levels and the time that plasma viral load remained undetected. The number of interviews and interventions performed in each patient in the first 12 months from the onset of the pharmaceutical care program (month 6), was related to a significant increase in adherence during this same time period. CONCLUSION: The results suggest that the establishment and permanence of a pharmaceutical care program may increase ART adherence, increase permanence time of the patient with undetectable plasma viral loads, and improve patients' lymphocyte count. PMID- 23983459 TI - The influence of symptoms of anxiety and depression on medication nonadherence and its causes: a population based survey of prescription drug users in Sweden. AB - PURPOSE: The purpose of this study was to evaluate the associations between self reported symptoms of anxiety and/or depression, nonadherent (NA) behaviors, and reasons for NA to medication regimens. METHODS: A population based cross sectional study with questionnaire was performed in the general Swedish population. The participants were 2,802 prescription drug users aged 18-84 years. The questionnaire covered use of prescription drugs, symptoms of anxiety and/or depression, based on the Hospital Anxiety and Depression Scale (HADS), various NA behavior types, intentional and unintentional, and various reasons for NA. RESULTS: Symptoms of anxiety and depression, independently and in combination, were associated with unintentional and intentional NA, with a stronger association with intentional NA. Regarding the reasons given for NA, for example anxiety, independently or in combination with depression, was associated with a fear of developing adverse drug reactions (ADRs). Depression, independently or in combination with anxiety, on the other hand, was associated with the actual development of ADRs. CONCLUSION: A cross-sectional design such as this does not allow assessment of causality derived from the results. However, the results indicate that patients experiencing symptoms of psychological distress are at increased risk of NA, especially intentional NA, and could therefore benefit from extra attention from the health care professional. Patients with symptoms of anxiety and/or depression should be identified and monitored for the development and/or fear of ADRs, in order to improve adherence to medication regimens. PMID- 23983460 TI - Effects of a complex intervention on fall risk in the general practitioner setting: a cluster randomized controlled trial. AB - PURPOSE: To study the feasibility of first, reaching functionally declined, but still independent older persons at risk of falls through their general practitioner (GP) and second, to reduce their physiological and psychological fall risk factors with a complex exercise intervention. We investigated the effects of a 16-week exercise intervention on physiological (function, strength, and balance) and psychological (fear of falling) outcomes in community-dwelling older persons in comparison with usual care. In addition, we obtained data on adherence of the participants to the exercise program. METHODS: Tests on physical and psychological fall risk were conducted at study inclusion, and after the 16 week intervention period in the GP office setting. The 16-week intervention included progressive and challenging balance, gait, and strength exercise as well as changes to behavioral aspects. To account for the hierarchical structure in the chosen study design, with patients nested in GPs and measurements nested in patients, a three-level linear mixed effects model was determined for analysis. RESULTS: In total, 33 GPs recruited 378 participants (75.4% females). The mean age of the participants was 78.1 years (standard deviation 5.9 years). Patients in the intervention group showed an improvement in the Timed-Up-and-Go-test (TUG) that was 1.5 seconds greater than that showed by the control group, equivalent to a small to moderate effect. For balance, a relative improvement of 0.8 seconds was accomplished, and anxiety about falls was reduced by 3.7 points in the Falls Efficacy Scale-International (FES-I), in the intervention group relative to control group. In total, 76.6% (N = 170) of the intervention group participated in more than 75% the supervised group sessions. CONCLUSION: The strategy to address older persons at high risk of falling in the GP setting with a complex exercise intervention was successful. In functionally declined, community dwelling, older persons a complex intervention for reducing fall risks was effective compared with usual care. PMID- 23983462 TI - Should chest examination be reinstated in the early diagnosis of chronic obstructive pulmonary disease? AB - BACKGROUND: Although proven to be associated with bronchial obstruction, chest signs are not listed among cues that should prompt spirometry in the early diagnosis of chronic obstructive pulmonary disease (COPD) in established guidelines. AIMS: We aimed to explore how chest findings add to respiratory symptoms and a history of smoking in the diagnosis of COPD. METHODS: In a cross sectional study, patients aged 40 years or older, previously diagnosed with either asthma or COPD in primary care, answered questionnaires and underwent physical chest examination and spirometry. RESULTS: Among the 375 patients included, 39.7% had forced expiratory volume in 1 second/forced vital capacity <0.7. Hyperresonance to percussion was the strongest predictor of COPD, with a sensitivity of 20.8, a specificity of 97.8, and likelihood ratio of 9.5. In multivariate logistic regression, where pack-years, shortness of breath, and chest findings were among the explanatory variables, three physical chest findings were independent predictors of COPD. Hyperresonance to percussion yielded the highest odds ratio (OR = 6.7), followed by diminished breath sounds (OR = 5.0), and thirdly wheezes (OR = 2.3). These three chest signs also gave significant diagnostic information when added to shortness of breath and pack years in receiver operating-characteristic curve analysis. CONCLUSION: We found that chest signs may add to respiratory symptoms and a history of smoking in the diagnosis of COPD, and we conclude that chest signs should be reinstated as cues to early diagnosis of COPD in patients 40 years or older. PMID- 23983461 TI - Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder. AB - BACKGROUND: Compelling evidence has shown that diabetic metabolic disorder plays a critical role in the pathogenesis of Alzheimer's disease, including increased expression of beta-amyloid protein (Abeta) and tau protein. Evidence has supported that minocycline, a tetracycline derivative, protects against neuroinflammation induced by neurodegenerative disorders or cerebral ischemia. This study has evaluated minocycline influence on expression of Abeta protein, tau phosphorylation, and inflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha) in the brain of diabetic rats to clarify neuroprotection by minocycline under diabetic metabolic disorder. METHOD: An animal model of diabetes was established by high fat diet and intraperitoneal injection of streptozocin. In this study, we investigated the effect of minocycline on expression of Abeta protein, tau phosphorylation, and inflammatory cytokines (interleukin-1beta and tumor necrosis factor-alpha) in the hippocampus of diabetic rats via immunohistochemistry, western blotting, and enzyme-linked immunosorbent assay. RESULTS: These results showed that minocycline decreased expression of Abeta protein and lowered the phosphorylation of tau protein, and retarded the proinflammatory cytokines, but not amyloid precursor protein. CONCLUSION: On the basis of the finding that minocycline had no influence on amyloid precursor protein and beta-site amyloid precursor protein cleaving enzyme 1 which determines the speed of Abeta generation, the decreases in Abeta production and tau hyperphosphorylation by minocycline are through inhibiting neuroinflammation, which contributes to Abeta production and tau hyperphosphorylation. Minocycline may also lower the self-perpetuating cycle between neuroinflammation and the pathogenesis of tau and Abeta to act as a neuroprotector. Therefore, the ability of minocycline to modulate inflammatory reactions may be of great importance in the selection of neuroprotective agents, especially in chronic conditions like diabetes and Alzheimer's disease. PMID- 23983463 TI - Dual effects and mechanism of TiO2 nanotube arrays in reducing bacterial colonization and enhancing C3H10T1/2 cell adhesion. AB - Competition occurs between the osteoblasts in regional microenvironments and pathogens introduced during surgery, on the surface of bone implants, such as joint prostheses. The aim of this study was to modulate bacterial and osteoblast adhesion on implant surfaces by using a nanotube array. Titanium oxide (TiO2) nanotube arrays, 30 nm or 80 nm in diameter, were prepared by a two-step anodization on titanium substrates. Mechanically polished and acid-etched titanium samples were also prepared to serve as control groups. The standard strains of Staphylococcus epidermidis (S. epidermidis, American Type Culture Collection [ATCC]35984) and mouse C3H10T1/2 cell lines with osteogenic potential were used to evaluate the different responses to the nanotube arrays, in bacteria and eukaryotic cells. We found that the initial adhesion and colonization of S. epidermidis on the surface of the TiO2 nanotube arrays were significantly reduced and that the adhesion of C3H10T1/2 cells on the surface of the TiO2 nanotube arrays was significantly enhanced when compared with the control samples. Based on a surface analysis of all four groups, we observed increased surface roughness, decreased water contact angles, and an enhanced concentration of oxygen and fluorine atoms on the TiO2 nanotube surface. We conclude that the TiO2 nanotube surface can reduce bacterial colonization and enhance C3H10T1/2 cell adhesion; multiple physical and chemical properties of the TiO2 nanotube surface may contribute to these dual effects. PMID- 23983465 TI - Formulating food protein-stabilized indomethacin nanosuspensions into pellets by fluid-bed coating technology: physical characterization, redispersibility, and dissolution. AB - BACKGROUND: Drug nanosuspensions are very promising for enhancing the dissolution and bioavailability of drugs that are poorly soluble in water. However, the poor stability of nanosuspensions, reflected in particle growth, aggregation/agglomeration, and change in crystallinity state greatly limits their applications. Solidification of nanosuspensions is an ideal strategy for addressing this problem. Hence, the present work aimed to convert drug nanosuspensions into pellets using fluid-bed coating technology. METHODS: Indomethacin nanosuspensions were prepared by the precipitation-ultrasonication method using food proteins (soybean protein isolate, whey protein isolate, beta lactoglobulin) as stabilizers. Dried nanosuspensions were prepared by coating the nanosuspensions onto pellets. The redispersibility, drug dissolution, solid-state forms, and morphology of the dried nanosuspensions were evaluated. RESULTS: The mean particle size for the nanosuspensions stabilized using soybean protein isolate, whey protein isolate, and beta-lactoglobulin was 588 nm, 320 nm, and 243 nm, respectively. The nanosuspensions could be successfully layered onto pellets with high coating efficiency. Both the dried nanosuspensions and nanosuspensions in their original amorphous state and not influenced by the fluid-bed coating drying process could be redispersed in water, maintaining their original particle size and size distribution. Both the dried nanosuspensions and the original drug nanosuspensions showed similar dissolution profiles, which were both much faster than that of the raw crystals. CONCLUSION: Fluid-bed coating technology has potential for use in the solidification of drug nanosuspensions. PMID- 23983464 TI - Delivery system for DNAzymes using arginine-modified hydroxyapatite nanoparticles for therapeutic application in a nasopharyngeal carcinoma model. AB - DNAzymes are synthetic, single-stranded, catalytic nucleic acids that bind and cleave target mRNA in a sequence-specific manner, and have been explored for genotherapeutics. One bottleneck restricting their application is the lack of an efficient delivery system. As an inorganic nanomaterial with potentially wide application, nano-hydroxyapatite particles (nHAP) have attracted increasing attention as new candidates for nonviral vectors. In this study, we developed an nHAP-based delivery system and explored its cellular uptake mechanisms, intracellular localization, and biological effects. Absorption of arginine modified nanohydroxyapatite particles (Arg-nHAP) and DZ1 (latent membrane protein 1 [LMP1]-targeted) reached nearly 100% efficiency under in vitro conditions. Using specific inhibitors, cellular uptake of the Arg-nHAP/DZ1 complex was shown to be mediated by the energy-dependent endocytosis pathway. Further, effective intracellular delivery and nuclear localization of the complex was confirmed by confocal microscopy. Biologically, the complex successfully downregulated the expression of LMP1 in nasopharyngeal carcinoma cells. In a mouse tumor xenograft model, the complex was shown to be delivered efficiently to tumor tissue, downregulating expression of LMP1 and suppressing tumor growth. These results suggest that Arg-nHAP may be an efficient vector for nucleic acid-based drugs with potential clinical application. PMID- 23983466 TI - Latent class analysis of reading, decoding, and writing performance using the Academic Performance Test: concurrent and discriminating validity. AB - AIM: To explore and validate the best returned latent class solution for reading and writing subtests from the Academic Performance Test (TDE). SAMPLE: A total of 1,945 children (6-14 years of age), who answered the TDE, the Development and Well-Being Assessment (DAWBA), and had an estimated intelligence quotient (IQ) higher than 70, came from public schools in Sao Paulo (35 schools) and Porto Alegre (22 schools) that participated in the 'High Risk Cohort Study for Childhood Psychiatric Disorders' project. They were on average 9.52 years old (standard deviation = 1.856), from the 1st to 9th grades, and 53.3% male. The mean estimated IQ was 102.70 (standard deviation = 16.44). METHODS: Via Item Response Theory (IRT), the highest discriminating items ('a'>1.7) were selected from the TDE subtests of reading and writing. A latent class analysis was run based on these subtests. The statistically and empirically best latent class solutions were validated through concurrent (IQ and combined attention deficit hyperactivity disorder [ADHD] diagnoses) and discriminant (major depression diagnoses) measures. RESULTS: A three-class solution was found to be the best model solution, revealing classes of children with good, not-so-good, or poor performance on TDE reading and writing tasks. The three-class solution has been shown to be correlated with estimated IQ and to ADHD diagnosis. No association was observed between the latent class and major depression. CONCLUSION: The three class solution showed both concurrent and discriminant validity. This work provides initial evidence of validity for an empirically derived categorical classification of reading, decoding, and writing performance using the TDE. A valid classification encourages further research investing correlates of reading and writing performance using the TDE. PMID- 23983467 TI - Temperamental characteristics in childhood migraine without aura: a multicenter study. AB - BACKGROUND: Children with migraine seem to be more anxious, sensitive, deliberate, cautious, fearful, vulnerable to frustration, tidy, and less physically enduring than comparisons. To the best our knowledge no studies about the temperamental and the characterial dimension aspects in childhood migraine was conducted. Therefore, the aim of the present study was to describe the temperamental and character aspects in a sample of children affected by migraine without aura (MoA) and their relationship with clinical aspects of MoA such as frequency, duration, and severity of attacks. MATERIALS AND METHODS: In our study, 486 children affected by MoA (239 male, 247 female) aged 7-12 years, (mean 10.04 +/- 2.53 years) and 518 typical developing children comparable for age (P = 0.227) and sex (P = 0.892) were enrolled to assess their temperamental characteristics. The mothers of all subjects filled out the Junior Temperament and Character Inventory: Parent Version. RESULTS: Children affected by migraine show a higher prevalence of harm avoidance and persistence temperamental domains (P < 0.001) and significantly lower prevalence of the self-directedness character trait (P = 0.023) with respect to the comparisons, according to Cloninger's model. The Spearman rank correlation analysis shows a significant relationship between migraine characteristics and temperamental domains. CONCLUSION: The present study first identified differences in temperamental characteristics in children affected by MoA with respect to the comparisons, suggesting the need for this evaluation in order for better psychological pediatric management of children with migraine, with possible consequences and impact on the future outcomes of these subjects. PMID- 23983468 TI - Quality of life and personality traits in patients with malignant pleural mesothelioma and their first-degree caregivers. AB - Asbestos exposure causes significant pleural diseases, including malignant pleural mesothelioma (MPM). Taking into account the impact of MPM on emotional functioning and wellbeing, this study aimed to evaluate the quality of life and personality traits in patients with MPM and their first-degree caregivers through the World Health Organization Quality of Life-BREF (WHOQOL-BREF) and the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF). The sample was composed of 27 MPM patients, 55 first-degree relatives enrolled in Casale Monferrato and Monfalcone (Italy), and 40 healthy controls (HC). Patients and relatives reported poorer physical health than the HC. Patients had a higher overall sense of physical debilitation and poorer health than relatives and the HC, more numerous complaints of memory problems and difficulties in concentrating, and a greater belief that goals cannot be reached or problems solved, while often claiming that they were more indecisive and inefficacious than the HC. First-degree relatives reported lower opinions of others, a greater belief that goals cannot be reached or problems solved, support for the notion that they are indecisive and inefficacious, and were more likely to suffer from fear that significantly inhibited normal activities than were HC. In multinomial regression analyses, partial models indicated that sex, physical comorbidities, and the True Response Inconsistency (TRIN-r), Malaise (MLS), and Behavior Restricting Fears (BRF) dimensions of the MMPI-2-RF had significant effects on group differences. In conclusion, health care providers should assess the ongoing adjustment and emotional wellbeing of people with MPM and their relatives, and provide support to reduce emotional distress. PMID- 23983469 TI - Comparing the influences of age and disease on the Brief Assessment of Cognition in Schizophrenia in Japanese patients with schizophrenia. AB - BACKGROUND: The Brief Assessment of Cognition in Schizophrenia (BACS) is an evaluation of cognitive function that can be completed with more cases. However, there are few studies that compare which factor, disease or aging, is a better determinant of performance on the BACS. The present study aimed to investigate the influences of disease and aging on BACS performance in schizophrenic patients using subjects with a wide range of ages. METHODS: Schizophrenic patients (n = 165) and a comparison group (n = 171) were recruited as subjects. All participants completed the Japanese language version of the BACS (BACS-J), and the influences of disease and aging on performance in the BACS were examined with the use of multiple regression analysis. RESULTS: There was a significant influence of diagnosis and level of education on all six tasks of the BACS and the performance and composite scores. In addition, age was found to influence five tasks and the composite score, the duration of illness influenced four tasks and the composite score, and gender influenced one task and the composite score. CONCLUSION: The present study suggests that performance on the BACS was impaired not only by disease but also by level of education and aging. PMID- 23983470 TI - Celiac plexus neurolysis for the treatment of upper abdominal cancer pain. AB - Optimal treatment of oncologic pain is a challenge to all professionals who deal with cancer and its complications. The management of upper abdominal pain is usually difficult and it is often refractory to conservative therapies. In this context, celiac plexus neurolysis (CPN) appears to be an important and indispensable tool because it alleviates pain, gives comfort to patients and is a safe procedure. In this study, the importance of CPN is reviewed by a retrospective study of 74 patients with pain due to upper abdominal cancer. Almost all cases evaluated (94.6%) had an excellent result after CPN and the majority of side effects were transitory. PMID- 23983471 TI - Intrastriatal injections of KN-93 ameliorates levodopa-induced dyskinesia in a rat model of Parkinson's disease. AB - BACKGROUND: Levodopa remains the most effective drug for the treatment of Parkinson's disease (PD). However, long-term levodopa treatment is associated with the emergence of levodopa-induced dyskinesia (LID), which has hampered its use for PD treatment. The mechanisms of LID are only partially understood. A previous study showed that KN-93, a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor, could be used to ameliorate LID in rats. However, the precise mechanisms by which KN-93 acts as an antidyskinetic are not fully understood. METHODS: In the present study, a rat model of PD was induced by 6-hydroxydopamine (OHDA) injections. Then, the successfully lesioned rats were intrastriatally administered with a different dose of KN-93 (1 MUg, 2 MUg, or 5 MUg) prior to levodopa treatment. Abnormal involuntary movements (AIMs) scores and apomorphine induced rotations were measured in PD rats. Phosphorylated levels of GluR1 at Serine-845 (pGluR1S845) levels were determined by western blot. Arc and Penk levels were measured by real-time polymerase chain reaction (PCR). RESULTS: We found that both 2 MUg and 5 MUg KN-93 treatment lowered AIMs scores in levodopa priming PD rats without affecting the antiparkinsonian effect of levodopa. In agreement with behavioral analysis, KN-93 treatment (2 MUg) reduced pGluR1S845 levels in PD rats. Moreover, KN-93 treatment (2 MUg) reduced the expression of Gad1 and Nur77 in PD rats. CONCLUSION: These data indicated that intrastriatal injections of KN-93 were beneficial in reducing the expression of LID by lowering the expression of pGluR1S845 via suppressing the activation of CaMKII in PD rats. Decreased expression of pGluR1S845 further reduced the expression of Gad1 and Nur77 in PD rats. PMID- 23983476 TI - Antigenic heterogeneity of capsid protein VP1 in foot-and-mouth disease virus (FMDV) serotype Asia 1. AB - Foot and mouth disease virus (FMDV), with its seven serotypes, is a highly contagious virus infecting mainly cloven-hoofed animals. The serotype Asia1 occurs mainly in Asian regions. An in-silico approach was taken to reveal the antigenic heterogeneities within the capsid protein VP1 of Asia1. A total of 47 VP1 sequences of Asia1 isolates from different countries of South Asian regions were selected, retrieved from database, and were aligned. The structure of VP1 protein was modeled using a homology modeling approach. Several antigenic sites were identified and mapped onto the three-dimensional protein structure. Variations at these antigenic sites were analyzed by calculating the protein variability index and finding mutation combinations. The data suggested that vaccine escape mutants have derived from only few mutations at several antigenic sites. Five antigenic peptides have been identified as the least variable epitopes, with just fewer amino acid substitutions. Only a limited number of serotype Asia1 antigenic variants were found to be circulated within the South Asian region. This emphasizes a possibility of formulating synthetic vaccines for controlling foot-and-mouth disease by Asia1 serotypes. PMID- 23983475 TI - Future directions in combined modality therapy for rectal cancer: reevaluating the role of total mesorectal excision after chemoradiotherapy. AB - Most patients who develop rectal cancer present with locoregionally advanced (T3 or node-positive) disease. The standard management of locoregionally advanced rectal cancer is neoadjuvant concurrent chemoradiotherapy (nCRT), followed by radical resection (low-anterior resection or abdominoperineal resection with total mesorectal excision). Approximately 15% of patients can have a pathologic complete response (pCR) at the time of surgery, indicating that some patients can have no detectable residual disease after nCRT. The actual benefit of surgery in this group of patients is unclear. It is possible that omission of surgery in these patients, termed selective nonoperative management, can limit the toxicities associated with standard, multimodal combined modality therapy without compromising disease control. In this review, we discuss the clinical experiences to date using selective nonoperative management and various attempts at escalation of nCRT to improve the number of patients who have a pCR. We also explore several clinical, laboratory, imaging, histopathologic, and genetic biomarkers that have been tested as tools to predict which patients are most likely to have a pCR after nCRT. PMID- 23983474 TI - Emerging families of biomarkers for coronary artery disease: inflammatory mediators. AB - INTRODUCTION: Inflammation has been implicated in the development of atherosclerosis in patients with acute coronary syndrome. C-reactive protein is an established nonspecific prognostic inflammatory biomarker for patients with acute coronary syndrome in the medical literature. This has led to a concerted effort to identify circulating inflammatory biomarkers to facilitate predicting the risk for and diagnosing coronary artery disease in at-risk subjects. The objective of this study was to search after novel inflammatory biomarkers reported as useful for diagnosing coronary artery disease. METHODS: The PubMed database was searched for reports published from January 1, 2000 to June 30, 2012 of novel circulating biomarkers for coronary artery disease in addition to the established biomarker, C-reactive protein. The search terms used were "infarction", "biomarkers", and "markers", and only original articles describing clinical trials that were written in English were included. All published articles were separately examined carefully after novel inflammatory markers for acute coronary syndrome. All irrelevant publications without content pertaining to inflammatory biomarkers for acute coronary syndrome were excluded from this study. Our results reflect all articles concerning biomarkers in humans. RESULTS: The PubMed search yielded 4,415 research articles. After further analysis, all relevant published original articles examining 53 biomarkers were included in this review, which identified 46 inflammation biomarkers useful for detecting coronary artery disease. CONCLUSION: The emergence of diverse novel biomarkers for coronary artery disease has provided insight into the varied pathophysiology of this disease. Inflammatory biomarkers have tremendous potential in aiding the prediction of acute coronary syndrome and recurrent ischemic episodes, and will eventually help improve patient care and management. PMID- 23983477 TI - Design of multiligand inhibitors for the swine flu H1N1 neuraminidase binding site. AB - Viral neuraminidase inhibitors such as oseltamivir and zanamivir prevent early virus multiplication by blocking sialic acid cleavage on host cells. These drugs are effective for the treatment of a variety of influenza subtypes, including swine flu (H1N1). The binding site for these drugs is well established and they were designed based on computational docking studies. We show here that some common natural products have moderate inhibitory activity for H1N1 neuraminidase under docking studies. Significantly, docking studies using AutoDock for biligand and triligand forms of these compounds (camphor, menthol, and methyl salicylate linked via methylene bridges) indicate that they may bind in combination with high affinity to the H1N1 neuraminidase active site. These results also indicate that chemically linked biligands and triligands of these natural products could provide a new class of drug leads for the prevention and treatment of influenza. This study also highlights the need for a multiligand docking algorithm to understand better the mode of action of natural products, wherein multiple active ingredients are present. PMID- 23983473 TI - Current status of NADPH oxidase research in cardiovascular pharmacology. AB - The implications of reactive oxygen species in cardiovascular disease have been known for some decades. Rationally, therapeutic antioxidant strategies combating oxidative stress have been developed, but the results of clinical trials have not been as good as expected. Therefore, to move forward in the design of new therapeutic strategies for cardiovascular disease based on prevention of production of reactive oxygen species, steps must be taken on two fronts, ie, comprehension of reduction-oxidation signaling pathways and the pathophysiologic roles of reactive oxygen species, and development of new, less toxic, and more selective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors, to clarify both the role of each NADPH oxidase isoform and their utility in clinical practice. In this review, we analyze the value of NADPH oxidase as a therapeutic target for cardiovascular disease and the old and new pharmacologic agents or strategies to prevent NADPH oxidase activity. Some inhibitors and different direct or indirect approaches are available. Regarding direct NADPH oxidase inhibition, the specificity of NADPH oxidase is the focus of current investigations, whereas the chemical structure-activity relationship studies of known inhibitors have provided pharmacophore models with which to search for new molecules. From a general point of view, small-molecule inhibitors are preferred because of their hydrosolubility and oral bioavailability. However, other possibilities are not closed, with peptide inhibitors or monoclonal antibodies against NADPH oxidase isoforms continuing to be under investigation as well as the ongoing search for naturally occurring compounds. Likewise, some different approaches include inhibition of assembly of the NADPH oxidase complex, subcellular translocation, post-transductional modifications, calcium entry/release, electron transfer, and genetic expression. High-throughput screens for any of these activities could provide new inhibitors. All this knowledge and the research presently underway will likely result in development of new drugs for inhibition of NADPH oxidase and application of therapeutic approaches based on their action, for the treatment of cardiovascular disease in the next few years. PMID- 23983479 TI - Cost and clinical consequences of smoking cessation in outpatients after cardiovascular disease: a retrospective cohort study. AB - This cohort retrospective study explored the cost and clinical consequences of smoking cessation in outpatients after cardiovascular events (CVEs), in Spain. A total of 2,540 patients (68.1 years; 60.7% male; 8.4% smokers, 52.9% ex-smokers, and 38.7% never smokers) fulfilling the selection criteria and followed up throughout a period of 36 months after the event were considered eligible for analysis. Total costs were higher among current smokers in comparison with ex smokers and never smokers (?7,981 versus [vs] ?7,322 and ?5,619, respectively) (P < 0.001). Both health care costs (?6,273 vs ?5,673 and ?4,823, respectively) (P < 001) and loss of productivity at work costs (?1,708 vs ?1,650 and ?796, respectively) (P < 001) accounted for such differences. There was also a difference in CVE recurrence rates (18.6% vs 16.5% and 9.6%, respectively) (P < 01). Smoking cessation in CVE outpatients was associated with lower cost and risk of CVE recurrence compared with smokers, and their health status was similar to that of never smokers, in routine clinical practice in Spain. PMID- 23983478 TI - The personal, societal, and economic burden of schizophrenia in the People's Republic of China: implications for antipsychotic therapy. AB - BACKGROUND: This article describes the personal, societal, and economic burden attributable to schizophrenia in the People's Republic of China and highlights the potential for effective outpatient treatment to reduce this burden given recent changes in the Chinese health care system. The importance of effective antipsychotic therapy in reducing the burden of schizophrenia is also examined. METHODS: Published research on the burden, disability, management, and economic costs of schizophrenia in the People's Republic of China was examined in the context of the larger body of global research. Research written in English or Chinese and published before June 2012 was identified using PubMed, CNKI, and Wanfang Med database searches. The contribution of effective antipsychotic therapy in reducing the risk for relapse and hospitalization and improving patients' functioning is described. RESULTS: Schizophrenia imposes a substantial burden on Chinese society, with indirect costs accounting for the majority of the total cost. Functional impairment is high, leading to lost wages and work impairment. In the People's Republic of China, schizophrenia is the most common diagnosis among hospitalized psychiatric patients. Ongoing changes in the Chinese health care system may reduce some barriers to effective relapse prevention in schizophrenia and potentially reduce hospitalizations. The use of antipsychotics for acute episodes and maintenance treatment has been shown to decrease symptom severity and reduce the risk for relapse and hospitalization. However, discontinuing antipsychotic medication appears common and is a strong predictor of relapse. Cost-effectiveness research in the People's Republic of China is needed to examine the potential gains from improved outpatient antipsychotic treatment. CONCLUSION: Schizophrenia is a very costly mental illness in terms of personal, economic, and societal burden, both in the People's Republic of China and globally. When treated effectively, patients tend to persist longer with antipsychotic treatment, have fewer costly relapses, and have improved functioning. Further research examining the long-term effects of reducing barriers to effective treatments on the societal burden of schizophrenia in the People's Republic of China is needed. PMID- 23983480 TI - Treatment outcome and prognostic indices in patients with hyperglycemic emergencies. AB - OBJECTIVE: The objective of this study is to assess the treatment outcomes in patients with hyperglycemic emergencies and to ascertain the factors associated with outcome, with emphasis on the determinants of outcome. METHOD: A total of 105 patients admitted to the Accident and Emergency unit, who fulfilled the criteria for hyperglycemic emergencies, were selected. The information extracted included sociodemographic, clinical, and laboratory data, as well as hospitalization outcome. RESULTS: Of the 105 subjects that participated in the study, hyperosmolar hyperglycemic nonketotic state (HHNK) was seen in 50% (53) of the subjects, while diabetic ketoacidosis (DKA) was seen in 31% (29), normo osmolar nonketotic hyperglycemic state (NNHS) in 12% (13), and mixed hyperglycemic emergency in 7% (10) of the subjects. The overall mortality rate in this study was 4.8%. Three deaths were recorded in patients with HHNK, while DKA and NNHS each had one death. Three of the deaths occurred within the first 24 hours of admission while the other two were more than 24 hours after admission. The mean (standard deviation) total duration of hospital stay was 24.2 days (SD), and the range of stay was 0.5-88 days. CONCLUSION: The most common type of hyperglycemic emergency seen in this study was HHNK. Also, the presence of infection, and sex of the study subject, were significant determinants of outcome in this study. PMID- 23983482 TI - Relationship between platelet count and hemodialysis membranes. AB - BACKGROUND: One factor associated with poor outcomes in hemodialysis patients is exposure to a foreign membrane. Older membranes are very bioincompatible and increase complement activation, cause leukocytosis by activating circulating factors, which sequesters leukocytes in the lungs, and activates platelets. Recently, newer membranes have been developed that were designed to be more biocompatible. We tested if the different "optiflux" hemodialysis membranes had different effects on platelet levels. METHODS: Ninety-nine maintenance hemodialysis patients with no known systemic or hematologic diseases affecting their platelets had blood drawn immediately prior to, 90 minutes into, and immediately following their first hemodialysis session of the week. All patients were dialyzed using a Fresenius Medical Care Optiflux polysulfone membrane F160, F180, or F200 (polysulfone synthetic dialyzer membranes, 1.6 m(2), 1.8 m(2), and 2.0 m(2) surface area, respectively, electron beam sterilized). Platelet counts were measured from each sample by analysis using a CBC analyzer. RESULTS: The average age of the patients was 62.7 years; 36 were female and 63 were male. The mean platelet count pre, mid, and post dialysis was 193 (standard deviation +/ 74.86), 191 (standard deviation +/-74.67), and 197 (standard deviation +/-79.34) thousand/mm3, respectively, with no statistical differences. CONCLUSION: Newer membranes have no significant effect on platelet count. This suggests that they are, in fact, more biocompatible than their predecessors and may explain their association with increased survival. PMID- 23983483 TI - Comorbidity of Kawasaki disease and group a streptococcal pleural effusion in a healthy child: a case report. AB - BACKGROUND: Kawasaki disease is an acute self-limiting vasculitis that affects children. The most dreaded complication of Kawasaki disease reported in the literature over the years is coronary artery disease, which is considered as the main cause of acquired heart disease. However, pulmonary associations with Kawasaki disease have been overlooked. We present a rare, if not unique, case of Kawasaki disease associated with group A streptococcus pleural effusion in the English language literature. A search of the PubMed database was carried out, using a combination of the terms "Kawasaki disease", "pneumonia", and "group A streptococcus". The majority of studies conducted in children with Kawasaki disease have concentrated on the coronary artery implications. Kawasaki disease is considered a self-limiting illness, but can have detrimental consequences if not diagnosed early. When there is a prolonged inflammatory reaction, with no infectious agent identified or remittent fever unresponsive to antibiotics, Kawasaki disease should be taken into consideration. Elevated Vbeta2+ T cells compared with healthy controls suggest possible involvement of a superantigen in the etiology of Kawasaki disease, so it is wise that the health care provider concentrates not only on the cardiac consequences, but also on pulmonary associations. PMID- 23983481 TI - Clinical applications of small bowel capsule endoscopy. AB - Video capsule endoscopy has revolutionized our ability to visualize the entire small bowel mucosa. This modality is established as a valuable tool for the diagnosis of obscure gastrointestinal bleeding, Crohn's disease, small bowel tumors, and other conditions involving the small bowel mucosa. This review includes an overview of the current and potential future clinical applications of small bowel video endoscopy. PMID- 23983484 TI - Spectrum of corrosive esophageal injury after intentional paraquat or glyphosate surfactant herbicide ingestion. AB - BACKGROUND: Data on the spectrum of corrosive injury to the esophagus after paraquat or glyphosate-surfactant ingestion are sparse in the literature and confined to case studies and brief reports. Therefore, this study aimed to examine the clinical features, degrees of esophageal injury, and clinical outcomes after paraquat or glyphosate herbicide ingestion, and sought to determine what association, if any, may exist between these findings. METHODS: We performed an observational study on 47 patients with paraquat or glyphosate ingestion who underwent endoscopic evaluation over a period of 11 years (2000 2011). RESULTS: Corrosive esophageal injuries were classified as grade 1 in 14 (glyphosate-surfactant) and three (paraquat), grade 2a in nine (glyphosate surfactant) and 18 (paraquat), and grade 2b in one (glyphosate-surfactant) and two (paraquat) patients. No patients had grade 0, 3a, or 3b esophageal injuries. Therefore, the severity of corrosive injury was more severe in the paraquat group (P = 0.005). After toxin ingestion, systemic toxicity occurred, with rapid development of systemic complications in many cases. Neurologic complications occurred more frequently in the glyphosate-surfactant group (29.2% versus 0%, P = 0.005), although respiratory failure (4.2% versus 34.8%, P = 0.008), hepatitis (12.5% versus 52.2%, P = 0.004), and renal failure (20.8% versus 52.2%, P = 0.025) developed more frequently in the paraquat group. Patients with glyphosate poisoning had shorter hospital stays than patients with paraquat poisoning (13.3 +/- 15.1 days versus 26.8 +/- 10.2 days, P = 0.001). Nevertheless, there was no significant difference in mortality rate between the glyphosate-surfactant and paraquat groups (8.3% versus 13.0%, P = 0.601). We ultimately found that patients with grade 2b esophageal injury suffered from a greater incidence of respiratory (100.0% versus 5.9%, P = 0.001) and gastrointestinal (66.7% versus 11.8%, P = 0.034) complications than patients with grade 1 injury, regardless of herbicide type. CONCLUSION: Paraquat and glyphosate are mild caustic agents that produce esophageal injuries of grades 1, 2a, and 2b only. Our data also suggest a potential relationship between the degree of esophageal injury and systemic complications. PMID- 23983485 TI - Cannabinoid hyperemesis syndrome with extreme hydrophilia. AB - Marijuana is the most widely used recreational drug in the US. Hyperemetic hydrophilic syndrome is a previously described but infrequently recognized condition of cannabinoid abuse with hyperemesis and obsessive hot showering. We present a 47-year-old male known marijuana addict with intractable abdominal pain who could not wait for physical examination, meal, or medication, because of obsessive compulsive warm baths. He had a history of epilepsy and addiction to marijuana, which he took on the day of admission. He presented to the hospital with a seizure, complicated by nausea, vomiting, and severe abdominal pain. His examination was unremarkable, except for mild epigastric tenderness. His laboratory and radiological tests were within normal limits, except for a positive urine drug screen for marijuana and opiates. He took himself immediately to the bathroom and remained under a hot shower with the exception of two 15 minute breaks for the rest of the day. He stated that it made him feel better than medication. Receiving medication and even eating was a problem because of this compulsive showering. Abstinence from marijuana during the hospital stay made the patient's nausea and vomiting resolve significantly. Cannabinoid hyperemesis is a differential diagnosis among patients with intractable nausea, vomiting, and obsessive hot bathing. The syndrome is an unmistakable indication of marijuana addiction. A thorough history and observation is very valuable. Recognition of this entity will reduce unnecessary testing and utilization of health care resources. PMID- 23983486 TI - Spontaneous bacterial peritonitis with a very high leukocyte count in ascitic fluid caused by Haemophilus influenzae. AB - We report on a case of spontaneous bacterial peritonitis (SBP) due to Haemophilus influenzae (H. influenzae) in an elderly patient with alcoholic cirrhosis. The patient presented with a 5 day history of fever, cough, and fatigue. Abdominal paracentesis revealed a very high neutrophil count (134,800 cells/MUL). Secondary peritonitis and abdominal abscess were ruled out. Peritoneal fluid culture displayed the growth of H. influenzae. The patient was treated with ceftriaxone and showed signs of improvement. Eventually, the patient died due to septic shock caused by other organisms. H. influenzae is a very rare cause of SBP. This case report demonstrates that (1) H. influenzae should be considered a potential cause of SBP, and (2) a very high leukocyte count in ascitic fluid can be found in patients with SBP. PMID- 23983487 TI - Metformin-induced mixed hepatocellular and cholestatic hepatic injury: case report and literature review. AB - INTRODUCTION: Metformin is a first-line drug choice for the treatment of type 2 diabetes mellitus (DM-2). Metformin-induced hepatotoxicity has rarely been reported. We report on a case of metformin-induced mixed hepatocellular and cholestatic liver injury in an elderly patient with DM-2 as well as review and summarize case reports of metformin hepatotoxicity available in English on the PubMed database. CASE: After receiving metformin 850 mg/day for 2 weeks, a 78 year-old male presented with a 10-day history of abdominal pain, vomiting, diarrhea, and jaundice. Laboratory analysis showed severe hepatocellular and cholestatic hepatic injury. Other causes for acute liver injury were ruled out. Discontinuation of metformin treatment led to significant subjective improvement after 1 week, and all hepatic abnormalities resolved by 2 months. CONCLUSION: Metformin is an important drug for the treatment of DM-2, which is also used for treatment of patients with fatty liver. It can, however, induce hepatocellular and cholestatic hepatic injury; both physicians and patients should be aware of this potential side effect. PMID- 23983488 TI - A comparison between acute pressure block of the sciatic nerve and acupressure: methodology, analgesia, and mechanism involved. AB - Acupressure is an alternative medicine methodology that originated in ancient China. Treatment effects are achieved by stimulating acupuncture points using acute pressure. Acute pressure block of the sciatic nerve is a newly reported analgesic method based on a current neuroscience concept: stimulation of the peripheral nerves increases the pain threshold. Both methods use pressure as an intervention method. Herein, we compare the methodology and mechanism of these two methods, which exhibit several similarities and differences. Acupressure entails variation in the duration of manipulation, and the analgesic effect achieved can be short-or long-term. The acute effect attained with acupressure presents a scope that is very different from that of the chronic effect attained after long-term treatment. This acute effect appears to have some similarities to that achieved with acute pressure block of the sciatic nerve, both in methodology and mechanism. More evidence is needed to determine whether there is a relationship between the two methods. PMID- 23983489 TI - Risk of miscarriage among users of corticosteroid hormones: a population-based nested case-control study. AB - BACKGROUND: The purpose of this nested case-control study in Denmark was to study the association between use of corticosteroids and risk of miscarriage. METHODS: We identified prescriptions for corticosteroids before the miscarriage/index date. We estimated odds ratios (ORs) for miscarriage and for early (<13 weeks) and late (13-21 weeks) miscarriage adjusting for age, history of diabetes and epilepsy, and nonsteroidal anti-inflammatory drug use. RESULTS: We identified 10,974 women with miscarriage and 109,740 controls. Prevalence of inhaled corticosteroid use within 60 days before the index date was 1.3% among the cases and 1.0% among the controls (OR = 1.20; 95% confidence interval [CI] 1.01-1.44). Prevalence of oral corticosteroid use within 60 days before the index date was 0.3% for both cases and controls (OR = 0.78; 95% CI 0.53-1.15). For inhaled and oral corticosteroids, the ORs of early miscarriage were 1.22 (95% CI 1.01-1.49) and 0.81 (95% CI 0.55-1.20), respectively. CONCLUSION: Use of inhaled corticosteroids was associated with a slightly increased risk of early miscarriage, but explanations alternative to causal ones were possible. PMID- 23983490 TI - Correlates of menstrual cycle characteristics among nulliparous Danish women. AB - OBJECTIVE: We examined the association between lifestyle factors and menstrual cycle characteristics among nulliparous Danish women aged 18-40 years who were participating in an Internet-based prospective cohort study of pregnancy planners. METHODS: We used cross-sectional data collected at baseline to assess the association of age, body mass index (BMI), physical activity, alcohol and caffeine consumption, and smoking with the prevalence of irregular cycles, short (<=25 days) and long (>=33 days) cycles, and duration and amount of menstrual flow. We used log-binomial and multinomial logistic regression to estimate prevalence ratios and 95% confidence intervals. RESULTS: Low physical activity and heavy alcohol consumption were associated with an increased prevalence of irregular periods. High BMI, smoking, and caffeine and alcohol consumption were related to an increased prevalence of short menstrual cycles and heavy menstrual bleeding. Women in their mid-to-late thirties had shorter and lighter menstrual flow, but a lower prevalence of irregular cycles, compared with women 18-25 years of age. DISCUSSION: In this study, increased age, high BMI, and sedentary behavior were associated with menstrual-pattern irregularities. These factors may influence the balance and level of endogenous hormones conducive to optimal menstrual function. PMID- 23983491 TI - Attrition of Canadian Internet pharmacy websites: what are the implications? AB - BACKGROUND: The unavailability of Internet pharmacy websites may impact a consumer's drug purchases and health care. OBJECTIVE: To address the issue of attrition, a defined set of Canadian Internet pharmacy websites was examined at three separate time intervals. METHODS: In February to March 2006, 117 distinct, fully functional "Canadian Internet pharmacy" websites were located using the advanced search options of Google and the uniform resource locator (URL) for each website was recorded. To determine website attrition, each of the 117 websites obtained and recorded from the previous study was revisited at two later periods of time within a 4-year period. RESULTS: After approximately 4 years and 5 months, only 59 (50.4%) sites were found in the original state. Thirty-four sites (29.1%) had moved to a new URL address and were not functioning as the original Internet pharmacy. For 24 sites (20.5%) the viewer was redirected to another Canadian Internet pharmacy site. CONCLUSION: Of concern for patients if Internet pharmacy sites were suddenly inaccessible would be the disruption of continuity of care. PMID- 23983492 TI - Retrospective cohort study of the effects of obesity in early pregnancy on maternal weight gain and obstetric outcomes in an obstetric population in Africa. AB - OBJECTIVE: The purpose of this study was to compare maternal weight gain in pregnancy and obstetric outcomes between women with obesity in early pregnancy and those with a normal body mass index (BMI) in early pregnancy. METHODS: This was a retrospective cohort study of women with obesity in early pregnancy and those with a normal BMI who were seen at three teaching hospitals in South-East Nigeria. Statistical analysis was performed using Statistical Package for the Social Sciences version 17.0 software, with descriptive and inferential statistics at the 95% level of confidence. RESULTS: The study sample consisted of 648 women (324 obese and 324 healthy-weight). The mean age of the obese women was 26.7 +/- 5.1 years and that of the healthy-weight women was 26.6 +/- 4.9 years. Although both excessive weight gain (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.23-0.54) and inadequate weight gain (OR 0.08, 95% CI 0.04-0.15) were less common in women with early pregnancy obesity than in healthy-weight women, a significantly higher proportion of obese women with excessive weight gain had adverse fetomaternal outcomes. Also, a significantly higher proportion of obese women had specific complications, such as premature rupture of membranes (OR 2.36, 95% CI 1.12-5.04), gestational hypertension/pre-eclampsia (OR 2.31, 95% CI 1.12-5.04), antepartum hemorrhage (OR 2.78, 95% CI 1.02-7.93), gestational diabetes (OR 4.24, 95% CI 1.62-11.74), cesarean delivery (OR 2.3, 95% CI 1.2 5.44), macrosomia (OR 4.08, 95% CI 1.06-8.41), severe birth asphyxia (OR 2.8, 95% CI 1.2-6.63), abnormal Apgar scores (OR 2.67, 95% CI 1.46-4.93), and newborn special care admissions (OR 1.18, 95% CI 1.0-3.29). CONCLUSION: Early pregnancy obesity was associated with a wide range of adverse fetomaternal outcomes, and could be a genuine risk factor for increased pregnancy-related morbidity and/or mortality in this population. Interventions to reduce prepregnancy obesity could therefore be useful in this low-resource African setting. PMID- 23983493 TI - Factors associated with severe preeclampsia and eclampsia in Jahun, Nigeria. AB - OBJECTIVE: To explore traditional herbal medicines as potential risk factors of severe preeclampsia and eclampsia in Nigeria. METHODS: We conducted a retrospective case-control study from October 2010 to May 2011. The cases were all pregnant women admitted to the Jahun Hospital during the study period with severe preeclampsia or eclampsia and women presenting with normal pregnancy after 22 weeks. RESULTS: During the study period, a total of 1,257 women (44%) were recorded as having normal pregnancy, and 419 (16%) women had severe preeclampsia/eclampsia (175 with severe preeclampsia and 244 with eclampsia). The risk factors found to be associated with a greater risk of severe preeclampsia/eclampsia included personal history of preeclampsia (odds ratio [OR] = 21.5; P < 0.001), personal history of preexisting hypertension (OR = 10.5; P < 0.001), primiparity (OR = 2.5; P = 0.001), occupation as housewife (OR = 1.9; P = 0.008), and fewer than four antenatal care visits (OR = 1.6; P = 0.02). Use of traditional treatments during pregnancy was associated with a higher risk of developing severe preeclampsia/eclampsia (OR = 1.6 95%; confidence interval [CI]: 1.2-2.1) by univariate analysis only. CONCLUSION: Use of traditional treatment, which increases delays before consulting the official health sector, might be a marker for harmful behavior. Community-based studies could provide additional information on the practice of herbal therapy in this population. PMID- 23983494 TI - Ectopic pregnancy: a life-threatening gynecological emergency. AB - BACKGROUND: Ectopic pregnancy is a life-threatening gynecological emergency, and a significant cause of maternal morbidity and mortality in Nigeria. OBJECTIVE: The aim of this work was to determine and evaluate the incidence, clinical presentation, risk factors, and management outcomes of ectopic pregnancies at Ebonyi State University Teaching Hospital (EBSUTH) in Abakaliki. METHODS: This was a retrospective, descriptive study of ectopic pregnancies managed in EBSUTH during the study period (June 1, 2002 to May 31, 2012). The medical records of the patients managed for ectopic pregnancy as well as the total birth record and gynecological admission records during the period under review were retrieved, and data were collected with the aid of data-entry forms designed for this purpose. There were 4,610 gynecological admissions and 9,828 deliveries, with 215 cases of ectopic pregnancies. A total of 205 cases were suitable for analysis after excluding cases with incomplete records. The relevant data collected were analyzed with SPSS version 15.0 for Windows. RESULTS: Ectopic pregnancy constituted 4.5% of all gynecological admissions, and its incidence was 2.1%. The mean age of the patients was 27 +/- 2 years, 196 of 205 (95.6%) had ruptured ectopic pregnancies, and the remaining nine (4.4%) were unruptured. The commonest (166 of 205, 80.0%) clinical presentation was abdominal pain, and the commonest (105 of 205, 51.2%) identified risk factor was a previous history of induced abortion. Three deaths were recorded, giving a case-fatality rate of 1.4% (three of 205). CONCLUSION: Ectopic pregnancy is a recognized cause of maternal morbidity and mortality and has remained a reproductive health challenge to Nigerian women, as well as a threat to efforts in achieving the UN's Millennium Development Goal 5 in sub-Saharan Africa. PMID- 23983495 TI - Magnetic resonance imaging findings and neurodevelopmental outcomes in neonates with urea-cycle defects. AB - The urea-cycle functions to facilitate ammonia excretion, a disruption of which results in the accumulation of toxic metabolites. The neurological outcome of neonatal-onset urea-cycle defects (UCDs) is poor, and there are no good predictors of prognosis beyond ammonia levels at presentation. The role of neuroimaging in the prognosis of neonatal-onset UCDs is unclear. We describe the magnetic resonance imaging (MRI) findings of two patients with neonatal-onset UCDs (argininosuccinic aciduria and citrullinemia) at presentation and at 2-year follow-up, and present a review of the literature on neuroimaging in this age group. We observed two potentially significant distinct patterns of cerebral involvement on MRI: (1) a central and focal pattern of involvement limited to the basal ganglia, perirolandic regions, and internal capsule; and (2) diffuse involvement of the cerebral cortex, internal capsule, basal ganglia, and variably thalami and brain stem. Patients with more diffuse findings tended to have higher serum glutamine peaks and worse neurological outcomes, while those with central involvement, aggressive acute management, and early liver transplantation tended to have better outcomes. We propose that MRI imaging of the brain may have prognostic value following presentation with neonatal UCDs, particularly in identifying patients at risk for poor outcome. The role and timing of follow-up neuroimaging is currently unclear. Further collaborative studies are necessary to evaluate whether patterns of MRI findings vary with specific UCD subtypes, and are predictive of clinical outcomes in neonatal UCDs. PMID- 23983496 TI - Tool guide for lifestyle behavior change in a cardiovascular risk reduction program. AB - Lifestyle medicine behaviors such as a healthy diet, physical activity, and tobacco avoidance, are the cornerstone of treatment in many chronic disease conditions, especially those related to the cardiovascular system. In fact, 80% of premature heart disease, stroke, and diabetes may be prevented through modification of these behaviors. The rate-limiting step in cardiovascular disease prevention is the implementation and maintenance of healthy lifestyle behaviors. The purpose of this paper is to provide and discuss a series of tools and strategies that can be used by health care providers to promote health behavior change in their practice. PMID- 23983497 TI - Teaching wound care to family medicine residents on a wound care service. AB - Primary care physicians often care for patients with chronic wounds, and they can best serve patients if they have knowledge and proficient skills in chronic wound care, including sharp debridement. The Oakwood Annapolis Family Medicine Residency in Michigan, USA developed a Wound Care Service, incorporating wound care training during the surgical rotation. Effectiveness of the wound care training was evaluated through pre- and posttesting of residents, to assess changes in knowledge and comfort in treating chronic wounds. The results demonstrate significant improvement in residents' knowledge and comfort in wound care. This innovation demonstrates the feasibility of educating residents in chronic wound care through hands-on experience. PMID- 23983498 TI - New record of the genus calyptella from Korea. AB - Calyptella capula is reported for the first time in Korea. It was found in spring in Chungcheongbuk-do, central Korea, growing in a dead stalk of Sesamum indicum. A description and molecular phylogenetic analyses are reported. PMID- 23983499 TI - Characterization of a Sapstaining Fungus, Ophiostoma floccosum, Isolated from the Sapwood of Pinus thunbergii in Korea. AB - An Ophiostoma fungus was isolated from a stump of Pinus thunbergii in a forest on the West coast of Korea. Microscopic analysis using a light microscope, a stereo microscope, and a scanning electron microscope revealed that it had morphological features of Pesotum and Sporothix synanarmorphs. Based on the beta-tubulin gene sequence analysis, the fungus was identified as the anamorph of Ophiostoma floccosum. Mycological properties of the species including its growth properties on different culture media were described. PMID- 23983500 TI - Ergosterol and Water Changes in Tricholoma matsutake Soil Colony during the Mushroom Fruiting Season. AB - The purpose of this study is to understand spatio-temporal changes of active fungal biomass and water in Tricholoma matsutake soil colonies during the mushroom fruiting season. The active fungal biomass was estimated by analyzing ergosterol content at four different points within four replicated locations in a single circular T. matsutake colony at Ssanggok valley in the Sogri Mt. National Park in Korea during 2003 to 2005. The four points were the ahead of the colony, the front edge of the colony and 20 cm and 40 cm back from the front edge of the colony. Ergosterol content was 0.0 to 0.7 ug per gram dried soil at the ahead, 2.5 to 4.8 ug at the front edge, 0.5 to 1.8 ug at the 20 cm back and 0.3 to 0.8 ug at the 40 cm back. The ergosterol content was very high at the front edge where the T. matsutake hyphae were most active. However, ergosterol content did not significantly change during the fruiting season, September to October. Soil water contents were lower at the front edge and 20 cm back from the front edge of the colony than at the ahead and 40 cm back during the fruiting season. Soil water content ranged from 12 to 19% at the ahead, 10 to 11% at the edge, 9 to 11% at the 20 cm back and 11 to 15% at the 40 cm back. Our results suggest that the active front edge of the T. matsutake soil colony could be managed in terms of water relation and T. matsutake ectomycorrhizal root development. PMID- 23983501 TI - Biodegradation of 2,4,6-Trinitrotoluene by White-Rot Fungus Irpex lacteus. AB - White-rot fungus Irpex lacteus degraded TNT significantly in proportion to the culture time. After 48 h incubation, about 95% of TNT was degraded. Two reduced metabolites were identified as 4-amino-2,6-dinitrotoluene (4-ADNT) and 2-amino 4,6-dinitrotoluene (2-ADNT) which was further degraded. PMID- 23983502 TI - Anti-cancer Activities of Ginseng Extract Fermented with Phellinus linteus. AB - In the present study, the anti-cancer effects of ginseng fermented with Phellinus linteus (GFPL) extract were examined through in vitro and in vivo assays. GFPL was produced by co-cultivating ginseng and Phellinus linteus together. Ginsenoside Rg3, Rh1 and Rh2 are important mediators of anti-angiogenesis and their levels in GFPL were enriched 24, 19 and 16 times, respectively, more than that of ginseng itself through the fermentation. GFPL exhibited distinct anti cancer effects, including growth inhibition of the human lung carcinoma cell line A549, and promotion of immune activation by stimulating nitric oxide (NO) production in Raw 264.7 cells. Further evidence supporting anti-cancer effects of GFPL was its significant prolongment of the survival of B16F10 cancer cell implanted mice. These results suggest that the GFPL may be a candidate for cancer prevention and treatment through immune activation and anti-angiogenic effects by enriching Rg3, Rh1 and Rh2. PMID- 23983503 TI - Effect of Ribitol and Plant Hormones on Aposymbiotical Growth of the Lichen forming Fungi of Ramalina farinacea and Ramalina fastigiata. AB - This study was aimed at evaluating the growth promoting effect of symbiotic algal polyol (ribitol) and plant hormones on the lichen-forming fungi (LFF), Ramalina farinacea (CH050010 and 40403) and Ramalina fastigiata. The addition of ribitol to basal (malt-yeast extract) medium enhanced the relative growth rates of all three LFF. R. farinacea (CH050010), R. farinacea (40403) and R. fastigiata (H06127) showed 35.3%, 29.0% and 29.3% higher growth rates, respectively, compared to the control. IBA (indole-3-butyric acid) and TIBA (2,3,5-tridobenzoic acid) also increased growth rates of the LFF by 34 to 64% and 7 to 28%, respectively, compared to the control. The combination of ribitol with IBA or TIBA synergistically increased the growth of all LFF. For example, ribitol and IBA treatments increased growth rates of R. farinacea (CH050010), R. farinacea (40403) and R. fastigiata (H06127) by 79.4%, 40.3% and 72.8% in, respectively, compared to those grown on the basal medium. The stimulating effect of ribitol and IBA on the LFF growth induced vertical development of the fungal mass in culture. We suggest that lichen-forming fungal growth of Ramalina lichens can be stimulated aposymbiotically by supplementing polyols and plant hormones to the basal medium in the mass production of lichen secondary metabolites under large scale culture conditions. PMID- 23983504 TI - Antimicrobial and Cytotoxic Activity of Di-(2-ethylhexyl) Phthalate and Anhydrosophoradiol-3-acetate Isolated from Calotropis gigantea (Linn.) Flower. AB - A phytochemical study on the flowe r of Calotropis gigantea (Linn.) using silica gel column chromatography and preparative thin layer chromatography, led to the first time isolation of Di-(2-ethylhexyl) phthalate (compound 1) and anhydrosophoradiol-3-acetate (compound 2). The structures of these compounds were confirmed by spectroscopic analyses (IR, HRTOFMS and NMR). The antibacterial and antifungal activities of ethyl acetate extract, compound 1 and compound 2 were measured using the disc diffusion method. Ethyl acetate extract and compound 1 presented better results than compound 2. The minimum inhibitory concentrations (MICs) of the extract and compounds were found to be in the range of 16~128 ug/ml. The cytotoxicity (LC50) against brine shrimp nauplii (Artemia salina) were also evaluated and found to be 14.61 ug/ml for ethyl acetate, 9.19 ug/ml for compound 1 and 15.55 ug/ml for compound 2. PMID- 23983505 TI - Comparative effects of oyster mushrooms on lipid profile, liver and kidney function in hypercholesterolemic rats. AB - Comparative effects of oyster mushrooms on plasma and fecal lipid profiles and on liver and kidney function were evaluated in hyper and normocholesterolemic rats. Feeding of hypercholesterolemic rats a 5% powder of oyster mushrooms (Pleurotus ostreatus, P. sajor-caju and P. florida) reduced the plasma total cholesterol level by 37%, 21% and 16%, respectively and reduced the triglyceride level by 45%, 24% and 14%, respectively. LDL/HDL ratio decreased by 64%, 45% and 41% for P. sajor-caju, P. ostreatus and P. florida fed rats, respectively. Mushroom feeding also reduced body weight in hypercholesterolemic rats. However, it had no adverse effect on plasma bilirubin, creatinin and urea nitrogen level. Mushroom feeding also increased the total lipid and cholesterol excretion in the feces. The present study reveals that feeding of 5% oyster mushroom powder does not have detrimental effects on the liver and kidneys rather may provide health benefits for the cardiovascular-related complication by decreasing the atherogenic lipid profiles. PMID- 23983506 TI - Ergothioneine contents in fruiting bodies and their enhancement in mycelial cultures by the addition of methionine. AB - The levels of ergothioneine (ERG), which have been shown to act as an excellent antioxidant, were determined in both fruiting bodies and mycelia of various mushroom species. We found that ERG accumulated at different levels in fruiting bodies of mushrooms and showed up to a 92.3-fold difference between mushrooms. We also found that ERG accumulated at higher levels in mycelia than in fruiting bodies of economically important mushroom species such as Ganoderma neo japonicum, G. applanatum and Paecilomyces tenuipes. The addition of 2 mM methionine (Met) to mycelial culture medium increased the ERG contents in most mushroom species tested, indicating that Met is a good additive to enhance the ERG levels in a variety of mushroom species. Taking these results into consideration, we suggest that the addition of Met to the mycelial culture medium is an efficient way to enhance the antioxidant properties in economically important mushroom species. PMID- 23983507 TI - Essential Oil Prepared from Cymbopogon citrates Exerted an Antimicrobial Activity Against Plant Pathogenic and Medical Microorganisms. AB - Essential oils are mixtures of volatile, lipophilic compounds originating from plants. Some essential oils have useful biological activities including antimicrobial, spasmolytic, antiplasmodial, and insect-repelling activities. In this study, we tested the antimicrobial activity of essential oil prepared from the aromatic plant, Cymbopogon citrates, against three important plant pathogenic and medical microorganisms, Pectobacterium carotovorum, Colletotrichum gloeosporioides, and Aspergillus niger. It effectively inhibited the growth of the bacterium, Pectobacterium carotovorum, in a dose-dependent fashion, and 0.5% of the oil inhibited the growth of bacteria completely. Similarly, the essential oil inhibited the growth of plant pathogenic fungus, Colletotrichum gloeosporioides, and the addition of 1% of essential oil completely inhibited the growth of fungus even after 5 days of culture. Finally, it effectively inhibited the growth of the medically and industrially important fungal species, Aspergillus spp. These results suggest that the essential oil from Cymbopogon citrates may be an environmentally safe alternative to inhibit antimicrobial agents for various uses. PMID- 23983508 TI - Screening of Biodegradable Function of Indigenous Ligno-degrading Mushroom Using Dyes. AB - The process of biodegradation in lingo-cellulosic materials is critically relevant to biospheric carbon. The study of this natural process has largely involved laboratory investigations, focused primarily on the biodegradation and recycling of agricultural by-products, generally using basidiomycetes species. In order to collect super white rot fungi and evaluate its ability to degrade lingo cellulosic material, 35 fungal strains, collected from forests, humus soil, livestock manure, and dead trees, were screened for enzyme activities and their potential to decolorize the commercially used Poly-R 478 dye. In the laccase enzymatic analysis chemical test, 33 white rot fungi and 2 brown rot fungi were identified. The degradation ability of polycyclic aromatic hydrocarbons (PAHs) according to the utilized environmental conditions was higher in the mushrooms grown in dead trees and fallen leaves than in the mushrooms grown in humus soil and livestock manure. Using Poly-R 478 dye to assess the PAH-degradation activity of the identified strains, four strains, including Agrocybe pediades, were selected. The activities of laccase, MnP, and Lip of the four strains with PAH degrading ability were highest in Pleurotus incarnates. 87 fungal strains, collected from forests, humus soil, livestock manure, and dead trees, were screened for enzyme activities and their potential to decolorize the commercially used Poly-R 478 dye on solid media. Using Poly-R 478 dye to assess the PAHdegrading activity of the identified strains, it was determined that MKACC 51632 and 52492 strains evidenced superior activity in static and shaken liquid cultures. Subsequent screening on plates containing the polymeric dye poly R-478, the decolorization of which is correlated with lignin degradation, resulted in the selection of a strain of Coriolus versicolor, MKACC52492, for further study, primarily due to its rapid growth rate and profound ability to decolorize poly R 478 on solid media. Considering our findings using Poly-R 478 dye to evaluate the PAH-degrading activity of the identified strains, Coriolus versicolor, MKACC 52492 was selected as a favorable strain. Coriolus versicolor, which was collected from Mt. Yeogi in Suwon, was studied for the production of the lignin modifying enzymes laccase, manganese-dependent peroxidase (MnP), and lignin peroxidase (LiP). PMID- 23983509 TI - Occurrence of Internal Stipe Necrosis of Cultivated Mushrooms (Agaricus bisporus) Caused by Ewingella americana in Korea. AB - The internal stipe necrosis of cultivated mushrooms (Agaricus bisporus) is caused by the bacterium Ewingella americana, a species of the Enterobacteriaceae. Recently, Ewingella americana was isolated from cultivated white button mushrooms in Korea evidencing symptoms of internal stipe browning. Its symptoms are visible only at harvest, and appear as a variable browning reaction in the center of the stipes. From these lesions, we isolated one bacterial strain (designated CH4). Inoculation of the bacterial isolate into mushroom sporocarps yielded the characteristic browning symptoms that were distinguishable from those of the bacterial soft rot that is well known to mushroom growers. The results of Gram stain, flagellal staining, and biochemical tests identified these isolates as E. americana. This was verified by pathogenicity, physiological and biochemical characteristics, and the results of an analysis of the 16S rRNA gene sequences and the fatty acids profile. This is the first report of the isolation of E. americana from cultivated white button mushrooms in Korea. PMID- 23983510 TI - In vitro Activity of Celery Essential Oil against Malassezia furfur. AB - Antifungal activity of celery essential oil against Malassezia furfur was investigated using broth microdilution and vapor contact methods. Potent antifungal activity was evident using both methods. Fungicidal activity was revealed in the vapor contact method. PMID- 23983511 TI - Occurrence of Clubroot on Pak-Choi Caused by Plasmodiophora brassicae. AB - Clubroot symptoms occurred severely on roots of Pak-Choi (Brassica campestris ssp. chinensis) grown in greenhouses in Gwangju city, Gyeonggi province, Korea in September, 2008. The incidence of the disease symptoms reached as high as 90% in three greenhouses investigated. The root galls collected from the greenhouses were sectioned using a scalpel and observed by light microscope. Many resting spores were found in the cells of the root gall tissues. Suspension of resting spores was prepared from the root galls and inoculated to roots of healthy Pak Choi plants. Each of five resting spore suspensions caused clubroot symptoms on the roots, which were similar to those observed during the greenhouse survey. Resting spores of the pathogen were observed in the cells of the affected roots. The clubroot pathogen was identified as Plasmodiophora brassicae based on its morphological and pathological characteristics. This is the first report that Plasmodiophora brassicae causes clubroot of Pak-Choi. PMID- 23983512 TI - Differential growth response of various crop species to arbuscular mycorrhizal inoculation. AB - To investigate the growth response of various crop species to mycorrhizal inoculation, arbuscular mycorrhizal fungi were applied to Glycine max, Vigna angularis, Senna tora, Hordeum vulgare var. hexastichon. Zea mays, Sorghum bicolor, Allium tuberosum, Solanum melongena, and Capsicum annuum. The biomass of the inoculated crops was measured every two weeks for the 12-week growth period. By measuring biomass, we calculated the mycorrhizal responsiveness of the nine crop species. Among the nine crop species, four species showed a significant response to mycorrhizal inoculation. The shoot biomasses of V. angularis, C. annuum, A. tuberosum, and S. tora significantly increased with mycorrhizal inoculation. PMID- 23983513 TI - Identification of the Fungal Pathogen that Causes Strawberry Anthracnose in Bangladesh and Evaluation of In Vitro Fungicide Activity. AB - This study was conducted to identify the Colletotrichum species causing anthracnose disease of strawberry in Balgladesh and to evaluate in vitro activity of commercial fungicides it. Based on morphological and cultural characteristics, all 22 isolates were identified as Colletotrichum gloeosporioides. They developed white or glittery colonies with grey to dark grey reverse colony colors and they produced cylindrical conidia. The efficacy of five commercial fungicides, Bavistin DF, Dithane M-45, Sulcox 50 WP, Corzim 50 WP and Rovral 50 WP, were tested against the fungus. Bavistin inhibited radial growth completely and was followed in efficacy by Dithane M-45. In Bavistin DF treated media, the fungus did not produce conidia. The percent inhibition of radial growth of the fungus was increased with the increasing concentrations of fungicide. PMID- 23983514 TI - Fungi associated with the hairs of goat and sheep in libya. AB - The mycoflora on the hair in 25 samples of each of goats and sheep collected from Libya was analyzed using two isolation methods at 25C. Seventy species and 3 varieties belonging to 31 genera were collected from the two substrates. The hairs of sheep were polluted with fungi than goat, contained high total counts and number of genera and species. Two species of true dermatophytes were isolated namely Trichophyton rubrum and T. terrestre. Several keratiophilic species were isolated of which Chrysosporium indicum, C. keratinophilum and C. tropicum were the most prevalent. The commonest saprophytes in order of frequency were members of the genera Aspergillus, Penicillium, Emericella, Alternaria and Cochliobolus. PMID- 23983515 TI - Optimal Culture Conditions for Mycelial Growth and Exo-polymer Production of Ganoderma applanatum. AB - The effect of fermentation parameters and medium composition on the simultaneous mycelial growth and exo-polymer production from submerged cultures of Ganoderma applanatum was investigated in shake-flask cultures. The optimum initial pH for mycelial growth and exo-polymer production was 5.0 and 6.0, respectively. The optimum temperature was 25C and the optimum inoculum content was 3.0% (v/v). The optimal carbon and nitrogen sources were glucose and corn steep powder, respectively. After 12 days fermentation under these conditions, the highest mycelial growth was 18.0 g/l and the highest exo-polymer production was 3.9 g/l. PMID- 23983516 TI - Culture Conditions for the Mycelial Growth of Ganoderma applanatum. AB - Ganoderma applanatum is one of the most popular medicinal mushrooms due to the various biologically active components it produces. This study was conducted to obtain basic information regarding the mycelial culture conditions of Ganoderma applanatum. Based on the colony diameter and mycelial density, PDA, YMA and MCM media were suitable for the mycelial growth of the mushroom. The optimum temperature for mycelial growth was found to be 25~30C. The optimum carbon and nitrogen sources were mannose and dextrin, respectively, and the optimum C/N ratio was 2 to 10 when 2% glucose was used. Other minor components required for the optimal growth included thiamine-HCl and biotin as vitamins, succinic acid and lactic acid as organic acids, and MgSO4.7H2O, KH2PO4 and NaCl as mineral salts. PMID- 23983517 TI - Optimal Conditions for the Mycelial Growth of Coprinus comatus Strains. AB - The principal objective of this study was to acquire basic data regarding the mycelial growth characteristics for the artificial cultivation of Coprinus comatus. 12 URP primers were employed to evaluate the genetic relationships of C. comatus, and the results were divided into three groups. Among six kinds of mushroom media, MYP medium was selected as the most favorable culture medium for C. comatus. The optimal temperature and pH ranges for the mycelial growth of C. comatus were 23~26C and pH 6~8, respectively. The carbon and nitrogen sources for optimal mycelial growth were sucrose and tryptone, respectively. PMID- 23983518 TI - Determination of mineral components in the cultivation substrates of edible mushrooms and their uptake into fruiting bodies. AB - The mineral contents of the cultivation substrates, fruiting bodies of the mushrooms, and the postharvest cultivation substrates were determined in cultivated edible mushrooms Pleurotus eryngii, Flammulina velutipes, and Hypsizigus marmoreus. The major mineral elements both in the cultivation substrates and in the fruiting bodies were K, Mg, Ca, and Na. Potassium was particularly abundant ranging 10~13 g/kg in the cultivation substrates and 26~30 g/kg in the fruiting bodies. On the contrary, the calcium content in the fruiting bodies was very low despite high concentrations in the cultivation substrates, indicating Ca in the cultivation substrates is in a less bio-available form or the mushrooms do not have efficient Ca uptake channels. Among the minor mineral elements determined in this experiment, Cu, Zn, and Ni showed high percentage of transfer from the cultivation substrates to the fruiting bodies. It is noteworthy that the mineral contents in the postharvest cultivation substrates were not changed significantly which implies that the spent cultivation substrates are nutritionally intact in terms of mineral contents and thus can be recycled as mineral sources and animal feeds. PMID- 23983519 TI - Isolation, Identification and Optimal Culture Conditions of Streptomyces albidoflavus C247 Producing Antifungal Agents against Rhizoctonia solani AG2-2. AB - Streptomyces albidoflavus C247 was isolated from the soil of the Gyeongsan golf course in Korea. Physiological, biochemical and 16S rDNA gene sequence analysis strongly suggested that the isolate belonged to Streptomyces albidoflavus. Preliminary screening revealed that the isolate was active against fungi and bacteria. Self-directing optimization was employed to determine the best combination of parameters such as carbon and nitrogen source, pH and temperature. Nutritional and culture conditions for the production of antibiotics by this organism under shake-flask conditions were also optimized. Maltose (5%) and soytone (5%) were found to be the best carbon and nitrogen sources for the production of antibiotics by S. albidoflavus C247. Additionally, 62.89% mycelial growth inhibition was achieved when the organism was cultured at 30C and pH 6.5. Ethyl acetate (EtOAc) was the best extraction solvent for the isolation of the antibiotics, and 100 ug/ml of EtOAc extract was found to inhibit 60.27% of the mycelial growth of Rhizoctonia solani AG2-2(IV) when the poison plate diffusion method was conducted. PMID- 23983520 TI - Purification and Characterization of Intracellular Cellulase from Aspergillus oryzae ITCC-4857.01. AB - Purification and characterization of intracellular cellulase produced by A. oryzae ITCC-4857.01 are reported. The enzyme was purified by ion-exchange chromatography using DEAE-cellulose followed by Gel filtration. The purification achieved was 41 fold from the crude extract with yield of 27%. The purified enzyme showed single band on poly acrylamide gel. The molecular weight as determined by SDS-PAGE and gel filtration was 38 KDa and 38.6 KDa respectively and contained only one subunit. The enzyme is glycoprotien as nature and contained 0.67% neutral sugar. The apparent Km value of the enzyme against cellulose was 0.83%. The enzyme showed the highest relative ativities on CMC followed by avicel, salicin and filter paper. The optimum pH of activity was 5.5 and very slight activity was observed at or above pH 7.5 as well as bellow pH 3.5. The optimum tempreture of the activity was 45C and the highest activity was exhibited in 35 to 45C. The enzyme lost their activities almost completely (95~100%) at 80 C or above and as well as bellow 25C. PMID- 23983521 TI - Antitumor Effects and Immunomodulating Activities of Phellinus linteus Extract in a CT-26 Cell-Injected Colon Cancer Mouse Model. AB - The antitumor effects of Phellinus linteus extract (Keumsa Linteusan) were investigated in a CT-26 cell-injected colon cancer mouse model. When administered orally (250~1,000 mg/kg body weight), Keumsa Linteusan significantly inhibited the growth of solid colon cancer. The highest dose was highly effective, reducing tumor formation by 26% compared with the control group. The anticomplementary activity of Keumsa Linteusan increased in a dose-dependent manner. Lysosomal enzyme activity of macrophages was increased by 2-fold (100 ug/ml) compared with the control group. Keumsa Linteusan can be regarded as a potent enhancer of the innate immune response, and can be considered as a very promising candidate for antitumor action. PMID- 23983522 TI - Improved Bioethanol Production Using Activated Carbon-treated Acid Hydrolysate from Corn Hull in Pachysolen tannophilus. AB - To optimally convert corn hull, a byproduct from corn processing, into bioethanol using Pachysolen tannophlius, we investigated the optimal conditions for hydrolysis and removal of toxic substances in the hydrolysate via activated carbon treatment as well as the effects of this detoxification process on the kinetic parameters of bioethanol production. Maximum monosaccharide concentrations were obtained in hydrolysates in which 20 g of corn hull was hydrolyzed in 4% (v/v) H2SO4. Activated carbon treatment removed 92.3% of phenolic compounds from the hydrolysate. When untreated hydrolysate was used, the monosaccharides were not completely consumed, even at 480 h of culture. When activated carbon-treated hydrolysate was used, the monosaccharides were mostly consumed at 192 h of culture. In particular, when activated carbon-treated hydrolysate was used, bioethanol productivity (P) and specific bioethanol production rate (Qp) were 2.4 times and 3.4 times greater, respectively, compared to untreated hydrolysate. This was due to sustained bioethanol production during the period of xylose/arabinose utilization, which occurred only when activated carbon-treated hydrolysate was used. PMID- 23983523 TI - Antifungal Activities of Copper(II) with Biosensitive Macrocyclic Schiff Base Ligands Derived from 4-Aminoantipyrine Derivatives. AB - Novel copper(II) complexes have been synthesized from the macrocyclic Schiff bases derived from Knoevenagel condensed beta-ketoanilides (obtained by the condensation of acetoacetanilide and substituted benzaldehydes), 4 aminoantipyrine and o-phenylene diamine. The structural features have been determined from their analytical and spectral data. All the Cu(II) complexes exhibit square planar geometry. Their high molar conductance values support their 1: 2 electrolytic nature. The magnetic moment data provide evidence for the monomeric nature of the complexes. The X-band ESR spectra of the [CuL(1)](OAc)2 in DMSO solution at 300 and 77 K were recorded and their salient features are reported. The in vitro biological screening effects of the investigated compounds were tested against the bacterial species Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris and Pseudomonas aeruginosa and fungal species Aspergillus niger, Rhizopus stolonifer, Aspergillus flavus, Rhizoctonia bataicola and Candida albicans by well diffusion method. A comparative study of inhibition values of the Schiff bases and their complexes indicate that complexes exhibit higher antimicrobial activity than the Schiff bases. Copper ions proved to be essential for the growth-inhibitor effect. The extent of inhibition appeared to be strongly dependent on the initial cell density and on the growth medium. PMID- 23983524 TI - The Wood-rotting Fungal Flora of Three Islands in the Yellow Sea, Korea. AB - The wood-rotting fungi of three Korean islands in the Yellow Sea, Soyeonpyung-do (SY), Oeyeon-do (OY), and Gageo-do (GG), were investigated from October 2004 to November 2005. During four sampling trips on each island, a total of 46, 44, and 44 specimens were collected from SY, OY, and GG, respectively. The identified wood-rotting fungi from SY included 29 species of 22 genera and nine families; OY had 31 species of 26 genera and 10 families; and GG had 34 species of 27 genera and 11 families. The majority of the fungi were in the Polyporaceae, which was represented by 23 genera and 30 species. Auricularia polytricha, Daedaleopsis tricolor, Daldinia concentrica, Hymenochaete cinnamomea, Hymenochaete yasudai, Hyphoderma setigerum, Lopharia mirabilis, Schizopora paradoxa, and Trametes versicolor were collected from all three islands. PMID- 23983525 TI - New Record of the Existence of Sarcographa tricosa (Lichenized Ascomycota, Graphidaceace) in Korea. AB - Lichen genus Sarcographa Fee, a stromatoid Graphidacean taxa, was newly found in Geomun Island, Jeonnam province. The lichen grew on the bark of Camellia japonica and Eurya emarginata along the coastal line of the island. It was identified as Sarcographa tricosa (Ach.) Mull. Arg. for the first time in Korea. PMID- 23983526 TI - Occurrence of Dumontinia tuberosa in Korea. AB - Thirty-seven single spore isolates were obtained from specimens of ascomycetous fruiting bodies collected from Mt. Suri, Anyang in Korea. The fungal specimens and isolates were identified as Dumontinia tuberosa based on their morphological and cultural characteristics. This is the first record of this fungus occurring in Korea. PMID- 23983527 TI - Occurrence of Fruit Rot of Melon Caused by Sclerotium rolfsii in Korea. AB - In 2007 to 2008, a fruit rot of Melon (Cucumis melo L.) caused by Sclerotium rolfsii occurred sporadically in a farmer's vinyl house in Jinju City. The symptoms started with watersoaking lesion and progressed into the rotting of the surface of fruit. White mycelial mats appeared on the lesion at the surface of the fruit and a number of sclerotia formed on the fruit near the soil line. The sclerotia were globoid in shape, 1~3 mm in size, and white to brown in color. The hyphal width was measured 3 to 8 um. The optimum temperature for mycelial growth and sclerotia formation was 30 on PDA. Typical clamp connections were observed in hyphae of grown for 4 days on PDA. On the basis of symptoms, mycological characteristics and pathogenicity to the host plant, this fungus was identified as Sclerotium rolfsii Saccardo. This is the first report of the fruit rot of Melon caused by S. rolfsii in Korea. PMID- 23983528 TI - The Stress-Activated Signaling (SAS) Pathways of a Human Fungal Pathogen, Cryptococcus neoformans. AB - Cryptococcus neoformans is a basidiomycete human fungal pathogen that causes meningoencephalitis in both immunocompromised and immunocompetent individuals. The ability to sense and respond to diverse extracellular signals is essential for the pathogen to infect and cause disease in the host. Four major stress activated signaling (SAS) pathways have been characterized in C. neoformans, including the HOG (high osmolarity glycerol response), PKC/Mpk1 MAPK (mitogen activated protein kinase), calcium-dependent calcineurin, and RAS signaling pathways. The HOG pathway in C. neoformans not only controls responses to diverse environmental stresses, including osmotic shock, UV irradiation, oxidative stress, heavy metal stress, antifungal drugs, toxic metabolites, and high temperature, but also regulates ergosterol biosynthesis. The PKC (Protein kinase C)/Mpk1 pathway in C. neoformans is involved in a variety of stress responses, including osmotic, oxidative, and nitrosative stresses and breaches of cell wall integrity. The Ca(2+)/calmodulin- and Ras-signaling pathways also play critical roles in adaptation to certain environmental stresses, such as high temperature and sexual differentiation. Perturbation of the SAS pathways not only impairs the ability of C. neoformans to resist a variety of environmental stresses during host infection, but also affects production of virulence factors, such as capsule and melanin. A drug(s) capable of targeting signaling components of the SAS pathway will be effective for treatment of cryptococcosis. PMID- 23983529 TI - Molecular Genetics of Emericella nidulans Sexual Development. AB - Many aspergilli that belongs to ascomycetes have sexuality. In a homothallic or self-fertile fungus, a number of fruiting bodies or cleistothecia are formed in a thallus grown from a single haploid conidia or ascospores. Genome-sequencing project revealed that two mating genes (MAT) encoding the regulatory proteins that are necessary for controlling partner recognition in heterothallic fungi were conserved in most aspergilli. The MAT gene products in some self-fertile species were not required for recognition of mating partner at pheromone signaling stage but required at later stages of sexual development. Various environmental factors such as nutritional status, culture conditions and several stresses, influence the decision or progression of sexual reproduction. A large number of genes are expected to be involved in sexual development of Emericella nidulans (anamorph: Aspergillus nidulans), a genetic and biological model organism in aspergilli. The sexual development process can be grouped into several development stages, including the decision of sexual reproductive cycle, mating process, growth of fruiting body, karyogamy followed by meiosis, and sporulation process. Complicated regulatory networks, such as signal transduction pathways and gene expression controls, may work in each stage and stage-to-stage linkages. In this review, the components joining in the regulatory pathways of sexual development, although they constitute only a small part of the whole regulatory networks, are briefly mentioned. Some of them control sexual development positively and some do negatively. Regarding the difficulties for studying sexual differentiation compare to asexual one, recent progresses in molecular genetics of E. nidulans enlarge the boundaries of understanding sexual development in the non-fertile species as well as in fertile fungi. PMID- 23983530 TI - Phylogenetic Relationship in Different Commercial Strains of Pleurotus nebrodensis Based on ITS Sequence and RAPD. AB - The molecular phylogeny in nine different commercial cultivated strains of Pleurotus nebrodensis was studied based on their internal transcribed spacer (ITS) region and RAPD. In the sequence of ITS region of selected strains, it was revealed that the total length ranged from 592 to 614 bp. The size of ITS1 and ITS2 regions varied among the strains from 219 to 228 bp and 211 to 229 bp, respectively. The sequence of ITS2 was more variable than ITS1 and the region of 5.8S sequences were identical. Phylogenetic tree of the ITS region sequences indicated that selected strains were classified into five clusters. The reciprocal homologies of the ITS region sequences ranged from 99 to 100%. The strains were also analyzed by RAPD with 20 arbitrary primers. Twelve primers were efficient to applying amplification of the genomic DNA. The sizes of the polymorphic fragments obtained were in the range of 200 to 2000 bp. RAPD and ITS analysis techniques were able to detect genetic variation among the tested strains. Experimental results suggested that IUM-1381, IUM-3914, IUM-1495 and AY 581431 strains were genetically very similar. Therefore, all IUM and NCBI gene bank strains of P. nebrodensis were genetically same with some variations. PMID- 23983531 TI - Taxonomic study of peltigera (peltigeraceae, ascomycota) in Korea. AB - A taxonomic study of Peltigera in South Korea was performed. The phylogenetic analysis based on nr DNA internal transcribed spacer sequences suggests that Peltigera is a well-supported monophyletic group. Important characteristics are the phycobiont type of thallus and the vein type at the lower cortex (wide and flat, or narrow and ridged). The vertical or horizontal arrangement of the apothecia is also important in distinguishing species in this genus. Eleven species of Peltigera were revealed and confirmed, which included one new record, P. elisabethae. A description of each species is presented with morphological, anatomic, and chemical characteristics, and comparisons between similar species are made. A key to the species is also presented. PMID- 23983532 TI - Notes on Some New Records of Macro- and Micro-lichens from Korea. AB - The paper describes nine new records of macro- and micro-lichens from Korea. A brief taxonomic description and comments are presented for all the studied taxa (Catapyrenium squamellum, Chrysothrix candelaris, Endocarpon pallidulum, Endocarpon petrolepideum, Lecanora oreinoides, Leprocaulon albicans, Parmotrema saccatilobum, Verrucaria glaucina and Xanthoria parietina). The lichen genera Catapyrenium, Chrysothrix and Verrucaria are reported for the first time in this country. PMID- 23983533 TI - Nutritional and Physicochemical Characteristics of the Antidementia Acetylcholinesterase-Inhibiting Methanol Extracts from Umbilicaria esculenta. AB - To develop new antidementia nutraceuticals, a potent acetylcholinesterase (AChE) inhibiting extract was screened from various extracts of nutritional mushrooms and lichens nutritional and its physicochemical properties were investigated. Among the several extracts tested, methanol extracts of Umbilicaria esculenta fruiting body showed the highest AChE inhibitory activity of 22.4%. U. esculenta AChE inhibitor was maximally extracted when fruiting bodies were treated with 80% methanol at 40C for 18 h. The methanol extracts contained 18.9% crude lipid, 18.8% crude protein, and 11.6% total sugar. In addition, they contained 444 mg/g glutamic acid, 44 mg/g histidine, and 41 mg/g aspartic acid. The methanol extracts were soluble in a solution of methanol and 20% dimethylsulfoxide, insoluble in n-hexane, chloroform, and water, and were stable at 20~60C and pH 1.0~5.0 for 1 h. PMID- 23983534 TI - Chemical Constituents of the Fruiting Body of Xylaria polymorpha. AB - Xylaria, belonging to the Ascomycotina, is known to produce diverse classes of bioactive substances. In an effort to identify the chemical constituents of the fruiting bodies of Xylaria polymorpha, linoleic acid (1), linoleic acid methyl ester (2), ergosterol (3), 4-acetyl-3,4-dihydro-6,8-dihydroxy-3-methoxy-5-methyl 1H-2-benzopyran-1-one (4), and 4-hydroxyscytalone (5) were isolated from its methanolic extract. Their structures were assigned on the basis of various spectroscopic studies. PMID- 23983535 TI - Optimal Conditions for Antimicrobial Metabolites Production from a New Streptomyces sp. RUPA-08PR Isolated from Bangladeshi Soil. AB - An actinomycete strain was isolated from northern part of Bangladesh and identified as a new Streptomyces species on the basis of its morphological, biochemical, cultural characteristics and 16S rRNA data. Attempts were made to optimize the culture conditions for the production of antimicrobial metabolites by this strain. Antimicrobial metabolites production was started after 7 days of incubation of culture broth and reached its maximum levels after 10 days and thereafter gradually decreased. The maximum production of antimicrobial metabolites was obtained when the culture medium pH was adjusted to 8. The optimum temperature for antimicrobial metabolites production was 39C, indicated the new strain as mesophilic organism. Basel medium supplemented with glucose and yeast extract as carbon and nitrogen sources, respectively, was proved to be the best for the production of bioactive metabolites. Maximum production of bioactive metabolites was when NaCl concentration was 1% and among different minerals tested, K2HPO4 and NaCl showed positive influence on antibiotic production by the strain. PMID- 23983537 TI - Production of Blastospore of Entomopathogenic Beauveria bassiana in a Submerged Batch Culture. AB - The principal objective of this study was to determine the optimal liquid culture conditions in shake flasks for maximal sporulation of Beauveria bassiana. The optimal initial pH for the spore production of B. bassiana using Potato Dextrose Broth was 5.2. The screening in shake flasks of carbon and nitrogen sources resulted in the identification of an optimal medium based on 3% sucrose and 1% casamino acid, with a C : N ratio of 22 : 4. Using this medium, a production level of 5.65 * 10(7) spores per ml was obtained after 5 days of culture. Using 3% corn meal, 2% corn steep powder, and 2% rice bran, the maximum spore concentration of 8.54 * 10(8)/ml was achieved 8 days after inoculation at 25C in a rotary shaking incubator operated at 200 rpm. This represents a yield gain of approximately 2.89 times that of pre-optimization. PMID- 23983536 TI - Grading of fermented and dried cocoa beans using fungal contamination, ergosterol index and ochratoxin a production. AB - Sixty four samples of cocoa beans replicated in quadruplicates were collected from five warehouses from southwest Nigeria and examined for fungal loads, ergosterol and ochratoxin A The levels of all the variables obtained were further used as indices for cocoa grading into food quality, FoQ (erg < 5 mg/kg; OTA < 1 ug/kg), feed quality, FeQ (erg = 5~10 mg/kg; OTA in the range of 1.1~3.11 ug/kg), Screen for mycotoxin, SFM (erg = 10~20 mg/kg; OTA from 3.12 ug/kg and above) with fuel quality, FuQ having erg > 20 mg/kg and OTA > 6.12 ug/kg. Using these ergosterol indices, 18.75% of the cocoa beans examined was classified with the FoQ, 18.75% with the FuQ while 31.25% was classified with both the FeQ and the SFM, respectively. In conclusion, ergosterol can be used as a rapid index to grade fermented, dried cocoa beans meant for export. PMID- 23983538 TI - Chinese Cabbage Clubroot Pathogen, Plasmodiophora brassicae, Is Genetically Stable. AB - Single spore isolates of Plasmodiophora brassicae e4 and e9 obtained from diseased Chinese cabbage were identified as race 4 and race 9, respectively, by the Williams' differential variety set. To confirm the possibility of variation in same generation and progeny of a single spore isolate of P. brassicae, random amplified polymorphic DNA (RAPD) analysis was conducted using the URP 3, 6 and OPA 7 primers. There was no difference in band type at each part of the gall of Chinese cabbage obtained by inoculation of e4 and e9 and amplification using the URP 3 and 6 primers when the same generation was analyzed. In addition, the progeny analysis, which was expanded to the third generation and conducted using the URP 3 and OPA 7 primers, revealed no differences in the band type of the e4 isolate. Based on these results, the single spore isolate of P. brassicae was genetically stable. PMID- 23983539 TI - Isolation of Genes Specifically Expressed in Different Developmental Stages of Pleurotus ostreatus Using Macroarray Analysis. AB - The oyster mushroom (Pleurotus ostreatus) is one of the most important edible mushrooms worldwide. The mechanism of P. ostreatus fruiting body development has been of interest both for the basic understanding of the phenotypic change of the mycelium-fruiting body and to improve breeding of the mushrooms. Based on our previous publication of P. ostreatus expressed sequence tag database, 1,528 unigene clones were used in macroarray analysis of mycelium, fruiting body and basidiospore developmental stages of P. ostreatus. Gene expression profile databases generated by evaluating expression levels showed that 33, 10, and 94 genes were abundantly expressed in mycelium, fruiting body and basidiospore developmental stages, respectively. Among them, the genes specifically expressed in the fruiting body stage were further analyzed by reverse transcription polymerase chain reaction and Northern blot to investigate temporal and spatial expression patterns. These results provide useful information for future studies of edible mushroom development. PMID- 23983540 TI - Occurrence of Fuligo gyrosa Causing Slime Mold of Oriental Melon. AB - Recently, a severe slime mold infestation affected oriental melon plants in fields in Chilgok county, Gyeongbuk province, Korea. Specimens were collected from the fields and examined for identification. A species of Myxomycetes, Fuligo gyrosa, was identified based on its morphological characteristics. This is the first report that F. gyrosa causes slime mold of oriental melon. PMID- 23983541 TI - An efficient method to prepare PCR cloning vectors. AB - An improved procedure for preparing PCR cloning vectors was developed. This procedure includes the incorporation of adapters to create XcmI restriction enzyme sites in pBluescript II SK(+) vectors, digestion with XcmI followed by further digestion of the small fragment produced by XcmI digestion with additional enzymes, and purification with PCR purification kits. Using this procedure, PCR cloning vectors with high ligation efficiencies and low blue or false-positive colonies were obtained. PMID- 23983542 TI - In vitro Antifungal Activity of Limonene against Trichophyton rubrum. AB - In this study, the antifungal activities of limonene against Trichophyton rubrum were evaluated via broth microdilution and vapor contact assays. In both assays, limonene was shown to exert a potent antifungal effect against T. rubrum. The volatile vapor of limonene at concentrations above 1 ul/800 ml air space strongly inhibited the growth of T. rubrum. The MIC value was 0.5% v/v in the broth microdilution assay. The antifungal activity of limonene against T. rubrum was characterized as a fungicidal effect. PMID- 23983543 TI - Mating Types and Optimum Culture Conditions for Sexual State Formation of Fusarium fujikuroi Isolates. AB - Twenty-five isolates of Fusarium fujikuroi acquired from rice seeds and rice plants evidencing symptoms of Bakanae disease were evaluated to determine their mating types and characterize the formation of their sexual state. The mating types of the isolates were evaluated via multiplex PCR with the diagnostic primers of the mating-type (MAT) region: GFmat1a, GFmat1b, GFmat2c, and GFmat2d. Among the 25 isolates, 11 were identified as MAT-1 (male), and 14 as MAT-2 (female). Four MAT-1 isolates and three MAT-2 isolates were mated and cultured to evaluate the optimal culture conditions for the production of their sexual states. Among four tested media, 10% V8 juice agar proved optimal for the perithecial production of the isolates. The isolates also generated the largest numbers of perithecia when incubated at 23C in alternating cycles of 12 hr fluorescent light and NUV fluorescent light and 12 hr darkness. PMID- 23983544 TI - Identification and Characterization of Eurotium rubrum Isolated from Meju in Korea. AB - We isolated and identified a strain of Eurotium rubrum from Meju that has not been reported in Korea. This fungus is yellowish brown; reverse dark brown on CYA and PDA while yellow on 2% MEA at 25C. Cleistothecia are first bright yellow and gradually turned brown. Mycerial growth on CYA attained a diameter of 30 mm at 20C, 37 mm at 25C and 32 mm at 30C after 15 days. The isolate grew slower on 2% MEA (< 20 mm 15 days at 25C) compared to CYA and PDA (< 40 mm 15 days at 25C). Cleistothecia are superficial, yellow to light brown, globose to subglobose, 40~75 um in diameter. Asci are 8-spored and globose to subglobose 8~11 um. Ascospores are disciform, 4.0~5.0 um in length and 4.2~4.5 um in width. Conidia are ovate or bacillar, finely roughened to densely spinulose, 4.6~6.0 um in length and 3.0~4.3 um in width. Compared to known Eurotium rubrum, the Korean isolate showed 99% sequence similarity in ITS rDNA (554 bp) and calmodulin (750 bp) gene and 100% in beta-tubulin (1016 bp) gene. The E. rubrum isolate also had weak beta-glucosidase and protease activities. PMID- 23983545 TI - Vegetative Growth and Phylogenetic Relationship of Commercially Cultivated Strains of Pleurotus eryngii based on ITS sequence and RAPD. AB - Pleurotus eryngii, known as king oyster mushroom has been widely used for nutritional and medicinal purposes. This study was initiated to screen the suitable conditions for mycelial growth and to determine the phylogenetic relationship of the selected strains. Optimal mycelial growth was observed at 30C and minimum mycelial growth observed at 10C. This mushroom tolerates a broad pH range for mycelial growth, with most favorable growth observed at pH 6. Results also indicated that glucose peptone, yeast malt extract and mushroom complete media were favorable growth media, while Hennerberg and Hoppkins media were unfavorable. Dextrin was the best and xylose the least effective carbon sources. Results revealed that inorganic nitrogen sources were less effective than organic sources for the mycelial growth of P. eryngii. Investigation of genetic diversity is necessary to identify the strains. The ITS region of rDNA were amplified using PCR. The size of the ITS1 and ITS2 regions of rDNA from the different strains varied from 214 to 222 bp and 145 to 236 bp, respectively. The sequence of ITS2 was more variable than that of ITS1, and the 5.8S sequences were identical. A phylogenetic tree based on the ITS region sequences indicated that selected strains could be classified into six clusters. Fourteen IUM and ATCC-90212 strains were also analyzed by RAPD with 20 arbitrary primers. Fourteen of these primers were efficiently amplified the genomic DNA. The number of amplified bands varied with the primers and strains, with polymorphic fragments in the range from 0.2 to 2.3 kb. PMID- 23983546 TI - Fungal strain improvement for cellulase production using repeated and sequential mutagenesis. AB - A fungal strain producing a high level of cellulase was selected from 320 fungal isolates and identified as Aspergillus sp. This strain was further improved for cellulase production by sequential treatments by two repeated rounds of gamma irradiation of Co(60), ultraviolet treatment and four repeated rounds of treatment with N-methyl-N'-nitro-N-nitrosoguanidine. The best mutant strain, Aspergillus sp. XTG-4, was selected after screening and the activities of carboxymethyl cellulase, filter paper cellulase and beta-glucosidase of the cellulase were improved by 2.03-, 3.20-, and 1.80-fold, respectively, when compared to the wild type strain. After being subcultured 19 times, the enzyme production of the mutant Aspergillus sp. XTG-4s was stable. PMID- 23983547 TI - Effect of organic farming on spore diversity of arbuscular mycorrhizal fungi and glomalin in soil. AB - In this study, eight soil samples were collected from organic and conventional farms in a central area of South Korea. Spore communities of arbuscular mycorrhizal fungi (AMF) and glomalin, a glycoprotein produced by AMF, were analyzed. Spores of Glomus clarum, G. etunicatum, G. mosseae, G. sp., Acaulospora longula, A. spinosa, Gigaspora margarita, and Paraglomus occultum were identified at the study sites, based on morphological and molecular characteristics. While Acaulospora longula was the most dominant species in soils at organic farms, Paraglomus occultum was the most dominant species in soils at conventional farms. Species diversity and species number in AMF communities found in soils from organic farms were significantly higher than in soils from conventional farms. Glomalin was also extracted from soil samples collected at organic and conventional farms and was analyzed using both Bradford and enzyme-linked immunosorbent assays. The glomalin content in soils from organic farms was significantly higher than in soils from conventional farms. These results indicate that agricultural practices significantly affect AMF abundance and community structure. PMID- 23983548 TI - Screening of Trichoderma Isolates as a Biological Control Agent against Ceratocystis paradoxa Causing Pineapple Disease of Sugarcane. AB - In this study, dual culture, poison agar, and direct methods were used to assess the ability of Trichoderma virens IMI-392430, T. pseudokoningii IMI-392431, T. harzianum IMI-392432, T. harzianum IMI-392433, and T. harzianum IMI-392434 to control Ceratocystis paradoxa, which causes the pineapple disease of sugarcane. The highest percentage inhibition of radial growth (PIRG) values were observed with T. harzianum IMI-392432 using two dual culture methods, 63.80% in Method I and 80.82% in Method II. The minimum colony overgrowth time was observed with T. harzianum IMI-392432 and the maximum was observed with T. pseudokoningii IMI 392431. Different concentrations of different day-old metabolites of Trichoderma isolates were tested against mycelial growth of C. paradoxa. The highest PIRG (84.685%) exhibited at 80% concentration of 30-day-old metabolites of T. harzianum IMI-392432 using the modified bilayer poison agar method. In the direct assay method the maximum mycelial growth weight (PIGW) was observed at the same concentration and the same day-old metabolites of T. harzianum IMI-392432. This study showed that Trichoderma isolates have a good antagonistic effect on C. paradoxa mycelial growth and T. harzianum IMI-392432 has the most potential to control the pineapple disease pathogen. PMID- 23983549 TI - Composition and partial structure characterization of tremella polysaccharides. AB - Heteropolysaccharides isolated from liquid cultures of nine Tremella species contained 0.3 to 1.2% protein, 2.7 to 5% ash, 0.9 to 3.4% acetyl groups, 76.5 to 84.2% carbohydrates and trace amounts of starch. The polysaccharides in aqueous solution were slightly acidic (pH 5.1 to 5.6). They consisted of the following monomeric sugars: fucose, ribose, xylose, arabinose, mannose, galactose, glucose and glucuronic acid. The backbones of the polysaccharide structures consisted of alpha-(1->3)-links while the side chains were beta-linked. PMID- 23983550 TI - New species of agaricales. AB - Clitocybe alboinfundibulliforme sp. nov. is widely distributed in Korea. Volvariella koreana sp. nov. is rarely distributed in Korea. These taxa were occasionally found together at the same place. Both of these species seem to be associated with each other. These two species are fully described and illustrated in this paper. PMID- 23983551 TI - A new species of the genus coreomyces (laboulbeniales ascomycotina) collected from the island of java, indonesia. AB - One new species of the genus Coreomyces was collected on Micronecta sedula from the island of Java; C. javanicus sp. nov. is very similar to and apparently closely related to C. corixae. This species is characterized by a receptacle that is bent towards one side with cell I, nearly rounded. The length of cell I is equal to that of cell II and the perithecia are longitudinal, elliptical or cylindrical. Thalli consistently occurred on the margin of the left elytron of the hosts. PMID- 23983552 TI - Thelotrema subtile and Verrucaria muralis New to Korea. AB - The paper describes two new records of micro-lichens from South Korea. Detailed taxonomic descriptions and comments are presented for both of the studied taxa. The lichen genus Thelotrema is reported for the first time in Korea. PMID- 23983553 TI - First Report of Ceriporiopsis resinascens (Phanerochaetaceae, Basidiomycota) in Korea. AB - An unrecorded Ceriporiopsis species was collected at Mt. Gariwang, Gangwon Province, in 2008. Based on morphological characteristics, such as a fully resupinate basidiocarp, a reddish white to pinkish poroid hymenophore and a monomitic hyphal system with clamp connections, the species was identified as Ceriporiopsis resinascens. This is the first report of Ceriporiopsis resinascens in Korea. We confirmed the identity of the species as Ceriporiopsis resinascens based on ITS sequence analysis. PMID- 23983554 TI - Lasiodiplodia theobromae is a Mycoparasite of a Powdery Mildew Pathogen. AB - Powdery mildews on over 40 plants in Bangalore were screened during July-December of 2003~2008. Isolates from mycoparasitised Oidium caesalpiniacearum of Bauhinia purpurea comprised Lasiodiplodia theobromae, in addition to Ampelomyces quisqualis. Koch's postulates were satisfied to establish the mycoparasitism of L. theobromae. This is the first report that L. theobromae acts as a mycoparasite of a powdery mildew. PMID- 23983555 TI - Occurrence of anthracnose on highbush blueberry caused by colletotrichum species in Korea. AB - A total of 82 isolates of Colletotrichum species were obtained from anthracnose symptoms of highbush blueberry trees grown in the Gochang area of Korea during a disease survey in 2008. Out of the isolates, 75 were identified as Colletotrichum gloeosporioides and the others as C. acutatum based on their morphological and cultural characteristics. Twenty six of C. gloeosporioides isolates produced their teleomorph Glomerella cingulata in PDA culture. Three isolates of each C. gloeosporioides and C. acutatum caused anthracnose symptoms on the leaves by artificial inoculation, which were similar to what was observed in the orchards. Previously in Korea, only C. gloeosporioides has been reported as causing anthracnose in blueberries. This is the first report that C. acutatum causes anthracnose in the highbush blueberry in Korea. PMID- 23983556 TI - Optimal Medium Conditions for the Detection of Cellulolytic Activity in Ganoderma lucidum. AB - To determine the optimal medium conditions for the detection of the cellulolytic activity in Ganoderma lucidum, we varied three media conditions: dye reagent, pH, and temperature. First, we evaluated the use of four dyes, Congo Red, Phenol Red, Remazol Brilliant Blue, and Trypan Blue. To observe the effect of pH on the chromogenic reaction, we also made and tested various media spanning acidic and alkaline pHs, ranging from 4.5 to 8.0. Furthermore, in order to research the effect of temperature on the clear zone and the fungus growing zone, we tested temperatures ranging from 15 to 35C. On the whole, the best protocol called for Ganoderma lucidum transfer onto media containing Congo red with pH adjusted to 7.0, followed by incubation at 25C for 5 days. Our results will be useful to researchers who aim to study extracellular enzyme activity in Ganoderma lucidum. PMID- 23983557 TI - Development of Specific Primer for Tricholoma matsutake. AB - In this study, in an effort to develop a method for the molecular detection of Tricholoma matsutake in Korea from other closely related Tricholomataceae, a species-specific PCR primer pair, TmF and TmR, was designed using nuclear ribosomal intertranscribed spacer (ITS) sequences. The DTmF and DTmR sequences were 5'-CCTGACGCCAATCTTTTCA-3' and 5'-GGAGAGCAGACTTGTGAGCA-3', respectively. The PCR primers reliably amplified only the ITS sequences of T. matsutake, and not those of other species used in this study. PMID- 23983558 TI - Impact of an education program on patient anxiety, depression, glycemic control, and adherence to self-care and medication in Type 2 diabetes. AB - BACKGROUND: Diabetes mellitus (DM) requires continuous medical care, patients' self-management, education, and adherence to prescribed medication to reduce the risk of long-term complications. The aim of this study was to assess the benefits of an education program on diabetes, patient self-management, adherence to medication, anxiety, depression and glycemic control in type 2 diabetics in Saudi Arabia. MATERIALS AND METHODS: This was a prospective study, conducted among 104 diabetic patients at a major tertiary hospital in Riyadh, Saudi Arabia, between May 2011 and October 2012. Education materials given to diabetic patients included pamphlets/handouts written in Arabic, the national language. Special videotapes about DM were made and distributed to all participants. In addition, specific educational programs through the diabetes educators and one-on-one counseling sessions with the doctor were also arranged. Patients were interviewed using a structured interview schedule both during the baseline, and after 6 months of the program. The interview schedule included, socio-demographics, clinical characteristics, diabetes self-management, adherence to medication, anxiety, and depression. Glycemic control was considered poor, if hemoglobin A1c (HbA1c) was >= 7%. RESULTS: The mean age of the study population was 57.3 +/- 14.4 years. Seventy one were males (68.3%) and 33 (31.7%) were females. After six months of the diabetes education program, there were significant improvements in patients' dietary plan (P = 0.0001), physical exercise (P = 0.0001), self monitoring of blood glucose (SMBG) (P = 0.0001), HbA1c (P = 0.04), adherence to medication (P = 0.007), and depression (P = 0.03). CONCLUSIONS: Implementation of education programs on diabetes among type 2 diabetic patients is associated with better outcomes such as their dietary plan, physical exercise, SMBG, adherence to medication, HbA1c and depression. PMID- 23983559 TI - The association between watching television and obesity in children of school-age in Saudi Arabia. AB - BACKGROUND: There is little information on the association between watching Television (TV) and obesity in the Arabian Peninsula. AIM OF THE STUDY: The aim of this study was to explore the association between the watching of television and obesity in Saudi children of school-age. MATERIALS AND METHODS: A case controlled study was conducted with students between the ages of 9 and 14 years who attended the school health clinic in King Abdulaziz Housing for National Guard (Iskan), Riyadh, Saudi Arabia, during the study period (February to April 2012). During each clinic, children were selected by simple random sampling (five obese and five non-obese). For data collection, two trained physicians interviewed the participants using a 20-item Arabic questionnaire. Well-trained nurses collected the anthropometric measurements of weight and height. RESULTS: The study included 397 students. Higher (body mass index) BMI was associated with a higher number of televisions at home (P < 0.001), watching TV for more than three hours per day at the weekend (P = 0.047), eating more than three snacks per day (P = 0.005), watching TV at night (P = 0.026), and siblings' decisions on how much TV to watch (P = 0.025). The prevalence of childhood obesity was significantly lower among those whose mothers determined how much TV they could watch (P = 0.03). In logistic regression analysis, the increase in the child's age, the presence of more than one TV at home, having his or her own TV, and an increase in the number of hours of watching TV over the weekend were significantly associated with an increased risk of childhood obesity. Personal computers and the Internet were not significantly associated with an increased risk of childhood obesity. CONCLUSION: The present investigation revealed that watching TV represents an important risk factor for obesity in children of school age. PMID- 23983560 TI - Blood pressure and its associated factors among primary school children in suburban Selangor, Malaysia: A cross-sectional survey. AB - BACKGROUND: Little is known about the relationship of blood pressure (BP) with adiposity indicators, dietary habits, physical activity, and sleep in school children in Malaysia. We aimed to study about the distribution of BP and its associated factors in primary school children. MATERIALS AND METHODS: A survey was carried out on a random sample of 335 children in five primary schools. BP was measured with a mercury sphygmomanometer. Anthropometry was done by standard methods. Demographic information, dietary habits, physical activity, and duration of sleep were collected by interviews. World Health Organization classification based on body mass index (BMI) and waist circumference (WC) cut-offs were used to define overweight/obesity. Elevated BP was defined according to US reference standards. RESULTS: A total 335 children (144 boys and 191 girls) were examined. Their mean age was 9.18 years (standard deviation [SD] = 0.28). Overall mean systolic blood pressure (SBP) and mean diastolic blood pressure (DBP) were 99.32 mmHg (SD = 10.79) and 67.11 mmHg (SD = 10.76), respectively. Mean BMI and WC were 16.39 (SD = 3.58) and 57.77 cm (SD = 8.98), respectively. The prevalence of pre hypertension was 12.23% (95% confidence intervals [CIs] 8.73, 15.75) and hypertension was 13.4% (95% CIs 9.78, 17.09). Mean SBP and DBP was higher among overweight and obese children than normal children. By multivariate linear regression analyses, BMI (beta = 0.250, P = 0.049) and WC (beta = 0.308, P = 0.015) were positively associated with SBP; age (beta = 0.111, P = 0.017), BMI (beta = 0.320, P = 0.012) were positively associated with DBP but total (weekly) hours of sleep (beta = -0.095, P = 0.037) was negatively associated with DBP. CONCLUSION: BP was associated with BMI and WC. Health promotion activities should be initiated in primary schools. PMID- 23983561 TI - The pattern of medical errors and litigation against doctors in Saudi Arabia. AB - BACKGROUND: Adverse events are frequent in clinical practice, but only a few studies in Saudi Arabia have addressed them. The current study was designed to review the lawsuits against healthcare professionals by analyzing records of the cases dealt with by the Medico-legal Committees (MLC) in various provinces in Saudi Arabia, in order to determine the pattern of medical errors and litigations in the country. MATERIALS AND METHODS: A pre-designed data sheet was used to collect data from the records of the Medical Violation Committee (MVC) and the Medical Jurisprudence Committee (MJC). The data sheets consisted of information on details of the cases, details on where the error had occurred, and details of the errors. RESULTS: The review of records revealed 642 cases, most of which were from hospitals run by the Ministry of Health (MOH). The operating room was where most of the errors (20.4%) had occurred, followed by the emergency room (18.1%). Surgery was at the top of the specialties (25.1%). Most of the deaths occurred in surgery and obstetrics (about 25% for each), followed by other medical specialties (17%). About half of the lawsuit cases studied (46.5%) involved patients belonging to a relatively young age group (20-50 years). CONCLUSION: Most of the medical error litigations involved surgeons and obstetricians especially in MOH hospitals. The process of litigations and documentation need to be improved, and access to the records for research and education need to be made easier. In addition, there is a need for more prospective field studies. PMID- 23983562 TI - Quality of life in dialysis patients from the United Arab Emirates. AB - BACKGROUND: The quality of life (QOL) has emerged as an important parameter for evaluating the quality of health-care for patients with renal failure. The literature suggests that many factors impact QOL. The QOL of dialysis patients in the United Arab Emirates (UAE) has not been studied before. This research examined the QOL of patients in the UAE on dialysis using two QOL tools. MATERIALS AND METHODS: A descriptive comparative survey design was used to study 161 dialysis patients. The participants completed the 36-Item Short Form Health Survey (SF-36) and the QOL index dialysis version tool. Comparative analyses of the results for both tools were done using descriptive statistics. Multiple linear regression analysis determines the effect of the variables on the QOL scores. RESULTS: The questionnaires return rate was 93%. The overall QOL for dialysis patients was rated low when self-assessed using the SF-36 (58.9) compared to QOL index (77.2). The multiple regression analysis revealed that having a chronic illness had the strongest impact on the total scores of both tools. The comparison between the statistically significant variables for both samples revealed contradictory results from the two tools used. This meant that the two tools measured QOL differently. CONCLUSION: The two QOL tools scores impacted very differently on most socio-demographic variables on the two samples. More studies are required to explore the concept of QOL in the Arab dialysis population. PMID- 23983563 TI - Discharge against medical advice from Neonatal Intensive Care Unit: 10 years experience at a University Hospital. AB - BACKGROUND: Discharging patients against medical advice is a problem of every age group. However, because of their physiological vulnerability, the risk for the neonatal population is greater when discharged against medical advice (DAMA). This article is a study of the prevalence of the problem, the possible causes and/or risk factors. MATERIALS AND METHODS: A retrospective review of 10 years of medical records of neonates discharged against medical advice from a Neonatal Intensive Care Unit (NICU) at a university hospital. RESULTS: The overall prevalence of DAMA was 1.6%. Most of the 51 infants who were taken out of hospital against medical advice (AMA) were term (72.5%) with a mean gestational age of 37.78 +/- 2.5 weeks, of normal birth weight, with a mean of 2736 +/- 661 g, Saudis (96%), those delivered vaginally (69%), and those that were provisionally diagnosed with transient tachypnea of newborn (TTN) and/or query sepsis (49%). There was no difference between males and females (M/F = 1.2). There was an association between DAMA and the timing of DAMA (27.5% of DAMA at weekends and 67% of DAMA from May to October). CONCLUSION: DAMA of neonates is particularly critical. The causes and risk factors are many and difficult to predict. In addition to several other factors, its prevalence is influenced negatively by some socio-cultural beliefs. PMID- 23983564 TI - Development of an assessment tool to measure students' perceptions of respiratory care education programs: Item generation, item reduction, and preliminary validation. AB - OBJECTIVES: Students who perceived their learning environment positively are more likely to develop effective learning strategies, and adopt a deep learning approach. Currently, there is no validated instrument for measuring the educational environment of educational programs on respiratory care (RC). The aim of this study was to develop an instrument to measure students' perception of the RC educational environment. MATERIALS AND METHODS: Based on the literature review and an assessment of content validity by multiple focus groups of RC educationalists, potential items of the instrument relevant to RC educational environment construct were generated by the research group. The initial 71 item questionnaire was then field-tested on all students from the 3 RC programs in Saudi Arabia and was subjected to multi-trait scaling analysis. Cronbach's alpha was used to assess internal consistency reliabilities. RESULTS: Two hundred and twelve students (100%) completed the survey. The initial instrument of 71 items was reduced to 65 across 5 scales. Convergent and discriminant validity assessment demonstrated that the majority of items correlated more highly with their intended scale than a competing one. Cronbach's alpha exceeded the standard criterion of >0.70 in all scales except one. There was no floor or ceiling effect for scale or overall score. CONCLUSIONS: This instrument is the first assessment tool developed to measure the RC educational environment. There was evidence of its good feasibility, validity, and reliability. This first validation of the instrument supports its use by RC students to evaluate educational environment. PMID- 23983565 TI - Evaluation of off-service rotations at National Guard Health Affairs: Results from a perception survey of off-service residents. AB - CONTEXT: "Off-service" clinical rotations are part of the necessary requirements for many residency training programs. Because these rotations are off-service, little attention is given to their structure and quality of training. This often leads to suboptimal educational experience for the residents on these rotations. AIMS: The aim of this study was to assess medical residents' perceptions, opinions, and levels of satisfaction with their "off-service" rotations at a major residency training site in Saudi Arabia. It was also to evaluate the reliability and validity of a questionnaire used for quality assurance in these rotations. Improved reliability and validity of this questionnaire may help to improve the educational experience of residents in their "off-service" rotations. MATERIALS AND METHODS: A close-ended questionnaire was developed, Pilot tested and distributed to 110 off-service residents in training programs of different specializations at King Fahad Naitonal Guard Hospital and King Abdulziz Medical City, Riyadh, Saudi Arabia, between September 2011 and December 2011. RESULTS: A total of 80 out of 110 residents completed and returned the questionnaire. Only 33% of these residents had a clear set of goals and educational learning objectives before the beginning of their off-service rotations to direct their training. Surgical specializations had low satisfaction mean scores of 57.2 (11.9) compared to emergency medicine, which had 70.7 (16.2), P value (0.03). The reliability of the questionnaire was Cronbach's alpha 0.57. The factor analysis yielded a 4-factor solution (educational environment, educational balance, educational goals and objectives, and learning ability); thus, accounting for 51% variance in the data. CONCLUSION: Our data suggest that there were significant weaknesses in the curriculum for off-service clinical rotations in KAMC and that residents were not completely satisfied with their training. PMID- 23983566 TI - Prevalence of oral mucosal lesions in dental patients with tobacco smoking, chewing, and mixed habits: A cross-sectional study in South India. AB - BACKGROUND: A variety of oral mucosal lesions and conditions are associated with the habit of smoking and chewing tobacco, and many of these carry a potential risk for the development of cancer. There have been no studies that report the prevalence of habits and associated oral changes in the population in Dharwad region, of Karnataka, south India. MATERIALS AND METHODS: A hospital-based, cross sectional study was carried out at SDM Dental College (Dharwad, Karnataka). A total of 2400 subjects (1200 subjects with and 1200 subjects without habits) attending the dental hospital were interviewed and examined by trained professionals to assess any oral mucosal changes. RESULTS: Oral mucosal lesions were found in 322 (26.8%) subjects who had tobacco smoking and chewing habits as compared to 34 (2.8%) subjects without those habits. Oral leukoplakia (8.2%) and oral submucous fibrosis (OSF) (7.1%) were the prevalent oral mucosal lesions found in subjects who had those habits, while the other lesions (1.7%) namely; oral candidiasis, median rhomboid glossitis, recurrent apthous ulcer, frictional keratosis, and oral lichen planus (0.9%) were frequently reported among individuals without those habits. The odds of developing oral lesions in subjects with tobacco habits was nearly 11.92 times that of abstainers (odds ratio, OR = 11.92, 95% confidence intervals, CI = 10.61-14.59%). CONCLUSION: The study showed that the risk of the development of oral lesions associated with tobacco smoking, chewing, or both is quite high. Males who had one or more of these habits showed more frequent oral changes than females. The study reinforces the association of OSF with gutkha and areca nut chewing, and leukoplakia, erythroplakia, and oral cancer with tobacco smoking, chewing, or mixed habits. PMID- 23983567 TI - Mycetoma foot. AB - Mycetoma is an uncommon chronic granulomatous infective disease of the skin, dermis and subcutaneous tissues predominantly seen in tropical countries. A patient presented to our hospital with the swelling of the left foot with a healed sinus and a painful nodule. He gave a history of sinuses in the left foot from which there was discharge of yellow granules. Culture of the ultrasound guided fine needle aspiration cytology of the nodule revealed growths of Nocardia species. The patient was treated with a multi-drug therapy along with debridement of the painful nodule. He experienced symptomatic relief and a regression of the swelling within the three months of follow-up so far. Due to the relatively slow progression of the disease, patients are diagnosed at a late stage. Hence, emphasis should be placed on health education and the importance of wearing footwear. PMID- 23983568 TI - Correlates of zinc deficiency among children in age group of six to sixty months belonging to the low-income group. PMID- 23983569 TI - Outcome of Rhabdomyosarcoma in First Year of Life: Children's Cancer Hospital 57357 Egypt. AB - Background. Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children. Fifty percent of RMS cases occur in the first 10 years of life and less commonly in infants younger than one-year old. These infants require adapted multimodality treatment approaches. Patients and Methods. We analyzed patients' characteristics, treatment modalities, and the outcome for RMS infants treated at Children's Cancer Hospital Egypt (CCHE) between July 2007 and December 2010 and compared them to patients above one year treated on the same protocol. Results. Out of the 126 RMS treated during this period, 18 were below the age of one year. The male: female ratio was 1.25 : 1. The median age at diagnosis was 0.7 +/- 0.2 years. Most of the cases (27.8%) were presented in head and neck regions. The estimated 4-years failure-free survival and overall survival for infants were 49 +/- 12% and 70 +/- 12%, respectively. These failure-free survival rate and overall survival rate did not differ from those for older patients (P = 0.2). Conclusion. Infants with RMS are a unique group of RMS who needs special concerns in tailoring treatment in addition to concerns regarding toxicity and morbidity in infants. PMID- 23983570 TI - Proteomics technology - a powerful tool for the biomedical scientists. AB - "Proteomics" refers to the systematic analysis of proteins. It complements other "omics" technologies such as genomics and transcriptomics in elucidating the identity of proteins of an organism, and understanding their functions. Proteomics is used in many areas of research such as discovery of markers for diagnosis and vaccine candidates, understanding pathogenic mechanisms, in the study of expression patterns at different time points and in response to different stimuli, and in elucidating functional protein networks. Proteomics analysis involves sample preparation, protein separation, and protein identification. The 'heart' of current proteomics is mass-spectrometry, with LC MS/MS and MALDI-TOF/TOF being commonly used equipment. However, the high costs of the equipment, software, databases, and the need for skilled personnel limit the wide utilization of this technology in the less developed countries. Therefore, there need to be sharing of facilities, better networking and collaborations among our scientists and laboratories to take advantage of this powerful technology. PMID- 23983571 TI - The influence of colour on memory performance: a review. AB - Human cognition involves many mental processes that are highly interrelated, such as perception, attention, memory, and thinking. An important and core cognitive process is memory, which is commonly associated with the storing and remembering of environmental information. An interesting issue in memory research is on ways to enhance memory performance, and thus, remembering of information. Can colour result in improved memory abilities? The present paper highlights the relationship between colours, attention, and memory performance. The significance of colour in different settings is presented first, followed by a description on the nature of human memory. The role of attention and emotional arousal on memory performance is discussed next. The review of several studies on colours and memory are meant to explain some empirical works done in the area and related issues that arise from such studies. PMID- 23983572 TI - Apoptotic activities in soft tissue sarcoma: immunohistochemical study and their association with tumour characteristics. AB - BACKGROUND: Many studies on the role of apoptosis in cancer development and management have been undertaken. Apoptotic activity depends partly on the balance between anti-apoptotic (Bcl-2) and pro-apoptotic (Bax) activities. This study compared Bcl-2 and Bax expression in the tumour cells and endothelial cells of tumour blood vessels in soft tissue sarcoma, and examined the association of these with tumour characteristics. METHODS: A cross sectional (retrospective) study was conducted on 101 cases of various types of soft tissue sarcoma tumour cells and endothelial cells of tumour blood vessels. The immunohistochemical expressions of Bcl-2 and Bax were compared by correlating them according to site, size, depth, tumour margin, lymph node involvement, and histological type. RESULTS: Higher Bax than Bcl-2 expression in tumour cells was observed, although the difference was not statistically significant. There was a significant direct association between Bcl-2 and Bax in tumour cells with endothelial cells. Among tumour characteristics, the only significant correlation was that of the Bcl-2 expression in tumour cells with tumour histological subtypes (synovial sarcoma and leiomyosarcoma). CONCLUSION: The findings in this study support the role of endothelial cells in the survival and regression of tumour cells in tumour genesis. Therefore, inhibition of endothelial cell survival and activation, or induction of tumour cell apoptosis offers a promising prospect for tumour management. PMID- 23983573 TI - Pulmonary Function Studies of Healthy Non-smoking Male University Students of Kolkata, India - Revisited. AB - BACKGROUND: Pulmonary function tests (PFTs) need to be revisited in light of rapid economic growth and industrial development. Questions have been raised about the validity of existing population-specific norms for predicting PFTs, and therefore, the present study aimed to determine the applicability of existing norms for PFTs in young healthy non-smoking male university students of Kolkata. METHODS: PFTs were carried out for 87 non-smoking male university students who were randomly sampled from the University of Calcutta, Kolkata, India. RESULTS: The PFTs data obtained in this study did not show a significant variation with that obtained in a previous study. Significant (P < 0.001) differences in the forced expiratory volume in 1 s (FEV1%) and peak expiratory flow rate (PEFR) between the two studies may be attributed to differences in the age and body height, which exhibited significant correlations with the vital capacity (VC), forced vital capacity (FVC), FEV1, FEV1%, and PEFR. Regression equations have been computed to predict PFTs parameters from age and body height. CONCLUSION: Pulmonary function in the university students of Kolkata was found to have remained mostly unchanged in the last 24 years. The equations computed in this study are considered preferable owing to their substantially smaller standard error of estimate (SEE) than those proposed in the previous study. PMID- 23983574 TI - Improving active and passive avoidance memories deficits due to permanent cerebral ischemia by pomegranate seed extract in female rats. AB - BACKGROUND: This study aimed to evaluate the effect of two weeks oral administration of pomegranate seed extract (PGSE) on active and passive avoidance memories after permanent bilateral common carotid arteries occlusion (2CCAO) to induce permanent cerebral ischemia in adult female rats. METHODS: Seventy adult female Wistar rats (250 +/- 20 g) were used. Animals were divided randomly into seven groups with 10 in each: 1) Sham-operated; 2) Ischemic; 3-6) Ischemic received PGSE (100, 200, 400, and 800 mg/2mL/kg, orally) for 14 days; 7) Ischemic received vehicle. In order to create 2CCAO, carotid arteries were ligatured and then cut bilaterally. Active and passive avoidance task were measured using criterion condition responses (CCRs) in Y-maze and step-through latency (STL) in two-way shuttle box in all female rats. RESULTS: Both active and passive avoidance memories were significantly impaired in rats after cerebral hypoxia ischemia (CHI) (P < 0.001). PGSE treatment significantly improved passive and active memory impairments with 2CCAO (P < 0.05, P < 0.01, and P < 0.001). No toxicity was observed even with high-dose PGSE consumption (800 mg/kg, for 14 days). CONCLUSION: PGSE exhibits therapeutic potential for avoidance memories, which is most likely related at least in part to its antioxidative and free radical scavenging actions. PMID- 23983575 TI - Preliminary study: effects of social instability stress on depressive behaviours in ovariectomised rats. AB - BACKGROUND: Depression is one of the common post-menopausal symptoms. In addition to estrogen deficiency, social instability stress may contribute as an additional underlying factor in the development of depressive behaviour in females. Therefore, this study was aimed at examining the influence of social instability stress on depressive behaviour in ovariectomized rats. METHODS: The rats were divided into four groups (n = 5 per group); (i) sham-operated control without stress, (ii) sham-operated control with stress, (iii) ovariectomized without stress, and (iv) ovariectomized with stress. These rats were subjected to social instability stress procedures for 15 days prior to an enforced swimming test. Struggling, immobility, and swimming times were recorded promptly. RESULTS: The results were analysed using the one-way analysis of variance (ANOVA) and a P value of < 0.05 was considered as significant. The mean durations of struggling, immobility, and swimming behaviour were significantly distinct among the four groups. Ovariectomized rats exhibited a substantial decrease in struggling and swimming behaviour, and an increase in immobility behaviour in comparison with the sham-operated controls (P < 0.05). Ovariectomized rats with stress displayed a supplementary decrease in struggling and swimming behaviour as well as an advanced increase in immobility behaviour, compared to sham-operated controls with or without stress (P < 0.05). CONCLUSION: In summary, these findings suggest that ovariectomized rats encountered an augmented amount of depressive behaviour following social instability stress. PMID- 23983576 TI - Prevalence of hepatitis B and C in donated blood from the jazan region of saudi arabia. AB - BACKGROUND: Infections caused by the hepatitis B virus (HBV) and the hepatitis C virus (HCV) are global public health problems. The safety of donated blood can be estimated by monitoring the prevalence of viral markers in the donor population. The present study was carried out in the Jazan region to determine the prevalence of HBV and HCV among Saudi blood donors. METHODS: Over a period of six years (January 2004 to December 2009), a total of 29 949 blood units were collected from healthy voluntary and replacement native Saudi blood donors. The donated units were serologically screened for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis C virus (anti-HCV). These data were then analysed. RESULTS: HBsAg was positive in 3.8% of the blood units that were collected, the blood units with anti-HCV seropositivity had the lowest prevalence (0.41%), and the prevalence of HBsAg was highest in the group that was > 46 years of age. A significant decline in the prevalence of HBV infection has been observed, from 5.6% in 2004 to 2.3% in 2009 (P < 0.001). CONCLUSION: The present study showed that the prevalence of HBV and HCV was in a significant decline from 2004 to 2009, and the prevalence of HBsAg and anti-HCV significantly increased with age. PMID- 23983577 TI - Suicide and forced marriage. AB - BACKGROUND: The prevailing view that the vast majority of those who complete suicide have an underlying psychiatric disorder has been recently challenged by research on the contribution of "predicaments", in the absence of mental illness, to suicide. In this paper, we sought data to support the notion that forced marriage may lead to suicide without the presence of psychiatric disorder. METHODS: Historical records, newspapers, and the electronic media were searched for examples. RESULTS: Two examples from ancient times and six from the last hundred years were located and described. CONCLUSION: These cases suggest that forced marriage may lead to suicide and complements earlier findings that loss of fortune, health, liberty, and reputation may lead to suicide in the absence of mental disorder. PMID- 23983578 TI - Knowledge, practices and attitudes towards adverse drug reaction reporting by private practitioners from klang valley in malaysia. AB - BACKGROUND: The study aimed to determine current status of knowledge, practices, and attitudes towards adverse drug reaction (ADR) reporting among private practitioners in Klang region of Malaysia. METHODS: A total of 238 private practitioners in Klang valley were distributed a questionnaire consisting of seven questions, two knowledge-related, two practice-related and three attitude related. Each favourable and unfavourable response was given a score of 1 and 0 respectively. Total score of 70% or more for each domain was considered "satisfactory" whereas less than 70% as "unsatisfactory". RESULTS: One hundred forty-five participants completed questionnaire. Knowledge assessment showed 83.4% responses stating that ADR reporting helps to identify safe drugs and 91.7% responded that it measures ADR incidence. Regarding practices, 76.6% respondents were willing to report only if confident that reaction is an ADR. Regarding attitudes, 81.9%, 66.9% and 23.5% participants showed complacency, ignorance, and indifference respectively. Unsatisfactory knowledge, practices, and attitudes were observed in 57.2%, 56.6%, and 73.1% respondents respectively. Satisfactory knowledge was significantly higher in respondent with higher qualification with odds ratio of 2.96 with 95% confidence interval of 1.48-5.93. CONCLUSION: The study showed unsatisfactory level of knowledge, practices, and attitudes towards ADR reporting among high proportion of private practitioners in Klang valley, Malaysia. PMID- 23983579 TI - New horizons in platelets flow cytometry. AB - Platelet flow cytometry is an emerging tool in diagnostic and therapeutic hematology. It is eminently suited to study the expression of platelet surface receptors both qualitatively as well as quantitatively. It can serve as a useful marker for the documentation of in vivo platelet activation, and thus, fore-warn the risk of thromboembolism in patients with diabetes mellitus, coronary syndromes, peripheral vascular diseases, and pre-eclampsia. This technique can also be extended to study and compare the effect of various antiplatelet drugs on the level of activation of platelets and to establish any dose-effect relationship of these drugs. Topographical localization of platelet granules and study of platelet-platelet and platelet-leukocyte interaction is also possible by this procedure. All these parameters serve as pointers towards the presence of activated platelets in the circulation with its thromboembolic consequences. This is a simple reliable and cost effective technique which has a wide application in the diagnosis of various inherited and acquired platelet disorders. Study of platelet cluster of differentiation (CD) markers in various inherited disorders i.e. Bernard Soulier's disease, von Willebrand disease, Glanzman's disease, and Grey platelet syndrome may help categories the molecular lesions in these oft under-studied disorders. PMID- 23983580 TI - Case of benign phyllodes tumour associated with hypoglycemia. AB - Benign phyllodes tumour is a rare non-cancerous growth of the breast characterized by a solitary unilateral tumour in one breast, or rarely multifocal in one or both breasts. It is diagnosed on the basis of physical examination, imaging studies, and fine-needle aspiration cytology. In this report, we present a case of benign phyllodes tumour with an unusual presentation of recurrent attacks of hypoglycemia, which can be attributed to secretion of insulin-like growth factor II from the tumour. PMID- 23983581 TI - Percutaneous catheter-based rheolytic thrombectomy for massive pulmonary embolism: a case report. AB - Pulmonary thromboembolism is a life-threatening cardiovascular condition. The mortality rate is high in its current management. Besides supportive treatments, systemic thrombolysis and surgical thrombectomy play important roles in the comprehensive management of pulmonary embolism (PE). The percutaneous catheter based rheolytic thrombectomy is a promising alternative for management of massive pulmonary emboli, particularly, when patients have contraindication with systemic thrombolysis or are not suitable for surgery. We present the case of a 36-year old Somalian man who came to our center for a total knee replacement (TKR). Three days after TKR, he developed sudden shortness of breath and decreased oxygen saturation. Computed tomography of pulmonary arteriogram showed extensive thrombi within the main pulmonary trunk, right and left pulmonary arteries, bilateral ascending and bilateral descending pulmonary arteries in keeping with massive PE. Because the patient was contraindicated for systemic thrombolysis, percutaneous, catheter-based rheolytic thrombectomy was chosen as the alternative treatment. His clinical symptoms improved immediately post-treatment. In conclusion, catheter-based rheolytic thrombectomy can serve as an alternative treatment for massive PE with a good clinical outcome. PMID- 23983582 TI - Uterine arteriovenous malformation. AB - Uterine arteriovenous malformation (AVM) is a rare condition, with fewer than 100 cases reported in the literature. Despite it being rare, it is a potentially life threatening condition. This case report describes a 33-year-old woman who presented with secondary post-partum hemorrhage. Transabdominal ultrasound (US) of the pelvis showed increased vascularity with multidirectional flow of the uterus and a prominent vessel, located on the left lateral wall. She also had retained product of conception, which complicated the diagnosis. A uterine artery angiogram confirmed an AVM in the fundal region with an early draining vein. Embolisation of the AVM was performed successfully. PMID- 23983583 TI - Widely infiltrating epithelioid malignant peripheral nerve sheath tumour of skull base. AB - The epithelioid variant of malignant peripheral nerve sheath tumours is a rare histological entity, and the occurrence of a malignant peripheral nerve sheath tumour in the skull base is even more unusual. We report a case of a 52-year-old man who presented with reduced hearing in the left ear, giddiness and left-sided facial weakness of short duration. He was a known hypertensive. On examination, left-sided 7th to 12th cranial nerve palsies were noted. Computed tomography (CT) and brain magnetic resonance imaging (MRI) were reported as an ill-defined heterogeneously enhancing mass left skull base suggestive of chondrosarcoma. Left tympanotomy and biopsy of the lesion were carried out. On light microscopy and immunohistochemical examination of the biopsy, a diagnosis of epithelioid malignant peripheral nerve sheath tumour was established. The patient underwent left extended modified radical mastoidectomy and selective neck dissection. Histopathological study of the resected surgical specimen confirmed left-sided extensive tumour involvement of skull base structures, as well as neck nodal metastases. PMID- 23983584 TI - Flotillin-2 expression in the human gut: from a cell model to human tissue in health and inflammatory bowel diseases. AB - BACKGROUND AND AIMS: The etiopathogenesis of inflammatory bowel diseases (IBD) remains largely unexplained. Flotillins (flotillin-1 and flotillin-2) are ubiquitous proteins which have been linked to inflammation and regeneration. We hypothesized that alterations in the expression of flotillin-2 in enterocytes may be related to the pathogenesis of IBD as a classical example of an inflammatory disorder of mostly unknown origin. METHODS: Cell and tissue localization of flotillin-2 (and -1) were investigated by immunofluorescent staining in 1. polarized and unpolarized CaCo-2w cells as a model of human enterocytes (native and after TNFalpha stimulation) and 2. intestinal biopsies from controls, patients with ulcerative colitis (UC) and patients with Crohn's disease (CD). For quantification of flotillin-2, we analyzed its expression in ileal and colonic biopsies from controls, UC patients and CD patients using real-time RT-PCR, Western blot and indirect immunofluorescence. RESULTS: In polarized CaCo-2w cells and human enterocytes in biopsies, flotillins were localized at the basolateral membrane and on subapical vesicles, but not in the apical membrane. Flotillin-2 expression did not differ between UC patients, CD patients and controls. However, it was significantly higher in colonic biopsies compared to ileal biopsies in all groups. CONCLUSIONS: By virtue of its abundant expression in enterocytes, flotillin-2 must have an essential function in intestinal physiology, especially in the colon. Yet our data could not link flotillin-2 to the pathogenesis of IBD. PMID- 23983585 TI - Heat shock protein27 expression and cell differentiation in ameloblastomas. AB - The expression of HSP27 and some CKs were examined the 40 cases of typical solid/multicystic ameloblastoma using immunohistochemical techniques. In order to examine the relevance of HSP in cell differentiation, we focused on the cytoskeletal expression of CK. CK19 is a marker of typical odontogenic epithelium widely observed in follicular and plexiform types of ameloblastomas. Since staining with CK14 is one of the measures of the differentiation potential of squamous cells and is extensively expressed in both follicular and plexiform types, it implies that squamous differentiation of each type can occur. CK8 was strongly detected in tumor nests in plexiform type but weakly detected in follicular type. It was considered that the expression of HSP27 in plexiform type correlated with the expression of CK8 suggesting that HSP27 might have regulated the expression of CK8. PMID- 23983586 TI - Sugammadex, a neuromuscular blockade reversal agent, causes neuronal apoptosis in primary cultures. AB - Sugammadex, a gamma-cyclodextrin that encapsulates selectively steroidal neuromuscular blocking agents, such as rocuronium or vecuronium, has changed the face of clinical neuromuscular pharmacology. Sugammadex allows a rapid reversal of muscle paralysis. Sugammadex appears to be safe and well tolerated. Its blood brain barrier penetration is poor (< 3% in rats), and thus no relevant central nervous toxicity is expected. However the blood brain barrier permeability can be altered under different conditions (i.e. neurodegenerative diseases, trauma, ischemia, infections, or immature nervous system). Using MTT, confocal microscopy, caspase-3 activity, cholesterol quantification and Western-blot we determine toxicity of Sugammadex in neurons in primary culture. Here we show that clinically relevant sugammadex concentrations cause apoptotic/necrosis neuron death in primary cultures. Studies on the underlying mechanism revealed that sugammadex-induced activation of mitochondria-dependent apoptosis associates with depletion of neuronal cholesterol levels. Furthermore SUG increase CytC, AIF, Smac/Diablo and CASP-3 protein expression in cells in culture. Potential association of SUG-induced alteration in cholesterol homeostasis with oxidative stress and apoptosis activation occurs. Furthermore, resistance/sensitivity to oxidative stress differs between neuronal cell types. PMID- 23983587 TI - Microcurrent electrical nerve stimulation facilitates regrowth of mouse soleus muscle. AB - Microcurrent electrical nerve stimulation (MENS) has been used to facilitate recovery from skeletal muscle injury. However, the effects of MENS on unloading associated atrophied skeletal muscle remain unclear. Effects of MENS on the regrowing process of unloading-associated atrophied skeletal muscle were investigated. Male C57BL/6J mice (10-week old) were randomly assigned to untreated normal recovery (C) and MENS-treated (M) groups. Mice of both groups are subjected to continuous hindlimb suspension (HS) for 2 weeks followed by 7 days of ambulation recovery. Mice in M group were treated with MENS for 60 min 1, 3, and 5 days following HS, respectively, under anesthesia. The intensity, the frequency, and the pulse width of MENS were set at 10 MUA, 0.3 Hz, and 250 msec, respectively. Soleus muscles were dissected before and immediately after, 1, 3 and 7 days after HS. Soleus muscle wet weight and protein content were decreased by HS. The regrowth of atrophied soleus muscle in M group was faster than that in C group. Decrease in the reloading-induced necrosis of atrophied soleus was facilitated by MENS. Significant increases in phosphorylated levels of p70 S6 kinase and protein kinase B (Akt) in M group were observed, compared with C group. These observations are consistent with that MENS facilitated regrowth of atrophied soleus muscle. MENS may be a potential extracellular stimulus to activate the intracellular signals involved in protein synthesis. PMID- 23983588 TI - Heart rate significantly influences the relationship between atrial fibrillation and arterial stiffness. AB - BACKGROUND: Atrial fibrillation (AF) and vascular disease share several risk factors and the two diseases often coexist. Heart rate (HR) is reported to be a major determinant of arterial stiffness. AF patients often have a transiently or persistently rapid HR. Hence, this study was to assess whether AF was significantly associated with arterial stiffness and HR could significantly influence the relationship between AF and arterial stiffness. Besides, we also determine the main correlates of arterial stiffness in AF patients and see whether HR was correlated with arterial stiffness in these patients. METHODS: We included 166 AF and 1336 non-AF patients from subjects arranged for echocardiographic examinations. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV). RESULTS: Compared to non-AF patients, AF patients had a higher baPWV (p <0.001). In a multivariate model, including covariates of age, sex, blood pressures and so on, the presence of AF was significantly associated with baPWV (beta = 0.079, P = 0.001). However, further adjustment for HR made this association disappear (beta = 0.005, P = 0.832). In addition to age and systolic blood pressure, increased HR (beta = 0.309, p <0.001) was a major determinant of increased baPWV in our AF patients. CONCLUSIONS: This study demonstrated the presence of AF was associated with increased baPWV, but this association became insignificant after further adjustment for HR, which suggested HR could significantly influence the relationship between AF and baPWV. Besides, HR was positively correlated with arterial stiffness in our AF patients. PMID- 23983590 TI - Microbleeds and silent brain infarctions are differently associated with cognitive dysfunction in patients with advanced periventricular leukoaraiosis. AB - BACKGROUND: Leukoaraiosis, microbleeds, and silent brain infarctions are phenotypes of small vessel disease. Leukoaraiosis is the most prevalent, and advanced periventricular leukoaraiosis is regarded as a strong predictor of cognitive dysfunction. Microbleeds and silent brain infarctions sometimes coexist with leukoaraiosis. This study aims to analyze the effects of microbleeds and silent brain infarctions on cognitive function of patients with advanced periventricular leukoaraiosis. METHODS: 227 patients with advanced periventricular leukoaraiosis were divided into control, MB, SBI, and MB&SBI groups. The presence and locations of microbleeds and silent brain infarctions were evaluated. Mini-Mental State Examination, Montreal Cognitive Assessment, Clock Drawing Test and Verbal Fluency Test were performed. Chi-square test and ANOVA to compare the characteristics of four groups, multiple linear regressions to identify the risk factors for cognitive dysfunction. RESULTS: The scores in all four tests were lower in the MB and MB&SBI groups while only the scores in Clock Drawing Test and Verbal Fluency Test were lower in the SBI group than in the control group. Age and the presence of microbleeds were independent risk factors for the lower scores in all four tests, whereas the presence of silent brain infarctions was the only independent risk factor for the lower scores in Clock Drawing Test and Verbal Fluency Test. Lobar microbleeds had the most significant effect on cognitive function. CONCLUSION: Microbleeds and silent brain infarctions were associated differently with cognitive impairment of patients with advanced periventricular leukoaraiosis. The effect of lobar microbleeds was the most significant. PMID- 23983589 TI - Lentivirus-based RNA silencing of Nemo-like kinase (NLK) inhibits the CAL 27 human adenosquamos carcinoma cells proliferation and blocks G0/G1 phase to S phase. AB - BACKGROUND: The Nemo-like kinase (NLK) is a serine/threonine-protein kinase that involved in a number of signaling pathways regulating cell fate. Variation of NLK has been shown to be associated with the risk of cancer. However, the function of NLK in oral adenosquamous carcinoma cells line CAL-27 is unknown. METHODS: In this study, we evaluated the function of NLK in CAL-27 cells by using lentivirus mediated RNA silence. The targeted gene expression, cell proliferation and cell cycle are investigated by RT-PCR, western-blot, MTT method, colony forming assay and flow cytometry analysis respectively. RESULTS: After NLK silencing, the number of colonies was significantly reduced (54 +/- 5 colonies/well compared with 262 +/- 18 colonies/well in non-infected or 226 +/- 4 colonies/well in negative control group (sequence not related to NLK sequence with mismatched bases). Using crystal violet staining, we also found that the cell number per colony was dramatically reduced. The RNA silencing of NLK blocks the G0/G1 phase to S phase progression during the cell cycle. CONCLUSIONS: These results suggest that NLK silencing by lentivirus-mediated RNA interference would be a potential therapeutic method to control oral squamous carcinoma growth. PMID- 23983591 TI - Antitumor effect of embryonic stem cells in a non-small cell lung cancer model: antitumor factors and immune responses. AB - Research in recent years has revealed that embryonic stem cells (ESCs) could generate obvious antitumor effects in both vitro and vivo. In vitro, ESCs could secrete soluble factors that are capable of blocking cancer cells proliferation, moreover, embryonic microenvironments could effectively inhibit tumorigenesis and metastasis; while in vivo, administration of ESCs in tumor-bearing mice could generate significant antitumor effects by indirectly activating the antitumor immune system. In this study, non-small cell lung cancer cells (Lewis Lung Carcinoma cells, LLCs) and ESCs were co-injected together into mice, after that subcutaneous tumor growth was monitored, cellular and humoral immune responses were detected, and different control groups were set to compare the results in different conditions. Our results suggested that compared to be injected alone, ESCs co-injected with cancer cells could inhibit cancer cell growth more efficiently in vivo, with more CD8+ lymphocytes generated in both peripheral circulation and spleen, and with higher serum anticancer cytokine level (interleukin (IL)-2 and interferon (IFN)-gamma). We conclude that the boosted antitumor effects induced by ESCs and cancer cells co-injection may be both the effects of antitumor factors secreted by ESCs and immune responses induced by ESCs in vivo. PMID- 23983592 TI - Promotion of transplanted bone marrow-derived cell migration into the periodontal tissues due to orthodontic mechanical stress. AB - BACKGROUND: Bone marrow-derived cells (BMCs) have abilities of cell migration and differentiation into tissues/organs in the body and related with the differentiation of teeth or periodontal tissue including fibroblasts. Then, we examined the effect of orthodontic mechanical stress to the transplanted BMC migration into periodontal tissues using BMC transplantation model. MATERIAL AND METHOD: BMC from green fluorescence protein (GFP) transgenic mice were transplanted into 8-week-old female C57BL/6 immunocompromised recipient mice, which had undergone 10 Gy of lethal whole-body-irradiation. Five mice as experimental group were received orthodontic mechanical stress using separator between first molar (M1) and second molar (M2) 1 time per week for 5 weeks and 5 mice as control group were not received mechanical stress. The maxilla with M1 and M2 was removed and was immunohistochemically analyzed using a Dako Envision + Kit-K4006 and a primary anti-GFP-polyclonal rabbit antibody. Immunohistochemically stained was defined as positive area and the pixel number of positive area in the periodontal tissue was compared with the previously calculated total pixel number of the periodontal tissue. RESULTS: The immunohistochemistry revealed that GFP positive cells were detected in the periodontal tissues, both in the experimental and control specimens. The ratio of pixel number in the examination group showed 5.77 +/- 3.24 % (mean +/- SD); and that in the control group, 0.71 +/- 0.45 % (mean +/- SD). The examination group was significantly greater than that of control group (Mann-Whitney U test: p<0.001). CONCLUSION: These results suggest that orthodontic mechanical stress accelerates transplanted BMC migration into periodontal tissues. PMID- 23983593 TI - Optimal dose of prophylactic dexmedetomidine for preventing postoperative shivering. AB - OBJECTIVE: The aim of this study was to investigate the optimum dosage of dexmedetomidine for prevention of postanesthetic shivering. METHODS: One-hundred thirty two ASA physical status I-II patients scheduled for elective laparoscopic total hysterectomy were enrolled in this randomised, placebo-controlled study. Patients were randomly allocated to receive dexmedetomidine in four groups: group S (0.9% normal saline), group D0.5 (dexmedetomidine 0.5 ug/kg), group D0.75 (dexmedetomidine 0.75 ug/kg), group D1.0 (dexmedetomidine 1.0 ug/kg). Time to extubation and tympanic temperature during and after operation were measured. Shivering was graded (0-3 scale) upon patients arrival to the PACU and every ten minutes thereafter up to forty minutes. Sedation and first rescue analgesic time at the PACU were evaluated. RESULTS: The incidence of shivering was significantly lower in group D0.75 and D1.0 than in group S (P < 0.05). There were significantly fewer patients with a shivering score of 2 or 3 in groups D0.75 and D1.0 than in group S (P < 0.05, P < 0.001). Extubation time was shorter in group S than in groups D0.75 and D1.0 (P < 0.05). Tympanic temperature at 40 minutes postoperatively in the recovery room was higher in group S than in the other dexmedetomidine groups (P < 0.05) Fewer patients required rescue analgesia in groups D0.75 and D1.0 than in group S (P < 0.001), and the time to rescue analgesia was longer in group D1.0 than in group S (P < 0.001). Modified Observer's Assessment of Alertness/Sedation (MOAA/S) at arrival in the PACU was lower in all dexmedetomidine groups than in group S (P < 0.05). CONCLUSIONS: Our results suggest that dexmedetomidine 0.75 or 1.0 ug/kg provides effective prophylaxis against postoperative shivering as well as an analgesic effect. Though potential for intraoperative requirement for atropine, sedation in the immediate recovery period and delayed extubation time with dexmedetomidine was noted, there were no major clinical impacts on the overall recovery from anesthesia. PMID- 23983594 TI - Allele dependent silencing of collagen type I using small interfering RNAs targeting 3'UTR Indels - a novel therapeutic approach in osteogenesis imperfecta. AB - Osteogenesis imperfecta, also known as "brittle bone disease", is a heterogeneous disorder of connective tissue generally caused by dominant mutations in the genes COL1A1 and COL1A2, encoding the alpha1 and alpha2 chains of type I (pro)collagen. Symptomatic patients are usually prescribed bisphosphonates, but this treatment is neither curative nor sufficient. A promising field is gene silencing through RNA interference. In this study small interfering RNAs (siRNAs) were designed to target each allele of 3'UTR insertion/deletion polymorphisms (indels) in COL1A1 (rs3840870) and COL1A2 (rs3917). For both indels, the frequency of heterozygous individuals was determined to be approximately 50% in Swedish cohorts of healthy controls as well as in patients with osteogenesis imperfecta. Cultures of primary human bone derived cells were transfected with siRNAs through magnet-assisted transfection. cDNA from transfected cells was sequenced in order to measure targeted allele/non-targeted allele ratios and the overall degree of silencing was assessed by quantitative PCR. Successful allele dependent silencing was observed, with promising results for siRNAs complementary to both the insertion and non-insertion harboring alleles. In COL1A1 cDNA the indel allele ratios were shifted from 1 to 0.09 and 0.19 for the insertion and non-insertion allele respectively while the equivalent resulting ratios for COL1A2 were 0.05 and 0.01. Reductions in mRNA abundance were also demonstrated; in cells treated with siRNAs targeting the COL1A1 alleles the average COL1A1 mRNA levels were reduced 65% and 78% compared to negative control levels and in cells treated with COL1A2 siRNAs the average COL1A2 mRNA levels were decreased 26% and 49% of those observed in the corresponding negative controls. In conclusion, allele dependent silencing of collagen type I utilizing 3'UTR indels common in the general population constitutes a promising mutation independent therapeutic approach for osteogenesis imperfecta. PMID- 23983595 TI - Prolidase, matrix metalloproteinases 1 and 13 activity, oxidative-antioxidative status as a marker of preterm premature rupture of membranes and chorioamnionitis in maternal vaginal washing fluids. AB - OBJECTIVE: Etiology of premature preterm rupture of membranes (PPROM) is not yet completely known and chorioamnionitis is one of the most important complications of its. We aimed to evaluate whether prolidase, matrix metalloproteinases, oxidative-antioxidative status, and inflammation markers in vaginal washing fluid (VWF) were associated with etiology of PPROM and whether these markers could be used to predict chorioamnionitis in PPROM. STUDY DESIGN: This prospective case control study enrolled fifty pregnant women with PPROM and 50 healthy pregnant women. The VWF samples were taken at the time of admission in the PPROM group and patients were followed for chorioamnionitis. Prolidase, matrix metalloproteinases, oxidative-antioxidative status, and inflammation markers in VWF were assayed. RESULTS: VWF levels of prolidase, matrix metalloproteinases 1 13 (p< 0.001), oxidative stress parameters, total oxidative stress (TOS) (p < 0.001) and oxidative stress index (OSI) (p = 0.002), and hs-CRP (p = 0.045) were significantly higher in the PPROM group than in the controls. Antioxidative status parameters, levels of paroxanase (PON-1) (p < 0.001) and total antioxidant capacity (TAC) (p < 0.001), were significantly lower in the PPROM group than in the controls. Mean VWF levels of prolidase (p < 0.001), metalloproteinases (p<0.05), and oxidative-antioxidative status parameters (p<0.05) were significantly different in women with versus women without chorioamnionitis in the PPROM group. Prolidase, MMP-13, TOS, TAC, and PON-1 were found as important predictors for chorioamnionitis in the PPROM group by the multivariate logistic regression analysis. When the ROC curve analysis for prolidase, MMP-13, TOS, TAC, and PON-1 were performed, all of them were statistically significant for area under the curve (areas under the curve were 0.94, 0.90, 0.80, 0.25, and 0.19, respectively). CONCLUSIONS: This study showed that collagen turnover mediators, especially prolidase, and increased oxidative stress are significantly associated with PPROM. Also, chorioamnionitis can be predicted with prolidase, MMP-13, TOS, TAC, and PON-1 in PPROM patients. PMID- 23983596 TI - Clustering patterns of comorbidities associated with in-hospital death in hospitalizations of US adults with venous thromboembolism. AB - BACKGROUND: Venous thromboembolism (VTE) is a significant source of mortality, morbidity, disability, and impaired health-related quality of life in the world. OBJECTIVE: We aimed to evaluate the clustering patterns and associations of 29 comorbidities with in-hospital death among adult hospitalizations with a diagnosis of VTE in the United States by analyzing data from the 2009 Nationwide Inpatient Sample. METHODS: This cross-sectional study included 153,124 adult hospitalizations with a diagnosis of VTE. Adjusted rate ratios and 95% confidence intervals (CI) for in-hospital death were generated by using multivariable log linear regression models to measure independent associations between comorbidities and in-hospital death. RESULTS: We estimated that 44,200 in hospital deaths occurred in 2009 among 773,273 US adult hospitalizations with a diagnosis of VTE. Subgroups of hospitalizations with comorbidities of "congestive heart failure," "chronic pulmonary disease," "coagulopathy," "liver disease," "lymphoma," "fluid and electrolyte disorders," "metastatic cancer," "peripheral vascular disorders," "pulmonary circulation disorders," "renal failure," "solid tumor without metastasis," or "weight loss" were positively and independently associated with 1.07 (95% CI: 1.02-1.12 ) to 2.06 (95% CI: 1.97-2.16) times increased likelihoods of in-hospital death, when compared to those without the corresponding comorbidities. The clustering patterns of these comorbidities by 4 disease categories (i.e., "cancer," "cardiovascular/respiratory/blood," "gastrointestinal/urologic," and "nutritional/bodyweight") were associated with 2.74 to 10.28 times increased likelihoods of in-hospital death, as compared to hospitalizations without any of these comorbidities. The overall increase in the cumulative number of comorbidities corresponded to significantly elevated risks (P-trend<0.01) for in-hospital death among hospitalizations with a diagnosis of VTE. CONCLUSION: The presence of multiple comorbidities is ubiquitous among hospitalizations of adults with VTE and among in-hospital deaths with VTE in the United States. The findings of our study further suggest that, among hospitalizations of adults with VTE, the presence of certain comorbidities or clustering of these comorbidities significantly elevates the risk of in-hospital death. PMID- 23983597 TI - Predictors of coronary and carotid atherosclerosis in patients with severe degenerative aortic stenosis. AB - BACKGROUND: Patients with degenerative aortic stenosis (AS) exhibit elevated prevalence of coronary artery disease (CAD) and internal carotid artery stenosis (ICAS). Our aim was to investigate prevalence of significant CAD and ICAS in relation to demographic and cardiovascular risk profile among patients with severe degenerative AS. METHODS: We studied 145 consecutive patients (77 men and 68 women) aged 49-91 years (median, 76) with severe degenerative AS who underwent coronary angiography and carotid ultrasonography in our tertiary care center. The patients were divided into two groups according to the presence of either significant CAD (n=86) or ICAS (n=22). RESULTS: The prevalence of significant CAD or ICAS was higher with increasing number of traditional risk factors (hypertension, hypercholesterolemia, diabetes, smoking habit) and decreasing renal function. We found interactions between age and gender in terms of CAD (p=0.01) and ICAS (p=0.06), which was confirmed by multivariate approach. With the reference to men with a below-median age, the prevalence of CAD or ICAS increased in men aged >76 years (89% vs. 55% and 28% vs. 14%, respectively), whereas the respective percentages were lower in older vs. younger women (48% vs. 54% and 7% vs. 17%). CONCLUSIONS: In severe degenerative AS gender modulates the association of age with coronary and carotid atherosclerosis with its lower prevalence in women aged >76 years compared to their younger counterparts. This may result from a hypothetical "survival bias", i.e., an excessive risk of death in very elderly women with severe AS and coexisting relevant coronary or carotid atherosclerosis. PMID- 23983598 TI - The role of serum procalcitonin levels in predicting ascitic fluid infection in hospitalized cirrhotic and non-cirrhotic patients. AB - OBJECTIVE: To determine the role of serum procalcitonin levels in predicting ascites infection in hospitalized cirrhotic and non-cirrhotic patients. METHODS: A total of 101 patients (mean age: 63.4 +/- 1.3, 66.3% were males) hospitalized due to cirrhosis (n=88) or malignancy related (n=13) ascites were included in this study. Spontaneous bacterial peritonitis (SBP, 19.8%), culture-negative SBP (38.6%), bacterascites (4.9%), sterile ascites (23.8%) and malign ascites (12.9%) groups were compared in terms of procalcitonin levels in predicting ascites infection. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of procalcitonin levels and predicting outcome of procalcitonin levels was compared with C-reactive protein (CRP). RESULTS: Culture positivity was determined in 26.7% of overall population. Serum procalcitonin levels were determined to be significantly higher in patients with positive bacterial culture in ascitic fluid compared to patients without culture positivity (median (min-max): 4.1 (0.2-36.4) vs. 0.4 (0.04-15.8), p<0.001). Using ROC analysis, a serum procalcitonin level of <0.61 ng/mL in SBP (area under curve (AUC): 0.981, CI 95%: 0.000-1.000, p<0.001), <0.225 ng/mL in culture-negative SBP (AUC: 0.743, CI 95%: 0.619-0.867, p<0.001), <0.42 ng/mL in SBP and culture negative SBP patients (AUC: 0.824, CI 95%: 0.732-0.916, p<0.001), and <1.12 ng/mL in bacterascites (AUC: 0.837, CI 95%: 0.000-1.000, p=0.019) were determined to accurately rule out the diagnosis of bacterial peritonitis. Predictive power of serum procalcitonin levels in SBP + culture-negative SBP group (AUCs: 0.824 vs 0.622, p=0.004, Fig 4), culture-positive SBP (AUCs: 0.981 vs 0.777, p=0.006, Fig 5) and (although less powerfull) in culture-negative SBP (AUCs: 0.743 vs 0.543, p=0.02, Fig 6) were found significantly higher than CRP. CONCLUSION: According to our findings determination of serum procalcitonin levels seems to provide satisfactory diagnostic accuracy in differentiating bacterial infections in hospitalized patients with liver cirrhosis related ascites. PMID- 23983599 TI - Effect of antisense oligodeoxynucleotides glucose transporter-1 on enhancement of radiosensitivity of laryngeal carcinoma. AB - PURPOSE: Laryngeal carcinomas always resist to radiotherapy. Hypoxia is an important factor in radioresistance of laryngeal carcinoma. Glucose transporter-1 (GLUT-1) is considered to be a possible intrinsic marker of hypoxia in malignant tumors. We speculated that the inhibition of GLUT-1 expression might improve the radiosensitivity of laryngeal carcinoma. METHODS: We assessed the effect of GLUT 1 expression on radioresistance of laryngeal carcinoma and the effect of GLUT-1 expressions by antisense oligodeoxynucleotides (AS-ODNs) on the radiosensitivity of laryngeal carcinoma in vitro and in vivo. RESULTS: After transfection of GLUT 1 AS-ODNs: MTS assay showed the survival rates of radiation groups were reduced with the prolongation of culture time (p<0.05); Cell survival rates were significantly reduced along with the increasing of radiation dose (p<0.05). There was significant difference in the expression of GLUT-1mRNA and protein in the same X-ray dose between before and after X-ray radiation (p<0.05). In vivo, the expressions of GLUT-1 mRNA and protein after 8Gy radiation plus transfection of GLUT-1 AS-ODNs were significant decreased compared to 8Gy radiation alone (p<0.001). CONCLUSION: Radioresistance of laryngeal carcinoma may be associated with increased expression of GLUT-1 mRNA and protein. GLUT-1 AS-ODNs may enhance the radiosensitivity of laryngeal carcinoma mainly by inhibiting the expression of GLUT-1. PMID- 23983600 TI - Can mean platelet volume serve as a marker for prostatitis? AB - AIM: The aim of the study was to compare the yield of mean platelet volume (MPV), total prostate specific antigen (tPSA), free prostate specific antigen (fPSA), f/t PSA ratio and complex prostate specific antigen (cPSA) in patients with prostatitis. MATERIAL AND METHOD: The study was designed in the Kayseri Education and Research Hospital. Ninety-six patients with prostatitis were enrolled retrospectively into the study. Laboratory data were obtained from the computerized patient database. We evaluated the correlation between tPSA, fPSa, f/t PSA ratio, cPSA, MPV and extent and aggressiveness of inflammation in the surgical specimens of patients who underwent surgery for benign prostatic hyperplasia (BPH). Inflammation in the prostatic tissues was scored for extent and aggressivity of inflammation using the grading system designed by Irani et al. RESULTS: The total PSA, fPSa, f/t PSA ratio, cPSA and pre- and post-treatment MPV values of each group did not differ (p>0.05) (Table 1). Also there was no correlation between the histopathological grades and the MPV, tPSA, fPSA, f/t PSA ratio and cPSA of patients. However, MPV values significantly decreased after treatment in all grades of prostatitis (p<0.001). CONCLUSION: MPV values may be used as an inflammation marker in patients with prostatitis. PMID- 23983601 TI - Effect of melatonin on the proliferation and differentiation of chondrocytes from rat vertebral body growth plate in vitro. AB - PURPOSE: Abnormal growth of vertebral body growth plate (VBGP) is considered as one of the etiologic factors in the adolescent idiopathic scoliosis (AIS). It was well-known that melatonin was correlated with the emergence and development of AIS. This study aimed to investigate the effect of melatonin on rat VBGP chondrocytes in vitro. METHODS: Chondrocytes were isolated from rat VBGP, and treated with or without melatonin. Cell proliferation was measured by the Alamar Blue assay. Gene expression of collagen type II and aggrecan were evaluated by real-time PCR. Expression of the melatonin receptors (MT1, MT2), proliferating cell nuclear antigen (PCNA, a cell proliferation marker), Sox9 (a chondrocytic differentiation marker) and Smad4 (a common mediator in regulating the proliferation and differentiation of chondrocytes) were detected by Western blotting. RESULTS: Expression of melatonin receptors (MT1, MT2) were detected in the rat VBGP chondrocytes. Melatonin, at 10 and 100 ug/mL concentration, significantly inhibited the proliferation of VBGP-chondrocytes and the gene expression of collagen type II and aggrecan, and down-regulated the protein expression of PCNA, Sox9 and Smad4. In addition, the inhibitory effect of melatonin was reversed by luzindole, a melatonin receptor antagonist. CONCLUSIONS: These results suggest that melatonin at high concentrations can inhibit the proliferation and differentiation of VBGP chondrocytes, which might give some new insight into the pathogenic mechanism of AIS. PMID- 23983602 TI - Differences of circulating inflammatory markers between large- and small vessel disease in patients with acute ischemic stroke. AB - BACKGROUND: The difference of inflammatory response between the pathogenesis of cerebral large- and small vessel disease after stroke remains unclear. In present study, we aim to determine the association of circulating inflammatory markers with different stroke subtype. METHODS: 99 patients with non-cardioembolic stroke were divided into large artery atherosclerosis (LAA) and small-artery occlusion (SAO) according to TOAST classification. A panel of plasma inflammatory markers including leukocyte, lymphocyte, CRP, fibrinogen, D-dimer, CD40L, IFN-gamma, IL 1alpha, IL-1beta, IL-6, IL-8, IL-17 and TNF-alpha were measured within 72 hours following cerebral ischemia. The relation of their levels in plasma with stroke subtype was further studied. All statistical data analysis was performed by SPSS 17.0 software. RESULTS: We found that only CRP were closely associated with stroke subtype (p<0.05). Compared to SAO subgroup, the plasma levels of CRP was higher in LAA subgroup (p<0.05). The predictive efficiency of CRP more than 3.2 for LAA was 85.7% sensitivity. The influencing factor of CRP includes IL-6, lymphocyte, fibrinogen and D-dimer. CONCLUSION: LAA had a stronger activation of inflammation than SAO in the pathogenesis, which was associated with the changes of CRP. PMID- 23983603 TI - Identification and determination of antibiotic susceptibilities of Brucella strains isolated from patients in van, Turkey by conventional and molecular methods. AB - PURPOSE: Brucellosis is a worldwide zoonotic disease and still constitutes a major public health problem. In this study, we aimed to identify biovars of Brucella strains isolated from clinical specimens taken from brucellosis patients from the Eastern Anatolia region as well determine the susceptibility of these isolates to tigecycline and azithromycin, drugs that may serve as alternatives to the conventional drugs used in the therapy. MATERIALS AND METHODS: Seventy-five Brucella spp. isolates were included in the study. All strains were identified by both conventional and molecular methods. Brucella Multiplex PCR kit (FC-Biotech, Code: 0301, Turkey) and B. melitensis biovar typing PCR kit (FC-Biotech, Code: 0302, Turkey) were used for molecular typing. Antimicrobial susceptibilities of all strains were determined by E-tests. RESULTS: By conventional biotyping, 73 strains were identified as B. melitensis biovar 3 and two strains as B. abortus biovar 3. Molecular typing results were compatible with conventional methods. The MIC50 and MIC90 values of doxycycline were 0.047 and 0.094; tigecycline 0.094 and 0.125; trimethoprim/sulfamethoxazole 0.064 and 0.19; ciprofloxacin 0.19 for both; streptomycin 0.75 and 1; rifampin 1 and 2 and azithromycin 4 and 8. According to the MIC values, doxycycline was found to be the most effective antibiotic, followed by tigecycline, trimethoprim-sulfamethoxazole and ciprofloxacin. CONCLUSION: Currently recommended antibiotics for the treatment of brucellosis such as doxycycline, rifampin, streptomycin, trimethoprim-sulfamethoxazole and ciprofloxacin were found to be still effective. While our results showed that tigecycline can be used an alternative agent in the treatment of brucellosis, azithromycin has not been confirmed as an appropriate agent for the treatment. PMID- 23983604 TI - The possible mechanisms underlying the impairment of HIF-1alpha pathway signaling in hyperglycemia and the beneficial effects of certain therapies. AB - Hypoxia-inducible factor 1 alpha (HIF-1alpha), an essential transcription factor which mediates the adaptation of cells to low oxygen tensions, is regulated precisely by hypoxia and hyperglycemia, which are major determinants of the chronic complications associated with diabetes. The process of HIF-1alpha stabilization by hypoxia is clear; however, the mechanisms underlying the potential deleterious effect of hyperglycemia on HIF-1alpha are still controversial, despite reports of a variety of studies demonstrating the existence of this phenomenon. In fact, HIF-1alpha and glucose can sometimes influence each other: HIF-1alpha induces the expression of glycolytic enzymes and glucose metabolism affects HIF-1alpha accumulation in some cells. Although hyperglycemia upregulates HIF-1alpha signaling in some specific cell types, we emphasize the inhibition of HIF-1alpha by high glucose in this review. With regard to the mechanisms of HIF-1alpha impairment, the role of methylglyoxal in impairment of HIF-1alpha stabilization and transactivation ability and the negative effect of reactive oxygen species (ROS) on HIF-1alpha are discussed. Other explanations for the inhibition of HIF-1alpha by high glucose exist: the increased sensitivity of HIF-1alpha to Von Hippel-Lindau (VHL) machinery, the role of osmolarity and proteasome activity, and the participation of several molecules. This review aims to summarize several important developments regarding these mechanisms and to discuss potentially effective therapeutic techniques (antioxidants eicosapentaenoic acid (EPA) and metallothioneins (MTs), pharmaceuticals cobalt chloride (CoCl2), dimethyloxalylglycine (DMOG), desferrioxamine (DFO) and gene transfer of constitutively active forms of HIF 1alpha) and their mechanisms of action for intervention in the chronic complications in diabetes. PMID- 23983605 TI - PITX2c loss-of-function mutations responsible for congenital atrial septal defects. AB - Congenital heart disease (CHD) is the most common form of developmental anomaly and is the leading non-infectious cause of infant mortality. A growing body of evidence demonstrates that genetic risk factors are involved in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disease and the genetic determinants for CHD in most patients remain unclear. In the present study, the entire coding region and splice junction sites of the PITX2c gene, which encodes a homeobox transcription factor crucial for normal cardiovascular genesis, was sequenced in 150 unrelated patients with various CHDs. The 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were explored using a dual-luciferase reporter assay system. As a result, two novel heterozygous PITX2c mutations, p.H98Q and p.M119T, were identified in 2 unrelated patients with atrial septal defects, respectively. The variations were absent in 400 control chromosomes and the affected amino acids were completely conserved evolutionarily. The two variants were both predicted to be disease-causing by MutationTaster and PolyPhen-2, and the functional analysis revealed that the PITX2c mutants were consistently associated with significantly reduced transcriptional activity compared with their wild-type counterpart. These findings firstly link PITX2c loss-of-function mutations to atrial septal defects in humans, which provide novel insight into the molecular mechanism responsible for CHD, suggesting potential implications for the early prophylaxis and allele specific treatment of CHD. PMID- 23983607 TI - Elevated miR-34c-5p mediates dermal fibroblast senescence by ultraviolet irradiation. AB - Previous studies showed that several miRNAs can regulate pathways involved in UVB induced premature senescence and response to ultraviolet irradiation. It has also been reported that miR-34c-5p may be involved in senescence-related mechanisms. We propose that miR-34c-5p may play a crucial role in senescence of normal human primary dermal fibroblasts. Here, we explored the roles of miR-34c-5p in UVB induced premature senescence on dermal fibroblasts. MiR-34c-5p expression was increased in dermal fibroblasts after repeated subcytotoxic UVB treatments. Underexpression of miR-34c-5p in dermal fibroblasts led to a marked delay of many senescent phenotypes induced by repeated UVB treatments. Furthermore, underexpression of miR-34c-5p in dermal fibroblasts can antagonize the alteration of G1-arrested fibroblasts. Moreover, E2F3, which can inactivate p53 pathway and play a role in cell cycle progression, is a down-stream target of miR-34c-5p. Forced down-expression of miR-34c-5p decreased the expression of UVB-SIPS induced P21 and P53 at both mRNA and protein levels. Our data demonstrated that down regulation of miR-34c-5p can protect human primary dermal fibroblasts from UVB induced premature senescence via regulations of some senescence-related molecules. PMID- 23983606 TI - Glutamate signaling in benign and malignant disorders: current status, future perspectives, and therapeutic implications. AB - Glutamate, a nonessential amino acid, is the major excitatory neurotransmitter in the central nervous system. As such, glutamate has been shown to play a role in not only neural processes, such as learning and memory, but also in bioenergetics, biosynthetic and metabolic oncogenic pathways. Glutamate has been the target of intense investigation for its involvement not only in the pathogenesis of benign neurodegenerative diseases (NDDs) such as Parkinson's disease, Alzheimer's disease, schizophrenia, multiple sclerosis, and amyotropic lateral sclerosis (ALS), but also in carcinogenesis and progression of malignant diseases. In addition to its intracellular activities, glutamate in secreted form is a phylogenetically conserved cell signaling molecule. Glutamate binding activates multiple major receptor families including the metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs), both of which have been implicated in various signaling pathways in cancer. Inhibition of extracellular glutamate release or glutamate receptor activation via competitive or non-competitive antagonists decreases growth, migration and invasion and induces apoptosis in breast cancer, melanoma, glioma and prostate cancer cells. In this review, we discuss the current state of glutamate signaling research as it relates to benign and malignant diseases. In addition, we provide a synopsis of clinical trials using glutamate antagonists for the treatment of NDD and malignant diseases. We conclude that in addition to its potential role as a metabolic biomarker, glutamate receptors and glutamate-initiated signaling pathways may provide novel therapeutic opportunities for cancer. PMID- 23983608 TI - Association study of single nucleotide polymorphisms in XRCC1 gene with the risk of gastric cancer in Chinese population. AB - Gastric cancer is one of highly cancer-related deaths in the world. Previous evidence suggests that the X-ray repair cross-complementing group 1 gene (XRCC1) is one of the most important candidate genes for influencing gastric cancer risk. The objective of this study was to detect the potential association of genetic variants in XRCC1 gene with gastric cancer risk in Chinese Han population. In total, we enrolled 395 gastric cancer patients and 398 cancer-free controls in this study. The genotyping of c.910A>G and c.1804C>A genetic variants in XRCC1 gene were investigate by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and created restriction site-PCR (CRS-PCR) methods, respectively. We found the genotypes/alleles from these two genetic variants were statistically associated with the increased risk of gastric cancer (for c.910A>G, GG versus (vs.) AA: OR = 2.00, 95% CI 1.21-3.31; AG vs. AA: OR = 1.50, 95% CI 1.12-2.02; GG/AG vs. AA: OR = 1.59, 95% CI 1.20-2.10; GG vs. AG/AA: OR = 1.68, 95% CI 1.03-2.73; G vs. A: OR = 1.47, 95% CI 1.18-1.83; for c.1804C>A, AA vs. CC: OR = 2.68, 95% CI 1.46-4.94; AA vs. CA/CC: OR = 2.62, 95% CI 1.44 4.76; A vs. C: OR = 1.33, 95% CI 1.06-1.66). The allele-G of c.910A>G and allele A of c.1804C>A genetic variants may contribute to gastric cancer susceptibility. These preliminary results indicate that these XRCC1 genetic variants are potentially related to gastric cancer susceptibility in Chinese Han population, and might be used as molecular markers. PMID- 23983609 TI - Chemokine-like factor 1 (CLFK1) is over-expressed in patients with atopic dermatitis. AB - BACKGROUND: Human chemokine-like factor 1 (CKLF1), a recently discovered chemokine, has a broad spectrum of biological functions in immune-mediated diseases. It is highly expressed on Th2 lymphocytes and is a functional ligand for human CCR4. CKLF1 has a major role in the recruitment and activation of leucocytes, which plays an important role in the pathogenesis of allergic diseases. The present study was designed to determine the expression of CKLF1 in skin and serum in patients with atopic dermatitis (AD). METHODS: The CKLF1 protein expression in skin lesion was analyzed by immunohistochemistry and ELISA. The mRNA expression of CKLF1 in skin lesion was detected by Real-time PCR. The serum levels of CKLF1, IgE, eotaxin, IL-4, IL-5, and IL-13 were measured by ELISA. RESULTS: Histopathological changes in the skin of AD patients showed local inflammation with epidermal thickening and significant inflammatory cellular infiltration. Immunohistochemistry results demonstrated that CKLF1-staining positive cells were located in the epidermal and dermis, and that the CKLF1 expression in AD patients was significantly higher than that in normal control. The CKLF1 mRNA expression in AD patients was significantly higher than that in healthy controls. Serum CKLF1 and IgE levels were significantly increased in AD patients, as were the serum levels of IL-4, IL-5, IL-13 and eotaxin. CONCLUSIONS: Both CKLF1 protien and mRNA levels are overexpressed in the skin lesion of AD patients, along with an increase in serum CKLF1 level, indicating that CKLF1 may play an important role in the development of atopic dermatitis. PMID- 23983610 TI - B19, a novel monocarbonyl analogue of curcumin, induces human ovarian cancer cell apoptosis via activation of endoplasmic reticulum stress and the autophagy signaling pathway. AB - BACKGROUND: The unfolded protein response, autophagy and endoplasmic reticulum (ER) stress-induced apoptosis regulate tumor cell fate and have become novel signaling targets for the development of cancer therapeutic drugs. Curcumin has been used to treat several different cancers, including ovarian cancer, in clinical trials and research; however, the role of ER stress and autophagy in the therapeutic effects of curcumin and new curcumin analogues remains unclear. METHODS: Cell viability was determined using the MTT assay. Apoptosis was detected using flow cytometry with PI/Annexin V-FITC staining. The expression levels of ER stress- and autophagy-related proteins were analyzed by western blotting. The activation of autophagy was detected using immunofluorescence staining. RESULTS: We demonstrated that B19 induced HO8910 cell apoptosis in a dose-responsive manner. We also determined and that this effect was associated with corresponding increases in a series of key components in the UPR and ER stress-mediated apoptosis pathways, followed by caspase 3 cleavage and activation. We also observed that B19 treatment induced autophagy in HO8910 cells. The inhibition of autophagy using 3-methyladenine (3-MA) increased levels of intracellular misfolded proteins, which enhanced ovarian cancer apoptosis. CONCLUSIONS: Our data indicate that ER stress and autophagy may play a role in the apoptosis that is induced by the curcumin analogue B19 in an epithelial ovarian cancer cell line and that autophagy inhibition can increase curcumin analogue-induced apoptosis by inducing severe ER stress. PMID- 23983612 TI - Exploring valid reference genes for quantitative real-time PCR analysis in Plutella xylostella (Lepidoptera: Plutellidae). AB - Quantitative real-time PCR (qRT-PCR), a primary tool in gene expression analysis, requires an appropriate normalization strategy to control for variation among samples. The best option is to compare the mRNA level of a target gene with that of reference gene(s) whose expression level is stable across various experimental conditions. In this study, expression profiles of eight candidate reference genes from the diamondback moth, Plutella xylostella, were evaluated under diverse experimental conditions. RefFinder, a web-based analysis tool, integrates four major computational programs including geNorm, Normfinder, BestKeeper, and the comparative DeltaCt method to comprehensively rank the tested candidate genes. Elongation factor 1 (EF1) was the most suited reference gene for the biotic factors (development stage, tissue, and strain). In contrast, although appropriate reference gene(s) do exist for several abiotic factors (temperature, photoperiod, insecticide, and mechanical injury), we were not able to identify a single universal reference gene. Nevertheless, a suite of candidate reference genes were specifically recommended for selected experimental conditions. Our finding is the first step toward establishing a standardized qRT-PCR analysis of this agriculturally important insect pest. PMID- 23983611 TI - Interaction of crk with Myosin-1c participates in fibronectin-induced cell spreading. AB - We previously reported a novel interaction between v-Crk and myosin-1c, and demonstrated that this interaction is essential for cell migration, even in the absence of p130CAS. We here demonstrate a role for Crk-myosin-1c interaction in cell adhesion and spreading. Crk-knockout (Crk -/-) mouse embryo fibroblasts (MEFs) exhibited significantly decreased cell spreading and reduced Rac1 activity. A stroboscopic analysis of cell dynamics during cell spreading revealed that the cell-spreading deficiency in Crk-/- MEFs was due to the short protrusion/retraction distances and long persistence times of membrane extensions. The low activity of Rac1 in Crk-/- MEFs, which led to delayed cell spreading in these cells, is consistent with the observed defects in membrane dynamics. Reintroduction of v-Crk into Crk-/- MEFs rescued these defects, restoring cell-spreading activity and membrane dynamics to Crk+/+ MEF levels, and normalizing Rac1 activity. Knockdown of myosin-1c by introduction of small interfering RNA resulted in a delay in cell spreading and reduced Rac1 activity to low levels, suggesting that myosin-1c also plays an essential role in cell adhesion and spreading. In addition, deletion of the v-Crk SH3 domain, which interacts with the myosin-1c tail, led to defects in cell spreading. Overexpression of the GFP-myosin-1c tail domain effectively inhibited the v-Crk myosin-1c interaction and led to a slight decrease in cell spreading and cell surface area. Collectively, these findings suggest that the v-Crk-myosin-1c interaction, which modulates membrane dynamics by regulating Rac1 activity, is crucial for cell adhesion and spreading. PMID- 23983613 TI - CD14 targets complement receptor 3 to lipid rafts during phagocytosis of Borrelia burgdorferi. AB - Phagocytosis of Borrelia burgdorferi, the causative agent of Lyme disease, is mediated partly by the interaction of the spirochete with Complement Receptor (CR) 3. CR3 requires the GPI-anchored protein, CD14, in order to efficiently internalize CR3-B. burgdorferi complexes. GPI-anchored proteins reside in cholesterol-rich membrane microdomains, and through its interaction with partner proteins, help initiate signaling cascades. Here, we investigated the role of CD14 on the internalization of B. burgdorferi mediated by CR3. We show that CR3 partly colocalizes with CD14 in lipid rafts. The use of the cholesterol sequestering compound methyl-beta-cyclodextran completely prevents the internalization of the spirochete in CHO cells that co-express CD14 and CR3, while no effect was observed in CD11b-deficient macrophages. These results show that lipid rafts are required for CR3-dependent, but not independent, phagocytosis of B. burgdorferi. Our results also suggest that CD14 interacts with the C-lectin domain of CR3, favoring the formation of multi-complexes that allow their internalization, and the use of beta-glucan, a known ligand for the C lectin domain of CR3, can compensate for the lack of CD14 in CHO cells that express CR3. These results provide evidence to understand the mechanisms that govern the interaction between CR3 and CD14 during the phagocytosis of B. burgdorferi. PMID- 23983614 TI - The neuroprotective effects of Coccomyxa gloeobotrydiformis on the ischemic stroke in a rat model. AB - Stroke is a major cause of mortality and the leading cause of permanent disability. In this study, we adopted the classic middle cerebral artery occlusion(MCAO) stroke model to observe the therapeutic effects of coccomyxa gloeobotrydiformis(CGD) on ischemic stroke, and discuss the underlying mechanisms. Low dose (50 mg/kg.day) and high dose (100 mg/kg.day) concentrations of the drug CGD were intragastrically administrated separately for 8 weeks. Infarct volumes, neurologic deficits and degree of stroke-induced brain edema were measured 24 hours after reperfusion. Furthermore, oxidative stress related factors (SOD and MDA), mitochondrial membrane potential, and apoptosis regulatory factors (mitochondrial Cyt-C, Bcl-2, Bax, and caspase-3) were all investigated in this research. We found that CGD attenuated cerebral infarction, brain edema and neurologic deficits; CGD maintained the mitochondrial membrane potential and decreased mitochondrial swelling. It also prevented oxidative damage by reducing MDA and increasing SOD. In addition, CGD could effectively attenuate apoptosis by restoring the level of mitochondrial Cyt C and regulating the expression of Bcl 2, Bax and caspase 3. These results revealed that CGD has a therapeutic effect on ischemic stroke, possibly by inducing mitochondrial protection and anti-apoptotic mechanisms. PMID- 23983615 TI - Stem cell research: a novel boulevard towards improved bovine mastitis management. AB - The dairy industry is a multi-billion dollar industry catering the nutritional needs of all age groups globally through the supply of milk. Clinical mastitis has a severe impact on udder tissue and is also an animal welfare issue. Moreover, it significantly reduces animal value and milk production. Mammary tissue damage reduces the number and activity of epithelial cells and consequently contributes to decreased milk production. The high incidence, low cure rate of this highly economic and sometimes deadly disease is an alarming for dairy sector as well as policy makers. Bovine mammary epithelial cells (MECs) and their stem cells are very important in milk production and bioengineering. The adult mammary epithelium consists of two main cell types; an inner layer of luminal epithelial cells, which produce the milk during lactation, and an outer layer of myoepithelial cells resting on a basement membrane, which are responsible for pushing the milk through the ductal network to the teat cistern. Inner layer of columner/luminal cells of bovine MECs, is characterized by cytokeratin18, 19 (CK18, CK19) and outer layer such as myoepithelial cells which are characterized by CK14, alpha-smooth muscle actin (alpha-SMA) and p63. Much work has been done in mouse and human, on mammary gland stem cell research, particularly in cancer therapy, but stem cell research in bovine is still in its infancy. Such stem/progenitor cell discoveries in human and mouse mammary gland bring some hope for application in bovines. These progenitors may be therapeutically adopted to correct the structural/cytological defects in the bovine udder due to mastitis. In the present review we focused on various kinds of stem/progenitor cells which can have therapeutic utility and their possibilities to use as a potential stem cell therapy in the management of bovine post-mastitis damage in orders to restore milk production. The possibilities of bovine mammary stem cell therapy offers significant potential for regeneration of tissues that can potentially replace/repair diseased and damaged tissue through differentiation into epithelial, myoepithelial and/or cuboidal/columnar cells in the udder with minimal risk of rejection and side effects. PMID- 23983616 TI - PTHrP expression in human MDA-MB-231 breast cancer cells is critical for tumor growth and survival and osteoblast inhibition. AB - This study examined the effects of parathyroid hormone-related protein (PTHrP) derived from human MDA-MB-231 breast cancer cells on the tumor growth and osteoblast inhibition. Results revealed that knocking down PTHrP expression in the breast cancer cells strikingly inhibited the formation of subcutaneous tumors in nude mice. PTHrP knockdown dramatically decreased the levels of cyclins D1 and A1 proteins and arrested the cell cycle progression at the G1 stage. PTHrP knockdown led to the cleavage of Caspase 8 and induced apoptosis of the tumor cells. Interestingly, knocking down PTHrP increased the levels of Beclin1 and LC3 II and promoted the formation of autophagosomes. Knocking down PTHrP expression significantly reduced the abilities of the breast cancer cells to inhibit osteoblast differentiation and bone formation in vitro and in vivo. Finally, we found that PTHrP activated its own expression through an autocrine mechanism in MDA-MB-231 cells. Collectively, these studies suggest that targeting PTHrP expression in the tumor cells could be a potential therapeutic strategy for breast cancers, especially those with skeletal metastases. PMID- 23983618 TI - Archaeal assemblages inhabiting temperate mixed forest soil fluctuate in taxon composition and spatial distribution over time. AB - This study explored the persistence and spatial distribution of a diverse Archaeal assemblage inhabiting a temperate mixed forest ecosystem. Persistence under native conditions was measured from 2001 to 2010, 2011, and 2012 by comparison of 16S rRNA gene clone libraries. The Archaeal assemblages at each of these time points were found to be significantly different (AMOVA, P < 0.01), and the nature of this difference was dependent on taxonomic rank. For example, the cosmopolitan genus g_Ca. Nitrososphaera (I.1b) was detected at all time points, but within this taxon the abundance of s_SCA1145, s_SCA1170, and s_Ca. N. gargensis fluctuated over time. In addition, spatial heterogeneity (patchiness) was measured at these time points using 1D TRFLP-SSCP fingerprinting to screen soil samples covering multiple spatial scales. This included soil collected from small volumes of 3 cubic centimeters to larger scales-over a surface area of 50 m(2), plots located 1.3 km apart, and a separate locality 23 km away. The spatial distribution of Archaea in these samples changed over time, and while g_Ca. Nitrososphaera (I.1b) was dominant over larger scales, patches were found at smaller scales that were dominated by other taxa. This study measured the degree of change for Archaeal taxon composition and patchiness over time in temperate mixed forest soil. PMID- 23983617 TI - Inorganic polyphosphates regulate hexokinase activity and reactive oxygen species generation in mitochondria of Rhipicephalus (Boophilus) microplus embryo. AB - The physiological roles of polyphosphates (poly P) recently found in arthropod mitochondria remain obscure. Here, the possible involvement of poly P with reactive oxygen species generation in mitochondria of Rhipicephalus microplus embryos was investigated. Mitochondrial hexokinase and scavenger antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione reductase were assayed during embryogenesis of R. microplus. The influence of poly P3 and poly P15 were analyzed during the period of higher enzymatic activity during embryogenesis. Both poly Ps inhibited hexokinase activity by up to 90% and, interestingly, the mitochondrial membrane exopolyphosphatase activity was stimulated by the hexokinase reaction product, glucose-6-phosphate. Poly P increased hydrogen peroxide generation in mitochondria in a situation where mitochondrial hexokinase is also active. The superoxide dismutase, catalase and glutathione reductase activities were higher during embryo cellularization, at the end of embryogenesis and during embryo segmentation, respectively. All of the enzymes were stimulated by poly P3. However, superoxide dismutase was not affected by poly P15, catalase activity was stimulated only at high concentrations and glutathione reductase was the only enzyme that was stimulated in the same way by both poly Ps. Altogether, our results indicate that inorganic polyphosphate and mitochondrial membrane exopolyphosphatase regulation can be correlated with the generation of reactive oxygen species in the mitochondria of R. microplus embryos. PMID- 23983619 TI - Assessment of the present and future offshore wind power potential: a case study in a target territory of the Baltic Sea near the Latvian coast. AB - Offshore wind energy development promises to be a significant domestic renewable energy source in Latvia. The reliable prediction of present and future wind resources at offshore sites is crucial for planning and selecting the location for wind farms. The overall goal of this paper is the assessment of offshore wind power potential in a target territory of the Baltic Sea near the Latvian coast as well as the identification of a trend in the future wind energy potential for the study territory. The regional climate model CLM and High Resolution Limited Area Model (Hirlam) simulations were used to obtain the wind climatology data for the study area. The results indicated that offshore wind energy is promising for expanding the national electricity generation and will continue to be a stable resource for electricity generation in the region over the 21st century. PMID- 23983620 TI - New photoplethysmographic signal analysis algorithm for arterial stiffness estimation. AB - The ability to identify premature arterial stiffening is of considerable value in the prevention of cardiovascular diseases. The "ageing index" (AGI), which is calculated from the second derivative photoplethysmographic (SDPPG) waveform, has been used as one method for arterial stiffness estimation and the evaluation of cardiovascular ageing. In this study, the new SDPPG analysis algorithm is proposed with optimal filtering and signal normalization in time. The filter parameters were optimized in order to achieve the minimal standard deviation of AGI, which gives more effective differentiation between the levels of arterial stiffness. As a result, the optimal low-pass filter edge frequency of 6 Hz and transitionband of 1 Hz were found, which facilitates AGI calculation with a standard deviation of 0.06. The study was carried out on 21 healthy subjects and 20 diabetes patients. The linear relationship (r = 0.91) between each subject's age and AGI was found, and a linear model with regression line was constructed. For diabetes patients, the mean AGI value difference from the proposed model y AGI was found to be 0.359. The difference was found between healthy and diabetes patients groups with significance level of P < 0.0005. PMID- 23983621 TI - CIB: an improved communication architecture for real-time monitoring of aerospace materials, instruments, and sensors on the ISS. AB - The Communications Interface Board (CIB) is an improved communications architecture that was demonstrated on the International Space Station (ISS). ISS communication interfaces allowing for real-time telemetry and health monitoring require a significant amount of development. The CIB simplifies the communications interface to the ISS for real-time health monitoring, telemetry, and control of resident sensors or experiments. With a simpler interface available to the telemetry bus, more sensors or experiments may be flown. The CIB accomplishes this by acting as a bridge between the ISS MIL-STD-1553 low-rate telemetry (LRT) bus and the sensors allowing for two-way command and telemetry data transfer. The CIB was designed to be highly reliable and radiation hard for an extended flight in low Earth orbit (LEO) and has been proven with over 40 months of flight operation on the outside of ISS supporting two sets of flight experiments. Since the CIB is currently operating in flight on the ISS, recent results of operations will be provided. Additionally, as a vehicle health monitoring enabling technology, an overview and results from two experiments enabled by the CIB will be provided. Future applications for vehicle health monitoring utilizing the CIB architecture will also be discussed. PMID- 23983622 TI - Online monitoring oxidative products and metabolites of nicotine by free radicals generation with Fenton reaction in tandem mass spectrometry. AB - In general, over 70% absorbed nicotine is metabolized to cotinine and trans-3' hydroxycotinine by cytochrome oxidase P450, and nicotine is also a major addictive and the psychoactive component in cigarettes. As a xenobiotic metabolism, hydrophobic compounds are usually converted into more hydrophilic products through enzyme systems such as cytochrome oxidase P450, sulfotransferases, and UDP-glucuronosyltransferases to deliver drug metabolites out of the cell during the drug metabolic process. In this study, an electrodeless electrochemical oxidation (EEO) reaction via Fenton reaction by producing free radical to react with nicotine to immediately monitor the oxidative products and metabolic derivatives of nicotine by tandem mass spectrometer (MS) is done. Fenton reaction generates free radicals via ferrous ion (Fe(2+)) and hydrogen peroxide (H2O2) to oxidize DNA and to degrade proteins in cells. In the EEO method, the oxidative products of nicotine including cotinine, cotinine-N-oxide, trans-3'-hydroxycotinine, nornicotine, norcotinine, 4 oxo-4-(3-pyridyl)-butanoic acid, 4-hydroxy-4-(3-pyridyl)-butanoic acid, and nicotine-N'-oxide were detected by tandem mass spectrometer to simulate the changes of nicotine and its derivatives in a time-dependent manner. PMID- 23983623 TI - Simulation of nonisothermal consolidation of saturated soils based on a thermodynamic model. AB - Based on the nonequilibrium thermodynamics, a thermo-hydro-mechanical coupling model for saturated soils is established, including a constitutive model without such concepts as yield surface and flow rule. An elastic potential energy density function is defined to derive a hyperelastic relation among the effective stress, the elastic strain, and the dry density. The classical linear non-equilibrium thermodynamic theory is employed to quantitatively describe the unrecoverable energy processes like the nonelastic deformation development in materials by the concepts of dissipative force and dissipative flow. In particular the granular fluctuation, which represents the kinetic energy fluctuation and elastic potential energy fluctuation at particulate scale caused by the irregular mutual movement between particles, is introduced in the model and described by the concept of granular entropy. Using this model, the nonisothermal consolidation of saturated clays under cyclic thermal loadings is simulated in this paper to validate the model. The results show that the nonisothermal consolidation is heavily OCR dependent and unrecoverable. PMID- 23983625 TI - Micropropagation of Origanum acutidens (HAND.-MAZZ.) IETSWAART using stem node explants. AB - Origanum acutidens (HAND.-MAZZ.) IETSWAART is a promising ornamental plant that can be widely used in landscape management. It is endemic to Eastern Anatolian region of Turkey. Tissue culture has not been used to micropropagate it. The study reports stem node explants from one-week-old seedlings of the plant for successful micropropagation. The stem nodes were cultured on MS medium containing 0.6, 1.2, 1.8, and 2.4 mg/L BAP with 0.2 mg/L NAA. Visible effects of culture media on shoot proliferation were recorded. Shoot regeneration rate was maximum on MS medium containing 1.80 mg/L BAP-0.2 mg/L NAA. The micropropagated shoots were rooted on MS medium containing 0.2 mg/L NAA. All microrooted plantlets survived during acclimatisation on peat moss. It was concluded that O. acutidens can be successfully micropropagated under in vitro conditions. PMID- 23983624 TI - Functional ginger extracts from supercritical fluid carbon dioxide extraction via in vitro and in vivo assays: antioxidation, antimicroorganism, and mice xenografts models. AB - Supercritical fluid carbon dioxide extraction technology was developed to gain the active components from a Taiwan native plant, Zingiber officinale (ginger). We studied the biological effects of ginger extracts via multiple assays and demonstrated the biofunctions in each platform. Investigations of ginger extracts indicated antioxidative properties in dose-dependant manners on radical scavenging activities, reducing powers and metal chelating powers. We found that ginger extracts processed moderate scavenging values, middle metal chelating levels, and slight ferric reducing powers. The antibacterial susceptibility of ginger extracts on Staphylococcus aureus, Streptococcus sobrinus, S. mutans, and Escherichia coli was determined with the broth microdilution method technique. The ginger extracts had operative antimicroorganism potentials against both Gram positive and Gram-negative bacteria. We further discovered the strong inhibitions of ginger extracts on lethal carcinogenic melanoma through in vivo xenograft model. To sum up, the data confirmed the possible applications as medical cosmetology agents, pharmaceutical antibiotics, and food supplements. PMID- 23983626 TI - Shoot organogenesis and plant regeneration from leaf explants of Lysionotus serratus D. Don. AB - The gesneriaceous perennial plant, Lysionotus serratus, has been used in traditional Chinese medicine. It also has a great development potential as an ornamental plant with its attractive foliage and beautiful flowers. An efficient propagation and regeneration system via direct shoot organogenesis from leaf explant was established in this study. High active cytokinin (6-benzyladenine (BA) or thidiazuron (TDZ)) was effective for direct organogenesis of initial induction. Murashige and Skoog (MS) growth media containing 0.5 mg L(-1) BA alone or with combination of 0.1 mg L(-1) alpha-Naphthaleneacetic acid (NAA) were the most effective for shoot proliferation. High BA concentration (1.0 mg L(-1)) in the media caused high percentage of vitrified shoots though they introduced high shoot proliferation rate. Histological observation indicated that adventitious shoot regeneration on the medium containing 0.5 mg L(-1) BA alone occurred directly from leaf epidermal cells without callus formation. Regenerated shoots rooted well on medium containing half-strength MS medium with 0.5 mg L(-1) indole 3-butyric acid (IBA) and indole-3-acetic acid (IAA), and the plantlets successfully acclimatized and grew vigorously in the greenhouse with a 94.2% and 92.1% survival rate. PMID- 23983627 TI - On weak exponential expansiveness of evolution families in Banach spaces. AB - The aim of this paper is to give several characterizations for the property of weak exponential expansiveness for evolution families in Banach spaces. Variants for weak exponential expansiveness of some well-known results in stability theory (Datko (1973), Rolewicz (1986), Ichikawa (1984), and Megan et al. (2003)) are obtained. PMID- 23983628 TI - Numerical simulation for thermal shock resistance of thermal protection materials considering different operating environments. AB - Based on the sensitivities of material properties to temperature and the complexity of service environment of thermal protection system on the spacecraft, ultrahigh-temperature ceramics (UHTCs), which are used as thermal protection materials, cannot simply consider thermal shock resistance (TSR) of the material its own but need to take the external constraint conditions and the thermal environment into full account. With the thermal shock numerical simulation on hafnium diboride (HfB2), a detailed study of the effects of the different external constraints and thermal environments on the TSR of UHTCs had been made. The influences of different initial temperatures, constraint strengths, and temperature change rates on the TSR of UHTCs are discussed. This study can provide a more intuitively visual understanding of the evolution of the TSR of UHTCs during actual operation conditions. PMID- 23983629 TI - Nitrate-nitrogen leaching and modeling in intensive agriculture farmland in China. AB - Protecting water resources from nitrate-nitrogen (NO3-N) contamination is an important public health concern and a major national environmental issue in China. Loss of NO3-N in soils due to leaching is not only one of the most important problems in agriculture farming, but is also the main factor causing nitrogen pollution in aquatic environments. Three typical intensive agriculture farmlands in Jiangyin City in China are selected as a case study for NO3-N leaching and modeling in the soil profile. In this study, the transport and fate of NO3-N within the soil profile and nitrate leaching to drains were analyzed by comparing field data with the simulation results of the LEACHM model. Comparisons between measured and simulated data indicated that the NO3-N concentrations in the soil and nitrate leaching to drains are controlled by the fertilizer practice, the initial conditions and the rainfall depth and distribution. Moreover, the study reveals that the LEACHM model gives a fair description of the NO3-N dynamics in the soil and subsurface drainage at the field scale. It can also be concluded that the model after calibration is a useful tool to optimize as a function of the combination "climate-crop-soil-bottom boundary condition" the nitrogen application strategy resulting for the environment in an acceptable level of nitrate leaching. The findings in this paper help to demonstrate the distribution and migration of nitrogen in intensive agriculture farmlands, as well as to explore the mechanism of groundwater contamination resulting from agricultural activities. PMID- 23983630 TI - Traumatic brain injury in Qatar: age matters--insights from a 4-year observational study. AB - BACKGROUND: Overall traumatic brain injury (TBI) incidence and related death rates vary across different age groups. Objectives. To evaluate the incidence, causes, and outcome of TBI in adolescents and young adult population in Qatar. METHOD: This was a retrospective review of all TBIs admitted to the trauma center between January 2008 and December 2011. Demographics, mechanism of injury, morbidity, and mortality were analyzed in different age groups. RESULTS: A total of 1665 patients with TBI were admitted; the majority were males (92%) with a mean age of 28 +/- 16 years. The common mechanism of injury was motor vehicle crashes and falls from height (51% and 35%, resp.). TBI was incidentally higher in young adults (34%) and middle age group (21%). The most frequent injuries were contusion (40%), subarachnoid (25%), subdural (24%), and epidural hemorrhage (18%). The mortality rate was 11% among TBI patients. Mortality rates were 8% and 12% among adolescents and young adults, respectively. The highest mortality rate was observed in elderly patients (35%). Head AIS, ISS, and age were independent predictors for mortality. CONCLUSION: Adolescents and adults sustain significant portions of TBI, whereas mortality is much higher in the older group. Public awareness and injury prevention campaigns should target young population. PMID- 23983631 TI - Desferrioxamine reduces oxidative stress in the lung contusion. AB - Our hypothesis in this study is that desferrioxamine (DFX) has therapeutic effects on experimental lung contusions in rats. The rats were divided into four groups (n = 8): control, control+DFX, contusion, and contusion+DFX. In the control+DFX and contusion+DFX groups, 100 mg/kg DFX was given intraperitoneally once a day just after the contusion and the day after the contusion. Contusions led to a meaningful rise in the malondialdehyde (MDA) level in lung tissue. MDA levels in the contusion+DFX group experienced a significant decline. Glutathione levels were significantly lower in the contusion group than in the control group and significantly higher in the contusion+DFX group. Glutathione peroxidase (GPx) and superoxide dismutase (SOD) levels in the contusion group were significantly lower than those in the control group. In the contusion+DFX group, SOD and GPx levels were significantly higher than those in the contusion group. In light microscopic evaluation, the contusion and contusion+DFX groups showed edema, hemorrhage, alveolar destruction, and leukocyte infiltration. However, histological scoring of the contusion+DFX group was significantly more positive than that of the contusion group. The iNOS staining in the contusion group was significantly more intensive than that in all other groups. DFX reduced iNOS staining significantly in comparison to the contusion group. This study showed that DFX reduced oxidative stress in lung contusions in rats and histopathologically ensured the recovery of the lung tissue. PMID- 23983632 TI - Feature selection method based on artificial bee colony algorithm and support vector machines for medical datasets classification. AB - This paper offers a hybrid approach that uses the artificial bee colony (ABC) algorithm for feature selection and support vector machines for classification. The purpose of this paper is to test the effect of elimination of the unimportant and obsolete features of the datasets on the success of the classification, using the SVM classifier. The developed approach conventionally used in liver diseases and diabetes diagnostics, which are commonly observed and reduce the quality of life, is developed. For the diagnosis of these diseases, hepatitis, liver disorders and diabetes datasets from the UCI database were used, and the proposed system reached a classification accuracies of 94.92%, 74.81%, and 79.29%, respectively. For these datasets, the classification accuracies were obtained by the help of the 10-fold cross-validation method. The results show that the performance of the method is highly successful compared to other results attained and seems very promising for pattern recognition applications. PMID- 23983633 TI - Phytoplankton and eutrophication degree assessment of Baiyangdian Lake wetland, China. AB - Eight typical sampling sites were chosen to investigate the phytoplankton community structure and to assess the eutrophication degree of Baiyangdian Lake in 2009. Our results showed that among the total 133 species identified, Cyanophyta, Chlorophyta, and Bacillariophyta dominated the phytoplankton community. In spring, Chlorophyta and Bacillariophyta were the dominant phyla, and the dominant species included Chlorella sp., Chroomonas acuta Uterm., and Microcystis incerta Lemm.; the density of the phytoplankton ranged from 496 * 10(4) to 6256 * 10(4) cells/L with an average of 2384 * 10(4) cells/L. However, Chlorophyta and Cyanophyta became the dominant phyla in summer, and the dominant species were Chlorella sp., Leptolyngbya valderiana Anagn., and Nephrocytium agardhianum Nageli.; the density of the phytoplankton varied from 318 * 10(4) to 4630 * 10(4) cells/L with an average of 1785 * 10(4) cells/L. The density of the phytoplankton has increased significantly compared to the previous investigations in 2005. The index of Carlson nutritional status (TSIM) and the dominant genus assessment indicated that the majority of Baiyangdian Lake was in eutrophic state. PMID- 23983634 TI - Effects of resveratrol on methotrexate-induced testicular damage in rats. AB - This study investigated the probable protective effects of resveratrol (RES), an antioxidant, against methotrexate- (MTX-) induced testis damage. Twenty-four male Sprague Dawley rats were randomly divided into four groups: control, RES, MTX, and MTX + RES groups. Rats were sacrificed at the end of the experiment. Plasma and tissue malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activity in tissue, testicular histopathological damage scores, and testicular and epididymal epithelial apoptotic index (AI) were evaluated. The MTX group had significantly higher plasma and tissue MDA levels and significantly lower SOD and CAT activity than those of the control group. In the MTX + RES group, plasma and tissue MDA levels decreased significantly and SOD activity rose significantly compared to the MTX group. The MTX group had significantly lower Johnsen's testicular biopsy score (JTBS) values than those of the control group. JTBS was significantly higher in the MTX + RES group than in the MTX group. AI increased in the testis and epididymis in the MTX group and significantly decreased in the MTX + RES group. Our results indicate that RES has protective effects against MTX-induced testis damage at the biochemical, histopathological, and apoptotic levels. PMID- 23983636 TI - Existence of multiple solutions for a p-Kirchhoff problem with nonlinear boundary conditions. AB - The paper considers the existence of multiple solutions of the singular nonlocal elliptic problem [formula: see text]. By the variational method on the Nehari manifold, we prove that the problem has at least two positive solutions when some conditions are satisfied. PMID- 23983635 TI - Genetic transformation in citrus. AB - Citrus is one of the world's important fruit crops. Recently, citrus molecular genetics and biotechnology work have been accelerated in the world. Genetic transformation, a biotechnological tool, allows the release of improved cultivars with desirable characteristics in a shorter period of time and therefore may be useful in citrus breeding programs. Citrus transformation has now been achieved in a number of laboratories by various methods. Agrobacterium tumefaciens is used mainly in citrus transformation studies. Particle bombardment, electroporation, A. rhizogenes, and a new method called RNA interference are used in citrus transformation studies in addition to A. tumefaciens. In this review, we illustrate how different gene transformation methods can be employed in different citrus species. PMID- 23983638 TI - A multiuser detector based on artificial bee colony algorithm for DS-UWB systems. AB - Artificial Bee Colony (ABC) algorithm is an optimization algorithm based on the intelligent behavior of honey bee swarm. The ABC algorithm was developed to solve optimizing numerical problems and revealed premising results in processing time and solution quality. In ABC, a colony of artificial bees search for rich artificial food sources; the optimizing numerical problems are converted to the problem of finding the best parameter which minimizes an objective function. Then, the artificial bees randomly discover a population of initial solutions and then iteratively improve them by employing the behavior: moving towards better solutions by means of a neighbor search mechanism while abandoning poor solutions. In this paper, an efficient multiuser detector based on a suboptimal code mapping multiuser detector and artificial bee colony algorithm (SCM-ABC-MUD) is proposed and implemented in direct-sequence ultra-wideband (DS-UWB) systems under the additive white Gaussian noise (AWGN) channel. The simulation results demonstrate that the BER and the near-far effect resistance performances of this proposed algorithm are quite close to those of the optimum multiuser detector (OMD) while its computational complexity is much lower than that of OMD. Furthermore, the BER performance of SCM-ABC-MUD is not sensitive to the number of active users and can obtain a large system capacity. PMID- 23983637 TI - Chemical constituents antioxidant and anticholinesterasic activity of Tabernaemontana catharinensis. AB - The present work aimed to analyze the alkaloid content of the ethanolic extract of Tabernaemontana catharinensis (Apocynaceae family) and its fractions as well as to evaluate their antioxidant and anticholinesterasic activities. The analyses of the ethanolic extract of T. catharinensis by mass spectrometry allowed identifying the presence of the alkaloids 16-epi-affinine, coronaridine hydroxyindolenine, voachalotine, voacristine-hydroxyindolenine, and 12-methoxy-n methyl-voachalotine, as well as an alkaloid with m/z 385.21 whose spectrum suggests a derivative of voacristine or voacangine. The extract and its alkaloid rich fractions showed antioxidant activity, especially those that contain the alkaloid m/z 385.21 or 16-epi-affinine with DPPH scavenging activity (IC50) between 37.18 and 74.69 MUg/mL. Moreover, the extract and its fractions exhibited anticholinesterasic activity, particularly the fractions characterized by the presence of 12-methoxy-n-methyl-voachalotine, with IC50 = 2.1 to 2.5 MUg/mL. Fractions with 16-epi-affinine combined good antioxidant (IC50 = 65.59 to 74.69 MUg/mL) and anticholinesterasic (IC50 = 7.7 to 8.3 MUg/mL) activities, representing an option for further studies aimed at treating neurodegenerative diseases. PMID- 23983639 TI - Applications of the MVWG multivariable stochastic weather generator. AB - Weather generators (WG) became significant modules of crop models and decision support systems in the past decade. Using a large meteorological database from North America; two basic problems, related to the applicability of WGs in case of short or lacking data series, were investigated in the framework of the Multivariable weather generator (MVWG). First, the minimum data series length, required for adequate parameterization of the WG, was determined. Our results suggest that 15 years of observed data are enough for adequate parameterization of the MVWG. We then investigated a possibility of spatial interpolation of WG parameters using the outputs of the WG for sites with no meteorological observations. Coupled with the presented interpolation technique, MVWG was able to generate realistic weather data for sites with no measurements situated in climatically and geographically homogeneous regions. PMID- 23983640 TI - Design and experimental evaluation of a robust position controller for an electrohydrostatic actuator using adaptive antiwindup sliding mode scheme. AB - A robust control scheme is proposed for the position control of the electrohydrostatic actuator (EHA) when considering hardware saturation, load disturbance, and lumped system uncertainties and nonlinearities. To reduce overshoot due to a saturation of electric motor and to realize robustness against load disturbance and lumped system uncertainties such as varying parameters and modeling error, this paper proposes an adaptive antiwindup PID sliding mode scheme as a robust position controller for the EHA system. An optimal PID controller and an optimal anti-windup PID controller are also designed to compare control performance. An EHA prototype is developed, carrying out system modeling and parameter identification in designing the position controller. The simply identified linear model serves as the basis for the design of the position controllers, while the robustness of the control systems is compared by experiments. The adaptive anti-windup PID sliding mode controller has been found to have the desired performance and become robust against hardware saturation, load disturbance, and lumped system uncertainties and nonlinearities. PMID- 23983641 TI - Proximate analysis of five wild fruits of Mozambique. AB - Mozambique is rich in wild fruit trees, most of which produce fleshy fruits commonly consumed in rural communities, especially during dry seasons. However, information on their content of macronutrients is scarce. Five wild fruit species (Adansonia digitata, Landolphia kirkii, Sclerocarya birrea, Salacia kraussii, and Vangueria infausta) from different districts in Mozambique were selected for the study. The contents of dry matter, fat, protein, ash, sugars, pH, and titratable acidity were determined in the fruit pulps. Also kernels of A. digitata and S. birrea were included in the study. The protein content in the pulp was below 5 g/100 g of dry matter, but a daily intake of 100 g fresh wild fruits would provide up to 11% of the recommended daily intake for children from 4 to 8 years old. The sugar content varied between 2.3% and 14.4% fresh weight. The pH was below 3, except for Salacia kraussii, for which it was slightly below 7. Kernels of A. digitata contained, on average, 39.2% protein and 38.0% fat, and S. birrea kernels 32.6% protein and 60.7% fat. The collection of nutritional information may serve as a basis for increased consumption and utilization. PMID- 23983643 TI - Optimal design of an ultrasmall SOI-based 1 * 8 flat-top AWG by using an MMI. AB - Four methods based on a multimode interference (MMI) structure are optimally designed to flatten the spectral response of silicon-on-insulator- (SOI-) based arrayed-waveguide grating (AWG) applied in a demodulation integration microsystem. In the design for each method, SOI is selected as the material, the beam propagation method is used, and the performances (including the 3 dB passband width, the crosstalk, and the insertion loss) of the flat-top AWG are studied. Moreover, the output spectrum responses of AWGs with or without a flattened structure are compared. The results show that low insertion loss, crosstalk, and a flat and efficient spectral response are simultaneously achieved for each kind of structure. By comparing the four designs, the design that combines a tapered MMI with tapered input/output waveguides, which has not been previously reported, was shown to yield better results than others. The optimized design reduced crosstalk to approximately -21.9 dB and had an insertion loss of 4.36 dB and a 3 dB passband width, that is, approximately 65% of the channel spacing. PMID- 23983642 TI - Cytochrome p450 metabolism of betel quid-derived compounds: implications for the development of prevention strategies for oral and pharyngeal cancers. AB - Betel quid (BQ) products, with or without tobacco, have been classified by the International Agency for Research on Cancer (IARC) as group I human carcinogens that are associated with an elevated risk of oral potentially malignant disorders (OPMDs) and cancers of the oral cavity and pharynx. There are estimated 600 million BQ users worldwide. In Taiwan alone there are 2 million habitual users (approximately 10% of the population). Oral and pharyngeal cancers result from interactions between genes and environmental factors (BQ exposure). Cytochrome p450 (CYP) families are implicated in the metabolic activation of BQ- and areca nut-specific nitrosamines. In this review, we summarize the current knowledge base regarding CYP genetic variants and related oral disorders. In clinical applications, we focus on cancers of the oral cavity and pharynx and OPMDs associated with CYP gene polymorphisms, including CYP1A1, CYP2A6, CYP2E1, and CYP26B1. Our discussion of CYP polymorphisms provides insight into the importance of screening tests in OPMDs patients for the prevention of oral and pharyngeal cancers. Future studies will establish a strong foundation for the development of chemoprevention strategies, polymorphism-based clinical diagnostic tools (e.g., specific single-nucleotide polymorphism (SNP) "barcodes"), and effective treatments for BQ-related oral disorders. PMID- 23983644 TI - The effects of different representations on static structure analysis of computer malware signatures. AB - The continuous growth of malware presents a problem for internet computing due to increasingly sophisticated techniques for disguising malicious code through mutation and the time required to identify signatures for use by antiviral software systems (AVS). Malware modelling has focused primarily on semantics due to the intended actions and behaviours of viral and worm code. The aim of this paper is to evaluate a static structure approach to malware modelling using the growing malware signature databases now available. We show that, if malware signatures are represented as artificial protein sequences, it is possible to apply standard sequence alignment techniques in bioinformatics to improve accuracy of distinguishing between worm and virus signatures. Moreover, aligned signature sequences can be mined through traditional data mining techniques to extract metasignatures that help to distinguish between viral and worm signatures. All bioinformatics and data mining analysis were performed on publicly available tools and Weka. PMID- 23983645 TI - Epidural catheter placement in morbidly obese parturients with the use of an epidural depth equation prior to ultrasound visualization. AB - BACKGROUND: Previously, Balki determined the Pearson correlation coefficient with the use of ultrasound (US) was 0.85 in morbidly obese parturients. We aimed to determine if the use of the epidural depth equation (EDE) in conjunction with US can provide better clinical correlation in estimating the distance from the skin to the epidural space in morbidly obese parturients. METHODS: One hundred sixty morbidly obese (>=40 kg/m(2)) parturients requesting labor epidural analgesia were enrolled. Before epidural catheter placement, EDE was used to estimate depth to the epidural space. This estimation was used to help visualize the epidural space with the transverse and midline longitudinal US views and to measure depth to epidural space. The measured epidural depth was made available to the resident trainee before needle insertion. Actual needle depth (ND) to the epidural space was recorded. RESULTS: Pearson's correlation coefficients comparing actual (ND) versus US estimated depth to the epidural space in the longitudinal median and transverse planes were 0.905 (95% CI: 0.873 to 0.929) and 0.899 (95% CI: 0.865 to 0.925), respectively. CONCLUSION: Use of the epidural depth equation (EDE) in conjunction with the longitudinal and transverse US views results in better clinical correlation than with the use of US alone. PMID- 23983646 TI - GmNAC5, a NAC transcription factor, is a transient response regulator induced by abiotic stress in soybean. AB - GmNAC5 is a member of NAM subfamily belonging to NAC transcription factors in soybean (Glycine max (L.) Merr.). Studies on NAC transcription factors have shown that this family functioned in the regulation of shoot apical meristem (SAM), hormone signalling, and stress responses. In this study, we examined the expression levels of GmNAC5. GmNAC5 was highly expressed in the roots and immature seeds, especially strongly in immature seeds of 40 days after flowering. In addition, we found that GmNAC5 was induced by mechanical wounding, high salinity, and cold treatments but was not induced by abscisic acid (ABA). The subcellular localization assay suggested that GmNAC5 was targeted at nucleus. Together, it was suggested that GmNAC5 might be involved in seed development and abiotic stress responses in soybean. PMID- 23983647 TI - Cyclosporine regimens in plaque psoriasis: an overview with special emphasis on dose, duration, and old and new treatment approaches. AB - Cyclosporine A (CsA) is one of the most effective systemic drugs available for the treatment of psoriasis, as evidenced by the results of several randomized studies and by a prolonged experience in dermatological setting. In clinical practice, CsA is usually used for the induction of psoriasis remission at a daily dose included in the range of 2.5-5 mg/kg and with intermittent short-term regimens, lasting on average 3-6 months. The magnitude and rapidity of response are dose dependent, as well as the risk of development of adverse events. Therefore, the dose should be tailored to patient's needs and general characteristics and adjusted during the treatment course according to both the efficacy and tolerability. Some studies support the feasibility of pulse administration of CsA for a few days per week for both the induction and the maintenance of response in psoriasis patients. This paper will review the data on CsA regimens for plaque-type psoriasis and will focus the attention on dose, treatment duration, novel schedules, and role in combination therapies, including the association with biologicals. PMID- 23983649 TI - Current Status of Endoscopic Stenting of the Pancreatic Duct as Prophylaxis Against Post-ERCP Pancreatitis. PMID- 23983648 TI - Multidisciplinary management of soft tissue sarcoma. AB - Soft tissue sarcoma is a rare malignancy, with approximately 11,000 cases per year encountered in the United States. It is primarily encountered in adults but can affect patients of any age. There are many histologic subtypes and the malignancy can be low or high grade. Appropriate staging work up includes a physical exam, advanced imaging, and a carefully planned biopsy. This information is then used to guide the discussion of definitive treatment of the tumor which typically involves surgical resection with a negative margin in addition to neoadjuvant or adjuvant external beam radiation. Advances in imaging and radiation therapy have made limb salvage surgery the standard of care, with local control rates greater than 90% in most modern series. Currently, the role of chemotherapy is not well defined and this treatment is typically reserved for patients with metastatic or recurrent disease and for certain histologic subtypes. The goal of this paper is to review the current state of the art in multidisciplinary management of soft tissue sarcoma. PMID- 23983650 TI - Letter from the editor. PMID- 23983651 TI - Gastro-hep news. PMID- 23983652 TI - What role does wheat play in the symptoms of irritable bowel syndrome? AB - Recently, increasing attention has been paid to the pathologic role of food in irritable bowel syndrome (IBS). Nevertheless, healthcare providers often avoid addressing diet with their patients because of a lack of training, guideline consensus, and high-quality data. Recent literature supports the existence of a subgroup of IBS patients with undiagnosed nonceliac gluten sensitivity (NCGS), a term that is used to describe individuals who experience gastrointestinal and extraintestinal symptoms as a result of immunologic, morphologic, or symptomatic abnormalities that are precipitated by the ingestion of gluten. NCGS represents an important subgroup of patients with IBS who are highly treatable via dietary modification. Gluten may influence gastrointestinal symptoms through immune activation or alteration of intestinal permeability, but the true role of food in functional gastrointestinal symptomatology remains unclear. For example, gluten is just 1 component of the complex milieu of nutrients found in wheat and related grains, and NCGS likely represents only the tip of the iceberg as it pertains to the role of food in IBS. PMID- 23983653 TI - The potential applications of capsule endoscopy in pediatric patients compared with adult patients. AB - Capsule endoscopy (CE) avoids the ionizing radiation, deep sedation, and general anesthesia required by other imaging modalities, making it particularly valuable in the evaluation of gastrointestinal disease in pediatric patients. In examining the use of CE in pediatric and adult patients through a review of the literature, it was observed that CE is most frequently indicated for the evaluation of Crohn's disease (CD) in pediatric patients and most frequently indicated for obscure gastrointestinal bleeding (OGIB) in adults, although OGIB is a more frequent indication than CD in pediatric patients younger than 8 years of age. Diagnostic accuracy has been good and comparable to that of magnetic resonance enterography, and capsule retention rates as well as other adverse events appear to be low in pediatric patients. Research is needed to explore broader indications and applications of CE in the diagnosis and monitoring of gastrointestinal disease. PMID- 23983654 TI - Endotherapy for organized pancreatic necrosis. PMID- 23983655 TI - Measuring structural damage in Crohn's disease. PMID- 23983656 TI - Early recognition of alpha-1 antitrypsin deficiency and considerations for liver transplantation. PMID- 23983657 TI - New tests for the evaluation of laryngopharyngeal reflux. PMID- 23983658 TI - A rare case of acute hepatitis B virus infection causing guillain-barre syndrome. PMID- 23983660 TI - Chemicals and health - thought for food. AB - In our contribution we concisely question and answer some basic notions on food, health, and safety. We show that for some food components such as flavonoids, a whole range of small toxicological effects that have been uncovered the last decade on the whole confer benefits to human health. This development underlines the notion that health is adaptation with respect to the exposures humans experience when consuming food. PMID- 23983659 TI - Extrahepatic manifestations of acute hepatitis B virus infection. PMID- 23983661 TI - Systems Cancer Biology and the Controlling Mechanisms for the J-Shaped Cancer Dose Response: Towards Relaxing the LNT Hypothesis. AB - The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transformation frequency. J-shaped dose response curves have been captured with consideration of cell cycle checkpoint control mechanisms. The simulation results indicate the shape of the dose response curve relates to the behavior of the saddle-node points of the model in the bifurcation diagram. A simplified version of the model in previous work of the authors was used mathematically to analyze behaviors relating to the saddle-node points for the J-shaped dose response curve. It indicates that low-linear energy transfer (LET) is more likely to have a J-shaped dose response curve. This result emphasizes the significance of systems biology approach, which encourages collaboration of multidiscipline of biologists, toxicologists and mathematicians, to illustrate complex cancer related events, and confirm the biphasic dose-response at low doses. PMID- 23983662 TI - Temperature, Not Fine Particulate Matter (PM2.5), is Causally Associated with Short-Term Acute Daily Mortality Rates: Results from One Hundred United States Cities. AB - Exposures to fine particulate matter (PM2.5) in air (C) have been suspected of contributing causally to increased acute (e.g., same-day or next-day) human mortality rates (R). We tested this causal hypothesis in 100 United States cities using the publicly available NMMAPS database. Although a significant, approximately linear, statistical C-R association exists in simple statistical models, closer analysis suggests that it is not causal. Surprisingly, conditioning on other variables that have been extensively considered in previous analyses (usually using splines or other smoothers to approximate their effects), such as month of the year and mean daily temperature, suggests that they create strong, nonlinear confounding that explains the statistical association between PM2.5 and mortality rates in this data set. As this finding disagrees with conventional wisdom, we apply several different techniques to examine it. Conditional independence tests for potential causation, non-parametric classification tree analysis, Bayesian Model Averaging (BMA), and Granger-Sims causality testing, show no evidence that PM2.5 concentrations have any causal impact on increasing mortality rates. This apparent absence of a causal C-R relation, despite their statistical association, has potentially important implications for managing and communicating the uncertain health risks associated with, but not necessarily caused by, PM2.5 exposures. PMID- 23983663 TI - Herbicide phosphinothricin causes direct stimulation hormesis. AB - Herbicide phosphinothricin (PPT) inhibits glutamine synthetase (GS), a key enzyme in nitrogen assimilation, thus causing ammonia accumulation, glutamine depletion and eventually plant death. However, the growth response of Lotus corniculatus L. plants immersed in solutions with a broad range of PPT concentrations is biphasic, with pronounced stimulating effect on biomass production at concentrations <= 50 MUM and growth inhibition at higher concentrations. The growth stimulation at low PPT concentrations is a result of activation of chloroplastic isoform GS2, while the growth suppression is caused by inhibition of both cytosolic GS1 and GS2 at higher PPT concentrations. Since the results are obtained in cell-free system (e.g. protein extracts), to which the principles of homeostasis are not applicable, this PPT effect is an unambiguous example of direct stimulation hormesis. A detailed molecular mechanism of concentration dependent interaction of both PPT and a related GS inhibitor, methionine sulfoximine, with GS holoenzymes is proposed. The mechanism is in concurrence with all experimental and literature data. PMID- 23983664 TI - Detection and assessment of chemical hormesis on the radial growth in vitro of oomycetes and fungal plant pathogens. AB - Although plant diseases can be caused by bacteria, viruses, and protists, most are caused by fungi and fungus-like oomycetes. Intensive use of fungicides with the same mode of action can lead to selection of resistant strains increasing the risk of unmanageable epidemics. In spite of the integrated use of nonchemical plant disease management strategies, agricultural productivity relies heavily on the use of chemical pesticides and biocides for disease prevention and treatment and sanitation of tools and substrates. Despite the prominent use of fungi in early hormesis studies and the continuous use of yeast as a research model, the relevance of hormesis in agricultural systems has not been investigated by plant pathologists, until recently. A protocol was standardized for detection and assessment of chemical hormesis in fungi and oomycetes using radial growth as endpoint. Biphasic dose-responses were observed in Pythium aphanidermatum exposed to sub-inhibitory doses of ethanol, cyazofamid, and propamocarb, and in Rhizoctonia zeae exposed to ethanol. This report provides an update on chemical hormesis in fungal plant pathogens and a perspective on the potential risks it poses to crop productivity and global food supply. PMID- 23983665 TI - Effect of low dose radiation on differentiation of bone marrow cells into dendritic cells. AB - Low dose radiation has been shown to be beneficial to living organisms using several biological systems, including immune and hematopoietic systems. Chronic low dose radiation was shown to stimulate immune systems, resulting in controlling the proliferation of cancer cells, maintain immune balance and induce hematopoietic hormesis. Since dendritic cells are differentiated from bone marrow cells and are key players in maintaining the balance between immune activation and tolerance, it may be important to further characterize whether low dose radiation can influence the capacity of bone marrow cells to differentiate into dendritic cells. We have shown that bone marrow cells from low dose-irradiated (gamma-radiation, 0.2Gy, 15.44mGy/h) mice can differentiate into dendritic cells that have several different characteristics, such as expression of surface molecules, cytokine secretion and antigen uptake capacity, when compared to dentritic cells differentiated from the control bone marrow cells. These differences observed in the low dose radiation group can be beneficial to living organisms either by activation of immune responses to foreign antigens or tumors, or maintenance of self-tolerance. To the best of our knowledge, this is the first report showing that total-body low dose radiation can modulate the capacity of bone marrow cells to differentiate into dendritic cells. PMID- 23983666 TI - Intermittent hypoxia-induced renal antioxidants and oxidative damage in male mice: hormetic dose response. AB - Obstructive sleep apnea causes cardiovascular disease via chronic intermittent hypoxia (IH), which may be related to oxidative stress. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important cellular defense mechanism against oxidative stress by regulating its down-stream multiple antioxidants. The present study was to define whether IH can induce renal pathogenic damage and if so, whether Nrf2 and its down-stream antioxidants are involved in IH-induced pathogenic changes. Mice were culled for exposure to intermittent air as control or IH that consisted of 20.9% O2/ 8% O2 FIO2 alternation cycles (30 episodes per h) with 20 seconds at the nadir FIO2 for 12 h a day during daylight. Short-term IH exposure (3 - 7 days) induced significant increases in renal inflammatory response and antioxidant levels along with a reduction of the spontaneous content of malondialdehyde while long-term IH exposure (8 weeks) induced a significant decrease of antioxidant levels and significant increases of renal inflammation, oxidative damage, cell death, and fibrosis. This study suggests that IH induces a hormetic response, i.e.: short-term IH exposure is able to induce a protective response to protect the kidney from oxidative damage while long-term IH exposure is able to induce a damage effect on the kidney. PMID- 23983667 TI - Protective Effect of gamma-Irradiation Against Hypochlorous Acid-Induced Haemolysis in Human Erythrocytes. AB - Radiations may trigger protective response within a threshold of doses applied. Exposures above an upper threshold are generally detrimental, while exposures below a lower threshold may or may not increase risks for health. We recently reported that a cellular protective response occurs in interventional cardiologists to counteract the oxidative damage caused by radiation. Here, we demonstrated in an in vitro model represented by whole blood of healthy donors gamma-irradiated with 220-440 mGy, that haemolysis of erythrocytes induced by hypochlorous acid was reduced by 40%. The protection triggered by gamma radiations made erythrocytes more resistant to oxidative insult caused by hypochlorous acid which was induced 3 h after irradiation and involved biochemical changes in the synthesis and turnover of glutathione. Overall, the biochemical remodelling induced by exposure to gamma-radiations might contribute to generate new guidelines in professionally exposed workers. PMID- 23983668 TI - Hormesis and Cellular Quality Control: A Possible Explanation for the Molecular Mechanisms that Underlie the Benefits of Mild Stress. AB - In contrast to the detrimental action of severe stress conditions, the beneficial effects of mild stress, known as hormesis, is increasingly discussed and studied. A variety of applications for hormesis in risk assessment processes, anti-ageing strategies and clinical therapies have been proposed. The molecular mechanisms underlying the phenomenon of hormesis, however, are not yet fully understood. A possible mechanism that has been proposed for hormesis, the homoeostasis overshoot hypothesis, assumes that an overshoot of repair- and self-recovery mechanisms in response to mild damage can be held responsible for the beneficial effects of hormesis. The present paper proposes 'cellular quality control' as a further explanation of the molecular mechanisms underlying the benefits observed after exposure to mild stress. The most important quality control mechanisms are outlined and their known and hypothesised actions in hormesis are discussed. As an example, different aspects of protein quality control will be described in more detail, which includes the reaction of the cell upon stress-induced protein damage and -aggregation. The regulation of Heat Shock Proteins and components from the ubiquitin proteasome system as part of cellular quality control is described in relation to its beneficial role in hormesis. PMID- 23983669 TI - Dose and Time Dependence of Targeted and Untargeted Effects after Very Low Doses of alpha-Particle Irradiation of Human Lung Cancer Cells. AB - Understanding the effects to human health resulting from exposure to low doses of ionizing radiation is a persisting challenge. No one questions the deleterious consequences for humans following exposure to high radiation doses; however, in the low dose range, the complex and to some extent unknown cellular responses raise important misgivings about the resulting protective or potentially detrimental effects. Bystander effects are involved in low dose exposures, being characterized by the appearance in unirradiated cells of a cellular damage associated with direct radiation exposure. The purpose of our work was to assess, by using clonogenic and micronuclei assays, the dose and time dependence of the bystander response after cells exposure to very low doses of alpha-particles and to evaluate its importance in the overall induced damage. The study includes an irradiated cells culture, a medium transfer culture with non-irradiated cells and a culture with irradiated cells after centrifugation. We observed a non negligible contribution of the bystander effects in the overall cellular damage. Low-dose hyper-sensitivity was observed for medium transfer and irradiated cells after centrifugation cultures. Delayed and earlier cellular damage were similar in almost all experiments, suggesting an effectiveness of irradiated medium to induce a bystander response soon after irradiation. PMID- 23983670 TI - Spectroscopic, Thermal, Electrochemical, and Antimicrobial Studies of Mononuclear Manganese(II) Ditolyldithiophosphates. AB - New complexes of manganese(II) corresponding to [{(ArO)2PS2}2Mn] and [{(ArO)2PS2}2Mn.nL] (Ar = o-, m-, p-CH3C6H4 and p-Cl-m-CH3C6H3; n = 1, L = N2C12H8, N2C10H8; n = 2, L = NC5H5, P(C6H5)3) have been synthesized and characterized by microelemental analyses (C, H, and N), magnetic susceptibility, molar conductance, thermogravimetric, cyclic voltammetry, and spectral analyses including ESI mass spectrometry, IR, and UV-visible. The presence of a four-and six coordinated Mn atoms has been established in the complexes and adducts, respectively. Antimicrobial screening of the complexes against gram negative bacteria E. coli, K. pneumonia, and P. aeruginosa and fungus S. rolfsii has shown potential bioactivity. PMID- 23983671 TI - Synthesis, Spectral, and In Vitro Antibacterial Studies of Organosilicon(IV) Complexes with Schiff Bases Derived from Amino Acids. AB - The present work stems from our interest in the synthesis, characterization, and antibacterial evaluation of organosilicon(IV) complexes of a class of amino-acid based Schiff base which have been prepared by the interaction of ethoxytrimethylsilane with the Schiff bases (N OH) in 1 : 1 molar ratio. These complexes have been characterized by elemental analysis, molar conductance, and spectroscopic studies including electronic IR and NMR ((1)H, (13)C, and (29)Si) spectroscopy. The analytical and spectral data suggest trigonal bipyramidal geometry around the silicon atom in the resulting complexes. The ligands and their organosilicon complexes have also been evaluated for in vitro antimicrobial activity against bacteria (Bacillus cereus, Nocardia spp., E. aerogenes, Escherichia coli, Klebsiella spp., and Staphylococcus spp.). The complexes were found to be more potent as compared to the ligands. PMID- 23983672 TI - Cu(II), Ni(II), and Zn(II) Complexes of Salan-Type Ligand Containing Ester Groups: Synthesis, Characterization, Electrochemical Properties, and In Vitro Biological Activities. AB - A salen ligand on reduction and N-alkylation affords a novel [N2O2] chelating ligand containing ester groups [L = diethyl-2,2'-(propane-1,3-diylbis((2-hydroxy 3-methoxy benzyl)azanediyl))diacetate]. The purity of the ligand was confirmed by NMR and HPLC chromatograms. Its Cu(II), Ni(II), and Zn(II) complexes were synthesized and characterized by a combination of elemental analysis, IR, NMR, UV Vis, and mass spectral data, and thermogravimetric analysis (TG/DTA). The magnetic moments, UV-Vis, and EPR spectral studies support square planar geometry around the Cu(II) and Ni(II) ions. A tetrahedral geometry is observed in four coordinate zinc with bulky N-alkylated salan ligand. The redox properties of the copper complex were examined in DMSO by cyclic voltammetry. The voltammograms show quasireversible process. The interaction of metal complexes with CT DNA was investigated by UV-Vis absorption titration, ethidium bromide displacement assay, cyclic voltammetry methods, and agarose gel electrophoresis. The apparent binding constant values suggest moderate intercalative binding modes between the complexes and DNA. The in vitro antioxidant and antimicrobial potentials of the synthesized compounds were also determined. PMID- 23983673 TI - Primary small cell carcinoma of the esophagus: patient data metaanalysis and review of the literature. AB - We analysed the typical features of primary small cell carcinoma of the esophagus (SCCE) with emphasis on occurrence, behaviour, outcome and treatment options. This metaanalysis was aimed at collecting and analyzing information from international studies about handling this disease. This seems necessary due to the rarity of this disease. Studies were acquired from electronic databases and reference lists. We finally analysed 313 patient cases from the literature with oesophageal SCC. A data extraction was accomplished referring to 13 evaluable features that are described in the "methods", whereof 7 were analyzed with univariate and multivariate tests. Three hundred thirteen cases were analyzed, 109 patients (35%) had limited stage (LS), whereas 167 (54%) had extensive stage (ES). There is no information about the remaining 35 patients concerning the stage. Univariate and multivariate analysis showed only age (<50 years vs. >50 years, HR 1.024; 95% CI 1.000-1.041, P<0.0001) and disease stage (LS vs. ES, HR 4.884; 95% CI 2.572-9.27, P<0.0001) as significant prognostic factors. There also was a statistically significant difference in survival between those patients who received therapy compared to those who only received best supportive care (11.6 months vs. 0.8 months, HR 0.093, CI 95% 0.053-0.16, P<0.001). In this first multivariate analysis for SCCE we show that SCCE is an aggressive type of tumour with a shorter survival rate compared to its counterpart from the lung. It is demonstrated that only disease stage (limited vs. extensive stage), age (<50 years vs. >50 years) and therapy are independent significant predictors of prognosis. PMID- 23983675 TI - Closed contour specular reflection segmentation in laparoscopic images. AB - Segmentation of specular reflections is an essential step in endoscopic image analysis; it affects all further processing steps including segmentation, classification, and registration tasks. The dichromatic reflectance model, which is often used for specular reflection modeling, is made for dielectric materials and not for human tissue. Hence, most recent segmentation approaches rely on thresholding techniques. In this work, we first demonstrate the limited accuracy that can be achieved by thresholding techniques and propose a hybrid method which is based on closed contours and thresholding. The method has been evaluated on 269 specular reflections in 49 images which were taken from 27 real laparoscopic interventions. Our method improves the average sensitivity by 16% compared to the state-of-the-art thresholding methods. PMID- 23983674 TI - The effects of rising atmospheric carbon dioxide on shoot-root nitrogen and water signaling. AB - Terrestrial higher plants are composed of roots and shoots, distinct organs that conduct complementary functions in dissimilar environments. For example, roots are responsible for acquiring water and nutrients such as inorganic nitrogen from the soil, yet shoots consume the majority of these resources. The success of such a relationship depends on excellent root-shoot communications. Increased net photosynthesis and decreased shoot nitrogen and water use at elevated CO2 fundamentally alter these source-sink relations. Lower than predicted productivity gains at elevated CO2 under nitrogen or water stress may indicate shoot-root signaling lacks plasticity to respond to rising atmospheric CO2 concentrations. The following presents recent research results on shoot-root nitrogen and water signaling, emphasizing the influence that rising atmospheric carbon dioxide levels are having on these source-sink interactions. PMID- 23983676 TI - Breast Tissue 3D Segmentation and Visualization on MRI. AB - Tissue segmentation and visualization are useful for breast lesion detection and quantitative analysis. In this paper, a 3D segmentation algorithm based on Kernel based Fuzzy C-Means (KFCM) is proposed to separate the breast MR images into different tissues. Then, an improved volume rendering algorithm based on a new transfer function model is applied to implement 3D breast visualization. Experimental results have been shown visually and have achieved reasonable consistency. PMID- 23983677 TI - Does Pro(12)Ala Polymorphism Enhance the Physiological Role of PPARgamma2? AB - Obesity and type 2 diabetes mellitus (T2D) are two major public health problems that have motivated the scientific community to investigate the high contribution of genetic factors to these disorders. The peroxisome proliferator activated by gamma 2 (PPARgamma2) plays an important role in the lipid metabolism. Since PPARgamma2 is expressed mainly in adipose tissue, a moderate reduction of its activity influences the sensitivity to insulin, diabetes, and other metabolic parameters. The present study aims to contribute to the elucidation of the impact of the Pro(12)Ala polymorphism associated with T2D and obesity through a meta analysis study of the literature that included approximately 11500 individuals, from which 3870 were obese and 7625 were diabetic. Statistical evidence supports protective effect in T2D of polymorphism Pro(12)Ala of PPARgamma2 (OR = 0.702 with 95% CI: 0.622; 0.791, P < 0.01). Conversely the same polymorphism Pro(12)Ala of PPARgamma2 seems to favor obesity since 1.196 more chance than nonobese was found (OR = 1.196 with 95% CI: 1.009; 1.417, P < 0.004). Our results suggest that Pro(12)Ala polymorphism enhances both adipogenic and antidiabetogenic physiological role of PPARgamma. Does Pro(12)Ala polymorphism represent an evolutionary step towards the stabilization of the molecular function of PPARgamma transcription factor signaling pathway? PMID- 23983678 TI - PPARgamma Agonists in Adaptive Immunity: What Do Immune Disorders and Their Models Have to Tell Us? AB - Adaptive immunity has evolved as a very powerful and highly specialized tool of host defense. Its classical protagonists are lymphocytes of the T- and B-cell lineage. Cytokines and chemokines play a key role as effector mechanisms of the adaptive immunity. Some autoimmune and inflammatory diseases are caused by disturbance of the adaptive immune system. Recent advances in understanding the pathogenesis of autoimmune diseases have led to research on new molecular and therapeutic targets. PPAR gamma are members of the nuclear receptor superfamily and are transcription factors involved in lipid metabolism as well as innate and adaptive immunity. PPAR gamma is activated by synthetic and endogenous ligands. Previous studies have shown that PPAR agonists regulate T-cell survival, activation and T helper cell differentiation into effector subsets: Th1, Th2, Th17, and Tregs. PPAR gamma has also been associated with B cells. The present review addresses these issues by placing PPAR gamma agonists in the context of adaptive immune responses and the relation of the activation of these receptors with the expression of cytokines involved in adaptive immunity. PMID- 23983679 TI - Botanical agents for the treatment of nonmelanoma skin cancer. AB - Nonmelanoma skin cancers, including basal cell carcinoma and squamous cell carcinoma, are common neoplasms worldwide and are the most common cancers in the United States. Standard therapy for cutaneous neoplasms typically involves surgical removal. However, there is increasing interest in the use of topical alternatives for the prevention and treatment of nonmelanoma skin cancer, particularly superficial variants. Botanicals are compounds derived from herbs, spices, stems, roots, and other substances of plant origin and may be used in the form of dried or fresh plants, extracted plant material, or specific plant derived chemicals. They possess multiple properties including antioxidant, anti inflammatory, and immunomodulatory properties and are, therefore, believed to be possible chemopreventive agents or substances that may suppress or reverse the process of carcinogenesis. Here, we provide a review of botanical agents studied for the treatment and prevention of nonmelanoma skin cancers. PMID- 23983680 TI - Helicobacter pylori-Induced Chronic Gastritis and Assessing Risks for Gastric Cancer. AB - Chronic gastritis is an inflammation of the gastric mucosa and has multiple etiologies. Here we discuss the pathological alterations induced by Helicobacter pylori (HP) leading to chronic gastritis and the epigenetic bases underlying these changes. We review the histology of the normal gastric mucosa and overview the role of HP in the multistep cascade of GC. We attempt to define the role of the Operative Link for Gastritis Assessment (OLGA) staging system in assessing the risk of GC. The epigenetic bases of chronic gastritis, mainly DNA methylation, are presented through examples such as (i) the methylation of the promoter region of E-cadherin in HP-induced chronic gastritis and its reversion after HP eradication and (ii) the association of methylation of the promoter region of Reprimo, a p53-mediated cell cycle arrest gene, with aggressive HP strains in high risk areas for GC. In addition, we discuss the finding of RPRM as a circulating cell-free DNA, offering the opportunity for noninvasive risk assessment of GC. Finally, the integration of OLGA and tissue biomarkers, by systems pathology approach, suggests that severe atrophy has a greater risk for GC development if, in addition, overexpressed p73. This trial is registered with ClinicalTrials.gov NCT01774266. PMID- 23983681 TI - Helicobacter pylori Infection and Upper Gastrointestinal Disorders. PMID- 23983682 TI - HPLC Evaluation of Phenolic Profile, Nutritive Content, and Antioxidant Capacity of Extracts Obtained from Punica granatum Fruit Peel. AB - This study revealed polyphenolic content, nutritive content, antioxidant activity, and phenolic profile of methanol and aqueous extracts of Punica granatum peel extract. For this, extracts were screened for possible antioxidant activities by free radical scavenging activity (DPPH), hydrogen peroxide scavenging activity and ferric-reducing antioxidant power (FRAP) assays. The total phenolics and flavonoid recovered by methanolic (MPE) and the water extract (AQPE) were ranged from 185 +/- 12.45 to 298.00 +/- 24.86 mg GAE (gallic acid equivalents)/gm and 23.05 +/- 1.54 to 49.8 +/- 2.14 quercetin (QE) mg/g, respectively. The EC50 of herbal extracts ranged from 100 ug/ml (0.38 quercetin equivalents), for AQPE, 168 ug/ml (0.80 quercetin equivalents), for MPE. The phenolic profile in the methanolic extracts was investigated by chromatographic (HPLC) method. About 5 different flavonoids, phenolic acids, and their derivatives including quercetin (1), rutin (2), gallic acid (3), ellagic acid (4), and punicalagin as a major ellagitannin (5) have been identified. Among both extracts, methanolic extract was the most effective. This report may be the first to show nutritive content and correlation analysis to suggest that phenols and flavonoids might contribute the high antioxidant activity of this fruit peel and establish it as a valuable natural antioxidant source applicable in the health food industry. PMID- 23983683 TI - Silicone-acyclovir controlled release devices suppress primary herpes simplex virus-2 and varicella zoster virus infections in vitro. AB - Following initial infection, herpesviruses retreat into a permanent latent state with periodic reactivation resulting in an enhanced likelihood of transmission and clinical disease. The nucleoside analogue acyclovir reduces clinical symptoms of the three human alpha herpesviruses, HSV-1, HSV-2, and VZV. Long-term administration of acyclovir (ACV) can reduce the frequency and severity of reactivation, but its low bioavailability and short half-life require a daily drug regimen. Our lab is working to develop a subcutaneous delivery system to provide long-lasting, sustained release of ACV. Previously, we demonstrated that an implantable silicone (MED-4050) device, impregnated with ACV protected against HSV-1 both in vitro and in vivo. Here, we extend our in vitro observations to include protection against both HSV-2 and VZV. We also demonstrate protection against HSV-2 in vitro using MED-4750, a silicone polymer designed for long-term use in humans. When release of ACV from MED-4750 is quantitated on a daily basis, an initial burst of 5 days is observed, followed by a long period of slow release with near-zero-order kinetics, with an average daily release of 1.3923 +/- 0.5908 MU g ACV over days 20-60. Development of a slow-release implant has the potential to significantly impact the treatment of human alpha herpesvirus infections. PMID- 23983684 TI - The effect of prophylactic dexmedetomidine on hemodynamic disturbances to double lumen endotracheal intubation: a prospective, randomized, double-blind, and placebo-controlled trial. AB - The purpose of this study was to determine the effect of dexmedetomidine on hemodynamic responses to DLT intubation compared to placebo and to assess the adverse effects related to dexmedetomidine. Sixty patients were randomly allocated to receive 0.7 MU g/kg dexmedetomidine (n = 30) or normal saline (n = 30) 10 minutes before general anesthesia. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), and rate pressure product (RPP) between groups were recorded. During intubation and 10 minutes afterward (T1-T10), the mean SBP, DBP, MAP, HR, and RPP in the control group were significantly higher than those in the dexmedetomidine group throughout the study period except at T1. The mean differences of SBP, DBP, MAP, HR, and RPP were significantly higher in the control group, with the value of 15.2 mmHg, 10.5 mmHg, 14 mmHg, 10.5 beats per minute, and 2,462.8 mmHg min(-1). Four patients in the dexmedetomidine group and 1 patient in the control group developed hypotension, while 2 patients in the dexmedetomidine group had bradycardia. Prophylactic dexmedetomidine can attenuate the hemodynamic responses to laryngoscopy and DLT intubation with minimal adverse effects. This trial is registered with ClinicalTrials.gov NCT01289769. PMID- 23983685 TI - Low bone mineral density in chinese adults with nonalcoholic Fatty liver disease. AB - Aim. To investigate bone metabolic characteristics in Chinese adults with nonalcoholic fatty liver disease (NAFLD). Methods. A total of 224 patients (99 males and 125 postmenopausal females) were recruited and divided into 4 groups: males without NAFLD, males with NAFLD, females without NAFLD, and females with NAFLD. Bone mineral density (BMD) was evaluated according to body mass index (BMI), waist circumference (WC), and serum biomarkers. beta cell function was evaluated by HOMA2%B, HOMA2%S, and HOMA2IR. Results. Males in the NAFLD group had lower BMD of the right hip and the femoral neck (0.852 +/- 0.117 versus 0.930 +/- 0.123, P = 0.002; 0.736 +/- 0.119 versus 0.812 +/- 0.132, P = 0.004), and females had lower BMD of the right hip (0.725 +/- 0.141 versus 0.805 +/- 0.145, P = 0.002) even after adjusted for weight, BMI, waist, HDL, and ALT. There was no significant difference in bone metabolic markers between patients with and without NAFLD. NAFLD was an important factor that affected the bone; moreover, the effect attenuated when HOMA2IR entered into the model (R (2) = 0.160, beta = 0.172, and P = 0.008). Conclusions. NAFLD exerts a detrimental effect on BMD in both males and females. Insulin resistance may play an important role in this pathophysiological process. PMID- 23983686 TI - Cardiometabolic risk factors related to vitamin d and adiponectin in obese children and adolescents. AB - Obesity-related diseases are becoming the most important causes of mortality worldwide. Several studies have suggested an association between low levels of vitamin D and obesity. In addition, plasma adiponectin levels have been found to be lower in obese subjects. We evaluated the association of metabolic risk factors with both adiponectin and vitamin D levels and that between adiponectin and vitamin D levels. The study consisted of 114 obese and healthy subjects. 25 Hydroxy vitamin D [25(OH)D] levels were positively correlated with adiponectin and HDL-cholesterol (HDL-C) and inversely correlated with body mass index (BMI), LDL-cholesterol (LDL-C), total cholesterol (T-C), triglyceride (TG), fasting glucose, homeostasis model assessment of insulin resistance (HOMA index), systolic blood pressure (SBP), and diastolic blood pressure (DBP). The mean 25(OH)D levels in the obese and nonobese groups were 22.5 +/- 5.7 and 32.3 +/- 5.8 ng/mL, respectively (P < 0.0001). The mean adiponectin level in the obese group was lower than that in the nonobese group (P < 0.0001). Lower vitamin D and adiponectin levels were strongly associated with metabolic risk factors and obesity in Turkish children and adolescents. PMID- 23983687 TI - Serum anti-mullerian hormone levels in patients with epithelial ovarian cancer. AB - Objectives. The aim of our study was to examine serum anti-Mullerian hormone (AMH) concentration in ovarian cancer patients in relation to clinicopathological features, such as a pathological subtype of the tumor, (FIGO) stage, grading, and overall 5-year survival. Material and Methods. We enrolled 72 epithelial ovarian cancer patients in our study, aged 45-79 years, who underwent optimal cytoreductive surgery. In all patients, serum AMH concentration was measured using a two-step sandwich type enzyme immunoassay before surgery. As a reference value for women over 45 years we accepted anti-Mullerian hormone concentration below 1 ng/mL. Results. In the whole group of patients with ovarian cancer, median serum concentration of AMH was 0.07 (0.0-0.37) ng/mL, whereas in the group of those with positive AMH values (>=0.14 ng/mL) it was 0.31 (0.15-0.73) ng/mL. No significant correlation was found between serum AMH levels and FIGO stage, histological subtype, or grading (P > 0.05). The analysis of five-year survival rate related to AMH levels showed no statistically significant differences. There were no differences in survival rates between patients with positive or negative serum AMH levels. Conclusion. Measurement of serum anti-Mullerian hormone levels was not useful in predicting clinicopathological features and survival in patients with ovarian cancer. PMID- 23983689 TI - Neoadjuvant therapy in operable breast cancer: application to triple negative breast cancer. AB - SYSTEMIC TREATMENT FOR TRIPLE NEGATIVE BREAST CANCER (TNBC: negative for the expression of estrogen receptor and progesterone receptor and HER2 amplification) has been limited to chemotherapy options. Neoadjuvant chemotherapy induces tumor shrinkage and improves the surgical outcomes of patients with locally advanced disease and also identifies those at high risk of disease relapse despite today's standard of care. By using pathologic complete response as a surrogate endpoint, novel treatment strategies can be efficiently assessed. Tissue analysis in the neoadjuvant setting is also an important research tool for the identification of chemotherapy resistance mechanisms and new therapeutic targets. In this paper, we review data on completed and ongoing neoadjuvant clinical trials in patients with TNBC and discuss treatment controversies that face clinicians and researchers when neoadjuvant chemotherapy is employed. PMID- 23983690 TI - Implant Restoration of Edentulous Jaws with 3D Software Planning, Guided Surgery, Immediate Loading, and CAD-CAM Full Arch Frameworks. AB - Purpose. The aim of this study was to analyze the clinical and radiographic outcomes of 23 edentulous jaws treated with 3D software planning, guided surgery, and immediate loading and restored with CAD-CAM full arch frameworks. Materials and Methods. This work was designed as a prospective case series clinical study. Twenty patients have been consecutively rehabilitated with an immediately loaded implant supported fixed full prosthesis. A total of 120 fixtures supporting 23 bridges were placed. 117 out of 120 implants were immediately loaded. Outcome measures were implants survival, radiographic marginal bone levels and remodeling, soft tissue parameters, and complications. Results. 114 of 117 implants reached a 30 months follow-up, and no patients dropped out from the study. The cumulative survival rate was 97.7%; after 30 months, mean marginal bone level was 1.25 +/- 0.31 mm, mean marginal bone remodeling value was 1.08 +/- 0.34, mean PPD value was 2.84 +/- 0.55 mm, and mean BOP value was 4% +/- 2.8%. Only minor prosthetic complications were recorded. Conclusion. Within the limitations of this study, it can be concluded that computer-guided surgery and immediate loading seem to represent a viable option for the immediate rehabilitations of completely edentulous jaws with fixed implant supported restorations. This trial is registered with Clinicaltrials.gov NCT01866696. PMID- 23983692 TI - A new weak chelator in endodontics: effects of different irrigation regimens with etidronate on root dentin microhardness. AB - This study investigated the effect of sodium hypochlorite (NaOCl), ethylenediaminetetraacetic (EDTA), etidronic (HEBP), and citric acid (CA) associated in different irrigation regimens on root dentin microhardness. Forty five root halves of single-rooted teeth were sectioned into thirds that were embedded in acrylic resin, polished, randomly assigned into 3 groups, and treated as follows: G1: saline solution; G2: 5% NaOCl + 18% HEBP, mixed in equal parts; and G3: 2.5% NaOCl. After measurements, the G3 samples were distributed into subgroups G4, G5, and G6, which were submitted to 17% EDTA, 10% CA and 9% HEBP, respectively. Following the new measurements, these groups received a final flush with 2.5% NaOCl, producing G7, G8, and G9. Microhardness was measured with Knoop indenter under a 25 g load for 15 seconds, before and after treatments. The data were statistically analyzed using paired Student's t-test (alpha<0.05) to compare values before and after treatments and analysis of variance (ANOVA) (alpha<0.05) to detect any differences among thirds. Except G1, all tested irrigation regimens significantly decreased the microhardness. There were no differences between root thirds before treatments, and all root thirds exhibited equal responses to same treatment. Except saline, all tested irrigation regimens reduced the root dentin microhardness. PMID- 23983691 TI - Detoxification of implant surfaces affected by peri-implant disease: an overview of surgical methods. AB - Purpose. Peri-implantitis is one of the major causes of implant failure. The detoxification of the implant surface is necessary to obtain reosseointegration. The aim of this review was to summarize in vitro and in vivo studies as well as clinical trials that have evaluated surgical approaches for detoxification of the implant body surfaces. Materials and Methods. A literature search was conducted using MEDLINE (PubMed) from 1966 to 2013. The outcome variables were the ability of the therapeutic method to eliminate the biofilm and endotoxins from the implant surface, the changes in clinical parameters, radiographic bone fill, and histological reosseointegration. Results. From 574 articles found, 76 were analyzed. The findings, advantages, and disadvantages of using mechanical, chemical methods and lasers are discussed. Conclusions. Complete elimination of the biofilms is difficult to achieve. All therapies induce changes of the chemical and physical properties of the implant surface. Partial reosseointegration after detoxification has been reported in animals. Combination protocols for surgical treatment of peri-implantitis in humans have shown some positive clinical and radiographic results, but long-term evaluation to evaluate the validity and reliability of the techniques is needed. PMID- 23983693 TI - Liquid chromatography/tandem mass spectrometry method for quantitation of cremophor el and its applications. AB - A rapid sensitive and selective MRM based method for the determination of Cremophor EL (CrEL) in rat plasma was developed using liquid chromatography/tandem mass spectrometry (LC-MS/MS). CrEL and polypropylene glycol (internal standard) were extracted from rat plasma with acetonitrile and analysed on C18 column (XBridge, 50 * 4.6 mm, 3.5 MU m). The most abundant molecular ions corresponding to PEG oligomers at m/z 828, 872, 916 and 960 with daughter ion at m/z 89 were selected for multiple reaction monitoring (MRM) in electrospray mode of ionisation. Plasma concentrations of CrEL were quantified after administration through oral and intravenous routes in male sprague dawley rats at a dose of 0.26 g/kg. The standard curve was linear (0.9972) over the concentration range of 1.00 to 200 MU g/mL. The lower limit of quantitation for CrEL was 1.00 MU g/mL using 50 MU L plasma. The coefficient of variation and relative error for inter and intra assay at three QC levels were 0.69 to 9.21 and -7.60 to 4.74 respectively. A novel proposal was conveyed to the scientific community, where formulation excipient can be analysed as qualifier in the analysis of NCEs to address the spiky plasma concentration profiles. PMID- 23983688 TI - A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors. AB - Obesity has reached epidemic proportions in the developed world. The progression from obesity to diabetes mellitus type 2, via metabolic syndrome, is recognised, and the significant associated increase in the risk of major human cancers acknowledged. We review the molecular basis of the involvement of morbidly high concentrations of endogenous or therapeutic insulin and of insulin-like growth factors in the progression from obesity to diabetes and finally to cancer. Epidemiological and biochemical studies establish the role of insulin and hyperinsulinaemia in cancer risk and progression. Insulin-like growth factors, IGF-1 and IGF-2, secreted by visceral or mammary adipose tissue have significant paracrine and endocrine effects. These effects can be exacerbated by increased steroid hormone production. Structural studies elucidate how each of the three ligands, insulin, IGF-1, and IGF-2, interacts differently with isoforms A and B of the insulin receptor and with type I IGF receptor and explain how these protagonists contribute to diabetes-associated cancer. The above should inform appropriate treatment of cancers that arise in obese individuals and in those with diabetes mellitus type 2. Novel drugs that target the insulin and insulin like growth factor signal transduction pathways are in clinical trial and should be effective if appropriate biomarker-informed patient stratification is implemented. PMID- 23983694 TI - Disulfide bonding in neurodegenerative misfolding diseases. AB - In recent years an increasing number of neurodegenerative diseases has been linked to the misfolding of a specific protein and its subsequent accumulation into aggregated species, often toxic to the cell. Of all the factors that affect the behavior of these proteins, disulfide bonds are likely to be important, being very conserved in protein sequences and being the enzymes devoted to their formation among the most conserved machineries in mammals. Their crucial role in the folding and in the function of a big fraction of the human proteome is well established. The role of disulfide bonding in preventing and managing protein misfolding and aggregation is currently under investigation. New insights into their involvement in neurodegenerative diseases, their effect on the process of protein misfolding and aggregation, and into the role of the cellular machineries devoted to disulfide bond formation in neurodegenerative diseases are emerging. These studies mark a step forward in the comprehension of the biological base of neurodegenerative disorders and highlight the numerous questions that still remain open. PMID- 23983696 TI - Random Mutagenesis of the Aspergillus oryzae Genome Results in Fungal Antibacterial Activity. AB - Multidrug-resistant bacteria cause severe infections in hospitals and communities. Development of new drugs to combat resistant microorganisms is needed. Natural products of microbial origin are the source of most currently available antibiotics. We hypothesized that random mutagenesis of Aspergillus oryzae would result in secretion of antibacterial compounds. To address this hypothesis, we developed a screen to identify individual A. oryzae mutants that inhibit the growth of Methicillin-resistant Staphylococcus aureus (MRSA) in vitro. To randomly generate A. oryzae mutant strains, spores were treated with ethyl methanesulfonate (EMS). Over 3000 EMS-treated A. oryzae cultures were tested in the screen, and one isolate, CAL220, exhibited altered morphology and antibacterial activity. Culture supernatant from this isolate showed antibacterial activity against Methicillin-sensitive Staphylococcus aureus, MRSA, and Pseudomonas aeruginosa, but not Klebsiella pneumonia or Proteus vulgaris. The results of this study support our hypothesis and suggest that the screen used is sufficient and appropriate to detect secreted antibacterial fungal compounds resulting from mutagenesis of A. oryzae. Because the genome of A. oryzae has been sequenced and systems are available for genetic transformation of this organism, targeted as well as random mutations may be introduced to facilitate the discovery of novel antibacterial compounds using this system. PMID- 23983695 TI - Alternative splicing programs in prostate cancer. AB - Prostate cancer (PCa) remains one of the most frequent causes of death for cancer in the male population. Although the initial antiandrogenic therapies are efficacious, PCa often evolves into a hormone-resistant, incurable disease. The genetic and phenotypic heterogeneity of this type of cancer renders its diagnosis and cure particularly challenging. Mounting evidence indicates that alternative splicing, the process that allows production of multiple mRNA variants from each gene, contributes to the heterogeneity of the disease. Key genes for the biology of normal and neoplastic prostate cells, such as those encoding for the androgen receptor and cyclin D1, are alternatively spliced to yield protein isoforms with different or even opposing functions. This review illustrates some examples of genes whose alternative splicing regulation is relevant to PCa biology and discusses the possibility to exploit alternative splicing regulation as a novel tool for prognosis, diagnosis, and therapeutic approaches to PCa. PMID- 23983697 TI - Role of intranasal steroid in the prevention of recurrent nasal symptoms after adenoidectomy. AB - Background. Intranasal steroid provides an efficient nonsurgical alternative to adenoidectomy for theimprovement of adenoid nasal obstruction. Objective. To demonstrate the role of intranasal steroid in the prevention of adenoid regrowth after adenoidectomy. Methods. Prospective randomized controlled study. Two hundred children after adenoidectomy were divided into 2 groups. Group I received postoperative intranasal steroid and group II received postoperative intranasal saline spray. Both medications were administered for 12 weeks postoperatively. Patients were followed up for 1 year. Followup was done using the nasopharyngeal lateral X-rays, reporting the degree of the symptoms. Results. Significant difference between both groups after 6 months and after 1 year. The intranasal steroid group had significantly lower score after 6 months and after 1 year as regards nasal obstruction, nasal discharge, and snoring than the intranasal saline group. 2 weeks postoperatively, there was no difference between both groups as regards nasal obstruction, discharge, or snoring. As regards lateral radiographs, there was statistically significant difference between both groups 1 year but not 6 months postoperatively. Conclusion. Factors influencing the outcome of intranasal steroids therapy in the prevention of adenoid regrowth have not been identified. However, this treatment may obtain successful results in children to avoid readenoidectomy. PMID- 23983698 TI - The Applicability of Behaviour Change in Intervention Programmes Targeted at Ending Female Genital Mutilation in the EU: Integrating Social Cognitive and Community Level Approaches. AB - With increased migration, female genital mutilation (FGM) also referred to as female circumcision or female genital cutting is no longer restricted to Africa, the Middle East, and Asia. The European Parliament estimates that up to half a million women living in the EU have been subjected to FGM, with a further 180,000 at risk. Aware of the limited success of campaigns addressing FGM, the World Health Organization recommended a behavioural change approach be implemented in order to end FGM. To date, however, little progress has been made in adopting a behaviour change approach in strategies aimed at ending FGM. Based on research undertaken as part of the EU's Daphne III programme, which researched FGM intervention programmes linked to African communities in the EU (REPLACE), this paper argues that behaviour change has not been implemented due to a lack of understanding relating to the application of the two broad categories of behaviour change approach: individualistic decision-theoretic and community change game-theoretic approaches, and how they may be integrated to aid our understanding and the development of future intervention strategies. We therefore discuss how these can be integrated and implemented using community-based participatory action research methods with affected communities. PMID- 23983699 TI - Preterm labor: understanding of the mechanism involved to improve prediction and prevention. PMID- 23983700 TI - Robotic-assisted transperitoneal aortic lymphadenectomy as part of staging procedure for gynaecological malignancies: single institution experience. AB - Introduction. This study was designed to confirm the feasibility and safety of robotic-assisted transperitoneal aortic lymphadenectomy as part of staging procedure for gynecologic malignancies. Methods. Chart review of 51 patients who had undergone robotic staging with aortic lymphadenectomy for different gynaecologic malignancies was performed. Results. The primary diagnosis was as follows: 6 cases of endometrial cancer, 31 epithelial ovarian cancer, 9 nonepithelial ovarian cancer, 4 tubal cancer, and 1 cervical cancer. Median BMI was 23 kg/m(2). Except for a single case of aortic lymphadenectomy only, both aortic and pelvic lymphadenectomies were performed at the time of the staging procedure. All the para-aortic lymphadenectomies were carried out to the level of the renal veinl but 6 cases were carried out to the level of the inferior mesenteric artery. Hysterectomy was performed in 24 patiens (47%). There was no conversion to LPT. The median console time was 285 (range 195-402) with a significant difference between patients who underwent hysterectomy and those who did not. The median estimated blood loss was 50 mL (range 20-200). The mean number of removed nodes was 29 +/- 9.6. The mean number of pelvic nodes was 15 +/ 7.6, whereas the mean number of para-aortic nodes was 14 +/- 6.6. Conclusions. Robotic transperitoneal infrarenal aortic lymphadenectomy as part of staging procedure is feasible and can be safely performed. Additional trocars are needed when pelvic surgery is also performed. PMID- 23983701 TI - Hepatic Artery Embolization prior to En Bloc Resection of an Encased Common Hepatic Artery in Adenocarcinoma of the Head of the Pancreas. AB - A 64-year-old female patient with adenocarcinoma of the head of the pancreas with encasement of the common hepatic artery and portal vein stenosis was reexplored after six cycles of gemcitabine (1000 mg/m(2)). Prior to surgery, the patient underwent balloon dilation and stenting of the portal vein in addition to successful coil embolisation of the common hepatic artery, proper hepatic artery, and proximal gastroduodenal artery. After embolisation, a pylorus-preserving pancreaticoduodenectomy was performed with resection of the common hepatic artery and portal vein confluens. Pathological examination showed a moderately differentiated pT3N0 (Stage IIa, TNM 7th edition) tumor with negative section margins. We show with this case that in selected cases of periampullary cancer with encasement of the common hepatic artery, it is technically feasible to perform pancreaticoduodenectomy with hepatic artery resection and negative surgical margins. Nevertheless, the oncological benefit of extended arterial resections remains controversial. PMID- 23983702 TI - Hypersensitivity reaction and tolerance induction to ethambutol. AB - Tuberculosis remains the leading cause of death worldwide from any infectious agent and the alarming increase in the annual incidence of new cases has been described as a global emergency. Mycobacterium infection requires simultaneous administration of multiple drugs. Although the majority of treatment courses progress with minor side effects, adverse reactions to antituberculosis drugs occur in about 5% of treated patients and can be responsible for cessation or switching the therapy. Both nonimmediate (mostly maculopapular rash) and immediate reactions (urticarial reactions) have been described with these drugs. The main problem is the occurrence of reactions while the patient is on treatment with multiple drugs. The diagnosis of the culprit drug is mostly based on stopping all medication, followed by the reintroduction of each drug with a time interval of four to five days. An alternative drug should be the first approach if it is equally effective. Most of the times, none of the alternative drugs are as effective as the culprit. If this is the case, a desensitization procedure should be performed. The authors describe a case of a woman with Mycobacterium avium complex (MAC) infection, to whom treatment with ethambutol was crucial to recovery, and present a modified desensitization protocol to this drug. PMID- 23983703 TI - Nonunion of the medial cuneiform: a rare case. AB - Isolated medial cuneiform fractures are quite rare. Conservative treatment is adequate in most cases, while deplaced or unstable fractures are treated surgically. Nonunion is seen extremely rarely after medial cuneiform fractures. There is only one case report in the literature. This case presented here is a 62 year-old male patient who had an isolated medial cuneiform fracture resulting from the impact of a falling metal object. Conservative treatment was performed initially. The patient was diagnosed as nonunion after physical and radiological examinations nine months after he presented to the outpatient clinic. Internal fixation with a mini plate and one staple after reduction was performed surgically. Defective region was filled with a 2 mL of autograft, and the operation was terminated. PMID- 23983704 TI - Methadone induced sensorineural hearing loss. AB - Background. Sudden sensorineural hearing loss (SSHL) caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published. Case Report. We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally. Discussion. This case is notable because unlike all but one previously reported case, the patient-who was restated on methadone-did not make a complete recovery. Conclusion. Methadone overuse in rare cases causes SSHL. PMID- 23983705 TI - DRESS Syndrome due to Nevirapine Treated with Methylprednisolone. AB - Nevirapine-induced DRESS syndrome is uncommon but a potentially life-threatening condition, with significant morbidity and mortality rates due to multiple-organ involvement. The authors report a case of a 47-year-old HIV-infected female patient who presented with fever, right hypochondrium pain, jaundice, and skin rash. The Nevirapine-induced DRESS syndrome was suspected based on clinical presentation and RegiSCAR scoring system. This case highlights the need for a high index of clinical suspicion among HIV-infected patients with severe skin eruption and systemic symptoms. PMID- 23983706 TI - Telescoping intestine in an adult. AB - Protrusion of a bowel segment into another (intussusception) produces severe abdominal pain and culminates in intestinal obstruction. In adults, intestinal obstruction due to intussusception is relatively rare phenomenon, as it accounts for minority of intestinal obstructions in this population demographic. Organic lesion is usually identifiable as the cause of adult intussusceptions, neoplasms account for the majority. Therefore, surgical resection without reduction is almost always necessary and is advocated as the best treatment of adult intussusception. Here, we describe a rare case of a 44-year-old male with a diffuse large B-cell lymphoma involving the terminal ileum, which had caused ileocolic intussusception and subsequently developed intestinal obstruction requiring surgical intervention. This case emphasizes the importance of recognizing intussusception as the initial presentation for bowel malignancy. PMID- 23983707 TI - Report of a case of radiation-induced new-onset vitiligo with collective review of cases in the literature of radiation-related vitiligo. AB - Radiation-induced hypopigmentation consistent vitiligo has been reported in a few case reports. We report herewith a case of vitiligo at the site of radiation delivery after a lag of several months in a patient with preexisting hypothyroidism without a previous or family history of vitiligo, and review the cases reported in the literature collectively. PMID- 23983708 TI - Massive intra-abdominal imatinib-resistant gastrointestinal stromal tumor in a 21 year-old male. AB - Gastrointestinal stromal tumors (GISTs) in adolescence are far less common than adult GISTs and have varied GIST genotypes that present diagnostic and therapeutic challenges. Here, we discuss a 21-year-old male with diagnosis of unresectable, imatinib-resistant GIST. At initial evaluation, a neoadjuvant treatment approach was recommended. As such, the patient received imatinib over the course of one year. Unfortunately, the GIST increased in size, and a subsequent attempt at surgical resection was aborted fearing infiltration of major vascular structures. The patient was then referred to our institution, at which time imatinib therapy was discontinued. Surgical intervention was again considered and the patient underwent successful resection of massive intra abdominal GIST with total gastrectomy and Roux-en-Y esophagojejunostomy. Since pediatric GISTs are typically resistant to imatinib, we performed genotype analysis of the operative specimen that revealed KIT mutations associated with imatinib sensitivity and resistance. Given the sequencing data and operative findings, the patient was started postoperatively on sunitinib. This case illustrates the importance of understanding both adult and pediatric GISTs when implementing appropriate treatment regimens. Since the genotype of GISTs dictates phenotypic behavior, mutational analysis is an important component of care especially for adolescents whose disease may mirror the pediatric or adult population. PMID- 23983709 TI - Multiple skeletal muscle metastases from colon carcinoma preceded by paraneoplastic dermatomyositis. AB - Skeletal muscle metastases are very rare events in colorectal carcinoma. By contrast, dermatomyositis is an idiopathic inflammatory myopathy with characteristic cutaneous manifestations and a well-recognized association with several human malignancies and, among others, colorectal cancer. Here, we report the case of a 71-year-old woman with paraneoplastic dermatomyositis followed by the development of a metastatic colon cancer. Interestingly, this patient developed multiple skeletal metastases which were preceded by the worsening of systemic symptoms of dermatomyositis. This observation suggests that, while muscle tissue is usually resistant to the development of tumor metastases, the inflammatory and immune response which characterizes and boosts paraneoplastic myopathy may represent a favorable soil for tumor cell invasion and metastasization to skeletal muscles. PMID- 23983710 TI - A novel case of resolved postherpetic neuralgia with subsequent development of trigeminal neuralgia: a case report and review of the literature. AB - A 72-year-old female patient is presented, who was diagnosed with herpes zoster along the left ophthalmic branch of the trigeminal nerve with associated cutaneous vesicles. The patient subsequently developed postherpetic neuralgia in the same dermatome, which, after remission, transformed into paroxysmal trigeminal pain. The two different symptom sets, with the former consistent with PHN and the later consistent with trigeminal neuralgia, were unique to our practice and the literature. PMID- 23983711 TI - Multimodality imaging of a giant aortic valve papillary fibroelastoma. AB - Papillary fibroelastomas (PFEs) are benign cardiac tumors arising from endocardium. They are commonly found on valvular surfaces and average 1.0-1.5 cm in size. Though often asymptomatic, PFEs can lead to potentially severe complications, primarily due to their embolic potential. Surgical resection is recommended for all symptomatic or large PFEs. We report the case of a patient presenting with cardiovascular symptoms who was found to have a very large aortic valve PFE, as diagnosed by histopathologic examination following surgical resection. Multimodality cardiovascular imaging demonstrates the classic morphologic findings, including a pedunculated appearance and oscillating "frond like" surface projections. PMID- 23983712 TI - A Case of Polymyxin b-Immobilized Fiber Column Treatment for Rapidly Progressive Interstitial Pneumonia Associated with Clinically Amyopathic Dermatomyositis. AB - We report a case of rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis who responded to single course of polymyxin b-immobilized fiber column treatment. Initial treatment with pulsed corticosteroids and cyclophosphamide, intravenous immunoglobulin, and cyclosporine seemed to suppress the activity of interstitial lung disease temporarily, but signs of relapse were detected such as elevation of serum KL-6 level and progressing pulmonary shadows in chest computed tomography scan. After polymyxin b-immobilized fiber column treatment, the areas of pulmonary shadows drastically decreased. Gradually, arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio recovered, and serum ferritin level and KL-6 level decreased. These findings indicate that polymyxin b-immobilized fiber column treatment could be promising in combination with conventional therapy for rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis, especially at the early phase of relapse. PMID- 23983713 TI - Multiple symmetric lipomatosis: a diagnostic dilemma. AB - Introduction. Multiple symmetric lipomatosis, or Madelung's disease, is a rare condition which is characterized with large symmetrical accumulation of noncapsulated fat tissue in upper arms, neck, and shoulder areas. The disease etiology is unknown, with the highest incidence in the Mediterranean region. Case Presentation. Here, we present the case of Madelung's disease with symmetric fat distribution throughout the neck and history of alcoholism. The patient was treated from several diseases associated with alcoholism and hospitalized several times, but the diagnosis of Madelung's disease was omitted. The thyroid gland disease was excluded, while enlargement of the neck adipose tissue was attributed to obesity. Conclusions. This study points out possible diagnostic mistakes when a physician is not aware of a differentiation diagnosis of symmetrically enlarged neck masses, especially in geographic regions with high incidence of this disease. PMID- 23983714 TI - Gastric Necrosis due to Acute Massive Gastric Dilatation. AB - Gastric necrosis due to acute massive gastric dilatation is relatively rare. Vascular reasons, herniation, volvulus, acute gastric dilatation, anorexia, and bulimia nervosa play a role in the etiology of the disease. Early diagnosis and treatment are highly important as the associated morbidity and mortality rates are high. In this case report, we present a case of gastric necrosis due to acute gastric dilatation accompanied with the relevant literature. PMID- 23983715 TI - Idiopathic spontaneous adrenal hemorrhage in the third trimester of pregnancy. AB - Spontaneous adrenal hemorrhage (SAH) is seen in the absence of trauma or adrenal tumor in adrenal glands. The incidence of SAH has been reported from 0.14% to 1.1% and it usually involves the right gland. During pregnancy, idiopathic unilateral SAH has been reported rarely. We present a case which comes to emergency department with an acute abdominal pain and the test results showed spontaneous left SAH. PMID- 23983716 TI - Meningitis-retention syndrome as a presentation of west nile virus meningitis. AB - A 26-year-old previously healthy man presented with fever, urinary retention, nuchal rigidity, and hyperreflexia but with a clear sensorium. His initial spinal fluid results were consistent with aseptic meningitis from West Nile virus infection, and this was confirmed by serological studies on blood and cerebrospinal fluid. Computed tomography and magnetic resonance imaging studies were unremarkable. He received supportive care and urinary catheterization to prevent bladder injury from overdistension. He was discharged home without recurrence of urinary retention after five days of hospitalization. Therefore, this case report describes the first case of West Nile virus meningitis in a patient with the meningitis-retention syndrome. PMID- 23983717 TI - Intracoronary Infusion of Autologous CD133(+) Cells in Myocardial Infarction and Tracing by Tc99m MIBI Scintigraphy of the Heart Areas Involved in Cell Homing. AB - CD133 mesenchymal cells were enriched using magnetic microbead anti-CD133 antibody from bone marrow mononuclear cells (BMMNCs). Flow cytometry and immunocytochemistry analysis using specific antibodies revealed that these cells were essentially 89 +/- 4% CD133(+) and 8 +/- 5% CD34(+). CD133(+)/CD34(+) BMMNCs secrete important bioactive proteins such as cardiotrophin-1, angiogenic and neurogenic factors, morphogenetic proteins, and proinflammatory and remodeling factors in vitro. Single intracoronary infusions of autologous CD133(+)/CD34(+) BMMNCs are effective and reduce infarct size in patients as analyzed by Tc99m MIBI myocardial scintigraphy. The majority of patients were treated via left coronary artery. Nine months after cell therapy, 5 out of 8 patients showed a net positive response to therapy in different regions of the heart. Uptake of Tc99 isotope and revitalization of the heart area in inferoseptal region are more pronounced (P = 0.016) as compared to apex and anterosptal regions after intracoronary injection of the stem cells. The cells chosen here have the properties essential for their potential use in cell therapy and their homing can be followed without major difficulty by the scintigraphy. The cell therapy proposed here is safe and should be practiced, as we found, in conjunction with scintigraphic observation of areas of heart which respond optimally to the infusion of autologous CD133(+)/CD34(+) BMMNCs. PMID- 23983718 TI - Phytochemical Analysis and Antimalarial Activity Aqueous Extract of Lecaniodiscus cupanioides Root. AB - Root aqueous extract of Lecaniodiscus cupanioides was evaluated for antimalarial activity and analyzed for its phytochemical constituents. Twenty-four (24) albino mice were infected by intraperitoneal injection of standard inoculum of chloroquine sensitive Plasmodium berghei (NK 65). The animals were randomly divided into 6 groups of 3 mice each. Group 1 served as the control while groups II-IV were orally administered 50, 150, and 250 mg/kg body weights of extract. Groups 5 and 6 received 1.75 and 5 mg/kg of artesunate and chloroquine, respectively. The results of the phytochemical analysis showed the presence of alkaloids (2.37%), saponin (0.336), tannin (0.012 per cent), phenol (0.008 per cent), and anthraquinone (0.002 per cent). There was 100 per cent parasite inhibition in the chloroquine group and 70 per cent in the 50 mg/kg body weight on day 12, respectively. The mean survival time (MST), for the control group was 14 days, artesunate 16 days, and chloroquine 30 days, while the groups that received 50 and 250 mg/kg body weight recorded similar MST of 17 days and the 150 mg/kg body weight group recorded 19 days. The results obtained indicated that the aqueous extract of Lecaniodiscus cupanioides may provide an alternative antimalarial. PMID- 23983719 TI - Do US ambient air lead levels have a significant impact on childhood blood lead levels: results of a national study. AB - INTRODUCTION: Although lead paint and leaded gasoline have not been used in the US for thirty years, thousands of US children continue to have blood lead levels (BLLs) of concern. METHODS: We investigated the potential association of modeled air lead levels and BLLs >= 10 MU g/dL using a large CDC database with BLLs on children aged 0-3 years. Percent of children with BLLs >= 10 MU g/dL (2000-2007) by county and proportion of pre-50 housing and SES variables were merged with the US EPA's National Air Toxics Assessment (NATA) modeled air lead data. RESULTS: The proportion with BLL >= 10 MU g/dL was 1.24% in the highest air lead counties, and the proportion with BLL >= 10 MU g/dL was 0.36% in the lowest air lead counties, resulting in a crude prevalence ratio of 3.4. Further analysis using multivariate negative binomial regression revealed that NATA lead was a significant predictor of % BLL >= 10 MU g/dL after controlling for percent pre l950 housing, percent rural, and percent black. A geospatial regression revealed that air lead, percent older housing, and poverty were all significant predictors of % BLL >= 10 MU g/dL. CONCLUSIONS: More emphasis should be given to potential sources of ambient air lead near residential areas. PMID- 23983721 TI - The relationship between family function and women's well-being. AB - BACKGROUND: Health measurement is one of the major challenges in today's researches. Various indicators including well-being are used to evaluate health. Many factors including culture, structures, and values can be effective on family health, quality of life, and well-being of family members that these elements themselves are effective on the whole society's health. One of other effective factors on these indicators is family function. MATERIALS AND METHODS: The data collecting tools included Bloom's Family Function questionnaire and well-being questionnaire, whose validity and reliability have been already confirmed. This study is a cross-sectional, descriptive, and analytical study carried out on 300 subjects in Isfahan in 2011. The inclusion criteria were the families residing in Isfahan for more than 1 year and the women who were willing to cooperate with the project. Sampling method was in the form of cluster. Isfahan has 13 clusters of which 50% (6 clusters) were randomly chosen. Fifty samples were chosen systematically on the basis of the sample volume (300 samples). The selection of the first sample was based on random numbers table and the next samples on the basis of K (the families lies numbers/K = 50). RESULTS: The sample's mean age was 45 (4.3) years, well-being dependent variable mean was 23.6, and family function variable mean was obtained as 183.6 by ANOVA. Well-being was better in families with higher function, compared to the other groups, but no significant difference was observed. CONCLUSIONS: Family function has direct and indirect effect on quality of life and well-being. It should be considered as a social determinant of health to improve well-being in family as a part of community. PMID- 23983720 TI - Nursing ethical values and definitions: A literature review. AB - BACKGROUND: Ethical values offer a framework for behavior assessment, and nursing values influence nurses' goals, strategies, and actions. A literature review was adopted in order to determine and define ethical values for nurses. MATERIALS AND METHODS: This literature review was conducted based on the Centre for Reviews and Dissemination guidelines. The key words used to search relevant sources were nursing, ethics, ethical values, and nursing values. The search of articles in English was carried out in Medline, CINAHL, PubMed, Scopus, Ovid, and Proquest databases. The search of articles in Persian was conducted in databases of Magiran, SID, and Irandoc publications. After assessing and analyzing the obtained data, 17 articles which had a distinct definition of ethical values were chosen and subjected to a thorough study. RESULTS: The search yielded 10 nursing ethical values: Human dignity, privacy, justice, autonomy in decision making, precision and accuracy in caring, commitment, human relationship, sympathy, honesty, and individual and professional competency. CONCLUSIONS: This study showed that common ethical values are generally shared within the global community. However, in several areas, influences of social, cultural, and economical status and religious beliefs on values result in a different definition of these values. This study revealed that based on humanistic nature of nursing, common values in nursing protect human dignity and respect to the patients. Recognizing and definition of ethical values can help to improve nursing practice and develop codes of ethics. PMID- 23983722 TI - The effects of 8 weeks of regular aerobic exercise on the symptoms of premenstrual syndrome in non-athlete girls. AB - BACKGROUND: Premenstrual syndrome (PMS) is a combination of physical, psychological, or behavioral changes in the late secretary phase of menstrual cycle and interferes with interpersonal relationships or activities. The purpose was to assess the effects of 8 weeks of regular aerobic exercise on PMS in non athlete girls. MATERIALS AND METHODS: This quasi-experimental study was conducted on 40 non-athlete girl students aged 18-25 years at Khorasgan Azad University, with a diagnosis of PMS. The instruments included personal information and a medical questionnaire, a form of premenstrual symptoms DSM-IV, the GHQ 28 questionnaire, and the Beck Depression and Anxiety questionnaire, and also, daily symptoms were recorded for 4 months (two courses before the training period and two during training). Individuals in the experimental group practiced aerobic exercise for 8 weeks, three sessions per week for 60 min. The subjects were evaluated during the first (the pre-test), second (the mid-test), and third menstrual period (the post-test). Statistical analysis used in this study is t test and repeated measurement analysis of variance (ANOVA). RESULTS: Results showed that the mean scores of PMS and symptoms declined after 8 weeks of training in the experimental group. The comparison of the two groups showed that the mean scores of PMS, for symptoms during and after exercise, were significantly different (P <= 0.001) and the percentages of scores PMS changes, physical, and psychological symptoms of experimental and control groups had a significant difference (P <= 0.001) after 8 weeks of training. CONCLUSIONS: Overall, the findings showed that 8 weeks of aerobic exercise is effective in reducing the symptoms of PMS and can be used as a treatment. PMID- 23983723 TI - Developing a blended learning program for nursing and midwifery students in Iran: Process and preliminary outcomes. AB - BACKGROUND: We aimed to develop and evaluate outcomes of a blended learning (BL) program for educating nursing and midwifery students of Tehran university of medical sciences (Tehran, Iran). MATERIALS AND METHODS: This was a participatory action research project. After designing BL website, providing technological infrastructures, and holding preparatory workshops, 22 blended courses were designed. BL method was implemented for one semester. Students' grade point average, participation with courses, and opinion about educational methods, and instructors' attitude and opinion about educational methods were assessed. RESULTS: Most students (n = 181; 72.1%) and 17 instructors (28.3%) consented to participate in the study. Students' grade point average and participation was significantly higher in BL rather than in face-to-face method (P < 0.0001). Most instructors (n = 11, 65%) had positive attitude toward BL method. Textual analysis of participants' opinion showed that most students preferred BL method and felt more independent in this method. However, they complained about lack of easy access to Internet and weakness in computer skills. Instructors admired the flexibility and incentives that had been provided in the program. However, some of them complained about the time-consuming nature of BL course design. CONCLUSION: The program showed positive effect on students' learning outcomes and participation. The strengths and weaknesses of the program should be considered for development of next phase of the project. Lessons learned in this phase might be helpful for decision makers who tend to develop similar programs in Iran. Motivational and communicational issues and users' IT skills should be addressed in every BL program. PMID- 23983724 TI - Preconception risk assessment of infertile couples. AB - BACKGROUND: With regard to the importance of preconception conditions in maternal health and fertility, preconception risk assessment makes treatment trends and pregnancy outcome more successful among infertile couples. This study has tried to investigate preconception risk assessment in infertile couples. MATERIALS AND METHODS: This is a descriptive analytical survey conducted on 268 subjects, selected by convenient sampling, referring to Isfahan infertility centers (Iran). The data were collected by questionnaires through interview and clients' medical records. Pre-pregnancy risk assessment including history taking (personal, familial, medical, medications, menstruation, and pregnancy), exams (physical, genital, and vital signs), and routine test requests (routine, cervix, infections, and biochemical tests) was performed in the present study. RESULTS: The results showed that the lowest percentage of taking a complete history was for personal history (0.4%) and the highest was for history of menstruation (100%). The lowest percentage of complete exam was for physical exam (3.4%) and the highest for genital exam (100%). With regard to laboratory assessment, the highest percentage was for routine tests (36.6%) and the lowest was for infection tests (0.4%). CONCLUSION: Based o the results of the present study, most of the risk assessment components are poorly assessed in infertile couples. With regard to the importance of infertility treatment, spending high costs and time on that, and existence of high-risk individuals as well as treatment failures, health providers should essentially pay special attention to preconception risk assessment in infertile couples in order to enhance the chance of success and promote treatment outcome. PMID- 23983726 TI - The relationship between spiritual intelligence with psychological well-being and purpose in life of nurses. AB - BACKGROUND: Spiritual intelligence is defined as the human capacity to ask questions about the ultimate meaning of life and the integrated relationship between us and the world in which we live. It results in an increase in psychological well-being of individuals as well as having a goal in their life. This study was conducted to investigate the relationship between spiritual intelligence with purpose in life and psychological well-being among the nurses. MATERIALS AND METHODS: The study was a descriptive correlation study. In this study, 270 nurses were selected from some hospitals of Tehran University through convenient sampling. Data were collected through a four-section questionnaire including demographic characteristics, a 24-item questionnaire of spiritual intelligence and its four components, psychological well-being questionnaire with six subscales and 84 questions, and the questionnaire of purpose in life with 20 questions. The data obtained from the questionnaires were analyzed through SPSS software. RESULTS: The results showed that there was a significant relationship between spiritual intelligence with psychological well-being and having a purpose in life. Furthermore, there was a significant association between the components of spiritual intelligence including conscious state expansion, personal meaning production, transcendental awareness, and critical existential thinking with psychological well-being. CONCLUSION: High level of spiritual intelligence in nurses helps them to improve their psychological well-being and have a purpose in life, which can lead to the health provision of them and their patients. PMID- 23983725 TI - Comparison of vaccination-related pain in infants who receive vapocoolant spray and breastfeeding during injection. AB - BACKGROUND: Vaccination is one of the most common painful procedures in infants. Despite the irreparable consequences and complications of acute pain in infants, and existence of pharmacological and non-pharmacological methods for pain control, pain control in infants has received less attention. Therefore, this research aimed to compare the vaccination-related pain in infants younger than 6 months who receive vapocoolant spray and breastfeeding during injection, in order to suggest a strategy to provide emotional, mental, and physical health for infants. MATERIALS AND METHODS: This is a randomized clinical trial study on 144 infants less than 6 months of age, referred to Ibn Sina Health Care Center in 2009, who were selected by convenience sampling. Forty-eight infants were allocated through systematic random sampling to each study group (i.e., breastfeeding, vapocoolant spray, and control group). Inclusion criteria were: Fully conscious infants, lack of any disease (sensory, motor abnormalities, cold, etc.), taking no medication, exclusive breastfeeding, vaccination for hepatitis B and DTP, regular visits to health care center, infants with Iranian nationality, and quiet infants who did not cry. The infant was excluded if he/she was crying and it was impossible to make him/her quiet before injection. Data were gathered by a questionnaire (six questions) and checklist [neonatal infant pain scale (NIPS)]. Data were analyzed by descriptive and inferential statistical methods through SPSS. RESULTS: The findings suggest that breastfeeding during vaccination has a more analgesic effect on vaccination pain, compared to application of vapocoolant spray before vaccination. In 64.6% of the infants, breastfeeding during vaccination caused analgesia, while 25% of the infants who received vapocoolant spray experienced analgesic effect. There was a significant difference in pain between the infants who received vapocoolant spray and those on breastfeeding during injection (P < 0.001). CONCLUSION: It seems that breastfeeding during vaccination in infants under 6 months of age is an effective, natural, safe, accessible, and inexpensive method without side effects to reduce vaccination-related pain. PMID- 23983727 TI - An investigation of coping styles of hemodialysis patients. AB - BACKGROUND: Hemodialysis patients are exposed to different stressful factors and have to use coping strategies as supportive processes. The goal of the present study is to investigate coping styles of hemodialysis patients. MATERIALS AND METHODS: This is a descriptive analytical study conducted on 96 patients referring to hemodialysis centers affiliated to Isfahan University of Medical Sciences in 2011. The data, collected by a questionnaire including two sections of demographic characteristics and patients' coping with the disease, were analyzed by parametric and non- parametric statistical tests. RESULTS: Patients used emotion focused coping strategies more (mean = 20.07, SD = 4.39) to adapt with the disease compared to problem focused coping strategies (mean = 14.65, SD = 5.08). There was a significant association in coping (P = 0.027) and emotion focused dimension (P = 0.008) in various ages, but there was no significant association in problem focused dimension (P = 0.134). CONCLUSION: Since most of the hemodialysis patients use emotion focused coping styles, it is suggested to consider educational programs on application of problem focused coping styles for these patients in order to decrease the pressures of the disease and treatment, and to promote their mental health, quality of life and efficiency. PMID- 23983728 TI - The effect of community health nurse home visit on self-care self-efficacy of the elderly living in selected Falavarjan villages in Iran in 2010. AB - BACKGROUND: Perceived self-efficacy is a strong predictor for behavior. Considering the importance of health-promoting self-care behaviors in increasing quality of life in the elderly, this study was aimed at defining the effect of nurse home visits on self-care self-efficacy of the elderly in rural areas. MATERIALS AND METHODS: This is a pre and post quasi-experimental study conducted on 33 older adults randomly selected from five villages in Falavarjan province in Iran. Intervention program was in the direction of self-care self-efficacy in four domains including nutrition, health practice, physical activity, and well being in the form of five home visit programs and one group session by a nurse during 6 weeks, and included two different sections of education and nursing interventions administered based on needs assessment and determination of the tasks for the clients and their families. Theoretical framework of this study was supported by Bandura's self-efficacy, Orem's self-care theory, and Pender's revised health promotion model. The data were collected by self-care self efficacy and demographic information questionnaire before and after the intervention. Data were analyzed by descriptive statistics and paired t-test. RESULTS: The mean elderly score in the four aforementioned domains increased after the home visit program. A significant difference was seen in the mean total scores of self-care self-efficacy and its subscales by paired t-test before and after intervention (P < 0.001). CONCLUSIONS: It was observed that home visit program, integrated with the theories, had a positive influence on improving self care self-efficacy of the elderly, and was supported by Bandura's theory of self efficacy suggesting four sources of performance accomplishment, vicarious experience, verbal persuasion, and emotional arousal. With regard to the importance of self-care behavior in health promotion of the elderly, multifaceted low-cost interventions with the highest effect seem essential. PMID- 23983729 TI - Chlorhexidine or povidone-iodine: Which solution is more effective on skin colonization in neonates? AB - BACKGROUND: Infection control should be an integrated part of patient care, especially to ensure safety and survival in hospitalized neonates. Although povidone-iodine (PVP-I) solution has been used as the most common antiseptic in hospitals of Iran, chlorhexidine is currently used in some wards for skin disinfection. However, there is no evidence about the superiority of either antiseptic solution over the other one. This clinical trial carried out in two university hospitals affiliated to Isfahan University of Medical Sciences, Isfahan, Iran, aimed to compare the effects of chlorhexidine and PVP-I solutions on skin bacterial colonization in hospitalized neonates. MATERIALS AND METHODS: The participants were 98 hospitalized infants. In each infant, one area on the skin was disinfected by chlorhexidine while the contralateral site was disinfected by PVP-I. Skin cultures were taken before and after disinfection. Microorganisms were determined and colony count was performed based on a standard method. The collected data were analyzed using descriptive and inferential statistical methods in SPSS v. 14. RESULTS: The mean of microorganism colony count before and after disinfection by either solution was statistically different (P < 0.001). There was no significant difference between the two groups in terms of mean microorganism colony count before disinfection. However, a significant difference was observed after disinfection. CONCLUSIONS: PVP-I is more efficacious than chlorhexidine for skin disinfection. Consequently, it seems better to use PVP-I for skin preparation before invasive procedures. PMID- 23983730 TI - Motives for entering nursing in Iran: A qualitative study. AB - CONTEXT: Choosing a career is an important decision for each individual, which is affected by many different factors. The process of entering nursing, as one of the pivotal healthcare discipline, certainly affects quality of care, and retention of nurses in the profession. AIMS: Exploring factors affecting the students' decision to enter nursing. SETTING AND DESIGN: This qualitative content analysis was carried at the school of Nursing and Midwifery of Tehran University of medical sciences. MATERIALS AND METHODS: The semi structured interview method was used to conduct this qualitative study on 11 nursing freshmen in 2010. We transcribed the interviews verbatim and analyzed them using the conventional content analysis approach. RESULTS: Four main categories, reflecting the factors affecting the participants' decision to enter nursing emerged in this study: Capabilities of the profession, coercion, having an interest in the medical and allied health fields, and receiving positive feedbacks. The participants had tried to gather information about nursing through different sources, including nurses and other health care professionals, counselors and Internet, which almost all the time, yielded to no useful information and sometimes with negative feedback. CONCLUSIONS: Findings revealed that, unlike other countries, few participants had entered nursing with a real interest in helping and caring for others, and other factors such as having an interest in the medical and allied health fields, coercion, and good employment opportunities were the most important motives. Students' lack of knowledge about the profession deserves special attention. Nursing managers' should try to introduce the reality of nursing to the public and as a result, attract more competent students to the profession. PMID- 23983731 TI - Exploring diabetes type 1-related stigma. AB - BACKGROUND: Empowerment of people with diabetes means integrating diabetes with identity. However, others' stigmatization can influence it. Although diabetes is so prevalent among Iranians, there is little knowledge about diabetes-related stigma in Iran. The present study explored diabetes-related stigma in people living with type 1 diabetes in Isfahan. MATERIALS AND METHODS: A conventional content analysis was used with in-depth interview with 26 people with and without diabetes from November 2011 to July 2012. RESULTS: A person with type 1 diabetes was stigmatized as a miserable human (always sick and unable, death reminder, and intolerable burden), rejected marriage candidate (busy spouse, high-risk pregnant), and deprived of a normal life [prisoner of (to must), deprived of pleasure]. Although, young adults with diabetes undergo all aspects of the social diabetes-related stigma; in their opinion they were just deprived of a normal life. CONCLUSION: It seems that in Isfahan, diabetes-related stigma is of great importance. In this way, conducting an appropriate intervention is necessary to improve the empowerment process in people with type 1 diabetes in order to reduce the stigma in the context. PMID- 23983732 TI - Factors affecting infant's transition from neonatal intensive care unit to home: A qualitative study. AB - BACKGROUND: The infants, hospitalized in the neonatal intensive care unit (NICU), engage with problems from admission to discharge, exploring of which ensures their safe transition. The purpose of this study was to identify the factors that influence infant's transition from the NICU to home. MATERIALS AND METHODS: A qualitative study was used for identifying the factors that affect infant's transition. Data were gathered by interviewing 16 nurses and physicians in NICUs of university hospitals in Iran; and were analyzed by qualitative content analysis method. MAXQDA, MAX Qualitative Data Analysis, is a software which has been developed in Berlin, Germany. software, the qualitative data analysis package, was used for coding and categorizing. RESULTS: There are 10 categories that affect infant's transition, as revealed in data analysis. These categories were delineated into three themes: Cognition of infant's needs, effectiveness of trainings, and organizational context. CONCLUSION: The results of this study further disclosed the factors that facilitate or hinder infant's transition from the NICU to home. The aspects of correct cognition along with more effective trainings must be fully introduced to the staff to meet infant's needs. Also, authorities are better to make policies to decrease organizational barriers. Therefore, it is suggested that applying developmental care can ease infant's transition. PMID- 23983733 TI - Triage effect on wait time of receiving treatment services and patients satisfaction in the emergency department: Example from Iran. AB - BACKGROUND: Long wait time interval in emergency department (ED) of hospitals, from the patients' point of view in ED is a major problem causing patients' dissatisfaction and may result increasing in patient morbidity and indirectly nurses dissatisfaction. Evaluation of wait time intervals in ED and giving nursing feedback may improve the quality of services, as well as patient satisfaction. The present study was designed to investigate the effect of nursing triage on receiving treatment of wait time interval and satisfaction of the patients referring to ED in Shahid Rajaee hospital. MATERIALS AND METHODS: This study was conducted on patients those referring to Shahid Rajaee hospital in Karaj, Iran employing quasi experimental design d ividing in two experiment and control groups during 2009. This is a quasi-experimental study of which the data were collected by standard questionnaire covering patient satisfaction and measuring wait time. T-test, Mann-Whitney and frequency analysis were used to evaluate the effect of triage on wait time from receiving treatment services and patients' satisfaction. RESULTS: The findings showed that there was a significant difference between experiment and control groups regarding wait time from receiving treatment services and patients' satisfaction. CONCLUSIONS: Triage could significantly reduce the wait time interval between patients' entrance to ED to receive treatment services and enhance patients' satisfaction. It may help nursing in emergency ward to have better performance and indirectly their satisfaction. PMID- 23983734 TI - The effect of empowerment program on empowerment level and self-care self efficacy of patients on hemodialysis treatment. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) who receive dialysis confront the burdens of long-term illness and numerous physical problems. MATERIALS AND METHODS: This was a quasi-experimental study. The selected patients from Gorgan Dialysis Centre were randomly assigned into an empowerment group (n = 40) and a control group (n = 40). Instruments comprised scales of Empowerment and the Strategies Used by People to Promote Health (SUPPH). Data were collected at baseline and at 6 weeks following the intervention. The data were analyzed by descriptive and inferential statistics through SPSS (version 17). RESULTS: The results indicate that scores of the empowerment (P <= 0.001) and self-care self efficacy (P = 0.003) in the empowerment group showed a significantly greater improvement than the control group. CONCLUSIONS: The study supports the effectiveness of the empowerment program to promote empowerment level and self care self-efficacy of hemodialysis patients. PMID- 23983735 TI - The effect of changes in patients' body position on the back pain intensity and hemodynamic status during and after radiofrequency catheter ablation of cardiac dysrhythmias. AB - BACKGROUND: After radiofrequency catheter ablation of arrhythmias, patients have to bed rest for 4-6 h to prevent bleeding and hematoma. However, such a rest may cause back pain in the patients. The aim of this study was to determine the effects of continuous change in body position during and after the radiofrequency ablation on the back pain. MATERIALS AND METHODS: In a quasi-experimental design 75 patients referring to university-affiliated hospitals were randomly assigned to a control group, receiving no change in body position, group A subjected to changes in body position during and after ablation, and group B subjected to changes in body position during ablation. The intensity of pain, blood pressure, heart rate, and extent of bleeding and hematoma were measured. RESULTS: The groups were not significantly different in terms of demographic characteristics, blood pressure, heart rate, overall bleeding, or hematoma at the entry into the coronary care unit. While not significantly different from each other, the intensity of back pain between group A and B were significantly lower than that of group C. Compared to group C, group A and B had a significantly lower pain score up to 6 and 4 h after the procedure, respectively. Group B had a significantly higher pain score at 2, 4, and 6 h post ablation than group A. CONCLUSIONS: The findings show that changing the body position during and after the ablation procedure would reduce or prevent the back pain without increasing the chance of bleeding and hematoma. PMID- 23983736 TI - Comparison of midwifery students' satisfaction with direct observation of procedural skills and current methods in evaluation of procedural skills in Mashhad Nursing and Midwifery School. AB - BACKGROUND: The clinical evaluation, as one of the most important elements in medical education, must measure students' competencies and abilities. The implementation of any assessment tool is basically dependent on the acceptance of students. This study tried to assess midwifery students' satisfaction with Direct Observation of Procedural Skills (DOPS) and current clinical evaluation methods. MATERIALS AND METHODS: This quasi-experimental study was conducted in the university hospitals affiliated to Mashhad University of Medical Sciences. The subjects comprised 67 undergraduate midwifery students selected by convenience sampling and allocated to control and intervention groups according to the training transposition. Current method was performed in the control group, and DOPS was conducted in the intervention group. The applied tools included DOPS rating scales, logbook, and satisfaction questionnaires with clinical evaluation methods. Validity and reliability of these tools were approved. At the end of training, students' satisfaction with the evaluation methods was assessed by the mentioned tools. The data were analyzed by descriptive and analytical statistics. RESULTS: Satisfaction mean scores of midwifery students with DOPS and current methods were 76.7 +/- 12.9 and 62.6 +/- 14.7 (out of 100), respectively. DOPS students' satisfaction mean score was significantly higher than the score obtained in current method (P < 0.000). The most satisfactory domains in the current method were "consistence with learning objectives" (71.2 +/- 14.9) and "objectiveness" in DOPS (87.9 +/- 15.0). In contrast, the least satisfactory domains in the current method were "interested in applying the method" (57.8 +/- 26.5) and "number of assessments for each skill" (58.8 +/- 25.9) in DOPS method. CONCLUSIONS: This study showed that DOPS method is associated with greater students' satisfaction. Since the students' satisfaction with the current method was also acceptable, we recommend combining this new clinical evaluation method with the current method, which covers its weaknesses, to promote the students' satisfaction with clinical evaluation methods in a perfect manner. PMID- 23983737 TI - An investigation on occupational stress of the operating room staffs in hospitals affiliated to Isfahan University of Medical Sciences and its association with some factors. AB - BACKGROUND: Stress is a nonspecific reaction to everything the body needs. Although occupational stress exists in every occupation, it is seen with more frequency and intensity amongst those occupations related to human health. In this study, we aimed to investigate the level of occupational stress in operating room staffs working in the hospitals affiliated to Isfahan University of Medical Sciences and its association with some factors. MATERIALS AND METHODS: This is a descriptive co-relational study conducted in summer 2010. The population studied comprised 100 OP staffs working in hospitals affiliated to Isfahan University of Medical Sciences. The data were collected by a questionnaire including two sections of personal information and Toft-Anderson Standard occupational stress inventory. The first section contained 13 questions and the second included 34 questions on stressful factors, measured through Likert's scale in which the scores of 0-33 indicated mild stress, 34-66 indicated moderate stress, and 67-100 indicated acute stress. The data were analyzed through SPSS. The statistical tests of Pearson correlation, variance analysis, and independent t-test were employed to analyze the data (P < 0 0.05 was considered significant). RESULTS: Based on the findings, mean score of staffs' stress (out of 100) was 32.3 (12.9) and was in the range of 1-65. The highest frequencies were for mild stress (57.4%) and moderate stress (42.6). In addition, mean score of stress was not the same in different domains. There was a significant inverse association between the score of stress and monthly working hours (r = -0.21, P = 0.049). Mean score of stress was 28.1 (12.3) among those with average income and 33.8 (12.8) for the low-income subjects, showing a significant difference (P = 0.048). DISCUSSION AND CONCLUSION: The present study showed that most of the subjects suffer from mild stress. Since the highest level of stress was for work overload, it is suggested to reduce the staffs' work overload by employing capable and knowledgeable work force and enhancing their scientific and practical abilities. PMID- 23983738 TI - Coping strategies, quality of life and pain in women with breast cancer. AB - BACKGROUND: Breast cancer is the most common malignancy among Iranian women and is a significant stressor in women's life that may affect their coping strategies and quality of life. This study aimed to investigate coping strategies, quality of life and pain of women with breast cancer. MATERIALS AND METHODS: This was a cross-sectional study which held in Seyed-AL shohada hospital and two private offices in Isfahan, Iran. Target population was women with confirmed diagnosis of breast cancer in a recent year and between 18 and 60 years old. Data were collected via3 questionnaires (Brief cope, EORTC QLQ-C30 and Brief pain Inventory). The reliability and validity of these questionnaires were confirmed in different studies. Sixty-two patients completed the questionnaires. Analysis included descriptive statistics and Pearson correlation coefficient and t-test where necessary. All analysis were conducted using the SPSS version 16.0 and P value of less than 0.05 considered as statistically significant. RESULTS: Sixty two women with breast cancer completed questionnaires. The mean age of respondents was 45/81+/-6/78 years; most married (93/5%), high school-educated (41/97%), house wife (82/3%) and stage II (46/8%). The most common coping strategies were religion, acceptance, self-distraction, planning, active coping, positive reframing and denial. Mean score for the worst pain during the past 24 hours was 6/24 +/- 2/55 and for the least pain was 3/19 +/- 2/17. The global health scale was 60.34 +/- 21.10. Emotion-focused coping strategies were positively and significantly related to symptom aspect of quality of life (r = 0/43 P <= 0/01) and affective interference of pain (r = 0/36 P = 0/004) and also was inversely correlated to functional health status (r = -0/38 P = 0/002). There was no significant correlation between problem-focused coping strategies and dimensions of quality of life and also different aspects of pain. CONCLUSIONS: The findings of this study indicated that the care of breast cancer should address physical, psychological and social wellbeing and the findings point to the importance of taking individual coping strategies into account when evaluating the impact of breast cancer on psychosocial wellbeing. Description of coping strategies might be useful for identifying patients in need to particular counseling and support. PMID- 23983739 TI - Comparison of halogen light and vibroacoustic stimulation on nonreactive fetal heart rate pattern. AB - BACKGROUND: One of the first-line assessment tools for fetal surveillance is nonstress test (NST), although it is limited by a high rate of false-nonreactive results. This study was performed to investigate if external stimulation from vibroacoustic and halogen light could help in provoking fetal responsiveness and altering NST results. MATERIALS AND METHODS: This is a clinical trial. Sampling was done from April to July 2010. One hundred pregnant women with nonreactive NST for 20 min were allocated in two groups: Vibroacoustic stimulated NST (VNST, n = 50) who received vibration from a standard fetal vibratory stimulator and halogen light stimulated NST (LNST, n = 50) who received a halogen light source for 3 and 10 sec, respectively. Results were compared together and then compared to biophysical profile (BPP) scores as a backup test. We used Mann-Whitney U test, Chi-square test, and Fisher's exact test to compare the variables in the two groups through SPSS version 14. P < 0.05 was considered as statistically significant. RESULTS: Following stimulations, 68% nonreactive subjects in halogen light stimulation group and 62% in vibroacoustic stimulation group changed to reactive patterns. Time to onset of the first acceleration (VNST: 2.17 min; LNST: 2.27 min) and the test duration (VNST: 4.91 min; LNST: 5.26 min) were the same in the two groups. In VNST 89.5% and in LNST 87.5% of nonreactivity followed by score 8 in BPP. There was no significant relation between stimulus NSTs and BPPs. CONCLUSION: Vibroacoustic and light stimulation offer benefits by decreasing the incidence of nonreactive results and reducing the test time. Both halogen light stimulation and vibroacoustic stimulation are safe and efficient in fetal well being assessment services. PMID- 23983741 TI - Consequences of nursing procedures measurement on job satisfaction. AB - BACKGROUND: Job satisfaction among nurses has consequences on the quality of nursing care and accompanying organizational commitments. Nursing procedure measurement (NPM) is one of the essential parts of the performance-oriented system. This research was performed in order to determining the job satisfaction rate in selected wards of Baqiyatallah (a. s.) Hospital prior and following the NPM. MATERIALS AND METHODS: An interventional research technique designed with an evaluation study approach in which job satisfaction was measured before and after NPM within 2 months in selected wards with census sampling procedure. The questionnaire contained two major parts; demographic data and questions regarding job satisfaction, salary, and fringe benefits. Data analyzed with SPSS version 13. RESULTS: Statistical evaluation did not reveal significant difference between demographic data and satisfaction and/or dissatisfaction of nurses (before and after nursing procedures measurement). Following NPM, the rate of salary and benefits dissatisfaction decreased up to 5% and the rate of satisfaction increased about 1.5%, however the statistical tests did not reveal a significant difference. Subsequent to NPM, the rate of job value increased (P = 0.019), whereas the rate of job comfort decreased (P = 0.033) significantly. CONCLUSIONS: Measuring procedures do not affect the job satisfaction of ward staff or their salary and benefits. Therefore, it is suggested that the satisfaction measurement compute following nurses' salary and therefore benefits adjusted based on NPM. This is our suggested approach. PMID- 23983740 TI - Comparing two levels of closed system suction pressure in ICU patients: Evaluating the relative safety of higher values of suction pressure. AB - BACKGROUND: Endotracheal suctioning (ETS) is one of the most common supportive measures in intensive care units (ICU). ETS may be associated with complications including hypoxia and tachycardia. Closed system suctioning (CSS) decreases the rate of cardiorespiratory complication mainly due to continuation of ventilatory support and oxygenation during procedure. CSS has questionable efficacy, therefore higher values of negative pressure has been recommended to enhance the efficacy of CSS. This study was designed to evaluate the effects on gas exchange of 200 mmHg suctioning pressure compared with 100 mmHg in CSS. MATERIALS AND METHODS: Fifty mechanically ventilated (MV) ICU patients were selected for the study. Two consecutive ten seconds CSS using suction pressures of 100 and 200 mmHg, in random order applied in each subject with the two hours wash out period. Effects of two levels of suction pressure on gas exchange were measured by recording the SPo2 values at 4 times. RESULTS: Repeated measure analysis of variance didn't show any significant difference between two levels of pressure (P = 0.315), but within each groups (100 and 200 mmHg) SPO2 changes was significant (P = 0.000). There was a mild but significant and transient increase in heart rate following both suction pressures, but no significant difference between two groups. CONCLUSION: The results show that CSS with suction pressure 200 mmHg has no detrimental effect on cardiorespiratory function of MV ICU patients. Since the safety of 200 mmHg suctioning pressure was approved, using 200 mmHg suction pressures is recommended for ETS of MV patients. PMID- 23983742 TI - Oral fennel (Foeniculum vulgare) drop effect on primary dysmenorrhea: Effectiveness of herbal drug. AB - BACKGROUND: Primary dysmenorrhea refers to the occurrence of painful menstrual cramps of uterus and is considered as a gynecological complaint. The common treatment for this problem is medical therapy such as mefenamic acid [non steroidal anti-inflammatory drugs (NSAIDs)] and oral contraceptive pills, both of which work by reducing myometrial activity. Fennel contains an antispasmodic and anethol agents and may be helpful for management of primary dysmenorrhea. MATERIAL AND METHODS: The aim of this study was to evaluate the effects of oral fennel drop for treating primary dysmenorrhea. Sixty college students suffering from primary dysmenorrhea were randomly assigned to two groups and followed up for two cycles. Statistical analysis was performed using SPSS version 16. P < 0.05 was considered to be statistically significant. Parametric and non parametric tests were adopted. RESULTS: Comparison of pain intensity in the two groups showed that there was no significant difference in pain relief between the two groups. Comparison of bleeding severity in the study group before and after intervention was demonstrated from the first day to the fifth day (PV on first day, second day, third day, fourth day, and fifth day 0.948, 0.330, 0.508, 0.583, 0.890, respectively). CONCLUSION: It seems that fennel can be effective in reducing the severity of dysmenorrhea, but it has an unpleasant taste in view of most of the volunteers. PMID- 23983743 TI - Factors influencing the patient education: A qualitative research. AB - BACKGROUND: The related literatures revealed that there is a lack of effective patient/family education in the health care centers. Several studies indicate that patients, while getting discharged from hospitals, receive insufficient information about their illness and self-care. AIMS: The purpose of the study was to explore the factors influencing patient education from the perspectives of nurses in Iran. SETTINGS AND DESIGN: We conducted a qualitative study using a content analysis approach. MATERIALS AND METHODS: We used a purposive sampling technique to recruit and interview 18 nurses with at least 2 years of working experience in the cardiac care unit (CCU) and post-CCU ward of two educational hospitals in Tehran related to Tehran University. Data were collected through face-to-face audio-taped interviews and field observations. STATISTICAL ANALYSIS USED: The interviews were transcribed verbatim and analyzed concurrently with data collection. RESULTS: THE MAJOR THEME EXTRACTED IN THIS STUDY WAS THE INAPPROPRIATE ORGANIZATIONAL CULTURE WHICH INCLUDES EIGHT CATEGORIES LISTED AS FOLLOWS: Not putting value on education, non-professional activities, physician oriented atmosphere, conflict and lack of coherence in education, inappropriate communication skills, ignoring patient's right in education, lack of motivation, rewarding system in the organization, and poor supervision and control. CONCLUSIONS: The results of this study show that according to the participants' perspective, organizational culture is in a poor level. So, to improve the performance of nurses, it is necessary to increase their motivation through optimization of organizational culture. PMID- 23983744 TI - The effect of sleep restriction treatment on quality of sleep, sleep medication intake, and daytime function among the elderly who were members of Shiraz Jahandidegan canter in 2010. AB - BACKGROUND: Studies showed that poor quality of sleep is a common problem among the elderly. Because of drug complications and side effects such as drug dependency and resistance and decrease of sleep depth in long-term intake of sleep medication, cognitive-behavior therapy including sleep restriction therapy which does not cause these problems is more considered. MATERIALS AND METHODS: This is a quasi-experimental study on 38 elderly who were members of jahandidegan canter in Shiraz. The subjects were selected according to the inclusion criteria and were divided into experimental and control groups. The Pittsburgh Sleep Quality Index (PSQI) was used for evaluation of sleep quality. A 4 week sleep restriction therapy was implemented for experimental group and finally both groups were compared. The data were analyzed by Kolmogorov-Smirnov test, independent and dependent t-tests in significance level of 0.05. RESULTS: Mean sleep quality decreased from 14.21 to 11.26 after the intervention in the experimental group while it was 13 before intervention and decreased to 12.78 after the intervention in the control group. Independent t-test showed a significant difference after the intervention (P = 0.038). Mean of sleep medication intake and daytime dysfunction after intervention were 0.947, 1.94 in experimental group and 0.894, 1.63 in control group respectively, which showed no significant difference (P = 0.903, P = 0.272). CONCLUSIONS: This study indicated that sleep restriction therapy can improve quality of sleep, but the amount of sleep medication intake and daytime dysfunction did not show a significant difference after intervention. PMID- 23983745 TI - Barriers to nursing care in emergency wards. AB - BACKGROUND: Caring is the essence of nursing. Since care is influenced by cultural, economic, and social factors, various diverse barriers exist in the realization of care. The aim of the study was to clarify barriers to caring in emergency patients based on experiences of nurses and patients and their relatives. MATERIALS AND METHODS: A qualitative design of content analysis was used to identify the barriers to caring in emergency patients. In-depth interviews were conducted with 18 Iranian nurses working in a university hospital emergency ward and with seven patients. Participants were selected purposefully. Data were analyzed according to qualitative content analysis. RESULTS: After the classification analyses and integration of codes, seven categories were acquired. Finally, following three themes were extracted: Identified barriers to nursing care in emergency wards - the nature of critical ward, performance weakness of nurses, and deficiency in clinical management. CONCLUSIONS: According to the results of this study fundamental and management education for nurses, empowerment of nurses, principle and scientific triage, effective supervision, nurses' support, wage increase, and motivation in nurses are important to achieve the research purpose. PMID- 23983746 TI - Effects of a family support program on self-care behaviors in patients with congestive heart failure. AB - BACKGROUND: Heart failure is one of the chronic heart diseases and a debilitating condition of increased prevalence in the elderly. One of the important and non pharmacological strategies for improving clinical outcomes in these patients is promotion of the self-care. Background and social environment in which a patient is trying to control his disease is an important factor in the self-care. The aim of this study was to evaluate the effects of family support intervention on the self-care behaviors in patients with heart failure. MATERIALS AND METHODS: This study was a randomized clinical trial conducted in university hospitals in Isfahan, Iran, in 2012. A total of 62 patients with heart failure were randomly assigned to experimental (n = 32) and control (n = 32) groups. Supportive intervention including three educational sessions with the delivery of educational booklet and follow-up by telephone was performed for caregivers of patients in the experimental group. Data were collected using the questionnaire of self-care behaviors, which was completed before and 1 month after the intervention in both the groups, and the questionnaires were analyzed using descriptive statistics and independent and paired t-tests. RESULTS: The results indicate that after the intervention, self-care behavior scores in the experimental group and control group were 47.2 and 28.4, respectively, and independent t-test revealed that the difference was statistically significant. CONCLUSION: Family-focused supportive interventions can be used as an effective method for improving the self-care behaviors in patients with heart failure. PMID- 23983747 TI - Women's perceived internal control of future pregnancy outcomes and its related factors. AB - BACKGROUND AND PURPOSE: With regards to the importance of women's beliefs in improving pregnancy outcomes, this study was performed to determine the perceived internal control on future pregnancy outcomes and its related factors in women who participated in pre-marital counseling. MATERIALS AND METHODS: In a cross sectional study, women's perceived internal control was investigated. The study population comprised the women in reproductive age of whom 400 were selected by random sampling. Data collection instrument was a questionnaire consisting of demographic, pre-conceptional care, and internal control questions. Two categories of favorite and not favorite levels of internal control were defined based on the total score. The validity of the questionnaire was determined via content validity method by use of experts' opinion and its reliability was evaluated through the calculation of Cronbach's alpha coefficient which was 0.76. Data were analyzed through frequency tables, correlation coefficient, and Chi square test at the confidence level of 0.95. RESULTS: Two hundred sixty-five (65%) women had a good perceived internal control and it was significantly associated with the age, educational level, and hearing about pre-conceptional care. The internal control score also showed a positive and significant correlation with both age and the subject knowledge about folic acid (r = 0.19 and r = 0.15, respectively). CONCLUSION: The majority of women had a favorite perceived internal control. Since age and educational level were the affecting factors on the perceived internal control of women, promoting the level of internal control in young women and those with low education in pre-marital counseling classes seems necessary. PMID- 23983748 TI - Exploring spirituality in Iranian healthy elderly people: A qualitative content analysis. AB - BACKGROUND: Spirituality is recognized as a personally important matter to the elderly, and there are evidences of its impact on their health. The aim of this study was to explore the concept of spirituality from the perspectives of Iranian healthy elderly individuals. MATERIALS AND METHODS: A conventional qualitative content analysis of carried out with 21 healthy elderly people from both male and female genders were chosen using a purposive sampling method in Tehran in 2010 2011. Data collection was done through semi structured interviews. A qualitative content analysis was used to analyze the participants' experiences and perceptions on spirituality, using a central question 'what characterizes the spirituality in the Iranian healthy elderly people?' RESULTS: THE FOLLOWING CATEGORIES EMERGED FROM THE DATA ANALYSIS: (1) Spiritual health, with four sub categories including saying prayer as a calming factor; beneficence as a way to God; loss of psychological and spiritual support; faith as a way to happiness; (2) spiritual beliefs, with three sub categories including seeking help from God in difficulties; God's power over life and death; doing good deeds is the God's will; and (3) religious practice with three sub categories including saying prayer; reading Quran; and going to mosque, religious ceremonies and pilgrimage. CONCLUSIONS: In this study was found that spirituality was a fundamental element in elderly individuals' lives that help them to adapt with daily living conditions. PMID- 23983749 TI - Prerequisites for electronic learning: Iranian postgraduate nursing students' points of view. AB - BACKGROUND: Nursing education is mostly conducted through electronic educational programs. We aimed at assessing the Iranian postgraduate nursing students' skills and attitudes regarding the electronic education. MATERIALS AND METHODS: Ninety seven postgraduate nursing students were surveyed using questionnaires assessing their individual-social and educational characteristics, electronic education skills, and attitudes toward the electronic education. RESULTS: Scores of the students' skills in using computer and the Internet were significantly associated with gender and the number of hours working with computer and the Internet at home and work. CONCLUSION: Prerequisites for performing electronic education programs are present at moderate levels in Iran. PMID- 23983750 TI - Obesity related factors in school-aged children. AB - BACKGROUND: Overweight and obesity is becoming an increasingly prevalent problem in both developed and developing world, and is one of the most serious public health challenges of the 21(st) century. Although various studies demonstrated pediatric obesity-related factors, but, due to its ongoing hazardous effects, researchers aimed to assess obesity-related factors in school-aged children in Rasht, Iran. MATERIALS AND METHODS: This was a case-control study which was performed in eight primary schools of Rasht. A cluster sampling method was used to select 320 students including 80 in case (BMI >=85(th) percentile for age and gender) and 240 in control group (BMI = 5(th)-85(th) percentile for age and gender). Data were collected by a scale, a tape meter, and a form which consisted of obesity-related factors, and were analyzed by Chi-square, Mann-Whitney, and stepwise multivariate regression tests in SPSS 19. RESULTS: Findings showed that the mean and standard deviation of birth weight (g) in case and control groups were 3671 +/- 5.64 and 190 +/- 5.46, respectively (P = 0.000). 82.5% of case and 92.9% of control group had exclusive breastfeeding for 4-6 months (P = 0.024). Also, multivariate regression analysis indicated that birth weight, age, exclusive breastfeeding, and frequency of meals have significant effects on body mass index (BMI). CONCLUSIONS: It seems that more accurate interventions for primordial prevention are essential to reduce childhood obesity risk factors, including promotion of pre-pregnancy and prenatal care to have neonates who are appropriate for gestational age and also improving exclusive breastfeeding in the first 6 months of life. In addition, identifying children at risk for adolescent obesity provides physicians and midwives with an opportunity for earlier intervention with the goal of limiting the progression of abnormal weight gain. PMID- 23983751 TI - Iranian patient's expectations about coronary angiography: A qualitative study. AB - BACKGROUND: Coronary angiography is recognized as the gold test for diagnosis of coronary artery diseases. Based on the literature review, little is known about patients' expectations about this procedure. Understanding the patient's expectations is an important way to achieve patient-centered care. The purpose of this study was to explore the expectations of Iranian patients undergoing coronary angiography. MATERIALS AND METHODS: This descriptive exploratory qualitative study was carried out between 2011 and 2012 in three hospitals in Shiraz, Iran, with a purposive sample of 15 patients (7 men and 8 women, about 28 70 years of age). Data were collected using semi-structured interviews to explore the patients' expectations. Interview data were analyzed using conventional qualitative content analysis approach. RESULTS: The interviews revealed that the participants had four main categories of expectations about coronary angiography. The patient's expectations were those from angiography, from the treatment team, and the need for preparation of angiography, education, and training. CONCLUSIONS: In general, the results of this study revealed a new insight into the expectations of patients undergoing coronary angiography. Patient education and preparation should include information addressing the expectations. Moreover, an appropriate care program based on the patients' expectations can promote the quality of care and satisfaction of patients. PMID- 23983752 TI - Investigation on the association between breast cancer and consumption patterns of combined oral contraceptive pills in the women of Isfahan in 2011. AB - BACKGROUND: Oral contraceptive pills are among the most popular contraceptive methods, but the fear of cancer and cardiovascular disease overshadows its continuous use among women. This study aimed to define the association between consumption patterns of combined oral contraceptives among women with breast cancer. MATERIALS AND METHODS: This is an analytical case-control study conducted on 175 women with breast cancer, referring to Seyed al Shohada Medical Center and private clinics in Isfahan to be treated and followed up in 2011, as well as 350 healthy women who were identical with the subjects in the study group regarding age and residential location. The data were collected using a researcher-made questionnaire. Content validity and Cronbach's alpha were employed to confirm validity and scientific reliability of the questionnaire, respectively. The data were analyzed by descriptive and analytical statistical methods through SPSS. RESULTS: The findings showed that there was a significant association between history of contraceptive pills' consumption and incidence of breast cancer (P < 0.001). It was shown that the risk of developing breast cancer is increased by 2.27-fold among those with pills' consumption compared to those with no history of that. It was also shown that pills' consumption for 36-72 months increased the risk of breast cancer by 2.18-fold, the age of the first use being less than 20 years increased the risk by 3.28-fold, and time since the last use of less than 25 years increased the risk by 2.63-fold. There was no significant association between duration of use, age of the first and last use, and time since the first and last use in the study and control groups. CONCLUSION: The results showed that history of pills' consumption is associated with incidence of breast cancer regardless of the consumption pattern. Use of oral contraceptives pills at any age and for any duration can increase the risk of breast cancer. PMID- 23983753 TI - Nurses'experiences of perceived support and their contributing factors: A qualitative content analysis. AB - BACKGROUND: Following professional standards is the main concern of all managers in organizations. The functions of nurses are essential for both productivity and improving health organizations. In human resources management, supporting nursing profession is of ultimate importance. However, nurses' experiences of perceived support, which are affected by various factors in workplace, have not been clearly explained yet. Thus, this study aimed to explain nurses' experiences of perceived support and their contributing factors. MATERIALS AND METHODS: This study is a qualitative research in which 12 nurses were selected through purposive sampling among nurses in university hospitals affiliated to University of Medical Sciences, Urmia, Iran, during 2011-2012. Data collection was conducted through deep interviews with semi-structural questions. All interviews were first recorded and then transcribed. Finally, data were analyzed through conventional content analysis. RESULTS: The four main themes indicated that nurses experienced their workplace as non-supportive. Themes such as poor organizational climate, low social dignity, poor work conditions, and managers' ignorance to individual and professional values were considered as inhibitory factors to support. CONCLUSION: Nursing managers can promote nurses' positive support perceptions through recognizing inhibitory factors and applying fair solutions and take benefits of their positive consequences including high efficacy, self-esteem, and organizational commitment to promote the quality of care. PMID- 23983754 TI - Factors associated with medical orders' compliance among hyperlipidemic patients. AB - BACKGROUND: Coronary artery diseases are one of the most important issues in health and social problems. One of the amendable risk factors in development of these diseases is high cholesterol which can be modified through correction of lifestyle (diet change, playing sports, and usage of lipid-lowering drugs). Patients' compliance to therapeutic programs is the most important element to achieve this goal. This study aims to define the factors associated with compliance to medications among hyperlipidemic patients. MATERIALS AND METHODS: This is a descriptive analytical study conducted on 82 hyperlipidemic patients. The data were collected by a questionnaire including two sections: The first section was about demographic characteristics and the second section contained a questionnaire extracted from Foley questionnaire (2005) to inquire medication compliance. The data were analyzed by descriptive statistics (mean), Pearson Spearman correlation coefficients, and independent t-test. RESULTS: Based on the findings, it was evident that most of the hyperlipidemic individuals were compliant. There was a significant association between scores of medication compliance and age (P = 0.035), the number of family members (P = 0.033), the number of consumed drugs (P = 0.022), and education (P < 0.001). CONCLUSION: The results obtained in the present study were consistent with those of other studies reporting high compliance to medication among hyperlipidemic patients and possibly are one of the reasons for the low number of consumed drugs. Since compliance was lower among the individuals with increased age, lesser number of family members, and lesser education, these groups should be supported to promote their level of compliance to medication orders, and this important issue should be included in their educational programs. PMID- 23983755 TI - Technology concept in the view of Iranian nurses. AB - BACKGROUND: Over the years, the concept technology has modified, especially from the viewpoint of the development of scientific knowledge as well as the philosophical and artistic aspects. However, the concept of technology in nursing are still poorly understood. Only small qualitative studies, especially in Iran, have investigated this phenomenon and they just are about information technology. The aim of this study is to gain a better understanding of the concept of technology in the view of Iranian nurses. MATERIALS AND METHODS: This study was qualitative explorative study which was done with a purposeful sampling of 23 nurses (staffs, supervisors and chief nurse managers) working in Isfahan hospitals. Unstructured interviews were including 13 individual interviews and 2 focused-group interviews. In addition to this, filed notes and memos were used in data collection. After this data transcribing was done and then conventional content analysis was used for data coding and classification. RESULTS: The results showed that there are various definitions for technology among nurses. In the view of nurses, technology means using new equipment, computers, information technology, etc). Data analysis revealed that nurses understand technology up to three main concepts: Change, Equipment and Knowledge. CONCLUSIONS: In deep overview on categories, we found that the most important concept about technology in nursing perspective is equipment. Therefore, it is necessary to develop deep understanding about the possible concepts technology among nurses. We suppose that technology concepts must be defined separately in all disciplines. PMID- 23983756 TI - The experiences of parents with infants in Neonatal Intensive Care Unit. AB - BACKGROUND: In recent years significant medical science advances have been made in the field midwifery and infant care. The premature, low birth weight and ill infants are admitted to the technologically advanced NICU for care and they often require long-term stay. This study addresses parental experiences with the infant care in NICU, explores their concerns regarding nursing supports for parents and offers nurses' perspectives on performing duties. MATERIALS AND METHODS: A qualitative inductive content analysis method was applied in 2011 that included a purposely selected group of parents, nurses and physicians from neonatal unit at the Medical Science University of Isfahan. Participants were surveyed and interviewed according to the institutional ethics committee approval and signed informed consents. RESULTS: THE CONTENT ANALYSIS IDENTIFIED TWO MAIN CATEGORIES: 1) the definition of stress, which consisted of misgivings, nervous pressure, imbalance, separation and 2) the parents' reaction to stress, which revealed emotional, psychotic and behavioral reactions as subcategories. DISCUSSION: The medical team awareness of NICU parent experiences is essential to the quality of care. Recognizing the type of parents' reaction to the whole process by the healthcare team seems essential to the optimum outcome. PMID- 23983757 TI - Nursing and midwifery students' perceptions of instructors' unethical behaviors. AB - BACKGROUND: Although nursing faculties may believe that they possess a core of knowledge about ethical interactions with students, they may unwittingly risk crossing an ethical boundary in the learning environment. The ethical dimension in education exists because the instructor has authority to contribute to or impede the students' acquisition of knowledge. Therefore, this study aimed to determine the views of Iranian baccalaureate nursing and midwifery students regarding the occurrence rate of their faculties' unethical behaviors. MATERIALS AND METHODS: In this study, 115 subjects, including 61 nursing and 54 midwifery students, completed a questionnaire (response rate = 67.6%). The questionnaire consisted of demographic data and 27 short statements which described the faculties' unethical behaviors. Reliability of instrument was confirmed (0.92) using Cronbach-Alpha. RESULTS: Delaying in announcing the exam results (40%), lack of a positive learning environment (35.7%), failure to keep regularly scheduled office appointments (35.7%), and failure to update lecture notes when teaching a course (31.3%) were reported by the students as the main faculties' unethical behaviors. Data analysis confirmed that there were no statistically significant differences between nursing and midwifery students' responses (the two-tailed t-test was not significant at alpha 0.05 levels; P > 0.05). CONCLUSION: The study findings suggest that more emphasis should be put on faculties being accessible for consultation out of class time, announcing the exam results in a timely manner, and creating a positive learning environment. PMID- 23983758 TI - Impacts of creating opportunities for parent empowerment on maternal stress: A quasi-experimental study. AB - BACKGROUND: This study aimed to determine the impact of an empowerment program on maternal stress. MATERIALS AND METHODS: During May 2009-May 2010, this quasi experimental study was performed in the neonatal intensive care unit (NICU) of Shahid Akbarabadi, Rasoul-e-Akram, and Aliasghar Hospitals affiliated to Tehran University of Medical Sciences (Iran). The program consists of an educational CD along with written information and reinforcing activities for parents in the intervention group, and routine education was performed in the control group. We evaluated 140 mothers who were aged 18-37 years, had a gestational age of 28-37 weeks with singleton pregrancy, and with the birth weight of the newborn being less than 2500 g. The participants did not have chronic mental or physical illnesses. They were randomly assigned to two groups of intervention and control. RESULTS: A statistically significant difference was observed between mean (SD) stress scores of mothers before and after the intervention in the intervention group [123.00 (97.24) vs. 75.00 (7.16); P < 0.01)]. CONCLUSION: This study showed the importance of training mothers in reducing their stress and enabling them to appropriately communicate with and care for their premature newborn. PMID- 23983759 TI - Internal conflicts of Iranian first-time mothers in adaptation to maternal role. AB - BACKGROUND: Studies indicate that becoming a mother is accompanied by prominent physical, social, and psychological changes which can affect not only mother's psychological healthiness, but also all other aspects of her personal and family life. The purpose of this research was to explore the struggles experienced by Iranian first-time mothers in adapting to their maternal role between 0 and 1 year after giving birth. MATERIALS AND METHODS: A qualitative design was used in this study. Twenty-one first-time mothers with diverse ethnic backgrounds were recruited in their home or healthcare centers in Tehran and Ahwaz. Data collected through in-depth interviews were analyzed by qualitative content analysis. RESULTS: THE ANALYSIS PRODUCED FOUR THEMES: "Unpreparedness," "lack of control," "incomplete maternal feelings," and "unstable relations." The main theme, "internal conflict," integrates all other categories and encapsulates the major changes to which women are subjected, as well as the factors distressing this experience. CONCLUSION: Discrepancies between subjective expectations and postnatal experiences take an influential role in causing postpartum conflict and strain. The more accurate information mothers and families have about this transitory stage, the better they can get prepared to deal with it. This specifies the pivotal role of midwives, midwifery educators, and healthcare policy makers in incorporating these concepts into training programs and protocols of healthcare and support services in due time, form, and content that is in accordance with mothers' mental and psychological needs. PMID- 23983760 TI - Types and causes of medication errors from nurse's viewpoint. AB - BACKGROUND: The main professional goal of nurses is to provide and improve human health. Medication errors are among the most common health threatening mistakes that affect patient care. Such mistakes are considered as a global problem which increases mortality rates, length of hospital stay, and related costs. This study was conducted to evaluate the types and causes of nursing medication errors. MATERIALS AND METHODS: This cross-sectional study was conducted in 2009. A total number of 237 nurses were randomly selected from nurses working in Imam Khomeini Hospital (Tehran, Iran). They filled out a questionnaire including 10 items on demographic characteristics and 7 items about medication errors. Data were analyzed using descriptive and inferential statistics in SPSS for Windows 16.0. RESULTS: Medication errors had been made by 64.55% of the nurses. In addition, 31.37% of the participants reported medication errors on the verge of occurrence. The most common types of reported errors were wrong dosage and infusion rate. The most common causes were using abbreviations instead of full names of drugs and similar names of drugs. Therefore, the most important cause of medication errors was lack of pharmacological knowledge. There were no statistically significant relationships between medication errors and years of working experience, age, and working shifts. However, a significant relationship was found between errors in intravenous injections and gender. Likewise, errors in oral administration were significantly related with number of patients. CONCLUSION: Medication errors are a major problem in nursing. Since most cases of medication errors are not reported by nurses, nursing managers must demonstrate positive responses to nurses who report medication errors in order to improve patient safety. PMID- 23983761 TI - Effect of Ramadan fasting on emotional reactions in nurses. AB - BACKGROUND: Today anxiety, depression, and stress are among the fundamental problems, and nursing due to ongoing relationships with patients is one of the stressful jobs. The present study has been carried out to investigate the effect of fasting on emotional reactions among nurses in selected hospitals of Tehran. MATERIALS AND METHODS: In a descriptive analytical study, 313 nurses working nurses of selected hospitals in Iran with the mean age of 37.82 +/- 7.17 years were sampled with randomized cluster sampling method from two selected hospitals, and level of their emotional reactions was assessed by DASS21 questionnaire in two stages over 1-2 weeks before and after Ramadan. Then, using the statistical software SPSS15 and with Wilcoxon and paired t-test, data were analyzed. RESULTS: The findings showed that depression and stress levels were significantly reduced after in comparison with before the holy month (P < 0.05). Despite the reduction of anxiety level in fasting caregivers after Ramadan, the difference was not significant. CONCLUSIONS: Fasting has been effective in diminishing stress and depression levels among nurses. PMID- 23983762 TI - Prevalence of episiotomy in primiparas, related conditions, and effects of episiotomy on suture materials used, perineal pain, wound healing 3 weeks postpartum, in Turkey: A prospective follow-up study. AB - BACKGROUND: Despite current recommendations against routine use of episiotomy, its incidence is still high in Turkey. The study aimed to identify the prevalence of episiotomy in primiparas, related conditions, and effects of episiotomy on suture materials used, perineal pain, and wound healing 3 weeks postpartum. MATERIALS AND METHODS: This study was designed as a prospective follow-up study. Data were collected via a questionnaire form between March 2007 and February 2009 in Aydin Government Hospital, Turkey. Three hundred ninety-six primiparas were included in the study by convenience sampling. RESULTS: It was determined that 56.3% of the women had episiotomies. The results of the study revealed that the probability of receiving an episiotomy was decreased in women with lack of legal marriage and unplanned pregnancies, and increased in women who had ineffective pushing efforts approximately four times, miscellaneous two times and baby's head circumference 1.27 times. Moreover, the results of the study demonstrated that an episiotomy increased the number of the suture materials used by approximately five-fold, as well as the prevalence of pain on the first postpartum day. On the third postpartum week evaluation, it was determined that the probability of problems with wound healing and experiencing pain was approximately two times higher among women who received episiotomies than those who did not receive episiotomies. CONCLUSION: The study revealed that episiotomies in primiparas increased the number of suture materials used and the probability of having perineal pain on the first postpartum day, as well as perineal pain and wound healing problems during the third postpartum week. PMID- 23983763 TI - The impact of isosorbide mononitrate on cervical ripening and labor induction in primiparous women with term pregnancy: A double-blind, randomized, controlled trial. AB - BACKGROUND: The most favorable method for cervical ripening is not fully agreed upon by practitioners; however, vaginal administration of isosorbide mononitrate (IMN) is considered a low-risk method of labor induction for pregnant women at full term. Our study was designed to assess the effect of IMN on cervical ripening and labor induction among primiparous women in Iran. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled trial was conducted on 90 primiparous women with Bishop score <= 5, term pregnancy, and no sign of labor. The women were allocated into two groups to receive either a 40 mg (2 * 20 mg) IMN tablet vaginally (n = 45) or placebo (n = 45) at 0 and 12 h. If uterine contractions were not present after 24 h, women were sent to the labor section for induction of labor. Bishop score, reason for induction, duration of active, second, and third phase of labor, and mode of delivery were assessed. RESULTS: There was a significant difference between the IMN group and the controls with respect to the Bishop score (4.92 vs. 4.03, P = 0.0.01), induction to active phase interval (387.6 vs. 520.4 min, P = 0.03), the length of induction (350 vs. 446 min, P = 0.03), and the drug administration to delivery interval (33.9 vs. 36.2 h, P = 0.03). The major side effect of IMN was headache, which responded to analgesia. CONCLUSIONS: IMN can be an effective alternative drug for cervical ripening and could decrease the labor interval. Further studies are necessary to fully address the benefits of IMN, especially in pregnancies of gestational age greater than 42 weeks. PMID- 23983764 TI - Education and implementing evidence-based nursing practice for diabetic patients. AB - BACKGROUND: Foot ulceration is one of the most common complications associated with diabetes that needs to be managed. In Iran, prevalence of diabetes foot ulcer is 3%. According to studies, evidence-based nursing (EBN) is an effective alternative to facilitate clinical decision making in patient care and may lead to quality improvement in nursing practice. The aims of this study are to assess the effects of EBN education on the knowledge, attitude, and practice of nurses who take care of patient with diabetes foot ulcer. MATERIALS AND METHODS: A quasi experimental study (based on IOWA model as a framework to improve nursing practice) was conducted using a before-and-after design. All of nurses (consisted of 19 baccalaureate nurses) who are working in an endocrinology ward were chosen and taught using EBN approach through different workshops. Before and after educational intervention, the data about nurses' knowledge, attitude, and practice were gathered by questionnaire and then compared. The nurses' performance in patient care was evaluated in 3 months by one checklist. The data were analyzed using descriptive and inferential statistics. RESULTS: There were statistically significant differences in knowledge, attitude, and practice of nurses before and after intervention (P = 0.001). The nurses' performance in caring for patient with diabetes foot ulcer, based on clinical guideline, showed the improvement in clinical practice. CONCLUSION: Education of EBN can improve the nurse's knowledge and attitude to EBN, and be used as a basis on which to influence the professional practice of nursing. PMID- 23983765 TI - Obstetrical antiphospholipid syndrome: from the pathogenesis to the clinical and therapeutic implications. AB - Antiphospholipid syndrome (APS) is an acquired thrombophilia with clinical manifestations associated with the presence of antiphospholipid antibodies (aPL) in patient plasma. Obstetrical APS is a complex entity that may affect both mother and fetus throughout the entire pregnancy with high morbidity. Clinical complications are as various as recurrent fetal losses, stillbirth, intrauterine growth restriction (IUGR), and preeclampsia. Pathogenesis of aPL targets trophoblastic cells directly, mainly via proapoptotic, proinflammatory mechanisms, and uncontrolled immunomodulatory responses. Actual first-line treatment is limited to low-dose aspirin (LDA) and low-molecular weight heparin (LMWH) and still failed in 30% of the cases. APS pregnancies should be a major field in obstetrical research, and new therapeutics are still in progress. PMID- 23983767 TI - Determinants of brachial-ankle pulse wave velocity in Chinese patients with rheumatoid arthritis. AB - OBJECTIVE: To investigate the relationship between Brachial-ankle pulse wave velocity (baPWV), and its associated risk factors in Chinese patients with RA. METHODS: 138 Chinese RA patients and 150 healthy subjects were included. baPWV of all the participants was measured. RA related factors were determined, as well as traditional cardiovascular risk factors. RESULTS: baPWV was significant higher in RA group (1705.44 +/- 429.20 cm/s) compared to the healthy control group (1386.23 +/- 411.09 cm/s) (P < 0.001). Compared with low baPWV group, high baPWV group patients were significantly older (P = 0.008) and taller (P = 0.033). Serum cholesterol (P = 0.035), triglycerides (P = 0.004), and LDL level (P = 0.006) were significantly higher in high baPWV group patients compared with low baPWV group patients. The baPWV of RA patients was positively correlated with age (r = 0.439, P < 0.001), and serum cholesterol level (r = 0.231, P = 0.035), serum triglycerides level (r = 0.293, P < 0.001), serum LDL level (r = 0.323, P = 0.003). Meanwhile, baPWV negatively correlated with the height of RA patients (r = -0.253, P = 0.043). Multivariate regression analysis showed that baPWV of RA group was independently associated with age and serum triglycerides level. CONCLUSIONS: The old age and high level of serum triglycerides may be the major determinants of arterial stiffness in Chinese RA patients. PMID- 23983766 TI - The controversial role of microglia in malignant gliomas. AB - Malignant gliomas contain stroma and a variety of immune cells including abundant activated microglia/macrophages. Mounting evidence indicates that the glioma microenvironment converts the glioma-associated microglia/macrophages (GAMs) into glioma-supportive, immunosuppressive cells; however, GAMs can retain intrinsic anti-tumor properties. Here, we review and discuss this duality and the potential therapeutic strategies that may inhibit their glioma-supportive and propagating functions. PMID- 23983768 TI - Asymptomatic preclinical rheumatoid arthritis-associated interstitial lung disease. AB - OBJECTIVE: Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA) and a significant cause of morbidity and mortality. The objective of this study was to define high-resolution chest CT (HRCT) and pulmonary function test (PFT) abnormalities capable of identifying asymptomatic, preclinical forms of RA-ILD that may represent precursors to more severe fibrotic lung disease. METHODS: We analyzed chest HRCTs in consecutively enrolled RA patients and subsequently classified these individuals as RA-ILD or RA-no ILD based on the presence/absence of ground glass opacification, septal thickening, reticulation, traction bronchiectasis, and/or honeycombing. Coexisting PFT abnormalities (reductions in percent predicted FEV1, FVC, TLC, and/or DLCO) were also used to further characterize occult respiratory defects. RESULTS: 61% (63/103) of RA patients were classified as RA-ILD based on HRCT and PFT abnormalities, while 39% (40/103) were designated as RA-no ILD. 57/63 RA-ILD patients lacked symptoms of significant dyspnea or cough at the time of HRCT and PFT assessment. Compared with RA-no ILD, RA-ILD patients were older and had longer disease duration, higher articular disease activity, and more significant PFT abnormalities. CONCLUSION: HRCT represents an effective tool to detect occult/asymptomatic ILD that is highly prevalent in our unselected, university based cohort of RA patients. PMID- 23983769 TI - MicroRNAs implicated in the immunopathogenesis of lupus nephritis. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the deposition of immune complexes due to widespread loss of immune tolerance to nuclear self-antigens. Deposition in the renal glomeruli results in the development of lupus nephritis (LN), the leading cause of morbidity and mortality in SLE. In addition to the well-recognized genetic susceptibility to SLE, disease pathogenesis is influenced by epigenetic regulators such as microRNAs (miRNAs). miRNAs are small, noncoding RNAs that bind to the 3' untranslated region of target mRNAs resulting in posttranscriptional gene modulation. miRNAs play an important and dynamic role in the activation of innate immune cells and are critical in regulating the adaptive immune response. Immune stimulation and the resulting cytokine milieu alter miRNA expression while miRNAs themselves modify cellular responses to stimulation. Here we examine dysregulated miRNAs implicated in LN pathogenesis from human SLE patients and murine lupus models. The effects of LN-associated miRNAs in the kidney, peripheral blood mononuclear cells, macrophages, mesangial cells, dendritic cells, and splenocytes are discussed. As the role of miRNAs in immunopathogenesis becomes delineated, it is likely that specific miRNAs may serve as targets for therapeutic intervention in the treatment of LN and other pathologies. PMID- 23983770 TI - Elevated cerebrospinal fluid neopterin concentration is associated with disease severity in acute Puumala hantavirus infection. AB - Nephropathia epidemica (NE) caused by Puumala hantavirus (PUUV) is the most common hemorrhagic fever with renal syndrome (HFRS) in Europe. The infection activates immunological mechanisms that contribute to the pathogenesis and characteristics of the illness. In this study we measured cerebrospinal fluid (CSF) neopterin concentration from 23 acute-phase NE patients. We collected data on kidney function, markers of tissue permeability, haemodynamic properties, blood cell count, length of hospitalisation, inflammatory parameters, and ophthalmological properties. The neopterin levels were elevated (> 5.8 nmol/L) in 22 (96%) NE-patients (mean 45.8 nmol/L); these were especially high in patients with intrathecal PUUV-IgM production (mean 58.2 nmol/L, P = 0.01) and those with elevated CSF protein concentrations (mean 63.6 nmol/L, P < 0.05). We also observed a correlation between the neopterin and high plasma creatinine value (r = 0.66, P = 0.001), low blood thrombocyte count (r = -0.42, P < 0.05), and markedly disturbed refractory properties of an eye (r = 0.47, P < 0.05). Length of hospitalisation correlated with the neopterin (r = 0.42, P < 0.05; male patients r = 0.69, P < 0.01). Patients with signs of tissue oedema and increased permeability also had high neopterin concentrations. These results reinforce the view that PUUV-HFRS is a general infection that affects the central nervous system and the blood-brain barrier. PMID- 23983772 TI - The Relationship between Traditional Chinese Medicine and Modern Medicine. AB - The essence of the traditional Chinese medicine has always been the most advanced and experienced therapeutic approach in the world. It has knowledge that can impact the direction of future modern medical development; still, it is easy to find simple knowledge with mark of times and special cultures. The basic structure of traditional Chinese medicine is composed of three parts: one consistent with modern medicine, one involuntarily beyond modern medicine, and one that needs to be further evaluated. The part that is consistent with modern medicine includes consensus on several theories and concepts of traditional Chinese medicine, and usage of several treatments and prescriptions of traditional Chinese medicine including commonly used Chinese herbs. The part that is involuntarily beyond modern medicine contains several advanced theories and important concepts of traditional Chinese medicine, relatively advanced treatments, formula and modern prescriptions, leading herbs, acupuncture treatment and acupuncture anesthesia of traditional Chinese medicine that affect modern medicine and incorporates massage treatment that has been gradually acknowledged by modern therapy. The part that needs to be further evaluated consists not only the knowledge of pulse diagnosis, prescription, and herbs, but also many other aspects of traditional Chinese medicine. PMID- 23983771 TI - Regulatory T cell in stroke: a new paradigm for immune regulation. AB - Stroke is a common, debilitating trauma that has an incompletely elucidated pathophysiology and lacks an effective therapy. FoxP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) suppress a variety of normal physiological and pathological immune responses via several pathways, such as inhibitory cytokine secretion, direct cytolysis induction, and antigen-presenting cell functional modulation. FoxP3(+)CD25(+)CD4(+) Tregs are involved in a variety of central nervous system diseases and injuries, including axonal injury, neurodegenerative diseases, and stroke. Specifically, FoxP3(+)CD25(+)CD4(+) Tregs exert neuroprotective effects in acute experimental stroke models. These beneficial effects, however, are difficult to elucidate. In this review, we summarized evidence of FoxP3(+)CD25(+)CD4(+) Tregs as potentially important immunomodulators in stroke pathogenesis and highlight further investigations for possible immunotherapeutic strategies by modulating the quantity and/or functional effects of FoxP3(+)CD25(+)CD4(+) Tregs in stroke patients. PMID- 23983773 TI - Analysis on outcome of 3537 patients with coronary artery disease: integrative medicine for cardiovascular events. AB - Aims. To investigate the treatment of hospitalized patients with coronary artery disease (CAD) and the prognostic factors in Beijing, China. Materials and Methods. A multicenter prospective study was conducted through an integrative platform of clinical and research at 12 hospitals in Beijing, China. The clinical information of 3537 hospitalized patients with CAD was collected from September 2009 to May 2011, and the efficacy of secondary prevention during one-year followup was evaluated. In addition, a logistic regression analysis was performed to identify some factors which will have independent impact on the prognosis. Results. The average age of all patients was 64.88 +/- 11.97. Of them, 65.42% are males. The medicines for patients were as follows: antiplatelet drugs accounting for 91.97%, statins accounting for 83.66%, beta -receptor blockers accounting for 72.55%, ACEI/ARB accounting for 58.92%, and revascularization (including PCI and CABG) accounting for 40.29%. The overall incidence of cardiovascular events was 13.26% (469/3537). The logistic stepwise regression analysis showed that heart failure (OR, 3.707, 95% CI = 2.756-4.986), age >= 65 years old (OR, 2.007, 95% CI = 1.587-2.53), and myocardial infarction (OR, 1.649, 95% CI = 1.322-2.057) were the independent risk factors of others factors for cardiovascular events that occurred during followup of one-year period. Integrative medicine (IM) therapy showed the beneficial tendency for decreasing incidence of cardiovascular events, although no statistical significance was found (OR, 0.797, 95% CI = 0.613~1.036). Conclusions. Heart failure, age >= 65 years old, and myocardial infarction were associated with an increase in incidence of cardiovascular events, and treatment with IM showed a tendency for decreasing incidence of cardiovascular events. PMID- 23983774 TI - Growth and Survival of Bagged Lucilia sericata Maggots in Wounds of Patients Undergoing Maggot Debridement Therapy. AB - Maggot debridement therapy (MDT) is an established method of debridement of nonhealing wounds. Despite intense clinical research about its efficacy and effects of substances produced by the larvae, growth and development of maggots in the wounds remain largely unexplored. In the present study, the bags with larvae (n = 52), which had been used to debride traumatic, ischemic, diabetic and venous ulcers, were collected and examined. Survival, length, width and larval instar of the maggots within each bag were recorded and analyzed with respect to the wound type and duration of the treatment. Survival of maggots after a 48-h cycle of MDT ranged between 63.6 and 82.7%. Maggots in venous ulcers had on average 9-19% higher mortality than maggots within traumatic, ischemic, and diabetic ulcers. Length of larvae after 48 h cycle of MDT reached on average 7.09 9.68 mm, and average width varied between 1.77 and 2.26 mm. Larvae in venous ulcers were significantly smaller after 48 h, but not after 72 h treatment compared to the other wound types. Further studies should be aimed to identify other patient-associated factors which might influence growth and survival of the larvae during maggot debridement therapy. PMID- 23983775 TI - Validity of the "streitberger" needle in a chinese population with acupuncture: a randomized, single-blinded, and crossover pilot study. AB - We studied the validity of a "Streitberger" needle as a valid approach in a Chinese population with experience of acupuncture. Volunteers were recruited from students of the School of Acupuncture and Moxibustion, Guangzhou University of Chinese Medicine. Sixty students receiving education in acupuncture theory and experience in practical acupuncture were tested in study determining whether needling with the placebo needle felt any different from conventional acupuncture. Outcomes included measures of penetration sensation, VAS ratings, and Deqi sensation questionnaire. As a result, needle penetration, VAS ratings for either needle and Deqi sensation were not significantly different between two kinds of needles. Our findings show that the use of "Streitberger" needle is credible in a Chinese population with acupuncture experience. PMID- 23983776 TI - CAM in Psychiatry. PMID- 23983778 TI - Effect of facial cosmetic acupuncture on facial elasticity: an open-label, single arm pilot study. AB - Background. The use of acupuncture for cosmetic purposes has gained popularity worldwide. Facial cosmetic acupuncture (FCA) is applied to the head, face, and neck. However, little evidence supports the efficacy and safety of FCA. We hypothesized that FCA affects facial elasticity by restoring resting mimetic muscle tone through the insertion of needles into the muscles of the head, face, and neck. Methods. This open-label, single-arm pilot study was implemented at Kyung Hee University Hospital at Gangdong from August through September 2011. Participants were women aged 40 to 59 years with a Glogau photoaging scale III. Participants received five treatment sessions over three weeks. Participants were measured before and after FCA. The primary outcome was the Moire topography criteria. The secondary outcome was a patient-oriented self-assessment scale of facial elasticity. Results. Among 50 women screened, 28 were eligible and 27 completed the five FCA treatment sessions. A significant improvement after FCA treatment was evident according to mean change in Moire topography criteria (from 1.70 +/- 0.724 to 2.26 +/- 1.059, P < 0.0001). The most common adverse event was mild bruising at the needle site. Conclusions. In this pilot study, FCA showed promising results as a therapy for facial elasticity. However, further large scale trials with a controlled design and objective measurements are needed. PMID- 23983777 TI - Can medical herbs stimulate regeneration or neuroprotection and treat neuropathic pain in chemotherapy-induced peripheral neuropathy? AB - Chemotherapy-induced neuropathy (CIPN) has a relevant impact on the quality of life of cancer patients. There are no curative conventional treatments, so further options have to be investigated. We conducted a systematic review in English and Chinese language databases to illuminate the role of medical herbs. 26 relevant studies on 5 single herbs, one extract, one receptor-agonist, and 8 combinations of herbs were identified focusing on the single herbs Acorus calamus rhizoma, Cannabis sativa fructus, Chamomilla matricaria, Ginkgo biloba, Salvia officinalis, Sweet bee venom, Fritillaria cirrhosae bulbus, and the herbal combinations Bu Yang Huan Wu, modified Bu Yang Huan Wu plus Liuwei Di Huang, modified Chai Hu Long Gu Mu Li Wan, Geranii herba plus Aconiti lateralis praeparata radix , Niu Che Sen Qi Wan (Goshajinkigan), Gui Zhi Jia Shu Fu Tang (Keishikajutsubuto), Huang Qi Wu Wu Tang (Ogikeishigomotsuto), and Shao Yao Gan Cao Tang (Shakuyakukanzoto). The knowledge of mechanism of action is still limited, the quality of clinical trials needs further improvement, and studies have not yielded enough evidence to establish a standard practice, but a lot of promising substances have been identified. While CIPN has multiple mechanisms of neuronal degeneration, a combination of herbs or substances might deal with multiple targets for the aim of neuroprotection or neuroregeneration in CIPN. PMID- 23983780 TI - Expression of stem cell markers in primo vessel of rat. AB - Accumulating line of evidence support that adult tissues contain a rare population of pluripotent stem cells (PSCs), which differentiate into all types of cells in our body. Bonghan microcell (primo microcells (PMCs)) discovered in 1960s was reported to have a pluripotency like a stem cell in vivo as well as in vitro condition. Here, we describe the detailed morphology and molecular features of PMCs. PMCs reside in Bonghan duct (primo vessel (PV)) reported as a corresponding structure of acupuncture points and meridian system. We found that PMCs were frequently observed in the liver surface of the rat between 300 g and 400 g from April to June, suggesting that the their detection frequency depends on the weight, the season, and the organ of rat. As reported, PMCs freshly isolated from PVs were spherical ~1-2 MU m microsized cells. In contrast, a unique bithread or budding-shaped PMCs emerged during tissue culture around 8 days. RT-PCR analysis demonstrated that PVs-derived cells express the Oct4, the most important PSCs gene, in addition to several PSCs markers (Sox2, Stella, Rex1, and Klf4). Thus, we for the first time provide the evidence about Oct4 expressing stem-like characteristics for cells resident in PVs, a possible novel stem cell enriched niche. PMID- 23983779 TI - Mechanisms of electroacupuncture-induced analgesia on neuropathic pain in animal model. AB - Neuropathic pain remains as one of the most difficult clinical pain syndromes to treat. Electroacupuncture (EA), involving endogenous opioids and neurotransmitters in the central nervous system (CNS), is reported to be clinically efficacious in various fields of pain. Although multiple experimental articles were conducted to assess the effect of EA-induced analgesia, no review has been published to assess the efficacy and clarify the mechanism of EA on neuropathic pain. To this aim, this study was firstly designed to evaluate the EA induced analgesic effect on neuropathic pain and secondly to guide and help future efforts to advance the neuropathic pain treatment. For this purpose, articles referring to the analgesic effect of acupuncture on neuropathic pain and particularly the work performed in our own laboratory were analyzed. Based on the articles reviewed, the role of spinal opioidergic, adrenergic, serotonergic, cholinergic, and GABAergic receptors in the mechanism of EA-induced analgesia was studied. The results of this research demonstrate that MU and delta opioid receptors, alpha 2-adrenoreceptors, 5-HT1A and 5-HT3 serotonergic receptors, M1 muscarinic receptors, and GABAA and GABAB GABAergic receptors are involved in the mechanisms of EA-induced analgesia on neuropathic pain. PMID- 23983781 TI - Mechanisms Underlying the Antiproliferative and Prodifferentiative Effects of Psoralen on Adult Neural Stem Cells via DNA Microarray. AB - Adult neural stem cells (NSCs) persist throughout life to replace mature cells that are lost during turnover, disease, or injury. The investigation of NSC creates novel treatments for central nervous system (CNS) injuries and neurodegenerative disorders. The plasticity and reparative potential of NSC are regulated by different factors, which are critical for neurological regenerative medicine research. We investigated the effects of Psoralen, which is the mature fruit of Psoralea corylifolia L., on NSC behaviors and the underlying mechanisms. The self-renewal and proliferation of NSC were examined. We detected neuron- and/or astrocyte-specific markers using immunofluorescence and Western blotting, which could evaluate NSC differentiation. Psoralen treatment significantly inhibited neurosphere formation in a dose-dependent manner. Psoralen treatment increased the expression of the astrocyte-specific marker but decreased neuron specific marker expression. These results suggested that Psoralen was a differentiation inducer in astrocyte. Differential gene expression following Psoralen treatment was screened using DNA microarray and confirmed by quantitative real-time PCR. Our microarray study demonstrated that Psoralen could effectively regulate the specific gene expression profile of NSC. The genes involved in the classification of cellular differentiation, proliferation, and metabolism, the transcription factors belonging to Ets family, and the hedgehog pathway may be closely related to the regulation. PMID- 23983782 TI - Hyperglycemia induces altered expressions of angiogenesis associated molecules in the trophoblast. AB - We previously reported that the increased level of perlecan with altered glycosaminoglycan (GAG) substitution was present in the placenta with gestational diabetes mellitus (GDM) and in the trophoblasts cultured under hyperglycemic condition. Trophoblast is the first cell lineage to differentiate, invasive, and migrate into the vessel tissues of placenta and fetal membrane during pregnancy. Therefore, active matrix remodeling and vessel formation must occur during placentation. In this study, we further investigated whether hyperglycemia induced alterations of perlecan in the extracellular matrix (ECM) affect the proliferation and the expressions of angiogenesis-related growth factors and cytokines in the trophoblasts. 3A-Sub-E trophoblastic cells cultured in high glucose medium were conducted to mimic the hyperglycemic condition. Results showed that the hyperglycemia-induced GAG alterations in the cell surface perlecan as well as in the ECM indeed upregulated the expressions of IL-6, IL-8, and MCP-1 and the activities of MMP-2 and MMP-9 and downregulated the expressions of TIMP-2. A regulatory molecular mechanism of hyperglycemia-induced alterations of the cell surface proteoglycans and the ECM remodeling on the expressions of angiogenesis-related cytokines and growth factors in trophoblasts was proposed. This mechanism may contribute to the aberrant placental structure and the maternal and fetal complications during development. PMID- 23983783 TI - Antileishmanial Phenylpropanoids from the Leaves of Hyptis pectinata (L.) Poit. AB - Hyptis pectinata, popularly known in Brazil as "sambacaita" or "canudinho," is an aromatic shrub largely grown in the northeast of Brazil. The leaves and bark are used in an infusion for the treatment of throat and skin inflammations, bacterial infections, pain, and cancer. Analogues of rosmarinic acid and flavonoids were obtained from the leaves of Hyptis pectinata and consisted of two new compounds, sambacaitaric acid (1) and 3-O-methyl-sambacaitaric acid (2), and nine known compounds, rosmarinic acid (3), 3-O-methyl-rosmarinic acid (4), ethyl caffeate (5), nepetoidin A (6), nepetoidin B (7), cirsiliol (8), circimaritin (9), 7-O methylluteolin (10), and genkwanin (11). The structures of these compounds were determined by spectroscopic methods. Compounds 1-5, and 7 were evaluated in vitro against the promastigote form of L. braziliensis, and the ethanol extract. The hexane, ethyl acetate, and methanol-water fractions were also evaluated. The EtOH extract, the hexane extract, EtOAc, MeOH:H2O fractions; and compounds 1, 2 and 4 exhibited antileishmanial activity, and compound 1 was as potent as pentamidine. In contrast, compounds 3, 5, and 7 did not present activity against the promastigote form of L. braziliensis below 100 uM. To our knowledge, compounds 1 and 2 are being described for the first time. PMID- 23983784 TI - The Protective Effects of Cobra Venom from Naja naja atra on Acute and Chronic Nephropathy. AB - This study investigated the effects of Naja naja atra venom (NNAV) on acute and chronic nephropathy in rats. Rats received 6 mg/kg adriamycin (ADR) once to evoke the chronic nephropathy or 8 ml/kg 50% v/v glycerol to produce acute renal failure (ARF). The NNAV was given orally once a day starting five days prior to ADR or glycerol injection and continued to the end of experiments. The animals were placed in metabolic cages for 24 h for urine collection for urinary protein determination. The kidney function-related biochemical changes and index of oxidative stress were determined with automatic biochemistry analyzer or colorimetric enzyme assay kits. The pathomorphological changes were observed using light and transmission electron microcopies. The levels of inflammatory cytokines and NF- kappa B activation were determined using ELISA kits, Western blot analysis, or immunofluorescence. The results showed that NNAV relieved ADR induced chronic nephropathy and glycerol-triggered acute renal failure syndromes including proteinuria, hypoalbuminemia, hyperlipidemia, serum electrolyte unbalance, renal oxidative stress, and pathological damages. NNAV reduced kidney levels of TNF- alpha and IL-1 beta , but it increased the levels of I kappa B- alpha and inhibited NF- kappa B p65 nuclear localization. These findings suggest that NNAV may be a valuable therapeutic drug for acute and chronic kidney diseases. PMID- 23983785 TI - Effects of qigong exercise on fatigue, anxiety, and depressive symptoms of patients with chronic fatigue syndrome-like illness: a randomized controlled trial. AB - Background. Anxiety/depressive symptoms are common in patients with chronic fatigue syndrome- (CFS-) like illness. Qigong as a modality of complementary and alternative therapy has been increasingly applied by patients with chronic illnesses, but little is known about the effect of Qigong on anxiety/depressive symptoms of the patients with CFS-like illness. Purpose. To investigate the effects of Qigong on fatigue, anxiety, and depressive symptoms in patients with CFS-illness. Methods. One hundred and thirty-seven participants who met the diagnostic criteria for CFS-like illness were randomly assigned to either an intervention group or a waitlist control group. Participants in the intervention group received 10 sessions of Qigong training twice a week for 5 consecutive weeks, followed by home-based practice for 12 weeks. Fatigue, anxiety, and depressive symptoms were assessed at baseline and postintervention. Results. Total fatigue score [F(1,135) = 13.888, P < 0.001], physical fatigue score [F(1,135) = 20.852, P < 0.001] and depression score [F(1,135) = 9.918, P = 0.002] were significantly improved and mental fatigue score [F(1,135) = 3.902, P = 0.050] was marginally significantly improved in the Qigong group compared to controls. The anxiety score was not significantly improved in the Qigong group. Conclusion. Qigong may not only reduce the fatigue symptoms, but also has antidepressive effect for patients with CFS-like illness. Trial registration HKCTR-1200. PMID- 23983786 TI - Mindful walking in psychologically distressed individuals: a randomized controlled trial. AB - Background. The aim of this randomized, controlled study was to investigate the effectiveness of a mindful walking program in patients with high levels of perceived psychological distress. Methods. Participants aged between 18 and 65 years with moderate to high levels of perceived psychological distress were randomized to 8 sessions of mindful walking in 4 weeks (each 40 minutes walking, 10 minutes mindful walking, 10 minutes discussion) or to no study intervention (waiting group). Primary outcome parameter was the difference to baseline on Cohen's Perceived Stress Scale (CPSS) after 4 weeks between intervention and control. Results. Seventy-four participants were randomized in the study; 36 (32 female, 52.3 +/- 8.6 years) were allocated to the intervention and 38 (35 female, 49.5 +/- 8.8 years) to the control group. Adjusted CPSS differences after 4 weeks were -8.8 [95% CI: -10.8; -6.8] (mean 24.2 [22.2; 26.2]) in the intervention group and -1.0 [-2.9; 0.9] (mean 32.0 [30.1; 33.9]) in the control group, resulting in a highly significant group difference (P < 0.001). Conclusion. Patients participating in a mindful walking program showed reduced psychological stress symptoms and improved quality of life compared to no study intervention. Further studies should include an active treatment group and a long-term follow up. PMID- 23983788 TI - A systematic review of experimental and clinical acupuncture in chemotherapy induced peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect that can be very disabling and can limit or delay the dose of chemotherapy that can be administered. Acupuncture may be effective for treating peripheral neuropathy. The aim of this study was to review the available literature on the use of acupuncture for CIPN. The systematic literature search was performed using MEDLINE, Google Scholar, Cochrane Database, CINHAL, and ISI Proceedings. Hand searching was conducted, and consensus was reached on all extracted data. Only papers in the English language were included, irrespective of study design. From 3989 retrieved papers, 8 relevant papers were identified. One was an experimental study which showed that electroacupuncture suppressed CIPN pain in rats. In addition, there were 7 very heterogeneous clinical studies, 1 controlled randomised study using auricular acupuncture, 2 randomized controlled studies using somatic acupuncture, and 3 case series/case reports which suggested a positive effect of acupuncture in CIPN. Conclusions. Only one controlled randomised study demonstrated that acupuncture may be beneficial for CIPN. All the clinical studies reviewed had important methodological limitations. Further studies with robust methodology are needed to demonstrate the role of acupuncture for treating CIPN resulting from cancer treatment. PMID- 23983789 TI - Microarray analysis reveals the molecular basis of antiarthritic activity of huo luo-xiao-ling dan. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune origin. Huo-luo-xiao-ling dan (HLXL) is an herbal mixture that has been used in traditional Chinese medicine over several decades to treat chronic inflammatory diseases including RA. However, the mechanism of the anti-arthritic action of this herbal remedy is poorly understood at the molecular level. In this study, we determined by microarray analysis the effects of HLXL on the global gene expression profile of the draining lymph node cells (LNC) in the rat adjuvant arthritis (AA) model of human RA. In LNC restimulated in vitro with the disease related antigen mycobacterial heat-shock protein 65 (Bhsp65), 84 differentially expressed genes (DEG) (64 upregulated and 20 downregulated) versus 120 DEG (94 upregulated and 26 downregulated) were identified in HLXL-treated versus vehicle (Water)-treated rats, respectively, and 62 DEG (45 upregulated and 17 downregulated) were shared between the two groups. The most affected pathways in response to HLXL treatment included immune response, inflammation, cellular proliferation and apoptosis, and metabolic processes, many of which are directly relevant to arthritis pathogenesis. These results would advance our understanding of the mechanisms underlying the anti-arthritic activity of HLXL. PMID- 23983790 TI - Cartilage Protective and Chondrogenic Capacity of WIN-34B, a New Herbal Agent, in the Collagenase-Induced Osteoarthritis Rabbit Model and in Progenitor Cells from Subchondral Bone. AB - We sought to determine the cartilage repair capacity of WIN-34B in the collagenase-induced osteoarthritis rabbit model and in progenitor cells from subchondral bone. The cartilage protective effect of WIN-34B was measured by clinical and histological scores, cartilage area, and proteoglycan and collagen contents in the collagenase-induced osteoarthritis rabbit model. The efficacy of chondrogenic differentiation of WIN-34B was assessed by expression of CD105, CD73, type II collagen, and aggrecan in vivo and was analyzed by the surface markers of progenitor cells, the mRNA levels of chondrogenic marker genes, and the level of proteoglycan, GAG, and type II collagen in vitro. Oral administration of WIN-34B significantly increased cartilage area, and this was associated with the recovery of proteoglycan and collagen content. Moreover, WIN 34B at 200 mg/kg significantly increased the expression of CD105, CD73, type II collagen, and aggrecan compared to the vehicle group. WIN-34B markedly enhanced the chondrogenic differentiation of CD105 and type II collagen in the progenitor cells from subchondral bone. Also, we confirmed that treatment with WIN-34B strongly increased the number of SH-2(CD105) cells and expression type II collagen in subchondral progenitor cells. Moreover, WIN-34B significantly increased proteoglycan, as measured by alcian blue staining; the mRNA level of type II alpha 1 collagen, cartilage link protein, and aggrecan; and the inhibition of cartilage matrix molecules, such as GAG and type II collagen, in IL 1 beta -treated progenitor cells. These findings suggest that WIN-34B could be a potential candidate for effective anti-osteoarthritic therapy with cartilage repair as well as cartilage protection via enhancement of chondrogenic differentiation in the collagenase-induced osteoarthritis rabbit model and progenitor cells from subchondral bone. PMID- 23983787 TI - Antiapoptotic Effects of EGb 761. AB - Ginkgo biloba extracts have long been used in Chinese traditional medicine for hundreds of years. The most significant extract obtained from Ginkgo biloba leaves has been EGb 761, a widely used phytopharmaceutical product in Europe. EGb 761 is a well-defined mixture of active compounds, which contains two main active substances: flavonoid glycosides (24-26%) and terpene lactones (6-8%). These compounds have shown antiapoptotic effects through the protection of mitochondrial membrane integrity, inhibition of mitochondrial cytochrome c release, enhancement of antiapoptotic protein transcription, and reduction of caspase transcription and DNA fragmentation. Other effects include the reduction of oxidative stress (which has been related to the occurrence of vascular, degenerative, and proliferative diseases), coupled to strong induction of phase II-detoxifying and cellular defense enzymes by Nrf2/ARE activation, in addition to the modulation of transcription factors, such as CREB, HIF-1 alpha , NF- kappa B, AP-1, and p53, involved in the apoptosis process. This work reviews experimental results about the antiapoptotic effects induced by the standardized extract of Ginkgo biloba leaves (EGb 761). PMID- 23983791 TI - Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes. AB - Adipose tissue development and function are widely studied to examine the relationship between obesity and the metabolic syndrome. It is well documented that the inability of adipose tissue to properly increase its lipid storage capacity during the obese state can lead to metabolic dysfunction. In a blind screen of 425 botanicals, we identified naringenin as an inhibitor of adipocyte differentiation. Naringenin is one of the most abundant citrus flavonoids, and recent studies have demonstrated antihyperlipidemic capabilities. These studies have largely focused on the effects of naringenin on the liver. Our biochemical studies clearly demonstrate that naringenin inhibits adipogenesis and impairs mature fat cell function. Naringenin specifically inhibited adipogenesis in a dose-dependent fashion as judged by examining lipid accumulation and induction of adipocyte marker protein expression. In mature 3T3-L1 adipocytes, naringenin reduced the ability of insulin to induce IRS-1 tyrosine phosphorylation and substantially inhibited insulin-stimulated glucose uptake in a dose-dependent manner and over a time frame of 1.5 to 24 hours. Exposure to naringenin also inhibited adiponectin protein expression in mature murine and human adipocytes. Our studies have revealed that naringenin may have a negative impact on adipocyte related diseases by limiting differentiation of preadipocytes, by significantly inducing insulin resistance, and by decreasing adiponectin expression in mature fat cells. PMID- 23983792 TI - Aconiti Lateralis Preparata Radix Activates the Proliferation of Mouse Bone Marrow Mesenchymal Stem Cells and Induces Osteogenic Lineage Differentiation through the Bone Morphogenetic Protein-2/Smad-Dependent Runx2 Pathway. AB - Mesenchymal stem cells have the capacity for self-renewal and under appropriate stimulation give rise to osteogenic, adipogenic, and chondrogenic lineages. To advance the clinical use of stem cell therapy, such as stem cell transplantation, it is important to find substances that promote endogenous stem cell proliferation and differentiation. We investigated whether medicinal herbs have the potential to promote stem cell proliferation and differentiation, using a cell cycle analysis and differentiation assay. We found that Aconiti Lateralis Preparata Radix (ALR) promoted the proliferation rate of mouse bone marrow mesenchymal stem cells (mBMMSCs) up to 122.24% compared to untreated cells. Fluorescence-activated cell sorter analysis showed that the percentage of cells in the G2/M phase increased to 17.33% in ALR-treated cells compared to 5.65% in normal cells. Signaling pathway analysis indicated that this was mediated through the extracellular signal-regulated kinase 1/2 pathway. A differentiation assay showed that ALR induced differentiation of mBMMSCs into an osteogenic lineage 2 weeks after treatment, whereas traditional osteogenic induction medium treatment did not promote differentiation for 3 weeks. This osteogenic differentiation was signaled by the bone morphogenetic protein-2/Smad-dependent Runx2 pathway. We found that ALR could promote mBMMSC proliferation and differentiation into the osteogenic lineage. PMID- 23983793 TI - 50 years of bong-han theory and 10 years of primo vascular system. AB - The primo vascular system (PVS) was first introduced by Bong-Han Kim via his five research reports. Among these the third report was most extensive and conclusive in terms of the PVS anatomy and physiology relating to the acupuncture meridians. His study results, unfortunately, were not reproduced by other scientists because he did not describe the materials and methods in detail. In 2002, a research team in Seoul National University reinitiated the PVS research, confirmed the existence of PVS in various organs, and discovered new characteristics of PVS. Two important examples are as follows: PVS was found in the adipose tissue and around cancer tissues. In parallel to these new findings, new methods for observing and identifying PVS were developed. Studies on the cell and material content inside the PVS, including the immune function cells and stem cells, are being progressed. In this review, Bong-Han Kim's study results in his third report are summarized, and the new results after him are briefly reviewed. In the last section, the obstacles in finding the PVS in the skin as an anatomical structure of acupuncture meridian are discussed. PMID- 23983794 TI - Deqi sensation in placebo acupuncture: a crossover study on chinese medicine students. AB - Objective. To evaluate the similarity of deqi sensation of real and noninvasive placebo acupuncture in healthy people with knowledge of Chinese medicine. Methods. In a crossover design, volunteers recruited from Chinese medicine college students were randomized to two groups to receive two phases of intervention with a one-week washout interval. In Group A, the participants were firstly treated by real acupuncture and then by sham needle, and the treatment sequence was reversed in Group B. VAS for pain intensity and deqi sensation was evaluated as outcomes. Results. Sixty-three volunteers were recruited and 60 were included and finished the study. In Group A, VAS was higher in Phase I than in Phase II (P = 0.017). Only treatment methods were selected as factor to VAS difference (P = 0.046) in ANOVA test. More positive deqi was reported in Group A in Phase I when treated by real acupuncture (P = 0.039), but the difference was not significant in Phase II (P = 0.301). Conclusion. The noninvasive placebo acupuncture device can effetely simulate the deqi sensation as real acupuncture, but it is less likely to evoke the active effect of deqi in real practice. This trial is registered with Chinese Clinical Trial Registry: ChiCTR-ORC-09000505. PMID- 23983795 TI - Spa treatment (balneotherapy) for fibromyalgia-a qualitative-narrative review and a historical perspective. AB - Aim. To perform a narrative review of spa therapy for management of the fibromyalgia syndrome (FMS), evaluating this traditional time-honored form of therapy in a historical perspective. Methods. Medline was searched using the terms "Spa therapy," "Balneotherapy," and "Fibromyalgia" between 1990 (year of ACR fibromyalgia criteria publication) and April 2013. The Cochrane database was also searched. Publications relating to the implementation of spa therapy and related practices over the centuries were identified through references, searched, and reviewed. Results. Reports of balneotherapy were described from diverse locations throughout Europe and Asia, and various forms of water-related therapy have been incorporated for many musculoskeletal indications. In the management of FMS, spa therapy has generally been shown to be well accepted and moderately effective for symptom reduction. Conclusion. While achieving high quality evidence-based conclusions is difficult for complex natural therapies such as spa therapy, the existing evidence indicates a positive effect in management of FMS. In view of the long history of this modality in the management of rheumatic pain as well as the inherent difficulties related to pharmacological treatment, the role of spa therapy should currently be recognized as part of a therapeutic program for FMS. PMID- 23983796 TI - Add-on effect of chinese herbal medicine bath to phototherapy for psoriasis vulgaris: a systematic review. AB - Psoriasis vulgaris is the most common form of psoriasis. Phototherapy has been proven effective for psoriasis, but side effects have become a concern. Chinese herbal medicine (CHM) bath combined with phototherapy has been used in clinical settings, but the additional benefit requires evaluation. This review aims to evaluate the additional benefit and safety of adding CHM bath to phototherapy for psoriasis vulgaris. Cochrane library, PubMed, Embase, CNKI, and CQVIP were searched from their inceptions to 6 August 2012. Randomized controlled trials (RCTs) comparing CHM bath plus phototherapy to phototherapy alone for psoriasis vulgaris were included. Data was analyzed using Review Manager 5.1.0. Thirteen RCTs were included in the review, and eight were included in the meta-analysis. Meta-analysis showed higher efficacy of CHM bath plus phototherapy when compared with phototherapy alone in terms of PASI 60 (RR 1.25; 95% CI: 1.18-1.32). Mild adverse events were reported in ten studies, but these could be alleviated by reducing UV dosage or applying emollient. In conclusion, CHM bath appears to be a beneficial and safe adjunctive therapy to phototherapy for psoriasis vulgaris. However, these results should be interpreted with caution due to the low methodological quality of the included studies. PMID- 23983797 TI - Effects of hydrogen-rich saline on taurocholate-induced acute pancreatitis in rat. AB - Oxidative stress plays an important role in the pathogenesis of acute pancreatitis (AP). As an ideal exterminator of poisonous free radicals, hydrogen can clearly reduce the degree of oxidative damage caused by severe acute pancreatitis (SAP) and lessen the presence of inflammatory cytokines. The aim of this study was to investigate the effects and mechanism of hydrogen-rich saline on SAP in rats. Serum TNF- alpha , IL-6, and IL-18 and histopathological score in the pancreas were reduced after hydrogen-rich saline treatment. Malondialdehyde (MDA) and myeloperoxidase (MPO) contents were obviously reduced, while superoxide dismutase (SOD) and glutathione (GSH) contents were increased after hydrogen-rich saline treatment. The expression of mRNA of tumor necrosis factor- alpha (TNF- alpha ) and intercellular adhesion molecule-1 (ICAM-1) in the pancreas was reduced in hydrogen-rich saline treated group. In conclusion, intravenous hydrogen-rich saline injections could attenuate the severity of AP, probably via inhibiting the oxidative stress and reducing the presence of inflammatory mediators. PMID- 23983799 TI - JNK1/2 Activation by an Extract from the Roots of Morus alba L. Reduces the Viability of Multidrug-Resistant MCF-7/Dox Cells by Inhibiting YB-1-Dependent MDR1 Expression. AB - Cancer cells acquire anticancer drug resistance during chemotherapy, which aggravates cancer disease. MDR1 encoded from multidrug resistance gene 1 mainly causes multidrug resistance phenotypes of different cancer cells. In this study, we demonstrate that JNK1/2 activation by an extract from the root of Morus alba L. (White mulberry) reduces doxorubicin-resistant MCF-7/Dox cell viability by inhibiting YB-1 regulation of MDR1 gene expression. When MCF-7 or MCF-7/Dox cells, where MDR1 is highly expressed were treated with an extract from roots or leaves of Morus alba L., respectively, the root extract from the mulberry (REM) but not the leaf extract (LEM) reduced cell viabilities of both MCF-7 and MCF 7/Dox cells, which was enhanced by cotreatment with doxorubicin. REM but not LEM further inhibited YB-1 nuclear translocation and its regulation of MDR1 gene expression. Moreover, REM promoted phosphorylation of c-Jun NH2-terminal kinase 1/2 (JNK1/2) and JNK1/2 inhibitor, SP600125 and rescued REM inhibition of both MDR1 expression and viabilities in MCF-7/Dox cells. Consistently, overexpression of JNK1, c-Jun, or c-Fos inhibited YB-1-dependent MDR1 expression and reduced viabilities in MCF-7/Dox cells. In conclusion, our data indicate that REM activated JNK-cJun/c-Fos pathway decreases the viability of MCF-7/Dox cells by inhibiting YB-1-dependent MDR1 gene expression. Thus, we suggest that REM may be useful for treating multidrug-resistant cancer cells. PMID- 23983800 TI - Antimalarial Activity of Cocos nucifera Husk Fibre: Further Studies. AB - In this study, the antimalarial and toxicity potentials of husk fibre extracts of five Nigerian varieties of Cocos nucifera were evaluated in vitro. The only active extract fraction, West African Tall (WAT) ethyl acetate extract fraction, was then evaluated for its phytochemical constituents, antimalarial and toxicity potentials at varying doses (31.25-500 mg/kg body weight) using various organ function indices. The results revealed that WAT ethyl acetate extract fraction (WATEAEF) contained alkaloids, tannins, and flavonoids and was active against Plasmodium falciparum W2 strain maintained in continuous culture, with a selectivity index of 30.3. The same extract fraction was active in vivo against Plasmodium berghei NK65, causing more than 50% reduction in parasitaemia on days 4 and 6 after inoculation at various doses administered. WATEAEF did not significantly alter (P > 0.05) function indices of the liver and cardiovascular system at all doses administered but significantly increased (P < 0.05) plasma creatinine concentration at 250 and 500 mg/Kg body weight compared to controls. The results of this study suggest that WATEAEF possesses antimalarial activity and may not adversely affect normal liver function nor predispose subjects to cardiovascular diseases but may impair normal kidney function at higher doses. Further studies are underway to isolate the active principles. PMID- 23983801 TI - Is deqi an indicator of clinical efficacy of acupuncture? A systematic review. AB - Objective. Despite the systematic literature review of the current evidence, we aim to answer the question " is Deqi an indicator of clinical effects in acupuncture treatment?" Methods. We systematically searched CNKI, VIP, Wanfang Data, PubMed, Embase, and the CENTRAL for three types of study: (1) empirical research probing into the role of Deqi in acupuncture; (2) mechanism studies examining the effect of Deqi on physiological parameters in animal models and human subjects; (3) clinical studies that compared the outcome of acupuncture with Deqi with that of acupuncture without Deqi. Two reviewers independently extracted data, undertook qualitative or quantitative analysis, and summarized findings. Results. The ancient Chinese acupuncturists valued the role of Deqi as a diagnostic tool, a prognosis predictor, and a necessary part of the therapeutic procedure. Findings from modern experimental research provided preliminary evidence for the physiological mechanism that produced Deqi. Few clinical studies generated conflicting evidence of the comparative effectiveness of acupuncture with Deqi versus acupuncture without Deqi for a variety of conditions. Conclusion. The current evidence base is not solid enough to draw any conclusion regarding the predicative value of natural Deqi for clinical efficacy or the therapeutic value of manipulation-facilitated Deqi. PMID- 23983798 TI - Navigating traditional chinese medicine network pharmacology and computational tools. AB - The concept of "network target" has ushered in a new era in the field of traditional Chinese medicine (TCM). As a new research approach, network pharmacology is based on the analysis of network models and systems biology. Taking advantage of advancements in systems biology, a high degree of integration data analysis strategy and interpretable visualization provides deeper insights into the underlying mechanisms of TCM theories, including the principles of herb combination, biological foundations of herb or herbal formulae action, and molecular basis of TCM syndromes. In this study, we review several recent developments in TCM network pharmacology research and discuss their potential for bridging the gap between traditional and modern medicine. We briefly summarize the two main functional applications of TCM network models: understanding/uncovering and predicting/discovering. In particular, we focus on how TCM network pharmacology research is conducted and highlight different computational tools, such as network-based and machine learning algorithms, and sources that have been proposed and applied to the different steps involved in the research process. To make network pharmacology research commonplace, some basic network definitions and analysis methods are presented. PMID- 23983802 TI - Effects of deqi on autonomic balance in adult tinnitus patients: study design of a randomized controlled trial. AB - Background. Recent reports suggest that a proportion of tinnitus patients suffer from mental illness. Autonomic nervous system plays a useful role in tinnitus therapy since electrical vagal nerve stimulation (VNS) has been frequently used to alleviate tinnitus-induced depression in clinic. heart rate variability (HRV), which is reflective of autonomic nervous system function, has been proved to be modulated by acupuncture. In the present study, we aim to compare the effect of deqi sensation on heart rate variability in adult tinnitus patients. Methods. Thirty participants are randomly assigned to verum acupuncture (creating deqi) or shallow acupuncture (not creating deqi) at Baihui (Du-20), Shenting (Du-24), Tinghui (GB-2), Waiguan (SJ-5), and Zulinqi (GB-41) for 3 weeks. The primary outcome measure is heart rate variability, which is measured at the first acupuncture, as well as the last acupuncture. Discussion. Completion of this trial will help to identify the role of deqi sensation in acupuncture effect for tinnitus and reveal an autonomic modulation mechanism for acupuncture effect. Trial Registration. This trial is registered with International Standard Randomised Controlled Trial Number ISRCTN58013563. PMID- 23983803 TI - The Effect of Sodium Tanshinone IIA Sulfate and Simvastatin on Elevated Serum Levels of Inflammatory Markers in Patients with Coronary Heart Disease: A Study Protocol for a Randomized Controlled Trial. AB - Background. Coronary heart disease (CHD) due to atherosclerotic inflammation remains a significant threat to global health despite the success of the lipid lowering, anti-inflammatory statins. Tanshinone IIA, a potent anti-inflammatory compound derived from Traditional Chinese Medicine (TCM), may be able to supplement statins by further reducing levels of circulating inflammatory markers correlated to cardiovascular risk. Here, we present the protocol of a randomized controlled trial (RCT) that will investigate the synergistic effect of sodium tanshinone IIA sulfate and simvastatin on reducing elevated inflammatory markers in patients with CHD. PARTICIPANTS: Seventy-two inpatients with confirmed CHD, elevated serum high-sensitivity C-reactive protein (Hs-CRP) level, and a TCM diagnosis of blood stasis syndrome will be enrolled and randomized 1 : 1 into the control or experimental group. Intervention. All subjects will receive a standard Western therapy including 20 mg simvastatin orally once per evening. Patients in the experimental group will additionally receive a daily 80 mg dose of sodium tanshinone IIA sulfate intravenously, diluted into 250 mL 0.9% NaCl solution. The treatment period will be 14 days. Outcomes. Primary outcome parameter: serum Hs CRP level. Secondary outcome parameters: other circulating inflammatory markers (including IL-6, TNF alpha , VCAM-1, CD40, sCD40L, MCP-1, and MMP-9), improvement in symptoms of angina and blood stasis syndrome, and safety. This trial is registered with ChiCTR-TRC-12002361. PMID- 23983804 TI - Long-term exercise and risk of metabolic and cardiac diseases: the erlangen fitness and prevention study. AB - In female subjects, ageing and the menopausal transition contribute to a rapid increase of metabolic and cardiac risk factors. Exercise may be an option to positively impact various risk factors prone to severe metabolic and cardiac diseases and events. This study was conducted to determine the long-term effect of a multipurpose exercise program on metabolic and cardiac risk scores in postmenopausal women. 137 osteopenic Caucasian females (55.4 +/- 3.2 yrs), 1-8 years postmenopausal, were included in the study. Eighty-six subjects joined the exercise group (EG) and performed an intense multipurpose exercise program which was carefully supervised during the 12-year period, while 51 females maintained their habitual physical activity (CG). Main outcome measures were 10-year coronary heart disease risk (10 y CHD risk), metabolic syndrome Z-score (MetS Index), and 10-year myocardial infarction risk (10 y hard CHD risk). Significant between-group differences all in favor of the EG were determined for 10 y-CHD risk (EG: 2.65 +/- 2.09% versus CG: 5.40 +/- 3.30%; P = 0.001), MetS-Index (EG: 0.42 +/- 1.03% versus CG: 1.61 +/- 1.88; P = 0.001), and 10 y-hard-CHD risk (EG: 2.06 +/- 1.17% versus CG: 3.26 +/- 1.31%; P = 0.001). Although the nonrandomized design may prevent definite evidence, the intense multi-purpose exercise program determined the long-term efficacy and feasibility of an exercise program to significantly impact metabolic and cardiac risk scores in postmenopausal women. This trial is registered with ClinicalTrials.gov NCT01177761. PMID- 23983805 TI - Biofeedback therapy combined with traditional chinese medicine prescription improves the symptoms, surface myoelectricity, and anal canal pressure of the patients with spleen deficiency constipation. AB - In order to observe the clinical therapeutic effects of Yiqi Kaimi Prescription and biofeedback therapy on treating constipation with deficiency of spleen qi, the 30 cases in the control group were given oral administration of Yiqi Kaimi Prescription, in combination with anus-lifting exercise; the 30 cases in the treatment group were given biofeedback therapy on the basis of the afore mentioned methods for the control group. The TCM symptom scores and anorectal pressures before and after treatment were observed and evaluated. There were significant differences in TCM symptom scores, anorectal pressure, and clinical recovery rate before and after treatment. In the treatment group, the total recovery rate was 86.66%, while in the control group it was 50%; there were significant differences between the two groups (P < 0.01). Yiqi Kaimi Prescription coupled with biofeedback therapy is clinically effective for treating constipation with deficiency of spleen qi, and thus this method is applicable for functional constipation with deficiency of spleen qi. PMID- 23983806 TI - Therapeutic Effect of the Tuber of Alisma orientale on Lipopolysaccharide-Induced Acute Lung Injury. AB - Although Alisma orientale, an ethnic herb, has been prescribed for treating various diseases in Asian traditional medicine, experimental evidence to support its therapeutic effects is lacking. Here, we sought to determine whether A. orientale has a therapeutic effect on acute lung injury (ALI). Ethanol extract of the tuber of A. orientale (EEAO) was prepared and fingerprinted by HPLC for its constituents. Mice received an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) for the induction of ALI. At 2 h after LPS treatment, mice received an intratracheal (i.t.) spraying of various amounts of EEAO to the lung. Bioluminescence imaging of transgenic NF- kappa B/luciferase reporter mice shows that i.t. EEAO posttreatment suppressed lung inflammation. In similar experiments with C57BL/6 mice, EEAO posttreatment significantly improved lung inflammation, as assessed by H&E staining of lung sections, counting of neutrophils in bronchoalveolar lavage fluid, and semiquantitative RT-PCR analyses of proinflammatory cytokines and Nrf2-dependent genes in the inflamed lungs. Furthermore, EEAO posttreatment enhanced the survival of mice that received a lethal dose of LPS. Together, our results provide evidence that A. orientale has a therapeutic effect on ALI induced by sepsis. PMID- 23983807 TI - Electroacupuncture and rosiglitazone combined therapy as a means of treating insulin resistance and type 2 diabetes mellitus: a randomized controlled trial. AB - Aims. To evaluate the efficacy of rosiglitazone (TZD) and electroacupuncture (EA) combined therapy as a treatment for type 2 diabetes mellitus (T2DM) patients by randomized single-blind placebo controlled clinical trial. Methods. A total of 31 newly diagnostic T2DM patients, who fulfilled the study's eligibility criteria, were recruited. The individuals were randomly assigned into two groups, the control group (TZD, N = 15) and the experimental group (TZD + EA, N = 16). Changes in their plasma free fatty acid (FFA), glucose, and insulin levels, together with their homeostasis model assessment (HOMA) indices, were statistically compared before and after treatment. Hypoglycemic activity (%) was also compared between these two groups. Results. There was no significant difference in hypoglycemic activity between the TZD and TZD + EA group. The effectiveness of the combined therapy seems to derive from an improvement in insulin resistance and a significant lowering of the secreted insulin rather than the effect of TZD alone on T2DM. The combined treatment had no significant adverse effects. A lower plasma FFA concentration is likely to be the mechanism that causes this effect. Conclusion. This combined therapy seems to suppress endogenous insulin secretion by improving insulin resistance via a mechanism involving a reduction in plasma FFA. This trial is registered with ClinicalTrials.gov NCT01577095. PMID- 23983808 TI - Study on parameter optimization for support vector regression in solving the inverse ECG problem. AB - The typical inverse ECG problem is to noninvasively reconstruct the transmembrane potentials (TMPs) from body surface potentials (BSPs). In the study, the inverse ECG problem can be treated as a regression problem with multi-inputs (body surface potentials) and multi-outputs (transmembrane potentials), which can be solved by the support vector regression (SVR) method. In order to obtain an effective SVR model with optimal regression accuracy and generalization performance, the hyperparameters of SVR must be set carefully. Three different optimization methods, that is, genetic algorithm (GA), differential evolution (DE) algorithm, and particle swarm optimization (PSO), are proposed to determine optimal hyperparameters of the SVR model. In this paper, we attempt to investigate which one is the most effective way in reconstructing the cardiac TMPs from BSPs, and a full comparison of their performances is also provided. The experimental results show that these three optimization methods are well performed in finding the proper parameters of SVR and can yield good generalization performance in solving the inverse ECG problem. Moreover, compared with DE and GA, PSO algorithm is more efficient in parameters optimization and performs better in solving the inverse ECG problem, leading to a more accurate reconstruction of the TMPs. PMID- 23983809 TI - Multiple active contours guided by differential evolution for medical image segmentation. AB - This paper presents a new image segmentation method based on multiple active contours guided by differential evolution, called MACDE. The segmentation method uses differential evolution over a polar coordinate system to increase the exploration and exploitation capabilities regarding the classical active contour model. To evaluate the performance of the proposed method, a set of synthetic images with complex objects, Gaussian noise, and deep concavities is introduced. Subsequently, MACDE is applied on datasets of sequential computed tomography and magnetic resonance images which contain the human heart and the human left ventricle, respectively. Finally, to obtain a quantitative and qualitative evaluation of the medical image segmentations compared to regions outlined by experts, a set of distance and similarity metrics has been adopted. According to the experimental results, MACDE outperforms the classical active contour model and the interactive Tseng method in terms of efficiency and robustness for obtaining the optimal control points and attains a high accuracy segmentation. PMID- 23983810 TI - Multiobjective optimization design of spinal pedicle screws using neural networks and genetic algorithm: mathematical models and mechanical validation. AB - Short-segment instrumentation for spine fractures is threatened by relatively high failure rates. Failure of the spinal pedicle screws including breakage and loosening may jeopardize the fixation integrity and lead to treatment failure. Two important design objectives, bending strength and pullout strength, may conflict with each other and warrant a multiobjective optimization study. In the present study using the three-dimensional finite element (FE) analytical results based on an L25 orthogonal array, bending and pullout objective functions were developed by an artificial neural network (ANN) algorithm, and the trade-off solutions known as Pareto optima were explored by a genetic algorithm (GA). The results showed that the knee solutions of the Pareto fronts with both high bending and pullout strength ranged from 92% to 94% of their maxima, respectively. In mechanical validation, the results of mathematical analyses were closely related to those of experimental tests with a correlation coefficient of 0.91 for bending and 0.93 for pullout (P < 0.01 for both). The optimal design had significantly higher fatigue life (P < 0.01) and comparable pullout strength as compared with commercial screws. Multiobjective optimization study of spinal pedicle screws using the hybrid of ANN and GA could achieve an ideal with high bending and pullout performances simultaneously. PMID- 23983811 TI - Hybrid mesh for nasal airflow studies. AB - The accuracy of the numerical result is closely related to mesh density as well as its distribution. Mesh plays a very significant role in the outcome of numerical simulation. Many nasal airflow studies have employed unstructured mesh and more recently hybrid mesh scheme has been utilized considering the complexity of anatomical architecture. The objective of this study is to compare the results of hybrid mesh with unstructured mesh and study its effect on the flow parameters inside the nasal cavity. A three-dimensional nasal cavity model is reconstructed based on computed tomographic images of a healthy Malaysian adult nose. Navier Stokes equation for steady airflow is solved numerically to examine inspiratory nasal flow. The pressure drop obtained using the unstructured computational grid is about 22.6 Pa for a flow rate of 20 L/min, whereas the hybrid mesh resulted in 17.8 Pa for the same flow rate. The maximum velocity obtained at the nasal valve using unstructured grid is 4.18 m/s and that with hybrid mesh is around 4.76 m/s. Hybrid mesh reported lower grid convergence index (GCI) than the unstructured mesh. Significant differences between unstructured mesh and hybrid mesh are determined highlighting the usefulness of hybrid mesh for nasal airflow studies. PMID- 23983812 TI - The approach to steady state using homogeneous and Cartesian coordinates. AB - Repeating an arbitrary sequence of RF pulses and magnetic field gradients will eventually lead to a steady-state condition in any magnetic resonance system. While numerical methods can quantify this trajectory, analytic analysis provides significantly more insight and a means for faster calculation. Recently, an analytic analysis using homogeneous coordinates was published. The current work further develops this line of thought and compares the relative merits of using a homogeneous or a Cartesian coordinate system. PMID- 23983813 TI - Iterative reweighted noninteger norm regularizing SVM for gene expression data classification. AB - Support vector machine is an effective classification and regression method that uses machine learning theory to maximize the predictive accuracy while avoiding overfitting of data. L2 regularization has been commonly used. If the training dataset contains many noise variables, L1 regularization SVM will provide a better performance. However, both L1 and L2 are not the optimal regularization method when handing a large number of redundant values and only a small amount of data points is useful for machine learning. We have therefore proposed an adaptive learning algorithm using the iterative reweighted p-norm regularization support vector machine for 0 < p <= 2. A simulated data set was created to evaluate the algorithm. It was shown that a p value of 0.8 was able to produce better feature selection rate with high accuracy. Four cancer data sets from public data banks were used also for the evaluation. All four evaluations show that the new adaptive algorithm was able to achieve the optimal prediction error using a p value less than L1 norm. Moreover, we observe that the proposed Lp penalty is more robust to noise variables than the L1 and L2 penalties. PMID- 23983814 TI - Risk strata-based therapy and outcome in stage Ib-IIa carcinoma cervix: single centre ten-year experience. AB - AIM: To review the outcome of stage (Ib, IIa), cervical cancer patients were primarily treated with radical hysterectomy and risk-based postoperative therapy. MATERIAL AND METHODS: Between January 2001 and December 2011, 601 cases underwent surgery followed by tailored therapy. Patients were classified into low risk (pelvic lymph node negative, tumour less than 4 cm, no evidence of lympho vascular invasion, less than one-third of thickness of surgical stoma involved), intermediate risk (positive lympho-vascular space invasion, tumour size more than 4 cm, and deep invasion of cervical stroma), and high risk (pelvic lymph node involved, positive parametrial, or vaginal margins) groups. Postoperative adju vant therapy in the form of radiotherapy alone to those with intermediate risk and chemo-radiotherapy to those with high risk was given to patients. The median follow-up was 60 months. RESULTS: The majority of patients had intermediate risk. The overall event-free survival (EFS) at five years was 74.37%, with EFS of 86.5% in those from the low-risk group, 73% in those from the intermediate-risk group, and 64% in those from the high-risk group. In conclusion, risk strata-based adjuvant postoperative therapy is able to provide a favourable outcome in patients with stage Ib-IIa cervical cancer with a nearly 11% improvement in survival compared with historical control. PMID- 23983815 TI - Heterogeneity of circulating epithelial tumour cells from individual patients with respect to expression profiles and clonal growth (sphere formation) in breast cancer. AB - BACKGROUND: The detection of tumour cells circulating in the peripheral blood of patients with breast cancer is a sign that cells have been able to leave the primary tumour and survive in the circulation. However, in order to form metastases, they require additional properties such as the ability to adhere, self-renew, and grow. Here we present data that a variable fraction among the circulating tumour cells detected by the Maintrac((r)) approach expresses mRNA of the stem cell gene NANOG and of the adhesion molecule vimentin and is capable of forming tumour spheres, a property ascribed to tumour-initiating cells (TICs). PATIENTS AND METHODS: Between ten and 50 circulating epithelial antigen-positive cells detected by the Maintrac approach were selected randomly from each of 20 patients with breast cancer before and after surgery and were isolated using automated capillary aspiration and deposited individually onto slides for expression profiling. In addition, the circulating tumour cells were cultured without isolation among the white blood cells from 39 patients with breast cancer in different stages of disease using culture methods favouring growth of epithelial cells. RESULTS: Although no epithelial cell adhesion molecule (EpCAM) positive cells expressing stem cell genes or the adhesion molecule vimentin was detected before surgery, 10%-20% of the cells were found to be positive for mRNA of these genes after surgery. Tumour spheres from circulating cells of 39 patients with different stages of breast cancer were grown without previous isolation in a fraction increasing with the aggressivity of the tumour. SUMMARY: Here we show that among the peripherally circulating tumour cells, a variable fraction is able to express stem cell and adhesion properties and can be grown into tumour spheres, a property ascribed to cells capable of initiating tumours and metastases. PMID- 23983816 TI - Bone Windows for Distinguishing Malignant from Benign Primary Bone Tumors on FDG PET/CT. AB - Objective. The default window setting on PET/CT workstations is soft tissue. This study investigates whether bone windowing and hybrid FDG PET/CT can help differentiate between malignant and benign primary bone tumors. Materials and methods. A database review included 98 patients with malignant (n=64) or benign primary bone (n=34) tumors. The reference standard was biopsy for malignancies and biopsy or >1 year imaging follow-up of benign tumors. Three radiologists and/or nuclear medicine physicians blinded to diagnosis and other imaging viewed the lesions on CT with bone windows (CT-BW) without and then with PET (PET/CT BW), and separate PET-only images for malignancy or benignity. Three weeks later the tumors were viewed on CT with soft tissue windows (CT-STW) without and then with PET (PET/CT-STW). Results. Mean sensitivity and specificity for identifying malignancies included: CT-BW: 96%, 90%; CT-STW: 90%, 90%; PET/CT-BW: 95%, 85%, PET/CT-STW: 95%, 86% and PET-only: 96%, 75%, respectively. CT-BW demonstrated higher specificity than PET-only and PET/CT-BW (p=0.0005 and p=0.0103, respectively) and trended toward higher sensitivity than CT-STW (p=0.0759). Malignant primary bone tumors were more avid than benign lesions overall (p<0.0001) but the avidity of benign aggressive lesions (giant cell tumors and Langerhans Cell Histiocytosis) trended higher than the malignancies (p=0.08). Conclusion. Bone windows provided high specificity for distinguishing between malignant and benign primary bone tumors and are recommended when viewing FDG PET/CT. PMID- 23983817 TI - Significantly increased medical expenditure on breast cancer failing to bring down its mortality and incidence rate. AB - BACKGROUND: The direct impact of medical expenses on breast cancer incidence and mortality rate has not been sufficiently addressed. The purpose of this study is to investigate the potential correlation between the incidence and mortality rate of breast cancer and the medical expenses in Taiwan. MATERIALS AND METHODS: Breast cancer cases were identified from the National Health Insurance Research Database (NHIRD) with corresponding to International Classification of Diseases, and the Ninth Revision (ICD-9) code 174, 1740-1749, 175, 1750 and 1759 from January 1999 to December 2006. Age-specific incidences were estimated by population data obtained from the Department of Statistics, Ministry of the Interior. Medical expenses, including outpatient and inpatient services, were also retrieved from the NHIRD. RESULTS: The incidence increased from 20.06 per 100,000 in 1999 to 30.34 per 100,000 in 2006; the total expenses increased from 1,449,333,521 in 1999 to 4,350,400,592 Taiwan dollars in 2006. The age standardized mortality rate for female breast cancer remained essentially unchanged, while the age-standardized incidence increased steadily (except 2002 2003). Among the top 20 coexisting ICD-9 codes for expenses, four are directly on cancers, while 16 are on other diseases or symptoms, which are not necessarily caused by breast cancer. CONCLUSIONS: Significantly increased medical expenditure on breast cancer failed to bring down its mortality and incidence rate. The finding has implications for healthcare policy planners in proposing strategies for breast cancer control and allocating the resources. PMID- 23983818 TI - A new method for identifying stem-like cells in esophageal cancer cell lines. AB - Cancer stem cells (CSCs) appear to resist chemo-radiotherapy and initiate tumor recurrence in patients. Isolation and further characterization of this subpopulation is important for targeting CSCs. Flow cytometry using Aldefluor, a fluorescent substrate of aldehyde dehydrogenase, has been used to isolate CSCs from various cancer cell lines. However, new techniques are needed to locate and identify CSCs in culture for live-cell analyses such as fluorescence microscopy without introducing artifacts during cell sorting and to observe CSC and non-CSC interactions. Previously, we characterized a distinct CSC subpopulation within human esophageal cancer cell lines (ESCC). In this study we introduce the attached-cell Aldefluor method (ACAM) to detect CSCs in ESCC cell lines (KY-5, KY 10, TE-1, TE-8, YES-1, YES-2). To validate this technique, we isolated CSCs from the YES-2 parental line using standard Aldefluor flow cytometry to create a cell line enriched in CSCs (YES-2CSC). This line showed significantly greater ACAM staining and higher CD44 levels than YES-2. ACAM also showed significantly higher ALDH activity in YES-2CSC than in YES-2S, a cell line that has a diminished CSC subpopulation after having survived treatment with curcumin. ACAM stained cells within tumorspheres made from the CSC-enriched line but not differentiating cells from the tumorspheres. This study also demonstrates a new method for generating and growing tumorspheres without the growth factor supplements normally used in medium to form tumorspheres. ACAM should be evaluated using other cancer cell lines to further substantiate its effectiveness and to characterize CSCs in culture through various imaging techniques. PMID- 23983819 TI - Use of ACE Inhibitors and Angiotensin Receptor Blockers and Primary Breast Cancer Outcomes. AB - BACKGROUND: ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may have anti-tumor properties. We investigated whether the use of ACEI/ARBs affects the clinical outcomes of primary breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy. METHODS: We included 1449 patients with diagnosis of invasive primary breast cancer diagnosed at the MD Anderson Cancer Center between 1995 and 2007 who underwent neoadjuvant chemotherapy. Of them, 160 (11%) patients were identified by review of their medical record, as ACEI/ARBs users. We compared pathologic complete response (pCR) rates, relapse free survival (RFS), disease-specific survival (DSS) and overall survival (OS) between ACEI/ARB users and non-users. Descriptive statistics and Cox proportional hazards model were used in the analyses. RESULTS: There was no difference in the pCR rates between ACEI/ARB users and non-users (16% vs 18.1%, p-=0.50). After adjustment for important demographic and clinical characteristics, no significant differences between ACEI/ARB users and nonusers were observed in RFS (HR=0.81; 95% CI=0.54-1.21), DSS (HR=0.83; 95% CI=0.52-1.31), or OS (HR=0.91; 95% CI =0.61 1.37). In a subgroup analysis, the 5-year RFS was 82% in ARB only users versus 71% in ACEI/ARB non-users (P=0.03). In the multivariable analysis, ARB use was also associated with a decreased risk of recurrence (HR=0.35; 95% CI=0.14-0.86). No statistically significant differences in DSS or OS were seen. CONCLUSION: No differences in pCR and survival outcomes were seen between ACEI/ARB users and non users among breast cancer patients receiving neoadjuvant chemotherapy. ARB use may be associated with improved RFS. Further research is needed to validate this finding. PMID- 23983820 TI - Antitumor Activity of TAK-285, an Investigational, Non-Pgp Substrate HER2/EGFR Kinase Inhibitor, in Cultured Tumor Cells, Mouse and Rat Xenograft Tumors, and in an HER2-Positive Brain Metastasis Model. AB - Breast cancer therapy has improved following the development of drugs with specific molecular targets, exemplified by inhibitors of human epidermal growth factor receptor-2 (HER2) or epidermal growth factor receptor (EGFR) such as trastuzumab and lapatinib. However, these drugs have little effect on brain metastasis due to the combined effects of poor penetration of the blood-brain barrier and their removal from the central nervous system (CNS) by the p glycoprotein (Pgp) drug efflux pump. We investigated the effects of TAK-285, a novel, investigational, dual EGFR/HER2 inhibitor that has been shown to penetrate the CNS and has comparable inhibitory efficacy to lapatinib which is a known Pgp substrate. Tested against a panel of 96 kinases, TAK-285 showed specificity for inhibition of HER family kinases. Unlike lapatinib, TAK-285 is not a substrate for Pgp efflux. In mouse and rat xenograft tumor models, TAK-285 showed antitumor activity against cancers that expressed HER2 or EGFR. TAK-285 was as effective as lapatinib in antitumor activity in a mouse subcutaneous BT-474 breast cancer xenograft model. TAK-285 was examined in a model of breast cancer brain metastasis using direct intracranial injection of BT-474-derived luciferase expressing cells and showed greater inhibition of brain tumor growth compared to animals treated with lapatinib. Our studies suggest that investigational drugs such as TAK-285 that have strong antitumor activity and are not Pgp substrates may be useful in the development of agents with the potential to treat brain metastases. PMID- 23983821 TI - TGF-beta2: A Novel Target of CD44-Promoted Breast Cancer Invasion. AB - We have developed a tetracycline (tet)-off regulated expression of CD44s gene in the breast cancer (BC) cell line MCF-7 (B5 clone) and identified TGF-beta2 (Transforming Growth Factor beta-2; 3 fold induction) as a potential CD44 downstream transcriptional target by microarray analysis. To further validate this finding, the same RNA samples, used for microarray analysis and their corresponding protein lysates, collected from the BC cell line MCF-7-B5, were examined for CD44 expression in the presence of HA. Our results showed that TGF beta2 mRNA levels were significantly elevated following the removal of tetracycline at 18, 24, and 48 h post-HA stimulation compared to the parental cells. Furthermore, the TGF-beta2 precursor protein increased in a time-dependent pattern upon HA-stimulation and in the absence of tetracycline. More interestingly, inhibition of CD44 gene by RNAi method decreased TGF-beta2 expression upon HA-stimulation, and subsequently inhibited BC cell invasion in vitro. In addition to identifying TGF-beta2 as a target for HA/CD44 signaling, this data suggests that ATF/CREB might be a potential transcription factor linking HA/CD44 activation to TGF-beta2 transcription and additional experiments are required for a better understanding of the molecular mechanisms underpinning the novel function of the CD44/ TGF-beta2 signaling pathway in breast cancer metastasis. PMID- 23983822 TI - Antineoplasic effect of aqueous extract of plectranthus amboinicus in ehrlich ascites carcinoma. AB - There are 46,000 new cases of peritoneal carcinomatosis per year in the USA and 17,700 in Brazil. New media, including plant derivatives, are being tested in its treatment. Plectranthus amboinicus is a medicinal plant widely used in Brazil, especially in the northeast region, for the treatment of various diseases, including cancer. This present study evaluates the intraperitoneal use of aqueous extracts of Plectranthus amboinicus (AEPa) at a dose of 200 mg / kg for the treatment of the ascitic form of Ehrlich carcinoma. It is concluded also the AEPa produced antineoplastic effect in ascitic form of Ehrlich carcinoma. PMID- 23983823 TI - Survival Advantage in Patients with Metastatic Breast Cancer Receiving Endocrine Therapy plus Sialyl Tn-KLH Vaccine: Post Hoc Analysis of a Large Randomized Trial. AB - BACKGROUND: A multicenter, double blinded, randomized phase III trial of the therapeutic cancer vaccine sialy1-Tn (STn) conjugated to keyhole-limpet Hemocyanin (KLH) was completed in an international cohort of 1,028 women with metastatic breast cancer who had nonprogressive disease or no evidence of disease after first-line chemotherapy (ClinicalTrials.gov, (NCT00003638). STn-KLH was safe and relatively well tolerated but did not affect time to progression (TTP) or overall survival (OS) duration. The purpose of this post hoc analysis was to explore whether patients who received concurrent endocrine therapy and STn-KLH had a TTP or OS benefit. METHODS: A retrospective, blinded review of the data from the phase III trial of STn-KLH was performed to ensure that strata assignments were appropriate. We then studied the effect of concomitant endocrine therapy and STn-KLH or KLH on TTP and OS in the cohort described above. We also assessed the TTP and OS by antibody responses in patients who received endocrine therapy. RESULTS: The women treated with concomitant endocrine therapy, a pre stratified subset comprising approximately one-third of the original study population, and STn-KLH had longer TTP and OS than the control group of women who received KLH alone. Moreover, of the women who received endocrine therapy, those who had a median or greater antibody response (titer >1:320 toward ovine sub maxillary mucin) to the STn-KLH vaccine had significantly longer median OS than those who had a below-median antibody response. CONCLUSION: Adding STn-KLH to endocrine therapy may improve clinical outcomes with few adverse effects for women with metastatic breast cancer. PMID- 23983824 TI - What is the best way to care for frail older adults? PMID- 23983825 TI - Acceptance of disability and the risk of frailty(*). AB - BACKGROUND: THE OBJECTIVES ARE TO DETERMINE IF: 1) accepting disability as a part of aging is associated with frailty; and 2) accepting disability is associated with becoming frail over a five-year period. METHODS: Secondary analysis of a prospective cohort study of 1,751 community-dwelling adults aged 65+. Participants were asked to rate their agreement with the statement: "When you reach my age, you have to accept a fair degree of discomfort and physical disability" on a five-point scale. Frailty was categorized as not frail or frail. The sample was re-interviewed five years later. RESULTS: The mean age was 75.5 years, 62.3% were women, and the mean education was 10.2 years. Accepting disability as a part of aging was strongly associated with frailty at time 1; the unadjusted Odds Ratio (OR) and 95% confidence interval (CI) was 1.47 (1.25, 1.72) and this association persisted after adjusting for confounding factors. Accepting disability was also associated with becoming frail; the unadjusted OR and 95% CI was 1.51 (1.20, 1.90), and this association also persisted after adjusting for potential confounding factors. CONCLUSIONS: Accepting disability as a part of aging is associated with being frail and becoming frail. PMID- 23983826 TI - Improving the quality of care for older adults using evidence-informed clinical care pathways. AB - BACKGROUND: There has been an intensified focus on quality initiatives within health care. Clinical Networks have been established in Alberta as a structure to improve care within and across settings. One method used by Clinical Networks to improve care is clinical care pathways. The objective of this study was to evaluate an evidence-informed hip fracture acute care pathway before broad implementation. METHODS: The pathway was developed by a provincial Clinical Network and implemented at four of 14 hospitals across the province. Within four months of implementing the pathway, experienced interviewers conducted focus groups with end-users at the four sites. Domains of inquiry focused on indentifying barriers and facilitators to use of the pathway. RESULTS: Fifteen physicians and 29 other health-care providers participated in eight focus groups. Common themes identified around the pathway order sets included issues with format, workflow and workload, and dissemination. The patient/family educational materials were deemed to be beneficial. Health-care provider education required better support. Overall the pathway was seen to be comprehensive. However, communication about the pathway could have been improved. CONCLUSIONS: This care model is novel in that it combines the concepts of clinical networks, care pathways, and knowledge translation in an effort to provide high-quality, evidence-informed care in a standardized equitable manner across a diverse geographic area. PMID- 23983827 TI - Medical Problems Referred to a Care of the Elderly Physician: Insight for Future Geriatrics CME. AB - PURPOSE: Family physicians provide the majority of elderly patient care in Canada. Many experience significant challenges in serving this cohort. This study aimed to examine the medical problems of patients referred to a care of the elderly physician, to better understand the geriatric continuing medical education (CME) needs of family doctors. METHODS: A retrospective chart review of patients assessed at an urban outpatient seniors' clinic between 2003 and 2008 was conducted. Data from 104 charts were analyzed and survey follow-up with 28 of the referring family physicians was undertaken. Main outcomes include the type and frequency of medical problems actually referred to a care of the elderly physician. Clarification of future geriatric CME topics of need was also assessed. RESULTS: Preventive care issues were addressed with 67 patients. Twenty four required discussion of advance directives. The most common medical problems encountered were osteoarthritis (42), hypertension (34), osteoporosis (32), and depression or anxiety (23). Other common problems encountered that have not been highly cited as being a target of CME included musculoskeletal and joint pain (41), diabetes (23), neck and back pain (20), obesity (11), insomnia (11), and neuropathic, fibromyalgia and "leg cramps" pain (10). The referring family physicians surveyed agreed that these were topics of need for future CME. CONCLUSIONS: The findings support geriatric CME for the common medical problems encountered. Chronic pain, diabetes, obesity and insomnia continue to be important unresolved issues previously unacknowledged by physicians as CME topics of need. Future CME focusing more on process of geriatric care may also be relevant. PMID- 23983828 TI - Systematic review of the evidence for Trails B cut-off scores in assessing fitness-to-drive. AB - BACKGROUND: Fitness-to-drive guidelines recommend employing the Trail Making B Test (a.k.a. Trails B), but do not provide guidance regarding cut-off scores. There is ongoing debate regarding the optimal cut-off score on the Trails B test. The objective of this study was to address this controversy by systematically reviewing the evidence for specific Trails B cut-off scores (e.g., cut-offs in both time to completion and number of errors) with respect to fitness-to-drive. METHODS: Systematic review of all prospective cohort, retrospective cohort, case control, correlation, and cross-sectional studies reporting the ability of the Trails B to predict driving safety that were published in English-language, peer reviewed journals. RESULTS: Forty-seven articles were reviewed. None of the articles justified sample sizes via formal calculations. Cut-off scores reported based on research include: 90 seconds, 133 seconds, 147 seconds, 180 seconds, and < 3 errors. CONCLUSIONS: There is support for the previously published Trails B cut-offs of 3 minutes or 3 errors (the '3 or 3 rule'). Major methodological limitations of this body of research were uncovered including (1) lack of justification of sample size leaving studies open to Type II error (i.e., false negative findings), and (2) excessive focus on associations rather than clinically useful cut-off scores. PMID- 23983830 TI - A message from the editor in chief. PMID- 23983829 TI - Corrigendum: the practice of geriatrics: specialized geriatric programs and home visits. PMID- 23983831 TI - The birth of neurohospitalists. PMID- 23983832 TI - A proposed roadmap for inpatient neurology quality indicators. AB - BACKGROUND/PURPOSE: In recent years, there has been increasing pressure to measure and report quality in health care. However, there has been little focus on quality measurement in the field of neurology for conditions other than stroke and transient ischemic attack. As the number of evidence-based treatments for neurological conditions grows, so will the demand to measure the quality of care delivered. The purpose of this study was to review essential components of hospital performance measures for neurological disease and propose potential quality indicators for commonly encountered inpatient neurological diagnoses. METHODS: We determined the most common inpatient neurological diagnoses at a major tertiary care medical center by reviewing the billing database. We then searched PubMed and the National Guidelines Clearinghouse to identify treatment guidelines for these conditions. Guideline recommendations with class I/level A evidence were evaluated as possible quality indicators. RESULTS: We found 94 guidelines for 14 inpatient neurological conditions other than stroke and transient ischemic attack. Of these, 36 guidelines contained at least 1 recommendation with class I evidence. Based on these, potential quality indicators for intracerebral hemorrhage, subarachnoid hemorrhage, pneumococcal meningitis, coma following cardiac arrest, encephalitis, Guillain-Barre syndrome, multiple sclerosis, and benign paroxysmal positional vertigo are proposed. CONCLUSIONS: There are several inpatient neurological conditions with treatments or diagnostic test routines supported by high levels of evidence that could be used in the future as quality indicators. PMID- 23983833 TI - Myasthenic crisis. AB - Myasthenic crisis is a complication of myasthenia gravis characterized by worsening of muscle weakness, resulting in respiratory failure that requires intubation and mechanical ventilation. Advances in critical care have improved the mortality rate associated with myasthenic crisis. This article reviews the epidemiology of myasthenic crisis and discusses patient evaluation. Therapeutic options including mechanical ventilation and pharmacological and surgical treatments are also discussed. PMID- 23983834 TI - Status epilepticus: current treatment strategies. AB - Status epilepticus is a neurological emergency that is commonly encountered by the neurohospitalist. Successful treatment depends upon the recognition of prolonged seizure activity and the acute mobilization of available resources. Pharmacologic treatment regimens have been shown to decrease the time needed for successful control of seizures and have provided for the rapid administration of anticonvulsant medications. Treatment strategies have evolved so that clinicians can administer effective doses of medication by whatever routes of administration are immediately available. Traditional algorithms for the treatment of status epilepticus have used a stepwise approach to the administration of first-, second , and third-order medications. More recent options have included aggressive anesthetic doses of medications while second-line medications are being titrated. PMID- 23983835 TI - Acute vestibulopathy. AB - The presentation of acute vertigo may represent both a common benign disorder or a life threatening but rare one. Familiarity with the common peripheral vestibular disorders will allow the clinician to rapidly "rule-in" a benign disorder and recognize when further testing is required. Key features of vertigo required to make an accurate diagnosis are duration, chronicity, associated symptoms, and triggers. Bedside tests that are critical to the diagnosis of acute vertigo include the Dix-Hallpike maneuver and canalith repositioning manuever, occlusive ophthalmoscopy, and the head impulse test. The goal of this review is to provide the clinician with the clinical and pathophysiologic background of the most common disorders that present with vertigo to develop a logical differential diagnosis and management plan. PMID- 23983837 TI - A 41-year-old man with new headache and altered mental status. PMID- 23983836 TI - Neuroleptic malignant syndrome: a review for neurohospitalists. AB - Neuroleptic malignant syndrome (NMS) is a life-threatening idiosyncratic reaction to antipsychotic drugs characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction. It has been associated with virtually all neuroleptics, including newer atypical antipsychotics, as well as a variety of other medications that affect central dopaminergic neurotransmission. Although uncommon, NMS remains a critical consideration in the differential diagnosis of patients presenting with fever and mental status changes because it requires prompt recognition to prevent significant morbidity and death. Treatment includes immediately stopping the offending agent and implementing supportive measures, as well as pharmacological interventions in more severe cases. Maintaining vigilant awareness of the clinical features of NMS to diagnose and treat the disorder early, however, remains the most important strategy by which physicians can keep mortality rates low and improve patient outcomes. PMID- 23983838 TI - If not neurohospitalists, who? If not now, when? PMID- 23983839 TI - Neurohospitalists reduce length of stay for patients with ischemic stroke. AB - BACKGROUND: Neurohospitalists may improve the efficiency and quality of care delivered to hospitalized patients with neurological disease. However, there is limited systematic data to support this hypothesis. The primary purpose of this study was to compare length of stay (LOS) for patients with ischemic stroke cared for by either neurohospitalists or community-based neurologists at a single institution. METHODS: A retrospective chart review was performed for all patients with ischemic stroke discharged from St. Luke's Hospital in Jacksonville, Florida, between January 2006 and December 2007. The LOS for patients cared for by neurohospitalists was compared to the LOS for patients cared for by community neurologists. Compliance with Joint Commission inpatient stroke quality metrics was also compared. RESULTS: A total of 533 patients were discharged with a principal diagnosis of ischemic stroke over the 24-month study period. Neurohospitalists cared for 313 patients with mean (+/- SD) LOS of 4.9 (5.2) days (95% CI: 4.3-5.5 days), and community-based neurologists cared for 220 patients with a mean LOS of 6.5 (8.2) days (95% CI: 5.4-7.6 days). The mean LOS was significantly less for the neurohospitalists compared to the community-based neurologists (P = .005). Neurohospitalists achieved a higher compliance rate in 10 of 11 inpatient stroke quality metrics and achieved significantly higher compliance rate of smoking cessation education (P = .019). CONCLUSIONS: Neurohospitalists achieved significantly shorter LOS for patients with ischemic stroke compared to community-based neurologists. These data suggest that neurohospitalists can also improve compliance with quality metrics necessary for Joint Commission Primary Stroke Center designation. PMID- 23983840 TI - Quality measures in stroke. AB - Stroke is a major public health burden, and accounts for many hospitalizations each year. Due to gaps in practice and recommended guidelines, there has been a recent push toward implementing quality measures to be used for improving patient care, comparing institutions, as well as for rewarding or penalizing physicians through pay-for-performance. This article reviews the major organizations involved in implementing quality metrics for stroke, and the 10 major metrics currently being tracked. We also discuss possible future metrics and the implications of public reporting and using metrics for pay-for-performance. PMID- 23983841 TI - Inpatient management of guillain-barre syndrome. AB - Guillain-Barre syndrome (GBS) is the most common cause of acute flaccid paralysis in the developed world. Guillain-Barre syndrome typically presents with ascending paralysis and is usually severe enough to warrant hospital admission for management. In the United States alone, GBS results in more than 6000 hospitalizations each year. Although GBS patients were historically cared for at tertiary referral centers, changing treatment practices have broadened the number of neurologists who care for the disease. This article provides a review of key issues in the inpatient management of GBS. A survey of the evidence base for treatment with plasma exchange or intravenous immunoglobulins is presented. Although either of these treatments can limit the severity of GBS, patients are still at risk for a broad range of complications, including respiratory failure, autonomic dysfunction, thromboembolic disease, pain, and psychiatric disorders. Awareness of these complications, their detection and management, may help limit the morbidity of GBS. PMID- 23983842 TI - Aspiration pneumonia after stroke: intervention and prevention. AB - Fifteen million strokes occur worldwide each year with 5 million associated deaths and an additional 5 million people left permanently disabled. In the United States, about 780 000 people suffer a new or recurrent stroke each year. There were an estimated total 5.8 million stroke survivors as of 2008. Mortality from stroke is the third leading cause of death in America following heart disease and cancer. Chest infection may affect up to as many as one-third of stroke patients. This increases the morbidity and mortality of this patient population. Pneumonia causes the highest attributable mortality of all medical complications following stroke. A comprehensive multidisciplinary team approach is required at the hospital level. This requires active administrative commitment and participation. Implementation of evidence-based management strategies can improve outcomes and reduce costs. We sought to review the problem of post-stroke pneumonia and discuss strategies for prevention and intervention. PMID- 23983843 TI - Aspirin resistance: a clinical review focused on the most common cause, noncompliance. AB - Aspirin is an inexpensive, readily available medication that reduces the risk of subsequent vascular disease by about 25% in patients with known occlusive vascular disease. Aspirin's beneficial effect is mediated via inhibition of arachidonic acid (AA) activation of platelets and is detected by demonstrating a decrease in platelet function and/or a decrease in prostaglandin metabolites. Patients who are assumed to be taking their aspirin, but who do not demonstrate an aspirin effect are labeled as, "aspirin resistant." This is an unfortunate designation as the vast majority of patients labeled as "aspirin resistant" are noncompliant. Noncompliance is demonstrated in multiple studies that use repeat testing for platelet inhibition in patients with an initial inadequate response to aspirin. When the test is repeated under condition where ingestion of the test aspirin is assured, the patients' platelets are inhibited. Instead of using the term "aspirin resistance," this review will use "inadequate response to aspirin." Patients with an inadequate aspirin response have an increased likelihood for subsequent vascular events. Detection and treatment of an inadequate aspirin response would be facilitated by the development of a bedside assay that uses whole blood, is technically simple, inexpensive, sensitive, specific, reproducible, and provides an answer in a few minutes. Future research in patients with an inadequate response to aspirin should focus on mechanisms to improve compliance, which should decrease their risk of future vascular events. PMID- 23983845 TI - Is fellowship training necessary for neurohospitalists? AB - Neurohospitalists are an emerging subspecialty group in neurology.(1) A recent survey of neurohospitalists found 75% of respondents had completed general neurology residency plus additional fellowship training (54% vascular neurology, 13% neurocritical care, and 33% other).(2) A limited number of neurohospitalist fellowship positions(3,4) are offered in the United States, however, a standardized curriculum or subspecialty certification examination does not currently exist. Given the recent dialogue surrounding the utility of neurohospitalist fellowship training, the purpose of this article is to provide 2 contrasting perspectives on the perceived need for neurohospitalist fellowship training. PMID- 23983844 TI - Acute neurological issues in pregnancy and the peripartum. AB - Acute neurological diseases requiring hospitalization are relatively rare in women of childbearing age. However, during pregnancy and the postpartum period, several diseases increase in prevalence. Some are unique to the pregnant/postpartum state including preeclampsia and delivery-associated neuropathies. Others, although indirectly related to pregnancy, such as cerebral venous thrombosis, ischemic stroke, and intracerebral hemorrhage, increase in frequency and carry considerable risk of morbidity and mortality. In addition, treatment options are often limited. This review discusses the diseases more commonly seen during pregnancy and the postpartum period, with a focus on emergent neurological diseases and their management. Interventional therapies will also be discussed. PMID- 23983846 TI - Cerebral air emboli with atrial-esophageal fistula following atrial fibrillation ablation: a case report and review. AB - BACKGROUND: Atrial-esophageal fistula (AEF) is a rare and early complication of radiofrequency ablation for medically refractory atrial fibrillation, but has devastating consequences when the diagnosis is delayed or difficult to make. METHODS: Single case in a neurosciences critical care center. RESULTS: A 69-year old man with significant cardiac and neurologic medical history who underwent atrial fibrillation ablation 50 days prior to admission to the neurocritical care unit presented with acute left-sided weakness and gram-positive bacterial sepsis. This is an exceptional case discussing the need for early detection of AEF presenting with sepsis, neurologic deficit along with complicated decision-making in the neurocritical care setting. His hospital course was complicated by acute stroke, left ventricular (LV) aneurysm with thrombus, gastrointestinal (GI) bleed discovered to be from left atrial esophageal fistula, and subsequent cerebral air emboli leading to death. CONCLUSIONS: This is the most delayed presentation of AEF following atrial fibrillation ablation reported in the literature to date. We emphasize the need for awareness of this complication even after such an unexpected time-frame postprocedure as well as the unintended complications of cerebral air emboli following upper endoscopy. PMID- 23983847 TI - The development of primary central nervous system B-cell lymphoma in multiple sclerosis. AB - When coupled with classical clinical signs and symptoms, magnetic resonance imaging can significantly aid in the diagnosis of multiple sclerosis (MS). However, the differential diagnosis of multiple sclerosis is large and, in the absence of pathognomonic clinical features, can be challenging to diagnose initially. Some conditions, such as primary central nervous system lymphoma (PCNSL) and progressive multifocal leukoencephalopathy (PML), can mimic clinically some of the symptoms prominent in multiple sclerosis. Early treatment with corticosteroids can dramatically improve patient symptoms in MS and PCNSL. We report a case of a man diagnosed with histologically confirmed relapsing remitting multiple sclerosis who subsequently developed histologically confirmed primary central nervous system lymphoma. Immunosuppressant therapy in the treatment of multiple sclerosis may be a potential catalyst in the development of central nervous system lymphoma. The course of his disease and treatment are presented and the current literature reviewed. PMID- 23983848 TI - The diffuse hyperdense intracranial circulation sign. PMID- 23983849 TI - Safety of thrombolysis in acute ischemic stroke: a review of complications, risk factors, and newer technologies. AB - Intravenous recombinant tissue plasminogen activator (r-tPA) was approved for use in acute ischemic stroke in the United States in 1996. Approximately 2% to 5% of patients with acute ischemic stroke receive r-tPA. Complications related to intravenous r-tPA include symptomatic intracranial hemorrhage, major systemic hemorrhage, and angioedema in approximately 6%, 2%, and 5% of patients, respectively. Risk factors for symptomatic hemorrhage include age, male gender, obesity, increased stroke severity, diabetes, hyperglycemia, uncontrolled hypertension, combination antiplatelet use, large areas of early ischemic change, atrial fibrillation, congestive heart failure, and leukoariosis. A risk factor for angioedema is the use of angiotensin-converting enzyme inhibitor. Risk assessment scores, novel imaging strategies, and telemedicine may offer methods of optimizing the risk-benefit ratio. PMID- 23983851 TI - Is asymptomatic vasospasm associated with poor outcome in subarachnoid hemorrhage? AB - BACKGROUND: Vasospasm occurs in up to 70% of aneurysmal subarachnoid hemorrhage (aSAH), but only half becomes symptomatic. It is unclear whether asymptomatic vasospasm (AV) detected by noninvasive testing affects outcome. Prophylactic hemodilutional, hypertensive, and hypervolemic (HHH) therapy is widely used but the benefit remains unproven. We aim to determine whether AV increases the risk of poor outcome and whether HHH is safe. METHODS: A total of 175 consecutive patients with aSAH without clinical vasospasm were included. Patients with sonographic (transcranial doppler) or radiologic (computed tomography [CT] Angiography) vasospasm were assigned to AV group, while those without were assigned to no vasospasm (NV) group. Logistic regression was used to determine the association between AV and HHH on poor outcome, defined as modified Rankin scale (mRS) >3 at discharge or 3 to 6 months' follow-up. RESULTS: In all, 106 patients had NV and 25 received HHH. A total of 69 patients had AV and 54 received HHH. Asymptomatic vasospasm compared to NV was not associated with poor outcome (odds ratio [OR] 2.6, 95% confidence interval [CI]: 0.75-8.9; P = .1). Hemodilutional, hypertensive, and hypervolemic use in patients with AV did not improve the outcome (OR 0.16, 95%CI: 0.009-2.84; P = .2). In patients with NV, HHH use showed trend toward poor outcome after multivariable adjustment (OR 12.6, 95%CI: 1.08-146.5 P = .04). CONCLUSION: Asymptomatic vasospasm does not appear to be associated with poor outcome in aSAH. Hemodilutional, hypertensive, and hypervolemic therapy in AV was not associated with improved outcome and may be harmful to patients who do not have vasospasm. Further research is needed to validate this finding. PMID- 23983850 TI - Update in intracerebral hemorrhage. AB - Spontaneous, nontraumatic intracerebral hemorrhage (ICH) is defined as bleeding within the brain parenchyma. Intracranial hemorrhage includes bleeding within the cranial vault and encompasses ICH, subdural hematoma, epidural bleeds, and subarachnoid hemorrhage (SAH). This review will focus only on ICH. This stroke subtype accounts for about 10% of all strokes. The hematoma locations are deep or ganglionic, lobar, cerebellar, and brain stem in descending order of frequency. Intracerebral hemorrhage occurs twice as common as SAH and is equally as deadly. Risk factors for ICH include hypertension, cerebral amyloid angiopathy, advanced age, antithrombotic therapy and history of cerebrovascular disease. The clinical presentation is "stroke like" with sudden onset of focal neurological deficits. Noncontrast head computerized tomography (CT) scan is the standard diagnostic tool. However, newer neuroimaging techniques have improved the diagnostic yield in terms of underlying pathophysiology and may aid in prognosis. Intracerebral hemorrhage is a neurological emergency. Medical care begins with stabilization of airway, breathing function, and circulation (ABCs), followed by specific measures aimed to decrease secondary neurological damage and to prevent both medical and neurological complications. Reversal of coagulopathy when present is of the essence. Blood pressure management can be key and continues as an area of debate and ongoing research. Surgical evacuation of ICH is of unproven benefit though a subset of well-selected patients may have improved outcomes. Ventriculostomy and intracranial pressure (ICP) monitoring are interventions also used in this patient population. To date, hemostatic medications and neuroprotectants have failed to result in clinical improvement. A multidisciplinary approach is recommended, with participation of vascular neurology, vascular neurosurgery, critical care, and rehabilitation medicine as the main players. PMID- 23983852 TI - Mobility criteria for upright sitting with patients in the neuro/trauma intensive care unit: an analysis of length of stay and functional outcomes. AB - BACKGROUND AND PURPOSE: Few studies have explored optimal advancement and variation in mobility and length of stay (LOS) data with critically ill patients in the intensive care unit (ICU). The purpose of this study was to analyze the outcomes and LOS of critically ill patients in the neurotrauma ICU involved in rehabilitation. METHODS: A bidirectional case-control study of a total of 30 patients admitted to a level 1 trauma hospital in the metropolitan Chicago area with Glasgow Coma Score (GCS) of <=12 (3-12) were studied. Functional outcomes of a structured mobility group were compared at first upright sitting and at ICU discharge using the functional independence measure (FIM). Retrospective LOS review of a group (n = 15) with unstructured activity advancement was compared. RESULTS: The main outcome measures were FIM scores and LOS in number of days. In the structured mobility group, a significant increase in functional performance between first upright sitting and ICU discharge was found (P < .005). Length of stay was shorter in the structured mobility groups but the difference was not statistically significant. CONCLUSIONS: Results from this study revealed favorable functional outcomes for patients involved in a structured mobility program with physical therapy in the neuro/trauma ICU. PMID- 23983853 TI - Autoimmune Limbic Encephalitis With GAD Antibodies. AB - The neurologic presentation of limbic encephalitis is variable and when it occurs due to a rare cause the diagnosis may be problematic. We present a case of autoimmune limbic encephalitis due to glutamic acid decarboxylase antibody and consider the magnetic resonance imaging and antineural antibody screening aspects in the diagnosis of this entity. PMID- 23983854 TI - The secret "spice": an undetectable toxic cause of seizure. AB - Neurologists and emergency department physicians are frequently involved in the comprehensive evaluation of a first generalized seizure. An important aspect of this evaluation is a detailed history which can identify a provoked seizure secondary to drug toxicity and hence avoid unnecessary treatment with antiepileptic drugs. "Spice" is an umbrella term for a variety of synthetic cannabinoid products whose inhalation has been associated with an increasing number of toxic side effects resulting in emergency department visits. These side effects (including psychosis, tachyarrhythmia, and seizures) are not typically seen with marijuana (Cannabis sativa) use. We report 2 patients with no prior history of neurological disease that experienced their first generalized tonic clonic seizure after smoking Spice. The mechanism behind the possible proconvulsant effect of synthetic cannabinoids is not known, but it may be due to their effects at the cannabinoid receptor CB1. Although the US Drug Enforcement Administration placed 5 synthetic cannabinoids into schedule 1 for a 12-month period beginning March 2011, new Spice products containing different synthetic cannabinoids continue to emerge. Because synthetic cannabinoids are not detectable on commercial drug screens it is important that neurologists and emergency department physicians consider Spice inhalation in their differential diagnosis of a first generalized seizure. PMID- 23983856 TI - Preventing the rebound. PMID- 23983855 TI - Computed Tomography Angiography in the Assessment of Patients With Stroke/TIA. AB - Rapid advance in medical technology has resulted in the availability of numerous tests and treatment strategies in the management of acute stroke. The increasingly evidence-based context of clinical medicine necessitates that clinicians use only appropriate tools to facilitate the diagnostic process and patient management. In this review, we seek to explore the use of computed tomography angiography (CTA) in the diagnosis and management of patients presenting with acute stroke (ischemic and hemorrhagic) or transient ischemic attack (TIA). We present evidence in favor of the use of CTA, highlight the disadvantages of this imaging modality, and present a heuristic model based on our experience at utilizing CTA for decision making in acute stroke and TIAs. PMID- 23983857 TI - Avoidable 30-day readmissions among patients with stroke and other cerebrovascular disease. AB - BACKGROUND: There are limited data on factors associated with 30-day readmissions and the frequency of avoidable readmissions among patients with stroke and other cerebrovascular disease. METHODS: University HealthSystem Consortium (UHC) database records were used to identify patients discharged with a diagnosis of stroke or other cerebrovascular disease at a university hospital from January 1, 2007 to December 31, 2009 and readmitted within 30 days to the index hospital. Logistic regression models were used to identify patient and clinical characteristics associated with 30-day readmission. Two neurologists performed chart reviews on readmissions to identify avoidable cases. RESULTS: Of 2706 patients discharged during the study period, 174 patients had 178 readmissions (6.4%) within 30 days. The only factor associated with 30-day readmission was the index length of stay >10 days (vs <5 days; odds ratio [OR] 2.3, 95% CI [1.4, 3.7]). Of 174 patients readmitted within 30 days (median time to readmission 10 days), 92 (53%) were considered avoidable readmissions including 38 (41%) readmitted for elective procedures within 30 days of discharge, 27 (29%) readmitted after inadequate outpatient care coordination, 15 (16%) readmitted after incomplete initial evaluations, 8 (9%) readmitted due to delayed palliative care consultation, and 4 (4%) readmitted after being discharged with inadequate discharge instructions. Only 5% of the readmitted patients had outpatient follow up recommended within 1 week. CONCLUSIONS: More than half of the 30-day readmissions were considered avoidable. Coordinated timing of elective procedures and earlier outpatient follow-up may prevent the majority of avoidable readmissions among patients with stroke and other cerebrovascular disease. PMID- 23983858 TI - ABCD2 Score and Large-Artery Atherosclerosis. AB - BACKGROUND AND PURPOSE: Extracranial stenosis (ECS) or intracranial stenosis (ICS) are independent risk factors for stroke after transient ischemic attack (TIA). We examined the association of the age, blood pressure, clinical features, duration of symptoms and diabetes (ABCD2) score, a validated risk prediction model for stroke after TIA, and the presence of ICS or ECS. METHODS: Vascular imaging and ABCD2 scores were obtained in a retrospective cohort of 77 consecutive patients diagnosed with TIA in a single center emergency department. The association between vascular stenosis and ABCD2 scores and how each related to clinical outcome was examined. RESULTS: In all, 30 (39.2%) TIA patients had 37 stenotic lesions; 15 (40.5%) stenotic lesions were ICS and 22 (59.5%) stenotic lesions were ECS. A total of 7 patients (9.5%) had both ECS and ICS lesions. Patients with ABCD2 > 3 were more likely to have ICS (odds ratio [OR] = 6.25, confidence interval [CI] 1.39-32.44, P = .009) and ECS (OR = 5.25, CI = 1.56 17.66, P = .005). Of the 37 stenotic lesions, 21 (56.7%) were symptomatic; 4 (19.2%) of these had an ABCD2 <= 3. At 7 days, there were 4 ischemic strokes, 3 had previously demonstrated symptomatic stenotic lesions, and all had ABCD2 scores > 3. CONCLUSIONS: Compared to patients in the low-risk ABCD2 scores, the patients with medium- to high-risk ABCD2 scores are more likely to have symptomatic and asymptomatic vascular stenotic lesions. However, 1 in 5 patients with low-risk ABCD2 score has symptomatic stenotic lesions, indicating ABCD2 score does not identify all patients with symptomatic stenotic lesions. PMID- 23983859 TI - CMS' Hospital-Acquired Conditions for the Neurohospitalist. AB - In 2008, the Centers for Medicare and Medicaid Services (CMS) implemented a provision that denies Medicare payment for hospital-acquired conditions (HACs). This provision brings attention to the quality of patient care and the financial impact associated with "never-events" occurring during a patient's hospitalization. Our review of HACs focuses on the 5 which are most pertinent to the neurohospitalist: stages III and IV pressure ulcers, catheter-associated urinary tract infection, vascular catheter-associated infection, manifestations of poor glycemic control, and falls resulting in fractures, dislocations, and/or intracranial injuries. We address why CMS came up with them, their impact on quality patient care and hospital finances, and how the neurohospitalist can continue to participate in the future of HAC prevention and management as they relate to one's patients, hospital, and community. PMID- 23983861 TI - Severe anemia leading to hypodensity of cerebral venous sinuses on computed tomography imaging. PMID- 23983860 TI - Inpatient management of Parkinson disease: current challenges and future directions. AB - Parkinson disease (PD) is usually managed through outpatient clinical care. Reasons for hospital admissions are either directly related to PD or may reflect comorbidities. When hospitalized, patients with PD may face many challenges. Most commonly these are related to medication management, falls, mental status changes, infections, and emergence of psychiatric symptoms. Timely recognition and proper management of PD-specific hospitalization-related problems may be delayed, given the common lack of expertise in PD management of hospital physicians, nurses, and allied health professionals. With increasing prevalence of PD, it is expected that more patients will require inpatient hospital care. It is therefore very important to recognize problems that may arise upon hospitalization of a patient with PD and provide education to health care professionals involved in the inpatient care of patients with PD. This approach may lead to reductions in complication rates and duration of hospital stays. AIM: In this review, we outline the most common reasons for hospitalization of patients with PD, discuss challenges related to inpatient hospital care of patients with PD, and comment on future directions aimed at optimizing hospitalization outcomes in the population with PD. PMID- 23983862 TI - A message from the editor in chief. PMID- 23983863 TI - Posterior circulation ischemic stroke-clinical characteristics, risk factors, and subtypes in a north Indian population: a prospective study. AB - BACKGROUND AND PURPOSE: Posterior circulation stroke accounts for approximately 20% of all strokes with varied clinical presentation, which differ from strokes in anterior circulation, with reference to etiology, clinical features, and prognosis. Short penetrating and circumferential branches in the posterior circulation supply the brain stem, thalamus, cerebellum, occipital, and medial temporal lobes. MATERIALS AND METHODS: We prospectively analyzed 80 participants of posterior circulation ischemic stroke from a registry of 944 participants attending a tertiary care referral university hospital. Patients were analyzed for demographics, stroke risk factors, clinical characteristics, neuroimaging, and stroke subtypes. RESULTS: Posterior circulation ischemic stroke accounted for 80 (8.5%) of 944 of all strokes and 80 (10.45%) of 765 of ischemic stroke. Sixty three were males with mean age 51.7 +/- 14.4 years. Twenty-one participants were young (defined as age less than 45 years). Hypertension was found to be the most common risk factor (63.75%). Vertigo was the most common clinical symptom reported in 45 (56.25%) cases. Sixty-eight (85%) patients had large artery disease, 8 (10%) had documented cardioembolic source, 3 (3.75%) small artery disease, and 2 (2.5%) vasculitis. Posterior cerebral artery was most commonly involved. Topographically distal intracranial involvement was most frequent (66.25%) followed by proximal (30%) and middle intracranial territory (3.75%). CONCLUSIONS: Our study demonatrated the occurrence of posterior circulation stroke in relatively younger age group compared to the Western world. We also found higher percentage of large artery disease, while cardioembolism as a less frequent cause of posterior circulation ischemic stroke in North Indian population. Distal territory involvement was most common in our study. PMID- 23983864 TI - Multimodal CT to Differentiate Acute Ischemic Stroke From Stroke Mimics. PMID- 23983865 TI - A 61-year-old woman with progressive weakness and rash. PMID- 23983866 TI - A descending cranial nerve palsy during the christmas holidays. PMID- 23983867 TI - The safety of lacosamide for treatment of seizures and seizure prophylaxis in adult hospitalized patients. AB - BACKGROUND: Lacosamide (LCM) is a newer antiepileptic drug (AED) with favorable properties for hospitalized patients including intravenous formulation, minimal hepatic metabolism, and no adverse respiratory effects. We sought to determine the safety profile of LCM in hospitalized patients. METHODS: We performed a retrospective medical record review of patients who received LCM between July 1, 2009, and January 31, 2010, at Mayo Clinic Hospital. Data included demographics, LCM dosing, concomitant AED therapy, documented seizure activity, hemodynamic variables, electrocardiogram (ECG), and laboratory data. Adverse drug reaction and drug-drug interactions were reviewed. RESULTS: Thirty-two patients were identified. No major hypotension or serious cardiac arrhythmias occurred. Heart rate increased, however, in seizure group compared with the prophylaxis group 2 hours postdrug infusion (median heart rate = 86 vs 164). The ECGs demonstrated a mean PR interval prolongation of about 6 milliseconds (ms) after LCM initiation (mean PR 185.5 ms, compared with baseline ECG mean of 179.3 ms). Laboratory data revealed no clinically significant changes 24 hours after LCM initiation. Three patients developed adverse events (9.4%): One with altered mental state and exceptionally prolonged ECG PR interval (212 vs 178 ms baseline); One with unexplained thrombocytopenia; and a third patient with dizziness, all of which resolved after drug discontinuation. CONCLUSION: The LCM demonstrated ECG PR prolongation as previously reported without systemic hypotension, with no discernable drug-drug interactions in hospitalized patients. About 9% of patients had transient adverse drug reactions after LCM, namely alteration in mental state, unexplained thrombocytopenia, and dizziness, which stopped after discontinuation of the drug. PMID- 23983868 TI - Impact of Protocol Deviations in Acute Ischemic Stroke Treated With Intravenous rt-PA Within 4.5 Hours After Symptom Onset. AB - BACKGROUND: There is limited experience in the community with intravenous tissue plasminogen activator (rt-PA) administered 3 to 4.5 hours after acute ischemic stroke (AIS) onset. Many patients do not meet entry criteria of pivotal clinical trials because of severe stroke, age >80, severe hypertension (sHTN), or history of previous stroke and diabetes. Whether rt-PA benefits these patients is unclear. Thus, we investigated the outcomes of stroke patients treated with rt-PA with or without these adverse clinical characteristics. METHODS: Chart review of patients with AIS treated with intravenous rt-PA at a single institution. Outcomes at discharge were compared between patients with severe stroke, age >80, sHTN, or previous stroke/diabetes and those without these characteristics. Good outcome was defined as modified Rankin score (mRS) of 0 to 1. Analysis of variance and t tests were used to compare the outcomes. RESULTS: Of the 118 cases analyzed, 103 (87%) were treated <=3 hours and 15 (13%) between 3 and 4.5 hours. Sixty-three (53%) patients had severe stroke, age >80, sHTN, or previous stroke/diabetes, whereas 55 (47%) did not. Compared to controls, patients with these adverse characteristics were less likely to have good outcomes (35% vs 56%, p = .02). No patients treated within the 3- to 4.5-hour window experienced symptomatic intracranial hemorrhage (sICH). Eight patients treated between 3 and 4.5 hours had severe stroke, age >80, sHTN, or previous stroke/diabetes. Of these, 6 had poor outcomes. CONCLUSIONS: In a highly selected group of patients treated with intravenous rt-PA, lack of adherence to current guidelines did not improve stroke outcomes. This was related to more severe strokes at baseline, not sICH. Prospective studies of this patient group are needed. PMID- 23983869 TI - Clinical characteristics and thrombolytic outcomes of infective endocarditis associated stroke. AB - OBJECTIVE: Our aim was to describe the clinical features of infective endocarditis (IE) in the acute stroke setting and outcomes following thrombolytic therapy. METHODS: This is a single-center, retrospective, descriptive case series of IE-related stroke (IES). Infective endocarditis diagnosis was based on the modified Duke criteria. RESULTS: From 2001 to 2007, 18 patients with acute stroke had definite or possible IE. Presenting stroke subtypes were: 11 ischemic stroke; 2 intracerebral hemorrhage; and 5 with a combination of ischemia and subarachnoid hemorrhage. On presentation, 6 had objective fever and 5 had subjective fever, 8 had heart murmur, and 3 had classic IE stigmata. The most common laboratory abnormalities were leukocytosis (n = 11) and anemia (n = 10). Sixteen patients had valvular vegetations on echocardiogram; 6 of 8 patients had vegetations visualized on transesophageal echocardiogram that were not detected by transthoracic echocardiogram. Two of the 3 patients with valve replacements had vegetations only on their native valves. Of 11 patients with pure ischemic stroke, 4 received thrombolytics and had hemorrhagic conversion. Overall mortality of IES was 56% (10 of 18). Mortality in pure ischemic IES patients was 29% (2 of 7, median National Institute of Health Stroke Scale [NIHSS] 13) in those not receiving thrombolytics and 75% (3 of 4, median NIHSS 14) in those receiving thrombolytics. CONCLUSIONS: Though diagnosis of IE in the acute stroke setting is difficult, features of the history, examination, and laboratory data may raise concern for IE. In this case series, thrombolytics in patients with IE associated stroke were associated with very poor outcomes. PMID- 23983870 TI - 1 and 1 is 11: New Ways to Mentor and Reorganize an Inpatient Neurosurgery Service. AB - Contemporary departments in academic medical centers face challenging obstructions to the sometimes conflicted missions of education, research, and patient care. While the ward demands of patients and families have remained stable or increased, the availability of both attending faculty and residents has often decreased due to the requirements of relative value unit production and trainee duty hour limitations. The Department of Neurological Surgery at the University of Washington has evolved a novel solution to provide senior level attending coverage and bedside mentoring to help fill these gaps. PMID- 23983872 TI - Aortogenic left middle cerebral artery ischemic stroke. PMID- 23983871 TI - Early Physical Rehabilitation in the ICU: A Review for the Neurohospitalist. AB - Advances in critical care have resulted in improved intensive care unit (ICU) mortality. However, improved ICU survival has resulted in a growing number of ICU survivors living with long-term sequelae of critical illness, such as impaired physical function and quality of life (QOL). In addition to critical illness, prolonged bed rest and immobility may lead to severe physical deconditioning and loss of muscle mass and muscle weakness. ICU-acquired weakness is associated with increased duration of mechanical ventilation and weaning, longer ICU and hospital stay, and increased mortality. These physical impairments may last for years after ICU discharge. Early Physical Medicine and Rehabilitation (PM&R) interventions in the ICU may attenuate or prevent the weakness and physical impairments occurring during critical illness. This article reviews the evidence regarding safety, feasibility, barriers, and benefits of early PM&R interventions in ICU patients and discusses the limited existing data on early PM&R in the neurological ICU and future directions for early PM&R in the ICU. PMID- 23983873 TI - A 48-year-old man with syncope and diffuse muscle twitches. PMID- 23983874 TI - Who Best to Create a Sense of Urgency for Acute Stroke Treatment? Commentary on "Neurohospitalists Improve Door-to-Needle Times for Patients With Ischemic Stroke Receiving Intravenous tPA". PMID- 23983875 TI - Neurohospitalists Improve Door-to-Needle Times for Patients With Ischemic Stroke Receiving Intravenous tPA. AB - PURPOSE: It is unknown whether neurohospitalist evaluation improves door-to needle times (DNT) in patients with acute ischemic stroke.The purpose of this study is to determine the impact of neurohospitalist evaluation on DNT for patients with ischemic stroke receiving intravenous tissue plasminogen activator (tPA) presenting within 4.5 hours of symptom onset. METHODS: We retrospectively identified consecutive patients with ischemic stroke who received tPA between 0 and 4.5 hours. We determined and compared DNT for nonneurohospitalists versus neurohospitalists for a 26-month period from 2009 to 2011. Our main outcome measure was percentage of patients receiving tPA within 60 minutes. RESULTS: Overall, out of the 107 consecutive ischemic stroke patients (mean age 67 years) who received intravenous tPA within 4.5 hours, 60 patients were evaluated by nonneurohospitalists (community and locums neurologists) and 47 patients were evaluated by neurohospitalists. Mean +/- standard deviation (SD) DNT with patients treated by nonneurohospitalists (93 +/- 24 minutes) were significantly longer than the DNT treated by neurohospitalists (68 +/- 18 minutes). Twenty-four patients (51%) treated by neurohospitalists had DNT less than or equal to 60 minutes, while 9 patients (15%) treated by nonneurohospitalists had DNT less than or equal to 60 minutes. Multivariate analysis showed that neurohospitalist evaluation (odds ratio [OR] 5.4, confidence interval [CI] 2.2-13.6, P = .022) was the only independent factor associated with patients receiving tPA within 60 minutes. CONCLUSION: Neurohospitialist evaluation is associated with faster DNT in patients with ischemic stroke. Neurohospitalist evaluation could be a part of a multidimensional initiative to improve the timeliness of tPA administration. PMID- 23983876 TI - Telemedicine in Leading US Neurology Departments. AB - OBJECTIVE: To determine the current practice and plans for telemedicine at leading US neurology departments. DESIGN AND SETTING: An electronic survey was sent to department chairs, administrators, or faculty involved in telemedicine at 47 neurology departments representing the top 50 hospitals as ranked by U.S. News and World Report. MAIN OUTCOME MEASURES: Current use, size, scope, reimbursement, and perceived quality of telemedicine services. RESULTS: A total of 32 individuals from 30 departments responded (64% response rate). The primary respondents were neurology faculty (66%) and department chairs (22%). Of the responding departments, 60% (18 of 30) currently provide telemedicine and most (n = 12) had initiated services within the last 2 years. Two thirds of those not providing telemedicine plan to do so within a year. Departments provide services to patients in state, out of state, and internationally, but only 6 departments had more than 50 consultations in the last year. The principal applications were stroke (n = 14), movement disorders (n = 4), and neurocritical care (n = 3). Most departments (n = 12) received external funding for telemedicine services, but few departments (n = 3) received payment from insurers (eg, Medicare, Medicaid). Reimbursement (n = 21) was the most frequently identified barrier to implementing telemedicine services. The majority of respondents (n = 20) find telemedicine to be equivalent to in-person care. CONCLUSIONS: Over 85% of leading US neurology departments currently use or plan to implement telemedicine within the next year. Addressing reimbursement may allow for its broader application. PMID- 23983877 TI - Acute loss of bladder control in a stroke of the frontal cortex. AB - Lesions of the medial frontal micturition center can result in the activation of the pontine and spinal micturition centers when the bladder is full, causing urinary incontinence. Recognition of acute bladder incontinence as part of a cortical hemispheric stroke syndrome may reduce the likelihood of false localization to the spinal cord in patients with acute ischemic stroke eligible for acute reperfusion therapy. We describe a case of urinary incontinence due to anterior cerebral artery infarction and discuss the cortical localization of voluntary bladder control to the anterior cingulate gyrus, inferior frontal gyrus, middle frontal gyrus, and superior frontal gyrus. PMID- 23983879 TI - Sepsis: a review for the neurohospitalist. AB - Sepsis represents a major challenge in medicine. It begins as a systemic response to infection that can affect virtually any organ system, including the central and peripheral nervous systems. Akin to management of stroke, early recognition and treatment of sepsis are just as crucial to a successful outcome. Sepsis can precipitate myasthenic crisis and lead to encephalopathy and critical illness neuropathy. Stroke and traumatic brain injury can predispose a patient to develop sepsis, whereas Guillain-Barre syndrome is similarly not uncommon following infection. This review article will first describe the essential principles of sepsis recognition, pathophysiology, and management and will then briefly cover the neurologic aspects associated with sepsis. Vigilant awareness of the clinical features of sepsis and timeliness of intervention can help clinicians prevent progression of this disease to a multisystem organ failure, which can be difficult to reverse even after the original source of infection is under control. PMID- 23983878 TI - Future neurohospitalist: teleneurohospitalist. AB - Despite the growing demand for emergency neurological evaluations and neurohospitalists, the supply of neurologists remains relatively fixed over time. Telemedicine is a unique tool that has the ability to put a medical specialist like a neurologist in 2 places in a relatively short period of time, expanding expertise in many rural and in some underserved urban facilities that would ordinarily be devoid of such expertise. Teleneurology is a branch of telemedicine that consults and practices through remote neurological evaluation. Telestroke is defined as remote stroke evaluation. The demand for timely neurological evaluation, especially acute stroke evaluation and treatment with intravenous recombinant tissue plasminogen activator (IV rtPA), continues to fuel the growth of neurohospitalists, telestroke, and teleneurology services. Remote, rural, or underserved urban emergency departments and hospitals which are unable to successfully recruit a neurologist or neurohospitalist to provide this service are uniquely suited to a teleneurology option. The number of private practices and academic centers providing telestroke services has grown significantly in the past decade with continued growth expected. We describe the benefits and drawbacks of teleneurology/telestroke, as well as other practical aspects for the teleneurohospitalist. PMID- 23983880 TI - Portable head computed tomography in the diagnosis of cerebral fat embolism secondary to cardiac surgery. AB - BACKGROUND AND PURPOSE: Cerebral fat embolism (CFE) has been diagnosed previously by both brain magnetic resonance imaging (MRI) and dedicated head computed tomography (HCT) studies. The most commonly reported feature on CT is the presence of the "hypodense artery sign," although the number of reported cases has been minimal to date. METHODS: Report of a single case involving a 88-year old patient who underwent cardiac surgery. Postoperatively, the patient developed right hemiparesis. Contraindications existed for performing brain MRI and dedicated head CT. Portable head CT (pHCT) was obtained. Hounsfield unit measurement was used. RESULTS: A hypodense artery sign was visualized, and Hounsfield unit measurement indicated fat density. Diagnosis was determined to be CFE. CONCLUSION: This case report emphasizes that pHCT quality may be sufficient to diagnose CFE and offers a viable alternative when MRI or HCT is contraindicated. PMID- 23983881 TI - Diagnostic dilemma of a young man with Fever and headaches. PMID- 23983882 TI - The use of neuroimaging studies and neurological consultation to evaluate dizzy patients in the emergency department. AB - BACKGROUND AND PURPOSE: Dizziness is a frequent reason for neuroimaging and neurological consultation, but little is known about the utility of either practice. We sought to characterize the patterns and yield of neuroimaging and neurological consultation for dizziness in the emergency department (ED). METHODS: We retrospectively identified consecutive adults presenting to an academic ED from 2007 to 2009, with a primary complaint of dizziness, vertigo, or imbalance. Neurologists reviewed medical records to determine clinical characteristics, whether a neuroimaging study (head computed tomography [CT] or brain magnetic resonance imaging [MRI]) or neurology consultation was obtained in the ED, and to identify relevant findings on neuroimaging studies. Two neurologists assigned a final diagnosis for the cause of dizziness. Logistic regression was used to evaluate bivariate and multivariate predictors of neuroimaging and consultation. RESULTS: Of 907 dizzy patients (mean age 59 years; 58% women), 321 (35%) had a neuroimaging study (28% CT, 11% MRI, and 4% both) and 180 (20%) had neurological consultation. Serious neurological disease was ultimately diagnosed in 13% of patients with neuroimaging and 21% of patients with neurological consultation, compared to 5% of the overall cohort. Headache and focal neurological deficits were associated with both neuroimaging and neurological consultation, while age >=60 years and prior stroke predicted neuroimaging but not consultation, and positional symptoms predicted consultation but not neuroimaging. CONCLUSION: In a tertiary care ED, neuroimaging and neurological consultation were frequently utilized to evaluate dizzy patients, and their diagnostic yield was substantial. PMID- 23983883 TI - Enhancing brain lesions in a renal transplant patient. AB - Neurologists should be familiar with the spectrum of central nervous system (CNS) pathology that renal transplants patients are prone to. We are presenting a case of posttransplant lymphoproliferative disorder of the CNS to highlight less commonly described imaging findings and review this disease entity. PMID- 23983884 TI - Pneumococcal meningitis, cerebral venous thrombosis, and cervical arterial dissection: a run of bad luck? AB - BACKGROUND: Pneumococcal meningitis in adults is widely associated with intracranial complications, which occur in up to 74.7% of the patients. METHOD: Case report. RESULTS: We report the case of a 40-year-old white female with pneumococcal meningitis after a sinus surgery, who developed a concomitant cerebral venous thrombosis and multiple cervical artery dissections. Following treatment with antibiotics and intravenous heparin, she had complete neurological recovery. CONCLUSIONS: Vascular complications should always be remembered and adequately treated in patients with bacterial meningitis. Cervical arterial dissections should be investigated as potential embolic sources of intracranial ischemic lesions. PMID- 23983886 TI - Ventilatory management and extubation criteria of the neurological/neurosurgical patient. AB - Approximately 200 000 patients per year will require mechanical ventilation secondary to neurological injury or disease. The associated mortality, morbidity, and costs are significant. The neurological patient presents a unique set of challenges to airway management, mechanical ventilation, and defining extubation readiness. Neurological injury and disease can directly or indirectly involve the process involved with respiration or airway control. This article will review the basics of airway management and mechanical ventilation in the neurological patient. The current state of the literature evaluating extubation criteria in the neurological patient will also be reviewed. PMID- 23983887 TI - Evolution of hypoxic-ischemic injury. PMID- 23983885 TI - Neurological complications of transplantation: part I: hematopoietic cell transplantation. AB - Hematopoietic cell transplantation (HCT) is the preferred treatment for an expanding range of neoplastic and nonmalignant conditions. Increasing numbers of solid organ transplantations (SOTs) add an additional population of immunosuppressed patients with multiple potential neurological problems. While the spectrum of neurological complications varies with conditioning procedure and hematopoietic cell or solid organ source, major neurological complications occur with all transplantation procedures. This 2 part review emphasizes a practical consultative approach to central and peripheral nervous system problems related to HCT or SOT with clinical and neuroimaging examples from the authors' institutional experience with the following conditions: the diversity of manifestations of common infections such as varicella zoster virus, Aspergillus, and progressive multifocal leukoencephalopathy (PML), drug therapy-related complications, stroke mechanisms, the spectrum of graft versus host disease (GVHD), and neurologically important syndromes of immune reconstitution inflammatory syndrome (IRIS), posterior reversible encephalopathy syndrome (PRES), and posttransplantation lymphoproliferative disorder (PTLD). These complications preferentially occur at specific intervals after HCT and SOT, and neurological consultants must recognize an extensive spectrum of syndromes in order to effect timely diagnosis and expedite appropriate treatment. PMID- 23983888 TI - Paraneoplastic and other autoimmune disorders of the central nervous system. AB - As a result of the burgeoning growth of disease-specific neural autoantibody markers available for diagnostic patient evaluation, there has been increasing awareness of autoimmune central nervous system (CNS) disorders in hospital practice. Hospital-based neurologists have also taken great interest in these disorders since many occur in the setting of an occult systemic cancer which can be detected and treated at an early stage, and many affected patients are responsive to immunotherapy. Associated neurological disorders are typically subacute in onset, some are common or classic (eg, limbic encephalitis, cerebellar degeneration), but others have atypical or multifocal presentations. For patients with a suspected paraneoplastic disorder, many and costly oncological evaluations may be required for diagnosis. Comprehensive serological and cerebrospinal fluid (CSF) evaluation for neural autoantibodies may permit a focused cancer evaluation (eg, antineuronal nuclear antibody type 1 [ANNA-1] is associated with small cell lung carcinoma), and in some circumstances may indicate the likelihood of a good response to therapy (eg, voltage-gated potassium channel complex antibody) or poor neurological prognosis (eg, purkinje cell cytoplasmic antibody type 1 [antiYo]). Positron-emission tomography-computed tomography (PET-CT) imaging of trunk may increase the diagnostic yield for certain cancers where other modalities have been negative. For some patients, rapid treatment with immunotherapy may facilitate marked improvement, or full recovery; multiple sequential trials of one or more of steroids, intravenous immunoglobulin or plasma exchange, or combination therapy are often required. For patients with N-methyl-d-aspartate receptor antibody encephalitis, early treatment with immunosuppressants and weeks or months of supportive intensive care may additionally be required. One or more of clinical examination, electroencephalogram (including video telemetry), and imaging provide objective parameters to which posttreatment outcomes can be compared. PMID- 23983890 TI - Fulminant demyelinating diseases. AB - Fulminant demyelinating disease is a heading that covers acute disseminated encephalomyelitis and its variant acute hemorrhagic leukoencephalitis (Hurst disease), severe relapses of multiple sclerosis (MS), variants of MS (tumefactive MS, Marburg variant, Balo concentric sclerosis, myelinoclastic diffuse sclerosis), and neuromyelitis optica-spectrum disorders associated with aquaporin autoimmunity. These categories of inflammatory demyelinating disease often prompt hospital admission and many necessitate intensive care monitoring due to the aggressive nature of the illness and associated neurologic morbidity. In this review, we highlight the discriminating clinical, radiographic, and pathologic features of these disorders. Acute management is often accomplished with use of high-dose intravenous steroids and plasma exchange. Aggressive disease may respond to immunosuppression. Prognosis for recovery varies among the disorders but most patients improve. Factors influencing outcome are also discussed. PMID- 23983892 TI - Variant lateral medullary syndrome in a patient presenting with inability to swallow. PMID- 23983891 TI - Glucocorticoids: complications to anticipate and prevent. AB - Glucocorticoids (GCs) are widely used for inflammatory and autoimmune diseases. Their mechanism of action is most commonly rooted in genomic effects that have both beneficial and adverse consequences. The purpose of this review is to discuss the potential complications and side effects that may occur with GC use. Many of these complications are related to the dose and duration of therapy used. Evidence-based preventative strategies are discussed. Many recommendations are based on expert opinion and not on strong evidence. A 54-year-old man presents with proximal upper and lower extremity weakness. There are no rashes. The antinuclear antibody is negative; the erythrocyte sedimentation rate and C reactive protein are 24 mm/h and 3 mg/dL, respectively. An electromyography displays myopathic motor unit potentials with fibrillation and a muscle biopsy confirms polymyositis. Prednisone of 60 mg/d is initiated. What are the risks associated with GC use? What other studies and interventions should occur in this patient starting long-term GC therapy? PMID- 23983893 TI - Cerebral amyloid angiopathy with asymmetric superficial hemosiderosis and transient focal neurological symptoms. PMID- 23983889 TI - Updates on clinically isolated syndrome and diagnostic criteria for multiple sclerosis. AB - Clinically isolated syndrome (CIS) is a central nervous system demyelinating event isolated in time that is compatible with the possible future development of multiple sclerosis (MS). Early risk stratification for conversion to MS helps with treatment decisions. Magnetic resonance imaging (MRI) is currently the most useful tool to evaluate risk. Cerebrospinal fluid studies and evoked potentials may also be used to assess the likelihood of MS. Four clinical trials evaluating the benefits of either interferon beta (IFN-beta) or glatiramer acetate (GA) within the first 3 months after a high-risk CIS demonstrate decreased rates of conversion to clinically definite MS (CDMS) and a lesser degree of MRI progression with early treatment. In the 3-, 5-, and 10-year extension studies of 2 formulations of IFN-beta, the decreased conversion rate to CDMS remained meaningful when comparing early treatment of CIS to treatment delayed by a median of 2 to 3 years. Diagnostic criteria have been developed based on the clinical and MRI follow-up of large cohorts with CIS and provide guidance on how to utilize clinical activity in combination with radiographic information to diagnose MS. The most recent 2010 McDonald criteria simplify requirements for dissemination in time and space and allow for diagnosis of MS from a baseline brain MRI if there are both silent gadolinium-enhancing lesions and nonenhancing lesions on the same imaging study. The diagnostic criteria for MS require special consideration in children at risk for acute disseminated encephalomyelitis (ADEM), in older adults who may have small vessel ischemic disease, and in ethnic groups that more commonly develop neuromyelitis optica (NMO). PMID- 23983894 TI - A 20-year-old woman with headache and transient numbness. PMID- 23983895 TI - Effects of resveratrol on daily rhythms of locomotor activity and body temperature in young and aged grey mouse lemurs. AB - In several species, resveratrol, a polyphenolic compound, activates sirtuin proteins implicated in the regulation of energy balance and biological clock processes. To demonstrate the effect of resveratrol on clock function in an aged primate, young and aged mouse lemurs (Microcebus murinus) were studied over a 4 week dietary supplementation with resveratrol. Spontaneous locomotor activity and daily variations in body temperature were continuously recorded. Reduction in locomotor activity onset and changes in body temperature rhythm in resveratrol supplemented aged animals suggest an improved synchronisation on the light-dark cycle. Resveratrol could be a good candidate to restore the circadian rhythms in the elderly. PMID- 23983896 TI - Hemeoxygenase-1 mediates an adaptive response to spermidine-induced cell death in human endothelial cells. AB - Spermidine (SPD) is a ubiquitous polycation that is commonly distributed in living organisms. Intracellular levels of SPD are tightly regulated, and SPD controls cell proliferation and death. However, SPD undergoes oxidation in the presence of serum, producing aldehydes, hydrogen peroxide, and ammonia, which exert cytotoxic effect on cells. Hemeoxygenase-1 (HO-1) is thought to have a protective effect against oxidative stress. Upregulation of HO-1 in endothelial cells is considered to be beneficial in the cardiovascular disease. In the present study, we demonstrate that the ubiquitous polyamine, SPD, induces HO-1 in human umbilical vein endothelial cells (HUVECs). SPD-induced HO-1 expression was examined by Western blot and reverse transcription-polymerase chain reaction (RT PCR). Involvement of reactive oxygen species, serum amine oxidase, PI3K/Akt signaling pathway, and transcription factor Nrf2 in the induction of HO-1 by SPD was also investigated. Furthermore, small interfering RNA knockdown of Nrf2 or HO 1 and treatment with the specific HO-1 inhibitor ZnPP exhibited a noteworthy increase of death of SPD-stimulated HUVECs. In conclusion, these results suggest that SPD induces PI3K/Akt-Nrf2-mediated HO-1 expression in human endothelial cells, which may have a role in cytoprotection of the cells against oxidative stress-induced death. PMID- 23983897 TI - Oxidative stress and the pathogenesis of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia in the elderly. Patients with AD suffer a gradual deterioration of memory and other cognitive functions, which eventually leads to a complete incapacity and death. A complicated array of molecular events has been implicated in the pathogenesis of AD. The major pathological characteristics of AD brains are the presence of senile plaques, neurofibrillary tangles, and neuronal loss. Growing evidence has demonstrated that oxidative stress is an important factor contributing to the initiation and progression of AD. However, the mechanisms that lead to the disruption of redox balance and the sources of free radicals remain elusive. The excessive reactive oxygen species may be generated from mechanisms such as mitochondria dysfunction and/or aberrant accumulation of transition metals, while the abnormal accumulation of Abeta and tau proteins appears to promote the redox imbalance. The resulted oxidative stress has been implicated in Abeta- or tau-induced neurotoxicity. In addition, evidence has suggested that oxidative stress may augment the production and aggregation of Abeta and facilitate the phosphorylation and polymerization of tau, thus forming a vicious cycle that promotes the initiation and progression of AD. PMID- 23983898 TI - Sulforaphane as a potential protective phytochemical against neurodegenerative diseases. AB - A wide variety of acute and chronic neurodegenerative diseases, including ischemic/traumatic brain injury, Alzheimer's disease, and Parkinson's disease, share common characteristics such as oxidative stress, misfolded proteins, excitotoxicity, inflammation, and neuronal loss. As no drugs are available to prevent the progression of these neurological disorders, intervention strategies using phytochemicals have been proposed as an alternative form of treatment. Among phytochemicals, isothiocyanate sulforaphane, derived from the hydrolysis of the glucosinolate glucoraphanin mainly present in Brassica vegetables, has demonstrated neuroprotective effects in several in vitro and in vivo studies. In particular, evidence suggests that sulforaphane beneficial effects could be mainly ascribed to its peculiar ability to activate the Nrf2/ARE pathway. Therefore, sulforaphane appears to be a promising compound with neuroprotective properties that may play an important role in preventing neurodegeneration. PMID- 23983900 TI - Polyphenols in exercise performance and prevention of exercise-induced muscle damage. AB - Although moderate physical exercise is considered an essential component of a healthy lifestyle that leads the organism to adapt itself to different stresses, exercise, especially when exhaustive, is also known to induce oxidative stress, inflammation, and muscle damage. Many efforts have been carried out to identify dietary strategies or micronutrients able to prevent or at least attenuate the exercise-induced muscle damage and stress. Unfortunately most studies have failed to show protection, and at the present time data supporting the protective effect of micronutrients, as antioxidant vitamins, are weak and trivial. This review focuses on those polyphenols, present in the plant kingdom, that have been recently suggested to exert some positive effects on exercise-induced muscle damage and oxidative stress. In the last decade flavonoids as quercetin, catechins, and other polyphenols as resveratrol have caught the scientists attention. However, at the present time drawing a clear and definitive conclusion seems to be untimely. PMID- 23983901 TI - Nitro-oxidative stress after neuronal ischemia induces protein nitrotyrosination and cell death. AB - Ischemic stroke is an acute vascular event that obstructs blood supply to the brain, producing irreversible damage that affects neurons but also glial and brain vessel cells. Immediately after the stroke, the ischemic tissue produces nitric oxide (NO) to recover blood perfusion but also produces superoxide anion. These compounds interact, producing peroxynitrite, which irreversibly nitrates protein tyrosines. The present study measured NO production in a human neuroblastoma (SH-SY5Y), a murine glial (BV2), a human endothelial cell line (HUVEC), and in primary cultures of human cerebral myocytes (HC-VSMCs) after experimental ischemia in vitro. Neuronal, endothelial, and inducible NO synthase (NOS) expression was also studied up to 24 h after ischemia, showing a different time course depending on the NOS type and the cells studied. Finally, we carried out cell viability experiments on SH-SY5Y cells with H2O2, a prooxidant agent, and with a NO donor to mimic ischemic conditions. We found that both compounds were highly toxic when they interacted, producing peroxynitrite. We obtained similar results when all cells were challenged with peroxynitrite. Our data suggest that peroxynitrite induces cell death and is a very harmful agent in brain ischemia. PMID- 23983899 TI - The proapoptotic effect of traditional and novel nonsteroidal anti-inflammatory drugs in mammalian and yeast cells. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used to treat pain, fever, and inflammation. However, mounting evidence shows that NSAIDs, such as aspirin, have very promising antineoplastic properties. The chemopreventive, antiproliferative behaviour of NSAIDs has been associated with both their inactivation of cyclooxygenases (COX) and their ability to induce apoptosis via pathways that are largely COX-independent. In this review, the various proapoptotic pathways induced by traditional and novel NSAIDs such as phospho NSAIDs, hydrogen sulfide-releasing NSAIDs and nitric oxide-releasing NSAIDs in mammalian cell lines are discussed, as well as the proapoptotic effects of NSAIDs on budding yeast which retains the hallmarks of mammalian apoptosis. The significance of these mechanisms in terms of the role of NSAIDs in effective cancer prevention is considered. PMID- 23983904 TI - Fulminant Clostridium difficile infection: An association with prior appendectomy? AB - AIM: To examine if fulminant Clostridium difficile infections (CDI) resulting in colectomy was associated with a prior appendectomy and whether any association affected the severity of the disease. METHODS: A retrospective chart review was performed on patients who underwent colectomy for CDI between 2001 and 2011. The appendectomy rate was calculated based on the absence of an appendix on the surgical pathology report. This was compared to an established lifetime risk of appendectomy in the general population. A chart review was performed for mortality and traditional markers of CDI disease severity. Fisher's exact test was used to calculate the likelihood of association between prior appendectomy, mortality, and clinical markers of severity of infection. RESULTS: Fifty-five specimens were identified with pseudomembranous colitis consistent with CDI. All patients had a clinical history consistent with CDI and 45 of 55 (81.8%) specimens also had microbiological confirmation of CDI. Appendectomy was observed in 24 of 55 specimens (0.436, 99%CI: 0.280-0.606). This was compared to the lifetime incidence of appendectomy of 17.6%. The rate of appendectomy in our sample was significantly higher than would be expected in the general population (43.6% vs 17.6%, P < 0.01). Disease severity did not differ based on presence or absence of an appendix and no association was detected between prior appendectomy and mortality (OR = 0.588, 95%CI: 0.174-1.970). CONCLUSION: The rate of appendectomy in the patients whose CDI led to colectomy, was significantly higher than the calculated lifetime risk, suggesting an association of appendectomy and severe CDI resulting in colectomy. Larger prospective studies are needed to assess any potential causal relationships affecting fulminant CDI. PMID- 23983903 TI - Brazilian green propolis suppresses the hypoxia-induced neuroinflammatory responses by inhibiting NF-kappaB activation in microglia. AB - Hypoxia has been recently proposed as a neuroinflammatogen, which drives microglia to produce proinflammatory cytokines, including interleukin-1beta (IL 1beta), tumor necrosis factor-alpha (TNF-alpha), and IL-6. Considering the fact that propolis has hepatoprotective, antitumor, antioxidative, and anti inflammatory effects, propolis may have protective effects against the hypoxia induced neuroinflammatory responses. In this study, propolis (50 MUg/mL) was found to significantly inhibit the hypoxia-induced cytotoxicity and the release of proinflammatory cytokines, including IL-1beta, TNF-alpha, and IL-6, by MG6 microglia following hypoxic exposure (1% O2, 24 h). Furthermore, propolis significantly inhibited the hypoxia-induced generation of reactive oxygen species (ROS) from mitochondria and the activation of nuclear factor-kappaB (NF-kappaB) in microglia. Moreover, systemic treatment with propolis (8.33 mg/kg, 2 times/day, i.p.) for 7 days significantly suppressed the microglial expression of IL-1beta, TNF-alpha, IL-6, and 8-oxo-deoxyguanosine, a biomarker for oxidative damaged DNA, in the somatosensory cortex of mice subjected to hypoxia exposure (10% O2, 4 h). These observations indicate that propolis suppresses the hypoxia induced neuroinflammatory responses through inhibition of the NF-kappaB activation in microglia. Furthermore, increased generation of ROS from the mitochondria is responsible for the NF-kappaB activation. Therefore, propolis may be beneficial in preventing hypoxia-induced neuroinflammation. PMID- 23983902 TI - SOD1 and DJ-1 converge at Nrf2 pathway: a clue for antioxidant therapeutic potential in neurodegeneration. AB - Neurodegenerative diseases share diverse pathological features and among these oxidative stress (OS) plays a leading role. Impaired activity and reduced expression of antioxidant proteins have been reported as common events in several aging-associated disorders. In this review paper, we first provide an overview of the involvement of reactive oxygen species- (ROS-) induced oxidative damage in Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Subsequently, we focus on DJ-1 and SOD1 proteins, which are involved in PD and ALS and also exert a prominent role in the interaction between redox homeostasis and neurodegeneration. Interestingly, recent studies demonstrated that DJ-1 and SOD1 are both tightly connected with Nrf2 protein, a transcriptional factor and master regulator of the expression of many antioxidant/detoxification genes. Nrf2 is emerging as a key neuroprotective protein in neurodegenerative diseases, since it helps neuronal cells to cope with toxic insults and OS. We herein summarize the recent literature providing a detailed picture of the promising therapeutic efficacy of Nrf2 natural and synthetic inducers as disease-modifying molecules for the treatment of neurodegenerative diseases. PMID- 23983905 TI - Small bowel carcinoid: Location isn't everything! AB - AIM: To investigate the prognostic significance of the primary site of disease for small bowel carcinoid (SBC) using a population-based analysis. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was queried for histologically confirmed SBC between the years 1988 and 2009. Overall survival (OS) and disease-specific survival (DSS) were analyzed using the Kaplan-Meier method and compared using Log rank testing. Log rank and multivariate Cox regression analyses were used to identify predictors of survival using age, year of diagnosis, race, gender, tumor histology/size/location, tumor-node-metastasis stage, number of lymph nodes (LNs) examined and percent of LNs with metastases. RESULTS: Of the 3763 patients, 51.2% were male with a mean age of 62.13 years. Median follow-up was 50 mo. The 10-year OS and DSS for duodenal primaries were significantly better when compared to jejunal and ileal primaries (P = 0.02 and < 0.0001, respectively). On multivariate Cox regression analysis, after adjusting for multiple factors, primary site location was not a significant predictor of survival (P = 0.752 for OS and P = 0.966 DSS) while age, number of primaries, number of LNs examined, T-stage and M-stage were independent predictors of survival. CONCLUSION: This 21-year, population-based study of SBC challenges the concept that location of the primary lesion alone is a significant predictor of survival. PMID- 23983906 TI - Comparison between open and laparoscopic reversal of Hartmann's procedure for diverticulitis. AB - AIM: To compare the open and laparoscopic Hartmann's reversal in patients first treated for complicated diverticulitis. METHODS: Forty-six consecutive patients with diverticular disease were included in this retrospective, single-center study of a prospectively maintained colorectal surgery database. All patients underwent conventional Hartmann's procedures for acute complicated diverticulitis. Other indications for Hartmann's procedures were excluded. Patients underwent open (OHR) or laparoscopic Hartmann's reversal (LHR) between 2000 and 2010, and received the same pre- and post-operative protocols of cares. Operative variables, length of stay, short- (at 1 mo) and long-term (at 1 and 3 years) post-operative complications, and surgery-related costs were compared between groups. RESULTS: The OHR group consisted of 18 patients (13 males, mean age +/- SD, 61.4 +/- 12.8 years), and the LHR group comprised 28 patients (16 males, mean age 54.9 +/- 14.4 years). The mean operative time and the estimated blood loss were higher in the OHR group (235.8 +/- 43.6 min vs 171.1 +/- 27.4 min; and 301.1 +/- 54.6 mL vs 225 +/- 38.6 mL respectively, P = 0.001). Bowel function returned in an average of 4.3 +/- 1.7 d in the OHR group, and 3 +/- 1.3 d in the LHR group (P = 0.01). The length of hospital stay was significantly longer in the OHR group (11.2 +/- 5.3 d vs 6.7 +/- 1.9 d, P < 0.001). The 1 mo complication rate was 33.3% in the OHR (6 wound infections) and 3.6% in the LHR group (1 hemorrhage) (P = 0.004). At 12 mo, the complication rate remained significantly higher in the OHR group (27.8% vs 10.7%, P = 0.03). The anastomotic leak and mortality rates were nil. At 3 years, no patient required re intervention for surgical complications. The OHR procedure had significantly higher costs (+56%) compared to the LHR procedure, when combining the surgery related costs and the length of hospital stay. CONCLUSION: LHR appears to be a safe and feasible procedure that is associated with reduced hospitality stays, complication rates, and costs compared to OHR. PMID- 23983907 TI - Successful bowel surgery at hemoglobin 2 g/dL without blood transfusion. AB - We were unable to find reports in the published medical literature of any cases of bowel surgery being successfully performed at such a low hemoglobin level, without blood transfusion or blood products pre or post-surgery, with the patient's uncomplicated recovery. This study is about such a case. A patient presenting with severe gastrointestinal bleeding was diagnosed with enteric fever and multiple ileal ulcers. He had an extremely low hemoglobin level (2 g/dL) and mild renal and hepatic impairment. He was immediately admitted for right hemicolectomy under general anesthesia though he refused transfusion of blood or blood products prior to, during, or after surgery on religious grounds (Jehovah's Witnesses). After the surgery and having survived these potentially life threatening circumstances, he left the hospital without major complications. In such circumstances, lives may be saved by prompt clinical decision-making, collaboration and swift surgical intervention coupled with the immediate consultation and input of the patient and family. PMID- 23983908 TI - Short-term effects of ivabradine in patients with chronic stable ischemic heart disease. AB - INTRODUCTION: Ivabradine is a novel selective If current inhibitor with anti ischemic and antianginal activity. OBJECTIVES: To assess the effect of the selective If current inhibitor ivabradine on heart rate, angina pectoris, and functional capacity in stable patients with chronic coronary artery disease on maximally tolerated medical therapy. MATERIALS AND METHODS: Consecutive patients from the out-patient cardiology clinic with stable coronary artery disease documented by coronary angiography were included. Patients had to be on maximally tolerated medical therapy with beta-blockers, angiotensin-converting enzyme inhibitors or receptor blockers (ACE-I or ARB), antiplatelets, statins, nitrates, and anti-metabolics with a baseline heart rate of at least 70 beats per minute. All patients underwent assessment of angina (Canadian Cardiovascular Society Angina Class: CCS I to IV) and functional capacity (using a validated self administered questionnaire), at baseline and after 4 months of ivabradine therapy. RESULTS: Twenty patients were enrolled (mean age 47 +/- 7 years, all male, 60% with hypertension, 30% with diabetes mellitus). Patients were on optimal medical regimen of aspirin (100%), beta-blocker (100%), statins (100%), clopidogrel (90%), nitrates (35%), anti-metabolics (90%), and ACE-I or ARB (95%). At baseline, the majority of patients (90%) were in CCS class II-IV. All patients were started on ivabradine 5 mg twice daily, and in 12 patients the dose was increased to 7.5 mg twice daily. After 4 months of treatment, the heart rate was significantly reduced from an average of 82 +/- 8 to 68 +/- 6 bpm (P < 0.001). The reduction in heart rate was accompanied by a significant improvement in functional capacity (score 3.5 +/- 0.9 to 4.7 +/- 0.7, P < 0.001) and angina classification; at baseline 10% of the patients were in CCS class I compared to 50% after 4 months of therapy (P = 0.01). No symptomatic bradycardia was reported with ivabradine. CONCLUSION: The addition of ivabradine to optimal medical therapy in patients with stable coronary artery disease is associated with significant improvement in anginal symptoms and functional capacity. PMID- 23983909 TI - Guidewires used in first intentional single wiring strategy for chronic total occlusions of the left anterior descending coronary artery. AB - BACKGROUND: Percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) of the left anterior descending (LAD) specifically is associated with improved long-term 5 year survival as compared to PCI failure. The procedure is associated with usage of different types of dedicated guidewires by simple or complex techniques aiming to reopen the occluded artery. AIM: To describe types and outcome of guidewires used in LAD-CTO utilizing a first intentional single wiring simple strategy. METHODS: A single center prospective registry for all consecutive patients with a PCI attempt to a native LAD CTO. The initial strategy for lesion crossing was Single wiring. RESULTS: A total of 30 patients with LAD CTO lesions (100%), were recorded. Mean age was 71.6 + 15 years, 77% were Males, risk factors Hypertension in 63%, Diabetes 27%, Dyslipidemia 57%, smoking 40%, hereditary in 13% of patients. Isolated guidewire (GW) success rate was very high 93%. Single wiring was the prevailing technique used in 97% of successfull lesions (83% of total cases) while only 3% were by multiple wiring techniques. Successful single antegrade wiring represented 63% with a GW success rate of 92% of cases. Successful single retrograde wiring represented 13% with a GW success rate of 67%. Successful Crossing GW types in our patients were 44% Soft Tapered GWs; fielder XT (44%), 36% were Soft Non Tapered Pilot 50 (28%), whisper (8%), while 16% were Stiff Non tapered GWs; Miracle 12 (8%), Miracle 6 (4%), Miracle 3 (4%), and 4% were Stiff Tapered GWs; Progress 200 (4%). CONCLUSIONS: Single wiring as an initial strategy in PCI for LAD-CTO lesions has a high success rate and is associated with a 44% majority of Soft Tapered GWs, 36% Soft Non Tapered, 16% Stiff Non tapered GWs, and 4% Stiff Tapered GWs. PMID- 23983910 TI - Intracoronary Reopro during Percutaneous Coronary Intervention in Acute and Stable Patient can Influence Stent Thrombosis Formation (IRPASST) Study. AB - BACKGROUND: In patients with acute myocardial infarction or unstable angina undergoing coronary angioplasty, abciximab reduces major adverse cardiac events (MACE). Most clinical trials have studied mainly intravenous administration. Intracoronary (IC) bolus application of abciximab causes very high local drug concentrations and may be more effective in reducing acute and sub-acute stent thrombosis (ST). We studied whether IC bolus administration of abciximab is associated with a reduced ST and target vessels revascularization (TVR); therefore, less MACE rate compared with the standard intravenous IV bolus and infusion application. MATERIALS AND METHODS: This was a single-center observational study conducted between June 2007 and 2009. We studied a total of 447 patients admitted with either acute coronary intervention (PCI) and stenting. Patients with bleeding disorder, recent major surgery and high blood pressure were excluded. Patients were divided into two groups: Group I (n = 199) patient received IC bolus of abciximab (reopro) 0.25 MUg/kg during the PCI in cath lab. Group II (n = 248) received the standard dose of reopro-a bolus intravenous 0.25 MUg/kg and maintenance dose of 0.125 MUg/kg over 12 h. RESULTS: There were no differences between the groups with regard to diabetes mellitus, group I (56%) vs. group II (58%), P = 0.613; ACS, group I (38%) vs. group II (44%), P = 0.175; Dietthylstilbestrol Drug eluted stent (DES) in group I (66.5%) vs. (57.6%) group II, P = 0.056; Bare Metal Stent (BMS) in group I (33%) vs. (40.7%) group II, P=0.093; target vessel revascularization (TRV) was seen in 9 patients (4%) in group I vs. 16 patients (6%) in group II. ST elevation was seen in 4 patients (2%) in group I vs. 7 patients (2.8%) in group II, all presented with STEMI. CONCLUSION: In this study, there was a trend toward less ST and TVR in patients who received IC reopro vs. intravenous route both in ACS and stable CAD. The percentage of DM was high in both groups (56%), especially in Saudi patients. In stent restenosis (ISR) was less in group I than in group II, this was mainly associated with BMS usage. The percentage of BMS was more than 30% in both groups, either due to STEMI cases or large vessel size. Randomized controlled trials are warranted to further assess IC application of abciximab in reducing ST. PMID- 23983911 TI - Right Ventricle Myocardial Performance Index Versus Simpson's Right Ventricle Ejection Fraction in Patients with Isolated Left Ventricle Anterior Myocardial Infarction. AB - INTRODUCTION: Right ventricle (RV) dysfunction may be secondary to left ventricle (LV) dysfunction in patients of isolated left ventricle anterior myocardial infarction as a consequence of "Ventricular Interdependence". As RV dysfunction is associated with high in-hospital morbidity and mortality, early recognization of RV dysfunction is warranted; but until today it remains a challenging task because of complex structure and asymmetric shape of RV. AIMS AND OBJECTIVES: Our aim in the present study was to compare Simpson's right ventricle ejection fraction (RVEF) with right ventricle myocardial performance index (RV-MPI) to predict RV function in patients with isolated left ventricle anterior myocardial infarction (LV-AMI). MATERIALS AND METHODS: We conducted the present study at the Department of Cardiology of Jawahar Lal Nehru Medical College and Associate Group of Hospitals, Ajmer. The control group comprised of twenty five. Age, sex, BMI, pulse and blood pressure matched healthy subjects without history of heart disease, systemic hypertension, diabetes, any other systemic illness and with normal findings in resting and exercise ECG, Echocardiography and Coronary Angiography. Sub-group-1 consisted of 25 patients with hemodynamically significant stenosis of proximal left anterior descending artery (LAD) with patent first septal perforator (S1). Sub-group-2 was composed of s5 patients with hemodynamically significant stenosis of both LAD and left circumflex artery (LCx.). Both subgroups had fully patent right coronary artery (RCA) from proximal to distal end. RESULTS: RV-MPI value determined using pulsed doppler echocardiography was 0.40 +/- 0.19 in healthy subjects. However RV-MPI was increased in both subgroups of LV-AMI with significant increase in subgroup-2 (P < 0.005) as compared to subgroup-1 patients (P < 0.01). Simpson's RVEF was not significantly different between the groups (P > 0.05). CONCLUSION: The findings in this study demonstrate that RV-MPI is a more sensitive, non-geometric echocardiographic parameter than Simpson's RVEF in detecting early RV dysfunction. Early detection of RV dysfunction is important to reduce morbidity and mortality in these patients. PMID- 23983913 TI - The place of carotico-subclavian bypass surgery in angina treatment. AB - Coronary-subclavian steal syndrome results from atherosclerotic disease of the proximal subclavian artery, causing reversal of flow in an internal mammary artery used as conduit for coronary artery bypass. In the present case, we discussed the diagnosis and the treatment of coronary steal syndrome in a patient hospitalized due to decompensated cardiac insufficiency. PMID- 23983912 TI - Stent fracture: how frequently is it recognized? AB - In spite of there being several case reports, coronary stent fracture is not a well-recognized entity and incidence rates are likely to be underestimated. In this article, we review different aspects of stent fracture, including incidence, classification, predictors, outcome, diagnosis, and management. PMID- 23983914 TI - Massive lipomatous hypertrophy of the right atria. AB - A case of a 70-year-old female with a history of hypertension, atrial fibrillation, pacer implantation for symptomatic bradycardia, and a prior cerebrovascular accident, and had developed persistent methicillin-sensitive Staphylococcus aureus bacteremia is reported here. As part of her evaluation, a transesophageal echocardiogram was performed, and even though no vegetations were seen on either pacer wires or cardiac valves, a massive homogeneous thickening of the superior portion of the interatrial septum extending to the posterior and roof portions of the right atrial wall as well as to the superior vena cava causing proximal compression of this vessel was noted. Computed tomographic examination of the chest helped to determine that this mass density was not a tumor but in fact intrapericardial fat. Imaging findings and existing literature on this topic are reviewed. PMID- 23983915 TI - Giant interatrial septal aneurysm mimicking a left atrial mass. AB - Interatrial septal aneurysm (IASA) consists of redundant atrial septal tissue, which bulges into either the left or the right atrium. The clinical implications of this entity are not entirely clear; however, if it is associated with other cardiac abnormalities such as patent foramen ovale and atrial septal defects. It may assume significance by increasing the risk of cardioembolic events such as stroke. We present a case of an individual with giant IASA detected by transesophageal echocardiography, which was mimicking a left atrial mass on transthoracic echocardiography. This case emphasizes the superiority of transesophageal imaging over transthoracic echocardiography for this clinical entity. PMID- 23983916 TI - Catheter-induced spiral dissection of the left main coronary artery. PMID- 23983917 TI - The medicine of old India. PMID- 23983918 TI - The Air of History (Part IV): Great Muslim Physicians Al Rhazes. PMID- 23983919 TI - Five essential principles of post-disaster psychosocial care: looking back and forward with Stevan Hobfoll. AB - In 2007, a leading article was published by Stevan Hobfoll and a team of international experts. The authors synthesized available scientific evidence and distinguished five essential principles of psychosocial care to people confronted with disaster, tragedy, and loss. Care givers should promote: (1) a sense of safety, (2) calming, (3) self- and community efficacy, (4) social connectedness, and (5) hope. After their publication, the "essential principles" influenced the thoughts of policy makers, care providers, and scholars from all over the world. They have been embedded in several guidelines. In this interview, Professor Hobfoll is invited to revisit the principles and to look forward: "The next step is to create passageways and mutual partnerships." PMID- 23983921 TI - Editorial for therapeutic advances. PMID- 23983920 TI - Validation of the Davidson Trauma Scale in its original and a new shorter version in people exposed to the F-27 earthquake in Chile. AB - BACKGROUND: On February 27, 2010 (F-27), an earthquake and tsunami occurred having a significant impact on the mental health of the Chilean population, leading to an increase in cases of post-traumatic stress disorder (PTSD). OBJECTIVES: Within this context, validated for the first time in Chile was the Davidson Trauma Scale (DTS) using three samples (each one consisting of 200 participants), two of them random from the Chilean population. RESULTS: Reliability analyses (i.e., alpha=0.933), concurrent validity (63% of the items are significantly correlated with the criteria variable "degree of damage to home") and construct validity (i.e., CMIN = 3.754, RMSEA = 0.118, NFI = 0.808, CFI = 0.850 and PNFI = 0.689) indicate validity between regular and good for DTS. However, a new short version of the scale (DTS-SF) created using the items with heavier factor weights, presented better fits (CMIN = 2.170, RMSEA = 0.077, NFI = 0.935, CFI = 0.963, PNFI = 0.697). DISCUSSION: Finally, the usefulness of DTS and DTS-SF is discussed, the latter being briefer, valid and having better psychometric characteristics. PMID- 23983923 TI - Melperone in treatment-refractory schizophrenia: a case series. AB - OBJECTIVE: Clozapine is the treatment of choice in refractory schizophrenia, but a substantial proportion of patients experience inadequate response or tolerate the drug poorly. Melperone has been suggested as a possible alternative in such patients. This case series examines the efficacy of melperone in refractory schizophrenia. METHOD: All patients prescribed melperone at the South London and Maudsley NHS Foundation Trust were identified using a pharmacy database. The main outcome was to determine the proportion of patients discharged on melperone. RESULTS: Three of 21 patients were discharged on melperone. The primary reason for discontinuation was lack of efficacy. CONCLUSION: Melperone may be an option in a very few patients with refractory schizophrenia, but it should not be considered as an alternative to clozapine. PMID- 23983922 TI - Glutamatergic antipsychotic drugs: a new dawn in the treatment of schizophrenia? AB - Growing evidence for glutamate abnormalities in schizophrenia support the development of novel antipsychotic agents targeting this system. Early studies investigating modulation of the glutamate system using glycine, D-serine and sarcosine in patients with schizophrenia have demonstrated significant effects, particularly on negative symptoms, conventionally thought to be refractory to antipsychotic drug treatment. Drugs targeting the glutamate system also have a completely different side-effect profile to dopamine D2 antagonists, with no propensity to extrapyramidal side effects, prolactinaemia or weight gain. It has been hypothesized that glutamatergic drugs may be of benefit to the 20-30% of individuals with schizophrenia who fail to show any response to dopaminergic agents, and may be particularly useful in the early stages of the illness, where they may be disease-modifying. A number of glutamatergic compounds have been reported as having promising results in phase II drug trials. If these reach the clinic, they will represent the first truly novel approach to pharmacotherapy in schizophrenia for more than 50 years. PMID- 23983924 TI - Physical complications in early clozapine treatment: a case report and implications for safe monitoring. AB - Treatment with the antipsychotic clozapine is often complicated by its wide ranging and sometimes serious adverse effect profile. A link between clozapine therapy and diabetes is well established, although the onset and severity of glucose metabolism abnormalities is variable. Recent literature also suggests there may be an association between clozapine therapy and pneumonia. We review the relevant background literature and present a case of a patient with pre existing type 2 diabetes mellitus and chronic obstructive pulmonary disease who presented with a diabetic emergency after a relatively short period of treatment with clozapine. He went on to develop pneumonia from which he died. We discuss the implications this case, and others alike, have for early routine physical health monitoring of this patient group. PMID- 23983925 TI - Perverse effects of the precautionary principle: how banning mephedrone has unexpected implications for pharmaceutical discovery. PMID- 23983926 TI - Increased use of antipsychotic long-acting injections with community treatment orders. AB - BACKGROUND: Community treatment orders (CTOs) are increasingly being used, despite a weak evidence base, and problems continue regarding Second Opinion Appointed Doctor (SOAD) certification of medication. AIMS: The aim of the current study was to describe current CTO usage regarding patient characteristics, prescribed medication and CTO conditions. METHOD: A 1-year prospective cohort study with consecutive sampling was conducted for all patients whose CTO was registered in a large mental health trust. Only the first CTO for each patient was included. Measures included sociodemographic variables, psychiatric diagnosis, CTO date of initiation and conditions, psychotropic medication and date of SOAD certification for medication. This study was conducted in the first year of CTO legislation in England and Wales. RESULTS: A total of195 patients were sampled (mean age 40.6 years, 65% male, 52% black ethnic origin). There was significant geographical variability in rates of CTO use (chi(2) = 11.3, p = 0.012). A total of 53% had their place of residence specified as a condition and 29% were required to allow access into their homes. Of those with schizophrenia, 64% were prescribed an antipsychotic long-acting injection (LAI). Of the total group, 7% received high-dose antipsychotics, 10% were prescribed two antipsychotics and only 15% received SOAD certification in time. CONCLUSIONS: There was geographical and ethnic variation in CTO use but higher rates of hospital detention in minority ethnic groups may be contributory. Most patients were prescribed antipsychotic LAIs and CTO conditions may not follow the least restrictive principle. PMID- 23983928 TI - Dose of Methylphenidate during Service Transition for Adults with ADHD. AB - OBJECTIVES: We wanted to investigate how one element of the transitional process of adolescents to an adult ADHD service, namely the use of medication, fared when compared to the recommendations of national guidelines. METHODS: We did a chart review of the dose of stimulants in a cohort of transitional patients after they were transferred to an adult ADHD service, whilst investigating if other variables such as severity of ADHD, age, gender and comorbidity played any role in determining the dose of stimulants at transition. RESULTS: The dose of stimulants when calculated in mg/kg was almost half the recommended whist the patients were also severely symptomatic. Reported comorbidity with Autistic Spectrum Disorders was also very high. CONCLUSIONS: A handover approach of adolescents with ADHD to an adult service, may hide gaps at least as far as prescribing is concerned. This gap may need considerable resources to address successfully. We suggest that establishing transitional processes may help minimise this problem. PMID- 23983927 TI - Clozapine-related EEG changes and seizures: dose and plasma-level relationships. AB - Clozapine is a widely used atypical antipsychotic with a unique effectiveness in treatment-resistant schizophrenia. An important adverse effect is seizures, which have been observed at all stages of clozapine treatment. Valproate has traditionally been considered the drug of choice for the prophylaxis of clozapine seizures, however it may not be the most suitable choice for all patients. There is disagreement as to the best point to prescribe valproate or a suitable antiepileptic: as seizure prophylaxis at a certain clozapine dose or level, or only as remedial treatment. In this review, we examine the relevant literature with an aim to evaluate the following relationships: clozapine dose and electroencephalogram (EEG) abnormalities, plasma levels and EEG abnormalities, dose and occurrence of seizures and plasma levels and occurrence of seizures. Weighted linear regression models were fitted to investigate these relationships. There was a strong relationship between clozapine dose and plasma level and occurrence of clozapine-induced EEG abnormalities. However, a statistically significant relationship between dose and occurrence of seizures was not found. A relationship between clozapine plasma level and occurrence of seizures was not established because of the scarcity of useful data although our review found three case reports which suggested that there is a very substantial risk of seizures with clozapine plasma levels exceeding 1300 MUg/l. Seizures are more common during the initiation phase of clozapine treatment, suggesting a slow titration to target plasma levels is desirable. An antiepileptic drug should be considered when the clozapine plasma level exceeds 500 MUg/l, if the EEG shows clear epileptiform discharges, if seizures, myoclonic jerks or speech difficulties occur and when there is concurrent use of epileptogenic medication. The antiepileptics of choice for the treatment and prophylaxis of clozapine induced seizures are valproate (particularly where there is mood disturbance) and lamotrigine (where there is resistance to clozapine). PMID- 23983929 TI - Aripiprazole use combined with depot antipsychotic medication: two cases demonstrating its ability to reduce prolactin levels in an adolescent forensic hospital. AB - Many patients maintained on depot medication have raised prolactin levels, which can lead to a range of long-term medical problems. The addition of aripiprazole can reduce prolactin levels and restore sexual function in these patients. The cases described demonstrate the potential role of aripiprazole in a forensic setting. PMID- 23983930 TI - Vilazodone: a brief pharmacological and clinical review of the novel serotonin partial agonist and reuptake inhibitor. AB - BACKGROUND: Vilazodone is the latest US Food and Drug Administration approved antidepressant agent available in the USA. Its putative mechanism of antidepressant action enhances the release of serotonin across the brain's serotonergic pathways specifically by inhibiting the serotonin transporter, similar to a selective serotonin reuptake inhibitor (SSRI), and simultaneously stimulating serotonin-1a receptors via partial agonism, similar to the anxiolytic bus-pirone. This combined activity in the single vilazodone agent has been termed by the authors as being a serotonin partial agonist and reuptake inhibitor or (SPARI). METHODS: A MEDLINE and Internet search was conducted and the resultant preclinical and clinical evidence was reviewed. The authors attempt to review laboratory data, animal model data and human trial data to develop a translational theory on the mechanism of antidepressant action of this agent and also its adverse effect potential. RESULTS: Randomized, controlled empirical data for vilazodone have gained it approval for treating major depressive disorder. It combines two well known pharmacodynamic mechanisms of serotonergic action into a novel agent. Although no head-to-head studies against other antidepressants have been published, the efficacy data for vilazodone appear comparable to other known antidepressants, with similar gastrointestinal side effects to SSRI or serotonin norepinephrine reuptake inhibitor (SNRI) antidepressants, but possibly with a lower incidence of sexual side effects and weight gain. DISCUSSION: Vilazodone will lend itself to the current armamentarium in the treatment of major depressive disorder and may hold promise for patients who cannot tolerate other antide-pressants. Its unique SPARI mechanism of action could also be efficacious for patients who do not respond to SSRI or SNRI antidepressant monotherapies. PMID- 23983932 TI - Editorial. PMID- 23983931 TI - Melatonin: a non-benzodiazepine hypnotic in an elderly blind female with dementia. PMID- 23983933 TI - The ANNSERS (Antipsychotic Non-Neurological Side Effects Rating Scale): Validation of Sexual Side-Effect Measurement. AB - Antipsychotic nonneurological side effects, such as sexual dysfunction, can adversely affect the quality of patients' relationships, their treatment adherence and their quality of life. In the UK CUtLASS (Cost Utility of the Latest Antipsychotics in Severe Schizophrenia) study, nonneurological side effects were assessed using the ANNSERSv1 (Antipsychotic Non-Neurological Side Effects Rating Scale version 1), a new scale to assess the side effects associated with both first- and second-generation antipsychotic drugs. A total of 26 participants also completed the Derogatis Interview for Sexual Functioning (self-report version, DISF-SR). A statistically significant, and specific, correlation was found between scores on the DISF-SR and the sexual side-effect section of the ANNSERS at baseline. The sexual side-effects subscale of the ANNSERS is a valid measure of sexual dysfunction in the treatment of schizophrenia. PMID- 23983934 TI - Medicines Reconciliation on Admission to Inpatient Psychiatric Care: Findings from a UK Quality Improvement Programme. AB - OBJECTIVE: Medication errors are a common cause of avoidable morbidity, and transfer between clinical settings is a known risk factor for such errors. Medicines reconciliation means there is no unintended discrepancy between the medication prescribed for a patient prior to admission and on admission. Our aim was to improve the quality of practice supporting medicines reconciliation at the point of admission to a psychiatric ward. METHODS: An audit-based quality improvement programme (QIP), using the proxy measure for medicines reconciliation of two or more sources of information being consulted about current medicines, and compared. RESULTS: At baseline audit, 42 Trusts submitted data for 1790 patients. At re-audit 16 months later, 43 Trusts submitted data for 2296 patients. While doctors were most commonly identified in Trust policies as having overall responsibility for medicines reconciliation, the task was most often undertaken by pharmacy staff, with most activity occurring within 24 h of admission. The proportion of patients in whom medicines reconciliation was possible was 71% at baseline and 79% at re-audit. In such patients, discrepancies were identified in 25% at baseline and 31% at re-audit; a small proportion of these discrepancies were clearly clinically significant. CONCLUSIONS: This QIP achieved modest improvement in medicines reconciliation practice. PMID- 23983936 TI - Serotonin Syndrome following Introduction of Venlafaxine following Withdrawal of Phenelzine: Implications for Drug Washout Periods. PMID- 23983935 TI - Tolerability of initiation doses of once-monthly paliperidone palmitate in patients with recently diagnosed schizophrenia in an acute treatment trial. AB - OBJECTIVE: To examine the tolerability of the recommended initiation doses for once-monthly injectable paliperidone palmitate in patients who have recently been diagnosed with schizophrenia and for whom high doses may pose tolerability concerns. METHODS: A post hoc analysis from a 13-week double-blind study of patients with schizophrenia randomized 1:1:1:1 to placebo or paliperidone palmitate at 25, 100, or 150 mg equivalents (mg eq) of paliperidone (corresponding to 39, 156, or 234 mg respectively). This analysis focused on the recently diagnosed subgroup (<=5 years; N = 146) who received the recommended initiation dosage of paliperidone palmitate [150 mg eq on day 1 (n = 109) followed by 100 mg eq on day 8 (n = 39)] or placebo (n = 37). Adverse events (AEs), reported in >=2% of patients receiving paliperidone palmitate during days 1-7 or >=5% during days 8-36, and in a higher percentage of patients receiving paliperidone palmitate than placebo, were identified. AE relative risks (RRs) and 95% confidence intervals (CIs) were determined. A RR was considered potentially significant when its 95% CI did not include 1. RESULTS: Overall, day 1-7 AE rates were 37.6% (41 of 109) and 29.7% (11 of 37) with paliperidone palmitate and placebo respectively; injection site pain (5.5% versus 2.7%, RR 2.0; 95% CI 0.25 to 16.37), agitation (4.6% versus 2.7%; RR 1.7; 95% CI 0.21 to 14.06), and headache (3.7% versus 0.0%; RR 3.1; 95% CI 0.17 to 56.41) met the >=2% criteria. Day 8-36 AE rates were 41.0% (16 of 39) and 37.8% (14 of 37) with paliperidone palmitate and placebo respectively; anxiety (5.1% versus 0.0%; RR 4.8; 95% CI 0.24 to 95.76) met the >=5% criteria. Key limitations were that some patients may have been ill for a significant time before formal diagnosis and that the number of patients is low in this subgroup, limiting the ability to detect statistical significance for AE RRs. CONCLUSIONS: Paliperidone palmitate initiation doses (150 mg eq day 1, 100 mg eq day 8) were tolerated in this subgroup of patients who were recently diagnosed with schizophrenia, with no unexpected findings. Although the same size was small, these data identified AEs that may be encountered during the week and month after initiation dosing. These findings may assist clinicians when paliperidone palmitate is considered an appropriate treatment choice for these patients. PMID- 23983937 TI - Editorial. PMID- 23983938 TI - A randomized trial of the effect of escitalopram versus placebo on cognitive function in healthy first-degree relatives of patients with depression. AB - The effect of selective serotonin receptor inhibitors (SSRIs) on healthy individuals remains unclear. The aim of the trial was to evaluate the effect of the SSRI escitalopram on cognitive function in healthy first-degree relatives of patients with major depressive disorder (FDRs). A total of 80 FDRs were randomized to escitalopram (10 mg/day) (n = 41) versus placebo (n = 39) for 4 weeks. Neuropsychological tests and ratings of mood were applied at entry (T0) and at 4 weeks (T4). The main outcome measure was calculated as the change (T4 T0) in a general cognition score, which was the standardized mean of 13 test measures. Mean change in the general cognition score was not significantly increased with escitalopram compared with placebo (p = 0.37) or for any of the specific tests. In univariate analyses no statistically significant correlations were found between change in the general cognitive score and the variables age, sex, Hamilton depression score 17 items, Danish Adult Reading Test-45, and plasma escitalopram levels, respectively. These results suggest that treatment with escitalopram does not improve or impair cognitive function in FDRs. Improvement in cognitive function following treatment of depressed patients with SSRIs seems to be related to the effects on depressive symptoms rather than to a direct effect of the SSRI. PMID- 23983939 TI - Psychotic exacerbation and emotional dampening in the daily life of patients with schizophrenia switched to aripiprazole therapy: a collection of standardized case reports. AB - BACKGROUND: Blockade of the dopamine D2 receptor is a key mechanism in the antipsychotic treatment of patients with a psychotic disorder, but may also induce emotional deficits. The partial D2 agonistic profile of aripiprazole has, therefore, been suggested to favor emotional wellbeing compared with the pure dopamine antagonistic properties of traditional antipsychotics. METHOD: The current study used the experience sampling method (a structured diary technique) to assess the effects of switching from treatment with traditional dopamine antagonist antipsychotics to treatment with the partial dopamine agonist aripiprazole on emotional wellbeing in the daily life of 13 patients with a diagnosis of schizophrenia. RESULTS: More than half of all patients experienced exacerbation of psychotic symptoms after they had switched to the aripiprazole medication regime, consequently resulting in dropout of the study. Furthermore, switching to aripiprazole treatment, when effective in terms of symptom reduction, was accompanied by decreased feelings of both positive and negative affect in daily life, suggestive of a general state of emotional dampening. CONCLUSIONS: Although the scale of the current study and the 54% dropout rate call for careful interpretation of the data, implementation of ecological monitoring in psychopharmacological research may open up new avenues for untangling the working mechanisms of compounds with regard to their impact on mental states. PMID- 23983942 TI - Editorial. PMID- 23983940 TI - Bipolar depression: clinically missed, pharmacologically mismanaged. AB - Bipolar affective disorders are common and frequently debilitating mental illnesses. Diagnostic criteria mean they are defined by the presence of pathological mood elevation, but research shows greater disease burden is inflicted by depressive phases (bipolar depression) both in terms of duration and impact of symptoms. Despite this there is consistent evidence for the underdiagnosis of bipolar depression and its misdiagnosis as a unipolar disorder, with significant subsequent impact on medication management. There is currently less robust evidence for the appropriate pharmacological approach in such individuals than in unipolar depression, and fewer guidelines for clinicians. Despite this there is clear and growing evidence that 'treatment as usual' of depressive symptomatology is ineffective at best, harmful at worst, and that there is little role for the use of antidepressants. Both mood stabilizers and antipsychotics demonstrate efficacy, and whilst there are emerging data on intraclass differences, more research is needed, particularly concerning bipolar II disorder. Present treatment strategies are limited by insufficient large randomized control trials, an inadequate understanding of the neuropathology of bipolar illnesses and a lack of tailored medications. Better clinical training, understanding and recognition of this common condition are essential. PMID- 23983943 TI - SSRI-induced coagulopathy: is it reality? AB - OBJECTIVES: To study the effect of escitalopram and fluoxetine on coagulation profile in patients with major depression. METHOD: This was a prospective, open label, single-centre study in 40 patients diagnosed with major depressive disorder. The patients were diagnosed using Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. Twenty patients receiving escitalopram 10 mg per day and 20 patients receiving fluoxetine 20 mg per day participated in the study and were followed up for 3 months. Coagulation parameters - bleeding time, clotting time, platelet count, prothrombin time and partial thromboplastin kaolin time - were evaluated at baseline and after 3 months. RESULTS: At the end of 3 months, a significant increase in bleeding time was seen in patients receiving fluoxetine, but within the normal range. No rise was seen in the group given escitalopram. CONCLUSION: In patients with depression, fluoxetine increases bleeding time whereas escitalopram has no effect on coagulation profile. However, both the drugs can be used safely for long-term treatment. PMID- 23983944 TI - Agomelatine in unipolar depression in clinical practice: a retrospective chart review. AB - Agomelatine (Valdoxan), a synthetic melatonergic receptor agonist at the MT1 and MT2 receptors, was first used in the management of sleep disorder. Its 5HT2C receptor antagonistic properties support its antidepressant potential. It is currently licensed in the UK, Europe and USA for the treatment of major depressive disorder. Although the randomized controlled evidence base for its use is growing, there are no retrospective, naturalistic studies available. We aimed to determine the tolerability and clinical effectiveness of agomelatine in unipolar depression. We also examined whether being refractory to treatment altered clinical outcome. Forty-eight patient records were examined. Twenty-five percent were treatment refractory: Clinical Global Impression (CGI) Severity score at the start of treatment was 3.81 compared with 3.38 at the end of treatment. Fifty-four percent improved at least minimally; only 12.5% were much or very much improved. Treatment-refractory patients had a poorer outcome with higher discontinuation rates and lower CGI Improvement (p = 0.0205). Treatment refractory patients also had a higher CGI Severity score at the end of treatment than at treatment commencement (3.92 versus 3.75), although this was not statistically significant. PMID- 23983945 TI - Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review. AB - BACKGROUND: Clozapine is the most effective antipsychotic in treatment-resistant schizophrenia but its use portends with a high burden of adverse reactions. One adverse event reported both in case reports and cross-sectional surveys is the emergence or worsening of obsessive compulsive symptoms (OCS). OBJECTIVES: This study presents a retrospective review of a UK cohort of clozapine-treated individuals with the aim to further investigate the complex relationship between clozapine and OCS. METHODS: An extensive review of the medical records of 49 patients receiving clozapine in the Southampton area was undertaken. We searched for a diagnosis of obsessive compulsive disorder, signs or symptoms of obsessive compulsive disorder or the prescribing of selected antidepressants the year before clozapine initiation and the year after. RESULTS: Fifteen patients (31%) had reports of OCS during the 2-year data collection period. Twelve patients (24%) had OCS before clozapine initiation while only 7 (14%) had symptoms after clozapine was initiated. De novo OCS were reported in three (6%) cases after 5-9 months of clozapine treatment. CONCLUSIONS: As with previous studies it was not possible to establish a definitive link between clozapine and OCS. Clinicians should be mindful of the common comorbidity of OCS and schizophrenia and the possible increased risk incurred when starting clozapine. PMID- 23983946 TI - Metabolic, endocrinologic and cardiac effects of amisulpride: a 24-week follow-up study. AB - BACKGROUND: Amisulpride is a second-generation antipsychotic which has been proved to be effective in the control of both positive and negative symptoms of schizophrenia. In this study we aimed to determine metabolic, endocrinologic and cardiac effects of amisulpride commonly used in our clinical practice. METHODS: A total of 18 patients (11 males, 7 females) diagnosed with schizophrenia received amisulpride at the dosage of 800 mg/day and were followed up for 24 weeks. Positive and negative psychotic symptoms, extrapyramidal and sexual side effects, metabolic, endocrinologic and cardiac parameters were evaluated at regular intervals. RESULTS: Significant improvement in both positive and negative symptoms was observed in patients starting from the second week of treatment. Prolactin levels increased significantly both in men and women starting from the measurement on day 4. Prolactin elevation was significantly higher in women than in men. Increase in total cholesterol level became significant at week 24. No other significant difference was observed between weeks 1 and 24 regarding the other parameters. CONCLUSIONS: The clinical data from the present study supports the fact that amisulpride is an effective and safe antipsychotic drug, but elevates prolactin levels in both sexes. PMID- 23983949 TI - Editorial. PMID- 23983947 TI - Receptor mechanisms of antipsychotic drug action in bipolar disorder - focus on asenapine. AB - The atypical antipsychotic drugs are considered a first-line treatment for mania in bipolar disorder with many having a proven superiority to the classical mood stabilisers. This review addresses the pharmacological mechanisms underlying this therapeutic efficacy, as well as those mechanisms considered responsible for the adverse effects of antipsychotic drugs, with a particular focus on the recently introduced asenapine. The high efficacy in bipolar mania of haloperidol, a relatively selective dopamine D2-like receptor antagonist, indicates that the one common receptor mechanism underlying antipsychotic effects on mania is antagonism at the D2 receptor. Serotonin receptors are implicated in antidepressant response, and relief of depressed mood in mixed states is likely to involve drug effects at one, or more likely several interacting, serotonin receptors. Asenapine shows a unique breadth of action at these sites, with potential effects at clinical doses at 5HT1A, 1B, 2A, 2C, 6 and 7 receptors. Antagonism at alpha2 adrenoceptors may also be involved. Adverse effects include those classically associated with dopamine D2 receptor blockade, the extrapyramidal side effects (EPS), and which are relatively diminished in the atypical (in comparison with the conventional) antipsychotics. A variety of protective mechanisms against EPS associated with different drugs include low D2 affinity, D2 partial agonism, high 5-HT2A and 2C antagonism. Similar effects at the D2 and 5-HT2C receptors may underlie the low propensity for hyperprolactinaemia of the atypicals, although the strong prolactin-elevating effect of risperidone reflects its relatively high blood/brain concentration ratio, a consequence of it being a substrate for the p glycoprotein pump. Weight gain is a further concern of antipsychotic treatment of bipolar disorder which is particularly severe with olanzapine. Histamine H1, alpha1 adrenergic and particularly 5-HT2C receptors are implicated in this effect, although the lower propensity for weight gain shown by asenapine which, like olanzapine, binds to these receptors, indicates that other protective receptor mechanisms, or subtle differences in the 5-HT2C receptor-mediated effects, may be important. Of other peripheral and central effects, the pharmacological basis of sedation (H1 receptors) and postural hypotension (alpha1 adrenoceptors) are rather better understood. The relative benefits of atypical antipsychotics like asenapine can be understood from their receptor pharmacology, and this understanding is key to the future development of improved treatment for bipolar disorder. PMID- 23983950 TI - Long-term antipsychotic polypharmacy: how does it start, why does it continue? AB - BACKGROUND: Antipsychotic polypharmacy remains a widespread and persistent practice, despite a lack of empirical evidence to support its safety and efficacy. This study aimed to assess antipsychotic treatment prior to the initiation of polypharmacy and ascertained clinicians' reasons for coprescribing long term. We also aimed to determine patterns of antipsychotic coprescription and associated outcome. METHOD: Prescription charts across a large mental health trust were reviewed to identify all patients coprescribed two or more antipsychotics excluding clozapine. For those receiving antipsychotic polypharmacy for at least 6 months, electronic patient records were examined to obtain demographic data, documented reasons for initiating polypharmacy and prior prescribing information. Sequence of prescribing, clinical outcome, adverse effects and prescriber considerations to revert to monotherapy were determined. RESULTS: In all, 38 patients had been receiving two antipsychotics excluding clozapine for longer than 6 months. In 39% of cases patients had been prescribed no or only one antipsychotic before initiation of polypharmacy while 48% had been trialled on clozapine. The most frequently documented reason for coprescribing was that residual psychotic symptoms remained with monotherapy. An improvement in psychotic symptoms was documented in 26% of patients receiving polypharmacy. Prescribers considered stopping polypharmacy in 23 patients. CONCLUSION: Antipsychotics were coprescribed largely to improve symptoms and clinical outcome in patients with inadequate response to monotherapy. Polypharmacy was not solely reserved for patients in whom all other therapeutic options had failed. There was some evidence to suggest that patients did benefit from coprescription, albeit at the expense of an increased adverse effect burden. Prospective randomized trials of specific antipsychotic combinations are required to assess the therapeutic utility of this under-researched practice. PMID- 23983951 TI - Drug-induced supersensitivity psychosis revisited: characteristics of relapse in treatment-compliant patients. AB - BACKGROUND: An association between abnormal involuntary movements and psychotic relapse was previously reported in a group of patients compliant with antipsychotic medication (Fallon and Dursun 2011). This was interpreted as the presence of an antipsychotic medication-induced supersensitivity psychosis. METHOD: From the results of that study and the Chouinard diagnostic criteria for supersensitivity psychosis an abbreviated diagnostic checklist was developed to identify the phenomenon. In the present study the checklist was used on a larger sample of medication-compliant individuals experiencing a psychotic relapse. RESULTS: The checklist demonstrated its utility by identifying a cause of relapse in 70% (29/41) of patients. Furthermore, it identified the presence of supersensitivity psychosis in 39% (16/41) of patients. This study also replicated a number of findings from the previous paper supporting the idea that supersensitivity psychosis is one cause of relapse in psychosis. DISCUSSION: These results suggested that clinicians should exercise caution in prescribing and may have to augment treatment with other agents or switch to low dopamine affinity antipsychotics. PMID- 23983952 TI - The influence of switching from oral risperidone to risperidone long-acting injection on the clinical symptoms and cognitive function in schizophrenia. AB - OBJECTIVE: This study was a comparative investigation of the effects on clinical symptoms and cognitive function of switching schizophrenia patients from oral risperidone to risperidone long-acting injection (RLAI) compared with a control group that continued receiving oral risperidone. METHODS: The subjects were 21 patients who had been diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Their clinical symptoms were assessed using the positive and negative syndrome scale (PANSS), and their cognitive function was assessed using the Wisconsin Card Sorting Test: Keio Version (KWCST) to assess executive function, and the St Marianna University School of Medicine's Computerized Memory Test (STM-COMET) to assess memory and concentration. RESULTS: No significant differences in clinical symptom improvement efficacy were seen between the group that was switched to RLAI and the control group. No significant differences were seen between the two groups in the mean change from baseline in any of the KWCST tests. The mean changes from baseline on the STM-COMET memory scanning test and memory filtering test were significantly greater in the group that switched to RLAI than in the control group. Furthermore, patients with RLAI needed less biperiden, even though they had similar risperidone-equivalent daily dosages as the group with oral risperidone. CONCLUSION: The results of this study suggested that switching from oral risperidone to RLAI may affect motor processing function and attention improvement efficacy by allowing the dosage of anti-Parkinson's medication to be reduced. PMID- 23983953 TI - High-dose tricyclics potentiation with mirtazapine, lithium and partial sleep deprivation: why not tricyclics in combination strategies for resistant melancholia? PMID- 23983955 TI - Editorial. PMID- 23983954 TI - Varenicline-induced psychotic depressive episode in a patient with bipolar disorder. AB - Varenicline is a relatively novel medication for smoking cessation. Increased neuropsychiatric symptoms have been reported with its use and it is listed among drugs with a black box warning. History of a psychiatric diagnosis is suggested to be a vulnerability factor for the development of some psychiatric side effects with its use. However, empirical evidence to support this point is very limited. Here, we report the case of a bipolar patient who developed a depressive episode with psychotic features immediately after varenicline use. Clinicians should be careful about the varenicline-induced neuropsychiatric effects. Healthcare professionals can provide an important role in helping to prevent and manage worsening psychiatric symptoms. PMID- 23983956 TI - Antidepressants, metoprolol and the risk of bradycardia. AB - Case reports and pharmacologic theory suggest that some antidepressants can interfere with the hepatic metabolism of metoprolol by cytochrome P450 2D6 (CYP2D6), potentially increasing the risk of bradycardia. The objective of this study was to characterize the clinical consequences of this potential drug interaction at the population level. We conducted a population-based, nested case control study of Ontario residents 66 years of age or older receiving metoprolol. Cases hospitalized for bradycardia were compared with matched controls (4:1) to explore the odds ratio for initiation of antidepressants that inhibit CYP2D6 (fluoxetine and paroxetine) and those that do not inhibit CYP2D6 (fluvoxamine, citalopram, venlafaxine, and sertraline) 30 days before hospitalization. From April 1997 to March 2009, we identified 332,254 older patients continuously receiving metoprolol, of whom 8232 (2.5%) were treated in hospital for bradycardia. The adjusted odds ratio for exposure to fluoxetine or paroxetine compared with other antidepressants 30 days prior to hospitalization for bradycardia was 0.76 (95% confidence interval 0.42-1.37). Among older patients receiving metoprolol, the initiation of antidepressants that inhibit CYP2D6 was not associated with a significant increase in the risk of bradycardia compared with antidepressants that do not inhibit CYP2D6. PMID- 23983957 TI - Increased plasma norepinephrine concentration in psychotic depression. AB - OBJECTIVE: We previously found psychotic depression (PSDEP) to have positively correlating plasma norepinephrine (NE) and vasopressin (AVP) concentrations. Since central noradrenergic activity and plasma NE concentration are highly correlated, this suggests an increased noradrenergic activation of the hypothalamus-pituitary-adrenal axis. We hypothesize the increased release of NE in PSDEP to be an associated mechanism. METHODS: To test this hypothesis we analyzed the relation between plasma NE and PSDEP in a comparison with non psychotically depressed patients. Potentially confounding variables were, among others, melancholia and two better validated subcategories in the field of melancholia and endogenous depression, three global dimensions of psychopathology - Emotional Dysregulation, Retardation and Anxiety - smoking habit, and different types of psychotropic and particularly antidepressant treatment. The data from nine patients with PSDEP and 69 patients with non-PSDEP were reanalysed. RESULTS: Analysis of covariance controlling for the effects of tricyclic antidepressant treatment (>=100 mg) and smoking habit showed that PSDEP had an increased concentration of plasma NE. The previously found correlation between plasma NE and AVP was still present after correcting for the effects of confounding variables. CONCLUSIONS: The results suggest an increased activity of the sympathetic nervous system in PSDEP that may act as a specific mechanism for increased vasopressinergic activation. This supports the view of PSDEP as a distinct subcategory of major depression. PMID- 23983959 TI - Ascertaining instances of neuroleptic malignant syndrome in a secondary mental healthcare electronic medical records database: the SLAM BRC Case Register. AB - OBJECTIVES: Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication of antipsychotic treatment. However, there is no single diagnostic test and a variety of overlapping criteria exist. Using a large case register of secondary mental healthcare in Southeast London, we aimed to identify suspected cases and quantify the levels of agreement between six different diagnostic criteria previously published. METHODS: Taking advantage of a recently developed case register sourced from full but anonymized electronic medical records (the South London and Maudsley NHS Foundation Trust), we applied text string searching to identify suspected NMS cases for which action had been taken to investigate or treat. Three psychiatrists manually reviewed case records for clinical data to compare diagnostic criteria. RESULTS: Analysis of the case register revealed 183 suspected NMS cases, of which 43 fulfilled at least one set of the six diagnostic criteria. Agreement between criteria was poor (kappa = 0.35 for all combined agreement; 95% confidence interval 0.31-0.39) and only one case fulfilled all six diagnostic criteria. However, among cases meeting any diagnostic criteria, pyrexia, extrapyramidal symptoms, altered consciousness, autonomic symptoms, and elevated CK concentrations were significantly more common than in cases not meeting diagnostic criteria (p < 0.01). On further analyses, the presence of two or more of these features significantly distinguished cases meeting criteria from those that did not (p < 0.01). Individual symptoms were also reported in suspected cases of NMS that did not fulfil any diagnostic criteria. CONCLUSIONS: In a large sample of NMS cases recorded in medical records, relatively poor agreement was found among published diagnostic criteria for NMS. However, core features of NMS were observed significantly more often among cases meeting diagnostic criteria. Individual symptoms were also described in suspected cases that did not meet diagnostic criteria. These findings suggest a continued need for consensus on standard criteria for NMS. PMID- 23983958 TI - Serum brain-derived neurotrophic factor, vascular endothelial growth factor and leptin levels in patients with a diagnosis of severe major depressive disorder with melancholic features. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and leptin have been hypothesized to be involved in the neurobiology of depression. The aim of this study was to investigate BDNF, VEGF and leptin levels in patients with severe melancholic depression. METHODS: A total of 40 drug-free patients with major depressive disorder (MDD) with melancholic features and 40 healthy controls were included in the study. Demographic information, psychiatric evaluation and physical examination were documented for both groups. Serum BDNF, VEGF levels were determined by enzyme linked immunosorbent assay and leptin with radioimmunoassay methods. The Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale were applied to the patients. RESULTS: There were no significant differences in serum BDNF, VEGF and leptin levels between the patient and control groups. There was a negative correlation between BDNF levels and the number of depressive episodes. It was noted that VEGF levels decreased with increasing severity of depression. CONCLUSIONS: These findings suggest that BDNF levels might be associated with the recurrence of depression and VEGF levels might be a determinant of the severity of depression. PMID- 23983961 TI - Editorial. PMID- 23983960 TI - Risperidone-induced acromegaly: a case report. AB - Today, considering their adverse side effects, the first-generation antipsychotics have been replaced by the new-generation antipsychotics (also known as second-generation antipsychotic agents). The superiority of new generation antipsychotics compared with first-generation antipsychotic agents in terms of side effects, especially movement disorders, are acknowledged by clinicians. But in recent years during the use of second-generation antipsychotic agents, endocrine side effects have been noteworthy. In our study with a diagnosis of paranoid schizophrenia treated with risperidone for 14 years and operated with the diagnosis of pituitary macroadenoma, a 32-year-old female patient is presented in the light of the literature examining the framework of the history of disease. PMID- 23983962 TI - Risperidone-associated prolactin elevation and markers of bone turnover during acute treatment. AB - OBJECTIVE: Prolactin elevation has been proposed as a risk factor for low bone density and potentially osteoporosis in patients on long-term treatment with prolactin-elevating antipsychotics. Our objective was to study the acute effects of prolactin elevation on serum markers of bone formation and resorption in patients treated with risperidone. METHODS: Thirty participants meeting Diagnostic and Statistical Manual of Mental Disorders fourth edition criteria for schizophrenia, major depressive disorder with psychotic features, or bipolar disorder with psychosis were enrolled. At baseline, subjects were antipsychotic free. Subjects were evaluated before and after 4 weeks of risperidone treatment. Assessments included symptom ratings along with testosterone, estradiol, prolactin, osteocalcin (marker of bone formation), and n-telopeptide crosslinks (NTx marker of bone resorption). Primary analysis examined the impact of risperidone treatment on change in the bone markers and hormone levels from pre to post treatment. RESULTS: Prolactin levels significantly increased from 12.1 +/ 1.9 ng/ml to 65.7 +/- 12.2 ng/ml after treatment (p < 0.001). NTx markers of bone resorption significantly decreased from 18.31 +/- 1.49 nM bone collagen equivalent (BCE) before treatment to 15.50 +/- 1.22 nM BCE after treatment in the study sample as a whole (p < 0.05). A trend was observed indicating that NTx may increase in individuals who have the greatest increases in prolactin after treatment r = 0.33, p = 0.07). CONCLUSIONS: These findings suggest that prolactin elevation is associated with changes in bone physiology very early in the course of treatment with risperidone. Bone resorption decreased in many subjects but higher levels of bone resorption occurred in patients with the greatest increases in prolactin. This may have important implications for prolactin monitoring or the periodic assessment of osteoporosis-related outcomes in patients requiring extended treatment. PMID- 23983963 TI - Plasma 1,8-cineole correlates with cognitive performance following exposure to rosemary essential oil aroma. AB - OBJECTIVE: The mode of influence of the aromas of plant essential oils on human behaviour is largely unclear. This study was designed to assess the potential pharmacological relationships between absorbed 1,8-cineole following exposure to rosemary aroma, cognitive performance and mood. METHODS: Twenty healthy volunteers performed serial subtraction and visual information processing tasks in a cubicle diffused with the aroma of rosemary. Mood assessments were made pre and post testing, and venous blood was sampled at the end of the session. Pearson correlations were carried out between serum levels of 1,8-cineole, cognitive performance measures and change in mood scores. RESULTS: Here we show for the first time that performance on cognitive tasks is significantly related to concentration of absorbed 1,8-cineole following exposure to rosemary aroma, with improved performance at higher concentrations. Furthermore, these effects were found for speed and accuracy outcomes, indicating that the relationship is not describing a speed-accuracy trade off. The relationships between 1,8-cineole levels and mood were less pronounced, but did reveal a significant negative correlation between change in contentment and plasma 1,8-cineole levels. CONCLUSION: These findings suggest that compounds absorbed from rosemary aroma affect cognition and subjective state independently through different neurochemical pathways. PMID- 23983965 TI - Editorial. PMID- 23983964 TI - A review of modafinil and armodafinil as add-on therapy in antipsychotic-treated patients with schizophrenia. AB - Schizophrenia is characterized by reality distortion, psychomotor poverty and cognitive disturbances. These characteristics contribute to a lesser social functioning and lower quality of life in patients with schizophrenia. It has been suggested that modafinil and its isomer armodafinil as an add-on strategy to antipsychotic treatment in patients with schizophrenia may improve cognitive functioning, attenuate fatigue, inactiveness and other negative functions as well as weight gain. In this paper we review the literature relevant to the question of whether modafinil and armodafinil are beneficial as add-on therapy in antipsychotic-treated patients with schizophrenia. A total of 15 articles were included in this review; of the 15 articles, 10 were randomized controlled trials (RCTs). Evidence for the use of modafinil or armodafinil as add-on therapy to antipsychotic drugs to alleviate fatigue, sleepiness and inactivity is inconclusive. One cohort study and one out of two single-dose crossover RCTs in which modafinil addition was studied could demonstrate a positive effect. All five RCTs of modafinil (three RCTs) and armodafinil (two RCTs) addition with a longer study duration could not demonstrate a positive effect. With respect to cognitive disturbances, animal models of cognitive deficits show clear improvements with modafinil. In RCTs with a treatment duration of 4 weeks or more, however, no positive effect could be demonstrated on cognitive functioning with modafinil and armodafinil addition. Yet, four single-dose crossover RCTs of modafinil addition show significant positive effects on executive functioning, verbal memory span, visual memory, working memory, spatial planning, slowing in latency, impulse control and recognition of faces expressing sadness and sadness misattribution in the context of disgust recognition. The addition of modafinil or armodafinil to an antipsychotic regime, despite theoretical and preclinical considerations, has not been proved to enhance cognitive function, attenuate fatigue, enhance activity, improve negative symptoms and reduce weight in patients with schizophrenia. PMID- 23983966 TI - The effects of quercetin supplementation on cognitive functioning in a community sample: a randomized, placebo-controlled trial. AB - BACKGROUND: The purpose of the present study was to examine the effects of quercetin supplementation on neurocognitive functioning. METHODS: A large community sample (n = 941) completed a 12-week supplementation protocol, and participants were randomly assigned to receive 500 mg/day or 1000 mg/day quercetin, or placebo. RESULTS: Results failed to indicate significant effects of quercetin on memory, psychomotor speed, reaction time, attention, or cognitive flexibility, despite large increases in plasma quercetin levels among the quercetin treatment groups. DISCUSSION: Consistent with recent research, this study raises concerns regarding the generalizability of positive findings of in vitro and animal quercetin research, and provides evidence that quercetin may not have an ergogenic effect on neurocognitive functioning in humans. PMID- 23983968 TI - Amantadine for olanzapine-induced weight gain: a systematic review and meta analysis of randomized placebo-controlled trials. AB - OBJECTIVE: The objective of this study was to conduct a systematic review and meta-analysis of randomized placebo-controlled trials of amantadine for the treatment of olanzapine-induced weight gain. METHODS: Studies were identified using online searches of PUBMED/MEDLINE and Cochrane database (CENTRAL), along with websites recording trial information such as ClinicalTrials.gov, Controlled trials.com, and Clinicalstudyresults.org. Study eligibility criteria included randomized, double-blind clinical trials comparing amantadine with placebo for olanzapine-induced weight gain with body weight as an outcome measure and study duration of at least 12 weeks. The methodological quality of included trials was assessed using the Jadad Scale. Separate meta-analyses were undertaken for each outcome (body weight and frequency of weight loss >7%) and treatment effects were expressed as weighted mean differences (WMD) and Mantel-Haenszel odds ratio for continuous and categorical outcomes, respectively. RESULTS: A systematic review of literature revealed six studies that had assessed amantadine for olanzapine induced weight gain. Of these, two studies (n = 144) met the review inclusion criteria and were included in the final analysis. Meta-analysis was performed to see the effect size of the treatment on body weight and frequency of body weight loss >7%. For body weight change, WMD was -1.85 (95% confidence interval [CI] 3.31 to -0.39) kg with amantadine as compared with placebo; the overall effect was statistically significant (p = 0.01). For frequency of body weight loss >7%, Mantel-Haenszel odds ratio for weight loss was 3.72 (95% CI 1.19-11.62), favoring amantadine as compared with placebo, and the overall effect was significant (p = 0.02). CONCLUSIONS: Existing data is limited to two studies, which support the efficacy of amantadine for olanzapine-induced weight gain and a significant proportion of patients might lose weight with amantadine compared with placebo. PMID- 23983967 TI - Metyrapone in treatment-resistant depression. AB - Depression affects a significant proportion of the population, with 1-year and lifetime prevalence of 3-5% and 10-30% respectively. Full remission is achieved in only a third of patients following treatment with first-line antidepressant. There is a need for novel treatments for treatment-resistant depression (TRD). Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been described in patients with depression. There is persistent rise in the levels of cortisol (end product of the HPA axis) and impairment of the negative feedback inhibition mechanism of the HPA axis. Dysregulation of the HPA axis has been found to be linked to nonresponse to antidepressants and relapse following successful treatment. The efficacy of pharmacological agents that intervene with the mechanisms involved in dysregulation of cortisol synthesis and release are being explored in depression, particularly in TRD. Studies have been carried out with these drugs as augmenting agents for antidepressants or as monotherapy. The strongest evidence has come from studies using metyrapone, a cortisol synthesis inhibitor, and this has been described in detail in this review. The most robust evidence for its antidepressant efficacy in depression comes from a double-blind, randomized, placebo-controlled study of augmentation of serotonergic antidepressants with metyrapone. A 3-week augmentation of serotonergic antidepressants with 1 g metyrapone daily was shown to be superior to placebo in reducing the Montgomery-Asberg Depression Rating Scale by 50%, 5 weeks following initiation of treatment. The mechanism of the antidepressant action of metyrapone is not clear but the evidence for various potential mechanisms is discussed. PMID- 23983969 TI - Lithium and tricyclic antidepressant-induced delirium presenting with prominent dyspraxia: case report. PMID- 23983970 TI - Respiratory arrest and oversedation in an adolescent given intramuscular clonazepam for rapid tranquillization. AB - Many young people in forensic adolescent units require intramuscular medication for rapid tranquillization. The efficacy and safety of the medications used is not well reported in this age group. Here we report a case of a 14-year-old girl experiencing severe oversedation and respiratory compromise on two occasions following intramuscular clonazepam. PMID- 23983971 TI - Editorial. PMID- 23983972 TI - The knowledge and attitudes of psychiatrists towards antipsychotic long-acting injections in Nigeria. AB - BACKGROUND: Antipsychotic long-acting injections (LAIs) reduce covert nonadherence with medication in the clinical management of psychotic disorders. However, they are variably utilised by clinicians, especially in the long term. Factors including poor knowledge, stigma and perceived coercion can all adversely influence LAI utilisation. Previous research has emanated almost exclusively from developed countries. This study explores the knowledge and attitudes of psychiatrists and trainees in Nigeria towards LAIs. METHODS: A cross-sectional study was undertaken among mental health professionals in Nigeria using a pre existing questionnaire. RESULTS: Participant psychiatrists (n = 128) expressed positive attitudes towards LAIs. Their knowledge concerning LAIs and its side effects was fair. The participants reported that nearly half (41.7%) of their patients with a psychotic illness were on LAIs. Those who reported a high prescribing rate for LAIs (>40%) were more likely to endorse more positive 'patient-centred attitudes' (p < 0.04). In contrast to previous reports, psychiatrists reported that patients were less likely to feel ashamed when on LAIs, though most endorsed the statement that force was required during LAI administration. CONCLUSION: The desirability of treatment by injections differs in Africa in comparison to Western cultures, possibly due to the increased potency that injections are perceived to have. This is perhaps evidenced by high rates reported for use of LAIs. Nigerian psychiatrists had positive attitudes to LAIs but their knowledge, particularly regarding side effects, was fair and needs to be improved. Providing information to patients prior to antipsychotic treatment may enhance informed consent in a country where medical paternalism is still relatively strong. PMID- 23983973 TI - The drugs don't work? antidepressants and the current and future pharmacological management of depression. AB - Depression is a potentially life-threatening disorder affecting millions of people across the globe. It is a huge burden to both the individual and society, costing over L9 billion in 2000 alone: the World Health Organisation (WHO) cited it as the third leading cause of global disability in 2004 (first in the developed world), and project it will be the leading cause by 2030. The serendipitous discovery of antidepressants has revolutionized both our understanding and management of depression: however, their efficacy in the treatment of depression has long been debated and recently been brought very much into the public limelight by a controversial publication by Kirsch, in which the role of placebo response in antidepressant efficacy trials is highlighted. Whilst antidepressants offer benefits in both the short and long term, important problems persist such as intolerability, delayed therapeutic onset, limited efficacy in milder depression and the existence of treatment-resistant depression. PMID- 23983974 TI - Olanzapine long-acting injection: insights from an early case series in the UK. AB - OBJECTIVE: Olanzapine long-acting injection depot (OLAI) has been licensed in the UK since 2008. As a result of the recognition during clinical trials that in 0.07% of injections there may be inadvertent intravenous administration leading to post-injection delirium/sedation syndrome (PDSS), the licence mandates a 3 h observation after each injection and accompaniment of the patient to their final destination. The administration of OLAI may thus necessitate organization of local service provisions. We report on how a single healthcare facility in Northern Ireland has treated three initial patients and present a brief case series on these patients and their clinical outcomes. METHODS: In the first three patients with schizophrenia to receive OLAI, the clinical notes were retrospectively examined to provide clinical data. RESULTS: All three patients had acceptable clinical outcomes showing sustained clinical improvement and have continued on OLAI for over 1 year. Observation has been undertaken within an existing daycare unit staffed by nursing staff and occupational therapists for 3 h after each injection. No issues have emerged from the use of this service that has also provided educational and psycho-educational programmes for the patients. No cases of post-injection delirium/sedation syndrome were reported. There have been no additional cost implications. CONCLUSIONS: In patients for whom OLAI may be clinically indicated, the utilization of an existing service to provide the 3 h of observation after each injection may represent a solution with a cost neutral outcome. PMID- 23983975 TI - Aripiprazole induced severe and extensive skin reaction: A case report. AB - Adverse cutaneous reactions are one of the most frequent types of adverse drug reactions, and have been reported with a wide range of psychotropics including typical and atypical antipsychotics. However the majority of adverse cutaneous reactions are relatively minor, and severe reactions are relatively rare. Aripiprazole is a third-generation atypical antipsychotic that has been available in the UK for over seven years. Here the author reports the first reported case of a lichenoid drug reaction to aripiprazole, a severe and potentially life threatening adverse cutaneous reaction that required medical and surgical intervention. PMID- 23983976 TI - Hallucinogen-persisting perception disorder. AB - A 33-year-old female patient developed a hallucinogen-persisting perception disorder (HPPD) after lysergic acid diethylamide (LSD) abuse for a year at the age of 18. Specifically, she reported after images, perception of movement in her peripheral visual fields, blurring of small patterns, halo effects, and macro- and micropsia. Previous treatment with antidepressants and risperidone failed to ameliorate these symptoms. Upon commencing drug therapy with lamotrigine, these complex visual disturbances receded almost completely. Based on its hypothesized neuroprotective and mood-stabilizing effects, the antiepileptic lamotrigine may offer a promising new approach in the treatment of HPPD. PMID- 23983977 TI - Case reports of patients with treatment-resistant schizophrenia and related psychotic disorders intolerant to clozapine responding to high doses of quetiapine. PMID- 23983978 TI - Unexpected effect of aripiprazole on nociceptive pain. PMID- 23983979 TI - Editorial. PMID- 23983980 TI - Use of quetiapine XR and quetiapine IR in clinical practice for hospitalized patients with schizophrenia: a retrospective study. AB - Quetiapine fumarate, a first-line treatment for schizophrenia, exists in two formulations: extended release (XR) and immediate release (IR). This naturalistic, noninterventional study evaluated use of quetiapine XR/IR among in patients with schizophrenia [ClinicalTrials.gov identifier: NCT01214135]. Data were collected from medical records. Categorical and numerical outcomes were compared using chi(2) and t tests. Of 178 enrolled patients, 66% and 34% used quetiapine XR and IR respectively. Based on mean daily dose, XR was used as antipsychotic medication in 64% of patients compared with 40% of patients on IR (dose >= 400 mg/day; p = 0.002) and in higher doses than IR (494 versus 345 mg/day; p = 0.001; calculated averages). Schizophrenia was more commonly reported as reason for use of XR than IR (20% versus 0%; p = 0.0003). Patients with comorbid substance abuse or somatic disease were more likely to receive XR (p = 0.003; p = 0.03). Treatment cessation due to nonadherence was less common in patients on XR (3.4% versus 12%; p = 0.03). Polypharmacy was seen in 98% of patients. Quetiapine XR/IR usage varies in hospitalized patients with schizophrenia. XR is more often used in antipsychotic dosage; IR is more commonly used at lower doses as add-on therapy. Both quetiapine XR and IR have their place in clinical practice and provide treatment choice in schizophrenia. PMID- 23983981 TI - A study of the efficacy and safety of switching from oral risperidone to risperidone long-acting injection in older patients with schizophrenia. AB - OBJECTIVE: We investigated the clinical efficacy and safety of switching to risperidone long-acting injection (RLAI) in older patients with schizophrenia receiving oral risperidone. METHODS: The subjects were 48 inpatients who had been diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Their clinical symptoms were assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impression - Severity of Illness scale, and their safety was assessed using the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS), body weight, body mass index, and blood biochemistry tests. RESULTS: No significant differences in clinical symptom improvement efficacy were seen between the group switched to RLAI and the control group. The mean changes from baseline on the DIEPSS total score and prolactin level were significantly greater in the older group switched to RLAI than in the control group. Furthermore, in older patients, RLAI allowed the dosage of the concomitant medication to be significantly reduced compared with the control group. CONCLUSION: The results of this study suggest that switching older patients from oral risperidone to RLAI may result in superior efficacy and safety, and may also make it possible to reduce the dosage of the concomitant medication. PMID- 23983982 TI - A successful treatment strategy for clozapine-induced parotid swelling: a clinical case and systematic review. AB - Parotid gland swelling is a less frequently reported side effect of clozapine and has no licensed treatment. A 58-year-old man treated with clozapine for treatment resistant schizophrenia developed bilateral painful parotid swellings and hypersalivation. Initial trials of dose alteration and antihypersalivatory medication had limited success. A combination of benzatropine and terazosin was successful in treating the parotid hyperplasia. Clozapine was the probable cause of parotid swelling in our case, as established using the Naranjo adverse drug reaction probability scale and World Health Organization causality categories. Literature for treatments of clozapine-induced parotid gland swellings was reviewed. None of the published articles suggested a treatment regimen for clozapine-induced parotid hyperplasia. Most reports only highlighted the occurrence of salivary gland swelling with clozapine. Others mentioned management strategies, which included spontaneous resolution, or resolution on discontinuing clozapine. One report, a trial with benzatropine and ipratropium, had variable success. In this case the re-emergence of parotid swelling when terazosin and benzatropine doses were missed followed by a quick resolution upon recompliance, goes some way in proving that this combination is indeed effective. The combination of terazosin and benzatropine appears to have a role in treating parotid gland swellings induced by clozapine. PMID- 23983984 TI - Transdermal patches: the emerging mode of drug delivery system in psychiatry. AB - Adherence to prescribed psychiatric and nonpsychiatric medication is a serious issue in people with mental illness that can contribute to poor health outcomes. Some of the factors influencing adherence include side effects of medication and the ease of use. With mental healthcare provision increasingly focusing on a community model of health delivery, there seems to be a renewed interest in addressing complex dilemmas of safety and adherence to treatment. The use of alternative methods of safely delivering medication in innovative ways may resolve some of these difficulties. There has been little discussion about the wider use of transdermal patches in the field of psychiatry in published literature. This article describes the findings from the literature on key principles underlying transdermal delivery strategies, the scope of clinical use in psychiatric illness and explores its challenges and advantages. PMID- 23983983 TI - Cannabis, a complex plant: different compounds and different effects on individuals. AB - Cannabis is a complex plant, with major compounds such as delta-9 tetrahydrocannabinol and cannabidiol, which have opposing effects. The discovery of its compounds has led to the further discovery of an important neurotransmitter system called the endocannabinoid system. This system is widely distributed in the brain and in the body, and is considered to be responsible for numerous significant functions. There has been a recent and consistent worldwide increase in cannabis potency, with increasing associated health concerns. A number of epidemiological research projects have shown links between dose-related cannabis use and an increased risk of development of an enduring psychotic illness. However, it is also known that not everyone who uses cannabis is affected adversely in the same way. What makes someone more susceptible to its negative effects is not yet known, however there are some emerging vulnerability factors, ranging from certain genes to personality characteristics. In this article we first provide an overview of the biochemical basis of cannabis research by examining the different effects of the two main compounds of the plant and the endocannabinoid system, and then go on to review available information on the possible factors explaining variation of its effects upon different individuals. PMID- 23983985 TI - Neonatal hypoglycaemia following maternal olanzapine therapy during pregnancy: a case report. PMID- 23983987 TI - Priapism associated with risperidone: a case report, literature review and review of the South London and Maudsley hospital patients' database. AB - Priapism is a urological emergency defined as persistent penile erection that is unrelated to sexual stimulation and typically involving only the corporal cavernosa. It can occur as a rare side effect of antipsychotic medications and is mediated via their alpha-adrenergic antagonist effect. In this paper we describe a case of priapism in a patient started on risperidone and sodium valproate. We also review the South London and Maudsley Case Register Interactive Search database to assess how many other cases of priapism were reported in patients taking risperidone. We add this information to a literature review of cases of priapism associated with risperidone. PMID- 23983988 TI - Buprenorphine augmentation in the treatment of refractory obsessive-compulsive disorder. AB - BACKGROUND: OCD is often refractory to treatment. There is a need for the development of new, non-invasive treatments for severe OCD. RATIONALE: There is evidence that opiates can be a useful adjunctive treatment in OCD. We summarise our experience with sublingual buprenorphine augmentation of standard pharmacological management of severe OCD. METHODS: Patients were recruited from a standard psychiatric outpatient clinic and gave their consent to the treatment trial. The severity of the OCD was rated with the Y-BOCS. The buprenorphine was introduced to their existing medication regime at a low dose and the dose increased according to response. In order to gauge the reproducibility of the response the buprenorphine was withdrawn and then reintroduced once symptoms had returned. RESULTS: 4 out of 7 patients with treatment resistant OCD showed a 30% reduction in the Y-BOCS score following buprenorphine augmentation. 3 of the responders were comorbid for other Axis 1 diagnoses. All of the responders had shown some improvement with SSRIs or clomipramine. Non-responders had not shown any improvement with either antidepressant or antipsychotic drugs. Typically improvement appeared within 2 days of initiating buprenorphine and waned within 1 to 2 days of its discontinuation. The dose of buprenorphine required varied between 400 ug and 600 ug a day. One responder managed on alternate day dosing. Reintroduction of buprenorphine resulted in symptom control within 2 to 3 days. The buprenorphine treatment was not associated with significant side-effects and the improvement was maintained without progressive dose escalation. CONCLUSIONS: Buprenorphine augmentation of standard treatment for OCD can result in clinically meaningful improvement in a proportion of refractory OCD cases. Further treatment trials are indicated. PMID- 23983989 TI - Effect of epigallocatechin gallate supplementation in schizophrenia and bipolar disorder: an 8-week, randomized, double-blind, placebo-controlled study. AB - OBJECTIVES: Strategies that focus on the reduction of oxidative stress and inflammation may have therapeutic benefit for the treatment of schizophrenia. This clinical trial sought to determine, in a double-blind study, whether epigallocatechin gallate (EGCG), a green tea extract, is a useful adjunct to maintenance antipsychotic medication. METHODS: Adults with schizophrenia, schizoaffective disorder or bipolar disorder who were maintained on antipsychotic and other psychotropic medications were randomized to supplemental EGCG or placebo. Study participants completed clinical assessments and blood draws to evaluate supplemental treatment effects on psychiatric symptoms and plasma inflammatory markers. RESULTS: A total of 34 participants (17 EGCG, 17 placebo) were randomized and 25 participants (14 EGCG, 11 placebo) completed the study. Both treatment groups showed significant reductions in psychotic, depressive and anxiety symptoms from baseline to end of treatment. However, EGCG did not significantly affect psychiatric symptoms or inflammatory markers, as compared with placebo. Adverse effects were mild and comparable between groups. CONCLUSION: There was no signal for a therapeutic effect of the green tea extract EGCG on psychiatric symptoms in this placebo-controlled pilot study. PMID- 23983990 TI - Head movements during conversational speech in patients with schizophrenia. AB - BACKGROUND: Motor abnormalities are frequently described in schizophrenia, and work by Altorfer and colleagues suggests that measuring head movements during conversational speech shows differences at the level of the individual. We wished to see whether their findings, conducted using computer analysis of video obtained in motion capture suites, could be replicated using compact, portable movement sensors, in a case-control study comparing the mean amplitude of head movements during general conversation. METHODS: A referred sample of inpatients and outpatients with a diagnosis of paranoid schizophrenia was identified from case note information. Movement sensors, mounted in a baseball cap worn by subjects, transmitted data via Bluetooth to a laptop, which simultaneously captured audio to identify who was speaking. Subjects also completed a series of rating scales. RESULTS: Data from the final 11 cases and 11 controls demonstrated a substantial group difference in mean amplitude of head movement velocity during speech (p < 0.0001), although this was not significant at the level of the individual. CONCLUSIONS: Movement sensors proved well suited to capturing head movements, demonstrating a large effect size in subjects with schizophrenia. PMID- 23983992 TI - Neuroleptic malignant syndrome associated with quetiapine and venlafaxine use: a case report and discussion. PMID- 23983993 TI - Plasma prolactin and bone mineral density in patients on long-term risperidone. PMID- 23983991 TI - The prevalence and mechanisms of metabolic syndrome in schizophrenia: a review. AB - Metabolic syndrome (MetS), a constellation of central obesity, hypertension, dyslipidaemia and glucose intolerance, is highly prevalent in individuals with schizophrenia and conveys significant cardiovascular risk and mortality. Associated risk factors are female sex, some ethnic groups, advanced age, long duration of illness, smoking and exposure to antipsychotic agents. The prevalence of MetS varies across countries and psychiatric populations, and its development can be very rapid. Regular monitoring of all features of MetS is the cornerstone of its early detection and management. Future research needs to focus more on genetic determinants of MetS in the context of schizophrenic illness. This review aims to update the reader with the latest knowledge about the prevalence of MetS in schizophrenia and what might be the underlying pathophysiological mechanisms. PMID- 23983994 TI - Post-Traumatic Stress Disorder (PTSD) Following Childbirth: Prevalence and Contributing Factors. AB - BACKGROUND: Childbirth might be a traumatic event for some women. OBJECTIVES: This study was conducted with the objective of investigating the prevalence of Post-Traumatic Stress Disorder (PTSD) following childbirth. PATIENTS AND METHODS: The study was designed using a descriptive correlation scheme. The participants were selected from the women referred to the healthcare centers affiliated with Zahedan University of Medical Sciences, Zahedan, Iran. Personal interviews were conducted with 600 women who were 6-8 weeks postpartum and had been undergone to this center for postpartum and child care. RESULTS: One hundred and three (17. 2%) women had symptoms of PTSD following childbirth based on the PTSD Symptom Scale (PSS). The results of logistic regression analysis revealed a significant correlation between maternal occupation (P = 0.01), depression level (P < 0.001) and anxiety level (P < 0.001) with PTSD following childbirth. CONCLUSIONS: PTSD from childbirth occurs in some women. Early identification of risk factors should lead to early therapeutic intervention in the mothers at risk of PTSD. PMID- 23983995 TI - Comparison of High Frequency Positive Pressure Mechanical Ventilation (HFPPV) With Conventional Method in the Treatment of Neonatal Respiratory Failure. AB - BACKGROUND: Respiratory failure is a major problem in neonatal medicine in all over the world and has different causes. Using mechanical ventilation is one of its major treatments. OBJECTIVES: Different strategies have been expressed in this context, including high frequency mechanical ventilation. PATIENTS AND METHODS: This study is a prospective randomized clinical trial conducted on all newborns with respiratory failure hospitalized in the NICU of Tehran vali-asr Hospital during 2009.These patients were divided in to two groups through block Randomization method; conventional mechanical ventilation group and high frequency ventilation group. RESULTS: Intraventricular hemorrhage (IVH) and air leak (e.g. pneumothorax) were less in HFPPV group than conventional group (P = 0.012 and P = 0.038). The mean time needed for mechanical ventilation was lower in HFPPV group, but this difference was not statistically significant (P = 0.922). Needing to O2 in 28 days of age was almost equal in both groups (P = 0. 99). Mortality, and refractory hypoxia and PVL were lower in HFPPV group, but the difference was not statistically significant (P = 0.301, P = 0. 508, P = 0. 113). CONCLUSIONS: Treatment of neonatal respiratory failure with high rate mechanical ventilation may reduce some complications. PMID- 23983996 TI - Prevalence and determinants of male adolescents' smoking in iran: an explanation based on the theory of planned behavior. AB - BACKGROUND: Adolescent smoking problem has still remained as a public health concern, but factors that attributing to the initiation of adolescent smoking are not well known in Iran. OBJECTIVES: The aim of this study is to estimate the prevalence of smoking, and its associations among high school male adolescents in Iran, in the context of the theory of planned behavior (TPB). PATIENTS AND METHODS: This was a cross-sectional study involving male adolescent students (high school) in the city of Zarandieh, Iran. A multiple-stage sampling protocol was used. The participants completed an anonymous, voluntary, and self-report questionnaire. Prevalence was estimated, and demographic variables, psychological factors, and the theory of planned behavior components were used to indicate factors contributing to adolescents' cigarette smoking. RESULTS: In all, 365 students were entered the study. The mean age of respondents was 16.49 +/- 1.11 years. The prevalence of current smoking was 15.1%. The result obtained from logistic regression analysis revealed that all theory of planned behavior (TPB) components [knowledge (OR = 0.75; 95% CI: (0.59-0.97), attitude (OR = 0.75; 95% CI: (0.65-0.86), self-efficacy (OR = 0.82; 95% CI: (0.71-0.95), subjective norms (OR = 0.84; 95% CI: (0.72-0.98)] were significant predating factors for adolescents smoking habits. In addition, having parents who smoke (OR = 4.75; 95% CI: (1.38-12.35), smoking friends (OR = 3.76; 95% CI: (1.20-11.76), and smoking siblings (OR = 4.21; 95% CI: (1.17-11.16) were significant contributing factors to adolescents' cigarette smoking behavior. CONCLUSIONS: The results showed that the prevalence of cigarette smoking in adolescents was high, and the theory of planned behavior (TPB) components were significant predictors of cigarette smoking. It seems that interventions targeting adolescents' smoking habits might benefit using the TPB model. PMID- 23983997 TI - The effect of vitamin a supplementation on biochemical parameters in multiple sclerosis patients. AB - BACKGROUND: Vitamin A has different functions in the body and after being converted to acid form; it can play many roles in immune system regulation. Therefore, this vitamin can be used as a supplement in the treatment of diseases, such as cancer and autoimmune diseases. Vitamin A is a fat-soluble compound and its long-term consumption in high doses can have some adverse effects. OBJECTIVE: The current study aimed to investigate the possible complications and find solutions to minimize the adverse effects. PATIENTS AND METHODS: This study was a double blind randomized clinical trial. In the main study, vitamin A (as retinyl palmitate) was given to 35 multiple sclerosis (MS) patients in order to regulate their immune system with a dose of 25000 IU/day for a period of six months. To investigate the possible biochemical complications, lipid profiles, fasting blood sugar (FBS), liver enzymes, and C-reactive protein (CRP) were tested. RESULTS: Vitamin A did not have a significant difference in lipid profiles, FBS and liver enzymes between the two groups receiving vitamin A and the placebo, but CRP increased in patients who were taking vitamin A, 1.65+/-0.43 (mg/L) and 2.88+/ 0.67, (Mean+/-SEM), before and after the intervention respectively (P=0.029), and statistical analysis showed significant differences with the group receiving placebo (P=0.011) and CRP level in vitamin A group was 1.3 mg/L more than those of the placebo group after intervention (P=0.011). CONCLUSIONS: Considering that no significant difference was found in the proven vitamin A side effects, due to the increase in CRP, frequent clinical and biochemical controls are required along with vitamin A supplementation. PMID- 23983999 TI - Conventional Agar-Based Culture Method, and Nucleic Acid Amplification Test (NAAT) of the cppB Gene for Detection of Neisseria gonorrhea in Pregnant Women Endocervical Swab Specimens. AB - BACKGROUND: Neisseria gonorrhea is the etiological agent of the sexually transmitted disease (STD) gonorrhea, and primarily infects the mucous membranes of the urethra, endocervix, pharynx or rectum of females which may result in substantial morbidity. N. gonorrhea also causes disseminated infection, with complications that may result in ectopic pregnancy, tubal infertility, chronic pelvic pain or maternal transmission of gonorrhea, and also increases susceptibility to HIV. OBJECTIVES: In the present investigation, we used conventional agar-based culture method, and nucleic acid amplification of CCPB gene for detection of Neisseria gonorrhea in endocervical swabs samples collected from pregnant women studied. PATIENTS AND METHODS: Endocervical swabs specimens for this study were obtained from 1100 pregnant women who presented to Shiraz (Iran) Hospitals from 2009 to 2011. In the present investigation we used conventional agar-based culture method, and nucleic acid amplification test (NAAT) of CCPB gene for detection of Neisseria gonorrhea in endocervical swabs samples collected from pregnant women studied. From each pregnant woman two endocervical swabs were taken: one swab placed in tubes containing phosphate buffered saline for Polymerase Chain Reaction, and the other to inoculate on culture media. RESULTS: Among 1100 endocervical swabs examined, 13 (1.18%) samples had positive results by polymerase chain reaction (PCR) on Neisseria gonorrhea CCPB gene. All endocervical swabs culture had negative results for Neisseria gonorrhea. 84 (7%) of the women had vaginal discharge, in whom PCR on endocervical swabs of these individuals had negative findings. CONCLUSIONS: Nucleic acid amplification tests (NAATs) are very appropriate in detection of infected individuals. Detection techniques such as NAATs are independent of bacterial viability, and have a potential to limit false negative samples, therefore, in our country, the application of different laboratory diagnosis methods including NAATs with culture as gold standard for determination antimicrobial susceptibility is essential. PMID- 23983998 TI - Differences in vaginal lactobacilli composition of Iranian healthy and bacterial vaginosis infected women: a comparative analysis of their cytotoxic effects with commercial vaginal probiotics. AB - BACKGROUND: Vaginal flora of healthy women is dominated by Lactobacillus species which can prevent bacterial vaginosis. OBJECTIVES: The current study aimed to determine the differences in vaginal lactobacilli composition of Iranian healthy and bacterial vaginosis (BV) infected women and compared their cytotoxic effects with commercial vaginal probiotics. PATIENTS AND METHODS: One hundred and seventy eight vaginal specimens were collected from healthy and BV infected women. Lactobacillus colonies were obtained by culturing on laked blood BHI and MRS medias and genetically defined by 16s rRNA sequencing. Differentiating the specimens to normal, intermediate and BV infected were carried out by Ison and Hey grading protocol. Identification of Lactobacillus strains in vaginal specimens were performed by Multiplex PCR. The inhibitory effects of lactobacilli on Hela (tumoral cervical cells) and HNCF-pi52 (normal cervical cells) were conducted by MTT and trypan blue assays. RESULTS: L. crispatus, L. gasseri, L. iners, L. jensenii, L. acidophilus and L. rhamnosus were the most frequently occurring species in vagina of healthy Iranian women. L. crispatus and L. jensenni were significantly higher in the normal than in the BV infected groups. Also the cytotoxic effect of L. crispatus on tumoral cervical cells was higher than other lactobacilli including commercial probiotics. CONCLUSIONS: As L. crispatus and L. jensenni were significantly higher in BV infected women and the cytotoxic effect of L. crispatus on tumoral cervical cells was high, introduction of new probiotics seems necessary. PMID- 23984000 TI - Alcohol and drug use prevalence and factors associated with the experience of alcohol use in Iranian adolescents. AB - BACKGROUND: Alcohol and other drugs use is a problem among adolescents leading to numerous physical, social, and educational damages. OBJECTIVE: For determining the prevalence of alcohol and other substance use as well as the factors associated with the experience of alcohol use in adolescents. PATIENTS AND METHODS: This is a population-based and cross-sectional study, which was conducted in August 2010 on adolescents aged 15-18 years in Tehran. Data were collected by a Youth Risk Behavior Surveillance System (YRBSS) in 1,201 adolescents. The multistage cluster sampling method was used. Questions belonging to the domain of alcohol and other substance use were analyzed. RESULTS: In general, 15.1% of adolescents had experienced alcohol, which is significantly higher in boys (21.9%) compared to girls (8.4%) (P = 0.000). 3.1% of adolescents had experience using opium and marijuana. 5.6% had used ecstasy. The results of multivariate logistic regression indicated that low parental control rather than medium control [AOR: 0.09], lifetime cigarette use [AOR: 10.41], having a tobacco user friend [AOR: 4.36], and having an alcohol user friend [AOR: 5.84] are factors that are significantly related to the experience of alcohol use in female adolescents. In addition, studying in private schools rather than public schools [AOR: 3.46], lifetime cigarette use [AOR: 3.41], lifetime water pipe use [AOR: 4.43], experience of sexual activity [AOR: 8.52], having an alcohol user friend [AOR: 12.60], and having a water pipe user in family [AOR: 2.98] are factors that are significantly related to the experience of alcohol use in male adolescents. CONCLUSIONS: We recommend interventional plans based gender aimed at improving adolescent health with regard substance abuse. PMID- 23984001 TI - Abnormal expression of e-cadherin in gastric adenocarcinoma, and its correlation with tumor histopathology and helicobacter pylori infection. AB - BACKGROUND: Gastric cancer is one of the leading cancers in the world especially in Iran. There are many genomic and molecular factors that cause gastric cancer to occur, and also there are many markers that associate with tumor invasiveness. E-cadherin is a tumor suppressor gene which produces E-cadherin transmembrane protein, a molecule which plays an important role in adhesion and differentiation of epithelial cells. OBJECTIVES: In this study, we evaluated the prevalence of abnormal E-cadherin expression in Iranian patients with gastric adenocarcinoma, and tried to find its correlation with H. pylori infection and tumor histopathology. MATERIALS AND METHODS: A historical cohort survey was performed on tissue samples obtained from 95 total or partial gastrectomy with gastric adenocarcinoma. The immunohistochemistry and Giemsa staining were used to assess E-cadherin expression, and H- pylori infection respectively. The association between abnormal E-cadherin expression and tumor histopathology characteristics include depth of tumor invasion, tumor differentiation, tumor phenotype, tumor type, tumor size, neurovascular invasion of tumor, and regional lymph node involvement and H- pylori infection and patient's age and sex, were evaluated in all patients. RESULTS: Abnormal E-cadherin expression was noted in 38% of patients, and 59% of patients were infected with H-pylori. A significant correlation was seen between abnormal E-cadherin expression, and tumor grade and regional lymph node involvement. We could not find any significant association between abnormal E-cadherin expression and H- pylori infection, patient's age and sex, tumor phenotype, tumor type, depth of tumor invasion, tumor size, and neurovascular invasion of tumor. CONCLUSIONS: Abnormal E-cadherin expression is a common phenomenon in gastric adenocarcinoma. The study showed a significant correlation between abnormal E-cadherin expression and tumor grade and regional lymph node involvement; so, abnormal E-cadherin expression may be used as a predictive factor for tumor invasiveness in gastric adenocarcinoma. PMID- 23984002 TI - The Effect of Cochlear Implantation on the Improvement of the Auditory Performance in 2-7 Years old Children, Shiraz 2004-2008. AB - BACKGROUND: Hearing loss is the most common sensorineural deficiency in human beings. Cochlear implantation is introduced worldwide to treat the severe to profound sensorineural hearing loss, and can result in both speech comprehension and production. OBJECTIVES: The present study aims to determine the effect of cochlear implantation on the improvement of the auditory performance in 2-7 years old children. PATIENTS AND METHODS: The present follow-up study is a kind of cohort study which was conducted on 98 children between 2-7 years old who had referred to Fars Cochlear Implantation Center. The patients' information was gathered from their profiles both before and after the operation. The auditory performance score was obtained in 3 stages; 6 months, 1 year, and 2 years after the cochlear implantation through the Cap test. The data was analyzed using the nonparametric Friedman test as well as Mann-Withney, Kruskal-Wallis, and Spearman's Ranks Correlation coefficients. RESULTS: The mean and the median of the auditory performance score of the children who had undergone the cochlear implantation revealed a significant improvement from 6 months to 1 year, and 2 years after the implantation. It showed a significant statistical association between implantation age, type of hearing loss, regular reference, and the length of being present in the rehabilitation program with the auditory performance. It showed no significant association between sex, mother's level of education, being monolingual or bilingual, and family size with the auditory performance. CONCLUSIONS: This study revealed that the type of hearing loss, Presence in the rehabilitation program, and the age of cochlear implantation can be major prognostic factors of the response to the treatment, then the country's health policy makers and health planners must executively take into account the infants' hearing screening program during the first 6 month of age. PMID- 23984003 TI - Incidence and risk factors of retinopathy of prematurity in mashhad, northeast iran. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a vascular retinal disease that can cause low vision or blindness and affects premature newborns of very low birth weight. OBJECTIVES: The purpose of this study was to determine the incidence and risk factors for ROP among very premature infants in Mashhad located northeast of Iran. MATERIAL AND METHODS: In this cross-sectional study performed between 2006 and 2010, predisposing factors and severity of ROP were evaluated in very premature infants (<32 gestational weeks). Consecutive infants were enrolled at birth and screened for ROP at 4 to 6 weeks of age by indirect ophthalmoscopy. Severe ROP was defined as stage 4 or 5. Chi-square, Student's t-, and Fisher's test were used for statistical analysis. RESULTS: The incidence of ROP was 26.2%. Significant differences between the ROP and control groups were observed, these include; gestational age, sex, birth weight, Apgar score, durationof parenteral nutrition, oxygen therapy, phototherapy, maximum PaO2 and minimum SpO2 (P < 0.05). Severe ROP was seen in 31.4% (11/32) of ROP cases (5.4% of newborns). CONCLUSION: The incidence of ROP is relatively high in this region. Risk factors for ROP among very premature infants include hypoxia, severe hyperoxia, relatively low blood SPO2, gestational age, birth weight, and Apgar score. PMID- 23984004 TI - Transcranial Doppler Ultrasonography in Beta-thalassemia Major Patients Without and With Thrombocytosis. AB - BACKGROUND: Beta-thalassemia is a type of anemia in which the patients may require splenectomy and this can lead to thrombocytosis with increased risk of stroke. Transcranial Doppler ultrasound is a method for determining cerebral vessel stenosis. OBJECTIVES: The aim of this study was to investigate whether the risk of a future stroke secondary to cerebral artery stenosis can be predicted with the use of transcranial Doppler ultrasound in beta-thalassemia major patients. PATIENTS AND METHODS: This study included 54 beta-thalassemia major patients divided into 2 groups; group A consisted of 28 patients who have thrombocytosis secondary to a previous splenectomy and group B comprised of 26 patients who did not have a splenectomy with normal platelet count, as well as a control group of 30 healthy individuals. RESULTS: Transcranial Doppler ultrasound of the cerebral vessels were performed in all participants, and the results for each group were compared with the controls. In addition, patients were evaluated for evidence of high flow velocity in the cerebral vessels that met the clinically significant criteria of >= 50% stenosis. Transcranial Doppler ultrasound velocity criteria for > 50% stenosis, indicating a risk of stroke, were not documented in any patients but increase in cerebral blood velocities in many arteries in group A and in some arteries in group B were revealed. CONCLUSION: Following splenectomy, thrombocytosis can predispose the patients to an increase in cerebral blood velocities more than respected with anemia. But by transcranial doppler ultrasonography no evidence of significant stenosis were found in intracerebral arteries to conclude that the beta-thalassemia major patients were more prone to the development of stroke secondary to this abnormality. PMID- 23984005 TI - Comparison of the Effect of Mindfulness-based Cognitive Therapy Accompanied by Pharmacotherapy With Pharmacotherapy Alone in Treating Dysthymic Patients. AB - BACKGROUND: Dysthimia in adults is a chronic depression disorder which is characterized by a mild depression for at least 2 years. Remarkable psycho-social involvements, greater disturbances in psycho-social functions compared to other forms of depression and lack of definite findings about preferred treatment for this disorder led us to evaluate the effectiveness of Mindfulness based cognitive therapy (MBCT) method adjunct to pharmacotherapy compared with pharmachothrapy alone in treating dysthymia in this thesis. OBJECTIVES: This study aimed to evaluate the effectiveness of mindfulness-based cognitive therapy on a chronic type of depression disorder called dysthymia. PATIENTS AND METHODS: This study is a clinical trial of an interventional method which was carried out on dysthymic and double depressed patients who had referred to psychiatric clinics of Shiraz University of Medical Sciences, Shiraz, Iran. In doing so, 50 patients above the age of 18 were selected through convenience sampling and assigned into intervention and control groups. The control group only received medications while the intervention group in addition to receiving medication, participated in 8 sessions of a mindfulness based cognitive therapy course which was held once a week and each session lasted for 2 to 2.5 hours. All the participants filled out Beck Depression Inventory II and five facet mindfulness questionnaire. The data were analyzed using the SPSS statistical software (version 16) and univariate covariance and independent t test statistical methods. RESULTS: In this study, no statistically significant differences were found between the two groups regarding the demographic characteristics. The mean difference between the two groups was statistically significant for the variables in post-test considering the pre test. The experimental group participants showed significant improvement in terms of the defined variables; a trend which was not observed in the control group participants. CONCLUSION: The results of this study show that adding MBCT to pharmacotherapy in treatment of dysthymic patients can cause significant improvement in depression symptoms and mindfulness skills in patients compared to pharmacotherapy alone. PMID- 23984006 TI - The prevalence of hepatitis B virus infection in mashhad, iran: a population based study. AB - BACKGROUND: Hepatitis B virus (HBV) infection is the most common and serious liver infection in the world. An estimated 350 million people are chronic carriers of this virus, of whom, more than 620,000 die from liver-related diseases annually. Due to the vaccination program, prevalence of HBV, particularly among the younger generation, is reported to have declined in recent years in Iran. OBJECTIVES: The aim of this study was to evaluate the prevalence of HBV infection in Mashhad, North-East of Iran. PATIENTS AND METHODS: Three thousand one hundred and ninety eight (3198) individuals living in Mashhad were studied using cluster sampling method. HBV infection was determined by HBsAg ELISA commercial kit. Positive results were subjected for PCR using HBV-specific primers. HBeAg, HBeAb, and HBcAb-IgM ELISA tests were performed for HBsAg positive samples. RESULTS: Patients' age ranged from 15 to 65 years (Mean = 35.54 +/- 14.85). Thirty four (1.0%) of the subjects were positive for HBsAg, of whom, 2.9 % (1 of 34 cases) were also positive in PCR-based screening. ELISA tests for HBeAg, HBeAb, and HBcAb IgM were positive in one (2.9 %), 27 (79.4%) and one (2.9 %) cases, respectively. CONCLUSIONS: According to our results, HBsAg was positive in 0.53 of the total population. The prevalence of HBV infection was seemingly low in Mashhad; however, an upward trend was observed in older subjects probably due to successful HBV vaccination coverage in the younger generation. Continuous surveillance and periodic population-based studies are essential to monitor the prevalence of HBV infection in Mashhad in the future. PMID- 23984007 TI - Serum level of homocysteine, folate and vitamin-B12 in epileptic patients under carbamazepine and sodium valproate treatment: a systematic review and meta analysis. AB - BACKGROUND: Numerous studies have shown that long term treatment with anticonvulsants may be an important risk factor for the onset of atherosclerosis, or worsening of its symptoms. There are many contradictory reports regarding these effects. OBJECTIVES: We performed a systematic review and meta-analysis of the published studies in order to see whether the atherogenic outcomes could be related to any serum biochemical abnormalities. MATERIALS AND METHODS: Published articles indexed in PubMed, ISI web of science, Science Direct and Scopus databases from 1990 to 2011 were retrieved using a comprehensive search strategy. After omitting the unrelated articles and duplicates, articles met the eligibility criteria for critical appraisal were included in the analysis. Data were summarized in standard data abstraction forms and subjected to analysis by STATA software. RESULTS: Finally, ten published studies were included in the meta analysis. Results showed that carbamazepine and sodium valproate consumption are associated with a significant elevation of the serum homocysteine levels. On the other hand, medication with carbamazepine is associated with a reduction of the level of folate in the serum and that of sodium valproate is associated with a reduction of serum level of vitamin B12. CONCLUSIONS: According to the results of this study, as carbamazepine and valproate sodium consumption can result in elevated serum levels of homocysteine and decreased levels of folate and vitamin B12, and the atherogenic effect of increased serum homocysteine level is well established, the patients under these medications should be monitored for possible atherogenic effects. PMID- 23984008 TI - Chronic cutaneus mucormycosis in an immunocompetent female. AB - INTRODUCTION: Cutaneous infection is an uncommon presentation of mucormycosis, usually seen after trauma, at the site of surgical drains or after occlusive dressings. The involved area is erythematous and painful, with varying degree of central necrosis. We report the case of chronic coetaneous infection of one year duration and without apparent necrosis in an immunocompetant patient. CASE PRESENTATION: A 32-year-old immunocompetent woman presented with a large unilateral firm infiltrative plaque resembling cancer lesions, disfiguring the eyelids, nose and lips. The punch biopsy and then surgical debridement was done and the diagnosis of cutaneous mucormycosis was confirmed on histologic examinations with granulomatous reaction and characteristic broad, nonseptate, pale-staining hyphae. CONCLUSIONS: Mucomycosis should be in differncial diagnosis of any chronic infiltrative lesions even without visible necrosis and normal immune status of the patient. PMID- 23984009 TI - Lateral Traumatic Esophago-Cutaneous fistula in a Child; Platelet-Rich Fibrin Glue Challenge. AB - INTRODUCTION: The endoscopic fibrin glue or platelet-rich fibrin glue (PRFG) injection is an easy, safe and effective technique for the fistula. So far, the use of fibrin glue has been limited to selected cases. CASE REPORT: Our case is a three years old male child with a neck trauma resulting in a Esophago-Cutaneous fistula after a 3 month period of follow up we decided to use PRFG for this lesion after fine debridement of the fistula tract, and the surrounding fibrosed tissue twice with a one week interval. Our visit after two weeks showed complete recovery and normal general condition. A contrast study revealed complete disappearance of the lesion. CONCLUSIONS: In our case the PRFG completely resolved a long-standing fistula resistant to exhaustive conservative management. The treatment with PRFG has been proved to be effective in the selected cases and it seems that traumatic esophago-cutaneous fistula may be one of these selections. Application of fibrin sealant should be considered early in the management of these difficult clinical problems. PMID- 23984010 TI - Incidence, risk factors and causes of severe neonatal hyperbilirubinemia in the South of iran (fars province). AB - BACKGROUND: Today, Severe hyperbilirubinemia is the most common cause of neonatal readmissions. Identification of the cause of neonatal hyperbilirubinemia is useful in determining whether therapeutic interventions can prevent severe hyperbilirubinemia. OBJECTIVES: We conducted this study to estimate the incidence of severe hyperbilirubinemia in Fars province and to determine the underlying causes and risk factors, which would be of value in identifying and implementing strategies to prevent morbidity from this condition. PATIENTS AND METHODS: All infants less than 28 days referred due to severe indirect hyperbilirubinemia were included. Complete history, physical examination and lab work up were performed. This is a longitudinal prospective study in 2009-2010. RESULTS: More common causes of severe indirect hyperbilirubinemia were blood group incompatibility, G6PD deficiency, sepsis and unknown. Risk factors of severe hyperbilirubinemia were Male sex, previous siblings with severe hyperbilirubinemia, early discharge, NVD, Breast feeding and cultural background of mothers. CONCLUSIONS: Our study showed severe neonate indirect hyperbilirubinemia is still prevalence in Fars province and ethnic and cultural background of the mothers was more effective than school education in preventing hyperbilirubinemia complication. PMID- 23984011 TI - Stroke in birjand, iran: a hospital-based study of acute stroke. AB - BACKGROUND: Stroke, or cerebrovascular accident (CVA), is the second leading cause of death in the world and based on the World Health Organization (WHO) report in 2006, it is responsible for 9.9% of all deaths in the world which over 85% of these deaths occurred in developing countries. OBJECTIVES: The aim of this study was to investigate the data related to the frequency, risk factors, types and mortality of stroke in Birjand city. PATIENTS AND METHODS: A retrospective cohort of consecutive patients with diagnosed stroke who were admitted to hospital (the only neurological center of Birjand) between 2002 and 2008 was designed. A stroke was defined according to clinical features and CT-scan which was confirmed by agreement of a staff neurologist. Collected data included date of admission, age, sex, and hospital outcome as well as related risk factors. RESULTS: Totally, 1219 stroke (85.4% ischemic type) with the mean age of 69.6 +/- 12.9 years and female: male ratio of 1.09 was included in over 6 years. The stroke hospital admission rates were 48.6 and 103.4 /100,000 population /year in the first and the last year of the study, respectively. There was an increasing trend in stroke incidence rate during the study (P < 0.01). The most common epidemiological risk factors for stroke in our region were hypertension, cardiac diseases, a history of stroke, diabetes mellitus, dyslipidemia, and smoking (54.7, 24.4, 20.1, 14.9, 12.2, and 9%, respectively). Overall in-hospital mortality rate was 17.1%. CONCLUSIONS: The stroke hospital admission rate might be increasing in Birjand. Therefore, health care administrators and public health authorities must work harder to promote the knowledge and practice of society about the stroke related risk factors and prevention methods. PMID- 23984012 TI - Quality of life and performing acupuncture on 150 patients suffering from chronic pains: a randomized and intervention study before and after performing. PMID- 23984013 TI - Analyzing the relationship between job stress to mental health, personality type and stressful life events of the nurses occupied in tehran 115 emergency. PMID- 23984014 TI - Diversity of neuromuscular disorders in referred patients to electro diagnostic units of yazd city. PMID- 23984015 TI - Sleep and Wakefulness Correction in Different Seasons From Avicenna's Perspective. PMID- 23984016 TI - Conspicuous Consumption and Sedentary Living: Is this our legacy to our children? PMID- 23984017 TI - Tobacco Smoking: Facts and actions. PMID- 23984018 TI - Tobacco Smoking and Lung Cancer: Perception-changing facts. AB - Tobacco smoking remains the most established cause of lung carcinogenesis and other disease processes. Over the last 50 years, tobacco refinement and the introduction of filters have brought a change in histology, and now adenocarcinoma has become the most prevalent subtype. Over the last decade, smoking also has emerged as a strong prognostic and predictive patient characteristic along with other variables. This article briefly reviews scientific facts about tobacco, and the process and molecular pathways involved in lung carcinogenesis in smokers and never-smokers. The evidence from randomised trials about tobacco smoking's impact on lung cancer outcomes is also reviewed. PMID- 23984019 TI - Recurrent Urinary Tract Infections Management in Women: A review. AB - Urinary tract infections (UTIs) are one of the most frequent clinical bacterial infections in women, accounting for nearly 25% of all infections. Around 50-60% of women will develop UTIs in their lifetimes. Escherichia coli is the organism that causes UTIs in most patients. Recurrent UTIs (RUTI) are mainly caused by reinfection by the same pathogen. Having frequent sexual intercourse is one of the greatest risk factors for RUTIs. In a subgroup of individuals with coexisting morbid conditions, complicated RUTIs can lead to upper tract infections or urosepsis. Although the initial treatment is antimicrobial therapy, use of different prophylactic regimens and alternative strategies are available to reduce exposure to antibiotics. PMID- 23984020 TI - The history of diabetes mellitus. PMID- 23984021 TI - Clinical Spectrum of Hereditary Spastic Paraplegia in Children: A study of 74 cases. AB - OBJECTIVES: The aim of the study was to explore the spectrum of hereditary spastic paraplegia (HSP) in children in Oman. METHODS: This retrospective study was carried out between January 1994 and August 2011 on children with delayed development, gait disorders and motor handicaps, with signs of symmetrical pyramidal tract involvement. A detailed perinatal and family history, including the age of onset of symptoms, was recorded. The children were labelled as having either the pure or complicated form of HSP based on the established diagnostic criteria. In families with more than one affected child, parents and all other siblings were also examined. RESULTS: Within the study, 74 children from 31 families were diagnosed with HSP. Parental consanguinity was seen in 91% of cases, with 44 children (59.4%) experiencing onset of the disease under one year of age. Complicated HSP was the most common type, seen in 81.1%. Speech involvement, mental retardation, and epilepsy were the most common associated abnormalities. Nonspecific white matter changes and corpus callosum abnormalities were noted in 24.3% of cases on magnetic resonance imaging. CONCLUSION: The study described clinical features of 74 children with HSP. Autosomal recessive complicated HSP was seen in 81.1% of cases. PMID- 23984022 TI - Characteristics of hepatitis B infection in a sample of omani patients. AB - OBJECTIVES: This study aimed to describe the demographic and virological characteristics of chronic hepatitis B virus (HBV) infection in a sample of Omani patients, and indirectly assess the efficacy of hepatitis B vaccination programmes and catch-up strategies. METHODS: A retrospective study was undertaken of all patients with chronic HBV infections evaluated and followed-up at the Hepatology Clinic of the Armed Forces Hospital (AFH), Muscat, Oman, between January 2009 and April 2011. RESULTS: A total of 154 patients met the inclusion criteria. The mean age of infected patients was 33 years with 72.7% being over 27 years. Females constituted 47.7% of the patients. Half of the cohort was referred either from the AFH's Obstetric Clinic (29.2%) or its Blood Bank (22.1%). A family history of chronic HBV infection was present in 70% of patients. A total of 95% had positive hepatitis B surface antigens, while only 5% had isolated total hepatitis B core antibodies. Most patients (96%) were hepatitis B e-antigen negative. The majority (77.9%) had low HBV dioribonucleic acid levels of <2,000 IU/ml. Radiological features of liver cirrhosis were observed in 5%. Patients requiring treatment were in the minority (9%). CONCLUSION: Almost 50% of the infected patients were female, the majority being of childbearing age. Medical authorities in Oman should consider enforcing a screening policy for all pregnant women using complete hepatitis B serological testing. PMID- 23984023 TI - Effects of Pre-Pregnancy Body Mass Index and Gestational Weight Gain on Low Birth Weight in Omani Infants: A case-control study. AB - OBJECTIVES: This study aimed to investigate the association between pre-pregnancy maternal body mass index (BMI), gestational weight gain and low birth weight (LBW) in babies born to a sample population of Omani women. METHODS: A case control study was carried out among deliveries registered between 1(st) May 2010 and 30(th) April 2011 at Sultan Qaboos University Hospital, Muscat, Oman. A case was defined as a woman who delivered a low birth weight baby (<2,500 g); a control was a woman delivering a baby weighing between 2,500 and 4,000 g. A random selection of 150 cases and 300 controls was carried out using the hospital information system. Maternal, pre-natal, and delivery data were extracted from the mothers' follow-up cards. Bivariate and multivariate logistic regression analyses were executed to examine the association between pre-pregnancy maternal BMI and LBW. RESULTS: The percentage of underweight mothers (BMI <18.5) was higher among the cases compared to the controls (17.3% versus 6%; P <0.001). The proportion of mothers with less-than-recommended weight gain was also higher among the cases compared to the controls (57.7% versus 33%; P <0.001). After adjustment for potential confounders, infants of underweight mothers had more than twice the risk of LBW compared to those of mothers with normal weight (odds ratio = 2.27; 95% confidence interval 1.09-4.71). CONCLUSION: Underweight Omani women as well as women with less-than-recommended gestational weight gain were at higher risk of delivering LBW babies. Maternal health promotion programmes should be directed towards improving mothers' nutrition before and during pregnancies. PMID- 23984024 TI - Self-Reported Knowledge of Diabetes among High School Students in Al-Amerat and Quriyat, Muscat Governate, Oman. AB - OBJECTIVES: Type 2 diabetes mellitus (T2DM) is emerging as one of the world's greatest health problems, and its incidence and prevalence are increasing at an alarming rate and globally reaching epidemic proportions. With this increasing incidence, emphasis is now being placed on implementing primary prevention, early detection, and educational prevention programmes. This study was undertaken to estimate the level of knowledge of T2DM among high school students and to explore the factors influencing the knowledge of T2DM. METHODS: A cross-sectional study was conducted in four secondary schools in two wilayats (districts) of Muscat governate, Oman, namely Al-Amerat and Quriyat. The study was conducted using a validated English questionnaire covering all aspects of T2DM in one-to-one interviews. A scoring system was used to assess the students' knowledge. RESULTS: Of the 541 students enrolled in the study (45% male and 55% female), only 24% achieved a score of over 10 out of 20. The key areas of poor knowledge were wrong perceptions about diabetic meals (73%), and the possibility of a cure for diabetes (63%). CONCLUSION: Overall poor knowledge levels about T2DM were found among school students. National efforts and school-health-based interventions are highly recommended to increase awareness about diabetes among this age group. PMID- 23984025 TI - The Frequency of Type 2 Diabetes Mellitus among Diabetic Children in El Minia Governorate, Egypt. AB - OBJECTIVES: Type 2 diabetes mellitus (T2DM) in children and adolescents is becoming an increasingly important public health concern throughout the world. This study aimed to estimate the frequency of T2DM among diabetic young people in El-Minia Governorate, Egypt, and to detect its risk factors. METHODS: A total of 210 diabetic patients under 18 years old in Minia Governorate were included in the study and underwent a thorough history-taking, a physical examination and laboratory investigations. RESULTS: T2DM was present in 28 patients (13.3%); it was significantly present in 18 females (64.3%) and 20 (71.4%) of them had a positive family history of DM. T2DM patients had significantly higher BMI and waist circumference centiles for age and sex than those with T1DM. Also, haemoglobin A1c %, serum C-peptide and cholesterol levels were significantly higher in T2DM than T1DM patients. Finally, there were weak significant positive correlations between C-peptide level and both BMI and waist circumference. CONCLUSION: T2DM is no longer a disease of adults but can also occur in children and adolescents. The results suggested that obesity, female gender and a positive family history of DM are risk factors for T2DM. Also, patients with T2DM had poorer glycaemic control and hypercholesterolemia than those with other types of diabetes. PMID- 23984026 TI - Prevalence of rabies in various species in yemen and risk factors contributing to the spread of the disease. AB - OBJECTIVES: This study aimed to describe for the first time the prevalence of the passively-reported rabies virus among different domestic and wild animals submitted to the Central Veterinary Laboratory from various areas in Yemen, and to study prevalence proportion ratios (PPR) that contributed to the spread of rabies among animals, and its transmission to humans. METHODS: A brain sample was obtained from each of the 180 animals and tested for rabies virus by a direct fluorescent antibody test. RESULTS: Out of the total number of animals involved in attacks on humans, 63.3 % were positive for rabies. Of these, dogs were the main animal involved in attacks with a percentage of 92%, of which 62.7% were positive for rabies. Of animals involved in attacks, 70.6% were males of which 60.6% were positive, and 29.4% were females of which 69.8% were positive. Males comprised 68.9% of the total human individuals attacked, of whom 62.9% were attacked by rabies-positive animals. The significant risk factors that contributed to the spread of rabies in general included the presence of poultry carcasses and other waste in the vicinity of the attacks (PPR = 9.5) with a percentage of 84.8%, followed by the time of year, in particular school vacations (PPR = 3.8) with a percentage of 78%. CONCLUSION: Rabies is endemic in Yemen with a very high rabies-positive rate for animals involved in attacks, particularly for stray male dogs. Male children were most often involved in attacks by rabies positive animals. The presence of food waste (particularly poultry carcasses) and school vacation periods were found to correlate significantly with increased risk for human exposure to rabies. PMID- 23984027 TI - Mitochondrial Oxygen Consumption by the Foreskin and its Fibroblast-rich Culture. AB - OBJECTIVES: This study investigated the feasibility of using a phosphorescence oxygen analyser to measure cellular respiration (mitochondrial O2 consumption) in foreskin samples and their fibroblast-rich cultures. METHODS: Foreskin specimens from normal infants were collected immediately after circumcision and processed for measuring cellular respiration and for culture. Cellular mitochondrial O2 consumption was determined as a function of time from the phosphorescence decay of the Pd (II) meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. RESULTS: In sealed vials containing a foreskin specimen and glucose, O2 concentration decreased linearly with time, confirming the zero-order kinetics of O2 consumption by cytochrome oxidase. Cyanide inhibited O2 consumption, confirming that the oxidation occurred mainly in the mitochondrial respiratory chain. The rate of foreskin respiration (mean +/- SD) was 0.074 +/- 0.02 MUM O2 min(-1) mg( 1) (n = 23). The corresponding rate for fibroblast-rich cultures was 9.84 +/- 2.43 MUM O2 min(-1) per 10(7) cells (n = 15). Fibroblast respiration was significantly lower in a male infant with dihydrolipoamide dehydrogenase gene mutations, but normalised with the addition of thiamine or carnitine. CONCLUSION: The foreskin and its fibroblast-rich culture are suitable for assessment of cellular respiration. However, the clinical utility of foreskin specimens to detect disorders of impaired cellular bioenergetics requires further investigation. PMID- 23984028 TI - Disease patterns and outcomes of neonatal admissions at a secondary care hospital in pakistan. AB - OBJECTIVES: This study aimed to determine the disease patterns and outcome of patients admitted to the neonatal unit of a secondary care hospital in Pakistan from January to December 2009. METHODS: Retrospective data from the medical records of all neonates admitted during the study period were reviewed and analysed for age, weight, sex, reason for admission, duration of hospital stay, diagnosis and final outcome. Trends were examined to identify the indicators of inpatient neonatal deaths. RESULTS: The total number of neonates admitted during the study period was 1,554; 979 were male (63%), and 575 were female (37%). A total of 891 patients (57.3%) were born in the hospital while 663 (42.7%) were born elsewhere. The majority were admitted during the first 24 hours of life (51.3%). A total of 13 patients (0.8%) weighed <1 Kg; 85 (5.4%) weighed 1-1.49 Kg, and 587 (37.7%) between 1.5-2.5 Kg. Prematurity and infection were the main reasons for admission (27.9% and 20.33%, respectively), followed by birth asphyxia (13%) and neonatal jaundice (11.3%). A total of 1,287 patients (82.8%) were discharged, 41 left against medical advice (2.6%), 59 were referred to tertiary care hospitals (3.79%) and 106 (6.8%) died. CONCLUSION: Prematurity, low birth weight, birth asphyxia and neonatal jaundice were the major causes of neonatal admissions. This could be reduced by appropriate antenatal care, timely intervention, and in-time referral to tertiary care centres for the deliveries of all high-risk pregnancies. The major cause of neonatal mortality was prematurity. PMID- 23984029 TI - A Study of Stress among Students of Professional Colleges from an Urban area in India. AB - OBJECTIVES: Various studies across the globe have emphasised that students undertaking professional courses, such as medical and dental studies, are subjected to higher stress. Excessive stress could lead to psychological problems like depression and anxiety. The objective of the current study was to assess stress among students of various professional colleges and its association with various academic, social and health-related factors. METHODS: This cross sectional study was conducted from September 2011 to February 2012 among students of medical, dental and engineering colleges from the urban area of Sangli district, Maharashtra, India, using a convenience sampling technique. The calculated total sample size was 1,200. A pretested self-administered questionnaire was used for the data collection. Analysis was done using percentage, the chi-square test, binary logistic regression and multinomial logistic regression. RESULTS: Out of the 1,224 respondents, 299 (24.4%) experienced stress. Among them 115 (38.5%), 102 (34.1%) and 82 (27.4%) were dental, medical and engineering students, respectively. There was a statistically significant association between stress and the field of education. Stress was observed in 187 (27.7%) females and 112 (20.4%) males; the association with gender was statistically significant. By applying binary logistic regression, medical studies, health and lifestyle factors, and academic factors were the significant predictors for stress. CONCLUSION: Students from all the three fields studied were exposed to stress. Academic factors were one of the most important stressors. The introduction of stress management education into the curriculum could prove useful in combatting this problem. PMID- 23984030 TI - Causes of stress and coping strategies adopted by undergraduate health professions students in a university in the United arab emirates. AB - OBJECTIVES: This study aimed to compare causes of stress and coping strategies adopted by a sample of undergraduate health-profession students at the Gulf Medical University, United Arab Emirates. METHODS: An anonymous voluntary questionnaire-based survey was conducted, from January to July 2011, among first- and second-year medicine, dentistry, pharmacy and physiotherapy students (N = 212) to identify causes of stress. Coping strategies were studied using the Brief COPE Inventory. RESULTS: Worries regarding the future (54.2%) and parental expectations (40.1%) were the major stressors. Poor diet (36.8%) and a lack of exercise (36.3%) were also reported to cause stress. Students used multiple strategies, mainly religion/praying (74.5%), planning (70.5%) and taking action (70.5%) to cope with stress. There were no significant differences observed in the stressors or coping strategies between genders or programmes. First-year students (62.5%) relied on emotional support significantly more (P <0.05) than second-year students (48.5%). CONCLUSION: The main causes of stress were worries regarding future and parental expectations. The majority of the students used positive coping strategies, with religion/praying found to be the most frequently used strategy. PMID- 23984031 TI - Improving vaginal examinations performed by midwives. AB - A vaginal examination (VE) is an essential part of midwifery care, and is routinely performed when assessing the progress of labour. As evidence shows that during labour women may find VEs unpleasant, embarrassing and sometimes painful, the aim of this article is to review literature on the use of VEs during labour and to synthesise information from the available literature on how to provide an effective VE. The studies considered were retrieved from three databases (the Cumulative Index to Nursing and Allied Health Literature [CINAHL], SCOPUS and MEDLINE) using the following search terms: "VEs in labour", "midwives and use of VEs" and "women experiences of VEs in labour". The literature reviewed suggests that midwives are not careful about VEs. Therefore, a concerted effort is needed to pay attention to the frequency of VEs, the management of pain and distress, information-giving and the preferences of the patient, so that the patient can feel in control during a VE. PMID- 23984032 TI - Managing Gastric Linitis Plastica: Keep the scalpel sheathed. AB - Gastric linitis plastica is a diffuse type of cancer which is characterised by a thickening and rigidity of the stomach wall. It is notorious for its failure to cause early symptoms, and patients with symptoms generally have a more advanced form of the disease. We report our 18-month-long experience of managing gastric linitis plastica at Barnsley District General Hospital, UK. In our series of 8 patients, only one patient was offered surgery; the rest were offered palliative or supportive treatment. The findings in our series were consistent with the available evidence that curative treatment is not an option for the majority of cases with linitis plastica. PMID- 23984033 TI - Anterior Segmental Distraction Osteogenesis in the Hypoplastic Cleft Maxilla: Report of five cases. AB - Orthognathic surgery and distraction osteogenesis play a prime role in the correction of maxillary hypoplasia in patients with cleft lip and palate (CLP). Advancement of the anterior maxilla alone without interfering with the velopharyngeal sphincter may be advantageous in cleft patients, who more commonly have speech deficits and dental crowding. We present a case series of anterior maxillary segmental distraction for maxillary hypoplasia in 5 CLP patients with a one-year follow-up. A custom-made tooth-borne distraction device with a hyrax screw positioned anteroposteriorly was used. The evaluation comprised of hard and soft tissue analysis and speech assessment. A stable occlusion with positive overjet and correction of dental-crowding without extraction was achieved at one year post-distraction. Facial profile and lip support improved. There was no deterioration in speech. PMID- 23984034 TI - Metastatic invasive lobular carcinoma of the breast masquerading as a primary renal malignancy. AB - Breast cancer is known to metastasise to different organs in the body, but an initial presentation of breast cancer with loin pain secondary to a metastatic renal mass is extremely rare. We report a 58-year-old woman who presented with recurrent left loin pain due to a metastatic deposit of invasive lobular carcinoma of the breast. The detection of a renal mass on computed tomography led to the assumption of a renal pelvic malignancy. The diagnostic dilemma posed by the detection of a breast mass during staging and the usefulness of immunohistochemistry in the confirmation of diagnosis are discussed. PMID- 23984035 TI - Large Right Atrial Vegetation in a Patient with Tunnelled Dialysis Catheter Related Staphylococcal Sepsis: Remove the catheter if not in use. PMID- 23984036 TI - Re: Lipoprotein(a) and SYNTAX Score Association with Severity of Coronary Artery Atherosclerosis in North India. PMID- 23984037 TI - Placental Tumour: What could it be? AB - Placental tumours include placental chorioangiomas, teratomas, haemangiomas, and haematomas. Placental chorioangiomas are benign vascular tumours and are the most common placental tumours, with a prevalence of 1%. Large placental chorioangiomas are rare and may lead to pregnancy complications and poor perinatal outcomes. These complications include fetal anaemia, hydrops fetalis, fetal growth restriction, polyhydramnios, and preterm delivery. We report a case of a large placental chorioangioma, the antenatal management and the maternal and fetal outcomes. PMID- 23984038 TI - Semilobar Holoprosencephaly with Neurogenic Hypernatraemia: Two new cases. AB - Holoprosencephaly (HPE) is a developmental defect of the embryonic forebrain and midface. It is due to the non-cleavage of the embryonic forebrain into two cerebral hemispheres and the incomplete development of the paramedian structures. The overall prevalence is 1.31 per 10,000 births. The aetiology could be genetic, environmental, or both. HPE is classified into alobar, semilobar, and lobar subtypes based on the degree of separation of the cerebral hemispheres. We report two new cases of semilobar HPE with neurogenic hypernatraemia. Lack of thirst and hypodypsia associated with chronic hypernatraemia in patients with HPE is highly suggestive of neurogenic hypernatraemia. Early identification of neurogenic hypernatraemia is important as it improves with forced fluid therapy and does not require any medication. PMID- 23984040 TI - Giant Spontaneous Femoral Artery Pseudoaneurysm Treated with Covered Stents: Report of a rare presentation and review of literature. AB - We report the case of a 62-year-old woman who presented with a one-month history of a pulsatile mass, with no antecedent trauma or intervention. Imaging showed a large pseudoaneurysm (PSA) of the distal portion of the left superficial femoral artery. The PSA was treated successfully with endovascular placement of covered stents. PMID- 23984039 TI - Anaesthesia Management of a Patient with Hereditary Angioedema with Prophylactic Administration of C1 Esterase Inhibitor: Case report and literature review. AB - Hereditary angioedema (HAE) is a rare disorder caused by a deficiency of C1 esterase inhibitor. Minor trauma and emotional stress are the most common initiating events leading to contact system activation and excessive uncontrolled bradykinin release. This manifests as angioedema, a vascular reaction of the deeper layers of the skin and mucous membranes, with vasodilatation and increased permeability resulting in tissue swelling. Severe angioedema can occur in the perioperative period, leading to fatal airway obstruction. We describe the anaesthetic management of a child with HAE for dental rehabilitation and provide an review of the relevant literature. PMID- 23984041 TI - Chloroquine-induced Acute Dystonic Reactions after a Standard Therapeutic Dose for Uncomplicated Malaria. AB - Acute dystonic reactions (ADR) are extrapyramidal effects that usually occur after the initiation of a wide variety of drugs or triggering factors besides neuroleptics. We report the case of a 54-year-old man who was admitted with an approximately 10-hour history of muscle twitching around the eyes, face and neck after he took the first dose of oral chloroquine phosphate (1 g [600 mg base]) prescribed for uncomplicated malaria. He was given intravenous diazepam (10 mg statum) followed by 10 mg of oral diazepam 3 times a day. The symptoms improved within 30 minutes of treatment, and he was discharged 14 hours later after a complete recovery. PMID- 23984042 TI - Post-traumatic blepharocele in an adult. AB - Cerebrospinal fluid (CSF) collection in the eyelid is known as blepharocele. It is rarely reported in adults. In this report, we describe one such patient who developed a non-resolving swelling of the left upper eyelid associated with mechanical ptosis following a head injury. He had fractures involving the left orbital rim and roof, and the medial and lateral walls. His left frontal sinus was hypoplastic. The diagnosis of CSF blepharocele was made based on clinical, biochemical and radiological findings. He underwent transcranial repair of the left frontobasal dural tear with a good recovery. PMID- 23984043 TI - Occurrence of Fatal and Nonfatal Adverse Outcomes after Heart Transplantation in Patients with Pretransplant Noncytotoxic HLA Antibodies. AB - HLA antibodies (HLA ab) in transplant candidates have been associated with poor outcome. However, clinical relevance of noncytotoxic antibodies after heart transplant (HT) is controversial. By using a Luminex-based HLA screening, we retested pretransplant sera from HT recipients testing negative for cytotoxic HLA ab and for prospective crossmatch. Out of the 173 consecutive patients assayed (52 +/- 13y; 16% females; 47% ischemic etiology), 32 (18%) showed pretransplant HLA ab, and 12 (7%) tested positive against both class I and class II HLA. Recipients with any HLA ab had poorer survival than those without (65 +/- 9 versus 82 +/- 3%; P = 0.02), accounting for a doubled independent mortality risk (P = 0.04). In addition, HLA-ab detection was associated with increased prevalence of early graft failure (35 versus 15%; P = 0.05) and late cellular rejection (29 versus 11%; P = 0.03). Of the subgroup of 37 patients suspected for antibody mediated rejection (AMR), the 9 with pretransplant HLA ab were more likely to display pathological AMR grade 2 (P = 0.04). By an inexpensive, luminex based, HLA-screening assay, we were able to detect non-cytotoxic HLA ab predicting fatal and nonfatal adverse outcomes after heart transplant. Allocation strategies and desensitization protocols need to be developed and prospectively tested in these patients. PMID- 23984044 TI - Expression of the Metastasis Suppressor KAI1 in Uveal Melanoma. AB - Introduction. Uveal melanoma (UM) is an intraocular tumor that leads to metastatic disease in approximately 50% of afflicted patients. There is no efficacious treatment for metastatic disease in this cancer. Identification of markers that can offer prognostic and therapeutic value is a major focus in this field at present. KAI1 is a metastasis suppressor gene that has been reported to play a role in various human malignancies, although it has not previously been evaluated in UM. Purpose. To investigate the expression of KAI1 in UM and its potential value as a prognostic marker. Materials and Methods. 18 cases of human primary UM were collected and immunostained for KAI1 expression. A pathologist evaluated staining intensity and distribution semiquantitatively. Each case was categorized as group 1 (low staining) or group 2 (high staining). Results. In group 2, two of the 12 cases presented with metastasis. Conversely, in group 1, five out of 6 cases had metastasis. The mean follow-up of patients who did not develop metastasis was 81.81 months (median: 75 months) versus 42.14 months (median: 44 months) for patients with metastasis. Conclusions. KAI1 is a promising candidate marker that may offer prognostic value in UM; it may also represent a therapeutic target in metastatic disease. PMID- 23984045 TI - Does fundus fluorescein angiography procedure affect ocular pulse amplitude? AB - Purpose. This study examines the effects of fundus fluorescein angiography (FFA) procedure on ocular pulse amplitude (OPA) and intraocular pressure (IOP). Materials and Methods. Sixty eyes of 30 nonproliferative diabetic retinopathy patients (15 males, 15 females) were included in this cross-sectional case series. IOP and OPA were measured with the Pascal dynamic contour tonometer before and after 5 minutes of intravenous fluorescein dye injection. Results. Pre FFA mean OPA value was 3.05 +/- 1.36 mmHg and post-FFA mean OPA value was 2.93 +/ 1.28 mmHg (P = 0.071). Pre-FFA mean IOP value was 17.97 +/- 1.99 mmHg and post FFA mean IOP value was 17.81 +/- 2.22 mmHg (P = 0.407). Conclusion. Although both mean OPA and IOP values were decreased after FFA procedure, the difference was not statistically significant. This clinical trial is registered with Australian New Zealand Clinical Trials Registry number ACTRN12613000433707. PMID- 23984046 TI - Ingestion of leucine + phenylalanine with glucose produces an additive effect on serum insulin but less than additive effect on plasma glucose. AB - Most individual amino acids stimulate insulin secretion and attenuate the plasma glucose response when ingested with glucose. We determined whether ingestion of two amino acids simultaneously with glucose would result in an additive effect on the glucose area response compared with ingestion of amino acids individually. Leucine and phenylalanine were chosen because they were two of the most potent glucose-lowering amino acids when given individually. Eight healthy subjects were studied on four separate days. Test meals were given at 0800. The first meal was a water control. Subjects then received 25 g glucose or leucine + phenylalanine (1 mmol/kg fat free body mass each) +/-25 g glucose in random order. Glucose, insulin and glucagon were measured frequently for 2.5 hours thereafter. Net areas under the curves were calculated using the mean fasting value as baseline. The insulin response to leucine + phenylalanine was additive. In contrast, the decrease in glucose response to leucine + phenylalanine + glucose was less than additive compared to the individual amino acids ingested with glucose. Interestingly, the insulin response to the combination was largely due to the leucine component, whereas the glucose response was largely due to the phenylalanine component. Glucose was unchanged when leucine or phenylalanine, alone or in combination, was ingested without glucose. This trial is registered with ClinicalTrials.gov NCT01471509. PMID- 23984047 TI - Cerebral white matter and retinal arterial health in hypertension and type 2 diabetes mellitus. AB - We examined 33 hypertensive (22 with comorbid type 2 diabetes mellitus (T2DM)) and 29 normotensive (8 with T2DM) middle-aged and elderly adults, comparable in age and education. Relative to normotensive participants, those with hypertension, in addition to a higher prevalence of periventricular white matter (WM) lesions, had significantly lower WM microstructural integrity of major fiber tracts as seen with MRI-based diffusion tensor imaging. Among participants with hypertension, those with co-morbid T2DM (n = 22) had more widespread WM pathology than those without T2DM (n = 11). Furthermore and consistent with previous research, both hypertension and T2DM were related to decreased retinal arterial diameter. Further exploratory analysis demonstrated that the observed retinal arteriolar narrowing among individual with hypertension was associated with widespread subclinical losses in WM microstructural integrity and these associations were present predominantly in the frontal lobe. We found that T2DM adds to the damaging effects of hypertension on cerebral WM, and notably these effects were independent of age and body mass index. Given that the decrease in retinal arteriolar diameter may be a biomarker for parallel pathology in cerebral arterioles, our data suggest that the frontal lobe may be particularly vulnerable to microvascular damage in the presence of hypertension and T2DM. PMID- 23984048 TI - Global cardiovascular risk assessment in the management of primary hypertension: the role of the kidney. AB - The knowledge of each patient's global risk profile is a prerequisite for effective therapeutic strategies in primary hypertension. Detecting the presence of subclinical organ damage at the cardiac, vascular, and renal levels is key for stratifying cardiovascular risk and may also be helpful in choosing antihypertensive agents and in monitoring the effectiveness of treatment. A systematic, in-depth search for subclinical organ damage, however, may be difficult to carry out because of logistic and economic problems related to the high prevalence of hypertension in the population. Renal abnormalities such as microalbuminuria and reduction in glomerular filtration rate have proven to be powerful predictors of cardiovascular and renal outcome. Thanks to their relatively low cost and wide applicability, more widespread use of these tests in the diagnostic workup will help detect subsets of patients at greater risk for whom additional preventive and therapeutic treatment is advisable. PMID- 23984049 TI - Does the admission blood pressure associate with short- and long term outcome in stroke patients treated with thrombolysis? A single centre study. AB - Background. The association between outcome and elevated admission blood pressure (BP) remains uncertain in acute stroke patients. The aim of the present study was to examine the association between admission blood pressure and outcome in ischemic stroke patients treated with tissue plasminogen activator (tPA). Method. This study included patients treated with tPA within 4.5 hours after symptom onset. Four quartiles based on the admission BP values were defined. BP development of the first 12 hours was compared to outcome parameters defined as NIHSS 24 hours after tPA and mRS after 3 months. Results. 265 patients were included. A trend with worse short- and long-term outcome was present in the quartiles with the lowest and highest admission BP compared to the quartile with admission values at 140-160 mm Hg systolic. BP in quartile 1 was insignificantly decreased after 12 hours while the BP in quartiles 3 and 4 remained above recommended levels. Conclusion. Admission BP is associated with short- and long term outcome after stroke. Low- or high-admission BP indicates cardiac comorbidity or preexisting hypertension, where close monitoring and further examinations are requested to prevent poorer outcome. PMID- 23984050 TI - Vagal blocking improves glycemic control and elevated blood pressure in obese subjects with type 2 diabetes mellitus. AB - BACKGROUND: An active device that downregulates abdominal vagal signalling has resulted in significant weight loss in feasibility studies. OBJECTIVE: To prospectively evaluate the effect of intermittent vagal blocking (VBLOC) on weight loss, glycemic control, and blood pressure (BP) in obese subjects with DM2. METHODS: Twenty-eight subjects were implanted with a VBLOC device (Maestro Rechargeable System) at 5 centers in an open-label study. Effects on weight loss, HbA1c, fasting blood glucose, and BP were evaluated at 1 week to 12 months. RESULTS: 26 subjects (17 females/9 males, 51 +/- 2 years, BMI 37 +/- 1 kg/m(2), mean +/- SEM) completed 12 months followup. One serious adverse event (pain at implant site) was easily resolved. At 1 week and 12 months, mean excess weight loss percentages (% EWL) were 9 +/- 1% and 25 +/- 4% (P < 0.0001), and HbA1c declined by 0.3 +/- 0.1% and 1.0 +/- 0.2% (P = 0.02, baseline 7.8 +/- 0.2%). In DM2 subjects with elevated BP (n = 15), mean arterial pressure reduced by 7 +/- 3 mmHg and 8 +/- 3 mmHg (P = 0.04, baseline 100 +/- 2 mmHg) at 1 week and 12 months. All subjects MAP decreased by 3 +/- 2 mmHg (baseline 95 +/- 2 mmHg) at 12 months. CONCLUSIONS: VBLOC was safe in obese DM2 subjects and associated with meaningful weight loss, early and sustained improvements in HbA1c, and reductions in BP in hypertensive DM2 subjects. This trial is registered with ClinicalTrials.gov NCT00555958. PMID- 23984051 TI - A six-month randomized controlled trial of whole soy and isoflavones daidzein on body composition in equol-producing postmenopausal women with prehypertension. AB - OBJECTIVES: This paper reported the effects of commonly used whole soy foods (soy flour) and purified daidzein (one of the major isoflavones and the precursor of equol) on changes in anthropometric measurements and body composition in a 6 month double-blind, randomized, placebo-controlled trial among prehypertensive postmenopausal women who are also equol producers. METHODS: 270 eligible women were randomized to either one of the three treatments: 40 g soy flour (whole soy group), 40 g low-fat milk powder + 63 mg daidzein (daidzein group), or 40 g low fat milk powder (placebo group) daily each for 6 months. Anthropometric indicators and body composition were measured before and after intervention. RESULTS: 253 subjects completed the study with good compliance. Urinary isoflavones levels suggested good compliance of subjects with supplementation. Whole soy and purified daidzein had no significant effect on body weight, body mass index (BMI), waist and hip circumferences, waist to hip ratio (WHR), body fat percentage, fat mass, and free fat mass. CONCLUSION: Six-month consumption of whole soy and purified daidzein at provided dosage had no improvement on body weight and composition compared with isocaloric milk placebo among prehypertensive equol-producing postmenopausal women. This trial is registered with ClinicalTrials.gov NCT01270737. PMID- 23984054 TI - Information and Communication Technology to Link Criminal Justice Reentrants to HIV Care in the Community. AB - The United States has the world's highest prison population, and an estimated one in seven HIV-positive persons in the USA passes through a correctional facility annually. Given this, it is critical to develop innovative and effective approaches to support HIV treatment and retention in care among HIV-positive individuals involved in the criminal justice (CJ) system. Information and communication technologies (ICTs), including mobile health (mHealth) interventions, may offer one component of a successful strategy for linkage/retention in care. We describe CARE+ Corrections, a randomized controlled trial (RCT) study now underway in Washington, that will evaluate the combined effect of computerized motivational interview counseling and postrelease short message service (SMS) text message reminders to increase antiretroviral therapy (ART) adherence and linkage and retention in care among HIV-infected persons involved in the criminal justice system. In this report, we describe the development of this ICT/mHealth intervention, outline the study procedures used to evaluate this intervention, and summarize the implications for the mHealth knowledge base. PMID- 23984053 TI - An adaptive CBPR approach to create weight management materials for a school based health center intervention. AB - PURPOSE: From our previous clinical work with overweight/obese youth, we identified the need for research to create an effective weight management intervention to address the growing prevalence of adolescent metabolic syndrome. Formative assessment through an adaptive community-based participatory research (CBPR) approach was conducted toward the development of a nutritional and physical activity (DVD) and clinician toolkit for a school-based health center (SBHC) weight management intervention. METHODS: We first conducted parent and adolescent interviews on views and experiences about obesity while convening a community advisory council (CAC) recruited from two participating urban New Mexico high schools. Thematic findings from the interviews were analyzed with the CAC to develop culturally and developmentally appropriate intervention materials. RESULTS: Themes from the parent and adolescent interviews included general barriers/challenges, factors influencing motivation, and change facilitators. The CAC and university-based research team reached consensus on the final content of nutrition and physical activity topics to produce a DVD and clinician toolkit through six monthly sessions. These materials used in the SBHC intervention resulted in a greater reduction of body mass index when compared to adolescents receiving standard care. CONCLUSIONS: Formative assessment using an adaptive CBPR approach resulted in the creation of culturally and age appropriate weight reduction materials that were acceptable to study participants. This trial is registered with ClinicalTrials.gov NCT00841334. PMID- 23984052 TI - Comparative effectiveness of after-school programs to increase physical activity. AB - BACKGROUND: We conducted a comparative effectiveness analysis to evaluate the difference in the amount of physical activity children engaged in when enrolled in a physical activity-enhanced after-school program based in a community recreation center versus a standard school-based after-school program. METHODS: The study was a natural experiment with 54 elementary school children attending the community ASP and 37 attending the school-based ASP. Accelerometry was used to measure physical activity. Data were collected at baseline, 6 weeks, and 12 weeks, with 91% retention. RESULTS: At baseline, 43% of the multiethnic sample was overweight/obese, and the mean age was 7.9 years (SD = 1.7). Linear latent growth models suggested that the average difference between the two groups of children at Week 12 was 14.7 percentage points in moderate-vigorous physical activity (P < .001). Cost analysis suggested that children attending traditional school-based ASPs-at an average cost of $17.67 per day-would need an additional daily investment of $1.59 per child for 12 weeks to increase their moderate vigorous physical activity by a model-implied 14.7 percentage points. CONCLUSIONS: A low-cost, alternative after-school program featuring adult-led physical activities in a community recreation center was associated with increased physical activity compared to standard-of-care school-based after school program. PMID- 23984055 TI - Socioeconomic, psychiatric and materiality determinants and risk of postpartum depression in border city of ilam, Western iran. AB - Background. Postpartum depression (PPD) is considered as one of the mood disturbances occurring during 2-3 months after delivery. The present study aimed to determine the prevalence of PPD and its associated risk factors in border city of Ilam, western Iran. Methods. Through a descriptive cross-sectional study in 2011, overall, 197 women who attended Obstetrics & Gynecology clinics postpartumly in the border city of Ilam, western Iran, were randomly recruited. A standard questionnaire that was completed by a trained midwife through face to face interviews was used for data gathering. Results. Mean age +/- standard deviations was 27.9 +/- 5.2 years. Prevalence of PPD was estimated to be 34.8% (95% CI: 27.7-41.7). A significant difference was observed among depression scores before and after delivery (P <= 0.001). Type of delivery (P = 0.044), low socioeconomic status (P = 0.011), and women having low educational level (P = 0.009) were the most important significant risk factors associated with PPD. The regression analysis showed that employed mothers compared to housekeepers were more at risk for PPD (adjusted OR = 2.01, 95% CI: 1.22-2.28, P = 0.003). Conclusions. Prevalence of PPD in western Iran was slightly higher than the corresponding rate from either national or international reports. PMID- 23984057 TI - Quality of life study following cytoreductive surgery and intraperitoneal chemotherapy for pseudomyxoma peritonei including redo procedures. AB - BACKGROUND: Our aim was to evaluate the quality of life following cytoreductive surgery and intraperitoneal chemotherapy for pseudomyxoma peritonei. We also conducted an analysis of all patients who underwent CRS and HIPEC for pseudomyxoma peritonei from 1997 to 2012. METHODS: We contacted 87 patients using the FACT C (version 4) quality of life questionnaire, and FACIT-TS-G (version 1) was also used. RESULTS: A total of 63 patients (response rate 72%) were available for quality of life interview and analysis. The median time from surgery to questionnaire evaluation was 31 months (range 6-161 months). 62% were females with an average age of 54 years. 22% of the patients had over one cytoreductive surgical procedure. We analysed our patients postoperatively based on physical, functional, social, and emotional well being who reported favourable outcomes in all sections. Patients who had a single procedure had a significantly higher score (P = 0.016) in the additional concerns section of the questionnaire. The patients who had a single procedure had better gastrointestinal digestion in terms of bowel control, appetite, and food digestion and also body appearance scoring. CONCLUSIONS: 79% of the patients stated that they would undergo further cytoreductive surgery and that redo procedures do not result in a significantly worse quality of life. PMID- 23984056 TI - Vitamin-responsive epileptic encephalopathies in children. AB - Untreated epileptic encephalopathies in children may potentially have disastrous outcomes. Treatment with antiepileptic drugs (AEDs) often may not control the seizures, and even if they do, this measure is only symptomatic and not specific. It is especially valuable to identify potential underlying conditions that have specific treatments. Only a few conditions have definitive treatments that can potentially modify the natural course of disease. In this paper, we discuss the few such conditions that are responsive to vitamin or vitamin derivatives. PMID- 23984058 TI - Health Literacy Influences Heart Failure Knowledge Attainment but Not Self Efficacy for Self-Care or Adherence to Self-Care over Time. AB - Background. Inadequate health literacy may be a barrier to gaining knowledge about heart failure (HF) self-care expectations, strengthening self-efficacy for self-care behaviors, and adhering to self-care behaviors over time. Objective. To examine if health literacy is associated with HF knowledge, self-efficacy, and self-care adherence longitudinally. Methods. Prior to education, newly referred patients at three HF clinics (N = 51, age: 64.7 +/- 13.0 years) completed assessments of health literacy, HF knowledge, self-efficacy, and adherence to self-care at baseline, 2, and 4 months. Repeated measures analysis of variance with Bonferroni-adjusted alpha levels was used to test longitudinal outcomes. Results. Health literacy was associated with HF knowledge longitudinally (P < 0.001) but was not associated with self-efficacy self-care adherence. In posthoc analyses, participants with inadequate health literacy had less HF knowledge than participants with adequate (P < 0.001) but not marginal (P = 0.073) health literacy. Conclusions. Adequate health literacy was associated with greater HF knowledge but not self-efficacy or adherence to self-care expectations over time. If nurses understand patients' health literacy level, they may educate patients using methods that promote understanding of concepts. Since interventions that promote self-efficacy and adherence to self-care were not associated with health literacy level, new approaches must be examined. PMID- 23984059 TI - Development of a regional nursing research partnership for academic and practice collaborations. AB - Background. Collaborative nursing research across academic and practice settings is imperative to generate knowledge to improve patient care. Models of academic/practice partnerships for nursing research are lacking. This paper reports data collected before and during a one-day retreat for nurse researchers and administrators from local universities and health care organizations designed to establish a regional nursing research partnership. Methods. Quantitative and qualitative methods were used to address the study aims: (1) to assess research involvement and institutional research resources; (2) to assess interest in and concerns regarding cross-institutional collaborations; and (3) to describe perceptions of the purpose of a partnership and resources needed to ensure success. Results. Participants (n = 49) had differing perceptions of accessibility to resources; participants in practice settings reported less accessibility to resources, notably grant development, informatics, and research assistant support. Participants were interested in collaboration although concerns about conflict of interest were expressed. Four themes related to partnering were identified: harnessing our nursing voice and identity; developing as researchers; staying connected; and positioning for a collaborative project. Conclusion. Academic-practice research collaborations will become increasingly important with health care system changes. Strategies to develop and sustain productive partnerships should be supported. PMID- 23984060 TI - Advanced nursing practice for older people. PMID- 23984061 TI - Endoscopic third ventriculostomy in previously shunted children. AB - Endoscopic third ventriculostomy (ETV) is a routine and safe procedure for therapy of obstructive hydrocephalus. The aim of our study is to evaluate ETV success rate in therapy of obstructive hydrocephalus in pediatric patients formerly treated by ventriculoperitoneal (V-P) shunt implantation. From 2001 till 2011, ETV was performed in 42 patients with former V-P drainage implantation. In all patients, the obstruction in aqueduct or outflow parts of the fourth ventricle was proved by MRI. During the surgery, V-P shunt was clipped and ETV was performed. In case of favourable clinical state and MRI functional stoma, the V-P shunt has been removed 3 months after ETV. These patients with V-P shunt possible removing were evaluated as successful. In our group of 42 patients we were successful in 29 patients (69%). There were two serious complications (4.7%) one patient died 2.5 years and one patient died 1 year after surgery in consequence of delayed ETV failure. ETV is the method of choice in obstructive hydrocephalus even in patients with former V-P shunt implantation. In case of acute or scheduled V-P shunt surgical revision, MRI is feasible, and if ventricular system obstruction is diagnosed, the hydrocephalus may be solved endoscopically. PMID- 23984062 TI - Confocal laser endomicroscopy in neurosurgery: a new technique with much potential. AB - Technical innovations in brain tumour diagnostic and therapy have led to significant improvements of patient outcome and recurrence free interval. The use of technical devices such as surgical microscopes as well as neuronavigational systems have helped localising tumours as much as fluorescent agents, such as 5 aminolaevulinic acid, have helped visualizing pathologically altered tissue. Nonetheless, intraoperative instantaneous frozen sections and histological diagnosis remain the only method of gaining certainty of the nature of the resected tissue. This technique is time consuming and does not provide close-to real-time information. In gastroenterology, confocal endoscopy closed the gap between tissue resection and histological examination, providing an almost real time histological diagnosis. The potential of this technique using a confocal laser endoscope EndoMAG1 by Karl Storz Company was evaluated by our group on pig brains, tumour tissue cell cultures, and fresh human tumour specimen. Here, the authors report for the first time on the results of applying this new technique and provide first confocal endoscopic images of various brain and tumour structures. In all, the technique harbours a very promising potential to provide almost real-time intraoperative diagnosis, but further studies are needed to provide evidence for the technique's potential. PMID- 23984063 TI - Complements and the wound healing cascade: an updated review. AB - Wound healing is a complex pathway of regulated reactions and cellular infiltrates. The mechanisms at play have been thoroughly studied but there is much still to learn. The health care system in the USA alone spends on average 9 billion dollars annually on treating of wounds. To help reduce patient morbidity and mortality related to abnormal or prolonged skin healing, an updated review and understanding of wound healing is essential. Recent works have helped shape the multistep process in wound healing and introduced various growth factors that can augment this process. The complement cascade has been shown to have a role in inflammation and has only recently been shown to augment wound healing. In this review, we have outlined the biology of wound healing and discussed the use of growth factors and the role of complements in this intricate pathway. PMID- 23984064 TI - Sensory recovery outcome after digital nerve repair in relation to different reconstructive techniques: meta-analysis and systematic review. AB - Good clinical outcome after digital nerve repair is highly relevant for proper hand function and has a significant socioeconomic impact. However, level of evidence for competing surgical techniques is low. The aim is to summarize and compare the outcomes of digital nerve repair with different methods (end-to-end and end-to-side coaptations, nerve grafts, artificial conduit-, vein-, muscle, and muscle-in-vein reconstructions, and replantations) to provide an aid for choosing an individual technique of nerve reconstruction and to create reference values of standard repair for nonrandomized clinical studies. 87 publications including 2,997 nerve repairs were suitable for a precise evaluation. For digital nerve repairs there was practically no particular technique superior to another. Only end-to-side coaptation had an inferior two-point discrimination in comparison to end-to-end coaptation or nerve grafting. Furthermore, this meta analysis showed that youth was associated with an improved sensory recovery outcome in patients who underwent digital replantation. For end-to-end coaptations, recent publications had significantly better sensory recovery outcomes than older ones. Given minor differences in outcome, the main criteria in choosing an adequate surgical technique should be gap length and donor site morbidity caused by graft material harvesting. Our clinical experience was used to provide a decision tree for digital nerve repair. PMID- 23984065 TI - Four-year cumulative radiation exposure in patients undergoing computed tomography angiography for suspected pulmonary embolism. AB - Purpose. The objective of this study was to determine the estimated effective radiation dose of pulmonary CT angiography (CTA) for suspected pulmonary embolism (PE) contributing to total medical radiation exposure over a 4-year period. Materials and Methods. This investigation retrospectively reviewed 300 patients who presented to the emergency department and received a pulmonary CTA scan for suspected PE. We evaluated these patients' electronic medical record to determine their estimated radiation exposure to CT scans during the following four years. Using DLP to E conversion coefficients, we calculated the cumulative effective radiation dose each subject received. Results. A total of 900 CT scans were reviewed in this study. Pulmonary CTA delivered an average effective radiation dose of 10.7 +/- 2.5 mSv and accounted for approximately 65% of subjects' 4-year cumulative medical radiation dose. Only 6.3% of subjects had a positive acute PE according to their radiology report. Conclusion. Pulmonary CTA accounted for the majority of subjects' medically related effective radiation dose over a 4-year period. With only a minority of subjects having positive findings for acute PE, increased efforts should be made to clinically assess pretest probability before the consideration of imaging. PMID- 23984066 TI - Comparison of the Number of Image Acquisitions and Procedural Time Required for Transarterial Chemoembolization of Hepatocellular Carcinoma with and without Tumor-Feeder Detection Software. AB - Purpose. To compare the number of image acquisitions and procedural time required for transarterial chemoembolization (TACE) with and without tumor-feeder detection software in cases of hepatocellular carcinoma (HCC). Materials and Methods. We retrospectively reviewed 50 cases involving software-assisted TACE (September 2011-February 2013) and 84 cases involving TACE without software assistance (January 2010-August 2011). We compared the number of image acquisitions, the overall procedural time, and the therapeutic efficacy in both groups. Results. Angiography acquisition per session reduced from 6.6 times to 4.6 times with software assistance (P < 0.001). Total image acquisition significantly decreased from 10.4 times to 8.7 times with software usage (P = 0.004). The mean procedural time required for a single session with software assisted TACE (103 min) was significantly lower than that for a session without software (116 min, P = 0.021). For TACE with and without software usage, the complete (68% versus 63%, resp.) and objective (78% versus 80%, resp.) response rates did not differ significantly. Conclusion. In comparison with software unassisted TACE, automated feeder-vessel detection software-assisted TACE for HCC involved fewer image acquisitions and could be completed faster while maintaining a comparable treatment response. PMID- 23984067 TI - Identification of Functional Regulatory Residues of the beta -Lactam Inducible Penicillin Binding Protein in Methicillin-Resistant Staphylococcus aureus. AB - Resistance to methicillin by Staphylococcus aureus is a persistent clinical problem worldwide. A mechanism for resistance has been proposed in which methicillin resistant Staphylococcus aureus (MRSA) isolates acquired a new protein called beta -lactam inducible penicillin binding protein (PBP-2'). The PBP-2' functions by substituting other penicillin binding proteins which have been inhibited by beta -lactam antibiotics. Presently, there is no structural and regulatory information on PBP-2' protein. We conducted a complete structural and functional regulatory analysis of PBP-2' protein. Our analysis revealed that the PBP-2' is very stable with more hydrophilic amino acids expressing antigenic sites. PBP-2' has three striking regulatory points constituted by first penicillin binding site at Ser25, second penicillin binding site at Ser405, and finally a single metallic ligand binding site at Glu657 which binds to Zn(2+) ions. This report highlights structural features of PBP-2' that can serve as targets for developing new chemotherapeutic agents and conducting site direct mutagenesis experiments. PMID- 23984068 TI - Single stance stability and proprioceptive control in older adults living at home: gender and age differences. AB - In developed countries, falls in older people represent a rising problem. As effective prevention should start before the risk becomes evident, an early predictor is needed. Single stance instability would appear as a major risk factor. Aims of the study were to describe single stance stability, its sensory components, and their correlation with age and gender. A random sample of 597 older adults (319 men, 278 women) living at home, aged 65-84, was studied. Stability tests were performed with an electronic postural station. The single stance test showed the impairment of single stance stability in older individuals (75-84 yrs). The significant decline of stability in the older subjects may be explained by the impairment of proprioceptive control together with the decrease in compensatory visual stabilization and emergency responses. Younger subjects (65-74 yrs) exhibited better, but still inadequate, proprioceptive control with compensatory visual stabilization. Gender differences appeared in older subjects: women were significantly less stable than men. The measurement of the sensory components of single stance stability could aid in the early detection of a decay in antigravity movements many years before the risk of falling becomes evident. Adequate proprioceptive control could mitigate the effects of all other risks of falling. PMID- 23984069 TI - Age-related increase in electromyography burst activity in males and females. AB - The rapid advancement of electromyography (EMG) technology facilitates measurement of muscle activity outside the laboratory during daily life. The purpose of this study was to determine whether bursts in EMG recorded over a typical 8-hour day differed between young and old males and females. Muscle activity was recorded from biceps brachii, triceps brachii, vastus lateralis, and biceps femoris of 16 young and 15 old adults using portable surface EMG. Old muscles were active 16-27% of the time compared to 5-9% in young muscles. The number of bursts was greater in old than young adults and in females compared to males. Burst percentage and mean amplitude were greater in the flexor muscles compared with the extensor muscles. The greater burst activity in old adults coupled with the unique activity patterns across muscles in males and females provides further understanding of how changes in neuromuscular activity effects age-related functional decline between the sexes. PMID- 23984070 TI - Genetic Basis for Variation of Metalloproteinase-Associated Biochemical Activity in Venom of the Mojave Rattlesnake (Crotalus scutulatus scutulatus). AB - The metalloproteinase composition and biochemical profiles of rattlesnake venom can be highly variable among rattlesnakes of the same species. We have previously shown that the neurotoxic properties of the Mojave rattlesnake (Crotalus scutulatus scutulatus) are associated with the presence of the Mojave toxin A subunit suggesting the existence of a genetic basis for rattlesnake venom composition. In this report, we hypothesized the existence of a genetic basis for intraspecies variation in metalloproteinase-associated biochemical properties of rattlesnake venom of the Mojave rattlesnake. To address this question, we PCR amplified and compared the genomic DNA nucleotide sequences that code for the mature metalloproteinase domain of fourteen Mojave rattlesnakes captured from different geographical locations across the southwest region of the United States. In addition, the venoms from the same rattlesnakes were tested for their ability to hydrolyze fibrinogen, fibrin, casein, and hide powder azure and for induction of hemorrhage in mice. Overall, based on genomic sequencing and biochemical data, we classified Mojave rattlesnake venom into four distinct groups of metalloproteinases. These findings indicate that differences in nucleotide sequences encoding the mature proteinase domain and noncoding regions contribute to differences in venom metalloproteinase activities among rattlesnakes of the same species. PMID- 23984071 TI - Association of a common variant at 10q26 and benign prostatic hyperplasia aggressiveness in han chinese descent. AB - Recent studies reported that rs2252004 at 10q26 was significantly associated with prostate cancer (PCa) risk in a Japanese population and was subsequently confirmed in a Chinese population. We aimed to assess the relationship between this locus and risk/aggressiveness of benign prostatic hyperplasia (BPH). The current study included 426 BPH cases and 1,008 controls from Xinhua Hospital in Shanghai, China. All BPH patients were treated with alpha -adrenergic blockers and 5 alpha -reductase inhibitors for at least 9 months. Associations between rs2252004 and BPH risk/aggressiveness were tested using logistic regression. Associations between rs2252004 and clinical parameters including International Prostate Symptom Score (IPSS), total prostate volume (TPV), total PSA (tPSA), and free PSA (fPSA) were evaluated by linear regression. Allele "A" in rs2252004 was significantly associated with increased risk for aggressiveness of BPH in a Chinese population (OR = 1.42, 95% CI: 1.04-1.96, P = 0.03). Patients with the genotype "A/A" (homozygous minor allele) had an increase of IPSS and TPV after treatment (P = 0.045 and 0.024, resp.). No association was observed between rs2252004, BPH risk, and baseline clinicopathological traits (All P > 0.05). Our study is the first to show that rs2252004 at 10q26 was associated with BPH aggressiveness and efficacy of BPH treatment. PMID- 23984072 TI - Maternal thyroid dysfunction and risk of seizure in the child: a Danish nationwide cohort study. AB - Thyroid hormones are essential for brain development, and maternal thyroid disease may affect child neurocognitive development. Some types of seizures may also depend upon early exposure of the developing central nervous system, and we hypothesized that maternal thyroid dysfunction could increase the risk of seizure in the child. In a Danish population-based study we included 1,699,693 liveborn singletons, and from the Danish National Hospital Register we obtained information on maternal diagnosis of hyper- or hypothyroidism and neonatal seizure, febrile seizure, and epilepsy in the child. Maternal diagnosis of thyroid dysfunction before or after birth of the child was registered in two percent of the singleton births. In adjusted analyses, maternal hyperthyroidism and hypothyroidism first time diagnosed after birth of the child were associated with a significant increased risk of epilepsy in the child. Moreover, hypothyroidism diagnosed after birth of the child was associated with a significant increased risk of neonatal and febrile seizures. No significant association was seen for maternal diagnosis prior to birth of the child. We speculate if some degree of maternal thyroid dysfunction was already present during the pregnancy in mothers diagnosed after birth of the child and if this untreated condition may present a neurodevelopmental risk. PMID- 23984073 TI - Image and imaging an emergency department: expense and benefit of different quality assessment methods. AB - Introduction. In this era of high-tech medicine, it is becoming increasingly important to assess patient satisfaction. There are several methods to do so, but these differ greatly in terms of cost, time, and labour and external validity. The aim of this study is to describe and compare the structure and implementation of different methods to assess the satisfaction of patients in an emergency department. Methods. The structure and implementation of the different methods to assess patient satisfaction were evaluated on the basis of a 90-minute standardised interview. Results. We identified a total of six different methods in six different hospitals. The average number of patients assessed was 5012, with a range from 230 (M5) to 20 000 patients (M2). In four methods (M1, M3, M5, and M6), the questionnaire was composed by a specialised external institute. In two methods, the questionnaire was created by the hospital itself (M2, M4).The median response rate was 58.4% (range 9-97.8%). With a reminder, the response rate increased by 60% (M3). Conclusion. The ideal method to assess patient satisfaction in the emergency department setting is to use a patient-based, in emergency department-based assessment of patient satisfaction, planned and guided by expert personnel. PMID- 23984074 TI - Prognostic value of the six-minute walk test in heart failure patients undergoing cardiac surgery: a literature review. AB - Background. The prognostic value of cardiopulmonary exercise testing (CPET) is known, but the predictive value of 6MWT in patients with heart failure (HF) and patients undergoing coronary artery bypass grafting (CABG) is not established yet. Objective. We conducted a systematic review exploring the prognostic value of 6MWT in HF patients undergoing cardiac surgery. The aim was to find out whether the change in the distance walked during follow-up visits was associated with prognosis. Data Source. We searched "PubMed" from January 1990 to December 2012 for any review articles or experimental studies investigating the prognostic value of 6MWT in HF patients and patients undergoing cardiac surgery. Results. 53 studies were included in the review, and they explored the role of 6MWT in cardiology, cardiac surgery, and rehabilitation. The results did not show the relation between the six-minute walk distance and adverse events after CABG. The predictive power of the distance walked for death in HF patients undergoing cardiac surgery was not found. It is not yet proved if the change in the six minute walk distance is associated with prognosis. The predictive power of the six-minute walk distance for death in HF patients undergoing cardiac surgery remains unclear. PMID- 23984075 TI - Sphingolipid metabolic pathway: an overview of major roles played in human diseases. AB - Sphingolipids, a family of membrane lipids, are bioactive molecules that participate in diverse functions controlling fundamental cellular processes such as cell division, differentiation, and cell death. Given that most of these cellular processes form the basis for several pathologies, it is not surprising that sphingolipids are key players in several pathological processes. This review discusses the role of the sphingolipid metabolic pathway in diabetes, Alzheimer's disease, and hepatocellular carcinoma, with a special emphasis on the changes in gene expression pattern in these disease conditions. For convenience, the sphingolipid metabolic pathway is divided into hypothetical compartments (modules) with each compartment representing a physiological process and changes in gene expression pattern are mapped to each of these modules. It appears that alterations in the gene expression pattern in these disease conditions are biased to manipulate the system in order to result in a particular disease. PMID- 23984076 TI - Hidden Y Chromosome Mosaicism in 48 Egyptian Patients with Turner's Syndrome. AB - Background. The presence of Y chromosome material in Turner's syndrome (TS) patients is a risk factor for the development of gonadoblastoma. Although conventional cytogenetic analysis is the definitive diagnosis of TS, low level Y chromosome mosaicism may be missed. Molecular analysis has demonstrated a higher proportion of mosaicism, but there is controversy regarding the prevalence of Y chromosome-derived material in those patients. Aim and Methods. This study was conducted to investigate the prevalence of hidden Y chromosome mosaicism in 48 TS Egyptian patients using polymerase chain reaction (PCR) for molecular DNA analysis of SRY gene and compare our results with those in the literature. Results. None of TS patients had a cytogenetically obvious Y chromosome; Y chromosome material was detected only at molecular analysis. SRY gene was found in 9 TS patients (18.75%) with the classical 45,X karyotype, whereas all other patients were SRY negative. Conclusion. Cytogenetically undetected Y chromosome mosaicism is common in TS patients; these data reinforce the need for adequate diagnosis of Y chromosome material in those patients. Molecular screening for Y chromosome-derived DNA should be routinely carried out in all TS patients. PMID- 23984077 TI - The Comprehensive Biomechanics and Load-Sharing of Semirigid PEEK and Semirigid Posterior Dynamic Stabilization Systems. AB - Alternatives to conventional rigid fusion have been proposed for several conditions related to degenerative disc disease when nonoperative treatment has failed. Semirigid fixation, in the form of dynamic stabilization or PEEK rods, is expected to provide compression under loading as well as an intermediate level of stabilization. This study systematically examines both the load-sharing characteristics and kinematics of these two devices compared to the standard of internal rigid fixators. Load-sharing was studied by using digital pressure films inserted between an artificially machined disc and two loading fixtures. Rigid rods, PEEK rods, and the dynamic stabilization system were inserted posteriorly for stabilization. The kinematics were quantified on ten, human, cadaver lumbosacral spines (L3-S1) which were tested under a pure bending moment, in flexion-extension, lateral bending, and axial rotation. The magnitude of load transmission through the anterior column was significantly greater with the dynamic device compared to PEEK rods and rigid rods. The contact pressures were distributed more uniformly, throughout the disc with the dynamic stabilization devices, and had smaller maximum point-loading (pressures) on any particular point within the disc. Kinematically, the motion was reduced by both semirigid devices similarly in all directions, with slight rigidity imparted by a lateral interbody device. PMID- 23984078 TI - Changes in water sorption and solubility of dental adhesive systems after cigarette smoke. AB - Aim. To evaluate the effect of cigarette smoke on water sorption and solubility of four adhesive systems. Materials and Methods. Sixteen disks of each adhesive system were prepared (Adper Scotchbond Multipurpose Adhesive (SA); Adper Scotchbond Multipurpose Adhesive System (Adhesive + Primer) (SAP); Adper Single Bond Plus (SB); Adper Easy One (EO)). Specimens were desiccated until a constant mass was obtained and divided into two groups (n = 8). One-half of the specimens were immersed in deionized water, while the other half were also immersed, but with daily exposure to tobacco smoke. After 21 days, disks were measured again and stored in desiccators until constant mass was achieved. Data were calculated according to ISO specifications and statistically analyzed. Results. The tobacco smoke only significantly affected the water sorption and solubility of EO. There were significant differences in both analyses among materials tested. The SB exhibited the highest water sorption, followed by EO, which demonstrated significantly higher solubility values than SB. The SA and SAP showed low water sorption and solubility, and there were no significant differences between the two. Conclusion. Regardless of smoke exposure, both simplified adhesive systems presented an inferior performance that could be related to the complex mixture of components in such versions. PMID- 23984079 TI - ERCP features and outcome in patients with periampullary duodenal diverticulum. AB - Background. Although periampullary diverticulum is usually asymptomatic and discovered incidentally in patients during endoscopic retrograde cholangiopancreatography (ERCP), it may lead to post-ERCP morbidity. We compared baseline characteristics and clinical data as well as ERCP results in patients with and without periampullary diverticulum. Methods. Clinical, laboratory, and ERCP data of 780 patients referred to the Taleghani Hospital, as a great referral endoscopy center, in Iran were prospectively analyzed. Results. The periampullary diverticulum was identified in 44 patients (5.6%). Cannulation of common bile duct was more failed in patients with diverticulum compared to others (35.5% versus 11.5, P < 0.001). Patients with diverticulum had eight times more often common bile duct stone compared to patients without diverticulum (54.5% versus 12.2%, P < 0.001). Post-ERCP complications were observed in 2.3% and 4.2% of patients with and without diverticulum, respectively, which did not significantly differ in both groups. Conclusion. Because of more failure cannulation in the presence of periampullary diverticulum, ERCP requires more skills in these patients. Prevalence of common bile duct stone was notably higher in patients with diverticulum; therefore, more assessment of bile stone and its complications in these patients is persistently recommended. PMID- 23984080 TI - Detailed analysis of diffuse large B cell lymphoma patients: a single-center, retrospective study. AB - The aim of this single-center, retrospective study was to investigate the impact of rituximab, reconsider the validity of International Prognostic Index (IPI), and evaluate the prognostic role of the cell of origin (CoO) in a relatively young cohort. Three hundred twelve diffuse large B cell lymphoma patients (median age: 52) were included. Rituximab significantly improved the 3- and 5-year progression free survival (PFS) (70% versus 65% and 41% versus 36%, resp.; P < 0.001) but led only to a slight, insignificant increase in 3- and 5-year overall survival (OS) (71% versus 77.3% and %67 versus 74.5%, resp.; P = 0.264). In the young, low risk patient subgroup (aaIPI = 0&1; n = 129), rituximab improved 3- and 5-year PFS and OS rates (P < 0.001 and P = 0.048, resp.). The efficacy of rituximab in young high risk patients was comparable to the literature. CoO data were available in 190 patients. The OS at 3 years was 79% for GC and 64% for non GC subgroups (P = 0.014). To the best of our knowledge, this is the first study which investigated the impact of R-CHOP in the context of CoO and IPI in a relatively young cohort. CoO was not an independent risk factor for prognosis in the multivariate analysis although patients with GC showed a significant survival advantage in the univariate analysis. CoO was also found to be a significant determinant of response in refractory/relapsed patients. Our results confirm the efficacy of rituximab in low and high risk, young patients outside of a randomized clinical trial setting. PMID- 23984081 TI - Expression of the h19 oncofetal gene in premalignant lesions of cervical cancer: a potential targeting approach for development of nonsurgical treatment of high risk lesions. AB - Background. Recent data suggest a role for H19 gene in promoting cancer transformation and progression. Cervical cancer, progresses from high-grade lesions (CIN3). At present, it is unclear if CIN lesions express H19. Objectives. To determine H19 expression in patient samples of CIN3 as well as the ability of a construct in which the promoter from the H19 gene drives expression of the diphtheria toxin A chain (DTA) to inhibit cervical cancer cell growth in vitro. Methods. H19 transcript levels were evaluated on 10 biopsies of CIN3 using in situ hybridization. PCR was used to examine H19 expression in cervical cancer cell lines and in two samples from a patient with cervical carcinoma. Cell lines were transfected with H19-DTA to determine its impact on cell number. Results. H19 gene was expressed in the area of CIN3 in 9 out of 10 samples. RT-PCR indicated expression of H19 in cervical cancer samples and in one of the three cell lines examined. Transfection of all cell lines with H19-DTA vector resulted in inhibited cell growth. Conclusions. H19 is expressed in the majority of CIN3 samples. These results suggest that most CIN3 lesions could be targeted by H19 DTA. Further in vivo preclinical studies are thus warranted. PMID- 23984082 TI - Treatment of Uterine Myoma with 2.5 or 5 mg Mifepristone Daily during 3 Months with 9 Months Posttreatment Followup: Randomized Clinical Trial. AB - Objectives. To evaluate the efficacy, safety, and quality of life by using 2.5 and mifepristone 5 mg daily doses to treat uterine fibroids over 3 months with a 9-month followup period. Design. Randomized clinical trial. Place. "Eusebio Hernandez" Hospital, Havana, Cuba. Subjects. 220 women with symptomatic uterine fibroids. Treatment. One-half (2.5 mg) or one-whole 5 mg mifepristone tablet. Variables to Evaluate Efficacy. Changes in fibroid and uterine volumes, in symptomatic prevalence and intensity, and in quality of life. Results. After 3 month treatment, fibroid volume decreased by 27.9% (CI 95% 20-35) and 45.5% (CI 95% 37-62), in the 2.5 and 5 mg groups, respectively, P = 0.003. There was no difference in the prevalence of symptoms at the end of treatment, unlike after 6- and 9-month followup when there was a difference. Amenorrhea was significantly higher in the 5 mg group, P = 0.001. There were no significant differences in mifepristone side effects between the groups. Both groups displayed a similar improvement in quality of life. Conclusions. The 2.5 mg dosage resulted in a lesser reduction in fibroid size but a similar improvement in quality of life when compared to the 5 mg dose. This trial is registered with ClinicalTrials.gov NCT01786226. PMID- 23984083 TI - Investigating the Relationship between Serum Level of s-Met (Soluble Hepatic Growth Factor Receptor) and Preeclampsia in the First and Second Trimesters of Pregnancy. AB - Introduction. Preeclampsia (PE) is an important cause of mortality and morbidity for mothers, fetuses, and the newborns. Placenta plays a pivotal role in pathogenesis of PE. Hepatic growth factor (HGF) is a cytokine expressed by the mesenchymal stalk of placental villi during pregnancy and assumes a paracrine role in trophoblasts which express its receptor (c-MET). In the present study, we investigate the diagnostic value of s-Met (the soluble form of the receptor) in the first and second trimesters of pregnancy for early diagnosis of preeclampsia. Method and Materials. This is a case-control study conducted on 95 pregnant women. The serum level of s-Met was measured in the first and second trimesters, and the participants were followed until delivery. 44 individuals with preeclampsia (the case group) and 51 individuals without preeclampsia (the control group) were evaluated. Results. Serum level of s-Met in preeclamptic participants was lower than that of the control group in both the first and the second trimesters (P < 0.0001). In addition, serum levels of s-Met were significantly lower during the first and second trimesters in patients with early, severe preeclampsia compared to those with late, mild preeclampsia (P < 0.0001). The sensitivity and specificity of s-Met in the first and second trimesters were, respectively, (83%, 94%) and (77%, 94%) for early preeclampsia and (88%, 92%) and (86%, 98%) for severe preeclampsia. Conclusion. Considering our findings, serum level of s-Met may be used as a predictive factor for early detection of preeclampsia. Further research is required to corroborate the functional and therapeutic value of s-Met in preeclampsia. PMID- 23984084 TI - Development and adaptation of Iranian youth reproductive health questionnaire. AB - Iran is a young country, and sexual behavior is shaped in this period. This research aimed to provide an assessment tool to evaluate Iranian youth reproductive health. This multistage research was conducted to design a valid questionnaire in the domains of knowledge, attitude, and behavior of the youth in order to evaluate behavior change programs. For this reason, after conducting a careful literature review and a qualitative research, the questionnaire was prepared. Forward and backward translations were performed. Professionals and students were used to make sure of qualitative and quantitative content and face validity. After conducting the pilot study on 100 students and eliminating defects in performance, reliability was evaluated by test-retest and Cronbach's alpha was calculated. In this study, out of 268 questions, 198 were retained after face and content validity. Self-efficacy of communication with father and mother, self-efficacy of condom use, and self-efficacy of abstinence had the highest Cronbach's alpha. Moreover, communication with parents regarding reproductive health issues and attitude to abstinence had a high Cronbach's alpha, as well. It seems to be a good instrument for assessment of Iranian reproductive health, and we are going to assess youth reproductive health in the future. PMID- 23984085 TI - Relationship between the Prevalence of Ectoparasites and Associated Risk Factors in Free-Range Pigs in Kenya. AB - A cross-sectional study was undertaken to determine the prevalence of ectoparasites and possible risk factors in free-range pigs from 135 farms of Busia District, Kenya. Three hundred and six pigs were examined for presence of external parasites using standard parasitological methods. Data on management practices including housing and history of acaricide spraying were also collected. The ectoparasites found in the pigs were Haematopinus suis (96.1%), Sarcoptes scabiei (63.7%), and ticks (29.7%). The tick species included Rhipicephalus appendiculatus (70%), Boophilus decoloratus (31%), and Amblyomma variegatum (12%). The occurrence of the infestations was associated with age, being highest in sows (S. scabiei) and finishers (ticks and H. suis). Male pigs had highest prevalences of H. suis and ticks, while female pigs had highest prevalence of S. scabiei. The prevalence of the parasitic infestations was significantly (P < 0.05) associated with their origin being either lower (H. suis and S. scabiei) or higher (ticks) in pigs originating from divisions with high rainfall. Housed pigs had significantly (P < 0.05) lower prevalence of H. suis and ticks than those from households without pig housing. It is concluded that the free-range pigs have high prevalence of ectoparasites, and effective control strategies focussing on improved animal husbandry and acaricide use should be implemented. PMID- 23984086 TI - Endothelin-1 levels in scleroderma patients: a pilot study. AB - Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, which mediates vascular wall cells proliferation, fibrosis, and inflammation through two types of ET-1 receptors (ET-A and ET-B). In our retrospective study the serum levels of ET-1 in 18 systemic sclerosis (SSc) patients with and without digital ulcers (DUs) were assessed to observe possible correlation between the levels of ET-1, the evolution of SSc, and the therapy with an ET-1 antagonist (bosentan). In all our patients, the levels of ET-1 were found higher than normal range and correlate with the severity of the disease. Furthermore we also observed that in patients without DUs the levels of ET-1 were higher and did not correlate with new DUs development. In conclusion, the levels of ET-1 in our studied patients do not correlate with the possible development of DUs. The reduction of ET-1 levels in DUs patients in therapy with bosentan confirms the efficacy of this molecule both for treatment and prevention of digital ulcers. The inhibition of ET-A receptor by its antagonist may activate the opposite ET-B receptors, with well known function ET-1 degradation and reducing of ET-1 serum level as confirmed in our pilot study. PMID- 23984087 TI - Hemostatic and Wound Healing Properties of Chromolaena odorata Leaf Extract. AB - Chromolaena odorata (L.) King and Robinson (Siam weed) extract has been used to stop bleeding and in wound healing in many tropical countries. However, its detailed mechanisms have not been elucidated. In this study, we examined the molecular mechanisms by which Siam weed extract (SWE) affected hemostatic and wound healing activities. SWE promoted Balb/c 3T3 fibroblast cell migration and proliferation. Subsequently, we found that heme oxygenase-1 (HO-1), the accelerating wound healing enzyme, was increased at the transcriptional and translational levels by SWE treatments. The HO-1 promoter analyzed with luciferase assay was also increased by treatment of SWE in a dose-dependent manner. This induction may be mediated by several kinase pathways including MEK, p38MAPK, AKT, and JNK. Quantitative real-time PCR using undifferentiated promonocytic cell lines revealed that thromboxane synthase (TXS), a potent vasoconstrictor and platelet aggregator, was increased and MMP-9, an anti platelet aggregator, was decreased in the presence of SWE. Our studies presented that SWE accelerated hemostatic and wound healing activities by altering the expression of genes, including HO-1, TXS, and MMP-9. PMID- 23984090 TI - Inhibition of endoplasmic reticulum stress and atherosclerosis by 2-aminopurine in apolipoprotein e-deficient mice. AB - We previously reported that the apolipoprotein (apo) B48-carrying lipoproteins obtained from apoE knockout (apoE (-/-) ) mice, so called E(-)/B48 lipoproteins, transformed mouse macrophages into foam cells and enhanced the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF-2 alpha ). Furthermore, the eIF-2 alpha phosphorylation inhibitor, 2-aminopurine (2-AP), attenuated E(-)/B48 lipoprotein-induced foam cell formation. The present report studied the effect of 2-AP on atherosclerosis in apoE (-/-) mice. Our results showed that the level of food intake, bodyweight, plasma cholesterol, and triglycerides was comparable in apoE (-/-) mice treated with or without 2-AP. However, the mean size of atherosclerotic lesions in the aorta sinus as well as the surface area of the entire aorta of 2-AP-treated apoE (-/-) mice were reduced by about 55% and 39%, respectively, compared to samples from untreated control apoE (-/-) mice. In addition, the 2-AP-treated apoE (-/-) mice showed a significant decrease in glucose-regulated protein 78 (GRP78) and phosphorylated eIF-2 alpha in their aortic samples as compared to levels in untreated control apoE (-/-) mice. These observations suggest that endoplasmic reticulum stress is a causal mechanism for the development of atherosclerosis in apoE (-/-) mice and that therapeutic strategies can be developed for using eIF-2 alpha phosphorylation inhibitors, such as 2-AP, to prevent or treat atherosclerosis. PMID- 23984089 TI - A Scientific Validation of Antihyperglycemic and Antihyperlipidemic Attributes of Trichosanthes dioica. AB - The present study was undertaken to scientifically validate the antidiabetic activity of aqueous fruit extract of Trichosanthes dioica Roxb. (Family: Cucurbitaceae) which has been traditionally used for managing diabetes mellitus. This plant commonly known as "Sespadula" in English has not been explored scientifically so far for its glycemic potential except by our research group. The study was conducted with variable doses on normal, mild, and severe diabetics models, and several biochemical parameters including blood glucose level (BGL) were assessed. Maximum fall in BGL of 23.8% in normal rats and of 31.3% in mild diabetic rats was observed during their fasting blood glucose (FBG) and glucose tolerance test (GTT) with the dose of 1000 mg kg(-1). In severely diabetic animals after 4 weeks treatment with FBG, postprandial glucose, total cholesterol, and triglyceride levels were reduced by 28.7, 30.7, 57.2, and 18.5%, whereas high density lipoprotein, total protein, hemoglobin, and body weight were increased by 33.0, 36.7, 15.7 and 16.7%, respectively. Moreover, urine sugar was reduced from +4 to +1. Thus, the study scientifically validates the traditional use of T. diocia in diabetes management and could be developed as an effective oral agent for treating diabetes mellitus and complications associated with it. PMID- 23984091 TI - Some Haematological and Biochemical Investigations on Duck Virus Hepatitis following Administration of Glycyrrhizin. AB - The present study aimed to investigate the protective effect of glycyrrhizin (locally isolated and purified from licorice root) against duck hepatitis virus through the assessment of some hematological and biochemical parameters. One hundred and sixty white Pekin ducklings-one day old-were randomly divided into four equal groups. Group (1) was kept as normal control. Group (2) was inoculated I/P with 10 mg glycyrrhizin/kg BW, three times per week for four weeks. Group (3) was inoculated I/M with 0.5 ml of live attenuated DHV vaccine. Group (4) was inoculated with both glycyrrhizin (10 mg/kg BW I/P, three times per week for four weeks) and live attenuated DHV vaccine (0.5 ml, I/M). Then, all groups of treatment were challenged using virulent DHV except for 20 ducklings from the normal control group which were continued to be kept as negative control. The results revealed that duck hepatitis virus (DHV) caused macrocytic hypochromic anemia, leukopenia, hypoproteinemia, hypoalbuminemia, hyperglycemia, hypercholesterolemia, and marked elevation of liver enzymes and renal parameters. In conclusion, glycyrrhizin injected alone or in combination with DHV vaccine protected or ameliorated the deteriorating effects induced by DHV vaccine and/or duck hepatitis virus infection by improvement of erythrogram and leukogram, as well as liver and kidney functions. PMID- 23984088 TI - Transforming growth factor-Beta and urokinase-type plasminogen activator: dangerous partners in tumorigenesis-implications in skin cancer. AB - Transforming growth factor-beta (TGF- beta ) is a pleiotropic factor, with several different roles in health and disease. TGF- beta has been postulated as a dual factor in tumor progression, since it represses epithelial tumor development in early stages, whereas it stimulates tumor progression in advanced stages. During tumorigenesis, cancer cells acquire the capacity to migrate and invade surrounding tissues and to metastasize different organs. The urokinase-type plasminogen activator (uPA) system, comprising uPA, the uPA cell surface receptor, and plasminogen-plasmin, is involved in the proteolytic degradation of the extracellular matrix and regulates key cellular events by activating intracellular signal pathways, which together allow cancer cells to survive, thus, enhancing cell malignance during tumor progression. Due to their importance, uPA and its receptor are tightly transcriptionally regulated in normal development, but are deregulated in cancer, when their activity and expression are related to further development of cancer. TGF- beta regulates uPA expression in cancer cells, while uPA, by plasminogen activation, may activate the secreted latent TGF- beta , thus, producing a pernicious cycle which contributes to the enhancement of tumor progression. Here we review the specific roles and the interplay between TGF- beta and uPA system in cancer cells and their implication in skin cancer. PMID- 23984093 TI - The effect of fluoxetine on progression in progressive multiple sclerosis: a double-blind, randomized, placebo-controlled trial. AB - Preclinical studies suggest that fluoxetine may have neuroprotective properties. In this pilot study forty-two patients with secondary or primary progressive MS were randomized to receive fluoxetine 20 mg twice daily or placebo for 2 years. Every 3 months the Expanded Disability Status Scale (EDSS), 9-hole peg test (9 HPT) and ambulation index (AI) were assessed. Brain MRI scans, Multiple Sclerosis Functional Composite, Fatigue Impact Scale, Guy's neurological disability Scale and SF-36 were performed at baseline, year 1 and year 2. Seven out of 20 (35%) patients in the fluoxetine group and 7 out of 22 (32%) patients in the placebo group had sustained progression on the EDSS, 9-HPT, or AI at 2 years. No differences were identified between the 2 treatment groups with respect to secondary clinical outcomes and T2 lesion load, grey matter volume and white matter volume. An unanticipated low rate of disability progression in the placebo group decreased the statistical power. At least 200 patients would have been needed to detect a 50% treatment effect. This trial shows that fluoxetine was generally well tolerated, but no assumptions can be made about a possible treatment effect. An adequately powered controlled trial of fluoxetine in progressive MS is still warranted. This trial is registered with Current Controlled Trials ISRCTN38456328. PMID- 23984094 TI - Vitamin E-Induced Changes in Glutamate and GABA Metabolizing Enzymes of Chick Embryo Cerebrum. AB - Vitamin E exists in eight different forms, four tocopherols and four tocotrienols. It forms an important component of our antioxidant system. The structure of Vitamin E makes it unique and indispensable in protecting cell membranes. alpha -tocopherol, one of the forms of Vitamin E, is also known to regulate signal transduction pathways by mechanisms that are independent of its antioxidant properties. Vitamin E compounds reduce the production of inflammatory compounds such as prostaglandins. Swollen, dystrophic axons are considered as the hallmark of Vitamin E deficiency in the brains of rats, monkeys, and humans. The present work aimed to study the Vitamin E- ( alpha -tochopherol acetate-) induced alterations of enzymes involved in metabolism of Glutamate and GABA during developmental neurogenesis of cerebrum. Therefore, cytosolic and crude mitochondrial enzyme activities of glutamine synthetase, aspartate transaminase, alanine transaminase, GABA transaminase, succinic Semialdehyde dehydrogenase, glutamic dehydrogenase, and alpha -Ketoglutarate dehydrogenase were analysed. Vitamin E induced significant changes in these enzymes thus altering the normal levels of glutamate and GABA during developmental neurogenesis. Such changes are surely to disturb the expression and/or intensity of neurotransmitter signaling during critical periods of brain development. PMID- 23984096 TI - Adequacy of cancer screening in adult women with congenital heart disease. AB - Adults with congenital heart disease (ACHD) face noncardiac healthcare challenges as the population ages. We assessed whether women with ACHD have comparable cancer screening rates to non-ACHD women in a cardiac practice and to the general population. We performed a retrospective review of 175 adult women seen in a cardiac care center in 2009-2011. Data on Pap tests, mammography, and colonoscopies, were collected through electronic medical records and primary care provider records. Adequate documentation was available for 100 individuals with ACHD and 40 comparator cardiac patients. The adequacy of screening was determined using guidelines set forth by the American Cancer Society in 2010. Compared with the national average, ACHD patients had significantly lower rates of Pap tests (60% versus 83%, P < 0.001) and mammography (48% versus 72%, P < 0.001). Compared with non-ACHD women in the same practice, ACHD patients had consistently lower rates of mammography (48% versus 81%, P = 0.02) and colonoscopies (54% versus 82%, P = 0.23). As the population of ACHD individuals ages, attention to cancer screening becomes increasingly important but may be overlooked in this population. Primary care physicians and cardiologists should collaborate to ensure appropriate cancer screening for this growing population. PMID- 23984092 TI - Heparin and related drugs: beyond anticoagulant activity. AB - Heparin has been widely used as an anticoagulant for more than 80 years. However, there is now considerable evidence that heparin also possesses anti-inflammatory activity, both experimentally and clinically. Importantly in many instances, the anti-inflammatory actions of heparin are independent of anticoagulant activity raising the possibility of developing novel drugs based on heparin that retain the anti-inflammatory activity. Heparin exhibits anti-inflammatory activities via a variety of mechanisms including neutralization of cationic mediators, inhibition of adhesion molecules, and the inhibition of heparanase, all involved in leukocyte recruitment into tissues. It is anticipated that furthering our understanding of the anti-inflammatory actions of heparin will lead to the development of novel anti-inflammatory drugs for a variety of clinical indications. PMID- 23984097 TI - Survival Analysis Based on Clinicopathological Data from a Single Institution: Chemotherapy Intensity Would Be Enhanced in Patients with Positive Hormone Receptors and Positive HER2 in China Who Cannot Afford the Target Therapy. AB - Background. Immunohistochemical markers were often used to classify breast cancer into subtypes. The aim of this study was to estimate death and tumor progression for patients with the major subtypes of breast cancer as classified using immunohistochemical assay and to investigate the patterns of benefit from the therapies over the past years. Methods. The study population included primary, operable 199 invasive ductal breast cancer patients, with the median age of 51.1 years old. All patients underwent local and/or systemic treatments. The clinicopathological characteristics and clinical outcomes were retrospectively reviewed. The expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki67 was analyzed by immunohistochemistry. All patients were classified into the following categories: luminal A, luminal B, HER2 overexpression, and triple-negative subtypes. Result. The median follow-up time was 33 months. Luminal A tumors had the lowest rate of tumor progression (0%, P = 0.006), while luminal B, HER2 over-expression, and triple-negative subtypes were associated with an increased risk of tumor progression (15.4, 19.2, 15.4%). Clinicopathological subtypes retained independent prognostic significance (P = 0.008). There were significant differences by Cox model analyzed in age, menopause, lymph node metastasis, and HER2 for the event of death and tumor progression (P < 0.05), and there were significant differences only in chemotherapy for the event, respectively (P < 0.05). Conclusion. Clinicopathological subtypes of breast cancer could robustly identify the risk of death and tumor progression and were significant in making therapeutic decision. HER2 was the important poor indicator. The chemotherapy intensity would be enhanced for patients with luminal B, especially for HER2 over expression subgroup. PMID- 23984095 TI - The challenge of delivering therapeutic aerosols to asthma patients. AB - The number of people with asthma continues to grow around the world, and asthma remains a poorly controlled disease despite the availability of management guidelines and highly effective medication. Patient noncompliance with therapy is a major reason for poor asthma control. Patients fail to comply with their asthma regimen for a wide variety of reasons, but incorrect use of inhaler devices is amongst the most common. The pressurised metered-dose inhaler (pMDI) is still the most frequently used device worldwide, but many patients fail to use it correctly, even after repeated tuition. Breath-actuated inhalers are easier to use than pMDIs. The rationale behind inhaler choice should be evidence based rather than empirical. When choosing an inhaler device, it is essential that it is easy to use correctly, dosing is consistent, adequate drug is deposited in both central and peripheral airways, and that drug deposition is independent of airflow. Regular checking of inhalation technique is crucial, as correct inhalation is one of the cornerstones of successful asthma management. PMID- 23984098 TI - Accuracy of Self-Reported Screening Mammography Use: Examining Recall among Female Relatives from the Ontario Site of the Breast Cancer Family Registry. AB - Evidence of the accuracy of self-reported mammography use among women with familial breast cancer risk is limited. This study examined the accuracy of self reported screening mammography dates in a cohort of 1,114 female relatives of breast cancer cases, aged 26 to 73 from the Ontario site of the Breast Cancer Family Registry. Self-reported dates were compared to dates abstracted from imaging reports. Associations between inaccurate recall and subject characteristics were assessed using multinomial regression. Almost all women (95.2% at baseline, 98.5% at year 1, 99.8% at year 2) accurately reported their mammogram use within the previous 12 months. Women at low familial risk (OR = 1.77, 95% CI: 1.00-3.13), who reported 1 or fewer annual visits to a health professional (OR = 1.97, 95% CI: 1.15, 3.39), exhibited a lower perceived breast cancer risk (OR = 1.90, 95% CI: 1.15, 3.15), and reported a mammogram date more than 12 months previous (OR = 5.22, 95% CI: 3.10, 8.80), were significantly more likely to inaccurately recall their mammogram date. Women with varying levels of familial risk are accurate reporters of their mammogram use. These results present the first evidence of self-reported mammography recall accuracy among women with varying levels of familial risk. PMID- 23984099 TI - Can axial-based nodal size criteria be used in other imaging planes to accurately determine "enlarged" head and neck lymph nodes? AB - Objective. We evaluate if axial-based lymph node size criteria can be applied to coronal and sagittal planes. Methods. Fifty pretreatment computed tomographic (CT) neck exams were evaluated in patients with head and neck squamous cell carcinoma (SCCa) and neck lymphadenopathy. Axial-based size criteria were applied to all 3 imaging planes, measured, and classified as "enlarged" if equal to or exceeding size criteria. Results. 222 lymph nodes were "enlarged" in one imaging plane; however, 53.2% (118/222) of these were "enlarged" in all 3 planes. Classification concordance between axial versus coronal/sagittal planes was poor (kappa = -0.09 and -0.07, resp., P < 0.05). The McNemar test showed systematic misclassification when comparing axial versus coronal (P < 0.001) and axial versus sagittal (P < 0.001) planes. Conclusion. Classification of "enlarged" lymph nodes differs between axial versus coronal/sagittal imaging planes when axial-based nodal size criteria are applied independently to all three imaging planes, and exclusively used without other morphologic nodal data. PMID- 23984100 TI - Effectiveness of 7.5 percent povidone iodine in comparison to 1 percent clotrimazole with lignocaine in the treatment of otomycosis. AB - Objectives. Otomycosis is a common ENT disease frequenting the tropics. Its recurrent nature poses a great challenge to the treating physician. In spite of a number of antifungals in the market, the frequent nature of this disease warrants repeated use of these drugs, contributing to drug resistance and financial burden on the rural population. Our primary aims were to evaluate the effectiveness of povidone iodine in the treatment of otomycosis and to identify the most common fungal isolate in our population. Study Design and Setting. A single blinded prospective longitudinal study was done over a period of 12 months in a tertiary referral center. 34 patients in the age group 15-70 years clinically diagnosed with otomycosis were included in this study. These individuals were divided into two groups selected randomly. One arm received 7.5% povidone iodine otic drops and the other 1% Clotrimazole and lignocaine drops. Evaluation was based on resolution of symptoms and signs after treatment. Result. Both arms showed improvements which were comparable thus suggesting the role of povidone iodine in the management of otomycosis. Conclusion. Povidone iodine is an effective antifungal in the treatment of otomycosis. PMID- 23984101 TI - Changing trends in oesophageal endoscopy: a systematic review of transnasal oesophagoscopy. AB - The safety, efficacy, and economic implications of using transnasal oesophagoscopy (TNE) are compared with conventional rigid or flexible oesophagoscopy for oesophageal disorders in otorhinolaryngology (ORL) clinics in this systematic review. Eleven electronic databases were searched for articles on transnasal oesophagoscopy. A total of 67 relevant titles were identified and 39 abstracts were screened of which 17 full- text articles were included in this report. There was fair level of evidence to suggest that TNE was effective for screening examination in patients with dysphagia, globus pharyngeus, and reflux symptoms and for detection of metachronous oesophageal carcinoma. TNE can also be used to biopsy suspicious lesions in the upper aerodigestive tract, placement of wireless pH capsule, transnasal balloon dilation of the oesophagus, secondary tracheoesophageal puncture, and management of foreign bodies. TNE was well tolerated and can be safely performed in an office setting with topical anaesthesia. Complications associated with TNE were mild and uncommon. There was evidence to suggest potential cost savings by performing TNE in the office setting compared with conventional investigation and examination for dysphagia. TNE may lead to a change in practice from investigation and treatment in the operating theatre or day care center to an office-based practice. PMID- 23984102 TI - The prevalence of frontal cells and their relation to frontal sinusitis: a radiological study of the frontal recess area. AB - Background. The frontal recess area represents a challenge to ENT surgeons due to its narrow confines and variable anatomy. Several types of cells have been described in this area. The agger nasi cells are the most constant ones. The frontal cells, originally classified by Kuhn into 4 types, have been reported in the literature to exist in 20%-41% of frontal recesses. Aim of the Study. To identify the prevalence of frontal recess cells and their relation to frontal sinus disease. Methods. Coronal and axial CT scans of paranasal sinuses of 70 patients admitted for functional endoscopic sinus surgery (FESS) were reviewed to identify the agger nasi, frontal cells, and frontal sinus disease. Data was collated for right and left sides separately. Results. Of the 140 sides reviewed, 126 (90%) had agger nasi and 110 (78.571%) had frontal cells. 37 frontal sinuses were free of mucosal disease, 48 were partly opacified, and 50 were totally opacified. There was no significant difference found in frontal sinus mucosal disease in presence or absence of frontal cells or agger nasi. Conclusions. The current study shows that frontal cells might be underreported in the literature, as the prevalence identified is noticeably higher than previous studies. PMID- 23984103 TI - Adverse effects of androgen deprivation therapy for prostate cancer: prevention and management. AB - The prostate is an androgen-dependent organ. The increase, growth, homeostasis, and function of the prostate largely depend upon the intraprostatic and serum concentrations of androgens. Therefore, androgens are essential for the physiologic growth of prostatic epithelium. Prostate cancer, the second leading cause of death for men, is also androgen dependent, and androgen suppression is the mainstay of treatment for advanced and metastatic disease. In the state of metastatic disease, androgen suppression is a palliative treatment leading to a median progression-free survival of 18-20 months and an overall survival of 24-36 months. Theoretically, the majority of patients will develop hormone-refractory disease provided that they will not die from other causes. Although androgen suppression therapy may be associated with significant and sometimes durable responses, it is not considered a cure, and its potential efficacy is further limited by an array of significant and bothersome adverse effects caused by the suppression of androgens. These effects have potentially significant consequences on a variety of parameters of everyday living and may further decrease health related quality of life. This review focuses on the aetiology of these adverse effects and provides information on their prevention and management. PMID- 23984104 TI - Should Finasteride Be Routinely Given Preoperatively for TURP? AB - Objective. The aim of the review was to compare the use of finasteride to placebo in patients undergoing TURP procedures. Material & Methods. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966-November 2011), EMBASE (1980-November 2011), CINAHL, Clinicaltrials.gov, Google Scholar, reference lists of articles, and abstracts from conference proceedings without language restriction for studies comparing finasteride to placebo patients needing TURPs. Results. Four randomised controlled trials were included comparing finasteride to a placebo. A meta-analysis was not conducted due to the disparity present in the results between the studies. Three of the studies found that finasteride could reduce either intra- or postoperative bleeding after TURP. One study found finasteride to significantly lower the microvessel density (MVD) and vascular endothelial growth factor (VEGF). None of the studies reported any long term complications related to either the medication or the procedure. Conclusion. finasteride reduces bleeding either during or after TURP. PMID- 23984105 TI - Emergent intervention criterias for controlling sever bleeding after percutaneous nephrolithotomy. AB - Objectives. To determine when emergent intervention for bleeding after percutaneous nephrolithotomy (PCNL) is required. Methods. We reviewed analysis data of 850 patients who had undergone PCNL in our center. Blood transfusion was needed for 60 (7%) patients during and/or after surgery. We routinely performed followup of the urine output per hour, blood pressure, and hemoglobin levels after PCNL. Five (0.6%) of them had severe bleeding that emergent intervention was needed. Results. The mean age of the 5 patients who had emergent surgery due to severe bleeding was 42.2 (19-56) years. Mean duration of surgery was 44.75 (25 65) minutes. Mean stone size was 27 (15-38) mm. Mean decrease of hemoglobin was 4.8 (3.4-5.8) ng/dL, and unit of transfused blood was 4.4 (3-6). Mean blood pH was 7.21. There were metabolic acidosis and anuria/oliguria in all these patients. One of 5 patients suffered from cardiopulmonary arrest because of massive bleeding four hours after the PCNL, and despite cardiac resuscitation, he died. Hemorrhaging was controlled by open surgery in the other 4 patients. Two patients experienced cardiac arrest during the open surgery but they responded to cardiac resuscitation. There were no metabolic asidosis and anuria/oliguria, and bleeding was managed only with blood transfusion for the other 55 patients. Conclusion. Severe bleeding after PCNL is rare and can be mortal. If metabolic asidosis and anuria/oliguria accompanied the drop of hemoglobin, emergent surgical intervention should be performed because vascular collapse may follow, and it may be too difficult to stabilise the patient. PMID- 23984106 TI - Comparison of various generations of superporous hydrogels based on chitosan acrylamide and in vitro drug release. AB - The aim of the current research work was to prepare and evaluate different generations of superporous hydrogels (SPH) of acrylamide and chitosan using gas blowing technique and evaluate them for swelling, mechanical properties, FTIR, SEM, XRD, and in vitro drug release. The ingredients used were acrylamide, N,N' methylene bisacrylamide, chitosan, Pluronic F127, ammonium per sulfate-N,N,N',N' tetramethylenediamine, and sodium bicarbonate. All ingredients were mixed sequentially with thorough stirring. The effect of different drying conditions on properties of SPH was also evaluated. Ethanol treated batched showed maximum swelling properties due to uniform pores as indicated in SEM studies. Equilibrium swelling time was less than 10 min in all batches. Freeze drying led to lowering of density which is also supported by porosity and void fraction data. Maximum mechanical strength was found in superporous hydrogel interpenetrating networks due to crosslinked polymeric network. 70% drug was released at the end of 2 h, and further the release was sustained till the end of 24 h. In vitro drug release kinetics showed that drug release occurs by diffusion and follows Super Case II transport indicating that mechanism of drug release is not clear. Superporous hydrogel interpenetrating networks can be successfully used as sustained release gastroretentive devices. PMID- 23984107 TI - An unusual case of sudden collapse in the immediate postoperative period in a young healthy female with myxofibroma of the maxilla. AB - Benign myxofibromas of heart are well known to cause systemic inflammatory mediator release causing multiple complications ranging from fever and widespread effusions to DIC and shock. We report that in a particular case of maxillary myxofibroma, a shock-like state and widespread serous cavities effusion presented in the immediate postoperative period. The occurrence was possibly due to release of inflammatory mediators by the tumour, disseminated during tumour resection causing diffuse capillary leak, precipitated by fluid resuscitation, leading to decrease in plasma oncotic pressure. PMID- 23984108 TI - Treatment of the atrophic upper jaw: rehabilitation of two complex cases. AB - In reconstructive surgery, the fresh frozen homologous bone (FFB) represents a valid alternative to the autologous bone, because FFB allows bone regeneration thanks to its osteoinductive and osteoconductive properties. The purpose of this work is to describe the surgical-implant-prosthetic treatment of two complex cases using FFB. In particular, fresh frozen homologous bone grafts were used to correct the severe atrophy of the maxilla, and, then, once the graft integration was obtained, implant therapy was performed and implants placed in native bone were immediately loaded. PMID- 23984109 TI - Orthodontic elastic embedded in gingiva for 7 years. AB - Dental materials especially orthodontic elastics often get embedded in gingival tissues due to iatrogenic factors. If retained for a long time, inflammatory response starts as asymptomatic crestal bone loss and may progress to severe periodontal abscess. Unsupported orthodontic elastics used for diastema closure may result in exfoliation of teeth, while elastic separators may get embedded in interdental gingiva if banding is performed without removing it. These cases of negligence are detrimental for survival of affected teeth. This paper highlights a case of orthodontic elastic embedded in interproximal gingiva of a 23-year-old healthy female for 7 years after completion of fixed orthodontic treatment. Surprisingly, there was no clinical sign of inflammation around elastic band and it was removed easily without any local anaesthesia. However, mild crestal bone loss was observed on periapical radiograph. The gingiva healed completely after sub gingival debridement. PMID- 23984110 TI - Fabrication of customized sectional impression trays in management of patients with limited mouth opening: a simple and unique approach. AB - Impression making is not only important but is also the most significant step in the fabrication of any fixed or removable prosthesis. Proper impression making may be hindered by certain pathologic conditions. Reduced mouth opening is one of the common mechanical obstructions for proper orientation of the impression tray in the patient's mouth. In patients with trismus induced by submucous fibrosis, the procedure may be even more difficult to carry out because of reduced tissue resiliency and obliteration of vestibular spaces. Use of sectional trays offers one of the alternatives to overcome the problem of restricted mouth opening. Fabrication of customized impression trays according to the patient dentition improves the accuracy of impression making. The present case reports describe the fabrication of sectional custom trays designed for dentulous patients with chronic tobacco-induced submucous fibrosis. PMID- 23984111 TI - Maxillary first molars with six canals diagnosed with the aid of cone beam computed tomography: a report of two cases. AB - The case reports present the endodontic management of two maxillary first molars with six canals. The diagnosis of morphology of multiple canal systems was identified under magnification of the dental operating microscope and was confirmed with the help of cone beam computed tomography. This paper discusses the variations in the canal morphology and the use of the latest adjuncts in successfully diagnosing and treating unusual canal anatomy. PMID- 23984112 TI - A Case of Old Calcifying Epithelioma Processed Symptomless over 40 Years. AB - Calcifying epithelioma, a benign tumor derived from the hair apparatus and consisted of hair matrix cells, is relatively prevalent in females. We report a case of right preauricular calcifying epithelioma that was incidentally detected at the examination of multiple facial fractures and became an old lesion without symptoms for 40 years. The patient who was a 42-year-old male visited our department for the first time in October 2011 with a chief complaint of multiple facial fractures. Radiographic imaging demonstrated fracture lines at the anterior and posterior walls of the left maxillary sinus and zygomatic arch and revealed a mass at a right preauricular area. The extraction was performed under general anaesthesia. No recurrence has been observed 15 months after surgery. We also reviewed the literature of calcifying epithelioma. PMID- 23984113 TI - Provisional Crown Dislodgement during Scuba Diving: A Case of Barotrauma. AB - Changes in ambient pressure, for example, during flying, diving, or hyperbaric oxygen therapy, can lead to barotrauma. Although it may seem that this issue was neglected in dental education and research in recent decades, familiarity with and understanding of these facts may be of importance for dental practitioners. We report the case of a patient who experienced barotrauma involving dislodgement of a provisional crown during scuba diving. Patients who are exposed to pressure changes as a part of their jobs or hobbies and their dentists should know the causes of barotrauma. In addition, the clinician must be aware of the possible influence of pressure changes on the retention of dental components. PMID- 23984114 TI - Dyskeratosis congenita: a report of two cases. AB - Oral manifestations play an important role in the diagnosis of many systemic conditions. Dyskeratosis congenita (DC) is a rare genodermatosis which exhibits oral leukoplakia, nail dystrophy, and reticular skin pigmentations as its primary features. DC has increased risk of developing constitutional anemias and malignancies and early diagnosis enables the patient to be monitored and proper interventional therapy to be instituted. Hence, dentists need to be aware of the various manifestations of this fatal syndrome. Only few cases have been reported on DC in the dental literature. Two cases of DC are reported here with a brief review of the literature. PMID- 23984115 TI - A novel approach for treatment of an unusual presentation of radicular cysts using autologous periosteum and platelet-rich fibrin in combination with demineralized freeze-dried bone allograft. AB - Radicular cysts are the most common cystic lesions affecting the jaws. They are most commonly found at the apices of the involved teeth. This condition is usually asymptomatic but can result in a slow-growth tumefaction in the affected region. The following case report presents the successful treatment of radicular cysts using autologous periosteum and platelet-rich fibrin with demineralized freeze-dried bone allograft. PMID- 23984116 TI - Isolated jejunal perforation following bicycle handlebar injury in adults: a case report. AB - The small intestine is the third in frequency intraperitoneal organ which is injured after blunt trauma of the abdomen. In most of the cases, this type of injuries is accompanied by other injuries, which make it more difficult to diagnose. Failure of diagnosis and delay in treating these injuries significantly increase the morbidity and mortality of these patients. Abdominal visceral injuries after flipping the handlebar of the bike are common in children. Such injuries can cause injury to both solid and hollow abdominal viscera. Unlike children, adults' abdominal visceral injuries after flipping the bike's handlebar are extremely rare. A 25-year-old man was admitted to our department due to progressively abdominal pain after an accident with the handlebar of his bike. The subsequent CT scan after per os administration of contrast medium revealed the presence of free intraperitoneal contrast. It is a rare case of jejunal perforation after flipping the handlebar of the bicycle which was treated by partial removal of the injured part of jejunum and end-to-end anastomosis. To the best of our knowledge this is the first time we describe such an injury with this mechanism to an adult. PMID- 23984117 TI - Spurious t3 thyrotoxicosis unmasking multiple myeloma. AB - Objective. To document a case of spurious T3 thyrotoxicosis in a 54-year-old woman. Methods. We present the diagnostic approach of a patient with euthyroid hypertri-iodothyronemia. Results. A 54-year-old, clinically euthyroid woman without personal or family history of thyroid disease referred to endocrinology for possible T3 thyrotoxicosis, after thyroid function tests revealed total T3 > 800 ng/dL (reference range 60-181), normal TSH, and T4. The laboratory data were not compatible with the clinical picture, so thyroid binding globulin abnormalities were suspected. Additional laboratory studies confirmed the diagnosis of multiple myeloma. Conclusion. Monoclonal gammopathy is characterized by the presence of a monoclonal immunoglobulin in the serum or urine, occurring in multiple myeloma, and can cause assay interference and spurious results. We identify a newly recognized cause of euthyroid hypertri-iodothyronemia, due to binding of T3 to monoclonal immunoglobulins in the setting of multiple myeloma. Our case is the only one to date suggesting that monoclonal immunoglobulins from multiple myeloma may exhibit binding to T3 only. PMID- 23984118 TI - A rare complication of an ingested foreign body: gallbladder perforation. AB - We present a 13-year-old child who admitted with a dull right upper quadrant pain that started 3 weeks before her referral. Several medications were given but they did not change the intensity and the frequency of the pain. Her physical examination was nonspecific except for slight right upper quadrant tenderness. The imaging studies revealed a sewing pin perforating the stomach and gallbladder. The patient was treated with a successful operation, and no postoperative complications were observed. To our knowledge, this is the first case of a sharp foreign body gallbladder perforation in a child. PMID- 23984119 TI - Atypical gastric ulcer in an elderly cocaine user. AB - Cocaine or Benzoylmethylecgonine is an alkaloid extracted from the leaves of the Erythroxylon plant, which can cause gastrointestinal ischemia from severe arterial vasoconstriction via stimulation of alpha-adrenergic receptors in the gastric and mesenteric arteries. We report this case of a 65-year-old man who presented with a single massive ulcer at the incisura of the stomach as a result of cocaine use. The size and location of this ulcer were atypical and illustrate the potential for serious gastrointestinal manifestations from cocaine use. PMID- 23984120 TI - Prenatal diagnosis of fetal peters' plus syndrome: a case report. AB - Peters' plus syndrome is a rare but clinically recognizable autosomal recessive ocular genetic syndrome. Diagnosis during the fetal life is challenging due to the presence of nonspecific findings such as ventriculomegaly in the growth retarded fetuses. We report the first case of fetal Peters' plus syndrome from India, where fetal ultrasound and the family history were helpful in providing a clue to the diagnosis that was confirmed later on by the DNA analysis. PMID- 23984121 TI - Child with deletion 9p syndrome presenting with craniofacial dysmorphism, developmental delay, and multiple congenital malformations. AB - A 4-month-old Sri Lankan male child case with a de novo terminal deletion in the p22->pter region of chromosome 9 is described. The child presented with craniofacial dysmorphism, developmental delay, and congenital malformations in agreement with the consensus phenotype. A distinctive feature observed in this child was complete collapse of the left lung due to malformation of lung tissue. Cytogenetic studies confirmed terminal deletion of the short arm of chromosome 9 distal to band p22 [46,XY,del(9)(p22->pter)]. This is the first reported case of a de novo deletion 9p syndrome associated with pulmonary hypoplasia. This finding contributes to the widening of the spectrum of phenotypic features associated with deletion 9p syndrome. PMID- 23984122 TI - Idiopathic central precocious puberty associated with 11 mb de novo distal deletion of the chromosome 9 short arm. AB - We report a girl with a de novo distal deletion of 9p affected by idiopathic central precocious puberty and intellectual disability. Genome-wide array-CGH revealed a terminal deletion of about 11 Mb, allowing to define her karyotype as 46; XX, del(9)(p23-pter). To our knowledge, this is the second reported case of precocious puberty associated with 9p distal deletion. A third case associates precocious puberty with a more proximal 9p deletion del(9)(p12p13,3). In our case, more than 40 genes were encompassed in the deleted region, among which, DMRT1 which is gonad-specific and has a sexually dimorphic expression pattern and ERMP1 which is required in rats for the organization of somatic cells and oocytes into discrete follicular structures. Although we cannot exclude that precocious puberty in our del(9p) patient is a coincidental finding, the report of the other two patients with 9p deletions and precocious puberty indeed suggests a causative relationship. PMID- 23984123 TI - Refractory thrombocytopenia responds to octreotide treatment in a case of evans syndrome with gastric neuroendocrine tumor. AB - A 37-year-old woman with history of Evans Syndrome with poor response to high dose corticoid treatment presented to the emergency department with gastrointestinal and vaginal bleeding. The patient was later diagnosed with severe thrombocytopenia and a stage G1, well-differentiated gastric neuroendocrine tumor, confirmed by a biopsy. A total gastrectomy was performed to eradicate the tumor. After being treated with a total splenectomy for her Evans Syndrome with no clinical or laboratory improvement, she began regular treatment with octreotide on the basis of a possible hepatic metastasis. Days after the initiation of the octreotide, an increase in the platelet count was evidenced by laboratory findings, from 2,000 platelets/mm(3) to 109,000 platelets/mm(3). Weeks later, the hepatic metastasis is discarded by a negative octreotide-body scan, and the octreotide treatment was interrupted. Immediately after the drug interruption, a progressive and evident descent in the platelet count was evidenced (4000 platelets/mm(3)). The present case report highlights the possible association between octreotide treatment and a severe thrombocytopenia resistant to conventional treatment. PMID- 23984124 TI - An acute transverse myelitis attack after total body irradiation: a rare case. AB - Total body irradiation (TBI) combined with chemotherapy is widely used as a pretreatment regimen of bone marrow transplantation (BMT) in hematologic disorders. Late complications related to TBI as part of the conditioning regimen for hematopoietic stem cell transplantation have been revealed. Acute transverse myelitis (ATM) is a neurological syndrome characterized by disorder of motor, sensorial, and autonomic nerves, and tracts at medulla spinalis, which is resulted from involvement of spinal cord. In this paper, we presented an ATM attack developed after TBI in a patient with acute lymphoblastic leukemia (ALL) as it is a rarely seen case. PMID- 23984125 TI - Kidney and pancreatic extramedullary relapse in adult acute lymphoblastic leukemia: a case report and review of the literature. AB - Extramedullary relapse of acute lymphoblastic leukemia (ALL) is rare and has been primarily reported in pediatric patients or hematopoietic stem cell transplant recipients. We report a case of a 62-year-old woman who presented with relapsed ALL involving her kidneys, pancreas, and bone marrow 2 years after completing chemotherapy with a standard ALL protocol. Unfortunately, her extramedullary disease progressed despite treatment. To the best of our knowledge, this is the first reported case of extramedullary relapse of B-cell ALL to the kidneys and pancreas occurring in an adult patient who had not previously undergone a hematopoietic stem cell transplant. A literature review of kidney and pancreatic extramedullary relapse in ALL is also included. PMID- 23984126 TI - Improvement of paraneoplastic limbic encephalitis after systemic treatment with rituximab in a patient with B-cell chronic lymphocytic leukemia. AB - Limbic encephalitis is an inflammatory disease of the central nervous system characterized by diverse neurologic symptoms including mnestic disturbances, hallucinations, and seizures as well as behavioral symptoms like depression, personality changes, and acute confusional states resembling dementia. Several antibodies have been described in the pathogenesis of limbic encephalitis. It is often a paraneoplastic syndrome associated with small cell lung cancer, breast cancer, or Hodgkin's lymphoma among others. Here, we report a patient with B-cell chronic lymphocytic leukemia (B-CLL), presenting with otherwise unexplained neurologic symptoms consistent with limbic encephalitis. Despite intensive diagnostic procedures, no causing agent could be identified. Pleocytosis consisting of T cells was detected in the cerebrospinal fluid (CSF). We initiated anti-B-cell therapy with Rituximab for B-CLL with quick and durable resolution of symptoms. We speculate that disruption of interaction between autoreactive T and malignant B cells is responsible for the therapeutic effect of Rituximab. PMID- 23984127 TI - Tuberculosis infection mimicking brain metastatic malignancy lesions in an elderly male. AB - An 83-year-old Caucasian Greek man was referred by his general practitioner to the emergency department of the general hospital in Crete because of seizures and agitation. His past medical history was negative for any neurological or medical condition. Electroencephalogram showed a bradyarrhythmic theta activity, without evidence of any focal or other specific abnormality. Magnetic resonance imaging of the brain demonstrated a number of diffuse nodular lesions and moderate perivascular edema. An axillary lymph node fine needle aspiration cytology suggested a granulomatous lymphadenitis along with signs of tuberculous infiltration. Tuberculin skin test was positive. We report a rare case of extrapulmonary tuberculosis mimicking brain metastatic lesions. PMID- 23984128 TI - Klebsiella pneumoniae Renal Abscess Syndrome: A Rare Case with Metastatic Involvement of Lungs, Eye, and Brain. AB - We describe a rare case of Klebsiella pneumoniae renal abscess with metastatic spread leading to endopthalmitis, pulmonary cavitary lesions, and cerebral emboli in a 41-year-old Hispanic female with diabetes mellitus who presented with a four to-five-day history of fevers, headache, eye pain, and vomiting. She was treated with IV antibiotics and made a gradual but full recovery. PMID- 23984129 TI - Cerebral Aneurysms: A Rare Feature of Behcet's Disease-A Case Report and Review of the Literature. AB - Behcet's disease (BD) is a multisystem vascular inflammatory disease with several clinical manifestations. Intracranial aneurysms are an extremely rare but nevertheless severe complication of BD. We report a case of a 44-year-old man. The diagnosis of BD was made based on the presence of recurrent oral aphthous ulcers and positive human leukocyte antigen (HLA-) B51 in the absence of evidence of other diseases. MRI showed an ancient ischemic right capsulolenticular lesion, subacute white matter hypersignals of the left capsule lenticular region, and multiple arterial aneurysms. The patient underwent two-month systemic high-dose corticosteroids and immunosuppressive therapy associated with severe neurological deficiency upon admission and severe impairment upon discharge. A thorough review of the literature showed 20 case reports of intracranial aneurysms in BD. PMID- 23984130 TI - Mature ovarian teratoma with carcinoid tumor in a 28-year-old patient. AB - Introduction. Coexistence of carcinoid tumor inside a mature cystic teratoma is an extremely rare phenomenon, especially in young women. We present the case of a 28-year-old woman diagnosed with a right ovarian carcinoid and treated uneventfully with conservative surgical approach. Case Report. A 28-year-old woman, gravid 0, parity 0, presented to our department for her annual gynecological examination and Pap smear test. During her examination, a mobile cystic mass was detected in the right lower abdomen. Ultrasound indicated a right ovarian mass 10.5 * 6.3 cm, confirmed by CT scan. Further investigation revealed AFP levels (1539 ng/mL). The ovarian mass was excised by laparoscopy, leaving intact the remaining right ovary. Frozen sections showed a mature cystic teratoma. However, paraffin sections revealed the presence of a small carcinoid within the teratoma's gastric-type mucosa. The patient was set to a close followup. Nine months postoperatively, ultrasound pelvis imaging and CT scan of the abdomen as well as serum tumor markers have shown no evidence of recurrence disease. Conclusion. Despite the weak evidence, fertility spare surgical approach for women wanting to preserve their genital tract might be a reasonable option. PMID- 23984131 TI - Maternal Perception of Decreased Fetal Movement in One Twin: A Clue Leading to the Early Detection of Absent Variability due to Acute Twin-to-Twin Transfusion Syndrome. AB - Decreased fetal movement (DFM) perceived by pregnant women sometimes indicates imminent fetal jeopardy. It is unknown whether this also holds true for twin pregnancy. A 27-year-old primiparous woman with monochorionic diamniotic (MD) pregnancy had a slight difference of amniotic fluid volume at 31(2/7) weeks of gestation. DFM only in one twin at 31(4/7) weeks of gestation prompted her to receive urgent consultation. Since cardiotocogram indicated absent variability of one twin, we performed Cesarean section. Male infants weighing 2060 g and 1578 g were delivered; hemoglobin was 20.7 versus 10.8 g/dL, respectively; cardiothoracic ratio was 70% versus 44%, respectively, indicating acute twin-to twin transfusion syndrome (TTTS). The recipient infant had heart failure, which was still observed at 1 month postpartum. In conclusion, maternal perception of DFM indicated imminent fetal death or jeopardy caused by acute TTTS, suggesting that education regarding DFM for women with twin pregnancy may be clinically important. PMID- 23984132 TI - Isolated fallopian tube torsion. AB - Isolated torsion of the Fallopian tube is a rare gynecological cause of acute lower abdominal pain, and diagnosis is difficult. There are no pathognomonic symptoms; clinical, imaging, or laboratory findings. A preoperative ultrasound showing tubular adnexal masses of heterogeneous echogenicity with cystic component is often present. Diagnosis can rarely be made before operation, and laparoscopy is necessary to establish the diagnosis. Unfortunately, surgery often is performed too late for tube conservation. Isolated Fallopian tube torsion should be suspected in case of acute pelvic pain, and prompt intervention is necessary. PMID- 23984133 TI - Repetitive breech presentations at term. AB - The authors present a case of 38-year-old laboring woman with four-time repetitive breech presentation of the fetus at term. This rare condition affects the mode of delivery and represents serious obstetrical problem as it is associated with increased perinatal morbidity or mortality. The authors give details on risk factors for breech presentation, its diagnosis, and the discussion points on possible causes leading to repetitive breeches in laboring women. PMID- 23984134 TI - Genital schistosomiasis leading to ectopic pregnancy and subfertility: a case for parasitic evaluation of gynaecologic patients in schistosomiasis endemic areas. AB - Female genital schistosomiasis is a significant risk factor for ectopic pregnancy and infertility in schistosomiasis-endemic areas. A case of one previous ectopic pregnancy and subsequent obstruction of the contralateral tube in a secondary subfertility patient with chronic genital schistosomiasis is presented, emphasizing the need for a detailed history and parasitic evaluation of patients presenting with ectopic pregnancy or subfertility in areas where the disease is endemic. PMID- 23984135 TI - Unilateral isolated proximal femoral focal deficiency. AB - Objective. To discuss a patient with a prenatal diagnosis of unilateral isolated femoral focal deficiency. Case. Antenatal diagnosis of unilateral isolated femoral focal deficiency was made at 20 weeks of gestation. The length of left femur was shorter than the right, and fetal femur length was below the fifth percentile. Proximal femoral focal deficiency was diagnosed. After delivery, the diagnosis was confirmed with skeletal radiographs and magnetic resonance imaging. In prenatal ultrasonographic examination, the early recognition and exclusion of skeletal dysplasias is important; moreover, treatment plans should be initiated, and valuable information should be provided to the family. PMID- 23984136 TI - Myoepithelial carcinoma of the breast treated with surgery and chemotherapy. AB - Myoepithelial carcinoma (malignant myoepithelioma) of the breast is a rare tumor, for which only a limited number of reports have been published. Most of the reports emphasized diagnosis and pathology but not biological behavior and treatment. We report a 61-year-old patient with breast myoepithelial carcinoma who developed locoregional and distant metastases and received many chemotherapy regimens. She presented with an elastic hard mass of the left breast. Breast conserving surgery was performed as part of both diagnosis and treatment. From the results of histological and immunohistochemical examinations, this case was considered to be a myoepithelial carcinoma. Fifteen months after the completion of adjuvant radiotherapy, distant metastasis of the left parasternal lymph node metastasis developed. She was treated by further excision and received a total of four regimens of chemotherapy including a combination of doxorubicin and cyclophosphamide. She received chemotherapy for 20 months after the diagnosis of metastasis. PMID- 23984137 TI - Toxic epidermal necrolysis associated with antiepileptic drugs and cranial radiation therapy. AB - Case reports on the development of toxic epidermal necrolysis (TEN) associated with concurrent administration of phenytoin with cranial radiation therapy (Ahmed (2004), Criton et al. (1997), and Rzany et al. (1996)), but reports about erythema multiforme, which can develop in patients treated with levetiracetam and cranial irradiation, are very limited. This paper presents evidence that TEN may be induced by concurrent use of radiation with both phenytoin and levetiracetam. Our case is a 42-year-old male patient, a case of gliosarcoma who developed purpuric dermatitis associated with phenytoin when combined with cranial radiation therapy; although phenytoin was discontinued and switched to levetiracetam, the patient had more severe symptoms of toxic epidermal necrolysis (TEN) on levetiracetam; the patient improved with aggressive symptom management, discontinuation of antiepileptic drugs (AEDs), and holding radiotherapy. Although TEN is a rare toxicity, physicians should pay a special attention to the monitoring of brain tumor patients on antiepileptic prophylaxis during cranial irradiation; furthermore, patients should be counselled to notify their physicians if they develop any new or unusual symptoms. PMID- 23984138 TI - Denosumab chemotherapy for recurrent giant-cell tumor of bone: a case report of neoadjuvant use enabling complete surgical resection. AB - Giant-cell tumor of the bone (GCTB) is a rare neoplasm that affects young adults. The tumor is generally benign but sometimes can be locally aggressive. There are no standardized approaches to the treatment of GCTB. Recently, the RANKL inhibitor denosumab has shown activity in this tumor type. We present the case of a young female who presented with locally advanced disease and was successfully managed with the neoadjuvant use of denosumab allowing for surgical resection of the tumor that was previously deemed unresectable. Following surgery, the patient is being managed with continued use of denosumab as 'maintenance,' and she continues to be free of disease. Our case highlights a novel approach for the management of locally advanced and aggressive giant cell tumor of the bone. PMID- 23984139 TI - Splitting of a Dexamethasone Implant (Ozurdex) following the Injection. AB - In this brief report, we share our observations on a splitted Dexamethasone implant (Ozurdex) which we discovered a week after the injection. It is likely that implant splitting neither changes the efficacy of the implant nor creates a mishap for the patient. PMID- 23984140 TI - Spontaneous isolated infection of the subacromial bursa. AB - Isolated infection of the subacromial bursa is a rare entity. We present the case of a previously fit man who was found to have staphylococcal infection of the sub acromial bursa, without an obvious precipitant. Preoperative MRI scanning determined the specific locus of infection, and the patient was successfully treated with arthroscopic washout of the sub-acromial bursa followed by empirical antibiotic therapy. PMID- 23984141 TI - Pseudoaneurysm of the Anterior Tibial Artery following Tibio-Talar-Calcaneum Fusion with a Retrograde Nail: A Rare Case and Literature Review. AB - This study reports the case of an 87-year-old woman who presented with a nonresolving haematoma 13 weeks following tibiotalar arthrodesis surgery on her right ankle using a retrograde nail. This was revealed by angiography to be a pseudoaneurysm of the anterior tibial artery. The patient subsequently underwent endovascular stenting of the pseudoaneurysm and has had a successful recovery. This case highlights the need for awareness of both the normal arterial supply to the leg and ankle as well as the potential for anatomical variations. Arterial variation may be as high as 6.7% based on published findings from cadaveric studies. As pseudoaneurysm is a rare complication, a high index of suspicion is needed in order to avoid a missed or delayed diagnosis. We urge surgeons to keep in mind the potential for pseudoaneurysm when a patient presents with a nonresolving haematoma and arrange appropriate further investigations as needed. PMID- 23984142 TI - Traumatic burst fracture with spinal channel involvement augmentation with bioactive strontium-hydroxyapatite cement. AB - In November 2011 a 75-year-old man was admitted to our emergency department with a low back pain caused by a traumatic L1 vertebral collapse with backward projection of posterior wall superior third. The indication for neurosurgical instrumentation was placed, although he refused the treatment. Hence he was treated conservatively without a significant improvement up to January 2012 when, still refusing surgery, he accepted to undergo percutaneous vertebroplasty with a novel bioactive injectable strontium-hydroxyapatite cement. Vertebroplasty was performed without complications. A CT scan, performed the day after the procedure, ruled out extravertebral cement leakage. Pain improvement was significant (preprocedure VAS 10, one-week VAS 4) with a gradual decrease up to three months when it stabilized at 2. CT examination after 1 year showed a good cement osseointegration with osteophytic spurs bridging the superior endplate of the level involved to the inferior one of the level above. The new bone ingrowing property of the strontium-hydroxyapatite containing cement permits to extend the treatment indication also to unstable collapses in which the risk of pseudoarthrosis is very high. In this reported case we evaluated the potential role of percutaneous vertebroplasty in traumatic burst fracture with spinal channel involvement. PMID- 23984143 TI - Simultaneous Bilateral Quadriceps Tendon Rupture following Long-Term Low-Dose Nasal Corticosteroid Application. AB - Simultaneous bilateral quadriceps tendon rupture is a very rare injury, which was previously only described in slightly more than 100 cases in the English literature. Occurrence after minor trauma is predominantly associated with certain medical conditions including chronic diseases and long-term use of certain drugs. We report the case of a 61-year-old healthy patient who sustained a simultaneous bilateral quadriceps tendon rupture following minor trauma. Medical history was completely clear except of a long-term nasal corticosteroid medication due to allergic rhinitis. PMID- 23984144 TI - A Case of Primary Non-Hodgkin's Lymphoma of the External Auditory Canal. AB - Lymphomas represent the second most frequent malignant tumor (incidence 2.5%) in the head and neck region. Non-Hodgkin lymphomas (NHLs) present with cervical lymph node involvement, but in 40% extranodal site could be primary involved: nasopharynx, the lacrimal sac, the temporal bone, or the others areas. NHLs of the ear are rarely reported. In this report, we described a patient with primary NHL of the external ear canal who was successfully treated with surgical excision and chemotherapy. PMID- 23984145 TI - Laryngeal synovial sarcoma: a rare clinical entity. AB - Introduction. Synovial sarcomas (SS) are aggressive malignant soft tissue tumours that are thought to arise from pluripotent mesenchymal cells. Clinical Report. A 20-year-old male presented with an acute onset of respiratory stridor. Computer tomography scanning confirmed a mass arising from the left supraglottic larynx and an emergency tracheostomy was performed. A diagnosis of biphasic synovial sarcoma was formed. A total laryngectomy and left hemithyroidectomy was performed in conjunction with a left modified radical neck dissection. The patient received adjuvant chemotherapy followed by a course of radiotherapy and remains alive and disease free at 18 months after treatment. Discussion. Prognosis for patients with SS is related to primary tumour extent, grade, and size. The presence of the diagnostic translocation, t(X;18), is being targeted and hopefully will lead to the development of new therapeutics (Guadagnolo et al., 2007). Conclusion. Laryngeal SS remains a rare and poorly understood entity. A multidisciplinary approach to treatment is essential and long-term followup is imperative. PMID- 23984146 TI - Bilateral lower cervical bifurcation of the common carotid artery. AB - Lower cervical bifurcation of cervical common carotid artery (CCA) is a very rarely encountered anatomic variation. Knowing the normal vascular anatomy and also its anomalies is important in preventing the vascular complications. Ill defined vascular anomalies may lead to massive hemorrhage and eventually death during head and neck surgery. Imaging of the neck by magnetic resonance Imaging (MRI), CT, or angiography is helpful for diagnosis. We present a 62-year-old male patient diagnosed with laryngeal carcinoma who had been treated. His MRI revealed bilateral low-level bifurcation of the cervical common carotid arteries as well as tumor localization and its boundaries. Total laryngectomy and right selective neck dissection was performed to the patient with the diagnosis of squamous cell carcinoma of the larynx. During the neck dissection, carotid bifurcation was detected in common border of Level 3 and Level 4 of the neck. PMID- 23984147 TI - Unexpected diagnosis of both adenocarcinoma of the colon and metastatic lobular carcinoma of the breast in the gastrointestinal tract. AB - Breast cancer rarely metastasises to the gastrointestinal tract. Lobular carcinoma more commonly metastasises to the uterus and appendages, peritoneum, and gastrointestinal tract than other types of breast cancer, while ductal carcinoma has a propensity to metastasise to the lungs, liver, and brain. We describe the case of a patient with no known history of breast cancer, whose primary presentation of lobular breast cancer was with malignant small intestinal and colonic strictures, with coexisting previously undiagnosed adenocarcinoma of the colon. PMID- 23984148 TI - Gynecomastia-like hyperplasia of axillary ectopic breast tissue in a young female. AB - Gynecomastia-like hyperplasia of orthotopic female breast tissue is a rare entity. We present the singularly unique case of a 22-year-old female who presented with a small axillary mass subsequently discovered to be a discrete deposit of ectopic breast tissue with gynecomastia-like hyperplasia. This case highlights the etiology, variable presentation, and evaluation of ectopic breast tissue. PMID- 23984149 TI - Portal Hypertension, Nodular Regenerative Hyperplasia of the Liver, and Obstructive Portal Venopathy due to Metastatic Breast Cancer. AB - Nodular regenerative hyperplasia (NRH) of the liver is associated with noncirrhotic portal hypertension, rheumatologic and hematologic disorders, administration of certain drugs, and other underlying conditions. This report describes a 64-year-old man with clinically presumed cirrhosis who presented to our institution with coffee-ground emesis, esophageal varices, ascites, and encephalopathy. Eleven years earlier he had been treated for breast cancer with mastectomy and chemo-radiotherapy. He died suddenly, and the autopsy showed no evidence of cirrhosis but instead demonstrated NRH with extensive emboli of recurrent breast carcinoma within the portal vein and its intrahepatic branches. Neoplastic occlusion of the portal vein as a cause of presinusoidal noncirrhotic portal hypertension has not previously been reported for metastatic breast carcinoma. This case highlights the importance of obstructive portal venopathy in the pathogenesis of NRH as well as the diagnostic difficulties that may be encountered in determining the cause of portal hypertension. PMID- 23984150 TI - Key diagnostic finding in a condition with variable clinical presentations. AB - This is an interesting case series on a very common genetic condition which are often diagnosed late as clinical signs are inconspicuous. We would like to highlight the principal clinical examination finding which led to diagnosis. PMID- 23984151 TI - Importance of Video-EEG Monitoring in the Diagnosis of Refractory Panic Attacks. AB - Partial seizures can be misdiagnosed as panic attacks. There is considerable overlap of symptoms between temporal lobe seizures and panic attacks making the diagnosis extremely challenging. Temporal lobe seizures can present with intense fear and autonomic symptoms which are also seen in panic disorders. This results in delay in diagnosis and management. We report an interesting case of a young woman who was diagnosed with right temporal lobe seizures with symptoms suggestive of a panic attack. PMID- 23984152 TI - Is the concept of delirious mania valid in the elderly? A case report and a review of the literature. AB - Delirious mania has been well recognized in the published literature and in the clinic. Over the years there has been refinement of understanding of its clinical features, course, and treatment. The literature suggests that delirious mania should be considered in individuals who present with a constellation of sudden onset delirium, mania, and psychosis. However, delirious mania is not recognized under a formal classification system nor are there any formal guidelines for its treatment. We, as such, question if the concept of delirious mania in the elderly is valid. We present a case of an elderly man with marked features of delirium with minimal manic or psychotic features who had a previous diagnosis of bipolar I disorder. On thorough clinical assessments no identifiable cause of his delirium was found. We therefore considered his presentation to be more likely due to delirious mania. Electroconvulsive therapy was considered and offered to which he responded very well. We invite the reader to consider whether delirious mania is a valid concept in the elderly, where features of delirium may be more prominent than manic or psychotic features. PMID- 23984153 TI - Venlafaxine-induced orthostatic hypotension in a geriatric patient. AB - Venlafaxine is not usually associated with risk of orthostatic hypotension. A 65 year-old US Caucasian female taking 225 mg/day of venlafaxine extended-release developed symptomatic orthostatic hypotension. The systolic and diastolic blood pressure dropped by 25 and 18 mm Hg, respectively, from supine position to standing position within 3 minutes. The patient was otherwise healthy and the orthostatic hypotension resolved with venlafaxine discontinuation. This was a probable venlafaxine adverse drug reaction according to the Naranjo scale. This case contributes to the scarce literature that indicates that clinicians need to be aware that occasionally venlafaxine can induce clinically significant orthostatic hypotension, particularly in geriatric patients. Our patient did not have orthostatic hypotension when she was taking venlafaxine at 60 years of age in higher venlafaxine doses (300 mg/day) but developed this adverse drug reaction when venlafaxine was restarted at the geriatric age. This case indicates that a history of prior tolerance to venlafaxine does not guarantee tolerance after 65 years of age. If a clinician decides to use venlafaxine in geriatric patients, the clinician should warn the patient about the risk of orthostatic hypotension and consider very slow titration and low doses. PMID- 23984154 TI - Empiric treatment of focal organizing pneumonia in a patient with a low-risk lung mass. AB - The authors present a case of a 57-year-old man presenting with a solitary lung mass. Transbronchial biopsy showed an organizing pneumonia pattern. A therapeutic trial of corticosteroids resulted in complete resolution avoiding surgery. The authors discuss the diagnosis of focal organizing pneumonia without surgical resection. PMID- 23984155 TI - Compression of the superior vena cava by an interatrial septal lipoma: a case report. AB - Primary cardiac tumours are rare; their prevalence ranges from 0.0017% to 0.28% in various autopsy series. Cardiac lipomas are well-encapsulated benign tumours typically composed of mature fat cells, and their reported size ranges from 1 to 15 cm. They are usually seen in the left ventricle and the right atrium. Lipomas are true neoplasms, as opposed to lipomatous hypertrophy of the interatrial septum, which is a nonencapsulated hyperplastic accumulation of mature and foetal adipose tissue. Cardiac lipomas occur in patients of all ages, and the frequency of occurrence has been found to be equal in both sexes. Patients are usually asymptomatic, although the manifestation of symptoms depends upon both size and location of the tumour. We present the case of a patient with an interatrial septal lipoma, causing obstruction of the superior vena cava. PMID- 23984156 TI - Pneumatosis cystoides intestinalis: a rare benign cause of pneumoperitoneum. AB - Pneumatosis cystoides intestinalis is a rare gastrointestinal complication in the course of connective tissue diseases, especially in scleroderma, that can lead to pneumoperitoneum or obstruction. Findings on plain radiography may reveal radiolucent linear or bubbly circular air bubbles in the bowel wall, with or without free gas accumulation in the peritoneal cavity. Treatment of pneumatosis cystoides intestinalis ranges from supportive care to laparotomy. PMID- 23984157 TI - Rupture of the Left External Iliac Artery and Right Groin Pseudoaneurysm Formation following Angioplasty in a Patient with Neurofibromatosis Type 1 and Undiagnosed Bilateral Phaeochromocytoma. AB - Neurofibromatosis type 1 (NF1) is a genetic condition, which affects 1 in every 3000 births. Patients with NF1 are at increased risk of a variety of vascular abnormalities. This report presents the case of a 60-year-old male with NF1 who suffered a left external iliac rupture and a right pseudoaneurysm following angioplasty. In addition, these were further complicated by previously undiagnosed, bilateral phaeochromocytomas. The inherent weakness in vessel wall architecture found in NF1 coupled with the hypertension evident during and after the procedure contributed to haemorrhage and pseudoaneurysm formation. Caution must be taken in such patients when considering vascular intervention. PMID- 23984158 TI - Malfunctioning plastic biliary endoprosthesis: percutaneous transhepatic balloon pulling technique. AB - Percutaneous transhepatic removal techniques for malfunctioning plastic biliary endoprosthesis are considered safe and efficient second-line strategies, when endoscopic procedures are not feasible. We describe the percutaneous transhepatic balloon pulling technique in a patient with an unresectable malignant hilar cholangiocarcinoma. PMID- 23984159 TI - Sterile osteitis and suppurative arthritis associated with pannus responding to colchicine. AB - Sterile suppurative arthritis is characterized by neutrophilic infiltration of joints without any causative pathogen. Here, we present a 32-year-old man with refractory osteitis and erosive suppurative oligoarthritis with pannus. Treatments with multiple disease modifying antirheumatic drugs were all unsuccessful. However, he had clinical response to colchicine and the synovial hypertrophy and the pannus in the MRI of his left shoulder resolved. In this case, the effects of colchicine on neutrophils might have played a role in treating neutrophilic sterile suppurative arthritis, which, in adults, might be a distinct oligoarticular disease. PMID- 23984160 TI - Role of (18)F-FDG PET Scan in Rheumatoid Lung Nodule: Case Report and Review of the Literature. AB - Flourine-18 fluoro-2-deoxy-glucose ((18)F-FDG) positron emission tomography combined with computed tomography (PET/CT) is a useful test for the management of malignant conditions. Inflammatory and infectious processes, however, can cause increased uptake on PET scanning, often causing diagnostic dilemmas. This knowledge is important to the rheumatologist not only because of the inflammatory conditions we treat but also because certain rheumatic diseases impose an increased risk of malignancy either due to the disease itself or as a consequence of medications used to treat the rheumatic diseases. There is an increasing body of evidence investigating the role of PET scans in inflammatory conditions. This paper describes a patient with rheumatoid arthritis who developed pulmonary nodules that showed increased uptake on PET/CT scan and reviews the use of PET scanning in the diagnosis and management of rheumatoid arthritis. PMID- 23984161 TI - Pachymeningitis in granulomatosis with polyangiitis: a case report and a review of the literature. AB - Central nervous involvement, mainly with symptoms of cranial neuropathies, occurs in 2-8% of patients with granulomatosis with polyangiitis (GPA). Meningeal involvement, with persistent and severe headache as main manifestation and abnormal thickening and enhancement of the dural mater on postcontrast magnetic resonance imaging, is extremely rare. We present a case of pachymeningitis due to limited GPA, providing simultaneously a literature review. PMID- 23984162 TI - A case of subacute cutaneous lupus erythematosus in a patient with mixed connective tissue disease: successful treatment with plasmapheresis and rituximab. AB - A 30-year-old woman affected by Mixed Connective Tissue Disease with scleroderma spectrum developed a facial eruption, a clinical and histological characteristic of subacute cutaneous lupus erythematosus (SCLE). Speckled anti-nuclear antibodies, high-titer anti-ribonucleoprotein1, anti-Sm, anti-Cardiolipin (aCL) IgG/IgM, and anti-Ro/SSA antibodies were positive. SCLE was resistant to Azathioprine, Hydroxychloroquine, and Methotrexate while Mycophenolate Mofetil was suspended due to side effects. Subsequently, the patient was treated with three cycles of therapeutic plasma exchange (TPE) followed, one month after the last TPE, by the anti-CD20 antibody Rituximab (RTX) (375 mg/m(2) weekly for 4 weeks). Eight and 16 months later the patient received other two TPE and RTX cycles, respectively. This therapeutic approach has allowed to obtain a complete skin healing persistent even after 8-month follow-up. Moreover, mitigation of Raynaud's phenomenon, resolution of alopecia, and a decline of aCL IgG/IgM and anti-Ro/SSA antibodies were observed. PMID- 23984163 TI - Purulent cutaneous fistula: as the first symptom of the late aortic stent-graft infection-a case report and review of the literature. AB - Purpose. Aortic stent-graft infection with fistula formation is a rare complication with high mortality rate when treated surgically by stent-graft removal. We report a case of a patient with aortic stent-graft infection, prosthetic-duodenal, and prosthetic-cutaneous fistulas operated without the removal of an infected prosthesis and ineffectively tailored antibiotic therapy. Case Report. A 66-year-old patient with high cardiovascular risk and endovascular stent-graft implantation developed a symptomatic infection of the aortic stent graft 42 months after procedure. It was manifested by iliolumbar muscle abscess and two fistulas: prosthetic cutaneous and prosthetic duodenal. The prosthetic duodenal fistula was excised and separated from the prosthesis. The perforation within the duodenum was closed in layers. Iliolumbar abscess was removed and drainage was effected .The stent graft was left. The patient received tailored antibiotic therapy. He was readmitted to hospital after 4 weeks with symptoms of infection and leakage of pus discharge in the lumbar area. Despite the antibiotic therapy, the total parenteral nutrition of the patient's clinical status and malnutrition deteriorated and he died of cardiac arrest. Conclusion. The presented case confirms that leaving off of the infected stent graft in the patient with severe comorbidity and treated with a tailored antibiotic therapy may not be effective. PMID- 23984164 TI - Adrenal gland metastasis is an unusual manifestation of endometrial cancer. AB - This case report describes a woman treated for stage 1 B grade 3 endometrial adenocarcinoma with surgery and adjuvant radiation therapy who presented 6 months later with pain and symptoms of adrenal insufficiency. A large right adrenal mass revealed adenocarcinoma consistent with the endometrial primary. PMID- 23984165 TI - Carcinoma of the colon in an adult with intestinal malrotation. AB - Colon cancer is the third most common cancer in the USA. Intestinal malrotation diagnosed in adulthood was, until recently, a very rare phenomenon. While patients may present with intestinal obstruction or abdominal pain, the diagnosis is now often made as an incidental finding by computed tomography (CT). Surprisingly we found only seven case reports of carcinoma of the colon in patients with malrotation; CT failed to make the preoperative diagnosis in a majority. Laparoscopic colon surgery is rapidly becoming standard of care for colon cancer. We present a case of carcinoma of the colon in an adult that thwarted attempts at laparoscopic resection due to failure to recognize malrotation preoperatively. The literature is reviewed, and the implications of malrotation in patients with colon cancer are examined. PMID- 23984166 TI - Lower Limb Ischemia: Aortoiliac Thrombosis Related to Antiphospholipid Syndrome (APS)-Case Report and Review of the Literature. AB - Antiphospholipid syndrome (APS) is recognized as one of the main determinants of hypercoagulable conditions. The literature reports the incidence of this syndrome in a third of patients who underwent surgery for peripheral revascularization. Antiphospholipid antibodies are divided into two categories in relation to specific diagnostic tests. The first group is called lupus anticoagulant and consists of immunoglobulins that inhibit the phospholipid dependent coagulation tests in vitro. The second group is defined by their ability to conduct the phospholipid in an ELISA test. The occurrence of thrombotic events in patients with systemic erythematosus lupus (SEL) and anticoagulant antibodies was described for the first time in 1963 by Bowie. The discovery of anti-cardiolipin antibodies in antiphospholipid syndrome is due to Harris et al. who described the syndrome. Primitive APS was consequently defined in the absence of further underlying illnesses. In this disease, arterial thrombosis occurs mainly in the brain. Peripheral arteries are affected less frequently. Thrombosis of the great vessels is reported as anecdotal. PMID- 23984167 TI - Laparoscopic cholecystectomy in the presence of lumboperitoneal shunt. AB - Laparoscopic cholecystectomy remains the mainstay of treatment in patients with gallstone disease. Nowadays more than ever before, patients present with more comorbidities and entities that make the laparoscopic approach composite. One of these is the presence of lumboperitoneal (LP) shunts. Herein, we describe a case of successful laparoscopic cholecystectomy in a patient with an LP shunt and an occipital nerve stimulator in the anterior abdominal wall. We describe alterations in technique, aiming at surgeons that perform laparoscopic cholecystectomies with useful tips in order to successfully deliver the operation. A brief review of the literature in the current subject is also given. PMID- 23984168 TI - Intracardiac Thrombosis during Adult Liver Transplantation. AB - Intracardiac thrombosis (ICT) and pulmonary embolism (PE) during adult liver transplantation are rare but potentially lethal complications. They are often overlooked because of significant diagnostic challenges. The combination of hemodynamic compromise and transesophageal echocardiography (TEE) findings allows for correct diagnosis. A large variety of putative risk factors for ICT and PE have been suggested, but these events are considered to be multifactorial. There are different proposed treatment modalities for these devastating complications. Unfortunately, in spite of growing knowledge in this area, intraoperative and postoperative mortalities remain very high. The retrospective nature of the study of these events makes the case reports extremely valuable. PMID- 23984169 TI - Treatment of recurrent posttransplant lymphoproliferative disorder of the central nervous system with high-dose methotrexate. AB - Posttransplant lymphoproliferative disorder (PTLD) is a frequent complication of intestinal transplantation and is associated with a poor prognosis. There is currently no consensus on optimal therapy. Recurrent PTLD involving the central nervous system (CNS) represents a particularly difficult therapeutic challenge. We report the successful treatment of CNS PTLD in a pediatric patient after liver/small bowel transplantation. Initial immunosuppression (IS) was with thymoglobulin, solucortef, tacrolimus, and mycophenolate mofetil. EBV viremia developed 8 weeks posttransplantation, and despite treatment with cytogam and valganciclovir the patient developed a polymorphic, CD20+, EBV+ PTLD with peripheral lymphadenopathy. Following treatment with rituximab, the lymphadenopathy resolved, but a new monomorphic CD20-, EBV+, lambda-restricted, plasmacytoid PTLD mesenteric mass emerged. Complete response of this PTLD was achieved with 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy; however, 4 months off therapy he developed CNS PTLD (monomorphic CD20-, EBV+, lambda-restricted, plasmacytoid PTLD) of the brain and spine. IS was discontinued and HD-MTX (2.5-5 gm/m(2)/dose) followed by intrathecal HD-MTX (2 mg/dose *2-3 days Q 7-10 days per cycle) was administered Q 4-7 weeks. After 3 cycles of HD-MTX, the CSF was negative for malignant cells, MRI of head/spine showed near-complete response, and PET/CT was negative. The patient remains in complete remission now for 3.5 years after completion of systemic and intrathecal chemotherapy. Conclusion. HD-MTX is an effective therapy for CNS PTLD and recurrent PTLD that have failed rituximab and CHOP chemotherapy. PMID- 23984170 TI - Aspergillus tracheobronchitis causing subtotal tracheal stenosis in a liver transplant recipient. AB - Invasive aspergillosis is recognized as one of the most significant opportunistic infections after liver transplantation. Diagnosis of invasive aspergillosis in transplant recipients has been proven to be challenging, and optimal approach to the treatment of invasive aspergillosis is still controversial. We here present an unusual case of Aspergillus tracheobronchitis in the setting of liver transplantation. A 47-year-old female patient with persistent dry cough after liver transplantation developed respiratory insufficiency and was readmitted to the intensive care unit 55 days after liver transplantation. A CT scan revealed subtotal tracheal stenosis; bronchoscopy was performed, and extended white mucus coverings causative of the tracheal stenosis were removed. Microbiological assessment isolated Aspergillus fumigatus. The diagnosis was obstructive Aspergillus tracheobronchitis. The patient was started on a treatment of voriconazole 200 mg orally twice daily, adjusted to a trough level of 1-4 mg/L. For further airway management, a tracheal stent had to be implanted. The patient is alive and well 28 months after liver transplantation. Invasive aspergillosis should be considered a possible etiology in liver transplant patients presenting with unspecific symptoms such as persistent dry cough. Optimal strategies for improved and early diagnosis as well as prophylaxis need to be defined. PMID- 23984171 TI - Neurofibromatosis type 1 with bladder involvement. AB - Neurofibromatosis type 1 is an autosomal dominant transmitted disease with various clinical manifestations. The bladder is the most commonly affected organ in the genitourinary system. The malignant transformation of the disease is rare, and unlike malign tumors, the treatment option for benign disease is usually conservative. The size and localization of the mass determine the symptoms, most of which are usually not specific. In this paper, we aim to present a 15-year-old patient with neurofibromatosis type 1 with bladder involvement. The clinical presentation and treatment options of this disease are discussed in the light of the literature. PMID- 23984172 TI - A novel type of ureteral stents in the treatment of a bilateral iatrogenic transaction of the ureters. AB - This report illustrates the case of a patient who suffered an iatrogenic complete injury of both ureters after a complex surgical procedure to remove a large sacral chordoma. Ureteral recanalization was achieved with two removable, autoexpandable, and polytetrafluoroethylene covered nitinol stents. To our knowledge, we describe the first application of this type of stents to treat a bilateral ureteral transection. Despite the bad general conditions of the patient, the ureteral stents successfully restored and maintained the bilateral ureteral continuity. PMID- 23984173 TI - Spiculated bladder calculi: the culprit for repeated catheter failure. AB - We report on the case of a frustrated 90-year-old gentleman who was seen in the Accident and Emergency department for the third time in four days with failure of his long-term urethral catheter. He reported that the catheter simply "fell out" with the balloon deflated. On each occasion previously, the catheter had been reinserted in A&E and the patient discharged home. These repeated visits to A&E were understandably a source of much frustration for the patient and his family. On the third presentation, plain abdominal radiography demonstrated a large spiculated bladder calculus. PMID- 23984174 TI - Prostate Cancer in a Male with Holt-Oram Syndrome: First Clinical Association of the TBX5 Mutation. AB - Holt-Oram syndrome is an autosomal dominant disorder which is caused by mutations of TBX5 and is characterised by cardiac and skeletal abnormalities. TBX5 is part of the T-box gene family and is thought to upregulate tumour cell proliferation and metastasis when mutated. We report the first clinical case of prostate cancer in an individual with Holt Oram syndrome. PMID- 23984175 TI - Simultaneous renal oncocytoma and lymphoma: interest of lymphadenectomy. AB - Kidney lesions may be difficult to diagnose only by radiological exams, often requiring proof by tissue biopsy. Moreover, if enlarged regional lymph nodes are also present, the spectrum of differential diagnoses is even greater. The role of regional lymph node dissection in this setting is not clearly established. We show the case of a patient with a kidney mass associated with a conglomerate of para-aortic and iliac lymphadenopathies corresponding to an oncocytoma and a nodular lymphocyte predominant Hodgkin' lymphoma, respectively. Diagnosis of these two lesions was performed by morphology and immunohistochemistry. This case reflects how imaging can mislead to diagnosis and how histological confirmation helps decide treatment management. PMID- 23984176 TI - A 22-year-old female with invasive epithelioid angiomyolipoma and tumor thrombus into the inferior vena cava: case report and literature review. AB - A 22-year-old female presented with back pain and was discovered to have a right sided abdominal mass. Computed tomography (CT) scan revealed a 9 cm enhancing right upper pole renal mass with suspicion for tumor thrombus into the right renal vein and possibly the inferior vena cava (IVC). Magnetic resonance imaging (MRI) confirmed tumor thrombus into the inferior vena cava approximately 3 cm below the hepatic venous confluence. Open right radical nephrectomy with inferior vena cava thrombectomy was performed with removal of right kidney and tumor thrombus en bloc. Pathology revealed malignant epithelioid angiomyolipoma (EAML or PEComa). Epithelioid angiomyolipoma is a rare tumor of mesenchymal tissue that has the potential for local invasion and disease progression. Diagnosis of EAML was confirmed by pathology and immunohistochemistry. She was referred to medical oncology for discussion of surveillance versus potential adjuvant therapy and ultimately opted for close surveillance. PMID- 23984177 TI - Adverse outcome of early recurrent ischemic stroke secondary to atrial fibrillation after repeated systemic thrombolysis. AB - Background. Recurrent ischemic stroke is associated with adverse neurological outcome in patients with atrial fibrillation. There is very scarce information regarding the neurological outcome of atrial fibrillation patients undergoing repeated systemic thrombolysis after early recurrent ischemic stroke. Clinical Case and Discussion. We describe a case of a 76-year-old woman with known paroxysmal atrial fibrillation who was admitted because of an acute right middle cerebral artery ischemic stroke and who underwent repeated systemic thrombolysis within 110 hours. The patient underwent systemic thrombolysis after the first ischemic stroke with almost complete neurological recovery. On the fourth day after treatment, an acute left middle cerebral artery ischemic stroke was diagnosed and she was treated with full-dose intravenous recombinant tissue plasminogen activator. A hemorrhagic transformation of the left middle cerebral artery infarction was noted on follow-up cranial computed tomographic scans. The patient did not recover from the second cerebrovascular event and died 25 days after admission. Conclusion. To the best of our knowledge, this is the second case reporting the adverse neurological outcome of a patient with diagnosis of atrial fibrillation undergoing repeated systemic thrombolysis after early recurrent ischemic stroke. Our report represents a contribution to the scarce available evidence suggesting that repeated systemic thrombolysis for recurrent ischemic stroke should be avoided. PMID- 23984178 TI - Successful Obliteration of a Pseudoaneurysm from Post-CEA Repair Secondary to a Pruitt-Inahara Shunt Using a Stent Graft. AB - Pseudoaneurysms of the carotid artery are very uncommon complications following carotid endarterectomy. Pseudoaneurysms are usually caused by any kind of blunt injury or trauma during carotid artery surgery. CEA has become an increasingly more common vascular surgery performed in the United States. The standard of treatment for a carotid PA has been open surgical repair with excision of the defect and then a graft reconstruction of the artery. Advancements in endovascular intervention have helped to make it a more popular choice in treatment because of the positive results and less invasive approach. This case report describes the successful obliteration of a large post-CEA PA using a stent graft. The PA was likely secondary to the use of a Pruitt-lnahara Shunt because it was found to be distal to the endarterectomized area of the carotid artery which means that the defect was likely caused by the balloon portion of the shunt. This case demonstrates the feasibility of using endovascular interventional techniques to treat a PA using a stent graft. PMID- 23984179 TI - An unusual presentation of scimitar syndrome in a military service member. AB - This is the case of a twenty-two-year-old active duty male soldier with nonexertional chest pain and worsening performance on his physical fitness test. His history was significant for a diagnosis of dextrocardia upon entry to the military. On acute presentation to the emergency department, he was deemed a candidate for the expedited coronary computed tomographic angiography (CCTA) protocol to assess for a possible anatomic cause of his symptoms. CCTA revealed the presence of an anomalous right pulmonary vein draining into the inferior vena cava. Additionally, the imaging showed dextroversion of the heart, dilation of the inferior vena cava, right atrium, and right ventricle, as well as a hypoplastic right lung, a collection of findings consistent with scimitar syndrome and not dextrocardia. PMID- 23984180 TI - Host-Microbe Interactions in Caenorhabditis elegans. AB - A good understanding of how microbes interact with hosts has a direct bearing on our capability of fighting infectious microbial pathogens and making good use of beneficial ones. Among the model organisms used to study reciprocal actions among microbes and hosts, C. elegans may be the most advantageous in the context of its unique attributes such as the short life cycle, easiness of laboratory maintenance, and the availability of different genetic mutants. This review summarizes the recent advances in understanding host-microbe interactions in C. elegans. Although these investigations have greatly enhanced our understanding of C. elegans-microbe relationships, all but one of them involve only one or few microbial species. We argue here that more research is needed for exploring the evolution and establishment of a complex microbial community in the worm's intestine and its interaction with the host. PMID- 23984181 TI - Role of flies as vectors of foodborne pathogens in rural areas. AB - This study aims to evaluate flies as a vector for foodborne pathogens. For this purpose, several flies were collected from different sites from rural areas. These flies were then analyzed for the presence of Enterobacteriaceae, Escherichia coli, Staphylococcus coagulase positive, and Listeria monocytogenes. Another aim of this study was to evaluate some virulence factors of the collected pathogens: susceptibility to some antibiotics and the presence of enterotoxigenic S. aureus. The results showed that flies in the presence of animals demonstrated a significantly higher prevalence of the studied pathogens than those collected in the kitchens, and kitchens situated in the closest proximity to the animal husbandry had a higher count than the kitchens in private houses. Enterobacteriaceae was the indicator organism with the highest microbial counts followed by E. coli and S. aureus. Listeria monocytogenes was not detected from any of the collected flies. The antimicrobial susceptibility test showed that the bacteria carried by the flies possessed multiantibiotic resistance profiles, and enterotoxin A was produced by 17.9% of the confirmed S. aureus isolates. These results demonstrate that flies can transmit foodborne pathogens and their associated toxin and resistance and the areas of higher risk are those in closer proximity to animal production sites. PMID- 23984182 TI - Depression symptoms improve after successful weight loss with emotional freedom techniques. AB - Ninety-six overweight or obese adults were randomly allocated to a four-week EFT treatment or waitlist condition. Waitlist participants crossed over to the EFT group upon completion of wait period. Degree of food craving, perceived power of food, restraint capabilities, and psychological symptoms were assessed at pretreatment, posttreatment and at 12-month follow-up for combined EFT groups. Significant improvements in weight, body mass index, food cravings, subjective power of food, craving restraint and psychological coping for EFT participants from pretreatment to 12-month follow-up (P < 0.05) were reported. The current paper isolates the depression symptom levels of participants, as well as levels of eight other psychological conditions. Significant decreases from pre- to posttreatment were found for depression, interpersonal sensitivity, obsessive compulsivity, paranoid ideation, and somatization (P < 0.05). Significant decreases from pretreatment to 12-month follow-up were found for depression, interpersonal sensitivity, psychoticism, and hostility. The results point to the role depression, and other mental health conditions may play in the successful maintenance of weight loss. PMID- 23984184 TI - Black tea may be a prospective adjunct for calcium supplementation to prevent early menopausal bone loss in a rat model of osteoporosis. AB - The present study was undertaken to find out the ability of black tea extract (BTE) as a suitable alternative of adjunct for calcium supplementation in treating an ovariectomized rat model of early osteoporosis. Female Wistar rats weighing 140-150 g were divided into four groups consisting of six animals in each group: (A) sham-operated control; (B) bilaterally ovariectomized; (C) bilaterally ovariectomized + BTE; (D) bilaterally ovariectomized + 17 beta estradiol. Results suggest that BTE could promote intestinal absorption of calcium significantly (P < 0.01 for duodenum and ileum; and P < 0.05 for jejunum). This was found associated with enhanced activities of two relevant intestinal mucosal enzymes alkaline phosphatase (P < 0.01 for duodenum, jejunum, and ileum) and Ca(2+) activated ATPase (P < 0.01 for duodenum, jejunum, and ileum). Such BTE-mediated promotion of calcium absorption was coupled with increase in serum estrogen titer (P < 0.01) and recovery of all urinary, bone, and serum osteoporotic marker parameters, including bone histological features. Serum parathyroid hormone level, however, was not altered in these animals (P > 0.05). A comparative study with 17 beta -estradiol, a well-known adjunct for calcium supplementation, indicated that efficacy of BTE in maintaining skeletal health is close to that of 17 beta -estradiol. This study suggests that simultaneous use of BTE is promising as a prospective candidate for adjunctive therapies for calcium supplementation in the early stage of menopausal bone changes. PMID- 23984185 TI - Increasing the radioiodine dose does not improve cure rates in severe graves' hyperthyroidism: a clinical trial with historical control. AB - Objective. It is generally accepted that higher doses of radioiodine ((131)I) improve cure rates in Graves' disease (GD). In this trial we sought to evaluate whether very high (131)I doses increase the efficacy of treatment in severe GD. Design. Clinical trial with historical control. Patients with GD and a goiter >=48 mL were eligible for the study. The patients in the contemporaneous intervention cohort were treated with 250 MU Ci of (131)I/mL thyroid tissue, corrected by 24-RAIU values (Group 1; n = 15). A subgroup of patients with GD and a goiter >=48 mL who were treated with 200 MU Ci of (131)I/mL/24-RAIU in a previously published randomized controlled trial served as a historical control group (Group 2; n = 15). The primary outcome evaluated was the one-year cure rate. Results. There were no significant baseline differences regarding age, gender, body mass index, smoking status, pretreatment with methimazole, thyroid volume, or thyroid hormone levels of the two treatment groups. The cumulative 12 month cure rate for the patients in Group 1 was 66.6%, a figure similar to the 12 month cure rate observed in Group 2 (60.0%; P = 0.99). Conclusions. Our results suggest that increasing the (131)I dose does not improve cure rates in severe GD. This trial is registered with ClinicalTrials.gov NCT01039818. PMID- 23984183 TI - RNA-Mediated Gene Duplication and Retroposons: Retrogenes, LINEs, SINEs, and Sequence Specificity. AB - A substantial number of "retrogenes" that are derived from the mRNA of various intron-containing genes have been reported. A class of mammalian retroposons, long interspersed element-1 (LINE1, L1), has been shown to be involved in the reverse transcription of retrogenes (or processed pseudogenes) and non-autonomous short interspersed elements (SINEs). The 3'-end sequences of various SINEs originated from a corresponding LINE. As the 3'-untranslated regions of several LINEs are essential for retroposition, these LINEs presumably require "stringent" recognition of the 3'-end sequence of the RNA template. However, the 3'-ends of mammalian L1s do not exhibit any similarity to SINEs, except for the presence of 3'-poly(A) repeats. Since the 3'-poly(A) repeats of L1 and Alu SINE are critical for their retroposition, L1 probably recognizes the poly(A) repeats, thereby mobilizing not only Alu SINE but also cytosolic mRNA. Many flowering plants only harbor L1-clade LINEs and a significant number of SINEs with poly(A) repeats, but no homology to the LINEs. Moreover, processed pseudogenes have also been found in flowering plants. I propose that the ancestral L1-clade LINE in the common ancestor of green plants may have recognized a specific RNA template, with stringent recognition then becoming relaxed during the course of plant evolution. PMID- 23984186 TI - The current state and needs of north american movement disorders fellowship programs. AB - Background. Movement disorders fellowships are an important source of future clinician-specialists and clinician-scientists for the field. Scant published information exists on the number and characteristics of North American movement disorders fellowship training programs. Methods. A 31-item internet-based survey was formulated and distributed to academic movement disorders listed in the American Academy of Neurology (AAN) directory as having a movement disorders fellowship and to all National Parkinson Foundation Centers of Excellence and Care Centers in North America. Results. There was a 77% response rate among academic movement disorders centers. Broad similarities in clinical training were identified. The two most important rated missions of maintaining a movement disorders fellowship were contributions to scholarly activities and to fulfilling a critical need for specialists. Almost a quarter of fellowship programs did not offer a fellowship slot during the most recent academic year. Fellowship directors cited a wide variety of funding sources, but their top concern was lack of available funding for fellowship programs. Conclusions. North American movement disorders fellowship training programs currently offer similar methods of clinical training and education. Lack of funding was the most important obstacle to maintaining fellowship programs and should be made a priority for discussion in the field. PMID- 23984187 TI - Upregulation of serum vascular endothelial growth factor in patients with salivary gland tumor. AB - Neoangiogenesis is essential for tumor development, invasion, and dissemination. The most potent of the cytokines associated with angiogenesis is vascular endothelial growth factor (VEGF). The aim of the present study was to determine VEGF serum level in patients with salivary gland tumor. Using an ELISA kit, the circulating levels of VEGF in sera from 58 patients with salivary gland tumor and 30 healthy controls were assessed. Mean VEGF levels in sera of patients with salivary gland tumors (574.9 +/- 414.3) were significantly higher than those in controls (263.9 +/- 310.0) (P = 0.009). Within the salivary gland tumor group, mean serum VEGF concentration in malignant tumors (n = 27) was 727.3 +/- 441.8 pg/mL, and that in benign tumors (n = 31) was 442.2 +/- 343.3 pg/mL. Mean serum VEGF concentration was significantly higher in malignant tumors than in benign tumors (P = 0.008) and was higher in benign tumors than in controls (P = 0.03). The data in the present study clearly show that VEGF level was consistently upregulated in benign and malignant tumors in comparison to healthy controls. However, the role of VEGF as a prognostic factor in salivary gland tumor and its application in antiangiogenic therapy require further clinical research. PMID- 23984188 TI - Non-obvious Problems in Clark Electrode Application at Elevated Temperature and Ways of Their Elimination. AB - Well-known cause of frequent failures of closed oxygen sensors is the appearance of gas bubbles in the electrolyte. The problem is traditionally associated with insufficient sealing of the sensor that is not always true. Study of a typical temperature regime of measurement system based on Clark sensor showed that spontaneous release of the gas phase is a natural effect caused by periodic warming of the sensor to a temperature of the test liquid. The warming of the sensor together with the incubation medium causes oversaturation of electrolyte by dissolved gases and the allocation of gas bubbles. The lower rate of sensor heating in comparison with the medium reduces but does not eliminate the manifestation of this effect. It is experimentally established, that with each cycle of heating of measuring system up to 37 degrees C followed by cooling the volume of gas phase in the electrolyte (KCl; 60 g/L; 400 MU L) increased by 0.6 MU L approximately. Thus, during just several cycles it can dramatically degrade the characteristics of the sensor. A method was developed in which the oxygen sensor is heated in contact with the liquid, (depleted of dissolved gases), allowing complete exclusion of the above-mentioned effect. PMID- 23984189 TI - Quantitative Determination of Flavonoids and Chlorogenic Acid in the Leaves of Arbutus unedo L. Using Thin Layer Chromatography. AB - The plant species Arbutus unedo shows numerous beneficial pharmacological effects (antiseptic, antidiabetic, antidiarrheal, astringent, depurative, antioxidant, antihypertensive, antithrombotic, and anti-inflammatory). For the medicinal use, standardization of extracts is a necessity, as different compounds are responsible for different biological activities. In this paper, we analyze monthly changes in the content of quercitrin, isoquercitrin, hyperoside, and chlorogenic acid. Methanolic extracts of the leaves are analyzed by HPTLC for the identification and quantification of individual polyphenol, and DPPH test is used to determine antioxidant activity. Based on the results obtained, the leaves should be collected in January to obtain the highest concentrations of hyperoside and quercitrin (0.35 mg/g and 1.94 mg/g, resp.), in June, July, and October for chlorogenic acid (1.45-1.46 mg/g), and for the fraction of quercitrin and isoquercitrin in November (1.98 mg/g and 0.33 mg/g, resp.). Optimal months for the collection of leaves with the maximum recovery of individual polyphenol suggested in this work could direct the pharmacological usage of the polyvalent herbal drugs. PMID- 23984190 TI - Species classification and quality assessment of cangzhu (atractylodis rhizoma) by high-performance liquid chromatography and chemometric methods. AB - Fast and sensitive high-performance liquid chromatography (HPLC) coupled with chemometric methods was utilized to assist in the quality assessment of Cangzhu (Atractylodis Rhizoma). By comparative analysis of chromatographic profiles, twelve common peaks were selected for multivariate analysis. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS DA) of the chromatographic data demonstrated that 16 batches of Cangzhu samples could be welldifferentiated and categorized into two groups, which were closely related to their species (Atractylodes chinensis and A. lancea). By loading plots of PCA and OPLS-DA, the "common peaks" 2, 10, and 12 were defined as "marker peaks," which were identified as atractylodinol, (4E,6E,12E)-tetradecatriene-8,10 diyne-1,3-diyl diacetate, and atractylodin, respectively. These three "marker peaks" were then simultaneously quantified for further controlling the quality of Cangzhu, which showed acceptable linearity, both intraday and interday precisions (RSD <= 2.30%), repeatability (RSD <= 2.82%), and the recoveries of the three analytes in the range of 96.57-100.16%, with RSDs less than 1.46%. Finally, linear discriminant analysis (LDA) was successfully used to build predictive models of the group membership based on the contents of three marker peaks. Results of the present study demonstrated that HPLC-based metabolic profiling coupled with chemometric methods and quantificational determination was a very flexible, reliable, and effective way for homogeneity evaluation and quality assessment of traditional Chinese medicine. PMID- 23984191 TI - Label-free glucose detection using cantilever sensor technology based on gravimetric detection principles. AB - Efficient maintenance of glucose homeostasis is a major challenge in diabetes therapy, where accurate and reliable glucose level detection is required. Though several methods are currently used, these suffer from impaired response and often unpredictable drift, making them unsuitable for long-term therapeutic practice. In this study, we demonstrate a method that uses a functionalized atomic force microscope (AFM) cantilever as the sensor for reliable glucose detection with sufficient sensitivity and selectivity for clinical use. We first modified the AFM tip with aminopropylsilatrane (APS) and then adsorbed glucose-specific lectin concanavalin A (Con A) onto the surface. The Con A/APS-modified probes were then used to detect glucose by monitoring shifts in the cantilever resonance frequency. To confirm the molecule-specific interaction, AFM topographical images were acquired of identically treated silicon substrates which indicated a specific attachment for glucose-Con A and not for galactose-Con A. These results demonstrate that by monitoring the frequency shift of the AFM cantilever, this sensing system can detect the interaction between Con A and glucose, one of the biomolecule recognition processes, and may assist in the detection and mass quantification of glucose for clinical applications with very high sensitivity. PMID- 23984193 TI - Editorial. PMID- 23984192 TI - Reliable HPLC determination of aflatoxin m1 in eggs. AB - Aflatoxin M1 is the foremost metabolite of aflatoxin B1 in humans and animals, which may be present in animal products from animals fed with aflatoxin B1 contaminated feed. In this study a high performance liquid chromatography method for determination of aflatoxin M1 in eggs was described. The egg samples were diluted with warmed water and the toxin was immunoextracted followed by fluorescence detection. The average recovery of aflatoxin M1 at the three different levels 0.05, 0.1, and 0.5 MU g/kg varied between 87% and 98%. The method is linear from the limit of quantification 0.05 MU g/kg up to 3 MU g/kg levels. This method is intended for aflatoxin M1 analyses in eggs simply with minimum toxin lose, excellent recovery, and accurate results with the limit of detection 0.01 MU g/kg. PMID- 23984194 TI - Extradural dermoid cyst of the parasellar region: a case report. AB - Dermoid cysts are rare congenital intracranial tumors. Among these tumors, extradural localization is extremely rare. We report a patient with an extradural dermoid cyst of the right parasellar region, causing right visual disturbance. Computed tomography revealed a hypodense mass lesion with rimlike calcification at the right parasellar region, accompanying marked erosion of the adjacent skull base. The tumor appeared as a heterogeneous intensity on magnetic resonance imaging and was surrounded by thin gadolinium enhancement without inner enhancement. The right optic nerve was compressed by the tumor. Surgical resection was successfully performed using a right frontotemporal extradural approach. The entire tumor was completely resided extradurally and was enclosed by saclike, stretched dura mater and extended deeply into the skull base. Histopathologic findings were consistent with the features of dermoid cyst. The postoperative course was uneventful, and the visual disturbance improved. Neuroradiological features, strategies for surgical treatment, and mechanisms responsible for preoperative symptoms are discussed. PMID- 23984195 TI - Degenerative Pannus Mimicking Clival Chordoma Resected via an Endoscopic Transnasal Approach. AB - Lesions of the lower clivus represent a technically challenging subset of skull base disease that requires careful treatment. A 75-year-old woman with tongue atrophy was referred for resection of a presumed clival chordoma. The lesion was resected via an endoscopic transnasal transclival approach with no complications. Pathology revealed only chronic inflammatory tissue consistent with a degenerative pannus. Degenerative pannus should be included in the differential diagnosis of lower clival extradural lesions. The endoscopic transnasal transclival corridor should be considered for resection of such lesions as an alternative to larger, more morbid, traditional skull base approaches. PMID- 23984196 TI - Breast Cancer Metastases of the Left Occipital Condyle Diagnosed through Extended Mastoidectomy: Case Report. AB - Skull base metastases are rare conditions. Usually breast or prostate cancers are responsible primary tumors. Definite diagnosis can only be obtained through biopsies. We report the first case of breast cancer metastases into left occipital condyle, which was biopsied successfully through radical extended mastoidectomy under computer-assisted intraoperative navigation. This access proved to be feasible and safe, and enough material could be obtained for histological examination. According to the result, optimal adjuvant treatment strategies could be planned. PMID- 23984197 TI - Frontal sinus schwannoma: case report and review of literature. AB - Although schwannomas are frequently found in the head and neck region, sinonasal tract involvement is extremely rare, especially those of the frontal sinus. We report a patient with an incidentally found right frontal sinus lesion. The patient underwent resection of the tumor via a right craniotomy. The histological diagnosis was consistent with a schwannoma. There has been no radiographic recurrence on 2-year follow-up. PMID- 23984198 TI - Rapid improvement of cranial neuropathies after endoscopic resection of sphenoid sinus mucocele. AB - Sinus mucoceles are benign, slowly enlarging, mucous-secreting, cystic lesions whose expansile growth may lead to compressive neuropathies. We present the case of a 70-year-old woman with a long-standing history of headaches and progressive ocular neuropathy who underwent an endoscopic resection of a large sphenoid sinus mucocele resulting in immediate improvement of her neurological symptoms. The endoscopic endonasal transsphenoidal approach offers a minimally invasive method to manage and treat symptomatic sinus mucoceles. PMID- 23984199 TI - Endoscopic endonasal management of recurrent petrous apex cholesterol granuloma. AB - Petrous apex cholesterol granulomas (PACG) are uncommon lesions. Recurrence following transcranial or endonasal approaches to aerate the cyst occurs in up to 60% of cases. We describe the technical nuances pertinent to the endonasal endoscopic management of a recurrent symptomatic PACG and review the literature. A 19-year-old woman presented with a recurrent right abducens nerve paresis. Four months prior, she underwent an endonasal transsphenoidal surgery (TSS) for drainage of a symptomatic PACG. Current imaging documented recurrence of the right PACG. Transsphenoidal and infrapetrous approaches were performed to obtain a wider bony opening along the petrous apex and drain the cyst. A Doyle splint was inserted into the cyst's cavity and extended out into the sphenoid, maintaining patency during the healing process. Three months after surgery, the splint was removed endoscopically, allowing visualization of a patent cylindrical communication between both aerated cavities. The patient remains symptom- and recurrence-free. Endoscopic endonasal surgery must be adapted to manage recurrent PACG. A TSS may not be sufficient. An infrapetrous approach with wider bony opening, extensive removal of the cyst's anterior wall, and use of a stent are indicated for the treatment of recurrent PACG and to prevent recurrences. PMID- 23984200 TI - Invasive sphenocavernous aspergilloma complicating an operated case of acromegaly. AB - There is a surge in fungal infections of the central nervous system due to an increase in the incidence of immunocompromised state and widespread use of antimicrobials. Despite myriad clinical presentations and skull base syndromes associated with Aspergillus infections, aspergilloma in the sella is relatively rare. We report a rare case of aspergilloma of the sella and parasellar region in a patient operated for acromegaly. A 30-year-old diabetic patient underwent two surgeries for a growth hormone-secreting pituitary adenoma, which included a transsphenoidal approach. During his last admission, magnetic resonance imaging revealed a heterogeneous mass in the sella, suprasellar region, sphenoid sinus, and cavernous sinus with multiple areas of necrosis. His presentation, surgical treatment, and response to antifungal therapy are discussed. The role of prior surgery and related comorbidities in developing the invasive granuloma are highlighted. PMID- 23984201 TI - Management of nonmissile penetrating brain injuries: a description of three cases and review of the literature. AB - Nonmissile penetrating intracranial injuries are uncommon events in modern times. Most reported cases describe trajectories through the orbit, skull base foramina, or areas of thin bone such as the temporal squama. Patients who survive such injuries and come to medical attention often require foreign body removal. Critical neurovascular structures are often damaged or at risk of additional injury resulting in further neurological deterioration, life-threatening hemorrhage, or death. Delayed complications can also be significant and include traumatic pseudoaneurysms, arteriovenous fistulas, vasospasm, cerebrospinal fluid leak, and infection. Despite this, given the rarity of these lesions, there is a paucity of literature describing the management of neurovascular injury and skull base repair in this setting. The authors describe three cases of nonmissile penetrating brain injury and review the pertinent literature to describe the management strategies from a contemporary cerebrovascular and skull base surgery perspective. PMID- 23984202 TI - Endoscopic removal of a bullet penetrating the middle cranial fossa. AB - Reports of intracranial retained foreign bodies are relatively rare in the literature. Such objects can cause numerous complications requiring removal, such as infection, persistent cerebrospinal fluid (CSF) leak, or new-onset seizures. The transnasal endoscopic approach provides an excellent alternative to craniotomy for repairing middle cranial fossa (MCF) defects. We describe a case of a 57-year-old woman with a self-inflicted bullet piercing the MCF, creating a persistent CSF leak. The details regarding the removal of this penetrating foreign body from the MCF, including the unique management in the setting of a contralateral spontaneous CSF leak, are discussed. PMID- 23984203 TI - Dural arteriovenous fistula following translabyrinthine resection of cerebellopontine angle tumors: report of two cases. AB - We describe two cases of dural arteriovenous fistula (DAVF) developing in a delayed fashion after translabyrinthine resection of cerebellopontine angle tumors. Two patients in an academic tertiary referral center, a 46-year-old woman and a 67-year-old man, underwent translabyrinthine resection of a 2-cm left vestibular schwannoma and a 4-cm left petrous meningioma, respectively. Both patients subsequently developed DAVF, and in each case the diagnosis was delayed despite serial imaging follow-up. In one patient, cerebrospinal fluid diversion before DAVF was identified as the cause of her intracranial hypertension; the other patient was essentially asymptomatic but with a high risk of hemorrhage due to progression of cortical venous drainage. Endovascular treatment was effective but required multiple sessions due to residual or recurrent fistulas. Dural arteriovenous fistula is a rare complication of translabyrinthine skull base surgery. Diagnosis requires a high index of clinical suspicion and an understanding of subtle imaging findings that may be present on follow-up studies performed for tumor surveillance. Failure to recognize this complication may lead to misguided interventions for treatment of hydrocephalus and other complications, as well as ongoing risks related to venous hypertension and intracranial hemorrhage. As this condition is generally curable with neurointerventional and/or surgical methods, timely diagnosis and treatment are essential. PMID- 23984204 TI - Subfrontal schwannoma mimicking neuroblastoma: case report. AB - Computed tomography (CT), performed in a healthy 28-year-old man after minor head injury, detected a frontal base tumor. Neurological examination revealed left hyposmia. On magnetic resonance imaging scans, there was a heterogeneously enhanced tumor located in the left paramedian frontal base with extension into the left ethmoid sinus. Angiography showed a hypervascular mass in the left anterior cranial fossa; it was mainly fed by the left ethmoidal artery. Positron emission tomography scanning showed moderate accumulation of 11-methylmethionine and low accumulation of 18-fluorodeoxyglucose (FDG) at the tumor site. Bone image CT disclosed compressive, nondestructive deformation of the left frontal base. The preoperative diagnosis was olfactory neuroblastoma or meningioma. The tumor was totally resected via bifrontal craniotomy. The tumor was histologically diagnosed as typical schwannoma; it was positive for S-100 protein. We report a rare subfrontal schwannoma with extension into the nasal cavity that mimicked neuroblastoma. Low FDG accumulation and compressive deformation of the anterior skull base may help in the differential diagnosis of these tumors. PMID- 23984205 TI - Temporal Chondroblastoma with a Novel Chromosomal Translocation (2;5) (q33;q13). AB - The case of a 51-year-old man with a large temporal mass is presented. The mass eroded the floor of the middle fossa medially to the sphenoid sinus. A combined approach with neurosurgery and otolaryngology was performed to achieve maximal resection of the mass. Pathology was typical for chondroblastoma: a rare, benign but locally invasive chondroid tumor. Genetic testing revealed a translocation of (2;5) (q33;q13). This is a unique genetic mutation in all chondroid tumors to our knowledge. The diagnostic utility or role of this mutation in the pathobiology of this tumor remains to be determined. PMID- 23984206 TI - Chondroblastoma of the temporal bone: a case series, review, and suggested management strategy. AB - Chondroblastoma of the temporal bone is a rare condition. Chondroblastomas account for less than 1% of primary bone tumors, and those involving the temporal bone represent a tiny fraction of these tumors with most arising from the knee, rib, and pelvis. We present a case series of two patients who presented with chondroblastomas of the temporal bone over a period of 8 years to the St. Vincent's Hospital in Melbourne, Victoria, Australia. In particular, we outline the presenting complaint, diagnostic imaging undertaken, and the importance of preoperative histopathology in coming to the diagnosis and subsequent resection undertaken. A review of the current literature is presented with a suggested management strategy for these tumors. PMID- 23984207 TI - Nasal glioma: prenatal diagnosis and multidisciplinary surgical approach. AB - Nasal gliomas are congenital, nonmalignant rests of neuroglial tissue that typically present as a craniofacial mass. The differential diagnosis of such masses includes lesions that often require the involvement of various surgical subspecialties, including otolaryngology, neurosurgery, plastic surgery, and ophthalmology. Early surgical excision of these masses is advised to minimize nasal and craniofacial distortion. Accordingly, early diagnosis and management planning are paramount, and advances in prenatal imaging are creating a new role for obstetricians and radiologists in the initiation of diagnostic and therapeutic interventions. We describe the case history of a young patient found to have a craniofacial mass on routine prenatal ultrasound and subsequently managed with a multidisciplinary team approach. PMID- 23984208 TI - Ganglioneuroma of the internal auditory canal presenting as a vestibular schwannoma. AB - In most series, 90% of cerebellopontine angle tumors are vestibular schwannomas. Meningiomas and epidermoid tumors follow with decreased frequency. Ganglioneuroma is a benign tumor usually found in the retroperitoneum and posterior mediastinum. We report a case of a 21-year-old man with gradual sensorineural hearing loss and a minimally enhancing lesion of the internal auditory canal, which was excised through a middle fossa approach and found histologically to be a ganglioneuroma. Like vestibular schwannomas, these lesions are benign in nature and may be managed in a similar fashion, although the possibility of malignant transformation may support surgical resection over conservative management or radiosurgery. Ganglioneuromas should be considered in patients with atypical radiographic findings for vestibular schwannomas. PMID- 23984209 TI - Hepatoid adenocarcinoma of the anterior skull base: a case report. AB - We report the first case of hepatoid adenocarcinoma of the skull base, as well as the first reported case in the head and neck region. Hepatoid adenocarcinoma is a rare, aggressive, extrahepatic malignancy with a distinct morphological similarity to hepatocellular carcinoma, in the absence of primary hepatic disease. A 45-year-old man presented with sinus headaches and retro-orbital pain and was found to have a nasopharyngeal mass on endoscopy and a large, destructive sinonasal mass extending intracranially on imaging. Histo- and cytopathological features were similar to hepatocellular carcinoma, and the cells were immunoreactive for alpha-fetoprotein, epithelial membrane antigen, periodic acid Schiff, cytokeratin (CK)8/18, CK19, and S100. PMID- 23984210 TI - Coexisting rathke cleft cyst and pituitary adenoma presenting with pituitary apoplexy: report of two cases. AB - The authors report two cases of coexisting Rathke cleft cyst (RCC) and pituitary macroadenoma. Both patients presented at the university hospital with pituitary apoplexy symptoms of sudden-onset headache while undergoing treatment with Coumadin (warfarin). Magnetic resonance imaging was consistent with a pituitary adenoma in one case and RCC in the other. Intraoperative findings and pathological work-up identified RCC along with adenomatous tissue displaying hemorrhagic pituitary adenoma in one and hemorrhagic RCC in the other. Clinical symptoms of pituitary apoplexy were present in both cases, making pituitary and RCC apoplexy clinically indistinguishable. RCC and concomitant pituitary adenoma are a rare intraoperative finding that must be considered as a differential diagnosis in patients with symptoms of pituitary adenoma apoplexy. PMID- 23984211 TI - Inflammatory pseudotumor of the skull base involving fissura petrooccipitalis: a rare case with challenging diagnosis. AB - Inflammatory pseudotumor (IPT) is a benign entity that may present as a solid mass mimicking a malignant neoplasm. Histologically, they are composed of varying proportions of myofibroblastic spindle cells, lymphocytes, and plasma cells. Skull base IPT is rare and usually occurs in adults with no sex predilection. The skull base IPT typically presents with headache, and/or cranial nerve palsy. There is no consensus regarding treatment of skull base IPT due to its rarity. Surgical resection and corticosteroid therapy have generally been used. The preoperative diagnosis of skull base IPT is usually difficult due to its nonspecific clinical and radiologic features. We report a case of a 42-year-old woman with IPT originating from the skull base. To our knowledge, this is the first case of IPT invading fissura petrooccipitalis. When a mass in the skull base appears hypointense on T2-weighted imaging with aggressive growth and bony destruction, IPT should be considered in the differential diagnosis. PMID- 23984212 TI - Aggressive inverted papilloma with intracranial invasion and short malignization time. AB - Inverted papillomas (IP) are considered benign lesions with a prevalence up to 4% among all sinunasal tumors; however, invasive growth and varying tendency for malignization are reported in literature. We report the case of a 69-year-old woman suffering from a large, aggressively growing IP invading the orbit, skull base, and frontal lobe of the brain. Within only 3 months' time the papilloma showed transformation into an invasive carcinoma, leaving surgical therapy in vain due to explosive recurrence. Intracranial and intraorbital expansion by IP is possible despite histology not showing signs of malignancy initially. In "regular" IP close endoscopic follow-up is mandatory to not overlook recurrence harboring malignancy. PMID- 23984213 TI - Posterior fossa neurenteric cysts can expand rapidly: case report. AB - Neurenteric cysts are considered congenital lesions that may slowly expand over time. Although more commonly found in the spinal canal, they may be found intracranially, particularly in the posterior fossa. Here, we present an unusual case of a large, rapidly expanding histologically confirmed posterior fossa neurenteric cyst in a 53-year-old woman, who presented with quadriparesis. Computed tomography imaging done ~1.5 years before admission failed to demonstrate any obvious abnormality; however, the lesion had grown to 4 cm in maximal dimension at presentation with significant mass effect. The lesion was resected microsurgically using a retrosigmoid approach. The patient improved postoperatively and was neurologically intact at last follow-up. We could find no other documented case of marked, rapid expansion of a neurenteric cyst in the literature. We conclude that, although neurenteric cysts are thought to be congenital, they can undergo rapid expansion even in adults. The mechanism of expansion is unknown but may involve increased secretion, hemorrhage, or inflammation. We discuss the surgical management and review the literature in view of this surprising finding. PMID- 23984214 TI - Flap reconstruction and hyperbaric oxygen therapy in the management of temporal bone osteoradionecrosis in an endolymphatic sac tumor: case report. AB - Endolymphatic sac tumors (ELSTs) are rare neuroectodermal neoplasms arising within the posterior petrous bone. We present a case of a 21-year-old man who presented with a 6-month history of intermittent morning headaches, fatigue, diplopia, and gait ataxia. Imaging and surgical pathology identified an adenocarcinoma of the endolymphatic sac compressing the cerebellum and brain stem. The tumor and multiple metastases were treated with surgery, radiation, and radiosurgery. Following insertion of a ventriculoperitoneal shunt for hydrocephalus, he developed symptomatic tension pneumocephalus secondary to radionecrosis of his petrous bone, requiring flap reconstruction and use of a programmable shunt valve complemented by hyperbaric oxygen (HBO) therapy. We document here a young patient with a rare adenocarcinoma of the endolymphatic sac. This case is unique for its initial presentation without any vestibuloauditory symptoms. Metastatic spread of ELSTs is also rare. While osteoradionecrosis (ORN) of the temporal bone has been reported previously in patients with nasopharyngeal carcinoma, this is the first time it has been presented in the context of an ELST. Tension pneumocephalus is a rare complication of skull base ORN. This is the first reported use of a programmable shunt valve and HBO therapy in the management of tension pneumocephalus. PMID- 23984215 TI - Esthesioneuroblastoma in an HIV-1 Infected Patient: Case Report. AB - Esthesioneuroblastoma (ENB) is an uncommon malignant tumor derived from the specialized neuroepithelium of the upper nasal cavity. The largest case series and meta-analyses suggest the combination of surgery and radiotherapy as the gold standard treatment for ENB. However, an increasing number of case series have reported excellent survival and few complications with minimally invasive endoscopic resection (MIER) in conjunction with radiotherapy of EBN in early stages of the disease. In this case report, the authors describe the first case of ENB in a young adult man who was human immunodeficiency virus (HIV)-1 and Hepatitis C virus (HCV) coinfected. The authors discuss all the aspects of this rare disease, focusing on treatment options and prognosis. PMID- 23984216 TI - Peripheral facial paralysis and bilateral carotid pseudoaneurysms of petrous localization: a case report. AB - Carotid pseudoaneurysms of petrous localization are rare. They are mostly due to trauma, tumoral or infectious diseases, or a result of iatrogenic complications after skull base surgery. Symptoms such as facial paralysis are exceptional and have rarely been described in the literature until now. We report the case of a 64-year-old woman, who developed left peripheral facial paralysis induced by two carotid pseudoaneurysms in their intrapetrous section. The treatment is endovascular, despite the high morbidity rate. She was first put on antiplatelet medications, before the left carotid aneurysm was bypassed thanks to a self expanding pipeline-type stent with flow diversion. The left peripheral facial paralysis was due to the compression exerted by the left carotid aneurysm, probably a congenital malformation. The progressive palsy recovery was fist due to the aneurysmal thrombosis, then to the secondary fibrosis. PMID- 23984217 TI - Transoral resection of a retropharyngeal myxoma: a case report. AB - This study was conducted to describe a retropharyngeal myxoma and discuss clinical concerns regarding this pathology and a retropharyngeal site of occurrence. We present a case report and review of literature. A 71-year-old woman presented with mild right neck pressure for 3 weeks. Imaging studies and head neck examination confirmed a 5.3 * 3.1 * 1.0 cm retropharyngeal mass with no communication to the vertebral column but was intimately involved with the pharyngeal mucosa. A transoral fine needle aspiration biopsy suggested a possible spindle cell neoplasm. A presurgical swallowing consultation was obtained. A transoral excision of the tumor was possible with no intraoperative complications. Histopathology was a cellular myxoma. Postoperative dysphagia required swallowing therapy and nasogastric tube feeding for 2 weeks before oral intake was possible. The patient has no evidence of clinical or radiological recurrence more than 1 year after surgical intervention. We present the second case of a myxoma in the retropharynx reported in English literature. Transoral excision was safe, feasible, and cosmetically appealing option in our patient. Additional clinical data are required to valid its safety and utility as an approach to tumors in the retropharynx. Postoperative dysphagia can be significant and consequently we recommend preoperative swallowing evaluation and counseling. PMID- 23984218 TI - Benign inverted papilloma with intracranial extension: prognostic factors and outcomes. AB - We describe a case of benign inverted papilloma with intracranial extension treated with endoscopic resection combined with craniotomy. Intracranial involvement of inverted papilloma, in the absence of malignancy, is uncommon. We present an analysis of the literature identifying the characteristics and outcomes of benign intracranial inverted papilloma. PubMed database was searched using keywords intracranial, inverted or inverting, and papilloma. There are 17 reports of benign inverted papilloma with intracranial extension reported with a mean age of 49.2 years (range, 23 to 92 years), a female predominance, 22% of cases with an associated mucocele, and 60% recurrent disease. The most common sites of invasion are the frontal sinus or cribriform plate. The prognosis for benign intracranial inverted papilloma is dependent on the presence of dural invasion and the achievement of total resection. There are no reported recurrences after craniofacial resection with a mean follow-up of 7.9 years. Adjuvant radiation therapy has demonstrated benefit in cases of residual disease after resection. We expect that endoscopic resection, the standard treatment for sinonasal inverted papilloma, will be increasingly used in the presence of intracranial extension. PMID- 23984219 TI - Computer-assisted coloring and illuminating based on a region-tree structure. AB - Colorization and illumination are key processes for creating animated cartoons. Computer assisted methods have been incorporated in animation/illustration systems to reduce the artists' workload. This paper presents a new method for illumination and colorization of 2D drawings based on a region- tree representation. Starting from a hand-drawn cartoon, the proposed method extracts geometric and topological information and builds a tree structure, ensuring independence among parts of the drawing, such as curves and regions. Based on this structure and its attributes, a colorization method that propagates through consecutive frames of animation is proposed, combined with an interpolation method that accurately computes a normal mapping for the illumination process. Different operators for curve and region attributes can be applied independently, obtaining different rendering effects. PMID- 23984221 TI - Mass spectrometric analysis of prefrontal cortex proteins in schizophrenia and bipolar disorder. AB - BACKGROUND: Schizophrenia and bipolar disorder are the two most serious and debilitating neuropsychiatric disorders that share many characteristics, both symptomatic and epidemiological. There has yet to be a single diagnostic biomarker discovered for schizophrenia and bipolar disorder. Proteomics holds promise in elucidating the pathophysiology of these neuropsychiatric disorders from each other and healthy individuals. FINDINGS: Postmortem prefrontal cortex tissue from schizophrenia, bipolar disorder, and psychiatric-free controls (n = 35 in each group) were subject to SELDI-TOF-MS protein profiling. There were 13 protein peaks distinguishing schizophrenia versus control and 15 in bipolar versus control. Using a predictor set of 10 peaks for each comparison, 73% prediction accuracy (p = 2.3*10(-4)) was achieved. Three peaks were in common between schizophrenia and bipolar disorder. CONCLUSIONS: This pilot study found protein profiles that distinguished schizophrenia and bipolar patients from controls and notably from each other. Identifying and characterizing the proteins in this study may elucidate neuropsychiatric phenotypes and uncover therapeutic targets. Further, applying class prediction bioinformatics may allow the clinician to differentiate the two phenotypes by profiling CSF or even serum. PMID- 23984222 TI - The age-phenome database. AB - Data linking specific ages or age ranges with disease are abundant in biomedical literature. However, these data are organized such that searching for age phenotype relationships is difficult. Recently, we described the Age-Phenome Knowledge-base (APK), a computational platform for storage and retrieval of information concerning age-related phenotypic patterns. Here, we report that data derived from over 1.5 million human-related PubMed abstracts have been added to APK. Using a text-mining pipeline, 35,683 entries which describe relationships between age and phenotype (such as disease) have been introduced into the database. Comparing the results to those obtained by a human reader reveals that the overall accuracy of these entries is estimated to exceed 80%. The usefulness of these data for obtaining new insight regarding age-disease relationships is demonstrated using clustering analysis, which is shown to capture obvious, as well as potentially interesting relationships between diseases. In addition, a new tool for browsing and searching the APK database is presented. We thus present a unique resource and a new framework for studying age-disease relationships and other phenotypic processes. PMID- 23984220 TI - Chronic traumatic encephalopathy: the dangers of getting "dinged". AB - Chronic traumatic encephalopathy (CTE) is a form of neurodegeneration that results from repetitive brain trauma. Not surprisingly, CTE has been linked to participation in contact sports such as boxing, hockey and American football. In American football getting "dinged" equates to moments of dizziness, confusion, or grogginess that can follow a blow to the head. There are approximately 100,000 to 300,000 concussive episodes occurring in the game of American football alone each year. It is believed that repetitive brain trauma, with or possibly without symptomatic concussion, sets off a cascade of events that result in neurodegenerative changes highlighted by accumulations of hyperphosphorylated tau and neuronal TAR DNA-binding protein-43 (TDP-43). Symptoms of CTE may begin years or decades later and include a progressive decline of memory, as well as depression, poor impulse control, suicidal behavior, and, eventually, dementia similar to Alzheimer's disease. In some individuals, CTE is also associated with motor neuron disease similar to amyotrophic lateral sclerosis. Given the millions of athletes participating in contact sports that involve repetitive brain trauma, CTE represents an important public health issue. In this review, we discuss recent advances in understanding the etiology of CTE. It is now known that those instances of mild concussion or "dings" that we may have previously not noticed could very well be causing progressive neurodegenerative damage to a player's brain. In the future, focused and intensive study of the risk factors could potentially uncover methods to prevent and treat this disease. PMID- 23984223 TI - Intimate partner violence against women and its related immigration stressors in Pakistani immigrant families in Germany. AB - This paper addresses the issue of intimate partner violence against women and its related immigration stressors in Pakistani immigrant families in Germany. Drawing on 32 in-depth interviews with Pakistani women in three cities in Germany, we found that psychological violence was the commonly reported violence among the study participants. The data showed that the process of immigration exacerbated tensions between spouses because of various immigration stressors such as threats to cultural identity, children's socialization, and social isolation. In order to cope with the stressful spousal relations, women applied various indigenous strategies, but avoided seeking help from the host country's formal care providing institutions. This study also debunks some stereotypes and popular media cliches about the "victimhood of women from conservative developing countries" and provides an understanding of the issue of intimate partner violence within an immigration context. Further research with a larger sample will be helpful to understand immigration-induced stress and intimate partner violence in immigrant families. PMID- 23984224 TI - A simple proof of orientability in colored group field theory. AB - BACKGROUND: Group field theory is an emerging field at the boundary between Quantum Gravity, Statistical Mechanics and Quantum Field Theory and provides a path integral for the gluing of n-simplices. Colored group field theory has been introduced in order to improve the renormalizability of the theory and associates colors to the faces of the simplices. The theory of crystallizations is instead a field at the boundary between graph theory and combinatorial topology and deals with n-simplices as colored graphs. Several techniques have been introduced in order to study the topology of the pseudo-manifold associated to the colored graph. Although of the similarity between colored group field theory and the theory of crystallizations, the connection between the two fields has never been made explicit. FINDINGS: In this short note we use results from the theory of crystallizations to prove that color in group field theories guarantees orientability of the piecewise linear pseudo-manifolds associated to each graph generated perturbatively. CONCLUSIONS: Colored group field theories generate orientable pseudo-manifolds. The origin of orientability is the presence of two interaction vertices in the action of colored group field theories. In order to obtain the result, we made the connection between the theory of crystallizations and colored group field theory. PMID- 23984225 TI - Adult onset atopic dermatitis: Under-recognized or under-reported? PMID- 23984226 TI - Achieving hemostasis in dermatology-Part II: Topical hemostatic agents. AB - Bleeding is a common occurrence during any dermatologic surgery that disrupts blood vessels. The complications of excess bleeding can include delayed wound healing, hematoma formation, infection, dehiscence, and necrosis. In part one of this review, we discussed the pre-operative, intra-operative, and post-operative management of patients undergoing dermatologic surgery. In Part two, we discuss traditional and new topical hemostatic agents used to achieve hemostasis in dermatological procedures and surgery. We will evaluate the caustic and non caustic hemostatic agents as well as hemostatic dressings. The mechanisms of action, side effect profile, and advantages and disadvantages of the topical hemostatic agents are provided. Sources for this article were found searching the English literature in PubMed for the time period 1940 to March 2012. A thorough bibliography search was also performed and key references examined. PMID- 23984227 TI - Hit hard and early: Can the march of psoriasis be halted? AB - Psoriasis is increasingly considered a systemic disease with comorbidities. There is sufficient evidence that systemic inflammation lies at the heart of these developments. Considering the chronic nature of psoriasis and its comorbidities, timely manipulation of systemic inflammation could avert both mortality and morbidity. Data from retrospective studies suggest that aggressive treatment of psoriasis with traditional systemic agents and/or biologic drugs improves health outcomes. To maximize treatment outcomes, severe psoriasis needs to be managed as a systemic disease with likely comorbidities. PMID- 23984228 TI - To evaluate the efficacy and safety of "RV2427B" cream in Irritant dermatitis care. AB - BACKGROUND: The treatment of various irritant dermatitis involves the elimination of the casual or favoring factor, the control of aggravating factors, and administration of topical agents. Even though corticosteroids are extensively used in these conditions to reduce the inflammation, it can also result in undesirable side effects. Hence, there is a need for a non steroidal topical agent to be used in these conditions. AIMS: To evaluate the efficacy and tolerance of repairing cream RV 2427B in children and adults in irritant dermatitis care. MATERIALS AND METHODS: In this phase III open labeled, multicenter, non-controlled, non-randomized trial, irritant dermatitis in children and adults either due to diaper rash, pityriasis alba and irritant dermatitis (eczema), perioral dermatitis, perleche or intertrigo were administered; repairing cream RV 2427 B containing a) 4 % zinc oxide, b) 2.5 % dry colloidal oat extract, (c) 0.5 % oat oil, (d) 0.2% copper sulfate, and (e) 0.1 % zinc sulfate to be applied twice-daily in the affected area. The subjects were evaluated on day 7 and day 21 for both efficacy and tolerance and last visit for cosmetic acceptability. The trial was conducted in accordance with the good clinical practices (GCP) after obtaining ethical clearance from respective Institutional Review Boards. Statistical evaluation was by variance analysis and student test for the quantitative variables, chi-square test for the qualitative variables. RESULTS: Of the 136 enrolled subjects, 95 completed the study. After 21 days of treatment, 84% of the subjects assessed by the investigator and 76% by the self-assessment for the cream found effective. Investigational product was considered to be safe after 7 and 21 days of use. CONCLUSION: Repairing cream RV 2427 B is effective and safe in the management of irritant dermatitis. PMID- 23984229 TI - Cutaneous metastasis from carcinoma of lung. AB - A 65-year-old male with a history of smoking since 30 years presented with breathlessness, hemoptysis, multiple swellings all over the body, and weakness in September 2010 at our hospital. Clinically, a diagnosis of chronic obstructive pulmonary disease (COPD) with cutaneous lymphoma or soft tissue tumor was made. Chest X-ray (CXR) and computed tomography (CT) scan revealed a neoplastic lesion in the right lung with secondary cavitation. Biopsy of the cutaneous nodules showed metastatic deposits from squamous cell carcinoma. Metastatic skin cancer is a relatively rare complication of internal malignancy. The clinical features of metastatic skin disease vary enormously. They may present as erysipeloid, sclerodermoid, alopecia neoplastica or in an inflammatory or bullous form or as multiple nodules as in our case. A high index of suspicion for metastatic deposits is required in an elderly male patient who is a known case of lung cancer or even one who is a chronic smoker and presents with such cutaneous lesions. PMID- 23984230 TI - Primary cutaneous leiomyosarcoma: A rare malignant neoplasm. AB - Primary cutaneous leiomyosarcoma (PCL) is an exceedingly uncommon malignant superficial soft tissue sarcoma with a predilection for middle-aged to elderly male. Morphologic differential diagnosis includes a host of other malignant spindle cell neoplasms, thereby necessitating the use of a panel of immunohistochemical markers to arrive at a definitive diagnosis. We report a case of PCL arising in the right leg of a 70-year-old male. PMID- 23984231 TI - Dowling-Degos disease and hidradenitis suppurativa: Co occurrence or association? AB - A 44 year old female patient presented with multiple, painful, relapsing, nodules, plaques with sinuses discharging pus and scars in apocrine gland bearing region since past 17 years. These lesions were clinically and histopathologically suggestive of hidradenitis suppurativa. Our patient was not aware about the flexural pigmentary lesions, comedones and pitted scars which were also clinically and histopathologically suggestive of Dowling-Degos disease. We are reporting a rare interesting association of Dowling Degos disease and hidradenitis suppurativa which is not reported in Indian literature till date. PMID- 23984232 TI - Facial plexiform neurofibromatosis: A surgical challenge. AB - Plexiform neurofibromatosis is a relatively common but potentially devastating manifestation of neurofibromatosis type 1 (NF1). It produces very hideous deformity if the face is involved. Surgical management remains the mainstay of therapy, but in the head and neck region it is limited by the infiltrating nature of these tumors, inherent operative morbidity and high rate of regrowth. We present two cases of facial neurofibromatosis managed in our hospital. The first patient presented with overhanging mass of skin folds on the right side of her face, completely obliterating her right eye. The other patient was a young male having a huge, unsightly swelling over the right cheek, resulting in pulled down right eyelids and right pinna. Physical examination revealed the presence of cafe au lait macules, freckling in the axillary region and multiple neurofibromas over the trunk. Reconstructive surgical procedure in the form of subtotal excision of tumor mass followed by re draping of the facial skin was performed in both cases. There was evidence of regrowth of the tumor on review after 6 months. PMID- 23984233 TI - Extensive and invasive lymphangioma circumscriptum in a young female: A rare case report and review of the literature. AB - Lymphatic malformations, or lymphangiomas, are benign proliferations of lymphatics, classified as superficial lymphangioma circumscriptum (LC) and deep (cavernous lymphangioma). LC, as the name suggests, is a well-circumscribed lesion but, rarely, extensive and invasive forms can also be seen. Surgical excision is the main modality of treatment. We report a case of extensive and invasive type of LC where surgical excision is difficult and recurrence is the rule. PMID- 23984234 TI - Multiple keratoacanthomas developing in healing plaques of Psoriasis. AB - A 22 year old male psoriatic patient presented with multiple reddish scaly plaques all over body. After hematological and biochemical investigations the patient was started on oral methotrexate 15 mg weekly. PASI score at the start of treatment was 26.2. After 3 months PASI dropped to 11.5, the dose of methotrexate was tapered to 7.5mg weekly and the patient was maintained on this dose and kept under monthly follow up. Four months later, the patient presented with reddish to hyperpigmented raised firm nodules having a central crater over the healing plaques of psoriasis. Few lesions showed self resolution over a period of 6-12 weeks. Histopathology of the lesion confirmed it to be Keratoacanthoma. We believe the most likely etiologic factors for the multiple KAs in our patient could be a genetic susceptibility stimulated by multiple causes. PMID- 23984235 TI - Necrolytic migratory ulceration. AB - Endocrine tumors of the gastroenteropancreatic system associated with specific skin manifestations are rare. We report a 53-year-old female who presented with migratory annular and arcuate ulcers on her limbs. Histopathology was similar to necrolytic erythema family which includes necrolytic migratory erythema (NME). Though initial CT scans were normal, follow up scans revealed multiple mass lesions in the tail of pancreas. Her skin lesions responded to oral zinc sulphate and monthly injections of octreotide. Prior to planned FNAC from the mass lesion, patient developed altered sensorium and succumbed to the disease. This case report seems to differ from NME clinically, due to unique finding of deep migrating ulcers which heal with scarring. 'Necrolytic migratory ulceration' thus appears to be a new paraneoplastic manifestation, secondary to pancreatic malignancy. PMID- 23984236 TI - Granulosis rubra nasi. AB - Granulosis rubra nasi is a rare disorder of the eccrine glands, inherited as an autosomal dominant trait. It is clinically characterized by hyperhidrosis of the central part of the face, most conspicuous on the tip of the nose, followed by appearance of diffuse erythema over the nose, cheeks, chin, and upper lip. It is commonly seen in childhood, but can also occur in adults. This is a case report of a 27-year-old male patient who presented with excessive sweating over the nose. Physical examination of the nose revealed erythema and multiple telangiectatic vesicles. Biopsy findings supported the diagnosis of granulosis rubra nasi. This case is being reported for its rarity since to the best of our knowledge, it has not been reported in Indian subjects so far. PMID- 23984237 TI - Cavernous lymphangioma: Two case reports. AB - Lymphangiomas are congenital malformation of the lymphatic system that involve the skin and subcutaneous tissues. We are reporting two cases of cavernous lymphangioma. These cases are presented for their rarity. PMID- 23984238 TI - Eruptive vellus hair cyst presenting as asymptomatic follicular papules on extremities. AB - Eruptive vellus hair cysts were first described in 1977. They usually appear as yellow to reddish-brown papules on the chest. Usual onset is between ages 17 and 24 years, but they may be congenital. Some believe that they may be inherited as an autosomal dominant disorder. Histologically the cyst has a stratified squamous epithelium and it contains laminated keratin and vellus hairs. They are felt to be caused by an abnormality at the infundibular level of the vellus hair. We present this because of this patient's unusual distribution of eruptive vellus hair cysts. PMID- 23984239 TI - Phacomatosis cesioflammea with Klippel Trenaunay syndrome: A rare association. AB - A 30-year-old Indian male presented with bilateral Nevus of Ota, extensive nevus flammeus over the trunk and left lower limb with soft tissue hypertrophy and varicosities affecting the left lower limb. He was otherwise in good general health. A diagnosis of Phacomatosis cesioflammea or Phacomatosis pigmentovasularis Type II with Klippel Trenaunay syndrome was made. The case is being reported on account of its rarity. PMID- 23984240 TI - A case of zosteriform Darier's disease with seasonal recurrence. AB - Darier's disease is an uncommon genodermatosis characterized by keratotic papules in seborrheic distribution. The disease can rarely present in unilateral zosteriform pattern, as a mosaic form following the Blaschko's line. We present a 35-year-old woman with zosteriform pattern of Darier's disease over right infra mammary region. The lesions occurred strictly during summers. Histologically, suprabasal acantholysis with abundant dyskeratotic cells were seen. PMID- 23984241 TI - A rare case of woolly hair with unusual associations. AB - Woolly hair is a congenital abnormality of scalp hair manifesting as short, kinked hair, which may also involve the hair over the other parts of the body. Keratosis pilaris has been a well known association of woolly hair, and can also be a part of the Naxos or Carvajal syndromes. We herein present a case of woolly hair with associated keratosis pilaris, canaliform dystrophy of nails, increased interdental spaces and recurrent bullous impetigo. Although keratosis pilaris and teeth abnormalities have been reported as isolated associations with woolly hair, such a combination of findings as seen in our patient has not been reported before. PMID- 23984242 TI - Pachyonychia congenita: A rare genodermatosis. AB - Pachyonychia congenita (PC) is a rare genodermatosis with only 450 cases reported since 1906. It is of two types, type I due to mutation in genes 6a and 16, and 6b and 17 in type II with an autosomal dominant inheritance in both types. A 22 yr old female patient presented in our OPD with hypertrophy of finger and toe nails, palmoplantar keratoderma, oral punctuate leukokeratosis, hyperhidrosis in palms and soles with maceration and malodour since childhood. She had a positive family history with father and grandfather affected but less severely. Microscopy and culture of nail clippings and scrapping were done to rule out fungal infection. On biopsy acanthotic epidermis, parakeratosis, orthokeratosis were seen. No evidence of any associated malignancy was found after thorough workup. She was diagnosed as PC Type 1. She was put on topical steroids and orally on acetretin 25 mg OD. Paring of the nails was done too reduce the thickness of nails & to provide symptomatic relief. She was on a regular treatment for 3-4 months and showed some improvement in the form of reduced palmoplantar hyperkeratosis and reduced oral punctate keratosis but was later lost on followup. She showed no adverse effect to therapy during this period. This case is being reported because of its rarity. PMID- 23984243 TI - Symmetrical peripheral gangrene associated with peripartum cardiomyopathy. AB - Symmetrical peripheral gangrene (SPG) is a rare clinical entity. It was first described in late 19(th) century and since then has been reported with array of medical conditions mainly those complicated with shock, sepsis, and disseminated intravascular coagulation (DIC). Here in, we describe a parturient with peripartum cardiomyopathy (PPCM) and SPG. Clinicians should be aware of this entity as early recognition can help in reducing morbidity and mortality. PMID- 23984244 TI - Acute generalized exanthematous pustulosis: A rare side effect of a common over the-counter drug, Acetylsalicylic acid. AB - Acute generalized exanthematous pustulosis is an uncommon cutaneous reaction characterized by sudden onset of generalized non-follicular aseptic pustules. It is most often secondary to drugs but causes as varied from viral infection to insect bites are reported. A case report of a 48-year-old male who developed pustular eruptions after taking acetylsalicylic acid is reported here. Clinicians need to be aware of this entity when dealing with pustular rash as this rare side effect of a very common drug is both, easy to miss and easy to manage. PMID- 23984245 TI - Speckled lentiginous nevus syndrome with median nerve paresis: A rare syndrome with a new association. AB - Speckled lentiginous nevus (SLN) represents a mosaic phenotype which consists of cafe au lait macule superimposed by melanocytic nevi. Recently, SLN syndrome has been characterized where ipsilateral neurological abnormalities have been reported in association with SLN with papular type of melanocytic nevi only. This case describes the presence of ipsilateral thenar muscle atrophy with median nerve paresis in nevus spilus which had melanocytic nevi of the macular type alone, thus delineating a new association in SLN syndrome, hitherto unreported. PMID- 23984246 TI - A rare case of malignant chondroid syringoma of scalp. AB - Chondroid syringoma represents the cutaneous counterpart of mixed tumor (pleomorphic adenoma) of salivary glands, therefore it is also termed "mixed tumour of the skin." It is generally accepted that there are both eccrine and apocrine variants of mixed tumors of skin. Malignant chondroid syringoma is a malignant eccrine neoplasm that is very rarely encountered in radio-pathological and clinical practice. Unlike the benign variety which occurs most often on the head and neck, malignant chondroid syringomas are most often found on the trunk and extremities. The usual presentation is that of an asymptomatic slow-growing mass in the region of head or neck. We present here a case report of histopathologically proven malignant chondroid syringoma of scalp in occipital region, with dural invasion. Malignant chondroid syringomas clinically appear as very large nodules and they metastasize at a very high rate. The treatment of these malignancies is surgical excision. PMID- 23984247 TI - Erosive adenomatosis of the nipple masquerading as Paget's disease. AB - Erosive adenomatosis of the nipple (EAN) is a rare, benign neoplasm of breast lactiferous ducts. Peak incidence is in the fifth decade in women. Clinically, it is mistaken for eczema during early stages and Paget's disease at later stages. We present a young lady with EAN who was advised mastectomy. It is important for dermatologists to be familiar with this entity to avoid topical steroid abuse and unwarranted breast removal. This case is presented for awareness and importance of correct and early diagnosis. PMID- 23984248 TI - A case report of focal dermal hypoplasia-Goltz syndrome. AB - Goltz syndrome is a rare multisystem disorder with cutaneous, ocular, dental and skeletal abnormalities. Other mesoectodermal abnormalities are also present. Its hallmark is thinning of the dermis resulting subcutaneous fat herniation. The present case is a 5 year old girl having linear skin atrophy with fat herniation, skeletal abnormalities in the form of polysyndactyly, facial asymmetry, squint with coloboma iris, deformed pinna, abnormal dentition, umbilical hernia along with osteopathia striata of long bones which is consistent with Goltz syndrome. We are presenting this case due to its rarity. PMID- 23984249 TI - Dermpath quiz. PMID- 23984250 TI - Ingenol mebutate: A novel topical drug for actinic keratosis. AB - The global incidence of non-melanoma skin cancer is rising. Significant morbidity leading to unacceptable cosmetic outcomes and/or functional impairment is a major concern. Search for non-surgical, non-invasive and tissue-sparing treatment modalities has led to development of new therapeutic agents. Actinic keratoses (AK) are one part of a continuous spectrum of benign sun damage to squamous cell carcinoma (SCC). Although it is not possible to predict which AK might progress to SCC, the presence of AK is a biomarker of risk for patients and must be treated to avoid possible morbidity and mortality. Ingenol mebutate is a novel topical drug from the latex sap of a plant-Euphorbia peplus that acts by chemoablative and immunostimulatory properties. Clinical studies have proven it to be safe and efficacious, leading to FDA approval of this chemotherapeutic agent for field therapy of AK in 2012. Current topical agents for field therapy of AK must be applied for weeks, whereas ingenol needs to be applied for three days. Ingenol offers a new therapeutic option that is convenient, safe, effective, acceptable and well-tolerated. PMID- 23984251 TI - A clinical study of the spectrum of vitiligo in children versus adults and its associations. PMID- 23984252 TI - Verrucous trichoadenoma - presenting as discharging sinus on face. PMID- 23984253 TI - Herpes zoster in infancy. PMID- 23984254 TI - Radiotherapy induced keobernisation of vitiligo. PMID- 23984255 TI - Cutaneous angiomyolipoma. PMID- 23984256 TI - SkIndia Quiz 10 Papulonodular lesions in a Human Immunodeficiency Virus-positive patient. PMID- 23984257 TI - Prayer sign. PMID- 23984258 TI - A baby with photosensitivity and red teeth. PMID- 23984259 TI - Porokeratosis of Mibelli: Giant variant. PMID- 23984260 TI - Human immunodeficiency virus type 1 infection alters enzymatic and ultrastructural features of peripheral blood monocytes. AB - INTRODUCTION: Human immunodeficiency virus-1 (HIV-1) infected monocytes are now believed to serve as a reservoir for HIV-1 infection, and to play a role in viral rebound phenomena in certain groups of patients who failed or stopped highly active antiretroviral therapy (HAART). Data characterizing the morphological changes of peripheral blood monocytes in HIV-1-infected individuals are limited. MATERIALS AND METHODS: In this study, we collected monocytes from 21 asymptomatic HIV-1-infected individuals with CD4 count more than 500 cells/mm(3) and healthy individuals. The monocytes ultrastructural morphologic changes and alpha-naphthyl butyrate esterase (ANBE) activity were compared between the two groups. RESULTS: In monocytes from patients infected with HIV-1, activity of alpha-naphthyl butyrate esterase (ANBE) was markedly increased compared with normal monocytes. In both light microscopic and ultrastructural studies, the cytoplasm of monocytes from HIV-1-infected patients contained a haphazard appearing network of thin fibrils. Cell surface expression of the activation marker HLA-DR molecule was upregulated. There were no discernible differences between the cell surface expression of CD4, CD14, and CD16 molecules comparing normal monocytes to those from HIV-1-infected patients. alpha-naphthyl butyrate esterase (ANBE) was markedly increased compared with normal monocytes. In both light microscopic and ultrastructural studies, the cytoplasm of monocytes from HIV-1-infected patients contained a haphazard appearing network of thin fibrils. Cell surface expression of the activation marker HLA-DR molecule was upregulated. There were no discernible differences between the cell surface expression of CD4, CD14, and CD16 molecules comparing normal monocytes to those from HIV-1-infected patients. CONCLUSIONS: Possibly, changes in the activity of ANBE along with a disrupted appearing cytoplasmic fibril network contribute to monocyte dysfunction in HIV-1 infected patients. PMID- 23984261 TI - Western and Islamic bioethics: How close is the gap? AB - The relation between Islam and medicine has been described as intimate. Muslims are expected to be moderate and balanced in all matters, including health. Islamic law is based on a complete system of morality that can provide a moral context in medicine from a legal perspective. Islamic teaching is also very flexible and adaptable to many new and novel situations. Islamic Ethics also upholds "the four principles" of biomedical ethics proposed by Beauchamp and Childress. Several authors claim that the roots of these principles are clearly identifiable in Islamic teachings. However, there are some differences in the applications of these principles. This article shed light on the roots of the four principles in Islamic teachings and elaborates on the differences between Islamic and contemporary western bioethics. PMID- 23984262 TI - Testicular adrenal rest "tumor" or Leydig cell tumor? A report of a challenging case with literature review. AB - Congenital adrenal hyperplasia (CAH) refers to group of inherited diseases resulting from impaired adrenal steroidogenesis, and its most common cause is 21 hydroxylase deficiency. Testicular adrenal rest tumors (TARTs) are an important complication of CAH, which probably develop from ectopic remnants of intra testicular adrenal tissue stimulated by Adrenocorticotropic hormone (ACTH) hypersecretion. These lesions are typically located within the rete testis and are bilateral, synchronous, nodular and multiple. TART usually, but not always, responses to suppressive medical therapy. TART leads to testicular structural damage, spermatogenesis disorders, infertility and most importantly, mass-forming lesions that could be mistaken for Leydig cell tumor (LCT). The later has a significantly different behavior with up to 10% of being malignant. Nowadays, due to advances in diagnosing and treating CAH, mass-forming TART is rarely encountered. As a result, there is the paucity in the medical literature regarding its features from pathological perspective. We herein present a case of mass-forming TART and we discuss the clinical, radiological, and morphological features as well as the major differential diagnosis of this rare lesion. PMID- 23984263 TI - Red discoloration of urine caused by Serratia rubidae: A rare case. AB - There have been only a few reported human cases of infections caused by Serratia rubidae in literature. Among these sparse cases there is only one reported case of urinary tract infection (UTI) due to S. rubidae in literature. The organism is known to produce a red pigment known as prodigiosin. We report a case of UTI caused by S. rubidae in a diabetic patient who presented with burning micturition and reddish discoloration of urine, which on laboratory diagnosis, was proved to be due to the reddish pigment produced by the organism. This case report highlights that this rare organism might be associated with UTI leading to reddish discoloration of urine. PMID- 23984264 TI - Renal artery embolization for managing uncontrolled hypertension in a kidney transplant candidate. AB - We report a case of pre-operative bilateral renal artery embolization to control the resistant and malignant hypertension in a patient prepared for kidney transplantation. A 34-year-old man with end-stage renal disease as a result of the focal segmental glomerulosclerosis and uncontrolled hypertension that precluded the transplantation surgery and the patient's post-transplant blood pressure and the renal function remained within normal limits following the transplant for 6 months of follow-up. PMID- 23984266 TI - Circumpolar health - what is next? PMID- 23984265 TI - Dietary intake of vitamin D in a northern Canadian Dene First Nation community. AB - BACKGROUND: Increased awareness of the wide spectrum of activity of vitamin D has focused interest on its role in the health of Canada's Aboriginal peoples, who bear a high burden of both infectious and chronic disease. Cutaneous vitamin D synthesis is limited at northern latitudes, and the transition from nutrient dense traditional to nutrient-poor market foods has left many Canadian Aboriginal populations food insecure and nutritionally vulnerable. OBJECTIVE: The study was undertaken to determine the level of dietary vitamin D in a northern Canadian Aboriginal (Dene) community and to determine the primary food sources of vitamin D. DESIGN: Cross-sectional study. METHODS: Dietary vitamin D intakes of 46 adult Dene men and women were assessed using a food frequency questionnaire and compared across age, gender, season and body mass index. The adequacy of dietary vitamin D intake was assessed using the 2007 Adequate Intake (AI) and the 2011 Recommended Dietary Allowance (RDA) values for Dietary Reference Intake (DRI). RESULTS: Mean daily vitamin D intake was 271.4 IU in winter and 298.3 IU in summer. Forty percent and 47.8% of participants met the vitamin D 1997 AI values in winter and summer, respectively; this dropped to 11.1 and 13.0% in winter and summer using 2011 RDA values. Supplements, milk, and local fish were positively associated with adequate vitamin D intake. Milk and local fish were the major dietary sources of vitamin D. CONCLUSIONS: Dietary intake of vitamin D in the study population was low. Only 2 food sources, fluid milk and fish, provided the majority of dietary vitamin D. Addressing low vitamin D intake in this population requires action aimed at food insecurity present in northern Aboriginal populations. PMID- 23984267 TI - Bridging storytelling traditions with digital technology. AB - OBJECTIVE: The purpose of this project was to learn how Community Health Workers (CHWs) in Alaska perceived digital storytelling as a component of the "Path to Understanding Cancer" curriculum and as a culturally respectful tool for sharing cancer-related health messages. DESIGN: A pre-course written application, end-of course written evaluation, and internet survey informed this project. METHODS: Digital storytelling was included in seven 5-day cancer education courses (May 2009-2012) in which 67 CHWs each created a personal 2-3 minute cancer-related digital story. Participant-chosen digital story topics included tobacco cessation, the importance of recommended cancer screening exams, cancer survivorship, loss, grief and end-of-life comfort care, and self-care as patient care providers. All participants completed an end-of-course written evaluation. In July 2012, contact information was available for 48 participants, of whom 24 completed an internet survey. RESULTS: All 67 participants successfully completed a digital story which they shared and discussed with course members. On the written post-course evaluation, all participants reported that combining digital storytelling with cancer education supported their learning and was a culturally respectful way to provide health messages. Additionally, 62 of 67 CHWs reported that the course increased their confidence to share cancer information with their communities. Up to 3 years post-course, all 24 CHW survey respondents reported they had shown their digital story. Of note, 23 of 24 CHWs also reported change in their own behavior as a result of the experience. CONCLUSIONS: All CHWs, regardless of computer skills, successfully created a digital story as part of the cancer education course. CHWs reported that digital stories enhanced their learning and were a culturally respectful way to share cancer-related information. Digital storytelling gave the power of the media into the hands of CHWs to increase their cancer knowledge, facilitate patient and community cancer conversations, and promote cancer awareness and wellness. PMID- 23984268 TI - Linkages between human health and ocean health: a participatory climate change vulnerability assessment for marine mammal harvesters. AB - BACKGROUND: Indigenous residents of Alaska's Bering Strait Region depend, both culturally and nutritionally, on ice seal and walrus harvests. Currently, climate change and resultant increases in marine industrial development threaten these species and the cultures that depend on them. OBJECTIVE: To document: (a) local descriptions of the importance of marine mammal hunting; (b) traditional methods for determining if harvested marine mammals are safe to consume; and (c) marine mammal outcomes that would have adverse effects on community health, the perceived causes of these outcomes, strategies for preventing these outcomes and community adaptations to outcomes that cannot be mitigated. DESIGN: Semi structured interviews and focus groups were conducted with 82 indigenous hunters and elders from the Bering Strait region. Standard qualitative analysis was conducted on interview transcripts, which were coded for both inductive and deductive codes. Responses describing marine mammal food safety and importance are presented using inductively generated categories. Responses describing negative marine mammal outcomes are presented in a vulnerability framework, which links human health outcomes to marine conditions. RESULTS: Project participants perceived that shipping noise and pollution, as well as marine mammal food source depletion by industrial fishing, posed the greatest threats to marine mammal hunting traditions. Proposed adaptations primarily fell into 2 categories: (a) greater tribal influence over marine policy; and (b) documentation of traditional knowledge for local use. This paper presents 1 example of documenting traditional knowledge as an adaptation strategy: traditional methods for determining if marine mammal food is safe to eat. CONCLUSIONS: Participant recommendations indicate that 1 strategy to promote rural Alaskan adaptation to climate change is to better incorporate local knowledge and values into decision-making processes. Participant interest in documenting traditional knowledge for local use also indicates that funding agencies could support climate change adaptation by awarding more grants for tribal research that advances local, rather than academic, use of traditional knowledge. PMID- 23984269 TI - The Nuka System of Care: improving health through ownership and relationships. AB - Southcentral Foundation's Nuka System of Care, based in Anchorage, Alaska, is a result of a customer-driven overhaul of what was previously a bureaucratic system centrally controlled by the Indian Health Service. Alaska Native people are in control as the "customer-owners" of this health care system. The vision and mission focus on physical, mental, emotional, and spiritual wellness and working together as a Native Community. Coupled with operational principles based on relationships, core concepts and key points, this framework has fostered an environment for creativity, innovation and continuous quality improvement. Alaska Native people have received national and international recognition for their work and have set high standards for performance excellence, community engagement, and overall impact on population health. In this article, the health care transformation led by Alaska Native people is described and the benefits and results of customer ownership and the relationship-based Nuka System of Care are discussed. PMID- 23984270 TI - Distance education for tobacco reduction with Inuit frontline health workers. AB - BACKGROUND: Tobacco reduction is a major priority in Canadian Inuit communities. However, many Inuit frontline health workers lacked the knowledge, confidence and support to address the tobacco epidemic. Given vast distances, high costs of face to-face training and previous successful pilots using distance education, this method was chosen for a national tobacco reduction course. OBJECTIVE: To provide distance education about tobacco reduction to at least 25 frontline health workers from all Inuit regions of Canada. DESIGN: Promising practices globally were assessed in a literature survey. The National Inuit Tobacco Task Group guided the project. Participants were selected from across Inuit Nunangat. They chose a focus from a "menu" of 6 course options, completed a pre-test to assess individual learning needs and chose which community project(s) to complete. Course materials were mailed, and trainers provided intensive, individualized support through telephone, fax and e-mail. The course ended with an open-book post-test. Follow-up support continued for several months post-training. RESULTS: Of the 30 participants, 27 (90%) completed the course. The mean pre-test score was 72% (range: 38-98%). As the post-test was done using open books, everyone scored 100%, with a mean improvement of 28% (range: 2-62%). CONCLUSIONS: Although it was often challenging to contact participants through phone, a distance education approach was very practical in a northern context. Learning is more concrete when it happens in a real-life context. As long as adequate support is provided, we recommend individualized distance education to others working in circumpolar regions. PMID- 23984271 TI - Adverse health effects of experiencing food insecurity among Greenlandic school children. AB - BACKGROUND: In vulnerable populations, food security in children has been found to be associated with negative health effects. Still, little is known about whether the negative health effects can be retrieved in children at the population level. OBJECTIVE: To examine food insecurity reported by Greenlandic school children as a predictor for perceived health, physical symptoms and medicine use. DESIGN: The study is based on the Greenlandic part of the Health Behavior in School-aged Children survey. The 2010 survey included 2,254 students corresponding to 40% of all Greenlandic school children in Grade 5 through 10. The participation rate in the participating schools was 65%. Food insecurity was measured as going to bed or to school hungry because there was no food at home. RESULTS: Boys, the youngest children (11-12 year-olds), and children from low affluence homes were at increased risk for food insecurity. Poor or fair self rated health, medicine use last month and physical symptoms during the last 6 months were all more frequent in children reporting food insecurity. Controlling for age, gender and family affluence odds ratio (OR) for self-rated health was 1.60 (95% confidence interval (CI 1.23-2.06) (p < 0.001), for reporting physical symptoms 1.34 (95% CI 1.06-1.68) (p = 0.01) and for medicine use 1.79 (95% CI 1.42-2.26) (p < 0.001). Stratification on age groups suggested that children in different age groups experience different health consequences of food insecurity. The oldest children reported food insecurity less often and experienced less negative health effects compared to the younger children. CONCLUSIONS: All 3 measures of health were negatively associated to the occurrence of food insecurity in Greenlandic school children aged 11-17. Food security must be seen as a public health issue of concern, and policies should be enforced to prevent food poverty particularly among boys, younger school children and children from low affluence homes. PMID- 23984272 TI - Disseminating research in rural Yup'ik communities: challenges and ethical considerations in moving from discovery to intervention development. AB - BACKGROUND: The native people of Alaska have experienced historical trauma and rapid changes in culture and lifestyle patterns. As a consequence, these populations shoulder a disproportionately high burden of psychological stress. The Yup'ik Experiences of Stress and Coping project originated from rural Yup'ik communities' concerns about stress and its effects on health. It aimed to understand the stressful experiences that affect Yup'ik communities, to identify coping strategies used to deal with these stressors and to inform culturally responsive interventions. OBJECTIVES: Here, we examine the process of moving from research (gaining understanding) to disseminating project findings to translation into intervention priorities. We highlight the importance of community participation and discuss challenges encountered, strategies to address these challenges and ethical considerations for responsible intervention research with indigenous communities that reflect their unique historical and current socio cultural realities. DESIGN: Community-wide presentations and discussions of research findings on stress and coping were followed by smaller Community Planning Group meetings. During these meetings, community members contextualized project findings and discussed implications for interventions. This process placed priority on community expertise in interpreting findings and translating results and community priorities into grant applications focused on intervention development and evaluation. RESULTS: Challenges included translation between English and Yup'ik, funding limitations and uncertainties, and the long timelines involved in moving from formative research to intervention in the face of urgent and evolving community needs. The lack of congruence between institutional and community worldviews in the intervention research enterprise highlights the need for "principled cultural sensitivity". CONCLUSIONS: Cultural sensitivity requires sharing results that have practical value, communicating openly, planning for sustainability and incorporating indigenous knowledge and expertise through a community-guided process. Our research findings will inform continued work within our partnership as we co-develop culturally based strategies for multilevel community interventions to address stress. PMID- 23984273 TI - Molecular epidemiology of serotype 19A Streptococcus pneumoniae among invasive isolates from Alaska, 1986-2010. AB - BACKGROUND: After the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Alaska, the incidence of invasive pneumococcal disease (IPD) due to non vaccine serotypes, particularly serotype 19A, increased. The aim of this study was to describe the molecular epidemiology of IPD due to serotype 19A in Alaska. METHODS: IPD data were collected from 1986 to 2010 through population-based laboratory surveillance. Isolates were serotyped by the Quellung reaction and MICs determined by broth microdilution. Genotypes were assessed by multilocus sequence typing. RESULTS: Among 3,294 cases of laboratory-confirmed IPD, 2,926 (89%) isolates were available for serotyping, of which 233 (8%) were serotype 19A. Across all ages, the proportion of IPD caused by serotype 19A increased from 3.5% (63/1823) pre-PCV7 (1986-2000) to 15.4% (170/1103) post-PCV7 (2001-2010) (p < 0.001); among children < 5 years of age, the proportion increased from 5.0% (39/776) to 33.0% (76/230) (p < 0.001). The annual incidence rate of IPD due to serotype 19A (all ages) increased from 0.73 cases pre-PCV7 to 2.56 cases/100,000 persons post-PCV7 (p < 0.001); rates among children < 5 years of age increased from 4.84 cases to 14.1 cases/100,000 persons (p < 0.001). Among all IPD isolates with reduced susceptibility to penicillin, 17.8% (32/180) were serotype 19A pre PCV7 and 64% (121/189) were serotype 19A post-PCV7 (p < 0.001). Eighteen different sequence types (STs) were identified; ST199 or single locus variants of ST199 (n = 150) and ST172 (n = 59) accounted for the majority of isolates. Multidrug-resistant isolates were clustered in ST199 and ST320. CONCLUSION: While PCV13 should significantly reduce the burden of disease due to 19A, these data highlight the need to continue surveillance for IPD to monitor the effects of vaccination on the expansion and emergence of non-PCV strains. PMID- 23984274 TI - Attitudes toward harm reduction and abstinence-only approaches to alcohol misuse among Alaskan college students. AB - BACKGROUND: Harm reduction is a public health approach that aims to guide hazardous drinkers to change unsafe drinking and minimize alcohol-related consequences without requiring abstinence. In contrast, abstinence-based interventions are designed for people with more severe alcohol problems and they aim to eliminate consequences via complete abstinence from alcohol. Current best practices for treating college student alcohol misuse involve harm reduction strategies, but no research has been conducted examining students' perceptions of these strategies. OBJECTIVE: Understanding attitudes is critical prior to the implementation of an intervention in a new setting, particularly when attitudes may serve as barriers to treatment enrolment and retention. For this reason, we sought to examine attitudes toward contrasting alcohol misuse interventions among college students in two large public universities in the circumpolar north. DESIGN: A web-based survey was conducted with 461 students from two public universities in Alaska. Participants completed questionnaires assessing attitudes toward alcohol treatment, current drinking behavior, and demographic information. RESULTS: Findings indicated that emerging adult (18-25 years old) students who would be targets of future interventions (hazardous drinkers) evidenced more positive attitudes toward harm reduction than abstinence-only approaches. CONCLUSION: This research provides support for the implementation of harm reduction intervention strategies for Alaskan college students who misuse alcohol. It is likely that harm reduction will be acceptable in this population. PMID- 23984275 TI - Smoking-related knowledge, attitudes, and behaviors among Alaska Native people: a population-based study. AB - BACKGROUND: Several studies have shown that Alaska Native people have higher smoking prevalence than non-Natives. However, no population-based studies have explored whether smoking-related knowledge, attitudes, and behaviors also differ among Alaska Native people and non-Natives. OBJECTIVE: We compared current smoking prevalence and smoking-related knowledge, attitudes, and behavior of Alaska Native adults living in the state of Alaska with non-Natives. METHODS: We used Alaska Behavioral Risk Factor Surveillance System data for 1996 to 2010 to compare smoking prevalence, consumption, and cessation- and second-hand smoke related knowledge, attitudes, and behaviors among self-identified Alaska Native people and non-Natives. RESULTS: Current smoking prevalence was 41% (95% CI: 37.9%-44.4%) among Alaska Native people compared with 17.1% (95% CI: 15.9%-18.4%) among non-Natives. Among current every day smokers, Alaska Natives were much more likely to smoke less than 10 cigarettes per day (OR = 5.0, 95% CI: 2.6-9.6) than non-Natives. Compared with non-Native smokers, Alaska Native smokers were as likely to have made a past year quit attempt (OR = 1.4, 95% CI: 0.9-2.1), but the attempt was less likely to be successful (OR = 0.5, 95% CI: 0.2-0.9). Among current smokers, Alaska Natives were more likely to believe second-hand smoke (SHS) was very harmful (OR = 4.5, 95% CI: 2.8-7.2), to believe that smoking should not be allowed in indoor work areas (OR = 1.9, 95% CI: 1.1-3.1) or in restaurants (OR = 4.2, 95% CI: 2.5-6.9), to have a home smoking ban (OR = 2.5, 95% CI: 1.6-3.9), and to have no home exposure to SHS in the past 30 days (OR = 2.3, 95% CI: 1.5-3.6) than non-Natives. CONCLUSION: Although a disparity in current smoking exists, Alaska Native people have smoking-related knowledge, attitudes, and behaviors that are encouraging for reducing the burden of smoking in this population. Programs should support efforts to promote cessation, prevent relapse, and establish smoke-free environments. PMID- 23984276 TI - Survey of northern informal and formal mental health practitioners. AB - BACKGROUND: This survey is part of a multi-year research study on informal and formal mental health support in northern Canada involving the use of qualitative and quantitative data collection and analysis methods in an effort to better understand mental health in a northern context. OBJECTIVE: The main objective of the 3-year study was to document the situation of formal and informal helpers in providing mental health support in isolated northern communities in northern British Columbia, northern Alberta, Yukon, Northwest Territories and Nunavut. The intent of developing a survey was to include more participants in the research and access those working in small communities who would be concerned regarding confidentiality and anonymity due to their high profile within smaller populations. DESIGN: Based on the in-depth interviews from the qualitative phase of the project, the research team developed a survey that reflected the main themes found in the initial qualitative analysis. The on-line survey consisted of 26 questions, looking at basic demographic information and presenting lists of possible challenges, supports and client mental health issues for participants to prioritise. RESULTS: Thirty-two participants identified various challenges, supports and client issues relevant to their mental health support work. A vast majority of the respondents felt prepared for northern practice and had some level of formal education. Supports for longevity included team collaboration, knowledgeable supervisors, managers, leaders and more opportunities for formal education, specific training and continuity of care to support clients. CONCLUSION: For northern-based research in small communities, the development of a survey allowed more participants to join the larger study in a way that protected their identity and confidentiality. The results from the survey emphasise the need for team collaboration, interdisciplinary practice and working with community strengths as a way to sustain mental health support workers in the North. PMID- 23984277 TI - Women's perspectives on illness when being screened for cervical cancer. AB - BACKGROUND: In Greenland, the incidence of cervical cancer caused by human papillomavirus (HPV) is 25 per 100,000 women; 2.5 times the Danish rate. In Greenland, the disease is most frequent among women aged 30-40. Systematic screening can identify women with cervical cell changes, which if untreated may cause cervical cancer. In 2007, less than 40% of eligible women in Greenland participated in screening. OBJECTIVE: To examine Greenlandic women's perception of disease, their understanding of the connection between HPV and cervical cancer, and the knowledge that they deem necessary to decide whether to participate in cervical cancer screening. STUDY DESIGN: The methods used to perform this research were 2 focus-group interviews with 5 Danish-speaking women and 2 individual interviews with Greenlandic-speaking women. The analysis involved a phenomenological-hermeneutic approach with 3 levels of analysis: naive reading, structural analysis and critical interpretation. RESULTS: These revealed that women were unprepared for screening results showing cervical cell changes, since they had no symptoms. When diagnosed, participants believed that they had early-stage cancer, leading to feelings of vulnerability and an increased need to care for themselves. Later on, an understanding of HPV as the basis for diagnosis and the realization that disease might not be accompanied by symptoms developed. The outcome for participants was a life experience, which they used to encourage others to participate in screening and to suggest ways that information about screening and HPV might reach a wider Greenlandic population. CONCLUSION: Women living through the process of cervical disease, treatment and follow-up develop knowledge about HPV, cervical cell changes, cervical disease and their connection, which, if used to inform cervical screening programmes, will improve the quality of information about HPV, cervical cancer and screening participation. This includes that verbal and written information given at the point of screening and diagnosis needs to be complemented by visual imagery. PMID- 23984278 TI - Prenatal alcohol exposure among Alaska Native/American Indian infants. AB - BACKGROUND: Recent reports indicate a decline in rates of Fetal Alcohol Syndrome (FAS) among Alaska Native and American Indian (AN/AI) infants. Nevertheless, AN/AI infants remain disproportionately impacted by the effects of prenatal alcohol exposure. METHODS: AN/AI pregnant women in their 3rd trimester completed a questionnaire on demographic data and the amount and frequency of their alcohol consumption in the month prior to conception and during pregnancy. Differences across demographics and trimesters were tested with the Chi-square, Fisher's exact or McNemar's test as appropriate. RESULTS: Of the 125 participants, 56% (n = 71) reported no alcohol consumption in the 1st through 3rd trimesters of pregnancy; 30% (n = 38) of the 125 participants also reported no alcohol consumption in the month before pregnancy. Of the 43% (n = 54) who reported consuming alcohol during pregnancy (1st, 2nd and/or 3rd trimester), most (35%) reported alcohol use only in the 1st trimester. Binge drinking in the 1st or 2nd trimester was reported amongst 20% (n = 25) of participants with an additional 18% (n = 29) reporting binge drinking in the month prior to pregnancy. Women who reported pre-conception binge drinking were significantly more likely to report binge drinking during their 1st trimester (p < 0.0001) and 2nd trimester (p < 0.0001). A history of tobacco use (p = 0.0403) and cigarette smoking during pregnancy (p < 0.0001) were also associated with binge drinking during pregnancy. CONCLUSION: Among study participants, reported use of alcohol was primarily limited to pre-conception and the 1st trimester, with a dramatic decrease in the 2nd and 3rd trimesters. Prevention programmes, such as the Alaska FAS Prevention Project, may have contributed to observed decreases in the 2nd and 3rd trimesters. Additional study and focus on pre-conception, the 1st trimester and binge drinking, as well as tobacco use might augment Fetal Alcohol Spectrum Disorder prevention efforts. PMID- 23984279 TI - No evidence of increasing Haemophilus influenzae non-b infection in Australian Aboriginal children. AB - BACKGROUND: High, or increasing, rates of invasive Haemophilus influenzae (Hi) type a disease have been reported from North American native children from circumpolar regions, raising the question of serotype replacement being driven by vaccination against Hi type b (Hib). Indigenous Australians from remote areas had high rates of invasive Hib disease in the past, comparable to those in North American Indigenous populations. OBJECTIVE: Evaluate incidence rates of invasive Hi (overall and by serotype) in Indigenous Australian children over time. DESIGN: Descriptive study of Hi incidence rates by serotype, in the Northern Territory (NT) and South Australia (SA) from 2001 to 2011. Comparison of NT data with a study that was conducted in the NT in 1985-1988, before Hib vaccine was introduced. RESULTS: The average annual rate of invasive Hi type a (Hia) disease in Indigenous children aged < 5 years was 11/100,000 population. Although the incidence of Hi infection in Indigenous children in 2001-2003 was lower than during 2004-2011, this may be due to changes in surveillance. No other trend over time in individual serotypes or total invasive Hi disease, in Indigenous or non Indigenous people, was identified. Compared to 1985-1988, rates in 2001-2011 were lower in all serotype groupings, by 98% for Hib, 75% for Hia, 79% for other serotypes and 67% for non-typeable Hi. CONCLUSIONS: There is no evidence of increases in invasive disease due to Hia, other specific non-b types, or non typeable Hi in Australian Indigenous children. These data suggest that the increase in Hia some time after the introduction of Hib vaccine, as seen in the North American Arctic Region, is not common to all populations with high pre vaccine rates of invasive Hib disease. However, small case numbers and the lack of molecular subtyping and PCR confirmation of pre-vaccine results complicate comparisons with North American epidemiology. PMID- 23984280 TI - Experience with cochlear implants in Greenlanders with profound hearing loss living in Greenland. AB - OBJECTIVE: Cochlear implant (CI) treatment was introduced to the world in the 1980s and has become a routine treatment for congenital or acquired severe-to profound hearing loss. CI treatment requires access to a highly skilled team of ear, nose and throat specialists, audiologists and speech-language pathologists for evaluation, surgery and rehabilitation. In particular, children treated with CI are in need of long-term post-operative auditory training and other follow-up support. DESIGN: The study is retrospective with updated information on present performance. RESULTS: Since 2001, a total of 11 Greenlandic patients living in Greenland have been treated with CI, 7 children and 4 adults. Of these children, 4 use oral communication only and are full-time CI-users, 2 with full-time use of CI are still in progress with use of oral communication, and 1 has not acquired oral language yet, but has started auditory and speech training. Six children attend mainstream public school while one child is in kindergarten. Of the adults, only 1 has achieved good speech perception with full-time use of CI while 3 do not use the CI. DISCUSSION: From an epidemiological point of view, approximately 1-3 children below 6 years are in need of a CI every second year in Greenland often due to sequelae from meningitis, which may cause postinfectious deafness. Screening of new-borns for hearing has been started in Greenland establishing the basis for early diagnosis of congenital hearing impairment and subsequent intervention. The logistics and lack of availability of speech therapists in Greenland hampers possibilities for optimal language and speech therapy of CI patients in Greenland. This study aims at describing the results of CI treatment in Greenlanders and the outcome of the CI operations along with the auditory and speech/language outcomes. Finally, we present a suggestion for the future CI treatment and recommendations for an increased effort in the treatment and rehabilitation of implanted patients in Greenland. PMID- 23984281 TI - HPV genotypes detected in cervical cancers from Alaska Native women, 1980-2007. AB - BACKGROUND: Human papillomavirus (HPV) vaccine prevents cervical pre-cancers and cancers caused by HPV types 16 and 18. This study provides information on the HPV types detected in cervical cancers of Alaska Native (AN) women. METHODS: Cases of invasive cervical cancer diagnosed in AN women aged 18 and above between 1980 and 2007 were identified from the Alaska Native Tumor Registry. A representative formalin-fixed, paraffin-embedded archived pathology block was retrieved and serially sectioned to allow histologic confirmation of lesion (first and last sections) and PCR testing of intervening sections. Extracted DNA was tested for HPV using Linear Array HPV Genotyping Test (Roche Diagnostics) with additional INNO-LiPA HPV Genotyping Assay (Innogenetics) testing on negative or inadequate specimens. All specimens were tested for a minimum 37 HPV types. RESULTS: Of 62 cervical cancer specimens evaluated, 57 (91.9%) contained one or more HPV types. Thirty-eight (61.2%) cancers contained HPV types 16 or 18, and 18 (29%) contained an oncogenic type other than type 16 or 18. CONCLUSIONS: Overall, almost two thirds (61.2%) of the archived cervical cancers had detectible HPV types 16 or 18, a finding similar to studies of US women. As expected, a proportion of cancers would not be prevented by the current vaccines. HPV vaccination and cervical cancer screening are important prevention strategies for AN women. PMID- 23984282 TI - Pathway to Hope: an indigenous approach to healing child sexual abuse. AB - BACKGROUND: The Alaska Native (AN) population has endured multiple historical traumatic events. This population has poorer health outcomes on nearly all factors compared with Alaska non-Natives with more than 75% reportedly being physically assaulted in their lifetime, and child sexual abuse nearly 6 times the national average. OBJECTIVE: This article describes the Pathway to Hope (PTH) program, which is an indigenous approach to ending silence and denial related to child sexual abuse and encourages multigenerational healing. DESIGN: PTH was developed by ANs who believe that each community is unique, thus strategies for ending denial and support for healing must be woven from the historical context, cultural strengths of individual communities. Strengths-based solutions built on truth, honesty, compassion and shared responsibility for healing and protecting today's children have been profound and successful. The PTH curriculum addresses child sexual abuse from a historical perspective; that the higher rates of sexual abuse among certain Tribes, regions and communities is linked in part to years of victimisation, but may also be perpetuated by internalised oppression and lateral violence among Tribal members. RESULTS: Data suggest that community-based dialogue and wisdom of Native elders and spiritual leaders paired with readiness of community service providers are necessary for sustained change. At all levels, this Indigenous model for learning, sharing, helping and healing brings hope for an end to denial and silence about child sexual abuse for Native people. CONCLUSION: The PTH program utilises the wisdom and values that have sustained Native people for generations. Ending silence and denial about child sexual abuse and building upon strengths have assisted many Indigenous communities begin the journey toward wellness. Through the PTH, communities have taken steps to accept the challenges associated with establishing safety for children, supporting child victims in healing and to holding offenders accountable. PMID- 23984283 TI - Tribal implementation of a patient-centred medical home model in Alaska accompanied by decreased hospital use. AB - BACKGROUND: Between 1995 and 1998, tribally owned Southcentral Foundation (SCF) incrementally assumed responsibility from the Indian Health Service (IHS) for primary care services on the Alaska Native Medical Center (ANMC) campus in Anchorage, Alaska. In 1999, SCF began implementing components of a Patient Centered Medical Home (PCMH) model to improve access and continuity of care. OBJECTIVE: To evaluate hospitalisation trends before, during and after PCMH implementation. DESIGN: Time series analysis of aggregated medical record data. METHODS: Regression analysis with correlated errors was used to estimate trends over time for the percent of customer-owners hospitalised overall and for specific conditions during 4 time periods (March 1996-July 1999: SCF assumes responsibility for primary care; August 1999-July 2000: PCMH implementation starts; August 2000-April 2005: early post-PCMH implementation; May 2005-December 2009: later post-PCMH implementation). Analysis was restricted to individuals residing in Southcentral Alaska and receiving health care at ANMC. RESULTS: The percent of SCF customer-owners hospitalised per month for any reason was steady before and during PCMH implementation, declined steadily immediately following implementation and subsequently stabilised. The percent hospitalised per month for unintentional injury or poisoning also declined during and after the PCMH implementation. Among adult asthma patients, the percent hospitalised annually for asthma declined prior to and during implementation and remained lower thereafter. The percent of heart failure patients hospitalised annually for heart failure remained relatively constant throughout the study period while the percent of hypertension patients hospitalised for hypertension shifted higher between 1999 and 2002 compared to earlier and later years. CONCLUSION: Implementation of PCMH at SCF was accompanied by decreases in the percent of customer-owners hospitalised monthly for any reason and for unintentional injury and in the percent of asthma patients hospitalised annually for asthma. Increased accessibility to empanelled care teams may have contributed to decreased need for hospitalisation. PMID- 23984284 TI - Increasing trend in the rate of infectious disease hospitalisations among Alaska Native people. AB - OBJECTIVES: To examine the epidemiology of infectious disease (ID) hospitalisations among Alaska Native (AN) people. METHODS: Hospitalisations with a first-listed ID diagnosis for American Indians and ANs residing in Alaska during 2001-2009 were selected from the Indian Health Service direct and contract health service inpatient data. ID hospitalisations to describe the general US population were selected from the Nationwide Inpatient Sample. Annual and average annual (2007-2009) hospitalization rates were calculated. RESULTS: During 2007 2009, IDs accounted for 20% of hospitalisations among AN people. The 2007-2009 average annual age-adjusted ID hospitalisation rate (2126/100,000 persons) was higher than that for the general US population (1679/100,000; 95% CI 1639-1720). The ID hospitalisation rate for AN people increased from 2001 to 2009 (17%, p < 0.001). Although the rate during 2001-2009 declined for AN infants (< 1 year of age; p = 0.03), they had the highest 2007-2009 average annual rate (15106/100,000), which was 3 times the rate for general US infants (5215/100,000; 95% CI 4783-5647). The annual rates for the age groups 1-4, 5-19, 40-49, 50-59 and 70-79 years increased (p < 0.05). The highest 2007-2009 age-adjusted average annual ID hospitalisation rates were in the Yukon-Kuskokwim (YK) (3492/100,000) and Kotzebue (3433/100,000) regions; infant rates were 30422/100,000 and 26698/100,000 in these regions, respectively. During 2007-2009, lower respiratory tract infections accounted for 39% of all ID hospitalisations and approximately 50% of ID hospitalisations in YK, Kotzebue and Norton Sound, and 74% of infant ID hospitalisations. CONCLUSIONS: The ID hospitalisation rate increased for AN people overall. The rate for AN people remained higher than that for the general US population, particularly in infants and in the YK and Kotzebue regions. Prevention measures to reduce ID morbidity among AN people should be increased in high-risk regions and for diseases with high hospitalisation rates. PMID- 23984285 TI - Cystatin C and lactoferrin concentrations in biological fluids as possible prognostic factors in eye tumor development. AB - OBJECTIVES: To investigate the possible role of cystatin C in eye biological fluids locally and in serum and lactoferrin revealing anti-tumor activity in eye tumor development. BACKGROUND: The increased number of eye tumors was registered recently not only in the countries with high insolation, but also in the northern countries including Russia (11 cases per million of population). Search for new biological markers is important for diagnosis and prognosis in eye tumors. Cystatin C, an endogenous inhibitor of cysteine proteases, plays an important protective role in several tumors. Lactoferrin was shown to express anti-tumor and antiviral activities. It was hypothesized that cystatin C and lactoferrin could serve as possible biomarkers in the diagnosis of malignant and benign eye tumors. STUDY DESIGN: A total of 54 patients with choroidal melanoma and benign eye tumors were examined (part of them undergoing surgical treatment). Serum, tear fluid and intraocular fluid samples obtained from the anterior chamber of eyes in patients with choroidal melanoma were studied. METHODS: Cystatin C concentration in serum and eye biological fluids was measured by commercial ELISA kits for human (BioVendor, Czechia); lactoferrin concentration--by Lactoferrin strip D 4106 ELISA test systems (Vector-BEST, Novosibirsk Region, Russia). RESULTS: Cystatin C concentration in serum of healthy persons was significantly higher as compared to tear and intraocular fluids. In patients with choroidal melanoma, increased cystatin C concentration was similar in tear fluid of both the eyes. Lactoferrin level in tear fluid of healthy persons was significantly higher than its serum level. Significantly increased lactoferrin concentration in tear fluid was noted in patients with benign and malignant eye tumors. CONCLUSION: Increased level of cystatin C in tear fluid seems to be a possible diagnostic factor in the eye tumors studied. However, it does not allow us to differentiate between malignant and benign eye tumors. Similar changes were noted for lactoferrin in tear fluid. PMID- 23984286 TI - Associations of deliberate self-harm with loneliness, self-rated health and life satisfaction in adolescence: Northern Finland Birth Cohort 1986 Study. AB - BACKGROUND: Deliberate self-harm (DSH) is an act with a non-fatal outcome in which an individual initiates a behavior, such as self-cutting or burning, with the intention of inflicting harm on his or her self. Interpersonal difficulties have been shown to be a risk factor for DSH, but the association between subjective experience of loneliness and DSH have rarely been examined. OBJECTIVE: To examine the frequency of DSH or its ideation and loneliness among 16-year-olds to determine if associations exist between DSH and loneliness, loneliness-related factors, self-rated health and satisfaction with life. DESIGN: The study population (n = 7,014) was taken from Northern Finland Birth Cohort 1986 (N = 9,432). Cross-tabulations were used to describe the frequency of DSH by factors selected by gender. Logistic regression analysis was used to describe the association between DSH and loneliness and other selected factors. RESULTS: Nearly 8.7% (n = 608) of adolescents reported DSH often/sometimes during the preceding 6 months, with girls (n = 488, 13.4%) reporting DSH almost 4 times than that of boys (n = 120, 3.6%). Nearly 3.2% of the adolescents (girls: n = 149, 4.1%; boys: n = 72, 2.2%) expressed that the statement I feel lonely was very/often true, and 26.4% (girls: n = 1,265, 34.8%; boys: n = 585, 17.4%) expressed that the statement was somewhat/sometimes true. Logistic regression showed that those who reported to be very/often lonely (girls: odds ratio (OR) 4.1; boys: OR 3.2), somewhat/sometimes lonely (girls: OR 2.4; boys: OR 2.4) were dissatisfied with life (girls: OR 3.3; boys: OR 3.3), felt unliked (girls: OR 2.2; boys: OR 6.0) and had moderate self-rated health (girls: OR 2.0; boys: OR 1.7), were more likely to report DSH than those without these feelings. CONCLUSION: The results show that loneliness is associated with DSH, and that loneliness should be considered as a risk for individual health and well-being. PMID- 23984287 TI - Health status of Native people living in the Republic of Sakha (Yakutia). AB - BACKGROUND: Native people of the Republic of Sakha (Yakutia) live mostly in northern regions in the so-called "national settlements". Natives usually experience more health-related problems as compared to the total population. As a result, life expectancy at the birth of Natives living in the Republic of Sakha (Yakutia) is lower compared to ethnic groups living in European countries, in the United States, and in Canada. OBJECTIVE OF THE STUDY: To determine the prevalence of diseases among Natives living in Yakutia and to compare the standards of living for Dolgans living in the Anabarsky region and Evenks living in Gigansky and Ust-Maysky regions. STUDY DESIGN/METHODS: The study was designed as a population-based, cross-sectional examination with the addition of a cross sectional survey for Dolgans and Evenks. Data were obtained from 324 Evenks, 43 Evens, 230 Dolgans, and 216 people of other ethnic groups, aged 17-86. In the additional cross-sectional survey, 155 Dolgans and 292 Evenks were included. RESULTS: Among Natives, the most prevalent diseases are digestive diseases (67.9 cases per 100 examined), diseases of the genitourinary system (45.3 per 100 examined), circulatory system diseases (44.4 per 100 examined), diseases of the respiratory system (36.9 cases per 100 examined) and diseases of the musculoskeletal system and connective tissue (28.4 cases per 100 examined). There are differences in the prevalence among Natives living in different regions. Anabarsky region has the lowest disease burden and Dolgans inhabiting this region have higher standards of living than Evenks living in Gigansky and Ust-Maysky regions. CONCLUSIONS: The prevalence of diseases among the Natives, living in the Republic of Sakha (Yakutia), is very high. Differences in raw prevalence rate between Native ethnic groups were found, but it is unknown whether these differences can be assigned rather to the difference in standards of living in the inhabited locality than to ethnicity itself. PMID- 23984288 TI - Traditional living and cultural ways as protective factors against suicide: perceptions of Alaska Native university students. AB - INTRODUCTION: Native peoples living in Alaska have one of the highest rates of suicide in the world. This represents a significant health disparity for indigenous populations living in Alaska. This research was part of a larger study that explored qualitatively the perceptions of Alaska Native university students from rural communities regarding suicide. This analysis explored the resilience that arose from participants' experiences of traditional ways, including subsistence activities. Previous research has indicated the importance of traditional ways in preventing suicide and strengthening communities. METHOD: Semi-structured interviews were conducted with 25 university students who had migrated to Fairbanks, Alaska, from rural Alaskan communities. An interview protocol was developed in collaboration with cultural and community advisors. Interviews were audio-recorded and transcribed. Participants were asked specific questions concerning the strengthening of traditional practices towards the prevention of suicide. Transcripts were analysed using the techniques of grounded theory. FINDINGS: Participants identified several resilience factors against suicide, including traditional practices and subsistence activities, meaningful community involvement and an active lifestyle. Traditional practices and subsistence activities were perceived to create the context for important relationships, promote healthy living to prevent suicide, contrast with current challenges and transmit important cultural values. Participants considered the strengthening of these traditional ways as important in suicide prevention efforts. However, subsistence and traditional practices were viewed as a diminishing aspect of daily living in rural Alaska. CONCLUSIONS: Many college students from rural Alaska have been affected by suicide but are strong enough to cope with such tragic events. Subsistence living and traditional practices were perceived as important social and cultural processes with meaningful lifelong benefits for participants. Future research should continue to explore the ways in which traditional practices can contribute towards suicide prevention, as well as the far-reaching benefits of subsistence living. PMID- 23984290 TI - An examination of the social determinants of health as factors related to health, healing and prevention of foetal alcohol spectrum disorder in a northern context- the Brightening Our Home Fires Project, Northwest Territories, Canada. AB - OBJECTIVE: The Brightening Our Home Fires (BOHF) project was conceptualized as an exploratory project to examine the issue of the prevention of foetal alcohol spectrum disorder (FASD) from a women's health perspective in the Northwest Territories (NT). While dominant discourse suggests that FASD is preventable by abstention from alcohol during pregnancy, a broader perspective would indicate that alcohol and pregnancy is a far more complex issue, that is, bound in location, economics, social and cultural views of health. This project was prevention focused and a social determinant of health (SDH) perspective informed this research. METHODS: The BOHF project was a qualitative research project using a participatory action research framework to examine women's health and healing in the north. The methodology utilized was Photovoice. Women were provided training in digital photography and given cameras to use and keep. The primary research question utilized was: What does health and healing look like for you in your community? Women described their photos, individually or in groups around this central topic. This research was FASD informed, and women participants were aware this was an FASD prevention funded project whose approach focused on a broader context of health and lived experience. RESULTS: This project drew 30 participants from: Yellowknife, Lutsel 'ke, Behchoko and Ulukhaktok. These four different communities across the NT represented Dene and Inuit culture. The qualitative data analysis offered themes of importance to women's health in the north including: land and tradition; housing; poverty; food; family; health, mental health and trauma, and travel. Photovoice provides a non-threatening way to engage in dialogue on complex health and social issues. PMID- 23984289 TI - Prevalence and risk factors of caregiver reported Severe Early Childhood Caries in Manitoba First Nations children: results from the RHS Phase 2 (2008-2010). AB - OBJECTIVES: The high prevalence and severity of caries among Canadian First Nations children is a growing concern. Dental surgery in hospital is often necessary to treat the signs of decay but does not address the underlying factors contributing to its development. The purpose of this study was to determine the prevalence and risk factors of caregiver-reported Baby Bottle Tooth Decay (BBTD), or Severe Early Childhood Caries (S-ECC), among preschool children recruited in Phase 2 of the First Nations Regional Longitudinal Health Survey (RHS). STUDY DESIGN: Cross-sectional study including interviews with caregivers. METHODS: This study was limited to data from Manitoba First Nations participating in the RHS Phase 2 (2008-10). Data were restricted to caregiver interviews for their child < 72 months of age. The main variable of interest was caregiver-reported BBTD, an antecedent term for S-ECC. Data analysis included descriptive statistics and bivariate analyses; p <= 0.05 was significant. RESULTS: Overall, caregivers of 431 preschool children responded. According to caregiver reports, 102/410 (24.9%) children had S-ECC. Further, 65.0% responded that their child had already undergone treatment for caries. Children with S-ECC were significantly older than those without. S-ECC was also associated with paternal education levels and employment status, and maternal smoking during pregnancy. Breastfed children were less likely to have S-ECC, while consuming drink crystal beverages in bottles, and daily intake of soft drinks, juice, sweets and fast food were associated with increased risk. Those who reported that healthcare services were not available and were not culturally appropriate were significantly more likely to have children with S-ECC. CONCLUSIONS: Caregiver reports suggest that nearly 1 in every 4 children has been affected by S-ECC. Identified risk factors for Manitoba First Nations children included age, education and employment, dietary practices, access to care, and disruption to family and culture. This local evidence can be used to help inform future caries prevention activities in these Manitoba communities. PMID- 23984291 TI - The nature of nursing practice in rural and remote areas of Greenland. AB - BACKGROUND: The Greenlandic Healthcare Reform (2010) required improved quality of services for health promotion, prevention of infectious and lifestyle diseases, family nursing and evidence-based clinical nursing. AIM: To investigate current nursing practice in Greenland and to identify whether it meets the requirements of healthcare reform. DESIGN: This ethnographic study utilised documentary analysis, participant observation and qualitative interviewing carried out in remote areas of Greenland during 2011-2012. Eight registered nurses, four women and four men, aged between 35 and 55, participated in this study. Four were working at healthcare centres in towns and four were working at nursing stations in villages. The nurses were educated in Greenland or a Nordic country and had been practicing nursing for at least 2 years in an Arctic region. They were observed for 1-5 days, and subsequently interviewed. Interviews included in-depth questioning, based on emerging outcomes from observation. Interviews were recorded and transcribed; they were analysed within a phenomenological hermeneutic approach. RESULTS: Nurses in rural and remote areas navigate their health promotion and preventive work with conflict between health strategies and everyday realities, where unpredictable tasks often lead to prioritisation of urgent, acute work. There is interaction between personal and professional skills. Everyday life is characterised by opportunities and challenges in the grey areas, namely nursing, medical and social work. CONCLUSION: The nature of nursing practice in rural and remote Greenland is characterised by a high degree of variability and complexity, with a requirement for a wide range of knowledge and skills. Nurses need to be better prepared with regard to acute medical care, preventive care, social work, humanistic approaches and information technology to implement the ideology of health strategies. PMID- 23984292 TI - The use of remote presence for health care delivery in a northern Inuit community: a feasibility study. AB - OBJECTIVE: To evaluate the feasibility of remote presence for improving the health of residents in a remote northern Inuit community. STUDY DESIGN: A pilot study assessed patient's, nurse's and physician's satisfaction with and the use of the remote presence technology aiding delivery of health care to a remote community. A preliminary cost analysis of this technology was also performed. METHODS: This study deployed a remote presence RP-7 robot to the isolated Inuit community of Nain, Newfoundland and Labrador for 15 months. The RP-7 is wirelessly controlled by a laptop computer equipped with audiovisual capability and a joystick to maneuver the robot in real time to aid in the assessing and care of patients from a distant location. Qualitative data on physician's, patient's, caregiver's and staff's satisfaction were collected as well as information on its use and characteristics and the number of air transports required to the referral center and associated costs. RESULTS: A total of 252 remote presence sessions occurred during the study period, with 89% of the sessions involving direct patient assessment or monitoring. Air transport was required in only 40% of the cases that would have been otherwise transported normally. Patients and their caregivers, nurses and physicians all expressed a high level of satisfaction with the remote presence technology and deemed it beneficial for improved patient care, workloads and job satisfaction. CONCLUSIONS: These results show the feasibility of deploying a remote presence robot in a distant northern community and a high degree of satisfaction with the technology. Remote presence in the Canadian North has potential for delivering a cost-effective health care solution to underserviced communities reducing the need for the transport of patients and caregivers to distant referral centers. PMID- 23984293 TI - Animal source food intake and association with blood cholesterol, glycerophospholipids and sphingolipids in a northern Swedish population. AB - BACKGROUND: The high intake of game meat in populations with a subsistence-based diet may affect their blood lipids and health status. OBJECTIVE: To examine the association between diet and circulating levels of blood lipid levels in a northern Swedish population. STUDY DESIGN: We compared a group with traditional lifestyle (TLS) based on reindeer herding (TLS group) with those from the same area with a non-traditional lifestyle (NTLS) typical of more industrialized regions of Sweden (NTLS group). The analysis was based on self-reported intake of animal source food (i.e. non-game meat, game meat, fish, dairy products and eggs) and the serum blood level of a number of lipids [total cholesterol (TC), low density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglycerides (TG), glycerophospholipids and sphingolipids]. RESULTS: The TLS group had higher cholesterol, LDL and HDL levels than the reference group. Of the TLS group, 65% had cholesterol levels above the threshold for increased risk of coronary heart disease (>= 240 mg/dl), as compared to 38% of the NTLS group. Self-reported consumption of game meat was positively associated with TC and LDL. CONCLUSIONS: The high game meat consumption of the TLS group is associated with increased cholesterol levels. High intake of animal protein and fat and low fibre is known to increase the risk of cardiovascular disease, but other studies of the TLS in northern Sweden have shown comparable incidences of cardiovascular disease to the reference (NTLS) group from the same geographical area. This indicates that factors other than TC influence disease risk. One such possible factor is dietary phospholipids, which are also found in high amounts specifically in game meat and have been shown to inhibit cholesterol absorption. PMID- 23984294 TI - Prevalence of postpartum depression in Nuuk, Greenland--a cross-sectional study using Edinburgh Postnatal Depression Scale. AB - OBJECTIVE: The aim of this study is to estimate the prevalence of postnatal depression in Nuuk, Greenland. STUDY DESIGN: Cross-sectional study. METHODS: The primary health care system in Nuuk initiated a project aiming to screen new mothers for depression using the Edinburgh Postnatal Depression Scale (EPDS). EPDS has a range on a scale from 0 to 30. All mothers residing in Nuuk who had given birth in 2011 were included in the study group. The screening was performed by health care visitors approximately 3 months following birth. Mothers who scored 13 points or above were defined as having possible postpartum depression (PPD). These mothers were then referred to a physician. A score at or less than 8 was defined as normal, whereas an intermediate score from 9 to 12 indicated a need for an extra visit. RESULTS: During 2011, a total of 217 mothers gave birth in Nuuk. Of them, 80.2% (174) were screened for PPD using EPDS. Fifteen mothers scored 13 points or above corresponding to a prevalence of possible PPD at 8.6% (15/174). Seventy-nine percentage scored less than 9 points (137/174), whereas 15% (22/174) scored from 9 to 12 points. CONCLUSION: PPD seems to be a common problem in Nuuk, Greenland. EPDS seems to be a valuable tool in identifying women with PPD and vulnerable mothers with extra needs for support in a Greenlandic context. Continual routine screening is recommended. PMID- 23984295 TI - Immunological parameters and gene polymorphisms (C-590T IL4, C-597A IL10) in severe bronchial asthma in children from the Krasnoyarsk region, West Siberia. AB - BACKGROUND: Bronchial asthma is a common disease caused by interplay between multiple determinants, including genetic and immune variations. OBJECTIVE: To investigate the main indices of humoral and cellular branches of immunity, features of cytokine regulation and cytokine genes in children with atopic bronchial asthma (BA) with different levels of disease control. DESIGN: Fifty children with controlled BA (CBA) and 50 with uncontrolled BA (UBA) were analyzed. Mean age in the sample was 13.36 +/- 2.24 years. A control group of healthy children (n = 50) was also studied. All individuals were Russians (Eastern Slavs) from the Krasnoyarsk Territory, West Siberia. Diagnoses, severity and level of disease control were defined according to the Global Initiative for Asthma (GINA) recommendations. The lymphocytes were counted in blood using fluorescent microscopy. Humoral branch indices and cytokine levels (IL-2, IL-4, IL-10 and TNF-alpha) in blood serum were measured by ELISA. Genotyping of single nucleotide polymorphism (SNP) in -590 position of the IL4 and -597 position of the IL10 gene was performed by restriction fragment length analysis. RESULTS: No statistically significant differences in total IgE and cytokines blood levels were found in CBA and UBA. However, significant differences between the groups were found for CD(3+), CD(4+) and CD(8+) cell counts. The T-590 allele of the IL4 gene, which is responsible for an increased serum level of IL-4, showed a tendency to an association with UBA. A decreased level of IL-10 enhances control over BA, which proves its association with the allelic variant A-597 IL10. CONCLUSION: Our data show that children with UBA have higher counts of CD(3+) cells and an increase of sub-population of CD(4+)-cells as well as higher levels of IgE, IL-4 and TNF-alpha in blood serum as compared to CBA. Polymorphisms of the IL4 and IL10 genes are associated with allergic inflammation in UBA. PMID- 23984296 TI - The polar bear in the room: diseases of poverty in the Arctic. AB - In the face of global warming, budgetary austerity and impoverished Arctic residents, the nations of the circumpolar region are presented with a number of difficult choices regarding the provision of health care to the far-flung and isolated regions of their northernmost provinces. Complicating that picture is the reality of neglected tropical diseases in areas far from their perceived normal equatorial range as well as endemic food-borne diseases, including protozoan and helminth parasites, respiratory and gastrointestinal diseases and vaccine-preventable illnesses. This paper discusses the problems of caring for the health and well-being of indigenous populations suffering from extreme poverty, isolation and discrimination in the circumpolar region. After presenting difficulties as supported by the extant literature, the paper continues by suggesting solutions that include novel telenursing applications, targeted distance-educational programs and local community-based health care assistant (HCA) vocational training. These programs will provide cost-effective care that increases life-spans, improves quality of life and provides opportunities to distressed populations in isolated rural communities of the Far North. The toolkit presented in the paper is intended to spur discussion on community health programs that could be adopted to provide proper and humane care for marginalized Arctic populations in an extreme and rapidly changing environment. PMID- 23984297 TI - Risk communication and trust in decision-maker action: a case study of the Giant Mine Remediation Plan. AB - BACKGROUND: The development and implementation of a remediation plan for the residual arsenic trioxide stored at the former Giant Mine site in the Canadian Northwest Territories has raised important issues related to trust. Social and individual trust of those responsible for making decisions on risks is critically important in community judgements on risk and the acceptability of risk management decisions. Trust is known to be affected by value similarity and confidence in past performance, which serve as interacting sources of cooperation in acting toward a common goal. OBJECTIVE: To explore the elements of trust associated with the development and implementation of the Giant Mine Remediation Plan. DESIGN: Semi-structured interviews were conducted with eight purposively selected key informants representing both various interested and affected parties and the two government proponents. RESULTS: Five primary issues related to trust were identified by the participants: (1) a historical legacy of mistrust between the community (particularly Aboriginal peoples) and government; (2) barriers to building trust with the federal government; (3) limited community input and control over the decision-making process; (4) the conflicted and confounded role of the government agencies being both proponent and regulator, and the resulting need for independent oversight; and (5) distrust of the government to commit to the perpetual care required for the remediation option selected. CONCLUSIONS: The dual-mode model of trust and confidence was shown to be a useful framework for understanding the pivotal role of trust in the development of the Giant Mine Remediation Plan. Failure to recognize issues of trust based on value dissimilarity and lack of confidence based on past performance have resulted in a lack of cooperation characterized by delayed remediation and a prolonged and expensive consultation process. Government recognition of the importance of trust to these issues will hopefully improve future communication and public engagement endeavours. PMID- 23984298 TI - Addressing historic environmental exposures along the Alaska Highway. AB - BACKGROUND: A World War II defense site at Northway, Alaska, was remediated in the 1990s, leaving complex questions regarding historic exposures to toxic waste. This article describes the context, methods, limitations and findings of the Northway Wild Food and Health Project (NWFHP). OBJECTIVE: The NWFHP comprised 2 pilot studies: the Northway Wild Food Study (NWFS), which investigated contaminants in locally prioritized traditional foods over time, and the Northway Health Study (NHS), which investigated locally suspected links between resource uses and health problems. DESIGN: This research employed mixed methods. The NWFS reviewed remedial documents and existing data. The NHS collected household information regarding resource uses and health conditions by questionnaire and interview. NHS data represent general (yes or no) personal knowledge that was often second hand. Retrospective cohort comparisons were made of the reported prevalence of 7 general health problems between groups based on their reported (yes or no) consumption of particular resources, for 3 data sets (existing, historic and combined) with a two-tailed Fisher's Exact Test in SAS (n = 325 individuals in 83 households, 24 of which no longer exist). RESULTS: The NWFS identified historic pathways of exposure to petroleum, pesticides, herbicides, chlorinated byproducts of disinfection and lead from resources that were consumed more frequently decades ago and are not retrospectively quantifiable. The NHS found complex patterns of association between reported resource uses and cancer and thyroid-, reproductive-, metabolic- and cardiac problems. CONCLUSION: Lack of detail regarding medical conditions, undocumented histories of exposure, time lapsed since the release of pollution and changes to health and health care over the same period make this exploratory research. Rather than demonstrate causation, these results document the legitimacy of local suspicions and warrant additional investigation. This article presents our findings, with discussion of limitations related to study design and limitations that are inherent to such research. PMID- 23984299 TI - Chlamydia screening practices among physicians and community nurses in Yukon, Canada. AB - BACKGROUND: Yukon, a territory in northern Canada, has one of the highest reported sexually transmitted chlamydia infection rates in the country. OBJECTIVE: We examined screening practices among physicians and community nurses to elucidate factors that may be contributing to the high rates. DESIGN: Cross sectional survey. METHODS: A questionnaire was distributed to all physicians in Yukon and all community nurses in Yukon's communities. We surveyed sexual health assessment frequency, chlamydia testing frequency and barriers to screening. Comparison of physician testing practices was performed to another Canadian jurisdiction, which previously undertook a similar survey. Survey results were compared to the available laboratory data in Yukon. RESULTS: Eligible physicians and nurses, 79% and 77%, respectively, participated in the survey. Physicians tested 15 to 24-year-old females more frequently than 15 to 24-year-old males for chlamydia (p = 0.007). Physicians who asked sexual health assessment questions were more likely to test for chlamydia in both females (p < 0.001) and males (p = 0.032). More physicians screened females based on risk factors compared to males. General practice physicians in Yukon were more likely to test females for chlamydia than general practice physicians in Toronto, Canada (p < 0.001). Community nurses had different testing patterns than physicians, with a lower overall frequency of testing, equal frequency of testing males and females, and in applying risk factor-based screening to both males and females. Barriers to screening included testing causing patient discomfort, patients reluctant to discuss screening, health provider uncomfortable conducting sexually transmitted infection tests and sexual health assessments, among others. Laboratory data in Yukon appear to confirm provider screening patterns. CONCLUSIONS: This survey provides valuable information on health provider screening patterns. We have some evidence which suggests that chlamydia testing rates may be higher among patients seen by physicians in Yukon in comparison to another Canadian jurisdiction. However, more consistent application of optimal screening methods with support to "start the conversation" around sexual health may assist in overcoming barriers to screening and in addressing Yukon's high rate of chlamydia. PMID- 23984300 TI - The future of successful aging in Alaska. AB - BACKGROUND: There is a paucity of research on Alaska Natives and their views on whether or not they believe they will age successfully in their home and community. There is limited understanding of aging experiences across generations. OBJECTIVE: This research explores the concept of successful aging from an urban Alaska Native perspective and explores whether or not they believe they will achieve a healthy older age. DESIGN: A cultural consensus model (CCM) approach was used to gain a sense of the cultural understandings of aging among young Alaska Natives aged 50 years and younger. RESULTS: Research findings indicate that aging successfully is making the conscious decision to live a clean and healthy life, abstaining from drugs and alcohol, but some of Alaska Natives do not feel they will age well due to lifestyle factors. Alaska Natives see the inability to age well as primarily due to the decrease in physical activity, lack of availability of subsistence foods and activities, and the difficulty of living a balanced life in urban settings. CONCLUSIONS: This research seeks to inform future studies on successful aging that incorporates the experiences and wisdom of Alaska Natives in hopes of developing an awareness of the importance of practicing a healthy lifestyle and developing guidelines to assist others to age well. PMID- 23984301 TI - The peculiarities of food allergies in accordance with the level of injury of respiratory tract in children of Eastern Siberia. AB - AIM: To determine the course of food allergy in accordance with the level of respiratory tract injury in children of Eastern Siberia. DESIGN OF THE RESEARCH: We have examined 70 children aged 2-16 , who have food sensibilization. We divided them into 2 groups: group I (n = 32) with diseases of the upper and middle respiratory tract; and group II (n = 38) with diseases of the lower respiratory tract. METHODS: Allergological medical history, clinical laboratory examination and immunological examination, including the determination of IgA, IgM, IgG and IgE in blood serum. In cases where causal allergens were found, elimination diets were recommended. RESULTS: Onset of upper respiratory tract injury in group I was more often registered in children aged 0-1; in group II, it was in the 3-7 age group. Isolated food sensibilization was more often marked in group I as compared to group II. Atopic mechanisms of respiratory tract injuries were more often registered in group II children. In the course of the elimination diet, we marked positive dynamics in 100% of group I and in 75% of group II. CONCLUSION: The most frequent allergens that cause respiratory forms of food allergy are hen eggs, cow milk, nutritive cereals, vegetables and fruit. Indices of a humoral link of immunity in the examined patients were more often registered as normal or their level is increased. Timely etiotropic therapy in the majority of cases allows for a stabilization of allergic inflammation. PMID- 23984302 TI - "What makes life good?" Developing a culturally grounded quality of life measure for Alaska Native college students. AB - BACKGROUND: Alaska Native (AN) college students experience higher attrition rates than their non-Native peers. Understanding the factors that contribute to quality of life ("what makes life good") for AN students will help inform supportive programs that are congruent with their culture and college life experiences. OBJECTIVES: Co-develop a conceptual model and a measure of quality of life (QOL) that reflects the experiences of AN college students. METHODS: Six focus groups were conducted with 26 AN college students. Within a community-academic partnership, interactive data collection activities, co-analysis workgroup sessions and an interactive findings forum ensured a participant-driven research process. FINDINGS: Students identified and operationally defined eight QOL domains (values, culture and traditions, spirituality, relationships, basic needs, health, learning and leisure). The metaphor of a tree visually illustrates how the domains values, culture and traditions and spirituality form the roots to the other domains that appear to branch out as students navigate the dual worldviews of Native and Western ways of living. CONCLUSIONS: The eight QOL domains and their items identified during focus groups were integrated into a visual model and an objective QOL measure. The hope is to provide a useful tool for developing and evaluating university-based programs and services aimed toward promoting a positive QOL and academic success for AN students. PMID- 23984303 TI - The RISC research project: injury in First Nations communities in British Columbia, Canada. AB - BACKGROUND: The project, Injury in British Columbia's Aboriginal Communities: Building Capacity while Developing Knowledge, funded by the Canadian Institutes of Health Research (CIHR), aims to expand knowledge on injury rates among First Nations communities in British Columbia (BC), Canada. OBJECTIVE: The purpose is to improve understanding of community differences and to identify community-level risk and protective factors. Generally, injury incidence rates in the Aboriginal population in Canada greatly exceed those found in the non-Aboriginal population; however, variability exists between Aboriginal communities, which have important implications for prevention. DESIGN: This study uses administrative records of deaths, hospitalizations, ambulatory care episodes, and workers' compensation claims due to injuries to identify communities that have been especially successful in maintaining low rates of injury. RESULTS: The analysis of risk and protective factors extends the work of Chandler and Lalonde who observed that community efforts to preserve and promote Aboriginal culture and to maintain local control over community life are strongly associated with lower suicide rates. CONCLUSION: The discussion on psychological and cultural considerations on healing and reducing the rates of injury expands the work of McCormick on substance use in Aboriginal communities. PMID- 23984304 TI - Preliminary analysis of immune activation in early onset type 2 diabetes. AB - INTRODUCTION: First Nations and other Aboriginal children are disproportionately affected by cardiometabolic diseases, including type 2 diabetes (T2D). In T2D, the disruption of insulin signalling can be driven by pro-inflammatory immunity. Pro-inflammatory responses can be fueled by toll-like receptors (TLR) on immune cells such as peripheral blood mononuclear cells (PBMC, a white blood cell population). TLR4 can bind to lipids from bacteria and food sources activating PBMC to produce cytokines tumour necrosis factor (TNF)-alpha and interleukin (IL) 1beta. These cytokines can interfere with insulin signalling. Here, we seek to understand how TLR4 activation may be involved in early onset T2D. We hypothesized that immune cells from youth with T2D (n = 8) would be more reactive upon TLR4 stimulation relative to cells from age and body mass index (BMI) matched controls without T2D (n = 8). METHODS: Serum samples were assayed for adipokines (adiponectin and leptin), as well as cytokines. Freshly isolated PBMC were examined for immune reactivity upon culture with TLR4 ligands bacterial lipopolysaccharide (LPS, 2 and 0.2 ng/ml) and the fatty acid palmitate (200 uM). Culture supernatants were evaluated for the amount of TNF-alpha and IL-1beta produced by PBMC. RESULTS: Youth with T2D displayed lower median serum adiponectin levels compared to controls (395 vs. 904 ng/ml, p < 0.05). PBMC isolated from youth with and without T2D produced similar levels of TNF-alpha and IL-1beta after exposure to the higher LPS concentration. However, at the low LPS dose the T2D cohort exhibited enhanced IL-1beta synthesis relative to the control cohort. Additionally, exposure to palmitate resulted in greater IL-1beta synthesis in PBMCs isolated from youth with T2D versus controls (p < 0.05). These differences in cytokine production corresponded to greater monocyte activation in the T2D cohort. CONCLUSION: These preliminary results suggest that cellular immune responses are exaggerated in T2D, particularly with respect to IL-1beta activity. These studies aim to improve the understanding of the biology behind early onset T2D and its vascular complications that burden First Nations people. PMID- 23984305 TI - Circumpolar Inuit health systems. AB - BACKGROUND: The Inuit are an indigenous people totalling about 160,000 and living in 4 countries across the Arctic - Canada, Greenland, USA (Alaska) and Russia (Chukotka). In essence, they are one people living in 4 countries. Although there have been significant improvements in Inuit health and survival over the past 50 years, stark differences persist between the key health indicators for Inuit and those of the national populations in the United States, Canada and Russia and between Greenland and Denmark. On average, life expectancy in all 4 countries is lower for Inuit. Infant mortality rates are also markedly different with up to 3 times more infant deaths than the broader national average. Underlying these statistical differences are a range of health, social, economic and environmental factors which have affected Inuit health outcomes. Although the health challenges confronting the Inuit are in many cases similar across the Arctic, the responses to these challenges vary in accordance with the types of health systems in place in each of the 4 countries. Each of the 4 countries has a different health care system with varying degrees of accessibility and affordability for Inuit living in urban, rural and remote areas. OBJECTIVE: To describe funding and governance arrangements for health services to Inuit in Canada, Greenland, USA (Alaska) and Russia (Chukotka) and to determine if a particular national system leads to better outcomes than any of the other 3 systems. STUDY DESIGN: Literature review. RESULTS: It was not possible to draw linkages between the different characteristics of the respective health systems, the corresponding financial investment and the systems' effectiveness in adequately serving Inuit health needs for several reasons including the very limited and inadequate collection of Inuit-specific health data by Canada, Alaska and Russia; and second, the data that are available do not necessarily provide a feasible point of comparison in terms of methodology and timing of the available data collection. CONCLUSIONS: Despite the variations in the health systems as well as national, political and economic approaches, none is adequately addressing Inuit health needs. All Inuit populations still have significant gaps between their health status and those of broader national populations. Meaningful measurement and evaluation of the effectiveness of the respective health systems is severely hindered by the lack of relevant, Inuit-specific health data. The inadequacy, and in a number of cases absence of relevant data, hinders the design and development of a better and potentially more effective approach to delivering health services to Inuit. PMID- 23984306 TI - Alaska Dental Health Aide Program. AB - BACKGROUND: In 1999, An Oral Health Survey of American Indian and Alaska Native (AI/AN) Dental Patients found that 79% of 2- to 5-year-olds had a history of tooth decay. The Alaska Native Tribal Health Consortium in collaboration with Alaska's Tribal Health Organizations (THO) developed a new and diverse dental workforce model to address AI/AN oral health disparities. OBJECTIVES: This paper describes the workforce model and some experience to date of the Dental Health Aide (DHA) Initiative that was introduced under the federally sanctioned Community Health Aide Program in Alaska. These new dental team members work with THO dentists and hygienists to provide education, prevention and basic restorative services in a culturally appropriate manner. RESULTS: The DHA Initiative introduced 4 new dental provider types to Alaska: the Primary Dental Health Aide, the Expanded Function Dental Health Aide, the Dental Health Aide Hygienist and the Dental Health Aide Therapist. The scope of practice between the 4 different DHA providers varies vastly along with the required training and education requirements. DHAs are certified, not licensed, providers. Recertification occurs every 2 years and requires the completion of 24 hours of continuing education and continual competency evaluation. CONCLUSIONS: Dental Health Aides provide evidence-based prevention programs and dental care that improve access to oral health care and help address well-documented oral health disparities. PMID- 23984307 TI - Collaborating toward improving food security in Nunavut. AB - BACKGROUND: Community members, Aboriginal organizations, public servants and academics have long been describing a desperate situation of food insecurity in the Eastern Canadian Arctic. OBJECTIVE: The Nunavut Food Security Coalition, a partnership of Inuit Organizations and the Government of Nunavut, is collaborating to develop a territorial food security strategy to address pervasive food insecurity in the context of poverty reduction. DESIGN: The Nunavut Food Security Coalition has carried out this work using a community consultation model. The research was collected through community visits, stakeholder consultation and member checking at the Nunavut Food Security Symposium. RESULTS: In this paper, we describe a continuous course of action, based on community engagement and collective action, that has led to sustained political interest in and public mobilization around the issue of food insecurity in Nunavut. CONCLUSIONS: The process described in this article is a unique collaboration between multiple organizations that has led to the development of a sustainable partnership that will inform policy development while representing the voice of Nunavummiut. PMID- 23984308 TI - Improving the state of health hardware in Australian Indigenous housing: building more houses is not the only answer. AB - BACKGROUND: This article outlines a program of applied research and development known as Housing for Health that, over the period 1999-2012, targeted health related improvements in housing for Indigenous householders in communities across regional and remote Australia. In essence, the program focuses on measuring the functionality of key appliances and structures (we term this "health hardware") against clear criteria and ensuring identified faults are fixed. METHODS: Detailed survey and assessment of all aspects of housing was undertaken, particularly focusing on the function of health hardware. All results were entered into a database and analyzed. RESULTS: The results demonstrate extremely poor initial performance of the health hardware. A key finding is that attention to maintenance of existing houses can be a cost-effective means of improving health outcomes and also suggests the need to superintend the health-conferring qualities of new infrastructure. We briefly outline the early foundations of the Housing for Health program, major findings from data gathered before and after improvements to household amenities, and our efforts to translate these findings into broader policy. CONCLUSIONS: These data demonstrate that simply injecting funds into housing construction is not sufficient for gaining maximum health benefit. PMID- 23984309 TI - Pharmaceutical health care and Inuit language communications in Nunavut, Canada. AB - BACKGROUND: Pharmaceutical communication is an essential component of pharmaceutical health care, optimally ensuring patients understand the proper administration and side effects of their medications. Communication can often be complicated by language and culture, but with pharmaceuticals, misunderstandings can prove particularly harmful. In Nunavut, to ensure the preservation and revitalization of Inuit languages, the Inuit Language Protection Act and Official Languages Act were passed requiring that all public and private sector essential services offer verbal and written communication in Inuit languages (Inuktitut and Inuinnaqtun) by 2012. METHODS: While the legislation mandates compliance, policy implementation for pharmaceutical services is problematic. Not a single pharmacist in Nunavut is fluent in either of the Inuit languages. Pharmacists have indicated challenges in formally translating written documentation into Inuit languages based on concerns for patient safety. These challenges of negotiating the joint requirements of language legislation and patient safety have resulted in pharmacies using verbal on-site translation as a tenuous solution regardless of its many limitations. RESULTS: The complex issues of pharmaceutical health care and communication among the Inuit of Nunavut are best examined through multimethod research to encompass a wide range of perspectives. This methodology combines the richness of ethnographic data, the targeted depth of interviews with key informants and the breadth of cross-Canada policy and financial analyses. CONCLUSIONS: The analysis of this information would provide valuable insights into the current relationships between health care providers, pharmacists and Inuit patients and suggest future directions for policy that will improve the efficacy of pharmaceuticals and health care spending for the Inuit in Canada. PMID- 23984310 TI - Comparative analysis of context-dependent mutagenesis in humans and fruit flies. AB - In general, mutation frequencies are context-dependent: specific adjacent nucleotides may influence the probability to observe a specific type of mutation in a genome. Recently, several hypermutable motifs were identified in the human genome. Namely, there is an increased frequency of T>C mutations in the second position of the words ATTG and ATAG and an increased frequency of A>C mutations in the first position of the word ACAA. Previous studies have also shown that there is a remarkable difference between the mutagenesis of humans and drosophila. While C>T mutations are overrepresented in the CG context in humans (and other vertebrates), this mutation regularity is not observed in Drosophila melanogaster. Such differences in the observed regularities of mutagenesis between representatives of different taxa might reflect differences in the mechanisms involved in mutagenesis. We performed a systematical comparison of mutation regularities within 2-4 bp contexts in Homo sapiens and Drosophila melanogaster and found that the aforementioned contexts are not hypermutable in fruit flies. It seems that most mutation contexts affect mutation rates in a similar manner in H. sapiens and D. melanogaster; however, several important exceptions are noted and discussed. PMID- 23984311 TI - Comparative study of genome divergence in salmonids with various rates of genetic isolation. AB - The aim of the study is a comparative investigation of changes that certain genome parts undergo during speciation. The research was focused on divergence of coding and noncoding sequences in different groups of salmonid fishes of the Salmonidae (Salmo, Parasalmo, Oncorhynchus, and Salvelinus genera) and the Coregonidae families under different levels of reproductive isolation. Two basic approaches were used: (1) PCR-RAPD with a 20-22 nt primer design with subsequent cloning and sequencing of the products and (2) a modified endonuclease restriction analysis. The restriction fragments were shown with sequencing to represent satellite DNA. Effects of speciation are found in repetitive sequences. The revelation of expressed sequences in the majority of the employed anonymous loci allows for assuming the adaptive selection during allopatric speciation in isolated char forms. PMID- 23984312 TI - Cardiovascular and renal effects of bromocriptine in diabetic patients with stage 4 chronic kidney disease. AB - OBJECTIVE: The objective of this study was to investigate the effect of bromocriptine (BEC) on left ventricular mass index (LVMI) and residual renal function (RRF) in chronic kidney disease (CKD) patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A 6-month double-blind randomized controlled trial was conducted in 28 patients with T2D and stage 4 CKD with increased LVMI. Fourteen patients received BEC (2.5 mg, initially 1 tablet with subsequent increase to three times a day) and 14 received a placebo (PBO; initially 1 tablet with subsequent increase to three times a day). Cardiovascular changes were assessed by monitoring 24 h ambulatory blood pressure, two-dimensional-guided M mode echocardiography, and N-terminal brain natriuretic peptide (NT-proBNP) plasma levels. RRF was evaluated by creatinine clearance and cystatin-C plasma levels. RESULTS: Both BEC and PBO groups decreased blood pressure-but the effect was more pronounced in the BEC group. Average 24 h, diurnal and nocturnal blood pressures, and circadian profile showed improved values compared to the PBO group; LVMI decreased by 14% in BEC and increased by 8% in PBO group. NT-proBNP decreased in BEC (0.54 +/- 0.15 to 0.32 +/- 0.17 pg/mL) and increased in PBO (0.37 +/- 0.15 to 0.64 +/- 0.17 pg/mL). Creatinine clearance did not change in the BEC group and decreased in the PBO group. CONCLUSIONS: BEC resulted in a decrease on blood pressure and LVMI. BEC also prevented the progression of CKD while maintaining the creatinine clearance unchanged. PMID- 23984313 TI - An attempted substitute study of total skin electron therapy technique by using helical photon tomotherapy with helical irradiation of the total skin treatment: a phantom result. AB - An anthropomorphic phantom was used to investigate a treatment technique and analyze the dose distributions for helical irradiation of the total skin (HITS) by helical tomotherapy (HT). Hypothetical bolus of thicknesses of 0, 10, and 15 mm was added around the phantom body to account for the dose homogeneity and setup uncertainty. A central core structure was assigned as a "complete block" to force the dose tangential delivery. HITS technique with prescribed dose (D p ) of 36 Gy in 36 fractions was generated. The radiochromic EBT2 films were used for the dose measurements. The target region with 95.0% of the D p received by more than 95% of the PTV was obtained. The calculated mean doses for the organs at risk (OARs) were 4.69, 3.10, 3.20, and 2.94 Gy for the lung, heart, liver, and kidneys, respectively. The measurement doses on a phantom surface for a plan with 10 mm hypothetical bolus and bolus thicknesses of 0, 1, 2, and 3 mm are 89.5%, 111.4%, 116.9%, and 117.7% of D p , respectively. HITS can provide an accurate and uniform treatment dose in the skin with limited doses to OARs and is safe to replace a total skin electron beam regimen. PMID- 23984315 TI - Biodistribution of amikacin solid lipid nanoparticles after pulmonary delivery. AB - The main purpose of the present work was studying the biodistribution of amikacin solid lipid nanoparticles (SLNs) after pulmonary delivery to increase its concentration in the lungs for treatment of cystic fibrosis lung infections and also providing a new method for clinical application of amikacin. To achieve this aim, (99m)Tc labelled amikacin was loaded in cholesterol SLNs and after in vitro optimization, the desired SLNs and free drug were administered through pulmonary and i.v. routes to male rats and qualitative and biodistribution studies were done. Results showed that pulmonary delivery of SLNs of amikacin by microsprayer caused higher drug concentration in lungs than kidneys while i.v. administration of free drug caused reverse conditions. It seems that pulmonary delivery of SLNs may improve patients' compliance due to reduction of drug side effects in kidneys and elongation of drug dosing intervals due to the sustained drug release from SLNs. PMID- 23984316 TI - Association study of single nucleotide polymorphisms in XRCC1 gene with risk of hepatocellular carcinoma in Chinese Han population. AB - Hepatocellular carcinoma (HCC) is one of the most frequently causing cancer related deaths worldwide. Previous evidence suggests that the X-ray repair cross complementing group 1 gene (XRCC1) is an important candidate gene for influencing the risk of HCC. The aim of this study was to assess the association of XRCC1 genetic polymorphisms with the risk of HCC in Chinese Han population. A total of 1314 subjects, including 651 HCC patients and 663 healthy controls, were enrolled in this case-control study. Two genetic variants (c.1254C>T and c.1517G>C) in XRCC1 gene were genotyped by created restriction site-polymerase chain reaction (CRS-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. Our data indicated that the allele and genotype frequencies of these two genetic variants were statistical difference in HCC cases and healthy controls. Association analyses suggested that these two genetic variants were statistically associated with the increased risk of HCC in all genetic models (for c.1254C>T, TT versus CC: OR = 2.30, 95% CI 1.61-3.28; CT versus CC: OR = 1.32, 95% CI 1.05 1.67; TT/CT versus CC: OR = 1.50, 95% CI 1.20-1.86; TT versus CT/CC: OR = 2.00, 95% CI 1.43-2.80; T versus C: OR = 1.47, 95% CI 1.25-1.73; for c.1517G>C, CC versus GG: OR = 1.90, 95% CI 1.34-2.69; GC versus GG: OR = 1.56, 95% CI 1.24 1.97; CC/GC versus GG: OR = 1.63, 95% CI 1.31-2.03; CC versus GC/GG: OR = 1.52, 95% CI 1.10-2.11; C versus G: OR = 1.45, 95% CI 1.23-1.70). The allele-T of c.1254C>T and allele-C of c.1517G>C genetic variants may contribute to HCC susceptibility in Chinese Han population. PMID- 23984314 TI - Celiac disease and autoimmune-associated conditions. AB - Celiac disease (CD) is frequently accompanied by a variety of extradigestive manifestations, thus making it a systemic disease rather than a disease limited to the gastrointestinal tract. This is primarily explained by the fact that CD belongs to the group of autoimmune diseases. The only one with a known etiology is related to a permanent intolerance to gluten. Remarkable breakthroughs have been achieved in the last decades, due to a greater interest in the diagnosis of atypical and asymptomatic patients, which are more frequent in adults. The known presence of several associated diseases provides guidance in the search of oligosymptomatic cases as well as studies performed in relatives of patients with CD. The causes for the onset and manifestation of associated diseases are diverse; some share a similar genetic base, like type 1 diabetes mellitus (T1D); others share pathogenic mechanisms, and yet, others are of unknown nature. General practitioners and other specialists must remember that CD may debut with extraintestinal manifestations, and associated illnesses may appear both at the time of diagnosis and throughout the evolution of the disease. The implementation of a gluten-free diet (GFD) improves the overall clinical course and influences the evolution of the associated diseases. In some cases, such as iron deficiency anemia, the GFD contributes to its disappearance. In other disorders, like T1D, this allows a better control of the disease. In several other complications and/or associated diseases, an adequate adherence to a GFD may slow down their evolution, especially if implemented during an early stage. PMID- 23984317 TI - Ursodeoxycholic acid improves bilirubin but not albumin in primary biliary cirrhosis: further evidence for nonefficacy. AB - BACKGROUND/AIM: In randomised controlled trials (RCTs) of ursodeoxycholic acid (UDCA), although serum bilirubin is frequently reduced, its effect on disease progression and mortality is unclear. As serum albumin is an established independent prognostic marker, one might expect less deterioration of serum albumin values in a UDCA-treated group. We therefore modelled the typical evolution of serum bilirubin and albumin levels over time in UDCA-untreated patients and compared it with the observed levels in UDCA RCTs. METHODS: Multilevel modelling was used to relate the evolution of serum albumin to serum bilirubin and time since patient referral. For each considered RCT, the derived model was used to predict the relationship between final mean serum albumin and bilirubin concentration, adjusted for mean serum albumin at referral and followup duration. RESULTS: Five RCTs were eligible in terms of available data, of which two had long followup. In all trials, serum albumin did not significantly differ between UDCA- and placebo-treated patients, despite the UDCA effect on serum bilirubin. Therefore, there is no evidence over time for changes or maintenance of albumin levels for UDCA-treated patients above the levels predicted for placebo-treated patients. CONCLUSIONS: Our findings suggest that UDCA does not alter serum albumin in a way that is consistent with its effect on serum bilirubin. Therefore, reductions in serum bilirubin of UDCA-treated PBC do not parallel another validated and independent prognostic marker, further questioning the validity of serum bilirubin reduction with UDCA as a surrogate therapeutic marker. PMID- 23984318 TI - Transmission model of hepatitis B virus with the migration effect. AB - Hepatitis B is a globally infectious disease. Mathematical modeling of HBV transmission is an interesting research area. In this paper, we present characteristics of HBV virus transmission in the form of a mathematical model. We analyzed the effect of immigrants in the model to study the effect of immigrants for the host population. We added the following flow parameters: "the transmission between migrated and exposed class" and "the transmission between migrated and acute class." With these new features, we obtained a compartment model of six differential equations. First, we find the basic threshold quantity Ro and then find the local asymptotic stability of disease-free equilibrium and endemic equilibrium. Furthermore, we find the global stability of the disease free and endemic equilibria. Previous similar publications have not added the kind of information about the numerical results of the model. In our case, from numerical simulation, a detailed discussion of the parameters and their numerical results is presented. We claim that with these assumptions and by adding the migrated class, the model informs policy for governments, to be aware of the immigrants and subject them to tests about the disease status. Immigrants for short visits and students should be subjected to tests to reduce the number of immigrants with disease. PMID- 23984319 TI - The effect of Msh2 knockdown on toxicity induced by tert-butyl-hydroperoxide, potassium bromate, and hydrogen peroxide in base excision repair proficient and deficient cells. AB - The DNA mismatch repair (MMR) and base excision repair (BER) systems are important determinants of cellular toxicity following exposure to agents that cause oxidative DNA damage. To examine the interactions between these different repair systems, we examined whether toxicity, induced by t-BOOH and KBrO3, differs in BER proficient (Mpg (+/+), Nth1 (+/+)) and deficient (Mpg (-/-), Nth1 (-/-)) mouse embryonic fibroblasts (MEFs) following Msh2 knockdown of between 79 and 88% using an shRNA expression vector. Msh2 knockdown in Nth1 (+/+) cells had no effect on t-BOOH and KBrO3 induced toxicity as assessed by an MTT assay; knockdown in Nth1 (-/-) cells resulted in increased resistance to t-BOOH and KBrO3, a result consistent with Nth1 removing oxidised pyrimidines. Msh2 knockdown in Mpg (+/+) cells had no effect on t-BOOH toxicity but increased resistance to KBrO3; in Mpg (-/-) cells, Msh2 knockdown increased cellular sensitivity to KBrO3 but increased resistance to t-BOOH, suggesting a role for Mpg in removing DNA damage induced by these agents. MSH2 dependent and independent pathways then determine cellular toxicity induced by oxidising agents. A complex interaction between MMR and BER repair systems, that is, exposure dependent, also exists to determine cellular toxicity. PMID- 23984321 TI - New morphological features for grading pancreatic ductal adenocarcinomas. AB - Pathological diagnosis is influenced by subjective factors such as the individual experience and knowledge of doctors. Therefore, it may be interpreted in different ways for the same symptoms. The appearance of digital pathology has created good foundation for objective diagnoses based on quantitative feature analysis. Recently, numerous studies are being done to develop automated diagnosis based on the digital pathology. But there are as of yet no general automated methods for pathological diagnosis due to its specific nature. Therefore, specific methods according to a type of disease and a lesion could be designed. This study proposes quantitative features that are designed to diagnose pancreatic ductal adenocarcinomas. In the diagnosis of pancreatic ductal adenocarcinomas, the region of interest is a duct that consists of lumen and epithelium. Therefore, we first segment the lumen and epithelial nuclei from a tissue image. Then, we extract the specific features to diagnose the pancreatic ductal adenocarcinoma from the segmented objects. The experiment evaluated the classification performance of the SVM learned by the proposed features. The results showed an accuracy of 94.38% in the experiment distinguishing between pancreatic ductal adenocarcinomas and normal tissue and a classification accuracy of 77.03% distinguishing between the stages of pancreatic ductal adenocarcinomas. PMID- 23984320 TI - Biomedical applications of fermenticin HV6b isolated from Lactobacillus fermentum HV6b MTCC10770. AB - Fermenticin HV6b is a class IIa antimicrobial peptide produced by Lactobacillus fermentum HV6b MTCC 10770 isolated from human vaginal ecosystem. It shows growth inhibition of a wide range of opportunistic pathogens of humans, for example, Bacteroides, Gardnerella vaginalis, Mobiluncus, Staphylococci, and Streptococci, associated with bacterial vaginosis in humans. It does possess an impressive sperm immobilization and spermicidal activity tested against human sperms which makes it an attractive proposition for formulating antibacterial vaginosis and contraceptive products. Apart from this, in vitro studies conducted against four different tissue models have indicated its potential to be used as a component of anticancerous drug therapy as it is reported to induce apoptosis in cancerous cells. This information could be integrated in future studies focusing on in vivo assessment of anticancerous activity of lactic acid bacterial toxins or bacteriocins. PMID- 23984322 TI - Enhancement of phosphate absorption by garden plants by genetic engineering: a new tool for phytoremediation. AB - Although phosphorus is an essential factor for proper plant growth in natural environments, an excess of phosphate in water sources causes serious pollution. In this paper we describe transgenic plants which hyperaccumulate inorganic phosphate (Pi) and which may be used to reduce environmental water pollution by phytoremediation. AtPHR1, a transcription factor for a key regulator of the Pi starvation response in Arabidopsis thaliana, was overexpressed in the ornamental garden plants Torenia, Petunia, and Verbena. The transgenic plants showed hyperaccumulation of Pi in leaves and accelerated Pi absorption rates from hydroponic solutions. Large-scale hydroponic experiments indicated that the enhanced ability to absorb Pi in transgenic torenia (AtPHR1) was comparable to water hyacinth a plant that though is used for phytoremediation causes overgrowth problems. PMID- 23984324 TI - Expression of bmi-1 in pediatric brain tumors as a new independent prognostic marker of patient survival. AB - Objectives. The B-cell-specific moloney leukemia virus insertion site 1 (the Bmi 1) gene is an important member in the family of polycomb group (PcG) genes that plays an oncogenic role in several types of cancer, but it's expression as a prognostic marker in pediatric brain tumors has not been indicated. Materials and Methods. The Bmi-1 gene expression, clinic pathological and prognostic significance in a series of pediatric brain tumors were examined by real-time PCR method in 56 pediatric brain tumors. Results. The Bmi-1 gene expression in various types of pediatric brain tumors compared to that in normal brain tissue was 4.85-fold. The relative expression varied from 8.64-fold in ependymomas to 2.89-fold in other types. Expression level in high-grade tumors compared to that in low-grade tumors was 2.5 times. In univariate survival analysis of the pediatric brain tumors, a significant association of high expression of the Bmi-1 with patient survival was demonstrated. In multivariate analysis, the Bmi-1 high expression provided significant independent prognostic factors. Conclusion. Increased expression of the Bmi-1 in pediatric brain tumors may be important in the acquisition of an aggressive phenotype. In addition, it can be used as a strong and independent molecular marker of prognosis in pediatric brain tumors. PMID- 23984323 TI - Long-term nitric oxide exposure enhances lung cancer cell migration. AB - Nitric oxide (NO) found in the vicinity of lung cancer cells may play a role in the regulation of cancer cell behaviors. To explore the possible effects of NO on cell motility, human lung cancer cells were exposed to nontoxic concentrations of NO for 0-14 days, and the migratory characteristics of the cells were determined. The present study found that long-term treatment with NO significantly enhanced cell migration in a dose- and time-dependent manner. Furthermore, we found that the increased migratory action was associated with the increased expression of caveolin-1 (Cav-1), which in turn activated the focal adhesion kinase (FAK) and ATP-dependent tyrosine kinase (Akt) pathways. Notably, the NO-treated cells exhibited an increased number of filopodia per cell, as well as an increase in the levels of cell division cycle 42 (Cdc42) protein. Together, these results indicate that extended NO exposure has a novel effect on cell migration through a Cav-1-dependent mechanism, a finding that strengthens our understanding of cancer biology. PMID- 23984325 TI - beta -Glucosidases from the fungus trichoderma: an efficient cellulase machinery in biotechnological applications. AB - beta-glucosidases catalyze the selective cleavage of glucosidic linkages and are an important class of enzymes having significant prospects in industrial biotechnology. These are classified in family 1 and family 3 of glycosyl hydrolase family. beta-glucosidases, particularly from the fungus Trichoderma, are widely recognized and used for the saccharification of cellulosic biomass for biofuel production. With the rising trends in energy crisis and depletion of fossil fuels, alternative strategies for renewable energy sources need to be developed. However, the major limitation accounts for low production of beta glucosidases by the hyper secretory strains of Trichoderma. In accordance with the increasing significance of beta-glucosidases in commercial applications, the present review provides a detailed insight of the enzyme family, their classification, structural parameters, properties, and studies at the genomics and proteomics levels. Furthermore, the paper discusses the enhancement strategies employed for their utilization in biofuel generation. Therefore, beta glucosidases are prospective toolbox in bioethanol production, and in the near future, it might be successful in meeting the requirements of alternative renewable sources of energy. PMID- 23984326 TI - Hematological disorders following gastric bypass surgery: emerging concepts of the interplay between nutritional deficiency and inflammation. AB - Obesity and the associated metabolic syndrome are among the most common and detrimental metabolic diseases of the modern era, affecting over 50% of the adult population in the United States. Surgeries designed to promote weight loss, known as bariatric surgery, typically involve a gastric bypass procedure and have shown high success rates for treating morbid obesity. However, following gastric bypass surgery, many patients develop chronic anemia, most commonly due to iron deficiency. Deficiencies of vitamins B1, B12, folate, A, K, D, and E and copper have also been reported after surgery. Copper deficiency can cause hematological abnormalities with or without neurological complications. Despite oral supplementation and normal serum concentrations of iron, copper, folate, and vitamin B12, some patients present with persistent anemia after surgery. The evaluation of hematologic disorders after gastric bypass surgery must take into account issues unique to the postsurgery setting that influence the development of anemia and other cytopenias. In this paper, the clinical characteristics and differential diagnosis of the hematological disorders associated with gastric bypass surgery are reviewed, and the underlying molecular mechanisms are discussed. PMID- 23984327 TI - Metabolite profile resulting from the activation/inactivation of 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine and 2-methyltetrahydro-beta-carboline by oxidative enzymes. AB - Metabolic enzymes are involved in the activation/deactivation of the 1-methyl-4 phenyl-1,2,3,6-tetrahydropyiridine (MPTP) neurotoxin and its naturally occurring analogs 2-methyltetrahydro-beta-carbolines. The metabolic profile and biotransformation of these protoxins by three enzymes, monoamine oxidase (MAO), cytochrome P450, and heme peroxidases (myeloperoxidase and lactoperoxidase), were investigated and compared. The metabolite profile differed among the enzymes investigated. MAO and heme peroxidases activated these substances to toxic pyridinium and beta-carbolinium species. MAO catalyzed the oxidation of MPTP to 1 methyl-4-phenyl-2,3-dihydropyridinium cation (MPDP(+)), whereas heme peroxidases catalyzed the oxidation of MPDP(+) to 1-methyl-4-phenylpyridinium (MPP(+)) and of 2-methyltetrahydro-beta-carboline to 2-methyl-3,4-dihydro-beta-carbolinium cation (2-Me-3,4-DH beta C(+)). These substances were inactivated by cytochrome P450 2D6 through N-demethylation and aromatic hydroxylation (MPTP) and aromatic hydroxylation (2-methyltetrahydro-beta-carboline). In conclusion, the toxicological effects of these protoxins might result from a balance between the rate of their activation to toxic products (i.e., N-methylpyridinium-MPP(+) and MPDP(+)- and N-methyl--beta--carbolinium- betaC(+)-) by MAO and heme peroxidases and the rate of inactivation (i.e., N-demethylation, aromatic hydroxylation) by cytochrome P450 2D6. PMID- 23984329 TI - Fitness and adiposity are independently associated with cardiometabolic risk in youth. AB - PURPOSE: The purpose of the study was to examine the independent associations of adiposity and cardiorespiratory fitness with clustered cardiometabolic risk. METHODS: A cross-sectional sample of 192 adolescents (118 boys), aged 14-16 years, was recruited from a South Lanarkshire school in the West of Scotland. Anthropometry and blood pressure were measured, and blood samples were taken. The 20 m multistage fitness test was the indicator of cardiorespiratory fitness (CRF). A clustered cardiometabolic risk score was constructed from HDL-C (inverted), LDL-C, HOMA, systolic blood pressure, and triglycerides. Interleukin 6, C-reactive protein, and adiponectin were also measured and examined relative to the clustered cardiometabolic risk score, CRF, and adiposity. RESULTS: Although significant, partial correlations between BMI and waist circumference (WC) and both CRF and adiponectin were negative and weak to moderate, while correlations between the BMI and WC and CRP were positive but weak to moderate. Weak to moderate negative associations were also evident for adiponectin with CRP, IL-6, and clustered cardiometabolic risk. WC was positively associated while CRF was negatively associated with clustered cardiometabolic risk. With the additional adjustment for either WC or CRF, the independent associations with cardiometabolic risk persisted. CONCLUSION: WC and CRF are independently associated with clustered cardiometabolic risk in Scottish adolescents. PMID- 23984330 TI - Efficiency of barley bran and oat bran in ameliorating blood lipid profile and the adverse histological changes in hypercholesterolemic male rats. AB - The efficiency of oat bran and barley bran in lowering the induced hyperlipidemia and hypercholesterolemia in blood of male Albino rats (Rattus rattus) was studied. Twenty rats were divided into four groups each consisted of five rats and fed the specified test diets for eight weeks. The first group (G1) is the negative group which was fed basal diet, the second group (G2) was fed 1.0% cholesterol, was the third group (G3) fed 1.0% cholesterol and 10% oats bran, and the fourth group (G4) was fed 1.0% cholesterol and 10% barley bran. Feeding rats on 1% cholesterol significantly increased serum total cholesterol, low density lipoprotein, and very low density lipoprotein and triglyceride and decreased serum high density lipoprotein. Furthermore, enzyme activity of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase was increased, and lipid peroxide was increased, whereas catalase and glutathione-S transferase were decreased. Kidney functions parameters in the cholesterol supplemented group were elevated compared with the negative control. In addition, histological alteration in kidney, liver, heart, and testes was observed, compared with the negative control. Hypercholesterolemic rats supplemented with oat bran and barley bran showed significant decrease in lipid parameters, significant increase in high density lipoprotein-cholesterol, improved antioxidant enzyme, and improved histopathology of kidney, liver, heart, and testes. In conclusion, both oat bran and barley bran had protective effects against induced hyperlipidemia and improved histological alterations. Oat bran appeared more efficient than barley bran in lowering the lipid profile levels in hypercholesterolemic rats. PMID- 23984328 TI - Genetics of Alzheimer's disease. AB - Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease. PMID- 23984332 TI - Relationship between pulsatility index and clinical course of acute ischemic stroke after thrombolytic treatment. AB - Background. The relationship between the arterial recanalization after intravenous recombinant tissue plasminogen activator (rtPA) and outcomes is still uncertain. The aim of our study was to evaluate whether there is an association between the pulsatility indexes (PI) of the middle cerebral artery (MCA) measured by transcranial Doppler (TCD) after iv rtPA treatment and short- and long-term outcomes in ischemic stroke patients. Methods. Forty-eight patients with acute ischemia in the MCA territory who achieved complete recanalization after the administration of intravenous thrombolytic treatment were included in the study. The TCD was applied to patients after the iv rtPA treatment. Clinical and functional outcomes were assessed by National Institutes of Health Stroke Scale (NIHSS) scores and modified Rankin Scores (mRS), respectively. Results. Significant positive correlations were found between the PI value and NIHSS score at 24 hours, NIHSS score at 3 months, and mRS at 3 months (P < 0.005 for all). The cut-off value for PI in predicting a favorable prognosis and a good prognosis might be less than or equal to 1.1 and less than or equal to 1.4, respectively. Conclusions. PI may play a role in predicting the functional and clinical outcome after thrombolytic therapy in acute ischemic stroke patients. PMID- 23984331 TI - A novel framework for the identification and analysis of duplicons between human and chimpanzee. AB - Human and other primate genomes consist of many segmental duplications (SDs) due to fixation of copy number variations (CNVs). Structure of these duplications within the human genome has been shown to be a complex mosaic composed of juxtaposed subunits (called duplicons). These duplicons are difficult to be uncovered from the mosaic repeat structure. In addition, the distribution and evolution of duplicons among primates are still poorly investigated. In this paper, we develop a statistical framework for discovering duplicons via integration of a Hidden Markov Model (HMM) and a permutation test. Our comparative analysis indicates that the mosaic structure of duplicons is common in CNV/SD regions of both human and chimpanzee genomes, and a subset of core duplicons is shared by the majority of CNVs/SDs. Phylogenetic analyses using duplicons suggested that most CNVs/SDs share common duplication ancestry. Many human/chimpanzee duplicons flank both ends of CNVs, which may be hotspots of nonallelic homologous recombination. PMID- 23984333 TI - Immunoinformatic docking approach for the analysis of KIR3DL1/HLA-B interaction. AB - KIR3DL1 is among the most interesting receptors studied, within the killer immunoglobulin receptor (KIR) family. Human leukocyte antigen (HLA) class I Bw4 epitope inhibits strongly Natural Killer (NK) cell's activity through interaction with KIR3DL1 receptor, while Bw6 generally does not. This interaction has been indicated to play an important role in the immune control of different viral infectious diseases. However, the structural interaction between the KIR3DL1 receptor and different HLA-B alleles has been scarcely studied. To understand the complexity of KIR3DL1-HLA-B interaction, HLA-B alleles carrying Bw4/Bw6 epitope and KIR3DL1*001 allele in presence of different peptides has been evaluated by using a structural immunoinformatic approach. Different energy minimization force fields (ff) have been tested and NOVA ff enables the successful prediction of ligand-receptor interaction. HLA-B alleles carrying Bw4 epitope present the highest capability of interaction with KIR3DL1*001 compared to the HLA-B alleles presenting Bw6. The presence of the epitope Bw4 determines a conformational change which leads to a stronger interaction between nonpolymorphic arginine at position 79 of HLA-B and KIR3DL1*001 136-142 loop. The data shed new light on the modalities of KIR3DL1 interaction with HLA-B alleles essential for the modulation of NK immune-mediated response. PMID- 23984334 TI - MicroRNA-mediated regulation in biological systems with oscillatory behavior. AB - As a class of small noncoding RNAs, microRNAs (miRNAs) regulate stability or translation of mRNA transcripts. Some reports bring new insights into possible roles of microRNAs in modulating cell cycle. In this paper, we focus on the mechanism and effectiveness of microRNA-mediated regulation in the cell cycle. We first describe two specific regulatory circuits that incorporate base-pairing microRNAs and show their fine-tuning roles in the modulation of periodic behavior. Furthermore, we analyze the effects of miR369-3 on the modulation of the cell cycle, confirming that miR369-3 plays a role in shortening the period of the cell cycle. These results are consistent with experimental observations. PMID- 23984336 TI - INF- alpha and ototoxicity. AB - INTRODUCTION: INF- alpha is a common drug for the treatment of hepatitis B and C. Although a variety of related complications are discussed, possible ototoxic effects of this mediation are not well described. METHODS AND MATERIALS: In a before-after control study, 24 patients who received INF- alpha for the treatment of hepatitis B and C and 30 normal controls were included. Subjective and objective ototoxicity evaluations via questionnaire, high frequency audiometry, and measuring transiently evoked otoacoustic emissions (TEOAEs) were performed one week before and one month after the prescription of the drug. Results. Subjective hearing complaint, tinnitus, and vertigo were seen in just 3 cases, which was not statistically significant (P = 0.083). In the frequency range of 4000 to 8000 Hz before (9.38 +/- 1.0 and 10.7 +/- 1.2, resp.) and after (17.9 +/- 2.6 and 17.6 +/- 2.6, resp.) one month of treatment, a significant difference (P = 0.083) was detected. Progressive decreases in amplitude of the OAE during TEOAE measurement in 1, 2, and 4 frequencies among 41.66%, 18.75 %, and 43.75% were observed, respectively. The hearing loss was seen more among older and male cases significantly. Conclusion. The results showed ototoxicity of INF- alpha that may encourage planning hearing monitoring in patients receiving this drug. PMID- 23984337 TI - Antigenicity and immunogenicity of rotavirus VP6 protein expressed on the surface of Lactococcus lactis. AB - Group A rotaviruses are the major etiologic agents of acute gastroenteritis worldwide in children and young animals. Among its structural proteins, VP6 is the most immunogenic and is highly conserved within this group. Lactococcus lactis is a food-grade, Gram-positive, and nonpathogenic lactic acid bacteria that has already been explored as a mucosal delivery system of heterologous antigens. In this work, the nisin-controlled expression system was used to display the VP6 protein at the cell surface of L. lactis. Conditions for optimal gene expression were established by testing different nisin concentrations, cell density at induction, and incubation times after induction. Cytoplasmic and cell wall protein extracts were analyzed by Western blot and surface expression was confirmed by flow cytometry. Both analysis provided evidence that VP6 was efficiently expressed and displayed on the cell surface of L. lactis. Furthermore, the humoral response of mice immunized with recombinant L. lactis was evaluated and the displayed recombinant VP6 protein proved to be immunogenic. In conclusion, this is the first report of displaying VP6 protein on the surface of L. lactis to induce a specific immune response against rotavirus. These results provide the basis for further evaluation of this VP6-displaying L. lactis as a mucosal delivery vector in a mouse model of rotavirus infection. PMID- 23984335 TI - IL-17 in the rheumatologist's line of sight. AB - Over the past decades, the identification of several new cytokines, including interleukin (IL)-17 and IL-23, and of new T helper cell subsets, including Th17 cells, has changed the vision of immunological processes. The IL-17/Th17 pathway plays a critical role during the development of inflammation and autoimmunity, and targeting this pathway has become an attractive strategy for a number of diseases. This review aims to describe the effects of IL-17 in the joint and its roles in the development of autoimmune and inflammatory arthritis. Furthermore, biotherapies targeting directly or indirectly IL-17 in inflammatory rheumatisms will be developed. PMID- 23984338 TI - Membrane localization of membrane type 1 matrix metalloproteinase by CD44 regulates the activation of pro-matrix metalloproteinase 9 in osteoclasts. AB - CD44, MT1-MMP, and MMP9 are implicated in the migration of osteoclast and bone resorption. This study was designed to determine the functional relationship between CD44 and MT1-MMP in the activation of pro-MMP9. We used osteoclasts isolated from wild-type and CD44-null mice. Results showed that MT1-MMP is present in multiple forms with a molecular mass ~63, 55, and 45 kDa in the membrane of wild-type osteoclasts. CD44-null osteoclasts demonstrated a 55 kDa active MT1-MMP form in the membrane and conditioned medium. It failed to activate pro-MMP9 because TIMP2 binds and inhibits this MT1-MMP (~55 kDa) in CD44-null osteoclasts. The role of MT1-MMP in the activation of pro-MMP9, CD44 expression, and migration was confirmed by knockdown of MT1-MMP in wild-type osteoclasts. Although knockdown of MMP9 suppressed osteoclast migration, it had no effects on MT1-MMP activity or CD44 expression. These results suggest that CD44 and MT1-MMP are directly or indirectly involved in the regulation of pro-MMP9 activation. Surface expression of CD44, membrane localization of MT1-MMP, and activation of pro-MMP9 are the necessary sequence of events in osteoclast migration. PMID- 23984339 TI - The influence of no-primer adhesives and anchor pylons bracket bases on shear bond strength of orthodontic brackets. AB - OBJECTIVE: The aim of this study was to compare the shear bond strength (SBS) and adhesive remnant index (ARI) scores of no-primer adhesives tested with two different bracket bases. MATERIALS AND METHODS: 120 bovine permanent mandibular incisors were divided into 6 groups of 20 specimens. Two brackets (ODP) with different bracket bases (anchor pylons and 80-gauge mesh) were bonded to the teeth using a conventional adhesive (Transbond XT) and two different no-primer adhesive (Ortho Cem; Heliosit) systems. Groups were tested using an instron universal testing machine. SBS values were recorded. ARI scores were measured. SEM microphotographs were taken to evaluate the pattern of bracket bases. Statistical analysis was performed. ANOVA and Tukey tests were carried out for SBS values, whereas a chi-squared test was applied for ARI scores. RESULTS: Highest bond strength values were reported with Transbond XT (with both pad designs), Ortho Cem bonded on anchor pylons and Heliosit on 80-gauge mesh. A higher frequency of ARI score of "3" was reported for Transbond XT groups. Other groups showed a higher frequency of ARI score "2" and "1." CONCLUSION: Transbond XT showed the highest shear bond strength values with both pad designs. PMID- 23984340 TI - Therapeutic effect of exendin-4, a long-acting analogue of glucagon-like peptide 1 receptor agonist, on nerve regeneration after the crush nerve injury. AB - Glucagon-like peptide-1 (GLP-1) is glucose-dependent insulinotropic hormone secreted from enteroendocrine L cells. Its long-acting analogue, exendin-4, is equipotent to GLP-1 and is used to treat type 2 diabetes mellitus. In addition, exendin-4 has effects on the central and peripheral nervous system. In this study, we administered repeated intraperitoneal (i.p.) injections of exendin-4 to examine whether exendin-4 is able to facilitate the recovery after the crush nerve injury. Exendin-4 injection was started immediately after crush injury and was repeated every day for subsequent 14 days. Rats subjected to sciatic nerve crush exhibited marked functional loss, electrophysiological dysfunction, and atrophy of the tibialis anterior muscle (TA). All these changes, except for the atrophy of TA, were improved significantly by the administration of exendin-4. Functional, electrophysiological, and morphological parameters indicated significant enhancement of nerve regeneration 4 weeks after nerve crush. These results suggest that exendin-4 is feasible for clinical application to treat peripheral nerve injury. PMID- 23984341 TI - Further evidence of mutational heterogeneity of the XPC gene in Tunisian families: a spectrum of private and ethnic specific mutations. AB - Xeroderma Pigmentosum (XP) is a rare recessive autosomal cancer prone disease, characterized by UV hypersensitivity and early appearance of cutaneous and ocular malignancies. We investigated four unrelated patients suspected to be XP-C. To confirm linkage to XPC gene, genotyping and direct sequencing of XPC gene were performed. Pathogenic effect of novel mutations was confirmed by reverse Transciptase PCR. Mutation screening revealed the presence of two novel mutations g.18246G>A and g.18810G>T in the XPC gene (NG_011763.1). The first is present in one patient XP50NEF, but the second is present in three unrelated patients (XP16KEB, XP28SFA, and XP45GB). These 3 patients are from three different cities of Southern Tunisia and bear the same haplotype, suggesting a founder effect. Reverse Transciptase PCR revealed the absence of the XPC mRNA. In Tunisia, as observed in an other severe genodermatosis, the mutational spectrum of XP-C group seems to be homogeneous with some clusters of heterogeneity that should be taken into account to improve molecular diagnosis of this disease. PMID- 23984342 TI - DHA inhibits protein degradation more efficiently than EPA by regulating the PPARgamma/NFkappaB pathway in C2C12 myotubes. AB - This study was conducted to evaluate the mechanism by which n-3 PUFA regulated the protein degradation in C2C12 myotubes. Compared with the BSA control, EPA at concentrations from 400 to 600 uM decreased total protein degradation (P < 0.01). However, the total protein degradation was decreased when the concentrations of DHA ranged from 300 uM to 700 uM (P < 0.01). DHA (400 uM, 24 h) more efficiently decreased the I kappa B alpha phosphorylation and increased in the I kappa B alpha protein level than 400 uM EPA (P < 0.01). Compared with BSA, 400 uM EPA and DHA resulted in a 47% or 68% induction of the NF kappa B DNA binding activity, respectively (P < 0.01). Meanwhile, 400 uM EPA and DHA resulted in a 1.3-fold and 2.0-fold induction of the PPAR gamma expression, respectively (P < 0.01). In C2C12 myotubes for PPAR gamma knockdown, neither 400 uM EPA nor DHA affected the levels of p-I kappa B alpha , total I kappa B alpha or NF kappa B DNA binding activity compared with BSA (P > 0.05). Interestingly, EPA and DHA both still decreased the total protein degradation, although PPAR gamma knockdown attenuated the suppressive effects of EPA and DHA on the total protein degradation (P < 0.01). These results revealed that DHA inhibits protein degradation more efficiently than EPA by regulating the PPAR gamma /NF- kappa B pathway in C2C12 myotubes. PMID- 23984343 TI - The efficacy of allergen immunotherapy with cat dander in reducing symptoms in clinical practice. AB - BACKGROUND: Allergy to cat dander is a common form of allergic disease. Allergen immunotherapy has been demonstrated to be effective in decreasing allergic symptoms. OBJECTIVES: To examine outcomes in allergic asthmatic patients on cat immunotherapy (CIT) compared to allergic asthmatics on traditional immunotherapy (IT) without cat sensitivity. METHODS: A retrospective review identified allergic asthmatics on CIT for at least three years. An equal number of allergic asthmatics on IT were identified for comparison. Outcomes investigated include measurements of risk of asthma exacerbation. RESULTS: Thirty-five patients were identified in each group. There were no differences in the CIT group versus the comparison group regarding total number of prednisone tapers (18 tapers versus 14 tapers, resp.), number of patients requiring prednisone tapers (10 patients versus 10 patients, resp.), total number of acute visits (29 visits versus 38 visits, resp.), and number of patients requiring acute visits (15 patients versus 21 patients, resp.). When stratified by concomitant ICS use, patients on CIT were less likely to require an acute visit (46% versus 78%, resp.). CONCLUSIONS: Allergic asthmatics with cat sensitivity on CIT with close dander exposure have similar risk of asthma exacerbation compared to allergic asthmatics without cat sensitivity on immunotherapy. PMID- 23984344 TI - A two-tube multiplex reverse transcription PCR assay for simultaneous detection of sixteen human respiratory virus types/subtypes. AB - There is a need for the development of a rapid and sensitive diagnosis of respiratory viral pathogens. With an intended application in provincial Centers for Diseases Control and Prevention, in this study, we present a two-tube multiplex RT-PCR assay (two-tube assay) using automatic electrophoresis to simultaneously detect sixteen common respiratory viruses. The specificity and the sensitivity of the assay were tested. The assay could detect 20-200 copies per reaction when each viral type was assayed individually, 2000 copies with 9 premixed viral targets in the multiplexed assay in tube 1, and 200 copies with 8 premixed templates in tube 2. A total of 247 specimens were used to evaluate the two-tube assay, and the results were compared with those obtained from the Luminex xTAG RVP Fast assay. The discordant results were confirmed by sequencing or by the Seeplex RV15 ACE detection kit. There were no false positives, but six false negatives occurred with the two-tube assay. In conclusion, the two-tube assay is demonstrated to have great potential for routine surveillance of respiratory virus infection in China. PMID- 23984345 TI - 1H NMR based targeted metabolite profiling for understanding the complex relationship connecting oxidative stress with endometriosis. AB - Accumulating evidence indicates the active role of oxidative stress in the development of endometriosis; however, the mechanism of reactive oxygen species generation is poorly understood. Metabonomics/metabolomics is a scientific discipline that can be used to study changes in metabolite ensembles associated with disease pathophysiology. The present study focuses on the use of proton nuclear magnetic resonance spectroscopy based targeted metabolite profiling approach to explore dysregulation in metabolites expression in women with endometriosis. Further, association of oxidative stress with the metabolite ensembles, if any, is investigated. Using multivariate statistics, partial least square discriminant analysis model was generated which could classify endometriosis patients with sensitivity and specificity of 92.83% and 100%, respectively, and with a classification rate of 96.4%. In conjunction with increased glucose metabolism, citrate and succinate were found to be elevated in endometriosis patients. Higher levels of reactive oxygen species, lipid peroxidation, and advanced oxidation protein products and lower levels of total antioxidant capacity, superoxide dismutase, catalase, and glutathione were also observed. Increased glucose metabolism and defects in the mitochondrial respiratory system are suggested to be the possible sources of excessive reactive oxygen species generation in endometriosis. PMID- 23984346 TI - Fructation in vivo: detrimental and protective effects of fructose. AB - There is compelling evidence that long-term intake of excessive fructose can have deleterious side effects in different experimental models. However, the role of fructose in vivo remains controversial, since acute temporary application of fructose is found to protect yeast as well as animal tissues against exogenous oxidative stress. This review suggests the involvement of reactive carbonyl and oxygen species in both the cytotoxic and defensive effects of fructose. Potential mechanisms of the generation of reactive species by fructose in the nonenzymatic reactions, their implication in the detrimental and protective effects of fructose are discussed. PMID- 23984347 TI - Spectroscopic studies on unfolding processes of apo-neuroglobin induced by guanidine hydrochloride and urea. AB - Neuroglobin (Ngb), a recently discovered globin, is predominantly expressed in the brain, retina, and other nerve tissues of vertebrates. The unfolding processes of apo-neuroglobin (apoNgb) induced by guanidine hydrochloride (GdnHCl) and urea were investigated by spectroscopic methods. In the unfolding processes, apoNgb's tertiary structural transition was monitored by the changes of intrinsic fluorescence emission spectra, and its secondary structural transition was measured by the changes of far-ultraviolet circular dichroism (CD) spectra. In addition, 8-anilino-1-naphthalenesulfonic acid (ANS), a hydrophobic cluster binding dye, was also used to monitor the unfolding process of apoNgb and to explore its intermediates. Results showed that GdnHCl-induced unfolding of apoNgb was via a three-state pathway, that is, Native state (N) -> Intermediate state (I) -> Unfolded state (U), during which the intermediate was inferred by an increase in fluorescence intensity and the change of CD value. Gibbs free energy changes are 10.2 kJ . mol(-1) for the first unfolding transition and 14.0 kJ . mol(-1) for the second transition. However, urea-induced unfolding of apoNgb only underwent a two-state transition: Native state (N) -> Partially unfolded state (P). The result showed that GdnHCl can efficiently affect the conformational states of apoNgb compared with those of urea. The work will benefit to have an understanding of the unfolding mechanism of apoNgb induced by GdnHCl and urea. PMID- 23984348 TI - The investigation of laparoscopic instrument movement control and learning effect. AB - Laparoscopic surgery avoids large incisions for intra-abdominal operations as required in conventional open surgery. Whereas the patient benefits from laparoscopic techniques, the surgeon encounters new difficulties that were not present during open surgery procedures. However, limited literature has been published in the essential movement characteristics such as magnification, amplitude, and angle. For this reason, the present study aims to investigate the essential movement characteristics of instrument manipulation via Fitts' task and to develop an instrument movement time predicting model. Ten right-handed subjects made discrete Fitts' pointing tasks using a laparoscopic trainer. The experimental results showed that there were significant differences between the three factors in movement time and in throughput. However, no significant differences were observed in the improvement rate for movement time and throughput between these three factors. As expected, the movement time was rather variable and affected markedly by direction to target. The conventional Fitts' law model was extended by incorporating a directional parameter into the model. The extended model was shown to better fit the data than the conventional model. These findings pointed to a design direction for the laparoscopic surgery training program, and the predictive model can be used to establish standards in the training procedure. PMID- 23984349 TI - Preserved transcallosal inhibition to transcranial magnetic stimulation in nondemented elderly patients with leukoaraiosis. AB - Structural corpus callosum (CC) changes in patients with leukoaraiosis (LA) are significantly associated with cognitive and motor impairment. The aim of this study is to investigate the transcallosal fibers functioning by means of transcranial magnetic stimulation (TMS) in elderly patients with LA. The resting motor threshold (rMT), the motor-evoked potentials (MEPs), and the controlateral (cSP) and ipsilateral silent periods (iSP) were determined using single-pulse TMS in 15 patients and 15 age-matched controls. The neuropsychological profile and the vascular burden at brain magnetic resonance imaging (MRI) were concomitantly explored. Patients reported abnormal scores at tests evaluating executive control functions. No significant difference was found in TMS measures of intra- and intercortical excitability. No CC lesion was evident at MRI. Transcallosal inhibitory mechanisms to TMS seem to be spared in LA patients, a finding which is in line with neuroimaging features and suggests a functional integrity of the CC despite the ischemic interruption of corticosubcortical loops implicated in cognition and behavior. The observed neurophysiological finding differs from that reported in degenerative dementia, even in the preclinical or early stage. In our group of patients, the pure extent of LA is more related to impairment of frontal lobe abilities rather than functional callosal changes. PMID- 23984350 TI - Relationship between vitamin D receptor gene polymorphisms and migraine without aura in an Iranian population. AB - BACKGROUND: Inflammation has a key role in migraine pathophysiology. Vitamin D is an effective anti-inflammatory agent. The aim of this study was to investigate the association between migraine and two vitamin D receptor (VDR) polymorphisms (TaqI and FokI) and also the relationship between VDR polymorphisms and headache severity. METHODS: In this case-control study we assessed 103 patients with newly diagnosed migraine without aura and 100 healthy subjects. Patients filled headache impact test-6 (HIT-6) as a tool to assess headache severity. RESULTS: Genotype frequencies of VDR were significantly different between control and migraine patients. Heterozygote genotypes (Ff and Tt) were statistically more frequent in the migraine patients than the control subjects both for TaqI gene (P = 0.018; OR = 1.81, 95% CI = 1.03-3.18) and FokI gene polymorphisms (P = 0.001; OR = 2.91, 95% CI = 1.47-5.77). Also f and t alleles were more frequent in the migraine patients. Total HIT-6 score was significantly different between FokI heterozygote and homozygote patients (60.32 +/- 1.87 versus 49.87 +/- 2.69, resp., P = 0.004). CONCLUSIONS: In conclusion our results showed that TaqI and FokI gene polymorphisms are associated with migraine without aura in Iranians patients. Also headache severity in FokI heterozygote patients was significantly greater than in the homozygote patients. PMID- 23984351 TI - Asymmetry of the active site loop conformation between subunits of glutamate-1 semialdehyde aminomutase in solution. AB - Glutamate-1-semialdehyde aminomutase (GSAM) is a dimeric, pyridoxal 5'-phosphate (PLP)- dependent enzyme catalysing in plants and some bacteria the isomerization of L-glutamate-1-semialdehyde to 5-aminolevulinate, a common precursor of chlorophyll, haem, coenzyme B12, and other tetrapyrrolic compounds. During the catalytic cycle, the coenzyme undergoes conversion from pyridoxamine 5'-phosphate (PMP) to PLP. The entrance of the catalytic site is protected by a loop that is believed to switch from an open to a closed conformation during catalysis. Crystallographic studies indicated that the structure of the mobile loop is related to the form of the cofactor bound to the active site, allowing for asymmetry within the dimer. Since no information on structural and functional asymmetry of the enzyme in solution is available in the literature, we investigated the active site accessibility by determining the cofactor fluorescence quenching of PMP- and PLP-GSAM forms. PLP-GSAM is partially quenched by potassium iodide, suggesting that at least one catalytic site is accessible to the anionic quencher and therefore confirming the asymmetry observed in the crystal structure. Iodide induces release of the cofactor from PMP-GSAM, apparently from only one catalytic site, therefore suggesting an asymmetry also in this form of the enzyme in solution, in contrast with the crystallographic data. PMID- 23984352 TI - Respiratory muscle training in patients recovering recent open cardiothoracic surgery: a randomized-controlled trial. AB - OBJECTIVES: To evaluate the clinical efficacy and feasibility of an expiratory muscle training (EMT) device (Respilift) applied to patients recovering from recent open cardiothoracic surgery (CTS). DESIGN: Prospective, double-blind, 14 day randomised-controlled trial. PARTICIPANTS AND SETTING: A total of 60 inpatients recovering from recent CTS and early admitted to a pulmonary rehabilitation program. Interventions. Chest physiotherapy plus EMT with a resistive load of 30 cm H2O for active group and chest physiotherapy plus EMT with a sham load for control group. MEASURES: Changes in maximal expiratory pressure (MEP) were considered as primary outcome, while maximal inspiratory pressures (MIP), dynamic and static lung volumes, oxygenation, perceived symptoms of dyspnoea, thoracic pain, and well being (evaluated by visual analogic scale VAS) and general health status were considered secondary outcomes. RESULTS: All outcomes recorded showed significant improvements in both groups; however, the change of MEP (+34.2 mmHg, P < 0.001 and +26.1%, P < 0.001 for absolute and % of predicted, resp.) was significantly higher in active group. Also VAS dyspnoea improved faster and more significantly (P < 0.05) at day 12, and 14 in active group when compared with control. The drop-out rate was 6%, without differences between groups. Conclusions. In patients recovering from recent CTS, specific EMT by Respilift is feasible and effective. This trial is registered with ClinicalTrials.gov NCT01510275. PMID- 23984353 TI - Identifying the association rules between clinicopathologic factors and higher survival performance in operation-centric oral cancer patients using the Apriori algorithm. AB - This study computationally determines the contribution of clinicopathologic factors correlated with 5-year survival in oral squamous cell carcinoma (OSCC) patients primarily treated by surgical operation (OP) followed by other treatments. From 2004 to 2010, the program enrolled 493 OSCC patients at the Kaohsiung Medical Hospital University. The clinicopathologic records were retrospectively reviewed and compared for survival analysis. The Apriori algorithm was applied to mine the association rules between these factors and improved survival. Univariate analysis of demographic data showed that grade/differentiation, clinical tumor size, pathology tumor size, and OP grouping were associated with survival longer than 36 months. Using the Apriori algorithm, multivariate correlation analysis identified the factors that coexistently provide good survival rates with higher lift values, such as grade/differentiation = 2, clinical stage group = early, primary site = tongue, and group = OP. Without the OP, the lift values are lower. In conclusion, this hospital-based analysis suggests that early OP and other treatments starting from OP are the key to improving the survival of OSCC patients, especially for early stage tongue cancer with moderate differentiation, having a better survival (>36 months) with varied OP approaches. PMID- 23984354 TI - Dietary intake as a link between obesity, systemic inflammation, and the assumption of multiple cardiovascular and antidiabetic drugs in renal transplant recipients. AB - We evaluated dietary intake and nutritional-inflammation status in ninety-six renal transplant recipients, 7.2 +/- 5.0 years after transplantation. Patients were classified as normoweight (NW), overweight (OW), and obese (OB), if their body mass index was between 18.5 and 24.9, 25.0 and 29.9, and >= 30 kg/m(2), respectively. Food composition tables were used to estimate nutrient intakes. The values obtained were compared with those recommended in current nutritional guidelines. 52% of the patients were NW, 29% were OW, and 19% were OB. Total energy, fat, and dietary n-6 PUFAs intake was higher in OB than in NW. IL-6 and hs-CRP were higher in OB than in NW. The prevalence of multidrug regimen was higher in OB. In all patients, total energy, protein, saturated fatty acids, and sodium intake were higher than guideline recommendations. On the contrary, the intake of unsaturated and n-6 and n-3 polyunsaturated fatty acids and fiber was lower than recommended. In conclusion, the prevalence of obesity was high in our patients, and it was associated with inflammation and the assumption of multiple cardiovascular and antidiabetic drugs. Dietary intake did not meet nutritional recommendations in all patients, especially in obese ones, highlighting the need of a long-term nutritional support in renal transplant recipients. PMID- 23984355 TI - Pinocembrin: a novel natural compound with versatile pharmacological and biological activities. AB - Pinocembrin (5,7-dihydroxyflavanone) is one of the primary flavonoids isolated from the variety of plants, mainly from Pinus heartwood, Eucalyptus, Populus, Euphorbia, and Sparattosperma leucanthum, in the diverse flora and purified by various chromatographic techniques. Pinocembrin is a major flavonoid molecule incorporated as multifunctional in the pharmaceutical industry. Its vast range of pharmacological activities has been well researched including antimicrobial, anti inflammatory, antioxidant, and anticancer activities. In addition, pinocembrin can be used as neuroprotective against cerebral ischemic injury with a wide therapeutic time window, which may be attributed to its antiexcitotoxic effects. Pinocembrin exhibits pharmacological effects on almost all systems, and our aim is to review the pharmacological and therapeutic applications of pinocembrin with specific emphasis on mechanisms of actions. The design of new drugs based on the pharmacological effects of pinocembrin could be beneficial. This review suggests that pinocembrin is a potentially promising pharmacological candidate, but additional studies and clinical trials are required to determine its specific intracellular sites of action and derivative targets in order to fully understand the mechanism of its anti-inflammatory, anticancer, and apoptotic effects to further validate its medical applications. PMID- 23984356 TI - Effect of folic acid and vitamin B12 on pemetrexed antifolate chemotherapy in nutrient lung cancer cells. AB - Pemetrexed (MTA) is a multitargeted antifolate drug approved for lung cancer therapy. Clinically, supplementation with high doses of folic acid (FA) and vitamin B12 (VB12) lowers MTA cytotoxicities. An antagonistic effect of FA/VB12 on MTA efficacy has been proposed. However, patients who receive FA/VB12 show better tolerance to MTA with improved survival. The aims of this study are to investigate the modulation of FA and VB12 on MTA drug efficacy in human nonsmall cell lung cancer (NSCLC) cell lines. The sensitivities of cells, apoptosis, and MTA-regulated proteins were characterized to determine the possible effects of high doses of FA and VB12 on MTA efficacy. MTA has the lowest efficacy under 10% serum conditions. However, supplementation with FA and VB12 individually and additively reversed the insensitivity of NSCLC cells to MTA treatment with 10% serum. The enhanced sensitivities of cells following FA/VB12 treatment were correlated with increasing apoptosis and were specific to MTA but not to 5 fluorouracil (5-FU). Enhanced sensitivity was also associated with p21(WAF1/Cip1) expression level. Our results revealed no antagonistic effect of high doses of FA/VB12 on MTA efficacy in cancer cells grown in nutrient medium. Furthermore, these data may partially explain why supplementation of FA and VB12 resulted in better survival in MTA-treated patients. PMID- 23984357 TI - Development of multiexon skipping antisense oligonucleotide therapy for Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is an incurable, X-linked progressive muscle degenerative disorder that results from the absence of dystrophin protein and leads to premature death in affected individuals due to respiratory and/or cardiac failure typically by age of 30. Very recently the exciting prospect of an effective oligonucleotide therapy has emerged which restores dystrophin protein expression to affected tissues in DMD patients with highly promising data from a series of clinical trials. This therapeutic approach is highly mutation specific and thus is personalised. Therefore DMD has emerged as a model genetic disorder for understanding and overcoming of the challenges of developing personalised genetic medicines. One of the greatest weaknesses of the current oligonucleotide approach is that it is a mutation-specific therapy. To address this limitation, we have recently demonstrated that exons 45-55 skipping therapy has the potential to treat clusters of mutations that cause DMD, which could significantly reduce the number of compounds that would need to be developed in order to successfully treat all DMD patients. Here we discuss and review the latest preclinical work in this area as well as a variety of accompanying issues, including efficacy and potential toxicity of antisense oligonucleotides, prior to human clinical trials. PMID- 23984359 TI - Erlotinib and concurrent chemoradiation in pretreated NSCLC patients: radiobiological basis and clinical results. AB - AIMS: To establish feasibility of the combination of Erlotinib and concurrent chemoradiation in pre-treated patients with locally advanced or metastatic NSCLC. MATERIALS AND METHODS: Data regarding 60 consecutive patients with NSCLC previously treated with chemotherapy alone were prospectically collected. All patients started Erlotinib concurrently with chemotherapy and radiation delivered to primary tumor. These data were retrospectively analyzed (observational study). Feasibility and toxicity were the primary endpoints, with response rate and progression being the secondary ones, while survival data are reported just as exploratory analysis. The EGFR mutational status was recorded in 32% of cases and it was always wild type. RESULTS: Compliance to the combination protocol was good. Grade 3-4 esophagitis and acute lung toxicity occurred in 2% and 8% of patients, respectively. No progressive disease was recorded in the majority of cases (65%). Median OS and PFS were 23.3 and 4.7 months, respectively. Patients not responding to chemotherapy administered prior to chemoradiation achieved an objective response rate of 53.3% and complete response in 13.3% of cases. CONCLUSIONS: The addition of Erlotinib to chemoradiation in inoperable NSCLCs is feasible with interesting efficacy profile. These preliminary results warrant further investigation in patients with locally advanced nonmetastatic NSCLC with EGFR mutations. PMID- 23984358 TI - Neuron-NG2 cell synapses: novel functions for regulating NG2 cell proliferation and differentiation. AB - NG2 cells are a population of CNS cells that are distinct from neurons, mature oligodendrocytes, astrocytes, and microglia. These cells can be identified by their NG2 proteoglycan expression. NG2 cells have a highly branched morphology, with abundant processes radiating from the cell body, and express a complex set of voltage-gated channels, AMPA/kainate, and GABA receptors. Neurons notably form classical and nonclassical synapses with NG2 cells, which have varied characteristics and functions. Neuron-NG2 cell synapses could fine-tune NG2 cell activities, including the NG2 cell cycle, differentiation, migration, and myelination, and may be a novel potential therapeutic target for NG2 cell-related diseases, such as hypoxia-ischemia injury and periventricular leukomalacia. Furthermore, neuron-NG2 cell synapses may be correlated with the plasticity of CNS in adulthood with the synaptic contacts passing onto their progenies during proliferation, and synaptic contacts decrease rapidly upon NG2 cell differentiation. In this review, we highlight the characteristics of classical and nonclassical neuron-NG2 cell synapses, the potential functions, and the fate of synaptic contacts during proliferation and differentiation, with the emphasis on the regulation of the NG2 cell cycle by neuron-NG2 cell synapses and their potential underlying mechanisms. PMID- 23984360 TI - The influence of gene-gene and gene-environment interactions on the risk of asbestosis. AB - This study investigated the influence of gene-gene and gene-environment interactions on the risk of developing asbestosis. The study comprised 262 cases with asbestosis and 265 controls with no asbestos-related disease previously studied for MnSOD, ECSOD, CAT, GSTT1, GSTM1, GSTP1, and iNOS polymorphisms. Data on cumulative asbestos and smoking were available for all subjects. To assess gene-gene and gene-environmental interactions, logistic regression was used. The associations between MnSOD Ala -9Val polymorphism and the risk of asbestosis and between iNOS genotypes and asbestosis were modified by CAT -262 C > T polymorphism (P = 0.038; P = 0.031). A strong interaction was found between GSTM1 null polymorphism and smoking (P = 0.007), iNOS (CCTTT) n polymorphism and smoking (P = 0.054), and between iNOS (CCTTT) n polymorphism and cumulative asbestos exposure (P = 0.037). The findings of this study suggest that the interactions between different genotypes, genotypes and smoking, and between genotypes and asbestos exposure have an important influence on the development of asbestosis and should be seriously considered in future research on occupational/environmental asbestos-related diseases. PMID- 23984361 TI - Enrichment, development, and assessment of Indian basil oil based antiseptic cream formulation utilizing hydrophilic-lipophilic balance approach. AB - The present work was aimed to develop an antiseptic cream formulation of Indian basil oil utilizing hydrophilic-lipophilic balance approach. In order to determine the required-hydrophilic lipophilic balance (rHLB) of basil oil, emulsions of basil oil were prepared by phase inversion temperature technique using water, Tween 80, and Span 80. Formulated emulsions were assessed for creaming (BE9; 9.8, BE10; 10.2), droplet size (BE18; 3.22 +/- 0.09 MU m), and turbidity (BE18; 86.12 +/- 2.1%). To ensure correctness of the applied methodology, rHLB of light liquid paraffin was also determined. After rHLB determination, basil oil creams were prepared with two different combinations of surfactants, namely, GMS : Tween 80 (1 : 3.45) and SLS : GMS (1 : 3.68), and evaluated for in vitro antimicrobial activity, skin irritation test, viscosity and consistency. The rHLB of basil oil and light liquid paraffin were found to be 13.36 +/- 0.36 and 11.5 +/- 0.35, respectively. Viscosity, and consistency parameters of cream was found to be consistent over 90 days. Cream formulations showed net zone of growth inhibition in the range of 5.0-11.3 mm against bacteria and 4.3-7.6 mm against fungi. Primary irritation index was found to be between 0.38 and1.05. Conclusively stable, consistent, non-irritant, enriched antiseptic basil oil cream formulations were developed utilizing HLB approach. PMID- 23984362 TI - Magnetic resonance sialography findings of submandibular ducts imaging. AB - PURPOSE: We aimed to assess the problem solving capability of magnetic resonance sialography (MR sialography), a noninvasive method for imaging submandibular gland ducts and determining duct-related pathologies, by comparing diseased and healthy cases. MATERIALS AND METHODS: We conducted radiological assessment on a total of 60 submandibular glands (mean age 44.7) in 20 cases and 10 volunteers. MR sialography examinations were conducted with single-shot fast spin-echo sequence by using a surface coil placed on the submandibular gland. Each gland was evaluated in terms of the length, width and stricture of the main duct, as well as the difference between the intraparenchymal duct width, and the main duct width. Statistical analysis was performed. RESULTS: In the MR sialography the primary duct mean length was determined as 51 mm (40-57 mm) in all submandibular glands. On the MR sialography imaging, the visualization ratio of the ductal system of submandibular gland was evaluated in the cases and volunteers. CONCLUSION: MR sialography is an effective and a noninvasive method in imaging submandibular gland ducts, demonstrating the presence, location and degree of stricture/dilatation, and elucidating the disease etiology. PMID- 23984363 TI - Development of composite scaffolds for load-bearing segmental bone defects. AB - The need for a suitable tissue-engineered scaffold that can be used to heal load bearing segmental bone defects (SBDs) is both immediate and increasing. During the past 30 years, various ceramic and polymer scaffolds have been investigated for this application. More recently, while composite scaffolds built using a combination of ceramics and polymeric materials are being investigated in a greater number, very few products have progressed from laboratory benchtop studies to preclinical testing in animals. This review is based on an exhaustive literature search of various composite scaffolds designed to serve as bone regenerative therapies. We analyzed the benefits and drawbacks of different composite scaffold manufacturing techniques, the properties of commonly used ceramics and polymers, and the properties of currently investigated synthetic composite grafts. To follow, a comprehensive review of in vivo models used to test composite scaffolds in SBDs is detailed to serve as a guide to design appropriate translational studies and to identify the challenges that need to be overcome in scaffold design for successful translation. This includes selecting the animal type, determining the anatomical location within the animals, choosing the correct study duration, and finally, an overview of scaffold performance assessment. PMID- 23984364 TI - Aorta structural alterations in term neonates: the role of birth and maternal characteristics. AB - AIM: To evaluate the influence of selected maternal and neonatal characteristics on aorta walls in term, appropriately grown-for-gestational age newborns. METHODS: Age, parity, previous abortions, weight, height, body mass index before and after delivery, smoking, and history of hypertension, of diabetes, of cardiovascular diseases, and of dyslipidemia were all assessed in seventy mothers. They delivered 34 males and 36 females healthy term newborns who underwent ultrasound evaluation of the anteroposterior infrarenal abdominal aorta diameter (APAO), biochemical profile (glucose, insulin, total cholesterol, HDL and LDL cholesterol, triglycerides, fibrinogen, and D-dimers homeostasis model assessment [HOMAIR]index), and biometric parameters. RESULTS: APAO was related to newborn length (r = +0.36; P = 0.001), head circumference (r = +0.37; P = 0.001), gestational age (r = +0.40, P = 0.0005), HOMA index (r = +0.24; P = 0.04), and D dimers (r = +0.33, P = 0.004). Smoke influenced APAO values (odds ratio: 1.80; confidence interval 95%: 1.05-3.30), as well as diabetes during pregnancy (r = +0.42, P = 0.0002). Maternal height influenced neonatal APAO (r = +0.47, P = 0.00003). Multiple regression analysis outlined neonatal D-dimers as still significantly related to neonatal APAO values. CONCLUSIONS: Many maternal and neonatal characteristics could influence aorta structures. Neonatal D-dimers are independently related to APAO. PMID- 23984365 TI - Sleep-disordered breathing in patients with heart failure: new trends in therapy. AB - Heart failure (HF) is a growing health problem which paradoxically results from the advances in the treatment of etiologically related diseases (especially coronary artery disease). HF is commonly accompanied by sleep-disordered breathing (SDB), which may directly exacerbate the clinical manifestations of cardiovascular disease and confers a poorer prognosis. Obstructive sleep apnoea predominates in mild forms while central sleep apnoea in more severe forms of heart failure. Identification of SDB in patients with HF is important, as its effective treatment may result in notable clinical benefits to the patients. Continuous positive airway pressure (CPAP) is the gold standard in the management of SDB. The treatments for central breathing disorders include CPAP, bilevel positive airway pressure (BPAP), and adaptive servoventilation (ASV), with the latter being the most modern method of treatment for the Cheyne-Stokes respiration and involving ventilation support with a variable synchronisation dependent on changes in airflow through the respiratory tract and on the patient's respiratory rate. ASV exerts the most favourable effect on long-term prognosis. In this paper, we review the current state of knowledge on the diagnosis and treatment of SDB with a particular emphasis on the latest methods of treatment. PMID- 23984366 TI - Ascorbic acid and BSA protein in solution and films: interaction and surface morphological structure. AB - This paper reports on the study of the interactions between ascorbic acid (AA) and bovine serum albumin (BSA) in aqueous solution as well as in films (BSA/AA films) prepared by the layer-by-layer technique. Regarding to solution studies, a hyperchromism (in the range of ultraviolet) was found as a function of AA concentration, which suggested the formation of aggregates from AA and BSA. Binding constant, K, determined for aggregates from BSA and AA was found to be about 10(2) M(-1), which indicated low affinity of AA with BSA. For the BSA/AA films, it was also noted that the AA adsorption process and surface morphological structures depended on AA concentration. By changing the contact time between the AA and BSA, a hypochromism was revealed, which was associated to decrease of accessibility of solvent to tryptophan due to formation of aggregates. Furthermore, different morphological structures of aggregates were observed, which were attributed to the diffusion-limited aggregation. Since most of studies of interactions of drugs and proteins are performed in solution, the analysis of these processes by using films can be very valuable because this kind of system is able to employ several techniques of investigation in solid state. PMID- 23984367 TI - Preparation, physicochemical characterization, and cell viability evaluation of long-circulating and pH-sensitive liposomes containing ursolic acid. AB - Cancer is one of the leading causes of death worldwide. Although several drugs are used clinically, some tumors either do not respond or are resistant to the existing pharmacotherapy, thus justifying the search for new drugs. Ursolic acid (UA) is a triterpene found in different plant species that has been shown to possess significant antitumor activity. However, UA presents a low solubility in aqueous medium, which presents a barrier to its biological applications. In this context, the use of liposomes presents a promising strategy to deliver UA and allow for its intravenous administration. In this work, long-circulating and pH sensitive liposomes containing UA (SpHL-UA) were developed, and their chemical and physicochemical properties were evaluated. SpHL-UA presented adequate properties, including a mean diameter of 191.1 +/- 6.4 nm, a zeta potential of 1.2 +/- 1.4 mV, and a UA entrapment of 0.77 +/- 0.01 mg/mL. Moreover, this formulation showed a good stability after having been stored for 2 months at 4 degrees C. The viability studies on breast (MDA-MB-231) and prostate (LNCaP) cancer cell lines demonstrated that SpHL-UA treatment significantly inhibited cancer cell proliferation. Therefore, the results of the present work suggest the applicability of SpHL-UA as a new and promising anticancer formulation. PMID- 23984369 TI - Qualitative and quantitative hippocampal MRI assessments in intractable epilepsy. AB - AIMS: To acquire normative data of hippocampal volumes and T2 relaxation times, to evaluate and compare qualitative and quantitative assessments in evaluating hippocampi in patients with different durations of intractable epilepsy, and to propose an imaging protocol based on performance of these techniques. METHODS: MRI analysis was done in 50 nonepileptic controls and 30 patients with intractable epilepsy on 1.5 T scanner. Visual assessment and hippocampal volumetry were done on oblique coronal IR/T2W and T1W MP-RAGE images, respectively. T2 relaxation times were measured using 16-echo Carr-Purcell Meiboom-Gill sequence. Volumetric data was normalized for variation in head size between individuals. Patients were divided into temporal (n = 20) and extratemporal (n = 10) groups based on clinical and EEG localization. RESULTS: In controls, right hippocampal volume was slightly more than the left with no effect of age or gender. In TLE patients, hippocampal volumetry provided maximum concordance with EEG. Visual assessment of unilateral pathology concurred well with measured quantitative values but poorly in cases with bilateral pathologies. There were no significant differences of mean values between extratemporal group and controls group. Quantitative techniques detected mild abnormalities, undetected on visual assessment. CONCLUSIONS: Quantitative techniques are more sensitive to diagnose bilateral and mild unilateral hippocampal abnormalities. PMID- 23984368 TI - Effects of an Agaricus blazei aqueous extract pretreatment on paracetamol-induced brain and liver injury in rats. AB - The action of an Agaricus blazei aqueous extract pretreatment on paracetamol injury in rats was examined not only in terms of the classical indicators (e.g., levels of hepatic enzymes in the plasma) but also in terms of functional and metabolic parameters (e.g., gluconeogenesis). Considering solely the classical indicators for tissue damage, the results can be regarded as an indication that the A. blazei extract is able to provide a reasonable degree of protection against the paracetamol injury in both the hepatic and brain tissues. The A. blazei pretreatment largely prevented the increased levels of hepatic enzymes in the plasma (ASP, ALT, LDH, and ALP) and practically normalized the TBARS levels in both liver and brain tissues. With respect to the functional and metabolic parameters of the liver, however, the extract provided little or no protection. This includes morphological signs of inflammation and the especially important functional parameter gluconeogenesis, which was impaired by paracetamol. Considering these results and the long list of extracts and substances that are said to have hepatoprotective effects, it would be useful to incorporate evaluations of functional parameters into the experimental protocols of studies aiming to attribute or refute effective hepatoprotective actions to natural products. PMID- 23984370 TI - Optimized periocular template selection for human recognition. AB - A novel approach for selecting a rectangular template around periocular region optimally potential for human recognition is proposed. A comparatively larger template of periocular image than the optimal one can be slightly more potent for recognition, but the larger template heavily slows down the biometric system by making feature extraction computationally intensive and increasing the database size. A smaller template, on the contrary, cannot yield desirable recognition though the smaller template performs faster due to low computation for feature extraction. These two contradictory objectives (namely, (a) to minimize the size of periocular template and (b) to maximize the recognition through the template) are aimed to be optimized through the proposed research. This paper proposes four different approaches for dynamic optimal template selection from periocular region. The proposed methods are tested on publicly available unconstrained UBIRISv2 and FERET databases and satisfactory results have been achieved. Thus obtained template can be used for recognition of individuals in an organization and can be generalized to recognize every citizen of a nation. PMID- 23984371 TI - Protective effect of 3,4-methylenedioxyphenol (sesamol) on stress-related mucosal disease in rats. AB - Stress-related mucosal disease (SRMD) causes considerable morbidity and mortality in critically ill patients. 3,4-Methylenedioxyphenol (sesamol) has been reported to have potent antioxidative and anti-inflammatory properties. The aim of this study was to investigate the effect of sesamol on water immersion restraint- (WIR ) induced SRMD in rats. Rat gastric ulcer and hemorrhage were induced by WIR. Rats were pretreated orally with various doses of sesamol (0.1, 0.3, and 1 mg/kg, resp.) 30 min before WIR. Gastric mucosal ulceration, hemoglobin, lipid peroxidation, mucus secretion, proinflammatory cytokines, and nuclear factor (NF) kappaB levels were determined 4 h after WIR. In addition, the infiltration of neutrophil and macrophage into gastric mucosa was also determined after WIR. Water immersion restraint increased gastric mucosal ulcer and hemorrhage, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 levels but failed to affect mucosal lipid peroxidation and mucus secretion compared with non-WIR. Sesamol significantly decreased gastric ulceration and hemorrhage and inhibited mucosal TNF-alpha, IL-1beta, and IL-6 production and NF-kappaB activity in WIR treated rats. In addition, increased myeloperoxidase and CD68 levels in gastric mucosa were found in WIR-treated rats compared to non-WIR rats. Sesamol did not affect myeloperoxidase but decreased CD68 levels in mucosa in WIR-treated rats. Sesamol may protect against SRMD by inhibiting gastric mucosal proinflammatory cytokines in rats. PMID- 23984372 TI - A novel technique of ultra-mini-percutaneous nephrolithotomy: introduction and an initial experience for treatment of upper urinary calculi less than 2 cm. AB - OBJECTIVES: To describe our novel modified technique of ultra-mini-percutaneous nephrolithotomy (UMP) using of a novel 6 Fr mininephroscope through an 11-13 Fr metal sheath to perform holmium: YAG laser lithotripsy. METHODS: The medical records of 36 patients with moderate-sized (<20 mm) kidney stones treated with UMP from April to July 2012 were retrospectively reviewed. Patients were assessed at the 1st day and 1st month postoperatively by KUB and US to assess stone-free status. RESULTS: The mean stone size was 14.9 +/- 4.1 mm (rang: 6-20). The average operative time was 59.8 +/- 15.9 (30-90) min. The stone-free rate at postoperative 1st day and 1st month was 88.9% and 97.2%. The mean hospital stay was 3.0 +/- 0.9 (2-5) days. Complications were noted in 6 (16.7%) cases according to the Clavien classification, including sepsis in 2 (5.6%) cases (grade II), urinary extravasations in 1 (2.8%) case (grade IIIa), and fever in 3 (8.3%) cases (grade II). No patients needed blood transfusion. CONCLUSIONS: UMP is technically feasible, safe, and efficacious for moderate-sized renal stones with an advantage of high stone-free rates and low complication rates. However, due to the limits of its current unexplored indications, UMP is therefore a supplement to, not a substitute for, the standard mini-PCNL technology. PMID- 23984373 TI - Apatite formation: why it may not work as planned, and how to conclusively identify apatite compounds. AB - Calcium phosphate apatites are inorganic compounds encountered in many different mineralized tissues. Bone mineral, for example, is constituted of nanocrystalline nonstoichiometric apatite, and the production of "analogs" through a variety of methods is frequently reported. In another context, the ability of solid surfaces to favor the nucleation and growth of "bone-like" apatite upon immersion in supersaturated fluids such as SFB is commonly used as one evaluation index of the "bioactivity" of such surfaces. Yet, the compounds or deposits obtained are not always thoroughly characterized, and their apatitic nature is sometimes not firmly assessed by appropriate physicochemical analyses. Of particular importance are the "actual" conditions in which the precipitation takes place. The precipitation of a white solid does not automatically indicate the formation of a "bone-like carbonate apatite layer" as is sometimes too hastily concluded: "all that glitters is not gold." The identification of an apatite phase should be carefully demonstrated by appropriate characterization, preferably using complementary techniques. This review considers the fundamentals of calcium phosphate apatite characterization discussing several techniques: electron microscopy/EDX, XRD, FTIR/Raman spectroscopies, chemical analyses, and solid state NMR. It also underlines frequent problems that should be kept in mind when making "bone-like apatites." PMID- 23984374 TI - Stepwise embryonic toxicity of silver nanoparticles on Oryzias latipes. AB - The developmental toxicity of silver nanoparticles (AgNPs) was investigated following exposure of Oryzias latipes (medaka) embryos to 0.1-1 mg/L of homogeneously dispersed AgNPs for 14 days. During this period, developmental endpoints, including lethality, heart rate, and hatching rate, were evaluated by microscopy for different stages of medaka embryonic development. To compare toxic sensitivity, acute adult toxicity was assessed. There was no difference in acute lethal toxicity between embryo and adult medaka. Interestingly, we found that the increase in stepwise toxicity was dependent on the developmental stage of the embryo. Lethal embryonic toxicity increased from exposure days 1 to 3 and exposure days 5 to 8, whereas there was no change from exposure days 3 to 5. In addition, 7 d exposure to 0.8 mg/L AgNPs resulted in significant heart beat retardation in medaka embryos. AgNPs also caused a dose-dependent decrease in the hatching rate and body length of larvae. These results indicate that AgNP exposure causes severe developmental toxicity to medaka embryos and that toxicity levels are enhanced at certain developmental stages, which should be taken into consideration in assessments of metallic NPs toxicity to embryos. PMID- 23984375 TI - Epidemiology of back pain in children and youth aged 10-19 from the area of the southeast of Poland. AB - OBJECTIVE: The aim of this work was to define the prevalence of back pain in children and youth aged 10-19 from the southeast of Poland. MATERIAL AND METHODS: The cross-sectional study included 1089 students (547 girls and 542 boys) aged 10 19. The prevalence of back pain, its intensity, location, and situations in which it occurred were assessed with a questionnaire. RESULTS: Among 1089 respondents, 830 (76.2%) admitted that they had experienced back pain at various frequencies within the year preceding the study. Back pain was located mainly in the lumbar segment (74.8%). Mild pains were dominant, which was declared by 44.7% of the respondents. Girls experienced back pain significantly more frequently than boys (52.2% versus 47.8%, P < 0.05). CONCLUSIONS: The research revealed that back pain is a common phenomenon. The prevalence of back pain in children and youth living in southeast Poland is similar to the frequency of occurrence of such complaints occurring in peers in other countries. It seems significant to monitor the remaining regions of Poland in order to define the scale of the problem and to look for the risk factors of back pain in children and youth to undertake efficient prophylactic actions. PMID- 23984376 TI - In systemic sclerosis, anxiety and depression assessed by hospital anxiety depression scale are independently associated with disability and psychological factors. AB - BACKGROUND: Anxious and depressive symptoms are frequent in Systemic Sclerosis (SSc). Our objective is to assess their prevalence and association with district and global disability and psychological variables. METHODS: 119 SSc patients were assessed by Hospital Anxiety Depression Scale (HADS). Clinical depression and anxiety were defined for HADS score cutoff >= 8. Patients were assessed for psychological symptoms (RSES, COPE-NIV), hand (HAMIS, CHFDS, fist closure, and hand opening) and face disability (MHISS, mouth opening), global disability, and fatigue (HAQ, FACIT). RESULTS: Both depression and anxiety in SSc are 36%. Depressive patients with comorbid anxiety have higher HADS-D score than patients with depression only (P = 0.001). HADS-A and -D are positively correlated with global disability, hands and mouth disability, fatigue, self-esteem and avoidance coping strategy, and, only HADS-A, also with social support (P < 0.05). By multiple regression, HADS-D is independently associated with FACIT-F (P < 0.001), RSES (P < 0.001), and MHISS total score (P = 0.016), together explaining 50% of variance. HADS-A is independently associated with RSES (P = 0.006), COPE-NIV SA (P = 0.003), COPE-NIV SS (P = 0.008), FACIT-F (P = 0.022), and MHISS mouth opening (P = 0.029), explaining 41% of variance. CONCLUSIONS: In SSc depression and anxiety correlate to local and global disabilities and psychological characteristics. Depressive patients with comorbid anxiety have higher level of depressive symptoms. PMID- 23984377 TI - Diagnosis value of the serum amyloid A test in neonatal sepsis: a meta-analysis. AB - Neonatal sepsis (NS), a common disorder for humans, is recognized as a leading global public health challenge. This meta-analysis was performed to assess the accuracy of the serum amyloid A (SAA) test for diagnosing NS. The studies that evaluated the SAA test as a diagnostic marker were searched in Pubmed, EMBASE, the Cochrane Library, and Google Network between January 1996 and June 2013. A total of nine studies including 823 neonates were included in our meta-analysis. Quality of each study was evaluated by the quality assessment of diagnostic accuracy studies tool (QUADAS). The SAA test showed moderate accuracy in the diagnosis of NS both at the first suspicion of sepsis and 8-96 h after the sepsis onset, both with Q* = 0.91, which is similar to the PCT and CRP tests for the diagnosis of NS in the same period. Heterogeneity between studies was also explained by cut-off point, SAA assay, and age of included neonates. On the basis of our meta-analysis, therefore, SAA could be promising and meaningful in the diagnosis of NS. PMID- 23984378 TI - Topical 100% serum eye drops for treating corneal epithelial defect after ocular surgery. AB - The purpose of this study was to investigate the efficacy and safety of topical 100% serum eye drops for corneal epithelial defect after ocular surgery. A total of 181 patients who received topical 100% serum therapy for the treatment of corneal epithelial defect following several different types of ocular surgery were recruited into this study. Each patient already failed conventional medical therapy before being prescribed 100% serum eye drops. Slit-lamp biomicroscopic examination with fluorescein staining was performed at baseline and all follow-up visits. The main outcome measures were the rate of complete healing of the corneal epithelial defect and incidence of adverse events. One hundred and seventy-eight eyes (98.34%) received autologous serum eye drops, and 3 (1.66%) received allogeneic serum eye drops. The overall success rate of treating persistent postoperative epithelial defect using 100% serum eye drops was 93.92% (95% CI 0.88-0.98). The median time to complete corneal epithelialization was 4 days (95% CI 4-5). Adverse reactions were observed in 3 patients (1.66%), including sticky sensation with minimal eye discomfort and asymptomatic trace corneal subepithelial infiltration. No serious complications were reported. In conclusion, 100% serum eye drops are effective, safe, and tolerable for treating postoperative corneal epithelial defect following ocular surgeries. PMID- 23984379 TI - CYP3A5*3 and C3435T MDR1 polymorphisms in prognostication of drug-resistant epilepsy in children and adolescents. AB - Drug-resistant epilepsies still remain one of the most profound problems of contemporary epileptology. Several mechanisms of drug resistance are possible; among them, genetic factors have a prominent place. Much importance is attached to genes, which encode enzymes that metabolize antiepileptic drugs CYP 3A, which belong to the family of cytochromes P450 and the genome of multidrug resistance, such as multidrug resistance 1 (MDR1) that expresses P-glycoprotein (P-gp), a drug transporter protein. The aim of the study was to assess the relation between polymorphism of gene CYP3A5 and polymorphism C3435T of MDR1 gene with the occurrence of focal, drug-resistant epilepsy in children and youths up to 18 years of age. The study comprised 85 patients, and their age range was from 33 months to 18 years of age, suffering from epilepsy, partly responding well to treatment, partly drug resistant. The polymorphism of both genes has been analysed using the PCR-RFLP method. The study failed to corroborate association between polymorphism CYP3A5*3 and C3435T polymorphism in MDR1 gene and pharmacoresistant epilepsy. The results of our research do not confirm the prognostic value of the polymorphisms examined in the prognostication of drug resistance in epilepsies. PMID- 23984380 TI - Development of bioadhesive chitosan superporous hydrogel composite particles based intestinal drug delivery system. AB - Bioadhesive superporous hydrogel composite (SPHC) particles were developed for an intestinal delivery of metoprolol succinate and characterized for density, porosity, swelling, morphology, and bioadhesion studies. Chitosan and HPMC were used as bioadhesive and release retardant polymers, respectively. A 3(2) full factorial design was applied to optimize the concentration of chitosan and HPMC. The drug loaded bioadhesive SPHC particles were filled in capsule, and the capsule was coated with cellulose acetate phthalate and evaluated for drug content, in vitro drug release, and stability studies. To ascertain the drug release kinetics, the drug release profiles were fitted for mathematical models. The prepared system remains bioadhesive up to eight hours in intestine and showed Hixson-Crowell release with anomalous nonfickian type of drug transport. The application of SPHC polymer particles as a biomaterial carrier opens a new insight into bioadhesive drug delivery system and could be a future platform for other molecules for intestinal delivery. PMID- 23984381 TI - Tuning aerosol particle size distribution of metered dose inhalers using cosolvents and surfactants. AB - OBJECTIVES: The purpose of these studies was to understand the influence of cosolvent and surfactant contributions to particle size distributions emitted from solution metered dose inhalers (pMDIs) based on the propellant HFA 227. METHODS: Two sets of formulations were prepared: (a) pMDIs-HFA 227 containing cosolvent (5-15% w/w ethanol) with constant surfactant (pluronic) concentration and (b) pMDIs-HFA 227 containing surfactant (0-5.45% w/w pluronic) with constant cosolvent concentration. Particle size distributions emitted from these pMDIs were analyzed using aerodynamic characterization (inertial impaction) and laser diffraction methods. RESULTS: Both cosolvent and surfactant concentrations were positively correlated with median particle sizes; that is, drug particle size increased with increasing ethanol and pluronic concentrations. However, evaluation of particle size distributions showed that cosolvent caused reduction in the fine particle mode magnitude while the surfactant caused a shift in the mode position. These findings highlight the different mechanisms by which these components influence droplet formation and demonstrate the ability to utilize the different effects in formulations of pMDI-HFA 227 for independently modulating particle sizes in the respirable region. CONCLUSION: Potentially, the formulation design window generated using these excipients in combination could be used to match the particle size output of reformulated products to preexisting pMDI products. PMID- 23984382 TI - Identifying interacting genetic variations by fish-swarm logic regression. AB - Understanding associations between genotypes and complex traits is a fundamental problem in human genetics. A major open problem in mapping phenotypes is that of identifying a set of interacting genetic variants, which might contribute to complex traits. Logic regression (LR) is a powerful multivariant association tool. Several LR-based approaches have been successfully applied to different datasets. However, these approaches are not adequate with regard to accuracy and efficiency. In this paper, we propose a new LR-based approach, called fish-swarm logic regression (FSLR), which improves the logic regression process by incorporating swarm optimization. In our approach, a school of fish agents are conducted in parallel. Each fish agent holds a regression model, while the school searches for better models through various preset behaviors. A swarm algorithm improves the accuracy and the efficiency by speeding up the convergence and preventing it from dropping into local optimums. We apply our approach on a real screening dataset and a series of simulation scenarios. Compared to three existing LR-based approaches, our approach outperforms them by having lower type I and type II error rates, being able to identify more preset causal sites, and performing at faster speeds. PMID- 23984383 TI - Advances in the applications of polyhydroxyalkanoate nanoparticles for novel drug delivery system. AB - Drug delivery technology is emerging as an interdisciplinary science aimed at improving human health. The controlled delivery of pharmacologically active agents to the specific site of action at the therapeutically optimal rate and dose regimen has been a major goal in designing drug delivery systems. Over the past few decades, there has been considerable interest in developing biodegradable drug carriers as effective drug delivery systems. Polymeric materials from natural sources play an important role in controlled release of drug at a particular site. Polyhydroxyalkanoates, due to their origin from natural sources, are given attention as candidates for drug delivery materials. Biodegradable and biocompatible polyhydroxyalkanoates are linear polyesters produced by microorganisms under unbalanced growth conditions, which have emerged as potential polymers for use as biomedical materials for drug delivery due to their unique physiochemical and mechanical properties. This review summarizes many of the key findings in the applications of polyhydroxyalkanoates and polyhydroxyalkanoate nanoparticles for drug delivery system. PMID- 23984384 TI - Cloning and characterization of EF-Tu and EF-Ts from Pseudomonas aeruginosa. AB - We have cloned genes encoding elongation factors EF-Tu and EF-Ts from Pseudomonas aeruginosa and expressed and purified the proteins to greater than 95% homogeneity. Sequence analysis indicated that P. aeruginosa EF-Tu and EF-Ts are 84% and 55% identical to E. coli counterparts, respectively. P. aeruginosa EF-Tu was active when assayed in GDP exchange assays. Kinetic parameters for the interaction of EF-Tu with GDP in the absence of EF-Ts were observed to be K M = 33 MUM, k cat (obs) = 0.003 s(-1), and the specificity constant k cat (obs)/K M was 0.1 * 10(-3) s(-1) MUM(-1). In the presence of EF-Ts, these values were shifted to K M = 2 MUM, k cat (obs) = 0.005 s(-1), and the specificity constant k(cat)(obs)/K M was 2.5 * 10(-3) s(-1) MUM(-1). The equilibrium dissociation constants governing the binding of EF-Tu to GDP (K GDP) were 30-75 nM and to GTP (K GTP) were 125-200 nM. EF-Ts stimulated the exchange of GDP by EF-Tu 10-fold. P. aeruginosa EF-Tu was active in forming a ternary complex with GTP and aminoacylated tRNA and was functional in poly(U)-dependent binding of Phe tRNA(Phe) at the A-site of P. aeruginosa ribosomes. P. aeruginosa EF-Tu was active in poly(U)-programmed polyphenylalanine protein synthesis system composed of all P. aeruginosa components. PMID- 23984385 TI - Mechanical elongation of the small intestine: evaluation of techniques for optimal screw placement in a rodent model. AB - INTRODUCTION: The aim of this study was to evaluate techniques and establish an optimal method for mechanical elongation of small intestine (MESI) using screws in a rodent model in order to develop a potential therapy for short bowel syndrome (SBS). MATERIAL AND METHODS: Adult female Sprague Dawley rats (n = 24) with body weight from 250 to 300 g (Sigma = 283) were evaluated using 5 different groups in which the basic denominator for the technique involved the fixation of a blind loop of the intestine on the abdominal wall with the placement of a screw in the lumen secured to the abdominal wall. RESULTS: In all groups with accessible screws, the rodents removed the implants despite the use of washers or suits to prevent removal. Subcutaneous placement of the screw combined with antibiotic treatment and dietary modifications was finally successful. In two animals autologous transplantation of the lengthened intestinal segment was successful. DISCUSSION: While the rodent model may provide useful basic information on mechanical intestinal lengthening, further investigations should be performed in larger animals to make use of the translational nature of MESI in human SBS treatment. PMID- 23984386 TI - Computational elucidation of structural basis for ligand binding with Leishmania donovani adenosine kinase. AB - Enzyme adenosine kinase is responsible for phosphorylation of adenosine to AMP and is crucial for parasites which are purine auxotrophs. The present study describes development of robust homology model of Leishmania donovani adenosine kinase to forecast interaction phenomenon with inhibitory molecules using structure-based drug designing strategy. Docking calculation using reported organic small molecules and natural products revealed key active site residues such as Arg131 and Asp16 for ligand binding, which is consistent with previous studies. Molecular dynamics simulation of ligand protein complex revealed the importance of hydrogen bonding with active site residues and solvent molecules, which may be crucial for successful development of drug candidates. Precise role of Phe168 residue in the active site was elucidated in this report that provided stability to ligand-protein complex via aromatic- pi contacts. Overall, the present study is believed to provide valuable information to design a new compound with improved activity for antileishmanial therapeutics development. PMID- 23984387 TI - Modulation of pineal melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through NF-kappaB activation. AB - The glutamatergic modulation of melatonin synthesis is well known, along with the importance of astrocytes in mediating glutamatergic signaling in the central nervous system. Pinealocytes and astrocytes are the main cell types in the pineal gland. The objective of this work was to investigate the interactions between astrocytes and pinealocytes as a part of the glutamate inhibitory effect on melatonin synthesis. Rat pinealocytes isolated or in coculture with astrocytes were incubated with glutamate in the presence of norepinephrine, and the melatonin content, was quantified. The expression of glutamate receptors, the intracellular calcium content and the NF- kappa B activation were analyzed in astrocytes and pinealocytes. TNF- alpha 's possible mediation of the effect of glutamate was also investigated. The results showed that glutamate's inhibitory effect on melatonin synthesis involves interactions between astrocytes and pinealocytes, possibly through the release of TNF- alpha . Moreover, the activation of the astrocytic NF- kappa B seems to be a necessary step. In astrocytes and pinealocytes, AMPA, NMDA, and group I metabotropic glutamate receptors were observed, as well as the intracellular calcium elevation. In conclusion, there is evidence that the modulation of melatonin synthesis by glutamate involves paracrine interactions between pinealocytes and astrocytes through the activation of the astrocytic NF- kappa B transcription factor and possibly by subsequent TNF- alpha release. PMID- 23984389 TI - Isolation and characterization of chicken dermis-derived mesenchymal stem/progenitor cells. AB - Dermis-derived mesenchymal stem/progenitor cells (DMS/PCs) were isolated from the skin tissue of 16-day-old chick embryos and then characterized by immunofluorescence and RT-PCR. We found that primary DMS/PCs could be expanded for 15 passages. Expression of beta -integrin, CD44, CD71, and CD73 was observed by immunofluorescence and RT-PCR. Passage 3 DMS/PCs were successfully induced to differentiate into osteoblasts, adipocytes, and neurocytes. The results indicate the potential for multilineage differentiation of DMS/PCs that may represent an ideal candidate for cellular transplantation therapy. PMID- 23984388 TI - Functions of heterogeneous nuclear ribonucleoproteins in stem cell potency and differentiation. AB - Stem cells possess huge importance in developmental biology, disease modelling, cell replacement therapy, and tissue engineering in regenerative medicine because they have the remarkable potential for self-renewal and to differentiate into almost all the cell types in the human body. Elucidation of molecular mechanisms regulating stem cell potency and differentiation is essential and critical for extensive application. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are modular proteins consisting of RNA-binding motifs and auxiliary domains characterized by extensive and divergent functions in nucleic acid metabolism. Multiple roles of hnRNPs in transcriptional and posttranscriptional regulation enable them to be effective gene expression regulators. More recent findings show that hnRNP proteins are crucial factors implicated in maintenance of stem cell self-renewal and pluripotency and cell differentiation. The hnRNPs interact with certain sequences in target gene promoter regions to initiate transcription. In addition, they recognize 3'UTR or 5'UTR of specific gene mRNA forming mRNP complex to regulate mRNA stability and translation. Both of these regulatory pathways lead to modulation of gene expression that is associated with stem cell proliferation, cell cycle control, pluripotency, and committed differentiation. PMID- 23984391 TI - Bisphenol A modifies the regulation exerted by testosterone on 5 alpha -reductase isozymes in ventral prostate of adult rats. AB - The development, growth, and function of the prostate gland depend on androgen stimulation. The primary androgen in prostate is 5alpha-dihydrotestosterone (DHT) which is synthesized from circulating testosterone (T) through the action of 5alpha-reductase (5alpha-R). Although 5alpha-R occurs as five isozymes, only 5alpha-R1 and 5alpha-R2 are physiologically involved in steroidogenesis. The endocrine disruptor bisphenol A (BPA) alters sexual organs, including the prostate. Our previous findings indicated that BPA decreased the expression of 5alpha-R1 and 5alpha-R2 in rat prostate but also circulating T. Thus, it is unclear whether BPA exerts this effect on 5alpha-R isozymes by reducing circulating T or by any other mechanism. In this study, we examine the effects of short-term exposure to BPA at doses below 25 MUg/Kg/d and above 300 MUg/Kg/d of the TDI on mRNA levels of 5alpha-R1 and 5alpha-R2 in prostate of adult castrated rats supplemented with T to achieve constant circulating T levels. mRNA levels were measured by absolute quantitative RT-PCR, T levels by RIA, and DHT levels by ELISA. Our results indicated that in castrated rats treated with T BPA at the two doses studied significantly decreased the mRNA levels of both 5alpha-R isozymes in a dose-dependent manner without modifications in circulating T. PMID- 23984392 TI - HyDEn: a hybrid steganocryptographic approach for data encryption using randomized error-correcting DNA codes. AB - This paper presents a novel hybrid DNA encryption (HyDEn) approach that uses randomized assignments of unique error-correcting DNA Hamming code words for single characters in the extended ASCII set. HyDEn relies on custom-built quaternary codes and a private key used in the randomized assignment of code words and the cyclic permutations applied on the encoded message. Along with its ability to detect and correct errors, HyDEn equals or outperforms existing cryptographic methods and represents a promising in silico DNA steganographic approach. PMID- 23984390 TI - Modulation of the rat hepatic cytochrome P4501A subfamily using biotin supplementation. AB - Studies have found that biotin favors glucose and lipid metabolism, and medications containing biotin have been developed. Despite the use of biotin as a pharmacological agent, few studies have addressed toxicity aspects including the possible interaction with cytochrome P450 enzyme family. This study analyzed the effects of pharmacological doses of biotin on the expression and activity of the cytochrome P4501A subfamily involved in the metabolism of xenobiotics. Wistar rats were treated daily with biotin (2 mg/kg, i.p.), while the control groups were treated with saline. All of the rats were sacrificed by cervical dislocation after 1, 3, 5, or 7 days of treatment. CYP1A1 and CYP1A2 mRNAs were modified by biotin while enzyme activity and protein concentration were not affected. The lack of an effect of biotin on CYP1A activity was confirmed using other experimental strategies, including (i) cotreatment of the animals with biotin and a known CYP1A inducer; (ii) the addition of biotin to the reaction mixtures for the measurement of CYP1A1 and CYP1A2 activities; and (iii) the use of an S9 mixture that was prepared from control and biotin-treated rats to analyze the activation of benzo[a]pyrene (BaP) into mutagenic metabolites using the Ames test. The results suggest that biotin does not influence the CYP1A-mediated metabolism of xenobiotics. PMID- 23984393 TI - The effect of ranitidine on olanzapine-induced weight gain. AB - Induced weight gain is a disturbing side effect of Olanzapine that affects the quality of life in psychotic patients. The aim of this study was to assess the efficacy of Ranitidine in attenuating or preventing Olanzapine-induced weight gain. A parallel 2-arm clinical trial was done on 52 patients with schizophrenia, schizoaffective and schizophreniform disorders who received Olanzapine for the first time. All these were first-episode admitted patients. They were randomly allocated to receive either Ranitidine or placebo. The trend of body mass index (BMI) was compared between groups over 16-week course of treatment. Mean weight was 62.3 (SD: 9.6) kg at baseline. Thirty-three subjects (63.5%) had positive family history of obesity. The average BMI increment was 1.1 for Ranitidine group and 2.4 for the placebo group. The multivariate analysis showed this effect to be independent of sex, family history of obesity, and baseline BMI value. The longitudinal modeling after controlling for baseline values failed to show the whole trend slope to be different. Although the slight change in trend's slope puts forward a hypothesis that combined use of Ranitidine and Olanzapine may attenuate the weight gain long run, this needs to be retested in future larger scale long-term studies. This trial is registered with IRCT.ir 201009112181N5. PMID- 23984394 TI - PSCA and Oct-4 expression in the benign and malignant lesions of gallbladder: implication for carcinogenesis, progression, and prognosis of gallbladder adenocarcinoma. AB - PSCA and Oct-4 have been thought as markers of cancer stem cells. Although overexpression of PSCA and Oct-4 in cancer has been reported, little is known about the clinical and pathological significance with PSCA and Oct-4 expression in gallbladder adenocarcinoma. In this study, overexpression of PSCA and Oct-4 was detected in gallbladder adenocarcinoma (54.6% and 55.6%). Less expression of PSCA and Oct-4 was detected in the pericancerous tissues (19.6% and 21.7%), gallbladder polyps (13.3% and 13.3%), and gallbladder epithelium with chronic cholecystitis (14.3% and 14.3%). The overexpression of PSCA and Oct-4 was significantly associated with differentiation, tumor mass, lymph node metastasis, invasion of gallbladder adenocarcinoma, and decreased overall survival. Our study suggested that overexpression of PSCA and Oct-4 might be closely related to the carcinogenesis, progression, metastasis, or invasive potential and prognosis of gallbladder carcinoma. PMID- 23984395 TI - The influence of hemocoagulation disorders on the development of posttraumatic cerebral infarction and outcome in patients with moderate or severe head trauma. AB - Posttraumatic cerebral infarction (PTCI) is a severe secondary insult of head injury and often leads to a poor prognosis. Hemocoagulation disorder is recognized to have important effects on hemorrhagic or ischemic damages. We sought to assess if posttraumatic hemocoagulation disorders were associated with cerebral infarction, and evaluate their influence on outcome among patients with moderate or severe head trauma. In this study, PTCI was observed in 28 (10.57%) of the 265 patients within the first week after injury. In multivariate analysis, the thrombocytopenia (odds ratio (OR) 2.210, 95% confidence interval (CI) 1.065 4.674), abnormal prothrombin time (PT) (OR 3.241, 95% CI 1.090-7.648), D-dimer (>2 mg/L) (OR 7.260, 95% CI 1.822-28.076), or disseminated intravascular coagulation (DIC) scores (>= 5) (OR 4.717, 95% CI 1.778-12.517) were each independently associated with an increased risk of PTCI. Admission Glasgow Coma Scale (GCS) score, abnormal activated partial thromboplastin time (APTT) and fibrinogen, and D-dimer (>2 mg/L) and DIC scores (>= 5) showed an independent predictive effect on poor outcome. In conclusion, recognition of this important treatable cause of PTCI and the associated risk factors may help identify the group at risk and tailor management of patients with TBI. PMID- 23984396 TI - Virus-like particles containing the tetrameric ectodomain of influenza matrix protein 2 and flagellin induce heterosubtypic protection in mice. AB - The ectodomain of matrix protein 2 (M2e) is highly conserved among influenza A viruses and can be a promising candidate antigen for a broadly cross-protective vaccine. In this study, a tetrameric M2e (tM2e) and a truncated form of flagellin (tFliC) were coincorporated into virus-like particles (VLPs) to enhance its immunogenicity. Our data showed that the majority of M2e in VLPs was presented as tetramers by introducing a foreign tetramerization motif GCN4. Intranasal immunization with tM2e VLPs significantly enhanced the levels of serum IgG and IgG subclasses compared to soluble M2e (sM2e) in mice. tM2e VLPs also induced higher M2e-specific T-cell and mucosal antibody responses, conferring complete protection against homologous influenza virus infection. The immunogenicity of tM2e VLPs was further enhanced by coincorporation of the membrane-anchored tFliC (tM2e chimeric VLPs) or coadministration with tFliC VLPs as a mixture, but not the soluble flagellin, inducing strong humoral and cellular immune responses conferring cross-protection against lethal challenge with heterotypic influenza viruses. These results support the development of tM2e chimeric VLPs as universal vaccines and warrant further investigation. PMID- 23984397 TI - Preliminary results of implantation in animal model and osteoblast culture evaluation of prototypes of biomimetic multispiked connecting scaffold for noncemented stemless resurfacing hip arthroplasty endoprostheses. AB - We present the new fixation method for RHA (resurfacing hip arthroplasty) endoprostheses by means of the biomimetic multispiked connecting scaffold (MSC Scaffold). Such connecting scaffold can generate new type of RHA endoprostheses, that is stemless and fixed entirely without cement. The preprototypes of this MSC Scaffold were manufactured with modern additive laser additive technology (SLM). The pilot surgical implantations in animal model (two laboratory swine) of MSC Scaffold preprototypes have showed after two months neither implant loosening, migration, and nor other early complications. From the results of performed histopathological evaluation of the periscaffold spikes bone tissue and 10-day culture of human osteoblasts (NHOst) we can conclude that (1) the scaffolding effect was obtained and (2) to improve the osseointegration of the scaffold spikes, their material surface should be physicochemically modified (e.g., with hydroxyapatite). Some histopathological findings in the periscaffold domain near the MSC-Scaffold spikes bases (fibrous connective tissue and metallic particles near the MSC-Scaffold spikes bases edges) prompt considering the necessity to optimize the design of the MSC-Scaffold in the regions of its interspike space near the spikes bases edges, to provide more room for new bone formation in this region and for indispensable post-processing (glass pearl blasting) after the SLM manufacturing. PMID- 23984398 TI - Characteristics of atopic bronchial asthma in seniors over 80 years of age. AB - BACKGROUND: Asthma in the elderly is an important public health problem. The aim of this study was to assess the prevalence and characteristics of asthma in seniors. MATERIALS AND METHODS: The study involved 105 people of at least 80 years of age (mean age of 84.1 +/- 3.9 years) selected from a group of 1860 individuals. Spirometry, the methacholine test, allergy diagnosis, a measurement of exhaled nitric oxide, and administration of the asthma quality of life questionnaire (AQLQ) were performed. RESULTS: The average morbidity of asthma in the study population of elderly people (at least 80 years of age) was 5.6% (105 people) of the confidence interval (95% CI: 5.1-6.0). In the study group, 34% of the elderly asthmatics had uncontrolled asthma, 47% had partly controlled asthma, and only 24% had fully controlled asthma. Allergy to house dust mites was predominant. The average total score on the AQLQ was 4.12 +/- 0.72 (arithmetic mean +/- standard deviation) for the seniors, which was significantly lower than the score for the young. CONCLUSION: The pathogenesis, natural history, and value of the basic diagnostic methods of asthma in the elderly are similar to those observed in younger age groups. PMID- 23984399 TI - Role of the plasma membrane transporter of organic cations OCT1 and its genetic variants in modern liver pharmacology. AB - Changes in the uptake of many drugs by the target cells may dramatically affect the pharmacological response. Thus, downregulation of SLC22A1, which encodes the organic cation transporter type 1 (OCT1), may affect the response of healthy hepatocytes and liver cancer cells to cationic drugs, such as metformin and sorafenib, respectively. Moreover, the overall picture may be modified to a considerable extent by the preexistence or the appearance during the pathogenic process of genetic variants. Some rare OCT1 variants enhance transport activity, whereas other more frequent variants impair protein maturation, plasma membrane targeting or the function of this carrier, hence reducing intracellular active drug concentrations. Here, we review current knowledge of the role of OCT1 in modern liver pharmacology, which includes the use of cationic drugs to treat several diseases, some of them of great clinical relevance such as diabetes and primary liver cancer (cholangiocarcinoma and hepatocellular carcinoma). We conclude that modern pharmacology must consider the individual evaluation of OCT1 expression/function in the healthy liver and in the target tissue, particularly if this is a tumor, in order to predict the lack of response to cationic drugs and to be able to design individualized pharmacological treatments with the highest chances of success. PMID- 23984400 TI - The immune interplay between the host and the pathogen in Aspergillus fumigatus lung infection. AB - The interplay between Aspergillus fumigatus and the host immune response in lung infection has been subject of studies over the last years due to its importance in immunocompromised patients. The multifactorial virulence factors of A. fumigatus are related to the fungus biological characteristics, for example, structure, ability to grow and adapt to high temperatures and stress conditions, besides capability of evading the immune system and causing damage to the host. In this context, the fungus recognition by the host innate immunity occurs when the pathogen disrupts the natural and chemical barriers followed by the activation of acquired immunity. It seems clear that a Th1 response has a protective role, whereas Th2 reactions are often associated with higher fungal burden, and Th17 response is still controversial. Furthermore, a fine regulation of the effector immunity is required to avoid excessive tissue damage associated with fungal clearance, and this role could be attributed to regulatory T cells. Finally, in this work we reviewed the aspects involved in the complex interplay between the host immune response and the pathogen virulence factors, highlighting the immunological issues and the importance of its better understanding to the development of novel therapeutic approaches for invasive lung aspergillosis. PMID- 23984401 TI - Evaluation of human body fluids for the diagnosis of fungal infections. AB - Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Because the etiologic agents of these infections are abundant in nature, their isolation from biopsy material or sterile body fluids is needed to document infection. This review evaluates and discusses different human body fluids used to diagnose fungal infections. PMID- 23984402 TI - Design and in vitro evaluation of a new nano-microparticulate system for enhanced aqueous-phase solubility of curcumin. AB - Curcumin, a yellow polyphenol derived from the turmeric Curcuma longa, has been associated with a diverse therapeutic potential including anti-inflammatory, antioxidant, antiviral, and anticancer properties. However, the poor aqueous solubility and low bioavailability of curcumin have limited its potential when administrated orally. In this study, curcumin was encapsulated in a series of novel nano-microparticulate systems developed to improve its aqueous solubility and stability. The nano-microparticulate systems are based entirely on biocompatible, biodegradable, and edible polymers including chitosan, alginate, and carrageenan. The particles were synthesized via ionotropic gelation. Encapsulating the curcumin into the hydrogel nanoparticles yielded a homogenous curcumin dispersion in aqueous solution compared to the free form of curcumin. Also, the in vitro release profile showed up to 95% release of curcumin from the developed nano-microparticulate systems after 9 hours in PBS at pH 7.4 when freeze-dried particles were used. PMID- 23984403 TI - Antibodies against food antigens in patients with autistic spectrum disorders. AB - PURPOSE: Immune system of some autistic patients could be abnormally triggered by gluten/casein assumption. The prevalence of antibodies to gliadin and milk proteins in autistic children with paired/impaired intestinal permeability and under dietary regimen either regular or restricted is reported. METHODS: 162 ASDs and 44 healthy children were investigated for intestinal permeability, tissue transglutaminase (tTG), anti-endomysium antibodies (EMA)-IgA, and total mucosal IgA to exclude celiac disease; HLA-DQ2/-DQ8 haplotypes; total systemic antibodies (IgA, IgG, and IgE); specific systemic antibodies: alpha-gliadin (AGA-IgA and IgG), deamidated-gliadin-peptide (DGP-IgA and IgG), total specific gliadin IgG (all fractions: alpha, beta, gamma, and omega), beta-lactoglobulin IgG, alpha lactalbumin IgG, casein IgG; and milk IgE, casein IgE, gluten IgE,-lactoglobulin IgE, and alpha-lactalbumin IgE. RESULTS: AGA-IgG and DPG-IgG titers resulted to be higher in ASDs compared to controls and are only partially influenced by diet regimen. Casein IgG titers resulted to be more frequently and significantly higher in ASDs than in controls. Intestinal permeability was increased in 25.6% of ASDs compared to 2.3% of healthy children. Systemic antibodies production was not influenced by paired/impaired intestinal permeability. CONCLUSIONS: Immune system of a subgroup of ASDs is triggered by gluten and casein; this could be related either to AGA, DPG, and Casein IgG elevated production or to impaired intestinal barrier function. PMID- 23984404 TI - Purity and enrichment of laser-microdissected midbrain dopamine neurons. AB - The ability to microdissect individual cells from the nervous system has enormous potential, as it can allow for the study of gene expression in phenotypically identified cells. However, if the resultant gene expression profiles are to be accurately ascribed, it is necessary to determine the extent of contamination by nontarget cells in the microdissected sample. Here, we show that midbrain dopamine neurons can be laser-microdissected to a high degree of enrichment and purity. The average enrichment for tyrosine hydroxylase (TH) gene expression in the microdissected sample relative to midbrain sections was approximately 200 fold. For the dopamine transporter (DAT) and the vesicular monoamine transporter type 2 (Vmat2), average enrichments were approximately 100- and 60-fold, respectively. Glutamic acid decarboxylase (Gad65) expression, a marker for GABAergic neurons, was several hundredfold lower than dopamine neuron-specific genes. Glial cell and glutamatergic neuron gene expression were not detected in microdissected samples. Additionally, SN and VTA dopamine neurons had significantly different expression levels of dopamine neuron-specific genes, which likely reflects functional differences between the two cell groups. This study demonstrates that it is possible to laser-microdissect dopamine neurons to a high degree of cell purity. Therefore gene expression profiles can be precisely attributed to the targeted microdissected cells. PMID- 23984405 TI - High glucose-induced oxidative stress increases the copy number of mitochondrial DNA in human mesangial cells. AB - Oxidative damage to mitochondrial DNA (mtDNA) has been linked to the pathogenicity of diabetic nephropathy. We tested the hypothesis that mtDNA copy number may be increased in human mesangial cells in response to high glucose induced reactive oxygen species (ROS) to compensate for damaged mtDNA. The effect of manganese superoxide dismutase mimetic (MnTBAP) on glucose-induced mtDNA copy number was also examined. The copy number of mtDNA was determined by real-time PCR in human mesangial cells cultured in 5 mM glucose, 25 mM glucose, and mannitol (osmotic control), as well as in cells cultured in 25 mM glucose in the presence and absence of 200 MU M MnTBAP. Intracellular ROS was assessed by confocal microscopy and flow cytometry in human mesangial cells. The copy number of mtDNA was significantly increased when human mesangial cells were incubated with 25 mM glucose compared to 5 mM glucose and mannitol. In addition, 25 mM glucose rapidly generated ROS in the cells, which was not detected in 5 mM glucose. Furthermore, mtDNA copy number was significantly decreased and maintained to normal following treatment of cells with 25 mM glucose and MnTBAP compared to 25 mM glucose alone. Inclusion of MnTBAP during 25 mM glucose incubation inhibited mitochondrial superoxide in human mesangial cells. Increased mtDNA copy number in human mesangial cells by high glucose could contribute to increased mitochondrial superoxide, and prevention of mtDNA copy number could have potential in retarding the development of diabetic nephropathy. PMID- 23984406 TI - Hemoglobin concentration and pregnancy outcomes: a systematic review and meta analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis of hemoglobin effect on the pregnancy outcomes. METHODS: We searched MEDLINE and SCOPUS from January 1, 1990 to April 10, 2011. Observational studies addressing association between hemoglobin and adverse pregnancy outcomes were selected. Two reviewers independently extracted data. A mixed logistic regression was applied to assess the effects of hemoglobin on preterm birth, low birth weight, and small for gestational age. RESULTS: Seventeen studies were included in poolings. Hemoglobin below 11 g/dL was, respectively, 1.10 (95% CI: 1.02-1.19), 1.17 (95% CI: 1.03 1.32), and 1.14 (95% CI: 1.05-1.24) times higher risk of preterm birth, low birth weight, and small for gestational age than normal hemoglobin in the first trimester. In the third trimester, hemoglobin below 11 g/dL was 1.30 (95% CI: 1.08-1.58) times higher risk of low birth weight. Hemoglobin above 14 g/dL in third trimester decreased the risk of preterm term with ORs of 0.50 (95% CI: 0.26 0.97), but it might be affected by publication bias. CONCLUSIONS: Our review suggests that hemoglobin below 11 g/dl increases the risk of preterm birth, low birth weight, and small gestational age in the first trimester and the risk of low birth weight in the third trimester. PMID- 23984407 TI - Distribution of ABO blood group and major cardiovascular risk factors with coronary heart disease. AB - The purpose of this study is to establish whether ABO blood group is related to coronary heart disease in an individual in Asian Indian Bengali population of eastern part of India. Two hundred and fifty (250) CHD patients and two hundred and fifty (250) age and sex matched healthy subjects were enrolled in the study. ABO blood group distribution in patients was compared with control group. Frequency of major cardiac risk factors was determined to find any correlation between blood groups and cardiovascular risk factors. The distribution of ABO blood groups in patients versus control group was A in 24.00 versus 21.60%, B in 30.80 versus 32.40%, O in 38.40 versus 21.60%, and AB in 6.80 versus 24.40%. The analysis showed significant difference in frequency of O (OR = 1.857, 95%CI = 1.112-3.100, P = 0.018) and AB (OR = 0.447, 95%CI = 0.227-0.882, P = 0.020) blood group between healthy controls and CHD individuals. Our results may suggest that the AB blood group decreases the risk of CHD in healthy controls, and it might be due to the higher concentration of high density lipoprotein cholesterol (HDL-c), while the O blood group increases the risk of CHD due to lower HDL-c levels in Bengali population of eastern part of India. PMID- 23984408 TI - Pesticide residue screening using a novel artificial neural network combined with a bioelectric cellular biosensor. AB - We developed a novel artificial neural network (ANN) system able to detect and classify pesticide residues. The novel ANN is coupled, in a customized way, to a cellular biosensor operation based on the bioelectric recognition assay (BERA) and able to simultaneously assay eight samples in three minutes. The novel system was developed using the data (time series) of the electrophysiological responses of three different cultured cell lines against three different pesticide groups (carbamates, pyrethroids, and organophosphates). Using the novel system, we were able to classify correctly the presence of the investigated pesticide groups with an overall success rate of 83.6%. Considering that only 70,000-80,000 samples are annually tested in Europe with current conventional technologies (an extremely minor fraction of the actual screening needs), the system reported in the present study could contribute to a screening system milestone for the future landscape in food safety control. PMID- 23984409 TI - Analgesic and anti-inflammatory activities of the methanolic stem bark extract of Nyctanthes arbor-tristis linn. AB - Stem bark of Nyctanthes arbor-tristis Linn. was extracted in methanol to evaluate their analgesic and anti-inflammatory activities. The analgesic activity was determined on Wistar albino rats by hot plate method, tail flick assay, and tail immersion method using Morphine sulphate as standard drug at a dose of 5 mg/kg of body weight and the results were expressed as mean increase in latency after drug administration +/- SEM. The anti-inflammatory activity was assessed by Carrageenan-induced rat paw oedema using diclofenac sodium as standard drug at a dose of 100 mg/kg of body weight and expressed in terms of mean increase in paw volume +/- SEM. Stem bark extract was given at a dose of 250 mg/kg and 500 mg/kg of body weight. Both standard drugs and extract were administered orally to the animals. Control received distilled water orally. Results showed that Nyctanthes arbor-tristis Linn. had potent analgesic and anti-inflammatory activities. PMID- 23984410 TI - Rotenone upregulates alpha-synuclein and myocyte enhancer factor 2D independently from lysosomal degradation inhibition. AB - Dysfunctions of chaperone-mediated autophagy (CMA), the main catabolic pathway for alpha-synuclein, have been linked to the pathogenesis of Parkinson's disease (PD). Since till now there is limited information on how PD-related toxins may affect CMA, in this study we explored the effect of mitochondrial complex I inhibitor rotenone on CMA substrates, alpha-synuclein and MEF2D, and effectors, lamp2A and hsc70, in a human dopaminergic neuroblastoma SH-SY5Y cell line. Rotenone induced an upregulation of alpha-synuclein and MEF2D protein levels through the stimulation of their de novo synthesis rather than through a reduction of their CMA-mediated degradation. Moreover, increased MEF2D transcription resulted in higher nuclear protein levels that exert a protective role against mitochondrial dysfunction and oxidative stress. These results were compared with those obtained after lysosome inhibition with ammonium chloride. As expected, this toxin induced the cytosolic accumulation of both alpha-synuclein and MEF2D proteins, as the result of the inhibition of their lysosome-mediated degradation, while, differently from rotenone, ammonium chloride decreased MEF2D nuclear levels through the downregulation of its transcription, thus reducing its protective function. These results highlight that rotenone affects alpha synuclein and MEF2D protein levels through a mechanism independent from lysosomal degradation inhibition. PMID- 23984411 TI - Intraoperative pachymetry using spectral-domain optical coherence tomography during accelerated corneal collagen crosslinking. AB - PURPOSE: To evaluate the role of spectral-domain optical coherence tomography (SDOCT) to measure corneal thickness during accelerated corneal crosslinking (CXL). METHODS: Intraoperative pachymetry was performed using SDOCT and ultrasound pachymetry (USP) in 6 eyes of 6 patients with keratoconus. Pachymetry readings were obtained at baseline, after epithelium removal and after 30 minutes of riboflavin instillation. SDOCT measurements of eyes with and without lid speculum during riboflavin instillation were compared. RESULTS: There was no statistically significant difference in central corneal thickness (CCT) measurements between SDOCT and USP (P > 0.05 for all). A significant decrease in both CCT (P = 0.031) and the thinnest corneal thickness (TCT) (P = 0.031) was observed during CXL. There was a greater reduction in CCT (38 +/- 6%) with the use of lid speculum as compared to the no-speculum eyes (18 +/- 9%) (P = 0.100). TCT was also reduced by a greater extent with the use of lid speculum (40 +/- 5% versus 26 +/- 7%; P = 0.100). CONCLUSION: SDOCT can be successfully used to measure intraoperative corneal pachymetry during corneal CXL. SDOCT measurements demonstrated corneal thinning intraoperatively during CXL, which was further accentuated by the use of a lid speculum during the procedure. PMID- 23984413 TI - Spleen stiffness correlates with the presence of ascites but not esophageal varices in chronic hepatitis C patients. AB - Although spleen stiffness has recently been identified as potential surrogate marker for portal hypertension, the relationship between spleen stiffness and portal hypertension has not been fully elucidated. We attempted to determine the relationship between the liver or spleen stiffness and the presence of ascites or esophageal varices by acoustic radiation force impulse (ARFI) imaging. A total of 33 chronic hepatitis C (CHC) patients (median age 68; range 51-84) were enrolled. We evaluated the relationship between the liver or spleen stiffness and indicators of portal hypertension as well as clinical and biochemical parameters. Fourteen healthy volunteers were used for validating the accuracy of AFRI imaging. The liver and spleen stiffness increased significantly with progression of liver disease. A significant positive correlation was observed between the liver and spleen stiffness. However, spleen stiffness, but not liver stiffness, was significantly associated with the presence of ascites (P < 0.05), while there was no significant association between the spleen stiffness and spleen index/presence of esophageal varices in CHC patients. The area under the receiver operating characteristic curve based on the spleen stiffness was 0.80. In conclusion, spleen stiffness significantly correlates with the presence of ascites but not esophageal varices in CHC patients. PMID- 23984412 TI - Heparan sulfate and heparanase as modulators of breast cancer progression. AB - Breast cancer is defined as a cancer originating in tissues of the breast, frequently in ducts and lobules. During the last 30 years, studies to understand the biology and to treat breast tumor improved patients' survival rates. These studies have focused on genetic components involved in tumor progression and on tumor microenvironment. Heparan sulfate proteoglycans (HSPGs) are involved in cell signaling, adhesion, extracellular matrix assembly, and growth factors storage. As a central molecule, HSPG regulates cell behavior and tumor progression. HS accompanied by its glycosaminoglycan counterparts regulates tissue homeostasis and cancer development. These molecules present opposite effects according to tumor type or cancer model. Studies in this area may contribute to unveil glycosaminoglycan activities on cell dynamics during breast cancer exploring these polysaccharides as antitumor agents. Heparanase is a potent tumor modulator due to its protumorigenic, proangiogenic, and prometastatic activities. Several lines of evidence indicate that heparanase is upregulated in all human sarcomas and carcinomas. Heparanase seems to be related to several aspects regulating the potential of breast cancer metastasis. Due to its multiple roles, heparanase is seen as a target in cancer treatment. We will describe recent findings on the function of HSPGs and heparanase in breast cancer behavior and progression. PMID- 23984414 TI - Association between allergic rhinitis and asthma control in Peruvian school children: a cross-sectional study. AB - BACKGROUND: Asthma and allergic rhinitis are highly prevalent conditions that cause major illness worldwide. This study aimed to assess the association between allergic rhinitis and asthma control in Peruvian school children. METHODS: A cross-sectional study was conducted among 256 children with asthma recruited in 5 schools from Lima and Callao cities. The outcome was asthma control assessed by the asthma control test. A score test for trend of odds was used to evaluate the association between allergic rhinitis severity and the prevalence of inadequate asthma control. A generalized linear regression model was used to estimate the adjusted prevalence ratios of inadequate asthma control. RESULTS: Allergic rhinitis was present in 66.4% of the population with asthma. The trend analysis showed a positive association between allergic rhinitis and the probability of inadequate asthma control (P < 0.001). It was associated with an increased prevalence of inadequate asthma control, with adjusted prevalence ratios of 1.53 (95% confidence interval: 1.19-1.98). CONCLUSION: This study indicates that allergic rhinitis is associated with an inadequate level of asthma control, giving support to the recommendation of evaluating rhinitis to improve asthma control in children. PMID- 23984415 TI - Development of conformation independent computational models for the early recognition of breast cancer resistance protein substrates. AB - ABC efflux transporters are polyspecific members of the ABC superfamily that, acting as drug and metabolite carriers, provide a biochemical barrier against drug penetration and contribute to detoxification. Their overexpression is linked to multidrug resistance issues in a diversity of diseases. Breast cancer resistance protein (BCRP) is the most expressed ABC efflux transporter throughout the intestine and the blood-brain barrier, limiting oral absorption and brain bioavailability of its substrates. Early recognition of BCRP substrates is thus essential to optimize oral drug absorption, design of novel therapeutics for central nervous system conditions, and overcome BCRP-mediated cross-resistance issues. We present the development of an ensemble of ligand-based machine learning algorithms for the early recognition of BCRP substrates, from a database of 262 substrates and nonsubstrates compiled from the literature. Such dataset was rationally partitioned into training and test sets by application of a 2-step clustering procedure. The models were developed through application of linear discriminant analysis to random subsamples of Dragon molecular descriptors. Simple data fusion and statistical comparison of partial areas under the curve of ROC curves were applied to obtain the best 2-model combination, which presented 82% and 74.5% of overall accuracy in the training and test set, respectively. PMID- 23984416 TI - Variables associated with performance of an active limb movement following within session instruction in people with and people without low back pain. AB - Modification of a movement pattern can be beneficial in decreasing low back pain (LBP) symptoms. There is variability, however, in how well people are able to modify performance of a movement. What has not been identified is the factors that may affect a person's ability to modify performance of a movement. We examined factors related to performance of active hip lateral rotation (HLR) following standardized instructions in people with and people without LBP. Data were collected during performance of HLR under 3 conditions: passive, active, and active instructed. In people with LBP, motion demonstrated during the passive condition (r = 0.873, P < 0.001), motion demonstrated during the active condition (r = 0.654, P = 0.008), and gender (r = 0.570, P = 0.027) were related to motion demonstrated during the active-instructed condition. Motion demonstrated during the passive condition explained 76% (P < 0.001) of the variance in motion demonstrated during the active-instructed condition. A similar relationship did not exist in people without LBP. The findings of the study suggest that it may be important to assess motion demonstrated during passive HLR to determine how difficult it will be for someone with LBP to modify the performance of HLR. Prognosis should be worst for those who display similar movement patterns during passive HLR and active-instructed HLR. PMID- 23984417 TI - Vitamin C intake reduces the cytotoxicity associated with hyperglycemia in prediabetes and type 2 diabetes. AB - Hyperglycemia leads to the formation of free radicals and advanced glycation end products (AGEs). Antioxidants can reduce the level of protein glycation and DNA damage. In this study, we compared the levels of vitamin C intake, which is among the most abundant antioxidants obtained from diet, with the levels of fasting plasma glucose (FPG), glycated hemoglobin (A1C), DNA damage, and cytotoxicity in prediabetic subjects and type 2 diabetic subjects. Our results indicated that there was no significant correlation between FPG or A1C and DNA damage parameters (micronuclei, nucleoplasmic bridges, and nuclear buds). FPG and A1C correlated with necrosis (r = 0.294; P = 0.013 and r = 0.401; P = 0.001, resp.). Vitamin C intake correlated negatively with necrosis and apoptosis (r = -0.246; P = 0.040, and r = -0.276; P = 0.021, resp.). The lack of a correlation between the FPG and A1C and DNA damage could be explained, at least in part, by the elimination of cells with DNA damage by either necrosis or apoptosis (cytotoxicity). Vitamin C appeared to improve cell survival by reducing cytotoxicity. Therefore, the present results indicate the need for clinical studies to evaluate the effect of low-dose vitamin C supplementation in type 2 diabetes. PMID- 23984418 TI - Crystal structure of the FAD-containing ferredoxin-NADP+ reductase from the plant pathogen Xanthomonas axonopodis pv. citri. AB - We have solved the structure of ferredoxin-NADP(H) reductase, FPR, from the plant pathogen Xanthomonas axonopodis pv. citri, responsible for citrus canker, at a resolution of 1.5 A. This structure reveals differences in the mobility of specific loops when compared to other FPRs, probably unrelated to the hydride transfer process, which contributes to explaining the structural and functional divergence between the subclass I FPRs. Interactions of the C-terminus of the enzyme with the phosphoadenosine of the cofactor FAD limit its mobility, thus affecting the entrance of nicotinamide into the active site. This structure opens the possibility of rationally designing drugs against the X. axonopodis pv. citri phytopathogen. PMID- 23984419 TI - Cytotoxicity testing of temporary luting cements with two- and three-dimensional cultures of bovine dental pulp-derived cells. AB - This study evaluated the cytotoxicity of eugenol-containing and eugenol-free temporary luting cements. For cytotoxicity testing, bovine pulp-derived cells transfected with Simian virus 40 Large T antigen were exposed to extracts of eugenol-containing (Rely X Temp E) and eugenol-free (Provicol, PreVISION CEM, and Rely X Temp NE) temporary luting cements for 24 h. The cytotoxicity of the same materials was also evaluated in a dentin barrier test device using three dimensional cell cultures of bovine pulp-derived cells. The results of the cytotoxicity studies with two-dimensional cultures of bovine dental pulp-derived cells revealed that cell survival with the extracts of Rely X Temp E, Provicol, PreVISION CEM, and Rely X Temp NE was 89.1%, 84.9%, 92.3%, and 66.8%, respectively. Rely X Temp NE and Provicol showed cytotoxic effects on bovine dental pulp-derived cells (P < 0.05). The results of the dentin barrier test revealed that cell survival with the above-mentioned temporary cement was 101.5%, 91.9%, 93.5%, and 90.6%, respectively. None of the temporary luting cements significantly reduced cell survival compared with the negative control in the dentin barrier test (P > 0.05). Biologically active materials released from temporary luting cements may not influence the dentine-pulp complex if the residual dentine layer is at least 0.5 mm thick. PMID- 23984420 TI - Isolation and characterisation of mesenchymal stem cells from different regions of the human umbilical cord. AB - Umbilical cords as a source of stem cells are of increasing interest for cell therapies as they present little ethical consideration and are reported to contain immune privileged cells which may be suitable for allogeneic based therapies. Mesenchymal stem cells (MSCs) sourced from several different cord regions, including artery, vein, cord lining, and Wharton's jelly, are described in the literature. However, no one study has yet isolated and characterised MSCs from all regions of the same cord to determine the most suitable cells for cell based therapeutics. PMID- 23984421 TI - Calcifications of vertebrobasilar arteries on CT: detailed distribution and relation to risk factors in 245 ischemic stroke patients. AB - INTRODUCTION: Intracranial atherosclerosis is responsible for a substantial proportion of strokes worldwide but its detailed morphology in the vertebrobasilar arteries (VBA) is unknown. SUBJECT AND METHODS: Cases with ischemic strokes were retrospectively sought from the hospital database. Native CT scans were assessed for vessel area and intracranial artery calcifications (ICACs) in VBA. The calcifications were classified as focal (FCs), crescent, and circular. RESULTS: 245 patients (mean age: 77.1 +/- 10.2 years, 57.6% females) had visible ICACs. Calcifications were found in 75.9%, 63.3%, and 17.1% in the left vertebral artery (LVA), the right vertebral artery (RVA), and the basilar artery (BA), respectively. FCs were present in 91.0%, 90.3%, and 100.0%; crescents in 30.3%, 29.0%, and 7.1%, and circulars in 6.4%, 4.8%, and 0.0% ) and 46 (27.4%) for RVA and LVA, respectively. Risk factors associated with vertical dispersion of ICACs were male gender (OR : 2.69, 1.38-5.28) and diabetes of the RVA, LVA, and BA, respectively. FCs in dorsolateral quadrant were least prevalent in both vertebral arteries (VAs): 46 (29.8%(OR : 2.28, 1.04-4.99). CONCLUSIONS: FCs in VAs are least prevalent in dorsolateral quadrants. The vertical dispersion of ICACs seems to be associated with the male gender and diabetes. PMID- 23984422 TI - The predictive value of adrenomedullin for development of severe sepsis and septic shock in emergency department. AB - OBJECTIVE: The aim of the study was to assess adrenomedullin (AM) as a predictor for development of severe sepsis and septic shock in emergency department (ED). METHOD: From December 2011 to October 2012, 372 consecutive septic patients admitted to ED were enrolled. AM was examined in every patient. All patients were followed up for 3 days. The outcome variable was development of severe sepsis or septic shock. The predictive ability of AM was evaluated by binary logistic regression analysis and receiver operating characteristic (ROC) curve. RESULT: On admission, the differences of AM among patients with different comorbidities, infections, and culture results were not significant. AM level was higher in patients who progressed than in who did not (41.63 +/- 6.55 versus 31.31 +/- 7.71 ng/L, P < 0.001). AM was the only independent predictor of outcome. The area under ROC curve of AM was 0.847. With a cutoff value of 41.24 ng/L, the sensitivity was 67.6%, the specificity was 90.0%, the positive predictive value was 61.5%, the negative predictive value was 92.2%, the positive likelihood ratio was 6.78, and the negative likelihood ratio was 0.36. CONCLUSION: Adrenomedullin is valuable for predicting development of severe sepsis and septic shock in ED. PMID- 23984424 TI - Evaluation of in vivo wound healing activity of Bacopa monniera on different wound model in rats. AB - Wound healing effects of 50% ethanol extract of dried whole plant of Bacopa monniera (BME) was studied on wound models in rats. BME (25 mg/kg) was administered orally, once daily for 10 days (incision and dead space wound models) or for 21 days or more (excision wound model) in rats. BME was studied for its in vitro antimicrobial and in vivo wound breaking strength, WBS (incision model), rate of contraction, period of epithelization, histology of skin (excision model), granulation tissue free radicals (nitric oxide and lipid peroxidation), antioxidants (catalase, superoxide dismutase, and reduced glutathione), acute inflammatory marker (myeloperoxidase), connective tissue markers (hydroxyproline, hexosamine, and hexuronic acid), and deep connective tissue histology (dead space wound). BME showed antimicrobial activity against skin pathogens, enhanced WBS, rate of contraction, skin collagen tissue formation, and early epithelization period with low scar area indicating enhanced healing. Healing effect was further substantiated by decreased free radicals and myeloperoxidase and enhanced antioxidants and connective tissue markers with histological evidence of more collagen formation in skin and deeper connective tissues. BME decreased myeloperoxidase and free radical generated tissue damage, promoting antioxidant status, faster collagen deposition, other connective tissue constituent formation, and antibacterial activity. PMID- 23984425 TI - NCBI2RDF: enabling full RDF-based access to NCBI databases. AB - RDF has become the standard technology for enabling interoperability among heterogeneous biomedical databases. The NCBI provides access to a large set of life sciences databases through a common interface called Entrez. However, the latter does not provide RDF-based access to such databases, and, therefore, they cannot be integrated with other RDF-compliant databases and accessed via SPARQL query interfaces. This paper presents the NCBI2RDF system, aimed at providing RDF based access to the complete NCBI data repository. This API creates a virtual endpoint for servicing SPARQL queries over different NCBI repositories and presenting to users the query results in SPARQL results format, thus enabling this data to be integrated and/or stored with other RDF-compliant repositories. SPARQL queries are dynamically resolved, decomposed, and forwarded to the NCBI provided E-utilities programmatic interface to access the NCBI data. Furthermore, we show how our approach increases the expressiveness of the native NCBI querying system, allowing several databases to be accessed simultaneously. This feature significantly boosts productivity when working with complex queries and saves time and effort to biomedical researchers. Our approach has been validated with a large number of SPARQL queries, thus proving its reliability and enhanced capabilities in biomedical environments. PMID- 23984426 TI - Sonication-based improvement of the physicochemical properties of Guar Gum as a potential substrate for modified drug delivery systems. AB - Guar Gum is a natural polysaccharide that, due to its physicochemical properties, is extensively investigated for biomedical applications as a matrix for modified drug delivery, but it is also used in the food industry as well as in cosmetics. A commercial sample of Guar Gum was sonicated for different periods of time, and the reduction in the average molecular weight was monitored by means of viscometric measurements. At the same time, the rheological behaviour was also followed, in terms of viscoelasticity range, flow curves, and mechanical spectra. Sonicated samples were used for the preparation of gels in the presence of borate ions. The effect of borax on the new samples was investigated by recording mechanical spectra, flow curves, and visible absorption spectra of complexes with Congo Red. The anisotropic elongation, observed in previous studies with tablets of Guar Gum and borax, was remarkably reduced when the sonicated samples were used for the preparation of the gels. PMID- 23984423 TI - Nutritional properties of dietary omega-3-enriched phospholipids. AB - Dietary fatty acids regulate several physiological functions. However, to exert their properties, they have to be present in the diet in an optimal balance. Particular attention has been focused on tissue highly polyunsaturated fatty acids (HPUFAs) n-6/n-3 ratio, influenced by the type and the esterified form of dietary fatty acids. Dietary EPA and DHA when esterified to phospholipids (PLs) are more efficiently incorporated into tissue PLs and seem to possess peculiar properties through specific mechanism(s) of action, such as the capacity to affect endocannabinoid biosynthesis at much lower doses than EPA and DHA in triglyceride form, probably because of the above mentioned higher incorporation into tissue PLs. Downregulation of the endocannabinoid system seems to mediate the positive effects exerted by omega-3-enriched PLs on several parameters of metabolic syndrome. PLs are one of the major dietary forms of EPA and DHA we are exposed to with the everyday diet; therefore, it is not surprising that it guarantees an effective EPA and DHA nutritional activity. Future studies should address whether EPA and DHA in PL form are also more effective than other formulations in ameliorating other pathological conditions where n-3 HPUFAs seem to exert beneficial activities such as cancer and psychiatric disorders. PMID- 23984427 TI - Growth factors serum levels in coronary artery disease patients scheduled for bypass surgery: perioperative dynamics and comparisons with healthy volunteers. AB - BACKGROUND: Vascular endothelial growth factors are important mediators for neovascularization of chronically ischemic adult heart, but their elevated values have also been connected with acute ischemia. Coronary artery bypass grafting (CABG) is associated with activation of inflammatory processes. We aimed to clarify whether the latter is also accompanied with acute changes in concentrations of vascular growth factors. METHODS: Concentrations of growth factors VEGF and EGF, monocyte chemoattractant protein-1 (MCP-1), and a set of cytokines of 39 patients with stable coronary artery disease (CAD) were evaluated before and after CABG. Preoperative values were compared with data of healthy volunteers. RESULTS: In comparison with CAD patients, healthy controls had significantly higher values of VEGF (15.5 (10.05-35.3) and 119.4 (55.7-136.9) pg/mL, resp.), EGF (1.70 (1.14-3.18) and 37.3 (27.1-51.9) pg/mL, resp.), and MCP 1 (111.6 (81.75-171.9) and 156.9 (134.7-241.3) pg/mL, resp.). MCP-1, but not others, demonstrated a significant rise throughout the postoperative period. Proinflammatory interleukin-6 was significantly higher and anti-inflammatory IL-4 and IL-10 lower in patients with CAD. CONCLUSIONS: Patients with stable CAD have lower serum levels of growth factors than healthy volunteers. MCP-1, but not VEGF and EGF, becomes elevated immediately after CABG. Inflammatory status of CAD patients was drifted towards proinflammatory state. PMID- 23984428 TI - Animal models of diabetic neuropathy: progress since 1960s. AB - Diabetic or peripheral diabetic neuropathy (PDN) is one of the major complications among some other diabetic complications such as diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. The use of animal models in the research of diabetes and diabetic complications is very common when rats and mice are most commonly used for many reasons. A numbers of animal models of diabetic and PDN have been developed in the last several decades such as streptozotocin-induced diabetic rat models, conventional or genetically modified or high-fat diet-fed C57BL/Ks (db/db) mice models, streptozotocin-induced C57BL6/J and ddY mice models, Chinese hamster neuropathic model, rhesus monkey PDN model, spontaneously diabetic WBN/Kob rat model, L-fucose-induced neropathic rat model, partial sciatic nerve ligated rat model, nonobese diabetic (NOD) mice model, spontaneously induced Ins2 Akita mice model, leptin-deficient (ob/ob) mice model, Otsuka Long-Evans Tokushima Fatty (OLETF) rat model, surgically-induced neuropathic model, and genetically modified Spontaneously Diabetic Torii (SDT) rat model, none of which are without limitations. An animal model of diabetic or PDN should mimic the all major pathogeneses of human diabetic neuropathy. Hence, this review comparatively evaluates the animal models of diabetic and PDN which are developed since 1960s with their advantages and disadvantages to help diabetic research groups in order to more accurately choose an appropriate model to meet their specific research objectives. PMID- 23984429 TI - Novel role of parathyroid hormone-related protein in the pathophysiology of the diabetic kidney: evidence from experimental and human diabetic nephropathy. AB - Parathyroid hormone-related protein (PTHrP) and its receptor type 1 (PTH1R) are extensively expressed in the kidney, where they are able to modulate renal function. Renal PTHrP is known to be overexpressed in acute renal injury. Recently, we hypothesized that PTHrP involvement in the mechanisms of renal injury might not be limited to conditions with predominant damage of the renal tubulointerstitium and might be extended to glomerular diseases, such as diabetic nephropathy (DN). In experimental DN, the overexpression of both PTHrP and the PTH1R contributes to the development of renal hypertrophy as well as proteinuria. More recent data have shown, for the first time, that PTHrP is upregulated in the kidney from patients with DN. Collectively, animal and human studies have shown that PTHrP acts as an important mediator of diabetic renal cell hypertrophy by a mechanism which involves the modulation of cell cycle regulatory proteins and TGF beta 1. Furthermore, angiotensin II (Ang II), a critical factor in the progression of renal injury, appears to be responsible for PTHrP upregulation in these conditions. These findings provide novel insights into the well-known protective effects of Ang II antagonists in renal diseases, paving the way for new therapeutic approaches. PMID- 23984430 TI - Outcome of acute renal injury in diabetic mice with experimental endotoxemia: role of hypoxia-inducible factor-1 alpha. AB - The role of diabetic nephropathy in the outcome of acute renal injury (AKI) is not well defined. Herein we evaluate the outcome of lipopolysaccharide- (LPS-) induced AKI in streptozotocin-induced diabetes, as well as the potential role of Hypoxia Inducible Factor (HIF-1 alpha ) in this condition. Although 6 h after LPS injection all mice developed a decrease in renal function, proteinuric diabetic mice showed a better recovery of this parameter throughout the study (72 h). Both HIF-1 alpha and vascular endothelium growth factor (VEGF) were found to be upregulated in diabetic mice. After LPS injection, all animals showed an upregulation of these factors, although it was higher in the diabetic group. Glycated albumin (GA) was found to upregulate HIF-1 alpha in HK-2 cells, which resulted in increased production of VEGF. Interestingly, LPS cooperated with GA to induce HIF-1 alpha upregulation. In conclusion, diabetic mice display a better recovery of AKI after experimental endotoxemia. Moreover, these animals showed an increased expression of both HIF-1 alpha and VEGF that was reproduced by incubating renal cells with GA. Since VEGF is considered a survival factor for tubular cells, our findings suggest that diabetes displays HIF-1 alpha upregulation that might function as a "precondition state" offering protection from endotoxic AKI. PMID- 23984432 TI - Traditional medicine in management of type 2 diabetes mellitus. PMID- 23984431 TI - Prevalence of type 2 diabetes mellitus in hepatitis C virus infected population: a Southeast Asian study. AB - PURPOSE: The study was aimed to investigate the frequency of diabetes mellitus type 2 in patients infected with chronic hepatitis C virus and its association with cirrhosis. PATIENTS AND METHODS: This prospective case series was conducted at Section of Gastroenterology and Hepatology, Isra University Hospital, Hyderabad, over a period of 4 months from June 2009 to October 2009. Hepatitis C virus seropositive patients who were older than 18 years, diabetic or nondiabetic, were included. Basic demographic data collected by questionnaire and laboratory investigations including fasting blood glucose levels, serum cholesterol, and liver function tests were done. A logistic regression model was used to explore the association between diabetic and nondiabetic HCV seropositives and type 2 diabetes mellitus with cirrhosis. RESULTS: A total of 361 patients with hepatitis C were analyzed; the prevalence of type 2 diabetes mellitus in HCV patients was 31.5%. Out of the total number of the participants, 58.4% (n = 211) were cirrhotics, while 41.6% (n = 150) were noncirrhotic HCV seropositives. In multivariate analysis, cirrhotic patients appeared significantly more likely (P = 0.01) to be diabetic as compared with noncirrhotic patients (OR = 2.005, 95% CI: 1.15, 3.43). CONCLUSION: Advancing age, increased weight, and HCV genotype 3 are independent predictors of type 2 diabetes in HCV seropositive patients, and there is a statistically significant association of cirrhosis observed with type 2 diabetes mellitus. PMID- 23984433 TI - Exploring the variability in acute glycemic responses to exercise in type 2 diabetes. AB - AIM: To explore the factors associated with exercise-induced acute capillary glucose (CapBG) changes in individuals with type 2 diabetes (T2D). METHODS: Fifteen individuals with T2D were randomly assigned to energy-matched high intensity interval exercise (HI-IE) and moderate intensity continuous exercise (MI-CE) interventions and performed a designated exercise protocol 5 days per week for 12 weeks. The duration of exercise progressed from 30 to 60 minutes. CapBG was measured immediately before and after each exercise session. Timing of food and antihyperglycemic medication intake prior to exercise was recorded. RESULTS: Overall, the mean CapBG was lowered by 1.9 mmol/L (P < 0.001) with the change ranging from -8.9 to +2.7 mmol/L. Preexercise CapBG (44%; P < 0.001), medication (5%; P < 0.001), food intake (4%; P = 0.043), exercise duration (5%; P < 0.001), and exercise intensity (1%; P = 0.007) were all associated with CapBG changes, explaining 59% of the variability. CONCLUSION: The greater reduction in CapBG seen in individuals with higher preexercise CapBG may suggest the importance of exercise in the population with elevated glycemia. Lower blood glucose can be achieved with moderate intensity exercise, but prolonging exercise duration and/or including brief bouts of intense exercise accentuate the reduction, which can further be magnified by performing exercise after meals and antihyperglycemic medication. This trial is registered with ClinicalTrial.gov NCT01144078. PMID- 23984436 TI - [Mass treatment and information against intestinal worms]. PMID- 23984437 TI - Current world literature. Movement disorders. PMID- 23984438 TI - Current world literature. Postoperative problems. PMID- 23984434 TI - Exercise and the aging endothelium. AB - The endothelium plays a critical role in the maintenance of cardiovascular health by producing nitric oxide and other vasoactive materials. Aging is associated with a gradual decline in this functional aspect of endothelial regulation of cardiovascular homeostasis. Indeed, age is an independent risk factor for cardiovascular diseases and is in part an important factor in the increased exponential mortality rates from vascular disease such as myocardial infarction and stroke that occurs in the ageing population. There are a number of mechanisms suggested to explain age-related endothelial dysfunction. However, recent scientific studies have advanced the notion of oxidative stress and inflammation as the two major risk factors underlying aging and age-related diseases. Regular physical activity, known to have a favorable effect on cardiovascular health, can also improve the function of the ageing endothelium by modulating oxidative stress and inflammatory processes, as we discuss in this paper. PMID- 23984439 TI - Current world literature. Minimally invasive gynecologic procedures. PMID- 23984440 TI - Activating silent argonautes. AB - Multiple Argonaute proteins are implicated in gene silencing by RNA interference (RNAi), but only one is known to be an endonuclease that can cleave target mRNAs. Chimeric Argonaute proteins now reveal an unexpected mechanism by which mutations distal to the catalytic center can unmask intrinsic catalytic activity, results hinting at structurally mediated regulation. PMID- 23984441 TI - Antibodies expose multiple weaknesses in the glycan shield of HIV. AB - A shield of glycans coats the viral-envelope proteins of HIV. Recent work shows how broadly neutralizing antibodies can recognize this shield despite structural variation in these 'self' carbohydrate structures. PMID- 23984442 TI - EMI1, a three-in-one ubiquitylation inhibitor. AB - The anaphase-promoting complex/cyclosome (APC/C) is restricted by metazoan protein early mitotic inhibitor 1 (EMI1), a natural, potent inhibitor. New findings suggest that the multimodal inhibitory mechanisms of EMI1 control APC/C dependent ubiquitylation. PMID- 23984443 TI - [Better visibility by reverse Trendelenburg position]. PMID- 23984444 TI - [Computer-assisted compensation acceleration]. PMID- 23984445 TI - [7th International Congress for mini-invasive and robotic surgery. 14-16 October. Brno, Czech Republic]. PMID- 23984447 TI - [6th Interactive Congress on Wound Healing]. PMID- 23984446 TI - Isolated plasmacytoma involving the brain parenchyma and cerebral spinal fluid. PMID- 23984448 TI - An unusual case of microangiopathic hemolytic anemia resulting from metastatic angiosarcoma. PMID- 23984449 TI - [David Baltimore]. PMID- 23984450 TI - If you have prediabetes, lose that gut. Not all excess body fat carries equal risk, but belly fat is a killer. PMID- 23984452 TI - Vegetarian diets aid longevity, reduce risk of all-cause mortality. But results are more significant in men than women. Further research is needed to determine why. PMID- 23984451 TI - The great salt controversy. If cutting back on sodium is good for you, consuming even less should be healthier--right? But the answer isn't clear, leaving us unsure how much salt is safe. PMID- 23984453 TI - Halting osteoarthritis progression. Bone underneath cartilage exacerbates OA damage via surplus bone formation. PMID- 23984455 TI - Can you tell me the pros and cons of brachytherapy versus external-beam therapy versus surgery for prostate cancer? PMID- 23984454 TI - Depression nearly doubles stroke risk in women. Researchers find that the risk is especially high among women around the age of 50. PMID- 23984456 TI - What's the usual treatment for rotator cuff injuries--and what generally causes them? PMID- 23984457 TI - What are the effects of taking steroids over a period of time? PMID- 23984458 TI - Lately I've been hearing about the "Nordic" diet. What can you tell me about this? PMID- 23984459 TI - Quality of life and health as existential values. PMID- 23984460 TI - Clinical snapshot: Dripping fluid from the prepuce of a paint horse. PMID- 23984461 TI - Reply: To PMID 23464951. PMID- 23984462 TI - [Issue of passive smoking in a smoke-free workplace that has no designated room for smokers]. PMID- 23984463 TI - [Incidents of bullying and harassment in the workplace]. PMID- 23984465 TI - Variables that matter. PMID- 23984464 TI - [Not Available]. PMID- 23984466 TI - [5th Croatian Symposium on Renal Replacement Therapy with international participation. Opatija, 11-14 October]. PMID- 23984467 TI - [6th Symposium of medical nurses and technicians in nephrology, dialysis and renal transplantation. Opatija, 13-14 October 2012]. PMID- 23984468 TI - Health care spending after adopting a full-replacement, high-deductible health plan with a health savings account: a five-year study. PMID- 23984469 TI - EMR? LOL (lots of luck): one ophthalmic nurse's experience. PMID- 23984470 TI - Gossip wisdom. PMID- 23984471 TI - Accommodation and presbyopia. PMID- 23984472 TI - Current issues in vision rehabilitation. PMID- 23984473 TI - Plaquenil toxicity. PMID- 23984474 TI - Stepping stones to success: How to keep OR staff trained and competent in low volume eye surgery. PMID- 23984475 TI - Why I certified. PMID- 23984476 TI - Glaucoma-related vision loss may increase risk for auto accidents: Study results show need for mandatory visual field testing for drivers. PMID- 23984477 TI - Take it outside. PMID- 23984478 TI - ANA nurses stand with Obama in calling for health care reform now; nation's "most trusted profession" adds to momentum at White House event. PMID- 23984479 TI - Lorrie Durbin, RN, BSN, COMT. PMID- 23984480 TI - Heart sounds: are you listening? Part 2. AB - The first of this two-part article on heart sounds was in the Spring 2013 issue of the Canadian Journal of Cardiovascular Nursing (Reimer-Kent, 2013). Part 1 emphasized the importance of all nurses having an understanding of heart sounds and being proficient in cardiac auscultation. The article also focused on an overview of the fundamentals of cardiac auscultation and basic heart sounds. This article provides an overview of the anatomy and pathophysiology related to valvular heart disease and describes the array of heart sounds associated with stenotic or regurgitant aortic and mitral valve conditions. PMID- 23984481 TI - Caring for patients receiving therapeutic hypothermia post cardiac arrest in the intensive care unit. AB - Survivors of ventricular fibrillation cardiac arrest have poor and often devastating neurological outcomes despite advances in resuscitation techniques and services (Bernard et al., 2002; Collins & Samworth, 2008). In an effort to increase survival rates, improve neurological outcomes and reduce mortality for surviving patients, clinical trials have shown that a mild state of therapeutic hypothermia (32 degrees C to 34 degrees C) has been linked to improved patient outcomes post cardiac arrest (Koran, 2008; Lee & Asare, 2010). Many hospitals in Canada currently use therapeutic hypothermia (TH), but the nursing care requires advanced nursing knowledge and skills. In an effort to prepare registered nurses to care for patients receiving TH, a specially designed education program was implemented at the Rouge Valley Health System Hospital (RVHS) in Ontario. Busy nurses need flexibility in the delivery of programs in the clinical setting, and this program was designed to meet that need with a combination of self-paced modules, lectures, discussions and a return demonstration. In this article, the authors discuss the nursing care of post cardiac arrest patients receiving TH, and the design and implementation of the education program. PMID- 23984482 TI - The transition from acute care to home: a review of issues in discharge teaching and a framework for better practice. AB - Patients are often sent home with complex discharge plans that can become overwhelming and difficult to follow. By contrast, implementing effective teaching at the time of discharge can lead to a decrease in the rate of hospital readmissions and mortality for patients post discharge (Koelling, Johnson, Cody, & Aaronson, 2005). Unfortunately, many of the discharge teaching practices and programs used in health care settings have been criticized as being ineffective. Ensuring that patients are prepared for the transition from hospital to home after a cardiac event will require a fundamental shift in how teaching is performed in acute care settings. In this paper, the authors identify and examine models and concepts relevant to improving the process of providing discharge education in acute care settings. This includes attention to adult education, self-management and patient-centred care. A practical framework was developed: Important Elements of Effective Discharge Teaching. This framework can be used by frontline staff to initiate realistic practice change and promote the use of evidence-based strategies related to discharge teaching in acute care settings. The Important Elements of Effective Discharge Teaching framework provides health care practitioners with a tool to evaluate and reflect on their current professional practice and provides examples of teaching strategies that are based on best evidence. Nurses can incorporate elements of this framework while providing health teaching to patients after a cardiac event. PMID- 23984483 TI - Child welfare culture: lessons learned from Patty O'Keeffe. PMID- 23984484 TI - What child welfare staff say about organizational culture. AB - This article examines the factors that can affect job satisfaction, organizational culture and climate, and intent to leave at a public child welfare agency. Findings from focus group data collected from direct line, middle, and senior managers revealed a passive defensive culture. The authors discuss concrete organizational interventions to assist the agency in shifting to a constructive oriented culture through enhancements in communication, including supervision and shared decisionmaking, recognition and rewards, and improvement in other areas related to working conditions. PMID- 23984485 TI - Promoting cross-sector partnerships in child welfare: qualitative results from a five-state strategic planning process. AB - Little is known about effective strategic planning for public and private child welfare agencies working together to serve families. During a professionally facilitated, strategic planning event, public and private child welfare administrators from five states explored partnership challenges and strengths with a goal of improving collaborative interactions in order to improve outcomes for children and families. Summarizing thematic results of session notes from the planning event, this article describes effective strategies for facilitation of such processes as well as factors that challenge or promote group processes. Implications for conducting strategic planning in jurisdictions seeking to improve public/private partnerships are discussed. PMID- 23984487 TI - Substantiation assessment criteria: a framework for evaluating contested substantiation in child protection practice. AB - This article presents substantiation assessment criteria as an evidentiary framework for evaluating contested substantiation of child maltreatment in child protection practice. To accomplish this purpose, the article discusses contested substantiation and judicial outcomes in contested cases as a means of underscoring the criteria's evidentiary relevance. The article presents conceptually and empirically driven substantiation assessment criteria and highlights their relevance for guiding substantiation decisions, evidentiary hearings, and future research in contested substantiation of child maltreatment. PMID- 23984486 TI - A profile of post-ASFA hearings in the U.S. Congress. AB - Examination of the policymaking process can yield a better understanding of the rationale behind policy content and prescriptions for shaping future policies. To this end, this study uses data from 38 child welfare hearings held by the U.S. Congress from 1999-2010 to describe key hearings, as well as Congress, committee member, and child welfare indicators. This manuscript concludes with implications for research and practice. PMID- 23984488 TI - Child custody disputes within the context of child protection investigations: secondary analysis of the Canadian Incident Study of Reported Child Abuse and Neglect. AB - This national study of child custody disputes within the context of child protection investigations confirms and reinforces the perception in the field that child custody disputes are more likely to reopen for investigations, include higher rates of malicious referrals and involve a higher proportion of children with emotional and functioning issues compared to non-custody-related investigations. Future research might consider the reasons for these higher rates so to improve the identification of these cases and to make more informed decisions about how best to respond to these families. The greatest contribution of this study is that it provides important new evidence to reinforce the need to prioritize child custody disputes within the context of child protection services given the unique challenges and opportunities for making well-informed case plan decisions. PMID- 23984489 TI - Parenting in recovery program: participant responses and case examples. AB - Approximately 80% of children served by child welfare agencies have parents who abuse or are dependent on alcohol or illicit drugs. Despite the devastating effects on children from living in substance abusing families, child protective service practitioners have limited options available to assist these families. The Parenting in Recovery program was created to address the needs of substance abusing mothers involved in child welfare. This manuscript describes this program and perceptions of participants concerning its effectiveness. PMID- 23984490 TI - "The environment as a cause of disease in children": Josef Friedjung's transnational influence on modern child welfare theory. AB - Josef K. Friedjung's Advanced Pediatrics--A Companion to Traditional Textbooks (Erlebte Kinderheilkunde--eine Erganzung er gebrauchlichen Lehrbucher), published in 1919 in Vienna, has cast a long but nearly-vanished shadow over modern child welfare theory. The originality of his focus on "the whole child" was in some ways a commentary on Sigmund Freud, but its overtly progressive political character gave Friedjung's argument visible applicability within the field of urban social welfare. As a pediatrician and an ardent cosmopolitan, Friedjung was willing to consider conflicting values between traditional family systems and the state. Had the Nazis not forced him into exile in Palestine, where he died in 1946, Friedjung's pioneering oeuvre would have joined our child welfare narrative long ago. Fortunately today archival evidence on which this study draws, fragmented as it is in both German and English, does confirm that the first and second generation psychoanalysts, Friedjung among them, built a mental health movement around a social justice core closely allied to the cultural context of central Europe from 1918 to 1933. In many ways, child welfare as we know it emerged as a practical implementation of that ideology. PMID- 23984491 TI - Sustainability of healthcare systems: aligning the safety and quality debate with the debate on the financing systems and mechanisms. PMID- 23984492 TI - The precautionary principle: is it safe. AB - The precautionary principle is generally acknowledged to be a powerful tool for protecting health but it was originally invoked by policy makers for dealing with environmental issues. In the 1990s, the principle was incorporated into many legislative and regulatory texts in international law. One can consider that the precautionary principle has turned into "precautionism" necessary to prove to the people, taking account of risk in decisions. There is now a risk that these abuses will deprive the principle of its meaning and value. When pushed to its limits, the precautionary principle can even be dangerous when applied to the healthcare field. This is why a critical analysis of the principle is necessary. Through the literature, it sometimes seems to deviate somehow from the essence of the precautionary principle as it is commonly used in relation to health. We believe that educational work is necessary to familiarize professionals, policy makers and public opinion of the precautionary principle and avoid confusion. We propose a critical analysis of the use and misuse of the precautionary principle. PMID- 23984493 TI - Liabilities of a physician confronted with child abuse. AB - Several research questions raises when physicians are confronted with a possible case of child abuse. First, there is a problem of professional secrecy. In most European countries, physicians have the right to speak when confronted with a state of emergency. In other countries, physicians have a duty to speak and alert the police when the life or physical integrity of a person is at stake. A second topic to be discussed involves the possible liability of physicians who do not report child abuse. By not reporting a case of possible child abuse, the physician is respecting the family life of the parents, even though the child might continue to suffer damages. Third and essentially, I analyse the possible liability of physicians who do inform the prosecutor ofa suspected child abuse. Specific criteria are elaborated to establish negligence when physicians report child abuse to the prosecutor. PMID- 23984494 TI - Finland on a road towards a modern legal biobanking infrastructure. AB - Finland has enacted a Biobank Act that will come into force on 1 September 2013. Finland is regarded as a highly successful environment for medical research using population samples and data for many reasons. One of the rationales behind the new legislation was to solve the problems due to the overly strict informed consent doctrine hindering access to old samples and data and asking for multi purpose consents. Yet although consent is the primary justification to use biobank samples and data, the Biobank Act allows asking for a consent for several unspecified future research purposes. The guiding principles of the Biobank Act are promotion of trust, equal access to data and samples, protection of privacy, acceleration of innovation activities, and bringing biobank activities under public scrutiny. To the author's knowledge, this is the first "all purpose" Biobank Act in Europe applied to all biobanks in one country. PMID- 23984495 TI - Treatments of low-priority and the Patient Mobility Directive 2011, an end to legal uncertainty for the English NHS? AB - The patient mobility case law of the Court of Justice of the European Union created legal uncertainty for the healthcare systems of EU Member States. The Patient Mobility Directive setting out patients' cross-border rights was adopted to end this uncertainty. With the Directive to be transposed into national law by October 2013 this article discusses whether the Directive achieves this objective for the English NHS. It contrasts the legal position of the NHS patient under case law and under the Directive regarding the need for prior authorisation of cross-border treatment, the level of reimbursement and the ambit of the healthcare benefits basket. It is argued that the risk of legal challenge may persist under the Directive, specifically regarding treatments which are classified by health authorities as low priority, namely treatments which are either not 'generally' available or only available subject to certain clinical criteria or access thresholds. PMID- 23984496 TI - European Court of Human Rights. ECHR 2013/9 Case of Costa and Pavan v. Italy, 28 August 2012, no. 54270/10 (Second Section). PMID- 23984497 TI - European Cout of Human Rights. ECHR 2013/10 Case of Spyra and Kranczkowski v. Poland, 25 September 2012, no. 19764/07 (Fourth Section). PMID- 23984498 TI - European Court of Human Rights. ECHR 2013/11 Case of Reshetnyak v. Russia, 8 January 2013, no. 56027/10 (First Section). PMID- 23984499 TI - European Court of Human Rights. ECHR 2013/12 Case of Jashi v. Georgia, 8 January 2013, no. 10799/06 (Third Section). PMID- 23984500 TI - European Court of Human Rights. ECHR 2013/13 Case of Claes v. Belgium, 10 January 2013, no. 43418/09 (Fifth Section). PMID- 23984501 TI - European Court of Justice. ECJ 2013/13, Skatteverket v. PFC Clinic AB, 21 March 2013 (C-91/12). PMID- 23984502 TI - HIM's evolving workforce. Preparing for the electronic age's HIM profession shake up. PMID- 23984503 TI - Taking the doctoral challenge. Educators push HIM professionals to add PhD to credentials. PMID- 23984504 TI - Celebrating 85 years of AHIMA. PMID- 23984505 TI - Reengineering the professional practice experience: with participation declining, one HIM program decided to revamp its PPE offering. PMID- 23984507 TI - The next HIM frontier. Population health information management presents a new opportunity for HIM. PMID- 23984506 TI - Embracing change ensures career resilience. AQ online program helps HIM professionals manage adversity. PMID- 23984508 TI - Focus on the future. Environmental scan illuminates the path ahead for HIM. PMID- 23984509 TI - Mapping the future of HIM education. PMID- 23984510 TI - Integrity of the healthcare record. Best practices for EHR documentation. PMID- 23984511 TI - [The associations between idiosyncratic adverse drug reactions and HLA alleles and their underlying mechanism]. AB - With the advent of Twenty-First century, more and more genome-wide association studies (GWAS) showed that idiosyncratic adverse drug reactions (ADRs) were closely related with human leukocyte antigen (HLA) alleles, such as the associations of abacavir-HLA-B*5701, allopurinol-HLA-B*5801, and carbamazepine HLA-B*1502, etc. To explore the mechanisms of these idiosyncratic drug reactions, hapten hypothesis, danger signal hypothesis, pharmacological interaction (P-I) concept and autoimmune mechanism are proposed. In this paper, recent GWAS studies on the HLA-mediated adverse drug reactions and underlying mechanism are reviewed in detail. PMID- 23984512 TI - [Mechanism of psoriasis generation in animal models]. AB - Psoriasis is a chronic inflammatory disease related to genome-wide and surroundings, it is important to develop a suitable animal model to research psoriasis pathogenesis and evolve pharmacotherapeutics. With the development of transgenetic technology in the past few years, psoriasis virulence gene animal model become a hotspot. Research of animal model of human psoriasis genes is reviewed in the paper. PMID- 23984513 TI - [The research progress of dynamic combinatorial chemistry]. AB - As a novel branch of combinational chemistry, dynamic combinatorial chemistry (DCC) can be viewed as a technique which combines library synthesis and screening in one pot. By addition of molecular target, ligangds, which show binding affinity or strong interaction with the molecular target, can be amplified an young but rapidly growing branch of combinatorial chemistry, has been widely used in organic chemistry, biochemistry, material fields. Ligands in the library can be amplified, since synthesis of the library is screened by a molecular target. Therefore, these structures could be identified easily. Consequently DCC has been widely used in the lead discovery, material chemistry and other fields. On the basis of the principle and method of DCC, this review emphasizes the three factors of DCC, including molecular targets (bio-enzyme, lectin, nucleic acid, organic molecule, inorganic molecule); reaction (disulphide chemistry, ammoniation reduction reaction, hydrazone chemistry, etc.) and analytical method. Meanwhile, limitation, current situation and future development of DCC were also discussed in this paper. PMID- 23984514 TI - [Research progresses of pharmacokinetics of traditional Chinese medicine]. AB - With the deepening of modernization of traditional Chinese medicine (TCM) and continuing emergence of new theories, methods and techniques, a very rapid and significant development has been achieved in the pharmacokinetics (PK) of TCM. This paper reviews the main research progresses of PK of TCM, including integrated PK of multiple effective components of TCM, fingerprint PK of TCM, novel dosage form PK of TCM, polysaccharide PK of TCM and drug interactions of TCM; and further sets up the prospects. PMID- 23984515 TI - [C2H2 zinc-finger recognition of biomolecules]. AB - C2H2 zinc-finger motif presents in 3% of proteins that are encoded in the human genome, and has the abilities to recognize DNA, RNA and protein. With nearly 3 decades of efforts, the mechanisms of zinc-finger mediated biomolecule recognitions have been studied to various extents. Zinc-finger binds into the major groove of DNA double helix, establishes an one-to-one recognition format between DNA bases and certain amino acids in a zinc-finger, and achieves specificity based on DNA sequences. While RNA molecules show a large variety in their structures, zinc-finger recognizes RNA through the collected information of specially displayed bases and special backbone folding. Initial studies have been performed on zinc-finger mediated protein-protein interactions. Existing data indicate multiple recognition modes. The studies on molecular mechanism have supported the development of engineered zinc-fingers, which have been introduced into applications. For its wide existence, large functional diversity and potential in translational applications, zinc-finger deserves a systematic study in every aspect. PMID- 23984516 TI - [Impact of AMPKgamma silencing on AMPK activation and intracellular lipids regulation]. AB - The study is aimed to confirm the silencing efficiency of the vector in human hepatocellular liver carcinoma cell line (HepG2), and observe effects of AMPKgamma silencing on the AMPK stimulating activity and lipid synthesis of cordycepin (CCS), a natural product with known AMPK activating function. The downregulating efficacy of siRNAs on AMPKgamma expression was confirmed in our previous study. The double stranded shRNA Oligo was ligated to lentivirus vector and verified by sequencing. The lentiviral which can effectively inhibited protein expression levels of AMPKgamma was selected by Western blotting, and the regulation of CCS on protein expression of AMPKgamma and p-AMPK in AMPKgamma silence cells were detected by Western blotting analysis. The lipid accumulation in cells was observed by Oil-Red O stain and cells were collected for the estimation of cholesterol (TC), triglyceride (TG). The results showed that the lentiviral vector carrying a shRNA targeting the AMPKgamma gene was successfully constructed. Western blotting analysis confirmed that GR085 had the highest interfering efficiency. Treatment with CCS can significantly increase the levels of phospho-AMPK in normal cells, and the level of TC, TG was reduced, but in AMPKgamma silence cells the effects of CCS on AMPK activation and lipid synthesis were almost completely abolished without changing the expression levels of total AMPK or AMPKgamma protein. In conclusion, the AMPKgamma gene may be related to AMPK activation and intracellular lipids regulation by CCS. PMID- 23984517 TI - [The activation effect of nobiletin on cystic fibrosis transmembrane conductance regulator chloride channel]. AB - Aim of the present study is to investigate activation effect of nobiletin on cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activity. CFTR-mediated iodide influx assay and patch-clamp tests were done on FRT cells stably co-transfected with human CFTR and EYFP/H148Q. Nobiletin potently activated CFTR chloride channel activity in a dose- and time-dependent manner. The CFTR blocker CFTR(inh)-172 could completely reverse the effect. Preliminary mechanism study indicated that nobiletin activated CFTR chloride channel through a direct binding way. In addition, ex vivo tests done on mice trachea showed that nobiletin time-dependently stimulated submucosal gland fluid secretion. Nobiletin may be a therapeutic lead compound in treating CFTR-related diseases including disseminated bronchiectasis. PMID- 23984518 TI - [Molecular mechanism of ophiopogonin B induced cellular autophagy of human cervical cancer HeLa cells]. AB - This study is to investigate the antitumor activity of ophiopogonin B (OP-B). MTT assay, flow cytometric analysis, acridine orange staining, Lyso-Tracker Red staining and HeLa-GFP-LC3 transfect cells assay were used to detect the proliferation activity, apoptosis and autophagy of HeLa cells. The results showed that OP-B exerted potent antiproliferative activity on HeLa cells, the cell growth inhibition effect of OP-B was not due to apoptosis and OP-B could induce autophagy of HeLa cells. OP-B also induced the protein expression up-regulation of Beclin-1 and promoted LC3 I transformation LC3 II, which were representative proteins of autophagy. Furthermore, 3-MA, an inhibitor of autophagy, not only inhibited OP-B-mediated autophagy but also almost completely reversed the antiproliferative effect of OP-B, suggesting that the growth inhibition effect of OP-B was autophagy dependent. Western blotting demonstrated that OP-B inhibited the phosphorylation of Akt and its' downstream vital protein, such as mTOR and p70S6K. In addition, OP-B also induced the protein expression up-regulation of PTEN, which is a negative regulation protein for Akt/mTOR signaling pathway. However, OP-B did not affect the protein expression of total Akt. Collectively, the antitumor effects of OP-B were autophagy-dependent via repression Akt/mTOR signaling pathway. Therefore, OP-B is a prospective inhibitor of Akt/mTOR and may be used as an alternative compound to treat cervical carcinoma. PMID- 23984519 TI - [Mechanism and action characteristics studies of a quinoxalinone compound against HIV-1 replication]. AB - This study is to investigate the mechanism and action characteristics of 6-chloro 3-methyl-4-(2-methyoxycarbonylthiophene-3-sulfonyl)-3, 4-dihydroquinoxa-lin-2-(1 H)-one (XU07011) against HIV-1 replication. XU07011 anti-HIV activity was tested by using VSVG/HIV pseudotype viral system and confirmed by HIV-1 live viruses' infectious assay. Time of addition was used to test HIV-1 reverse transcription process. RNA-dependent DNA polymerase activity and RNase H activity were tested by using enzyme linked immunoabsorbent assay and fluorescence method. Wild type and nine NNRTIs-resistant reverse transcriptase enzymatic models and cell-based pharmacological models were used to evaluate XU07011 bio-characteristics. The results showed that XU07011 inhibited HIV-1 replication with IC50 of (0.057 +/- 0.01) micromol x L(-1) which was comparable to nevirapine [IC50: (0.046 +/- 0.01) micromol x L(-1)]. Mechanism study data indicated that XU07011 blocked HIV-1 reverse transcription process through acting on reverse transcriptase RNA dependent DNA polymerase with IC 50 of (1.1 +/- 0.3) micromol x L(-1). The compound showed no effect on RNase H activity. XU07011 exhibited better activities comparing with nevirapine on K103N mutated NNRTIs-resistant HIV-1 strains. This study could provide a theoretical basis for novel anti-HIV reagents development. PMID- 23984520 TI - [Annexin A1 increases the sensitivity of K562 cell to imatinib]. AB - Annexin A1 (ANXA1) is a kind of endogenous scaffold protein. Previous research showed that ANXA1 could increase markedly with multiple increase of drug resistance in K562/imatinib cell lines in vitro. Here the stable transfection cell strains K562-pEGFP-N1 which was the native control and K562-pEGFP-N1-ANXA1 which can stably express ANXA1 were established using the Lipofectamine 2000 in order to find whether ANXA1 involved in the drug resistance. Cell growth inhibition experiment via MTT and cell proliferation experiment via MTS showed that K562-pEGFP-N1-ANXA1 cell strain was more sensitive to imatinib than the K562 pEGFP-N1 cell strain, and however the ability of proliferation of K562-pEGFP-N1 ANXA1 cell strain did not change compared with the negative control. Western blotting results showed that the expression of proteins in Annexin family did not change; drug resistance proteins, Bcr-Abl/p-Bcr-Abl (Tyr245), Src family kinase for example, did not change; proteins related with cell proliferation and cell cycle, such as ERK1/2MAPK, p-38MAPK, CDK1 and Wee 1, did not change either in the K562-pEGFP-N1-ANXA1 cell strain compared with the negative control. The co immunoprecipitation result showed that the interaction between ANXA1 and beta actin in the K562-pEGFP-N1-ANXA1 cell strain increased markedly. The deduction was that ANXA1 may make the K562-pEGFP-N1-ANXA1 cell strain more sensitive to imatinib due to the increased uptake of imatinib via the increase of ANXA1 and the interaction between ANXA1 and beta-actin in the K562-pEGFP-N1-ANXA1 cell strain in vitro. PMID- 23984521 TI - [Design, synthesis and antitumor activity of valproic acid salicylanilide esters]. AB - A series of valproic acid salicylanilide esters were designed and synthesized based on the principle of prodrug. The structures of the target compounds were confirmed by MS, 1H NMR and 13C NMR. Anti-tumor activities of these compounds against K562, A549, A431 cells in vitro were investigated by MTT assay and SRB assay. The results indicated that the compounds 6h-6j were found to have stronger cell growth inhibitory action than gefitinib, and comparable to niclosamide, which are worth to be intensively studied further. PMID- 23984522 TI - [Design, synthesis and biological activity evaluation of adenosine analogues]. AB - N6-(2-Hydroxyethyl) adenosine, HEA (1), an active ingredient isolated from cultured mycelia of cordyceps species which is a famous traditional tonic in China, showed brain protective, sedative hypnotic activity in pharmacological tests. In order to explore novel non-benzodiazepine sedative-hypnotic agents, HEA was treated as the lead compound. Twenty three target compounds were designed and synthesized. Their chemical structures were characterized by 1H NMR, MS and elemental analysis. Pharmacological test in vivo showed that target compounds 8, 4, 13 were more active than HEA on locomotor and gasping activities of mice. Structure-activity relationships showed that the ribose moiety at N-9 position of adenine base was critical for activity. PMID- 23984523 TI - [A new triterpenoid from Pittosporum glabratum Lindl]. AB - The roots of Pittosporum glabratum Lindl. (Pittosporaceae) have been used as a folk medicine for the treatment of rheumatic arthritis, insomnia and hypertension. Only a few chemical or biological studies on P. glabratum have been reported. As part of our ongoing phytochemical research on this plant, four compounds were isolated. Their structures were identified as 3beta, 6beta, 19alpha, 21alpha, 24-pentahydroxy-12-en-28-oleanolic acid (1), 3-O-beta-D glucuronopyranosyl-28-O-beta-D-glucopyranosyl siaresinolic acid (2), 3, 4, 5 trimethoxyphenyl-1-O-beta-D-(5-O-syringoyl)-apiofuranosyl-(1 --> 6)-beta-D glucopyranoside (3) and 3, 4, 5-trimethoxyphenol-1-O-beta-D-apiofuranosyl-(1 --> 6)-beta-D-glucopyranoside (4) on the basis of physical evidence and spectroscopic analysis. Among them, compound 1 is a new triterpenoid, and compounds 2-4 are isolated from the genus Pittosporum for the first time. PMID- 23984524 TI - [A new sesquiterpenoid from fungus Colletotrichum sp. and its cytotoxicity]. AB - A novel sesquiterpenoid (1) and three known compounds identified as isoaltenuene (2), altenuene (3), and alternariol 4, 10-O-dimethyl ether (4), were isolated in our investigation of the cytotoxic constituents from solid cultures of the endophytic fungus Colletotrichum sp. The structures of these compounds were elucidated through spectroscopic data analysis. All compounds exhibited cytotoxic activity against lung cancer cell line A549, breast cancer cell line MDA-MB-231 and pancreatic cancer cell line PANC-1. Compound 4 could induce the PANC-1 cells inflation or death, but couldn't induce apoptosis at the IC50 of 60.2 microg x mL(-1). PMID- 23984525 TI - [Characterization of the primary structure of TNK-tissue plasminogen activator using LC-MS]. AB - The primary structure of TNK-tissue plasminogen activator (TNK-tPA) was characterized using liquid chromatography-mass spectrometry (LC-MS). Firstly, the molecular mass of deglycosylated protein was measured. Then peptide mass mapping and MS/MS of the reduced, alkylated and trypsin-digested sample were tested and analyzed so as to verify its amino acid sequence and identify post-translational modifications. Results show that the amino acid sequence was consistent with designed structure; about 5% of M207 was oxidized; T61 was fucosylated with -80% occupancy; N103, N448 and N184 (-15% occupancy) were glycosylated with complex type oligosaccharides. LC-MS coupled with proper sample pretreatment is approved to be a rapid and powerful approach to characterize the primary structure of TNK tPA. PMID- 23984526 TI - [Determination of doxazosin enantiomers in rat plasma and investigation of their chiral inversion]. AB - The study is to establish an HPLC method using fluorescence detector for the determination of doxazosin enantiomers and investigate their chiral inversion in vitro and in vivo. Ultron ES-OVM was taken as the chiral chromatographic column, and the column temperature was 30 degrees C. Isocratic elution using a mobile phase of phosphate buffer-acetonitrile (85 : 15, v/v) at a flow rate of 0.8 mL x min(-1) was done. The fluorescence detection was set at lambda(Ex) = 255 nm and lambda(Em) = 385 nm. Prazosin was used as the internal standard. (-) Doxazosin or (+) doxazosin added into rat plasma in vitro was determined after incubating in 37 degrees C water bath for 2, 5 and 10 days. (-) Doxazosin or (+) doxazosin was administered orally to the rats for one months. Plasma samples were taken at 8 h after the last administration. A good linear relationship was achieved when the concentration of doxazosin enantiomers was within the range of 4 - 2 000 ng x mL( 1). The average recovery for (-) doxazosin was 99.5% with RSD 3.6%, and for (+) doxazosin was 99.3% with RSD 4.3%. Chiral inversion was observed neither in vitro nor in vivo studies. The method is selective, accurate and reproducible, which is suitable for the detection of doxazosin enantiomers in rat plasma. The in vitro and in vivo studies indicate that chiral inversion occurs uneasily between (-) doxazosin and (+) doxazosin in the rat. PMID- 23984527 TI - [Effects of ligustrazine on extracellular dopamine levels in rat brain dialysate]. AB - Using brain microdialysis and LC-ECD, the content of dopamine in rat brain was detected to investigate the effects of ligustrazine. A liquid chromatography electrochemical detector method has been established and validated for the determination of dopamine in rat brain dialysate. The results indicate that ligustrazine administration by subcutaneous injection significantly increased dopamine release in rat medial prefrontal cortex, nucleus accumbens and hippocampus in a dose-related manner. The drug's effects on dopa release in rat brain could be directly detected by microdialysis combined with HPLC-ECD and this method has the preponderance over traditional neurology methods. PMID- 23984528 TI - Structure elucidation of degradation products of Z-ligustilide by UPLC-QTOF-MS and NMR spectroscopy. AB - Z-Ligustilide, a major phthalide isolated from a widely used traditional Chinese medicine Ligusticum chuanxiong, possesses various pharmacological activities including neuroprotective, anti-inflammatory, antiproliferative and vasorelaxing effects. However, it is unstable and inclined to degrade in natural conditions, which limits its study and application greatly. In this study, degradation behavior of Z-ligustilide and its degradation products stored at room temperature under direct sunlight were investigated and structure elucidated by HPLC-UV, UPLC QTOF-MS and NMR. Z-ligustilide degradation and total five degradation products were generated and detected. Two degradation products were unequivocally identified as senkyunolide I and senkyunolide H by comparison with reference compounds. Another two degradation products were further isolated by semi preparative HPLC and structure elucidated as (E)-6, 7-trans-dihydroxyligustilide and (Z)-6, 7-epoxyligustilide by 1H and 13C NMR, respectively. The degradation pathways of Z-ligustilide were finally proposed. Oxidation, hydrolysis and isomerization are the major degradation reactions. PMID- 23984529 TI - [LC-MS quantification and pharmacokinetics of the multi-constituents of Huangqin Tang in rat plasma after different single oral doses]. AB - The current study aims to investigate the pharmacokinetic properties of Huangqin Tang on different oral doses. An LC-MS method for simultaneous determination of flavonoids and terpenoids in rat plasma was developed and validated. Plasma samples were treated with hydrochloric acid (containing 1% ascorbic acid), precipitated with acetonitrile, separated on a Zorbax SB-C18 column, detected by single quadruple mass spectrometry with an electrospray ionization interface, and quantified using selected ion monitoring mode. All pharmacokinetic parameters were processed by non-compartmental analysis using WinNonlin software. The results of specificity, linearity, intra-day and inter-day precisions, accuracy, and stability for LC-MS assay were suitable for the quantification of paeoniflorin, baicalin, wogonoside, baicalein, wogonin, oroxylin A, glycyrrhizic acid and glycyrrhetinic acid in rat plasma. The concentration-time profiles of baicalin, wogonoside, baicalein, wogonin, oroxylin A and glycyrrhizic acid showed double-peak phenomenon after Huangqin Tang was orally administered at 40 g x kg( 1) dose; all eight constituents in rat plasma showed good dose-exposure relationship within the dosage of 10-40 g x kg(-1); although plasma concentrations were different, the flavonoids with the same backbone showed the similar fate in the body with the corresponding dosage. In conclusion, the LC-MS assay was successfully applied for the pharmacokinetic study of multi constituents of Huangqin Tang with different doses. Additionally, these constituents demonstrated good pharmacokinetic properties in the body. PMID- 23984530 TI - [The influence of spray drying process conditions on physical, chemical properties and lung inhaling performance of Panax notoginseng saponins - tanshinone II A composite particles]. AB - This study is to report the influence of conditions in spray drying process on physical and chemical properties and lung inhaling performance of Panax notoginseng Saponins - Tanshinone II A composite particles. According to the physical and chemical properties of the two types of components within the composite particles, three solvent systems were selected including ethanol, ethanol : acetone (9 : 1, v/v) and ethanol : acetone (4 : 1, v/v), and three inlet temperature: 110 degrees C, 120 degrees C, 130 degrees C to prepare seven different composite particle samples; each sample was characterized using laser diffraction, scanning electron microscopy (SEM), dynamic vapour sorption (DVS) and atomic force microscope (AFM), and their aerodynamic behavior was evaluated by a Next Generation Impactor (NGI). The results indicate that under the conditions of using the mixed solvent system of ethanol--acetone volume ratio of 9 : 1, and the inlet temperature of 110 degrees C, the resulting composite particles showed rough surface, with more tanshinone II A distributing in the outer layer, such composite particles have the best lung inhaling performance and the fine particle fraction (FPF) close to 60%. Finally it is concluded that by adjusting the conditions in co-spray drying process, the distribution amount and existence form of tanshinone II A in the outer layer of the particles can be changed so that to enhance lung inhaling performance of the drug composite particles. PMID- 23984531 TI - [In vitro transdermal delivery of the active fraction of xiangfusiwu decoction based on principal component analysis]. AB - The objective of the present study was to establish a method based on principal component analysis (PCA) for the study of transdermal delivery of multiple components in Chinese medicine, and to choose the best penetration enhancers for the active fraction of Xiangfusiwu decoction (BW) with this method. Improved Franz diffusion cells with isolated rat abdomen skins were carried out to experiment on the transdermal delivery of six active components, including ferulic acid, paeoniflorin, albiflorin, protopine, tetrahydropalmatine and tetrahydrocolumbamine. The concentrations of these components were determined by LC-MS/MS, then the total factor scores of the concentrations at different times were calculated using PCA and were employed instead of the concentrations to compute the cumulative amounts and steady fluxes, the latter of which were considered as the indexes for optimizing penetration enhancers. The results showed that compared to the control group, the steady fluxes of the other groups increased significantly and furthermore, 4% azone with 1% propylene glycol manifested the best effect. The six components could penetrate through skin well under the action of penetration enhancers. The method established in this study has been proved to be suitable for the study of transdermal delivery of multiple components, and it provided a scientific basis for preparation research of Xiangfusiwu decoction and moreover, it could be a reference for Chinese medicine research. PMID- 23984532 TI - [Pharmacokinetics and tissue distribution of irinotecan hydrochloride nanoparticles]. AB - To investigate the pharmacokinetics of irinotecan hydrochloride (CPT-11) in rats and the tissue distribution of CPT-11 in mice after injection of irinotecan hydrochloride nanoparticles (CPT-11 NPs) via tail veins, separately, a LC-MS/MS method was established to determine the concentration of CPT-11 in whole blood of rats and in different tissues of mice. The pharmacokinetics and tissue distribution of CPT-11 were compared after the intravenous injection of CPT-11 NPs and CPT-11 solution. Compared with CPT-11 solution, the elimination half-life of CPT-11 was prolonged from 2.28 h to 3.95 h after the intravenous injection of CPT-11 NPs, and its AUC was 1.47 times than that of CPT-11 solution. After the injection of CPT-11 NPs in mice, the concentrations of CPT-11 loaded in CPT-11 NPs were significantly higher in the whole blood, colon and lungs than those in CPT-11 solution, but lower in the spleen, liver, kidney and heart, but the least in brain. CPT-11 NPs could improve CPT-11 's AUC, and help CPT-11 to reach long circulation activity. PMID- 23984533 TI - [Molecular cloning and characterization of S-adenosyl-L-methionine decarboxylase gene (DoSAMDC1) in Dendrobium officinale]. AB - S-Adenosyl-L-methionine decarboxylase (SAMDC) is a key enzyme in the polyamines biosynthesis, thus is essential for basic physiological and biochemical processes in plant. In the present study, a full length cDNA of DoSAMDC1 gene was obtained from symbiotic germinated seeds of an endangered medicinal orchid species Dendrobium officinale, using the rapid amplification of cDNA ends (RACE)-PCR technique for the first time. The full length cDNA was 1 979 bp, with three open reading frames, i.e. tiny-uORF, small-uORF and main ORF (mORF). The mORF was deduced to encode a 368 amino acid (aa) protein with a molecular mass of 40.7 kD and a theoretical isoelectric point of 5.2. The deduced DoSAMDC1 protein, without signal peptide, had two highly conserved function domains (proenzyme cleavage site and PEST domain) and a 22-aa transmembrane domain (89-110). Multiple sequence alignments and phylogenetic relationship analyses revealed DoSAMDC1 had a higher level of sequence similarity to monocot SAMDCs than those of dicot. Expression patterns using qRT-PCR analyses showed that DoSAMDC1 transcripts were expressed constitutively without significant change in the five tissues (not infected with fungi). While in the symbiotic germinated seeds, the expression level was enhanced by 2.74 fold over that in the none-germinated seeds, indicating possible involvement of the gene in symbiotic seed germination of D. officinale. PMID- 23984534 TI - [Cloning and expression analysis of HMG-CoA reductase from Aquilaria sinensis (Lour.) Gilg]. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) is the first rate-limiting enzyme for sesquiterpene synthesis in the mevalonate (MVA) pathway. The specific primers were designed according to the transcript sequence of AsHMGR2 from the Aquilaria sinensis (Lour.) Gilg transcriptome database. The full-length cDNA of AsHMGR2 was cloned by RT-PCR and rapid amplification of cDNA ends (RACE) technology, and was analyzed at bioinformatics levels; AsHMGR2 expression profiles in different tissues and in responds to different treatments were analyzed by real-time PCR. The length of AsHMGR2 Open Reading Frame (ORF) was 1 749 bp, encoding 582 amino acids. The GenBank accession number is KC140287. Tissue expression analysis indicated that AsHMGR2 was mainly expressed in root and shoot tips, followed by stem, and was lowest in leaves. Inducible-experiments showed that the genes were induced by mechanical wound as well as chemical liquid induction, and reached the highest expression level at 6 h and 8 h, separately. The full-length cDNA of AsHMGR2 and its expression patterns will provide a foundation for further research on its function in agarwood sesquiterpene biosynthesis. PMID- 23984535 TI - [Effect of genistein on rat femoral bone metabolic activity in vitro]. AB - This study is to investigate effects of genistein on rat femoral bone metabolic in vitro. Rat femoral tissues was isolated and randomly divided into two groups including control group and genistein (1 x 10(-5) mol x(-1)) group. Determinations of alkaline phosphatase (ALP) activity, calcium content and osteoprotegerin (OPG), type I-collagen (Collagen-I), RANKL, Runx-2 and bone morphogenetic protein (BMP-2) mRNA expression were done by real-time PCR. The results showed that 1 x 10(-5) mol x L(-1) genistein could increase the activity of ALP and contents of Ca, regulate bone metabolism activity of OPG, RANKL, BMP 2, Collagen-I and Runx-2 mRNA expression level. Genistein can significantly modulate bone metabolism related gene expression level of rat femoral tissue in vitro, and can increase calcium content and the activity of ALP. PMID- 23984537 TI - The 62th Japan Hospital Association Congress. Healthcare for the future. PMID- 23984536 TI - Healthcare for the future. PMID- 23984538 TI - Japan Hospital Association QI Project 2011: results and future issues. PMID- 23984539 TI - Ongoing physician practice evaluation (OPPE): challenges in implementation in Japan--an opinion. PMID- 23984540 TI - Evidence-based policy making for sustainable healthcare in Japan: 2025 and beyond. PMID- 23984541 TI - The challenge of estimating the prevalence of dementia in the elderly. AB - AIM: To examine the validity of the estimation of the prevalence of dementia in the elderly based on long-term care insurance (LTCI) data. METHODS: Japanese LTCI data among frail elders over 65 years of age (193 men, 360 women) from a central area of Osaka prefecture in 2005 was analyzed using the dementia discrimination criteria of a dementia autonomy level higher than level 2. Of those, no cases with a prior diagnosis of dementia were reexamined to ascertain dementia equivalent status. RESULTS: Of the 70 reexamined cases (25 men, 45 women), 6 men and 16 women scored as dementia-equivalent. In addition, 7 men and 7 women experienced severe sequelae of cerebrovascular disease (CVD). Two men and 8 women showed symptoms equivalent to mild cognitive impairment (MCI). Ten men and 14 women showed no dementia/MCI. Based on the sum of subjects previously diagnosed with dementia and those with symptoms equivalent to dementia upon reexamination, the estimated prevalence of dementia in subjects over 65 years in the study region was 5%. CONCLUSIONS: Assuming a 50% capture rate of dementia based on the LTCI data (N = 553) from a review of previous research, the estimated prevalence of dementia was increased to 10% after incorporating the results of this study. The prevalence of elderly dementia according to LTCI data should be estimated based on a determination of dementia-equivalence in terms of the level of care required: dementia, equivalent to dementia (i.e., requiring daily care similar to that for dementia), and severe sequelae of CVD. Furthermore, the capture rate should be carefully considered. PMID- 23984542 TI - Clinical manifestation and outcome of oldest old patients with cancer. PMID- 23984544 TI - [The techniques to detect apoptosis of spermatozoids]. AB - The article presents the classification and evaluation of techniques applied in documentation of apoptosis of spermatozoids. The main point of techniques detecting the changes in DNA of apoptosis spermatozoids (SCSA technique, TUNEL test and Comet assay) is revealed The annexin technique, the technique of detection of changes of cells transmembrane potential, the technique of detection of activity of caspase and technique of detection the degree of expression of proteins-regulators of apoptosis are discussed too. The advantages and shortcomings of these techniques are considered. PMID- 23984543 TI - A trial of improvement of immunity in cancer patients by laughter therapy. AB - PURPOSE: The study was on the impact of laughter therapy on immunological improvement of patients with gastrointestinal cancer undergoing surgery and chemotherapy. MATERIALS & METHOD: Immunological measurements were performed in 41 cases with patients aged 68.9 years suffering from gastric or colorectal cancer. Intervention using Laughter Therapy was applied to 12 out of the 25 patients subjected to laproscopic surgery and 12 out of 19 patients subjected to chemotherapy. RESULTS: Immunity of patients within the control group who had surgery decreased. Immunity of patients within the control group who had chemotherapy decreased. With intervention of Laughter Therapy, the immunity of patients with surgery had either decreased or was the same. However, with intervention of Laughter Therapy using the Smile-Sun Method, the immunity of chemotherapy patients increased, notably in patients with colorectal cancer. The improvement of immunity within the control group was 0 out of 7. CONCLUSION: Patients with advanced cancer have lower immunity which is further decreased with surgery or chemotherapy. Chemotherapy patients who undertook the Laughter Therapy using the Smile-Sun Methodology during treatment in the hospital showed significantly higher immunity levels. The results of this study indicate that patients with gastrointestinal cancer, who undergo laparoscopic surgery or chemotherapy for stomach or colorectal cancer, benefit from a formal program of psychotherapeutic support during the in-patient hospital stay in terms of immunological improvement. PMID- 23984545 TI - [Annexin-5 as a biochemical marker of early vascular disorders under chronic disease of kidneys]. AB - The study evaluated the significance of annexin-5 as a biochemical marker of atherosclerosis in patients with chronic disease of kidneys. The sample consisted of 46 patients with chronic disease of kidneys without clinical symptoms of atherosclerosis. The indicators of lipidogram, intima-media complex of carotid artery reactivity of vessels of microcirculatory channel and concentration of annexin-5 are determined. The decrease of velocity of glomerular filtration is accompanied by the increase of concentration of annexin-5 related to indicators of lipidogram. The increase of concentration level of annexin-5 is accompanied by the most expressed dysfunction of endothelium. The increase 3a level of annexin-5 in blood of patients with chronic disease of kidneys is especially informative in case of lacking of clinical symptomatic of atherosclerosis and it testifies the presence of vasomotor endothelial dysfunction. The dynamic detection of concentration of annexin-5 can ameliorate the prognosis of possibility of development of cardio-vascular complications under diseases of kidneys. PMID- 23984546 TI - [The concentration of growth factors in patients with inherent and acquired shortenings of limbs bones]. AB - The article deals with the results of study of level of growth factors in blood serum of patients with inherent and post-traumatic shortenings of limbs' bones. The detection in blood serum the level of epidermal growth factor insulin-like growth factor I and angiopoetins is proposed to monitor in given patients the reparative bone formation. PMID- 23984547 TI - [The evaluation of eosinophilogram of peripheral blood in children with eosinophilia]. AB - The need in study and interpretation of eosinophilograms in children with allergic diseases is conditioned by higher rate of eosinophilia, large specter of morphologic and functional signs of eosinophils, dependence of indicators from character of clinical course of disease, presence of complications and schemes of treatment. The level of laboratory techniques applied in routine clinical practice to evaluate morphological and functional characteristics of eosinophils is not developed enough. The implementation of such modern high-tech techniques as computer morphometry, highly sensitive and highly specific modifications ELISA, which are applied to detect associated with eosinophilia cytokines, chemokines and growth factors make it possible to approach to this issue at the new qualitative level. PMID- 23984548 TI - [The impact of blood smear preparation on effectiveness of functioning of Vision Hema--the digital system of automatic blood analysis]. AB - The article deals with study of the impact of standardization of blood smears preparation on effectiveness of functioning of Vision Hema system. The analysis was applied to the results of counting of 200 leukocytes in 30 blood smears prepared from venous blood stabilized with ethylenediaminetetraacetic acid using thoroughly degreased slide plates and applying automatic device to prepare blood smears (comparative group) and in 49 preparations prepared manually from non stabilized capillary blood (control group). The standardization of the procedure of preparation of glass samples resulted in five time decrease of total amount of artifacts and in disappearance of thrombocytes aggregates and pavement epithelium cells. The absolute amount of destroyed leukocytes decreased in 2.4 times and particles of dirt in 9.5 time. The proposed technique of preparation of smear increased velocity of automatic analysis of leukogram by the Vision Hema system in 2 times and speeded up validation by physician of derived results in 3 times. PMID- 23984549 TI - [The noninvasive technique of analysis of aggregation activity of thrombocytes, leukocytes and erythrocytes]. AB - The article considers the noninvasive technique of analysis of aggregation activity of thrombocytes and formation of leukocytic-erythrocytic-thrombocytic aggregates and some particular indicators of hemostasis system. The speckle analysis of characteristics of coherent light dispersion from surface of erythrocytes moving in artificially isolated vessel section. The study established high correlation ratio between light dispersion index and spontaneous ADP-, adrenalin- and collagen-induced aggregation of thrombocytes, formation of leukocytic-erythrocytic and thrombocytic-erythrocytic aggregations. The established facts permits to consider that analysis noninvasive technique makes it possible to estimate approximately the aggregation activity of blood corpuscles. PMID- 23984550 TI - [The immune-enzyme analysis based on chimeric molecule and oligopeptide fragmentations to detect autoantibodies to beta-adrenergic receptor in patients with dilation cardiomyopathy]. AB - The article deals with specification of technique of immune-enzyme analysis to detect autoantibodies to beta-adrenergic receptors (beta1-AP) using compound of oligopeptids representing the fragmentations of extracellular sites beta1-AP and chimeric molecule of extracellular section of receptor This technique significantly exceeds the analogues defined in publications by its sensitivity and correlation with diagnosis. PMID- 23984551 TI - [The specific sensitization and local immunity of oral cavity in conditions of chronic aerogenic load]. AB - The article considers the results of analysis of concentration of IgA, IgM, IgG, IgE, sIgA, sICAM-1 in non-stimulated saliva of female workers of poultry sector who underwent aerogenic impact of complex of occupational factors. The changes in indicators are analyzed depending on intensity of sensitization. The study demonstrated that the greatest changes in concentration of sICAM-1 are detected primarily in case of fungous infection. PMID- 23984552 TI - [The clinical economic rationale of practicability of immunologic examination of patients with chronic infectious inflammatory diseases]. AB - The article presents the results of clinical economic analysis providing the evaluation of implementation of immunologic examination of patients with chronic infectious inflammatory diseases. To calculate the clinical economic indicators the factor costs and indirect costs were determined in case of immunologic examination and without examination according the data of prospective (80 patients) and retrospective study (500 outpatient cards). To evaluate the significance of approach based on immunologic examination methods the percentage of patients with relapse-free period was calculated. The clinical economic evaluation of methods of diagnostic and treatment made it possible to determine economic advantages of application of immunologic methods of examination independently of localization of chronic torpid process and to assess relationship between costs of immunologic methods of examination and effectiveness of applied treatment. PMID- 23984553 TI - [The formation and spread of MRSA strains in patients with pyoinflammatory diseases]. AB - The article considers the results of study of formation and spread of MRSA in patients with suppurative focuses of stafillococus ethiology after application of antibacterial therapy. The antibacterial therapy applied to these patients used one of the following pharmaceuticals--cefazolin, lincomycin, gentamicin, oxampicin, ciprofloxacin, ofloxacin. All the strains of S. aureus ssp. aureus isolated from patients were tested on MRSA. Their phagovars were detected using international kit of phages for grouping of S. aureus ssp. aureus. The comparison of data received after analysis of resistance to oxacillin of strains and their phages isolated at the onset of disease and after applied treatment was carried out. The study established that against the background of applied antibacterial therapy in 10.7% of patients, MRSA formed and in 15.4% of patients, the change of initial strains of S. aureus ssp. aureus by MRSA strains of other phages groups was established. The presented results testified the need of obligatory testing of strains isolated from patients with staphylococcus infection on antibiotics resistance. The application of antibacterial therapy and its correction taking in account the laboratory data on antibiotics resistance and strict following the sanitary hygienic standards. PMID- 23984554 TI - [The sensitivity of plague agent from Siberian natural focuses of disease to antibacterial preparations in vitro]. AB - The comparative analysis was applied concerning antimicrobic action of different groups of antibacterial preparations on the plague agent strains isolated from Siberian natural focuses of disease. The analysis was applied to results obtained using such different methods as disco-diffusive technique, serial dilution and HiCOMB MIC test. It is established that freshly isolated cultures of Yersinia pestis have high sensitivity to antibacterial preparations of different groups. The results obtained using three technical approaches intercorrelate in significant degree. The HiCOMB MIC test was applied for the first time for analysis Y. pestis strains from natural focuses of plague of Siberia. PMID- 23984555 TI - [The microbiocenosis of upper parts of digestive tract of children with gastroesophageal reflux disease and chronic gastroduodenitis]. AB - The article considers the microbe specter of mucous coat of esophagus and stomach in children with gastro esophageal reflux disease and chronic gastroduodenitis. In patients with diseases of upper parts of digestive tract, the opportunistic pathogenic bacteria are isolated more often and their strains have aggression factors and cytotoxicity. In children with reflux disease the microbe landscape of esophagus is larger both in numerical and specific respect as compared to healthy adolescents and children with isolated gastroduodenitis. PMID- 23984556 TI - [The mode of identification of microscopic fungi of genus of Coccididoides spp. in vitro]. AB - The article deals with analysis of morphologic characteristics of microscopic fungi of genus of Coccididoides spp. under cultivation on culture of mouse splenocytes culture. During two days, the strains of C. imitis and C. posadasii converse from filamentous to spherulic form. This process makes it possible to apply this test to identify agents of coccidioidomycosis. PMID- 23984557 TI - [The challenges of standardization in clinical diagnostic laboratories of medical organizations]. AB - The generalized data concerning the conditions of application of regulations of national standards in clinical diagnostic laboratories of medical organizations is presented. The primary information was provided by 14 regions of 6 federal administrative okrugs of Russia. The causes of challenges of application of requirements of standards are presented. They are mostly related with insufficient financial support, lacking of manpower, difficulties with reagents supply, inadequate technical maintenance of devices and absence of support of administration of medical organizations. The recommendations are formulated concerning the necessity of publishing the document of Minzdrav of Russia to determine the need in application of standards in laboratory practice. PMID- 23984558 TI - [The system of quality management in medical laboratory: the problematic issues of implementation of GOST RKS 9001-2008, GOST R ISO 15189-2009 and GOST R ISO 53079-2008]. AB - The article presents the approaches to development and implementation of system of quality management in laboratory as an integral part of the given system in whole medical institution. The costs of works execution concerning quality support are to be weighted with economic profitability and timeliness of medical care provision to ill people considering pre-analytic stage (out-laboratory and in-laboratory) laboratory analysis. Factually it is a matter of development of system of balanced indicators concerning quality management of institution and laboratory functioning. The problematic issues are presented concerning maintenance of particular requirements of GOSTR ISO 15189 about quality of production. The emphasis is made on the necessity of training of administrations of laboratories in the field of quality management and economics of laboratory business. PMID- 23984559 TI - [For the discussion on the article by A.V. Emanuel and al. "The practice of development and implementation of systems of quality management in medical institutions]. PMID- 23984560 TI - [The assurance of analytical validity of results of cytological analysis: the requirements to reagents]. AB - The cytological analysis is an important diagnostic method in many clinical disciplines. In particular cases, the cytological and histologic analysis provides ultimate interpretation of observed form of human pathology, including the most intricate for clinical diagnostic cases of oncologic diseases. The verity of cytological and histologic conclusion about the results of analysis of tissue assay is based on the structural characteristics of tissues, cells and their components. All this, in its turn, significantly depends on stain applied In the laboratory medicine, the standardization provides settings of requirements to applied reagents with purpose to increase the validity of laboratory information. The project of national standard of the Russian Federation is presented founded on ISO 19001 regulating information provided by manufacturer with diagnostic reagents in vitro for staining in biology i.e. in cytological and histochemical analysis. PMID- 23984561 TI - [The project GOST R ISO 19001. The articles of medicine for diagnostic in vitro. Information presented by manufacturer with diagnostic reactants in vitro for staining in biology]. PMID- 23984562 TI - [Why do we need general anesthesia?]. PMID- 23984563 TI - [Effect of different preoperative rehydration on sugar metabolism; comparison between Arginaid Water and OS-1]. AB - BACKGROUND: Enhanced Recovery After Surgery (ERAS) program recommends carbohydrate load before surgery. However, the dose and dosing method of carbohydrate load are not clear. In this paper, effect of different preoperative rehydration on sugar metabolism in healthy volunteers is reported. METHODS: Arginaid Water (ArgW) and OS-1 (OS) used as preoperative rehydration in Japan were employed for measuring sequential changes in sugar metabolism in blood. Both ArgW intake group and OS intake group started fasting at 9 PM. At 8 AM in the morning, respective preoperative rehydration 250 ml was taken as a bolus. Blood test was performed before intake, 30 minutes, 2 hours and 4 hours after intake. RESULTS: Subject included 10 healthy volunteers for ArgW and OS respectively. Subjects drank each preoperative rehydration two hours before entering operating room. In ArgW intake group, free fatty acid (FFA) and beta-hydroxybutyric acid concentration (beta-OHB) were reduced and sugar metabolism was favorably maintained. Meanwhile, OS intake group, FFA and beta-OHB were elevated and catabolism of adipose began. However, even if ArgW were taken, rebound increases of FFA and beta-OHB were observed after entering operating room. CONCLUSIONS: Optimum dosage and dosing method of preoperative carbohydrate should be scientifically verified in the future. PMID- 23984564 TI - [Perioperative management of the elderly patients undergoing hip fracture surgical repair under spinal anesthesia--a comparison between bipolar hip prosthesis and open reduction and internal fixation]. AB - BACKGROUND: We investigated the perioperative courses of 129 elderly patients with hip fracture with different types of surgical repair under spinal anesthesia. METHODS: All patients above 80 years of age were divided into the following two groups: bipolar hip prosthesis group (BH group, n = 54) and open reduction and internal fixation group (OR group, n = 75). We examined their perioperative courses retrospectively using medical and anesthetic records. RESULTS: No significant differences were observed between two groups in pre- and postoperative complications; hemodynamics, oxygenation and amount of bleeding during surgery; perioperative blood transfusion and postoperative 1-month morbidity. Only the final morbidity of OR group was significantly higher than that of BH group (10.7% vs. 0%). However, perioperative course was almost stable in both groups. CONCLUSIONS: Although the elderly patients with hip fracture have several pre- and postoperative complications, it is likely that they can fare well during perioperative period under spinal anesthesia regardless of the type of surgical repair. PMID- 23984565 TI - [Ultrasound guided transversus abdominis plane block in early infancy]. AB - We retrospectively examined the transversus abdominis plane (TAP) block performed in 8 infants (range, 1-115 days) from July 2010 to March 2011. Ultrasound images clearly visualized the fascial plane between the transversus abdominis and the internal oblique muscle and it was possible to confirm proper administration of local anesthetics into the plane in all patients. Complications resulting from opioid overdose were noted in two cases. One infant required reintubation. Another infant developed delayed emergence from anesthesia. We should tailor the dose of systemic opioid, considering the fact that the simultaneous administration of nerve block and systemic opioids may cause sedation and respiratory depression in young infants. PMID- 23984566 TI - [Evaluation of neuromuscular blockade using TOF-Watch SX in type 2 diabetes patients]. AB - BACKGROUND: Differences in the supramaximal current (STIM) and sensitivity of the transducer (SENS) after calibration using mode "CAL2" of the neuromuscular accelermyography (TOF-Watch SX, MSD, Japan) between type 2 diabetic and non diabetic patients were evaluated undergoing general anesthesia. METHODS: Thirty four elective surgical patients (20-69 years) were enrolled in this study. We evaluated STIM, SENS, onset time of rocuronium (onset time), time from onset to first T1 appearance (T1 appearance) and time from T1 appearance to T2 appearance (T1-T2 time) by using TOF stimulation between type 2 diabetic patients and non diabetic patients, retrospectively. RESULTS: Thirteen diabetic patients (DM group) and twenty one non-diabetic patients (non-DM group) were included in this analysis. The values of SENS in DM group were significantly higher compared to non-DM patients (207 +/- 59 vs 113 +/- 44). However, STIM did not differ significantly between the two groups. Anesthesia in the 6 patients in DM group (SEV-DM group) and 14 patients in the non-DM group (SEV-non DM group) were maintained with sevoflurane. The other 14 patients were maintained with desflurane (DES-DM: n = 7 and DES-non DM: n = 7). A significant difference in the SENS values only was observed between the two SEV groups. On the other hand, the onset time, T1 appearance and T1-T2 time were significantly longer in DES-DM patients than those in the DES-non DM group. CONCLUSIONS: It is demonstrated that the values in the SENS and the recovery speed (T1-T2 time) under measuring the degree of neuromuscular blockade by TOF stimulation were significantly higher in diabetic patients compared to non-diabetic patients. The present study provides additional confirmation of low neuromuscular response under peripheral electrical stimulation using TOF-Watch SX in type 2 diabetes patients, and attention should be paid to the evaluation of neuromuscular block using TOF-Watch SX in diabetic patients. PMID- 23984567 TI - Impact of preoperative anticonvulsant therapy on vecuronium-induced neuromuscular block under sevoflurane anesthesia: a retrospective clinical study. PMID- 23984568 TI - [Nasal high-flow therapy in a patient with postanesthetic hypoxia after tracheal extubation]. AB - A 63-year-old female with obesity (body mass index of 32.0 kg x m(-2)) was scheduled for total abdominal hysterectomy under combined epidural general anesthesia. The surgical procedure was completed without any troubles. Immediately after tracheal extubation, however, the patient developed acute respiratory distress, and the percutaneous oxygen saturation (Spo2) decreased from 97 to 44% for 1 minute. When the patient was admitted to our intensive care unit due to hypoxia, arterial blood gas values showed pH 7.37, Paco2 40.4 mmHg, Pao2 67.5 mmHg, and Spo2 94% on 5 l x min(-1) of oxygen via face mask. Her respiratory rate was 23 breaths x min(-1). We used a nasal high-flow humidified oxygen system (Optiflow) to improve oxygenation. We set the initial flow rate at 35 l x min(-1) with 50% oxygen. One hour after initiating the nasal high-flow system, the patient's respiratory rate fell to 18 breaths x min(-1), and Spo2 rose up to 98%. Arterial blood gas showed improved Pao2 of 98.0 mmHg. Nasal high flow therapy was useful to avoid intubation in a patient with postanesthetic respiratory failure. PMID- 23984569 TI - [Fiberoptic tracheal intubation through the supraglottic airway device air-Q in a patient with Shprintzen-Goldberg syndrome]. AB - We report a case of successful fiberoptic tracheal intubation through the supraglottic airway device air-Q in a 14-year-old boy in whom intubation was difficult because of Shprintzen-Goldberg syndrome. Shprintzen-Goldberg syndrome is a rare congenital disorder of connective tissue. The patient showed dysmorphic facies and weakness of connective tissue, and was scheduled to undergo abdominal surgery. After induction of general anesthesia, both attempts of laryngoscope guided and AirwayScope -guided tracheal intubation failed, but a size-2 air-Q could be easily inserted. Fiberoptic tracheal intubation through the air-Q was successfully performed without any difficulty and was safe for his weak airway connective tissue. Supraglottic airway air-Q is a useful conduit for fiberoptic tracheal intubation under general anesthesia, especially in the case of a patient with weak connective tissue in whom intubation is difficult. PMID- 23984570 TI - [A case of subglottic stenosis with bridging granuloma after intubation with double-lumen endotracheal tube]. AB - We present a case of subglottic stenosis with rare bridging granuloma after intubation with double-lumen endotracheal tube. An 81-year-old woman was diagnosed with the lung tumor and scheduled for the thoracoscopic surgery. We induced anesthesia with propofol, remifentanil and rocuronium. A 35 Fr double lumen intratracheal tube was inserted to the trachea with some resistance, when the tube passed through the glottis. A few days later, she suffered from respiratory discomfort. An otolaryngologist examined her larynx and subglottis. Laryngoscopic examination revealed bridging granuloma leading to tracheal stenosis. Tracheostomy and resection of granuloma were performed, and her symptom improved. If we feel resistance in intubating a double-lumen endotracheal tube in a patient with a history of intubation with a tracheal tube, we should operate gently adjusting the size of the tracheal tube. PMID- 23984571 TI - [A report of 6 cases with facial flushing, decreased arterial blood pressure and increased heart rate during thoracic surgery]. AB - We report 6 cases with facial flushing, decreased arterial blood pressure and increased heart rate during thoracic surgery. These symptoms appeared 28 +/- 9 minutes (mean +/- SD) after the beginning of the surgery. Arterial blood pressure decreased significantly from 92/48 mmHg to 72/40 mmHg. While heart rate increased significantly from 66 to 83 beats x min(-1). Arterial blood pressure returned to the original values 22 +/- 9 minutes from the appearance of the symptoms. When facial flushing concomitant with circulatory instability occurs during lung surgery, it is important to rule out immediately anaphylactic reaction to the drugs administered and to maintain circulation appropriately. PMID- 23984572 TI - [Comparison of Pentax-AWS, GlideScope Cobalt, and Macintosh laryngoscope in patients for nasotracheal intubation]. AB - BACKGROUND: We compared the time for instrumentation in nasotracheal intubation using Pentax-AWS and Glidescope to that using the Macintosh laryngoscope in patients with normal airway. METHODS: After local ethics board approval, 60 patients requiring dental or oral surgery were allocated randomly to Pentax-AWS, Glidescope and Macintosh groups. One experienced anesthesiologist performed nasotracheal intubation in all patients. RESULTS: The times for instrumentation using Pentax-AWS and Glidescope, and Macintosh laryngoscope were 37 +/- 12s, 33 +/- 9s, and 30 +/- 12s, respectively. There were no differences among the three devices. CCONCLUSIONS: When operated by experienced anesthesiologists, both Pentax-AWS and Glidescope showed similar performance for nasotracheal intubation compared with Macintosh laryngoscope in normal airway patients. PMID- 23984573 TI - [A case of large tracheoesophageal fistula after repair of the right discending aortic arch]. AB - A 77-year-old woman with right aortic arch was diagnosed as aortic dissection (De Bakey IIIb) and hospitalized for conservative treatment. But, her respiratory condition deteriorated due to tracheal stenosis with aortic dissection. Surgical graft replacement of the descending aorta was performed to release tracheal stenosis. Six days after surgery, tracheoesophageal fistula (TEF) was noticed. The size of the fistula was 3 cm in diameter, located 3cm to the oral side from the carina and 23 cm from the incisors. Nineteen days after surgery, an esophageal stent was placed leading to temporary improvement of the respiratory status, but it aggravated again. Unfortunately, she died due to ventricular fibrillation 26 days after surgery. The case is extremely rare with dissection of the right aortic arch. Such a case is considered to be a high risk of TEF, and it is necessary to perform early preventive measures. PMID- 23984574 TI - [A case of ilioinguinal hernia with Mobius syndrome]. AB - We gave general anesthesia for an infant with ilioinguinal hernia and Mobius syndrome. Anesthesia was performed with sevoflurane inhalation and intravenous infusion of remifentanil. Intraoperative anesthetic course was uneventful. Mobius syndrome is a syndrome of rhombencephalic maldevelopment involving predominantly motor nuclei and axons, as well as traversing long tracts. Airway management is a great challenge in these patients. Micrognathia, retrognathia, mandibular hypoplasia, and palatine cleft are some of the manifestations seen in these patients. PMID- 23984575 TI - [General anesthesia for a patient with post-polio syndrome]. AB - We gave anesthesia for a patient with post-polio syndrome undergoing laparoscopic sigmoid colectomy. She is a 68-year-old woman and had been diagnosed as post polio syndrome since she was 55 years of age. Before the operation, paralysis was observed in her right leg. After inducing anesthesia using propofol, muscle relaxation was obtained by rocuronium bromide for intubation. Remifentanil was used during the operation, and good pain relief was obtained by iv-PCA (fentanyl) after operation. PMID- 23984576 TI - [A case of suspected dry tap during spinal anesthesia for caesarean section]. AB - Spinal anesthesia was attempted in a 21-year-old woman for acute cesarean section with lumbar puncture at L3-4 and L4-5 in another hospital, but it was abandoned after more than 10 attempts because no cerebrospinal fluid (CSF) was seen flowing. She was transferred to our hospital, and we attempted spinal anesthesia at L2-3 and CSF was seen flowing. Although 0.5% hyperbaric bupivacaine 2.0ml was injected, the anesthetic effect was insufficient. At this point we injected 0.5% hyperbaric bupivacaine 1.5 ml in the same space and she developed sensory block up to T3. Surgery proceeded uneventfully. There were no postoperative neurological complications related to spinal anesthesia. PMID- 23984577 TI - [Sugammadex reversal after extubation under muscle relaxation to prevent cough reflex in a patient with intractable spontaneous pneumothorax]. AB - A 40-year-old man (168 cm tall and weighing 71 kg) with intractable pneumothorax was operated for resection of a bulla in the left lung. After insertion of epidural catheter via T 5-6 interspace, general anesthesia was induced and maintained with propofol, remifentanil and rocuronium. The duration of surgery was 1h 48 min and rocuronium given during surgery was 110 mg. After completion of surgery, the double-lumen tube was replaced with laryngeal mask airway to prevent cough reflex. However, infusion of sugammadex 200 mg induced mild cough reflex, resulting in air leakage from thoracic drainage. Because air leakage still continued after extubation, reoperation must be done and re-intubation was required. Since rocuronium 50 mg did not provide satisfactory muscle relaxation measured by train of four, additional dose of rocuronium 40 mg was administered and re-intubation was successfully performed without cough reflex. Reoperation lasted for 43 minutes and rocuronium infused was 100 mg. Nasal airway was inserted to prevent airway obstruction by the tongue and extubation was performed under muscle relaxation with infusion of rocuronium 10 mg. And then, immediate administration of sugammadex 400 mg could elicit spontaneous respiration without cough reflex. PMID- 23984578 TI - [Reversal of rocuronium induced neuromuscular block with sugammadex in a patient with myasthenia gravis]. AB - We report a patient with myasthenia gravis whose rocuronium induced neuromuscular block was reversed with sugammadex. A 26-year-old man, 175 cm and 76 kg, with myasthenia gravis, was scheduled for extended thymectomy under general anesthesia. An epidural catheter was inserted at the T5-6 interspace before induction of general anesthesia. Anesthesia was induced with propofol and remifentanil. Rocuronium was given in divided doses to obtain > 95% neuromuscular block to intubate the trachea. The ED50 and ED95 of rocuronium for this patient were 0.18 mg x kg(-1) and 0.39 mg x kg(-1), respectively. The values were similar to the ED50 and ED95 of rocuronium for normal patients. General anesthesia was maintained with propofol and remifentanil. Additional doses of rocuronium were given intermittently. Sugammadex, 2 mg x kg(-1), was given at the end of the surgery. The train-of-four ratio reached 93% 105 sec later. His postoperative course was uneventful. PMID- 23984579 TI - [A case of massive perioperative bleeding in a patient on two-drug antiplatelet therapy undergoing abdominal surgery]. AB - We report a patient on two-drug antiplatelet therapy who underwent total gastrectomy, and developed massive perioperative bleeding. The operation was performed seven months after the placement of a drug-eluting stent (DES) for unstable angina. In perioperative care of patients with placed DES, we need to remember the risks of stent thrombosis and hemorrhagic complications, and consider the withdrawal of the antiplatelet drugs. PMID- 23984580 TI - [Epidural anesthesia for femoral head replacement in a spinocerebellar ataxia patient: a case report]. AB - Perioperative management of a spinocerebellar ataxia patient by epidural anesthesia is reported. A 67-year-old woman with left femur neck fracture underwent femoral head replacement. An epidural catheter was placed without difficulty at the L3-4 interspace using the loss of resistance technique. A total of 1% mepivacaine 13 ml was administered in divided doses to obtain bilateral T5 analgesic level. Hypotension (79 mmHg systolic) was observed transiently, and ephedrine 8 mg was administered which successfully elevated blood pressure. Overall, hemodynamics and respiratory status were stable. Postoperative analgesia was maintained by infusion of 0.2% ropivacaine at 2 ml x hr(-1). The patient's postoperative course was uneventful, and her neurologic conditions remained unchanged. PMID- 23984581 TI - [A case of myocardial ischemia induced by oxytocin during cesarean section]. AB - A 38-year-old pregnant woman underwent cesarean section with combined spinal epidural anesthesia. Immediately after intravenous administration of oxytocin, she developed chest and bilateral shoulder pain. Simultaneously, face flushing and ST segment depression on electrocardiogram were observed. Her blood pressure decreased and heart rate increased. She was treated with bolus injection of phenylephrine and continuous infusion of nicorandil and noradrenaline. At the end of surgery, all the symptoms disappeared. Because oxytocin may induce myocardial ischemia probably due to coronary vasoconstriction and peripheral vasodilation, it is important for anesthesiologists to note that oxytocin should be given to patients as slowly as possible. Alternative agents such as mythylergometrine may be used safely for an individual who is susceptive to oxytocin. PMID- 23984582 TI - [A case of trismus at anesthesia induction possibly attributable to traumatic cervical syndrome]. AB - We recently had a 41-year-old male who developed trisms at anesthesia induction, probably due to traumatic cervical syndrome. Preoperatively, this patient had been able to open his mouth sufficiently to an extent of at least three finger breadths in width. However, when anesthesia was induced, his mouth could be manually opened only to an extent of about one finger breadth in width. As a result, intubation was difficult. As the trismus did not respond to a muscle relaxant, we were forced to use the Airwayscope for intubation. When the patient awoke from anesthesia, he was again capable of spontaneously opening his mouth to the three-finger breadth extent recorded before surgery. MRI revealed no abnormalities and the patient was diagnosed as having temporomandibular arthrosis based on clinical signs. Regarding the relationship between traumatic cervical syndrome and trismus due to temporomandibular arthrosis, while reports began to be published overseas in the 1990s, few such reports are yet available in Japan. Under the recent trend of increased day surgery, assessments made before surgery tend to be confined to routinely adopted items. Considering that even mild trauma after a car accident triggers temporomandibular arthrosis, the author proposes that preoperative examinations should include checking for a history of traumatic cervical syndrome within one year. Furthermore, the anesthetist should keep in mind the possibility of difficulty with intubation and be prepared to take appropriate measures immediately. PMID- 23984583 TI - [Rectus sheath block and transversus abdominis plane block for a patient with Lambert-Eaton myasthenic syndrome undergoing low anterior resection]. AB - A 55-year-old male with Lambert-Eaton myasthenic syndrome underwent low anterior resection. Before anesthetic induction, his arterial blood gas analysis showed chronic hypercapnia (pH 7.404, Paco2 59 mmHg, BE 9.1). Anesthesia was induced with propofol, remifentanil and ketamine. Uneventful tracheal intubation was achieved after superior laryngeal nerve block without using muscle relaxants. Then ultrasound-guided bilateral rectus sheath block and transversus abdominis plane block were performed using 60 ml of 0.375% ropivacaine. Anesthesia was maintained with propofol, remifentanil monitoring bispectral index. Good surgical condition was maintained even without using muscle relaxants. Although only a small amount of morphine was required during the early postoperative days, his postoperative course was smooth and uneventful. The present case shows that ultrasound-guided rectus sheath block and transversus abdominis plane block are safe and useful for abdominal surgery in patients with neuromuscular disease. PMID- 23984584 TI - [Experience of mismatched blood transfusion for an rh negative patient and reconsideration of emergency blood transfusion manual in the hospital]. AB - We report a B Rh negative patient undergoing total pelvic exenteration, who received both ABO and Rh incompatible packed red blood cells in an emergency situation. After this experience, we revised the manual of emergency blood transfusion. We defined level of severity to share information with surgeon, nurses, anesthesiologists and the member of the blood center. We changed anesthesia information management system for showing blood type including Duffy blood group system and checking out whether we can transfuse Rh positive blood to Rh negative patient in an emergency situation at the timeout of surgery. PMID- 23984585 TI - [Efficacy of Glidescope video laryngoscope in difficult airways: a meta-analysis of randomized controlled trials]. AB - BACKGROUND: Increased evidence indicates that the Glidescope video laryngoscope (GVL) is useful for difficult tracheal intubations. The aim of this meta-analysis was to assess the efficacy of the GVL in difficult tracheal intubations, comparing with that of Macintosh laryngoscopy. METHODS: The systematic search, data extraction, critical appraisal, and pooled analysis were performed according to the PRISMA statement. The relative risk (RR), mean difference (MD), and their corresponding 95% confidence intervals (CIs) were calculated by the Comprehensive Meta-analysis version 2.2.040 software for dichotomous and continuous outcomes, respectively. RESULTS: Fifteen randomized controlled trials including 860 tracheal intubations by GVL and 860 tracheal intubations by Macintosh laryngoscopy. GVL showed higher success rate (RR 1.065, 95% CI 1.017-1.117, P < 0.008) than does the Macintosh laryngoscope, whereas no difference was found in the duration for instrumentation. CONCLUSIONS: Our meta-analysis showed that GVL has an advantage over Macintosh laryngoscope in respect to the success rate for difficult tracheal intubations. PMID- 23984586 TI - [Anesthetic management for children undergoing magnetic resonance imaging (MRI) at Department of Anesthesia and ICU, National Center for Child Health and Development (NCCHD)]. AB - We present here anesthetic management for children undergoing MRI at the Department of Anesthesia in NCCHD. Remaining motionless in the scanner of MRI is extremely important for data integrity because motion will blur the image. In patients who cannot remain still and in small children, general anesthesia or sedation is required for MRI. The MRI room is different from the conventional operating room as follows; the MRI machine emits the large sound continuously: the MRI room is the powerful magnetic field and the generation of radio frequency emissions necessitate the use of special equipment to provide continuous patient monitoring: the temperature in the MRI room is kept at 23 degrees to maintain the MRI machine: the patients positioned at the restricted area during the MRI scanning are hard to be accessed. We describe two cases of anesthetic management for children undergoing MRI by using propofol and in these cases we found that it should be better to follow the conventional setting for general anesthesia including monitoring system. Some hospitals encountered with serious complications such as cardiac arrest during MRI scanning under general anesthesia/sedation. MRI scanning under general anesthesia/sedation has a high risk due to the environment, indicating that we should be careful about the safety of the patients. PMID- 23984587 TI - [The role of anesthesiologist in the palliative care team in a public hospital]. AB - BACKGROUND: The Japanese government promotes palliative care and our hospital has the palliative care team including an anesthesiologist for better end of lives of cancer patients. METHODS: From the new point of an anesthesiologist, the outcome and characteristics of patients receiving palliative care in our hospital were examined. RESULTS: From August 2010 to March 2012, 93 patients were treated by the team. They were terminal patients whose remaining days were expected to be several months. The most common problem among them was severe pain amenable to opioid administration. CONCLUSIONS: Anesthesiologists familiar with pain, sedation and nausea control are important specialists in the palliative care team. PMID- 23984588 TI - [Survey of the preoperative smoking cessation in patients for elective surgery in a university hospital]. AB - BACKGROUND: In 2006, we reported the smoking status of surgical patients, and the factors relating to preoperative abstinence from cigarettes. Recently implementation of smoke-free policies has increased in Japan. Therefore we performed preoperative interview of 1,124 patients scheduled for elective surgery in 2011 (during 6 months), and compared the results with those of the same interview of 1,968 patients in 2006 (during 12 months). METHODS: Anesthesiologists interviewed all patients using a standardized questionnaire regarding: medical history, smoking history, and awareness of the risks of perioperative smoking. RESULTS: Current smoking rate was not different between 2006 (7%) and 2011 (7%). It was more difficult to quit smoking preoperatively for female patients in 2011 (P = 0.030), and those with benign disease in both 2006 (P = 0.006) and 2011 (P = 0.050) [smoker vs ex-smoker (< three months)]. There was no improvement in awareness of the perioperative risk of smoking between 2006 and 2011. CONCLUSIONS: At present, the importance of perioperative smoking cessation has not been sufficiently well-known for the surgical patients. Health care workers should be more aware of the importance of informing patients that preoperative abstinence from cigarettes may decrease perioperative complications. PMID- 23984589 TI - [Immunogenicity of additional varicella vaccination 3-5 years after the initial vaccination]. AB - Additional varicella vaccination was carried out targeting 16 subjects who had immune adherence hemagglutination (IAHA) seroconversion following the initial varicella vaccination and did not contract breakthrough varicella after the initial vaccination. The median ages at the initial and additional vaccination were 2.1 (1.1-6.9) years old and 6.1 (4.4-10.5) years old, respectively. The mean interval between the initial and additional vaccination was 4.0 (3.2-5.2) years. IAHA and glycoprotein-based enzyme-linked immunosorbent assay (gpELISA) antibody titers were measured just before and 4-6 weeks after the additional vaccination. Side reaction was surveyed at four weeks after the additional vaccination, and compared with the results at the initial vaccination. IAHA and gpELISA seroconversion rates at the initial vaccination were 100% and 88% respectively. Prior to the additional vaccination, IAHA antibody titers significantly decreased in 50% of the subjects, and became negative in 38% of the subjects. On the other hand, a significant increase in IAHA antibody titers was observed in 25% of the subjects, and this is assumed to be the result of a subclinical infection after the initial vaccination. The positive rate of both antibodies after the additional vaccination was 100%, the mean IAHA antibody titer (Log2) after the initial/additional vaccination in seropositive subjects was 4.6/6.5, and the mean gpELISA antibody titer (Log10) was 2.3/4.0. The mean IAHA and gpELISA antibody titers were higher after the additional vaccination than after the initial vaccination (p < 0.01, p < 0.01). This is considered to be the booster effect due to the additional vaccination. At 0-2 days after the additional vaccination, a rash at the injection site was observed in 56% of the subjects, higher than the incidence after the initial vaccination (13%) (p < 0.05), but no severe systemic side reactions were observed at either the initial or the additional vaccination. In conclusion, an additional varicella vaccination 3-5 years after the initial vaccination is thought to have greater immunogenicity and is considered effective. PMID- 23984590 TI - [Evaluation of a new vesion of the human immunodeficiency virus antigen and antibody combination assay with improved sensitivity in HIV-1 p24 antigen detection]. AB - The performance of a new version of the HIV p24 antigen and antibody combination assays (Genscreen Ultra HIV Ag-Ab) was evaluated by comparing it with three other fourth-generation enzyme immunoassays (Architect HIV Ag/Ab Combo assay, VIDAS HIV DUO Quick and Genscreen Plus HIV Ag-Ab). The assays were examined with 200 HIV positive samples, 1,000 HIV negative samples, 30 samples (28 positives including 24 samples of subtype A, B, B', C, D, F, G, B/D, CRF01_AE in HIV-1 group M, one sample of HIV-1 group O, three samples of HIV-2 and two negatives) of one worldwide HIV performance panel, 59 samples of ten HIV-1 seroconversion panels and the WHO international standard HIV-1 p24 antigen. Both the sensitivity and specificity of Genscreen Ultra HIV Ag-Ab were 100%. All of the 28 positive samples in the worldwide HIV performance panel were positive. The days of the earliest detection in the ten seroconversion panels were the same in three assays (Genscreen Ultra HIV Ag-Ab, Architect HIV Ag/Ab combo assay and VIDAS HIV DUO Quick). Genscreen Plus HIV Ag-Ab which is a former version of the Genscreen Ultra HIV Ag-Ab detected the earliest positive sample one bleed slower than the other three assays in 5 of 10 seroconversion panels. The p24 antigen limit of detection was determined in two ways, using the WHO international standard and three samples from HIV-1 antigen panels; the values obtained were 1IU/mL and 3.5-9.9 pg/mL for Genscreen Ultra HIV Ag-Ab, 1U/mL and 7.1-9.9 pg/mL for Architect HIV Ag/Ab combo assay, 0.5IU/mL and 4.0-7.1 pg/mL for VIDAS HIV DUO Quick, and 32.0 56.5 pg/mL for Genscreen Plus HIV Ag-Ab. In this study, we have shown that Genscreen Ultra HIV Ag-Ab has the sensitivity, specificity and p24 antigen limit of detection that is equal to those of two typical fourth-generation assays. This assay can be considered useful and reliable for HIV screening. PMID- 23984591 TI - [The outbreak of nosocomial infection by Mycobacterium chelonae chemovar niacinogenes and the cause of its spread]. AB - Mycobacteria consist of 2 large groups: one is the tuberculosis complex, and the other is nontuberculous mycobacterium (NTM). Most of the NTM are generally non virulent bacteria, but some NTMs have pathogenicity to humans. There are many reports of nosocomial infection cases caused by common bacteria such as multidrug resistant Pseudomonas aeruginosa. Also, some cases of in-hospital infection due to NTM were reported. Unlike common bacteria, detection of mycobacteria is affected by various factors, such as stainability, time for colony forming, temperature and nutrition Mycobacterium chelonae chemovar niacinogenes was isolated from 5 patients in 73 nosocomial infection cases (60 patients and 13 suspected cases) at a certain hospital during the period from March 2007 until January 2009. One of the reasons for the expansion of infection and difficulty in identification of the bacteria was the properties of this mycobacterium. This bacterium was very faintly stained with Gram-staining. Therefore, this mycobacterium could only be detected at a hospital when Ziehl-Neelsen stain and the cultivation at 28 degrees C for more than 5 days were performed. MICs for Cefmenoxime and Tosufloxacin of the isolates were more than 128 microg/mL. The isolates and type strasin of M. chelonae chemovar niacinogenes were also resistant to other drugs. PMID- 23984592 TI - [Evaluation of an immunochromatographic fourth generation test for the rapid diagnosis of acute HIV infection]. AB - The early diagnosis of human immunodeficiency virus (HIV) infection is important to provide effective antiviral treatment and to prevent transmission of HIV. One of the key issues to achieve this goal is to shorten the so-called "diagnostic window period" when the humoral immune response toward the virus is not fully developed during the acute phase of HIV-1 infection. In 2008, the Espline HIV Ag/Ab test kit (E4G, Fujirebio Inc. Japan) was marketed in Japan belonging to the fourth generation of HIV test kits characterized by its ability to detect both viral antigens (Ag) and anti-HIV-1/2 antibodies (Ab). E4G is the first and only fourth generation immunochromatographic HIV test kit approved in Japan at present. To evaluate its performance to diagnose acute HIV infection (AHI), E4G was compared with fourth generation Ag/Ab ELISA test kits, a third generation PA test kit, WB and real-time PCR for the testing of 25 AHI clinical specimens. E4G detected HIV infection in 18/25 specimens (sensitivity : 72.0%), of which the viral Ag was detected in only 2 specimens (8.0%) bearing a viral load > 10 million copies/mL. No spesimens were simultaneously reactive to both Ag and Ab against HIV. The third generation PA achieved a positive score of 17/ 25 specimens (68.0%), which was almost the same as the E4G figure. In contrast the fourth generation Ag/ Ab ELISA scored all the 25 AHI specimens positive (sensitivity : 100%). Overall, although having the merit of offering a rapid diagnostic test for HIV infection, E4G does not provide a sensitivity in AHI diagnosis superior to test kits currently available. PMID- 23984593 TI - [Status of use and side effects of atovaquone for the treatment and prevention of pneumocystis pneumonia in HIV infected patients in Japan--from 1997 to 2012--The Clinical Study Group for AIDS Drugs, supported by Health and Labor Science Grants from the Ministry of Health, Labor and Welfare, Japan]. AB - PURPOSE: Atovaquone is effective and well-tolerated for the treatment of mild or moderate Pneumocystis pneumonia (PCP) and the prevention of PCP. When atovaquone was not yet approved in Japan, it was supplied by the Clinical Study Group for AIDS Drugs, which has been supported by the Japan Health Science Foundation since 1997. We investigated the status of use and the reported side effects, since atovaquone has recently been approved and made available in Japan. METHOD: We retrospectively examined the application and adverse events associated with atovaquone use between January 1997 and March 2012. RESULTS: During this period, there were 721 new applications, increasing over time, with the highest rate of increase observed in recent years. Fifty-seven adverse events in 39 patients were reported. Drug eruption was the most common side effect (20 cases), followed by cytopenia (11 cases), fever (10 cases), and liver dysfunction (8 cases). Two deaths were reported (one with an unknown correlation, another with no comments provided). One case of liver dysfunction attributable to atovaquone was severe. In this case, the AST and ALT levels increased to 1,921 IU/L, and 1,062 IU/L, respectively on day 4 of atovaquone administration, but these levels improved after atovaquone discontinuation. No other severe side effects were reported. DISCUSSION: This study revealed that as in other countries, few side effects caused by atovaquone were reported in Japan. Moreover, there were no side effects unique to the Japanese population. However, caution is required when administering atovaquone, because a low incidence of severe atovaquone-induced liver dysfunction has been reported. PMID- 23984594 TI - [CMV-induced duodenal papillitis in a patient with HIV-1 infection]. AB - We present herein a case report of a 59-year-old patient with HIV-1 infection who developed a CMV-induced pseudotumor of the duodenum. The patient presented with oral pain and dysphagia. Physical examination revealed oral thrush. An EIA and a Western blot assay for antibodies to HIV were positive. His CD4-positive lymphocyte count was initially 49/microL with an HIV viral load of 2.6 x 10(5) copies/mL. Cytomegalovirus (CMV) reactivation was detected with the CMV antigenemia assay. He had CMV retinitis in both eyes with unilateral blurring. An endoscopic study revealed candida esophagitis, and a tumor-like lesion with an irregular ulcer at the papilla of Vater. Histological and immunohistochemical studies revealed a CMV-induced pseudotumor and severely inflamed duodenal mucosa with infiltration of CMV-positive cells. The patient was treated with oral valganciclovir and fluconazole for three weeks. As the oral thrush and retinitis showed improvement, he began antiretroviral therapy (ART), consisting of raltegravir and TDF/ FTC. One month later the patient's CD4-positive cells increased to 130/microL and the level of HIV-RNA decreased to 160 copies/mL, The CMV retinitis had transiently worsened because of an ART-induced inflammatory response, immune reconstitution inflammatory syndrome (IRIS). Six months after the ART initiation, an endoscopic study revealed that the esophagitis and the lesion at the papilla had improved. Biopsy showed no CMV-positive cells in the epithelium. The patient was now in a relatively healthy condition. CMV-induced pseudotumors of the duodenum are rare, and sometimes resemble malignancy. However, because this tomor responds to medical treatment physicians treating severely immunocompromised patients should be aware of its presentation and treatment. PMID- 23984595 TI - [Plasmodium malariae malaria with more than a 4-month incubation period: difficult to distinguish from a relapse of Plasmodium vivax malaria]. AB - We report herein on a case of Plasmodium malariae malaria with more than a 4 month incubation period. A 35-year-old Japanese man who first presented to our clinic with fever and history of travel to Papua New Guinea was suspected of having Plasmodium vivax malaria based on peripheral smear results. We admitted him and initiated treatment with mefloquine. After two days of therapy, he became afebrile. We discharged him, and P. vivax was later confirmed with PCR. We started mefloquine prophylaxis for a planned trip to Papua New Guinea. After his return, a standard dose of primaquine (15 mg x 14 days) was prescribed for a radical cure of P. vivax. About 4 months after his last visit to Papua New Guinea, he returned to our clinic with fever. We suspected a relapse of P. vivax malaria and admitted him for a second time. After two days of mefloquine therapy, his symptoms improved. We discharged him and restarted a higher dose of primaquine (30 mg x 14 days) therapy for a radical cure of P. vivax. Subsequently, the PCR test revealed the parasite was P. malariae and not P. vivax. Only 13 cases of Plasmodium malariae malaria have been reported in Japan during the past 10 years. Blood-stage schizonticides such as mefloquine is not active against the liver stage. Therefore, the use of these drugs for prophylaxis will not be effective for prevention of malaria if its liver stage is longer than the duration of effective chemoprophylaxis. Although the incubation period of P. malariae is typically 13 to 28 days, it occasionally lasts for months or even years. Careful attention should be given to the possibility that P. malariae occasionally has a long incubation period even in the absence of the hypnozoite stage. PMID- 23984596 TI - [A case of influenza pneumonia following pneumococcal infection in an adult patient with concurrent encephalopathy with a lesion in the splenium of the corpus callosum]. AB - A 35-year-old male patient had a fever, cough, and other symptoms since the end of December 2010. The patient then developed a high fever and decreased SpO2, suggesting possible pneumonia. The patient was admitted to our hospital on the 6th day of illness. Chest computed tomography revealed multiple infiltrative shadows and ground-glass opacities distributed in a patchy pattern in the bilateral lungs. An atypical pneumonia was suspected, and we initiated antibiotic treatment with minocycline. However, the patient developed consciousness disturbance in the afternoon of the 7th day of illness. The high fever persisted, suggesting the patient's poor response to minocycline treatment, which was then replaced with ciprofloxacin and imipenem/cilastatin on the 8th day of illness. Streptococcus pneumoniae was detected in the blood culture bottles submitted at the time of admission. A head magnetic resonance imaging performed on that day showed a high intensity area in the splenium of the corpus callosum, leading to a diagnosis of encephalopathy. Methylprednisolone pulse therapy and gamma globulin treatment were initiated. The patient then recovered consciousness gradually with improvement of inflammatory responses and imaging findings. Subsequently, an influenza virus (H1N1) antibody level was found to have increased from less than 10 times to 640 times. Thus, it was determined that the patient's pneumonia and encephalopathy were attributable to the influenza A (H1N1) pdm09 virus during the flu season and Streptcoccal infection. Combination therapy, such as steroid pulse treatment, appropriate antibiotics and gamma globulin preparation was effective for both the flu-induced mixed pneumonia and encephalopathy in this patient. PMID- 23984597 TI - [Amiodarone treatment and thyroid disorders]. AB - Amiodarone is a benzofuranic iodine-rich antiarrhythmic drug used in the treatment of severe tachyarrhythmias, especially ventricular. Drug causes many adverse effects including thyroid disorders in 14-18% of patients: amiodarone induced thyrotoxicosis type I and type II (AIT I, AIT II) and amiodarone induced hypothyroidism (AIH). AIT occurs more frequently in geographical areas with low iodine intake, whereas AIH is more frequent in iodine-sufficient areas. AIH may appear both in normal thyroid gland and Hashimoto's disease. AIT I occurs most often on the basis of Greave's disease or goiter. In contrast to AIT, AIH does not cause difficulties with diagnosis and treatment. In order to differentiate between AIT I and AIT II such methods as USG, CFDS, RAIU, MIBI and IL-6 are used. Increased vascularization showed in CFDS, increased MIBI uptake in scintigraphy, increased 131I uptake in RAIU in some cases are typical for AIT I. In opposition to AIT I, all this parameters are decreased in AIT II and it is possible that the level of serum IL-6 is increased. However, the usefulness of IL-6 is controversial. After diagnosis discontinuation of amiodarone should be taken into consideration. In addition, AIT I is preferably treated with methimazole and potassium perchlorate. AIT II is treated with glucocorticoids. In the case of unclear diagnosis and mixed types of AIT the combination of all foregoing drugs should be instituted. If the case is refractory, thyreidectomy should be taken into consideration, especially if a patient suffers from left ventricular systolic dysfunction. RIT--radioiodine therapy is also possible. PMID- 23984598 TI - [Clinical efficacy and safety of prolonged use of the valganciclovir for the treatment of cytomegalovirus disease in patients after kidney transplantation]. AB - Cytomegalovirus infection is particularly dangerous for patients undergoing solid organs transplantation. Among these patients cytomegalovirus disease (CMV) may occur. CMV disease is associated with increased mortality, organ damage and reduced graft survival. THE AIM OF THE STUDY was to determine the clinical outcomes (clinical efficacy and safety profile) for the use of valganciclovir administered for 200 days compared to standard period of 100 days in the prevention of cytomegalovirus disease in seronegative patients after kidney transplantation from infected donor (high risk patients). MATERIAL AND METHODS: A systematic review of literature published during the period: 1st January 1966 31st October 2010, was performed in order to assess the efficacy and safety of valganciclovir in the treatment of cytomegalovirus disease. Databases MEDLINE (PubMed), EMBASE and Cochrane were searched. RESULTS: A systematic review yielded 1 randomized and 3 nonrandomized clinical trials. 200 days prophylaxis with valganciclovir significantly decreased a risk of: cytomegalovirus disease, CMV viral load, opportunistic infections; percentage of patients with high viral load was also significantly decreased compared to 100 days therapy. The safety profile of extended therapy was similar to that observed within 100 days prophylaxis. The higher risk of leucopenia in the 200 days than 100 days group was the only one adverse event that met statistical significance. The results of non-randomized trials were comparable to those mentioned above. CONCLUSION: Prolonged prophylaxis of cytomegalovirus till 200 days in high-risk patients (D+/B-) is safe and provides significant therapeutic benefits. PMID- 23984599 TI - [Gallbladder contractility in children with functional abdominal pain or irritable bowel syndrome]. AB - III Rome Criteria of functional gastrointestinal disorders in children, distinguished the disturbances with abdominal pain, to which irritable bowel syndrome, functional abdominal pains, functional dyspepsia and abdominal migraine were included. THE AIM OF THE STUDY was sonographic assessment of the gallbladder and its contractility in functional abdominal pain and irritable bowel syndrome in children. MATERIAL AND METHODS: The study comprised 96 children aged 6 to 18 years, 59 girls and 37 boys. Depending on diagnosis, the children were divided into three groups. 38 children with functional abdominal pain constituted the first group, 26 children with irritable bowel syndrome were included to the second group, the third group consisted of 32 healthy children (control group). Diagnosis of functional abdominal pain and irritable bowel syndrome was made based on the III Rome Criteria. In irritable bowel syndrome both forms with diarrhea (13) and with constipation (13) were observed. Anatomy and contractility of the gallbladder were assessed by ultrasound examination. The presence of septum, wall thickness, thick bile, vesicle volume in fasting state and 30th and 60th minute after test meal were taken into consideration. Test meal comprised about 15% of caloric requirement of moderate metabolism. Children with bile stones and organic diseases were excluded from the study. RESULTS: Thickened vesicle wall and thick bile were present more frequently in children with irritable bowel syndrome and functional abdominal pain than in control group (p < 0.02). Fasting vesicle volume was significantly greater in children with functional abdominal pain than in irritable bowel syndrome and control group (p = 0.003, p = 0.05). Vesicle contractility after test meal was greatest in children with functional abdominal pain. Evaluation of diminished (smaller than 30%) and enlarged (greater then 80%) gallbladder contractility at 30th and 60th minute after test meal demonstrated disturbances of contractility in children with irritable bowel syndrome and functional abdominal pain. CONCLUSIONS: In children with functional abdominal pain and irritable bowel syndrome disturbances of gallbladder anatomy, fasting volume and contractility after test meal were demonstrated. The observed disturbances require further studies for explanation of their role in functional gastrointestinal disturbances with abdominal pain in children. PMID- 23984600 TI - [Assessment of concentrations of A, C and E vitamins in the plasma of patients with NSCLC undergoing first-line chemotherapy]. AB - Lung cancer is one of the most common cancer types and it usually takes the form of non-small cell lung cancer (NSCLC). ROS take part in the process of carcinogenesis. What more, chemotherapy used in cancer treatment augments their production, leading to the weakening of the antioxidative barrier. As a result in cancer patients undergoing chemotherapy the reduction-oxidation processes are imbalanced. Vitamins A, C and E form an important part of the nonenzymatic antioxidative barrier in humans. THE AIM OF THE STUDY was an assessment of concentrations of A, C and E vitamins in the plasma of patients with NSCLC before and after chemotherapy MATERIAL AND METHODS: 25 first-line chemotherapy patients with inoperable NSCLC have undergone examination, including 20 men and 5 women aged between 50-75 years (average age 62.6 +/- 6.1 years). 24 healthy individuals including 18 men and 6 women aged between 49-71 years (average age 59.5 +/- 6.6 years) formed a control group. In cancer patients the concentration of vitamins A, C and E was assessed by spectrophotometry using T60V spectrophotometer (PG Instruments) before and after first-line chemotherapy, while in control group it was assessed only once. RESULTS: The concentration of A, C and E vitamins in plasma of NSCLC patients was lower (p < 0.05) than in the control group. After 6 weeks of chemotherapy another significant drop in vitamin concentrations in NSCLC patients was observed (p < 0.05) and was biggest for vitamin C (39.1%). CONCLUSIONS: Lowering of A, C and E vitamins concentrations in the plasma of NSCLCpatients suggests a weakening of antioxidative barrier. Chemotherapy leads to further fall in the concentration of those vitamins in patients' plasma. PMID- 23984601 TI - [Assessment of the influence of rehabilitation in patients treated in a hospital rehabilitation ward due to consequences of neurological diseases]. AB - THE AIM OF THE STUDY was evaluation effects of rehabilitation in patients with consequences of neurological diseases. MATERIAL AND METHODS: The study was conducted in the hospital department of rehabilitation. The study involved group of 30 patients consisting of 12 men aged from 48 to 76 years (mean age 64.3 +/- 7.9), and 18 women aged from 45 to 82 years (mean age 65.4 +/- 13,2). These were patients mostly after stroke, multiple sclerosis or Parkinson's disease enrolled in rehabilitation. TESTS were performed before and after 21 days rehabilitation, using the following scales and ratings: Activities of Daily Living (ADL), Instrumental Activities of Daily Living Scale (IADL), Scale Barthel, test Tinetti, Expanded "Get-Up-and-Go" Test (ETGUG) and Geriatric Depression Scale (GDS). RESULTS. In men, the average number of points in the scale of ADL, IADL, Barthel increased statistically significant, the results obtained in the test Tinetti, ETGUG, GSD were changed not significant statistically. In women, the average number of points in the IADL scale, Barthel scale and GDS increased, and the test ETGUG were reduced, all statistically significant. The results of the scale ADL and test Tinetti, improved statistically not significant. CONCLUSIONS. The physical rehabilitation in patients with neurological consequences had a positive impact on the ability to perform simple and complex activities of daily living, physical and mental condition. TESTS: ADL, IADL, Barthel scale, GDS, test Tinetti and ETGUG can be used for evaluation of rehabilitation results. PMID- 23984602 TI - [Comparative analyses of reference values used in Polish medical diagnostic laboratories for selected biochemical investigations]. AB - The establishment of reference values comparative ranges for each laboratory test result does not meet expectations. THE AIM OF THE STUDY was to make a comparative analysis of the reference values (RV) used in medical diagnostic laboratories (MLD) in Poland for concentrations in serum or plasma biochemical parameters (potassium, calcium, creatinine, and glucose) in adults. MATERIAL AND METHODS: The data source was the information sent to the Centre for Quality Assessment in Laboratory Medicine by MLD participating in programs interlaboratory surveys. RESULTS: Studies have shown that there is a great diversity of reference values for the analyzed biochemical parameters used in MLD. The study also demonstrated the use by MLD various units of measurement systems (SI and weight-volume). CONCLUSION: A large variation of the reference values in the parameters significantly hinders the interpretation of laboratory results by physician. PMID- 23984603 TI - [Tumor markers used in the diagnosis, monitoring, treatment, and prognosis head and neck cancer]. AB - Cancer is currently the second to heart disease and vascular cause of death and observed tends to increase the number of cases. The cause of high mortality from cancer it is too late malignant diagnosis. In the case of head and neck cancers at diagnosis in about 40% of patients found to have metastatic lymph nodes within. Therefore, an important issue for modem oncology is the early diagnosis of the disease cancer. Currently high hopes for the early detection and diagnosis of treatmen cancer is put in simple, accessible and low-cost testing to determine the biochemical tumor markers. THE AIM OF THE STUDY was to examine the latest reports on biochemical markers useful in cancer diagnosis, disease staging, prognosis and monitoring the treatment of the most common cancers of the head and neck. MATERIALS AND METHODS: The material consisted of references of the last 17 years. Criterion search accounted for password: biochemical tumor markers, diagnostics, monitoring treatment of cancer. 10 of 90 works were selected to examine. CONCLUSIONS: Usefulness of biochemical tumor markers in monitoring course of the disease and evaluation of treatment effectiveness was demonstrated. In combination with other diagnostic methods as they apply to screening, as well as in the detection of cancer in the study population. PMID- 23984604 TI - [Assessment the lifestyle in patients after recent acute coronary syndrome qualified for cardiac rehabilitation and in healthy subjects]. AB - Results of a lot of research indicate that preventive activities consisting in the fighting of risk factors have the greatest influence on the reduction of the incidence of ischaemic heart disease. THE AIM OF THE STUDY was to assess the lifestyle in patients after recent acute coronary syndrome (ACS) qualified for cardiac rehabilitation and in healthy subjects (with no diagnosis of coronary thrombosis). MATERIAL AND METHODS: The research included 86 patients, 64 men and 22 women aged 42-78 (mean age 61.7 +/- 9.6 years) after recent ACS, treated with PCI (percutaneous coronary interventions), and qualified for cardiac rehabilitation (stage II)--group I. The control group included 88 people, 54 men and 34 women aged 34-75 (mean age 56.2 +/- 9.7 years), who were clinically healthy--group II. The assessment of a lifestyle was performed based on the presence of four positive behaviours, i.e. eating appropriate amount of vegetables and (or) fruit every day, refraining from smoking, satisfactory levels of physical activity, and correct body mass. Based on these factors, a lifestyle index was calculated, from 0 (no positive health behaviours) to 4 (all positive health behaviours present), the so-called healthy lifestyle index. RESULTS: Among the examined elements of lifestyle index in ill and healthy subjects, satisfactory physical activity was the rarest (in 16.67% of men and in 9.09% women after ACS and in 16.22% of healthy men and 11.63% healthy women). Healthy lifestyle index was determined in 4.88% of patients after ACS. It was not found in healthy subjects. CONCLUSION: The analysis of the lifestyle index shows that a change of one's lifestyle is necessary as an initial and secondary prevention. PMID- 23984605 TI - [Comorbidity in organic depressive disorders in patients Specialist Hospital Dr. J. Babinski in Cracow in the years 2008-2010]. AB - With age occurs the aging central nervous system, and therefore increases the risk of mental disorders in this medium, including depressive disorders. In particular, a large proportion of depressive disorders in the organic substrate is observed in people over 65 years of age. Literature says that in this age group as 15-30% of people receiving assistance from family doctors have diagnosed depression. THE AIM OF THE STUDY was to investigate the comorbidity in patients with a diagnosis of organic depression. MATERIALS AND METHODS: We analyzed 227 medical records of diagnosed depressive disorders coexisting with other organic mental disorders in patients hospitalized in 2008-2010 in the Specialist Hospital Dr. J. Babinski in Cracow. We analyzed the medical records of outpatient treatment of the above. Analyses were made medical history by questionnaire of our own design. RESULTS: It has been shown that in the organic comorbidity depressive disorders related in most men, between 60 and 70 years of age. Most were people about the origin of the workers and peasants, mainly in vocational education. Every second person was unmarried. The subjects usually receive disability benefits and retirement. The organic depressive disorders frequently co-exist: the teams dementia, anxiety, personality disorders, delusional teams. The subjects were mainly dependent on alcohol and sedative drugs from the group of benzodiazepines. In every other test persons experienced cardiovascular disease. Among patients diagnosed with alcohol dependence disorder typical of taking psychoactive substances such as liver, pancreas, gastrointestinal tract. The treatment was particularly detrimental in people addicted to drugs. CONCLUSIONS: In the study population were two main groups of comorbid namely to psychoactive drugs and mental disorders not related with dependence on psychoactive substances. Comparative analysis of the dynamics of the disease has a significant adverse course and prognosis in children with addiction. In both groups, somatic concern comorbidity cardiovascular disease and in the control group significantly frequent somatic disorders typical of alcoholics (liver, pancreas). PMID- 23984606 TI - [Refractory celiac disease]. AB - Refractory celiac disease is characterized by the persistence or recurrence of symptoms connected with enteropathy, presence of specific antibodies in the serum: EMA, tTG2 and DPG, and (or) intestinal villous atrophy despite strict adherence to gluten-free diet for 6 to 12 months. Correct initial diagnosis of celiac disease, exclusion of other causes of the lack of response to gluten-free diet and persistence of villous atrophy are necessary conditions of diagnosis of refractory celiac disease. Options of the treatment, depending on the patient condition are: gluten-free diet, elementary diet, parenteral nutrition, immunosuppression and biological therapy. PMID- 23984607 TI - [Collagen based dressings in the treatment of wound healing]. AB - Collagen is the fundamental protein forming the connective tissues matrix, improves the ability of keratinocytes to migrate to sites that require rebuilding of the damaged epidermis, is one of the component of dressings used to accelerate wound healing. Because of the potential risk of the presence of pathogenic prions in bovine collagen, part of collagen dressings is formed on the basis of porcine collagen. Currently, a least of an immunogenic form of collagen is atelocollagen, which is subjected to enzyme-treated collagen, in which the terminal amino acids are removed from the collagen. It is assumed that in the near future atelocollagen will be used also as a carrier for drugs which support the healing processes. PMID- 23984608 TI - [The system of protection of scientific biomedical research participants in France and in Poland]. AB - Realizing scientific biomedical research conducted on human-beings demands obeying ample ethical rules. However, states keep independence in the means of implementing deontological guidelines to legislative acts. The aim of the article is to compare rules of law relative to protection of scientific biomedical research participants in two European Union member states--France and Poland. French regulations cover more types of scientific biomedical research than those in Poland. In France almost all types of interventional scientific biomedical research including research on human biological samples and research on cosmetics are covered by the rules of law. Polish regulations are limited to interventional research conducted by doctors and dentists. In both states projects of clinical trials of medicinal products demands double acceptance - from bioethics committee and from competent state authority. In protection of scientific biomedical research participants the role of state authority competent for personal data is more vital in France than it is in Poland. In France there is also National Ethics Advisory Committee whereas in Poland there is no such institution. The systems protecting scientific biomedical research participants differs therefore in both states in many vital aspects and French measures cover more types of scientific biomedical research, hence the level of participants protection in various types of research is more equitable. PMID- 23984609 TI - "Eppur si muove" ("and yet it moves"). PMID- 23984610 TI - Differences in the bioenergetic potential of athletes participating in team sports. AB - BACKGROUND/AIM: In modern training technology, assessment of aerobic bioenergetic potential in athletes is commonly performed by standard laboratory procedures to determine basic or specific functional abilities for specific sport activity or discipline. The aim of study was to assess the aerobic bioenergetic potential of athletes participating in basketball, football and handball. METHODS: The study included 87 athletes (29 basketball players, 29 football players, and 29 handball players) aged 21-24. Evaluation of the aerobic bioenergetic potential of athletes participating in basketball, football and handball was performed followed by both univariate (ANOVA) and multivariate (MANOVA) statistical methods to determine differences among the athletes in relative (VO2 mL/kg/min) and absolute oxygen consumption (VO2 L/min). RESULTS: Statistically significant differences between absolute and relative oxygen consumption were found in basketball players (Mb), football players (Mf), and handball players (Mh) (MANOVA, p = 0.00). ANOVA also revealed significant differences in relative oxygen consumption (VO2 mL/kg/min) (p = 0.00). The football players (55.32 mL/kg/min) had the highest relative oxygen consumption, followed by the handball players (51.84 mL/kg/min) and basketball players (47.00 mL/kg/min). The highest absolute oxygen consumption was recorded in the basketball players (4.47 L/min), followed by the handball players (4.40 L/min) and footballers (4.16 L/min). CONCLUSION: Statistically significant differences in the aerobic bioenergetic potential, expressed by the relative oxygen consumption were found among atletes participating in different team sports. It can be assumed that the player from the sports in which it is necessary to cross greater distance in total during the match have a greater need for aerobic capacity. PMID- 23984611 TI - Proton magnetic resonance spectroscopy and apparent diffusion coefficient in evaluation of solid brain lesions. AB - BACKGROUND/AIM: Advanced magnetic resonance techniques can provide insight in physiological changes within pathological canges and contribute to better distinquishing between different tumor types and their discrimination from non neoplastic lesions. The aim of this study was to evaluate the role of proton magnetic resonance spectroscopy (1H-MRS) and apparent diffusion coefficients (ADC) in distinguishing intracranial glial tumors from tumor like nonneoplastic lesions, as well as for differentiating high- from low-grade gliomas. METHODS: This retrospective study included 47 patients with solid brain lesions (25 nonneoplastic, 14 low-grade and 8 anaplastic glial tumors). In all patients 1H MRS (at a TE of 135 ms and 30 ms) and diffusion-weighted imaging (DWI) were performed. The choline to creatine (Cho/Cr), choline to N-acetyl aspartate (Cho/NAA), N-acetyl aspartate to creatine (NAA/Cr) and myoinositol to creatine (mIn/Cr) ratios and the apparent diffusion coefficient (ADC) were determined. RESULTS: The Cho/Cr ratio was significantly higher in glial tumors grade II than in non-neoplastic lesions (p = 0.008) and in glial tumors grade III than in non neoplastic lesions (p = 0.001). The Cho/NAA ratio was significantly higher in glial tumors grade II than in non-neoplastic lesions (p = 0.037). AADC/ADC between glial tumors grade II and glial tumors grade III showed a statistical significance (p = 0.023). CONCLUSION: Our study showed that 1H-MRS and apparent diffusion coefficients can help in evaluation and differentiation of solid brain lesions. PMID- 23984612 TI - Cephalometric assessment of maxillary length in Serbian children with skeletal class III. AB - BACKGROUND/AIM: Malocclusion of skeletal class III is a complex irregularity of sagittal inter-jaw relationship, which is due to irregularities of sagittal position of one or both of the jaw bones, which is often associated with disproportionate ratio of their length. The aim of this study was to determine whether the length of the jaw of children with skeletal class III in the period of mixed dentition was changed. METHODS: Fifty children with skeletal class III and the same number of those with skeletal class I, of both sexes, have been selected on the basis of cephalometric analysis of profile tele-x-ray of the head. All the children aged 6-12 had mixed dentition, and were divided according to sex and age into three subgroups within each group. The length of maxilla, mandible and cranial base were measured. Proportions among the lengths measured within each group were found and difference significance in the measured lengths and their proportions among groups and subgroups were evaluated. RESULTS: The children with skeletal class III, compared with the findings in the control group, had significantly lower values of maxillary length, total maxillary length, as well as lower values of their lengths in proportion to lengths of the front or the total length of cranial base and in proportion to mandibular lengths (p < 0.05). Among the patients of different sexes, both in the test and the control group, a significant difference in the values of the measured lengths was found. CONCLUSION: The children with skeletal class III have significantly shorter maxilla than those with skeletal class I. PMID- 23984613 TI - The significance of biometric parameters in determining anterior teeth width. AB - BACKGROUND/AIM: An important element of prosthetic treatment of edentulous patients is selecting the size of anterior artificial teeth that will restore the natural harmony of one's dento-labial structure as well as the whole face. The main objective of this study was to determine the correlation between the inner canthal distance (ICD) and interalar width (IAW) on one side and the width of both central incisors (CIW), the width of central and lateral incisors (CLIW), the width of anterior teeth (ATW), the width between the canine cusps (CCW), which may be useful in clinical practice. METHODS: A total of 89 subjects comprising 23 male and 66 female were studied. Their age ranged from 19 to 34 years with the mean of 25 years. Only the subjects with the preserved natural dentition were included in the sample. All facial and intraoral tooth measurements were made with a Boley Gauge (Buffalo Dental Manufacturing Co., Brooklyn NY, USA) having a resolution of 0.1mm. RESULTS: A moderate correlation was established between the interalar width and combined width of anterior teeth and canine cusp width (r = 0.439, r = 0.374). A low correlation was established between the inner canthal distance and the width of anterior teeth and canine cusp width (r = 0.335, r = 0.303). The differences between the two genders were highly significant for all the parameters (p < 0.01). The measured facial distances and width of anterior teeth were higher in men than in women. CONCLUSION: The results of this study suggest that the examined interalar width and inner canthal distance cannot be considered reliable guidelines in the selection of artificial upper anterior teeth. However, they may be used as a useful additional factor combined with other methods for objective tooth selection. The final decision should be made while working on dentures fitting models with the patient's consent. PMID- 23984614 TI - The effect of intravitreal administration of bevacizumab on macular edema and visual acuity in age-related macular degeneration with subfoveolar choroidal neovascularisation. AB - BACKGROUND/AIM: Age-related macular degeneration (AMD) is a leading cause of the loss of central visual acuity in population older than 70 years. We can distinguish wet and dry form of AMD. The aim of the study was to present our early results in treatment of the wet (neovascular) form of AMD with intravitreal administration of bevacizumab. METHODS: The study included 39 patients. Each patient underwent a complete ophthalmological examination, fluorescein angiography (FA) and optical coherence tomography (OCT). All the patients received 1.25 mg of intravitreal bevacizumab (0.05 mL of commercial phial of Avastin). The total of three doses was given with a one-month interval between doses. RESULTS: Among 39 patients, 24 were women and 15 men. The average best corrected visual acuity (BCVA) was improved from 0.09 before the therapy to 0.24 after the administration of all the three doses of bevacizumab (p < 0.001). The average central macular thickness (CMT) measured by OCT was improved from 474 microm in the beginning to 341 microm after the administration of all the three doses of the drug (p < 0.001). There were no side effects. CONCLUSIONS: Our short term experience indicates that intravitreal administration of three doses of bevacizumab in one-month intervals between the doses leads to a significant reduction of macular edema and improvement of BCVA in patients with neovascular AMD. PMID- 23984615 TI - Therapeutic efficacy of connective tissue autotransplants with periosteum and platelet rich plasma in the menagement of gingival recession. AB - BACKGROUND/AIM: Gingival recession progression in clinical practice has influenced the development of various surgical procedures and techniques for solving esthetic imperfections and subjective difficulties coused by gingival recession. The aim of this study was to verify efficacy of surgical procedures and to compare both of surgical procedures through the keratinized tissue width. METHODS: The study included 20 teeth with gingival recesion, Muller class I and II. Ten teeth with gingival recession were treated with connective tissue autotransplants with periosteum in combination with coronary guided surgical flap (CTG group). On the contralateral side 10 teeth with gingival recession were treated with the same surgical procedures but in combination with platelet-rich plasma (CTG-PRP group). We measured the keratinized tissue width. For statistical significance we used the Student's t-test. RESULTS: The study reveled a statistical significance in reducing vertical deepress of recession by both used treatments. Root deepness in CTG and CTG-PRP group was 90% and 93.5%, respectively. With both surgical techniques we achieved larger zone of keratinized gingiva but with a wide zone of keratinized tissue in CTG--the PRP group. CONCLUSION: The concept regeneration technique with PRP and with the stimulating influence of platele activated growth factors results in the regeneration of deep periodontal tissue as an important prerequisite for the successfull treatment of gingival recession. PMID- 23984616 TI - The effects of acclimatization on blood clotting parameters in exertional heat stress. AB - BACKGROUND/AIM: Exertional heat stress is a common problem in military services. Considering the coagulation abnormalities are of major importance in development of severe heat stroke, we wanted to examine changes in hemostatic parameters in soldiers during exertional heat stress test as well as the effects of a 10-day passive or active acclimatization in a climatic chamber. METHODS: A total of 40 male soldiers with high aerobic capacity performed exertional heat stress test (EHST) either in cool [20 degrees C, 16 degrees C wet bulb globe temperature (WBGT)], or hot (40 degrees C, 29 degrees C, (WBGT) environment, unacclimatized (U) or after 10 days of passive (P) or active (A) acclimatization. Physiological strain was measured by tympanic temperatures (Tty) and heart rates (HR). Platelet count (PC), antithrombin III (AT), and prothrombin time (PT) were assessed in blood samples collected before and immediately after the EHST. RESULT: EHST in hot conditions induced physiological heat stress (increase in Tty and HR), with a significant increase in prothrombin time in the groups U and A. Platelet counts were significantly higher after the EHST compared to the basic levels in all the investigated groups, regardless environmental conditions and acclimatization state. Antithrombin levels were not affected by EHST whatsoever. CONCLUSION: In the trained soldiers, physiological heat stress caused mild changes in some serum parameters of blood clotting such as prothrombin time, while others such as antithrombin levels were not affected. Platelet counts were increased after EHST in all groups. A 10-day passive or active acclimatization in climatic chamber showed no effect on parameters investigated. PMID- 23984617 TI - Reactive oxygen species, apoptosis and cancer. PMID- 23984618 TI - Long-term ventricular assist devices in current clinical practice. PMID- 23984619 TI - Acute meningoencephalitis in a patient with systemic lupus erythematosus. AB - INTRODUCTION: Infections in patients with systemic lupus erythematosus (SLE) are a significant factor of morbidity and mortality. Although central nervous system infections, including septic meningitis, are rare in patients with SLE, they can be significant causes of mortality inspite of the prompt and accurate diagnosis and proper management. CASE REPORT: We presented a woman with the diagnosis of SLE and diffuse proliferative lupus nephritis. Because of disease activity we introduced cytostatic immunosuppressive therapy, cyclophosphamide and then azathioprine. Meningoencephalitis, staphylococcal sepsis and abscess of the brain, with resulting seizures developed. CONCLUSION: This case alerts to the need of careful examination of patients with SLE, collection of adequate cultures and evaluation of predisposition towards infections, before the introduction of immunosuppressants due to potentially fatal infection. PMID- 23984620 TI - Liposarcoma of the paratesticular tissue and spermatic cord: a case report. AB - INTRODUCTION: Liposarcomas are malignant tumors derived from fat tissues. Liposarcoma of the paratesticular tissue is rare. CASE REPORT: We presented a 51 year-old man with liposarcoma of paratesticular tissue and the spermatic cord, mimicking a testicular tumor. Ultrasound examination of this scrotal mass was hyperechogenic and homogeneous and separated from the testis and epididymis. The patient was operated, and the orchidectomy was performed. Histology revealed well differentiated lipoma-like liposarcoma of the paratesticular tissue and spermatic cord. After a 6 month follow-up the patient did not show any evidence of tumor progression or recurrence. CONCLUSION: Liposarcomas of the paratesticular tissue and seminal cord represent a rare type of tumors, often misdiagnosed preoperatively. Therapy should include radical surgical excision, usually radical inguinal orchiectomy. If the margin status is in doubt, adjuvant radiation should be performed. Local relapse is common and may occur after several years, so follow-up period has to be sufficiently long. PMID- 23984621 TI - Paravesical haematoma following placement of an isolated anterior mesh for cystocele repair. AB - INTRODUCTION: Pelvic organ prolapse is a substantial health problem for women around the world. Given the limitations of traditional surgery in the reconstruction of normal vaginal anatomy and function in genitourinary prolapse, various synthetic implants have been developed for surgical repair. Mesh procedures are gaining in popularity, encouraged by preliminary data. Although minimally invasive and relatively safe, serious complications following these procedures have been described. CASE REPORT: We presented a patient who had underwent an isolated anterior mesh procedure and developed postoperative haematoma which required surgical intervention. CONCLUSION: This report suggests that minimally invasive urogynecological procedures could result in significant complications. Thus, surgeons should be familiar with effective interventions in order to manage them. PMID- 23984622 TI - Churg-Strauss syndrome: a case report. AB - INTRODUCTION: Churg-Strauss syndrome (CSS) is an allergic granulomatous angiitis, a rare disease of small and medium arteries and veins, associated with the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA). According to the American College of Rheumatology (ACR), there are four or more criteria out of six for the diagnosis: asthma, eosinophilia (> 10% in peripheral blood), paranasal sinusitis, pulmonary infiltrates, histological evidence of vasculitis with extravascular eosinophils, and mononeuritis multiplex or polyneuropathy. CASE REPORT: We reported a female patient, aged 80 years, with asthma for many decades and repeatedly verified eosinophilia in peripheral blood, in which CSS was suspected only after the occurrence of skin changes in the form of vesicles, vesiculopustule, purpuric macula, papule and petechiae. Further tests verified pulmonary infiltrates, paranasal sinusitis, extravascular eosinophils on histopathologic sample of skin tissue, and polyneuropathy. The treatment started with methylprednisolone (60 mg/d, with decreasing doses), and continued with pulse doses of cyclophosphamide (800 mg once monthly), also corticosteroid ointment for skin lesions. CONCLUSION: Despite long-standing pulmonary symptoms and laboratory findings of eosinophilia, the appearance of skin changes raised suspicion of possible CSS. Skin changes resolved and the patient was reffered to rheumatologist. PMID- 23984623 TI - History of infectious diseases development in the Old and the Middle Ages with the emphasis on the plague and leprosy. PMID- 23984624 TI - Impact of imaging diagnostics on the budget--are we spending too much? PMID- 23984626 TI - Design and synthesis of molecular donors for solution-processed high-efficiency organic solar cells. AB - Organic semiconductors incorporated into solar cells using a bulk heterojunction (BHJ) construction show promise as a cleaner answer to increasing energy needs throughout the world. Organic solar cells based on the BHJ architecture have steadily increased in their device performance over the past two decades, with power conversion efficiencies reaching 10%. Much of this success has come with conjugated polymer/fullerene combinations, where optimized polymer design strategies, synthetic protocols, device fabrication procedures, and characterization methods have provided significant advancements in the technology. More recently, chemists have been paying particular attention to well defined molecular donor systems due to their ease of functionalization, amenability to standard organic purification and characterization methods, and reduced batch-to-batch variability compared to polymer counterparts. There are several critical properties for efficient small molecule donors. First, broad optical absorption needs to extend towards the near-IR region to achieve spectral overlap with the solar spectrum. Second, the low lying highest occupied molecular orbital (HOMO) energy levels need to be between -5.2 and -5.5 eV to ensure acceptable device open circuit voltages. Third, the structures need to be relatively planar to ensure close intermolecular contacts and high charge carrier mobilities. And last, the small molecule donors need to be sufficiently soluble in organic solvents (>=10 mg/mL) to facilitate solution deposition of thin films of appropriate uniformity and thickness. Ideally, these molecules should be constructed from cost-effective, sustainable building blocks using established, high yielding reactions in as few steps as possible. The structures should also be easy to functionalize to maximize tunability for desired properties. In this Account, we present a chronological description of our thought process and design strategies used in the development of highly efficient molecular donors that achieve power conversion efficiencies greater than 7%. The molecules are based on a modular D(1)-A-D(2)-A-D(1) architecture, where A is an asymmetric electron deficient heterocycle, which allowed us to quickly access a library of compounds and develop structure-property-performance relationships. Modifications to the D1 and D2 units enable spectral coverage throughout the entire visible region and control of HOMO energy levels, while adjustments to the pendant alkyl substituents dictate molecular solubility, thermal transition temperatures, and solid-state organizational tendencies. Additionally, we discuss regiochemical considerations that highlight how individual atom placements can significantly influence molecular and subsequently device characteristics. Our results demonstrate the utility of this architecture for generating promising materials to be integrated into organic photovoltaic devices, call attention to areas for improvement, and provide guiding principles to sustain the steady increases necessary to move this technology forward. PMID- 23984627 TI - Synthesis of 3,6-O-(o-xylylene)glucopyranosyl fluoride, an axial-rich glycosyl donor of beta-glycosylation. AB - Despite the reported complete beta-selectivity in glycosylation with 2,4-di-O benzyl-3,6-O-(o-xylylene)glucopyranosyl fluoride, its preparation has been inefficient. This paper describes an improved route for the donor, including the formation of the 3,6-bridge on 1,2,4-orthoacetylglucose, the preparation of which was also refined, along with a discovered feature that the 3,6-bridged glucose prefers the furanose form. Although this feature made the synthesis of the desired glucopyranosyl donor difficult, application of thermal glycosylation solved the problem. With a modifiable intermediate, the improved availability of the donor would expand the applications. PMID- 23984625 TI - Discoipyrroles A-D: isolation, structure determination, and synthesis of potent migration inhibitors from Bacillus hunanensis. AB - Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase involved in a variety of cellular response pathways, including regulation of cell growth, proliferation, and motility. Using a newly developed platform to identify the signaling pathway/molecular target of natural products, we identified a family of alkaloid natural products, discoipyrroles A-D (1-4), from Bacillus hunanensis that inhibit the DDR2 signaling pathway. The structure of 1-4, determined by detailed two-dimensional (2D) NMR methods and confirmed by X-ray crystallographic analysis has an unusual 3H-benzo[d]pyrrolo][1,3]oxazine-3,5-dione core. Discoipyrroles A-D potently inhibit DDR2 dependent migration of BR5 fibroblasts and show selective cytotoxicity to DDR2 mutant lung cancer cell lines (IC50 120 400 nM). Examination of the biosynthesis has led to the conclusion that the discoipyrroles are formed through a nonenzymatic process, leading to a one-pot total synthesis of 1. PMID- 23984628 TI - Efficient thermal deglycosylation of ginsenoside Rd and its contribution to the improved anticancer activity of ginseng. AB - The root of ginseng is a famous functional food and a herbal medicine. Research into the development of a method for increasing the pharmaceutical effect of ginseng by conversion of ginsenosides, the major active components of ginseng, by high-temperature and high-pressure thermal processing has been conducted. However, changes in the structures of each ginsenoside by heat processing and their contributions to anticancer activity have not yet been fully elucidated. Here, we investigated whether anticancer activity of ginsenosides, such as Rb1, Rb2, Rc, Rd, and Re, was associated with changes in the structures of each ginsenoside by heat processing in human stomach cancer AGS cells. Upon heat processing at 120 degrees C, most peaks of ginsenosides Rb1, Rb2, Rc, and Rd disappeared and the contents of less-polar ginsenosides 20(S,R)-Rg3, Rk1, and Rg5 were newly detected. From the quantitative analysis of ginsenosides, the generated amounts of less-polar ginsenosides were the highest after heat processing of ginsenoside Rd. After heat processing, the diol-type ginsenosides Rb1, Rb2, Rc, and Rd gained significant antiproliferative activity. In particular, ginsenoside Rd induced the strongest cell death among the diol-type ginsenosides, whereas the triol-type gisenoside Re showed weak antiproliferative activity. Ginsenoside Rd-induced cell death was associated with caspase-dependent apoptosis. Taken together, these results demonstrate that deglycosylation of Rd contributes to improved anticancer activity of ginseng and provide new insight on the mechanism of increased anticancer effects of ginsenosides upon heat processing. PMID- 23984629 TI - Elevated Pb(II) release from the reduction of Pb(IV) corrosion product PbO2 induced by bromide-catalyzed monochloramine decomposition. AB - The stability of Pb(IV) corrosion product PbO2 has been linked to lead contamination in chloraminated drinking water. Recent studies have shown that autodecomposition of monochloramine (NH2Cl) can cause lead release from PbO2 via reductive dissolution. Bromide (Br(-)) is a known catalyst for NH2Cl decomposition. In this study, we investigated whether Br(-)-catalyzed NH2Cl decomposition could further enhance lead release from PbO2. Our results showed that Br(-_)catalyzed NH2Cl decomposition did accelerate the reduction of PbO2, and the rate was enhanced by the lower pH value, higher Br(-), and NH2Cl concentrations. A single linear correlation was found between the amount of NH2Cl decomposed and the amount of total Pb(II) released either in the absence or presence of Br(-), suggesting that Br(-)-catalyzed NH2Cl decomposition and NH2Cl autodecomposition may generate the same intermediate toward PbO2 reduction. The kinetics of total Pb(II) release can be successfully modeled by considering the overall rate of NH2Cl decomposition with NOH as the reactive intermediate responsible for PbO2 reduction. Our findings suggested that special attentions on lead contamination should be paid to systems with PbO2 scales and high Br(-) containing source waters when switching disinfectant from free chlorine to monochloramine. PMID- 23984630 TI - The clinical utility of bone marker measurements in osteoporosis. AB - Osteoporosis is characterised by low bone mass and structural deterioration of bone tissue, resulting in increased fragility and susceptibility to fracture. Osteoporotic fractures are a significant cause of morbidity and mortality. Direct medical costs from such fractures in the UK are currently estimated at over two billion pounds per year, resulting in a substantial healthcare burden that is expected to rise exponentially due to increasing life expectancy. Currently bone mineral density is the WHO standard for diagnosis of osteoporosis, but poor sensitivity means that potential fractures will be missed if it is used alone. During the past decade considerable progress has been made in the identification and characterisation of specific biomarkers to aid the management of metabolic bone disease. Technological developments have greatly enhanced assay performance producing reliable, rapid, non-invasive cost effective assays with improved sensitivity and specificity. We now have a greater understanding of the need to regulate pre-analytical sample collection to minimise the effects of biological variation. However, bone turnover markers (BTMs) still have limited clinical utility. It is not routinely recommended to use BTMs to select those at risk of fractures, but baseline measurements of resorption markers are useful before commencement of anti-resorptive treatment and can be checked 3-6 months later to monitor response and adherence to treatment. Similarly, formation markers can be used to monitor bone forming agents. BTMs may also be useful when monitoring patients during treatment holidays and aid in the decision as to when therapy should be recommenced. Recent recommendations by the Bone Marker Standards Working Group propose to standardise research and include a specific marker of bone resorption (CTX) and bone formation (P1NP) in all future studies. It is hoped that improved research in turn will lead to optimised markers for the clinical management of osteoporosis and other bone diseases. PMID- 23984631 TI - Direct and mediated effects of cognitive function with multidimensional outcome measures in schizophrenia: the role of functional capacity. AB - Although cognitive ability is a known predictor of real-world functioning in schizophrenia, there has been an expanded interest in understanding the mechanisms by which it explains real-world functioning in this population. We examined the extent to which functional capacity (i.e., skills necessary to live independently) mediated the relationship between cognitive ability and both observer and self-reported real-world functioning in 138 outpatients with schizophrenia. Functional capacity significantly mediated the relations between cognitive ability and observer-rated real-world functioning, but not self reported real-world functioning, with small to medium effect sizes observed for all outcomes. The role of cognitive ability in observer versus self-reported real world functioning may be explained by different mechanisms. PMID- 23984632 TI - Chlorophyll c(CS-170) isolated from Ostreococcus sp. is [7-methoxycarbonyl-8 vinyl]protochlorophyllide a. AB - The controversial molecular identification of the so-called chlorophyll cCS-170 has been settled. Despite its relevance as a potential biomarker in the study of eukaryotic picophytoplankton, the structure of this chlorophyll remained so far uncertain. A full characterization by NMR, UV-vis, and ESI-MS is reported, revealing this chlorophyll as [7-methoxycarbonyl-8-vinyl]-protochlorophyllide a. PMID- 23984633 TI - Probing the influence of a 4,6-O-acetal on the reactivity of galactopyranosyl donors: verification of the disarming influence of the trans-gauche conformation of C5-C6 bonds. AB - The effect of a 4,6-O-alkylidene acetal on the rate of acid-catalyzed hydrolysis of methyl galactopyranosides and of spontaneous hydrolysis of 2,4-dinitrophenyl galactopyranosides has been studied through the synthesis and hydrolysis of analogs in which O6 is replaced by a methoxymethylene unit in which the methoxy group adopts either an equatorial or an axial position according to the configuration. Consistent with earlier studies under both acid-catalyzed and spontaneous hydrolysis conditions, the alkylidene acetal, or its 7-carba analog, retards hydrolysis with respect to comparable systems lacking the cyclic protecting group. The configuration at C6 in the 7-carba analogs does not influence the rate of acid-catalyzed hydrolysis but has a minor influence on the rate of spontaneous hydrolysis of the 2,4-dinitrophenyl galactosides, confirming earlier studies on the role played by the hydroxymethyl group conformation on glycoside reactivity. The benzylidene acetal is found to stabilize the alpha anomer of galactopyranose derivatives relative to monocyclic analogs. Reasons for the alpha-selectivity of 4,6-O-benzylidene-protected galactopyranosyl donors bearing neighboring group-active protecting groups at O2 are discussed. PMID- 23984635 TI - Unexpected side effect of methylnaltrexone. PMID- 23984637 TI - Palliative medicine and psychiatry: a reply. PMID- 23984636 TI - Geriatric palliative care in long-term care settings with a focus on nursing homes. AB - Almost 1.7 million older Americans live in nursing homes, representing a large proportion of the frailest, most vulnerable elders needing long-term care. In the future, increasing numbers of older adults are expected to spend time and to die in nursing homes. Thus, understanding and addressing the palliative care needs of this population are critical. The goals of this paper are to describe briefly the current state of knowledge about palliative care needs, processes, and outcomes for nursing home residents; identify gaps in this knowledge; and propose priorities for future research in this area. PMID- 23984638 TI - A qualitative study examining the sustainability of shared care in the delivery of palliative care services in the community. AB - BACKGROUND: This paper focuses on the sustainability of existing palliative care teams that provide home-based care in a shared care model. For the purposes of this study, following Evashwick and Ory (2003), sustainability is understood and approached as the ability to continue the program over time. Understanding factors that influence the sustainability of teams and ways to mitigate these factors is paramount to improving the longevity and quality of service delivery models of this kind. METHODS: Using qualitative data collected in interviews, the aim of this study is twofold: (1) to explore the factors that affect the sustainability of the teams at three different scales, and; (2) based on the results of this study, to propose a set of recommendations that will contribute to the sustainability of PC teams. RESULTS: Sustainability was conceptualized from two angles: internal and external. An overview of external sustainability was provided and the merging of data from all participant groups showed that the sustainability of teams was largely dependent on actors and organizations at the local (community), regional (Local Health Integration Network or LHIN) and provincial scales. The three scales are not self-contained or singular entities but rather are connected. Integration and collaboration within and between scales is necessary, as community capacity will inevitably reach its threshold without support of the province, which provides funding to the LHIN. While the community continues to advocate for the teams, in the long-term, they will need additional supports from the LHIN and province. The province has the authority and capacity to engrain its support for teams through a formal strategy. The recommendations are presented based on scale to better illustrate how actors and organizations could move forward. CONCLUSIONS: This study may inform program and policy specific to strategic ways to improve the provision of team-based palliative home care using a shared care model, while simultaneously providing direction for team based program delivery and sustainability for other jurisdictions. PMID- 23984640 TI - Anticipating the course of an action: evidence from corticospinal excitability. AB - BACKGROUND: Anticipatory planning, the ability to anticipate future perceptual motor demands of a goal-oriented action sequence, is essential for flexible, purposeful behavior. Once an action goal has been defined, movement details necessary to achieve that goal can be selected. Here, we investigate if anticipatory planning takes place even when multi-step actions are being carried out. How, we may ask, are the cerebral circuits involved in movement selection influenced by anticipated object-center task demands? Transcranial magnetic stimulation (TMS) was used to investigate how changes in corticospinal excitability (CSE) are dependent on anticipated task variables of intended future actions. Specifically, single- and paired-pulse TMS was used to evaluate corticospinal excitability during the action selection phase preparatory to grasp execution. RESULTS: We found that during the premovement phase, there is an object- and muscle-specific modulation in the intrinsic hand muscle that will be used during a forthcoming grasping action. Depending on whether the participants were instructed to perform a single- or double-step movement sequence, modulation of the corticospinal output to the appropriate hand muscles was dependent on what object was to be grasped and what type of movement was being prepared. No modulation in excitability was observed during one-step movements. CONCLUSIONS: Anticipation of intended task demands plays an important role in controlling multi- step actions during which ongoing behavior may need to be adjusted. This finding supports the notion that the cortico-cortical mechanism involving movement planning is specific for an object's properties as well as for the goal of the movement sequence. PMID- 23984639 TI - The miRNA world of polyomaviruses. AB - Polyomaviruses are a family of non-enveloped DNA viruses infecting several species, including humans, primates, birds, rodents, bats, horse, cattle, raccoon and sea lion. They typically cause asymptomatic infection and establish latency but can be reactivated under certain conditions causing severe diseases. MicroRNAs (miRNAs) are small non-coding RNAs that play important roles in several cellular processes by binding to and inhibiting the translation of specific mRNA transcripts. In this review, we summarize the current knowledge of microRNAs involved in polyomavirus infection. We review in detail the different viral miRNAs that have been discovered and the role they play in controlling both host and viral protein expression. We also give an overview of the current understanding on how host miRNAs may function in controlling polyomavirus replication, immune evasion and pathogenesis. PMID- 23984641 TI - The effect of female sexual hormones on the intestinal and serum cytokine response after traumatic brain injury: different roles for estrogen receptor subtypes. AB - The purpose of this study was to evaluate the effect of female sexual hormones on intestinal and serum cytokines following traumatic brain injury (TBI). Adult female rats were ovariectomized and distributed among the following 9 groups: (i) sham trauma, (ii) TBI (Marmarou's method), (iii) vehicle (dimethylsulfoxide) treated, (iv) estrogen (E2) treated, (v) progesterone (P) treated, (vi) treated with E2+P, (vii) propylpyrazole triol (PPT) treated, (viii) diarylpropionitrile (DPN) treated, and (ix) control. PPT and DPN are estrogen receptor alphaand beta agonists, respectively. Serum and intestinal levels of interleukin (IL)-1beta were increased by TBI (P < 0.001). The level of intestinal IL-1beta was increased in the group treated with E2 (P < 0.001). There was a reduction in serum IL-1beta (P < 0.01) and an increase in intestinal IL-1beta level (P < 0.001) in the PPT treated group compared with the vehicle-treated group. TBI reduced serum IL-6 (P < 0.01) and increased intestinal IL-6 (P < 0.001). Serum IL-6 was increased in the group treated with E2 (P < 0.001), P (P < 0.001), E2+P (P < 0.01), and DPN (P < 0.001) after TBI; however, intestinal IL-6 was higher in the E2-treated group compared with the vehicle-treated group (P < 0.01). Intestinal tumor necrosis factor alpha (TNF-alpha) was increased by TBI (P < 0.001). Progesterone decreased serum TNF-alpha (P < 0.01). Intestinal TNF-alpha in the E2 (P < 0.01), E2+P (P < 0.001), and PPT (P < 0.001) treatment groups was less than in the vehicle-treated group. In conclusion, estrogen influences the intestinal levels of proinflammatory cytokines, in particular TNF-alpha, mediated through estrogen receptor alpha. PMID- 23984643 TI - Polyaniline nanowire arrays aligned on nitrogen-doped carbon fabric for high performance flexible supercapacitors. AB - A combination of vertical polyaniline (PANI) nanowire arrays and nitrogen plasma etched carbon fiber cloths (eCFC) was fabricated to create 3D nanostructured PANI/eCFC composites. The small size of the highly ordered PANI nanowires can greatly reduce the scale of the diffusion length, allowing for the improved utilization of electrode materials. A two-electrode flexible supercapacitor based on PANI/eCFC demonstrates a high specific capacitance (1035 F g(-1) at a current density of 1 A g(-1)), good rate capability (88% capacity retention at 8 A g( 1)), and long-term cycle life (10% capacity loss after 5000 cycles). The lightweight, low-cost, flexible composites are promising candidates for use in energy storage device applications. PMID- 23984642 TI - New antibiotics for bad bugs: where are we? AB - Bacterial resistance to antibiotics is growing up day by day in both community and hospital setting, with a significant impact on the mortality and morbidity rates and the financial burden that is associated. In the last two decades multi drug resistant microorganisms (both hospital- and community-acquired) challenged the scientific groups into developing new antimicrobial compounds that can provide safety in use according to the new regulation, good efficacy patterns, and low resistance profile. In this review we made an evaluation of present data regarding the new classes and the new molecules from already existing classes of antibiotics and the ongoing trends in antimicrobial development. Infectious Diseases Society of America (IDSA) supported a proGram, called "the '10 * '20' initiative", to develop ten new systemic antibacterial drugs within 2020. The microorganisms mainly involved in the resistance process, so called the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and enterobacteriaceae) were the main targets. In the era of antimicrobial resistance the new antimicrobial agents like fifth generation cephalosporins, carbapenems, monobactams, beta-lactamases inhibitors, aminoglycosides, quinolones, oxazolidones, glycopeptides, and tetracyclines active against Gram-positive pathogens, like vancomycin-resistant S. aureus (VRSA) and MRSA, penicillin-resistant streptococci, and vancomycin resistant Enterococcus (VRE) but also against highly resistant Gram-negative organisms are more than welcome. Of these compounds some are already approved by official agencies, some are still in study, but the need of new antibiotics still does not cover the increasing prevalence of antibiotic-resistant bacterial infections. Therefore the management of antimicrobial resistance should also include fostering coordinated actions by all stakeholders, creating policy guidance, support for surveillance and technical assistance. PMID- 23984644 TI - Screening biomarkers of prostate cancer by integrating microRNA and mRNA microarrays. AB - OBJECTIVE: In this study, we screened microRNA (miRNA) target genes of prostate cancer by integrating miRNA and mRNA expression profiles after target prediction and performed function enrichment analysis for selected candidate genes. METHODS: The miRNA expression profile (GSE36802) and mRNA expression profile (GSE36801) were downloaded from the Gene Expression Omnibus database. We processed data and identified the differentially expressed miRNAs and mRNAs with R packages. Verified targets of miRNAs were identified through miRecods and miRTarBase. Then, software of Search Tool for the Retrieval of Interacting Genes was used to construct the interaction network of target genes. Finally, we performed function enrichment analysis for genes in the interaction network with the Functional Classification Tool. RESULTS: A total of 22 upregulated and 8 downregulated miRNAs were detected in this study, of which, hsa-mir-31 was the most overexpressed miRNA in prostate cancer. Both ITGA5 and RDX, two target genes of hsa-mir-31, were found to be differentially expressed from mRNA profiles by overexpressing hsa-mir-31. The cell adhesion molecule was found to be the most significant pathway enriched by ITGA5 and RDX. CONCLUSION: Overexpression of hsa mir-31 can be a significant marker to distinguish cancer tissues from benign tissues. The targets such as ITGA5 and RDX regulated by hsa-mir-31 are candidate genes of prostate cancer, which provide new treatment strategies for its gene therapy. PMID- 23984646 TI - Reply to "Comment on 'Role of (NO)2 dimer in reactions of Fe(+) with NO and NO2 studied by ICP-SIFT mass spectrometry'". PMID- 23984647 TI - The Angle Society: the future is now. PMID- 23984645 TI - RNA-Seq effectively monitors gene expression in Eutrema salsugineum plants growing in an extreme natural habitat and in controlled growth cabinet conditions. AB - BACKGROUND: The investigation of extremophile plant species growing in their natural environment offers certain advantages, chiefly that plants adapted to severe habitats have a repertoire of stress tolerance genes that are regulated to maximize plant performance under physiologically challenging conditions. Accordingly, transcriptome sequencing offers a powerful approach to address questions concerning the influence of natural habitat on the physiology of an organism. We used RNA sequencing of Eutrema salsugineum, an extremophile relative of Arabidopsis thaliana, to investigate the extent to which genetic variation and controlled versus natural environments contribute to differences between transcript profiles. RESULTS: Using 10 million cDNA reads, we compared transcriptomes from two natural Eutrema accessions (originating from Yukon Territory, Canada and Shandong Province, China) grown under controlled conditions in cabinets and those from Yukon plants collected at a Yukon field site. We assessed the genetic heterogeneity between individuals using single-nucleotide polymorphisms (SNPs) and the expression patterns of 27,016 genes. Over 39,000 SNPs distinguish the Yukon from the Shandong accessions but only 4,475 SNPs differentiated transcriptomes of Yukon field plants from an inbred Yukon line. We found 2,989 genes that were differentially expressed between the three sample groups and multivariate statistical analyses showed that transcriptomes of individual plants from a Yukon field site were as reproducible as those from inbred plants grown under controlled conditions. Predicted functions based upon gene ontology classifications show that the transcriptomes of field plants were enriched by the differential expression of light- and stress-related genes, an observation consistent with the habitat where the plants were found. CONCLUSION: Our expectation that comparative RNA-Seq analysis of transcriptomes from plants originating in natural habitats would be confounded by uncontrolled genetic and environmental factors was not borne out. Moreover, the transcriptome data shows little genetic variation between laboratory Yukon Eutrema plants and those found at a field site. Transcriptomes were reproducible and biological associations meaningful whether plants were grown in cabinets or found in the field. Thus RNA Seq is a valuable approach to study native plants in natural environments and this technology can be exploited to discover new gene targets for improved crop performance under adverse conditions. PMID- 23984648 TI - Re: Correlation between body mass index and orthodontic treatment outcome": J. von Bremen; J. Wagner and S. Ruf. The Angle Orthodontist 2013;83:371-375. PMID- 23984649 TI - Re: response to: Correlation between body mass index and orthodontic treatment outcome, J. von Bremen, J. Wagner and S. Ruf. The Angle Orthodontist 2013;83:371 375. PMID- 23984650 TI - Re: Long-term skeletal and dental effects and treatment timing for functional appliances in Class II malocclusion. The Angle Orthodontist 2013(2) 334-340. PMID- 23984651 TI - Re: response to: Long-term skeletal and dental effects and treatment timing for functional appliances in Class II malocclusion. The Angle Orthodontist 2013(2) 334-340. PMID- 23984653 TI - In vitro drug metabolism testing using blood-monocyte derivatives. AB - INTRODUCTION: Monocytes and their cell derivatives can participate in drug metabolism. These cells express different Phase-I or -II drug metabolizing enzymes and can be differentiated into neo-hepatocytes (NeoHep) and represent a promising alternative strategy to test drug metabolism. This is particularly useful as primary human hepatocytes (PHH), are difficult to obtain and maintain in culture. AREAS COVERED: The authors analyze the use of blood monocytes and their derivatives for the study of drug metabolism. They also compare them to the in vitro ability of cells from different sources including: PHH, immortalized hepatocytes, tumor cell lines and NeoHep. EXPERT OPINION: The use of monocytes, macrophages, dendritic or Kupffer cells, to test drug metabolism, has serious limitations because these cells express lower levels of cytochrome P450 enzymes than PHH. The best available option, to replace PHH, have been tumor cell lines such as HepaRG, as well as immortalized hepatocytes from adult or fetal sources. Monocyte-derived NeoHep cells are novel and easily accessible cells, which express many drug metabolizing enzymes at levels comparable to PHH. These cells allow drug evaluation under a diverse genetic background. While these cells are in the early stages of evaluation and do need to be examined more thoroughly, they constitute a promising new tool for in vitro drug testing. PMID- 23984654 TI - N95-companion measurement of cout/cin ratios for two n95 filtering facepiece respirators and one surgical mask. AB - A previous study in our laboratory measured the ratio of particle concentration outside (Cout)/inside (Cin) of three N95 filtering facepiece respirator (FFR) models with an N95-Companion and other aerosol instruments using a breathing manikin. Results showed that the Companion measured Cin was contributed by particle penetration through face seal leakage and not through filter media suggesting that the Cout/Cin ratio should be similar for different N95 models at any given leak size. To better understand the phenomenon, the current study analyzed the influence of factors, including filter penetration, resistance, and flow rate on the Companion ratios for two N95 FFR (N1 and N2) and one surgical mask (SM1) models using a manikin. Cout/Cin ratios were measured at 10 and 40 L breathing minute volumes with sealed condition and at artificially introduced leaks. Filter efficiency and resistance were measured at 10 and 40 L/min constant flow rates. Results showed that filter efficiency and resistance were higher for N1 than for N2 and SM1. The ratio for N1was also higher than those of N2 and SM1 at sealed condition at both breathing rates. The result can be due to the higher filtration efficiency of N1. With increasing leak sizes, however, the ratios were higher for N2 than for N1 at 10 and 40 L breathing rates. Higher ratios for N2 can be attributed to the lower resistance that allowed higher aerosol flow through the filter media and captured more negatively charged particles to produce lesser Cin or greater Cout/Cin ratio. Ratios obtained for SM1 at different leak sizes were higher than the ratios of N1 at 10 L. SM1 ratios, however, decreased dramatically at 40 L indicating that high flow rate may adversely affect the ratios. Further studies are needed to better understand the influence of filter media characteristics on the Companion measured Cout/Cin ratios. PMID- 23984672 TI - Prescription-drug coupons--no such thing as a free lunch. PMID- 23984673 TI - Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy. AB - OBJECTIVE: Assessment of 12-month safety of ospemifene 60 mg/day for treatment of postmenopausal women with vulvar and vaginal atrophy (VVA). METHODS: In this 52 week, randomized, double-blind, placebo-controlled, parallel-group study, women 40-80 years with VVA and an intact uterus were randomized 6 : 1 to ospemifene 60 mg/day or placebo. The primary objective was 12-month safety, particularly endometrial; 12-week efficacy was assessed. Safety assessments included endometrial histology and thickness, and breast and gynecological examinations. Efficacy evaluations included changes from baseline to week 12 in percentage of superficial and parabasal cells and vaginal pH. RESULTS: Of 426 randomized subjects, 81.9% (n = 349) completed the study with adverse events the most common reason for discontinuation (ospemifene 9.5%; placebo 3.9%). Most (88%) treatment emergent adverse events with ospemifene were considered mild or moderate. Three cases (1.0%) of active proliferation were observed in the ospemifene group. For one, active proliferation was seen at end of study week 52, and diagnosed as simple hyperplasia without atypia on follow-up biopsy 3 months after the last dose. This subsequently resolved with progestogen treatment and dilatation and curettage. In six subjects (five ospemifene (1.4%), one placebo (1.6%)) endometrial polyps were found (histopathology); however, only one (ospemifene) was confirmed as a true polyp during additional expert review. Endometrial histology showed no evidence of carcinoma. Statistically significant improvements were seen for all primary and secondary efficacy measures and were sustained through week 52 with ospemifene vs. placebo. CONCLUSIONS: The findings of this 52 week study confirm the tolerance and efficacy of oral ospemifene previously reported in short- and long-term studies. PMID- 23984675 TI - Apelin-13 deteriorates hypertension in rats after damage of the vascular endothelium by ADMA. AB - Asymmetric dimethylarginine (ADMA) is a risk factor for endothelial dysfunction. The polypeptide apelin has biphasic effects on blood vessels in vivo and in vitro. We investigated the effect of apelin-13 on ADMA-damaged vessels. Rats were divided among ADMA-treated and control groups, which were treated with ADMA (10 mg.(kg body mass)(-1).day(-1)) or saline, respectively, for 4 weeks. Systolic blood pressure (SBP) was measured before and after the injection of apelin-13. The ultrastructure of endothelial cells in caudal arteries was examined using transmission electron microscopy. The reactivities of isolated caudal artery rings were observed after exposure to apelin-13, and myosin light chain (MLC) phosphorylation was assessed by immunohistochemistry in rings treated with or without apelin-13. ADMA induced hypertension and endothelial dysfunction. After injection of apelin-13, SBP declined in the control group but was elevated in the ADMA-treated group. In vitro, apelin-13 caused relaxation in rings in the control group, but it contracted rings in the ADMA-treated group. Apelin-13 promoted MLC phosphorylation in vascular smooth muscle cells (VSMCs) in the ADMA group. These results indicate that apelin-13 might pass through ADMA-damaged endothelium and act on VSMCs to increase MLC phosphorylation, thus contributing to vasoconstriction and exacerbating hypertension. PMID- 23984676 TI - Fit of evidence-based treatment components to youths served by wraparound process: a relevance mapping analysis. AB - This study investigated whether and which evidence-based treatment (EBT) components might generalize to youths served by the wraparound process. To examine these questions, the study used relevance mapping, an empirical methodology that compares youths in a given clinical population with participants in published randomized trials to determine who may be "coverable" by EBTs and which treatments may collectively be most applicable. In a large diverse clinical sample, youths receiving wraparound services (n = 828) were compared with youths receiving other services (n = 3,104) regarding (a) demographic and clinical profiles, (b) "coverability" by any EBTs, and (c) specific practices from those EBTs that most efficiently applied to each group. Participants in studies of EBTs matched the demographic and clinical characteristics of nearly as many youths receiving wraparound (58-59%) as those receiving non-wraparound services (61 64%). Moreover, the best-fitting solutions of relevant sets of practices were highly similar across groups. These results provide the first large-scale empirical characterization of fit between EBTs and youths receiving wraparound and suggest that these youths are well suited to benefit from clinical strategies commonly used in EBTs. PMID- 23984677 TI - Do breastfeeding and bottle feeding influence occlusal parameters? AB - OBJECTIVE: A study was made of the influence of breastfeeding and bottle feeding on development of the dental arches and occlusion in an infant population. SUBJECTS AND METHODS: In total, 298 infants (163 girls and 135 boys) were selected from a series of 1,643 preschool children in Seville, Spain, evaluating the type of feeding received after birth (breastfeeding only or bottle feeding only), the duration of such feeding, and its influence upon the parameters that define occlusion of the dental arches. The study comprised a full exploration of the stomatognathic system of the infants and a questionnaire for the parents. SPSS Statistical Package software (SPSS, Inc., Chicago, IL) was used to analyze the results. RESULTS: In total, 109 children were exclusively breastfed (36.6%) for an average of 6.8+/-5.8 months, whereas 189 children were exclusively bottle fed (63.4%) for an average of 17.99+/-11.5 months. On comparing the occlusal parameters of the two groups, the most beneficial effects (straight terminal plane, canine class I relationship, diastemas, and primate spaces) corresponded to the infants who were breastfed. CONCLUSIONS: Breastfed infants show better development of the dental arches and a lesser incidence of dental occlusion disorders than bottle-fed infants. PMID- 23984678 TI - Editorial comment for Ghani et al. PMID- 23984679 TI - Case study. Health hazards of automotive repair mechanics: thermal and lighting comfort, particulate matter and noise. AB - An indoor environmental quality survey was conducted in a small private automotive repair shop during May 2009 (hot season) and February 2010 (cold season). It was established that the detached building, which is naturally ventilated and lit, had all the advantages of the temperate local climate. It provided a satisfactory microclimatic working environment, concerning the thermal and the lighting comfort, without excessive energy consumption for air conditioning or lighting. Indoor number concentrations of particulate matter (PM) were monitored during both seasons. Their size distributions were strongly affected by the indoor activities and the air exchange rate of the building. During working hours, the average indoor/outdoor (I/O) number concentration ratio was 31 for PM0.3-1 in the hot season and 69 for the cold season. However I/O PM1 10 number concentration ratios were similar, 33 and 32 respectively, between the two seasons. The estimated indoor mass concentration of PM10 for the two seasons was on average 0.68 mg m(-3) and 1.19 mg m(-3), i.e., 22 and 36 times higher than outdoors, during the hot and the cold seasons, respectively. This is indicative that indoor air pollution may adversely affect mechanics' health. Noise levels were highly variable and the average LEX, 8 h of 69.3 dB(A) was below the European Union exposure limit value 87db (A). Noise originated from the use of manual hammers, the revving up of engines, and the closing of car doors or hoods. Octave band analysis indicated that the prevailing noise frequencies were in the area of the maximum ear sensitivity. PMID- 23984680 TI - Unveiling the details of electron transfer in multicenter redox proteins. AB - Metalloproteins modulate the intrinsic properties of transition metals to achieve controlled catalysis, electron transfer, or structural stabilization. Those performing electron transport, redox proteins, are a diverse class of proteins with central roles in numerous metabolic and signaling pathways, including respiration and photosynthesis. Many redox proteins have applications in industry, especially biotechnology, making them the focus of intense research. Redox proteins may contain one or multiple redox centers of the same or a different type. The complexity of proteins with multiple redox centers makes it difficult to establish a detailed molecular mechanism for their activity. Thermodynamic and kinetic information can be interpreted using the molecular structure to elucidate the protein's functional mechanism. This Account reviews experimental strategies developed in recent years to determine the detailed thermodynamic properties of multicenter redox proteins and their kinetic properties during interactions with redox partners. These strategies allow the discrimination of thermodynamic and kinetic properties of each individual redox center. The thermodynamic characterization of the redox transitions results from the combined analysis of data from NMR and UV-visible spectroscopy. Meanwhile, the kinetic characterization of intermolecular electron transfer comes from stopped-flow spectrophotometry. We illustrate an application of these strategies to a particular redox protein, the small tetraheme cytochrome from the periplasmic space of Shewanella oneidensis MR-1. This protein is a convenient prototype for developing methods for the detailed analysis of multicenter electron transfer proteins because hemes have strong UV-visible absorption bands and because heme resonances have exquisite discrimination in NMR spectra. Nonetheless, the methods are fully generalizable. Ultimately, this Account highlights the relevance of detailed characterization of the thermodynamic and kinetic properties of redox proteins. These properties are responsible for the directionality and specificity of the electron transfer process in bioenergetic pathways; a more thorough characterization of these properties should allow better-designed proteins for industrial applications. PMID- 23984681 TI - Early detection of subclinical ventricular deterioration in aortic stenosis with cardiovascular magnetic resonance and echocardiography. AB - BACKGROUND: Severe aortic stenosis (AS) patients with late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) or left ventricular (LV) systolic dysfunction are known to have worse outcome. We aimed to investigate whether LGE on CMR would be useful in early detection of subclinical LV structural and functional derangements in AS patients. METHODS: 118 patients with moderate to severe AS were prospectively enrolled. Echocardiography and CMR images were taken and the patients were divided into groups according to the presence/absence of LGE and of LV systolic dysfunction (LV ejection fraction (EF) <50%). The stiffness of LV was calculated based on Doppler and CMR measurements. RESULTS: Patients were grouped into either group 1, no LGE and normal LVEF, group 2, LGE but normal LVEF and group 3, LGE with depressed LVEF. There was a significant trend towards increasing LV volumes, worsening of LV diastolic function (E/e', diastolic elastance), systolic function (end-systolic elastance) and LV hypertrophy between the three groups, which coincided with worsening functional capacity (all p-value < 0.001 for trend). Also, significant differences in the above parameters were noted between group 1 and 2 (E/e', 14.6 +/- 4.3 (mean +/- standard deviation) in group 1 vs. 18.2 +/- 9.4 in group 2; end systolic elastance, 3.24 +/- 2.31 in group 1 vs. 2.38 +/- 1.16 in group 2, all p value < 0.05). The amount of myocardial fibrosis on CMR correlated with parameters of diastolic (diastolic elastance, Spearman's rho = 0.256, p-value = 0.005) and systolic function (end-systolic elastance, Spearman's rho = -0.359, p value < 0.001). CONCLUSIONS: These findings demonstrate the usefulness of CMR for early detection of subclinical LV structural and functional deterioration in AS patients. PMID- 23984682 TI - Glycolipid metabolic status of overweight/obese adolescents aged 9- to 15-year old and the BMI-SDS/BMI cut-off value of predicting dyslipidemiain boys, Shanghai, China: a cross-sectional study. AB - BACKGROUND: The prevalence of adolescents' obesity and overweight has dramatically elevated in China. Obese children were likely to insulin resistance and dyslipidemia, which are risk factors of cardiovascular diseases. However there was no cut-off point of anthropometric values to predict the risk factors in Chinese adolescents. The present study was to investigate glycolipid metabolism status of adolescents in Shanghai and to explore the correlations between body mass index standard deviation score (BMI-SDS) and metabolic indices, determine the best cut-off value of BMI-SDS to predict dyslipidemia. METHODS: Fifteen schools in Shanghai's two districts were chosen by cluster sampling and primary screening was done in children aged 9-15 years old. After screening of bodyweight and height, overweight and obese adolescents and age-matched children with normal body weight were randomly recruited in the study. Anthropometric measurements, biochemical measurements of glycolipid profiles were done. SPSS19.0 was used to analyze the data. Receiver operating characteristic (ROC) curves were made and the best cut-off values of BMI-SDS to predict dyslipidemia were determined while the Youden indices were maximum. RESULTS: Five hundred and thirty-eight adolescents were enrolled in this research, among which 283 have normal bodyweight, 115 were overweight and 140 were obese. No significant differences of the ages among 3 groups were found. There were significant differences of WC-SDS (p<0.001), triacylglycerol (p<0.05), high and low density lipoprotein cholesterol (p<0.01), fasting insulin (p<0.01) and C-peptide (p<0.001) among 3 groups. Significant difference of fasting glucose was only found between normal weight and overweight group. Significant difference of total cholesterol was found between obese and normal weight group. There was no significant difference of glycated hemoglobin among 3 groups. The same tendency was found in boys but not in girls. Only HDL-C reduced and TG increased while BMI elevated in girls. The best cut-off value of BMI-SDS was 1.22 to predict dyslipidemia in boys. The BMI cut-off was 21.67 in boys. CONCLUSION: Overweight and obese youths had reduced insulin sensitivity and high prevalence of dyslipidemia.When BMI-SDS elevated up to 1.22 and BMI was higher than 21.67 in boys, dyslipidemia may happen. PMID- 23984683 TI - Ferrocenoyl phenylalanine: a new strategy toward supramolecular hydrogels with multistimuli responsive properties. AB - In this paper we present a new paradigm for designing hydrogelators that exhibit sharp phase transitions in response to a series of disparate stimuli, including oxidation-reduction reactions (redox), guest-host interactions, and pH changes. We have serendipitously discovered that ferrocenoyl phenylalanine (Fc-F) monomers aggregate in water via a rapid self-assembly mechanism to form stable, multistimuli hydrogels. In comparison to other known mono- and multiresponsive gelators, Fc-F is unique because of its small size, economy of gel-forming components, and exceptionally simple molecular structure. Density functional theory (DFT) ab initio calculations suggest gel formation initially involves an antiparallel, noncovalent dimerization step wherein the ferrocenoyl moiety of one axe-like monomer conjoins with the phenyl group of the second monomer via a pi-pi stacking interaction to form brick-like dimers. This stacking creates a cavity in which the carboxylic acid groups of each monomer mutually interact via hydrogen bond formation, which affords additional stability to the dimer. On the basis of structural analysis via optical and electrical measurements and additional DFT calculations, we propose a possible stepwise hierachical assembly mechanism for fibril formation. Insights into the self-assembly pathway of Fc-F should prove useful for understanding gelation processes of more complex systems. We expect that Fc-F will serve as a helpful archetypical template for others to use when designing new, stimuli specific hydrogelation agents. PMID- 23984684 TI - Controlling patients' pain. PMID- 23984686 TI - Practice of 'boarding' increases length of inpatient stays. PMID- 23984690 TI - Dementia care in hospitals still poor. PMID- 23984691 TI - New advice to support staff as end of life care reviewed. PMID- 23984692 TI - Healthcare assistant certification seen as a positive move to define role. PMID- 23984697 TI - Practice question. PMID- 23984701 TI - Assessing and treating faecal incontinence. AB - Compared with the rest of the population, older people receive inequitable care for faecal incontinence. Good care improves symptoms and minimises the effects of this common problem on quality of life. Faecal incontinence is a symptom rather than a diagnosis and there are a number of options for investigation and treatment depending on the suspected underlying cause. Although there are clear guidelines for assessment and management, there are significant gaps in the evidence base and in service provision. There are many opportunities for improving care and nurses should be encouraging, supporting and leading these improvements. PMID- 23984702 TI - Identifying barriers to pain management in long-term care. AB - AIM: The aim of this study was to identify barriers to optimal pain management in long-term care (LTC) from a nursing perspective. METHOD: A quantitative, cross sectional, descriptive design was used. RESULTS: Patient-related barriers were seen as interfering more often with optimal pain management than organisational related or caregiver-related barriers. Difficulty assessing pain due to problems with cognition, older patients' inability to complete pain scales and communication difficulties as a result of sensory impairment were common barriers. CONCLUSION: A targeted approach to address the identified barriers would help improve pain management practices in LTC. PMID- 23984703 TI - Prescribing and medicines management in older people. AB - The aim of this article is to explore prescribing and medicines management in older people. The author discusses the physiological changes that occur as people age and how these changes affect the use of drugs in this group. Additionally, inappropriate prescribing with specific reference to polypharmacy in older people is explored. Finally, drugs that should be used with care are highlighted. PMID- 23984704 TI - Self-assembly in mixtures of an anionic and a cationic surfactant: a comparison between small-angle neutron scattering and cryo-transmission electron microscopy. AB - The self-assembly in SOS-rich mixtures of the anionic surfactant sodium octyl sulfate (SOS) and the cationic surfactant hexadecyltrimethylammonium bromide (CTAB) has been investigated with the complementary techniques small-angle neutron scattering (SANS) and cryo-transmission electron microscopy (cryo-TEM). Both techniques confirm the simultaneous presence of open and closed bilayer structures in highly diluted samples as well as the existence of small globular and large elongated micelles at higher concentrations. However, the two techniques sometimes differ with respect to which type of aggregates is present in a particular sample. In particular, globular or wormlike micelles are sometimes observed with cryo-TEM in the vicinity of the micelle-to-bilayer transition, although only bilayers are present according to SANS and the samples appear bluish to the eye. A similar discrepancy has previously been reported but could not be satisfactorily rationalized. On the basis of our comparison between in situ (SANS) and ex situ (cryo-TEM) experimental techniques, we suggest that this discrepancy appears mainly as a result of the non-negligible amount of surfactant adsorbed at interfaces of the thin sample film created during the cryo TEM specimen preparation. Moreover, from our detailed SANS data analysis, we are able to observe the unusually high amount of free surfactant monomers present in SOS-rich mixtures of SOS and CTAB, and the experimental results give excellent agreement with model calculations based on the Poisson-Boltzmann mean field theory. Our careful comparison between model calculations and experiments has enabled us to rationalize the dramatic microstructural transformations frequently observed upon simply diluting mixtures of an anionic and a cationic surfactant. PMID- 23984705 TI - 7,14-Diaryl-substituted zethrene diimides as stable far-red dyes with tunable photophysical properties. AB - Synthesis and physical characterizations of a series of 7,14-diaryl-substituted zethrene diimides (ZDIs) bearing different substituents (alkyl chain, oligoethyleneglycol ether chain, and aryl group) at the imide sites as well as at the bay regions are described in this study. The synthesis takes advantage of Pd catalyzed cyclodimerization reaction that allows construction of zethrene core and substitution at the bay region in one single step. The partially cyclized ZDI is also separated as a minor product. The carboxylic acid group is introduced to the bay region for the purpose of further bioconjugation. The photophysical properties, electrochemical properties, and photostability of these ZDI dyes are investigated with UV/vis spectroscopic measurements, cyclic voltammetry measurements, and photoirradiation tests. These dyes exhibit tunable photophysical properties in the far-red spectral region with moderate fluorescent quantum yields and good stability. The enhanced stability as compared to the parent zethrene and the 7,14-substituted zethrenes can be attributed to the electron-withdrawing effect of the imide groups and the kinetic blocking of the most reactive sites at the bay region. PMID- 23984706 TI - Confined crystals of the smallest phase-change material. AB - The demand for high-density memory in tandem with limitations imposed by the minimum feature size of current storage devices has created a need for new materials that can store information in smaller volumes than currently possible. Successfully employed in commercial optical data storage products, phase-change materials, that can reversibly and rapidly change from an amorphous phase to a crystalline phase when subject to heating or cooling have been identified for the development of the next generation electronic memories. There are limitations to the miniaturization of these devices due to current synthesis and theoretical considerations that place a lower limit of 2 nm on the minimum bit size, below which the material does not transform in the structural phase. We show here that by using carbon nanotubes of less than 2 nm diameter as templates phase-change nanowires confined to their smallest conceivable scale are obtained. Contrary to previous experimental evidence and theoretical expectations, the nanowires are found to crystallize at this scale and display amorphous-to-crystalline phase changes, fulfilling an important prerequisite of a memory element. We show evidence for the smallest phase-change material, extending thus the size limit to explore phase-change memory devices at extreme scales. PMID- 23984707 TI - Synthesis and photovoltaic applications of a 4,4'-spirobi[cyclopenta[2,1-b;3,4 b']dithiophene]-bridged donor/acceptor dye. AB - A new donor/acceptor (D-A) spiro dye (SCPDT1) featuring two bithiophene units, connected through an sp(3)-hybridized carbon atom, was prepared by a multistep synthetic sequence involving the convenient assembly of the spiro system under mild catalytic conditions. The photocurrent spectrum of dye-sensitized solar cells incorporating SCPDT1 covers the spectral region ranging from 350 to 700 nm and reaches a wide maximum of ~80% in the 420-560 nm range. Power conversion efficiencies of up to 6.02% were obtained. PMID- 23984708 TI - Study of sensory interactions among red wine fruity esters in a model solution. AB - Our study focused on the impact of 12 red wine esters, in complex mixtures, on the perception of fruity aromas. Aromatic reconstructions were prepared in dilute alcohol solution at the average concentrations found in red wines, using pure commercial products. The impact of ethyl propanoate, ethyl-3-hydroxybutanoate, butyl acetate, and 2-methylpropyl acetate was detected by omission tests, although they were present at subthreshold concentrations in the fruity mixture. The "olfactory threshold" of the fruity pool, consisting of all of the esters excluding ethyl propanoate, ethyl-3-hydroxybutanoate, butyl acetate, or 2 methylpropyl acetate was calculated in two different matrices: dilute alcohol solution and dilute alcohol solution supplemented with each of the four compounds mentioned above. The presence of ethyl-3-hydroxybutanoate and 2-methylpropyl acetate in the mixture led to a significant decrease in the olfactory threshold of the fruity pool, demonstrating their synergistic effect in increasing the overall intensity. Sensory profiles revealed that besides ethyl-3 hydroxybutanoate, the omission of each of these compounds had a significant attenuating effect on blackberry and fresh-fruit aroma intensity. These compounds with similar chemical structures participate, both quantitatively and qualitatively, in modulating fruity aromas and, specifically, naturally enhancing blackberry and fresh-fruit aromas. PMID- 23984709 TI - Interaction between two rice mitogen activated protein kinases and its possible role in plant defense. AB - BACKGROUND: The canonical mitogen activated protein kinase (MAPK) signaling pathway plays a vital role in carrying out the normal growth and development of the plant. The pathway, connecting the upstreams signal with the downstream target is considered to be linear, mostly starting with a MAPKKK and ending in a MAPK. RESULTS: Here we report a novel interaction between two rice MAPKs, OsMPK20 4 and OsMPK3 suggesting the complex nature of the pathway rather than a linear one at individual steps. The interaction between OsMPK20-4 and OsMPK3 found by yeast two-hybrid analysis was confirmed in planta by co-immunoprecipitation and fluorescence resonance energy transfer (FRET) assays. The interaction is specific and is phosphorylation independent. The results suggest a role of the interaction between OsMPK20-4 and OsMPK3 in basic plant defense. CONCLUSIONS: The current novel work showing the physical interaction between two plant MAPKs, OsMPK20-4 and OsMPK3 is the diversion from the dogma of a typical MAPK cascade thereby opening a new dimension to the MAPK signal transduction. PMID- 23984711 TI - Short-term outcome of attention and executive functions from aorta no-touch and traditional off-pump coronary artery bypass surgery. AB - OBJECTIVES: Postoperative cognitive dysfunction (POCD) is an important neuropsychiatric complication of coronary artery bypass grafting (CABG). It is most likely caused by microembolic brain damage and affects domains of attention, memory, executive functions and dexterity. In order to achieve better neuroprotection, surgeons introduced some advantageous operating procedures. Noteworthy among them is a state-of-the-art off-pump CABG aorta no-touch technique ("no touch" OPCABG). The aim of this study was to investigate the short term effect of "no touch" OPCABG on patients' attention and executive functions. METHODS: In this prospective, observational, single-surgeon trial, 74 patients scheduled for elective CABG were studied. Thirty-five patients underwent "no touch" OPCABG and were compared to 39 patients who underwent "traditional" OPCABG. Subjects underwent neurological and neuropsychological evaluation at the time of admission (7 +/- 2 days preoperatively) and discharge (7 days postoperatively). RESULTS: Patients who underwent "traditional" OPCABG showed a significant decline in postoperative performance on 4 neuropsychological tests, while patients treated with "no touch" OPCABG showed a significant decline on 1 test. Twenty patients from "traditional" OPCABG group and ten patients from "no touch" OPCABG group were diagnosed with POCD. CONCLUSIONS: Use of "no touch" OPCABG was associated with better attention and executive functions 1 week after surgery compared with "traditional" OPCABG. PMID- 23984710 TI - (1)H-MRS of hippocampus in patients after first manic episode. AB - OBJECTIVES: The investigation of the pathophysiology of bipolar disorder in patients at disease onset is a strategy to avoid the confounding effect of progression of disease or duration of treatment. Our purpose was to investigate in vivo neuronal metabolites in the hippocampus of bipolar disorder patients using proton magnetic resonance spectroscopy ((1)H-MRS) within 3 months after their first manic episode. METHODS: Fifty-eight BD I patients meeting DSM-IV criteria following their first episode of mania and 27 healthy subjects were studied using (1)H-MRS with a 3.0 T Philips Achieva scanner. Voxels with 30 * 15 * 15 mm were placed in the hippocampus on both sides of the brain and the signal was collected using a PRESS sequence with TE = 35 ms and TR = 2000 ms. Data analysis was performed using the LC Model software. RESULTS: N-Acetyl-aspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cre) and glutamine + glutamate (Glx) levels were compared between the groups and no statistically significant differences were found. CONCLUSIONS: Our results suggest that early in the course of BD there are no alterations in neuronal metabolism or vulnerability in the hippocampus after the first manic episode. PMID- 23984712 TI - Diagnosis, treatment characteristics, and survival of women with breast cancer aged 65 and above: a hospital-based retrospective study. AB - BACKGROUND: Breast cancer incidence in women increases with age, while survival rates decrease. Studies interpret this result as meaning higher comorbidity, diagnosis at later stages of the disease, and less effective treatment in the elderly. The aim of this study is to evaluate the diagnosis and treatment characteristics of breast cancer and their effect on the survival of women aged 65 and above. METHODS: The data within the files of 1064 women with breast cancer, who were followed-up in Dokuz Eylul University Medical Faculty Hospital between 2000 and 2006, were reviewed retrospectively. The survival probabilities at years 1 and 5 were calculated by life table analysis. The Kaplan-Meier test was used for calculating mean survival time, and the differences between groups were evaluated by log-rank test. The backward elimination method was used for multivariate analysis, and a -2 log-likelihood ratio was used for comparison of different models. RESULTS: Of the patients, 25.3% were aged 65 and above at the time of the diagnosis. Patients in this group had more comorbidities and were more likely to be diagnosed at advanced stages than younger patients. Additionally, they had lower rates of surgical treatment, chemotherapy or radiotherapy. One and 5-year survival probabilities among age groups were 96.1% and 84.5%, respectively, for <65 years, 93.5% and 84.8%, respectively, for 65-69, 98.7% and 84.0%, respectively, for 70-74, and 85.5% and 59.6%, respectively, for 75 years and above. In the multivariate model, age, clinical stage, and comorbidity were found to be negatively associated with the survival rate. CONCLUSIONS: The survival of women with breast cancer aged 65 and above was affected negatively by age at diagnosis, clinical stage, and the presence of comorbidity. Early diagnosis also is very important for elderly women. Additionally, because of higher comorbidity, their evaluation and treatment should be planned by an interdisciplinary team. PMID- 23984713 TI - Comment on "Role of (NO)2 dimer in reactions of Fe(+) with NO and NO2 studied by ICP-SIFT mass spectrometry". PMID- 23984714 TI - Chikungunya virus capsid protein contains nuclear import and export signals. AB - BACKGROUND: Chikungunya virus (CHIKV) is an alphavirus of the Togaviridae family. After autoproteolytic cleavage, the CHIKV capsid protein (CP) is involved in RNA binding and assembly of the viral particle. The monomeric CP is approximately 30 kDa in size and is small enough for passive transport through nuclear pores. Some alphaviruses are found to harbor nuclear localization signals (NLS) and transport of these proteins between cellular compartments was shown to be energy dependent. The active nuclear import of cytoplasmic proteins is mediated by karyopherins and their export by exportins. As nuclear and cytoplasmic trafficking may play a role in the life cycle of CHIKV, we have sought to identify nuclear localization and nuclear export signals in CHIKV CP in a virus-free system. METHODS: EGFP-fusion proteins of CHIKV CP and mutants thereof were created and used to monitor their intracellular localization. Binding of cellular proteins was confirmed in pull down assays with purified CP using co-immuoprecipitation. Nuclear localization was demonstrated in a virus-free system using fluorescence microscopy. RESULTS: Here we show that CHIKV CP is a nuclear-cytoplasmic shuttling protein with an active NLS that binds to karyopherin alpha (Karalpha) for its nuclear translocation. We also found that the Karalpha4 C-terminal NLS binding site is sufficient for this interaction. We further demonstrate that CHIKV CP interacts directly with the export receptor CRM1 to transport this viral protein out of the nucleus via a nuclear export signal (NES). The CHIKV CP NES was mapped between amino acids 143 and 155 of CP. Deduced from in silico analyses we found that the NES has a mode of binding similar to the snurportin-1 CRM1 complex. CONCLUSIONS: We were able to show that in a virus-free system that the CHIKV capsid protein contains both, a NLS and a NES, and that it is actively transported between the cytoplasma and the nucleus. We conclude that CHIKV CP has the ability to shuttle via interaction with karyopherins for its nuclear import and, vice versa, by CRM1 dependent nuclear export. PMID- 23984716 TI - Re: Improvised method to retrieve a proximally displaced ureteral stent in a remote surgical setting. (From: Fisher JD, Monahan M, Johnston WK III J Endourol 2013; 27:922-4). PMID- 23984715 TI - Molecular footprints of domestication and improvement in soybean revealed by whole genome re-sequencing. AB - BACKGROUND: Artificial selection played an important role in the origin of modern Glycine max cultivars from the wild soybean Glycine soja. To elucidate the consequences of artificial selection accompanying the domestication and modern improvement of soybean, 25 new and 30 published whole-genome re-sequencing accessions, which represent wild, domesticated landrace, and Chinese elite soybean populations were analyzed. RESULTS: A total of 5,102,244 single nucleotide polymorphisms (SNPs) and 707,969 insertion/deletions were identified. Among the SNPs detected, 25.5% were not described previously. We found that artificial selection during domestication led to more pronounced reduction in the genetic diversity of soybean than the switch from landraces to elite cultivars. Only a small proportion (2.99%) of the whole genomic regions appear to be affected by artificial selection for preferred agricultural traits. The selection regions were not distributed randomly or uniformly throughout the genome. Instead, clusters of selection hotspots in certain genomic regions were observed. Moreover, a set of candidate genes (4.38% of the total annotated genes) significantly affected by selection underlying soybean domestication and genetic improvement were identified. CONCLUSIONS: Given the uniqueness of the soybean germplasm sequenced, this study drew a clear picture of human-mediated evolution of the soybean genomes. The genomic resources and information provided by this study would also facilitate the discovery of genes/loci underlying agronomically important traits. PMID- 23984717 TI - Curcumin protects rat heart mitochondria against anoxia-reoxygenation induced oxidative injury. AB - It is an important therapeutic strategy to protect mitochondria from oxidative stress, especially during ischemia-reperfusion. Curcumin is a naturally occurring phenolic compound isolated as a yellow pigment from turmeric (Curcuma longa). This compound has received much attention due to its diversity of biological and pharmacological activities. In this study, an attempt has been made to evaluate the protective effects of curcumin on rat heart mitochondrial injuries induced by in vitro anoxia-reoxygenation. It was found that curcumin added before anoxia or immediately prior to reoxygenation exhibited remarkable protective effects against anoxia-reoxygenation induced oxidative damage to mitochondria, in concentrations ranging from picomoles to micromoles, with EC50s in the nanomolar range. The protective effects include inhibition of the decrease of state 3 respiratory activity, the decrease of respiratory control ratio (RCR) and ADP:oxygen (ADP:O) ratio, as well as the increase of state 4 respiratory activity; inhibition of the decrease of the membrane fluidity; inhibition of lipoperoxidation and protein carbonylation; as well as inhibition of the enhanced release of cardiolipin (CL) and cytochrome c (Cyt c). These results demonstrate the superior antioxidative properties of curcumin, and make it a promising candidate for the prevention and (or) therapy for ischemia-reperfusion injuries and the related free radical initiated diseases. PMID- 23984719 TI - InAs/GaAs quantum dots with wide-range tunable densities by simply varying V/III ratio using metal-organic chemical vapor deposition. AB - The complicated behaviors of InAs/GaAs quantum dots with increasing V/III ratio associated with several competing mechanisms have been described. The results demonstrate that the densities of InAs quantum dots can be tuned in a wide range from 105 to 1010 cm-2 by simply manipulating V/III ratio via metal-organic chemical vapor deposition. These results are mainly ascribed to the changes of coverage and In adatom migration length due to the increasing V/III ratio. PMID- 23984718 TI - Stainless steel leaches nickel and chromium into foods during cooking. AB - Toxicological studies show that oral doses of nickel and chromium can cause cutaneous adverse reactions such as dermatitis. Additional dietary sources, such as leaching from stainless steel cookware during food preparation, are not well characterized. This study examined stainless steel grades, cooking time, repetitive cooking cycles, and multiple types of tomato sauces for their effects on nickel and chromium leaching. Trials included three types of stainless steels and a stainless steel saucepan, cooking times of 2-20 h, 10 consecutive cooking cycles, and four commercial tomato sauces. After a simulated cooking process, samples were analyzed by ICP-MS for Ni and Cr. After 6 h of cooking, Ni and Cr concentrations in tomato sauce increased up to 26- and 7-fold, respectively, depending on the grade of stainless steel. Longer cooking durations resulted in additional increases in metal leaching, where Ni concentrations increased 34-fold and Cr increased approximately 35-fold from sauces cooked without stainless steel. Cooking with new stainless steel resulted in the largest increases. Metal leaching decreases with sequential cooking cycles and stabilized after the sixth cooking cycle, although significant metal contributions to foods were still observed. The tenth cooking cycle resulted in an average of 88 MUg of Ni and 86 MUg of Cr leached per 126 g serving of tomato sauce. Stainless steel cookware can be an overlooked source of nickel and chromium, where the contribution is dependent on stainless steel grade, cooking time, and cookware usage. PMID- 23984720 TI - Dengue: how imported mosquito-borne diseases take hold. PMID- 23984721 TI - Electrospinning of calixarene-functionalized polyacrylonitrile nanofiber membranes and application as an adsorbent and catalyst support. AB - Polyacrylonitrile (PAN) nanofiber membranes functionalized with calix[8]arenes (C[8]) were successfully prepared by electrospinning of PAN solutions with addition of various calixarenes. Uniform electrospun C[8]/PAN nanofibers were obtained by incorporating three types of calix[8]arenes into the PAN matrix and characterized by scanning electron microscopy (SEM), attenuated total reflection Fourier transform infrared (ATR-FTIR), thermal gravimetric analysis (TGA), and X ray powder diffraction (XRD). The SEM results showed that the addition of calix[8]arenes resulted in a decrease in the diameter of PAN nanofibers. Static adsorption behavior was studied by using C[8]/PAN nanofibers as an adsorbent and Congo red and Neutral red as model dye molecules. The adsorption of Congo red onto Amide-Cal[8]-15/PAN nanofibers fitted the second-order kinetic model, and the apparent adsorption rate constant was 1.1 * 10(-3) g.mg(-1).min(-1) at 25 degrees C. Then, by virtue of electrostatic attraction, as-prepared Au nanoparticles were immobilized on Amide-Cal[8]/PAN nanofibers to form Au/Amide Cal[8]/PAN composite nanofibers. The catalytic activity of the as-prepared Au/Amide-Cal[8]/PAN composite nanofibers was investigated by monitoring the reduction of Congo red in the presence of NaBH4. The reduction kinetics was explained by the assumption of a pseudo-first-order reaction with regard to Congo red. Au/Amide-Cal[8]/PAN composite nanofibers exhibited high catalytic activity, excellent stability, and convenient recycling. PMID- 23984723 TI - Effect of fetal bovine serum on foamy and lentiviral vector production. PMID- 23984724 TI - Supramolecular beta-cyclodextrin adducts of boron-rich DNA metallointercalators containing dicarba-closo-dodecaborane(12). AB - A chiral, isomeric series of novel boron-rich Pt(II) metallointercalators ([PtL2(phen)](NO3)2: L = (x)-(1,y-closo-carboran-1-yl)pyrid-z-ylmethanol: x = R, S; y = 7, 12; z = 3, 4) wre prepared and fully characterized. By means of variable-temperature NMR spectroscopy, different combinations of Delta-head-to tail, head-to-head, and Lambda-head-to-tail rotamers were identified, and the free energies of activation for Pt-N bond rotation were determined for the pyrid 4-yl complexes with DeltaG(?)307 = 16.1 +/- 0.3 kcal mol(-1) and DeltaG(?)325 = 16.2 +/- 0.5 kcal mol(-1) for the 1,7-carboranyl derivative and DeltaG(?)307 = 16.4 +/- 0.5 kcal mol(-1) and DeltaG(?)325 = 16.2 +/- 0.5 kcal mol(-1) for the 1,12-carboranyl derivative. The corresponding 2:1 host-guest beta-cyclodextrin (beta-CD) adducts ([PtL2(phen).2beta-CD](NO3)2) were also prepared and fully characterized by high resolution electrospray ionization mass spectrometry and 2D (1)H{(11)B} nuclear Overhauser enhancement spectroscopy and rotating-frame Overhauser effect spectroscopy NMR experiments. The interaction of the novel supramolecular adducts with calf thymus DNA was investigated by means of linear dichroism, ultraviolet-visible spectroscopy, thermal denaturation, and isothermal titration calorimetry experiments which revealed a bimodal binding regime with DNA intercalation favored at low [drug]/[DNA] ratios, while at higher drug loading, surface aggregation was observed. Furthermore, the data were also consistent with some degree of dissociation of the beta-CD host-guest adducts upon DNA binding. When we used a single binding-site model, interpreted as a weighted average of all of the possible equilibrium interactions, the compounds showed high affinity for ct-DNA with K(assoc) ranging from (1.3 +/- 0.1) * 10(5) M(-1) to (5.7 +/- 0.4) * 10(5) M(-1). In general, the overall DNA-binding behavior was enthalpically driven with a minor or unfavorable entropic component, which is consistent with the thermodynamics of an intercalation-dominated process. A higher degree of DNA intercalation was observed for the R-isomer in the pyrid-3-yl compounds, and the opposite trend was observed in the case of pyrid-4-yl derivatives. PMID- 23984725 TI - Patenting the PKU test--federally funded research and intellectual property. PMID- 23984726 TI - Patents, profits, and the American people--the Bayh-Dole Act of 1980. PMID- 23984727 TI - "Good" patients and "difficult" patients--rethinking our definitions. PMID- 23984729 TI - Safety and efficacy of RNAi therapy for transthyretin amyloidosis. AB - BACKGROUND: Transthyretin amyloidosis is caused by the deposition of hepatocyte derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin. METHODS: We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN TTR02, respectively. Each formulation was studied in a single-dose, placebo controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers. RESULTS: Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN TTR02, respectively. CONCLUSIONS: ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.). PMID- 23984728 TI - Macitentan and morbidity and mortality in pulmonary arterial hypertension. AB - BACKGROUND: Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. METHODS: We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. RESULTS: A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. CONCLUSIONS: Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.). PMID- 23984730 TI - Use of oral fluconazole during pregnancy and the risk of birth defects. AB - BACKGROUND: Case reports suggest that long-term, high-dose fluconazole treatment for severe fungal infections during pregnancy causes a pattern of birth defects. It is unclear whether commonly used lower doses increase the risk of specific birth defects. METHODS: In a registry-based cohort of liveborn infants in Denmark, we evaluated first-trimester oral fluconazole exposure and the risk of birth defects overall and of birth defects previously linked to azole antifungal agents. RESULTS: The majority of fluconazole-exposed pregnancies were in women who received common therapeutic doses of 150 mg (56% of pregnancies) or 300 mg (31%). Oral fluconazole exposure was not associated with an increased risk of birth defects overall (210 birth defects among 7352 fluconazole-exposed pregnancies [prevalence, 2.86%] and 25,159 birth defects among 968,236 unexposed pregnancies [prevalence, 2.60%]; adjusted prevalence odds ratio, 1.06; 95% confidence interval [CI], 0.92 to 1.21). In addition, oral fluconazole exposure was not associated with a significantly increased risk of 14 of 15 types of birth defects previously linked to azole antifungal agents: craniosynostosis, other craniofacial defects, middle-ear defects, cleft palate, cleft lip, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, pulmonary-artery hypoplasia, ventricular septal defects, and hypoplastic left heart. A significantly increased risk of tetralogy of Fallot was observed (7 cases in fluconazole-exposed pregnancies [prevalence, 0.10%] as compared with 287 cases in unexposed pregnancies [prevalence, 0.03%]; adjusted prevalence odds ratio, 3.16; 95% CI, 1.49 to 6.71). CONCLUSIONS: Oral fluconazole was not associated with a significantly increased risk of birth defects overall or of 14 of the 15 specific birth defects of previous concern. Fluconazole exposure may confer an increased risk of tetralogy of Fallot. (Funded by the Danish Medical Research Council.). PMID- 23984731 TI - Severe sepsis and septic shock. PMID- 23984732 TI - Images in clinical medicine. Staphylococcal toxic shock syndrome. PMID- 23984733 TI - Case records of the Massachusetts General Hospital. Case 27-2013. A 6.5-month-old boy with fever, rash, and cytopenias. PMID- 23984734 TI - A new era in the treatment of amyloidosis? PMID- 23984735 TI - Medical emergencies on commercial airline flights. PMID- 23984736 TI - Medical emergencies on commercial airline flights. PMID- 23984737 TI - Medical emergencies on commercial airline flights. PMID- 23984738 TI - Medical emergencies on commercial airline flights. PMID- 23984739 TI - HCV infection and miravirsen. PMID- 23984740 TI - HCV infection and miravirsen. PMID- 23984741 TI - Human infection with H7N9 virus. PMID- 23984742 TI - Human infection with H7N9 virus. PMID- 23984743 TI - Human infection with H7N9 virus. PMID- 23984744 TI - Penicillin to prevent recurrent leg cellulitis. PMID- 23984745 TI - Penicillin to prevent recurrent leg cellulitis. PMID- 23984746 TI - Penicillin to prevent recurrent leg cellulitis. PMID- 23984747 TI - Mechanisms of acute coronary syndromes. PMID- 23984748 TI - Mechanisms of acute coronary syndromes. PMID- 23984749 TI - Mechanisms of acute coronary syndromes. PMID- 23984750 TI - Mechanisms of acute coronary syndromes. PMID- 23984751 TI - Images in clinical medicine. Severe vitamin D deficiency--rickets. PMID- 23984753 TI - Identification of the +2 oxidation state for uranium in a crystalline molecular complex, [K(2.2.2-cryptand)][(C5H4SiMe3)3U]. AB - Flash reduction of Cp'3U (Cp' = C5H4SiMe3) in a column of potassium graphite in the presence of 2.2.2-cryptand generates crystalline [K(2.2.2-cryptand)][Cp'3U], the first isolable molecular U(2+) complex. To ensure that this was not the U(3+) hydride, [K(2.2.2-cryptand)][Cp'3UH], which could be crystallographically similar, the hydride complex was synthesized by addition of KH to Cp'3U and by reduction of H2 by the U(2+) complex and was confirmed to be a different compound. Density functional theory calculations indicate a 5f(3)6d(1) quintet ground state for the [Cp'3U](-) anion and match the observed strong transitions in its optical spectrum. PMID- 23984755 TI - Development and evaluation of pluronic- and methylcellulose-based thermoreversible drug delivery system for insulin. AB - The objective of the current work was to develop and evaluate thermoreversible subcutaneous drug delivery system for Insulin. Thermoreversible in-situ gel system was developed and evaluated both in-vitro and in-vivo comprising of pluronic F-127 alone or in combination with methylcellulose in different ratios. The drug release kinetics and mechanism was predicted by applying various mathematical models to the in-vitro dissolution data. Rabbits were used as animal model following subcutaneous injection to predict various pharmacokinetic parameters by applying Pk-Summit(r) software. The in-vitro and in-vivo data revealed that the formulation IPM 15/3 consisting of the pluronic F-127 (15% w/v) and methylcellulose (3% w/v) was the most robust and capable formulation for extending the drug release and maintaining basal plasma insulin level between 10 and 40 uU/ml for 240 h (10 d). PMID- 23984754 TI - Attitudes to aging mediate the relationship between older peoples' subjective health and quality of life in 20 countries. AB - BACKGROUND: With ever-increasing life expectancy globally, it is imperative to build knowledge of how older peoples' views of their own aging, considering their health-related circumstances, affect quality of life for practitioners and policy makers alike. Based on our literature review, we wanted to determine whether older adults' attitudes toward their own aging would partly mediate the effect of their health satisfaction ratings upon their quality of life. Furthermore, would these attitudes mediate the relationship between health satisfaction and quality of life in the same way when we account for older adults' country of origin, and their age and gender? METHODS: This was a secondary analysis of cross-sectional survey data collected in 20 countries taking part in the 2003 WHOQOL-OLD Field study. The study sample consisted of 4593 adults whom were, on average, 72.10 years of age (range = 60 to 100 years of age); 42.8% were female. The WHOQOL-BREF measured quality of life and health satisfaction. The Attitudes to Aging Questionnaire measured participants' attitudes toward physical change, psychosocial loss, and psychological growth. All items in both questionnaires were measured on a 5-point Likert scale. Questionnaire responses were analyzed using multilevel modeling and path analysis. RESULTS: All three attitudes to aging partly mediated the relationship between health satisfaction and physical, psychological, social, environmental, and global quality of life. These partial mediations manifested in the same way across all 20 country samples, regardless of age or gender. Attitudes toward physical change were the strongest mediator of health satisfaction upon global and domain-specific quality of life, followed by psychosocial loss and psychosocial growth. CONCLUSIONS: Our study is the first cross-cultural study with a large sample to show that quality of life judgements, between 60 to 100 years of age, are a product of older men's and women's perceptions of health-related circumstances, and attitudes toward physical and psychosocial aspects of the aging self. A prospective study of the linkages between older peoples' subjective views of health and attitudes toward the aging self over time using multiple subjective measures of health is warranted. Understanding these linkages may help practitioners and policy makers consider strategies to enhance quality of life. PMID- 23984756 TI - Edith Kaplan and the Boston Process Approach. AB - The history including some of the intellectual origins of the Boston Process Approach and some misconceptions about the Boston Process Approach are reviewed. The influence of Gestalt psychology and Edith Kaplan's principal collaborators regarding the development of the Boston Process Approach is discussed. PMID- 23984757 TI - Prospective memory and chronic heart failure. AB - BACKGROUND: Patients with chronic heart failure (CHF) experience a number of debilitating symptoms, which impact on activities of daily living and result in poor quality of life. Prospective memory, which is defined as memory to carry out future intentions, has not been investigated in this group. However, emerging evidence suggests CHF patients have difficulties with cognitive processes related to prospective memory. Self-care, which partly relies on prospective memory, is essential in symptom management and preventing acute clinical deterioration. This study aims to measure prospective memory in CHF patients, and examine the relationship between prospective memory and CHF self-care. METHODS/DESIGN: A comprehensive neuropsychological assessment will be conducted to assess a range of cognitive functions and psychopathology. The primary focus will be an assessment of prospective memory using a well-established behavioral measure; Virtual Week. Thirty CHF patients attending a nurse-led management program will be recruited from three hospital sites in Melbourne, Australia and their self care behaviors will be assessed using the Self-care Chronic Heart Failure Index (SCHFI), a validated self-report tool. An additional 30 healthy controls, matched on age, gender, and IQ will be recruited from the general community. DISCUSSION: This is a group comparison study that will provide an evaluation of the prospective memory abilities of CHF patients. The findings of this research will provide insight into whether prospective memory may be hindering patients' ability to perform adequate self-care. PMID- 23984758 TI - Au-Cu(2-x)Se heterodimer nanoparticles with broad localized surface plasmon resonance as contrast agents for deep tissue imaging. AB - We report a new type of heterogeneous nanoparticles (NPs) composed of a heavily doped semiconductor domain (Cu2-xSe) and a metal domain (Au), which exhibit a broad localized surface plasmon resonance (LSPR) across visible and near-infrared (NIR) wavelengths, arising from interactions between the two nanocrystal domains. We demonstrate both in vivo photoacoustic imaging and in vitro dark field imaging, using the broad LSPR in Cu2-xSe-Au hybrid NPs to achieve contrast at different wavelengths. The high photoacoustic imaging depth achieved, up to 17 mm, shows that these novel contrast agents could be clinically relevant. More broadly, this work demonstrates a new strategy for tuning LSPR absorbance by engineering the density of free charge carriers in two interacting domains. PMID- 23984759 TI - Chronic exposure of adult rats to low doses of methylmercury induced a state of metabolic deficit in the somatosensory cortex. AB - Because of the ever-increasing bioaccumulation of methylmercury (MeHg) in the marine food chain, human consumers are exposed to low doses of MeHg continually through seafood consumption. Epidemiological studies strongly suggest that chronic prenatal exposure to nanomolar of MeHg has immense negative impacts on neurological development in neonates. However, effects of chronic exposure to low doses (CELDs) of MeHg in adult brains on a molecular level are unknown. The current study aims to investigate the molecular effects of CELD of MeHg on adult somatosensory cortex in a rat model using proteomic techniques. Young adult rats were fed with a low dose of MeHg (40 MUg/kg body weight/day) for a maximum of 12 weeks. Whole proteome expression of the somatosensory cortex (S1 area) of normal rats and those with CELD to MeHg were compared. Levels of MeHg, total calcium, adenosine triphosphate (ATP), and pyruvate were also measured. Comparative proteomic studies of the somatosensory cortexes revealed that 94 proteins involved in the various metabolic processes (including carbohydrate metabolism, generation of precursors for essential metabolites, energy, proteins, cellular components for morphogenesis, and neurotransmission) were down-regulated. Consequently, levels of important end products of active metabolism including ATP, pyruvate, and total calcium were also found to be significantly reduced concomitantly. Our results showed that CELD of MeHg induced a state of metabolic deficit in the somatosensory cortex of adult rats. PMID- 23984760 TI - Synergistic effects between Lewis and Bronsted acids: application to the Prins cyclization. AB - Bronsted and Lewis acids can catalyze the Prins cyclization, an efficient method for the synthesis of tetrahydropyrans from homoallylic alcohols and carbonyl compounds. Synergistic effects between weak Bronsted and Lewis acids in these reactions have been analyzed by density functional theory [M06-L/def2 QZVP/IEFPCM(CH2Cl2)//M06-L/6-311+G(2df,2p)]. In order to characterize the reactivities of the employed Lewis acids, methyl anion and hydroxide affinities were determined. On the basis of our calculations, we found that the coordination of Lewis acids to carboxylic and sulfonic acids results in a significant increase in the Bronsted acidities of the latter. PMID- 23984761 TI - Cinchona alkaloid squaramide catalyzed enantioselective hydrazination/cyclization cascade reaction of alpha-isocyanoacetates and azodicarboxylates: synthesis of optically active 1,2,4-triazolines. AB - An efficient enantioselective hydrazination/cyclization cascade reaction of alpha substituted isocyanoacetates to azodicarboxylates catalyzed by Cinchona alkaloid derived squaramide catalysts has been investigated, affording the optically active 1,2,4-triazolines in excellent yields (up to 99%) and good to excellent enantioselectivities (up to 97% ee) under mild conditions. PMID- 23984763 TI - Can we avert a diabetes catastrophe in Australia? PMID- 23984764 TI - The history of insulin: the mystery of diabetes. PMID- 23984765 TI - Hand transplantation. PMID- 23984768 TI - Comprehensive primary health care and social determinants as top priorities. PMID- 23984769 TI - Better information to drive health investment decisions. PMID- 23984770 TI - Time to reconsider steroid injections in the spine? PMID- 23984771 TI - Extending the medical workforce debate: let's talk about self-sufficiency. PMID- 23984772 TI - Dabigatran - neurosurgical anathema? PMID- 23984773 TI - The Bettering the Evaluation and Care of Health (BEACH) program: where to from here? PMID- 23984774 TI - The Bettering the Evaluation and Care of Health (BEACH) program: where to from here? PMID- 23984775 TI - Inequalities in bariatric surgery in Australia: findings from 49,364 obese participants in a prospective cohort study. PMID- 23984776 TI - Consistently high incidence of diabetic ketoacidosis in children with newly diagnosed type 1 diabetes. PMID- 23984777 TI - Severe symptomatic hypocalcaemia following a single dose of denosumab. PMID- 23984779 TI - National guidelines for the management of absolute cardiovascular disease risk. PMID- 23984778 TI - National guidelines for the management of absolute cardiovascular disease risk. PMID- 23984780 TI - The rationale for combining GLP-1 receptor agonists with basal insulin. AB - * Type 2 diabetes mellitus (T2DM) is progressive; the more intensively it is treated, the greater is the risk of hypoglycaemia and weight gain. Achieving treatment intensification while mitigating these risks presents a challenge to patient management. * Basal insulins provide control of fasting glucose; however, their utility in the control of postprandial glucose excursions is limited. * Glucagon-like peptide-1 (GLP-1) receptor agonists stimulate glucose-medicated insulin secretion, suppress glucagon secretion, delay gastric emptying and decrease appetite. Use of GLP-1 receptor agonists in combination therapy with basal insulin offers an alternative approach to intensification of insulin therapy. * Prospective interventional trials demonstrate that GLP-1 receptor agonists added to basal insulin decrease postprandial glucose levels, lower HbA1c levels, decrease weight and lower basal insulin requirements without increasing the risk of major hypoglycaemic events. * The current clinical data are limited by the lack of any data on the long-term effects of GLP-1 receptor agonists over additional prandial regimens; they may be beneficial or deleterious. * Although cost, gastrointestinal side effects and long-term safety should be taken into account when considering this combination, it appears to be growing in popularity and is likely to be an important therapeutic option for T2DM in the future. PMID- 23984781 TI - Are we there yet? A journey of health reform in Australia. AB - * Five years on from the establishment of the National Health and Hospitals Reform Commission, it is timely to review the context for reform and some of the actions taken to date, and to highlight remaining areas of concern and priority. * The Commission's final report was released in July 2009 and presented 123 recommendations organised under four reform themes: Taking responsibility: individual and collective action to build good health and wellbeing - by people, families, communities, health professionals, employers, health funders and governments Connecting care: comprehensive care for people over their lifetime Facing inequities: recognise and tackle the causes and impacts of health inequities Driving quality performance: leadership and systems to achieve best use of people, resources and evolving knowledge. * Overall, the Australian Government's response to the Commission's report has been very positive, but challenges remain in some key areas: Financial sustainability and the vertical fiscal imbalance between the federal and state governments Getting the best value from the health dollar by reducing inefficiency and waste and using value-based purchasing across the public and private health sectors National leadership across the system as a whole Getting the right care in the right place at the right time Health is about more than health care - increasing focus on prevention and recognising and tackling the broader social determinants of health. PMID- 23984782 TI - Trials and tribulations in the removal of dextropropoxyphene from the Australian Register of Therapeutic Goods. AB - * The Therapeutic Goods Administration determined in November 2011 that dextropropoxyphene should be removed from the Australian Register of Therapeutic Goods. This is consistent with this drug's removal from the market in many other developed countries. * However, dextropropoxyphene is still on the market in Australia owing to a series of appeals made to the Administrative Appeals Tribunal (AAT) by the drug's manufacturer. * There is a difference between the standards by which the AAT judges the safety and efficacy of medicines and the standards used for registering therapeutic goods by regulatory agencies worldwide. * This raises the question as to whether the appeal process against TGA decisions appropriately serves the Australian public interest. PMID- 23984783 TI - Impact on diabetes management of General Practice Management Plans, Team Care Arrangements and reviews. AB - OBJECTIVES: To investigate whether General Practice Management Plans (GPMPs), Team Care Arrangements (TCAs) and reviews of these improve the management and outcomes of patients with diabetes when supported by cdmNet, a web-based chronic disease management system; and to investigate adherence to the annual cycle of care (ACOC), as recommended in diabetes guidelines. DESIGN, PARTICIPANTS AND SETTING: A before-and-after study to analyse prospectively collected data on 577 patients with type 1 or 2 diabetes mellitus who were managed with a GPMP created using cdmNet between June 2008 and November 2012. MAIN OUTCOME MEASURES: Completion of the clinical tests in the ACOC (process outcome) and values of six of these clinical measurements (clinical outcomes). RESULTS: Significant improvements were seen after creation of a GPMP in the proportion of ACOC clinical tests completed (57.9% v 74.8%, P < 0.001), total cholesterol level (P < 0.01), low-density lipoprotein (LDL) cholesterol level (P < 0.001) and body mass index (BMI) (P < 0.01). Patients using GPMPs and TCAs also improved their glycated haemoglobin (HbA1c) level (P < 0.05). Patients followed up with irregular reviews had significant improvements in the proportion of ACOC clinical tests completed (59.2% v 77.6%, P < 0.001), total cholesterol level (P < 0.05), and BMI (P < 0.01), but patients with regular reviews had greater improvements in the proportion of ACOC clinical tests completed (58.9% v 85.0%, P < 0.001), HbA(1c) level (57.7 v 53.0 mmol/mol, P < 0.05), total cholesterol level (4.8 v 4.5 mmol/L, P < 0.05), LDL cholesterol level (2.8 v 2.4 mmol/L, P < 0.01) and diastolic blood pressure (76.0 v 74.0 mmHg, P < 0.05). CONCLUSION: There were significant improvements in process and clinical outcomes for patients on a GPMP or a GPMP and TCA, particularly when these were followed up by regular reviews. Patients using cdmNet were four times more likely to have their GPMP or TCA followed up through regular reviews than the national average. PMID- 23984784 TI - Prevalence and perceptions of overweight and obesity in Aboriginal and non Aboriginal young people in custody. AB - OBJECTIVE: To describe prevalence of and risk factors for overweight, obesity and self-perceived weight gain of Aboriginal and non-Aboriginal Australian young people in custody at baseline and over 12 months of follow-up. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort study of youths in custody in New South Wales, from August 2009, with follow-up at 3, 6 and 12 months. MAIN OUTCOME MEASURES: Body mass index at baseline, categorised as overweight or obese using international cut-points; waist-to-height ratio (WHtR) at baseline, categorised as increased metabolic risk (>= 0.5) or low metabolic risk (< 0.5); and self perceived weight change at follow-up. RESULTS: At baseline, 452 youths were incarcerated, 361 (79.9%) consented to participate, and complete anthropometry measurements were taken for 303 (67.0%). At 3, 6 and 12 months, there were 231 (76.2%), 158 (52.1%) and 143 (47.2%) participants, respectively. Two-hundred and sixty-four (87.1%) were male, 151 (49.8%) were Aboriginal, and 145 (47.9%) had been incarcerated for < 3 months at baseline. One hundred and forty-five (47.9%) were overweight or obese and 112 (37.0%) had a WHtR of >= 0.5 at baseline. However, only 72 (24.1%) perceived themselves as overweight at baseline, and 154 (71.6%) perceived a weight increase since incarceration despite improvements in diet and exercise. Longer incarceration time was strongly associated with overweight and obesity in Aboriginal youths at baseline and with self-perceived weight gain in non-Aboriginal youths at follow-up. CONCLUSIONS: Overweight and obesity were highly prevalent but poorly recognised in young people in custody. A longer incarceration time had the strongest association with overweight obesity and self-reported weight gain. From a population health and policy perspective, changes to the liberal food environment and the approach to increasing physical activity in custody are warranted. PMID- 23984785 TI - Educational support for specialist international medical graduates in anaesthesia. AB - OBJECTIVE: To measure specialist international medical graduates' (SIMGs) level of learning through participation in guided tutorials, face-to-face or through videoconferencing (VC), and the effect of tutorial attendance and quality of participation on success in specialist college examinations. DESIGN AND SETTING: Tutorials were conducted at the Royal Brisbane and Women's Hospital between 19 September 2007 and 23 August 2010, and delivered through VC to participants at other locations. Tutorials were recorded and transcribed, and speaker contributions were tagged and ranked using content analysis software. Summary examination results were obtained from the Australian and New Zealand College of Anaesthetists. MAIN OUTCOME MEASURES: Tutorial participation and attendance, and college examination pass and fail rates. RESULTS: Transcripts were obtained for 116 tutorials. The median participation percentage for those who subsequently failed the college examinations was 1% (interquartile range [IQR], 0%-1%), while for those who passed the exams it was 5% (IQR, 2%-8%; P < 0.001). There was also an association between attendance and exam success; the median (IQR) attendance of those who failed was 24% (IQR, 14%-39%), while for those who passed it was 59% (IQR, 39%-77%; P < 0.001). CONCLUSIONS: Use of VC technology was found to be a feasible method to assist SIMGs to become aware of the requirements of the exam and to prepare more effectively. PMID- 23984786 TI - The influence of Australian eye banking practices on corneal graft survival. AB - OBJECTIVE: To identify eye banking practices that influence corneal graft survival. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort study of records of 19,254 followed corneal grafts in 15160 patients, submitted to the Australian Corneal Graft Registry between May 1985 and July 2012. MAIN OUTCOME MEASURES: Influence of corneal preservation method (organ culture, moist pot, Optisol, other); death-to-enucleation, death-to-preservation and enucleation-to-graft times; transportation by air; graft era; and indication for graft on probability of graft survival at most recent follow-up. RESULTS: In multivariate analysis, 919 penetrating grafts performed using corneas transported interstate by air exhibited worse survival than 14,684 grafts performed using corneas retrieved and used locally (hazard ratio [HR], 1.44; 95% CI, 1.21-1.73; P = 0.001). This was also the case for traditional lamellar grafts (64 corneas transported by air and 813 used locally; HR, 1.69; 95% CI, 1.03-2.78; P = 0.038). Indication for graft influenced survival of penetrating grafts (4611 keratoconus, 727 emergency or high-risk, 10,265 other indication; global P < 0.001) and traditional lamellar grafts (65 keratoconus, 212 emergency or high-risk, 600 other indication; global P < 0.001). The preservation medium in which corneas used for traditional lamellar grafts were stored exerted a marginal influence on graft survival (global P = 0.047). CONCLUSIONS: Donor corneas transported interstate exhibited poorer survival after transplantation than those retrieved and grafted locally. Higher proportions of emergency procedures involving transported corneas did not account for this difference. Where possible, efforts to avoid transportation of corneal tissue by air freight within Australia may be warranted. PMID- 23984787 TI - Human rights trauma and the mental health of West Papuan refugees resettled in Australia. AB - OBJECTIVES: To document the extent and nature of human rights violations and other traumatic events reported by West Papuan refugees resettled in Australia and to assess trauma-related psychological disorders, distress and disability. DESIGN AND SETTING: Australian-based sample, mixed-methods design with 44 participants, conducted in Australia between October 2007 and November 2010 in communities in North Queensland and Melbourne. PARTICIPANTS: West Papuan refugees aged 18 years and over (88% response rate). MAIN OUTCOME MEASURES: Post-traumatic stress disorder (PTSD) symptoms (Harvard Trauma Questionnaire) and premigration potentially traumatic events (PTEs), psychological distress (Kessler Psychological Distress Scale [K10]), post-migration living difficulties, days out of role. RESULTS: Of the 44 West Papuan refugees, 40 reported one or more PTE, including inability to access medical care for family (40), lack of food and water (39) and lack of access to medical treatment (38). The most frequent postmigration stressors were separation from and worries about family members remaining in West Papua (43) and being unable to return home in an emergency because of ongoing conflict (41). Twenty-six participants reached a lower threshold for PTSD symptoms of 2.0, and 13 reached the clinical threshold of 2.5. Fourteen reported severe psychological distress. CONCLUSIONS: West Papuan refugees resettled in Australia report a wide range of premigration PTEs including human rights violations, as well as symptoms of PTSD and distress. The data add to concerns about the state of human rights and mental health among West Papuans. PMID- 23984788 TI - First hand transplant procedure in Australia: outcome at 2 years. PMID- 23984789 TI - Research using autologous cord blood - time for a policy change. AB - * Type 1 diabetes results from the loss of normal immunological self-tolerance, which may be attributable to the failure of Foxp3+ regulatory T cells (Tregs). Umbilical cord blood is rich in Tregs and therefore has the potential to prevent or delay the onset of type 1 diabetes. A pilot trial is currently underway in Australia to examine whether infusion of autologous cord blood can prevent type 1 diabetes in high-risk children with serum antibodies to multiple beta-cell antigens. * A number of other potential therapeutic indications for autologous cord blood have been proposed, including cerebral palsy and hypoxic-ischaemic encephalopathy. * Recruitment to clinical trials using cord blood is influenced by divergent public and private cord blood banking policy in Australia. The burgeoning consumer demand for storage of cord blood highlights the need for regulatory bodies to develop and adapt policies to facilitate research that may extend the use of cord blood beyond currently recognised indications. * Consumers, researchers and policymakers must also recognise specific ethical issues associated with collection and storage of cord blood, including storage in public and private banks, informed consent, ownership, access and the principle of beneficence. PMID- 23984790 TI - Ethical and legal issues raised by cord blood banking - the challenges of the new bioeconomy. AB - * Cord blood banking raises ethical and legal issues which highlight the need for careful regulatory approaches to the emerging bioeconomy. * Consent processes for both private and public banking should be inclusive and representative of the different familial interests in the cord blood. * Property law is a potentially useful way of understanding the mechanisms for donation to both public and private banks. * Increasing tensions between public and private models of banking may require the adoption of hybrid forms of banking. PMID- 23984791 TI - MJA Dr Eric Dark Creative Writing Prize - Joy to Mary. PMID- 23984793 TI - Effects of exenatide and metformin in combination on some adipocytokine levels: a comparison with metformin monotherapy. AB - The aim of this study was to evaluate the effects of exenatide on levels of serum adipocytokines and on beta-cell function. The study was conducted between 2008 and 2012. After a run-in period with metformin, 174 patients with type-2 diabetes were randomly distributed to either a group receiving exenatide at 10 MUg twice daily, or a group receiving the placebo, for 12 months. We evaluated body mass index (BMI), blood pressure, glycemic control, lipid profile, fasting plasma insulin (FPI), HOMA-IR, HOMA-beta, fasting plasma proinsulin (FPPr), proinsulin : fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, retinol binding protein-4 (RBP-4), visfatin, omentin-1, and microalbuminuria. We used ELISA methods to assess the various parameters. Patients also underwent a combined euglycemic-hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. After 12 months, a combination of exenatide and metformin produced a better decrease in body mass, BMI, glycemic control, FPI, FPPr, FPPr/FPI ratio, HOMA-IR, and glucagon level. Treatment with exenatide + metformin was superior to the placebo + metformin in increasing HOMA-beta, C-peptide, and beta-cell function. Significant negative correlations were found between M value, an index of insulin sensitivity, and measured adipocytokines. In conclusion, the combination of exenatide + metformin plays a role in improving some adipocytokine levels, and is better than metformin alone. The significant negative correlation between M value and measured adipocytokines is another confirmation of the positive effects linked to the improvement in insulin sensitivity. PMID- 23984794 TI - Charge storage characteristics of Au nanocrystal memory improved by the oxygen vacancy-reduced HfO2 blocking layer. AB - This study characterizes the charge storage characteristics of metal/HfO2/Au nanocrystals (NCs)/SiO2/Si and significantly improves memory performance and retention time by annealing the HfO2 blocking layer in O2 ambient at 400 degrees C. Experimental evidence shows that the underlying mechanism can be effectively applied to reduce oxygen vacancy and suppress unwanted electron trap-assisted tunneling. A memory window of 1 V at an applied sweeping voltage of +/-2 V is also shown. The low program/erase voltage (+/-2 V) and the promising retention performances indicate the potential application of NCs in low-voltage, non volatile memory devices. PMID- 23984796 TI - Time course production of urolithins from ellagic acid by human gut microbiota. AB - Ellagic acid (EA) is converted to urolithins by gut microbiota. Urolithins have beneficial biological effects in humans, but differences in urolithin production capacity among individuals have been shown. Therefore, the identification of the urolithin production pathways and the microorganisms implicated is of high interest. EA was incubated with gut microbiota from two volunteers able to produce urolithins but with different in vivo urolithin profiles (urolithin A and isourolithin A producers). The metabolic capabilities observed in vivo were retained in vitro. Both individuals showed a much higher abundance of Clostridium leptum group of Firmicutes phylum than Bacteroides / Prevotella . EA was either dissolved in DMSO or suspended in water. DMSO increased EA solubility but decreased urolithin production rate due to a delay in growth of some microbial groups, principally, Clostridium coccoides . This allowed the detection of catabolic intermediates [urolithins M-5, M-6, M-7, C, and 2,3,8,10-tetrahydroxy urolithin (urolithin E)]. Bacteria from C. coccoides group (or genera co occurring in vivo with this group) seem to be involved in production of different urolithins. PMID- 23984795 TI - The anti-HBV effect mediated by a novel recombinant eukaryotic expression vector for IFN-alpha. AB - BACKGROUND: Chronic hepatitis B is a primary cause of liver-related death. Interferon alpha (IFN-alpha) is able to inhibit the replication of hepadnavirus, and the sustained and stable expression of IFN-alpha at appropriate level may be beneficial to HBV clearance. With the development of molecular cloning technology, gene therapy plays a more and more important role in clinical practice. In light of the findings, an attempt to investigate the anti-HBV effects mediated by a eukaryotic expression plasmid (pSecTagB-IFN-alpha) in vitro was carried out. METHODS: HBV positive cell line HepG2.2.15 and its parental cell HepG2 were transfected with pSecTagB-IFN-alpha or empty plasmid by using LipofectamineTM 2000 reagent. The expression levels of IFN-alpha were determined by reverse transcriptase polymerase chain reaction (RT-PCR) and ELISA methods. The effects of pSecTagB-IFN-alpha on HBV mRNA, DNA and antigens were analyzed by real-time fluorescence quantitative PCR (qRT-PCR) and ELISA assays. RT-PCR, qRT PCR and western blot were employed to investigate the influence of pSecTagB-IFN alpha on IFN-alpha-induced signal pathway. Furthermore, through qRT-PCR and ELISA assays, the suppressive effects of endogenously expressed IFN-alpha and the combination with lamivudine on HBV were also examined. RESULTS: pSecTagB-IFN alpha could express efficiently in hepatoma cells, and then inhibited HBV replication, characterized by the decrease of HBV S gene (HBs) and HBV C gene (HBc) mRNA, the reduction of HBV DNA load, and the low contents of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg). Mechanism research showed that the activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal pathway, the up-regulation of IFN-alpha-induced antiviral effectors and double-stranded (ds) RNA sensing receptors by delivering pSecTagB-IFN-alpha, could be responsible for these phenomena. Furthermore, pSecTagB-IFN-alpha vector revealed effectively anti-HBV effect than exogenously added IFN-alpha. Moreover, lamivudine combined with endogenously expressed IFN alpha exhibited stronger anti-HBV effect than with exogenous IFN-alpha. CONCLUSION: Our results showed that endogenously expressed IFN-alpha can effectively and persistently inhibit HBV replication in HBV infected cells. These observations opened a promising way to design new antiviral genetic engineering drugs based on IFN-alpha. PMID- 23984797 TI - A comparison of electronic health records at two major Peking University Hospitals in China to United States meaningful use objectives. AB - BACKGROUND: In accordance with the People's Republic of China's (China) National Health Reform Plan of 2009, two of the nation's leading hospitals, located in Beijing, have implemented electronic medical record (EMR) systems from different vendors.To inform future EMR adoption and policy in China, as well as informatics research in the US, this study compared the United State's Hospital Meaningful Use (MU) Objectives (phase 1) objectives to the EMR functionality of two early hospital EMR adopters in China. METHODS: At both hospitals, the researchers observed a physician using the EMR and noted MU functionality that was seen and functionality that was not seen yet was available in the EMR. The information technology department was asked about the availability of functionality neither observed nor known to the physician. RESULTS AND CONCLUSIONS: Approximately half the MU objectives were available in each EMR. Some differences between the EMRs in the study and MU objectives were attributed to operational differences between the health systems and the cultures in the two countries. PMID- 23984799 TI - Probing the electronic properties of a trinuclear molecular wire involving isocyanoferrocene and iron(II) phthalocyanine motifs. AB - A new trinuclear iron(II) complex involving two isocyanoferrocene ligands axially coordinated to iron(II) phthalocyanine, (FcNC)2FePc [Fc = ferrocenyl; Pc = phthalocyaninato(2-) anion], was isolated and characterized using a variety of spectroscopic methods as well as single-crystal X-ray diffraction. The redox behavior of the above molecular wire was investigated through electrochemical, spectroelectrochemical, and chemical oxidation approaches and compared to that of the bis(tert-butylisocyano)iron(II) phthalocyanine reference compound, (t BuNC)2FePc. For both complexes, the first oxidation involves the phthalocyanine ligand and results in the formation of a red phthalocyanine cation-radical centered [(RNC)2FePc](+) species, as evidenced by their UV-vis and electron paramagnetic resonance spectra. Despite the ~11.5 A distance between the isocyanoferrocene iron centers, the second and third oxidation potentials for (FcNC)2FePc are separated by ~80 mV, which is indicative of a weak long-range metal-metal coupling in this system. Spectroscopic signatures of the mixed valence [(FcNC)2FePc](2+) dication were obtained using spectroelectrochemical and chemical oxidation approaches. These experimentally assessed characteristics were also correlated with the electronic structure, redox properties, and spectroscopic signatures predicted by density functional theory (DFT) and time dependent DFT analyses. PMID- 23984798 TI - Genome-wide modeling of complex phenotypes in Caenorhabditis elegans and Drosophila melanogaster. AB - BACKGROUND: The genetic and molecular basis for many intermediate and end stage phenotypes in model systems such as C. elegans and D. melanogaster has long been known to involve pleiotropic effects and complex multigenic interactions. Gene sets are groups of genes that contribute to multiple biological or molecular phenomena. They have been used in the analysis of large molecular datasets such as microarray data, Next Generation sequencing, and other genomic datasets to reveal pleiotropic and multigenic contributions to phenotypic outcomes. Many model systems lack species specific organized phenotype based gene sets to enable high throughput analysis of large molecular datasets. RESULTS AND DISCUSSION: Here, we describe two novel collections of gene sets in C. elegans and D. melanogaster that are based exclusively on genetically determined phenotypes and use a controlled phenotypic ontology. We use these collections to build genome wide models of thousands of defined phenotypes in both model species. In addition, we demonstrate the utility of these gene sets in systems analysis and in analysis of gene expression-based molecular datasets and show how they are useful in analysis of genomic datasets connecting multigenic gene inputs to complex phenotypes. CONCLUSIONS: Phenotypic based gene sets in both C. elegans and D. melanogaster are developed, characterized, and shown to be useful in the analysis of large scale species-specific genomic datasets. These phenotypic gene set collections will contribute to the understanding of complex phenotypic outcomes in these model systems. PMID- 23984800 TI - Endophytic fungi: resource for gibberellins and crop abiotic stress resistance. AB - The beneficial effects of endophytes on plant growth are important for agricultural ecosystems because they reduce the need for fertilizers and decrease soil and water pollution while compensating for environmental perturbations. Endophytic fungi are a novel source of bioactive secondary metabolites; moreover, recently they have been found to produce physiologically active gibberellins as well. The symbiosis of gibberellins producing endophytic fungi with crops can be a promising strategy to overcome the adverse effects of abiotic stresses. The association of such endophytes has not only increased plant biomass but also ameliorated plant-growth during extreme environmental conditions. Endophytic fungi represent a trove of unexplored biodiversity and a frequently overlooked component of crop ecology. The present review describes the role of gibberellins producing endophytic fungi, suggests putative mechanisms involved in plant endophyte stress interactions and discusses future prospects in this field. PMID- 23984801 TI - Loss of electrostatic interactions causes increase of dynamics within the plastocyanin-cytochrome f complex. AB - Recent studies on the electron transfer complex formed by cytochrome f and plastocyanin from Nostoc revealed that both hydrophobic and electrostatic interactions play a role in the process of complex formation. To study the balance between these two types of interactions in the encounter and the final state, the complex between plastocyanin from Phormidium laminosum and cytochrome f from Nostoc sp. PCC 7119 was investigated using NMR spectroscopy and Monte Carlo docking. Cytochrome f has a highly negative charge. Phormidium plastocyanin is similar to that from Nostoc, but the net charge of the protein is negative rather than positive. NMR titrations of Zn-substituted Phormidium plastocyanin and Nostoc cytochrome f indicated that a complex with an affinity intermediate between those of the Nostoc and Phormidium complexes is formed. Plastocyanin was found in a head-on orientation, as determined using pseudocontact shifts, similar to that in the Phormidium complex, in which the hydrophobic patch represents the main site of interaction on plastocyanin. However, the interaction in the cross complex is dependent on electrostatics, similar to that in the Nostoc complex. The negative charge of plastocyanin decreases, but not abolishes, the attraction to cytochrome f, resulting in the formation of a more diffuse encounter complex than in the Nostoc case, as could be determined using paramagnetic relaxation spectroscopy. This work illustrates the subtle interplay of electrostatic and hydrophobic interactions in the formation of transient protein complexes. The results are discussed in the context of a model for association on the basis of hydrophobic contacts in the encounter state. PMID- 23984802 TI - Effects of laparoscopic sleeve gastrectomy in patients with morbid obesity and metabolic disorders. AB - PURPOSES: Obesity and its correlation with other pathological conditions determine the onset of the metabolic syndrome, which exposes the patient to a higher risk of major cardiovascular complications. Laparoscopic sleeve gastrectomy (LSG) is a bariatric surgical procedure that appears to influence both the reduction of fat mass and the action of some gastrointestinal hormones. PATIENTS AND METHODS: Between January 2011 and July 2013, 23 patients with morbid obesity underwent LSG and follow-up. In the evaluation of patients, the criteria for metabolic syndrome given by the International Diabetes Federation were followed. A multidisciplinary team of experts evaluated patients before surgery and in subsequent scheduled postoperative visits at 7, 30, 60, and 90 days and 4, 5, 6, 9, and 12 months. Anthropometric and metabolic parameters were analyzed. RESULTS: The mean excess weight loss was 8.57+/-3.02%, 17.65+/-6.40%, 25.47+/ 7.90%, 33.76+/-9.27%, 41.83+/-10.71%, 46.02+/-13.90%, 52.60+/-14.05%, 58.48+/ 16.07%, and 62.59+/-21.29% at 7, 30, 60, and 90 days and 4, 5, 6, 9, and 12 months, respectively. In the same observational period there was an excellent improvement of metabolic indices. None of the patients previously taking prescribed hypoglycemic drugs restarted therapy. Mean fasting plasma glucose significantly decreased compared with the preoperative values. Blood pressure had a statistically significant improvement. Modification in the lipid profile was more variable. During the period of observation 22 of 23 patients reported in this study did not fit the criteria for metabolic syndrome. CONCLUSIONS: Morbid obesity and related diseases may benefit from a surgical approach in selected patients. Randomized controlled trials are needed to evaluate the role of LSG. PMID- 23984803 TI - Risk factors correlated with plantar pressure in Chinese patients with type 2 diabetes. AB - BACKGROUND: Plantar pressure is a key factor for predicting ulceration in the foot of a diabetes patient. SUBJECTS AND METHODS: We recruited a group of 100 Chinese patients with type 2 diabetes and an age-, sex-, weight-, and height matched group of 100 Chinese subjects without diabetes. We obtained plantar pressure data using a Footscan((r)) gait system (RsScan International, Olen, Belgium) when the subjects with and without diabetes walked barefoot across a sensor platform. We recorded the maximum force, maximum pressure, impulse, pressure-time integral, and loading rate from 10 regions of the foot. We collected the data of 11 history-based variables, 10 anthropometric variables, and three metabolic variables regarding the clinical characteristics of the diabetes patients. RESULTS: Weight was identified as a determining factor for high plantar pressure. Height, the Neuropathy Symptom Score (NSS), and ankle brachial index (ABI) were correlated positively with plantar pressure measurements, respectively. The sex, history of ulcer and callus, intima-media membrane of the lower limb blood vessels, and fasting blood glucose (FBG) could also explain a portion of the variability of the plantar pressure measurements. However, the correlations were low or weak. CONCLUSIONS: High plantar pressure in diabetes patients could be predicted, in part, based on weight, height, NSS, ABI, sex, history of ulcer and callus, intima-media membrane of the lower limb blood vessels, and FBG. Therefore, interventions should be taken specifically before high plantar pressure emerges. PMID- 23984804 TI - Agonists of luteinizing hormone-releasing hormone in prostate cancer. AB - INTRODUCTION: Androgen deprivation therapy (ADT) has been the first-line standard of care for treating patients with hormone-sensitive advanced prostate cancer (PCa) for many decades. The agonists of luteinizing hormone-releasing hormone (LHRH), also called gonadotropin-releasing hormone, are still the most frequently used form of medical ADT. AREAS COVERED: This article reviews the available data and most recent information concerning the use of LHRH agonists in advanced PCa. This article also reviews the discovery and development of LHRH agonists and summarizes the clinical evidence for their efficacy in PCa. EXPERT OPINION: The introduction and application of agonists of LHRH has modernized and improved the treatment of advanced PCa. The life-saving benefits of LHRH agonists are well established, yet underestimated. Despite their efficacy, agonists of LHRH have several disadvantages or drawbacks including disease flare. The approach to ADT has been recently further refined with the development of the LHRH antagonist degarelix. Degarelix, a highly clinically effective third-generation LHRH antagonist, is currently available in most countries for therapy of advanced PCa. This new drug offers attractive alternatives to LHRH agonists for treatment of advanced PCa. A therapy for castration-resistant PCa based on a targeted cytotoxic analog of LHRH, AEZS-108, is also emerging. PMID- 23984805 TI - Current concerns of undertreatment and overtreatment in chronic myeloid leukemia based on European LeukemiaNet 2013 recommendations. AB - INTRODUCTION: The aim of this paper is to indicate optimal tyrosine kinase inhibitor (TKI) administration practices based on European LeukemiaNet (ELN) 2013 recommendations for chronic myeloid leukemia (CML). Likewise, current concerns of undertreatment and overtreatment with TKIs during the long-term clinical course of CML will be outlined. AREAS COVERED: Currently available TKIs for the management of CML are reviewed. The survival benefit of TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib) for the CML is excellent. The CML and TKI literature search was made in PubMed with particular focus on the clinical trials, recommendations, guidelines and expert opinions, as well as the ELN CML 2013 recommendations. EXPERT OPINION: Initial TKI treatment for low-risk chronic phase CML is imatinib 400 mg; high-Sokal risk and/or CML patients with complex karyotypic abnormalities would require more powerful second-generation TKIs (dasatinib 100 mg or nilotinib 600 mg). Absence of early molecular response after 6 months, complete cytogenetic response after 12 months and major molecular response after 18 months may require a more powerful TKI switch. If one of the two second-generation TKIs (nilotinib or dasatinib) was used as first-line therapy and failed, the other (dasatinib or nilotinib) could be administered. PMID- 23984806 TI - Effects of canrenone in patients with metabolic syndrome. AB - BACKGROUND: Metabolic syndrome is becoming a common disease due to a rise in obesity rates among adults. OBJECTIVES: The aim was to evaluate the effects of canrenone compared to placebo on metabolic and inflammatory parameters in patients affected by metabolic syndrome. A total of 145 patients were treated with placebo or canrenone, 50 mg/day, for 3 months and then 50 mg b.i.d. till the end of the study. Blood pressure, body weight, body mass index, fasting plasma glucose (FPG), fasting plasma insulin, HOMA-IR, lipid profile, plasma aldosterone, brain natriuretic peptide, high-sensitivity C-reactive protein (Hs CRP), tumor necrosis factor-alpha (TNF-alpha) and M value were evaluated. RESULTS: A decrease of blood pressure was observed in canrenone group compared to baseline; moreover, systolic blood pressure value recorded after 6 months of canrenone therapy was lower than the one recorded with placebo. Canrenone gave a significant decrease of FPI and HOMA index, and an increase of M value both compared to baseline and to placebo. Canrenone also decreased triglycerides and FPG was not observed with placebo. Canrenone also decreased plasma aldosterone, Hs-CRP and TNF-alpha compared to baseline and to placebo. CONCLUSION: Canrenone seems to be effective in reducing some factors involved in metabolic syndrome and in improving insulin-resistance and the inflammatory state observed in these patients. PMID- 23984807 TI - Targeting angiogenesis in renal cell carcinoma. AB - INTRODUCTION: Understanding the molecular pathogenesis of renal cell carcinomas (RCC) has identified targets for therapeutic intervention. The recognition of the importance of hypoxia-inducible factor-1alpha (HIF-1alpha) signaling in the pathogenesis of clear-cell RCC has led to widespread study of angiogenesis inhibitors. While the major component of the angiogenic process in RCC is VEGF, targeting of the mTOR pathway is important because activation of the upstream PI3K/Akt/mTOR signaling pathways is one method by which constitutive HIF-1alpha activation or upregulation occurs. AREAS COVERED: Current FDA-approved anti angiogenic agents as first- and second-line treatment for RCC, as well as agents in development will be reviewed. EXPERT OPINION: Novel agents targeting non-VEGFR signals in kidney cancer will be met with new successes and new challenges in therapeutic development. While several of these agents will likely show activity, they may accentuate toxicity. Careful triage of these agents paired with biomarker studies will facilitate development of these agents and identification of those patients most likely to benefit from these emerging therapies. PMID- 23984808 TI - Correlation between tumor oxygenation and 18F-fluoromisonidazole PET data simulated based on microvessel images. AB - BACKGROUND: Assessing hypoxia with oxygen probes provides a sparse sampling of tumor volumes only, bearing a risk of missing hypoxic regions. Full coverage is achieved with positron emission tomography (PET) using the tracer (18)F fluoromisonidazole (FMISO). In this study, the correlation between different FMISO PET imaging parameters and the median voxel PO2 (medianPO2) was analyzed. A measure of the median PO2 characterizes the microenvironment in consistency with probe measurements. MATERIAL AND METHODS: Tissue oxygenations and FMISO diffusion retention dynamics were simulated. Transport of FMISO and O2 molecules into and out of tissue was modeled by vessel maps derived from histology of head-and-neck squamous cell cancer xenograft tumor lines. Parameter sets were evaluated for 300 distinct 2 * 2 mm(2) vessel configurations, including medianPO2 and two FMISO PET parameters: FH denotes the sub-regional signal four hours post injection (pi) and FH/P denotes the ratio between FH and the time-averaged signal 0-15 min pi. Correlations between O2 and FMISO parameters were evaluated. A receiver operating characteristics (ROC) analysis was performed, regarding the accuracy of FH and FH/P in identifying voxels with medianPO2 < 2.5 mmHg. RESULTS: In hypoxic sub regions, the correlation between FH and medianPO2 is low (R(2) = 0.37), while the correlation between FH/P and median PO2 is high (R(2) = 0.99). The ROC analysis showed that hypoxic regions can be identified using FH/P with a higher diagnostic accuracy (YI = sensitivity+ specificity-1 = 1.0), than using FH alone (YI = 0.83). Both FMISO parameters are moderately effective in identifying hypoxia on the microscopic length scale (YI = 0.63 and 0.60). CONCLUSIONS: A combination of two FMISO PET scans acquired 0-15 min and four hours pi may yield an accurate measure of the medianPO2 in a voxel (FH/P). This measure is comparable to averaged oxygen probe measurements and has the advantage of covering the entire tumor volume. Therefore, it may improve the prediction of radiotherapy outcome and facilitate individualized dose prescriptions. PMID- 23984809 TI - Biology-guided adaptive radiotherapy (BiGART)--more than a vision? PMID- 23984810 TI - Improved quality of computed tomography substitute derived from magnetic resonance (MR) data by incorporation of spatial information--potential application for MR-only radiotherapy and attenuation correction in positron emission tomography. AB - BACKGROUND: Estimation of computed tomography (CT) equivalent data, i.e. a substitute CT (s-CT), from magnetic resonance (MR) images is a prerequisite both for attenuation correction of positron emission tomography (PET) data acquired with a PET/MR scanner and for dose calculations in an MR-only radiotherapy workflow. It has previously been shown that it is possible to estimate Hounsfield numbers based on MR image intensities, using ultra short echo-time imaging and Gaussian mixture regression (GMR). In the present pilot study we investigate the possibility to also include spatial information in the GMR, with the aim to improve the quality of the s-CT. MATERIAL AND METHODS: MR and CT data for nine patients were used in the present study. For each patient, GMR models were created from the other eight patients, including either both UTE image intensities and spatial information on a voxel by voxel level, or only UTE image intensities. The models were used to create s-CT images for each respective patient. RESULTS: The inclusion of spatial information in the GMR model improved the accuracy of the estimated s-CT. The improvement was most pronounced in smaller, complicated anatomical regions as the inner ear and post-nasal cavities. CONCLUSIONS: This pilot study shows that inclusion of spatial information in GMR models to convert MR data to CT equivalent images is feasible. The accuracy of the s-CT is improved and the spatial information could make it possible to create a general model for the conversion applicable to the whole body. PMID- 23984811 TI - Time-resolved dose reconstruction by motion encoding of volumetric modulated arc therapy fields delivered with and without dynamic multi-leaf collimator tracking. AB - BACKGROUND: Organ motion during treatment delivery in radiotherapy (RT) may lead to deterioration of the planned dose, but can be mitigated by dynamic multi-leaf collimator (DMLC) tracking. The purpose of this study was to implement and experimentally validate a method for time-resolved motion including dose reconstruction for volumetric modulated arc therapy (VMAT) treatments delivered with and without DMLC tracking. MATERIAL AND METHODS: Tracking experiments were carried out on a linear accelerator (Trilogy, Varian) with a prototype DMLC tracking system. A motion stage carrying a biplanar dosimeter phantom (Delta4PT, Scandidos) reproduced eight representative clinical tumor trajectories (four lung, four prostate). For each trajectory, two single-arc 6 MV VMAT treatments with low and high modulation were delivered to the moving phantom with and without DMLC tracking. An existing in-house developed program that adds target motion to treatment plans was extended with the ability to split an arc plan into any number of sub-arcs, allowing the calculated dose for different parts of the treatment to be examined individually. For each VMAT sub-arc, reconstructed and measured doses were compared using dose differences and 3%/3 mm gamma-tests. RESULTS: For VMAT sub-arcs the reconstructed dose distributions had a mean root mean-square (rms) dose difference of 2.1% and mean gamma failure rate of 2.0% when compared with the measured doses. For final accumulated doses the mean rms dose difference was 1.6% and the gamma failure rate was 0.7%. CONCLUSION: The time-resolved motion including dose reconstruction was experimentally validated for complex tracking and non-tracking treatments with patient-measured tumor motion trajectories. The reconstructed dose will be of high value for evaluation of treatment plan robustness facing organ motion and adaptive RT. PMID- 23984812 TI - Dynamic (18)F-FDG-PET for monitoring treatment effect following anti-angiogenic therapy in triple-negative breast cancer xenografts. AB - INTRODUCTION: Dynamic (18)F-FDG PET allows the study of glucose distribution in tissues as a function of time and space. Using pharmacokinetics, the temporal uptake pattern of (18)F-FDG may be separated into components reflecting perfusion and metabolism. Bevacizumab is an angiogenesis inhibitor which prevents the growth of new blood vessels, and may potentially lead to normalization of the blood circulation in the tumor. The purpose of the study was to explore the use of dynamic PET as a tool for monitoring treatment effect, reflected by changes in perfusion and metabolism. MATERIALS AND METHODS: Twelve athymic nude mice, bearing the bilateral triple-negative human breast cancer xenograft MAS98.12 were treated with bevacizumab (5 mg/kg i.p.). Dynamic PET data was acquired prior to and 24 and 72 hours after treatment for 1 hour after injection of 10 MBq (18)F FDG and fitted with a FDG two-tissue compartment model. The changes in the rate constants k1, k3, MRFDG and the vascular fraction nuB were assessed. To evaluate the effect of treatment regimes, 30 mice, randomized in 5 groups, received either vehicle (0.9% NaCl), bevacizumab (5 mg/kg i.p.), doxorubicin (8 mg/kg i.v.) or bevacizumab and doxorubicin either together, or doxorubicin 24 hours after bevacizumab treatment. Tumor volume was measured twice a week. RESULTS: The perfusion-related rate parameter k1 and the metabolic rate constant k3 decreased significantly 24 hours after treatment. This decrease was followed by an increase, albeit non-significant, at 72 hours post treatment. Doxorubicin given 24 hours after bevacizumab showed less antitumor effect compared to concomitant treatment. CONCLUSIONS: Dynamic PET can detect changes in tumor perfusion and metabolism following anti-angiogenic therapy in mouse xenograft models. Longitudinal dynamic PET, used to assess the efficacy of anti-angiogenic treatment, can identify the time frame of potential tumor vasculature re normalization and allow optimal timing of supplementary therapy (radiation or chemotherapy). PMID- 23984813 TI - Potential position errors using fiducial markers for gated image guided radiotherapy. AB - BACKGROUND: Fiducials can be used as surrogate for target position during radiotherapy. However, fiducial motion could lead to potential position errors when using fiducials in four-dimensional computed tomography (4DCT) treatment planning and for gated image guided radiotherapy (IGRT). MATERIAL AND METHODS: One gold marker (GM) and 5, 10 and 15 mm nickel-titanium (NiTi) stents were inserted in a moving phantom for the purpose of fiducial detection in 4DCT and gated IGRT. Fiducial position errors in 4DCT and BrainLAB's gated IGRT were defined as residuals between fiducial detection and the actual physical position at the instance of image acquisition. RESULTS: Fiducials position errors correlate to speed, fiducial type and orientation during 4DCT acquisition. Lower detection accuracy was measured for the 5 mm NiTi-stent relative to the 10 and 15 mm NiTi stents and GM. Fiducials with orientation 45 degrees relative to the scan direction showed a lower detection accuracy relative to parallel and perpendicular orientations. The standard deviation of position errors in 4DCT were up to 2.2 mm with a maximum deviation of 4.0 mm. Using BrainLAB's gated IGRT the fiducials were detected with a standard deviation of 0.6 mm and a maximum deviation of 1.9 mm. For gated IGRT no correlation to fiducial speed was found. CONCLUSIONS: Clinical use of fiducials in combination with treatment planning on mid-ventilation CT phase for moving target should include margins up to 5.5 mm due to potential systematic position errors. PMID- 23984814 TI - Invasive adenocarcinoma arising from a mixed hyperplastic/adenomatous polyp and synchronous transverse colon cancer. AB - An admixture of hyperplastic and adenomatous components within the same polyp is unusual. Adenocarcinoma arising from a mixed hyperplastic/adenomatous polyp (MHAP) occurs even more rarely. We report the first case of a 59-year-old male who presented with invasive adenocarcinoma originating from a MHAP at a sigmoid colon and synchronous transverse colon cancer. PMID- 23984815 TI - Do practitioners and friends support patients with coronary heart disease in lifestyle change? a qualitative study. AB - BACKGROUND: Healthy lifestyles help to prevent coronary heart disease (CHD) but outcomes from secondary prevention interventions which support lifestyle change have been disappointing. This study is a novel, in-depth exploration of patient factors affecting lifestyle behaviour change within an intervention designed to improve secondary prevention for patients with CHD in primary care using personalised tailored support. We aimed to explore patients' perceptions of factors affecting lifestyle change within a trial of this intervention (the SPHERE Study), using semi-structured, one-to-one interviews, with patients in general practice. METHODS: Interviews (45) were conducted in purposively selected general practices (15) which had participated in the SPHERE Study. Individuals, with CHD, were selected to include those who succeeded in improving physical activity levels and dietary fibre intake and those who did not. We explored motivations, barriers to lifestyle change and information utilised by patients. Data collection and analysis, using a thematic framework and the constant comparative method, were iterative, continuing until data saturation was achieved. RESULTS: We identified novel barriers to lifestyle change: such disincentives included strong negative influences of social networks, linked to cultural norms which encouraged consumption of 'delicious' but unhealthy food and discouraged engagement in physical activity. Findings illustrated how personalised support within an ongoing trusted patient-professional relationship was valued. Previously known barriers and facilitators relating to support, beliefs and information were confirmed. CONCLUSIONS: Intervention development in supporting lifestyle change in secondary prevention needs to more effectively address patients' difficulties in overcoming negative social influences and maintaining interest in living healthily. PMID- 23984816 TI - Comparative profiling of N-glycans isolated from serum samples of ovarian cancer patients and analyzed by microchip electrophoresis. AB - Ovarian cancer is the fifth leading cause of cancer-related mortalities for women in the United States and the most lethal gynecological cancer. Aberrant glycosylation has been linked to several human diseases, including ovarian cancer, and accurate measurement of changes in glycosylation may provide relevant diagnostic and prognostic information. In this work, we used microchip electrophoresis coupled with laser-induced fluorescence detection to determine quantitative differences among the N-glycan profiles of control individuals and late-stage recurrent ovarian cancer patients prior to and after an experimental drug treatment that combined docetaxel and imatinib mesylate. N-Glycans were enzymatically released from 5-MUL aliquots of serum samples, labeled with the anionic fluorescent tag, 8-aminopyrene-1,3,6-trisulfonic acid, and analyzed on microfluidic devices. A 22-cm long separation channel, operated at 1250 V/cm, generated analysis times less than 100 s, separation efficiencies up to 8 * 10(5) plates (3.6 * 10(6) plates/m), and migration time reproducibilities better than 0.1% relative standard deviation after peak alignment. Principal component analysis (PCA) and analysis of variance (ANOVA) tests showed significant differences between the control and both pre- and post-treatment cancer samples and subtle differences between the pre- and post-treatment cancer samples. Area under-the-curve (AUC) values from receiver operating characteristics (ROC) tests were used to evaluate the diagnostic merit of N-glycan peaks, and specific N glycan peaks used in combination provided AUCs > 0.90 (highly accurate test) when the control and pretreatment cancer samples and control and post-treatment samples were compared. PMID- 23984817 TI - Self-destructing "mothership" capsules for timed release of encapsulated contents. AB - We describe a new class of hierarchical containers that are formed via single step assembly and, at a later time, self-destruct because of their packaged contents. These containers are spherical capsules formed by electrostatic complexation of the anionic biopolymer, gellan gum, with the cationic biopolymer, chitosan. The capsules are termed "motherships" and are engineered to carry a cargo of much smaller containers (e.g., nanoscale liposomes ("babyships")), within their lumen. Additionally, we package an enzyme, chitosanase, in the capsule that is capable of degrading polymeric chitosan into short oligomers. Thereby, we create motherships that self-destruct, liberating their cargo of babyships into the external solution. The time scale for self-destruction can be engineered based on the internal concentration of enzyme. The motherships are stable when stored in a freeze-dried form and can be readily dispersed into water or buffer solutions at a later time, whereupon their "internal clock" for self destruction is initiated. The above concept could be useful for the triggered release of a variety of payloads including drugs, biological therapeutics, cosmetics, and flavor ingredients. PMID- 23984818 TI - Long-wavelength, photostable, two-photon excitable BODIPY fluorophores readily modifiable for molecular probes. AB - Near-infrared (NIR) fluorescent probes are increasingly popular in biological imaging and sensing, as long-wavelength (650-900 nm) excitation and emission have the advantages of minimum photodamage, deep tissue penetration, and minimum interference from autofluorescence in living systems. Here, a series of long wavelength BODIPY dyes SPC, DC-SPC, DPC, and DC-DPC are synthesized conveniently and efficiently. They exhibit excellent photophysical properties in far red to near-infrared region, including large extinction coefficients, high fluorescence quantum yields, good photostability, and reasonable two-photon absorption cross section. Comparison of single-molecular imaging confirms that DPC is a much more efficient and more photostable NIR fluorophore than the commonly used Cy5. Also importantly, two kinds of convenient functionalization sites have been reserved: the aryl iodide for organometallic couplings and the terminal alkyne groups for click reactions. Further derivatives DC-SPC-PPh3 exhibit specificity to localize in mitochondria. The introduction of triphenylphosphonium (TPP) moieties mediates its hydrophilic-lipophilic balance and makes DC-SPC-PPh3 appropriate for cell labeling. Their long-wavelength emission at ~650 nm can efficiently avoid the spectral crosstalk with other probes emitting in the visible light region. Superior photostability, low cytotoxicity, and two-photon excitable properties demonstrate its utility as a standard colocalizing agent to estimate the other probes' local distribution. PMID- 23984820 TI - Assessment of the American Medical Association guide to the evaluation of binaural hearing impairment. AB - OBJECTIVE: To assess the American Medical Association (AMA) guide to the evaluation of binaural hearing impairment (BHI) as a procedure for estimating severity of hearing loss from audiograms. DESIGN: The BHIs of Australian war veterans were calculated from their hearing threshold levels (HTLs) and compared with their scores on a hearing questionnaire, the hearing measurement scale (HMS). STUDY SAMPLE: The HTLs of 282 Australian war veterans were measured at frequencies from 0.25 to 8 kHz and scores on the HMS were obtained from 154 of those veterans. RESULTS: No grounds could be found for altering the frequencies included in the average HTL or the high fence of 92 dB HL used in calculating the monaural hearing impairments (MHIs) of the veterans, and no grounds could be found for altering the ratio of 5:1 used in determining the BHI from the MHIs of the better and worse ears. However, agreement between HMS score and BHI was improved by reducing the low fence used in calculating MHI from 25 to 15 dB HL. CONCLUSION: A modified version of BHI provided an improved procedure for estimating severity of hearing loss from audiograms but would not be suitable for compensation purposes. PMID- 23984819 TI - Focal amplification of HOXD-harboring chromosome region is implicated in multiple walled carbon nanotubes-induced carcinogenicity. AB - Multiple-walled carbon nanotubes (MWCNTs) may cause carcinogenesis. We found that long-term exposure to MWCNTs can induce irreversible oncogenic transformation of human bronchial epithelial cells and tumorigenicity in vivo. A genome-wide array comparative genomic hybridization (aCGH) analysis revealed global chromosomal aberration in MWCNTs-treated clones, predominantly at chromosome 2q31-32, where the potential oncogenes HOXD9 and HOXD13 are located. Functional assays confirmed that this variation can modulate oncogenic signaling and plays a part in MWCNTs induced tumorigenesis, suggesting that MWCNTs are carcinogens that act by altering genomic stability and oncogenic copy numbers. PMID- 23984822 TI - Analysis of BRCA1 and mtDNA haplotypes and mtDNA polymorphism in familial breast cancer. AB - Mitochondrial DNA (mtDNA) defects have been postulated to play an important role in the modulation and/or progression of cancer. In the past decade, a wide spectrum of mtDNA variations have been suggested as potentially sensitive and specific biomarkers for several human cancer types. In this context, single nucleotide polymorphisms (SNPs) described as protective or risk variants have been published, in particular in breast cancer, though not without controversy. Moreover, many mtDNA haplogroups have been associated with different phenotypes and diseases. We genotyped 18 SNPs, 15 of them defining European mtDNA haplogroups, including SNPs described as protective or risk variants, 7 SNPs that determine BRCA1 haplotypes and a BRCA1 intron 7 polymorphism. We included in this study 90 Caucasian unrelated women with breast cancer with familial criteria and 96 controls. Our aim was to clarify the importance of any of these SNPs, mitochondrial haplogroups and BRCA1 haplotypes in the modulation of breast cancer. We detected no significant differences in the distribution of BRCA1 haplotypes between patients and controls. Haplogroup U and the 12308G variant of mtDNA were overrepresented within the control group (p = 0.005 and p = 0.036, respectively) compared to breast cancer. Finally, we identified a significant association between the BRCA1 intron 7 polymorphism and BRCA1 haplotypes. Specifically, (TTC)6/6 and (TTC)6/7 genotypes with the seven polymorphic site cassette of "H2-like" haplotypes, and the (TTC)7/7 genotype associated with the "H1-like" haplotypes (p < 0.001). PMID- 23984821 TI - CXCL12 inhibits cortical neuron apoptosis by increasing the ratio of Bcl-2/Bax after traumatic brain injury. AB - CXCL12 and its physiologic receptor CXCR4 are involved in controlling cell survival, proliferation and migration in adult tissues. This study aimed to investigate the effects of CXCL12 on cortical neuron apoptosis in rats after traumatic brain injury (TBI) and the potential mechanisms involved. At 3 days after TBI, in situ terminal transferase d-UTP nick-end labeling assay (TUNEL) showed that the apoptotic index (AI) deceased significantly in the CXCL12 treatment group compared with the control group (p < 0.05). Immunofluorescence double-labeled staining revealed that most of the TUNEL positive cells were NeuN positive neurons. The change trends of active caspase-3 expression were similar as those of the AI. The Bcl-2:Bax ratio was upregulated in the CXCL12 group compared with the control group. However, the effect of CXCL12 could be partially reverted by the additional use of AMD3100 (a kind of antagonist of CXCR4) (p < 0.05). Our results indicated that after TBI in rats CXCL12 combing CXCR4 receptors could inhibit the caspase-3 pathway by upregulating Bcl-2:Bax ratio, which protect neurons from apoptosis. PMID- 23984823 TI - Complete mitochondrial genome of Canis lupus campestris. AB - In this study, blood sample was obtained from a female Mongolian wolf (Canis lupus campestris) captured from Mongolia and its complete mitochondrial genome was sequenced for the first time. PMID- 23984824 TI - 4-Phenyl-alpha-cyanocinnamic acid amide: screening for a negative ion matrix for MALDI-MS imaging of multiple lipid classes. AB - Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) has become a method of choice in lipid analysis, as it provides localization information for defined lipids that is not readily accessible with nonmass spectrometric methods. Most current MALDI matrices have been found empirically. Nevertheless, preferential matrix properties for many analyte classes are poorly understood and may differ between lipid classes. We used rational matrix design and semiautomated screening for the discovery of new matrices suitable for MALDI IMS of lipids. Utilizing Smartbeam- and nitrogen lasers for MALDI, we systematically compared doubly substituted alpha-cyanocinnamic acid derivatives (R(1)-CCA-R(2)) with respect to their ability to serve as negative ion matrix for various brain lipids. We identified 4-phenyl-alpha-cyanocinnamic acid amide (Ph CCA-NH2) as a novel negative ion matrix that enables analysis and imaging of various lipid classes by MALDI-MS. We demonstrate that Ph-CCA-NH2 displays superior sensitivity and reproducibility compared to matrices commonly employed for lipids. A relatively small number of background peaks and good matrix suppression effect could make Ph-CCA-NH2 a widely applicable tool for lipid analysis. PMID- 23984825 TI - Protective effects of farrerol against hydrogen-peroxide-induced apoptosis in human endothelium-derived EA.hy926 cells. AB - Vascular endothelium plays an important role in the physiological homeostasis of blood vessels. Endothelial injury is considered to be implicated in the pathogenesis of many cardiovascular diseases, including atherosclerosis. Farrerol, a flavonoid considered to be the major bioactive component in a traditional Chinese herb, "Man-shan-hong", which is the dried leaves of Rhododendron dauricum L., displays many bioactive properties, including antibechic, antibacterial, anti-inflammatory, and the inhibition of vascular smooth muscle cell (VSMC) proliferation. In this study, the protective effects of farrerol on hydrogen peroxide (H2O2)-induced apoptosis in human endothelium derived EA.hy926 cells were investigated. The results showed that farrerol significantly inhibited the loss of cell viability and enhanced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in H2O2-induced EA.hy926 cells. Meanwhile, farrerol inhibited H2O2-induced elevation in the levels of intracellular malondialdehyde and reactive oxygen species, as well as cell apoptosis. Furthermore, real time RT-PCR and Western blot analysis showed that farrerol significantly decreased the expression of Bax mRNA, Bax, cleaved caspase-3, and phosph-p38 MAPK, while increasing the exporession of Bcl-2 mRNA and Bcl-2 in H2O2-induced EA.hy926 cells. These results are the first demonstration that farrerol has protective effects against H2O2-induced apoptosis in EA.hy926 cells, and suggests that farrerol is a potential candidate for the intervention of endothelial-injury-associated cardiovascular diseases. PMID- 23984827 TI - Interface traps and quantum size effects on the retention time in nanoscale memory devices. AB - Based on the analysis of Poisson equation, an analytical surface potential model including interface charge density for nanocrystalline (NC) germanium (Ge) memory devices with p-type silicon substrate has been proposed. Thus, the effects of Pb defects at Si(110)/SiO2, Si(111)/SiO2, and Si(100)/SiO2 interfaces on the retention time have been calculated after quantum size effects have been considered. The results show that the interface trap density has a large effect on the electric field across the tunneling oxide layer and leakage current. This letter demonstrates that the retention time firstly increases with the decrease in diameter of NC Ge and then rapidly decreases with the diameter when it is a few nanometers. This implies that the interface defects, its energy distribution, and the NC size should be seriously considered in the aim to improve the retention time from different technological processes. The experimental data reported in the literature support the theoretical expectation. PMID- 23984826 TI - Prevalence of adenovirus in children with acute respiratory tract infection in Lanzhou, China. AB - BACKGROUND: Human adenovirus (HAdV) is an important agent causing respiratory tract infection in children. Information on the epidemiological and clinical features of HAdV is limited in children with acute respiratory tract infections (ARTIs) in China, especially those of a novel genotype, Ad55. METHODS: In total, 1169 nasopharyngeal aspirates were collected from children younger than 14 years with ARTIs between November 2006 and November 2009. The polymerase chain reaction (PCR) was used to screen HAdVs. All PCR-positive products were sequenced. RESULTS: 74 of 1169 (6.33%) specimens were positive for HAdVs. Among positive cases, AdV3 (58/74) was detected most frequently, followed by AdV11 (10/74), AdV2 (2/74), AdV7 (2/69), AdV6 (1/74), and AdV1 (1/74). AdV55 was found in one case. The incidence of HAdV infection peaked in children aged 3-7 years. The most common clinical diagnosis was upper respiratory infection, and the most common syndrome was fever and cough.The comparison of HAdV and RSV group revealed that Children infected with group AdV were significant older than children infected with group RSV, had more fever but less frequently wheezing, and cough, crackles, and cyanosis, The duration of hospitalization between the AdV group and RSV group was not significant, but a greater frequency of LRTIs was observed in RSV group. CONCLUSIONS: HAdV is an important viral agent in children with ARTIs in Lanzhou City, China. Multiple HAdV serotypes co-circulated with Ad3, which was predominant in this 3-year study. The novel AdV55 genotype was found in one case. No fixed seasonal rhythm could be identified. PMID- 23984828 TI - Thermal deactivation kinetics of Pseudomonas fluorescens lipase entrapped in AOT/isooctane reverse micelles. AB - Thermostability of the lipase (EC 3.1.1.3) was found to be increased by the enzyme-entrapment in 50 mM AOT/isooctane reverse micelles. The half-life (15.75 h) of Pseudomonas fluorescens lipase entrapped in reverse micelles at 70 degrees C was 9.72- and 11.41-fold longer than those solubilized in a glycerol pool or in 10 mM phosphate buffer (pH 8.0), respectively. The enzyme deactivation model considering a two-step series-type was employed, and deactivation constants for the second step (k2) at all temperatures were drastically decreased after the lipase was entrapped in reverse micelles. In particular, k2 (0.0354 h-1) at 70 degrees C in reverse micelles was 12.33- and 13.14-fold lower than in a glycerol pool or in the phosphate buffer, respectively. The deactivation energies (from k1, k2) for the lipase entrapped in the reverse micelles, solubilized in a glycerol pool, or in the aqueous buffer were 7.51, 26.35 kcal/mol, 5.93, 21.08 kcal/mol, and 5.53, 17.57 kcal/mol, respectively. PMID- 23984829 TI - Drug analogs of COX-2 selective inhibitors lumiracoxib and valdecoxib derived from in silico search and optimization. AB - The medicinal activity of COX-2 inhibitors are sufficiently beneficial to urge the search for new drug designs. This study presents 16 analogs of lumiracoxib and 10 analogs to valdecoxib having properties suitable as COX-2 inhibitors. For lumiracoxib analogs the mean Log P, polar surface area, and formula weight are 3.00, 70.46 A(2), and 276.60, respectively. For valdecoxib analogs the mean Log P, polar surface area, and formula weight are 3.65, 68.46 A(2), and 322.32, respectively. Grubb's test analysis of seven properties for seven known COX-2 selective inhibitors and those of 26 analog compounds indicated no outliers. The unpaired t-test compared Log P and polar surface area of seven known COX-2 inhibitors to all 26 analogs and found no difference. All 26 analogs showed no violation of the Rule of 5, this being an indicator of favorable bioavailability. Hierarchical cluster analysis by single linkage indicated lumiracoxib is most similar to analogs 2, 4, 5, 6, 7, 9, 10, 11, 14, 15, 16, and 17. Valdecoxib has highest similarity to analogs 8, 19, 21, 22, 23, 26, 27, and 28. Multiple regression analysis successfully produced equations for prediction of similar compounds to lumiracoxib and valdecoxib. Path analysis indicated that number of atoms, oxygen & nitrogen atoms, and Log P are the greatest determinants for formula weight for known COX-2 inhibitors. Criteria for molecular properties is established for identifying COX-2 inhibitors. These 26 analogs show much potential for active COX-2 inhibition. PMID- 23984830 TI - A multicentre, double-blind, randomised, controlled, parallel-group study of the effectiveness of a pharmacist-acquired medication history in an emergency department. AB - BACKGROUND: Admission to an emergency department (ED) is a key vulnerable moment when patients are at increased risk of medication discrepancies and medication histories are an effective way of ensuring that fewer errors are made. This study measured whether a pharmacist-acquired medication history in an ED focusing on a patient's current home medication regimen, and available to be used by a doctor when consulting in the ED, would reduce the number of patients having at least 1 medication discrepancy related to home medication. METHODS: This multicentre, double-blind, randomised, controlled parallel-group study was conducted at 3 large teaching hospitals. Two hundred and seventy participants were randomly allocated to an intervention (n = 134) or a standard care (n = 136) arm. All consecutive patients >18 years old admitted through the ED were eligible. The intervention consisted of pharmacists conducting a standardised comprehensive medication history interview focusing on a patient's current home medication regimen, prior to being seen by a doctor. Data recorded on the admission medication order form was available to be used by a doctor during consultation in the ED. The admission medication order form was given to doctors at a later stage in the control arm for them to amend prescriptions. The effect of the intervention was assessed primarily by comparing the number of patients having at least 1 admission medication discrepancy regarding medication being taken at home. Secondary outcomes concerned the characteristics and clinical severity of such medication discrepancies. RESULTS: The intervention reduced discrepancies occurring by 33% (p < 0.0001; 0.1055 odds ratio, 0.05-0.24 95% confidence interval), despite recall bias. Regarding total discrepancies, omitting medication occurred most frequently (55.1%) and most discrepancies (42.7%) were judged to have the potential to cause moderate discomfort or clinical deterioration. CONCLUSIONS: A pharmacist-acquired medication history in an ED focusing on a patient's current home medication regimen available to be used by a doctor at the time of consulting in the ED reduced the number of patients having at least 1 home medication-related discrepancy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN63455839. PMID- 23984831 TI - 'It's in the eyes': how family members and care staff understand awareness in people with severe dementia. AB - OBJECTIVES: In this study, we explored how family members and care staff understand awareness in people with severe dementia and what this awareness means to them. METHOD: We conducted four focus groups between 2007 and 2009 in the UK with 11 family members and 12 care staff. Transcripts of the focus groups were analysed using thematic analysis. RESULTS: A model of awareness emerged in which the perceived level of awareness in the person with dementia was influenced by an interaction between attributes of the person with dementia and the environment, with expressions of awareness being hindered by environmental factors and facilitated through appropriate stimulation. Awareness did fluctuate, and differences in interpretations of awareness were linked to the meaning assigned to particular kinds of responses. For family members, awareness was intrinsically linked to their emotional connection with the person with dementia. For care staff, identifying signs of awareness helped them to do their job and enabled them to feel that they had connected with the person with dementia. CONCLUSION: The findings of this study suggest that care staff would benefit from training both on identifying awareness and on providing suitable activities for people with severe dementia. Care staff and family members would also benefit from greater sharing of information about the person with dementia. This could help to enhance quality of life for person with dementia and improve quality of care. PMID- 23984832 TI - Quantitative fluorescent detection of pyrophosphate with quinoline-ligated dinuclear zinc complexes. AB - Dinuclear zinc complex [Zn2(TQHPN)(AcO)](2+) exhibits characteristic fluorescence response (lambdaex = 317 nm and lambdaem = 455 nm) toward pyrophosphate (PPi) with maximum fluorescence upon 1:1 Zn2(TQHPN)-PPi complex formation. The crystallographic investigation utilizing P(1)P(2)-Ph2PPi revealed that the fluorescent response mechanism is due to intramolecular excimer formation of two quinoline rings. PMID- 23984833 TI - The impact of breed and tissue compartment on the response of pig macrophages to lipopolysaccharide. AB - BACKGROUND: The draft genome of the domestic pig (Sus scrofa) has recently been published permitting refined analysis of the transcriptome. Pig breeds have been reported to differ in their resistance to infectious disease. In this study we examine whether there are corresponding differences in gene expression in innate immune cells RESULTS: We demonstrate that macrophages can be harvested from three different compartments of the pig (lungs, blood and bone-marrow), cryopreserved and subsequently recovered and differentiated in CSF-1. We have performed surface marker analysis and gene expression profiling on macrophages from these compartments, comparing twenty-five animals from five different breeds and their response to lipopolysaccharide. The results provide a clear distinction between alveolar macrophages (AM) and monocyte-derived (MDM) and bone-marrow-derived macrophages (BMDM). In particular, the lung macrophages express the growth factor, FLT1 and its ligand, VEGFA at high levels, suggesting a distinct pathway of growth regulation. Relatively few genes showed breed-specific differential expression, notably CXCR2 and CD302 in alveolar macrophages. In contrast, there was substantial inter-individual variation between pigs within breeds, mostly affecting genes annotated as being involved in immune responses. CONCLUSIONS: Pig macrophages more closely resemble human, than mouse, in their set of macrophage expressed and LPS-inducible genes. Future research will address whether inter individual variation in macrophage gene expression is heritable, and might form the basis for selective breeding for disease resistance. PMID- 23984835 TI - Weekday and weekend patterns of physical activity and sedentary time among Liverpool and Madrid youth. AB - Levels of physical inactivity and sedentary behaviour among English and Spanish youth are high and vary within different regions of each country. Little though is known about these during specific periods of the day. The purpose of this study was to describe physical activity (PA) and sedentary time during segments of the day and week, and compare these critical contexts between youth in the Liverpool and Madrid areas of England and Spain, respectively. PA was objectively assessed in 235 Liverpool- and 241 Madrid youth (aged 10-14 years) who wore accelerometers for seven consecutive days. Minutes of sedentary time, moderate PA, vigorous PA and moderate-to-vigorous physical activity (MVPA) were calculated for weekdays, weekend days, school time, non-school time and after-school. Between-country differences were analysed using analysis of covariance (ANCOVA). Madrid youth spent significantly more time in sedentary activities than their Liverpool counterparts. Madrid youth engaged in more minutes of moderate intensity physical activity (MPA) than Liverpool youth during weekdays, school time and non-school time (P<0.01). Liverpool children recorded more time in vigorous physical activity (VPA) than Madrid peers during week days and weekend days (P<0.01) and during school time and after-school periods (P<0.01). The MVPA was significantly higher among Madrid youth during non-school time (P<0.01). Around 25% of all youth achieved recommended levels of MVPA. Low levels of MVPA and systematic differences in sedentary time, MPA and VPA exist between Liverpool and Madrid youth. Interventions targeted at the least-active children during weekends, after-school and non-school periods within the cultural contexts common to each city are required. PMID- 23984834 TI - Conservation of apolipoprotein A-I's central domain structural elements upon lipid association on different high-density lipoprotein subclasses. AB - The antiatherogenic properties of apolipoprotein A-I (apoA-I) are derived, in part, from lipidation-state-dependent structural elements that manifest at different stages of apoA-I's progression from lipid-free protein to spherical high-density lipoprotein (HDL). Previously, we reported the structure of apoA-I's N-terminus on reconstituted HDLs (rHDLs) of different sizes. We have now investigated at the single-residue level the conformational adaptations of three regions in the central domain of apoA-I (residues 119-124, 139-144, and 164-170) upon apoA-I lipid binding and HDL formation. An important function associated with these residues of apoA-I is the activation of lecithin:cholesterol acyltransferase (LCAT), the enzyme responsible for catalyzing HDL maturation. Structural examination was performed by site-directed tryptophan fluorescence and spin-label electron paramagnetic resonance spectroscopies for both the lipid-free protein and rHDL particles 7.8, 8.4, and 9.6 nm in diameter. The two methods provide complementary information about residue side chain mobility and molecular accessibility, as well as the polarity of the local environment at the targeted positions. The modulation of these biophysical parameters yielded new insight into the importance of structural elements in the central domain of apoA-I. In particular, we determined that the loosely lipid-associated structure of residues 134-145 is conserved in all rHDL particles. Truncation of this region completely abolished LCAT activation but did not significantly affect rHDL size, reaffirming the important role of this structural element in HDL function. PMID- 23984836 TI - Alcohol addiction: toward a patient-oriented pharmacological treatment. AB - Very few medications (i.e., disulfiram, naltrexone and acamprosate) are approved for the treatment of alcoholism and their effects are suboptimal. The development of new effective and safe pharmacological agents to treat alcoholic patients is crucial, together with the need to identify predictors of outcomes in different subsets of patients. PMID- 23984837 TI - Gregarines infecting Ischnura spp. in Texas, U.S.A., including description of Septemlaterospora rasberryi n. gen. n. sp. (Apicomplexa: Actinocephalidae: Acanthosporinae) and revision of Steganorhynchus dunwoodyi (Apicomplexa: Actinocephalidae: Menosporinae). AB - Septemlaterospora rasberryi n. gen. n. sp. (Apicomplexa: Eugregarinida: Actinocephalidae: Acanthosporinae) is described from adults of Ischnura ramburii (Odonata: Zygoptera: Coenagrionidae). Septemlaterospora n. gen is distinguished by the form of the oocysts: terminally truncated heptagonal bipyramids bearing 7 equatorial spines, 1 at each equatorial vertex, 7 terminal spines obliquely inserted at each pole, 1 at each vertex created by polar truncation; 21 spines total. The holdfast is compound, comprising a terminal epimerite and intercalating diamerite; epimerite is a thick disk or linearly crateriform sucker; diamerite is short (less than half of the total holdfast length) and very broadly obdeltoid. Association occurs immediately before syzygy and is cephalolateral and biassociative. Gametocysts are spherical with a conspicuous hyaline coat. Lacking conspicuous sporoducts, they dehisce by simple rupture. Steganorhynchus dunwoodyi is redescribed utilizing a new complete taxonomic data set, consisting of a larger set of metric characters and based on uniformly prepared, permanent specimens. New host and geographic records are reported for Calyxocephalus karyopera, Domadracunculus janovyi, Nubenocephalus secundus, and Steganorhynchus dunwoodyi, and the type host of D. janovyi is amended. PMID- 23984838 TI - Simultaneous laparoscopic splenectomy and right hemihepatectomy for littoral cell angiosarcoma accompanied with liver metastases. AB - Despite the wide acceptance of laparoscopic resection for treatment of abdominal tumors, only few cases of simultaneous laparoscopic removal of the spleen and the right liver have been reported to date. Littoral cell angiosarcoma (LCAS), which arises from the littoral cells lining the sinus channels of the splenic red pulp, is a rare condition, and there is limited literature on littoral cell angiosarcoma with liver metastases. We present the case of a 28-year-old woman with postoperative pathologically-proven LCAS with right liver metastases. The patient's surgery was safely performed, and her postoperative course was uneventful until now. This case suggests that concomitant laparoscopic splenectomy (LS) and right hemihepatectomy is a suitable surgical option for selected patients. PMID- 23984839 TI - Do rural and remote areas really have limited accessibility to health care? Geographic analysis of dialysis patients in Hiroshima, Japan. AB - INTRODUCTION: For an equitable distribution of health resources, resource allocation policies focus on rural and also remote areas, assuming that these areas are underserved. However, definitions of 'rural' and 'remote' vary, and are not necessarily synonymous with 'underserved'. This Japanese study evaluated the association between the rurality/remoteness of the community in which a patient lives and his/her geographic accessibility to dialysis facilities. METHODS: Based on 1867 communities (census blocks) in Hiroshima Prefecture, Japan, predictive powers of five community-level rural/remote parameters (population size, population density, elderly rate, agriculture rate, and distance to the nearest city) were evaluated to identify communities where dialysis patients had a longer commute time to dialysis facilities. The proportion of low-access communities was examined when those communities were merged to form larger geographic units (four level stepwise merger). One-way driving times of dialysis patients were used as the access parameter of a community and were calculated using geographic information systems based on the addresses of all the 7374 patients certified by municipalities as having renal disability, and on the addresses and capacities of all 98 dialysis facilities in Hiroshima. RESULTS: The average driving time was negatively correlated with population and population density, and positively correlated with elderly rate, agriculture rate, and distance to nearest city. When low-access was defined as >20, >30 & >40 min driving time, all rural/remote parameters showed better sensitivities (range 63.5-94.9%) than specificities (55.2-77.9%) to identify low-access communities, and positive predictive values were less than 50% for most parameters. When low-access was defined as >30 min driving time, the proportion of low-access communities substantially decreased when the geographic unit was expanded. In the administrative 'rural' area, the largest geographic unit, the percentage of low-access communities was 30%. CONCLUSIONS: In any definition of 'rural/remote', and in any definition of 'low access', the rural/remote areas contain a substantial proportion of high-access communities. In addition, a substantial proportion of low-access communities was excluded from rural/remote areas. The accuracy of the term 'low-access' deteriorated when the geographic unit of analysis was expanded. In order to identify underserved areas precisely, it is necessary to set the geographic unit of analysis as small as possible and measure the geographic accessibility itself, rather than designate some areas as 'rural' or 'remote', based on conventional geographic/demographic/distance parameters. PMID- 23984840 TI - Cluster randomized, controlled trial on patient safety improvement in general practice: a study protocol. AB - BACKGROUND: An open, constructive safety culture is key in healthcare since it is seen as a main condition for patient safety. Studies have examined culture improvement strategies in hospitals. In primary care, however, not much is known about effective strategies to improve the safety culture yet. The purpose of this study is to examine the effect of two patient safety culture interventions: a patient safety culture questionnaire solely, the SCOPE, or the SCOPE questionnaire combined with a patient safety workshop. The purpose of this paper is to describe the rationale and design of this trial. METHODS/DESIGN: The SCOPE Intervention Study is a cluster randomized, three-armed controlled trial, that will be conducted in 30 general practices in the Netherlands. Ten practices in the first intervention arm will complete the SCOPE questionnaire and are expected to draw and implement their own improvement initiatives based on a computerised feedback report. In the second intervention arm, staff of the ten practices also will be asked to complete the SCOPE questionnaire and in addition will be given a complementary workshop. This workshop is theoretical and interactive, educating staff and facilitating discussion, leading to a practice specific action plan for patient safety improvement. The results of the SCOPE questionnaire are incorporated in the workshop. The ten practices in the control arm continue care as usual. Baseline and follow-up measurements will be conducted with an implementation period of one year. The primary outcome will include the number of incidents reported and secondary several quality and safety indicators and the patient safety culture. Moreover, interviews will be conducted at follow-up to evaluate the implementation process of the intervention. DISCUSSION: Results of this study will give insight in the effect of administering a culture questionnaire or the questionnaire with a complementary workshop. This knowledge will aid implementation of patient safety tools and future research. Attention has been given to the strengths and limitations of the study. TRIAL REGISTRATION: Netherlands Trial Register: NTR3277. PMID- 23984841 TI - Serum metabolic signatures induced by a three-day intensified exercise period persist after 14 h of recovery in runners. AB - This study investigated changes in the human serum metabolome elicited by a 3-day period of intensified training. Runners (N = 15, mean +/- SD age, 35.2 +/- 8.7 years) ran for 2.5 h/day on treadmills at ~70% VO2max for 3 days in a row, with blood samples collected pre-exercise, and immediately and 14 h post-exercise. Samples were analyzed using gas and liquid chromatography/mass spectrometry (GC MS, LC-MS), with compounds identified based on comparison to more than 2800 purified standards. Repeated measures ANOVA was used to identify metabolites that differed significantly across time, with multiple testing corrected by the false discovery rate (FDR) (q-value). Immediately following the 3-day exercise period, significant 2-fold or higher increases in 75 metabolites were measured, with all but 22 of these metabolites related to lipid/carnitine metabolism, 13 to amino acid/peptide metabolism, 4 to hemoglobin/porphyrin metabolism, and 3 to Krebs cycle intermediates (q-values < 0.001). After a 14 h overnight recovery period, 50 of the 75 metabolites remained elevated, with 8 decreased (primarily amino acid-related metabolites) (q-values < 0.05). Among the top 20 metabolites, the mean fold changes were 12.4 +/- 5.3 and 2.9 +/- 1.3 immediately and 14-h post exercise, respectively. Significant decreases (40-70%, q < 0.01) in 22 metabolites (primarily related to lysolipid and bile acid metabolism) were measured post-exercise, with all but 4 of these still decreased after 14 h rest recovery (q < 0.025). Runners experienced a profound systemic shift in blood metabolites related to energy production especially from the lipid super pathway following 3 days of heavy exertion that was not fully restored to pre-exercise levels after 14 h recovery. PMID- 23984842 TI - NIS-PPh3: a selective reagent for the spiroannulation of o-allyl phenols. Total synthesis of corallidictyal D. AB - Treatment of o-allyl phenols with catalytic NIS-PPh3 affords the corresponding spirodihydrobenzofuran derivatives in high yield with high regio- and total stereoselectivity under mild conditions. These results were utilized to achieve the first total synthesis of the protein kinase C inhibitor corallidictyal D starting from alpha-ionone. PMID- 23984843 TI - Flexible transparent and free-standing silicon nanowires paper. AB - If the flexible transparent and free-standing paper-like materials that would be expected to meet emerging technological demands, such as components of transparent electrical batteries, flexible solar cells, bendable electronics, paper displays, wearable computers, and so on, could be achieved in silicon, it is no doubt that the traditional semiconductor materials would be rejuvenated. Bulk silicon cannot provide a solution because it usually exhibits brittleness at below their melting point temperature due to high Peierls stress. Fortunately, when the silicon's size goes down to nanoscale, it possesses the ultralarge straining ability, which results in the possibility to design flexible transparent and self-standing silicon nanowires paper (FTS-SiNWsP). However, realization of the FTS-SiNWsP is still a challenging task due largely to the subtlety in the preparation of a unique interlocking alignment with free-catalyst controllable growth. Herein, we present a simple synthetic strategy by gas flow directed assembly of a unique interlocking alignment of the Si nanowires (SiNWs) to produce, for the first time, the FTS-SiNWsP, which consisted of interconnected SiNWs with the diameter of ~10 nm via simply free-catalyst thermal evaporation in a vertical high-frequency induction furnace. This approach opens up the possibility for creating various flexible transparent functional devices based on the FTS-SiNWsP. PMID- 23984844 TI - Signal-to-noise-optimal scaling of heterogenous population codes. AB - Similarity measures for neuronal population responses that are based on scalar products can be little informative if the neurons have different firing statistics. Based on signal-to-noise optimality, this paper derives positive weighting factors for the individual neurons' response rates in a heterogeneous neuronal population. The weights only depend on empirical statistics. If firing follows Poisson statistics, the weights can be interpreted as mutual information per spike. The scaling is shown to improve linear separability and clustering as compared to unscaled inputs. PMID- 23984845 TI - Silicon nanopillars as a platform for enhanced fluorescence analysis. AB - The importance of fluorescent detection in many fields is well established. While advancements in instrumentation and the development of brighter fluorophore have increased sensitivity and lowered the detection limits of the method, additional gains can be made by manipulating the local electromagnetic field. Herein we take advantage of silicon nanopillars that exhibit optical resonances and field enhancement on their surfaces and demonstrate their potential in improving performance of biomolecular fluorescent assays. We use electron beam lithography and wafer scale processes to create silicon nanoscale pillars with dimensions that can be tuned to maximize fluorescence enhancement in a particular spectral region. Performance of the nanopillar based fluorescent assay was quantified using two model bioaffinity systems (biotin-streptavidin and immunoglobulin G antibody) as well as covalent binding of fluorescently tagged bovine serum albumin (BSA). The effects of pillar geometry and number of pillars in arrays were evaluated. Color specific and pillar diameter dependent enhancement of fluorescent signals is clearly demonstrated using green and red labels (FITC, DyLight 488, Alexa 568, and Alexa 596). The ratios of the on pillar to off pillar signals normalized by the nominal increase in surface area due to nanopillars were found to be 43, 75, and 292 for the IgG-antibody assay, streptavidin-biotin system, and covalently attached BSA, respectively. Applicability of the presented approaches to the detection of small numbers of molecules was evaluated using highly diluted labeled proteins and also control experiments without biospecific analytes. Our analysis indicates that detection of fewer than 10 tagged proteins is possible. PMID- 23984846 TI - Aging and the segmentation of narrative film. AB - The perception of event structure in continuous activity is important for everyday comprehension. Although the segmentation of experience into events is a normal concomitant of perceptual processing, previous research has shown age differences in the ability to perceive structure in naturalistic activity, such as a movie of someone washing a car. However, past research has also shown that older adults have a preserved ability to comprehend events in narrative text, which suggests that narrative may improve the event processing of older adults. This study tested whether there are age differences in event segmentation at the intersection of continuous activity and narrative: narrative film. Younger and older adults watched and segmented a narrative film, The Red Balloon, into coarse and fine events. Changes in situational features, such as changes in characters, goals, and objects predicted segmentation. Analyses revealed little age difference in segmentation behavior. This suggests the possibility that narrative structure supports event understanding for older adults. PMID- 23984847 TI - Structural influence of C8-phenoxy-guanine in the NarI recognition DNA sequence. AB - Phenoxyl radicals can covalently attach to the C8 site of 2'-deoxyguanosine (dG) to generate oxygen-linked biaryl ether C8-dG adducts. To assess the structural impact of an O-linked C8-dG adduct in duplex DNA, C8-phenoxy-G ((PhO)G) and C8-4 fluorophenoxy-G ((4FPhO)G) were incorporated into the G(3) position of the 12-mer NarI recognition sequence (5'-CTCGGCXCCATC, where X = G, (PhO)G, or (4FPhO)G) using solid-phase DNA synthesis with O-linked C8-dG phosphoramidites. The modified strands were hybridized to six different complementary strands that include regular base pairing to C [NarI'(C)], mismatches with G, A, T [NarI'(N)], and an abasic site [NarI'(THF)], and a 10-mer sequence to model a -2 deletion duplex [NarI'(-2)]. All duplex structures were characterized using UV-vis thermal melting temperature analysis, and in each instance, the O-linked C8-phenoxy-G adducts were found to destabilize the duplex relative to the unmodified controls. The most stable duplex structures match the O-linked C8-dG adduct against C and a G mismatch, which are comparable in terms of stability. These duplexes were further characterized using circular dichroism, dynamic (19)F nuclear magnetic resonance experiments, and molecular dynamics simulations. On the basis of these findings, (PhO)dG adopts the B conformation opposite C, with the phenoxy moiety residing in the solvent-exposed major groove. However, opposite the G mismatch, (PhO)dG adopts a "W-type" wedge conformation with the phenoxy group residing in the minor groove. These studies predict that the O-linked C8-dG lesion (PhO)G will have a weak mutagenic effect, as determined for the corresponding single ringed nitrogen-linked C8-dG adduct derived from aniline. PMID- 23984848 TI - Correlational study: illness representations and coping styles in caregivers for individuals with schizophrenia. AB - BACKGROUND: Caring for individuals with schizophrenia can create distress for caregivers which can, in turn, have a harmful impact on patient progress. There could be a better understanding of the connections between caregivers' representations of schizophrenia and coping styles. This study aims at exploring those connections. METHODS: This correlational descriptive study was conducted with 92 caregivers of individuals suffering from schizophrenia. The participants completed three questionnaires translated and validated in French: (a) a socio demographic questionnaire, (b) the Illness Perception Questionnaire for Schizophrenia and (c) the Family Coping Questionnaire. RESULTS: Our results show that illness representations are slightly correlated with coping styles. More specifically, emotional representations are correlated to an emotion-focused coping style centred on coercion, avoidance and resignation. CONCLUSION: Our results are coherent with the Commonsense Model of Self-Regulation of Health and Illness and should enable to develop new interventions for caregivers. PMID- 23984849 TI - Cardiac structure/function, protein expression, and DNA methylation are changed in adult female mice exposed to diethylstilbestrol in utero. AB - The detrimental effects of in utero exposure to the non-steroidal estrogen diethylstilbestrol (DES) are particularly marked in women. Fetal hearts express estrogen receptors, making them potentially responsive to DES. To examine whether gestational exposure to DES would impact the heart, we exposed pregnant C57bl/6n dams to DES (0.1, 1.0, and 10.0 MUg.(kg body mass)(-1).day(-1)) on gestation days 11.5-14.5, and examined the measured cardiac structure/function and calcium homeostasis protein expression in adult females. At baseline, echocardiography revealed eccentric hypertrophy in mice treated with 10.0 MUg.(kg body mass)( 1).day(-1) DES, and immunoblots showed increased SERCA2a in all DES-treated mice. Mice were swim-trained to assess cardiac remodeling. Swim-trained vehicle-treated mice developed eccentric hypertrophy without changing SERCA2 or calsequestrin 2 expression. In contrast, no DES-treated mice hypertrophied, and all increased in SERCA2a and calsequestrin 2 expression after training. To determine whether DES induced changes in DNA methylation is part of the mechanism for its long-term effects, we measured DNA methyltransferase expression and DNA methylation. Global DNA methylation and DNA methyltransferase 3a expression were unchanged. However, DES-treated mice had increased DNA methylation in the calsequestrin 2 promoter. Thus, gestational exposure to DES altered female ventricular DNA, cardiac structure/function, and calcium homeostasis protein expression. We conclude that gestational exposure to estrogenizing compounds may impact cardiac structure/function in adult females. PMID- 23984850 TI - Feeding our kids, kidding ourselves. PMID- 23984851 TI - Bioavailability of endomorphins and the blood-brain barrier--a review. AB - Opioid peptides have the potential to be pharmaceutical agents for the treatment of pain because they modulate nociceptive pathways at supraspinal, spinal and peripheral levels. Unfortunately, peptides are generally hydrophilic compounds and therefore unable to cross the blood-brain barrier (BBB) by passive diffusion to reach the central nervous system (CNS) in an amount sufficient to activate appropriate receptors. Endomorphins (EMs) belong to the class of endogenous opioids eliciting the strongest analgesic effect, but only after direct administration to the CNS. Extensive research is in progress to better understand the relationships between EM structure and bioavailability. This article deals with the recent investigations that allow the design of stable and neuroactive EM analogs with enhanced brain passage and uptake. PMID- 23984852 TI - New class of phosphine oxide donor-based supramolecular coordination complexes from an in situ phosphine oxidation reaction or phosphine oxide ligands. AB - A one-pot, multicomponent, coordination-driven self-assembly approach was used to synthesize the first examples of neutral bridging phosphine oxide donor-based supramolecular coordination complexes. The complexes were self-assembled from a fac-Re(CO)3 acceptor, an anionic bridging O donor, and a neutral soft phosphine or hard phosphine oxide donor. PMID- 23984853 TI - Circadian behavior of mice deficient in PER1/PML or PER2/PML. AB - BACKGROUND: Our recent studies demonstrate that the murine homolog of the human tumor suppressor promyelocytic leukemia (PML) regulates circadian behavior of mice. To further gather insight into PML's contribution to circadian behavior, we generated two strains of mice deficient in one of the two period (Per) genes and the PML gene, with Per1-/-/Pml-/- and Per2-/-/Pml-/- genotypes. RESULTS: Here we report the circadian behavior of these mice based on wheel-running behavioral analysis. In a free-running environment, the Per1-/-/Pml-/- mice maintained circadian rhythm but displayed a significantly shorter period of 22.2 h. In addition, these mice displayed significantly enhanced phase response to a light pulse given at zeitgeber time (ZT) 14 and 22. The Per2-/-/Pml-/- mice lose persistent rhythm when in a free-running environment, as also the case for Per2-/ mice. A transient post-light pulse rhythm seen in the arrhythmic Per2-/- mice was less apparent in Per2-/-/Pml-/- mice. Both the Per1-/-/Pml-/- and Per2-/-/Pml /- mice displayed a more advanced phase angle of entrainment activity during light-dark cycles than the single gene deficient mice. CONCLUSIONS: Beyond merely regulating PER1 and PER2, the current behavioral studies suggest PML has additional roles in mouse circadian behavior. PMID- 23984854 TI - Genetic variability of Mycobacterium tuberculosis complex in patients with no known risk factors for MDR-TB in the North-Eastern part of Lima, Peru. AB - BACKGROUND: The aim of this study was to investigate the genetic diversity among Mycobacterium tuberculosis complex circulating in patients with no known risk factors for multi-drug resistant (MDR) tuberculosis (TB) living in a high MDR burden area and analyze the relationship between genotypes, primary drug resistance and age. METHODS: Samples were collected during January-July 2009. Isolates were tested for drug susceptibility to first-line drugs and were genotyped by spoligotyping and the 15-loci Mycobacterial Interspersed Repetitive Unit (MIRU15). RESULTS: Among the 199 isolates analyzed, 169 (84.9%) were identified in the SpolDB4.0 and 30 (15.1%) could not be matched to any lineage. The most prevalent lineage was Haarlem (29.6%), followed by T (15.6%), Beijing (14.1%), Latin American Mediterranean (12.6%) and U (8.5%). A few isolates belonged to the X and S clades (4.5%). Spoligotype analysis identified clustering among 148 of 169 isolates, whereas with MIRU15 all isolates were unique. Out of 197 strains; 31.5% were resistant to at least one drug, 7.5% were MDR and 22.3% showed any resistance to isoniazid. CONCLUSION: In contrast with other Latin American countries where LAM lineage is the most predominant, we found the spoligotype 50 from the Haarlem lineage as the most common. None of the prevailing lineages showed a significant association with age or resistance to isoniazid and/or rifampicin. PMID- 23984856 TI - Blabericola rhyparobiae n. comb. (Apicomplexa: Eugregarinida: Blabericolidae), parasitizing the Madeira cockroach, Rhyparobia maderae (Dictyoptera: Blaberidae). AB - Blabericola rhyparobiae n. comb. (Apicomplexa: Eugregarinida: Blabericolidae) is redescribed from the Madeira cockroach, Rhyparobia maderae (Dictyoptera: Blaberidae: Oxyhaloinae: Nauphoetini). Oocysts within the genus are typically dolioform with nonprojecting polar plates. Those of B. rhyparobiae differ from all other species of Blabericola in being oblong rather than dolioform. Morphometrically, the oocysts of B. rhyparobiae are significantly narrower than those of any other known species in the genus; they are significantly longer than those of Blabericola haasi, Blabericola migrator, and Blabericola princisi, but they are significantly shorter than those of Blabericola cubensis (oocyst width 4.47 MUm vs. 4.74 MUm, 4.70 MUm, 5.06 MUm, 5.21 MUm, respectively; oocyst length 8.98 MUm vs. 7.94 MUm, 7.93 MUm, 8.85 MUm, 9.26 MUm, respectively). All 5 species are also distinguished by unique sporozoite-bearing cavity sizes and morphometric ratios. Gametocysts of Blabericola species are either orbicular (B. cubensis, B. princisi) or elliptoid (B. haasi , B. migrator, B. rhyparobiae). Among Blabericola species with elliptoid gametocysts, the gametocysts of B. rhyparobiae are intermediate in size relative to the much larger gametocysts of B. migrator and the much smaller gametocysts of B. haasi (gametocyst length 462.06 MUm vs. 728.11 MUm, 272.02 MUm; gametocyst width 297.12 MUm vs. 461.31 MUm, 178.36 MUm, respectively). No structurally unique feature of the gamont distinguishes among species of Blabericola, but gamonts of all 5 species differ morphometrically. Gamonts of B. rhyparobiae differ significantly from all other species in the genus in the primite's protomerite and deutomerite lengths, the satellite' deutomerite lengths, and the total length of both primite and satellite in association. The gamonts of B. rhyparobiae are significantly smaller than those of B. cubensis, B. migrator, and B. princisi but significantly larger than those of B. haasi and can be readily distinguished based on size alone (primite total length 460 MUm vs. 563 MUm, 800 MUm, 547 MUm, 316 MUm, respectively; satellite total length 419 MUm vs. 507 MUm, 695 MUm, 526 MUm, 298 MUm, respectively). PMID- 23984855 TI - DEER EPR measurements for membrane protein structures via bifunctional spin labels and lipodisq nanoparticles. AB - Pulsed EPR DEER structural studies of membrane proteins in a lipid bilayer have often been hindered by difficulties in extracting accurate distances when compared to those of globular proteins. In this study, we employed a combination of three recently developed methodologies, (1) bifunctional spin labels (BSL), (2) SMA-Lipodisq nanoparticles, and (3) Q band pulsed EPR measurements, to obtain improved signal sensitivity, increased transverse relaxation time, and more accurate and precise distances in DEER measurements on the integral membrane protein KCNE1. The KCNE1 EPR data indicated an ~2-fold increase in the transverse relaxation time for the SMA-Lipodisq nanoparticles when compared to those of proteoliposomes and narrower distance distributions for the BSL when compared to those of the standard MTSL. The certainty of information content in DEER data obtained for KCNE1 in SMA-Lipodisq nanoparticles is comparable to that in micelles. The combination of techniques will enable researchers to potentially obtain more precise distances in cases where the traditional spin labels and membrane systems yield imprecise distance distributions. PMID- 23984857 TI - The association between amalgam dental surfaces and urinary mercury levels in a sample of Albertans, a prevalence study. AB - OBJECTIVE: The objective of this study was to quantify the relationship between number of dental amalgam surfaces and urinary mercury levels. METHODS: This study uses participant data from a large philanthropic chronic disease prevention program in Calgary, Alberta, Canada. Urine samples were analysed for mercury levels (measured in MUg/g-creatinine). T-tests were used to determine if differences in urine mercury were statistically significant between persons with no dental amalgam surfaces and one or more dental amalgam surfaces. Linear regression was used to estimate the change in urinary mercury per amalgam surface. RESULTS: Urinary mercury levels were statistically significantly higher in participants with amalgam surfaces, with an average difference of 0.55 MUg/g creatinine. Per amalgam surface, we estimated an expected increase of 0.04 MUg/g creatinine. Measured urinary mercury levels were also statistically significantly higher in participants with dental amalgam surfaces following the oral administration of 2,3-dimercaptopropane-l-sulfonate (DMPS) and meso-2,3 dimercaptosuccinic acid (DMSA) which are used to mobilize mercury from the blood and tissues. DISCUSSION: Our estimates indicate that an individual with seven or more dental amalgam surfaces has 30% to 50% higher urinary mercury levels than an individual without amalgams. This is consistent with past literature that has identified seven amalgam surfaces as an unsafe level of exposure to mercury vapor. Our analysis suggests that continued use of silver amalgam dental fillings for restorative dentistry is a non-negligible, unnecessary source of mercury exposure considering the availability of composite resin alternatives. PMID- 23984860 TI - A novel tetranucleotide repeat polymorphism within KCNQ1OT1 confers risk for hepatocellular carcinoma. AB - KCNQ1 overlapping transcript 1 (KCNQ1OT1), a long noncoding RNA responsible for silencing a cluster of genes in cis, has been shown to be involved in multiple cancers. However, much remains unclear of how KCNQ1OT1 contributes to carcinogenesis. By thoroughly analyzing 510 hepatocellular carcinoma (HCC) cases and 1014 healthy controls in a Chinese population, we identified a novel short tandem repeat (STR) polymorphism (rs35622507) within the KCNQ1OT1 coding region and evaluated its association with HCC susceptibility. Logistic regression analysis showed that compared with individuals carrying the homozygote 10-10 genotype, those heterozygote subjects who carry only one allele 10 had a significantly decreased risk of HCC (adjusted odds ratio [OR]=0.67, 95% confidence interval [CI]=0.53-0.86, p=0.0009), with the risk decreased even further in those without allele 10 (adjusted OR=0.38, 95% CI=0.21-0.69, p=0.0005). Furthermore, genotype-phenotype correlation studies using four hepatoma cell lines support a significant association between STR genotypes and the expression of KCNQ1OT1. Cell lines without allele 10 conferred a 20.9-33.3 fold higher expression of KCNQ1OT1. Meanwhile, KCNQ1OT1 expression was reversely correlated with the expression of the cyclin-dependent kinase inhibitor 1C (CDKN1C), a tumor suppressor gene located within the CDKN1C/KCNQ1OT1 imprinted region, in three hepatoma cell lines. Finally, in silico prediction suggested that different alleles could alter the local structure of KCNQ1OT1. Taken together, our findings suggest that the STR polymorphism within KCNQ1OT1 contributes to hepatocarcinogenesis, possibly by affecting KCNQ1OT1 and CDKN1C expression through a structure-dependent mechanism. The replication of our studies and further functional studies are needed to validate our hypothesis and understand the roles of KCNQ1OT1 polymorphisms in predisposition for HCC. PMID- 23984861 TI - Response to Algarabel et al., 2012 "Recognition memory deficits in mild cognitive impairment". Reconsidering claims of familiarity disruptions in mild cognitive impairment. AB - There is some debate over the relative impairment of recollection and familiarity in mild cognitive impairment (MCI). A recent publication by Algarabel et al. (2012, Recognition memory deficits in mild cognitive impairment, Aging, Neuropsychology, and Cognition, 19, 608-619) claims to undermine previous studies reporting preserved familiarity in patients with MCI. Here, we respond to their main criticisms, concluding that they are not sufficiently supported by the data presented. The role of recollection and familiarity in MCI remains unresolved and further work will be required to disentangle the mixed literature. PMID- 23984863 TI - Safety and administration of treatment with botulinum neurotoxin for sialorrhoea in ALS patients: review of the literature and a proposal for tailored treatment. AB - Botulinum neurotoxin (BoNT) is a second-line treatment of sialorrhoea in ALS (amyotrophic lateral sclerosis) patients. This article is a review of the published literature concerning safety and administration of this treatment to ALS patients. A PubMed search was performed. All original publications on BoNT treatment of sialorrhoea in ALS patients were included in the review. Only a few adverse events were observed concerning treatment with BoNT. The studies performed to date have applied different treatment strategies with different dosages. In conclusion, BoNT treatment for sialorrhoea in ALS patients is safe with few adverse effects. The authors advocate for the implementation of a personalized treatment strategy. Special precautions must be taken when patients do not have the assistance of a ventilator and a feeding tube. PMID- 23984864 TI - Understanding the responses of rice to environmental stress using proteomics. AB - Diverse abiotic and biotic stresses have marked effects on plant growth and productivity. To combat such stresses, plants have evolved complex but not well understood responses. Common effects upon perception of environmental stress are differential expression of the plant proteome and the synthesis of novel regulatory proteins for protection from and acclimation to stress conditions. Plants respond differently in terms of activation of stress-responsive signaling pathways depending upon the type and nature of the stresses to which they are exposed. Progress in proteomics and systems biology approaches has made it possible to identify the novel proteins and their interactions that function in abiotic stress responses. This will enable elucidation of the functions of individual proteins and their roles in signaling networks. Proteomic analysis of the responses to various stress conditions is performed most commonly using 2D gel electrophoresis and high-throughput identification by LC-MS/MS. Because of recent developments in proteomics techniques, numerous proteomics studies of rice under abiotic stress conditions have been performed. In this review, proteomics studies addressing rice responses to the major environmental stresses--including cold, heat, drought, salt, heavy metals, minerals, UV radiation, and ozone--are discussed. Unique or common protein responses to these stress conditions are summarized and interpreted according to their possible physiological responses in each stress. Additionally, proteomics studies on various plant systems under various abiotic stress conditions are compared to provide deeper understanding of specific and common proteome responses in rice and other plant systems, which will further contribute to the identification of abiotic stress tolerance factor at protein level. Functional analysis of stress-responsive proteins will provide new research objectives with the aim of achieving stable crop productivity in the face of the increasing abiotic stress conditions caused by global climate change. PMID- 23984865 TI - Identification of differential expression genes associated with host selection and adaptation between two sibling insect species by transcriptional profile analysis. AB - BACKGROUND: Cotton bollworm (Helicoverpa armigera) and oriental tobacco budworm (Helicoverpa assulta) are noctuid sibling species. Under artificial manipulation, they can mate and produce fertile offspring. As serious agricultural insect pests, cotton bollworms are euryphagous insects, but oriental tobacco budworms are oligophagous insects. To identify the differentially expressed genes that affect host recognition and host adaptation between the two species, we constructed digital gene expression tag profiles for four developmental stages of the two species. High-throughput sequencing results indicated that we have got more than 23 million 17nt clean tags from both species, respectively. The number of unique clean tags was nearly same in both species (approximately 357,000). RESULTS: According to the gene annotation results, we identified 83 and 68 olfaction related transcripts from H. armigera and H. assulta, respectively. At the same time, 1137 and 1138 transcripts of digestion enzymes were identified from the two species. Among the olfaction related transcripts, more odorant binding protein and G protein-coupled receptor were identified in H. armigera than in H. assulta. Among the digestion enzymes, there are more detoxification enzyme, e.g. P450, carboxypeptidase and ATPase in H. assulta than in H. armigera. These differences partially explain that because of the narrow host plant range of H. assulta, more detoxification enzymes would help them increase the food detoxification and utilization efficiency. CONCLUSIONS: This study supplied some differentially expressed genes affecting host selection and adaptation between the two sibling species. These genes will be useful information for studying on the evolution of host plant selection. It also provides some important target genes for insect species-specific control by RNAi technology. PMID- 23984862 TI - Enabling systems biology approaches through microfabricated systems. AB - With the experimental tools and knowledge that have accrued from a long history of reductionist biology, we can now start to put the pieces together and begin to understand how biological systems function as an integrated whole. Here, we describe how microfabricated tools have demonstrated promise in addressing experimental challenges in throughput, resolution, and sensitivity to support systems-based approaches to biological understanding. PMID- 23984866 TI - Low-temperature Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to alpha,beta-unsaturated carbonyl compounds. AB - Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to alpha,beta unsaturated carbonyl compounds was achieved at temperatures below 0 degrees C using a Rh/MeO-F12-BIPHEP catalyst. The reaction of cyclohexenone or N-R maleimide with arylboronic acids proceeded even at -80 degrees C in the presence of the Rh catalyst. In the latter case, high enantioselectivity was observed because a low-temperature method was used, regardless of the type of substituent on maleimide. PMID- 23984868 TI - Made in Canada. PMID- 23984867 TI - An integrative review and evidence-based conceptual model of the essential components of pre-service education. AB - BACKGROUND: With decreasing global resources, a pervasive critical shortage of skilled health workers, and a growing disease burden in many countries, the need to maximize the effectiveness and efficiency of pre-service education in low-and middle-income countries has never been greater. METHODS: We performed an integrative review of the literature to analyse factors contributing to quality pre-service education and created a conceptual model that shows the links between essential elements of quality pre-service education and desired outcomes. RESULTS: The literature contains a rich discussion of factors that contribute to quality pre-service education, including the following: (1) targeted recruitment of qualified students from rural and low-resource settings appears to be a particularly effective strategy for retaining students in vulnerable communities after graduation; (2) evidence supports a competency-based curriculum, but there is no clear evidence supporting specific curricular models such as problem-based learning; (3) the health workforce must be well prepared to address national health priorities; (4) the role of the preceptor and preceptors' skills in clinical teaching, identifying student learning needs, assessing student learning, and prioritizing and time management are particularly important; (5) modern, Internet-enabled medical libraries, skills and simulation laboratories, and computer laboratories to support computer-aided instruction are elements of infrastructure meriting strong consideration; and (6) all students must receive sufficient clinical practice opportunities in high-quality clinical learning environments in order to graduate with the competencies required for effective practice. Few studies make a link between PSE and impact on the health system. Nevertheless, it is logical that the production of a trained and competent staff through high-quality pre-service education and continuing professional development activities is the foundation required to achieve the desired health outcomes. Professional regulation, deployment practices, workplace environment upon graduation and other service delivery contextual factors were analysed as influencing factors that affect educational outcomes and health impact. CONCLUSIONS: Our model for pre-service education reflects the investments that must be made by countries into programmes capable of leading to graduates who are competent for the health occupations and professions at the time of their entry into the workforce. PMID- 23984869 TI - Inhibition of Myosin light-chain kinase attenuates cerebral edema after traumatic brain injury in postnatal mice. AB - Traumatic brain injury (TBI) in children less than 8 years of age leads to decline in intelligence and executive functioning. Neurological outcomes after TBI correlate to development of cerebral edema, which affect survival rates after TBI. It has been shown that myosin light-chain kinase (MLCK) increases cerebral edema and that pretreatment with an MLCK inhibitor (ML-7) reduces cerebral edema. The aim of this study was to determine whether inhibition of MLCK after TBI in postnatal day 24 (PND-24) mice would prevent breakdown of the blood-brain barrier (BBB) and development of cerebral edema and improve neurological outcome. We used a closed head injury model of TBI. ML-7 or saline treatment was administered at 4 h and every 24 h until sacrifice or 5 days after TBI. Mice were sacrificed at 24 h, 48 h, and 72 h and 7 days after impact. Mice treated with ML-7 after TBI had decreased levels of MLCK-expressing cells (20.7+/-4.8 vs. 149.3+/-40.6), less albumin extravasation (28.3+/-11.2 vs. 116.2+/-60.7 mm(2)) into surrounding parenchymal tissue, less Evans Blue extravasation (339+/-314 vs. 4017+/-560 ng/g), and showed a significant difference in wet/dry weight ratio (1.9+/-0.07 vs. 2.2+/-0.05 g), compared to saline-treated groups. Treatment with ML-7 also resulted in preserved neurological function measured by the wire hang test (57 vs. 21 sec) and two-object novel recognition test (old vs. new, 10.5 touches). We concluded that inhibition of MLCK reduces cerebral edema and preserves neurological function in PND-24 mice. PMID- 23984870 TI - Cyanogenic glycosides in plant-based foods available in New Zealand. AB - Cyanogenic glycosides occur in a wide range of plant species. The potential toxicity of cyanogenic glycosides arises from enzymatic degradation to produce hydrogen cyanide, which may result in acute cyanide poisoning and has also been implicated in the aetiology of several chronic diseases. One hundred retail foods were sampled and analysed for the presence of total hydrocyanic acid using an acid hydrolysis-isonicotinic/barbituric acid colourimetric method. Food samples included cassava, bamboo shoots, almonds and almond products, pome fruit products, flaxseed/linseed, stone fruit products, lima beans, and various seeds and miscellaneous products, including taro leaves, passion fruit, spinach and canned stuffed vine leaves. The concentrations of total hydrocyanic acid (the hydrocyanic acid equivalents of all cyanogenic compounds) found were consistent with or lower than concentrations reported in the scientific literature. Linseed/flaxseed contained the highest concentrations of total hydrocyanic acid of any of the analysed foods (91-178 mg kg(-1)). Linseed-containing breads were found to contain total hydrocyanic acid at concentrations expected from their linseed content, indicating little impact of processing on the total hydrocyanic acid content. Simulation modelling was used to assess the risk due to the total hydrocyanic acid in fruit juice and linseed-containing bread. PMID- 23984871 TI - Multifunctional cyclic D,L-alpha-peptide architectures stimulate non-insulin dependent glucose uptake in skeletal muscle cells and protect them against oxidative stress. AB - Oxidative stress directly correlates with the early onset of vascular complications and the progression of peripheral insulin resistance in diabetes. Accordingly, exogenous antioxidants augment insulin sensitivity in type 2 diabetic patients and ameliorate its clinical signs. Herein, we explored the unique structural and functional properties of the abiotic cyclic D,L-alpha peptide architecture as a new scaffold for developing multifunctional agents to catalytically decompose ROS and stimulate glucose uptake. We showed that His-rich cyclic D,L-alpha-peptide 1 is very stable under high H2O2 concentrations, effectively self-assembles to peptide nanotubes, and increases the uptake of glucose by increasing the translocation of GLUT1 and GLUT4. It also penetrates cells and protects them against oxidative stress induced under hyperglycemic conditions at a much lower concentration than alpha-lipoic acid (ALA). In vivo studies are now required to probe the mode of action and efficacy of these abiotic cyclic D,L-alpha-peptides as a novel class of antihyperglycemic compounds. PMID- 23984872 TI - Strengthening brittle semiconductor nanowires through stacking faults: insights from in situ mechanical testing. AB - Quantitative mechanical testing of single-crystal GaAs nanowires was conducted using in situ deformation transmission electron microscopy. Both zinc-blende and wurtzite structured GaAs nanowires showed essentially elastic deformation until bending failure associated with buckling occurred. These nanowires fail at compressive stresses of ~5.4 GPa and 6.2 GPa, respectively, which are close to those values calculated by molecular dynamics simulations. Interestingly, wurtzite nanowires with a high density of stacking faults fail at a very high compressive stress of ~9.0 GPa, demonstrating that the nanowires can be strengthened through defect engineering. The reasons for the observed phenomenon are discussed. PMID- 23984873 TI - Elevated dopamine D2 receptor in prefrontal cortex of CUMS rats is associated with downregulated cAMP-independent signaling pathway. AB - Because depression is associated with significant morbidity and functional disability, it is important to reveal the mechanism of action. A variety of studies have suggested the involvement of dopaminergic receptors in the pathophysiological mechanism of non-stress-associated depression-like behavior in rodents. Nevertheless, controversy exists about whether chronic stress acts on dopaminergic receptors in the prefrontal cortex. Thus, we investigated the level of dopamine D2 receptors (DRD2) and the possible mechanisms involved in a chronic unpredictable mild stress (CUMS) rat model of depression. The results showed CUMS induced, depression-like symptoms in the rat, characterized by reduced sucrose consumption and body mass, and increased duration of immobility in a forced swimming test. Moreover, chronic stress upregulated the expression of DRD2 but downregulated protein kinase A (PKA), transcription factor cAMP response element binding protein (CREB), and phospho-CREB (p-CREB) in the prefrontal cortex, as demonstrated by Western blot. Notably, in the rat model of depression, decreased cyclic adenine monophosphate (cAMP) levels and PKA activity were present at the same time, which is consistent with clinical findings in depressed patients. Our findings suggested that dopaminergic system dysfunction could play a central role in stress-related disorders such as depression. PMID- 23984874 TI - Thermodynamics and kinetics of adaptive binding in the malachite green RNA aptamer. AB - Adaptive binding, the ability of molecules to fold themselves around the structure of a ligand and thereby incorporating it into their three-dimensional fold, is a key feature of most RNA aptamers. The malachite green aptamer (MGA) has been shown to bind several closely related triphenyl dyes with planar and nonplanar structures in this manner. Competitive binding studies using isothermal titration calorimetry and stopped flow kinetics have been conducted with the aim of understanding the adaptive nature of RNA-ligand interaction. The results of these studies reveal that binding of one ligand can reduce the ability of the aptamer pocket to adapt to another ligand, even if this second ligand has a significantly higher affinity to the free aptamer. A similar effect is observed in the presence of Mg(2+) ions which stabilize the binding pocket in a more ligand bound-like conformation. PMID- 23984875 TI - Kudoa thunni from blackfin tuna (Thunnus atlanticus) harvested off the island of St. Kitts, West Indies. AB - Numerous myxozoan cysts (~ 1 mm) were found in the musculature of blackfin tuna (Thunnus atlanticus) harvested off the Caribbean island of St. Kitts. Myxospores were consistent with quadrate members of the Kudoidae, measuring 8.8 (8.2-9.4) MUm wide, 7.3 (6.6-8.3) MUm thick, and 6.2 (5.8-6.9) MUm long with 4 uniform drop like polar capsules measuring 2.7 (2.2-3.2) MUm long and 2.0 (1.7-2.2) MUm wide. The 18S small-subunit (SSU) and 28S large-subunit (LSU) ribosomal DNA sequences did not result in direct matches to any published sequences. However, the SSU sequences (1,786 base pairs [bp]) obtained from 6 individual cysts were identical and demonstrated high homology to Kudoa thunni (99.0%) from albacore (Thunnus alalunga). Alternatively, 33 unique sequences were obtained for the LSU (~ 800 bp), demonstrating 0.1 to 5.0% variability between them, although a majority of these sequences (60%) demonstrated high homology (>99%) to K. thunni. Morphologically, the case isolate was smaller than published descriptions of K. thunni; however, rDNA sequence homology, and phylogenetic placement based on concatenated SSU and LSU rDNA sequences suggests this case isolate and K. thunni are conspecific. To our knowledge this is the first report of K. thunni infection in blackfin tuna from the Caribbean. PMID- 23984876 TI - Preparation of vinyl silyl ethers and disiloxanes via the silyl-Heck reaction of silyl ditriflates. AB - Vinyl silyl ethers and disiloxanes can now be prepared from aryl-substituted alkenes and related substrates using a silyl-Heck reaction. The reaction employs a commercially available catalyst system and mild conditions. This work represents a highly practical means of accessing diverse classes of vinyl silyl ether substrates in an efficient and direct manner with complete regiomeric and geometric selectivity. PMID- 23984877 TI - From aging worms to the influence of the microbiota: an interview with David Weinkove. PMID- 23984878 TI - An exceptionally stable, porphyrinic Zr metal-organic framework exhibiting pH dependent fluorescence. AB - A reaction between a Zr(IV) salt and a porphyrinic tetracarboxylic acid leads to a metal-organic framework (MOF) with two types of open channels, representing a MOF featuring a (4,8)-connected sqc net. The MOF remains intact in both boiling water and aqueous solutions with pH ranging from 1 to 11, a remarkably extensive pH range that a MOF can sustain. Given its exceptional stability and pH-dependent fluorescent intensity, the MOF can potentially be applied in fluorescent pH sensing. PMID- 23984880 TI - C-24-methylation of 26-fluorocycloartenols by recombinant sterol C-24 methyltransferase from soybean: evidence for channel switching and its phylogenetic implications. AB - The tightly coupled nature of the electrophilic alkylation reaction sequence catalysed by 24-SMT (sterol C-24-methyltransferase) of land plants and algae can be distinguished by the formation of cationic intermediates that yield phyla specific product profiles. C-24-methylation of the cycloartenol substrate by the recombinant Glycine max (soybean) 24-SMT proceeds to a single product 24(28) methylenecycloartanol, whereas the 24-SMT from green algae converts cycloartenol into two products cyclolaudenol [?(25(27))-olefin] and 24(28) methylenecycloartanol [(?24(28))-olefin]. Substrate analogues that differed in the steric-electronic features at either end of the molecule, 26-homocycloartenol or 3beta-fluorolanostadiene, were converted by G. max SMT into a single 24(28) methylene product. Alternatively, incubation of the allylic 26-fluoro cyclosteroid with G. max SMT afforded a bound intermediate that converted in favour of the ?(25(27))-olefin product via the cyclolaudenol cation formed initially during the C-24-methylation reaction. A portion of the 26 fluorocycloartenol substrate was also intercepted by the enzyme and the corresponding hydrolysis product identified by GC-MS as 26-fluoro-25-hydroxy-24 methylcycloartanol. Finally, the 26-fluorocycloartenols are competitive inhibitors for the methylation of cycloartenol and 26-monofluorocycloartenol generated timedependent inactivation kinetics exhibiting a kinact value of 0.12 min(-1). The ability of soybean 24-SMT to generate a 25-hydroxy alkylated sterol and fluorinated ?(25(27))-olefins is consistent with our hypothesis that (i) achieving the cyclolaudenyl cation intermediate by electrophilic alkylation of cycloartenol is significant to the overall reaction rate, and (ii) the evolution of variant sterol C-24-methylation patterns is driven by competing reaction channels that have switched in algae from formation of primarily ?(25(27)) products that convert into ergosterol to, in land plants, formation of ?(24(28)) products that convert into sitosterol. PMID- 23984881 TI - Interaction with a person with profound intellectual and multiple disabilities: a case study in dialogue with an experienced staff member. AB - BACKGROUND: The aim of this descriptive single case study was to describe a unique interaction with a person with profound intellectual and multiple disabilities (PIMD) in a holistic way-focusing on the client, the staff member, and the interacting dyad-and to include the experiential knowledge of the interaction partner. METHOD: A videotaped interaction of the staff-client dyad was analysed by triangulating data from video analysis, documents, observational rating scales, and an interview with the staff member. RESULTS: The interactional pattern revealed in this study is that of a staff member who offers an activity that is considered to be stimulating for the client, by using a variety of initiatives and structuring strategies, and a client who is alert and responsive, but has limited chances to take own initiatives. Rather low scores were obtained on observations from a dialogical perspective. CONCLUSIONS: This study highlights the value of video analysis for practitioners, demonstrates the usefulness of describing an interaction episode supported by an integrative theoretical framework, and confirms the importance of combining observations by an independent researcher with experiential staff knowledge. PMID- 23984879 TI - Advanced glycation end products evoke endothelial cell damage by stimulating soluble dipeptidyl peptidase-4 production and its interaction with mannose 6 phosphate/insulin-like growth factor II receptor. AB - BACKGROUND: Advanced glycation end products (AGEs) and receptor RAGE interaction play a role in diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is a potential therapeutic target for type 2 diabetes. However, the role of DPP-4 in AGE-induced endothelial cell (EC) damage remains unclear. METHODS: In this study, we investigated the effects of DPP-4 on reactive oxygen species (ROS) generation and RAGE gene expression in ECs. We further examined whether an inhibitor of DPP-4, linagliptin inhibited AGE-induced soluble DPP-4 production, ROS generation, RAGE, intercellular adhesion molecule-1 (ICAM 1) and plasminogen activator inhibitor-1 (PAI-1) gene expression in ECs. RESULTS: DPP-4 dose-dependently increased ROS generation and RAGE gene expression in ECs, which were prevented by linagliptin. Mannose 6-phosphate (M6P) and antibodies (Ab) raised against M6P/insulin-like growth factor II receptor (M6P/IGF-IIR) completely blocked the ROS generation in DPP-4-exposed ECs, whereas surface plasmon resonance revealed that DPP-4 bound to M6P/IGF-IIR at the dissociation constant of 3.59 x 10-5 M. AGEs or hydrogen peroxide increased soluble DPP-4 production by ECs, which was prevented by N-acetylcysteine, RAGE-Ab or linagliptin. Linagliptin significantly inhibited the AGE-induced ROS generation, RAGE, ICAM-1 and PAI-1 gene expression in ECs. CONCLUSIONS: The present study suggests that AGE-RAGE-induced ROS generation stimulates the release of DPP-4 from ECs, which could in turn act on ECs directly via the interaction with M6P/IGF-IIR, further potentiating the deleterious effects of AGEs. The blockade by linagliptin of positive feedback loop between AGE-RAGE axis and DPP-4 might be a novel therapeutic target for vascular injury in diabetes. PMID- 23984882 TI - Too much or too little: hyper- and hypo-reactivity in high-functioning autism spectrum conditions. AB - BACKGROUND: Sensory reactivity in people with autism spectrum conditions (ASC) has been found to differ in comparison to reactivity in people without ASC. In this study sensory experiences of high-functioning individuals with ASC were explored and described. METHOD: Interview data from 15 participants with a diagnosis of ASC were analysed by content analysis. RESULTS: Seven aspects of sensory experiences were identified: Being hyper- and hypo-reactive, reacting to general overload, having strong stimuli preferences, managing attentiveness to stimuli, managing sensory/motor stimuli, and dealing with consequences of sensory reactions in daily life. CONCLUSIONS: The categorisation of sensory reactivity in this study can guide clinicians on how to pose questions about sensory issues to individuals with ASC. The assessment of spectrum-specific sensory experiences in high-functioning ASC and their association with other social and nonsocial features of ASC are goals for further research. PMID- 23984883 TI - Arranging and ordering in autism spectrum disorder: characteristics, severity, and environmental correlates. AB - BACKGROUND: There is a need for a more accurate characterisation of higher level restricted and repetitive behaviour (RRB) in autism spectrum disorder (ASD), including why it might be considered problematic and events associated with its occurrence. METHOD: We selected one form of higher level RRB-arranging and ordering-that was rated as severe for a large percentage of the population sampled. We interviewed 20 students' teachers and conducted naturalistic observations for 15 of those students. RESULTS: The characteristics of arranging and ordering varied across, and sometimes within, individuals. Problems associated with compulsive-like (1) behaviour also varied, with several unanticipated reported problems. With the exception of attention, social consequences were relatively infrequent. CONCLUSIONS: These data highlight the need for research on the assessment and treatment of arranging and ordering and clinical attention to compulsive-like behaviour in ASD. Interviews and naturalistic observations are useful for structuring additional observations and analyses. PMID- 23984885 TI - Comparison of two types of Actiwatch with polysomnography in older adults with intellectual disability: a pilot study. AB - BACKGROUND: The Actiwatch is increasingly being used to investigate sleep. The aim of this study was to investigate which sensitivity setting of the Actiwatch is most suitable to detect sleep disturbance in older adults with intellectual disability (ID). METHOD: Two Actiwatch types were compared to polysomnography (PSG) in 10 older adults with mild ID, using a 1-min epoch-to-epoch comparison. Outcome measures were sleep detection percentage, wake detection percentage, and overall accuracy of both Actiwatches, and several sleep parameters. RESULTS: The high sensitivity setting of the Actiwatch appeared most suitable to detect sleep disturbance in older adults with ID (wake detection percentage = 54.6%, sleep detection percentage = 89.7%). Sleep parameters calculated using the high sensitivity setting corresponded well to PSG outcomes. Outcomes were similar for both Actiwatches. CONCLUSIONS: We recommend using the high sensitivity setting of the Actiwatch for clinical evaluation of sleep, and for epidemiological research in older adults with ID. PMID- 23984884 TI - A more "normal" life: residents', family, staff, and managers' experience of active support at a residential facility for people with physical and intellectual impairments. AB - BACKGROUND: Active support (AS) has gained popularity as an approach for assisting people with intellectual disability to engage more fully in everyday activities. Although research has identified changes in the extent that residents are engaged in meaningful activities, the experience of stakeholders such as residents, staff, and family in AS is underexplored. METHOD: A general inductive approach was used to analyse focus group and interview transcripts of residents (n = 4), staff (n = 13), and family (n = 2) about their experience of involvement in an AS pilot project at one residential care facility in New Zealand. RESULTS: Three superordinate themes common to all stakeholders' experiences emerged: "living normal lives," "caring means doing with," and "engaging with risk." CONCLUSION: Transitioning to AS had been enriching but at times challenging for all stakeholders. Valuing resident autonomy and preparedness for greater exposure to risk are significant considerations in the implementation of AS. PMID- 23984887 TI - The expression of V-ATPase is associated with drug resistance and pathology of non-small-cell lung cancer. AB - OBJECTIVE: This article aims to investigate the expression of vacuolar-H + ATPase (V-ATPase) in non-small cell lung cancer (NSCLC) and its variations with pathological type and grade. Furthermore, to evaluate the chemotherapy drug sensitivity of different cancer tissues as well as its correlation with V-ATPase expression in NSCLC. METHODS: V-ATPase expression was examined in 92 NSCLC tissue samples using the immunohistochemical Envision method and immunofluorescence assay. The location of V-ATPase expression was observed by confocal laser scanning microscopy and the difference of its expression rate was evaluated. The sensitivity of cancer tissues to chemotherapy drug was examined using MTT assay and its correlation with the V-ATPase expression was tested in NSCLC by Spearman rank correlation analysis. RESULTS: V-ATPase expression was mainly localized in the cell membrane and cytoplasm. The expression rate of V-ATPase was 71.43% in squamous cell lung cancer, significantly lower than that of the lung adenocarcinoma (83.72%, P = 0.000). In different pathological grades of squamous cell lung cancer, the expression rate of V-ATPase was 58.33% in grade II, significantly lower than that of the grade III (84.00%, P = 0.014). The expression rate of V-ATPase in grade II lung adenocarcinoma was 76.67%, significantly lower than that of the grade IotaIotaIota adenocarcinoma (100.0%, P = 0.012). Correlation analysis showed that the sensitivity of NSCLC tissues to cyclophosphamide, gemcitabine, doxorubicin, paclitaxel and cisplatin was significantly correlated with the V-ATPase expression rate (P < 0.05). CONCLUSIONS: V-ATPase was overexpressed in NSCLC. The expression of V-ATPase was related to the pathological type and grade of cancer and was likely associated with chemotherapy drug resistance in NSCLC. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7515811511020000. PMID- 23984889 TI - Monitoring neurochemical release from astrocytes using in vitro microdialysis coupled with high-speed capillary electrophoresis. AB - We have developed a novel in vitro approach for monitoring fast neurochemical dynamics in model cell systems using microdialysis sampling coupled with high speed capillary electrophoresis (CE). Cells from an immortalized astrocyte line (C8-D1A) were cultured in direct contact with the porous membrane of a microdialysis probe. Confocal microscopy was used to confirm cell viability and confluency over the microdialysis sampling region. Small molecules released from the astrocytes were efficiently sampled by the probe due to the direct contact with the membrane. Microdialysis sampling was coupled with online, high-speed CE allowing changes in the dialysate concentration of small molecule amine neurochemicals to be monitored with 20 s temporal resolution. Basal release of a number of important analytes was detected including glycine, taurine, D-serine, and glutamate. The ability of the in vitro microdialysis-CE instrument to monitor dynamic changes in analyte concentration was assessed by transferring a probe cultured with astrocytes from a solution containing artificial cerebrospinal fluid (aCSF) to a high K(+) solution (100 mM K(+)-aCSF). Upon stimulation, the observed concentration of a number of key neurochemicals increased dramatically including glycine (700%), taurine (185%), and serine (215%). Amino acids such as phenylalanine and valine, which are not known to respond to cellular swelling mechanisms, were unaffected by the K(+) stimulation. PMID- 23984890 TI - Minimal functional brain differences between older adults with and without mild cognitive impairment during the stroop. AB - This investigation compared the neural correlates of inhibition in normal older adults (OAs) and OAs with mild cognitive impairment (MCI). It was hypothesized the MCI group would require a greater amount of resources for inhibition, and therefore display greater functional activation in specific regions of interest (ROIs). Twenty-six OAs without and 17 with MCI completed the Stroop task during functional neuroimaging, and completed additional out-of-scanner neuropsychological measures. During inhibition, there were minimal functional Magnetic Resonance Imaging (fMRI) differences found between groups in a priori specified ROIs and with post-hoc multiple regression analyses. However, these minimal differences did not survive corrected thresholds. Robust differences were found with several tasks of a neuropsychological screening battery. The results of this study suggest only very minimal group differences in fMRI activation during inhibition which may not reliably identify MCI, and this condition may be best detected by traditional neuropsychological techniques. PMID- 23984891 TI - Aging: an important risk factor in chemotherapy-associated vascular diseases. PMID- 23984888 TI - ITGB5 and AGFG1 variants are associated with severity of airway responsiveness. AB - BACKGROUND: Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity. METHODS: A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects. RESULTS: The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1. CONCLUSIONS: Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings. PMID- 23984893 TI - Pertuzumab for the treatment of metastatic breast cancer. AB - Approximately 15% of primary breast cancers have amplification/overexpression of the cell surface receptor HER2. Despite the major improvements in survival achieved by the use of adjuvant trastuzumab, many of these patients still develop metastatic disease, and other patients with HER2 overexpressing breast cancer have overt metastases at first diagnosis. There remains therefore a pressing medical need to identify better therapies for these patients. Pertuzumab is a humanized antibody that targets and binds HER2. Although only modestly active against breast cancer when used as a single agent, pertuzumab has demonstrated significant activity when combined with trastuzumab against trastuzumab-resistant and -sensitive disease. Multiple clinical trials are underway to define the optimal use of pertuzumab (combined with either trastuzumab or trastuzumab-DM1) together with a range of cytotoxic agents or endocrine therapy in multiple settings of HER2-overexpressing breast cancer. This article summarizes the use of pertuzumab in the metastatic disease setting. PMID- 23984894 TI - Palonosetron for the prevention of chemotherapy-induced nausea and vomiting. AB - Chemotherapy-induced nausea and vomiting (CINV) remains both a feared side effect of cancer treatment and a focus of many supportive care initiatives/guidelines. The class of medications known as serotonin receptor antagonists (5-HT3RAs) are integral in the prevention of CINV from both moderately and highly emetogenic chemotherapy. Palonosetron (ALOXI((r))), a second-generation 5-HT3RA, has a higher affinity for the 5-HT3 receptor, has a longer half-life and has unique interactions with the 5-HT3 receptor compared with the current first-generation 5 HT3RA such as ondansetron, granisetron, dolasetron and tropisetron. This may allow palonosetron an advantage in control of CINV. This review article examines the available evidence, the pharmacokinetics and the safety and tolerability of palonosetron in the prevention of CINV. PMID- 23984895 TI - Rational cotargeting of Pim-1 and Akt in prostate cancer. AB - Evaluation of: Cen B, Mahajan S, Wang W, Kraft AS. Elevation of receptor tyrosine kinases by small molecule AKT inhibitors in prostate cancer is mediated by Pim-1. Cancer Res. 73(11), 3402-3411 (2013). The PI3K/Akt pathway is a key pathway in many advanced and aggressive cancers. Targeted inhibition of this pathway is currently an actively pursued therapeutic strategy. However, blockade of this pathway with inhibitors has been challenging, with up-regulation of reciprocal feedback pathways contributing to treatment failures. The article evaluated presents mechanistic data on how Pim is a critical mediator of the receptor tyrosine elevation induced by Akt inhibition. Pim-1 kinases are overexpressed in resistant and aggressive cancers. Following Akt inhibition, Pim- regulates receptor tyrosine kinases up-regulation, at least in part, through a cap independent translation. This research leads the way for further evaluation of co targeting strategies using Pim-1 inhibitors in combination with PI3K/Akt pathway inhibitors. PMID- 23984896 TI - The classification of invasive carcinoma of the breast. AB - The classification of invasive breast carcinoma assists diagnosis, allows for comparison of different patient groups in clinical trials and facilitates epidemiological analysis. For the individual patient, accurate tumor classification informs clinical decision-making with emphasis on assessment of prognosis and treatment formulation. Tumor grade is an independent prognostic indicator and is calculated by assessing specific tumor characteristics microscopically. The Tumor Node Metastasis staging system, produced by the American Joint Committee on Cancer Union for International Cancer Control, combines information about the primary tumor size, the status of the regional lymph nodes and the presence or absence of distant metastases at diagnosis to classify disease. In recent years, the use of gene expression profiling technology has led to the development of the molecular classification of breast cancer and has highlighted the importance of hormone receptor and HER2 oncogenic pathways, with particular reference to targeted chemotherapy. Tumor typing involves the identification of 'no special type' carcinoma with variable clinical, histological and molecular characteristics and 'special type' carcinomas that are usually associated with a particular set of prognostic and predictive indices. Some special type carcinomas have unique biological features that influence diagnostic investigation and clinical management. PMID- 23984897 TI - Ductal carcinoma in situ: an overview. AB - Advances in methods used to diagnose breast cancer have resulted in the increased detection of ductal carcinoma in situ; most of these are detected by screening mammograms and are confirmed by core needle biopsy. Currently, classification schemas are moving toward a molecular approach. Treatment options for patients with ductal carcinoma in situ are multiple and take into consideration end points such as local, regional or distant recurrence, overall survival and quality of life. Treatment methods continue to be controversial and debated in the oncology community. The quality of local control is multifactorial and depends on adequate surgical clearance, biological characteristics of the tumor, clinical presentation and the possibility of radiation therapies. PMID- 23984898 TI - The challenges of individualized care for older patients with localized breast cancer. AB - Individualized care is achieved when the appropriate screening and/or evaluative tests are used, the treatment plan is driven by evidence-based data and the patient's functional ability, physical and mental health, preference and social situation are incorporated into treatment decisions. Breast cancer is a disease of aging; yet, the management of breast cancer in older women in most cases lacks evidence from prospective randomized clinical trials (i.e., level 1 evidence) to support treatment recommendations. Older women are underrepresented in therapeutic clinical studies, even though studies show that selected fit older women enrolled on clinical trials derive similar benefits as younger women. Very few studies have focused on the distribution and biological behavior of different molecular subtypes of breast cancer in older women making it difficult to conclude whether old age adds extra biological complexity. A comprehensive geriatric assessment that includes a multidimensional process designed to assess functional ability, physical health, cognitive and mental health, social issues and environmental situation of elderly person should be an integral part of individualized care for older patients with breast cancer. However, incorporation of this tool into standard oncology practice is very slow despite the expected steep increase in older individuals with cancer projected over the next 25 years. All of the factors mentioned above hinder progress in delivering individualized care to older patients with breast cancer. This article provides an overview on progress and challenges of individualized and personalized health care in older women with breast cancer. PMID- 23984899 TI - Senescence bypass in mesenchymal stem cells: a potential pathogenesis and implications of pro-senescence therapy in sarcomas. AB - Cellular senescence is a mechanism that limits the lifespan of somatic cells as the results of replicative proliferation and response to stresses, and that prevents undesired oncogenic changes constituting a barrier against immortalization and tumorigenesis. Mesenchymal stem cells (MSCs) reside in a variety of tissues, and participates in tissue maintenance with their multipotent differentiation ability. MSCs are also considered to be as cells of origin for certain type of sarcomas. We reviewed the mechanisms of cellular senescence in MSCs and hypothesized senescence bypass as the potential pathogenesis for sarcoma development, and proposed the possibility of senescence induction therapy for an alternative treatment strategy against sarcomas, especially cells with the resistance to conventional chemo and radiotherapy including sarcoma stem cells. PMID- 23984900 TI - Antineoplastic therapy-induced pulmonary toxicity. AB - Pulmonary complications of antineoplastic therapy are common and are an important cause of respiratory morbidity. The pulmonary toxicity should be taken into account in every patient with respiratory problems who is or has been treated with antineoplastic agents. The diagnosis of drug-induced pulmonary toxicity is complex and should be based on the medical history, clinical, radiological and pathological findings. None of them are specific but they can guide the diagnostic process. The treatment of pulmonary abnormalities caused by chemotherapy is mostly supportive and based on cessation of the causative agent. However, the therapeutic options in oncology setting are usually limited thus the decision about changing the treatment should be taken with caution. PMID- 23984901 TI - Delayed times to tissue fixation result in unpredictable global phosphoproteome changes. AB - Protein phosphorylation controls the activity of signal transduction pathways regulated by kinases and phosphatases. Little is known, however, about the impact of preanalytical factors, for example, delayed times to tissue fixation, on global phosphoprotein levels in tissues. The aim of this study was to characterize the potential effects of delayed tissue preservation (cold ischemia) on the levels of phosphoproteins using targeted and nontargeted proteomic approaches. Rat and murine liver samples were exposed to different cold ischemic conditions ranging from 10 to 360 min prior to cryopreservation. The phosphoproteome was analyzed using reverse phase protein array (RPPA) technology and phosphoprotein-enriched quantitative tandem mass spectrometry (LC-MS/MS). RPPA analysis of rat liver tissues with long (up to 360 min) cold ischemia times did not reveal statistically significant alterations of specific phosphoproteins even though nonphosphorylated cytokeratin 18 (CK18) showed increased levels after 360 min of delay to freezing. Keeping the samples on ice prior to cryopreservation prevented this effect. LC-MS/MS-based quantification of 1684 phosphorylation sites in rat liver tissues showed broadening of their distribution compared to time point zero, but without reaching statistical significance for individual phosphosites. Similarly, RPPA analysis of mouse liver tissues with short (<60 min) cold ischemia times did not reveal directed or predictable changes of protein and phosphoprotein levels. Using LC-MS/MS and quantification of 791 phosphorylation sites, we found that the distribution of ratios compared to time point zero broadens with prolonged ischemia times, but these were rather undirected and diffuse changes, as we could not detect significant alterations of individual phosphosites. On the basis of our results from RPPA and LC-MS/MS analysis of rat and mouse liver tissues, we conclude that prolonged cold ischemia results in unspecific phosphoproteome changes that can be neither predicted nor assigned to individual proteins. On the other hand, we identified a number of phosphosites which were extraordinarily stable even after 360 min of cold ischemia and, therefore, may be used as general reference markers for future companion diagnostics for kinase inhibitors. PMID- 23984902 TI - The potential of cell-based therapy in lung diseases. AB - INTRODUCTION: Many lung diseases have high morbidity and mortality rates and there are no cures or treatments apart from mechanical ventilation or transplantation. Cell-based therapies are currently an area of intense research, and many groups are working to translate successful in vitro results into treatments that are safe for patients. AREAS COVERED: This review discusses several types of stem and progenitor cells that have been proven likely candidates for cell therapies, as well as their applications so far in specific acute and chronic lung diseases, focusing on their mechanisms of action and how best they can be directed toward clinical aims. EXPERT OPINION: The research on cell therapies for the lung, particularly regarding mesenchymal stem cells (MSCs), is promising, but there is still much uncertainty surrounding the mechanisms of MSC action and the factors relevant to clinical applications such as the optimal timing of dosage. Future studies will focus on the microenvironment of the stem cells, including the role of microRNAs and extracellular vesicles. PMID- 23984904 TI - The application of Ussing chambers for determining the impact of microbes and probiotics on intestinal ion transport. AB - Host-microbe interactions have gained considerable attention in recent years with regards to their role in various organic disorders and diseases. In particular, research efforts have focused on the intestinal microbiota, where the largest and most diverse populations not only co-exist with the host, but also directly influence the state and function of the gastrointestinal (GI) tract. Moreover, both human and animal studies alike are now beginning to show a positive influence of probiotic bacteria on GI disorders associated with diarrhoea or constipation. Diarrheagenic GI diseases, such as those caused by Vibreo cholera or enterpathogenic Eschericia coli, have well-characterised interactions with the host that explain much of the observed symptoms, in particular severe diarrhoea. However, the mechanisms of action of nonpathogenic bacteria or probiotics on host physiology are less clearly understood. In the context of defining the mechanisms of action of probiotics in vitro, the Ussing chamber has proven to be a particularly useful tool. Here, we will present data from several studies that have defined molecular targets for microbes and putative probiotics in the regulation of intestinal secretory and absorptive function, and we will discuss these in the context of their application in pathogen- or inflammation-induced alterations in intestinal ion transport. PMID- 23984903 TI - Genome-wide gene expression profiling of stress response in a spinal cord clip compression injury model. AB - BACKGROUND: The aneurysm clip impact-compression model of spinal cord injury (SCI) is a standard injury model in animals that closely mimics the primary mechanism of most human injuries: acute impact and persisting compression. Its histo-pathological and behavioural outcomes are extensively similar to human SCI. To understand the distinct molecular events underlying this injury model we analyzed global mRNA abundance changes during the acute, subacute and chronic stages of a moderate to severe injury to the rat spinal cord. RESULTS: Time series expression analyses resulted in clustering of the majority of deregulated transcripts into eight statistically significant expression profiles. Systematic application of Gene Ontology (GO) enrichment pathway analysis allowed inference of biological processes participating in SCI pathology. Temporal analysis identified events specific to and common between acute, subacute and chronic time points. Processes common to all phases of injury include blood coagulation, cellular extravasation, leukocyte cell-cell adhesion, the integrin-mediated signaling pathway, cytokine production and secretion, neutrophil chemotaxis, phagocytosis, response to hypoxia and reactive oxygen species, angiogenesis, apoptosis, inflammatory processes and ossification. Importantly, various elements of adaptive and induced innate immune responses span, not only the acute and subacute phases, but also persist throughout the chronic phase of SCI. Induced innate responses, such as Toll-like receptor signaling, are more active during the acute phase but persist throughout the chronic phase. However, adaptive immune response processes such as B and T cell activation, proliferation, and migration, T cell differentiation, B and T cell receptor-mediated signaling, and B cell- and immunoglobulin-mediated immune response become more significant during the chronic phase. CONCLUSIONS: This analysis showed that, surprisingly, the diverse series of molecular events that occur in the acute and subacute stages persist into the chronic stage of SCI. The strong agreement between our results and previous findings suggest that our analytical approach will be useful in revealing other biological processes and genes contributing to SCI pathology. PMID- 23984905 TI - Mangiferin mitigates diabetic cardiomyopathy in streptozotocin-diabetic rats. AB - The purpose of this study was to investigate the cardioprotective effect of mangiferin on diabetic cardiomyopathy (DCM). The DCM model was induced by a high fat diet and a low dose of streptozotocin. We evaluated the characteristics of DCM by serial echocardiography, electron microscopy, histopathologic analysis of cardiomyocyte fibrosis area, and Western blot analysis of matrix metalloproteinase-2 (MMP-2) and MMP-9 expression. Rats with DCM showed severe left ventricular dysfunction and cardiac fibrosis. Mangiferin mitigated DCM and prevented the accumulation of myocardial collagen. These anatomic findings were accompanied by significant improvements in cardiac function. Based on these results, we conclude that mangiferin has a therapeutic effect on DCM and improves cardiac function. PMID- 23984908 TI - Three new species of coccidia (Apicomplexa: Eimeriidae) from skinks, Lipinia spp. (Sauria: Scincidae), from Oceania. AB - Between September 1991 and March 1993, 25 moth skinks (Lipinia noctua) were collected from various localities on the Cook Islands, Fiji, Papua New Guinea (PNG), and Vanuatu and examined for coccidians. In addition, a single Roux's lipinia skink (Lipinia rouxi) was collected from PNG and examined for coccidia. Sixteen (64%) L. noctua were found to harbor 2 new eimerians, and L. rouxi harbored another new Eimeria sp. Oocysts of Eimeria lipinia n. sp. from 9 (36%) L. noctua from the Cook Islands, Fiji, and PNG were subspherical with a bilayered wall and measured (L * W) 18.6 * 16.9 MUm, with a L/W ratio of 1.1. Both micropyle and oocyst residuum were absent, but a polar granule was present. Oocysts of Eimeria melanesia n. sp. from 6 (24%) L. noctua from Fiji and Vanuatu and a single L. rouxi from PNG were subspherical to ellipsoidal with a bilayered wall and measured 19.8 * 17.5 MUm, and L/W was 1.1. Both micropyle and oocyst residuum were absent, but a single or fragmented polar granule was present. Oocysts of Eimeria lessoni n. sp. from 1 (4%) L. noctua from PNG were cylindroidal with a bilayered wall and measured 28.1 * 15.7 MUm, and L/W was 1.8. Both micropyle and oocyst residuum were absent, but a single polar granule was present. These represent the third report of Eimeria spp. reported from any host on PNG and the only coccidians, to our knowledge, ever described from L. noctua and L. rouxi and from the Cook Islands and Vanuatu. PMID- 23984906 TI - Heterogeneity in cost-effectiveness of lifestyle counseling for metabolic syndrome risk groups -primary care patients in Sweden. AB - BACKGROUND: Clinical trials have indicated that lifestyle interventions for patients with lifestyle-related cardiovascular and diabetes risk factors (the metabolic syndrome) are cost-effective. However, patient characteristics in primary care practice vary considerably, i.e. they exhibit heterogeneity in risk factors. The cost-effectiveness of lifestyle interventions is likely to differ over heterogeneous patient groups. METHODS: Patients (62 men, 80 women) in the Kalmar Metabolic Syndrome Program (KMSP) in primary care (Kalmar regional healthcare area, Sweden) were divided into three groups reflecting different profiles of metabolic risk factors (low, middle and high risk) and gender. A Markov model was used to predict future cardiovascular disease and diabetes, including complications (until age 85 years or death), with health effects measured as QALYs and costs from a societal perspective in Euro (EUR) 2012, discounted 3%. Simulations with risk factor levels at start and at 12 months follow-up were performed for each group, with an assumed 4-year sustainability of intervention effects. RESULTS: The program was estimated cost-saving for middle and high risk men, while the incremental cost vs. do-nothing varied between EUR 3,500 - 18,000 per QALY for other groups. There is heterogeneity in the cost effectiveness over the risk groups but this does not affect the overall conclusion on the cost-effectiveness of the KMSP. Even the highest ICER (for high risk women) is considered moderately cost-effective in Sweden. The base case result was not sensitive to alternative data and methodology but considerably affected by sustainability assumptions. Alternative risk stratifications did not change the overall conclusion that KMSP is cost-effective. However, simple grouping with average risk factor levels over gender groups overestimate the cost effectiveness. CONCLUSIONS: Lifestyle counseling to prevent metabolic diseases is cost-effective in Swedish standard primary care settings. The use of risk stratification in the cost-effectiveness analysis established that the program was cost-effective for all patient groups, even for those with very high levels of lifestyle-related risk factors for the metabolic syndrome diseases. Heterogeneity in the cost-effectiveness of lifestyle interventions in primary care patients is expected, and should be considered in health policy decisions. PMID- 23984907 TI - Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. AB - Recently the clinical importance of human organic cation transporters 1 (hOCT1/SLC22A1) and 2 (hOCT2/SLC22A2) in drug disposition, for example, clearance, toxicity, and drug-drug interactions, have been highlighted [Annu. Rev. Pharmacol. Toxicol. 2012, 52, 249-273; Nat. Rev. Drug Discovery 2010, 9 (3), 215-236]. Consequently, there is an extensive need for experimental assessment of structure-transport relationships as well as tools to predict drug uptake by these transporters in ADMET (absorption, distribution, metabolism, excretion, toxicity) investigations. In the present study, we developed a robust assay for screening unlabeled compound uptake by hOCT1 and hOCT2 using transfected HEK293 cells. For the first time, an extensive data set comprising uptake of 354 compounds is presented. As expected, there was a large overlap in substrate specificity between the two organic cation transporters. However, several compounds selectively taken up by either hOCT1 or hOCT2 were identified. In particular, a chemical series of phenylthiophenecarboxamide ureas was identified as selective hOCT1 substrates. Moreover, the drivers for transport differed: molecular volume was the most important determinant of hOCT1 substrates, whereas H-bonding parameters like polar surface area (PSA) dominated for hOCT2. PMID- 23984909 TI - Isolation and structural characterisation of a propoxyphenyl-linked thiohomosildenafil analogue found in a herbal product. AB - A propoxyphenyl-linked thiohomosildenafil analogue, one of the sildenafil analogues, was found in an herbal product. It was isolated by semi-preparative high-performance liquid chromatography (HPLC). The structure was established based on a comparison of chromatographic and spectroscopic behaviour with other sildenafil analogues using HPLC with diode array detection, quadrupole time-of flight mass spectrometry (Q-TOF/MS), and nuclear magnetic resonance (NMR) spectroscopy. The HPLC analysis showed separation from known sildenafil analogues with a similar chromatographic retention time. An [M + H](+) ion at m/z 519.22 was detected by mass spectrometry corresponding to an empirical formula of C24H34N6O3S2. The structure was similar to that of thiohomosildenafil, except that the ethoxy group attached to the phenyl ring was substituted for a propoxy group. It was assigned as 5-[2-propoxy-5-(4-ethylpiperazin-4-ylsulfonyl)phenyl]-3 methyl-1-n-propyl-4,5,dihydro-1H-pyrazole[7,1,d]pyrimidin-4-thione and named as propoxyphenyl-thiohomosildenafil because the structure was considerably similar to thiohomosildenafil. PMID- 23984910 TI - Unveiling stable group IV alloy nanowires via a comprehensive search and their electronic band characteristics. AB - By means of density functional theory calculations, the cluster expansion method, and Monte Carlo simulations, we identify the stable spatial configurations (ground states) for [100] CSi, GeSi, and SnSi alloy nanowires (NWs) across compositions. In particular, we find that stable configurations of GeSiNWs and SnSiNWs exhibit core-shell segregation tendencies, while those of CSiNWs favor ordering. Moreover, we show compositional ranges where the band gaps are expected to vary linearly with composition, allowing predictable band gap fine-tuning. We also predict composition ranges where the spatial separation of near-band gap states are imminent, making it possible for electron-hole charge separation. By addressing both the issues of stability and the compositional trend of electronic band structure, our work should prove useful for designing alloy NWs of smaller dimensions. PMID- 23984911 TI - Synthesis of open-shell, bimetallic Mn/Fe trinuclear clusters. AB - Concomitant deprotonation and metalation of hexadentate ligand platform (tbs)LH6 ((tbs)LH6 = 1,3,5-C6H9(NHC6H4-o-NHSiMe2(t)Bu)3) with divalent transition metal starting materials Fe2(Mes)4 (Mes = mesityl) or Mn3(Mes)6 in the presence of tetrahydrofuran (THF) resulted in isolation of homotrinuclear complexes ((tbs)L)Fe3(THF) and ((tbs)L)Mn3(THF), respectively. In the absence of coordinating solvent (THF), the deprotonation and metalation exclusively afforded dinuclear complexes of the type ((tbs)LH2)M2 (M = Fe or Mn). The resulting dinuclear species were utilized as synthons to prepare bimetallic trinuclear clusters. Treatment of ((tbs)LH2)Fe2 complex with divalent Mn source (Mn2(N(SiMe3)2)4) afforded the bimetallic complex ((tbs)L)Fe2Mn(THF), which established the ability of hexamine ligand (tbs)LH6 to support mixed metal clusters. The substitutional homogeneity of ((tbs)L)Fe2Mn(THF) was determined by (1)H NMR, (57)Fe Mossbauer, and X-ray fluorescence. Anomalous scattering measurements were critical for the unambiguous assignment of the trinuclear core composition. Heating a solution of ((tbs)LH2)Mn2 with a stoichiometric amount of Fe2(Mes)4 (0.5 mol equiv) affords a mixture of both ((tbs)L)Mn2Fe(THF) and ((tbs)L)Fe2Mn(THF) as a result of the thermodynamic preference for heavier metal substitution within the hexa-anilido ligand framework. These results demonstrate for the first time the assembly of mixed metal cluster synthesis in an unbiased ligand platform. PMID- 23984912 TI - Fine modulation of the respiratory syncytial virus M2-1 protein quaternary structure by reversible zinc removal from its Cys(3)-His(1) motif. AB - Human respiratory syncytial virus (hRSV) is a worldwide distributed pathogen that causes respiratory disease mostly in infants and the elderly. The M2-1 protein of hRSV functions as a transcription antiterminator and partakes in virus particle budding. It is present only in Pneumovirinae, namely, Pneumovirus (RSV) and Metapneumovirus, making it an interesting target for specific antivirals. hRSV M2 1 is a tight tetramer bearing a Cys3-His1 zinc-binding motif, present in Ebola VP30 protein and some eukaryotic proteins, whose integrity was shown to be essential for protein function but without a biochemical mechanistic basis. We showed that removal of the zinc atom causes dissociation to a monomeric apo-M2-1 species. Surprisingly, the secondary structure and stability of the apo-monomer is indistinguishable from that of the M2-1 tetramer. Dissociation reported by a highly sensitive tryptophan residue is much increased at pH 5.0 compared to pH 7.0, suggesting a histidine protonation cooperating in zinc removal. The monomeric apo form binds RNA at least as well as the tetramer, and this interaction is outcompeted by the phosphoprotein P, the RNA polymerase cofactor. The role of zinc goes beyond stabilization of local structure, finely tuning dissociation to a fully folded and binding competent monomer. Removal of zinc is equivalent to the disruption of the motif by mutation, only that the former is potentially reversible in the cellular context. Thus, this process could be triggered by a natural chelator such as glutathione or thioneins, where reversibility strongly suggests a modulatory role in the participation of M2-1 in the assembly of the polymerase complex or in virion budding. PMID- 23984913 TI - SU6668 suppresses proliferation of triple negative breast cancer cells through down-regulating MTDH expression. AB - BACKGROUND: The multiple tyrosine kinase inhibitors SU6668 have a promising therapeutic effect on the progression of hematological malignancies and some solid tumors. Here, we determined its effect on triple negative breast cancer (TNBC) cells and explored the potential molecular mechanism. METHODS: In this study, MDA-MB-231 cells were treated with SU6668 (15 MUM, 30 MUM) for 72 h and the change of proliferation was examined by MTT and tablet cloning. DNA ploidy was detected by flow cytometric analysis with PI staining. Double-label immunofluorescence method was used to detect the expression and distribution of MTDH proteins. VEGFR2, HIF-1alpha, MTDH, E-cadhrein, and SMA expressions were detected by Western bolt assay. RESULTS: This study showed that SU6668 inhibited the proliferation and induced polyploidization of MDA-MB-231 cells in a dose dependent form. SU6668 exposure increased the distribution of MTDH in cytoplasm and decreased its distribution in nuclei. After the treatment of SU6668, VEGFR2, HIF-1alpha, MTDH and SMA proteins were down-regulated, while E-cadhrein was up regulated in MDA-MB-231 cells. CONCLUSIONS: In conclusion, SU6668 exposure maybe induces polyploidization, inhibit EMT and influence the expression of MTDH, which suppresses the proliferation in TNBC cells. MTDH is a key signal protein in downstream of VEGF/HIF-1alphapathway in MDA-MB-231 cells, which may be used as the potential target in the treatment of TNBC. PMID- 23984914 TI - Influences of developmental age on the resolution of diffuse traumatic intracranial hemorrhage and axonal injury. AB - This study investigated the age-dependent injury response of diffuse traumatic axonal injury (TAI) and regional subdural and subarachnoid intracranial hemorrhage (ICH) in two pediatric age groups using a porcine head injury model. Fifty-five 5-day-old and 40 four-week-old piglets-which developmentally correspond to infants and toddlers, respectively-underwent either a sham injury or a single rapid non-impact rotational injury in the sagittal plane and were grouped by post-TBI survival time (sham, 3-8 h, one day, 3-4 days, and 5-6 days). Both age groups exhibited similar initial levels of ICH and a significant reduction of ICH over time (p<0.0001). However, ICH took longer to resolve in the five-day-old age group. At 5-6 days post-injury, ICH in the cerebrum had returned to sham levels in the four-week-old piglets, while the five-day-olds still had significantly elevated cerebral ICH (p=0.012). Both ages also exhibited similar resolution of axonal injury with a peak in TAI at one day post-injury (p<0.03) and significantly elevated levels even at 5-6 days after the injury (p<0.008), which suggests a window of vulnerability to a second insult at one day post injury that may extend for a prolonged period of time. However, five-day-old piglets had significantly more TAI than four-week-olds overall (p=0.016), which presents some evidence for an increased vulnerability to brain injury in this age group. These results provide insight into an optimal window for clinical intervention, the period of increased susceptibility to a second injury, and an age dependency in brain injury tolerance within the pediatric population. PMID- 23984915 TI - Iron/tetramethylethylenediamine-catalyzed ambient-temperature coupling of alkyl Grignard reagents and aryl chlorides. AB - Tetramethylethylenediamine (TMEDA) acts as cheap and readily removed ligand in the iron-catalyzed coupling of alkyl Grignard reagents and activated aryl chlorides. The use of TMEDA allows for low ligand and iron catalyst loading as well as an increased reaction concentration and an ambient reaction temperature on a mole scale. PMID- 23984916 TI - Anomalous stereoselectivity in the Wittig reaction: the role of steric interactions. AB - Density functional theory calculations combined with a distortion/interaction energy analysis show that the anomalous Z selectivity observed in Wittig reactions of ortho-substituted benzaldehydes is not caused by phosphorus heteroatom interactions in the addition transition state, as assumed in earlier work, but is predominantly steric in nature. The calculations reproduced correctly the stereoselectivity preferences for a wide range of reactant pairs as well as relative reactivities for different substituent types, providing deeper structural insight into the mechanism of Wittig olefination. PMID- 23984917 TI - The down-regulation of GNAO1 and its promoting role in hepatocellular carcinoma. AB - GNAO1 (guanine nucleotide-binding protein, alpha-activating activity polypeptide O) is a member of the subunit family of Galpha proteins, which are molecular switchers controlling signal transductions and whose deregulation can promote oncogenesis. HCC (hepatocellular carcinoma) is one of the malignant tumours around the world, which summons novel biomarkers or targets for effective diagnosis and treatments. The present study was aimed to investigate the expression of GNAO1 in HCC patient tissues and the possible mechanisms by which it took effects. The expression of GNAO1 was detected by IHC (immunohistochemistry) and real-time qPCR (quantitative PCR). Cell proliferation test and cell senescence test were then performed to explore the role of GNAO1 in the occurrence and development of HCC. It was revealed that the level of GNAO1 was comparably less in HCC tissues than in the adjacent tissues. Furthermore, down-regulation of GNAO1 increased cell proliferation, while suppressing the senescence of HCC cells. In conclusion, our findings revealed and confirmed the importance of GNAO1 in HCC, indicating that GNAO1 is a potential biomarker as well as a promising therapeutic target for HCC. PMID- 23984918 TI - Top-down processing modulates older adults' susceptibility to noise. AB - The present study examined older and younger adults' ability to use top-down processes to mitigate the effects of display noise during simple feature, visual search. As display noise levels increased, older adults (age 60-74 years, n = 32) exhibited greater top-down search reaction time (RT) benefits (bottom-up minus top-down search RT), compared to younger adults (age 18-27, n = 32). Older adults' ability to mitigate the effects of noise was further assessed with RT variability, as measured by intra-individual standard deviations across trials. Older adults again exhibited larger top-down benefits (i.e., less RT variability) compared to younger adults, and more so when display noise was present vs. absent. These results suggest a sparing of top-down processes with age (Madden, Whiting, Spaniol, & Bucur, 2005; Psychology and Aging, 20, 317), and that top down processes in older adults enhance search efficiency by optimizing signal-to noise ratios. PMID- 23984919 TI - Ethnomedicinal study of plants used for human ailments in Ankober District, North Shewa Zone, Amhara Region, Ethiopia. AB - BACKGROUND: Ankober District has long been inhabited by people who have a long tradition of using medicinal plants to treat human ailments. Overexploitation of medicinal plants coupled with an ever-increasing population growth, deforestation and agricultural land expansion threatens plants in the area. Hence, this study aimed at documenting and analyzing the plant-based ethnomedicinal knowledge of the people in order to preserve the dwindling indigenous knowledge. METHODS: Ethnobotanical data were collected using semi-structured interviews, focus group discussions, participant observation and walk-in-the-woods. Quantitative approaches were used to determine Informant Consensus Factor (ICF) and Fidelity level (FL) values. Statistical tests were used to compare the indigenous knowledge on medicinal plants among different informant categories. RESULTS: A total of 135 medicinal plant species belonging to 128 genera and 71 botanical families were reported to treat human diseases in the District. Families Asteraceae (12 species, 9%) and Fabaceae (10, 7.4%) were found to be best represented in the area. About 44% of preparations were reported to be obtained from roots. Significant difference (P < 0.05) was observed on the mean number of medicinal plants reported by groups of respondents compared within age, literacy level and experience parameters. Highest ICF values were recorded for gastro intestinal & parasitic and dermatological disease categories (0.70 each) indicating best agreement among informants knowledge on medicinal plants used to treat aliments in these categories. Highest fidelity level values were recorded for Zehneria scabra (95%) and Hagenia abyssinica (93.75%) showing conformity of knowledge on species of best healing potential. Podocarpus falcatus was ranked first in a direct matrix ranking exercise of multipurpose medicinal plants. The output of preference ranking exercise indicated that Olea europaea subsp. cuspidata was the most preferred species to treat atopic eczema. CONCLUSION: The study revealed that Ankober District is rich in medicinal plant diversity and associated indigenous knowledge. However, anthropogenic factors coupled with acculturation and very poor conservation efforts threaten medicinal plant survival in the area. Promoting a complementary in situ and ex situ conservation strategy for medicinal plants of the District is highly recommended. PMID- 23984920 TI - Novel identification of arsenolipids using chemical derivatizations in conjunction with RP-HPLC-ICPMS/ESMS. AB - The identification of molecular structures of an arsenolipid is pivotal for its toxicological assessment and in understanding the arsenic cycling in the environment. However, the analysis of these compounds in a lipid matrix is an ongoing challenge. So far, only a few arsenolipids have been reported, including arsenic fatty acids (AsFAs) and arsenic hydrocarbons (AsHCs). By means of RP-HPLC ICPMS/ESMS, we investigated Capelin oil ( Mallotus villosus ) for possible new species of arsenolipids. Twelve arsenolipids were identified in the fish oil including three AsFAs and seven AsHCs. Among the AsHCs, four that were identified had protonotated molecular masses of 305, 331, 347, and 359 and have not been reported before. In addition, the compounds with molecular formulas C20H44AsO(+) and C24H44AsO(+) were found in low concentrations and showed chromatographic properties and MS data consistent with cationic trimethylarsenio fatty alcohols. Derivatization by acetylation and thiolation coupled with accurate mass spectrometry was successfully used to establish the occurrence of this new class of arsenolipids as cationic trimethylarsenio fatty alcohols (TMAsFOH). PMID- 23984921 TI - The next 10 years in personalized medicine in cardiology. PMID- 23984922 TI - The end of ENDEAVOR IV: the stent comparison trial's final follow-up. PMID- 23984925 TI - Platelet reactivity tests for assessing antiplatelet drug response: what the clinician needs to know. AB - Antiplatelet therapy is a cornerstone in the treatment of cardiovascular disease to prevent ischemic events. Various tests have become clinically available to measure platelet function after antiplatelet treatment. A wide interpatient variability in the magnitude of platelet inhibition has been demonstrated in numerous studies, especially in response to clopidogrel. Several reasons including clinical, pharmacological and genetic factors have been identified. High on-clopidogrel platelet reactivity has been linked to adverse clinical outcome, in particular to stent thrombosis after percutaneous coronary interventions. New antiplatelet drugs including prasugrel and ticagrelor have been advocated to overcome the limitations of clopidogrel. Several studies addressed the concept of tailored antiplatelet treatment according to the results of platelet function testing. Within this review, we summarize the current status of personalized antiplatelet therapy for cardiovascular disease. PMID- 23984926 TI - Gene therapy for heart disease: molecular targets, vectors and modes of delivery to myocardium. AB - Despite the numerous hurdles that gene therapy has encountered along the way, clinical trials over the last few years are showing promising results in many fields of medicine, including cardiology, where many targets are moving toward clinical development. In this review, the authors discuss the current state of the art in terms of clinical and preclinical development. They also examine vector technology and available vector-delivery strategies. PMID- 23984924 TI - Cell and gene therapy for severe heart failure patients: the time and place for Pim-1 kinase. AB - Regenerative therapy in severe heart failure patients presents a challenging set of circumstances including a damaged myocardial environment that accelerates senescence in myocytes and cardiac progenitor cells. Failing myocardium suffers from deterioration of contractile function coupled with impaired regenerative potential that drives the heart toward decompensation. Efficacious regenerative cell therapy for severe heart failure requires disruption of this vicious circle that can be accomplished by alteration of the compromised myocyte phenotype and rejuvenation of progenitor cells. This review focuses upon potential for Pim-1 kinase to mitigate chronic heart failure by improving myocyte quality through preservation of mitochondrial integrity, prevention of hypertrophy and inhibition of apoptosis. In addition, cardiac progenitors engineered with Pim-1 possess enhanced regenerative potential, making Pim-1 an important player in future treatment of severe heart failure. PMID- 23984927 TI - Is bleeding a necessary evil? The inherent risk of antithrombotic pharmacotherapy used for stroke prevention in atrial fibrillation. AB - Current European atrial fibrillation (AF) guidelines have assigned a strong recommendation for the initiation of antithrombotic therapy to prevent thromboembolism in all but those AF patients at low risk (or with contraindications). Furthermore, the selection of antithrombotic therapy is based on the absolute risks of thromboembolism and bleeding, and the relative risk and benefit for a given patient. By their very mechanism of action, antithrombotic agents used for stroke prevention in AF will potentially increase the risk of bleeding events. Moreover, the introduction of novel oral anticoagulation agents have introduced new, hitherto ill-defined, deficiencies in the authors' knowledge with respect to anticoagulation monitoring, availability of direct antidotes, drug-drug interactions and the ability to appropriately control and reverse their actions if bleeding events occur. The authors present a comprehensive review on all aspects of bleeding related to currently licensed antithrombotic agents used for stroke prevention in patients with AF. PMID- 23984928 TI - Should ischemia be the main target in selecting a percutaneous coronary intervention strategy? AB - Contemporary studies have demonstrated that revascularization therapy targeted at coronary anatomy alone has not been able to consistently yield significant prognostic clinical outcomes. The practice of specific ischemia-targeted intervention for coronary disease in certain study populations has, however, produced important and reproducible clinical outcomes in terms of both symptoms and prognosis. We discuss the recent evidence and propose an ischemia-driven approach for selecting a percutaneous coronary intervention strategy. PMID- 23984929 TI - Screening methods in the diagnosis and assessment of children and adolescents with familial hypercholesterolemia. AB - Familial hypercholesterolemia is an autosomal dominant disorder. Heterozygous familial hypercholesterolemia (FH) has an estimated incidence of 1 per 300-500 births and is characterized by increased serum total- and low-density lipoprotein cholesterol levels and an increased risk of coronary heart disease. Early diagnosis and cholesterol-lowering treatment are essential to prevent premature coronary heart disease. Effective screening strategies are therefore of great importance. Screening can be done as selective or general population screening. There is no generally accepted screening program for FH in children and adolescents. In The Netherlands a systematic genetic family cascade screening program has been going on since 1994. In most countries there is no systematic screening for the disease, but clinical and genetic family cascade screening has been applied. Selective screening programs have failed to identify a large number of FH cases. Recommendations for general pediatric population screening have therefore emerged. Controversy exists as to which approach should be adopted. Family cascade screening has been estimated to be the most cost-effective screening method. No general pediatric screening program has been tested on a larger scale, validated or subjected to cost-benefit analyses. PMID- 23984930 TI - Non-invasive measurement of coronary plaque from coronary CT angiography and its clinical implications. AB - Coronary CT angiography (CTA) is increasingly used worldwide for direct, non invasive evaluation of the coronary arteries. Advances in computed tomography (CT) technology over the last decade have enabled such reliable imaging of the coronary arteries. Beyond arterial stenosis, coronary CTA also permits assessment of atherosclerotic plaque (including plaque burden) and coronary artery remodeling, previously only achievable through invasive means. It has been shown that coronary plaque volumes for non-calcified and mixed plaques and the arterial remodeling index, correlate closely with invasive intravascular ultrasound. Several studies have also shown a strong relationship of adverse plaque features imaged by coronary CTA with acute coronary syndrome, all-cause death, major adverse cardiovascular events and myocardial ischemia. The aim of this review is to summarize current methods for quantitative measurement of atherosclerotic plaque features from coronary CTA and to discuss their clinical implications. PMID- 23984931 TI - Probucol inhibits JAK2-STAT pathway activation and protects human glomerular mesangial cells from tert-butyl hydroperoxide induced premature senescence. AB - Human mesangial cells (HMCs) have a finite lifespan and eventually enter irreversible growth arrest known as cellular senescence, which is thought to contribute to kidney ageing and age-related kidney disorders such as chronic kidney disease. The JAK2-STAT pathway plays a pivotal role in transmitting cytokine signals, including cell proliferation, apoptosis, and differentiation, but whether it could regulate HMC senescence still remains to be explored. In our study, tert-butyl hydroperoxide (tBHP)-induced cells accelerated HMC senescence, as judged by increased senescence-associated beta-galactosidase stained positive cells, morphological changes, and G0-G1 cell cycle arrest. STAT1 and STAT3 activity were increased in tBHP-induced cells. After tBHP treatment, Bcl-2 protein expression decreased and Bax protein expression increased. Blocking the JAK2-STAT pathway with AG490 and using probucol significantly inhibited the progression of HMC senescence. Bax protein expression decreased, but Bcl-2 protein expression increased after AG490 and probucol treatment. Our results indicated that the JAK2-STAT pathway might mediate tBHP-induced HMC senescence through the Bcl-2-Bax pathway, and that probucol could attenuate HMC senescence by regulating STATs. PMID- 23984933 TI - Duodenal application of Li+ in a submaximal therapeutic dose inhibits exocrine pancreatic secretion and modulates gastro-duodenal myoelectrical activity in a conscious pig model. AB - This study tested whether duodenal application of lithium inhibits gastroduodenal motility, and whether it suppresses secretion from the exocrine pancreas. Five suckling pigs, 16-18 days old, were surgically fitted with 3 serosal electrodes on the wall of the gastric antrum and the duodenum for electromyography of smooth muscles, and with a pancreatic duct catheter and a duodenal T-cannula for collection and re-entrant flow of pancreatic juice. After the recovery period, on alternative days, each animal was tested once with an intraduodenal infusion of Li+ (100 mmol.L(-1) C3H5LiO3, 10 mL.kg(-1).h(-1)) for 1 h, and once with an intraduodenal infusion of NaCl (154 mM, 10 ml.kg(-1).h(-1)), also for 1 h, with the first treatment, i.e., Li+ or NaCl, randomly assigned. Individual pigs served as their own controls, with data recorded prior to a treatment being used as the baseline. Li+ increased the duration of quiescence (P < 0.05) and activity phase (P < 0.05) in the antrum, thus increasing (P < 0.05) the duration of antral myoelectrical cycles. Li+ shortened (P < 0.05) phase I, but it did not affect phase II or phase III or the MMC in the duodenum. Li+ inhibited pancreatic juice outflow as well as pancreatic enzyme and bicarbonate output (P < 0.05 for all pancreatic parameters). PMID- 23984932 TI - Endogenous retroviruses and multiple sclerosis-new pieces to the puzzle. AB - The possibility that retroviruses play a role in multiple sclerosis (MS) has long been considered; accumulating findings suggest this to be most likely in the form of human endogenous retroviruses (HERVs). A genetic test series of fifty endogenous retroviral loci for association with MS in Danes showed SNP markers near a specific endogenous retroviral locus, HERV-Fc1 located on the X chromosome, to be positive. Bout Onset MS was associated with the HERV-Fc1 locus, while a rarer form, Primary Progressive MS, was not. Moreover, HERV-Fc1 Gag RNA in plasma was increased 4-fold in patients with recent history of attacks, relative to patients in a stable state and to healthy controls.Finally, genetic variations in restriction genes for retroviruses influence the risk of MS, providing further support for a role of retroviral elements in disease.We speculate that endogenous retroviruses may activate the innate immune system in a variety of ways, involving the host proteins, TRIMs, TLRs, TREXs and STING. Observations in HIV-positive patients suggest that antiretroviral drugs can curb MS. Thus, these new findings regarding the etiology and pathogenesis of MS, suggest alternative ways to challenge autoimmune diseases. PMID- 23984934 TI - Zostavax : a subcutaneous vaccine for the prevention of herpes zoster. AB - INTRODUCTION: Herpes zoster (HZ) occurs as a reactivation of dormant varicella zoster virus (VZV), and occurs more frequently in the aging population or the immunocompromised due to waning cell-mediated immunity. Up to 1 million cases of HZ are reported annually in the USA with an estimated 10 - 30% of the population being affected by shingles in their lifetime. HZ is a debilitating illness, and while mortality is low, morbidity remains a significant cause for concern with prevention efforts aimed at reducing VZV reactivation and its complications. The HZ vaccine was approved by the US Food and Drug Administration for individuals aged 50-years or older. However, the Center for Disease Control and Prevention's Advisory Committee for Immunization Practices recommends the vaccine in individuals aged 60-years or older. AREAS COVERED: Recent literature investigating the efficacy and indications of live attenuated zoster vaccine. EXPERT OPINION: Live attenuated zoster vaccine is safe and efficacious in preventing HZ and decreasing the morbidity associated with postherpetic neuralgia. The vaccine is FDA approved in individuals aged 50-years or older but further studies are warranted to investigate the vaccine's efficacy in immunosuppressed and immunocompromised patients. PMID- 23984936 TI - Crystallization of micrometer-sized particles with molecular contours. AB - The crystallization of micrometer-sized particles with shapes mimicking those of tetrabenzoheptacene (TBH) and 1,2:5,6-dibenzanthracene (DBT), both flat polyacenes, in an electric field results in the formation of ordered 2D packings that mimic the plane group symmetries in their respective molecular crystal equivalents. Whereas the particles packed in low-density disordered arrangements under a gravitational gradient, dielectrophoresis (under an ac electric field) produced ordered high-density packings with readily identifiable plane group symmetry. The ordered colloidal assemblies were stable for hours, with the packing density decreasing slowly but with recognizable symmetry for up to 12 h for the TBH-shaped particles and up to 4 h for the DBT-shaped particles. This unexpected stability is attributed to jamming behavior associated with interlocking of the dogbone-shaped (TBH) and Z-block (DBT) particles, contrasting with the more rapid reduction of packing density and loss of hexagonal symmetry for disk-shaped particles upon removal of the electric field. The TBH-shaped and DBT-shaped particles assemble into the p2 plane group, which corresponds to the densest particle packing among the possible close-packed plane groups for these particle symmetries. The p2 symmetry observed for the TBH-shaped and DBT-shaped colloid crystal emulates the p2 symmetry of the (010) layers in their respective molecular crystals, which crystallize in monoclinic lattices. Notably, DBT-shaped particles also form ordered domains with pgg symmetry, replicating the plane group symmetry of the (100) layer in the orthorhombic polymorph of DBT. These observations illustrate that the 2D ordering of colloid particles can mimic the packing of molecules with similar shapes, demonstrating that packing can transcend length scales from the molecular to the colloidal. PMID- 23984938 TI - HIV and interferon regulatory factor 1: a story of manipulation and control. AB - Members of the interferon regulatory factor (IRF) family control the expression of numerous proteins, many of which are central to regulating host immune responses. IRF1 is one of the central mediators of the innate and adaptive immune responses required for antigen processing and presentation, Th1/Th2 differentiation, and natural killer (NK) cell and macrophage function. Many viruses have evolved mechanisms to target the IRF1 pathway in order to promote viral pathogenesis. During early HIV infection, IRF1 acts as a double-edged sword, critical for driving viral replication as well as eliciting antiviral responses. In this review, we describe the strategies that HIV-1 has evolved to modulate IRF1 in order to enhance viral replication and to disarm the host immune system. IRF1 has been shown to be an important factor in natural protection against HIV in highly exposed seronegative (HESN) individuals and is crucial in regulating the initial stages of HIV replication and HIV disease progression, as well as the establishment of latency. An understanding of how the protective effects of IRF1 responses are controlled in HESN individuals, naturally resistant to HIV infection, may provide important clues on how to regain control of HIV and tip the balance of immunity in favor of the host, or provide new opportunities to eliminate HIV in its host altogether. PMID- 23984937 TI - Inferring the expression variability of human transposable element-derived exons by linear model analysis of deep RNA sequencing data. AB - BACKGROUND: The exonization of transposable elements (TEs) has proven to be a significant mechanism for the creation of novel exons. Existing knowledge of the retention patterns of TE exons in mRNAs were mainly established by the analysis of Expressed Sequence Tag (EST) data and microarray data. RESULTS: This study seeks to validate and extend previous studies on the expression of TE exons by an integrative statistical analysis of high throughput RNA sequencing data. We collected 26 RNA-seq datasets spanning multiple tissues and cancer types. The exon-level digital expressions (indicating retention rates in mRNAs) were quantified by a double normalized measure, called the rescaled RPKM (Reads Per Kilobase of exon model per Million mapped reads). We analyzed the distribution profiles and the variability (across samples and between tissue/disease groups) of TE exon expressions, and compared them with those of other constitutive or cassette exons. We inferred the effects of four genomic factors, including the location, length, cognate TE family and TE nucleotide proportion (RTE, see Methods section) of a TE exon, on the exons' expression level and expression variability. We also investigated the biological implications of an assembly of highly-expressed TE exons. CONCLUSION: Our analysis confirmed prior studies from the following four aspects. First, with relatively high expression variability, most TE exons in mRNAs, especially those without exact counterparts in the UCSC RefSeq (Reference Sequence) gene tables, demonstrate low but still detectable expression levels in most tissue samples. Second, the TE exons in coding DNA sequences (CDSs) are less highly expressed than those in 3' (5') untranslated regions (UTRs). Third, the exons derived from chronologically ancient repeat elements, such as MIRs, tend to be highly expressed in comparison with those derived from younger TEs. Fourth, the previously observed negative relationship between the lengths of exons and the inclusion levels in transcripts is also true for exonized TEs. Furthermore, our study resulted in several novel findings. They include: (1) for the TE exons with non-zero expression and as shown in most of the studied biological samples, a high TE nucleotide proportion leads to their lower retention rates in mRNAs; (2) the considered genomic features (i.e. a continuous variable such as the exon length or a category indicator such as 3'UTR) influence the expression level and the expression variability (CV) of TE exons in an inverse manner; (3) not only the exons derived from Alu elements but also the exons from the TEs of other families were preferentially established in zinc finger (ZNF) genes. PMID- 23984939 TI - Alloglossidium floridense n. sp. (Digenea: Macroderoididae) from a spring run in North Central Florida. AB - A new species of Alloglossidium is described from the intestines of 2 madtom species (Noturus leptacanthus and Noturus gyrinus) that were collected from the run of a small, unnamed spring system that drains into the Santa Fe River, Florida. Alloglossidium floridense n. sp. is morphologically very similar to other nonprecocious Alloglossidium spp. that use ictalurids as definitive hosts, but can be distinguished by a combination of its smaller overall size (length and width), large eggs in relation to its small body size, position of the vitellaria, ovary shape, and position of the ovary in relation to the cirrus sac. A comparison of nuclear rDNA sequences (spanning partial 18s, complete ITS1, 5.8s, ITS2, and partial 28s regions) showed that A. floridense n. sp. diverged by 0.70-3.17% from the other 4, nonprecocious species that infect ictalurids (Alloglossidium corti, Alloglossidium fonti, Alloglossidium geminum, and Alloglossidium kenti). The new species of Alloglossidium, described herein, is the first of the genus to be reported from Florida and the first to be recorded from N. leptacanthus . In light of the subtle morphological differences among the nonprecocious species that infect ictalurids, we discuss how previous descriptions of species traits that are not supported with genetic data are difficult to interpret because of the possible past nonrecognition of distinct species. PMID- 23984940 TI - Donor wave functions delocalization in silicon nanowires: the peculiar [011] orientation. AB - The localization of the donor electron wave function can be of key importance in various silicon applications, since for example it determines the interactions between neighboring donors. Interestingly, the physical confinement of the electrons in quasi-one-dimensional nanostructures, like silicon nanowires, noticeably affects this property. Using fully ab initio calculations, we show that the delocalization of the donor electron wave function along the axis of a nanowire is much greater in [011] oriented nanowires for phosphorus and selenium donors. We also demonstrate that its value can be controlled by applying a compressive or tensile uniaxial strain. Finally, we discuss the implications of these features from both an experimental and a theoretical point of view. PMID- 23984941 TI - Evaluation of the beta value of the phenylene ethynylene unit by probing the exchange interaction between two nitronyl nitroxides. AB - A series of nitronyl nitroxide radicals having different lengths of phenylene ethynylene molecular wire were synthesized to investigate the decay constant of p phenylene ethynylene. By the measurement and simulation of the ESR spectra of the biradicals, it was found that the exchange interaction decreased with a decay constant (beta) of 0.39 A(-1) as the length of the molecule increased. This result indicates that the spin-spin exchange interaction between neutral radicals has a decay constant similar to that of the molecular conductance. This value of the decay constant indicates that a hopping mechanism does not take place in the measurement of the exchange interaction between neutral radicals even when the molecular wire has enough length to show hopping conduction of electrons. PMID- 23984943 TI - Thought is a material: talking with Mel Bochner about space, art, and language. Interview by Alexander Kranjec. PMID- 23984942 TI - A trade-off between local and distributed information processing associated with remote episodic versus semantic memory. AB - Episodic memory and semantic memory produce very different subjective experiences yet rely on overlapping networks of brain regions for processing. Traditional approaches for characterizing functional brain networks emphasize static states of function and thus are blind to the dynamic information processing within and across brain regions. This study used information theoretic measures of entropy to quantify changes in the complexity of the brain's response as measured by magnetoencephalography while participants listened to audio recordings describing past personal episodic and general semantic events. Personal episodic recordings evoked richer subjective mnemonic experiences and more complex brain responses than general semantic recordings. Critically, we observed a trade-off between the relative contribution of local versus distributed entropy, such that personal episodic recordings produced relatively more local entropy whereas general semantic recordings produced relatively more distributed entropy. Changes in the relative contributions of local and distributed entropy to the total complexity of the system provides a potential mechanism that allows the same network of brain regions to represent cognitive information as either specific episodes or more general semantic knowledge. PMID- 23984944 TI - Negative emotional experiences during navigation enhance parahippocampal activity during recall of place information. AB - It is known that the parahippocampal cortex is involved in object-place associations in spatial learning, but it remains unknown whether activity within this region is modulated by affective signals during navigation. Here we used fMRI to measure the neural consequences of emotional experiences on place memory during navigation. A day before scanning, participants undertook an active object location memory task within a virtual house in which each room was associated with a different schedule of task-irrelevant emotional events. The events varied in valence (positive, negative, or neutral) and in their rate of occurrence (intermittent vs. constant). On a subsequent day, we measured neural activity while participants were shown static images of the previously learned virtual environment, now in the absence of any affective stimuli. Our results showed that parahippocampal activity was significantly enhanced bilaterally when participants viewed images of a room in which they had previously encountered negatively arousing events. We conclude that such automatic enhancement of place representations by aversive emotional events serves as an important adaptive mechanism for avoiding future threats. PMID- 23984946 TI - Strengthening procedural memories by reactivation in sleep. AB - There is robust evidence that sleep facilitates procedural memory consolidation. The exact mechanisms underlying this process are still unclear. We tested whether an active replay of prior experience can underlie sleep effects on procedural memory. Participants learned a finger-tapping task in which key presses were associated with tones during practice. Later, during a consolidation interval spent either sleeping or awake, we presented auditory cues to reactivate part of the learned sequence. We show that reactivation strengthens procedural memory formation during sleep, but not during wakefulness. The improvement was restricted to those finger transitions that were cued. Thus, reactivation is a very specific process underpinning procedural memory consolidation. When comparing periods of sleep with and without reactivation, we find that it is not the time spent in a specific stage of sleep per se, but rather the occurrence of reactivation that mediates the effect of sleep on memory consolidation. Our data show that longer sleep time as well as additional reactivation by cueing during sleep can enhance later memory performance. PMID- 23984948 TI - Solid-phase microextraction in targeted and nontargeted analysis: displacement and desorption effects. AB - An aqueous multicomponent mixture containing a wide range of volatility and polarity compounds (log Kow range 1.26-8.72) was used to clearly define the capabilities and limitations of headspace solid-phase microextraction in quantification of multicomponent complex samples. Commercially available fiber coatings were evaluated by investigating the extraction efficiency and desorption carryover. Comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry was selected to map out the differences between the coatings. The investigated components were chosen to represent several homologous groups of metabolites most frequently present in complex food and environmental samples, including straight-chain hydrocarbons, primary alcohols, secondary alcohols, 2 ketones, aldehydes, ethyl esters, and terpenes. Particular emphasis was placed on examination of coating saturation and interanalyte displacements. These effects were assessed by evaluating the linear dynamic range obtained for spiked aqueous samples with divinylbenzene/Carboxen/poly(dimethylsiloxane) fiber. This coating was found to provide the optimum extraction coverage and sensitivity for the widest range of analytes. Displacement investigations were extended to apple homogenate characterized by high chemical diversity. The results indicate that interanalyte displacements are infrequent in the naturally occurring samples considered in this study. When displacements take place, they tend to occur for analytes characterized by small distribution constants, and they can be effectively detected by adding such compounds to the sample and corrected by selecting a shorter extraction time. PMID- 23984945 TI - Robust selectivity for faces in the human amygdala in the absence of expressions. AB - There is a well-established posterior network of cortical regions that plays a central role in face processing and that has been investigated extensively. In contrast, although responsive to faces, the amygdala is not considered a core face-selective region, and its face selectivity has never been a topic of systematic research in human neuroimaging studies. Here, we conducted a large scale group analysis of fMRI data from 215 participants. We replicated the posterior network observed in prior studies but found equally robust and reliable responses to faces in the amygdala. These responses were detectable in most individual participants, but they were also highly sensitive to the initial statistical threshold and habituated more rapidly than the responses in posterior face-selective regions. A multivariate analysis showed that the pattern of responses to faces across voxels in the amygdala had high reliability over time. Finally, functional connectivity analyses showed stronger coupling between the amygdala and posterior face-selective regions during the perception of faces than during the perception of control visual categories. These findings suggest that the amygdala should be considered a core face-selective region. PMID- 23984947 TI - Oscillatory coupling reveals the dynamic reorganization of large-scale neural networks as cognitive demands change. AB - Cognitive operations are thought to emerge from dynamic interactions between spatially distinct brain areas. Synchronization of oscillations has been proposed to regulate these interactions, but we do not know whether this large-scale synchronization can respond rapidly to changing cognitive demands. Here we show that, as task demands change during a trial, multiple distinct networks are dynamically formed and reformed via oscillatory synchronization. Distinct frequency-coupled networks were rapidly formed to process reward value, maintain information in visual working memory, and deploy visual attention. Strong single trial correlations showed that networks formed even before the presentation of imperative stimuli could predict the strength of subsequent networks, as well as the speed and accuracy of behavioral responses seconds later. These frequency coupled networks better predicted single-trial behavior than either local oscillations or ERPs. Our findings demonstrate the rapid reorganization of networks formed by dynamic activity in response to changing task demands within a trial. PMID- 23984949 TI - Impact of the implementation of the AAN epilepsy quality measures on the medical records in a university hospital. AB - BACKGROUND: The American Academy of Neurology (AAN) suggested eight quality measures to be observed at every patient visit. The aim of this work is to compare the percentage of documentation of each measure before and after the implementation of a new worksheet in a third-level center. METHODS: Quasi experimental study including medical records filled by medical school seniors and junior residents supervised by an epileptologist. The authors surveyed 80 consecutive charts of people with epilepsy who were seen in the outpatient clinic before and after the intervention. McNemar change test was used to compare the percentages of documentation of each quality measure-i.e., seizure type and frequency, etiology, EEG, MRI/CT head scans, AED side effects, surgical therapy referral, safety counseling, preconception counseling-and physical exam. Each quality measure was considered to be fulfilled only if it was assessed and properly recorded. RESULTS: Mean age was 35(+/-13) years, 55% women, mean epilepsy onset at age 18(+/-15), 82% presented with partial-onset seizures. The reporting rate improved for all quality measures (previous vs new), reaching statistical significance for: seizure type 80vs94% (p < 0.05), AED side effects 8vs24%, etiology 66vs88% (p < 0.01), safety counseling 5vs64%, preconception counseling 4vs20%, and physical exam 63vs94% (p < 0.001). CONCLUSION: A quality oriented epilepsy worksheet led to a better practice standardization and documentation of AAN standards for diagnostic and counseling purposes. Further evaluations should be undertaken to assess the impact on medical education and patient care. PMID- 23984950 TI - A large solvent isotope effect on protein association thermodynamics. AB - Solvent reorganization can contribute significantly to the energetics of protein protein interactions. However, our knowledge of the magnitude of the energetic contribution is limited, in part, by a dearth of quantitative experimental measurements. The biotin repressor forms a homodimer as a prerequisite to DNA binding to repress transcription initiation. At 20 degrees C, the dimerization reaction, which is thermodynamically coupled to binding of a small ligand, bio-5' AMP, is characterized by a Gibbs free energy of -7 kcal/mol. This modest net dimerization free energy reflects underlying, very large opposing enthalpic and entropic driving forces of 41 +/- 3 and -48 +/- 3 kcal/mol, respectively. The thermodynamics have been interpreted as indicating coupling of solvent release to dimerization. In this work, this interpretation has been investigated by measuring the effect of replacing H2O with D2O on the dimerization thermodynamics. Sedimentation equilibrium measurements performed at 20 degrees C reveal a solvent isotope effect of -1.5 kcal/mol on the Gibbs free energy of dimerization. Analysis of the temperature dependence of the reaction in D2O indicates enthalpic and entropic contributions of 28 and -37 kcal/mol, respectively, considerably smaller than the values measured in H2O. These large solvent isotope perturbations to the thermodynamics are consistent with a significant contribution of solvent release to the dimerization reaction. PMID- 23984951 TI - Impact of molecular flexibility on double polymorphism, solid solutions and chiral discrimination during crystallization of diprophylline enantiomers. AB - The polymorphic behavior of racemic and enantiopure diprophylline (DPL), a chiral derivative of theophylline marketed as a racemic solid, has been investigated by combining differential scanning calorimetry, powder X-ray diffraction, hot-stage microscopy and single-crystal X-ray experiments. The pure enantiomers were obtained by a chemical synthesis route, and additionally an enantioselective crystallization procedure was developed. The binary phase diagram between the DPL enantiomers was constructed and revealed a double polymorphism (i.e., polymorphism both of the racemic mixture and of the pure enantiomer). The study of the various equilibria in this highly unusual phase diagram revealed a complex situation since mixtures of DPL enantiomers can crystallize either as a stable racemic compound, a metastable conglomerate, or two distinct metastable solid solutions. Crystal structure analysis revealed that the DPL molecules adopt different conformations in the crystal forms suggesting that the conformational degrees of freedom of the substituent that carries the only two H-bond donor groups might be related to the versatile crystallization behavior of DPL. The control of these equilibria and the use of a suitable solvent allowed the design of an efficient protocol for the preparative resolution of racemic DPL via preferential crystallization. Therefore, the resolution of DPL enantiomers despite the existence of a racemic compound stable at any temperature demonstrates that the detection of a stable conglomerate is not mandatory for the implementation of preferential crystallization. PMID- 23984952 TI - Impaired reading not due to visual field loss in a patient with a right hemipsheric lesion. AB - We describe a right-handed patient (M.B.), who developed left hemianopsia and a severe reading impairment after right occipital-parietal hemorrhage. The pattern of his reading deficit was very similar to that of pure alexia (alexia-without agraphia): extremely slow reading times with frequent grapheme substitutions and omissions. A test of letter reading while controlling for saccadic eye movements and hemifield of presentation ruled out hemianoptic alexia. Although there have already been reports of reading impairments in right handers following right- hemispheric lesions, ours is, to the best of our knowledge, the first where visual field loss can be definitely excluded as the main cause. Based on a standard neuropsychological assessment and on additional behavioral tests, we argue that M.B.'s difficulties are unlikely to be due to right-hemisphere dominance for language. After considering several candidate explanations, we suggest that M.B.'s symptoms may be related to an impairment in attentional processes related to reading. PMID- 23984953 TI - Gastric acid secretion in experimental acute uremia. AB - This study was conducted to evaluate gastric acid secretion in acute renal failure, highlighting the roles of renal mass and gastrin hormone. Acute uremic rats were divided into bilateral nephrectomized and bilateral ureteric obstruction groups. Gastric juice was collected for 2 h and analyzed for volume, free acidity, total acidity, and total acid output. Plasma levels of creatinine, urea, and gastrin were also determined. Bilateral nephrectomized and bilateral ureteric obstruction groups showed a significant increase in levels of free acidity, total acidity, and plasma gastrin. Compared with the ureteric obstruction group, nephrectomized rats showed a significant increase in gastric juice volume, total acid output, and plasma gastrin levels. Following pentagastrin stimulation, gastric juice volume, total acid output, free acidity, and total acidity were increased in the bilateral nephrectomy and ureteric obstruction groups compared with the respective control groups. The free and total acidity and total acid output also increased compared with the respective non-stimulated groups. Plasma creatinine and urea levels were significantly positively correlated with plasma gastrin, free acidity, and total acidity. Creatinine was positively correlated with total acid output, and gastrin was positively correlated with total acidity. In conclusion, acute renal failure promotes gastric acid hypersecretion that could potentially be attributed to high levels of gastrin hormone and uremic state per se. PMID- 23984954 TI - Matrix-M adjuvant: enhancing immune responses by 'setting the stage' for the antigen. PMID- 23984955 TI - Preparing for a potential A(H7N9) pandemic: lessons from the deployment of A(H1N1) pandemic vaccines. PMID- 23984957 TI - A multicomponent serogroup B meningococcal vaccine is licensed for use in Europe: what do we know, and what are we yet to learn? AB - The first meningococcal vaccine with the potential to provide broad coverage against serogroup B disease has recently been approved for use in Europe. This vaccine, multi-component serogroup B vaccine (4CMenB), contains recombinant proteins and outer membrane vesicles, and has been extensively studied in clinical trials involving over 7500 adults, children and infants. As well as demonstrating immunogenicity against a range of serogroup B meningococcal strains, these trials have also demonstrated relatively high rates of fever following infant immunization. This article will summarize the vaccine composition, clinical trials and suggested schedules of this vaccine, with specific attention to immunogenicity, reactogenicity, safety, potential coverage and optimal implementation of this vaccine. PMID- 23984958 TI - IXIARO updated: overview of clinical trials and developments with the inactivated vaccine against Japanese encephalitis. AB - The mosquito-borne Japanese encephalitis virus causes an estimated 50,000 cases in Asia, accounting for at least 10,000 deaths and 15,000 cases of neuropsychiatric sequelae. IXIARO (Intercell AG, Vienna, Austria), an inactivated, Vero cell-derived vaccine against Japanese encephalitis was introduced in 2009. The vaccine is highly immunogenic, showing significantly higher geometric mean antibody titers compared with previous, mouse brain-derived vaccines. Postmarketing studies have confirmed the excellent safety profile. Studies on children aged 2 months to 18 years have been published. Based on these data, positive opinion from the EMA for vaccination of children has recently been given. Since a safe and effective vaccine against Japanese encephalitis is now available, outdated guidelines and recommendations have to be revised: travelers to rural areas of Asia should generally be recommended vaccination. PMID- 23984959 TI - Type I interferon regulation of natural killer cell function in primary and secondary infections. AB - The priming of natural killer (NK) cells by type I interferon (IFN) is necessary for protection against primary and secondary viral infections. However, the pathway by which type I IFN activates NK cells to elicit antiviral responses is controversial. There is evidence to suggest that type I IFN priming of NK cells occurs through both direct and indirect pathways. As with many innate mechanisms, type I IFN and NK cells also orchestrate the adaptive immune response and thus aid in protection against secondary infections. Type I IFN can shape CD4(+) T cell, B cell and humoral memory formation. In addition, long-lived NK cells can perform specific and enhanced memory-like protection in secondary infections. This review outlines the different mechanisms underlying type I IFN regulation of NK cells and how type I IFN and NK cells can be used as a therapeutic target in vaccinations. PMID- 23984960 TI - Vaccines and febrile seizures. AB - Vaccine administration is the second leading cause of febrile seizures (FS). FS occurrence in children is a serious concern because it leads to public apprehension of vaccinations. This review discusses the clinical implications of FS, its potential link to vaccinations and its impact on official recommendations for vaccinations in children. Vaccines such as the pertussis antigen-containing vaccine, the measles-containing vaccine and the influenza vaccine have been linked to FS. However, FS events are very rare and are not usually associated with downstream complications or severe neurologic diseases. Considering their significant health benefits, vaccinations have not been restricted in the pediatric population. Nevertheless, vaccine-induced FS could be a problem, particularly in genetically predisposed children. Therefore, post-marketing surveillance studies are required to accurately assess the incidence of FS and identify individuals who are particularly susceptible to FS after vaccination. PMID- 23984961 TI - Measles elimination: progress, challenges and implications for rubella control. AB - Measles and rubella are major vaccine-preventable causes of child mortality and disability. They have been eliminated from the Americas and some other regions have also come close to elimination. In this paper, we review regional progress toward measles and rubella control/elimination goals, describe the recent epidemiology of these infections and discuss challenges to achieving the goals. Globally, measles vaccination is estimated to prevent nearly 2 million deaths each year. Despite this remarkable progress, large measles outbreaks have occurred in recent years, often involving older persons who were not vaccinated in earlier years. Such an occurrence would be particularly damaging for rubella control programmes as it could lead to peaks in congenital rubella syndrome. Challenges to achieving and sustaining high vaccination coverage include civil conflict, weak health systems, geographic, cultural and economic barriers to reaching certain population groups and inadequate monitoring and use of data for action. Countries and regions aiming to eliminate measles and control rubella urgently need to improve the implementation and monitoring of both routine and mass vaccination campaign strategies. PMID- 23984963 TI - Anthrax vaccines: present status and future prospects. AB - The management of anthrax remains a top priority among the biowarfare/bioterror agents. It was the Bacillus anthracis spore attack through the US mail system after the September 11, 2001, terrorist attacks in the USA that highlighted the potential of B. anthracis as a bioterrorism agent and the threat posed by its deliberate dissemination. These attacks invigorated the efforts toward understanding the anthrax pathogenesis and development of more comprehensive medical intervention strategies for its containment in case of both natural disease and manmade, accidental or deliberate infection of a non-suspecting population. Currently, efforts are directed toward the development of safe and efficacious vaccines as well as intervention tools for controlling the disease in the advanced fulminant stage when toxemia has already developed. This work presents an overview of the current understanding of anthrax pathogenesis and recent advances made, particularly after 2001, for the successful management of anthrax and outlines future perspectives. PMID- 23984962 TI - Dengue vaccines: recent developments, ongoing challenges and current candidates. AB - Dengue is among the most prevalent and important arbovirus diseases of humans. To effectively control this rapidly spreading disease, control of the vector mosquito and a safe and efficacious vaccine are critical. Despite considerable efforts, the development of a successful vaccine has remained elusive. Multiple factors have complicated the creation of a successful vaccine, not the least of which are the complex, immune-mediated responses against four antigenically distinct serotypes necessitating a tetravalent vaccine providing long-lasting protective immunity. Despite the multiple impediments, there are currently many promising vaccine candidates in preclinical and clinical development. Here, the recent advances in dengue virus vaccine development are reviewed and the challenges associated with the use of these vaccines as a public health tool are briefly discussed. PMID- 23984965 TI - Composite PLGA/AgNpPGA/AscH nanospheres with combined osteoinductive, antioxidative, and antimicrobial activities. AB - The global rise in the resistance of pathogens to conventional antibiotics has created an intensive search for alternative materials with antimicrobial properties. This study is performed with an intention to investigate the combined effects of poly(l-glutamic acid)-capped silver nanoparticles (AgNpPGA) and ascorbic acid (AscH) encapsulated within freeze-dried poly(lactide-co-glycolide) (PLGA) nanospheres to obtain a nanomaterial with simultaneous osteoinductive, antioxidative, and prolonged antimicrobial properties. The influence of PLGA/AgNpPGA/AscH particles on (i) viability and superoxide production of human umbilical vein endothelial cells in vitro, (ii) morphology and expression of osteogenic markers in osteoblastic MC3T3-E1 cells in vitro, and (iii) antimicrobial activity against a Gram-positive bacterium, methicillin-resistant Staphylococcus aureus, and a Gram-negative bacterium, Escherichia coli, was investigated. PLGA/AgNpPGA/AscH nanoparticles showed a superior and extended antibacterial activity against both types of bacteria. The nanoparticles appeared to be capable of delivering ascorbate to the cells, which was evidenced by the significant decrease in the level of superoxides in human umbilical vein endothelial cells and which could have a therapeutic potential in preventing oxidative stress. PLGA/AgNpPGA/AscH nanoparticles had a positive effect on MC3T3 E1 osteoblastic cells in vitro, promoting: (i) an intimate contact with the cells and preservation of their healthy morphologies; (ii) unreduced cell viability; and (iii) multiple-fold upregulation of two osteogenic markers: osteocalcin and type I procollagen. It is concluded that PLGA/AgNpPGA/AscH nanospheres present a promising new material for the treatment of infections and use in wound dressings and other prophylactic applications. PMID- 23984966 TI - Cobalt-catalyzed asymmetric addition of silylacetylenes to 1,1-disubstituted allenes. AB - The asymmetric addition of silylacetylenes to 1,1-disubstituted allenes proceeded in the presence of a cobalt/chiral bisphosphine ligand to give the corresponding enynes with high enantioselectivity. The results of deuterium-labeling experiments indicated that a hydrogen atom at the chiral center is originated from the terminal alkyne, and they were in good agreement with the proposed catalytic cycle where enantioselectivity is determined by the reaction of the proposed pi-allylcobalt intermediate with the terminal alkyne. PMID- 23984967 TI - Comparative genomics of Campylobacter concisus isolates reveals genetic diversity and provides insights into disease association. AB - BACKGROUND: In spite of its association with gastroenteritis and inflammatory bowel diseases, the isolation of Campylobacter concisus from both diseased and healthy individuals has led to controversy regarding its role as an intestinal pathogen. One proposed reason for this is the presence of high genetic diversity among the genomes of C. concisus strains. RESULTS: In this study the genomes of six C. concisus strains were sequenced, assembled and annotated including two strains isolated from Crohn's disease patients (UNSW2 and UNSW3), three from gastroenteritis patients (UNSW1, UNSWCS and ATCC 51562) and one from a healthy individual (ATCC 51561). The genomes of C. concisus BAA-1457 and UNSWCD, available from NCBI, were included in subsequent comparative genomic analyses. The Pan and Core genomes for the sequenced C. concisus strains consisted of 3254 and 1556 protein coding genes, respectively. CONCLUSION: Genes were identified with specific conservation in C. concisus strains grouped by phenotypes such as invasiveness, adherence, motility and diseased states. Phylogenetic trees based on ribosomal RNA sequences and concatenated host-related pathways for the eight C. concisus strains were generated using the neighbor-joining method, of which the 16S rRNA gene and peptidoglycan biosynthesis grouped the C. concisus strains according to their pathogenic phenotypes. Furthermore, 25 non-synonymous amino acid changes with 14 affecting functional domains, were identified within proteins of conserved host-related pathways, which had possible associations with the pathogenic potential of C. concisus strains. Finally, the genomes of the eight C. concisus strains were compared to the nine available genomes of the well established pathogen Campylobacter jejuni, which identified several important differences in the respiration pathways of these two species. Our findings indicate that C. concisus strains are genetically diverse, and suggest the genomes of this bacterium contain respiration pathways and modifications in the peptidoglycan layer that may play an important role in its virulence. PMID- 23984968 TI - Prevalence and distribution of human Plasmodium infection in Pakistan. AB - BACKGROUND: Both Plasmodium vivax and Plasmodium falciparum are prevalent in Pakistan, yet up-to-date data on the epidemiology of malaria in Pakistan are not available. This study was undertaken to determine the current prevalence and distribution of Plasmodium species across the country. METHODS: A malariometric population survey was conducted in 2011 using blood samples collected from 801 febrile patients of all ages in four provinces and the capital city of Islamabad. Microscopically confirmed Plasmodium-positive blood samples were reconfirmed by polymerase chain reaction (PCR). Confirmed parasite-positive samples were subjected to species-specific PCR capable of detecting four species of human malaria. RESULTS: Of the 707 PCR-positive samples, 128 (18%) were P. falciparum, 536 (76%) were P. vivax, and 43 (6%) were mixed P. falciparum and P. vivax. Ninety-four microscopy-positive samples were PCR-negative, and Plasmodium malariae and Plasmodium ovale were not detected. Prevalence of P. vivax ranged from 2.4% in Punjab Province to 10.8% in Sindh Province and prevalence of P. falciparum ranged from 0.1% in Islamabad to 3.8% in Balochistan. CONCLUSIONS: Plasmodium infections in Pakistan are largely attributed to P. vivax but P. falciparum and mixed species infections are also prevalent. In addition, regional variation in the prevalence and species composition of malaria is high. PMID- 23984969 TI - Complexity perplexity: a systematic review to describe the measurement of medication regimen complexity. AB - INTRODUCTION: Complex medication regimens are error prone and challenging for patients, which may impact medication adherence and safety. No universal method to assess the complexity of medication regimens (CMRx) exists. The authors aim to review literature for CMRx measurements to establish consistencies and, secondarily, describe CMRx impact on healthcare outcomes. AREAS COVERED: A search of EMBASE and PubMed for studies analyzing at least two medications and complexity components, among those self-managing medications, was conducted. Out of 1204 abstracts, 38 studies were included in the final sample. The majority (74%) of studies used one of five validated CMRx scales; their components and scoring were compared. EXPERT OPINION: Universal CMRx assessment is needed to identify and reduce complex regimens, and, thus, improve safety. The authors highlight commonalities among five scales to help build consensus. Common components (i.e., regimen factors) included dosing frequency, units per dose, and non-oral routes. Elements (e.g., twice daily) of these components (e.g., dosing frequency) and scoring varied. Patient-specific factors (e.g., dexterity, cognition) were not addressed, which is a shortcoming of current scales and a challenge for future scales. As CMRx has important outcomes, notably adherence and healthcare utilization, a standardized tool has potential for far-reaching clinical, research, and patient-safety impact. PMID- 23984970 TI - Adverse effects of golimumab in the treatment of rheumatologic diseases. AB - INTRODUCTION: A number of new biological immune modulators have become available as treatments for inflammatory diseases over the past two decades. Most prominent among them are TNF-alpha inhibitors (TNFi) which have been available in the clinic since the late 1990s. TNFi have demonstrated efficacy in various rheumatologic diseases as well as in inflammatory bowel disease and psoriasis. Golimumab is one of the most recently introduced TNFi. AREAS COVERED: Although golimumab is generally well tolerated, as is the case with other TNFi and indeed with most of the marketed immunomodulatory drugs, potential adverse events may be associated with its use. Herein, we the potential adverse effects associated with golimumab therapy are reviewed. Adverse effects are divided into target-related and agent-related categories. EXPERT OPINION: Golimumab has been demonstrated to be generally safe and well tolerated. Its safety profile seems to be very comparable to the other available TNFi. Long-term studies of golimumab and other TNFi will help establish the durability of response to golimumab as well as identify any potential delayed or cumulative adverse effects. PMID- 23984971 TI - Effect of atorvastatin on atherosclerotic plaque formation and platelet activation in hypercholesterolemic rats. AB - We aimed to investigate whether atorvastatin influenced the CD40-CD40L pathway in atherosclerosis formation in rats fed a high cholesterol diet. Thirty-six male Wistar rats were divided among 4 groups as follows: control (C), statin (S), 5% cholesterol fed (HC), and statin-administered hypercholesterolemic (HCS). Serum levels of lipids, soluble CD40L, platelet factor 4, and interleukin-6 were assayed with commercial kits. The number of platelets expressing surface P selectin, CD40, and CD40L were determined by flow cytometry. Aortas were examined for fatty streaks. In the HC group, we observed a significant increase in serum lipid levels and platelet activation markers compared with the control group. Rats in the HCS group had a significant decrease in lipid levels and downregulation in the number of platelets expressing surface P-selectin, CD40, and CD40L compared with the HC group. We observed decreased fatty streak formations in aortas in HCS rats. A positive correlation was found for platelet activation markers and atherosclerotic fatty streak formations. Regression analysis revealed that the predictor of atherosclerosis was CD40L. Our study suggests that in a rat hypercholesterolemic model, statin treatment may influence the CD40-CD40L dyad, and that this effect is parallelled by a suppression of progression of atherosclerotic plaque formation. PMID- 23984972 TI - A new deferiprone controlled release system obtained by ultrasound-assisted compression. AB - OBJECTIVES: This study implements the design of an innovative dosage form using ultrasound-assisted compression of thermoplastic polymers and the development of controlled release tablets for the oral administration of deferiprone in two doses per day. METHODS: Binary matrix tablets containing deferiprone and thermoplastic polymers have been prepared using an ultrasound-assisted tableting machine. Scanning electron microscopy has been employed to determine a sintering phenomenon of the excipients. Water uptake and drug release studies have been carried out to evaluate the ability of the polymers to control the drug release. RESULTS: SEM micrographs showed that some polymers underwent the sintering process and the in vitro dissolution test showed good fit of the release data from these tablets to the zero-order kinetic model. CONCLUSIONS: Carbopol 974P and 971P have been selected as matrix forming polymers for the final formulation. The polymer percolation threshold has been exceeded with 15% w/w of polymer. Therefore, sustained release tablets have been developed with only 15% of excipient. This implies that matrix tablets containing 750 mg of API, intended for two administrations a day, can be obtained with a similar weight to those existing in the market containing 500 mg of API for three administrations a day. PMID- 23984973 TI - Exploring near and far regions of space: distance-specific visuospatial neglect after stroke. AB - Visuospatial neglect has been observed in the horizontal (left/right) and vertical (up/down) dimension and depends on the distance at which a task is presented (near/far). Previously, studies have mainly focused on investigating the overall severity of neglect in near and far space in a group of neglect patients instead of examining subgroups of neglect patients with different types of distance-specific neglect. We investigated the spatial specificity (near vs. far space), frequency, and severity of neglect in the horizontal and vertical dimensions in a large group of stroke patients. We used three tasks to assess neglect in near (30 cm) and far (120 cm) space: a shape cancellation, letter cancellation, and a line bisection task. Patients were divided into four groups based on their performance: a group without neglect (N-F-), a near only neglect (N+F-), a far only neglect (N-F+), and a near and far neglect group (N+F+). About 40% of our sample showed neglect. Depending on the task, N+F- was observed in 8 to 22% of the sample, whereas N-F+ varied between 8% and 11%, and N+F+ varied between 11% to 14% of the sample. The current findings indicate that horizontal and vertical biases in performance can be confined to one region of space and are task dependent. We recommend testing for far space neglect during neuropsychological assessments in clinical practice, because this cannot be diagnosed using standard paper-and-pencil tasks. PMID- 23984974 TI - Plasma monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels predict the presence of coronary artery calcium in HIV-infected individuals independent of traditional cardiovascular risk factors. AB - Coronary artery calcium (CAC) is a validated subclinical measure of atherosclerosis. Studies in the general population have linked blood inflammatory biomarkers including monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor (TNF)-alpha with the burden of CAC, but this relationship is often lost following correction for traditional cardiovascular risk factors. We assessed the relationship of various biomarkers to CAC, specifically in HIV infected individuals on potent antiretroviral therapy (ART). Analyses utilized entry data from participants in the Hawaii Aging with HIV-Cardiovascular (HAHC CVD) study. Computerized tomography examinations for CAC were obtained locally and analyzed by a central reading center in blinded fashion. Plasma biomarkers were assessed by multiplexing using Milliplex Human Cardiovascular Disease panels. Among a cohort of 130 subjects [88% male, median (IQR) age of 51 (46-57) years, CD4 count of 492 (341-635) cells/mm(3), 86.9% with HIV RNA <=50 copies/ml], CAC was present in 46.9% of subjects. In univariate analyses higher levels of log-transformed MCP-1 and TNF-alpha were associated with the presence of CAC (p<0.05). In multivariate logistic regression models, MCP-1 and TNF-alpha remained significant after adjustment for traditional cardiovascular (CVD) risk factors. Similar results were found when analyses were assessed by Framingham risk score categories or when restricted to subjects with plasma HIV RNA <=50 copies/ml. In contrast to findings in the general population, higher MCP-1 and TNF-alpha predict the presence of CAC independent of traditional CVD risk factors in HIV-infected subjects fully suppressed on ART, suggesting that HIV-mediated immune activation may play a role in CVD risk. PMID- 23984975 TI - Divergent structure-activity relationships of structurally similar acetylcholinesterase inhibitors. AB - The molecular interactions between the enzyme acetylcholinesterase (AChE) and two compound classes consisting of N-[2-(diethylamino)ethyl]benzenesulfonamides and N [2-(diethylamino)ethyl]benzenemethanesulfonamides have been investigated using organic synthesis, enzymatic assays, X-ray crystallography, and thermodynamic profiling. The inhibitors' aromatic properties were varied to establish structure activity relationships (SAR) between the inhibitors and the peripheral anionic site (PAS) of AChE. The two structurally similar compound classes proved to have distinctly divergent SARs in terms of their inhibition capacity of AChE. Eight X ray structures revealed that the two sets have different conformations in PAS. Furthermore, thermodynamic profiles of the binding between compounds and AChE revealed class-dependent differences of the entropy/enthalpy contributions to the free energy of binding. Further development of the entropy-favored compound class resulted in the synthesis of the most potent inhibitor and an extension beyond the established SARs. The divergent SARs will be utilized to develop reversible inhibitors of AChE into reactivators of nerve agent-inhibited AChE. PMID- 23984977 TI - Ochratoxin A in traditional dry-cured meat products produced from sub-chronic exposed pigs. AB - The presence of ochratoxin A (OTA) was determined in traditional dry-cured meat products made from sub-chronically OTA-exposed pigs. The experimental group of pigs (n = 5) was treated with 300 ug OTA kg(-1) of feed during 30 days, whereas the control group (n = 5) remained untreated. After the household production of six types of dry-cured meat products based on traditional recipes, OTA residues were determined in final products produced from each treated and untreated animal using an immunoenzymatic technique (ELISA) and HPLC with fluorescence detection (HPLC-FD). The analytical methods showed acceptable analytical performance results and high correlation coefficients. Mean OTA concentrations ranged from 4.51 +/- 0.11 ug kg(-1) in smoked ham to 6.87 +/- 2.01 ug kg(-1) in home-made Slavonian sausage. The study demonstrated that pig exposure to OTA leads to the accumulation of OTA residues in muscle and adipose tissue used for the production, and consequently results in contamination of the final meat products. PMID- 23984976 TI - GRK2 blockade with betaARKct is essential for cardiac beta2-adrenergic receptor signaling towards increased contractility. AB - BACKGROUND: beta1- and beta2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. beta1AR is pro-contractile and pro-apoptotic but beta2AR anti apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes betaAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (betaarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the beta2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on beta2AR signaling under normal conditions and in heart failure (HF). RESULTS: We crossed beta1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the betaARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post myocardial infarction (MI). betaARKct expression in vivo proved essential for beta2AR-dependent contractile function, as beta2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of betaARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac beta2AR, which is normally mediated by the actions of GRK2 and betaarrs on the receptor. The molecular "brake" that PDE4D poses on beta2AR signaling to contractility stimulation is thus "released". Regarding the other beneficial functions of cardiac beta2AR, betaARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed. CONCLUSIONS: GRK2 inhibition in vivo with betaARKct is absolutely essential for cardiac beta2AR pro contractile signaling and function. In addition, beta2AR anti-apoptotic signaling in post-MI HF is augmented by betaARKct, although this effect is short-lived. PMID- 23984978 TI - Knockout of TLR4 and TLR2 impair the nerve regeneration by delayed demyelination but not remyelination. AB - BACKGROUND: Knockout of either toll-like receptor 4 (TLR4) or 2 (TLR2) had been reported to delay the Wallerian degeneration after peripheral nerve injury by deterring the recruitment of the macrophages and clearance of myelin debris. However, the impact on the remyelination process is poorly understood. In this study, the effect of TLR2 and TLR4 knockout on the nerve regeneration and on the remyelination process was studied in a mouse model of sciatic nerve crush injury. RESULTS: A standard sciatic nerve crush injury by a No. 5 Jeweler forcep for consistent 30 seconds was performed in Tlr4-/- (B6.B10ScN-Tlr4lps-del/JthJ), Tlr2 /- (B6.129-Tlr2tm1Kir/J) and C57BL/6 mice. One centimeter of nerve segment distal to the crushed site was harvested for western blot analysis of the myelin structure protein myelin protein zero (Mpz) and the remyelination transcription factors Oct6 and Sox10 at day 0, 3, 7, 10, 14, 17, 21, 28. Nerve segment 5-mm distal to injured site from additional groups of mice at day 10 after crush injury were subjected to semi-thin section and toluidine blue stain for a quantitative histomorphometric analysis. With less remyelinated nerves and more nerve debris, the histomorphometric analysis revealed a worse nerve regeneration following the sciatic nerve crush injury in both Tlr4-/- and Tlr2-/- mice than the C57BL/6 mice. Although there was a delayed expression of Sox10 but not Oct6 during remyelination, with an average 4-day delay in the demyelination process, the subsequent complete formation of Mpz during remyelination was also delayed for 4 days, implying that the impaired nerve regeneration was mainly attributed to the delayed demyelination process. CONCLUSIONS: Both TLR4 and TLR2 are crucial for nerve regeneration after nerve crush injury mainly by delaying the demyelination but not the remyelination process. PMID- 23984979 TI - Fluorescent nanowire heterostructures as a versatile tool for biology applications. AB - Nanowires are increasingly used in biology, as sensors, as injection devices, and as model systems for toxicity studies. Currently, in situ visualization of nanowires in biological media is done using organic dyes, which are prone to photobleaching, or using microscopy methods which either yield poor resolution or require a sophisticated setup. Here we show that inherently fluorescent nanowire axial heterostructures can be used to localize and identify nanowires in cells and tissue. By synthesizing GaP-GaInP nanowire heterostructures, with nonfluorescent GaP segments and fluorescent GaInP segments, we created a barcode labeling system enabling the distinction of the nanowire morphological and chemical properties using fluorescence microscopy. The GaInP photoluminescence stability, combined with the fact that the nanowires can be coated with different materials while retaining their fluorescence, make these nanowires promising tools for biological and nanotoxicological studies. PMID- 23984980 TI - In situ modification of a semiconductor surface by an enzymatic process: a general strategy for photoelectrochemical bioanalysis. AB - Usually, the photoelectrochemical (PEC) bioanalysis necessitates ready photoactive materials as signal sources to convert the specific biological events into electrical signals. Herein, the first PEC bioanalysis without the necessity of ready visible-light-active species was demonstrated. We use an enzyme catalytic process to couple with the unique surface chemistry of semiconductive nanocrystalline, whereby its electronic properties could be modified spontaneously during the enzymatic reaction. Specifically, the enzymatic hydrolysis of ascorbic acid 2-phosphate by alkaline phosphatase is allowed to interact on the TiO2 nanoparticles (NPs) matrix. PEC tests reveal that the self coordination of the biocatalyzed enediol-ligands onto the undercoordinated surface defect sites would in situ form a ligand-to-metal charge transfer (CT) complex, endowing the inert semiconductor with strong absorption bands in the visible region, and hence underlying a novel and general PEC bioanalysis strategy. PMID- 23984981 TI - Procalcitonin beyond the acute phase: novel biomediator properties? AB - Since inflammation has been linked to carcinogenic events, discovery of relevant biomarkers may have important preventative implications. Procalcitonin (ProCT) has been shown to be an important prognostic biomarker in severe inflammatory conditions, but there is no data regarding its biomarker role, if any, beyond the acute phase. In a recent study published in BMC Medicine, Cotoi et al. analyzed whether serum ProCT levels in healthy individuals are associated with mortality outcomes. The results are affirmative in that baseline ProCT was shown to be strongly and independently associated with all-cause and cancer mortality and with the incidence of colon cancer in men. By contrast, the study indicated that high sensitivity C-reactive protein was independently associated with cardiovascular mortality but not with cancer mortality in men. Thus, baseline levels of ProCT appear to have prognostic biomarker implications potentially related to its emerging biomediator action(s). PMID- 23984982 TI - A study protocol for applying the co-creating knowledge translation framework to a population health study. AB - BACKGROUND: Population health research can generate significant outcomes for communities, while Knowledge Translation (KT) aims to expressly maximize the outcomes of knowledge producing activity. Yet the two approaches are seldom explicitly combined as part of the research process. A population health study in Port Lincoln, South Australia offered the opportunity to develop and apply the co KT Framework to the entire research process. This is a new framework to facilitate knowledge formation collaboratively between researchers and communities throughout a research to intervention implementation process. DESIGN: This study employs a five step framework (the co-KT Framework) that is formulated from engaged scholarship and action research principles. By following the steps a knowledge base will be cumulatively co-created with the study population that is useful to the research aims. Step 1 is the initiating of contact between the researcher and the study contexts, and the framing of the research issue, achieved through a systematic data collection tool. Step 2 refines the research issue and the knowledge base by building into it context specific details and conducting knowledge exchange events. Step 3 involves interpreting and analysing the knowledge base, and integrating evidence to inform intervention development. In Step 4 the intervention will be piloted and evaluated. Step 5 is the completion of the research process where outcomes for improvement will be instituted as regular practice with the facilitation of the community.In summary, the model uses an iterative knowledge construction mechanism that is complemented by external evidence to design interventions to address health priorities within the community. DISCUSSION: This is a systematic approach that operationalises the translational cycle using a framework for KT practice. It begins with the local context as its foundation for knowledge creation and ends with the development of contextually applicable interventions. It will be of interest to those involved in KT research, participatory action research, population health research and health care systems studies. The co-KT Framework is a method for embedding the principles of KT into all stages of a community-based research process, in which research questions are framed by emergent data from each previous stage. PMID- 23984983 TI - Synthesis of a suite of bioorthogonal glutathione S-transferase substrates and their enzymatic incorporation for protein immobilization. AB - Label-free protein immobilization allows precise detection of biomolecular events. Preserving enzyme function is intrinsically challenging for these strategies. Considering that glutathione S-transferase (GST) is a broadly employed enzymatic fusion tag, we reported a label-free self-catalyzed immobilization for Schistosoma japonicum GST. We now report the synthesis, structure, and enzymology of a set of 20 smSNAREs (small molecule SNAr electrophiles). These smSNAREs mimic (electronically) the canonical GST substrate 1-chloro-2,4-dinitrobenzene (CDNB), and bear a wide variety of bioorthogonal functionalities such as alkynes, aldehydes, acetals, and azides. Sixteen analogues including the chloro- and nitro-substituted 1, 3, 5, 6, 7, 11, 12, and 13 participated in the GST-catalyzed conjugation, indicating the substrate tolerance of the enzymatic H-site of SjGST. Using UV-vis spectroscopy, we estimate the efficiency of conjugation as a function of substrate diversity. Using LC-MS, we characterized the conjugates formed under each enzymatic transformation. Significant deviations from the canonical CDNB architecture are tolerated. Relative rates between nitro and chloro substituents indicate the nucleophilic addition step is rate determining. Enzyme immobilization on glass slides is affected by additional surface interactions and therefore does not reflect kinetic profiles observed in solution. This new class of heterobifunctional linkers enables a single-step and uniform protein capture on designer surfaces. PMID- 23984984 TI - Targeting VDAC-bound hexokinase II: a promising approach for concomitant anti cancer therapy. AB - INTRODUCTION: Enhancement of glucose metabolism and repression of oxidative phosphorylation followed by the Warburg effect is the common hallmark of cancer cells. Hexokinase II (HKII) plays a dual role - first, HKII up-regulation results in increased glycolysis rates. Second, association of VDAC and HKII contributes to inhibition of apoptosis through repression of the formation of mitochondrial permeability transition pores. AREAS COVERED: In this review, the role of HKII in evasion of apoptosis, aspects of HKII expression regulation, novel approaches targeting HKII and VDAC-HKII complexes and their application areas are discussed. EXPERT OPINION: The dual role of HKII in cancer cells makes it an attractive target for anti-cancer therapy. Several agents, either synthetic or plant derived, that target hexokinase and induce VDAC-HK complex dissociation have been identified to date. Targeting hexokinase, HK-VDAC complexes as well as other glycolytic proteins not only improves the efficacy of commonly used drugs. The most prominent benefit of this approach is the ability to overcome drug resistance, for example, to cisplatin or sorafenib. In some cases, it could create an insurmountable challenge for selection of appropriate therapy. Future studies and trials should address the issue of how to transfer these approaches into clinical practice. PMID- 23984985 TI - Non-canonical IKKs, IKKepsilon and TBK1, as novel therapeutic targets in the treatment of non-small cell lung cancer. AB - It is well known that non-canonical IkappaB kinases (IKK), IKKepsilon and Tank binding kinase 1 (TBK1), play a key role in anti-viral responses. Interestingly, they have recently emerged as novel survival kinases in several human cancers including lung cancer, given their roles in maintaining cancer cell survival and promoting oncogenic transformation. However, the molecular mechanisms by which IKKepsilon/TBK1 are activated and IKKepsilon/TBK1 mediate survival signal in cancer cells are still controversial. This article will briefly describe signaling pathways mediated by these non-canonical IKKs, especially focusing in lung cancer, and discuss their potential as molecular targets for lung cancer treatment. PMID- 23984987 TI - High-spin ribbons and antiferromagnetic ordering of a Mn(II)-biradical-Mn(II) complex. AB - A binuclear metal coordination complex of the first thiazyl-based biradical ligand 1 is reported (1 = 4,6-bis(1,2,3,5-dithiadiazolyl)pyrimidine; hfac =1,1,1,5,5,5,-hexafluoroacetylacetonato-). The Mn(hfac)2-biradical-Mn(hfac)2 complex 2 is a rare example of a discrete, molecular species employing a neutral bridging biradical ligand. It is soluble in common organic solvents and can be easily sublimed as a crystalline solid. Complex 2 has a spin ground state of S(T) = 4 resulting from antiferromagnetic coupling between the S(birad) = 1 biradical bridging ligand and two S(Mn) = 5/2 Mn(II) ions. Electrostatic contacts between atoms with large spin density promote a ferromagnetic arrangement of the moments of neighboring complexes in ribbon-like arrays. Weak antiferromagnetic coupling between these high-spin ribbons stabilizes an ordered antiferromagnetic ground state below 4.5 K. This is an unusual example of magnetic ordering in a molecular metal-radical complex, wherein the electrostatic contacts that direct the crystal packing are also responsible for providing an efficient exchange coupling pathway between molecules. PMID- 23984986 TI - Azadirachta indica ethanolic extract protects neurons from apoptosis and mitigates brain swelling in experimental cerebral malaria. AB - BACKGROUND: Cerebral malaria is a rapidly developing encephalopathy caused by the apicomplexan parasite Plasmodium falciparum. Drugs currently in use are associated with poor outcome in an increasing number of cases and new drugs are urgently needed. The potential of the medicinal plant Azadirachta indica (Neem) for the treatment of experimental cerebral malaria was evaluated in mice. METHODS: Experimental cerebral malaria was induced in mice by infection with Plasmodium berghei ANKA. Infected mice were administered with Azadirachta indica ethanolic extract at doses of 300, 500, or 1000 mg/kg intraperitoneally (i.p.) in experimental groups, or with the anti-malarial drugs chloroquine (12 mg/kg, i.p.) or artemether (1.6 mg/kg, i.p.), in the positive control groups. Treatment was initiated at the onset of signs of brain involvement and pursued for five days on a daily basis. Mice brains were dissected out and processed for the study of the effects of the extract on pyramidal cells' fate and on markers of neuroinflammation and apoptosis, in the medial temporal lobe. RESULTS: Azadirachta indica ethanolic extract mitigated neuroinflammation, decreased the severity of brain oedema, and protected pyramidal neurons from apoptosis, particularly at the highest dose used, comparable to chloroquine and artemether. CONCLUSIONS: The present findings suggest that Azadirachta indica ethanolic extract has protective effects on neuronal populations in the inflamed central nervous system, and justify at least in part its use in African and Asian folk medicine and practices. PMID- 23984988 TI - The spinning dancer illusion and spontaneous brain fluctuations: an fMRI study. AB - The brain activation associated with the Spinning Dancer Illusion, a cognitive visual illusion, is not entirely known. Inferences from other study modalities point to the involvement of the dorso-parieto-occipital areas in the spontaneous switchings of perception in other bistable non-kinetic illusions. fMRI is a mature technique used to investigate the brain responses associated with mental changes. Resting-state fMRI is a novel technique that may help ascertain the effects of spontaneous brain changes in the top-down regulation of visual perception. The purpose of this report is to describe the brain activation associated with the subjective illusory changes of perception of a kinetic bistable stimulus. We hypothesize that there is a relationship between the perception phases with the very slow cortical spontaneous fluctuations, recently described. A single normal subject who was trained to produce voluntarily perception phase switches underwent a series of fMRI studies whose blocks were either defined post-hoc or accordingly with a predefined timeline to assess spontaneous and voluntarily evoked visual perception switches, respectively. Correlation of findings with resting-state fMRI and independent component analysis of the task series was sought. Phases of the rotation direction were found associated with right parietal activity. Independent component analysis of the task series and their comparison with basal resting-state components suggest that this activity is related to one of the very slow spontaneous brain fluctuations. The spontaneous fluctuations of the cortical activity may explain the subjective changes in perception of direction of the Spinning Dancer Illusion. This observation is a proof-of-principle, suggesting that the spontaneous brain oscillations may influence top-down sensory regulation. PMID- 23984989 TI - Involvement of the phosphatidylinositol kinase pathway in augmentation of ATP sensitive K(+) channel currents by hypo-osmotic stress in rat ventricular myocytes. AB - The objective of this study was to investigate the mechanisms of increase in the efficacy of ATP-sensitive K(+) channel (KATP) openings by hypo-osmotic stress. The whole-cell KATP currents (IK,ATP) stimulated by 100 MUmol/L pinacidil, a K(+) channel opening drug, were significantly augmented during hypo-osmotic stress (189 mOsmol/L) compared with normal conditions (303 mOsmol/L). The EC50 and Emax value for pinacidil-activated IK,ATP (measured at 0 mV) was 154 MUmol/L and 844 pA, respectively, in normal solution and 16.6 MUmol/L and 1266 pA, respectively, in hypo-osmotic solution. Augmentation of IK,ATP during hypo-osmotic stress was attenuated by wortmannin (50 MUmol/L), an inhibitor of phosphatidylinositol 3- and 4-kinases, but not by (i) phalloidin (30 MUmol/L), an actin filament stabilizer, (ii) the absence of Ca(2+) from the internal and external solutions, and (iii) the presence of creatine phosphate (3 mmol/L), which affects creatine kinase regulation of the KATP channels. In the single-channel recordings, an inside-out patch was made after approximately 5 min exposure of the myocyte to hypo-osmotic solution. However, the IC50 value for ATP under such conditions was not different from that obtained in normal osmotic solution. In conclusion, hypo osmotic stress could augment cardiac IK,ATP through intracellular mechanisms involving the phosphatidylinositol kinase pathway. PMID- 23984990 TI - Localization of ODAM, PCNA, and CK14 in regenerating junctional epithelium during orthodontic tooth movement in rats. AB - OBJECTIVE: To identify the regenerating junctional epithelium (JE) during orthodontic tooth movement in rats. MATERIALS AND METHODS: Closed-coil springs were used to create a 20 g mesial force to the maxillary first molars. On days 1, 3, 7, 10, and 14 after force application, histologic changes in JE were examined by immunohistochemistry using proliferating cell nuclear antigen (PCNA), odontogenic ameloblast-associated protein (ODAM), and cytokeratin 14 (CK14). RESULTS: On day 1, JE was destroyed and lost attachment to the tooth surface. Cell division activity was rarely observed in JE, and ODAM localization was weakly detected in damaged JE. By day 3, regenerating JE had not fully recovered. High cell proliferation activity and CK14 expression started to appear in most basal cells of JE. ODAM expression was reduced and appeared in a small area. By day 7, JE had almost recovered. Cell proliferation activity was still observed in several basal cells of JE, and ODAM expression was detected among JE cells. CK14 was hardly observed in JE except in the basal cells. By days 10 and 14, regenerated JE appeared. ODAM, PCNA, and CK14 expression was similar to that of the control. CONCLUSIONS: Damaged JE might recover rapidly during orthodontic tooth movement because basal cells of the remaining JE, which show higher proliferation activity, are involved in JE regeneration. Reduced ODAM expression during proliferation of JE cells may increase again after JE regeneration is complete. Therefore, ODAM may be associated with the normal function of JE. PMID- 23984991 TI - Esthetic comparison of white-spot lesion treatment modalities using spectrometry and fluorescence. AB - OBJECTIVE: To compare the esthetic improvements of white-spot lesions (WSLs) treated by fluoride, casein phosphopeptide amorphous calcium phosphate (CPP-ACP), or resin infiltration. MATERIALS AND METHODS: WSLs were created on human enamel and randomly assigned to four groups: NaF (500 ppm), CPP-ACP, resin infiltration (Icon), or distilled deionized water (DDW; control group). The color change (DeltaE) of each specimen was measured with a Crystaleye spectrophotometer, and fluorescence loss (DeltaQ) was measured by quantitative light-induced fluorescence (QLF), at different time points after treatment: baseline (0 weeks), 2 weeks, 4 weeks, and 6 weeks. RESULTS: The DeltaE and DeltaQ baseline values for the four groups before the treatments did not differ significantly. Icon treatment improved the WSL color significantly and gave the lowest DeltaE (2.9 +/ 1.2 on average) compared with other treatments (P < .01). The Icon treatment also resulted in a significant change in the DeltaQ of WSLs compared with baseline (P < .01). In the NaF and CPP-ACP treatment groups, DeltaQ showed significant recovery compared with the baseline values only after 4 weeks after treatment (P < .05). CONCLUSIONS: Resin infiltration is more effective than NaF or CPP-ACP in providing esthetic improvement of WSLs. PMID- 23984992 TI - A qualitative analysis of orthodontic-related posts on Twitter. AB - OBJECTIVE: To investigate the content of orthodontic-related Twitter posts in order to improve our understanding of orthodontic patients' perceptions and treatment experiences. MATERIALS AND METHODS: Some 131 consecutive posts were collected from Twitter over a 5-day period. Twitter's advanced-search function was used to limit the sampling frame to New Zealand. The posts were qualitatively analyzed for themes using discourse analysis. RESULTS: Four main themes were identified: (1) excitement about getting braces off, (2) problems with braces, (3) positive comments about braces, and (4) negative comments about braces. Various language tools and symbols were often used to convey different degrees of emotion. The present study explores these themes and discusses how they relate to modern-age orthodontics. CONCLUSION: This is the first study to qualitatively analyze orthodontic-related posts in the social media era. Our findings suggest that orthodontic patients use social media sites such as Twitter to convey positive and negative feelings about braces. PMID- 23984993 TI - Interface control of semiconducting metal oxide layers for efficient and stable inverted polymer solar cells with open-circuit voltages over 1.0 volt. AB - Inverted polymer solar cells (PSCs) with high open-circuit voltages of 1.00-1.06 V are fabricated by using an indenofluorene-containing copolymer (PIFTBT8) as an electron donor material and [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) as an electron acceptor material. To improve the photovoltaic performance, interface control of various low-temperature processed ZnO films as cathode buffer layers is systematically investigated for effective electron transportation, while transition metal oxides including MoO3, WO3, NiO, and Cu2O are employed as anode buffer layers for hole-extraction. Incorporation of optimized semiconducting metal oxide interlayers can minimize interfacial power losses, which thus affords large open-circuit voltages (Voc), increased short circuit current densities (Jsc), and fill factors (FF), eventually contributing to higher power conversion efficiencies (PCEs) as well as better device stability. Due to the improved interfacial contacts and fine-matching energy levels, inverted PSCs with a device configuration of ITO/ZnO/PIFTBT8:PC71BM/MoO3/Ag exhibit a high PCE of 5.05% with a large Voc of 1.04 V, a Jsc of 9.74 mA cm(-2), and an FF of 50.1%. For the single junction inverted PSCs with efficiencies over 5.0%, 1.04 V is the largest Voc ever achieved. By controlling the processing conditions of the active layer, the Voc can further be improved to 1.05 and 1.06 V, with PCEs of 4.70% and 4.18%, respectively. More importantly, the inverted PSCs are ascertained to maintain a PCE of 4.55% (>90% of its initial efficiency) and a Voc of 1.05 V over 180 days, demonstrating good long-term stability, which is much better than that of the conventional devices. The results suggest that the interface engineering of metal oxide interlayers is an important strategy to develop PSCs with good performance. PMID- 23984994 TI - A qualitative study of perceived risk for HIV transmission among police officers in Dar es Salaam, Tanzania. AB - BACKGROUND: Understanding people's views about HIV transmission by investigating a specific population may help to design effective HIV prevention strategies. In addition, knowing the inherent sexual practices of such a population, as well as the risky circumstances that may facilitate HIV transmission, is crucial for the said strategies to become effective. In this article, we report how police officers in Dar es Salaam, Tanzania, perceived the problem of HIV and AIDS in their local context, particularly in relation to unsafe sexual practices. The study was done with the view to recommending ways by which HIV transmission could be minimised within the police force. METHODS: The study was conducted among members of the police force in Dar es Salaam, Tanzania. Eight focus group discussions (FGDs) were conducted, with a total of 66 participants who were mixed in terms of age, gender, and marital status. Some of these were caregivers to patients with AIDS. Data were analysed using the interpretive description approach. RESULTS: The participants believed that both individual sexual behaviour and work-related circumstances were sources of HIV infection. They also admitted that they were being tempted to engage in risky sexual practices because of the institutional rules that prohibit officers from getting married during their training and for three years after. Nevertheless, as members of the Police Force, they stressed the fact that the risky sexual behaviour that exposes them to HIV is not limited to the force; it is rather a common problem that is faced by the general population. However, they complained, the nature of their job exposes them to road accident victims, subjecting them further to possible infection, especially when they have to handle these road accident casualties without proper protective gear. CONCLUSION: Individual sexual behaviour and job related circumstances are worth investigating if proper advice is to be given to the police regarding HIV prevention strategies. In order to improve the lives of these police officers, there is a need to review the existing institutional rules and practices to accommodate individual sexual needs. In addition, improving their working environment may minimize the risk of HIV transmission from handling casualties in emergency situations. PMID- 23984996 TI - New insights on fibrosis in Crohn's disease. PMID- 23984995 TI - Statins for chemoprevention of hepatocellular carcinoma: assessing the evidence. PMID- 23984997 TI - The great debate: stopping immunomodulators and biologics in Crohn's disease patients in remission. PMID- 23984999 TI - Predicting risk in patients with acetaminophen overdose. AB - Acetaminophen (APAP) overdose is a very common cause of drug overdose and acute liver failure in the US and Europe. Mechanism-based biomarkers of APAP toxicity have the potential to improve the clinical management of patients with large-dose ingestions of APAP. The current approach to the management of APAP toxicity is limited by imprecise and time-constrained risk assessments and late-stage markers of liver injury. A recent study of 'low-risk' APAP overdose patients who all received treatment with N-acetylcysteine found that cell death biomarkers were more sensitive than alanine aminotransferase (ALT) and APAP concentrations in predicting the development of acute liver injury. The data suggest a potential role for new biomarkers to identify 'low-risk' patients following APAP overdose. However, a practical and ethical consideration that complicates predictive biomarker research in this area is the clinical need to deliver antidote treatment within 10 h of APAP overdose. The treatment effect and time-dependent nature of N-acetylcysteine treatment must be considered in future 'predictive' toxicology studies of APAP-induced liver injury. PMID- 23985000 TI - Leptin in the treatment of lipodystrophy-associated nonalcoholic fatty liver disease: are we there already? AB - Evaluation of: In general, nonalcoholic fatty liver disease (NAFLD) consists of ectopic fat accumulation in the liver, when the ability to store fat in inert reservoirs is overcome. That occurs either when we have an excess of energy/fat such as in obesity, or when adipose tissue is defective, not being able to store even regular amounts of energy, such as in lipodystrophies (LDs). LD associates with metabolic deregulation: insulin resistance/diabetes mellitus and dyslipidemia. Several small studies have shown a beneficial effect of leptin replacement, an adipocyte-derived hormone, in the metabolic profile of patients with LD. The paper under evaluation studied 50 patients with LD-associated NAFLD treated with leptin, suggesting a beneficial effect in liver histology and in decreasing not only steatosis, but also nonalcoholic steatohepatitis, although with no effect on fibrosis after 2 years of treatment. PMID- 23985001 TI - Diagnosis and treatment of hereditary hemochromatosis: an update. AB - Hereditary hemochromatosis is an inherited iron overload disorder caused by inappropriately low hepcidin secretion leading to increased duodenal absorption of dietary iron, most commonly in C282Y homozygous individuals. This can result in elevated serum ferritin, iron deposition in various organs and ultimately end organ damage, although there is incomplete biochemical and clinical penetrance and variable phenotypic expression of the HFE mutation in hereditary hemochromatosis. An elevated SF >1000 mg/l [corrected] is associated with an increased risk of cirrhosis and mortality in C282Y homozygotes.Conversely, a SF <1000 ug/l is associated with a very low likelihood of cirrhosis, making liver biopsy unnecessary among C282Y homozygotes in the absence of concomitant risk factors for liver disease. Phlebotomy remains the mainstay of treatment and new treatments being studied include erythrocytapheresis and 'mini-hepcidins'. Iron overload is being recognized to play a carcinogenic role in hepatocellular carcinoma and other cancers, possibly supporting iron depletion in these patients. PMID- 23985002 TI - Improving ERCP quality and decreasing risk to patients and providers. AB - Endoscopic retrograde cholangiopancreatography (ERCP) continues to be one of the most complex gastrointestinal procedures and carries the highest risk of complications. Optimizing the outcome of ERCP requires a fine balance between the risk and the benefit of every maneuver performed. This fine balance has to include an analysis of the indication for the procedure, the optimal timing, the setting where the procedure is performed, the endoscopist and staff training and expertise, availability of surgical and interventional radiology support, the risk of every maneuver and ways to minimize this risk. As in any other procedure, it is very important to know one's limitations and have a plan for failed procedures including consulting a colleague or referring the patient to a center with more expertise. In addition, a process of quality improvement is integral to every endoscopy center to address areas of underperformance, improve patient care and decrease liability. PMID- 23985003 TI - Helicobacter pylori infection in Europe: current perspectives. AB - There is a commonly held perception that Helicobacter pylori related diseases are declining, however these are still associated with a high risk of morbidity and mortality. In recent years worrying themes have emerged such as increasing levels of antibiotic resistance and falling cure rates which illustrate there is no room for complacency with respect to H. pylori. In addition there are many significant issues which have not been elucidated regarding the role played by H. pylori in very serious pathologies such as gastric and esophageal cancer and other more benign disorders common in the developed world such as gastroesophageal reflux disease, functional dyspepsia and perhaps obesity which carry a significant impact both economically and as regards to symptoms. Future guidelines aimed at European practitioners and patients will need to address the questions raised by these issues as well as the more familiar areas such as constituents and duration of therapy. PMID- 23985004 TI - Personalizing therapy for inflammatory bowel diseases. AB - Inflammatory bowel diseases (IBDs; e.g., Crohn's disease [CD] and ulcerative colitis [UC]) are chronic immunologically mediated diseases characterized by frequent relapses, often requiring hospitalization and surgery. There is substantial heterogeneity in the progressive natural history of disease with cumulative accrual of bowel damage and impairment of functioning. Recent advances in therapeutics have significantly improved our ability to achieve disease remission; yet therapies remain expensive and are associated with significant side effects precluding widespread use in all patients with IBD. Consequently, algorithms for the management of patients with IBD require a personalized approach incorporating an individual's projected likely natural history, the probability of response to a specific therapeutic agent and an informed approach to management of loss of response to current therapies. PMID- 23985005 TI - Endoscopic resection for gastrointestinal neuroendocrine tumors. AB - Gastrointestinal (GI) and neuroendocrine tumors (NETs) can be treated by mini invasive endoscopic resection when localized in the superficial layers of the bowel wall and their size is <20 mm. Endoscopic diagnosis of NETs is usually incidental or suspected after clinical, laboratory or imaging findings. Endoscopic mucosal resection is the most commonly used technique for NET removal, endoscopic submucosal dissection is indicated in selected cases, while papillectomy is feasible for ampullary lesions. Histopathologic assessment of the resection margin (circumferential and deep) is important for staging. Incidence of endoscopic mucosal resection-/endoscopic submucosal dissection-related complications for removal of GI NETs are similar to those reported for other GI lesions. Endoscopic follow-up is based on histopathologic characteristics of the resected NETs and its site. NETs >20 mm in size, with penetration of the muscle layer and/or serosa are at high risk for metastases and surgical approach is recommended when feasible. PMID- 23985006 TI - Patient selection for liver transplantation. AB - Improved outcomes in liver transplant recipients reflect advances in surgical technique, post-operative care, immunosuppression as well as better selection of potential candidates. The pre-transplant evaluation is a multidisciplinary process intended to recognize and treat important comorbid conditions that may impair outcomes during the peri- and post-transplant periods. Important psychosocial issues should also be ascertained and tackled early during the pre transplant evaluation with an overarching intention to improve the success of liver transplantation. PMID- 23985007 TI - Computerized adaptation of The Placing Test for early detection of both mild cognitive impairment and Alzheimer's disease. AB - Changes in the hippocampal system have been proposed as a possible marker of incipient Alzheimer's disease (AD) at the mild cognitive impairment (MCI) stage. The Placing Test (TPT) evaluates the efficiency of the hippocampal system by measuring the ability to remember associations between images and their locations. Our aim was to validate a novel paper-and-pencil (PnP) version of TPT featuring people's faces in color (versus the traditional test carried out with black-and-white images) and a computerized Placing test with categories of objects, faces, and animals (versus a version featuring the categories of objects, faces, and shapes). A total of 78 subjects were divided into 2 groups; each group included 20 normal control subjects, 10 subjects with MCI, and 9 with AD. All subjects underwent TPT. The correlation between the two versions of the test was highly significant (r=.770, p<.001), demonstrating that the transfer of the test format from PnP to computer was acceptable. Computerized object and animal subtests had the highest overall sensitivity and specificity for discriminating MCI from AD, while PnP faces in color discriminated controls from MCI best. Although this was a preliminary assessment on a small sample of subjects, the results of our study demonstrated that total scores on both the traditional and computerized versions of the test discriminate all three diagnostic categories, but the subtests had varying discriminatory abilities. PMID- 23985008 TI - Patient-derived tissue slice grafts accurately depict response of high-risk primary prostate cancer to androgen deprivation therapy. AB - BACKGROUND: Effective eradication of high-risk primary prostate cancer (HRPCa) could significantly decrease mortality from prostate cancer. However, the discovery of curative therapies for HRPCa is hampered by the lack of authentic preclinical models. METHODS: We improved upon tumorgraft models that have been shown to predict drug response in other cancer types by implanting thin, precision-cut slices of HRPCa under the renal capsule of immunodeficient mice. Tissue slice grafts (TSGs) from 6 cases of HRPCa were established in mice. Following androgen deprivation by castration, TSGs were recovered and the presence and phenotype of cancer cells were evaluated. RESULTS: High-grade cancer in TSGs generated from HRPCa displayed characteristic Gleason patterns and biomarker expression. Response to androgen deprivation therapy (ADT) was as in humans, with some cases exhibiting complete pathologic regression and others showing resistance to castration. As in humans, ADT decreased cell proliferation and prostate-specific antigen expression in TSGs. Adverse pathological features of parent HRPCa were associated with lack of regression of cancer in corresponding TSGs after ADT. Castration-resistant cancer cells remaining in TSGs showed upregulated expression of androgen receptor target genes, as occurs in castration-resistant prostate cancer (CRPC) in humans. Finally, a rare subset of castration-resistant cancer cells in TSGs underwent epithelial-mesenchymal transition, a process also observed in CRPC in humans. CONCLUSIONS: Our study demonstrates the feasibility of generating TSGs from multiple patients and of generating a relatively large number of TSGs from the same HRPCa specimen with similar cell composition and histology among control and experimental samples in an in vivo setting. The authentic response of TSGs to ADT, which has been extensively characterized in humans, suggests that TSGs can serve as a surrogate model for clinical trials to achieve rapid and less expensive screening of therapeutics for HRPCa and primary CRPC. PMID- 23985009 TI - Aromatic glucosides from the seeds of Prunus davidiana. AB - Chemical investigation of the seeds of Prunus davidiana afforded seven new aromatic glucosides, i.e., the prupersins A-E (1-5) and compounds 6 and 7, as well as 11 known compounds. The structures of 1-7 were elucidated by spectroscopic data analysis and chemical evidence, and configurations were determined by hydrolysis experiments (1, 2, and 5) or electronic circular dichroism (6). Compounds 1-6 exhibited antioxidant activity aganist Fe2+-cysteine induced rat liver microsomal lipid peroxidation, with malondialdehyde inhibitory rates of 50-67% and 53-57% at concentrations of 10-5 and 10-6 mol/L, respectively. PMID- 23985010 TI - The importance of tissue specificity for RNA-seq: highlighting the errors of composite structure extractions. AB - BACKGROUND: A composite biological structure, such as an insect head or abdomen, contains many internal structures with distinct functions. Composite structures are often used in RNA-seq studies, though it is unclear how expression of the same gene in different tissues and structures within the same structure affects the measurement (or even utility) of the resulting patterns of gene expression. Here we determine how complex composite tissue structure affects measures of gene expression using RNA-seq. RESULTS: We focus on two structures in the honey bee (the sting gland and digestive tract) both contained within one larger structure, the whole abdomen. For each of the three structures, we used RNA-seq to identify differentially expressed genes between two developmental stages, nurse bees and foragers. Based on RNA-seq for each structure-specific extraction, we found that RNA-seq with composite structures leads to many false negatives (genes strongly differentially expressed in particular structures which are not found to be differentially expressed within the composite structure). We also found a significant number of genes with one pattern of differential expression in the tissue-specific extraction, and the opposite in the composite extraction, suggesting multiple signals from such genes within the composite structure. We found these patterns for different classes of genes including transcription factors. CONCLUSIONS: Many RNA-seq studies currently use composite extractions, and even whole insect extractions, when tissue and structure specific extractions are possible. This is due to the logistical difficultly of micro-dissection and unawareness of the potential errors associated with composite extractions. The present study suggests that RNA-seq studies of composite structures are prone to false negatives and difficult to interpret positive signals for genes with variable patterns of local expression. In general, our results suggest that RNA seq on large composite structures should be avoided unless it is possible to demonstrate that the effects shown here do not exist for the genes of interest. PMID- 23985012 TI - Development and characterization of lutein-loaded SNEDDS for enhanced absorption in Caco-2 cells. AB - A self-nanoemulsifying drug delivery system (SNEDDS) has been developed for enhanced oral bioavailability of lutein. Its permeation enhancement has been evaluated using monolayers of Caco-2 cells. SNEDDS is composed of a mixture of Lexol(r) and Emulmetik(r) 900, Labrasol(r), and Tween 80 as oil, surfactant and co-surfactant, respectively. Upon dilution of lutein-loaded SNEDDS with water, a nanoemulsion was obtained in <10 s with spherical droplets of 40-150 nm in diameter. The zeta potential was in the range of -19 to -32 mV. Increasing the ratio of surfactant to co-surfactant decreased the mean droplet size. Dissolution studies showed that lutein was released rapidly (<5 min) from SNEDDS into 0.1 N HCl and pH 6.8 phosphate buffer solution without any aggregation. In vitro studies using Caco-2 cells revealed that lutein-loaded SNEDDS showed shorter lag time and greater (2-fold) cellular accumulation compared with the lutein dispersion. PMID- 23985013 TI - Biocatalytic release of an anticancer drug from nucleic-acids-capped mesoporous SiO2 Using DNA or molecular biomarkers as triggering stimuli. AB - DNA-gated mesoporous SiO2 nanoparticles, MP-SiO2 NPs, loaded with rhodamine B, RhB, act as "smart" materials that reveal complementary "sense" and "release" functionalities. The unlocking of the DNA pore-capping units is achieved by the biocatalytic cleavage of the DNA, and the unlocking process is amplified by the regeneration of the analyte-trigger. The RhB-loaded MP-SiO2 NPs are capped with nucleic acid hairpin structures that lock the RhB in the pores. Opening of the hairpin structures by a nucleic acid analyte trigger or by the formation of an aptamer-substrate (ATP) complex leads to the formation of duplex structures being cleaved by exonuclease III, Exo III, or the nicking enzyme, Nb. BbvCI. This results in the regeneration of the target analytes, the autonomous unlocking of the pores, and the release of RhB. The systems reveal selectivity, and one-, two , three-base mutations in the target DNA, or substitution of ATP with other triphosphate nucleotides, prohibit the unlocking of the pores. In analogy to the biocatalytic release of the model fluorophore substrates, the anticancer drug camptothecin, CPT, was entrapped in the pores and locked by the 1 or 11 hairpin structures. The drug was released from the pores in the presence of the nucleic acid 2 or ATP and the Exo III, as biocatalyst. Similarly, CPT locked in the pores by the 6 or 12 hairpins were released from the pores in the presence of ATP and Nb. BbvCI, as nicking enzyme, respectively. The effects of the CPT-loaded MP-SiO2 NPs, capped with the ATP-dependent lock 6, on the viability of MDA-231 breast cancer cells and MCF-10a normal breast cells were examined. We find that after 48 h, 65% cell death was observed for the MDA-231 cancer cells, where only 25% cell death was observed for the normal cells. The higher cell death of the cancer cells correlates well with the enhanced metabolic synthesis of ATP in the cancerous cells. PMID- 23985014 TI - In silico modelling for predicting the cationic hydrophobicity and cytotoxicity of ionic liquids towards the Leukemia rat cell line, Vibrio fischeri and Scenedesmus vacuolatus based on molecular interaction potentials of ions. AB - In this study we present prediction models for estimating in silico the cationic hydrophobicity and the cytotoxicity (log [1/EC50]) of ionic liquids (ILs) towards the Leukemia rat cell line (IPC-81), the marine bacterium Vibrio fischeri and the limnic green algae Scenedesmus vacuolatus using linear free energy relationship (LFER) descriptors computed by COSMO calculations. The LFER descriptors used for the prediction model (i.e. excess molar refraction (E), dipolarity/polarizability (S), hydrogen-bonding acidity (A), hydrogen-bonding basicity (B) and McGowan volume (V)) were calculated using sub-descriptors (sig2, sig3, HBD3, HBA4, MR, and volume) derived from COSMO-RS, COSMO and OBPROP. With the combination of two solute descriptors (B, V) of the cation we were able to predict cationic hydrophobicity values (log ko ) with r (2) = 0.987 and standard error (SE) = 0.139 log units. By using the calculated log k o values, we were able to deduce a linear toxicity prediction model. In the second prediction study for the cytotoxicity of ILs, analysis of descriptor sensitivity helped us to determine that the McGowan volume (V) terms of the cation was the most important predictor of cytotoxicity and to simplify prediction models for cytotoxicity of ILs towards the IPC-81 (r (2) of 0.778, SE of 0.450 log units), Vibrio fischeri (r (2) of 0.762, SE of 0.529 log units) and Scenedesmus vacuolatus (r (2) of 0.776, SE of 0.825 log units). The robustness and predictivity of the two models for IPC-81 and Vibrio fischeri were checked by comparing the calculated SE and r (2) (coefficient of determination) values of the test set. PMID- 23985011 TI - Lexical retrieval in discourse: an early indicator of Alzheimer's dementia. AB - We examined the progression of lexical-retrieval deficits in individuals with neuropathologically determined Alzheimer's disease (AD; n = 23) and a comparison group without criteria for AD (n = 24) to determine whether linguistic changes were a significant marker of the disease. Our participants underwent multiple administrations of a neuropsychological battery, with initial administration occurring on average 16 years prior to death. The battery included the Boston Naming Test (BNT), a letter fluency task (FAS) and written description of the Cookie Theft Picture (CTP). Repeated measures analysis revealed that the AD-group showed progressively greater decline in FAS and CTP lexical performance than the comparison group. Cross-sectional time-specific group comparisons indicated that the CTP differentiated performance between the two groups at 7-9 years prior to death and FAS and BNT only at 2-4 years. These results suggest that lexical retrieval deficits in written discourse serve as an early indicator of AD. PMID- 23985015 TI - Ultrasensitive detection and quantification of acidic disaccharides using capillary electrophoresis and quantum dot-based fluorescence resonance energy transfer. AB - Rapid and highly sensitive detection of the carbohydrate components of glycoconjugates is critical for advancing glycobiology. Fluorescence (or Forster) resonance energy transfer (FRET) is commonly used in detection of DNA, in protein structural biology, and in protease assays but is less frequently applied to glycan analysis due to difficulties in inserting two fluorescent tags into small glycan structures. We report an ultrasensitive method for the detection and quantification of a chondroitin sulfate disaccharide based on FRET, involving a CdSe-ZnS core-shell nanocrystal quantum dot (QD) streptavidin conjugate donor and a Cy5 acceptor. The disaccharide was doubly labeled with biotin and Cy5. QDs then served to concentrate the target disaccharide, enhancing the overall energy transfer efficiency, with unlinked QDs and Cy5 hydrazide producing nearly zero background signal in capillary electrophoresis using laser-induced fluorescence detection with two different band-pass filters. This method is generally applicable to the ultrasensitive analysis of acidic glycans and offers promise for the high-throughput disaccharide analysis of glycosaminoglycans. PMID- 23985016 TI - Kinetic rotating droplet electrochemistry: a simple and versatile method for reaction progress kinetic analysis in microliter volumes. AB - Here, we demonstrate a new generic, affordable, simple, versatile, sensitive, and easy-to-implement electrochemical kinetic method for monitoring, in real time, the progress of a chemical or biological reaction in a microdrop of a few tens of microliters, with a kinetic time resolution of ca. 1 s. The methodology is based on a fast injection and mixing of a reactant solution (1-10 MUL) in a reaction droplet (15-50 MUL) rapidly rotated over the surface of a nonmoving working electrode and on the recording of the ensuing transient faradaic current associated with the transformation of one of the components. Rapid rotation of the droplet was ensured mechanically by a rotating rod brought in contact atop the droplet. This simple setup makes it possible to mix reactants efficiently and rotate the droplet at a high spin rate, hence generating a well-defined hydrodynamic steady-state convection layer at the underlying stationary electrode. The features afforded by this new kinetic method were investigated for three different reaction schemes: (i) the chemical oxidative deprotection of a boronic ester by H2O2, (ii) a biomolecular binding recognition between a small target and an aptamer, and (iii) the inhibition of the redox-mediated catalytic cycle of horseradish peroxidase (HRP) by its substrate H2O2. For the small target/aptamer binding reaction, the kinetic and thermodynamic parameters were recovered from rational analysis of the kinetic plots, whereas for the HRP catalytic/inhibition reaction, the experimental amperometric kinetic plots were reproduced from numerical simulations. From the best fits of simulations to the experimental data, the kinetics rate constants primarily associated with the inactivation/reactivation pathways of the enzyme were retrieved. The ability to perform kinetics in microliter-size samples makes this methodology particularly attractive for reactions involving low-abundance or expensive reagents. PMID- 23985018 TI - Highly populated and nearly monodispersed nanosilica particles in an organic medium and their epoxy nanocomposites. AB - An organic aminopropyl-functionalized nanosilica sol was synthesized in the presence of ethyl silicate, gamma-(aminopropyl)triethoxysilane (KH550), and N,N dimethylformamide (DMF) via a sol-gel technique and then used to prepare epoxy nanocomposites. Structure and morphology analyses of the obtained aminopropyl functionalized nanosilicas were observed by dynamic light scattering (DLS), transmission electron microscopy (TEM), and high-resolution TEM (HRTEM). TEM and DLS showed that modified nanosilicas with an average diameter of 30 nm dispersed homogeneously in DMF. The effects of the aminopropyl-functionalized nanosilica particles on the flexural modulus, impact strength, glass transition temperature (Tg), and bulk resistivity (rhov) of the epoxy nanocomposites were investigated. The toughening mechanisms and microstructures were determined in terms of the impact fracture surface morphology using scanning electron microscopy. PMID- 23985019 TI - The amnestic syndrome: applying the Rorschach Inkblot method for differential diagnosis. AB - Dissociative processes were investigated in a man diagnosed with focal retrograde amnesia (FRA) following a traumatic head injury without any anterograde memory deficit. Findings were derived from the Rorschach Inkblot method, which was administered together with other performance-based tests and a self-report inventory for evaluating dissociative proneness in personality functioning. A substantial set of behavioral and test response variables indicated dissociation proneness and the activation of dissociative mechanisms. This conception was supported a few months following the evaluation when the patient reported a total spontaneous recovery of the memory deficit. The interplay between neurological and functional factors in FRA is discussed with a view for creating an integrated model. PMID- 23985017 TI - Cardiac rehabilitation barriers by rurality and socioeconomic status: a cross sectional study. AB - INTRODUCTION: Despite greater need, rural inhabitants and individuals of low socioeconomic status (SES) are less likely to undertake cardiac rehabilitation (CR). This study examined barriers to enrollment and participation in CR among these under-represented groups. METHOD: Cardiac inpatients from 11 hospitals across Ontario were approached to participate in a larger study. Rurality was assessed by asking participants whether they lived within a 30-minute drive-time from the nearest hospital, with those >30 minutes considered "rural." Participants completed a sociodemographic survey, which included the MacArthur Scale of Subjective Social Status. One year later, they were mailed a survey which assessed CR utilization and included the Cardiac Rehabilitation Barriers Scale. In this cross-sectional study, CR utilization and barriers were compared by rurality and SES. RESULTS: Of the 1809 (80.4%) retained, there were 215 (11.9%) rural participants, and the mean subjective SES was 6.37 +/- 1.76. The mean CRBS score was 2.03 +/- 0.73. Rural inhabitants reported attending significantly fewer CR sessions (p < .05), and greater CR barriers overall compared to urban inhabitants (p < .01). Patients of lower subjective SES were significantly less likely to be referred, enroll, and participate in CR, and reported significantly greater barriers to CR compared to their high SES counterparts (p < .01). Prominent barriers for both groups included distance, cost, and transportation problems. These relationships sustained adjustment, and a significant relationship between having undergone coronary artery bypass graft surgery and lower barriers was also identified. CONCLUSIONS: The results confirm that rural inhabitants and patients of low SES experience greater barriers to CR utilization when compared to their urban, high SES counterparts. It is time to implement known strategies to overcome these barriers, to achieve equitable and greater use of CR. PMID- 23985020 TI - Change of the magnetic coupling of a metal-organic complex with the substrate by a stepwise ligand reaction. AB - The surface-assisted intramolecular ligand reaction of a porphyrin molecule adsorbed on Au(111) is studied by scanning tunneling microscopy and spectroscopy. The temperature-induced stepwise transformation of iron octaethylporphyrin proceeds via a concentric electrocyclic ring closure, with the final product iron tetrabenzoporphyrin being identified by its characteristic Kondo resonance. Along with the transformation of the organic ligand, changes in the magnetic fingerprint are observed, indicating an increasing coupling of the iron spin with the substrate electrons. PMID- 23985021 TI - Mixed silane monolayers for controlling the surface areal density of click reactive alkyne groups: a method to assess preferential surface adsorption on flat substrates and a method to verify compositional homogeneity on nanoparticles. AB - SAMs formed from mixtures of alkyne-silanes and alkane-silanes are used to control the areal density of click-reactive alkyne groups on the surface of flat germanium substrates, silicon wafers, and silica nanoparticles. Two new analytical tools are described for characterization of the mixed SAMs: a thermogravimetric analysis (TGA) technique for quantifying the compositional homogeneity of the mixed monolayers formed on nanoparticles, and an infrared spectroscopy (IR) technique to detect preferential surface adsorption. The TGA technique involves measurement of the change in weight when azide-terminated polymers react with surface alkyne groups on silica nanoparticles via a click reaction, while the IR technique is based on the use of attenuated total reflectance infrared spectroscopy (ATR-IR) to monitor click reactions between azide compounds with infrared "labels" and alkyne-functional mixed SAMs deposited on germanium ATR plates. Upon application of the new characterization techniques, we are able to prove that the mixed silane monolayers show neither phase separation nor preferential surface adsorption on any of the three substrates studied. When reacted with azide terminal polymers, the areal density at saturation, sigma(sat) is found to scale with molecular weight according to sigma(sat) ~ N(-0.57). We conclude that mixed monolayers of alkyne-silanes and alkane-silanes are an effective means of controlling the surface areal density of click-reactive alkyne groups on both flat and nanoparticle substrates. PMID- 23985022 TI - Cocaine-associated hemoperitoneum following atraumatic splenic rupture: a case report and literature review. AB - INTRODUCTION: Splenic hematoma or rupture of the spleen is rare in the absence of trauma. This case report with a brief review of the literature is intended to raise awareness of splenic bleeding as an etiology of abdominal pain; it highlights the importance of a detailed social history. PRESENTATION OF CASE: This report of an otherwise healthy 42-year old man details hemoperitoneum with splenic rupture as a cause for hemorrhage following cocaine use. The patient was managed non-operatively in the surgical intensive care unit. He did not require transfusion and was discharged home on hospital day four with close follow-up. DISCUSSION: While splenic pathology associated with cocaine use has been described, this case illustrates a novel report of cocaine-associated splenic hemorrhage. A plausible mechanism is transient vasospasm with subsequent bleeding into the infarcted area. CONCLUSION: Although uncommon, atraumatic splenic rupture should be recognized early because it is potentially fatal. This case is the first to describe hemoperitoneum of splenic etiology following cocaine use. PMID- 23985024 TI - Letter to the editor: re: "periodontal diagnosis affected by variation in terminology". PMID- 23985023 TI - B cell lymphoma in HIV transgenic mice. AB - BACKGROUND: Human Immunodeficiency Virus Type I (HIV-1) infection is associated with a high incidence of B-cell lymphomas. The role of HIV in these lymphomas is unclear and currently there are no valid in vivo models for better understanding HIV-related lymphomagenesis. Transgenic (Tg) 26 mice have a 7.4-kb pNL4-3 HIV-1 provirus lacking a 3.1-kb sequence encompassing parts of the gag-pol region. Approximately 15% of these HIV Tg mice spontaneously develop lymphoma with hallmark pre-diagnostic markers including skin lesions, diffuse lymphadenopathy and an increase in pro-inflammatory serum cytokines. Here we describe the phenotypic and molecular characteristics of the B cell leukemia/lymphoma in the Tg mice. RESULTS: The transformed B cell population consists of CD19+pre BCR+CD127+CD43+CD93+ precursor B cells. The tumor cells are clonal and characterized by an increased expression of several cellular oncogenes. Expression of B cell-stimulatory cytokines IL-1beta, IL-6, IL-10, IL-12p40, IL-13 and TNFalpha and HIV proteins p17, gp120 and nef were elevated in the Tg mice with lymphoma. CONCLUSIONS: Increased expression of HIV proteins and the B-cell stimulatory factors is consistent with the interpretation that one or more of these factors play a role in lymphoma development. The lymphomas share many similarities with those occurring in HIV/AIDS+ patients and may provide a valuable model for understanding AIDS-related lymphomagenesis and elucidating the role played by HIV-1. PMID- 23985025 TI - Authors' response. PMID- 23985027 TI - Improving clarity and stability of skim milk powder dispersions by dissociation of casein micelles at pH 11.0 and acidification with citric acid. AB - Casein micelles in milk cause turbidity and have poor stability at acidic conditions. In this study, skim milk powder dispersions were alkalized to pH 10.0 or 11.0, corresponding to reduced particle mass. In the following acidification with hydrochloric or citric acid, the re-formation of casein particles was observed. The combination of treatment at pH 11.0 and acidification with citric acid resulted in dispersions with the lowest turbidity and smallest particles, which enabled translucent dispersions at pH 5.5-7.0, corresponding to discrete nanoparticles. The concentration of ionic calcium was lower when acidified with citric acid than hydrochloric acid, corresponding to smaller particles with less negative zeta potential. The pH 11.0 treatment followed by acidification with citric acid also resulted in smaller particles than the simple chelating effects (directly implementing sodium citrate). The produced casein nanoparticles with reduced dimensions can be used for beverage and other novel applications. PMID- 23985028 TI - S-Nitrosylation of parkin as a novel regulator of p53-mediated neuronal cell death in sporadic Parkinson's disease. AB - BACKGROUND: Mutations in the gene encoding parkin, a neuroprotective protein with dual functions as an E3 ubiquitin ligase and transcriptional repressor of p53, are linked to familial forms of Parkinson's disease (PD). We hypothesized that oxidative posttranslational modification of parkin by environmental toxins may contribute to sporadic PD. RESULTS: We first demonstrated that S-nitrosylation of parkin decreased its activity as a repressor of p53 gene expression, leading to upregulation of p53. Chromatin immunoprecipitation as well as gel-shift assays showed that parkin bound to the p53 promoter, and this binding was inhibited by S nitrosylation of parkin. Additionally, nitrosative stress induced apoptosis in cells expressing parkin, and this death was, at least in part, dependent upon p53. In primary mesencephalic cultures, pesticide-induced apoptosis was prevented by inhibition of nitric oxide synthase (NOS). In a mouse model of pesticide induced PD, both S-nitrosylated (SNO-)parkin and p53 protein levels were increased, while administration of a NOS inhibitor mitigated neuronal death in these mice. Moreover, the levels of SNO-parkin and p53 were simultaneously elevated in postmortem human PD brain compared to controls. CONCLUSIONS: Taken together, our data indicate that S-nitrosylation of parkin, leading to p53 mediated neuronal cell death, contributes to the pathophysiology of sporadic PD. PMID- 23985030 TI - The role of afatinib in the management of non-small cell lung carcinoma. AB - INTRODUCTION: Despite initial patient benefit, drug resistance to first generation EGFR tyrosine kinase inhibitors (TKIs) is inevitable. One of the key mechanisms responsible for the development of acquired drug resistance is the secondary T790M missense mutation in exon 20 of the EGFR kinase domain. Afatinib is an ATP-competitive small molecule inhibitor that potently and irreversibly inhibits EGFR and mutated EGFR including the T790M variant, as well as other members of the ErbB family in preclinical studies. AREAS COVERED: The authors describe the rationale and provide the preclinical background to afatinib and its potential as a NSCLC therapy. Specifically, the authors detail the drug's pharmaco-kinetic profile and review its clinical efficacy and toxicity profile. EXPERT OPINION: Afatinib is an effective treatment option for therapy-naive advanced NSCLC harboring an activating EGFR mutation. Furthermore, it is also of potential benefit to patients with acquired resistance to EGFR kinase inhibitors. In the future, the authors envision the clinical development of third-generation EGFR mutation-specific inhibitors in NSCLC, which may potentially spare normal tissue toxicity. Nevertheless, afatinib currently represents a bona fide treatment option in the NSCLC therapeutic armamentarium. PMID- 23985029 TI - Anti-tumour activity of longikaurin A (LK-A), a novel natural diterpenoid, in nasopharyngeal carcinoma. AB - BACKGROUND: Longikaurin A is a natural ent-kaurene diterpenoid isolated from Isodon genus. The ent-kaurene diterpenoids isolated from medicinal plants have been shown to have anti-disease effects. The present study was designed to examine the anti-tumour effects of longikaurin A (LK-A) in nasopharyngeal carcinoma in vitro and in vivo. METHODS: Apoptosis and cell cycle arrest were determined by flow cytometry analysis of the cells treated with Longikaurin A. The proteins of apoptosis signaling pathway were detected by western blotting analysis. Finally, we examined whether LK-A exhibits anti-tumour activity in xenograft models. RESULTS: Longikaurin A inhibited the cell growth by inducing apoptosis and cell cycle arrest. At low concentrations, longikaurin A induced S phase arrest and at higher concentrations, longikaurin A induced caspase dependent apoptosis by regulating apoptotic molecules. Finally, longikaurin A significantly inhibited the tumour growth of CNE2 xenografts in vivo and showed no obvious effect on the body weights of the mice. CONCLUSION: Our results suggest that Longikaurin A exhibited anti-tumour activity in nasopharyngeal carcinoma in vitro and in vivo. PMID- 23985031 TI - Biofilm-like Lactobacillus rhamnosus probiotics encapsulated in alginate and carrageenan microcapsules exhibiting enhanced thermotolerance and freeze-drying resistance. AB - Microcapsules containing high-density biofilm-like Lactobacillus rhamnosus probiotics, in place of planktonic cells, are developed in order to enhance the cell viability upon exposures to stresses commonly encountered during food lifecycle (i.e., heating, freeze-drying, refrigerated storage, and acid). The high-density (HD) capsules are prepared by in situ cultivation of the planktonic cells in the confined space of polysaccharide-based capsules (i.e., chitosan coated alginate and carrageenan capsules). Compared to their planktonic counterparts, the HD capsules exhibit higher freeze-drying resistance (~40*) and higher thermotolerance upon prolonged wet heat exposures at 60 and 70 degrees C (~12-8000*), but not at higher temperatures even for short exposures (i.e., 80 and 100 degrees C). The enhanced viability of the HD capsules, however, is not observed during the refrigerated storage and exposure to the simulated gastric juice. The alginate capsules are superior to carrageenan owed to their better cell release profile in the simulated intestinal juice and storage viability. PMID- 23985032 TI - Directed hydrogenation of acyclic homoallylic alcohols: enantioselective syntheses of (+)- and (-)-laurenditerpenol. AB - Laurenditerpenol is the first marine natural product shown to inhibit hypoxia inducible factor 1 (HIF-1) activation. Preclinical studies support that the inhibition of HIF-1 is one of the molecular targets for antitumor drug discovery. The synthetically challenging molecular architecture of laurenditerpenol, its absolute stereostructure, and the biological activity of several diastereoisomers were accomplished by our group in 2007 by diastereoselective synthesis. Herein, we report enantioselective syntheses of both enantiomers of laurenditerpenol involving sequential Michael addition and remote homoallylic hydroxyl group directed asymmetric hydrogenation at ambient temperature and pressure as key reaction steps. The current approach is elegant and overall more efficient than the ones previously reported in the literature. PMID- 23985034 TI - Evaluation of mandibular volume using cone-beam computed tomography and correlation with cephalometric values. AB - OBJECTIVE: To investigate the association between maxillofacial morphology and mandibular bone volume in patients with skeletal malocclusion. MATERIALS AND METHODS: Subjects were 118 adult Japanese (58 males and 60 females). Skeletal malocclusion was classified, based on cephalometric analysis, into skeletal Classes I (-1 degrees <= ANB < 4 degrees ), II (ANB >= 4 degrees ), and III (ANB < -1 degrees ). Using cone-beam computed tomography and three-dimensional image analysis software, the dental crowns and mandible were separated, with only the mandible extracted. This was then reconstructed as a three-dimensional model, from which the mandibular volume was measured. RESULTS: No significant difference in mandibular volume was noted among skeletal Classes I, II, and III, nor was there any significant correlation between mandibular volume and the ANB, SNB, or mandibular plane angles. There was occasional and limited correlation between mandible volume and gonial angle and certain cephalometric distance parameters. CONCLUSION: We conclude that proper understanding of the three-dimensional maxillofacial morphology requires not only cephalometric radiographic tracings but also high-resolution analysis of the mandibular area, width, and volume. PMID- 23985035 TI - The inclination of mandibular incisors revisited. AB - OBJECTIVE: To reassess the inclination of lower incisors and evaluate possible associations with gender, age, symphyseal parameters, and skeletal pattern. MATERIALS AND METHODS: Twelve hundred and seventy-two (605 females, 667 males) cephalograms of untreated subjects of a craniofacial growth study (age: 8-16 years) were evaluated. Correlations between the angulation of the lower incisors and age, symphyseal distances (height, width, and depth), symphyseal ratios (height-width, height-depth), and skeletal angles (divergence of the jaws and gonial angle) were investigated for all ages separately and for both sexes independently. RESULTS: The inclination of lower incisors increased over age (8 years: girls = 93.9 degrees [95% CI, 92.3 degrees -95.7 degrees ], boys = 93.3 degrees [95% CI, 91.8 degrees -94.9 degrees ]; 16 years: girls = 96.1 degrees [95% CI, 94.1 degrees -98.2 degrees ], boys = 97.1 degrees [95% CI, 95.6 degrees -98.6 degrees ]). Inclination of lower incisors correlated with the divergence of the jaws for all ages significantly or highly significantly, except for boys and girls 9 years of age and girls 11 and 12 years of age, for which only a tendency was observed. Similarly, a strong correlation to gonial angle could be observed. No correlation could be found between the inclination of lower incisors and any symphyseal parameters (absolute measurements and ratios), except for symphyseal depth. CONCLUSION: Lower incisor inclination is linked to the subject's sex, age, and skeletal pattern. It is not associated with symphyseal dimensions, except symphyseal depth. Factors related to natural inclination of lower incisors should be respected when establishing a treatment plan. PMID- 23985033 TI - Priming adult stem cells by hypoxic pretreatments for applications in regenerative medicine. AB - The efficiency of regenerative medicine can be ameliorated by improving the biological performances of stem cells before their transplantation. Several ex vivo protocols of non-damaging cell hypoxia have been demonstrated to significantly increase survival, proliferation and post-engraftment differentiation potential of stem cells. The best results for priming cultured stem cells against a following, otherwise lethal, ischemic stress have been obtained with brief intermittent episodes of hypoxia, or anoxia, and reoxygenation in accordance with the extraordinary protection afforded by the conventional maneuver of ischemic preconditioning in severely ischemic organs. These protocols of hypoxic preconditioning can be rather easily reproduced in a laboratory; however, more suitable pharmacological interventions inducing stem cell responses similar to those activated in hypoxia are considered among the most promising solutions for future applications in cell therapy. Here we want to offer an up-to-date review of the molecular mechanisms translating hypoxia into beneficial events for regenerative medicine. To this aim the involvement of epigenetic modifications, microRNAs, and oxidative stress, mainly activated by hypoxia inducible factors, will be discussed. Stem cell adaptation to their natural hypoxic microenvironments (niche) in healthy and neoplastic tissues will be also considered. PMID- 23985036 TI - Neuropsychological investigation of motor impairments in autism. AB - It is unclear how standardized neuropsychological measures of motor function relate to brain volumes of motor regions in autism spectrum disorder (ASD). An all-male sample composed of 59 ASD and 30 controls (ages 5-33 years) completed three measures of motor function: strength of grip (SOG), finger tapping test (FTT), and grooved pegboard test (GPT). Likewise, all participants underwent magnetic resonance imaging with region of interest (ROI) volumes obtained to include the following regions: motor cortex (precentral gyrus), somatosensory cortex (postcentral gyrus), thalamus, basal ganglia, cerebellum, and caudal middle frontal gyrus. These traditional neuropsychological measures of motor function are assumed to differ in motor complexity, with GPT requiring the most followed by FTT and SOG. Performance by ASD participants on the GPT and FTT differed significantly from that of controls, with the largest effect size differences observed on the more complex GPT task. Differences on the SOG task between the two groups were nonsignificant. Since more complex motor tasks tap more complex networks, poorer GPT performance by those with ASD may reflect less efficient motor networks. There was no gross pathology observed in classic motor areas of the brain in ASD, as ROI volumes did not differ, but FTT was negatively related to motor cortex volume in ASD. The results suggest a hierarchical motor disruption in ASD, with difficulties evident only in more complex tasks as well as a potential anomalous size-function relation in motor cortex in ASD. PMID- 23985038 TI - Factors associated with burnout among Chinese hospital doctors: a cross-sectional study. AB - BACKGROUND: Burnout has been a major concern in the field of occupational health. However, there is a paucity of research exploring the factors related to burnout among Chinese doctors. Investigation of these factors is important to improve the health of doctors and the quality of healthcare services in China. METHODS: The study population consisted of 1,618 registered hospital doctors from Liaoning province of China. Burnout was measured using the Chinese version of the Maslach Burnout Inventory-General Survey. Occupational stress was measured using the Chinese versions of the Job Content Questionnaire and the Effort-Reward Imbalance Questionnaire. Data were collected on the respondents' demographic characteristics and work situations. Of the doctors solicited for enrollment, 1,202 returned the completed questionnaire (555 men, 647 women), giving a response rate of 74.3%. A general linear regression model was applied to analyze the factors associated with burnout. RESULTS: The burnout mean scores were 11.46 (7.51) for emotional exhaustion, 6.93 (5.15) for cynicism, and 24.07 (9.50) for professional efficacy. In descending order of standardized estimates, variables that predicted a high level of emotional exhaustion included: high extrinsic effort, dissatisfaction with doctor-patient relationship, high overcommitment, working >40 h per week, low reward, and high psychological job demands. Variables that predicted a high level of cynicism included: high extrinsic effort, low reward, dissatisfaction with doctor-patient relationship, high overcommitment, low decision authority, low supervisor support, and low skill discretion. Variables that predicted a low perceived professional efficacy included: high psychological job demands, low coworker support, high extrinsic effort, low decision authority, low reward, and dissatisfaction with doctor-patient relationship. CONCLUSIONS: These findings suggest that occupational stress is strongly related to burnout among hospital doctors in China. Strategies that aim to improve work situations and decrease occupational stress are necessary to reduce burnout, including health education, health promotion, and occupational training programs. PMID- 23985037 TI - Comprehensive characterization of erythroid-specific enhancers in the genomic regions of human Kruppel-like factors. AB - BACKGROUND: Mapping of DNase I hypersensitive sites (DHSs) is a powerful tool to experimentally identify cis-regulatory elements (CREs). Among CREs, enhancers are abundant and predominantly act in driving cell-specific gene expression. Kruppel like factors (KLFs) are a family of eukaryotic transcription factors. Several KLFs have been demonstrated to play important roles in hematopoiesis. However, transcriptional regulation of KLFs via CREs, particularly enhancers, in erythroid cells has been poorly understood. RESULTS: In this study, 23 erythroid-specific or putative erythroid-specific DHSs were identified by DNase-seq in the genomic regions of 17 human KLFs, and their enhancer activities were evaluated using dual luciferase reporter (DLR) assay. Of the 23 erythroid-specific DHSs, the enhancer activities of 15 DHSs were comparable to that of the classical enhancer HS2 in driving minimal promoter (minP). Fifteen DHSs, some overlapping those that increased minP activities, acted as enhancers when driving the corresponding KLF promoters (KLF-Ps) in erythroid cells; of these, 10 DHSs were finally characterized as erythroid-specific KLF enhancers. These 10 erythroid-specific KLF enhancers were further confirmed using chromatin immunoprecipitation coupled to sequencing (ChIP-seq) data-based bioinformatic and biochemical analyses. CONCLUSION: Our present findings provide a feasible strategy to extensively identify gene- and cell-specific enhancers from DHSs obtained by high-throughput sequencing, which will help reveal the transcriptional regulation and biological functions of genes in some specific cells. PMID- 23985039 TI - Superlocalization surface-enhanced Raman scattering microscopy: comparing point spread function models in the ensemble and single-molecule limits. AB - In this report, we compare the effectiveness of various dipole and Gaussian point spread function (PSF) models for fitting diffraction-limited surface-enhanced Raman scattering (SERS) emission images from rhodamine 6G-labeled nanoparticle dimers at both the high-concentration and single-molecule limit. Of all models tested, a 3-axis dipole PSF gives the best approximation to the experimental PSF, although none of the models utilized in the study were without systematic error when fitting the experimental data. In the high-concentration regime, all models localize the SERS emission to a stationary centroid position, with the dipole models providing additional orientation parameters that closely match the geometry of the dimer, indicating that the molecules are coupled to all resonant plasmon modes of the nanostructure. In the single-molecule case, the different models show a mobile SERS centroid, consistent with single-molecule motion on the surface, but the behavior of the centroid is model-dependent. Despite the centroid mobility in the single-molecule regime, the dipole PSF models still give accurate orientation information on the underlying dimer structure, although with less precision than the ensemble-averaged samples. PMID- 23985040 TI - African schistosomiasis in mainland China: risk of transmission and countermeasures to tackle the risk. AB - Schistosomiasis is a major disease of public health importance in humans occurring in 76 countries of the tropics and sub-tropics. In China, schistosomiasis japonica is one of the highest priorities in communicable disease control defined by the central government. Since 1970s, the habitats of Biomphalaria straminea, an intermediate host of Schistosoma mansoni in South America, have been identified in Hong Kong Special Administrative Region and Shenzhen city, Guangdong province of China. With the sharp growth in the China aided projects in Africa and labor services export to Africa, a gradual rise in the cases infected with S. haematobium or S. mansoni is reported in those returning from Africa to China. The existence of intermediate snail hosts and import of infectious source of schistosomiasis results in concern about the transmission of African schistosomiasis in mainland China in the context of global climate change. This paper evaluates the risk of transmission of African schistosomiasis in China, and proposes countermeasures and research priorities to tackle the risk. PMID- 23985041 TI - Parabens in sediment and sewage sludge from the United States, Japan, and Korea: spatial distribution and temporal trends. AB - Parabens (alkyl esters of p-hydroxybenzoic acid) are widely used in cosmetics, pharmaceuticals, and foodstuffs as broad-spectrum antimicrobial preservatives. Laboratory animal studies have shown that parabens possess weak estrogenic activity. Widespread exposure of humans to parabens has raised significant public health concerns. Despite such concern, little is known about the occurrence of parabens in the environment. In this study, six paraben analogues, methyl- (MeP), ethyl- (EtP), propyl- (PrP), butyl- (BuP), benzyl-(BzP), and heptyl parabens (HepP), were determined in surface sediment and sediment core samples collected from several locations in the United States (U.S.), Japan, and Korea by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Concentrations of parabens also were determined in sewage sludge collected from several wastewater treatment plants (WWTPs) in Korea. MeP was found in all samples, including surface sediment, sediment core, and sludge samples, at concentrations ranging from 0.312 to 540 ng/g dry weight (dw). PrP was detected in the majority of samples (79%), and the concentrations were, in general, 1-2 orders of magnitude lower than MeP concentrations. Significant positive correlations were found among the concentrations of paraben analogues in sediment and sludge, which suggested the existence of similar sources of origin for these compounds. The sum concentrations of six parabens (?PBs) in sludge (geometric mean: 66.3, median: 89.5 ng/g dw) were remarkably higher than those in sediment (5.48, 5.24 ng/g dw). Vertical profiles of parabens in sediment cores from the U.S. showed a gradual increase in concentrations in the past decade, although such a trend was not clear in sediment core from Tokyo Bay, Japan. PMID- 23985043 TI - Serum calcitonin may falsely estimate tumor burden in chronic hypercalcemia: a case of prostatic and multiple bone metastases from medullary thyroid cancer. AB - BACKGROUND: Medullary thyroid cancer (MTC) is a calcitonin (Ct)-secreting tumor of the parafollicular or C cells of the thyroid gland. Higher serum Ct levels are associated with larger tumor size, distant metastases, and prognosis. We report herein a case of prostate and multiple bone metastases of nonfamilial MTC with mildly elevated Ct levels. PATIENT FINDINGS: A 73-year-old man who was found to have a 2.5 cm MTC in the left thyroid lobe with cervical lymph node metastases presented with confused mental status because of severe hypercalcemia (albumin modified serum calcium concentration 15.2 mg/dL) associated with multiple bone metastases. Prostate biopsy was performed because the patient had frequent urination with mildly elevated serum prostate-specific antigen (5.297 ng/mL). Histologically, the prostate was diagnosed as MTC metastasis, forming a tissue architecture closely resembling the previously diagnosed MTC, and the cells were positive for Ct, carcinoembryonic antigen, and thyroid transcription factor 1. Although the patient had multiple MTC metastases, basal and calcium-stimulated serum Ct levels were not significantly elevated, measuring 22.7 pg/mL (normal <10 pg/mL) and 22.1 pg/mL, respectively. CONCLUSIONS: A chronic hypercalcemic state may exhaust Ct reserves and diminish the Ct response to an acute intravenous calcium injection. Therefore, the Ct level of a patient in a hypercalcemic state should be carefully interpreted. To our knowledge, this is the first reported case in the literature in which serum Ct levels were not significantly increased when associated with hypercalcemia, and an MTC metastasis to the prostate. PMID- 23985042 TI - Molecular connections between nuclear and ciliary import processes. AB - As an organelle, the cilium contains a unique complement of protein and lipid. Recent work has begun to shed light on the mechanisms that regulate entry of ciliary proteins into the compartment. Here, we focus on the mechanisms that regulate ciliary entry of cytosolic molecules. Studies have revealed a size exclusion mechanism for ciliary entry that is similar to the barrier to nuclear entry. Active import into the ciliary compartment involves nuclear trafficking components including importins, a Ran-guanosine triphosphate gradient, and nucleoporins. Together, this work indicates that nuclei and cilia share molecular, structural and mechanistic components that regulate import into the compartments. PMID- 23985044 TI - Time trends in socio-economic inequalities for women and men with disabilities in Australia: evidence of persisting inequalities. AB - INTRODUCTION: The socio-economic circumstances and health of people with disabilities has been relatively ignored in public health research, policy and practice in Australia and internationally. This is despite emerging evidence that the socio-economic circumstances that people with disabilities live in contributes to their poorer health. Compared to other developed countries, Australians with disabilities are more likely to live in disadvantaged circumstances, despite being an economically prosperous country; it is therefore likely that the socio-economic disadvantage experienced by Australians with disabilities makes a significant contribution to their health. Despite the importance of this issue Australia does not routinely monitor the socio-economic inequalities for people with disabilities. This paper addresses this gap by describing time trends in socio-economic conditions for Australians with and without disabilities according to the severity of the disability and sex. METHODS: Cross-sectional analyses of the Australian Bureau of Statistics Survey of Disability, Ageing and Carers were carried out at three time points (1998, 2003 and 2009) to estimate the proportions of women and men (aged between 25 and 64 years) who were living on low incomes, had not completed year 12, were not in paid work, living in private rental and experiencing multiple disadvantage (three or more of the indicators). RESULTS: People with disabilities are less likely to have completed year 12, be in paid work and are more likely to be living on low incomes and experiencing multiple disadvantage. These conditions worsened with increasing severity of disability and increased or persisted over time, with most of the increase between 1998 and 2003. While women with milder disabilities tended to fare worse than men, the proportions were similar for those with moderate and severe/profound disabilities. CONCLUSION: People with disabilities experience high levels of socio-economic disadvantage which has increased or persisted over time and these are likely to translate into poorer health outcomes. A large proportion experience multiple forms of disadvantage, reinforcing the need to tackle disadvantage in a coordinated way across sectors.People with disabilities should be a priority population group for public health. Monitoring socio-economic conditions of people with disabilities is critical for informing policy and assessing the impact of disability reforms. PMID- 23985046 TI - Toward an integrated, causal, and psychological model of climato-economics. AB - Van de Vliert puts forward a model of how climate and economics interact to shape human needs, stresses, and freedoms. Although we applaud the construction of this model, we suggest that more needs to be done. Specifically, by adopting a multi level and experimental approach, we can develop an integrated, causal, and psychological model of climato-economics. PMID- 23985045 TI - Gold and BINOL-phosphoric acid catalyzed enantioselective hydroamination/N sulfonyliminium cyclization cascade. AB - A highly enantioselective hydroamination/N-sulfonyliminium cyclization cascade is reported using a combination of gold(I) and chiral phosphoric acid catalysts. An initial 5-exo-dig hydroamination and a subsequent phosphoric acid catalyzed cyclization process provide access to complex sulfonamide scaffolds in excellent yield and high enantiocontrol. The method can be extended to lactam derivatives, with excellent yields and enantiomeric excesses of up to 93% ee. PMID- 23985047 TI - Real-time PCR assay in differentiating Entamoeba histolytica, Entamoeba dispar, and Entamoeba moshkovskii infections in Orang Asli settlements in Malaysia. AB - BACKGROUND: Amebiasis caused by Entamoeba histolytica is the third leading cause of death worldwide. This pathogenic amoeba is morphologically indistinguishable from E. dispar and E. moshkovskii, the non-pathogenic species. Polymerase chain reaction is the current method of choice approved by World Health Organization. Real-time PCR is another attractive molecular method for diagnosis of infectious diseases as post-PCR analyses are eliminated and turnaround times are shorter. The present work aimed to compare the results of Entamoeba species identification using the real-time assay against the established nested PCR method. METHODS: In this study, a total of 334 human faecal samples were collected from different Orang Asli settlements. Faecal samples were processed by direct wet smear and formalin ethyl acetate concentration methods followed by iodine staining and was microscopically examined for Entamoeba species and other intestinal parasites. Microscopically positive samples were then subject to nested PCR and real-time PCR. RESULTS: The overall prevalence of Entamoeba infection was 19.5% (65/334). SK Posh Piah recorded highest Entamoeba prevalence (63.3%) while Kampung Kemensah had the lowest prevalence (3.7%) of Entamoeba. Microscopically positive samples were then tested by real-time PCR and nested PCR for the presence of Entamoeba histolytica, Entamoeba dispar, and Entamoeba moshkovskii infection. Real-time PCR showed higher Entamoeba detection (86.2%) compared to nested PCR (80%), although the McNemar test value showed no significant difference between the two methods (p = 0.221). CONCLUSIONS: This study is the first in Malaysia to report the use of real-time PCR in identifying and differentiating the three Entamoeba infections. It is also proven to be more effective compared to the conventional nested PCR molecular method. PMID- 23985048 TI - Protein delivery of a Ni catalyst to photosystem I for light-driven hydrogen production. AB - The direct conversion of sunlight into fuel is a promising means for the production of storable renewable energy. Herein, we use Nature's specialized photosynthetic machinery found in the Photosystem I (PSI) protein to drive solar fuel production from a nickel diphosphine molecular catalyst. Upon exposure to visible light, a self-assembled PSI-[Ni(P2(Ph)N2(Ph))2](BF4)2 hybrid generates H2 at a rate 2 orders of magnitude greater than rates reported for photosensitizer/[Ni(P2(Ph)N2(Ph))2](BF4)2 systems. The protein environment enables photocatalysis at pH 6.3 in completely aqueous conditions. In addition, we have developed a strategy for incorporating the Ni molecular catalyst with the native acceptor protein of PSI, flavodoxin. Photocatalysis experiments with this modified flavodoxin demonstrate a new mechanism for biohybrid creation that involves protein-directed delivery of a molecular catalyst to the reducing side of Photosystem I for light-driven catalysis. This work further establishes strategies for constructing functional, inexpensive, earth-abundant solar fuel producing PSI hybrids that use light to rapidly produce hydrogen directly from water. PMID- 23985062 TI - The effect of venovenous extra-corporeal membrane oxygenation (ECMO) therapy on immune inflammatory response of cerebral tissues in porcine model. AB - BACKGROUND: Extra-Corporeal Membrane Oxygenation (ECMO) therapy is associated with high risk of neurologic injury. But the mechanism of neurologic injury during and/or after ECMO therapy is still unclear. Recent animal experiments confirmed that ECMO treatment increases the immune inflammatory response. The aim of this study is to investigate the effect of VV- ECMO on immune inflammatory response of cerebral tissues and neurological impairment. METHODS: 18 porcine were randomly divided into control, sham and ECMO group (n = 6/group). ECMO was run 24 h in the ECMO group, and serum collected at 0, 2, 6, 12 and 24 h during ECMO treatment for the analysis of cytokine (IL-1beta, IL-6, IL-10, TNF-a) and cerebral injury specific biomarker S100B and NSE. After 24 h ECMO treatment, all animals were euthanized and cerebral tissues (hypothalamus, hippocampus and cortex) were collected for measure of mRNA and protein levels of cytokine (IL 1beta, IL-6, IL-10, TNF-a). RESULTS: The results during ECMO treatment showed that all the pro-inflammation cytokines were increased significantly after 2 h, and anti-inflammation IL-10 showed transient hoist in the first 2 h in serum. After 24 h ECMO therapy, the mRNA levels of pro-inflammation cytokines and anti inflammation IL-10 were simultaneously up-regulated in cerebral tissues (hypothalamus, hippocampus and cortex). And protein concentrations also showed different increasing levels in cerebral tissues. However, during the ECMO treatment, S100B and NSE protein in serum did not change significantly. CONCLUSION: These findings suggest VV-ECMO treatment can not only lead to immune inflammatory response in blood, but can also produce immune and inflammatory response in cerebral tissues. However the extent of immune inflammation was not sufficient to cause significant neurological impairment in this study. But the correlation between cerebral inflammatory response and cerebral impairment need to further explore. PMID- 23985063 TI - The significance of translation regulation in the stress response. AB - BACKGROUND: The stress response in bacteria involves the multistage control of gene expression but is not entirely understood. To identify the translational response of bacteria in stress conditions and assess its contribution to the regulation of gene expression, the translational states of all mRNAs were compared under optimal growth condition and during nutrient (isoleucine) starvation. RESULTS: A genome-scale study of the translational response to nutritional limitation was performed in the model bacterium Lactococcus lactis. Two measures were used to assess the translational status of each individual mRNA: the fraction engaged in translation (ribosome occupancy) and ribosome density (number of ribosomes per 100 nucleotides). Under isoleucine starvation, half of the mRNAs considered were translationally down-regulated mainly due to decreased ribosome density. This pattern concerned genes involved in growth related functions such as translation, transcription, and the metabolism of fatty acids, phospholipids and bases, contributing to the slowdown of growth. Only 4% of the mRNAs were translationally up-regulated, mostly related to prophagic expression in response to stress. The remaining genes exhibited antagonistic regulations of the two markers of translation. Ribosome occupancy increased significantly for all the genes involved in the biosynthesis of isoleucine, although their ribosome density had decreased. The results revealed complex translational regulation of this pathway, essential to cope with isoleucine starvation.To elucidate the regulation of global gene expression more generally, translational regulation was compared to transcriptional regulation under isoleucine starvation and to other post-transcriptional regulations related to mRNA degradation and mRNA dilution by growth. Translational regulation appeared to accentuate the effects of transcriptional changes for down-regulated growth related functions under isoleucine starvation although mRNA stabilization and lower dilution by growth counterbalanced this effect. CONCLUSIONS: We show that the contribution of translational regulation to the control of gene expression is significant in the stress response. Post-transcriptional regulation is complex and not systematically co-directional with transcription regulation. Post transcriptional regulation is important to the understanding of gene expression control. PMID- 23985064 TI - Combustion of 1,5-dinitrobiuret (DNB) in the presence of nitric acid using ReaxFF molecular dynamics simulations. AB - In this study we have examined the combustion dynamics of 1,5-dinitrobiuret (DNB) and nitric acid using reactive molecular dynamics simulations. Simulations were performed using the ReaxFF force field with parameters that were fitted against quantum mechanical calculations on model compounds/clusters relevant for this particular chemical system. Several different compositions were investigated, at densities of 0.5 and 1.0 g/mL, to examine the reaction kinetics in a dense vapor and liquid phase of these mixtures. Our simulations show that at certain compositions of the mixture reaction kinetics result in a very sharp release of thermal energy, which we associate with spontaneous ignition or hypergolicity. Analysis of key reaction mechanisms responsible for this process is discussed. PMID- 23985061 TI - Genome-wide analysis of the Hsp20 gene family in soybean: comprehensive sequence, genomic organization and expression profile analysis under abiotic and biotic stresses. AB - BACKGROUND: The Hsp20 genes are associated with stress caused by HS and other abiotic factors, but have recently been found to be associated with the response to biotic stresses. These genes represent the most abundant class among the HSPs in plants, but little is known about this gene family in soybean. Because of their apparent multifunctionality, these proteins are promising targets for developing crop varieties that are better adapted to biotic and abiotic stresses. Thus, in the present study an in silico identification of GmHsp20 gene family members was performed, and the genes were characterized and subjected to in vivo expression analysis under biotic and abiotic stresses. RESULTS: A search of the available soybean genome databases revealed 51 gene models as potential GmHsp20 candidates. The 51 GmHsp20 genes were distributed across a total of 15 subfamilies where a specific predicted secondary structure was identified. Based on in vivo analysis, only 47 soybean Hsp20 genes were responsive to heat shock stress. Among the GmHsp20 genes that were potentials HSR, five were also cold induced, and another five, in addition to one GmAcd gene, were responsive to Meloidogyne javanica infection. Furthermore, one predicted GmHsp20 was shown to be responsive only to nematode infection; no expression change was detected under other stress conditions. Some of the biotic stress-responsive GmHsp20 genes exhibited a divergent expression pattern between resistant and susceptible soybean genotypes under M. javanica infection. The putative regulatory elements presenting some conservation level in the GmHsp20 promoters included HSE, W-box, CAAT box, and TA-rich elements. Some of these putative elements showed a unique occurrence pattern among genes responsive to nematode infection. CONCLUSIONS: The evolution of Hsp20 family in soybean genome has most likely involved a total of 23 gene duplications. The obtained expression profiles revealed that the majority of the 51 GmHsp20 candidates are induced under HT, but other members of this family could also be involved in normal cellular functions, unrelated to HT. Some of the GmHsp20 genes might be specialized to respond to nematode stress, and the predicted promoter structure of these genes seems to have a particular conserved pattern related to their biological function. PMID- 23985065 TI - Occurrence and characterization of methicillin-resistant staphylococci from bovine mastitis milk samples in Finland. AB - BACKGROUND: Methicillin-resistant staphylococci (MRS) are increasingly being isolated in bovine mastitis. The aim of our study was to evaluate the occurrence of MRS in Finnish mastitis milk samples and characterize the MRS isolates using molecular methods. RESULTS: Methicillin-resistant S. aureus (MRSA) was a rare finding in bovine mastitis in Finland. Only two out of 135 (1.5%) S. aureus isolates were positive for mec genes. One of these carried mecA and was of spa type t172, SCCmec type IV and ST375, and the other harboured mecC, being spa type t3256, and ST130. MRSA ST375 is common among human MRSA isolates in Finland, but this is the first report in the country of bovine mecC MRSA. In coagulase negative staphylococci (CoNS) originating from bovine mastitis, methicillin resistance was more common. In the two CoNS collections studied, 5.2% (17/324) and 1.8% (2/110) of the isolates were mecA positive. Eighteen of these were methicillin-resistant S. epidermidis (MRSE), which were divided into 6 separate PFGE clusters. One pulsotype was detected in different parts of the country, indicating clonal spread. Most MRSE (13/18) were of SCCmec type IV, one was of type V and four were non-typeable. Comparison with a human staphylococcal database indicated that bovine MRSE strains were not closely related to human MRSE isolates. CONCLUSIONS: The occurrence of MRS, especially MRSA, in bovine mastitis in Finland was low. Most methicillin-resistant bovine CoNS are MRSE, and we found evidence of a bovine MRSE strain that may spread clonally. This is the first report of a Finnish bovine isolate of MRSAmecC ST130. The study provides a baseline for further MRS monitoring. PMID- 23985067 TI - Play, animals, resources: the need for a rich (and challenging) comparative environment. AB - Van de Vliert proposes a comprehensive explanation for differences in "freedoms" in diverse human populations based on climate and monetary resources. This intriguing approach, though derived from an evolutionary view covering all species, is based exclusively on human populations. This anthropocentric lens is challenged by ways of testing Van de Vliert's thesis more generally using playfulness as a surrogate for freedom. PMID- 23985066 TI - Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections. AB - The Drugs for Neglected Diseases initiative (DNDi) has defined and implemented an early discovery strategy over the last few years, in fitting with its virtual R&D business model. This strategy relies on a medium- to high-throughput phenotypic assay platform to expedite the screening of compound libraries accessed through its collaborations with partners from the pharmaceutical industry. We review the pragmatic approaches used to select compound libraries for screening against kinetoplastids, taking into account screening capacity. The advantages, limitations and current achievements in identifying new quality series for further development into preclinical candidates are critically discussed, together with attractive new approaches currently under investigation. PMID- 23985068 TI - Electroless deposition of platinum nanoparticles in room-temperature ionic liquids. AB - The electroless deposition of Pt nanoparticles (Pt-NPs) could be carried out by dissolving potassium tetrachloroplatinate(II) (K2[PtCl4]) in 1-ethyl-3 methylimidazolium (EMI(+)) room-temperature ionic liquids (RTILs) containing bis(trifluoromethylsulfonyl) imide (NTf2(-)) or tetrafluoroborate (BF4(-)) anion and small cations, such as H(+), K(+), and Li(+). In this case, no deposition of Pt-NPs occurred in RTILs without such small cations. The formation of Pt-NPs was only observed in RTILs containing trifluoromethanesulfonimide (HNTf2) and protons at high temperature (>=80 degrees C) when potassium hexachloroplatinate(IV) (K2[PtCl6]) was dissolved in the RTILs. The obtained Pt-NPs gave a characteristic absorption spectrum of ultrasmall Pt-NPs. The ultrasmall and uniform Pt-NPs of ca. 1-4 nm in diameter were produced and the Pt-NPs/EMI(+)NTf2(-) dispersion was kept stably for several months without adding any additional stabilizers or capping molecules. The identified Fourier-transform patterns along the [0 1 1] zone axis were observed for the TEM images of Pt-NPs. On the basis of the results obtained, a probable mechanism of the electroless formation of Pt-NPs is discussed. PMID- 23985069 TI - Prolonged mechanical ventilation associated with hypothyroidism after paediatric cardiac surgery. AB - Hypothyroidism in patients undergoing congenital heart defect surgery is known to be possible. This generally temporary condition can progress as it involves yet other factors, increasing the patients' time to heal. The case presented here is that of a 5-month-old girl who was dependent in the long term on mechanical ventilation following cardiac surgery. After having been diagnosed with hypothyroidism, she was extubated on the fourth day of her hormone replacement therapy, and discharged from hospital on the tenth day. PMID- 23985070 TI - Angucycline C5 glycosides: regio- and stereocontrolled synthesis and cytotoxicity. AB - This study discloses a general and convergent route for the regio- and stereospecific construction of the C5 glycosyl angucycline framework of mayamycin. C-Glycosidation, dearomatization, and Hauser annulation are the key steps. The synthetic analogues show cytotoxicity against different human cancer cell lines with IC50 values between 16.4 and 1.2 MUM. PMID- 23985071 TI - Stereoisomeric isolation and stereoselective fate of insecticide paichongding in flooded paddy soils. AB - Chiral insecticide paichongding (IPP) is one of the prospective substitutes for imidacloprid used in China due to its higher activity against imidacloprid resistant insects. However, little is known about the fate of IPP in soils, including especially the different behaviors among its stereoisomers. In this study, four stereoisomers of IPP were separated and applied in flooded soils. Kinetics of mineralization, extractable residues, and bound residues showed diastereoselectivity in IPP degradation, with enantiomers (5S,7R)-IPP (IPP-SR) and (5R,7S)-IPP (IPP-RS) being more readily mineralized and preferentially bound to soils than enantiomers (5R,7R)-IPP (IPP-RR) and (5S,7S)-IPP (IPP-SS). The overall mineralization was rather limited and did not exceed 4% of the spiked rate. Concurrent to the decreases of extractable residues, the fraction of bound residues increased with time and reached about 34% of the applied radioactivity for (14)C-IPP-SR and (14)C-IPP-RS as compared to about 23% for (14)C-IPP-RR or (14)C-IPP-SS. Soil properties such as organic matter content and pH likely contributed to the variability. Relatively rapid formation of bound residue suggests that IPP may be quickly detoxified in flooded paddy soil, decreasing the potential for off-site transport such as leaching or runoff, especially for enantiomers IPP-SR and IPP-RS. PMID- 23985073 TI - Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity. AB - Vinyl acetate monomer (VAM) is a site-of-contact carcinogen in rodents. It is also DNA reactive and mutagenic, but only after its carboxylesterase mediated conversion to acetaldehyde (AA), a metabolic reaction that also produces acetic acid and protons. As VAM's mutagenic metabolite, AA is normally produced endogenously; detoxification by aldehyde dehydrogenase (ALDH) is required to maintain intra-cellular AA homeostasis. This review examines VAM's overall genotoxicity, which is due to and limited by AA, and the processes leading to mutation induction. VAM and AA have both been universally negative in mutation studies in bacteria but both have tested positive in several in vitro studies in higher organisms that usually employed high concentrations of test agents. Recently however, in vitro studies evaluating submillimolar concentrations of VAM or AA have shown threshold dose-responses for mutagenicity in human cultured cells. Neither VAM nor AA induced systemic mutagenicity in in vivo studies in metabolically competent mice when tested at non-lethal doses while treatments of animals deficient in aldehyde dehydrogenase (Aldh in animals) did induce both gene and chromosome level mutations. The results of several studies have reinforced the critical role for aldehyde dehydrogenase 2 (ALDH2 in humans) in limiting AA's (and therefore VAM's) mutagenicity. The overall aim of this review of VAM's mutagenic potential through its AA metabolite is to propose a mode of action (MOA) for VAM's site-of-contact carcinogenesis that incorporates the overall process of mutation induction that includes both background mutations due to endogenous AA and those resulting from exogenous exposures. PMID- 23985074 TI - Letter to the Editor re Bernstein et al: Health risk of chrysotile revisited. Crit Rev Toxicol, 2013; 43(2): 154-183. PMID- 23985072 TI - The use of genetically modified mice in cancer risk assessment: challenges and limitations. AB - The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53+/-, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program's conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals. PMID- 23985076 TI - Cultural adaptations to the differential threats posed by hot versus cold climates. AB - Hot and cold climates have posed differential threats to human survival throughout history. Cold temperatures can pose direct threats to survival in themselves, whereas hot temperatures may pose threats indirectly through higher prevalence of infectious disease. These differential threats yield convergent predictions for the relationship between more demanding climates and freedom of expression, but divergent predictions for freedom from discrimination. PMID- 23985075 TI - Response to Murray M. Finkelstein, letter to the editor re Bernstein et al: Health risk of chrysotile revisited. Crit Rev Toxicol, 2013; 43(2): 154-183. PMID- 23985077 TI - Lymnaea palustris and Lymnaea fuscus are potential but uncommon intermediate hosts of Fasciola hepatica in Sweden. AB - BACKGROUND: Lymnaea palustris and L. fuscus are members of the European stagnicolines (Gastropoda: Lymnaeidae). The role of stagnicolines in transmission of Fasciola hepatica has been often proposed. To assess the possible relationship between these two stagnicolines and F. hepatica in Sweden, field monitoring in parallel with experimental infections of L. palustris and L. fuscus were conducted. METHODS: Stagnicoline snails were collected and identified on pastures grazed by either sheep or cattle on four farms suffering from fasciolosis in Sweden during 2011-2012. Field-collected L. palustris and L. fuscus were examined for F. hepatica DNA by PCR. In the laboratory, different age groups of L. palustris, L. fuscus and G. truncatula were each exposed to two F. hepatica miracidia and main infection characteristics were obtained. RESULTS: One field collected L. palustris (out of n = 668) contained F. hepatica as determined by PCR. On the other hand, stagnicolines artificially exposed to F. hepatica miracidia resulted in successful infection with fully differentiated cercariae, but only in juvenile snails (size, 1-2 mm at exposure) and with a prevalence of 51% and 13% in L. palustris and L. fuscus, respectively. In contrast, 90% of juvenile (size, 1-2 mm) and 92% of preadult G. truncatula (size, >= 2-4 mm), respectively, were successfully infected. Delayed, reduced and/or no spontaneous cercarial shedding was observed in the two stagnicolines when compared to G. truncatula. However, at snail dissection most cercariae from L. fuscus and L. palustris were able to encyst similarly to those from G. truncatula. CONCLUSION: Both L. fuscus and L. palustris can sustain larval development of F. hepatica but with an apparent level of age resistance. The finding of a single F. hepatica positive specimen of L. palustris, together with infection characteristics from the experimental infection, suggest that L. palustris is a more suitable snail vector of F. hepatica than L. fuscus. The reduced growth observed in both stagnicolines was contrary to the 'parasitic gigantism' theory. Overall, it seems that the epidemiological role of L. palustris in transmission of F. hepatica in Sweden is likely to be much lower than for G. truncatula. PMID- 23985079 TI - Native fluorescent detection with sequential injection chromatography for doping control analysis. AB - BACKGROUND: Sequential injection chromatography (SIC) is a young, ten years old, separation technique. It was proposed with the benefits of reagent-saving, rapid analysis, system miniaturization and simplicity. SIC with UV detection has proven to be efficient mostly for pharmaceutical analysis. In the current study, a stand alone multi-wavelength fluorescence (FL) detector was coupled to an SIC system. The hyphenation was exploited for developing an SIC-FL method for the separation and quantification of amiloride (AML) and furosemide (FSM) in human urine and tablet formulation. RESULTS: AML and FSM were detected using excitation maxima at 380 and 270 nm, respectively, and emission maxima at 413 and 470 nm, respectively. The separation was accomplished in less than 2.0 min into a C18 monolithic column (50 * 4.6 nm) with a mobile phase containing 25 mmol/L phosphate buffer (pH 4.0): acetonitrile: (35:65, v/v). The detection limits were found to be 12 and 470 ng/mL for AML and FSM, respectively. CONCLUSIONS: The proposed SIC-FL method features satisfactory sensitivity for AML and FSM in urine samples for the minimum required performance limits recommended by the World Anti Doping Agency, besides a downscaled consumption of reagents and high rapidity for industrial-scale analysis of pharmaceutical preparations. PMID- 23985081 TI - Nevoid hypertrichosis of the face in a 3-month-old girl with Aicardi syndrome. PMID- 23985078 TI - Translational HIV-1 research: from routine diagnostics to new virology insights in Amsterdam, the Netherlands during 1983-2013. AB - An HIV-1 diagnostic laboratory was established in the Academic Medical Center (AMC) of the University of Amsterdam after the discovery of human immunodeficiency virus (HIV) as the cause of the acquired immunodeficiency syndrome (AIDS). The first AIDS patients were diagnosed here in 1981 and since 1983 we have tested the samples of 50992 patients using a variety of assays that greatly improved over the years. We will describe some of the basic results from this diagnostic laboratory and then focus on the spin-off in terms of the development of novel virus assays to detect super-infections and ultra-sensitive assays to measure the intracellular HIV-1 RNA load. We also review several original research findings in the field of HIV-1 virology that stem from initial observations made in the diagnostic unit. This includes the study of genetic defects in the HIV-1 genome and time trends of the replication fitness over 30 years of viral evolution, but also the description of novel HIV-1 variants in difficult-to-diagnose clinical specimen. PMID- 23985082 TI - Structure and mechanism of acetolactate decarboxylase. AB - Acetolactate decarboxylase catalyzes the conversion of both enantiomers of acetolactate to the (R)-enantiomer of acetoin, via a mechanism that has been shown to involve a prior rearrangement of the non-natural (R)-enantiomer substrate to the natural (S)-enantiomer. In this paper, a series of crystal structures of ALDC complex with designed transition state mimics are reported. These structures, coupled with inhibition studies and site-directed mutagenesis provide an improved understanding of the molecular processes involved in the stereoselective decarboxylation/protonation events. A mechanism for the transformation of each enantiomer of acetolactate is proposed. PMID- 23985084 TI - Cultural adaptation to environmental change versus stability. AB - The target article provides an intermediate account of culture and freedom that is conceived to be curvilinear by treating economic development not as an adaptive outcome in response to climate but as a cause of culture parallel to climate. We argue that the extent of environmental variability, including climatic variability, affects cultural adaptation. PMID- 23985083 TI - A protocol for a systematic review of research on managing behavioural and psychological symptoms in dementia for community-dwelling older people: evidence mapping and syntheses. AB - BACKGROUND: Non-cognitive behavioural and psychological symptoms of dementia affect up to 90% of people with dementia during the disease course and result in distress, increased carer burden, high service utilization and unwanted moves to care homes. Research has focused on long-term settings and has not considered people with dementia living at home and at different stages of the disease trajectory. Our aim is to review systematically the evidence concerning non pharmacological strategies to minimise behavioural and psychological symptoms in community-dwelling older people with dementia. METHODS/DESIGN: Our approach is a two-stage co-design: a systematic mapping of the broad evidence around behavioural and psychological symptoms followed by an in-depth systematic review of studies of non-pharmacological interventions for behavioural and psychological symptoms from the perspective of their impact on community-dwelling older people with dementia and their carers. The review will include published literature involving a wide range of electronic databases using sensitive and comprehensive searches and lateral searching including checking citations.We will produce a descriptive map of the studies by design and by the focus of interventions and apply further inclusion criteria, developed in conjunction with lay experts, to select studies for an in-depth systematic review that will include independent quality assessment and detailed data extraction by two reviewers.The review process will be integrated with stakeholder meetings and a multidisciplinary expert advisory group to guide the review parameters and shape the research questions on the management of behavioural and psychological symptoms in people with dementia. Because studies are likely to be diverse in methodology and interventions, we will conduct a narrative synthesis of the in-depth systematic review. If appropriate, we will pool studies in a meta-analysis. We will explore review findings at both stages through focus groups and interviews with service providers, practitioners, people with dementia and carers. DISCUSSION: This integrated review in collaboration with key stakeholders will synthesise research evidence to identify appropriate interventions for effective management of behavioural and psychological symptoms that supports people with dementia living at home and their carers, and which reflects their priorities. It will make recommendations for research and practice. STUDY REGISTRATION: PROSPERO registration number: CRD42013004344. PMID- 23985085 TI - Dermoscopic patterns of 158 acral melanocytic nevi in a Latin American population. AB - BACKGROUND: Melanocytic nevi are frequently found on acral volar skin. Differentiation between nevi and melanoma is essential and sometimes difficult, although dermoscopy has enabled a more specific diagnosis of pigmented lesions. Dermoscopic patterns of lesions on acral volar skin have mostly been described in European and Asian populations. The Latin American population is heterogeneous, and particularly so in the case of Uruguayans, who largely descend from 3 distinct populations. OBJECTIVE: To describe dermoscopic patterns of acral melanocytic nevi and evaluate their applicability in a Latin American population in Uruguay. PATIENTS AND METHODS: This was an observational, descriptive, cross sectional study conducted by 2 dermatologists from 4 dermatology clinics in Uruguay. Uruguayan patients older than 18 years with acral melanocytic nevi were included. Digital dermoscopic images were captured and jointly analyzed by 2 investigators. RESULTS: A total of 158 acral volar nevi in 80 patients were analyzed. The most-prevalent pattern was the parallel furrow pattern (51.3% of nevi), followed by the latticelike pattern (13.3%), the homogeneous pattern (12.7%), the globular pattern (9.5%), the fibrillar pattern (7%), the globulostreaklike pattern (3.8%), and the nontypical pattern (2.5%). The reticular and transition patterns were not observed in our population. CONCLUSIONS: The parallel furrow pattern, followed by the latticelike and homogeneous patterns, was the most-prevalent pattern in acral melanocytic nevi in the Uruguayan population. The fibrillar pattern was found exclusively on the soles. No new dermoscopic patterns were observed. The patterns described in Asian and European literature apply to our population. PMID- 23985086 TI - Purpura fulminans associated with Streptococcus pneumoniae septicemia in an asplenic pediatric patient. AB - Purpura fulminans is a rapidly progressive syndrome of small-vessel thrombosis and hemorrhagic necrosis of the skin accompanied by disseminated intravascular coagulation. We describe a case of Streptococcus pneumoniae septicemia in an asplenic 5-year-old boy on oral tacrolimus, with a past medical history of multivisceral organ transplantation and subsequent development of purpura fulminans on his chest and distal extremities. The acute infectious form of purpura fulminans is usually caused by gram-negative bacteria. Cases secondary to gram-positive encapsulated bacteria usually occur when individuals are immuno suppressed or have anatomic or functional asplenia. Our patient had both, which likely increased his susceptibility, and he responded well to antimicrobial therapy in addition to prophylactic coverage in the setting of his immunosuppression. We review the literature for similar cases due to S. pneumoniae in the pediatric population and discuss the etiology and treatment of purpura fulminans. PMID- 23985087 TI - Comment on: late-onset acquired generalized lipodystrophy with muscle involvement. PMID- 23985089 TI - Low-voltage electron-probe microanalysis of Fe-Si compounds using soft X-rays. AB - Conventional electron-probe microanalysis has an X-ray analytical spatial resolution on the order of 1-4 MUm width/depth. Many of the naturally occurring Fe-Si compounds analyzed in this study are smaller than 1 MUm in size, requiring the use of lower accelerating potentials and nonstandard X-ray lines for analysis. Problems with the use of low-energy X-ray lines (soft X-rays) of iron for quantitative analyses are discussed and a review is given of the alternative X-ray lines that may be used for iron at or below 5 keV (i.e., accelerating voltage that allows analysis of areas of interest <1 MUm). Problems include increased sensitivity to surface effects for soft X-rays, peak shifts (induced by chemical bonding, differential self-absorption, and/or buildup of carbon contamination), uncertainties in the mass attenuation coefficient for X-ray lines near absorption edges, and issues with spectral resolution and count rates from the available Bragg diffractors. In addition to the results from the traditionally used Fe Lalpha line, alternative approaches, utilizing Fe Lbeta, and Fe Ll-eta lines, are discussed. PMID- 23985088 TI - Randomized controlled trial and uncontrolled 9-month follow-up of an adjunctive emotion regulation group therapy for deliberate self-harm among women with borderline personality disorder. AB - BACKGROUND: Despite the clinical importance of deliberate self-harm (DSH; also referred to as non-suicidal self-injury) within borderline personality disorder (BPD), empirically supported treatments for this behavior among individuals with BPD are difficult to implement in many clinical settings. To address this limitation, a 14-week, adjunctive emotion regulation group therapy (ERGT) for DSH among women with BPD was developed. The current study examined the efficacy of this ERGT in a randomized controlled trial (RCT) and the durability of treatment gains over a 9-month uncontrolled follow-up period. METHOD: Female out-patients with BPD and recent recurrent DSH were randomly assigned to receive this ERGT in addition to their ongoing out-patient therapy immediately (n = 31) or after 14 weeks (n = 30). Measures of DSH and other self-destructive behaviors, psychiatric symptoms, adaptive functioning and the proposed mechanisms of change (emotion dysregulation/avoidance) were administered pre- and post-treatment or -waitlist (to assess treatment efficacy), and 3 and 9 months post-treatment (to assess durability of treatment gains). RESULTS: Intent-to-treat (ITT) analyses (n = 61) revealed significant effects of this ERGT on DSH and other self-destructive behaviors, emotion dysregulation, BPD symptoms, depression and stress symptoms, and quality of life. Analyses of all participants who began ERGT (across treatment and waitlist conditions; n = 51) revealed significant improvements from pre- to post-treatment on all outcomes, additional significant improvements from post-treatment to 9-month follow-up for DSH, emotion dysregulation/avoidance, BPD symptoms and quality of life, and no significant changes from post-treatment to 9 month follow-up on the other measures. CONCLUSIONS: The results support the efficacy of this ERGT and the durability of treatment gains. PMID- 23985090 TI - [Dear legal group]. PMID- 23985091 TI - Does real-time elastography aid in differentiating canine splenic nodules? AB - Real-time elastography is a new ultrasonographic technology for measurement of tissue elasticity. Malignant lesions in the human breast, prostate, thyroid and lymph nodes show significantly reduced elasticity. The present study investigated the use of real-time elastography in the spleen of 22 dogs (8 benign and 6 malignant nodules, and 8 normal spleens) and results were compared to contrast enhanced ultrasound findings. In summary, real-time elastography was neither able to differentiate benign from malignant splenic lesions, nor normal from diseased splenic tissue. No significant associations with contrast-enhanced ultrasound results were found. Real-time elastography, therefore, does not appear a useful tool for the differentiation of splenic nodules in the dog. PMID- 23985092 TI - Factors influencing the onset and progression of pododermatitis in captive flamingos (Phoenicopteridae). AB - Pododermatitis is a worldwide problem in captive flamingos. We performed an evaluation of different influence factors (age, sex, weight, origin, breeding status) and a comparison of foot lesions between several zoological institutions and the feet of free-ranging Greater flamingos (Phoenicopterus roseus). A scoring system was used to determine the prevalence and types of lesions and severity. Cracks and nodules developed as early as 3 months of age and papillomatous growths as early as 6 to 7 months of age in captivity. Nodules with ulceration occurred significantly more often in birds older than 31 years and heavier than 4 kg. The comparison of different institutions revealed that birds kept in enclosures with natural-floored water ponds had significantly less severe lesions than birds kept in concrete water ponds. None of the free-ranging flamingos, which live on a muddy underground, showed any lesion. This study demonstrates that flooring, weight and age are important in the onset and progression of pododermatitis in flamingos. PMID- 23985093 TI - Repair of a canine patellar ligament rupture using the ComPact UniLock 2.4/3.0 mm System. AB - An 11-year old, female, Mix Breed dog was presented after being hit by a car with a rupture of the left patellar ligament. Due to a suspected wound infection close to the stifle joint, surgical repair was delayed for 10 days. The ruptured ligament was sutured and augmented with fascia lata. Additionally, two ComPact UniLock 2.4/3.0 mm plates connected with 1.0 mm orthopaedic wire were used to protect the primary repair. No immobilization of the stifle joint was needed. The implants were removed after 7 weeks, because of suspected infection and loosening. The successful utilization of an alternative surgical technique for the repair of the patellar ligament rupture in the dog has also been documented by pre- and post-operative temporal-spatial gait analysis (GaitFour(r)). PMID- 23985094 TI - Branchial cyst in a dog. AB - A French bulldog was presented with a facial swelling. Histology revealed a branchial cleft cyst. The first attempt to treat by incision, aspiration and drainage was unsuccessful. A complete surgical excision of the mass using a CO2 Laser lead to a full recovery. The location, size and type of tissues were compatible with a first branchial cleft cyst Type II. PMID- 23985095 TI - [Reduced performance and high somatic cell counts in a dairy herd fed high amounts of brewers' grain]. AB - The present case report describes a herd problem on a Holstein Friesian dairy farm in Switzerland, which could be attributed to the feeding of high amounts of wet brewers' grain over several months. Apathy and reduced general appearance, reduced feed intake as well as a decline in milk yield could be observed. A strong increase in milk somatic cell counts as well as an increase in the incidence of mastitis could be found. The milk fat content was highly elevated in all cows, whereas the milk protein content was reduced. The exclusion of wet brewers' grain from the partial mixed ration resulted in a considerable improvement of the general appearance of the cows and a decrease of the milk somatic cell counts. Feed that is easily spoiled could be a health risk for animals, particularly under hot and humid weather conditions and if fed in high amounts. PMID- 23985097 TI - Occurrence of Mycobacterium avium subsp. paratuberculosis in fecal samples of hunted deer, chamois and ibex in Switzerland. PMID- 23985096 TI - Possible influence of herd health management and hygiene on the in-herd prevalence of Clostridium perfringens type C in pig breeding farms. PMID- 23985101 TI - Factors influencing support for National Health Insurance among patients attending specialist clinics in Malaysia. AB - This study was carried out to determine the level of support towards the proposed National Health Insurance scheme among Malaysian patients attending specialist clinics at the National University of Malaysia Medical centre and its influencing factors. The cross sectional study was carried out from July-October 2012. 260 patients were selected using multistage sampling method. 71.2% of respondents supported the proposed National Health insurance scheme. 61.4% of respondents are willing to pay up to RM240 per year to join the National Health Insurance and 76.6% of respondents are of the view that enrollment in NHI should be made compulsory. Knowledge had a positive influence on respondent's support towards National Health Insurance. National Health Insurance when implemented in Malaysia can be used to raise funds for health care financing, increase access to health services and achieve the desired health status. More efforts should be taken to promote the scheme and educate the public in order to achieve higher support towards the proposed National Health Insurance. The cost to enroll in NHI as well as services to be included under the scheme should be duly considered. PMID- 23985103 TI - Listen to the voices of unwed teenage mothers in Malaysian shelter homes: an explorative study. AB - This qualitative research aims to explore the daily life experiences of Malaysian unwed teenage mothers in shelter homes. The research is based on the thematic analysis of interviews with seventeen respondents aged from 12 to 18 years. Eight sub-themes described the experience of the unwed teenage mothers in the shelter home and led to three overall themes: rules and regulations, relationship with the staff and relationship with the other girls at the shelter home. The findings indicated that the shelter homes involved were not fulfilling the standard of the Malaysian national laws and United Nations Convention on the Rights of the Child. We strongly suggest that the authorities provide a clear guideline concerning the implementation of Malaysian national laws and United Nations Convention on the Rights of the Child. PMID- 23985102 TI - Heart failure and mechanical circulatory assist devices. AB - During the last 20 years, the management of heart failure has significantly improved by means of new pharmacotherapies, more timely invasive treatments and device assisted therapies. Indeed, advances in mechanical support, namely with the development of more efficient left ventricular assist devices (LVAD), and the total artificial heart have reduced mortality and morbidity in patients with end stage heart failure awaiting for transplantation. However, the transplant cannot be the only solution, due to an insufficient number of available donors, but also because of the high number of patients who are not candidates for severe comorbidities or advanced age. New perspectives are emerging in which the VAD is no longer conceived only as a "Bridge to Transplant", but is now seen as a destination therapy. In this review, the main VAD classification, current basic indications, functioning modalities, main limitations of surgical VAD and the total artificial heart development are described. PMID- 23985104 TI - How public home care officers reason when making a needs assessment for food distribution to homebound elderly persons in Sweden. AB - Food distribution (FD) is a part of the public social and care service in Sweden aiming to prevent improper food intake for persons that they are unable to do their own shopping, and prepare their own meals, and in that way ensure reasonable standard of living. Before a person can be granted the FD service, from any municipality, an assessment of their individual requirements has to be made by a public home care officer. The aim of this study was to explore how public home care officers reason when they make a needs assessment for homebound elderly people. The data was collected through individual interviews (n=18). The transcribed interview material was analysed by means of the grounded theory method. The findings showed that the public home care officers were confronted with many challenges when making an assessment of a person's individual needs. They are influenced by their subjective feelings related to their personal views as to what should be the right solution for the individual. However, they remained aware that they needed to be guided by the legal requirements. Further, they described that the level of an individual's living standard is a leading concept in the governing laws that they need to interpret. Interpretation of this concept is very subjective with the possible consequence that an assessment result may lead to inefficient support. In conclusion, the concept of a reasonable standard of living needs to be clearly defined, decision regarding FD should not take long time, need assessment and decision should be based on the whole picture behind each individual case and there are needs to develop general guidelines for making needs assessment. The findings in this study have implications for public administration, nursing and gerontology. PMID- 23985105 TI - "There is no other option; we have to feed our families...who else would do it?": The financial lives of women engaging in sex work in Ulaanbaatar, Mongolia. AB - INTRODUCTION: This article provides an overview of the financial lives of women (n = 204) engaging in sex work in Ulaanbaatar, Mongolia. METHODS: This paper presents findings from a computer-based, interviewer-administered baseline assessment administered with women recruited for participation in a randomized controlled trial testing the feasibility of a combined HIV risk reduction and savings-led microfinance intervention for women engaging in sex work in Mongolia. FINDINGS: Findings demonstrate that most women are the primary financial providers for their households, using an array of earning strategies to provide for themselves and other dependents, with sex work often constituting the primary household income source. Financial instability in the lives of people engaging in sex work may increase their risk for HIV and STIs due to a compromised ability to negotiate safer sex with partners in times of economic crisis or need. High levels of financial responsibility for household welfare, when combined with low reported savings, the presence of debt, higher premiums offered for sex without a condom, and high levels of harmful alcohol use, may heighten women's risk for HIV and other STIs. CONCLUSION: Further research that documents the financial lives of people working in sex work is needed in order to understand the complex relationship between financial stability and engagement in sex work, and to inform the development and testing of structural HIV prevention interventions which target the economic determinants of risk. These findings highlight the importance of economic support programming for women engaged in sex work in Mongolia at a time of rapid economic change in Mongolia. PMID- 23985106 TI - Gender difference and characteristics attributed to coronary artery disease in Gaza-Palestine. AB - Traditionally coronary artery disease (CAD) has been considered as disease affecting men, and for long time women were not included in researches programme. In both sexes, coronary heart disease risk increases with age. Extensive clinical and statistical studies have identified serial factors that increase the risk of coronary heart disease, some of them can be modified, and some cannot. This study was performed to analyze the extent to which cardiovascular risk factors can explain the gender difference in coronary heart disease. METHODS: The study design is a cross sectional study based on 155 cardiac patients admitted to cardiology department in Al-shifa hospital Gaza. The following cardiac risk factors were determined from the patient's records, smoking, diabetes, high blood pressure, Dyslipedemia and presence of family history of coronary artery disease. Catheterization results review were done. Statistical Package for Social Science version 17 was used for data entry and analysis. Frequency and cross tabulation were done to explore the relationship between the study variables. Chi-square test was used for testing statistical and P-value less than 0.05 were considered as significant. RESULTS: Most of risk factors were more favorable in females and increase with age. Myocardial infarction in male compared with female was 2 times higher, and chronic angina pain is common in female than male respectively 71.4% and 46.7%. Around 77% of female have two vessels disease and more. No great differences in number of diseased vessels among patients with myocardial infarction or chronic stable angina. Patients with low EF <50% have higher chance of affected vessels (82.9%). CONCLUSION: CAD stay the major problem in male and female, certain patient's characteristics and clinical conditions may place female at higher risk of coronary artery disease development or progression. This article addresses emerging knowledge regarding gender differences in CAD risk factors and responsiveness to risk reduction interventions. PMID- 23985107 TI - Need for multilevel strategies and enhanced acceptance of contraceptive use in order to combat the spread of HIV/AIDS in a Muslim society: a qualitative study of young adults in urban Karachi, Pakistan. AB - This qualitative study explored knowledge, attitudes, beliefs and perceptions of sexual and reproductive health, focusing specifically on contraceptive use and HIV prevention among young unmarried men and women, 17-21 years, in urban Karachi, Pakistan. The main theme, identified as underlying meaning in the focus group discussions was "Societal norms and perceptions create barriers to knowledge and awareness about sexual and reproductive health matters among young adults". A knowledge gap was revealed concerning HIV/AIDS and contraceptive use among young males and females, who have to rely on media and peers for information seeking. Study participants perceived that HIV/AIDS is incurable and carries a social stigma. It was further revealed, that there is an opposition towards contraceptive use from religious leaders. Young adults in Pakistan are in need of improved knowledge about HIV/AIDS and contraceptive use. Youth clinics and schools/colleges may play a significant role in this regard. The religious leaders need to be informed about the beneficial effects of contraceptives and they should be part of any family planning/contraceptive use program to ensure better community acceptance. At the structural level there is an urgent need for policies targeting the issue of sexual and reproductive health, particularly HIV/AIDS information and contraceptive use to target the young population. The health care services should be able to respond by offering relevant services. PMID- 23985108 TI - Maternal health-seeking behavior: the role of financing and organization of health services in Ghana. AB - This paper examines how organization and financing of maternal health services influence health-seeking behavior in Bosomtwe district, Ghana. It contributes in furthering the discussions on maternal health-seeking behavior and health outcomes from a health system perspective in sub-Saharan Africa. From a health system standpoint, the paper first presents the resources, organization and financing of maternal health service in Ghana, and later uses case study examples to explain how Ghana's health system has shaped maternal health-seeking behavior of women in the district. The paper employs a qualitative case study technique to build a complex and holistic picture, and report detailed views of the women in their natural setting. A purposeful sampling technique is applied to select 16 women in the district for this study. Through face-to-face interviews and group discussions with the selected women, comprehensive and in-depth information on health- seeking behavior and health outcomes are elicited for the analysis. The study highlights that characteristics embedded in decentralization and provision of free maternal health care influence health-seeking behavior. Particularly, the use of antenatal care has increased after the delivery exemption policy in Ghana. Interestingly, the study also reveals certain social structures, which influence women's attitude towards their decisions and choices of health facilities. PMID- 23985109 TI - Assessing whether parents and children perceive the meaning of the items in the PedsQLTM 4.0 quality of life instrument consistently: a differential item functioning analysis. AB - Limited studies have examined the effect of differential item functioning (DIF) on comparing health related quality of life (HRQoL) scores across child self reports and parent proxy-reports. This study aims to determine whether parents and children respond differently to the items in the Persian version of the PedsQoLTM 4.0 measure. The PedsQLTM 4.0 Generic Core Scales was completed by 938 child-parent dyads. The graded response model (GRM) was used to detect DIF between parents and children. The IRT analyses were conducted using IRTPRO 2.1.On the whole, our findings showed that 50% (4 out of 8) of the items in the physical subscale and 40% (2 out of 5) in both emotional and school subscales were flagged with DIF. Among the DIF items, 62.5% (5 out of 8) were uniform and the remaining 37.5% (3 out of 8) were non-uniform. Parents and children interpret certain items of the PedsQLTM 4.0 in a different ways, except for the social subscale. Hence, we should be cautious about using parent proxy-report as a substitute for a child's ratings. PMID- 23985110 TI - A medication safety model: a case study in Thai hospital. AB - Reaching zero defects is vital in medication service. Medication error can be reduced if the causes are recognized. The purpose of this study is to search for a conceptual framework of the causes of medication error in Thailand and to examine relationship between these factors and its importance. The study was carried out upon an in-depth case study and survey of hospital personals who were involved in the drug use process. The structured survey was based on Emergency Care Research Institute (ECRI) (2008) questionnaires focusing on the important factors that affect the medication safety. Additional questionnaires included content to the context of Thailand's private hospital, validated by five-hospital qualified experts. By correlation Pearson analysis, the result revealed 14 important factors showing a linear relationship with drug administration error except the medication reconciliation. By independent sample t-test, the administration error in the hospital was significantly related to external impact. The multiple regression analysis of the detail of medication administration also indicated the patient identification before administration of medication, detection of the risk of medication adverse effects and assurance of medication administration at the right time, dosage and route were statistically significant at 0.05 level. The major implication of the study is to propose a medication safety model in a Thai private hospital. PMID- 23985111 TI - Hearing loss in patients with systemic lupus erythematosus. AB - OBJECTIVES: Systemic lupus erythematosus has its unique complications which warrant careful examination and assessment during follow/up visits of patients. The present study was conducted to evaluate prevalence of hearing loss in patients with SLE. MATERIALS & METHODS: At present a case- control study has been performed on 45 patients with SLE in a clinic of a teaching university hospital, Qazvin city, Iran. The patients were examined and evaluated for auditory and hearing problems as well as parameters related to their disease severity and progression. The control group was selected from the same clinic. RESULTS: Five patients (11.1%) complained from hearing loss, 4 patients s (8.9%) complained from otorrhea, 3 patients (6.7%) had tinnitus in research group, moreover twelve patients (26.7%) in case group and 4 patients (8.9%) in control group had sensorineural hearing loss. The difference was found to be statistically significant. No statistical significant relationship was found between severity, age of onset, and duration of the disease, and the lab tests of the patients with hearing loss. CONCLUSION: The present study implies that patients with systemic lupus erythematosus may develop sensorineural hearing loss during their course of the disease. It is recommended that audiology examination and/or audiometry become a part of routine follow/up studies of the patients. PMID- 23985112 TI - Investigation of depression in Greek patients with diabetic peripheral neuropathy. AB - BACKGROUND: Considerable studies directly connect the complications in diabetic patients, and especially peripheral neuropathy, with the emergence of depression. Neuropathetic pain may deteriorate the general health status of the diabetic patient and glycaemic regulation. PURPOSE: The purpose of this study was to investigate the appearance and degree of diabetic peripheral neuropathy and its correlation with depression, with other parameters of the disease and also duration. METHODS: 57 diabetic patients participated with diagnosed diabetic peripheral neuropathy (male n=27, female n= 30, mean of age 72.7+/-6.35 years). The first part of Michigan Neuropathy Screening Instrument and the Zung Depression Rating Scale were used as tools for our study. Data was analysed with the SPSS 18.0 statistic program. RESULTS: 57.9% of the patients were overweight, 35.1% were obese and only 7% were within normal weight range. The BMI findings between the two genders indicate that male participants are more often obese than females. Women surpassed men in the category of overweight patients (p < 0.05). The score based on MNSI was high and between 3 to 12 (mean average of 8.19+/-2.60 with 8 as intermediate rate). Almost 60% of patients had severe neuropathy, only 2 were found with mild symptoms and the rest had moderate neuropathtic symptoms, based on the score summary from the questionnaire. Investigating in detail the relation of diabetic neuropathy and depression, it derives that a high degree of diabetic neuropathy is related with high score of depression [F(3.160)=9.821, p=0.001]. Moderate and severe neuropathy was found with almost the same levels of depression. CONCLUSIONS: The correlation between diabetic neuropathy and depression is confirmed, while a very high depression rate was found in patients with severe neuropathy. The issue needs further study by using common instruments to obtain comparative results from the scientific community. PMID- 23985113 TI - The effect of socio-economic predictors of chronic diseases in Ghana: results of a nationwide survey. AB - Socio-economic predictors of chronic diseases in Ghana are not well understood and their influence has been relatively overlooked. This paper seeks to examine the influence of socio-economic predictors of chronic diseases in Ghanaians three different age groups. The data employed in the study were drawn from Global Ageing and Adult Health survey conducted in Ghana by SAGE and was based on the design for the World Health Survey. The survey was conducted in 2007 and collected data on socio-economic characteristics and other variables of the individuals interviewed. The overall results suggest that chronic diseases in relatively older Ghanaians reflects social and economic exposures with the differentials observed only partially explained by current social and economic conditions. Our results were by and large very much expected from the current medical knowledge available. PMID- 23985114 TI - The impact of Preventive Health Behaviors and Risk Factors on Health Status of Ghanaians. AB - The article here investigated the impact of Preventive Health Behaviors and Risk Factors as measures of Health Status of Ghanaians. We carry out a cross-sectional analysis of 5573 adults who participated and had indicated that they needed to state their health description in the three years prior to the phase 2007 World Health Organization, a study on Global Ageing and Adult health (SAGE) conducted in Ghana. The ordinal logistic regression model was employed for analysis using R. The results suggest that, there is incontrovertible evidence showing a strong relationship between preventive health behaviors and health status of Ghanaians. Again, the lifestyle of Ghanaians clearly manifests in their positive correlation with the good and moderate health state due to the high percentage (38.96% and 39.04%) respectively. The outcome points to a potential link with the Ghanaian social and health policies. PMID- 23985115 TI - Toxoplasmosis preventive behavior and related knowledge among Saudi pregnant women: an exploratory study. AB - INTRODUCTION: Many cases of congenital toxoplasmosis can be prevented provided that pregnant women following hygienic measures to avert risk of infection and to reduce severity of the condition if primary prevention failed. OBJECTIVES: This descriptive exploratory study aimed to assess the risk behavior and knowledge related to toxoplasmoisis among Saudi pregnant women attending primary health care centers (PHCs) in Al Hassa, Saudi Arabia and to determine socio-demographic characteristics related to risk behavior and knowledge. METHODS: All Saudi pregnant women attending antenatal care at randomly selected six urban and four rural PHCs were approached. Those agreed to participate were interviewed using a pre-tested structured questionnaire collecting data regarding socio-demographic, obstetric history, toxoplasmosis risk behaviors and related knowledge. RESULTS: Of the included pregnant women, 234 (26.8%) have fulfilled the criteria for toxoplasmosis preventive behavior recommended by Centers for Disease Prevention and Control to prevent congenital toxoplasmosis, while 48.9% reported at least one risk behavior and 24.3% reported ? two risk behaviors. Logistic regression model revealed that pregnant women aged 20 to < 30 years and those with previous history of unfavorable pregnancy outcome were more likely to follow toxoplasmosis preventive behavior. Toxoplasmosis-related knowledge showed that many women had identified the role of cats in disease transmission while failed to identify other risk factors including consumption of undercooked meats, unwashed fruits and vegetables, and contacting with soil. Predictors for pregnant women to be knowledgeable towards toxoplasmosis included those aged 30 to <40 years (OR=1.53), with ? secondary education (OR=1.96), had previous unfavorable pregnancy outcomes (OR=1.88) and investigated for toxoplasmosis (OR=2.08) as reveled by multivariate regression model. CONCLUSION: Pregnant women in Al Hasas, Saudi Arabia, are substantially vulnerable to toxoplasmosis infection as they are lacking the necessary preventive behavior. A sizable portion have no sufficient knowledge for primary prevention of congenital toxoplasmosis, health education at primary care is necessary to avert the potential toxoplasmosis related complications especially in the neonates. PMID- 23985116 TI - Investigating the nursing practitioners perspectives about undergraduate nursing internship and apprenticeship courses: is renewing required? AB - Nurses' professional capacity plays an important role in the health system to achieve their mission. This study aimed to investigate the perspectives of nursing practitioners about undergraduate nursing internship and apprenticeship courses and possible ways of renewing the courses. This cross sectional survey was performed over 258 bachelors and practitioners of nursing graduates of Alborz University of medical sciences in the second half of 2012. Based on a multi-stage sampling schedule, questionnaires were used to collect data about the perspectives of nursing practitioners about undergraduate nursing internship and apprenticeship courses. There were 81.4% of females and 80.6%, 17.1% and 2.3% of organizational post of participants were nurse, head nurse and supervisor respectively. The occupied posts for 60.1%, 25.6% and 14.1% of subjects, respectively were nurse, head nurse and the supervisor. The application of the internship and apprenticeship courses in bachelor of nursing were in moderate to high levels. The highest percentages of responses for internship and apprenticeship training courses were in internal surgery nursing and special nursing and the minimum percentage of responses were for community hygiene nursing and mental health nursing. Due to observing moderate to high levels of fulfillment and lack of compliance of training courses, renewing to improve the quality and effectiveness of training programs are highly recommended. This can be effective in the future of nursing career and provide a practical training environment to achieve the goals of theoretical training and can lead nurses to become specialized in their field. PMID- 23985117 TI - Influences of social capital on health and well-being from qualitative approach. AB - The social capital surrounding health including health and well-being, the way in which they function as multi-dimensional constructs, and the potential stability of relationships among the social capital were examined across universities in Hawaii and Japan. Maintaining or strengthening social factors of collective and individual health and well-being is a core factor of social capital and is instrumental in reducing worry and increasing trust. Qualitative in-depth interviews with 64 male and female college students (32 college students at the University of Hawaii at Manoa; 32 college students at Reitaku University in Japan) were used to collect information on social capital of health and well being and associated concepts; students' perceptions were grouped under 11 themes. The data indicates that social capital has an impact on college students' health and well-being. They also suggest that differences in health status and well-being can be plausibly attributed to processes associated with socio environmental circumstances and situations. PMID- 23985118 TI - Mentoring, training and support to global health innovators: a scoping review. AB - Global health innovators must navigate substantial complexities to successfully develop, implement and sustain global health innovations with impact through application of an Integrated InnovationTM approach. We sought to examine the nature of the literature and evidence around mentoring, training and support of global health innovators. We conducted a scoping review searching eight databases with terms capturing different kinds of innovation and support. Assessment of relevance and mapping was completed by two reviewers, with interpretation by the review team. Twenty-eight relevant papers provided perspectives on fostering global health innovators and innovation. Fifteen included empirical data on supports to global health innovators involving a wide range of innovators. Eight included documentation of outcomes but without designs to determine effectiveness. The diverse mentoring, training and support activities included: business incubators, support organizations and centres for entrepreneurship, technology transfer and intellectual property management, internship programs for business skill development, initiatives to bridge industry and researchers, and platforms for South-led innovation for global health. We propose the cultivation of a pipeline of global health innovators to increase the number of appropriate, sustainable innovations with impact in global health. Further empirical work on how to effectively support global health innovators is needed. PMID- 23985119 TI - Prevalence of pulmonary arterial hypertension among sickle cell disease patients in Al Hassa. AB - BACKGROUND: The prevalence of pulmonary arterial hypertension (PAH) in Saudi adults with sickle cell disease (SCD), the mechanism of its development, and its prospective prognostic significance are unknown. OBJECTIVE: To assess the prevalence of PAH among sickle cell disease patients attended hematology outpatient clinic at King Fahad Hospital, Al Hassa, Saudi Arabia. METHODS: Doppler echocardiography was performed for assessments of pulmonary- arterial systolic pressure (PASP) on 203 consecutive patients (102 men and 101 women) aged > 11 years, attending hematology clinic at King Fahad Hospital, Al Hassa, Saudi Arabia. Pulmonary hypertension was prospectively defined as a tricuspid regurgitant jet velocity (TRJV) of at least 2.5 m per second which can be estimate PASP equal or more than 25 mmHg. RESULTS: Doppler-defined pulmonary arterial hypertension was diagnosed in 37.1% among 202 patients included in study (after one female patient was excluded) using a cutoff of PASP >=25 mmHg. CONCLUSION: The prevalence of PAH among adults Saudis with SCD is higher than that reported from the developed countries. Further assessment using invasive techniques is required coupled employing analytical study design to predict the factors that favor the development of PAH among Saudi patients are required. PMID- 23985120 TI - Barriers of modern contraceptive practices among Asian women: a mini literature review. AB - Family planning has been cited as essential to the achievement of Millennium Development Goals (MDG). Family planning has a direct impact on women's health and consequence of each pregnancy. The use of modern contraception among Asian women is less than global average. In Asia a majority of unintended pregnancies are due to using traditional contraceptive or no methods which lead to induced unsafe abortion. Cultural attitudes, lack of knowledge of methods and reproduction, socio demographic factors, and health service barriers are the main obstacles to modern contraceptive practice among Asian women. Culturally sensitive family planning program, reforming health system, and reproductive health education through mass media to create awareness of the benefits of planned parenthood are effective strategies to improve modern contraceptive practice among Asian women. PMID- 23985121 TI - Use of hospital appointment registration systems in China: a survey study. AB - BACKGROUND: Hospitals have expressed no knowledge of patients' opinions regarding diversified appointment registration systems, despite efforts to develop novel appointment registration systems that assist patients and increase hospital efficiency. Therefore, the aim of this study was to investigate the use of diversified appointment registration systems and explore the factors influencing patients' registration system choices. METHODS: A survey study using a questionnaire was conducted in West China Hospital in February 2012. Outpatients were randomly selected from different hospital departments and the questionnaire was distributed and collected on-site. RESULTS: Data from 1,009 patients were available for analysis. Of these, 63.4% used appointment systems to register while others chose a traditional queuing method to register. 114 telephone (30.4%) and on-site (22.9%) appointments were made, whereas other systems were less used by patients. Between the non-appointment and appointment groups there were significant differences in gender, educational degree, and residence location (P < 0.05), but no significant difference in age (P > 0.05). While the clinical appointment system had the greatest number of appointment days (25.75), the bank's self-service terminal appointment had the least number of appointment days (5.05). Leaflets sent from the hospital (50.70%) and the recommendations of friends or families (40.77%) were the two main ways of knowing about the appointment registration systems. With the exception of those who felt no need to make an appointment (30.12%), not having the capability to use the appointment systems (24.10%) and the lack of a registered health card (34.53%) were the two main reasons for not using appointment registration systems. CONCLUSIONS: Convenience was a major motivation for patients' use of appointment registration systems. Personal knowledge and capability were the two important factors that influenced patients' appointment system choices. Hospitals must improve the design and promotion of appointment registration systems to better facilitate their use. PMID- 23985122 TI - Dietary habits among adolescent girls and their association with parental educational levels. AB - BACKGROUND: Adolescence is a period of rapid psychological development and the appearance of secondary sex characteristics. Changes in facial structure are the most visible manifestation during this period. It is during adolescence period that the importance of optimal nutrients is greatest. Improving the nutrition of teenage girls especially is important girls because consequently will affect the health in future. In present study hypothesis is that improving the nutrition of teenage girls is correlated with the level of parental education and the adolescents' eating habits. METHODS: In this study, 386 random selected adolescent girls were selected by cluster sampling. We used questionnaire to study the level of knowledge to major nutritional problems and consuming optimal nutrients. Finally, collected data were analyzed by using descriptive techniques and statistical analysis. RESULTS: According to the results of present study the mean of age, weight and height of the participants were 13/2 years, 159/1 cm, and 52.05 kg respectively. The 48.4 percent of the participants not eat breakfast. The 67.4 percentages of girls daily were consuming bread and cereals, 57.5 fruits and vegetables, 62.7 dairy products, and 27.7 meat and eggs. In addition, 36.3 percentages of these girls consumed sweets everyday as part of their diet. The nutritional knowledge of participating in diet was on the average and common source of information were counselors and teachers at school (36 percentages). The results of our study revealed that there was a significant relationship between variations in level of parental educational level and dietetic safety of offspring (p < 0.05). Our conclusion is the interactive education and parental literacy especially is important regarding to the adolescent nutrition and health. PMID- 23985123 TI - Designing an educational and training program for diabetes health educators at Diabetic Health Centers, Khartoum State, Sudan; 2007-2010. AB - BACKGROUND: By the year 2030 the number of diabetic patients is expected to reach 366 million worldwide (World Health Organization [WHO], 2013). METHODS: It was an intervention-facility based. The study focused on designing and implementing an educational and training program for health educators and to assess its effects on achievements of diabetes health educators; at Diabetic Health Centers in Khartoum State, Sudan; 2007-2010. The study population composed of diabetes health educators working in Diabetic Health Centers. Their total number was (36) and all were included in the study. Pre and post tests were done. Data was entered using SPSS. Parametric methods including t-test to assess result of training program before and after intervention were used. P-value ? 0.05 was considered statistically significant. RESULTS: Thirty six diabetes health educators attended the program. There was a significant statistical difference (p=0.001) between mean of Pre and post test concerning knowledge of diabetes health educators. To my knowledge there were no studies done, before, in Sudan to evaluate knowledge of diabetes health educators after attending an educational program in order to compare results with. CONCLUSION AND RECOMMENDATIONS: The designed education program improved health educators' knowledge. Educating diabetes health educators is important in program of diabetes management. In serving training of diabetes health educators, aiding diabetic health centers with educational materials, and more research on evaluation of impact of education on diabetes health educators; was recommended. PMID- 23985124 TI - Contextual freedom: absoluteness versus relativity of freedom. AB - Our commentary is focused on the idea that "freedom" takes on its full significance whenever its relativistic nature, in the short- and long terms, is taken into account. Given the transformations brought about by "globalization," application of a general model of freedom based on ecological-economic factors clearly seems to be rather untimely. We examine this idea through egocentric and ethnocentric views of the social and environmental analyses of "freedom." PMID- 23985125 TI - Foot loading patterns in normal weight, overweight and obese children aged 7 to 11 years. AB - BACKGROUND: Childhood obesity is thought to predispose to structural foot changes and altered foot function. Little is currently understood about whether similar changes occur in overweight children. The aim of this study was determine foot loading characteristics in obese, overweight and normal weight children aged 7 to 11 years during level walking. METHODS: Dynamic plantar pressures were measured in 22 obese, 22 overweight and 56 normal weight children recruited from local primary and secondary schools in East London. Peak pressure, peak force, normalised peak force, pressure-time and force-time integrals were analysed at six regions of the plantar foot: lateral heel, medial heel, midfoot, 1st metatarsophalangeal joint, 2nd-5th metatarsophalangeal joint and hallux. A one way ANOVA was used to test for significant differences in variables across the groups. Where differences existed Tukey post-hoc tests were used to ascertain the location of the difference. RESULTS: Children who were obese and overweight demonstrated significantly (p<0.05) higher peak pressures and peak forces as well as significantly higher force-time and pressure-time integrals under the midfoot and 2nd-5th metatarsal regions. After normalisation of peak force, similar trends existed where the obese and overweight children demonstrated significantly (p<0.05) greater loading at the midfoot and 2nd-5th metatarsals. CONCLUSION: Findings from this study indicated that overweight children, as young as seven, displayed differences in foot loading during walking, when compared with normal weight children. These findings were consistent with loading patterns of children who were obese and suggest that early assessment and intervention may be required in overweight children to mitigate against the development of musculoskeletal complications associated with excessive body mass. PMID- 23985129 TI - Estimating nonresponse bias in a telephone-based health surveillance survey in New York City. AB - Despite concerns about nonresponse bias due to decreasing response rates, telephone surveys remain a viable option for conducting local population-based surveillance. However, this becomes problematic for urban populations, which typically have higher nonresponse rates. Unfortunately, traditional methods of evaluating nonresponse bias pose challenges for public health practitioners due to high costs. In this study, we sought to increase understanding of survey nonresponse at the zip code level in an urban area and to demonstrate the use of a practical tool for assessing nonresponse bias. Data from the 2008 New York City Community Health Survey, a landline telephone survey of residential households in New York, New York, were matched with zip-code-level data from the 2000 US Census. Although response rates varied across zip codes and zip-code-level sociodemographic characteristics, estimated nonresponse bias for the 5 health measures (general health status, current health insurance coverage, asthma, binge drinking, and physical activity) was not substantial (ranging from -3.8% to 2.4%). Findings confirmed previous research that survey participation rates can vary a great deal across small areas and that there is no direct relationship between response rates and nonresponse bias. This study highlights the importance of assessing nonresponse bias for local urban surveys and demonstrates a workable assessment tool. PMID- 23985130 TI - RE: "Synergism between obesity and alcohol in increasing the risk of hepatocellular carcinoma: a prospective cohort study". PMID- 23985131 TI - The cytologic category of oncocytic (Hurthle) cell neoplasm mostly includes low risk lesions at histology: an institutional experience. AB - DESIGN: The cytological diagnosis of oncocytic/Hurthle cell neoplasms (OCN) represents a challenge with which cytopathologists face up to in their practice. The majority of these lesions undergo surgery for a definitive characterization of the nature mainly due to their more aggressive behavior than other malignant follicular lesions. In this study, we aimed at the evaluation of the effective malignant rate in a large cohort of OCNs. METHODS: From January 2008 to December 2011, we analyzed 150 cyto-histological OCNs and 64 benign oncocytic/Hurthle lesions (BOL). Both groups of patients were analyzed for clinical and cyto histological parameters. All the nodules were sampled under sonographic guidance and processed with the liquid-based cytological method. RESULTS: In agreement with literature, we found a significant correlation only with female gender in both OCN (P=0.0160) and BOL groups. The 64 BOLs were histologically diagnosed as 15 Hashimoto thyroiditis (HT), 45 hyperplastic nodules in HT, and four papillary thyroid carcinomas (PTC, 6.2%). The 150 OCNs resulted in 141 (94%) oncocytic adenomas and nine (6%) malignant lesions. The latter group included five oncocytic carcinomas (OCC), three oncocytic variants of PTC, and one macrofollicular PTC featured by mild nuclear clearing with a dispersive cellular pattern. The malignant rate was respectively 6.2% in BOLs without any OCC whereas 3.3% OCC diagnosed in the OCN category. CONCLUSIONS: Our OCNs mostly resulted in histological adenomas with a lower rate of malignancy than in other series. Some morphological parameters (nuclear clearing, dysplasia, and dispersive cellular pattern) might be helpful in stratifying OCN patients into different risks of malignancy. PMID- 23985132 TI - Cushing's syndrome: a structured short- and long-term management plan for patients in remission. AB - One hundred years have passed since Harvey Williams Cushing presented the first patient with the syndrome that bears his name. In patients with Cushing's syndrome (CS), body composition and lipid, carbohydrate and protein metabolism are dramatically affected and psychopathology and cognitive dysfunction are frequently observed. Untreated patients with CS have a grave prognosis with an estimated 5-year survival of only 50%. Remission can be achieved by surgery, radiotherapy and sometimes with medical therapy. Recent data indicate that the adverse metabolic consequences of CS are present for years after successful treatment.In addition, recent studies have demonstrated that health-related quality of life and cognitive function are impaired in patients with CS in long term remission. The focus of specialised care should therefore be not only on the diagnostic work-up and the early postoperative management but also on the long term follow-up. In this paper, we review the long-term consequences in patients with CS in remission with focus on the neuropsychological effects and discuss the importance of these findings for long-term management. We also discuss three different phases in the postoperative management of surgically-treated patients with CS, each phase distinguished by specific challenges: the immediate postoperative phase, the glucocorticoid dose tapering phase and the long-term management. The focus of the long-term specialised care should be to identify cognitive impairments and psychiatric disorders, evaluate cardiovascular risk, follow pituitary function and detect possible recurrence of CS. PMID- 23985133 TI - Efficient production of l-lactic acid by an engineered Thermoanaerobacterium aotearoense with broad substrate specificity. AB - BACKGROUND: Efficient conversion of lignocellulosic biomass to optically pure lactic acid is a key challenge for the economical production of biodegradable poly-lactic acid. A recently isolated strain, Thermoanaerobacterium aotearoense SCUT27, is promising as an efficient lactic acid production bacterium from biomass due to its broad substrate specificity. Additionally, its strictly anaerobic and thermophilic characteristics suppress contamination from other microoragnisms. Herein, we report the significant improvements of concentration and yield in lactic acid production from various lignocellulosic derived sugars, achieved by the carbon flux redirection through homologous recombination in T. aotearoense SCUT27. RESULTS: T. aotearoense SCUT27 was engineered to block the acetic acid formation pathway to improve the lactic acid production. The genetic manipulation resulted in 1.8 and 2.1 fold increase of the lactic acid yield using 10 g/L of glucose or 10 g/L of xylose as substrate, respectively. The maximum l lactic acid yield of 0.93 g/g glucose with an optical purity of 99.3% was obtained by the engineered strain, designated as LA1002, from 50 g/L of substrate, which is very close to the theoretical value (1.0 g/g of glucose). In particular, LA1002 produced lactic acid at an unprecedented concentration up to 3.20 g/L using 10 g/L xylan as the single substrate without any pretreatment after 48 h fermentation. The non-sterilized fermentative production of l-lactic acid was also carried out, achieving values of 44.89 g/L and 0.89 g/g mixed sugar for lactic acid concentration and yield, respectively. CONCLUSIONS: Blocking acetic acid formation pathway in T. aotearoense SCUT27 increased l-lactic acid production and yield dramatically. To our best knowledge, this is the best performance of fermentation on lactic acid production using xylan as the sole carbon source, considering the final concentration, yield and fermentation time. In addition, it should be mentioned that the performance of non-sterilized simultaneous fermentation from glucose and xylose was very close to that of normal sterilized cultivation. All these results used the mutant strain, LA1002, indicated that it is a new promising candidate for the effective production of optically pure l-lactic acid from lignocellulosic biomass. PMID- 23985134 TI - Frontier migration fosters ethos of independence: deconstructing the climato economic theory of human culture. AB - Evidence Van de Vliert draws on is more consistent with the idea that settlement in the frontier encourages independent mentality and individualistic social institutions. This cultural system can sometimes flourish, generating both wealth and power, but clearly not always. In our view, wealth is, for the most part, a measure of success of any given cultural group, and climate is important to the extent that it plays a role in creating rugged lands of frontier. PMID- 23985135 TI - Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. AB - Complex mental activity induces improvements in cognition, brain function, and structure in animals and young adults. It is not clear to what extent the aging brain is capable of such plasticity. This study expands previous evidence of generalized cognitive gains after mental training in healthy seniors. Using 3 MRI based measurements, that is, arterial spin labeling MRI, functional connectivity, and diffusion tensor imaging, we examined brain changes across 3 time points pre, mid, and post training (12 weeks) in a randomized sample (n = 37) who received cognitive training versus a control group. We found significant training-related brain state changes at rest; specifically, 1) increases in global and regional cerebral blood flow (CBF), particularly in the default mode network and the central executive network, 2) greater connectivity in these same networks, and 3) increased white matter integrity in the left uncinate demonstrated by an increase in fractional anisotropy. Improvements in cognition were identified along with significant CBF correlates of the cognitive gains. We propose that cognitive training enhances resting-state neural activity and connectivity, increasing the blood supply to these regions via neurovascular coupling. These convergent results provide preliminary evidence that neural plasticity can be harnessed to mitigate brain losses with cognitive training in seniors. PMID- 23985137 TI - Money and transmission of bacteria. AB - Money is one of the most frequently passed items in the world. The aim of this study was to ascertain the survival status of bacteria including Staphylococcus aureus, Escherichia coli, and Vancomycin- Resistant Enterococci (VRE) on banknotes from different countries and the transmission of bacteria to people who come in contact with the banknotes. The survival rate was highest for the Romanian Leu yielding all three microorganisms used after both three and six hours of drying. Furthermore, the Leu was the only banknote to yield VRE after one day of drying. Other currencies either enabled the survival of Extended Spectrum Beta-Lactamases (ESBL) and VRE (e.g. Euro), but not of MRSA, or the other way round (e.g. US Dollar). While a variety of factors such as community hygiene levels, people's behaviour, and antimicrobial resistance rates at community level obviously have influence on the transmission of resistant microorganisms, the type of banknote-paper may be an additional variable to consider. PMID- 23985136 TI - Severe multisensory speech integration deficits in high-functioning school-aged children with Autism Spectrum Disorder (ASD) and their resolution during early adolescence. AB - Under noisy listening conditions, visualizing a speaker's articulations substantially improves speech intelligibility. This multisensory speech integration ability is crucial to effective communication, and the appropriate development of this capacity greatly impacts a child's ability to successfully navigate educational and social settings. Research shows that multisensory integration abilities continue developing late into childhood. The primary aim here was to track the development of these abilities in children with autism, since multisensory deficits are increasingly recognized as a component of the autism spectrum disorder (ASD) phenotype. The abilities of high-functioning ASD children (n = 84) to integrate seen and heard speech were assessed cross sectionally, while environmental noise levels were systematically manipulated, comparing them with age-matched neurotypical children (n = 142). Severe integration deficits were uncovered in ASD, which were increasingly pronounced as background noise increased. These deficits were evident in school-aged ASD children (5-12 year olds), but were fully ameliorated in ASD children entering adolescence (13-15 year olds). The severity of multisensory deficits uncovered has important implications for educators and clinicians working in ASD. We consider the observation that the multisensory speech system recovers substantially in adolescence as an indication that it is likely amenable to intervention during earlier childhood, with potentially profound implications for the development of social communication abilities in ASD children. PMID- 23985138 TI - Foul play is associated with injury incidence: an epidemiological study of three FIFA World Cups (2002-2010). AB - BACKGROUND: Foul play has been considered as one of the most important known extrinsic risk factors for injuries in football. AIMS: To compare the incidence and characteristics of foul play injuries and non-foul injuries. METHODS: Team physicians' postmatch injury reports and official match statistics were obtained from all matches of the 2002, 2006 and 2010 Federation Internationale de Football Association World Cups. RESULTS: The number of injuries was associated with the number of fouls in a match. The incidence of foul play injuries (20.6/1000 match hours, 95% CI 17.3 to 24.4) was significantly lower than that of non-foul injuries (42.6, 37.7 to 47.9), which also applied to all playing positions. The causation of injury (foul/non-foul), match period and teams' drawing/losing/winning status were associated with the injury incidence. The interactions between the causation of injury (foul/non-foul) and match time, as well as the teams' drawing/losing/winning status or playing position were not statistically significant. The median (IQR) days of absence resulting from foul play injuries were significantly shorter than that of non-foul injuries. The lower leg and ankle were more common locations for foul play injuries than for non-foul injuries, whereas the opposite was observed for thigh injuries. Contusions were a more common type of foul play injuries than non-foul injuries, while the opposite was found for muscle strains/ruptures/tears. CONCLUSIONS: The numbers of injuries and fouls in a match were significantly associated. No significant differences in the variation of foul play and non-foul injury incidences regarding match period, teams' current winning/drawing/losing status and playing position were observed, suggesting that foul play injuries and non foul injuries may share similar underlying risk factors. PMID- 23985139 TI - Chronic graft-versus-host disease presenting with coexisting diffuse melanoderma and hypopigmented patches: A peculiar presentation. PMID- 23985140 TI - Re: international multicenter tool to predict the risk of nonsentinel node metastases in breast cancer. PMID- 23985141 TI - Lymphovascular invasion. PMID- 23985143 TI - RcsB determines the locus of enterocyte effacement (LEE) expression and adherence phenotype of Escherichia coli O157 : H7 spinach outbreak strain TW14359 and coordinates bicarbonate-dependent LEE activation with repression of motility. AB - The 2006 US spinach outbreak of Escherichia coli O157 : H7, characterized by unusually severe disease, has been attributed to a strain (TW14359) with enhanced pathogenic potential, including elevated virulence gene expression, robust adherence and the presence of novel virulence factors. This study proposes a mechanism for the unique virulence expression and adherence phenotype of this strain, and further expands the role for regulator RcsB in control of the E. coli locus of enterocyte effacement (LEE) pathogenicity island. Proteomic analysis of TW14359 revealed a virulence proteome consistent with previous transcriptome studies that included elevated levels of the LEE regulatory protein Ler and type III secretion system (T3SS) proteins, secreted T3SS effectors and Shiga toxin 2. Basal levels of the LEE activator and Rcs phosphorelay response regulator, RcsB, were increased in strain TW14359 relative to O157 : H7 strain Sakai. Deletion of rcsB eliminated inherent differences between these strains in ler expression, and in T3SS-dependent adherence. A reciprocating regulatory pathway involving RcsB and LEE-encoded activator GrlA was identified and predicted to co-ordinate LEE activation with repression of the flhDC flagellar regulator and motility. Overexpression of grlA was shown to increase RcsB levels, but did not alter expression from promoters driving rcsB transcription. Expression of rcsDB and RcsB was determined to increase in response to physiological levels of bicarbonate, and bicarbonate-dependent stimulation of the LEE was shown to be dependent on an intact Rcs system and ler activator grvA. The results of this study significantly broaden the role for RcsB in enterohaemorrhagic E. coli virulence regulation. PMID- 23985142 TI - Alcohol intake between menarche and first pregnancy: a prospective study of breast cancer risk. AB - BACKGROUND: Adult alcohol consumption during the previous year is related to breast cancer risk. Breast tissue is particularly susceptible to carcinogens between menarche and first full-term pregnancy. No study has characterized the contribution of alcohol consumption during this interval to risks of proliferative benign breast disease (BBD) and breast cancer. METHODS: We used data from 91,005 parous women in the Nurses' Health Study II who had no cancer history, completed questions on early alcohol consumption in 1989, and were followed through June 30, 2009, to analyze breast cancer risk. A subset of 60,093 women who had no history of BBD or cancer in 1991 and were followed through June 30, 2001, were included in the analysis of proliferative BBD. Relative risks (RRs) were estimated using Cox proportional hazard regression. RESULTS: We identified 1609 breast cancer cases and 970 proliferative BBD cases confirmed by central histology review. Alcohol consumption between menarche and first pregnancy, adjusted for drinking after first pregnancy, was associated with risks of breast cancer (RR = 1.11 per 10 g/day intake; 95% confidence interval [CI] = 1.00 to 1.23) and proliferative BBD (RR = 1.16 per 10 g/day intake; 95% CI = 1.02 to 1.32). Drinking after first pregnancy had a similar risk for breast cancer (RR = 1.09 per 10 g/day intake; 95% CI = 0.96 to 1.23) but not for BBD. The association between drinking before first pregnancy and breast neoplasia appeared to be stronger with longer menarche to first pregnancy intervals. CONCLUSIONS: Alcohol consumption before first pregnancy was consistently associated with increased risks of proliferative BBD and breast cancer. PMID- 23985144 TI - The role of MADS-box transcription factors in secondary metabolism and sexual development in the maize pathogen Fusarium verticillioides. AB - MADS-box transcription factors (TFs) regulate functionally diverse gene targets in eukaryotes. In select ascomycetes, MADS-box TFs have been shown to play a role in virulence, and vegetative and sexual development. Here, we characterized Fusarium verticillioides MADS-box TFs, Mads1 and Mads2, in terms of their roles in secondary metabolism and sexual mating. Sequence analyses showed that MADS1 and MADS2 encode TFs with a SRF-type dimerization domain and a MEF2-type dimerization domain, respectively. The MADS1 and MADS2 knockout mutants (Fmt1 and Fmt2 strains, respectively) exhibited decreased vegetative growth and FB1 production when compared to the wild-type. Fmt1 showed reduced expression of 14 polyketide synthase (PKS) genes present in the organism, whereas Fmt2 did not display a change in PKS gene expression. Significantly, the deletion of MADS1 and MADS2 in the MAT1-2 genotype (Fmt4 and Fmt5 strains, respectively) led to strains that failed to produce perithecia and ascospores when crossed with the MAT1-1 wild-type strain. Notably, deletion of either gene did not have an effect on the ability of the fungus to colonize maize stalk or kernels. FB1 production and PKS expression data suggest that Mads1 is a broad regulator of secondary metabolism in F. verticillioides, and may target regulons upstream of Mads2 to influence FB1 production. In addition, MADS-box TFs in F. verticillioides play a critical role in the perithecia development. PMID- 23985146 TI - [Back pain]. PMID- 23985145 TI - Lipid dependencies, biogenesis and cytoplasmic micellar forms of integral membrane sugar transport proteins of the bacterial phosphotransferase system. AB - Permeases of the prokaryotic phosphoenolpyruvate-sugar phosphotransferase system (PTS) catalyse sugar transport coupled to sugar phosphorylation. The lipid composition of a membrane determines the activities of these enzyme/transporters as well as the degree of coupling of phosphorylation to transport. We have investigated mechanisms of PTS permease biogenesis and identified cytoplasmic (soluble) forms of these integral membrane proteins. We found that the catalytic activities of the soluble forms differ from those of the membrane-embedded forms. Transport via the latter is much more sensitive to lipid composition than to phosphorylation, and some of these enzymes are much more sensitive to the lipid environment than others. While the membrane-embedded PTS permeases are always dimeric, the cytoplasmic forms are micellar, either monomeric or dimeric. Scattered published evidence suggests that other integral membrane proteins also exist in cytoplasmic micellar forms. The possible functions of cytoplasmic PTS permeases in biogenesis, intracellular sugar phosphorylation and permease storage are discussed. PMID- 23985147 TI - [Back pain in the emergency setting]. AB - Back pain is the second most common symptom-related reason for clinician visits and counts for 3.15 % of all US-emergency visits. Spontaneous evolution is beneficial in about 90 % of cases and therefore back pain is called "common". However, the doctor has to know the large differential diagnosis and especially some life threatening conditions. With a good history (including "red flags") and some examinations the doctor is able to stop further examinations and to guide the patient with motivation for daily activities and for some self-exercises. PMID- 23985148 TI - [Back pain in children and adolescents]. AB - The differential diagnosis of back pain in children and adolescents is wide. The prevalence of low back pain is increasing with age and after puberty is similar to what is known from the adult population, but in smaller children a structural cause for the pain is more common. Careful history taking and physical examination will help with the decision of when to perform further investigations. This article lists the most common differential diagnoses of back pain in children. PMID- 23985149 TI - [Back pain in the working age population]. AB - Back pain in the working age population can coincide with work-related activities and may lead to temporary or permanent work disability in the case of functional impairment that interacts with workplace demands. This can lead to economic if not existential problems for the affected individual. Although neurogenic or inflammatory back pain may be the cause, the big majority of all cases is caused by "common" low back pain with or without irradiating pain, the main problem being frequent recurrencies of acute pain episodes (periodic or relapsing course). After early exclusion of specific causes (i. e. "red flags": usually identified through history and simple laboratory findings!) repetitive examinations should be avoided. Structural changes and physical job demands should not be overestimated as causal factors. In the early phase of a work disability more emphasis should be laid however on appropriate information and medication and, in case of persistent impairment, active treatment (after 3 weeks or relapse). Longtime workplace absence has important individual and socioeconomic consequences. The risk for chronification can be estimated through evaluation of "yellow flags" and observation of characteristics of the course in the individual case. An early return to work and to activities of daily life is urgent. In cases at risk for chronification and/or with obstacles to reintegration at work an interdisciplinary work-oriented rehabilitation or social and occupational reintegration should be organised. PMID- 23985150 TI - [Low back pain in the elderly]. AB - Elderly people often complain of back pain which lead to functional limitation and reduced independence. Degenerative changes together with their consequences are in the fore, on top of it illnesses which go hand-in-hand and lead to a certain deconditioning have to be considered. Lumbar spinal stenosis leads to progressingly reduced walking distances and is often surgically treated. Degenerative scoliosis is a progressive course of disease and should first of all be treated conservatively although surgical options are also possible. In old age vertebral osteomyelitis is more frequent and should be conspired when assessing a case. Here typical causes of back problems are shown in case studies. PMID- 23985151 TI - [Imaging for back pain]. AB - Next to conventional x-ray examinations, modern imaging modalities as computed tomography (CT) and magnetic resonance imaging (MRI) play an important role in the assessment of back pain. Guidelines and recommendations should be helpful for the - not always simple - indication for imaging for back pain. However, the latter have to be individually adapted regarding clinical symptoms and appearance for every patient. Choosing the adequate imaging modality depends on several criteria, as the suspected- and differential diagnosis, the acuteness, age of patient and the temporal availability of the examination. PMID- 23985152 TI - [Back pain and somatisation]. AB - Back pain ist frequently found in patients with somatoform disorders, particularly in somatisation and somatoform pain disorders. About 10 % to 20 % of patients suffering from back pain can be diagnosed with somatoform pain disorders. Additionally, up to 50 % of back pain patients suffer from other psychiatric disorders like major depression or anxiety disorders. Diagnostically, somatoform pain disorders must be distinguished from other chronic widespread pain disorders like fibromaylgia and chronic fatigue syndrome. Treatment usually consists of psychological/behavioral interventions in combination with relaxation techniques, physical activation and antidepressants. PMID- 23985153 TI - [Physiotherapy and rehabilitation for low back pain]. AB - Low back pain (LBP) continues to be a major health problem causing personal suffering and enormous socioeconomic costs. Evidence suggests that more than 85 % of individuals with LBP suffer from non-specific low back pain. Physiotherapy for non-specific LBP includes educational, physical, manual and movement therapy measures. In the acute phase, it is very important to prevent chronicity by identifying barriers for a full recovery and a quick return to everyday activities. If there is a chronicity of symptoms, the treatment must focus on improvement of the general physical activity despite the pain and promote participation in the social and work context. These aims are more important than pain relief. Therefore in the acute phase educational and activity-promoting measures are the primary treatment options. In the sub-acute and chronic phase a multidimensional treatment approach including exercise therapy with the aim of improving function, including return to work, should be applied. By now, there is scientific evidence that physiotherapy can reduce pain and disability due to LBP, and that return to usual activities including work can be achieved. PMID- 23985154 TI - [Drug treatment and interventional pain therapy in back pain patients]. AB - The treatment of chronic, non-malignant low-back pain is based on the patients' history and the clinical examination. It can be assumed that half of the cases present with a neuropathic pain component which needs to be treated with antidepressive and antiepileptic drugs instead of "pure" analgesics. Opioids should be considered with extreme caution because of their toxicity. Chronic non malignant back pain is the prototype for interdisciplinary treatment approaches and multi-modal interdisciplinary settings, including pain programmes. However, a personalised strategy has to be preferred in most cases. A quick relief of pain is important in order to improve function as well as to re-integrate the patient into professional life. Spinal infiltrations can be of both diagnostic as well as therapeutic benefits. Their indication must be considered carefully, especially if the invasive diagnostic intervention has no therapeutic consequences. The interventional procedures should only be used as part of a multimodal approach in patients without any psychological problem. The sole use of interventions supports the purely somatic orientation of many patients and thus leads us in the wrong direction. PMID- 23985156 TI - Energy loss by channeled electrons: a quantitative study on transition metal oxides. AB - Electron energy-loss spectroscopy (EELS) attached to current transmission electron microscopes can probe not only element-selective chemical information, but also site-selective information that depends on the position that a specific element occupies in a crystal lattice. The latter information is exploited by utilizing the Bloch waves symmetry in the crystal, which changes with its orientation with respect to the incident electron wave (electron channeling). We demonstrate the orientation dependence of the cross-section of the electron energy-loss near-edge structure for particular crystalline sites of spinel ferrites, by quantitatively taking into account the dynamical diffraction effects with a large number of the diffracted beams. The theoretical results are consistent with a set of experiments in which the transition metal sites in spinel crystal structures are selectively excited. A new measurement scheme for site-selective EELS using a two-dimensional position-sensitive detector is proposed and validated by theoretical predictions and trial experiments. PMID- 23985155 TI - Cognitive performance in irritable bowel syndrome: evidence of a stress-related impairment in visuospatial memory. AB - BACKGROUND: Central nervous system (CNS) dysfunction is a prominent feature of the functional gastrointestinal (GI) disorder, irritable bowel syndrome (IBS). However, the neurobiological and cognitive consequences of key pathophysiological features of IBS, such as stress-induced changes in hypothalamic-pituitary-adrenal (HPA)-axis functioning, is unknown. Our aim was to determine whether IBS is associated with cognitive impairment, independently of psychiatric co-morbidity, and whether cognitive performance is related to HPA-axis function. METHOD: A cross-sectional sample of 39 patients with IBS, a disease control group of 18 patients with Crohn's disease (CD) in clinical remission and 40 healthy age- and IQ-matched control participants were assessed using the Paired Associates Learning (PAL), Intra-Extra Dimensional Set Shift (IED) and Spatial Working Memory (SWM) tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and a computerized Stroop test. HPA-axis function was determined by measuring the cortisol awakening response (CAR). RESULTS: IBS patients exhibited a subtle visuospatial memory deficit at the PAL six- pattern stage (p = 0.03), which remained after psychiatric co-morbidity was controlled for (p = 0.04). Morning cortisol levels were lower in IBS (p = 0.04) and significantly associated with visuospatial memory performance within IBS only (p = 0.02). CONCLUSIONS: For the first time, altered cognitive function on a hippocampal-mediated test of visuospatial memory, which was related to cortisol levels and independent of psychiatric co-morbidity, has been identified in IBS. Visuospatial memory impairment may be a common, but currently neglected, component of IBS. Further elucidation of the nature of this impairment may lead to a greater understanding of the underlying pathophysiology of IBS, and may provide novel therapeutic approaches. PMID- 23985157 TI - MONA - Interactive manipulation of molecule collections. AB - : Working with small-molecule datasets is a routine task for cheminformaticians and chemists. The analysis and comparison of vendor catalogues and the compilation of promising candidates as starting points for screening campaigns are but a few very common applications. The workflows applied for this purpose usually consist of multiple basic cheminformatics tasks such as checking for duplicates or filtering by physico-chemical properties. Pipelining tools allow to create and change such workflows without much effort, but usually do not support interventions once the pipeline has been started. In many contexts, however, the best suited workflow is not known in advance, thus making it necessary to take the results of the previous steps into consideration before proceeding.To support intuition-driven processing of compound collections, we developed MONA, an interactive tool that has been designed to prepare and visualize large small molecule datasets. Using an SQL database common cheminformatics tasks such as analysis and filtering can be performed interactively with various methods for visual support. Great care was taken in creating a simple, intuitive user interface which can be instantly used without any setup steps. MONA combines the interactivity of molecule database systems with the simplicity of pipelining tools, thus enabling the case-to-case application of chemistry expert knowledge. The current version is available free of charge for academic use and can be downloaded at http://www.zbh.uni-hamburg.de/mona. PMID- 23985158 TI - Shared adaptiveness is not group adaptation. AB - Climate stresses and monetary resources seem to lead to different collective adaptations. However, the reference to adaptation and to ambiguous collective dimensions appears premature; populations may entertain nothing more than shared adaptiveness. At this point, the intricacy of the underlying evolutionary processes (cultural selection, fitness-utility decoupling) very much obscures any diagnosis based on correlations. PMID- 23985159 TI - Arabic-speaking religious leaders' perceptions of the causes of mental illness and the use of medication for treatment. AB - OBJECTIVES: The Arabic-speaking clergy is highly revered and considered the first point of contact for people who suffer from mental illness within their community. The current study aimed to explore the beliefs of Arabic-speaking religious leaders regarding the causes of mental illness and the use of medication for their treatment. METHOD: Participants consisted of 170 Arabic speaking clerics of Muslim (n = 85) and Christian (n = 85) denominations residing in Sydney, Australia. A questionnaire was administered during face-to-face interviews and included items regarding the causes of mental illness and beliefs about whether psychiatric medications were viewed as helpful or harmful. RESULTS: Most of the Arabic-speaking clerics viewed drug and alcohol addiction and psychosocial factors as the most important causes of mental illness. Biological causes such as a chemical imbalance in the brain were less frequently endorsed. Although medications were viewed by most religious clerics as helpful in the treatment of mental illness, there were also concerns about the potential harms of medications, particularly among Muslim clerics. Muslim clerics also endorsed the religious causes for mental illness, such as spiritual poverty, as being more important more so than did Christian clerics. CONCLUSIONS: The beliefs of Arabic speaking religious leaders influence how they respond to people with mental illness and may determine whether they refer people to professional mental health services or not. Understanding their perspectives allows opportunities to share information to facilitate collaborative work in the care of Arabic-speaking people with mental illness. Arabic-speaking religious leaders need to be better educated about the mechanisms of action and benefits of medication in the treatment of mental illness. PMID- 23985160 TI - Safety of long-term clozapine administration. Frequency of cardiomyopathy and hyponatraemia: two cross-sectional, naturalistic studies. AB - BACKGROUND: The antipsychotic drug (APD) clozapine (CLZ) is under-prescribed because of concerns about its safety. We evaluated in separate protocols the frequency of cardiomyopathy and hyponatraemia, which are adverse drug effects, where few comparative studies are available. METHODS: Cross-sectional studies in subjects treated for at least 3 consecutive months with the same drug were conducted. Cardiomyopathy: Patients undergoing treatment either with CLZ (n = 125) or with other typical or atypical APDs (n = 59) were examined by a cardiologist who also recorded echocardiograms and electrocardiograms in order to diagnose cardiomyopathy. Hyponatraemia: Fasting sodium levels were assessed in patients receiving any of the following treatments: CLZ (n = 88), other atypical APDs (n = 61), typical APDs (n = 23), typical + atypical APDs (n = 11), and other drugs/drug-free (n = 36). RESULTS: Cardiomyopathy: No case of cardiomyopathy was detected. The frequency of abnormal ventricular ejection fraction (< 55%) was similar in both treatment groups (p = 1). Hyponatraemia: The frequency of hyponatraemia (percentage; 95% CI) was: CLZ (3.4%; -0.7, 7.1); other atypical APDs (4.9%; -0.5, 10.3); typical APDs (26.1%; 8.2, 44.0); typical + atypical APDs (9.1%; -7.8, 26.0); other drugs/drug-free (0%). None of the CLZ hyponatraemia subjects were on monotherapy. CONCLUSIONS: Our results are at odds with previous studies of CLZ-associated cardiomyopathy. However, they must be compared to further cross-sectional or prospective studies because most published data come from either case reports or pharmacovigilance systems. The frequency of hyponatraemia during CLZ administration was similar to that observed with other atypical APDs, and it was significantly lower than that recorded with typical agents. These results, along with numerous case reports on the effects of CLZ in patients with polydipsia and water intoxication, point to a safe or even positive profile of CLZ on electrolytic regulation. PMID- 23985161 TI - Long-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy. AB - OBJECTIVES: This work aims to prospectively assess the long-term effects of intravenous immunoglobulin (IVIG Flebogamma(r)) in a small cohort of patients affected by primary or secondary antiphospholipid syndrome (APS), in addition to conventional therapy. METHODS: Three primary and four secondary APS patients (6 women and 1 man), aged between 40 and 62 years, were treated with IVIG in addition to conventional therapy with anticoagulants or antiplatelets, while six primary and one secondary APS patients (6 women and 1 man), aged between 31 and 61 years, continued their regular conventional therapy. One infusion of IVIG was administered at a dose of 0.4 g/kg/day every month to the first group of patients for two years. Patients were assessed at baseline, after 1 year and 2 years from the beginning of the study and were evaluated for the occurrence of any thromboembolic events and by laboratory measurement of antiphospholipides antibodies (aPL). RESULTS: No venous or arterial thromboses occurred in patients treated with IVIG, whereas in the control group two patients presented cerebral ischaemic attacks and one patient reported a deep vein thrombosis during the follow-up. At the end of the study, in the group treated with IVIG, we observed a statistically significant decrease of anticardiolipin antibodies (IgG and IgM) and of IgM anti-beta2-glycoprotein I antibodies. CONCLUSIONS: Our results show the efficacy of IVIG in addition to conventional therapy, in primary and secondary APS patients, preventing the occurrence of thromboembolic events. However, further clinical studies on a larger group of patients are necessary to fully understand the mechanisms of action and the optimal doses of IVIG in APS. PMID- 23985162 TI - Acquired del(9)(p22.3) in a primary plasma cell leukemia. AB - BACKGROUND: Plasma cell leukemia (PCL) is a rare lymphoproliferative disorder, accounting for 1-2% of all plasma cell neoplasms, characterized by the presence of >2 * 109/l of plasma cells circulating in the peripheral blood, and exists in two forms: primary PCL (pPCL, 60% of the cases), and secondary PCL (sPCL), the latter being a leukemic transformation in patients with a previously diagnosed multiple myeloma. PCL is an aggressive disease with poor prognosis and a short median survival of 7 months. RESULTS: Here, we report a pPCL case with hepatosplenomegaly, anemia, thrombocytopenia, fever, fatigue, weight loss, and plasma cell count up to 60% in peripheral blood and 80% in bone marrow. Immunophenotype was compatible with PCL. A del(9)(p22.3) was characterized using banding cytogenetics and array-proven multicolor banding (aMCB), the latter being of enormous significance to characterize breakpoint regions in detail. CONCLUSION: To the best of our knowledge, this is the first report of pPCL associated with a partially monosomy 9pter to 9p22.3 as a sole chromosomal abnormality. PMID- 23985163 TI - Is there a role for "climatotherapy" in the sustainable development of mental health? AB - Climate, diet, lifestyle, and environmental settings have all been shown to modulate mood, play a role in mental disorders, and even pose a mental health risk. Can climatotherapy, in its adaptive approach aiming to restore balance among the economic, social, and ecological realms of human societies, situate itself as a therapeutic avenue for the promotion of sustainable mental health? PMID- 23985164 TI - Clinical significance of the uPA system in gastric cancer with peritoneal metastasis. AB - BACKGROUND: It has been demonstrated that urokinase-type plasminogen activator (uPA) is involved in tumor cell metastasis by degrading the extracellular matrix. However, there is little direct evidence of clinical uPA system expression in peritoneal metastatic tissues of gastric cancer. The objective of this study was to investigate uPA system expression in peritoneal tissues of peritoneal and nonperitoneal metastasis patients, and to explore the diagnostic value of the uPA system. METHODS: Expressions of uPA, uPAR, and PAI-1 were measured by semi quantitative RT-PCR and ELISA. uPA activity was detected using a uPA activity kit. RESULTS: There was no significant difference in uPA, uPAR, and PAI-1 expression in two types of peritoneal tissue in seven patients with peritoneal metastasis. However, uPA, uPAR, and PAI-1 expressions in peritoneal metastatic lesions were significantly higher than those in normal peritoneal tissues of 24 nonperitoneal metastasis patients (P <0.05). Moreover, no statistical discrepancy of uPA activity was observed in various different tissues. CONCLUSIONS: The expression of the uPA system positively correlates with peritoneal metastasis of gastric cancer. This expression difference in peritoneal or nonperitoneal metastasis patients may provide a reference for diagnosis of peritoneal metastasis. PMID- 23985165 TI - Transmission of pathogens by Stomoxys flies (Diptera, Muscidae): a review. AB - Stomoxys flies are mechanical vectors of pathogens present in the blood and skin of their animal hosts, especially livestock, but occasionally humans. In livestock, their direct effects are disturbance, skin lesions, reduction of food intake, stress, blood loss, and a global immunosuppressive effect. They also induce the gathering of animals for mutual protection; meanwhile they favor development of pathogens in the hosts and their transmission. Their indirect effect is the mechanical transmission of pathogens. In case of interrupted feeding, Stomoxys can re-start their blood meal on another host. When injecting saliva prior to blood-sucking, they can inoculate some infected blood remaining on their mouthparts. Beside this immediate transmission, it was observed that Stomoxys may keep some blood in their crop, which offers a friendly environment for pathogens that could be regurgitated during the next blood meal; thus a delayed transmission by Stomoxys seems possible. Such a mechanism has a considerable epidemiological impact since it allows inter-herd transmission of pathogens. Equine infectious anemia, African swine fever, West Nile, and Rift Valley viruses are known to be transmitted by Stomoxys, while others are suspected. Rickettsia (Anaplasma, Coxiella), other bacteria and parasites (Trypanosoma spp., Besnoitia spp.) are also transmitted by Stomoxys. Finally, Stomoxys was also found to act as an intermediate host of the helminth Habronema microstoma and may be involved in the transmission of some Onchocerca and Dirofilaria species. Being cosmopolite, Stomoxys calcitrans might have a worldwide and greater impact than previously thought on animal and human pathogen transmission. PMID- 23985166 TI - Schistosoma mansoni experimental infection in Mus spretus (SPRET/EiJ strain) mice. AB - Most Schistosoma mansoni experimental infections are developed in several inbred strains of Mus musculus as definitive host. In contrast, Mus spretus is unexplored in Schistosoma infection studies. Mus spretus provides a high variation of immunological phenotypes being an invaluable tool for genetic studies and gene mapping. The aim of this study is to characterize hematological and immunological responses against Schistosoma mansoni infection in Mus spretus (SPRET/EiJ strain) vs. Mus musculus (CD1 strain) mice. Nine weeks after cercarial exposure, animals were perfused and the parasite burden was assessed. The parasitological data suggests that SPRET/EiJ mice tolerate higher parasite loads compared to CD1 strain. In addition, hematological parameters measured in Mus spretus group showed a significant increase in granulocytes population in early stages of infection compared to the CD1 cohort. Meanwhile, CD1 presented higher levels of lymphocytes and IgG1 in the late stages of S. mansoni experimental infection. PMID- 23985167 TI - Spermatological characteristics of Pleurogenidae (Digenea) inferred from the ultrastructural study of Pleurogenes claviger, Pleurogenoides medians and Prosotocus confusus. AB - The present work constitutes the first ultrastructural analysis of the spermatozoon in the Pleurogenidae, with the study of three species belonging to three of the 16 genera included in this family, namely Pleurogenes claviger, Pleurogenoides medians and Prosotocus confusus. The mature spermatozoa of these pleurogenids present two axonemes of the 9+"1" trepaxonematan pattern, a nucleus, two mitochondria, two bundles of parallel cortical microtubules, external ornamentation, spine-like bodies and granules of glycogen. The organization of these characters in the sperm cell is similar in the three species. Thus, the anterior spermatozoon extremity is filiform and a continuous and submembranous layer of parallel cortical microtubules surrounds the axonemes at their anterior end. The posterior spermatozoon extremity exhibits the second axoneme and corresponds to the Cryptogonimidean type of Quilichini et al. (2010). Slight differences were noted between the spermatozoon of P. confusus and those of the two remaining species in the location of mitochondria. PMID- 23985168 TI - Paget phenomenon of the vulva with histopathological features of high-grade urothelial carcinoma (transitional cell carcinoma). PMID- 23985170 TI - Antiepileptic drugs and breastfeeding. AB - INTRODUCTION: This review provides a synopsis for clinicians on the use of antiepileptic drugs (AEDs) in the breastfeeding mother. METHODS: For each AED, we collected all retrievable data from Hale's "Medications and Mother Milk" (2012), from the LactMed database (2013) of the National Library of Medicine, and from a MedLine Search of relevant studies in the past 10 years. RESULTS: Older AEDs, such as carbamazepine, valproic acid, phenytoin, phenobarbital, primidone are considered to have a good level of safety during lactation, due to the long term clinical experience and the consequent amount of available data from the scientific literature. On the contrary, fewer data are available on the use of new AEDs. Therefore, gabapentin, lamotrigine, oxcarbazepine, vigabatrin, tiagabine, pregabalin, leviracetam and topiramate are compatible with breastfeeding with a less documented safety profile. Ethosuximide, zonisamide and the continue use of clonazepam and diazepam are contraindicated during breastfeeding. CONCLUSIONS: Although the current available advice on the use of AEDs during breastfeeding, given by different accredited sources, present some contradictions, most AEDs can be considered safe according to our review. PMID- 23985171 TI - Fundamental freedoms and the psychology of threat, bargaining, and inequality. AB - Van de Vliert's findings may be explained by the psychology of threat and bargaining. Poor people facing extreme threats must cope by surrendering individual freedom in service of shared group needs. Wealthier people are more able to flee from threats and/or resist authoritarianism, so their leaders must concede greater freedom. Incorporating these factors (plus inequality) can sharpen researchers' predictions. PMID- 23985172 TI - The impact of social media on medical professionalism: a systematic qualitative review of challenges and opportunities. AB - BACKGROUND: The rising impact of social media on the private and working lives of health care professionals has made researchers and health care institutions study and rethink the concept and content of medical professionalism in the digital age. In the last decade, several specific policies, original research studies, and comments have been published on the responsible use of social media by health care professionals. However, there is no systematic literature review that analyzes the full spectrum of (1) social media-related challenges imposed on medical professionalism and (2) social media-related opportunities to both undermine and improve medical professionalism. OBJECTIVE: The aim of this systematic qualitative review is to present this full spectrum of social media related challenges and opportunities. METHODS: We performed a systematic literature search in PubMed (restricted to English and German literature published between 2002 and 2011) for papers that address social media-related challenges and opportunities for medical professionalism. To operationalize "medical professionalism", we refer to the 10 commitments presented in the physicians' charter "Medical professionalism in the new millennium" published by the ABIM Foundation. We applied qualitative text analysis to categorize the spectrum of social media-related challenges and opportunities for medical professionalism. RESULTS: The literature review retrieved 108 references, consisting of 46 original research studies and 62 commentaries, editorials, or opinion papers. All references together mentioned a spectrum of 23 broad and 12 further-specified, narrow categories for social media-related opportunities (n=10) and challenges (n=13) for medical professionalism, grouped under the 10 commitments of the physicians' charter. CONCLUSIONS: The accommodation of the traditional core values of medicine to the characteristics of social media presents opportunities as well as challenges for medical professionalism. As a profession that is entitled to self-regulation, health care professionals should proactively approach these challenges and seize the opportunities. There should be room to foster interprofessional and intergenerational dialogue (and eventually guidelines and policies) on both challenges and opportunities of social media in modern health care. This review builds a unique source of information that can inform further research and policy development in this regard. PMID- 23985173 TI - Characterization of a case of follicular lymphoma transformed into B lymphoblastic leukemia. AB - Follicular lymphoma (FL) is a common form of non-Hodgkin lymphoma with an ability to transform into a more aggressive disease, albeit infrequently to B lymphoblastic leukemia/lymphoma. While t(14;18)(q32;q21) has been associated with approximately 90% cases of FL, that alteration alone is insufficient to cause FL and associated mutations are still being elucidated. The transformation of FL to B-lymphoblastic leukemia generally includes the dysregulation of MYC gene expression, typically through IGH rearrangement. Such cases of "double-hit" leukemia/lymphoma with both BCL2 and MYC translocations warrant further study as they are often not identified early, are associated with a poor prognosis, and are incompletely understood in molecular terms. Here we describe a patient with a diagnosis of FL that transformed to B-lymphoblastic leukemia. Detailed cytogenetic characterization of the transformed specimen using karyotype, fluorescence in situ hybridization, microarray and gene rearrangement analyses revealed a complex karyotype comprised principally of whole chromosome or whole arm copy number gains or losses. Smaller, single-gene copy number alterations identified by microarray were limited in number, but included amplification of a truncated EP300 gene and alterations in NEIL1 and GPHN. Analyses defined the presence of an IGH/BCL2 fusion due to a translocation as well as a MYC/IGH fusion due to an insertion, with both rearrangements involving the same IGH allele. The data illustrate the value in characterizing double-hit lymphoma cases with both traditional and novel technologies in the detailed cytogenetic workup. PMID- 23985174 TI - Level set methods for modelling field evaporation in atom probe. AB - Atom probe is a nanoscale technique for creating three-dimensional spatially and chemically resolved point datasets, primarily of metallic or semiconductor materials. While atom probe can achieve local high-level resolution, the spatial coherence of the technique is highly dependent upon the evaporative physics in the material and can often result in large geometric distortions in experimental results. The distortions originate from uncertainties in the projection function between the field evaporating specimen and the ion detector. Here we explore the possibility of continuum numerical approximations to the evaporative behavior during an atom probe experiment, and the subsequent propagation of ions to the detector, with particular emphasis placed on the solution of axisymmetric systems, such as isolated particles and multilayer systems. Ultimately, this method may prove critical in rapid modeling of tip shape evolution in atom probe tomography, which itself is a key factor in the rapid generation of spatially accurate reconstructions in atom probe datasets. PMID- 23985176 TI - A new measure of dietary social support among African American adolescents. AB - OBJECTIVE: To develop and evaluate a measure of social support for fruit and vegetable (FV) consumption among economically disadvantaged African American adolescents. METHODS: Focus groups (N = 30) and pilot testing procedures (N = 17) were used to develop and pretest questionnaire items. Item, reliability, and validity analyses were conducted in a separate sample of 93 youth. RESULTS: The measure was internally consistent (Cronbach alpha = .93) and valid, as evidenced by significant correlations found with construct (diet-specific family support) and criterion (FV consumption) measures. CONCLUSION: The measure is a promising method for assessing social support for FV consumption in this population. PMID- 23985175 TI - Contrasts in rural and urban barriers to colorectal cancer screening. AB - OBJECTIVES: To contrast barriers to colon cancer (CRC) screening and Fecal Occult Blood Test (FOBT) completion between rural and urban safety-net patients. METHODS: Interviews were administered to 972 patients who were not up-to-date with screening. RESULTS: Rural patients were more likely to believe it was helpful to find CRC early (89.7% vs 66.1%, p < .0001), yet were less likely to have received a screening recommendation (36.4% vs. 45.8%, p = .03) or FOBT information (14.5% vs 32.3%, p < .0001) or to have completed an FOBT (22.0% vs 45.8%, p < .0001). CONCLUSIONS: Interventions are needed to increase screening recommendation, education and completion, particularly in rural areas. PMID- 23985177 TI - Reliability and validity of the Glover-Nilsson smoking behavioral questionnaire. AB - OBJECTIVES: To establish reliability/validity of the Glover-Nilsson Smoking Behavioral Questionnaire (GN-SBQ). METHODS: The GN-SBQ and the Fagerstrom Test for Nicotine Dependence (FTND) were completed by 100 smokers. The number of cigarettes smoked, smoking duration, and craving were obtained. RESULTS: The GN SBQ was internally consistent (Cronbach alpha = .82), temporally stable (r = .86), and uncorrelated with FTND. There was a significant main effect for craving, F(3, 73) = 14.68, p < .001; and the GN-SBQ was a significant predictor of craving levels (beta = .476, p < .001). CONCLUSIONS: The GN-SBQ shows promise as a tool for distinguishing behavioral from physical nicotine dependence. PMID- 23985178 TI - Physical activity during recess in low-income third-grade Texas students. AB - OBJECTIVES: To estimate the prevalence of recess-based moderate and vigorous physical activity (MVPA) and vigorous physical activity (VPA) among third-grade students attending low-income, urban schools in Texas. METHODS: Structured observations (N = 77 class and 616 student observations) using SOFIT were conducted over 3 months in 8 elementary schools with majority Hispanic students. RESULTS: Students engaged in 66.4% and 19.2% of their ~20-minute recess time in MVPA and VPA, respectively. Boys engaged in more MVPA and VPA (p < .007). Contextual differences in activity (setting and activity type) were identified. CONCLUSIONS: Findings underscore the importance of scheduled recess time for children's physical activity. PMID- 23985179 TI - Factors associated with small cigar use among college students. AB - OBJECTIVE: To assess small cigar use among college students in the southeastern United States. METHODS: Data from a 2010 online survey were analyzed to examine small cigar smoking and its sociodemographic and psychosocial correlates among 4388 college students, aged 18-30. RESULTS: Small cigar users were more likely to be younger, male, black, and current cigarette, cigar, hookah, or marijuana smokers (p's < .05). They reported lower perceived harm of smoking and greater sensation seeking and perceived stress. Menthol cigarette smokers were more likely to smoke small cigars. CONCLUSIONS: Small cigar use and the co-occurrence of other tobacco and substance use should be addressed among college students. PMID- 23985180 TI - Neighborhood vigilance, health locus of control, and smoking abstinence. AB - OBJECTIVES: To examine whether health locus of control mediated relations of self reported neighborhood vigilance and biochemically verified, continuous short-term smoking abstinence among 200 smokers enrolled in a cohort study. METHODS: A nonparametric bootstrapping procedure was used to assess mediation. RESULTS: Health locus of control-chance mediated relations between neighborhood vigilance and smoking abstinence in analyses adjusted for sociodemographics and tobacco dependence (p < .05). Greater vigilance was associated with greater attributions that health was affected by chance, which was associated with a lower likelihood of smoking abstinence. CONCLUSIONS: Results suggest that neighborhood perceptions influence residents' attributions for health outcomes, which can affect smoking abstinence. PMID- 23985181 TI - Findings toward a multidimensional measure of adolescent health literacy. AB - OBJECTIVE: To explore a multidimensional measure of health literacy that incorporates skills necessary to manage one's health environment. METHODS: We designed a questionnaire to assess variation in an expanded understanding of health literacy among publicly insured adolescents in California (N = 1208) regarding their health care experiences and insurance. RESULTS: Factor loading and item clustering patterns reflected in the exploratory principal components factor analysis suggest that the data are parsimoniously described by 6 domains. CONCLUSION: This multidimensional measure becomes relevant in an era of health care reform in which many will for the first time have health insurance requiring them to navigate a system that uses a managed care model. PMID- 23985182 TI - Enhancing informed choice to undergo health screening: a systematic review. AB - OBJECTIVE: To assess the effectiveness of health screening interventions aimed at enhancing informed choice. METHODS: Studies were selected if (1) they were randomized controlled trials conducted between January 1, 2000, and March 30, 2010, (2) participants in one arm underwent a prescreening intervention aimed at improving informed choice, and (3) informed choice was the primary outcome. RESULTS: Eight studies that met the inclusion criteria involved screening for prostate, colorectal and breast cancer, and diabetes. Five of the 8 prescreening interventions led to greater informed choice. CONCLUSIONS: With researchers mindful of the limited number of studies, findings were encouraging, but conclusions regarding the most effective ways of facilitating informed choice for screening are at best tentative. PMID- 23985183 TI - Associations between cholesterol, colon cancer screening, behavior, and diet. AB - OBJECTIVE: To investigate the association between high blood cholesterol diagnosis and colorectal cancer screening practices. METHODS: Data were obtained from the 2007 Behavioral Risk Factor Surveillance System files. RESULTS: Among individuals diagnosed with high cholesterol, 97% did not engage in colon cancer screenings compared to 3% who engaged in screenings (p < .001); 72% were more likely to be overweight/obese compared to 28% of normal weight; 76% consumed fewer fruits and vegetables per day compared to 24% who consumed more; 54% did not participate in physical activity compared to 46% who were active (p < .001). CONCLUSION: The behaviors of individuals diagnosed with high blood cholesterol are different relative to colon cancer screening practices. PMID- 23985185 TI - Colorectal cancer screening knowledge, beliefs, and practices of Korean Americans. AB - OBJECTIVES: To examine (1) Korean Americans' colorectal cancer (CRC) screening practices and (2) significant factors that affect the population's CRC screening. METHODS: A cross-sectional survey of Korean Americans (N = 167) aged 50+ was conducted. Covariates included sociodemographics, acculturation, health status, health care access, CRC-related beliefs, and knowledge about screening. RESULTS: Knowledge, acculturation, and health care access were significantly associated with adherence to screening guidelines. In multivariate relationships of covariates, knowledge (OR = 2.57; 95% CI: 1.64 to 4.02) and number of visits to health care (OR = 1.80; 95% CI: 1.18 to 2.76) were significant predictors. CONCLUSION: Identified factors influencing CRC screening can help inform targeted interventions for Korean Americans. PMID- 23985184 TI - Energy cost and game flow of 5 exer-games in trained players. AB - OBJECTIVES: To determine energy expenditure and player experience in exer-games designed for novel platforms. METHODS: Energy cost of 7 trained players was measured in 5 music-based exer-games. Participants answered a questionnaire about "game flow," experience of enjoyment, and immersion in game play. RESULTS: Energy expenditure during game play ranged from moderate to vigorous intensity (4 - 9 MET). Participant achieved highest MET levels and game flow while playing StepMania and lowest MET levels and game flow when playing Wii Just Dance 3((r)) and Kinect Dance CentralTM. CONCLUSIONS: Game flow scores positively correlated with MET levels. Physiological measurement and game flow testing during game development may help to optimize exer-game player activity and experience. PMID- 23985186 TI - Junk food consumption and screen time: association with childhood adiposity. AB - OBJECTIVES: To determine the joint association of junk food consumption (JFC) and screen time (ST) with adiposity in children. METHODS: Two hundred fourteen (121 girls, 93 boys) third-to-fifth-grade students (54% Hispanic, 35% African American, 8% white) completed a lifestyle behavior survey, which included self reported JFC and ST, as part of a school-based lifestyle intervention program. RESULTS: Neither JFC nor ST, independently or jointly, was associated with adiposity measures. JFC and ST were significantly correlated (r = .375). CONCLUSIONS: The low achievement of physical activity and screen time recommendations and high prevalence of overweight/obesity in this mostly minority, low socioeconomic status population indicates a potential focus for intervention. PMID- 23985187 TI - Depressive symptoms among immigrant Latino sexual minorities. AB - OBJECTIVE: To estimate the prevalence and identify correlates of depressive symptoms among immigrant Latino sexual minorities. METHODS: Respondent-driven sampling (RDS) was used to estimate the prevalence of depressive symptoms, and univariate and multivariable analyses were conducted to identify correlates of depressive symptoms. RESULTS: Unweighted and RDS-weighted prevalence estimates of depressive symptoms were 69.2% and 74.8%, respectively. In the multivariable analysis, low social support, sexual compulsivity, and high self-esteem were significantly associated with increased depressive symptoms. CONCLUSIONS: A need exists for culturally congruent mental health services for immigrant Latino sexual minorities in the southern United States. PMID- 23985189 TI - New media use and sexual behavior among Latino adolescents. AB - OBJECTIVES: To examine the relationship between SMS/social media use and sexual behavior among Latino adolescents. METHODS: Four hundred twenty-eight 9(th)- and 10(th)-grade Latino adolescents were recruited to participate in a survey. Bivariate and multivariate analyses were conducted to examine associations between new media use and sexual behaviors. RESULTS: There is a significant association between frequency of SMS/social media use and sexual behavior after controlling for age, gender, survey language, and nativity. CONCLUSIONS: Latino adolescents using SMS and social media at higher frequencies are more likely to have ever had sex. Future research must continue to explore this relationship. PMID- 23985188 TI - Problem behavior, victimization, and soda intake in high school students. AB - OBJECTIVE: To examine associations of problem behaviors and victimization with nondiet soda intake among a national sample of 16,188 US high school students. METHODS: We used the 2009 national Youth Risk Behavior Survey. The outcome measure was daily nondiet soda intake. RESULTS: Smoking, having any sex partners, not always wearing a seat belt, being bullied/threatened/injured on school property, and being physically hurt by their boyfriend/girlfriend were significantly associated with daily nondiet soda intake after adjustment for age, sex, race/ethnicity, and weight status. CONCLUSIONS: Our findings suggest a need to examine why nondiet soda intake is associated with these behaviors to understand potential mechanisms. PMID- 23985190 TI - [Translational medicine promotes the development of burn surgery in China]. AB - This article endeavours to reiterate the advances in six vital aspects of burn injury, i.e. shock/ischemia-hypoxia, infection/sepsis, inhalation injury, regenerative medicine/tissue engineering and wound repair, hypermetabolism after burn, and integration of early treatment and rehabilitation in the last three decades. They originated from the papers dealing with ten main episodes in the care of burn trauma as a token to commemorate the 10th anniversary of Chinese Journal of Burns, as well as the 30th anniversary of the inauguration of Chinese Burn Association. PMID- 23985191 TI - [Regenerative medicine and burn care in China]. AB - In the recent 30 years, regenerative medicine has become a discipline with full vitality and hope owing to its tremendous demands in China. Chinese scientists in these areas have been making remarkable achievements in fields of stem cells, tissue engineering, and burns. PMID- 23985192 TI - [Diagnosis and comprehensive management of sepsis after burn]. AB - Sepsis induced by invasive infection is a challenging problem and the major cause of death after severe burn. With the increasing understanding of sepsis, diagnostic criteria of sepsis were proposed and revised consecutively so that they could be consistent with the clinical practice. Being different from other trauma and critical diseases, diagnostic criteria of sepsis after severe burn were also proposed, and they need further clinical verification. It is believed that comprehensive measures for the treatment of severe sepsis after burn should be advocated. These measures include rapid and effective resuscitation of burn shock, early escharotomy and closure of burn wound, metabolic support, immunoregulation and anti-inflammation, reinforcement of organ support, etc. Although a number of advances have been achieved in the past decades, the mechanism of sepsis need further elucidation, diagnostic criteria of sepsis need further revision, and novel therapeutic measures for burn sepsis should be developed. PMID- 23985193 TI - [Roles and mechanism of vascular and cardiac factors in the pathogenesis of burn shock and its prevention and treatment]. AB - Shock is one of the most important and common complications in the early stage following severe burn. This article focuses on the main advances in the roles and mechanism of vascular and cardiac factors in the pathogenesis of burn shock, and the new measures for prevention and treatment of it. Further studies are still needed to elucidate the precise mechanism of increased capillary permeability and the effective measures for decreasing fluid leakage from blood vessels, and to prevent hypoxic/ischemic damage and complications of visceral tissues arising thereof. PMID- 23985194 TI - [Study and translation of systemic control technology for the burn and trauma related lung injuries]. AB - Burns and traumas are common injuries during both peace time and wartime. Lung is the earliest organ subjected to dysfunction and the incidence is highest. The systemic protective technology for the burn and trauma related lung injuries is based on evidence-based medicine and translational medicine. It includes a series of effective measures, such as rescue and treatment scheme for massive burn casualties, prophylactic tracheostomy, protective ventilation strategy, sequential cell protection, and prevention and treatment of sequelae, which prevents aggravation of lung injuries caused by ischemia reperfusion, oxidative stress, and iatrogenic factors, as well as reduces the incidence of complications to ensure the recovery after burns and traumas. PMID- 23985195 TI - [Lay further emphasis on the research of translational medicine in burn surgery]. AB - Translational medicine is an emerging arena in the 21st century, and it bridges research results of basic sciences to clinical applications. The importance of translational research attracted considerable concern of scientists worldwide, including clinicians and researchers in the field of burn surgery in China. This review highlights some key points on translational medicine practised in the basic and clinical research of burn surgery, and they are summarized here as: the motive of the research project should be focused on how to solve problems of patients; much attention should be drawn to the difference between the cell biology and biochemical reaction in vitro and that in vivo; an animal model which simulates human pathology as much as possible should be reproduced; collaboration and sharing of resources among different disciplines should be strengthened; national and standardized criteria should be established for evaluation of the experimental result and guiding for clinical application. The aforementioned suggestions would be helpful for the application of new medicine and therapeutic approach in treating severe burn. PMID- 23985196 TI - [Pay close attention to the quality of life of patients and look to the future of burn rehabilitation]. AB - After 50 years' development, a rather comprehensive burn care system has been built up in China, and it has played key roles in wound healing and salvaging victims of burn trauma. Since survival is no longer the main priority of treatment, more efforts should be made to cut down the incidence of disabilities and to improve the quality of life of the survivors. The further progress on burn rehabilitation therapies, including functional improvement, psychological rehabilitation, aesthetic recovery, and occupational and social recuperation, would bring new perspectives to our burn care system. PMID- 23985197 TI - [Tissue engineered skin and regenerative wound repair]. AB - Various skin defects resulting from mechanical injury, burns, chronic ulcers, and resection of tumor etc. are very common in clinic. The traditional treatment measure, such as grafting of autologous split-thickness skin remains the gold standard. However, its limitations are obvious, such as shortage of donor sites, creation of new injury, and scar formation. To realize regenerative or scarless repair of tissue defects has always been the dream of human being. The advent of tissue engineered skin (TES) provides an ideal access to tissue regeneration. After decades of development, several kinds of TES products have been developed and used in clinic, with promising effects. However, a large number of basic scientific problems regarding TES, as well as difficulties in translation of basic research to bedside should be taken into serious consideration. This article presents a comprehensive overview of strategies of construction of TES, the role of TES in regenerative wound repair, and its opportunities and challenges. PMID- 23985198 TI - [An overview on the establishment of the system of burn prevention and treatment in China by comparing with that of foreign countries]. AB - The number of burn patients in China is still huge because of the demographic and socio-economical reasons. Distinguished achievements have been made in Chinese burn surgery during decades of development, with a generally acknowledged high survival rate of burn victims. However, there are still many problems, including an emphasis on the treatment rather than on prevention, poor pre-hospital care system, unbalanced development of burn centers, shortage of burn rehabilitation and psycho-social support, shortage of financial support, and underdevelopment of social charity for burn patients. Only if the efforts of the burn centers, government, and the whole society join together can the problems be solved and a good system of burn prevention, clinical care, and rehabilitation be established and perfected. The deficiencies in the development of the system in China and the possible solutions are reviewed and discussed in this paper. PMID- 23985199 TI - [Mechanism of scar formation and strategy of treatment]. AB - So far, studies on the mechanism of scar formation have mainly focused on cells, cytokines and extracellular matrix. Some studies have shown that fibroblast is one of the most important element in the process of scar formation, while epidermal and endothelial cells exert synergistic effects as well. Genetic factor can not be ignored in scar formation, either. Recently, studies have shown decisively the loss or damage of the three-dimensional structure of dermal tissue is the initiator of scar formation. Thus, the defect of epidermis template is proposed as a theory in order to explain the mechanism of scar formation. There are various techniques for scar treatment. The commonly accepted methods are physical therapy, pressure therapy, pharmaceutical therapy, radiotherapy, etc. PMID- 23985200 TI - [Respiratory support and treatment of severe inhalation injury]. AB - Although the study of inhalation injury is deepening gradually, its clinical treatment is still difficult, and its mortality rate remains high due to the complicated pathophysiologic characteristics. This article reviews the recent progress in research and treatment of inhalation injury, acute lung injury, and acute respiratory distress syndrome at home and abroad, focusing on the effect of mechanical ventilation models, including the non-invasive ventilation, lung protective ventilation, liquid ventilation, high frequency ventilation, on respiratory support in early stage of inhalation injury. The effects of medications for inhalation injury are summarized, and the prospect of stem cell therapy for inhalation injury is also discussed. PMID- 23985201 TI - [Further understanding of the hypermetabolism mechanism in burn injury and the strategy of regulation and control]. AB - The pattern of metabolism changes obviously after severe burn trauma, and it is characterized by an immensely increase in energy consumption, persistent strengthening in catabolism, and impediment of utilization of nutrient substrate. It will lead to autophagy, continuous consumption, and progressive emaciation, etc. If these pathological phenomena can not be effectively corrected, the prognosis of patients with serious burn will be poor, with complications of organ damage, immune dysfunction, and delayed wound healing, etc. Hypermetabolism after burn has become one of the leading causes of multiple organ dysfunction and even death. After many years' research, we have a certain understanding of burn hypermetabolism, but it is still difficult to clearly explain the mechanism up to now. Moreover, the measures of regulating hypermetabolism are still not perfect, hampering the advance of treatment of serious burn trauma. The purpose of the article is to analyze and discuss the essential mechanism of hypermetabolism after burn, basing on the new literature and a series of our experimental and clinical studies. Meanwhile the regulation strategy concerning burn hypermetabolism is proposed. It focuses on regulation of endocrine and inflammatory mediators, as well as maintenance of gastrointestinal structure and function. PMID- 23985202 TI - [Selection of antifungal agents for burn patients]. AB - Fungal infection is one of the serious complications of severely burned patients with high mortality. Application of antifungal agents timely and rationally is very important to control the infection. Antifungal agents including polyenes,triazoles, and echinocandins have been used widely in burned patients and are proved to be effective. Since diagnosis of fungal infection remains difficult, prophylactic and empirical therapies appear to be particularly necessary. In order to improve the efficacy and safety of antifungal agents, the factors of fungal strains, infection sites, hepatic and renal functions, and age, etc. should be considered in selecting antifungal agents. PMID- 23985203 TI - [Plasma gelsolin level and its relationship with the prognosis of patients with severe burns]. AB - OBJECTIVE: To observe the changes in plasma gelsolin (pGSN) level of patients with severe burn and to explore its relationship with sepsis and death of patients. METHODS: One hundred and two patients with total burn area equal to or larger than 30% TBSA hospitalized from May 2010 to May 2012 were included as burn group. Twenty-five healthy volunteers were recruited as healthy control group. Peripheral venous blood of patients was harvested on post burn day (PBD) 1, 3, 7, 14, and 21 to determine the pGSN level with double antibody sandwich ELISA kits, and the same maneuver was carried out in healthy volunteers. (1) Patients in burn group were divided into three groups by burn size: small burn area group (30% - 49% TBSA, n = 39), medium burn area group (larger than 49% and smaller than or equal to 69% TBSA, n = 33), and large burn area group (larger than 69% and smaller than or equal to 99% TBSA, n = 30). (2) According to diagnostic criteria of burn sepsis, patients in burn group were divided into sepsis group (n = 43) and non-sepsis group (n = 59). (3) According to the prognosis of patients with sepsis, patients in sepsis group were further divided into non-survival sepsis group (n = 14) and survival sepsis group (n = 29). The levels of pGSN in above groups were compared, and their relationship with sepsis and death of patients was analyzed. Data were analyzed with analysis of variance, LSD test and one-way Logistic regressions. RESULTS: (1) Levels of pGSN in burn group were obviously lower than those of healthy control group on PBD 1, 3, 7, 14, and 21 (with F values respectively 140.01, 369.52, 702.15, 360.14, 84.16, P values all below 0.01). (2) The mean levels of pGSN in large, medium, and small burn area groups at five time points were (43 +/- 11), (85 +/- 23), (124 +/- 38) mg/L, showing statistically significant differences among them (F = 367.76, P < 0.01), and they were all lower than that of healthy control group [(326 +/- 51) mg/L, P values all below 0.01]. (3) The mean levels of pGSN in sepsis group and non-sepsis group at the five time points were (77 +/- 12), (122 +/- 38) mg/L. Levels of pGSN in sepsis group were lower than those in non-sepsis group on PBD 3, 7, 14, and 21 (with F values respectively 30.35, 111.59, 209.36, 422.76, P values all below 0.01). (4) The mean levels of pGSN in non-survival sepsis group and survival sepsis group at the five time points were (53 +/- 8) and (103 +/- 25) mg/L. Levels of pGSN in non-survival sepsis group were lower than those in survival sepsis group on PBD 1, 3, 7, 14, and 21 (with F values respectively 9.05, 18.48, 41.34, 107.11, 180.48, P values all below 0.01). (5) Logistic regression analysis showed that the level of pGSN is the independent risk factor related to the complication of sepsis (odds ratio: 5.44, 95% confidence interval: 2.35 - 12.74, P < 0.01) and death (odds ratio: 5.52, 95% confidence interval: 2.34 - 12.19, P < 0.01) in burn patients. CONCLUSIONS: Severe burn injury could down-regulate the pGSN level of patients, and it decreases along with the increase in the area and severity of burn trauma. pGSN level appears to be an early prognostic marker for patients suffering from severe burns. PMID- 23985204 TI - [Effects of exogenous carbon monoxide-releasing molecules 2 on the vitality and toxicity of E.coli]. AB - OBJECTIVE: To explore the effects of exogenous carbon monoxide-releasing molecules 2 (CORM-2) on the vitality and toxicity of E. coli ATCC 25922, and to analyze the potential mechanism. METHODS: (1) In vitro experiments. Standard strains of E. coli ATCC 25922 were divided into groups A (without addition), B, C, D, and E according to the random number table, and then the latter 4 groups were respectively cultured with 1.2 mmol/L CORM-2, 1.6 mmol/L CORM-2, 1.2 mmol/L inactive CORM-2 (iCORM-2), 1.6 mmol/L iCORM-2, with six samples in each group. After being cultured for 0, 3, 5, 8, 10, 12, 16, 20, 24, 27, 30, 48 hours, proliferative vitality of E. coli was examined (denoted as absorption value under 600 nm wavelength), and bacteria number was counted. Other standard strains of E. coli ATCC 25922 were divided into groups F (without addition) and G (cultured with 0.8 mmol/L CORM-2), the expressions of genes fliA, dnaK, marA, and waaQ related to E. coli were detected by quantitative real-time (qRT)-PCR. (2) In vivo experiments. Other standard strains of E. coli ATCC 25922 were grouped as A', B', C', D', and E' and treated with the same method as that in groups A, B, C, D, and E, and 0.5 mL bacterial liquid of each group were collected when the absorption value of bacterial liquid in group A' was equal to 0.4 (under 600 nm wavelength). Seventy-two C57BL/6 mice were divided into groups, namely blank control (without treatment), H, I, J, K, and L according to the random number table, with 12 mice in each group. The mice in the latter 5 groups were intraperitoneally injected with 0.5 mL bacterial suspension of groups A', B', C', D', and E' respectively. After injection, general condition of mice in groups H, I, J, K, and L was observed. The serum levels of TNF-alpha and IL-6 were determined at post injection hour (PIH) 6, 12. The liver and lung samples were harvested for determination of myeloperoxidase (MPO) activity at PIH 12. The same process was carried out in blank control group. Data were processed with repeated measure analysis of variance (ANOVA), factorial design ANOVA, one-way ANOVA, and t test. RESULTS: (1) In vitro experiments. Compared with those of groups A and D, the proliferative vitality and bacteria number of E. coli in group B were all decreased (with F values respectively 1170.80, 217.52, P values all below 0.01). Compared with those of groups A and E, the proliferative vitality and bacteria number of E. coli in group C were also obviously decreased (with F values respectively 7948.34, 14 432.85, P values all below 0.01). Compared with those in group F, the expression of fliA was downregulated, while the expressions of dnaK, marA, and waaQ were upregulated in group G (with t values 30.28, -165.54, 168.88, -187.28, P values all below 0.01). (2) In vivo experiments. Symptoms including listlessness and tachypnea were observed in mice in groups H, K, and L, and they were ameliorated or not obvious in groups I and J. At PIH 6, the serum levels of TNF-alpha and IL-6 in groups H and K were respectively (647.3 +/- 3.8) pg/mL, (3.44 +/- 0.22) ng/mL and (639.3 +/- 0.8) pg/mL, (2.47 +/- 0.32) ng/mL, which were obviously higher than those in group I [(124.6 +/- 10.7) pg/mL, (1.03 +/- 0.16) ng/mL, with t values from 15.22 to 84.03, P values all below 0.01]. The serum levels of TNF-alpha and IL-6 in group J at PIH 6, 12 were also obviously decreased as compared with those in groups H and L (with t values from 19.27 to 245.34, P values all below 0.01). MPO activity of liver and lung tissues were significantly attenuated in group I at PIH 12 as compared with those in groups H and K, and it was also attenuated in group J when compared with those in groups H and L (with t values respectively from 17.36 to 18.92 and 2.35 to 3.61, P values all below 0.01). CONCLUSIONS: CORM-2 can obviously inhibit the vitality and toxicity of E. coli, which might be attributable to regulation of expressions of genes fliA, dnaK, marA, and waaQ of E. coli. PMID- 23985205 TI - [Effect of high mobility group box protein 1 on the Kupffer cells of rats with severe burn and the role of receptor for advanced glycation end products in the process]. AB - OBJECTIVE: To investigate the effect of high mobility group box protein 1 (HMGB1) on the production of pro-inflammatory cytokines by Kupffer cell (KC) of rats with severe burn and the role of receptor for advanced glycation end products (RAGE) in the process. METHODS: Model of 30% TBSA full-thickness burn was reproduced in 32 SD rats through immersing the back in 98 degrees C water for 12 s. KC (32 samples) was isolated from rat liver 24 h after injury and inoculated in 24-well plate in the concentration of 1*10(6) cell per well. (1) Cells were divided into control group (cultured with 1 mL PBS) and HMGB1 group (stimulated with 100 ng/mL HMGB1 in the volume of 1 mL) according to the random number table, with 8 samples in each group. At post culture hour (PCH) 48, the expression of RAGE (denoted as grey value ratio) was detected with Western blotting. (2) Another portion of cells were divided into control group (cultured with 1 mL PBS), HMGB1 group (treated with 100 ng/mL HMGB1 in the volume of 1 mL), HMGB1 + anti-RAGE antibody group (treated with 100 ng/mL HMGB1 in the volume of 1 mL after being pre incubated with 20 ug/mL anti-RAGE monoclonal antibody in the volume of 1 mL for 2 hours), HMGB1 + recombinant rat RAGE/Fc chimera (rrRAGE/Fc) group (treated with the mixture of 100 ng/mL HMGB1 in the volume of 0.5 mL and 5 ug/mL rrRAGE/Fc in the volume of 0.5 mL which were pre-incubated for 2 hours) according to the random number table, with 8 samples in each group. At PCH 48, the protein levels of TNF-alpha and IL-1beta in supernatant were determined with enzyme-linked immunosorbent assay, while the mRNA expression of TNF-alpha and IL-1beta (denoted as grey value ratio) were determined with Northern blotting. Data were processed with one-way analysis of variance, t test, and LSD test. RESULTS: (1) The expression of RAGE in HMGB1 group (1.036 +/- 0.101) was significantly higher than that of control group at PCH 48 (0.191 +/- 0.024, t = -23.158, P = 0.000). (2) In HMGB1 group, HMGB1 + anti-RAGE antibody group, and HMGB1 + rrRAGE/Fc group, the contents of TNF-alpha in supernatant were respectively (10.59 +/- 1.39), (9.91 +/ 1.68), (11.51 +/- 2.27) ng/mL; the contents of IL-1beta in supernatant were respectively (2.49 +/- 0.33), (2.08 +/- 0.32), (2.42 +/- 0.42) ng/mL; the mRNA levels of TNF-alpha in cells were respectively 0.311 +/- 0.009, 0.301 +/- 0.047, 0.326 +/- 0.016; the mRNA levels of IL-1beta in cells were respectively 0.237 +/- 0.021, 0.244 +/- 0.041, 0.245 +/- 0.013. There were no statistically significant differences in the above indexes among these three groups (with P values all above 0.05). Their levels were all significantly higher than those of control group [with contents of TNF-alpha and IL-1beta in supernatant respectively (2.69 +/- 0.14), (0.43 +/- 0.05) ng/mL, and mRNA levels of TNF-alpha and IL-1beta in cells respectively 0.140 +/- 0.022, 0.077 +/- 0.005, P values all below 0.01]. CONCLUSIONS: HMGB1 can induce the production of pro-inflammatory cytokines TNF alpha and IL-1beta from the KC in rats with severe burn. However, RAGE does not play a predominant role in this process. PMID- 23985206 TI - [Advancement in the research of mechanism of immune dysfunction in sepsis and the regulatory effects of Xuebijing injection]. AB - Sepsis is a systemic inflammatory response syndrome resulting from a host response to infection. The early stage of sepsis is characterized by excessive inflammatory response, accompanied by immune dysfunction characterized by aggravating cellular immunosuppression. The vast majority of patients with sepsis survive the initial excessive inflammatory response, but die of hospital-acquired infection, opportunistic pathogenic bacteria infection, latent virus reactivation, and multiple organ dysfunction syndrome. These facts indicate that immunosuppression may be a significant cause of exacerbation of the illness even death of the septic patients. The primary cellular mechanisms in inducing immune dysfunction include immune dysfunction of T lymphocytes, negative regulation of regulatory T lymphocytes and dendritic cells, and damage of intestinal mucosa associated lymphoid tissue. Xuebijing injection is a complex Chinese patent medicine, which is widely used in the treatment of sepsis. It has a potential immunoregulation ability, as well as effects on bacteriostasis, anti-endotoxin and anti-inflammation. Its target and mechanism of action need to be explored further. PMID- 23985207 TI - [Advancement in the research of early detection of bacterial nucleic acid in molecular diagnosis of sepsis]. AB - Early diagnosis of sepsis helps make effective clinical decisions and improve the survival rate of patients with severe infection. However, the timely and accurate diagnosis of sepsis is still a great challenge in clinic. In order to settle the very problem, the scientists in the world have made a lot of exploration and research in the field of rapid molecular identification of pathogens. Nowadays, the nucleic acid detection of sepsis is mainly composed of 3 types of methodological strategies, either based on positive blood culture, single colonies, or directly on blood specimens. This paper presents a comprehensive overview of advances in the research of early detection of bacterial nucleic acid as molecular diagnosis of sepsis. PMID- 23985208 TI - [Treatment of osteomyelitis and soft tissue defects at distal region of leg and foot by pedicled peroneus brevis muscle flaps and reverse island flaps with sural nerve and blood supplying vessels]. AB - OBJECTIVE: To observe the clinical effect of distally pedicled peroneus brevis muscle flaps and reverse island flaps with sural nerve and blood supplying vessels on repairing osteomyelitis and soft tissue defects at distal region of leg and foot. METHODS: Twelve patients with osteomyelitis and soft tissue defects at distal region of leg and foot hospitalized from March 2008 to December 2010. Among them, 7 patients suffered from acute or chronic osteomyelitis and soft tissue defects at the distal end of tibia, 1 patient suffered from chronic osteomyelitis and chronic ulcer in the posterior aspect of achilles tendon, 4 patients suffered from acute or chronic osteomyelitis, soft tissue defects, and exposure of internal fixator in the lateral aspect of calcaneus. After debridement, soft tissue defect sizes ranged from 4 cm*2 cm to 13 cm*9 cm, and bone defect sizes ranged from 3.0 cm*3.0 cm*3.0 cm to 6.0 cm*3.0 cm*4.0 cm. The distally pedicled peroneus brevis muscle flaps with size ranging from 11 cm*3 cm to 16 cm*4 cm were used to fill the wound cavities of bone defects, and reverse island flaps with sural nerve and blood supplying vessels with size ranging from 5 cm*3 cm to 14 cm*10 cm were used for the repair of soft tissue defects. Flap donor sites were closed by direct suture or skin grafting. RESULTS: Muscle flaps and flaps survived in 11 cases, and the wounds healed well. Necrosis appeared in flap and muscle flap at the distal end in one patient, which was repaired with posterior tibial artery perforator myocutaneous flap. Patients were followed up for 6 to 24 months. Osteomyelitis did not recur, and both the texture and shape of flaps were satisfactory. CONCLUSIONS: The distally pedicled peroneus brevis muscle flaps and reverse island flaps with sural nerve and blood supplying vessels are suitable for the repair of osteomyelitis and soft tissue defects at distal region of leg and foot. The operation is simple, safe, reliable, and easy to perform. PMID- 23985209 TI - [Multi-center clinical trial of FLAMIGEL (hydrogel dressing) for the treatment of residual burn wound]. AB - OBJECTIVE: To evaluate the effect of FLAMIGEL (hydrogel dressing) on the repair of residual burn wound. METHODS: Sixty burn patients with residual wounds hospitalized in 6 burn units from November 2011 to May 2012 were enrolled in the multi-center, randomized, and self-control clinical trial. Two residual wounds of each patient were divided into groups T (treated with FLAMIGEL) and C (treated with iodophor gauze) according to the random number table. On post treatment day (PTD) 7 and 14, wound healing rate was calculated, with the number of completely healed wound counted. The degree of pain patient felt during dressing change was evaluated using the visual analogue scale (VAS). The mean numbers of wounds with score equal to zero, more than zero and less than or equal to 3, more than 3 and less than or equal to 6, more than 6 and less than or equal to 10 were recorded respectively. Wound secretion or exudate samples were collected for bacterial culture, and the side effect was observed. Data were processed with repeated measure analysis of variance, t test, chi-square test, and nonparametric rank sum test. RESULTS: Wound healing rate of groups T, C on PTD 7 was respectively (67 +/ 24)%, (45 +/- 25)%, and it was respectively (92 +/- 16)%, (72 +/- 23)% on PTD 14. There was statistically significant difference in wound healing rate on PTD 7, 14 between group T and group C (F = 32.388, P < 0.01). Ten wounds in group T and four wounds in group C were healed completely on PTD 7, with no significant difference between them (chi(2) = 0, P > 0.05). Forty-two wounds in group T and seven wounds in group C healed completely on PTD 14, with statistically significant difference between them (chi(2) = 42.254, P < 0.01). Patients in group T felt mild pain during dressing change for 37 wounds, with VAS score higher than zero and lower than or equal to 3. Evident pain was observed in patients of group C during dressing change for 43 wounds, and it scored higher than 3 and less than or equal to 6 by VAS evaluation. There was statistically significant difference in mean number of wounds with different grade of VAS score between group T and group C (Z = -4.638, P < 0.01). Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, E. coli, Baumanii, and Staphylococcus epidermidis were all detected in both groups, but there was no statistical difference between group T and group C (chi(2) = 0.051, P > 0.05). No side effect was observed in either of the two groups during the whole trial. CONCLUSIONS: FLAMIGEL can accelerate the healing of residual burn wounds and obviously relieve painful sensation during dressing change. PMID- 23985210 TI - [Influence of intensive insulin therapy on insulin resistance of patients with severe burn or trauma]. AB - OBJECTIVE: To discuss the influence of intensive insulin therapy on insulin resistance of patients with severe burn or trauma. METHODS: Sixty patients with severe burn or trauma hospitalized in the Third People's Hospital of Chongqing or Southwest Hospital of the Third Military Medical University from January 2010 to December 2011 were randomly divided into intensive insulin therapy group (IT, treated with intensive insulin therapy to control the blood glucose to the level of 6.0-8.0 mmol/L) and control group (C, treated with routine therapy) according to the paired grouping method, with 30 patients in each group. Before treatment and on post treatment day (PTD) 1, 3, 7, 10, 14, the levels of fasting blood glucose and fasting plasma insulin were determined. Insulin resistance index and beta-cell function index were calculated using homeostasis model assessment. Data were processed with t test, analysis of variance, and LSD test. RESULTS: On PTD 1, 3, 7, 10, levels of fasting blood glucose in group IT [(6.8 +/- 1.4), (6.7 +/- 1.3), (5.8 +/- 1.9), (5.4 +/- 1.6) mmol/L] were significantly lower than those of group C [(14.8 +/- 4.9), (12.7 +/- 3.7), (7.7 +/- 1.9), (6.6 +/- 1.3) mmol/L, with t values respectively 12.453, 11.386, 5.563, 4.731, P < 0.05 or P < 0.01]. On PTD 3, 7, levels of fasting insulin in group IT [(14 +/- 5), (10 +/- 3) mU/L] were significantly lower than those of group C [(16 +/- 4), (13 +/- 4) mU/L, with t values respectively 4.212, 4.364, P values below 0.05]. Levels of fasting blood glucose and fasting insulin in the two groups at each time point were statistically significantly different from those before treatment (with P values below 0.01), except for the level of fasting blood glucose on PTD 3. On PTD 1, 3, 7, 10, levels of insulin resistance index in group IT (1.60 +/- 0.80, 1.46 +/- 0.70, 0.96 +/- 0.21, 0.90 +/- 0.23) were significantly lower than those in group C (2.15 +/- 1.35, 2.21 +/- 1.21, 1.50 +/- 0.95, 1.17 +/- 0.66, with t values respectively 8.316, 10.607, 7.825, 5.217, P < 0.05 or P < 0.01). Levels of insulin resistance index of patients in the two groups at each time point after treatment were significantly lower than those before treatment (with P values below 0.01). On PTD 1, 3, 7, levels of beta-cell function index in group IT (4.6 +/- 2.9, 4.5 +/- 3.3, 4.5 +/- 3.6) were significantly higher than those in group C (3.4 +/- 2.5, 3.6 +/- 2.2, 4.2 +/- 2.5, with t values respectively 8.243, 7.914, 4.338, P < 0.05 or P < 0.01). Levels of beta-cell function index in group C on PTD 1 and 3 were significantly lower than that before therapy (with P values below 0.05). CONCLUSIONS: Intensive insulin therapy can alleviate insulin resistance of patients with severe burn or trauma. PMID- 23985211 TI - [Expressions of the related genes in fibroblasts of human keloid and the effect of artesunate]. AB - OBJECTIVE: To verify whether abnormal expression of calcium/calmodulin dependent serine protein kinase (CASK) and inhibitors of differentiation 1 (ID1) exist in Fb of keloid, and to observe the effect of artesunate on two genes. METHODS: Fifteen samples of keloid and 12 samples of normal skin tissue (discarded) excised from patients admitted to our hospital were collected. Tissue particle adherent method was used in the primary culture of Fb, and cells from the third to the eighth passage were used for test. Expressions of CASK and ID1 in Fb harvested from both sources were observed with immunofluorescence staining. Fb of keloid were stimulated with artesunate in various concentration for different time, and the median inhibitory concentration (IC50) was determined with the MTT colorimetric assay, which served as the intervention concentration of artesunate. Fb of normal skin were set as normal control group (NC, treated with medium solution). Fb of keloid were divided into scar control group (SC, treated with medium solution) and scar administration group (SA, treated with artesunate in IC50). The cycle and apoptosis of Fb were detected with flow cytometric assay, and the nucleic acid and protein expressions of CASK and ID1 of Fb in each group were determined with RT-PCR and Western blotting. Data were processed with one way analysis of variance and LSD-t test. RESULTS: Expressions of CASK and ID1 were detected in two kinds of Fb. The concentration of 75 mg/L was selected as the intervention concentration of artesunate. (1) There were statistically significant differences among the three groups in the percentages of cells in G0/G1 phase and G2/M phase (with F values respectively 118.064 and 163.840, P values all below 0.01). The percentage of cells in G0/G1 phase of group SA was (91.4 +/- 1.4)%, which was significantly higher than that of group SC and group NC [respectively (80.7 +/- 0.3)% and (82.4 +/- 0.6)%, with t values respectively 12.740 and 9.872, P values all below 0.05]. The percentage of cells in G2/M phase of group SA was (6.9 +/- 0.3)%, which was significantly lower than that of group SC and group NC [respectively (13.7 +/- 0.3)% and (12.7 +/- 0.8)%, with t values respectively 43.702 and 12.276, P values all below 0.05]. (2) There were statistically significant differences among the three groups in the early and late apoptotic rates (with F values respectively 61.879 and 4710.862, P values all below 0.01). The early and late apoptotic rates of group SA were respectively (7.1 +/- 1.0)% and (14.9 +/- 0.3)%, which were significantly higher than those of group SC and group NC [with early apoptotic rate respectively (2.6 +/- 0.4)% and (2.7 +/- 0.3)%, t values respectively 7.974 and 7.767, P values all below 0.05; with late apoptotic rate respectively (2.3 +/- 0.3)% and (2.5 +/- 0.4)%, t values respectively 72.882 and 69.792, P values all below 0.05]. (3) The mRNA expression of CASK in group SC was 0.658 +/- 0.024, and it was lower than that of group NC (1.076 +/- 0.008, t = 28.997, P < 0.01) and group SA (0.855 +/- 0.008, t = 13.549, P < 0.01). The protein expression of CASK in group SC was 0.067 +/- 0.007, and it was lower than that of group NC (0.179 +/- 0.015, t = 12.042, P < 0.01) and group SA (0.132 +/- 0.010, t = 9.498, P < 0.01). (4) The mRNA expression of ID1 in group SC was 0.416 +/- 0.006, which was higher than that of group NC (0.317 +/- 0.020, t = 8.299, P < 0.01) and group SA (0.217 +/- 0.009, t = 32.417, P < 0.01). The protein expression of ID1 in group SC was 0.789 +/- 0.034, and it was higher than that of group NC (0.366 +/- 0.029, t = 16.341, P < 0.01) and group SA (0.114 +/- 0.006, t = 33.978, P < 0.01). CONCLUSIONS: It is speculated that CASK and ID1 participate in the proliferation of Fb in keloid. The mechanism of artesunate in inhibiting the proliferation of Fb in keloid may be related to the up-regulation of CASK and down-regulation of ID1. PMID- 23985212 TI - [Systemic therapy for defects of skin and soft tissue on the knees after severe trauma or burn]. AB - OBJECTIVE: To explore the methods of systemic treatment of defects of skin and soft tissue on the knees after severe trauma or burn. METHODS: Twenty patients with defects of skin and soft tissue on the knees after severe trauma or burn hospitalized in our center from January 2009 to December 2011. The injury areas on the knees ranged from 5 cm*4 cm to 30 cm*20 cm. The wounds were treated with radical debridement, vacuum sealing drainage, and douche through dripping to control infection in early stage. Then they were covered with transplantation of skin grafts plus flap or only with flap. Totally 8 local flaps (including 6 local rotation or transposition flaps and 2 saphenous artery flaps) and 12 free flaps (including 8 anterolateral thigh flaps and 4 latissimus dorsi musculocutaneous flaps) were used. The flap size ranged from 6 cm*5 cm to 32 cm*22 cm. The rehabilitation training of the knee joints was carried out in the early stage after wound healing. RESULTS: All free skin grafts and flaps used in 15 patients survived. Thirteen of them were primarily healed, while some small parts of skin grafts of the other two patients were in poor condition because of infection, and they healed after another session of skin transplantation. Infection occurred under the free flap in one of the 5 patients transplanted with flaps only, which was healed after continuous douche through dripping and another surgical debridement following wet dressing. The knee joints were in good function during the follow-up period of 1 - 3 years. CONCLUSIONS: The systemic therapy of radical debridement, vacuum sealing drainage technique, douche through dripping, transplantation of large autologous grafts and flaps, and the early rehabilitation training are effective and reliable in repairing defects of skin and soft tissue at the knee region after severe injuries. PMID- 23985213 TI - [Influence of educational status, burn area and coping behaviors on the complication of psychological disorders in severely burned patients]. AB - OBJECTIVE: To discuss how the educational status, burn area and coping behaviors influence the psychological disorders in severely burned patients. METHODS: Sixty four severely burned patients hospitalized in Guangzhou Red Cross Hospital, Guangdong Provincial Work Injury Rehabilitation Center, and Guangdong General Hospital were enrolled with cluster random sampling method. Data of their demography and situation of burns were collected. Then their coping behavior, psychological disorders including anxiety, depression and post-traumatic stress disorder (PTSD) plus its core symptoms of flashback, avoidance, and hypervigilance were assessed by medical coping modes questionnaire, self-rating anxiety scale (SAS), self-rating depression scale (SDS), PTSD checklist-civilian version (PCL-C) respectively. Correlation was analyzed between demography, burn area, coping behavior and psychological disorders. The predictive powers of educational status, burn area and coping behaviors on the psychological disorders were analyzed. The qualitative variables were assigned values. Data were processed with t test, Spearman rank correlation analysis, and multiple linear regression analysis. RESULTS: (1) The patients scored (19.0 +/- 3.4) points in confrontation coping behavior, which showed no statistically significant difference from the domestic norm score (19.5 +/- 3.8) points (t = -1.13, P > 0.05). The patients scored (16.6 +/- 2.4) and (11.0 +/- 2.2) points in avoidance and resignation coping behaviors, which were significantly higher than the domestic norm score (14.4 +/- 3.0), (8.8 +/- 3.2) points (with t values respectively 7.06 and 7.76, P values both below 0.01). The patients' standard score of SAS, SDS, PCL-C were (50 +/- 11), (54 +/- 11), and (38 +/- 12) points. Respectively 89.1% (57/64), 60.9% (39/64), 46.9% (30/64) of the patients showed anxiety, depression, and PTSD symptoms. (2) Four independent variables: age, gender, marital status, and time after burns, were correlated with the psychological disorders, but the correlativity was not statistically significant (with rs values from -0.089 to 0.245, P values all above 0.05). Educational status was significantly negatively correlated with anxiety, depression, PTSD and its core symptoms of flashback, avoidance (with rs values from -0.361 to -0.253, P values all below 0.05). Educational status was negatively correlated with hypervigilance, but the correlativity was not statistically significant (rs = 0.187, P > 0.05). Burn area was significantly positively correlated with the psychological disorders (with rs values from 0.306 to 0.478, P values all below 0.05). Confrontation coping behavior was positively correlated with the psychological disorders, but the correlativity was not statistically significant (with rs values from 0.121 to 0.550, P values all above 0.05). Avoidance coping behavior was correlated with the psychological disorders, but the correlativity was not statistically significant (with rs values from -0.144 to 0.193, P values all above 0.05). Resignation coping behavior was significantly positively correlated with the psychological disorder (with rs values from 0.377 to 0.596, P values all below 0.01). (3) Educational status had predictive power on the anxiety, PTSD and flash back symptoms of patients (with t values from -2.19 to 2.02, P values all below 0.05), but not on depression, avoidance and hypervigilance (with t values from -1.95 to -0.99, P values all above 0.05). Burn area had no predictive power on the psychological disorders (with t values from 0.55 to 1.78, P values all above 0.05). Resignation coping behavior had predictive power on the psychological disorders (with t values from 3.10 to 6.46, P values below 0.01). Confrontation and avoidance coping behaviors had no predictive power on the psychological disorders (with t values from 0.46 to 2.32 and -0.89 and 1.75 respectively, P values all above 0.05). CONCLUSIONS: The severely burned patients with lower educational status, larger burn area, and the more frequently adapted resignation coping behavior are more likely to suffer from anxiety, depression, and PTSD. PMID- 23985214 TI - Improving climato-economic theorizing at the individual level. AB - Using representative data from 55 nations, I show that individual level wealth interacts with climate in predicting individual happiness but not postmaterialism values. I propose that more research is needed to identify (a) the specific mechanisms of how wealth buffers climatic demands at the individual level and (b) the neurocognitive and physiological reactions of individuals situated in different ecological niches. PMID- 23985215 TI - Clinical significance of incidental thyroid nodules identified on low-dose CT for lung cancer screening. AB - BACKGROUND: Incidental thyroid nodules (ITNs) are defined as newly encountered nodules identified on imaging performed for an unrelated purpose. In practice, ITNs are often detected on chest computed tomography (CT). We investigated the prevalence and clinical significance of ITNs detected on low-dose chest CT (LDCT) for lung cancer screening. METHODS: We retrospectively reviewed the electronic medical records of patients with no history of thyroid disease who underwent LDCT for lung cancer screening between March 2009 and February 2012 at Jeju National University Hospital (Korea). RESULTS: Among 1,941 patients that underwent LDCT, 55(2.8%) were found to have ITNs. Seven (12.7%) of those cases were malignant. The positive and negative predictive values of chest LDCT for the detection of incidental malignant thyroid nodules were 26.9% and 73.4%, respectively. Factors considered to be predictive of malignancy on LDCT were a mean attenuation value of 55 HU or more (p = 0.036) and the presence of dense calcifications (p = 0.048). Sex, age, location of the nodule, longest diameter of the lesion, AP/T (anteroposterior/transverse dimension) ratio, margins, density, presence of punctate calcifications, and thyroid enlargement had no significant predictive value in discriminating benign and malignant nodules. On multivariate analyses, a mean attenuation value above 55 was the only statistically significant feature (p = 0.048). CONCLUSIONS: A mean attenuation value greater than 55 HU on LDCT may be a useful predictive factor for differentiating malignant from benign lesions. Therefore, a careful assessment of the thyroid gland is necessary for patients undergoing LDCT for lung cancer screening. PMID- 23985216 TI - Mobile leiomyoma of the skin. PMID- 23985217 TI - The incidence and prevalence of dementia with Lewy bodies is underestimated. PMID- 23985218 TI - Long-term ultrastructural indices of lead intoxication in pulmonary tissue of the rat. AB - In the present research long-term pulmonary toxicity of lead was investigated in rats treated by intraperitoneal administration of lead acetate for three consecutive days (25 mg/kg per day). Five weeks after treatment average lead content in the whole blood was 0.41 MUg/dL +/- 0.05, in the lung homogenates it measured 3.35 MUg/g +/- 0.54, as compared to the control values of 0.13 +/- 0.07 MUg/dL and 1.03 MUg/g +/- 0.59, respectively. X-ray microanalysis of lung specimens displayed lead localized mainly within type II pneumocytes and macrophages. At the ultrastructural level the effects of lead toxicity were found in lung capillaries, interstitium, epithelial cells, and alveolar lining. Alveolar septa showed intense fibrosis, consisting of collagen, elastin, and fibroblasts. Thinned alveolar septa had emphysematous tissue with some revealing signs of angiogenesis. Type II pneumocytes contained lamellar bodies with features of laminar destruction. Fragments of the surfactant layer were often detached from the alveolar epithelium. These findings indicate that 5 weeks after exposure, lead provokes reconstruction of the alveolar septa including fibrosis and emphysematous changes in the lung tissue. PMID- 23985219 TI - Intracranial arachnoid cysts: impairment of higher cognitive functions and postoperative improvement. AB - BACKGROUND: Intracranial arachnoid cysts have been shown to yield cognitive impairment over a range of basic mental functions, and these functions normalize after surgical cyst decompression. We wanted to investigate whether such cysts may also impair executive cognitive functions, and whether surgical cyst decompression leads to an improvement. METHODS: This study included 22 patients with arachnoid cysts and 13 control patients scheduled for low back surgery. All subjects were tested with Delis-Kaplan Executive Function System (D-KEFS) tests, assessing executive function 1 day before surgery and a minimum of 3 months after surgery. The data were analyzed according to scaled score computations based on raw scores provided by D-KEFS, adjusted for age, gender, and educational norms. RESULTS: Preoperatively, the patients with cysts group performed worse than the control group in verbal knowledge, mental flexibility, inhibitory capacity, problem solving, and planning skills. Postoperatively, the patients with cysts group significantly improved performance and were no longer different from the control group in the following subtests: inhibition, inhibition/switching, letter fluency, category switching, and total switching accuracy. The patients with cysts group also significantly improved performance in color naming, category fluency, and in the Tower test, but nevertheless remained impaired at follow-up compared with the control group. The control group did not show a similar improvement, except for the Tower test. Cyst size or postoperative volume reduction did not correlate with cognitive performance or postoperative improvement. Patients with left-sided temporal cysts performed poorer than patients with right-sided cysts on a complex verbal task demanding mental flexibility. CONCLUSIONS: Arachnoid cysts seem to impair not only basic cognition, but also executive functions. Most of this impairment appears to be reversible after surgical cyst decompression. These results may have implications for future preoperative considerations for patients with intracranial arachnoid cysts. PMID- 23985220 TI - Physician choice making and characteristics associated with using physician rating websites: cross-sectional study. AB - BACKGROUND: Over the past decade, physician-rating websites have been gaining attention in scientific literature and in the media. However, little knowledge is available about the awareness and the impact of using such sites on health care professionals. It also remains unclear what key predictors are associated with the knowledge and the use of physician-rating websites. OBJECTIVE: To estimate the current level of awareness and use of physician-rating websites in Germany and to determine their impact on physician choice making and the key predictors which are associated with the knowledge and the use of physician-rating websites. METHODS: This study was designed as a cross-sectional survey. An online panel was consulted in January 2013. A questionnaire was developed containing 28 questions; a pretest was carried out to assess the comprehension of the questionnaire. Several sociodemographic (eg, age, gender, health insurance status, Internet use) and 2 health-related independent variables (ie, health status and health care utilization) were included. Data were analyzed using descriptive statistics, chi square tests, and t tests. Binary multivariate logistic regression models were performed for elaborating the characteristics of physician-rating website users. Results from the logistic regression are presented for both the observed and weighted sample. RESULTS: In total, 1505 respondents (mean age 43.73 years, SD 14.39; 857/1505, 57.25% female) completed our survey. Of all respondents, 32.09% (483/1505) heard of physician-rating websites and 25.32% (381/1505) already had used a website when searching for a physician. Furthermore, 11.03% (166/1505) had already posted a rating on a physician-rating website. Approximately 65.35% (249/381) consulted a particular physician based on the ratings shown on the websites; in contrast, 52.23% (199/381) had not consulted a particular physician because of the publicly reported ratings. Significantly higher likelihoods for being aware of the websites could be demonstrated for female participants (P<.001), those who were widowed (P=.01), covered by statutory health insurance (P=.02), and with higher health care utilization (P<.001). Health care utilization was significantly associated with all dependent variables in our multivariate logistic regression models (P<.001). Furthermore, significantly higher scores could be shown for health insurance status in the unweighted and Internet use in the weighted models. CONCLUSIONS: Neither health policy makers nor physicians should underestimate the influence of physician-rating websites. They already play an important role in providing information to help patients decide on an appropriate physician. Assuming there will be a rising level of public awareness, the influence of their use will increase well into the future. Future studies should assess the impact of physician-rating websites under experimental conditions and investigate whether physician-rating websites have the potential to reflect the quality of care offered by health care providers. PMID- 23985221 TI - Personality traits, national character stereotypes, and climate-economic conditions. AB - Cross-cultural personality research suggests that individuals from wealthier countries tend to be more open-minded. This openness to values may support more democratic governments and the expansion of fundamental freedoms. The link between wealth and freedom is evident in cold-to-temperate climates, but not across wealthy nations in hot climates. Furthermore, temperature and economic conditions shape perceptions of national character stereotypes. PMID- 23985224 TI - The predictive utility of attitudes toward hookah tobacco smoking. AB - OBJECTIVE: To determine associations between positive and negative attitudes and hookah tobacco smoking (HTS) among college students. METHODS: Among a random sample of university students (N = 852), multivariable logistic regression models assessed associations between positive and negative attitudes toward HTS. RESULTS: Positive attitudes were associated with adjusted odds of 4.32 (95% CI = 3.20, 5.82) for current HTS, whereas negative attitudes were associated with lower adjusted odds for current smoking HTS (AOR = 0.64, 95% CI = 0.53, 0.76). Positive attitudes were also associated with adjusted odds of 9.31 (95% CI = 6.77, 12.80) for intention for future hookah use among non-HTS users. CONCLUSION: Positive attitudes toward HTS were more strongly associated with HTS compared to negative attitudes. It may be particularly valuable for future research and interventions to focus on decreasing positive attitudes toward HTS. PMID- 23985225 TI - Smoking restrictions in the homes of children with cancer. AB - OBJECTIVES: To examine smoking restrictions in households of children with cancer and their effect on biological measures of children's secondhand smoke exposure (SHSe). METHODS: A sample of 135 parents of nonsmoking children with cancer who lived with a smoker completed structured interviews. RESULTS: Approximately 43% of families prohibited smoking in the home. Children living in homes that prohibited smoking had median cotinine levels that were 71% and 52% lower than did those from homes with no and partial restrictions. CONCLUSIONS: Parents should be directed to completely ban all smoking from the home and car to best protect their children from SHSe. PMID- 23985226 TI - "Causes" of pesticide safety behavior change in Latino farmworker families. AB - OBJECTIVE: To identify the source of behavior change resulting from a health education intervention focused on pesticide safety. METHODS: Data were from the La Familia Sana demonstration project, a promotora-delivered pesticide safety education intervention conducted with immigrant Latinos (N = 610). RESULTS: The La Familia Sana program produced changes in 3 sets of pesticide safety behaviors. Changes in the conceptual targets of the intervention and promotora attributes explained 0.45-6% and 0.5-3% of the changes in pesticide-related behavior, respectively. DISCUSSION: The conceptual targets of the La Familia Sana program explained the greatest amount of change in pesticide-related behavior. Promotora attributes also contributed to intervention success. PMID- 23985227 TI - An exploratory study of 2 parenting styles and family health behaviors. AB - OBJECTIVE: To examine the relationships between 2 parenting styles and family nutrition and physical activity. METHODS: Parents of elementary/primary school children in the southeastern United States (N = 145) completed surveys regarding family relationships and health behaviors. RESULTS: Parents exhibiting a laissez faire parenting style reported lower levels of family nutrition and physical activity. In addition, parent BMI moderated the relationship between laissez faire parenting and these health behaviors. CONCLUSIONS: This study indicates that family-oriented nutrition and physical activity programs may benefit from including a focus on decreasing laissez-faire parenting, as well as helping overweight parents reduce their BMIs. PMID- 23985228 TI - Understanding parental support of child physical activity behavior. AB - OBJECTIVE: To examine parental support of child physical activity with an adapted theory of planned behavior model. METHODS: A representative sample of Canadian mothers (N = 663) who completed measures of family priorities, social cognition, and child physical activity. RESULTS: An assessment of family priorities showed that mothers ranked physical activity almost as high as homework and far higher than other activities. Attitude about providing support for child physical activity predicted intention, yet only perceived control over support predicted behavior. CONCLUSIONS: Mothers perceive great import of physical activity for their children but they are inhibited by a low perception of control. PMID- 23985229 TI - Predictors of behavior change intention using health risk appraisal data. AB - OBJECTIVES: To investigate predictors of behavior change intention and discuss potential implications for practitioners. METHODS: Health risk appraisal (HRA) data from 2 organizations were used to develop and confirm a path analysis model for predictors of intention to change behavior. RESULTS: Lower self-rated health perception and higher ratings of stress corresponded to higher behavior-change intention scores. Stress was associated with poorer health perception. CONCLUSIONS: Higher stress and lower perception of health status were directly associated with intention to change behavior. Incorporating stress management and awareness of health perception into health promotion strategies could enhance wellness programs by aligning programs with motivating factors. PMID- 23985230 TI - Intentions modify program impact after a nutrition education intervention. AB - OBJECTIVE: To examine whether expressed intentions modified program impact on diet. METHODS: A nutrition education intervention was conducted with African American women in Washington, DC. Dietary recalls and surveys at post intervention and follow-up were analyzed. RESULTS: At 20-week follow-up, frequent attenders reported .13 more fruit and vegetable servings per additional point post-intervention behavioral intentions score (p = .03) and .10 servings per point on follow-up intentions score (p = .07). CONCLUSIONS: Sustained intentions predicted dietary change, informing measurement and theory for nutrition interventions. PMID- 23985231 TI - Relationship among females' weight status and beliefs about diet and health. AB - OBJECTIVES: To assess reliability/validity of psychosocial surveys and explore health beliefs across weight status in female freshmen. METHODS: Participants (N = 259) completed Weight Efficacy Lifestyle Questionnaire and Eating Among Teens II survey; results evaluated by weight status (Cronbach alpha; principal components analysis; Mann-Whitney U). RESULTS: Factor structures generally differed by weight group but "trigger situations" and "social pressure" were consistent. For comparable constructs with Cronbach alpha >= .70, scores were neutral or slightly positive for self-efficacy, emotional eating, and social pressure. Scores did not differ between weight groups. CONCLUSIONS: Surveys demonstrated reliability but could benefit from further development to accurately evaluate psychosocial variables by weight status. PMID- 23985232 TI - Knowing quitters predicts smoking cessation in a homeless population. AB - OBJECTIVES: To examine the impact of knowing quitters on cessation among homeless smokers. METHODS: Secondary analysis of data derived from a community-based randomized controlled trial of 430 homeless smokers. We conducted multivariable logistic regression analysis to determine whether knowing quitters impacted the likelihood of cessation (salivary cotinine <= 20 ng/ml) at 26-week follow-up. RESULTS: Multivariable logistic regression showed cessation was more likely for smokers who knew >= 5 quitters compared with those who knew no quitters (Odds Ratio = 3.79, CI = 1.17, 12.27, p = .008), adjusting for age, education, income, and time to first cigarette in morning. CONCLUSIONS: Knowing former smokers was associated with increased likelihood of achieving smoking abstinence among homeless smokers. PMID- 23985233 TI - Smoker identity among occasional smokers: findings from Minnesota. AB - OBJECTIVES: To investigate characteristics of occasional smokers who deny being smokers (ie, deniers). METHODS: Data were from 3 rounds of the Minnesota Adult Tobacco Survey (MATS 2003, 2007, and 2010), a statewide, cross-sectional, and random-digit-dial telephone survey. RESULTS: Nearly half of occasional smokers did not view themselves as smokers. Characteristics that were predictive of being a denier included less perceived harm from secondhand smoke, fewer days smoked, and fewer cigarettes smoked per day. CONCLUSIONS: Denial of being a smoker is primarily characterized by very light smoking. Future communication efforts should be tailored for this group. PMID- 23985234 TI - Homicide-followed-by-suicide incidents involving child victims. AB - OBJECTIVES: To describe homicide-followed-by-suicide incidents involving child victims METHODS: Using 2003-2009 National Violent Death Reporting System data, we characterized 129 incidents based on victim and perpetrator demographic information, their relationships, the weapons/mechanisms involved, and the perpetrators' health and stress-related circumstances. RESULTS: These incidents accounted for 188 child deaths; 69% were under 11 years old, and 58% were killed with a firearm. Approximately 76% of perpetrators were males, and 75% were parents/caregivers. Eighty-one percent of incidents with paternal perpetrators and 59% with maternal perpetrators were preceded by parental discord. Fifty-two percent of incidents with maternal perpetrators were associated with maternal psychiatric problems. CONCLUSIONS: Strategies that resolve parental conflicts rationally and facilitate detection and treatment of parental mental conditions might help prevention efforts. PMID- 23985235 TI - Social ecological influences on work-related active commuting among adults. AB - OBJECTIVE: To examine influences on active commuting (AC) behavior using a social ecological framework. METHODS: Participants (N = 1234) responded to an online survey about AC patterns and social ecological influences on AC. Multiple regression analysis determined the relative influence of individual, interpersonal, institutional, community, and environmental levels on AC. RESULTS: Significant relationships were found between AC and individual, interpersonal, institutional, community, and environmental influences; 70% of the variance in AC was explained with the full model. CONCLUSIONS: The social ecological model provides a framework for understanding a range of influences on AC and should inform strategies to improve AC behavior. PMID- 23985236 TI - Feelings and intervention judgments as mediators in the risk perception-intention relationship. AB - OBJECTIVES: To explore the mediating role of measures of persuasion in the relationship between risk perceptions and intentions. METHODS: The first study included 413 obese subjects (mean age = 45.3 years); the second study, 781 overweight subjects (mean age = 46.6 years). All measures were assessed by self report. RESULTS: Feelings and intervention judgments were mediators in the relationship between risk perceptions and intention to eat healthier, do more physical activity (study 1) and intention to reduce saturated fat (study 2). Feelings was the only mediator in the relationship between risk perceptions and intention to stop smoking (study 1). CONCLUSIONS: Future interventions targeting risk perceptions to increase intentions are likely to be more effective if subjects find the information emotionally impactful, credible, and engaging. PMID- 23985237 TI - Using latent variable techniques to understand DSM-IV alcohol use disorder criteria functioning. AB - OBJECTIVES: To use factor analytic and item response theory methods to understand diagnostic Alcohol Use Disorder (AUD) criteria functioning in non-college young adults. METHODS: The current study examined data from the 2009 National Survey of Drug Use and Health. Participants were non-college attending young adults (18 to 25) who consumed alcohol in the prior year. Confirmatory factor analysis (CFA) and item response theory (IRT) techniques were used to assess the dimensionality of DSM-IV AUD criteria. RESULTS: CFA results indicated a dominant single factor, whereas IRT difficulty parameters revealed that the difficulty (severity) parameter estimates were intermixed across the latent AUD continuum. CONCLUSIONS: Findings are consistent with research showing that the DSM-IV alcohol abuse and dependence criteria should be combined into a single disorder. PMID- 23985238 TI - [New business model for medical specialists]. AB - The reforms in the field of medical specialist care have important implications for the professional practice of medical specialists and their working relationship with the hospital. This leads to a considerable amount of pressure placed upon the way physicians have traditionally practiced their liberal professions, which is by forming partnerships and practicing from within the hospitals based on an admission agreement. As of 2015, the tax benefits for entrepreneurs will be abolished and the formation of regional partnerships will be discouraged. These developments not only pose threats but also offer opportunities for both the entrepreneurial medical specialist and the innovative hospital. In this article, the prospect of a future business model for specialist medical care will be outlined and explored by proposing three new organizational forms. The central vision of this model is that physicians who wish to retain their status of liberal professional practitioners in the twenty-first century should be more involved in the ownership structure of hospitals. The social importance of responsible patient care remains paramount. PMID- 23985239 TI - [Surgical treatment of gastric cancer: focus on centralisation and laparoscopic resections]. AB - Approximately 2000 patients are diagnosed with gastric carcinoma in the Netherlands each year; about 500 will be eligible for curative surgical treatment. The 5-year survival rate after therapy aimed at curing the condition is 45%, which can increase by an average of 10% if perioperative chemotherapy is added to the treatment regimen. Surgical treatment consists of a distal or total gastrectomy with spleen-preserving lymphadenectomy. Centralising this type of treatment leads to less postoperative mortality and better oncological outcomes. There are indications that laparoscopic surgery can accelerate postoperative recovery time. There are insufficient long-term data on outcomes of laparoscopic surgery to date to be able to conclude whether the laparoscopic or open approach to total gastric resection is preferable. PMID- 23985240 TI - [Clinical studies in developing countries]. AB - In general, clinical trials in developing countries are met with resistance because the people are particularly vulnerable and medical assistance is often unaffordable. The prospect of free medication can then lead to exploitation since the local population can be persuaded to participate in trials that would never be allowed in Western countries due to ethical concerns. Placebo-controlled research that tests cheaper alternatives for treatments already registered could greatly improve the situation in developing countries, however. Expensive registered treatments are often unavailable in these countries. Therefore, I call for allowing such studies when the registered treatment is locally unavailable. This should be based on the four most important principles of medical ethics: the duty to help patients, avoid harm, justice and respect for autonomy. On the condition, however, that the population in developing countries benefits in the long term. PMID- 23985241 TI - [A woman with a swelling of the right elbow]. AB - A 74-year-old woman with longlasting rheumatoid arthritis came to our clinic because of a swollen bursa olecrani. Aspiration of the swelling yielded a yellow fluid; polarized light microscopy showed cholesterol crystals. PMID- 23985242 TI - [Evaluation of treatment strategies in obstetrics and gynaecology]. AB - Randomised clinical trials are the preferred tool to assess the effectiveness of new treatment strategies and to compare the effectiveness of existing techniques. Since it is virtually impossible to complete studies with the required sample sizes in a single centre or even a few centres, from 2003 onwards 70 Dutch hospitals have since joined forces in the initiation and execution of large clinical studies. The consortia address pragmatic questions in the fields of obstetrics, gynaecology and reproductive medicine. The construction of a common infrastructure for ethical approval, recruitment of patients, data management and analysis is central to this collaboration. Research nurses and midwives play a key role in the recruitment of participants and the collection of data. In this article we consider if in view of the results obtained, funding from government and insurance companies and the participation of health care providers can continue to be as liberal as it has been up to now. PMID- 23985243 TI - [Acute upper abdominal pain after excessive vomiting: Boerhaave's syndrome]. AB - BACKGROUND: Boerhaave's syndrome is a spontaneous oesophageal rupture caused by excessive vomiting. Left untreated the mortality rate is high. Surgical intervention was always the treatment of first choice, but increasingly a minimally invasive approach involving the endoscopic placement of an oesophageal stent is being carried out. CASE STUDY: A 55-year-old man with no previous history presented at the Emergency Department complaining of pain in the upper abdomen that had come on suddenly after excessive vomiting. On CT scan Boerhaave's syndrome was diagnosed. An oesophageal stent was placed. The postoperative course was complicated by mediastinal and pleural abscesses for which surgical debridement was required. After 2 months the patient was discharged to a rehabilitation centre. CONCLUSION: Surgical intervention is indicated if a patient with Boerhaave's syndrome is haemodynamically unstable or has sepsis, and the diagnosis is made within 24 hours. In all other cases a minimally invasive approach involving antibiotics, pleural drainage and endoscopic stent placement should be considered. PMID- 23985246 TI - [Summary of the 'Thyroid disorders' guideline of the Dutch College of General Practitioners' (NHG)]. AB - The 'Thyroid disorders' guideline of the Dutch College of General Practitioners (NHG) provides recommendations for the diagnosis and management of hypothyroidism, hyperthyroidism and changes in the size of the thyroid gland, such as goitre and thyroid nodules. Hypothyroid patients younger than 60 years and without cardiac comorbidity should receive the full substitution dose of levothyroxine at treatment onset. In case of hypothyroidism in pregnancy, the levothyroxine dose should be immediately increased by 25%. All pregnant patients with (a history of) thyroid diseases should be tested for TSH-receptor antibodies at the start of the pregnancy. Management of subclinical hypo- and hyperthyroidism consists of monitoring laboratory values due to the great likelihood of normalization of the TSH value. All patients with a solitary nodule or a dominant nodule in a multinodular goitre should be referred to an endocrinologist for further investigation. PMID- 23985247 TI - The impact of patient narratives on self-efficacy and self-care in Australians with type 2 diabetes: stage 1 results of a randomized trial. AB - A randomized-controlled trial (RCT) was conducted from September 2009 to June 2011. National Diabetes Services Scheme registrants diagnosed with type 2 diabetes and aged 30-70 years were invited to participate in a 3-week intervention programme with follow-up at 4 weeks and 6 months. Data were collected using self-report questionnaires in the participant's homes. The intervention group received diabetes factsheets and a DVD comprising patient stories (narratives) of type 2 diabetes management. The control group (CG) received factsheets only. The RCT evaluated the impact of patient narratives on the study outcomes, self-efficacy and self-care, using the Aust/English Diabetes Management Self-efficacy Scale and the Summary Diabetes Self-care Activities measure. Participants were randomly assigned to the intervention or CG using block randomization. The study was not blinded. Six hundred and seventy people enrolled into the study with 335 allocated to each group. At 4 weeks, data were available for 598 participants. t-tests were used to analyse the results. The mean difference between the groups for self-efficacy was 7.2 units (P < 0.001, 95% Confidence Interval (CI) 3.8, 10.7) favouring the intervention group. Change in self-care behaviours during the previous 7 days was also significantly greater for the intervention group: general diet (0.31 days, 95% CI 0.13, 0.48), specific diet (0.26 days, 95% CI 0.05, 0.46), exercise (0.51 days, 95% CI 0.23, 0.80), blood glucose (0.52 days, 95% CI 0.19, 0.85) and foot care (0.38 days, 95% CI 0.06, 0.71). Narrative communication shows promise as a valuable component of type 2 diabetes self-management programmes. REGISTRATION: ACTRN 12609000210279. PMID- 23985248 TI - Gender differences in health information behaviour: a Finnish population-based survey. AB - Narrowing the gaps in health outcomes, including those between men and women, has been a pronounced goal on the agenda of the Finnish health authorities since the mid-1980s. But still there is a huge gap in favour of women when it comes to life expectancy at birth. People's health information behaviour, that is how people seek, obtain, evaluate, categorize and use relevant health-related information to perform desired health behaviours, is a critical prerequisite to appropriate and consistent performances of these behaviours. With respect to gender, it has been noted that men often are unwilling and lack the motivation to engage with health related information. The purpose of this study was to investigate how gender affects health information behaviour in the Finnish population aged 18-65 years. The survey data were collected via a questionnaire which was posted to a representative cross section consisting of 1500 Finnish citizens. The statistical analysis consists of ANOVA F-tests and Fisher's exact tests. The results show that women were more interested in and reported much more active seeking of health-related information, paid more attention to potential worldwide pandemics and were much more attentive as to how the goods they purchase in everyday life affect their health than men did. Women also reported receiving far more informal health-related information from close family members, other kin and friends/workmates than men did. Thus, to succeed in public health promotion and interventions the measures taken should be much more sensitive to the gender gap in health information behaviour. PMID- 23985249 TI - [Relationship between UGT1A and irinotecan-related toxicity]. PMID- 23985250 TI - [Inhibitory effect of silencing of HMGB1 gene expression on the invasive and metastatic abilities of MGC-803 gastric cancer cells]. AB - OBJECTIVE: To investigate the effect of high mobility group box-1 (high mobility group box B 1, HMGB1) on the invasive and metastatic abilities of gastric cancer cell line MGC-803 and analyze the possible mechanisms. METHODS: HMGB1 gene targeting siRNA was designed and synthesized, and HMGB1 siRNA oligonucleotides were transfected into the MGC-803 cells with Lipofectamine 2000. The invasive and migratory abilities were detected by transwell assay and scratch assay. The Matrigel matrix glue adhesive ability of MGC-803 cells was evaluated by MTT assay. NF-kappaB activity was detected by electrophoretic mobility shift assay. The mRNA and protein levels of HMGB1 and MMP-9 were determined by RT-PCR and Western blot, respectively. RESULTS: The siRNA down-regulated the levels of HMGB1 mRNA and protein. Compared with that of the control group, the number of invasive (142.7 +/- 3.4 /view vs. 303.5 +/- 4.3/view) and migratory (293.7 +/- 4.4/view vs. 445.5 +/- 5.6/view) cells was significantly increased (P < 0.05) and the adhesive ability of MGC-803 cells to Matrigel was significantly elevated (33.4 +/ 0.03% vs. 57.4 +/- 4.2%, P < 0.05). In addition, silencing of HMGB1 gene significantly inhibited the activity of NF-kappaB and the relative expression folds of mRNA (0.2 +/- 0.1 vs. 1.4 +/- 0.4, P < 0.05)and protein (0.4 +/- 0.1 vs. 2.3 +/- 0.7, P < 0.05) of MMP-9. CONCLUSION: Silencing of HMGB1 can effectively inhibit the invasion and migration of gastric cancer cells and this effect of HMGB1 may be partly due to its regulation of NF-kappaB and MMP-9 expressions. PMID- 23985251 TI - [Abnormal expression of APRIL in colorectal cancer cells promotes tumor growth and metastasis]. AB - OBJECTIVE: To investigate the effects of a proliferation-inducing ligand (APRlL) on colorectal cancer (CRC) cell growth and migration, and to observe the role of APRIL in CRC biological behavior. METHODS: The siRNA plasmid vector targeting APRIL gene (APRIL-siRNA) was transfected into human colorectal cancer SW480 cells and recombinant human APRIL (rhAPRIL) was used to stimulate human colorectal cancer HCT-116 cells. Cell proliferation activity was analyzed using cell counting kit-8 (CCK-8), cell cycle was detected by flow cytometry, and the protein expression of cyclin D1, p21 and Bcl-2 was detected by Western blot analysis. Tumor cell migration and invasion were measured by Transwell chambers. RT-PCR was applied to examine the mRNA expression level of MMP-2 and MMP-9. APRIL siRNA was used to transfect directly SW480 cells, which were injected subcutaneously into nude mice, then the tumor growth and metastasis were observed. RESULTS: Cell proliferation ability of APRIL-siRNA-transfected SW480 cells was drastically repressed, and the percentage of G0/G1 phase cells was significantly increased (t = 4.12, P < 0.05), accompanied with depressed cyclin D1, Bcl-2 expression and elevated p21 expression. Cell proliferation ability of rhAPRIL-stimulated HCT-116 cells was promoted with a decreased G0/G1 phase ratio (t = 3.31, P < 0.05). cyclin D1 and Bcl-2 protein expression was up-regulated while p21 was down-regulated by rhAPRIL stimulation. Metastatic and invasive capacities of APRIL-siRNA-transfected SW480 cells were significantly inhibited compared with their respective controls (both P < 0.05), accompanied with the deregulated MMP-2 and MMP-9 mRNA expression. Metastatic and invasive capacities of rhAPRIL-stimulated HCT-116 cells were promoted with up-regulated MMP-2 and MMP 9 mRNA expression(both P < 0.05). Tumor growth in the group transfected with APRIL-siRNA appeared to be slower than that in the control groups and the expression of MMP-2, MMP-9 in tumor tissues was depressed in the APRIL-siRNA group. CONCLUSIONS: APRIL facilitates tumor growth and metastasis, and is associated with carcinogenesis and prognosis. Our findings suggest that APRIL might be used as a novel target for the intervention and therapy of colorectal cancer. PMID- 23985252 TI - [Antitumor effect of capsaicin on colorectal carcinoma xenograft in nude mice]. AB - OBJECTIVE: To evaluate the effect of capsaicin on nude mice xenografted with colorectal carcinoma cells, and to explore its mechanism of action. METHODS: A nude mouse model of colorectal cancer was established by subcutaneous inoculation of human colorectal carcinoma HT-29 cells. Terminal deoxynucleotidyl transferase mediated nicked labeling assay (TUNEL) was undertaken to detect the cell proliferation and apoptosis in the xenograft tissue in nude mice. Immunohistochemical (IHC) staining and Western blot were used to detect the expression of HSP27, Cyt-C and active caspase-3. RESULTS: The tumor growth of the groups C10 and C20 was significantly slower than that of the group NS. The integrated optical density (IOD) of both the group C5 (2532.14 +/- 578.11) and group C10 (6364.03 +/- 1137.98) was significantly higher than that of the group NS (760.12 +/- 238.05), (P < 0.05). The integrated optical density (IOD) of the group C20 was (15743.96 +/- 1855.95), significantly higher than that of the groups C10, C5 and NS (all were P < 0.01). Immunohistochemistry showed that the cytoplasmic expression of HSP27 was strongly positive in the group NS, and significantly reduced with the increasing dose of capsaicin in the treated groups. The expression of active caspase-3 and Cyt-C in the group NS was weakly positive, and was significantly increased with the increasing dose of capsaicin in the groups C5 and C10 (P < 0.05), and the expression of active caspase-3 and Cyt-C of the group C20 was significantly higher than that of the groups C5, C10 and NS (P < 0.01). Western blot analysis showed that both the expressions of HSP27 of the group C5 (0.73 +/- 0.05) and the group C10 (0.41 +/- 0.03) were significantly lower than that of the group NS (P < 0.05). The expression of HSP27 of the group C20 (0.22 +/- 0.06) was significantly lower than that of the groups C5, C10 and NS (P < 0.01). The expressions of active-caspase-3 and Cyt-C in the group C5 were (2.57 +/- 0.34) and (2.03 +/- 0.38), significantly higher than those of the group NS (P < 0.05). The expressions of active-caspase-3 and Cyt-C in the group C10 were (4.23 +/- 0.45) and (3.13 +/- 0.44), also significantly higher than those of the group NS (P < 0.05). The expressions of active-caspase-3 and Cyt-C in the group C20 were (5.78 +/- 0.48) and (4.92 +/- 0.52), significantly higher than those of the group C5, C10 and NS (P < 0.01). TUNEL analysis showed that there was a significant difference of cell apoptosis in comparison of each two groups. The higher dose of capsaicin was used, the more apoptosis was observed. CONCLUSIONS: Capsaicin can significantly inhibit the tumor growth and induce cell apoptosis in the colorectal carcinoma xenograft in nude mice. Its mechanism of action is possibly related with the down-regulation of HSP27 expression and up-regulation of expression of active caspase-3 and Cyt-C in the colorectal carcinoma xenograft in nude mice. PMID- 23985253 TI - [Association of TET2, LMTK2 and FAM84B gene expression with prostate cancer risk in Chinese patients]. AB - OBJECTIVE: To explore the association between the common variations of TET2 (rs7679673, A), MTK2 (rs6465657, T) and FAM84B (rs12543663, C) genes and prostate cancer (Pca) risk in Chinese population in Beijing, and to understand the relationship between genotypes and phenotypes including clinical characteristics and life style, etc. in patients with prostate cancer. METHODS: Based on a case control study, 124 patients with prostate cancer and 138 age-matched control subjects were recruited. Information of clinical phenotype and life style, etc. in the prostate cancer patients was collected. We compared the differences of allele and genotype frequencies of TET2 (rs7679673, A), LMTK2 (rs6465657, T) and FAM84B (rs12543663, C) gene expressions between the two groups for the allele and genotype frequencies, and explored the relationship between different genotypes and clinical features such as patient age, BMI, Gleason score, PSA level and tumor stage, by Chi-square test in patients with PCa. Multifactor dimensionality reduction was used to detect the gene-gene interactions. RESULTS: The FAM84B (rs12543663, C) C carriers frequency had significant difference between the case group and the control group (chi(2) = 3.980 P = 0.046; OR = 1.883; 95%CI = 1.006 3.526). The allele and genotype frequencies of TET2 gene (rs7679673, A) and LMTK2 gene (rs6465657, T) were not significantly different between the case group and the control group (P > 0.05). Analysis of the genotypes and clinical phenotypes showed that the genetic type of FAM84B C carriers [CX (CC + CA)] were significantly associated with cancer stage (chi(2) = 9.585; P = 0.002; OR = 3.740; 95%CI = 1.580 - 8.853). Association between three loci and 12 kind of relevant outcomes was found in TET2 A carriers and the smoking and drinking patients (all P < 0.05). Significant correlation was also found between LMTK2 (rs6465657, T) TX carriers and surgery (chi(2) = 8.612; P = 0.003; OR = 0.174; 95%CI 0.049 - 0.620). No significant correlation was seen with other covariates (P > 0.05). Dendrogram analysis among the three loci showed that the best model consisted of the three sites (P = 0.0270), cross validation consistency: 10/10, and testing balanced accuracy: 0.5120. There may be gene-gene interaction among TET2 (rs7679673, A), LMTK2 (rs6465657, T), and FAM84B (rs12543663, C). CONCLUSIONS: There may be obvious association of FAM84B (rs12543663, C) gene with prostate cancer risk and the stages, and the synergistic effects of TET2 (rs7679673, A), LMTK2 (rs6465657, T) and FAM84B (rs12543663, C) genes may have an association with prostate cancer risk in Chinese population. PMID- 23985254 TI - [Impact of CCND1 A870G polymorphism on acute adverse events in postoperative rectal cancer patients treated with adjuvant concurrent chemoradiotherapy]. AB - OBJECTIVE: The purpose of this study was to investigate the association between single nucleotide polymorphism (SNP) of CCND1 A870G and acute adverse events (AEs) in postoperative rectal cancer patients who received capecitabine-based postoperative chemoradiotherapy (CRT). METHODS: Four hundred patients with stage II and III rectal cancer received postoperative CRT of capecitabine with or without oxaliplatin were accumulated and prostectively studied in this study. The patients were randomly divided into two groups. Two hundred and twenty-eight patients were treated with concurrent capecitabine and radiotherapy (Cap-CRT), and 172 patients were treated with capecitabine and oxaliplatin plus radiotherapy (Cap-Oxa-CRT). Adverse events were graded according to the Common Terminology Criteria for Adverse Events, v. 3.0 (CTCAE v3.0). The genotype of CCND1 A870G in the patients was detected by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analysis. The associations between the SNP and acute AEs were indicated by odds ratios (ORs) and 95% confidence intervals (CIs), which were computed with logistic regression model. RESULTS: A total of 136 patients presented severe AEs. Among them the frequencies of the three genotypes GG, GA and AA were 16.9%, 50.7% and 32.4%, compared with 24.6%, 48.1% and 27.3%, respectively, among the patients without severe AEs. Diarrhea was the most common AE, and severe diarrhea occurred in 109 patients. The frequencies of the three genotypes GG, GA and AA were 15.6%, 47.7% and 36.7% among these patients, compared with 24.4%, 49.5% and 26.1%, respectively, among patients without severe diarrhea. Multivariate logistic regression analysis showed a 1.66-fold increased risk for severe diarrhea in patients with AA genotype (95%CI 1.03 - 2.67, P = 0.038) compared with the cases with GG or GA genotypes. Stratified analysis showed that in the Cap-Oxa-CRT group, patients with AA genotype showed a 2.34 fold increased risk for severe diarrhea (95%CI 1.16 - 4.76, P = 0.018) compared with those with GG or GA genotypes, but in the Cap-CRT group, the SNP was not associated with the risk of severe diarrhea. CONCLUSIONS: The genetic polymorphism of CCND1 A870G might be a potential biomarker for predicting acute AEs in postoperative stage II and III rectal cancer patients treated with adjuvant concurrent chemoradiotherapy of capecitabine and oxaliplatin. PMID- 23985255 TI - [Analysis of therapeutic effect and prognosis in patients with metastatic colorectal cancer and different K-ras status]. AB - OBJECTIVE: To evaluate the correlation of clinical effect and prognosis between patients with metastatic colorectal cancer (mCRC) and different K-ras status. METHODS: The clinical characteristics, chemotherapeutic regimens and survival of 153 mCRC patients with different K-ras status were analyzed retrospectively. RESULTS: The median overall survival (OS) in patients without K-ras mutation were 31.7 months, significantly longer than 21.3 months in the patients with K-ras mutation (P = 0.037). The median progression-free survival (PFS) and OS in patients who received chemotherapy followed by anti-EGFR antibody treatment were 11.5 and 39.3 months, respectively, significantly longer as compared with the PFS and OS in those received chemotherapy in combination with anti-EGFR antibody concomitantly (5.7, P = 0.02, and 28.7 months, P = 0.034, respectively). CONCLUSIONS: K-ras status is a prognostic biomarker for mCRC patients treated with anti-EGFR antibody. The combination settings of anti-EGFR in combination with chemotherapy may improve survival of mCRC patients with wild-type K-ras status. PMID- 23985256 TI - [Expression of molecular markers detected by immunohistochemistry and risk of lymph node metastasis in stage T1 and T2 colorecrectal cancers]. AB - OBJECTIVE: To study the molecular risk factors of lymph node metastasis in stage T1 and T2 colorectal cancers by tissue microarray and immunohistochemistry techniques. METHODS: Two hundred and three patients with stage T1 and T2 colorectal carcinoma who underwent radical surgery from 1999 to 2010 in our department were included in this study. Their clinicopathological data were retrospectively analyzed. Expression of the following 14 molecular markers were selected and assayed by tissue microarray and immunohistochemistry: VEGFR-3, HER2, CD44v6, CXCR4, TIMP-1, EGFR, IGF-1R, IGF-2, IGFBP-1, ECAD, MMP-9, RKIP, CD133, MSI. Chi-squared test and logistic regression were used to evaluate the variables as potential risk factors for lymph node metastasis. RESULTS: The positive expression rates of biomarkers were as following: VEGFR-3 (44.3%), EGFR (30.5%), HER-2 (28.1%), IGF-1R (63.5%), IGF-2 (44.8%), IGFBP-1 (70.9%), ECAD (45.8%), CD44v6 (51.2%), MMP-9 (44.3%), TIMP-1 (41.4%), RKIP (45.3%), CXCR4 (40.9%), and CD133 (49.8%). The positive rate of MSI expression was 22.2%. Both univariate and multivariate analyses showed that VEGFR-3, HER-2, and TIMP-1 were significant predictors of lymph node metastasis. Univariate analysis showed that CD44v6 and CXCR4 were significant significant predictors of lymph node metastasis. CONCLUSIONS: VEGFR-3, HER2 and TIMP-1 are independent factors for lymph node metastasis in stage T1 and T2 colorectal cancers. PMID- 23985257 TI - [Correlation between androgen receptor expression and hepatitis B virus X protein and its clinical significance in hepatocellular carcinoma]. AB - OBJECTIVE: To investigate the expression of androgen receptor (AR) and hepatitis B virus X protein (HBx) in hepatocellular carcinoma (HCC), and analyze the relationship between AR and HBx expressions. METHODS: Tumor tissues and peritumoral tissues of 83 HBV-associated HCC cases were investigated in this study. Fourteen cases of HBV-negative HCC and 13 cases of hemangioma peritumoral tissues were considered as control. AR and HBx mRNA levels were determined by quantitative fluorescence real-time RT-PCR and their protein levels were assayed by Western blot. The expression of AR and HBx proteins in tissues were examined with EnVision immunohistochemical staining. The methylation status of AR promoter was determined using methylation-specific PCR (MSP). RESULTS: Both expression levels of AR mRNA and protein of the peritumoral tissues were significantly higher (0.17) than that of tumor tissues (0.09) in HBV-associated HCC (P < 0.01), but such a difference was not found in HBV-negative HCC (0.06 vs. 0.07, P > 0.05). The level of AR expression in peritumoral tissues was associated with tumor differentiation in HBV-associated HCC. AR mRNA and protein levels of peritumoral tissues in HBV-associated HCC were significantly higher than that in HBV-negative HCC and hemangioma (all P < 0.05). In the tumor tissues, HBV associated HCC had significantly higher AR expression than HBV-negative HCC at mRNA level (P < 0.05), but not at protein level. Spearman rank correlation analysis showed that the AR mRNA or AR protein levels were positively correlated with HBx in both tumor and peritumoral tissues in HBV-associated HCC, but the expressions of AR and HBx were not associated with AR promoter methylation status. The relative expression levels of AR mRNA and protein in the HBV associated peritumoral tissues were negatively correlated with tumor differentiation (r = -0.213, P < 0.05; r = -0.313, P < 0.05), the higher the AR expression, the poorer differentiation. But this correlation of AR mRNA and protein was not shown in the hepatocellular carcinoma tissues. CONCLUSIONS: HBx may enhance AR expression in HBV-associated HCC, but AR promoter demethylation maybe not been involved in its main mechanism. An increased AR expression is probably an early event during the development and progression of HBV-associated HCC, and AR expression in the peritumoral tissue is correlated with HBV associated HCC differentiation. AR may play different roles in HBV-associated HCC and HBV-negative HCC. PMID- 23985258 TI - [Clinical characteristics of lymph node metastasis in Siewert type II adenocarcinoma of the gastroesophageal junction]. AB - OBJECTIVE: To explore the pattern of lymph node metastasis (LNM) in advanced Siewert type II adenocarcinoma of the gastroesophageal junction (AGEJ) in order to properly guide lymphadenectomy. METHODS: From January 2009 to Jun 2011, a total of 86 patients with advanced Siewert type II AGEJ underwent radical esophagogastrectomy by thoracic-abdominal incision and two-field lymphadenectomy. The clinical characteristics, pathologic features, LNM, and influence factor of thoracic metastasis were retrospectively analyzed. RESULTS: LNM was observed in 65 of the 86 cases (75.6%). Simple abdominal lymph node metastasis was observed in 49 of the 86 cases (57.0%), simple thoracic lymph node metastasis was 2.3%, and thoracic-abdominal metastasis was 16.3%, with a significant difference between the abdominal and thoracic metastatic patterns. LNM frequency was found in the lymph node groups No. 3, No. 1, No. 7, No. 110, No. 2 and No. 9 (from the highest to the lowest). The incidences of those lymph node metastases were 46.5%, 41.9%, 17.4%, 14.0%, 10.5%, and 5.8%, respectively. Vascular tumor embolus was the only independent factor for thoracic lymph node metastasis. CONCLUSIONS: Abdominal lymph node metastases of advanced Siewert type II AGEJ mainly occur around the proximal stomach and the coeliac trunk. The metastatic rate of distal stomach and splenic perihilar lymph nodes is low, but metastatic rate of the group No.110 lymph nodes is high. The thoracic lymph node metastasis is only correlated with vascular tumor embolus. PMID- 23985259 TI - [Clinical analysis of 17 cases of gastric small cell carcinoma]. AB - OBJECTIVE: To analyze the clinical data and prognosis of gastric small cell carcinoma (GSCC), summarize recent progress in diagnosis and therapy of this disease reported in the literature, and to provide the theoretical basis for its appropriate treatment. METHODS: Clinicopathological data of 17 patients with pathologically confirmed GSCC, treated in our hospital between 1999 to 2012, were retrospectively reviewed. RESULTS: There were 16 males and 1 female, ranged from 46 to 75 years (mean 64.6 years). The tumor was located in the gastric cardia in 13 cases, three in the gastric fundus, and one in the gastric body. All the 17 patients received surgery and 10 of them received postoperative adjuvant chemotherapy, one received preoperative adjuvant chemotherapy. Thirteen patients were followed up. Among them, two 1ived for 40 months all along, the other 3 cases died of recurrence and extensive metastasis in 6 month after operation. The median survival was 13.0 months. The median survival of the patients with and without lymph node metastasis were 42 months and 13 months, respectively. The median survival time of stage II and III patients were 24 months and 14 months, respectively. CONCLUSIONS: It is difficult to make a definite diagnosis before or during the operation for GSCC. Radical operation could be done according to other gastric cancers and lymph node dissection could be simplified. Postoperative chemotherapy with the same scheme as lung small cell carcinoma may help to improve the outcome and prolong the survival of the patients. PMID- 23985260 TI - [Trastuzumab in combination with chemotherapy versus chemotherapy alone for first line treatment of HER2-positive advanced gastric or gastroesophageal junction cancer: a Phase III, multi-center, randomized controlled trial, Chinese subreport]. AB - OBJECTIVE: To evaluate the efficacy and safety of trastuzumab in combination with chemotherapy versus chemotherapy alone in the first-line treatment of HER-2 positive advanced gastric or gastro-oesophageal junction cancer. METHODS: Fifteen Chinese research centers are involved in the BO18255 (ToGA) study. Patients with gastric or gastro-oesophageal junction cancer were eligible for inclusion if their tumor showed overexpression of HER-2 protein by immunohistochemistry +++ or FISH-positive. Patients were randomly assigned in a 1:1 ratio to receive a chemotherapy regimen consisting of capecitabine or 5-FU plus cisplatin or chemotherapy in combination with intravenous trastuzumab. The primary endpoint was overall survival. RESULTS: Eighty-five Chinese patients were enrolled in this study, of whom 84 were included in the primary analysis: trastuzumab plus chemotherapy (FP/H) (n = 36) and chemotherapy alone (FP)(n = 48). The median follow-up was 15.2 months in the FP/H group and 14.2 months in the FP group. The median survival time was 12.6 months in the FP/H group compared with 9.7 months in the FP group [hazard ratio 0.72, 95%CI (0.40; 1.29)]. Grade 3/4 adverse events were higher in the FP/H(63.9%)than FP (47.9%) groups, including neutropenia, vomiting and nausea. Two mild cardiac adverse events occurred in the FP/H group. Severe adverse events occurred in 3 cases of both two groups, respectively. CONCLUSIONS: Addition of trastuzumab to chemotherapy is well tolerated and shows improved survival in Chinese patients with advanced gastric or gastro-oesophageal junction cancer. These results are consistent with the results of ToGA whole population trial. Trastuzumab in combination with chemotherapy can be considered as a new option for patients with HER-2-positive advanced gastric or gastro oesophageal junction cancer. PMID- 23985261 TI - [Effect of second-line treatment with capecitabine and thalidomide in patients with advanced pancreatic cancer]. AB - OBJECTIVE: This study investigates the efficacy and tolerability of capecitabine plus thalidomide in patients with advanced pancreatic cancer who previously underwent gemcitabine-based therapy. METHODS: Sixty-one patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem containing regimen were enrolled. The patients were randomly divided into two groups. One group (31 patients) was treated with capecitabine alone, and another group was treated with capecitabine plus thalidomide. Capecitabine was administered orally twice a day at a dose of 1, 250 mg/m(2) for 14-day followed by 7-day rest and oral thalidomide 100 mg was given daily without interruption until disease progression or occurrence of unacceptable toxicity. RESULTS: The PFS was 2.8 months (95%CI 2.4 - 3.2) vs. 3.1 months (95%CI 2.6-3.6, P < 0.05) and the OS was 6.1 months (95%CI 5.3 - 6.9) vs. 6.3 months (95%CI 5.2 - 7.4, P = 0.426). In the capecitabine alone group, one patient experienced a partial response (PR), 10 patients showed stable disease (SD) and 20 patients had progressive disease (PD). The another group, two patients experienced a partial response (PR), 11 patients SD, and 17 patients PD. The disease control rates were 35.5% and 43.3%, respectively. The major adverse reaction in the two groups was grade 3 diarrhea. CONCLUSION: Capecitabine plus thalidomide regimen is marginally effective and well tolerated in the second-line setting in patients with gemcitabine-refractory advanced pancreatic cancer. PMID- 23985262 TI - [Diagnosis and treatment of primary colorectal non-Hodgkin's lymphoma: analysis of 52 cases]. AB - OBJECTIVE: To summarize and analyze the diagnosis, clinical features and therapy of primary colorectal non-Hodgkin's lymphoma (NHL). METHODS: The clinicopathological data of 52 patients with primary colorectal NHL diagnosed and treated in our department from January 2000 to January 2010 were reviewed and analyzed retrospectively in this study. RESULTS: This group of patients was composed of 45 cases of B cell and 7 T cell lymphomas, including 33 males and 19 females, with a male to female ratio of 1.7:1, and the age at diagnosis was 16 - 74 years old, with a median age of 50 years. The ileocecal region was most frequently involved site, acounted for 48.1%. The common symptoms encountered were abdominal pain (66.7%), diarrhea (15.6%), blood stool (24.4%), and body weight loss (8.9%). All patients were eventually diagnosed by histopathology, and the DLBCL subtype took up 64.4%. Among the 45 cases of B cell subtype, 33 cases (73.3%) were of early stage (IE and IIE confirmed), and the 5-year survival rate was 78.1%, while those of stage IIIE and IVE comprised 26.7%, with a 5-year survival rate of 45.5% (P < 0.05). The 5-year survival rate of all patients was 71.1%. Surgery was employed in 36 cases, and 9 patients received chemotherapy alone. Radical surgery could significantly increase the patients' overall survival rate, as compared with the chemotherapy alone group and palliative surgery group (P < 0.05). CONCLUSIONS: Colorectal non-Hodgkin's lymphoma is a rare malignancy of the gastrointestinal tract. B cell type, male predominance and DLBCL subtype are most encountered manifestations in clinics. Multi-modality management with radical surgical resection of the primary lesion followed by standard chemotherapy, affords better local disease control, and a better survival outcome. Early detection and tailored immunotherapy can obviously prolong the long-term survival time. PMID- 23985263 TI - [Comparison of the efficacy of three neoadjuvant therapy regimens on locally advanced cervical cancer]. PMID- 23985264 TI - [A missense SNP in the codon of ADD1 phosphorylation site associated with non cardia gastric cancer susceptibility in a Chinese population]. AB - OBJECTIVE: This study investigated the association between a missense SNP in the codon of ADD1 phosphorylation site and the susceptibility of non-cardia gastric cancer in a Chinese population. METHODS: PhosphoSitePlus and dbSNP database were combined to discover missense SNPs in the codon of phosphorylation site. Then, we genotyped the missense SNP in 1, 998 cases with non-cardia gastric cancer and 2, 008 cancer-free controls of Chinese descent. Analysis was conducted by using Logistic model adjusted by gender and age. RESULTS: The rs4963 in the codon of ADD1 phosphorylation site was found. The frequencies of the 3 rs4963 genotypes, CC, CG, GG, among controls were 25.2%, 50.4%, and 24.4%, respectively, among patients were 20.1%, 50.6%, and 29.3%, respectively. Compared with CC genotype, the rs4963 CG genotype and GG genotype significantly increased the risk of non cardia gastric cancer with the odds ratios being 1.24 (95%CI: 1.06 ~ 1.46, P = 0.008) and 1.49 (95%CI: 1.25 ~ 1.78, P < 0.001), respectively. CONCLUSIONS: Fnnctional polymorphism in the phosphorylation site of ADD1 (rs4963) may influence the susceptibility of non-cardia gastric cancer. PMID- 23985265 TI - [Chinese expert consensus on the molecular-targeted therapy for HER-2-positive advanced gastric cancer]. PMID- 23985266 TI - Multiple myeloma in a patient under ustekinumab--are they related? PMID- 23985267 TI - An unexpected case of Ramsay Hunt syndrome: case report and literature review. AB - BACKGROUND: Ramsay Hunt Syndrome (RHS) is a rare, severe complication of varicella zoster virus (VZV) reactivation in the geniculate ganglion. Facial paralysis is one of the features and without treatment, it fully recovers in as little as 20% of cases; this is much improved if treatment is started within 72 hours. This case is noteworthy in that coexistence of facial palsy with cervical dermatome involvement by VZV is not typical of RHS. Yet, it has been reported before. CASE PRESENTATION: A 54 year old Caucasian woman presented with right ear discomfort, difficulty hearing and a vesicular rash along the pinnae, 8 days after the eruption of a similar rash in the right C2-C4 dermatomes. 2 days later, she awoke with a partial right-sided facial paralysis, which improved with treatment (valacyclovir and prednisone). CONCLUSIONS: This case is most pertinent to Family Practice, Otolaryngology and Neurology. It highlights the possible co existence of RHS with cervical VZV reactivation and encourages physicians to monitor for this complication even before geniculate ganglion reactivation occurs. RHS is a rare disease that can present with vague symptoms. A high index of suspicion and close follow up are essential. Early intervention with antivirals and corticosteroids has shown significantly improved outcomes in these patients. PMID- 23985268 TI - Properties of the newly isolated extracellular thermo-alkali-stable laccase from thermophilic actinomycetes, Thermobifida fusca and its application in dye intermediates oxidation. AB - Laccases are diphenol oxidases that have numerous applications to biotechnological processes. In this study, the laccase was produced from the thermophilic actinomycetes, Thermobifida fusca BCRC 19214. After 36 h of fermentation in a 5-liter fermentor, the culture broth accumulated 4.96 U/ml laccase activity. The laccase was purified 4.64-fold as measured by specific activity from crude culture filtrate by ultrafiltration concentration, Q Sepharose FF and SephacrylTM S-200 column chromatography. The overall yield of the purified enzyme was 7.49%. The molecular mass of purified enzyme as estimated by SDS-PAGE and by gel filtration on SephacrylTM S-200 was found to be 73.3 kDa and 24.7 kDa, respectively, indicating that the laccase from T. fusca BCRC 19214 is a trimer. The internal amino acid sequences of the purified laccase, as determined by LC-MS/MS, had high homology with a superoxide dismutase from T. fusca YX. Approximately 95% of the original activity remained after treatment at 50 degrees C for 3 h. and approximately 75% of the original activity remained after treatment at pH 10.0 for 24 h. This laccase could oxidize dye intermediates, especially 2,6-dimethylphenylalanine and p-aminophenol, to produce coloring. This is the first report on laccase properties from thermophilic actinomycetes. These properties suggest that this newly isolated laccase has potential for specific industrial applications. PMID- 23985269 TI - Ecological priming: convergent evidence for the link between ecology and psychological processes. AB - This commentary describes the use of ecological priming methods to address the limitations of the correlational research discussed in the target article. We provide examples from our own work on cultural tightness-looseness to illustrate how we can bring ecological and societal conditions into the laboratory in order to study the impact of ecological threats on psychological processes experimentally. PMID- 23985270 TI - Climato-economic habitats support patterns of human needs, stresses, and freedoms. AB - This paper examines why fundamental freedoms are so unevenly distributed across the earth. Climato-economic theorizing proposes that humans adapt needs, stresses, and choices of goals, means, and outcomes to the livability of their habitat. The evolutionary process at work is one of collectively meeting climatic demands of cold winters or hot summers by using monetary resources. Freedom is expected to be lowest in poor populations threatened by demanding thermal climates, intermediate in populations comforted by undemanding temperate climates irrespective of income per head, and highest in rich populations challenged by demanding thermal climates. This core hypothesis is supported with new survey data across 85 countries and 15 Chinese provinces and with a reinterpretative review of results of prior studies comprising 174 countries and the 50 states in the United States. Empirical support covers freedom from want, freedom from fear, freedom of expression and participation, freedom from discrimination, and freedom to develop and realize one's human potential. Applying the theory to projections of temperature and income for 104 countries by 2112 forecasts that (a) poor populations in Asia, perhaps except Afghans and Pakistanis, will move up the international ladder of freedom, (b) poor populations in Africa will lose, rather than gain, relative levels of freedom unless climate protection and poverty reduction prevent this from happening, and (c) several rich populations will be challenged to defend current levels of freedom against worsening climato-economic livability. PMID- 23985271 TI - Subtle variation in ambient room temperature influences the expression of social cognition. AB - Social signaling models predict that subtle variation in climatic temperature induces systematic changes in expressed cognition. An experiment showed that perceived room temperature was associated with variability in self-descriptions, social reactions of others, and desiring differing types of social networks. The findings reflect the tendency to inflate capacity demonstrations in warmer climates as a result of the social networking opportunities they enable. PMID- 23985273 TI - Development, preimaginal phases and adult sensillar equipment in Aganaspis parasitoids (Hymenoptera: Figitidae) of fruit flies. AB - Aganaspis daci and Aganaspis pelleranoi (Hymenoptera: Figitidae) are important parasitoids of fruit flies. Here we studied, with light and scanning electron microscopy, aspects of their morphology that could help with plans to mass rear and thus contribute to improved pest control (preimaginal phases) and to shed light on parasitoid-pest relationships (sensillar equipment). The two species present a stalked egg, eucoiliform first and second-instar larvae and hymenopteriform third instar and mature larvae. The first instar presents tegumental differentiations in the mesoma and first metasomal segment in A. daci, but not in A. pelleranoi, while unlike other figitids, neither species displays setae in the mesosomal processes. Second and third instar and mature larvae present tegumental differentiations in A. daci, but not in A. pelleranoi. The moniliform (female) and filiform (male) antennae of A. daci and A. pelleranoi harbor seven types of sensilla, four of them (sensilla campaniformia, sensilla coeloconica type II, and two types of sensilla trichoidea) described here for the first time in Cynipoidea. The largest sensilla were the multiporous placoid sensilla, which were smaller and more numerous in A. pelleranoi. Species also differed to some extent in morphology of sensilla coeloconica. Observations on the ovipositor revealed the presence of coeloconic sensilla on Valva I in both species. PMID- 23985272 TI - Mst1 and Mst2 kinases: regulations and diseases. AB - The Hippo signaling pathway has emerged as a critical regulator for organ size control. The serine/threonine protein kinases Mst1 and Mst2, mammalian homologs of the Hippo kinase from Drosophila, play the central roles in the Hippo pathway controlling the cell proliferation, differentiation, and apoptosis during development. Mst1/2 can be activated by cellular stressors and the activation of Mst1/2 might enforce a feedback stimulation system to regulate oxidant levels through several mechanisms, in which regulation of cellular redox state might represent a tumor suppressor function of Mst1/2. As in Drosophila, murine Mst1/Mst2, in a redundant manner, negatively regulate the Yorkie ortholog YAP in multiple organs, although considerable diversification in the pathway composition and regulation is observed in some of them. Generally, loss of both Mst1 and Mst2 results in hyperproliferation and tumorigenesis that can be largely negated by the reduction or elimination of YAP. The Hippo pathway integrates with other signaling pathways e.g. Wnt and Notch pathways and coordinates with them to impact on the tumor pathogenesis and development. Furthermore, Mst1/2 kinases also act as an important regulator in immune cell activation, adhesion, migration, growth, and apoptosis. This review will focus on the recent updates on those aspects for the roles of Mst1/2 kinases. PMID- 23985274 TI - Primary esophageal cancer: heterogeneity as potential prognostic biomarker in patients treated with definitive chemotherapy and radiation therapy. AB - PURPOSE: To determine the association between tumor heterogeneity, morphologic tumor response, and overall survival in primary esophageal cancer treated with chemotherapy and radiation therapy (CRT). MATERIALS AND METHODS: After an institutional review board waiver was obtained, contrast material-enhanced computed tomographic (CT) studies in 36 patients with stage T2 or greater esophageal tumors who underwent contrast-enhanced CT before and after CRT between 2005 and 2008 were analyzed in terms of whole-tumor texture, with quantification of entropy, uniformity, mean gray-level intensity, kurtosis, standard deviation of the histogram, and skewness for fine to coarse textures (filters 1.0-2.5, respectively). The association between texture parameters and survival time was assessed by using Kaplan-Meier analysis and a Cox proportional hazards model. Survival models involving texture parameters and combinations of texture and morphologic response assessment were compared with morphologic assessment alone by means of receiver operating characteristic (ROC) analysis. RESULTS: Posttreatment medium entropy of less than 7.356 (median overall survival, 33.2 vs 11.7 months; P = .0002), coarse entropy of less than 7.116 (median overall survival, 33.2 vs 11.7 months; P = .0002), and medium uniformity of 0.007 or greater (median overall survival, 33.2 vs 11.7 months; P = .0002) were associated with improved survival time. These remained significant prognostic factors after adjustment for stage and age: entropy (filter 2.0: hazard ratio [HR] = 5.038, P = .0004; filter 2.5: HR = 5.038, P = .0004) and uniformity (HR = 0.199, P = .0004). Survival models that included a combination of pretreatment entropy and uniformity with maximal wall thickness assessment, respectively, performed better than morphologic assessment alone (area under the ROC curve, 0.767 vs 0.487 [P = .00005] and 0.802 vs 0.487 [P = .0003]). CONCLUSION: Posttreatment texture parameters are associated with survival time, and the combination of pretreatment texture parameters and maximal wall thickness performed better in survival models than morphologic tumor response alone. PMID- 23985275 TI - Response assessment in pediatric rhabdomyosarcoma: can response evaluation criteria in solid tumors replace three-dimensional volume assessments? AB - PURPOSE: To investigate (a) interobserver variability for three-dimensional (3D) (based on European Pediatric Soft-Tissue Sarcoma Study Group [EpSSG] guidelines) and one-dimensional (1D) (based on Response Evaluation Criteria in Solid Tumors [RECIST]) response assessments, (b) intermethod variability between EpSSG guidelines and RECIST, and (c) clinically relevant consequences of interobserver and intermethod variability in pediatric patients with rhabdomyosarcoma. MATERIALS AND METHODS: The study was approved by the Academic Medical Center Ethics Committee and the Great Ormond Street Hospital Ethics Committee; both committees waived the requirement for informed consent because of the retrospective nature of the study. Data were analyzed from 124 consecutive male and female children and young adults (age range, 1-18 years) with rhabdomyosarcoma at two institutions (1999-2009) with relevant imaging studies. Tumors were measured by two radiologists (1D and 3D measurements) at diagnosis and after induction chemotherapy. Interobserver variability was analyzed by using three different tests, and the intermethod variation was calculated. RESULTS: Sixty-four eligible patients were included (median age, 4.6 years). Agreement between observers for EpSSG guidelines and RECIST was moderate (kappa = 0.565 and 0.592, respectively); interobserver variation led to different potential treatment decisions in nine (14%) and 11 (17%) of the 64 patients, respectively. Comparison of EpSSG guidelines and RECIST resulted in 13 discrepant response classifications (20%), which were equally distributed (under- and overestimation of response) and led to consequences for treatment choice in five patients (8%). CONCLUSION: EpSSG guidelines and RECIST are not interchangeable; neither technique demonstrated superiority in this study. These findings should be taken into account in future study protocol design. Online supplemental material is available for this article. PMID- 23985276 TI - Serial cranial US for detection of cerebral sinovenous thrombosis in preterm infants. AB - PURPOSE: To report the incidence of cerebral sinovenous thrombosis (CSVT) in a prospective cohort of preterm infants with a gestational age of less than 29 weeks. MATERIALS AND METHODS: The local medical ethics review board approved this study, and written parental consent was obtained. Preterm infants with a gestational age of less than 29 weeks who were admitted to the neonatal intensive care unit were prospectively studied with cranial ultrasonography (US). The scanning protocol included visualization with color Doppler imaging of the superior sagittal sinus and transverse sinuses through the anterior (8.5-MHz probe) and mastoid (13-MHz probe) fontanelles. When feasible, magnetic resonance imaging was performed to confirm cranial US-diagnosed CSVT. The differences between preterm infants with and those without CSVT were analyzed by using Mann Whitney tests for continuous variables and Fisher exact tests for categorical data. RESULTS: Cranial US was used to document CSVT in 11 of 249 preterm infants with a gestational age of less than 29 weeks. Transverse sinuses were most frequently affected (in all 11 patients with CSVT). All infants with CSVT were asymptomatic. Postnatal age at diagnosis ranged from 5 to 34 days. The mean gestational age was significantly lower in infants with CSVT (25.9 weeks vs 26.8 weeks, P = .038). Of the risk factors studied, only duration of mechanical ventilation was associated with CSVT; it was significantly longer in the CSVT group. CONCLUSION: Systematic serial cranial US of infants with a gestational age of less than 29 weeks showed a remarkably high incidence of CSVT of 4.4%. Cranial US including color Doppler imaging with scans obtained through the mastoid fontanelle can depict CSVT at an early stage. Treatment of this possibly important condition needs attention. PMID- 23985277 TI - FDG PET uptake as a predictor of pain response in palliative radiation therapy in patients with bone metastasis. AB - PURPOSE: To evaluate the relationship between fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) maximum standardized uptake value (SUV(max)) and pain response to radiation therapy (RT) in patients with bone metastasis. MATERIALS AND METHODS: Institutional ethical board approval for the study was obtained, with informed consent, for this prospective study. Thirty-one patients with metastatic bone pain who underwent FDG PET/computed tomography before RT were included. Patients were diagnosed with lung (n = 16), breast (n = 7), stomach (n = 2), and head and neck cancers (n = 3), as well as unknown primary tumor (n = 3). Eighty-five painful metastatic locations with FDG PET scans geographically corresponding to 40 treatment fields were evaluated. Pain scores using visual analog scale or faces pain rating scale and SUV(max) at each location were recorded. All patients were treated with a single fraction 8 Gy RT. Pain scores after RT were assessed at weeks 2, 4, 8, 12, 16, 20, and 24. The pretreatment pain scores and pain response to RT were compared with FDG PET SUV(max) of each location. Pearson correlation, independent t test, one-way analysis of variance, and chi(2) tests were used for statistical analysis. RESULTS: Median SUV(max) and initial pain scores for all locations were 7.2 (range, 1.5-22.5) and 6 (range, 2-8), respectively. Median follow-up time was 24 (range, 3-112) weeks. Median SUV(max) was 4.5 (range, 3.1-7.3), 4.75 (range, 1.5 10.3), 8.8 (range, 5.2-11.9), and 12.1 (range, 7-22.5) for pretreatment pain scores of 2, 4, 6, and 8, respectively. SUV(max) was correlated with pretreatment pain scores (P < .0001). SUV(max) and pretreatment pain scores were also significantly associated with pain response to RT. Median SUV(max) for locations with complete response, partial response, pain progression, and indeterminate response was 5.2, 9.75, 10.8, and 6.4, respectively (P <= .001). CONCLUSION: FDG PET SUV(max) correlated with initial pain severity and pain response to RT and can be used as a predictive factor for treatment response in patients with painful bone metastasis treated with palliative RT. PMID- 23985278 TI - Pulmonary ultrashort echo time 19F MR imaging with inhaled fluorinated gas mixtures in healthy volunteers: feasibility. AB - PURPOSE: To perform static breath-hold fluorine 19 ((19)F) three-dimensional (3D) ultrashort echo time (UTE) magnetic resonance (MR) imaging of the lungs in healthy volunteers by using a mixture of 79% perfluoropropane (PFP) and 21% O2. MATERIALS AND METHODS: This study protocol was approved by the local research ethics board and by Health Canada. All volunteers provided written informed consent. Ten healthy volunteers underwent MR imaging at 3.0 T. Fluorine 19 3D UTE MR images were acquired during a 15-second breath hold according to one of two breathing protocols: protocol A, a 1-L inhalation of a mixture of 79% PFP and 21% O2, and protocol B, continuous breathing from a 5-L bag of a mixture of 79% PFP and 21% O2 followed by a 1-L inhalation of the same PFP-O2 mixture from a separate bag and a subsequent breath hold. The signal-to-noise ratio (SNR) was measured in the three most central image sections and was compared between breathing protocols by using an unpaired t test. RESULTS: Overall, the SNR was significantly greater for breathing protocol B (continuous breathing) than for breathing protocol A (single breath) (P = .018). The mean SNRs were 18 +/- 6 (standard deviation) and 32 +/- 6 for images acquired by using breathing protocols A and B, respectively. Breathing protocol B improves SNR by "washing out" the air from the lungs and increasing the PFP concentration prior to (19)F imaging. CONCLUSION: This study demonstrates the feasibility of (19)F 3D UTE static breath-hold MR imaging of human lungs with inert fluorinated gases. PMID- 23985279 TI - Management of infants born to women infected with hepatitis B in the military healthcare system. AB - BACKGROUND: Hepatitis B virus (HBV) is endemic worldwide. Given significant rates of infectivity, all infants born to Hepatitis B surface antigen positive mothers need to receive treatment at birth, immunization and post-vaccination serologic testing. However, not all infants complete these requirements. FINDINGS: We performed a retrospective review of the management of infants born to Hepatitis B infected mothers at two large military hospitals in the United States that use a global electronic medical record to track patient results. We then compared these results to those recently published by the National Perinatal Hepatitis B Prevention Program (PHBPP), which does not include hospitals in the United States Military Healthcare System. Our results show that although all infants were managed appropriately at birth and immunization rates were very high, post vaccination follow-up testing rates were much lower than those seen in centers participating in the PHBPP. The rates of post vaccination serological testing were significantly higher for infants born to Hepatitis B e antigen positive mothers and those referred to a pediatric infectious disease specialist. CONCLUSIONS: Despite use of a global electronic medical record in the United States Military Healthcare System, management of HBV-exposed infants does not always follow recommended guidelines. These infants could benefit from a more systematic method of follow-up, similar to the PHBPP, to ensure HBV serologic testing is obtained after the vaccination series is complete. PMID- 23985280 TI - Cognitive rationalizations for tanning-bed use: a preliminary exploration. AB - OBJECTIVES: To examine construct and predictive utility of an adapted cognitive rationalization scale for tanning-bed use. METHODS: Current/former tanning bedusing undergraduate students (N = 216; 87.6% females; 78.4% white) at a large northeastern university participated in a survey. A cognitive rationalization for tanning-bed use scale was adapted. Standardized self-report measures of past tanning-bed use, advantages of tanning, perceived vulnerability to photoaging, tanning-bed use dependence, and tanning-bed use intention were also administered. RESULTS: The cognitive rationalization scale exhibited strong construct and predictive validity. Current tanners and tanning-bed-use-dependent participants endorsed rationalizations more strongly than did former tanners and not-tanning bed-use-dependent participants respectively. CONCLUSIONS: Findings indicate that cognitive rationalizations help explain discrepancy between inconsistent cognitions. PMID- 23985282 TI - Antecedents of university students' hookah smoking intention. AB - OBJECTIVES: To examine antecedents of university students' intention to smoke hookah using the Theory of Reasoned Action (TRA) as a conceptual framework. METHODS: We sampled students at a US university using 3 strategies: intercept interviews (N = 62) with hookah smokers and nonsmokers; 3 focus groups (smokers only N = 21); and online survey (N = 369). We evaluated TRA constructs regarding intention to smoke hookah and used factor analysis to identify antecedent domains concerning attitudes toward hookah smoking. RESULTS: Three domains emerged: benefits, negative health effects, meeting expectations. Attitudes toward hookah smoking were more positively correlated with intention than was subjective norm. CONCLUSIONS: Benefits and attitudes were strong determinants of future intention. PMID- 23985281 TI - Mechanisms linking socioeconomic disadvantage and BMI in smokers. AB - OBJECTIVES: To evaluate a conceptual model of the psychosocial pathways linking socioeconomic status and body mass index (BMI) among smokers. METHODS: A latent variable modeling approach was used to evaluate the interrelationships among socioeconomic status, perceived neighborhood disadvantage, social support, negative affect, and BMI among smokers recruited from the Houston metropolitan area (N = 424). RESULTS: A total of 42.4% of participants were obese, with the highest prevalence of obesity among Latinos followed by African Americans. Across all racial/ethnic groups, perceived neighborhood disadvantage, social support, and negative affect functioned as pathways linking socioeconomic status and BMI. CONCLUSIONS: Findings indicate the need for interventions that target obesity among socioeconomically disadvantaged smokers and provide potential intervention targets for the prevention and treatment of obesity. PMID- 23985283 TI - Teasing apart the effects of cognition, stress, and depression on health. AB - OBJECTIVE: To test whether cognitive vulnerability could explain the link between depression and poor health. METHODS: A 4-week longitudinal design was used to examine health problems (eg, diabetes), health behaviors (eg, smoking), depressive symptoms, cognitive vulnerability, and life stress in a sample of 154 undergraduates. RESULTS: Contrary to hypotheses, depressive symptoms, but not cognitive vulnerability, were associated with health problems. However, as predicted, cognitive vulnerability was a better predictor of prospective changes in specific health behaviors than were depressive symptoms. Unexpectedly, life stress was the best predictor of prospective changes in specific health behaviors. CONCLUSIONS: These results are among the first to show that the factors associated with health problems are different than those associated with specific health behaviors. PMID- 23985284 TI - Social support among immigrant Latino men: a validation study. AB - OBJECTIVE: To explore the factor structure of the Index of Sojourner's Social Support (ISSS) within a sample of Spanish-speaking immigrant Latino men. METHODS: We explored the factor structure and calculated correlations to examine associations between the ISSS subscales and self-esteem, mastery, and depression. RESULTS: Mean age of the 244 participants was 26.9 years old and most were from Mexico, had less than high school educational attainment, and worked in construction. The ISSS did not perform as well as expected. CONCLUSIONS: Although the ISSS may prove useful as we begin to conceptualize the role and meaning of social support within the context of immigration, more research is needed to develop meaningful measures of constructs among immigrant Latinos in the United States. PMID- 23985285 TI - Associations of menthol use with motivation and confidence to quit smoking. AB - OBJECTIVES: To examine associations of menthol cigarette use with motivation and confidence to quit smoking, and potential moderation by race, among adult current smokers (N = 1067; 85% White, 15% Black). METHODS: Regression analyses, adjusted for sociodemographics and tobacco dependence, examined associations of menthol use with motivation and confidence to quit smoking with and without an interaction term for race. RESULTS: Main effects were not significant; however, there was a significant interaction for confidence to quit smoking (p = .02). Stratified analyses indicated that Black menthol users were more confident about quitting than Black non-menthol users (p = .01). CONCLUSIONS: Given their relatively lower quit rates as cited in previous literature, Black menthol users appear overly confident about their ability to quit smoking. PMID- 23985286 TI - Physical activity and self-efficacy in normal and over-fat children. AB - OBJECTIVE: To examine the independent and combined association of self-efficacy and fatness with physical activity in 5(th) grade children. METHODS: Participants were 281 students (10.4 +/- 0.7 years). Physical activity was assessed using a self-report question. Self-efficacy to be physically active was assessed using a 5-point scale. Body fatness was assessed by bioelectrical impedance. Descriptive statistics, ANOVA, and t-tests were used. RESULTS: There were no differences in reported days of physical activity between boys and girls, and normal-fat and over-fat children. However, children with high self-efficacy participated in significantly more physical activity compared to their low self-efficacy counterparts (3.4 +/- 2.0 days vs. 5.4 +/- 1.8 days, respectively, p < .001). CONCLUSIONS: Only physical activity self-efficacy was related to physical activity, fatness was not. PMID- 23985287 TI - Demographic trends in alcohol use: the value of a surveillance system. AB - OBJECTIVE: To determine trends in alcohol consumption in South Australia. METHODS: Data collection from 2003 to 2011. Time series trends overall and by age, sex, education level, and income by proportion of drinkers, mean number of drinks, drinking less than one day, drinking on six or more days per week, lifetime alcohol risk and injury risk. RESULTS: An overall decline in the proportion of alcohol drinkers, an increase in the overall proportion of adults drinking alcohol less than one day per week. No overall change in mean number of drinks consumed per day but with differences by demographic groups. CONCLUSION: This study presents multiple consumption-related variables over time and has highlighted important demographic variations in alcohol consumption. PMID- 23985288 TI - Reactions of adult smokers and former smokers to current US warning labels. AB - OBJECTIVE: To assess current and former smokers' reactions to US warning labels as a baseline for comparison to new labels. METHODS: The mail-in Consumer-Styles survey was sent to a representative sample of US adult consumers in 2010 (N = 10,328). RESULTS: Among current smokers, 51.5% (95% CI: 47.5-55.5) reported that they had 'never/rarely' seen or looked closely at the labels in the past 30 days. Current smokers (91.1%) reported that warning labels never stopped them from having a cigarette (95% CI: 89.1-93.1) and that the labels had no effect on their likelihood of quitting (75.5%; 95% CI: 71.6-79.4). CONCLUSIONS: Current warning labels do not make smokers think about the risks of smoking or have an effect on their likelihood of forgoing cigarettes or quitting. PMID- 23985290 TI - Screening mammography behavior and barriers in Singaporean Asian women. AB - OBJECTIVES: To determine attitudes of Singaporean women toward screening mammography and its potential barriers. METHODS: The study included 208 cancer free Asian women. Data about mammogram knowledge, motivators, barriers, and adherence to surveillance mammography were obtained. RESULTS: Only 37% underwent regular mammography. Lack of time (56.7%) and cost (54.3%) were the most commonly cited barriers. On multivariate analysis, being Chinese, having higher education, mammography knowledge, positive motivator scores, and receiving reminders were predictors to regular mammography. Participants were only willing to pay ~US$24 for mammogram compared to subsidized cost of ~US$40. Older Malays were less likely than Chinese and Indians to undergo regular mammography (p = .003). CONCLUSIONS: Surveillance adherence may be improved by lowering cost and increasing public education. PMID- 23985289 TI - Correlates of physician trust among rural older adults with diabetes. AB - OBJECTIVES: To examine the demographic, health and diabetes management correlates of physician trust in a rural, multiethnic population with diabetes. METHODS: 563 older (>= 60 years) African American, American Indian and White adults completed in-home surveys, including the 11-item General Trust in Physicians Scale. RESULTS: Higher trust scores were seen among: older (>75) participants (p < .01), those with fewer (<3) chronic health conditions (p < .01), and those who adhered to physical activity (p < .05) and dilated eye exam (p < .01) guidelines; the latter remained significant (eye exam, p = .019) or approached significance (physical activity, p = .051) after adjustment for potential confounders. CONCLUSIONS: Physician trust may influence patient adherence to diabetes management recommendations. Efforts should be made to build trust in the patient provider relationship to enhance patient outcomes. PMID- 23985291 TI - The association between neighborhood social capital and cancer screening. AB - OBJECTIVES: To examine the association between social capital and adherence to cancer screening exams. METHODS: Data from a population-based survey assessed perceived neighborhood social capital as well as cancer screening behavior. We analyzed the influence of social capital on adherence to screening guidelines for cervical, breast, and colorectal cancer. RESULTS: Data from 2668 adults documented that those with greater perceived neighborhood social capital were more likely to be screened for cancer. The effect was strongest for colorectal cancer and weakest for cervical cancer. CONCLUSIONS: Research on understanding the effect of the neighborhood social environment on efforts related to cancer screening behavior may be helpful for increasing cancer screening rates. PMID- 23985293 TI - A mixed-methods approach to targeting college students' dairy behaviors. AB - OBJECTIVES: To assess dairy consumption among students and uncover female students' self-efficacy, perceived benefits and barriers of not consuming dairy, and cues that prompt behavior change. METHODS: A survey (N = 6499) identified the approximate dairy servings consumed on a daily basis and 28 participants shared their perceptions of dairy foods in 3 focus groups. RESULTS: Students do not consume enough calcium in their daily diets and do not have knowledge about serving size or the importance of dairy consumption. CONCLUSIONS: Students preferred health campaigns specific to the student population. Messages that focus on overall health and substitution of unhealthy behaviors with healthier behaviors may encourage behavior change. PMID- 23985294 TI - Multi-level barriers to obtaining mammograms for women with mobility limitations: post workshop evaluation. AB - OBJECTIVES: To assess the barriers and facilitators to mammogram use in middle aged women with mobility limitations who had completed an educational workshop, Promoting Access to Health Service (PATHS), on clinical preventive services. METHODS: Women aged 40 to 64 with mobility impairments who reported not receiving a mammogram in the last 2 years were randomly assigned to a PATHS workshop and received follow-up monthly phone call interviews over 6 months. RESULTS: Individual (eg, comorbidities, family responsibilities), interpersonal (eg, unclear provider communication, negative history), and environmental (eg, healthcare availability, insurance coverage, finances) factors were identified as unsolved barriers and potential facilitators (eg, reminders, physical proximity), to obtaining a mammogram. CONCLUSIONS: A multi-level intervention approach is required to promote mammogram use by women with disabilities. PMID- 23985292 TI - Understanding the durability of a fire department wellness program. AB - OBJECTIVES: To understand the influences associated with durability and diffusion of benefits of a fire service wellness program. METHODS: Qualitative assessment of group interviews. RESULTS: Five years following a controlled worksite wellness trial, behavioral improvements were durable and had diffused to control participants. These findings were associated with firefighters' team orientation, enacted healthy norms and competitiveness regarding the results of annual health assessments. The original intervention trial appeared to initiate individual change that coalesced into group effects. Secondary influences included increasing public awareness about health, newly hired younger firefighters, and a modicum of administrative support. Culture shift was achieved at the workplace. CONCLUSIONS: Although the fire service is a unique occupation, these findings suggest general strategies to achieve durable positive health change in other occupational settings. PMID- 23985295 TI - Increased serum apelin-12 and lipid profile in patients with and without psoriasis. PMID- 23985296 TI - Echocardiography in newly diagnosed atrial fibrillation patients: a systematic review and economic evaluation. AB - OBJECTIVE: To investigate the clinical effectiveness and cost-effectiveness of transthoracic echocardiography (TTE) in all patients who are newly diagnosed with atrial fibrillation (AF). DESIGN: Narrative synthesis reviews were conducted on the prognostic and diagnostic accuracy of TTE for, and prevalence of, pathologies in patients with AF. Databases were searched from inception. MEDLINE searches were conducted from March to August 2010, and reference lists of articles checked. There were 44 diagnostic accuracy studies, five prognostic studies, and 16 prevalence studies accepted into the review. Given the complexity of the many pathologies identified by TTE, the variety of potential changes to clinical management, and paucity of data, the model focused on changes to oral anticoagulation (OAC). The mathematical model assessed the cost-effectiveness of TTE for patients with AF who were not routinely given OAC, assuming, if left atrial abnormality was detected, that the higher risk of stroke warranted OAC; this meant that patients with a CHADS2 (cardiac failure, hypertension, age, diabetes, stroke doubled) score of 0 [dabigatran etexilate (Pradaxa, Boehringer Ingelheim)/rivaroxaban (Xarelto, Bayer Schering)] or 0/1 (warfarin) were included. A simplified approach evaluated the additional quality-adjusted life years (QALYs) required in order for TTE to be perceived as cost-effective at a threshold of L20,000 per QALY. SETTING: Transthoracic echocardiography is usually performed in cardiology clinics but may be used in primary or non-specialist secondary care. PARTICIPANTS: Patients with newly diagnosed AF. INTERVENTION: Transthoracic echocardiography. MAIN OUTCOME MEASURES: Prognosis, diagnostic sensitivity or specificity of TTE, prevalence of pathologies in patients with AF, cost-effectiveness and QALYs. RESULTS: Prognostic studies indicated that TTE diagnosed left ventricular dysfunction, increased left atrial diameter and valvular abnormality were significantly associated with an increased risk of stroke, mortality or thromboembolism. There was a high prevalence (around 25-30%) of ischaemic heart disease, valvular heart disease and heart failure in patients with AF. Diagnostic accuracy of TTE was high, with most pathologies having specificity of >= 0.8 and sensitivity of >= 0.6. The mathematical model predicted that when the CHADS2 tool is used the addition of TTE in identifying patients with left atrial abnormality appears to be cost-effective for informing some OAC decisions. In the simplified approach a threshold of 0.0033 was required for a TTE to be cost-effective. CONCLUSIONS: When CHADS2 was used, the addition of TTE in identifying patients with left atrial abnormality was cost-effective for informing some OAC decisions. A simple analysis indicates that the number of QALYs required for TTE to be cost-effective is small, and that if benefits beyond those associated with a reduction in stroke are believed probable then TTE is likely to be cost-effective in all scenarios. Our findings suggest that further research would be useful, following up newly diagnosed patients with AF who have undergone TTE, to study treatments given as a result of TTE diagnoses and subsequent cardiovascular events. This could identify additional benefits of routine testing, beyond stroke prevention. Studies assessing the proportion of people with a CHADS2 score of 0 or 1 that have left atrial abnormality would provide better estimates of the cost-effectiveness of TTE, and allow more accurate estimates of the sensitivity and specificity of TTE for identifying left atrial abnormality in AF to be obtained. STUDY REGISTRATION: PROSPERO CRD42011001354. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 23985297 TI - Age-associated differential production of IFN-gamma, IL-10 and GM-CSF by porcine alveolar macrophages in response to lipopolysaccharide. AB - The aim of the present study was to investigate the age-related production variation of T helper (Th)-type cytokines (IL-2, IL-4, IFN-gamma and IL-10), granulocyte macrophage-colony stimulating factor (GM-CSF) and nitric oxide (NO) by lipopolysaccharide (LPS)-stimulated porcine alveolar macrophages (AMs) in a time-dependent manner. For this purpose, AMs were isolated from 5-days (newborn), 40-days (post-weaned) and 120-days (young) old pigs. Cells were incubated for 24h in the absence or presence of increasing concentrations of LPS (0.0, 0.01, 1.0, 5.0 and 10.0 MUg/mL). IL-10, IFN-gamma and GM-CSF mRNA expression was upregulated in a dose-dependent manner for all age groups (P<0.05). Age-related differences included a significantly increased IL-10 mRNA and protein production in newborn piglets compared to post-weaned and young pigs. IL-10 production pattern was similar with a higher peak between 12 and 36 h post-induction in all age groups. In contrast, IFN-gamma mRNA and protein level was significantly elevated in young pigs 12h and 24h post-induction, respectively, while the time course production of IFN-gamma was mostly consistent in newborn and post-weaned piglets. GM-CSF mRNA expression was significantly lower in newborn piglets than in post-weaned and young pigs. The kinetic of GM-CSF expression peaked at 12h in young and post weaned pigs and at 24h in newborn piglets. IL-4 mRNA levels were very low and no apparent change of IL-2 expression was observed following LPS stimulation in all age groups. Only very low levels of NO were detected in the cell supernatants of young pigs. Collectively, these studies suggest age-related differences in time dependent production of IL-10, IFN-gamma and GM-CSF by porcine AMs with potential immunoregulatory consequences to be explored further. PMID- 23985298 TI - Unsurprising, in a good way. AB - Van de Vliert associates a greater difference between upper- and lower-class freedoms under less favorable environmental conditions. This pattern is similar to models of the emergence of state-level hierarchies. I argue that Van de Vliert has provided a supportive strand to the history of ancient Near East religion. PMID- 23985299 TI - Electrical activity of the diaphragm (EAdi) as a monitoring parameter in difficult weaning from respirator: a pilot study. AB - INTRODUCTION: A reliable prediction of successful weaning from respiratory support may be crucial for the overall outcome of the critically ill patient. The electrical activity of the diaphragm (EAdi) allows one to monitor the patients' respiratory drive and their ability to meet the increased respiratory demand. In this pilot study, we compared the EAdi with conventional parameters of weaning failure, such as the ratio of respiratory rate to tidal volume. METHODS: We studied 18 mechanically ventilated patients considered difficult to wean. For a spontaneous breathing trial (SBT), the patients were disconnected from the ventilator and given oxygen through a T-piece. The SBT was evaluated by using standard criteria. RESULTS: Twelve patients completed the SBT successfully, and six failed. The EAdi was significantly different in the two groups. We found an early increase in EAdi in the failing patients that was more pronounced than in any of the patients who successfully passed the SBT. Changes in EAdi predicted an SBT failure earlier than did conventional parameters. CONCLUSIONS: EAdi monitoring adds valuable information during weaning from the ventilator and may help to identify patients who are not ready for discontinuation of respiratory support. PMID- 23985300 TI - Children's perception of dialect variation. AB - A speaker's regional dialect is a rich source of information about that person. Two studies examined five- to six-year-old children's perception of regional dialect: Can they perceive differences among dialects? Have they made meaningful social connections to specific dialects? Experiment 1 asked children to categorize speakers into groups based on their accent; Experiment 2 asked them to match speakers to (un)familiar cultural items. Each child was tested with two of the following: the child's Home dialect, a Regional variant of that dialect, and a Second-Language variant. Results showed that children could successfully categorize only with a Home vs. Second-Language dialect contrast, but could reliably link cultural items with either a Home vs. Second-Language or a Regional vs. Second-Language dialect contrast. These results demonstrate five- to six-year old children's developing perceptual skill with dialect, and suggest that they have a gradient representation of dialect variation. PMID- 23985301 TI - Open source drug discovery - a limited tutorial. AB - Open science is a new concept for the practice of experimental laboratory-based research, such as drug discovery. The authors have recently gained experience in how to run such projects and here describe some straightforward steps others may wish to take towards more openness in their own research programmes. Existing and inexpensive online tools can solve many challenges, while some psychological barriers to the free sharing of all data and ideas are more substantial. PMID- 23985302 TI - Role of toll-like receptors in systemic sclerosis. AB - Accumulative evidence demonstrates the crucial role of evolutionary conserved Toll-like receptors (TLRs) in identifying microbial or viral compounds. TLRs are also able to recognise endogenous molecules which are released upon cell damage or stress and have been shown to play a key role in numerous autoimmune diseases including systemic sclerosis (SSc). A classic feature of SSc, is vascular injury manifested as Raynaud's phenomenon and ischaemia of the skin, resulting in the release of endogenous TLR ligands during inflammation and local tissue damage. These locally released TLR ligands bind TLRs possibly complexed to autoantibodies, and initiate intracellular signalling pathways and may be one of the mechanisms that initiate and drive autoimmunity and subsequent fibrosis. Activation of the immune system results in interferon (IFN) sensitive gene transcription. There is also an IFN gene signature in SSc peripheral blood. TLRs may represent the link between immune activation, common in SSc, and tissue fibrosis. Therefore, a better understanding of the mechanisms of TLR-mediated pathogenesis and therapies targeting individual TLRs, may provide a more specific approach of treating multi-systemic autoimmune diseases. This review aims to integrate the current knowledge of TLR function in the autoimmune disorders with particular emphasis on SSc. We suggest the TLR system as a new therapeutic target. PMID- 23985303 TI - Interpersonal exchange and freedom for resource acquisition. AB - The relationship of climate and monetary resources to various freedoms can be enriched if the conceptual links - "psychobehavioral adaptations" - are conceptualized more broadly as reflections of a richer cultural context that involves multiple physical and psychological resources, as proposed by social resource theory and a number of models of the emergence of social meaning. PMID- 23985304 TI - Construction of Y376C-FGFR4 eukaryotic expression plasmid and its biological activity in HEK293 cell. PMID- 23985305 TI - TLR4 is required for the obesity-induced pancreatic beta cell dysfunction. AB - Obesity is an important inducing factor for type 2 diabetes. However, the mechanism underlying high-fat-(HF) diet-induced obesity in pancreatic beta cell dysfunction is still unclear. Toll-like receptor-4 (TLR4) is a key mediator of innate immunity. To investigate the effects of TLR4 in obesity-induced pancreatic beta cell dysfunction, we used male diabetic (db/db), obese (ob/ob) mice, TLR4 wild type (WT), and TLR4-knockout mice that were fed with normal diet or HF diet for 24 weeks. Immunostaining of TLR4 and TLR4 mRNA level in pancreatic islet were assessed. The results from biological characteristics, glucose tolerance test, insulin tolerance test, and insulin release test showed that the function of pancreatic islet was impaired in HF-fed TLR4 WT mice, but was protected in HF-fed TLR4 deficient (TLR4(-/-)) mice. By electron microscope detection, we observed that beta cell insulin secretory vesicles increased in HF-fed TLR4 WT mice. Ultrastructure of beta cell in HF-fed TLR4(-/-) mice was similar to that in normal chow diet-fed TLR4 WT mice. Then, glucose-stimulated insulin secretion assay by using primary pancreatic islet showed that the secretion function of pancreatic islet in HF-fed TLR4(-/-) mice was better than that in HF-fed TLR4 WT mice. Furthermore, in HF-fed TLR4(-/-) mice, the mRNA levels of IL-6, TNF-alpha, and MCP-1 genes in pancreatic islet were significantly lower than those in HF-fed TLR4 WT mice. Consistent with the change in gene expression, HF-fed TLR4 WT mice but not HF-fed TLR4(-/-) mice exhibited macrophage invasion in pancreatic island. Taken together, our data indicated that HF diet-induced obesity can stimulate the up-regulation of TLR4 locating on the surface of pancreatic beta cell, and subsequently lead to the recruitment of macrophage into pancreatic islet, which finally results in pancreatic beta cell dysfunction. This process is a possible mechanism involved in obesity-induced pancreatic beta cell dysfunction. PMID- 23985306 TI - Unanticipated role of apelin: regulation of miRNA generation. PMID- 23985308 TI - Cardiac safety of the adjuvant Trastuzumab in a Moroccan population: observational monocentric study of about 100 patients. AB - BACKGROUND: Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor 2 (HER 2) and inhibits carcinoma cellular proliferation. Its use as an adjuvant for a period of one year is currently an internationally recognised standard for the treatment of localized breast cancer. Its use is generally well tolerated, with the most salient side effect being a particular cardiotoxicity that is typically manifested by an asymptomatic decrease in the left ventricular ejection fraction (LVEF) requiring careful monitoring before and during treatment. To evaluate the cardiac safety of trastuzumab we conducted a retrospective observational study of patients with HER2-positive localized breast cancer treated with trastuzumab between May 2008 and May 2010 in Morocco. FINDINGS: The study comprised of 100 patients. The average in LVEF before the start of trastuzumab was 70%, and at the end of treatment 66%, a decrease in absolute terms of 4%; this difference was statistically significant. 38% of the patients exhibited cardiotoxicity. 97% of our patients have completed treatment, of whom 23% with a provisional arrest because of a regressive fall in LVEF. A final arrest has been made in 3% of cases due to a non regressive reduction in LVEF. A symptomatic heart failure was found in three patients. Analysis of risk factors toxicity found a baseline LVEF higher in the patients who met cardiotoxicity than the rest of our sample. CONCLUSIONS: The cardiac safety in our study seems comparable with the literature data but located in the upper range of levels of toxicity. Cardiotoxicity is the major complication of Trastuzumab, of which LV dysfunction is the most common. Most instances are transient, asymptomatic and reversible. PMID- 23985307 TI - Regulation and functions of mammalian LATS/NDR kinases: looking beyond canonical Hippo signalling. AB - The metazoan Hippo pathway is an essential tumour suppressor signalling cascade that ensures normal tissue growth by co-ordinating cell proliferation, cell death and cell differentiation. Over the past years, various genetic and biochemical studies in Drosophila and mammals have defined a conserved core Hippo signalling module, composed of members of the Ste20-like kinase, the MOB co-activator and the AGC kinase families. In Drosophila, stimulated Hippo kinase phosphorylates and thereby activates the Mats/Warts complex, which consequently phosphorylates and inactivates the transcriptional co-activator Yorkie. In mammals, the counterparts of the Hippo/Mats/Warts/Yorkie cascade, namely MST1/2, MOB1A/B, LATS1/2 and YAP/TAZ, function in a similar fashion. These canonical Hippo pathways are so highly conserved that human MST2, hMOB1A and LATS1 can compensate for the loss of Hippo, Mats and Warts in flies. However, recent reports have shown that Hippo signalling is more diverse and complex, in particular in mammals. In this review, we summarize our current understanding of mammalian LATS1/2 kinases together with their closest relatives, the NDR1/2 kinases. The regulation of the LATS/NDR family of kinases will be discussed, followed by a summary of all currently known LATS/NDR substrates. Last, but not least, the biological roles of LATS/NDR kinases will be reviewed with specific emphasis on recent discoveries of canonical and non-canonical LATS/NDR functions in the extended Hippo pathway. PMID- 23985309 TI - Management of autism in children and young people: summary of NICE and SCIE guidance. PMID- 23985310 TI - Acute kidney injury: summary of NICE guidance. PMID- 23985311 TI - Mental disorders in children conceived after fertility treatment. PMID- 23985312 TI - The best medicine. Surgical error. PMID- 23985313 TI - NHS England slips further behind on its efficiency savings target. PMID- 23985314 TI - Acute kidney injury is a more important safety issue than MRSA, says NICE. PMID- 23985315 TI - German medical training comes under scrutiny after manslaughter conviction. PMID- 23985316 TI - The genome and transcriptome of Haemonchus contortus, a key model parasite for drug and vaccine discovery. AB - BACKGROUND: The small ruminant parasite Haemonchus contortus is the most widely used parasitic nematode in drug discovery, vaccine development and anthelmintic resistance research. Its remarkable propensity to develop resistance threatens the viability of the sheep industry in many regions of the world and provides a cautionary example of the effect of mass drug administration to control parasitic nematodes. Its phylogenetic position makes it particularly well placed for comparison with the free-living nematode Caenorhabditis elegans and the most economically important parasites of livestock and humans. RESULTS: Here we report the detailed analysis of a draft genome assembly and extensive transcriptomic dataset for H. contortus. This represents the first genome to be published for a strongylid nematode and the most extensive transcriptomic dataset for any parasitic nematode reported to date. We show a general pattern of conservation of genome structure and gene content between H. contortus and C. elegans, but also a dramatic expansion of important parasite gene families. We identify genes involved in parasite-specific pathways such as blood feeding, neurological function, and drug metabolism. In particular, we describe complete gene repertoires for known drug target families, providing the most comprehensive understanding yet of the action of several important anthelmintics. Also, we identify a set of genes enriched in the parasitic stages of the lifecycle and the parasite gut that provide a rich source of vaccine and drug target candidates. CONCLUSIONS: The H. contortus genome and transcriptome provide an essential platform for postgenomic research in this and other important strongylid parasites. PMID- 23985317 TI - The tails of apical scaffolding proteins EBP50 and E3KARP regulate their localization and dynamics. AB - The closely related apical scaffolding proteins ERM-binding phosphoprotein of 50 kDa (EBP50) and NHE3 kinase A regulatory protein (E3KARP) both consist of two postsynaptic density 95/disks large/zona occludens-1 (PDZ) domains and a tail ending in an ezrin-binding domain. Scaffolding proteins are thought to provide stable linkages between components of multiprotein complexes, yet in several types of epithelial cells, EBP50, but not E3KARP, shows rapid exchange from microvilli compared with its binding partners. The difference in dynamics is determined by the proteins' tail regions. Exchange rates of EBP50 and E3KARP correlated strongly with their abilities to precipitate ezrin in vivo. The EBP50 tail alone is highly dynamic, but in the context of the full-length protein, the dynamics is lost when the PDZ domains are unable to bind ligand. Proteomic analysis of the effects of EBP50 dynamics on binding-partner preferences identified a novel PDZ1 binding partner, the I-BAR protein insulin receptor substrate p53 (IRSp53). Additionally, the tails promote different microvillar localizations for EBP50 and E3KARP, which localized along the full length and to the base of microvilli, respectively. Thus the tails define the localization and dynamics of these scaffolding proteins, and the high dynamics of EBP50 is regulated by the occupancy of its PDZ domains. PMID- 23985318 TI - Integrins on eggs: focal adhesion kinase is activated at fertilization, forms a complex with integrins, and is necessary for cortex formation and cell cycle initiation. AB - We investigate the proposal that integrins and focal adhesion kinase (FAK) form a complex that has structural and signaling functions in eggs. FAK protein is present in eggs and is phosphorylated at fertilization. pY(397)FAK localizes to the membrane 30 min after fertilization, which correlates with the expression of betaC integrins and egg cortex development. The betaC integrin and pY(397)FAK coimmunoprecipitate from egg cortex lysates. PF573 228 and Y11, inhibitors of FAK, interfere with pronuclear fusion and reduce the abundance of pY(397)FAK and cortical actin without affecting microvillar actin. Cyclin E normally accumulates in the nucleus 15 min after fertilization, then returns to background levels. PF573 228- or Y11-treated eggs accumulate cyclin E in the nucleus; however, levels remain high. In addition, PF573 228 interferes with the accumulation of pERK1/2 in the nucleus and in eggs initiating mitosis. Injection of eggs with a fusion protein consisting of the focal adhesion-targeting domain of FAK fused to green fluorescent protein interferes with cortex formation and produces abnormal nuclei. These data indicate that an integrin-FAK adhesion complex forms at the egg surface that functions in formation of actin arrays in the egg cortex and provides signaling inputs for cell cycle initiation. PMID- 23985319 TI - Dissociation of the H3K36 demethylase Rph1 from chromatin mediates derepression of environmental stress-response genes under genotoxic stress in Saccharomyces cerevisiae. AB - Cells respond to environmental signals by altering gene expression through transcription factors. Rph1 is a histone demethylase containing a Jumonji C (JmjC) domain and belongs to the C(2)H(2) zinc-finger protein family. Here we investigate the regulatory network of Rph1 in yeast by expression microarray analysis. More than 75% of Rph1-regulated genes showed increased expression in the rph1-deletion mutant, suggesting that Rph1 is mainly a transcriptional repressor. The binding motif 5'-CCCCTWA-3', which resembles the stress response element, is overrepresented in the promoters of Rph1-repressed genes. A significant proportion of Rph1-regulated genes respond to DNA damage and environmental stress. Rph1 is a labile protein, and Rad53 negatively modulates Rph1 protein level. We find that the JmjN domain is important in maintaining protein stability and the repressive effect of Rph1. Rph1 is directly associated with the promoter region of targeted genes and dissociated from chromatin before transcriptional derepression on DNA damage and oxidative stress. Of interest, the master stress-activated regulator Msn2 also regulates a subset of Rph1-repressed genes under oxidative stress. Our findings confirm the regulatory role of Rph1 as a transcriptional repressor and reveal that Rph1 might be a regulatory node connecting different signaling pathways responding to environmental stresses. PMID- 23985320 TI - Wounded cells drive rapid epidermal repair in the early Drosophila embryo. AB - Epithelial tissues are protective barriers that display a remarkable ability to repair wounds. Wound repair is often associated with an accumulation of actin and nonmuscle myosin II around the wound, forming a purse string. The role of actomyosin networks in generating mechanical force during wound repair is not well understood. Here we investigate the mechanisms of force generation during wound repair in the epidermis of early and late Drosophila embryos. We find that wound closure is faster in early embryos, where, in addition to a purse string around the wound, actomyosin networks at the medial cortex of the wounded cells contribute to rapid wound repair. Laser ablation demonstrates that both medial and purse-string actomyosin networks generate contractile force. Quantitative analysis of protein localization dynamics during wound closure indicates that the rapid contraction of medial actomyosin structures during wound repair in early embryos involves disassembly of the actomyosin network. By contrast, actomyosin purse strings in late embryos contract more slowly in a mechanism that involves network condensation. We propose that the combined action of two force-generating structures--a medial actomyosin network and an actomyosin purse string- contributes to the increased efficiency of wound repair in the early embryo. PMID- 23985321 TI - Chromosome replication and segregation govern the biogenesis and inheritance of inorganic polyphosphate granules. AB - Prokaryotes and eukaryotes synthesize long chains of orthophosphate, known as polyphosphate (polyP), which form dense granules within the cell. PolyP regulates myriad cellular functions and is often localized to specific subcellular addresses through mechanisms that remain undefined. In this study, we present a molecular-level analysis of polyP subcellular localization in the model bacterium Caulobacter crescentus. We demonstrate that biogenesis and localization of polyP is controlled as a function of the cell cycle, which ensures regular partitioning of granules between mother and daughter. The enzyme polyphosphate kinase 1 (Ppk1) is required for granule production, colocalizes with granules, and dynamically localizes to the sites of new granule synthesis in nascent daughter cells. Localization of Ppk1 within the cell requires an intact catalytic active site and a short, positively charged tail at the C-terminus of the protein. The processes of chromosome replication and segregation govern both the number and position of Ppk1/polyP complexes within the cell. We propose a multistep model in which the chromosome establishes sites of polyP coalescence, which recruit Ppk1 to promote the in situ synthesis of large granules. These findings underscore the importance of both chromosome dynamics and discrete protein localization as organizing factors in bacterial cell biology. PMID- 23985324 TI - Bilateral breast edema associated with nephrotic syndrome. PMID- 23985322 TI - Ste20-like protein kinase SLK (LOSK) regulates microtubule organization by targeting dynactin to the centrosome. AB - The microtubule- and centrosome-associated Ste20-like kinase (SLK; long Ste20 like kinase [LOSK]) regulates cytoskeleton organization and cell polarization and spreading. Its inhibition causes microtubule disorganization and release of centrosomal dynactin. The major function of dynactin is minus end-directed transport along microtubules in a complex with dynein motor. In addition, dynactin is required for maintenance of the microtubule radial array in interphase cells, and depletion of its centrosomal pool entails microtubule disorganization. Here we demonstrate that SLK (LOSK) phosphorylates the p150(Glued) subunit of dynactin and thus targets it to the centrosome, where it maintains microtubule radial organization. We show that phosphorylation is required only for centrosomal localization of p150(Glued) and does not affect its microtubule-organizing properties: artificial targeting of nonphosphorylatable p150(Glued) to the centrosome restores microtubule radial array in cells with inhibited SLK (LOSK). The phosphorylation site is located in a microtubule binding region that is variable for two isoforms (1A and 1B) of p150(Glued) expressed in cultured fibroblast-like cells (isoform 1B lacks 20 amino acids in the basic microtubule-binding domain). The fact that SLK (LOSK) phosphorylates only a minor isoform 1A of p150(Glued) suggests that transport and microtubule organizing functions of dynactin are distinctly divided between the two isoforms. We also show that dynactin phosphorylation is involved in Golgi reorientation in polarized cells. PMID- 23985323 TI - Identification of Xin-repeat proteins as novel ligands of the SH3 domains of nebulin and nebulette and analysis of their interaction during myofibril formation and remodeling. AB - The Xin actin-binding repeat-containing proteins Xin and XIRP2 are exclusively expressed in striated muscle cells, where they are believed to play an important role in development. In adult muscle, both proteins are concentrated at attachment sites of myofibrils to the membrane. In contrast, during development they are localized to immature myofibrils together with their binding partner, filamin C, indicating an involvement of both proteins in myofibril assembly. We identify the SH3 domains of nebulin and nebulette as novel ligands of proline rich regions of Xin and XIRP2. Precise binding motifs are mapped and shown to bind both SH3 domains with micromolar affinity. Cocrystallization of the nebulette SH3 domain with the interacting XIRP2 peptide PPPTLPKPKLPKH reveals selective interactions that conform to class II SH3 domain-binding peptides. Bimolecular fluorescence complementation experiments in cultured muscle cells indicate a temporally restricted interaction of Xin-repeat proteins with nebulin/nebulette during early stages of myofibril development that is lost upon further maturation. In mature myofibrils, this interaction is limited to longitudinally oriented structures associated with myofibril development and remodeling. These data provide new insights into the role of Xin actin-binding repeat-containing proteins (together with their interaction partners) in myofibril assembly and after muscle damage. PMID- 23985325 TI - Common CYP2D6 polymorphisms affecting alternative splicing and transcription: long-range haplotypes with two regulatory variants modulate CYP2D6 activity. AB - Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 25% of clinically used drugs. Genetic polymorphisms cause substantial variation in CYP2D6 activity and serve as biomarkers guiding drug therapy. However, genotype-phenotype relationships remain ambiguous except for poor metabolizers carrying null alleles, suggesting the presence of yet unknown genetic variants. Searching for regulatory CYP2D6 polymorphisms, we find that a SNP defining the CYP2D6*2 allele, rs16947 [R296C, 17-60% minor allele frequency (MAF)], previously thought to convey normal activity, alters exon 6 splicing, thereby reducing CYP2D6 expression at least 2-fold. In addition, two completely linked SNPs (rs5758550/rs133333, MAF 13-42%) increase CYP2D6 transcription more than 2-fold, located in a distant downstream enhancer region (>100 kb) that interacts with the CYP2D6 promoter. In high linkage disequilibrium (LD) with each other, rs16947 and the enhancer SNPs form haplotypes that affect CYP2D6 enzyme activity in vivo. In a pediatric cohort of 164 individuals, rs16947 alone (minor haplotype frequency 28%) was associated with reduced CYP2D6 metabolic activity (measured as dextromethorphan/metabolite ratios), whereas rs5758550/rs133333 alone (frequency 3%) resulted in increased CYP2D6 activity, while haplotypes containing both rs16947 and rs5758550/rs133333 were similar to the wild-type. Other alleles used in biomarker panels carrying these variants such as CYP2D6*41 require re evaluation of independent effects on CYP2D6 activity. The occurrence of two regulatory variants of high frequency and in high LD, residing on a long haplotype, highlights the importance of gene architecture, likely shaped by evolutionary selection pressures, in determining activity of encoded proteins. PMID- 23985327 TI - Cold climates demand more intertemporal self-control than warm climates. AB - A climate that is too cold to grow crops for part of the year demands foresight and self-control skills. To the extent that a culture has developed intertemporal bargaining, its members will have more autonomy, but pay the cost of being more compulsive, than members of societies that have not. Monetary resources will be a consequence but will also be fed back as a cause. PMID- 23985326 TI - Dog ownership, dog behaviour and transmission of Echinococcus spp. in the Alay Valley, southern Kyrgyzstan. AB - Echinococcosis is a re-emerging zoonotic disease in Kyrgyzstan, and the incidence of human infection has increased substantially since the collapse of the Soviet Union in 1991. Domestic dogs are hosts of Echinococcus spp. and play an important role in the transmission of these parasites. The demography, ecology and behaviour of dogs are therefore relevant in studying Echinococcus spp. transmission. Dog demographics, roles of dogs, dog movements and faecal environmental contamination were assessed in four rural communities in the Alay Valley, southern Kyrgyzstan. Arecoline purge data revealed for the first time that E. granulosus, E. canadensis and E. multilocularis were present in domestic dogs in the Alay Valley. Surveys revealed that many households had dogs and that dogs played various roles in the communities, as pets, guard dogs or sheep dogs. Almost all dogs were free to roam, and GPS data revealed that many moved outside their communities, thus being able to scavenge offal and consume rodents. Faecal environmental contamination was high, presenting a significant infection risk to the local communities. PMID- 23985328 TI - Questioning photostasis. AB - Photostasis is a phenomenon where the photoreceptor outer segment (OS) length and its rhodopsin content vary depending on environmental lighting. When light is reduced for extended periods, it is argued that OS lengthen and its rhodopsin concentration rises to increase photon capture in darker environment. Increases in OS length may occur because the retinal pigment epithelium (RPE) cells reduce OS consumption in prolonged darkness. But sample sizes in assessing changes in OS length have been small, and results highly varied with no statistical analysis ever offered. Further, animals used were often albinos, which have abnormal RPE cells. Here we keep pigmented and albino mice for 21 days in darkness and compare OS length with those in a normal 12:12 light/dark environment. We measured approximately 1300 OS but found no statistically significant difference in their lengths between light and dark groups in either pigmentation phenotype, although there was a small trend in the data favoring OS extension in the dark. Given that earlier studies were undertaken on limited samples with no statistical analysis, our data pose serious questions for the notion of mammalian photostasis in terms of significant OS plasticity. PMID- 23985334 TI - Integration of mechanical and chemical signals by YAP and TAZ transcription coactivators. AB - YAP and TAZ are transcription coactivators and effectors of the Hippo pathway, which play a key role in organ size control. Through interaction with transcription factors such as TEADs, they activate gene transcription and thus promote cell proliferation, inhibit apoptosis, and regulate cell differentiation. Dysregulation of YAP/TAZ was found to correlate with human cancers. The oncogenic roles of these proteins were also demonstrated in animal models. The growth promoting activity of YAP/TAZ is limited by the Hippo tumor suppressor pathway through phosphorylation-induced cytoplasmic retention and destabilization. Recently, it was found that YAP and TAZ mediate responses to several extracellular signals including mechanical stress, GPCR signaling, and the Wnt signaling pathway. All these growth-regulating signals play important roles in normal development and cancer. In this review, we would like to discuss the function of YAP and TAZ as effectors of these physiological signals. PMID- 23985335 TI - The predictive value of self-rated health in the presence of subjective memory complaints on permanent nursing home placement in elderly primary care patients over 4-year follow-up. AB - BACKGROUND: self-rated health (SRH) predicts nursing home (NH) placement; subjective memory complaints (SMC) too. However, the predictive value of SRH in the presence of SMC is unclear. METHODS: seven-hundred fifty-seven non-nursing home residents >=65 years from general practices in Central Copenhagen were followed for 4 years (2002-2006). Patients gave information on SRH, cognition (SMC and MMSE), quality of life (EQ-5D) and socio-demographics. Information on comorbidities and permanent NH placement came from registries. The association between SRH (dichotomised into good versus poor) and SMC, and permanent NH placement was assessed using Cox proportional hazard regression adjusted for potential confounders. RESULTS: NH placement totaled 6.5% at 4-year follow-up. Poor SRH increased NH placement [hazard ratio (HR) = 2.07, 95% CI: 1.11-3.87] adjusted for age, SMC, MMSE, sex and comorbidities. SRH was not associated with NH placement if accounting for additional health information; however, SMC was (HR = 2.47, 95% CI: 1.26-4.86). Increased placement was seen for patients with good SRH and SMC (HR = 6.64, 95% CI: 2.31-19.12), but not among patients with poor SRH and SMC (HR = 1.37, 95% CI: 0.59-3.20) when compared with the reference group (good SRH and without SMC). CONCLUSIONS: both poor SRH and SMC were associated with permanent NH placement risk among elderly primary care patients. However, when SMC was present a reverse association was found for SRH: good SRH increased NH placement. Since SRH is integrated in widely used psychometric instruments, further research is needed to establish the mechanism and implications of this finding. PMID- 23985336 TI - Mycelial mass production of fungi Duddingtonia flagrans and Monacrosporium thaumasium under different culture conditions. AB - BACKGROUND: Duddingtonia flagrans and Monacrosporium thaumasium are promising fungus species in veterinary biological control of gastrointestinal nematodes because of their production capacity of fungal structures (conidia and/or chlamydospores), growth efficiency in laboratory solid media and especially their predatory capacity. However, their large-scale production remains a challenge. This work aimed at evaluating the mycelial mass production of D. flagrans (AC001 and CG722) and M. thaumasium (NF34A) nematophagous fungi under different culture conditions. RESULTS: The results did not present significant differences (p > 0.05) in mycelia mass production between the isolates cultured under pH 4.0. Furthermore, after 168 hrs., the isolate CG722 presented a lower production of mycelial mass in medium CM (corn meal) (p < 0.05). CONCLUSION: We therefore concluded the use of culture media SD (soy dextrose) and CG (corn grits) at pH values between 6.0 and 7.0 is suitable for high mycelial mass production of D. flagrans and M. thaumasium. PMID- 23985337 TI - What is freedom--and does wealth cause it? AB - The target article's climato-economic theory will benefit by allowing for bidirectional effects and the heterogeneity of types of freedom, in order to more fully capture the coevolution of societal wealth and freedom. We also suggest alternative methods of testing climato-economic theory, such as longitudinal analyses of these countries' histories and micro-level experiments of each of the theory's hypotheses. PMID- 23985338 TI - Familial resemblance for serum metabolite concentrations. AB - Metabolomics is the comprehensive study of metabolites, which are the substrates, intermediate, and end products of cellular metabolism. The heritability of the concentrations of circulating metabolites bears relevance for evaluating their suitability as biomarkers for disease. We report aspects of familial resemblance for the concentrations in human serum of more than 100 metabolites, measured using a targeted metabolomics platform. Age- and sex-corrected monozygotic twin correlations, midparent-offspring regression coefficients, and spouse correlations in subjects from two independent cohorts (Netherlands Twin Register and Leiden Longevity Study) were estimated for each metabolite. In the Netherlands Twin Register subjects, who were largely fasting, we found significant monozygotic twin correlations for 121 out of 123 metabolites. Heritability was confirmed by midparent-offspring regression. For most detected metabolites, the correlations between spouses were considerably lower than those between twins, indicating a contribution of genetic effects to familial resemblance. Remarkably high heritability was observed for free carnitine (monozygotic twin correlation 0.66), for the amino acids serine (monozygotic twin correlation 0.77) and threonine (monozygotic twin correlation 0.64), and for phosphatidylcholine acyl-alkyl C40:3 (monozygotic twin correlation 0.77). For octenoylcarnitine, a consistent point estimate of approximately 0.50 was found for the spouse correlations in the two cohorts as well as for the monozygotic twin correlation, suggesting that familiality for this metabolite is explained by shared environment. We conclude that for the majority of metabolites targeted by the used metabolomics platform, the familial resemblance of serum concentrations is largely genetic. Our results contribute to the knowledge of the heritability of fasting serum metabolite concentrations, which is relevant for biomarker research. PMID- 23985339 TI - Is the case-mix of patients who self-present to ED similar to general practice and other acute-care facilities? AB - OBJECTIVE: To benchmark walk-in presentations to emergency departments (ED) with those presenting to other local acute healthcare facilities. SETTING: A large teaching hospital with an annual ED census of 140, 000 adult patients and surrounding associated acute healthcare providers. METHODS: A random sample of 384 patients who self-presented to the ED was obtained. Benchmarking data were drawn from two general practices; the Tower Hamlets Community Services walk-in centre (co-located on-site with the ED) and the GP-run out-of-hours service. RESULTS: The case-mix presenting to the ED was characterised by a higher proportion of injuries and chest pain, but fewer simple infections and non traumatic musculoskeletal conditions as compared to other acute care facilities in our region. CONCLUSIONS: Patients with injuries and possible cardiac chest pain were more likely to attend the ED, and those with infection or musculoskeletal problems less likely, as compared with other acute healthcare facilities. The population presenting to the ED is distinct from that presenting to general practice, out-of-hours clinics, or walk-in centres. PMID- 23985340 TI - Extensive soft tissue trauma due to prolonged cardiopulmonary resuscitation using an automated chest compression (ACC) device. PMID- 23985342 TI - Trends of etiology and drug resistance in enteric fever in the last two decades in Nepal: a systematic review and meta-analysis. AB - Prospective time-trend analyses on shifting etiology and trends of drug resistance in enteric fever are scarce. Using published and unpublished datasets from Nepal, we performed a systematic review and meta-analysis to understand the trends in etiology and resistance to antimicrobials that have occurred since 1993. Thirty-two studies involving 21 067 Salmonella enterica serotype Typhi (ST) and S. enterica serotype Paratyphi A (SPA) isolates were included. There was an increasing trend in enteric fever caused by SPA during the last 2 decades (P < .01). We observed sharply increasing trends in resistance to nalidixic acid and ciprofloxacin for both ST and SPA. In contrast, multi-drug resistance (MDR), resistance to traditional first-line antibiotics such as chloramphenicol and co trimoxazole have significantly decreased for both organisms. The resistance to ceftriaxone has remained low, suggesting it is likely to remain useful as a reserve antibiotic for treatment. Trends in decreasing resistance to traditional first-line antibiotics and decreasing MDR provide an opportunity to reconsider these first-line antimicrobials as therapeutic options. PMID- 23985343 TI - The empirical combination of vancomycin and a beta-lactam for Staphylococcal bacteremia. AB - The high prevalence of methicillin resistance among Staphylococcus aureus bacteremias leads to common use of vancomycin as empirical therapy. However, investigators have reported poor outcomes with vancomycin treatment for methicillin-susceptible Staphylococcus aureus bacteremia. We review the evidence supporting empirical combination of both vancomycin and a beta-lactam agent for Staphylococcus aureus bacteremia. Vancomycin therapy for methicillin-susceptible Staphylococcus aureus bacteremia is associated with 2-3 times the risk of morbidity and mortality compared to an antistaphylococcal penicillin (oxacillin and nafcillin) or first-generation cephalosporin (cefazolin). De-escalation of empirical vancomycin to definitive beta-lactam therapy still appears inferior to initial beta-lactam therapy. Although there is no clinical trial supporting combination therapy, a scientific rationale for benefit exists and should be weighed against the risks (adverse events, antibiotic resistance, and cost) of additional pharmacotherapy. The empirical combination of vancomycin and a beta lactam (either nafcillin, oxacillin, or cefazolin) for staphylococcal bacteremia may improve infection-related clinical outcomes. PMID- 23985344 TI - Mortality and neurological complications after early or late surgery for infective endocarditis and stroke. PMID- 23985341 TI - The genome and developmental transcriptome of the strongylid nematode Haemonchus contortus. AB - BACKGROUND: The barber's pole worm, Haemonchus contortus, is one of the most economically important parasites of small ruminants worldwide. Although this parasite can be controlled using anthelmintic drugs, resistance against most drugs in common use has become a widespread problem. We provide a draft of the genome and the transcriptomes of all key developmental stages of H. contortus to support biological and biotechnological research areas of this and related parasites. RESULTS: The draft genome of H. contortus is 320 Mb in size and encodes 23,610 protein-coding genes. On a fundamental level, we elucidate transcriptional alterations taking place throughout the life cycle, characterize the parasite's gene silencing machinery, and explore molecules involved in development, reproduction, host-parasite interactions, immunity, and disease. The secretome of H. contortus is particularly rich in peptidases linked to blood feeding activity and interactions with host tissues, and a diverse array of molecules is involved in complex immune responses. On an applied level, we predict drug targets and identify vaccine molecules. CONCLUSIONS: The draft genome and developmental transcriptome of H. contortus provide a major resource to the scientific community for a wide range of genomic, genetic, proteomic, metabolomic, evolutionary, biological, ecological, and epidemiological investigations, and a solid foundation for biotechnological outcomes, including new anthelmintics, vaccines and diagnostic tests. This first draft genome of any strongylid nematode paves the way for a rapid acceleration in our understanding of a wide range of socioeconomically important parasites of one of the largest nematode orders. PMID- 23985345 TI - Reply to Wang. PMID- 23985346 TI - The journey to antiretroviral therapy in Karnataka, India: who was lost on the road? AB - INTRODUCTION: One important operational challenge facing antiretroviral treatment (ART) programmes in low- and middle-income countries is the loss to follow-up between diagnosis of human immunodeficiency virus (HIV) and initiation of ART. This is a major obstacle to achieving universal access to ART. This study from Karnataka, India, tried to measure such losses by determining the number of HIV positive individuals diagnosed, the number of them reaching ART centres, the number initiated on ART and the reasons for non-initiation of ART. METHODS: A review of records routinely maintained under the National AIDS Control Programme (NACP) was carried out in six districts of Karnataka. HIV-positive persons diagnosed during the months from January to June 2011 in 233 public HIV-testing sites were followed up until December 2011 based on the pre-ART registers. A chi square test was used to assess statistical significance. RESULTS: Of 2291 HIV positive persons diagnosed (52% male; mean age of 35 years), 1829 (80%) reached ART centres. Of the latter, 1166 (64%) were eligible for ART, and 959 (82%) were initiated on treatment. Overall losses (attrition) on the road between HIV diagnosis and ART initiation were 669 (29%). Deaths, migration and not willing to go to the ART centres were cited as the main known reasons for not reaching ART centres. For ART-eligible individuals who did not initiate ART, the most common known reasons for non-initiation included dying before initiation of ART and not being willing to start ART. CONCLUSIONS: In a large state of India, eight in ten HIV-positive persons reached ART centres, and of those found ART eligible, 82% start treatment. Although this is an encouraging achievement, the programme needs to take further steps to improve the current performance by further reducing pre ART attrition. We recommend online registering of diagnosed HIV-positive patients to track the patients more efficiently. PMID- 23985347 TI - Does the aquatic invertebrate nipple array prevent bubble adhesion? An experiment using nanopillar sheets. AB - The nipple array is a submicrometre-scale structure found on the cuticle surfaces of various invertebrate taxa. Corneal nipples are an antiglare surface in nocturnal insects, but the functional significance of the nipple array has not been experimentally investigated for aquatic organisms. Using nanopillar sheets as a mimetic model of the nipple array, we demonstrated that significantly fewer bubbles adhered to the nanopillar surface versus a flat surface when the sheets were hydrophilic. Many more bubbles adhered to the hydrophobic surface than the hydrophilic surfaces. Bubbles on the body surface may cause buoyancy problems, movement interference and water flow occlusion. Here, bubble repellence is proposed as a function of the hydrophilic nipple array in aquatic invertebrates and its properties are considered based on bubble adhesion energy. PMID- 23985348 TI - Plastic proteans: reduced predictability in the face of predation risk in hermit crabs. AB - Variation in behaviour occurs at multiple levels, including between individuals (personality) and between situations (plasticity). Behaviour also varies within individuals, and intra-individual variation (IIV) in behaviour describes within individual residual variance in behaviour that remains after the effects of obvious external and internal influences on behaviour have been accounted for. IIV thus describes how predictable an individual's behaviour is. Differences in predictability, between individuals and between situations, might be biologically significant. For example, behaving unpredictably under predation threat might reduce the chance of capture. Here, we investigated the duration of startle responses in hermit crabs, in the presence and absence of a predator cue. Individuals differed in startle response duration (personality) and while individuals also varied in their sensitivity to risk, mean response time was greater in the presence of a predator (plasticity). Moreover, IIV was greater in the presence of a predator, providing some of the first evidence that the facultative injection of unpredictability into behaviour might represent a strategy for dealing with risk. PMID- 23985349 TI - Batch spawning facilitates transfer of an essential nutrient from diet to eggs in a marine fish. AB - Fatty acid composition of eggs affects development, growth and ecological performance of fish embryos and larvae, with potential consequences for recruitment success. Essential fatty acids in eggs derive from the maternal diet, and the time between ingestion and deposition in eggs is ecologically important but unknown. We examined the dynamics of diet-egg transfer of arachidonic acid (ARA) in the batch-spawning fish, red drum (Sciaenops ocellatus), by measuring ARA concentrations in eggs after a single diet shift and during a period of irregular variations in diet. ARA concentrations in eggs changed within 2-16 days of a diet shift. The rate of change was proportional to the magnitude of the shift, with no evidence of equilibration. These results are not consistent with eggs being assembled entirely from accumulated body stores. The immediate source of ARA in eggs appears to be the recent diet. We propose that batch spawning produces rapid diet-egg transfer of ARA because it removes large amounts of fatty acids from the body and prevents equilibration. The immediacy of the diet-egg connection suggests that spawning migration combined with short-interval batch spawning may have evolved to take advantage of nutrients critical for offspring survival that are available at the spawning site. PMID- 23985350 TI - A humanin analog decreases oxidative stress and preserves mitochondrial integrity in cardiac myoblasts. AB - A potent analog (HNG) of the endogenous peptide humanin protects against myocardial ischemia-reperfusion (MI-R) injury in vivo, decreasing infarct size and improving cardiac function. Since oxidative stress contributes to the damage from MI-R we tested the hypotheses that: (1) HNG offers cardioprotection through activation of antioxidant defense mechanisms leading to preservation of mitochondrial structure and that, (2) the activity of either of a pair of non receptor tyrosine kinases, c-Abl and Arg is required for this protection. Rat cardiac myoblasts (H9C2 cells) were exposed to nanomolar concentrations of HNG and to hydrogen peroxide (H2O2). Cells treated with HNG in the presence of H2O2 demonstrated reduced intracellular reactive oxygen species (ROS), preserved mitochondrial membrane potential, ATP levels and mitochondrial structure. HNG induced activation of catalase and glutathione peroxidase (GPx) within 5 min and decreased the ratio of oxidized to reduced glutathione within 30 min. siRNA knockdown of both Abl and Arg, but neither alone, abolished the HNG-mediated reduction of ROS in myoblasts exposed to H2O2. These findings demonstrate an HNG mediated, Abl- and Arg-dependent, rapid and sustained activation of critical cellular defense systems and attenuation of oxidative stress, providing mechanistic insights into the observed HNG-mediated cardioprotection in vivo. PMID- 23985351 TI - How is freedom distributed across the earth? AB - Although Van de Vliert presented an entertaining story containing several original observations, an implicit assumption that climate affects human society identically through the history is not realistic. If almost everything is explained by cold winters or hot summers, then nothing is explained. Ignoring rival explanations does not make the proposed theory more convincing. PMID- 23985353 TI - Modelling of multi-nutrient interactions in growth of the dinoflagellate microalga Protoceratium reticulatum using artificial neural networks. AB - This study examines the use of artificial neural networks as predictive tools for the growth of the dinoflagellate microalga Protoceratium reticulatum. Feed forward back-propagation neural networks (FBN), using Levenberg-Marquardt back propagation or Bayesian regularization as training functions, offered the best results in terms of representing the nonlinear interactions among all nutrients in a culture medium containing 26 different components. A FBN configuration of 26 14-1 layers was selected. The FBN model was trained using more than 500 culture experiments on a shake flask scale. Garson's algorithm provided a valuable means of evaluating the relative importance of nutrients in terms of microalgal growth. Microelements and vitamins had a significant importance (approximately 70%) in relation to macronutrients (nearly 25%), despite their concentrations in the culture medium being various orders of magnitude smaller. The approach presented here may be useful for modelling multi-nutrient interactions in photobioreactors. PMID- 23985352 TI - Reinfection studies of canine echinococcosis and role of dogs in transmission of Echinococcus multilocularis in Tibetan communities, Sichuan, China. AB - In the eastern Tibetan plateau both human cystic and alveolar echinococcosis (AE) caused by infection with Echincoccus granulosus or Echinococcus multilocularis, respectively are highly endemic. The domestic dog plays a key role in zoonotic transmission in this region. Our primary objective was to investigate the role of domestic dogs in maintaining transmission of E. multilocularis in Shiqu county, Sichuan. A cohort of 281 dogs was followed up over one year after a single treatment with praziquantel followed by re-infection surveillance at 2, 5 and 12 months post-treatment. Faecal samples were tested by an Echinococcus genus specific coproantigen ELISA and two species-specific copro-PCR tests. Total Echinococcus coproantigen prevalence in Shiqu at baseline was 21% and 9.6% after 2 months. E. multilocularis copro-PCR was positive in 11.2% of dogs before treatment (vs 3.6% with E. granulosus copro-DNA), 2.9% at 2 months post treatment, and 0% at 5 month and 12 months. The results suggest that dogs may have the potential to maintain E. multilocularis transmission within local pastoral communities, and thus dog dosing could be an effective strategy to reduce transmission of E. multilocularis as well as E. granulosus in these co endemic Tibetan communities. PMID- 23985354 TI - Novel physico-biological treatment for the remediation of textile dyes-containing industrial effluents. AB - In this work, a novel remediation strategy consisting of a sequential biological and physical process is proposed to remove dyes from a textile polluted effluent. The decolorization ability of Anoxybacillus flavithermus in an aqueous effluent containing two representative textile finishing dyes (Reactive Black 5 and Acid Black 48, as di-azo and antraquinone class, respectively) was proved. The decolorization efficiency for a mixture of both dyes reached almost 60% in less than 12h, which points out the suitability of the selected microorganism. In a sequential stage, an aqueous biphasic system consisting of non-ionic surfactants and a potassium-based organic salt, acting as the salting out agent, was investigated. The phase segregation potential of the selected salts was evaluated in the light of different thermodynamic models, and remediation levels higher than 99% were reached. PMID- 23985355 TI - Music therapy for prisoners: pilot randomised controlled trial and implications for evaluating psychosocial interventions. AB - Mental health problems are common among prison inmates. Music therapy has been shown to reduce mental health problems. It may also be beneficial in the rehabilitation of prisoners, but rigorous outcome research is lacking. We compared group music therapy with standard care for prisoners in a pilot randomised controlled trial that started with the establishment of music therapy services in a prison near Bergen in 2008. In all, 113 prisoners agreed to participate. Anxiety (STAI-State [State-Trait Anxiety Inventory], STAI-Trait), depression (HADS-D [Hospital Anxiety and Depression Scale]), and social relationships (Quality of Life Enjoyment and Satisfaction Questionnaire [Q-LES Q]) were assessed at baseline; every 2 weeks in the experimental group; after 1, 3, and 6 months in the control group; and at release. No restrictions were placed on the frequency, duration, or contents of music therapy. Duration of stay in the institution was short (62% stayed less than 1 month). Only a minority reached clinical cutoffs for anxiety and depression at baseline. Between-group analyses of effects were not possible. Music therapy was well accepted and attractive among the prisoners. Post hoc analysis of within-group changes suggested a reduction of state anxiety after 2 weeks of music therapy (d = 0.33, p = .025). Short sentences and low baseline levels of psychological disturbance impeded the examination of effects in this study. Recommendations for planning future studies are given, concerning the careful choice of participants, interventions and settings, comparison condition and design aspects, choice of outcomes, and integration of research approaches. Thus, the present study has important implications for future studies evaluating interventions for improving prisoners' mental health. TRIAL REGISTRATION: ISRCTN22518605. PMID- 23985356 TI - Cutaneous plasmacytosis as a skin manifestation of IgG4-related disease. PMID- 23985359 TI - Diversity in function and regulation of the Hippo pathway. PMID- 23985360 TI - In vitro development rate of preimplantation rabbit embryos cultured with different levels of melatonin. AB - This study aimed to investigate the effect of melatonin supplementation at different levels in culture medium on embryo development in rabbits. Embryos of 2 4 cells, 8-16 cells and morula stages were recovered from nulliparous Red Baladi rabbit does by laparotomy technique 24, 48 and 72 h post-insemination, respectively. Normal embryos from each stage were cultured to hatched blastocyst stages in either control culture medium (TCM-199 + 20% fetal bovine serum) or control supplemented with melatonin at 10(-3) M, 10(-6) M or 10(-9) M. No effect of melatonin was found on development of embryos recovered at 24 h post insemination. The high level of melatonin at 10(-3) M adversely affected the in vitro development rates of embryos recovered at 48 h post-insemination (52 versus 86, 87 and 80% blastocyst rate; 28 versus 66, 78 and 59% hatchability rate for 10(-3) M versus 10(-9) M, 10(-6) M and control, respectively, P< 0.05). At the morula stage, melatonin at 10-3 M significantly increased the in vitro development of embryos (92% for 10(-3) M versus 76% for control, P < 0.05), while the hatchability rate of these embryos was not improved by melatonin (16-30% versus 52% for melatonin groups versus control, P < 0.05). Results show that a moderate level of melatonin (10(-6) M) may improve the development and hatchability rates of preimplantation rabbit embryos. The addition of melatonin at a 10-3 M concentration enhances the development of rabbit morulae but may negatively affect the development of earlier embryos. More studies are needed to optimize the use of melatonin in in vitro embryo culture in rabbits. PMID- 23985361 TI - Extending climato-economic theory: when, how, and why it explains differences in nations' creativity. AB - The climato-economic theory postulates mechanisms of threat and challenge to explain differences between countries. Interestingly, both of these mechanisms are often considered to be components of the models of organizational climate for creativity. We show that among rich countries, climatic demands are related to creative achievement in a reversed-U manner, whereas the relationship is linear among poor countries. PMID- 23985362 TI - Depression, neuroticism, and urinary incontinence in premenopausal women: a nationwide twin study. AB - Previous studies have found that major depression and neuroticism are positively associated with urinary incontinence (UI). However, the genetic contribution to these associations has never been investigated. In 2005, a total of 14,094 female twins born 1959-1985 in the Swedish Twin Registry participated in a comprehensive survey on common exposures and complex diseases. Structured questions provided information on UI, depressive symptoms, major depression, and neuroticism. A logistic regression model based on generalized estimating equations (GEE) was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Environmental and genetic influences were assessed in co-twin control analyses and quantitative genetic analyses, which were also used to determine the proportion of the phenotypic correlation explained by familial factors. Major depression, depressive symptoms, and neuroticism were positively associated with all UI subtypes (overall, stress, urge, and mixed UI). In a trivariate Cholesky model with neuroticism, depressive symptoms (or depression), and UI a modest genetic correlation was found between indicators of depression and overall, or stress, UI. The majority of this correlation was independent from neuroticism. In contrast, the genetic factors shared between indicators of depression and urge or mixed UI were entirely in common with neuroticism. In conclusion, depression and neuroticism are associated with UI among premenopausal women: the associations are in part determined by genetic factors in common to the disorders. PMID- 23985364 TI - Employers need to commit to flexible working for carers, says report. PMID- 23985366 TI - Most drugs are safe to use during breastfeeding, says report. PMID- 23985367 TI - A case of celiacomesenteric trunk in a Tanzanian man. AB - BACKGROUND: Variation in the branching patterns of the three major arteries that supply the digestive system may occur due to different embryological mechanisms. CASE PRESENTATION: The present case report describes the celiac artery and the superior mesenteric artery originating from the abdominal aorta through a common trunk. The celiac artery in turn gave rise to the splenic artery and a common trunk for common hepatic and left gastric artery. The superior and inferior mesenteric arteries had normal branching patterns. CONCLUSION: Awareness of these variations on the part of the surgical team before surgery can help avoid iatrogenic arterial injury. PMID- 23985363 TI - Human infertility: are endocrine disruptors to blame? AB - Over recent decades, epidemiological studies have been reporting worrisome trends in the incidence of human infertility rates. Extensive detection of industrial chemicals in human serum, seminal plasma and follicular fluid has led the scientific community to hypothesise that these compounds may disrupt hormonal homoeostasis, leading to a vast array of physiological impairments. Numerous synthetic and natural substances have endocrine-disruptive effects, acting through several mechanisms. The main route of exposure to these chemicals is the ingestion of contaminated food and water. They may disturb intrauterine development, resulting in irreversible effects and may also induce transgenerational effects. This review aims to summarise the major scientific developments on the topic of human infertility associated with exposure to endocrine disruptors (EDs), integrating epidemiological and experimental evidence. Current data suggest that environmental levels of EDs may affect the development and functioning of the reproductive system in both sexes, particularly in foetuses, causing developmental and reproductive disorders, including infertility. EDs may be blamed for the rising incidence of human reproductive disorders. This constitutes a serious public health issue that should not be overlooked. The exposure of pregnant women and infants to EDs is of great concern. Therefore, precautionary avoidance of exposure to EDs is a prudent attitude in order to protect humans and wildlife from permanent harmful effects on fertility. PMID- 23985368 TI - Press freedom, oil exports, and risk for natural disasters: a challenge for climato-economic theory? AB - Does the interaction between climactic demands, monetary resources, and freedom suggest a more general relationship between the environmental challenges that human societies face and their resources to meet those challenges? Using data on press freedom (Van de Vliert 2011a), we found no evidence of a similar interaction with natural resources (as measured by oil exports) or risk for natural disasters. PMID- 23985369 TI - Activation energy and entropy for viscosity of wormlike micelle solutions. AB - The viscosities of two surfactant solutions which form wormlike micelles (WLMs) were studied over a range of temperatures and strain rates. WLM solutions appear to differ from many other shear thinning systems in that, as the shear rate increases, stress-shear rate curves tend to converge with temperature rather than diverge and this can sometimes lead to higher temperature curves crossing those at lower. Behaviour was analysed in terms of activation kinetics. It is suggested that two mechanisms are involved: Newtonian flow, following an Arrhenius law superimposed on a non-Newtonian flow described by a stress assisted kinetic law, this being a more general form of the Arrhenius law. Anomalous flow is introduced into the kinetic equation via a stress dependent activation entropy term. PMID- 23985370 TI - Facile preparation of partially functionalized gold nanoparticles via a surfactant-assisted solid phase approach. AB - Herein, we report a versatile solid phase synthesis approach for partial functionalization of gold nanoparticles (AuNPs) via the assistance of surfactant. Hexadecyl trimethyl ammonium bromide (CTAB) is used as the bifunctional ligand to link the solid substrate and the AuNPs. This brings at least two advantages comparing to other bifunctional ligands: first, the thickness of the CTAB bilayer is flexible. During the "catch" process, the bilayer bound on different sites of the AuNPs could shrink or extend to a total thickness difference of ~2.5 nm, which protects a spherical cap of the AuNPs with the height of ~2.5 nm from chemical modification; second, after chemical modification, the "release" of the AuNPs from the substrate is quite simple. Not any second ligand, but only sonication is enough to release the AuNPs. As a result, the proposed approach produces partially functionalized AuNPs with a large surface area (80-95%) covered with unreactive ligands, while keeps the other small spatially limited region of the surface unmodified. This small unmodified surface can be directly used for further chemistry. Finally, the partially modified AuNPs is demonstrated for a one-step synthesis of AuNP dimers. PMID- 23985371 TI - Advances in diagnosis and spatial analysis of cysticercosis and taeniasis. AB - Human cysticercosis, caused by accidental ingestion of eggs of Taenia solium, is one of the most pathogenic helminthiases and is listed among the 17 WHO Neglected Tropical Diseases. Controlling the life-cycle of T. solium between humans and pigs is essential for eradication of cysticercosis. One difficulty for the accurate detection and identification of T. solium species is the possible co existence of two other human Taenia tapeworms (T. saginata and T. asiatica, which do not cause cysticercosis in humans). Several key issues for taeniasis/cysticercosis (T/C) evidence-based epidemiology and control are reviewed: (1) advances in immunological and molecular tools for screening of human and animals hosts and identification of Taenia species, with a focus on real-time detection of taeniasis carriers and infected animals in field community screenings, and (2) spatial ecological approaches that have been used to detect geospatial patterns of case distributions and to monitor pig activity and behaviour. Most recent eco-epidemiological studies undertaken in Sichuan province, China, are introduced and reviewed. PMID- 23985372 TI - Improvement of the enzymatic hydrolysis of furfural residues by pretreatment with combined green liquor and hydrogen peroxide. AB - A potential commercial pretreatment for furfural residues (FRs) was investigated by using a combination of green liquor and hydrogen peroxide (GL-H2O2). The results showed that 56.2% of lignin removal was achieved when the sample was treated with 0.6 g H2O2/g-DS (dry substrate) and 6 mL GL/g-DS at 80 degrees C for 3 h. After 96 h hydrolysis with 18 FPU/g-cellulose for cellulase, 27 CBU/g cellulose for beta-glucosidase, the glucose yield increased from 71.2% to 83.6%. Ethylenediaminetetraacetic acid was used to reduce the degradation of H2O2, the glucose yield increased to 90.4% after the addition of 1% (w/w). The untreated FRs could bind more easily to cellulase than pretreated FRs could. The structural changes on the surface of sample were characterized by X-ray photoelectron spectroscopy. The results indicated that the surface lignin could be effectively removed during pretreatment, thereby decreasing the enzyme-lignin binding activity. Moreover, the carbonyl from lignin plays an important role in cellulase binding. PMID- 23985374 TI - The subjective experience of community treatment orders: patients' views and clinical correlations. AB - BACKGROUND: There is little objective evidence to support the use of community treatment orders (CTOs) from randomized controlled trials. Qualitative research indicates more negative than positive responses to the use of CTOs. Nonetheless, the use of CTOs is growing internationally. There is no research to identify for whom CTOs may be a positive experience. AIM: To assess patients' perspectives of CTOs, assessing for correlates with clinical and demographic variables. METHODS: Patients currently or previously subject to a CTO were assessed quantitatively to identify their experience. Demographic data, the experience of coercion, views of detention, satisfaction with care, social functioning and psychopathology were correlated using SPSS. RESULTS: Fifty-three per cent of patients felt that they were, on balance, better off when treated informally in the community. Patients described greater coercion and less satisfaction with care when subject to a CTO. These factors, and being in employment, identified patients whom felt harmed by CTOs 61% of the time. CONCLUSIONS: This paper highlights that more than half of patients under a CTO consider it negatively. This group is identified by patients who work, experience coercion and are unsatisfied with care. This has implications for the application of CTOs. PMID- 23985373 TI - Evaluation of substituted phenalenone analogues as antiplasmodial agents. AB - A set of derivatives encompassing structural modifications on the privileged phenalenone scaffold were assessed for their antiplasmodial activities against a strain of chloroquine sensitive Plasmodium falciparum F32. Two compounds exhibited considerable effects against the malaria parasite (IC50 <= 1 MUg/mL), one of which maintained the same level of activity in a chloroquine-resistant strain. This is the first record of antiplasmodial activity on this type of scaffold, providing a new structural motif as a new lead for antimalarial activity. PMID- 23985375 TI - Cutaneous ancient schwannoma of the forehead. PMID- 23985376 TI - Public health science agenda for congenital heart defects: report from a Centers for Disease Control and Prevention experts meeting. PMID- 23985377 TI - Thymic stromal lymphopoietin attenuates the development of atherosclerosis in ApoE-/- mice. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine with multiple effects on the body. For one thing, TSLP induces Th2 immunoreaction and facilitates allergic reaction; for another, it promotes the differentiation of naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) and maintains immune tolerance. However, the exact role of TSLP in atherosclerosis remains unknown. METHODS AND RESULTS: In vitro, we examined the phenotype of TSLP conditioned bone marrow dendritic cells (TSLP-DCs) of apolipoprotein E-deficient (ApoE-/-) mice and their capacity to induce the differentiation of Tregs. Our results indicated that TSLP-DCs obtained the characteristics of tolerogenic dendritic cells and increased a generation of CD4+ latency-associated peptide (LAP)+ Tregs and nTregs when cocultured with naive T cells. In addition, the functional relevance of TSLP and TSLP-DCs in the development of atherosclerosis was also determined. Interestingly, we found that TSLP was almost absent in cardiovascular tissue of ApoE-/- mice, and TSLP administration increased the levels of antioxidized low-density lipoprotein IgM and IgG1, but decreased the levels of IgG2a in plasma. Furthermore, mice treated with TSLP and TSLP-DCs developed significantly fewer (32.6% and 28.2%, respectively) atherosclerotic plaques in the aortic root compared with controls, along with increased numbers of CD4+LAP+ Tregs and nTregs in the spleen and decreased inflammation in the aorta, which could be abrogated by anti-TGF-beta antibody. CONCLUSIONS: Our results revealed a protective role for TSLP in atherosclerosis that is possibly mediated by reestablishing a tolerogenic immune response, which may represent a novel possibility for treatment or prevention of atherosclerosis. PMID- 23985379 TI - Methodological suggestions for climato-economic theory. AB - To evaluate and extend climato-economic theory, the use of more micro units of analysis, such as cities and families, may open up new data sources. The consideration of environmental demands other than thermal climate may also broaden the range of useful data. Longitudinal designs can provide causal evidence, and so can experiments if the theory can be applied to individuals. PMID- 23985378 TI - Glycosaminoglycan overproduction in the aorta increases aortic calcification in murine chronic kidney disease. AB - BACKGROUND: Vascular calcification accompanying chronic kidney disease increases the mortality and morbidity associated with cardiovascular disorders, but no effective therapy is available. We hypothesized that glycosaminoglycans may contribute to osteoblastic differentiation of vascular smooth muscle cells during vascular calcification. METHODS AND RESULTS: We used exostosin-like glycosyltranferase 2-deficient (EXTL2 knockout) mice expressing high levels of glycosaminoglycans in several organs including the aorta. We performed 5/6 subtotal nephrectomy and fed the mice a high-phosphate diet to induce chronic kidney disease. Overexpression of glycosaminoglycans in the aorta enhanced aortic calcification in chronic kidney disease in EXTL2 knockout mice. Ex vivo and in vitro, matrix mineralization in aortic rings and vascular smooth muscle cells of EXTL2 knockout mice was augmented. Furthermore, removal of glycosaminoglycans in EXTL2 knockout and wild-type mice-derived vascular smooth muscle cells effectively suppressed calcium deposition in a high-phosphate environment. CONCLUSIONS: These results illustrate an important role for glycosaminoglycans in the development of vascular calcification. Manipulation of glycosaminoglycan expression may have beneficial effects on the progression of vascular calcification in chronic kidney disease patients. PMID- 23985380 TI - Complex atrial arrhythmias as first manifestation of catecholaminergic polymorphic ventricular tachycardia: an unusual course in a patient with a new mutation in ryanodine receptor type 2 gene. AB - Catecholaminergic polymorphic ventricular tachycardia is a rare life-threatening arrhythmogenic disorder. An association with paroxysmal atrial fibrillation and other atrial arrhythmias has been described, but in all published cases the initial manifestation of the disease was ventricular arrhythmia. This is the first report about a patient who presented with complex atrial tachycardia and sinus node dysfunction about 1 year before the typical ventricular arrhythmias were observed, leading to the diagnosis of catecholaminergic polymorphic ventricular tachycardia. In this girl, a mutation of the ryanodine receptor type 2 gene, which has not been described so far, was discovered. PMID- 23985381 TI - Oral cancer in the UAE: a multicenter, retrospective study. AB - AIM: To determine the prevalence of various malignant oral lesions in the UAE and correlate cases of squamous cell carcinomas with age, gender, site, grade, clinical presentations at the time of diagnosis, and the prevalence of neck metastasis. MATERIALS AND METHODS: A multicenter, retrospective study was conducted at four major hospitals in the UAE. The study was based on histopathology reports of biopsies of oral tissues. RESULTS: Of the 992 oral biopsy reports retrieved, 147 cases of malignant tumors were found which accounted for 14.9% of the total biopsies. Fifteen different types of malignant lesions were diagnosed, of which oral squamous cell carcinoma (OSCC) was the most prevalent and made up 11.4% of the overall oral biopsies retrieved. The commonest presentation of cancer was ulceration (31.17%), followed by lumps and white lesions. The most common site where the lesions were diagnosed was the tongue (51.9%), followed by the cheeks and lips. OSCC accounted for 77% of all malignancies reported. Neck dissections were conducted in only 20.8% of all OSCC cases diagnosed at Mafraq and Tawam hospitals, of which 43.75% showed evidence of neck metastasis. CONCLUSION: Oral cancer is not an uncommon disease in the UAE. This may mandate more awareness campaigning, including screening procedures for early detection of cancerous lesions and other potentially malignant oral diseases. Elective neck dissections to detect lymph node metastasis should be more routinely performed, in particular for tongue carcinomas because of the early neck involvement potential. PMID- 23985382 TI - Relationship of mode of conception and sex concordance with mortality/morbidity in preterm twins. AB - OBJECTIVE: To assess the association of mode of conception and sex concordance with neonatal outcomes in very preterm twins. STUDY DESIGN: Twin pairs born at gestational age <= 32 weeks and admitted to a Level 3 neonatal intensive care unit (NICU) in 2010-2011 were retrospectively identified from the Canadian Neonatal NetworkTM database. A composite outcome representing neonatal mortality or any severe morbidity (intraventricular hemorrhage grades >= 3 or periventricular leukomalacia, retinopathy of prematurity stages >= 3, bronchopulmonary dysplasia, or necrotizing enterocolitis stages >= 2) was compared between twins conceived using assisted reproduction technologies (ARTs) or spontaneously (SP), and tested for association with sex concordance in individual-level and pair-wise multivariable logistic regression analyses. RESULTS: Study subjects included 1,508 twins from 216 ART (53 [25%] male-male, 104 [48%] male-female, and 59 [27%] female-female) and 538 SP (192 [36%] male male, 123 [23%] male-female, and 223 [41%] female-female) pairs. No statistically significant association was detected between mode of conception and the composite outcome of mortality/morbidities. The composite outcome was significantly higher in same-sex than in opposite-sex twins (OR = 1.68; 95% CI = [1.09, 2.59]). This relationship was most pronounced in ART pairs (OR = 2.25; 95% CI = [1.02, 4.98]), with increased rates in one or both twins from male-male versus opposite-sex ART pairs (OR = 3.0; 95% CI = [1.07, 8.36]). CONCLUSION: Same-sex pairing was associated with higher mortality/morbidities in very preterm twins admitted to the NICU, and can be used in clinical practice to identify twins at higher risk of adverse neonatal outcomes. PMID- 23985384 TI - Individual identity and freedom of choice in the context of environmental and economic conditions. AB - Van de Vliert's findings fit nicely with our recent arguments implying that (1) differentiated selfhood is partly motivated by requirements of cultural groups, and (2) free will mainly exists within culture. Some cultural groups promote individual freedom, whereas others constrict it so as to maintain elites' power and privilege. Thus, freedom is, to a great extent, a creation of culture. PMID- 23985383 TI - Characteristics of intramural scar in patients with nonischemic cardiomyopathy and relation to intramural ventricular arrhythmias. AB - BACKGROUND: Ventricular arrhythmias have been described to originate from intramural locations. Intramural scar can be assessed by delayed-enhanced MRI, but MRIs cannot be performed on every patient. The objective of this study was to assess the value of voltage mapping to detect MRI-defined intramural scar and to correlate the scar with ventricular arrhythmias. METHODS AND RESULTS: In 15 consecutive patients (3 women; age 55+/-16 years; ejection fraction, 49+/-13%) with structural heart disease, intramural scar was detected by delayed-enhanced MRI. All patients underwent endocardial unipolar and bipolar voltage mapping guided by the registered intramural scar. Scar volume by MRI was 11.7+/-8 cm3 with a scar thickness of 4.6+/-0.7 mm and a preserved endocardial/epicardial rim of 3.3+/-1.6 and 4.8+/-2.6 mm, respectively. Endocardial bipolar voltage was 1.6+/-1.73 mV at the scar, 2.12+/-2.15 mV in a 1 cm perimeter around the scar, and 2.83+/-3.39 mV in remote myocardium without scar. The corresponding unipolar voltage was 4.94+/-3.25, 6.59+/-3.81, and 8.32+/-3.39 mV, respectively (P<0.0001). Using receiver-operator characteristic curves, a unipolar cut-off value of 6.78 mV (area under the curve, 0.78) and a bipolar cut-off value of 1.55 mV (area under the curve, 0.69) best separated endocardial measurements overlying scar as compared with areas not overlying a scar. At least 1 intramural ventricular arrhythmia was eliminated in all but 2 patients in this series. CONCLUSIONS: Intramural scar can be detected by unipolar and bipolar voltage, unipolar voltage being more useful. Mapping and ablation of intramural arrhythmias originating from an intramural focus can be accomplished. PMID- 23985385 TI - Genetic diversity of Echinococcus spp. in Russia. AB - In Russia, both alveolar and cystic echinococcoses are endemic. This study aimed to identify the aetiological agents of the diseases and to investigate the distribution of each Echinococcus species in Russia. A total of 75 Echinococcus specimens were collected from 14 host species from 2010 to 2012. Based on the mitochondrial DNA sequences, they were identified as Echinococcus granulosus sensu stricto (s.s.), E. canadensis and E. multilocularis. E. granulosus s.s. was confirmed in the European Russia and the Altai region. Three genotypes, G6, G8 and G10 of E. canadensis were detected in Yakutia. G6 was also found in the Altai region. Four genotypes of E. multilocularis were confirmed; the Asian genotype in the western Siberia and the European Russia, the Mongolian genotype in an island of Baikal Lake and the Altai Republic, the European genotype from a captive monkey in Moscow Zoo and the North American genotype in Yakutia. The present distributional record will become a basis of public health to control echinococcoses in Russia. The rich genetic diversity demonstrates the importance of Russia in investigating the evolutionary history of the genus Echinococcus. PMID- 23985386 TI - Sexual orientation identity in relation to smoking history and alcohol use at age 18/19: cross-sectional associations from the Longitudinal Study of Young People in England (LSYPE). AB - OBJECTIVES: Information about the health behaviours of minority groups is essential for addressing health inequalities. We evaluated the association among lesbian, gay or bisexual (LGB) sexual orientation identity and smoking and alcohol use in young people in England. DESIGN: Data drawn from wave 6 of the Longitudinal Study of Young People in England (LSYPE). SETTING: Self-completion questionnaires during home visits, face-to-face interviews and web-based questionnaires. PARTICIPANTS: Data from 7698 participants (3762 men) with information on sexual orientation identity and health behaviours at age 18/19. OUTCOME MEASURES: Cigarette smoking history, alcohol drinking frequency and risky single occasion drinking (RSOD). RESULTS: LGB identity was reported by 3.1% of participants (55 gay, 33 lesbian, 35 bisexual male, 111 bisexual female), 3.5% when adjusting for the survey design. Adjusting for a range of covariates, identification as lesbian/gay was found to be associated with smoking (OR=2.23, 95% CI 1.42 to 3.51), alcohol drinking >2 days/week (OR=1.99, 95% CI 1.25 to 3.17) and RSOD (OR=1.80, 95% CI 1.13 to 2.86) more than weekly. Bisexual identity was associated with smoking history (OR=1.84, 95% CI 1.30 to 2.61) but not alcohol drinking >2 days/week (OR=1.20, 95% CI 0.79 to 1.81) or RSOD (OR=1.04, 95% CI 0.71 to 2.86). CONCLUSIONS: In a sample of more than 7600 young people aged 18/19 years in England, lesbian/gay identity is associated with cigarette smoking, drinking alcohol frequency and RSOD. Bisexual identity is associated with smoking but not RSOD or frequent alcohol drinking. PMID- 23985387 TI - Nausea and vomiting in hospice patients. PMID- 23985388 TI - Ketamine for pain in hospice patients. PMID- 23985389 TI - Custom-making medications for the hospice patient. PMID- 23985391 TI - Compounding using hazardous drugs. PMID- 23985390 TI - Surviving cancer: how the comounding pharmacist can help. PMID- 23985392 TI - Providing Positive Outcomes through Compounding for Animal Cancer Patients. PMID- 23985394 TI - The basics of compounding: compounding suppositores: part one-theoretical considerations. PMID- 23985393 TI - Nicotinamide-Adenine Dinucleotide (NADH) in Parkinson's Disease and Alzheimer's Disease. PMID- 23985395 TI - Experimenting with a new emulsifying agent (tahini) in mineral oil emulsion. AB - The use of tahini, a sesame paste, as an emulsifying agent was the subject of this investigation. Mineral oil emulsion, USP was used as an emulsion model. Tahini partially or completely replaced acacia in the oficial emulsion. The rate of creaming (expressed as percent) and the viscosity of the resulting emulsions were measured. Also, emulsions were prepared containing tahini only. The results show that tahini-prepared emulsions had lower creaming rates and viscosity after one month of storage at room temperature. Thus, a better physical stability was achieved when tahini was used as and emulsifying agent. PMID- 23985396 TI - Microbiological stability of a fentanyl, bupivacaine and clonidine mixture in a 0.9% sodium chloride infusion stored in syringes and reservoirs. AB - Combinations of extradural opioids and local anesthetic solutions are used in clinical practice, although little information exists on their microbiological or chemical stability. Currently there are no commercially available, prepacked, ready-to-use epidural mixtures of these medications and all mixtures must be prepared by the pharmacist. Epidural analgesic mixtures have been prepared on an as-needed basis. The aim of this study was to investigate the microbiological stability of a fentanyl, bupivacaine and clonidine mixture in a 0.9% sodium chloride infusion (without preservatives), prepared by the pharmacist in order to provide a basis for recommendations on the exchange of containgers (polypropylene syringes and polyvinylchloride [PVC] reservoirs). This mixture maintained microbiological stability for at least 28 days when prepared under aseptic conditions using a laminar air flow station, with a grade A environment and a B background, and using sterile clothes and equipment. During aseptic preparation in a grade A environment, less than 1 colony forming unit (CFU)/m3 and less than 3500 particles greater than 0.5 micrometers with no particle being greater than 5 micrometers, and in a grade B environment less than 10 CFU/m3 and less than 350,000 particles greater than 0.5 micrometers and less than 2,000 particles greater than 5 micrometers are allowed. Putatuive in situ antimicrobial activity of the drug mixture did not interfere with sterility testing. A pH difference was observed over time between the polypropylene syringes and the PVC reservoirs. PMID- 23985397 TI - Stability of 5-Fluorouracil in an extemporaneously compounded ophthalmic solution. AB - 5-Fluorouracil (5-FU) is used in the treatment of a variety of ophthalmic conditions, including glaucoma, pterygium, retinal detachment and premalignant eye lesions. Specifically for the treatment of pterygium, intravitreal injections of 5-FU have been extemporaneously compounded by pharmacists and typically stored in syringes. No data exist concerning the chemical and physical stability of these solutions. With this in mind, the stability of 5-FU (1mg/0.1mL) in 0.9% sodium chloride injection prepared in the hospital pharmacy laboratory at the University of South Carolina was studied with respect to time and temperature. Admixtures of 5-FU were aseptically prepared and stored in 1-mL tuberculin syringes. The stability of these solutions was evaluated in a freezer, in a refrigerator, at room temperature and in an oven set at 40 deg C. Immediately after prepareation, samples were collected to determine initial concentration using a stability-indicating high-performance liquid chromatography method and to assess the pH of the solution. The same tests were repeated after one, three, five and seven days of storage. Samples were also visually inspected at these times for signs of physical incompatibility. Tuberculin syringes stored at each of the temperatures showed no signs of physical incompatibility (precipitate) or loss of drug. There was also no appreciable change in pH of the solution over the study period. This study showed that aseptically prepared 5-FU ophthalmic solutions packaged in tuberculin syringes can be stored safely for up to seven days at temperatures ranging form -10 to 40 deg C/ PMID- 23985398 TI - [Effectiveness of simultaneous cardiac resynchronization therapy in surgical valvular patients with severe heart failure]. AB - BACKGROUND: Cardiac resynchronization therapy (CRT)has been accepted broadly as an alternative to medical treatment in managing severe heart failure patients. Despite advance in CRT, the presence of a significant valvular heart disease was currently specific exclusion criteria and a response to this therapy remains unclear. The purpose of this study was to determine the effectiveness of CRT in heart failure patients undergoing valvular operation simultaneously. PATIENTS AND METHODS: Between July 2010 and May 2012, 8 heart failure patients who underwent CRT in conjunction with valvular surgery were experienced. Right and left ventricular and atrial epicardial leads were implanted after completion of valvular procedures. In patients with chronic atrial fibrillation(Af),maze procedure was performed in order to eliminate Af. To evaluate the improvement of ventricular mechanical dyssynchrony, the echocardiographic assessment was repeated on admission and 1 month after the CRT implantation. RESULTS: There was no operative death. One patient of ischemic cardiomyopathy died of sustained ventricular tachycardia 2 months after the operation. Postoperative course of severe heart failure patients was uneventful and all patients except 1 discharged on foot with improved New York Heart Association (NYHA) class. Echocardiographic parameters of dyssynchrony did not reach to statistical significance, but several parameters, left ventricular( LV)-pre-ejectionperiod( PEP) and interventricular mechanical delay (IVMD) showing time delay of cardiac contraction, tended to be improve, suggesting contribution to satisfactory postoperative course. CONCLUSION: The acceptable outcome was demonstrated with our concept to recover the intraventricular and atrioventricular synchrony. Although it might be difficult to establish the patient selection criteria for concomitant CRT and valvular surgery, our strategy is considered to be a feasible procedure to improve the morbidity and mortality in patients with severe heart failure due to valvular disease. PMID- 23985399 TI - [Beating mitral valve surgery in patients with poor left ventricular function]. AB - Mitral valve surgery is usually performed under the arrested heart condition. However, cardioplegic arrest techniques will inevitably produce some degree of reperfusion injury. We expected that keeping heart beating decrease the reperfusion injury in patients with poor left ventricular function. The present study compared the results of beating heart technique and conventional mitral valve surgery to demonstrate the merit of this technique. Thirty six patients with low left ventricular function[ ejection fraction (EF)<=35%] who underwent mitral valve surgery between April 2004 and July 2012 were enrolled in this study. On-pump beating mitral valve surgery were performed in 21 patients (beating group). Fifteen patients underwent conventional mitral valve surgery with cardiac arrest using blood cardioplegia (arrest group). Postoperative cardiac events in the beating group were less than that in the arrest group. However, this difference in both groups was not statistically significant. The visual field of the beating heart was equal to that of conventional surgery, and technical accuracy was not compromised. To decrease postoperative cardiac events, beating-heart mitral valve surgery may be suitable surgical option for patients with poor left ventricular function. PMID- 23985400 TI - [Surgical ventricular restoration for functional mitral regurgitation]. AB - BACKGROUND: This study evaluated the effectiveness and limitations of the surgical ventricular restoration(SVR)procedure in patients with functional mitral regurgitation(FMR)due to severe leaflet tethering. METHODS: From 2008 to 2012, FMR was treated in 39 patients by either mitral annuloplasty(MAP)alone( group M:n=17) or MAP combined with SVR( group S:n=22). Preoperatively, patients in group S had lower ejection fraction( EF), larger left ventricle, and more severe mitral regurgiation( MR) comparing to group M. RESULTS: The SVR performed in group S included posterior wall exclusion(Batista)in 10, septal anteriorventricular exclusion in 8, overlapping ventriculoplasty in 2, and others in addition to papillary muscle approximation(PMA). Coronary revascularization was more common in the group M. Hospital mortality were 18% in group S and 0 in group M. There were no significant improvement on EF in both group, but left ventricular( LV) dimensions decreased significantly in both groups. Also, MR grade decreased significantly in both groups. Leaflet tethering was improved significantly in group S. There were 5 and 1 late deaths in group S and M, respectively. CONCLUSION: SVR in addition to MAP yielded excellent reduction of leaflet tethering and MR in patients with severe LV dilatation. However, long term outcomes were poor in those requiring SVR. PMID- 23985402 TI - [Preserving autologous heart operation for dilated cardiomyopathy]. AB - OBJECTIVE: We report non transplant surgical procedure (preserving autologous heart operation) for the patients with dilated cardiomyopathy( DCM), clinical outcomes, and the factor of predict prognosis. PATIENT AND METHOD: Since May 2000, 258 patients received surgical procedure for 11 years. SURGICAL PROCEDURES: We performed mitral surgery (plasty or replacement) for the patients with more than mild mitral regurgitation (MR). We performed papirally muscule plication since 2005, and we performed 2nd chordal cutting since 2008, for the patients with MR due to mitral tethering. The surgical left ventricular reconstruction( SVR) was performed for the patients with dilated left ventricular. We use spackle tracking echocardiography to decide the type of SVR since 2008. RESULT: Hospital death was 18.2%, and late cardiac death was 27.5%.Almost the cause of death was congestive heart failure and ventricular arrhythmia. Five years survival was 58%, 10 years survival was 39%. Preoperative condition, emergent operation, inotropic support, intra aortic balloon pumping(IABP),affect the prognosis. But left ventricular size did not affect it. CONCLUSION: Surgical treatment for the patient with DCM should be performed with stable preoperative condition. PMID- 23985401 TI - [Optimal indication for surgical ventricular restoration for dilated cardiomyopathy]. AB - In this study, we assessed mid-term results of surgical ventricular restoration (SVR) for dilated cardiomyopathy. The study subjects were 107 patients who underwent SVR for both ischemic (ischemic cardiomyopathy:ICM, n=57) and non ischemic (dilated cardiomyopathy:DCM, n=50) dilated cardiomyopathy. In 49(86%)patients ICM was associated with New York heart Association(NYHA) class III or more. Preoperative left ventricular ejection fraction (LVEF) and left ventricular end-diastolic dimension(LVDd)were 22+/-6% and 67+/-9 mm, respectively. Hospital mortality was 14% and 5-year mortality was 40%. In contrast, 46( 92%) of the DCM patients presented with NYHA class III or more. Preoperative LVEF and LVDd were 20+/-6% and 74+/-9 mm, respectively. Hospital mortality was 28% and 5-year mortality was 63%. For NYHA class III or less, however, 5-year mortality rates were 23% and 39% in those with ICM and DCM, respectively. For those with NYHA functional class III or less, SVR was associated with a satisfactory survival rate and is recommended. For those with severe heart failure, however, ventricular assist devices or heart transplantation may have to be indicated. PMID- 23985403 TI - [Donor heart preservation with University of Wisconsin solution and immunosuppressive therapy with drip-infusion of tacrolimus]. AB - Clinical approach for heart transplantation in Kyushu University Hospital Heart Center about donor heart preservation and immunosuppressive therapy is reviewed. University of Wisconsin solution has been used for donor heart preservation as the 1st-line solution, because left ventricular function after both 6-hour and 24 hour preservation with University of Wisconsin solution was superior to that with Celsior solution on the cross-circulated rabbit heart preparation model. Donor hearts are arrested by the extracellular-type cardioplegia to prevent coronary vasoconstriction associated with preservation in University of Wisconsin solution. Tacrolimus has been used as immunosuppressive agent. Drip-infusion of tacrolimus (0.02 mg/kg per day) is started immediately after heart transplantation aiming at definitive blood level control. PMID- 23985404 TI - [Treatment of end-stage heart failure by implantable ventricular assist devices]. AB - The strategy for severe heart failure treatment has changed dramatically since 2011 by the initiation of clinical use of implantable continuous flow ventricular assist devices( LVADs) in Japan. The continuous flow LVADs include DeBakey ventricular assist device (VAD), HeartMate II, HeartWare, Dura-Heart, and EVAHEART, although EVAHEART alone is clinically available in Japan currently. Hear-Mate II is the most popular LVAD with more than 10,000 worldwide implants, while its clinical result is superior to implantable pulsatile LVADs. Crucial complications with implantable LVADs include infection, aortic valve insufficiency, thromboembolism, bleeding, and right heart failure during circulatory support. Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) has started in the United States, while Japanese Registry for Mechanically Assisted Circulatory Support(JMACS) initiated in Japan in 2010. These registries are essential for clinical evaluation of implantable LVADs as well as research and development in this field. The circulatory support with implantable LVADs is expected to be further contribution for the treatment of for end-stage heart failure patients. PMID- 23985405 TI - [Mid-long term result of implantable ventricular assist device treatment for end stage heart failure in the University of Tokyo Hospital]. AB - Two implantable left ventricular assist devices(I-LVADs)were approved in Japan in 2011. I-LVADs were used for end-stage heart failure of 20 patients in our institute until March 2012. We examine the clinical course of these 20 patients who were treated with I-LVADs. End points are transplantation, death, or weaning from I-LVADs. Mean hospital days after I-LVAD implantation were 58.1 days, and all 20 patients could discharge from hospital alive. Until September 2012, mean follow up interval was 515 days. Five patients reached heart transplantation, 2 died, weaning from an I-LVAD could be done in 1 patient, and 12 continued to wait for heart transplantation. Survival rate was 100% at 1 month, 95% at 3 months, and 89% at 1 year, respectively. Mean follow up duration after discharge were 457 days, and 16 patients(80%)needed a total of 41 times of readmission in this period. Freedom from readmission was 75% at 1 month, 60% at 3 months, and 25% at 1 year, respectively. In conclusion, prognosis of I-LVAD treatment was good, but many patients needed readmission after I-LVAD implantation and follow up system for I-LVAD treatment should be improved immediately. PMID- 23985406 TI - [Clinical results of continuous-flow left ventricular assist device(LVAD) for severe heart failure patients]. AB - BACKGROUND: Continuous-flow left ventricular assist device(LVAD)has undergone dramatic change into strategy of treating severe heart failure. In this report, we describe our clinical results and problems of continuous-flow LVAD and discuss the future strategy for heart failure patients. METHODS AND RESULTS: Twenty-nine heart failure patients (34.9+/-12.2 year-old, 20 male) underwent continuous-flow LVAD at Osaka University Hospital since approval of reimbursement of health insurance at 2010. The overall survival and the LVAD related complications were retrospectively evaluated in these 29 patients. The overall survival rate was 96% at 1 year and 96% at 2 years. Seven patients required right ventricular assist device (RVAD) including 3 patients converted to durable RVAD. Cerebrovascular complications was developed in 7 patients and 1 of the 7 patients died from hemorrhagic infarction. Device related infection was detected in only 1 patient with immunosuppressive therapy. CONCLUSIONS: The clinical results of continuous flow LVAD were sufficient and the trend of recent increment of aging donor demands reconsideration of comprehensive strategy for severe heart failure. PMID- 23985407 TI - [Heart transplantation and ventricular assit systems]. AB - Since the organ transplantation law was passed, we performed 50 heart transplantation at National Cerebral and Cardiovascular Center. Of those, 2 patients have been doing well over 13 years and 10 years survival rate was 93.4%.During those years, we performed 139 applications of left ventricular assist systems( LVAS). Initially, extracorporeal LVASs had been used. Now, 2 implantable LVAS were approved by medical insurance as bridge to transplant in 2011. Now, our 1st option as bridge to transplantation(BTT) is implantable LVAS. PMID- 23985408 TI - [Molecular biological review of esophageal cancer]. AB - Esophageal squamous cell carcinoma accounts for most esophageal cancers in East Asia. Esophageal adenocarcinoma arises from Barrett's esophagus. However, patients with advanced disease remain poor prognosis. Therefore, it is needed to clarify the carcinogenic mechanism and cancer metastatic process in esophageal cancer. Here, we described the recent research approaches of microarray and next generation sequence in esophageal squamous cell carcinoma and esophageal adenocarcinoma. PMID- 23985409 TI - Biocatalyst mediated production of 6beta,11alpha-dihydroxy derivatives of 4-ene-3 one steroids. AB - Biotransformation of steroids with 4-ene-3-one functionality such as progesterone (I), testosterone (II), 17alpha-methyltestosterone (III), 4-androstene-3,17-dione (IV) and 19-nortestosterone (V) were studied by using a fungal system belonging to the genera of Mucor (M881). The fungal system efficiently and quantitatively converted these steroids in regio- and stereo-selective manner into corresponding 6beta,11alpha-dihydroxy compounds. Time course experiments suggested that the transformation was initiated by hydroxylation at 6beta- or 11alpha-(10beta hydroxy in case of V) to form monohydroxy derivatives which upon prolonged incubation were converted into corresponding 6beta,11alpha-dihydroxy derivatives. The fermentation studies carried out using 5L table-top fermentor with substrates (I and II) clearly indicates that 6beta,11alpha-dihydroxy derivatives of steroids with 4-ene-3-one functionality can be produced in large scale by using M881. PMID- 23985410 TI - Epicardial catheter-based ventricular reconstruction: a novel therapy for ischaemic heart failure with anteroapical aneurysm. AB - OBJECTIVES: Surgical ventricular reconstruction has been used to treat ischaemic cardiomyopathy with large akinetic or dyskinetic areas. However, application of this approach requires a sternotomy, cardiopulmonary bypass and a left ventriculotomy. This study assessed the feasibility and efficacy of minimally invasive, off-pump, epicardial catheter-based ventricular reconstruction (ECVR) in an anteroapical aneurysm ovine model. METHODS: Left ventricular (LV) anteroapical myocardial infarction was induced percutaneously by coil embolization of the left anterior descending coronary artery. Eight weeks after infarction, via mini left thoracotomy and without cardiopulmonary bypass, ECVR was performed in six sheep. The scar was excluded by placing anchor pairs on the LV epicardial anterior wall and the right ventricular side of the interventricular septum under fluoroscopic guidance. LV performance was evaluated before, immediately after device implantation and after 6 weeks by echocardiography. Terminal histopathology was performed. RESULTS: ECVR was completed expeditiously in all animals without complications. Parameters obtained 6 weeks after device implantation were compared with baseline (pre-device). End systolic volume was decreased by 38% (25.6 +/- 6.1 ml vs baseline 41.2 +/- 7.2 ml, P = 0.02) with preservation of stroke volume. Ejection fraction was significantly increased by 13% (48.5 +/- 7% vs baseline 35.8 +/- 7%, P = 0.02). The circumferential strain in the anterior septum (-7.67 +/- 5.12% vs baseline 0.96 +/- 2.22%, P = 0.03) and anterior wall (-9.01 +/- 3.51% vs baseline -4.15 +/ 1.36%, P = 0.01) were significantly improved. The longitudinal strain in apex was reversed (-3.08 +/- 1.53% vs baseline 3.09 +/- 3.39%, P = 0.01). Histopathology showed full endocardial healing over the anchors with appreciable reduction of the chronic infarct in the LV. CONCLUSIONS: ECVR without cardiopulmonary bypass is a less invasive alternative to current standard therapies, reverses LV remodelling and improves cardiac performance in an ovine model of anteroapical aneurysm. PMID- 23985411 TI - Perioperative sildenafil therapy for pulmonary hypertension in infants undergoing congenital cardiac defect closure. AB - OBJECTIVES: Pulmonary hypertension in paediatric patients with ventricular septal defect remains one of the most important determinants of perioperative morbidity and mortality. Sildenafil is an oral, well-tolerated pulmonary vasodilator with few drug interactions. We studied the effect of oral sildenafil, when given before and after surgical closure compared with starting it postoperatively, on the pulmonary artery pressure and patients' outcome. METHODS: We enrolled 101 infants with large ventricular septal defects who had moderate-to-severe pulmonary hypertension scheduled for surgical closure. They were randomly assigned to the sildenafil group (n = 51, mean age 10 months and mean weight 6.5 kg), in which oral sildenafil was started 2 weeks before surgery to be continued postoperatively, and to the control group (n = 50, mean age 11 months and mean weight 7.3 kg), in which sildenafil was started only postoperatively. It was started at 0.5 mg/kg and increased gradually to a maximum dose of 2 mg/kg in both groups. RESULTS: Overall hospital mortality was 4.9%. Mean pulmonary artery pressure decreased significantly at all time points of recording in both groups (P < 0.0001). In the sildenafil group, it decreased preoperatively after sildenafil administration from 75.4 to 59.4 mmHg and postoperatively from 50.4 mmHg immediate post-cardiopulmonary bypass to reach 44.2 mmHg before discharge. In the control group, it decreased from 74.6 mmHg to 51 mmHg immediate post cardiopulmonary bypass to reach 42.7 mmHg before discharge. No adverse effects have been recorded. Although there was no difference in the duration of mechanical ventilation and hospital stay between the two groups, intensive care unit stay was significantly shorter in the sildenafil group. Dobutamine doses were significantly higher in the sildenafil group; however, milrinone and epinephrine have been used more significantly in the control group. CONCLUSIONS: The low cost, the oral availability and the good tolerability of sildenafil make it a suitable and simple alternative therapy for secondary pulmonary hypertension including persistent postoperative pulmonary hypertension associated with ventricular septal defect in resource limited places. However, starting sildenafil early before surgery does not add a great benefit in terms of improving postoperative pulmonary hypertension or patients' outcome. PMID- 23985412 TI - Minimally invasive direct coronary artery bypass in a child with an occlusion of left main coronary artery after arterial switch operation. AB - We present a case of a 13-year old girl experiencing recurring angina pectoris due to an occlusion of the left main coronary artery after arterial switch operation in infancy. To avoid a repeat sternotomy and the use of cardiopulmonary bypass, the patient underwent uncomplicated operative myocardial revascularization in the minimally invasive direct coronary artery bypass (MIDCAB) technique. PMID- 23985413 TI - Disseminated skin lesions of IgG4-related disease. PMID- 23985414 TI - The need for psychological needs: a role for social capital. AB - Van de Vliert embraces a "supply side" model of human needs, underplaying a "demand" model whereby individuals, motivated by psychological needs, develop coping strategies that help them meet their personal goals and collectively exert an influence on social and economic systems. Undesirable climates may inflate the value of financial capital, but they also boost the value of social capital. PMID- 23985415 TI - Digoxigenin-labeled in situ hybridization for the detection of Streptococcus suis DNA in polyserositis and a comparison with biotinylated in situ hybridization. AB - The objective of this study was to develop digoxigenin-labeled in situ hybridization (ISH) for the detection of Streptococcus suis in naturally infected pigs with polyserositis and to compare it with biotinylated ISH. Digoxigenin labeled hybridization signals for S. suis were observed in cells that had infiltrated the fibrous polyserositis and microcolonies in the blood vessels. Mock hybridization showed no hybridization signals for endogenous digoxigenin. Biotinylated hybridization signals for S. suis were observed in cells that had infiltrated the fibrous polyserositis. However, similar hybridization signals were also observed in the fibrous inflammatory area using mock hybridization for endogenous biotin. The present study demonstrated that digoxigenin-labeled ISH is a valuable diagnostic tool for specific detection of S. suis in polyserositic tissues without nonspecific reactions compared with biotinylated ISH. PMID- 23985416 TI - Therapeutic effect of exogenous hsp70 in mouse models of Alzheimer's disease. AB - Brain deterioration resulting from "protein folding" diseases, such as the Alzheimer's disease (AD), is one of the leading causes of morbidity and mortality in the aging human population. Heat shock proteins (Hsps) constitute the major cellular quality control system for proteins that mitigates the pathological burden of neurotoxic protein fibrils and aggregates. However, the therapeutic effect of Hsps has not been tested in a relevant setting. Here we report the dramatic neuroprotective effect of recombinant human Hsp70 in the bilateral olfactory bulbectomy model (OBX mice) and 5XFAD mouse models of neurodegeneration. We show that intranasally-administered Hsp70 rapidly enters the afflicted brain regions and mitigates multiple AD-like morphological and cognitive abnormalities observed in model animals. In particular, in both cases it normalizes the density of neurons in the hippocampus and cortex which correlates with the diminished accumulation of amyloid-beta (Abeta) peptide and, in the case of 5XFAD mice, reduces Abeta plaque formation. Consistently, Hsp70 treatment also protects spatial memory in OBX and 5XFAD mice. These studies demonstrate that exogenous Hsp70 may be a practical therapeutic agent for treatment of neurodegenerative diseases associated with abnormal protein biogenesis and cognitive disturbances, such as AD, for which neuroprotective therapy is urgently needed. PMID- 23985417 TI - Does study partner type impact the rate of Alzheimer's disease progression? AB - Most patients with Alzheimer's disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse versus adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer's Coordinating Center Uniform Data Set to examine disease progression in participants age 55-90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal. PMID- 23985418 TI - Vascular impairment in Alzheimer's disease: the role of obstructive sleep apnea. AB - Epidemiological studies have suggested a pathophysiological link between obstructive sleep apnea syndrome (OSAS) and Alzheimer's disease (AD). The mechanism by which sleep disturbance can affect cognitive impairment is not clear. The aim of this study was to investigate whether AD patients with OSAS have an impairment in cerebrovascular disease markers. We included 69 patients without OSAS and 93 patients with OSAS. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). Pathological values of IMT and BHI were significantly associated with the presence of OSAS (IMT > 1.0 mm: OR 2.98, 95%CI: 1.37-6.46; p < 0.05; BHI < 0.69: OR 5.25, 95%CI: 2.35-11.74; p < 0.05, multivariate adjusted analysis). Furthermore, the extent of cerebrovascular impairment was correlated with the severity of OSAS. The finding of alterations of cerebral vessel functional and anatomic status in AD patients with OSAS suggests the potential for effective treatment for sleep-related disturbances in a subgroup of AD patients. PMID- 23985419 TI - Can we teach old dogs new tricks? Neuroprotective cell therapy in Alzheimer's and Parkinson's disease. AB - Human neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease represent unmet medical need. There is no effective cure available on the market. Several novel therapeutic approaches targeting fundamental features of these disorders have been proposed during the last two decades. Cell therapy represents one of the most promising therapeutic avenues targeting different pathological traits of these disorders. However, there are some caveats that should be taken into the consideration including ethical issues and limited utilization for routine clinical practice. It is unlikely that cell therapy constitutes the 'magic bullet' therapeutic approach that would meet all therapeutic needs. However, in the future it can potentially bolster the effect of disease modifying drugs by improving the brain environment and regulation of inflammatory and neurotrophic pathways. PMID- 23985420 TI - Targeting synaptic dysfunction in Alzheimer's disease by administering a specific nutrient combination. AB - Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer's disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models. PMID- 23985421 TI - Binding investigation on the interaction between Methylene Blue (MB)/TiO2 nanocomposites and bovine serum albumin by resonance light-scattering (RLS) technique and fluorescence spectroscopy. AB - The interaction between Methylene Blue (MB)/TiO2 nanocomposites and bovine serum albumin (BSA) was investigated by resonance light scattering (RLS), fluorescence, three-dimension spectra and UV-vis absorbance spectroscopy. Several factors which may influence the RLS intensity were also investigated before characterizing MB/TiO2-BSA complex. It was proved that the mechanism of MB/TiO2 nanocomposites binding to BSA was mainly a result of the formation of MB/TiO2-BSA complex. The binding constant of MB/TiO2-BSA is 0.762 * 10(-5) L mol(-1) at 298K. By calculating the binding constant at different temperature, the thermodynamic parameters DeltaH, DeltaG, and DeltaS can be observed and deduced that the hydrophobic interactions played an important role to stabilize the complex. The distance r (3.73 nm) between donor (BSA) and acceptor (MB/TiO2) was obtained according to fluorescence resonance energy transfer (FRET). The binding site for MB/TiO2 on BSA was mainly located in sub-domain IIA. The UV-vis absorbance, circular dichroism and three dimension fluorescence have also been used to investigate the effect of MB/TiO2 on the conformation of BSA. PMID- 23985422 TI - Combination of positioning therapy and venovenous extracorporeal membrane oxygenation in ARDS patients. AB - Positioning therapy may improve lung recruitment and oxygenation and is part of the standard care in severe acute respiratory distress syndrome (ARDS). Venovenous extracorporeal membrane oxygenation (vvECMO) is a rescue strategy that may ensure sufficient gas exchange in ARDS patients failing conventional therapy. The aim of this case series was to describe the feasibility and pitfalls of combining positioning therapy and vvECMO in patients with severe ARDS. A retrospective cohort of nine patients is described. The patients received 20 (15 86) hours (median, 25(th) and 75(th) percentile) of positioning therapy while being treated with vvECMO. The initial PaO2/FiO2 index was 64 (51-67) mmHg and the arterial carbon dioxide tension was 60 (50-71) mmHg. Positioning therapy included 135 degrees prone, prone positioning and continuous lateral rotational therapy. During the first three days, the oxygenation index improved from 47 (41 47) to 12 (11-14) cmH2O/mmHg. The lung compliance improved from 20 (17-28) to 42 (27-43) ml/cmH2O. Complications related to positioning therapy were facial oedema (n=9); complications related to vvECMO were entrance of air (n=1) and pump failure (n=1). However, investigation of root causes revealed no association with the positioning therapy and had no documented effect on the outcome. The reported cases suggest that positioning therapy can be performed safely in ARDS patients treated with vvECMO, providing appropriate precautions are in place and a very experienced team is present. PMID- 23985423 TI - Efficacy and safety of strategies to preserve stable extracorporeal life support flow during simulated hypovolemia. AB - AIM: Without volume-buffering capacity in extracorporeal life support (ELS) systems, hypovolemia can acutely reduce support flow. This study aims at evaluating efficacy and safety of strategies for preserving stable ELS during hypovolemia. MATERIAL & METHODS: Flow and/or pressure-guided servo pump control, a reserve-driven control strategy and a volume buffer capacity (VBC) device were evaluated with respect to pump flow, venous line pressure and arterial gaseous microemboli (GME) during simulated normovolemia and hypovolemia. RESULTS: Normovolemia resulted in a GME-free pump flow of 3.1 +/- 0.0 L/min and a venous line pressure of -10 +/- 1 mmHg. Hypovolemia without servo pump control resulted in a GME-loaded flow of 2.3 +/- 0.4 L/min with a venous line pressure of -114 +/- 52 mmHg. Servo control resulted in an unstable and GME-loaded flow of 1.5 +/- 1.2 L/min. With and without servo pump control, the VBC device stabilised flow (SD = 0.2 and 0.0 L/min, respectively) and venous line pressure (SD=51 and 4 mmHg, respectively) with near-absent GME activity. Reserve-driven pump control combined with a VBC device restored a near GME-free flow of 2.7 +/- 0.0 L/min with a venous line pressure of -9 +/- 0 mmHg. CONCLUSION: In contrast to a reserve driven pump control strategy combined with a VBC device, flow and pressure servo control for ELS show evident deficits in preserving stable and safe ELS flow during hypovolemia. PMID- 23985424 TI - Prospects for using a hemoconcentrator as an alternative hemodialysis method in cardiopulmonary bypass surgeries. AB - OBJECTIVE: Cardioplegic solutions often cause high blood concentrations of potassium. The conventional hemoconcentration circuit was improved to correct electrolyte imbalances through a method involving dilutional ultrafiltration (DUF) and an alternative hemodialysis (ALTHD) method. This study aimed to determine the effectiveness of this ALTHD method. METHODS: Bovine blood was used, in conjunction with a hemoconcentrator, in an experimental hemodialysis (HD) circuit to evaluate an ALTHD method. The effectiveness of the method was determined by electrolyte and hematocrit measurements following the procedure. RESULTS: The ALTHD method corrected electrolyte levels as effectively as DUF and was less affected by dilution than DUF. CONCLUSION: The ALTHD method may provide faster electrolyte adjustments than DUF because its efficiency depends on both the blood and dialysate flow rates. In addition, the ALTHD method is expected to provide increased efficiency. Thus, our DUF/ALTHD circuit-switching method may be clinically useful when rapid electrolyte correction is required. PMID- 23985425 TI - Commentary on: Efficacy and safety of strategies to preserve stable extracorporeal life support flow during hypovolemia. PMID- 23985426 TI - Does the presence of thyroid antibodies affect the course and outcome of pregnancy in type 1 diabetic women? AB - OBJECTIVE: The aim of the study was to evaluate the significance of the presence of thyroid peroxidase autoantibodies (anti-TPO Abs) in type 1 diabetes mellitus (DM1) pregnant women relative to the course of pregnancy and, especially, with regard to metabolic control, thyroid function, maternal complications and neonatal outcome. METHODS: In a prospective observational study of 91 DM1 women with singleton pregnancies, anti-TPO, anti-thyroglobulin, thyroid-stimulating hormone (TSH), and free thyroxine index (T4/thyroid binding capacity) were measured in each trimester. At each visit, HbA1c, body mass index, and units of insulin per kilogram were recorded, as were complications and pregnancy outcome. RESULTS: Twenty-one (27%) of the 78 women who met the inclusion criteria presented with positive anti-TPO Abs. There were no differences regarding glycemic control (HbA1c) or insulin dose. First-trimester TSH levels were significantly higher in the anti-TPO-positive group than in the anti-TPO-negative group. Finally, no differences were observed regarding diabetic or obstetric complications and neonatal outcome. CONCLUSION: One fourth of DM1 pregnant women presented with positive anti-TPO Abs. However, the presence of anti-TPO Abs does not seem to be related with worse metabolic control or adverse pregnancy outcome. Further investigation is needed; meanwhile, the effort for early treatment of thyroid dysfunction and strict metabolic control in all DM1 women should be continued. PMID- 23985427 TI - The prevalence and clinical features of twin-twin transfusion syndrome with onset during the third trimester. AB - OBJECTIVE: To describe the incidence and clinical features of twin-twin transfusion syndrome (TTTS) with third trimester onset. METHODS: We performed a retrospective chart review of monochorionic diamniotic (MD) twin pregnancies delivered during a recent 4-year period. The inclusion criterion was women who received prenatal care at our center from the first trimester onward. Serial ultrasound examinations were performed at least every 2 weeks until delivery to evaluate fetal growth as well as to estimate amniotic fluid volume. The prevalence of TTTS onset after 28 weeks of gestation and clinical features, including neonatal outcomes and placental findings, were elucidated. RESULTS: Meeting our inclusion criterion were 143 MD twin pregnancies, including 15 TTTS cases (10%). Five cases (4%) developed TTTS during the third trimester and underwent a cesarean section immediately after the diagnosis. All of these women exhibited either abdominal distension or uterine contractions. Recipient twins tended to require more intensive cardiopulmonary treatment than donors, however, neither a recipient nor a donor twin suffered neonatal death or neurological impairment. Placental arterio-arterial anastomoses were detected in three out of five cases. Arteriovenous anastomoses were present in all cases, however, venovenous anastomoses were not found in any case. CONCLUSIONS: TTTS is a relatively rare complication during the third trimester. It is imperative to be observant for the development of TTTS in MD twin pregnancies with any abdominal symptoms, even if they appear insignificant. PMID- 23985428 TI - Resuscitation at birth in neonates with meningomyelocele. AB - AIMS: Compare the need for neonatal resuscitation procedures between newborn infants with and without meningomyelocele (MMC). RESULTS: This retrospective case control study included 94 neonates with MMC, defined as open spinal dysraphism with exposure of nervous tissue, and 94 controls without malformations, paired with MMC infants by gender, mode of delivery, gestational age and time of birth. Infants were born at a university hospital in Sao Paulo, Brazil, from 2001 to 2010. After adjusting for perinatal variables (prenatal care, maternal hypertension, birth during the day shift, cephalic presentation, meconium in the amniotic fluid, gestational age <37 weeks and small-for-gestational-age infants), MMC increased the chance of positive pressure ventilation at birth [odds ratio (OR) 4.55 95% confidence interval (CI) 1.82-11.41], intubation at birth (OR 3.94 95% CI 1.14-13.59) and 1-min Apgar score 95% CI 0.99-7.57). CONCLUSION: MMC is an independent factor associated with the need for positive pressure ventilation and intubation at birth. PMID- 23985429 TI - Influence of different maintenance times of torque application on the removal torque values to loosen the prosthetic abutment screws of external hexagon implants. AB - PURPOSE: To analyze the torque application on prosthetic abutment screws using different maintenance times, to determine an influence on the removal torque values. MATERIALS AND METHODS: A total of 40 external hexagon implants, 40 titanium screws, and 40 customized abutments were used. In group 1, the screws received a torque of 30 N.cm by instant torque application; in groups 2, 3, and 4, torque of 30 N.cm was applied and maintained for 10, 20, and 30 seconds, respectively. Removal torque was performed 10 minutes after torque application. Data were statistically analyzed using 1-way ANOVA and Tukey HSD test (alpha = 0.05). RESULTS: The mean and standard deviation (+/-SD) of removal torque values found were 11.61 +/- 1.43 N.cm for group 1; 18.64 +/- 1.71 N.cm for group 2; 21.62 +/- 0.97 N.cm for group 3; and 21.48 +/- 1.55 N.cm for group 4. Groups 3 and 4 exhibited statistically higher values than group 2, which demonstrated significantly higher values than group 1 (P < 0.05). CONCLUSIONS: A torque of 30 N.cm applied for 20 seconds seemed to be the best option when considering the removal torque values of external hexagon implants. PMID- 23985430 TI - Evidence-based preconceptional lifestyle interventions. AB - Although the evidence for the associations between preconceptional risk factors and adverse pregnancy outcomes is extensive, the effectiveness of preconceptional interventions to reduce risk factors and to improve pregnancy outcomes remains partly unclear. The objective of this review is to summarize the available effectiveness of lifestyle interventions prior to pregnancy for women in terms of behavior change and pregnancy outcome. A predefined search strategy was applied in electronic databases, and citation tracking was performed. Study selection was performed by 2 independent reviewers according to predefined criteria for eligibility: The intervention was performed preconceptionally on women regarding alcohol use, smoking, weight, diet/nutrition, physical activity, and folic acid status (fortification and supplementation) to achieve behavior change and/or improve pregnancy outcome. Quality and strength of evidence were assessed by 2 independent reviewers. A total of 4,604 potentially relevant records were identified, of which 44 records met the inclusion criteria. Overall, there is a relatively short list of core interventions for which there is substantial evidence of effectiveness when applied in the preconception period. PMID- 23985431 TI - Pediatric heart transplantation from donors with depressed ventricular function: an analysis of the United Network of Organ Sharing Database. AB - BACKGROUND: Wait-list mortality for children awaiting heart transplantation remains high. Potential donor hearts with depressed ventricular function are often declined. We aimed to test the hypothesis that pediatric heart transplant recipients of grafts with depressed ventricular function would have comparable survival with those with normal function. METHODS AND RESULTS: A retrospective study was performed for pediatric heart transplants from the United Network of Organ Sharing Database from October 26, 1999, to June 30, 2011. Patients were grouped based on accepted donor left ventricular ejection fraction (LVEF): normal function (LVEF >=55%), mildly depressed function (LVEF 45%-54%), or moderately-to severely depressed function (LVEF <45%). During the study period, there were 3672 pediatric heart transplants; 3306 (90%) had a LVEF reported. Ventricular function was mildly depressed in 245 (7%) and moderately-to-severely depressed in 172 (5%). Patients receiving grafts with moderately-to-severely depressed function were more likely to be younger and weigh less (P<0.001 for both) than those receiving grafts with normal function. Median graft survival from accepted donors with normal ventricular function (10.6 years) was similar to survival from accepted donors with mildly depressed ventricular function (9.7 years; P=0.24) and from accepted donors with moderately-to-severely depressed ventricular function (9.1 years; P=0.13). On propensity-matched analysis, donor ventricular function was not associated with graft survival. CONCLUSIONS: The use of donors with depressed ventricular function is uncommon in pediatric heart transplantation (<15% of all transplants), yet graft survival does not differ significantly from accepted donors with normal ventricular function. Hearts from donors with depressed ventricular function may be considered in selected patients. PMID- 23985433 TI - The development and validation of a new technology, based upon 1.5% arginine, an insoluble calcium compound and fluoride, for everyday use in the prevention and treatment of dental caries. AB - OBJECTIVE: This paper briefly discusses caries prevalence, the multi-factorial nature of caries etiology, caries risk and the role and efficacy of fluoride. The paper also highlights research on bacterial metabolism which provided understanding of the mouth's natural defenses against caries and the basis for the development of a new technology for the everyday prevention and treatment of caries. Finally, evidence that the technology complements and enhances the anti caries efficacy of fluoride toothpaste is summarized. CONCLUSIONS: Global data show that dental caries is a prevalent disease, despite the successful introduction of fluoride. Caries experience depends on the balance between consumption of sugars and oral hygiene and the use of fluoride. Three scientific concepts are fundamental to new measures to detect, treat and monitor caries: (1) dental caries is a dynamic process, (2) dental caries is a continuum of stages from reversible, pre-clinical to irreversible, clinically detectable lesions, and (3) the caries process is a balance of pathological and protective factors that can be modulated to manage caries. Fluoride functions as a protective factor by arresting and reversing the caries process, but fluoride does not prevent pathological factors that initiate the process. A novel technology, based upon arginine and an insoluble calcium compound, has been identified which targets dental plaque to prevent initiation of the caries process by reducing pathological factors. As the mechanisms of action of arginine and fluoride are highly complementary, a new dentifrice, which combines arginine with fluoride, has been developed and clinically proven to provide superior caries prevention. PMID- 23985434 TI - The caries continuum: opportunities to detect, treat and monitor the re mineralization of early caries lesions. AB - The aim of this review is to discuss dental caries as a dynamic process of de mineralization and re-mineralization with progression, arrest or reversal of lesions reflecting the balance between them. The need for new clinical trial designs to assess oral care products which reflect and monitor these processes is highlighted and discussed. The research evidence to support the use of two state of-the-art methods that focus on re-mineralization of natural root caries lesions and natural enamel lesions is described. The use of the Electrical Caries Monitor (ECM) in combination with clinical scoring of lesions to assess the hardness of root dentin and the use of Quantitative Light-induced Fluorescence (QLF) to measure enamel lesions are described together with a number of studies that have employed the methods to assess the efficacy of oral care products. It can be concluded that quantification of the re-mineralization provided by oral care products assessed using both buccal caries and root caries study designs is a valid approach to developing understanding of the mechanism of action of a new technology and to establishing its clinical efficacy in respect of arresting and reversing early caries lesions, and it complements, enhances and may ultimately supplant the information from a conventional two- to three-year clinical trial measuring effects at the cavitation level. PMID- 23985432 TI - Low-sodium DASH diet improves diastolic function and ventricular-arterial coupling in hypertensive heart failure with preserved ejection fraction. AB - BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) involves failure of cardiovascular reserve in multiple domains. In HFPEF animal models, dietary sodium restriction improves ventricular and vascular stiffness and function. We hypothesized that the sodium-restricted dietary approaches to stop hypertension diet (DASH/SRD) would improve left ventricular diastolic function, arterial elastance, and ventricular-arterial coupling in hypertensive HFPEF. METHODS AND RESULTS: Thirteen patients with treated hypertension and compensated HFPEF consumed the DASH/SRD (target sodium, 50 mmol/2100 kcal) for 21 days. We measured baseline and post-DASH/SRD brachial and central blood pressure (via radial arterial tonometry) and cardiovascular function with echocardiographic measures (all previously invasively validated). Diastolic function was quantified via the parametrized diastolic filling formalism that yields relaxation/viscoelastic (c) and passive/stiffness (k) constants through the analysis of Doppler mitral inflow velocity (E-wave) contours. Effective arterial elastance (Ea) end-systolic elastance (Ees) and ventricular-arterial coupling (defined as the ratio Ees:Ea) were determined using previously published techniques. Wilcoxon matched-pairs signed-rank tests were used for pre-post comparisons. The DASH/SRD reduced clinic and 24-hour brachial systolic pressure (155 +/- 35 to 138 +/- 30 and 130 +/- 16 to 123 +/- 18 mm Hg; both P=0.02), and central end-systolic pressure trended lower (116 +/- 18 to 111 +/- 16 mm Hg; P=0.12). In conjunction, diastolic function improved (c=24.3 +/- 5.3 to 22.7 +/- 8.1 g/s; P=0.03; k=252 +/- 115 to 170 +/- 37 g/s(2); P=0.03), Ea decreased (2.0 +/- 0.4 to 1.7 +/- 0.4 mm Hg/mL; P=0.007), and ventricular-arterial coupling improved (Ees:Ea=1.5 +/- 0.3 to 1.7 +/- 0.4; P=0.04). CONCLUSIONS: In patients with hypertensive HFPEF, the sodium-restricted DASH diet was associated with favorable changes in ventricular diastolic function, arterial elastance, and ventricular-arterial coupling. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00939640. PMID- 23985435 TI - The anti-caries efficacy of a dentifrice containing 1.5% arginine and 1450 ppm fluoride as sodium monofluorophosphate assessed using Quantitative Light-induced Fluorescence (QLF). AB - OBJECTIVE: To compare the efficacy of a new dentifrice containing 1.5% arginine, an insoluble calcium compound and 1450 ppm fluoride to arrest and reverse naturally occurring buccal caries lesions in children relative to a positive control dentifrice containing 1450 ppm fluoride alone. STUDY DESIGN: Participants from Chengdu, Sichuan Province, China tested three dentifrices: a new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride, as sodium monofluorophosphate, a positive control dentifrice containing 1450 ppm fluoride, as sodium fluoride, in a silica base, and a matched negative control dentifrice without arginine and fluoride. Quantitative Light-induced Fluorescence (QLF) was used to assess buccal caries lesions at baseline and after 3 and 6 months of product use. RESULTS: 438 participants (initial age 9-13 years (mean 11.1+/-0.78) and 48.6% female) completed the study. No adverse events attributable to the products were reported during the course of the study. The subject mean DeltaQ (mm(2)%), representing lesion volume, was 27.26 at baseline. After 6 months of product use, the DeltaQ values for the arginine-containing, positive and negative control dentifrices were 13.46, 17.99 and 23.70 representing improvements from baseline of 50.6%, 34.0% and 13.1%. After 6 months product use, the differences between the pair wise comparisons for all three groups were statistically significant (p<0.01). The arginine-containing dentifrice demonstrated an improvement after only 3 months that was almost identical to that achieved by the conventional 1450 ppm fluoride dentifrice after 6 months. CONCLUSION: The new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride provides statistically significantly superior efficacy in arresting and reversing buccal caries lesions to a conventional dentifrice containing 1450 ppm fluoride alone. PMID- 23985436 TI - Comparison of the efficacy of a dentifrice containing 1.5% arginine and 1450 ppm fluoride to a dentifrice containing 1450 ppm fluoride alone in the management of early coronal caries as assessed using Quantitative Light-induced Fluorescence. AB - OBJECTIVE: To compare the efficacy of a new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride to a matched, positive control dentifrice containing 1450 ppm fluoride in arresting and reversing early coronal caries lesions in children using Quantitative Light-induced Fluorescence (QLF). STUDY DESIGN: 331 children from Chiang Mai, Thailand, aged 7-14 years, with one or more visible early enamel caries lesions on the upper anterior teeth, completed the study. The new dentifrice contained 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride, as sodium monofluorophosphate; the matched positive control contained 1450 ppm fluoride only. Subjects brushed twice daily at home and additionally once on school days under teacher's supervision. Digital images of the upper six anterior teeth were captured at the baseline, 3- and 6-month examinations using a custom apparatus for reproducible acquisition of Quantitative Light-induced Fluorescence data. RESULTS: At the 3-month examination, the DeltaQ (representing lesion volume) for the test group decreased from a mean of 28.62 at baseline to 20.53 mm(2)% and for the positive control group to 23.38 mm(2)%. The difference between groups was not statistically significant (p=0.055). At the 6-month examination, the DeltaQ decreased for the test group to 15.85 mm(2)% and for the positive control group to 20.35 mm(2)%. The difference between groups was statistically significant (p<0.001). CONCLUSION: A new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride, as sodium monofluorophosphate, provided statistically significant superior efficacy in arresting and reversing active coronal caries lesions in children than brushing with a matched positive control dentifrice containing fluoride alone. PMID- 23985440 TI - Issues and opportunities: compounding for dentistry. PMID- 23985437 TI - Comparing the efficacy of a dentifrice containing 1.5% arginine and 1450 ppm fluoride to a dentifrice containing 1450 ppm fluoride alone in the management of primary root caries. AB - OBJECTIVE: To compare the efficacy of a new dentifrice containing 1.5% arginine and 1450 ppm fluoride to a positive control dentifrice containing 1450 ppm fluoride alone in arresting and reversing primary root caries lesions in adults. STUDY DESIGN: A total of 3779 subjects from Piracicaba, Sao Paulo, Brazil were screened; 284 had at least one leathery primary root caries lesion and were eligible for the study. The new dentifrice contained 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride, as sodium monofluorophosphate; the matched positive control dentifrice contained 1450 ppm fluoride. One lesion for each subject was selected for inclusion in the study and was examined at baseline, 3 and 6 months. RESULTS: A total of 253 subjects completed the study with 129 of 144 subjects included in the final statistical analysis for the test dentifrice and 124 of 140 for the positive control. The mean age of subjects was 45.7 (+/-9.19) years and 56.5% were female. After 6 months product use, 70.5% of root caries lesions improved for subjects using the arginine-containing dentifrice compared to 58.1% for subjects using the positive control. The difference in the number of root caries lesions becoming hard in the two groups was statistically significant (p=0.038). CONCLUSION: A new dentifrice containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride, as sodium monofluorophosphate, provided statistically significantly superior efficacy in arresting and reversing active root caries lesions in adults compared to a matched positive control dentifrice containing fluoride alone. PMID- 23985441 TI - Compounding mouthwashes and rinses for oral ulcerations. PMID- 23985443 TI - Toxicity of amalgams. PMID- 23985442 TI - Mouthwash, toothpaste and toothgel vehicles. PMID- 23985444 TI - Dental compounding in denmark. PMID- 23985445 TI - The basics of compounding: compounding ointments and pastes. PMID- 23985446 TI - FDAMA Proposed List of Agents Not to be Compounded due to Withdrawal for Safety/Efficacy Concerns. PMID- 23985447 TI - Ringworm in cats. PMID- 23985448 TI - Stability of four commercial products delivered by mail order. AB - The purpose of this study was to investigate the stability of four commercial tablets commonly shipped via mail-order delivery. The products were: enalapril maleate 10-mg tablets, digoxin 0.25-mg tablets, clorazepate dipotassium 7.5 mg tablets, and pyridostigmine bromide 60-mg tablets. The stability studies were conducted at 50 deg C, and tablets were exposed for three, seven and 14 days to that temperature. The results demonstrated that all tablets studied were stable in these conditions for their exposure time. Therefore, it appears that all the tablets remained stable and could be used with confidence in mail-order delivery provided the original product packaging is not compromised. PMID- 23985449 TI - Y-site stability of fosphenytoin and sodium phenobarbital. AB - Fosphenytoin and sodium phenobarbital in 0.9% sodium chloride injection were analyzed in a simulated Y-site admixture. Each drug was analyzed for stability by high-pressure liquid chromatography (HPLC) from three simulated Y-site samples over an eight-hour period. The HPLC assay results indicate that both fosphenytoin and sodium phenobarbital are stable together at a Y site over an eight-hour period. In addition, there was no change in sample clarity or pH over the same period. The results indicate that, when medically necessary, fosphenytoin and sodium phenobarbital in 0.9% sodium chloride injection can be administered via the same intravenous line. PMID- 23985450 TI - Five-day Stability of Vinorelbine in 5% Dextrose Injection and in 0.9% Sodium Chloride Injection at Room Temperature. AB - The stability of vinorelbine tartrate in 5% dextrose injection or 0.9% sodium chloride injection stored in polyvinyl chloride minibags was studied. Vinorelbine was diluted to concentrations of 0.5 mg/mL or 2 mg/mL in the above vehicles, and the solution was placed at room temperature and exposed to constant fluorescent lighting. Three bags were prepared for each concentration and solution and each bag was assayed for vinorelbine concentration by stability-indicating high performance liquid chromatography at 0, 24, 48, 96, and 120 hours. Each solution was inspected for clarity, color and precipitation. Throughtout the study, the mean concentration of vinorelbine remaining was more than 94% of the initial concentration in both vehicles. No precipitation, color change or haziness was seen. Vinorelbine, at concentrations of 0.5 mg/mL or 2 mg/mL in 5% dextrose injeciotn or 0.9% sodium chloride injection, was stable for at least 120 hours at room temperature under fluorescent lighting. PMID- 23985451 TI - Protective effect of compounds from the flowers of Citrus aurantium L. var. amara Engl against carbon tetrachloride-induced hepatocyte injury. AB - 5-Hydroxy-6,7,3',4'-tetramethoxyflavone (HTF), limonexic acid (LA) are two compounds isolated from the flowers of Citrus aurantium L. var. amara Engl with various biological activities. This study was designed to investigate their protective effects against carbon tetrachloride (CCl4)-induced hepatocyte injury, using human hepatic cell line HL-7702 to determine the cell cytotoxicity, cell viability, levels of hepatic marker enzymes, malondialdehyde (MDA). Results showed that pretreatment with HTF, LA could significantly reverse CCl4-induced HL 7702 cell viability decrease, LA displayed a higher activity. HTF, LA also showed their capability of decreasing the CCl4-induced leakage of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), inhibiting the lipid peroxidation, HTF showed more significant activity. Given that HTF, LA were not toxic, it is concluded that HTF, LA could effectively protect hepatocyte against CCl4-induced injury. PMID- 23985452 TI - Multiple mycotoxin exposure determined by urinary biomarkers in rural subsistence farmers in the former Transkei, South Africa. AB - Subsistence farmers are exposed to a range of mycotoxins. This study applied novel urinary multi-mycotoxin LC-MS/MS methods to determine multiple exposure biomarkers in the high oesophageal cancer region, Transkei, South Africa. Fifty three female participants donated part of their maize-based evening meal and first void morning urine, which was analysed both with sample clean-up (single and multi-biomarker) and by a 'dilute-and-shoot' multi-biomarker method. Results were corrected for recovery with LOD for not detected. A single biomarker method detected fumonisin B1 (FB1) (87% incidence; mean+/-standard deviation 0.342+/ 0.466 ng/mg creatinine) and deoxynivalenol (100%; mean 20.4+/-49.4 ng/mg creatinine) after hydrolysis with beta-glucuronidase. The multi-biomarker 'dilute and-shoot' method indicated deoxynivalenol-15-glucuronide was predominantly present. A multi-biomarker method with beta-glucuronidase and immunoaffinity clean-up determined zearalenone (100%; 0.529+/-1.60 ng/mg creatinine), FB1 (96%; 1.52+/-2.17 ng/mg creatinine), alpha-zearalenol (92%; 0.614+/-1.91 ng/mg creatinine), deoxynivalenol (87%; 11.3+/-27.1 ng/mg creatinine), beta-zearalenol (75%; 0.702+/-2.95 ng/mg creatinine) and ochratoxin A (98%; 0.041+/-0.086 ng/mg creatinine). These demonstrate the value of multi-biomarker methods in measuring exposures in populations exposed to multiple mycotoxins. This is the first finding of urinary deoxynivalenol, zearalenone, their conjugates, ochratoxin A and zearalenols in Transkei. PMID- 23985454 TI - [Cryosurgery for prostate cancer: a comprehensive review]. AB - OBJECTIVES: Cryosurgery for prostate cancer has evolved to become a reasonable treatment alternative for localized prostate cancer. The advent of third generation machines and smaller cryoprobes together with better imaging modalities allows for precise treatment of the prostate in the primary, salvage and focal setting. METHODS: A comprehensive review of the literature was performed from 1980 to January 2013 searching the Medline database. Information was extracted regarding oncologic and functional outcomes. RESULTS: The outcomes of cryosurgery improved over time with intermediate biochemical disease free survival rates now comparable to other treatment modalities. Initially reported in the salvage setting after radiation therapy, the technology was subsequently expanded as primary treatment and more recently for focal therapy. With introduction of the third-generation cryosurgery system and better imaging modalities, the treatment related morbidities have decreased. CONCLUSIONS: Oncologic and functional outcomes have improved and the procedure is increasing in use. Variable inclusion criteria and follow-up protocols still call for prospective studies to establish the efficacy of the procedure as compared to established local management options. PMID- 23985455 TI - [Editorial comment of: cryosurgery for prostate cancer: a comprehensive review]. PMID- 23985456 TI - [Evolution of the clinical presentation of renal cancer. Fifteen years experience]. AB - OBJECTIVE: To evaluate the evolution of the clinical presentation of this malignancy over time, and its possible prognostic repercussions. METHODS: A retrospective study of 538 patients subjected to surgery due to renal cancer in our hospital during the period 1995-2011. An analysis was made of the evolution of the clinical manifestations at the time of diagnosis, stratifying the results by years during four time periods. RESULTS: At the time of diagnosis, 53,4% of the patients were asymptomatic for 1995-1999 and 72% in the period 2008-2011. Pain is the symptom that occurs most frequently (18.8%) followed by hematuria (15.4% ). The proportion of symptomatic patients increases in relation to stage and histopathological grade. CONCLUSIONS: The clinical presentation of renal cancer has evolved over the years, not in terms of symptoms, which when present are still similar, but in terms of their incidence. PMID- 23985457 TI - [Preoperative predictive model for biochemical recurrence in patients with localized prostate cancer treated with radical prostatectomy]. AB - OBJECTIVES: To identify pre-prostatectomy clinical prognostic factors for biochemical recurrence (BR) and to create a predictive model for BR based or predictive clinical variables prior to radical prostatectomy (RP). METHODS: a retrospective case-records study of patients with clinically localized prostate cancer treated with RPas monotherapy pN0-pNx and monitored at least for 12 months between 1996 and 2007. We considered BR the PSA persistence or elevation after RP greater than 0.4 ng/ml. The clinical variables analyzed were PSA, clinical stage and Gleason score from the biopsy (GS). Univariate and multivariate analysis were carried out using the chi squared test and logistic regression to determine the variables associated with BR. In order to estimate BR based on the variables identified we developed a mathematical model and designed an Excel spreadsheet to apply it. Calibration and discrimination were performed using the Hosmer-Lemeshow test and an ROC curve determining the area under the curve. RESULTS: We included 627 patients. The mean age was 64 years with a mean follow- up of 87 months. The mean PSA was 8 ng/ml. 68.6% of patients had a PSA <= 10 ng/ml, 53,1% had a GS <= 6 and 61,7% had a clinical stage of cT1a-c. BR was observed in 204 (32,5%) patients, 39 due to biochemical persistence. The mean time to BR was 28 months with 89,7% of instances occurring in the first 8 years. On the multivariate analysis, PSA and GS were independent predictors of BR ( p=0.001), while the cT2c stage had a tendency towards statistical significance ( p=0.06). The three variables were included in the equation for the model with different specific weight. Specificity was 93.6%, sensitivity was 36.8% and an overall precision of 75.1%. The model had a predictive capacity of 73% and a p-value < 0.001. CONCLUSIONS: PSA and GS are independent prognostic clinical variables associated with BR-free survival. The predictive model developed allows the risk of BR to be estimated with 73% reliability. PMID- 23985458 TI - [Prostate adenocarcinoma. Predictive clinical model of seminal vesicle involvement]. AB - OBJECTIVES: Our aim is to design a predictive model of seminal vesicle involvement. using clinical data. METHODS: We studied 1128 patients with clinically localized adenocarcinoma treated by radical prostatectomy (127 were pT3b). We identified (logistic regression) clinical variables related with pT3b. With the multivariate study influential variables a seminal vesicle involvement risk model is designed. RESULTS: Seminal vesicle involvement related factors: In univariate study: the influential variables are: Gleason 7 (OR:2);Gleason 8-10 (OR:4.5) T2 (OR:2.6); bilateral involvement in biopsy (OR:3.1); PSA 10-20 ng/ml ( OR:3.3); PSA >20 ng/ ml (OR:9.5). In the multivariate study are influential: Gleason 7 (OR:1.56) Gleason 8-10 ( OR: 3.4); T2 (OR:1.9); PSA 10-20 ng/ml (OR:3.1) and PSA >20 ng/,ml (OR:8.8). Predictive model: using multivariate logistic regression the weight of each variable is valued and a value between 1 and 4 is given. Gleason 2-6, T1; PSA<10 ng/ml value 1; Gleason 7; T2 y PSA 10-20 ng/ml value 2; Gleason 8-10 and PSA >20 ng/ml value 4. Each patient has a marker that fluctuates between 3 and 10. 5 Groups are designed with significantly different risks (p<0.05 in all cases ): Group 1 (3 points) (OR:1) (risk: 2.4% 95%IC 0.7%-4.3%) Group 2 (4 points) (OR:2.7) (risk: 6.5% 95%IC 5%-7.9%); Group 3(5-6 points) (OR:7.1)( risk:15% 95%IC 11%-19%) Group 4 ( 7--8 points) (OR:33.4) (risk: 45.5%; 95%IC 30%-59%) Group 5 (9-10 points) (OR:57.3) (risk: 58.8% 95%IC 35%- 82%). CONCLUSION: The clinical model allows an accurate approximation to the seminal vesicles involvement risk. PMID- 23985459 TI - [Urolift(r), a new minimally invasive treatment for patients with low urinary tract symptoms secondary to BPH. Preliminary results]. AB - OBJECTIVES: To report the preliminary results of one of the first series of patients treated with a new simple surgical technique for the treatment of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and to evaluate its safety and feasibility. METHODS: We have performed a novel surgical treatment of BPH, the UroLift(r) System (Neotract, Inc). It opens the urethra directly by retracting the obstructing prostatic lobes without applying incisions, surgical resection or thermal injury to the prostate. RESULTS: The procedure was carried out in 20 patients with a mean age of 74.3 (43 hyphen;-90) years, with mean prostate volume of 42.6 mL (19 hyphen;109) using the same operative protocol in all case subjects. Mean operative time was 19.1 min (range: 12-45). International Prostate Symptom Score (IPSS) ) at 4 weeks reduced from 26.7 to 16.7 and peak urinary flow rate (Qmax) increased from 8.6 mL/s to 13.2 mL/s. No major complications were encountered, neither sexual dysfunction. Mean follow-up: 12.3 (2-22) months. CONCLUSIONS: The UroLift(r) System procedure appears to be safe and efficient at short term. This technique minimizes the bleeding of the urethra and, therefore, makes bladder catheter not always necessary, and can preserve sexual function with low morbidity. Further studies are warranted to determine long-term outcome. PMID- 23985460 TI - [Page kidney: subcapsular haematoma and arterial hypertension. A new case report and review of the literature]. AB - OBJECTIVE: We present the case of a spontaneous subcapsular renal hematoma with increase of the levels of blood pressure in a patient previously normotensive. METHODS: Patient with abdominal pain, spontaneous without previous trauma. CT showed a right subcapsular kidney hematoma. High levels of blood pressure were noticed at the admission in urology. CONCLUSION: Page kidney is a cause of arterial hypertension due to external compression of renal parenchyma. It could be unnoticed as essential hypertension if high suspicion is not taken into account. Nowadays, the main cause of Page kidney is the renal biopsy in the context of kidney transplantation. The treatment is not recommended in the guidelines although the conservative management is proposed as first option. PMID- 23985461 TI - [Renal cell carcinoma of the collecting ducts of bellini with retroperitoneal recurrence by another histological subtype Of renal tumor]. AB - OBJECTIVE: Collecting Duct Carcinoma or Bellini Carcinoma (CDC) is a rare aggressive histological subtype. We present a case of CDC with retroperitoneal recurrence by another histological subtype of renal tumor and review of the literature. METHODS: A 59-year-old man with no relevant clinical history presented gross hematuria. At the time of diagnosis, a computed tomography ( CT) showed a tumor mass occupying the left renal pelvis. Left Laparoscopic radical nephroureterectomy was performed with endoscopic intramural ipsilateral ureter disinsertion. RESULTS: The pathological diagnosis was CDC with negative surgical margins. A CT scan control was performed 10 months later, showed a left retroperitoneal tumor compatible with a local recurrence. We performed a left subcostal laparotomy with complete resection of the mass. Histological diagnosis was large cell carcinoma with components of granular cells and clear cell. CONCLUSIONS: The CDC is a rare subtype of renal cell carcinoma (RCC) and has an aggressive behavior that is associated with poor prognosis. Surgical resection remains the treatment of choice. We present the first reported case of CDC with retroperitoneal recurrence by another histological subtype of renal tumor. PMID- 23985462 TI - [Renal allograft rupture: case report and bibliographic review]. AB - OBJECTIVE: To improve the knowledge about complications of renal transplantation and, in particular, graft rupture. METHODS: Case report and literature review. OUTCOME: We present the case of a 37 year-old patient receiving a second renal transplant. In the third postoperative day, he suffered an abrupt change from the correct evolution, with intense pain in the left iliac fossa (the side of the implant) and hemodynamic instability. Imaging tests suggested retroperitoneal collection and adjacent to the implant. In this situation we decided reoperation, we found a ruptured renal unit and transplant nephrectomy was carried out. The pathologic study confirmed that the cause of this rupture was acute rejection of the implant. CONCLUSION: The rupture of the graft is one of the most serious complications in renal transplantation. Rapid diagnosis and surgical treatment are required. Conservative management is the treatment of choice for possible preservation of the renal unit, but there are some situations in which it is dangerous and removal of the graft must be carried out. PMID- 23985463 TI - [Endosalpingiosis of the bladder. A case report]. AB - OBJECTIVE: To describe a case of endo-salpingiosis of bladder and review of the literature. METHOD: A 38 years old women referred to an outpatient urology clinic with postmenstrual voiding symptoms. RESULTS: We studied her and ultrasound imaging detects tumor that was confirmed by cystoscopy. She is diagnosed of endosalpingiosis of the bladder after transurethral resection, and a CT shows a consistent mass next to left adnexal with high probablility of being an endometrioma. CONCLUSIONS: Endosalpingiosis of the bladder is a rare disease that occurs in young women with cyclic urinary symptoms. The implantation of tubular tissue in the bladder is diagnosed and treated definitively by tumor excision and anatomopathologic examination. PMID- 23985464 TI - [Urachal adenocarcinoma treated with robotic assisted laparoscopy partial cystectomy]. AB - OBJECTIVE: To describe a case of urachal adenocarcinoma treated with robotic assisted laparoscopic partial cystectomy and en-bloc exeresis of urachus and umbilicus and bibliographic review. METHODS: A 63 year-old man with hematuria and hypogastric pain. He was diagnosed of urachal adenocarcinoma by transurethral resection and axial tomography. We performed a robotic assisted laparoscopic partial cystectomy using a da Vinci(r) S HD (Intuitive Surgical System) device. We describe the surgical technique and examine total length of time for surgery and for console, pathology report, margin status, postoperative outcome and oncological status 7 months after surgery. RESULTS: 4 ports were used for robotic arms and one additional for the assistant. Cystoscopy was performed during surgery to mark tumor margins. Bladder was closed using a running suture with Poliglactin 0. Total length time for surgery was 2hs 28 minutes, console time was 1h54'. Two days later patient was discharged and no complication was reported. After two weeks Foley cathether was removed and bladder volume was 300ml. Pathology report informed undifferentiated urachal adenocarcinoma with perivesical tissue infiltration with margins free from tumor, corresponding to Sheldon IIIB and Ontario III classification. Seven months later patient was fee from recurrence. CONCLUSION: Robotic assisted laparoscopy partial cystectomy with en-bloc exeresis of urachal and umbilicus is feasible. PMID- 23985465 TI - [Multisistemic and renal infarction]. PMID- 23985466 TI - [Mucinous and colloid changes in vesical carcinomas]. PMID- 23985469 TI - Neonatal eosinophilic gastroenteritis: possible in utero sensitization to cow's milk protein. AB - Rectal bleeding in neonates is an alarming sign that suggests a possible serious underlying condition, such as infection or bleeding disorder that would necessitate hospitalization and prompt intervention. We report a case of eosinophilic gastroenteritis caused by cow's milk protein allergy in a one-day- old infant, who presented with frankly bloody stools associated with massive gastrointestinal and peripheral blood eosinophilia prior to initiation of enteral feedings. The patient's outcome was favorable, with complete spontaneous recovery in one week, after a period of bowel rest, parenteral nutrition, and use of amino acid formula. The eosinophilia was also transient and gradually resolving by two months of age. Rectal bleeding secondary to allergic colitis caused by cow's milk sensitization may occur in neonates, and failure to appreciate this possibility may lead to inappropriate diagnostic or therapeutic intervention. PMID- 23985470 TI - Parents' perceptions regarding readiness for their infant's discharge from the NICU. AB - PURPOSE: To identify what parents need to feel ready for the discharge of their infant from the neonatal intensive care unit (NICU). DESIGN: Qualitative. SAMPLE: 20 parents of infants admitted to a Canadian Level III NI CU were interviewed (2011-2012) and asked to identify what they require to feel ready for discharge. Interview transcripts underwent qualitative content analysis to produce a descriptive summary of parents' perceptions of their needs. RESULTS: Parents indicated a need for information and hands-on experience to enhance their readiness for discharge. Observations of their infant and of the NI CU environment impacted parents' perceptions of their infant's readiness for discharge, which influenced perceptions of their own readiness for discharge. Finally, parents require tailoring of information and experiences to meet the unique needs of their family. PMID- 23985471 TI - Communicating with Chinese American families in the NICU using the Giger and Davidhizar transcultural model. AB - Having an infant admitted to the neonatal intensive care unit (NICU) can be a frightening experience for parents. However, it can be even more frightening for them when they are from a different culture and speak a different language than the health care team. Hence, a nurse needs to be culturally competent in order to provide proper care to a multicultural society. The purpose of this article is to describe how NICU nurses can communicate with one such culture, the Chinese American, the largest Asian group in the United States. A transcultural nursing model will be described to use as a guide to help the nurse. The culture, Chinese Americans, will be described to help nurses provide culturally competent care. Research studies will be presented so the reader can develop an understanding of how parents of Chinese descent perceive the care they receive. Interventions and recommendations will be presented on how to enhance communication between the nurses and this cultural group. PMID- 23985472 TI - Jeune syndrome: considerations for management of asphyxiating thoracic dystrophy. AB - Jeune syndrome (JS), or asphyxiating thoracic dystrophy, is a rare genetic disorder characterized by a small, narrow thorax, with associated shortening of limbs. Children with JS present with variable degrees of respiratory distress, frequently lethal in the neonatal period. Other associated complications include renal, hepatic, gastrointestinal, and retinal dysfunction. Management focuses on stabilization and support of respiratory function. Treatment may be palliative in nature or corrective. In recent years, the advance in surgical treatment of the thoracic hypoplasia in JS offers hope to those families with a child suffering from the syndrome. Even with increased research into treatment of this disorder, prognosis is usually poor. Comorbidities associated with JS lead to serious organ dysfunction in later years. Families who have a child with JS need genetic counseling and education focusing on the seriousness of the disorder, the risks and benefits of treatment, and the lifelong needs of those with JS. PMID- 23985473 TI - Ergonomic procedure for heel sticks and shots in Kangaroo Care (skin-to-skin) position. AB - Kangaroo Care (KC) has been recommended as a pain-reducing strategy in neonates; however, KC has not been widely used to minimize procedural pain caused in part by nurses'/phlebotomists' discomfort when positioning themselves and the infant for blood drawing and injections. Therefore, an ergonomically designed setup incorporating the use of KC was introduced into clinical practice to facilitate blood draws and injections. The step-by-step procedure used for heel sticks and injections is presented in this manuscript. After implementing the ergonomic step by-step protocol, complaints of discomfort by nurses and phlebotomists ceased, and an additional benefit was that infant pain responses were significantly reduced. PMID- 23985474 TI - Contact hours, skills fairs, and competency assessment. AB - Various regulatory agencies have indicated the need to measure initial and ongoing competency among health care workers. Yet, what is competency and how can it be measured? In reality, competency assessment is about outcomes. Maintaining and advancing our knowledge, skills, and analytical abilities is important for achieving optimal patient outcomes. Competency assessment should go beyond the act of attending lectures and skills fairs. Competency assessment should be a time when nurses can demonstrate and document their problem-solving and decision making skills, inclusion of best practices, and evidence of how those skills make a difference for the patients they care for. PMID- 23985475 TI - Troponin. AB - Troponin T and I can be found within the myocardial filaments. Measuring these cardiac troponin levels in full-term newborns and premature infants has not become a common practice in the neonatal intensive care unit and newborn nurseries. Research studies are discovering that an elevation in troponin T and I levels can be directly correlated with the severity of the infant's illness, and it can be potentially prognostic of morbidity. This literature analysis discusses what can be considered normal cardiac troponin levels along with what elevated levels are and possible conditions associated with those elevations. PMID- 23985476 TI - Delayed cord clamping: a collaborative practice to improve outcomes. AB - Delayed cord clamping is a collaboration between the obstetric team and the neonatal team. Although the optimal timing for clamping the umbilical cord after birth continues to be subject to study, delaying clamping for at least 30-60 seconds, with the newborn held at or below the level of the uterus/placenta supports normal physiology and has proven benefits. Practical issues such as thermoregulation and equipment can be overcome with team collaboration and prebriefing planning. Neonatal nurses who attend deliveries are perfectly poised to influence this practice and improve short- and long-term outcomes for their patients. PMID- 23985479 TI - Two-photon interference of weak coherent laser pulses recalled from separate solid-state quantum memories. AB - Quantum memories allowing reversible transfer of quantum states between light and matter are central to quantum repeaters, quantum networks and linear optics quantum computing. Significant progress regarding the faithful transfer of quantum information has been reported in recent years. However, none of these demonstrations confirm that the re-emitted photons remain suitable for two-photon interference measurements, such as C-NOT gates and Bell-state measurements, which constitute another key ingredient for all aforementioned applications. Here, using pairs of laser pulses at the single-photon level, we demonstrate two-photon interference and Bell-state measurements after either none, one or both pulses have been reversibly mapped to separate thulium-doped lithium niobate waveguides. As the interference is always near the theoretical maximum, we conclude that our solid-state quantum memories, in addition to faithfully mapping quantum information, also preserve the entire photonic wavefunction. Hence, our memories are generally suitable for future applications of quantum information processing that require two-photon interference. PMID- 23985481 TI - A plausible mechanism for the antimalarial activity of artemisinin: A computational approach. AB - Artemisinin constitutes the frontline treatment to aid rapid clearance of parasitaemia and quick resolution of malarial symptoms. However, the widespread promiscuity about its mechanism of action is baffling. There is no consensus about the biochemical target of artemisinin but recent studies implicate haem and PfATP6 (a calcium pump). We investigated the role of iron and artemisinin on PfATP6, in search of a plausible mechanism of action, via density functional theory calculations, docking and molecular dynamics simulations. Results suggest that artemisinin gets activated by iron which in turn inhibits PfATP6 by closing the phosphorylation, nucleotide binding and actuator domains leading to loss of function of PfATP6 of the parasite and its death. The mechanism elucidated here should help in the design of novel antimalarials. PMID- 23985482 TI - Synthesis and spectral characterization of Schiff base complexes of Cu(II), Co(II), Zn(II) and VO(IV) containing 4-(4-aminophenyl)morpholine derivatives: antimicrobial evaluation and anticancer studies. AB - Metal(II) chelates of Schiff bases derived from the condensation of 4 morpholinoaniline with substituted salicylaldehyde have been prepared and characterized by (1)H NMR, IR, electronic, EPR, and magnetic measurement studies. The complexes are of the type M(X-MPMP)2 [where M=Cu(II), Co(II)), Zn(II), or VO(IV); MPMP=2-[(4 morpholinophenyl imino) methyl] 4-X-phenol, X=Cl, (L1H), X=Br (L2H)]. Single crystal X-ray crystallography studies confirm the structure of newly synthesized Schiff bases. The Schiff bases act as bidentate monobasic ligands, coordinating through deprotonated phenolic oxygen and azomethine nitrogen atoms. The free ligands and metal complexes are screened for their biopotency. Metal complexes exhibit better activity than ligands. Anticancer activity of ligands and their metal complexes are evaluated in human heptocarcinoma(HepG2) cells. The preliminary bioassay indicates that the Schiff base and its zinc complex exhibit inhibitory activity against the human gastric cancer cell lines. PMID- 23985483 TI - Self-assembled fullerene nanostructures. AB - This review briefly summarizes recent developments in fabrication techniques of shape-controlled nanostructures of fullerene crystals across different length scales and the self-assembled mesostructures of functionalized fullerenes both in solutions and solid substrates. PMID- 23985484 TI - Application of FTIR-ATR spectroscopy coupled with multivariate analysis for rapid estimation of butter adulteration. AB - In dairy product sector, butter is one of the potential sources of fat soluble vitamins, namely vitamin A, D, E, K; consequently, butter is taken into account as high valuable price from other dairy products. This fact has attracted unscrupulous market players to blind butter with other animal fats to gain economic profit. Animal fats like mutton fat (MF) are potential to be mixed with butter due to the similarity in terms of fatty acid composition. This study focused on the application of FTIR-ATR spectroscopy in conjunction with chemometrics for classification and quantification of MF as adulterant in butter. The FTIR spectral region of 3910-710 cm-1 was used for classification between butter and butter blended with MF at various concentrations with the aid of discriminant analysis (DA). DA is able to classify butter and adulterated butter without any mistakenly grouped. For quantitative analysis, partial least square (PLS) regression was used to develop a calibration model at the frequency regions of 3910-710 cm-1. The equation obtained for the relationship between actual value of MF and FTIR predicted values of MF in PLS calibration model was y = 0.998x + 1.033, with the values of coefficient of determination (R2) and root mean square error of calibration are 0.998 and 0.046% (v/v), respectively. The PLS calibration model was subsequently used for the prediction of independent samples containing butter in the binary mixtures with MF. Using 9 principal components, root mean square error of prediction (RMSEP) is 1.68% (v/v). The results showed that FTIR spectroscopy can be used for the classification and quantification of MF in butter formulation for verification purposes. PMID- 23985485 TI - Characterization of aroma-active compounds in dry flower of Malva sylvestris L. by GC-MS-O analysis and OAV calculations. AB - In this study, the aroma-active compounds in the dried flower of Malva sylvestris L. were extracted by hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS), and gas chromatography-olfactometry (GC-O) and aroma extraction dilution analysis (AEDA). A light yellow oil with a sweet odor was obtained with a percentage yield of 0.039% (w/w), and 143 volatile compounds (89.86%) were identified by GC-MS. The main compounds were hexadecanoic acid (10.1%), pentacosane (4.8%) and 6,10,14-trimethyl-2-pentadecanone (4.1%). The essential oil consisted mainly of hydrocarbons (25.40%) followed by, alcohols (18.78%), acids (16.66%), ethers (5.01%) ketones (7.28%), esters(12.43%), aldehydes (2.30%) and others (2.00%). Of these compounds, 20 were determined by GC-O and AEDA, to be odor-active (FD (flavor dilution) factor >= 1). beta Damascenone (FD = 9, sweet), phenylacetaldehyde (FD = 8, floral, honey-like) and (E)-beta-ocimene (FD = 8, spicy) were the most intense aroma-active compounds in M. sylvestris. In order to determine the relative contribution of each of the compounds to the aroma of M. sylvestris, odor activity values (OAVs) were used. beta-Damascenone had the highest odor activity values (OAV) (50,700), followed by (E)-beta-ionone (15,444) and decanal (3,510). In particular, beta-damascenone had a high FD factors, and therefore, this compound was considered to be the main aroma-active components of the essential oil. On the basis of AEDA, OAVs, and sensory evaluation results, beta-damascenone is estimated to be the main aroma active compound of the essential oil. PMID- 23985486 TI - Solution properties of amphiphilic telomers with multiple sugar chains and terminal alkyl chain. AB - Amphiphilic telomers with multiple sugar chains and a terminal undecyl or heptadecyl chain (i.e., C(n)Am-mGEMA, where n and m represent alkyl chain lengths of 11 or 17 with a degree of polymerization of 2.0 or 3.0 for glucosyloxyethyl methacrylate (GEMA) units, respectively) were synthesized via monomeric radical telomerization in the presence of 2-aminoethanethiol hydrochloride. Surface tension, pyrene fluorescence, and dynamic light scattering were measured to characterize the solution properties of the synthesized telomers. In addition, the effects of alkyl chain length and degree of polymerization of hydrophilic GEMA units on the measured properties were evaluated by comparison with those of conventional polyoxyethylene dodecyl ether nonionic surfactants. C(n)Am-mGEMA telomers exhibited higher critical micelle concentration (CMC) values than polyoxyethylene dodecyl ether surfactants with similar number of hydrophilic groups did. The synthesized telomers are highly efficient in reducing the surface tension of water, despite the relatively large hydrophilic structures within the sugar units (GEMA). A unique behavior was observed in that adsorption at the air water interface and solution aggregation occurred simultaneously at a concentration below CMC (as determined by the surface tension method). This suggests that aggregate formation occurs readily in solution along with the adsorption at the interface because of strong attractive interactions between multiple sugar GEMA chains. Further, aggregates formed by C(n)Am-mGEMA telomers differ depending on the number of sugar chains, i.e., an increase in the degree of polymerization of the telomers increases the size of the aggregates. This indicates that it is easier for telomers with more sugar GEMA chains to form large aggregates due to the interactions between their hydroxyl groups. PMID- 23985487 TI - Solution properties and emulsification properties of amino acid-based gemini surfactants derived from cysteine. AB - Amino acid-based anionic gemini surfactants (2C(n)diCys, where n represents an alkyl chain with a length of 10, 12, or 14 carbons and "di" and "Cys" indicate adipoyl and cysteine, respectively) were synthesized using the amino acid cysteine. Biodegradability, equilibrium surface tension, and dynamic light scattering were used to characterize the properties of gemini surfactants. Additionally, the effects of alkyl chain length, number of chains, and structure on these properties were evaluated by comparing previously reported gemini surfactants derived from cystine (2C(n)Cys) and monomeric surfactants (C(n)Cys). 2C(n)diCys shows relatively higher biodegradability than does C(n)Cys and previously reported sugar-based gemini surfactants. Both critical micelle concentration (CMC) and surface tension decrease when alkyl chain length is increased from 10 to 12, while a further increase in chain length to 14 results in increased CMC and surface tension. This indicates that long-chain gemini surfactants have a decreased aggregation tendency due to the steric hindrance of the bulky spacer as well as premicelle formation at concentrations below the CMC and are poorly packed at the air/water interface. Formation of micelles (measuring 2 to 5 nm in solution) from 2C(n)diCys shows no dependence on alkyl chain length. Further, shaking the mixtures of aqueous 2C(n)diCys surfactant solutions and squalane results in the formation of oil-in-water type emulsions. The highly stable emulsions are formed using 2C12diCys or 2C14diCys solution and squalane in a 1:1 or 2:1 volume ratio. PMID- 23985488 TI - Preparation and characterization of fractal elastomer surfaces. AB - The elastomer materials with hierarchical structure and suitable wettability are useful as biological surface model. In the present study, urethane resin and silicone resin elastomers with hierarchical rough surfaces were prepared and referred to as "fractal elastomers". We found a hierarchy of small projections that existed over larger ones on these surfaces. These elastomers were synthesized by transferring a fractal surface structure of alkylketene dimer. The rough structure enhanced the hydrophobicity and weakened friction resistance of the elastomer surfaces. These materials can be useful for artificial skin with biomimetic surface properties. PMID- 23985489 TI - Lipase-catalyzed synthesis of ascorbyl oleate in acetone: optimization of reaction conditions and lipase reusability. AB - Lipase-catalyzed ascorbyl oleate synthesis is eco-friendly and selective way of production of liposoluble biocompatible antioxidants, but still not present on an industrial level due to the high biocatalyst costs. In this study, response surface methodology was applied in order to estimate influence of individual experimental factors, identify interactions among them, and to determine optimum conditions for enzymatic synthesis of ascorbyl oleate in acetone, in terms of limiting substrate conversion, product yield, and yield per mass of consumed enzyme. As a biocatalyst, commercial immobilized preparation of lipase B from Candida antarctica, Novozym 435, was used. In order to develop cost-effective process, at reaction conditions at which maximum amount of product per mass of biocatalyst was produced (60 degrees C, 0.018 % (v/v) of water, 0.135 M of vitamin C, substrates molar ratio 1:8, and 0.2 % (w/v) of lipase), possibilities for further increase of ester yield were investigated. Addition of molecular sieves at 4(th) hour of reaction enabled increase of yield from 16.7 mmol g-1 to 19.3 mmol g-1. Operational stability study revealed that after ten reaction cycles enzyme retained 48 % of its initial activity. Optimized synthesis with well-timed molecular sieves addition and repeated use of lipase provided production of 153 mmol per gram of enzyme. Further improvement of productivity was achieved using procedure for the enzyme reactivation. PMID- 23985490 TI - Efficient conversion of crude glycerol into triacylglycerol by the yeast Pseudozyma sp. TYC-2187 for biodiesel production. AB - Crude glycerol is a byproduct of biodiesel production. In this study, we isolated a yeast strain that grows vigorously using crude glycerol as a carbon source, and tested the effects of culture conditions on triacylglycerol (TG) production. TYC 2187, isolated from wild grapes and identified as Pseudozyma sp., converted high concentration crude glycerol into TG more efficiently than other strains of the genus Pseudozyma. Sequence analysis of the 26S rRNA gene D1/D2 domain indicated that TYC-2187 diverged from other strains of the genus Pseudozyma. Optimum culture temperature and optimum initial pH of culture medium, that maximized TG yield of TYC-2187, were 25 degrees C and pH 6.0, respectively. Optimum nitrogen source was yeast extract and optimum concentration was 10 g/L. Optimum concentration of glycerol, when the yeast was cultured for 48 h under optimum conditions, was 80 g/L. TG yield peaked at 15.7 g/L at 48 h and then remained at this level until 66 h. In addition, much of the glycerol in the medium had been consumed by 48 h. Fatty acid composition of TG produced by TYC-2187, including linolenic acid methyl ester content, iodine value, and cetane number, complied with biodiesel standards. These results suggest that the TYC-2187 yeast strain is superbly able to produce TG that is suitable for biodiesel production using crude glycerol. PMID- 23985491 TI - Induction of defense responses in cucumber plants by using the cell-free filtrate of the plant growth-promoting fungus Penicillium simplicissimum GP17-2. AB - Penicillium simplicissimum GP17-2 is a plant growth-promoting fungus (PGPF) and an inducer of systemic defense responses. The mechanisms underlying the effect of GP17-2 on the reduction of cucumber leaf damage caused by the anthracnose pathogen Colletotrichum orbiculare were investigated. Cucumber leaves treated with the culture filtrate (CF) of GP17-2 exhibited a clear systemic resistance against subsequent infection with C. orbiculare. The number and size of lesions caused by the disease were reduced in CF-treated plants, in comparison with that in the control plants. The results showed that CF treatment could trigger a set of defense responses, including the production of hydrogen peroxide, formation of lignin, emission of ultra-weak photons, accumulation of salicylic acid, and increase in the transcription of the genes for the defense-related enzymes chitinase and peroxidase. Furthermore, subsequent inoculation of CF-pretreated plants with C. orbiculare resulted in higher systemic expression of the genes for chitinase, beta-1,3-glucanase, and peroxidase relative to nontreated, inoculated plants; this indicated that CF mediates a potentiation state in the plant, enabling it to mount a rapid and effective response on infection by C. orbiculare. Our results indicate that the ability of CF of GP17-2 to stimulate active oxygen species, lignification, SA accumulation, and defense gene activation and potentiation in the host is the possible mode of action of the GP17-2 elicitor and inducer of induced systemic resistance against C. orbiculare infection in cucumber plants. PMID- 23985492 TI - Isolation of a reduced form of cyanidin 3-O-beta-D-glucoside from immature black soybean (Glycine max (L.) Merr.) and its reducing properties. AB - 5,7,3',4'-Tetrahydroxyflav-2-en-3-ol 3-O-beta-D-glucoside was isolated from the seed coats of immature black soybeans (Glycine max (L.) Merr.). This compound is a reduced form of cyanidin 3-O-beta-D-glucoside (cyanidin 3-G) which was obtained by reaction with hydrochloric acid. The molecule has reducing activity for a tetrazolium derivative (WST-1) in the presence of 1-methoxy-5-methylphenazinium methylsulfate (1-methoxy PMS) in a similar manner to NADH. The seed coats of immature black soybeans also contain epicatechin as a major constituent, while cyanidin 3-G and procyanidin B2 are present at lower concentrations. Immature brown soybeans did not contain 5,7,3',4'-tetrahydroxyflav-2-en-3-ol 3-O-beta-D glucoside, but did contain both epicatechin and procyanidin B2. Immature yellow soybeans contained none of them. PMID- 23985493 TI - Comparison of volatile compounds with characteristic odor in flowers and leaves of nojigiku (Chrysanthemum japonense). AB - The aim of the present study was to investigate the essential oils isolated from flower and leaf in order to get insight into similarities and differences as to their aroma-active composition. The essential oil obtained from the two parts were analyzed by gas chromatography-mass spectrometry and gas chromatography olfactometry (GC-O). Flower and leaf oils, 38 and 36 constituents, representing 96.4 and 91.0% of the total oil composition, respectively, were identified. The main compounds in flower oil were camphor (47.64%), bornyl acetate (11.87%), and nojigiku alcohol (6.29%), whereas those in leaf oil were camphor (39.14%), nojigiku alcohol (10.76%) and gamma-muurolene (7.02%). 13 Aroma-active compounds were identified by GC-O analysis in flower oil and 12 in leaf oil. The main aroma active compounds in flower oil were camphor (camphor, FD (flavor dilution) = 7, OAV (odor active value) = 136913), bornyl acetate (camphor, FD = 6, OAV = 113711), and beta-caryophyllene (spicy, FD = 5, OAV = 116480). In leaf oil, the main aroma-active compounds were camphor (camphor, FD = 7, OAV = 106784), nojigiku alcohol (camphor, FD = 5, OAV = not determined), and beta-caryophyllene (spicy, FD = 6, OAV = 526267). PMID- 23985494 TI - Preparation of hollow titania nanoparticles of single-nanometer size using a PAMAM dendrimer template. AB - Hollow titania nanoparticles of single-nanometer size have been prepared from titanium oxysulfate (TiOSO4) using poly(amidoamine) (PAMAM) dendrimer molecules (Generations 5 with amino terminal groups) as a template. At low pH (pH 1), hydrolysis of the titania precursor was attenuated and the sol-gel reaction preferentially proceeded at the dendrimer surface. Calcination at 450 degrees C yielded crystalline titania nanoparticles of 5.5 nm diameter with a ~2 nm cavity. These hollow titania nanoparticles showed a larger band-gap energy than solid particles of corresponding size. PMID- 23985496 TI - National and state vaccination coverage among adolescents aged 13-17 years- United States, 2012. AB - At ages 11 through 12 years, the Advisory Committee on Immunization Practices (ACIP) recommends that preteens receive 1 dose of tetanus, diphtheria, and acellular pertussis (Tdap) vaccine, 1 dose of meningococcal conjugate (MenACWY) vaccine, and 3 doses of human papillomavirus (HPV) vaccine. ACIP recommends administration of all age-appropriate vaccines during a single visit. ACIP also recommends that pre-teens and older adolescents receive an annual influenza vaccine as well as any overdue vaccines (e.g., varicella). To monitor vaccination coverage among persons aged 13-17 years, CDC analyzed data from the National Immunization Survey-Teen (NIS-Teen). This report highlights findings of that analysis. From 2011 to 2012, coverage increased for >=1 Tdap vaccine dose (from 78.2% to 84.6%), >=1 MenACWY vaccine dose (from 70.5% to 74.0%) and, among males, >=1 HPV vaccine dose (from 8.3% to 20.8%). Among females, vaccination coverage estimates for each HPV vaccine series dose were similar in 2012 compared with 2011. Coverage varied substantially among states. Regarding Healthy People 2020 targets for adolescents, 36 states achieved targets for Tdap, 12 for MenACWY, and nine for varicella vaccine coverage. Large and increasing coverage differences between Tdap and other vaccines recommended for adolescents indicate that substantial missed opportunities remain for vaccinating teens, especially against HPV infection. Health-care providers should administer recommended HPV and meningococcal vaccinations to boys and girls during the same visits when Tdap vaccine is given. In addition, whether for health problems or well-checks, providers, parents, and adolescents should use every health-care visit as an opportunity to review adolescents' immunization histories and ensure that every adolescent is fully vaccinated. PMID- 23985497 TI - Multidrug-resistant bacteroides fragilis--Seattle, Washington, 2013. AB - The Bacteroides fragilis group consists of species of obligate anaerobic bacteria that inhabit the human gut. They are among the leading pathogens isolated in the setting of intra-abdominal infections. B. fragilis strains, especially in the United States, are virtually always susceptible to metronidazole, carbapenems, and beta-lactam antibiotics. Although isolated cases of resistance to single agents have been reported, multidrug-resistant (MDR) B. fragilis strains are exceptionally rare. In May 2013, an MDR B. fragilis strain was isolated from the bloodstream and intra-abdominal abscesses of a patient who had recently received health care in India. This is only the second published case of MDR B. fragilis in the United States. This report summarizes the case and highlights the need for awareness of multidrug-resistant organisms (MDROs) in returning travelers who have received inpatient medical care outside the United States, both for timely implementation of proper infection control measures and to ensure administration of appropriate antimicrobials. PMID- 23985498 TI - CDC grand rounds: public health practices to include persons with disabilities. AB - "Persons with disabilities" is a vague designation that might not always be understood. Persons with disabilities are persons with limitations in hearing, vision, mobility, or cognition, or with emotional or behavioral disorders. What they have in common is that they all experience a significant limitation in function that can make it harder to engage in some activity of daily living without accommodations or supports. PMID- 23985499 TI - Recurrent outbreak of Campylobacter jejuni infections associated with a raw milk dairy--Pennsylvania, April-May 2013. AB - During May 2013, the Pennsylvania Department of Health investigated an outbreak of campylobacteriosis among consumers of raw (unpasteurized) milk from a dairy certified by the Pennsylvania Department of Agriculture (PDA) to sell raw milk onsite, at retail stores, and at off-farm pick-up sites. Investigation by the Pennsylvania Department of Health and PDA identified six confirmed and two probable cases of campylobacteriosis associated with raw milk from the dairy. A confirmed case was defined as laboratory-confirmed campylobacteriosis in a person who drank the dairy's raw milk. A probable case was defined as diarrheal illness without laboratory confirmation in a person who had consumed the dairy's raw milk and was linked to a confirmed case. Four cases involved children aged <=18 years. PDA identified Campylobacter in bulk tank and retail milk samples from the dairy. Available isolates from patient stool (n = 1), bulk tank milk (n = 1), and retail milk (n = 1) were identified by CDC as Campylobacter jejuni and were indistinguishable by pulsed-field gel electrophoresis (PFGE). PMID- 23985500 TI - Acetyl fentanyl overdose fatalities--Rhode Island, March-May 2013. AB - In May 2013, the Rhode Island State Health Laboratories noticed an unusual pattern of toxicology results among 10 overdose deaths of suspected illicit drug users that had occurred during March 7-April 11, 2013. An enzyme-linked immunosorbent assay (ELISA) for fentanyl in blood was positive for fentanyl in all 10 cases, but confirmatory gas chromatography/mass spectrometry (GC/MS) did not detect fentanyl. The mass spectrum was instead consistent with acetyl fentanyl, a fentanyl analog. Acetyl fentanyl, a synthetic opioid, has not been documented in illicit drug use or overdose deaths, and is not available as a prescription drug anywhere. Animal studies suggest that acetyl fentanyl is up to five times more potent than heroin as an analgesic. PMID- 23985501 TI - Radar-raingauge data combination techniques: a revision and analysis of their suitability for urban hydrology. AB - The applicability of the operational radar and raingauge networks for urban hydrology is insufficient. Radar rainfall estimates provide a good description of the spatiotemporal variability of rainfall; however, their accuracy is in general insufficient. It is therefore necessary to adjust radar measurements using raingauge data, which provide accurate point rainfall information. Several gauge based radar rainfall adjustment techniques have been developed and mainly applied at coarser spatial and temporal scales; however, their suitability for small scale urban hydrology is seldom explored. In this paper a review of gauge-based adjustment techniques is first provided. After that, two techniques, respectively based upon the ideas of mean bias reduction and error variance minimisation, were selected and tested using as case study an urban catchment (~8.65 km(2)) in North East London. The radar rainfall estimates of four historical events (2010-2012) were adjusted using in situ raingauge estimates and the adjusted rainfall fields were applied to the hydraulic model of the study area. The results show that both techniques can effectively reduce mean bias; however, the technique based upon error variance minimisation can in general better reproduce the spatial and temporal variability of rainfall, which proved to have a significant impact on the subsequent hydraulic outputs. This suggests that error variance minimisation based methods may be more appropriate for urban-scale hydrological applications. PMID- 23985502 TI - Characterization: a necessary tool in sludge management. AB - Sludge management is one of the critical issues facing modern society due to the fast increase in its production as a result of extended sewerage, new work installations and up-grading of existing facilities. In order to (i) properly perform the utilization and disposal operations, (ii) correctly fulfil the legal requirements and (iii) build stakeholder and public confidence, it will be necessary to establish defined outlet procedures/routes and guarantee a good sludge quality. Therefore, characterization to evaluate sludge chemical, biological and physical properties is a necessary tool in sludge management. However, characterization procedures often specify different methodologies, materials and accessories; so results obtained in different places may not be fully reliable. Also comparison of the results can be problematic because they have not been obtained under standardized conditions. Consequently, the development of standardized validated characterization methods and procedures becomes necessary too. Further, the development of standardized characterization methods and procedures should be supported by the preparation of 'guidelines' of good practice for the different options of sludge use and disposal in order to give guidance to producers/users on how to meet legislation requirements and perform sustainable operations. In this paper the main parameters for sludge characterization are discussed and developments in European standardization outlined. PMID- 23985503 TI - Sedimentation dynamics in combined sewer systems. AB - Sediments in combined sewers may negatively affect the performance of sewer systems and significantly promote the formation of hydrogen sulfide. To prevent this, German sewer systems are cleaned regularly but at high costs. In order to optimize the cleaning intervals, this study investigates how deposits build up and change over a defined period under constant conditions. The experiments were performed using real wastewater at a pilot plant consisting of three 10 m long acrylic glass pipes with a diameter of 300 mm, a slope of I = 10/00, a discharge of Q = 2 L/s and a roughness of kS = 0.4 mm. Within the first 30 d, a slow increase of the deposit height (averaged over the pipe length) of 0.75 mm/d was observed. The deposits did not build up continuously, but in between times also decreased due to erosion. The daily changes in deposit amounts occurred partly as a function of the rainfall conditions and could go beyond the average growth many times. Within a day, the deposit height (averaged over pipe length) changed by up to 20 mm, at single measuring points even up to 100 mm. After about 50 d under constant test conditions, the deposit height came to a state of equilibrium between sedimentation and erosion. PMID- 23985504 TI - Three years of operation of North America's first nutrient recovery facility. AB - The first full-scale nutrient recovery installation in North America became operational in May 2009 at the Clean Water Service's Durham Advanced Wastewater Treatment Plant in Tigard, Oregon. Recovering ammonia and phosphorus from the dewatering side stream as struvite has a positive impact on plant operations. Significantly reducing the phosphorus recycle lowers the phosphorus loading on the plant, stabilizes biological phosphorus removal, reduces the amount of chemicals needed to remove phosphorus, reduces both the dry tonnes of biosolids generated and the phosphorus content of the biosolids, and provides revenue from the sale of the struvite. To increase struvite production and to decrease struvite potential in the digestion system, the Waste Activated Sludge Stripping To Remove Internal Phosphorus (WASSTRIPTM) process was implemented full-scale in summer 2011. Results indicate a potential 60% increase in struvite production is achievable. PMID- 23985505 TI - A generic hydrological model for a green roof drainage layer. AB - A rainfall simulator of length 5 m and width 1 m was used to supply constant intensity and largely spatially uniform water inflow events to 100 different configurations of commercially available green roof drainage layer and protection mat. The runoff from each inflow event was collected and sampled at one-second intervals. Time-series runoff responses were subsequently produced for each of the tested configurations, using the average response of three repeat tests. Runoff models, based on storage routing (dS/dt = I-Q) and a power-law relationship between storage and runoff (Q = kS(n)), and incorporating a delay parameter, were created. The parameters k, n and delay were optimized to best fit each of the runoff responses individually. The range and pattern of optimized parameter values was analysed with respect to roof and event configuration. An analysis was performed to determine the sensitivity of the shape of the runoff profile to changes in parameter values. There appears to be potential to consolidate values of n by roof slope and drainage component material. PMID- 23985506 TI - Seasonal changes in the performance of a catch crop for mitigating diffuse agricultural pollution. AB - An in situ technology for mitigating diffuse agricultural pollution using catch crops was developed for simultaneously preventing nitrate groundwater pollution, reducing nitrous oxide (N2O) gas emissions, and removing salts from the topsoil. Seasonal changes in the performance of a catch crop were investigated using lysimeters in a full-scale greenhouse experiment with 50 d cultivation of dent corn. Catch crop cultivation significantly reduced the leached mineral nitrogen by 89-91% in summer, 87-89% in spring, and 61-82% in winter, and it also significantly reduced the N2O emission by 68-84% in summer. The amounts of nitrogen uptake by the catch crop were remarkably higher than those of leached nitrogen and N2O emission in each season. Catch crop cultivation is a promising technology for mitigating diffuse agricultural pollution. PMID- 23985507 TI - Comparing the effect of biosurfactant and chemical surfactant on bubble hydrodynamics in a flotation column. AB - Bubble hydrodynamics is fundamental to the performance of the flotation process widely used in the separation industry. To compare the effect of biosurfactants and chemical synthetic surfactants on bubble hydrodynamics in the flotation process, the motion of a single bubble and the size distribution of bubble swarms in various surfactants (rhamnolipid, tea saponin and Triton X-100) solutions were observed directly using a high-speed video camera in a laboratory scale flotation column. Bubble trajectory, dimensions, velocity and size distribution were then determined through image analysis. The results indicated that the addition of biosurfactants had the same significant effects on bubble motion and size distribution as chemosynthetic surfactants. The biosurfactant effect on bubble behavior was also found to depend on their type and concentration. In general, the effect of tea saponin was stronger than another biosurfactant (rhamnolipid) used in the present study. The present findings implied that some biosurfactants like tea saponin can replace chemosynthetic surfactants in controlling bubble behavior in flotation operation. This will contribute to promoting the use of green environmentally friendly flotation agents in the separation industry. PMID- 23985508 TI - Comprehensive flood control involving citizens in a Japanese watershed. AB - In July 2009, the city of Fukuoka, Japan experienced a flood disaster along the Hii River, which runs through densely populated, concrete-covered areas of the city. The drainage system was overwhelmed and the river overflowed due to heavy rainfall and rapid runoff. The event led citizens in its watershed to plan and implement comprehensive flood control. The plan aims not only to mitigate floods but also to revitalize the river environment and populated communities in urban areas. This study reports the activities led by the citizens. They organized and carried out civic forums, workshops, and fieldwork to share views as to how the flood disaster was caused, how floods in the watershed should be controlled, and how the river environment should be rehabilitated. This study illuminates how people, including the flood victims and municipal engineers, can change drastically and communicate effectively in the course of discussing and implementing the comprehensive flood control measures. PMID- 23985509 TI - Intermittent operation of low pressure UF membranes for sewage reuse at household level. AB - A household-scale wastewater treatment system was operated with domestic sewage. The system could recover gardening/irrigation water from raw sewage or secondary effluent by low pressure ultrafiltration (UF). The UF membranes (surface area = 3.5 m(2), pore size = 0.04 MUm) were operated at constant transmembrane pressure (0.13 bar). The proposed technology was examined for approximately 2 months without membrane cleaning. Membrane operation was performed periodically (one or two times per week), simulating water usage for gardening irrigation. During raw sewage filtration (chemical oxygen demand (COD) total = 242 +/- 71 mg L(-1), COD soluble = 105 +/- 51 mg L(-1), suspended solids = 188 +/- 58 mg L(-1)), low permeate COD was achieved (52 +/- 25 mg L(-1)), whereas nitrogen and phosphorus were recovered in the permeate. The water recovered during 1 h of operation displayed a gradual decrease from 42 to 22 L m(-2)h(-1) during the 50-d time period. For the secondary effluent filtration, the UF module achieved consistently a recovery rate of 39.6 +/- 8.0 L m(-2)h(-1), with an average permeate COD of 37 mg L(-1). In this case, the fouling layer (cake layer) was completely reversible after the relaxation period, rendering the process suitable for unattended household applications. PMID- 23985510 TI - A novel multistage kinetic modeling of flotation for wastewater treatment. AB - This study develops a new model for description of flotation kinetics. It defines flotation as a process that consists of several stages: separated air bubbles and particles, air bubbles and particles forming an aggregate, aggregate rising to the froth layer. This description significantly differs from known models, which are much simplified. The multistage model gives a novel in-depth description and considers different aspects of flotation, i.e. aggregate formation, which is critically important for flotation to take place. Experimental approval of the new model resulted in its accuracy. The model is to be used for a description of kinetics of all flotation processes in wastewater treatment. It helps in accurate design of flotation treatment plants and may be used for further research of the flotation process. PMID- 23985511 TI - Hydrolysis of polydimethylsiloxane fluids in controlled aqueous solutions. AB - Accelerated degradation tests were performed on polydimethylsiloxane (PDMS) fluids in aqueous solutions and in extreme chemical conditions (pH 2-4 and 9-12). Results confirmed that silicones can be degraded by hydrolysis. Higher degradation levels were achieved in very acidic and alkaline conditions. Degradation products are probably polar siloxanols. In alkaline conditions, the counter-ion was found to have a strong influence on degradation level. Degradation kinetic studies (46 days) were also performed at different pH values. Supposing zeroth-order kinetics, degradation rate constants at 24 degrees C were estimated to 0.28 mgSi L(-1) day(-1) in NaOH solution (pH 12), 0.07 mgSi L(-1) day(-1) in HCl solution (pH 2) and 0.002 mgSi L(-1) day(-1) in demineralised water (pH 6). From these results, the following hypothesis was drawn: PDMS hydrolysis could occur in wastewater treatment plants and in landfill cells. It may be a first step in the formation of volatile organic silicon compounds (VOSiCs, including siloxanes) in biogas: coupled to biodegradation and (self-) condensation of degradation products, it could finally lead to VOSiCs. PMID- 23985512 TI - Evaluation of the AquaCrop model for simulating yield response of winter wheat to water on the southern Loess Plateau of China. AB - The objective of this study was to evaluate the performance of the FAO-AquaCrop model in winter wheat in the southern Loess Plateau of China. Multi-year field experimental data from 2004 and 2011 were used to calibrate and validate the model for simulating biomass, canopy cover (CC), soil water content, and grain yield under rainfed conditions. The model performance was evaluated using root mean square error (RMSE) and Willmott index of agreement (d) as criteria. The RMSE ranged from 0.16 to 0.38 t/ha for simulating aboveground biomass, 1.87 to 4.15% for CC, 0.50 to 1.44 t/ha for grain yield, and 5.70 to 22.56 mm for soil water content. The d ranged from 0.22 to 0.89, 0.25 to 0.43, 0.36 to 0.62 and 0.95 to 0.98 for aboveground biomass, CC, soil water content and grain yield, respectively. Generally, the model performed better for simulating CC and yield than biomass and soil water content. The results further indicated that AquaCrop is capable of simulating winter wheat yield under rainfed conditions. Further improvement may be needed to capture the variation of different management practices such as fertility and irrigation levels in this region. PMID- 23985513 TI - Methodology for qualitative urban flooding risk assessment. AB - Pluvial or surface flooding can cause significant damage and disruption as it often affects highly urbanised areas. Therefore it is essential to accurately identify consequences and assess the risks associated with such phenomena. The aim of this study is to present the results and investigate the applicability of a qualitative flood risk assessment methodology in urban areas. This methodology benefits from recent developments in urban flood modelling, such as the dual drainage modelling concept, namely one-dimensional automatic overland flow network delineation tools (e.g. AOFD) and 1D/1D models incorporating both surface and sewer drainage systems. To assess flood risk, the consequences can be estimated using hydraulic model results, such as water velocities and water depth results; the likelihood was estimated based on the return period of historical rainfall events. To test the methodology two rainfall events with return periods of 350 and 2 years observed in Alcantara (Lisbon, Portugal) were used and three consequence dimensions were considered: affected public transportation services, affected properties and pedestrian safety. The most affected areas in terms of flooding were easily identified; the presented methodology was shown to be easy to implement and effective to assess flooding risk in urban areas, despite the common difficulties in obtaining data. PMID- 23985514 TI - Development of a diagnostic tool: the wastewater collection network odour wheel. AB - The assessment of nuisance odour problems and the application of an effective odour management programme for the associated industrial activity may be achieved using a representative odour wheel and Odour Profile Analysis methodology. The odour wheel is a very useful tool for conducting odour quality control monitoring and developing a constructive dialogue regarding nuisance odours with the public. Previously, odours from wastewater treatment plant activities have been identified and described with a dedicated odour wheel. The oxidation state of the organic chemicals responsible for a given odour depends on multiple parameters specific to the individual wastewater collection networks (residence time of wastewater, topographic disposition and network slope, aeration and on line chemical treatment processes). This is especially important for odorous nitrogen, sulfur and volatile fatty acids. Trained sensory odour panels combined with chemical analyses have been used to study wastewater collection network odours and to adapt the wastewater odour wheel accordingly. The wastewater collection network odour wheel has been produced using the results of five sampling campaigns; eight out of the 11 odour families constituting the wastewater odour wheel have been identified and consequently validated for sewer networks. Different groups of odours have been perceived according to the presence or absence of wastewater effluents at the various sampling points. PMID- 23985515 TI - Bentonite for ciprofloxacin removal from aqueous solution. AB - Ciprofloxacin hydrochloride (CIP) is the second generation of fluoroquinolone antibiotics whose residues are found in wastewater and surface water. CIP has high aqueous solubility under different pH conditions and high stability in the soil system. In this study, bentonite was used as a potential sorbent for the removal of CIP from aqueous solutions using batch experiments. The effects of various parameters such as contact time, pH, adsorbent dosage, agitation speed, ionic strength and initial concentration of CIP in aqueous solution on the adsorption capacity were investigated. The optimum contact time, pH, agitation speed and adsorbent dosage were found to be 30 min, 4.5 pH, 150 rpm and 2.5 g L( 1), respectively. When the ionic strength was increased from 5 to 50 mM, the adsorption of CIP decreased from 97.8 to 93.4%. The isotherm adsorption data fitted well with the Langmuir model, Kl and qe were found to be 0.27 L mg(-1) and 147.06 mg g(-1), and the data fitted well with the pseudo-second order kinetics, whereby k was found to be 2.19 g mg(-1) h(-1). PMID- 23985516 TI - A statistical experimental design approach for mineralization and detoxification of diethyl phthalate by H2O2/UV-C process. AB - In the present study, a three-factor central composite design (CCD) was implemented to evaluate the major factors (treatment time, initial H2O2 dose and initial diethyl phthalate (DEP) concentration) influencing the H2O2/UV-C treatment of aqueous DEP solution. Significant regression models for total organic carbon (TOC) removal and residual H2O2 concentration were derived using analysis of variance (ANOVA), which were found to be adequate to perform the process variables optimization. According to the applied ANOVA, treatment time (positive effect) and initial H2O2 dose (negative effect after an optimum value) were found to be significant on the H2O2/UV-C process performance. TOC removal efficiencies were enhanced with increasing initial H2O2 dose up to an optimum value, and further increases in H2O2 dose resulted in a decrease in TOC removals due to the hydroxyl radical scavenging effect. When initial H2O2 dose increased from 10 to 30 mM, the TOC removal efficiency improved from 41 to 100% for DEPo of 100 mg/L for treatment time of 50 min. Further increase in initial H2O2 dose to 50 mM decreased the TOC removal efficiency down to 38%. The results of toxicity assessments with Vibrio fischeri on aqueous DEP solutions subjected to H2O2/UV-C treatment revealed complete detoxification at the optimum conditions. PMID- 23985517 TI - Paraquat adsorption on porous materials synthesized from rice husk silica. AB - The goal of this work was to utilize rice husk silica (RHS) and porous materials synthesized with RHS, including mesoporous material (MCM-41) and microporous materials (zeolite NaY and NaBEA), for adsorption of herbicide paraquat. The adsorption occurred although cation exchange and the capacity decreased in the following order: NaY > NaBEA > MCM-41 > RHS, consistent with the amount of Al. The adsorption on all adsorbents fitted well with the Langmuir model and the maximum adsorption capacity of 185.2 mg/g-adsorbent was obtained on NaY. In addition, blue dye in commercial grade paraquat did not interfere with paraquat adsorption. Although MCM-41 was the most efficient adsorbent for the blue dye, RHS was favorable in terms of production cost. A mixture of NaY and RHS is recommended for simultaneous adsorption of paraquat and blue dye. PMID- 23985518 TI - Role of primary sedimentation on plant-wide energy recovery and carbon footprint. AB - The goal of this paper is to show the effect of primary sedimentation on the chemical oxygen demand (COD) and solids fractionation and consequently on the carbonaceous and energy footprints of wastewater treatment processes. Using a simple rational procedure for COD and solids fraction quantification, we quantify the effects of varying fractions on CO2 and CO2-equivalent mass flows, process energy demand and energy recovery. Then we analysed two treatment plants with similar biological nutrient removal processes in two different climatic regions and quantified the net benefit of gravity separation before biological treatment. In the cases analysed, primary settling increases the solid fraction of COD that is processed in anaerobic digestion, with an associated increase in biogas production and energy recovery, and a reduction in overall emissions of CO2 and CO2-equivalent from power importation. PMID- 23985519 TI - Wastewater salinity assessment using near infrared spectroscopy. AB - The visible and near infrared spectroscopy is a fast and inexpensive non destructive technique for the prediction of concentrations of salts in wastewater. Conventional chemical methods are usually used, which are very accurate, take more time and require special techniques for sampling, storing and pretreatment of wastewater. In this work we studied the spectral characteristics of water and the effect of salts on the perturbations in the water absorption bands. The generation of multiple regression models with principal components was carried out on standard solutions with composition of salts similar to that of wastewater samples taken along the drainage channel network of the Mexico City Metropolitan Area. The spectral signatures were obtained in situ and in the laboratory using a portable high-resolution spectroradiometer (ASD FieldSpec 3). The prediction model generated showed high precision in the estimation of salinity in wastewater, a coefficient of determination of 89.6% and a low root mean square error of 0.120/00. Other compounds, which are not discussed here, cause distortion of the absorption bands of water at wavelengths less than 900 nm or near the visible region, while our results showed distortions in the water spectrum at higher wavelengths (>1,000 nm). PMID- 23985520 TI - Carbon footprints of Scandinavian wastewater treatment plants. AB - This study estimates the carbon footprints of 16 municipal wastewater treatment plants (WWTPs), all situated in Scandinavian countries, by using a simple model. The carbon footprint calculations were based on operational data, literature emission factors (efs) and measurements of greenhouse gas emissions at some of the studied WWTPs. No carbon neutral WWTPs were found. The carbon footprints ranged between 7 and 108 kg CO2e P.E.(-1) year(-1). Generally, the major positive contributors to the carbon footprint were direct emissions of nitrous oxide from wastewater treatment. Whether heat pumps for effluents have high coefficient of performance or not is extremely important for the carbon footprint. The choice of efs largely influenced the carbon footprint. Increased biogas production, efficient biogas usage, and decreased addition of external fossil carbon source for denitrification are important activities to decrease the carbon footprint of a WWTP. PMID- 23985521 TI - Occurrence of tylosin in swine wastewater in Mexico. AB - This study determined a tylosin concentration in swine wastewater located in a Mexican pig farm, during different stages of the pigs' growth. The detection of antibiotics in swine wastewater is complex due to its high concentration of solids. Analytical method was developed for detection of tylosin in swine wastewater and swine slurry. Average recoveries of tylosin in the liquid and solid phase were greater than 51 and 44%, respectively, with a greater total recovery of 95%. The results indicated the presence of tylosin in swine wastewater and slurry at concentrations greater than the ones reported in the literature. In grab samples of swine wastewater, the tylosin detected showed concentrations of 56, 72 and 8.6 MUg L(-1), in breeding-gestation, nursery pigs, and grow-finishing area, respectively. In composite samples, the concentration of tylosin was 11.8 MUg L(-1) for the breeding-gestation area and 2.4 MUg L(-1) for the grow-finishing area. For slurry, the concentration of tylosin was 20.6 and 17.8 MUg L(-1), for the breeding-gestation and grow-finishing area, respectively. This study presents the detection of a high concentration of tylosin in breeding gestation and nursery pigs. Traces of tylosin in wastewater from grow-finishing stage were found although the animals were not receiving antibiotics. PMID- 23985522 TI - Facile fouling resistant surface modification of microfiltration cellulose acetate membranes by using amino acid L-DOPA. AB - A major obstacle in the widespread application of microfiltration membranes in the wet separation processes such as wastewater treatment is the decline of permeates flux as a result of fouling. This study reports on the surface modification of cellulose acetate (CA) microfiltration membrane with amino acid L 3,4-dihydroxy-phenylalanine (L-DOPA) to improve fouling resistance of the membrane. The membrane surface was characterised using Fourier transform infrared spectroscopy (FTIR), water contact angle and zeta potential measurement. Porosity measurement showed a slight decrease in membrane porosity due to coating. Static adsorption experiments revealed an improved resistance of the modified membranes towards the adhesion of bovine serum albumin (BSA) as the model foulant. Dead end membrane filtration tests exhibited that the fouling resistance of the modified membranes was improved. However, the effect of the modification depended on the foulant solution concentration. It is concluded that L-DOPA modification is a convenient and non-destructive approach to enable low-BSA adhesion surface modification of CA microfiltration membranes. Nevertheless, the extent of fouling resistance improvement depends on the foulant concentration. PMID- 23985523 TI - Fecal coliform removal in a lightly loaded surface-flow constructed treatment wetland polishing agricultural runoff. AB - Constructed treatment wetlands can be an effective and sustainable method to remove pathogens that pose health risks from agricultural runoff. This study evaluated the removal of fecal coliform (FC) from agricultural runoff in a lightly loaded surface-flow treatment wetland prior to discharge to the Yakima River, Washington State, USA. The 1.6 ha system consisted of a sedimentation basin (1.4 d hydraulic retention time) followed by two wetlands (5-6 d hydraulic retention time). FC in inflow ranged from 100 to 1,000 cfu/100 mL. Mean annual FC log-removal in the sedimentation basin was 0.66 +/- 0.17 (mean plus/minus standard deviation; n = 7). However, there was a comparable production of FC within the two wetlands where annual log-removal averaged -0.71 +/- 0.39 in the north wetland and -0.57 +/- 0.17 in the south wetland. FC removal in the sedimentation basin weakly correlated with turbidity removal (R(2) = 0.13, p < 0.01, n = 61), suggesting that settling was an important FC loss mechanism. FC removal in the wetlands negatively correlated with temperature (R(2) = 0.27-0.33, p < 0.01, n = 26) indicating that survival and/or reproduction was an important FC production mechanism. Muskrat colonization in the wetlands in 2007 and 2008 corresponded with a marked increase in FC in wetland outflow. Results suggest that, regardless of the presence of muskrats, sedimentation basins alone are more effective than a combined sedimentation basin-wetland system in removing FC from dilute agricultural runoff. PMID- 23985524 TI - Efficient recovery of carbon, nitrogen, and phosphorus from waste activated sludge. AB - Carbon, nitrogen, and phosphorus need to be recovered to reduce the environmental impact of waste activated sludge (WAS). In this study the improved short-chain fatty acid (SCFA) production from WAS by the addition of kitchen waste to adjust the ratio of carbon to nitrogen (C/N), and the efficient recovery of nitrogen and phosphorus from the fermentation liquid were reported. Firstly, the optimum conditions for SCFA production were found to be pH 8, temperature 35 degrees C, C/N ratio 21 mg-C/1 mg-N, and fermentation time 6 d, using the response surface methodology. After alkaline fermentation, the struvite precipitation method was applied to efficiently and simultaneously recover the released ammonia and phosphorus from the fermentation liquid. Finally, the fermentation liquid was used as the additional carbon source for biological nitrogen and phosphorus removal. It was observed that, compared with acetic acid, the use of fermentation liquid as carbon source showed greater removal efficiencies of total nitrogen and total phosphorus. PMID- 23985525 TI - Highly efficient treatment of industrial wastewater by solution plasma with low environmental load. AB - Advanced oxidation techniques are efficient processes to dispose of organic contaminants in industrial wastewater with low secondary pollution. The solution plasma technique was featured as an advanced oxidation technique with low secondary pollution and high efficiency. However, the solution plasma technique reported previously could only treat wastewater of less than 200 mL owing to the limited plasma generated by only one pair of electrodes. In this work, multiple pairs of electrodes were installed at the bottom of the reaction vessel to generate plasma for decomposing methylene blue trihydrate (MB) and methyl orange (MO) solutions with a batch amount of 18 L/batch. The solution plasma technique was compared with direct ozonation in decomposition of MB and MO wastewater. A surprising phenomenon is that MO was more readily decomposed than MB by using direct ozonation, whereas the removal of MO was too low, and MB was more readily decomposed than MO by using the solution plasma technique. PMID- 23985526 TI - PVC-piping promotes growth of Ralstonia pickettii in dialysis water treatment facilities. AB - Biofilms forming inside dialysis water treatment systems are one of the main sources of microbiological contamination. Among the bacteria found in biofilms, Ralstonia pickettii is frequently encountered in dialysis water treatment systems and has been shown to develop extreme oligotrophic talents. In Austria, R. pickettii was exclusively detected in high numbers in dialysis water treatment facilities equipped with chlorinated polyvinyl chloride (PVC-C) piping. In this laboratory study it was shown that PVC-C effectively promotes growth of R. pickettii biofilms, while residual organic carbon in purified dialysis water is sufficient for promoting substantial growth of planktic R. pickettii. This provides evidence that PVC-C is an unsuitable material for piping in dialysis water treatment systems. PMID- 23985527 TI - Preparation of N-doped TiO2 by oxidizing TiN and its application on phenol degradation. AB - Incomplete oxidation of titanium nitride (TiN) to prepare nitrogen-doped TiO2 was verified by calcining TiN at different temperatures in air for 30 min. The as prepared samples were characterized by X-ray diffraction, UV-Vis diffuse reflectance spectra and X-ray photoelectron spectroscopy. The results confirmed that oxidizing TiN incompletely is an effective and simple method to prepare nitrogen-doped TiO2. Photocatalytic degradation of phenol was conducted to evaluate the photocatalytic activity of as-prepared samples. The results showed that phenol can be degraded efficiently by the as-prepared samples under visible light; low phenol concentration was conducive to degradation; the optimum calcination temperature and photocatalyst dosage are 650 degrees C and 0.5 g/L, respectively. The effects of different light sources on phenol degradation were compared. The reusability of nitrogen-doped TiO2 was tested and the results indicated a relatively good reusability under laboratory conditions. PMID- 23985528 TI - Bacterial community structure in cooling water and biofilm in an industrial recirculating cooling water system. AB - Microbial fouling is a serious problem in open recirculating cooling water systems. The bacterial communities that cause it have not been fully understood. In this study, we analyzed the community structure of free-living bacteria and particle-attached bacteria in cooling water, and bacteria in biofilm collected from the wall of the water reservoir in an industrial recirculating cooling water system by construction of a 16S rRNA gene clone library. Based on amplified ribosomal DNA restriction analysis, clones of all three libraries were clustered into 45 operational taxonomic units (OTUs). Thirteen OTUs displaying 91-96% sequence similarity to a type strain might be novel bacterial species. Noted differences in community structure were observed among the three libraries. The relative species richness of the free-living bacteria in cooling water was much lower than that of particle-attached bacteria and bacteria in biofilm. The majority of the free-living bacterial community (99.0%) was Betaproteobacteria. The predominant bacteria in the particle-attached bacterial community were Alphaproteobacteria (20.5%), Betaproteobacteria (27.8%) and Planctomycetes (42.0%), while those in the biofilm bacterial community were Alphaproteobacteria (47.9%), Betaproteobacteria (11.7%), Acidobacteria (13.1%) and Gemmatimonadetes (11.3%). To control microbial fouling in industrial recirculating cooling water systems, additional physiological and ecological studies of these species will be essential. PMID- 23985529 TI - Pilot-scale experiment on thermally hydrolyzed sludge liquor anaerobic digestion using a mesophilic expanded granular sludge bed reactor. AB - A pilot process of thermal hydrolysis combined with an expanded granular sludge bed reactor (EGSB) was carried out to evaluate pretreated sludge liquor into biogas conversion, process stability, and energy input/output balance. Approximately 25% of suspended solids of sludge were liquefied into aqueous phase during thermal hydrolysis pretreatment, which resulted in chemical oxygen demand (COD) concentration of 20.0 to 35.0 g/L. A mesophilic EGSB reactor was operated for 206 days treating pretreated liquor. Under an organic loading rate of 11.0 kg COD/(m(3).d) and hydraulic retention time of 60 h, COD conversion efficiency was maintained at 63%. The energy from biogas provided 80% of that demand for heating pretreatment. Dewatered sludge after thermal hydrolysis could be incinerated with municipal solid waste in an industrial-scale incinerator. Total energy production from combined biogas anaerobic digestion and sludge incineration, treating 1.0 kg raw sludge with moisture content of 82%, was 2419 kJ. The energy demand of thermal hydrolysis pretreatment was 340 kJ. PMID- 23985530 TI - Sludge accumulation and conversion to methane in a septic tank treating domestic wastewater or black water. AB - Although the septic tank is the most applied on-site system for wastewater pre treatment, limited research has been performed to determine sludge accumulation and biogas production in the tank. Therefore a dynamic mathematical model based on the Anaerobic Digestion Model No. 1 (ADM1) was developed for anaerobic digestion of the accumulated sludge in a septic tank treating domestic wastewater or black water. The results showed that influent chemical oxygen demand (COD) concentration and hydraulic retention time (HRT) of the tank mainly control the filling time with sludge, while operational temperature governs characteristics of the accumulated sludge and conversion to methane. For obtaining stable sludge and high conversion, the tank needs to be operated for a period more than a year without sludge wasting. Maximum conversion to methane in the tank is about 50 and 60% for domestic wastewater and black water, respectively. The required period for sludge wasting depends on the influent COD concentration and the HRT, while characteristics of the wasted sludge are affected by operational temperature followed by the influent COD concentration and the HRT. Sludge production from the tank ranges between 0.19 to 0.22 and 0.13 to 0.15 L/(person.d), for the domestic wastewater and black water, respectively. PMID- 23985531 TI - Bioreactance is not reliable for estimating cardiac output and the effects of passive leg raising in critically ill patients. AB - BACKGROUND: Bioreactance estimates cardiac output in a non-invasive way. We evaluated the ability of a bioreactance device (NICOM(r)) to estimate cardiac index (CI) and to track relative changes induced by volume expansion. METHODS: In 48 critically ill patients, we measured CI estimated by the NICOM(r) device (CINicom) and by transpulmonary thermodilution (CItd, PiCCO2TM device) before and after a 500 ml saline infusion. Before volume expansion, we performed a passive leg raising (PLR) test and measured the changes it induced in CINicom and in pulse contour analysis-derived CI. RESULTS: Considering the values recorded before PLR and before and after volume expansion (n=144), the bias (lower and upper limits of agreement) between CItd and CINicom was 0.9 (-2.2 to 4.1) litre min(-1) m(-2). The percentage error was 82%. There was no significant correlation between the changes in CItd and CINicom induced by volume expansion (P=0.24). An increase in CI estimated by pulse contour analysis >9% during the PLR test predicted fluid responsiveness with a sensitivity of 84% (95% confidence interval 60-97%) and a specificity of 97% (95% confidence interval 82-100%). The area under the receiver operating characteristic curve constructed to test the ability of the PLR-induced changes in CINicom in predicting fluid responsiveness did not differ significantly from 0.5 (P=0.77). CONCLUSIONS: The NICOM(r) device cannot accurately estimate the cardiac output in critically ill patients. Moreover, it could not predict fluid responsiveness through the PLR test. PMID- 23985532 TI - Measuring the quality of anaesthesia from a patient's perspective: development, validation, and implementation of a short questionnaire. AB - BACKGROUND: The primary aim of this study was to develop and validate a short psychometric instrument to assess the patient's perception of the quality of anaesthesia. METHODS: In Part 1, the Perception of Quality in Anaesthesia (PQA) questionnaire was developed, pilot tested, and validated. Attributes of high quality anaesthesia were identified using a process that restricted input to patients and members of the public. In Part 2, patient cohorts completed the PQA before, and after, a 6 month period where anaesthetists were given individualized performance data using questions from the PQA. RESULTS: In Part 1, items in the PQA were identified and ranked by 120 patients and members of the public. Validity and reliability of the PQA was assessed by 714 patients. Principal component analysis showed that the PQA comprised five factors: attention/gentleness; pain management; information/confidence; postoperative nausea or vomiting (PONV); and concerns addressed. In Part 2, there were 2046 patient participants in the pre-feedback cohort, 4251 in the feedback cohort, and 1421 in the post-feedback cohort. Unsatisfactory experience in at least one PQA factor was described by 45.2% [95% confidence interval (CI) 43.1-47.4%] during the pre-feedback period, and 35.0% (95% CI 32.6-37.6%) during the post-feedback period. CONCLUSIONS: We developed and validated a patient-derived questionnaire to measure the patient's perception of anaesthesia quality. PONV, postoperative pain management, and communication with the anaesthetist are the most important features of the patient's experience. Feedback of PQA performance scores to anaesthetists can lead to improved patient experience. PMID- 23985534 TI - Freeze-dried and spray-dried zinc-containing silica microparticles entrapping insulin. AB - New approaches for oral administration of insulin are strongly related to novel insulin carriers. The aim of this study was the insulin microencapsulation in a new zinc-silica matrix for drug protection and controlled release. Zinc-silica microparticles loaded with insulin were obtained by sol-gel process via spray drying and freeze drying methods. Inorganic silica matrix isolates and constrains the movement of the biomolecules preventing their aggregation and denaturation, while the zinc oxide improves the system stability. Moreover, formation of insulin hexamers in the presence of zinc ions leads to an increased stability of the insulin three-dimensional structure during preparation, storage and release. The particles were characterized with respect to average size, specific surface area, porosity and morphology. In vitro behavior of insulin-loaded particles together with protein structural conformation was also evaluated. The release profile can be adapted by synthesis route of microparticles. PMID- 23985533 TI - The importance of Raf dimerization in cell signaling. AB - The Raf family of protein kinases are key signaling intermediates, acting as a central link between the membrane-bound Ras GTPases and the downstream kinases MEK and ERK. Raf kinase regulation is well-known for its complexity but only recently has it been realized that many of the mechanisms involved in Raf regulation also modulate Raf dimerization, now acknowledged to be a required step for Raf signaling in multiple cellular contexts. Recent studies have shown that Raf dimerization is necessary for normal Ras-dependent Raf kinase activation and contributes to the pathogenic function of disease-associated mutant Raf proteins with all but high intrinsic kinase activity. Raf dimerization has also been found to alter therapeutic responses and disease progression in patients treated with ATP-competitive Raf inhibitors as well as certain other kinase-targeted drugs. This demonstration of clinical significance has stimulated the recent development of biosensor assays that can monitor inhibitor-induced Raf dimerization as well as studies demonstrating the therapeutic potential of blocking Raf dimerization. PMID- 23985535 TI - Multifunctional nanocarrier based on clay nanotubes for efficient intracellular siRNA delivery and gene silencing. AB - RNA interference-mediated gene silencing relating to disease has recently emerged as a powerful method in gene therapy. Despite the promises, effective transport of siRNA with minimal side effects remains a challenge. Halloysites are cheap and naturally available aluminosilicate clay nanotubes with high mechanical strength and biocompatibility. In this study, a novel multifunctional nanocarrier based on functionalized halloysite nanotubes (f-HNTs) has been developed via electrostatic layer-by-layer assembling approach for loading and intracellular delivery of therapeutic antisurvivin siRNA and simultaneously tracking their intracellular transport, in which PEI-modified HNTs are used as gene vector, antisurvivin siRNA as gene therapeutic agent, and mercaptoacetic acid-capped CdSe quantum dots as fluorescent labeling probes. The successful assembly of the f-HNTs-siRNA complexes was systematically characterized by transmission electron microscopy (TEM), UV-visible spectrophotometry, Zeta potential measurement, fluorescence spectrophotometry, and electrochemical impedance spectroscopy. Confocal microscopy, biological TEM, and flow cytometry studies revealed that the complexes enabled the efficient intracellular delivery of siRNA for cell-specific gene silencing. MTT assays exhibited that the complexes can enhance antitumor activity. Furthermore, Western blot analysis showed that f-HNTs-mediated siRNA delivery effectively knocked down gene expression of survivin and thereby decreased the levels of target proteins of PANC-1 cells. Therefore, this study suggested that the synthesized f-HNTs were a new effective drug delivery system for potential application in cancer gene therapy. PMID- 23985536 TI - Gelatin-apatite bone mimetic co-precipitates incorporated within biopolymer matrix to improve mechanical and biological properties useful for hard tissue repair. AB - Synthetic biopolymers are commonly used for the repair and regeneration of damaged tissues. Specifically targeting bone, the composite approach of utilizing inorganic components is considered promising in terms of improving mechanical and biological properties. We developed gelatin-apatite co-precipitates which mimic the native bone matrix composition within poly(lactide-co-caprolactone) (PLCL). Ionic reaction of calcium and phosphate with gelatin molecules enabled the co precipitate formation of gelatin-apatite nanocrystals at varying ratios. The gelatin-apatite precipitates formed were carbonated apatite in nature, and were homogeneously distributed within the gelatin matrix. The incorporation of gelatin apatite significantly improved the mechanical properties, including tensile strength, elastic modulus and elongation at break, and the improvement was more pronounced as the apatite content increased. Of note, the tensile strength increased to as high as 45 MPa (a four-fold increase vs. PLCL), the elastic modulus was increased up to 1500 MPa (a five-fold increase vs. PLCL), and the elongation rate was ~240% (twice vs. PLCL). These results support the strengthening role of the gelatin-apatite precipitates within PLCL. The gelatin apatite addition considerably enhanced the water affinity and the acellular mineral-forming ability in vitro in simulated body fluid; moreover, it stimulated cell proliferation and osteogenic differentiation. Taken together, the GAp-PLCL nanocomposite composition is considered to have excellent mechanical and biological properties, which hold great potential for use as bone regenerative matrices. PMID- 23985537 TI - Effect of photofunctionalization on fluoride-treated nanofeatured titanium. AB - The objective of this study was to evaluate the effect of ultraviolet light treatment, known as photofunctionalization, on the biological and osseointegration capability of nanofeatured titanium created by a combination of sandblasting and hydrofluoric acid treatment. Titanium samples in disk and cylinder forms were photofunctionalized by treatment with ultraviolet light for 15 min. The nanofeatured surface was converted from hydrophobic to superhydrophilic after photofunctionalization. The strength of osseointegration measured by a biomechanical push-in test in a rat model was stronger for photofunctionalized implants than for untreated implants by 2.2 and 2.3 times, respectively, at the early (week 2) and late (week 4) stages of healing, implying that photofunctionalization did not only accelerate but also increased the degree of osseointegration. Culture studies using bone marrow-derived osteoblasts showed that the attachment, spread, and functional phenotypes of osteogenic cells, such as alkaline phosphatase activity and mineralization, were remarkably increased on photofunctionalized titanium. In conclusion, photofunctionalization substantially increased biological and osseointegration capability of a nanofeatured titanium surface. In light with proven effectiveness on microfeatured surfaces in the literature, photofunctionalization may provide a novel and practical avenue to further improve osseointegration capability of implants in a wide range of surface morphology with micro-to-nano features. PMID- 23985538 TI - The toxic Doppelganger: on the ionic and molecular mimicry of cadmium. AB - Cadmium is a toxic heavy metal which can cause numerous alterations in cell functioning. Exposure to cadmium leads to generation of reactive oxygen species, disorders in membrane structure and functioning, inhibition of respiration, disturbances in ion homeostasis, perturbations in cell division, and initiation of apoptosis and necrosis. This heavy metal is considered a carcinogen by the Agency for Toxic Substances and Disease Registry. At least some of the described toxic effects could result from the ability of cadmium to mimic other divalent ions and alert signal transduction networks. This review describes the role of cadmium mimicry in its uptake, reactive oxygen species generation, alterations in calmodulin, Wnt/beta-catenin and estrogen signaling pathways, and modulation of neurotransmission. The last section is dedicated to the single known case of a favorable function performed by cadmium mimicry: marine diatoms, which live in zinc deficient conditions, utilize cadmium as a cofactor in carbonic anhydrase - so far the only described cadmium enzyme. PMID- 23985539 TI - Single dose of green tea extract decreases lipid digestion and absorption from a test meal in humans. AB - BACKGROUND & AIMS: Green tea is known worldwide for its high content of polyphenolic compounds and multifactorial beneficial effects on human health. The role of green tea as an inhibitor of lipid hydrolysis is widely discussed. The aim of the study was to assess the influence of green tea extract on lipid digestion and absorption. METHODS: The study comprised 32 healthy volunteers aged 23 to 30 years with normal exocrine pancreatic function. In all subjects (13)C labelled mixed triglyceride breath test was performed twice with and without green tea extract ingestion. Cumulative percentage dose recovery was considered to reflect digestion and absorption of lipids. Values are expressed as medians and 1st-3rd quartile distribution. RESULTS: In all subjects, cumulative percentage dose recovery values were normal in a placebo test (36.8% <30.1 43.3%>). These results were significantly higher (p=0.021) than those obtained in green tea extract test (28.8% <23.1-37.2%>). Results of six tests with GTE were abnormal. CONCLUSIONS: Single dose of green tea extract taken with a test meal decreases lipid digestion and absorption in humans. PMID- 23985540 TI - A poly(3-hexylthiophene) block copolymer with macroscopically aligned hierarchical nanostructure induced by mechanical rubbing. AB - A highly ordered, uniformly aligned nanostructure with good crystallinity was first achieved on a P3HT block copolymer possessing a low weight fraction (19.4 wt%) of a flexible polyisoprene segment via a mechanical rubbing process without the use of solution based fabrication and thermal annealing. The attachment of the short polyisoprene segment to P3HT would significantly promote the main chain mobility to allow the orientation control of P3HT and of the self-assembled nanostructure by rubbing. PMID- 23985541 TI - Effect of orally administered Lactobacillus brevis HY7401 in a food allergy mouse model. AB - We had found that orally administered Lactobacillus species were effective immune modulators in ovalbumin (OVA)-sensitized mice. To validate these findings, we investigated the effects of orally administered Lactobacillus brevis HY7401 in OVA-T cell receptor transgenic mice. This strain showed a tendency to induce Th1 cytokines and inhibit Th2 cytokines. All assayed isotypes of OVA-specific antibody were effectively reduced. Systemic anaphylaxis was also relatively reduced with the probiotic administration. These results reveal that L. brevis HY7401 might be useful to promote anti-allergic processes through oral administration. PMID- 23985542 TI - Isolation of an indigenous imidacloprid-degrading bacterium and imidacloprid bioremediation under simulated in situ and ex situ conditions. AB - The Bacterial community structure and its complexity of the enrichment culture during the isolation and screening of imidacloprid-degrading strain were studied using denaturating gradient gel electrophoresis analysis. The dominant bacteria in the original tea rhizosphere soil were uncultured bacteria, Rhizobium sp., Sinorhizobium, Ochrobactrum sp., Alcaligenes, Bacillus sp., Bacterium, Klebsiella sp., and Ensifer adhaerens. The bacterial community structure was altered extensively and its complexity reduced during the enrichment process, and four culturable bacteria, Ochrobactrum sp., Rhizobium sp., Geobacillus stearothermophilus, and Alcaligenes faecalis, remained in the final enrichment. Only one indigenous strain, BCL-1, with imidacloprid-degrading potential, was isolated from the sixth enrichment culture. This isolate was a gram-negative rod shaped bacterium and identified as the genus Ochrobactrum based on its morphological, physiological, and biochemical properties and its 16S rRNA gene sequence. The degradation test showed that approximately 67.67% of the imidacloprid (50 mg/l) was degraded within 48 h by strain BCL-1. The optimum conditions for degradation were a pH of 8 and 30 degrees C. The simulation of imidacloprid bioremediation by strain BCL-1 in soil demonstrated that the best performance in situ (tea soil) resulted in the degradation of 92.44% of the imidacloprid (100 mg/g) within 20 days, which was better than those observed in the ex situ simulations that were 64.66% (cabbage soil), 41.15% (potato soil), and 54.15% (tomato soil). PMID- 23985543 TI - Biominerlization and possible endosulfan degradation pathway adapted by Aspergillus niger. AB - Endosulfan is a chlorinated pesticide; its persistence in the environment and toxic effects on biota are demanding its removal. This study aims at improving the tolerance of the previously isolated fungus Aspergillus niger (A. niger) ARIFCC 1053 to endosulfan. Released chloride, dehalogenase activity, and released proteins were estimated along with analysis of endosulfan degradation and pathway identification. The culture could tolerate 1,000 mg/ml of technical grade endosulfan. Complete disappearance of endosulfan was seen after 168 h of incubation. The degradation study could easily be correlated with increase in released chlorides, dehalogenase activity and protein released. Comparative infrared spectral analysis suggested that the molecule of endosulfan was degraded efficiently by A. niger ARIFCC 1053. Obtained mass ion values by GC-MS suggested a hypothetical pathway during endosulfan degradation by A. niger ARIFCC 1053. All these results provide a basis for the development of bioremediation strategies to remediate the pollutant under study in the environment. PMID- 23985544 TI - Effects of melatonin on nervous system aging: neurogenesis and neurodegeneration. AB - Neural aging as a progressive loss of function involves central and peripheral post-mitotic neurons and neural stem cells (NSCs). It promotes neurodegeneration, impairs neurogenesis, and can be considered a cause of cognitive impairment and sensory and motor deficits in the elderly. Age-related morphological atrophic changes and cellular alterations are addressed by neural aging mechanisms. Neurogenesis declines during aging through several mechanisms such as an increase in quiescence state, changes in lineage fate, telomerase dysfunction, the failure of the DNA repair system, increased apoptosis, and the impairment of self renewal. The self-renewal transcriptional factor Sox2 has been correlated with retrotransposon L1 and certain cell-cycle- and epigenetic-related factors, which are sometimes considered age-related factors in NSC aging. As neurogenesis decreases, non-mitotic neurons undergo neurodegeneration by oxidative stress, sirtuin, insulin signaling and mTOR alteration, mitochondrial dysfunction, and protein misfolding and aggregation. As neurodegeneration and impaired neurogenesis promote the nervous system aging process, the identification of neuronal anti-aging is required to raise life expectancy. The role of melatonin in increasing neurogenesis and protecting against neurodegeneration has been investigated. Here, we review nervous system aging that is correlated with mechanisms of neurodegeneration and the impairment of neurogenesis and evaluate the effects of melatonin on these processes. PMID- 23985546 TI - Men's Health: Practical Solutions to a Profoundly Underrated Health-Care Crisis. PMID- 23985547 TI - Male impotency and the compounding pharmacist. PMID- 23985545 TI - Long-term changes in carotid intima-media thickness among HIV-infected children and young adults. AB - BACKGROUND: HIV-infected patients are at increased risk of cardiovascular disease (CVD). This study assessed long-term changes in carotid intima-media thickness (IMT) as a surrogate marker for CVD risk in HIV-infected children and young adults. METHODS: This was a longitudinal, observational study comparing carotid IMT in HIV-infected subjects who were 2-21 years old to matched controls over 144 weeks. RESULTS: A total of 34 HIV-infected subjects and 29 controls were included in the analyses. Among the HIV-infected group, median age was 10 years, 74% were black, and 65% were female. Overall, 91% were perinatally-infected with 82% on antiretroviral therapy and a median CD4(+) T-cell count of 681 cells/mm(3). At baseline, HIV-infected subjects had increased internal carotid artery (ICA) and common carotid artery (CCA) IMT (ICA, HIV-infected 0.90 mm versus controls 0.73 mm; P<0.01; CCA, HIV-infected 1.00 mm versus controls 0.90 mm; P=0.02). Relatively large changes in ICA and CCA IMT were seen from year to year in both groups. However, by week 144, there were no net changes in ICA or CCA IMT within the HIV-infected group. In the controls, CCA increased 0.1 mm and ICA increased 0.17 mm from baseline to week 144. ICA and CCA IMT were similar between groups by 144 weeks. CONCLUSIONS: Despite variations from year to year in carotid IMT in HIV-infected children and healthy controls, likely due to arterial growth and/or luminal diameter change, little or no net change occurred in carotid IMT over the entire 144-week study period. This suggests that only small net changes occur over time in HIV-infected children despite an increased long-term risk of CVD. PMID- 23985548 TI - Complementary medical approaches to benign prostatic hyperplasia. PMID- 23985549 TI - Natural testosterone: hormone of the heart. PMID- 23985550 TI - Use of saw palmetto and pygeum in men. PMID- 23985552 TI - Compounding for athletes: a primer for rookies. PMID- 23985551 TI - An aftershave lotion for pseudofolliculitis barbae. PMID- 23985553 TI - Natural HRT: Corrective Measures When the System Goes Down. PMID- 23985554 TI - The basics of compounding: compounding creams and lotions. PMID- 23985555 TI - Analysis of extemporaneous alprostadil formulaions. AB - Twenty-two extemporaneous alprostadil (PGE1) injection solutions samples from five different suppliers and three Caverject (Pharmacia and Upjohn, Inc., Bridgewater, NJ) samples from three different lots, all intended for the clinical treatment of erectile dysfunction, were analyzed to determine PGE1 concentration, assess formation of the PGE1 aqueous breakdown product (PGA1), define pH and assess active microbial contamination. High-pressure liquid chromatography (HPLC), pH meter and cell culture techniques were used to conduct the analyses. Of the 22 extemporaneously formulated samples, six showed PGE1 concentrations 10% greater than their listed amounts and seven showed PGA1 weight fractions corresponding to at least 1.5% of the total prostaglandidn content. It should be noted that no standard has been published in the United States Pharmacopeia/National Formulary for this preparation as of this date. All samples were within the pH range 4.5 to 6.0. Four samples tested positive for active microbial contamination. In adition, nearly all the extemporaneously formulated samples contained what appeared to be benzyl alcohol, and about one half had at least two other undefined peaks within their HPLC chromatograms. In contrast, all three Caverject samples were within +/- 7.5% of their listed PGE1 concentrations while showing PGA1 prostaglandins weight fractions of less 0.6%, all were within the pH range 4.0 to 4.5 and all tested negative for active microbial contamination. Chromatograms of the Caverject samples also diplayed peaks consistent with the presence of benzyl alcohol but did not exhibit addtional undefined peaks. The results suggest that significant variations in PGE1 concentration and in PGA1 formation, accompanied by the possibility of microbial contamination, can occur as a result of the extemporaneous formulation and subsequent transfer of this type of product as a premixed solution intended for treating erectile dysfunction. PMID- 23985556 TI - Stability of extemporaneously prepared sterile testosterone solution in 0.9% sodium chloride solution large-volume parenterals in plastic bags. AB - The stability of extemporaneously compounded testosterone sterile solution in large-volume parenterals (LVPs) in plastic bags containing 0.9% sodium chloride solution was evaluated. Two LVPs were prepared; one remained at room temperature and the other was refrigerated. Samples were withdrawn and frozen at 0, 1, 3, 6, 9 and 24 hours. The concentrations of the samples at each time point were determined using a specific radioimmunoassay. Stability was defined as 90% or greater of the original concentration remaining. No color change was observed at any time during hte study. Inravenous testosterone solutions compounded extemporaneously in 0.9% sodium chloride solution containing LVPs in plastic bags were stable for nine hours at 5 deg C but were unstable at 24 deg C after only one hour. PMID- 23985557 TI - Quantitation of Testosterone Propionate in an Injection Using High-Performance Liquid chromatography. AB - A high-performance liquid chromatography assay method for the quantition of testosterone propionate in an injection has been developed. The assay method is very simple, precise and accurate, with a percent relative standard deviation of 1.3 based on five injections. The benzyl alcohol (the preservative) and sesame oil (the vehicle) did not interfere with the assay procedure. The extraction procedure is very simple compared with a tedious and time-consuming method recommended in the USP-NF. The other similar compounds, testosterone, methyltestosterone, testosterone cypionate and testosterone enanthate, did not interfere with the assay method. Hence, the method developed is specific for this drug, versus the USP-NF method, which is nonspecific. PMID- 23985558 TI - Cellular responses of novel human pancreatic beta-cell line, 1.1B4 to hyperglycemia. AB - The novel human-derived pancreatic beta-cell line, 1.1B4 exhibits insulin secretion and beta-cell enriched gene expression. Recent investigations of the cellular responses of this novel cell line to lipotoxicity and cytokine toxicity revealed similarities to primary human beta cells. The current study has investigated the responses of 1.1B4 cells to chronic 48 and 72 h exposure to hyperglycemia to probe mechanisms of human beta-cell dysfunction and cell death. Exposure to 25 mM glucose significantly reduced insulin content (p<0.05) and glucokinase activity (p<0.01) after 72 h. Basal insulin release was unaffected but acute secretory response to 16.7 mM glucose was impaired (p<0.05). Insulin release stimulated by alanine, GLP-1, KCl, elevated Ca (2+) and forskolin was also markedly reduced after exposure to hyperglycemia (p<0.001). In addition, PDX1 protein expression was reduced by 58% by high glucose (p<0.05). Effects of hyperglycemia on secretory function were accompanied by decreased mRNA expression of INS, GCK, PCSK1, PCSK2, PPP3CB, GJA1, ABCC8, and KCNJ11. In contrast, exposure to hyperglycemia upregulated the transcription of GPX1, an antioxidant enzyme involved in detoxification of hydrogen peroxide and HSPA4, a molecular chaperone involved in ER stress response. Hyperglycemia-induced DNA damage was demonstrated by increased % tail DNA and olive tail moment, assessed by comet assay. Hyperglycemia-induced apoptosis was evident from increased activity of caspase 3/7 and decreased BCL2 protein. These observations reveal significant changes in cellular responses and gene expression in novel human pancreatic 1.1B4 beta cells exposed to hyperglycemia, illustrating the usefulness of this novel human-derived cell line for studying human beta-cell biology and diabetes. PMID- 23985559 TI - Clonogenic multiple myeloma cells have shared stemness signature associated with patient survival. AB - Multiple myeloma is the abnormal clonal expansion of post germinal B cells in the bone marrow. It was previously reported that clonogenic myeloma cells are CD138-. Human MM cell lines RPMI8226 and NCI H929 contained 2-5% of CD138- population. In this study, we showed that CD138- cells have increased ALDH1 activity, a hallmark of normal and neoplastic stem cells. CD138-ALDH+ cells were more clonogenic than CD138+ALDH- cells and only CD138- cells differentiated into CD138+ populations. In vivo tumor initiation and clonogenic potentials of the CD138- population was confirmed using NOG mice. We derived a gene expression signature from functionally validated and enriched CD138- clonogenic population from MM cell lines and validated these in patient samples. This data showed that CD138- cells had an enriched expression of genes that are expressed in normal and malignant stem cells. Differentially expressed genes included components of the polycomb repressor complex (PRC) and their targets. Inhibition of PRC by DZNep showed differential effect on CD138- and CD138+ populations. The 'stemness' signature derived from clonogenic CD138- cells overlap significantly with signatures of common progenitor cells, hematopoietic stem cells, and Leukemic stem cells and is associated with poorer survival in different clinical datasets. PMID- 23985560 TI - microRNA-9 targets the long non-coding RNA MALAT1 for degradation in the nucleus. AB - microRNAs regulate the expression of over 60% of protein coding genes by targeting their mRNAs to AGO2-containing complexes in the cytoplasm and promoting their translational inhibition and/or degradation. There is little evidence so far for microRNA-mediated regulation of other classes of non-coding RNAs. Here we report that microRNA-9 (miR-9) regulates the expression of the Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT-1), one of the most abundant and conserved long non-coding RNAs. Intriguingly, we find that miR-9 targets AGO2 mediated regulation of MALAT1 in the nucleus. Our findings reveal a novel direct regulatory link between two important classes of non-coding RNAs, miRs and lncRNAs, and advance our understanding of microRNA functions. PMID- 23985562 TI - Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. AB - OBJECTIVE: To update and expand the previous position statement of The North American Menopause Society (NAMS) on the management of symptomatic vulvovaginal atrophy (VVA) in postmenopausal women. METHODS: NAMS searched PubMed for medical literature on VVA published since their 2007 position statement on the role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women. A panel of acknowledged experts in the field of genitourinary health reviewed the literature to evaluate new evidence on local estrogen as well as on other management options available or in development for symptomatic VVA. The panel's conclusions and recommendations were reviewed and approved by the NAMS Board of Trustees. RESULTS: Symptomatic VVA can significantly impair the quality of life (QOL) of postmenopausal women and may be underdiagnosed. In most cases, it can be managed successfully. A number of over-the-counter and government-approved prescription therapies available in the United States and Canada demonstrate effectiveness, depending on the severity of VVA symptoms. These include vaginal lubricants and moisturizers, vaginal estrogen, hormone therapy, and the selective estrogen-receptor modulator ospemifene (indicated for dyspareunia). Long-term studies on the endometrial safety of local estrogen and ospemifene are lacking. Changes in the vaginal microbiome have various effects on symptoms. CONCLUSIONS: Clinicians can improve the sexual health and QOL of postmenopausal women by educating women about, diagnosing, and appropriately managing symptomatic VVA. Choice of therapy depends on the severity of symptoms, the effectiveness and safety of therapy for the individual patient, and patient preference. Estrogen therapy is the most effective treatment for moderate to severe symptoms, although a direct comparison of estrogen and ospemifene is not available. Nonhormonal therapies available without a prescription provide sufficient relief for most women with mild symptoms. When low-dose estrogen is administered locally, a progestogen is not indicated for women without a uterus and generally is not indicated for women with an intact uterus. However, endometrial safety has not been studied in clinical trials beyond 1 year. There are insufficient data to confirm the safety of local estrogen in women with breast cancer; management of VVA should take the woman's needs and the recommendation of her oncologist into consideration. Research on the vaginal microbiome may lead to other therapies in the future. PMID- 23985564 TI - Metabolic network as a progression biomarker of premanifest Huntington's disease. AB - BACKGROUND: The evaluation of effective disease-modifying therapies for neurodegenerative disorders relies on objective and accurate measures of progression in at-risk individuals. Here we used a computational approach to identify a functional brain network associated with the progression of preclinical Huntington's disease (HD). METHODS: Twelve premanifest HD mutation carriers were scanned with [18F]-fluorodeoxyglucose PET to measure cerebral metabolic activity at baseline and again at 1.5, 4, and 7 years. At each time point, the subjects were also scanned with [11C]-raclopride PET and structural MRI to measure concurrent declines in caudate/putamen D2 neuroreceptor binding and tissue volume. The rate of metabolic network progression in this cohort was compared with the corresponding estimate obtained in a separate group of 21 premanifest HD carriers who were scanned twice over a 2-year period. RESULTS: In the original premanifest cohort, network analysis disclosed a significant spatial covariance pattern characterized by progressive changes in striato-thalamic and cortical metabolic activity. In these subjects, network activity increased linearly over 7 years and was not influenced by intercurrent phenoconversion. The rate of network progression was nearly identical when measured in the validation sample. Network activity progressed at approximately twice the rate of single region measurements from the same subjects. CONCLUSION: Metabolic network measurements provide a sensitive means of quantitatively evaluating disease progression in premanifest individuals. This approach may be incorporated into clinical trials to assess disease-modifying agents. TRIAL REGISTRATION: Registration is not required for observational studies. FUNDING: NIH (National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering) and CHDI Foundation Inc. PMID- 23985565 TI - Preparation of sewage sludge based activated carbon by using Fenton's reagent and their use in 2-naphthol adsorption. AB - In this study, Fenton's reagents (H2O2/Fe(2+)) are used to activate raw sewage sludge for the preparation of the sludge based activated carbon. The effect of the amount of hydrogen peroxide addition on carbon's chemical composition, texture properties, surface chemistry and morphology are investigated. Choosing an appropriate H2O2 dosage (5 v%) (equivalent to 70.7 mM/(g VS)), it is possible to obtain a comparatively highly porous materials with SBET and the total pore volume being 321 m(2)/g and 0.414 cm(3)/g, respectively. Continuously increasing the oxidant ratio resulted in a decreased SBET value. Further adsorption experiments by using 2-naphthol as model pollutant revealed that the adoption followed a pseudo-second-order kinetics better than pseudo-first-order. The calculated adsorption capacity is 111.9 mg/g on the carbon with 5% H2O2 pretreatment while this value is just 51.5mg/g on carbons without any pretreatment. PMID- 23985567 TI - Functional polypyrrole-silica composites as photothermal agents for targeted killing of bacteria. AB - We demonstrate for the first time that PPy-SiO2-GTA composites can be used as efficient photothermal agents for killing pathogenic bacteria under NIR irradiation. The cell growth of both gram-positive and gram-negative bacteria targeted by PPy-SiO2-GTA composites could be inhibited effectively after photothermal treatment. PMID- 23985566 TI - Modulation of beta-catenin function maintains mouse epiblast stem cell and human embryonic stem cell self-renewal. AB - Wnt/beta-catenin signalling has a variety of roles in regulating stem cell fates. Its specific role in mouse epiblast stem cell self-renewal, however, remains poorly understood. Here we show that Wnt/beta-catenin functions in both self renewal and differentiation in mouse epiblast stem cells. Stabilization and nuclear translocation of beta-catenin and its subsequent binding to T-cell factors induces differentiation. Conversely, retention of stabilized beta-catenin in the cytoplasm maintains self-renewal. Cytoplasmic retention of beta-catenin is effected by stabilization of Axin2, a downstream target of beta-catenin, or by genetic modifications to beta-catenin that prevent its nuclear translocation. We also find that human embryonic stem cell and mouse epiblast stem cell fates are regulated by beta-catenin through similar mechanisms. Our results elucidate a new role for beta-catenin in stem cell self-renewal that is independent of its transcriptional activity and will have broad implications in understanding the molecular regulation of stem cell fate. PMID- 23985568 TI - Localization of alpha7 nicotinic acetylcholine receptor immunoreactivity on GABAergic interneurons in layers I-III of the rat retrosplenial granular cortex. AB - The rat retrosplenial granular cortex (RSG) receives cholinergic input from the medial septum-diagonal band (MS-DB) of the cholinergic basal forebrain (CBF), with projections terminating in layers I-III of RSG. The modulatory effects of acetylcholine (ACh) on cortical GABAergic interneurons in these layers are mediated by alpha7 nicotinic acetylcholine receptors (alpha7nAChRs). alpha7nAChRs are most abundant in the cerebral cortex and are largely localized to GABAergic interneurons. However, the CBF projection to the RSG has not been studied in detail, and the cellular or subcellular distribution of alpha7nAChRs in the rat RSG remains unclear. The main objective of this study was to test that alpha7nAChRs reside on GABAergic interneurons in CBF terminal fields of the rat RSG. First, we set out to define the characteristics of CBF projections from the MS-DB to layers of the RSG using anterograde neural tracing and immunohistochemical labeling with cholinergic markers. These results revealed that the pattern of axon terminal labeling in layer Ia, as well as layer II/III of the RSG is remarkably similar to the pattern of cholinergic axons in the RSG. Next, we investigated the relationship between alpha7nAChRs, labeled using either alpha-bungarotoxin or alpha7nAChR antibody, and the local neurochemical environment by labeling surrounding cells with antibodies against glutamic acid decarboxylase (GAD), parvalbumin (PV) and reelin (a marker of the ionotropic serotonin receptor-expressing GABAergic interneurons). alpha7nAChRs were found to be localized on both somatodendritic and neuronal elements within subpopulations of GABAergic PV-, reelin-stained and non PV-stained neurons in layers I-III of the RSG. Finally, electron microscopy revealed that alpha7nAChRs are GAD- and PV positive cytoplasmic and neuronal elements. These results strongly suggest that ACh released from CBF afferents is transmitted via alpha7nAChR to GAD-, PV-, and reelin-positive GABAergic interneurons in layers I-III of the RSG. PMID- 23985570 TI - Genome-wide expression analysis suggests unique disease-promoting and disease preventing signatures in Pemphigus vulgaris. AB - To evaluate pathogenetic mechanisms underlying disease development and progression in the autoimmune skin disease Pemphigus vulgaris (PV), we examined global peripheral blood gene expression in patients and healthy controls. Our goals were to: (1) assign blood gene expression signatures to patients and controls; (2) identify differentially expressed genes (DEGs) and investigate functional pathways associated with these signatures; and (3) evaluate the distribution of DEGs across the genome to identify transcriptional 'hot spots'. Unbiased hierarchical clustering clearly separated patients from human leukocyte antigen (HLA)-matched controls (MCRs; 'disease' signature), and active from remittent patients ('activity' signature). DEGs associated with these signatures are involved in immune response, cytoskeletal reorganization, mitogen-activated protein kinase (MAPK) signaling, oxidation-reduction and apoptosis. We further found that MCRs carrying the PV-associated HLA risk alleles cluster distinctly from unmatched controls (UMCR) revealing an HLA-associated 'control' signature. A subset of DEGs within the 'control' signature overlap with the 'disease' signature, but are inversely regulated in MCR when compared with either PV patients or UMCR, suggesting the existence of a 'protection' signature in healthy individuals carrying the PV HLA genetic risk elements. Finally, we identified 19 transcriptional 'hot spots' across the signatures, which may guide future studies aimed at pinpointing disease risk genes. PMID- 23985569 TI - [Ruxolitinib prescription in myelofibrosis]. AB - Ruxolitinib is a JAK/STAT inhibitor, which has demonstrated clinical benefits in patients with intermediate-2 and high-risk myelofibrosis. Moreover, first results of recent clinical trials show a trend to better overall survival with ruxolitinib, which allows to hope that we will soon be able to change the natural evolution of this poor outcome disease. With such results, ruxolitinib quickly obtained the Food and Drug Administration (FDA) approval in the United States of America. In France, ruxolitinib is now available, allowing its administration to symptomatic myelofibrosis patients. PMID- 23985571 TI - Association of IRF5 polymorphism with MPO-ANCA-positive vasculitis in a Japanese population. AB - Interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are shared susceptibility genes for various autoimmune diseases. In this study, we investigated whether these genes also contribute to susceptibility to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a Japanese population. A case-control study was carried out on IRF5 rs10954213 and STAT4 rs7574865 in 232 Japanese myeloperoxidase (MPO)-ANCA positive AAV patients, including 177 microscopic polyangiitis and 710 healthy controls. IRF5 rs10954213G was significantly increased in MPO-ANCA-positive AAV (additive model, P=0.023, odds ratio=1.27, 95% confidence interval=1.03-1.57). The risk allele was previously shown to be associated with lower mRNA level of IRF5. On the other hand, significant association of STAT4 rs7574865T with AAV was not detected. These observations suggested that IRF5 may contribute to susceptibility to MPO-ANCA-positive AAV in a Japanese population. PMID- 23985572 TI - HNRNPA1 interacts with a 5'-flanking distal element of interleukin-6 and upregulates its basal transcription. AB - Interleukin-6 (IL-6) is an important pro-inflammatory cytokine involved in many autoimmune and inflammatory diseases. We have shown previously that a region from -5307 to -5202 bp upstream of the IL-6 transcriptional start site is responsible for basal IL-6 gene expression, and that there were DNA-binding proteins involved from electrophoretic mobility shift assay (EMSA) and transient expression experiments. Here we have combined surface plasmon resonance technology with mass spectrometry analysis and have identified nuclear proteins bound to this region. HNRNPA1 and HNRNPA2B1 were found consistently. EMSA supershift and chromatin immunoprecipitation assays confirmed the involvement of HNRNPA1, but not of HNRNPA2B1. Knocking down the HNRNPA1 expression by small interfering RNA resulted in reduced IL-6 transcriptional activity as assessed from transfection experiments using reporter constructs, mRNA and protein measurements. Overexpression of HNRNPA1 cDNA increased IL-6 mRNA expression. This regulation was dependent on the presence of the sequence from -5307 to -5202 bp of the IL-6 gene. Thus, HNRNPA1 is a novel transcriptional regulator of IL-6 expression, acting via the 5'-flanking sequence of the gene. PMID- 23985573 TI - IL7RA haplotype-associated alterations in cellular immune function and gene expression patterns in multiple sclerosis. AB - Interleukin-7 receptor alpha (IL7RA) is among the top listed candidate genes influencing the risk to develop multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Soluble IL-7RA (sIL-7RA) protein and mRNA levels vary among the four common IL7RA haplotypes. Here we show and confirm that protective haplotype carriers have three times lower sIL-7RA serum levels than the other three haplotypes. High sIL-7RA concentrations significantly decrease IL-7-mediated STAT5 phosphorylation in CD4(+) T cells. Transcriptome analysis of unstimulated and stimulated CD4(+) T cells of MS patients carrying the different IL7RA haplotypes revealed complex and overlapping patterns in genes participating in cytokine signaling networks, apoptosis, cell cycle progression and cell differentiation. Our findings indicate that genetic variants of IL7RA result in haplotype-associated differential responsiveness to immunological stimuli that influence MS susceptibility not exclusively by varying levels of sIL-7RA. PMID- 23985574 TI - Role of masseter muscle beta2-adrenergic signaling in regulation of muscle activity, myosin heavy chain transition, and hypertrophy. AB - Chronic administration of clenbuterol (CB), a lipophilic beta2-adrenoceptor (beta2-AR) agonist, induces skeletal muscle hypertrophy and slow-to-fast fiber type transitions in mammalian species, but the mechanism and pathophysiological roles of these changes have not been explored. Here, we examined the effects of CB not only on masseter muscle mass, fiber diameter, and myosin heavy chain (MHC) composition, but also on daily muscle activity, a factor influencing muscle phenotype, by means of electromyogram analysis in rats. MHC transition towards faster isoforms was induced by 2-week CB treatment. In addition, daily duty time was increased at 1 day, 1 week, and 2 weeks after the start of CB treatment and its increase was greater at high activity level (6-fold) than at low activity level (2-fold). In order to examine whether these effects of CB were mediated through muscle or CNS beta2-AR stimulation, we compared these effects of CB with those of salbutamol (SB), a hydrophilic beta2-AR agonist. SB treatment induced masseter hypertrophy and MHC transition, like CB, but did not increase daily activity. These results suggest that CB-mediated slow-to-fast MHC transition with hypertrophy was induced through direct muscle beta2-AR stimulation, but the increase of daily duty time was mediated through the CNS. PMID- 23985575 TI - Swinging at a cocktail party: voice familiarity aids speech perception in the presence of a competing voice. AB - People often have to listen to someone speak in the presence of competing voices. Much is known about the acoustic cues used to overcome this challenge, but almost nothing is known about the utility of cues derived from experience with particular voices--cues that may be particularly important for older people and others with impaired hearing. Here, we use a version of the coordinate-response measure procedure to show that people can exploit knowledge of a highly familiar voice (their spouse's) not only to track it better in the presence of an interfering stranger's voice, but also, crucially, to ignore it so as to comprehend a stranger's voice more effectively. Although performance declines with increasing age when the target voice is novel, there is no decline when the target voice belongs to the listener's spouse. This finding indicates that older listeners can exploit their familiarity with a speaker's voice to mitigate the effects of sensory and cognitive decline. PMID- 23985576 TI - Do girls really experience more anxiety in mathematics? AB - Two studies were conducted to examine gender differences in trait (habitual) versus state (momentary) mathematics anxiety in a sample of students (Study 1: N = 584; Study 2: N = 111). For trait math anxiety, the findings of both studies replicated previous research showing that female students report higher levels of anxiety than do male students. However, no gender differences were observed for state anxiety, as assessed using experience-sampling methods while students took a math test (Study 1) and attended math classes (Study 2). The discrepant findings for trait versus state math anxiety were partly accounted for by students' beliefs about their competence in mathematics, with female students reporting lower perceived competence than male students despite having the same average grades in math. Implications for educational practices and the assessment of anxiety are discussed. PMID- 23985577 TI - A double-blind, randomized, neoadjuvant study of the tissue effects of POMx pills in men with prostate cancer before radical prostatectomy. AB - Pomegranates slow prostate cancer xenograft growth and prolong prostate-specific antigen (PSA) doubling times in single-arm human studies. Pomegranates' effects on human prostate tissue are understudied. We hypothesized that orally administered pomegranate extract (POMx; Pom Wonderful) would lower tissue 8 hydroxy-2'-deoxyguanosine (8-OHdG), an oxidative stress biomarker. Seventy men were randomized to two tablets, POMx or placebo, daily up to four weeks before radical prostatectomy. Tissue was analyzed for intraprostatic urolithin A, a pomegranate metabolite, benign and malignant 8-OHdG, and cancer pS6 kinase, NF kappaB, and Ki67. Primary endpoint was differences in 8-OHdG, and the study was powered to detect 35% reduction. POMx was associated with 16% lower benign tissue 8-OHdG (P = 0.095), which was not statistically significant. POMx was well tolerated with no treatment-related withdrawals. There were no differences in baseline clinicopathological features between arms. Urolithin A was detected in 21 of the 33 patients in the POMx group versus 12 of the 35 in the placebo group (P = 0.031). Cancer pS6 kinase, NF-kappaB, Ki67, and serum PSA changes were similar between arms. POMx before surgery results in pomegranate metabolite accumulation in prostate tissues. Our primary endpoint in this modest-sized short term trial was negative. Future larger longer studies are needed to more definitively test whether POMx reduces prostate oxidative stress, as well as further animal testing to better understand the multiple mechanisms through which POMx may alter prostate cancer biology. PMID- 23985579 TI - Improving undergraduate medical education about pain assessment and management: a qualitative descriptive study of stakeholders' perceptions. AB - BACKGROUND: Pain is one of the most common reasons for individuals to seek medical advice, yet it remains poorly managed. One of the main reasons that poor pain management persists is the lack of adequate knowledge and skills of practicing clinicians, which stems from a perceived lack of pain education during the training of undergraduate medical students. OBJECTIVE: To identify gaps in knowledge with respect to pain management as perceived by students, patients and educators. METHODS: A qualitative descriptive study was conducted. Data were generated through six focus groups with second- and fourth-year medical students, four focus groups with patients and individual semistructured interviews with nine educators. All interviews were audiotaped and an inductive thematic analysis was performed. RESULTS: A total of 70 individuals participated in the present study. Five main themes were identified: assessment of physical and psychosocial aspects of pain; clinical management of pain with pharmacology and alternative therapies; communication and the development of a good therapeutic relationship; ethical considerations surrounding pain; and institutional context of medical education about pain. CONCLUSION: Participating patients, students and pain experts recognized a need for additional medical education about pain assessment and management. Educational approaches need to teach students to gather appropriate information about pain, to acquire knowledge of a broad spectrum of therapeutic options, to develop a mutual, trusting relationship with patients and to become aware of their own biases and prejudice toward patients with pain. The results of the present study should be used to develop and enhance existing pain curricula content. PMID- 23985581 TI - It's about the patients. PMID- 23985578 TI - Synergistic interaction between metformin and sulfonylureas on diclofenac-induced antinociception measured using the formalin test in rats. AB - BACKGROUND: There is evidence that biguanides and sulfonylureas block diclofenac induced antinociception (DIA) in rat models. However, little is known about the interaction between these hypoglycemics with respect to DIA. OBJECTIVE: To determine whether metformin-sulfonylurea combinations affect DIA during the formalin test. METHODS: Rats received the appropriate vehicle or diclofenac before 1% formaldehyde was injected into the paw. Rats were also pretreated with vehicle, glibenclamide, glipizide, metformin or glibenclamide/metformin and glipizide/metformin combinations before the diclofenac and formaldehyde injections, and the effect on antinociception was assessed. Isobolograms of the combinations were constructed to test for a synergistic interaction. RESULTS: Systemic injection of diclofenac resulted in antinociception during the second phase of the test. Systemic pretreatment with the combinations of glibenclamide (0.56 mg/kg to 10 mg/kg)/metformin (10 mg/kg to 180 mg/kg) and glipizide (0.56 mg/kg to10 mg/kg)/metformin (10 mg/kg to 180 mg/kg) blocked DIA. The derived theoretical effective doses for 50% of subjects (ED50) for the glibenclamide/metformin and glipizide/metformin combinations were 32.52 mg/kg and 32.42 mg/kg, respectively, and were significantly higher than the actual observed experimental ED50 values (7.57 mg/kg and 8.43 mg/kg, respectively). CONCLUSION: Pretreatment with glibenclamide, glipizide or metformin blocked DIA in a dose dependent manner, and combining either sulfonylurea with metformin produced even greater effects. The observed ED50s for the combinations were approximately fourfold lower than the calculated additive effects. These data indicate that sulfonylureas interact to produce antagonism of DIA. Combination therapy is a common second-line treatment for patients with diabetes and metabolic syndrome, a group that experiences pain from multiple sources. The results suggest that at least some anti-inflammatory agents may not be effective in this group. PMID- 23985580 TI - Spirometry-related pain and distress in adolescents and young adults with cystic fibrosis: the role of acceptance. AB - OBJECTIVE: To investigate the occurrence of spirometry-related pain and distress in adolescents and young adults with cystic fibrosis (CF), and to investigate the role of acceptance of illness in spirometry-related pain and distress. METHODS: A total of 36 adolescents and young adults with CF (12 to 22 years of age) completed a questionnaire assessing acceptance of illness. Spirometry-related distress was assessed using self-report (ie, anxiety/worry about the procedure) and physiological outcomes (ie, heart rate and heart rate variability) before spirometry. Spirometry-related pain was assessed using self-report (ie, expected pain and pain-related thoughts). Self-reported distress and pain during spirometry were also assessed. RESULTS: Eighty-nine per cent of subjects reported distress before spirometry, 67% experienced distress during spirometry, 28% expected pain during spirometry and 22% actually experienced pain. Interestingly, partial correlations revealed that more acceptance was related to less expected pain and pain-related thoughts. Acceptance, however, was unrelated to distress, anxiety and pain during spirometry. DISCUSSION: The present study suggests that a non-negligible number of adolescents and young adults with CF experience pain and distress during spirometry. Furthermore, results indicate that acceptance may play a protective role in the more indirect consequences of CF such as expected pain and pain-related thoughts during medical procedures. Acceptance, however, was not related to distress before and during spirometry, nor to experienced pain. These findings contribute to the increasing evidence that acceptance may play a protective role in managing the consequences of living with CF. PMID- 23985582 TI - Our national obsession with flu vaccine. PMID- 23985583 TI - Veteran care. PMID- 23985584 TI - Pediatric mental health. PMID- 23985585 TI - Education and safety. PMID- 23985586 TI - An evolving profession. PMID- 23985587 TI - NPs continue to break down practice barriers. PMID- 23985592 TI - Improvements in end-of-life care promising but not uniform. PMID- 23985594 TI - Preexposure prophylaxis reduces HIV risk in injection-drug users. PMID- 23985598 TI - U.S. organ donations: nurses can make a difference. PMID- 23985599 TI - Rural nursing. 1906. PMID- 23985600 TI - Gun violence and the role of health care: a confusing state of affairs. PMID- 23985607 TI - Using crew resource management and a 'read-and-do checklist' to reduce failure-to rescue events on a step-down unit. PMID- 23985609 TI - MedlinePlus.gov: quality health information for your patients. PMID- 23985608 TI - The AAWC pressure ulcer guidelines. PMID- 23985610 TI - Nurse academy. PMID- 23985612 TI - Compounding and the specialty veterinary practice. PMID- 23985611 TI - Every three months. PMID- 23985613 TI - Call of the wild: compounding for zoos and exotics. PMID- 23985614 TI - Improving profitability with veterinary compounding. PMID- 23985615 TI - Compounding for creatures: what works. PMID- 23985616 TI - The top ten veterinary compound preparations. PMID- 23985617 TI - Veterinary flavor suggestions. PMID- 23985618 TI - When is compounding for animals legal? PMID- 23985619 TI - Use of fenbendazole in treating trichuriasis in colobus monkeys. PMID- 23985620 TI - Returning to our roots. PMID- 23985621 TI - The basics of compounding: compounding powder-filled capsules. PMID- 23985622 TI - Fosphenytoin y-site stability studies with Lorazepam and midazolam hydrochloride. AB - The treatment of status epilepticus may require in certain situations the concurrent administration of lorazepam or midazolam with fosphenytoin. Simulated Y-site fosphenytoin/lorazepam and fosphenytoin/midazolam hydrochloride admixtures, respectively, in 0.9% sodium chloride injection were analyzed using a stability-indicating high-performance liquid chromatography (HPLC) method. Each drug was analyzed for stability by HPLC from three simulated Y-site samples over an eight-hour period. The HPLC assay results indicate that both fosphenytoin and lorazepam are stable together at a Y site over an eight-hour period. In addition, there was neither a change in sample clarity nor a change in pH over the same period. The results indicate that, when medically necessary, fosphenytoin and lorazepam in 0.9% sodium chloride injection can be administered via the same intravenous (IV) line. Midazolam free base was precipitated upon admixture of midazolam hydrochloride and fosphenytoin solutions. Therefore, midazolam hydrochloride and fosphenytoin should not be given via the same IV line. PMID- 23985623 TI - Quantitation of testosterone in a suspension using high-performance liquid chromatography. AB - An assay method based on high-performance liquid chromatography (HPLC), for the quantitation of testosterone in an aqueous suspension, has been developed. The method is very simple compared with a tedious and time-consuming method recommended by the USP-NF. It is an accurate and precise method; the percent relative standard deviation based on five injections was 1.15. The average recovery from four batches of suspension was 100% (percent relative standard deviation, 1.3) A number of inactive ingredients present in the suspension vehicle did not interfere with the assay procedure. Testosterone appears to be a very stable drug since it did not decompose significantly, even on heating. A 15 cm column gave sharper peaks vs. a 25-cm column and the sensitivity of the assay method increased by 400%. PMID- 23985624 TI - Compatibility of Docetaxel with Selected Drugs during Simulated Y-Site Administration. AB - The compatibility of docetaxel with 81 secondary additives during simlated Y-site injection was evaluated by visual observation with the unaided eye and a Tyndall beam as well as with electronic turbidity measurement. Five milliliters of docetaxel 0.9 mg/mL in 5% dextrose injection was combined with 5 mL of solutions of 81 secondary additives including suportive-care drugs and anti-infectives in 5% dextrose injection or, if necessary to avoid incompatibilities with the diluent, 0.9% sodium chloride injection. Visual examinations were performed in fluorescent light with the unaided eye and a Tyndall beam (high-intensity monodirectional light beam) to enhance visualization of small particles and low level turbidity. The turbidity of each sample was quantitated as well. Evaluation of the samples was performed initially and at one and four hours after preparation. Most of the drugs tested were physically compatible with docetaxel at 0.9 mg/mL. However, three drugs exhibited incompatibilites with docetaxel within the four-hour observation period, Amphotericin B resulted in the formation of a substantially more intense haze measuring about 11.5 nephelometric turbidity units (NTU) after four hours; the haze was visible in normal room light. The nalbuphine hydrochloride mixtures resulted in a small increase of about 0.8 NTU in sub-visual haze. The methylprednisolone sodium succinate combination resulted in a small loss of the expected natural haze of about 0.5 to 0.6 NTU. Docetaxel was physically compatible with 78 supportive care and anti-infective drugs during simulated simultaneous Y-site administration. However, amphotericin B, nalbuphine hydrochloride, and mehtylprednisolone sodium succinate resulted in physical incompatibilites. Simultaneous Y-site administration of these three drugs with docetaxel should be avoided. PMID- 23985626 TI - Electric-field-induced metal maintained by current of the Mott insulator Ca2RuO4. AB - Recently, "application of electric field (E-field)" has received considerable attention as a new method to induce novel quantum phenomena since application of E-field can tune the electronic states directly with obvious scientific and industrial advantages over other turning methods. However, E-field-induced Mott transitions are rare and typically require high E-field and low temperature. Here we report that the multiband Mott insulator Ca2RuO4 shows unique insulator-metal switching induced by applying a dry-battery level voltage at room temperature. The threshold field Eth ~40 V/cm is much weaker than the Mott gap energy. Moreover, the switching is accompanied by a bulk structural transition. Perhaps the most peculiar of the present findings is that the induced metal can be maintained to low temperature by a weak current. PMID- 23985625 TI - Intravenous peramivir for treatment of influenza in hospitalized patients. AB - BACKGROUND: Influenza causes over 200,000 hospitalizations a year in the United States, but few antiviral treatment studies have focused on patients hospitalized with influenza. This open-label, randomized study was initiated during the 2009 H1N1 pandemic to help assess the antiviral activity, safety and tolerability of 5 10 days treatment with two different dosing regimens of the intravenous neuraminidase inhibitor, peramivir, in hospitalized subjects with influenza. METHODS: Quantitative virology was done on nasopharyngeal swab specimens from subjects >=6 years of age to measure change from baseline in tissue culture infective dose (primary end point) and quantitative viral RNA levels by real-time PCR. Clinical end points included time to clinical resolution, a composite end point of four vital signs and oxygen saturation. RESULTS: A total of 234 hospitalized patients were randomized to peramivir 300 mg twice daily or 600 mg once daily; 127 had laboratory confirmed influenza. In those with detectable virus at baseline, viral titres declined without differences between regimens. There were no significant differences in clinical or virological end points between treatment arms, and apparent differences were explained by baseline disease severity differences in the groups. Peramivir was generally safe and well tolerated for treated patients hospitalized with pandemic influenza with outcomes similar to those described in the literature. CONCLUSIONS: This open-label trial of intravenous peramivir in subjects hospitalized predominantly with 2009 influenza A (H1N1) demonstrated that once- or twice-daily administration was associated with decreases in viral shedding and clinical improvement. ClinicalTrials.gov number NCT00957996. PMID- 23985627 TI - Treatment of capsular contracture using complete implant coverage by acellular dermal matrix: a novel technique. AB - BACKGROUND: Capsular contracture is a frequent complication of breast reconstruction that affects 2.8 to 15.9 percent of patients. Use of acellular dermal matrix has been reported for treatment of contracture, with a recurrence rate of 6.3 percent, but this was limited to partial implant coverage only. The authors describe a novel surgical technique using acellular dermal matrix to completely cover the implant anteriorly to treat and prevent capsular contracture. METHODS: Charts were reviewed to identify patients who had received implant insertion with complete acellular dermal matrix coverage performed by a single surgeon. Patient demographic information, history of irradiation or capsular contracture, prior treatment, and postoperative complications were recorded. RESULTS: Eleven patients (16 breasts) were identified. Mean age and body mass index were 52.3 +/- 6.9 years and 23.6 +/- 4.4 kg/m, respectively. Four patients (five breasts) had a history of capsular contracture requiring previous capsulectomy and implant exchange. Ten cases were for correction of new-onset grade III (n = 2) or IV (n = 8) capsular contracture and one was to prevent future capsular contracture. Mean acellular dermal matrix size was 229.8 +/- 46.5 cm (range, 144 to 256 cm). Average follow-up was 9.2 months (range, 2.4 to 18.8 months). One patient (one breast) developed an infection requiring implant removal. No patients experienced recurrent capsular contracture. CONCLUSIONS: Capsular contracture may be treated successfully using complete acellular dermal matrix coverage. This technique may be a useful addition to therapies currently used to treat recalcitrant capsular contracture (early recurrence or refractory to standard therapy). PMID- 23985628 TI - Discussion: Treatment of capsular contracture using complete implant coverage by acellular dermal matrix: a novel technique. PMID- 23985629 TI - Use of autologous and microsurgical breast reconstruction by U.S. plastic surgeons. AB - BACKGROUND: Concern exists that plastic surgeons are performing fewer autologous and microsurgical breast reconstructions, despite superior long-term outcomes. The authors describe the proportion of U.S. plastic surgeons performing these procedures and evaluate motivating factors and perceived barriers. METHODS: A random national sample of American Society of Plastic Surgeons members was surveyed (n = 325; response rate, 76 percent). Surgeon and practice characteristics were assessed, and two multiple logistic regression models were created to evaluate factors associated with (1) high-volume autologous providers and (2) microsurgical providers. Qualitative assessments of motivating factors and barriers to microsurgery were also performed. RESULTS: Fewer than one-fifth of plastic surgeons perform autologous procedures for more than 50 percent of their breast cancer patients, and only one-quarter perform any microsurgical breast reconstruction. Independent predictors of a high-volume autologous practice include involvement with resident education (odds ratio, 2.57; 95 percent CI, 1.26 to 5.24) and a microsurgical fellowship (odds ratio, 2.09; 95 percent CI, 1.04 to 4.27). Predictors of microsurgical breast reconstruction include involvement with resident education (odds ratio, 6.8; 95 percent CI, 3.32 to 13.91), microsurgical fellowship (odds ratio, 2.4; 95 percent CI, 1.16 to 4.95), and high breast reconstruction volume (odds ratio, 6.68; 95 percent CI, 1.76 to 25.27). The primary motivator for microsurgery is superior outcomes, and the primary deterrents are time and reimbursement. CONCLUSIONS: The proportion of U.S. plastic surgeons with a high-volume autologous or microsurgical breast reconstruction practice is low. Involvement with resident education appears to facilitate both, whereas time constraints and reimbursement are primary deterrents. Future efforts should focus on improving the feasibility and accessibility of all types of breast reconstruction. PMID- 23985630 TI - Analysis and classification of the upper lip aesthetic unit. AB - BACKGROUND: Disharmonies of the upper lip aesthetic unit generally stem from tall ergotrids and/or thin lips. Comprehension and correction of such defects has been stifled by a lack of metrics and organized systems of diagnosis and treatment. METHODS: The philtral-labial score was devised to better analyze the upper lip region. Measurements were made with Adobe Photoshop CS6, and computations were performed on a standard calculator. A retrospective medical records review identified 908 patients of the senior authors' (P.R. and S.W.H.) practices who underwent perioral rejuvenation between January 1, 2001, and July 31, 2012. Two hundred patients were randomly selected and assessed for disharmonies in three surveys that sequentially built on data points provided. RESULTS: When preoperative anteroposterior and lateral photographs, dental show measurements, and philtral-labial scores were available, diagnostic concordance between the authors approached 100 percent. Pattern analysis resulted in a classification system (labral classification system), designating patients as either type 0 (no defects), type 1 (thin upper lip), type 2 (long philtrum), or type 3 (both) defects. Characteristic dental show values, philtral-labial scores, and suggested treatments were paired with each type. CONCLUSIONS: The labral classification system and its associated analytical tools serve as useful references in consultation, simplify discussion of patients with upper lip defects, furnish a practical alternative to complex algorithms, enable documentation of changes, and facilitate analysis of large sample sizes. When implemented judiciously, the tools described in this article will help surgeons confidently address upper lip problems by streamlining accurate diagnosis and guiding proper treatment. PMID- 23985631 TI - Reshaping the medial nostril and columellar base: five-step medial crural footplate approximation. AB - Achieving ideal shape and position of the medial nostril and columellar base is a crucial component of successful rhinoplasty. The lateral border of the basal columella should exhibit slight concavity and a relatively smooth contour. Both nasal aesthetics and functionality may be compromised if such a result is not obtained. Herein, a reproducible technique is described which allows for treatment of this region. PMID- 23985632 TI - Composite breast augmentation: soft-tissue planning using implants and fat. AB - BACKGROUND: A variety of suboptimal results arise in breast augmentation due to failure of the overlying soft tissue to adequately cover the implant. The authors describe a new concept of composite breast augmentation surgery that combines the core volume projection of breast implants with the natural look and feel of overlying fat. METHODS: A total of 197 patients were treated over a 3-year period. This new approach was used when the overlying soft tissue was thin or insufficient to adequately cover the underlying prosthesis, in both breast implant revision and primary breast augmentation. In a subset of cases, quantitative three-dimensional breast imaging evaluated transplanted fat volume in the subcutaneous space of the breast. In primary cosmetic augmentation cases, preexpansion was not performed. In revision cases, preexpansion was performed to support the desired volume of fat required to achieve the aesthetic result. In a second subset of patients, preoperative and 1-year postoperative mammograms were evaluated by breast radiologists. RESULTS: Fifty-seven percent of the volume of graft injected persisted at 1 year. Because fat provided soft-tissue implant coverage, there was less need to place the prosthesis beneath the muscle; many implants were placed in the subfascial plane. Evaluation revealed no cysts, masses, or fat necrosis, presumably because the recipient site was not overloaded with fat. CONCLUSIONS: Breast augmentation with simultaneous implants and fat affords a more powerful and versatile approach, and achieves a synergistic outcome. Composite breast augmentation should be added to the list of applications where fat grafting to the breasts may have clinical utility beyond simple core volume enhancement. PMID- 23985633 TI - Molecular analysis and differentiation capacity of adipose-derived stem cells from lymphedema tissue. AB - BACKGROUND: Many breast cancer patients are plagued by the disabling complication of upper limb lymphedema after axillary surgery. Conservative treatments using massage and compression therapy do not offer a lasting relief, as they fail to address the chronic transformation of edema into excess adipose tissue. Liposuction to address the adipose nature of the lymphedema has provided an opportunity for a detailed analysis of the stromal fraction of lymphedema associated fat to clarify the molecular mechanisms for this adipogenic transformation. METHODS: Adipose-derived stem cells were harvested from human lipoaspirate of the upper extremity from age-matched patients with lymphedema (n = 3) or subcutaneous adipose tissue from control patients undergoing cosmetic procedures (n = 3). Immediately after harvest, adipose-derived stem cells were analyzed using single-cell transcriptional profiling techniques. Osteogenic, adipogenic, and vasculogenic gene expression and differentiation were assessed by quantitative real-time polymerase chain reaction and standard in vitro differentiation assays. RESULTS: Differential transcriptional clusters of adipose derived stem cells were found between lymphedema and subcutaneous fat. Interestingly, lymphedema-associated stem cells had a much higher adipogenic gene expression and enhanced ability to undergo adipogenic differentiation. Conversely, they had lower vasculogenic gene expression and diminished capability to form tubules in vitro, whereas the osteogenic differentiation capacity was not significantly altered. CONCLUSIONS: Adipose-derived stem cells from extremities affected by lymphedema appear to exhibit transcriptional profiles similar to those of abdominal adipose-derived stem cells; however, their adipogenic differentiation potential is strongly increased and their vasculogenic capacity is compromised. These results suggest that the underlying pathophysiology of lymphedema drives adipose-derived stem cells toward adipogenic differentiation. PMID- 23985635 TI - Tendon transfer for the restoration of thumb opposition: the effects of friction and pulley location. AB - BACKGROUND: The authors compared the gliding resistance among three commonly used pulley sites used for oppositional transfers. METHODS: Eight fresh-frozen cadaver forearms were studied. The ring finger's flexor digitorum superficialis was used as a donor tendon in all specimens. An oppositional transfer was created to the thumb using three pulley sites: the Royle-Thompson, the Guyon canal, and the flexor carpi ulnaris tendon loop pulleys. The flexor digitorum superficialis was inserted into the palmar radial portion of the abductor pollicis brevis in all cases. Gliding resistance was then measured and compared. Final thumb position was measured to assess the amount of thumb palmar abduction and opposition created with each pulley configuration. RESULTS: The average gliding resistance of tendons passed within the Royle-Thompson, Guyon canal, and flexor carpi ulnaris loop pulley were 1.27, 0.58, and 0.44 N, respectively. Gliding resistance for the Royle-Thompson pulley was found to be significantly higher than that for the Guyon canal or flexor carpi ulnaris loop pulley (p < 0.05). There was no significant difference between the Guyon canal and flexor carpi ulnaris loop pulleys with regard to gliding resistance. The flexor carpi ulnaris loop pulley produced the greatest amount of palmar abduction (p < 0.05), whereas the Guyon canal and Royle-Thompson pulleys produced the greatest amount of thumb opposition. CONCLUSIONS: The Guyon canal and flexor carpi ulnaris loop pulleys produced lower friction than the Royle-Thompson pulley. The Guyon canal pulley produced greater thumb opposition compared with the flexor carpi ulnaris loop pulley and represents an ideal pulley site for restoration of thumb opposition. PMID- 23985634 TI - The effect of swan neck and boutonniere deformities on the outcome of silicone metacarpophalangeal joint arthroplasty in rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis patients with swan neck deformities are postulated to have greater metacarpophalangeal joint arc of motion because of their need to flex the joint to make a fist, whereas the boutonniere deformity places the fingers into the flexed position, creating less demand on the joint for grip. This study analyzes the effect of these deformities on the joint's arc of motion and hand function. METHODS: The authors measured the metacarpophalangeal joint arc of motion in 73 surgical patients. Data were allocated into groups by finger and hand deformity. Linear regression models were used to analyze the effect of the deformity on the joint's arc of motion. Functional outcomes were measured by the Michigan Hand Outcomes Questionnaire and the Jebson-Taylor Test. RESULTS: Nineteen fingers had boutonniere deformity, 95 had swan neck deformities, and 178 had no deformity. The no-deformity group had the least arc of motion at baseline (16 degrees) compared with the boutonniere (26 degrees) and swan neck (26 degrees) groups. Mean arc of motion in the no deformity group compared with the boutonniere group at baseline was statistically significant, but all groups had similar arc of motion at long-term follow-up. Only mean Jebson-Taylor Test scores at baseline between the boutonniere and no deformity groups were significantly different. CONCLUSIONS: The results did not support the hypothesis that swan neck deformities have better arc of motion compared with boutonniere deformity. Boutonniere deformity has worse function at baseline, but there was no difference in function among groups at long-term follow-up. PMID- 23985636 TI - Discussion: The Children's Hospital of Philadelphia modification of the Furlow double-opposing Z-palatoplasty: 30-year experience and long-term speech outcomes. PMID- 23985637 TI - Virtual surgical planning in complex composite maxillofacial reconstruction. AB - BACKGROUND: Complex osteocutaneous maxillofacial reconstruction requiring multiple free flaps and with an extensive zone of injury can be fraught with complications and difficulty. Often, the remnants of native mandible are malpositioned and the skeletal structure of the upper face is distorted. The authors seek to extend the use of virtual planning to complex maxillofacial reconstruction by presenting their early experience in these difficult patients. METHODS: A retrospective chart review of 10 consecutive patients who underwent complex maxillofacial reconstruction using virtual surgical planning was undertaken. The authors define complex maxillofacial reconstruction as that requiring an osteocutaneous flap in which multiple osteotomies were required in addition to at least one of the following: need for multiple free flaps, history of osteoradionecrosis, and ballistic injury. Synthes Proplan CMF surgical planning was performed using computed tomographic scanning of the maxillofacial area and the donor site. Jigs and cutting guides were created and plates were prebent. The flap was harvested and osteotomized using the jigs and inset. Postoperative computed tomographic scanning was performed to evaluate the reconstruction. RESULTS: Ten consecutive patients who met the criteria underwent review. There were no intraoperative complications. Postoperative computed tomographic scans showed excellent contour of the osseous flaps. All patients had functional mandibular range of motion. CONCLUSIONS: Use of virtual surgical planning allows for complex maxillofacial reconstruction with multiple simultaneous free flaps to be performed reliably and successfully. The use of prefabricated jigs and precontoured plates eases osteocutaneous flap molding and inset, allowing for a more complex procedure to be successful. PMID- 23985638 TI - A comparative study of two different techniques for complete bilateral cleft lip repair using two-dimensional photographic analysis. AB - BACKGROUND: The aim of this study was to compare the clinical outcomes of two techniques to repair complete bilateral cleft lip by using indirect two dimensional photographic analysis. METHODS: One hundred eight bilateral cleft patients were included in this study, 54 patients operated on with the Millard technique and 54 patients operated on with the Afroze technique. Each group of patients was further separated into two subgroups containing symmetrical and asymmetrical cleft lips. All patients were photographed preoperatively and 4 years postoperatively in frontal and submentovertical views in a reproducible way. Eight measurements were performed on the photographs. From these measurements, seven ratios were calculated to compare the two techniques. RESULTS: The outcomes of the interobserver and intraobserver measurements were analyzed using the Pearson correlation test. There was a statistically significant reliability in the intraobserver and interobserver ratios. Analysis of the ratios was performed using the independent samples t test (5 percent level of significance). The authors found that the Afroze technique was better than the Millard technique in six of the seven parameters for symmetrical clefts and in four of the seven parameters for asymmetrical clefts; however, there was no statistically significant difference seen between the two techniques. CONCLUSIONS: The Afroze technique seems to have good clinical outcomes on bilateral cleft lip patients, but more research and long-term follow-up are needed to determine the full outcome of the technique in various parameters. PMID- 23985639 TI - The mushroom-shaped anterolateral thigh perforator flap for subtotal tongue reconstruction. AB - BACKGROUND: Reconstruction of a functional tongue with proper motility and sensation after subtotal resection is a demanding procedure. The authors describe the reinnervated mushroom-shaped anterolateral thigh perforator flap for subtotal tongue reconstruction. METHODS: Thirteen patients (mean age, 54.8 years; range, 49 to 71 years) diagnosed with T3 and T4 squamous cell carcinomas were allocated prospectively to anterior total mobile (n = 7) or subtotal tongue resection (n = 6). All patients received the mushroom-shaped anterolateral thigh perforator flap. A Likert scale ranging from 1 to 4 was used to assess speech intelligibility, swallowing function, and cosmetic results. Epicritic and proprioceptive sensitivity testing was performed with the Pressure-Specified Sensory Device on the tip of the tongue preoperatively, on the neotongue at the donor site preoperatively, and at the recipient site 12 months postoperatively; protopathic thermoreceptor and nociceptors were clinically investigated. Outcomes were analyzed, and values of p < 0.05 were considered significant. RESULTS: All flaps healed uneventfully (mean follow-up, 18 months). Six patients (46.2 percent) recovered a nearly natural deglutition, whereas seven (53.8 percent) had mild impairment (p = 0.274). Normal intelligible speech was achieved in seven cases (53.8 percent), and acceptable intelligible speech was achieved in six (46.2 percent) (p = 0.286). Aesthetic results were excellent in eight patients (61.5 percent) and good in five (38.5 percent) (p = 0.592). All patients recovered epicritic, proprioceptive, and protopathic sensitivity; cortical upgrading phenomena of the recipient nerve were observed. CONCLUSION: The reinnervated mushroom-shaped anterolateral thigh perforator flap was found to be an innovative and effective option for subtotal tongue reconstruction. PMID- 23985640 TI - Minimizing the pain of local anesthesia injection. AB - BACKGROUND: Local anesthetic injection is often cited in literature as the most painful part of minor procedures. It is also very possible for all doctors to get better at giving local anesthesia with less pain for patients. The purpose of this article is to illustrate and simplify how to inject local anesthesia in an almost pain-free manner. METHODS: The information was obtained from reviewing the best evidence, from an extensive review of the literature (from 1950 to August of 2012) and from the experience gained by asking over 500 patients to score injectors by reporting the number of times they felt pain during the injection process. RESULTS: The results are summarized in a logical stepwise pattern mimicking the procedural steps of an anesthetic injection-beginning with solution selection and preparation, followed by equipment choices, patient education, topical site preparation, and finally procedural techniques. CONCLUSIONS: There are now excellent techniques for minimizing anesthetic injection pain, with supporting evidence varying from anecdotal to systematic reviews. Medical students and residents can easily learn techniques that reliably limit the pain of local anesthetic injection to the minimal discomfort of only the first fine needlestick. By combining many of these conclusions and techniques offered in the literature, tumescent local anesthetic can be administered to a substantial area such as a hand and forearm for tendon transfers or a face for rhytidectomy, with the patient feeling just the initial poke. PMID- 23985641 TI - Superficial lymphatic drainage of the lower extremity: anatomical study and clinical implications. AB - BACKGROUND: Knowledge of the lymphatic anatomy in the lower extremity is inadequate. A reevaluation is needed to assist in guiding clinical management. METHODS: A total of five lower extremities from three unembalmed human cadavers were studied. Under a surgical microscope, 6% hydrogen peroxide was used to detect the lymphatic vessels commencing from the foot, the leg, and the thigh. A 30-gauge needle was inserted into the vessels and injected with a radiopaque lead oxide mixture. The vessels were traced, photographed, and radiographed to demonstrate the superficial lymphatic pathways of the lower extremity. The final results were transferred to the computer for image analysis. RESULTS: Numerous lymph collecting vessels were identified in the subcutaneous tissue and the superficial femoral vascular bundle of the lower extremity. They originated beneath the dermis of each side of the toes, the foot, and the lateral side of the thigh. The diameters of the vessels varied from 0.2 to 2.2 mm. The vessels traveled in the subcutaneous tissue of the lower limb toward the popliteal, femoral, superficial, and deep inguinal lymph nodes. During their tortuous course, some vessels branched, diverged, and converged; sometimes, they anastomosed with neighboring vessels or crossed them. Most vessels converged to form larger collectors and then diverged into small branches before entering the lymph nodes. CONCLUSIONS: Accurate lymphatic distribution within the lower extremity has been described. This information upgrades our anatomical knowledge, and the results will be of benefit for clinical management. PMID- 23985644 TI - Impact of surgical techniques, biomaterials, and patient variables on rate of nipple necrosis after nipple-sparing mastectomy. AB - BACKGROUND: Nipple-sparing mastectomy is appropriate for selected patients with early-stage breast cancer or high breast cancer risk. However, the postoperative rate of nipple necrosis is relatively high (10 to 30 percent). This study analyzed the impact of clinicopathologic and surgical variables on partial and total nipple necrosis rates after nipple-sparing mastectomy and compared overall complication rates between nipple-sparing and skin-sparing mastectomy. METHODS: The study included 233 cases; 113 had nipple-sparing mastectomy and immediate breast reconstruction and 120 were matched cases of skin-sparing mastectomy and immediate reconstruction performed at the authors' institution from September of 2003 through May of 2011. RESULTS: The overall complication rate was 28 percent for nipple-sparing mastectomy and 27 percent for skin-sparing mastectomy (p > 0.99). In patients who did not have axillary surgery (those undergoing risk reducing mastectomy), the overall rate was significantly higher in the nipple sparing group (26 percent versus 9 percent; p = 0.06). However, in patients who had axillary surgery (either sentinel lymph node biopsy or axillary lymphadenectomy), the rate did not differ between the two groups. For nipple sparing mastectomy, the overall incidence of any (partial or total) nipple necrosis was 20 percent. Only two cases (2 percent) had total necrosis. Larger breasts (C cup or larger) were associated with a higher rate of nipple necrosis (p = 0.003). CONCLUSIONS: The authors found no significant difference in the overall incidence of complications in patients who had nipple-sparing mastectomy or skin-sparing mastectomy. Exclusion of axillary lymphatic surgery in nipple sparing mastectomy patients did not decrease the incidence of complications. PMID- 23985645 TI - Processes of care in autogenous breast reconstruction with pedicled TRAM flaps: expediting postoperative discharge in an ambulatory setting. AB - BACKGROUND: A multidisciplinary patient care plan was developed to facilitate early discharge following autogenous breast reconstruction and included (1) preadmission patient education, (2) perioperative multimodal pain management, (3) intraoperative nerve blocks, and (4) postdischarge telephone advice. This study evaluated the success of this care plan in the first 18 months after its implementation. METHODS: A retrospective cohort study of all consecutive women undergoing pedicled transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction (November of 2009 to May of 2011) was performed. The primary outcome was time to discharge; secondary outcomes included complications, readmission, and self-report pain at discharge. Predictors of discharge time were analyzed using stepwise multivariable regression modeling. RESULTS: Ninety-one women (mean age, 50.0 +/- 8.5 years) underwent pedicled TRAM flap reconstruction (76 percent unilateral and 81 percent delayed), with 77 percent receiving the intended multimodal analgesia protocol. Mean time to discharge was 38.7 +/- 27.6 hours. Overall, 40 percent of patients were discharged within 24 hours, but successful early discharge increased significantly over the study period. Key predictors of shorter time to discharge were use of multimodal analgesia, lower American Society of Anesthesiologists class, and surgery more than 6 months after implementation of the care plan. CONCLUSIONS: The authors' initial experience has supported the safety and feasibility of expedited discharge following pedicled TRAM flap breast reconstruction, with adherence to the authors' care plan improving steadily over the study period. Multimodal pain management proved a key modifiable factor in facilitating early discharge. A prospective study is currently underway to evaluate patient-reported quality of recovery following ambulatory surgery in this population. PMID- 23985646 TI - The natural history of Becker expandable breast implants: a single-center 10-year experience. AB - BACKGROUND: Use of Becker expandable breast implants in single-stage breast surgery is a well-established technique; however, replacement with fixed-volume implants is common. The authors sought to analyze the long-term natural history of these implants over a wide range of surgical indications. METHODS: A retrospective review of 330 consecutive patients who underwent 384 Becker expander breast reconstructions over a 10-year period in a dedicated plastic surgery unit was undertaken. Implant indication, Becker type, volume and site, complications, expander lifespan, and explant reasons were assessed. RESULTS: Two hundred twenty-eight patients (267 implants) and 102 patients (117 implants) underwent implantation for congenital deformities and breast cancer reconstruction, respectively. One hundred eighty-seven (48 percent) were explanted at a median period of 13.0 months (range, 9.0 to 26.0 months), 149 (39 percent) for aesthetic reasons and 38 (10 percent) for complications. Complication rates were higher in breast cancer reconstruction compared with congenital patients (19.6 percent versus 7.9 percent; p = 0.002), driven by an increased rate of wound complications (13.7 percent versus 4.4 percent; p = 0.003). Cancer-related surgery and advancing age were the only predictors of complication risk. The overall Becker expander retention rate was 24.9 percent and 46.8 percent at 150 months in the cancer reconstruction and congenital groups, respectively. CONCLUSIONS: Forty-seven percent of Becker implants were retained long term after congenital corrective surgery; only 25 percent were retained after postmastectomy reconstruction. Poor aesthetics was driving the exchange for fixed-volume implants, indicating that after breast cancer reconstruction, Becker expanders were being used as part of a two-stage reconstructive strategy. PMID- 23985647 TI - Corticosteroid use in cosmetic plastic surgery. AB - BACKGROUND: Steroids have been used in cosmetic plastic surgery to reduce postoperative edema and ecchymosis. We performed a systematic review of the literature addressing postoperative steroid use after rhinoplasty. Due to a paucity of studies, a review of the literature was also performed for postoperative steroid use in rhytidectomy and body contouring surgery. METHODS: An exhaustive literature search was performed using: MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and PubMed. A total of 12 articles were chosen to be included in the rhinoplasty systematic review. Cohen's kappa for level of agreement between the two reviewers was 1.0. Data recorded from each of the studies included: author, year, sample size, age, follow-up, statistical analyses, eyelid/edema assessment, significant findings, p values, and steroid regimens. A general review of the current rhytidectomy and body contouring literature associated with corticosteroids was performed as well. RESULTS: No statistically significant long-term reduction in postoperative edema or ecchymosis after rhinoplasty. Significant reductions were noted in the short term (<2 days). Review of the rhytidectomy literature described no significant decrease in postoperative edema or ecchymosis. Steroid use was noted to reduce postoperative nausea and vomiting when combined with other therapies in body contouring. CONCLUSIONS: Steroid use is not warranted in the postoperative period and only reduces transient edema and ecchymosis. A significant benefit for steroid use after rhytidectomy is not evident as well. Steroid use may benefit in postoperative nausea and vomiting. PMID- 23985648 TI - Angiotensin-converting enzyme inhibitor enalapril reduces formation of hypertrophic scars in a rabbit ear wounding model. AB - BACKGROUND: Angiotensin-converting enzyme inhibitors are widely used in medicine because of their antihypertensive and antifibrogenic effects. Angiotensin converting enzyme activates angiotensin I to angiotensin II, which plays an important regulatory role in wound healing and collagen production. The authors investigated whether systemic administration of angiotensin-converting enzyme inhibitors has any effect on formation of hypertrophic scars using the rabbit ear wound model. METHODS: Sixteen New Zealand albino rabbits were divided into four groups, and four punch defects were created on each ear. The first group received oral enalapril immediately after the creation of punch defects. The second group received oral enalapril on day 28 after the formation of scars. The third group received intralesional steroid injections on days 28 and 35. The fourth group was the control group. The rabbits were killed on day 40. The harvested specimens were analyzed histomorphometrically and immunohistochemically. RESULTS: Early enalapril application decreased the scar elevation index and fibroblast and capillary counts significantly, compared with the values in the control group. Late enalapril application decreased fibroblast counts significantly; however, there was no difference in scar elevation index compared with the control group. There was no difference between early enalapril application and steroid therapy in terms of scar elevation index and capillary and fibroblast counts. However, early and late enalapril groups displayed lower collagen type III immunoreactivity compared with the steroid and control groups. CONCLUSION: Early application of enalapril following dermal injury reduces formation of hypertrophic scars, probably because of its down-regulatory effects on type III collagen production. PMID- 23985649 TI - Large prefabricated skin flaps based on the venous system in rabbits: a preliminary study. AB - BACKGROUND: Flap prefabrication offers a bridging role between traditional reconstructive surgery and tissue engineering; however, because flap prefabrication is based on the concept of implanting a nourishing vascular pedicle in the target tissues before transfer, survival remains unreliable. Furthermore, the extended period required for neovascularization hampers its clinical application. METHODS: Based on two different venous angiosomes involving two sides of thoracoepigastric veins (taken as the vascular carrier) in rabbits, a large abdominal flap measuring 12 * 13 cm was designed by anastomosing the transferred femoral artery with the thoracoepigastric vein distally and prefabricated by incision of the proximal and distal ends of the flap for 1 week. Traditional arterial flaps, arterialized venous flaps, and composite skin grafts of the same size were used as control groups. Flap viability, status of vascular perfusion and microvasculature, and level of epidermal metabolite in each group were assessed. RESULTS: The large prefabricated flaps achieved results similar to the traditional flaps in terms of flap viability, status of vascular perfusion and microvasculature, and level of epidermal metabolite. CONCLUSIONS: Large skin flaps with good quality can be prefabricated within a shorter period for aesthetic and plastic surgery reconstruction using the inherent venous system. This technique may prove to be a viable alternative for successful flap prefabrication. PMID- 23985650 TI - Does the gatekeeper model work in hand surgery? AB - BACKGROUND: Most managed care plans use a physician "gatekeeper" to control referrals to hand surgeons. The appropriateness of this model for upper extremity complaints has never been challenged. The purpose of this study was to evaluate the prior management of patients with elective hand disorders who present to a hand surgery clinic. METHODS: All patients presenting to a tertiary, academic medical center for a new-patient hand surgery evaluation from February 3, 2011, to June 15, 2011, were prospectively enrolled. Patients were evaluated for prior provider, diagnosis, treatment, and complications. Actual diagnosis, recommended workup, and appropriate treatment were determined independently by two experienced hand examiners. Traumatic injuries and surgeon disagreements in diagnosis and treatment were excluded, leaving 125 patients. RESULTS: Ninety eight percent of patients had been evaluated by a primary care provider. Overall, the correct diagnosis was established 34 percent of the time. Nerve compression syndromes were diagnosed with the greatest accuracy (64 percent), whereas stenosing tenosynovitis was diagnosed correctly only 15 percent of the time. Before presentation, 74 percent of patients had undergone a study or intervention. On review, 70 percent of studies/interventions were deemed unnecessary. Advanced imaging was unwarranted in 90 percent of patients who received it. Seventeen percent of patients experienced a complication. Most (67 percent) were caused by a delay in diagnosis, whereas 33 percent resulted from an intervention. CONCLUSIONS: Health care providers less familiar with an examination of the hand often misdiagnose and mistreat common problems. A referral system may not be the most efficient means of delivering care to patients with elective hand maladies. PMID- 23985651 TI - Soft-tissue coverage of the elbow. AB - The elbow requires a durable and pliable soft-tissue envelope. Injuries, infections, or tumors that result in exposed tendon, bone, or implants require expedient soft-tissue coverage. Familiarity with various options for coverage can help tailor treatment to the defect size and minimize donor-site morbidity. In this article, emphasis is placed on muscle and fasciocutaneous flaps that have been shown to have reliable vascularity and predictable outcomes. PMID- 23985652 TI - Temporal morphomics as a model for determining preoperative risk of blood transfusion in nonsyndromic craniosynostosis patients. AB - BACKGROUND: Estimates of blood loss during craniosynostosis surgeries have ranged from 42 to 126 percent of infant's total blood volume. Currently, no risk model has been developed to determine the likelihood of needing a blood transfusion. The authors propose an objective model, based on patients' three-dimensional anatomical characteristics, to stratify the likelihood of needing perioperative packed red blood cells. METHODS: High-throughput image analysis from already ordered preoperative computed tomographic scans was used to reconstruct the three dimensional anatomy of the temporalis muscle and overlying temporal fat pad. Using these morphomic measurements, the authors created a risk assessment model of the amount of packed red blood cells infused based on morphomic variations in temporal soft tissue. RESULTS: The authors evaluated 139 infants with nonsyndromic craniosynostosis from the University of Michigan Health System. Results show the need for blood transfusion ranged from 94.1 percent among patients in the smallest quartile for temporal fat pad volume compared with 65.7 percent among the group with the largest quartile for temporal fat pad volume (p = 0.0057). Using multivariable linear regression, temporal fat pad volume (p = 0.012) and fat pad thickness (p = 0.036) were independent predictors for amount of packed red blood cells required. CONCLUSIONS: The authors demonstrate that patients with diminished temporal fat pad volume are significantly more likely to need increased packed red blood cell transfusions. In addition, by use of multivariable linear regression, their data suggest that temporal fat pad volume and thickness were independent predictors for the amount of required transfusion of packed red blood cells. PMID- 23985653 TI - Alloplastic mandibular reconstruction: a systematic review and meta-analysis of the current century case series. AB - BACKGROUND: Alloplastic mandibular reconstruction remains insufficiently predictable, with no systematic reviews to assess its scope and limitations. METHODS: The PubMed, CINAHL, EMBASE, and Web of Science databases were searched for English study reports, published in the current century, of mere alloplastic surgical reconstruction of mandibular ablative defects. RESULTS: In 14 articles, there were 944 patients, with a median age of 58.7 years (interquartile range, 53.2 to 62 years); 58.7 percent (interquartile range, 66.7 to 78.6 percent) were male. Cases of squamous cell carcinoma per study constituted 93.5 percent (interquartile range, 81.5 to 100 percent). Defects were mostly lateral (Boyd classification) (60.5 percent; interquartile range, 56.2 to 62 percent) and received mostly conventional bridging plates (in 64.3 percent of the studies) and pedicled flaps (45.3 percent; interquartile range, 37.1 to 58.3 percent); 60.7 percent (interquartile range, 53.5 to 58.8 percent) received adjuvant therapy. At 32-month follow-up, the complication and failure rates were 40.1 percent (interquartile range, 26.7 to 58.6 percent) and 30.8 percent (interquartile range, 11.7 to 48.1 percent), respectively. The overall survival rate was 55 percent (interquartile range, 27.8 to 74 percent). Radiotherapy seemed to be a relative risk factor for complications (1.387; p = 0.014) and plate loss (1.585; p = 0.006). Crossing the midline seemed to be a relative risk factor for plate exposure (1.533; p = 0.000) and overall complications (1.385; p = 0.002). CONCLUSIONS: The results should be generalized cautiously. Alloplastic reconstructive surgery faces a remarkable lack of evidence. Relatively high complication and failure rates are areas of further concern. PMID- 23985654 TI - One-stage reconstruction of composite extremity defects with a sural neurocutaneous flap and a vascularized fibular graft: a novel chimeric flap based on the peroneal artery. AB - BACKGROUND: The fibula flap has been widely used for reconstruction of composite bone and soft-tissue defects. The skin paddle of the fibula flap has played a critical role in providing a cutaneous component and good monitor for the bone component. In this report, the authors designed a perforator-based sural neurocutaneous flap instead of a peroneal perforator flap to enlarge a skin paddle for wound coverage. METHODS: A novel chimeric flap was harvested based on the peroneal artery, and consisted of a sural neurocutaneous flap and a fibular graft. The sural neurocutaneous flap was elevated based on a single peroneal perforator and connected with the bone component by means of the peroneal artery. Two patients with complex bone and soft-tissue defects were treated by using this chimeric flap. In case 1, the radius defect was 8 cm in length and the soft tissue defect measured 23 * 10 cm. In case 2, the distal radius was injured and the defect was 16 cm in length. The area of soft-tissue defect was 23 * 8 cm. In this case, the fibula head was used for wrist reconstruction. The soft-tissue defects in the two cases stretched across the palmar and dorsal surfaces of the forearm. RESULTS: The lengths of the bone components were 10 and 16.5 cm, respectively, and the areas of the skin components were 24 * 12 cm and 25 * 10 cm, respectively. Both chimeric flaps survived completely without complications. The follow-up period was 42 months in case 1 and 16 months in case 2. Complete bone union was observed in both cases, and no remarkable degeneration of the fibular head occurred in case 2. The sural neurocutaneous flap showed good texture match and contour. No serious donor-site complications occurred. The two patients were satisfied with their daily lives relative to the severity of their injuries. CONCLUSION: The chimeric flap composed of a sural neurocutaneous flap and a fibular graft by means of the peroneal artery is a good candidate for reconstruction of long bone defects associated with extensive soft-tissue defects in the extremities. PMID- 23985655 TI - Neuromusculotendinous transfer: an original surgical concept for the treatment of drop foot with long-term follow-up. AB - BACKGROUND: An original surgical technique for the correction of drop foot is demonstrated. METHODS: Eighteen patients with drop foot underwent transfer of the lateral, medial, or both heads of the gastrocnemius muscle to the tendons of the anterior and/or lateral muscle group of the lower leg. The transferred muscle was reinnervated by nerve coaptation between the undamaged proximal part of the deep peroneal nerve and the motor branch of the tibial nerve supplying the gastrocnemius muscle. RESULTS: In all patients, the transferred gastrocnemius muscle showed signs of reinnervation within an average of 6 months after operation. Ten patients achieved excellent results, having regained stable, fully automatic walking without foot inversion/eversion and active range of foot movement of at least 40 degrees. Four patients achieved good results with active range of movement of less than 40 degrees but very stable functional gait. Satisfactory results were presented in three cases with stable ankle motion. Two of three cases had dual transfer of the gastrocnemius muscle and had a very stable ankle joint. In one fair case, the treatment improved stability and the patient was able to walk. CONCLUSIONS: To compensate for the loss of function of the anterior muscle compartment, neuromusculotendinous transfer of the gastrocnemius muscle has proved to be highly successful. Voluntary movement of the transferred muscle and fully automatic walking was achieved in the majority of patients treated. In contrast to the commonly used treatment of tibialis posterior muscle transfer, no reeducation of the transferred muscle was needed. PMID- 23985656 TI - Managing malignant melanoma. AB - The incidence of melanoma is increasing worldwide. Melanomas represent 3 percent of all skin cancers but 65 percent of skin cancer deaths. Melanoma is now the fifth most common cancer diagnosed in the United States. Excisional biopsy should be performed for lesions suspicious for melanoma. The pathologist's report provides essential information for surgical treatment; the most important information is the Breslow depth of the lesion. In addition to wide surgical excision of the primary lesion, sentinel lymph node biopsy is the standard of care for early identification of regional metastasis. Nodal metastasis found in the sentinel lymph node biopsy should be followed with a complete lymph node dissection. Although surgery remains the primary treatment of melanoma, recent advances in chemotherapy may offer further survival benefits to patients with metastatic disease. PMID- 23985657 TI - New perspectives on the surgical anatomy and nomenclature of the temporal region: literature review and dissection study. PMID- 23985658 TI - Aesthetic refinements of the island V-Y advancement cheek flap. PMID- 23985659 TI - Reply: Aesthetic refinements of the island V-Y advancement cheek flap. PMID- 23985660 TI - An original technique for securing the inflation port in Becker implant-based breast reconstruction. PMID- 23985661 TI - Reply: An original technique for securing the inflation port in Becker implant based breast reconstruction. PMID- 23985662 TI - The subpectoral technique for aesthetic placement of pacemakers and implantable cardioverter defibrillators. PMID- 23985663 TI - Reply: The subpectoral technique for aesthetic placement of pacemakers and implantable cardioverter defibrillators. PMID- 23985664 TI - The island perforator flap design augments vascularity. PMID- 23985665 TI - Role of fluorescence lymphographic imaging in lymphedema prevention. PMID- 23985666 TI - Reply: Role of fluorescence lymphographic imaging in lymphedema prevention. PMID- 23985667 TI - Subclinical lymphedema: understanding is the clue to decision making. PMID- 23985668 TI - Reply: Subclinical lymphedema: understanding is the clue to decision making. PMID- 23985669 TI - Venous flow of the free flap perfused by reversed recipient artery. PMID- 23985670 TI - Reply: Venous flow of the free flap perfused by reversed recipient artery. PMID- 23985671 TI - Survival area of free flap perfused by retrograde artery inflow. PMID- 23985672 TI - Reply: Survival area of free flap perfused by retrograde artery. PMID- 23985673 TI - Role of aesthetic surgery in improving the quality of life: only vanity or a solution to physical and psychorelational problems? PMID- 23985674 TI - Evaluation of a facial transplant candidate with a facegram: a baseline analysis. PMID- 23985675 TI - Fat transfer for breast reconstruction: three-dimensional ligamentous band release using a Tuohy needle. PMID- 23985676 TI - Successful preterm pregnancy after reconstruction using a deep inferior epigastric artery perforator free flap. PMID- 23985677 TI - Thigh girth loss in women with lower body fat distribution increases breast volume. PMID- 23985679 TI - It's not the economy, it's economics: the future of plastic surgery. PMID- 23985678 TI - Novel perforator imaging utilization for distal lower extremity injury reconstruction. PMID- 23985680 TI - Nuclear reprogramming and the cancer genome. PMID- 23985681 TI - APOBEC3B mutagenesis in cancer. AB - Recent evidence has implicated APOBEC3B as a source of mutations in cervical, bladder, lung, head and neck, and breast cancers. APOBEC enzymes normally function in innate immune responses, including those that target retroviruses, suggesting links between mutagenesis, immunity and viral infection in the process of cancer development. PMID- 23985682 TI - Cholesterol metabolism and Rett syndrome pathogenesis. AB - Rett syndrome is caused by mutations in the gene encoding the transcriptional regulator MECP2. A new study demonstrates that cholesterol homeostasis is disrupted in Mecp2 mutant mice and suggests new therapeutic options for this disease. PMID- 23985683 TI - A developmental program for Candida commensalism. AB - Candida albicans is a frequent pathogen of immunologically compromised individuals, but it is an even more common commensal of healthy humans, where it resides in the gut in a benign state. A new study shows that a specific commensal form of the fungus is induced in the gut through a developmental program that downregulates virulence factors and induces metabolic functions, enabling it to thrive on the nutrients that are available in the large intestine without damaging its host. PMID- 23985689 TI - Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase-LEDGF/p75 interaction. AB - Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase-LEDGF/p75 interaction in vitro. Following a structure-activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound's structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency. PMID- 23985690 TI - Differences between rat strains in the development of PRL-secreting pituitary tumors with long-term estrogen treatment: In vitro insulin-like growth factor-1 induced lactotroph proliferation and gene expression are affected in Wistar-Kyoto rats with low estrogen-susceptibility. AB - There are differences in the susceptibility of rat strains to pituitary growth and lactotroph proliferation caused by long-term treatment with estrogens. To investigate the pituitary mechanism for this strain difference in estrogen induced lactotroph proliferation, we compared the abilities of 17-beta estradiol (E2) and insulin-like growth factor-1 (IGF-1) to modulate lactotroph proliferation and gene expression in vitro in Wistar and Wistar-Kyoto (WKY) rats. These two strains of rats have a high and very low susceptibility to estrogen, respectively. Long-term in vivo treatment with E2 was confirmed to markedly increase pituitary weight and lactotroph proliferation in ovariectomized Wistar, but not in WKY rats. Pituitary lactotrophs in primary cultures showed similar proliferative responsiveness to the culture condition-dependent, stimulatory and inhibitory actions of E2 in both strains. The only difference in lactotroph proliferation in vitro was a lower response to IGF-1 in WKY cells compared with Wistar cells. This difference in proliferation was associated with strain differences in IGF-1-induced gene expression in Wistar and WKY cultured cells. Of the genes tested, IGF-1-induced expression of the Wnt4, Stc1, Mybl1, and Myc genes was attenuated or abolished in WKY cells. These results suggest that the proliferative response to estrogen in lactotrophs in primary culture does not reflect the proliferative response to long-term estrogen treatment observed in vivo in Wistar and WKY rats. The strain difference in proliferation and gene expression to IGF-1 may be implicated in the variable degree of susceptibility for lactotroph proliferation observed in different strains of rats following long term estrogen treatment. PMID- 23985691 TI - Effect of nematode Trichinella infection on glucose tolerance and status of macrophage in obese mice. AB - We investigated the effect of Trichinella infection on glucose tolerance and (pro or anti-inflammatory) macrophage status in adipose tissue. Ob/ob mice and high fat-fed mice (obesity model) and C57/BL mice (control mice) were orally infected with (infected group) or without (uninfected group) 400 Trichinella per mouse. Four weeks later, the mice were subjected to investigation, which showed that fasting plasma glucose levels decreased in the infected group of C57/BL and ob/ob mice. Glucose tolerance, evaluated with intraperitoneal GTT, improved in the infected group of ob/ob mice and high fat-fed mice compared with the uninfected groups. Additional assay included anti-inflammatory macrophage (M2) markers and pro-inflammatory macrophage (M1) markers, with the aim to explore the effect of Trichinella infection on adipose tissue inflammation, since our previous study identified anti-inflammatory substances in secreted proteins by Trichinella. The result showed that mRNA levels of M2 markers, such as CD206, arginase and IL-10, increased, whereas M1 markers, such as CD11c, iNOS and IL-6, decreased in the stromal vascular fraction (SVF) isolated from epididymal fat in ob/ob mice. Residential macrophages obtained from the peritoneal lavage exhibited lower M1 markers and higher M2 markers levels in the infected group than in the uninfected group. Trichinella infection increases the ratio of M2/M1 systemically, which results in an improvement in pro-inflammatory state in adipose tissue and amelioration of glucose tolerance in obese mice. PMID- 23985692 TI - [Use of midazolam in hospitalized patients: analysis of medical practice]. AB - To evaluate the prevalence and the characteristics of use of midazolam among hospitalized patients and to analyze physicians' representation of this medicine. We conducted a retrospective study between 1st May and 22nd May 2011 in Grenoble University Hospital in France. All patients receiving midazolam during the study period were included, excepted if the prescription was performed in intensive care units, operating rooms or in pediatric units. Physicians from the different units were asked about the characteristics of patients receiving midazolam and about their practice concerning the use of midazolam. Forty-four patients were included, 82 % of whom having a cancer. The prevalence of prescription of midazolam was 3.3 % (44/1,323), 2.8 % (37/1,323) for anxiety relieving and 0.8 % (11/1,323) for sedation. The main refractory symptoms that justified the prescription were dyspnea (36.4 %), confusion (29.5 %), pain (27.3 %) and psychological suffering (27.3 %). Twenty-eight physicians were asked about their practice. The main representations of midazolam were the stop of active treatment (46.5 %) and premature cause of death (46.5 %). Practice of sedation is under estimated by physicians as they have difficulties to differentiate anxiety relieving and sedation and they have difficulties to initiate a sedation. A guideline to help physicians using midazolam could improve practice. PMID- 23985693 TI - Templated alkylation of hexahistidine with Baylis-Hillman esters. AB - Alkylation of one of the imidazole rings of hexahistidine with Baylis-Hillman esters tethered to nitrilotriacetate residue was achieved in aqueous solutions at neutral pH and at micromolar concentrations in the presence of Ni(2+), Cu(2+), or Zn(2+) cations. The utility of the approach for selective functionalization of His-tagged recombinant proteins was demonstrated by attachment of a fluorescent label to recombinant protein A with an alkynyl group followed by a "click" 1,3 dipolar cycloaddition reaction. PMID- 23985694 TI - Faster non-renal clearance of metoprolol in streptozotocin-induced diabetes mellitus rats. AB - Metoprolol is a selective beta1-adrenergic receptor antagonist metabolized by hepatic cytochrome P450s (CYPs). In this study, we evaluated pharmacokinetic changes following intravenous (i.v.) and oral metoprolol in rats with diabetes mellitus induced by streptozotocin (DMIS). Metoprolol has an intermediate hepatic extraction ratio in rats (0.586-0.617), and it is assumed that the liver is exclusively responsible for metoprolol metabolism. Thus, the hepatic clearance, CL(H) (the non-renal clearance, CL(NR)) of metoprolol depends on the hepatic blood flow rate (Q(H)), the free fraction in plasma (f(p)), and in vitro hepatic intrinsic clearance, CL(int). After i.v. administration of 1.5 mg/kg metoprolol to DMIS rats, its CLNR was 40.9% faster than control animals. This could be due to a significantly faster QH because hepatic CL(int) and fp were comparable between the two groups of rats due to unchanged hepatic CYP2D activity. After oral administration of 1.5 mg/kg metoprolol to DMIS rats, gastrointestinal absorption was >99% of the oral dose for both groups, while the area under the curve (AUC) was 27.9% smaller, which could be caused by the greater hepatic metabolism seen in the i.v. study. These findings have potential therapeutic implications, assuming that the DMIS rats qualitatively reflect similar changes in patients with diabetes. PMID- 23985695 TI - Microdialysis sampling for investigations of tetramethylpyrazine following transdermal and intraperitoneal administration. AB - The pharmacokinetic behaviors of tetramethylpyrazine (TMP) were investigated in rat plasma and microdialysates of various sites such as brain, blood and skin after tetramethylpyrazine hydrochloride (TMPH) transdermal or intraperitoneal (i.p.) administration. Samples were collected at timed intervals for the measurement of TMP by a quick and sensitive HPLC-UV method. The pharmacokinetic parameters were calculated by non-compartmental analysis using DAS 2.0. The results of pharmacokinetics indicated that the Cmax in brain and plasma after transdermal administration (20 mg/cm(2), 1.2 cm(2)) was similar to that after i.p. administration (40 mg/kg). The value of Cmax after i.p. administration in brain, blood microdialysates and plasma were 8.17 +/- 2.06, 11.58 +/- 2.66 and 15.54 +/- 3.87 mg/l, respectively. After gel transdermal administration, the value of Cmax in brain, blood, skin microdialysates and plasma were 7.29 +/- 2.65, 8.53 +/- 1.98, 43.39 +/- 29.57 and 15.50 +/- 2.99 mg/l, respectively. Compared with traditional administration, gel transdermal administration is a promising alternative to transport TMP to the brain. PMID- 23985696 TI - Arming cytokine-induced killer cells with chimeric antigen receptors: CD28 outperforms combined CD28-OX40 "super-stimulation". AB - Cytokine-induced killer (CIK) cells raised interest for use in cellular antitumor therapy due to their capability to recognize and destroy autologous tumor cells in a HLA-independent fashion. The antitumor attack of CIK cells, predominantly consisting of terminally differentiated CD8(+)CD56(+) cells, can be improved by redirecting by a chimeric antigen receptor (CAR) that recognizes the tumor cell and triggers CIK cell activation. The requirements for CIK cell activation were, however, so far less explored and are likely to be different from those of "younger" T cells. We revealed that CD28 and OX40 CARs produced higher interferon secretion as compared with the first-generation zeta-CAR; CD28-zeta and the third-generation CD28-zeta-OX40 CAR, however, performed similar in modulating most CIK cell effector functions. Compared with the CD28-zeta CAR, however, the CD28-zeta-OX40 CAR accelerated terminal maturation of CD56(+) CIK cells producing high frequencies in activation-induced cell death (AICD) and reduced antitumor efficiency in vivo. Consequently, CD28-zeta CAR CIK cells of CD56(-) phenotype were superior in redirected tumor cell elimination. CAR-mediated CIK cell activation also increased antigen-independent target cell lysis; the CD28-zeta CAR was more efficient than the CD28-zeta-OX40 CAR. Translated into therapeutic strategies, CAR-redirected CIK cells benefit from CD28 costimulation; "super costimulation" by the CD28-zeta-OX40 CAR, however, performed less in antitumor efficacy due to increased AICD. PMID- 23985700 TI - New editor-in-chief. PMID- 23985697 TI - Vaccinia virus induces programmed necrosis in ovarian cancer cells. AB - The mechanisms by which oncolytic vaccinia virus induces tumor cell death are poorly understood. We have evaluated cell death pathways following infection of ovarian cancer cells with both wild-type and thymidine kinase-deleted (dTK) Lister strain vaccinia. We show that death does not rely upon classical apoptosis despite the appearances of some limited apoptotic features, including phosphatidylserine externalization and appearance of sub-G1 DNA populations. Vaccinia infection induces marked lipidation of LC3 proteins, but there is no general activation of the autophagic process and cell death does not rely upon autophagy induction. We show that vaccinia induces necrotic morphology on transmission electron microscopy, accompanied by marked by reductions in intracellular adenosine triphosphate, altered mitochondrial metabolism, and release of high mobility group box 1 (HMGB1) protein. This necrotic cell death appears regulated, as infection induces formation of a receptor interacting protein (RIP1)/caspase-8 complex. In addition, pharmacological inhibition of both RIP1 and substrates downstream of RIP1, including MLKL, significantly attenuate cell death. Blockade of TNF-alpha, however, does not alter virus efficacy, suggesting that necrosis does not result from autocrine cytokine release. Overall, these results show that, in ovarian cancer cells, vaccinia virus causes necrotic cell death that is mediated through a programmed series of events. PMID- 23985698 TI - Exploiting human CD34+ stem cell-conditioned medium for tissue repair. AB - Despite the progress in our understanding of genes essential for stem cell regulation and development, little is known about the factors secreted by stem cells and their effect on tissue regeneration. In particular, the factors secreted by human CD34+ cells remain to be elucidated. We have approached this challenge by performing a cytokine/growth factor microarray analysis of secreted soluble factors in medium conditioned by adherent human CD34+ cells. Thirty-two abundantly secreted factors have been identified, all of which are associated with cell proliferation, survival, tissue repair, and wound healing. The cultured CD34+ cells expressed known stem cell genes such as Nanog, Oct4, Sox2, c-kit, and HoxB4. The conditioned medium containing the secreted factors prevented cell death in liver cells exposed to liver toxin in vitro via inhibition of the caspase-3 signaling pathway. More importantly, in vivo studies using animal models of liver damage demonstrated that injection of the conditioned medium could repair damaged liver tissue (significant reduction in the necroinflammatory activity), as well as enable the animals to survive. Thus, we demonstrate that medium conditioned by human CD34+ cells has the potential for therapeutic repair of damaged tissue in vivo. PMID- 23985699 TI - Triptolide-mediated inhibition of interferon signaling enhances vesicular stomatitis virus-based oncolysis. AB - Preclinical and clinical trials demonstrated that use of oncolytic viruses (OVs) is a promising new therapeutic approach to treat multiple types of cancer. To further improve their viral oncolysis, experimental strategies are now combining OVs with different cytotoxic compounds. In this study, we investigated the capacity of triptolide - a natural anticancer molecule - to enhance vesicular stomatitis virus (VSV) oncolysis in OV-resistant cancer cells. Triptolide treatment increased VSV replication in the human prostate cancer cell line PC3 and in other VSV-resistant cells in a dose- and time-dependent manner in vitro and in vivo. Mechanistically, triptolide (TPL) inhibited the innate antiviral response by blocking type I interferon (IFN) signaling, downstream of IRF3 activation. Furthermore, triptolide-enhanced VSV-induced apoptosis in a dose dependent fashion in VSV-resistant cells, as measured by annexin-V, cleaved caspase-3, and B-cell lymphoma 2 staining. In vivo, using the TSA mammary adenocarcinoma and PC3 mouse xenograft models, combination treatment with VSV and triptolide delayed tumor growth and prolonged survival of tumor-bearing animals by enhancing viral replication. Together, these results demonstrate that triptolide inhibition of IFN production sensitizes prostate cancer cells to VSV replication and virus-mediated apoptosis. PMID- 23985701 TI - Inhibition of farnesyl pyrophosphate synthase prevents norepinephrine-induced fibrotic responses in vascular smooth muscle cells from spontaneously hypertensive rats. AB - Both norepinephrine (NE) and connective tissue growth factor (CTGF) contribute to vascular fibrosis during hypertension. Recent studies indicate that farnesyl pyrophosphate synthase (FPPS) plays an important role in cardiac remodeling in hypertension. However, the role of FPPS in NE-induced fibrotic responses and related molecular mechanisms is unknown. Vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were stimulated with NE. The fibrotic responses were assessed by measuring CTGF, hydroxyproline (hyp), and alpha-1 procollagen I levels using Western blot, a hydroxyproline test kit, and real-time quantitative PCR assays, respectively. Ras activity was determined by a pull-down assay using a Ras activation assay kit and detected by Western blot. NE dose-dependently increased fibrosis in SHR-VSMCs, and this increase was significantly reduced by ibandronate, an inhibitor of FPPS. The addition of farnesol, but not geranylgeraniol, partially reversed the inhibitory effects of ibandronate. Furthermore, the anti-fibrotic effects of ibandronate could be mimicked by FTI-276 but not by GGTI-286. A pull-down assay showed that ibandronate reduced the NE-induced Ras activation. Moreover, ibandronate inhibited the NE-induced activation of p38, JNK, and ERK1/2. Only SB203580 (specific inhibitor of p38) diminished the NE-induced CTGF production. These results demonstrated that inhibiting FPPS prevents NE-induced fibrotic responses in SHR-VSMCs and that the Ras kinase and p38 pathways were the underlying mechanisms involved in this process. PMID- 23985702 TI - Renal inflammatory markers during the onset of hypertension in spontaneously hypertensive rats. AB - Early blockade of the renin-angiotensin system is successful in delaying the development of hypertension in spontaneously hypertensive rats (SHRs) and ameliorating organ damage by inhibition of the inflammatory response. In this study, we investigated the role of the angiotensin II type 1 receptor (AT1R) in the early renal inflammatory response in SHR. Blood pressure development and renal inflammatory markers were measured in 4-, 8- and 12-week-old SHR and age matched Wistar Kyoto (WKY) rats. Separate groups of SHRs were transiently treated with the AT1R blocker losartan between 4 and 8 weeks of age. Urinary excretion of the renal injury markers osteopontin and neutrophil gelatinase-associated lipocalin increased in young SHR. Further, renal expression of inflammatory genes was also increased in young SHR. Losartan inhibited the increase of these inflammatory markers. In contrast, gene expression of the renal injury marker and T-cell inducer kidney injury molecule-1 (KIM-1) was reduced in 4-week-old SHR when compared with WKY. Similarly, the T-cell marker CD3 was significantly decreased in 4-week-old SHR. These effects were not antagonized by AT1R blockade. This study confirms the presence of an early renal inflammatory response in SHR that can be blocked by AT1R antagonism. In addition, it demonstrates that KIM-1 does not behave as a pure kidney injury marker in young SHR, but may reflect kidney maturation. PMID- 23985703 TI - Effects of a benidipine-based combination therapy on the risk of stroke according to stroke subtype: the COPE trial. AB - The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial compared the dihydropyridine T/L-type calcium channel blocker benidipine based therapies when combined with an angiotensin receptor blocker (ARB), a beta blocker (BB) or a thiazide diuretic (TD). The results suggested that benidipine combined with a BB appeared to be less beneficial in reducing the risk of stroke compared with the benidipine-TD combination (hazard ratio (HR): 2.31, P=0.0109). We further evaluated the treatment effects on different stroke subtypes among the three benidipine-based regimens. The COPE trial was an investigator-initiated, multicenter study with PROBE design. Patients with atrial fibrillation or flutter were excluded from the study. All stroke events were subclassified with the Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria. The total incidence of stroke was 4.7, hemorrhagic stroke was 1.6 and ischemic stroke was 2.5 per 1000 person-years. The incidence of lacunar stroke was 1.1, large-artery stroke was 0.6, cardioembolic stroke was 0.3, unknown ischemic type was 0.6 and transient ischemic attack was 0.6 per 1000 person-years. Although few differences in stroke subtypes were observed among the three treatment groups, multi-adjusted HRs for the incidence rates of all types of stroke, hemorrhagic stroke and ischemic stroke were significantly higher with the benidipine-BB regimen than with the benidipine-TD regimen. The incidence of both hemorrhagic and ischemic stroke in the benidipine-ARB regimen was not different compared with the other two treatment regimens. This prespecified sub-analysis suggested that a blood pressure-lowering therapy with a benidipine-TD regimen might be beneficial for hypertensive patients to prevent both hemorrhagic and ischemic stroke. PMID- 23985704 TI - Synthesis and evaluation of curcumin-related compounds containing benzyl piperidone for their effects on human cancer cells. AB - Eleven curcumin-related compounds containing a benzyl piperidone moiety were synthesized and evaluated for their effects on cultured prostate cancer PC-3 cells, pancreas cancer BxPC-3 cells, colon cancer HT-29 cells and lung cancer H1299 cells. Inhibitory effects of these compounds on the growth of PC-3, BxPC-3, HT-29 and H1299 cells were determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and trypan blue exclusion assay. Compounds benzyl piperidone 2 (P2), P4, P7, 4-bromo-2-fluoro-benzyl piperidone 2 (PFBr2), PFBr3 and PFBr4 (see syntheses and structures in Figs. 1, 2) exhibited potent inhibitory effects on the growth of cultured PC-3, BxPC-3, HT-29 and H1299 cells. The IC50 for these compounds was lower than 2 uM in all four cell lines. PFBr4 was 41-, 36-, 40- and 46-fold more active than curcumin for inhibiting the growth of PC-3, BxPC-3, HT-29 and H1299 cells, respectively. The benzyl piperidone-containing compounds studied also stimulated apoptosis in PC-3 cells. Mechanistic studies indicate that the effects of both curcumin and PFBr4 on PC-3 cells were associated with a decrease in phospho-Akt and phospho-extracellular signal-regulated kinase (Erk)1/2. The present study indicates that P2, P4, P7, PFBr2, PFBr3 and PFBr4 may have useful effects on human cancer cells. PMID- 23985705 TI - Improvement of hydrothermal stability of zeolitic imidazolate frameworks. AB - The metal-organic framework ZIF-8, which undergoes hydrolysis under hydrothermal conditions, is endowed with high water-resistance after a shell-ligand-exchange reaction. The stabilized ZIF-8 retains its structural characteristics with improved application performances in adsorption and membrane separation. PMID- 23985707 TI - Improving the management, operations and cost effectiveness of sterile-product compounding. PMID- 23985708 TI - "Green" IV Nutritionals. PMID- 23985706 TI - Comparison of cardiovascular disease risk markers in HIV-infected patients receiving abacavir and tenofovir: the nucleoside inflammation, coagulation and endothelial function (NICE) study. AB - BACKGROUND: The association between abacavir (ABC) and cardiovascular disease (CVD) risk in HIV-infected individuals is unclear. Putative mechanisms for an effect of ABC on CVD risk including endothelial dysfunction have been proposed; however, a biological mechanism has not been established. METHODS: This was a cross-sectional study of HIV-infected subjects with HIV RNA levels <400 copies/ml, who were randomly assigned to ABC or tenofovir (TDF) as initial therapy during a prior clinical trial. A small cohort of subjects on zidovudine (AZT; not randomly assigned) were studied to explore long-term exposure to this agent. All underwent brachial artery ultrasound for flow-mediated dilation (FMD), and D-dimer, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and fasting lipids were measured. Between-arm differences were evaluated by multivariable linear or logistic regression modelling. RESULTS: There were 148 subjects (46 on ABC, 72 on TDF and 30 on AZT). Demographic characteristics were balanced across the groups except, as expected, AZT-treated participants were older, had higher CD4(+) T-cell counts, and longer antiretroviral therapy duration. After adjusting for age, brachial artery diameter, and treatment duration, FMD was similar in those on ABC (3.9%) and TDF (5.4%; P=0.181). FMD was higher in those on AZT (6.1%; P<0.005). Levels of IL-6, hsCRP and detectable D dimer were similar between groups. CONCLUSIONS: Among individuals assigned to ABC or TDF in randomized clinical trials there were no significant differences in FMD or markers of inflammation and coagulation. Whether ABC contributes to risk of CVD remains unclear, but our results suggest that endothelial dysfunction, heightened inflammation, and altered coagulation are unlikely to be mechanisms by which the drug could increase CVD risk above that seen with TDF. PMID- 23985709 TI - Sterilization and depyrogenation principles and methods. PMID- 23985710 TI - Sterile-Product Compounding: A Comparison of ASHP and USP Guidelines. PMID- 23985711 TI - Extemporaneous formulation in pediatric patients. PMID- 23985713 TI - The basics of compounding: compounding special capsules. PMID- 23985712 TI - Compounding for Athletes: Common Questions about Sports Medicine. PMID- 23985714 TI - Quantitation of Testosterone,Cypionate-in-Oil Injection Using High-Performance Liquid Chromatography. AB - A high-performance liquid chromatography assay method for the quantitation of testosterone-cypionate-in-oil injection has been developed. The assay method is very simple, accurate and precise, with a percent relative standard deviation of 1.2 based on five readings. The extraction procedure is very simple compared with a very tedious and time-consuming procedure given in the United States Pharmacopoeia/National Formulary. The USP-NF assay method is based on gas chromatography. The benzyl alcohol (preservative) did not interfere with the assay preocedure. The newly developed method could not be applied to the quantitation of testosterone enanthate since the results were consistently low ( 87%). The average recovery of testosterone cypionate from a commercial dosage form was 98.7%. PMID- 23985715 TI - Stability of amphotericin B in 5% dextrose ophthalmic solution. AB - The stability of amphotericin B 5 mg/mL in 5% dextrose ophthalmic solution prepared by the Hospital Pharmacy Service was studied in different conditions of storage and use. Admixtures of amphotericin B were aseptically prepared in low density polyethylene dropper bottles. The stability of amphotericin B was evaluated in ophthalmic dropper bottles stored in a refrigerator, at room temperature, protected from, or exposed to, light. To simulate the effect of exposure to air, some ophthalmic dropper bottles were opened twice daily and two drops were removed. Immediately after preparation, samples were collected to determine the initial drug concentration by high-performance liquid chromatography and to assess pH, osmolality and sterility. The same tests were conducted after four, eight and 15 days of storage in ophthalmic containers opened daily and unopened after eight, 15, 30, 60, 75 and 120 days of storage. Samples were visually inspected daily for signs of physical incompatibility. An additional study was conducted in four ophthalmic containers collected in the ophthalmology unit after eight or 15 days of current patient use testing the same parameters. Ophthamlic containers stored in the refrigerator (the closed and the opened daily set) showed no loss or deterioration of amphotericin B during the corresponding period of storage (120 and 15 days, respectively). We observed precipitation and degradation after 13 days of storage in ophthalmic containers exposed to normal lighting conditions at room temperature, and after 16 days in ophthalmic containers protected from light. There was no appreciable change in pH or osmolality in any of the samples. Microbiological invesigation disclosed negative culture results for all samples. This study shows that aseptically prepared amphotericin B ophthalmic solution packaged in low-density polyethylene bottles can be stored safely for up to 120 days when unopened and stored at 4 deg C and protected from light, for 16 days when stored at 22 deg C and protected from light and for 13 days when stored at 22 deg C and exposed to light. PMID- 23985716 TI - Rapid pharmacokinetic evaluation of topical drug formulations. AB - A new in vitro test system was developed to efficiently determine the effect of formulation on topical drug delivery. Sheets of viable, excised pig skin were sandwiched betwween two standard 24-well plates. The lower wells contained receptor fluid and a magnetic stirrer. The upper wells were opened to the atmosphere for formulation application. Using 14C-salicylic acid as a model compound, eight different formulations were evaluated representing hydrophilic and lipophilic solutions, a suspension and o/w and w/o emulsions. Formulations were applied to the skin surface in six different wells on three sets of plates. Twenty-four hours after application, excess drug was wiped from the skin surface and assayed for radiolabel. The stratum corneum was removed by tape stripping. Radiolabel contained in the remaining epidermis, dermis and receptor fluid was also determined. Statistical analysis (ANOVA, Student-Newman-Keuls multiple-range test, p=0.05) of radiolabel penetrating into the dermis and receptor fluid revealed the following order of formulations: ethanol= aqueous surfactant less than o/w emulsion = w/o emulsion less than lipophilic solution. These results demonstrate the importance of vehicle in directing drug delivery using a test system capable of simultaneously evaluating a large number of formulations. PMID- 23985717 TI - Manipulating acoustic wavefront by inhomogeneous impedance and steerable extraordinary reflection. AB - We unveil the connection between the acoustic impedance along a flat surface and the reflected acoustic wavefront, in order to empower a wide wariety of novel applications in acoustic community. Our designed flat surface can generate double reflections: the ordinary reflection and the extraordinary one whose wavefront is manipulated by the proposed impedance-governed generalized Snell's law of reflection (IGSL). IGSL is based on Green's function and integral equation, instead of Fermat's principle for optical wavefront manipulation. Remarkably, via the adjustment of the designed specific acoustic impedance, extraordinary reflection can be steered for unprecedented acoustic wavefront while that ordinary reflection can be surprisingly switched on or off. The realization of the complex discontinuity of the impedance surface has been proposed using Helmholtz resonators. PMID- 23985719 TI - Abrogation of chronic rejection in rat model system involves modulation of the mTORC1 and mTORC2 pathways. AB - BACKGROUND: Current immunosuppressive regimens fail to avert chronic rejection (CR) of transplanted organs; however, selective targeting of actin-cytoskeletal regulators decreases T-cell motility and abrogates CR in rat model system. Administration of mutated class I major histocompatibility complex molecules or selective targeting of the RhoA pathway, which controls T-cell cytoskeletal activity, using Y27632 (a selective Rock1 inhibitor) resulted in reduced T-cell infiltration and abrogation of CR as judged from the neointimal index (13.9+/ 19.7 vs. 45+/-37.5; P<0.001) and the number of affected vessels (30% vs. 60%; P<0.01). Here, we examined the role of mammalian target of rapamycin (mTOR) pathway in inhibition of CR. METHODS: A mutated class I major histocompatibility complex molecule that eliminates CR was delivered into ACI recipients of Wistar Furth hearts at the time of transplantation with subtherapeutic cyclosporine (10 mg/kg on days 0-2). Controls included untreated and cyclosporine A-treated (10 mg/kg on days 0-2) heart allograft recipients. RESULTS: Western blotting and immunostaining showed that rat heart allografts with abolished CR exhibited down regulation of the RAPA-sensitive mTORC1 components such as mTOR and Raptor and down-regulation of the RAPA-insensitive mTORC2 elements Rictor and Sin1. The mTOR regulator Deptor and its downstream target Rac1 were also inhibited. CONCLUSIONS: Abrogation of CR in rat model system involves modulation of two mTOR pathways: a RAPA-sensitive mTORC1 pathway regulating cellular proliferation and a RAPA insensitive mTORC2 pathway regulating T-cell motility. Selective targeting of T cell actin cytoskeletal pathways shows potential for pathway-targeted immunosuppression therapies. PMID- 23985720 TI - Regulation of molecular pathways in ischemia-reperfusion injury after liver transplantation. AB - BACKGROUND: Ischemia-reperfusion (I/R) injury is a multifactorial phenomenon that occurs during the transplant event and frequently compromises early graft function after liver transplantation (LT). Current comprehension of molecular mechanisms and regulation processes of I/R injury lacks clarity. MicroRNA (miRNA) regulation results critical in several biological processes. METHODS: This study evaluated gene expression and miRNA expression profiles using microarrays in 34 graft biopsies collected at preimplantation (L1) and at 90 min postreperfusion (L2) from consecutives deceased-donor LT recipients. miRNA profiles were first analyzed. Data integration analysis (gene expression/miRNA expression) aimed to identify potential target genes for each identified miRNA from the L1/L2 differential gene expression profile. RESULTS: Pairwise comparison analyses identified 40 miRNAs and 3168 significantly differentially expressed genes at postreperfusion time compared with preimplantation time. Pathway analysis of miRNAs associated these profiles with antiapoptosis, inhibition of cellular proliferation, and proinflammatory processes. Target analysis identified an miRNA associated molecular profile of 2172 genes involved in cellular growth and proliferation modulation by cell cycle regulation, cell death and survival, and proinflammatory and anti-inflammatory processes. miRNA-independent genes involved proinflammatory molecules. CONCLUSION: We identified a miRNA profile involved in posttranscriptional regulatory mechanisms in I/R injury post-LT. A better understanding of these molecular processes involved in I/R may contribute to develop new strategies to minimize graft injury. PMID- 23985721 TI - Kinetics of homeostatic proliferation and thymopoiesis after rATG induction therapy in kidney transplant patients. AB - BACKGROUND: Lymphocyte-depleting therapy is associated with long-lasting effects on repopulated T cells and subsequent increased rates of infections and malignancies. The mechanisms of T-cell repopulation and their posttransplantation kinetics are not fully understood. METHODS: We studied thymopoiesis by CD31(+) naive T cells (recent thymic emigrants) and homeostatic proliferation by Ki-67(+) T cells in rabbit antithymocyte globulin (rATG)-treated patients the first 6 months after transplantation. Patients receiving basiliximab or no induction therapy served as controls. RESULTS: At 6 months after transplantation, T-cell numbers were lower than before transplantation in rATG-treated patients, whereas T-cell numbers remained stable in both control groups. In this time period, thymopoiesis was similar between the three treatment groups; CD8(+) T cells showed the highest percentage of recent thymic emigrants. At month 1, percentages of Ki-67(+) naive and memory CD4(+) and CD8(+) T cells were the highest in rATG treated patients, but these percentages declined in the months thereafter. When CD31 was used to distinguish between cytokine- and antigen-driven proliferation in naive T cells, we found evidence for cytokine-dependent proliferation. Cytokine-dependent proliferation was also shown by in vivo increased percentages of phosphorylated STAT5 and high expression levels of the interleukin-7 receptor alpha and interleukin-15 receptor-alpha by T cells. CONCLUSION: These findings demonstrate that, in the first month after rATG therapy, cytokine-induced homeostatic proliferation is involved in T-cell repopulation of both naive and memory T cells. At later time points, the contribution of homeostatic proliferation diminished, which explains the observed incomplete T-cell recovery. PMID- 23985722 TI - Factors associated with blood transfusion in donor hepatectomy: results from 2344 donors at a large single center. AB - BACKGROUND: The safety of healthy living donors undergoing hepatic resection for living-donor liver transplantation is of paramount concern. Although blood transfusions have been associated with morbidity and mortality after hepatectomy, there is limited information about the risk factors associated with blood transfusion in living liver donors. METHODS: We retrospectively analyzed 2344 donors who underwent a hepatectomy for living-donor liver transplantation. Logistic regression analysis was performed to determine blood transfusion predictors in living-donor hepatectomy. RESULTS: Of these donors, 48 (2.0%) and 97 (4.1%) were transfused with packed red blood cell (PRBC) and fresh-frozen plasma (FFP), respectively. The amount of PRBC and FFP administered to donors transfused with blood products were 1.9+/-0.8 and 3.7+/-2.5 units, respectively. In multivariate logistic regression analysis, a low preoperative hemoglobin level was found to be an independent predictor of PRBC transfusion in donor hepatectomy (odds ratio=0.585; 95% confidence interval=0.451-0.758; P<0.001). A high graft-to donor weight ratio predicted an FFP transfusion in donor hepatectomy (odds ratio=2.997; 95% confidence interval=1.226-7.327; P=0.016). CONCLUSIONS: These results indicate that, in donor hepatectomy, the preoperative hemoglobin value and graft-to-donor weight ratio can provide useful information on the probability of PRBC and FFP transfusion, respectively. PMID- 23985723 TI - Association between 276G/T adiponectin gene polymorphism and new-onset diabetes after kidney transplantation. AB - BACKGROUND: New-onset diabetes after transplantation (NODAT) is a well-recognized complication of kidney transplantation and is associated with poor outcomes. Both adiponectin and chemokine ligand 5 (CCL5) proteins are related to glucose metabolism and genetic variations in their genes can lead to development of NODAT. The aim of this study was to investigate the association of adiponectin and CCL5 genes polymorphisms with NODAT in a population of Caucasian kidney transplant recipients. METHODS: Two hundred seventy Caucasian kidney transplant recipients (83 with NODAT and 187 without NODAT) were included in a nested case control study. Patients with pretransplantation diabetes mellitus and multiorgan transplantation were excluded. NODAT diagnosis was determined by American Diabetes Association criteria. Subjects were genotyped for 276G/T adiponectin gene polymorphism (rs1501299) and rs2280789 and rs3817655 CCL5 gene polymorphisms by real-time polymerase chain reaction. RESULTS: The TT genotype of 276G/T adiponectin gene polymorphism was significantly more frequent in NODAT than non NODAT patients compared with GG/GT genotypes (recessive model; P=0.031). TT genotype was identified as an independent risk factor for NODAT in Caucasian kidney transplant recipients after adjusting for age at transplantation, pretransplantation body mass index, and use of tacrolimus (TT vs. GG/GT, hazard ratio=1.88, 95% confidence interval=1.03-3.45, P=0.041). There were no differences in genotype distribution and allele frequency of rs2280789 and rs3817655 CCL5 gene polymorphisms between NODAT and non-NODAT groups. CONCLUSIONS: The 276G/T adiponectin gene polymorphism is associated with NODAT in Caucasian kidney transplant recipients. PMID- 23985724 TI - Is exposure to night-time traffic noise a risk factor for purchase of anxiolytic hypnotic medication? A cohort study. AB - BACKGROUND: Studies suggest that road traffic noise increases risks of sleep disturbances, anxiety and depressive symptoms, but few have focused on psychotropic drug use. We examined whether exposure to night-time road traffic noise in Marseilles (France) is associated with an increased risk of purchasing anxiolytic or hypnotic medications. METHODS: Cohort of 190,617 inhabitants of Marseilles (aged 18-64 years) covered by the National Health Insurance Fund. We used the CadnaA noise propagation prediction model to calculate a potential road noise exposure indicator at dwellings for the night-period: Ln. Association between the number of purchases of anxiolytics-hypnotics in 2008-9 and the Ln was analysed with a zero-inflated negative binomial (ZINB) model adjusted for characteristics of individuals (sociodemographic, consultations with general practitioners, presence of chronic psychiatric disorder), prescribers (demographic, specialty, workload) and neighbourhoods (medical density, complaints filed for environmental noise). Analyses were stratified by the deprivation level of the census block of residence to control for the confounding effects of neighbourhood socio-economic status. RESULTS: The ZINB model showed a small but significant increase in the risk of purchasing higher numbers of anxiolytics-hypnotics for Ln greater than 55 dB(A) only in the low deprivation stratum. CONCLUSION: We found some evidence that potential exposure to night-time road traffic noise might affect individual use of anxiolytics-hypnotics. Further research based on strictly individual approaches is warranted to assess exposure to road traffic noise more precisely and reliably than allowed by noise propagation prediction models. PMID- 23985725 TI - A comparison of older workers' and retired older people's social capital and sense of mastery. AB - AIM: To assess if older people with higher levels of social capital experience higher levels of sense of mastery than those with lower levels of social capital and to assess whether this association is stronger for retired older people than for older workers. METHODS: The data originates from a general population mental health survey conducted among 2610 older people (50 years of age or older) in Finland in 2011. The response rate was 57.1%. The association between sense of mastery, measured by Pearlin's Sense of Mastery Scale, and social capital, measured by social networks, organisational activities, trust, and sense of belonging, were tested by logistic regression analyses. RESULTS: The results showed that older workers experienced greater sense of mastery than retired older people. Trust and neighbourhood belonging were positively associated with sense of mastery. CONCLUSIONS: Inequalities in mental wellbeing between older people included in or excluded from the workforce are a public health challenge. Our findings imply that social capital needs to be prioritised as a means for enhancing mental health. More attention should be paid to promote mental wellbeing in retired older people. PMID- 23985726 TI - ESTOOLS Data@Hand: human stem cell gene expression resource. PMID- 23985727 TI - Calling the next generation of affinity reagents. PMID- 23985728 TI - Visualizing networks of mobility in proteins. PMID- 23985729 TI - Sculpting genomes with a hammer and chisel. PMID- 23985730 TI - Ethical reproducibility: towards transparent reporting in biomedical research. AB - Optimism about biomedicine is challenged by the increasingly complex ethical, legal and social issues it raises. Reporting of scientific methods is no longer sufficient to address the complex relationship between science and society. To promote 'ethical reproducibility', we call for transparent reporting of research ethics methods used in biomedical research. PMID- 23985732 TI - Modelling the efficacy of hyperthermia treatment. AB - Multimodal oncological strategies which combine chemotherapy or radiotherapy with hyperthermia, have a potential of improving the efficacy of the non-surgical methods of cancer treatment. Hyperthermia engages the heat-shock response (HSR) mechanism, the main component of which are heat-shock proteins. Cancer cells have already partially activated HSR, thereby hyperthermia may be more toxic to them relative to normal cells. On the other hand, HSR triggers thermotolerance, i.e. hyperthermia-treated cells show an impairment in their susceptibility to a subsequent heat-induced stress. This poses questions about efficacy and optimal strategy for anti-cancer therapy combined with hyperthermia treatment. To address these questions, we adapt our previous HSR model and propose its stochastic extension. We formalize the notion of a HSP-induced thermotolerance. Next, we estimate the intensity and the duration of the thermotolerance. Finally, we quantify the effect of a multimodal therapy based on hyperthermia and a cytotoxic effect of bortezomib, a clinically approved proteasome inhibitor. Consequently, we propose an optimal strategy for combining hyperthermia and proteasome inhibition modalities. In summary, by a mathematical analysis of HSR, we are able to support the common belief that the combination of cancer treatment strategies increases therapy efficacy. PMID- 23985731 TI - Multiparametric imaging of biological systems by force-distance curve-based AFM. AB - A current challenge in the life sciences is to understand how biological systems change their structural, biophysical and chemical properties to adjust functionality. Addressing this issue has been severely hampered by the lack of methods capable of imaging biosystems at high resolution while simultaneously mapping their multiple properties. Recent developments in force-distance (FD) curve-based atomic force microscopy (AFM) now enable researchers to combine (sub)molecular imaging with quantitative mapping of physical, chemical and biological interactions. Here we discuss the principles and applications of advanced FD-based AFM tools for the quantitative multiparametric characterization of complex cellular and biomolecular systems under physiological conditions. PMID- 23985733 TI - Designing experiments to understand the variability in biochemical reaction networks. AB - Exploiting the information provided by the molecular noise of a biological process has proved to be valuable in extracting knowledge about the underlying kinetic parameters and sources of variability from single-cell measurements. However, quantifying this additional information a priori, to decide whether a single-cell experiment might be beneficial, is currently only possible in systems where either the chemical master equation is computationally tractable or a Gaussian approximation is appropriate. Here, we provide formulae for computing the information provided by measured means and variances from the first four moments and the parameter derivatives of the first two moments of the underlying process. For stochastic kinetic models for which these moments can be either computed exactly or approximated efficiently, the derived formulae can be used to approximate the information provided by single-cell distribution experiments. Based on this result, we propose an optimal experimental design framework which we employ to compare the utility of dual-reporter and perturbation experiments for quantifying the different noise sources in a simple model of gene expression. Subsequently, we compare the information content of a set of experiments which have been performed in an engineered light-switch gene expression system in yeast and show that well-chosen gene induction patterns may allow one to identify features of the system which remain hidden in unplanned experiments. PMID- 23985734 TI - Age-dependent partnering and the HIV transmission chain: a microsimulation analysis. AB - Efficient planning and evaluation of human immunodeficiency virus (HIV) prevention programmes requires an understanding of what sustains the epidemic, including the mechanism by which HIV transmission keeps pace with the ageing of the infected population. Recently, more detailed population models have been developed which represent the epidemic with sufficient detail to characterize the dynamics of ongoing transmission. Here, we describe the structure and parameters of such a model, called EMOD-HIV v. 0.7. We analyse the chains of transmission that allow the HIV epidemic to propagate across age groups in this model. In order to prevent the epidemic from dying out, the virus must find younger victims faster than its extant victims age and die. The individuals who enable such transmission events in EMOD-HIV v. 0.7 are higher concurrency, co-infected males aged 26-29 and females aged 23-24. Prevention programmes that target these populations could efficiently interrupt the mechanisms that allow HIV to transmit at a pace that is faster than the progress of time. PMID- 23985735 TI - What can information-asymmetric games tell us about the context of Crick's 'frozen accident'? AB - This paper describes a novel application of information-asymmetric (signalling) games to molecular biology in which utility is determined by the message complexity (rate) in addition to the error in information transfer (distortion). We show using a computational model how it is possible for the agents in one such game to evolve a signalling convention (separating equilibrium) that is suboptimal in terms of information transfer, but is nonetheless stable. In the context of an RNA world merging with a nascent amino acid one, such a game's equilibrium is alluded to by the genetic code, which is nearly optimal in terms of information transfer, but is also near-universal and nearly immutable. Such a framework suggests that cellularity may have emerged to encourage coordination between RNA species and sheds light on other aspects of RNA world biochemistry yet to be fully understood. PMID- 23985736 TI - Design and interpretation of cell trajectory assays. AB - Cell trajectory data are often reported in the experimental cell biology literature to distinguish between different types of cell migration. Unfortunately, there is no accepted protocol for designing or interpreting such experiments and this makes it difficult to quantitatively compare different published datasets and to understand how changes in experimental design influence our ability to interpret different experiments. Here, we use an individual-based mathematical model to simulate the key features of a cell trajectory experiment. This shows that our ability to correctly interpret trajectory data is extremely sensitive to the geometry and timing of the experiment, the degree of motility bias and the number of experimental replicates. We show that cell trajectory experiments produce data that are most reliable when the experiment is performed in a quasi-one-dimensional geometry with a large number of identically prepared experiments conducted over a relatively short time-interval rather than a few trajectories recorded over particularly long time-intervals. PMID- 23985737 TI - Passive elastic mechanism to mimic fish-muscle action in anguilliform swimming. AB - Swimmers in nature use body undulations to generate propulsive and manoeuvring forces. The anguilliform kinematics is driven by muscular actions all along the body, involving a complex temporal and spatial coordination of all the local actuations. Such swimming kinematics can be reproduced artificially, in a simpler way, by using the elasticity of the body passively. Here, we present experiments on self-propelled elastic swimmers at a free surface in the inertial regime. By addressing the fluid-structure interaction problem of anguilliform swimming, we show that our artificial swimmers are well described by coupling a beam theory with the potential flow model of Lighthill. In particular, we show that the propagative nature of the elastic wave producing the propulsive force is strongly dependent on the dissipation of energy along the body of the swimmer. PMID- 23985738 TI - Hierarchically engineered fibrous scaffolds for bone regeneration. AB - Surface properties of biomaterials play a major role in the governing of cell functionalities. It is well known that mechanical, chemical and nanotopographic cues, for example, influence cell proliferation and differentiation. Here, we present a novel coating protocol to produce hierarchically engineered fibrous scaffolds with tailorable surface characteristics, which mimic bone extracellular matrix. Based on the sol-gel method and a succession of surface treatments, hollow electrospun polylactic acid fibres were coated with a silicon-calcium phosphate bioactive organic-inorganic glass. Compared with pure polymeric fibres that showed a completely smooth surface, the coated fibres exhibited a nanostructured topography and greater roughness. They also showed improved hydrophilic properties and a Young's modulus sixfold higher than non-coated ones, while remaining fully flexible and easy to handle. Rat mesenchymal stem cells cultured on these fibres showed great cellular spreading and interactions with the material. This protocol can be transferred to other structures and glasses, allowing the fabrication of various materials with well-defined features. This novel approach represents therefore a valuable improvement in the production of artificial matrices able to direct stem cell fate through physical and chemical interactions. PMID- 23985740 TI - Hierarchical porous polymeric microspheres as efficient adsorbents and catalyst scaffolds. AB - Novel polymeric microspheres with a hierarchical porous structure are facilely fabricated using double Pickering emulsion templates. This unique hierarchical porous structure makes them excellent candidates for adsorption and catalyst scaffold materials. PMID- 23985739 TI - Evaluation of cytotoxicity, biophysics and biomechanics of cells treated with functionalized hybrid nanomaterials. AB - Hybrids consisting of carboxylated, single-walled carbon nanotube (c-SWNT)-silver nanoparticles (AgNPs)-DNA-poly vinyl alcohol (PVA) are synthesized via sequential functionalization to mimic the theragnostic (therapy and diagnosis) system. Carboxylation of SWNT has minimized the metal impurities with plenty of -COOH groups to produce hybrid (c-SWNT-AgNPs). The hybrid is further wrapped with DNA (hybrid-DNA) and encapsulated with PVA as hybrid composite (HC). Materials were tested against human alveolar epithelial cells (A549), mouse fibroblasts cells (NIH3T3) and human bone marrow stromal cells (HS-5). The composition-sensitive physico-chemical interactions, biophysics and biomechanics of materials-treated cells are evaluated. The cell viability was improved for HC, hybrid-PVA and c SWNT when compared with SWNT and hybrid. SWNT and hybrid showed cell viability less than 60% at high dose (40 ug ml(-1)) and hybrid-PVA and HC retained 80% or more cell viability. The treatment of hybrid nanomaterials considerably changed cell morphology and intercellular interaction with respect to the composition of materials. Peculiarly, PVA-coated hybrid was found to minimize the growth of invadopodia of A549 cells, which is responsible for the proliferation of cancer cells. Surface roughness of cells increased after treatment with hybrid, where cytoplasmic regions specifically showed higher roughness. Nanoindentation results suggest that changes in biomechanics occurred owing to possible internalization of the hybrid. The changes in force spectra of treated cells indicated a possible greater interaction between the cells and hybrid with distinct stiffness and demonstrated the surface adherence and internalization of hybrid on or inside the cells. PMID- 23985741 TI - The (d)evolution of methanotrophy in the Beijerinckiaceae--a comparative genomics analysis. AB - The alphaproteobacterial family Beijerinckiaceae contains generalists that grow on a wide range of substrates, and specialists that grow only on methane and methanol. We investigated the evolution of this family by comparing the genomes of the generalist organotroph Beijerinckia indica, the facultative methanotroph Methylocella silvestris and the obligate methanotroph Methylocapsa acidiphila. Highly resolved phylogenetic construction based on universally conserved genes demonstrated that the Beijerinckiaceae forms a monophyletic cluster with the Methylocystaceae, the only other family of alphaproteobacterial methanotrophs. Phylogenetic analyses also demonstrated a vertical inheritance pattern of methanotrophy and methylotrophy genes within these families. Conversely, many lateral gene transfer (LGT) events were detected for genes encoding carbohydrate transport and metabolism, energy production and conversion, and transcriptional regulation in the genome of B. indica, suggesting that it has recently acquired these genes. A key difference between the generalist B. indica and its specialist methanotrophic relatives was an abundance of transporter elements, particularly periplasmic-binding proteins and major facilitator transporters. The most parsimonious scenario for the evolution of methanotrophy in the Alphaproteobacteria is that it occurred only once, when a methylotroph acquired methane monooxygenases (MMOs) via LGT. This was supported by a compositional analysis suggesting that all MMOs in Alphaproteobacteria methanotrophs are foreign in origin. Some members of the Beijerinckiaceae subsequently lost methanotrophic functions and regained the ability to grow on multicarbon energy substrates. We conclude that B. indica is a recidivist multitroph, the only known example of a bacterium having completely abandoned an evolved lifestyle of specialized methanotrophy. PMID- 23985742 TI - Community shifts of actively growing lake bacteria after N-acetyl-glucosamine addition: improving the BrdU-FACS method. AB - In aquatic environments, community dynamics of bacteria, especially actively growing bacteria (AGB), are tightly linked with dissolved organic matter (DOM) quantity and quality. We analyzed the community dynamics of DNA-synthesizing and accordingly AGB by linking an improved bromodeoxyuridine immunocytochemistry approach with fluorescence-activated cell sorting (BrdU-FACS). FACS-sorted cells of even oligotrophic ecosystems in winter were characterized by 16S rRNA gene analysis. In incubation experiments, we examined community shifts of AGB in response to the addition of N-acetyl-glucosamine (NAG), one of the most abundant aminosugars in aquatic systems. Our improved BrdU-FACS analysis revealed that AGB winter communities of oligotrophic Lake Stechlin (northeastern Germany) substantially differ from those of total bacteria and consist of Alpha-, Beta-, Gamma-, Deltaproteobacteria, Actinobacteria, Candidatus OP10 and Chloroflexi. AGB populations with different BrdU-fluorescence intensities and cell sizes represented different phylotypes suggesting that single-cell growth potential varies at the taxon level. NAG incubation experiments demonstrated that a variety of widespread taxa related to Alpha-, Beta-, Gammaproteobacteria, Bacteroidetes, Actinobacteria, Firmicutes, Planctomycetes, Spirochaetes, Verrucomicrobia and Chloroflexi actively grow in the presence of NAG. The BrdU-FACS approach enables detailed phylogenetic studies of AGB and, thus, to identify those phylotypes which are potential key players in aquatic DOM cycling. PMID- 23985743 TI - Community history affects the predictability of microbial ecosystem development. AB - Microbial communities mediate crucial biogeochemical, biomedical and biotechnological processes, yet our understanding of their assembly, and our ability to control its outcome, remain poor. Existing evidence presents conflicting views on whether microbial ecosystem assembly is predictable, or inherently unpredictable. We address this issue using a well-controlled laboratory model system, in which source microbial communities colonize a pristine environment to form complex, nutrient-cycling ecosystems. When the source communities colonize a novel environment, final community composition and function (as measured by redox potential) are unpredictable, although a signature of the community's previous history is maintained. However, when the source communities are pre-conditioned to their new habitat, community development is more reproducible. This situation contrasts with some studies of communities of macro-organisms, where strong selection under novel environmental conditions leads to reproducible community structure, whereas communities under weaker selection show more variability. Our results suggest that the microbial rare biosphere may have an important role in the predictability of microbial community development, and that pre-conditioning may help to reduce unpredictability in the design of microbial communities for biotechnological applications. PMID- 23985744 TI - Linkage between bacterial and fungal rhizosphere communities in hydrocarbon contaminated soils is related to plant phylogeny. AB - Phytoremediation is an attractive alternative to excavating and chemically treating contaminated soils. Certain plants can directly bioremediate by sequestering and/or transforming pollutants, but plants may also enhance bioremediation by promoting contaminant-degrading microorganisms in soils. In this study, we used high-throughput sequencing of bacterial 16S rRNA genes and the fungal internal transcribed spacer (ITS) region to compare the community composition of 66 soil samples from the rhizosphere of planted willows (Salix spp.) and six unplanted control samples at the site of a former petrochemical plant. The Bray-Curtis distance between bacterial communities across willow cultivars was significantly correlated with the distance between fungal communities in uncontaminated and moderately contaminated soils but not in highly contaminated (HC) soils (>2000 mg kg(-1) hydrocarbons). The mean dissimilarity between fungal, but not bacterial, communities from the rhizosphere of different cultivars increased substantially in the HC blocks. This divergence was partly related to high fungal sensitivity to hydrocarbon contaminants, as demonstrated by reduced Shannon diversity, but also to a stronger influence of willows on fungal communities. Abundance of the fungal class Pezizomycetes in HC soils was directly related to willow phylogeny, with Pezizomycetes dominating the rhizosphere of a monophyletic cluster of cultivars, while remaining in low relative abundance in other soils. This has implications for plant selection in phytoremediation, as fungal associations may affect the health of introduced plants and the success of co-inoculated microbial strains. An integrated understanding of the relationships between fungi, bacteria and plants will enable the design of treatments that specifically promote effective bioremediating communities. PMID- 23985745 TI - The microbial gene diversity along an elevation gradient of the Tibetan grassland. AB - Tibet is one of the most threatened regions by climate warming, thus understanding how its microbial communities function may be of high importance for predicting microbial responses to climate changes. Here, we report a study to profile soil microbial structural genes, which infers functional roles of microbial communities, along four sites/elevations of a Tibetan mountainous grassland, aiming to explore the potential microbial responses to climate changes via a strategy of space-for-time substitution. Using a microarray-based metagenomics tool named GeoChip 4.0, we showed that microbial communities were distinct for most but not all of the sites. Substantial variations were apparent in stress, N and C-cycling genes, but they were in line with the functional roles of these genes. Cold shock genes were more abundant at higher elevations. Also, gdh converting ammonium into urea was more abundant at higher elevations, whereas ureC converting urea into ammonium was less abundant, which was consistent with soil ammonium contents. Significant correlations were observed between N-cycling genes (ureC, gdh and amoA) and nitrous oxide flux, suggesting that they contributed to community metabolism. Lastly, we found by Canonical correspondence analysis, Mantel tests and the similarity tests that soil pH, temperature, NH4(+) N and vegetation diversity accounted for the majority (81.4%) of microbial community variations, suggesting that these four attributes were major factors affecting soil microbial communities. On the basis of these observations, we predict that climate changes in the Tibetan grasslands are very likely to change soil microbial community functional structure, with particular impacts on microbial N-cycling genes and consequently microbe-mediated soil N dynamics. PMID- 23985747 TI - Host-specific adaptation governs the interaction of the marine diatom, Pseudo nitzschia and their microbiota. AB - The association of phytoplankton with bacteria is ubiquitous in nature and the bacteria that associate with different phytoplankton species are very diverse. The influence of these bacteria in the physiology and ecology of the host and the evolutionary forces that shape the relationship are still not understood. In this study, we used the Pseudo-nitzschia-microbiota association to determine (1) if algal species with distinct domoic acid (DA) production are selection factors that structures the bacterial community, (2) if host-specificity and co adaptation govern the association, (3) the functional roles of isolated member of microbiota on diatom-hosts fitness and (4) the influence of microbiota in changing the phenotype of the diatom hosts with regards to toxin production. Analysis of the pyrosequencing-derived 16S rDNA data suggests that the three tested species of Pseudo-nitzschia, which vary in toxin production, have phylogenetically distinct bacterial communities, and toxic Pseudo-nitzschia have lower microbial diversity than non-toxic Pseudo-nitzschia. Transplant experiments showed that isolated members of the microbiota are mutualistic to their native hosts but some are commensal or parasitic to foreign hosts, hinting at co evolution between partners. Moreover, Pseudo-nitzschia host can gain protection from algalytic bacteria by maintaining association with its microbiota. Pseudo nitzschia also exhibit different phenotypic expression with regards to DA production, and this depends on the bacterial species with which the host associates. Hence, the influences of the microbiota on diatom host physiology should be considered when studying the biology and ecology of marine diatoms. PMID- 23985746 TI - Compartmentalized microbial composition, oxygen gradients and nitrogen fixation in the gut of Odontotaenius disjunctus. AB - Coarse woody debris is an important biomass pool in forest ecosystems that numerous groups of insects have evolved to take advantage of. These insects are ecologically important and represent useful natural analogs for biomass to biofuel conversion. Using a range of molecular approaches combined with microelectrode measurements of oxygen, we have characterized the gut microbiome and physiology of Odontotaenius disjunctus, a wood-feeding beetle native to the eastern United States. We hypothesized that morphological and physiological differences among gut regions would correspond to distinct microbial populations and activities. In fact, significantly different communities were found in the foregut (FG), midgut (MG)/posterior hindgut (PHG) and anterior hindgut (AHG), with Actinobacteria and Rhizobiales being more abundant toward the FG and PHG. Conversely, fermentative bacteria such as Bacteroidetes and Clostridia were more abundant in the AHG, and also the sole region where methanogenic Archaea were detected. Although each gut region possessed an anaerobic core, micron-scale profiling identified radial gradients in oxygen concentration in all regions. Nitrogen fixation was confirmed by (15)N2 incorporation, and nitrogenase gene (nifH) expression was greatest in the AHG. Phylogenetic analysis of nifH identified the most abundant transcript as related to Ni-Fe nitrogenase of a Bacteroidetes species, Paludibacter propionicigenes. Overall, we demonstrate not only a compartmentalized microbiome in this beetle digestive tract but also sharp oxygen gradients that may permit aerobic and anaerobic metabolism to occur within the same regions in close proximity. We provide evidence for the microbial fixation of N2 that is important for this beetle to subsist on woody biomass. PMID- 23985748 TI - Shotgun metagenomics indicates novel family A DNA polymerases predominate within marine virioplankton. AB - Virioplankton have a significant role in marine ecosystems, yet we know little of the predominant biological characteristics of aquatic viruses that influence the flow of nutrients and energy through microbial communities. Family A DNA polymerases, critical to DNA replication and repair in prokaryotes, are found in many tailed bacteriophages. The essential role of DNA polymerase in viral replication makes it a useful target for connecting viral diversity with an important biological feature of viruses. Capturing the full diversity of this polymorphic gene by targeted approaches has been difficult; thus, full-length DNA polymerase genes were assembled out of virioplankton shotgun metagenomic sequence libraries (viromes). Within the viromes novel DNA polymerases were common and found in both double-stranded (ds) DNA and single-stranded (ss) DNA libraries. Finding DNA polymerase genes in ssDNA viral libraries was unexpected, as no such genes have been previously reported from ssDNA phage. Surprisingly, the most common virioplankton DNA polymerases were related to a siphovirus infecting an alpha-proteobacterial symbiont of a marine sponge and not the podoviral T7-like polymerases seen in many other studies. Amino acids predictive of catalytic efficiency and fidelity linked perfectly to the environmental clades, indicating that most DNA polymerase-carrying virioplankton utilize a lower efficiency, higher fidelity enzyme. Comparisons with previously reported, PCR-amplified DNA polymerase sequences indicated that the most common virioplankton metagenomic DNA polymerases formed a new group that included siphoviruses. These data indicate that slower-replicating, lytic or lysogenic phage populations rather than fast replicating, highly lytic phages may predominate within the virioplankton. PMID- 23985749 TI - Physiologic and metagenomic attributes of the rhodoliths forming the largest CaCO3 bed in the South Atlantic Ocean. AB - Rhodoliths are free-living coralline algae (Rhodophyta, Corallinales) that are ecologically important for the functioning of marine environments. They form extensive beds distributed worldwide, providing a habitat and nursery for benthic organisms and space for fisheries, and are an important source of calcium carbonate. The Abrolhos Bank, off eastern Brazil, harbors the world's largest continuous rhodolith bed (of ~21,000 km(2)) and has one of the largest marine CaCO3 deposits (producing 25 megatons of CaCO3 per year). Nevertheless, there is a lack of information about the microbial diversity, photosynthetic potential and ecological interactions within the rhodolith holobiont. Herein, we performed an ecophysiologic and metagenomic analysis of the Abrolhos rhodoliths to understand their microbial composition and functional components. Rhodoliths contained a specific microbiome that displayed a significant enrichment in aerobic ammonia oxidizing betaproteobacteria and dissimilative sulfate-reducing deltaproteobacteria. We also observed a significant contribution of bacterial guilds (that is, photolithoautotrophs, anaerobic heterotrophs, sulfide oxidizers, anoxygenic phototrophs and methanogens) in the rhodolith metagenome, suggested to have important roles in biomineralization. The increased hits in aromatic compounds, fatty acid and secondary metabolism subsystems hint at an important chemically mediated interaction in which a functional job partition among eukaryal, archaeal and bacterial groups allows the rhodolith holobiont to thrive in the global ocean. High rates of photosynthesis were measured for Abrolhos rhodoliths (52.16 MUmol carbon m(-2 )s(-1)), allowing the entire Abrolhos rhodolith bed to produce 5.65 * 10(5) tons C per day. This estimate illustrates the great importance of the Abrolhos rhodolith beds for dissolved carbon production in the South Atlantic Ocean. PMID- 23985750 TI - Bacterial genome replication at subzero temperatures in permafrost. AB - Microbial metabolic activity occurs at subzero temperatures in permafrost, an environment representing ~25% of the global soil organic matter. Although much of the observed subzero microbial activity may be due to basal metabolism or macromolecular repair, there is also ample evidence for cellular growth. Unfortunately, most metabolic measurements or culture-based laboratory experiments cannot elucidate the specific microorganisms responsible for metabolic activities in native permafrost, nor, can bulk approaches determine whether different members of the microbial community modulate their responses as a function of changing subzero temperatures. Here, we report on the use of stable isotope probing with (13)C-acetate to demonstrate bacterial genome replication in Alaskan permafrost at temperatures of 0 to -20 degrees C. We found that the majority (80%) of operational taxonomic units detected in permafrost microcosms were active and could synthesize (13)C-labeled DNA when supplemented with (13)C acetate at temperatures of 0 to -20 degrees C during a 6-month incubation. The data indicated that some members of the bacterial community were active across all of the experimental temperatures, whereas many others only synthesized DNA within a narrow subzero temperature range. Phylogenetic analysis of (13)C-labeled 16S rRNA genes revealed that the subzero active bacteria were members of the Acidobacteria, Actinobacteria, Chloroflexi, Gemmatimonadetes and Proteobacteria phyla and were distantly related to currently cultivated psychrophiles. These results imply that small subzero temperature changes may lead to changes in the active microbial community, which could have consequences for biogeochemical cycling in permanently frozen systems. PMID- 23985751 TI - [Role of the surgical pathologist for tissue management in oncology]. AB - Currently, the increasing number of ancillary methods to be performed from tumoral tissues in a pathology laboratory determines the necessity to have an optimal strategy for tissue management. The size of tissue samples dedicated for a pathological examination becomes smaller and smaller, as the diagnosis can be made with non or less invasive methods. However, the samples should also allow to provide the prognosis as well as to realise biological molecular testing in order to found a genomic alteration. Thus, it is critical to think about how to share and to pool the different expertises and abilities in a pathology laboratory in order to optimize the achievement of the different ancillary methods. Thus, following the morphological study made in hematoxylin-eosin staining, it is necessary to preempt the number of immunohistochemical and in situ hybridization studies, which will be potentially done from the tissue samples. Moreover, since the genomic alteration detection in tumours is mainly performed from DNA extracted from tissues, it is necessary to take in account some numerous parameters, in particular the nature and the time of fixation, the percentage of tumour cells, the presence of necrotic area, the percentage of inflammatory cells and the sample size. The strategy for an optimal tissue management in an oncology pathology laboratory is critical and takes part of the different steps allowing to get an accreditation according the ISO15189 norm. PMID- 23985752 TI - Chemokines mRNA expression in relation to the Macrophage Migration Inhibitory Factor (MIF) mRNA and Vascular Endothelial Growth Factor (VEGF) mRNA expression in the microenvironment of endometrial cancer tissue and normal endometrium: a pilot study. AB - Tumor microenvironment inflammatory cells play a major role in cancer progression. Among these, the Tumor Associated Macrophages (TAMs) infiltration depends on the kind of chemokine, cytokines and growth factors secreted by the tumor cells and by the stroma in response to the cancer invasion. TAMs have been found to promote anti-tumor response in early stages and to stimulate neovascularization and metastases in advanced disease. In the microenvironment chemo-attractants of many human cancers, MIF and VEGF correlate with an increased TAMs recruitment. In addition, MIF enhances tumor cells metastases by modulating the immune responses and by promoting the angiogenesis related to VEGF. On the contrary the inhibition of MIF can lead to cell cycle arrest and apoptosis. Some chemokines (e.g. CXCL12, CXCL11, CXCL8) and their receptors, thanks to their ability to modulate migration and proliferation, are involved in the angiogenetic process. In this study we compared the expression of MIF mRNA with VEGF mRNA expression and with mRNA expression of other chemokines related to neo angiogenesis, such as CXCL12, CXCL11, CXCL8 and CXCR4, in human endometrial cancer tissue (EC) and normal endometrium (NE). Fresh samples of EC tissue and NE were extracted from 15 patients with FIGO stage I-III undergoing primary surgery. Some of the tissue was sent for histology and part of it was treated with RNA later and stored at -80 degrees C. Four patients dropped out. A significant up regulation of MIF mRNA in EC tissue versus NE samples (P=0.01) was observed in all 11 patients. The MIF mRNA over-expression was coincident with a VEGF mRNA overexpression in 54% of patients (P=NS). MIF mRNA was inversely related to CXCL12 mRNA expression (P=0.01). MIF over-expression was significantly related to low grading G1-2 (P=0.01), endometrial type I (P=0.05), no lymphovascular spaces invasion (P=0.01) and 3years DFS (P=0.01). As reported in previous studies on patients with breast cancer, our data suggest that the up-regulation of MIF in patients with endometrial cancer might be related to the inhibition of distant and lymphatic spread. PMID- 23985753 TI - Myristoylated derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (stavudine) bi-functional prodrugs with potent anti-HIV-1 activity and low cytotoxicity. AB - BACKGROUND: To improve in vitro antiviral activity and selectivity of stavudine (d4T), a range of its bi-functional prodrugs, 5'-O-myristoylated derivatives, have been synthesized. METHODS: Stavudine 5'-O-myristoylated esters were synthesized using modified Parang's procedure. The cytotoxicity and anti-HIV activity was evaluated in the established MT-4 cell line. The level of p24 protein in culture medium was assayed, and EC50 and EC90 values were determined. RESULTS: Excellent anti-HIV activity was obtained for stavudine derivatives 2',3' didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine, 2',3'-didehydro 2',3'-dideoxy-5'-O-(12-thioethyldodecanoyl) thymidine and 5'-O-(12 azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine with C10 and C11 alkyl chains bearing thioethyl- and azido- substituents. These prodrugs were more potent than the parent stavudine, as is clear from their EC50 values: 2',3' didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine (R=CO(CH2)10SC2H5, EC50 0.06 MUM), 2',3'-didehydro-2',3'-dideoxy-5'-O-(12 thioethyldodecanoyl) thymidine (R=CO(CH2)11SC2H5, EC50 0.09 MUM) and 5'-O-(12 azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine (R=CO(CH2)11N3, EC50 0.06 MUM), while 50% cytotoxic concentration was >16.65 MUM, >7.5 MUM and >18.53 MUM, respectively. CONCLUSIONS: Overall data demonstrate that compounds 2',3' didehydro-2',3'-dideoxy-5'-O-(11-thioethylundecanoyl) thymidine, 2',3'-didehydro 2',3'-dideoxy-5'-O-(12-thioethyldodecanoyl) thymidine and 5'-O-(12 azidododecanoyl)-2',3'-didehydro-2',3'-dideoxythymidine are very potent and selective anti-HIV agents and could be useful in treatment of HIV infections of the central nervous system. PMID- 23985754 TI - Successful treatment of an intra-pelvic fungal pseudomycetoma causing constipation and hypercalcaemia in a Persian cat. AB - This case report describes the successful treatment of a Persian cat diagnosed with intra-abdominal fungal pseudomycetoma causing hypercalcaemia and constipation due to an extra-luminal mechanical obstruction of the colon. Treatment included surgical excision, supportive care and itraconazole for 6 months. PMID- 23985755 TI - Reference values and repeatability of buccal mucosal bleeding time in healthy sedated cats. AB - Bleeding time is a screening test for the evaluation of primary haemostasis. As there is currently limited information on the reference interval (RI) and repeatability of the test in the cat compared with the dog, the purpose of the study was to establish the RI of buccal mucosa bleeding time (BMBT) in healthy cats and to investigate the intra-observer repeatability of the test. Fifty-six cats were prospectively enrolled in the study. The animals were deemed to be healthy based on history, physical examination, complete blood count, serum biochemistry, and negative serological testing for feline leukaemia and immunodeficiency viruses. All cats were sedated with ketamine, dexmedetomidine and morphine, and the BMBT was sequentially measured in the left and right exposed buccal mucosa following a standardised incision made by a commercially available, disposable, bleeding time device. The mean BMBT was 58.6 s and the RIs ranged from 34 to 105 s (Bootstrap estimation). The intra-observer repeatability was up to 87 s (Bland-Altman plot). The results of this study imply that the combination of ketamine, dexmedetomidine and morphine is a safe and useful sedative protocol allowing for the reliable measurement of BMBT in the cat. The RI of feline BMBT may range from 34 to 105 s and the BMBT may differ by up to 87 s for any two consecutive readings for an individual cat. PMID- 23985756 TI - Finding the balance. PMID- 23985757 TI - The Top Ten HRT Compound Preparations. PMID- 23985758 TI - Wilson's Syndrome and T3 Therapy-A Clinical Guide to Safe and Effective Patient Management. PMID- 23985759 TI - Assessment and management of thermoregulation. PMID- 23985760 TI - Preventing leakage in oil-filled capsules. PMID- 23985761 TI - Feline urologic syndrome and diet formulation. PMID- 23985762 TI - Chemical facial peel formulations: an overview. PMID- 23985763 TI - Tamoxifen citrate-a potential therapy for the treatment of keloids. PMID- 23985764 TI - Compounding for athletes: successful sports compounds. PMID- 23985765 TI - The basics of compounding: compounding gels. PMID- 23985766 TI - In vitro studies on the release of morphine sulfate from compounded slow-release morphine-sulfate capsules. AB - Morphine sulfate is a commonly prescribed drug for the relief of pain. This study investigated the dissolution profile of extemporaneously prepared slow-release morphine-sulfate capsules and MS Contin (Purdue Frederick, Norwalk, CT). Extemporaneously prepared capsules obtained from one pharmacist were compared with MS Contin tablets. In addition, we compared capsules prepared by 15 different pharmacists and three different batches prepared by the same phaarmacist. A dissolution test was used to generate the dissolution profile for drug products. The compounded capsules demonstrated a slow-release profile that was similar to the commercial preparation except that the morphine sulfate was released at a faster rate. The zero-order dissolution rate constant (k0, milligrams/hour) was calculated from the dissolution profiles. Statistical analysis of k0 showed that caapsules prepared extemporaneously by pharmacist one showed a faster dissolution compared to MS Contin (p=0.0368); the difference was a rate of 0.81 mg/hour during the first four hours. When variability among compounding pharmacists was compared, only one batch of compounded capsules prepared from 15 different pharmacies showed a significantly different rate of morphine release. When reproducibility by a single pharmacist was examined, capsules showed some variation from batch to batch (p=0.05). Although variation was seen from one pharmacy to another and even between different batches made by the same pharmacist, the compounded capsules showed a remarkably consistent in vitro slow-release profile. PMID- 23985767 TI - Stability of Dobutamine Hydrochloride 4mg/mL in 5% Dextrose Injection at 5 and 23 deg C. AB - The stability of dobutamine hydrochloride 4 mg/mL in 5% dextrose injection has been studied using a stability-indicating, high-performance liquid chromatography assay method. The admixture injections were stable for 30 days at 5 and 23 deg C. Concentrations ranged between 98.5% and 102.6% for the room-temperature samples, and 99.6% and 101.8% for the refrigerated samples, of the initial mean concentrations. The standard curves demonstrated linearity (r2>.999). Variations within and between days were less than 3%. None of the samples appeared to form a visible precipitate or changed in color or clarity and the pH of the samples remained between 3.5 and 3.7. PMID- 23985768 TI - Physical Compatibility of Calcium Acetate and Potassium Phosphates in Parenteral Nutrition Solutions Containing Aminosyn II. AB - Numerous factors have been identified that influence the amount of calcium and phosphates that can remain in solution or will precipitate from parenteral nutrition solutions. Two of the most important such factors are the specific formulation of the amino acid source and the salt form of the calcium source. The purpose of this study was to evaluate the physical compatibility of calcium (as acetate) and potassium phophates in Aminosyn II-based parenteral nutrition solutions. Five representative core parenteral nutrition formulations containing Aminosyn II 2% to 5% were evaluated. Varying amounts of calcium acetate and potassium phosphates were added to samples of the core formulations to identify the concentrations at which precipitation just began to occur. A total of five series of concentrations was tested wiht maxima of calcium 40 mEq/L and phosphates 40 mM/L. The samples were evaluated by visual observation with the unaided eye and by use of a Tyndall beam to accentuate the visibility of small particles and low-level turbidity. For samples not exhibiting visible particles or haze, the turbidity and particle content were measured electronically. Evaluations were performed initially during the first 15 minutes after mixing and after 48 hours of storage at 23 deg and 37 deg C. The precipitation potential of calcium and phosphates in the five representative parenteral nutrition solutions containing Aminosyn II at a a variety of concentrations has been evaluated over a broad range of concentrations has been evaluated over a broad rage of concentrations. The results are presented in tabular form and were used to determine the boundary between compatibility and incompatibility in each of the five core parenteral nutrtion formulations. The boundary lines or compatibility curves were constructed for each of the formulations and are presented graphically. PMID- 23985769 TI - Optimal method to stimulate cytokine production and its use in immunotoxicity assessment. AB - Activation of lymphocytes can effectively produce a large amount of cytokines. The types of cytokines produced may depend on stimulating reagents and treatments. To find an optimal method to stimulate cytokine production and evaluate its effect on immunotoxicity assessments, the authors analyzed production of IL-2, IL-4, IL-6, IL-10, IL-13, IFN-gamma, TNF-alpha, GM-CSF, RANTES and TGF-beta in undiluted rat whole blood culture (incubation for 0, 2, 4, 6, 8 or 10 h) with different concentrations of PMA/ionomycin, PHA, Con A, LPS and PWM. We also evaluated the effects of cyclosporin A and azathioprine on cytokine production. The results revealed a rapid increase of IL-2, IFN-gamma, TNF-alpha, RANTES and TGF-beta secretion within 6 h after stimulation with 25 ng/mL PMA and 1 MUg/mL ionomycin. The inhibition of these cytokine profiles reflected the effects of immunosuppressants on the immune system. Therefore, the results of this is study recommend the detection of cytokine profiles in undiluted whole blood stimulated 6 h with 25 ng/mL PMA and 1 MUg/mL ionomycin as a powerful immunotoxicity assessment method. PMID- 23985770 TI - Neurotoxicity of acrylamide in exposed workers. AB - Acrylamide (ACR) is a water-soluble chemical used in different industrial and laboratory processes. ACR monomer is neurotoxic in humans and laboratory animals. Subchronic exposure to this chemical causes neuropathies, hands and feet numbness, gait abnormalities, muscle weakness, ataxia, skin and in some cases, cerebellar alterations. ACR neurotoxicity involves mostly the peripheral but also the central nervous system, because of damage to the nerve terminal through membrane fusion mechanisms and tubulovescicular alterations. Nevertheless, the exact action mechanism is not completely elucidated. In this paper we have reviewed the current literature on its neurotoxicity connected to work-related ACR exposure. We have analyzed not only the different pathogenetic hypotheses focusing on possible neuropathological targets, but also the critical behavior of ACR poisoning. In addition we have evaluated the ACR-exposed workers case studies. Despite all the amount of work which have being carried out on this topic more studies are necessary to fully understand the pathogenetic mechanisms, in order to propose suitable therapies. PMID- 23985771 TI - Population-based study of smoking behaviour throughout pregnancy and adverse perinatal outcomes. AB - There has been limited research addressing whether behavioural change in relation to smoking is maintained throughout pregnancy and the effect on perinatal outcomes. A cohort study addressed lifestyle behaviours of 907 women who booked for antenatal care and delivered in a large urban teaching hospital in 2010-2011. Adverse perinatal outcomes were compared for "non-smokers", "ex-smokers" and "current smokers". Of the 907 women, 270 (30%) reported smoking in the six months prior to pregnancy, and of those 160 (59%) had stopped smoking and 110 (41%) continued to smoke at the time of the first antenatal visit. There was virtually no change in smoking behaviour between the first antenatal visit and the third trimester of pregnancy. Factors associated with continuing to smoke included unplanned pregnancy (OR 1.9; 95% CI 1.3, 2.9), alcohol use (OR 3.4; 95% CI 2.1, 6.0) and previous illicit drug use (OR 3.6; 95% CI 2.1, 6.0). Ex-smokers had similar perinatal outcomes to non-smokers. Current smoking was associated with an average reduction in birth weight of 191 g (95% CI -294, -88) and an increased incidence of intrauterine growth restriction (24% versus 13%, adjusted OR 1.39 (95% CI 1.06, 1.84). Public Health campaigns emphasise the health benefits of quitting smoking in pregnancy. The greatest success appears to be pre-pregnancy and during the first trimester where women are largely self-motivated to quit. PMID- 23985772 TI - Family process and peer influences on substance use by adolescents. AB - This study explores the association of family process and peer influences with risk behaviors of adolescents. A total of 805 students were recruited from secondary schools. The results showed that adolescents who have parents who are "authoritarian" (OR = 1.856) were more likely to smoke. Adolescents who have conflicts with their parents (OR = 1.423) were more likely to drink. Those who have parents who are "permissive" were less likely to drink (OR = 0.885). Having friends who smoked (OR = 5.446) or drank (OR = 1.894), and friends' invitation to smoke (OR = 10.455) or drink (OR = 11.825) were the dominant contributors to adolescent smoking and drinking. Interventions are needed that recognize the strength of the parent-child relationship, as well as strengthen family functioning through improved interpersonal, parenting, and monitoring skills. PMID- 23985774 TI - Anti-invasion effect of crebanine and O-methylbulbocapnine from Stephania venosa via down-regulated matrix metalloproteinases and urokinase plasminogen activator. AB - The alkaloids isolated from Stephania venosa (S. venosa) have been shown to inhibit the proliferation and to induce the apoptosis of cancer cells. However, the anti-metastatic effect of the alkaloids on cancer cell invasion is unknown. In this study, we investigated the anti-invasive properties of four alkaloids from S. venosa, crebanine (CN), O-methylbulbocapnine (OMBC), tetrahydropalmatine (THP), and N-methyltetrahydropalmatine (NMTHP), in HT1080 human fibrosacroma cells. Treatment of the cells with 15 ug/mL of CN and OMBC reduced the chemo invasion of HT1080 cells to 45 and 50%, respectively, whereas THP and NMTHP had a negative effect. On the other hand, CN and OMBC had no effect on cell migration. Matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA) are the extracellular matrix (ECM) degradation enzymes that play an important role in cancer cell metastasis. Results from zymography and western blot analysis showed that CN and OMBC comparatively reduced MMP-2, MMP-9, MT1-MMP and uPA expression in a dose-dependent manner. However, CN and OMBC had no effect on the activity of collagenase, MMP-2 and MMP-9. We also found that CN and OMBC reduced the nuclear translocation and DNA binding activity of nuclear factor kappa B (NF-kappaB), which is the expressed mediator of ECM degradation enzymes. These findings demonstrated that CN and OMBC mediated HT1080 cell invasion by the reduction of MMP-2, MMP-9, uPA and MT1-MMP expression, possibly by targeting of NF-kappaB signaling pathway in the HT1080 cells. PMID- 23985775 TI - Predictability of drug release from water-insoluble polymeric matrix tablets. AB - The purpose of this study was to extend the predictability of an established solution of Fick's second law of diffusion with formulation-relevant parameters and including percolation theory. Kollidon SR (polyvinyl acetate/polyvinylpyrrolidone, 80/20 w/w) matrix tablets with various porosities (10-30% v/v) containing model drugs with different solubilities (Cs=10-170 mg/ml) and in different amounts (A=10-90% w/w) were prepared by direct compression and characterized by drug release and mass loss studies. Drug release was fitted to Fick's second law to obtain the apparent diffusion coefficient. Its changes were correlated with the total porosity of the matrix and the solubility of the drug. The apparent diffusion coefficient was best described by a cumulative normal distribution over the range of total porosities. The mean of the distribution coincided with the polymer percolation threshold, and the minimum and maximum of the distribution were represented by the diffusion coefficient in pore-free polymer and in aqueous medium, respectively. The derived model was verified, and the applicability further extended to a drug solubility range of 10-1000 mg/ml. The developed mathematical model accurately describes and predicts drug release from Kollidon SR matrix tablets. It can efficiently reduce experimental trials during formulation development. PMID- 23985773 TI - Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms. AB - Reactive oxygen or nitrogen species (ROS, RNS) and oxidative stress in the respiratory system increase the production of mediators of pulmonary inflammation and initiate or promote mechanisms of carcinogenesis. The lungs are exposed daily to oxidants generated either endogenously or exogenously (air pollutants, cigarette smoke, etc.). Cells in aerobic organisms are protected against oxidative damage by enzymatic and non-enzymatic antioxidant systems. Recent epidemiologic investigations have shown associations between increased incidence of respiratory diseases and lung cancer from exposure to low levels of various forms of respirable fibers and particulate matter (PM), at occupational or urban air polluting environments. Lung cancer increases substantially for tobacco smokers due to the synergistic effects in the generation of ROS, leading to oxidative stress and inflammation with high DNA damage potential. Physical and chemical characteristics of particles (size, transition metal content, speciation, stable free radicals, etc.) play an important role in oxidative stress. In turn, oxidative stress initiates the synthesis of mediators of pulmonary inflammation in lung epithelial cells and initiation of carcinogenic mechanisms. Inhalable quartz, metal powders, mineral asbestos fibers, ozone, soot from gasoline and diesel engines, tobacco smoke and PM from ambient air pollution (PM10 and PM2.5) are involved in various oxidative stress mechanisms. Pulmonary cancer initiation and promotion has been linked to a series of biochemical pathways of oxidative stress, DNA oxidative damage, macrophage stimulation, telomere shortening, modulation of gene expression and activation of transcription factors with important role in carcinogenesis. In this review we are presenting the role of ROS and oxidative stress in the production of mediators of pulmonary inflammation and mechanisms of carcinogenesis. PMID- 23985777 TI - A rechargeable non-aqueous Mg-O2 battery. AB - We propose a catalytic cycle using the iodine-dimethylsulfoxide (I2-DMSO) complex for the realization of secondary Mg-O2 batteries. We have demonstrated that the Mg-O2 battery incorporating an I2-DMSO complex electrolyte showed evidence of being rechargeable. PMID- 23985776 TI - Dynamic interaction between membrane-bound full-length cytochrome P450 and cytochrome b5 observed by solid-state NMR spectroscopy. AB - Microsomal monoxygenase enzymes of the cytochrome-P450 family are found in all biological kingdoms, and play a central role in the breakdown of metabolic as well as xenobiotic, toxic and 70% of the drugs in clinical use. Full-length cytochrome-b5 has been shown to be important for the catalytic activity of cytochrome-P450. Despite the significance in understanding the interactions between these two membrane-associated proteins, only limited high-resolution structural information on the full-length cytochrome-P450 and the cytochromes-b5 P450 complex is available. Here, we report a structural study on a functional ~72 kDa cytochromes-b5-P450 complex embedded in magnetically-aligned bicelles without having to freeze the sample. Functional and solid-state NMR (Nuclear Magnetic Resonance) data reveal interactions between the proteins in fluid lamellar phase bilayers. In addition, our data infer that the backbone structure and geometry of the transmembrane domain of cytochrome-b5 is not significantly altered due to its interaction with cytochrome-P450, whereas the mobility of cytochrome-b5 is considerably reduced. PMID- 23985778 TI - Current evidence for effectiveness of interventions for cubital tunnel syndrome, radial tunnel syndrome, instability, or bursitis of the elbow: a systematic review. AB - OBJECTIVE: To provide an evidence-based overview of the effectiveness of interventions for 4 nontraumatic painful disorders sharing the anatomic region of the elbow: cubital tunnel syndrome, radial tunnel syndrome, elbow instability, and olecranon bursitis. METHODS: The Cochrane Library, PubMed, Embase, PEDro, and CINAHL were searched to identify relevant reviews and randomized clinical trials (RCTs). Two reviewers independently extracted data and assessed the quality of the methodology. A best-evidence synthesis was used to summarize the results. RESULTS: One systematic review and 6 RCTs were included. For the surgical treatment of cubital tunnel syndrome (1 review, 3 RCTs), comparing simple decompression with anterior ulnar nerve transposition, no evidence was found in favor of either one of these. Limited evidence was found in favor of medial epicondylectomy versus anterior transposition and for early postoperative therapy versus immobilization. No evidence was found for the effect of local steroid injection in addition to splinting. No RCTs were found for radial tunnel syndrome. For olecranon bursitis (1 RCT), limited evidence for effectiveness was found for methylprednisolone acetate injection plus naproxen. Concerning elbow instability, including 2 RCTs, one showed that nonsurgical treatment resulted in similar results compared with surgery, whereas the other found limited evidence for the effectiveness in favor of early mobilization versus 3 weeks of immobilization after surgery. DISCUSSION: In this review no, or at best, limited evidence was found for the effectiveness of nonsurgical and surgical interventions to treat painful cubital tunnel syndrome, radial tunnel syndrome, elbow instability, or olecranon bursitis. Well-designed and well-conducted RCTs are clearly needed in this field. PMID- 23985779 TI - Relationship between bathing habits and the serum lipid profile among Japanese Americans. PMID- 23985780 TI - Synergistic anti-breast cancer effect of a combined treatment with the methyl donor S-adenosyl methionine and the DNA methylation inhibitor 5-aza-2' deoxycytidine. AB - DNA-demethylating agents activate tumor suppressor genes that are silenced by DNA methylation in cancer and are therefore emerging as a novel approach to cancer therapy. 5-azacytidine (VIDAZA), the first representative of this class of drugs was approved for treatment of myelodysplastic syndromes and is currently being tested on other cancers including solid tumors. However, 5-azacytidine or its deoxy-analog, 5-aza-2'-deoxycytidine (5-azaCdR) could also induce methylated prometastatic genes by DNA demethylation and induce cancer cell invasiveness. Since 5-azacytidine is a potent cancer growth inhibitor, we tested whether combining it with a DNA-methylating agent, the methyl donor S-adenosyl methionine (SAM), would block the adverse demethylating activity of 5-azaCdR while maintaining its growth suppression effects. We show here using several invasive and non-invasive breast cancer cell lines that SAM inhibits global- and gene specific demethylation induced by 5-azaCdR, prevents 5-azaCdR activation of prometastatic genes uPA and MMP2, resulting in inhibition of cell invasiveness while augmenting the growth inhibitory effects of 5-azaCdR and its effects on tumor suppressor genes. Combination of drugs acting on the DNA methylation machinery at different levels is proposed as a new strategy for epigenetic therapy of cancer. PMID- 23985781 TI - Circulating C-reactive protein and colorectal cancer risk: a report from the Shanghai Men's Health Study. AB - Chronic inflammation has been implicated in the pathogenesis of colorectal cancer. The objective of this study was to evaluate the association of prediagnostic circulating levels of C-reactive protein (CRP), a biomarker of systemic inflammation, with subsequent development of colorectal cancer. Prediagnostic plasma CRP levels were examined among 288 colorectal cancer cases and 576 individually-matched controls nested within the Shanghai Men's Health Study (2002-06), a population-based cohort study of 61 482 Chinese men. The association between CRP levels and colorectal cancer risk was investigated. Baseline plasma CRP levels were 53% higher among men who subsequently developed colorectal cancer than among those who remained free of the disease (1.15 versus 0.75 MUg/ml; P < 0.001). Multivariate analyses showed a dose-dependent relationship between CRP and colorectal cancer risk (P trend = 0.003); men in the highest tertile (CRP > 1.19 MUg/ml) had 1.88-fold (95% confidence interval (CI): 1.24-2.86) increased odds of developing colorectal cancer compared with men in the lowest tertile (CRP < 0.45 MUg/ml). The association was only significant for colon cancer, when cancer site was considered, and was predominantly seen for cases diagnosed within 4 years of blood collection; adjusted odds ratios for the highest versus the lowest tertiles were 3.28 (95% CI: 1.28-8.37), 3.68 (95% CI: 1.62-8.38) and 1.05 (95% CI: 0.56-1.97), respectively, for cases diagnosed <2, 2 4 and >4 years after blood collection. The findings from our study suggest that circulating CRP level is positively associated with colorectal cancer risk in Chinese men, and this association, at least in part, is explained by inflammation related cancerous or precancerous processes. PMID- 23985782 TI - Chronic administration of the methylxanthine propentofylline impairs reinstatement to cocaine by a GLT-1-dependent mechanism. AB - In recent years, interactions between neurons and glia have been evaluated as mediators of neuropsychiatric diseases, including drug addiction. In particular, compounds that increase expression of the astroglial glutamate transporter GLT-1 (N-acetylcysteine and ceftriaxone) can decrease measures of drug seeking. However, it is unknown whether the compounds that influence broad measures of glial physiology can influence behavioral measures of drug relapse, nor is it clear whether the upregulated GLT-1 is functionally important for suppressing of drug seeking. To address these questions, we sought to determine whether the glial modulator and neuroprotective agent propentofylline (PPF) modifies drug seeking in rats using a reinstatement model of cocaine relapse. We found that 7 days of chronic (but not acute) administration of PPF significantly decreased both cue- and cocaine-induced reinstatement of cocaine seeking. We next determined whether the effect of systemic PPF on reinstatement depended upon its ability to restore expression of GLT-1 in the nucleus accumbens. PPF restored the cocaine-induced decrease in GLT-1 in the accumbens core; then, using an antisense strategy against glutamate transporter GLT-1, we found that restored transporter expression was necessary for PPF to inhibit cue-primed cocaine seeking. These findings indicate that modulating glial physiology with atypical xanthine derivatives like PPF is a potential avenue for developing new medications for cocaine abuse, and support the hypothesis that neuron-glial interactions contribute to mechanisms of psychostimulant addiction, particularly via expression and function of astroglial glutamate transporters. PMID- 23985783 TI - Panic disorder and serotonin reuptake inhibitors predict coupling of cortical and cardiac activity. AB - Panic attacks, the cardinal symptom of panic disorder (PD), are characterized by intense physiological reactions including accelerated heart activity. Although cortical processes are thought to trigger and potentiate panic attacks, it is unknown whether individuals with PD have a general tendency to show elevated cortico-cardiac interactions, which could predispose them for brain-driven modulations of heart activity during panic. Consistent with this hypothesis, serotonin, a highly relevant neurotransmitter for panic and PD presumably affects the cortical control of the heart. The current study thus aimed to test whether PD and serotonin reuptake inhibitor (SRI) intake are related to cortico-cardiac interactions in the absence of acute panic. Human participants with PD (N=22), major depression (MD, clinical control group, N=21) or no psychiatric diagnosis (healthy control group, N=23) performed a gambling task. To measure cortico cardiac coupling, the within-subject covariation of single-trial EEG after feedback presentation and subsequent changes in heart period was determined. As in prior studies, there was a significant time-lagged covariation of EEG and heart activity indicating that trial-by-trial fluctuations of feedback-evoked EEG amplitude determined how much heart activity accelerated seconds later. Importantly, this covariation pattern was significantly potentiated in PD vs control participants. Moreover, concurrent SRI intake further augmented brain heart covariation in individuals with PD and MD. The present findings demonstrate that PD and serotonin are associated with altered brain-heart interactions in a non-panic situation. Future work should clarify whether brain-heart coupling has a causal role in PD, for example by facilitating panic attacks. PMID- 23985784 TI - Island biogeography, the effects of taxonomic effort and the importance of island niche diversity to single-island endemic species. AB - Island biogeography theory is fundamentally reliant on measuring the number of species per island and hence has taxonomy at its foundation. Yet as a metric used in tests of the theory, island species richness (S) has varied with time according to the level of taxonomic effort (a function of the rate of finding and describing species). Studies using a derivative of S, single-island endemic species richness (SIE S), may be prone to change in taxonomic effort. Decreases or increases in species numbers resulting from taxonomic revision or increased sampling are likely to have a large effect on values of SIE S, as they tend to be smaller than total S for the same island. Using simple biogeography models, we analysed estimates of SIE S in plants, land snails, beetles, and fungi from comprehensive data sets for eight island groups, produced species accumulation curves and applied Bayesian regression over five time periods. Explanatory power differed across taxa, but area and island age were not always the best explanatory variables, and niche diversity appeared to be important. Changing levels of SIE S over time had different effects on models with different taxa and between island archipelagos. The results indicated that the taxonomic effort that determines SIE S is important. However, as this cannot often be quantified, we suggest Bayesian approaches should be more useful than frequentist methods in evaluating SIE S in island biogeography theory. Fundamentally, the article highlights the importance of taxonomy to theoretical biogeography. PMID- 23985785 TI - Poor fit to the multispecies coalescent is widely detectable in empirical data. AB - Model checking is a critical part of Bayesian data analysis, yet it remains largely unused in systematic studies. Phylogeny estimation has recently moved into an era of increasingly complex models that simultaneously account for multiple evolutionary processes, the statistical fit of these models to the data has rarely been tested. Here we develop a posterior predictive simulation-based model check for a commonly used multispecies coalescent model, implemented in *BEAST, and apply it to 25 published data sets. We show that poor model fit is detectable in the majority of data sets; that this poor fit can mislead phylogenetic estimation; and that in some cases it stems from processes of inherent interest to systematists. We suggest that as systematists scale up to phylogenomic data sets, which will be subject to a heterogeneous array of evolutionary processes, critically evaluating the fit of models to data is an analytical step that can no longer be ignored. PMID- 23985786 TI - "Assisted" reshaping of the fetal heart? PMID- 23985787 TI - Assisted reproductive technologies are associated with cardiovascular remodeling in utero that persists postnatally. AB - BACKGROUND: Assisted reproductive technologies (ARTs) have been shown to be associated with general vascular dysfunction in late childhood. However, it is unknown whether cardiac remodeling is also present and if these changes already manifest in prenatal life. Our aim was to assess fetal and infant (6 months of age) cardiovascular function in ART pregnancies. METHODS AND RESULTS: This prospective cohort study included 100 fetuses conceived by ART and 100 control pregnancies. ART fetuses showed signs of cardiovascular remodeling, including a more globular heart with thicker myocardial walls, decreased longitudinal function (tricuspid ring displacement in controls: median, 6.5 mm [interquartile range, 6.1-7.1 mm]; tricuspid ring displacement in ART: 5.5 mm [interquartile range, 5.1-6.1]; P<0.001), impaired relaxation, and dilated atria (atrial area in controls, 1.46 cm(2) [interquartile range, 1.2-1.5 cm(2)]; atrial area in ART, 1.6 cm(2) [interquartile range, 1.3-1.8 cm(2)]; P<0.001). Additionally, ART infants showed persistence of most cardiac changes and a significant increase in blood pressure and aortic intima-media thickness (systolic blood pressure in controls, 74 mm Hg [interquartile range, 67-83 mm Hg]; systolic blood pressure in ART, 83 mm Hg [interquartile range, 75-94 mm Hg]; P<0.001; aortic intima-media thickness in controls, 0.52 mm [interquartile range, 0.45-0.56 mm]; aortic intima media thickness in ART, 0.64 mm [interquartile range, 0.62-0.67]; P<0.001). We could not demonstrate that our findings were directly caused by ART because of their association with various confounding factors, including intrauterine growth restriction or factors related to the cause of infertility. CONCLUSIONS: Children conceived by ART manifest cardiac and vascular remodeling that is present in fetal life and persists in postnatal life, suggesting opportunities for early detection and potential intervention. The underlying mechanisms and the effect of potential confounders such as growth restriction or prematurity remain to be elucidated. PMID- 23985788 TI - Fractional flow reserve-guided versus angiography-guided coronary artery bypass graft surgery. AB - BACKGROUND: Fractional flow reserve (FFR) is well established for patients undergoing percutaneous coronary intervention, yet little is known about candidates for coronary artery bypass graft surgery. METHODS AND RESULTS: From 2006 to 2010, we retrospectively included in this registry 627 consecutive patients treated by coronary artery bypass graft surgery having at least 1 angiographically intermediate stenosis. In 429 patients, coronary artery bypass graft surgery was based solely on angiography (angiography-guided group). In 198 patients, at least 1 intermediate stenosis was grafted with an FFR <=0.80 or deferred with an FFR >0.80 (FFR-guided group). The end point was major adverse cardiovascular events at 3 years, defined as the composite of overall death, myocardial infarction, and target vessel revascularization. The rate of angiographic multivessel disease was similar in the angiography-guided and FFR guided groups (404 [94.2%] versus 186 [93.9%]; P=0.722). In the FFR-guided group, this was significantly downgraded after FFR measurements to 86.4% (P<0.001 versus before FFR) and was associated with a smaller number of anastomoses (3 [2-3] versus 3 [2-4]; P<0.001) and rate of on-pump surgery (49% versus 69%; P<0.001). At 3 years, major adverse cardiovascular events were not different between the angiography-guided and FFR-guided groups (12% versus 11%; hazard ratio, 1.030; 95% confidence interval, 0.627-1.692; P=0.908). However, the FFR-guided group compared with the angiography-guided group presented a significantly lower rate of angina (Canadian Cardiovascular Society class II-IV, 31% versus 47%; P<0.001). CONCLUSIONS: FFR-guided coronary artery bypass graft surgery was associated with a lower number of graft anastomoses and a lower rate of on-pump surgery compared with angiography-guided coronary artery bypass graft surgery. This did not result in a higher event rate during up to 36 months of follow-up and was associated with a lower rate of angina. PMID- 23985789 TI - Fractional flow-guided coronary artery bypass grafting: a word of caution. PMID- 23985790 TI - Opinions, data and policy. PMID- 23985791 TI - Disease, illness, sickness and the contract with patients. PMID- 23985792 TI - The need for specialist services for serious and recurrent mood disorders. PMID- 23985793 TI - Video-gaming disorder and the DSM-5: some further thoughts. PMID- 23985794 TI - Why is clozapine unique? PMID- 23985795 TI - Psychological autopsies. PMID- 23985797 TI - An Xp22.12 microduplication including RPS6KA3 identified in a family with variably affected intellectual and behavioral disabilities. AB - The ribosomal protein S6 kinase, 90 kb, polypeptide 3 gene (RPS6KA3) is responsible for Coffin-Lowry syndrome (CLS), which is characterized by intellectual disability (ID) and facial and bony abnormalities. This gene also affects nonsyndromic X-linked ID and nonsyndromic X-linked ID without bony abnormalities. Two families have been previously reported to have genetic microduplication including RPS6KA3. In the present study, we used array comparative genomic hybridization (CGH) analysis with Agilent Human genome CGH 180K and detected a 584-kb microduplication spanning 19.92-20.50 Mb of Xp22.12 (including RPS6KA3) in the members of one family, including three brothers, two sisters, and their mother. The 15-year-old male proband and one of his brothers had mild ID and localization-related epilepsy, whereas his other brother presented borderline intelligence quotient (IQ) and attention-deficit hyperactivity disorder (ADHD). One sister presented pervasive development disorder (PDD). Analysis of this family suggests that RPS6KA3 duplication is responsible for mild ID, ADHD, and localization-related epilepsy, and possibly for PDD. PMID- 23985796 TI - Molecular design for enhanced sensitivity of a FRET aptasensor built on the graphene oxide surface. AB - We designed a biomolecular probe for highly sensitive protein detection by modifying an aptamer with a DNA spacer. The spacer controls the distance between a fluorescence dye and a quencher, which is crucial for FRET-based sensors. We successfully demonstrated an improvement in the sensitivity of an on-chip graphene oxide aptasensor. PMID- 23985798 TI - Single-nucleotide polymorphisms in Toll-like receptor (TLR)-2, TLR4 and heat shock protein 70 genes and susceptibility to scrub typhus. AB - Scrub typhus is a highly prevalent bacterial infection in India and South Asia that is caused by Orientia tsutsugamushi. The innate immune response to infections is modulated by Toll-like receptors (TLRs) and heat shock proteins (HSPs). This study was done to assess the prevalence and possible association of TLR and HSP polymorphisms in scrub typhus. TLR4 Asp299Gly, TLR4 Thr399Ile, TLR2 Arg753Gln and HSP70-2 A1267G are single-nucleotide polymorphisms (SNPs) that may modulate their activities, and these SNPs were assessed in 137 scrub typhus patients and 134 controls by PCR restriction fragment length polymorphism. We found that the two TLR4 mutations, TLR4 D299G and TLR4T399I, were present in 19.5% and 22% of the study population, respectively, and was in significant linkage disequilibrium with a D' of 0.8. The TLR2 mutation was found to be rare, whereas the HSP A>G mutation was very common (77.5%). Compared with the controls, the prevalence of heterozygous genotype of the TLR4D299G SNP, but not any of the other SNPs, was significantly higher among scrub typhus patients. Further studies using a larger sample size and more candidate genes may better enable in determining the role of these associations in susceptibility and severity of scrub typhus. PMID- 23985799 TI - Novel PKD1 and PKD2 mutations in Taiwanese patients with autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous disease caused by mutations in PKD1 and PKD2. The genotype-phenotype correlations are not completely understood. We performed direct PCR-sequencing plus multiplex ligation dependent probe amplification for PKD1 and PKD2 in 46 unrelated patients. Disease causing mutations were identified in 30 (65%) patients: 23 (77%) patients have mutations in PKD1 and 7 (23%) have mutations in PKD2. Nonsense, splicing or frame shifting mutations were found in 18 patients, exon duplication in 1 and missense mutations in 11 patients. Two likely PKD1 hypomorphic alleles (p.Arg2477His and p.Arg3439Trp) segregated with mild disease in a family. A total of 34 mutations were identified and 17 (50%) of which are novel. The median age at onset of dialysis was significantly earlier in patients with PKD1 mutations (52 years) than in patients with PKD2 mutations (65.5 years) and those with an undetermined genotype (67 years) by survival analysis (log-rank test, P=0.014). Patients carrying PKD1-truncating mutations have a trend toward earlier initiation of dialysis compared with carriers of non-truncating mutations (52 years vs 57 years, P=0.061). A family history of dialysis before 55 years was more common in PKD1 patients than in others (P<0.05). In conclusion, this study identified novel mutations in PKD1 and PKD2 and demonstrated the presence of PKD1 hypomorphic alleles in Taiwanese patients. Patients carrying PKD1 mutations, especially those with truncating mutations, could have a more rapidly progressive disease than others. These results might have implications for diagnosis and risk stratification in patients with ADPKD. PMID- 23985800 TI - Translational up-regulation of polycystic kidney disease protein PKD2 by endoplasmic reticulum stress. AB - Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 or PKD2, and it affects over 10 million people worldwide. It is characterized by cyst formation in the kidney, liver and pancreas. Dosage changes in PKD1/PKD2 are important in ADPKD pathogenesis; therefore, their expression and function has to be strictly regulated. However, how they are regulated remain poorly understood. Recent studies have linked PKD2 regulation to endoplasmic reticulum (ER) stress that is implicated in neuronal, cardiac, and renal diseases. One major ER stress downstream is phosphorylation of eukaryotic initiation factor eIF2alpha by kinase PERK, which attenuates global protein translation and enhances translation of selected proteins. Here, we showed in several mammalian cell lines that PKD2 protein expression is up-regulated by different stresses that all increase phosphorylated eIF2alpha (P-eIF2alpha). Increasing P-eIF2alpha by overexpression or inhibiting the phosphatase activity resulted in increased PKD2. PCR and polysome-binding assays showed that ER stress does not affect the PKD2 mRNA level but increase its binding with ribosomes, indicating that P-eIF2alpha translationally up-regulates PKD2. By mutation analysis, we found that the upstream open reading frame (uORF) in the 5' untranslated region of PKD2 mRNA represses PKD2 translation. Thus, ER stress and P-eIF2alpha translationally up-regulates PKD2 through bypassing the inhibitory uORF. PMID- 23985801 TI - Structure and interaction with phospholipids of a prokaryotic lipoxygenase from Pseudomonas aeruginosa. AB - Lipoxygenases (LOXs), which are essential in eukaryotes, have no confirmed function in prokaryotes that are devoid of polyunsaturated fatty acids. The structure of a secretable LOX from Pseudomonas aeruginosa (Pa_LOX), the first available from a prokaryote, presents significant differences with respect to eukaryotic LOXs, including a cluster of helices acting as a lid to the active center. The mobility of the lid and the structural variability of the N-terminal region of Pa_LOX was confirmed by comparing 2 crystal forms. The binding pocket contains a phosphatidylethanolamine phospholipid with branches of 18 (sn-1) and 14/16 (sn-2) carbon atoms in length. Carbon atoms from the sn-1 chain approach the catalytic iron in a manner that sheds light on how the enzymatic reaction might proceed. The findings in these studies suggest that Pa_LOX has the capacity to extract and modify unsaturated phospholipids from eukaryotic membranes, allowing this LOX to play a role in the interaction of P. aeruginosa with host cells. PMID- 23985802 TI - Ischemic leg ulcer due to vasculopathy associated with neurofibromatosis type 1. PMID- 23985803 TI - An implantable neural probe with monolithically integrated dielectric waveguide and recording electrodes for optogenetics applications. AB - OBJECTIVE: Optogenetics promises exciting neuroscience research by offering optical stimulation of neurons with unprecedented temporal resolution, cell-type specificity and the ability to excite as well as to silence neurons. This work provides the technical solution to deliver light to local neurons and record neural potentials, facilitating local circuit analysis and bridging the gap between optogenetics and neurophysiology research. APPROACH: We have designed and obtained the first in vivo validation of a neural probe with monolithically integrated electrodes and waveguide. High spatial precision enables optical excitation of targeted neurons with minimal power and recording of single-units in dense cortical and subcortical regions. MAIN RESULTS: The total coupling and transmission loss through the dielectric waveguide at 473 nm was 10.5 +/- 1.9 dB, corresponding to an average output intensity of 9400 mW mm(-2) when coupled to a 7 mW optical fiber. Spontaneous field potentials and spiking activities of multiple Channelrhodopsin-2 expressing neurons were recorded in the hippocampus CA1 region of an anesthetized rat. Blue light stimulation at intensity of 51 mW mm(-2) induced robust spiking activities in the physiologically identified local populations. SIGNIFICANCE: This minimally invasive, complete monolithic integration provides unmatched spatial precision and scalability for future optogenetics studies at deep brain regions with high neuronal density. PMID- 23985804 TI - Weight loss-induced reduction in physical activity recovers during weight maintenance. AB - BACKGROUND: Weight loss due to a negative energy balance is considered to be accompanied by a decrease in physical activity. OBJECTIVE: The aim of this study was to investigate whether a decrease in physical activity is sustained during weight maintenance. DESIGN: Subjects were 20 men and 31 women [mean (+/-SD) age: 42 +/- 8 y; BMI (in kg/m(2)): 31.4 +/- 2.8]. Weight loss was achieved by an 8-wk very-low-energy diet period, followed by 44 wk of weight maintenance. Physical activity measures were total energy expenditure expressed as a multiple of sleeping metabolic rate (PALSMR) and resting metabolic rate (PALRMR), activity induced energy expenditure divided by body weight (AEE/kg), and activity counts measured by a triaxial accelerometer. Measurements took place at 0, 8, and 52 wk. RESULTS: Body mass decreased significantly during the diet period (10.5 +/- 3.8%, P < 0.001), and this reduction was sustained after 52 wk (6.0 +/- 5.1%, P < 0.001). PALSMR and PALRMR decreased from 1.81 +/- 0.23 and 1.70 +/- 0.22, respectively, before the diet to 1.69 +/- 0.20 and 1.55 +/- 0.19 after the diet (P < 0.001) and increased again after weight maintenance to 1.85 +/- 0.27 and 1.71 +/- 0.23, respectively, compared with 8-wk measurements (P < 0.001). AEE/kg decreased from 0.043 +/- 0.015 MJ/kg at baseline to 0.037 +/- 0.014 MJ/kg after the diet (P < 0.001) and was higher after 52 wk (0.044 +/- 0.17 MJ/kg) compared with after 8 wk (P < 0.001). Activity counts decreased from 1.64 +/- 0.37 megacounts/d at baseline to 1.54 +/- 0.35 megacounts/d after the diet (P < 0.05) and were higher after 52 wk (1.73 +/- 0.49 megacounts/d) compared with 8 wk (P < 0.01). CONCLUSION: A weight loss-induced reduction in physical activity returns to baseline values when weight loss is maintained. This trial was registered at clinicaltrials.gov as NCT01015508. PMID- 23985805 TI - Body composition from birth to 6 mo of age in Ethiopian infants: reference data obtained by air-displacement plethysmography. AB - BACKGROUND: Data on body composition in infancy may improve the understanding of the relation between variability in fetal and infant growth and disease risk through the life course. Although new assessment techniques have recently become available, body composition is rarely described in infants from low-income settings. OBJECTIVE: The aim of this study was to provide reference data for fat mass (FM) and fat-free mass (FFM) from birth to the age of 6 mo from an urban African population. DESIGN: We conducted a prospective cohort study among infants from Jimma, Ethiopia. FM and FFM were measured at birth and at 1.5, 2.5, 3.5, 4.5, and 6 mo of age with air-displacement plethysmography (ADP) validated against a stable isotope method in a subsample. Reference charts and reference tables with z scores and percentiles for FM, FFM, FM index (FMI; in kg/m(2)), and FFM index (FFMI: in kg/m(2)) were constructed with the lambda-mu-sigma method. RESULTS: Body composition growth charts were based on a total of 2026 measurements of body composition obtained from 378 infants. FM and FMI gain progressed in a logarithmic-shaped curve and variation increased with increasing age, whereas FFM increased in an almost linear manner with a minor deceleration at around 3 mo of age. The FFMI curve showed a very modest exponential increase with age. CONCLUSIONS: By presenting z scores and centile reference charts for an apparently healthy urban Ethiopian infant population, this study represents a first step toward providing reference data on FM and FFM for an urban African context, which is important for future clinical care and research. This study was registered at www.controlled-trials.com as ISRCTN46718296. PMID- 23985806 TI - Kynurenine pathway metabolites: relevant to vitamin B-6 deficiency and beyond. PMID- 23985807 TI - Hormonal responses and test meal intake among obese teenagers before and after laparoscopic adjustable gastric banding. AB - BACKGROUND: Relatively little is known about changes in eating behavior or hormonal responses to food after bariatric surgery in adolescents. OBJECTIVE: This study compared eating behavior and hormones among adolescents in a bariatric surgery program with those in nonoverweight control adolescents and evaluated changes before and after laparoscopic adjustable gastric banding (LAGB). DESIGN: Fasting leptin, peptide YY (PYY), and ghrelin concentrations were obtained, and postprandial ghrelin and PYY area under the curve (AUC) were assessed after a single-item breakfast. Intake from an ad libitum lunchtime multi-item meal was measured. RESULTS: Compared with controls (n = 9), all presurgical candidates (n = 20) had significantly greater fasting leptin, lower fasting ghrelin, and lower AUC ghrelin but similar PYY and AUC PYY. Preoperative candidates did not differ from controls in total energy consumed during the test meal. Postoperatively, among the 11 participants with data both before and after surgery, BMI (in kg/m(2)) decreased by 3.5 (P < 0.001), significantly less energy was consumed in the test meal, and a smaller number of foods were selected. AUC ghrelin and PYY did not significantly change before or after LAGB. CONCLUSIONS: Few significant short-term changes were observed in appetitive hormones after LAGB. It is unclear whether objective measures of eating behavior will prove useful in evaluating the impact of bariatric surgery on outcomes. This trial was registered at clinicaltrials.gov as CT00764127. PMID- 23985808 TI - Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism. AB - BACKGROUND: Genetic factors that predispose individuals to nonalcoholic fatty liver disease (NAFLD) and associated diabetes and cardiovascular disease are unclear. The transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) modulates lipogenesis and insulin sensitivity and was experimentally connected to NAFLD. OBJECTIVE: We assessed the impact of a common SREBF-1c polymorphism on the incidence and severity of NAFLD and on associated glucose and lipoprotein dysmetabolism. DESIGN: We followed up 212 randomly selected, nonobese, nondiabetic, insulin-sensitive participants in a population-based study without NAFLD or metabolic syndrome at baseline who were characterized for the common SREBF-1c gene rs11868035 A/G polymorphism, dietary habits, physical activity, adipokine profile, C-reactive protein (CRP), and circulating markers of endothelial dysfunction. A comparable cohort of NAFLD patients underwent a liver biopsy, an oral-glucose-tolerance test with minimal model analysis of glucose homeostasis variables, and an oral-fat-tolerance test with measurement of plasma lipoproteins, adipokines, and cytokeratin-18 fragments. RESULTS: SREBF-1c predicted the 7-y incidence of NAFLD (OR: 1.71; 95% CI: 1.15, 2.53) and diabetes and the 7-y elevation in CRP and endothelial dysfunction markers. In biopsy proven NAFLD patients, the SREBF-1c A allele conferred increased risk of severe steatosis and nonalcoholic steatohepatitis; more-severe hepatic, muscle, and adipose tissue insulin resistance; and pancreatic beta cell dysfunction. SREBF-1c A allele carriers also had an impaired oral fat tolerance with a postprandial accumulation of large triglyceride-rich lipoproteins and oxidized LDLs, lower HDL cholesterol and adiponectin concentrations, and cytokeratin-18 fragment elevation. CONCLUSION: SREBF-1c polymorphism is associated with increased risk of developing NAFLD with more severe liver histology and derangement in glucose and lipoprotein metabolism, which contribute to the presentation and natural history of NAFLD. PMID- 23985809 TI - Absorption, metabolism, and excretion of (-)-epicatechin in humans: an evaluation of recent findings. PMID- 23985810 TI - Lifetime adiposity and risk of pancreatic cancer in the NIH-AARP Diet and Health Study cohort. AB - BACKGROUND: The association of excess body weight across a lifetime with pancreatic cancer has not been examined extensively. OBJECTIVE: We determined the association for body mass index (BMI) at different ages and adiposity duration and gain with incident pancreatic adenocarcinoma in the NIH-AARP Diet and Health Study cohort. DESIGN: Participants aged 50-71 y completed questionnaires at baseline (1995-1996) and 6 months later that queried height and weight history. We calculated HRs and 95% CIs by using Cox proportional hazards models adjusted for age, smoking, sex, and intakes of energy and total fat. RESULTS: Over an average follow-up of 10.5 y, 1206 and 2122 pancreatic cancer cases were identified in the subcohort who completed the second questionnaire (n = 273,975) and the baseline cohort (n = 501,698), respectively. Compared with normal weight, overweight or obesity at ages 18, 35, 50, or >50 y (baseline BMI) was significantly associated with pancreatic cancer, with HRs ranging from 1.15 to 1.53. A longer duration of BMI (in kg/m(2)) >25.0 was significantly associated with pancreatic cancer (overall HR per 10-y increment of duration: 1.06; 95% CI: 1.02, 1.09), with individuals who reported diabetes having the greatest risk (HR per 10-y increment of duration: 1.18; 95% CI: 1.05, 1.32; P-interaction = 0.01) and rates. A substantial gain in adiposity (>10 kg/m(2)) after age 50 y was significantly associated with increased pancreatic cancer risk. The etiologic fraction of pancreatic cancer explained by adiposity at any age was 14% overall and 21% in never smokers. CONCLUSION: Overweight and obesity at any age are associated with increased pancreatic cancer. PMID- 23985812 TI - The basics of compounding: compounding hard, soft and chewable troches/lozenges/drops. PMID- 23985811 TI - Genetic and environmental factors in associations between infant growth and adult cardiometabolic risk profile in twins. AB - BACKGROUND: Accelerated infant growth is associated with an altered, mostly adverse adult cardiometabolic risk profile. The importance of genetic and environmental factors to these associations is unclear. OBJECTIVE: The objective was to examine the importance of genetic and environmental factors in the associations between infant growth and adult cardiometabolic risk factors (anthropometric characteristics, lipids, insulin sensitivity, leptin, blood pressure, and fibrinogen) in twins. DESIGN: Cardiometabolic risk factors were assessed in 240 twin pairs (aged 18-34 y) from the East Flanders Prospective Twin Survey. Infant growth was defined as change in weight z score. We regressed intrapair differences in growth during 4 growth windows (0-1, 1-6, 6-12, and 12 24 mo) against intrapair differences in the risk factors in monozygotic and dizygotic twins separately. RESULTS: Within monozygotic twin pairs only, associations between infant growth and most adult lipids, glucose, leptin, and blood pressure (eg, systolic blood pressure: b = 5.95 mm Hg per change in z score, P = 0.01 in monozygotic twins; b = -1.64, P = 0.82 in dizygotic twins from 12 to 24 mo) were found. Within dizygotic twin pairs only, associations between growth and triglycerides and fibrinogen (eg, fibrinogen: b = 0.07 ln mg/dL per change in z score, P = 0.31 in monozygotic twins; b = 0.79, P = 0.01 in dizygotic twins from 0 to 1 mo) were identified. Most associations showed a detrimental effect of accelerated growth, but beneficial associations were also identified (eg, total-to-high-density-lipoprotein cholesterol ratio: b = -0.22 per change in z score from 1 to 6 mo, P = 0.008 in monozygotic twins). CONCLUSION: Our data showed that environmental factors play a role in the associations between infant growth and most adult lipids, glucose, leptin, and blood pressure, whereas genetic factors are involved regarding triglycerides and fibrinogen. PMID- 23985813 TI - Glucosamine sulfate: a review of efficacy for the pharmacy professional. PMID- 23985815 TI - Electronically controlled drug delivery. PMID- 23985814 TI - Osteoarthritis: other options. PMID- 23985816 TI - Case reports: iontophoresis with lidocaine and dexamethasone for treating rotator cuff injury in a hockey player. PMID- 23985818 TI - Compounding radiolabeled blood cells for diagnostic imaging. PMID- 23985819 TI - Extemporaneous formulations: how to evaluate HPLC stability studies. PMID- 23985817 TI - Case report: iontophoresis and phonophoresis for treating epicondylitis. PMID- 23985820 TI - Calamine lotion: experimenting with a new suspending agent. AB - The use of a new suspending agent is investigated. Calamine lotion, USP contains bentonite magma as a suspending agent. In this study, bentonite magma was partially or completely replaced with a new suspending agent called tahini. Tahini is sesame paste composed of crushed sesame seeds in sesame oil. It is frequently used in middle eastern food as a thickening and suspending agent. Calamine lotion was prepared, generally, according to the USP method. The formula contained 40% v/v magma. Tahini was added instead of bentonite magma by replacing 100%, 99%, 90%, 75%, 50% and 25% of the magma. The sedimentation volume and the degree of flocculation were calculated for the resulting preparations. Rheological characteristics of bentonite- and tahini-containing lotions were also determined. Sedimentation volume showed 0.723 and 0.851 (p=0.05) for the lotions containing 100% bentonite and 100% tahini, respectively. The degree of flocculation was 2.00 and 2.35 (p=0.05) for the 100% bentonite and 100% tahini lotions, respectively. The rheograms of all the suspensions showed pseudoplastic flow. Overall, the use of tahini in calamine lotion has improved the physical stability of the formula. PMID- 23985821 TI - Use of an Oxygen Extractor to Minimize Oxidation of compounded Preparations. AB - A number of drugs are sensitive to the presence of oxygen resulting in oxidative degradation and a shortened shelf-life. This is usually minimized by either the addition of antioxidants to the formulation or the replacement of headspace air with an inert gas, such as nitrogen. A new alternative is presented and involves the use of an oxygen extractor. The purpose of this study was to demonstrate the effectiveness of the device in removing oxygen from drug vials. Aqueous epinephrine solutions were prepared from deoxygenated water. Twenty milliliters of the solution was filled into vials to which caps were affixed; some caps contained the oxygen extractor and others did not. The oxygen content of the headspace was analyzed and the appearance of the solutions was observed over a period of up to 19 days. The results showed that the vials with the oxygen extractor remained clear for the 19 days' duration with essentially no oxygen present; whereas the vials without the unit discolored within 24 hours, turning to black, oily films in 15 days. This technology may provide compounding pharmacists with a method of packaging oxygen-sensitive preparations with enhanced stability. PMID- 23985822 TI - Enhancement of skin penetration of nonsteroidal anti-inflammatory drugs from extemporaneously compounded topical-gel formulations. AB - Ketoprofen and ibuprofen topical gels were compounded with decyl methyl sulfoxide and the terpenes d-limonene, (-)-menthone, terpinen-4-ol, and a-terpineol as penetration enhancers. Transdermal penetration profiles for both ketoprofen and ibuprofen were determined using full-thickness human skin, modified Franz diffusion cells and an isotonic (pH7.4) phosphate buffer solution. Human skin was used in these experiments to approximate the therapeutic use of these gels. Ibuprofen was found to have superior transdermal kinetics when compared to ketoprofen. Ibuprofen is a smaller and more lipophilic molecule than ketoprofen, which gives it better penetration properties. All enhancers tested significantly increased the penetration (except (-)-menthone) and skin retention (except terpinen-4-ol) of ketoprofen. None of the enhancers tested significantly increased the penetration or retention of ibuprofen. Despite the lack of enhancer activity, ibuprofen still demonstrated higher skin penetration and retention than enhanced delivery of ketoproen. The results of these studies suggest that the addition of penetration enhancers can significantly increase the amount of ketoprofen penetration, while enhancers demonstrated no significant increase (and can actually decrease) the amount of ibuprofen penetrating into and through the skin. PMID- 23985823 TI - High-density lipoprotein and prostate cancer: an overview. AB - Prostate cancer is a common disease in modern, developed societies and has a high incidence and mortality. High-density lipoprotein cholesterol (HDL-C) has recently received much attention as a possible risk marker of prostate cancer development and prognosis. In the present article, we summarized findings from epidemiologic studies of the association between HDL-C and prostate cancer. Low HDL-C level was found to be a risk and prognostic factor of prostate cancer in several epidemiologic studies, although the overall linkage between HDL and prostate cancer has not been definitively established. The mechanisms for this association remain uncertain; however, limited data from experimental studies imply a possible role of HDL in the pathophysiology of prostate cancer. More epidemiologic research, in combination with experimental studies, is needed in this field. PMID- 23985824 TI - Functional and molecular changes of the bladder in rats with crushing injury of nerve bundles from major pelvic ganglion to the bladder: role of RhoA/Rho kinase pathway. AB - Voiding dysfunction is a common complication after radical pelvic surgery. To reduce this complication, nerve-sparing radical pelvic surgery was introduced. However, several patients experienced voiding difficulty despite nerve-sparing radical pelvic surgery. Thus, we investigated the functional and molecular changes of the bladder in rats, which demonstrated voiding dysfunction induced by nerve damage during nerve-sparing radical pelvic surgery. Male rats were used and assigned to normal, sham-operated, and bilateral crushing nerve bundles from major pelvic ganglion (MPG) to bladder group. After one, two, and four-week crushing injury, significantly decreased contractile response and increased connective tissue of the detrusor were observed and these results were reliable findings with voiding difficulty following nerve-sparing radical pelvic surgery. After crushing injury, significantly increased M2 muscarinic receptor expression was observed and this might be regarded as the compensatory response. However, M3 muscarinic receptor expression was not significantly changed. The expression of RhoA, ROCK-alpha, and ROCK-beta was significantly increased after one, two, and four-week crushing injury. From these results, the down-regulation of RhoA/Rho kinase pathway might lead to the decreased bladder contractility after crushing injury of nerve bundles from MPG to the bladder despite of the compensated up regulation of M2 muscarinic receptor. PMID- 23985825 TI - Cytogenetic abnormalities in lymphocytes from victims exposed to cobalt-60 radiation. AB - The present study investigates cytogenetic damage in lymphocytes, derived from three victims who were unfortunately exposed to cobalt-60 (60Co) radiation (the 1999 accident occurred in a village in China's Henan province). Case A of the three victims was exposed to a higher dose of 60Co radiation than Cases B and C. The chromosomal aberrations, cytokinesis-block micronucleus (CBMN, the CBMN assay), and DNA double-strand breaks (DSBs, the comet assay) examined in this study are biomarkers for cytogenetic abnormalities. After the lymphocytes collected from the victims were cultured, the frequencies of dicentric chromosomes and rings (dic + r) and CBMN in the first mitotic division detected in the lymphocytes of Case A were found to be substantially higher than in Cases B and C. Similarly, the DNA-DSB level found in the peripheral blood collected from Case A was much higher than those of Cases B and C. These results suggest that an acutely enhanced induction of the 60Co-induced cytogenetic abnormality frequency in humans depends on the dose of 60Co radiation. This finding is supported by the data obtained using practical techniques to evaluate early lymphoid-tissue abnormalities induced after exposure to acute radiation. PMID- 23985826 TI - Assessment of blood flow in hepatocellular carcinoma: correlations of computed tomography perfusion imaging and circulating angiogenic factors. AB - Hepatocellular carcinoma (HCC) is a highly vascular tumor through the process of angiogenesis. To evaluate more non-invasive techniques for assessment of blood flow (BF) in HCC, this study examined the relationships between BF of HCC measured by computer tomography (CT) perfusion imaging and four circulating angiogenic factors in HCC patients. Interleukin 6 (IL-6), interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) in plasma were measured using Bio-Plex multiplex immunoassay in 21 HCC patients and eight healthy controls. Circulating IL-6, IL-8 and VEGF showed higher concentrations in HCC patients than in controls (p < 0.05), and predicted HCC occurrence better than chance (p < 0.01). Twenty-one patients with HCC received 21-phase liver imaging using a 64-slice CT. Total BF, arterial BF, portal BF, arterial fraction (arterial BF/total BF) of the HCC and surrounding liver parenchyma, and HCC-parenchyma ratio were measured using a dual-vessel model. After analyzing the correlations between BF in HCC and four circulating angiogenic factors, we found that the HCC-parenchyma ratio of arterial BF showed a significantly positive correlation with the level of circulating IL-8 (p < 0.05). This circulating biomarker, IL-8, provides a non-invasive tool for assessment of BF in HCC. PMID- 23985828 TI - Photovoltage enhancement from cyanobiphenyl liquid crystals and 4-tert butylpyridine in Co(II/III) mediated dye-sensitized solar cells. AB - Two cyanobiphenyl liquid crystals (LCs), 5CB (4-cyano-4'-pentylbiphenyl) and 8CB (4-cyano-4'-octylbiphenyl), are introduced as additives into Co(II/III) electrolytes for dye-sensitized solar cells (DSCs). An electrolyte containing a combination of these LCs and 4-tert-butylpyridine (TBP) exhibits higher photovoltage than one with only TBP, resulting in higher power conversion efficiency. PMID- 23985829 TI - Chlorogenic acid inhibits osteoclast differentiation and bone resorption by down regulation of receptor activator of nuclear factor kappa-B ligand-induced nuclear factor of activated T cells c1 expression. AB - Excessive osteoclastic bone resorption plays a critical role in inflammation induced bone loss such as rheumatoid arthritis and periodontal bone erosion. Therefore, identification of osteoclast targeted-agents may be a therapeutic approach to the treatment of pathological bone loss. In this study, we isolated chlorogenic acid (CGA) from fructus of Gardenia jasminoides to discover anti-bone resorptive agents. CGA is a polyphenol with anti-inflammatory and anti-oxidant activities, however, its effects on osteoclast differentiation is unknown. Thus, we investigated the effect of CGA in receptor activator of nuclear factor-kappa B (NF-kappaB) ligand (RANKL)-induced osteoclast differentiation and RANKL signaling. CGA dose-dependently inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without any evidence of cytotoxicity. CGA inhibited the phosphorylation of p38, Akt, extracellular signal regulated kinase (ERK), and inhibitor of nuclear factor-kappa B (IkappaB), and IkappaB degradation by RANKL treatment. CGA suppressed the mRNA expression of nuclear factor of activated T cells c1 (NFATc1), TRAP and OSCAR in RANKL-treated bone marrow macrophages (BMMs). Also, overexpression of NFATc1 in BMMs blocked the inhibitory effect of CGA on RANKL-mediated osteoclast differentiation. Furthermore, to evaluate the effects of CGA in vivo, lipopolysaccharide (LPS) induced bone erosion study was carried out. CGA remarkably attenuated LPS-induced bone loss based on micro-computed tomography and histologic analysis of femurs. Taken together, our findings suggest that CGA may be a potential treatment option for osteoclast-related diseases with inflammatory bone destruction. PMID- 23985827 TI - Renal dopamine receptors, oxidative stress, and hypertension. AB - Dopamine, which is synthesized in the kidney, independent of renal nerves, plays an important role in the regulation of fluid and electrolyte balance and systemic blood pressure. Lack of any of the five dopamine receptor subtypes (D1R, D2R, D3R, D4R, and D5R) results in hypertension. D1R, D2R, and D5R have been reported to be important in the maintenance of a normal redox balance. In the kidney, the antioxidant effects of these receptors are caused by direct and indirect inhibition of pro-oxidant enzymes, specifically, nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase, and stimulation of anti oxidant enzymes, which can also indirectly inhibit NADPH oxidase activity. Thus, stimulation of the D2R increases the expression of endogenous anti-oxidants, such as Parkinson protein 7 (PARK7 or DJ-1), paraoxonase 2 (PON2), and heme oxygenase 2 (HO-2), all of which can inhibit NADPH oxidase activity. The D5R decreases NADPH oxidase activity, via the inhibition of phospholipase D2, and increases the expression of HO-1, another antioxidant. D1R inhibits NADPH oxidase activity via protein kinase A and protein kinase C cross-talk. In this review, we provide an overview of the protective roles of a specific dopamine receptor subtype on renal oxidative stress, the different mechanisms involved in this effect, and the role of oxidative stress and impairment of dopamine receptor function in the hypertension that arises from the genetic ablation of a specific dopamine receptor gene in mice. PMID- 23985830 TI - Role of MerC, MerE, MerF, MerT, and/or MerP in resistance to mercurials and the transport of mercurials in Escherichia coli. AB - The characteristics of bacteria take up mercury into cells via membrane potential dependent sequence-divergent members of the mercuric ion (Mer) superfamily, i.e., a periplasmic mercuric ion scavenging protein (MerP) and one or more inner membrane-spanning proteins (MerC, MerE, MerF, and MerT), which transport mercuric ions into the cytoplasm, have been applied in engineering of bioreactor used for mercurial bioremediation. We engineered bacteria to express MerC, MerE, MerF, or MerT with or without MerP to clarify their individual role and potential in transport of mercurial. By immunoblot analysis using specific polyclonal antibody, the proteins encoded by merC, merE, merF, merT or merP, were certainly expressed and identified in the membrane fraction. Bacteria expressing MerC, MerE, MerF or MerT in the absence of MerP transported significantly more C6H5Hg(I) and Hg(II) across bacterial membrane than their isogenic strain. In vivo expression of MerP in the presence of all the transporters did not cause apparent difference to the C6H5Hg(I) transport, but gives an apparently higher Hg(II) transport than that did by MerE, MerF or MerT but not by MerC. Among the four transporters studied, MerC showed more potential to transport Hg(II) across bacterial membrane than MerE, MerF and MerT. Together these findings, we demonstrated for the first time that in addition to MerE and MerT, MerF and MerC are broad-spectrum mercury transporters that mediate both Hg(II) and phenylmercury transport into cells. Our results suggested that MerC is the most efficient tool for designing mercurial bioremediation systems, because MerC is sufficient for mercurial transport into cells. PMID- 23985831 TI - Neural development: Double agent sonic hedgehog. PMID- 23985832 TI - Neuroendocrinology: Signalling starvation. PMID- 23985833 TI - Visual system: Mapping motion detection. PMID- 23985834 TI - Pathophysiology of the brain extracellular matrix: a new target for remyelination. AB - The extracellular matrix (ECM) occupies a notable proportion of the CNS and contributes to its normal physiology. Alterations to the ECM occur after neural injury (for example, in multiple sclerosis, spinal cord injury or Alzheimer's disease) and can have drastic consequences. Of note, injury-induced changes in chondroitin sulphate proteoglycans (CSPGs)--a family of ECM proteoglycans--can lead to the inhibition of myelin repair. Here, we highlight the pathophysiological roles of the brain's ECM, particularly those of CSPGs, after neural insults and discuss how the ECM can be targeted to promote remyelination. PMID- 23985835 TI - Influence of anesthetic agent, depth of anesthesia and body temperature on cardiovascular functional parameters in the rat. AB - Sedating animals is sometimes necessary in experimental research. This paper presents and discusses the influence of four of the most common anesthetic agents on cardiovascular parameters in rats. We also studied the influence of body temperature. Ten-week-old Sprague-Dawley rats were anesthetized with either isoflurane, pentobarbital, ketamine/xylazine or tiletamine/zolazepam (n = 12 in each group). A pressure-sensing catheter was placed in the right carotid artery for the continuous measurement of arterial pressure, and echocardiography was performed. Indices of cardiac function were significantly higher in the tiletamine/zolazepam rats compared with the other groups. Heart rate was highest but stroke volume lowest with pentobarbital. Left ventricular diastolic dimension was lower in the pentobarbital and tiletamine/zolazepam rats compared with the isoflurane or ketamine/xylazine rats. Intraventricular diastolic pressure was similar in all groups whereas intraventricular systolic pressure, as well as both systolic and diastolic aortic pressures, was significantly higher in the tiletamine/zolazepam rats compared with the other groups. No hemodynamic indices differed significantly among the isoflurane, pentobarbital and ketamine/xylazine rats. Lowering body temperature significantly reduced heart rate and cardiac output but had no apparent effect on hemodynamic parameters. In conclusion, although cardiac functional parameters differed between the different anesthetic agents in ways that could be of relevance to the researcher, they may all have a role in experimental cardiology. Importantly, tiletamine/zolazepam anesthesia resulted in significantly higher indices of cardiac function and elevated blood pressures compared with the other anesthetic agents, a finding that should be kept in mind when interpreting data obtained in rats sedated on this regimen. PMID- 23985837 TI - A coordinated approach is key for open access. PMID- 23985836 TI - A longitudinal study on alpha-synuclein in blood plasma as a biomarker for Parkinson's disease. AB - There have been no longitudinal studies on alpha-synuclein as a potential biomarker for the progression of Parkinson's disease (PD). Here, blood plasma 'total alpha-synuclein' and 'Ser-129 phosphorylated alpha-synuclein' were assayed at 4-6 monthly intervals from a cohort of 189 newly-diagnosed patients with PD. For log-transformed data, plasma total alpha-synuclein levels increased with time for up to 20 yrs after the appearance of initial symptoms (p = 0.012), whereas phosphorylated alpha-synuclein remained constant over this same period. The mean level of phosphorylated alpha-synuclein, but not of total alpha-synuclein, was higher in the PD plasma samples taken at first visit than in single samples taken from a group of 91 healthy controls (p = 0.012). Overall, we conclude that the plasma level of phosphorylated alpha-synuclein has potential value as a diagnostic tool, whereas the level of total alpha-synuclein could act as a surrogate marker for the progression of PD. PMID- 23985849 TI - Green fuels blast off. PMID- 23985850 TI - Brazilian citation scheme outed. PMID- 23985851 TI - Summer storms bolster Arctic ice. PMID- 23985852 TI - Biotech boom prompts fears of bust. PMID- 23985853 TI - African genes tracked back. PMID- 23985854 TI - Theoretical physics: The origins of space and time. PMID- 23985855 TI - Economics: Value judgements. PMID- 23985856 TI - Communication: Mind the metaphor. PMID- 23985860 TI - Arctic: Speed of methane release. PMID- 23985861 TI - Arctic: Warming impact is uneven. PMID- 23985862 TI - Neuroscience: Brain stimulation has a long history. PMID- 23985863 TI - Arctic: Uncertainties in methane link. PMID- 23985864 TI - Hugh Huxley (1924-2013). PMID- 23985865 TI - Biogeochemistry: Ancient algae crossed a threshold. PMID- 23985866 TI - Neuroscience: Dopamine ramps up. PMID- 23985867 TI - Astrophysics: Radioactive glow as a smoking gun. PMID- 23985868 TI - Astrophysics: A dark cloud unveils its secrets. PMID- 23985869 TI - Microbiology: Wealth management in the gut. PMID- 23985871 TI - A rigid and weathered ice shell on Titan. AB - Several lines of evidence suggest that Saturn's largest moon, Titan, has a global subsurface ocean beneath an outer ice shell 50 to 200 kilometres thick. If convection is occurring, the rigid portion of the shell is expected to be thin; similarly, a weak, isostatically compensated shell has been proposed to explain the observed topography. Here we report a strong inverse correlation between gravity and topography at long wavelengths that are not dominated by tides and rotation. We argue that negative gravity anomalies (mass deficits) produced by crustal thickening at the base of the ice shell overwhelm positive gravity anomalies (mass excesses) produced by the small surface topography, giving rise to this inverse correlation. We show that this situation requires a substantially rigid ice shell with an elastic thickness exceeding 40 kilometres, and hundreds of metres of surface erosion and deposition, consistent with recent estimates from local features. Our results are therefore not compatible with a geologically active, low-rigidity ice shell. After extrapolating to wavelengths that are controlled by tides and rotation, we suggest that Titan's moment of inertia may be even higher (that is, Titan may be even less centrally condensed) than is currently thought. PMID- 23985872 TI - Crystallites of magnetic charges in artificial spin ice. AB - Artificial spin ice is a class of lithographically created arrays of interacting ferromagnetic nanometre-scale islands. It was introduced to investigate many-body phenomena related to frustration and disorder in a material that could be tailored to precise specifications and imaged directly. Because of the large magnetic energy scales of these nanoscale islands, it has so far been impossible to thermally anneal artificial spin ice into desired thermodynamic ensembles; nearly all studies of artificial spin ice have either treated it as a granular material activated by alternating fields or focused on the as-grown state of the arrays. This limitation has prevented experimental investigation of novel phases that can emerge from the nominal ground states of frustrated lattices. For example, artificial kagome spin ice, in which the islands are arranged on the edges of a hexagonal net, is predicted to support states with monopolar charge order at entropies below that of the previously observed pseudo-ice manifold. Here we demonstrate a method for thermalizing artificial spin ices with square and kagome lattices by heating above the Curie temperature of the constituent material. In this manner, artificial square spin ice achieves unprecedented thermal ordering of the moments. In artificial kagome spin ice, we observe incipient crystallization of the magnetic charges embedded in pseudo-ice, with crystallites of magnetic charges whose size can be controlled by tuning the lattice constant. We find excellent agreement between experimental data and Monte Carlo simulations of emergent charge-charge interactions. PMID- 23985870 TI - Richness of human gut microbiome correlates with metabolic markers. AB - We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus gut bacterial richness. They contain known and previously unknown bacterial species at different proportions; individuals with a low bacterial richness (23% of the population) are characterized by more marked overall adiposity, insulin resistance and dyslipidaemia and a more pronounced inflammatory phenotype when compared with high bacterial richness individuals. The obese individuals among the lower bacterial richness group also gain more weight over time. Only a few bacterial species are sufficient to distinguish between individuals with high and low bacterial richness, and even between lean and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities. PMID- 23985873 TI - Late Miocene threshold response of marine algae to carbon dioxide limitation. AB - Coccolithophores are marine algae that use carbon for calcification and photosynthesis. The long-term adaptation of these and other marine algae to decreasing carbon dioxide levels during the Cenozoic era has resulted in modern algae capable of actively enhancing carbon dioxide at the site of photosynthesis. This enhancement occurs through the transport of dissolved bicarbonate (HCO3(-)) and with the help of enzymes whose expression can be modulated by variable aqueous carbon dioxide concentration, [CO2], in laboratory cultures. Coccolithophores preserve the geological history of this adaptation because the stable carbon and oxygen isotopic compositions of their calcite plates (coccoliths), which are preserved in the fossil record, are sensitive to active carbon uptake and transport by the cell. Here we use a model of cellular carbon fluxes and show that at low [CO2] the increased demand for HCO3(-) at the site of photosynthesis results in a diminished allocation of HCO3(-) to calcification, which is most pronounced in larger cells. This results in a large divergence between the carbon isotopic compositions of small versus large coccoliths only at low [CO2]. Our evaluation of the oxygen and carbon isotope record of size separated fossil coccoliths reveals that this isotopic divergence first arose during the late Miocene to the earliest Pliocene epoch (about 7-5 million years ago). We interpret this to be a threshold response of the cells' carbon acquisition strategies to decreasing [CO2]. The documented coccolithophore response is synchronous with a global shift in terrestrial vegetation distribution between 8 and 5 Myr ago, which has been interpreted by some studies as a floral response to decreasing partial pressures of carbon dioxide () in the atmosphere. We infer a global decrease in carbon dioxide levels for this time interval that has not yet been identified in the sparse proxy record but is synchronous with global cooling and progressive glaciations. PMID- 23985874 TI - Rapid, climate-driven changes in outlet glaciers on the Pacific coast of East Antarctica. AB - Observations of ocean-terminating outlet glaciers in Greenland and West Antarctica indicate that their contribution to sea level is accelerating as a result of increased velocity, thinning and retreat. Thinning has also been reported along the margin of the much larger East Antarctic ice sheet, but whether glaciers are advancing or retreating there is largely unknown, and there has been no attempt to place such changes in the context of localized mass loss or climatic or oceanic forcing. Here we present multidecadal trends in the terminus position of 175 ocean-terminating outlet glaciers along 5,400 kilometres of the margin of the East Antarctic ice sheet, and reveal widespread and synchronous changes. Despite large fluctuations between glaciers--linked to their size--three epochal patterns emerged: 63 per cent of glaciers retreated from 1974 to 1990, 72 per cent advanced from 1990 to 2000, and 58 per cent advanced from 2000 to 2010. These trends were most pronounced along the warmer western South Pacific coast, whereas glaciers along the cooler Ross Sea coast experienced no significant changes. We find that glacier change along the Pacific coast is consistent with a rapid and coherent response to air temperature and sea-ice trends, linked through the dominant mode of atmospheric variability (the Southern Annular Mode). We conclude that parts of the world's largest ice sheet may be more vulnerable to external forcing than recognized previously. PMID- 23985875 TI - Dietary intervention impact on gut microbial gene richness. AB - Complex gene-environment interactions are considered important in the development of obesity. The composition of the gut microbiota can determine the efficacy of energy harvest from food and changes in dietary composition have been associated with changes in the composition of gut microbial populations. The capacity to explore microbiota composition was markedly improved by the development of metagenomic approaches, which have already allowed production of the first human gut microbial gene catalogue and stratifying individuals by their gut genomic profile into different enterotypes, but the analyses were carried out mainly in non-intervention settings. To investigate the temporal relationships between food intake, gut microbiota and metabolic and inflammatory phenotypes, we conducted diet-induced weight-loss and weight-stabilization interventions in a study sample of 38 obese and 11 overweight individuals. Here we report that individuals with reduced microbial gene richness (40%) present more pronounced dys-metabolism and low-grade inflammation, as observed concomitantly in the accompanying paper. Dietary intervention improves low gene richness and clinical phenotypes, but seems to be less efficient for inflammation variables in individuals with lower gene richness. Low gene richness may therefore have predictive potential for the efficacy of intervention. PMID- 23985877 TI - Apparent treatment-resistant hypertension among elderly Korean hypertensives: an insight from the HIT registry. AB - The aim of this study was to determine the clinical characteristics of patients with resistant hypertension (RH) and predictors among elderly Korean hypertensives. This prospective, multi-center, observational study evaluated 2439 elderly hypertensive patients between December 2008 and November 2011, who visited secondary hypertension clinics for high blood pressure (BP). Patients were categorized as resistant if their BP was >=140/90 mm Hg and if they reported using antihypertensive medications from three different drug classes, including a diuretic or drugs from >=4 antihypertensive drug classes, regardless of BP. Characteristics of patients with RH were compared with those of patients who were controlled with one or two antihypertensive medications after 6-month antihypertensive treatment. In comparison with 837 patients with non-RH, 404 patients with RH were more likely to be aware of their status of high BP before enrollment and have a high baseline systolic BP >=160 mm Hg, microalbuminuria, high body mass index (BMI) >=24 kg m(-2) and diabetes mellitus (DM). In drug naive patients, awareness of hypertension at baseline was the only independent predictor for RH. In elderly Korean hypertensives, BMI (>=24 kg m(-2)), baseline systolic BP (>=160 mm Hg), microalbuminuria, DM and awareness of hypertension showed an association with RH. PMID- 23985878 TI - Are we using blood pressure-lowering drugs appropriately? Perhaps now is the time for a change. AB - This topic seems particularly appropriate since this year is the 20th Anniversary of the Cochrane Collaboration. The Cochrane Collaboration and the Hypertension Review Group have played a leading role in advancing the evidence-based agenda that has challenged many of our ways of thinking and approaches to treating patients. PMID- 23985880 TI - First principles calculation of inhomogeneous broadening in solid-state cw-EPR spectroscopy. AB - We present a scheme for the first-principles calculation of EPR lineshapes for continuous-wave-EPR spectroscopy (cw-EPR) of spin centers in complex chemical environments. We specifically focus on poorly characterized systems, e.g. powders and frozen glasses with variable microsolvation structures. Our approach is based on ab initio molecular dynamics simulations and ab initio calculations of the ensemble of g- and A-tensors along the trajectory. The method incorporates temperature effects as well as the full anharmonicity of the intra- and intermolecular degrees of freedom of the system. We apply this scheme to compute the lineshape of a prototypical spin probe, the nitrosodisulfonate dianionic radical (Fremy's salt), dissolved in a 50 : 50 mixture of water and methanol. We are able to determine the specific effect of variations of local solvent composition and microsolvation structure on the cw-EPR lineshape. Our molecular dynamics reveal a highly anisotropic solvation structure with distinct spatial preferences for water and methanol around Fremy's salt that can be traced back to a combination of steric and polar influences. The overall solvation structure and conformational preferences of Fremy's salt as found in our MD simulations agree very well with the results obtained from EPR and orientation-selective ENDOR spectroscopy performed on the frozen glass. The simulated EPR lineshapes show good agreement with the experimental spectra. When combined with our MD results, they characterize the lineshape dependence on local morphological fluctuations. PMID- 23985881 TI - Vaccination with plasmid DNA encoding a mutant toxic shock syndrome toxin-1 ameliorates toxin-induced lethal shock in mice. AB - Staphylococcal toxic shock syndrome toxin-1 (TSST-1), a superantigenic toxin produced by Staphylococcus (S.) aureus, is a major cause of septic shock and toxic shock syndrome. To investigate whether vaccination with a plasmid DNA encoding a non-toxic mutant TSST-1 (mTSST-1) can protect mice against wild-type TSST-1-induced lethal shock, the mice were intranasally immunized with the plasmid DNA (named pcDNA-mTSST-1) plus a mucosal adjuvant, a non-toxic mutant labile toxin (mLT). After the immunization, the mice were challenged with TSST-1 and lipopolysaccharide (LPS). The survival rate of mice immunized with pcDNA mTSST-1 plus mLT was higher than that of the control mice immunized with PBS alone, mLT alone, pcDNA-mTSST-1 alone, or a parent plasmid plus mLT. The titers of interferon-gamma (IFN-gamma) in the sera of mice immunized with pcDNA-mTSST-1 plus mLT were significantly lower than those of the mLT control mice. Immunization with pcDNA-mTSST-1 plus mLT increased the serum levels of TSST-1 specific antibodies, especially immunoglobulin G1 (IgG1) and IgG2a subclasses. Furthermore, the sera obtained from mice immunized with pcDNA-mTSST-1 plus mLT significantly inhibited the TSST-1-induced secretion of IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) in murine spleen cells in vitro. These results indicate that immunization with pcDNA-mTSST-1 plus mLT provides protection against the lethal toxic shock of mice induced by wild-type TSST-1. The protective effect could be due to TSST-1-specific neutralizing antibodies as well as the inhibition of IFN-gamma and TNF-alpha secretions. Since TSST-1 is commonly released by invasive S. aureus, the pcDNA-mTSST-1 should be useful in preventing toxin-induced shock resulting from S. aureus infection. PMID- 23985879 TI - Resistant hypertension: patient characteristics, risk factors, co-morbidities and outcomes. AB - Among the vast population of hypertensive subjects, between 10 and 15% do not achieve an adequate blood pressure (BP) control despite the use of at least three antihypertensive agents. This group, designated as having resistant hypertension (RH), represents one of the most important clinical challenges in hypertension evaluation and management. Resistant hypertensives are characterized by several clinical particularities, such as a longer history of hypertension, obesity and other accompanying factors, such as diabetes, left ventricular hypertrophy, albuminuria and renal dysfunction. In addition to other diagnostic and therapeutic maneuvers, such as excluding secondary hypertension, ensuring treatment adherence and optimizing therapeutic schemes, ambulatory BP monitoring (ABPM) is crucial in the clinical evaluation of patients with RH. ABPM distinguish between those with out-of-office BP elevation (true resistant hypertensives) and those having white-coat RH (WCRH; normalcy of 24-h BPs), the prevalence of the latter estimated in about one-third of the population with RH. True resistant hypertensives also exhibit more frequently other co-morbidities, more severe target organ damage and a worse cardiovascular prognosis, in comparison to those with WCRH. Some device-based therapies have recently been developed for treatment of RH. This requires a better characterization of a potential candidate population. A better knowledge of the clinical features of resistant hypertensive subjects, the confirmation of elevated BP values out of the doctor's office, and improvements in the search for secondary causes would help to select those candidates for newer therapies, once the pharmacological possibilities have been exhausted. PMID- 23985882 TI - Severe hypokalemic paralysis as a manifestation of a mitochondrial disorder. AB - Mitochondrial disorder (MtD) is usually a multisystem disease due to impaired mitochondrial energy production. Severe hypokalemia resulting in muscle weakness and rhabdomyolysis has not been reported as a phenotypic feature of MtD. Here we describe a 60-year-old male patient who developed myalgias followed by generalized muscle weakness a few days before admission. Symptoms were attributed to severe hypokalemia that occurred after the patient had discontinued spironolactone, a competitive antagonist of the aldosterone receptor, four months earlier on his own judgment. Spironolactone was given for 10 years to treat suspected primary hyperaldosteronism (Conn's syndrome). He presented with myopathic face, bilateral ptosis, hypertelorism, brachydactylia, weakness of the axial and limb muscles, and bilateral leg edema. Hypertelorism and brachydactylia are known as physical traits of MtD. Laboratory investigations revealed hypokalemia of 1.7 mmol/l and elevated serum levels of creatine kinase (2,772 U/l). Electrocardiogram showed sinus rhythm, left bundle-branch-block, repolarization abnormalities, and prolonged QTc (571 ms), which is associated with a propensity to ventricular arrhythmias. Diagnostic work-up revealed bilateral adenomas of the suprarenal glands. Conn's syndrome was regarded as a manifestation of MtD, since MtDs are frequently associated with endocrine abnormalities. The patient also presented with occasional double vision, ptosis, renal insufficiency, bilateral renal cysts, hypertriglyceridemia, arterial hypertension, and hypertrophic cardiomyopathy. Taken together, we have made the diagnosis of MtD. In conclusion, MtD may be associated with adrenal adenomas, which may cause severe symptomatic hypokalemia, manifesting as generalized weakness and myalgias due to rhabdomyolysis. Endocrine involvement may be a phenotypic feature of MtD. PMID- 23985883 TI - Prediction of severe retinopathy of prematurity using the WINROP algorithm in a birth cohort in South East Scotland. AB - PURPOSE: We tested the ability of the 'Weight, IGF-1, Neonatal Retinopathy of Prematurity (WINROP)' clinical algorithm to detect preterm infants at risk of severe Retinopathy of Prematurity (ROP) in a birth cohort in the South East of Scotland. In particular, we asked the question: 'are weekly weight measurements essential when using the WINROP algorithm?' STUDY DESIGN: This was a retrospective cohort study. Anonymised clinical data were uploaded to the online WINROP site, and infants at risk of developing severe ROP were identified. The results using WINROP were compared with the actual ROP screening outcomes. Infants with incomplete weight data were included in the whole group, but were excluded from a subgroup analysis of infants with complete weight data. In addition, data were manipulated to test whether missing weight data points in the early neonatal period would lead to loss of sensitivity of the algorithm. RESULTS: The WINROP algorithm had 73% sensitivity for detecting infants at risk of severe ROP when all infants were included and 87% when the complete weight data subgroup was analysed. Manipulation of data from the complete weight data subgroup demonstrated that one or two missing weight data points in the early postnatal period lead to loss of sensitivity performance by WINROP. IMPLICATIONS: The WINROP program offers a non-invasive method of identifying infants at high risk of severe ROP and also identifying those not at risk. However, for WINROP to function optimally, it has to be used as recommended and designed, namely weekly body weight measurements are required. PMID- 23985884 TI - Chronic neuropathic pain: pharmacological interventions in the new millennium. PMID- 23985885 TI - The psychology of pain. PMID- 23985886 TI - Opioids: a review of the pharmacology. PMID- 23985887 TI - Compounding intrathecal medications. PMID- 23985888 TI - Postherpetic neuralgia. PMID- 23985889 TI - Particulates in parenterals. PMID- 23985890 TI - The basics of compounding: compounding medication sticks. PMID- 23985891 TI - Stability of alatrofloxacin mesylate in 5% dextrose injection and 0.45% sodium chloride injecion. AB - A high-performance liquid chromatographic assay method for the quantitation of alatrofloxacin in intravenous (IV) admixtures has been developed. The method is accurate and precise, with a percent relative standard deviation of 1.2% based on five injections. The method is stability indicating since the product of decomposition, trovafloxacin, did not interfere with the assay procedure. The IV admixtures of alatrofloxacin (1.88 mg/mL) in 5% dextrose and 0.45% sodium chloride injections were stable for at least nine days when stored at room themperature. The pH values of the admixtures did not change and they remained clear throughout this study. PMID- 23985892 TI - Naratriptan hydrochloride in extemporaneosly compounded oral suspensions. AB - The purpose of this study was to determine the pharmaceutical acceptability and chemical stability of naratriptan hydrochloride in three extemporaneously compounded suspension formulations. The naratriptan-hydrochloride oral suspensions were prepared from 2.5-mg commercial tablets yielding a nominal naratriptan concentration of 0.5 mg/mL. The suspension vehicles selected for testing were Syrpalta, an equal-parts mixture of Ora-Plus and Ora-Sweet, and an equal-parts mixture of Ora-Plus and Ora-Sweet SF. The tablets were crushed and thoroughly triturated to a fine powder using a porcelain mortar and pestle. The powder was incorporated into a portion of the Syrpalta or Ora-Plus suspension vehicle and mixed until homogeneous. The mixtures were then brought to volume with Syrpalta, Ora-Sweet or Ora-Sweet SF, as appropriate. The suspensions were packaged in amber, plastic, screw-cap prescription bottles and stored at 23 deg C for seven days and 4 deg C for 90 days. An adequate suspension was never achieved in Syrpalta. The crushed-tablet powder did not produce a uniformly dispersed mixture and exhibited clumping and a high rate of sedimentation. A distinct layer of the solid tablet material settled immediately after shaking. Over the next four hours, a densely packed, yellow, caked layer formed at the bottom of the containers, making resuspension difficult. During storage, the caking became worse. Chemical analysis was not performed. The Ora-Plus and Ora-Sweet or Ora Sweet SF suspensions had a slight greenish cast and were resuspended without difficulty by shaking for approximately ten seconds, yielding easily poured and homogeneous mixtures throughout the study. Visible settling and layering did not begin for four hours with the Ora-Sweet suspension and 24 hours for the Ora-Sweet SF suspension. High pressure liquid chromatographic analysis found that the naratriptan concentration in both suspension-vehicle combinations exhibited little or no loss for seven days at 23 deg C and 90 days at 4 deg C. At least 96% of the inital concentration remained at all time points. Naratriptan hydrochloride extemporaneously prepared as oral suspensions from tablets in equal parts mixtures of Ora-Plus suspension vehicle with Ora-Sweet and with Ora-Sweet SF syrups was pharmaceutically acceptable and chemically stable for at least seven days at 23 deg C and 90 days at 4 deg C. Syrpalta was unacceptable for use as a vehicle for naratriptan hydrochloride suspensions prepared from tablets. PMID- 23985893 TI - Physicochemical Stability of Compounded Creams Containing a-Hydroxy Acids. AB - The stability of creams containing the a-hydroxy acids (AHAs), lactic acid and glycolic acid, extemporaneously added to aqueous cream, BP or hydrophilic oinment, USP and subjected to five freeze-thaw cycles ranging form -4 to 40 deg C was studied. The pH, viscosity, spreadability, density, appearance and potency were measured after each freeze-thaw cycle. Compounding with hydrophilic ointment, USP produced the most stable creams; but the addition of the AHAs caused a significant decrease in preservative levels. The preservatives methylparaben and propylparaben were not hydrolyzed in the hydrophilic creams if the AHA ws partially neutralized to pH above 3.5. PMID- 23985894 TI - Fibromyalgia. PMID- 23985895 TI - Photophysical origin of the reduced photodynamic therapy activity of temocene compared to Foscan(r): insights from theory. AB - In order to explain the reduced photodynamic (PDT) activity of a recently proposed m-tetra (hydroxyphenyl) porphycene derivative (temocene or THPPo) in terms of singlet oxygen quantum yields compared to porphyrin analogue Foscan (m THPC), a time dependent DFT investigation has been carried out. Computed electronic transitions, singlet-triplet energy gaps and spin-orbit coupling matrix elements (SOCME) can be related to the reduced PDT activity. PMID- 23985896 TI - Enhanced bimolecular exchange reaction through programmed coordination of a five coordinate oxovanadium complex for efficient redox mediation in dye-sensitized solar cells. AB - Electrochemical reversibility and fast bimolecular exchange reaction found for VO(salen) gave rise to a highly efficient redox mediation to enhance the photocurrent of a dye-sensitized solar cell, leading to an excellent photovoltaic performance with a conversion efficiency of 5.4%. A heterogeneous electron transfer rate constant at an electrode (k0) and a second-order rate constant for an electron self-exchange reaction (k(ex)) were proposed as key parameters that dominate the charge transport property, which afforded a novel design concept for the mediators based on their kinetic aspects. PMID- 23985897 TI - RNA expression profiling in brains of familial hemiplegic migraine type 1 knock in mice. AB - BACKGROUND: Various CACNA1A missense mutations cause familial hemiplegic migraine type 1 (FHM1), a rare monogenic subtype of migraine with aura. FHM1 mutation R192Q is associated with pure hemiplegic migraine, whereas the S218L mutation causes hemiplegic migraine, cerebellar ataxia, seizures, and mild head trauma induced brain edema. Transgenic knock-in (KI) migraine mouse models were generated that carried either the FHM1 R192Q or the S218L mutation and were shown to exhibit increased CaV2.1 channel activity. Here we investigated their cerebellar and caudal cortical transcriptome. METHODS: Caudal cortical and cerebellar RNA expression profiles from mutant and wild-type mice were studied using microarrays. Respective brain regions were selected based on their relevance to migraine aura and ataxia. Relevant expression changes were further investigated at RNA and protein level by quantitative polymerase chain reaction (qPCR) and/or immunohistochemistry, respectively. RESULTS: Expression differences in the cerebellum were most pronounced in S218L mice. Particularly, tyrosine hydroxylase, a marker of delayed cerebellar maturation, appeared strongly upregulated in S218L cerebella. In contrast, only minimal expression differences were observed in the caudal cortex of either mutant mice strain. CONCLUSION: Despite pronounced consequences of migraine gene mutations at the neurobiological level, changes in cortical RNA expression in FHM1 migraine mice compared to wild type are modest. In contrast, pronounced RNA expression changes are seen in the cerebellum of S218L mice and may explain their cerebellar ataxia phenotype. PMID- 23985899 TI - Secosteroids and norcembranoids from the soft coral Sinularia nanolobata. AB - Two new 9,11-secosteroids, 22alpha-acetoxy-24-methylene-3beta,6alpha,11 trihydroxy-9, 11-seco-cholest-7-en-9-one (1) and 11-acetoxy-24-methylene 1beta,3beta,6alpha-trihydroxy-9, 11-seco-cholest-7-en-9-one (2), as well as two known norcembranoids, 5-epi-sinuleptolide (3) and sinuleptolide (4), were isolated from the soft coral Sinularia nanolobata. The structures of these metabolites were elucidated on the basis of extensive spectroscopic analysis. The anti-HCMV (human cytomegalovirus) activity of 1-4 and its cytotoxicity against selected cell lines were evaluated. PMID- 23985901 TI - Diluted bee venom injection reduces ipsilateral mechanical allodynia in oxaliplatin-induced neuropathic mice. AB - Oxaliplatin, which is used as one of anti-cancer drugs, commonly induces peripheral neuropathic pain. We have previously reported that an injection of diluted bee venom (DBV) produced a significant anti-nociceptive effects in several pain models of mice or rats. In this study, we evaluated time- and dose dependent development of oxaliplatin-induced mechanical allodynia in bilateral hind paws of mice, and investigated the effect of DBV injection on this mechanical allodynia. DBV (0.1 mg/kg) was subcutaneously injected into the Zusanli acupoint 2 weeks after oxaliplatin (10 mg/kg) injection. One hour after DBV injection, we observed a significant reduction of mechanical allodynia in the ipsilateral hind paw, but not in the contralateral hind paw to DBV injection site. We subsequently examined whether this effect of DBV was related to the activation of peripheral nerves in DBV injected site, and then whether it was mediated by the activation of spinal cord alpha-2 adrenoceptors or opioid receptors. Subcutaneous pre-injection of 2% lidocaine (40 mg/kg) into the Zusanli acupoint completely blocked the anti-allodynic effect of DBV. Intrathecal pretreatment with yohimbine (25 ug/mouse), an alpha-2 adrenoceptor antagonist, also prevented the anti-allodynic effect of DBV, whereas pretreatment with naloxone (20 ug/mouse), an opioid receptor antagonist, did not block the effect of DBV. Taken together, these findings demonstrate that DBV injection into the Zusanli acupoint significantly reduces ipsilateral mechanical allodynia generated by oxaliplatin in mice, and also suggest that this anti-allodynic effect is dependent on the peripheral nerve activation in injected site and spinal cord alpha-2 adrenoceptors. PMID- 23985900 TI - beta-Arrestin 2 mediates G protein-coupled receptor 43 signals to nuclear factor kappaB. AB - G-protein coupled receptor 43 (GPR43) serves as a receptor for short-chain fatty acids (SCFAs), implicated in neutrophil migration and inflammatory cytokine production. However, the intracellular signaling pathway mediating GPR43 signaling remains unclear. Here, we show that beta-arrestin 2 mediates the internalization of GPR43 by agonist. Agonism of GPR43 reduced the phosphorylation and nuclear translocation of nuclear factor-kappaB (NF-kappaB), which was relieved by short interfering RNA (siRNA) of beta-arrestin 2. Subsequently, mRNA expression of proinflammatory cytokines, interleukin (IL)-6 and IL-1beta, was downregulated by activation of GPR43 and knockdown of beta-arrestin 2 recovered the expression of the cytokines. Taken together, these results suggest that GPR43 may be a plausible target for a variety of inflammatory diseases. PMID- 23985898 TI - Apo-9'-fucoxanthinone, isolated from Sargassum muticum, inhibits CpG-induced inflammatory response by attenuating the mitogen-activated protein kinase pathway. AB - Sargassum muticum (S. muticum) is a brown edible alga and widely distributed in Korea. This report was designed to evaluate the anti-inflammatory properties of apo-9'-fucoxanthinone (APO-9') isolated from S. muticum on pro-inflammatory cytokine production. S. muticum extract (SME) exhibited significant inhibitory effects on pro-inflammatory cytokine production in bone marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs). APO-9' pre-treatment in the CpG DNA-stimulated BMDMs and BMDCs showed a strong dose-dependent inhibitory effect on interleukin (IL)-12 p40, IL-6 and tumor necrosis factor (TNF)-alpha production with IC50 values ranging from 5.31 to 13.79. It exhibited a strong inhibitory effect on the phosphorylation of ERK1/2 and on activator protein (AP)-1 reporter activity. APO-9' pre-treatment exhibited significant inhibition of CpG DNA induced production of inducible nitric oxide synthase. Taken together, these data suggest that SME and APO-9' have a significant anti-inflammatory property and warrant further studies concerning the potentials of SME and APO-9' for medicinal use. PMID- 23985902 TI - Calcineurin activity is required for cardiac remodelling in pregnancy. AB - AIMS: Calcium fluctuations and cardiac hypertrophy occur during pregnancy, but the role of the well-studied calcium-activated phosphatase, calcineurin, has not been studied in this setting. The purpose of this study was to determine whether calcineurin signalling is required for cardiac remodelling during pregnancy in mice. METHODS AND RESULTS: We first examined calcineurin expression in the heart of mice during pregnancy. We found both calcineurin levels and activity were significantly increased in early-pregnancy and decreased in late-pregnancy. Since progesterone levels start to rise in early-pregnancy, we investigated whether progesterone alone was sufficient to modulate calcineurin levels in vivo. After implantation of progesterone pellets in non-pregnant female mice, cardiac mass increased, whereas cardiac function was maintained. In addition, calcineurin levels increased, which is also consistent with early-pregnancy. To determine whether these effects were occurring in the cardiac myocytes, we treated neonatal rat ventricular myocytes (NRVMs) with pregnancy-associated sex hormones. We found that progesterone treatment, but not oestradiol, increased calcineurin levels. To obtain a functional read-out of increased calcineurin activity, we measured the activity of the transcription factor NFAT, a downstream target of calcineurin. Progesterone treatment significantly increased NFAT activity in NRVMs, and this was blocked by the calcineurin inhibitor cyclosporine A (CsA), showing that the progesterone-mediated increase in NFAT activity requires calcineurin activity. Importantly, CsA treatment of mice completely blocked pregnancy-induced cardiac hypertrophy. CONCLUSION: Our results show that calcineurin is required for pregnancy-induced cardiac hypertrophy, and that calcineurin activity in early pregnancy is due at least in part to increased progesterone. PMID- 23985903 TI - Oxidative stress modulates vascular smooth muscle cell phenotype via CTGF in thoracic aortic aneurysm. AB - AIMS: Dissection and rupture of the ascending aorta are life-threatening conditions resulting in 80% mortality. Ascending aortic replacement in patients presenting with thoracic aortic aneurysm (TAA) is determined by metric measurement. However, a significant number of dissections occur outside of the parameters suggested by the current guidelines. We investigate the correlation among altered haemodynamic condition, oxidative stress, and vascular smooth muscle cell (VSMC) phenotype in controlling tissue homoeostasis. METHODS AND RESULTS: We demonstrate using finite element analysis (FEA) based on computed tomography geometries that TAA patients have higher wall stress in the ascending aorta than non-dilated patients. We also show that altered haemodynamic conditions are associated with increased levels of reactive oxygen species (ROS), direct regulators of the VSMC phenotype in the microregional area of the ascending aorta. Using in vitro and ex vivo studies on human tissues, we show that ROS accumulation correlates with media layer degeneration and increased connective tissue growth factor (CTGF) expression, which modulate the synthetic VSMC phenotype. Results were validated by a murine model of TAA (C57BL/6J) based on Angiotensin II infusion showing that medial thickening and luminal expansion of the proximal aorta is associated with the VSMC synthetic phenotype as seen in human specimens. CONCLUSIONS: Increased peak wall stress correlates with change in VSMC towards a synthetic phenotype mediated by ROS accumulation via CTGF. Understanding the molecular mechanisms that regulate VSMC towards a synthetic phenotype could unveil new regulatory pathways of aortic homoeostasis and impact the risk-stratification tool for patients at risk of aortic dissection and rupture. PMID- 23985904 TI - Multi-electrode stimulation in somatosensory cortex increases probability of detection. AB - OBJECTIVE: Brain machine interfaces (BMIs) that decode control signals from motor cortex have developed tremendously in the past decade, but virtually all rely exclusively on vision to provide feedback. There is now increasing interest in developing an afferent interface to replace natural somatosensation, much as the cochlear implant has done for the sense of hearing. Preliminary experiments toward a somatosensory neuroprosthesis have mostly addressed the sense of touch, but proprioception, the sense of limb position and movement, is also critical for the control of movement. However, proprioceptive areas of cortex lack the precise somatotopy of tactile areas. We showed previously that there is only a weak tendency for neighboring neurons in area 2 to signal similar directions of hand movement. Consequently, stimulation with the relatively large currents used in many studies is likely to activate a rather heterogeneous set of neurons. APPROACH: Here, we have compared the effect of single-electrode stimulation at subthreshold levels to the effect of stimulating as many as seven electrodes in combination. MAIN RESULTS: We found a mean enhancement in the sensitivity to the stimulus (d') of 0.17 for pairs compared to individual electrodes (an increase of roughly 30%), and an increase of 2.5 for groups of seven electrodes (260%). SIGNIFICANCE: We propose that a proprioceptive interface made up of several hundred electrodes may yield safer, more effective sensation than a BMI using fewer electrodes and larger currents. PMID- 23985905 TI - Biographical feature: Eileen L. Randall, Ph.D. PMID- 23985906 TI - National surveillance of methicillin-resistant Staphylococcus aureus in China highlights a still-evolving epidemiology with 15 novel emerging multilocus sequence types. AB - The global spread of methicillin-resistant Staphylococcus aureus (MRSA) is a serious problem, particularly in mainland China. In order to better understand the national molecular epidemiology and resistance profiles of hospital associated MRSA (HA-MRSA) in China, a laboratory-based multicenter surveillance study was conducted. Sixty-nine hospitals in 45 large cities in 27 provinces were involved, and a total of 1,141 HA-MRSA isolates were collected during the 6-month study period in 2011. All MRSA isolates were characterized by multilocus sequence typing (MLST), staphylococcal cassette chromosome mec (SCCmec) typing, spa typing, detection of the Panton-Valentine leukocidin (PVL) locus (lukS-PV and lukF-PV), and antibiogram analysis. ST239-III-t030, ST239-III-t037, and ST5-II t002 were the predominant HA-MRSA clones (overall prevalence rates, 57.1%, 12.9%, and 8.1%, respectively), although the prevalence rates of these major clones varied markedly in different administrative regions. Of note, 6.6% of the HA-MRSA isolates were found to belong to ST59, which had typical community-associated MRSA (CA-MRSA) features, including carriage of SCCmec type IV or V and PVL and less antimicrobial resistance than other major HA-MRSA clones. Moreover, among 36 MLST sequence types (STs) identified, 15 STs, accounting for 3.5% of total isolates, were novel. A novel ST designated ST2590, which is a single-locus variant of ST5-II-t002, was identified in three hospitals in two large cities, with a total of 17 isolates. To further monitor trends in HA-MRSA prevalence, epidemic clonal shifts, clone emergence, and transmission between community and health care settings, longitudinal national MRSA surveillance is required. PMID- 23985907 TI - Dynamics of defective hepatitis C virus clones in reinfected liver grafts in liver transplant recipients: ultradeep sequencing analysis. AB - Hepatitis C virus (HCV) reinfects liver allografts in transplant recipients by replicating immediately after transplantation, causing a rapid increase in blood serum HCV RNA levels. We evaluated dynamic changes in the viral genetic complexity after HCV reinfection of the graft liver; we also identified the characteristics of replicating HCV clones using a massively parallel ultradeep sequencing technique to determine the full-genome HCV sequences in the liver and serum specimens of five transplant recipients with genotype 1b HCV infection before and after liver transplantation. The recipients showed extremely high genetic heterogeneity before transplantation, and the HCV population makeup was not significantly different between the liver and blood serum specimens of the individuals. Viral quasispecies complexity in serum was significantly lower after liver transplantation than before it, suggesting that certain HCV clones selectively proliferated after transplantation. Defective HCV clones lacking the structural region of the HCV genome did not increase in number, and full-genome HCV clones selectively increased in number immediately after liver transplantation. A re-increase in the same defective clone existing before transplantation was detected 22 months after transplantation in one patient. Ultradeep sequencing technology revealed that the genetic heterogeneity of HCV was reduced after liver transplantation. Dynamic changes in defective HCV clones after liver transplantation indicate that these clones have important roles in the HCV life cycle. PMID- 23985908 TI - Classical molecular tests using urine samples as a potential screening tool for human papillomavirus detection in human immunodeficiency virus-infected women. AB - Human papillomavirus (HPV) is the main risk factor associated with the development of cervical cancer (CC); however, there are other factors, such as immunosuppression caused by the human immunodeficiency virus (HIV), that favor progression of the illness. This study was thus aimed at evaluating the functionality of classical PCR-based molecular tests for the generic identification of HPV DNA (GP5+/GP6+, MY09/MY11, and pU1M/2R primers, individually or in combination) using cervical and urine samples from 194 HIV positive women. Infected samples were tested with type-specific primers for six high-risk types (HPV-16, -18, -31, -33, -45, and -58) and two low-risk types (HPV 6 and -11). HPV infection prevalence rates were 70.1% for the cervical samples and 63.9% for the urine samples. HPV-16 was the most prevalent viral type in the cervical and urine samples, with higher rates of multiple infections than single infections detected in such samples. HPV DNA detection by PCR (mainly with the pU1M/2R primer set) in urine samples was positively associated with abnormal cytological findings (atypical squamous cells of undetermined significance/squamous intraepithelial lesions [ASCUS/SIL]). It was determined that the operative characteristics for detection of cytological abnormalities were similar for cervical and urine samples. This suggested using PCR for the detection of HPV DNA in urine samples as a potential screening strategy for CC prevention in future prevention and control programs along with currently implemented strategies for reducing the impact of the disease, i.e., urine samples are economical, are easy to collect, have wide acceptability among women, and have operative characteristics similar to those of cervical samples. PMID- 23985909 TI - Simultaneous detection of major drug resistance mutations in the protease and reverse transcriptase genes for HIV-1 subtype C by use of a multiplex allele specific assay. AB - High-throughput, sensitive, and cost-effective HIV drug resistance (HIVDR) detection assays are needed for large-scale monitoring of the emergence and transmission of HIVDR in resource-limited settings. Using suspension array technology, we have developed a multiplex allele-specific (MAS) assay that can simultaneously detect major HIVDR mutations at 20 loci. Forty-five allele specific primers tagged with unique 24-base oligonucleotides at the 5' end were designed to detect wild-type and mutant alleles at the 20 loci of HIV-1 subtype C. The MAS assay was first established and optimized with three plasmid templates (C-wt, C-mut1, and C-mut2) and then evaluated using 148 plasma specimens from HIV 1 subtype C-infected individuals. All the wild-type and mutant alleles were unequivocally distinguished with plasmid templates, and the limits of detection were 1.56% for K219Q and K219E, 3.13% for L76V, 6.25% for K65R, K70R, L74V, L100I, K103N, K103R, Q151M, Y181C, and I47V, and 12.5% for M41L, K101P, K101E, V106A, V106M, Y115F, M184V, Y188L, G190A, V32I, I47A, I84V, and L90M. Analyses of 148 plasma specimens revealed that the MAS assay gave 100% concordance with conventional sequencing at eight loci and >95% (range, 95.21% to 99.32%) concordance at the remaining 12 loci. The differences observed were caused mainly by 24 additional low-abundance alleles detected by the MAS assay. Ultradeep sequencing analysis confirmed 15 of the 16 low-abundance alleles. This multiplex, sensitive, and straightforward result-reporting assay represents a new efficient genotyping tool for HIVDR surveillance and monitoring. PMID- 23985910 TI - Development of a treatment algorithm for streptococci and enterococci from positive blood cultures identified with the Verigene Gram-positive blood culture assay. AB - Seventy-eight blood cultures with a Gram stain result of Gram-positive cocci in pairs and/or chains were evaluated with the Nanosphere Verigene Gram-positive blood culture (BC-GP) assay. The overall concordance of the assay with culture was 89.7% (70/78 cultures), allowing for the development of a targeted treatment algorithm. PMID- 23985911 TI - Evaluation of bactec mycosis IC/F and Plus Aerobic/F blood culture bottles for detection of Candida in the presence of antifungal agents. AB - Clinical practice guidelines recommend performing follow-up cultures for patients with candidemia in order to determine the time when Candida is cleared from the bloodstream. Since this requires culturing blood samples from patients undergoing antifungal treatment, we evaluated two blood culture bottles (the Bactec Mycosis IC/F [MICF], specifically adapted to the growth of fungi, and the Bactec Plus Aerobic/F [PAF], containing resins to inactivate anti-infective agents) for their effectiveness in detecting Candida albicans and Candida glabrata when seeded in concentrations of 1 CFU/ml and 10 CFU/ml, respectively, together with human whole blood and various antifungal agents in therapeutic peak serum concentrations (Cmax). Significant differences between the MICF and PAF vials for the detection of Candida spp. were found when inoculated with caspofungin (0/12 versus 8/12) (P < 0.001) or amphotericin B (3/12 versus 12/12) (P < 0.001). Inoculation of fluconazole or voriconazole did not influence the effectiveness of detection in the MICF and PAF bottles (P = 1.0). Neither the MICF nor the PAF bottles detected Candida spp. reliably when seeded together with anidulafungin (1/12 versus 1/12) (P = 1.0) or micafungin (0/12 versus 1/12) (P = 1.0). The times to positivity of both bottles were significantly prolonged when antifungal agents were added compared to those of controls without antimycotic drugs (P < 0.001). Overall, the results of this in vitro study indicate that the PAF bottles detected Candida spp. more reliably than the MICF bottles when supplemented with certain antifungal agents. Consequently, clinical studies should evaluate whether this holds true when blood cultures from patients undergoing antifungal treatment are performed. PMID- 23985912 TI - The Aptima HPV assay fulfills the cross-sectional clinical and reproducibility criteria of international guidelines for human papillomavirus test requirements for cervical screening. AB - The Aptima HPV assay (Hologic Gen-Probe, San Diego, CA) is an FDA-approved assay for detecting human papillomavirus (HPV) E6/E7 mRNA from 14 high-risk HPV types. This study evaluated the clinical performance of the Aptima HPV assay for cervical intraepithelial neoplasia of grade 2 or worse (CIN2+), relative to the high-risk HPV GP5+/GP6+ PCR, in a cross-sectional clinical equivalence analysis using the noninferiority score test with cervical samples from population-based screening, i.e., 69 cervical scraping samples from women with CIN2+ and 843 from women without evidence of CIN2+. In addition, intralaboratory reproducibility over time and interlaboratory agreement of the Aptima HPV assay results were assessed with another set of 548 cervical samples. The Aptima HPV assay showed a clinical sensitivity for CIN2+ of 94.2% (95% confidence interval [CI], 85.5 to 97.8%) and a clinical specificity for CIN2+ of 94.5% (95% CI, 92.8 to 95.9%); by comparison, these figures were 97.1% (95% CI, 89.1 to 99.3%) (67/69 samples) and 93.6% (95% CI, 91.7 to 95.0%) (785/839 samples), respectively, for GP5+/GP6+ PCR. The clinical sensitivity and specificity of the Aptima HPV assay were noninferior to those of GP5+/GP6+ PCR (P = 0.039 and 0.00016, respectively). In addition, high reproducibility of the Aptima HPV assay, as reflected by the intralaboratory reproducibility over time of 96.0% (95% CI, 94.4 to 97.3%) (526/548 samples; kappa = 0.89) and interlaboratory agreement of 96.7% (95% CI, 95.4 to 98.1%) (531/548 samples; kappa = 0.91), was found. Altogether, these data show that the Aptima HPV assay meets the cross-sectional clinical and reproducibility criteria of the international guidelines for HPV test requirements for cervical screening. Longitudinal data are needed to ensure that the long-term negative predictive value of this mRNA assay is similar to those of validated HPV DNA tests. PMID- 23985913 TI - Rapid determination of colistin resistance in clinical strains of Acinetobacter baumannii by use of the micromax assay. AB - Colistin is an old antibiotic which has been used as a therapeutic option for carbapenem- and multidrug-resistant Gram-negative bacteria, like Acinetobacter baumannii. This pathogen produces life-threatening infections, mainly in patients admitted to intensive care units. Rapid detection of resistance to colistin may improve patient outcomes and prevent the spread of resistance. For this purpose, Micromax technology was evaluated in four isogenic A. baumannii strains with known mechanisms of resistance to colistin and in 66 isolates (50 susceptible and 16 resistant). Two parameters were determined, DNA fragmentation and cell wall damage. To assess DNA fragmentation, cells trapped in a microgel were incubated with a lysing solution to remove the cell wall, and the released nucleoids were visualized under fluorescence microscopy. Fragmented DNA was observed as spots that diffuse from the nucleoid. To assess cell wall integrity, cells were incubated with a lysis solution which removes only weakened cell walls, resulting in nucleoid release exclusively in affected cells. A dose-response relationship was demonstrated between colistin concentrations and the percentages of bacteria with DNA fragmentation and cell wall damage, antibiotic effects that were delayed and less frequent in resistant strains. Receiver operating characteristic (ROC) curves demonstrated that both DNA fragmentation and cell wall damage were excellent parameters for identifying resistant strains. Obtaining <=11% of bacteria with cell wall damage after incubation with 0.5 MUg/ml colistin identified resistant strains of A. baumannii with 100% sensitivity and 96% specificity. Results were obtained in 3 h 30 min. This is a simple, rapid, and accurate assay for detecting colistin resistance in A. baumannii, with strong potential value in critical clinical situations. PMID- 23985914 TI - Splitting of a prevalent Mycobacterium bovis spoligotype by variable-number tandem-repeat typing reveals high heterogeneity in an evolving clonal group. AB - Mycobacterium bovis populations in countries with persistent bovine tuberculosis usually show a prevalent spoligotype with a wide geographical distribution. This study applied mycobacterial interspersed repetitive-unit-variable-number tandem repeat (MIRU-VNTR) typing to a random panel of 115 M. bovis isolates that are representative of the most frequent spoligotype in the Iberian Peninsula, SB0121. VNTR typing targeted nine loci: ETR-A (alias VNTR2165), ETR-B (VNTR2461), ETR-D (MIRU4, VNTR580), ETR-E (MIRU31, VNTR3192), MIRU26 (VNTR2996), QUB11a (VNTR2163a), QUB11b (VNTR2163b), QUB26 (VNTR4052), and QUB3232 (VNTR3232). We found a high degree of diversity among the studied isolates (discriminatory index [D] = 0.9856), which were split into 65 different MIRU-VNTR types. An alternative short-format MIRU-VNTR typing targeting only the four loci with the highest variability values was found to offer an equivalent discriminatory index. Minimum spanning trees using the MIRU-VNTR data showed the hypothetical evolution of an apparent clonal group. MIRU-VNTR analysis was also applied to the isolates of 176 animals from 15 farms infected by M. bovis SB0121; in 10 farms, the analysis revealed the coexistence of two to five different MIRU types differing in one to six loci, which highlights the frequency of undetected heterogeneity. PMID- 23985915 TI - Molecular detection of culture-confirmed bacterial bloodstream infections with limited enrichment time. AB - Conventional blood culturing using automated instrumentation with phenotypic identification requires a significant amount of time to generate results. This study investigated the speed and accuracy of results generated using PCR and pyrosequencing compared to the time required to obtain Gram stain results and final culture identification for cases of culture-confirmed bloodstream infections. Research and physician-ordered blood cultures were drawn concurrently. Aliquots of the incubating research blood culture fluid were removed hourly between 5 and 8 h, at 24 h, and again at 5 days. DNA was extracted from these 6 time point aliquots and analyzed by PCR and pyrosequencing for bacterial rRNA gene targets. These results were then compared to those of the physician-ordered blood culture. PCR and pyrosequencing accurately identified 92% of all culture-confirmed cases after a mean enrichment time of 5.8 +/- 2.9 h. When the time needed to complete sample processing was included for PCR and pyrosequencing protocols, the molecular approach yielded results in 11.8 +/- 2.9 h compared to means of 27.9 +/- 13.6 h to obtain the Gram stain results and 81.6 +/- 24.0 h to generate the final culture-based identification. The molecular approach enabled accurate detection of most bacteria present in incubating blood culture bottles on average about 16 h sooner than Gram stain results became available and approximately 3 days sooner than the phenotypic identification was entered in the Laboratory Information System. If implemented, this more rapid molecular approach could minimize the number of doses of unnecessary or ineffective antibiotics administered to patients. PMID- 23985917 TI - Comparison of nucleic acid amplification assays with BD affirm VPIII for diagnosis of vaginitis in symptomatic women. AB - A commercially available, nonamplified, nucleic acid probe-based test system (BD Affirm VPIII) was compared with nucleic acid amplification (NAA)-based assays for determining the etiology of vaginitis in a cohort of 323 symptomatic women. First, a semiquantitative, multiplexed PCR assay (BV-PCR) and the Affirm VPIII Gardnerellavaginalis test were compared with a unified bacterial-vaginosis (BV) reference standard incorporating both Nugent Gram stain scores and Amsel clinical criteria. In the evaluable population of 305 patients, BV-PCR was 96.9% (191/197) sensitive and 92.6% specific (100/108) for BV, while Affirm VPIII was 90.1% sensitive (179/197) and 67.6% specific (73/108). Second, a multiplexed PCR assay detecting Candida albicans and Candida glabrata (CAN-PCR) was compared with the Affirm VPIII Candida test using a reference standard for vulvovaginal candidiasis (VVC) of yeast culture plus exclusion of alternate vaginitis etiologies. In the population evaluated (n = 102), CAN-PCR was 97.7% sensitive (42/43) and 93.2% specific (55/59) and Affirm VP III was 58.1% sensitive (25/43) and 100% specific (59/59) for VVC. Finally, the results of a commercial NAA test (GenProbe Aptima Trichomonas vaginalis assay; ATV) for T. vaginalis were compared with the Affirm VPIII Trichomonas vaginalis test. In the absence of an independent reference standard for trichomonal vaginitis (TV), a positive result in either assay was deemed to represent true infection. In the evaluable cohort of 388 patients, the sensitivity of ATV was 98.1% (53/54) versus 46.3% (25/54) for Affirm VPIII. The diagnostic accuracy of the combined NAA-based test construct was approximately 20 to 25% higher than that of the Affirm VPIII when modeled in populations with various prevalences of infectious vaginitis. PMID- 23985916 TI - Detection of cytomegalovirus drug resistance mutations by next-generation sequencing. AB - Antiviral therapy for cytomegalovirus (CMV) plays an important role in the clinical management of solid organ and hematopoietic stem cell transplant recipients. However, CMV antiviral therapy can be complicated by drug resistance associated with mutations in the phosphotransferase UL97 and the DNA polymerase UL54. We have developed an amplicon-based high-throughput sequencing strategy for detecting CMV drug resistance mutations in clinical plasma specimens using a microfluidics PCR platform for multiplexed library preparation and a benchtop next-generation sequencing instrument. Plasmid clones of the UL97 and UL54 genes were used to demonstrate the low overall empirical error rate of the assay (0.189%) and to develop a statistical algorithm for identifying authentic low abundance variants. The ability of the assay to detect resistance mutations was tested with mixes of wild-type and mutant plasmids, as well as clinical CMV isolates and plasma samples that were known to contain mutations that confer resistance. Finally, 48 clinical plasma specimens with a range of viral loads (394 to 2,191,011 copies/ml plasma) were sequenced using multiplexing of up to 24 specimens per run. This led to the identification of seven resistance mutations, three of which were present in <20% of the sequenced population. Thus, this assay offers more sensitive detection of minor variants and a higher multiplexing capacity than current methods for the genotypic detection of CMV drug resistance mutations. PMID- 23985918 TI - Alerting physicians during electronic order entry effectively reduces unnecessary repeat PCR testing for Clostridium difficile. AB - Hospital information systems (HIS) alerts restricting repeat Clostridium difficile PCR ordering by physicians in patients with a prior result within 7 days eliminated 91% of repeat tests, from 14.5% (282/1,949) repeats preintervention to 1.3% (135/10,285) postintervention. HIS alerting is an effective, targeted, patient-specific tool for improving the quality and utilization of C. difficile results. PMID- 23985919 TI - Novel approach for differentiating Shigella species and Escherichia coli by matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - Shigella species are so closely related to Escherichia coli that routine matrix assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) cannot reliably differentiate them. Biochemical and serological methods are typically used to distinguish these species; however, "inactive" isolates of E. coli are biochemically very similar to Shigella species and thus pose a greater diagnostic challenge. We used ClinProTools (Bruker Daltonics) software to discover MALDI-TOF MS biomarker peaks and to generate classification models based on the genetic algorithm to differentiate between Shigella species and E. coli. Sixty-six Shigella spp. and 72 E. coli isolates were used to generate and test classification models, and the optimal models contained 15 biomarker peaks for genus-level classification and 12 peaks for species-level classification. We were able to identify 90% of E. coli and Shigella clinical isolates correctly to the species level. Only 3% of tested isolates were misidentified. This novel MALDI TOF MS approach allows laboratories to streamline the identification of E. coli and Shigella species. PMID- 23985920 TI - Rapid Identification of microbes in positive blood cultures by use of the vitek MS matrix-assisted laser desorption ionization-time of flight mass spectrometry system. AB - Sepsis is a major cause of death worldwide among nonhospitalized people and hospitalized patients. A wide range of pathogens are involved, and the correct identification and correct antimicrobial therapy are critical to ensure optimal clinical outcomes. With the recent introduction of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), rapid identification of bacteria and fungi is now possible. The purpose of this study was to develop a rapid technique for identifying organisms in positive blood cultures using the Vitek MS system (bioMerieux). This technique is a lysis centrifugation method which involves a four-step washing and centrifugation procedure. A total of 253 positive monomicrobial blood cultures (Bactec Plus aerobic, anaerobic, and pediatric bottles) were tested using the Vitek MS system (KnowledgeBase version 2.0), with 92.1% and 88.1% of organisms overall being identified to the genus level and the species level, respectively. Of 161 Gram positive bacterial isolates, 95.7% and 90.1% were identified to the genus level and the species level, respectively; of 92 Gram-negative bacterial isolates, 84.7% and 83.7% were identified to the genus level and the species level, respectively. The results obtained using this method demonstrate that the Vitek MS system can be used for rapid and effective identification of bacteria from positive blood cultures within 30 to 45 min after the positive signal has been provided by the Bactec FX blood culture system (Becton, Dickinson). This will lead to faster administration of the appropriate antimicrobial therapy and increase the chances for optimal clinical outcomes for patients. PMID- 23985921 TI - Implications of culture-independent panel-based detection of Cyclospora cayetanensis. PMID- 23985922 TI - Detection and identification of yeasts from formalin-fixed, paraffin-embedded tissue by use of PCR-electrospray ionization mass spectrometry. AB - Diagnosis of yeast infection is typically accomplished by fungal smear and culture, histopathologic examination, and/or serologic studies. Newer assays based on mass spectrometry may be useful for yeast identification when histologic examination is inconclusive, fungal cultures are not ordered, or cultures fail to yield a causative agent. The purpose of this study was to evaluate the ability of the PLEX-ID broad fungal assay to accurately detect and identify yeasts in formalin-fixed paraffin-embedded (FFPE) tissues. Tissue samples from 78 FFPE specimens with both histopathology and corresponding culture results for a variety of yeasts were tested using the PLEX-ID broad fungal assay. A 40-MUm FFPE tissue section from each specimen was digested with proteinase K followed by nucleic acid extraction and PCR using broad-range fungal primers. Yeast DNA in amplified products was identified using electrospray ionization mass spectrometry. Discordant results were resolved by D2 rRNA gene sequencing. PLEX ID analysis detected yeast DNA in 78.2% (61/78) of the cases, of which 91.8% (56/61) were concordant with culture results. Of the 5 discordant positive results, 4 PLEX-ID results were considered to result from environmental contaminants, while 1 clinically important discrepancy was observed (Blastomyces dermatitidis by culture and Cryptococcus neoformans by PLEX-ID). Sequencing of the discordant sample was unsuccessful. The majority of histopathology results (89.7% [70/78]) correlated with culture results. The PLEX-ID broad fungal assay identifies fungi directly from FFPE tissues and can be a useful adjunct to traditional culture and histopathology tests. PMID- 23985923 TI - Outbreak of extensively drug-resistant Acinetobacter baumannii indigo-pigmented strains. AB - Acinetobacter baumannii pigmented strains are not common in clinical settings. Here, we report an outbreak caused by indigo-pigmented A. baumannii strains isolated in an acute care hospital in Argentina from March to September 2012. Pan PCR assays exposed a unique pattern belonging to the recently described regional CC113(B)/CC79(P) clonal complex that confirms the relevant relationships among the indigo-pigmented A. baumannii strains. All of them were extensively drug resistant and harbored different genetic elements associated with horizontal genetic transfer, such as the transposon Tn2006, class 2 integrons, AbaR-type islands, IS125, IS26, strA, strB, florR, and the small recombinase ISCR2 associated with the sul2 gene preceded by ISAba1. PMID- 23985925 TI - Molecular typing of "Candidatus Bartonella ancashi," a new human pathogen causing verruga peruana. AB - A recently described clinical isolate, "Candidatus Bartonella ancashi," was obtained from a blood sample of a patient presenting with verruga peruana in the Ancash region of Peru. This sample and a second isolate obtained 60 days later from the same patient were molecularly typed using multilocus sequence typing (MLST) and multispacer sequence typing (MST). The isolates were 100% indistinguishable from each other but phylogenetically distant from Bartonella bacilliformis and considerably divergent from other known Bartonella species, confirming their novelty. PMID- 23985924 TI - Global study of IS6110 in a successful Mycobacterium tuberculosis strain: clues for deciphering its behavior and for its rapid detection. AB - The Mycobacterium tuberculosis insertion sequence IS6110, besides being a very useful tool in molecular epidemiology, seems to have an impact on the biology of bacilli. In the present work, we mapped the 12 points of insertion of IS6110 in the genome of a successful strain named M. tuberculosis Zaragoza (which has been referred to as the MTZ strain). This strain, belonging to principal genetic group 3, caused a large unsuspected tuberculosis outbreak involving 85 patients in Zaragoza, Spain, in 2001 to 2004. The mapping of the points of insertion of IS6110 in the genome of the Zaragoza strain offers clues for a better understanding of the adaptability and virulence of M. tuberculosis. Surprisingly, the presence of one copy of IS6110 was found in Rv2286c, as was recently described for a successful Beijing sublineage. As a result of this analysis, a rapid method for detecting this particular M. tuberculosis strain has been designed. PMID- 23985927 TI - Effects of cross-sectional area on the tunneling-junction array in octahedral PbSe colloidal-nanocrystal solids. AB - Octahedral PbSe colloidal nanocrystals (NCs) are used to assemble a solid. Because of the special feature of the apexes of the octahedrons, the cross sectional area of the inter-dot tunneling junctions is much smaller than that formed between spherical NCs. The inter-dot separation between NCs is easily adjusted by mild thermal treatment. Like a spherical NC-solid, the resistance of the octahedral NC-solid is exponentially dependent on the inter-dot separation. On the contrary, due to the difference in the cross-sectional area between the NCs, electron transport in the octahedral NC-solid does not follow the same model used for the explanation of electron transport in a spherical NC-solid. Through analyses of current-voltage and resistance-temperature behaviors, we have confirmed that the model of fluctuation-induced tunneling conduction fits very well with all of the data and explains the variation in the electrical properties of octahedral PbSe colloidal NC-solids after thermal annealing. PMID- 23985933 TI - Molecular dynamics simulations of the ionic liquid [EMIM+][TFMSI-] confined inside rutile (110) slit nanopores. AB - The structure and dynamics of the ionic liquid (IL) [EMIM(+)][TFMSI(-)] inside a rutile (110) slit nanopore of width H = 5.2 nm at T = 333 K are studied using classical molecular dynamics (MD) simulations. These results are compared against those obtained in our previous study (N. N. Rajput et al., J. Phys. Chem. C, 2012, 116, 5169-5181) for the same IL inside a slit graphitic nanopore of the same width. Electrostatic and dispersion interactions are present between the IL and the rutile walls, whereas only weaker van der Waals interactions are present between the IL and the graphitic walls. Our results suggest that the strength of the interactions between the pore walls and the IL can significantly affect the structure and dynamics of the confined IL. Layering effects were more pronounced for the IL inside a rutile pore as compared to inside a graphitic pore. The ions near the rutile pore walls had a liquid structure that was significantly different from that of the bulk IL; in contrast, the same ions near graphitic pore walls had a liquid structure that was similar to that of the bulk IL. Cations and anions adopted multiple orientations near the rutile walls, which contrast with the parallel orientations that were uniformly observed for the same ions near graphitic walls. The dynamics of [EMIM(+)][TFMSI(-)] inside a slit rutile pore are significantly slower than those observed inside a slit graphitic pore. Near the rutile walls, the dynamics of the ions were about an order of magnitude slower than those of ions near graphitic walls. The ions in the center of a rutile pore exhibit enhanced mobilities, but still about 2-4 times slower than those observed for ions in the center of a graphitic pore. The effects of variations in the amount of IL on the dynamics were very marked inside a rutile pore, with reductions of up to 4 times in the mobilities of the ions in the different regions of the pore; in contrast, pore loading seems to cause smaller variations in the dynamics of ILs inside a graphitic slit nanopore. PMID- 23985926 TI - Non-uniformity of cell density and networks in the monkey brain. AB - The brain is a very complex structure. Over the past several decades, many studies have aimed to understand how various non-uniform variables relate to each other. The current study compared the whole-brain network organization and global spatial distribution of cell densities in the monkey brain. Wide comparisons between 27 graph theoretical measures and cell densities revealed that only participation coefficients (PCs) significantly correlated with cell densities. Interestingly, PCs did not show a significant correlation with spatial coordinates. Furthermore, the significance of the correlation between cell densities and spatial coordinates disappeared only with the removal of the visual module, while the significance of the correlation between cell densities and PCs disappeared with the removal of any one module. Taken together, these results suggested the presence of a combinatorial effect of modular architectures in the network organization related to the non-uniformity of cell densities additional to the spatially monotonic change. PMID- 23985935 TI - Complexation of glutarimidedioxime with Fe(III), Cu(II), Pb(II), and Ni(II), the competing ions for the sequestration of U(VI) from seawater. AB - The stability constants of the complexes of Fe(III), Cu(II), Pb(II), and Ni(II) with glutarimidedioxime, a ligand that has significant implications in the sequestration of uranium from seawater with amidoxime-based sorbents, were determined by potentiometry. The enthalpies of complexation for the Fe(III)/glutarimidedioxime complexes were determined by microcalorimetry. Compared with the data for the complexation of U(VI) with glutarimidedioxime in the literature, Fe(III) forms much stronger complexes with glutarimidedioxime and is expected to affect the efficiency of uranium sequestration from seawater by competing for the sorption sites of the amidoxime-based sorbents. The structures of two Fe(III)/glutarimidedioxime complexes were identified by single-crystal X ray diffractometry, and helped to interpret the stronger complexation of Fe(III) with glutarimidedioxime than that of U(VI). PMID- 23985937 TI - In situ synthesis of LiV3O8 nanorods on graphene as high rate-performance cathode materials for rechargeable lithium batteries. AB - We developed a facile two-step hydrothermal procedure to prepare hybrid materials of LiV3O8 nanorods on graphene sheets. The special structure endows them with the high-rate transportation of electrolyte ions and electrons throughout the electrode matrix, resulting in remarkable electrochemical performance when they were used as cathodes in rechargeable lithium batteries. PMID- 23985936 TI - [Studies on the mode of action of bacterial AB5 toxins]. AB - Bacterial AB5 toxins are proteins, produced by pathogenic bacteria including of Vibrio cholerae, Shigella dysenteriae, and enterohaemorrhagic Escherichia coli, which are usually released into the extracellular medium and cause disease by killing or altering the metabolism of target eukaryotic cells. The toxins are usually composed of one A subunit (a toxic domain) and five B subunits (a receptor-binding domain). This article overviews the characteristics and mode of actions of AB5 toxins including cholera toxin, Shiga-like toxin, and subtilase cytotoxin, and highlights current topics related to the roles of the effectors in promoting bacterial infection. PMID- 23985940 TI - Sugar substitutes. PMID- 23985939 TI - Th Clinical Pharmacist's Role in Compounding for the Diabetic Patient. PMID- 23985941 TI - Complications of diabetes. PMID- 23985942 TI - Transdermal gels in the treatment of diabetic neuropathy. PMID- 23985943 TI - L-arginine and ascorbic Acid for diabetic foot ulcers. PMID- 23985944 TI - Natural-product therapies for treating diabetic neuropathy. PMID- 23985945 TI - Complementary medicine- a wellness plan for people with diabetes. PMID- 23985946 TI - Analytical testing of extemporaneously compounded preparations. PMID- 23985947 TI - Natural estrogens: a review of the primary literature. PMID- 23985948 TI - The basics of compounding: compounding solutions. PMID- 23985949 TI - Some studies of the stability of compounded cefazolin ophthalmic solution. AB - The chemical stability of three compounded batches of cefazolin ophthalmic solution was monitored by a stability-indicating high-performance liquid chromatography assay. The degradation was governed by first-order kinetics, and the effect of temperature on reaction rate was in accordance with the Arrhenius equation at and above 17 deg C. Although the stability of all three batches was essentially the same, buffering the formulations may be useful. Even using a most cautious and conservative approach to the assignment of a beyond-use date for this type of product, it appears that, if the product is stored at controlled room temperature, a beyond-use date of six days would be fully justifiable. If the product is stored in a refrigerator, then a beyond-use date of 14 days could be assigned. PMID- 23985950 TI - Stability of Ranitidine Hydrochloride with Cefazolin Sodium, Cefbuperazone Sodium, Cefoxitin Sodium and Cephalothin Sodium during Simulated Y-Site Administration. AB - The compatibility and stability of ranitidine hydrochloride when comixed with four cephalosporins (cefazolin sodium, cefoxitin sodium, cephalothin sodium and cefbuperazone sodium) during simulated Y-site injection were studied. The mixtures were prepared by mixing equal volumes (2 mL) of ranitidine hydrochloride (1mg/mL) and each tested cephalosporin (20 mg/mL) in a 10 mL glass test tube. All study mixtures were prepared in triplicate and stored at room temperature under normal fluorescent room lighting. The physical appearaance and pH of each mixture were recorded; the chemical stability of each drug was immediatedly determined by stability-indicating high-performance liquid chromatography from samples stored for up to four hours after mixing. Stability was defined as the retention of more than 90% of the initial concentration of each drug. Visual inspection revealed no color or clarity change and the pH changes were less than 0.2 pH units in the tested mixtures for cefazolin and cefoxitin: however, there were significant pH changes for cefbuperazone and cephalothin after four hours of storage. Ranitidine retained greater than 90% of its original concentration within the tested period in the mixture with 20 mg/mL of each tested cephalosporin, except for cephalothin (86.6% of control). In the presence of 10 mg/mL cephalothin, however, ranitidine retained greater than 90% for four hours. Meanwhile, all four cephalosporins retained greater than 90% of their original concentrations for up to four hours in the mixture with ranitidine. From the results obtained, it is clear that ranitidine solution may be coadministered with a solution of either cefazolin, cefoxitin or cefbuperazone during Y-site administration for up to four hours after mxining. On the other hand, since ranitidine with cephalothin (20 mg/mL) fell below 90%, the amount of cephalothin should not exceed 10 mg/mL when coadminstered with ranitidine solution. PMID- 23985951 TI - Effect of some antioxidants on the color change of white lotion. AB - The purpose of this study was to improve the physical color stability of official white lotion to a point where a freshly prepared lotion would not be necessary. Three anioxidants (ascorbic acid, sodium metabisulfite and sodium sulfite) were added into official white lotion in a concentration of 0.1% w/v. Sodium sulfite was found to be the most suitable. PMID- 23985952 TI - Passing-Bablok regression is inappropriate for assessing association between structure and function in glaucoma. PMID- 23985953 TI - Author response: Passing-Bablok regression is inappropriate for assessing association between structure and function. PMID- 23985954 TI - Restoring hemidesmosomes to prevent cancer cell invasiveness. PMID- 23985955 TI - 3-Bromo-1-hydroxy-9,10-anthraquinone (BHAQ) inhibits growth and migration of the human breast cancer cell lines MCF-7 and MDA-MB231. AB - Breast cancer is becoming more prominent in women today. As of now, there are no effective treatments in treating metastatic breast cancer. We have tested the cytotoxic and anti-migration effects of BHAQ, a synthesized anthraquinone, on two breast cancer cell lines, MCF-7 and MDA-MB231. Anthraquinones are an interesting class of molecules that display a wide spectrum of biological applications, including anticancer properties. Cellular inhibition was tested through a MTT assay, double acridine orange/propidium iodide staining and FACS cell cycle analysis. Inhibition of migration was tested by the wound healing method, and migration through a Boyden chamber. BHAQ was cytotoxic towards both cell lines in a dose dependent and possibly cell-dependent manner. Additionally, BHAQ also inhibited the migration of the highly metastatic MDA-MB231 cell line. PMID- 23985957 TI - Point-of-care and over-the-counter qualitative human chorionic gonadotropin (hCG) devices remain susceptible to false-negative results caused by excess hCG beta core fragment. PMID- 23985956 TI - Antitumor, antioxidant and antimicrobial studies of substituted pyridylguanidines. AB - A series of N-pivaloyl-N'-(alkyl/aryl)-N''-pyridylguanidine of general formula C4H9CONHC(NR1R2)NPy have been synthesized and characterized using elemental analysis, FT-IR, multinuclear NMR spectroscopy, and in the case of compounds 7 and 11, by single crystal X-ray diffraction (XRD). The synthesized guanidines were tested for antitumor activities against potato tumor, and showed excellent inhibition against Agrobacterium tumefaciens (AT10)-induced tumor. The antioxidant and antimicrobial activities of these new compounds against various bacterial and fungal strains were also investigated. PMID- 23985958 TI - In reply. PMID- 23985959 TI - Historical response factor-based quantification for LC-MS/MS. PMID- 23985960 TI - BCILAB: a platform for brain-computer interface development. AB - OBJECTIVE: The past two decades have seen dramatic progress in our ability to model brain signals recorded by electroencephalography, functional near-infrared spectroscopy, etc., and to derive real-time estimates of user cognitive state, response, or intent for a variety of purposes: to restore communication by the severely disabled, to effect brain-actuated control and, more recently, to augment human-computer interaction. Continuing these advances, largely achieved through increases in computational power and methods, requires software tools to streamline the creation, testing, evaluation and deployment of new data analysis methods. APPROACH: Here we present BCILAB, an open-source MATLAB-based toolbox built to address the need for the development and testing of brain-computer interface (BCI) methods by providing an organized collection of over 100 pre implemented methods and method variants, an easily extensible framework for the rapid prototyping of new methods, and a highly automated framework for systematic testing and evaluation of new implementations. MAIN RESULTS: To validate and illustrate the use of the framework, we present two sample analyses of publicly available data sets from recent BCI competitions and from a rapid serial visual presentation task. We demonstrate the straightforward use of BCILAB to obtain results compatible with the current BCI literature. SIGNIFICANCE: The aim of the BCILAB toolbox is to provide the BCI community a powerful toolkit for methods research and evaluation, thereby helping to accelerate the pace of innovation in the field, while complementing the existing spectrum of tools for real-time BCI experimentation, deployment and use. PMID- 23985962 TI - Will the combination of public education and medical innovation improve the outcomes of sudden cardiac death? PMID- 23985961 TI - Mitochondrial autophagy--an essential quality control mechanism for myocardial homeostasis. AB - Efficient and functional mitochondrial networks are essential for myocardial contraction and cardiomyocyte survival. Mitochondrial autophagy (mitophagy) refers to selective sequestration of mitochondria by autophagosomes, which subsequently deliver them to lysosomes for destruction. This process is essential for myocardial homeostasis and adaptation to stress. Elimination of damaged mitochondria protects against cell death, as well as stimulates mitochondrial biogenesis. Mitophagy is a tightly controlled and highly selective process. It is modulated by mitochondrial fission and fusion proteins, BCL-2 family proteins, and the PINK1/Parkin pathway. Recent studies have provided evidence that miRNAs can regulate mitophagy by controlling the expression of essential proteins involved in the process. Disruption of autophagy leads to rapid accumulation of dysfunctional mitochondria, and diseases associated with impaired autophagy produce severe cardiomyopathies. Thus, autophagy and mitophagy pathways hold promise as new therapeutic targets for clinical cardiac care. PMID- 23985963 TI - Thromboxane A(2) generation, in the absence of platelet COX-1 activity, in patients with and without atherothrombotic myocardial infarction. AB - BACKGROUND: Aspirin's therapeutic action is via inhibition of platelet cyclooxygenase 1 (COX-1) thromboxane A2 (TxA2) production. The aim of this study was to evaluate TxA2 production, in the absence of platelet COX-1 activity, in coronary atherosclerotic heart disease patients with and without atherothrombotic myocardial infarction (MI). METHODS AND RESULTS: TxA2 production, in the absence of platelet COX-1 activity, was evaluated in 44 patients taking aspirin on 3 commercially available assays that detect metabolites of TxA2 in the urine. Two assays measure urine 11-dehydro-thromboxane B2 (TxB2) alone and 1 measures urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2. Platelet COX-1 inhibition was confirmed on <10% platelet aggregation in response to >=1 mmol/L arachidonic acid. Median urine 11-dehydro-TxB2 was no different in those with and without a diagnosis of atherothrombotic MI (325 vs. 311 pg/mg creatinine, P=0.59 via polyclonal ELISA) and (312 vs. 244 pg/mg creatinine, P=0.11 via LC-MS/MS). Median urine 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2, however, was higher in those with vs. those without a diagnosis of atherothrombotic MI (1,035 vs. 606 pg/mg creatinine, P=0.03 via monoclonal ELISA). CONCLUSIONS: Differences in TxA2 production, in the absence of platelet COX-1 activity, between those with vs. without atherothrombotic MI were not observed when TxA2 generation was assessed on 11-dehydro-TxB2 production alone (polyclonal ELISA or LC-MS/MS), but differences were observed when TxA2 generation was assessed using 11-dehydro-TxB2 plus 11-dehydro-2,3-dinor-TxB2 (monoclonal ELISA). These findings highlight important differences between different commercially available assays for TxA2 generation and suggest that 11-dehydro-2,3-dinor-TxB2 may be critical to the biology of atherothrombosis. PMID- 23985964 TI - Impurity-band induced transport phenomenon and thermoelectric properties in Yb doped PbTe(1-x)I(x). AB - In the present investigation, we report the effect of ytterbium (Yb) impurity band on charge transport and thermoelectric properties in PbTe1-xIx. The temperature dependent interaction of Yb-states with charge carriers and host energy-bands is found to significantly affect the electrical transport parameters in all the investigated samples. Our result indicates that, in the presence of Yb band, the carrier concentration did not increase as effectively as it was found in pristine PbTe with increasing iodine content. An anomalous switching of positive thermopower into negative was found in the samples with lower iodine content. Such phenomena were explained by the redistribution of charge carriers within the different available bands and promotion of vacancy like defects via substitutional impurity. Due to the optimum doping levels, the sample with the highest iodine content showed a decent figure of merit with a peak value of 0.69 at 575 K in the sample with x = 0.007. PMID- 23985965 TI - Pulmonary cryptococcosis in childhood systemic lupus erythematosus and Sjogren syndrome overlap: a rare opportunistic infection. AB - Meningitis is the main manifestation of cryptococcosis in adult systemic lupus erythematosus (SLE) patients, and other organs and systems, such as the lungs, are rarely affected in this fungal infection. To our knowledge, no case of pulmonary cryptococcosis has been described in the pediatric lupus population. Therefore, we report herein one patient with childhood SLE (C-SLE) and Sjogren's syndrome overlap that presented encapsulated Cryptococcus yeast cells in lung tissue. A 14-year-old girl was diagnosed with C-SLE. At the age of 16 years and 5 months, she presented with fever, cough and dyspnea, without headache, vomiting, and also without signs of meningeal irritation or other clinical manifestations. She was being treated with mycophenolate mofetil, hydroxychloroquine and prednisone. Chest radiography and chest computer tomography showed a single nodule in the left posterior apex and three nodular lesions in the left hemithorax respectively. Bronchoalveolar lavage and transbronchial biopsy were normal and without isolation of bacteria or fungi. Voriconazole was empirically introduced for 21 days. Fifteen days after the first biopsy, she underwent open thoracotomy with surgical left lung biopsy and was diagnosed with pulmonary cryptococcosis. Voriconazole was replaced with oral fluconazole and this antifungal therapy was maintained with improvement of clinical manifestations and without marked alteration of radiological images. In conclusion, we report the first case of pulmonary cryptococcosis in Sjogren's and C-SLE patient with a satisfactory clinical response to antifungal therapy. Fungal infections should be excluded in the presence of lung nodules and etiological identification is required for proper treatment. PMID- 23985966 TI - Computer simulations of ionic liquids at electrochemical interfaces. AB - Ionic liquids are widely used as electrolytes in electrochemical devices. In this context, many experimental and theoretical approaches have been recently developed for characterizing their interface with electrodes. In this perspective article, we review the most recent advances in the field of computer simulations (mainly molecular dynamics). A methodology for simulating electrodes at constant electrical potential is presented. Several types of electrode geometries have been investigated by many groups in order to model planar, corrugated and porous materials and we summarize the results obtained in terms of the structure of the liquids. This structure governs the quantity of charge which can be stored at the surface of the electrode for a given applied potential, which is the relevant quantity for the highly topical use of ionic liquids in supercapacitors (also known as electrochemical double-layer capacitors). A key feature, which was also shown by atomic force microscopy and surface force apparatus experiments, is the formation of a layered structure for all ionic liquids at the surface of planar electrodes. This organization cannot take place inside nanoporous electrodes, which results in a much better performance for the latter in supercapacitors. The agreement between simulations and electrochemical experiments remains qualitative only though, and we outline future directions which should enhance the predictive power of computer simulations. In the longer term, atomistic simulations will also be applied to the case of electron transfer reactions at the interface, enabling the application to a broader area of problems in electrochemistry, and the few recent works in this field are also commented upon. PMID- 23985967 TI - Pharmacometrics: opportunity for reducing disease burden in the developing world: the case of Africa. AB - Pharmacometricians are virtually nonexistent in Africa and the developing world. The unrelenting burden of infectious diseases, which are often treated using medicines with narrow effectiveness and safety dose ranges, and the growing prevalence and recognition of non-communicable diseases represent significant threats for the patients, although affording an opportunity for advancing science. This article outlines the case for pharmacometricians to redirect their expertise to focus on the disease burden affecting the developing world.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e69; doi:10.1038/psp.2013.45; published online 28 August 2013. PMID- 23985968 TI - Opinion: the pharmacometrics of infectious disease. AB - The application of pharmacometric principles to the treatment of infectious diseases must address important biological issues across the diversity of pathogenic organisms. Recent applications of pharmacometric tools in this therapeutic area have had important translational impact not only in drug development but on real-world clinical practice. The fruitful fusion of preclinical and population methodologies promises increasingly personalized and mechanistic approaches.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e70; doi:10.1038/psp.2013.46; published online 28 August 2013. PMID- 23985969 TI - Structural insights into VirB-DNA complexes reveal mechanism of transcriptional activation of virulence genes. AB - VirB activates transcription of virulence genes in Shigella flexneri by alleviating heat-stable nucleoid-structuring protein-mediated promoter repression. VirB is unrelated to the conventional transcriptional regulators, but homologous to the plasmid partitioning proteins. We determined the crystal structures of VirB HTH domain bound by the cis-acting site containing the inverted repeat, revealing that the VirB-DNA complex is related to ParB-ParS-like complexes, presenting an example that a ParB-like protein acts exclusively in transcriptional regulation. The HTH domain of VirB docks DNA major groove and provides multiple contacts to backbone and bases, in which the only specific base readout is mediated by R167. VirB only recognizes one half site of the inverted repeats containing the most matches to the consensus for VirB binding. The binding of VirB induces DNA conformational changes and introduces a bend at an invariant A-tract segment in the cis-acting site, suggesting a role of DNA remodeling. VirB exhibits positive cooperativity in DNA binding that is contributed by the C-terminal domain facilitating VirB oligomerization. The isolated HTH domain only confers partial DNA specificity. Additional determinants for sequence specificity may reside in N- or C-terminal domains. Collectively, our findings support and extend a previously proposed model for relieving heat stable nucleoid-structuring protein-mediated repression by VirB. PMID- 23985971 TI - Strain engineering induced interfacial self-assembly and intrinsic exchange bias in a manganite perovskite film. AB - The control of complex oxide heterostructures at atomic level generates a rich spectrum of exotic properties and unexpected states at the interface between two separately prepared materials. The frustration of magnetization and conductivity of manganite perovskite at surface/interface which is inimical to their device applications, could also flourish in tailored functionalities in return. Here we prove that the exchange bias (EB) effect can unexpectedly emerge in a (La,Sr)MnO3 (LSMO) "single" film when large compressive stress imposed through a lattice mismatched substrate. The intrinsic EB behavior is directly demonstrated to be originating from the exchange coupling between ferromagnetic LSMO and an unprecedented LaSrMnO4-based spin glass, formed under a large interfacial strain and subsequent self-assembly. The present results not only provide a strategy for producing a new class of delicately functional interface by strain engineering, but also shed promising light on fabricating the EB part of spintronic devices in a single step. PMID- 23985970 TI - Phylogenomic data support a seventh order of Methylotrophic methanogens and provide insights into the evolution of Methanogenesis. AB - Increasing evidence from sequence data from various environments, including the human gut, suggests the existence of a previously unknown putative seventh order of methanogens. The first genomic data from members of this lineage, Methanomassiliicoccus luminyensis and "Candidatus Methanomethylophilus alvus," provide insights into its evolutionary history and metabolic features. Phylogenetic analysis of ribosomal proteins robustly indicates a monophyletic group independent of any previously known methanogenic order, which shares ancestry with the Marine Benthic Group D, the Marine Group II, the DHVE2 group, and the Thermoplasmatales. This phylogenetic position, along with the analysis of enzymes involved in core methanogenesis, strengthens a single ancient origin of methanogenesis in the Euryarchaeota and indicates further multiple independent losses of this metabolism in nonmethanogenic lineages than previously suggested. Genomic analysis revealed an unprecedented loss of the genes coding for the first six steps of methanogenesis from H2/CO2 and the oxidative part of methylotrophic methanogenesis, consistent with the fact that M. luminyensis and "Ca. M. alvus" are obligate H2-dependent methylotrophic methanogens. Genomic data also suggest that these methanogens may use a large panel of methylated compounds. Phylogenetic analysis including homologs retrieved from environmental samples indicates that methylotrophic methanogenesis (regardless of dependency on H2) is not restricted to gut representatives but may be an ancestral characteristic of the whole order, and possibly also of ancient origin in the Euryarchaeota. 16S rRNA and McrA trees show that this new order of methanogens is very diverse and occupies environments highly relevant for methane production, therefore representing a key lineage to fully understand the diversity and evolution of methanogenesis. PMID- 23985972 TI - Supramolecular design of biocompatible nanocontainers based on amphiphilic derivatives of a natural compound isosteviol. AB - Two diterpenoid surfactants with ammonium head groups and bromide (S1) or tosylate (S2) counterions have been synthesized. Exploration of these biomimetic species made it possible to demonstrate that even minor structural changes beyond their chemical nature may dramatically affect their solution behavior. While their aggregation thresholds differ inconsiderably, morphological behavior and affinity to lipid bilayer are strongly dependent on the counterion nature. Compound S2 demonstrates properties of typical surfactants and forms small micelle-like aggregates above critical micelle concentration. For surfactant S1, two critical concentrations and two types of aggregates occur. Structural transitions have been observed between small micelles and aggregates with higher aggregation numbers and hydrodynamic diameter of ca. 150 nm. Unlike S2, surfactant S1 is shown to integrate with liposomes based on dipalmitoylphosphatidylcholine, resulting in a decrease of the temperature of the main phase transition. Both surfactants demonstrate an effective complexation capacity toward oligonucleotide (ONu), which is supported by recharging the surfactant-ONu complexes and the ethidium bromide exclusion at a low N/P ratio. Meanwhile, a very weak complexation of plasmid DNA with the surfactants has been revealed in the gel electrophoresis experiment. The DNA transfer to bacterial cells mediated by the surfactant S1 is shown to depend on the protocol used. In the case of the electroporation, the inhibition of the cell transformation occurs in the presence of the surfactant, while upon the chemical treatment no surfactant effect has been observed. The variability in the morphology, the biocompatibility, the nanoscale dimension and the high binding capacity toward the DNA decamer make it possible to nominate the designed surfactants as promising carriers for biosubstrates or as a helper surfactant for the mixed liposome-surfactant nanocontainers. PMID- 23985977 TI - Correlations between foam posturography and vestibular-evoked myogenic potential tests in Meniere's disease. AB - OBJECTIVES: This study adopted foam posturography coupled with inner ear test battery including audiometry, and cervical Vestibular-Evoked Myogenic Potential (cVEMP), ocular Vestibular-Evoked Myogenic Potential (oVEMP) and Caloric tests in patients with Meniere's disease to investigate the relations between them. DESIGN: Fifty patients with unilateral definite Meniere's disease were enrolled. All patients underwent Audiometry, and Caloric, oVEMP, and cVEMP tests. In addition, posturography was also performed under 4 conditions: A (firm surface, eyes open), B (firm surface, eyes closed), C (foam pad, eyes open), and D (foam pad, eyes closed). Romberg quotient (RQ) was measured as the value from eyes closed divided by that from eyes open. RESULTS: No correlation existed between Meniere stage and RQ measured with foam pad. Mean RQ of the sway area on foam pad in Meniere's patients with abnormal oVEMPs (1.75 +/- 0.95) was significantly larger than 1.20 +/- 0.70 in those with normal oVEMPs. However, neither cVEMP nor Caloric test results were associated with RQ on foam pad (p > 0.05). Further, the area under the receiver operating characteristic curve of the RQ of sway area on foam pad in discrimination between normal and abnormal oVEMP test was 0.65 (95% CI, 0.51 to 0.79; p < 0.05), implying that RQ of the sway area on foam pad may serve as a significant predictor for abnormal oVEMP test. CONCLUSIONS: By removing or reducing both visual and somatosensory inputs from foam posturography, the remaining vestibular cue, represented as RQ of sway area on foam pad, may reflect utricular function. PMID- 23985978 TI - Monotic versus dichotic multiple-stimulus auditory steady state responses in young children. AB - In their recent study on infant multiple auditory steady state responses (ASSR), the authors found that ASSR amplitudes unexpectedly decreased when switching from 1-ear stimulation to 2-ear stimulation, a result not present in adults. In addition, residual EEG noise levels increased in the 2-ear condition. In the present study, to determine whether to use 1-ear or 2-ear multiple ASSR Protocols clinically, the authors tested a new group of 19 young children to determine whether these unexpected findings could be replicated. ASSR amplitude and EEG noise were compared for 1-ear (4 stimuli) versus 2-ear (8 stimuli) multiple stimuli presented at 60 dBHL. Results indicated a small but significant decrease in amplitudes going from 1-ear (40.1 nV) to 2-ear (37.9 nV) multiple stimuli. EEG noise was not significantly different between the 2 conditions. Despite small amplitude decreases, the 2-ear stimulus condition was more efficient for infants and young children with normal hearing. PMID- 23985979 TI - Atomic force microscopy as a tool for the investigation of living cells. AB - Atomic force microscopy is a valuable and useful tool for the imaging and investigation of living cells in their natural environment at high resolution. Procedures applied to living cell preparation before measurements should be adapted individually for different kinds of cells and for the desired measurement technique. Different ways of cell immobilization, such as chemical fixation on the surface, entrapment in the pores of a membrane, or growing them directly on glass cover slips or on plastic substrates, result in the distortion or appearance of artifacts in atomic force microscopy images. Cell fixation allows the multiple use of samples and storage for a prolonged period; it also increases the resolution of imaging. Different atomic force microscopy modes are used for the imaging and analysis of living cells. The contact mode is the best for cell imaging because of high resolution, but it is usually based on the following: (i) image formation at low interaction force, (ii) low scanning speed, and (iii) usage of "soft," low resolution cantilevers. The tapping mode allows a cell to behave like a very solid material, and destructive shear forces are minimized, but imaging in liquid is difficult. The force spectroscopy mode is used for measuring the mechanical properties of cells; however, obtained results strongly depend on the cell fixation method. In this paper, the application of 3 atomic force microscopy modes including (i) contact, (ii) tapping, and (iii) force spectroscopy for the investigation of cells is described. The possibilities of cell preparation for the measurements, imaging, and determination of mechanical properties of cells are provided. The applicability of atomic force microscopy to diagnostics and other biomedical purposes is discussed. PMID- 23985980 TI - New insights into pathophysiological mechanisms regulating conventional aqueous humor outflow. AB - The aim of the article was to overview the pathophysiology of the conventional outflow pathway, trabecular meshwork, and intraocular pressure and to discuss the options of future glaucoma treatment directed to improvement in aqueous outflow. The literature search in the Medline, Embase, and Cochrane databases from April to May 2012 was performed; a total of 47 articles analyzed. The diminished conventional pathway may be altered by several pathophysiological mechanisms like TM obstruction caused by transforming growth factor-beta2, clastic nondeformable cells, macrophages leaking from hypermature cataract, iris pigment, lens capsular fragments after YAG-laser posterior capsulotomy, proteins and their subfragments. It is known that trabecular meshwork contraction reduces outflow, and the actomyosin system is directly linked to this mechanism. New glaucoma drugs are still under investigation, but it is already proven that agents such as latranculin-B are effective in improving aqueous drainage. Selective Rho associated coiled coilforming protein kinase inhibitors have been shown to cause a significant improvement in outflow facility and may become a new option for glaucoma treatment. Caldesmon negatively regulates actin-myosin interactions and thus increases outflow. Stem cells may replace missing or nonfunctional trabecular meshwork cells and hopefully will bring a new treatment solution. Pathophysiological mechanisms regulating conventional aqueous humor outflow are still not fully understood and require further investigations. Future treatment decisions should be directed to a specific mechanism regulating an elevation in intraocular pressure. PMID- 23985981 TI - Influences of genetic variation of endothelin-1 gene on effects of 16-week combined exercise on clinical and physical parameters in middle-aged women. AB - BACKGROUND AND OBJECTIVE. In this study, we attempted to determine whether the C/T polymorphism of the ET-1 gene was significantly associated with changes in several clinical characteristics after the 16-week combined exercise program in overweight middle-aged women. MATERIAL AND METHODS. The C/T polymorphism of the ET-1 gene was assayed using polymerase chain reaction, i.e., the TaqI restriction fragment length polymorphism method. RESULTS. The genetic variation in the ET-1 gene showed a significant association with the serum LDL cholesterol level as well as several parameters of physical fitness, including muscular endurance and power of the participants (P<0.05). In addition, this genetic variation showed a significant association with changes in muscular strength of the participants after the 16-week combined exercise program (P<0.05). CONCLUSIONS. Our data suggest that the C/T substitution on intron 4 of the ET-1 gene may be a useful genetic marker influencing muscular strength through a gene-exercise interaction and is associated with an interindividual difference of cardiovascular risk factors and parameters of physical fitness. PMID- 23985982 TI - Association Between Polymorphisms of VDR, COL1A1, and LCT genes and bone mineral density in Belarusian women with severe postmenopausal osteoporosis. AB - BACKGROUND AND OBJECTIVE. Variation of osteoporosis in the population is the result of an interaction between the genotype and the environment, and the genetic causes of osteoporosis are being widely investigated. The aim of this study was to analyze the association between the polymorphisms of the vitamin D receptor (VDR), type I collagen (COL1A1), and lactase (LCT) genes and severe postmenopausal osteoporosis as well as bone mineral density (BMD). MATERIAL AND METHODS. A total of 54 women with severe postmenopausal osteoporosis and 77 controls (mean age, 58.3 years [SD, 6.2] and 56.7 years [SD, 7.42], respectively) were included into the study. The subjects were recruited at the City Center for Osteoporosis Prevention (Minsk, Belarus). Dual-energy x-ray absorptiometry was used to measure bone mineral density at the lumbar spine and the femoral neck. Severe osteoporosis was diagnosed in the women with the clinical diagnosis of postmenopausal osteoporosis and at least 1 fragility fracture. The control group included women without osteoporosis. Polymorphic sites in osteoporosis predisposition genes (ApaI, BsmI, TaqI, and Cdx2 of the VDR gene, G2046T of the COL1A1 gene, and T-13910C of the LCT gene) were determined using the polymerase chain reaction on the deoxyribonucleic acid isolated from dried bloodspots. RESULTS. The data showed that the ApaI and BsmI polymorphisms of the VDR gene and T- 13910C of the LCT gene were associated with severe postmenopausal osteoporosis in the analyzed Belarusian women (P<0.01). A statistically significant positive correlation between the VDR risk genotypes ApaI and TaqI and bone mineral density was found (P<0.05). CONCLUSIONS. The findings of this study suggest that at least the ApaI and BsmI polymorphisms of the VDR gene and T-13910C of the LCT gene are associated with the risk of postmenopausal osteoporosis in our sample of the Belarusian women. PMID- 23985984 TI - Endoscopic removal of the osteochondroma of the fibular head. AB - We report the case of the osteochondroma of the fibular head in a 40-year-old female patient who underwent an endoscopic extirpation of a relapsed benign tumor. Initially, open surgery was performed, and the tumor was removed 3 years ago. Following the reoccurrence of the symptoms 3 years after the initial open extirpation, an x-ray and computed tomography of the calf were performed. The tumor was endoscopically removed, and the diagnosis of a relapsed osteochondroma measuring 1.5 * 1.5 * 2 cm was established. Endoscopic surgery can be applied for a successful extirpation of the osteochondroma of the fibular head. PMID- 23985983 TI - Relevance of nasal potential difference in diagnosis of cystic fibrosis among children. AB - OBJECTIVE. The aim of this study was to estimate the significance of nasal potential difference (NPD) in the diagnosis of cystic fibrosis (CF) in children with clinical symptoms suggestive of the disease, positive sweat test results, and/or genetically confirmed diagnosis. MATERIAL AND METHODS. NPD measurements according to the modifications by Alton were performed in 50 children with clinical CF symptoms supported by positive sweat test results, 50 children with other obstructive lung diseases, and 50 healthy children. A subgroup of 17 children with the diagnosis confirmed by 2 identified mutations in the CF transmembrane regulatory gene was analyzed individually. RESULTS. The mean NPD value recorded in 50 children with clinical symptoms of CF supported by positive sweat test results and/or genetic analysis was -28.0 mV [SD, 10.2]. The mean NPD value in the subgroup of children with 2 identified mutations in the CF gene (n=17) was more negative than in the subgroup of children with unrecognized mutations (n=33) (-37.1 mV [SD, 7.0] vs. -23.4 mV [SD, 8.3], P<0.001). The mean NPD value in patients with other obstructive lung diseases and healthy children was significantly more positive than in the group of CF children with positive sweat test results and/or identified mutations (-18.1 mV [SD, 3.6] and -15.5 mV [SD, 4.3] vs. -28.0 mV [SD, 10.2], P<0.001). The NPD cut point value for the genetically confirmed diagnosis of CF was -35.0 mV (sensitivity, 93.9%; specificity, 88.2%), while in general, the NPD prognostic value was -24.0 mV (sensitivity, 58.0%; specificity, 98.0%). CONCLUSIONS. The NPD measurement is a valuable tool for the diagnosis of CF in children, but further studies are necessary to establish NPD values related to the CF genotype and to reduce the intrasubject variability of this test. PMID- 23985985 TI - A comparative electron microscopic study of bone repair after internal fracture, osteotomy, and perforation of rat tibia. AB - BACKGROUND AND OBJECTIVE. Although previous studies have provided new information on bone repair, there are still gaps in knowledge about resorptive and formative processes during bone repair at the electron microscopic level. The aim of this study was to compare bone repair after the internal fracture, osteotomy, and bicortical perforation of the tibia by means of electron microscopy. MATERIAL AND METHODS. An electron microscopic study of bone repair after the internal fracture, osteotomy, and bicortical perforation of the tibia was performed on 72 male Wistar rats. Rats undergoing osteotomy and perforation were further subdivided into the control and immobilization subgroups. Bone repair was observed during the first posttraumatic weeks. RESULTS. Although bone repair in general had similar bone healing stages in all the groups, the repair process depended on the mode and degree of injury thus being different in the experimental groups. After the internal fracture, indirect ossification was observed; after osteotomy, primary periosteal, secondary endosteal ossification was noted; and after perforation, primary endosteal, secondary periosteal ossification was documented. Immobilization had an inhibitory effect on bone repair. CONCLUSIONS. The results of the present study gave new information at the electron microscopic level about intracellular changes and intercellular matrix synthesis during different types of posttraumatic bone repair and confirmed our previous reports on similar posttraumatic bone repair in histomorphometric and immunohistochemical studies. PMID- 23985986 TI - Surgical treatment of ventricular septal defect following myocardial infarction: a case report. AB - Ventricular septal defect after myocardial infarction is a rare but often life threatening mechanical complication. The keys of management are a prompt diagnosis of ventricular septal defect and an aggressive approach to stabilize patient's hemodynamics. Invasive monitoring, judicious use of inotropes and vasodilators, and an intra-aortic balloon pump are recommended for the optimal support of patient's hemodynamics. The best results are achieved if optimally medically managed patients survive at least 4 weeks before elective surgery necessary for scar formation in a friable infarcted tissue. We report a case of acute myocardial infarction complicated by the rupture of ventricular septum. Instead of attempting an immediate surgical closure of ventricular septal defect, the postponed surgery was successfully performed 3 weeks after the occurrence of ventricular septal defect. Preoperatively, clinical and hemodynamic conditions of the patient were maintained stable with the support of an intra-aortic balloon pump and inotropes. PMID- 23985987 TI - Duration of shoot elongation in Scots pine varies within the crown and between years. AB - BACKGROUND AND AIMS: Shoot elongation in boreal and temperate trees typically follows a sigmoid pattern where the onset and cessation of growth are related to accumulated effective temperature (thermal time). Previous studies on leader shoots suggest that while the maximum daily growth rate depends on the availability of resources to the shoot, the duration of the growth period may be an adaptation to long-term temperature conditions. However, other results indicate that the growth period may be longer in faster growing lateral shoots with higher availability of resources. This study investigates the interactions between the rate of elongation and the duration of the growth period in units of thermal time in lateral shoots of Scots pine (Pinus sylvestris). METHODS: Length development of 202 lateral shoots were measured approximately three times per week during seven growing seasons in 2-5 trees per year in a mature stand and in three trees during one growing season in a sapling stand. A dynamic shoot growth model was adapted for the analysis to determine (1) the maximum growth rate and (2) the thermal time reached at growth completion. The relationship between those two parameters and its variation between trees and years was analysed using linear mixed models. KEY RESULTS: The shoots with higher maximum growth rate within a crown continued to grow for a longer period in any one year. Higher July August temperature of the previous summer implied a higher requirement of thermal time for growth completion. CONCLUSIONS: The results provide evidence that the requirement of thermal time for completion of lateral shoot extension in Scots pine may interact with resource availability to the shoot both from year to year and among shoots in a crown each year. If growing season temperatures rise in the future, this will affect not only the rate of shoot growth but its duration also. PMID- 23985989 TI - Coherent multidimensional optical spectra measured using incoherent light. AB - Four-wave mixing measurements can reveal spectral and dynamics information that is hidden in linear spectra by the interactions among light-absorbing molecules and with their environment. Coherent multidimensional optical spectroscopy is an important variant of four-wave mixing because it resolves a map of interactions and correlations between absorption bands. Previous coherent multidimensional optical spectroscopy measurements have used femtosecond pulses with great success, and it may seem that femtosecond pulses are necessary for such measurements. Here we present coherent two-dimensional electronic spectra measured using incoherent light. The spectra of model molecular systems using broadband spectrally incoherent light are similar but not identical to those expected from measurements using femtosecond pulses. Specifically, the spectra show particular sensitivity to long-lived intermediates such as photoisomers. The results will motivate the design of similar experiments in spectral ranges where femtosecond pulses are difficult to produce. PMID- 23985988 TI - Phylogenomics and taxonomy of Lecomtelleae (Poaceae), an isolated panicoid lineage from Madagascar. AB - BACKGROUND AND AIMS: An accurate characterization of biodiversity requires analyses of DNA sequences in addition to classical morphological descriptions. New methods based on high-throughput sequencing may allow investigation of specimens with a large set of genetic markers to infer their evolutionary history. In the grass family, the phylogenetic position of the monotypic genus Lecomtella, a rare bamboo-like endemic from Madagascar, has never been appropriately evaluated. Until now its taxonomic treatment has remained controversial, indicating the need for re-evaluation based on a combination of molecular and morphological data. METHODS: The phylogenetic position of Lecomtella in Poaceae was evaluated based on sequences from the nuclear and plastid genomes generated by next-generation sequencing (NGS). In addition, a detailed morphological description of L. madagascariensis was produced, and its distribution and habit were investigated in order to assess its conservation status. KEY RESULTS: The complete plastid sequence, a ribosomal DNA unit and fragments of low-copy nuclear genes (phyB and ppc) were obtained. All phylogenetic analyses place Lecomtella as an isolated member of the core panicoids, which last shared a common ancestor with other species >20 million years ago. Although Lecomtella exhibits morphological characters typical of Panicoideae, an unusual combination of traits supports its treatment as a separate group. CONCLUSIONS: The study showed that NGS can be used to generate abundant phylogenetic information rapidly, opening new avenues for grass phylogenetics. These data clearly showed that Lecomtella forms an isolated lineage, which, in combination with its morphological peculiarities, justifies its treatment as a separate tribe: Lecomtelleae. New descriptions of the tribe, genus and species are presented with a typification, a distribution map and an IUCN conservation assessment. PMID- 23985990 TI - Several (4,4)- and (5,6,8)-connected lanthanide-organic frameworks: structures, luminescence and magnetic properties. AB - A series of lanthanide-based organic frameworks with formulas of {[PrL(H2O)2].2H2O}n () and {[Ln3L3(H2O)2].2H2O}n (Ln = Eu (), Gd (), Tb (), Dy (), Ho (), Er (); H3L = 4-(carboxymethoxy)isophthalic acid), were hydrothermally synthesized and structurally characterized. It is the first time that 4 (carboxymethoxy)isophthalic acid is employed in producing lanthanide compounds. The seven compounds exhibit two types of structures with the decreasing radius of the lanthanide ions, representing the lanthanide contraction effect. Compound with the large Pr(3+) ion displays a 2D layered structure with a binodal (4,4) connected topology with the Schlafli symbol of (3(3)6(3))2, whereas compounds with small Ln(3+) ions feature a 3D framework constructed from carboxyl groups with a (5,6,8)-connected topology with the Schlafli symbol of (3(2)4(4)5(4)).(3(4)4(4)5(4)6(3)).(3(4)4(8)5(6)6(9)8). The luminescence and magnetic properties were investigated, and the results indicate that the H3L ligand can sensitize the lanthanide luminescence in compounds , and and makes a contribution to the antiferromagnetic interactions in compound or the uncertain magnetic interactions in compounds . Additionally, the thermal analyses suggest the high thermal stability of compounds . PMID- 23985991 TI - Fossilization causes organisms to appear erroneously primitive by distorting evolutionary trees. AB - Fossils are vital for calibrating rates of molecular and morphological change through geological time, and are the only direct source of data documenting macroevolutionary transitions. Many evolutionary studies therefore require the robust phylogenetic placement of extinct organisms. Here, we demonstrate that the inevitable bias of the fossil record to preserve just hard, skeletal morphology systemically distorts phylogeny. Removal of soft part characters from 78 modern vertebrate and invertebrate morphological datasets resulted in significant changes to phylogenetic signal; it caused individual taxa to drift from their original position, predominately downward toward the root of their respective trees. This last bias could systematically inflate evolutionary rates inferred from molecular data because first fossil occurrences will not be recognised as such. Stem-ward slippage, whereby fundamental taphonomic biases cause fossils to be interpreted as erroneously primitive, is therefore a ubiquitous problem for all biologists attempting to infer macroevolutionary rates or sequences. PMID- 23985992 TI - Galectin-7 is epigenetically-regulated tumor suppressor in gastric cancer. AB - Gastric cancer is the second leading cause of cancer death and remains a major clinical challenge due to poor prognosis and limited treatment options. Therefore, the basic mechanisms underlying gastric tumorigenesis deserve investigation. Although regulation of the galactoside-binding lectin galectin-7 in cancer has been studied, its role in tumor formation and progression remains controversial. In this study, we investigated galectin-7 expression and its role in gastric cancer. Immunohistochemical staining using a tissue microarray of gastric cancer patients revealed significantly low expression levels of galectin 7 in malignant tissues compared with matched normal tissues, and decreased expression of galectin-7 in malignant tissues was associated with advanced TMN stage disease (p=0.034). Importantly, low expression of galectin-7 in normal tissues was associated with a poor survival rate (p=0.0561). Over-expression of galectin-7 in AGS gastric adenocarcinoma cells suppressed cell proliferation, migration, and invasion, whereas ablation of galectin-7 in KATO III gastric carcinoma cells reversed these properties. AGS cells that overexpressed galectin 7 could not form gastric tumors in xenografted mice. More than 70% hypermethylation was observed in 7 of 9 gastric cancer cell lines tested and 5 aza-cytidine treatment lowered galectin-7 expression by reducing methylation in 24 cancer cell lines from five different organ origins. We analyzed CpG islands in the galectin-7 genomic region and detected hypermethylation at +1566bp of exon 2, the predicted p53 binding region. DNA hypermethylation of this region was also detected in gastric cancer tissues from 20 patients. Taken together, our data indicate that galectin-7 has a tumor suppressive function, and that the gene is epigenetically modified by DNA methylation and significantly down-regulated in gastric cancer. Further study of galectin-7 regulation may lead to improved gastric cancer diagnosis and therapy. PMID- 23985993 TI - A natural variant of NAL1, selected in high-yield rice breeding programs, pleiotropically increases photosynthesis rate. AB - Improvement of leaf photosynthesis is an important strategy for greater crop productivity. Here we show that the quantitative trait locus GPS (GREEN FOR PHOTOSYNTHESIS) in rice (Oryza sativa L.) controls photosynthesis rate by regulating carboxylation efficiency. Map-based cloning revealed that GPS is identical to NAL1 (NARROW LEAF1), a gene previously reported to control lateral leaf growth. The high-photosynthesis allele of GPS was found to be a partial loss of-function allele of NAL1. This allele increased mesophyll cell number between vascular bundles, which led to thickened leaves, and it pleiotropically enhanced photosynthesis rate without the detrimental side effects observed in previously identified nal1 mutants, such as dwarf plant stature. Furthermore, pedigree analysis suggested that rice breeders have repeatedly selected the high photosynthesis allele in high-yield breeding programs. The identification and utilization of NAL1 (GPS) can enhance future high-yield breeding and provides a new strategy for increasing rice productivity. PMID- 23985994 TI - SLC24A5 mutations are associated with non-syndromic oculocutaneous albinism. PMID- 23985997 TI - Compounding ear, nose and throat preparations. PMID- 23985995 TI - Anti-psoriatic therapy recovers high-density lipoprotein composition and function. AB - Psoriasis is a chronic inflammatory disorder associated with increased cardiovascular mortality. Psoriasis affects high-density lipoprotein (HDL) composition, generating dysfunctional HDL particles. However, data regarding the impact of anti-psoriatic therapy on HDL composition and function are not available. HDL was isolated from 15 psoriatic patients at baseline and after effective topical and/or systemic anti-psoriatic therapy and from 15 age- and sex matched healthy controls. HDL from psoriatic patients showed a significantly impaired capability to mobilize cholesterol from macrophages (6.4 vs. 8.0% [(3)H]cholesterol efflux, P<0.001), low paraoxonase (217 vs. 350 MUM(-1) minute( 1) mg(-1) protein, P=0.011) and increased Lp-PLA2 activities (19.9 vs. 12.1 nM( 1) minute(-1) mg(-1) protein, P=0.028). Of particular interest, the anti psoriatic therapy significantly improved serum lecithin-cholesterol acyltransferase activity and decreased total serum lipolytic activity but did not affect serum levels of HDL-cholesterol. Most importantly, these changes were associated with a significantly improved HDL-cholesterol efflux capability. Our results provide evidence that effective anti-psoriatic therapy recovers HDL composition and function, independent of serum HDL-cholesterol levels, and support to the emerging concept that HDL function may be a better marker of cardiovascular risk than HDL-cholesterol levels. PMID- 23985996 TI - Halogen bond induced phosphorescence of capped gamma-amino acid in the solid state. AB - The Boc and N,N'-dicyclohexylurea capped gamma-amino acid upon monobromination showed phosphorescence in the solid state. The compound exhibited different photoluminescence intensity and lifetimes in crystals obtained from ethyl acetate and methanol. X-ray crystallography revealed that the intermolecular C=O...Br halogen bond directs the heavy atom effect to produce the phosphorescence. PMID- 23985998 TI - Xylitol in the prevention of otitis media. PMID- 23985999 TI - Sildenafil 0.2% otic drops. PMID- 23986000 TI - Xerostomia. PMID- 23986001 TI - Pharmacological treatment options for snoring. PMID- 23986002 TI - Compounding OTC Drugs: A Legal Perspective. PMID- 23986003 TI - Three drug stability lives. PMID- 23986004 TI - The future of compounding: an industry perspective. PMID- 23986005 TI - Dry-heat sterilization of parenteral oil vehicles. AB - The purpose of this study was to evalutate the effect of temperature and time on the dry-heat sterilization conditions of cottonseed, peanut and sesame-seed oils used as vehicles for parenteral drugs. The three oils were inidividually spiked wiht Bacillus subtilis spores and exposed to dry heat at four temperatures (150, 160, 170, and 180 deg C) for three different time intervals (one, 1.5 and two hours). Following inoculation and dry-heat sterilization, samples were placed in a laminar airflow hood and processed according to 71, "Sterility Tests" of the USP XXIV/NF 19 using thioglycolate broth and fluid D. The specimens were then placed into an incubator at 30 deg C and observed for three, five and seven days for bacterial growth. All tests were performed in triplicate. Positive and negative controls were conducted with each group. All three oils were found to be free of viable Bacillus subtilis following dry-heat sterilization at 150, 160, 170 and 180 deg C for one, 1.5 and two hours after incubation for seven days. The positive controls had no observed bacterial growth. Dry-heat sterilization of the three oils at 150 deg C for one hour appeared to be sufficient for time and temperature conditions. However, the authors recommend dry-heat sterilization procedures be validated for each product. PMID- 23986006 TI - Stability of Morphine-Ketamine Mixtures in 0.9% Sodium Chloride Injection Packaged in Syringes, Plastic Bags and MEDICATION CASSETTE Reservoirs. AB - The purpose of this study was to determine the stablilty of different intravenous mixtures of morphine and ketamine in 0.9% sodium chloride injection, USP packaged in plastic syringes, plastic bags and MEDICATION CASSETTE reservoirs (SIMS Deltec, Inc., Minneapolis, MN). Nine morphine (1-,10-,and 25-mg/mL) and ketamine (1-,10-,and 25-mg/mL) mixtures in syringes; two morphine and ketamine mixutres (1 mg/mL and 25 mg/mL of each drug) in plastic bags: and one morpnhine and ketamine mixture (25 mg/mL of each drug) in a MEDICATION CASSETTE reservoir were investigated using a high-performance liquid chromatography analytical technique to measure drug concentrations after one to six days at room temperatue. No loss of drug was observed during the study. PMID- 23986007 TI - Simple high-performance liquid chromatographic method for simultaneous determination of fusidic Acid and betamethasone dipropionate in a cream formulation. AB - A simple and selective high-performance liquid chromatography (HPLC) method using ultraviolet detection was developed for simultaneous determination of fusidic acid and betamethasone dipropionate in a cream formulation. A Supelcosil LC18 column was used for chromatographic separation. The mobile phase consisted of acetonitrile and 0.01 M disodium hydrogen orthophosphate (70:30, % v/v) adjusted to pH 6 with glacial acetic acid. Analysis was run at a flow rate of 1.0 mL/minute with the detector operating at 235 nm. The standard calibration curve was linear over a concentration range of 0.3 to 1.2 mg/mL for fusidic acid and 9.6 to 38.4 micrograms/mL for betamethasone dipropionate. The average recovery values for fusidic acid and betamethasone dipropionate were almost 100%. The within-run and between-run coefficient of variation and percent error values for the two drugs were all less than 2% and +/- 3%, respectively. PMID- 23986008 TI - Stability of an oral liquid dosage form of trovafloxacin mesylate and its quantitation in tablets using high-performance liquid chromatography. AB - A high-performance liquid chromatographic assay method for the quantitation of trovafloxacin in film-coated tablets and an oral liquid dosage form (10 mg/mL) prepared from tablets has been developed. The assay method is very simple, precise and accurate, with a percent relative standard deviation of 1.8 based on five injections. The recovery from the tablets and the oral liquid dosage form was very close to the label claims. The method is stablilty indicating, since the peak from a degraded sample (using sodium hydroxide) did not interfere with the assay procedure. Furthermore, a number of excipients present in the tablets and the oral liquid dosage form did not interfere with the developed method. The oral liquid dosage form gave uniform results and the drug was stable for at least 14 days when stored in an amber-colored glass bottle at 25 deg C(+/-1). The pH of the formulation did not change. PMID- 23986009 TI - Topological characterization of crystalline ice structures from coordination sequences. AB - Topological properties of crystalline ice structures are studied by considering ring statistics, coordination sequences, and topological density of different ice phases. The coordination sequences (number of sites at topological distance k from a reference site) have been obtained by direct enumeration until at least 40 coordination spheres for different ice polymorphs. This allows us to study the asymptotic behavior of the mean number of sites in the k-th shell, Mk, for high values of k: Mk~ak(2), a being a structure-dependent parameter. Small departures from a strict parabolic dependence have been studied by considering first and second differences of the series {Mk} for each structure. The parameter a ranges from 2.00 for ice VI to 4.27 for ice XII, and is used to define a topological density for these solid phases of water. Correlations between such topological density and the actual volume of ice phases are discussed. Ices Ih and Ic are found to depart from the general trend in this correlation due to the large void space in their structures. PMID- 23986010 TI - The bite force and craniofacial morphology in patients with acromegaly: a pilot study. AB - OBJECTIVES: Acromegaly is a metabolic disorder caused by increased growth hormone secretion. As a consequence of acromegaly some typical craniofacial morphology changes appear. This pilot study was conducted to compare the bite force and the characteristic size and shape of the craniofacial components of acromegalic patients with the healthy Turkish individuals. In addition, the correlations between bite force and craniofacial morphology of patients with acromegaly and control individuals were evaluated. STUDY DESIGN: The maximum bite force of the participants was recorded with strain-gage transducer. Lateral x-ray scans were made under standard conditions, in centric occlusion. On cephalograms, the linear and angular measurements was performed. RESULTS: Patients with acromegaly showed increased anterior and posterior total face height, ramus length, width of frontal sinuses, gonial angle and a negative difference between maxillary and mandibular protrusions. In addition, females with acromegaly showed larger lower anterior face height and sella turcica, decreased facial angle, increased mandibular plane angle. The cephalometric measurements, except one did not showed correlation with the bite force in acromegalic patients. In control group, significant correlations were observed between anterior total face height and anterior lower face height, mandibular plane angle and gonial angle. CONCLUSIONS: The greater changes were observed in the mandible. The maximum bite force of patients with acromegaly showed no difference from healthy individuals. The non significant difference of bite force between healthy participants and acromegalic patients provide important information for dental treatment and prosthetic rehabilitation of acromegalic patients. PMID- 23986011 TI - Molecular markers of cell adhesion in ameloblastomas. An update. AB - Ameloblastoma is the most common odontogenic tumor of epithelial origin, and though it is of a benign nature, it frequently infiltrates the bone, has a high rate of recurrence and could potentially become malignant. Cellular adhesion potentially plays an important role in the manifestation of these characteristics and in the tumor biology of ameloblastomas. Losses of cell-cell and extracellular matrix adhesion and cohesion are among the first events that occur in the invasion and growth of tumors of epithelial origin. The present review includes a description of the molecules that are involved in cell adhesion as reported for various types of ameloblastomas and discusses the possible roles of these molecules in the biological behaviors of this odontogenic tumor. Knowledge of the complex mechanisms in which these molecules play a role is critical for the research and discovery of future therapeutic targets. PMID- 23986012 TI - Management of children with autism spectrum disorder in the dental setting: concerns, behavioural approaches and recommendations. AB - OBJECTIVES: This article reviews the present literature on the issues encountered while coping with children with autistic spectrum disorder from the dental perspective. The autistic patient profile and external factors affecting the oral health status of this patient population are discussed upon the existing body of evidence. MATERIAL AND METHODS: The MEDLINE database was searched using the terms 'Autistic Disorder', 'Behaviour Control/methods', 'Child', 'Dental care for disabled', 'Education', 'Oral Health', and 'Pediatric Dentistry' to locate related articles published up to January 2013. RESULTS: Most of the relevant studies indicate poor oral hygiene whereas they are inconclusive regarding the caries incidence in autistic individuals. Undergraduate dental education appears to determine the competence of dental professionals to treat developmentally disabled children and account partly for compromised access to dental care. Dental management of an autistic child requires in-depth understanding of the background of the autism and available behavioural guidance theories. The dental professional should be flexible to modify the treatment approach according to the individual patient needs. PMID- 23986013 TI - Cross-sectional study of malocclusion in Spanish children. AB - OBJECTIVES: This study was conducted to determine the orthodontic treatment need of the child population of the Valencia region of Spain, employing the DAI and the IOTN, to examine the relations between treatment need, socio-economic data and gender and to assess the diagnostic agreement between the two indices. STUDY DESIGN: A cross-sectional descriptive study was conducted in a random representative sample of the schoolchild population of the Valencia region of Spain. The sample size was a total of 765 children aged 12 and 15 years at 39 schools. RESULTS: The orthodontic treatment need assessed by the DAI was 21.7% at 12 years of age and 14.1% at 15 years. The orthodontic treatment need assessed by the IOTN DHC was 20.9% at 12 years of age and 12.7% at 15 years. The diagnostic agreement between the DAI and the modified IOTN was moderate, with Kappa scores of 0.426 at 12 years of age and 0.415 for the 15-year-old group. CONCLUSIONS: Approximately 20% of the children needed orthodontic treatment. Neither gender nor social class appeared to exert a significant influence on orthodontic treatment need. PMID- 23986014 TI - Minor salivary gland biopsy in Sjogren's syndrome: a review and introduction of a new tool to ease the procedure. AB - OBJECTIVES: To review the existing techniques for minor salivary gland biopsy (MSGB) in the lip and to suggest a new approach to ease the procedure and reduce post-operative complications. STUDY DESIGN: A comprehensive literature review and a descriptive study of a new surgical technique. RESULTS: Diverse incisions have been suggested for MSGB with different designs (ellipse, circular, linear), different directions (parallel, oblique, vertical) and a wide range of lengths (from 1 mm up to 3 cm), but no comparative studies supporting the advantages of a particular type of incision over the others could be retrieved. A variety of features of the existing techniques for MSGB are linked to undesired events and surgical complications which could be minimized by modifying certain aspects of these procedures. The technique described, together with the use of the S forceps, represents a significant improvement over the already described chalazion forceps because it allows for a better access and positioning of the lower lip, improves the ergonomic conditions of the assistant, and facilitates the identification of lip areas with more superficial gland lobules. CONCLUSION: The suggested approach for lip MSGB includes a specifically designed instrument whose performance during lip biopsy may contribute to minimize post-operative complications. PMID- 23986015 TI - Effect of posterior gingival smile on the perception of smile esthetics. AB - OBJECTIVES: To evaluate and compare the influence of posterior gummy smile on the perception of smile esthetics by orthodontists, general-dentists and laypersons. STUDY DESIGN: A frontal photograph of a smile with normal gum exposure was chosen and manipulated digitally using Adobe Photoshop C3 to generate three further images with posterior gum exposure of 4, 6 and 8mm. These four images were assessed by the three evaluator groups: orthodontists (n=40), general-dentists (n=40) and laypersons (n=40). Both orthodontists and dentists had at least ten years professional experience and laypersons were aged between 40-50 years. The proportion of men to women was 20:20 in each group. Evaluators awarded a score to the smile esthetics of each image: 1=acceptable, 2=moderately acceptable, 3=unacceptable. Afterwards, each evaluator placed the four images in order of esthetic preference. RESULTS: No significant differences (p>0.05) were detected between the three evaluator groups for the photo without posterior gummy smile. The perception of smile esthetics for a the 4mm posterior gummy smile (median for orthodontists=2, general-dentists= 1, laypersons=1), the 6mm (median for orthodontists=2, general-dentists=1, laypersons=1) and the 8mm (median for orthodontists=3, general-dentists=2, laypersons=2) was significantly different between orthodontists and the other two evaluator groups (p<0.0017). The three evaluator groups coincided in placing the image with the 6mm gum exposure in first place in order of esthetic preference. CONCLUSIONS: Posterior gummy smile influences the perception of smile esthetics more negatively among orthodontists than the rest of the groups. PMID- 23986017 TI - Burkitt's lymphoma of the jaws in the Amazon region of Brazil. AB - OBJECTIVE: To describe the clinicopathologic and immunohistochemical features of Burkitt's lymphoma of the jaws in 7 patients of Northern Brazil. STUDY DESIGN: Clinical data concerning gender, age, affected site, clinical presentation, symptomatology and follow-up were collected from the clinical files. Histopathology was complemented with a broad immunohistochemical panel and in situ hybridization for Epstein-Barr virus (EBV). RESULTS: Most of the patients were infants and 5 out of 7 were males. The mandible was affected in 5 cases and all patients also presented abdominal involvement. All cases were positive for CD45, CD20, CD79a, CD10, Bcl-6 and EBV. Ki-67 proliferative index was approximately 100%. Six patients were treated with R-CHOP (Rituximab + Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone) chemotherapy, and 2 of these died of the disease. One young adult patient refused treatment and died 3 months after initial diagnosis. CONCLUSION: Burkitt's lymphoma of the jaws diagnosed in the Amazon region of Brazil present similar clinicopathologic features to those described in endemic areas of Africa, including EBV positivity. PMID- 23986016 TI - Immunomodulatory drugs: oral and systemic adverse effects. AB - OBJECTIVE: The main objectives are to present the different adverse effects of the immunomodulatory drugs that can impair the quality of life of the immunosuppressed patients and study the impact of immunomodulation on oral diseases. Immunomodulatory drugs have changed the treatment protocols of many diseases where immune functions play a central role, such as rheumatic diseases. Their effect on oral health has not been systematically investigated, however. STUDY DESIGN: We review current data on the new immunomodulatory drugs from the oral health perspective based on open literature search of the topic. RESULTS: These target specific drugs appear to have less drug interactions than earlier immunomodulating medicines but have nevertheless potential side effects such as activating latent infections. There are some data showing that the new immunomodulatory drugs may also have a role in the treatment of certain oral diseases such as lichen planus or ameliorating symptoms in Sjogren's syndrome, but the results have not been overly promising. CONCLUSION: In general, data are sparse of the effect of these new drugs vs. oral diseases and there are no properly powered randomized controlled trials published on this topic. PMID- 23986018 TI - Influence of bruxism on survival of porcelain laminate veneers. AB - OBJECTIVE: This study aims to determine whether bruxism and the use of occlusal splints affect the survival of porcelain laminate veneers in patients treated with this technique. MATERIAL AND METHODS: Restorations were made in 70 patients, including 30 patients with some type of parafunctional habit. A total of 323 veneers were placed, 170 in patients with bruxism activity, and the remaining 153 in patients without it. A clinical examination determined the presence or absence of ceramic failure (cracks, fractures and debonding) of the restorations; these incidents were analyzed for association with bruxism and the use of splints. RESULTS: Analysis of the ceramic failures showed that of the 13 fractures and 29 debonding that were present in our study, 8 fractures and 22 debonding were related to the presence of bruxism. CONCLUSIONS: Porcelain laminate veneers are a predictable treatment option that provides excellent results, recognizing a higher risk of failure in patients with bruxism activity. The use of occlusal splints reduces the risk of fractures. PMID- 23986019 TI - Epidemiology of pediatric facial trauma in Chile: a retrospective study of 7,617 cases in 3 years. AB - OBJECTIVES: To describe the epidemiology of facial trauma injuries in a group of Chilean children aged 15 years or less. STUDY DESIGN: Retrospective study of case series. Between 2006 and 2009, clinical records of 293,090 patients were reviewed. Data of patients with trauma injuries to the face were collected and evaluated for: age, sex, day and month of hospital admission, cause of injury, anatomical location, type of injury and presence of associated injuries. RESULTS: A total of 7,617 patients with 8,944 injuries were found. Boy to girl ratio was 1,7:1. Preschool age children were most frequently affected. Main cause of injury were falls, soft tissue injuries the most common type of injury. Associated injuries occurred in 11% of cases. CONCLUSIONS: Facial trauma presents a significant frequency in the group of Chilean children studied. Preeschool age boys were prone to present facial trauma of mild severity associated to falls. PMID- 23986020 TI - Alendronate-associated osteonecrosis of the jaws: a review of the main topics. AB - Bisphosphonates is a group of inorganic pyrophosphates analogues that suppress bone resorption by inducing osteoclast inactivation, being frequently used for management of diseases affecting bone metabolism, bone metastases and bone tumors. However, since 2003 many cases describing the presence of necrotic bone exposures in the jaws have been described in patients receiving these drugs, what represent a significant complication of bisphosphonates treatment. The overall incidence of bisphosphonate-related osteonecrosis of the jaws is low, ranging from 0.7% to 12%, mainly observed in those patients receiving intravenously treatment. Osteonecrosis of the jaws associated to oral bisphosphonate, particularly alendronate, has also been reported by a number of authors. Considering that alendronate is one of the most used drug worldwide, specially for treatment of osteoporosis, a better understanding of osteonecrosis of the jaws related to its use and how to manage these patients is extremely important. Therefore, in the current manuscript the authors aim to review the most important topics related to this pathological presentation. PMID- 23986021 TI - Comparison of two different labial salivary gland biopsy incision techniques: a randomized clinical trial. AB - OBJECTIVE: To compare the reliability of two different labial salivary gland biopsy (LSGB) incision techniques (vertical versus horizontal incision techniques) and to report the related complications and discomfort. STUDY DESIGN: 163 patients who underwent LSGB were included in this study. Patients were randomly divided as vertical incision group (n=81) and horizontal incision group (n=82). Demographic and clinical information of each patient were recorded. A questionnaire was prepared and applied together with Visual Analog Scale (VAS) on the subjects verbally at the 7th day, postoperatively. Intraoperative, short- term and delayed complications were evaluated. RESULTS: The mean age of patients (117 female, 46 male) was 47.3 years (range 19-79 years). Vertical incision technique was associated with less pain (p<0.001), less swelling (p<0.05), less scar formation (p<0.05) and less difficulty in eating (p<0.05) when compared with horizontal incision technique. No statistically significant differences were observed between the 2 groups in terms of hematoma, parasthesia and speech difficulty (p>0.05). Additionally, two subjects in the horizontal incision group revealed permanent paresthesia during the follow-up period of two years. CONCLUSION: This prospective study demonstrated that the subjects in the vertical incision group had less complication rates and discomfort after labial salivary gland procedure than those in the horizontal incision group. PMID- 23986022 TI - In vivo antiplaque effect of three edible toothpastes. AB - OBJECTIVES: The objective of this study was to analyse the antibacterial and antiplaque activity of three edible toothpastes with the widest worldwide distribution: KidScentsTM, which contains essential oils; Browning B& BTM, with medicinal plants; and Wysong ProbiodentTM, which contains probiotics. STUDY DESIGN: The study group was formed of twenty healthy volunteers (dental students) with a good oral health status. Using a balanced randomisation system, all volunteers performed toothbrushing with four products (the three edible toothpastes and water) at intervals of one week. Bacterial vitality in the saliva was analysed by epifluorescence microscopy and plaque regrowth was evaluated using the Turesky-Quigley-Hein plaque index. RESULTS: Bacterial vitality in the saliva was significantly higher after toothbrushing with water (positive control) than with the three toothpastes (P=0.002, P=0.003 and P<0.001, respectively). The plaque index was significantly higher after using these three toothpastes than after toothbrushing with water (P=0.047, P=0.032 and P<0.001, respectively). CONCLUSIONS: The three edible toothpastes analysed have some antimicrobial activity but favour plaque regrowth. PMID- 23986023 TI - Decontamination of dental implant surface in peri-implantitis treatment: a literature review. AB - Etiological treatment of peri-implantitis aims to reduce the bacterial load within the peri-implant pocket and decontaminate the implant surface in order to promote osseointegration. The aim of this literature review was to evaluate the efficacy of different methods of implant surface decontamination. A search was conducted using the PubMed (Medline) database, which identified 36 articles including in vivo and in vitro studies, and reviews of different decontamination systems (chemical, mechanical, laser and photodynamic therapies). There is sufficient consensus that, for the treatment of peri-implant infections, the mechanical removal of biofilm from the implant surface should be supplemented by chemical decontamination with surgical access. However, more long-term research is needed to confirm this and to establish treatment protocols responding to different implant characterics. PMID- 23986024 TI - Detection and classification of movement-related cortical potentials associated with task force and speed. AB - OBJECTIVE: In this study, the objective was to detect movement intentions and extract different levels of force and speed of the intended movement from scalp electroencephalography (EEG). We then estimated the performance of the closed loop system. APPROACH: Cued movements were detected from continuous EEG recordings using a template of the initial phase of the movement-related cortical potential in 12 healthy subjects. The temporal features, extracted from the movement intention, were classified with an optimized support vector machine. The system performance was evaluated when combining detection with classification. MAIN RESULTS: The system detected 81% of the movements and correctly classified 75 +/- 9% and 80 +/- 10% of these at the point of detection when varying the force and speed, respectively. When the detector was combined with the classifier, the system detected and correctly classified 64 +/- 13% and 67 +/- 13% of these movements. The system detected and incorrectly classified 21 +/- 7% and 16 +/- 9% of the movements. The movements were detected 317 +/- 73 ms before the movement onset. SIGNIFICANCE: The results indicate that it is possible to detect movement intentions with limited latencies, and extract and classify different levels of force and speed, which may be combined with assistive technologies for patient-driven neurorehabilitation. PMID- 23986025 TI - Carbon coated Co-SiC nanocomposite with high-performance microwave absorption. AB - A carbon coated Co-SiC nanocomposite was fabricated via in situ pyrolysis of methane on a hierarchical Co3O4-SiC nanostructure, which was obtained by hydrothermal synthesis. By the reduction of methane, the Co3O4 was in situ converted to cobalt nanoparticles, and coated by carbon or filled in the CNTs. The as-prepared composite exhibits excellent microwave absorption performance in the frequency range of 2-18 GHz. When the match thickness is 1.8 mm, the composite has a reflection loss value below -10 dB in the range 12.2 to 18 GHz, which nearly covers the whole Ku-band (12-18 GHz). When the thickness is 2.6 mm, the reflection loss value below -10 dB distributes at 8.2-11.5 GHz, covering most of the X-band (8-12 GHz). Moreover, by further tuning the match thickness, the composite can selectively absorb some certain frequency bands of microwaves. PMID- 23986026 TI - [(18)F]-fluorodeoxyglucose. A new imaging modality for atherosclerotic plaque thrombogenicity. PMID- 23986028 TI - Detection of QT prolongation through approximation of the T wave on Gaussian mixture modeling. AB - BACKGROUND: To establish a simple and accurate method for the automated identification of the end of a T wave, we approximated electrocardiograph (ECG) traces using a Gaussian mixture model in conjunction with a split-and-merge expectation-maximization algorithm. METHODS AND RESULTS: A total of 286 ECG traces of heart beats of 50 healthy men were used as control data and ECGs from 15 subjects recorded before and after 400mg oral moxifloxacin as positive controls. An experienced cardiologist determined the reference points by visual inspection of the original ECGs. The primary estimated point for the end of the T wave was selected as the point 2 ms before the point at which the gradient of the approximated wave was not steeper than the common threshold value. This point was then adjusted by applying modification rules proposed by an experienced cardiologist. The absolute value of the average interval between the resulting final estimated point and the manually selected reference point was 1.8+/-7.7 ms for the control data. After treatment with moxifloxacin, the average QT interval, corrected by Bazett's formula, showed a 17.2+/-27.1 ms prolongation with a lower bound of the 95% confidence interval of 4.9 ms. CONCLUSIONS: When the modification rules were applied, the accuracy of QT measurement was improved, and the present system was capable of detecting QT prolongation correctly. PMID- 23986029 TI - Successful diet and exercise therapy as evaluated on self-assessment score significantly improves endothelial function in metabolic syndrome patients. AB - BACKGROUND: Simple office-based counseling for diet and exercise does not appear to positively affect success rates in metabolic syndrome (MetS) patients. The utility of the lifestyle modification self-assessment score (Self-AS) in the improvement of endothelial function by office-based counseling for patients with MetS was investigated. METHODS AND RESULTS: Patients with MetS (n=207) and age- and sex-matched individuals without MetS (n=124) were enrolled in this cross sectional study. Endothelial function was assessed using reactive hyperemia peripheral arterial tonometry index (RHI). Patients with MetS had significant endothelial dysfunction compared with those without MetS (RHI, 0.502+/-0.178 vs. 0.614+/-0.229; P<0.001). Seventy MetS patients participating in the prospective interventional study received simple office-based lifestyle modification counseling that was accompanied by Self-AS questionnaire after 10 months. RHI was significantly improved following lifestyle modifications (from 0.452+/-0.136 to 0.547+/-0.202, P<0.001). Reductions in waist circumference (R(2)=0.094, P=0.01) and increased high-density lipoprotein cholesterol (R(2)=0.227, P<0.001) independently correlated with improved RHI. Self-AS significantly correlated with changes in waist circumference (r=-0.57, P<0.001) and RHI (r=0.30, P=0.02). Patients with a good achievement of lifestyle modifications (higher Self-AS) had significant improvement in endothelial function compared with those with lower scores (% change in RHI, +48.7+/-61.6 vs. +7.8+/-35.1, P=0.001). CONCLUSIONS: Good achievement of lifestyle modifications as evaluated on Self-AS significantly improved endothelial function with concomitant reductions in waist circumferences in MetS patients. PMID- 23986030 TI - Elastic properties of the ascending aorta in healthy children and adolescents. Age-related reference values for aortic wall stiffness and distensibility obtained on M-mode echocardiography. AB - BACKGROUND: Compliance of the aorta is important in maintaining normal cardiovascular physiology. Pathological conditions can induce changes in elastic properties, having profound effects on their prognosis. The aim of this study was to establish age-related reference values for distensibility and wall stiffness index of the ascending aorta. METHODS AND RESULTS: A total of 165 normal subjects (mean age, 11.92+/-4.0 years) were investigated on transthoracic echocardiography. Ascending aortic diameter was recorded in M-mode above the sinotubular junction. Blood pressure was measured simultaneously at the right arm. Aortic pulse pressure, distensibility and aortic wall stiffness index were calculated offline. Distensibility decreased significantly with age (r=-0.462, P<0.001); the regression line indicated an average decrease of 5.1 10(-3)kPa(-1) (95% confidence interval [CI]: 3.9-6.8 10(-3)kPa(-1)) per year. Significant correlations could be found between distensibility and weight, height, body surface area (BSA) and body mass index (BMI) (P<0.001). Stiffness index increased significantly with age (r=0.399, P<0.001); the regression line indicated an average increase of 0.066 (95% CI: 0.047-0.085) per year; significant correlations could be found between wall stiffness index and weight, height, BSA and BMI (P<0.001). The 2.5th and 97.5th percentiles of the distribution of distensibility and stiffness index related to age, weight, height, BSA and BMI were calculated. CONCLUSIONS: Normal values of arterial elastic properties throughout childhood and adolescence have been provided, and might serve as a reference for individuals with cardiovascular and metabolic disease. PMID- 23986031 TI - Ratiometric fluorescence imaging of cellular hypochlorous acid based on heptamethine cyanine dyes. AB - A series of ratiometric probes based on heptamethine cyanine dyes for detecting hypochlorous acid have been developed. Here we present the synthesis, characterization and fluorescence properties of these probes. And it turns out that the probes are highly sensitive and selective toward hypochlorous acid. More importantly, the application in living cells for ratiometric imaging of hypochlorous acid has been achieved successfully. PMID- 23986032 TI - Vapour pressure dependence and thermodynamics of cylindrical metal-organic framework mesoparticles: an ESEM study. AB - Self-assembly of neodymium nitrate and 2,5-dihydroxyl-1,4-benzoquinone (DHBQ) leads to the formation of a metal organic framework (MOF) of formula [Nd2(DHBQ)3(H2O)6].18H2O. X-ray diffraction studies show that its crystalline structure is that of a two-dimensional coordination polymer packed in parallel sheets, with organised clusters of water molecules lying between the sheets and bridging them via a dense H-bond network. However, instead of forming faceted crystals, this MOF assembles into unusually shaped cylindrical particles of micrometre size. Scanning electron microscopy revealed that the particles are indeed mesoparticles from aggregated MOF crystalline nano-grains. The mesoparticles are stimuli-responsive and shrink in size upon exposure to reduced water vapour pressure. The shrinkage is isotropic and depends on temperature, which allows measuring the coexistence curve of water inside the particles and in the gas phase. Owing to an elaborated environmental scanning-electron microscopy (ESEM) study, it was possible to determine the association energy of water in the mesoparticles. We found a value of 16 +/- 6.5 kJ mol(-1). Since the only water present in the particles is the lattice water in the nano-grains, this association energy is the lattice energy of water in the nano-sized MOF crystals. This value allowed us to draw a model for the building process of these originally shaped cylindrical mesoparticles. This is the first example of determination of a thermodynamic value by ESEM. PMID- 23986033 TI - How do physicians provide statistical information about antidepressants to hypothetical patients? AB - BACKGROUND: Little is known about how physicians provide statistical information to patients, which is important for informed consent. METHODS: In a survey, obstetricians and gynecologists (N = 142) received statistical information about the benefit and side effects of an antidepressant. They received information in various formats, including event rates (antidepressant v. placebo), absolute risks, and relative risks. Participants had to imagine 2 hypothetical patients, 1 for whom they believed the drug to be safe and effective and 1 for whom they did not, and select the information they would give those patients. We assessed whether the information they selected for each patient was complete, transparent, interpretable, or persuasive (i.e., to nudge patients toward a particular option) and compared physicians who gave both patients the same information with those who gave both patients different information. RESULTS: A similar proportion of physicians (roughly 25% each) selected information that was 1) complete and transparent, 2) complete but not transparent, 3) not interpretable for the patient because necessary comparative information was missing, or 4) suited for nudging. Physicians who gave both patients the same information (61% of physicians) more often selected at least complete information, even if it was often not transparent. Physicians who gave both patients different information (39% of physicians), in contrast, more often selected information that was suited for nudging in line with the belief they were asked to imagine. A limitation is that scenarios were hypothetical. CONCLUSIONS: Most physicians did not provide complete and transparent information. Clinicians who presented consistent information to different patients tended to present complete information, whereas those who varied what information they chose to present appeared more prone to nudging. PMID- 23986034 TI - Reflected wavefront manipulation based on ultrathin planar acoustic metasurfaces. AB - The introduction of metasurfaces has renewed the Snell's law and opened up new degrees of freedom to tailor the optical wavefront at will. Here, we theoretically demonstrate that the generalized Snell's law can be achieved for reflected acoustic waves based on ultrathin planar acoustic metasurfaces. The metasurfaces are constructed with eight units of a solid structure to provide discrete phase shifts covering the full 2pi span with steps of pi/4 by coiling up the space. By careful selection of the phase profiles in the transverse direction of the metasurfaces, some fascinating wavefront engineering phenomena are demonstrated, such as anomalous reflections, conversion of propagating waves into surface waves, planar aberration-free lens and nondiffracting Bessel beam generated by planar acoustic axicon. Our results could open up a new avenue for acoustic wavefront engineering and manipulations. PMID- 23986035 TI - Measurement of crystal growth velocity in a melt-quenched phase-change material. AB - Phase-change materials are the basis for next-generation memory devices and reconfigurable electronics, but fundamental understanding of the unconventional kinetics of their phase transitions has been hindered by challenges in the experimental quantification. Here we obtain deeper understanding based on the temperature dependence of the crystal growth velocity of the phase-change material AgInSbTe, as derived from laser-based time-resolved reflectivity measurements. We observe a strict Arrhenius behaviour for the growth velocity over eight orders of magnitude (from ~10 nm s(-1) to ~1 m s(-1)). This can be attributed to the formation of a glass at elevated temperatures because of rapid quenching of the melt. Further, the temperature dependence of the viscosity is derived, which reveals that the supercooled liquid phase must have an extremely high fragility (>100). Finally, the new experimental evidence leads to an interpretation, which comprehensively explains existing data from various different experiments reported in literature. PMID- 23986036 TI - [Economic evaluation of targeted cancer therapy]. AB - Medical technology, especially cancer therapy, has been recognized as having a major role both in improving health care and in increasing costs. Economic evaluation is considered the basis for resource allocation because it allows decision makers to consider the relative value of alternative uses of available resources. Analytical techniques used for economic evaluation in the healthcare sector are designed to compare alternative treatment strategies in terms of cost and outcome. There are 4 types of economic evaluation: cost-minimization analysis, cost-effectiveness analysis, cost-utility analysis, and cost-benefit analysis. The difference between these techniques relates to the way in which the outcomes are measured. Cost-utility analysis reflects value for money in terms of a single type of health outcome, such as quality-adjusted life year(QALY). This approach incorporates both an increase in survival time(extra life years)and changes in the quality of life(with or without increased survival)into 1 measure. An increase in the quality of life is expressed as a utility value on a scale of 0(dead)to 1 (perfect quality of life). The incremental cost-effectiveness ratio(ICER)in this case is expressed as the incremental cost to gain an extra QALY. The main attraction of cost-utility analysis is its ability to compare different interventions for different diseases, and this type of economic evaluation is widely used for targeted cancer therapy. PMID- 23986037 TI - [Surgical treatment for curable and incurable recurrent gastric cancer]. AB - Recurrent gastric cancer(RGC)after curative resection(R0)is difficult to treat and is often incurable. In such case, patients undergo palliative therapy. However, a small number of patients with RGC can be cured by multimodality therapy. The impact of surgical treatment on patient outcome was studied for each RGC pattern of recurrence. Dissection of GC in combination with lymphadenectomy is a promising treatment strategy for patients with P0CY1 or P1 GC. In contrast, there is no viable treatment option for patients with P2 or P3 GC. A clinical trial is currently ongoing in order to develop new treatment approaches for such patients. In patients presenting with metachronous liver metastasis or para aortic lymph node(PAN) recurrence, liver resection or PAN dissection are good options and long-term survival is expected if the primary tumor is controlled, if there are no other remote metastases, and if the recurrent lesion is limited. Complete resectability of the tumor is the only significant prognostic factor. In cases where complete resection is not possible, palliative surgery and non surgical approaches yield similar patient outcomes. In conclusion, RGC is commonly treated with systemic chemotherapy. However, surgery, as part of multimodality therapy, should be considered in cases where complete resection of RGC is achievable. PMID- 23986038 TI - [Therapeutic strategy for recurrent gastric cancer and efforts aimed at finding a cure]. AB - Recurrent gastric cancer, in general, is an incurable systemic disease for which the standard of care is systemic chemotherapy. Combination treatment with fluoropyrimidine plus platinum and the addition of trastuzumab for patients with human epidermal growth factor receptor 2(HER2)-positive tumors are widely accepted standard regimens. Fluoropyrimidines include 5-fluorouracil(5-FU), S-1, and capecitabine. There has been an accumulation of data showing the non inferiority of oxaliplatin to cisplatin. Moreover, the importance of salvage chemotherapy has also been proven in prospective studies. However, retrospective analyses still indicate that the 5-year survival rates associated with metastatic gastric cancer are only a few percent with chemotherapy. To improve survival, newer triplet regimens, such as a combination of docetaxel, cisplatin, and S 1(DCS)and modified folinic acid, 5-FU, oxaliplatin, and irinotecan(modified FOLFOXIRI), are now under clinical investigation. Despite the limitations of retrospective data, surgical resection for gastric cancer liver metastases appears to be beneficial in carefully selected patients. Currently, the implication of surgical resection for metastatic gastric cancer is being evaluated in clinical trials. These efforts will result in further clinical advances with tailored treatment strategies. PMID- 23986039 TI - [How does we treat liver metastases from colorectal cancer by cure-intent surgery ?]. AB - Surgery is the most optimal and curative intent strategy for liver recurrence from colorectal cancer. There are scoring systems and grade classification for liver resection. If we carry out preoperative imaging of liver metastases strictly following to liver resection, we can expect to get a cure state satisfactory. Early detection and repeated liver resection improve the outcome of residual liver recurrence after liver resection. The maximum number of liver metastases for cure intent liver resection is unclear. Further examination is necessary. PMID- 23986040 TI - [Evaluation of non-surgical therapy as a treatment option for patients with colorectal cancer]. AB - In recent times, the incidence of colorectal cancer(CRC)in Japan as well as in Western countries has been increasing, and the various treatment strategies for CRC include endoscopic mucosal resection(EMR), curative hepatectomy for a solitary liver metastasis, and chemotherapy. Although the 5-year survival rate of patients with stage I-III CRC after complete resection is high, when the disease recurs, approximately 70% of the recurrent tumors become unresectable. Most patients with unresectable recurrent CRC receive chemotherapy, and, in recent years, the survival benefit has improved greatly because of the addition of molecular targeted drugs. The prognosis of patients with disease recurrence is poor and complete response and cure is not achieved. Therefore, the development of both new medication as well as multidisciplinary treatment is indispensable. PMID- 23986041 TI - [Recurrent hepatocellular carcinoma]. AB - Long-term prognosis after curative resection or local ablation therapy in patients with hepatocellular carcinoma(HCC) remains unsatisfactory because of a high recurrence rate. The prognosis of these patients depends on the effectiveness of treatment for recurrent HCC. It is recommended that the treatment policy for recurrent HCC is based on the same criteria as that for primary HCC. Repeat hepatectomy is advisable for patients with less than 3 hepatocellular carcinomas who have good liver function(patients with non cirrhotic livers or Child-Pugh class A cirrhosis). PMID- 23986042 TI - [Recurrent hepatocellular carcinoma]. AB - The patients with chronic viral hepatitis or cirrhosis are a high-risk group for hepatocellular carcinoma. Thus, those who should be screened for detecting HCC can be specified easily. Early detection of HCC leads to performing the curative therapy. However, HCC is easy to recur because of the underlying viral hepatitis and intrahepatic metastasis. After radical therapy, strict surveillance should be performed and if HCC recurs, strategy of treatment should follow the treatment algorithm of Japanese Clinical Practice Guidelines for hepatocellular carcinoma. PMID- 23986043 TI - [Treatable and untreatable forms of recurrent prostate cancer]. AB - The incidence of prostate cancer in the Japanese population has increased because of the increase in life expectancy, consumption of westernized diets, and improvements in prostate cancer screening by using the prostate-specific antigen (PSA)test. Further, in the past 10 years, there have been great advancements in the treatment options available for prostate cancer. Radical treatment methods, such as robot-assisted surgery, intensity-modulated radiation therapy, and particle beam radiation therapy, may have anticancer effects and may improve the quality of life by preserving micturition ability and sexual function. Radiotherapy and endocrine therapy have been shown to prevent postoperative recurrence. Endocrine therapy has been demonstrated to be effective in preventing recurrence after radiotherapy. Moreover, endocrine therapy can be administered to patients at all stages of prostate cancer and is often used as the initial treatment for advanced prostate cancer, particularly in patients with metastasis. However, recurrence(relapse)after endocrine therapy is associated with a poor prognosis. In this study, we describe all the available treatment options for prostate cancer and the treatable and untreatable forms of recurrent prostate cancer. PMID- 23986044 TI - [Efficacy and tolerability of controlled-release oxycodone against nab-paclitaxel induced musculoskeletal pain in breast cancer patients]. AB - Paclitaxel therapy often causes musculoskeletal pain, and some clinical studies have indicated that this pain is due to nerve injury, rather than muscle or joint lesion. We report four clinical cases in which controlled-release oxycodone improved pain intensity in breast cancer patients with severe musculoskeletal pain caused by nab-paclitaxel therapy. In each case, oxycodone was well-tolerated and the symptoms of peripheral neuropathy were quite mild, indicating that oxycodone exhibited a preventive or therapeutic effect on peripheral neuropathy. Therefore, oxycodone may have favorable efficacy and tolerability against cancer therapy-related pain with a neuropathic element in breast cancer patients. PMID- 23986045 TI - [Human immunodeficiency virus-related non-hodgkin lymphoma: a clinical investigation at our hospital]. AB - We investigated 8 cases of non-Hodgkin lymphoma(NHL)in human immunodeficiency virus(HIV)seropositive individuals who were diagnosed and treated at Osaka City General Hospital between April 2002 and October 2012. All patients were men, and the average age at the onset of NHL was 46 years(range: 30-61). Histological types were as follows: diffuse large B cell lymphoma in 4 patients, plasmablastic lymphoma in 2 patients, primary effusion lymphoma in 1 patient, and Burkitt lymphoma in 1 patient. In 3 cases, HIV infection was identified before the onset of NHL. Highly active anti-retroviral therapy (HAART)was initiated in 6 cases, and in 4 of these, we administered antineoplastic chemotherapy. Three patients who did not receive antineoplastic chemotherapy died within 1 month of diagnosis. Although 1 of the patients who received chemotherapy achieved complete remission, this patient died of BK virus nephritis. The remaining 3 patients achieved complete remission and are currently alive after 6 to 9 months. We believe that the combination of antineoplastic chemotherapy with HAART will lead to prognostic improvement in HIV-seropositive patients with NHL. PMID- 23986046 TI - [A search for the risk factors for hiccups and evaluation of antiemetic therapy in CDDP-based chemotherapy, using cluster analysis]. AB - Hiccups are often observed in patients treated with cisplatin(CDDP)-based chemotherapy. It has been reported that gender and specific dosages of CDDP and antiemetic drugs(e.g., dexamethasone and 5-HT3 receptor antagonist)using standard therapy are major risk factors in the onset of hiccups. Recently, aprepitant has been added to the antiemetic therapy in CDDP-based chemotherapy. However, it is not known how the onset of hiccups takes place in antiemetic therapy including aprepitant according to the guideline. In this study, we used cluster analysis to classify 229 patients treated with CDDP-based chemotherapy, to investigate the effect of antiemetic therapy on the onset of hiccups and chemotherapy-induced nausea and vomiting(CINV). Our analysis indicated that aprepitant was not a major risk factor for the onset of hiccups in the high CDDP dose group(>=70 mg/m(2)). However, an effect of antiemesis was confirmed in the standard therapy with aprepitant. In conclusion, we suggest that aprepitant is effective for CINV, without causing the onset of hiccups in patients treated with high-dose CDDP based chemotherapy. PMID- 23986047 TI - [A study on the antiemetic effect and extrapyramidal symptoms of prochlorperazine versus perospirone for the control of nausea and vomiting due to opioid introduction]. AB - Prochlorperazine is often used to prevent opioid-induced nausea; however, this drug causes extrapyramidal symptoms. It is important to determine the incidence of such symptoms and identify coping mechanisms because these symptoms induce intense and possibly life-threatening patient suffering. The purpose of this study was to determine the incidences of nausea and extrapyramidal symptoms associated with the use of prochlorperazine and perospirone as preventive antiemetics when initiating opioid treatment(a sustained-release tablet of oxycodone at a dose of 10 mg/day)and to compare the benefits of the 2 drugs. A total of 100 cancer patients who received medical care from a physician in the palliative care department of our center between May 2007 and September 2008 were consecutively enrolled for a retrospective review of the medical records. Of the patients, 50 had received prochlorperazine treatment(10 or 15 mg/day, orally)and 50 had received perospirone treatment(4 or 8 mg/day, orally)concomitantly with oxycodone treatment(10 mg/day)on an in-patient or outpatient basis. The incidence of nausea and vomiting within 1 week after starting treatment with opioids and the extrapyramidal symptoms during treatment were evaluated. The results showed that the incidence of nausea and vomiting was 8. 0% for the prochlorperazine group and 4. 0% for the perospirone group, and this difference was not statistically significant; however, the incidence of extrapyramidal symptoms was significantly higher for the prochlorperazine group(14%)than for the perospirone group(0%). Furthermore, the extrapyramidal symptom observed in the prochlorperazine group was akathisia, which occurred within a week. The results of this study suggest that careful attention should be paid so as not to overlook akathisia when using prochlorperazine as an antiemetic in cancer patients and that atypical antipsychotics, such as perospirone, could be used as alternatives. PMID- 23986048 TI - Survey on the incidence and management of pseudomyxoma peritonei in Japan. AB - PURPOSE: Pseudomyxoma peritonei(PMP)is a rare condition characterized by massive ascites accumulation due to mucinous tumor dissemination in the peritoneal cavity. More recently, Sugarbaker has defined radical cytoreductive surgery and intraperitoneal chemotherapy as standardized therapy for PMP. The objective of this study was to investigate the incidence of PMP and the recent therapeutic approaches for this condition in Japan. METHODS: Questionnaires answered by PMP patients between 2006 and 2010 were evaluated in this study. The study included 1, 084 gastroenterological surgery and gynecology institutions in Japan. RESULTS: Data from 379 institutions were analyzed(response rate: 35. 0%). The mean number of diffuse PMP cases at a single institution in 5 years was 0. 78. Of 266 diffuse cases, surgery was performed in 232 cases(87. 2%)and chemotherapy was administered in 138 cases(51. 9%). However, complete cytoreduction was achieved in only 31 of 232 operated cases(13. 4%)and intraperitoneal chemotherapy was administered to only 45 of 138 patients receiving chemotherapy( 32. 6%). CONCLUSION: Despite the limited data, our results suggest that PMP occurs rarely in Japan, similar to the trend reported in Western countries. Further, the Sugarbaker procedure was not widely used in Japanese institutions. PMID- 23986049 TI - [Incidence of dysgeusia associated with chemotherapy for cancer]. AB - Chemotherapy for cancer has been reported to have many side effects. Dysgeusia or taste disorder is a common complaint among cancer patients undergoing ambulatory chemotherapy. The present study was undertaken to establish the importance of dysgeusia as a side effect of chemotherapy in these patients. The study included 356 patients who visted Shikoku Cancer Center to undergo outpatient cancer chemotherapy. Of these patients, 156(43.8%)experienced dysgeusia. Of the 156 patients, 34 were male and 122 were female. The incidence of dysgeusia was higher in patients receiving FOLFOX6(oxaliplatin+ 5-FU), docetaxel(DTX), paclitaxel(PTX), docetaxel+cyclophosphamide(TC)or epirubicin+cyclophosphamide(EC) than in those receiving other regimens. When the occurrence of dysgeusia was difficult to define, the changes in taste sensations were subtle for salty and umami taste. This disorder affected appetite: 87.2%of patients experienced loss of appetite. In addition, 66.7% of patients were distressed by this disorder. Dysgeusia may significantly reduce the quality of life of patients undergoing chemotherapy for cancer. Therefore, patient support is important for patients who experience dysgeusia. PMID- 23986050 TI - [Bendamustine-rituximab therapy is effective for transformed follicular lymphoma with significant expression of p53]. AB - We describe a patient with transformed follicular lymphoma(FL), expressing p53 but remaining in complete remission(CR) due to bendamustine-rituximab(BR)therapy. She was a 64-year-old female diagnosed with stage IV FL(grade 3A)in July 2007 when she was admitted with right lower abdominal pain and body weight loss. Colonoscopy revealed Bauhin' valve lymphoma of the terminal ileum, and computed tomography(CT)scan showed lymphadenopathy, involving the cervical, mediastinal para-aortic lymph nodes and right tonsil. She received chemotherapy with eight courses of CHOP therapy with rituximab and achieved CR. Two and a half years later, mediastinal lymph node swelling relapsed, and ibritumomab tiuxetan therapy induced the second CR. After ten months, however, a third relapse occurred as a submucosal tumor(SMT)of the stomach. Gastric SMT biopsy showed diffuse large B cell lymphoma(DLBCL)transformation with immunohistochemical expression of p53. Although gastric SMT disappeared after radiotherapy, which achieved the third CR, lymph node swelling was detected again in the para-aortic and-iliac artery lymph nodes in September 2011. Subsequently, she was treated with five courses of BR therapy, because bendamustine had been reported to be effective for p53 gene deficient B cell neoplasms. The therapy was successful and achieved the fourth CR, demonstrating that BR therapy was effective for p53-expressing DLBCL. PMID- 23986051 TI - [Serotonin syndrome in a patient with small cell lung cancer]. AB - The patient was a 67-year-old male who had been treated for several years with 150 mg fluvoxamine maleate due to depression. He visited our hospital with primary symptoms of swelling of the right upper extremity and dyspnea in August, XXXX. As a result of examinations, he was diagnosed with stage IIIB extended small cell lung cancer(T4N3M0). One course of carboplatin/etoposide(CBDCA/VP 16)therapy was started on October 1. Since the tumor size was reduced, thoracic effusion disappeared, and superior vena cava syndrome was alleviated, the therapy was changed to cisplatin/irinotecan (CDDP/CPT-11)on October 23, and the 3rd course was initiated on November 22. Anxiety and tremor appeared on the 4th day of the 3rd course and because they were exacerbated, and myoclonus appeared, a diagnosis of serotonin syndrome was made on the 38th day, and the administration of fluvoxamine maleate was discontinued. The symptoms were alleviated after the discontinuation, and the 4th course could be implemented. In this patient, serotonin syndrome was considered to have been induced by serotonin secretion promoted by the CDDP administration, and by serotonin in the brain increasing abnormally due to the SSRI. PMID- 23986052 TI - [A case with double primary cancers in both lung and nasal cavity]. AB - Our patient, a 77-year-old male, underwent a medical examination for lower back pain. A careful investigation revealed two large tumors both in his lung and nose. The diagnosis was well-differentiated squamous cell carcinoma by biopsy in both sides. Radiation therapy(36 Gy)was performed on his nasal cavity, and nasal tumor volume was reduced considerably. Because the primary lesion could not be determined we used docetaxel chemotherapy which can be applied for both lung cancer and head and neck cancer. As a result, dissociation of the treatment's effect was seen, and we suspected the presence of overlapping cancer in both lung and nasal cavity. We could not use immunostaining to identify the primary lesion in squamous cell carcinoma as we did for adenocarcinoma. In this case we could infer the presence of overlapping cancer over the course of treatment with chemotherapy. PMID- 23986053 TI - [A case of lung adenocarcinoma wtih exon19 and T790M mutations in EGFR having good response to erlotinib after gefitinib treatment failure]. AB - A 83-year-old woman was referred to our hospital due to an abnormal shadow in the right lower lung field and pleural effusion on chest X-ray. Cytology of the pleural fluid showed adenocarcinoma. EGFR sequencing showed exon19 and T790M mutations. Gefitinib was prescribed as first-line treatment for stage IV(pulmonary metastasis)lung adenocarcinoma from March 2011. The response to the treatment was improved pleural effusion and shrunken tumors. She showed recurrence 13 months after administration of gefitinib. Erlotinib was given as second-line treatment from May 2012. She showed good response with shrinkage of the pulmonary metastases, and was alive with no sign of recurrence for 3 months after administration of erlotinib. PMID- 23986054 TI - [Emergency oncology cases for whom stereotactic radiotherapy by cyberknife proved effective for cerebellar metastasis of lung cancer]. AB - BACKGROUND: Cerebellar metastasis sometimes causes symptoms such as ataxia and dizziness, or hydrocephalus by compression of the fourth ventricle, making emergency treatment necessary. We report two cases for whom we performed emergency stereotactic radiotherapy, and whose tumors decreased and symptoms improved. Case 1: A 58-year-old male was diagnosed with small cell lung cancer in December 2008, and received chemotherapy and conventional radiotherapy at another hospital. He developed difficulty in walking and experienced nausea from March 2010 on. Because neoplastic lesions had been found in the cerebellar vermis on computed tomography(CT)scan, he was referred to our hospital. We urgently performed stereotactic radiotherapy by CyberKnife, and his symptoms then improved. As a chest CT scan revealed a mass lesion in his right upper lobe, the diagnosis of recurrent small cell lung cancer was made, and we performed chemotherapy sequentially. Case 2: A 73-year-old female experienced severe headache and dizziness and noticed difficulty in walking in July 2010. Because neoplastic lesions had been found in the left cerebellar hemisphere on CT scan at another hospital, she was referred to our hospital. Chest X-ray films showed a mass lesion in the left middle lung field and cytologic examination of sputum showed squamous cell carcinoma. We urgently performed stereotactic radiotherapy by CyberKnife, and her symptoms then improved. Therefore, we performed chemotherapy sequentially. CONCLUSION: Stereotactic radiotherapy by CyberKnife is less invasive, and is one good treatment option in the event of an emergency. PMID- 23986055 TI - [Complete remission of hepatocellular carcinoma with multiple lung metastases by oral administration of tegafur/uracil]. AB - We report a case of multiple lung metastases from hepatocellular carcinoma(HCC)successfully treated by oral administration of tegafur/uracil(UFT). A 70-year-old man underwent left hepatic lobectomy for HCC. Intrahepatic recurrence appeared 3 months after the operation and multiple lung metastases appeared at 6 months. Transarterial chemoembolization and radiofrequency ablation were applied for intrahepatic recurrences, and oral administration of UFT(300 mg/day)was initiated for lung metastases. Four months after the initiation of UFT therapy, CT scan showed complete remission(CR)of liver and lung lesions, and elevated AFP and PIVKA-II levels returned to normal. Although the patient underwent a partial hepatectomy for solitary intrahepatic recurrence 2 years later, CR of lung metastases was maintained. The present case suggests the clinical usefulness of UFT for HCC with extrahepatic recurrences, given that effective systemic treatments for HCC are currently limited. PMID- 23986056 TI - [A long-term survivor of advanced gallbladder carcinoma treated with curative operation and hepatic arterial infusion]. AB - 60-year-old woman was referred to us for epigastralagia under the diagnosis of chronic cholecystitis. Cholecystectomy was performed, and gallbladder carcinoma was pinpointed by postoperative pathological diagnosis. Because liver invasion should have been detected by pathological diagnosis, we conducted liver S4a+S5 resection, extrahepatic bile duct resection and D2 lymphadenectomy. The pathological diagnosis was advanced gallbladder carcinoma with liver metastasis. We treated a patient with curative operation and hepatic arterial infusion adjuvant chemotherapy by low-dose FP therapy for advanced gallbladder carcinoma, and she is doing well now without disease recurrence eight years after surgery. PMID- 23986058 TI - [A case of advanced esophagogastric junction cancer responding to pre-operative combination chemotherapy of docetaxel, cisplatin, S-1, and trastuzumab]. AB - We have no consensus on surgical treatment and chemotherapy for esophagogastric junction cancer in Japan. A 51-yearold man reporting dysphagia was examined, and through upper gastrointestinal endoscopy was found to have a tumor at the esophagogastric junction. Histologically, biopsy specimens indicated adenocarcinoma with genetic amplification of human epidermal growth factor receptor type 2(HER2). Positron emission tomography showed swelling of several abdominal lymph nodes with accumulation of fluorodeoxyglucose. He was treated with esophagogastorectomy with left thoracotomy after combination chemotherapy of docetaxel, cisplatin, S-1, and trastuzumab. He had no complication from the operation and had no adverse effect from the combination chemotherapy. Histopathological examination of the resected specimen showed a minute residual cancer nest at the muscularis propria of the esophagus, but no lymph node metastasis. This regimen could be useful for advanced junctional cancer with HER2 amplification as preoperative chemotherapy. PMID- 23986057 TI - [A case of gastric metastasis and carcinomatous peritonitis of breast cancer with improved QOL by stent implantation and gemcitabine]. AB - A 73-year-old woman had undergone mastectomy for left breast cancer. One year later, bone metastasis was detected. After 7 years, the patient experienced epigastric discomfort, and gastrointestinal endoscopy showed stenosis of the pylorus and enlarged gastric folds. Stomach cancer was suspected at first, but gastric metastasis of breast cancer was diagnosed on the basis of endoscopic reexamination and computed tomography(CT)images. The patient could not drink water, and therefore, gastrointestinal stenting was performed, which facilitated ingestion to some extent. However, at the same time, an elevated serum carcinoembryonic antigen(CEA)level and jaundice were observed. Therefore, biliary tract stenosis due to carcinomatous peritonitis was diagnosed. We attempted to treat the jaundice with endoscopic retrograde cholangiopancreatography( ERCP)or percutaneous transhepatic cholangiography(PTCD), but the treatment was not successful, and an increase in ascites was noted. Accordingly, gemcitabine was administered as systemic therapy. As a result, ascites decreased and jaundice improved. Patients with gastric metastasis of breast cancer have poor quality of life(QOL)because of difficulties in ingestion or vomiting, and poor prognoses, because of frequent concurrent carcinomatous peritonitis. We experienced a case of gastric metastasis and carcinomatous peritonitis, and were able to improve the patient's QOL by gastrointestinal stenting and gemcitabine administration. PMID- 23986059 TI - [A case of liver metastasis from gastric cancer responding completely to S 1/docetaxel chemotherapy]. AB - A 68-year-old man was introduced to our hospital with right lower abdominal pain. Endoscopic examination and abdominal CT revealed gastric cancer with liver metastasis. We started chemotherapy using S-1(120 mg/body/day), orally administered for 2 weeks followed by a 2-week rest period, and docetaxel(35 mg/m(2)), administered intravenously on day 1 and 15 as 1 course. After 4 courses of chemotherapy, the liver tumor reduced markedly and no new cancerous region was found by examination; therefore total gastrectomy and partial hepatectomy were performed. Histological examination showed an undifferentiated adenocarcinoma remaining as Grade 1b in the resected stomach. A resected specimen of the liver showed necrotic tissue without any cancer cells. This case suggests that S 1/docetaxel chemotherapy may reduce the stage of unresectable liver metastasis from gastric cancer and make a curative operation possible. PMID- 23986060 TI - [A case of advanced colon cancer with atrial fibrillation and the use of dabigatran for safe chemotherapy using fluoropyrimidine-based antitumor agents]. AB - A 77-year-old man with colon cancer and multiple metastases to the liver and lungs underwent resection of the primary tumor and D3 lymph node dissection. He presented with chronic atrial fibrillation; therefore, warfarin was used initially as an anticoagulant. Because of the need to administer a fluoropyrimidine-based antineoplastic agent[5-fluorouracil(5-FU)] during chemotherapy, we changed the anticoagulant from warfarin to dabigatran etexilate(dabigatran)before initiating chemotherapy. No complications or excessive decrease in coagulability was observed after changing the anticoagulant; chemotherapy was safely continued. Unlike warfarin, dabigatran undergoes renal excretion, and thus, can be safely used in anticoagulant therapy without any drug interaction with 5-FU. Thus, we believe that dabigatran may be the anticoagulant of choice in the future for cancer patients who are scheduled to undergo chemotherapy using fluoropyrimidine-based antineoplastic agents. PMID- 23986061 TI - [A case of mucinous adenocarcinoma of the sigmoid colon with disseminated carcinomatosis of the bone marrow successfully treated with FOLFOX4/bevacizumab]. AB - A 68-year-old man complaining of back pain was given the diagnosis of mucinous adenocarcinoma of the sigmoid colon with disseminated carcinomatosis of bone marrow and disseminated intravascular coagulation(DIC). We started chemotherapy using FOLFOX4. After we confirmed that DIC had improved following 2 courses of FOLFOX4, bevacizumab was added to FOLFOX4. Laboratory studies revealed a serum CEA level of 11, 432 ng/mL, which improved to 245 ng/mL after a total of 9 courses of chemotherapy. Chemotherapy is continuing as scheduled at 6 months from the onset of this disease. PMID- 23986062 TI - [Case report of long-term survival obtained for advanced sigmoid colon cancer with para-aortic lymph nodes by resection and chemotherapy]. AB - The patient was a 66-year-old male. He underwent sigmoidectomy with D1 for an advanced sigmoid colon cancer with massive metastasis to the para-aortic lymph nodes. After the resection he underwent chemotherapy, and CT showed that the para aortic lymph node metastasis had disappeared. However, CT showed other lymph node(No. 252, No. 273 lt)swelling. We therefore resected No. 252 and No. 273 lt lymph nodes. Two years after the resection the patient is alive and shows no sign of recurrence while being without chemotherapy. PMID- 23986063 TI - [A case of metastatic colorectal cancer with icterus due to multiple liver metastases treated effectively by FOLFOX plus bevacizumab]. AB - A 64-year-old male with fatigue and icterus was referred to our hospital. Computed tomography(CT)demonstrated multiple liver metastases and colonoscopic examination revealed advanced rectal cancer, which was diagnosed as moderately- differentiated adenocarcinoma without KRAS mutation. His serum total bilirubin level was 15.6 mg/dL. We started combination chemotherapy with 5-fluorouracil, Leucovorin and oxaliplatin(modified FOLFOX6)at a 20% lower than standard dosage for safety. When his bilirubin fell to 2.3 mg/dL after 4 courses of mFOLFOX6, the doses of 5-fluorouracil and oxaliplatin were increased to standard doses, and treatment with bevacizumab of 5 mg/kg every 2 weeks was begun. After another 3 courses of chemotherapy, his bilirubin was normalized to 0.8 mg/dL. No significant toxicity was observed. Combination chemotherapy with mFOLFOX6 plus bevacizumab was effective and feasible in this case of metastatic rectal cancer with icterus due to diffuse liver metastases. PMID- 23986064 TI - [Asymptomatic longterm survival in a patient with sigmoid colon lymph node metastasis with cancerous ascites of unknown origin]. AB - A 63-year-old man bearing a palpable tumor had a lymph node metastasis adjacent to the sigmoid colon that was detected by computed tomography and positron emission tomography. The sigmoid colon and enlarged lymph nodes were surgically resected, and cancerous ascites were present. Pathologically, the tumor in the lymph node was a poorly-differentiated adenocarcinoma that was positive for CA19 9 as well as CK7(-/+), CK20(+/-), VEGF(+), p 53(+)and MIB-1 (>10%). We treated this case as a pancreatic or bile duct carcinoma due to the patient's markedly elevated serum levels of CA19-9 and SPan-1. However, we could not make a conclusive diagnosis. Gemcitabine-based chemotherapy was administered, and the patient had no signs of recurrence for 24 months after the operation. Then, a recurrence was identified by imaging studies, and the chemotherapy was changed to paclitaxel and carboplatin. The patient had stable disease until tumor regrowth was identified 38 months after the operation, chemotherapy was then stopped. However, at 48 months after the operation, the patient remains well and has no symptoms. Our case suggests that surgery and the appropriate choice of anticancer drugs may contribute to the long-term survival of patients with cancer of an unknown primary origin. PMID- 23986065 TI - [Support of the family with schizophrenia in case of home hospice care]. AB - There are various types of families of terminally-ill cancer patients, and care for the family should therefore be individualized. In cases where the primary caregivers have schizophrenia, caring for the patients at home might cause a serious burden to a family. From this aspect, two patients who were cared for by family with schizophrenia were reviewed. Four important factors were obtained. First, assessment of psychiatric conditions of the family collaborating with the psychiatrist or public health nurse; second, confirmation of the patients'/family's wills concerning living through death at home; third, death education given to a family; and fourth, efficient collaboration with social services by an other organization. It was considered that these factors would constitute a model for providing home hospice care to a family with schizophrenia. PMID- 23986066 TI - Expression and localization of aging markers in lacrimal gland of chronic graft versus-host disease. AB - Aging is commonly defined as the accumulation of diverse deleterious changes in cells and tissues with advancing age. To investigate whether aging changes are involved in the lacrimal glands of chronic graft-versus-host disease (cGVHD) model mice, we obtained the specimens from cGVHD model mice, untreated aged and young mice, and examined by histopathology, and immunoblotting. Oxidative stress markers, 8-OHdG, 4-HNE, and hexonoyl lesion (HEL), and other aging markers, p16 and p38, were used to assess the samples. The infiltrating mononuclear cells and endothelia of capillaries in the cGVHD and aged mice expressed the oxidative stress markers and other aging markers, but not in the young mice. Histological changes and the expression of aging markers in the samples from cGVHD mice exhibited similar features to those in aging mice. These results suggest that changes that typically appear with advanced age occur earlier in the lives of mice with lacrimal gland cGVHD. PMID- 23986068 TI - Understanding and addressing disparities in diabetes and obesity. PMID- 23986069 TI - Assessing the feasibility of an HIV risk-reduction program for young heterosexual African American men in barbershops. PMID- 23986070 TI - Nurse's Desk: food bank-based outreach and screening to decrease unmet referral needs. AB - The Nurse's Desk health screening project used the Intervention Wheel model to conduct outreach, screening, education, and referral for food bank clients (n = 506). Blood glucose, blood pressure, health care utilization, and unmet referral needs were assessed. Screening results identified 318 clients (62.8%) with 1 or more unmet referral needs, including 6 clients (3.16%) with capillary blood glucose more than 199 mg/dL and 132 (31.9%) with hypertension. Clients had higher than-average systolic and diastolic blood pressures and undiagnosed diabetes than in the general population. A client-approved method for tracking completed referrals is needed for this potentially high-risk population. PMID- 23986071 TI - Free afterschool program for at-risk African American children: findings and lessons. AB - A promising afterschool intervention to increase health knowledge and influence choices to reduce risks related to type II diabetes in school-aged, low-income, African American youth is described. Researchers used a community-based program called CASTLES (Communities and Students Together for Learning Enhanced Service). Repeated measures were used to test the effect of the afterschool program on exercise and nutrition. Forty-six children participated in this free program. Significant results demonstrated decreased consumption of sugar-sweetened beverages and screen time and increased exercise and health knowledge. Communities interested in influencing behaviors related to childhood obesity should develop strong community-based programs, such as the CASTLES model, incorporating nutrition information and structured physical activity. PMID- 23986073 TI - Living with diabetes in the 4-fold World of the Coeur d' Alene tribe. AB - Despite national initiatives, diabetes disproportionately affects Native Americans. Although many studies have focused on the needs of Native Americans for culturally relevant diabetes programs, few have focused on Northwest tribes. This article presents the results of a phenomenological study exploring the experience of Coeur d'Alene tribal members living with type 2 diabetes. The main theme to emerge was perseverance while balancing tensions between burdens and strengths in 4 areas: valuing tribal traditions, being inattentively caring, struggling with disease burdens, and experiencing patient-provider tensions. This article provides new understanding about barriers and supports for diabetes self management in one Native American tribe. PMID- 23986072 TI - Asian Indian views on diet and health in the United States: importance of understanding cultural and social factors to address disparities. AB - This study describes Asian Indian immigrant perspectives surrounding dietary beliefs and practices to identify intervention targets for diabetes and heart disease prevention. Participants were asked about conceptualizations of relationships between culture, food, and health during 4 focus groups (n = 38). Findings reveal influences of beliefs from respondents' native India, preservation of cultural practices within the US social structure, conflicts with subsequent generations, and reinterpretation of health-related knowledge through a lens, hybridizing both "native" and "host" contexts. Galvanization of ethnically valued beliefs incorporating family and community structures is needed for multipronged approaches to reduce disproportionate burdens of disease among this understudied minority community. PMID- 23986074 TI - Faithful five: exploring African American faith leaders' perspectives on factors affecting childhood obesity. AB - This study used a community-based participatory research tool called photovoice to understand African American faith leaders' perspectives on the factors that influence childhood obesity in their communities. Five African American women, who self-identified as faith leaders, took photographs and discussed photographs and emergent themes in 5 meetings. Qualitative analysis involved identifying recurring themes from the transcriptions of the photograph discussions, as well as the photographs themselves. The results suggest that the cycle of stress related to family responsibilities influences childhood obesity in this community. The implications for further research and public health practice are discussed. PMID- 23986076 TI - Does decreasing ion-ion association improve cation mobility in single ion conductors? AB - We report on poly(ethylene oxide) based single ion conductors for solid polymer electrolytes. The widely agreed upon vehicle for cation movement in PEO-based solid polymer electrolytes is the single cation, in which the cation is solvated by PEO ether oxygens. Here we report a different vehicle that becomes active with strong anion-cation interactions. In the common perspective, increasing ion-ion interactions would increase ion association, decrease cation solvation, and disable cation movement. Decreasing these interactions would have the opposite effect. We vary cation-anion interaction strength, using anion charge delocalization in molecular dynamics simulations. This creates a series of systems with levels of ion aggregation from single cations (weak interaction) to mostly ion aggregates (strong interaction). Although in the weak model single cations are faster than those in ion pairs and aggregates, with stronger interactions a different mechanism emerges. Paired cations move the fastest by visiting different anion partners in succession. The importance of this observation lies in the possibility of decoupling cation movement from polymer motion, which is required to prevent dendrite formation in both Li and Na ion batteries. PMID- 23986075 TI - Effects of a healthy eating intervention on Latina migrant farmworker mothers. AB - This is a report of a 2-group pre-/post-quasi-experimental pilot intervention study, Dietary Intake and Nutrition Education-Phase Three. The purpose of the study was to present self-management health education on healthy eating to Latina migrant farmworker mothers. The intervention had three 1-hour classes. Surveys included household food security, general self-efficacy, acculturation, knowledge, and children's food patterns and anthropometric measurements. Positive results were seen in mothers' nutrition knowledge. Intervention children had decreased body mass index percentiles. Children whose mothers had higher acculturation had greater reduction in body mass index percentiles. Mothers living alone had higher probability to attend intervention classes. Lessons learned will guide future health promotion research. PMID- 23986077 TI - The ERA-EDTA Database on Recurrent Glomerulonephritis following renal transplantation. PMID- 23986078 TI - A sum rule for Inelastic Electron Tunneling Spectroscopy: an ab initio study of a donor (TTF) and acceptors (TCNE, TCNQ and DCNQI) parallelly oriented on Cu(100). AB - We performed first-principles simulations of Inelastic Electron Tunneling Spectroscopy (IETS) for horizontally lying individual molecules that form popular donor-acceptor pairs (the TTF donor and its possible partner acceptors TCNE, TCNQ and DCNQI) on Cu(100). We find that the highest frequency C-H stretching modes are highly active for the (electron-rich) donor molecule but inactive for the (electron-poor) acceptors. We explain this contrasting response by the spatial extension of sp(3) rehybridization upon adsorption: the donor molecule entirely deforms into sp(3) while the acceptors rehybridize only at their outer ends leaving the central spacer unaffected. The sp(3)-induced buckling permits in plane vibration modes to overlap with the pi-type tunneling states and hence to be detected in IETS. In addition, the IET-spectra of a family of cyano-group acceptors, TCNE, TCNQ and DCNQI, show a recurring pattern of signals from vibrations involving their common CN outer ends plus a set of compound-dependent signals arising from the spacing moiety. The IET-response of individual chemical groups thus adds up for these flat-lying acceptor molecules, evidencing a sum rule that may facilitate their identification. PMID- 23986079 TI - A single-molecule magnet featuring a parallelogram [Dy4(OCH2-)4] core and two magnetic relaxation processes. AB - An alkoxido-bridged tetranuclear Dy(iii) complex, [Dy4(H3L)2(OAc)6].2EtOH {, H6L = 1,3-bis[tris(hydroxymethyl)methylamino]propane}, has been solvothermally synthesized and characterized. An X-ray crystallographic study revealed that complex possesses a novel "parallelogram" [Dy4(OCH2-)4] core, and a new binding mode eta(3):eta(3):eta(1):eta(1):eta(1):eta(2):MU(4) of the Bis-tris propane ligand was observed. Magnetic investigations indicated that it is a single molecule magnet (SMM), showing two distinct magnetic relaxation processes with the energy barriers of 44 K and 107 K, respectively. Such a two-step magnetic relaxation process could be well described by the sum of two modified Debye functions. PMID- 23986080 TI - Reaction of [eta(1):eta(5)-(Me2NCH2CH2)C2B9H10]TaMe3 with aryl isonitriles: tantallacarborane-mediated facile cleavage of C-N multiple bonds. AB - Reaction of [eta(1):eta(5)-(Me2NCH2CH2)C2B9H10]TaMe3 with ArNC at room temperature gave the C-N bond cleavage products, and their type depends upon the aryl group and the amount of ArNC used. A reaction mechanism involving sequential methyl migratory insertion into the C-N multiple bond, followed by an isopropyl carbene insertion into the cage B-H bond, was proposed. All complexes were fully characterized including single-crystal X-ray analyses. PMID- 23986081 TI - Remote ischemic pre-conditioning alleviates contrast-induced acute kidney injury in patients with moderate chronic kidney disease. AB - BACKGROUND: Although remote ischemic preconditioning (RIPC) is shown to preserve kidney function in patients at high risk of contrast-induced acute kidney injury (CI-AKI), the effect in patients at low-moderate risk remains unknown. The preventive effects of RIPC in patients not at high risk of CI-AKI were examined, and biomarkers with anticipated roles in renal protection via RIPC investigated. METHODS AND RESULTS: Sixty patients who had moderate chronic kidney disease and who underwent angiography were randomly assigned to the control (n=30) or RIPC (intermittent arm ischemia, n=30) group. The baseline characteristics in the 2 groups did not differ significantly. CI-AKI was evaluated by measuring urinary liver-type fatty acid-binding protein (L-FABP). Biomarkers were measured before and 24 and 48 h after angiography. Twenty-four hours after angiography, the percent change in urinary L-FABP level in the RIPC group was significantly smaller than in the control group (41.3+/-15.6 vs. 159+/-34.1%, P=0.003). L-FABP based CI-AKI developed in 8 control patients (26.9%) vs. only 2 patients in the RIPC group (7.7%), suggesting that RIPC prevents CI-AKI. Factors contributing to CI-AKI were analyzed. Neither high-sensitivity C-reactive protein nor pentraxine 3 level differed significantly between the 2 groups, while the percent change in asymmetrical dimethy larginine (ADMA) level and blood derivatives of reactive oxidative metabolite levels were significantly smaller in the RIPC group. CONCLUSIONS: RIPC alleviates CI-AKI in patients at low-moderate risk. This effect might be mediated partly by decreasing oxidative stress and plasma ADMA level. PMID- 23986082 TI - Clinical features differ substantially between Caucasian and Asian populations of Marfan syndrome. AB - BACKGROUND: Prevention of aortic dissection and sudden death in patients with Marfan syndrome (MFS) requires accurate diagnosis. MFS is diagnosed by the Ghent criteria, which are primarily based on clinical features of Caucasian MFS populations. We determined whether the Ghent criteria apply to Asian MFS populations. METHODS AND RESULTS: In this multicenter study, we included 255 adult MFS patients according to the Ghent criteria of 2010. Patients were excluded if they were neither Caucasian nor Asian. The Asian MFS population (n=49) had a smaller body surface area (BSA: 1.8 m2 vs. 2.0 m2, P<0.001), a more severely affected aortic root (absolute aortic diameter: 42.9 mm vs. 43.3mm, P=0.802; corrected for BSA: 24.9 mm vs. 21.7 mm, P<0.001; Z-score: 4.5 vs. 3.6, P=0.013), and more often a positive systemic score (75.5% vs. 60.0%, P=0.045), but less frequently ectopia lentis (24.5% vs. 48.1%, P=0.004) compared with the Caucasian population (n=206). CONCLUSIONS: The Ghent criteria do not necessarily apply to Asian MFS populations, resulting in a more severely affected cardiovascular system. This may be related to under diagnosis of MFS by multiple factors, including the use of Z-score, and genetic and racial differences. The Ghent criteria should be adapted for Asian populations in order to accurately diagnose MFS. PMID- 23986084 TI - A mixed methods exploration of family members'/friends' roles in a self-care intervention for depressive symptoms. AB - OBJECTIVES: The aims of this exploratory study were to examine the: (1) family and friend (F/F) support patients reported receiving and F/F reported providing to patients while participating in a self-care intervention (SCI) for depressive symptoms and (2) associations between different types of F/F support and patients' use of the self-care tools in the SCI. METHODS: Fifty-seven patients aged 40 + participating in an uncontrolled feasibility study of an SCI, completed structured telephone interviews about the support they received from F/F while participating in the SCI. Eighteen F/F completed questionnaires on the support they provided to patients during the SCI. Seven F/F participated in a post-study qualitative interview on their involvement in the SCI. RESULTS: About 35% of patients reported receiving F/F support with the SCI. Patients' use of the behavioral tools was positively associated with patients' report of F/F support, and with F/F's report of instrumental support provided. F/F reported uncertainty about the type of support they should offer to patients in the SCI. DISCUSSION: F/F involvement in SCIs for depressive symptoms may be helpful to patients and may foster adherence to these interventions. More research is warranted on the nature of such involvement from the perspective of patients and F/F. PMID- 23986083 TI - Comparison of triple anti-platelet therapy and dual anti-platelet therapy in patients with acute myocardial infarction who had no-reflow phenomenon during percutaneous coronary intervention. AB - BACKGROUND: No-reflow phenomenon is a serious complication of percutaneous coronary intervention (PCI) and associated with poor prognosis. The aim of this study was to determine whether triple anti-platelet therapy could improve clinical outcome in patients with acute myocardial infarction (AMI) who had no reflow phenomenon during PCI compared with dual anti-platelet therapy. METHODS AND RESULTS: A total of 727 eligible patients received either dual anti-platelet therapy (aspirin and clopidogrel; dual group, n=532) or triple anti-platelet therapy (aspirin, clopidogrel, and cilostazol; triple group, n=195). The triple group received additional cilostazol for at least 1 month. One-year major adverse cardiac events (MACE) including death, myocardial infarction (MI), target vessel revascularization (TVR) and coronary artery bypass graft (CABG) were evaluated. The triple group had a similar incidence of major bleeding and in-hospital mortality compared with the dual group. At 1 year, the triple group had significantly lower cardiac mortality (17.7% vs. 11.8%, log-rank P=0.039), lower all-cause mortality (19.0% vs. 12.3%, log-rank P=0.035), and lower incidence of composite MACE (25.9% vs. 16.9%, adjusted hazard ratio, 0.50; 95% confidence interval: 0.31-0.80, P=0.004) compared with the dual group with no differences in MI and TVR. CONCLUSIONS: Triple anti-platelet therapy seems to be superior to dual anti-platelet therapy in patients with AMI who had no-reflow phenomenon during PCI. PMID- 23986085 TI - Illness perceptions in Turkish migrants with diabetes: a qualitative study. AB - OBJECTIVES: Illness perceptions are usually conceptualized using the self regulatory model of illness. Although a few examinations of illness perceptions among Turkish language populations exist, the validity of the self-regulatory model of illness has never been confirmed for this population group. The aim of our study was to explore the validity of the self-regulatory model of illness in chronically ill Turkish migrants residing in Germany using diabetes mellitus type 2 as an example. METHODS: Qualitative semi-structured interviews were conducted with 24 Turkish migrants with self-reported diabetes who were recruited through key persons. The core aspects of the qualitative data were extracted through a hermeneutic approach. Subsequently, a system of categories and sub-categories was developed by means of content analysis. RESULTS: Seven distinct core dimensions of illness perceptions, each with a different number of sub-domains, could be identified in the sample. They comprised the perceived timeline of diabetes, its consequences, its causes, its controllability as well as the identity/coherence and the emotional response with respect to the condition. DISCUSSION: As regards the conceptualization of illness perceptions, the dimensions identified are in line with the self-regulatory model of illness. Addressing illness perceptions through tailored interventions may contribute to improving health care and health outcomes in Turkish migrants. PMID- 23986087 TI - The effect of channel height and electrode aspect ratio on redox cycling at carbon interdigitated array nanoelectrodes confined in a microchannel. AB - Redox cycling is a commonly used electrochemical sensing scheme for enhancing faradaic current signals. This effect can be improved by either optimizing electrode geometries or restricting electrochemical reactions within a limited volume. Here, we demonstrate a simple batch fabrication of 1 : 1 aspect ratio carbon interdigitated array nanoelectrodes integrated in a polydimethylsiloxane microchannel that enables current amplification by up to 1116 times. We also examine the factors that influence the effect of redox cycling, including the electrode aspect ratio and channel height, by using experiments and simulations. PMID- 23986086 TI - Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin. AB - Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%. Thus, metformin can no longer be considered as a bona fide DR mimetic, at least in terms of anti cancer activity, because tumors harboring the insulin-unresponsive, DR-resistant, PIK3CA-activating mutation H1047R remain sensitive to the anti-tumoral effects of the drug. Given the high prevalence of PIK3CA mutations in human carcinomas and the emerging role of PIK3CA mutation status in the treatment selection process, these findings might have a significant impact on the design of future trials evaluating the potential of combining metformin with targeted therapy. PMID- 23986088 TI - Synthesis and photophysics of novel biocompatible fluorescent oxocines and azocines in aqueous solution. AB - The spectroscopic properties in water solution of the different prototropic forms of the strongly fluorescent hemiacetal 4,9-dihydroxy-1,2-dihydro-4,11a methanooxocino[4,5-b]benzofuran-5(4H)-one (1a, monardine), the aza analogue 4,9 dihydroxy-3,4-dihydro-1H-4,11a-methanobenzofuro[2,3-d]azocin-5(2H)-one (2a, azamonardine) and the respective 2-carboxyl derivatives (1b, 2b) have been studied by experimental and quantum-chemical methods. Monardine and carboxymonardine are the major products of new fluorogenic, room-temperature reactions of hydroxytyrosol or salvianic acid in aqueous solution, respectively, and present unique photophysical properties. Near neutral pH (pKa = 7.2) monardine switches from a weakly emitting, UV-absorbing (382 nm) neutral species to a VIS-absorbing (426 nm), blue emitting (464 nm) anion form, with a fluorescence quantum yield phiF = 1 and single-exponential decay tauF = 2.74 ns. This binary-like spectroscopic change from the neutral to the anionic form was interpreted based on time-dependent density functional theory (TDDFT) calculations as due to (i) the reversal of (n,pi*) and (pi,pi*) lowest-lying singlet excited states, and (ii) a change in the triplet-state distribution accompanying monardine ionization which may abolish de-excitation via intersystem crossing. A similar fluorogenic reaction takes place with catecholamines such as dopamine and DOPA, to yield fluorescent azocines 2a and 2b which, depending on pH, may be present as cationic, neutral or anionic species. TDDFT computations of these forms were also carried out to assign the corresponding excitation transitions and emission properties. Besides the analytical interest of the fluorogenic reactions, the photochemical stability and biocompatibility of the bright-dark pH-controlled molecular switches 1a and 1b may facilitate novel labels and probes to be developed for superresolution fluorescence microscopy. PMID- 23986089 TI - Different clinical electrodes achieve similar electrical nerve conduction block. AB - OBJECTIVE: We aim to evaluate the suitability of four electrodes previously used in clinical experiments for peripheral nerve electrical block applications. APPROACH: We evaluated peripheral nerve electrical block using three such clinical nerve cuff electrodes (the Huntington helix, the Case self-sizing Spiral and the flat interface nerve electrode) and one clinical intramuscular electrode (the Memberg electrode) in five cats. Amplitude thresholds for the block using 12 or 25 kHz voltage-controlled stimulation, onset response, and stimulation thresholds before and after block testing were determined. MAIN RESULTS: Complete nerve block was achieved reliably and the onset response to blocking stimulation was similar for all electrodes. Amplitude thresholds for the block were lowest for the Case Spiral electrode (4 +/- 1 Vpp) and lower for the nerve cuff electrodes (7 +/- 3 Vpp) than for the intramuscular electrode (26 +/- 10 Vpp). A minor elevation in stimulation threshold and reduction in stimulus-evoked urethral pressure was observed during testing, but the effect was temporary and did not vary between electrodes. SIGNIFICANCE: Multiple clinical electrodes appear suitable for neuroprostheses using peripheral nerve electrical block. The freedom to choose electrodes based on secondary criteria such as ease of implantation or cost should ease translation of electrical nerve block to clinical practice. PMID- 23986091 TI - Mammary herpes: a little known mode of neonatal herpes contamination. AB - Neonatal herpes is a severe disease. We report a case with a fatal outcome, whose transmission was linked to mammary herpes. The lack of early diagnosis delayed appropriate therapeutic management. The purpose of this report is to alert clinicians to this potential mode of transmission. PMID- 23986090 TI - A randomized phase II study comparing erlotinib versus erlotinib with alternating chemotherapy in relapsed non-small-cell lung cancer patients: the NVALT-10 study. AB - BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) administered concurrently with chemotherapy did not improve outcome in non-small cell lung cancer (NSCLC). However, in preclinical models and early phase noncomparative studies, pharmacodynamic separation of chemotherapy and TKIs did show a synergistic effect. PATIENTS AND METHODS: A randomized phase II study was carried out in patients with advanced NSCLC who had progressed on or following first-line chemotherapy. Erlotinib 150 mg daily (monotherapy) or erlotinib 150 mg during 15 days intercalated with four 21-day cycles docetaxel for squamous (SQ) or pemetrexed for nonsquamous (NSQ) patients was administered (combination therapy). After completion of chemotherapy, erlotinib was continued daily. Primary end point was progression-free survival (PFS). RESULTS: Two hundred and thirty-one patients were randomized, 115 in the monotherapy arm and 116 in the combination arm. The adjusted hazard ratio for PFS was 0.76 [95% confidence interval (CI) 0.58-1.02; P = 0.06], for overall survival (OS) 0.67 (95% CI 0.49 0.91; P = 0.01) favoring the combination arm. This improvement was primarily observed in NSQ subgroup. Common Toxicity Criteria grade 3+ toxic effect occurred in 20% versus 56%, rash in 7% versus 15% and febrile neutropenia in 0% versus 6% in monotherapy and combination therapy, respectively. CONCLUSIONS: PFS was not significantly different between the arms. OS was significantly improved in the combination arm, an effect restricted to NSQ histology. STUDY REGISTRATION NUMBER: NCT00835471. PMID- 23986092 TI - Accidental overheating of a newborn under an infant radiant warmer: a lesson for future use. AB - A fully functional radiant warmer induced rapid and continuous increases in regional skin temperatures, heart rate, mean arterial blood pressure and respiratory rate in a newborn patient without corrective action. We report this case of passive overheating to create awareness of the risks associated with regulating radiant heat output based upon a single servo-controlled temperature. PMID- 23986093 TI - Late-onset Leclercia adecarboxylata sepsis in a premature neonate. AB - The epidemiology, etiology and outcome of neonatal sepsis are changing over time. While monitoring longitudinal trends in neonatal sepsis in our institution, we encountered a case of late-onset neonatal sepsis due to Leclercia adecarboxylata. A Gram-negative rod previously not encountered in the clinical setting, L. adecarboxylata has recently emerged as a human pathogen, primarily in immunosuppressed patients. This report describes the clinical and laboratory features of this case of late-onset L. adecarboxylata sepsis, and reviews significant features of infection associated with this emerging pathogen. PMID- 23986094 TI - Reply to Drs Hiraizumi and Suzuki. PMID- 23986095 TI - Maternal ABO blood group and adverse pregnancy outcomes in Japanese population. PMID- 23986096 TI - Noninvasive measurement of respiratory activity of mouse embryoid bodies and its correlation with mRNA levels of undifferentiation/differentiation markers. AB - Mouse embryoid bodies (mEBs) were evaluated in detail on the basis of respiratory activity and high-throughput quantitative reverse transcription-PCR (RT-qPCR) analysis. The hanging drop culture method was applied to prepare various sizes of mEBs ranging from 100 to 250 MUm in radius by causing the aggregation of embryonic cells. The respiratory activity of individual mEBs was noninvasively measured using scanning electrochemical microscopy in a cone-shaped microwell. For gene expression analysis, we used 48.48 Dynamic Array chips (Fluidigm) integrating microfluidic circuits, which allowed high-throughput qPCR analysis in parallel. The respiratory activity of the mEBs that were cultured for 1 to 6 days could predict the mRNA levels of undifferentiation and differentiation markers. However, the sizes of the mEBs could also predict the gene expression of the undifferentiation/differentiation markers because the radii of the mEBs increased by more than 2-fold after incubation in hanging drop culture for 6 days. Next, mEBs with identical sample sizes were evaluated for respiratory activity and gene expression. For mEBs cultured at 1500 cells per droplet for 3 days, the respiratory activity was negatively correlated with the mRNA levels of pluripotent markers such as Nanog and Sox2. Many differentiation markers were positively correlated with the respiratory activity. However, there was no significant difference in respiration activity between the beating and nonbeating samples on day 3. Finally, principal component analysis (PCA) confirmed the relationship between respiratory activity and the mRNA levels of undifferentiation/differentiation markers. PMID- 23986097 TI - Role of intravenous immunoglobulin in the treatment of acute relapses of neuromyelitis optica: experience in 10 patients. AB - Prompt treatment of neuromyelitis optica (NMO) relapses with steroids or plasma exchange (PLEX) often prevents irreversible disability. The objective of this study is to report the use of intravenous immunoglobulins (IVIG) as treatment for acute relapses in NMO. A retrospective review of 10 patients treated with IVIG for acute relapses was conducted. IVIG was used in the majority of cases because of lack of response to steroids with/without PLEX. Improvement was noted in five of 11 (45.5%) events; the remaining had no further worsening. One patient, a 79 year-old woman, had a myocardial infarction seven days after IVIG. IVIG may have a role in treating acute NMO relapses. PMID- 23986099 TI - Quantitation of fluphenazine in equine serum following fluphenazine decanoate administration. AB - Fluphenazine, a potent antipsychotic used to treat schizophrenia in humans, is used in racehorses as a performance-enhancing drug, and for that reason it has been banned by the Association of Racing Commissioners International. A liquid chromatography-tandem mass spectrometry method for detecting and quantitating fluphenazine in equine serum was developed and validated. The method was then employed to quantitate fluphenazine in serum samples collected from three study horses after intramuscular injection of fluphenazine decanoate. Stability testing showed that fluphenazine is stable in unextracted and processed samples as well as samples that have been subjected to up to three freeze-thaw cycles. The limit of detection and lower limit of quantitation of fluphenazine were determined to be 0.05 and 0.1 ng/mL, respectively. Precision was evaluated based on one-way analysis of variance of replicate quality control samples and was determined to be 27.2% at the 0.2 ng/mL level and 18.1% at the 2 ng/mL level. Bias was determined to be 0.55% at the 0.2 ng/mL level and 3.66% at the 2 ng/mL level. In two of three horses, fluphenazine was detected in serum up to 14 days post administration. The highest detected concentration of fluphenazine in serum was 1.4 ng/mL. PMID- 23986098 TI - Daily rhythms in antennal protein and olfactory sensitivity in the malaria mosquito Anopheles gambiae. AB - We recently characterized 24-hr daily rhythmic patterns of gene expression in Anopheles gambiae mosquitoes. These include numerous odorant binding proteins (OBPs), soluble odorant carrying proteins enriched in olfactory organs. Here we demonstrate that multiple rhythmically expressed genes including OBPs and takeout proteins, involved in regulating blood feeding behavior, have corresponding rhythmic protein levels as measured by quantitative proteomics. This includes AgamOBP1, previously shown as important to An. gambiae odorant sensing. Further, electrophysiological investigations demonstrate time-of-day specific differences in olfactory sensitivity of antennae to major host-derived odorants. The pre dusk/dusk peaks in OBPs and takeout gene expression correspond with peak protein abundance at night, and in turn coincide with the time of increased olfactory sensitivity to odorants requiring OBPs and times of increased blood-feeding behavior. This suggests an important role for OBPs in modulating temporal changes in odorant sensitivity, enabling the olfactory system to coordinate with the circadian niche of An. gambiae. PMID- 23986100 TI - Discrimination between patterns of drug exposure by toxicological analysis of decomposed skeletal tissues. Part II: Amitriptyline and citalopram. AB - Decomposed bone and plasma samples of rats exposed to amitriptyline (AMI) and citalopram (CIT) under different dosing patterns were analyzed. Wistar rats received one acute dose (120 mg AMI/kg and 40 mg CIT/kg; n = 5) or two doses (40 mg AMI/kg and 13 mg CIT/kg, n = 5) 40 min apart. After collection of perimortem blood, the rats were euthanized and placed outdoors to decompose to skeleton. Recovered bone was ground and subjected to methanolic extraction. Bone extracts and plasma samples underwent solid-phase extraction and were analyzed using ultra high-performance liquid chromatography. Concentrations of drugs and the primary metabolites [nortriptyline (NORT), desmethylcitalopram (DMCIT) and didesmethylcitalopram (DDMCIT)] were expressed as mass-normalized response ratios (RR/m). Concentrations (RR/m) of AMI, CIT and metabolites did not differ significantly between exposure types in plasma and all bone types examined or for the pooled bone samples (P > 0.05). However, ratios of concentrations of NORT to those of AMI differed significantly between exposure patterns for all bone types except for rib (P < 0.05). Values of DMCIT/CIT differed significantly between exposure patterns in rib, pelvi and femora (P < 0.05). Values of DDMCIT/CIT did not differ significantly between exposure types (P > 0.05), while those of DDMCIT/DMCIT were significantly different for all bones except the vertebrae and rib (P < 0.05). PMID- 23986102 TI - Controlled synthesis of linear and branched Au@ZnO hybrid nanocrystals and their photocatalytic properties. AB - Colloidal Au@ZnO hybrid nanocrystals with linear and branched shape were synthesized. The number of ZnO domains on the Au seeds can be controlled by the solvent mixture. Imidazole-functionalized Au@ZnO hybrid nanocrystals were soluble in water and exhibited a greatly enhanced photocatalytic activity compared to ZnO nanocrystals. The pristine heterodimeric NPs were characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), and UV-Vis spectroscopy. PMID- 23986101 TI - Activation and splitting of carbon dioxide on the surface of an inorganic electride material. AB - Activation of carbon dioxide is the most important step in its conversion into valuable chemicals. Surfaces of stable oxide with a low work function may be promising for this purpose. Here we report that the surfaces of the inorganic electride [Ca24Al28O64](4+)(e(-))4 activate and split carbon dioxide at room temperature. This behaviour is attributed to a high concentration of localized electrons in the near-surface region and a corrugation of the surface that can trap oxygen atoms and strained carbon monoxide and carbon dioxide molecules. The [Ca24Al28O64](4+)(e(-))4 surface exposed to carbon dioxide is studied using temperature-programmed desorption, and spectroscopic methods. The results of these measurements, corroborated with ab initio simulations, show that both carbon monoxide and carbon dioxide adsorb on the [Ca24Al28O64](4+)(e(-))4 surface at RT and above and adopt unusual configurations that result in desorption of molecular carbon monoxide and atomic oxygen upon heating. PMID- 23986103 TI - WO3-reduced graphene oxide composites with enhanced charge transfer for photoelectrochemical conversion. AB - Hybrid structures between semiconducting metal oxides and carbon with rational synthesis represent unique device building blocks to optimize the light absorption and charge transfer process for the photoelectrochemical conversion. Here we demonstrate the realization of a WO3-reduced graphene oxide (RGO) nanocomposite via hydrothermal growth of ultrathin WO3 nanoplates directly on fluorine-doped tin oxide (FTO) substrates, followed by in situ photo-reduction to deposit RGO layers on WO3 nanoplate surface. Photoanodes made of the WO3-RGO nanocomposites have achieved a photocurrent density of 2.0 mA cm(-2) at 1.23 V vs. reversible hydrogen electrode (RHE), which is among the highest reported values for photoanodes based on hydrothermally grown WO3. Electrochemical impedance spectroscopy reveals that the increase of photoactivity is attributed to the enhanced charge transfer by the incorporation of RGO, thus suggesting a general approach for designing other metal oxide-RGO hybrid architectures. PMID- 23986104 TI - Co-ordinative properties of a tripodal trisamide ligand with a capped octahedral preference. AB - An investigation into the co-ordination chemistry of tris(6-pivaloylamino-2 pyridylmethyl)amine (TPPA) shows a preference for capped octahedral geometry when no additional donors are present. This tripodal ligand yields capped octahedral complexes upon co-ordination to a series of first row transition metals when the counter-ion is a perchlorate, bromide or iodide ion. The exact geometry has been confirmed by shape mapping calculations. The largest variation from the capped octahedral geometry is observed in the case of nickel(ii), indicating a greater octahedral preference of this metal ion. PMID- 23986105 TI - Echolocation versus echo suppression in humans. AB - Several studies have shown that blind humans can gather spatial information through echolocation. However, when localizing sound sources, the precedence effect suppresses spatial information of echoes, and thereby conflicts with effective echolocation. This study investigates the interaction of echolocation and echo suppression in terms of discrimination suppression in virtual acoustic space. In the 'Listening' experiment, sighted subjects discriminated between positions of a single sound source, the leading or the lagging of two sources, respectively. In the 'Echolocation' experiment, the sources were replaced by reflectors. Here, the same subjects evaluated echoes generated in real time from self-produced vocalizations and thereby discriminated between positions of a single reflector, the leading or the lagging of two reflectors, respectively. Two key results were observed. First, sighted subjects can learn to discriminate positions of reflective surfaces echo-acoustically with accuracy comparable to sound source discrimination. Second, in the Listening experiment, the presence of the leading source affected discrimination of lagging sources much more than vice versa. In the Echolocation experiment, however, the presence of both the lead and the lag strongly affected discrimination. These data show that the classically described asymmetry in the perception of leading and lagging sounds is strongly diminished in an echolocation task. Additional control experiments showed that the effect is owing to both the direct sound of the vocalization that precedes the echoes and owing to the fact that the subjects actively vocalize in the echolocation task. PMID- 23986106 TI - First in situ observations of the deep-sea squid Grimalditeuthis bonplandi reveal unique use of tentacles. AB - The deep-sea squid Grimalditeuthis bonplandi has tentacles unique among known squids. The elastic stalk is extremely thin and fragile, whereas the clubs bear no suckers, hooks or photophores. It is unknown whether and how these tentacles are used in prey capture and handling. We present, to our knowledge, the first in situ observations of this species obtained by remotely operated vehicles (ROVs) in the Atlantic and North Pacific. Unexpectedly, G. bonplandi is unable to rapidly extend and retract the tentacle stalk as do other squids, but instead manoeuvres the tentacles by undulation and flapping of the clubs' trabecular protective membranes. These tentacle club movements superficially resemble the movements of small marine organisms and suggest the possibility that G. bonplandi uses aggressive mimicry by the tentacle clubs to lure prey, which we find to consist of crustaceans and cephalopods. In the darkness of the meso- and bathypelagic zones the flapping and undulatory movements of the tentacle may: (i) stimulate bioluminescence in the surrounding water, (ii) create low-frequency vibrations and/or (iii) produce a hydrodynamic wake. Potential prey of G. bonplandi may be attracted to one or more of these as signals. This singular use of the tentacle adds to the diverse foraging and feeding strategies known in deep sea cephalopods. PMID- 23986107 TI - The evolution of genetic architectures underlying quantitative traits. AB - In the classic view introduced by R. A. Fisher, a quantitative trait is encoded by many loci with small, additive effects. Recent advances in quantitative trait loci mapping have begun to elucidate the genetic architectures underlying vast numbers of phenotypes across diverse taxa, producing observations that sometimes contrast with Fisher's blueprint. Despite these considerable empirical efforts to map the genetic determinants of traits, it remains poorly understood how the genetic architecture of a trait should evolve, or how it depends on the selection pressures on the trait. Here, we develop a simple, population-genetic model for the evolution of genetic architectures. Our model predicts that traits under moderate selection should be encoded by many loci with highly variable effects, whereas traits under either weak or strong selection should be encoded by relatively few loci. We compare these theoretical predictions with qualitative trends in the genetics of human traits, and with systematic data on the genetics of gene expression levels in yeast. Our analysis provides an evolutionary explanation for broad empirical patterns in the genetic basis for traits, and it introduces a single framework that unifies the diversity of observed genetic architectures, ranging from Mendelian to Fisherian. PMID- 23986108 TI - Antagonism between two intestinal parasites in humans: the importance of co infection for infection risk and recovery dynamics. AB - Co-infection may affect transmission and recovery from infection, but remains an understudied element of disease ecology, particularly with regard to antagonism between parasites sharing a host. Helminth and giardia infections are often endemic in the same populations and both occupy the small intestine; yet few studies have examined interactions between these parasites. We report on helminth giardia co-infections in a panel study of forager-horticulturalists in the Bolivian lowlands. Parasites were identified in faecal samples from 3275 participants, collected during 5235 medical exams over 6 years. Longitudinal co infection patterns were examined using logistic mixed and multi-state Markov models. The most prevalent infections were hookworm (56%), Giardia lamblia (30%) and Ascaris lumbricoides (15%). Cross-sectionally, hookworm and A. lumbricoides were negatively associated with G. lamblia (OR = 0.60; OR = 0.65, respectively). Longitudinally, giardia infection was less likely in helminth-infected individuals (HR: 0.46). Infection with helminths was also less likely for individuals infected with giardia (HR: 0.71). Finally, treatment with mebendazole reduced subsequent hookworm infections, but resulted in a marginal increase in the odds of G. lamblia infection. Our results provide evidence for an antagonistic relationship between helminths and giardia, and suggest that co infection should be considered in disease transmission models and treatment decisions. PMID- 23986109 TI - Sleep facilitates long-term face adaptation. AB - Adaptation is an automatic neural mechanism supporting the optimization of visual processing on the basis of previous experiences. While the short-term effects of adaptation on behaviour and physiology have been studied extensively, perceptual long-term changes associated with adaptation are still poorly understood. Here, we show that the integration of adaptation-dependent long-term shifts in neural function is facilitated by sleep. Perceptual shifts induced by adaptation to a distorted image of a famous person were larger in a group of participants who had slept (experiment 1) or merely napped for 90 min (experiment 2) during the interval between adaptation and test compared with controls who stayed awake. Participants' individual rapid eye movement sleep duration predicted the size of post-sleep behavioural adaptation effects. Our data suggest that sleep prevented decay of adaptation in a way that is qualitatively different from the effects of reduced visual interference known as 'storage'. In the light of the well established link between sleep and memory consolidation, our findings link the perceptual mechanisms of sensory adaptation--which are usually not considered to play a relevant role in mnemonic processes--with learning and memory, and at the same time reveal a new function of sleep in cognition. PMID- 23986110 TI - Experience overrides personality differences in the tendency to follow but not in the tendency to lead. AB - In many animal groups, coordinated activity is facilitated by the emergence of leaders and followers. Although the identity of leaders is to some extent predictable, most groups experience frequent changes of leadership. How do group members cope with such changes in their social role? Here, we compared the foraging behaviour of pairs of stickleback fish after a period of either (i) role reinforcement, which involved rewarding the shyer follower for following, and the bolder leader for leading, or (ii) role reversal, which involved rewarding the shyer follower for leading, and the bolder leader for following. We found that, irrespective of an individual's temperament, its tendency to follow is malleable, whereas the tendency to initiate collective movement is much more resistant to change. As a consequence of this lack of flexibility in initiative, greater temperamental differences within a pair led to improved performance when typical roles were reinforced, but to impaired performance when typical roles were reversed. PMID- 23986111 TI - Phylogenomics demonstrates that breviate flagellates are related to opisthokonts and apusomonads. AB - Most eukaryotic lineages belong to one of a few major groups. However, several protistan lineages have not yet been robustly placed in any of these groups. Both the breviates and apusomonads are two such lineages that appear to be related to the Amoebozoa and Opisthokonta (i.e. the 'unikonts' or Amorphea); however, their precise phylogenetic positions remain unclear. Here, we describe a novel microaerophilic breviate, Pygsuia biforma gen. nov. sp. nov., isolated from a hypoxic estuarine sediment. Ultrastructurally, this species resembles the breviate genera Breviata and Subulatomonas but has two cell morphologies, adherent and swimming. Phylogenetic analyses of the small sub-unit rRNA gene show that Pygsuia is the sister to the other breviates. We constructed a 159-protein supermatrix, including orthologues identified in RNA-seq data from Pygsuia. Phylogenomic analyses of this dataset show that breviates, apusomonads and Opisthokonta form a strongly supported major eukaryotic grouping we name the Obazoa. Although some phylogenetic methods disagree, the balance of evidence suggests that the breviate lineage forms the deepest branch within Obazoa. We also found transcripts encoding a nearly complete integrin adhesome from Pygsuia, indicating that this protein complex involved in metazoan multicellularity may have evolved earlier in eukaryote evolution than previously thought. PMID- 23986112 TI - The radiation of cynodonts and the ground plan of mammalian morphological diversity. AB - Cynodont therapsids diversified extensively after the Permo-Triassic mass extinction event, and gave rise to mammals in the Jurassic. We use an enlarged and revised dataset of discrete skeletal characters to build a new phylogeny for all main cynodont clades from the Late Permian to the Early Jurassic, and we analyse models of morphological diversification in the group. Basal taxa and epicynodonts are paraphyletic relative to eucynodonts, and the latter are divided into cynognathians and probainognathians, with tritylodonts and mammals forming sister groups. Disparity analyses reveal a heterogeneous distribution of cynodonts in a morphospace derived from cladistic characters. Pairwise morphological distances are weakly correlated with phylogenetic distances. Comparisons of disparity by groups and through time are non-significant, especially after the data are rarefied. A disparity peak occurs in the Early/Middle Triassic, after which period the mean disparity fluctuates little. Cynognathians were characterized by high evolutionary rates and high diversity early in their history, whereas probainognathian rates were low. Community structure may have been instrumental in imposing different rates on the two clades. PMID- 23986113 TI - Dynamics of mitochondrial inheritance in the evolution of binary mating types and two sexes. AB - The uniparental inheritance (UPI) of mitochondria is thought to explain the evolution of two mating types or even true sexes with anisogametes. However, the exact role of UPI is not clearly understood. Here, we develop a new model, which considers the spread of UPI mutants within a biparental inheritance (BPI) population. Our model explicitly considers mitochondrial mutation and selection in parallel with the spread of UPI mutants and self-incompatible mating types. In line with earlier work, we find that UPI improves fitness under mitochondrial mutation accumulation, selfish conflict and mitonuclear coadaptation. However, we find that as UPI increases in the population its relative fitness advantage diminishes in a frequency-dependent manner. The fitness benefits of UPI 'leak' into the biparentally reproducing part of the population through successive matings, limiting the spread of UPI. Critically, while this process favours some degree of UPI, it neither leads to the establishment of linked mating types nor the collapse of multiple mating types to two. Only when two mating types exist beforehand can associated UPI mutants spread to fixation under the pressure of high mitochondrial mutation rate, large mitochondrial population size and selfish mutants. Variation in these parameters could account for the range of UPI actually observed in nature, from strict UPI in some Chlamydomonas species to BPI in yeast. We conclude that UPI of mitochondria alone is unlikely to have driven the evolution of two mating types in unicellular eukaryotes. PMID- 23986114 TI - A coumarin-indole-based near-infrared ratiometric pH probe for intracellular fluorescence imaging. AB - New pH-activatable ratiometric fluorescent probes have been developed that have a coumarin structure attached to benzothiazole or indole units with one or two conjugated bonds. They have optical responses in acidic conditions. Probes with benzothiazole (1) and indole (2, 3) units have opposite responses to changes in pH, in terms of shifts in absorption and emission. Quantum chemical calculations with the B3LYP exchange functional provide insights into the differences in optical properties between 1 and 2/3. Probe 3 (7-diethylamino-3-[4-(3,3-dimethyl 3H-indol-2-yl)-buta-1,3-dienyl]-chromen-2-one) displayed a significant 122 nm red shift of the emission maximum; the new peak is located in the near-infrared region. In vitro assays demonstrate that probe 3 can be used in quantitative fluorescence imaging for the detection of intracellular pH distributions. In addition to the large Stokes shift, it has rapid responsivity, excellent cell permeability, and high selectivity. This study reveals that the conjugation of coumarin with benzothiazole or indole to form an intramolecular charge transfer (ICT) platform is an effective method to construct new fluorescent pH probes for acidic microenvironments. PMID- 23986115 TI - Bridging the Gray and Yang, Sal'nikov and one-step, non-isothermal reaction schemes for oscillatory and explosive behaviour. AB - Explosions may occur as a result of thermal and branching effects in combustion processes. The aim of this work is to study the effects of chain branching and termination in a "Gray and Yang" three-step, chain-thermal reaction scheme, and the role of thermal diffusion and convection in determining the global behaviour. The response includes steady, exothermic combustion, oscillatory reaction and explosion. This was done by solving numerically the governing equations for the underlying kinetics and the heat transport, and analysing solutions for the limits at which each transport phenomenon dominates. Using scales to describe the different transport mechanisms, a 3D regime diagram is used to characterise the behaviour of the system. The results show how branching and heating by reaction enhance the oscillatory and explosive behaviour. The integration of a two-step Sal'nikov reaction scheme and a one-step reaction model in the Gray and Yang scheme is presented and the Frank-Kamenteskii and Semenov limits are identified on the regime diagram. Comparison is made with some experimental, numerical and analytical results. PMID- 23986116 TI - High energy resolution core-level X-ray spectroscopy for electronic and structural characterization of osmium compounds. AB - A comprehensive study of the bulk solid OsCl3 and the molecular ion [Os(bpy)2(CO)Cl](+) is presented illustrating the application of RIXS and HERFD XANES spectroscopies to the investigation of both bulk materials and molecular complexes. In order to analyze the experimental results, DFT simulations were performed taking into account spin-orbit interaction. Calculations for both compounds resulted in good agreement with the experimental RIXS and HERFD XANES data, shedding light on the details of their local atomic and electronic structure. In particular, the spatial distribution of molecular orbitals was obtained, which allowed the determination of the origin of the absorption peaks. It was shown that for materials containing heavy atoms, only the application of advanced RIXS and HERFD XANES spectroscopies makes it possible to extract the information on local atomic and electronic structure details from XANES data. PMID- 23986117 TI - Genetic analysis of an H5N2 highly pathogenic avian influenza virus isolated from a chicken in a live bird market in Northern Vietnam in 2012. AB - In August 2012, A/chicken/Vietnam/OIE-2215/2012 (H5N2) was isolated from a chicken in a live bird market (LBM) in Northern Vietnam. Intravenous pathogenicity test revealed that this virus is highly pathogenic in chickens. The PA, HA, NP and M, PB2 and NA, and PB1 and NS genes of the isolate were phylogenetically closely related to those of A/duck/Vietnam/OIE-2202/2012 (H5N1) of clade 2.3.2.1, A/chicken/Vietnam/OIE-1611/2012 (H9N2) and A/chicken/Vietnam/OIE-2468/2012 (H9N2), respectively. All of these viruses were isolated from birds in LBMs in the same province. These results indicate that A/chicken/Vietnam/OIE-2215/2012 (H5N2) is a genetic reassortant and that surveillance of avian influenza in LBMs and stamping out policy are essential for the eradication of highly pathogenic avian influenza viruses from Asia. PMID- 23986118 TI - The presence of disease-associated prion protein in skeletal muscle of cattle infected with classical bovine spongiform encephalopathy. AB - The aim of this study was to investigate the presence of disease-associated prion protein (PrP(Sc)) in the skeletal muscle of cattle infected with classical bovine spongiform encephalopathy (C-BSE). The study was carried out systematically in 12 different muscle samples from 43 (3 field and 40 experimental) cases of C-BSE; however, muscle spindles were not available in many of these cases. Therefore, analysis became restricted to a total of 31 muscles in 23 cattle. Even after this restriction, low levels of PrP(Sc) were detected in the muscle spindles of the masseter, intercostal, triceps brachii, psoas major, quadriceps femoris and semitendinosus muscles from 3 field and 6 experimental clinical-stage cases. The present data indicate that small amounts of PrP(Sc) are detectable by immunohistochemistry in the skeletal muscles of animals terminally affected with C-BSE. PMID- 23986120 TI - Health protection in times of economic crisis: challenges and opportunities for Europe. AB - STOA, the European Parliament's technology assessment body, and the European Observatory on Health Systems and Policies recently organised a workshop on the impacts of the economic crisis on European health systems. Evidence of the impact of the recent financial crisis on health outcomes is only just beginning to emerge. Data suggests that this latest recession has led to more frequent poor health status, rising incidence of some communicable diseases, and higher suicide rates. Further, available data are likely to underestimate the broader mental health crisis linked to increased rates of stress, anxiety, and depression among the economically vulnerable. Not only does recession affect factors that determine health, but it also affects the financial capacity to respond. Many European governments have reduced public expenditure on health services during the financial crisis, while introducing or increasing user charges. The recession has driven structural reforms, and has affected the priority given to public policies that could be used to help protect population health. The current economic climate, while challenging, presents an opportunity for reforming and restructuring health promotion actions and taking a long-term perspective. PMID- 23986121 TI - Least untruthful, a new standard? PMID- 23986119 TI - Valproic acid, a histone deacetylase inhibitor, decreases proliferation of and induces specific neurogenic differentiation of canine adipose tissue-derived stem cells. AB - Adipose tissue-derived stem cells (ADSCs) isolated from adult tissue have pluripotent differentiation and self-renewal capability. The tissue source of ADSCs can be obtained in large quantities and with low risks, thus highlighting the advantages of ADSCs in clinical applications. Valproic acid (VPA) is a widely used antiepileptic drug, which has recently been reported to affect ADSC differentiation in mice and rats; however, few studies have been performed on dogs. We aimed to examine the in vitro effect of VPA on canine ADSCs. Three days of pretreatment with VPA decreased the proliferation of ADSCs in a dose-dependent manner; VPA concentrations of 4 mM and above inhibited the proliferation of ADSCs. In parallel, VPA increased p16 and p21 mRNA expression, suggesting that VPA attenuated the proliferative activity of ADSCs by activating p16 and p21. Furthermore, the effects of VPA on adipogenic, osteogenic or neurogenic differentiation were investigated morphologically. VPA pretreatment markedly promoted neurogenic differentiation, but suppressed the accumulation of lipid droplets and calcium depositions. These modifications of ADSCs by VPA were associated with a particular gene expression profile, viz., an increase in neuronal markers, that is, NSE, TUBB3 and MAP2, a decrease in the adipogenic marker, LPL, but no changes in osteogenic markers, as estimated by reverse transcription-PCR analysis. These results suggested that VPA is a specific inducer of neurogenic differentiation of canine ADSCs and is a useful tool for studying the interaction between chromatin structure and cell fate determination. PMID- 23986122 TI - Single-step noninjection synthesis of highly luminescent water soluble Cu+ doped CdS quantum dots: application as bio-imaging agents. AB - Novel highly luminescent Cu(+) doped CdS quantum dots (QDs) were directly synthesized in aqueous phase through a facile single-step noninjection method. Due to their bright red fluorescence, ultrasmall size, and good biocompatibility, as-prepared CdS:Cu(+) QDs have potential as probes in bio-imaging. PMID- 23986123 TI - Manipulation and coherence of ultra-cold atoms on a superconducting atom chip. AB - The coherence of quantum systems is crucial to quantum information processing. Although superconducting qubits can process quantum information at microelectronics rates, it remains a challenge to preserve the coherence and therefore the quantum character of the information in these systems. An alternative is to share the tasks between different quantum platforms, for example, cold atoms storing the quantum information processed by superconducting circuits. Here we characterize the coherence of superposition states of (87)Rb atoms magnetically trapped on a superconducting atom chip. We load atoms into a persistent-current trap engineered next to a coplanar microwave resonator structure, and observe that the coherence of hyperfine ground states is preserved for several seconds. We show that large ensembles of a million of thermal atoms below 350 nK temperature and pure Bose-Einstein condensates with 3.5 * 10(5) atoms can be prepared and manipulated at the superconducting interface. This opens the path towards the rich dynamics of strong collective coupling regimes. PMID- 23986124 TI - Suppression of respiratory papillomatosis with malignant transformation by erlotinib in a kidney transplant recipient. AB - A 52-year-old non-smoker and renal transplant recipient developed an incessant cough. A CT scan of the thorax revealed ill-defined hazy opacities in the right upper lung. He was diagnosed with non-tuberculosis Mycobacterium chelonae/abscessus infection based on sputum culture results. A trial of antibiotics initially resulted in some clinical improvement. A subsequent CT of the thorax documented worsening of the lesions in the right lung and new lesions on the left. An intratracheal growth was noted. Bronchoscopy with biopsy of the tracheal lesions documented respiratory papillomatosis with transformation to squamous cell cancer. Test for high-risk human papilloma virus was positive. Video-assisted thoracoscopic surgery biopsy with wedge resection of the left lower lobe revealed metastatic squamous cell lung cancer. He was treated with one ablation followed by four cycles of chemotherapy. He has been maintained on erlotinib ever since. There has been no recurrence of the cough or papillomas. PMID- 23986125 TI - High-dose thiamine as initial treatment for Parkinson's disease. AB - Parkinson's disease (PD) is a systemic disease with motor and non-motor deficits. We recruited three patients with newly diagnosed PD. They were not under anti Parkinson's therapy. Plasmatic thiamine was within healthy reference range. We performed the Unified Parkinson's Disease Rating Scale (UPDRS) and started a parenteral therapy with high doses of thiamine. The therapy led to a considerable improvement in the motor part of the UPDRS ranging from 31.3% to 77.3%. From this clinical observation, it is reasonable to infer that a focal, severe thiamine deficiency due to a dysfunction of thiamine metabolism could cause a selective neuronal damage in the centres that are typically hit in this disease. Injection of high doses of thiamine was effective in reversing the symptoms, suggesting that the abnormalities in thiamine-dependent processes could be overcome by diffusion-mediated transport at supranormal thiamine concentrations. PMID- 23986126 TI - Clinical and histological resolution of collagenous sprue following gluten-free diet and discontinuation of non-steroidal anti-inflammatory drugs (NSAIDs). AB - Collagenous sprue is a rare small bowel enteropathy that has overlapping clinical features with coeliac disease; it is commonly associated with arthritic autoimmune conditions, which often require non-steroidal anti-inflammatory drugs (NSAIDs). In the limited published literature available, there are putative suggestions of a link between NSAID use and collagen deposition in intestinal subepithelia in such patients. The authors present a case of a 43-year-old woman with long-standing NSAID use for autoimmune polyarthropathy and positive coeliac antibodies. However, distal duodenal biopsies revealed a thickened band of subepithelial collagen with villous atrophic appearances consistent with collagenous sprue. The patient was treated with a gluten-free diet and her NSAIDs were discontinued. After 6 months, her gastrointestinal symptoms had resolved with complete histological resolution of the collagenous subepithelial bands and villous atrophy on duodenal biopsy. PMID- 23986127 TI - Primer hydatid cyst of the deltoid muscle. AB - A primary intramuscular hydatid cyst should be considered for the differential diagnosis of cystic soft tissue masses especially in endemic areas, although primary muscular hydatidosis is a rare clinical entity. A case of a 48-year-old male patient with a primary intramuscular hydatid cyst located in the deltoid muscle is reported. PMID- 23986128 TI - Identification of Mycobacterium tuberculosis from pericardial fluid using the new Xpert MTB/RIF assay. AB - Extrapulmonary tuberculosis (EPTB) is common in HIV-infected patients, especially at lower CD4 cell counts, yet is often difficult to diagnose with certainty. A 35 year-old man presented with dyspnoea and constitutional symptoms of tuberculosis (TB). Laboratory investigations included a positive HIV test and a CD4 cell count of 138 cells/MUL. Chest radiography revealed a globular-shaped heart and bilateral pleural effusions, while echocardiography confirmed a massive pericardial effusion. The new Xpert MTB/RIF (Xpert) assay detected rifampicin sensitive Mycobacterium tuberculosis in pericardial as well as sputum samples. Smear of the pericardial sample was negative. The patient was started on anti-TB treatment and is presently well. He will initiate antiretroviral therapy after 4 6 weeks. To the best of our knowledge, this is the first case report of EPTB diagnosed on pericardial fluid using the Xpert assay in Africa. This report also summarises the use of this assay in the diagnosis of EPTB in HIV-associated TB. PMID- 23986129 TI - Spontaneous subdural haemorrhage in a child with bilateral middle cranial fossa arachnoid cysts. PMID- 23986131 TI - Paraplegia following thoracic and lumbar transforaminal epidural steroid injections: how relevant is physician negligence? PMID- 23986130 TI - Association of circulating sTRAIL and high-sensitivity CRP with type 2 diabetic nephropathy and foot ulcers. AB - BACKGROUND: Hyperglycemia is among the potent factors that may induce or facilitate apoptosis. TNF-Related Apoptosis-Inducing Factor (TRAIL) is known for its apoptotic and immunomodulatory effects that have recently been correlated with diabetes. We examined serum-soluble TRAIL (sTRAIL) and high-sensitivity CRP (hs-CRP) levels and their association with various distinct parameters in type 2 diabetic nephropathy patients with diabetic foot disease. MATERIAL/METHODS: Twenty-two diabetic nephropathy patients with foot ulcers were enrolled in our study. Patients had been diagnosed with diabetes at age 24+/-10.58 years. Circulating sTRAIL and Hs-CRP levels were compared with control values, and possible correlations were investigated with parameters such as age, Wagner's Grade (WG), BMI, HbA1c, and creatinine. RESULTS: Serum sTRAIL levels were significantly reduced in the patient group, compared to healthy subjects. High HsCRP levels correlated with age, and WGS correlated with BMI and creatinine levels. CONCLUSIONS: Significantly suppressed sTRAIL levels in diabetic nephropathy patients with foot ulcers compared to healthy controls suggest a protective role for TRAIL in the disease setting. PMID- 23986132 TI - Endovascular treatment of pediatric intracranial aneurysms: a retrospective study of 35 aneurysms. AB - BACKGROUND: Pediatric intracranial aneurysms are rare and not well characterized in comparison with those in adults. OBJECTIVE: To analyze our institution's longitudinal experience of endovascular treatment for pediatric aneurysms to better understand this rare condition. METHODS: A retrospective record review was performed of patients aged <20 years treated with endovascular methods for intracranial aneurysms between 1995 and 2012. There were 31 patients (average 14.4+/-4.2 years; 20 male, 11 female) with 35 intracranial aneurysms. RESULTS: The rate of subarachnoid hemorrhage as the initial presentation was 48% and the rates of multiple and giant aneurysms were 13% and 31%, respectively; 28.5% of the cases were posterior circulation aneurysms. Fifteen saccular aneurysms occurred in 14 patients and 17 fusiform aneurysms were noted in 14 patients. Two infectious aneurysms were diagnosed in two patients and one traumatic aneurysm occurred in another patient. Thirty-four aneurysms were treated endovascularly and one had thrombosed spontaneously on a follow-up angiogram. Of the 15 saccular aneurysms, 11 were treated with conventional coiling, one was treated with stent assisted coiling, one was treated with a flow-diverting stent and two were treated with parent vessel occlusion (PVO). Of the 17 fusiform aneurysms, 15 were treated with PVO with or without prior bypass surgery and one was treated with a flow-diverting stent. The rate of permanent complications and a favorable outcome were 2.9% and 87%, respectively. CONCLUSIONS: Endovascular treatment of pediatric aneurysms is technically feasible with an acceptable complication rate despite the high incidence of fusiform aneurysms. PMID- 23986133 TI - Novel porphyrin-psoralen conjugates: synthesis, DNA interaction and cytotoxicity studies. AB - A Cu(i)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) has been utilized to prepare novel triazole-linked cationic porphyrin-psoralen conjugates that exhibited significant photocytotoxicity against A549 cancer cells (IC50 = 84 nM). PMID- 23986134 TI - Slow magnetic relaxation in four square-based pyramidal dysprosium hydroxo clusters ligated by chiral amino acid anions - a comparative study. AB - The synthesis and characterization of three chiral and one achiral amino acid anion ligated dysprosium hydroxo clusters [Dy5(OH)5(alpha-AA)4(Ph2acac)6] (alpha AA = d-PhGly, l-Pro, l-Trp, Ph2Gly; Ph2acac = dibenzoylmethanide) are reported. The solid state structures were determined using single crystal X-ray diffraction and show that five Dy(iii) ions are arranged in a square-based pyramidal geometry with NO7-donor-sets for the basal and O8-donor-sets for the apical Dy atom. Both static (dc) and dynamic (ac) magnetic properties were investigated for all four compounds and show a slow relaxation of magnetization, indicative of single molecule magnet (SMM) behaviour below 10 K in all cases. The similar SMM behaviour observed for all four compounds suggests that the very similar coordination geometries seen for the dysprosium atoms in all members of this family, which are independent of the amino acid ligand used, play a decisive role in steering the contribution of the single ion anisotropies to the observed magnetic relaxation. PMID- 23986135 TI - Annexin-V modified QCM sensor for the label-free and sensitive detection of early stage apoptosis. AB - An easily-made Annexin-V modified quartz crystal microbalance (QCM) sensor was constructed for the quantitative detection of early stage apoptosis for the first time, achieving the goals of specific capture and sensitive detection of target cells in one step without the need for cell labelling. PMID- 23986136 TI - Preparation of crystal-like periodic mesoporous phenylene-silica derivatized with ferrocene and its use as a catalyst for the oxidation of styrene. AB - The surface silanol groups in crystal-like mesoporous phenylene-silica have been derivatized with trimethylsilyl, benzyldimethylsilyl and dimethylsilyl(ferrocene) groups by performing a post-synthetic grafting reaction with the corresponding chlorosilane precursors. The success of the grafting procedure was demonstrated by transmission FT-IR spectroscopy and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), and (13)C and (29)Si magic-angle spinning (MAS) NMR spectroscopy. Powder X-ray diffraction (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM) and N2 adsorption data for the modified materials indicated preservation of the mesostructure as well as the molecular-scale periodicity in the pore walls. Ferrocene and the ferrocenyl modified periodic mesoporous organosilica (PMO) were employed in the catalytic oxidation of styrene at 55 degrees C using either hydrogen peroxide or tert butylhydroperoxide as an oxidant. The main reaction product was always benzaldehyde (BzCHO), and other products included styrene oxide, benzoic acid and 2-hydroxyacetophenone. Using a styrene:H2O2 molar ratio of 1:5, the highest BzCHO yields at 24 h were 65% (85% selectivity) for ferrocene (semibatch conditions involving stepwise addition of H2O2, 1 mol% Fe) and 34% (83% selectivity) for the modified PMO (batch conditions, 0.06 mol% Fe). The modified PMO could be recovered and reused, albeit with a drop in catalytic activity due to partial metal leaching during the first catalytic run. PMID- 23986137 TI - Change can be a good thing! PMID- 23986138 TI - Periodontal pathogens and reactivation of latent HIV infection: a review of the literature. AB - PURPOSE: Infection by the human immunodeficiency virus (HIV) causes the host to have a compromised immune system due to the virus's ability to infect cells of the immune system, such as helper T-cells (specifically CD4+ T-cells), macrophages and dendritic cells. HIV remains latent within these cells, which function as memory cells and remains in the body for years. People who have a compromised immune system caused by HIV are more highly susceptible to other infections, including periodontal disease. Until recently, very little attention has been given to the potential interactions between chronic oral infections, such as periodontal disease and latent HIV reactivation/upregulation. This review focuses on the literature available between 2009 and 2011, evaluating the potential link between bacterial infections, including oral infections caused by periodontal pathogens, the reactivation of latent HIV leading to the potential failure of highly active antiretroviral therapy and acquired immunodeficiency syndrome (AIDS) progression. It has been hypothesized that infections by periodontal pathogens can stimulate reactivation of HIV-latently infected cells. Studies showed that soluble factors produced in response to periodontal pathogens by gingival cells could be indirect contributors to HIV-1 promoter activation. It was also found that the oral bacteria stimulated the HIV promoter activation in a dose-dependent and time-dependent manner. While these preliminary studies present a potential link between oral periodontal pathogens and HIV reactivation, additional clinical and epidemiological studies are needed to clarify the causal link and mechanisms of HIV latency reactivation associated with oral pathogens. PMID- 23986139 TI - Collaborative learning in pre-clinical dental hygiene education. AB - PURPOSE: Dental hygiene education continues to move beyond mastery of content material and skill development to learning concepts that promote critical thinking and problem-solving skills. The purpose of this research was to evaluate the effectiveness of collaborative learning and determine the growth in intellectual development of 54 first-year dental hygiene students. METHODS: The control group used traditional pre-clinical teaching and the experimental group used collaborative pedagogy for instrument introduction. All students were subjected to a post-test evaluating their ability to apply the principles of instrumentation. Intellectual development was determined using pre- and post tests based on the Perry Scheme of Intellectual Development. Student attitudes were assessed using daily Classroom Assessment Activities and an end-of-semester departmental course evaluation. RESULTS: Findings indicated no significant difference between collaborative learning and traditional learning in achieving pre-clinical competence as evidenced by the students' ability to apply the principles of instrumentation. Advancement in intellectual development did not differ significantly between groups. Value added benefits of a collaborative learning environment as identified by the evaluation of student attitudes included decreased student reliance on authority, recognition of peers as legitimate sources of learning and increased self-confidence. A significant difference in student responses to daily classroom assessments was evident on the 5 days a collaborative learning environment was employed. CONCLUSION: Dental hygiene students involved in a pre-clinical collaborative learning environment are more responsible for their own learning and tend to have a more positive attitude toward the subject matter. Future studies evaluating collaborative learning in clinical dental hygiene education need to investigate the cost/benefit ratio of the value added outcomes of collaborative learning. PMID- 23986140 TI - Chronic HPA axis response to stress in temporomandibular disorder. AB - PURPOSE: Perceived stress is associated with temporomandibular disorder (TMD), but whether cortisol levels are elevated in individuals with TMD is unknown. We hypothesized that cortisol concentration, a biomarker of hypothalamic-pituitary adrenal (HPA) axis function, was elevated in TMD cases relative to controls, and that perceived stress was positively correlated with cortisol concentration. METHODS: In this case control study, TMD case status was determined by examiners using TMD Research Diagnostic Criteria. Participants (n=116) aged 18 to 59 years were recruited from within a 50 mile radius of the University of North Carolina at Chapel Hill. Following examination, cases (n=45) and controls (n=71) completed the 14-item Perceived Stress Scale using a reference interval of the past 3 months. Approximately 100 strands of hair were cut from the posterior vertex segment of their scalp. The 3 centimeters of hair most proximal to the scalp was analyzed with a commercially available salivary cortisol enzyme immunoassay adapted for hair cortisol. This length corresponds to the last 3 months of systemic HPA axis activity. RESULTS: TMD cases perceived higher stress than controls (p=0.001). However, hair cortisol concentration was lower in TMD cases than controls (p<0.001). The correlation coefficient revealed a weak negative relationship (r=-0.188) between perceived stress and hair cortisol concentration (p=0.044). In analysis stratified by case status, the relationship of perceived stress and hair cortisol concentration was non-significant for cases (p=0.169) and controls (p=0.498). CONCLUSION: Despite greater perceived stress, TMD cases had lower hair cortisol concentrations than controls and the 2 measures of stress were weakly and negatively correlated. PMID- 23986141 TI - Diabetes-related knowledge and sources of information among periodontal patients: is there a role for dental hygienists? AB - PURPOSE: Although there is a bidirectional relationship between periodontal disease and diabetes, little is known about the diabetes-related knowledge of periodontal patients. This study examines what patients with periodontal disease know about diabetes and its association with periodontitis. It also examines their sources of diabetes-related information. METHODS: Patients (n=111) with or at risk for diabetes who were receiving care at a university-based periodontics and implant clinic completed a written survey assessing their socio-demographic characteristics, health-related activities, diabetes knowledge and sources of diabetes-related information. Survey results were summarized using descriptive statistics. Fisher's exact tests were used to compare patients who had and had not been diagnosed with diabetes according to responses on diabetes-related knowledge items and sources of diabetes information. RESULTS: Although respondents endorsed various diabetes-related information sources, including family and friends and health care providers, respondents demonstrated very limited knowledge about the diabetes and periodontal disease association. There were no statistically significant differences between patients who had, and had not been diagnosed with diabetes regarding their diabetes-related knowledge. As compared with patients not diagnosed with diabetes, patients with diabetes were significantly more likely to have learned about diabetes from a health care provider (p=0.05) and significantly less likely to have learned about it from friends or family (p=0.05). CONCLUSION: Periodontal patients need education about the periodontitis-diabetes relationship. Dental hygienists' regular and ongoing involvement with these patients and their primary role in the patients' periodontal care places them in an optimal position to provide this education. PMID- 23986142 TI - Setting and validating the pass/fail score for the NBDHE. AB - PURPOSE: This report describes the overall process used for setting the pass/fail score for the National Board Dental Hygiene Examination (NBDHE). METHODS: The Objective Standard Setting (OSS) method was used for setting the pass/fail score for the NBDHE. The OSS method requires a panel of experts to determine the criterion items and proportion of these items that minimally competent candidates would answer correctly, the percentage of mastery and the confidence level of the error band. A panel of 11 experts was selected by the Joint Commission on National Dental Examinations (Joint Commission). Panel members represented geographic distribution across the U.S. and had the following characteristics: full-time dental hygiene practitioners with experience in areas of preventive, periodontal, geriatric and special needs care, and full-time dental hygiene educators with experience in areas of scientific basis for dental hygiene practice, provision of clinical dental hygiene services and community health/research principles. Utilizing the expert panel's judgments, the pass/fail score was set and then the score scale was established using the Rasch measurement model. RESULTS: Statistical and psychometric analysis shows the actual failure rate and the OSS failure rate are reasonably consistent (2.4% vs. 2.8%). The analysis also showed the lowest error of measurement, an index of the precision at the pass/fail score point and that the highest reliability (0.97) are achieved at the pass/fail score point. CONCLUSION: The pass/fail score is a valid guide for making decisions about candidates for dental hygiene licensure. This new standard was reviewed and approved by the Joint Commission and was implemented beginning in 2011. PMID- 23986143 TI - Influence of continuing education on dental hygienists' knowledge and behavior related to oral cancer screening and tobacco cessation. AB - PURPOSE: There are more than 35,000 new cases of oral and pharyngeal cancers (OPC) diagnosed each year. Most OPCs are diagnosed in advanced stages, requiring aggressive treatment and resulting in higher morbidity and mortality than when diagnosed early. The overall 5 year survival rate of OPC is about 60%. Early detection of OPC lesions are the key to survival. A major risk factor for OPC is chronic tobacco use. The purpose of this paper is to report changes in dental hygienists' knowledge, attitudes and behaviors 6 months after attending a standardized lecture format continuing education (CE) course on early OPC detection and tobacco cessation counseling compared to baseline values. METHODS: A total of 64 CE courses were given for dental professionals throughout the 10 U.S. public health districts to determine if OPC screenings and tobacco cessation counseling behaviors could be modified at 6 months post-training. Questionnaires were obtained at baseline and 6 months later using a pre-/post-test design. RESULTS: A total of 1,463 dental hygienists participated at baseline and 543 at a 6 month follow-up. Data showed a significant difference in knowledge and behavior compared to baseline values. CONCLUSION: CE appeared to have a significant influence on participants' OPC and tobacco cessation knowledge and behavior, and could potentially make a difference on prevention, early detection and ultimately on OPC control. PMID- 23986144 TI - Sugar furanoid trans-vicinal diacid as a gamma-turn inducer: synthesis and conformational study. AB - A simple method for the synthesis of a sugar furanoid trans vicinal diacid and its incorporation into the N-terminal tetrapeptide sequence (H-Phe-Trp-Lys-Thr OH) to get glycopeptide has been described. 2D NMR and MD simulation studies of clearly show that the sugar diacid adopts a gamma-turn conformation towards the N terminus. PMID- 23986145 TI - Electron donor ionic liquids entrapped in anionic and cationic reverse micelles. Effects of the interface on the ionic liquid-surfactant interactions. AB - The behavior of two ionic liquids (ILs) with high electron donor ability such as 1-butyl-3-methylimidazolium trifluoromethanesulfonate (bmimTfO) and 1-butyl-3 methylimidazolium trifluoroacetate (bmimTfA) entrapped in anionic and cationic reverse micelles (RMs) was investigated using dynamic light scattering (DLS) and FT-IR spectroscopy. The systems studied were chlorobenzene/sodium 1,4-bis-2 ethylhexylsulfosuccinate (AOT)/bmimTfO, chlorobenzene/AOT/bmimTfA, chlorobenzene/benzyl-n-hexadecyldimethylammonium chloride (BHDC)/bmimTfO and chlorobenzene/BHDC/bmimTfA. DLS results reveal the formation of RMs containing bmimTfO and bmimTfA as polar components since the droplet size values increase as Ws (Ws = [IL]/[surfactant]) increases. To the best of our knowledge this is the first report where it is shown that both ILs are entrapped by AOT and BHDC surfactants to effectively create RMs. Furthermore, it is shown that the RMs consist of discrete spherical and non-interacting droplets of IL stabilized by the surfactants. The larger droplet size values and the larger changes obtained for bmimTfO entrapped in AOT and BHDC RMs in comparison with those for bmimTfA in both RMs can be explained considering the different IL-surfactant interactions. The FT-IR results suggest that the ionic interactions (with the surfactant polar head groups, surfactant counterions or with the IL counterions) are substantially modified upon confinement. These interactions produce segregation of ILs's ions altering the composition of the RM interfaces. These facts show the versatility of this kind of organized systems to alter the ionic organization, information that can be very important if these media are used as nanoreactors because unique microenvironments can be easily created simply changing the RM components and Ws. PMID- 23986146 TI - Synthesis of rGO-supported layered MoS2 for high-performance rechargeable Mg batteries. AB - Distinctive rGO-supported MoS2 hybrids have been fabricated via a hydrothermal method followed by a heat treatment. Characterizations demonstrate that layered MoS2 and graphene nanosheets in the hybrids interlace with each other to form novel sandwich-structured microspheres, which exhibit preferable electrochemical performance in rechargeable Mg batteries. PMID- 23986147 TI - Revolution of nephrology research by deep sequencing: ChIP-seq and RNA-seq. AB - The recent and rapid advent of next-generation sequencing (NGS) has made this technology broadly available not only to researchers in various molecular and cellular biology fields but also to those in kidney disease. In this paper, we describe the usage of ChIP-seq (chromatin immunoprecipitation with sequencing) and RNA-seq for sample preparation and interpretation of raw data in the investigation of biological phenomenon in renal diseases. ChIP-seq identifies genome-wide transcriptional DNA-binding sites as well as histone modifications, which are known to regulate gene expression, in the intragenic as well as in the intergenic regions. With regard to RNA-seq, this process analyzes not only the expression level of mRNA but also splicing variants, non-coding RNA, and microRNA on a genome-wide scale. The combination of ChIP-seq and RNA-seq allows the clarification of novel transcriptional mechanisms, which have important roles in various kinds of diseases, including chronic kidney disease. The rapid development of these techniques requires an update on the latest information and methods of NGS. In this review, we highlight the merits and characteristics of ChIP-seq and RNA-seq and discuss the use of the genome-wide analysis in kidney disease. PMID- 23986148 TI - Hypomagnesemia is a significant predictor of cardiovascular and non cardiovascular mortality in patients undergoing hemodialysis. AB - Although previous studies in the general population showed that hypomagnesemia is a risk for cardiovascular diseases (CVD), the impact of magnesium on the prognosis of patients on hemodialysis has been poorly investigated. To gain information on this we conducted a nationwide registry-based cohort study of 142,555 hemodialysis patients to determine whether hypomagnesemia is an independent risk for increased mortality in this population. Study outcomes were 1-year all-cause and cause-specific mortality with baseline serum magnesium levels categorized into sextiles. During follow-up, a total of 11,454 deaths occurred, of which 4774 had a CVD cause. In a fully adjusted model, there was a J shaped association between serum magnesium and the odds ratio of all-cause mortality from the lowest to highest sextile, with significantly higher mortality in sextiles 1-3 and 6. Similar associations were found between magnesium and both CVD and non-CVD mortality. The proportion of patients with a baseline intact parathyroid hormone level under 50 pg/ml was significantly higher in the highest sextile; however, after excluding these patients, the CVD mortality risk in the highest sextile was attenuated. Thus, hypomagnesemia was significantly associated with an increased risk of mortality in hemodialysis patients. Interventional studies are needed to clarify whether magnesium supplementation is beneficial for improving patient prognosis. PMID- 23986149 TI - Suicide note on the palm: three case reports and discussion of medico-legal aspects. AB - Suicide notes are usually written by the victim on paper or readily accessible things such as notebooks, walls or mirrors. Though writing may be found on the body of the deceased, suicide notes in a structured manner written on the palm have not been reported in forensic literature. In all the three cases presented here, we found a handwritten note on the palm of the deceased at the time of autopsy. The victims had written a brief note in their own handwriting, citing the reasons for ending their lives. The suicide note in one case also mentioned details regarding the custody of the victim's children to be given to her mother. Since we have not found similar cases in the literature, we present and discuss our three cases herein. PMID- 23986150 TI - Survival of a victim of Isadora Duncan syndrome: a case report. AB - Incidents of accidental strangulation by uncovered (open-spoked) wheels of vehicles are not uncommon but survival following such incidents is quite a rare phenomenon. The possibility of death from strangulation by a scarf getting caught in the wheel spokes of a vehicle was brought to the public's attention when the world famous dancer Isadora Duncan died on 14 September 1929. Cycle-powered rickshaws, bicycles and bullock-carts remain common forms of transport in India. However, the uncovered spokes of the vehicle wheel can trap the dupatta/chunni/odhani (long scarf worn around neck) worn by Indian women. A number of cases of fatal accidental strangulation have been described by different authors involving vehicles like cycle-powered rickshaws, bicycles and bullock-carts, with very few cases of reported survivors. Here we report a case of accidental strangulation involving a young girl with the dupatta getting caught in moving wheel of a bullock-cart, in which the victim survived in spite of severe injury to neck structures. PMID- 23986151 TI - A nanostructured cathode architecture for low charge overpotential in lithium oxygen batteries. AB - The lithium-oxygen battery, of much interest because of its very high-energy density, presents many challenges, one of which is a high-charge overpotential that results in large inefficiencies. Here we report a cathode architecture based on nanoscale components that results in a dramatic reduction in charge overpotential to ~0.2 V. The cathode utilizes atomic layer deposition of palladium nanoparticles on a carbon surface with an alumina coating for passivation of carbon defect sites. The low charge potential is enabled by the combination of palladium nanoparticles attached to the carbon cathode surface, a nanocrystalline form of lithium peroxide with grain boundaries, and the alumina coating preventing electrolyte decomposition on carbon. High-resolution transmission electron microscopy provides evidence for the nanocrystalline form of lithium peroxide. The new cathode material architecture provides the basis for future development of lithium-oxygen cathode materials that can be used to improve the efficiency and to extend cycle life. PMID- 23986152 TI - A hemorrhagic-crusted papule with a central crater on the heel. Tungiasis. PMID- 23986154 TI - Fast and robust infiltration of functional material inside titania nanotube layers: case study of a chalcogenide glass sensitizer. AB - Fast and robust infiltration of anodic TiO2 nanotube layers with a model chalcogenide As3S7 glass via spin-coating is reported for the first time. Effective sensitization leads to a significant visible light photocurrent response. This easy and cheap infiltration method can be extended for deposition of other absorbers into nanotubular layers. PMID- 23986153 TI - Illustrating the relevance of updated diagnostic criteria for sporadic Creutzfeldt-Jakob disease: a teaching neurocase. AB - A 75-year-old woman with unremarkable medical history, consulted for a 5-month history of involuntary shaking of left upper limb. Clinical examination revealed polyminimyoclonus of the upper limbs with cogwheel-like rigidity, hyperreflexia, bradykinesia, inconstant spastic-like rigidity in the lower limbs and a stiff and cautious gait. These symptoms, together with the memory impairment found on neuropsychological assessment yielded suspicion for a subacute encephalopathy probably due to a non-conventional infectious agent. There was no 14-3-3 protein found in the cerebrospinal fluid and no periodic sharp wave complexes on EEG. These findings made the diagnosis of Creutzfeldt-Jakob disease (CJD) rather unlikely according to the current WHO diagnostic criteria. However, typical isolated cortical hyperintensity of right temporal, parietal and occipital lobes on MRI suggested a probable CJD and prompted cerebral biopsy which confirmed the diagnosis. This article emphasises the need to update the current WHO criteria by including radiological findings. PMID- 23986155 TI - The continued evolution of drugs for psoriasis. PMID- 23986156 TI - Response to article: postoperative wound care after dermatologic procedures: a comparison of 2 commonly used petrolatum-based ointments. PMID- 23986157 TI - A double-blind, randomized clinical trial of 20% alpha/poly hydroxy acid cream to reduce scaling of lesions associated with moderate, chronic plaque psoriasis. AB - BACKGROUND: Salicylic acid is a topical keratolytic agent used to reduce scaling and hyperkeratosis associated with psoriasis vulgaris. However, its use is limited due to potential systemic toxicity. Hydroxyacids also modulate keratinization and desquamation. Therefore, they may serve a beneficial role in the treatment of hyperkeratotic conditions. To date, there are no clinical studies in the literature regarding the efficacy of hydroxyacids for psoriasis treatment. PURPOSE: To evaluate the therapeutic efficacy of topical 20% alpha hydroxy/polyhydroxy acid versus standard salicylic acid to reduce scaling in patients with moderate, chronic psoriasis. METHODS: Twenty-five subjects with moderate, chronic psoriasis were enrolled in a 2-week, double-blind, left-right, randomized, bilateral comparison clinical trial to compare the efficacy of 20% alpha-hydroxy/polyhydroxy acid emollient versus 6% salicylic acid cream and 24 were randomized/completed. Clinical evaluations to assess the severity of psoriasis and scaling were performed using a 6-point scale prior to treatment, as well as following 1 and 2 weeks of therapy. RESULTS: Twenty-four participants completed the study. Both 20% alpha-hydroxy/polyhydroxy acid emollient and 6% salicylic acid cream were efficacious in reducing scale of psoriatic lesions. The topical 20% alpha-hydroxy/polyhydroxyacid reduced scaling at a faster rate; however, following 2 weeks of treatment the efficacy of both products were relatively the same. CONCLUSION: 20% alpha-hydroxy/polyhydroxyacid is as efficacious as salicylic acid in regards to the de-scaling of psoriatic plaques. Additionally, 20% alpha-hydroxy/polyhydroxyacid cream may yield quicker results and less toxicity than salicylic acid. PMID- 23986158 TI - Comparison of the efficacy of biologics versus conventional systemic therapies in the treatment of psoriasis at a comprehensive psoriasis care center. AB - BACKGROUND: The efficacy of biologic treatment for psoriasis has not been compared to that of conventional systemic therapies and phototherapy outside of clinical trial settings. DESIGN: Retrospective, cross-sectional. METHODS: All patient visits with a code for psoriasis (ICD-9 696.1) in the clinical practice of two dermatologists with a high percentage (over 70% of chief complaints) of psoriasis patients from Jan 1, 2008 to Jan 4, 2012 inclusive were included in this retrospective data analysis. Patients were excluded if the baseline Physician's Global Assessment (PGA) at start of treatment was unknown, or less than 3 (moderate). The practice is a comprehensive psoriasis care center in the Northeastern United States serving a metropolitan population of over 4 million people. Patients were divided by treatment type (biologic, conventional systemic or both) and history of previous treatments. Patients were evaluated by Body Surface Area (BSA), PGA, Simple-Measure for Assessing Psoriasis Activity (S-MAPA, calculated by BSA multiplied by PGA). Patients were evaluated at baseline, 8, 12, 16, and 24 weeks after start of treatment. Patients must have completed at least 8 weeks on a single treatment in order to be included. RESULTS: 46 courses of biologics, 12 courses of conventional systemic therapies, and 18 courses of both together were identified with PGA 3 or greater at baseline. Baseline S-MAPA for biologics was 74, for non-biologic systemics was 62.25. At week 24, S-MAPA improved 70.2% over baseline in patients treated with biologics, patients treated with non-biologic systemics improved by only 40.4% (P<0.05). The average number of prior treatments for patients on biologics was 1.87 versus 1.25 for patients on conventional systemic therapies (P=0.169). CONCLUSION: Biologics show superior results to conventional systemic therapies (70% improvement versus 40% improvement) for the treatment of patients with moderate to severe psoriasis, as measured by decrease in S-MAPA (PGA multiplied by BSA) at week 24. These results were observed despite the fact that patients on biologics had a greater baseline severity and had a greater number of previous treatments. PMID- 23986159 TI - Comparative evaluation of topical calcipotriol versus coal tar and salicylic acid ointment in chronic plaque psoriasis. AB - BACKGROUND: Calcipotriol is a newer topical treatment option available for plaque psoriasis and coal tar being one of the oldest treatment and still in use. AIMS: To evaluate and compare the differences in terms of efficacy, safety and relapse with Calcipotriol 0.005% (50 mcg/gm) and 6% coal tar and 3% salicylic ointment in patients with Plaque psoriasis. SETTING and DESIGNS: Study conducted on 60 patients of plaque psoriasis, who attended the skin OPD in our hospital. METHODS: The patients with mild to moderate plaque psoriasis were selected. 60 patients were enrolled for the study after obtaining informed consent. Subjects were asked to apply Calcipotriol 0.005% (50 mcg/gm) (Heximar Win care) twice a day on the right side plaques and on left side plaques, Petroleum jelly (Vaseline) in the morning and 6% coal tar and 3% salicylic ointment (Protar(r) Percos) at nighttime. PASI score was used to assess the reponse to therapy at 2nd, 4th, 6th and 8th week. After treatment subjects were observed for 6 weeks for any relapse. STATISTICAL ANALYSIS: It was done by paired t-test and independent sample t-test. CONCLUSIONS: The results showed that statistically significant difference was seen in the mean percentage reduction of PASI score between both the groups, at all the assessment visits, 2, 4, 6, and 8 weeks, the mean percentage reduction at 2 weeks for calcipotriol being 21+/-12.06 and for coal tar being 13.44+/-11.19 (P=0.000), at 4 weeks for calcipotriol was 40+/-16.71 and for coal tar 25+/-99 (P=0.000), at 6 weeks for calcipotriol was 53.99+-22.43 and for coal tar 41+/ 21.23 (P=0.002), at 8 weeks for calcipotriol was 62.73+/-24.04 and for coal tar was 51.53+/-23.27 (P=0.11). Relapse was seen in 5/60 (8.3%) of patients on calcipotriol treated side and 9/60 (15%) of patients with coal tar treated side. Thus it can be concluded that calcipotriol cream is more efficacious when compared with coal tar and does have a quick response. It is well tolerated and acceptable cosmetically. PMID- 23986160 TI - Effect of infliximab on health-related quality of life and disease activity by body region in patients with moderate-to-severe psoriasis and inadequate response to etanercept: results from the PSUNRISE trial. AB - BACKGROUND: Treatment with tumor necrosis factor (TNF)-alpha antagonists is effective in patients with moderate-to-severe plaque psoriasis, including those with impaired health-related quality of life (HRQoL). METHODS: PSUNRISE is a multicenter, open-label, prospective study evaluating the efficacy and safety of switching from etanercept to infliximab in psoriasis patients with an inadequate response to etanercept. Patients received intravenous infusions of infliximab 5 mg/ kg at weeks 0, 2, 6, 14, and 22. HRQoL was assessed using the Dermatology Life Quality Index (DLQI), the 36-item Short-Form Health Survey (SF-36), and the EuroQoL (EQ-5D) index and EQ-5D visual analog scale (VAS; 0-100 cm) among patients receiving at least one infliximab infusion. Subgroup analyses (t- test) were performed to compare mean DLQI improvement between patients who achieved and did not achieve clinical response (Physician's Global Assessment [PGA] 0/1 and at least a 75% improvement in the Psoriasis Area and Severity Index [PASI 75]) at weeks 10 and 26. RESULTS: A total of 215 patients received at least one infliximab infusion. A DLQI score of 0 or 1 (no negative effect on HRQoL) was achieved by 3.7%, 44.2%, and 41.4% of patients at weeks 0, 10 and 26, respectively. Mean changes in SF-36 Physical Component Summary scores were 1.8 (week 10) and 2.4 (week 26); corresponding changes in Mental Component Summary scores were 4.5 and 5.0. The mean change in EQ-5D index score was 0.08 at week 10 and 0.09 at week 26; respective mean changes in EQ-5D VAS score were 7.73 and 9.49. Mean improvements in DLQI were significantly higher for patients achieving versus those not achieving PGA 0/1 (P=0.0193 [week 10] and P=0.0010 [week 26]) and PASI 75 response (P<0.0001 [week 10]; P=0.0012 [week 26]). CONCLUSION: Psoriasis patients with prior inadequate response to etanercept demonstrated sustained improvements in HRQoL after switching to infliximab, and HRQoL improvements were associated with clinical responses. PMID- 23986161 TI - Effect of calcipotriene plus betamethasone dipropionate topical suspension on the hypothalamic-pituitary-adrenal axis and calcium homeostasis in subjects with extensive psoriasis vulgaris: an open, non-controlled, 8-week trial. AB - BACKGROUND: The two-compound topical suspension/gel containing calcipotriene plus betamethasone dipropionate is effective and safe in the treatment of psoriasis on the body and scalp within the general psoriasis patient population. OBJECTIVE: To evaluate the systemic effects of once-daily use of two-compound topical suspension/gel on the hypothalamic-pituitary-adrenal (HPA) axis and calcium homeostasis in subjects with extensive psoriasis vulgaris. METHODS: An open label, single-group, 8-week trial in 43 subjects with extensive psoriasis covering 15-30% of the body surface area. Blood and 24-hour urine samples were collected and a standard-dose adrenocorticotropic hormone (ACTH) stimulation test was performed at baseline, weeks 4 and 8. Primary endpoints were serum cortisol 30 minutes after ACTH injection (HPA axis response abnormal at serum cortisol <=18 MUg/dL) and changes from baseline in albumin-corrected serum calcium (sCa), 24-hour urinary calcium excretion (24hCa) and urine calcium:creatinine ratio (Ca:Crea). RESULTS: Two (4.7%) subjects showed signs of adrenal suppression based on the ACTH stimulation test results at week 4; both were withdrawn from treatment and had normal serum cortisol 30-minute values at follow-up 4 weeks later. None of the subjects who continued treatment to week 8 showed signs of adrenal suppression. There were no clinically relevant mean changes from baseline to weeks 4 and 8 in sCa, 24hCa or Ca:Crea and no subject had sCa above the reference range. CONCLUSION: The two-compound topical suspension/gel containing calcipotriene plus betamethasone dipropionate may be applied once daily to extensive psoriasis vulgaris without generally causing adrenal suppression or disturbance of calcium homeostasis, consistent with previous findings. In a small number of patients with extensive psoriasis treated with large volumes of topical suspension, adrenal suppression may be observed. In the real-world setting, it is anticipated that systemic side-effects would occur in only a few cases within the general psoriasis patient population. ClinicalTrials.gov Identifier: PMID- 23986162 TI - Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. AB - BACKGROUND: Apremilast, a small molecule specific inhibitor of phosphodiesterase 4, works intracellularly to modulate pro-inflammatory and anti-inflammatory mediators. This phase II, multicenter, open-label study evaluated the efficacy, tolerability, and pharmacodynamics of apremilast in patients with recalcitrant plaque psoriasis.
METHODS: This multicenter, open-label study comprised four phases: pre-treatment (<=35 days), treatment (12 weeks), extension (12 weeks), and observational follow-up (4 weeks). Patients with recalcitrant plaque psoriasis received apremilast 20 mg BID for 12 weeks. Responders (>=75% improvement in Psoriasis Area and Severity Index [PASI-75]) continued treatment and non-responders (< PASI-75) were titrated to apremilast 30 mg BID through week 24. Efficacy assessments included change in static Physician's Global Assessment, PASI, and body surface area, and proportion of patients achieving PASI-50, PASI 75, and PASI-90. Other assessments included adverse events, lesional skin biopsies to assess changes in epidermal thickness, and immunohistochemistry to assess changes in peripheral blood subsets. RESULTS: A total of 30 patients were enrolled. At week 12, 67% of patients had a >=1-point improvement in static Physician's Global Assessment, meeting treatment effect criterion. Mean percent decreases (improvements) from baseline were -59% for PASI score and -53% for body surface area. Most adverse events were mild. Median reduction in epidermal thickness was 34% at week 12 (P=0.083); five patients showed absence of keratin 16. Significant reductions in CD11c, CD3, and CD56 indicate that apremilast reduced myeloid dendritic cell, T-cell, and NK-cell or NK-T-cell infiltration into the epidermis and dermis. Reduced inflammatory leukocytes, with a pattern of broad, partial inhibition, suggested reduced IL-23/Th17 and Th22 response pathways. CONCLUSIONS: These results confirm apremilast's biological and clinical activity and support ongoing studies in psoriasis. Clinicaltrials.gov Identifier: NCT00521339. PMID- 23986163 TI - Association between the type and length of tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis. AB - OBJECTIVE: We sought to assess whether the type of TNF inhibitor therapy (soluble receptor versus monoclonal antibody) has an effect on MI risk; and determine whether length of TNF inhibitor therapy has an effect on MI risk. DESIGN: Retrospective cohort study. SETTING: Between January 1, 2004 and November 30, 2010. PARTICIPANTS: At least 3 ICD9 codes for psoriasis (696.1) or psoriatic arthritis (696.0) (without antecedent MI). INTERVENTION: None. MAIN OUTCOME MEASURE: Incident MI. RESULTS: In the 3 subgroups of TNF inhibitors, 976 received etanercept; 217 received monoclonal antibody; and 480 received etanercept or monoclonal antibody, in addition, 5075 received topical therapy and 2097 received oral therapy. In the Cox proportional hazards analysis, etanercept (HR, 0.53; 95% CI, 0.31-0.92) was associated with a significant reduction of MI risk, compared to topical agents and, monoclonal antibody only (HR, 0.25; 95% CI, 0.06-1.03), and etanercept or monoclonal antibody (HR, 0.53; 95% CI, 0.27-1.06) were associated with a non-significant reduction of MI risk compared to topical agents. Using year 1 as reference, those who received TNF inhibitor therapy at year 2 (HR, 1.15; 95% CI, 0.30-4.44), at year 3 (HR, 1.89; 95% CI, 0.64-5.58), and at year 4 and above (HR, 1.16; 95% CI, 0.46-2.94) had a non-significant increase of MI risk. CONCLUSIONS: Treatment with etanercept, compared to treatment with topical agents, was associated with a significant decreased risk of MI in psoriasis patients. Treatment with monoclonal antibody and etanercept or monoclonal antibody, compared to treatment with topical agents, was associated with a non-significant decreased risk of MI risk in psoriasis patients. There were no statistically significant changes in risk of MI associated with length of TNF inhibitor treatment. PMID- 23986164 TI - Patterns of vitamin D analog use for the treatment of psoriasis. AB - BACKGROUND: Psoriasis is a chronic disease that significantly impacts patients' quality of life. It most commonly manifests as localized disease, for which there are various treatment options. OBJECTIVE: To determine the prescription patterns of topical corticosteroids and vitamin D analogs for the treatment of psoriasis in the United States and how their use has changed over time. METHODS: Data from the National Ambulatory Medical Care Survey (NAMCS) from 1994 to 2010 were queried for visits linked with a psoriasis diagnosis. Prescriptions for topical corticosteroids and vitamin D analogs were described. Vitamin D analogs usage was compared across physician specialties. For each sampled visit reported in the NAMCS, visits meeting our inclusion criteria that also mentioned the following medications were identified: topical calcipotriene, topical calcipotriene/betamethasone or any topical corticosteroid indicated for the treatment of psoriasis. RESULTS: There were an estimated 2.05 million psoriasis visits per year over the 1994-2010 interval. Dermatologists were responsible for 67% of these encounters followed by family practice (14%) and internal medicine (11%). Dermatologists prescribed a vitamin D product at 15% of psoriasis visits, followed by family physicians at 12%, and internists at 5%. Dermatologists prescribed calcipotriene, calcipotriene/betamethasone, and topical corticosteroids in 15%, 4% and 59% of psoriasis visits, respectively. Over time, there was no significant change in the use of topical steroids or vitamin D products by physicians.This study is limited by the inability to determine the severity of psoriasis from the data collected, and the lack of data on the length of treatment with different medications. CONCLUSIONS: Despite their demonstrated efficacy and safer side effect profile, vitamin D analogs are used less often than topical corticosteroids for the treatment of psoriasis. These findings suggest that vitamin D products may not be utilized to their fullest potential as effective topical therapy or adjuncts to therapy for localized plaque psoriasis. PMID- 23986165 TI - Efficacy and safety of naftifine HCl Gel 2% in the treatment of interdigital and moccasin type tinea pedis: pooled results from two multicenter, randomized, double-blind, vehicle-controlled trials. AB - BACKGROUND: Tinea pedis is the most common chronic fungal infection. Naftifine hydrochloride is a topical antifungal of the allylamine class, displaying fungicidal activity and clinically significant anti-bacterial and anti inflammatory effects. OBJECTIVE: To evaluate the efficacy and safety of two-weeks once daily application of naftifine gel 2% in the treatment of tinea pedis. METHODS: At baseline, 1715 subjects were randomly assigned 2:1 to naftifine gel 2% (n=1144) and vehicle (n=571). Efficacy consisting of mycologic determination (KOH and dermatophyte cultures) and scoring of clinical symptom severity was evaluated at baseline and weeks 2, 4, and 6. Efficacy was analyzed in 1174 subjects (n=782, naftifine; n=392, vehicle) with a positive baseline dermatophyte culture and KOH for whom week 6 assessments were available. Safety was evaluated by adverse events (AE) and laboratory values in 1714 subjects (n=1143, naftifine; n=571, vehicle). RESULTS: Subjects treated with naftifine gel 2% for interdigital type tinea pedis demonstrated greater improvement from baseline for complete cure (P=0.001), mycological cure (P<0.0001), and treatment effectiveness (P<0.0001) as early as 2 weeks when compared to vehicle; however the highest response rates were seen 4-weeks post treatment (P<0.0001, for all endpoints). Statistically significant results for complete cure, mycological cure, and treatment effectiveness (P<0.0001, for all endpoints) were also seen at week 6 among subjects with moccasin-type tinea pedis. Treatment related adverse events were minimal. CONCLUSIONS: Treatment with naftifine gel 2% applied once daily for two weeks is well-tolerated and is effective in treating both interdigital-type and moccasin-type tinea pedis. Continuous improvement is observed from the end of treatment to four-weeks after treatment cessation among key outcome measures (complete cure, mycological cure, and treatment effectiveness) as well as clinical signs and symptoms (erythema, scaling, and pruritus) PMID- 23986167 TI - Current methods for photodynamic therapy in the US: comparison of MAL/PDT and ALA/PDT. AB - There is some debate regarding the rate of progression of actinic keratosis (AK) into squamous cell carcinoma (SCC).1-4 However, it is clear that treatment for AK lesions is warranted. Results from numerous studies with aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) photodynamic therapy (PDT) for the treatment of AKs, SCC, and Bowen's disease show high rates of clearance for these lesions. MAL/PDT provides similar efficacy to ALA/PDT with the benefits of shorter incubation times according to the approved FDA labeling, greater selectivity, reduced pain during and immediately following therapy, and fewer systemic side effects. Cosmetic outcomes are better with PDT than with cryosurgery or excisional surgery. A number of case reports show efficacy with ALA/PDT and MAL/PDT for acne, photorejuvenation, and other off-label indications. Side effects with PDT tend to be mild to moderate and transient in nature. Overall, ALA/PDT and MAL/PDT are effective for a variety of skin diseases and conditions. MAL/PDT provides some advantages over ALA/PDT. PMID- 23986166 TI - Management of rosacea-prone skin: evaluation of a skincare product containing Ambophenol, Neurosensine, and La Roche-Posay Thermal spring water as monotherapy or adjunctive therapy. AB - OBJECTIVE: The objective of these studies was to investigate whether a skincare product containing Ambophenol, Neurosensine, and La Roche-Posay thermal spring water formulated in a highly protective packaging can have an impact in the management of rosacea-prone skin subjects. METHODS: Several studies were performed to evaluate the efficacy of this product in the management of rosacea prone skin, as either monotherapy or adjunctive therapy or to maintain the efficacy of a Metronidazole treatment. The first study was performed on 37 women aged 18-45 with added stage 2 erythro-couperosis, who applied test formula as monotherapy twice a day for 4 weeks. During a second study, a dermatological evaluation was performed on patients with stage I or II rosacea, a questionnaire containing information about patient characteristics, tolerance, clinical signs, symptoms and skin reactivity to "trigger factors" was completed by dermatologists at baseline and 2 months after treatment with the test formula as either monotherapy or adjunctive therapy. Finally, in a third study, 65 patients finishing a Metronidazole treatment applied once daily and the tested formula twice daily were divided into 2 groups using the test formula or vehicle control, twice a day for 8 weeks for the evaluation of efficacy as adjunctive therapy. RESULTS: We noted that the test formula, as an adjunctive therapy, helped prolong the efficacy of a Metronidazole treatment. In monotherapy, there was a significant efficacy of the test formula associated with an excellent tolerance. A significant improvement of all the clinical signs and symptoms of rosacea and a reduction of the skin reactivity to "trigger factors" were shown. CONCLUSIONS: These studies highlight the interest value and impact of a skincare product containing Ambophenol, Neurosensine, and La Roche-Posay thermal spring water formulated in a highly protective packaging in monotherapy or in combination with or after a therapeutic treatment in the management of patients suffering from rosacea. PMID- 23986168 TI - A two-center, open-label, randomized, split-face study to assess the efficacy and safety of one versus three intradermal injection sites of abobotulinumtoxinA in the treatment of lateral periocular rhytides. AB - BACKGROUND: Lateral canthal rhytides partly result from repetitive muscular actions of the orbicularis oculi. OBJECTIVE: To determine the efficacy of one versus three injection sites of AbobotulinumtoxinA (ABO) in the treatment of lateral canthal rhytides. METHODS: This was a two-center, evaluator-masked, 120 day study in which 40 patients with moderate to severe hyperdynamic lateral canthal rhytides at maximal contracture were randomized to receive one injection of 36 Units of ABO into the middle of the lateral orbital rhytides on one side, with the contralateral side treated with the same total dose of ABO, divided into three intradermal injections of 12 Units each, along the lateral canthal area. A blinded evaluator assessed lateral orbital rhytides at rest and maximal contraction at baseline, 7, 42, 90, and 120 days post treatment. Standardized digital photography and subject self- assessment were performed at each visit. RESULTS: No statistically significant difference was seen at any visit between sides treated with one injection and those treated with three injections in any evaluation category. There was no difference in adverse events between the two sides. CONCLUSION: Sites treated with three injections of ABO showed no statistically significant difference from those treated with one injection. PMID- 23986169 TI - Infliximab-induced psoriasis in treatment of Crohn's disease-associated ankylosing spondylitis: case report and review of 142 cases. AB - TNF-alpha inhibitors are used to treat numerous inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Recent reports have illustrated the paradoxical development of psoriasis with TNF-alpha inhibitor therapy. We present here a review of 142 cases of new-onset psoriasis with infliximab, adalimumab, and etanercept therapy. This review illustrates the diverse conditions responsible for TNF-alpha-inhibitor induced psoriasis, the variable time prior to psoriasis development, and the most predominant forms of psoriasis. An analysis of the various therapeutic regimens applied may help provide guidelines for patient management. PMID- 23986170 TI - Dronaderone-induced phototoxicity. AB - Phototoxicity is a skin reaction that occurs in patients using photosensitizing drugs in combination with exposure to ultraviolet light. Common photosensitizing pharmacologic agents include antibiotics, non-steroidal anti-inflammatory drugs, diuretics, neuroleptics, retinoids, and amiodarone. Dronaderone is a novel antiarrhythmic that is similar in composition to amiodarone, but is non-iodinated and also has a methane-sulfonyl group, significantly decreasing its incidence of adverse effects as compared to amiodarone. While phototoxicity is a commonly reported complication of amiodarone, this reaction has rarely been documented in patients using dronaderone. We report the case of a 63 year-old woman with a history of atrial fibrillation that presented with a phototoxic drug eruption following use of dronaderone for maintenance of normal sinus rhythm. PMID- 23986171 TI - News, views, and reviews. Carrots before sticks: appealing to vanity promotes sun protection. AB - Daily broad-spectrum sunscreen use is an important intervention to prevent squamous cell carcinoma and invasive melanoma. Now dermatologists can feel confident confirming that it prevents photoaging in middle aged adults as well. A new randomized trial from Australia confirms that consistent use of broad spectrum sunscreen can slow photoaging in adults in as little as four years in middle-aged adults. Because young adults respond better to anti-aging messages than anti-cancer messages regarding sun exposure, this data may help motivate younger patients to avoid indoor tanning and pursue consistent sun protection. Visual examples of aging over time are particularly effective for teens and young adults. PMID- 23986172 TI - Effect of systemic isotretinoin therapy on mucociliary clearance and nasal surface mucosa in acne patients. AB - BACKGROUND: Currently, there are no studies investigating the topical or systemic effects of retinoids on human nasal mucosa. We aimed to investigate the effect of systemic isotretinoin therapy on mucociliary transport and nasal surface mucosa using the saccharine test (ST) and nasal cytology techniques. METHODS: A total of 30 patients with severe or moderate acne were enrolled in this study. The median prescribed dose of isotretinoin was 0.75 mg per kg per day. Clinical and biochemical examinations were carried out periodically. The ST and nasal cytology were performed before treatment and during the third month of therapy. RESULTS: Of the 30 patients who initially agreed to participate in the research, 21 completed the study (18 female and 3 male, mean +/- standard deviation (SD) aged 20.9 +/- 4.7 years, range 15-32 years). There was a significant difference between the mucociliary clearance time for subjects in the pre- and post treatment periods (173.8 +/- 89.2 seconds vs 245.2 +/- 191.6 seconds, respectively; P=.009). Cytological examination revealed that the squamous cell ratio was significantly lower and the reactive changes of the respiratory epithelium were significantly higher 3 months after isotretinoin therapy than before therapy (P=.010, P=.002, respectively). There were mild signs of inflammation according to the number of neutrophilic leukocytes (8.3% vs 26.6%, P=.06) after 3 months of isotretinoin therapy. CONCLUSION: Systemic isotretinoin alters the mucociliary transport, decreases the squamous cell ratio, increases the reactive changes in the respiratory epithelium significantly, and increases neutrophils in the nasal surface mucosa in the third month of treatment PMID- 23986173 TI - The biological rationale for use of vitamin d analogs in combination with corticosteroids for the topical treatment of plaque psoriasis. AB - Topical corticosteroids and vitamin D analogs are well established as safe and effective first-line treatments for mild to moderate plaque psoriasis. They act via distinct and complementary mechanisms of action: vitamin D analogs primarily counter epidermal dysregulation, inhibiting epidermal hyperproliferation and inducing keratinocyte differentiation, whereas corticosteroids act primarily as immunosuppressors, targeting pro-inflammatory cytokines and chemokines. Furthermore, both agents have additional activity that may complement their main effects: vitamin D analogs have some immunomodulatory properties and corticosteroids may impact on keratinocyte differentiation. Based on their dominant mechanisms of action, there is a strong scientific rationale for the combination of corticosteroids and vitamin D analogs in the treatment of plaque psoriasis. Indeed, the combination has been shown to have a greater effect on the immune-mediated mechanisms of psoriasis than either monotherapy used alone. There is also a strong biological rationale for decreased side effects with the combination. Vitamin D may restore epidermal barrier function, which is impaired with corticosteroid use, and counteract steroid-induced skin atrophy. Corticosteroids may reduce perilesional skin irritation induced by vitamin D analogs. Although clinical data strongly support improved efficacy and tolerability with a combination of calcipotriol and betamethasone dipropionate, additional studies are needed to further investigate their underlying mechanisms. PMID- 23986174 TI - Do we really need topical antibiotics in our new treatment paradigm of acne vulgaris? A novel question to consider based on an updated model of pathogenesis. PMID- 23986176 TI - The sequence of inflammation, relevant biomarkers, and the pathogenesis of acne vulgaris: what does recent research show and what does it mean to the clinician? AB - Acne vulgaris (AV) remains one of the most common skin disorders seen in dermatology practices worldwide. Despite an abundance of publications, AV continues to be a formidable therapeutic challenge due to its complex pathogenesis and chronicity. Regarding the sequence of AV lesion formation, the traditional model teaches that the primary lesion is the microcomedone, a subclinical lesion caused by follicular hyperkeratinization. From the microcomedone, visible AV emerges with development of comedonal ("noninflammatory") and inflammatory lesions. Research published over the past decade has provided information about inflammatory mechanisms that warrant us reconsidering the traditional model of AV pathogenesis. More specifically, there is evidence that specific cascades of inflammation occur early during the initial subclinical formation and visible emergence of AV lesions, later during progression, and finally during resolution including scarring. It has also been shown that subclinical inflammation occurs before or concurrently with microcomedone formation. This article reviews an updated model of acne lesion development and its progression based on a literature review that highlights the role of inflammatory mediators, cellular infiltration patterns, and expression of receptors that signal specific immunologic and inflammatory responses. Clinical relevance related to this updated model is also addressed. PMID- 23986177 TI - What makes physicians go to work while sick: a comparative study of sickness presenteeism in four European countries (HOUPE). AB - QUESTIONS UNDER STUDY: Sickness presenteeism is common in the health sector, especially among physicians, leading to high costs in terms of medical errors and loss in productivity. This study investigates predictors of sickness presenteeism in university hospitals, which might be especially exposed to competitive presenteeism. The study included comparisons of university hospitals in four European countries. METHODS: A cross-sectional survey analysis of factors related to sickness behaviour and work patterns in the field of academic medicine was performed among permanently employed physicians from the HOUPE (Health and Organisation among University Physicians Europe) study: (Sweden n = 1,031, Norway n= 354, Iceland n = 242, Italy n = 369). The outcome measure was sickness presenteeism. RESULTS: Sickness presence was more common among Italian physicians (86%) compared with physicians in other countries (70%-76%). Country-stratified analyses showed that sickness presenteeism was associated with sickness behaviour and role conflicts in all countries. Competition in the form of publishing articles was a predictor in Italy and Sweden. Organisational care for physician well-being reduced sickness presenteeism in all countries. CONCLUSION: Sickness presenteeism in university hospitals is part of a larger behavioural pattern where physicians seem to neglect or hide their own illness. Factors associated with competitive climate and myths about a healthy doctor might contribute to these behaviours. Importantly, it is suggested that managers and organisations should work actively to address these questions since organisational care might reduce the extent of these behaviours. PMID- 23986178 TI - A rhodamine-based fluorescent probe for detecting Hg(2+) in a fully aqueous environment. AB - A water-soluble fluorescent probe for Hg(2+) based on a rhodamine B derivative was designed and synthesized. The new probe showed reversible colorimetric and fluorescent response to Hg(2+) in a fully aqueous solution. The probe exhibited real-time detection of Hg(2+) with high selectivity in media containing less than 1% organic cosolvent. Furthermore, bioimaging studies indicated that the new probe was cell permeable and suitable for the real-time imaging of Hg(2+) in living cells by confocal microscopy. PMID- 23986179 TI - First principles study of the permeability of graphene to hydrogen atoms. AB - Using calculations from first principles and harmonic transition state theory, we investigated the permeability of a single graphene sheet to protons and hydrogen atoms. Our results show that while protons can readily pass through a graphene sheet with a low tunneling barrier, for hydrogen atoms the barriers are substantially higher. At the same time, the presence of defects in the membrane can significantly reduce the penetration barrier in a region that extends beyond the defect site itself. PMID- 23986180 TI - Surface molecular-imprinting engineering of novel cellulose nanofibril/conjugated polymer film sensors towards highly selective recognition and responsiveness of nitroaromatic vapors. AB - We designed and synthesized two conjugated polymer-grafted cellulose nanofibril film sensors via surface molecular-imprinting. These two surface TNT- or DNT imprinted film sensors exhibit highly selective recognition and fast response towards target explosive vapor. PMID- 23986181 TI - Hydration water and peptide dynamics--two sides of a coin. A neutron scattering and adiabatic calorimetry study at low hydration and cryogenic temperatures. AB - In the present work we bridge neutron scattering and calorimetry in the study of a low-hydration sample of a 15-residue hybrid peptide from cecropin and mellitin CA(1-7)M(2-9) of proven antimicrobial activity. Quasielastic and low-frequency inelastic neutron spectra were measured at defined hydration levels - a nominally 'dry' sample (specific residual hydration h = 0.060 g/g), a H2O-hydrated (h = 0.49) and a D2O-hydrated one (h = 0.51). Averaged mean square proton mobilities were derived over a large temperature range (50-300 K) and the vibrational density of states (VDOS) were evaluated for the hydrated samples. The heat capacity of the H2O-hydrated CA(1-7)M(2-9) peptide was measured by adiabatic calorimetry in the temperature range 5-300 K, for different hydration levels. The glass transition and water crystallization temperatures were derived in each case. The existence of different types of water was inferred and their amounts calculated. The heat capacities as obtained from direct calorimetric measurements were compared to the values derived from the neutron spectroscopy by way of integrating appropriately normalized VDOS functions. While there is remarkable agreement with respect to both temperature dependence and glass transition temperatures, the results also show that the VDOS derived part represents only a fraction of the total heat capacity obtained from calorimetry. Finally our results indicate that both hydration water and the peptide are involved in the experimentally observed transitions. PMID- 23986183 TI - [Highlights from yesterday's Clinical Monatsblatter of Ophthalmology]. PMID- 23986182 TI - Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds. AB - A head-to-head study of representative examples of N-hydroxyindole-2-carboxylates (NHI) and malonic derivatives (Mal) as LDH-A inhibitors was conducted, comparing the enzyme inhibition potency, cellular uptake, reduction of lactate production in cancer cells and anti-proliferative activity. Among the compounds tested, methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (2, NHI-2), a methyl ester belonging to the NHI class, displayed optimal properties in the cell-based assays, proving to be an efficient anti-glycolytic agent against cancer cells. PMID- 23986184 TI - [Highlights from current Monatsblatter Clinical Ophthalmology]. PMID- 23986185 TI - [Retinal detachment in childhood]. PMID- 23986186 TI - [Trauma-associated juvenile rhegmatogenous retinal detachment]. AB - BACKGROUND: Rhegmatogenous retinal detachments (RRD) in children and adolescents are uncommon and present about 3-5 % of all retinal detachments. Etiology, pathogenesis and therapy differ significantly from adults. The current study addresses juvenile RRD after trauma to contribute to the limited knowledge about this condition. PATIENTS/MATERIAL AND METHODS: The current study includes 27 eyes of 25 patients aged up to 18 years that were operated on between 2000 and 2012. They presented 42.4 % of all RRD of that age group. We analyzed the following parameters: demographic data, retinal detachment characteristics, surgical techniques and outcomes. RESULTS: Mean age was 15,3 years and 77 % were boys. Retinal detachment occurred between 3 days and 11 years after trauma (median: 3,5 months). Two thirds of RRDs were classified as acute, the remainder showed symptoms of chronicity, e.g. pigment demarcation and subretinal strands or PVR. The macula was detached in 81,5 %. Retinal dialysis was the most common type of break (44,8), followed by giant retinal tears (18,5 %). In 3 out of 5 eyes with severe PVR due to self-aggressive behavior a causative retinal defect was not identified. Episcleral buckling surgery was the preferred method in any case that deemed manageable with a segmental sponge or encircling band (14 eyes). Primary vitrectomy was performed in more complex retinal detachments (13 eyes), and most of them had silicone oil tamponade. Primary reattachment was achieved in 83 % in the buckling group and 80 % in the vitrectomy group (3 eyes with self-harm excluded). Finally, all eyes had attached retinas. Postoperatively, visual acuity improved or remained stable in successfully treated eyes. Late complications in the vitrectomy group were cataract development in half of the phakic eyes. CONCLUSIONS: Retinal dialysis and giant retinal tears are the most frequent retinal lesions in posttraumatic RRD. Delayed diagnosis is a common problem, as most of the cases preset with macula-off detachments and clinical signs of chronic RRD. A conventional approach to traumatic RRD using scleral buckling techniques is recommended whenever possible. Differently from adults, strong vitreoretinal adhesions are present and the vitreous is rarely detached which makes a complete vitrectomy challenging. Furthermore there is a significant risk of postoperative cataract despite of the young age. However, cases with giant retinal tear and complex detachments due to PVR require vitrectomy maneuvers, usually with the use of silicone oil. A special subgroup presents PVR-detachments due to chronic auto-aggressive behavior of disabled young patients. Despite of extreme vitreoretinal maneuvers used, those eyes might be inoperable or late failures due to chronic aggressive PVR. On the whole, delayed diagnosis and advanced RRD limit final vision. However, after successful surgery, approximately half of the eyes improve, many retain vision. As preserving vision in young patients is of great impact for their whole lifespan, any attempt should be made to achieve a stable retinal situation. PMID- 23986187 TI - [Ocular malformation and paediatric retinal detachment]. AB - A range of posterior segment abnormalities, especially anomalies of the optic papilla, coloboma, and persistent hyperplastic primary vitreous are associated with the high risk to develop a retinal detachment. Most of these retinal detachments develop in the first and second decade of life. In most cases of retinal detachment caused by malformations, vitreoretinal surgery is indicated. Results of surgery depend on the nature of malformations. In spite of an anatomic re-attachment of the retina, in some eyes the functional results are limited. Especially in cases of severe PHPV, the aim of vitrectomy is only to prevent complications. Vitreoretinal surgery should not be performed in eyes with no light perception, without papillary light reflex, and/or with unrecordable visually evoked potential. PMID- 23986188 TI - [Childhood retinal detachment: ROP and myopia]. AB - This article reviews the cause and treatment options for retinopathy of prematurity (ROP)-related tractional detachment and detachments in ROP residuals during childhood and early adulthood. Retinal vascularisation is incomplete after premature birth. Phase I of ROP consists of a delayed retinal vascular growth and vessel loss after premature birth resulting in hypoxia, phase II results in hypoxia-induced vascular proliferation and as a consequence to vitreoretinal traction. The anatomic and functional outcome of tractional detachment in ROP is determined by the previous treatment (e.g., laser to the avascular periphery or anti-VEGF). While the literature reports re-attachment rates > 70 % in ROP IV a, functional and anatomic outcome in the later stages is limited. ROP residuals may cause rhegmatogenous rather than tractional detachments in childhood or early adulthood. Myopia is associated with ROP and may further complicate the retinal situation and the risk for rhegmatogenous detachment. The retinal changes due to ROP warrant lifelong controls. PMID- 23986189 TI - [Retinal exudative disease in childhood: Coats' disease and familial exudative vitreoretinopathy (FEVR)]. AB - This article reviews the pathophysiology of retinal vascular disease with emphasis on Coats' disease and familial exudative vitreoretinopathy (FEVR). Both Coats' disease and FEVR demonstrate vascular abnormalities and associated exudation. Coats' disease manifests as teleangiectasia and aneurysms. Exudative subretinal lipid deposits can be extensive. Coats' disease is in 90 % unilateral and affects predominantly otherwise healthy young males. If the retina is attached, laser and cryocoagulation are the method of choice. Vitreoretinal surgery is only rarely indicated in advanced cases after a retinoblastoma has been excluded prior to surgery. FEVR inheritance is 56 % dominant (FZD4 und TSPAN12) and 44 % recessive (LRP5 und NDP). Temporal dragging of the vascular arcades and heterotopia of the macula are characteristic for FEVR. Subretinal exudates are indicators for progression of the disease with visual loss due to subsequent exudative or tractive retinal detachment. Exudative forms require treatment and reduction of peripheral ischaemia with laser photocoagulation and cryopexia. In cases of tractive detachments vitreoretinal surgery is necessary. Coats' disease and FEVR are both progressive diseases requiring lifelong follow up and therapy. PMID- 23986190 TI - [Paediatric retinal detachment and hereditary vitreoretinal disorders]. AB - The number of retinal detachments in children is very low in comparison to the number in adults. One predisposing factor for development of paediatric retinal detachment is suffering from hereditary vitreoretinal degeneration (e.g., Stickler syndrome, Wagner syndrome, Kniest dysplasia, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, Knobloch syndrome, incontinentia pigmenti, Norrie disease). Hereditary vitreoretinopathies are characterised by an abnormal-appearing vitreous gel with associated retinal changes. In most of these eyes further ocular abnormalities can be diagnosed. A group of hereditary disorders is associated with characteristic systemic abnormalities. Allied conditions should be considered in the clinical diagnosis. Vitreoretinopathies are the most common cause of inherited retinal detachment. In most eyes primary vitrectomy is necessary, and disease-specific surgical treatment is discussed. PMID- 23986191 TI - [Mechanisms of retinal neurodegeneration as a result of diabetes mellitus]. AB - Diabetic retinopathy is characterised by microvascular damage to the retina caused by diabetes mellitus. Early vascular findings are microaneurysms and a breakdown of the blood-retina barrier. Recent studies indicate that neurodegeneration and neuroinflammation of the retina play an important role in the pathogenesis of diabetic retinal changes. They can occur early and preceed vascular changes. Important features of neurodegeneration of the retina are apoptosis and glia activation. This results in the loss of neuroretinal tissue. PMID- 23986192 TI - [Assessment of contrast vision by the Mars letter contrast sensitivity test - which illumination should be used?]. AB - BACKGROUND: For expert opinions on mesopic and contrast vision as stipulated in the recent version of the German driving licence regulations (2011), a standardised implementation of the relevant test method is crucial. DIN 58220, part 7, regulates the assessment of mesopic vision and the required parameters of evaluation are guaranteed by the respective test instruments. Because no standard exists for photopic contrast vision, it is recommended that it conform to that of DIN EN ISO 8596 for visual acuity. For test equipment with integrated viewing fields, the application of such tests may not be difficult. But if visual charts are used the question of standardised illumination arises. The present paper investigates this question when using the Mars Letter Contrast Sensitivity Test in the light of the recommendations by the producer to use a desk lamp for illumination. METHODS: The Mars Chart was illuminated by three different commercially available desk lights from different directions at a distance of 50 cm, which is the test distance recommended by the producer. The luminance distribution was measured on the chart at twelve equally distributed test points. RESULTS: For all conditions, the asymmetric illumination produced by a single light source leads to an extremely inhomogeneous luminance distribution over the chart. Adherence to the tolerance ranges for brightness, as well as the homogeneity of illumination from such light sources is left to chance and a subjective judgment of both parameters is not adequate. CONCLUSION: Illumination of the Mars Chart with a desk light only does not necessarily satisfy the requirement of reproducible test conditions that is mandatory for expert evaluations. For comparable test outcomes for contrast vision, illumination devices that produce a uniform illumination should be employed. PMID- 23986193 TI - [Spontaneous intraorbital haemorrhage]. PMID- 23986194 TI - [On the 75th Anniversary of the Withdrawal of the Medical License and the "Reichspogromnacht" - Jewish Ophthalmologists during National Socialism]. PMID- 23986195 TI - Understanding the cellular mechanism for inhaled hyperosmotic saline therapy for patients with cystic fibrosis. Focus on "Effect of apical hyperosmotic sodium challenge and amiloride on sodium transport in human bronchial epithelial cells from cystic fibrosis donors". PMID- 23986196 TI - Multiple cell death pathways are independently activated by lethal hypertonicity in renal epithelial cells. AB - When hypertonicity is imposed with sufficient intensity and acuteness, cells die. Here we investigated the cellular pathways involved in death using a cell line derived from renal epithelium. We found that hypertonicity rapidly induced activation of an intrinsic cell death pathway-release of cytochrome c and activation of caspase-3 and caspase-9-and an extrinsic pathway-activation of caspase-8. Likewise, a lysosomal pathway of cell death characterized by partial lysosomal rupture and release of cathepsin B from lysosomes to the cytosol was also activated. Relationships among the pathways were examined using specific inhibitors. Caspase inhibitors did not affect cathepsin B release into the cytosol by hypertonicity. In addition, cathepsin B inhibitors and caspase inhibitors did not affect hypertonicity-induced cytochrome c release, suggesting that the three pathways were independently activated. Combined inhibition of caspases and cathepsin B conferred significantly more protection from hypertonicity-induced cell death than inhibition of caspase or cathepsin B alone, indicating that all the three pathways contributed to the hypertonicity-induced cell death. Similar pattern of sensitivity to the inhibitors was observed in two other cell lines derived from renal epithelia. We conclude that multiple cell death pathways are independently activated early in response to lethal hypertonic stress in renal epithelial cells. PMID- 23986197 TI - Effect of apical hyperosmotic sodium challenge and amiloride on sodium transport in human bronchial epithelial cells from cystic fibrosis donors. AB - Hypertonic saline (HS) inhalation therapy benefits cystic fibrosis (CF) patients [Donaldson SH, Bennet WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. N Engl J Med 354: 241-250, 2006; Elkins MR, Robinson M, Rose BR, Harbour C, Moriarty CP, Marks GB, Belousova EG, Xuan W, Bye PT; the National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. N Engl J Med 354: 229-240, 2006]. Surprisingly, these benefits are long-lasting and are diminished by the epithelial Na(+) channel blocker amiloride (Donaldson SH, Bennet WD, Zeman KL, Knowles MR, Tarran R, Boucher RC. N Engl J Med 354: 241-250, 2006). Our aim was to explain these effects. Human bronchial epithelial (hBE) cells from CF lungs were grown in inserts and were used in three experimental approaches: 1) Ussing chambers to measure amiloride-sensitive short-circuit currents (INa); 2) continuous perfusion Ussing chambers; and 3) near "thin-film" conditions in which the airway surface of the inserts was exposed to a small volume (30 MUl) of isosmotic or HS solution as the inserts were kept in their incubation tray and were subsequently used to measure INa under isosmotic conditions (near thin-film experiments; Tarran R, Boucher RC. Methods Mol Med 70: 479-492, 2002). HS solutions (660 mosmol/kgH2O) were prepared by adding additional NaCl to the isosmotic buffer. The transepithelial short-circuit current (ISC), conductance (GT), and capacitance (CT) were measured by transepithelial impedance analysis (Danahay H, Atherton HC, Jackson AD, Kreindler JL, Poll CT, Bridges RJ. Am J Physiol Lung Cell Mol Physiol 290: L558-L569, 2006; Singh AK, Singh S, Devor DC, Frizzell RA, van Driessche W, Bridges RJ. Methods Mol Med 70: 129-142, 2002). Exposure to apical HS inhibited INa, GT, and CT. The INa inhibition required 60 min of reexposure to the isosmotic solution to recover 75%. The time of exposure to HS required to inhibit INa was <2.5 min. Under near thin-film conditions, apical exposure to HS inhibited INa, but as osmotically driven water moved to the apical surface, the aqueous apical volume increased, leading to an amiloride-insensitive decrease in its osmolality and to recovery of INa that lagged behind the osmotic recovery. Amiloride significantly accelerated the recovery of INa following exposure to HS. Our conclusions are that exposure to HS inhibits hBE INa and that amiloride diminishes this effect. PMID- 23986198 TI - Enhanced K(+) secretion in dextran sulfate-induced colitis reflects upregulation of large conductance apical K(+) channels (BK; Kcnma1). AB - Defective colonic Na(+) and Cl(-) absorption is a feature of active ulcerative colitis (UC), but little is known about changes in colonic K(+) transport. We therefore investigated colonic K(+) transport in a rat model of dextran sulfate induced colitis. Colitis was induced in rat distal colon using 5% dextran sulfate sodium (DSS). Short-circuit current (Isc, indicating electrogenic ion transport) and (86)Rb (K(+) surrogate) fluxes were measured in colonic mucosa mounted in Ussing chambers under voltage-clamp conditions in the presence of mucosal orthovanadate (a P-type ATPase inhibitor). Serum aldosterone was measured by immunoassay. Control animals exhibited zero net K(+) flux. By contrast, DSS treated animals exhibited active K(+) secretion, which was inhibited by 98, 76, and 22% by Ba(2+) (nonspecific K(+) channel blocker), iberiotoxin (IbTX; BK channel blocker), and TRAM-34 (IK channel blocker), respectively. Apical BK channel alpha-subunit mRNA abundance and protein expression, and serum aldosterone levels in DSS-treated animals, were enhanced 6-, 3-, and 6-fold respectively, compared with controls. Increasing intracellular Ca(2+) with carbachol (CCH), or intracellular cAMP with forskolin (FSK), stimulated both active Cl(-) secretion and active K(+) secretion in controls but had no or little effect in DSS-treated animals. In DSS-induced colitis, active K(+) secretion involves upregulation of apical BK channel expression, which may be aldosterone dependent, whereas Cl(-) secretion is diminished. Since similar ion transport abnormalities occur in patients with UC, diarrhea in this disease may reflect increased colonic K(+) secretion (rather than increased Cl(-) secretion), as well as defective Na(+) and Cl(-) absorption. PMID- 23986199 TI - Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics. AB - Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b(-/-)) mice, hydroxyurea PK was analyzed in vivo by measuring [(14)C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled (14)CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b(-/-) mice compared with wild-type (area under the curve of 38.64 or 48.45 MUg.h(-1).ml(-1), respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b(-/-) mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b(-/-) mice, respectively) correlating with a decrease in exhaled (14)CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK. PMID- 23986200 TI - Mutant hERG channel traffic jam. Focus on "Pharmacological correction of long QT linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum". PMID- 23986202 TI - Evidence for paracrine/autocrine regulation of GLP-1-producing cells. AB - Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our results show that palmitate induced production of reactive oxygen species and caspase-3 activity and reduced cell viability are significantly attenuated by preincubation with insulin/exendin-4. The indicated lipoprotective effect of insulin/exendin-4 was not detectable in the presence of the GLP-1 receptor (GLP-1R) antagonist exendin (9-39) and attenuated in response to pharmacological inhibition of exchange protein activated by cAMP (Epac) signaling, while protein kinase A inhibition had no significant effect. Insulin/exendin-4 also significantly stimulate acute and long-term GLP-1 secretion in the presence of glucose, suggesting novel beneficial effects of insulin signaling and GLP-1R activation on glycemia through enhanced mass of GLP 1-producing cells and enhanced GLP-1 secretion. In addition, the effects of insulin indicate that not only is GLP-1 important for insulin secretion but altered insulin signaling may contribute to an altered GLP-1 secretion. PMID- 23986201 TI - Functional vacuolar ATPase (V-ATPase) proton pumps traffic to the enterocyte brush border membrane and require CFTR. AB - Vacuolar ATPases (V-ATPases) are highly conserved proton pumps that regulate organelle pH. Epithelial luminal pH is also regulated by cAMP-dependent traffic of specific subunits of the V-ATPase complex from endosomes into the apical membrane. In the intestine, cAMP-dependent traffic of cystic fibrosis transmembrane conductance regulator (CFTR) channels and the sodium hydrogen exchanger (NHE3) in the brush border regulate luminal pH. V-ATPase was found to colocalize with CFTR in intestinal CFTR high expresser (CHE) cells recently. Moreover, apical traffic of V-ATPase and CFTR in rat Brunner's glands was shown to be dependent on cAMP/PKA. These observations support a functional relationship between V-ATPase and CFTR in the intestine. The current study examined V-ATPase and CFTR distribution in intestines from wild-type, CFTR(-/-) mice and polarized intestinal CaCo-2BBe cells following cAMP stimulation and inhibition of CFTR/V ATPase function. Coimmunoprecipitation studies examined V-ATPase interaction with CFTR. The pH-sensitive dye BCECF determined proton efflux and its dependence on V ATPase/CFTR in intestinal cells. cAMP increased V-ATPase/CFTR colocalization in the apical domain of intestinal cells and redistributed the V-ATPase Voa1 and Voa2 trafficking subunits from the basolateral membrane to the brush border membrane. Voa1 and Voa2 subunits were localized to endosomes beneath the terminal web in untreated CFTR(-/-) intestine but redistributed to the subapical cytoplasm following cAMP treatment. Inhibition of CFTR or V-ATPase significantly decreased pHi in cells, confirming their functional interdependence. These data establish that V-ATPase traffics into the brush border membrane to regulate proton efflux and this activity is dependent on CFTR in the intestine. PMID- 23986205 TI - Protein C and protein S deficiency - practical diagnostic issues. AB - Protein C (PC) and protein S (PS) are vitamin K-dependent glycoproteins, that act as natural anticoagulants. The proteolytic activation of PC by thrombin occurs on the surface of endothelial cells and involves thrombomodulin and endothelial PC receptor. In the presence of PS, phospholipids and calcium, activated PC (APC) inactivates membrane bound factors V (FVa) and FVIIIa by their cleavage at the specific arginine residues. PC and PS deficiencies are inherited as autosomal dominant disorders associated with recurrent venous thromboembolism (VTE) and, in most cases, derived from heterozygous missense mutations (78% and 63%, respectively). Heterozygous PC deficiency is found in 6% of families with inherited thrombophilia, in 3% of patients with a first-time deep vein thrombosis (DVT) and 0.2-0.3% of healthy individuals. The PS deficiency is detected more commonly than PC deficiency and its prevalence has been estimated with a less than 0.5% in the general European population and 2% to 12% of selected groups of thrombophilic patients. Approximately 75% of PC-deficient patients have type I deficiency and 95% of PS-deficient patients develop type I and type III of PS deficiency. The diagnosis of PC and PS deficiencies is challenging, many preanalytical and analytical factors may affect the PC/PS levels. Molecular analysis of the PC and PS genes (PROC and PROS1, respectively) involves direct gene sequencing and if negative, multiplex ligation-dependent probe amplification (MLPA) method. Patients with low PC and PS levels and the known mutation within PROC or PROS1 genes combined with other genetic or environmental thrombosis factors are at increased risk of recurrent thromboembolic events and require lifelong oral anticoagulation. PMID- 23986206 TI - The influence of different therapeutic modalities and platelet rich plasma on apexogenesis: a preliminary study in monkeys. AB - BACKGROUND: Traumatic injuries of permanent teeth with incomplete root formation are frequent during childhood. Adequate therapy is important for the further destiny of teeth with damaged pulp. OBJECTIVES: To evaluate the effect of pulpotomy and high pulpotomy on the pulp and on root development, and the effect of platelet rich plasma (PRP) with hydroxyapatite (HAP) as a carrier and hydroxyapatite alone on apexogenesis. MATERIAL AND METHODS: The study included eight monkeys (Cercopithecus aethiops) in which high pulpotomies were performed on the mandibular lateral incisors and canines, and pulpotomies were performed on the mandibular central incisors and premolars. The materials used in the study were commercial HAP (Apatec(r), Stomygen) and PRP (prepared at the Torlak Institute of Immunology and Virology, Belgrade, Serbia.). Histological and radiological evaluations were done six months after the treatment. RESULTS: Considering the differences between HAP+PRP treated teeth in the pulpotomy group and teeth in the high pulpotomy group, two times more root growth retardation was observed in the high pulpotomy group. In the high pulpotomy group, root growth retardation was less common in HAP+PRP treated teeth (42.9%) than in HAP treated teeth (50%). In the pulpotomy group, retardation of root development was also less common in HAP+PRP treated teeth (25%) compared to HAP treated teeth (50%). There were differences between the pulpotomy and high pulpotomy groups, but without statistical significance. CONCLUSIONS: The application of endogenous growth factors in conjunction with the preservation of dental pulp vitality can result in a good outcome for pulp therapy of injured teeth, which means successfully completed apexogenesis. PMID- 23986203 TI - Pre- and postsynaptic modulations of hypoglossal motoneurons by alpha adrenoceptor activation in wild-type and Mecp2(-/Y) mice. AB - Hypoglossal motoneurons (HNs) control tongue movement and play a role in maintenance of upper airway patency. Defects in these neurons may contribute to the development of sleep apnea and other cranial motor disorders including Rett syndrome (RTT). HNs are modulated by norepinephrine (NE) through alpha adrenoceptors. Although postsynaptic mechanisms are known to play a role in this effect, how NE modulates the synaptic transmissions of HNs remains poorly understood. More importantly, the NE system is defective in RTT, while how the defect affects HNs is unknown. Believing that information of NE modulation of HNs may help the understanding of RTT and the design of new therapeutical interventions to motor defects in the disease, we performed these studies in which glycinergic inhibitory postsynaptic currents and intrinsic membrane properties were examined in wild-type and Mecp2(-/Y) mice, a mouse of model of RTT. We found that activation of alpha1-adrenoceptor facilitated glycinergic synaptic transmission and excited HNs. These effects were mediated by both pre- and postsynaptic mechanisms. The latter effect involved an inhibition of barium sensitive G protein-dependent K(+) currents. The pre- and postsynaptic modulations of the HNs by alpha1-adrenoceptors were not only retained in Mecp2 null mice but also markedly enhanced, which appears to be a compensatory mechanism for the deficiencies in NE and GABAergic synaptic transmission. The existence of the endogenous compensatory mechanism is an encouraging finding, as it may allow therapeutical modalities to alleviate motoneuronal defects in RTT. PMID- 23986204 TI - Coronary endothelial dysfunction and mitochondrial reactive oxygen species in type 2 diabetic mice. AB - Endothelial cell (EC) dysfunction is implicated in cardiovascular diseases, including diabetes. The decrease in nitric oxide (NO) bioavailability is the hallmark of endothelial dysfunction, and it leads to attenuated vascular relaxation and atherosclerosis followed by a decrease in blood flow. In the heart, decreased coronary blood flow is responsible for insufficient oxygen supply to cardiomyocytes and, subsequently, increases the incidence of cardiac ischemia. In this study we investigate whether and how reactive oxygen species (ROS) in mitochondria contribute to coronary endothelial dysfunction in type 2 diabetic (T2D) mice. T2D was induced in mice by a high-fat diet combined with a single injection of low-dose streptozotocin. ACh-induced vascular relaxation was significantly attenuated in coronary arteries (CAs) from T2D mice compared with controls. The pharmacological approach reveals that NO-dependent, but not hyperpolarization- or prostacyclin-dependent, relaxation was decreased in CAs from T2D mice. Attenuated ACh-induced relaxation in CAs from T2D mice was restored toward control level by treatment with mitoTempol (a mitochondria specific O2(-) scavenger). Coronary ECs isolated from T2D mice exhibited a significant increase in mitochondrial ROS concentration and decrease in SOD2 protein expression compared with coronary ECs isolated from control mice. Furthermore, protein ubiquitination of SOD2 was significantly increased in coronary ECs isolated from T2D mice. These results suggest that augmented SOD2 ubiquitination leads to the increase in mitochondrial ROS concentration in coronary ECs from T2D mice and attenuates coronary vascular relaxation in T2D mice. PMID- 23986207 TI - Comparison of topical sucralfate and silver sulfadiazine cream in second degree burns in rats. AB - BACKGROUND: The most prevalent topical treatment for partial thickness burns is silver sulfadiazine 1% (SSD). Recent studies have shown that the healing of partial thickness burns is delayed with the use of SSD. One of the potential burn dressings is sucralfate. OBJECTIVES: With this study the authors have aimed to analyze comparatively the effects of sucralfate and SSD on second degree burn wounds in rats. MATERIAL AND METHODS: Forty-eight male rats were divided into three equal groups. A burn model was constituted on the back of all rats. The burned areas in the first, second and third groups were covered daily with sucralfate, SSD and cold cream (control), respectively. At the end of the 7th, 14th, 21st and 28th day, the rats were anesthetized and the burned skin tissue samples were collected for histopathological examination. RESULTS: At the end of the study, the epidermis and horny layer was completely formed in the SSD and sucralfate group; however the appendix of skin was just formed in the sucralfate group. Also the percentage of wound healing was calculated at 76%, 91% and 100% respectively in the control, silver sulfadiazine and sucralfate groups. CONCLUSIONS: Sucralfate is known to have multiple beneficial effects on wound healing. Using topical sucralfate accelerates the burn wound healing process in comparison with both the control and SSD groups and can be used as an adjunctive or alternative agent in the future. PMID- 23986208 TI - The effects of age, metabolic syndrome, nocturnal polyuria and sleep disorders on nocturia. AB - BACKGROUND: Nocturia, which is especially frequent among older men, adversely affects the individual's quality of life. It is regarded as one of the most bothersome lower urinary tract symptoms (LUTS). OBJECTIVES: The aim of the study was to investigate factors contributing to the frequency of nocturia. MATERIAL AND METHODS: Men >= 40 years with LUTS were enrolled in this study. After medical histories were taken and physical examinations conducted, biochemical tests and measures for LUTS were carried out. Anthropometric measurements were performed and Epworth scores (ES) were examined. Patients were divided into two groups with respect to nocturia: the first group having no nocturia or one incident of nocturia per night, and the second group with two or more nightly incidents of nocturia. The data were analyzed statistically; p < 0.05 was considered significant. RESULTS: A total of 118 consecutive patients (56 +/- 10 years) were enrolled in the study. The first group consisted of 31 participants, while the second group contained 87 patients. The groups differed significantly with respect to age, body height, body weight, waist circumference and body mass index (BMI). ES, prostatic volumes, maximum flow rates (Qmax) and international prostate symptom scores (IPSS) were significantly different. Fasting blood glucose levels were similar for both groups. Homeostasis model assessment (HOMA) scores showed borderline significance. Insulin levels were different, while insulin resistance (IR) was similar between the groups. Nocturnal polyuria was associated with nocturia, systolic blood pressure and IPSS. CONCLUSIONS: Age, nocturnal polyuria, metabolic syndrome and sleep disturbances have been shown to be contributing factors in the frequency of nocturia and LUTS. Therefore, steps taken to alleviate factors that can be altered - such as hypertension, weight gain, sleep disturbances and IPSS - may improve the individual's quality of life. PMID- 23986210 TI - The quality of primary health care for chronically ill patients: a cross sectional study. AB - BACKGROUND: Patients with at least one chronic disease requiring regular contact with their GP, additional tests and systematic use of medicines constitute one of the challenges for the future of primary medical care. To date, no studies have been published describing the most important factors in increasing the quality of care for the chronically ill. OBJECTIVES: To evaluate correlations between patients' characteristics and their assessments of the quality of health care and to identify the primary factors influencing the quality of care for chronically ill patients. MATERIAL AND METHODS: The sample for the current analysis included 232 chronically ill adult patients of primary care clinics in Poland. The patients' opinions regarding subjective and objective examinations, their participation in clinical decision-making processes, psychosocial factors, contact with the doctor in emergency situations and confidence in the doctor were investigated. RESULTS: The strongest correlations defining the quality of care for the chronically ill were identified as the occurrence of hypertension (0.248, p < 0.001), the patient's gender (0.271, p < 0.001), the patient's level of education (0.169, p < 0.01) and the patient's age (0.155, p = 0.018). The results of the ANOVA test were statistically significant (p < 0.05) for the occurrence of myocardial infarction, hypertension, type 2 diabetes, psoriasis, multiple sclerosis, the doctor's gender, the patient's gender, age and education. CONCLUSIONS: The areas that the participants gave the highest ratings to are subjective and objective examinations, kindness and willingness to help. The strongest correlations between high assessments of the quality of care provided for chronically ill patients at primary care clinics were observed in the following variables: gender, age, level of education, frequency of visits, therapy conducted by a doctor at a specialist clinic, arterial hypertension, COPD and/or myocardial infarction. PMID- 23986209 TI - The clinicopathological determinants of native arteriovenous fistula failure in patients on maintenance hemodialysis. AB - BACKGROUND: Progressive narrowing of the venous part of dialysis fistulae is caused by hemodynamic and inflammatory factors. OBJECTIVES: The pathogenic and clinical determinants of deterioration of the functioning of arteriovenous fistulae in chronically hemodialyzed patients were evaluated. MATERIAL AND METHODS: The hemodynamic parameters and the activity of inflammatory growth factors in the vessel wall of newly implanted fistulae were assessed and correlated with the clinical course of 34 hemodialyzed patients. Measurements taken at the time of implanting the fistulae included blood flow in the venous part of the anastomosis and its widest diameter by ultrasound Power Doppler, a histopathologic examination of fistula wall samples and measurements of mRNA expression for growth factors PDGFbeta1 and TGFbeta in the fistula wall. The results were correlated with clinical data from 36 months' observation: duration of fistula maturation, adequacy of dialysis treatment (eKt/V), the patient's survival, morbidity linked with vascular access problems and general cardiovascular morbidity. RESULTS: The mean duration of fistula maturation was 44.9 days (N = 43, SD = 38.6), whereas the average duration of fistula usage as dialysis access was 795.9 +/- 480.6 days. Fistula blood flow at the time of implantation, averaged 1782.2 +/- 1735.3 ml/min. The mean number of hospitalization days due to vascular access morbidity was 9.9 +/- 15.6 days and it correlated positively with the fistula blood flow (R = 0.596, P = 0.004). There was a negative correlation between the expression of PDGFbeta1 mRNA and fistula blood flow (R = -0.673, P = 0.011), as well as between TGFbeta expression and patient survival (R = -0.722, P = 0.002). CONCLUSIONS: Inflammatory activity of the vessel wall growth factors PDGFbeta1 and TGFbeta implies impairment of fistula function and the patient's cardiovascular morbidity. PMID- 23986211 TI - Expression of metallothionein and Ki-67 antigen in GISTs of different grade of malignancy. AB - BACKGROUND: Metallothioneins (MTs) are low molecular weight proteins (6-7 kDa), which have been shown to regulate zinc ion homeostasis. MTs exert anti-apoptotic and pro-proliferative effect on cancer cells. Overexpression of MT-I and MT-II isoforms has been noted in many malignant tumors, but the role of their expression in gastrointestinal stromal tumors (GISTs) remains unclear. OBJECTIVES: The aim of the study was to examine the relationship between expression of MT-I/II and K-67 proliferation antigen in a subset of GISTs presenting differential grade of malignancy. MATERIAL AND METHODS: The study was conducted using immunohistochemical methods on archival paraffin sections of 34 cases of GISTs. Of those, 17 tumors were classified as benign (GISTB) and 17 tumors as malignant (GISTM). RESULTS: The GISTM cases demonstrated higher MT-I/II expression as compared to the GISTB cases, but not significantly higher (p = 0.08). The GISTM tumors showed significantly higher expression of Ki-67 antigen than the GISTB cases (p = 0.01). MT-I/II and Ki-67 expression positively correlated in GISTBs (r = 0.48, p = 0.0463), but not in GISTMs. CONCLUSION: The results of this study may point to a potential role of MT-I/II in the proliferation of GIST cells and disease progression. PMID- 23986212 TI - Temporary resolution of chronic atrial fibrillation after cardiac surgery and the prolongation of ventricular repolarization. AB - BACKGROUND: Chronic atrial fibrillation may temporarily resolve after cardiac surgery. Prolongation of the ventricular repolarization period may be the electrophysiological background for this phenomenon. OBJECTIVES: The aim of the study was to assess the association between resolution of atrial fibrillation and changes in the duration of the ventricular repolarization period in patients with pre-operative chronic atrial fibrillation who underwent cardiac surgery. MATERIAL AND METHODS: A retrospective analysis of the medical recordings of patients with chronic atrial fibrillation who underwent cardiac surgery was performed. After exclusions the study group comprised 51 patients with chronic atrial fibrillation who underwent surgery in the Cardiac Surgery Department of Wroclaw Medical University in 2008 and 2009. The 12-lead EKGs performed before and after the surgery were assessed and the QT and R-R intervals were measured. The patients were divided into Group 1, in whom atrial fibrillation persisted after the cardiac surgery, and Group 2, whose atrial fibrillation resolved after the surgery. RESULTS: In 31 patients (60.8%) atrial fibrillation disappeared during the first 24 hours after cardiac surgery. A significant prolongation of the QT interval after the surgery was found in Group 2 that was not observed in Group 1. Multiple regression analysis revealed that QT interval duration after surgery is related to the resolution of atrial fibrillation independently from the duration of the R-R interval duration and the need for cardiac pacing. CONCLUSIONS: Spontaneous temporary resolution of atrial fibrillation is a common finding after cardiac surgery in patients with chronic atrial fibrillation. This phenomenon is related to a prolonged QT interval, therefore it may have an electrophysiological basis rather than a hemodynamic background. Further studies are required to assess the clinical importance of the prolongation of the QT interval after cardiac surgery. PMID- 23986213 TI - The effect of structural white matter abnormalities on the clinical course of epilepsy. AB - OBJECTIVES: The aim of this study was to assess the impact of the extent of brain white matter lesions on the development of cognitive and psychoemotional disorders, and to investigate correlations between the degree of integration of brain pathway structures and the clinical features of epilepsy. MATERIAL AND METHODS: Forty-six epileptic patients (36 with pharmacoresistant epilepsy and 10 who had been in remission for over a year) and 10 normal volunteers (the control group) were examined. To evaluate diffusion tensor MRI findings, the index of fractional anisotropy (FA) and index of apparent diffusion coefficient (ADC) were used. For an intergroup comparison of DTI data, the Mann-Whitney test was used, criterion; correlation analysis was performed using the Spearman rank correlation coefficient. The threshold of statistical significance was set at r < 0.05. RESULTS: A significant difference was noted in the ADC data on the side of the epileptic focus in the patients in persistent remission as compared to the pharmacoresistant patients (r < 0.05). No differences were found between the patient groups' fractional anisotropy data. In cases of mesial temporal sclerosis in patients with pharmacoresistant epilepsy, a "weakening" of the tractography pattern in the opposite hemisphere was found (r = 0.66, p = 0.0005). Decreases in the tracts appearing in brain temporal lobes was typical of patients with pharmacoresistant forms of epilepsy (r = 0.46, p = 0.0005). A pathological decrease in FA and an increase in ADC correlated with the results on the Beck scale and the Spielberger-Khanin anxiety scale (r = -0.2, p < 0.001) as well as with P300 peak latency data (r = 0.23, p < 0.001). Analyses of the peculiarities of EEG patterns and FA data demonstrated a correlation between the existence of epileptic activity and a decrease in FA (r = -0.7, t = -2.44, p = 0.01). CONCLUSIONS: Microstructural brain matter changes make it possible to assess the course of epilepsy to predict the outcomes of medicamental correction of paroxysmal states. PMID- 23986214 TI - Surgical management in patients with aneurysmal subarachnoid hemorrhage. The outcomes in the paradigm shift period. AB - BACKGROUND: The treatment of cerebral aneurysms has undergone significant evolution since the 1990s when the endovascular methods were introduced. After the results of ISAT were published in 2002, a change in practice occurred which resulted in more ruptured aneurysms treated endovascularly rather than by surgical clipping. This change in practice was referred to as a paradigm shift. OBJECTIVES: The aim of this study was to review the treatment outcomes in patients with ruptured anterior cerebral aneurysms and to delineate the trends in surgical management in the age of the formation of centers for interventional neuroradiology. MATERIAL AND METHODS: The number of patients with subarachnoid hemorrhage treated by surgical means annually between 2004 and 2010 was identified. The patients' data and aneurysm characteristics were collected from the clinical database. The primary outcome measure was the GOS on discharge. Multivariable logistic regression was derived to define independent predictors of the outcomes. RESULTS: The study enrolled 361 SAH patients in which the total number of 409 aneurysm was clipped. Most of the aneurysms (75.7%) were equal to or less than 10mm. In late 2006, after the new center for interventional neuroradiology was established in WMU, the number of aneurysmal SAH patients treated surgically decreased significantly and has remained at that level for subsequent years. Favorable outcomes were achieved in 62.8% of the patients, unfavorable outcomes in 37.1%, including 77 deaths (21.3%). In multivariable analysis, unfavorable outcome was associated with increasing age, worsening neurological grade assessed by the Glasgow Coma Scale (GCS), hemiparesis or aphasia on admission, high Fisher grade, intracerebral hematoma, chronic comorbidities and delayed vasospasm. CONCLUSIONS: The introduction of endovascular methods in the treatment of patients with aneurismal SAH resulted in an almost halving of the number of patients treated surgically. The outcomes of patients with cerebral aneurysms depend mainly on non-modifiable factors (the neurological state of the patients on admission and age). GCS has a better predictive value for outcomes in patients with aneurysmal SAH than the commonly used WFNS and Hunt-Hess scales. Due to the fact that the majority of aneurysms are small or medium sized, the authors recommend the treatment of unruptured aneurysms less than 10 millimeters as a prevention of SAH. PMID- 23986215 TI - The influence of eyeball rotation on the results of auditory steady-state responses. AB - BACKGROUND: Testing auditory steady-state responses consists in recording the electrophysiological response to an auditory stimulus. Due to this response, in addition to changes in electric potentials caused by neuron impulses in the auditory path, the sonomotor reflex can also be observed. The sonomotor reflex shows muscle responses to auditory events, and in the case of auditory evoked potentials it mainly consists of post-auricular muscle responses. When the eyes are rolled to the side during testing, the post-auricular muscle response to an auditory stimulus is stronger, which in turn can contribute to improving response detection. OBJECTIVES: The aim of this study was to test the influence of eyeball rotation on the results of auditory steady-state responses. MATERIAL AND METHODS: Auditory evoked potentials were tested in a group of ten people with normal hearing. Each person was examined three times: (i) with eyes closed, (ii) with eyes open looking straight ahead and (iii) with eyes open and rolled to the side. RESULTS: The median electrophysiological response amplitude recorded when the eyes were rolled to the side was approximately 40% higher than the median response amplitude recorded in other positions (with eyes closed, and with eyes open looking straight ahead). At the same time, during tests with the eyes rolled to the side, a 170% increase in the noise median observed, compared to the tests conducted with the eyes closed. CONCLUSIONS: Rolling the eyes to the side does not improve the detection of response, as the observed increase in noise amplitude is much higher than the increase in the amplitude of the electrophysiological response. PMID- 23986216 TI - Clinical relevance of drug-drug interactions in hospitalized dermatology patients. AB - BACKGROUND: Potential drug-drug interactions (DDIs) are known to be a risk factor for the development of adverse drug reactions (ADRs). Data on the occurrence of ADRs related to DDIs is scarce and comes from different groups of patients. OBJECTIVES: The aim of the study was to evaluate the frequency, nature and determinants of potential DDIs in hospitalized dermatology patients and assess their contribution for the development of ADRs. MATERIAL AND METHODS: A prospective observational study comprising all consecutive inpatients admitted to the Clinic of Dermatology and Venereology, University Hospital, Stara Zagora for the period March 2009 - August 2011 was carried out. Systemic medication was screened for potential DDIs using an electronic drug interactions checker. DDIs were then verified with Stockley's Drug Interactions and divided into "clinically important" and "clinically unimportant". ADRs were classified by clinical manifestation, type and severity. Causality was scored according to Naranjo et al. (1981). RESULTS: The study included 674 patients, 513 (76.1%) of them with established comorbidities. Totally, 504 potential DDIs were identified (441 "clinically important" and 63 "clinically unimportant") in 236 patients. Hypotension was the most common expected clinical presentation of the potential DDIs. The strongest predictor for the development of DDIs was the number of systemic drugs (OR 2.25, 95% CI 1.97-2.58). Overall 43 ADRs were recorded, 53.5% "type B" and 46.5% "type A" reactions, most commonly with cutaneous and cardiovascular manifestations. The development of ADRs was attributed to 13 DDIs (2.6% of all detected potential DDIs) in 10 of these cases (23.25%). CONCLUSIONS: Potential DDIs were frequent in hospitalized dermatology patients. The drug groups most commonly involved were cardiovascular drugs. The proportion of DDIs associated with the occurrence of ADRs was relatively low, but close monitoring of patients on multiple drug regimens is essential because these reactions may be severe. PMID- 23986218 TI - Interdisciplinary therapy in Cornelia de Lange syndrome - review of the literature. AB - Cornelia de Lange syndrome (CdLS, also called Brachmann-de Lange syndrome - BdLS) is a multisystem developmental disorder characterized by distinctive facial features, growth and mental retardation, microcephaly, and various malformations. According to their clinical status, patients with CdLS require individual interdisciplinary therapy. The therapy is difficult and mainly symptomatic. To optimize the therapy results, early diagnosis programs and appropriate developmental and therapeutic intervention are recommended. The interdisciplinary approach described in the article needs further clinical research and detailed guidelines. PMID- 23986217 TI - Totally tubeless percutaneous nephrolithotomy: selecting for success in children. AB - BACKGROUND: The placement of a nephrostomy tube or internal ureteral stent after PCNL has been considered standard practice. OBJECTIVES: To investigate the inclusion criteria for totally tubeless PCNL in pediatric cases. MATERIAL AND METHODS: A total of 27 children who underwent PCNL included in the study: Twelve of the 27 patients who underwent totally tubeless PCNL (group 1; tubeless and stentless), and the remaining 15 patients underwent Standard PCNL (group 2; tube with or without stent). Whether or not to perform totally tubeless technique was decided intraoperatively. The length of hospitalization, drop in hemoglobin level, the operation time, stone burden and the fluoroscopy time of group 1 and 2 were compared statistically. Also stone free and complication rates were evaluated in both groups. RESULTS: The mean age was 5 years and 9.5 years in group 1 and 2, respectively (p = 0.01). The mean operative time was 15.83 min in group 1, and 48.6 min in group 2 (p = 0.0001). The mean change in hemoglobin levels between preoperative and postoperative measurements was -1.83 mg/dl for group 1, and -5.2 mg/dl for group 2 (p = 0.0001). No blood transfusion was needed during or after the operation in any cases for group 1. The mean length of hospital stay was 1.83 day in group 1 and 5.53 day in group 2 (p = 0.001). Stone free rate for group 1 was 100% (12/12) and 93.3% (14/15) for group 2. There were no major operative or postoperative complications in both groups. CONCLUSIONS: Provided an optimal patient selection, the success and safety rates of PCNL's performed via totally tubeless technique are similar to those. PMID- 23986220 TI - Hepcidin and its role in inflammatory bowel disease. AB - Anemia is one of the most common extraintestinal symptoms of inflammatory bowel disease (IBD). The pathophysiology of anemia in IBD is complex. It may be developed in the course of inflammation, intestinal bleeding or disorders of iron absorption. Hepcidin, discovered in the year 2000, is an endogenous peptide responsible for iron homeostasis. Recent data suggests that hepcidin is a major mediator of anemia and plays a central role in iron homeostasis and metabolism. This paper presents information about hepcidin structure and function, mechanisms of the regulation of the synthesis and current data about the role of this hormone in IBD-related anemia. Assessment of hepcidin levels in patients with IBD may become a key element in the treatment of anemia in the near future. PMID- 23986219 TI - The influence of genetic RFC1, MS and MTHFR polymorphisms on the risk of acute lymphoblastic leukemia relapse in children and the adverse effects of methotrexate. AB - Polymorphism in genes coding drug-metabolizing enzymes may cause individual differences in the effectiveness and toxicity of many medications, including cytostatics. Although in recent years intensive treatment has positively influenced the prognosis in leukemias, many adverse effects resulting from nonspecific actions and the narrow therapeutic index of anti-cancer drugs are still observed during therapy. Determining selected gene polymorphisms may increase both the safety and the efficacy of treatment, and might help in developing individual therapies. PMID- 23986221 TI - Caspases and their role in gastric cancer. AB - Caspases (Cysteine Aspartate Specific Proteases) are a group of cysteine containing proteolytic enzymes produced by the cells of living organisms. They participate in immunological functions, proliferation, cell migration and organization. Caspases also influence the secretion of various regulative factors. Moreover, they are responsible for cellular maturation and reconstruction, and for regulating the number and quality of cells initiating the apoptosis of old cells or those that cannot play their normal role due to abnormalities. Multiple pathological processes are associated with disorders in the activity of caspases. Changes in expression of individual caspases have been observed in gastric cancer. The expression of some caspases is also correlated with particular histological traits and the frequency of metastases, which suggests their possible use as a prognostic factor. It has also been discovered that some somatic mutations in caspase coding genes might lead to inhibition of apoptosis and the progression of the disease. Gene polymorphism may be a gastric cancer risk factor, but may also play a protective function. Considering the less than satisfactory effects of conventional therapeutic methods, the search for alternative ways to activate apoptosis - through gene therapy or selective activation of individual elements of the apoptotic pathways - constitutes a promising direction for studies of new therapeutic strategies. Caspases, enzymes playing a central role in the process of programmed cellular death, may possibly be a key to the development of a more effective anti-cancer therapy. PMID- 23986222 TI - Rapamycin regulates connective tissue growth factor expression of lung epithelial cells via phosphoinositide 3-kinase. AB - The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains largely unknown. It is believed that IPF is mainly driven by activated alveolar epithelial cells that have a compromised migration capacity, and that also produce substances (such as connective tissue growth factor, CTGF) that contribute to fibroblast activation and matrix protein accumulation. Because the mechanisms regulating these processes are unclear, the aim of this study was to determine the role of rapamycin in regulating epithelial cell migration and CTGF expression. Transformed epithelial cell line A549 and normal human pulmonary alveolar or bronchial epithelial cells were cultured in regular medium or medium containing rapamycin. Real time reverse transcriptase polymerase chain reaction was employed to determine CTGF mRNA expression. Western blotting and an enzyme-linked immunosorbent assay were used for detecting CTGF protein. Wound healing and migration assays were used to determine the cell migration potential. Transforming growth factor (TGF)-beta type I receptor (TbetaRI) inhibitor, SB431542 and phosphoinositide 3-kinase (PI3K) inhibitor, LY294002 were used to determine rapamycin's mechanism of action. It was found that treatment of A549 and normal human alveolar or bronchial epithelial cells with rapamycin significantly promoted basal or TGF-beta1 induced CTGF expression. LY294002, not SB431542 attenuated the promotional effect of rapamycin on CTGF expression. Cell mobility was not affected by rapamycin in wound healing and migration assays. These data suggest rapamycin has a profibrotic effect in vitro and underscore the potential of combined therapeutic approach with PI3K and mammalian target of rapamycin inhibitors for the treatment of animal or human lung fibrosis. PMID- 23986223 TI - Non-Hodgkin's B-cell lymphoma: advances in molecular strategies targeting drug resistance. AB - Non-Hodgkin's lymphoma (NHL) is a heterogeneous class of cancers displaying a diverse range of biological phenotypes, clinical behaviours and prognoses. Standard treatments for B-cell NHL are anthracycline-based combinatorial chemotherapy regimens composed of cyclophosphamide, doxorubicin, vincristine and prednisolone. Even though complete response rates of 40-50% with chemotherapy can be attained, a substantial proportion of patients relapse, resulting in 3-year overall survival rates of about 30%. Relapsed lymphomas are refractory to subsequent treatments with the initial chemotherapy regimen and can exhibit cross resistance to a wide variety of anticancer drugs. The emergence of acquired chemoresistance thus poses a challenge in the clinic preventing the successful treatment and cure of disseminated B-cell lymphomas. Gene-expression analyses have increased our understanding of the molecular basis of chemotherapy resistance and identified rational targets for drug interventions to prevent and treat relapsed/refractory diffuse large B-cell lymphoma. Acquisition of drug resistance in lymphoma is in part driven by the inherent genetic heterogeneity and instability of the tumour cells. Due to the genetic heterogeneity of B-cell NHL, many different pathways leading to drug resistance have been identified. Successful treatment of chemoresistant NHL will thus require the rational design of combinatorial drugs targeting multiple pathways specific to different subtypes of B-cell NHL as well as the development of personalized approaches to address patient-to-patient genetic heterogeneity. This review highlights the new insights into the molecular basis of chemorefractory B-cell NHL that are facilitating the rational design of novel strategies to overcome drug resistance. PMID- 23986224 TI - Cellular mechanisms underlying failed beta cell regeneration in offspring of protein-restricted pregnant mice. AB - Low birth weight and poor foetal growth following low protein (LP) exposure are associated with altered islet development and glucose intolerance in adulthood. Additionally, LP-fed offspring fail to regenerate their beta-cells following depletion with streptozotocin (STZ) in contrast to control-fed offspring that restore beta-cell mass. Our objective was to identify signalling pathways and cellular functions that may be critically altered in LP offspring rendering them susceptible to developing long-term glucose intolerance and decreased beta-cell plasticity. Pregnant Balb/c mice were fed a control (C; 20% protein) or an isocaloric LP (8% protein) diet throughout gestation and C diet thereafter. Female offspring were injected intraperitoneally with 35 mg/kg STZ or vehicle on days 1 to 5 for each dietary treatment. At 30 days of age, total RNA was extracted from pancreatic tissue for microarray analysis using the Affymetrix GeneChip Mouse Genome 430 2.0. Gene and protein expression were quantified from isolated islets. Finally, beta-cell proliferation was determined in vitro following REG1alpha treatment. The microarray data and GO enrichment analysis indicated that foetal protein restriction alters the early expression of genes necessary for many cell functions, such as oxidative phosphorylation and free radical scavenging. Expression of Reg1 was upregulated following STZ, whereas protein content was decreased in LP + STZ islets. Furthermore, REG1alpha failed to stimulate beta-cell proliferation in vitro in LP + STZ islets. Therefore, early nutritional insults may programme the Reg1 pathway resulting in a limited ability to increase beta-cell mass during metabolic stress. In conclusion, this study implicates the Reg1 pathway in beta-cell regeneration and describes altered programming of gene expression in LP offspring, which underlies later development of cell dysfunction and glucose intolerance in adulthood. PMID- 23986225 TI - Topical treatment with the opioid antagonist naltrexone accelerates the remodeling phase of full-thickness wound healing in type 1 diabetic rats. AB - Wound repair involves a series of overlapping phases that include inflammation, proliferation, and tissue remodeling, with the latter phase requiring months for proper healing. Delays in any of these processes can result in infection, chronic ulceration, and possible amputation. Diabetes is a major risk factor for improper wound repair, and impaired wound healing is a major complication for more than 26 million people in the US diagnosed with diabetes. Previous studies have demonstrated that the opioid antagonist naltrexone (NTX) dissolved in moisturizing cream reverses delays in wound closure in streptozotocin-induced type 1 diabetic (T1D) rats. NTX accelerated DNA synthesis and increased the number of epithelial and mast cells, as well as new blood vessel formation. In this study, remodeling was evaluated in T1D rats up to eight weeks after initial wounding. Twenty days following wounding, diabetic rats treated with vehicle had elevated numbers of MMP-2+ fibroblasts, suggesting delayed healing processes; birefringence of granulation tissue stained with Sirius red revealed diminished collagen formation and maturation. Wound tissue from NTX-treated T1D rats had comparable numbers of MMP-2+ fibroblasts to control specimens, as well as accelerated maturation of granulation tissue. The integrity of wounded skin was evaluated by tensile strength measurements. T1D resulted in delayed wound healing, and wounded skin that displayed reduced tensile strength relative to normal rats. Topical NTX applied to wounds in T1D rats resulted in enhanced collagen formation and maturation over a 60-day period of time. Moreover, the force required to tear skin of NTX-treated T1D rats was elevated relative to the force necessary to tear the skin of vehicle-treated T1D rats, and comparable to that for normal rats. These data reveal that complications in wound healing associated with T1D involve the novel OGF-OGFr pathway, and that topical NTX is an effective treatment to enhance wound healing. PMID- 23986226 TI - Synergistic effects of prostacyclin analogs and phosphodiesterase inhibitors on cyclic adenosine 3',5' monophosphate accumulation and adenosine 3'5' triphosphate release from human erythrocytes. AB - Prostacyclin (PGI2) and phosphodiesterase 5 (PDE5) inhibitors are potent vasodilators that are used alone and in combination for the treatment of pulmonary arterial hypertension (PAH). Although these vasodilators are known to stimulate relaxation of vascular smooth muscle directly, other cells in circulation, including erythrocytes, express prostacyclin receptor (IPR) and contain PDE5. The binding of PGI2 analogs to the erythrocyte IPR results in activation of a signaling pathway that increases cyclic adenosine 3',5' monophosphate (cAMP), a requirement for adenosine 3'5' triphosphate (ATP) release. Within this pathway, cAMP levels are regulated by phosphodiesterase 3 (PDE3), a PDE that is inhibited by cGMP, a cyclic nucleotide regulated by the activity of PDE5. Since inhibition of PDE3 enhances ATP release in response to PGI2 analogs, we investigated if the selective PDE5 inhibitors, zaprinast (ZAP) and tadalafil (TAD), would similarly increase cAMP and ATP release from human erythrocytes in response to the same stimulus. We determined that pretreatment of erythrocytes with one of two chemically dissimilar PDE5 inhibitors (ZAP or TAD, 10 uM) potentiated increases in cAMP and ATP release in response to incubation of human erythrocytes with the PGI2 analog, UT-15C (100 nM). These results suggest that a heretofore unrecognized synergism exists between IPR agonists and PDE5 inhibitors that could provide a new rationale for the co-administration of these agents as vasodilators in humans with PAH. PMID- 23986227 TI - Acceptor-donor-acceptor-based small molecules with varied crystallinity: processing additive-induced nanofibril in blend film for photovoltaic applications. AB - A series of acceptor-donor-acceptor-based small molecules (SMs) with varied crystallinity were successfully synthesized. The processing additive can induce the SMs to self-organize as nanofibrils with higher crystallinity and controlled scales of nanofibrils, which have significant influence on the photovoltaic performance. PMID- 23986228 TI - Understanding molecular mechanisms of traditional Chinese medicine for the treatment of influenza viruses infection by computational approaches. AB - The battle against influenza is an enduring one. For hundreds of years, people have fought such small viruses with practices such as traditional Chinese medicine (TCM), however only recently has it been possible to use cutting-edge technology to investigate their mechanisms. Here, we re-created this ancient Chinese knowledge to explore the chemistry of herbs and elucidate their mechanism of action using molecular computational methods. Our results show that TCM compounds can inhibit influenza viral proteins in a multi-target/multi-component manner, revealing the versatility of TCM for treating different influenza virus subtypes, including the recently emerged H7N9. PMID- 23986229 TI - Illuminating the opponent process: cocaine effects on habenulomesencephalic circuitry. PMID- 23986230 TI - Thalamic afferents and neocortical arealization: an ongoing journey. PMID- 23986231 TI - Emergent properties of the optic tectum revealed by population analysis of direction and orientation selectivity. AB - How local circuits within the brain process visual information has classically been addressed at the single neuron level. Such reductionist approaches, however, struggle to capture the full scope of functional properties associated with even "simple" brain nuclei. Using population functional calcium imaging, we aim to describe how local circuits within the zebrafish optic tectum process visual information. Specifically, how are previously identified direction-selective (DS) and orientation-selective (OS) retinal ganglion cell (RGC) inputs (Nikolaou et al., 2012) represented in tectal cells? First, we identify an emergent population of DS tectal cell with a direction preference not explicitly present in any one of the RGC inputs. Second, this is associated with a striking shift from a tiled and triangular representation of directional space (RGC inputs) into an overlapping cardinal representation by tectal cell populations. Third, and in contrast, we find that orientation space is represented similarly in both the RGC input and tectal cell populations illustrating feature-dependent differences in how tectal circuits process their inputs. Finally, we identify OS and two populations of DS cells at the superficial border of the tectal neuropil, one of which is an emergent population. This study, together with our previous one (Nikolaou et al., 2012), demonstrate that direction-selectivity is established in both the retina and tectum. PMID- 23986233 TI - Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons. AB - Neuronal respiration is controlled by ATP demand and Ca2+ but the roles played by each are unknown, as any Ca2+ signal also impacts on ATP demand. Ca2+ can control mitochondrial function through Ca2+-regulated mitochondrial carriers, the aspartate-glutamate and ATP-Mg/Pi carriers, ARALAR/AGC1 and SCaMC-3, respectively, or in the matrix after Ca2+ transport through the Ca2+ uniporter. We have studied the role of Ca2+ signaling in the regulation of mitochondrial respiration in intact mouse cortical neurons in basal conditions and in response to increased workload caused by increases in [Na+]cyt (veratridine, high-K+ depolarization) and/or [Ca2+]cyt (carbachol). Respiration in nonstimulated neurons on 2.5-5 mm glucose depends on ARALAR-malate aspartate shuttle (MAS), with a 46% drop in aralar KO neurons. All stimulation conditions induced increased OCR (oxygen consumption rate) in the presence of Ca2+, which was prevented by BAPTA-AM loading (to preserve the workload), or in Ca2+-free medium (which also lowers cell workload). SCaMC-3 limits respiration only in response to high workloads and robust Ca2+ signals. In every condition tested Ca2+ activation of ARALAR-MAS was required to fully stimulate coupled respiration by promoting pyruvate entry into mitochondria. In aralar KO neurons, respiration was stimulated by veratridine, but not by KCl or carbachol, indicating that the Ca2+ uniporter pathway played a role in the first, but not in the second condition, even though KCl caused an increase in [Ca2+]mit. The results suggest a requirement for ARALAR-MAS in priming pyruvate entry in mitochondria as a step needed to activate respiration by Ca2+ in response to moderate workloads. PMID- 23986232 TI - A systems-based dissection of retinal inputs to the zebrafish tectum reveals different rules for different functional classes during development. AB - We have examined the form, diversity, and organization of three functional classes of retinal inputs to the zebrafish optic tectum during development. Our systems-based approach was to analyze data from populations of retinal ganglion cells labeled with a presynaptic targeted calcium indicator, synaptophysin GCaMP3 (SyGCaMP3). Collectively, our findings provide an insight as to the degree of visual encoding during retino-tectal development and how it dynamically evolves from a nascent and noisy presynaptic neural-scape to an increasingly complex and refined representation. We report five key features: (1) direction-selective inputs are developmentally invariant; (2) orientation-selective inputs exhibit highly dynamic properties over the same period, with changes in their functional characteristics and spatial organization; (3) inputs defined as anisotropic are an early dominant functional class, with heterogeneous response profiles, which progressively diminish in incidence and spatial extent; (4) dark rearing selectively affects the orientation-selective responses: both functional characteristics and relative spatial distributions; and (5) orientation-selective inputs exhibit four subtypes, two more than previously identified in any species. Our approach was to label RGC axon terminals with an indicator of activity and quantitatively characterize coherent response properties to different visual stimuli. Its application in the zebrafish, given its small size and the accessibility of the tectum, has enabled a quick yet robust assessment of multiple functional populations of responses. PMID- 23986234 TI - Block of gap junctions eliminates aberrant activity and restores light responses during retinal degeneration. AB - Retinal degeneration leads to progressive photoreceptor cell death, resulting in vision loss. Subsequently, inner retinal neurons develop aberrant synaptic activity, compounding visual impairment. In retinal ganglion cells, light responses driven by surviving photoreceptors are obscured by elevated levels of aberrant spiking activity. Here, we demonstrate in rd10 mice that targeting disruptive neuronal circuitry with a gap junction antagonist can significantly reduce excessive spiking. This treatment increases the sensitivity of the degenerated retina to light stimuli driven by residual photoreceptors. Additionally, this enhances signal transmission from inner retinal neurons to ganglion cells, potentially allowing the retinal network to preserve the fidelity of signals either from prosthetic electronic devices, or from cells optogenetically modified to transduce light. Thus, targeting maladaptive changes to the retina allows for treatments to use existing neuronal tissue to restore light sensitivity, and to augment existing strategies to replace lost photoreceptors. PMID- 23986235 TI - Raphe GABAergic neurons mediate the acquisition of avoidance after social defeat. AB - Serotonin (5-HT) modulates neural responses to socioaffective cues and can bias approach or avoidance behavioral decisions, yet the cellular mechanisms underlying its contribution to the regulation of social experiences remain poorly understood. We hypothesized that GABAergic neurons in the dorsal raphe nucleus (DRN) may participate in socioaffective regulation by controlling serotonergic tone during social interaction. We tested this hypothesis using whole-cell recording techniques in genetically identified DRN GABA and 5-HT neurons in mice exposed to social defeat, a model that induces long-lasting avoidance behaviors in a subset of mice responsive to serotonergic antidepressants. Our results revealed that social defeat engaged DRN GABA neurons and drove GABAergic sensitization that strengthened inhibition of 5-HT neurons in mice that were susceptible, but not resilient to social defeat. Furthermore, optogenetic silencing of DRN GABA neurons disinhibited neighboring 5-HT neurons and prevented the acquisition of social avoidance in mice exposed to a social threat, but did not affect a previously acquired avoidance phenotype. We provide the first characterization of GABA neurons in the DRN that monosynaptically inhibit 5-HT neurons and reveal their key role in neuroplastic processes underlying the development of social avoidance. PMID- 23986236 TI - Cue-evoked cocaine "craving": role of dopamine in the accumbens core. AB - Drug-associated cues can acquire powerful motivational control over the behavior of addicts, and can contribute to relapse via multiple, dissociable mechanisms. Most preclinical models of relapse focus on only one of these mechanisms: the ability of drug cues to reinforce drug-seeking actions following a period of extinction training. However, in addicts, drug cues typically do not follow seeking actions; they precede them. They often produce relapse by evoking a conditioned motivational state ("wanting" or "craving") that instigates and/or invigorates drug-seeking behavior. Here we used a conflict-based relapse model to ask whether individual variation in the propensity to attribute incentive salience to reward cues predicts variation in the ability of a cocaine cue to produce conditioned motivation (craving) for cocaine. Following self administration training, responding was curtailed by requiring rats to cross an electrified floor to take cocaine. The subsequent response-independent presentation of a cocaine-associated cue was sufficient to reinstate drug-seeking behavior, despite the continued presence of the adverse consequence. Importantly, there were large individual differences in the motivational properties of the cocaine cue, which were predicted by variation in the propensity to attribute incentive salience to a food cue. Finally, a dopamine antagonist injected into the nucleus accumbens core attenuated, and amphetamine facilitated, cue-evoked cocaine seeking, implicating dopamine signaling in cocaine cue-evoked craving. These data provide a promising preclinical approach for studying sources of individual variation in susceptibility to relapse due to conditioned craving and implicate mesolimbic dopamine in this process. PMID- 23986237 TI - Postnatal refinement of auditory hair cell planar polarity deficits occurs in the absence of Vangl2. AB - The distinctive planar polarity of auditory hair cells is evident in the polarized organization of the stereociliary bundle. Mutations in the core planar cell polarity gene Van Gogh-like 2 (Vangl2) result in hair cells that fail to properly orient their stereociliary bundles along the mediolateral axis of the cochlea. The severity of this phenotype is graded along the length of the cochlea, similar to the hair cell differentiation gradient, suggesting that an active refinement process corrects planar polarity phenotypes in Vangl2 knock-out (KO) mice. Because Vangl2 gene deletions are lethal, Vangl2 conditional knock outs (CKOs) were generated to test this hypothesis. When crossed with Pax2-Cre, Vangl2 is deleted from the inner ear, yielding planar polarity phenotypes similar to Vangl2 KOs at late embryonic stages except that Vangl2 CKO mice are viable and do not have craniorachischisis like Vangl2 KOs. Quantification of planar polarity deficits through postnatal development demonstrates the activity of a Vangl2 independent refinement process that rescues the planar polarity phenotype within 10 d of birth. In contrast, the Pax2-Cre;Vangl2 CKO has profound changes in the shape and distribution of outer pillar cell and Deiters' cell phalangeal processes that are not corrected during the period of planar polarity refinement. Auditory brainstem response analyses of adult mice show a 10-15 dB shift in auditory threshold, and distortion product otoacoustic emission measurements indicate that this mild hearing deficit is of cochlear origin. Together, these data demonstrate a Vangl2-independent refinement mechanism that actively reorients auditory stereociliary bundles and reveals an unexpected role of Vangl2 during supporting cell morphogenesis. PMID- 23986239 TI - Echoes of the brain within default mode, association, and heteromodal cortices. AB - Intrinsic connectivity networks (ICNs), such as the default mode, frontoparietal control, and salience networks, provide a useful large-scale description of the functional architecture of the brain. Although ICNs are functionally specialized, the information that they process needs to be integrated for coherent cognition, perception, and behavior. A region capable of performing this integration might be expected to contain traces, or "echoes," of the neural signals from multiple ICNs. Here, using fMRI in humans, we show the existence of specific "transmodal" regions containing echoes of multiple ICNs. These regions include core nodes of the default mode network, as well as multimodal association regions of the temporoparietal and temporo-occipito-parietal junction, right middle frontal gyrus, and dorsal anterior cingulate cortex. In contrast, "unimodal" regions such as the primary sensory and motor cortices show a much more singular pattern of activity, containing traces of few or even single ICNs. The presence of ICN echoes might explain how transmodal regions are involved in multiple different cognitive states. Our results suggest that these transmodal regions have a particular local spatial organization containing topographic maps that relate to multiple ICNs. This makes transmodal regions uniquely placed to be able to mediate the cross talk between the brain's functional networks through local modulation of adjacent regions that communicate with different ICNs. PMID- 23986240 TI - Working memory and anticipatory set modulate midbrain and putamen activity. AB - To behave adaptively, an organism must balance the accurate maintenance of information stored in working memory with the ability to update that information when the context changes. This trade-off between fidelity and flexibility may depend upon the anticipated likelihood that updating will be necessary. To address the neurobiological basis of anticipatory optimization, we acquired functional magnetic resonance imaging data, while healthy human subjects performed a modified delayed-response task. This task used cues that predicted memory updating, with high or low probability, followed by a contingent updating or maintenance event. This enabled us to compare behavior and neuronal activity during conditions in which updating was anticipated with high and low probability, and measure responses to expected and unexpected memory updating. Based on the known role of dopamine in cognitive flexibility and working memory updating, we hypothesized that differences in anticipatory set would be manifest in the dopaminergic midbrain and striatum. Consistent with our predictions, we identified sustained activation in the dopaminergic midbrain and the striatum, associated with anticipations of high versus low updating probability. We also found that this anticipatory factor affected neural responses to subsequent updating processes, which suppressed, rather than elevated, midbrain and striatal activity. Our study addresses for the first time an important and hitherto understudied aspect of working memory. PMID- 23986238 TI - Cortico-amygdala-striatal circuits are organized as hierarchical subsystems through the primate amygdala. AB - The prefrontal and insula cortex, amygdala, and striatum are key regions for emotional processing, yet the amygdala's role as an interface between the cortex and striatum is not well understood. In the nonhuman primate (Macaque fascicularis), we analyzed a collection of bidirectional tracer injections in the amygdala to understand how cortical inputs and striatal outputs are organized to form integrated cortico-amygdala-striatal circuits. Overall, diverse prefrontal and insular cortical regions projected to the basal and accessory basal nuclei of the amygdala. In turn, these amygdala regions projected to widespread striatal domains extending well beyond the classic ventral striatum. Analysis of the cases in aggregate revealed a topographic colocalization of cortical inputs and striatal outputs in the amygdala that was additionally distinguished by cortical cytoarchitecture. Specifically, the degree of cortical laminar differentiation of the cortical inputs predicted amygdalostriatal targets, and distinguished three main cortico-amygdala-striatal circuits. These three circuits were categorized as "primitive," "intermediate," and "developed," respectively, to emphasize the relative phylogenetic and ontogenetic features of the cortical inputs. Within the amygdala, these circuits appeared arranged in a pyramidal-like fashion, with the primitive circuit found in all examined subregions, and subsequent circuits hierarchically layered in discrete amygdala subregions. This arrangement suggests a stepwise integration of the functions of these circuits across amygdala subregions, providing a potential mechanism through which internal emotional states are managed with external social and sensory information toward emotionally informed complex behaviors. PMID- 23986241 TI - Scaling of topologically similar functional modules defines mouse primary auditory and somatosensory microcircuitry. AB - Mapping the flow of activity through neocortical microcircuits provides key insights into the underlying circuit architecture. Using a comparative analysis we determined the extent to which the dynamics of microcircuits in mouse primary somatosensory barrel field (S1BF) and auditory (A1) neocortex generalize. We imaged the simultaneous dynamics of up to 1126 neurons spanning multiple columns and layers using high-speed multiphoton imaging. The temporal progression and reliability of reactivation of circuit events in both regions suggested common underlying cortical design features. We used circuit activity flow to generate functional connectivity maps, or graphs, to test the microcircuit hypothesis within a functional framework. S1BF and A1 present a useful test of the postulate as both regions map sensory input anatomically, but each area appears organized according to different design principles. We projected the functional topologies into anatomical space and found benchmarks of organization that had been previously described using physiology and anatomical methods, consistent with a close mapping between anatomy and functional dynamics. By comparing graphs representing activity flow we found that each region is similarly organized as highlighted by hallmarks of small world, scale free, and hierarchical modular topologies. Models of prototypical functional circuits from each area of cortex were sufficient to recapitulate experimentally observed circuit activity. Convergence to common behavior by these models was accomplished using preferential attachment to scale from an auditory up to a somatosensory circuit. These functional data imply that the microcircuit hypothesis be framed as scalable principles of neocortical circuit design. PMID- 23986242 TI - Joint representation of depth from motion parallax and binocular disparity cues in macaque area MT. AB - Perception of depth is based on a variety of cues, with binocular disparity and motion parallax generally providing more precise depth information than pictorial cues. Much is known about how neurons in visual cortex represent depth from binocular disparity or motion parallax, but little is known about the joint neural representation of these depth cues. We recently described neurons in the middle temporal (MT) area that signal depth sign (near vs far) from motion parallax; here, we examine whether and how these neurons also signal depth from binocular disparity. We find that most MT neurons in rhesus monkeys (Macaca Mulatta) are selective for depth sign based on both disparity and motion parallax cues. However, the depth-sign preferences (near or far) are not always aligned: 56% of MT neurons have matched depth-sign preferences ("congruent" cells) whereas the remaining 44% of neurons prefer near depth from motion parallax and far depth from disparity, or vice versa ("opposite" cells). For congruent cells, depth-sign selectivity increases when disparity cues are added to motion parallax, but this enhancement does not occur for opposite cells. This suggests that congruent cells might contribute to perceptual integration of depth cues. We also found that neurons are clustered in MT according to their depth tuning based on motion parallax, similar to the known clustering of MT neurons for binocular disparity. Together, these findings suggest that area MT is involved in constructing a representation of 3D scene structure that takes advantage of multiple depth cues available to mobile observers. PMID- 23986244 TI - Small-fiber neuropathy Nav1.8 mutation shifts activation to hyperpolarized potentials and increases excitability of dorsal root ganglion neurons. AB - Idiopathic small-fiber neuropathy (I-SFN), clinically characterized by burning pain in distal extremities and autonomic dysfunction, is a disorder of small caliber nerve fibers of unknown etiology with limited treatment options. Functional variants of voltage-gated sodium channel Nav1.7, encoded by SCN9A, have been identified in approximately one-third of I-SFN patients. These variants render dorsal root ganglion (DRG) neurons hyperexcitable. Sodium channel Nav1.8, encoded by SCN10A, is preferentially expressed in small-diameter DRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutations in SCN9A, and report a novel I-SFN-related Nav1.8 mutation I1706V in a patient with painful I-SFN. Whole-cell voltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistent current, and show that these pro-excitatory gating changes confer hyperexcitability on peripheral sensory neurons, which may contribute to pain in this individual with I-SFN. PMID- 23986243 TI - Dopamine D2 receptors regulate collateral inhibition between striatal medium spiny neurons. AB - The principle neurons of the striatum are GABAergic medium spiny neurons (MSNs), whose collateral synapses onto neighboring neurons play critical roles in striatal function. MSNs can be divided by dopamine receptor expression into D1 class and D2-class MSNs, and alterations in D2 MSNs are associated with various pathological states. Despite overwhelming evidence for D2 receptors (D2Rs) in maintaining proper striatal function, it remains unclear how MSN collaterals are specifically altered by D2R activation. Here, we report that chronic D2R stimulation regulates MSN collaterals in vitro by presynaptic and postsynaptic mechanisms. We used corticostriatal cultures from mice in which MSN subtypes were distinguished by fluorophore expression. Quinpirole, an agonist for D2/3 receptors, was used to chronically activate D2Rs. Quinpirole increased the rate and strength of collateral formation onto D2R-containing MSNs as measured by dual whole-cell patch-clamp recordings. Additionally, these neurons were more sensitive to low concentrations of GABA and exhibited an increase in gephyrin puncta density, suggesting increased postsynaptic GABAA receptors. Last, quinpirole treatment increased presynaptic GABA release sites, as shown by increased frequency of sIPSCs and mIPSCs, correlating with increased VGAT (vesicular GABA transporter) puncta. Combined with the observation that there were no detectable differences in sensitivity to specific GABAA receptor modulators, we provide evidence that D2R activation powerfully transforms MSN collaterals via coordinated presynaptic and postsynaptic alterations. As the D2 class of MSNs is highly implicated in Parkinson's disease and other neurological disorders, our findings may contribute to understanding and treating the changes that occur in these pathological states. PMID- 23986245 TI - Neural networks of colored sequence synesthesia. AB - Synesthesia is a condition in which normal stimuli can trigger anomalous associations. In this study, we exploit synesthesia to understand how the synesthetic experience can be explained by subtle changes in network properties. Of the many forms of synesthesia, we focus on colored sequence synesthesia, a form in which colors are associated with overlearned sequences, such as numbers and letters (graphemes). Previous studies have characterized synesthesia using resting-state connectivity or stimulus-driven analyses, but it remains unclear how network properties change as synesthetes move from one condition to another. To address this gap, we used functional MRI in humans to identify grapheme specific brain regions, thereby constructing a functional "synesthetic" network. We then explored functional connectivity of color and grapheme regions during a synesthesia-inducing fMRI paradigm involving rest, auditory grapheme stimulation, and audiovisual grapheme stimulation. Using Markov networks to represent direct relationships between regions, we found that synesthetes had more connections during rest and auditory conditions. We then expanded the network space to include 90 anatomical regions, revealing that synesthetes tightly cluster in visual regions, whereas controls cluster in parietal and frontal regions. Together, these results suggest that synesthetes have increased connectivity between grapheme and color regions, and that synesthetes use visual regions to a greater extent than controls when presented with dynamic grapheme stimulation. These data suggest that synesthesia is better characterized by studying global network dynamics than by individual properties of a single brain region. PMID- 23986246 TI - Neuropeptides amplify and focus the monoaminergic inhibition of nociception in Caenorhabditis elegans. AB - Monoamines and neuropeptides interact to modulate most behaviors. To better understand these interactions, we have defined the roles of tyramine (TA), octopamine, and neuropeptides in the inhibition of aversive behavior in Caenorhabditis elegans. TA abolishes the serotonergic sensitization of aversive behavior mediated by the two nociceptive ASH sensory neurons and requires the expression of the adrenergic-like, Galphaq-coupled, TA receptor TYRA-3 on inhibitory monoaminergic and peptidergic neurons. For example, TA inhibition requires Galphaq and Galphas signaling in the peptidergic ASI sensory neurons, with an array of ASI neuropeptides activating neuropeptide receptors on additional neurons involved in locomotory decision-making. The ASI neuropeptides required for tyraminergic inhibition are distinct from those required for octopaminergic inhibition, suggesting that individual monoamines stimulate the release of different subsets of ASI neuropeptides. Together, these results demonstrate that a complex humoral mix of monoamines is focused by more local, synaptic, neuropeptide release to modulate nociception and highlight the similarities between the tyraminergic/octopaminergic inhibition of nociception in C. elegans and the noradrenergic inhibition of nociception in mammals that also involves inhibitory peptidergic signaling. PMID- 23986247 TI - Differences in neural activation for object-directed grasping in chimpanzees and humans. AB - The human faculty for object-mediated action, including tool use and imitation, exceeds that of even our closest primate relatives and is a key foundation of human cognitive and cultural uniqueness. In humans and macaques, observing object directed grasping actions activates a network of frontal, parietal, and occipitotemporal brain regions, but differences in human and macaque activation suggest that this system has been a focus of selection in the primate lineage. To study the evolution of this system, we performed functional neuroimaging in humans' closest living relatives, chimpanzees. We compare activations during performance of an object-directed manual grasping action, observation of the same action, and observation of a mimed version of the action that consisted of only movements without results. Performance and observation of the same action activated a distributed frontoparietal network similar to that reported in macaques and humans. Like humans and unlike macaques, these regions were also activated by observing movements without results. However, in a direct chimpanzee/human comparison, we also identified unique aspects of human neural responses to observed grasping. Chimpanzee activation showed a prefrontal bias, including significantly more activity in ventrolateral prefrontal cortex, whereas human activation was more evenly distributed across more posterior regions, including significantly more activation in ventral premotor cortex, inferior parietal cortex, and inferotemporal cortex. This indicates a more "bottom-up" representation of observed action in the human brain and suggests that the evolution of tool use, social learning, and cumulative culture may have involved modifications of frontoparietal interactions. PMID- 23986248 TI - Using IQ discrepancy scores to examine the neural correlates of specific cognitive abilities. AB - The underlying neural determinants of general intelligence have been studied intensively, and seem to derive from the anatomical and functional characteristics of a frontoparietal network. Little is known, however, about the underlying neural correlates of domain-specific cognitive abilities, the other factors hypothesized to explain individual performance on intelligence tests. Previous preliminary studies have suggested that spatially distinct neural structures do not support domain-specific cognitive abilities. To test whether differences between abilities that affect performance on verbal and performance tasks derive instead from the morphological features of a single anatomical network, we assessed in two independent samples of healthy human participants (N=83 and N=58; age range, 5-57 years) the correlation of cortical thickness with the magnitude of the verbal intelligence quotient (VIQ)-performance intelligence quotient (PIQ) discrepancy. We operationalized the VIQ-PIQ discrepancy by regressing VIQ onto PIQ (VIQ-regressed-on-PIQ score), and by regressing PIQ onto VIQ (PIQ-regressed-on-VIQ score). In both samples, a progressively thinner cortical mantle in anterior and posterior regions bilaterally was associated with progressively greater (more positive) VIQ-regressed-on-PIQ scores. A progressively thicker cortical mantle in anterior and posterior regions bilaterally was associated with progressively greater (more positive) PIQ regressed-on-VIQ scores. Variation in cortical thickness in these regions accounted for a large portion of the overall variance in magnitude of the VIQ-PIQ discrepancy. The degree of hemispheric asymmetry in cortical thickness accounted for a much smaller but statistically significant portion of variance in VIQ-PIQ discrepancy. PMID- 23986249 TI - Extrasynaptic muscarinic acetylcholine receptors on neuronal cell bodies regulate presynaptic function in Caenorhabditis elegans. AB - Acetylcholine (ACh) is a potent neuromodulator in the brain, and its effects on cognition and memory formation are largely performed through muscarinic acetylcholine receptors (mAChRs). mAChRs are often preferentially distributed on specialized membrane regions in neurons, but the significance of mAChR localization in modulating neuronal function is not known. Here we show that the Caenorhabditis elegans homolog of the M1/M3/M5 family of mAChRs, gar-3, is expressed in cholinergic motor neurons, and GAR-3-GFP fusion proteins localize to cell bodies where they are enriched at extrasynaptic regions that are in contact with the basal lamina. The GAR-3 N-terminal extracellular domain is necessary and sufficient for this asymmetric distribution, and mutation of a predicted N-linked glycosylation site within the N-terminus disrupts GAR-3-GFP localization. In transgenic animals expressing GAR-3 variants that are no longer asymmetrically localized, synaptic transmission at neuromuscular junctions is impaired and there is a reduction in the abundance of the presynaptic protein sphingosine kinase at release sites. Finally, GAR-3 can be activated by endogenously produced ACh released from neurons that do not directly contact cholinergic motor neurons. Together, our results suggest that humoral activation of asymmetrically localized mAChRs by ACh is an evolutionarily conserved mechanism by which ACh modulates neuronal function. PMID- 23986250 TI - Stimulation of mGluR5 in the accumbens shell promotes cocaine seeking by activating PKC gamma. AB - Recent studies indicate a critical role for metabotropic glutamate receptor 5 (mGluR5) in the reinstatement of cocaine seeking. However, the signal transduction pathways through which mGluR5s regulate cocaine seeking have not been identified. Here, we show that intra-accumbens shell administration of an mGluR5 (9.0 MUm MPEP), but not mGluR1 (50.0 MUm YM 298198), antagonist before a priming injection of cocaine (10 mg/kg) attenuated the reinstatement of drug seeking in rats. Consistent with these results, intra-shell microinjection of the mGluR1/5 agonist DHPG (250 MUm) promoted cocaine seeking. Intra-shell administration of a phospholipase C (PLC) inhibitor (40.0 MUm U73122) or a protein kinase C (PKC) inhibitor (10.0 MUm Ro 31-8220 or 30.0 MUm chelerythrine chloride) attenuated cocaine seeking. Pharmacological inhibition of PKC in the shell also blocked intra-shell DHPG-induced reinstatement of cocaine seeking. In addition, cocaine priming-induced reinstatement of drug seeking was associated with increased phosphorylation of PKCgamma, but not PKCalpha or PKCbetaII, in the shell. Cocaine seeking previously was linked to increased phosphorylation of GluA2 at Ser880, a PKC phosphorylation site, which promotes the endocytosis of GluA2-containing AMPA receptors via interactions with Protein Associated with C Kinase (PICK1). The present results indicated that inhibition of PICK1 (100 MUm FSC-231) in the shell attenuated cocaine seeking. There were no effects of any drug treatment in the shell on sucrose seeking. Together, these findings indicate that accumbens shell mGluR5 activation promotes cocaine seeking, in part, through activation of PLC and PKCgamma. Moreover, the endocytosis of shell GluA2 containing AMPARs during cocaine seeking may depend on interactions with PKCgamma and PICK1. PMID- 23986251 TI - Synaptic protein alpha1-takusan mitigates amyloid-beta-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. AB - The synaptic toxicity of soluble amyloid-beta (Abeta) oligomers plays a critical role in the pathophysiology of Alzheimer's disease (AD). Here we report that overexpressed alpha1-takusan, which we previously identified as a protein that enhances synaptic activity via interaction with PSD-95, mitigates oligomeric Abeta-induced synaptic loss. In contrast, takusan knockdown results in enhanced synaptic damage. alpha1-Takusan interacts with tau either directly or indirectly, and prevents Abeta-induced tau hyperphosphorylation and mitochondrial fragmentation. Deletion analysis identified the second domain (D2) within the takusan protein that is required for PSD-95 clustering and synaptic protection from Abeta. A 51 aa sequence linking D2 to the PDZ-binding C terminus was found to be as effective as full-length takusan in protecting synapses from Abeta induced damage. Moreover, a sequence containing the D2 from the human protein discs large homolog 5, when linked to a C-terminal PDZ-binding motif, can also increase the clustering of PSD-95 in cortical dendrites. In summary, alpha1 takusan protects synapses from Abeta-induced insult via interaction with PSD-95 and tau. Thus, takusan-based protein sequences from either mouse or human may be of potential therapeutic benefit in AD. PMID- 23986252 TI - Reversible information flow across the medial temporal lobe: the hippocampus links cortical modules during memory retrieval. AB - A simple cue can be sufficient to elicit vivid recollection of a past episode. Theoretical models suggest that upon perceiving such a cue, disparate episodic elements held in neocortex are retrieved through hippocampal pattern completion. We tested this fundamental assumption by applying functional magnetic resonance imaging (fMRI) while objects or scenes were used to cue participants' recall of previously paired scenes or objects, respectively. We first demonstrate functional segregation within the medial temporal lobe (MTL), showing domain specificity in perirhinal and parahippocampal cortices (for object-processing vs scene-processing, respectively), but domain generality in the hippocampus (retrieval of both stimulus types). Critically, using fMRI latency analysis and dynamic causal modeling, we go on to demonstrate functional integration between these MTL regions during successful memory retrieval, with reversible signal flow from the cue region to the target region via the hippocampus. This supports the claim that the human hippocampus provides the vital associative link that integrates information held in different parts of cortex. PMID- 23986253 TI - Rhythmic whisking area (RW) in rat primary motor cortex: an internal monitor of movement-related signals? AB - Vibrissae-related sensorimotor cortex controls whisking movements indirectly via modulation of lower-level sensorimotor loops and a brainstem central pattern generator (CPG). Two different whisker representations in primary motor cortex (vM1) affect whisker movements in different ways. Prolonged microstimulation in RF, a larger anterior subregion of vM1, gives rise to complex face movements and whisker retraction while the same stimulation evokes large-amplitude rhythmic whisker movement in a small caudo-medial area (RW). To characterize the motor cortex representation of explorative whisking movements, here we recorded RW units in head-fixed rats trained to contact a moving object with one whisker. RW single units were found to encode two aspects of whisker movement independently, albeit on slow time scales (hundreds of milliseconds). The first is whisker position. The second consists of speed (absolute velocity), intensity (instantaneous power), and frequency (spectral centroid). The coding for the latter three parameters was tightly correlated and realized by a continuum of RW responses-ranging from a preference of movement to a preference of rest. Information theory analysis indicated that RW spikes carry most information about position and frequency, while intensity and speed are less well represented. Further, investigating multiple and single RW units, we found a lack of phase locking, movement anticipation, and contact-related tactile responses. These findings suggest that RW neither programs detailed whisker trajectories nor initiates them. Nor does it play a role in processing object touch. Its relationship to whisking is thus indirect and may be related to movement monitoring, perhaps using feedback from the CPG. PMID- 23986254 TI - Ventral tegmental dopamine dysregulation prevents appetitive memory destabilization. AB - Through the process of reconsolidation, memories can be updated to maintain their relevance. To reconsolidate, a memory must first be destabilized in a process that we have hypothesized is initiated by a prediction error signal. Here we demonstrate that dysregulation of ventral tegmental area (VTA) signaling, which is thought to mediate prediction errors, prevented the destabilization of an appetitive goal-tracking memory in rats. We additionally show that intra-VTA infusion of either the competitive NMDA antagonist AP5 or the noncompetitive NMDA antagonist MK-801 does not selectively disrupt reconsolidation, indicating that the VTA may not be an important neural locus of reconsolidation-related neural plasticity. PMID- 23986255 TI - Theta oscillations in the medial prefrontal cortex are modulated by spatial working memory and synchronize with the hippocampus through its ventral subregion. AB - The rodent medial prefrontal cortex (mPFC) is critical for spatial working memory (SWM), but the underlying neural processes are incompletely understood. During SWM tasks, neural activity in the mPFC becomes synchronized with theta oscillations in the hippocampus, and the strength of hippocampal-prefrontal synchrony is correlated with behavioral performance. However, to what extent the mPFC generates theta oscillations and whether they are also modulated by SWM remains unclear. Furthermore, it is not known how theta oscillations in the mPFC are synchronized with theta oscillations in the hippocampus. Although the ventral hippocampus (vHPC) projects directly to the mPFC, previous studies have only examined synchrony between the mPFC and the dorsal hippocampus (dHPC), with which it is not directly connected. To address these issues, we recorded simultaneously from the dHPC, vHPC, and mPFC of mice performing a SWM task in a T-maze. The local field potential recorded in the mPFC displayed robust theta oscillations that were reflected in local measures of neuronal activity and modulated by SWM performance. mPFC theta oscillations were also synchronized with theta oscillations in both the vHPC and dHPC, and the magnitude of theta synchrony was modulated by SWM. Removing the influence of the vHPC either computationally (through partial correlations) or experimentally (through pharmacological inactivation) reduced theta synchrony between the mPFC and dHPC. These results reveal theta oscillations as a prominent feature of neural activity in the mPFC and a candidate neural mechanism underlying SWM. Furthermore, our results suggest that the vHPC plays a major role in synchronizing theta oscillations in the mPFC and the hippocampus. PMID- 23986256 TI - Better safe than sorry? The safety margin surrounding the body is increased by anxiety. AB - The defensive peripersonal space represents a "safety margin" advantageous for survival. Its spatial extension and the possible relationship with personality traits have never been investigated. Here, in a population of 15 healthy human participants, we show that the defensive peripersonal space has a sharp boundary, located between 20 and 40 cm from the face, and that within such space there is a thin, "highest-risk area" closest to the face (i.e., an "ultra-near" defensive space). Single-subject analysis revealed clear interindividual differences in the extension of such peripersonal space. These differences are positively related to individual variability in trait anxiety. These findings point to the potential for measuring a range of defensive behaviors in relation to individual levels of anxiety. Such measures will allow developing procedures to test risk assessment abilities, particularly in professions that require reacting quickly to aversive stimuli near the body, such as firemen, policemen, and military officers. This may also lead to possible interventions to improve their performance under pressure. PMID- 23986257 TI - PD-L1 expression by neurons nearby tumors indicates better prognosis in glioblastoma patients. AB - Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor. In general, tumor growth requires disruption of the tissue microenvironment, yet how this affects glioma progression is unknown. We studied program death-ligand (PD L)1 in neurons and gliomas in tumors from GBM patients and associated the findings with clinical outcome. Remarkably, we found that upregulation of PD-L1 by neurons in tumor-adjacent brain tissue (TABT) associated positively with GBM patient survival, whereas lack of neuronal PD-L1 expression was associated with high PD-L1 in tumors and unfavorable prognosis. To understand the molecular mechanism of PD-L1 signaling in neurons, we investigated PD-L1 function in cerebellar and cortical neurons and its impact on gliomas. We discovered that neuronal PD-L1-induced caspase-dependent apoptosis of glioma cells. Because interferon (IFN)-beta induces PD-L1 expression, we studied the functional consequences of neuronal Ifnb gene deletion on PD-L1 signaling and function. Ifnb /- neurons lacked PD-L1 and were defective in inducing glioma cell death; this effect was reversed on PD-L1 gene transfection. Ifnb-/- mice with intracerebral isografts survived poorly. Similar to the observations in GBM patients, better survival in wild-type mice was associated with high neuronal PD-L1 in TABT and downregulation of PD-L1 in tumors, which was defective in Ifnb-/- mice. Our data indicated that neuronal PD-L1 signaling in brain cells was important for GBM patient survival. Reciprocal PD-L1 regulation in TABT and tumor tissue could be a prognostic biomarker for GBM. Understanding the complex interactions between tumor and adjacent stromal tissue is important in designing targeted GBM therapies. PMID- 23986258 TI - TGF-beta signaling protects retinal neurons from programmed cell death during the development of the mammalian eye. AB - We investigated the influence of transforming growth factor-beta (TGF-beta) signaling on developmental programmed cell death in the mouse retina by direct and specific molecular targeting of TGF-beta type II receptor (TbetaRII) and Smad7 in retinal progenitor cells. Mice were generated carrying a conditional deletion of the TbetaRII in cells that originate from the inner layer of the optic cup. The animals showed a significant decrease of phosphorylated Smad3 in both the central and peripheral retina, which indicates the diminished activity of TGF-beta signaling. TbetaRII deficiency significantly increased the apoptotic death of retinal neurons during embryonic and postnatal development without affecting their proliferation. In contrast, treatment with TGF-beta2 inhibited cell death of retinal ganglion cells in dissociated retinal cell cultures, an effect that was blocked by inhibiting the phosphorylation of Smad3. The increase in apoptosis during development resulted in a significant reduction in the number of neurons in adult TbetaRII-deficient mice. The effect was most pronounced in the inner retina neurons and resulted in functional deficits as determined by electroretinography. In contrast, a conditional deletion of TGF-beta-inhibiting Smad7 in retinal neurons significantly enhanced Smad3 phosphorylation and significantly decreased apoptosis of retinal neurons in embryos and pups. Moreover, the number of retinal ganglion cells was significantly higher in Smad7 deficient mice compared with control littermates. TbetaRII-deficient pups showed a lower level of nerve growth factor (NGF) in its mRNA; however, higher levels were observed in Smad7-deficient pups, which strongly suggests that the protective effects of TGF-beta signaling on developmental cell death are mediated through NGF. PMID- 23986259 TI - Optimal multimodal integration in spatial localization. AB - Saccadic eye movements facilitate rapid and efficient exploration of visual scenes, but also pose serious challenges to establishing reliable spatial representations. This process presumably depends on extraretinal information about eye position, but it is still unclear whether afferent or efferent signals are implicated and how these signals are combined with the visual input. Using a novel gaze-contingent search paradigm with highly controlled retinal stimulation, we examined the performance of human observers in locating a previously fixated target after a variable number of saccades, a task that generates contrasting predictions for different updating mechanisms. We show that while localization accuracy is unaffected by saccades, localization precision deteriorates nonlinearly, revealing a statistically optimal combination of retinal and extraretinal signals. These results provide direct evidence for optimal multimodal integration in the updating of spatial representations and elucidate the contributions of corollary discharge signals and eye proprioception. PMID- 23986260 TI - Na+/K+-ATPase is a new interacting partner for the neuronal glycine transporter GlyT2 that downregulates its expression in vitro and in vivo. AB - The neuronal glycine transporter GlyT2 plays a fundamental role in the glycinergic neurotransmission by recycling the neurotransmitter to the presynaptic terminal. GlyT2 is the main supplier of glycine for vesicle refilling, a process that is absolutely necessary to preserve quantal glycine content in synaptic vesicles. Alterations in GlyT2 activity modify glycinergic neurotransmission and may underlie several neuromuscular disorders, such as hyperekplexia, myoclonus, dystonia, and epilepsy. Indeed, mutations in the gene encoding GlyT2 are the main presynaptic cause of hyperekplexia in humans and produce congenital muscular dystonia type 2 (CMD2) in Belgian Blue cattle. GlyT2 function is strictly coupled to the sodium electrochemical gradient actively generated by the Na+/K+-ATPase (NKA). GlyT2 cotransports 3Na+/Cl-/glycine generating large rises of Na+ inside the presynaptic terminal that must be efficiently reduced by the NKA to preserve Na+ homeostasis. In this work, we have used high-throughput mass spectrometry to identify proteins interacting with GlyT2 in the CNS. NKA was detected as a putative candidate and through reciprocal coimmunoprecipitations and immunocytochemistry analyses the association between GlyT2 and NKA was confirmed. NKA mainly interacts with the raft-associated active pool of GlyT2, and low and high levels of the specific NKA ligand ouabain modulate the endocytosis and total expression of GlyT2 in neurons. The ouabain mediated downregulation of GlyT2 also occurs in vivo in two different systems: zebrafish embryos and adult rats, indicating that this NKA-mediated regulatory mechanism is evolutionarily conserved and may play a relevant role in the physiological control of inhibitory glycinergic neurotransmission. PMID- 23986261 TI - Heteroleptic diimine copper(I) complexes with large extinction coefficients: synthesis, quantum chemistry calculations and physico-chemical properties. AB - Using the HETPHEN approach, five new heteroleptic copper(I) complexes composed of a push-pull 4,4'-styryl-6,6'-dimethyl-2,2'-bipyridine ligand and a bulky bis[(2 diphenylphosphino)phenyl]-ether (DPEphos) or a bis2,9-mesityl phenanthroline (Mes2Phen) were prepared and characterized by electronic absorption spectroscopy, electrochemistry, and TD-DFT calculations. These complexes exhibit very intense absorption bands in the visible region with extinction coefficient in the range of 5-7 * 10(4) M(-1) cm(-1). The analysis of the position, intensity and band shape indicates a strong contribution from an intra-ligand charge-transfer transition centered on the styrylbipyridine ligand along with MLCT transitions. These new complexes experimentally demonstrate that good light harvesting properties with bis-diimine copper(I) complexes are a reality if one chooses suitable ligands in the coordination sphere. This constitutes a milestone towards using bis-diimine copper(I) complexes for solar energy conversion (artificial photosynthesis and solar cells). PMID- 23986262 TI - Risk of malignant disease and biologic response modifiers: fact, fiction, and future concerns. PMID- 23986263 TI - Microchemostat array with small-volume fraction replenishment for steady-state microbial culture. AB - A chemostat is a bioreactor in which microorganisms can be cultured at steady state by controlling the rate of culture medium inflow and waste outflow, thus maintaining media composition over time. Even though many microbial studies could greatly benefit from studying microbes in steady-state conditions, high instrument cost, complexity, and large reagent consumption hamper the routine use of chemostats. Microfluidic-based chemostats (i.e. microchemostats) can operate with significantly smaller reagent consumption while providing accurate chemostatic conditions at orders of magnitude lower cost compared to conventional chemostats. Also, microchemostats have the potential to significantly increase the throughput by integrating arrays of microchemostats. We present a microchemostat array with a unique two-depth culture chamber design that enables small-volume fraction replenishment of culture medium as low as 1% per replenishment cycle in a 250 nl volume. A system having an array of 8 microchemostats on a 40 * 60 mm(2) footprint could be automatically operated in parallel by a single controller unit as a demonstration for potential high throughput microbial studies. The model organism, Saccharomyces cerevisiae, successfully reached a stable steady-state of different cell densities as a demonstration of the chemostatic functionality by programming the dilution rates. Chemostatic functionality of the system was further confirmed by quantifying the budding index as a function of dilution rate, a strong indicator of growth dependent cell division. In addition, the small-volume fraction replenishment feature minimized the cell density fluctuation during the culture. The developed system provides a robust, low-cost, and higher throughput solution to furthering studies in microbial physiology. PMID- 23986264 TI - Synthesis and structural characterization of tris(2-pyridonyl)methyl complexes of zinc and thallium: a new class of metallacarbatranes and a monovalent thallium alkyl compound. AB - Tris(2-pyridonyl)methanes may be synthesized via the reactions of the respective 2-pyridone with CHX3 (X = Cl, Br) and K2CO3 in the presence of [Bu(n)4N]Br, followed by acid-catalyzed isomerization with camphorsulfonic acid. These compounds provide access to a new class of alkyl ligands that feature oxygen donors and are capable of forming metallacarbatranes and a monovalent thallium alkyl compound. PMID- 23986265 TI - Emotional reactivity to threat modulates activity in mentalizing network during aggression. AB - Aggression is a common response to provocation, albeit with considerable interindividual differences. In this fMRI study, we investigated emotional reactivity to threat as possible link between provocation and aggression, as well as the neural correlates of this relationship. We hypothesized that emotional reactivity, measured as fear potentiation (FP) of the startle response, would be negatively associated with aggressive behavior and would modulate neural activity during an aggressive interaction. In 30 healthy female participants, FP was measured as the difference between blink amplitudes while watching threatening vs neutral pictures. Participants subsequently engaged in a variant of the Taylor Aggression Paradigm (TAP), while being scanned. During the TAP, participants selected a punishment level for either a highly provoking or a nonprovoking opponent. There was no difference in aggressive behavior between participants high and low in FP. However, we found a negative correlation between FP and the neural provocation effect in several regions of a network previously associated with mentalizing including the medial prefrontal cortex, precuneus and the temporo-parietal junction. Independently of the FP variability, aggressive behavior correlated with the provocation effect on activity in the caudate nucleus. Our results indicate that during a provocative confrontation, high emotional reactivity to threat suppresses recruitment of the mentalizing network. PMID- 23986267 TI - Aversive disinhibition of behavior and striatal signaling in social avoidance. AB - Social avoidance is a major factor contributing to the development and maintenance of anxiety and depressive symptoms. Converging evidence suggests that social avoidance is associated with abnormal aversive processing and hyperactive amygdala signaling. However, what are the consequences of such abnormal aversive processing for action and for the neural mechanisms implementing action is unclear. Existing literature is conflicting, pointing at either enhanced or reduced action inhibition. We investigated the interaction between aversion and action in social avoidance by comparing the effects of aversive vs appetitive faces on a go/no-go task and associated striatal signals in 42 high and low socially avoidant individuals. We combined fMRI with a novel probabilistic learning task, in which emotional valence (angry and happy faces) and optimal response (go- and no-go-responses) were manipulated independently. High compared with low socially avoidant individuals showed reduced behavioral inhibition (proportion no-go-responses) for angry relative to happy faces. This behavioral disinhibition correlated with greater striatal signal during no-go-responses for angry relative to happy faces. The results suggest that social avoidant coping style is accompanied by disinhibition of action and striatal signal in the context of social threat. The findings concur with recent theorizing about aversive disinhibition and affective disorders. PMID- 23986266 TI - 5-HTTLPR, anxiety and gender interaction moderates right amygdala volume in healthy subjects. AB - Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, none have investigated how these effects are modulated by gender and anxiety. We investigated this issue using two complementary region of interest-based structural neuroimaging approaches (voxel based morphometry and Freesurfer) in 138 healthy individuals categorized into 'no anxiety' and 'subclinical anxiety' groups based on the Hamilton Rating Scale for Anxiety (HAM-A). Preliminarily, using anxiety as a continuous variable, we found a significant interaction effect of genotype by gender on anxiety. Females homozygous for the Short allele showed the highest HAM-A scores and males the lowest. In addition, a three-way significant interaction among genotype, gender and anxiety category was found for the right amygdala volume. Post hoc tests revealed that homozygous females carrying the Short variant with a subclinical anxiety condition had larger volume. The reported interaction effects demonstrate that gender strongly modulates the relationship between 5-HTTLPR genotype and subclinical expression of anxiety acting on amygdala, one region of the emotional neural network specifically involved in the anxiety-like behaviours. PMID- 23986268 TI - Disease-based modeling to predict fluid response in intensive care units. AB - OBJECTIVE: To compare general and disease-based modeling for fluid resuscitation and vasopressor use in intensive care units. METHODS: Retrospective cohort study involving 2944 adult medical and surgical intensive care unit (ICU) patients receiving fluid resuscitation. Within this cohort there were two disease-based groups, 802 patients with a diagnosis of pneumonia, and 143 patients with a diagnosis of pancreatitis. Fluid resuscitation either progressing to subsequent vasopressor administration or not was used as the primary outcome variable to compare general and disease-based modeling. RESULTS: Patients with pancreatitis, pneumonia and the general group all shared three common predictive features as core variables, arterial base excess, lactic acid and platelets. Patients with pneumonia also had non-invasive systolic blood pressure and white blood cells added to the core model, and pancreatitis patients additionally had temperature. Disease-based models had significantly higher values of AUC (p < 0.05) than the general group (0.82 +/- 0.02 for pneumonia and 0.83 +/- 0.03 for pancreatitis vs. 0.79 +/- 0.02 for general patients). CONCLUSIONS: Disease-based predictive modeling reveals a different set of predictive variables compared to general modeling and improved performance. Our findings add support to the growing body of evidence advantaging disease specific predictive modeling. PMID- 23986269 TI - Novel therapeutic options in inflammatory cardiomyopathy. AB - Inflammatory dilated cardiomyopathy (iDCM) denotes cardiac dysfunction due to myocardial inflammation (myocarditis). Progressively impaired cardiac contractility, fibrosis and dilation of heart chambers characterise iDCM phenotypically, and are associated with poor clinical prognosis. Cardiotropic infections followed by autoimmune responses against heart tissue are the most common cause of iDCM. The pathophysiology of iDCM is still poorly understood. Nevertheless, our understanding of the molecular mechanisms of inflammatory heart failure advanced during recent years. In fact, recent mechanistic insights might open the view for novel diagnostic and therapeutic approaches for iDCM patients in the future. In this review we update our knowledge on disease mechanisms, summarise current clinical approaches for iDCM patients, and discuss future therapeutic options. PMID- 23986270 TI - Membrane destabilization by monomeric hIAPP observed by imaging fluorescence correlation spectroscopy. AB - Monomeric hIAPP significantly destabilizes both model and live cell membranes by increasing membrane fluidity. This interaction with membranes happens via carpet formation followed by lipid extraction in a concentration dependent manner and thus we propose that hIAPP aggregation prior to membrane interaction may not be necessary for its cytotoxicity. PMID- 23986271 TI - Open access - is this the future of medical publishing? PMID- 23986273 TI - Ultrasound measurements of carotid intima-media thickness and plaque in HIV infected patients on the Mediterranean diet. AB - AIM: To evaluate the influence of food habits, specifically adherence to the Mediterranean diet, on carotid intima-media thickness (CIMT) and the presence of plaques in HIV-infected patients taking antiretroviral therapy (ART) and non-HIV infected participants and to determine if HIV infection contributes independently to subclinical atherosclerosis. METHODS: We conducted a cross-sectional study of 110 HIV-infected patients on ART and 131 non-HIV-infected participants at the University Hospital for Infectious Diseases in Zagreb, Croatia, from 2009-2011. CIMT measurement and determination of carotid plaque presence was detected by ultrasound. Adherence to the Mediterranean diet was assessed by a 14-point food item questionnaire. Subclinical atherosclerosis was defined by CIMT>=0.9 mm or >=1 carotid plaque. RESULTS: In HIV-infected patients, subclinical atherosclerosis was associated with older age (Plt;0.001; Mann-Whitney test), higher body mass index (P=0.051; Mann-Whitney test), hypertension (Plt;0.001; chi(2) test), and a lower Mediterranean diet score (P=0.035; Mann-Whitney test), and in non-HIV-infected participants with older age (P lt; 0.001; Mann-Whitney test) and hypertension (P=0.006; chi(2) test). Multivariate analysis showed that decreased adherence to the Mediterranean diet was associated with higher odds of subclinical atherosclerosis (odds ratio [OR] 2.28, 95% confidence interval [CI] 1.10-4.72, P=0.027) as was current smoking (OR 2.86, 95% CI 1.28-6.40), hypertension (OR 3.04, 95% CI 1.41-6.57), and male sex (OR 2.35, 95% CI 0.97 5.70). There was a significant interaction of age and HIV status, suggesting that older HIV-infected patients had higher odds of subclinical atherosclerosis than controls (OR 3.28, 95% CI 1.24-8.71, P=0.017 at the age of 60 years). CONCLUSION: We confirmed the association between lower adherence to the Mediterranean diet and increased risk of subclinical atherosclerosis and found that treated HIV infection was a risk factor for subclinical atherosclerosis in older individuals. PMID- 23986272 TI - Stem cell systems informatics for advanced clinical biodiagnostics: tracing molecular signatures from bench to bedside. AB - Development of innovative high throughput technologies has enabled a variety of molecular landscapes to be interrogated with an unprecedented degree of detail. Emergence of next generation nucleotide sequencing methods, advanced proteomic techniques, and metabolic profiling approaches continue to produce a wealth of biological data that captures molecular frameworks underlying phenotype. The advent of these novel technologies has significant translational applications, as investigators can now explore molecular underpinnings of developmental states with a high degree of resolution. Application of these leading-edge techniques to patient samples has been successfully used to unmask nuanced molecular details of disease vs healthy tissue, which may provide novel targets for palliative intervention. To enhance such approaches, concomitant development of algorithms to reprogram differentiated cells in order to recapitulate pluripotent capacity offers a distinct advantage to advancing diagnostic methodology. Bioinformatic deconvolution of several "-omic" layers extracted from reprogrammed patient cells, could, in principle, provide a means by which the evolution of individual pathology can be developmentally monitored. Significant logistic challenges face current implementation of this novel paradigm of patient treatment and care, however, several of these limitations have been successfully addressed through continuous development of cutting edge in silico archiving and processing methods. Comprehensive elucidation of genomic, transcriptomic, proteomic, and metabolomic networks that define normal and pathological states, in combination with reprogrammed patient cells are thus poised to become high value resources in modern diagnosis and prognosis of patient disease. PMID- 23986274 TI - Prevalence and types of persistent dyslipidemia in patients treated with statins. AB - AIM: To determine the prevalence and types of persistent dyslipidemia in patients treated with different statins to reduce cardiovascular disease (CVD) risk, as well as to determine the proportion of high risk patients who did not reach the lipid target values and assess cardiologists' further treatment advice for these patients. METHODS: This cross-sectional, observational study recruited 1849 outpatients from all parts of Croatia between January and September 2011 (44.6% women), 19 to 90 years old (average age 63.13) treated with statins for at least 6 months. We analyzed how the potency and type of lipid-lowering treatment were correlated with CVD risk level and achieving treatment goals according to 2007 Joint European Guidelines on CVD prevention. RESULTS: Most patients (81.3%) were at high risk for CVD. The most frequently used statin was atorvastatin (42.8%), followed by simvastatin (27.6%) and rosuvastatin (22.8%). Only 35.5% patients achieved low density lipoprotein-cholesterol treatment target. Patients treated with more potent statins had better results. A total of 22.3% of patients had high density lipoprotein-cholesterol below 1.0 mmol/L (~40 mg/dL) for men and below 1.2 (~45 mg/dL) for women and 46.4% had triglycerides above 1.7 mmol/L (~150 mg/dL) but there were no significant differences between statins in improving these parameters. Most of the patients on more potent statins were not advised by their cardiologists to change the type or dosage of statin, which was more common in patients on less potent statins. CONCLUSION: A considerable number of patients treated with statins did not achieve the treatment goal values. The results were better in patients treated with more potent statins and cardiologists advised them much less frequently to change the type and dosage of statin. There is a need for more intensive treatment, especially for high-risk patients. This could be accomplished by optimizing patients' adherence, using more potent statins, titrating current statin therapy to higher doses, or using a combined lipid-lowering treatment. PMID- 23986275 TI - Multiple presence of prothrombotic risk factors in Croatian children with arterial ischemic stroke and transient ischemic attack. AB - AIM: To determine the frequency of inherited and acquired prothrombotic risk factors in children with arterial ischemic stroke (AIS) and transient ischemic attacks (TIA) in Croatia. METHODS: We investigated 14 prothrombotic risk factors using blood samples from 124 children with AIS or TIA and 42 healthy children. Prothrombotic risk factors were classified into five groups: natural coagulation inhibitors (antithrombin, protein C, protein S), blood coagulation factors (FV Leiden and FII 20210), homocysteine, lipid and lipoprotein profile (lipoprotein (a), triglycerides, total, high- and low-density lipoprotein), and antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and antiphosphatidylserine antibodies). RESULTS: The most common prothrombotic risk factor was elevated lipoprotein (a), which was identified in about 31% of patients and in 24% of controls. Natural coagulation inhibitors were decreased in about 19% of patients, but not in controls. Pathological values of homocysteine, blood coagulation factor polymorphisms, and antiphospholipid antibodies were found in similar frequencies in all groups. Fourteen children with AIS and TIA (11.3%) and no children from the control group had three or more investigated risk factors. CONCLUSION: The presence of multiple prothrombotic risk factors in children with cerebrovascular disorder suggests that a combination of risk factors rather than individual risk factors could contribute to cerebrovascular disorders in children. PMID- 23986276 TI - Metabolic syndrome increases risk for pulmonary embolism after hip and knee arthroplasty. AB - AIM: To investigate whether patients with metabolic syndrome (MetS) undergoing total hip or knee replacement have an increased risk for pulmonary embolism (PE). METHODS: We studied patients undergoing total hip or total knee replacement from January 2001 to April 2006. The diagnosis of PE was based on a positive finding with a chest CT or a lung scan. Components of MetS were defined as 1) BMI>=30 kg/m(2) , 2) non-fasting preadmission glucose >=11.1 mmol/L or diagnosis of diabetes, 3) hypertension, and 4) dyslipidemia. MetS was diagnosed if at least three of these components were present. RESULTS: Of 7282 patients, 107 (1.47%) were diagnosed with PE. The incidence of PE in patients with 0, 1, 2, 3, and 4 MetS components was respectively 0.85% (16/1888; 95% confidence interval [CI] 0.5%-1.4%), 1.24% (31/2500; 95% CI 0.9%-1.8%), 1.76% (34/1936; 95% CI 1.2%-2.5%), 2.64% (21/796; 95% CI 1.7%-4.1%), and 3.09% (5/162; 95% CI 1.1%-7.4%). The independent risk factors for PE were age >=70, knee as opposite to hip replacement, bilateral knee surgery, congestive heart failure, and MetS or the number of MetS components. The odds of PE independently increased 1.6 times (95% CI 1.01-2.56; P=0.043) for patients with MetS and 1.23 times (95% CI 1.02-1.48; P=0.028) per each additional MetS component. CONCLUSION: Patients with MetS are at increased risk for PE after total joint arthroplasty. The increasing number of MetS components significantly increased the incidence of PE. PMID- 23986277 TI - The effect of maternal exercise during pregnancy on abnormal fetal growth. AB - AIM: To assess the effect of maternal physical activity during pregnancy on abnormal fetal growth. METHODS: The study group of 166 women in gestational week 6-8 exercised regularly three days per week at submaximal intensity during their entire pregnancy and the control group of 168 women received standard antenatal care. The main outcomes were macrosomia and intrauterine growth restriction. RESULTS: The study group had a lower frequency of macrosomia in newborns (6.0% vs 12.5%, P=0.048) and gestational diabetes (1.8% vs 8.3%, P=0.008) than the control group, but there was no significant difference in intrauterine growth restriction (7.2% vs 6.5%). There was also no significant differences in other perinatal outcomes. CONCLUSIONS: The beneficial effect of maternal physical activity on fetal growth may be caused the impact of aerobic exercise on glucose tolerance. Fitness trainers and kinesiologists, as well as health care providers, should be educated on the benefits of regular exercise during pregnancy and safe physical exercise for pregnant women. PMID- 23986278 TI - Pancreatic cancer mortality in Serbia from 1991-2010 - a joinpoint analysis. AB - AIM: To analyze the trends of pancreatic cancer mortality in Serbia. METHODS: The study covered the population of Serbia in the period 1991 to 2010. Mortality trends were assessed by the joinpoint regression analysis by age and sex. RESULTS: Age-standardized mortality rates ranged from 5.93 to 8.57 per 100 000 in men and from 3.51 to 5.79 per 100 000 in women. Pancreatic cancer mortality in all age groups was higher among men than among women. It was continuously increasing since 1991 by 1.6% (95% confidence interval [CI] 1.1 to 2.0) yearly in men and by 2.2% (95% CI 1.7 to 2.7) yearly in women. Changes in mortality were not significant in younger age groups for both sexes. In older men (>=55 years), mortality was increasing, although in age groups 70-74 and 80-84 the increase was not significant. In 65-69 years old men, the increase in mortality was significant only in the period 2004 to 2010. In >=50 years old women, mortality significantly increased from 1991 onward. In 75-79 years old women, a non significant decrease in the period 1991 to 2000 was followed by a significant increase from 2000 to 2010. CONCLUSION: Serbia is one of the countries with the highest pancreatic cancer mortality in the world, with increasing mortality trend in both sexes and in most age groups. PMID- 23986279 TI - Students' and parents' attitudes toward basic life support training in primary schools. AB - AIM: To assess attitudes of students and their parents toward basic life support (BLS) training in primary schools, along with their perceptions of students' fears toward applying and training BLS. METHODS: In October 2011, a specifically designed, voluntary and anonymous questionnaire was distributed to 7th and 8th grade students and to their parents in two primary schools in Split, Croatia. Completed questionnaires were analyzed to determine the validity of the scale, and to determine sex and group differences in individual items and the whole scale. RESULTS: The questionnaires were completed by 301 school children and 361 parents. Cronbach's alpha of the whole scale was 0.83, indicating good internal consistency. The students' score for the whole attitude scale was 73.7 ? 11.1 out of maximum 95, while the parents' score was 68.0 ? 11.9. Students' attitude was significantly more positive than that of the parents (U=29.7, P<0.001). The greatest perceived students' fear toward applying BLS was that they would harm the person in need of BLS. CONCLUSION: Our study showed that in Croatia both students in their last two years of primary school and their parents had a positive attitude toward BLS training in primary schools. Implementing compulsory BLS training in Croatia's primary schools could help increase students' confidence, quell their fears toward applying BLS, and possibly even increase the survival of bystander-witnessed cardiac arrests. PMID- 23986280 TI - Prediction of eye color in the Slovenian population using the IrisPlex SNPs. AB - AIM: To evaluate the accuracy of eye color prediction based on six IrisPlex single nucleotide polymorphisms (SNP) in a Slovenian population sample. METHODS: Six IrisPlex predictor SNPs (HERC2 - rs12913832, OCA2 - rs1800407, SLC45A2 - rs16891982 and TYR - rs1393350, SLC24A4 - rs12896399, and IRF4 - rs12203592) of 105 individuals were analyzed using single base extension approach and SNaPshot chemistry. The IrisPlex multinomial regression prediction model was used to infer eye color probabilities. The accuracy of the IrisPlex was assessed through the calculation of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the area under the receiver characteristic operating curves (AUC). RESULTS: Blue eye color was observed in 44.7%, brown in 29.6%, and intermediate in 25.7% participants. Prediction accuracy expressed by the AUC was 0.966 for blue, 0.913 for brown, and 0.796 for intermediate eye color. Sensitivity was 93.6% for blue, 58.1% for brown, and 0% for intermediate eye color. Specificity was 93.1% for blue, 89.2% for brown, and 100% for intermediate eye color. PPV was 91.7% for blue and 69.2% for brown color. NPV was 94.7% for blue and 83.5% for brown eye color. These values indicate prediction accuracy comparable to that established in other studies. CONCLUSION: Blue and brown eye color can be reliably predicted from DNA samples using only six polymorphisms, while intermediate eye color defies prediction, indicating that more research is needed to genetically predict the whole variation of eye color in humans. PMID- 23986281 TI - Decomposition and entomological colonization of charred bodies - a pilot study. AB - AIM: To use forensic entomological approach to estimate the post mortem interval (PMI) in burnt remains. METHODS: Two experiments were performed in a field in the outskirts of Milan, in winter and summer 2007. Four 60-kg pigs were used: two for each experiment. One pig carcass was burnt until it reached the level 2-3 of the Glassman-Crow scale and the not-burnt carcass was used as a control. In order to describe the decomposition process and to collect the data useful for minimum PMI estimation, macroscopic, histological, and entomological analyses were performed. RESULTS: In the winter part of the experiment, the first insect activity on the burnt carcass began in the third week (Calliphora vomitoria) and at the beginning of the fourth week an increase in the number of species was observed. In the summer part, adult flies and first instar maggots (Phormia regina) appeared a few minutes/hours after the carcass exposure. Both in winter and summer, flies belonging to the first colonization wave (Calliphoridae) appeared on burnt and control pigs at the same time, whereas other species (Diptera and Coleoptera) appeared earlier on burnt pigs. CONCLUSION: In forensic practice, burnt bodies are among the most neglected fields of entomological research, since they are supposed to be an inadequate substratum for insect colonization. Entomological approach for PMI estimation proved to be useful, although further studies on larger samples are needed. PMID- 23986282 TI - Early postoperative interventional ASD-closure for severe atrial right to left shunt in a neonate with common arterial trunk. AB - Although closure of an atrial septal defect (ASD II) with an occluding device in the first year of life is not a routine procedure, it is a feasible treatment, even in neonates. Case reports on the off-label use of Amplatzer devices have been repeatedly published, but there are no reports on using the Amplatzer Duct Occluder (ADO) to close an atrial septal defect in a neonate. We report on a successful catheter closure of an ASD II with ADO in a severely cyanotic neonate, seven days after surgical repair of common arterial trunk. Due to progressive cyanosis and clinical signs of right ventricular failure, which developed after common arterial trunk repair, the neonate underwent cardiac catheterization. Diastolic filling impairment of the right ventricle (right ventricle hypertrophy, pulmonary regurgitation, and residual right ventricle outflow tract obstruction) was thought to be the cause of impaired right ventricle diastolic filling, resulting in the right-to-left shunt at the atrial level. Under transesophageal echocardiographic guidance, ADO was delivered through a 5 French sheath into the atrial septal defect. Amplatzer duct occluder closed the defect and proved to be stable in position after disconnection. During the procedure, the child was stable and then transferred to the intensive care unit with significantly improved oxygen saturation. This is the first report on placing a duct occluder in the atrial septal position, which is a novel procedure for-small neonates. PMID- 23986283 TI - Representing life as opposed to being: the bio-objectification process of the HeLa cells and its relation to personalized medicine. AB - The immortal HeLa cells case is an intriguing example of bio-objectification processes with great scientific, social, and symbolic impacts. These cells generate questions about representation, significance, and value of the exceptional, variety, individuality, and property. Of frightening (a lethal cancer) and emarginated (a black, poor woman) origins, with their ability to "contaminate" cultures and to "spread" into spaces for becoming of extraordinary value for human knowledge, well-being, and economy advancements, HeLa cells have represented humanity, and emphasized the importance of individual as a core concept of the personalized medicine. Starting from the process leading from HeLa "cells" to HeLa "bio-objects," we focus on their importance as high quality bio specimen. We discuss the tension between phenomenological characteristic of fundamental biological research and the variety of material and methodologies in epidemiology and personalized medicine. The emerging methodologies and societal changes reflect present EU policies and lead toward a new paradigm of science. PMID- 23986284 TI - Open access: changing global science publishing. AB - The article reflects on open access as a strategy of changing the quality of science communication globally. Successful examples of open-access journals are presented to highlight implications of archiving in open digital repositories for the quality and citability of research output. Advantages and downsides of gold, green, and hybrid models of open access operating in diverse scientific environments are described. It is assumed that open access is a global trend which influences the workflow in scholarly journals, changing their quality, credibility, and indexability. PMID- 23986285 TI - Croatian smoke-free law and smoking habits among employees of health care facilities in Koprivnica-Krizevci County. PMID- 23986286 TI - May chest pain describe coronary heart disease? PMID- 23986287 TI - [About patient education in medical rehabilitation]. PMID- 23986288 TI - [DGRW-Update: Rehabilitation in Diabetes Mellitus]. AB - In the years to come, prevalence and socio-medical relevance of diabetes mellitus will continue to increase. Therapeutic aims must be defined on an individual basis considering risks and benefits. No longer is it reasonable to insist on normoglycaemia as a general therapeutic aim. There are numerous effective and evidence-based therapeutic modules for diabetes mellitus which are also offered within the scope of rehabilitation. Reliable evidence exists to confirm that therapy should start as early as possible, because it is less effective during later phases of the disease when concomitant cardiovascular illnesses may occur. In most cases, medical rehabilitation of diabetic patients is based on other diagnoses. There is a considerable need for rehabilitation among diabetics who are in ambulant care but do not intend to file a request for rehabilitative measures. Sustainability of rehabilitative effects must be improved by means of follow-up treatment and networking with the ambulant structures of long-term care. Provided that the indication makes it appropriate, bariatric surgery constitutes a new effective therapy. PMID- 23986289 TI - [Phase e of the german phase model of neurological rehabilitation as a bridge to inclusion - position on the realignment of post-acute rehabilitation and aftercare for adults with acquired brain injuries]. PMID- 23986290 TI - [Announcements]. PMID- 23986291 TI - Boron-substituted graphyne as a versatile material with high storage capacities of Li and H2: a multiscale theoretical study. AB - Based on density functional theory (DFT), first-principles molecular dynamics (MD), and the grand canonical ensemble Monte Carlo (GCMC) method, we investigated the boron substitution in aromatic rings of graphyne in terms of geometric and electronic structures as well as its bifunctional application including Li and H2 storage. The calculated binding energies of B-doped graphyne (BG) are significantly enhanced at two adsorptive sites compared to pristine graphyne, leading to high lithiation potentials of 2.7 V in 6Li@1BG, and even higher with 3.0 V in 6Li@3BG. Thus, 6Li@1BG with a capacity of 1125 mA h g(-1), which is much larger than other carbon materials, is proposed to be a good anode material in lithium-ion batteries. For further hydrogen storage in 6Li@nBG, the results show that it can steadily adsorb at least 8H2 in DFT, MD and GCMC computations, and the excess gravimetric H2 uptake is 7.4 wt% at ambient conditions, exceeding the 2017 DOE target. Our multiscale simulations demonstrate that chemical modifications in two-dimensional carbon structures are very promising for high lithium storage and hydrogen uptake. PMID- 23986293 TI - Electroencephalogram global field synchronization analysis: a new method for assessing the progress of cognitive decline in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia. Global field synchronization (GFS) can measure functional synchronization in frequency-domain electroencephalogram (EEG) data. The aim of this study is to explore GFS values and its clinical significance for severity of cognitive decline in AD. EEGs were recorded from 37 AD patients and 37 age-matched healthy individuals. GFS values were calculated in delta, theta, alpha, beta 1, beta 2, beta 3, gamma, and full frequency bands. The Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating scale (CDR) were employed to assess symptom severity in AD patients. Correlation analysis, clustering analysis, and concordance analysis were performed to analyze the relationship between GFS values and MoCA scores in AD patients. GFS values of the beta 1, beta 2, beta 3, and full bands were lower in AD patients than in healthy individuals, and positively correlated with MoCA and CDR scores in the combined group (AD patients and healthy individuals). GFS values were positively correlated with MoCA socres in 3 beta bands and full bands, and with CDR scores in the delta band. There was a good concordance between K-means clustering algorithm calculating of GFS values and MoCA scoring (kappa = .913, P < .001). In conclusion, the present results indicated that GFS can serve as an indicator of cognitive decline or impairment in AD patients. Furthermore, the GFS method of EEG holds considerable promise to distinguish mild cognitive impairment from serious cognitive impairment in patients with AD. PMID- 23986294 TI - Dermatologic relationships between the United States and German-speaking countries: part 2--the exodus of Jewish dermatologists. AB - The rise to power of the National Socialist (Nazi) party led by Adolf Hitler and the subsequent tumultuous 12 years of their rule in Germany resulted in catastrophes including World War II, the most destructive war ever, and the premeditated and systematic murder of 5 to 6 million European Jews. Despite their notable contributions to the academic excellence that existed in German-speaking countries at that time, Jewish physicians were particularly vulnerable to persecution and death. Between 1933 and 1938, a series of repressive measures eliminated them from the practice of medicine in Germany and other countries. Although some died in concentration camps and others committed suicide, many were able to emigrate from Europe. Dermatology in the United States particularly benefited from the influx of several stellar Jewish dermatologists who were major contributors to the subsequent flowering of academic dermatology in the United States. A number of representative biographies of these immigrants are briefly recounted to illustrate their lasting influence on our specialty. PMID- 23986295 TI - Impact of reducing agent, temperature, and substrate topology on diastereoselectivity of the intermolecular coupling reactions, or how "free" are cobalt-complexed propargyl radicals? AB - Applicability of the term "free radical" to organometallic radicals was studied by using the stereoselectivity of radical C-C bond formation as a diagnostic tool. Based on diastereoselectivity data, it was concluded that the reduction of pi-bonded, Co2(CO)6-complexed propargyl cations with heterogeneous reducing agents (Zn, Mg) generates "free radicals", while homogeneous reductants (Cp2Co, Na-Ph2CO) produce "sequestered radicals", presumably associated with reductant derived oxidized species. The latter are comparable in molecular volume to the requisite radical species, thus restricting the motion and conformational freedoms of converging, transition metal-complexed propargyl radicals. Diastereoselectivity of intermolecular reactions is determined to be much less sensitive toward temperature variation (Deltade = 6-22%) than in intramolecular radical cyclizations (Deltade = 106%). PMID- 23986297 TI - Picturing the body in spatial neglect: descending a staircase. AB - Spatial neglect-a syndrome in which there is asymmetric perception, orienting, or response associated with functional disability(1)-has a potentially devastating effect on self-care and safety after stroke. Still, it frequently goes unrecognized.(2) How is this possible? A tremendously disabling disorder should be easy to detect. In this issue of Neurology((r)), Rousseaux et al.(3) present a study that may give us an inkling of the problem: we may be assessing the eyes, but not the body. PMID- 23986296 TI - Octreotide-functionalized and resveratrol-loaded unimolecular micelles for targeted neuroendocrine cancer therapy. AB - Medullary thyroid cancer (MTC) is a neuroendocrine tumor (NET) that is often resistant to standard therapies. Resveratrol suppresses MTC growth in vitro, but it has low bioavailability in vivo due to its poor water solubility and rapid metabolic breakdown, as well as lack of tumor-targeting ability. A novel unimolecular micelle based on a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for NET-targeted delivery. The hyperbranched amphiphilic block copolymer consisted of a dendritic Boltorn(r) H40 core, a hydrophobic poly(l-lactide) (PLA) inner shell, and a hydrophilic poly(ethylene glycol) (PEG) outer shell. Octreotide (OCT), a peptide that shows strong binding affinity to somatostatin receptors, which are overexpressed on NET cells, was used as the targeting ligand. Resveratrol was physically encapsulated by the micelle with a drug loading content of 12.1%. The unimolecular micelles exhibited a uniform size distribution and spherical morphology, which were determined by both transmission electron microscopy (TEM) and dynamic light scattering (DLS). Cellular uptake, cellular proliferation, and Western blot analyses demonstrated that the resveratrol-loaded OCT-targeted micelles suppressed growth more effectively than non-targeted micelles. Moreover, resveratrol-loaded NET-targeted micelles affected MTC cells similarly to free resveratrol in vitro, with equal growth suppression and reduction in NET marker production. These results suggest that the H40-based unimolecular micelle may offer a promising approach for targeted NET therapy. PMID- 23986298 TI - Neuroanatomy of space, body, and posture perception in patients with right hemisphere stroke. AB - OBJECTIVE: To specify the neuroanatomical correlates of biases in the representations of the gravitational vertical (subjective vertical [SV]) and body axis (subjective straight ahead [SSA]), as well as postural difficulties, in patients with hemispheric stroke. METHODS: The analysis focused on right hemisphere lesions in 21 neglect patients and 21 non-neglect patients (using MRIcro software) and related performance in 2 experimental tasks (SV and SSA) and a clinical balance assessment. Voxel-based lesion-symptom mapping was used to highlight brain areas in which lesions best explained the severity of task biases (p < 0.01). RESULTS: The bias in the representation of body orientation was found to be strongly related to lesions of the anterior parietal cortex and the middle part of the superior temporal gyrus. The SV errors were associated with more widespread lesions of the posterior parietal and temporal cortices. Imbalance was preferentially associated with lesions of the posterior insula and the adjacent temporoparietal cortex. CONCLUSION: This study evidenced a cortical dissociation for body-centered and gravitational representations biases, which may reflect the differential involvement of these brain regions in spatial information processing. The lesions involved in representation biases (especially of the SV) and postural difficulties overlapped to some extent in the temporoparietal, superior temporal, and posterior insular regions of the cortex. PMID- 23986299 TI - Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To evaluate the evidence since the 1999 assessment regarding efficacy and safety of vagus nerve stimulation (VNS) for epilepsy, currently approved as adjunctive therapy for partial-onset seizures in patients >12 years. METHODS: We reviewed the literature and identified relevant published studies. We classified these studies according to the American Academy of Neurology evidence-based methodology. RESULTS: VNS is associated with a >50% seizure reduction in 55% (95% confidence interval [CI] 50%-59%) of 470 children with partial or generalized epilepsy (13 Class III studies). VNS is associated with a >50% seizure reduction in 55% (95% CI 46%-64%) of 113 patients with Lennox-Gastaut syndrome (LGS) (4 Class III studies). VNS is associated with an increase in >= 50% seizure frequency reduction rates of ~ 7% from 1 to 5 years postimplantation (2 Class III studies). VNS is associated with a significant improvement in standard mood scales in 31 adults with epilepsy (2 Class III studies). Infection risk at the VNS implantation site in children is increased relative to that in adults (odds ratio 3.4, 95% CI 1.0-11.2). VNS is possibly effective for seizures (both partial and generalized) in children, for LGS-associated seizures, and for mood problems in adults with epilepsy. VNS may have improved efficacy over time. RECOMMENDATIONS: VNS may be considered for seizures in children, for LGS associated seizures, and for improving mood in adults with epilepsy (Level C). VNS may be considered to have improved efficacy over time (Level C). Children should be carefully monitored for site infection after VNS implantation. PMID- 23986300 TI - Antisaccade task reflects cortical involvement in mild cognitive impairment. AB - OBJECTIVE: The aims of this study were to examine executive dysfunction using an antisaccade (AS) task in normal elderly (NE) and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) as well as to evaluate the relationship between AS performance and cortical thinning within AD-associated regions. METHODS: We recorded eye movements in 182 subjects (NE: 118; MCI: 36; AD: 28) during an AS task. We also performed neuropsychological measures of executive function for comparison. Brain MRI scans were collected on most subjects, and cortical thickness was determined in 9 regions known to exhibit atrophy in AD dementia ("AD signature"). We investigated the relationships between AS and neuropsychological performance, as well as possible correlations between AS performance and cortical thickness. RESULTS: AS performance in MCI resembled that in NE; subjects with AD were impaired relative to both MCI and NE. In all subjects, AS performance correlated with neuropsychological measures of executive function, even after controlling for disease severity. In the subjects with MCI but not in NE, cortical thickness in frontoparietal AD signature regions correlated with AS performance. CONCLUSIONS: The AS task is a useful measure of executive function across the AD spectrum. In MCI, AS performance may reflect disease burden within cortical brain regions involved in oculomotor control; however, AS impairments in NE may have etiologies other than incipient AD. PMID- 23986301 TI - Migraine and structural changes in the brain: a systematic review and meta analysis. AB - OBJECTIVE: To evaluate the association between migraine without aura (MO) and migraine with aura (MA) and 3 types of structural brain abnormalities detected by MRI: white matter abnormalities (WMAs), infarct-like lesions (ILLs), and volumetric changes in gray and white matter (GM, WM) regions. METHODS: PubMed as well as the reference lists of identified studies and reviews were used to identify potentially eligible studies through January 2013. Candidate studies were reviewed and eligible studies were abstracted. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated for WMAs and ILLs. RESULTS: Six population-based and 13 clinic-based studies were identified. The studies suggested that structural brain changes, including WMAs, silent ILLs, and volumetric changes in GM and WM regions, were more common in migraineurs than in control groups. The results were strongest for MA. The meta-analysis of WMAs showed an association for MA (OR 1.68; 95% CI 1.07-2.65; p = 0.03) but not for MO (OR 1.34; 95% CI 0.96-1.87; p = 0.08). The association of ILLs was greater for MA (OR 1.44; 95% CI 1.02-2.03; p = 0.04) than for MO, but no association was found for MA (p = 0.52) and MO (p = 0.08) compared to controls. CONCLUSION: These data suggest that migraine may be a risk factor for structural changes in the brain. Additional longitudinal studies are needed to determine the differential influence of migraine without and with aura, to better characterize the effects of attack frequency, and to assess longitudinal changes in brain structure and function. PMID- 23986302 TI - Epidemiology of infections with enteric salmonellae in Switzerland with particular consideration of travelling activities. AB - QUESTIONS UNDER STUDY: To describe the current epidemiological situation of enteric salmonellosis in Switzerland and its development in the last two decades, particularly by determining the ratio between domestic and travel-associated cases. METHODS: Between 1 February 2011 and 31 January 2012, 14 medical laboratories continuously reported their isolations of enteric salmonellae to the Federal Office of Public Health (FOPH). Data on the travel history of salmonellosis patients was actively acquired from their treating physicians. These data were compared with the results of a case-control study on sporadic salmonellosis that was performed in 1993. RESULTS: It could be shown that, concomitantly with the pronounced decline in incidence of reported laboratory notifications of enteric salmonellae since the early 1990s, the travel-associated portion of isolates belonging to the most frequently isolated serovar Enteritidis has increased significantly (more than doubled). The three serovars that followed S. Enteritidis in frequency of isolation (Typhimurium, Bardo, monophasic 4,12:i: ) are predominantly of domestic origin. CONCLUSIONS: The significant increase in the percentage of travel-related S. Enteritidis infection, demonstrated by the comparison between the data from 2012 and 1993, might be a consequence of the reduction in domestic infections during this period. The fact that infections due to this serovar are now significantly more often travel-related than domestic clearly illustrates the success of the preventive measures taken. These consist of legal measures that were necessary to reduce the transmission of the pathogen in raw eggs, and sanitation measures taken by the producers that aimed to contain the chicken meat reservoir. PMID- 23986304 TI - Al13Fe4 selectively catalyzes the hydrogenation of butadiene at room temperature. AB - The hydrogenation of butadiene has been investigated for the first time on Al13Fe4. The model (010) surface of this non-noble metal combination appears to be both active and selective under mild reaction conditions. The performances of Al13Fe4 for C=C bond hydrogenation are compared with those of the reference noble metal, palladium. PMID- 23986303 TI - Early intermodal integration in offspring of parents with psychosis. AB - Identifying early developmental indicators of risk for schizophrenia is important for prediction and possibly illness prevention. Disturbed intermodality has been proposed as one important neurodevelopmental risk for schizophrenia. Early intermodal integration (EII) is the infant's ability to link motility and perception and to relate perception across modalities. We hypothesized that infants of parents with schizophrenia would have more EII abnormalities than infants of healthy parents and that infants of parents with affective psychosis would be intermediate in severity. The New England Family Study high-risk sample, ascertained from community populations, was utilized. Eight-month-old infants of parents with schizophrenia (n = 58), affective psychoses (n = 128), and healthy controls (n = 174) were prospectively assessed. Diagnoses of parents were determined 30 years later blind to offspring data. EII measures were grouped into 3 domains characterizing different aspects of infant development: (1) one's own body, (2) objects, and (3) social interactions. Results demonstrated that body- and object-related EII abnormalities were significantly increased for infants of parents with schizophrenia compared with control infants and not significantly increased for infants of parents with affective psychoses. EII abnormalities in relation to social interactions were significantly increased in infants of parents with schizophrenia and affective psychoses. Thus, body- and object related EII abnormalities were most severe in infants of parents with schizophrenia, supporting the importance of intermodality dysfunction as an early indicator of the vulnerability to schizophrenia. Future research should evaluate how this dysfunction evolves with development and its associations with other psychopathological and neurodevelopmental deficits in youth at risk for psychosis. PMID- 23986305 TI - The first asymmetric total synthesis of (+)-coriandrone A and B. AB - The first enantioselective total synthesis of (+)-coriandrone A and B, two bioactive natural products, has been achieved in 10 steps and 11 steps starting from commercially available methyl 2-hydroxy-4-methoxybenzoate. Key reactions include a Claison rearrangement, a Shi-type epoxidation-cyclization sequence and ortho-metallation of t-butylbenzamides with (S)-(-)-propylene oxide reaction. PMID- 23986306 TI - Use of lavage fluids in arthroplasty to prevent postoperative infections. AB - OBJECTIVE: Lavage techniques are used every day all over the world to clean wounds and surgical approaches. The solutions used vary depending on the application range; there are, for instance, normal saline, antibiotic or antiseptic solutions. This review describes the lavage solutions actually used during arthroplasty and their outcome related to postoperative infections. DATA SOURCES AND EXTRACTION: This is a retrospective review of published articles and books. The information was obtained from online browsers for scientific articles. RESULTS: The lavage fluids used in arthroscopy and those used in experimental studies were normal saline, bacitracin, castile soap, benzalkonium chloride, povidone iodine, Ringer's solution, neomycin sulphate, ethanol, chlorhexidine gluconate, cephalothin sodium, and carbenicillin indanyl sodium. CONCLUSIONS: As few clinical studies were carried out with lavage solutions, most of the results are based on experimental studies. A "golden standard" is still missing. PMID- 23986307 TI - Drug release kinetic analysis and prediction of release data via polymer molecular weight in sustained release diltiazem matrices. AB - This study was conducted to investigate the effects of HPMC (K4M and K100M) as well as tragacanth on the drug release rate of diltiazem (DLTZ) from matrix tablets prepared by direct compression method.Mechanism of drug transport through the matrices was studied by fitting the release data to the 10 kinetic models. 3 model independent parameters; i. e., mean dissolution time (MDT), mean release rate (MRR) and release rate efficacy (RE) as well as 5 time point approaches were established to compare the dissolution profiles. To find correlation between fraction of drug released and polymer's molecular weight, dissolution data were fitted into two proposed equations.All polymers could sustain drug release up to 10 h. The release data were fitted best to Peppas and Higuchi square root kinetic models considering squared correlation coefficient and mean percent error (MPE). RE and MRR were decreased when polymer to drug ratio was increased. Conversely, t60% was increased with raising polymer /drug ratio. The fractions of drug released from the formulations prepared with tragacanth were more than those formulated using the same amount of HPMC K4M and HPMC K100M.Preparation of DLTZ matrices applying HPMCK4M, HPMC K100M and tragacanth could effectively extend the drug release. PMID- 23986308 TI - Systemic and local peripheral injections of vitamin B12 suppressed orofacial nociception induced by formalin in rats. AB - Vitamin B12 has many biological functions including antinociceptive property. This study was designed to investigate the effects of local peripheral (into upper lip) and systemic injection of vitamin B12 and diclofenac on the orofacial pain. Orofacial pain was induced by subcutaneous injection 50 uL of a diluted formalin solution (1.5%) in the right upper lip. The time spent face rubbing performed with ipsilateral forepaw was measured in 3 min blocks for a period of 45 min. Formalin produced a biphasic pattern (early phase: 0-3 min and second phase: 15-33 min) of pain response. Systemic (1, 2 and 4 mg/kg) and local peripheral (2.5, 5 and 10 ug/rat) injections of vitamin B12 significantly attenuated the second phase of formalin-induced pain. The same results were obtained from systemic (2 and 4 mg/kg) and local peripheral (100 and 200 ug/rat) injections of diclofenac. Systemic co-administrations of vitamin B12 and diclofenac increased vitamin B12-induced antinociception. Local co administrations of vitamin B12 and diclofenac enhanced antinociception induced by diclofenac. The obtained results indicated that vitamin B12 and diclofenac produced powerful suppressing effects on orofacial inflammatory pain. Co treatments with vitamin B12 and diclofenac produced more antinociceptive effects. Inhibition of cyclooxygenase (COX) pathway may be involved in antinociception induced by vitamin B12. PMID- 23986309 TI - Synthesis and anti-inflammatory activities of novel 5-(3,4-dichlorophenyl)-3-[(4 substitutedpiperazin-1-yl)methyl]-1,3,4-oxadiaxole-2(3H)-thiones. AB - To synthesize a new series of 5-(3,4-dichlorophenyl)-3-[(4-substitutedpiperazin-1 yl)methyl]-1,3,4-oxadiaxole-2-thiones for their anti-inflammatory activity.The title compounds synthesized by Mannich reaction of prepared 5-(3,4-dichloro phenyl)-1,3,4-oxadiazole-2-thione and appropriate substituted piperazine derivatives. The structures of the compounds were confirmed by IR, NMR and elemental analyses. The newly synthesized compounds were evaluated for their anti inflammatory and ulcerogenic activities.Most of the compounds were found to have significant anti-inflammatory profile in carrageenan footpad edema test. The compounds showed anti-inflammatory activity ranging from 30.6% to 57.8% inhibition.The compounds 5b, 5f, 5i, 5p and 5r showed most prominent anti inflammatory activity with low gastric ulceration incidence than the reference drug indomethacine. These compounds could serve as lead molecules for further modifications. PMID- 23986310 TI - Development of health supplement probiotic in relation to physical strength and biological activity in experimental animal. AB - A probiotic nutritive health supplement having a healthy nutritive value was formulated to enhance body function. A 90 days study proved the formulated health supplement to improve the body weight with a maintained normal level of cholesterol and triglycerides in blood which is needful for the proper cardiac function. The supplement also maintained the blood parameters to avoid any illness in the body. In the present study, the health supplement was able to maintain the Haemoglobin level, RBC Count, WBC Count, Platelet Count in Sprague Dawley rats. It is also found that the supplement maintained the cardiac rhythm in the stressful condition and increased in the time of swimming in the force swimming test which indicates an increase in the physical strength. PMID- 23986312 TI - Out, damned spot! Why Rorschach's famous ink-blots continue to intrigue almost 100 years on. PMID- 23986313 TI - Can fMRI safely replace the Wada test for preoperative assessment of language lateralisation? A meta-analysis and systematic review. AB - Recent studies have shown that fMRI (functional magnetic resonance imaging) may be of value for pre-surgical assessment of language lateralisation. The aim of this study was to systematically review and analyse the available literature. A systematic electronic search for studies comparing fMRI with Wada testing was conducted in the PubMed database between March 2009 and November 2011. Studies involving unilateral Wada testing, study population consisting exclusively of children younger than 12 years of age or involving five patients or fewer were excluded. 22 studies (504 patients) were included. A random effects meta-analysis was conducted to obtain pooled estimates of the positive and negative predictive values of the fMRI using the Wada test as the reference standard. The impact of several study features on the performance of fMRI was assessed. The results showed that 81% of patients were correctly classified as having left or right language dominance or mixed language representation. Techniques were discordant in 19% of patients. fMRI and Wada test agreed in 94% for typical language lateralisation and in 51% for atypical language lateralisation. Language production or language comprehension tasks and different regions of interest did not yield statistically significant different results. It can be concluded that fMRI is reliable when there is strong left-lateralised language. The Wada test is warranted when fMRI fails to show clear left-lateralisation. PMID- 23986314 TI - It is high time to reevaluate QuantiFERON-TB gold for clinical practice. PMID- 23986315 TI - Development of an unbiased antigen-mining approach to identify novel vaccine antigens and diagnostic reagents for bovine tuberculosis. AB - Previous experiments for the identification of novel diagnostic or vaccine candidates for bovine tuberculosis have followed a targeted approach, wherein specific groups of proteins suspected to contain likely candidates are prioritized for immunological assessment (for example, with in silico approaches). However, a disadvantage of this approach is that the sets of proteins analyzed are restricted by the initial selection criteria. In this paper, we describe a series of experiments to evaluate a nonbiased approach to antigen mining by utilizing a Gateway clone set for Mycobacterium tuberculosis, which constitutes a library of clones expressing 3,294 M. tuberculosis proteins. Although whole-blood culture experiments using Mycobacterium bovis-infected animals and M. bovis BCG-vaccinated controls did not reveal proteins capable of differential diagnosis, several novel immunogenic proteins were identified and prioritized for efficacy studies in a murine vaccination/challenge model. These results demonstrate that Rv3329-immunized mice had lower bacterial cell counts in their spleens following challenge with M. bovis. In conclusion, we demonstrate that this nonbiased approach to antigen mining is a useful tool for identifying and prioritizing novel proteins for further assessment as vaccine antigens. PMID- 23986316 TI - Inhibition of mycobacterial growth in vitro following primary but not secondary vaccination with Mycobacterium bovis BCG. AB - Despite the widespread use of the Mycobacterium bovis BCG vaccine, there are more than 9 million new cases of tuberculosis (TB) every year, and there is an urgent need for better TB vaccines. TB vaccine candidates are selected for evaluation based in part on the detection of an antigen-specific gamma interferon (IFN gamma) response. The measurement of mycobacterial growth in blood specimens obtained from subjects immunized with investigational TB vaccines may be a better in vitro correlate of in vivo vaccine efficacy. We performed a clinical study with 30 United Kingdom adults who were followed for 6 months to evaluate the abilities of both a whole-blood- and a novel peripheral blood mononuclear cell (PBMC)-based mycobacterial growth inhibition assay to measure a response to primary vaccination and revaccination with BCG. Using cryopreserved PBMCs, we observed a significant improvement in mycobacterial growth inhibition following primary vaccination but no improvement in growth inhibition following revaccination with BCG (P < 0.05). Mycobacterial growth inhibition following primary BCG vaccination was not correlated with purified protein derivative (PPD) antigen-specific IFN-gamma enzyme-linked immunospot (ELISPOT) responses. We demonstrate that a mycobacterial growth inhibition assay can detect improved capacity to control growth following primary immunization, but not revaccination, with BCG. This is the first study to demonstrate that an in vitro growth inhibition assay can identify a difference in vaccine responses by comparing both primary and secondary BCG vaccinations, suggesting that in vitro growth inhibition assays may serve as better surrogates of clinical efficacy than the assays currently used for the assessment of candidate TB vaccines. PMID- 23986317 TI - Increasing the potency of an alhydrogel-formulated anthrax vaccine by minimizing antigen-adjuvant interactions. AB - Aluminum salts are the most widely used vaccine adjuvants, and phosphate is known to modulate antigen-adjuvant interactions. Here we report an unexpected role for phosphate buffer in an anthrax vaccine (SparVax) containing recombinant protective antigen (rPA) and aluminum oxyhydroxide (AlOH) adjuvant (Alhydrogel). Phosphate ions bind to AlOH to produce an aluminum phosphate surface with a reduced rPA adsorption coefficient and binding capacity. However, these effects continued to increase as the free phosphate concentration increased, and the binding of rPA changed from endothermic to exothermic. Crucially, phosphate restored the thermostability of bound rPA so that it resembled the soluble form, even though it remained tightly bound to the surface. Batches of vaccine with either 0.25 mM (subsaturated) or 4 mM (saturated) phosphate were tested in a disease model at batch release, which showed that the latter was significantly more potent. Both formulations retained their potency for 3 years. The strongest aluminum adjuvant effects are thus likely to be via weakly attached or easily released native-state antigen proteins. PMID- 23986318 TI - Investigating the use of protein saver cards for storage and subsequent detection of bovine anti-Brucella abortus smooth lipopolysaccharide antibodies and gamma interferon. AB - Brucella abortus, a smooth strain of the genus Brucella, is the causative agent of bovine brucellosis. To support the ongoing development of diagnostic tests for bovine brucellosis, the use of Protein Saver cards (Whatman) for bovine blood serum and plasma sample collection has been evaluated. These cards offer significant logistical and safety alternatives to transporting and storing liquid samples and may aid in diagnostic programs and validation studies. To evaluate the utility of these cards, 204 bovine blood serum samples from Brucella-infected and noninfected animals were stored on and eluted from the Protein Saver cards. Anti-Brucella smooth lipopolysaccharide (sLPS) antibody titers for the serum eluates were compared to those of the unprocessed original serum samples by indirect enzyme-linked immunosorbent assay (ELISA). The results showed a highly significant correlation between titers from the serum eluates and the unprocessed sera. Therefore, under these circumstances, serum eluates and unprocessed serum samples may be used interchangeably. Blood plasma from 113 mitogen-stimulated whole-blood samples was added to and eluted from the Protein Saver cards. The gamma interferon (IFN-gamma) titers in the plasma eluates were compared to those of the unprocessed plasma samples obtained by IFN-gamma ELISA. The results showed a significant correlation between the plasma eluates and the unprocessed plasma samples. To derive a signal in the plasma eluate, it was necessary to develop a novel and highly sensitive ELISA for the detection of IFN-gamma. The serum samples stored on cards at room temperature over a 10-day period showed little variation in antibody titers. However, the plasma eluates showed a progressive loss of IFN-gamma recovery over 10 days when stored at room temperature. PMID- 23986320 TI - Layered transition metal carboxylates: synthesis, structural aspects and observation of multi-step magnetic transition through phase diagram. AB - Two new layered transition metal carboxylate frameworks, [Co3(L)2(H2O)6].2H2O () and [Ni3(L)2(H2O)6].2H2O () (L = tartronate anion or hydroxymalonic acid), have been synthesized and characterized by X-ray single crystal analysis. Both compounds have similar 2D structures. In both compounds there are two types of metal centers where one center is doubly bridged by the alkoxy oxygen atoms through MU2-O bridging to form a 1D infinite chain parallel to the crystallographic b-axis with the corners shared between the metal polyhedra. Magnetic susceptibility measurements revealed the existence of antiferromagnetic short range correlations between Co(Ni) intra-chain metal centers (with exchange constants JCo = -22.6 and JNi = -35.4 K). At low temperatures, long range order is observed in both compounds at Neel temperatures of 11 (for ) and 16 (for ) K, revealing that other exchange interactions, rather than the intra-chain ones, play a role in these systems. Whereas compound has an antiferromagnetic ground state, compound exhibits a ferromagnetic component, probably due to spin canting. Isothermal magnetization data unveiled a rich phase diagram with three metamagnetic phase transitions below 8 K in compound . PMID- 23986319 TI - Enhancement of serum and mucosal immune responses to a Haemophilus influenzae Type B vaccine by intranasal delivery. AB - Intranasal (i.n.) vaccination is potentially the most direct method for conveying upper respiratory and mucosal immunity to respiratory pathogens. However, for unclear reasons, vaccines introduced into the nasal sinuses often have lower efficacy than vaccines administered by the more frequently used parenteral routes. We examined i.n. vaccination in a mouse immune-response model with a commonly used Haemophilus influenzae type B vaccine (Hibv) composed of the polyribosylribitol phosphate (PRP) capsule antigen conjugated to tetanus toxoid. Intranasal vaccination with Hibv using a Toll-like receptor 4 (TLR4) agonist as an adjuvant significantly increased the levels of IgA specific for the PRP capsule antigen in blood serum, saliva, and mucosal secretion specimens. In contrast, control mice vaccinated transdermally (t.d.) with Hibv did not produce significant levels of PRP-specific IgA in the blood serum and saliva, and anti PRP IgG was increased only in serum. The i.n. and t.d. vaccinations resulted in equivalent bactericidal antibody responses in blood serum, suggesting that vaccine-derived IgG is protective against infection. Elevated levels of IgG specific for the tetanus toxoid carrier protein were measured in nasal sinuses and vaginal secretions in mice vaccinated by either the t.d. or i.n. route. Tissue culture studies confirmed that the nasopharynx-associated lymphoid tissue (NALT) was at least one of the sources of PRP-specific IgA and carrier-specific IgG within the nasal sinuses. We conclude that i.n. vaccination aided by a TLR4 agonist results in robust immune responses to both the carrier protein and bacterial polysaccharide components of the Hibv. PMID- 23986321 TI - Stabilization, fragmentation and rearrangement reactions in low-energy electron interaction with tetrafluoro-para-benzoquinone: a combined theoretical and experimental study. AB - Quinones are a class of organic compounds whose extraordinary electron transfer properties are fundamental in ubiquitous processes such as the ATP production and the photosynthesis. Here, we report a combined theoretical and experimental study to shed some light on low-energy electron interaction with tetrafluoro-para benzoquinone (TFQ) and para-benzoquinone (p-BQ). Similar to it's native counterpart; p-BQ, TFQ forms a metastable molecular anion at unusually high incident energies in electron attachment under single collision conditions. Transition state calculations are used for both p-BQ and TFQ to explore possible stabilization of the molecular anion through isomerization reactions, and stabilization through intramolecular vibrational energy redistribution (IVR) is discussed in relation to the electronic structure of these compounds. We also report exceptionally extensive and complex rearrangement reactions in dissociative electron attachment to TFQ and discuss possible reaction paths based on thermochemical threshold calculations. The observed fragmentation reactions can at large be described by two dissociation series, i.e., the formation of [TFQ - CO -nF](-) (n = 0, 1, 2 or 3) and [TFQ - 2CO -nF](-) (n = 0, 1, 2, 3 or 4). In the latter series we observe, at incident electron energy as low as ~0.5 eV, the excision of two CO molecules followed by recombination of the remaining moiety to form an anionic carbon chain with two terminal CF2 groups. To our knowledge such excision of two non-adjacent carbon atoms and recombination of the remaining moiety have not been observed before in low energy electron attachment. PMID- 23986322 TI - Brain structural alterations induced by fetal exposure to cocaine persist into adolescence and affect behavior. PMID- 23986323 TI - Suppression of thermally activated carrier transport in atomically thin MoS2 on crystalline hexagonal boron nitride substrates. AB - We present the temperature-dependent carrier mobility of atomically thin MoS2 field-effect transistors on crystalline hexagonal boron nitride (h-BN) and SiO2 substrates. Our results reveal distinct weak temperature dependence of the MoS2 devices on h-BN substrates. The room temperature mobility enhancement and reduced interface trap density of the single and bilayer MoS2 devices on h-BN substrates further indicate that reducing substrate traps is crucial for enhancing the mobility in atomically thin MoS2 devices. PMID- 23986324 TI - Survey on the need for bone graft in foot and ankle fusion surgery. AB - BACKGROUND: Generally, autologous bone graft is felt to be an important treatment adjunct in the presence of structural deformity, surface irregularities, defects (due to trauma, surgery, or degenerative changes), or underlying comorbidities that predispose the patient to healing challenges. This study assessed the prognostic and predictive factors used in the clinical decision making for bone graft supplementation in foot and ankle fusion surgery. METHODS: Utilizing standard survey research methodology, key-informant interviews, pretesting, and pilot testing; a survey was constructed. The survey consisted of a web-based 5 point Likert-type scale (never, seldom, sometimes, almost always, always) listing 14 clinical and 11 radiologic criteria that may influence the use of autologous bone grafting or other biologic augmentation in foot and ankle surgery. This survey was sent to Orthopaedic Foot and Ankle Surgeons in North America and Canada. RESULTS: A total of 48 foot and ankle surgeons completed the blinded survey (73% response rate). More than 70% of responders felt bone graft was almost always (AA) or always (A) indicated in prior nonunion of the indicated joint (96%). Fewer than 50% of respondents felt poor soft tissue integrity (20%), prior foot and ankle infection (20%), and current foot and ankle infection (4%) needed bone graft. Radiologic factors marked as AA or A in over 70% of responders include radiographic evidence of nonunion (96%), avascular necrosis (87%), and others. Factors chosen as AA or A by fewer than 50% of surgeons include prior adjacent joint fusions (47%), intra-articular deformity (31%), and extra articular deformity (13%). CONCLUSIONS: There was some uniformity of agreement on the number of both clinical and radiologic factors that prompt a surgeon to utilize autologous bone graft to try to avoid the complication of nonunion. Surgeons may wish to consider these factors when making a decision on the use of bone graft to supplement fusion. PMID- 23986326 TI - Dental hygienists and interprofessional collaboration: thoughts from 1927. PMID- 23986325 TI - Designing a thiol specific fluorescent probe for possible use as a reagent for intracellular detection and estimation in blood serum: kinetic analysis to probe the role of intramolecular hydrogen bonding. AB - A new and simple chemodosimetric probe L1 is utilized for the selective detection of biothiols in the presence of other relevant amino acids under physiological conditions (pH = 7.4). This eventually led to a turn-off luminescence response due to an effective photoinduced electron transfer based signaling mechanism. A comparison of the results of the fluorescence kinetic analysis and (1)H NMR studies of the reaction between thiol and L1 or the analogous compound L2 revealed the role of intramolecular hydrogen bonding in activating the imine functionality towards nucleophilic addition. Such an example is not common in contemporary literature. Conventional MTT assay studies revealed that this probe (L1) has low cytotoxicity. Results of the cell imaging studies revealed that this probe was cell membrane permeable and could detect the intracellular distribution of biothiols within living HeLa cells. Furthermore, our studies with human blood plasma demonstrated the possibility of using this reagent for the quantitative optical detection of total biothiols in biological fluid. Such an example for the detection of biothiols in real biological samples is rare in the contemporary literature. These results clearly demonstrate the possibility of using this reagent in medicinal biology and diagnostic applications. PMID- 23986327 TI - A retrospective comparison of dental hygiene supervision changes from 2001 to 2011. AB - PURPOSE: The purpose of this study is to evaluate the extent of change in the professional practice environment for dental hygienists in the 50 states and District of Columbia by comparing the state supervision requirements for dental hygienists during 2001 to 2011 to the previous 7 year period, 1993 to 2000. METHODS: A retrospective comparison evaluation was conducted using the 2 tables entitled "Tasks Permitted and Mandated Supervision of Dental Hygienists by State, 1993, 1998 and 2000" and "Dental Hygiene Practice Act Overview: Permitted Functions and Supervision Levels by State." To score the net change in supervision, a numerical score was assigned to each level of alteration in supervision with a +1 or -1 for each level of change. RESULTS: With a 95% confidence level, the mean change in dental hygiene supervision from 2001 to 2011 was 6.57 with a standard deviation of 5.70 (p-value=0.002). The mean change of supervision from 1993 to 2000 was 2.61 with a standard deviation of 4.36 (p value=0.0002). The difference in the mean scores for the periods 1993 to 2000 and 2001 to 2011 was 3.96 (p-value=0.06). CONCLUSION: This study shows that the majority of the states are moving toward a decrease in dental hygiene supervision. Study results suggest that the movement appears to be accelerating with more states adopting fewer supervision regulations at a faster rate. Therefore, direction is moving toward more access to dental health care for underserved populations. PMID- 23986328 TI - Catalogue of tooth brush head designs. AB - PURPOSE: Manual toothbrushes (MTBs) and power toothbrushes (PTBs) are effective oral physiotherapy aids for plaque removal. End-rounded bristles are safer and reduce damage to oral tissues. Nylon bristles are more effective in plaque removal because the bristle is stiffer than natural bristles. In the last 10 years the number of options for MTBs and PTBs has expanded significantly and there is very little information providing a reference frame for the design characteristics of the heads. The present in vitro study characterized a variety of MTB and PTB heads to provide a reference library for other research comparisons which might be made. METHODS: Various commercial MTB and PTB heads were used to characterize the following: bristle size, shape, diameter, number of tufts, number of bristles per tuft and surface characteristics. Photographs were collected from the side, at 45 degrees and the top of each toothbrush (TB) head using a scanning electron microscope and digital camera. Images were analyzed (Soft Imaging System) for bristle features and designs. One-way ANOVA (p <= 0.05) was performed to detect differences among TB types within MTB and PTB groups and between pooled values for MTB and PTB groups. RESULTS: There were significant differences (p <= 0.05) in toothbrush bristle diameter and bristle shape. In contrast, there were no significant differences between PTB vs. MTB in regards to bristle diameter, bristle count and tuft count. CONCLUSION: The results suggest that although there are wide variations in toothbrush head designs, significant differences were found only in relation to bristle diameter and shape. PMID- 23986329 TI - Inter-rater reliability of the Mallampati classification for patients in a dental hygiene clinic. AB - PURPOSE: The purpose of this study was to assess the inter-rater reliability between dental hygiene students and a supervising dentist using the Mallampati classification to evaluate and classify the pharyngeal soft tissues. METHODS: A sample of 234 patients volunteered for the study. Mallampati classifications were performed by 21 dental hygiene students for patients during a 12 month period. During that same time period, the clinic dentist performed an independent assessment on the same patients. Quantitative research methods were used to evaluate the inter-rater reliability between dental hygiene students and the clinical dentist in performing the Mallampati classification. The data was analyzed using adjusted McNemar test for non-independent data, Kappa score and percentage of agreement with 95% bootstrap confidence interval. RESULTS: There was an agreement between the dental hygiene student and the dentist in the majority of the independent assessments with a p-value=0.498 from the adjusted McNemar test. Inter-rater agreement measured by Cohen's Kappa coefficient was 0.54 with a 95% bootstrap confidence interval of 0.42, 0.64. The percentage agreement was around 77% with a 95% confidence interval of 72%, 82%. CONCLUSION: It was concluded that dental hygiene students can evaluate and classify the pharyngeal soft tissues comparable to a supervising dentist in the clinical dental hygiene setting. PMID- 23986330 TI - A survey of United States dental hygienists' knowledge, attitudes, and practices with infection control guidelines. AB - PURPOSE: To assess knowledge, attitudes and practices of U.S. dental hygienists with infection control guidelines (ICG). Research has shown improved compliance with specific aspects of dental ICG is needed. This study supports the American Dental Hygienists' Association National Research Agenda's Occupational Health and Safety objective to investigate methods to decrease errors, risks and or hazards in health care. Data are needed to assess compliance, prevention and behavioral issues with current ICG practices. METHODS: A proportional stratified random sample (n=2,500) was recruited for an online survey. Descriptive statistics summarized demographic characteristics and knowledge, attitudes and practices responses. Spearman's rho correlations determined relationships between knowledge, attitudes and practices responses (p<0.05). Dominant themes were identified from open-ended responses. RESULTS: A 31% response rate (n=765) was attained. Respondents agreed/strongly agreed with familiarity with ICG (86%) and believed ICG are relevant to their patients (88%). Responses indicated low compliance (rarely/never used) with handpiece sterilization (n=209, 31%), utility glove use (n=317, 47%), and pre-procedural rinsing (n=324, 48%). Significant relationships were found between ICG implementation and access to necessary supplies (rs=0.549), supervisors' expectations for using ICG (rs=0.529) and no time to use (rs=-0.537). Themes from comments indicated time is a barrier, and respondents' perceived a need for involvement of all co-workers. CONCLUSION: Dental hygienists are adhering with most aspects of the ICG. High compliance with ICG among respondents in this study was associated with positive safety beliefs and practices, whereas lower compliance with ICG was associated with less positive safety beliefs and practices. A safety culture appears to be a factor in compliance with ICG. PMID- 23986332 TI - The attitudes of Ohio dentists and dental hygienists regarding the use of automated external defibrillators in the dental setting--a follow-up study. AB - PURPOSE: In 2004, the attitudes toward and use of automated external defibrillators (AEDs) by Ohio dental professionals were examined. While willing to use an AED, most did not have access to one. With new AED-related legislation and increased awareness of the benefits of AEDs since the initial study in 2004, the purpose of this study was to document the prevalence of and attitudes toward AED usage in the dental setting 7 years following the initial study. METHODS: A 2 page survey instrument was mailed to a random sample of 1,629 dentists and 1,801 dental hygienists in Ohio. RESULTS: A 24% overall response rate was achieved (36% dentists and 64% hygienists). Data were analyzed using SPSS. Results indicate 16% of respondents experienced a cardiac emergency in their practice that required contacting emergency personnel. AEDs are available in 48% of dental practices. Comparing the 2004 and 2011 data, statistically significant differences were found between the responses of dentists and dental hygienists. CONCLUSION: While hygienists reported more positive attitudes toward AEDs than dentists, the majority of all respondents feel AEDs should be mandated in the dental setting. These findings suggest an increase in cardiac emergencies in Ohio dental settings, an increase in the prevalence of AEDs in Ohio dental settings and that the perceptions of dental professionals are changing in favor of the use of AEDs in the dental setting since the 2004 study. PMID- 23986331 TI - A pilot study comparing the outcome of scaling/root planing with and without PerioscopeTM technology. AB - PURPOSE: The purpose of this study was to determine if the use of a periodontal endoscope improves periodontal outcomes of scaling/root planing when compared to scaling/root planing alone. METHODS: Thirty subjects with moderate periodontitis were recruited from the University of Minnesota School of Dentistry. Of these, 26 completed the study. A randomized split mouth design was used to evaluate periodontal outcomes at 6 to 8 weeks and 3 month intervals after sites within 2 quadrants of each subject were scaled and root planed with or without the use of the PerioscopeTM. Paired t-tests were used to test whether there were within patient differences in improvement between PerioscopeTM and non-PerioscopeTM sites as measured by periodontal measurements (probing depth, clinical attachment level) and indices of gingival inflammation, including bleeding on probing (BOP) and gingival inflammation (GI). P-values less than 0.05 were declared to be statistically significant. RESULTS: Less BOP and GI were found in the PerioscopeTM sites at visit 1 and visit 2. Reduction in pocket depth and clinical attachment loss was achieved for all sites but probing depth and clinical attachment level changes were found to be unrelated to the use of the PerioscopeTM. Mean probing depth (SD) was reduced from 5.29 mm (0.4) to 3.55 mm (0.8) in the PerioscopeTM sites and 5.39 mm (0.5) to 3.83 mm (1.2) in non PerioscopeTM sites from baseline measurements to visit 2. CONCLUSION: The adjunctive use of the periodontal endoscope improved periodontal outcomes with respect to gingival inflammation and bleeding upon probing. The adjunctive use of the PerioscopeTM was not found to be superior to traditional scaling and root planing with regard to pocket depth reduction and clinical attachment loss. PMID- 23986333 TI - 3D scaffolds co-seeded with human endothelial progenitor and mesenchymal stem cells: evidence of prevascularisation within 7 days. AB - Blood supply is a critical issue in most tissue engineering approaches for large defect healing. As vessel ingrowth from surrounding tissues is proven to be insufficient, current strategies are focusing on the neo-vascularisation process. In the present study, we developed an in vitro pre-vascularised construct using 3D polyurethane (PU) scaffolds, based on the association of human Endothelial Progenitor Cells (EPC, CD34+ and CD133+) with human Mesenchymal Stem Cells (MSC). We showed the formation of luminal tubular structures in the co-seeded scaffolds as early as day 7 in culture. These tubular structures were proven positive for endothelial markers von Willebrand Factor and PECAM-1. Of special significance in our constructs is the presence of CD146-positive cells, as a part of the neovasculature scaffolding. These cells, coming from the mesenchymal stem cells population (MSC or EPC-depleted MSC), also expressed other markers of pericyte cells (NG2 and alphaSMA) that are known to play a pivotal function in the stabilisation of newly formed pre-vascular networks. In parallel, in co-cultures, osteogenic differentiation of MSCs occurred earlier when compared to MSCs monocultures, suggesting the close cooperation between the two cell populations. The presence of angiogenic factors (from autologous platelet lysates) in association with osteogenic factors seems to be crucial for both cell populations' cooperation. These results are promising for future clinical applications, as all components (cells, growth factors) can be prepared in an autologous way. PMID- 23986334 TI - Measurement of resident workload in paediatric intensive care. AB - OBJECTIVE: To measure the workload of residents in a paediatric intensive care unit (PICU) and to compare this value with the possible explanatory variables "nine equivalents of nursing manpower use score" (NEMS), length of stay (LOS), patient age and severity of illness at admission. METHODS: This was a prospective study in a tertiary, interdisciplinary neonatal-paediatric intensive care unit. In 2010 and 2011, residents estimated their workload for each patient they looked after at admission and then twice a day (morning and night shift) (minor workload 0-30 minutes, medium >30-90 minutes, high >90 minutes). The following demographic and illness severity parameters were also collected prospectively: age, LOS, NEMS, Paediatric Index of Mortality (PIM2), and main diagnosis at admission. RESULTS: There were 2,513 admissions to PICU. Independent predictors of residents' workload were LOS (coefficient in multiple regression 8.9, p <0.0001) and NEMS (coefficient 1.4, p <0.0001). R2 of 0.928 indicated a strong overall relationship. Severity of illness at admission and patient age did not explain overall workload for the whole patient stay in PICU. CONCLUSIONS: NEMS, a therapeutic intervention score, and LOS are both independent predictors of clinical workload of residents in PICU. The correlation with LOS means that workload depends mainly on routine procedures (rounds, discussions with parents, administrative tasks) unrelated to the severity of illness. After calibration, LOS or NEMS, two widely used measures, may be used to calculate resident workload. PMID- 23986336 TI - Rare complication after viral illness. PMID- 23986337 TI - 6-Substituted purines containing thienyl or furyl substituents as artificial nucleobases for metal-mediated base pairing. AB - The artificial nucleobases 6-(2'-thienyl)-purine (6TP) and 6-(2'-furyl)-purine (6FP) have been investigated in terms of their applicability in metal-mediated base pairs. In principle, these nucleobases should be capable of providing an S,N and O,N-coordination environment, respectively. Two metal complexes have been synthesized and structurally characterized, using the N9-methylated derivatives of 6TP and 6FP as model nucleobases. The silver(I) complex [Ag(9 Me6TP)(CH3CN)(NO3)]n is of polymeric nature. The thienyl substituent is not involved in metal binding. In contrast, the dinuclear copper(II) complex [Cu(9 Me6FP)Cl2(OH2)]2 clearly shows that the furyl substituent can participate in the coordination of the metal ion. Oligonucleotide double helices comprising a 6TP:6TP or a 6FP:6FP mispair are slightly stabilized in the presence of silver(I). However, a distinction between the formation of a metal-mediated base pair and an unspecific binding event cannot be finally made. Based on these studies, it is proposed that the formation of Hoogsteen-type metal-mediated base pairs should be the more promising alternative compared with the originally anticipated Watson-Crick-type metal-mediated base pairs. PMID- 23986338 TI - The experience of symptoms of depression in men vs women: analysis of the National Comorbidity Survey Replication. AB - IMPORTANCE: When men are depressed they may experience symptoms that are different than what is included in the current diagnostic criteria. OBJECTIVE: To explore whether sex disparities in depression rates disappear when alternative symptoms are considered in the place of, or in addition to, more conventional depression symptoms. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOMES AND MEASURES: Using data from the National Comorbidity Survey Replication, a nationally represented mental health survey, we evaluated sex differences in symptom endorsement in 2 new scales that included alternative depression symptoms. We analyzed sex differences in symptom endorsement using 2-sided, design-based, .05-level t tests and multivariate logistic regression to identify predictors of depression. RESULTS; Men reported higher rates of anger attacks/aggression, substance abuse, and risk taking compared with women. Analyses using the scale that included alternative, male-type symptoms of depression found that a higher proportion of men (26.3%) than women (21.9%) (P = .007) met criteria for depression. Analyses using the scale that included alternative and traditional depression symptoms found that men and women met criteria for depression in equal proportions: 30.6% of men and 33.3% of women (P = .57). CONCLUSIONS AND RELEVANCE: When alternative and traditional symptoms are combined, sex disparities in the prevalence of depression are eliminated. Further study is needed to clarify which symptoms truly describe men's experiences of depression. PMID- 23986339 TI - Invasive bladder cancer: ignoring the data. PMID- 23986342 TI - Cancer survivorship and the young breast cancer patient: addressing the important issues. PMID- 23986343 TI - Zoledronic acid and its accentuating effect on tumor radiosensitivity. PMID- 23986344 TI - gammadelta T cells predict outcome in zoledronate-treated breast cancer patients. PMID- 23986345 TI - Adjuvant therapy with zoledronic Acid and menopausal status. PMID- 23986346 TI - Role of zoledronate in aromatase activity should be considered in future studies. PMID- 23986347 TI - In reply. PMID- 23986348 TI - IMPACT Study: Targeted Prostate Cancer Screening. PMID- 23986349 TI - Free-standing nitrogen-doped carbon nanofiber films as highly efficient electrocatalysts for oxygen reduction. AB - Free-standing nitrogen-doped carbon nanofiber (NCNF) films based on polyacrylonitrile (PAN) were prepared simply by the combination of electrospinning and thermal treatment. We reused the nitrogen-rich gas generated as the byproduct of PAN at elevated temperature, mainly NH3, for surface etching and nitrogen doping. The as-obtained NCNFs exhibited a rougher surface and smaller diameter than pristine carbon nanofibers. Despite the decreased total N content, a significant increase in the content of pyrrolic-N was observed for the NCNFs. In application to electrochemistry, the free-standing NCNF films showed comparable catalytic activity with a close four-electron pathway to a commercial Pt/C catalyst in alkaline medium toward oxygen reduction reaction (ORR), which can be attributed to the nitrogen doping and high hydrophilicity. More importantly, the ORR current density on the NCNFs only dropped 6.6% after 10,000 s of continuous operation, suggesting an enhanced long-time durability. In addition, the NCNFs also showed better electrocatalytic selectivity than Pt/C. Our work reveals a facile but efficient approach for the synthesis of free standing NCNF films as a promising alternative to Pt-based electrocatalysts in fuel cells. PMID- 23986350 TI - Injuries in agriculture--injury severity and mortality. AB - PRINCIPALS: Accidents in agriculture are a problem of global importance. The hazards of working in agriculture are manifold (machines, animals, heights). We therefore assessed injury severity and mortality from accidents in farming. METHODS: We retrospectively analysed all farming accidents treated over a 12-year period in the emergency department (ED) of our level I trauma centre. RESULTS: Out of 815 patients 96.3% were male and 3.7% female (p <0.0001). A total of 70 patients (8.6%, 70/815) were severely injured. Patients with injuries to the chest were most likely to suffer from severe injuries (odds ratio [OR] 9.45, 95% confidence interval [CI] 5.59-16.00, p <0.0001), followed by patients with injuries to the abdomen (OR 7.06, 95% CI 3.22-15.43, p <0.0001) and patients with injuries to the head (OR 5.03, 95% CI 2.99-8.66, p <0.0001). Hospitalisation was associated with machine- and fall-related injuries (OR 22.39, 95% CI 1.95-4.14, p <0.0001 and OR 2.84 95% CI 1.68-3.41 p <0.001, respectively). Patients suffering from a fall and patients with severe injury were more likely to die than others (OR 3.32, 95% CI 1.07-10.29, p <0.037 and OR 9.17, 95% CI 6.20-13.56, p <0.0001, respectively). Fall height correlated positively with the injury severity score , hospitalisation and mortality (all p <0.0001). CONCLUSION: Injuries in agriculture are accompanied by substantial morbidity and mortality, and range from minor injuries to severe multiple injuries. Additional prospective studies should be conducted on injury severity, long-term disability and mortality. PMID- 23986351 TI - Fundoplication versus postoperative medication for gastro-oesophageal reflux in children with neurological impairment undergoing gastrostomy. AB - BACKGROUND: Children with neurological impairments frequently experience feeding difficulties, which can lead to malnutrition and growth failure. Gastrostomy feeding is now the preferred method of providing nutritional support to children with neurological impairments who are unable to feed adequately by mouth. Complications may arise as a result of gastrostomy placement, and the development or worsening of gastro-oesophageal reflux (GOR) has been widely reported. This has led to the frequent use of surgical antireflux treatment in the form of a fundoplication, or other antireflux procedures. Fundoplication is associated with a high recurrence rate, surgical failure, and significant morbidity and mortality.Since proton pump inhibitors (PPIs) were introduced in the 1990s, they have come to play a larger part in the medical management of GOR in children with neurological impairments. Uncontrolled studies suggest that PPIs may be a safe, appropriate treatment for GOR. Other agents currently used include milk thickeners, acid suppression drugs, acid buffering agents, gut motility stimulants and sodium alginate preparations.There are risks and benefits associated with both surgical and medical interventions and further comparison is necessary to determine the optimal treatment choice. OBJECTIVES: To compare the effectiveness of antireflux surgery and antireflux medications for children with neurological impairments and GOR who are undergoing placement of a gastrostomy feeding tube. SEARCH METHODS: We searched the following databases on 23 March 2012: the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, EMBASE, CINAHL, LILACS and ISI Web of Science. Previously, we searched the Child Health Library in June 2009. We also performed online searches of trial registries, medical journals, conference proceedings, dissertations and theses. We contacted specialists in the medical and industry setting for knowledge of completed or ongoing trials. SELECTION CRITERIA: We sought to include randomised controlled trials that recruited children up to the age of 18 years with neurological impairments and GOR who were undergoing gastrostomy tube insertion. DATA COLLECTION AND ANALYSIS: The review authors worked independently to select trials; none were identified. MAIN RESULTS: We identified no trials that satisfied the criteria for this review. AUTHORS' CONCLUSIONS: There remains considerable uncertainty regarding the optimal treatment when faced with the decision of fundoplication surgery versus antireflux medications for children with GOR and neurological impairment who are undergoing gastrostomy insertion. There is a need for robust scientific evidence in order to provide data on the comparable risks or benefits of the two interventions. PMID- 23986352 TI - Anharmonic vibrations of N-H in Cl(-)(N-methylacetamide)1(H2O)(0-2)Ar2 cluster ions. Combined IRPD experiments and BOMD simulations. AB - Infrared Predissociation (IRPD) spectra of Cl(-)(NMA)1(H2O)0-2Ar2 combined with Born-Oppenheimer Molecular Dynamics (BOMD) IR spectra have been acquired, providing the structure and dynamics of these systems. We show that the chloride ion is bound to the hydrogen of the amide N-H group, forming a strong ionic hydrogen bond, weakening the N-H stretch, and shifting it to lower frequency. The presence of water molecules enhances the ionic hydrogen bond by binding to the amide carbonyl oxygen of NMA and shifts the N-H stretch further to lower frequency. The BOMD IR spectra can recapture all, but about 100 cm(-1), of the 600 to 700 cm(-1) shifts due to the strong N-H stretch anharmonicities observed in experiments. This residual error was found to be due to the lack of zero point energy in the classical treatment of motion in the BOMD method. PMID- 23986353 TI - Comparative mortality risk in adult patients with schizophrenia, depression, bipolar disorder, anxiety disorders, and attention-deficit/hyperactivity disorder participating in psychopharmacology clinical trials. AB - IMPORTANCE: There is concern that increased mortality risk among patients with psychiatric illness may be worsened by psychopharmacological agents. OBJECTIVES: To assess mortality risk among adult patients with a diagnosis of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention deficit/hyperactivity disorder participating in clinical trials conducted by pharmaceutical companies for US Food and Drug Administration (FDA) approval to market and to evaluate if psychopharmacological agents worsen this risk. DATA SOURCES: The FDA Summary Basis of Approval (SBA) reports of new drug applications and supplemental applications for 28 psychopharmacological agents approved between 1990 and 2011. STUDY SELECTION: The FDA SBA reports detailing exposure data from acute placebo-controlled trials and safety extension studies including 92,542 patients from 47 adult drug approval programs for treatment of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention deficit/hyperactivity disorder and SBA reports on combination and maintenance therapy programs for treatments of bipolar disorder. DATA EXTRACTION AND SYNTHESIS: We reviewed and synthesized mortality data from SBA reports that combined mortality rates across the clinical trials, including information on patient exposure years (PEY) for active treatments and placebo for individual indications. MAIN OUTCOMES AND MEASURES: Overall mortality rate per 100,000 PEY in relation to the psychiatric diagnosis of the patients participating in psychopharmacology clinical trials. Also, the overall mortality rates using PEY technique among patients assigned to psychopharmacological agents or placebo were evaluated. RESULTS: Overall, mortality risk was high and significantly associated with psychiatric diagnosis (chi24 = 1760; P < .001). Compared with the general adult population, patients with schizophrenia had the highest mortality risk (3.8 fold increase), followed by patients with depression (3.15-fold increase) and bipolar disorder (3.0-fold increase). The mortality risk was not increased when patients were assigned to psychotropic agents rather than placebo except for heterocyclic antidepressants. Suicide accounted for 109 of all 265 deaths (41.1%). CONCLUSIONS AND RELEVANCE: These data suggest that increased mortality rates reported in population studies are detectable among adult patients with psychiatric illnesses participating in psychopharmacological trials. Furthermore, 3- to 4-month exposure to modern psychotropic agents, such as atypical antipsychotic agents, selective serotonin reuptake inhibitors, and selective serotonin-norepinephrine reuptake inhibitors does not worsen this risk. Given the inherent limitations of the FDA SBA reports, further research is needed to support firm conclusions. PMID- 23986355 TI - Pattern and clinical predictors of lymph node involvement in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). AB - IMPORTANCE: Nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs) are often indolent neoplasms without lymph node (LN) metastasis at diagnosis. Therefore, in patients with low risk of LN metastasis, the extent of surgery and lymphadenectomy could be limited and follow-up adjusted to the very low risk of relapse. OBJECTIVE: To construct a predicting model to assess the risk of pN+ prior to surgical resection for NF-PanNETs using preoperative retrievable variables. DESIGN: Retrospective review using multiple logistic regression analysis to construct predictive model of pN+ based on preoperatively available data. SETTING: The combined prospective databases of the Surgical Departments of the University of Verona, Verona, Italy, and Beaujon Hospital, Clichy, France, were queried for clinical and pathological data. PARTICIPANTS: All patients with resected (R0 or R1), pathologically confirmed NF-PanNETs between January 1, 1993 and December 31, 2009. MAIN OUTCOME AND MEASURE: Risk of lymph node metastases in patients with pancreatic neuroendocrine tumors. RESULTS: Among 181 patients, nodal metastases were reported in 55 patients (30%) and were associated with decreased 5-year disease-free survival (70% vs 97%, P < .001). Multivariable analysis showed that independent factors associated with nodal metastasis were radiological nodal status (rN) (odds ratio [OR], 5.58; P < .001) and tumor grade (NET-G2 vs NET-G1: OR, 4.87; P < .001) (first model). When the tumor grade was excluded, rN (OR, 4.73; P = .001) and radiological tumor size larger than 4 cm (OR, 2.67; P = .03) were independent predictors of nodal metastasis (second model). The area under the receiver operating characteristic curve for the first and second models were 80% and 74%, respectively. CONCLUSIONS AND RELEVANCE: Patients with NF-PanNET-G1 have a very low risk of pN+ in the absence of radiological signs of node involvement. When preoperative grading assessment is not achieved, the radiological size of the lesion is a powerful alternative predictor of pN+. The risk of pathological nodal involvement in patients with NF PanNETs can be accurately estimated by a clinical predictive model. PMID- 23986356 TI - Dynamic covalent capture of hydrazides by a phosphonate-target immobilized on resin. AB - A protocol is described that permits the self-selection of hydrazides from a small library by a phosphonate-target immobilized on resin. Hydrazides are captured by a neighbouring aldehyde group through reversible hydrazone bond formation. Stabilizing intramolecular interactions between the phosphonate-target and functional groups of the hydrazides drive the selection process. The phosphonate-target is introduced onto commercially available Tentagel resin through straightforward synthetic steps. The functionalized resin could be conveniently characterized by HR-MAS NMR spectroscopy using a recently developed transverse relaxation filter that eliminates the strong phase defects commonly observed with CPMG sequences. In addition, a protocol was developed to quantitatively remove the captured hydrazides from resin in order to analyse their composition by LC/MS. Kinetic experiments were used to study hydrazone formation and exchange on resin yielding similar results to those obtained previously in solution. Competition experiments showed that the system reaches thermodynamic equilibrium if multiple hydrazides are added to the resin. Finally, competition experiments showed that the immobilized phosphonate-target indeed amplifies the capture of those hydrazides able to develop stabilizing interactions with the target. Importantly, the obtained amplification profile was nearly identical to the ones obtained previously in solution studies. Notably, the observed amplification factors for the self-selected hydrazides were higher, which was attributed to steric effects imposed by the resin. PMID- 23986357 TI - Ligand/PTC-free intramolecular Heck reaction: synthesis of pyrroloquinoxalines and their evaluation against PDE4/luciferase/oral cancer cell growth in vitro and zebrafish in vivo. AB - A series of 1,3-disubstituted pyrrolo[2,3-b]quinoxalines has been designed for the potential inhibition of PDE4 without inhibiting luciferase. A ligand/PTC (phase transfer catalyst) free intramolecular Heck cyclization strategy was used to prepare these compounds, some of which showed significant inhibition of PDE4B (IC50~ 5-14 MUM) and growth inhibition of oral cancer cells (CAL 27) but not inhibition of luciferase in vitro. They also showed acceptable safety profiles but no apoptosis in zebrafish embryos. PMID- 23986360 TI - Chronic carbon monoxide inhalation during pregnancy augments uterine artery blood flow and uteroplacental vascular growth in mice. AB - End-tidal breath carbon monoxide (CO) is abnormally low in women with preeclampsia (PE), while women smoking during pregnancy have shown an increase in CO levels and a 33% lower incidence of PE. This effect may be, in part, due to lowered sFLT1 plasma levels in smokers, and perhaps low-level CO inhalation can attenuate the development of PE in high-risk women. Our previous work showed maternal chronic CO exposure (<300 ppm) throughout gestation had no maternal or fetal deleterious effects in mice. Our current study evaluated the uteroplacental vascular effects in CD-1 maternal mice that inhaled CO (250 ppm) both chronically, gestation day (GD) 0.5 to 18.5, and acutely, 2.5 h on each of GD 10.5 and 14.5. We demonstrated, using microultrasound measurements of blood velocity and microcomputed tomography imaging of the uteroplacental vasculature, that chronic maternal exposure to CO doubled uterine artery blood flow and augmented uteroplacental vascular diameters and branching. This finding may be of benefit to women with PE, as they exhibit uteroplacental vascular compromise. The ratio of VEGF protein to its FLT1 receptor was increased in the placenta, suggesting a shift to a more angiogenic state; however, maternal circulating levels of VEGF, sFLT1, and their ratio were not significantly changed. Doppler blood velocities in the maternal uterine artery and fetal umbilical artery and vein were unaltered. This study provides in vivo evidence that chronic inhalation of 250 ppm CO throughout gestation augments uterine blood flow and uteroplacental vascular growth, changes that may protect against the subsequent development of preeclampsia. PMID- 23986358 TI - Role of collecting duct endothelin in control of renal function and blood pressure. AB - Over 26,000 manuscripts have been published dealing with endothelins since their discovery 25 years ago. These peptides, and particularly endothelin-1 (ET-1), are expressed by, bind to, and act on virtually every cell type in the body, influencing multiple biological functions. Among these actions, the effects of ET 1 on arterial pressure and volume homeostasis have been most extensively studied. While ET-1 modulates arterial pressure through regulation of multiple organ systems, the peptide's actions in the kidney in general, and the collecting duct in particular, are of unique importance. The collecting duct produces large amounts of ET-1 that bind in an autocrine manner to endothelin A and B receptors, causing inhibition of Na(+) and water reabsorption; absence of collecting duct ET 1 or its receptors is associated with marked salt-sensitive hypertension. Collecting duct ET-1 production is stimulated by Na(+) and water loading through local mechanisms that include sensing of salt and other solute delivery as well as shear stress. Thus the collecting duct ET-1 system exists, at least in part, to detect alterations in, and maintain homeostasis for, extracellular fluid volume. Derangements in collecting duct ET-1 production may contribute to the pathogenesis of genetic hypertension. Blockade of endothelin receptors causes fluid retention due, in large part, to inhibition of the action of ET-1 in the collecting duct; this side effect has substantially limited the clinical utility of this class of drugs. Herein, the biology of the collecting duct ET-1 system is reviewed, with particular emphasis on key issues and questions that need addressing. PMID- 23986359 TI - Leptin-sensitive neurons in the arcuate nucleus integrate activity and temperature circadian rhythms and anticipatory responses to food restriction. AB - Previously, we investigated the role of neuropeptide Y and leptin-sensitive networks in the mediobasal hypothalamus in sleep and feeding and found profound homeostatic and circadian deficits with an intact suprachiasmatic nucleus. We propose that the arcuate nuclei (Arc) are required for the integration of homeostatic circadian systems, including temperature and activity. We tested this hypothesis using saporin toxin conjugated to leptin (Lep-SAP) injected into Arc in rats. Lep-SAP rats became obese and hyperphagic and progressed through a dynamic phase to a static phase of growth. Circadian rhythms were examined over 49 days during the static phase. Rats were maintained on a 12:12-h light-dark (LD) schedule for 13 days and, thereafter, maintained in continuous dark (DD). After the first 13 days of DD, food was restricted to 4 h/day for 10 days. We found that the activity of Lep-SAP rats was arrhythmic in DD, but that food anticipatory activity was, nevertheless, entrainable to the restricted feeding schedule, and the entrained rhythm persisted during the subsequent 3-day fast in DD. Thus, for activity, the circuitry for the light-entrainable oscillator, but not for the food-entrainable oscillator, was disabled by the Arc lesion. In contrast, temperature remained rhythmic in DD in the Lep-SAP rats and did not entrain to restricted feeding. We conclude that the leptin-sensitive network that includes the Arc is required for entrainment of activity by photic cues and entrainment of temperature by food, but is not required for entrainment of activity by food or temperature by photic cues. PMID- 23986361 TI - Temporal characteristics of nitric oxide-, prostaglandin-, and EDHF-mediated components of endothelium-dependent vasodilation in the kidney. AB - Endothelium-dependent vasodilation is mediated by nitric oxide (NO), prostaglandins (PG), and endothelium-derived hyperpolarizing factor (EDHF). We studied the contributions and temporal characteristics of these components in the renal vasodilator responses to acetylcholine (ACh) and bradykinin (BK) and in the buffering of vasoconstrictor responses to norepinephrine (NE) and angiotensin II (ANG II). Renal blood flow (RBF) and vascular conductance (RVC) were studied in anesthetized rats in response to renal arterial bolus injections before and after inhibition of NO-synthase (N(G)-nitro-L-arginine methyl ester, L-NAME), cyclooxygenase (indomethacin, INDO), or both. ACh increased RVC peaking at maximal time (tmax) = 29 s. L-NAME (n = 8) diminished the integrated response and made it substantially faster (tmax = 18 s). The point-by-point difference caused by L-NAME (= NO component) integrated to 74% of control and was much slower (tmax = 38 s). INDO (n = 9) reduced the response without affecting tmax (36 vs. 30 s). The difference (= PG) reached 21% of the control with tmax = 25 s. L-NAME+INDO (n = 17) reduced the response to 18% and markedly accelerated tmax to 16s (= EDHF). Results were similar for BK with slightly more PG and less NO contribution than for ACh. Constrictor responses to NE and ANG II were augmented and decelerated by L-NAME and L-NAME+INDO. The calculated difference (= buffering by NO or NO+PG) was slower than the constriction. It is concluded that NO, PG, and EDHF contribute >50%, 20-40%, and <20% to the renal vasodilator effect of ACh and BK, respectively. EDHF acts substantially faster and less sustained (tmax = 16 s) than NO and PG (tmax = 30 s). Constrictor buffering by NO and PG is not constant over time, but renders the constriction less sustained. PMID- 23986363 TI - Relationship between diet quality and cognition depends on socioeconomic position in healthy older adults. AB - Both diet quality and socioeconomic position (SEP) have been linked to age related cognitive changes, but there is little understanding of how the socioeconomic context of dietary intake may shape its cognitive impact. We examined whether equal adherence to "prudent" and "Western" dietary patterns, identified by principal components analysis, was associated with global cognitive function [Modified Mini-Mental State Examination (3MS)] in independently living older adults with different SEPs (aged 68-84 y; n = 1099). The interaction of dietary pattern adherence with household income, educational attainment, occupational prestige, and a composite indicator of SEP combining all 3 was examined in multiple-adjusted mixed models over 3 y of follow-up in participants of the NuAge study (Quebec Longitudinal Study on Nutrition and Successful Aging). Adherence to the prudent pattern (vegetables, fruits, fish, poultry, and lower fat dairy products) was related to higher 3MS scores at recruitment only in the upper categories of income [parameter estimate (B): 0.56; 95% CI: 0.11, 1.01], education (B: 0.44; 95% CI: 0.080, 0.80), or composite SEP (B: 0.37; 95% CI: 0.045, 0.70). High prudent pattern adherence was associated with less cognitive decline only in those with low composite SEP (B: 0.25; 95% CI: 0.0094, 0.50). Conversely, adherence to the Western pattern (meats, potatoes, processed foods, and higher-fat dairy products) was associated with more cognitive decline (B: 0.23; 95% CI: -0.43, -0.032) only in those with low educational attainment. In summary, among individuals with equivalent diet quality, the magnitude and characteristics of the diet-cognition relationship depended on their socioeconomic circumstances. These results suggest that interventions promoting retention of cognitive function through improved diet quality would provide maximum benefit to those with relatively low SEP. PMID- 23986362 TI - Hemoglobin isoform differentiation and allosteric regulation of oxygen binding in the turtle, Trachemys scripta. AB - When freshwater turtles acclimatize to winter hibernation, there is a gradual transition from aerobic to anaerobic metabolism, which may require adjustments of blood O2 transport before turtles become anoxic. Here, we report the effects of protons, anionic cofactors, and temperature on the O2-binding properties of isolated hemoglobin (Hb) isoforms, HbA and HbD, in the turtle Trachemys scripta. We determined the primary structures of the constituent subunits of the two Hb isoforms, and we related the measured functional properties to differences in O2 affinity between untreated hemolysates from turtles that were acclimated to normoxia and anoxia. Our data show that HbD has a consistently higher O2 affinity compared with HbA, whereas Bohr and temperature effects, as well as thiol reactivity, are similar. Although sequence data show amino acid substitutions at two known beta-chain ATP-binding site positions, we find high ATP affinities for both Hb isoforms, suggesting an alternative and stronger binding site for ATP. The high ATP affinities indicate that, although ATP levels decrease in red blood cells of turtles acclimating to anoxia, the O2 affinity would remain largely unchanged, as confirmed by O2-binding measurements of untreated hemolysates from normoxic and anoxic turtles. Thus, the increase in blood-O2 affinity that accompanies winter acclimation is mainly attributable to a decrease in temperature rather than in concentrations of organic phosphates. This is the first extensive study on freshwater turtle Hb isoforms, providing molecular evidence for adaptive changes in O2 transport associated with acclimation to severe hypoxia. PMID- 23986364 TI - Chronic physical and mental health conditions among adults may increase vulnerability to household food insecurity. AB - Analyses of cross-sectional population survey data in Canada and the United States have indicated that household food insecurity is associated with poorer self-rated health and multiple chronic conditions. The causal inference has been that household food insecurity contributes to poorer health, but there has been little consideration of how adults' health status may relate to households' vulnerability to food insecurity. Our objectives were to examine how the presence of an adult with one or more chronic physical or mental health conditions affects the odds of a household being food insecure and how the chronic ill-health of an adult within a food-insecure household affects the severity of that household's food insecurity. Using household- and respondent-level data available for 77,053 adults aged 18-64 y from the 2007-2008 Canadian Community Health Survey, we applied logistic regression analyses, controlling for household sociodemographic characteristics, to examine the association between health and household food insecurity. Most chronic conditions increased the odds of household food insecurity independent of household sociodemographic characteristics. Compared with adults with no chronic condition, the odds of household food insecurity were 1.43 (95% CI: 1.28, 1.59), 1.86 (95% CI: 1.62, 2.14), and 3.44 (95% CI: 3.02, 3.93) for adults with 1, 2, and 3 or more chronic conditions, respectively. Among food-insecure households, adults with multiple chronic conditions had higher odds of severe household food insecurity than adults with no chronic condition. The chronic ill-health of adults may render their households more vulnerable to food insecurity. This has important practice implications for health professionals who can identify and assist those at risk, but it also suggests that appropriate chronic disease management may reduce the prevalence and severity of food insecurity. PMID- 23986365 TI - Health, behavioral, cognitive, and social correlates of breakfast skipping among women living in socioeconomically disadvantaged neighborhoods. AB - Breakfast skipping is a potentially modifiable behavior that has negative effects on health and is socioeconomically patterned. This study aimed to examine the intrapersonal (health, behavioral, and cognitive) and social factors associated with breakfast skipping. Nonpregnant women (n = 4123) aged 18-45 y from socioeconomically disadvantaged neighborhoods throughout Victoria, Australia, completed a postal questionnaire. Sociodemographic characteristics, diet, physical activity, sedentary behaviors, and cognitive and social factors were assessed by self-report. Breakfast skipping was defined in 2 ways: 1) "rarely/never" eating breakfast (n = 498) and 2) eating breakfast <=2 d/wk (includes those who rarely/never ate breakfast; n = 865). Poisson regression was used to calculate prevalence ratios and linear trends, adjusting for covariates. The P values for linear trends are reported below. Compared with breakfast consumers, women who reported rarely/never eating breakfast tended to have poorer self-rated health (P-trend < 0.001), be current smokers (P-trend < 0.001), pay less attention to health (P-trend < 0.001), not prioritize their own healthy eating when busy looking after their family (P-trend < 0.001), have less nutrition knowledge (P-trend < 0.001), and a lower proportion were trying to control their weight (P-trend < 0.020). When breakfast skipping was defined as eating breakfast <=2 d/wk, additional associations were found for having lower leisure-time physical activity (P-trend = 0.012) and less self-efficacy for eating a healthy diet (P-trend < 0.043). In conclusion, a range of intrapersonal and social factors were significantly associated with breakfast skipping among women living in socioeconomically disadvantaged areas. Acknowledging the cross sectional design and need for causal confirmation, programs that aim to promote breakfast consumption in this population group should consider targeting family related barriers to healthy eating and nutrition knowledge. PMID- 23986367 TI - Conversion to prolonged release tacrolimus formulation in stable kidney transplant recipients. AB - PRINCIPLES: The once-daily tacrolimus formulation (Advagraf(r)), with the potential for improving medical adherence, has been advocated to improve long term kidney allograft outcomes. However, experience with late conversion from the twice-daily tacrolimus formulation (Prograf(r)) to Advagraf in the daily care of stable kidney transplant recipients has been limited. METHODS: The aim of this study was to observe the efficacy and safety of conversion from Prograf to Advagraf in chronic stable kidney transplant recipients in routine clinical practice. The recruited patients had postconversion follow-up at least once monthly for a total of six months, unless they had discontinued the use of Advagraf, had been lost the follow-up or had lost the graft. RESULTS: The mean age of the 199 patients was 51.5 +/- 10.4 years (60.8% male). The mean time from transplantation to the conversion to Advagraf was 8.3 +/- 3.2 years and the mean tacrolimus trough level at conversion was 4.2 +/- 1.4 ng/ml. After conversion, 147 patients (73.8 %) had a reduced trough level at one month and the mean change in trough level postconversion was -13.5%. The mean serum creatinine level between conversion and six months postconversion was not significantly different (1.12 +/- 0.36 vs 1.10 +/- 0.42 mg/dl). Thirty-four patients (17%) discontinued the treatment with Advagraf and two (1%) developed biopsy-proved acute rejection. CONCLUSIONS: In conclusion, frequent conversion caused by a high discontinuation rate may further raise the potential risk of allograft rejection and increase unnecessary cost. In view of this, the policy of converting to Advagraf with the purpose of improving medical adherence should be individualised in routine clinical practice. PMID- 23986366 TI - Intake of specific nonfermented soy foods may be inversely associated with risk of distal gastric cancer in a Chinese population. AB - Because the association between soy consumption and gastric cancer is inconsistent, we evaluated the putative preventive effect of soy food on gastric cancer risk in the Shanghai Women's and Men's Health Studies, comprising a total of 128,687 participants. Intake of nonfermented soy foods was estimated using 2 validated food-frequency questionnaires. HRs were calculated with 95% CIs for intake amounts of total nonfermented soy food intake, soy protein, and isoflavones as well as individual soy food groups using Cox proportional hazards regression. A total of 493 distal gastric cancer cases were identified by 2010. Although all risk estimates for summary measures of soy food intake above the lowest quartile (quartile 1) were suggestive of a protective effect, no statistically significant associations with risk of distal gastric cancer were found. Among the separate soy food groups, significant reductions in risk of distal gastric cancer by increasing intake of tofu were found in men in quartile 2 (HR: 0.59; 95% CI: 0.40, 0.86), quartile 3 (HR: 0.62; 95% CI: 0.44, 0.88), and quartile 4 (HR: 0.64; 95% CI: 0.42, 0.99), resulting in a significant trend (P trend = 0.02). Dry bean intake was also inversely associated with decreased risk of gastric cancer, but in postmenopausal women only [quartile 2 (HR: 0.54; 95% CI: 0.30, 0.96); quartile 3 (HR: 0.90; 95% CI: 0.64, 1.27); and quartile 4 (HR: 0.63; 95% CI: 0.43, 0.91)], resulting in a significant trend (P-trend = 0.03). Overall, our study found no statistically significant association between nonfermented soy food intake and distal gastric cancer risk, though the data supported the hypothesis that tofu may protect against distal gastric cancer in men and dry bean consumption may decrease the risk of gastric cancer in postmenopausal women. PMID- 23986368 TI - On the flexibility of the gold-thiolate interface: racemization of the Au40(SR)24 cluster. AB - The two enantiomers of the Au40(2-PET)24 cluster were collected using HPLC and analyzed by MALDI-TOF mass spectrometry, UV-vis- and CD-spectroscopy. The flexibility of the cluster surface allows racemization of the intrinsically chiral cluster at elevated temperatures (80-130 degrees C) which was monitored following the optical activity. The determined activation energy (25 kcal mol( 1)) lies in the range of previously reported values for Au38 nanoclusters whereas the activation entropy deviates significantly from the one in Au38. The latter may indicate that the racemization can take place via different mechanisms. PMID- 23986369 TI - Trimodal detection of early childhood caries using laser light scanning and fluorescence spectroscopy: clinical prototype. AB - There is currently a need for a safe and effective way to detect and diagnose early stages of childhood caries. A multimodal optical clinical prototype for diagnosing caries demineralization in vivo has been developed. The device can be used to quickly image and screen for any signs of demineralized enamel by obtaining high-resolution and high-contrast surface images using a 405-nm laser as the illumination source, as well as obtaining autofluorescence and bacterial fluorescence images. When a suspicious region of demineralization is located, the device also performs dual laser fluorescence spectroscopy using 405- and 532-nm laser excitation. An autofluorescence ratio of the two excitation lasers is computed and used to quantitatively diagnose enamel health. The device was tested on five patients in vivo as well as on 28 extracted teeth with clinically diagnosed carious lesions. The device was able to provide detailed images that highlighted the lesions identified by the clinicians. The autofluorescence spectroscopic ratios obtained from the extracted teeth successfully quantitatively discriminated between sound and demineralized enamel. PMID- 23986370 TI - Breast cancer: a review for the general surgeon. AB - Breast cancer care is complex and requires a multidisciplinary approach. In this study, we provide an overview of current practices for the diagnosis and treatment of breast cancer for surgical practitioners who do not focus on this disease. We include studies published in high-impact, peer-reviewed journals that have informed or altered the standard of care, with preference given to large, multicenter, randomized clinical trials when available. Our study highlights that the surgical management of breast cancer has changed dramatically over the past decades. As our understanding of the disease process increases, practice guidelines will continue to evolve. PMID- 23986371 TI - "Mauled by a Bear": narrative analysis of self-injury among adolescents in US news, 2007-2012. AB - Self-injury among adolescents has been widely documented in the United States, Canada, Europe, and Asia; however, news coverage of self-injury has not been examined. This study analyzes 78 news accounts of self-injury among adolescents in the United States from 2007 to 2012, using critical cultural studies as a theoretical foundation and a methodology informed by Kenneth Burke's dramatism. Narrative elements within the sample are examined in relationship to one another in order to reveal implicit meanings within the news stories. Looking across the sample, I then use a framework developed by Labov and Waletzky to examine a dominant meta-narrative that downplays social causes of self-injury-notably, various forms of trauma such as childhood sexual abuse-and instead frames self injury as a personal choice. As a result, the remedy to the problem is not constructed as redress of contemporary pressures placed upon young people, but rather, as the responsibility of adolescents to conform to the social system that causes them to hurt themselves. PMID- 23986372 TI - Exploring the relationship between multi-morbidity, resilience and social connectedness across the lifecourse. AB - Multi-morbidity is receiving considerable attention in public policy, health and social care. From the perspective of the individual, multi-morbidity is a more complex experience than solely having a clinical diagnosis. In this article, we will argue that understanding multi-morbidity can be facilitated by considering the relationship between adversity (in this case multi-morbidity), resilience and social connectedness within a life course framework. This provides an approach that can capture the dynamics of social relationships, social connectedness and the fluctuations in the experience of multi-morbidity. We draw on a qualitative study of 17 people who have multiple conditions, but consider themselves as being able to maintain a sense of identity and self over time and in the face of adversity. From their accounts, a more varied picture emerges of living with multi-morbidity. This then depicts a more realistic representation of how each person shapes their multi-morbidity and resilient responses within their own social context, which can help to formulate more effective ways of supporting them. PMID- 23986373 TI - Transformations of self and sexuality: psychologically modified experiences in the context of forensic mental health. AB - Forensic mental health inpatients in medium-secure settings have a limited capacity for sexual expression during their stay in hospital. This is due to a number of factors, including a lack of willingness on behalf of staff to engage with sexual issues, as a result of safety fears and ambiguity regarding the ability of the patient to consent. Furthermore, UK forensic medium-secure units do not provide conjugal suites for patients to have sexual relations, with their spouse or other patients. To date, there is no empirical research on how forensic psychiatric patients (or service users) manage their sexuality, while in hospital and when released into the community. Here, we present an analysis of semi structured interviews with patients at a UK medium forensic unit, in order to explore these issues further. More specifically, we examine how the public exclusion of sexuality from these units results in sexuality being experienced as sectioned off or amputated, such that a new form of sexuality emerges, one that has been cultivated by the psychologically informed practices operating within the unit. This process, we argue, produces a psychologically modified experience, a new form of self-relation that continues to modify when released into the broader ecology of the community. PMID- 23986374 TI - Networks of knowledge or just old wives' tales?: A diary-based analysis of women's self-care practices and everyday lay expertise. AB - Complementary and alternative medicine is increasingly popular in Australia and particularly among women. While existing research provides some understanding of women's engagement with complementary and alternative medicine and biomedicine, there has been comparatively little examination of the day-to-day character of their experiences. In this study, we utilise solicited diaries with women aged 60 65 years drawn from the 1946-1951 cohort of the Australian Longitudinal Study on Women's Health to capture the temporal dimension of their therapeutic engagement. Focusing on 30 active complementary and alternative medicine users, we explore women's experiences of managing their health, illness and well-being over a 1 month period. The themes that emerge from their diaries illustrate the day-to-day enactment of lay expertise through informal knowledge networks, practices of self trialling and experimentation and the moralities underpinning self-care. The diaries provide unprecedented temporal insight into the (often problematic) enactment of lay expertise at the nexus of complementary and alternative medicine and biomedicine. They also point to the value of longitudinal techniques of data collection for augmenting more traditional sociological ways of exploring therapeutic pluralism. PMID- 23986375 TI - Urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL) and contrast-induced acute kidney injury after coronary angiogram. AB - QUESTIONS UNDER STUDY: Diagnosis of acute kidney injury (AKI) relies on measurement of serum creatinine (SCr). SCr is a late marker of impaired renal function. Urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL) has given encouraging results for an early and sensitive detection of AKI. This cohort study was conducted (1) to assess the value of uNGAL as early marker of contrast induced AKI (CI-AKI) in unselected patients undergoing percutaneous coronary procedure (PCP) and (2) to investigate whether uNGAL levels correlate with the volume of contrast medium (CM) used during the procedure. METHODS: We enrolled 244 consecutive adult patients undergoing PCP done with the low-osmolar CM Iomeprolum (median volume of CM 122 [88-168] ml per procedure). uNGAL was measured at its peak with a standardised clinical laboratory platform (ARCHITECT uNGAL assay, Abbott). RESULTS: Overall, the post-PCP uNGAL levels were extremely low in our cohort with a median value of 7.7 [4.0-14.5] ng/ml (N <=132 ng/ml). Twenty-five (10%) patients developed CI-AKI according to the classical diagnostic criteria (>=25% or >=44.2 umol/l increase in SCr) and 8 (3.3%) patients according to the AKIN criteria. Regardless of the definition considered, uNGAL levels did not significantly differ in patients with or without CI-AKI. Similarly, we found no significant correlation between the volume of CM used and the post-PCP uNGAL levels (r = -0.11). CONCLUSIONS: In a large cohort of unselected adult patients, uNGAL measured four to six hours after PCP was ineffective to predict the risk of CI-AKI and did not correlate with the volume of CM used during the procedure. PMID- 23986376 TI - Child obesity in Latin America: a challenge for health promotion. PMID- 23986377 TI - Child diet and healthy growth in the context of rural poverty in the peruvian andes: what influences primary caregivers' opportunities and choices? AB - This study explored opportunities and choices related to child feeding among women living in a remote and low-income district in the Andean highlands. Data were collected through in-depth interviews with mothers (N = 7) with reputations for providing good child care, and who participated in an NGO-run social and health programme. The aim of this study was to learn about women's positive experience with child feeding, in the context of living in low-income communities. Such knowledge could be of substantial practical value to health promotion practitioners, in illuminating existing local circumstances and practices that produce good child nutrition. The women who were most knowledgeable about child health and diet were better educated and had relatively higher social positions in the community. Regarding contextual factors related to child feeding, numerous references were made to the extensive use of own crops and food stuffs, seen to provide a better diet than that available in cities where people buy their food. In discussing food and meal preparation habits, there were clear references to child welfare and health as motivating factors in the choices that were made. The NGO programme was not mentioned by the interviewer, to avoid prompting, yet the respondents referred to it explicitly, and attributed improved health-related knowledge and skills to the NGO education interventions (e.g. education about nutritious meal preparation, child care skills, and sanitation practices). It is concluded that the women were concerned about providing a good diet to their children, they were aware of the impact of feeding practices on child health, and that education about health and diet helped them to improved feeding practices. PMID- 23986378 TI - Does law enforcement awareness affect motorcycle helmet use? evidence from urban cities in Thailand. AB - Although helmet use has been compulsory for motorcycle drivers and passengers in Thailand since the enactment of the Helmet Act in 1994, recent surveys show that the prevalence of helmet usage remains low, particularly among passengers. This paper has sought to explore motorcyclists' awareness of helmet law enforcement in Thailand and examine whether it affects their helmet use behaviour. A total of 2,429 drivers and 1,328 passengers in urban cities nationwide were interviewed in 2009, and the data were analysed using a multivariate ordered logit regression technique. About 60% of the drivers and only 28% of the passengers reported that they always wore a motorcycle helmet. Apart from basic demographics (i.e. age and gender) and riding frequency, our analysis reveals that the awareness of helmet law enforcement was among the contributing factors influencing the use of motorcycle helmets in Thailand. Regardless of riding position, the prevalence of helmet use tended to be greater among those frequently observing the police's checkpoints for helmet wearing and those perceiving the high risk of being caught for non-helmet use. However, the use of helmets appeared to be lower among drivers who perceived the checkpoints to take place at the same times and locations, which were likely predicted. For motorcycle passengers, it was found that the low prevalence of helmet use was potentially attributable to the absence of knowledge on the compulsory helmet law for passengers and the perception that the law was not enforced by the police. Thus, if motorcycle helmet use in Thailand is to be increased, considerable efforts need to be given to increasing the perceived risk of apprehension for non-helmet use (e.g. more police presence and random scheduling of enforcement activities), improving the awareness of the existing helmet law for passengers, and ensuring that helmet wearing by passengers is more strictly enforced. PMID- 23986379 TI - The impact of public expenditure on undernourishment distribution in Mexico. AB - The status of undernourishment in children under the age of five in Mexico is open to debate. Linked to poverty, underweight and stunting, the rates of undernourishment are reported to be diminishing, although poverty remains an incessant problem. This study was done to determine whether there is an association between public expenditure and underweight and stunting distribution in Mexico based on data from the 2006 health and population census and from macroeconomic, social, and demographic variables. We used principal component analysis to reduce the number of variables and analyze their behavior. Multiple regressions showed that underweight and stunting are significantly associated with the marginalization index, support from the Sistema Nacional para el Desarrollo Integral de la Familia (DIF) supplies and breakfast program, the gross domestic product per capita, and expenditure from the Opportunities program. Further, public expenditure aimed to combat undernourishment is inadequately oriented to address the needs of the poor. PMID- 23986380 TI - Date rape among Cypriot female college students: an explorative study. AB - This study examined the prevalence and reporting of date rape among female college students (aged 18-24) in Cyprus and assessed the students' attitudes and awareness regarding date rape. In addition, the study examined how date rape is perceived among representatives of related private and governmental organizations in Cyprus. This is part of a larger multi-country study. This paper will focus only on the results pertaining to Cyprus. The study was coordinated by the Mediterranean Institute of Gender Studies. This study used quantitative and qualitative methods. In total, 476 female college students responded to an anonymous questionnaire, two focus group discussions were carried out, and five key-informant interviews with relevant institutional representatives were conducted. The results of the study indicated that unwanted sexual experiences and sexual violence, including date rape, do exist among young Cypriot women. Specifically, 1.3% of the research participants reported experiencing an attempted rape by their date, and 1.9 % of the study participants reported being raped on a date. Often this was caused by their boyfriend, friend or sexual partner (54.2%). The results of the qualitative study showed that young female Cypriots agreed that many women give in to psychological pressure because they feel guilty about letting the other person down or because they 'didn't satisfy him' or fear they might lose him. Despite the explorative nature of the study, it is significant as research on date rape in Cyprus is almost non-existent. The authors anticipate that the results of the study will be useful to other researchers and policy-makers involved in this area of research. PMID- 23986381 TI - Neglected tropical diseases: is it time to add Helicobacter pylori to the list? AB - Neglected tropical diseases (NTDs) disproportionately affect disadvantaged populations as the 2012 World Health Organization (WHO) report on the global impact of NTDs points out. The same social determinants that impact the prevalence of the 17 current NTDs: inadequate drinking water and sanitation, crowded living conditions, environmental impacts on food and water, ethnicity as well as poverty contribute to Helicobacter pylori infections worldwide. PMID- 23986382 TI - Health activism: the way forward to improve health in difficult times. AB - Health activism is an action on behalf of a cause, action that goes beyond what is conventional or routine in society. It involves a challenge to the existing order whenever it is perceived to lead to a social injustice or inequality. Today social injustice is killing people on a grand scale and it is timely for health activism to be used as a way forward to improve health during difficult economic and political times. Health activism is essential because it can create the necessary conditions for people to take control over their own lives when others cannot or will not act on their behalf. Health promotion agencies and the practitioners that they employ, professional organisations and researchers can also play an important role. What is clear is that if greedy corporations and complacent governments are not challenged, we will continue to have limited success in improving health. PMID- 23986384 TI - [Include representations of caregivers coping with nosocomial Clostridium difficile in Quebec to promote better health]. PMID- 23986385 TI - [Contributions of people using mental health services as partners in teaching psychiatry]. PMID- 23986387 TI - [Impact of training actions in the risk perception of university students: A preliminary study]. PMID- 23986388 TI - [Dating violence and mental health in Mexican college students]. PMID- 23986389 TI - Design and synthesis of the stabilized analogs of belactosin A with the unnatural cis-cyclopropane structure. AB - The belactosin A analog 2a, having the unnatural cis-cyclopropane structure instead of the trans-cyclopropane structure in belactosin A, is a much more potent proteasome inhibitor than belactosin A. However, its cell growth inhibitory effect is rather lower than that expected from its remarkable proteasome inhibitory effect, probably due to its instability under cellular conditions. We hypothesized that the instability of 2a was due to chemical and enzymatic hydrolysis of the strained beta-lactone moiety. Thus, to increase the stability of 2a by chemical modification, its analogs with a sterically more hindered beta-lactone moiety and/or cyclopropylic strain-based conformational restriction were designed and synthesized, resulting in the identification of a stabilized analog 6a as a proteasome inhibitor with cell growth inhibitory effects. Our findings suggest that the chemical and biological stability of 2a is significantly affected by the steric hindrance around its beta-lactone carbonyl moiety and the conformational flexibility of the molecule. PMID- 23986390 TI - Obesity hypoventilation syndrome: does the current definition need revisiting? PMID- 23986391 TI - Non-tuberculous mycobacteria: a retrospective review of Scottish isolates from 2000 to 2010. AB - There is growing recognition of the clinical importance of non-tuberculous mycobacteria (NTM), a group of versatile opportunistic bacterial pathogens. We describe the characteristics of NTM isolates in Scotland over an 11-year period using data held by the Scottish Mycobacteria Reference Laboratory. American Thoracic Society microbiological criteria were used to evaluate the clinical significance of isolates. Data presented include analysis of trends across time, species/body site associations, gender and age differences, geographical variations and the association between cystic fibrosis and Mycobacterium abscessus. We emphasise the need for standardised reporting criteria for NTM isolates to ensure optimal surveillance of NTM disease. PMID- 23986392 TI - Diffuse reflectance relations based on diffusion dipole theory for large absorption and reduced scattering. AB - Diffuse reflectance spectra are used to determine the optical properties of biological samples. In medicine and forensic science, the turbid objects under study often possess large absorption and/or scattering properties. However, data analysis is frequently based on the diffusion approximation to the radiative transfer equation, implying that it is limited to tissues where the reduced scattering coefficient dominates over the absorption coefficient. Nevertheless, up to absorption coefficients of 20 mm-1 at reduced scattering coefficients of 1 and 11.5 mm-1, we observed excellent agreement (r2=0.994) between reflectance measurements of phantoms and the diffuse reflectance equation proposed by Zonios et al. [Appl. Opt.38, 6628-6637 (1999)], derived as an approximation to one of the diffusion dipole equations of Farrell et al. [Med. Phys.19, 879-888 (1992)]. However, two parameters were fitted to all phantom experiments, including strongly absorbing samples, implying that the reflectance equation differs from diffusion theory. Yet, the exact diffusion dipole approximation at high reduced scattering and absorption also showed agreement with the phantom measurements. The mathematical structure of the diffuse reflectance relation used, derived by Zonios et al. [Appl. Opt.38, 6628-6637 (1999)], explains this observation. In conclusion, diffuse reflectance relations derived as an approximation to the diffusion dipole theory of Farrell et al. can analyze reflectance ratios accurately, even for much larger absorption than reduced scattering coefficients. This allows calibration of fiber-probe set-ups so that the object's diffuse reflectance can be related to its absorption even when large. These findings will greatly expand the application of diffuse reflection spectroscopy. In medicine, it may allow the use of blue/green wavelengths and measurements on whole blood, and in forensic science, it may allow inclusion of objects such as blood stains and cloth at crime scenes. PMID- 23986393 TI - Mercury(II) complex formation with N-acetylcysteine. AB - N-Acetylcysteine (H2NAC) is a potent antioxidant, a precursor for cysteine and glutathione, and a potential antidote against certain metal ions such as cadmium and mercury. Little is known about the structural aspects of complexes formed between Hg(II) and N-acetylcysteine, despite many biological tests on its ability to bind to organic and inorganic mercury, and a few reports on formation constants for Hg(NAC)n (n = 1-3) complexes. We have combined several techniques, including Hg L3-edge EXAFS (extended X-ray absorption fine structure), (199)Hg NMR and Raman spectroscopy, to investigate the nature and structure of Hg(II) N acetylcysteine complexes formed in aqueous solution at pH 7.5 and 10.5. To allow measurements on the same samples, rather concentrated solutions containing CHg(II) = 0.1 M and variable H2NAC/Hg(II) mole ratios = 2.0-10.0 were used. At physiological pH, Hg(NAC)2(2-) and Hg(NAC)3(4-) complexes form, while in ligand excess and at alkaline pH (H2NAC/Hg(II) > 4), a novel tetra-thiolate species Hg(NAC)4(6-) dominates. Comparison between the Hg(II) complex formation with cysteine, penicillamine and N-acetylcysteine in alkaline aqueous solution has been made to elucidate the influence of the blocked amino group of N acetylcysteine. PMID- 23986394 TI - Dermatomyositis induced by anti-tumor necrosis factor in a patient with juvenile idiopathic arthritis. AB - IMPORTANCE: Biologic therapies, including anti-tumor necrosis factor (TNF) agents, are increasingly used to treat a variety of autoimmune diseases. Paradoxically, these agents have been reported to induce some of the very diseases they were designed to treat, including dermatomyositis (DM). We describe the first case of anti-TNF-associated DM without muscle involvement presenting in an adult patient with a history of arthritis since childhood. This cutaneous eruption recurred after rechallenge with an alternate anti-TNF agent. OBSERVATIONS: A 46-year-old man with juvenile idiopathic arthritis developed a pruritic cutaneous eruption while receiving etanercept. Given concern about a drug-induced eruption, etanercept therapy was discontinued and the cutaneous findings improved. However, after rechallenge with adalimumab, he developed similar findings consistent with the skin manifestations of DM. After discontinuation of all anti-TNF drug therapy and the addition of methotrexate sodium, his eruption improved. CONCLUSIONS AND RELEVANCE: Because the use of these agents is increasing, practitioners should be aware of the possibility of anti-TNF-induced autoimmune disorders, including DM. The case described herein is unique in that anti-TNF-induced autoimmune disease occurred in a patient with existing arthritis since childhood and recurred with rechallenge, adding further evidence to support the existence of anti-TNF-induced DM. PMID- 23986395 TI - Protein-DNA force assay in a microfluidic format. AB - The detailed study of protein-DNA interactions is a core effort to elucidate physiological processes, including gene regulation, DNA repair and the immune response. The molecular force assay (MFA) is an established method to study DNA binding proteins. In particular, high-affinity binder dissociation is made possible by the application of force. Microfluidic lab-on-a-chip approaches have proven helpful for parallelization, small sample volumes, reproducibility, and low cost. We report the successful combination of these two principles, forming a microfluidic molecular force assay and representing a novel use for the established MITOMI chip design. We present, characterize, validate and apply this integrated method. An alternative confocal fluorescence microscopy readout and analysis method is introduced and validated. In a multiplexing application, EcoRI binding is detected and characterized. This method paves the way for quantitative on-chip force measurements. It is suited for integration with DNA micro-spotting and in vitro expression of transcription factors to form a high-throughput chip for detailed DNA-protein interaction studies. PMID- 23986396 TI - Universal flu vaccines: primum non nocere. AB - Envisioning universal influenza vaccines that induce antibodies to conserved viral epitopes is exciting, but first we need to better understand the balance of effects caused by neutralizing and nonneutralizing antibodies (Khurana et al., this issue). PMID- 23986397 TI - Curing consortium fatigue. AB - The complex pathology of consortium fatigue provides diagnostic data on how to improve collaboration in biomedical innovation. PMID- 23986398 TI - Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease. AB - Vaccine-induced disease enhancement has been described in connection with several viral vaccines in animal models and in humans. We investigated a swine model to evaluate mismatched influenza vaccine-associated enhanced respiratory disease (VAERD) after pH1N1 infection. Vaccinating pigs with whole inactivated H1N2 (human-like) virus vaccine (WIV-H1N2) resulted in enhanced pneumonia and disease after pH1N1 infection. WIV-H1N2 immune sera contained high titers of cross reactive anti-pH1N1 hemagglutinin (HA) antibodies that bound exclusively to the HA2 domain but not to the HA1 globular head. No hemagglutination inhibition titers against pH1N1 (challenge virus) were measured. Epitope mapping using phage display library identified the immunodominant epitope recognized by WIV-H1N2 immune sera as amino acids 32 to 77 of pH1N1-HA2 domain, close to the fusion peptide. These cross-reactive anti-HA2 antibodies enhanced pH1N1 infection of Madin-Darby canine kidney cells by promoting virus membrane fusion activity. The enhanced fusion activity correlated with lung pathology in pigs. This study suggests a role for fusion-enhancing anti-HA2 antibodies in VAERD, in the absence of receptor-blocking virus-neutralizing antibodies. These findings should be considered during the evaluation of universal influenza vaccines designed to elicit HA2 stem-targeting antibodies. PMID- 23986399 TI - Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. AB - To distinguish age-related memory loss more explicitly from Alzheimer's disease (AD), we have explored its molecular underpinning in the dentate gyrus (DG), a subregion of the hippocampal formation thought to be targeted by aging. We carried out a gene expression study in human postmortem tissue harvested from both DG and entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of AD. Using expression in the EC for normalization, we identified 17 genes that manifested reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation. To test whether the RbAp48 decline could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. We next generated a transgenic mouse that expressed a dominant-negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG, and this corresponded to a regionally selective decrease in histone acetylation. Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation. Together, these findings show that the DG is a hippocampal subregion targeted by aging, and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention. PMID- 23986400 TI - Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. AB - Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8(+) T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell-inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3(+) regulatory T cells (T(regs)), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8(+) T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of T(regs), in the tumor microenvironment depended on the presence of CD8(+) T cells. The former was driven by interferon-gamma and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell inflamed tumor microenvironment. PMID- 23986402 TI - Predictors of early postpartum mental distress in mothers with midwifery home care--results from a nested case-control study. AB - PRINCIPLES: The prevalence of early postpartum mental health conditions is high. Midwives and other health professionals visiting women at home may identify mothers at risk. This seems crucial given decreasing trends of length of hospital stay after childbirth. This study aimed to identify predictors of maternal mental distress in a midwifery home care setting. METHODS: Using the statistical database of independent midwives' services in Switzerland in 2007, we conducted a matched nested case-control study. Out of a source population of 34,295 mothers with midwifery home care in the first ten days after childbirth, 935 mothers with maternal distress and 3,645 controls, matched by midwife, were included. We analysed whether socio-demographic, maternal and neonatal factors predict maternal mental distress by multivariable conditional logistic regression analysis. RESULTS: Infant crying problems and not living with a partner were the strongest predictors for maternal distress, whereas higher parity was the most protective factor. Significantly elevated risks were also found for older age, lower educational levels, breast/breastfeeding problems, infant weight gain concerns, neonatal pathologies and use of midwifery care during pregnancy. A lower likelihood for maternal distress was seen for non-Swiss nationality, full time employment before birth, intention to return to work after birth and midwife led birth. CONCLUSION: The study informs on predictors of maternal mental distress identified in a home care setting in the early postpartum period. Midwives and other health care professionals should pay particular attention to mothers of excessively crying infants, single mothers and primipara, and assess the need for support of these mothers. PMID- 23986403 TI - Improving the organ donor card system in Switzerland. AB - This paper analyses the current organ donor card system in Switzerland and identifies five problems that may be partially responsible for the country's low deceased organ donation rates. There are two minor issues concerning the process of obtaining a donor card: the Swisstransplant website understates the prospective benefits of donation, and the ease with which donor cards can be obtained raises questions regarding whether any consent to donation provided is truly informed. Furthermore, there are two major practical problems that might affect those who carry an organ donor card: the lack of a central donor registry increases the likelihood that donors' wishes will be "lost", and there is a high probability that family members will veto organ donation. The fact that these two practical problems are not mentioned to potential donors by Swisstransplant constitutes the fifth problem. Donation rates would probably improve if more accurate information about the benefits of donation were provided to potential donors, a central donor registry were created, and families were not permitted to veto donation from those on the registry. PMID- 23986401 TI - Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. AB - Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting. PMID- 23986404 TI - Contributions of altered permeability of intestinal barrier and defecation behavior to toxicity formation from graphene oxide in nematode Caenorhabditis elegans. AB - Graphene oxide (GO) has been extensively studied for potential biomedical applications. Meanwhile, potential GO toxicity arises in both biomedical applications and non-biomedical products where environmental exposures may occur. In the present study, we examined the potential adverse effects of GO and the underlying mechanism using nematode Caenorhabditis elegans as the assay system. We compared the in vivo effects of GO between acute exposure and prolonged exposure, and found that prolonged exposure to 0.5-100 mg L(-1) of GO caused damage on functions of both primary (intestine) and secondary (neuron and reproductive organ) targeted organs. In the intestine, ROS production was significantly correlated with the formation of adverse effects on functions of both primary and secondary targeted organs. GO could be translocated into intestinal cells with loss of microvilli, and distributed to be adjacent to or surrounding mitochondria. Prolonged exposure to GO resulted in a hyper-permeable state of the intestinal barrier, an increase in mean defecation cycle length, and alteration of genes required for intestinal development and defecation behavior. Thus, our data suggest that prolonged exposure to GO may cause potential risk to environmental organisms after release into the environment. GO toxicity may be due to the combinational effects of oxidative stress in the intestinal barrier, enhanced permeability of the biological barrier, and suppressed defecation behavior in C. elegans. PMID- 23986405 TI - Proteomic analysis of formalin-fixed paraffin-embedded colorectal cancer tissue using tandem mass tag protein labeling. AB - In clinical research, repositories of biological samples form a rich source of clinical material for biomarker studies. Banked material, however, is often not stored in optimal conditions regarding the technology used for biomarker research. A case in point is formalin-fixed paraffin-embedded (FFPE) tissue that could be used to obtain large cohorts of samples over a short period of time, as these tissues are routinely prepared for pathological analysis. However, in the context of mass spectrometry based peptide-centric proteomics, protein extraction and identification can be hampered by formalin-induced crosslinking. Furthermore, the molecular formalin crosslinks might be entangled differently across various samples, making it more difficult to reproducibly extract the same proteins from different samples. In this study, we establish the crosslink variability using Tandem Mass Tag (TMT) protein labeling followed by digestion, separation, identification and quantification of proteins extracted from FFPE colorectal cancer and paired healthy tissues. Moreover, by applying de novo interpretation of tandem mass spectra and subsequent analysis by Peaks PTM, unspecified modifications could be elucidated, leading to increased protein and proteome coverage. This approach might be useful for future FFPE proteomics studies. PMID- 23986406 TI - Herbal medicines for viral myocarditis. AB - BACKGROUND: Herbal medicines are used as treatment for viral diseases such as viral myocarditis, and numerous clinical trials have been conducted to investigate their efficacy. Despite this wealth of evidence, the role of herbal medicines in the treatment of viral myocarditis has yet to be established. This is an update of a review published in 2012. OBJECTIVES: To assess the benefits and harms of herbal medicines on clinical (e.g. mortality, incidence of complications) and indirect outcomes (e.g. cardiac function, biochemical response) in patients with viral myocarditis, irrespective of the patients' age, gender or type (including acute and chronic viral myocarditis). SEARCH METHODS: We searched CENTRAL (2013, Issue 1) on The Cochrane Library, MEDLINE (Ovid, 1946 to January Week 4 2013), EMBASE (Ovid, 1980 to 2013 Week 04) and LILACS (Bireme) on 1 February 2013. We previously searched The Chinese Biomedical Database (1979 to 2011), China National Knowledge Infrastructure (1979 to 2011), Chinese VIP Information (1989 to 2011), Chinese Academic Conference Papers Database and Chinese Dissertation Database (1980 to 2011), AMED (June 2011) and the Cochrane Complementary Medicine Field Trials Register (June 2011). We handsearched Chinese journals and conference proceedings. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials of herbal medicines (with a minimum duration of seven days of treatment) compared with placebo, no intervention, or conventional interventions were included. Trials of herbal medicine plus a conventional drug versus the drug alone were also included. We included only trials that reported an adequate description of allocation sequence generation. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and evaluated trial quality. Information on adverse effects was collected from the trial reports. MAIN RESULTS: We did not identify any new trials with the updated search in February 2013. The 2011 update of this review included twenty randomised controlled trials involving 2177 people. All the trials were conducted and published in China. The controls included anti arrhythmic drugs, corticosteroids, and antiviral therapies such as ribavirin or interferon. Combining the risk of bias for random sequence generation, allocation concealment, selective reporting, and incomplete outcome data, we assessed the included trials as being at a high risk of bias. Thirteen different herbal medicines were tested in the included trials. One of the trials reported outcomes on mortality. The trials reported electrocardiogram results, levels of myocardial enzymes, cardiac function, and adverse effects.Compared with supportive therapy, Astragalus membranaceus injection did not show a significant reduction in the number of patients that died of cardiac failure.A meta-analysis showed a significant effect ofAstragalus membranaceus injection plus supportive therapy on the number of participants with an abnormal electrocardiogram (RR 0.28, 95% CI 0.13 to 0.61), ST-T changes (RR 0.72, 95% CI 0.54 to 0.95), creatine phosphate kinase (CPK) levels (MD -21.54, 95% CI -33.80 to -9.28), and lactate dehydrogenase (LDH) levels (MD -30.33, 95% CI -46.78 to -13.88).Shengmai injection plus supportive therapy showed a significant effect on the number of patients with an abnormal electrocardiogram (RR 0.11, 95% CI 0.01 to 0.86), CPK levels (MD -103.90, 95% CI -114.97 to -92.83), LDH levels (MD -34.60, 95% CI 51.25 to -17.95), and on myocardial enzyme CK-MB levels (MD -10.87, 95% CI -14.50 to -7.24). Shengmai decoction plus supportive therapy showed a significant effect on improving quality of life measured by the SF-36 (MD 40.20, 95% CI 18.13 to 62.27) compared to supportive therapy. Data on adverse events were only available from six of the included trials and no serious adverse effects were reported. AUTHORS' CONCLUSIONS: Since no new trials were identified in the updated search in 2013, the conclusions remain the same as they were in 2012. There is no evidence of benefit of herbal medicine on all cause mortality. Some herbal medicines may lead to improvement of ventricular premature beat, electrocardiogram, levels of myocardial enzymes, and cardiac function in viral myocarditis. However, these findings should be interpreted with care, due to the risk of bias of the included studies, small sample size, and limited number of trials on individual herbs. Further robust trials are needed to explore the use of herbal medicines for viral myocarditis. PMID- 23986407 TI - Press for an underestimated nemesis. PMID- 23986409 TI - The dental hygienist in research: progress over 100 years. PMID- 23986408 TI - The choice of discount brand cigarettes: a comparative analysis of International Tobacco Control surveys in Canada and the USA (2002-2005). AB - BACKGROUND: Increasing tobacco taxes to increase price is a proven tobacco control measure. This article investigates how smokers respond to tax and price increases in their choice of discount brand cigarettes versus premium brands. OBJECTIVE: To estimate how increase in the tax rate can affect smokers' choice of discount brands versus premium brands. METHODS: Using data from International Tobacco Control surveys in Canada and the USA, a logit model was constructed to estimate the probability of choosing discount brand cigarettes in response to its price changes relative to premium brands, controlling for individual-specific demographic and socioeconomic characteristics and regional effects. The self reported price of an individual smoker is used in a random-effects regression model to impute price and to construct the price ratio for discount and premium brands for each smoker, which is used in the logit model. FINDINGS: An increase in the ratio of price of discount brand cigarettes to the price of premium brands by 0.1 is associated with a decrease in the probability of choosing discount brands by 0.08 in Canada. No significant effect is observed in case of the USA. CONCLUSIONS: The results of the model explain two phenomena: (1) the widened price differential between premium and discount brand cigarettes contributed to the increased share of discount brand cigarettes in Canada in contrast to a relatively steady share in the USA during 2002-2005 and (2) increasing the price ratio of discount brands to premium brands-which occurs with an increase in specific excise tax-may lead to upward shifting from discount to premium brands rather than to downward shifting. These results underscore the significance of studying the effectiveness of tax increases in reducing overall tobacco consumption, particularly for specific excise taxes. PMID- 23986410 TI - Air polishing: a review of current literature. AB - PURPOSE: Routine tooth polishing continues to be an integral part of clinical practice even though the concept of selective polishing was introduced in the 1980s. This procedure assists in the removal of stains and plaque biofilm and provides a method for applying various medicaments to the teeth, such as desensitizing agents. Use of traditional polishing methods, i.e. a rubber-cup with prophylaxis paste, has been shown to remove the fluoride-rich outer layer of the enamel and cause significant loss of cementum and dentin over time. With the growing body of evidence to support alternative tooth polishing methods, dental hygiene practitioners should familiarize themselves with contemporary methods including air polishing. The purpose of this review is to provide a comprehensive overview of recent advancements in air polishing. The effect of air-powder polishing on hard and soft tissues, restorative materials, sealants, orthodontic appliances and implants, as well as health risks and contraindications to air polishing are discussed. A comprehensive computer based search made use of the following databases: CINAHL, Ovid Medline and PubMed. Articles that were not available on these sites were requested from Wilson Interlibrary. PMID- 23986411 TI - The care and management of bisphosphonate--associated osteonecrosis of the jaw in the patient with multiple myeloma: a case study. AB - PURPOSE: This is a case study of a patient with multiple myeloma presenting with bisphosphonate-associated osteonecrosis of the jaw after an extraction of tooth #18 while receiving intravenous bisphosphonates. The class of drugs known as bisphosphonates is discussed. The patient's presenting signs and symptoms are reviewed. Bisphosphonate induced osteonecrosis definition, management and professional education are reviewed. PMID- 23986412 TI - Obstructive sleep apnea in association with periodontitis: a case-control study. AB - PURPOSE: Periodontitis is associated with several cardio-metabolic disorders that are co-morbid with sleep-disordered breathing. A relationship between periodontitis and obstructive sleep apnea (OSA) is plausible, but has received little attention. This study investigated the strength of association between periodontitis and risk for OSA. METHODS: In this case-control study, cases had moderate or severe periodontitis (n = 50, 32.5%) and controls had gingivitis or slight periodontitis (n = 104, 67.5%). Sixty-one males (39.6%) and 93 females (60.4%) with a mean age of 61 years were sampled from the dental hygiene preventive care clinic in the School of Dentistry at the University of North Carolina at Chapel Hill between February and April 2011. Patients received a full mouth periodontal examination that included probing pocket depths and clinical attachment levels at 6 sites per tooth. The case definition for moderate or severe periodontitis was that of the American Dental Association (ADA). Risk for OSA was determined by the 4 item "STOP" OSA screening questionnaire, which assesses self-reported snoring, excessive daytime sleepiness, witnessed apnea during sleep and history of hypertension. Demographic, general health and orofacial characteristics were recorded that were considered putative predictors of either periodontitis or OSA. A multivariate binary logistic regression assessed odds of moderate or severe periodontitis according to OSA risk with adjustment for potential confounders. RESULTS: In all, 59 patients (38.3%) screened at high risk for OSA by providing 2 or more affirmative responses on the STOP questionnaire. Sixty percent of periodontitis cases (n = 30) screened high risk of OSA compared with only 28% of controls (n = 29). Cases were 4.1 times more likely (95% CI: 1.9, 11.4) to be at high risk for OSA than controls (p = 0.007) after adjustment for potential confounders. CONCLUSION: A significant association was observed between moderate or severe periodontitis and risk for OSA. PMID- 23986413 TI - Comparison of the impact of scaler material composition on polished titanium implant abutment surfaces. AB - PURPOSE: The purpose of this study was to compare the impact of the removal of biofilm with hand scalers of different material composition on the surface of implant abutments by assessing the surface topography and residual plaque after scaling using scanning electron microscopy (SEM). METHODS: Titanium implant analogs from 3 manufacturers (Straumann USA LLC, Andover, Maine, Nobel BioCare USA LLC, Yorba Linda, Cali, Astra Tech Implant Systems, Dentsply, Molndal, Sweden) were mounted in stone in plastic vials individually with authentic prosthetic abutments. Plaque samples were collected from a healthy volunteer, inoculated into growth medium and incubated with the abutments anaerobically for 1 week. A blinded, calibrated hygienist performed scaling to remove the biofilm using 6 implant scalers (in triplicate), 1 scaler for 1 abutment. The abutments were mounted on an imaging stand and processed for SEM. Images were captured in 3 randomly designated areas of interest on each abutment. Analysis of the implant polished abutment surface and plaque area measurements were performed using ImageJ image analysis software. Surface alterations were characterized by the number, length, depth and the width of the scratches observed. RESULTS: Glass filled resin scalers resulted in significantly more and longer scratches on all 3 abutment types compared to other scalers, while unfilled resin scalers resulted in the least surface change (p < 0.05). Filled resin-graphite reinforced scalers, carbon fiber reinforced resin scalers and titanium scalers resulted in more superficial scratches compared to glass filled resin, as well as more scratches than unfilled resin. No statistically significant differences were found between scalers and abutments with regard to plaque removal. CONCLUSION: The impact of scalers on implant abutment surfaces varies between abutment types presumably due to different surface characteristics with no apparent advantage of one abutment type over the other with regard to resistance to surface damage. Unfilled resin was found consistently to be the least damaging to abutment surfaces, although all scalers of all compositions caused detectable surface changes to polished surfaces of implant abutments. PMID- 23986414 TI - Use of recommended communication techniques by Maryland dental hygienists. AB - PURPOSE: The purpose of this study was to determine dental hygienists' use of recommended techniques to communicate science-based information for intervention and prevention of oral disease. METHODS: A 30-item survey containing 18 communication techniques representing 5 domains including 7 basic skills were mailed to a random sample of 1,258 Maryland dental hygienists to determine their use of recommended communication techniques. RESULTS: The response rate was 43% (n = 540). Nearly all were females (98%) and 58% practiced in solo settings. About half of respondents used 6 of the 18 techniques routinely. Approximately three-quarters of respondents reported they rarely or never used 3 of the 7 basic recommended techniques. Only one basic technique (use of simple language) was used by over 90%. Respondents who had taken a communications course other than in dental hygiene school were significantly more likely to use communication techniques on a routine basis than those who had not (p < 0.01). CONCLUSION: Dental hygienists and their patients would benefit from using the recommended communication tools and techniques to address individual patient needs. To improve oral health outcomes, dental hygiene education must strengthen health literacy knowledge and communication skills in dental hygiene education programs and through continuing education courses for practicing hygienists. PMID- 23986415 TI - Predicting undergraduates' intentions to improve oral health behaviors: the importance of self-identity--a pilot study. AB - PURPOSE: The purpose of this study was to explore the predictive ability of factors associated with the Theory of Planned Behavior (TPB) on oral health behaviors. METHODS: The participants of this descriptive, cross-sectional study were 179 first year medical students at the Carol Davila University of Medicine and Pharmacy that completed a questionnaire assessing TPB variables, self identity and their current oral hygiene behaviors. RESULTS: Significant differences in self-identity regarding the toothbrushing behavior and reason for the dental visit were observed (p < 0.0001). When participants were classified in 2 groups according to their levels of self-identity, significant differences were found according to their age, toothbrushing frequency, attitudes, perceived behavioral control and intention for improving oral hygiene (p < 0.0001). Self identity had a statistically significant positive correlation with affective attitudes, cognitive attitudes, subjective norms, perceived behavioral control and intention for improving oral hygiene. Hierarchical multiple regressions for toothbrushing frequency revealed that the TPB factors and self-identity explained 31% and 35% from the intention to improving behaviors, the coefficients for self identity being significant. The structural equation model revealed the effect of self-identity on intention on improving oral health behaviors and the effect of past-behavior on self-identity. CONCLUSION: The findings revealed the value of the extended TPB model as a predictor of intention to improve oral health behaviors. Dental educators should focus on issues of students' self-identity as a person concerned by their oral health. PMID- 23986416 TI - Student perception of travel service learning experience in Morocco. AB - PURPOSE: This study explores the perceptions of health profession students participating in academic service learning in Morocco with respect to adapting health care practices to cultural diversity. METHODS: Authors utilized semi structured, open-ended interviews to explore the perceptions of health profession students. Nine dental hygiene and nursing students who traveled to Morocco to provide oral and general health services were interviewed. After interviews were recorded, they were transcribed verbatim to ascertain descriptive validity and to generate inductive and deductive codes that constitute the major themes of the data analysis. Thereafter, NVIVO 8 was used to rapidly determine the frequency of applied codes. The authors compared the codes and themes to establish interpretive validity. Codes and themes were initially determined independently by co-authors and applied to the data subsequently. The authors compared the applied codes to establish intra-rater reliability. RESULTS: International service learning experiences led to perceptions of growth as a health care provider among students. The application of knowledge and skills learned in academic programs and service learning settings were found to help in bridging the theory-practice gap. The specific experience enabled students to gain an understanding of diverse health care and cultural practices in Morocco. CONCLUSION: Students perceived that the experience gained in international service learning can heighten awareness of diverse cultural and health care practices to foster professional growth of health professionals. PMID- 23986417 TI - HIV prevalence and related risk behaviours among prisoners in Iran: results of the national biobehavioural survey, 2009. AB - OBJECTIVES: To estimate the prevalence of HIV and related risk behaviours among prisoners in Iran in 2009. METHODS: Using multistage random sampling, we recruited 5,530 prisoners from 27 prisons in Iran. Behavioural data were collected using a face-to-face questionnaire-based interview, and HIV status was determined by ELISA of dried blood spots. Weighted estimates were calculated based on the sampling probability and response rate. RESULTS: HIV prevalence was 2.1% (95% CI 1.2 to 3.6). One in eight prisoners (12.3%, 95% CI 8.0% to 16.6%) had been tested for HIV in the last year and received results, 20.5% (95% CI 15.1 to 27.4%) had comprehensive knowledge about HIV and 24.7% (95% CI 17.9% to 32.9%) reported condom use at last vaginal/anal sex in prison. Although 16.5% (95% CI 12.5% to 21.5%) acknowledged a lifetime history of drug injection, only 22 prisoners reported drug injection inside the prison in the month preceding the interview. Of note, 12.9% (95% CI 10.6% to 15.6%) had been tattooed in prison. There were significant associations between HIV prevalence and a history of drug injection (adjusted odds ratio (AOR): 7.8, 95% CI 4.7 to 13.2), tattooing (AOR: 2.1, 95% CI 1.1 to 4.2) and age over 30 years (AOR: 1.4, 95% CI 1.1 to 1.9). CONCLUSIONS: Considerable HIV prevalence among prisoners is found in Iran. Expanding harm reduction programmes inside prisons with inclusion of sexual risk reduction programmes and post-release programmes will help directly prevent acquisition and transmission of infection inside prisons and indirectly slow onward transmission in the outside communities. PMID- 23986418 TI - Zurich University Hospital lung transplantation programme: update 2012. AB - Lung transplantation is an established therapeutic option for end-stage lung disease in selected patients. During the last 30 years more than 34,000 transplantations have been performed worldwide. Emphysema, pulmonary fibrosis, cystic fibrosis and primary pulmonary hypertension are the most common indications. This type of surgical treatment is increasingly successful, with better early and late survival rates. However, lung transplantation is still hampered by persisting problems such as donor organ shortage, primary graft dysfunction, late graft dysfunction and morbidity related to long-term immunosuppression. The first lung transplantation in Switzerland was performed the 10th November 1992 at Zurich University Hospital. Since then the lung transplant programme has progressively increased its yearly transplant volume. Since the beginning of our lung transplantation programme, overall patient survival has increased steadily and has been at benchmark levels since the year 2000. The most important factors influencing this result are presumably good teamwork among all involved specialists, improved surgical techniques, and close and long-term patient follow-up by the transplant pulmonologists. In this paper we present our programme structure, managing strategies for some specific problems and outcome after lung transplantation. The results presented here are from recipients who underwent lung transplantation up to the end of 2011. PMID- 23986419 TI - [Management of acute stroke - guidelines from the Expert Group of the Section of Cerebrovascular Diseases of the Polish Neurological Society. Update 2013: thrombolysis]. AB - Thrombolysis is the most effective therapy for ischaemic stroke. The current guidelines and approvals have limited its use to patients available for treatment within 4.5 hours of onset and those aged 80 or less. There are also a number of other limitations derived from clinical trial protocols, i.e. minor and major strokes. The available evidence has indicated its possible efficacy in patients treated within 6 hours of onset and not fulfilling other limitations. Last year, the results of the IST-3 (Third International Stroke Trial: Thrombolysis) and a meta-analysis of all available trials including IST-3 were published. They point out the possible benefit of thrombolysis in patients not meeting the current criteria, which has been acknowledged in the Polish guidelines for management of stroke. PMID- 23986420 TI - The efficacy and safety of intravenous thrombolysis with alteplase in the treatment of ischaemic stroke in a rural hospital. AB - BACKGROUND AND PURPOSE: Ongoing evaluation of the results of thrombolytic therapy in patients with ischaemic stroke (IS) in regions with different health care organization is absolutely crucial for making this method of treatment safer and efficient. The aim of this study was to analyse the efficacy and safety of treatment with intravenous alteplase in patients with acute IS in a rural hospital. MATERIAL AND METHODS: Between 2006 and 2011, 1392 pa-tients with IS were treated (including 200 patients treated with alteplase; 14.37%). In patients treated with alteplase, we analysed the influence of several variables on the functional status after 3 months according to the modified Rankin Scale (mRS), case-fatality rate during 3 months after onset and symptomatic intracerebral haemorrhage (SICH). RESULTS: In the studied population, good outcome (mRS 0-2) at 3 months was related to younger age (p = 0.001), male sex (p = 0.02) and low scores (< 15 points) on the National Institutes of Health Stroke Scale (NIHSS) (p < 0.0001). Deaths within 3 months were related to older age (p = 0.027), female sex (p = 0.004), severity of stroke measured by NIHSS score (p < 0.0001) and presence of radiological signs of previous stroke in baseline computed tomography (CT)(p = 0.002). Patients with SICH had higher mean age (p = 0.014) and higher severity of neurological deficit measured on the NIHSS scale (p = 0.03). CONCLUSIONS: The indications for intravenous thrombolysis in patients with IS should be strictly analysed so that the treatment is effective and safe especially in older patients, patients with greater severity of neurological symptoms and patients with old post-stroke lesions in baseline CT. PMID- 23986421 TI - Incidence of mutations in the PARK2, PINK1, PARK7 genes in Polish early-onset Parkinson disease patients. AB - BACKGROUND AND PURPOSE: Parkinson disease (PD) is a complex disease, comprising genetic and environmental factors. Despite the vast majority of sporadic cases, three genes, i.e. PARK2, PINK1 and PARK7 (DJ-1), have been identified as responsible for the autosomal recessive form of early-onset Parkinson disease (EO PD). Identified changes of these genes are homozygous or compound heterozygous mutations. The frequency of PARK2, PINK1 and PARK7 mutations is still under debate, as is the significance and pathogenicity of the single heterozygous mutations/variants, which are also detected among PD patients. The aim of the study was to analyze the incidence of autosomal recessive genes PARK2, PINK1, PARK7 mutations in Polish EO-PD patients. MATERIAL AND METHODS: The analysis of the PARK2, PINK1 and PARK7 genes was performed in a group of 150 Polish EO-PD patients (age of onset < 45 years). Mutation analysis was based on sequencing and gene dosage abnormality identification. RESULTS: Mutations were identified only in the PARK2 and PINK1 genes with the frequency of 4.7% and 2.7% of subjects, respectively. In PARK2, point mutations and exons' rearrangements, and in PINK1 only missense mutations were detected. In both genes mutations were found as compound heterozygous/homozygous and single heterozygous. EO-PD patients' genotype-phenotype correlation revealed similarities of clinical features in mutation carriers and non-carriers. CONCLUSIONS: The frequency of the PARK2, PINK1, PARK7 mutations among Polish EO-PD patients seems to be low. The role of single heterozygous mutations remains a matter of debate and needs further investigations. PMID- 23986422 TI - Markers of angiogenesis (CD31, CD34, rCBV) and their prognostic value in low grade gliomas. AB - BACKGROUND AND PURPOSE: Antigens CD31 and CD34 and relative cerebral blood volume (rCBV) in gliomas reflect in different ways neoangiogenesis of the tumour. Thus, we decided: (1) to estimate the correlation between the values of CD31 and CD34 and the value of rCBV in low-grade gliomas (LGG), and (2) to establish the prognostic value of these markers. MATERIAL AND METHODS: The investigated group consisted of 53 patients with LGG who were operated on in the Neurosurgical Department at Sosnowiec between 2005 and 2011. On the basis of perfusion-weighted imaging (PWI-MRI) in the tumour texture, rCBV was calculated. The values of CD31 and CD34 were estimated on the basis of immunohistochemical investigation. Three outcome measures were assessed: (1) overall survival, (2) progression-free survival, and (3) malignant-free survival. Statistical analyses were done using the STATISTICA 9.0 program. RESULTS: Higher value of rCBV in the texture of LGG significantly correlated with higher CD31 (p = 0.0006) and CD34 values (p = 0.0043). Progression-free survival was significantly longer in patients with rCBV < 1.75 than for persons with rCBV > 1.75 (p = 0.015). Lower expression of CD31 correlated with probability of longer survival of the patients after the operation of LGG (p = 0.068). CONCLUSIONS: Density of microvessels as assessed immunohistochemically with CD31+ and CD34+ in LGG correlated with the value of rCBV in the tumour. The value of 1.75 for rCBV may be the threshold for better or poorer outcome of these patients. Expression of CD31 antigen is an important prognostic factor for the time of survival for patients with LGG. PMID- 23986423 TI - Meningiomas of the upper and middle part of the clivus and surrounding structures: early and long-term outcome. AB - BACKGROUND AND PURPOSE: Meningiomas of the upper and middle parts of the clivus and surrounding structures are removed using petrosal approaches: anterior, posterior, combined and complete. The purpose of this study is to show the results of treatment of these meningiomas and to present our interpretation of the treatment strategy. MATERIAL AND METHODS: Twenty-six patients (17 women, 9 men) were included in the study. The neurological status of the patients was assessed before and after surgery as well as at the conclusion of the treatment. The following measurements and data were collected and recorded: approximate volume of the treated lesion, its relation to large blood vessels, cranial nerves and the brainstem, as well as tumour consistency and vascularisation. RESULTS: Symptoms duration ranged from 1 to 60 months (median: 16 months). In 57.7% of patients, imbalance was the predominant sign. Less frequent symptoms were: head aches, dysacusis and hemiparesis. Approximate volumes of the tumours ranged from 4 to 65 mL (mean: 32 mL). Total or subtotal resection was achieved in 73.1% of patients. The patients' performance improved postoperatively in 34.5%, remained unchanged in 46.2% and deteriorated in 11.5% of patients. Two (7.8%) patients died after the surgery. CONCLUSIONS: The use of petrosal approaches in the surgical treatment of meningiomas of the upper and middle parts of the clivus and the surrounding structures facilitates good or at least satisfactory neurological outcome with a high proportion of complete resections and relatively low mortality. PMID- 23986424 TI - The dose-dependent neuroprotective effect of alpha-lipoic acid in experimental spinal cord injury. AB - BACKGROUND AND PURPOSE: Free radical production after spinal cord injury (SCI) plays an important role in secondary damage. The aim of this study was to investigate neuroprotective effects of the powerful antioxidant alpha-lipoic acid (ALA) in a spinal cord clip compression injury model. MATERIAL AND METHODS: Fifty six Sprague-Dawley rats, weighing between 210 and 300 g, were randomly divided into seven groups. Spinal cord injury was performed by an aneurysm clip placed extradurally at the level of T9. Group 1 (sham) received laminectomy only. Group 2 (control) received SCI; Group 3 received 30 mg/kg of methylprednisolone sodium succinate (MPSS); Groups 4, 5, 6 and 7 received ALA at doses of 50, 100, 150, 200 mg/kg, respectively, via the intraperitoneal route immediately after SCI. The rats were neurologically tested 24 hours after trauma. Spinal cord samples from injury sites were harvested for measurement of lipid peroxidation products and histopathological evaluation. RESULTS: Spinal cord malonyldialdehyde levels of rats in treatment groups decreased after administration of ALA. The difference between the trauma group and groups receiving MPSS-ALA was statistically significant. The difference between the ALA (50, 100, 150 mg/kg) and MPSS groups was insignificant. Group 7 (ALA 200 mg/kg) was excluded from the study because of the possible toxic effect. Alpha lipoic acid and MPSS had similar effects on spinal cord injury in terms of lipid peroxidation, neurological recovery and histopathological changes. CONCLUSIONS: Alpha lipoic acid at a dose range of 50 150 mg/ kg is as effective as MPSS (30 mg/kg) in neuroprotection after SCI. Further, more detailed experimental studies are needed to determine the effects of ALA on the detrimental results of secondary SCI before its use in humans. PMID- 23986425 TI - Variability of the blink reflex in patients with migraine. AB - BACKGROUND AND PURPOSE: Sensitization of brainstem trigeminal nuclei and activation of the trigeminovascular system are thought to play an important role in migraine. The blink reflex has become a valuable tool for investigating trigeminal nerve function. The aim of the study was to assess the differences in electrophysiological examinations of the trigeminal nerve (blink reflex) in a group of patients with migraine in comparison with a healthy control group. MATERIAL AND METHODS: The examination was conducted among 58 patients. Patients were diagnosed in the Polyclinic or hospitalized in the Department of Neurology of Warsaw Medical University in Bielanski Hospital. The study group included 29 patients suffering from migraine (diagnosed according to the International Classification of Headache Disorders, 2nd edition) and 29 patients without headaches served as controls. All patients underwent neurological examination and magnetic resonance imaging to identify organic disorders. The blink reflex was tested among all patients in accordance with electrophysiological laboratory standards. RESULTS: The latency of the R1 response was significantly shorter among patients with migraine. The latency of R2 and R2' responses was similar in patients and controls. A significant inverse correlation was observed between latency of R2 and R2' responses and frequency of migraine attacks. CONCLUSIONS: The inverse correlation between the frequency of attacks and the latency of R2 and R2' responses of the blink reflex confirms the abnormal eaxcitability induced by the high frequency of migraine attacks. PMID- 23986426 TI - Evaluation of serum transforming growth factor beta1 and C-reactive protein levels in migraine patients. AB - BACKGROUND AND PURPOSE: Migraine is a frequent form of head-ache. Although many mechanisms describing onset of migraine with and without visual aura have been suggested, the aetiology of migraine headaches is still not clear. Neurogenic inflammation may play a key role in the development of migraine headaches. We evaluated the discriminative power of serum levels of C-reactive protein (CRP) and transforming growth factor beta 1 (TGF-beta1) in patients who presented to our clinic with migraine headaches with or without visual aura. MATERIAL AND METHODS: We designed a prospective case-control study of 51 patients with migraine (27 with migraine with aura and 24 with migraine without aura; all had headache) and compared them with 27 healthy subjects during the study period. Demographic and clinical characteristics recorded were age, sex, marital status, occupation, characteristics of headache, laboratory values, and serum CRP and TGF beta1 levels. Statistical analyses used Student t-test, the chi2 test, and ANOVA followed by the post-hoc Bonferroni test for multiple comparisons. Receiver operator characteristic (ROC)-curve analysis for CRP and TGF-beta1 was also conducted. RESULTS: There was no difference between the groups in terms of demographic characteristics, marital status, and socioeconomic status. Statistically, white blood cell levels, serum glucose levels, triglyceride levels, high-density lipoprotein levels, and serum CRP and TGF-beta1 were significantly higher in patients with migraine (p < 0.05). The ROC curve results in this study identified that CRP and TGF-beta1 may discriminate patients who have different types of migraine headache. CONCLUSIONS: This study suggests that serum CRP and TGF-beta1 levels may be diagnostic factors to differentiate migraine patients with and without aura. These findings show that neurogenic inflammation may have a role in the aetiology of migraines. PMID- 23986427 TI - [Anterior petrosal approach - analysis of the surgical technique in cadavers simulation]. AB - The aim of the study was to present consecutive stages of the anterior petrosal approach (APA). Eight simulations of APA were performed on non-fixed human cadavers without any known pathologies of the head and neck. The consecutive stages of the procedure were documented with photographs and schemes. The starting point for APA is a temporal craniotomy and extradural exposition of the base of the middle cranial fossa. Mobilisation of the trigeminal nerve allows for removal of the apex of the petrous bone. Approach to the upper part of the clivus is achieved by elevation of the temporal lobe and section of the tentorium and superior petrosal sinus with surrounding dura. Anterior petrosal approach is a reproducible technique, which provides surgical penetration of the upper clivus and related regions. This approach is particularly useful in the treatment of tumors of the mentioned above anatomical areas. PMID- 23986428 TI - [Posterior petrosal approach - analysis of the surgical technique in cadavers simulation]. AB - The aim of the study was to present consecutive stages of the posterior petrosal approach (PPA). Eighteen simulations of PPA were performed on non-fixed human cadavers without any known pathologies in the head and neck. The consecutive stages of the procedure were documented with photographs and schemes. The starting point for PPA is a temporal craniotomy, suboccipital craniectomy and mastoidectomy with keeping the bony labyrinth intact. Approach to the middle part of the clivus is achieved by raise of the temporal lobe and section of the superior petrosal sinus and tentorium and by mobilization the sigmoid sinus. Posterior petrosal approach is a reproducible technique, which provides surgical penetration of the middle clivus and related regions. It reduces the operating distance and allows to limit the cerebellum and temporal lobe traction and to preserve the anatomic integrity of the brain stem and cranial nerves of the cerebellopontine angle. PMID- 23986429 TI - Hemiparkinsonism-hemiatrophy syndrome - report on two cases and review of the literature. AB - Hemiparkinsonism-hemiatrophy (HPHA) is a rare neurological syndrome. The main clinical features of HPHA consist of atrophy of one side of the body (face, trunk, limbs), ipsilateral hemiparkinsonism (bradykinesia, rigidity, tremor) and in many cases dystonia. There are no data on prevalence of HPHA as the condition is rare. The mean age of parkinsonism onset is earlier than in idiopathic Parkinson disease (43.7 years, range: 15-63). Changes in magnetic resonance imaging (MRI) (cortical, basal ganglia atrophy contralaterally to the side of clinical presentation) are described in 30% of patients. The pathogenesis of HPHA is unknown, but in many cases a history of prenatal injuries was reported. We present two male patients with HPHA - 45 and 55 years old, with left-sided parkinsonism, dystonia and hemiatrophy (to our knowledge, the first Polish cases). Both patients had no atrophic changes in MRI and levodopa treatment was ineffective. In the discussion the authors review current literature on HPHA. PMID- 23986430 TI - Effect of liver transplantation on brain magnetic resonance imaging pathology in Wilson disease: a case report. AB - The authors present a case report of a 28-year-old patient with hepatic, but no neurological, signs of Wilson disease, with pathological changes in both the globi pallidi and caudate found with routine brain magnetic resonance imaging (MRI). The patient was recommended for liver transplantation by hepatologists, and during the two years of observation after liver transplantation, MRI brain abnormalities due to Wilson disease completely regressed. On the basis of this case, the authors present an argument for the prognostic significance of brain MRI in Wilson disease as well as current recommendations concerning liver transplantation in Wilson disease. PMID- 23986431 TI - Nummular headache after trans-sphenoidal surgery: a referred pain-based headache syndrome. AB - Nummular headache (NH) is a newly categorized primary headache characterized by a consistent location, shape and size of painful area in each attack. The etiopathogenesis is entirely unknown. Currently, the peripheral theory of epicranial neuralgia is accepted more widely than the central theory but it cannot fully explain the clinical picture. We report a patient who suffered from a relapsing and remitting course of NH at the high parietal area and vertex shortly after resection for pituitary prolactinoma via a trans-sphenoidal approach. There was no focal trophic change or paresthesia but a mild allodynia in the painful area. The patient did not exhibit trigeminal sensory disorder or cranial trauma thoroughly. The pain responded well to gabapentin. Therefore, physicians should be aware of postoperative NH, which is amenable to treatment. The findings in our patient support a dual mechanism of NH and suggest that central NH is a form of referred pain. PMID- 23986432 TI - A kinetic study of oxygen reduction reaction and characterization on electrodeposited gold nanoparticles of diameter between 17 nm and 40 nm in 0.5 M sulfuric acid. AB - Kinetic and mechanistic studies of the oxygen reduction reaction (ORR) in oxygen saturated 0.5 M sulfuric acid at 298 K at a gold macroelectrode and at an electrodeposited gold nanoparticle-modified glassy carbon electrode are reported. The conditions of electrodeposition are optimized to obtain small nanoparticles of diameter from 17 nm to 40 nm. The mechanism and kinetics of ORR on the gold macroelectrode are investigated and compared with those obtained for nanoparticle modified electrodes. The mechanism for this system includes two electron and two proton transfers and hydrogen peroxide as the final product. The first electron transfer step corresponding to the reduction of O2 to O2(-) is defined as the rate determining step. No significant changes are found for the nanoparticles here employed: electron transfer rate constant (k0) is k0,bulk = 0.30 cm s(-1) on the bulk material and k0,nano = 0.21 cm s(-1) on nanoparticles; transfer coefficient (alpha) changes from alphabulk = 0.45 on macro-scale to alphanano = 0.37 at the nano-scale. PMID- 23986433 TI - Treatment options for pityriasis rubra pilaris including biologic agents: a retrospective analysis from an academic medical center. PMID- 23986434 TI - Infraclavicular brachial plexus block for regional anaesthesia of the lower arm. AB - BACKGROUND: Several approaches exist to produce local anaesthetic blockade of the brachial plexus. It is not clear which is the technique of choice for providing surgical anaesthesia of the lower arm, although infraclavicular blockade (ICB) has several purported advantages. We therefore performed a systematic review of ICB compared to the other brachial plexus blocks (BPBs). This review was originally published in 2010 and was updated in 2013. OBJECTIVES: The objective of this review was to evaluate the efficacy and safety of infraclavicular block (ICB) compared to other approaches to the brachial plexus in providing regional anaesthesia for surgery on the lower arm. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 5); MEDLINE (1966 to June 2013) via OvidSP; and EMBASE (1980 to June 2013) via OvidSP. We also searched conference proceedings (from 2004 to 2012) and the www.clinicaltrials.gov trials registry. The searches for the original review were performed in September 2008. SELECTION CRITERIA: We included any randomized controlled trials (RCTs) that compared ICB with other BPBs as the sole anaesthetic technique for surgery on the lower arm. DATA COLLECTION AND ANALYSIS: The primary outcome was adequate surgical anaesthesia within 30 minutes of block completion. Secondary outcomes included sensory block of individual nerves, tourniquet pain, onset time of sensory blockade, block performance time, block associated pain and complications related to the block. MAIN RESULTS: In our original review we included 15 studies with 1020 participants and excluded two. In this updated review we included seven new studies and excluded six, bringing the total number of included studies to 22 and involving 1732 participants. The control group intervention was the axillary block in 14 studies, supraclavicular block in six studies, mid-humeral block in two studies, and parascalene block in one study. One study compared ICB to both axillary and supraclavicular blocks. Nine studies employed ultrasound-guided ICB. The risk of failed surgical anaesthesia 30 minutes after block completion was similar for ICB and all other BPBs (11.4% versus 12.9%, risk ratio (RR) 0.88, 95% CI 0.51 to 1.52, P = 0.64), but tourniquet pain was less likely with ICB (11.9% versus 18.0%; RR of experiencing tourniquet pain 0.66, 95% CI 0.47 to 0.92, P = 0.02). Subgroup analysis by method of nerve localization, and by control group intervention, did not show any statistically significant differences in the risk of failed surgical anaesthesia. However when compared to a single-injection axillary block, ICB was better at providing complete sensory block of the musculocutaneous nerve (RR for failure 0.46, 95% CI 0.27 to 0.60, P < 0.0001). ICB had a slightly longer sensory block onset time (mean difference (MD) 1.9 min, 95% CI 0.2 to 3.6, P = 0.03) but was faster to perform than multiple-injection axillary (MD -2.7 min, 95% CI -3.4 to -2.0, P < 0.00001) or mid-humeral (MD -4.8 min, 95% CI -6.0 to -3.6, P < 0.00001) blocks. AUTHORS' CONCLUSIONS: ICB is as safe and effective as any other BPBs, regardless of whether ultrasound or neurostimulation guidance is used. The advantages of ICB include a lower likelihood of tourniquet pain during surgery, more reliable blockade of the musculocutaneous nerve when compared to a single injection axillary block, and a significantly shorter block performance time compared to multi-injection axillary and mid-humeral blocks. PMID- 23986435 TI - The Bcl-2 homology domain 3 (BH3)-only proteins Bim and bid are functionally active and restrained by anti-apoptotic Bcl-2 family proteins in healthy liver. AB - An intrinsic pathway of apoptosis is regulated by the B-cell lymphoma-2 (Bcl-2) family proteins. We previously reported that a fine rheostatic balance between the anti- and pro-apoptotic multidomain Bcl-2 family proteins controls hepatocyte apoptosis in the healthy liver. The Bcl-2 homology domain 3 (BH3)-only proteins set this rheostatic balance toward apoptosis upon activation in the diseased liver. However, their involvement in healthy Bcl-2 rheostasis remains unknown. In the present study, we focused on two BH3-only proteins, Bim and Bid, and we clarified the Bcl-2 network that governs hepatocyte life and death in the healthy liver. We generated hepatocyte-specific Bcl-xL- or Mcl-1-knock-out mice, with or without disrupting Bim and/or Bid, and we examined hepatocyte apoptosis under physiological conditions. We also examined the effect of both Bid and Bim disruption on the hepatocyte apoptosis caused by the inhibition of Bcl-xL and Mcl 1. Spontaneous hepatocyte apoptosis in Bcl-xL- or Mcl-1-knock-out mice was significantly ameliorated by Bim deletion. The disruption of both Bim and Bid completely prevented hepatocyte apoptosis in Bcl-xL-knock-out mice and weakened massive hepatocyte apoptosis via the additional in vivo knockdown of mcl-1 in these mice. Finally, the hepatocyte apoptosis caused by ABT-737, which is a Bcl xL/Bcl-2/Bcl-w inhibitor, was completely prevented in Bim/Bid double knock-out mice. The BH3-only proteins Bim and Bid are functionally active but are restrained by the anti-apoptotic Bcl-2 family proteins under physiological conditions. Hepatocyte integrity is maintained by the dynamic and well orchestrated Bcl-2 network in the healthy liver. PMID- 23986436 TI - Cathepsin B contributes to autophagy-related 7 (Atg7)-induced nod-like receptor 3 (NLRP3)-dependent proinflammatory response and aggravates lipotoxicity in rat insulinoma cell line. AB - Impairment of glucose-stimulated insulin secretion caused by the lipotoxicity of palmitate was found in beta-cells. Recent studies have indicated that defects in autophagy contribute to pathogenesis in type 2 diabetes. Here, we report that autophagy-related 7 (Atg7) induced excessive autophagic activation in INS 1(823/13) cells exposed to saturated fatty acids. Atg7-induced cathepsin B (CTSB) overexpression resulted in an unexpected significant increase in proinflammatory chemokine and cytokine production levels of IL-1beta, monocyte chemotactic protein-1, IL-6, and TNF-alpha. Inhibition of receptor-interacting protein did not affect the inflammatory response, ruling out involvement of necrosis. CTSB siRNA suppressed the inflammatory response but did not affect apoptosis significantly, suggesting that CTSB was a molecular linker between autophagy and the proinflammatory response. Blocking caspase-3 suppressed apoptosis but did not affect the inflammatory response, suggesting that CTSB induced inflammatory effects independently of apoptosis. Silencing of Nod-like receptor 3 (NLRP3) completely abolished both IL-1beta secretion and the down-regulation effects of Atg7-induced CTSB overexpression on glucose-stimulated insulin secretion impairment, thus identifying the NLRP3 inflammasome as an autophagy-responsive element in the pancreatic INS-1(823/13) cell line. Combined together, our results indicate that CTSB contributed to the Atg7-induced NLRP3-dependent proinflammatory response, resulting in aggravation of lipotoxicity, independently of apoptosis in the pancreatic INS-1(823/13) cell line. PMID- 23986437 TI - Ablation of promyelocytic leukemia protein (PML) re-patterns energy balance and protects mice from obesity induced by a Western diet. AB - The promyelocytic leukemia protein is a well known tumor suppressor, but its role in metabolism is largely unknown. Mice with a deletion in the gene for PML (KO mice) exhibit altered gene expression in liver, adipose tissue, and skeletal muscle, an accelerated rate of fatty acid metabolism, abnormal glucose metabolism, constitutive AMP-activating kinase (AMPK) activation, and insulin resistance in skeletal muscle. Last, an increased rate of energy expenditure protects PML KO mice from the effects of obesity induced by a Western diet. Collectively, our study uncovers a previously unappreciated role of PML in the regulation of metabolism and energy balance in mice. PMID- 23986438 TI - Cryptosporidium parvum induces an endoplasmic stress response in the intestinal adenocarcinoma HCT-8 cell line. AB - Invasion of human intestinal epithelial cells (HCT-8) by Cryptosporidium parvum resulted in a rapid induction of host cell spermidine/spermine N(1) acetyltransferase 1 (hSSAT-1) mRNA, causing a 4-fold increase in SSAT-1 enzyme activity after 24 h of infection. In contrast, host cell SSAT-2, spermine oxidase, and acetylpolyamine oxidase (hAPAO) remained unchanged during this period. Intracellular polyamine levels of C. parvum-infected human epithelial cells were determined, and it was found that spermidine remained unchanged and putrescine increased by 2.5-fold after 15 h and then decreased after 24 h, whereas spermine decreased by 3.9-fold after 15 h. Concomitant with these changes, N(1)-acetylspermine and N(1)-acetylspermidine both increased by 115- and 24-fold, respectively. Increased SSAT-1 has previously been shown to be involved in the endoplasmic reticulum (ER) stress response leading to apoptosis. Several stress response proteins were increased in HCT-8 cells infected with C. parvum, including calreticulin, a major calcium-binding chaperone in the ER; GRP78/BiP, a prosurvival ER chaperone; and Nrf2, a transcription factor that binds to antioxidant response elements, thus activating them. However, poly(ADP-ribose) polymerase, a protein involved in DNA repair and programmed cell death, was decreased. Cumulatively, these results suggest that the invasion of HCT-8 cells by C. parvum results in an ER stress response by the host cell that culminates in overexpression of host cell SSAT-1 and elevated N(1)-acetylpolyamines, which can be used by a parasite that lacks ornithine decarboxylase. PMID- 23986439 TI - Mutations in SLC2A2 gene reveal hGLUT2 function in pancreatic beta cell development. AB - The structure-function relationships of sugar transporter-receptor hGLUT2 coded by SLC2A2 and their impact on insulin secretion and beta cell differentiation were investigated through the detailed characterization of a panel of mutations along the protein. We studied naturally occurring SLC2A2 variants or mutants: two single-nucleotide polymorphisms and four proposed inactivating mutations associated to Fanconi-Bickel syndrome. We also engineered mutations based on sequence alignment and conserved amino acids in selected domains. The single nucleotide polymorphisms P68L and T110I did not impact on sugar transport as assayed in Xenopus oocytes. All the Fanconi-Bickel syndrome-associated mutations invalidated glucose transport by hGLUT2 either through absence of protein at the plasma membrane (G20D and S242R) or through loss of transport capacity despite membrane targeting (P417L and W444R), pointing out crucial amino acids for hGLUT2 transport function. In contrast, engineered mutants were located at the plasma membrane and able to transport sugar, albeit with modified kinetic parameters. Notably, these mutations resulted in gain of function. G20S and L368P mutations increased insulin secretion in the absence of glucose. In addition, these mutants increased insulin-positive cell differentiation when expressed in cultured rat embryonic pancreas. F295Y mutation induced beta cell differentiation even in the absence of glucose, suggesting that mutated GLUT2, as a sugar receptor, triggers a signaling pathway independently of glucose transport and metabolism. Our results describe the first gain of function mutations for hGLUT2, revealing the importance of its receptor versus transporter function in pancreatic beta cell development and insulin secretion. PMID- 23986440 TI - Arylsulfatase K, a novel lysosomal sulfatase. AB - The human sulfatase family has 17 members, 13 of which have been characterized biochemically. These enzymes specifically hydrolyze sulfate esters in glycosaminoglycans, sulfolipids, or steroid sulfates, thereby playing key roles in cellular degradation, cell signaling, and hormone regulation. The loss of sulfatase activity has been linked to severe pathophysiological conditions such as lysosomal storage disorders, developmental abnormalities, or cancer. A novel member of this family, arylsulfatase K (ARSK), was identified bioinformatically through its conserved sulfatase signature sequence directing posttranslational generation of the catalytic formylglycine residue in sulfatases. However, overall sequence identity of ARSK with other human sulfatases is low (18-22%). Here we demonstrate that ARSK indeed shows desulfation activity toward arylsulfate pseudosubstrates. When expressed in human cells, ARSK was detected as a 68-kDa glycoprotein carrying at least four N-glycans of both the complex and high mannose type. Purified ARSK turned over p-nitrocatechol and p-nitrophenyl sulfate. This activity was dependent on cysteine 80, which was verified to undergo conversion to formylglycine. Kinetic parameters were similar to those of several lysosomal sulfatases involved in degradation of sulfated glycosaminoglycans. An acidic pH optimum (~4.6) and colocalization with LAMP1 verified lysosomal functioning of ARSK. Further, it carries mannose 6-phosphate, indicating lysosomal sorting via mannose 6-phosphate receptors. ARSK mRNA expression was found in all tissues tested, suggesting a ubiquitous physiological substrate and a so far non-classified lysosomal storage disorder in the case of ARSK deficiency, as shown before for all other lysosomal sulfatases. PMID- 23986441 TI - Silencing of maternal heme-binding protein causes embryonic mitochondrial dysfunction and impairs embryogenesis in the blood sucking insect Rhodnius prolixus. AB - The heme molecule is the prosthetic group of many hemeproteins involved in essential physiological processes, such as electron transfer, transport of gases, signal transduction, and gene expression modulation. However, heme is a pro oxidant molecule capable of propagating reactions leading to the generation of reactive oxygen species. The blood-feeding insect Rhodnius prolixus releases enormous amounts of heme during host blood digestion in the midgut lumen when it is exposed to a physiological oxidative challenge. Additionally, this organism produces a hemolymphatic heme-binding protein (RHBP) that transports heme to pericardial cells for detoxification and to growing oocytes for yolk granules and as a source of heme for embryo development. Here, we show that silencing of RHBP expression in female fat bodies reduced total RHBP circulating in the hemolymph, promoting oxidative damage to hemolymphatic proteins. Moreover, RHBP knockdown did not cause reduction in oviposition but led to the production of heme-depleted eggs (white eggs). A lack of RHBP did not alter oocyte fecundation. However, produced white eggs were nonviable. Embryo development cellularization and vitellin yolk protein degradation, processes that normally occur in early stages of embryogenesis, were compromised in white eggs. Total cytochrome c content, cytochrome c oxidase activity, citrate synthase activity, and oxygen consumption, parameters that indicate mitochondrial function, were significantly reduced in white eggs compared with normal dark red eggs. Our results showed that reduction of heme transport from females to growing oocytes by RHBP leads to embryonic mitochondrial dysfunction and impaired embryogenesis. PMID- 23986442 TI - Active and accurate trans-translation requires distinct determinants in the C terminal tail of SmpB protein and the mRNA-like domain of transfer messenger RNA (tmRNA). AB - Unproductive ribosome stalling in eubacteria is resolved by the actions of SmpB protein and transfer messenger (tm) RNA. We examined the functional significance of conserved regions of SmpB and tmRNA to the trans-translation process. Our investigations reveal that the N-terminal 20 residues of SmpB, which are located near the ribosomal decoding center, are dispensable for all known SmpB activities. In contrast, a set of conserved residues that reside at the junction between the tmRNA-binding core and the C-terminal tail of SmpB play an important role in tmRNA accommodation. Our data suggest that the highly conserved glycine 132 acts as a flexible hinge that enables movement of the C-terminal tail, thus permitting proper positioning and establishment of the tmRNA open reading frame (ORF) as the surrogate template. To gain further insights into the function of the SmpB C-terminal tail, we examined the tagging activity of hybrid variants of tmRNA and the SmpB protein, in which the tmRNA ORF or the SmpB C-terminal tail was substituted with the equivalent but highly divergent sequences from Francisella tularensis. We observed that the hybrid tmRNA was active but resulted in less accurate selection of the resume codon. Cognate hybrid SmpB was necessary to restore activity. Furthermore, accurate tagging was observed when the identity of the resume codon was reverted from GGC to GCA. Taken together, these data suggest that the engagement of the tmRNA ORF and the selection of the correct translation resumption point are distinct activities that are influenced by independent tmRNA and SmpB determinants. PMID- 23986443 TI - The temperature sensitivity of a mutation in the essential tRNA modification enzyme tRNA methyltransferase D (TrmD). AB - Conditional temperature-sensitive (ts) mutations are important reagents to study essential genes. Although it is commonly assumed that the ts phenotype of a specific mutation arises from thermal denaturation of the mutant enzyme, the possibility also exists that the mutation decreases the enzyme activity to a certain level at the permissive temperature and aggravates the negative effect further upon temperature upshifts. Resolving these possibilities is important for exploiting the ts mutation for studying the essential gene. The trmD gene is essential for growth in bacteria, encoding the enzyme for converting G37 to m(1)G37 on the 3' side of the tRNA anticodon. This conversion involves methyl transfer from S-adenosyl methionine and is critical to minimize tRNA frameshift errors on the ribosome. Using the ts-S88L mutation of Escherichia coli trmD as an example, we show that although the mutation confers thermal lability to the enzyme, the effect is relatively minor. In contrast, the mutation decreases the catalytic efficiency of the enzyme to 1% at the permissive temperature, and at the nonpermissive temperature, it renders further deterioration of activity to 0.1%. These changes are accompanied by losses of both the quantity and quality of tRNA methylation, leading to the potential of cellular pleiotropic effects. This work illustrates the principle that the ts phenotype of an essential gene mutation can be closely linked to the catalytic defect of the gene product and that such a mutation can provide a useful tool to study the mechanism of catalytic inactivation. PMID- 23986444 TI - Heterogeneous seeding of a prion structure by a generic amyloid form of the fungal prion-forming domain HET-s(218-289). AB - The fungal prion-forming domain HET-s(218-289) forms infectious amyloid fibrils at physiological pH that were shown by solid-state NMR to be assemblies of a two rung beta-solenoid structure. Under acidic conditions, HET-s(218-289) has been shown to form amyloid fibrils that have very low infectivity in vivo, but structural information about these fibrils has been very limited. We show by x ray fiber diffraction that the HET-s(218-289) fibrils formed under acidic conditions have a stacked beta-sheet architecture commonly found in short amyloidogenic peptides and denatured protein aggregates. At physiological pH, stacked beta-sheet fibrils nucleate the formation of the infectious beta-solenoid prions in a process of heterogeneous seeding, but do so with kinetic profiles distinct from those of spontaneous or homogeneous (seeded with infectious beta solenoid fibrils) fibrillization. Several serial passages of stacked beta-sheet seeded solutions lead to fibrillization kinetics similar to homogeneously seeded solutions. Our results directly show that structural mutation can occur between substantially different amyloid architectures, lending credence to the suggestion that the processes of strain adaptation and crossing species barriers are facilitated by structural mutation. PMID- 23986445 TI - The herbal compound cryptotanshinone restores sensitivity in cancer cells that are resistant to the tumor necrosis factor-related apoptosis-inducing ligand. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis and kills cancer cells but not normal cells. However, TRAIL resistance due to low level of TRAIL receptor expression is widely found in cancer cells and hampers its development for cancer treatment. Thus, the agents that can sensitize the tumor cells to TRAIL-mediated apoptosis are urgently needed. We investigated whether tanshinones, the major bioactive compounds of Salvia miltiorrhiza (danshen), can up-regulate TRAIL receptor expression. Among the major tanshinones being tested, cryptotanshinone (CT) showed the best ability to induce TRAIL receptor 2 (DR5) expression. We further showed that CT was capable of promoting TRAIL-induced cell death and apoptosis in A375 melanoma cells. CT-induced DR5 induction was not cell type-specific, as DR5 induction was observed in other cancer cell types. DR5 knockdown abolished the enhancing effect of CT on TRAIL responses. Mechanistically, induction of the DR5 by CT was found to be p53-independent but dependent on the induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). Knockdown of CHOP abolished CT-induced DR5 expression and the associated potentiation of TRAIL-mediated cell death. In addition, CT-induced ROS production preceded up-regulation of CHOP and DR5 and consequent sensitization of cells to TRAIL. Interestingly, CT also converted TRAIL-resistant lung A549 cancer cells into TRAIL-sensitive cells. Taken together, our results indicate that CT can potentiate TRAIL-induced apoptosis through up-regulation of DR5. PMID- 23986446 TI - Activation of the leukotriene B4 receptor 2-reactive oxygen species (BLT2-ROS) cascade following detachment confers anoikis resistance in prostate cancer cells. AB - The majority of prostate cancer-related deaths are associated with advanced and metastatic malignancies. Although anoikis resistance has been recognized as one of the hallmarks of metastatic prostate malignancies, the molecular events that cause anoikis resistance are poorly understood. In this study, we found that the detachment of PC-3 prostate cancer cells caused a time-dependent increase in the expression level of the leukotriene B4 receptor-2 (BLT2) and that BLT2 played a critical role in establishing anoikis resistance in these cells. Blocking BLT2 with the pharmacological inhibitor LY255283 or with RNAi knockdown clearly abolished anoikis resistance and resulted in severe apoptotic death. Additionally, we demonstrated that the activation of NADPH oxidase (NOX) and subsequent generation of reactive oxygen species (ROS) were downstream of BLT2 signaling and led to the activation of NF-kappaB, thus establishing anoikis resistance during cell detachment. Furthermore, we observed that the ectopic expression of BLT2 in normal prostate PWR-1E cells rendered the cells resistant to anoikis and apparently diminished apoptotic cell death following detachment. Taken together, our results suggest that BLT2-NOX-ROS-NF-kappaB cascade induction during detachment confers a novel mechanism of anoikis resistance in prostate cancer cells and potentially contributes to prostate cancer progression. PMID- 23986447 TI - Control of DNA replication by the nucleus/cytoplasm ratio in Xenopus. AB - The nucleus/cytoplasm (N/C) ratio controls S phase dynamics in many biological systems, most notably the abrupt remodeling of the cell cycle that occurs at the midblastula transition in early Xenopus laevis embryos. After an initial series of rapid cleavage cycles consisting only of S and M phases, a critical N/C ratio is reached, which causes a sharp increase in the length of S phase as the cell cycle is reconfigured to resemble somatic cell cycles. How the N/C ratio determines the length of S phase has been a longstanding problem in developmental biology. Using Xenopus egg extracts, we show that DNA replication at high N/C ratio is restricted by one or more limiting substances. We report here that the protein phosphatase PP2A, in conjunction with its B55alpha regulatory subunit, becomes limiting for replication origin firing at high N/C ratio, and this in turn leads to reduced origin activation and an increase in the time required to complete S phase. Increasing the levels of PP2A catalytic subunit or B55alpha experimentally restores rapid DNA synthesis at high N/C ratio. Inversely, reduction of PP2A or B55alpha levels sharply extends S phase even in low N/C extracts. These results identify PP2A-B55alpha as a link between DNA replication and N/C ratio in egg extracts and suggest a mechanism that may influence the onset of the midblastula transition in vivo. PMID- 23986448 TI - Inhibition of the first step in synthesis of the mycobacterial cell wall core, catalyzed by the GlcNAc-1-phosphate transferase WecA, by the novel caprazamycin derivative CPZEN-45. AB - Because tuberculosis is one of the most prevalent and serious infections, countermeasures against it are urgently required. We isolated the antitubercular agents caprazamycins from the culture of an actinomycete strain and created CPZEN 45 as the most promising derivative of the caprazamycins. Herein, we describe the mode of action of CPZEN-45 first against Bacillus subtilis. Unlike the caprazamycins, CPZEN-45 strongly inhibited incorporation of radiolabeled glycerol into growing cultures and showed antibacterial activity against caprazamycin resistant strains, including a strain overexpressing translocase-I (MraY, involved in the biosynthesis of peptidoglycan), the target of the caprazamycins. By contrast, CPZEN-45 was not effective against a strain overexpressing undecaprenyl-phosphate-GlcNAc-1-phosphate transferase (TagO, involved in the biosynthesis of teichoic acid), and a mutation was found in the tagO gene of the spontaneous CPZEN-45-resistant strain. This suggested that the primary target of CPZEN-45 in B. subtilis is TagO, which is a different target from that of the parent caprazamycins. This suggestion was confirmed by evaluation of the activities of these enzymes. Finally, we showed that CPZEN-45 was effective against WecA (Rv1302, also called Rfe) of Mycobacterium tuberculosis, the ortholog of TagO and involved in the biosynthesis of the mycolylarabinogalactan of the cell wall of M. tuberculosis. The outlook for WecA as a promising target for the development of antituberculous drugs as a countermeasure of drug resistant tuberculosis is discussed. PMID- 23986449 TI - Factor V activator from Daboia russelli russelli venom destabilizes beta-amyloid aggregate, the hallmark of Alzheimer disease. AB - Formation of plaque by fibrils of beta-amyloid (Abeta) peptide in the brain is the characteristic feature of Alzheimer disease (AD). Inhibition of the process of aggregate formation from Abeta-monomer and destabilization of the aggregate could be useful for prevention and propagation of the disease respectively. Russell's viper venom (RVV) contains protein(s) that destabilize Abeta aggregates as revealed from the thioflavin T assay. The active component was identified as factor V activator (RVV-V). Among the possible mechanisms of destabilization, RVV V-mediated proteolysis was ruled out from mass spectrometric data and the thioflavin T assay. The alternate hypothesis that small peptides derived from RVV V destabilize the aggregate is better supported by experimental results. Six small peptides were synthesized using RVV-V as the template, and three unrelated peptides were synthesized to serve as controls. Destabilization of Abeta aggregate by these peptides was studied using spectrofluorometric assays, atomic force microscopy, transmission electron microscopy, and confocal microscopy. Among the peptides, CTNIF and the mixture of the six peptides were most potent in converting the aggregates to the monomeric state and thus, preventing cytotoxicity in SH-SY5Y human neuroblastoma cells. The control peptides failed to show similar effects. Moreover, some of these peptides are stable in blood for 24 h. Therefore, these venom-derived peptides offer an encouraging opportunity to prevent amyloidosis and may provide information to combat AD. PMID- 23986450 TI - The first identification of carbohydrate binding modules specific to chitosan. AB - Two carbohydrate binding modules (DD1 and DD2) belonging to CBM32 are located at the C terminus of a chitosanase from Paenibacillus sp. IK-5. We produced three proteins, DD1, DD2, and tandem DD1/DD2 (DD1+DD2), and characterized their binding ability. Transition temperature of thermal unfolding (Tm) of each protein was elevated by the addition of cello-, laminari-, chitin-, or chitosan-hexamer (GlcN)6. The Tm elevation (DeltaTm) in DD1 was the highest (10.3 degrees C) upon the addition of (GlcN)6 and was markedly higher than that in DD2 (1.0 degrees C). A synergistic effect was observed (DeltaTm = 13.6 degrees C), when (GlcN)6 was added to DD1+DD2. From isothermal titration calorimetry experiments, affinities to DD1 were not clearly dependent upon chain length of (GlcN)n; DeltaGr degrees values were -7.8 (n = 6), -7.6 (n = 5), -7.6 (n = 4), -7.6 (n = 3), and -7.1 (n = 2) kcal/mol, and the value was not obtained for GlcN due to the lowest affinity. DD2 bound (GlcN)n with the lower affinities (DeltaGr degrees = 5.0 (n = 3) ~ -5.2 (n = 6) kcal/mol). Isothermal titration calorimetry profiles obtained for DD1+DD2 exhibited a better fit when the two-site model was used for analysis and provided greater affinities to (GlcN)6 for individual DD1 and DD2 sites (DeltaGr degrees = -8.6 and -6.4 kcal/mol, respectively). From NMR titration experiments, (GlcN)n (n = 2~6) were found to bind to loops extruded from the core beta-sandwich of individual DD1 and DD2, and the interaction sites were similar to each other. Taken together, DD1+DD2 is specific to chitosan, and individual modules synergistically interact with at least two GlcN units, facilitating chitosan hydrolysis. PMID- 23986452 TI - The Lewis X-related alpha1,3-fucosyltransferase, Fut10, is required for the maintenance of stem cell populations. AB - Lewis X (Le(X), Galbeta1-4(Fucalpha1-3)GlcNAc) is a carbohydrate epitope that is present at the nonreducing terminus of sugar chains of glycoproteins and glycolipids, and is abundantly expressed in several stem cell populations. Le(X) antigen can be used in conjunction with fluorescence-activated cell sorting to isolate neurosphere-forming neural stem cells (NSCs) from embryonic mouse brains. However, its function in the maintenance and differentiation of stem cells remains largely unknown. In this study, we examined mice deficient for fucosyltransferase 9 (Fut9), which is thought to synthesize most, if not all, of the Le(X) moieties in the brain. We found that the number of NSCs was increased in the brain of Fut9(-/-) embryos, suggesting that Fut9-synthesized Le(X) is dispensable for the maintenance of NSCs. Another alpha1,3-fucosyltransferase gene, fucosyltransferase 10 (Fut10), is expressed in the ventricular zone of the embryonic brain. Overexpression of Fut10 enhanced the self-renewal of NSCs. Conversely, suppression of Fut10 expression induced the differentiation of NSCs and embryonic stem cells. In addition, knockdown of Fut10 expression in the cortical ventricular zone of the embryonic brain by in utero electroporation of Fut10-miRNAs impaired the radial migration of neural precursor cells. Our data suggest that Fut10 is involved in a unique alpha1,3-fucosyltransferase activity with stringent substrate specificity, and that this activity is required to maintain stem cells in an undifferentiated state. PMID- 23986451 TI - Engineered protease-resistant antibodies with selectable cell-killing functions. AB - Molecularly engineered antibodies with fit-for-purpose properties will differentiate next generation antibody therapeutics from traditional IgG1 scaffolds. One requirement for engineering the most appropriate properties for a particular therapeutic area is an understanding of the intricacies of the target microenvironment in which the antibody is expected to function. Our group and others have demonstrated that proteases secreted by invasive tumors and pathological microorganisms are capable of cleaving human IgG1, the most commonly adopted isotype among monoclonal antibody therapeutics. Specific cleavage in the lower hinge of IgG1 results in a loss of Fc-mediated cell-killing functions without a concomitant loss of antigen binding capability or circulating antibody half-life. Proteolytic cleavage in the hinge region by tumor-associated or microbial proteases is postulated as a means of evading host immune responses, and antibodies engineered with potent cell-killing functions that are also resistant to hinge proteolysis are of interest. Mutation of the lower hinge region of an IgG1 resulted in protease resistance but also resulted in a profound loss of Fc-mediated cell-killing functions. In the present study, we demonstrate that specific mutations of the CH2 domain in conjunction with lower hinge mutations can restore and sometimes enhance cell-killing functions while still retaining protease resistance. By identifying mutations that can restore either complement- or Fcgamma receptor-mediated functions on a protease-resistant scaffold, we were able to generate a novel protease-resistant platform with selective cell-killing functionality. PMID- 23986454 TI - A novel mouse model for phenytoin-induced liver injury: involvement of immune related factors and P450-mediated metabolism. AB - Drug-induced liver injury is an important issue for drug development and clinical drug therapy; however, in most cases, it is difficult to predict or prevent these reactions due to a lack of suitable animal models and the unknown mechanisms of action. Phenytoin (DPH) is an anticonvulsant drug that is widely used for the treatment of epilepsy. Some patients who are administered DPH will suffer symptoms of drug-induced liver injury characterized by hepatic necrosis. DPH induced liver injury occurs in 1 in 1000 or 1 in 10 000 patients. Clinically, 75% of patients who develop liver injury develop a fever and 63% develop a rash. In this study, we established a mouse model for DPH-induced liver injury and analyzed the mechanisms for hepatotoxicity in the presence of immune-related or inflammation-related factors and metabolic activation. Female C57BL/6 mice were administered DPH for 5 days in combination with L-buthionine-S,R-sulfoximine. Then, the plasma alanine aminotransferase (ALT) levels were increased, hepatic lesions were observed during the histological evaluations, the hepatic glutathione levels were significantly reduced, and the oxidative stress marker levels were significantly increased. The inhibition of cytochrome P450-dependent oxidative metabolism significantly suppressed the elevated plasma ALT levels and depleted hepatic glutathione. Among the innate immune factors, the hepatic mRNA levels of NACHT, LRR, pyrin domain-containing protein 3, interleukin-1beta, and damage-associated molecular patterns were significantly increased. Prostaglandin E1 treatment ameliorated the hepatic injury caused by DPH. In conclusion, cytochrome P450-dependent metabolic activation followed by the stimulation of the innate immune responses is involved in DPH-induced liver injury. PMID- 23986453 TI - Substrate inhibition of uracil phosphoribosyltransferase by uracil can account for the uracil growth sensitivity of Leishmania donovani pyrimidine auxotrophs. AB - The pathogenic protozoan parasite Leishmania donovani is capable of both de novo pyrimidine biosynthesis and salvage of pyrimidines from the host milieu. Genetic analysis has authenticated L. donovani uracil phosphoribosyltransferase (LdUPRT), an enzyme not found in mammalian cells, as the focal enzyme of pyrimidine salvage because all exogenous pyrimidines that can satisfy the requirement of the parasite for pyrimidine nucleotides are funneled to uracil and then phosphoribosylated to UMP in the parasite by LdUPRT. To characterize this unique parasite enzyme, LdUPRT was expressed in Escherichia coli, and the recombinant enzyme was purified to homogeneity. Kinetic analysis revealed apparent Km values of 20 and 99 MUM for the natural substrates uracil and phosphoribosylpyrophosphate, respectively, as well as apparent Km values 6 and 7 MUM for the pyrimidine analogs 5-fluorouracil and 4-thiouracil, respectively. Size exclusion chromatography revealed the native LdUPRT to be tetrameric and retained partial structure and activity in high concentrations of urea. L. donovani mutants deficient in de novo pyrimidine biosynthesis, which require functional LdUPRT for growth, are hypersensitive to high concentrations of uracil, 5-fluorouracil, and 4-thiouracil in the growth medium. This hypersensitivity can be explained by the observation that LdUPRT is substrate inhibited by uracil and 4-thiouracil, but 5-fluorouracil toxicity transpires via an alternative mechanism. This substrate inhibition of LdUPRT provides a protective mechanism for the parasite by facilitating purine and pyrimidine nucleotide pool balance and by sparing phosphoribosylpyrophosphate for consumption by the nutritionally indispensable purine salvage process. PMID- 23986455 TI - Diffusion-weighted MRI of metastatic liver lesions: is there a difference between hypervascular and hypovascular metastases? AB - BACKGROUND: Different perfusion characteristics and histopathologic features of liver metastasis may potentially lead to different diffusion-weighted magnetic resonance imaging (DW-MRI) characteristics which can affect the performance of DW MRI in their diagnosis. PURPOSE: To compare ADC values of hypervascular and hypovascular metastases and the added value of DW-MRI to T2-weighted (T2-w) images in their detection. MATERIAL AND METHODS: In this retrospective study, 46 patients (21 with hypervascular, 25 with hypovascular liver metastases) who had undergone abdominal MRI were included. Two independent observers first reviewed T2-w images only and then T2-w+DW-MR images and recorded number of metastases in each session. Lesion detection rate was compared using McNemar test. ADC of metastases in each patient was measured and compared between hypo- and hypervascular lesions using t-test. RESULTS: A total of 153 hypervascular and 187 hypovascular metastases were detected at consensus review. Two observers detected significantly more hypervascular metastases on T2-w+DW-MR image review session compared to T2-w image only review session (reader 1: 148 [96.7%] vs. 129 [84.3%], P=0.002; reader 2: 125 [81.9%] vs. 113 [73.8%], P=0.004). Detection rate of hypovascular metastases was similar between two sessions for both observers (reader 1: 180 [96.2%] vs. 184 [98.4%]; reader 2: 176 [94.1%] vs. 180 [96.2%], P>0.05). The mean ADC value of hypervascular metastases was significantly lower than mean ADC value of hypovascular metastases (1.23+/-0.31 * 10(-3)mm(2)/s vs. 1.49+/-0.19 * 10(-3)mm(2)/s) (P=0.001). CONCLUSION: Liver metastases are not a homogenous group of lesions with uniform DW-MRI features. Hypervascular metastases demonstrate significantly lower ADC values compared to hypovascular metastases. DW-MRI improved detection of hypervascular metastases compared to T2 w images alone and is a useful adjunct to T2-w images for their detection. PMID- 23986456 TI - [Encephalitis due to autoimmune processes: intriguing neuropsychiatric disorders]. PMID- 23986457 TI - [Neuropsychological assessment early after stroke--an overview of diagnostic instruments available in German and introduction of a new screening tool]. AB - Stroke-induced neuropsychological sequelae are frequent and highly relevant for the patient's prognosis, so that their diagnostic assessment at an early point in time is highly advisable to allow for the initiation of appropriate treatment. Because stroke patients in the acute and sub-acute phase of a stroke often show a general slowing and restricted resilience, investigation may be limited and is often only manageable by means of instruments that can be used at bedside. Preferably such neuropsychological tests should also be normalised for the target group. An overview of the neuropsychological instruments available in German, which were developed for or applied to stroke patients in the early phases of stroke and rehabilitation, is provided here. One of the nine instruments presented is the newly developed Cologne Neuropsychological Screening for Stroke Patients (German: Kolner Neuropsychologisches Screening fur Schlaganfall Patienten), which is introduced here. The instruments differ in form of investigation, duration, material volume and standardisation. The choice of a particular instrument in a given clinical or scientific context explicitly depends on the diagnostic goal as well as the resilience of the patient. PMID- 23986458 TI - [Impulsive-compulsive behaviours in a German Parkinson's disease outpatient sample]. AB - BACKGROUND: Impulsive-compulsive behaviours (ICBs) are frequent complications of Parkinson's disease (PD), associated with treatment by dopamine agonists (DAs). These include impulse control disorders (ICDs), repetitive behaviour (RB) and the dopamine-dysregulation syndrome (DDS). METHODS: A subsample of 72 patients of a large longitudinal study (n = 739) was screened with the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (QUIP). Results were associated with socio-demographic, clinical and neuropsychological parameters. RESULTS: A large proportion of the sample reported ICBs (60%), RBs were most frequent (47 %). Patients with ICBs consumed higher doses of DAs (343 +/- 177 mg vs. 390 +/- 153 mg; p < 0.01). Pramipexole was associated with RB but not ICDs (273 +/- 225 mg and 53 +/- 106 mg vs. 151 +/- 209 mg in patients without ICB). Patients with ICDs reported more dyskinesias (UPDRS IV: 1.78 +/- 1.6 vs. 0.55 +/- 1.1 points; p = 0.012) and patients with multiple ICBs a longer duration of PD (9.3 +/- 5.0 vs. 6.2 +/- 4.0 years; p = 0.026) and worse quality of life (PDQ39: 29.9 +/- 13.8 vs. 20.3 +/- 13.4 points; p = 0.036) compared to patients without any ICB. CONCLUSIONS: ICBs are frequent even in outpatients with moderate duration and severity of PD and associated with DA dose. Because of possible serious psychosocial consequences, detecting and managing them is of high importance. PMID- 23986459 TI - [The German guideline "legal evaluation after closed head injury"]. AB - In 2005, the "Deutsche Gesellschaft fur Neurowissenschaftliche Begutachtung" (German Society for Neuroscientific Legal Evaluation) together with other Societies published a guideline for the legal evaluation of patients with closed head injuries. Meanwhile, not only scientific progress in imaging techniques but also in other fields such as neuropsychology has necessitated a revision, which is presented here. In the mean time, the handling of guidelines has been systematised in Germany so that a registration with the Cooperation of German Medical Learned Societies is applied for and publication in the German Guideline Registry is expected. PMID- 23986460 TI - [Autoimmune encephalitis]. PMID- 23986461 TI - A randomised controlled trial of combined EEG feedback and methylphenidate therapy for the treatment of ADHD. AB - PURPOSE: To evaluate the efficacy of combined methylphenidate and EEG feedback treatment for children with ADHD. METHODS: Forty patients with ADHD were randomly assigned to the combination group (methylphenidate therapy and EEG feedback training) or control group (methylphenidate therapy and non-feedback attention training) in a 1:1 ratio using the double-blind method. These patients, who met the DSM-IV diagnostic criteria and were aged between 7 and 16 years, had obtained optimal therapeutic effects by titrating the methylphenidate dose prior to the trial. The patients were assessed using multiple parameters at baseline, after 20 treatment sessions, after 40 treatment sessions, and in 6-month follow-up studies. RESULTS: Compared to the control group, patients in the combination group had reduced ADHD symptoms and improved in related behavioural and brain functions. CONCLUSION: The combination of EEG feedback and methylphenidate treatment is more effective than methylphenidate alone. The combined therapy is especially suitable for children and adolescents with ADHD who insufficiently respond to single drug treatment or experience drug side effects. PMID- 23986462 TI - EGFRvIII expression in squamous cell carcinoma of the skin. PMID- 23986464 TI - Self-reported prosthetic sock use among persons with transtibial amputation. AB - BACKGROUND: Daily changes in the shape and size of the residual limb affect prosthetic socket fit. Prosthetic socks are often added or removed to manage changes in limb volume. Little has been published about how persons with transtibial amputations use socks to manage diurnal changes in volume and comfort. OBJECTIVES: To investigate prosthetic sock use with a customized, self report questionnaire. STUDY DESIGN: Cross-sectional survey. METHODS: Persons with transtibial amputation reported number, thickness, and timing of socks used over a 14-day period. RESULTS: Data from 23 subjects (16 males and 7 females) were included. On average, socks were changed less than once per day (0.6/day) and ply increased over the day (4.8-5.5 ply). Subjects wore prostheses significantly longer (15.0-14.1 h, p = 0.02) and changed socks significantly more often (0.6/day-0.4/day, p = 0.03) on weekdays compared to weekends. Participants were also divided into two subgroups: those who used socks to manage limb volume and those who used socks for socket comfort. Sock use did not differ (p > 0.05) between subgroups. CONCLUSIONS: Sock changes are infrequent among persons with lower limb loss. Initial, verbal reports of sock use were often inconsistent with data measured by logs. Tools (e.g. sock logs or objective instruments) to better understand sock-use habits among persons with limb loss are needed. CLINICAL RELEVANCE: Knowledge of prosthetic patients' sock use may help practitioners enhance volume management strategies or troubleshoot fitting issues. Results showed that subjects generally added socks to account for volume loss, and end-of day sock thickness frequently exceeded 5 ply. Use of sock logs in clinical practice may facilitate improved residual limb health. PMID- 23986463 TI - Mosquito larval source management for controlling malaria. AB - BACKGROUND: Malaria is an important cause of illness and death in people living in many parts of the world, especially sub-Saharan Africa. Long-lasting insecticide treated bed nets (LLINs) and indoor residual spraying (IRS) reduce malaria transmission by targeting the adult mosquito vector and are key components of malaria control programmes. However, mosquito numbers may also be reduced by larval source management (LSM), which targets mosquito larvae as they mature in aquatic habitats. This is conducted by permanently or temporarily reducing the availability of larval habitats (habitat modification and habitat manipulation), or by adding substances to standing water that either kill or inhibit the development of larvae (larviciding). OBJECTIVES: To evaluate the effectiveness of mosquito LSM for preventing malaria. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CABS Abstracts; and LILACS up to 24 October 2012. We handsearched the Tropical Diseases Bulletin from 1900 to 2010, the archives of the World Health Organization (up to 11 February 2011), and the literature database of the Armed Forces Pest Management Board (up to 2 March 2011). We also contacted colleagues in the field for relevant articles. SELECTION CRITERIA: We included cluster randomized controlled trials (cluster-RCTs), controlled before-and-after trials with at least one year of baseline data, and randomized cross-over trials that compared LSM with no LSM for malaria control. We excluded trials that evaluated biological control of anopheline mosquitoes with larvivorous fish. DATA COLLECTION AND ANALYSIS: At least two authors assessed each trial for eligibility. We extracted data and at least two authors independently determined the risk of bias in the included studies. We resolved all disagreements through discussion with a third author. We analyzed the data using Review Manager 5 software. MAIN RESULTS: We included 13 studies; four cluster-RCTs, eight controlled before-and-after trials, and one randomized cross-over trial. The included studies evaluated habitat modification (one study), habitat modification with larviciding (two studies), habitat manipulation (one study), habitat manipulation plus larviciding (two studies), or larviciding alone (seven studies) in a wide variety of habitats and countries. Malaria incidenceIn two cluster-RCTs undertaken in Sri Lanka, larviciding of abandoned mines, streams, irrigation ditches, and rice paddies reduced malaria incidence by around three-quarters compared to the control (RR 0.26, 95% CI 0.22 to 0.31, 20,124 participants, two trials, moderate quality evidence). In three controlled before-and-after trials in urban and rural India and rural Kenya, results were inconsistent (98,233 participants, three trials, very low quality evidence). In one trial in urban India, the removal of domestic water containers together with weekly larviciding of canals and stagnant pools reduced malaria incidence by three quarters. In one trial in rural India and one trial in rural Kenya, malaria incidence was higher at baseline in intervention areas than in controls. However dam construction in India, and larviciding of streams and swamps in Kenya, reduced malaria incidence to levels similar to the control areas. In one additional randomized cross-over trial in the flood plains of the Gambia River, where larval habitats were extensive and ill-defined, larviciding by ground teams did not result in a statistically significant reduction in malaria incidence (2039 participants, one trial). Parasite prevalenceIn one cluster-RCT from Sri Lanka, larviciding reduced parasite prevalence by almost 90% (RR 0.11, 95% CI 0.05 to 0.22, 2963 participants, one trial, moderate quality evidence). In five controlled before-and-after trials in Greece, India, the Philippines, and Tanzania, LSM resulted in an average reduction in parasite prevalence of around two-thirds (RR 0.32, 95% CI 0.19 to 0.55, 8041 participants, five trials, moderate quality evidence). The interventions in these five trials included dam construction to reduce larval habitats, flushing of streams, removal of domestic water containers, and larviciding. In the randomized cross-over trial in the flood plains of the Gambia River, larviciding by ground teams did not significantly reduce parasite prevalence (2039 participants, one trial). AUTHORS' CONCLUSIONS: In Africa and Asia, LSM is another policy option, alongside LLINs and IRS, for reducing malaria morbidity in both urban and rural areas where a sufficient proportion of larval habitats can be targeted. Further research is needed to evaluate whether LSM is appropriate or feasible in parts of rural Africa where larval habitats are more extensive. PMID- 23986465 TI - Prosthetic fitting in a patient with a transtibial amputation due to a congenital vascular malformation of the right leg. AB - BACKGROUND: The problems of prescribing a prosthesis for a young girl with severe congenital vascular malformation deformity leading to a transtibial amputation. CASE DESCRIPTION AND METHODS: Due to the high risk of recurrent bleeding and limitations regarding full weight bearing of the stump, a normal socket fitting process was not possible. Using a multidisciplinary approach, a prosthesis was designed to enable full weight bearing in a flexed knee position with ischial tuberosity support to prevent full weight bearing on the tibial part of the stump. FINDINGS AND OUTCOMES: After training and adjustments to the design, a definitive prosthesis with a free motion mechanical knee joint could be used. During the training with this prosthesis, no skin problems were observed, and at the end of the rehabilitation, the patient had a high level of activities of daily living and sports. CONCLUSION: The above prosthetic solution with an adjusted socket design proved to be successful in this case. Clinical relevance In a patient with severe congenital vascular malformation deformity leading to a transtibial amputation, fitting of a good prosthesis without full weight bearing of the stump proved to be successful. PMID- 23986466 TI - Immediate effect of orthopedic shoe and functional foot orthosis on center of pressure displacement and gait parameters in juvenile flexible flat foot. AB - BACKGROUND: Flat foot in children is a common deformity in which the medial longitudinal arch is reduced or eliminated. OBJECTIVES: The objective of this article was to compare flat foot and healthy children on the displacement of the center of pressure and walking parameters in children with two common orthoses (functional foot orthosis and medical shoe). STUDY DESIGN: Comparative study. METHODS: This study included 30 children with flat foot and 20 healthy children as a control group. The step length and width, walking velocity, symmetry, and center of pressure (CoP) displacements were recorded and compared for three conditions: functional foot orthosis and regular shoe, a medical shoe and barefoot. RESULTS: The results from the CoP displacements showed that the regular shoe with functional foot orthosis caused a significant decrease in the level of displacement of the CoP in flat foot children. The findings indicated a significant improvement in symmetry of steps and walking speed with the functional foot orthosis in comparison to the medical shoe in flat foot children. CONCLUSION: The CoP displacement was decreased and the percentage of gait symmetry and walking speed were increased by the use of regular shoes with a functional foot orthosis in comparison to the medical shoes. CLINICAL RELEVANCE: An orthopaedic shoe can be expensive, and in particular heavy with most children reluctant to wear it. This study focussed on the CoP displacement and selected gait parameters with an orthopaedic shoe and functional foot orthosis, and showed that a combined prescription of a functional foot orthosis and with regular shoes may be a useful alternative for children with moderate flat foot. PMID- 23986467 TI - Effect of rocker shoes on pain, disability and activity limitation in patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis is a chronic inflammatory joint disease which affects the joints and soft tissues of the foot and ankle. Rocker shoes may be prescribed for the symptomatic foot in rheumatoid arthritis; however, there is a limited evidence base to support the use of rocker shoes in these patients. OBJECTIVES: The aim of this study was to evaluate the effectiveness of heel-to toe rocker shoes on pain, disability, and activity limitation in patients with rheumatoid arthritis. STUDY DESIGN: Clinical trial. METHODS: Seventeen female patients with rheumatoid arthritis of 1 year or more duration, disease activity score of less than 2.6, and foot and ankle pain were recruited. Heel-to-toe rocker shoe was made according to each patient's foot size. All the patients were evaluated immediately, 7 and 30 days after their first visit. Foot Function Index values were recorded at each appointment. RESULTS: With the use of rocker shoes, Foot Function Index values decreased in all subscales. This reduction was noted in the first visit and was maintained throughout the trials. CONCLUSION: Rocker shoe can improve pain, disability, and activity limitation in patients with rheumatoid foot pain. All the subjects reported improved comfort levels. CLINICAL RELEVANCE: The results of this study showed that high-top, heel-to-toe rocker shoe with wide toe box was effective at reducing foot and ankle pain. It was also regarded as comfortable and acceptable footwear by the patients with rheumatoid foot problems. PMID- 23986468 TI - Wearing an active spinal orthosis improves back extensor strength in women with osteoporotic vertebral fractures. AB - BACKGROUND: Vertebral fractures are the most common clinical manifestations of osteoporosis. Vertebral fractures and reduced back extensor strength can result in hyperkyphosis. Hyperkyphosis is associated with diminished daily functioning and an increased risk of falling. Improvements in back extensor strength can result in decreased kyphosis and thus a decreased risk of falls and fractures. OBJECTIVES: The aim was to examine the effects of an active spinal orthosis - Spinomed III - on back extensor strength, back pain and physical functioning in women with osteoporotic vertebral fractures. STUDY DESIGN: Experimental follow up. METHODS: The women used the active spinal orthosis for 3 months. Outcomes were changes in isometric back extensor strength, changes in back pain and changes in physical functioning. RESULTS: A total of 13 women were included in the trial. Wearing the orthosis during a 3-month period was associated with an increase in back extensor strength of 50% (p = 0.01). The study demonstrated a 33% reduction in back pain and a 6.5-point improvement in physical functioning. The differences in pain and physical functioning were borderline significant. CONCLUSION: The women demonstrated a clinically relevant improvement in the back extensor strength. The differences in pain and physical functioning were clinically relevant and borderline significant. CLINICAL RELEVANCE: The results imply that Spinomed III could be recommended for women with vertebral fractures as a supplement to traditional back strengthening exercises. It is essential that the orthosis is adjusted correctly and that there is an individual programme concerning the amount of time the orthosis has to be worn every day. PMID- 23986469 TI - The biomechanical effect of arm mass on long jump performance: A case study of a paralympic upper limb amputee. AB - BACKGROUND: The role of arm motion during the long jump has been well studied. The aim of this study was to quantify the effect of forearm mass on impulse and the kinematics of the flight phase in an upper limb amputee. CASE DESCRIPTION AND METHODS: A world-record paralympic long jumper carried out jumps in three conditions: wearing his usual forearm prosthesis and with 0.3 and 0.4 kg added mass. A motion capture system including force plates was used to record the jump. FINDINGS AND OUTCOME: At take-off, the addition of 0.4 kg to the prosthesis decreased the vertical velocity of the centre of mass but increased horizontal velocity. These modifications were associated with an increase in landing distance and an improvement of the synchronization between arms. CONCLUSION: Increasing forearm mass appears to improve long jump performance. Further studies need to evaluate the optimal prosthetic mass for both training and competition. CLINICAL RELEVANCE: This biomechanical analysis of the long jump highlighted the effects of changing prosthesis mass on performance. This methodological approach may be useful in the context of sport and performance research. PMID- 23986470 TI - Foot clearance strategy for step-over-step stair climbing in transfemoral amputees. AB - BACKGROUND AND AIM: Stair ascent is a particularly challenging task for transfemoral amputees. The aim of this clinical note was to describe the kinematic features of foot clearance in transfemoral amputee who can ascend stairs using a step-over-step strategy. TECHNIQUE: The marker trajectories of the first metatarsophalangeal joint (Mt1) and clearance height were measured in two transfemoral amputees who could (TF1) and could not (TF2) climb stairs using a step-over-step strategy. DISCUSSION: The Mt1 marker trajectories of the TF1 moved backward in the early swing phase, and the trajectory followed an off-centered parabolic arc to achieve a similar clearance height as able-bodied subjects. TF2 could not climb the stairs without tripping in each step. An effective compensatory strategy to avoid tripping during stair climbing may be to use the hip joint for a backward extension and rapid flexion of the prosthetic leg during the early swing phase. CLINICAL RELEVANCE: The foot clearance strategy in transfemoral amputees who can climb stairs using a step-over-step strategy will help us better understand adaptive prosthetic control and thus develop more effective gait rehabilitation programs. PMID- 23986471 TI - Energetic consequences of using a prosthesis with adaptive ankle motion during slope walking in persons with a transtibial amputation. PMID- 23986472 TI - A facile total synthesis of drospirenone isomers containing 14beta-hydrogen configuration. AB - A facile strategy for the preparation of two isomeric drospirenones 13 and 16 possessing a 14beta-hydrogen was developed, using 3beta-hydroxyandrost-5-en-17 one as the starting material. The total synthetic route involves eight steps, giving 2% overall yield. The structures of the main compounds 11, 13, 14 and 16 were determined by single crystal XRD analysis. PMID- 23986473 TI - Trans-induced cis interaction in the tripartite NGL-1, netrin-G1 and LAR adhesion complex promotes development of excitatory synapses. AB - The initial contact between axons and dendrites at early neuronal synapses is mediated by surface adhesion molecules and is thought to induce synaptic maturation through the recruitment of additional synaptic proteins. The initiation of synaptic maturation should be tightly regulated to ensure that synaptic maturation occurs selectively at subcellular sites of axo-dendritic adhesion. However, the underlying mechanism is poorly understood. Here, we report that the initial trans-synaptic adhesion mediated by presynaptic netrin-G1 and postsynaptic NGL-1 (netrin-G1 ligand-1) induces a cis interaction between netrin G1 and the receptor protein tyrosine phosphatase LAR (leukocyte antigen-related), and that this promotes presynaptic differentiation. We propose that trans synaptic adhesions at early neuronal synapses trigger recruitment of neighboring adhesion molecules in a cis manner in order to couple initial axo-dendritic adhesion with synaptic differentiation. PMID- 23986474 TI - Mutation of a conserved residue enhances the sensitivity of analogue-sensitised kinases to generate a novel approach to the study of mitosis in fission yeast. AB - The chemical genetic strategy in which mutational enlargement of the ATP-binding site sensitises of a protein kinase to bulky ATP analogues has proved to be an elegant tool for the generation of conditional analogue-sensitive kinase alleles in a variety of model organisms. Here, we describe a novel substitution mutation in the kinase domain that can enhance the sensitivity of analogue-sensitive kinases. Substitution of a methionine residue to phenylalanine in the +2 position after HRDLKxxN motif of the subdomain VIb within the kinase domain markedly increased the sensitivities of the analogue-sensitive kinases to ATP analogues in three out of five S. pombe kinases (i.e. Plo1, Orb5 and Wee1) that harbor this conserved methionine residue. Kinome alignment established that a methionine residue is found at this site in 5-9% of kinases in key model organisms, suggesting that a broader application of this structural modification may enhance ATP analogue sensitivity of analogue-sensitive kinases in future studies. We also show that the enhanced sensitivity of the wee1.as8 allele in a cdc25.22 background can be exploited to generate highly synchronised mitotic and S phase progression at 36 degrees C. Proof-of-principle experiments show how this novel synchronisation technique will prove of great use in the interrogation of the mitotic or S-phase functions through temperature sensitivity mutation of molecules of interest in fission yeast. PMID- 23986475 TI - Spd1 accumulation causes genome instability independently of ribonucleotide reductase activity but functions to protect the genome when deoxynucleotide pools are elevated. AB - Cullin4, Ddb1 and Cdt2 are core subunits of the ubiquitin ligase complex CRL4(Cdt2), which controls genome stability by targeting Spd1 for degradation during DNA replication and repair in fission yeast. Spd1 has an inhibitory effect on ribonucleotide reductase (RNR), the activity of which is required for deoxynucleotide (dNTP) synthesis. The failure to degrade Spd1 in mutants where CRL4(Cdt2) is defective leads to DNA integrity checkpoint activation and dependency. This correlates with a lower dNTP pool. Pools are restored in a spd1 deleted background and this also suppresses checkpoint activation and dependency. We hypothesized that fission yeast with RNR hyperactivity would display a mutator phenotype on their own, but also possibly repress aspects of the phenotype associated with the inability to target Spd1 for degradation. Here, we report that a mutation in the R1 subunit of ribonucleotide reductase cdc22 (cdc22-D57N), which alleviated allosteric feedback inhibition, caused a highly elevated dNTP pool that was further increased by deleting spd1. The Deltaspd1 cdc22-D57N double mutant had elevated mutation rates and was sensitive to damaging agents that cause DNA strand breaks, demonstrating that Spd1 can protect the genome when dNTP pools are high. In ddb1-deleted cells, cdc22-D57N also potently elevated RNR activity, but failed to allow cell growth independently of the intact checkpoint. Our results provide evidence that excess Spd1 interferes with other functions in addition to its inhibitory effect on ribonucleotide reduction to generate replication stress and genome instability. PMID- 23986477 TI - A core hSSB1-INTS complex participates in the DNA damage response. AB - Human single-stranded DNA-binding protein 1 (hSSB1) plays an important role in the DNA damage response and the maintenance of genomic stability. It has been shown that the core hSSB1 complex contains hSSB1, INTS3 and C9orf80. Using protein affinity purification, we have identified integrator complex subunit 6 (INTS6) as a major subunit of the core hSSB1 complex. INTS6 forms a stable complex with INTS3 and hSSB1 both in vitro and in vivo. In this complex, INTS6 directly interacts with INTS3. In response to the DNA damage response, along with INTS3 and hSSB1, INTS6 relocates to the DNA damage sites. Moreover, the hSSB1 INTS complex regulates the accumulation of RAD51 and BRCA1 at DNA damage sites and the correlated homologous recombination. PMID- 23986476 TI - SNX15 links clathrin endocytosis to the PtdIns3P early endosome independently of the APPL1 endosome. AB - Sorting nexins (SNXs) are key regulators of the endosomal network. In designing an RNAi-mediated loss-of-function screen, we establish that of 30 human SNXs only SNX3, SNX5, SNX9, SNX15 and SNX21 appear to regulate EGF receptor degradative sorting. Suppression of SNX15 results in a delay in receptor degradation arising from a defect in movement of newly internalised EGF-receptor-labelled vesicles into early endosomes. Besides a phosphatidylinositol 3-phosphate- and PX-domain dependent association to early endosomes, SNX15 also associates with clathrin coated pits and clathrin-coated vesicles by direct binding to clathrin through a non-canonical clathrin-binding box. From live-cell imaging, it was identified that the activated EGF receptor enters distinct sub-populations of SNX15- and APPL1-labelled peripheral endocytic vesicles, which do not undergo heterotypic fusion. The SNX15-decorated receptor-containing sub-population does, however, undergo direct fusion with the Rab5-labelled early endosome. Our data are consistent with a model in which the EGF receptor enters the early endosome following clathrin-mediated endocytosis through at least two parallel pathways: maturation through an APPL1-intermediate compartment and an alternative more direct fusion between SNX15-decorated endocytic vesicles and the Rab5-positive early endosome. PMID- 23986478 TI - Disruption of disulfide restriction at integrin knees induces activation and ligand-independent signaling of alpha4beta7. AB - Control of integrin activation and signaling plays crucial roles in cell adhesion, spreading and migration. Here, we report that selective breakage of two conserved disulfide bonds located at the knees of integrin alpha4C589-C594 and beta7C494-C526 activated alpha4beta7. This activated integrin had a unique structure that was different from the typical extended conformation of active integrin. In addition, these activated alpha4beta7 integrins spontaneously clustered on the cell membrane and triggered integrin downstream signaling independent of ligand binding. Although these disulfide bonds were not broken during alpha4beta7 activation by inside-out signaling or Mn(2+), they could be specifically reduced by 0.1 mM dithiothreitol, a reducing strength that could be produced in vivo under certain conditions. Our findings reveal a novel mechanism of integrin activation under specific reducing conditions by which integrin can signal and promote cell spreading in the absence of ligand. PMID- 23986479 TI - Soluble amyloid-beta precursor protein binds its cell surface receptor in a cooperative fashion with glypican and syndecan proteoglycans. AB - Proteolytic processing of amyloid-beta precursor protein (APP) generates the amyloid-beta peptide, which plays a central role in Alzheimer disease. The physiological function of APP and its proteolytic fragments, however, remains barely understood. Here we show that, on the basis of its binding characteristics, the secreted ectodomain of APP (sAPP) is a new member of the heparin-binding growth factor superfamily. Like other of its members, sAPP binds in a bivalent manner to the plasma membrane with two different subdomains. The N terminal growth-factor-like domain (GFLD) is necessary and sufficient for protein receptor binding, whereas the E2-domain mediates interaction with membrane anchored heparan sulfate proteoglycans (HSPGs). The membrane-anchored HSPGs function as low-affinity co-receptors for sAPP and enhance the affinity to the sAPP receptor. Our findings provide a solid basis for the further identification of this receptor. PMID- 23986480 TI - Embryonic stem cells stably expressing BDNF-GFP exhibit a BDNF-release-dependent enhancement of neuronal differentiation. AB - Brain-derived neurotrophic factor (BDNF) is known to be a crucial regulator of neuronal survival and synaptic plasticity in the mammalian brain. Furthermore, BDNF positively influences differentiation of embryonic neural precursors, as well as that of neural stem cells from adult neurogenic niches. To study the impact of cell-released BDNF on neural differentiation of embryonic stem cells (ESCs), which represent an attractive source for cell transplantation studies, we have generated mouse ESC clones overexpressing BDNF-GFP by use of knock-in technology. After neural differentiation in vitro, we observed that ESC clones overexpressing BDNF-GFP gave rise to an increased number of neurons as compared to control ESCs. Neurons derived from BDNF-GFP-expressing ESCs harbored a more complex dendritic morphology and differentiated into the GABAergic lineage more than controls. Moreover, we show that ESC-derived neurons released BDNF-GFP in an activity-dependent manner and displayed similar electrophysiological properties as cortical neurons. Thus, our study describes the generation of ESCs stably overexpressing BDNF-GFP, which are ideally suited to investigate the ameliorating effects of BDNF in cell transplantation studies of various neuropathological conditions. PMID- 23986481 TI - Centromeric motion facilitates the mobility of interphase genomic regions in fission yeast. AB - Dispersed genetic elements, such as retrotransposons and Pol-III-transcribed genes, including tRNA and 5S rRNA, cluster and associate with centromeres in fission yeast through the function of condensin. However, the dynamics of these condensin-mediated genomic associations remains unknown. We have examined the 3D motions of genomic loci including the centromere, telomere, rDNA repeat locus, and the loci carrying Pol-III-transcribed genes or long-terminal repeat (LTR) retrotransposons in live cells at as short as 1.5-second intervals. Treatment with carbendazim (CBZ), a microtubule-destabilizing agent, not only prevents centromeric motion, but also reduces the mobility of the other genomic loci during interphase. Further analyses demonstrate that condensin-mediated associations between centromeres and the genomic loci are clonal, infrequent and transient. However, when associated, centromeres and the genomic loci migrate together in a coordinated fashion. In addition, a condensin mutation that disrupts associations between centromeres and the genomic loci results in a concomitant decrease in the mobility of the loci. Our study suggests that highly mobile centromeres pulled by microtubules in cytoplasm serve as 'genome mobility elements' by facilitating physical relocations of associating genomic regions. PMID- 23986482 TI - Functional expression of the voltage-gated Na+-channel Nav1.7 is necessary for EGF-mediated invasion in human non-small cell lung cancer cells. AB - Various ion channels are expressed in human cancers where they are intimately involved in proliferation, angiogenesis, invasion and metastasis. Expression of functional voltage-gated Na(+) channels (Nav) is implicated in the metastatic potential of breast, prostate, lung and colon cancer cells. However, the cellular mechanisms that regulate Nav expression in cancer remain largely unknown. Growth factors are attractive candidates; they not only play crucial roles in cancer progression but are also key regulators of ion channel expression and activity in non-cancerous cells. Here, we examine the role of epidermal growth factor receptor (EGFR) signalling and Nav in non-small cell lung carcinoma (NSCLC) cell lines. We show unequivocally, that functional expression of the alpha subunit Nav1.7 promotes invasion in H460 NSCLC cells. Inhibition of Nav1.7 activity (using tetrodotoxin) or expression (by using small interfering RNA), reduces H460 cell invasion by up to 50%. Crucially, non-invasive wild type A549 cells lack functional Nav, whereas exogenous overexpression of the Nav1.7 alpha subunit is sufficient to promote TTX-sensitive invasion of these cells. EGF/EGFR signalling enhances proliferation, migration and invasion of H460 cells but we find that, specifically, EGFR-mediated upregulation of Nav1.7 is necessary for invasive behaviour in these cells. Examination of Nav1.7 expression at mRNA, protein and functional levels further reveals that EGF/EGFR signalling via the ERK1/2 pathway controls transcriptional regulation of channel expression to promote cellular invasion. Immunohistochemistry of patient biopsies confirms the clinical relevance of Nav1.7 expression in NSCLC. Thus, Nav1.7 has significant potential as a new target for therapeutic intervention and/or as a diagnostic or prognostic marker in NSCLC. PMID- 23986483 TI - TRAPPIII is responsible for vesicular transport from early endosomes to Golgi, facilitating Atg9 cycling in autophagy. AB - Autophagy is a bulk protein-degradation process that is regulated by many factors. In this study, we quantitatively assessed the contribution of each essential yeast gene to autophagy. Of the contributing factors that we identified, we focused on the TRAPPIII complex, which was recently shown to act as a guanine-nucleotide exchange factor for the Rab small GTPase Ypt1. Autophagy is defective in the TRAPPIII mutant under nutrient-rich conditions (Cvt pathway), but starvation-induced autophagy is only partially affected. Here, we show that TRAPPIII functions at the Golgi complex to receive general retrograde vesicle traffic from early endosomes. Cargo proteins in this TRAPPIII-dependent pathway include Atg9, a transmembrane protein that is essential for autophagy, and Snc1, a SNARE unrelated to autophagy. When cells were starved, further disruption of vesicle movement from late endosomes to the Golgi caused defects in Atg9 trafficking and autophagy. Thus, TRAPPIII-dependent sorting pathways provide Atg9 reservoirs for pre-autophagosomal structure and phagophore assembly sites under nutrient-rich conditions, whereas the late endosome-to-Golgi pathway is added to these reservoirs when nutrients are limited. This clarification of the role of TRAPPIII elucidates how general membrane traffic contributes to autophagy. PMID- 23986484 TI - ERK and phosphoinositide 3-kinase temporally coordinate different modes of actin based motility during embryonic wound healing. AB - Embryonic wound healing provides a perfect example of efficient recovery of tissue integrity and homeostasis, which is vital for survival. Tissue movement in embryonic wound healing requires two functionally distinct actin structures: a contractile actomyosin cable and actin protrusions at the leading edge. Here, we report that the discrete formation and function of these two structures is achieved by the temporal segregation of two intracellular upstream signals and distinct downstream targets. The sequential activation of ERK and phosphoinositide 3-kinase (PI3K) signalling divides Xenopus embryonic wound healing into two phases. In the first phase, activated ERK suppresses PI3K activity, and is responsible for the activation of Rho and myosin-2, which drives actomyosin cable formation and constriction. The second phase is dominated by restored PI3K signalling, which enhances Rac and Cdc42 activity, leading to the formation of actin protrusions that drive migration and zippering. These findings reveal a new mechanism for coordinating different modes of actin-based motility in a complex tissue setting, namely embryonic wound healing. PMID- 23986486 TI - The Italian CUMI. AB - The purpose of this review is to evaluate the historical development, growth and evolution in the past decade of the Italian network for emergencies of the hand. The complete story from its roots to model of efficiency that required so many efforts and fatigue to be created and tuned up. PMID- 23986485 TI - The architectural relationship of components controlling mast cell endocytosis. AB - Eukaryotic cells use multiple routes for receptor internalization. Here, we examine the topographical relationships of clathrin-dependent and clathrin independent endocytic structures on the plasma membranes of leukemia-derived mast cells. The high affinity IgE receptor (FcepsilonRI) utilizes both pathways, whereas transferrin receptor serves as a marker for the classical clathrin mediated endocytosis pathway. Both receptors were tracked by live-cell imaging in the presence or absence of inhibitors that established their differential dependence on specific endocytic adaptor proteins. The topology of antigen-bound FcepsilonRI, clathrin, dynamin, Arf6 and Eps15-positive structures were analyzed by 2D and 3D immunoelectron microscopy techniques, revealing their remarkable spatial relationships and unique geometry. We conclude that the mast cell plasma membrane has multiple specialized domains for endocytosis. Their close proximity might reflect shared components, such as lipids and adaptor proteins, that facilitate inward membrane curvature. Intersections between these specialized domains might represent sorting stations that direct cargo to specific endocytic pathways. PMID- 23986487 TI - A C69-family cysteine dipeptidase from Lactobacillus farciminis JCM1097 possesses strong Gly-Pro hydrolytic activity. AB - Dipeptide Gly-Pro, a hard-to-degrade and collagenous peptide, is thought to be hydrolysed by prolidases that can work on various X-Pro dipeptides. Here, we found an entirely different type of dipeptidase from Lactobacillus farciminis JCM1097 that cleaves Gly-Pro far more efficiently and with higher specificity than prolidases, and then investigated its properties by use of a recombinant enzyme. Although L. farciminis dipeptidase was expressed in the form of an inclusion body in Escherichia coli at 37 degrees C, it was smoothly over expressed in a soluble form at a lower temperature. The maximal Gly-Pro hydrolytic activity was attained in E. coli at 30 degrees C. In contrast to prolidases that are metallopeptidases showing the modest or marginal activity toward Gly-Pro, this L. farciminis dipeptidase belongs to the cysteine peptidase family C69. Lactobacillus farciminis dipeptidase occurs in cytoplasm and utilizes the side chain of an amino-terminal cysteine residue to perform the nucleophilic attack on the target amide bond between Gly-Pro after processing eight amino acid residues at the N-terminus. Furthermore, L. farciminis dipeptidase is potent enough to synthesize Gly-Pro from Gly and Pro by a reverse reaction. These novel properties could be revealed by virtue of the success in preparing recombinant enzymes in higher yield and in a stable form. PMID- 23986488 TI - Vemurafenib-induced DRESS. PMID- 23986489 TI - Validating the WHO dose pole in the Philippines for school-based mass drug administration of praziquantel for morbidity control of schistosomiasis. AB - BACKGROUND: Praziquantel typically requires weight-based field administration when used to treat helminthic diseases. Proper dosage adjustment of praziquantel by bodyweight can be difficult to achieve if accurate weighing scales are unavailable. The WHO has recommended for use a dose pole that substitutes height for weight during field administrations of praziquantel. METHODS: This cross sectional study aims to validate the WHO dose pole for Philippine populations using height and drug administration data collected from 1427 Filipino schoolchildren. This study expands upon prior studies by specifically targeting Filipino schoolchildren and by introducing statistical techniques to increase the rigor of the validation process. RESULTS: The study found an average dose of 42.7 mg per kg (mg/kg) administered among 1427 students with a standard deviation of 3.5 mg/kg. The dose pole estimated a WHO-recommended dose (40-60 mg/kg) in 93.5% of students and a WHO-accepted dose (30-60 mg/kg) in 99.7% of all students. The 95% CIs showed that 99-100% of all tested students fell within the WHO-accepted dose range, while 91-93% of all tested students fell within the WHO-recommended dose range. CONCLUSIONS: The results suggest that the WHO dose pole is valid for mass treatment of Filipino schoolchildren with praziquantel. Further validation studies are recommended. PMID- 23986490 TI - Submental muscular medialization and suspension. AB - BACKGROUND: Many techniques have been presented over recent decades to address the neck contour in facial rejuvenation surgery. Despite advances, limitations remain when dealing with the obtuse cervical angle. OBJECTIVE: The authors describe a technique for improving the obtuse cervicomental angle. METHODS: The authors reviewed the charts of 295 patients who underwent the authors' submental muscular medialization and suspension (SMMS) technique to improve their neck contour, either alone or in combination with a facelift, between January 1, 2001, and December 30, 2003. The technique medializes and suspends the medial free edges of the platysma muscle and, when anatomy dictates, the anterior bellies of the digastric muscle to the deeper mylohyoid muscle. RESULTS: Eighty-seven (30.5%) of the 285 facelift patients examined underwent SMMS, and 10 additional patients underwent isolated SMMS. No patient required reoperation for hemostasis or evacuation. Three (1.05%) of the facelift with SMMS patients required reoperation for dehiscence of the submental suspension. None of the isolated SMMS patients had muscular suspension dehiscence or required reoperation. Seven (2.4%) patients (5 with SMMS and 2 without SMMS) with excessive facial and cervical tissue preoperatively developed a small amount of postoperative submental skin redundancy and subsequently underwent submental skin excision at 1 year postoperatively. CONCLUSIONS: Submental muscular medialization and suspension is a simple yet highly effective surgical technique that can result in dramatic and enduring improvement in the cervicomental angle. PMID- 23986491 TI - Use of electronic cigarettes among young Swiss men. PMID- 23986492 TI - Achieving high and equitable coverage of adolescent HPV vaccine in Scotland. AB - BACKGROUND AND METHODS: The national immunisation records of over 220,000 girls offered vaccine in the routine or catch-up programme of the Human papillomavirus (HPV) programme in Scotland were analysed. Descriptive statistics and multilevel modelling were used to determine individual and organisational factors associated with uptake. Age, school year, school denomination, deprivation and, for school leavers, mode of delivery were explored. Additional aggregate data were used to examine the effect of late uptake of missed doses in the routine vaccination programme. RESULTS: School-based delivery initially achieved over 80% uptake of complete courses in routine and catch-up age groups. Within this context of generally high coverage, there was an association between individual level deprivation and lower uptake, and a decline in in-year course completion over time. However, later uptake of missed doses in the following year substantially decreased these effects. There was no influence on uptake of the type of school (non-denominational/denominational). Vaccination of school-leavers in the catch up campaign had lower coverage, with 50% starting and 30% completing the course in-year. There was no clear advantage of vaccination through general practice or through Board-run clinics in reaching this group. CONCLUSIONS: School-based vaccination can achieve high and equitable uptake of a multidose vaccine in a routine immunisation programme. Sustained high coverage with HPV vaccine across Scotland provides a stable platform for planning future strategies for cervical screening and understanding the impact of the vaccination at a population level. PMID- 23986493 TI - Glossary for the implementation of Health in All Policies (HiAP). AB - Health in All Policies (HiAP) is becoming increasingly popular as a governmental strategy to improve population health by coordinating action across health and non-health sectors. A variety of intersectoral initiatives may be used in HiAP that frame health determinants as the bridge between policies and health outcomes. The purpose of this glossary is to present concepts and terms useful in understanding the implementation of HiAP as a cross-sectoral policy. The concepts presented here were applied and elaborated over the course of case studies of HiAP in multiple jurisdictions, which used key informant interviews and the systematic review of literature to study the implementation of specific HiAP initiatives. PMID- 23986494 TI - Activation of the canonical IKK complex by K63/M1-linked hybrid ubiquitin chains. AB - Polyubiquitin (pUb) chains formed between the C terminus of ubiquitin and lysine 63 (K63) or methionine 1 (M1) of another ubiquitin have been implicated in the activation of the canonical IkappaB kinase (IKK) complex. Here, we demonstrate that nearly all of the M1-pUb chains formed in response to interleukin-1, or the Toll-Like Receptors 1/2 agonist Pam3CSK4, are covalently attached to K63-pUb chains either directly as K63-pUb/M1-pUb hybrids or indirectly by attachment to the same protein. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK) 1 is modified first by K63-pUb chains to which M1-pUb linkages are added subsequently, and myeloid differentiation primary response gene 88 (MyD88) and IRAK4 are also modified by both K63-pUb and M1-pUb chains. We show that the heme-oxidized IRP2 ubiquitin ligase 1 interacting protein (HOIP) component of the linear ubiquitin assembly complex catalyzes the formation of M1-pUb chains in response to interleukin-1, that the formation of K63-pUb chains is a prerequisite for the formation of M1-pUb chains, and that HOIP interacts with K63-pUb but not M1-pUb linkages. These findings identify K63-Ub oligomers as a major substrate of HOIP in cells where the MyD88-dependent signaling network is activated. The TGF-beta activated kinase 1 (TAK1)-binding protein (TAB) 2 and TAB3 components of the TAK1 complex and the NFkappaB Essential Modifier (NEMO) component of the canonical IKK complex bind to K63-pUb chains and M1-pUb chains, respectively. The formation of K63/M1-pUb hybrids may therefore provide an elegant mechanism for colocalizing both complexes to the same pUb chain, facilitating the TAK1-catalyzed activation of IKKalpha and IKKbeta. Our study may help to resolve the debate about the relative importance of K63-pUb and M1-pUb chains in activating the canonical IKK complex. PMID- 23986495 TI - Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. AB - The transcription factor NF-E2 p45-related factor 2 (Nrf2), a master regulator of cytoprotective genes, is controlled by dimeric Kelch-like ECH associated protein 1 (Keap1), a substrate adaptor protein for Cullin3/RING-box protein 1 ubiquitin ligase, which normally targets Nrf2 for ubiquitination and degradation but loses this ability in response to electrophiles and oxidants (inducers). By using recombinant proteins and populations of cells, some of the general features of the regulation of Nrf2 by Keap1 have been outlined. However, how the two proteins interact at a single-cell level is presently unknown. We now report the development of a quantitative Forster resonance energy transfer-based system using multiphoton fluorescence lifetime imaging microscopy and its application for investigating the interaction between Nrf2 and Keap1 in single live cells. By using this approach, we found that under homeostatic conditions, the interaction between Keap1 and Nrf2 follows a cycle in which the complex sequentially adopts two distinct conformations: "open," in which Nrf2 interacts with a single molecule of Keap1, followed by "closed," in which Nrf2 binds to both members of the Keap1 dimer. Inducers disrupt this cycle by causing accumulation of the complex in the closed conformation without release of Nrf2. As a consequence, free Keap1 is not regenerated, and newly synthesized Nrf2 is stabilized. On the basis of these findings, we propose a model we have named the "cyclic sequential attachment and regeneration model of Keap1-mediated degradation of Nrf2." This previously unanticipated dynamism allows rapid transcriptional responses to environmental changes and can accommodate multiple modes of regulation. PMID- 23986496 TI - Auxin controls seed dormancy through stimulation of abscisic acid signaling by inducing ARF-mediated ABI3 activation in Arabidopsis. AB - The transition from dormancy to germination in seeds is a key physiological process during the lifecycle of plants. Abscisic acid (ABA) is the sole plant hormone known to maintain seed dormancy; it acts through a gene expression network involving the transcription factor ABSCISIC ACID INSENSITIVE 3 (ABI3). However, whether other phytohormone pathways function in the maintenance of seed dormancy in response to environmental and internal signals remains an important question. Here, we show that the plant growth hormone auxin, which acts as a versatile trigger in many developmental processes, also plays a critical role in seed dormancy in Arabidopsis. We show that disruptions in auxin signaling in MIR160-overexpressing plants, auxin receptor mutants, or auxin biosynthesis mutants dramatically release seed dormancy, whereas increases in auxin signaling or biosynthesis greatly enhance seed dormancy. Auxin action in seed dormancy requires the ABA signaling pathway (and vice versa), indicating that the roles of auxin and ABA in seed dormancy are interdependent. Furthermore, we show that auxin acts upstream of the major regulator of seed dormancy, ABI3, by recruiting the auxin response factors AUXIN RESPONSE FACTOR 10 and AUXIN RESPONSE FACTOR 16 to control the expression of ABI3 during seed germination. Our study, thus, uncovers a previously unrecognized regulatory factor of seed dormancy and a coordinating network of auxin and ABA signaling in this important process. PMID- 23986497 TI - Reversible shear-induced crystallization above equilibrium freezing temperature in a lyotropic surfactant system. AB - We demonstrate a unique shear-induced crystallization phenomenon above the equilibrium freezing temperature (T(K) degrees ) in weakly swollen isotropic (Li) and lamellar (La) mesophases with bilayers formed in a cationic-anionic mixed surfactant system. Synchrotron rheological X-ray diffraction study reveals the crystallization transition to be reversible under shear (i.e., on stopping the shear, the nonequilibrium crystalline phase Lc melts back to the equilibrium mesophase). This is different from the shear-driven crystallization below T(K) degrees , which is irreversible. Rheological optical observations show that the growth of the crystalline phase occurs through a preordering of the Li phase to an La phase induced by shear flow, before the nucleation of the Lc phase. Shear diagram of the Li phase constructed in the parameter space of shear rate (gamma) vs. temperature exhibits Li -> Lc and Li -> La transitions above the equilibrium crystallization temperature T(K) degrees , in addition to the irreversible shear driven nucleation of Lc in the Li phase below T(K) degrees . In addition to revealing a unique class of nonequilibrium phase transition, the present study urges a unique approach toward understanding shear-induced phenomena in concentrated mesophases of mixed amphiphilic systems. PMID- 23986498 TI - Reconstructing dynamic microRNA-regulated interaction networks. AB - The regulation of gene expression in cells, including by microRNAs (miRNAs), is a dynamic process. Current methods for identifying miRNA targets by combining sequence and miRNA and mRNA expression data do not adequately use the temporal information and thus miss important miRNAs and their targets. We developed the MIRna Dynamic Regulatory Events Miner (mirDREM), a probabilistic modeling method that uses input-output hidden Markov models to reconstruct dynamic regulatory networks that explain how temporal gene expression is jointly regulated by miRNAs and transcription factors. We measured miRNA and mRNA expression for postnatal lung development in mice and used mirDREM to study the regulation of this process. The reconstructed dynamic network correctly identified known miRNAs and transcription factors. The method has also provided predictions about additional miRNAs regulating this process and the specific developmental phases they regulate, several of which were experimentally validated. Our analysis uncovered links between miRNAs involved in lung development and differentially expressed miRNAs in idiopathic pulmonary fibrosis patients, some of which we have experimentally validated using proliferation assays. These results indicate that some disease progression pathways in idiopathic pulmonary fibrosis may represent partial reversal of lung differentiation. PMID- 23986499 TI - Dissociable effects of surprise and model update in parietal and anterior cingulate cortex. AB - Brains use predictive models to facilitate the processing of expected stimuli or planned actions. Under a predictive model, surprising (low probability) stimuli or actions necessitate the immediate reallocation of processing resources, but they can also signal the need to update the underlying predictive model to reflect changes in the environment. Surprise and updating are often correlated in experimental paradigms but are, in fact, distinct constructs that can be formally defined as the Shannon information (IS) and Kullback-Leibler divergence (DKL) associated with an observation. In a saccadic planning task, we observed that distinct behaviors and brain regions are associated with surprise/IS and updating/DKL. Although surprise/IS was associated with behavioral reprogramming as indexed by slower reaction times, as well as with activity in the posterior parietal cortex [human lateral intraparietal area (LIP)], the anterior cingulate cortex (ACC) was specifically activated during updating of the predictive model (DKL). A second saccade-sensitive region in the inferior posterior parietal cortex (human 7a), which has connections to both LIP and ACC, was activated by surprise and modulated by updating. Pupillometry revealed a further dissociation between surprise and updating with an early positive effect of surprise and late negative effect of updating on pupil area. These results give a computational account of the roles of the ACC and two parietal saccade regions, LIP and 7a, by which their involvement in diverse tasks can be understood mechanistically. The dissociation of functional roles between regions within the reorienting/reprogramming network may also inform models of neurological phenomena, such as extinction and Balint syndrome, and neglect. PMID- 23986500 TI - ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion. AB - AMPA-type glutamate receptor (AMPAR) trafficking is essential for modulating synaptic transmission strength. Prior studies that have characterized signaling pathways underlying AMPAR trafficking have identified the cAMP/PKA-mediated phosphorylation of GluA1, an AMPAR subunit, as a key step in the membrane insertion of AMPAR. Inhibition of ERK impairs AMPAR membrane insertion, but the mechanism by which ERK exerts its effect is unknown. Dopamine, an activator of both PKA and ERK, induces AMPAR insertion, but the relationship between the two protein kinases in the process is not understood. We used a combination of computational modeling and live cell imaging to determine the relationship between ERK and PKA in AMPAR insertion. We developed a dynamical model to study the effects of phosphodiesterase 4 (PDE4), a cAMP phosphodiesterase that is phosphorylated and inhibited by ERK, on the membrane insertion of AMPAR. The model predicted that PKA could be a downstream effector of ERK in regulating AMPAR insertion. We experimentally tested the model predictions and found that dopamine-induced ERK phosphorylates and inhibits PDE4. This regulation results in increased cAMP levels and PKA-mediated phosphorylation of DARPP-32 and GluA1, leading to increased GluA1 trafficking to the membrane. These findings provide unique insight into an unanticipated network topology in which ERK uses PDE4 to regulate PKA output during dopamine signaling. The combination of dynamical models and experiments has helped us unravel the complex interactions between two protein kinase pathways in regulating a fundamental molecular process underlying synaptic plasticity. PMID- 23986501 TI - Opioids for neuropathic pain. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3, 2006, which included 23 trials. The use of opioids for neuropathic pain remains controversial. Studies have been small, have yielded equivocal results, and have not established the long-term profile of benefits and risks for people with neuropathic pain. OBJECTIVES: To reassess the efficacy and safety of opioid agonists for the treatment of neuropathic pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (to 24th October 2012), MEDLINE (1966 to 24th October 2012 ), and EMBASE (1980 to 24th October 2012) for articles in any language, and reference lists of reviews and retrieved articles. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which opioid agonists were given to treat central or peripheral neuropathic pain of any etiology. Pain was assessed using validated instruments, and adverse events were reported. We excluded studies in which drugs other than opioid agonists were combined with opioids or opioids were administered epidurally or intrathecally. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and included demographic variables, diagnoses, interventions, efficacy, and adverse effects. MAIN RESULTS: Thirty-one trials met our inclusion criteria, studying 10 different opioids: 23 studies from the original 2006 review and eight additional studies from this updated review.Seventeen studies (392 participants with neuropathic pain, average 22 participants per study) provided efficacy data for acute exposure to opioids over less than 24 hours. Sixteen reported pain outcomes, with contradictory results; 8/16 reported less pain with opioids than placebo, 2/16 reported that some but not all participants benefited, 5/16 reported no difference, and 1/16 reported equivocal results. Six studies with about 170 participants indicated that mean pain scores with opioid were about 15/100 points less than placebo.Fourteen studies (845 participants, average 60 participants per study) were of intermediate duration lasting 12 weeks or less; most studies lasted less than six weeks. Most studies used imputation methods for participant withdrawal known to be associated with considerable bias; none used a method known not to be associated with bias. The evidence, therefore, derives from studies predominantly with features likely to overestimate treatment effects, i.e. small size, short duration, and potentially inadequate handling of dropouts. All demonstrated opioid efficacy for spontaneous neuropathic pain. Meta-analysis demonstrated at least 33% pain relief in 57% of participants receiving an opioid versus 34% of those receiving placebo. The overall point estimate of risk difference was 0.25 (95% confidence interval (CI) 0.13 to 0.37, P < 0.0001), translating to a number needed to treat for an additional beneficial outcome (NNTB) of 4.0 (95% CI 2.7 to 7.7). When the number of participants achieving at least 50% pain relief was analyzed, the overall point estimate of risk difference between opioids (47%) and placebo (30%) was 0.17 (95% CI 0.02 to 0.33, P = 0.03), translating to an NNTB of 5.9 (3.0 to 50.0). In the updated review, opioids did not demonstrate improvement in many aspects of emotional or physical functioning, as measured by various validated questionnaires. Constipation was the most common adverse event (34% opioid versus 9% placebo: number needed to treat for an additional harmful outcome (NNTH) 4.0; 95% CI 3.0 to 5.6), followed by drowsiness (29% opioid versus 14% placebo: NNTH 7.1; 95% CI 4.0 to 33.3), nausea (27% opioid versus 9% placebo: NNTH 6.3; 95% CI 4.0 to 12.5), dizziness (22% opioid versus 8% placebo: NNTH 7.1; 95% CI 5.6 to 10.0), and vomiting (12% opioid versus 4% placebo: NNTH 12.5; 95% CI 6.7 to 100.0). More participants withdrew from opioid treatment due to adverse events (13%) than from placebo (4%) (NNTH 12.5; 95% CI 8.3 to 25.0). Conversely, more participants receiving placebo withdrew due to lack of efficacy (12%) versus (2%) receiving opioids (NNTH -11.1; 95% CI -20.0 to -8.3). AUTHORS' CONCLUSIONS: Since the last version of this review, new studies were found providing additional information. Data were reanalyzed but the results did not alter any of our previously published conclusions. Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain. Intermediate-term studies demonstrated significant efficacy of opioids over placebo, but these results are likely to be subject to significant bias because of small size, short duration, and potentially inadequate handling of dropouts. Analgesic efficacy of opioids in chronic neuropathic pain is subject to considerable uncertainty. Reported adverse events of opioids were common but not life-threatening. Further randomized controlled trials are needed to establish unbiased estimates of long-term efficacy, safety (including addiction potential), and effects on quality of life. PMID- 23986502 TI - Exploring the school nutrition policy environment in Canada using the ANGELO framework. AB - Excess body weight has become a major public health issue. Given the link between poor nutrition, obesity, and chronic disease in youth, increasing attention is being paid to the school as an ideal setting for promoting nutritious eating practices. Informed by the ANGELO (Analysis Grid for Environments Linked to Obesity) framework, we employ a documentary analysis to investigate the context of school nutrition in Canada, particularly the relationship between regional- and upper-level policies. In doing so, we examine policy documents and technical reports across three levels. We used mixed methods to analyze relevant English language policy documents and technical reports across Canada (n = 58), published between 1989 and 2011. Results reveal distinct differences across federal, provincial, and regional levels. The availability of nutritious food in schools and having nutrition education as part of the curriculum were key components of the physical environment across federal and provincial levels. Federal and provincial priorities are guided by a health promotion framework and adopting a partnership approach to policy implementation. Gaps in regional-level policy include incorporating nutrition education in the curriculum and making the link between nutrition and obesity. Policy implications are provided, in addition to future research opportunities to explore the connections between these environments at the local level. PMID- 23986503 TI - Provider communication and role modeling related to patients' perceptions and use of a federally qualified health center-based farmers' market. AB - Farmers' markets have the potential to improve the health of underserved communities, shape people's perceptions, values, and behaviors about healthy eating, and serve as a social space for both community members and vendors. This study explored the influence of health care provider communication and role modeling for diabetic patients within the context of a farmers' market located at a federally qualified health center. Although provider communication about diet decreased over time, communication strategies included: providing patients with "prescriptions" and vouchers for market purchases; educating patients about diet; and modeling healthy purchases. Data from patient interviews and provider surveys revealed that patients enjoyed social aspects of the market including interactions with their health care provider, and providers distributed prescriptions and vouchers to patients, shopped at the market, and believed that the market had potential to improve the health of staff and patients of the federally qualified health center. Provider modeling of healthy behaviors may influence patients' food-related perceptions and dietary behaviors. PMID- 23986504 TI - A 4-year-old girl with gastroenteritis, anemia, thrombocytopenia, and hematuria. PMID- 23986505 TI - Commentary. PMID- 23986506 TI - Commentary. PMID- 23986507 TI - Puzzling phosphorus: unlikely results. PMID- 23986508 TI - The automated pathologist. PMID- 23986509 TI - The grass is greener on the other side. PMID- 23986510 TI - Quo vadis? PMID- 23986511 TI - The biological aesthetic. PMID- 23986512 TI - Direct inhibition of basolateral Kir4.1/5.1 and Kir4.1 channels in the cortical collecting duct by dopamine. AB - It is recognized that dopamine promotes natriuresis by inhibiting multiple transporting systems in the proximal tubule. In contrast, less is known about the molecular targets of dopamine actions on water-electrolyte transport in the cortical collecting duct (CCD). Epithelial cells in the CCD are exposed to dopamine, which is synthesized locally or secreted from sympathetic nerve endings. Basolateral K(+) channels in the distal renal tubule are critical for K(+) recycling and controlling basolateral membrane potential to establish the driving force for Na(+) reabsorption. Here, we demonstrate that Kir4.1 and Kir5.1 are highly expressed in the mouse kidney cortex and are localized to the basolateral membrane of the CCD. Using patch-clamp electrophysiology in freshly isolated CCDs, we detected highly abundant 40-pS and scarce 20-pS single channel conductances, most likely representing Kir4.1/5.1 and Kir4.1 channels, respectively. Dopamine reversibly decreased the open probability of both channels, with a relatively greater action on the Kir4.1/5.1 heterodimer. This effect was mediated by D2-like but not D1-like dopamine receptors. PKC blockade abolished the inhibition of basolateral K(+) channels by dopamine. Importantly, dopamine significantly decreased the amplitude of Kir4.1/5.1 and Kir4.1 unitary currents. Consistently, dopamine induced an acute depolarization of basolateral membrane potential, as directly monitored using current-clamp mode in isolated CCDs. Therefore, we demonstrate that dopamine inhibits basolateral Kir4.1/5.1 and Kir4.1 channels in CCD cells via stimulation of D2-like receptors and subsequently PKC. This leads to depolarization of the basolateral membrane and a decreased driving force for Na(+) reabsorption in the distal renal tubule. PMID- 23986513 TI - CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. AB - Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function. PMID- 23986514 TI - Cellular localization of adenine receptors in the rat kidney and their functional significance in the inner medullary collecting duct. AB - The Gi-coupled adenine receptor (AdeR) binds adenine with high affinity and potentially reduces cellular cAMP levels. Since cAMP is an important second messenger in the renal transport of water and solutes, we localized AdeR in the rat kidney. Real-time RT-PCR showed higher relative expression of AdeR mRNA in the cortex and outer medulla compared with the inner medulla. Immunoblots using a peptide-derived and affinity-purified rabbit polyclonal antibody specific for an 18-amino acid COOH-terminal sequence of rat AdeR, which we generated, detected two bands between ~30 and 40 kDa (molecular mass of native protein: 37 kDa) in the cortex, outer medulla, and inner medulla. These bands were ablated by preadsorption of the antibody with the immunizing peptide. Immunofluorescence labeling showed expression of AdeR protein in all regions of the kidney. Immunoperoxidase revealed strong labeling of AdeR protein in the cortical vasculature, including the glomerular arterioles, and less intense labeling in the cells of the collecting duct system. Confocal immunofluorescence imaging colocalized AdeR with aquaporin-2 protein to the apical plasma membrane in the collecting duct. Functionally, adenine (10 MUM) significantly decreased (P < 0.01) 1-deamino-8-d-arginine vasopressin (10 nM)-induced cAMP production in ex vivo preparations of inner medullary collecting ducts, which was reversed by PSB 08162 (20 MUM, P < 0.01), a selective antagonist of AdeR. Thus, we demonstrated the expression of AdeR in the renal vasculature and collecting ducts and its functional relevance. This study may open a new avenue for the exploration of autocrine/paracrine regulation of renal vascular and tubular functions by the nucleobase adenine in health and disease. PMID- 23986515 TI - CXCR2 knockout mice are protected against DSS-colitis-induced acute kidney injury and inflammation. AB - Organ cross talk exists in many diseases of the human and animal models of human diseases. A recent study demonstrated that inflammatory mediators can cause acute kidney injury and neutrophil infiltration in a mouse model of dextran sodium sulfate (DSS)-colitis. However, the chemokines and their receptors that may mediate distant organ effects in colitis are unknown. We hypothesized that keratinocyte chemoattractant (KC)/IL-8 receptor chemokine (C-X-C motif) ligand 2 (CXCL2) mediates DSS-colitis-induced acute kidney injury. Consistent with our hypothesis, wild-type (WT) mice developed severe colitis with DSS treatment, which was associated with inflammatory cytokine and chemokine expression and neutrophil infiltration in the colon. DSS-colitis in WT was accompanied by acute kidney injury and enhanced expression of inflammatory cytokines in the kidney. However, CXCR2 knockout mice were protected against DSS-colitis as well as acute kidney injury. Moreover, the expression of cytokines and chemokines and neutrophil infiltration was blunted in CXCR2 knockout mice in the colon and kidney. Administration of recombinant KC exacerbated DSS-colitis-induced acute kidney injury. Our results suggest that KC/IL-8 and its receptor CXCR2 are critical and major mediators of organ cross talk in DSS colitis and neutralization of CXCR2 will help to reduce the incidence of acute kidney injury due to ulcerative colitis and Crohn's disease in humans. PMID- 23986516 TI - Amino acid mutations in the caldesmon COOH-terminal functional domain increase force generation in bladder smooth muscle. AB - Caldesmon (CaD), a component of smooth muscle thin filaments, binds actin, tropomyosin, calmodulin, and myosin and inhibits actin-activated ATP hydrolysis by smooth muscle myosin. Internal deletions of the chicken CaD functional domain that spans from amino acids (aa) 718 to 731, which corresponds to aa 512-530 including the adjacent aa sequence in mouse CaD, lead to diminished CaD-induced inhibition of actin-activated ATP hydrolysis by myosin. Transgenic mice with mutations of five aa residues (Lys(523) to Gln, Val(524) to Leu, Ser(526) to Thr, Pro(527) to Cys, and Lys(529) to Ser), which encompass the ATPase inhibitory determinants located in exon 12, were generated by homologous recombination. Homozygous (-/-) animals did not develop, but heterozygous (+/-) mice carrying the expected mutations in the CaD ATPase inhibitory domain (CaD mutant) matured and reproduced normally. The peak force produced in response to KCl and electrical field stimulation by the detrusor smooth muscle from the CaD mutant was high compared with that of the wild type. CaD mutant mice revealed nonvoiding contractions during bladder filling on awake cystometry, suggesting that the CaD ATPase inhibitory domain suppresses force generation during the filling phase and this suppression is partially released by mutations in 50% of CaD in heterozygous. Our data show for the first time a functional phenotype, at the intact smooth muscle tissue and in vivo organ levels, following mutation of a functional domain at the COOH-terminal region of CaD. PMID- 23986518 TI - A vasoconstrictor role for cyclooxygenase-1-mediated prostacyclin synthesis in mouse renal arteries. AB - This study was to determine whether prostacyclin [prostaglandin I2 (PGI2)] evokes mouse renal vasoconstriction and, if so, the underlying mechanism(s) and how its synthesis via cyclooxygenase-1 (COX-1) influences local vasomotor reaction. Experiments were performed on vessels from C57BL/6 mice and/or those with COX-1 deficiency (COX-1(-/-)). Results showed that in renal arteries PGI2 evoked contraction more potently than in carotid arteries, where COX-1 is suggested to mediate prominent endothelium-dependent contraction. A similar result was observed with the thromboxane-prostanoid (TP) receptor agonist U46619. However, in renal arteries TP receptor antagonism, which inhibited the contraction, did not result in any relaxation in response to PGI2. Moreover, we noted that the endothelial muscarinic receptor agonist ACh evoked an increase in the production of the PGI2 metabolite 6-keto-PGF1alpha, which was prevented by endothelial denudation or COX-1(-/-). Interestingly, COX-1(-/-) was further found to abolish a force development that was sensitive to TP receptor antagonism and result in enhanced relaxation evoked by ACh following NO synthase inhibition. Also, in renal arteries the COX substrate arachidonic acid evoked a vasoconstrictor response, which was again abolished by COX-1(-/-). Meanwhile, nonselective COX inhibition did not show any effect in vessels from COX-1(-/-) mice. Thus, in mouse renal arteries, high expression of TP receptors together with little functional involvement from the vasodilator PGI2 receptors results in a potent vasoconstrictor effect evoked by PGI2. Also, our data imply that endogenous COX-1 mediated PGI2 synthesis leads to vasoconstrictor activity and this could be an integral part of endothelium-derived mechanisms in regulating local renal vascular function. PMID- 23986517 TI - Angiotensin II-induced hypertension increases plasma membrane Na pump activity by enhancing Na entry in rat thick ascending limbs. AB - Thick ascending limbs (TAL) reabsorb 30% of the filtered NaCl load. Na enters the cells via apical Na-K-2Cl cotransporters and Na/H exchangers and exits via basolateral Na pumps. Chronic angiotensin II (ANG II) infusion increases net TAL Na transport and Na apical entry; however, little is known about its effects on the basolateral Na pump. We hypothesized that in rat TALs Na pump activity is enhanced by ANG II-infusion, a model of ANG II-induced hypertension. Rats were infused with 200 ng.kg(-1).min(-1) ANG II or vehicle for 7 days, and TAL suspensions were obtained. We studied plasma membrane Na pump activity by measuring changes in 1) intracellular Na (Nai) induced by ouabain; and 2) ouabain sensitive oxygen consumption (QO2). We found that the ouabain-sensitive rise in Nai in TALs from ANG II-infused rats was 12.8 +/- 0.4 arbitrary fluorescent units (AFU).mg(-1).min(-1) compared with only 9.9 +/- 1.1 AFU.mg(-1).min(-1) in controls (P < 0.024). Ouabain-sensitive oxygen consumption was 17 +/- 5% (P < 0.043) greater in tubules from ANG II-treated than vehicle rats. ANG II infusion did not alter total Na pump expression, the number of Na pumps in the plasma membrane, or the affinity for Na. When furosemide (1.1 mg.kg(-1).day(-1)) was coinfused with ANG II, no increase in plasma membrane Na pump activity was observed. We concluded that in ANG II-induced hypertension Na pump activity is increased in the plasma membrane of TALs and that this increase is caused by the chronically enhanced Na entry occurring in this model. PMID- 23986519 TI - Excretion of urinary exosomal AQP2 in rats is regulated by vasopressin and urinary pH. AB - Urinary exosomes are small vesicles secreted into urine from all renal epithelial cell types and known to contain proteins that are involved in renal secretion and reabsorption. Among these proteins, urinary exosomal aquaporin-2 (AQP2) has been suggested to be useful for diagnosis of renal disease. However, the mechanisms underlying the excretion of urinary exosomal AQP2 are largely unknown. In this study, we examined the mechanisms of urinary exosomal AQP2 excretion in vivo, using diuretics including furosemide (FS), an inhibitor of the sodium-potassium chloride symporter; acetazolamide (ACTZ), an inhibitor of carbonic anhydrase; OPC 31260 (OPC), a vasopressin type 2 receptor antagonist; and NaHCO3, a urinary alkalizing agent. Samples of urine from rats were collected for 2 h just after treatment with each diuretic, and urinary exosomes were isolated by ultracentrifugation. Urinary exosomal AQP2 excretion was dramatically increased by treatment with FS accompanied by urine acidification or with ACTZ accompanied by urine alkalization. Immunohistochemistry showed that apical localization of AQP2 was clearly evident and the plasma vasopressin level was increased after each treatment. Although treatment with OPC alone had no significant effect, coadministration of OPC completely inhibited the FS-induced and partially reduced the ACTZ-induced responses, respectively. Treatment with NaHCO3 increased the excretion of urinary exosomal AQP2 accompanied by urine alkalization. This increased response was partially inhibited by coadministration of OPC. These data suggest that an increased plasma level of vasopressin promoted the excretion of urinary exosomal AQP2 and that urine alkalinization also increased it independently of vasopressin. PMID- 23986520 TI - K+-induced natriuresis is preserved during Na+ depletion and accompanied by inhibition of the Na+-Cl- cotransporter. AB - During hypovolemia and hyperkalemia, the kidneys defend homeostasis by Na(+) retention and K(+) secretion, respectively. Aldosterone mediates both effects, but it is unclear how the same hormone can evoke such different responses. To address this, we mimicked hypovolemia and hyperkalemia in four groups of rats with a control diet, low-Na(+) diet, high-K(+) diet, or combined diet. The low Na(+) and combined diets increased plasma and kidney ANG II. The low-Na(+) and high-K(+) diets increased plasma aldosterone to a similar degree (3-fold), whereas the combined diet increased aldosterone to a greater extent (10-fold). Despite similar Na(+) intake and higher aldosterone, the high-K(+) and combined diets caused a greater natriuresis than the control and low-Na(+) diets, respectively (P < 0.001 for both). This K(+)-induced natriuresis was accompanied by a decreased abundance but not phosphorylation of the Na(+)-Cl(-) cotransporter (NCC). In contrast, the epithelial Na(+) channel (ENaC) increased in parallel with aldosterone, showing the highest expression with the combined diet. The high K(+) and combined diets also increased WNK4 but decreased Nedd4-2 in the kidney. Total and phosphorylated Ste-20-related kinase were also increased but were retained in the cytoplasm of distal convoluted tubule cells. In summary, high dietary K(+) overrides the effects of ANG II and aldosterone on NCC to deliver sufficient Na(+) to ENaC for K(+) secretion. K(+) may inhibit NCC through WNK4 and help activate ENaC through Nedd4-2. PMID- 23986521 TI - Hydration status affects sodium, potassium, and chloride transport across rat urothelia. AB - Recent data suggest possible net transport of urinary constituents across mammalian urinary tract epithelia (urothelia). To evaluate the effect of animal hydration status on such transport, we instilled urine collected during 2-day water deprivation, water loading, or ad libitum water intake into isolated in situ bladder(s) of groups of rats undergoing one of the same three hydration states. After 1-h bladder dwell, we retrieved the urine and measured differences in volume and solute concentrations between instilled and retrieved urine. We previously reported results regarding changes in urine volume and net urea and creatinine transport and herein report the results of net urinary sodium, potassium, and chloride transport in the same animals. During water-loading conditions, urinary concentrations of Na, K, and Cl rose 4.9 (30.7%), 2.6 (16.5%), and 6.0 meq/l (26.8%), respectively, indicating urothelial secretion into urine. During ad libitum water intake, urinary K and Cl concentrations fell 33.6 (14.8%) and 28.4 meq/l (12%), respectively (Na did not change), and during water deprivation urine Na, K, and Cl concentrations fell dramatically by 53.2 (18.6%), 159.4 (34.6%) and 133.7 meq/l (33.8%), respectively, reflecting urothelial reabsorption of each ion. For each ionic species, two factors independently influenced transport: instilled urinary ion concentration and animal hydration state. These results demonstrate significant regulated ion transport across mammalian urothelia, support the notion that lower urinary tract modifies final urine, and suggest that the lower urinary tract may play a role in local and whole animal solute homeostasis. PMID- 23986522 TI - Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes. AB - Growth differentiation factor 15 (GDF15) is emerging as valuable biomarker in cardiovascular disease and diabetic kidney disease. Also, GDF15 represents an early response gene induced after tissue injury and studies performed in GDF15 knockout (KO) mice suggest that GDF15 plays a protective role after injury. In the current study, we investigated the role of GDF15 in the development of diabetic kidney damage in type 1 and type 2 models of diabetes. Renal damage was assessed in GDF15 KO mice and wild-type (WT) mice in streptozotocin type 1 and db/db type 2 diabetic models. Genetic deletion of GDF15 augmented tubular and interstitial damage in both models of diabetes, despite similar diabetic states in KO and WT mice. Increased tubular damage in KO animals was associated with increased glucosuria and polyuria in both type 1 and type 2 models of diabetes. In both models of diabetes, KO mice showed increased interstitial damage as indicated by increased alpha-smooth muscle actin staining and collagen type 1 expression. In contrast, glomerular damage was similarly elevated in diabetic KO and WT mice. In type 1 diabetes, GDF15 KO mice demonstrated increased expression of inflammatory markers. In type 2 diabetes, elevated levels of plasma creatinine indicated impaired kidney function in KO mice. GDF15 protects the renal interstitium and tubular compartment in experimental type 1 and 2 diabetes without affecting glomerular damage. PMID- 23986523 TI - Commentary on "child-adult differences in muscle activation--a review". PMID- 23986524 TI - Effects of two different resistance-training programs on mean tennis-serve velocity in adolescents. AB - The purpose of the current study was to evaluate the transferability of 2 different resistance training protocols on service velocity and its precision consistency in junior tennis players. Thirty-six male athletes (15.03 +/- 1.64 years) were randomly assigned to a machine-based resistance-training group (RG, n = 12), a plyometric training group (PG, n = 12), and a control group (CG, n = 12). For a period of 8 weeks, both intervention groups resistance trained 2 days per week in addition to their regular tennis training, whereas the CG had no extra training. Mean service velocity over 20 maximum-velocity serves increased significantly more in PG (3.78%; p < .05) when compared with CG, whereas no such changes could be found in the RG (1.18%; p > .05). Service precision did not change from pre- to posttest in all three groups (p > .05). Only the plyometric training program tested, improved mean service velocity over 20 maximum-velocity serves in junior tennis players but did not affect service precision. PMID- 23986525 TI - Allogeneic stem cell transplantation versus conventional therapy for advanced primary cutaneous T-cell lymphoma. AB - BACKGROUND: Primary cutaneous T-cell lymphomas (CTCL) belong to the group of non Hodgkin lymphomas and usually run an indolent course. However, some patients progress to advanced tumour or leukaemic stages. To date, there is no cure for those cases. In the last few years, several publications reported durable responses in some patients following allogeneic stem cell transplantation (alloSCT). This is an update of a Cochrane review first published in 2011 and updated in 2013. OBJECTIVES: To compare the efficacy and safety of conventional therapies with allogeneic stem cell transplantation in patients with advanced primary cutaneous T-cell lymphomas. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1), MEDLINE (1950 to January 2013), Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology (ASCO, 2009 to July 2013) and the American Society of Hematology (ASH, 2009 to July 2013). We also contacted members of the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force to check for ongoing study activities. We handsearched citations from identified trials and relevant review articles. In addition, we handsearched randomised controlled trials from the European Group for Blood and Marrow Transplantation (EBMT) and International Conference on Cutaneous T-cell Lymphoma, ASCO and ASH up to July 2013. SELECTION CRITERIA: Trials eligible for inclusion were genetically randomised controlled trials (RCTs) comparing alloSCT plus conditioning therapy (regardless of agents) with conventional therapy as treatment for advanced CTCL. DATA COLLECTION AND ANALYSIS: Two review authors would have extracted data from eligible studies and assessed their quality. The primary outcome measure was overall survival; secondary outcomes were time to progression, response rate, treatment-related mortality, adverse events and quality of life. MAIN RESULTS: We did not identify any randomised controlled trials from the updated search in January 2013. In 2011, we found 2077 citations but none were relevant genetically or non genetically randomised controlled trials. All 41 studies that were thought to be potentially suitable were excluded after full text screening for being non randomised, not including CTCL or being review articles. AUTHORS' CONCLUSIONS: We planned to report evidence from genetically or non-genetically randomised controlled trials comparing conventional therapy and allogeneic stem cell transplantation. However, we did not identify any randomised controlled trials addressing this question. Nevertheless, prospective genetically randomised controlled trials need to be initiated to evaluate the precise role of alloSCT in advanced CTCL. PMID- 23986526 TI - Postpartum headache: diagnostic considerations. AB - Headache is a frequent presentation following childbirth. Headache assessment in postpartum women justifies specific diagnostic considerations, the main points of which are discussed in this review. PMID- 23986527 TI - Fibrinogen concentrate in bleeding patients. AB - BACKGROUND: Hypofibrinogenaemia is associated with increased morbidity and mortality, but the optimal treatment level, the use of preemptive treatment and the preferred source of fibrinogen remain disputed. Fibrinogen concentrate is increasingly used and recommended for bleeding with acquired haemostatic deficiencies in several countries, but evidence is lacking regarding indications, dosing, efficacy and safety. OBJECTIVES: We assessed the benefits and harms of fibrinogen concentrate compared with placebo or usual treatment for bleeding patients. SEARCH METHODS: We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 8); MEDLINE (1950 to 9 August 2013); EMBASE (1980 to 9 August 2013); International Web of Science (1964 to 9 August 2013); CINAHL (1980 to 9 August 2013); LILACS (1982 to 9 August 2013); and the Chinese Biomedical Literature Database (up to 10 November 2011), together with databases of ongoing trials. We contacted trial authors, authors of previous reviews and manufacturers in the field. SELECTION CRITERIA: We included all randomized controlled trials (RCTs), irrespective of blinding or language, that compared fibrinogen concentrate with placebo/other treatment or no treatment in bleeding patients, excluding neonates and patients with hereditary bleeding disorders. DATA COLLECTION AND ANALYSIS: Three review authors independently abstracted data; we resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed subgroup and sensitivity analyses to assess the effects of fibrinogen concentrate in adults and children in terms of various clinical and physiological outcomes. We presented pooled estimates of the effects of intervention on dichotomous outcomes as risk ratios (RRs) and on continuous outcomes as mean differences, with 95% confidence intervals (CIs). We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis. MAIN RESULTS: We included six RCTs with a total of 248 participants; none of the trials were determined to have overall low risk of bias. We found 12 ongoing trials, from which we were unable to retrieve any data. Only two trials provided data on mortality, and one was a zero event study; thus the meta-analysis showed no statistically significant effect on overall mortality (2.6% vs 9.5%, RR 0.28, 95% CI 0.03 to 2.33). Our analyses on blood transfusion data suggest a beneficial effect of fibrinogen concentrate in reducing the incidence of allogenic transfusions (RR 0.47, 95% CI 0.31 to 0.72) but show no effect on other predefined outcomes, including adverse events such as thrombotic episodes. AUTHORS' CONCLUSIONS: In the six available RCTs of elective surgery, fibrinogen concentrate appears to reduce transfusion requirements, but the included trials are of low quality with high risk of bias and are underpowered to detect mortality, benefit or harm. Furthermore, data on mortality are lacking, heterogeneity is high and acute or severe bleeding in a non-elective surgical setting remains unexplored. Currently, weak evidence supports the use of fibrinogen concentrate in bleeding patients, as tested here in primarily elective cardiac surgery. More research is urgently needed. PMID- 23986528 TI - Health research, development and innovation in England from 1988 to 2013: from research production to knowledge mobilization. AB - This paper presents a critical analysis of the development of government policy and practice on health research, development and innovation over the last 25 years - starting from the publication of a seminal report from the House of Lords Science and Technology Committee in 1988. We first set out to map and analyse the trends in ideas and thinking that have shaped research policy and practice over this period, and to put the development of health research, development and innovation in the wider context of health system reforms and changes. We argue that though this has been a transformative period for health research, rather less progress has been made in the domains of development and innovation, and we offer an analysis of why this might be the case. Drawing on advances in our understanding about how research informs practice, we then make the case for a more integrative model of research, development and innovation. This leads us to conclude that recent experiments with Collaborations for Leadership in Applied Health Research and Care and Academic Health Science Centres and Networks offer some important lessons for future policy directions. PMID- 23986529 TI - Strategies to identify future shortages due to interruptions in the health care procurement supply chain and their impact on health services: a method from the English National Health Service. AB - OBJECTIVES: The uninterrupted supply of essential items for patient care is crucial for organizations that deliver health care. Many products central to health care are derived from natural resources such as oil and cotton, supplies of which are vulnerable to climate change and increasing global demand. The purpose of this study was to identify which items would have the greatest effect on service delivery and patient outcomes should they no longer be available. METHODS: Using a consensus development approach, all items bought by one hospital, over one year, were subjected to a filtering process. Criteria were developed to identify at-risk products and assess them against specific risks and opportunities. Seventy-two items were identified for assessment against a range of potential impacts on service delivery and patient outcomes, from no impact to significant impact. Clinical and non-clinical participants rated the items. RESULTS: In the category of significant impact, consensus was achieved for 20 items out of 72. There were differences of opinion between clinical and non clinical participants in terms of significant impact in relation to 18 items, suggesting that priority over purchasing decisions may create areas of conflict. Reducing reliance on critically scarce resources and reducing demand were seen as the most important criteria in developing sustainable procurement. CONCLUSION: The method was successful in identifying items vulnerable to supply chain interruption and should be repeated in other areas to test its ability to adapt to local priorities, and to assess how it functions in a variety of public and private settings. PMID- 23986530 TI - Recruitment to clinical trials: a meta-ethnographic synthesis of studies of reasons for participation. AB - OBJECTIVES: Randomized controlled trials are important for evaluating health care interventions, but recruitment can be difficult. Studies of potential participants' perspectives on trial participation are accumulating, but their collective contribution is not obvious. In 2007, we conducted a meta-ethnographic synthesis of people's reasons for accepting or declining participation. This paper reports a second synthesis, conducted separately on the same topic, using studies published subsequently. It discusses both the substantive findings and the methodological implications for updating meta-ethnographies. METHODS: Systematic searches identified relevant papers published between 1996 and 2005 (first synthesis), then 2005 and 2010 (second synthesis). We used a meta ethnographic interpretive process of translation to examine the relationships between study findings. FINDINGS: The two syntheses were broadly compatible, but the line of argument developed in the second more clearly highlighted how potential participants' health states and health care situations at the time of recruitment could interact with other considerations. In particular, they could influence the nature and significance for trial entry decisions of people's judgements about: their communication and relationship with trial recruiters; the personal implications of trial interventions and processes; and the 'common good' (helping others) and what their non/participation might say about their identity. CONCLUSIONS: Our work highlights the need for trialists to consider potential participants' health and health care situations when designing recruitment approaches. It also provides the first empirical insights on the process of updating meta-ethnographies that we are currently aware of. Approaches to updating meta-ethnographies need further investigation. PMID- 23986531 TI - Synthetic oligodeoxynucleotides containing suppressive TTAGGG motifs inhibit AIM2 inflammasome activation. AB - Synthetic oligodeoxynucleotides (ODNs) comprised of the immunosuppressive motif TTAGGG block TLR9 signaling, prevent STAT1 and STAT4 phosphorylation and attenuate a variety of inflammatory responses in vivo. In this study, we demonstrate that such suppressive ODN abrogate activation of cytosolic nucleic acid-sensing pathways. Pretreatment of dendritic cells and macrophages with the suppressive ODN-A151 abrogated type I IFN, TNF-alpha, and ISG induction in response to cytosolic dsDNA. In addition, A151 abrogated caspase-1-dependent IL 1beta and IL-18 maturation in dendritic cells stimulated with dsDNA and murine CMV. Inhibition was dependent on A151's phosphorothioate backbone, whereas substitution of the guanosine residues for adenosine negatively affected potency. A151 mediates these effects by binding to AIM2 in a manner that is competitive with immune-stimulatory DNA and as a consequence prevents AIM2 inflammasome complex formation. Collectively, these findings reveal a new route by which suppressive ODNs modulate the immune system and unveil novel applications for suppressive ODNs in the treatment of infectious and autoimmune diseases. PMID- 23986532 TI - Cutting edge: DNA sensing via the STING adaptor in myeloid dendritic cells induces potent tolerogenic responses. AB - Cytosolic DNA sensing via the stimulator of IFN genes (STING) adaptor incites autoimmunity by inducing type I IFN (IFN-alphabeta). In this study, we show that DNA is also sensed via STING to suppress immunity by inducing IDO. STING gene ablation abolished IFN-alphabeta and IDO induction by dendritic cells (DCs) after DNA nanoparticle (DNP) treatment. Marginal zone macrophages, some DCs, and myeloid cells ingested DNPs, but CD11b(+) DCs were the only cells to express IFN beta, whereas CD11b(+) non-DCs were major IL-1beta producers. STING ablation also abolished DNP-induced regulatory responses by DCs and regulatory T cells, and hallmark regulatory responses to apoptotic cells were also abrogated. Moreover, systemic cyclic diguanylate monophosphate treatment to activate STING induced selective IFN-beta expression by CD11b(+) DCs and suppressed Th1 responses to immunization. Thus, previously unrecognized functional diversity among physiologic innate immune cells regarding DNA sensing via STING is pivotal in driving immune responses to DNA. PMID- 23986533 TI - Calpastatin prevents NF-kappaB-mediated hyperactivation of macrophages and attenuates colitis. AB - Calpain enzymes proteolytically modulate cellular function and have been implicated in inflammatory diseases. In this study, we found that calpain levels did not differ between intestinal tissues from inflammatory bowel disease (IBD) patients and healthy controls, but IBD tissues showed increased levels of the endogenous calpain inhibitor, calpastatin (CAST). To investigate the role of CAST in the immune system during IBD, mice were x-ray irradiated, reconstituted with either CAST-knockout (KO) or wild-type (WT) bone marrow, and subjected to dextran sulfate sodium-induced colitis. CAST-KO recipients with induced colitis exhibited more severe weight loss, bloody diarrhea, and anemia compared with WT controls. Histological evaluation of colons from KO recipients with colitis revealed increased inflammatory pathology. Macrophages purified from the colons of KO recipients had higher IL-6, TNF-alpha, and IFN-gamma mRNA levels compared with WT controls. Mechanistic investigations using small interfering RNA and KO bone marrow to generate CAST-deficient macrophages showed that CAST deficiency during activation with bacterial pathogen associated molecular patterns, including heat killed Enterococcus faecalis or CpG DNA, led to increased IkappaB cleavage, NF kappaB nuclear localization, and IL-6 and TNF-alpha secretion. Thus, CAST plays a central role in regulating macrophage activation and limiting pathology during inflammatory disorders like IBD. PMID- 23986534 TI - Differential response of regulatory and conventional CD4+ lymphocytes to CD3 engagement: clues to a possible mechanism of anti-CD3 action? AB - Several clinical trials have shown anti-CD3 treatment to be a promising therapy for autoimmune diabetes, but its mechanism of action remains unclear. Foxp3(+) regulatory T cells (Tregs) are likely to be involved, but through unknown mechanistic pathways. We profiled the transcriptional consequences in CD4(+) Tregs and conventional T cells (Tconvs) in the first hours and days after anti CD3 treatment of NOD mice. Anti-CD3 treatment led to a transient transcriptional response, terminating faster than most Ag-induced responses. Most transcripts were similarly induced in Tregs and Tconvs, but several were differential, in particular, those encoding the IL-7R and transcription factors Id2/3 and Gfi1, upregulated in Tregs but repressed in Tconvs. Because IL-7R was a plausible candidate for driving the homeostatic response of Tregs to anti-CD3, we tested its relevance by supplementation of anti-CD3 treatment with IL-7/anti-IL-7 complexes. Although ineffective alone, IL-7 significantly improved the rate of remission induced by anti-CD3. Four anti-human CD3 mAbs exhibited the same differential effect on IL-7R expression in human as in mouse cells, suggesting that the mechanism also underlies therapeutic effect in human cells, and perhaps a rationale for testing a combination of anti-CD3 and IL-7 for the treatment of recent-onset human type 1 diabetes. Thus, systems-level analysis of the response to anti-CD3 in the early phase of the treatment demonstrates different responses in Tregs and Tconvs, and provides new leads to a mechanistic understanding of its mechanism of action in reverting recent-onset diabetes. PMID- 23986535 TI - The locus of color sensation: cortical color loss and the chromatic visual evoked potential. AB - Color losses of central origin (cerebral achromatopsia and dyschromatopsia) can result from cortical damage and are most commonly associated with stroke. Such cases have the potential to provide useful information regarding the loci of the generation of the percept of color. One available tool to examine this issue is the chromatic visual evoked potential (cVEP). The cVEP has been used successfully to objectively quantify losses in color vision capacity in both congenital and acquired deficiencies of retinal origin but has not yet been applied to cases of color losses of cortical origin. In addition, it is not known with certainty which cortical sites are responsible for the generation of the cVEP waveform components. Here we report psychophysical and electrophysiological examination of a patient with color deficits resulting from a bilateral cerebral infarct in the ventral occipitotemporal region. Although this patient demonstrated pronounced color losses of a general nature, the waveform of the cVEP remains unaffected. Contrast response functions of the cVEP are also normal for this patient. The results suggest that the percept of color arises after the origin of the cVEP and that normal activity in those areas that give rise to the characteristic negative wave of the cVEP are not sufficient to provide for the normal sensation of color. PMID- 23986537 TI - Sparing of coarse stereopsis in stereodeficient children with a history of amblyopia. AB - Stereoscopic depth perception may be obtained from small retinal disparities that can be fused for single vision (fine stereopsis), but reliable depth information is also obtained from larger disparities that produce double vision (coarse stereopsis). Here we assess the possibility that the early development of coarse stereopsis makes it resilient to the factors that cause amblyopia by comparing performance in children with a history of strabismic, anisometropic, or aniso strabismic amblyopia and age-matched controls (5-12 years). The task was to indicate whether a cartoon character was nearer or farther away than a zero disparity reference frame. Test disparities were grouped into fine and coarse ranges based on preliminary assessment of diplopia thresholds. In the fine range, accuracy increased with disparity for both groups, but children in the amblyopia group performed significantly worse than children in the control group, particularly when their amblyopia was associated with strabismus. In the coarse range, accuracy was constant across all disparities for both groups although performance appeared to be poorer in the aniso-strabismic group. These results suggest that, under some conditions, stereopsis for large disparities may be spared when stereopsis for small disparities is disrupted by early visual deprivation. This undetected residual binocular function has important clinical implications given recent efforts to improve amblyopia treatment outcomes by employing binocular treatment protocols. PMID- 23986536 TI - Reducing magnocellular processing of various motion trajectories tests single process theories of visual position perception. AB - Spatial projection and temporal integration are two prominent theories of visual localization for moving stimuli which gain most of their explanatory power from a single process. Spatial projection theories posit that a moving stimulus' perceived position is projected forwards in order to compensate for processing delays (Eagleman & Sejnowski, 2007; Nijhawan, 2008). Temporal integration theories (Krekelberg & Lappe, 2000) suggest that an averaging over positions occupied by the moving stimulus for a period of time is the dominant process underlying perception of position. We found that when magnocellular (M) pathway processing was reduced, there were opposite effects on localization judgments when a smooth, continuous trajectory was used, compared to when the moving object suddenly appeared, or suddenly reversed direction. The flash-lag illusion was decreased for the continuous trajectory, but increased for the onset and reversal trajectories. This cross-over interaction necessitates processes additional to those proposed by either the spatial projection or temporal integration theories in order to explain the perception of the position of moving stimuli across all our conditions. Differentiating our onset trajectory conditions from a Frohlich illusion, in a second experiment, we found a null Frohlich illusion under normal luminance-defined conditions, significantly smaller than the corresponding flash lag illusion, but significantly increased when M processing was reduced. Our data are most readily accounted for by Kirschfeld and Kammer's (1999) backward inhibition and focal attention theory. PMID- 23986538 TI - What is next generation sequencing? AB - Next generation sequencing (NGS), massively parallel or deep sequencing are related terms that describe a DNA sequencing technology which has revolutionised genomic research. Using NGS an entire human genome can be sequenced within a single day. In contrast, the previous Sanger sequencing technology, used to decipher the human genome, required over a decade to deliver the final draft. Although in genome research NGS has mostly superseded conventional Sanger sequencing, it has not yet translated into routine clinical practice. The aim of this article is to review the potential applications of NGS in paediatrics. PMID- 23986540 TI - Nighttime aircraft noise exposure: flying towards arterial disease. PMID- 23986539 TI - The effects of task difficulty on visual search strategy in virtual 3D displays. AB - Analyzing the factors that determine our choice of visual search strategy may shed light on visual behavior in everyday situations. Previous results suggest that increasing task difficulty leads to more systematic search paths. Here we analyze observers' eye movements in an "easy" conjunction search task and a "difficult" shape search task to study visual search strategies in stereoscopic search displays with virtual depth induced by binocular disparity. Standard eye movement variables, such as fixation duration and initial saccade latency, as well as new measures proposed here, such as saccadic step size, relative saccadic selectivity, and x-y target distance, revealed systematic effects on search dynamics in the horizontal-vertical plane throughout the search process. We found that in the "easy" task, observers start with the processing of display items in the display center immediately after stimulus onset and subsequently move their gaze outwards, guided by extrafoveally perceived stimulus color. In contrast, the "difficult" task induced an initial gaze shift to the upper-left display corner, followed by a systematic left-right and top-down search process. The only consistent depth effect was a trend of initial saccades in the easy task with smallest displays to the items closest to the observer. The results demonstrate the utility of eye-movement analysis for understanding search strategies and provide a first step toward studying search strategies in actual 3D scenarios. PMID- 23986541 TI - Modulation of the antidepressant-like effects of sustained administration of carisbamate and lamotrigine on monoaminergic systems: electrophysiological studies in the rat brain. AB - Carisbamate and lamotrigine are anticonvulsants that act on neuronal voltage gated sodium channels. Carisbamate has shown antidepressant-like effects in animal models of depression, and lamotrigine is a mood stabilizer with a therapeutic effect in depressive episodes of patients with bipolar disorder. This study examined the effects of carisbamate and lamotrigine on monoaminergic transmission in rodents, which could contribute to their antidepressant action. In vivo electrophysiological recordings were carried out in rats after 2 and 14 days administration of vehicle, carisbamate (60 mg/kg daily), or lamotrigine (25 mg/kg daily). Overall firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus norepinephrine, and ventral tegmental area dopamine (DA) neurons was decreased with carisbamate. Lamotrigine also decreased 5-HT neuronal firing, and this effect was abolished by lesion of the prefrontal cortex. Despite these decreases in firing activity after their prolonged administration, both anticonvulsants exhibited a significant increase in tonic activation of hippocampus 5-HT1A receptors, as shown by a disinhibition of the firing activity of pyramidal neurons in response to the selective antagonist WAY-100635 (N-{2 [4(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). This finding reveals an increase in the 5-HT level that may be attributed to a desensitization of the terminal 5-HT1B autoreceptors. This study demonstrates that sustained carisbamate and lamotrigine administration decreases 5-HT firing in the DRN but nevertheless enhances 5-HT transmission in the forebrain. This serotonergic effect may be associated with an antiglutamatergic action and may contribute to the antidepressant-like effect of carisbamate in the forced swim test and the antidepressant properties of lamotrigine. PMID- 23986542 TI - Implementing risk-stratified screening for common cancers: a review of potential ethical, legal and social issues. AB - BACKGROUND: The identification of common genetic variants associated with common cancers including breast, prostate and ovarian cancers would allow population stratification by genotype to effectively target screening and treatment. As scientific, clinical and economic evidence mounts there will be increasing pressure for risk-stratified screening programmes to be implemented. METHODS: This paper reviews some of the main ethical, legal and social issues (ELSI) raised by the introduction of genotyping into risk-stratified screening programmes, in terms of Beauchamp and Childress's four principles of biomedical ethics--respect for autonomy, non-maleficence, beneficence and justice. Two alternative approaches to data collection, storage, communication and consent are used to exemplify the ELSI issues that are likely to be raised. RESULTS: Ultimately, the provision of risk-stratified screening using genotyping raises fundamental questions about respective roles of individuals, healthcare providers and the state in organizing or mandating such programmes, and the principles, which underpin their provision, particularly the requirement for distributive justice. CONCLUSIONS: The scope and breadth of these issues suggest that ELSI relating to risk-stratified screening will become increasingly important for policy-makers, healthcare professionals and a wide diversity of stakeholders. PMID- 23986543 TI - Influence of surgical rate on patients' reported clinical need and outcomes in English NHS. AB - BACKGROUND: To determine if higher rates of surgery are associated with lower levels of need (patients' pre-operative reports of their symptoms, functional status and quality of life) and with less benefit (patients' post-operative reports). METHODS: Patient-reported outcome measures (PROMs) collected before and after joint replacement, hernia repair or varicose vein (VV) surgery in National Health Service (NHS)-funded patients (2009/11). Regression analysis for associations between 10% increase in rates and mean PROM score for Primary Care Trust (PCT) populations. RESULTS: National rate for hip and knee replacement increased by 6%, unchanged for hernia repair and decreased by 26% for VV surgery. Changes in PCT rates varied but had little or no association with the mean level of need of patients: 10% increase in the rate was associated with only 0.3% decline in the pre-operative PROM score for knee replacement (P < 0.05) and VV surgery (P < 0.001) and no significant change for other procedures. There was no significant association between a 10% change in the rate and the amount of benefit from surgery apart from a slight reduction (0.46%; P < 0.001) in the disease-specific PROM score for VV surgery. CONCLUSION: Policies by commissioners to reduce surgical rates in the English NHS cannot be justified on the grounds of avoiding inappropriate operations or increasing cost-utility. PMID- 23986544 TI - Risk factors for the development of gastrointestinal colonization with fluoroquinolone-resistant Escherichia coli in residents of long-term care facilities. AB - BACKGROUND: The objective of this study was to assess risk factors for the development of fluoroquinolone (FQ)-resistant Escherichia coli gastrointestinal tract colonization in long-term care facility (LTCF) residents. METHODS: A prospective cohort study was conducted from 2006 to 2008 at 3 LTCFs. Residents initially colonized with FQ-susceptible E. coli were followed by means of serial fecal sampling for new FQ-resistant E. coli colonization for up to 12 months or until discharge or death. A Cox proportional hazards regression model was developed to identify risk factors for new FQ-resistant E. coli colonization, with antibiotic and device exposures modeled as time-varying covariates. RESULTS: Fifty-seven (47.5%) of 120 residents became newly colonized with FQ-resistant E. coli, with a median time to colonization of 57 days. Fecal incontinence (hazard ratio [HR], 1.78; 95% confidence interval [CI], 1.04-3.06; P = .04) was significantly associated with FQ-resistant E. coli acquisition. Receipt of amoxicillin-clavulanate (HR, 6.48; 95% CI, 1.43-29.4; P = .02) and the presence of a urinary catheter (HR, 3.81; 95% CI, 1.06-13.8; P = .04) during LTCF stay increased the risk of new FQ-resistant E. coli colonization. CONCLUSIONS: Acquisition of FQ-resistant E. coli was common, with nearly half of LTCF residents developing new FQ-resistant E. coli colonization. Further studies are needed on interventions to limit the emergence of FQ-resistant E. coli in LTCFs. PMID- 23986545 TI - Complications and associated bacterial coinfections among children hospitalized with seasonal or pandemic influenza, United States, 2003-2010. AB - BACKGROUND: Data on the range and severity of influenza-associated complications among children are limited. We describe the frequency and severity of complications in hospitalized children aged <18 years with seasonal influenza (during 2003-2009) and 2009 pandemic influenza A(H1N1) (during 2009-2010). METHODS: Population-based surveillance for laboratory-confirmed influenza hospitalizations was conducted among 5.3 million children in 10 states. Complications were identified by International Classification of Diseases, Ninth Revision (ICD-9) codes in medical records. RESULTS: During 2003-2010, 7293 children hospitalized with influenza were identified, of whom 6769 (93%) had complete ICD-9 code data. Among the 6769 children, the median length of hospitalization was 3 days (interquartile range, 2-4 days), 975 (14%) required intensive care, 359 (5%) had respiratory failure, and 40 (1%) died. The most common complications were pneumonia (in 28% of children), asthma exacerbations (in 22% [793/3616] aged >= 2 years), and dehydration (in 21%). Lung abscess/empyema, tracheitis, encephalopathy, bacteremia/sepsis, acute renal failure, and myocarditis were rare (each <= 2% of children) but associated with a median hospitalization duration of >= 6 days, and 48%-70% of children required intensive care. Bacterial cultures with positive results were identified in 2% of children (107/6769); Staphylococcus aureus and Streptococcus pneumoniae were most commonly identified. CONCLUSIONS: Complications contribute substantially to the disease burden among children hospitalized with influenza, through intensive care requirements and prolonged hospitalization, highlighting the importance of primary prevention with influenza vaccination. PMID- 23986546 TI - Tumour markers fluctuations in patients with medullary thyroid carcinoma receiving long-term RET inhibitor therapy: ordinary lapping or alarming waves foreshadowing disease progression? PMID- 23986547 TI - Role of second-line chemotherapy in advanced pancreatic cancer and its influence on phase II/III study results. PMID- 23986550 TI - Expression profile of cord blood neutrophils and dysregulation of HSPA1A and OLR1 upon challenge by bacterial peptidoglycan. AB - In newborn infants, the innate cellular system plays a crucial role in the first line of defense against pathogens. Neutrophils are the most abundant leukocytes, and their response to the commonly encountered nosocomial bacterial (Gram positive) infection in newborns remains largely unclear. In this study, a genome wide expression array analysis was performed on CB neutrophils after challenge by PGN in vitro and compared with neutrophils in CTL cultures without PGN. We investigated responses of neutrophils to PGN and LPS, with respect to cytokine synthesis, chemotaxis, ROS production, cell death, and pathways of HSP response. Our results provide the first comprehensive expressional profile of neonatal neutrophils stimulated by PGN. mRNA levels of 16 up-regulated genes and 6 down regulated genes were validated by qPCR. Their regulatory networks were identified downstream of TLR-2 and NOD-2, which work in concert toward signals of death, cytoprotection, inflammation, and stress responses. Members of the HSP family were significantly up-regulated in PGN-stimulated neutrophils, compared with those in LPS-stimulated cells. We confirmed protein co-precipitation of HSPA1A and OLR1 in stimulated neutrophils, and their transcription, induced by NF-kappaB but not by MAPK signals. We found increased CD11b, chemotaxis, TNF-alpha, and IL 8 in neutrophils stimulated by PGN or LPS. PGN, but not LPS, increased ROS production. We conclude that neonatal neutrophils are capable of vigorous molecular and functional responses to PGN and suggest that HSP plays a critical role in the host defense mechanism, possibly involving proinflammatory OLR1 and CD11b-facilitated chemotaxis. PMID- 23986549 TI - An essential role for Rab27a GTPase in eosinophil exocytosis. AB - Eosinophil degranulation has been implicated in inflammatory processes associated with allergic asthma. Rab27a, a Rab-related GTPase, is a regulatory intracellular signaling molecule expressed in human eosinophils. We postulated that Rab27a regulates eosinophil degranulation. We investigated the role of Rab27a in eosinophil degranulation within the context of airway inflammation. Rab27a expression and localization in eosinophils were investigated by using subcellular fractionation combined with Western blot analysis, and the results were confirmed by immunofluorescence analysis of Rab27a and the granule membrane marker CD63. To determine the function of eosinophil Rab27a, we used Ashen mice, a strain of Rab27a-deficient animals. Ashen eosinophils were tested for degranulation in response to PAF and calcium ionophore by measuring released EPX activity. Airway EPX release was also determined by intratracheal injection of eosinophils into mice lacking EPX. Rab27a immunoreactivity colocalized with eosinophil crystalloid granules, as determined by subcellular fractionation and immunofluorescence analysis. PAF induced eosinophil degranulation in correlation with redistribution of Rab27a(+) structures, some of which colocalized with CD63(+) crystalloid granules at the cell membrane. Eosinophils from mice had significantly reduced EPX release compared with normal WT eosinophils, both in vitro and in vivo. In mouse models, Ashen mice demonstrated reduced EPX release in BAL fluid. These findings suggest that Rab27a has a key role in eosinophil degranulation. Furthermore, these findings have implications for Rab27a-dependent eosinophil degranulation in airway inflammation. PMID- 23986552 TI - Medical microbiology training needs and trainee experience. AB - BACKGROUND: Training in microbiology is continuing to evolve. Standardisation of this process has, in part, been achieved through the development of a training curriculum by the Royal College of Pathologists (RCPath). A substantial proportion of microbiology training occurs through telephone consultations. AIMS: To ascertain the content of these interactions and the extent to which the necessary skills outlined by the curriculum are attainable via these consultations. METHODS: Records of telephone consultations made by microbiology registrars (SpR) on the Laboratory Information Management System (LIMS) over a 6 month period were analysed with regard to who initiated contact and the type of advice provided. RESULTS: An average of 426 SpR entries per month were made on the LIMS following telephone consultations. These consultations were predominantly initiated by fellow clinicians as opposed to the SpR. The majority (79%) of advice entailed guidance as to the use of antimicrobials which resulted in an alteration of the current regimen in 54% of cases. CONCLUSIONS: This study represents the first attempt to quantify the telephone consultations of microbiology trainees. It is concluded that although such interactions provide a means of attaining some of the competencies outlined by the RCPath curriculum, the bias towards antimicrobial advice reflects a discrepancy between the needs of the service users and the broad skill set advocated by the current microbiology training programme. Future modifications will need to take this into account to ensure both the training of SpRs and the microbiology service is fit for purpose. PMID- 23986551 TI - Expression of cancer stem cell markers is more frequent in anaplastic thyroid carcinoma compared to papillary thyroid carcinoma and is related to adverse clinical outcome. AB - BACKGROUND: Thyroid cancer is one of the most commonly detected cancers worldwide, and papillary thyroidal carcinoma (PTC) accounts for the majority of thyroid cancers. In contrast to the indolent nature of PTC, anaplastic thyroid carcinoma (ATC) shows an extremely poor prognosis and has not responded to any therapeutic modalities. Many researchers postulate that the dedifferentiation of thyroid follicular cells into primitive cells might be related to the pathogenesis of ATC because several cases of ATC have revealed pre-existing PTC lesions. Additionally, the cancer stem cell (CSC) theory has been widely accepted in the pathogenesis of ATC. OBJECTIVE: To explore the expression of various CSC markers in thyroid carcinoma tissues and analyse their clinical significance. METHODS: 133 patients with PTC and 25 patients with ATC were enrolled. Immunohistochemistry for aldehyde dehydrogenase 1 (ALDH1), CD133, CXCR4, ATP binding cassette (ABC)G2, multidrug resistance associated protein-1 (MRP1), lung resistance protein-1 (LRP), P-glycoprotein 1 (P-Gp1), SOX2, SOX9 and Oct4 was performed using tissue microarray. RESULTS: CSC marker expression was significantly high in ATC, particularly chemoresistance markers such as ABCG2, MRP1, LRP and CXCR4. In PTC, ABCG2 was highly positive in more advanced pathological stages and was associated with lymph node involvement, with borderline significance. In ATC, high expression of CXCR4 correlated with distant metastasis, and LRP showed a tendency to correlate with lymph node metastasis. High expression of CSC markers was related to shorter overall survival in patients with ATC. CONCLUSIONS: These results provide strong evidence that CSCs are related to the pathogenesis of ATC and can explain the frequent treatment failure and aggressiveness of ATC. PMID- 23986553 TI - Molecular genetic tests for JAK2V617F, Exon12_JAK2 and MPLW515K/L are highly informative in the evaluation of patients suspected to have BCR-ABL1-negative myeloproliferative neoplasms. AB - Polycythaemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MF), are the most common myeloproliferative neoplasms (MPN) in patients without the BCR-ABL1 gene rearrangement. They are caused by clonal expansion of haematopoietic stem cells and share, as a diagnostic criterion, the identification of JAK2V617F mutation. Classically, when other clinical criteria are present, a JAK2V617F negative case requires the analysis of Exon12_JAK2 for the diagnosis of PV, and of MPL515K/L mutations for the diagnosis of ET and MF. Here, we evaluated 78 samples from Brazilian patients suspected to have MPN, without stratification for PV, ET or MF. We found that 28 (35.9%) are JAK2V617F carriers; from the 50 remaining samples, one (2%) showed an Exon12_JAK2 mutation, and another (2%) was positive for MPLW515L mutation. In summary, the investigation of JAK2V617F, Exon12_JAK2 and MPLW515K/L was relevant for the diagnosis of 38.4% of patients suspected to have BCR-ABL1-negative MPN, suggesting that molecular genetic tests are useful for a quick and unequivocal diagnosis of MPN. PMID- 23986554 TI - M2-polarised macrophages in infantile haemangiomas: correlation with promoted angiogenesis. AB - AIMS: The pathogenesis of infantile haemangiomas (IHs) is still far from clear despite the fact that they are common vascular tumours distinctive for their perinatal presentation, rapid growth during the first year of life and subsequent slow involution. AIMS: To determine the role of M2-polarised macrophages in IHs. METHODS: M2-polarised macrophages were initially identified in 20 specimens of IHs by both immunochemistry and immunofluorescence for CD68 and CD163. The immunopositive M2-polarised macrophages in different phases of IHs were quantified, and further analysed for their correlations with the expression levels of Ki67, vascular endothelial growth factor (VEGF) and macrophage colony stimulating factor (M-CSF). RESULTS: The infiltrating macrophages in proliferative IHs were predominantly CD68/CD163, thus of the M2-polarised phenotype, whereas the density of these cells was significantly decreased in the involuting IHs. The high density of M2-polarised macrophages in proliferative IHs was closely correlated with overexpression of M-CSF, one of the cytokines considered to induce macrophages to polarise towards an M2 phenotype. The infiltrating M2-polarised macrophages probably contributed to the proliferation and angiogenesis of haemangioma endothelial cells, as evidenced by their close correlations with the immunoreactivities of Ki67 and VEGF. CONCLUSIONS: Results indicate that the infiltrating M2-polarised macrophages may contribute to the progression of IHs by promoting the angiogenic process. PMID- 23986555 TI - A prospective study comparing contamination rates between a novel mid-stream urine collection device (Peezy) and a standard method in renal patients. AB - INTRODUCTION: It is imperative that laboratories receive uncontaminated urine samples to avoid giving false-positive results and reduce antimicrobial use. AIM: The aim of the study was to investigate a novel urine collection device (Peezy) in a renal outpatient clinic to determine whether it reduced contamination of urine samples. METHODS: The novel device was used in 420 renal transplant recipients and the results were compared with 424 matched historical controls, who used the standard method of urine collection. High epithelial cell counts on microscopy and mixed urine cultures were used to identify contaminated samples. RESULTS: Peezy increased the rates of both epithelial cells and mixed growths in the urine samples when compared with the historical controls. CONCLUSIONS: Further randomised studies in other more generalisable populations need to be performed. PMID- 23986556 TI - Strong association of fascin expression with triple negative breast cancer and basal-like phenotype in African-American women. AB - BACKGROUND: Fascin, an actin bundling protein, plays a critical role in cell motility due to formation of actin rich protrusions called filopodia, important in cell migration, invasion and metastatic spread. Fascin overexpression has been associated with epithelial to mesenchymal transition and correlates with progression and unfavourable prognosis in breast carcinoma. OBJECTIVE: To evaluate fascin expression by immunohistochemistry and correlate the expression pattern with clinicopathological parameters in breast cancer in African-American (AA) women, in whom triple negative breast cancer (TNBC), an aggressive subtype, is more prevalent. METHODS: Tissue microarrays were constructed from formalin fixed, paraffin-embedded blocks of tumour tissue from primary breast carcinomas in 202 AA women. Immunohistochemical detection of fascin was correlated with four major subtypes of breast carcinoma (luminal A, luminal B, human epidermal growth factor receptor 2 and triple negative (TN)) and other clinicopathological factors, including age, grade, tumour size, stage, regional lymph node status and survival. RESULTS: We observed a significant association between fascin expression and TN subtype, oestrogen receptor (ER) negativity, progesterone receptor (PR) negativity, Elston-Nottingham (EN) grade 3 and decreased overall survival. There was also a significant association between expression of CK 5/6, a marker of basal-like phenotype, and fascin expression. CONCLUSION: These results suggest that fascin is a marker for TN subtype having a basal-like phenotype and decreased overall survival. Fascin may represent a target for therapy in TNBC in AA women. PMID- 23986557 TI - External validation of the ImmunoRatio image analysis application for ERalpha determination in breast cancer. AB - The aim of this study was to validate ImmunoRatio, a web-based automated image analysis application, by comparing the manual and automated analysis scores for oestrogen receptor alpha (ERalpha) in breast carcinomas. Tissue microarrays comprising 200 breast cancer cases prestained for ERalpha were scanned and scored manually using ImageScope viewing software. Corresponding images were then uploaded and assessed according to the web-based ImmunoRatio programme. There was excellent correlation between manual and ImmunoRatio ERalpha scores (Spearman correlation=0.872; p>=0.001). The manual and ImmunoRatio ERalpha scores showed only a moderate agreement (kappa=0.421; Weighted kappa=0.874 (CI 0.839 to 0.902)), most probably due to lack of specificity of the algorithm to differentiate between cancer and non-cancer nuclei. Further development to enable differentiation of cancer and non-cancer elements should improve the specificity of the application. Our results support the use of ImmunoRatio software for analysing ERalpha immunohistochemistry in breast cancer tissues for the purposes of research. PMID- 23986558 TI - n-3 PUFAs enhance the frequency of murine B-cell subsets and restore the impairment of antibody production to a T-independent antigen in obesity. AB - The role of n-3 polyunsaturated fatty acids (PUFA) on in vivo B-cell immunity is unknown. We first investigated how n-3 PUFAs impacted in vivo B-cell phenotypes and antibody production in the absence and presence of antigen compared with a control diet. Lean mice consuming n-3 PUFAs for 4 weeks displayed increased percentage and frequency of splenic transitional 1 B cells. Upon stimulation with trinitrophenylated-lipopolysaccharide, n-3 PUFAs increased the number of splenic transitional 1/2, follicular, premarginal, and marginal zone B cells. n-3 PUFAs also increased surface, but not circulating, IgM. We next tested the effects of n 3 PUFAs in a model of obesity that is associated with suppressed humoral immunity. An obesogenic diet after ten weeks of feeding, relative to a lean control, had no effect on the frequency of B cells but lowered circulating IgM upon antigen stimulation. Administration of n-3 PUFAs to lean and obese mice increased the percentage and/or frequency of transitional 1 and marginal zone B cells. Furthermore, n-3 PUFAs in lean and obese mice increased circulating IgM relative to controls. Altogether, the data show n-3 PUFAs enhance B cell-mediated immunity in vivo, which has implications for immunocompromised populations, such as the obese. PMID- 23986559 TI - New understanding of adolescent brain development: relevance to transitional healthcare for young people with long term conditions. AB - Whether or not adolescence should be treated as a special period, there is now no doubt that the brain changes much during adolescence. From an evolutionary perspective, the idea of an under developed brain which is not fit for purpose until adulthood is illogical. Rather, the adolescent brain is likely to support the challenges specific to that period of life. New imaging techniques show striking changes in white and grey matter between 11 and 25 years of age, with increased connectivity between brain regions, and increased dopaminergic activity in the pre-frontal cortices, striatum and limbic system and the pathways linking them. The brain is dynamic, with some areas developing faster and becoming more dominant until other areas catch up. Plausible mechanisms link these changes to cognitive and behavioural features of adolescence. The changing brain may lead to abrupt behavioural change with attendant risks, but such a brain is flexible and can respond quickly and imaginatively. Society allows adolescent exuberance and creativity to be bounded and explored in relative safety. In healthcare settings these changes are especially relevant to young people with long term conditions as they move to young adult life; such young people need to learn to manage their health conditions with the support of their healthcare providers. PMID- 23986560 TI - Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children. AB - The revised BSPGHAN guidelines for the diagnosis and management of coeliac disease represent an important shift in diagnostic strategy, aimed at simplifying and shortening the diagnostic process in selected cases. Guidance is given concerning the indications for testing for coeliac disease, which is still significantly underdiagnosed in the UK. While screening data suggest a likely incidence of 1 in 100 persons, only 10%-20% of this figure is currently being diagnosed.The BSPGHAN guidelines follow the new ESPGHAN guidelines in overall diagnostic strategy, while providing more didactic stratagems, which should be of assistance for paediatricians in specialties other than gastroenterology. PMID- 23986561 TI - Nonlinear temporal receptive fields of neurons in the dorsal cochlear nucleus. AB - Studies of the dorsal cochlear nucleus (DCN) have focused on spectral processing because of the complex spectral receptive fields of the DCN. However, temporal fluctuations in natural signals convey important information, including information about moving sound sources or movements of the external ear in animals like cats. Here, we investigate the temporal filtering properties of DCN principal neurons through the use of temporal weighting functions that allow flexible analysis of nonlinearities and time variation in temporal response properties. First-order temporal receptive fields derived from the neurons are sufficient to characterize their response properties to low-contrast (3-dB standard deviation) stimuli. Larger contrasts require the second-order terms. Allowing temporal variation of the parameters of the first-order model or adding a component representing refractoriness improves predictions by the model by relatively small amounts. The importance of second-order components of the model is shown through simulations of nonlinear envelope synchronization behavior across sound level. The temporal model can be combined with a spectral model to predict tuning to the speed and direction of moving sounds. PMID- 23986563 TI - Saccades curve away from previously inhibited locations: evidence for the role of priming in oculomotor competition. AB - The oculomotor system serves as the basis for representing concurrently competing motor programs. Here, we examine whether the oculomotor system also keeps track of the outcome of competition between target and distractor on the previous trial. Participants had to perform a simple task of making a saccade toward a predefined direction. On two-thirds of the trials, an irrelevant distractor was presented to either the left or right of the fixation. On one-third of the trials, no distractor was present. The results show that on trials without a distractor, saccades curved away from the empty location that was occupied by a distractor on the previous trial. This result was replicated and extended to cases when different saccade directions were used. In addition, we show that repetition of distractor location on the distractor-present trials results in a stronger curvature away and in a shorter saccade latency to the target. Taken together, these results provide strong evidence that the oculomotor system automatically codes and retains locations that had been ignored in the past to bias future behavior. PMID- 23986562 TI - Corollary discharge contributes to perceived eye location in monkeys. AB - Despite saccades changing the image on the retina several times per second, we still perceive a stable visual world. A possible mechanism underlying this stability is that an internal retinotopic map is updated with each saccade, with the location of objects being compared before and after the saccade. Psychophysical experiments have shown that humans derive such location information from a corollary discharge (CD) accompanying saccades. Such a CD has been identified in the monkey brain in a circuit extending from superior colliculus to frontal cortex. There is a missing piece, however. Perceptual localization is established only in humans and the CD circuit only in monkeys. We therefore extended measurement of perceptual localization to the monkey by adapting the target displacement detection task developed in humans. During saccades to targets, the target disappeared and then reappeared, sometimes at a different location. The monkeys reported the displacement direction. Detections of displacement were similar in monkeys and humans, but enhanced detection of displacement from blanking the target at the end of the saccade was observed only in humans, not in monkeys. Saccade amplitude varied across trials, but the monkey's estimates of target location did not follow that variation, indicating that eye location depended on an internal CD rather than external visual information. We conclude that monkeys use a CD to determine their new eye location after each saccade, just as humans do. PMID- 23986565 TI - Identifying differentially expressed proteins in two-dimensional electrophoresis experiments: inputs from transcriptomics statistical tools. AB - BACKGROUND: Two-dimensional electrophoresis is a crucial method in proteomics that allows the characterization of proteins' function and expression. This usually implies the identification of proteins that are differentially expressed between two contrasting conditions, for example, healthy versus diseased in human proteomics biomarker discovery and stressful conditions versus control in animal experimentation. The statistical procedures that lead to such identifications are critical steps in the 2-DE analysis workflow. They include a normalization step and a test and probability correction for multiple testing. Statistical issues caused by the high dimensionality of the data and large-scale multiple testing have been a more active topic in transcriptomics than proteomics, especially in microarray analysis. We thus propose to adapt innovative statistical tools developed for microarray analysis and incorporate them in the 2-DE analysis pipeline. RESULTS: In this article, we evaluate the performance of different normalization procedures, different statistical tests and false discovery rate calculation methods with both real and simulated datasets. We demonstrate that the use of statistical procedures adapted from microarrays lead to notable increase in power as well as a minimization of false-positive discovery rate. More specifically, we obtained the best results in terms of reliability and sensibility when using the 'moderate t-test' from Smyth in association with classic false discovery rate from Benjamini and Hochberg. AVAILABILITY: The methods discussed are freely available in the 'prot2D' open source R-package from Bioconductor (http://www.bioconductor.org//) under the terms of the GNU General Public License (version 2 or later). CONTACT: sebastien.artigaud@univ-brest.fr or sebastien.artigaud@gmx.com. PMID- 23986564 TI - Practice improves motor control in older adults by increasing the motor unit modulation from 13 to 30 Hz. AB - Practice of a motor task decreases motor output variability in older adults and is associated with adaptations of discharge activity of single motor units. In this study we were interested in the practice-induced modulation of multiple motor units within 13-30 Hz because theoretically it enhances the timing of active motoneurons. Our purpose, therefore, was to determine the neural adaptation of multiple motor units and related improvements in movement control following practice. Nine healthy older adults (65-85 yr) performed 40 practice trials of a sinusoidal task (0.12 Hz) with their index finger (10 degrees range of motion). Multi-motor unit activity was recorded intramuscularly from the first dorsal interosseus muscle. The mean spike rate (MSR), spike rate variability (CV(ISI)), and frequency modulation (5-60 Hz) of the spike rate were calculated from the multi-motor unit activity and were correlated with movement accuracy and variability of index finger position. A decrease in movement trajectory variability was associated with an increase in MSR (R(2) = 0.58), a decrease in CV(ISI) (R(2) = 0.58), and an increase in total power within a 13- to 30-Hz band (R(2) = 0.48). The increase in total power within a 13- to 30-Hz band was associated significantly (P < 0.005) with an increase in MSR (R(2) = 0.75) and the decrease in CV(ISI) (R(2) = 0.70). We demonstrate that practice-induced improvements in movement control are associated with changes in activity of multiple motor units. These findings suggest that practice-induced improvements in movement steadiness of older adults are associated with changes in the modulation of the motoneuron pool from 13 to 30 Hz. PMID- 23986566 TI - Discovering causal pathways linking genomic events to transcriptional states using Tied Diffusion Through Interacting Events (TieDIE). AB - MOTIVATION: Identifying the cellular wiring that connects genomic perturbations to transcriptional changes in cancer is essential to gain a mechanistic understanding of disease initiation, progression and ultimately to predict drug response. We have developed a method called Tied Diffusion Through Interacting Events (TieDIE) that uses a network diffusion approach to connect genomic perturbations to gene expression changes characteristic of cancer subtypes. The method computes a subnetwork of protein-protein interactions, predicted transcription factor-to-target connections and curated interactions from literature that connects genomic and transcriptomic perturbations. RESULTS: Application of TieDIE to The Cancer Genome Atlas and a breast cancer cell line dataset identified key signaling pathways, with examples impinging on MYC activity. Interlinking genes are predicted to correspond to essential components of cancer signaling and may provide a mechanistic explanation of tumor character and suggest subtype-specific drug targets. AVAILABILITY: Software is available from the Stuart lab's wiki: https://sysbiowiki.soe.ucsc.edu/tiedie. CONTACT: jstuart@ucsc.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23986567 TI - The code structure of the p53 DNA-binding domain and the prognosis of breast cancer patients. AB - MOTIVATION: The tumor-suppressor gene TP53 mutations are diverse in the central region encoding the DNA-binding domain. It has not been clear whether the prognostic significance for survival in breast cancer patients is the same for all types of mutations. Are there specific types of mutations carrying a worse prognosis? To understand the correlation between the mutations in the gene encoding the DNA-binding domain and the prognosis of breast cancer, we studied the code structure of the DNA-binding domain of breast cancer patients by using various artificial codes in information transmission. RESULTS: We indicated that the prognostic significance of all types of mutations in the DNA-binding domain is not the same, and that the DNA-binding domain having a certain code structure is important for estimating the prognosis of breast cancer patients. CONTACT: keiko@is.noda.tus.ac.jp or hara@is.noda.tus.ac.jp. PMID- 23986568 TI - lDDT: a local superposition-free score for comparing protein structures and models using distance difference tests. AB - MOTIVATION: The assessment of protein structure prediction techniques requires objective criteria to measure the similarity between a computational model and the experimentally determined reference structure. Conventional similarity measures based on a global superposition of carbon alpha atoms are strongly influenced by domain motions and do not assess the accuracy of local atomic details in the model. RESULTS: The Local Distance Difference Test (lDDT) is a superposition-free score that evaluates local distance differences of all atoms in a model, including validation of stereochemical plausibility. The reference can be a single structure, or an ensemble of equivalent structures. We demonstrate that lDDT is well suited to assess local model quality, even in the presence of domain movements, while maintaining good correlation with global measures. These properties make lDDT a robust tool for the automated assessment of structure prediction servers without manual intervention. AVAILABILITY AND IMPLEMENTATION: Source code, binaries for Linux and MacOSX, and an interactive web server are available at http://swissmodel.expasy.org/lddt. CONTACT: torsten.schwede@unibas.ch. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23986569 TI - Regulatory B10 cells restore pregnancy tolerance in a mouse model. AB - During mammalian pregnancy, the immune system defies a double challenge: to tolerate the foreign growing fetus and to fight off infections that could affect both mother and fetus. Minimal disturbances to the fine equilibrium between immune activation and tolerance would compromise fetal survival. Here, we show that regulatory B10 cells are important for pregnancy tolerance in mice. The frequency of these cells increases during normal murine pregnancies, while mice presenting spontaneous abortion do not show elevated levels of regulatory B10 cells. When B10 cells are transferred to the abortion-prone mice, dendritic cells are kept in an immature state, and regulatory T cells increase, thus avoiding immunological rejection of the fetuses. In vitro, we could identify IL-10 secreted by B10 cells as the main mediator of these salutary effects. Our data add an important piece of information to the complex immune crosstalk during pregnancy. This study opens novel lines of work to better understand how to help women who have trouble in maintaining a pregnancy. PMID- 23986570 TI - The effects of chemotherapy with bleomycin, etoposide, and cis-platinum (BEP) on rat sperm chromatin remodeling, fecundity and testicular gene expression in the progeny. AB - During spermiogenesis, histones are replaced first by transition proteins and then by protamines, resulting in a very condensed sperm DNA structure that is absolutely critical for normal sperm function. We have demonstrated previously that, despite a 9-wk recovery period, mature sperm from rats treated for 9 wk with bleomycin, etoposide, and cis-platinum (BEP), the drugs used to treat testicular cancer, have reduced levels of protamine 1 and a concomitant upregulation of specific histones, highlighting a problem in histone eviction. Here, we demonstrate that regulators of histone removal are increased in elongating spermatids following recovery; however, Ac-H4 and gamma H2AX histones remain elevated in elongating spermatids or caudal epididymal spermatozoa 9 wk post-BEP treatment. This indicates that chromatin remodelers and effector proteins that respond to histone removal cues may be a target of BEP treatment. A decrease in the expression of SMARCE1 in elongating spermatids may explain the persistent retention of histones in cauda epididymal sperm 9 wk after the cessation of BEP treatment. Remarkably, proteins implicated in the translational control and posttranslational processing of protamine 1 are also significantly elevated 9 wk post-BEP treatment, suggesting that histone eviction may dictate the DNA availability for protamine binding. Males mated to control females 9 wk after BEP treatment have reduced litter sizes; moreover, the profile of gene expression in the developing testes of their pups is altered. Altering the proportion of histones to protamine in mature spermatozoa has an adverse impact on male fecundity, with modifications to epigenetic marks potentially threatening normal progeny development. PMID- 23986571 TI - Adaptations in placental phenotype depend on route and timing of maternal dexamethasone administration in mice. AB - Synthetic glucocorticoids, like dexamethasone (dex), restrict growth of the fetus and program its adult physiology, in part by altering placental phenotype. The route and timing of dex administration determine the fetal and adult outcomes, but whether these factors affect placental phenotype remains unknown. This study compared placental morphology, amino acid transport, and gene expression in mice given dex orally or by subcutaneous injection over the periods of most rapid placental (Days [D] 11-16) or fetal (D14-19) growth (term is D21). Compared with untreated and saline-injected controls, both dex treatments reduced placental weight at D16 and 19 and fetal weight and total labyrinthine volume at D19 to a similar extent. Only oral dex treatment from D11 to D16 reduced labyrinthine fetal capillary volume on D16 and increased placental 14C-methylaminoisobutyric acid (MeAIB) clearance at D19, 3 days after treatment ended. Neither route of dex treatment altered placental expression of Slc38a, Hsd11b, or the glucocorticoid receptor, Nr3c1, at D16. In contrast, both routes of dex treatment from D14 to D19 increased placental Hsd11b2 expression and labyrinthine maternal vessel volume. Furthermore, injection per se altered placental expression of Nr3c1, Hsd11b1, and specific Slc38a isoforms in an age-related manner. Overall, MeAIB clearance was not related to Slc38a transporter expression but was correlated inversely with maternal corticosterone concentrations when dex was undetectable in maternal plasma at D19. The effects of dex on placental phenotype, therefore, depend on both the route and timing of administration and may relate to local glucocorticoid availability during and after the treatment period. PMID- 23986572 TI - Expression patterns and regulatory functions of microRNAs during the initiation of primordial follicle development in the neonatal mouse ovary. AB - The initiation of primordial follicle development is essential for female fertility, but the signals that trigger this process are poorly understood. Given the potentially important roles of microRNAs (miRNAs) in the ovary, we aimed to study the expression patterns and regulatory functions of miRNAs during the initiation of primordial follicle development. Expression patterns of miRNA in the neonatal mouse ovary were profiled by microarray, and 24 miRNAs whose abundances differed significantly between ovaries from 3- and 5-day-old mice were identified. Pathway enrichment analysis revealed that 48 signal transduction pathways are modulated by the up-regulated miRNAs and 29 pathways are modulated by the down-regulated miRNAs (P-value and false discovery rate < 0.001). A miRNA mRNA regulatory network was established for TGF-beta signaling pathway-related genes. Among the miRNAs involved in this pathway, miR-145 was chosen for further analysis. Down-regulation of miR-145 using an antagomir (AT) decreased the proportion and number of the primordial follicles and increased that of the growing follicles in the cultured ovaries (P < 0.05). The mean oocyte diameter in the primordial follicles was significantly greater in the AT group relative to the AT-negative control group (P < 0.05), whereas the mean oocyte diameter in growing follicles was smaller in the AT group than in the AT-negative control group. In addition, we confirmed that miR-145 targets Tgfbr2. The miR-145 AT caused an increase in TGFBR2 expression and activation of Smad signaling but did not affect the p38 MAPK or JNK pathway. These data suggest that miRNAs and the signaling pathways they modulate are involved in the initiation of primordial follicle development, and miR-145 targets Tgfbr2 to regulate the initiation of primordial follicle development and maintain primordial follicle quiescence. PMID- 23986573 TI - A decision-theoretical alternative to testing many hypotheses. AB - Testing a large number of hypotheses is a key problem in the analysis of microarray experiments and in other studies in which many elementary experiments are conducted, and the exceptions among them, for which a particular hypothesis does not hold, have to be identified. A class of approaches to this problem is based on controlling the false discovery rate, even though failure to discover should also be considered. We develop a decision-theoretical approach in which errors (misclassifications) of the two kinds are associated with uneven losses, and the total expected loss in the collection of the classifications (decisions made or options selected) is minimized. PMID- 23986574 TI - The toll and Imd pathways are not required for wolbachia-mediated dengue virus interference. AB - Wolbachia blocks dengue virus replication in Drosophila melanogaster as well as in Aedes aegypti. Using the Drosophila model and mutations in the Toll and Imd pathways, we showed that neither pathway is required for expression of the dengue virus-blocking phenotype in the Drosophila host. This provides additional evidence that the mechanistic basis of Wolbachia-mediated dengue virus blocking in insects is more complex than simple priming of the host insect innate immune system. PMID- 23986575 TI - Inhibition of CUL4A Neddylation causes a reversible block to SAMHD1-mediated restriction of HIV-1. AB - The deoxynucleoside triphosphohydrolase SAMHD1 restricts retroviral replication in myeloid cells. Human immunodeficiency virus type 2 (HIV-2) and a simian immunodeficiency virus from rhesus macaques (SIVmac) encode Vpx, a virion packaged accessory protein that counteracts SAMHD1 by inducing its degradation. SAMHD1 is thought to work by depleting the pool of intracellular deoxynucleoside triphosphates but has also been reported to have exonuclease activity that could allow it to degrade the viral genomic RNA or viral reverse-transcribed DNA. To induce the degradation of SAMHD1, Vpx co-opts the cullin4a-based E3 ubiquitin ligase, CRL4. E3 ubiquitin ligases are regulated by the covalent attachment of the ubiquitin-like protein Nedd8 to the cullin subunit. Neddylation can be prevented by MLN4924, a drug that inhibits the nedd8-activating enzyme. We report that MLN4924 inhibits the neddylation of CRL4, blocking Vpx-induced degradation of SAMHD1 and maintaining the restriction. Removal of the drug several hours postinfection released the block. Similarly, Vpx-containing virus-like particles and deoxynucleosides added to the cells more than 24 h postinfection released the SAMHD1-mediated block. Taken together, these findings support deoxynucleoside triphosphate pool depletion as the primary mechanism of SAMHD1 restriction and argue against a nucleolytic mechanism, which would not be reversible. PMID- 23986577 TI - Mutations in DNA binding and transactivation domains affect the dynamics of parvovirus NS1 protein. AB - The multifunctional replication protein of autonomous parvoviruses, NS1, is vital for viral genome replication and for the control of viral protein production. Two DNA-interacting domains of NS1, the N-terminal and helicase domains, are necessary for these functions. In addition, the N and C termini of NS1 are required for activation of viral promoter P38. By comparison with the structural and biochemical data from other parvoviruses, we identified potential DNA interacting amino acid residues from canine parvovirus NS1. The role of the identified amino acids in NS1 binding dynamics was studied by mutagenesis, fluorescence recovery after photobleaching, and computer simulations. Mutations in the predicted DNA-interacting amino acids of the N-terminal and helicase domains increased the intranuclear binding dynamics of NS1 dramatically. A substantial increase in binding dynamics was also observed for NS1 mutants that targeted the metal ion coordination site in the N terminus. Interestingly, contrary to other mutants, deletion of the C terminus resulted in slower binding dynamics of NS1. P38 transactivation was severely reduced in both N-terminal DNA recognition and in C-terminal deletion mutants. These data suggest that the intranuclear dynamics of NS1 are largely characterized by its sequence-specific and -nonspecific binding to double-stranded DNA. Moreover, binding of NS1 is equally dependent on the N-terminal domain and conserved beta-loop of the helicase domain. PMID- 23986576 TI - The open chromatin landscape of Kaposi's sarcoma-associated herpesvirus. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus which establishes latent infection in endothelial and B cells, as well as in primary effusion lymphoma (PEL). During latency, the viral genome exists as a circular DNA minichromosome (episome) and is packaged into chromatin analogous to human chromosomes. Only a small subset of promoters, those which drive latent RNAs, are active in latent episomes. In general, nucleosome depletion ("open chromatin") is a hallmark of eukaryotic regulatory elements such as promoters and transcriptional enhancers or insulators. We applied formaldehyde-assisted isolation of regulatory elements (FAIRE) followed by next-generation sequencing to identify regulatory elements in the KSHV genome and integrated these data with previously identified locations of histone modifications, RNA polymerase II occupancy, and CTCF binding sites. We found that (i) regions of open chromatin were not restricted to the transcriptionally defined latent loci; (ii) open chromatin was adjacent to regions harboring activating histone modifications, even at transcriptionally inactive loci; and (iii) CTCF binding sites fell within regions of open chromatin with few exceptions, including the constitutive LANA promoter and the vIL6 promoter. FAIRE-identified nucleosome depletion was similar among B and endothelial cell lineages, suggesting a common viral genome architecture in all forms of latency. PMID- 23986578 TI - Kaposi's sarcoma-associated herpesvirus-positive primary effusion lymphoma tumor formation in NOD/SCID mice is inhibited by neomycin and neamine blocking angiogenin's nuclear translocation. AB - Angiogenin (ANG) is a 14-kDa multifunctional proangiogenic secreted protein whose expression level correlates with the aggressiveness of several tumors. We observed increased ANG expression and secretion in endothelial cells during de novo infection with Kaposi's sarcoma-associated herpesvirus (KSHV), in cells expressing only latency-associated nuclear antigen 1 (LANA-1) protein, and in KSHV latently infected primary effusion lymphoma (PEL) BCBL-1 and BC-3 cells. Inhibition of phospholipase Cgamma (PLCgamma) mediated ANG's nuclear translocation by neomycin, an aminoglycoside antibiotic (not G418-neomicin), resulted in reduced KSHV latent gene expression, increased lytic gene expression, and increased cell death of KSHV(+) PEL and endothelial cells. ANG detection in significant levels in KS and PEL lesions highlights its importance in KSHV pathogenesis. To assess the in vivo antitumor activity of neomycin and neamine (a nontoxic derivative of neomycin), BCBL-1 cells were injected intraperitoneally into NOD/SCID mice. We observed significant extended survival of mice treated with neomycin or neamine. Markers of lymphoma establishment, such as increases in animal body weight, spleen size, tumor cell spleen infiltration, and ascites volume, were observed in nontreated animals and were significantly diminished by neomycin or neamine treatments. A significant decrease in LANA-1 expression, an increase in lytic gene expression, and an increase in cleaved caspase-3 were also observed in neomycin- or neamine-treated animal ascitic cells. These studies demonstrated that ANG played an essential role in KSHV latency maintenance and BCBL-1 cell survival in vivo, and targeting ANG function by neomycin/neamine to induce the apoptosis of cells latently infected with KSHV is an attractive therapeutic strategy against KSHV-associated malignancies. PMID- 23986579 TI - Kaposi's sarcoma-associated herpesvirus encodes a mimic of cellular miR-23. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) expresses ~20 viral microRNAs (miRNAs) in latently infected cells. We have previously shown that two of these miRNAs function as mimics of the cellular miRNAs miR-155 and miR-142-3p. Two additional KSHV miRNAs, miR-K3+1 and miR-K3, share perfect and offset 5' homology with cellular miR-23, respectively. Here, we report a single nucleotide polymorphism that causes miR-K3+1 expression in a subset of KSHV-infected primary effusion lymphoma cell lines as a consequence of altered processing of the primary transcript by the Microprocessor complex. We confirm that miR-K3+1 regulates miR-23 targets, which is expected because these miRNAs share the entire seed region (nucleotides 2 to 8). Surprisingly, we found that miR-K3 also regulates miR-23 targets, despite offset seed sequences. In addition, the offset homology of miR-K3 to miR-23 likely allows this viral miRNA to expand its target repertoire beyond the targets of miR-23. Because miR-23 is highly expressed in endothelial cells but expressed at only low levels in B cells, we hypothesize that miR-K3 may function to introduce miR-23-like activities into KSHV-infected B cells. Together, our data demonstrate that KSHV has evolved at least three distinct viral miRNAs to tap into evolutionarily conserved cellular miRNA regulatory networks. Furthermore, our data allow fundamental insights into the generation and functional impact of miRNA 5' end variation. PMID- 23986580 TI - Preservation of dendritic cell function during vesicular stomatitis virus infection reflects both intrinsic and acquired mechanisms of resistance to suppression of host gene expression by viral M protein. AB - Inhibition of host-directed gene expression by the matrix (M) protein of vesicular stomatitis virus (VSV) effectively blocks host antiviral responses, promotes virus replication, and disables the host cell. However, dendritic cells (DC) have the capacity to resist these effects and remain functional during VSV infection. Here, the mechanisms of DC resistance to M protein and their subsequent maturation were addressed. Flt3L-derived murine bone marrow dendritic cells (FDC), which phenotypically resemble resident splenic DC, continued to synthesize cellular proteins and matured during single-cycle (high-multiplicity) and multicycle (low-multiplicity) infection with VSV. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived myeloid DC (GDC), which are susceptible to M protein effects, were nevertheless capable of maturing, but the response was delayed and occurred only during multicycle infection. FDC resistance was manifested early and was type I interferon (IFN) receptor (IFNAR) and MyD88 independent, but sustained resistance required IFNAR. MyD88-dependent signaling contributed to FDC maturation during single-cycle infection but was dispensable during multicycle infection. Similar to FDC, splenic DC were capable of maturing in vivo during the first 24 h of infection with VSV, and neither Toll like receptor 7 (TLR7) nor MyD88 was required. We conclude that FDC resistance to M protein is controlled by an intrinsic, MyD88-independent mechanism that operates early in infection and is augmented later in infection by type I IFN. In contrast, while GDC are not intrinsically resistant, they can acquire resistance during multicycle infection. In vivo, splenic DC resist the inhibitory effects of VSV, and as in multicycle FDC infection, MyD88-independent signaling events control their maturation. PMID- 23986581 TI - The product of Kaposi's sarcoma-associated herpesvirus immediate early gene K4.2 regulates immunoglobulin secretion and calcium homeostasis by interacting with and inhibiting pERP1. AB - Chaperones are proteins that assist the noncovalent folding and assembly of macromolecular polypeptide chains, ultimately preventing the formation of nonfunctional or potentially toxic protein aggregates. Plasma cell-induced endoplasmic reticulum (ER)-resident protein 1 (pERP1) is a cellular chaperone that is preferentially expressed in marginal-zone B cells and is highly upregulated during plasma cell differentiation. While initially identified as a dedicated factor for the assembly of secreted IgM, pERP1 has since been implicated in suppressing calcium mobilization, and its expression is misregulated in multiple tumors. A number of herpesvirus immediate early gene products play important roles in the regulation of viral gene expression and/or evasion of host immune responses. Here, we report that the Kaposi's sarcoma associated herpesvirus (KSHV) immediate early viral gene K4.2 encodes an endoplasmic reticulum-localized protein that interacts with and inhibits pERP1. Consequently, K4.2 expression interfered with immunoglobulin secretion by delaying the kinetics of immunoglobulin assembly and also led to increased responsiveness of B-cell receptor signal transduction by enhancing phosphotyrosine signals and intracellular calcium fluxes. Furthermore, K4.2 expression also appeared to contribute to maximal lytic replication by enhancing viral glycoprotein expression levels and ultimately promoting infectious-virus production. Finally, immunohistochemistry analysis showed that pERP1 expression was readily detected in KSHV-positive cells from multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS) lesions, suggesting that pERP1 may have potential roles in the KSHV life cycle and malignancy. In conclusion, our data suggest that K4.2 participates in lytic replication by enhancing calcium flux and viral glycoprotein expression, but also by interfering with immunoglobulin assembly to potentially dampen the adaptive immune response. PMID- 23986582 TI - The viral polymerase inhibitor 2'-C-methylcytidine inhibits Norwalk virus replication and protects against norovirus-induced diarrhea and mortality in a mouse model. AB - Human noroviruses are a major cause of food-borne illness, accountable for 50% of all-etiologies outbreaks of acute gastroenteritis (in both developing and developed countries). There is no vaccine or antiviral drug for the prophylaxis or treatment of norovirus-induced gastroenteritis. We recently reported the inhibitory effect of 2'-C-methylcytidine (2CMC), a hepatitis C virus polymerase inhibitor, on the in vitro replication of murine norovirus (MNV). Here we evaluated the inhibitory effect of 2CMC on in vitro human norovirus replication through a Norwalk virus replicon model and in a mouse model by using AG129 mice orally infected with MNV. Survival, weight, and fecal consistency were monitored, and viral loads in stool samples and organs were quantified. Intestines were examined histologically. 2CMC reduced Norwalk virus replicon replication in a dose-dependent manner and was able to clear cells of the replicon. Treatment of MNV-infected AG129 mice with 2CMC (i) prevented norovirus-induced diarrhea; (ii) markedly delayed the appearance of viral RNA and reduced viral RNA titers in the intestine, mesenteric lymph nodes, spleen, lungs, and stool; (iii) completely prevented virus-induced mortality; and (iv) resulted in protective immunity against a rechallenge. We demonstrate for the first time that a small-molecule inhibitor of norovirus replication protects from virus-induced disease and mortality in a relevant animal model. These findings pave the way for the development of potent and safe antivirals as prophylaxis and therapy of norovirus infection. PMID- 23986583 TI - Genome-wide analysis of T cell responses during acute and latent simian varicella virus infections in rhesus macaques. AB - Varicella zoster virus (VZV) is the etiological agent of varicella (chickenpox) and herpes zoster (HZ [shingles]). Clinical observations suggest that VZV specific T cell immunity plays a more critical role than humoral immunity in the prevention of VZV reactivation and development of herpes zoster. Although numerous studies have characterized T cell responses directed against select VZV open reading frames (ORFs), a comprehensive analysis of the T cell response to the entire VZV genome has not yet been conducted. We have recently shown that intrabronchial inoculation of young rhesus macaques with simian varicella virus (SVV), a homolog of VZV, recapitulates the hallmarks of acute and latent VZV infection in humans. In this study, we characterized the specificity of T cell responses during acute and latent SVV infection. Animals generated a robust and broad T cell response directed against both structural and nonstructural viral proteins during acute infection in bronchoalveolar lavage (BAL) fluid and peripheral blood. During latency, T cell responses were detected only in the BAL fluid and were lower and more restricted than those observed during acute infection. Interestingly, we identified a small set of ORFs that were immunogenic during both acute and latent infection in the BAL fluid. Given the close genome relatedness of SVV and VZV, our studies highlight immunogenic ORFs that may be further investigated as potential components of novel VZV vaccines that specifically boost T cell immunity. PMID- 23986584 TI - Antirepression system associated with the life cycle switch in the temperate podoviridae phage SPC32H. AB - Prophages switch from lysogenic to lytic mode in response to the host SOS response. The primary factor that governs this switch is a phage repressor, which is typically a host RecA-dependent autocleavable protein. Here, in an effort to reveal the mechanism underlying the phenotypic differences between the Salmonella temperate phages SPC32H and SPC32N, whose genome sequences differ by only two nucleotides, we identified a new class of Podoviridae phage lytic switch antirepressor that is structurally distinct from the previously reported Sipho- and Myoviridae phage antirepressors. The SPC32H repressor (Rep) is not cleaved by the SOS response but instead is inactivated by a small antirepressor (Ant), the expression of which is negatively controlled by host LexA. A single nucleotide mutation in the consensus sequence of the LexA-binding site, which overlaps with the ant promoter, results in constitutive Ant synthesis and consequently induces SPC32N to enter the lytic cycle. Numerous potential Ant homologues were identified in a variety of putative prophages and temperate Podoviridae phages, indicating that antirepressors may be widespread among temperate phages in the order Caudovirales to mediate a prudent prophage induction. PMID- 23986585 TI - Mitochondrial nucleases ENDOG and EXOG participate in mitochondrial DNA depletion initiated by herpes simplex virus 1 UL12.5. AB - Herpes simplex virus 1 (HSV-1) rapidly eliminates mitochondrial DNA (mtDNA) from infected cells, an effect that is mediated by UL12.5, a mitochondrial isoform of the viral alkaline nuclease UL12. Our initial hypothesis was that UL12.5 directly degrades mtDNA via its nuclease activity. However, we show here that the nuclease activities of UL12.5 are not required for mtDNA loss. This observation led us to examine whether cellular nucleases mediate the mtDNA loss provoked by UL12.5. We provide evidence that the mitochondrial nucleases endonuclease G (ENDOG) and endonuclease G-like 1 (EXOG) play key redundant roles in UL12.5-mediated mtDNA depletion. Overall, our data indicate that UL12.5 deploys cellular proteins, including ENDOG and EXOG, to destroy mtDNA and contribute to a growing body of literature highlighting roles for ENDOG and EXOG in mtDNA maintenance. PMID- 23986586 TI - Middle East respiratory syndrome coronavirus spike protein delivered by modified vaccinia virus Ankara efficiently induces virus-neutralizing antibodies. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) has recently emerged as a causative agent of severe respiratory disease in humans. Here, we constructed recombinant modified vaccinia virus Ankara (MVA) expressing full-length MERS-CoV spike (S) protein (MVA-MERS-S). The genetic stability and growth characteristics of MVA-MERS-S make it a suitable candidate vaccine for clinical testing. Vaccinated mice produced high levels of serum antibodies neutralizing MERS-CoV. Thus, MVA-MERS-S may serve for further development of an emergency vaccine against MERS-CoV. PMID- 23986587 TI - Systemic toll-like receptor ligation and selective killing of dendritic cell subsets fail to dissect priming pathways for anti-vaccinia virus CD8+ T cells. AB - CD8+ T cell responses can be generated by direct or cross-priming mechanisms, and several mouse models have been used to reveal which of these is the most important pathway for various viruses. Among these models is systemic treatment of mice with a CpG-containing oligodeoxynucleotide (CpG) to mature all dendritic cells (DCs), rendering them incapable of cross-presentation. A second is the use of cytochrome c (cytc) as a selective poison of the subsets of DCs able to cross present antigen. In this study, using two vaccinia virus (VACV) strains, namely, WR and MVA, we found that the CpG and cytc methods gave conflicting data. Moreover, we show for both strains of VACV that treatment of mice with CpG and cytc inhibited CD8+ T cell responses to antigens designed to prime exclusively by direct presentation. Further investigation of the CpG method found that the extent to which priming is inhibited depends on the antigen examined, immunization route, replication ability of the virus, and, crucially, immunization dose. We suggest that greater caution is required when interpreting data using these methods and that priming pathways for antiviral CD8+ T cells are not simply separated according to DC subsets or their maturation state. PMID- 23986588 TI - Herpes simplex virus 1 ubiquitin-specific protease UL36 inhibits beta interferon production by deubiquitinating TRAF3. AB - Interferon (IFN)-mediated innate immune defense is a potent antiviral mechanism. Viruses evade innate immunity and limit secretion of beta interferon (IFN-beta) to replicate and survive in the host. The largest tegument protein of herpes simplex virus 1 (HSV-1), UL36, contains a novel deubiquitinase (DUB) motif embedded in its N terminus, denoted UL36 ubiquitin-specific protease (UL36USP). In the present study, we demonstrate that HSV-1 UL36USP inhibits Sendai virus (SeV)-induced interferon regulatory factor 3 (IRF3) dimerization, promoter activation, and transcription of IFN-beta. The DUB activity of UL36USP is essential to block IFN-beta production. UL36USP also inhibited IFN-beta promoter activity induced by overexpression of the N terminus of RIG-I (RIG-IN) and MAVS, but not TBK-1, IkappaB kinase epsilon (IKKepsilon), and IRF3/5D. UL36USP was subsequently shown to deubiquitinate TRAF3 and prevent the recruitment of the downstream adaptor TBK1. The recombinant HSV-1 lacking UL36USP DUB activity was generated. Cells infected with the mutant virus produced more IFN-beta than wild type (WT) HSV-1-infected cells. These findings demonstrate HSV-1 UL36USP removes polyubiquitin chains on TRAF3 and counteracts the IFN-beta pathway. PMID- 23986589 TI - Recombination-dependent oligomerization of human papillomavirus genomes upon transient DNA replication. AB - We describe the extensive and progressive oligomerization of human papillomavirus (HPV) genomes after transfection into the U2OS cell line. The HPV genomic oligomers are extrachromosomal concatemeric molecules containing the viral genome in a head-to-tail orientation. The process of oligomerization does not depend on the topology of the input DNA, and it does not require any other viral factors besides replication proteins E1 and E2. We provide evidence that oligomerization of the HPV18 and HPV11 genomes involves homologous recombination. We also demonstrate oligomerization of the HPV18 and HPV11 genomes in SiHa, HeLa, and C 33 A cell lines and provide examples of oligomeric HPV genomes in clinical samples obtained from HPV-infected patients. PMID- 23986590 TI - Vif proteins from diverse primate lentiviral lineages use the same binding site in APOBEC3G. AB - APOBEC3G (A3G) is a cytidine deaminase that restricts human immunodeficiency virus type 1 (HIV-1) and other lentiviruses. Most of these viruses encode a Vif protein that directly binds A3G and leads to its proteasomal degradation. Both Vif proteins of HIV-1 and African green monkey simian immunodeficiency virus (SIVagm) bind residue 128 of A3G. However, this position does not control the A3G degradation by Vif variants derived from HIV-2 and SIVmac, which both originated from SIV of sooty mangabey monkeys (SIVsmm), suggesting that the A3G binding site for Vif proteins of the SIVsmm/HIV-2 lineage differs from that of HIV-1. To map the SIVsmm Vif binding site of A3G, we performed immunoprecipitations of individual A3G domains, Vif/A3G degradation assays and a detailed mutational analysis of human A3G. We show that A3G residue 129, but not the adjacent position 128, confers susceptibility to degradation by SIVsmm Vif. An artificial A3G mutant, the P129D mutant, was resistant to degradation by diverse Vifs from HIV-1, HIV-2, SIVagm, and chimpanzee SIV (SIVcpz), suggesting a conserved lentiviral Vif binding site. Gorilla A3G naturally contains a glutamine (Q) at position 129, which makes its A3G resistant to Vifs from diverse lineages. We speculate that gorilla A3G serves as a barrier against SIVcpz strains. In summary, we show that Vif proteins from distinct lineages bind to the same A3G loop, which includes positions 128 and 129. The multiple adaptations within this loop among diverse primates underscore the importance of counteracting A3G in lentiviral evolution. PMID- 23986591 TI - Quantifying selection against synonymous mutations in HIV-1 env evolution. AB - Intrapatient evolution of human immunodeficiency virus type 1 (HIV-1) is driven by the adaptive immune system resulting in rapid change of HIV-1 proteins. When cytotoxic CD8(+) T cells or neutralizing antibodies target a new epitope, the virus often escapes via nonsynonymous mutations that impair recognition. Synonymous mutations do not affect this interplay and are often assumed to be neutral. We test this assumption by tracking synonymous mutations in longitudinal intrapatient data from the C2-V5 part of the env gene. We find that most synonymous variants are lost even though they often reach high frequencies in the viral population, suggesting a cost to the virus. Using published data from SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) assays, we find that synonymous mutations that disrupt base pairs in RNA stems flanking the variable loops of gp120 are more likely to be lost than other synonymous changes: these RNA hairpins might be important for HIV-1. Computational modeling indicates that, to be consistent with the data, a large fraction of synonymous mutations in this genomic region need to be deleterious with a cost on the order of 0.002 per day. This weak selection against synonymous substitutions does not result in a strong pattern of conservation in cross-sectional data but slows down the rate of evolution considerably. Our findings are consistent with the notion that large scale patterns of RNA structure are functionally relevant, whereas the precise base pairing pattern is not. PMID- 23986592 TI - A cholesterol recognition amino acid consensus domain in GP64 fusion protein facilitates anchoring of baculovirus to mammalian cells. AB - Baculoviridae is a large family of double-stranded DNA viruses that selectively infect insects. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is the best-studied baculovirus from the family. Many studies over the last several years have shown that AcMNPV can enter a wide variety of mammalian cells and deliver genetic material for foreign gene expression. While most animal viruses studied so far have developed sophisticated mechanisms to selectively infect specific cells and tissues in an organism, AcMNPV can penetrate and deliver foreign genes into most cells studied to this date. The details about the mechanisms of internalization have been partially described. In the present study, we have identified a cholesterol recognition amino acid consensus (CRAC) domain present in the AcMNPV envelope fusion protein GP64. We demonstrated the association of a CRAC domain with cholesterol, which is important to facilitate the anchoring of the virus at the mammalian cell membrane. Furthermore, this initial anchoring favors AcMNPV endocytosis via a dynamin- and clathrin-dependent mechanism. Under these conditions, efficient baculovirus-driven gene expression is obtained. In contrast, when cholesterol is reduced from the plasma membrane, AcMNPV enters the cell via a dynamin- and clathrin-independent mechanism. The result of using this alternative internalization pathway is a reduced level of baculovirus-driven gene expression. This study is the first to document the importance of a novel CRAC domain in GP64 and its role in modulating gene delivery in AcMNPV. PMID- 23986593 TI - Assessing activity and inhibition of Middle East respiratory syndrome coronavirus papain-like and 3C-like proteases using luciferase-based biosensors. AB - Middle East respiratory syndrome coronavirus (MERS-CoV) is associated with an outbreak of more than 90 cases of severe pneumonia with high mortality (greater than 50%). To date, there are no antiviral drugs or specific therapies to treat MERS-CoV. To rapidly identify potential inhibitors of MERS-CoV replication, we expressed the papain-like protease (PLpro) and the 3-chymotrypsin-like protease (3CLpro) from MERS-CoV and developed luciferase-based biosensors to monitor protease activity in cells. We show that the expressed MERS-CoV PLpro recognizes and processes the canonical CoV-PLpro cleavage site RLKGG in the biosensor. However, existing CoV PLpro inhibitors were unable to block MERS-CoV PLpro activity, likely due to the divergence of the amino acid sequence in the drug binding site. To investigate MERS-CoV 3CLpro activity, we expressed the protease in context with flanking nonstructural protein 4 (nsp4) and the amino-terminal portion of nsp6 and detected processing of the luciferase-based biosensors containing the canonical 3CLpro cleavage site VRLQS. Importantly, we found that a small-molecule inhibitor that blocks replication of severe acute respiratory syndrome (SARS) CoV and murine CoV also inhibits the activity of MERS-CoV 3CLpro. Overall, the protease expression and biosensor assays developed here allow for rapid evaluation of viral protease activity and the identification of protease inhibitors. These biosensor assays can now be used to screen for MERS-CoV specific or broad-spectrum coronavirus PLpro and 3CLpro inhibitors. PMID- 23986594 TI - Autocatalytic cleavage within classical swine fever virus NS3 leads to a functional separation of protease and helicase. AB - Classical swine fever virus (CSFV) is a positive-stranded RNA virus belonging to the genus Pestivirus within the Flaviviridae family. Pivotal for processing of a large portion of the viral polyprotein is a serine protease activity within nonstructural protein 3 (NS3) that also harbors helicase and NTPase activities essential for RNA replication. In CSFV-infected cells, NS3 appears as two forms, a fully processed NS3 of 80 kDa and the precursor molecule NS2-3 of 120 kDa. Here we report the identification and mapping of additional autocatalytic intramolecular cleavages. One cleavable peptide bond occurs between Leu1781 and Met1782, giving rise to a helicase subunit of 55 kDa and, depending on the substrate, a NS2-3 fragment of 78 kDa (NS2-3p) or a NS3 protease subunit of 26 kDa (NS3p). In trans-cleavage assays using NS4-5 as a substrate, NS3p acts as a fully functional protease that is able to process the polyprotein. NS3p comprises the minimal essential protease, as deletion of Leu1781 results in inactivation. A second intramolecular cleavage was mapped to the Leu1748/Lys1749 peptide bond that yields a proteolytically inactive NS3 fragment. Deletion of either of the cleavage site residues resulted in a loss of RNA infectivity, indicating the functional importance of amino acid identity at the respective positions. Our data suggest that internal cleavage within the NS3 moiety is a common process that further extends the functional repertoires of the multifunctional NS2-3 or NS3 and represents another level of the complex polyprotein processing of Flaviviridae. PMID- 23986596 TI - Foot-and-mouth disease virus 3C protease induces fragmentation of the Golgi compartment and blocks intra-Golgi transport. AB - Picornavirus infection can cause Golgi fragmentation and impose a block in the secretory pathway which reduces expression of major histocompatibility antigens at the plasma membrane and slows secretion of proinflammatory cytokines. In this study, we show that Golgi fragmentation and a block in secretion are induced by expression of foot-and-mouth disease virus (FMDV) 3C(pro) and that this requires the protease activity of 3C(pro). 3C(pro) caused fragmentation of early, medial, and late Golgi compartments, but the most marked effect was on early Golgi compartments, indicated by redistribution of ERGIC53 and membrin. Golgi fragments were dispersed in the cytoplasm and were able to receive a model membrane protein exported from the endoplasmic reticulum (ER). Golgi fragments were, however, unable to transfer the protein to the plasma membrane, indicating a block in intra-Golgi transport. Golgi fragmentation was coincident with a loss of microtubule organization resulting from an inhibition of microtubule regrowth from the centrosome. Inhibition of microtubule regrowth also required 3C(pro) protease activity. The loss of microtubule organization induced by 3C(pro) caused Golgi fragmentation, but loss of microtubule organization does not block intra Golgi transport. It is likely that the block of intra-Golgi transport is imposed by separate actions of 3C(pro), possibly through degradation of proteins required for intra-Golgi transport. PMID- 23986595 TI - A host YB-1 ribonucleoprotein complex is hijacked by hepatitis C virus for the control of NS3-dependent particle production. AB - Hepatitis C virus (HCV) orchestrates the different stages of its life cycle in time and space through the sequential participation of HCV proteins and cellular machineries; hence, these represent tractable molecular host targets for HCV elimination by combination therapies. We recently identified multifunctional Y box-binding protein 1 (YB-1 or YBX1) as an interacting partner of NS3/4A protein and HCV genomic RNA that negatively regulates the equilibrium between viral translation/replication and particle production. To identify novel host factors that regulate the production of infectious particles, we elucidated the YB-1 interactome in human hepatoma cells by a quantitative mass spectrometry approach. We identified 71 YB-1-associated proteins that included previously reported HCV regulators DDX3, heterogeneous nuclear RNP A1, and ILF2. Of the potential YB-1 interactors, 26 proteins significantly modulated HCV replication in a gene silencing screening. Following extensive interaction and functional validation, we identified three YB-1 partners, C1QBP, LARP-1, and IGF2BP2, that redistribute to the surface of core-containing lipid droplets in HCV JFH-1-expressing cells, similarly to YB-1 and DDX6. Importantly, knockdown of these proteins stimulated the release and/or egress of HCV particles without affecting virus assembly, suggesting a functional YB-1 protein complex that negatively regulates virus production. Furthermore, a JFH-1 strain with the NS3 Q221L mutation, which promotes virus production, was less sensitive to this negative regulation, suggesting that this HCV-specific YB-1 protein complex modulates an NS3-dependent step in virus production. Overall, our data support a model in which HCV hijacks host cell machinery containing numerous RNA-binding proteins to control the equilibrium between viral RNA replication and NS3-dependent late steps in particle production. PMID- 23986597 TI - Cytokine-dependent induction of CD4+ T cells with cytotoxic potential during influenza virus infection. AB - Recent evidence has identified the role of granzyme B- and perforin-expressing CD4(+) T cells with cytotoxic potential in antiviral immunity. However, the in vivo cytokine cues and downstream pathways governing the differentiation of these cells are unclear. Here, we have identified that CD4(+) T cells with cytotoxic potential are specifically induced at the site of infection during influenza virus infection. The development of CD4(+) T cells with cytotoxic potential in vivo was dependent on the cooperation of the STAT2-dependent type I interferon signaling and the interleukin-2/interleukin-2 receptor alpha pathway for the induction of the transcription factors T-bet and Blimp-1. We showed that Blimp-1 promoted the binding of T-bet to the promoters of cytolytic genes in CD4(+) T cells and was required for the cytolytic function of the in vitro- and in vivo generated CD4(+) T cells with cytotoxic potential. Thus, our data define the molecular basis of regulation of the in vivo development of this functionally cytotoxic Th subset during acute respiratory virus infection. The potential implications for the functions of these cells are discussed. PMID- 23986598 TI - Promyelocytic leukemia protein modulates establishment and maintenance of latent gammaherpesvirus infection in peritoneal cells. AB - Promyelocytic leukemia protein (PML) is an essential organizer of PML nuclear bodies (NBs), which carry out a variety of activities, including antiviral functions. Herpesviruses from all subfamilies encode proteins that counteract PML NB-mediated antiviral defenses by multiple mechanisms. However, because of the species specificity of herpesviruses, only a limited number of in vivo studies have been undertaken to investigate the effect of PML or PML NBs on herpesvirus infection. To address this central issue in herpesvirus biology, we studied the course of infection in wild-type and PML-/- mice using murine gammaherpesvirus 68 (MHV68), which encodes a tegument protein that induces PML degradation. While acute infection in PML-/- mice progressed similarly to that in wild-type mice, the lytic reactivation frequency was higher in peritoneal exudate cells, due to both an increase of MHV68 genome-positive cells and greater reactivation efficiency. We also detected a higher frequency of persistent infection in PML-/- peritoneal cells. These findings suggest that the PML protein can repress the establishment or maintenance of gammaherpesvirus latency in vivo. Further use of the PML-/- mouse model should aid in dissecting the molecular mechanisms that underlie the role of PML in gammaherpesvirus latency and may yield clues for how PML modulates herpesvirus latency in general. PMID- 23986599 TI - The kissing-loop T-shaped structure translational enhancer of Pea enation mosaic virus can bind simultaneously to ribosomes and a 5' proximal hairpin. AB - The Pea enation mosaic virus (PEMV) 3' translational enhancer, known as the kissing-loop T-shaped structure (kl-TSS), binds to 40S subunits, 60S subunits, and 80S ribosomes, whereas the Turnip crinkle virus (TCV) TSS binds only to 60S subunits and 80S ribosomes. Using electrophoretic mobility gel shift assay (EMSA) based competition assays, the kl-TSS was found to occupy a different site in the ribosome than the P-site-binding TCV TSS, suggesting that these two TSS employ different mechanisms for enhancing translation. The kl-TSS also engages in a stable, long-distance RNA-RNA kissing-loop interaction with a 12-bp 5'-coding region hairpin that does not alter the structure of the kl-TSS as revealed by molecular dynamics simulations. Addition of the kl-TSS in trans to a luciferase reporter construct containing either wild-type or mutant 5' and 3' PEMV sequences suppressed translation, suggesting that the kl-TSS is required in cis to function, and both ribosome-binding and RNA interaction activities of the kl-TSS contributed to translational inhibition. Addition of the kl-TSS was more detrimental for translation than an adjacent eIF4E-binding 3' translational enhancer known as the PTE, suggesting that the PTE may support the ribosome binding function of the kl-TSS. Results of in-line RNA structure probing, ribosome filter binding, and high-throughput selective 2'-hydroxyl acylation analyzed by primer extension (hSHAPE) of rRNAs within bound ribosomes suggest that kl-TSS binding to ribosomes and binding to the 5' hairpin are compatible activities. These results suggest a model whereby posttermination ribosomes/ribosomal subunits bind to the kl-TSS and are delivered to the 5' end of the genome via the associated RNA-RNA interaction, which enhances the rate of translation reinitiation. PMID- 23986600 TI - Role of interleukin-2 and herpes simplex virus 1 in central nervous system demyelination in mice. AB - We have reported previously that ocular infection of different strains of mice with recombinant herpes simplex virus 1 (HSV-1) constitutively expressing interleukin-2 (IL-2) provokes central nervous system (CNS) demyelination and optic neuropathy, as determined by changes in visual evoked cortical potentials and pathological changes in the optic nerve and CNS, whereas recombinant viruses expressing IL-4, gamma interferon, IL-12p35, IL-12p40, or IL-12p70 do not induce this neuropathy. The goal of this study was to dissect the mechanism underlying the interplay between the immune system (elevation of IL-2) and an environmental factor (infection with HSV-1) that elicits this pathology. Similar results were obtained upon delivery of IL-2 into the mouse brain using osmotic minipumps or injection of mice with recombinant IL-2 protein, IL-2 DNA, or IL-2 synthetic peptides prior to infection with wild-type (wt) HSV-1 strains McKrae and KOS. The critical role of IL-2 is further supported by our data, indicating that a single mutation at position T27A in IL-2 completely blocks the HSV-1-induced pathology. This study shows a novel model of autoimmunity in which viral infection and enhanced IL-2 cause CNS demyelination. PMID- 23986601 TI - Comparative analysis of the complete genome sequence of the California MSW strain of myxoma virus reveals potential host adaptations. AB - Myxomatosis is a rapidly lethal disease of European rabbits that is caused by myxoma virus (MYXV). The introduction of a South American strain of MYXV into the European rabbit population of Australia is the classic case of host-pathogen coevolution following cross-species transmission. The most virulent strains of MYXV for European rabbits are the Californian viruses, found in the Pacific states of the United States and the Baja Peninsula, Mexico. The natural host of Californian MYXV is the brush rabbit, Sylvilagus bachmani. We determined the complete sequence of the MSW strain of Californian MYXV and performed a comparative analysis with other MYXV genomes. The MSW genome is larger than that of the South American Lausanne (type) strain of MYXV due to an expansion of the terminal inverted repeats (TIRs) of the genome, with duplication of the M156R, M154L, M153R, M152R, and M151R genes and part of the M150R gene from the right hand (RH) end of the genome at the left-hand (LH) TIR. Despite the extreme virulence of MSW, no novel genes were identified; five genes were disrupted by multiple indels or mutations to the ATG start codon, including two genes, M008.1L/R and M152R, with major virulence functions in European rabbits, and a sixth gene, M000.5L/R, was absent. The loss of these gene functions suggests that S. bachmani is a relatively recent host for MYXV and that duplication of virulence genes in the TIRs, gene loss, or sequence variation in other genes can compensate for the loss of M008.1L/R and M152R in infections of European rabbits. PMID- 23986602 TI - TLR3- and MyD88-dependent signaling differentially influences the development of West Nile virus-specific B cell responses in mice following immunization with RepliVAX WN, a single-cycle flavivirus vaccine candidate. AB - Recognition of conserved pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs) results in the activation of innate signaling pathways that drive the innate immune response and ultimately shape the adaptive immune response. RepliVAX WN, a single-cycle flavivirus (SCFV) vaccine candidate derived from West Nile virus (WNV), is intrinsically adjuvanted with multiple PAMPs and induces a vigorous anti-WNV humoral response. However, the innate mechanisms that link pattern recognition and development of vigorous antigen-specific B cell responses are not completely understood. Moreover, the roles of individual PRR signaling pathways in shaping the B cell response to this live attenuated SCFV vaccine have not been established. We examined and compared the role of TLR3- and MyD88-dependent signaling in the development of anti-WNV specific antibody-secreting cell responses and memory B cell responses induced by RepliVAX WN. We found that MyD88 deficiency significantly diminished B cell responses by impairing B cell activation, development of germinal centers (GC), and the generation of long-lived plasma cells (LLPCs) and memory B cells (MBCs). In contrast, TLR3 deficiency had more effect on maintenance of GCs and development of LLPCs, whereas differentiation of MBCs was unaffected. Our data suggest that both TLR3- and MyD88-dependent signaling are involved in the intrinsic adjuvanting of RepliVAX WN and differentially contribute to the development of vigorous WNV-specific antibody and B cell memory responses following immunization with this novel SCFV vaccine. PMID- 23986603 TI - The current hepatitis C virus prevalence in China may have resulted mainly from an officially encouraged plasma campaign in the 1990s: a coalescence inference with genetic sequences. AB - In this study, we investigated hepatitis C virus (HCV) molecular epidemiology and evolutionary dynamics. Both E1 and NS5B sequences were characterized in 379 of 433 patients in southern China and classified into five major subtypes: 1b in 256 patients, 6a in 67 patients, 2a in 29 patients, 3a in 14 patients, and 3b in 13 patients. Using the E1 sequences obtained, along with those from other studies using samples from China, we inferred the HCV epidemic history by means of coalescence strategies. Five Bayesian skyline plots (BSPs) were estimated for the five subtypes. They concurrently highlighted the rapid growth in the HCV-infected population size from 1993 to 2000, followed by an abrupt slowing. Although flanked on both sides by variable population sizes, the plots showed distinct patterns of rapid HCV growth. Coincidently, 1993 to 2000 was a period when contaminated blood transfusions were common in China due to a procedural error in an officially encouraged plasma campaign. The abrupt slowing in 1998 to 2000 corresponded to the central government outlawing paid blood donations in 1998. Using a parametric model, the HCV population growth rates were estimated during 1993 to 2000. It was revealed that the 6a rate was the highest, followed by those of 1b, 2a, 3b, and 3a. Because these rates differed significantly (P < 1e-9) from each other, they may help explain why 6a is increasingly prevalent in southern China and 1b is predominant nationwide. These rates are approximately 10-fold higher than those reported elsewhere. These findings suggested that during the plasma campaign, certain barriers to efficient viral transmission were removed, allowing wide HCV dissemination. PMID- 23986604 TI - EBNA3C-mediated regulation of aurora kinase B contributes to Epstein-Barr virus induced B-cell proliferation through modulation of the activities of the retinoblastoma protein and apoptotic caspases. AB - Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that is implicated in several human malignancies, including Burkitt's lymphoma (BL), posttransplant lymphoproliferative disease (PTLD), nasopharyngeal carcinoma (NPC), and AIDS associated lymphomas. Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential EBV latent antigens, can induce mammalian cell cycle progression through its interaction with cell cycle regulators. Aurora kinase B (AK-B) is important for cell division, and deregulation of AK-B is associated with aneuploidy, incomplete mitotic exit, and cell death. Our present study shows that EBNA3C contributes to upregulation of AK-B transcript levels by enhancing the activity of its promoter. Further, EBNA3C also increased the stability of the AK B protein, and the presence of EBNA3C leads to reduced ubiquitination of AK-B. Importantly, EBNA3C in association with wild-type AK-B but not with its kinase dead mutant led to enhanced cell proliferation, and AK-B knockdown can induce nuclear blebbing and cell death. This phenomenon was rescued in the presence of EBNA3C. Knockdown of AK-B resulted in activation of caspase 3 and caspase 9, along with poly(ADP-ribose) polymerase 1 (PARP1) cleavage, which is known to be an important contributor to apoptotic signaling. Importantly, EBNA3C failed to stabilize the kinase-dead mutant of AK-B compared to wild-type AK-B, which suggests a role for the kinase domain in AK-B stabilization and downstream phosphorylation of the cell cycle regulator retinoblastoma protein (Rb). This study demonstrates the functional relevance of AK-B kinase activity in EBNA3C regulated B-cell proliferation and apoptosis. PMID- 23986606 TI - Throwing the baby out with the bathwater: a critique of Sparrow's inclusive definition of the term 'in vitro eugenics'. AB - Sparrow highlights three potential applications of in vitro eugenics, that is, (a) research into the heredity of genetic disorders, (b) production of cell lines with specific genotypes, and (c) breeding better babies, and points to the need for researchers to discuss in advance the potential ethical problems that may emerge if the realization of this technology occurs in the near future. In this commentary, we pose a question for the sake of discussion. Is it, in fact, appropriate to label all three applications raised by Sparrow as eugenics? By doing so, an unnecessary level of concern might be borne among the public, and as a result, the sound development of this specialized technology would be affected. If the label of eugenics is to be applied to all three of these applications, then Sparrow must justify how he perceives (a) and (b) as not inherently different from (c). PMID- 23986605 TI - Role of DNA methylation in expression and transmission of porcine endogenous retroviruses. AB - Porcine endogenous retroviruses (PERV) represent a major safety concern in pig-to human xenotransplantation. To date, no PERV infection of a xenograft recipient has been recorded; however, PERVs are transmissible to human cells in vitro. Some recombinants of the A and C PERV subgroups are particularly efficient in infection and replication in human cells. Transcription of PERVs has been described in most pig cells, but their sequence and insertion polymorphism in the pig genome impede identification of transcriptionally active or silenced proviral copies. Furthermore, little is known about the epigenetic regulation of PERV transcription. Here, we report on the transcriptional suppression of PERV by DNA methylation in vitro and describe heavy methylation in the majority of PERV 5' long terminal repeats (LTR) in porcine tissues. In contrast, we have detected sparsely methylated or nonmethylated proviruses in the porcine PK15 cells, which express human cell-tropic PERVs. We also demonstrate the resistance of PERV DNA methylation to inhibitors of methylation and deacetylation. Finally, we show that the high permissiveness of various human cell lines to PERV infection coincides with the inability to efficiently silence the PERV proviruses by 5'LTR methylation. In conclusion, we suggest that DNA methylation is involved in PERV regulation, and that only a minor fraction of proviruses are responsible for the PERV RNA expression and porcine cell infectivity. PMID- 23986607 TI - Some doubts about in vitro eugenics as a human enhancement technology. PMID- 23986610 TI - Presidential address. PMID- 23986609 TI - Creating writers for tomorrow: The initial steps. PMID- 23986608 TI - MDCT Imaging Findings of Liver Cirrhosis: Spectrum of Hepatic and Extrahepatic Abdominal Complications. AB - Hepatic cirrhosis is the clinical and pathologic result of a multifactorial chronic liver injury. It is well known that cirrhosis is the origin of multiple extrahepatic abdominal complications and a markedly increased risk of hepatocellular carcinoma (HCC). This tumor is the sixth most common malignancy worldwide and the third most common cause of cancer related death. With the rising incidence of HCC worldwide, awareness of the evolution of cirrhotic nodules into malignancy is critical for an early detection and treatment. Adequate imaging protocol selection with dynamic multiphase Multidetector Computed Tomography (MDCT) and reformatted images is crucial to differentiate and categorize the hepatic nodular dysplasia. Knowledge of the typical and less common extrahepatic abdominal manifestations is essential for accurately assessing patients with known or suspected hepatic disease. The objective of this paper is to illustrate the imaging spectrum of intra- and extrahepatic abdominal manifestations of hepatic cirrhosis seen on MDCT. PMID- 23986611 TI - Utility of mobile devices in the computerized tomography evaluation of intracranial hemorrhage. AB - AIM: To evaluate the utility of a mobile device to detect and assess intracranial hemorrhage (ICH) on head computed tomographys (CT) performed in the emergency setting. MATERIALS AND METHODS: 100 head CT scans were randomly selected from our emergency radiology database and anonymized for patient demographics and clinical history. The studies were independently interpreted by two experienced radiologists in a blinded manner, initially on a mobile device (iPad, Apple computers) and subsequently, at an interval of one week, on a regular desktop workstation. Evaluation was directed towards detection, localization and characterization of hemorrhage. The results were assessed for accuracy, sensitivity, specificity and positive predictive value. Statistical significance was ascertained using Fisher's exact test. RESULTS: 27 of the examinations were positive for ICH, of which 11 had multiple hemorrhages. Of these there were 17 subdural, 18 intraparenchymal, 8 subarachnoid, 4 intraventricular and 2 extradural hemorrhages. In 96 of the studies there was complete concurrence between the iPad and desktop interpretations for both radiologists. Of 49 hemorrhages, 48 were accurately detected on the iPad by one of the radiologists. In the remaining case, a tiny intraventricular hemorrhage was missed by both radiologists on the iPad as well as on the workstation, indicating that the miss was more likely related to the very small size of the hemorrhage than the viewer used. CONCLUSION: We conclude that in the emergency setting, a mobile device with appropriate web-based pictue archiving and communication system (PACS) is effective in the detection of intracranial hemorrhage present on head CT. PMID- 23986612 TI - Inadvertent chest tube insertion in congenital cystic adenomatoid malformation and congenital lobar emphysema-highlighting an important problem. AB - BACKGROUND: Chest tube insertion in congenital cystic lung lesions is an important problem in children with acute respiratory distress having a cystic lucent lesion on chest radiograph. OBJECTIVE: To evaluate the imaging findings and complications in cases of congenital cystic lung lesions with chest tube insertion and suggest the role of appropriate imaging for management of these patients. MATERIALS AND METHODS: Chest radiographs and CT scans of children with congenital cystic lung lesions who had inadvertent chest tube insertion preoperatively were retrospectively reviewed for imaging appearances and complications. RESULTS: Fifteen patients comprising 10 cases of congenital cystic adenomatoid malformation (CCAM) and 5 cases of congenital lobar emphysema (CLE) were included. Majority of the cases were infants. CCAM was misdiagnosed as complicated pneumatocele (n = 5) and pneumothorax (n = 5), while CLE was misdiagnosed as tension pneumothorax (n = 5) on the chest radiograph findings. Final diagnosis was made on CT and operative findings with histopathology. Complications noted were pneumothorax, hydropneumothorax, and infection in cases of CCAM, and change in imaging appearance and pneumothorax in cases of CLE. CONCLUSION: Chest tube insertion in congenital cystic lesions increases the rate of associated complications. Chest CT has a definite role in early diagnosis and deciding appropriate management in these cases. PMID- 23986613 TI - Dendriform pulmonary ossification: Report of two cases. AB - Dendriform pulmonary ossification is a rare form of diffuse pulmonary ossification that is usually detected incidentally on chest radiographs or chest computed tomography (CT) imaging. In this article, we present two patients who were incidentally found to have dendriform pulmonary ossification on chest imaging. The article will present the history and imaging findings of these two cases and then review the clinical, histological, and radiographic manifestations of dendriform pulmonary ossification. PMID- 23986614 TI - Role of quantitative pharmacokinetic parameter (transfer constant: K(trans)) in the characterization of breast lesions on MRI. AB - BACKGROUND: The semi-quantitative analysis of the time-intensity curves in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has a limited specificity due to overlapping enhancement patterns after gadolinium administration. With the advances in technology and faster sequences, imaging of the entire breast can be done in a few seconds, which allows measuring the transit of contrast (transfer constant: K(trans)) through the vascular bed at capillary level that reflects quantitative measure of porosity/permeability of tumor vessels. AIM: Our study aims to evaluate the pharmacokinetic parameter K(trans) for enhancing breast lesions and correlate it with histopathology, and assess accuracy, sensitivity, and specificity of this parameter in discriminating benign and malignant breast lesions. MATERIALS AND METHODS: One hundred and fifty one women with 216 histologically proved enhancing breast lesions underwent high temporal resolution DCE-MRI for the early dynamic analysis for calculation of pharmacokinetic parameters (K(trans)) using standard two compartment model. The calculated values of K(trans) were correlated with histopathology to calculate the sensitivity, specificity, and accuracy. RESULTS: Receiver operating characteristic (ROC) curve analysis revealed a mean K(trans) value of 0.56, which reliably distinguished benign and malignant breast lesions with a sensitivity of 91.1% and specificity of 90.3% with an overall accuracy of 89.3%. The area under curve (AUC) was 0.907. CONCLUSION: K(trans) is a reliable quantitative parameter for characterizing benign and malignant lesions in routine DCE-MRI of breasts. PMID- 23986615 TI - Multimodality imaging of carotid atherosclerotic plaque: Going beyond stenosis. AB - Apart from the degree of stenosis, the morphology of carotid atherosclerotic plaques and presence of neovascularization are important factors that may help to evaluate the risk and 'vulnerability' of plaques and may also influence the choice of treatment. In this article, we aim to describe the techniques and imaging findings on CTA, high resolution MRI and contrast enhanced ultrasound in the evaluation of carotid atherosclerotic plaques. We also discuss a few representative cases from our institute with the related clinical implications. PMID- 23986616 TI - Congenital duplication of mastoid segment of facial nerve: A rare case report. AB - Congenital duplication of facial nerve is a very rare anomaly commonly associated with inner and middle ear anomalies. There can be duplication of mastoid, tympanic, or labyrinthine segments. We describe duplication of mastoid segment of facial nerve in a young female who also showed middle ear anomalies and external auditory canal atresia. PMID- 23986617 TI - Comparing percutaneous primary and secondary biliary stenting for malignant biliary obstruction: A retrospective clinical analysis. AB - PURPOSE: Percutaneous transhepatic primary biliary stenting (PS) is an alternative to the widely used staged procedure (secondary biliary stenting, SS) for treating obstructive jaundice in cancer patients. To evaluate the efficacy and safety of PS and SS, a retrospective analysis was carried out. MATERIALS AND METHODS: The percutaneous biliary stenting procedures performed between January 2000 and December 2007 at one hepatobiliary center were retrospectively analyzed, comparing the technical success rates, complications, and length of hospitalization of the two procedures. Of 61 patients (mean age 65.5 +/- 13.1 years; range 31.1-92.7 years) suffering from obstructive jaundice caused by primary or metastatic tumors, 30 received PS and 31 received SS. The groups were comparable in the anatomical level of the obstruction, stent configuration, or the concurrent presence of cholangitis. Placement of metallic stents required one session for patients in the PS group and an average of 2.6 +/- 1.1 sessions for patients in the SS group. RESULTS: The overall technical success rate was 98.4% with 1 (1/61) failed approach to transcend the occlusion in the SS group. The rate of minor complications was 10% in the PS group and 6.5% in the SS group. The corresponding rates of major complications were 23.3% and 54.8%, respectively. SS patients had a higher rate of complications in general (P < 0.05), as well as a higher rate of severe complications in particular (P < 0.05). Procedural mortality was 0% for both the groups. The mean overall length of hospitalization was 7.7 +/- 9.6 days for PS and 20.6 +/- 19.6 days for SS (P < 0.001). CONCLUSION: Primary percutaneous biliary stenting of malignant biliary obstructions is as efficacious and safer than a staged procedure with secondary stenting. By virtue of requiring shorter hospital stays, primary stenting is likely to be more cost-effective. PMID- 23986618 TI - Tuberculosis of the genitourinary system-Urinary tract tuberculosis: Renal tuberculosis-Part I. AB - Tuberculosis (TB) remains a worldwide scourge and its incidence appears to be increasing due to various factors, such as the spread of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). The insidious onset and non-specific constitutional symptoms of genitourinary tuberculosis (GUTB) often lead to delayed diagnosis and rapid progression to a non-functioning kidney. Due to hematogenous dissemination of TB, there is a potential risk of involvement of the contralateral kidney too. Imaging plays an important role in the making of a timely diagnosis and in the planning of treatment, and thus helps to avoid complications such as renal failure. Imaging of GUTB still remains a challenge, mainly on account of the dearth of literature, especially related to the use of the newer modalities such as magnetic resonance imaging (MRI). This two-part article is a comprehensive review of the epidemiology, pathophysiology, and imaging findings in renal TB. Various imaging features of GUTB are outlined, from the pathognomonic lobar calcification on plain film, to finer early changes such as loss of calyceal sharpness and papillary necrosis on intravenous urography (IVU); to uneven caliectasis and urothelial thickening, in the absence of renal pelvic dilatation, as well as the hitherto unreported 'lobar caseation' on ultrasonography (USG). Well-known complications of GUTB such as sinus tracts, fistulae and amyloidosis are described, along with the relatively less well-known complications such as tuberculous interstitial nephritis (TIN), which may remain hidden because of its 'culture negative' nature and thus lead to renal failure. The second part of the article reviews the computed tomography (CT) and MRI features of GUTB and touches upon future imaging techniques along with imaging of TB in transplant recipients and in immunocompromised patients. PMID- 23986620 TI - Multiphasic contrast-enhanced CT and MRI findings of adult mesoblastic nephroma: A report of two cases. AB - Mesoblastic nephroma (MN) presenting in an adult is extremely rare. The computed tomography (CT) and magnetic resonance imaging (MRI) features of this tumor in adulthood have not been widely reported. We present two additional cases of adult MN and describe the multiphasic contrast-enhanced CT and MRI findings. PMID- 23986619 TI - Tuberculosis of the genitourinary system-Urinary tract tuberculosis: Renal tuberculosis-Part II. AB - This article reviews the computed tomography and magnetic resonance imaging (MRI) features of renal tuberculosis (TB), including TB in transplant recipients and immunocompromised patients. Multi detector computed tomography (MDCT) forms the mainstay of cross-sectional imaging in renal TB. It can easily identify calcification, renal scars, mass lesions, and urothelial thickening. The combination of uneven caliectasis, with urothelial thickening and lack of pelvic dilatation, can also be demonstrated on MDCT. MRI is a sensitive modality for demonstration of features of renal TB, including tissue edema, asymmetric perinephric fat stranding, and thickening of Gerota's fascia, all of which may be clues to focal pyelonephritis of tuberculous origin. Diffusion-weighted MR imaging with apparent diffusion coefficient (ADC) values may help in differentiating hydronephrosis from pyonephrosis. ADC values also have the potential to serve as a sensitive non-invasive biomarker of renal fibrosis. Immunocompromised patients are at increased risk of renal TB. In transplant patients, renal TB, including tuberculous interstitial nephritis, is an important cause of graft dysfunction. Renal TB in patients with HIV more often shows greater parenchymal affection, with poorly formed granulomas and relatively less frequent findings of caseation and stenosis. Atypical mycobacterial infections are also more common in immunocompromised patients. PMID- 23986621 TI - Appearances of the circumcaval ureter on excretory urography and MR urography: A single-center case series. AB - OBJECTIVES: To describe Magnetic Resonance Urography (MRU) appearances of the circumcaval ureter, a rare congenital cause of hydronephrosis. MATERIALS AND METHODS: Seven cases of circumcaval ureter, suspected on intravenous urography (IVU), underwent subsequent static MRU using heavily T2-weighted sequences. RESULTS: The various appearances of circumcaval ureter on IVU and MRU were studied and compared. The circumcaval portion of the ureter was especially well seen on axial MRU sections, though this portion was routinely not visualized on IVU. In one case with a ureteric calculus, MRU also depicted a circumcaval course of the ureter, thus providing a complete diagnosis. In yet another case, where a circumcaval ureter was suspected on IVU, MRU proved the actual cause of ureteric obstruction to be a crossing vessel. CONCLUSION: Static MRU using heavily T2 weighted coronal and axial sequences can make or exclude the diagnosis of circumcaval ureter unequivocally. PMID- 23986622 TI - MRI enterography with divided dose oral preparation: Effect on bowel distension and diagnostic quality. AB - AIM: To assess the impact of an extended oral preparation magnetic resonance (MR) enterography protocol on bowel distension, timing of imaging, and the quality of diagnostic images. MATERIALS AND METHODS: An analysis of 52 patients who underwent divided oral preparation and 39 patients who underwent standard preparation for MR enterography examination was done. Distension was assessed by measuring the transverse diameters of the jejunum, ileum, and the ileocecal region. Diagnostic quality of the examination was assessed subjectively by two radiologists and graded as poor, diagnostic, and excellent (Grades 1-3). Correlation between bowel diameter and diagnostic quality was assessed using regression analysis. RESULTS: The mean diameters of the jejunum, ileum, and colon in patients who underwent divided preparation were 1.90 +/- 0.47, 2.14 +/- 0.41, and 4.27 +/- 0.96 cm, respectively, and the mean diameters in patients who underwent standard preparation were 1.46 +/- 0.47, 2.02 +/- 0.47, and 4.45 +/- 0.90 cm, respectively. A total of 96.6% of patients on divided dose had diagnostic distension of the bowel (Grades 2 and 3). A total of 87.9% of the patients on standard dose had diagnostic distension of the bowel (Grades 2 and 3). A greater number of patients who underwent divided preparation had diagnostic quality examinations compared to those given standard preparation (96.6% vs. 87.9%). A greater number of patients who underwent divided preparation had Grade 3 quality examinations compared to those on standard preparation (75.5% vs. 68.5%). There was significant difference between diagnostic (Grades 2 and 3) and optimal grades (Grade 3) of the jejunal diameters in patients having divided or standard preparation (89.7% vs. 66.6%, P < 0.05; 40.8% vs. 25%, P < 0.05, respectively). Linear regression showed a positive correlation between increasing bowel diameter and diagnostic grade of the examination (rho = 0.76). CONCLUSION: Using an extended oral preparation with divided dose resulted in the majority of patients being scanned in a single visit to the MRI suite. Dividing the oral contrast into aliquots can promote uniform distension of the entire small bowel and provide better bowel distension and improve the diagnostic quality. PMID- 23986623 TI - Does conventional defecography has a role to play in evaluation of evacuatory disorders in Indian population? AB - Barium studies are one of the best investigations for evaluating submucosal and extrinsic mass lesions. However, barium studies bring less money, are operator dependent and one of the more difficult investigations for radiologists to master. Economic factors have acted as powerful disincentives for performing gastrointestinal (GI) fluoroscopy in most radiology practices. In this pictorial essay, we discuss the role of conventional defecography in evaluating evacuatory disorders in the Indian population. PMID- 23986624 TI - "Flow comp off": An easy technique to confirm CSF flow within syrinx and aqueduct. AB - Flow compensation, a gradient pulse used for artifact reduction, often used to suppress cerebrospinal fluid (CSF) flow artifacts in spinal magnetic resonance imaging (MRI), can be switched off to make the CSF flow voids within syrinx (syringomyelia) and within aqueduct [normal pressure hydrocephalus (NPH)] more obvious (thus confirming CSF flow). It is a simple method which does not require much time or expertise. PMID- 23986625 TI - A simplified staging system based on the radiological findings in different stages of ochronotic spondyloarthropathy. AB - This study describes a group of 26 patients with ochronotic spondyloarthropathy who were on regular treatment and follow-up at a tertiary level hospital and proposes a simplified staging system for ochronotic spondyloarthropathy based on radiographic findings seen in the thoracolumbar spine. This proposed classification makes it easy to identify the stage of the disease and start the appropriate management at an early stage. Four progressive stages are described: an inflammatory stage (stage 1), the stage of early discal calcification (stage 2), the stage of fibrous ankylosis (stage 3), and the stage of bony ankylosis (stage 4). To our knowledge, this is the largest reported series of radiological description of spinal ochronosis, and emphasizes the contribution of the spine radiograph in the diagnosis and staging of the disease. PMID- 23986626 TI - Coping in a calamity: Radiology during the cloudburst at Leh. AB - The service hospital at Leh is a multispeciality hospital situated at an altitude of 11000 feet above mean sea level. On the nights of 4 and 5 Aug 2010, Leh was struck by a cloudburst leading to mudslides and consequently extensive damage to life and property. Being the only functional hospital, over a period of about 48 hours, 331 casualties were received. 549 casualties were received over the week with 108 admissions, 16 major surgeries and 138 minor surgeries. 178 radiographs, 17 CT scans and 09 ultrasound-colour Doppler examinations were performed on an urgent basis over 48 hours apart from the routine radiological investigations. Apart from chronicling the event, we hope that sharing the unique experience of the Radiology Department in dealing with the large influx of patients would provide an insight into the role of Radiology during the disaster and help in planning and developing management protocols during other calamities. PMID- 23986627 TI - Medical negligence: A difficult challenge for radiology. PMID- 23986629 TI - Successful treatment of syphilitic uveitis in HIV-positive patients. AB - We report successful treatment of syphilitic uveitis in a case series of three Human immunodeficiency virus (HIV)-positive patients at Malaysia's Selayang Hospital eye clinic. All three patients with syphilitic uveitis were male, aged from 23 to 35 years old, with a history of high-risk behaviors. Of the patients, two presented with blurring of vision and only one patient presented with floaters in the affected eye. Ocular examination revealed intermediate uveitis (case 1 and case 3) and panuveitis (case 2). Each patient showed a high Venereal Disease Research Laboratory (VDRL) titer at presentation and they were also newly diagnosed as HIV positive with variable CD4 counts. All three patients responded well to a neurosyphilis regimen of intravenous penicillin G. At 3 months posttreatment, there was reduction in VDRL titer with improvement of vision in the affected eye. Diagnosis of syphilis needs to be ruled out in all cases of uveitis. All syphilitic uveitis cases should have HIV screening and vice versa, as syphilis is one of the most common infectious diseases associated with HIV positive patients. Early detection and treatment are important for a good visual outcome. PMID- 23986628 TI - Avidity of antibodies against HSV-2 and risk to neonatal transmission among Mexican pregnant women. AB - OBJECTIVE: To determine HSV-2 seroprevalence, risk factors, and antibody avidity among a sample of Mexican pregnant women. MATERIAL AND METHODS: The avidity test was standardized with different urea concentrations and incubation times; the cut off point was calculated to determine the low avidity (early infection). IgG antibodies against HSV-2 were detected from pregnant and postpartum women from Morelos, Mexico, and the avidity test was performed to positive samples. Multivariate regression logistic analysis was employed to evaluate demographic and sexual behavior characteristics associated with HSV-2 infection. RESULTS: HSV 2 seroprevalence among Mexican women analyzed was 14.5% (333/2300), demographic factors (location of General Hospital, age, education level, and civil status), and risky sexual behaviors (STI self-report and number of sexual partners during last year) were associated with HSV-2 infection. Seventeen women were detected with low avidity antibodies (early infection) with a cut-off point of 66.1%. CONCLUSIONS: HSV-2 infection was common among this group of women from Mexico; the avidity test detected women with recent infections, and these women were more likely to transmit HSV-2 to their neonates. Neonatal herpes has no epidemiological surveillance, the disease could be overlooked, and so more studies are needed to estimate the magnitude of neonatal infection. PMID- 23986630 TI - Wait time as a driver of overall patient satisfaction in an ophthalmology clinic. AB - PURPOSE: The purpose of this study was to determine whether the actual time patients spend waiting is correlated with overall patient satisfaction scores. METHODS: This was a cross-sectional survey study conducted in an outpatient ophthalmology clinic. The actual time each patient waited to be called by the provider was recorded, and a survey was given at the end of the visit. RESULTS: There was a significant correlation between the time patients spent waiting and overall patient satisfaction scores (P < 0.001). Patients who were not completely satisfied waited twice as long as those who were completely satisfied (P < 0.001), regardless of whether patients received free care. Satisfaction with the amount of time spent waiting was the strongest driver of overall satisfaction score. CONCLUSION: Minimizing the time patients spend waiting to see a provider can result in higher overall patient satisfaction scores, regardless of financial status. PMID- 23986631 TI - Adherence to antidepressant medications: an evaluation of community pharmacists' counseling practices. AB - BACKGROUND: Recent studies have shown that pharmacists have a role in addressing antidepressant nonadherence. However, few studies have explored community pharmacists' actual counseling practices in response to antidepressant adherence related issues at various phases of treatment. The purpose of this study was to evaluate counseling practices of community pharmacists in response to antidepressant adherence-related issues. METHODS: A simulated patient method was used to evaluate pharmacist counseling practices in Sydney, Australia. Twenty community pharmacists received three simulated patient visits concerning antidepressant adherence-related scenarios at different phases of treatment: 1) patient receiving a first-time antidepressant prescription and hesitant to begin treatment; 2) patient perceiving lack of treatment efficacy for antidepressant after starting treatment for 2 weeks; and 3) patient wanting to discontinue antidepressant treatment after 3 months due to perceived symptom improvement. The interactions were recorded and analyzed to evaluate the content of consultations in terms of information gathering, information provision including key educational messages, and treatment recommendations. RESULTS: There was variability among community pharmacists in terms of the extent and content of information gathered and provided. In scenario 1, while some key educational messages such as possible side effects and expected benefits from antidepressants were mentioned frequently, others such as the recommended length of treatment and adherence-related messages were rarely addressed. In all scenarios, about two thirds of pharmacists explored patients' concerns about antidepressant treatment. In scenarios 2 and 3, only half of all pharmacists' consultations involved questions to assess the patient's medication use. The pharmacists' main recommendation in response to the patient query was to refer the patient back to the prescribing physician. CONCLUSION: The majority of pharmacists provided information about the risks and benefits of antidepressant treatment. However, there remains scope for improvement in community pharmacists' counseling practice for patients on antidepressant treatment, particularly in providing key educational messages including adherence-related messages, exploring patients' concerns, and monitoring medication adherence. PMID- 23986632 TI - Rifampicin-resistant Mycobacterium leprae in an elderly leprosy patient in the people's Republic of China. AB - The reported number of registered leprosy patients worldwide declined with the introduction of multidrug therapy. However, the emergence of rifampicin resistance in leprosy patients engenders difficulties for an individual patient, and its dissemination could pose a threat to leprosy control. This study reports an elderly patient who was diagnosed with rifampicin-resistant lepromatous leprosy. This case indicates that inadequate treatment and poor compliance may eventually result in rifampicin resistance in Mycobacterium leprae and clinical relapse. PMID- 23986633 TI - The Rapid Assessment Interface and Discharge service and its implications for patients with dementia. AB - The rising prevalence of dementia will have an effect on acute care hospitals around the world. At present, around 40% of patients older than 70 years with acute medical admissions have dementia, but only half of these patients have been diagnosed. Patients with dementia have poorer health outcomes, longer hospital stays, and higher rates of readmissions and institutionalization. Worldwide, health care budgets are severely constrained. National Institute for Health and Care Excellence (NICE) has listed ten quality standards for supporting people in living well with dementia. NICE resource implications and commissioning support to implement these guidelines and improve dementia services have been recently published. Although most of the frail elderly patients with dementia are cared for by geriatricians, obstacles to making a diagnosis and to the management of dementia have been recognized. To provide a timely diagnosis of dementia, better care in acute hospital settings, and continuity of care in the community, services integrating all these elements are warranted. Extra resources also will be required for intermediate, palliative care, and mental health liaison services for people with dementia. The Birmingham Rapid Assessment Interface and Discharge service model uses a multiskilled team that provides comprehensive assessment of a person's physical and psychological well-being in a general hospital setting. It has been shown to be an effective model in terms of reducing both length of stay and avoiding readmission. The aim of this review is to discuss the implications of the Rapid Assessment Interface and Discharge model in people with dementia and to critically compare this model with similar published service provisions. PMID- 23986635 TI - Combined efficacy of biologically synthesized silver nanoparticles and different antibiotics against multidrug-resistant bacteria. AB - Biological synthesis of nanoparticles is a growing innovative approach that is relatively cheaper and more environmentally friendly than current physicochemical processes. Among various microorganisms, fungi have been found to be comparatively more efficient in the synthesis of nanomaterials. In this research work, extracellular mycosynthesis of silver nanoparticles (AgNPs) was probed by reacting the precursor salt of silver nitrate (AgNO3) with culture filtrate of Aspergillus flavus. Initially, the mycosynthesis was regularly monitored by ultraviolet-visible spectroscopy, which showed AgNP peaks of around 400-470 nm. X ray diffraction spectra revealed peaks of different intensities with respect to angle of diffractions (2theta) corresponding to varying configurations of AgNPs. Transmission electron micrographs further confirmed the formation of AgNPs in size ranging from 5-30 nm. Combined and individual antibacterial activities of the five conventional antibiotics and AgNPs were investigated against eight different multidrug-resistant bacterial species using the Kirby-Bauer disk diffusion method. The decreasing order of antibacterial activity (zone of inhibition in mm) of antibiotics, AgNPs, and their conjugates against bacterial group (average) was; ciprofloxacin + AgNPs (23) . imipenem + AgNPs (21) > gentamycin + AgNPs (19) > vancomycin + AgNPs (16) > AgNPs (15) . imipenem (14) > trimethoprim + AgNPs (14) > ciprofloxacin (13) > gentamycin (11) > vancomycin (4) > trimethoprim (0). Overall, the synergistic effect of antibiotics and nanoparticles resulted in a 0.2-7.0 (average, 2.8) fold-area increase in antibacterial activity, which clearly revealed that nanoparticles can be effectively used in combination with antibiotics in order to improve their efficacy against various pathogenic microbes. PMID- 23986634 TI - Highly deformable and highly fluid vesicles as potential drug delivery systems: theoretical and practical considerations. AB - Vesicles that are specifically designed to overcome the stratum corneum barrier in intact skin provide an efficient transdermal (systemic or local) drug delivery system. They can be classified into two main groups according to the mechanisms underlying their skin interaction. The first group comprises those possessing highly deformable bilayers, achieved by incorporating edge activators to the bilayers or by mixing with certain hydrophilic solutes. The vesicles of this group act as drug carriers that penetrate across hydrophilic pathways of the intact skin. The second group comprises those possessing highly fluid bilayers, owing to the presence of permeation enhancers. The vesicles of this group can act as carriers of drugs that permeate the skin after the barrier of the stratum corneum is altered because of synergistic action with the permeation enhancers contained in the vesicle structure. We have included a detailed overview of the different mechanisms of skin interaction and discussed the most promising preclinical applications of the last five years of Transfersomes(r) (IDEA AG, Munich, Germany), ethosomes, and invasomes as carriers of antitumoral and anti inflammatory drugs applied by the topical route. PMID- 23986636 TI - Dextran-b-poly(L-histidine) copolymer nanoparticles for ph-responsive drug delivery to tumor cells. AB - PURPOSE: Nanoparticles based on stimuli-sensitive drug delivery have been extensively investigated for tumor targeting. Among them, pH-responsive drug targeting using pH-sensitive polymers has attracted attention because solid tumors have an acidic environment. A dextran-b-poly(L-histidine) (DexPHS) copolymer was synthesized and pH-responsive nanoparticles were fabricated for drug targeting. METHODS AND RESULTS: A DexPHS block copolymer was synthesized by attaching the reductive end of dextran to the amine groups of poly(L-histidine). pH-responsive nanoparticles incorporating doxorubicin were fabricated and studied in HuCC-T1 cholangiocarcinoma cells. Synthesis of DexPHS was confirmed by 1H nuclear magnetic resonance spectroscopy, with specific peaks of dextran and PHS observed at 2-5 ppm and 7.4-9.0 ppm, respectively. DexPHS nanoparticles showed changes in particle size with pH sensitivity, ie, the size of the nanoparticles increased at an acidic pH and decreased at a basic pH. DexPHS block copolymer nanoparticles incorporating doxorubicin were prepared using the nanoprecipitation dialysis method. The doxorubicin release rate was increased at acidic pH compared with basic pH, indicating that DexPHS nanoparticles have pH-sensitive properties and that drug release can be controlled by variations in pH. The antitumor activity of DexPHS nanoparticles incorporating doxorubicin were studied using HuCC-T1 cholangiocarcinoma cells. Viability was decreased in cells treated with nanoparticles at acidic pH, whereas cell viability in response to treatment with doxorubicin did not vary according to changes of pH. CONCLUSION: Our results indicated that DexPHS polymeric micelles are promising candidates for antitumor drug targeting. PMID- 23986637 TI - Cellular uptake and imaging studies of glycosylated silica nanoprobe (GSN) in human colon adenocarcinoma (HT 29 cell line). AB - PURPOSE: In recent years, molecular imaging by magnetic resonance imaging (MRI) has gained prominence in the detection of tumor cells. The scope of this study is on molecular imaging and on the cellular uptake study of a glycosylated silica nanoprobe (GSN). METHODS: In this study, intracellular uptake (HT 29 cell line) of GSN was analyzed quantitatively and qualitatively with inductively coupled plasma atomic emission spectroscopy, flow cytometry, and fluorescent microscopy. In vitro and in vivo relaxometry of this nanoparticle was determined using a 3 Tesla MRI; biodistribution of GSN and Magnevist(r) were measured in different tissues. RESULTS: Results suggest that the cellular uptake of GSN was about 70%. The r1 relaxivity of this nanoparticle in the cells was measured to be 12.9 +/- 1.6 mM(-1) s(-1) and on a per lanthanide gadolinium (Gd(3+)) basis. Results also indicate an average cellular uptake of 0.7 +/- 0.009 pg Gd(3+) per cell. It should be noted that 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay demonstrated that the cells were effectively labeled without cytotoxicity, and that using MRI for quantitative estimation of delivery and uptake of targeted contrast agents and early detection of human colon cancer cells using targeted contrast agents, is feasible. CONCLUSION: These results showed that GSN provided a critical guideline in selecting these nanoparticles as an appropriate contrast agent for nanomedicine applications. PMID- 23986638 TI - Altered heart rate dynamics associated with antipsychotic-induced subjective restlessness in patients with schizophrenia. AB - BACKGROUND: Antipsychotic-induced subjective inner restlessness is one of the common and distressing adverse effects associated with antipsychotics; however, its underlying neurobiological basis is not well understood. We examined the relationship between antipsychotic-induced subjective inner restlessness and autonomic neurocardiac function. METHODS: Twenty-two schizophrenia patients with antipsychotic-induced subjective restlessness, 28 schizophrenia patients without antipsychotic-induced subjective restlessness, and 28 matched healthy control subjects were evaluated. Assessments of the linear and nonlinear complexity measures of heart rate dynamics were performed. Multivariate analysis of variance and correlation analysis were conducted. RESULTS: The mean interbeat (RR) interval value was significantly higher in control subjects than in patients with and without antipsychotic-induced subjective restlessness (P < 0.05). The low frequency/high frequency ratio was significantly higher in patients with antipsychotic-induced subjective restlessness than in control subjects and in patients without antipsychotic-induced subjective restlessness (P < 0.05), while the approximate entropy value was significantly lower in patients with antipsychotic-induced subjective restlessness than in control subjects and in patients without antipsychotic-induced subjective restlessness (P < 0.05). Correlation analyses controlling for psychotic symptom severity showed that the degree of antipsychotic-induced restlessness had a significant negative correlation with the value of approximate entropy (P < 0.05). CONCLUSION: The results indicate that antipsychotic-induced subjective restlessness is associated with altered heart rate dynamics parameters, particularly the nonlinear complexity measure, suggesting that it might adversely affect autonomic neurocardiac integrity. Further prospective research is necessary to elucidate the precise interrelationships and causality. PMID- 23986639 TI - A discriminated conditioned punishment model of phobia. AB - Traditionally, the signaled avoidance (SA) paradigm has been used in an attempt to better understand human phobia. Animal models of this type have been criticized for ineffectively representing phobia. The SA model characterizes phobia as an avoidance behavior by presenting environmental cues, which act as warning signals to an aversive stimulus (ie, shock). Discriminated conditioned punishment (DCP) is an alternative paradigm that characterizes phobia as a choice behavior in which fear serves to punish an otherwise adaptive behavior. The present study quantifies the differences between the paradigms and suggests that DCP offers an alternative paradigm for phobia. Rats trained on either SA or DCP were compared on a number of behavioral variables relevant to human phobia. Results indicate that rats in the DCP paradigm responded significantly earlier to warning signals and were more effective at preventing shocks than rats in the SA paradigm. Implications of this alternative paradigm are discussed. PMID- 23986640 TI - Potential therapeutic hazards due to drug-drug interaction between topically and systemically coadministered medications. PMID- 23986641 TI - Effect of transarterial chemoembolization with miriplatin plus epirubicin on local control of hepatocellular carcinoma: a retrospective comparison with miriplatin monotherapy. AB - OBJECTIVE: We aimed to evaluate local tumor control after transarterial chemoembolization (TACE) for hepatocellular carcinoma using miriplatin and low dose epirubicin combination therapy. METHODS: We retrospectively analyzed the records of patients who underwent TACE using miriplatin plus low-dose epirubicin (30 patients, 61 nodules, August 2011-March 2012) and control patients who underwent TACE using miriplatin alone (36 patients, 70 nodules, June 2010-July 2011). The local control rate was compared between the two groups using the Kaplan-Meier estimator and the log-rank test. Factors affecting local tumor recurrence were analyzed using multivariate logistic regression analysis. Treatment-related toxicity was evaluated using the Common Terminology Criteria for Adverse Events. RESULTS: The local control rates at 6 months and 1 year were 87% and 65% for the miriplatin plus low-dose epirubicin group, and 61% and 43% for the miriplatin group, respectively. Local tumor control rates were significantly better in the miriplatin plus low-dose epirubicin group than in the miriplatin group (P = 0.038). Multivariate analysis showed that the addition of epirubicin was an independent factor associated with better local tumor control (hazard ratio 0.2, P = 0.001). Overall incidence rates for adverse events were not significantly different between the two groups. CONCLUSION: Additional usage of low-dose epirubicin for TACE using miriplatin improved local tumor control of hepatocellular carcinoma with adverse effects comparable to those observed with TACE using miriplatin alone. PMID- 23986642 TI - Potential of ponatinib to treat chronic myeloid leukemia and acute lymphoblastic leukemia. AB - Development of BCR-ABL tyrosine kinase inhibitors (TKIs) have improved outcomes for patients diagnosed with chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia. However, resistance or intolerance to these TKIs still leaves some patients without many treatment options. One point mutation in particular, the T315I mutation, has been shown to be resistant to first and second generation TKIs. The third generation TKI, ponatinib, may provide an option for these patients. Ponatinib (Iclusig(r)), an orally available, pan-tyrosine kinase inhibitor has a unique binding mechanism allowing inhibition of BCR-ABL kinases, including those with the T315I point mutation. A Phase II study evaluated ponatinib in patients who were resistant or intolerant to nilotinib or dasatinib or patients who had the T315I mutation. In the Phase II study, ponatinib produced a major cytogenetic response in 54% of chronic phase chronic myeloid leukemia patients. It further achieved major hematologic response in 52% of patients in the accelerated phase, 31% of patients in the blast phase, and 41% of Philadelphia chromosome positive acute lymphoblastic leukemia patients. Ponatinib also showed efficacy in patients with the T315I mutation. Serious adverse events included arterial thrombosis, hepatotoxicity, cardiovascular risks, pancreatitis, hemorrhage, fluid retention, myelosuppression, rash, abdominal pain, and embryo-fetal toxicity. Due to the risk of these adverse events and potential drug interactions, the use of ponatinib must be carefully weighed against the benefits in treating patients who have limited treatment options. PMID- 23986643 TI - Influence of the oncolytic parvovirus H-1, CTLA-4 antibody tremelimumab and cytostatic drugs on the human immune system in a human in vitro model of colorectal cancer cells. AB - INTRODUCTION: Tumor-directed and immune-system-stimulating therapies are of special interest in cancer treatment. Here, we demonstrate the potential of parvovirus H-1 (H-1PV) to efficiently kill colorectal cancer cells and induce immunogenicity of colorectal tumors by inducing maturation of dendritic cells (DCs) alone and also in combination with cytostatic drugs in vitro. Using our cell culture model, we have additionally investigated the effects of anti-CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) receptor antibody tremelimumab on this process. MATERIALS AND METHODS: Colon carcinoma cell lines were treated with different concentrations of cytostatic drugs or tremelimumab or were infected with H-1PV in different multiplicities of infection (MOIs), and viability was determined using MTT assays. Expression of CTLA-4 in colon carcinoma cell lines was measured by FACScanTM. For the coculture model, we isolated monocytes using adherence, and differentiation into immature DCs (iDCs) was stimulated using interleukin-4 and granulocyte-macrophage colony-stimulating factor. Maturation of iDCs into mature DCs (mDCs) was induced by a cytokine cocktail. SW480 colon carcinoma cells were infected with H-1PV or treated with cytostatic drugs. Drug treated and H-1PV-infected SW480 colon carcinoma cells were cocultured with iDCs and expression of maturation markers was measured using FACScanTM. Cytokine measurements were performed using enzyme-linked immunosorbent assay. RESULTS: Colon carcinoma cells SW480 were potently infected and killed by H-1PV. CTLA-4 expression in SW480 cells increased after infection with H-1PV and also after treatment with cytostatic drugs. Tremelimumab had no influence on viability of the colon carcinoma cell line. There was no maturation of iDCs after coculture with SW480; instead, H-1PV-infected or drug pretreated SW480 induced maturation. Cytokine production was higher for H-1PV-infected cells but was not significantly enhanced by tremelimumab treatment alone or in combination. Addition of tremelimumab did not interfere with the maturation process as measured by markers of maturation as well as by determination of cytokine levels. CONCLUSION: By enhancing both cell death and immunogenicity of tumors, H-1PV is of special interest for tumor-directed therapy. These features make it a promising candidate for clinical application in human colorectal cancer. As tremelimumab does not significantly interfere with this process, an interesting therapeutic combination of active enhancement of tumor immunogenicity and independent masking of the CTLA 4 silencing process on tumor cells is highlighted. PMID- 23986645 TI - Proton pump inhibitors and hypomagnesemia monitoring. PMID- 23986644 TI - Combined upregulation of matrix metalloproteinase-1 and proteinase-activated receptor-1 predicts unfavorable prognosis in human nasopharyngeal carcinoma. AB - BACKGROUND: The upregulation of matrix metalloproteinase-1 (MMP-1) has been demonstrated to be correlated with lymph node metastasis of nasopharyngeal carcinoma (NPC), while the activation of protease-activated receptor-1 (PAR-1) mediates proliferation and invasion of NPC cells. The present study investigated the clinical significance of the coexpression of MMP-1 and PAR-1 in NPC patients in determining the prognosis. METHODS: Immunohistochemistry was performed to detect the expression of MMP-1 and PAR-1 in tumor tissue samples from 266 NPC patients. RESULTS: Overexpression of MMP-1 and PAR-1 proteins were, respectively, detected in 190 (71.43%) and 182 (68.42%) of the 266 NPC patients. In addition, the combined MMP-1 and PAR-1 expression was significantly associated with advanced T-stage (P = 0.01), advanced clinical stage (P = 0.002), positive recurrence (P = 0.01), and metastatic status (P = 0.01) of NPC. Moreover, the overall survival in NPC patients with MMP-1 and PAR-1 dual overexpression was significantly shorter than in those with dual low expression (P < 0.001). Furthermore, the multivariate analyses indicated that the combined MMP-1 and PAR 1 overexpression was an independent prognostic factor for overall survival (P = 0.001) in NPC patients, but the upregulation of MMP-1 and PAR-1 alone was, in each case, not an independent prognostic factor for this disease. CONCLUSION: Our data provide convincing evidence, for the first time, that the activation of the MMP-1 and PAR-1 axis may be involved in the tumorigenesis and progression of NPC. The upregulation of MMP-1 in combination with PAR-1 overexpression is an unfavorable prognostic marker for NPC and might offer the possibility of future therapeutic targets. PMID- 23986646 TI - Impact and indication of early systemic corticosteroids for very severe community acquired pneumonia. AB - BACKGROUND: The efficacy of systemic corticosteroids in community-acquired pneumonia (CAP) has not yet been confirmed. We prospectively investigated the clinical features of patients treated with early adjunctive systemic corticosteroids and its clinical impact in very severe CAP. METHODS: One hundred and one consecutive CAP patients having a pneumonia severity index of >130 points were enrolled from August 2010 through February 2013. Early adjunctive systemic corticosteroids were defined as administration of systemic corticosteroids equivalent to prednisone of >=20 mg/day added to initial antibiotics. The multivariate analysis was performed to evaluate the independent factors associated with mortality. RESULTS: Thirty-two patients (31.7%) died within 28 days of admission. Early adjunctive systemic corticosteroids were administered in 30 patients (29.7%), who more frequently had alteration of mental status, serious respiratory failure, or underlying lung diseases and received fluoroquinolones as initial antibiotics. In most patients treated with early adjunctive systemic corticosteroids, the dosage was less than 60 mg/day of an equivalent to prednisone by bolus intravenous infusion for a period shorter than 8 days. The occurrence of adverse events did not differ between the groups. Factors independently associated with mortality were blood urea nitrogen (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.00-1.04), serum albumin (HR 0.44, 95% CI 0.22-0.86), a requirement for intensive care (HR 4.93, 95% CI 1.75-13.87), and the therapy with early adjunctive systemic corticosteroids (HR 0.29, 95% CI 0.11 0.81). CONCLUSION: Early adjunctive systemic corticosteroids may have an effect to reduce the mortality in very severe CAP, although a larger-scale study is necessary. PMID- 23986647 TI - Finisher and performance trends in female and male mountain ultramarathoners by age group. AB - BACKGROUND: This study examined changes according to age group in the number of finishers and running times for athletes in female and male mountain ultramarathoners competing in the 78 km Swiss Alpine Marathon, the largest mountain ultramarathon in Europe and held in high alpine terrain. METHODS: The association between age and performance was investigated using analysis of variance and both single and multilevel regression analyses. RESULTS: Between 1998 and 2011, a total of 1,781 women and 12,198 men finished the Swiss Alpine Marathon. The number of female finishers increased (r(2) = 0.64, P = 0.001), whereas the number of male finishers (r(2) = 0.18, P = 0.15) showed no change. The annual top ten men became older and slower, whereas the annual top ten women became older but not slower. Regarding the number of finishers in the age groups, the number of female finishers decreased in the age group 18-24 years, whereas the number of finishers increased in the age groups 30-34, 40-44, 45-49, 50-54, 55-59, 60-64, and 70-74 years. In the age groups 25-29 and 35-39 years, the number of finishers showed no changes across the years. In the age group 70-74 years, the increase in number of finishers was linear. For all other age groups, the increase was exponential. For men, the number of finishers decreased in the age groups 18-24, 25-29, 30-34, and 35-39 years. In the age groups 40-44, 45-49, 50-54, 55-59, 60-64, 70-74, and 75-79 years, the number of finishers increased. In the age group 40-44 years, the increase was linear. For all other age groups, the increase was exponential. Female finishers in the age group 40-44 years became faster over time. For men, finishers in the age groups 18-24, 25-29, 30 34, 40-44, and 45-49 years became slower. CONCLUSION: The number of women older than 30 years and men older than 40 years increased in the Swiss Alpine Marathon. Performance improved in women aged 40-44 years but decreased in male runners aged 18-49 years. PMID- 23986648 TI - Cigarette smoking among female students in five medical and nonmedical colleges. AB - OBJECTIVES: This study was conducted to determine the prevalence of smoking, knowledge about the ill effects of smoking on health, and the influence of family members' smoking habits among Saudi female students. METHODS: This is a type of cross-sectional study. A sample of 1,070 female students was selected by a nonrandom and convenient sampling method from five colleges (Medicine, Business and Administration, Computer Sciences, Education, and Languages and Translation) of King Saud University, Riyadh, Saudi Arabia. A self-administrated questionnaire was used to determine the personal, social, and educational characteristics of the respondents. In addition, questions about their smoking types, status, duration of smoking, knowledge about the ill effects of smoking, daily cigarette consumption, and reasons for quitting smoking were included. RESULTS: The students' response rate was 85%. The prevalence of current smoking was 4.3% and 5.6% for cigarettes and water-pipes, respectively, whereas 3.9% of the participants were ex-smokers. The prevalence of current smoking was highest in the College of Business and Administration (10.81%) and lowest in the College of Medicine (0.86%). The majority (77%) of the smokers' parents (current and ex smokers) were also smokers. More than half (54%) of the smokers started their smoking habit for entertainment, and 44.4% of the participants did not know that smoking causes serious health problems. The most common factors for quitting smoking were health concerns (54%), religious beliefs (29%), and parent's advice (17%). CONCLUSION: The study concludes that the prevalence of smoking varies in different subject streams and that family and friends have a great influence on individuals starting or stopping smoking. Extensive health education programs are needed to educate young women on the health hazards of smoking and help stop them from smoking. PMID- 23986649 TI - Prevalence of hypertension and its risk factors in southwest Ethiopia: a hospital based cross-sectional survey. AB - BACKGROUND: Hypertension is a common medical condition worldwide. It is an important public health challenge because of the associated morbidity, mortality, and the cost to the society. The objective of this study was to determine the prevalence of hypertension and its risk factors among attendants of adult outpatient departments at Jimma University Specialized Hospital in southwest Ethiopia. MATERIALS AND METHODS: A hospital-based cross-sectional study was conducted on 734 participants aged 15 years or older from May 2012 to June 2012. A pretested structured questionnaire consisting of characteristics related to sociodemographic profiles and risk factors for hypertension was used for data collection. Three separate measurements of blood pressure and relevant anthropometric evaluation were taken according to current recommended standards. Chi-square test and other statistical analyses were done to employ appropriate interpretations of the findings. P-values of <0.05 were considered statistically significant. RESULTS: The mean age of the participants was 42.3 +/- 13.2 years and 71.7% of them were 35 years and older; 58% of them were females. Overall prevalence of hypertension - defined by systolic blood pressure >=140 and/or diastolic blood pressure >=90 or reporting history of hypertension - was found to be 13.2%. Only 35.1% of them were aware of their hypertension and only 23.7% were on treatment. The overall control rate was 15.5%. Family history of hypertension, having diabetes mellitus, being overweight, and oral contraceptive use were associated with high blood pressure. CONCLUSION: Hypertension was found to be prevalent; morbidity, awareness, treatment, and control in those with hypertension were low. Hence, intervention measures should be undertaken at the community level; particular emphasis should be placed on prevention by introducing lifestyle modifications and creating awareness about the problem so that early detection and intervention is possible. PMID- 23986651 TI - Reasons for and patterns relating to the extraction of permanent teeth in a subset of the Saudi population. AB - BACKGROUND: The purpose of this study was to investigate the reasons for and patterns of extraction of permanent teeth in a subset of the Saudi population. METHODS: During a 3-month period, dentists were asked to record, using a specially designed survey form, the reasons for every extraction of a permanent tooth. The reasons for tooth extraction were assigned to different causes, ie, dental caries, periodontal disease, eruption problems, trauma, orthodontics, failed root canal treatment, and others. The data requested for each extraction were: patient age, gender, nationality, and type of tooth removed and the reason for its extraction. RESULTS: The highest percentage of extractions was observed in young females aged 10-30 years. Presence of caries was observed to be the main reason for extraction (50.2%) followed by orthodontic problems (18.2%), eruption problems (17.5%), and periodontal problems (8.2%). The most frequently extracted posterior teeth were the third mandibular molar (19.4%), the third maxillary molar (16.4%), the first maxillary premolar (13.2%), and the first mandibular molar (10.9%). CONCLUSION: Dental caries was found to be the most common reason for extraction of teeth. Molar teeth were found to be the most frequently extracted, with an increased number of extracted first premolars as a result of orthodontic treatment. The highest percentage of extractions was observed in young females aged 10-30 years. PMID- 23986650 TI - The role of epithelial-mesenchymal transition programming in invasion and metastasis: a clinical perspective. AB - Epithelial-mesenchymal transition (EMT) is involved in normal developmental cellular processes, but it may also be co-opted by a subset of cancer cells, to enable them to invade and form metastases at distant sites. Several gene transcription factors regulate EMT, including Snail1, Snail2, Zeb1, Zeb2, and Twist; ongoing studies continue to identify and elucidate other drivers. Specific micro ribonucleic acids (RNAs) have also been found to regulate EMT, including the microRNA-200 (miR-200) family, which targets Zeb1/Zeb2. Cancer "stem cells" - with the ability to self-renew and to regenerate all the cell types within the tumor - have been found to express EMT markers, further implicating both cancer stem cells and EMT with metastasis. Microenvironmental cues, including transforming growth factor-beta, can direct EMT tumor metastasis, such as by regulating miR-200 expression. In human tumors, EMT markers and regulators may be expressed in a subset of tumor cells, such as in cells at the invasive front or tumor-microenvironment interface, though certain subtypes of cancer can show widespread mesenchymal-like features. In terms of therapeutic targeting of EMT in patients, potential areas of exploration could include targeting the cancer stem cell subpopulation, as well as microRNA-based therapeutics that reintroduce miR 200. This review will examine evidence for a role of EMT in invasion and metastasis, with the focus being on studies in lung and breast cancers. We also carry out analyses of publicly-available gene expression profiling datasets in order to show how EMT-associated genes appear coordinately expressed across human tumor specimens. PMID- 23986652 TI - Access to antiretroviral therapy among HIV/AIDS patients in Chiang Mai province, Thailand. AB - The objective of this study is to investigate the access to antiretroviral treatment among human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients in Chiang Mai province, Thailand. Access to antiretroviral treatment is defined in terms of availability, affordability, and acceptability. The data for the study were collected during the period of April 1, 2012-May 31, 2012 from a sample of 380 HIV/AIDS patients in eight hospitals who had received antiretroviral treatment for more than 6 months at the time of data collection. The results of the study show that for most patients, the average traveling time to access health care was acceptable, but the nearly half day waiting time caused them to be absent from their work. In particular, it took longer for patients in the rural and lower income groups to access the treatment than the other groups. Their travel times and food costs relating to the treatment were found to be relatively high and therefore these patients had a higher tendency to borrow or seek financial assistance from their relatives. However, due to improvements in the access to treatment, most patients were satisfied with the services they received. The results imply that policy should be implemented to raise the potential of subdistrict hospitals where access to antiretroviral treatment is available, with participating HIV/AIDS patients acting as volunteers in providing services and other forms of health promotion to new patients. Privacy issues could be reduced if the antiretroviral treatment was isolated from other health services. Additionally, efforts to educate HIV/AIDS patients and society at large should be made. PMID- 23986653 TI - Computational analysis of LDDMM for brain mapping. AB - One goal of computational anatomy (CA) is to develop tools to accurately segment brain structures in healthy and diseased subjects. In this paper, we examine the performance and complexity of such segmentation in the framework of the large deformation diffeomorphic metric mapping (LDDMM) registration method with reference to atlases and parameters. First we report the application of a multi atlas segmentation approach to define basal ganglia structures in healthy and diseased kids' brains. The segmentation accuracy of the multi-atlas approach is compared with the single atlas LDDMM implementation and two state-of-the-art segmentation algorithms-Freesurfer and FSL-by computing the overlap errors between automatic and manual segmentations of the six basal ganglia nuclei in healthy subjects as well as subjects with diseases including ADHD and Autism. The high accuracy of multi-atlas segmentation is obtained at the cost of increasing the computational complexity because of the calculations necessary between the atlases and a subject. Second, we examine the effect of parameters on total LDDMM computation time and segmentation accuracy for basal ganglia structures. Single atlas LDDMM method is used to automatically segment the structures in a population of 16 subjects using different sets of parameters. The results show that a cascade approach and using fewer time steps can reduce computational complexity as much as five times while maintaining reliable segmentations. PMID- 23986654 TI - Spatial ICA reveals functional activity hidden from traditional fMRI GLM-based analyses. PMID- 23986655 TI - Differential regulation of proliferation and neuronal differentiation in adult rat spinal cord neural stem/progenitors by ERK1/2, Akt, and PLCgamma. AB - Proliferation of endogenous neural stem/progenitor cells (NSPCs) has been identified in both normal and injured adult mammalian spinal cord. Yet the signaling mechanisms underlying the regulation of adult spinal cord NSPCs proliferation and commitment toward a neuronal lineage remain undefined. In this study, the role of three growth factor-mediated signaling pathways in proliferation and neuronal differentiation was examined. Adult spinal cord NSPCs were enriched in the presence of fibroblast growth factor 2 (FGF2). We observed an increase in the number of cells expressing the microtubule-associated protein 2 (MAP2) over time, indicating neuronal differentiation in the culture. Inhibition of the mitogen-activated protein kinase or extracellular signal regulated kinase (ERK) kinase 1 and 2/ERK 1 and 2 (MEK/ERK1/2) or the phosphoinositide 3-kinase (PI3K)/Akt pathways suppressed active proliferation in adult spinal cord NSPC cultures; whereas neuronal differentiation was negatively affected only when the ERK1/2 pathway was inhibited. Inhibition of the phospholipase Cgamma (PLCgamma) pathway did not affect proliferation or neuronal differentiation. Finally, we demonstrated that the blockade of either the ERK1/2 or PLCgamma signaling pathways reduced neurite branching of MAP2+ cells derived from the NSPC cultures. Many of the MAP2+ cells expressed synaptophysin and had a glutamatergic phenotype, indicating that over time adult spinal cord NSPCs had differentiated into mostly glutamatergic neurons. Our work provides new information regarding the contribution of these pathways to the proliferation and neuronal differentiation of NSPCs derived from adult spinal cord cultures, and emphasizes that the contribution of these pathways is dependent on the origin of the NSPCs. PMID- 23986656 TI - Hippocampal Lipocalin 2: an emotional link between neurons and glia. PMID- 23986657 TI - Variability in micro RNA (miRNA) abundance, speciation and complexity amongst different human populations and potential relevance to Alzheimer's disease (AD). PMID- 23986658 TI - The interplay of microRNA and neuronal activity in health and disease. AB - MicroRNAs (miRNAs) are small 19-23 nucleotide regulatory RNAs that function by modulating mRNA translation and/or turnover in a sequence-specific fashion. In the nervous system, miRNAs regulate the production of numerous proteins involved in synaptic transmission. In turn, neuronal activity can regulate the production and turnover of miRNA through a variety of mechanisms. In this way, miRNAs and neuronal activity are in a reciprocal homeostatic relationship that balances neuronal function. The miRNA function is critical in pathological states related to overexcitation such as epilepsy and stroke, suggesting miRNA's potential as a therapeutic target. We review the current literature relating the interplay of miRNA and neuronal activity and provide future directions for defining miRNA's role in disease. PMID- 23986659 TI - Pluripotent stem cells as a model to study non-coding RNAs function in human neurogenesis. AB - As fine regulators of gene expression, non-coding RNAs, and more particularly micro-RNAs (miRNAs), have emerged as key players in the development of the nervous system. In vivo experiments manipulating miRNAs expression as neurogenesis proceeds are very challenging in the mammalian embryo and totally impossible in the human. Human pluripotent stem cells (hPSCs), from embryonic origin (hESCs) or induced from adult somatic cells (iPSCs), represent an opportunity to study the role of miRNAs in the earliest steps of human neurogenesis in both physiological and pathological contexts. Robust protocols are now available to convert pluripotent stem cells into several sub-types of fully functional neurons, recapitulating key developmental milestones along differentiation. This provides a convenient cellular system for dissecting the role of miRNAs in phenotypic transitions critical to brain development and plasticity that may be impaired in neurological diseases with onset during development. The aim of this review is to illustrate how hPSCs can be used to recapitulate early steps of human neurogenesis and summarize recent reports of their contribution to the study of the role of miRNA in regulating development of the nervous system. PMID- 23986660 TI - Universal organization of resting brain activity at the thermodynamic critical point. AB - Thermodynamic criticality describes emergent phenomena in a wide variety of complex systems. In the mammalian cortex, one type of complex dynamics that spontaneously emerges from neuronal interactions has been characterized as neuronal avalanches. Several aspects of neuronal avalanches such as their size and life time distributions are described by power laws with unique exponents, indicating an underlying critical branching process that governs avalanche formation. Here, we show that neuronal avalanches also reflect an organization of brain dynamics close to a thermodynamic critical point. We recorded spontaneous cortical activity in monkeys and humans at rest using high-density intracranial microelectrode arrays and magnetoencephalography, respectively. By numerically changing a control parameter equivalent to thermodynamic temperature, we observed typical critical behavior in cortical activities near the actual physiological condition, including the phase transition of an order parameter, as well as the divergence of susceptibility and specific heat. Finite-size scaling of these quantities allowed us to derive robust critical exponents highly consistent across monkey and humans that uncover a distinct, yet universal organization of brain dynamics. Our results demonstrate that normal brain dynamics at rest resides near or at criticality, which maximizes several aspects of information processing such as input sensitivity and dynamic range. PMID- 23986661 TI - Toward a pluri-component, multimodal, and dynamic organization of the ventral semantic stream in humans: lessons from stimulation mapping in awake patients. PMID- 23986664 TI - Hyperleptinemia is associated with parameters of low-grade systemic inflammation and metabolic dysfunction in obese human beings. AB - Leptin is an adipose tissue-derived hormone that has been involved in hypothalamic and systemic inflammation, altered food-intake patterns, and metabolic dysfunction in obese mice. However, it remains unclear whether leptin has a relationship with parameters of systemic inflammation and metabolic dysfunction in humans. We thus evaluated in a cross-sectional study the circulating levels of leptin in 40 non-obese and 41 obese Mexican individuals, examining their relationship with tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 12, IL-10, central obesity, serum glucose and insulin levels, and serum triglyceride and cholesterol concentrations. Circulating levels of leptin, TNF-alpha, IL-12, IL-10, and insulin were measured by ELISA, while concentrations of glucose, triglyceride, and cholesterol were determined by enzymatic assays. As expected, serum levels of leptin exhibited a significant elevation in obese individuals as compared to non-obese subjects, showing a clear association with increased body mass index (r = 0.4173), central obesity (r = 0.4678), and body fat percentage (r = 0.3583). Furthermore, leptin also showed a strong relationship with serum TNF-alpha (r = 0.6989), IL-12 (r = 0.3093), and IL 10 (r = -0.5691). Interestingly, leptin was also significantly related with high concentrations of fasting glucose (r = 0.5227) and insulin (r = 0.2229), as well as elevated levels of insulin resistance (r = 0.3611) and circulating triglyceride (r = 0.4135). These results suggest that hyperleptinemia is strongly associated with the occurrence of low-grade systemic inflammation and metabolic alteration in obese subjects. Further clinical research is still needed to determine whether hyperleptinemia may be a potential marker for recognizing the advent of obesity-related metabolic disorders in human beings. PMID- 23986662 TI - The role of the dorsal raphe nucleus in reward-seeking behavior. AB - Pharmacological experiments have shown that the modulation of brain serotonin levels has a strong impact on value-based decision making. Anatomical and physiological evidence also revealed that the dorsal raphe nucleus (DRN), a major source of serotonin, and the dopamine system receive common inputs from brain regions associated with appetitive and aversive information processing. The serotonin and dopamine systems also have reciprocal functional influences on each other. However, the specific mechanism by which serotonin affects value-based decision making is not clear. To understand the information carried by the DRN for reward-seeking behavior, we measured single neuron activity in the primate DRN during the performance of saccade tasks to obtain different amounts of a reward. We found that DRN neuronal activity was characterized by tonic modulation that was altered by the expected and received reward value. Consistent reward dependent modulation across different task periods suggested that DRN activity kept track of the reward value throughout a trial. The DRN was also characterized by modulation of its activity in the opposite direction by different neuronal subgroups, one firing strongly for the prediction and receipt of large rewards, with the other firing strongly for small rewards. Conversely, putative dopamine neurons showed positive phasic responses to reward-indicating cues and the receipt of an unexpected reward amount, which supports the reward prediction error signal hypothesis of dopamine. I suggest that the tonic reward monitoring signal of the DRN, possibly together with its interaction with the dopamine system, reports a continuous level of motivation throughout the performance of a task. Such a signal may provide "reward context" information to the targets of DRN projections, where it may be integrated further with incoming motivationally salient information. PMID- 23986663 TI - Immune responses at brain barriers and implications for brain development and neurological function in later life. AB - For a long time the brain has been considered an immune-privileged site due to a muted inflammatory response and the presence of protective brain barriers. It is now recognized that neuroinflammation may play an important role in almost all neurological disorders and that the brain barriers may be contributing through either normal immune signaling or disruption of their basic physiological mechanisms. The distinction between normal function and dysfunction at the barriers is difficult to dissect, partly due to a lack of understanding of normal barrier function and partly because of physiological changes that occur as part of normal development and ageing. Brain barriers consist of a number of interacting structural and physiological elements including tight junctions between adjacent barrier cells and an array of influx and efflux transporters. Despite these protective mechanisms, the capacity for immune-surveillance of the brain is maintained, and there is evidence of inflammatory signaling at the brain barriers that may be an important part of the body's response to damage or infection. This signaling system appears to change both with normal ageing, and during disease. Changes may affect diapedesis of immune cells and active molecular transfer, or cause rearrangement of the tight junctions and an increase in passive permeability across barrier interfaces. Here we review the many elements that contribute to brain barrier functions and how they respond to inflammation, particularly during development and aging. The implications of inflammation-induced barrier dysfunction for brain development and subsequent neurological function are also discussed. PMID- 23986665 TI - Reentry: a key mechanism for integration of brain function. AB - Reentry in nervous systems is the ongoing bidirectional exchange of signals along reciprocal axonal fibers linking two or more brain areas. The hypothesis that reentrant signaling serves as a general mechanism to couple the functioning of multiple areas of the cerebral cortex and thalamus was first proposed in 1977 and 1978 (Edelman, 1978). A review of the amount and diversity of supporting experimental evidence accumulated since then suggests that reentry is among the most important integrative mechanisms in vertebrate brains (Edelman, 1993). Moreover, these data prompt testable hypotheses regarding mechanisms that favor the development and evolution of reentrant neural architectures. PMID- 23986666 TI - Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol. AB - The development of successful pharmacotherapeutics for the treatment of alcoholism is predicated upon understanding the biological action of alcohol. A limitation of the alcohol research field has been examining the effects of alcohol only and ignoring the multiple biological active metabolites of alcohol. The concept that alcohol is a "pro-drug" is not new. Alcohol is readily metabolized to acetaldehyde within the brain. Acetaldehyde is a highly reactive compound that forms a number of condensation products, including salsolinol and iso-salsolinol (acetaldehyde and dopamine). Recent experiments have established that numerous metabolites of alcohol have direct CNS action, and could, in part or whole, mediate the reinforcing actions of alcohol within the mesolimbic dopamine system. The mesolimbic dopamine system originates in the ventral tegmental area (VTA) and projects to forebrain regions that include the nucleus accumbens (Acb) and the medial prefrontal cortex (mPFC) and is thought to be the neurocircuitry governing the rewarding properties of drugs of abuse. Within this neurocircuitry there is convincing evidence that; (1) biologically active metabolites of alcohol can directly or indirectly increase the activity of VTA dopamine neurons, (2) alcohol and alcohol metabolites are reinforcing within the mesolimbic dopamine system, (3) inhibiting the alcohol metabolic pathway inhibits the biological consequences of alcohol exposure, (4) alcohol consumption can be reduced by inhibiting/attenuating the alcohol metabolic pathway in the mesolimbic dopamine system, (5) alcohol metabolites can alter neurochemical levels within the mesolimbic dopamine system, and (6) alcohol interacts with alcohol metabolites to enhance the actions of both compounds. The data indicate that there is a positive relationship between alcohol and alcohol metabolites in regulating the biological consequences of consuming alcohol and the potential of alcohol use escalating to alcoholism. PMID- 23986667 TI - Stress enhances the consolidation of extinction memory in a predictive learning task. AB - Extinction is not always permanent, as indicated by several types of recovery effects, such as the renewal effect, which may occur after a context change and points towards the importance of contextual cues. Strengthening the retrieval of extinction memory is a crucial aim of extinction-based psychotherapeutic treatments of anxiety disorders to prevent relapse. Stress is known to modulate learning and memory, with mostly enhancing effects on memory consolidation. However, whether such a consolidation-enhancing effect of acute stress can also be found for extinction memory has not yet been examined in humans. In this study, we investigated the effect of stress after extinction learning on the retrieval of extinction memory in a predictive learning renewal paradigm. Participants took the part of being the doctor of a fictitious patient and learned to predict whether certain food stimuli were associated with "stomach trouble" in two different restaurants (contexts). On the first day, critical stimuli were associated with stomach trouble in context A (acquisition phase). On the second day, these associations were extinguished in context B. Directly after extinction, participants were either exposed to a stressor (socially evaluated cold pressor test; n = 22) or a control condition (n = 24). On the third day, we tested retrieval of critical associations in contexts A and B. Participants exposed to stress after extinction exhibited a reduced recovery of responding at test in context B, suggesting that stress may context-dependently enhance the consolidation of extinction memory. Furthermore, the increase in cortisol in response to the stressor was negatively correlated with the recovery of responding in context A. Our findings suggest that in parallel to the known effects of stress on the consolidation of episodic memory, stress also enhances the consolidation of extinction memory, which might be relevant for potential applications in extinction-based psychotherapy. PMID- 23986668 TI - The cognitive aging of episodic memory: a view based on the event-related brain potential. AB - A cardinal feature of older-adult cognition is a decline, relative to the young, in the encoding and retrieval of personally relevant events, i.e., episodic memory (EM). A consensus holds that familiarity, a relatively automatic feeling of knowing that can support recognition-memory judgments, is preserved with aging. By contrast, recollection, which requires the effortful, strategic recovery of contextual detail, declines as we age. Over the last decade, event related brain potential (ERPs) have become increasingly important tools in the study of the aging of EM, because a few, well-researched EM effects have been associated with the cognitive processes thought to underlie successful EM performance. EM effects are operationalized by subtracting the ERPs elicited by correctly rejected, new items from those to correctly recognized, old items. Although highly controversial, the mid-frontal effect (a positive component between ~300 and 500 ms, maximal at fronto-central scalp sites) is thought to reflect familiarity-based recognition. A positivity between ~500 and 800 ms, maximal at left-parietal scalp, has been labeled the left-parietal EM effect. A wealth of evidence suggests that this brain activity reflects recollection-based retrieval. Here, I review the ERP evidence in support of the hypothesis that familiarity is maintained while recollection is compromised in older relative to young adults. I consider the possibility that the inconsistency in findings may be due to individual differences in performance, executive function, and quality of life indices, such as socio-economic status. PMID- 23986669 TI - Differential Cortical c-Fos and Zif-268 Expression after Object and Spatial Memory Processing in a Standard or Episodic-Like Object Recognition Task. AB - Episodic memory reflects the capacity to recollect what, where, and when a specific event happened in an integrative manner. Animal studies have suggested that the medial temporal lobe and the medial pre-frontal cortex are important for episodic-like memory (ELM) formation. The goal of present study was to evaluate whether there are different patterns of expression of the immediate early genes c Fos and Zif-268 in these cortical areas after rats are exposed to object recognition (OR) tasks with different cognitive demands. Male rats were randomly assigned to five groups: home cage control, empty open field (CTR-OF), open field with one object (CTR-OF + Obj), novel OR task, and ELM task and were killed 1 h after the last behavioral procedure. Rats were able to discriminate the objects in the OR task. In the ELM task, rats showed spatial (but not temporal) discrimination of the objects. We found an increase in the c-Fos expression in the dorsal dentate gyrus (DG) and in the perirhinal cortex (PRh) in the OR and ELM groups. The OR group also presented an increase of c-Fos expression in the medial prefrontal cortex (mPFC). Additionally, the OR and ELM groups had increased expression of Zif-268 in the mPFC. Moreover, Zif-268 was increased in the dorsal CA1 and PRh only in the ELM group. In conclusion, the pattern of activation was different in tasks with different cognitive demands. Accordingly, correlation tests suggest the engagement of different neural networks in the tasks used. Specifically, perirhinal-DG co-activation was detected after the what where memory retrieval, but not after the novel OR task. Both regions correlated with the respective behavioral outcome. These findings can be helpful in the understanding of the neural networks underlying memory tasks with different cognitive demands. PMID- 23986670 TI - The roles of the "ventral" semantic and "dorsal" pathways in conduite d'approche: a neuroanatomically-constrained computational modeling investigation. AB - Ever since the 19th century, the standard model for spoken language processing has assumed two pathways for repetition-a phonological pathway and a semantic pathway-and this idea has gained further support in the last decade. First, recent in vivo tractography studies have demonstrated both the "dorsal" (via arcuate fasciculus) and "ventral" (via extreme capsule and uncinate fasciculus) pathways connecting from the primary auditory area to the speech-motor area, the latter of which passes through a brain area associated with semantic processing (anterior temporal lobe). Secondly, neuropsychological evidence for the role of semantics in repetition is conduite d'approche, a successive phonological improvement (sometimes non-improvement) in aphasic patients' response by repeating several times in succession. Crucially, conduite d'approche is observed in patients with neurological damage in/around the arcuate fasciculus. Successful conduite d'approche is especially clear for semantically-intact patients and it occurs for real words rather than for non-words. These features have led researchers to hypothesize that the patients' disrupted phonological output is "cleaned-up" by intact lexical-semantic information before the next repetition. We tested this hypothesis using the neuroanatomically-constrained dual dorsal ventral pathway computational model. The results showed that (a) damage to the dorsal pathway impaired repetition; (b) in the context of recovery, the model learned to compute a correct repetition response following the model's own noisy speech output (i.e., successful conduite d'approche); (c) this behavior was more evident for real words than non-words; and (d) activation from the ventral pathway contributed to the increased rate of successful conduite d'approche for real words. These results suggest that lexical-semantic "clean-up" is key to this self-correcting mechanism, supporting the classic proposal of two pathways for repetition. PMID- 23986671 TI - Suspiciousness perception in dynamic scenes: a comparison of CCTV operators and novices. AB - Perception of scenes has typically been investigated by using static or simplified visual displays. How attention is used to perceive and evaluate dynamic, realistic scenes is more poorly understood, in part due to the problem of comparing eye fixations to moving stimuli across observers. When the task and stimulus is common across observers, consistent fixation location can indicate that that region has high goal-based relevance. Here we investigated these issues when an observer has a specific, and naturalistic, task: closed-circuit television (CCTV) monitoring. We concurrently recorded eye movements and ratings of perceived suspiciousness as different observers watched the same set of clips from real CCTV footage. Trained CCTV operators showed greater consistency in fixation location and greater consistency in suspiciousness judgements than untrained observers. Training appears to increase between-operators consistency by learning "knowing what to look for" in these scenes. We used a novel "Dynamic Area of Focus (DAF)" analysis to show that in CCTV monitoring there is a temporal relationship between eye movements and subsequent manual responses, as we have previously found for a sports video watching task. For trained CCTV operators and for untrained observers, manual responses were most highly related to between observer eye position spread when a temporal lag was introduced between the fixation and response data. Several hundred milliseconds after between-observer eye positions became most similar, observers tended to push the joystick to indicate perceived suspiciousness. Conversely, several hundred milliseconds after between-observer eye positions became dissimilar, observers tended to rate suspiciousness as low. These data provide further support for this DAF method as an important tool for examining goal-directed fixation behavior when the stimulus is a real moving image. PMID- 23986672 TI - Comparison of activation patterns between masking and inattention tasks: a coordinate-based meta-analysis of implicit emotional face processing. AB - Neuroimaging studies of implicit emotional processing are important for understanding the neural mechanisms and its social and evolutionary significance. Two major experimental tasks are used to explore the mechanisms of implicit emotional processing: masking tasks and inattention tasks, both using emotional faces as stimuli. However, it is unclear whether they have identical or distinct neural substrates since few studies have compared the two tasks. The purpose of the present study was to explore the mechanisms of implicit processing of emotional faces, and compare the activation patterns between different tasks. Through a literature search, 41 studies exploring implicit processing of emotional faces were collected. A total of 830 healthy subjects and 513 foci were obtained. Separate activation likelihood estimation (ALE) meta-analyses were conducted for the entire group of studies and for different tasks for comparison purposes. The results showed that there were differences, as well as overlap, in activation patterns between masking and inattention tasks. Bilateral amygdala, middle occipital gyrus and fusiform gyrus were activated across both tasks. While masking tasks were more associated with inferior temporal gyrus, parahippocampal gyrus and amygdala, inattention tasks were more associated with right fusiform gyrus. The differences in activation patterns between masking and inattention tasks may be indicative of separate mechanisms underlying early and late stages of implicit emotional face processing. PMID- 23986673 TI - GroupICA dual regression analysis of resting state networks in a behavioral variant of frontotemporal dementia. AB - Functional MRI studies have revealed changes in default-mode and salience networks in neurodegenerative dementias, especially in Alzheimer's disease (AD). The purpose of this study was to analyze the whole brain cortex resting state networks (RSNs) in patients with behavioral variant frontotemporal dementia (bvFTD) by using resting state functional MRI (rfMRI). The group specific RSNs were identified by high model order independent component analysis (ICA) and a dual regression technique was used to detect between-group differences in the RSNs with p < 0.05 threshold corrected for multiple comparisons. A y concatenation method was used to correct for multiple comparisons for multiple independent components, gray matter differences as well as the voxel level. We found increased connectivity in several networks within patients with bvFTD compared to the control group. The most prominent enhancement was seen in the right frontotemporal area and insula. A significant increase in functional connectivity was also detected in the left dorsal attention network (DAN), in anterior paracingulate-a default mode sub-network as well as in the anterior parts of the frontal pole. Notably the increased patterns of connectivity were seen in areas around atrophic regions. The present results demonstrate abnormal increased connectivity in several important brain networks including the DAN and default-mode network (DMN) in patients with bvFTD. These changes may be associated with decline in executive functions and attention as well as apathy, which are the major cognitive and neuropsychiatric defects in patients with frontotemporal dementia. PMID- 23986675 TI - What would be the benefits of a collaboration between psychoanalysis and cognitive neuroscience? The opinion of a neuroscientist. PMID- 23986674 TI - Making choice between competing rewards in uncertain vs. safe social environment: role of neuronal nicotinic receptors of acetylcholine. AB - In social environments, choosing between multiple rewards is modulated by the uncertainty of the situation. Here, we compared how mice interact with a conspecific and how they use acoustic communication during this interaction in a three chambers task (no social threat was possible) and a Social Interaction Task, SIT (uncertain situation as two mice interact freely). We further manipulated the motivational state of the mice to see how they rank natural rewards such as social contact, food, and novelty seeking. We previously showed that beta2-subunit containing nicotinic receptors-beta2(*)nAChRs- are required for establishing reward ranking between social interaction, novelty exploration, and food consumption in social situations with high uncertainty. Knockout mice for beta2(*)nAChRs-beta2(-/-)mice- exhibit profound impairment in making social flexible choices, as compared to control -WT- mice. Our current data shows that being confronted with a conspecific in a socially safe environment as compared to a more uncertain environment, drastically reduced communication between the two mice, and changed their way to deal with a social conspecific. Furthermore, we demonstrated for the first time, that beta2(-/-) mice had the same motivational ranking than WT mice when placed in a socially safe environment. Therefore, beta2(*)nAChRs are not necessary for integrating social information or social rewards per se, but are important for making choices, only in a socially uncertain environment. This seems particularly important in the context of Social Neuroscience, as numerous animal models are used to provide novel insights and to test promising novel treatments of human pathologies affecting social and communication processes, among which Autistic spectrum disorders and schizophrenia. PMID- 23986676 TI - A standardized motor imagery introduction program (MIIP) for neuro rehabilitation: development and evaluation. AB - BACKGROUND: For patients with central nervous system (CNS) lesions and sensorimotor impairments a solid motor imagery (MI) introduction is crucial to understand and use MI to improve motor performance. The study's aim was to develop and evaluate a standardized MI group introduction program (MIIP) for patients after stroke, multiple sclerosis (MS), Parkinson's disease (PD), and traumatic brain injury (TBI). METHODS: Phase 1: Based on literature a MIIP was developed comprising MI theory (definition, type, mode, perspective, planning) and MI practice (performance, control). Phase 2: Development of a 27-item self administered MIIP evaluation questionnaire, assessing MI knowledge self evaluation of the ability to perform MI and patient satisfaction with the MIIP. Phase 3: Evaluation of MIIP and MI questionnaire by 2 independent MI experts based on predefined criteria and 2 patients using semi-structured interviews. Phase 4: Case series with a pre-post design to evaluate MIIP (3 * 30 min) using the MI questionnaire, Imaprax, Kinaesthetic and Visual Imagery Questionnaire, and Mental Chronometry. The paired t-test and the Wilcoxon signed-rank test were used to determine significant changes. RESULTS: Data of eleven patients were analysed (5 females; age 62.3 +/- 14.1 years). Declarative MI knowledge improved significantly from 5.4 +/- 2.2 to 8.8 +/- 2.9 (p = 0.010). Patients demonstrated good satisfaction with MIIP (mean satisfaction score: 83.2 +/- 11.4%). MI ability remained on a high level but showed no significant change, except a significant decrease in the Kinaesthetic and Visual Imagery Questionnaire score. CONCLUSION: The presented MIIP seems to be valid and feasible for patients with CNS lesions and sensorimotor impairments resulting in improved MI knowledge. MIIP sessions can be held in groups of four or less. MI ability and Mental Chronometry remained unchanged after 3 training sessions. PMID- 23986677 TI - High-speed real-time resting-state FMRI using multi-slab echo-volumar imaging. AB - We recently demonstrated that ultra-high-speed real-time fMRI using multi-slab echo-volumar imaging (MEVI) significantly increases sensitivity for mapping task related activation and resting-state networks (RSNs) compared to echo-planar imaging (Posse et al., 2012). In the present study we characterize the sensitivity of MEVI for mapping RSN connectivity dynamics, comparing independent component analysis (ICA) and a novel seed-based connectivity analysis (SBCA) that combines sliding-window correlation analysis with meta-statistics. This SBCA approach is shown to minimize the effects of confounds, such as movement, and CSF and white matter signal changes, and enables real-time monitoring of RSN dynamics at time scales of tens of seconds. We demonstrate highly sensitive mapping of eloquent cortex in the vicinity of brain tumors and arterio-venous malformations, and detection of abnormal resting-state connectivity in epilepsy. In patients with motor impairment, resting-state fMRI provided focal localization of sensorimotor cortex compared with more diffuse activation in task-based fMRI. The fast acquisition speed of MEVI enabled segregation of cardiac-related signal pulsation using ICA, which revealed distinct regional differences in pulsation amplitude and waveform, elevated signal pulsation in patients with arterio-venous malformations and a trend toward reduced pulsatility in gray matter of patients compared with healthy controls. Mapping cardiac pulsation in cortical gray matter may carry important functional information that distinguishes healthy from diseased tissue vasculature. This novel fMRI methodology is particularly promising for mapping eloquent cortex in patients with neurological disease, having variable degree of cooperation in task-based fMRI. In conclusion, ultra high-real-time speed fMRI enhances the sensitivity of mapping the dynamics of resting-state connectivity and cerebro-vascular pulsatility for clinical and neuroscience research applications. PMID- 23986678 TI - Atypical modulation of distant functional connectivity by cognitive state in children with Autism Spectrum Disorders. AB - We examined whether modulation of functional connectivity by cognitive state differed between pre-adolescent children with Autism Spectrum Disorders (ASD) and age and IQ-matched control children. Children underwent functional magnetic resonance imaging (fMRI) during two states, a resting state followed by a sustained attention task. A voxel-wise method was used to characterize functional connectivity at two levels, local (within a voxel's 14 mm neighborhood) and distant (outside of the voxel's 14 mm neighborhood to the rest of the brain) and regions exhibiting Group * State interaction were identified for both types of connectivity maps. Distant functional connectivity of regions in the left frontal lobe (dorsolateral [BA 11, 10]; supplementary motor area extending into dorsal anterior cingulate [BA 32/8]; and premotor [BA 6, 8, 9]), right parietal lobe (paracentral lobule [BA 6]; angular gyrus [BA 39/40]), and left posterior middle temporal cortex (BA 19/39) showed a Group * State interaction such that relative to the resting state, connectivity reduced (i.e., became focal) in control children but increased (i.e., became diffuse) in ASD children during the task state. Higher state-related increase in distant connectivity of left frontal and right angular gyrus predicted worse inattention in ASD children. Two graph theory measures (global efficiency and modularity) were also sensitive to Group * State differences, with the magnitude of state-related change predicting inattention in the ASD children. Our results indicate that as ASD children transition from an unconstrained to a sustained attentional state, functional connectivity of frontal and parietal regions with the rest of the brain becomes more widespread in a manner that may be maladaptive as it was associated with attention problems in everyday life. PMID- 23986680 TI - The ethology of empathy: a taxonomy of real-world targets of need and their effect on observers. AB - Empathy is inherently interpersonal, but the majority of research has only examined observers. Targets of need have been largely held constant through hypothetical and fictionalized depictions of sympathetic distress and need. In the real world, people's response to life stressors varies widely-from stoicism to resilience to complete breakdown-variations that should profoundly influence the prosocial exchange. The current study examined naturally-varying affect in real hospital patients with serious chronic or terminal illness during videotaped interviews about quality of life. Participants viewed each video while psychophysiological data were recorded and then rated each patient's and their own emotion. Patients displayed three major emotion factors (disturbed, softhearted, and amused) that were used to classify them into five basic types (distraught, resilient, sanguine, reticent, wistful). These types elicited four major emotions in observers [personal distress (PD), empathic concern (EC), horror, pleasure], two of which were never discovered previously with fictionalized targets. Across studies and measures, distraught targets usually received the greatest aid, but approximately as many observers preferred the positive and likeable resilient patients or the quietly sad wistful targets, with multiple observers even giving their greatest aid to sanguine or reticent targets who did not display distress or need. Trait empathy motivated aid toward more emotive targets while perspective taking (PT) motivated aid for those who did not overtly display distress. A second study replicated key results without even providing the content of patients' speech. Through an ecological examination of real need we discovered variation and commonality in the emotional response to need that interacts strongly with the preferences of observers. Social interactions need to be studied in ethological contexts that retain the complex interplay between senders and receivers. PMID- 23986679 TI - Acute responsivity of the serotonergic system to S-citalopram and positive emotionality-the moderating role of the 5-HTTLPR. AB - According to the idea that the central serotonergic system has a modulatory function on behavior and personality in general, we aimed to highlight its association to habitual positive emotionality. In a placebo-controlled double blind and randomized cross-over neuroendocrine challenge design (n = 72 healthy males) we investigated the association of the central serotonergic responsivity, 5-HTTLPR-genotype as well as their combined effects on positive emotionality. Regression analyses revealed an involvement of the serotonergic system in positive emotionality. There was, however, no direct association between positive emotionality and cortisol responses to S-citalopram; rather 5-HTTLPR-genotype showed an association (p < 0.05). That is, positive emotionality scores increased with the number of s-alleles carried by the individuals. Most notable was the moderating role of 5-HTTLPR-genotype (p < 0.05) on the association between acute serotonergic responsivity and positive emotionality. Indeed, this association was only found in ss-homozygotes, in which the acute responsivity of the serotonergic system additionally seems to contribute to the level of positive emotionality (r = 0.70, p < 0.05). The findings correspond to previous research demonstrating that the 5-HTTLPR is not only involved in the negative-emotional aspects of behavior and temperament, but is associated, moreover, with positive affectivity supporting the assumption of its valence-neutrality. In addition, our data are in line with the idea of possible influences of the 5-HTTLPR-genotype on early neuronal development. They also indicate the need for further studies in order to clearly elucidate the role of the serotonergic system and its subcomponents in the regulation of positive emotionality. PMID- 23986681 TI - Tracking the neuroplastic changes associated with transcranial direct current stimulation: a push for multimodal imaging. PMID- 23986682 TI - Introducing the special topic "The when and why of sensorimotor processes in conceptual knowledge and abstract concepts". PMID- 23986683 TI - Food related processes in the insular cortex. AB - The insular cortex is a multimodal brain region with regional cytoarchitectonic differences indicating various functional specializations. As a multisensory neural node, the insular cortex integrates perception, emotion, interoceptive awareness, cognition, and gustation. Regarding the latter, predominantly the anterior part of the insular cortex is regarded as the primary taste cortex. In this review, we will specifically focus on the involvement of the insula in food processing and on multimodal integration of food-related items. Influencing factors of insular activation elicited by various foods range from calorie content to the internal physiologic state, body mass index or eating behavior. Sensory perception of food-related stimuli including seeing, smelling, and tasting elicits increased activation in the anterior and mid-dorsal part of the insular cortex. Apart from the pure sensory gustatory processing, there is also a strong association with the rewarding/hedonic aspects of food items, which is reflected in higher insular activity and stronger connections to other reward related areas. Interestingly, the processing of food items has been found to elicit different insular activation in lean compared to obese subjects and in patients suffering from an eating disorder (anorexia nervosa (AN), bulimia nervosa (BN)). The knowledge of functional differences in the insular cortex opens up the opportunity for possible noninvasive treatment approaches for obesity and eating disorders. To target brain functions directly, real-time functional magnetic resonance imaging neurofeedback offers a state-of-the-art tool to learn to control the anterior insular cortex activity voluntarily. First evidence indicates that obese adults have an enhanced ability to regulate the anterior insular cortex. PMID- 23986684 TI - The association between creativity and 7R polymorphism in the dopamine receptor D4 gene (DRD4). AB - Creativity can be defined as the ability to produce responses that are both novel and appropriate. One way to assess creativity is to measure divergent thinking (DT) abilities that involve generating multiple novel and meaningful responses to open-ended questions. DT abilities have been shown to be associated with dopaminergic (DA) activity, and impaired DT has been reported in populations with DA dysfunctions. Given the strong association between DT and the DA system, the current study examined a group of healthy individuals (N = 185) to determine the role of repeat polymorphism in exon3 of the DRD4 gene in creativity. The results show that individuals carrying the DRD4-7R allele scored significantly lower on tests of DT, particularly on the flexibility dimension of DT, compared to non carriers. The current findings link creative cognition to the DA system and suggest that DA dysfunctions in neurological and psychiatric disorders may account for impaired creativity and cognitive flexibility in these individuals. PMID- 23986685 TI - Self-related processing and deactivation of cortical midline regions in disorders of consciousness. AB - Self-related stimuli activate anterior parts of cortical midline regions, which normally show task-induced deactivation. Deactivation in medial posterior and frontal regions is associated with the ability to focus attention on the demands of the task, and therefore, with consciousness. Studies investigating patients with impaired consciousness, that is, patients in minimally conscious state and patients with unresponsive wakefulness syndrome (formerly vegetative state), demonstrate that these patients show responses to self-related content in the anterior cingulate cortex. However, it remains unclear if these responses are an indication for conscious processing of stimuli or are due to automatic processing. To shed further light on this issue, we investigated responses of cortical midline regions to the own and another name in 27 patients with a disorder of consciousness and compared them to task-induced deactivation. While almost all of the control subjects responding to the own name demonstrated higher activation due to the self-related content in anterior midline regions and additional deactivation, none of the responding patients did so. Differences between groups showed a similar pattern of findings. Despite the relation between behavioral responsiveness in patients and activation in response to the own name, the findings of this study do not provide evidence for a direct association of activation in anterior midline regions and conscious processing. The deficits in processing of self-referential content in anterior midline regions may rather be due to general impairments in cognitive processing and not particularly linked to impaired consciousness. PMID- 23986686 TI - Social exclusion modulates fairness consideration in the ultimatum game: an ERP study. AB - Previous neuroimaging research has identified brain regions activated when people's fairness consideration changes under conditions of social exclusion. The current study used EEG data to examine the temporal process of changes in fairness consideration under social exclusion. In this study, a Cyberball game was administered to manipulate participants' social exclusion or inclusion. Then, in the following Ultimatum game (UG), participants' brain potentials were recorded while they received fair/unfair offers from someone who previously excluded them, someone who previously included them, or a stranger. Results showed that feedback-related negativity (FRN) after onset of distribution outcome was more pronounced for unfair offers compared to fair offers. Moreover, the FRN was more negative-going in response to unfair offers from people who previously excluded them than from the includer and the stranger. Fair offers elicited a larger P300 than unfair offers. In addition, P300 was more positive-going for unfair offers from the stranger than from the excluder and the includer. This study reveals a temporal process in which the effects of social exclusion on fair consideration are reflected in FRN in the early stage of outcome evaluation. These data also suggest that the FRN is modulated by the subjective evaluation of outcome events in a social context. PMID- 23986687 TI - Translating tDCS into the field of obesity: mechanism-driven approaches. AB - Transcranial direct current stimulation (tDCS) is emerging as a promising technique for neuromodulation in a variety of clinical conditions. Recent neuroimaging studies suggest that modifying the activity of brain circuits involved in eating behavior could provide therapeutic benefits in obesity. One session of tDCS over the dorsolateral prefrontal cortex can induce an acute decrease in food craving, according to three small clinical trials, but the extension of these findings into the field of obesity remains unexplored. Importantly, there has been little/no interaction of our current understanding of tDCS and its mechanisms with obesity-related research. How can we start closing this gap and rationally guide the translation of tDCS into the field of obesity? In this mini-review I summarize some of the challenges and questions ahead, related to basic science and technical aspects, and suggest future directions. PMID- 23986688 TI - Neuromotor recovery from stroke: computational models at central, functional, and muscle synergy level. AB - Computational models of neuromotor recovery after a stroke might help to unveil the underlying physiological mechanisms and might suggest how to make recovery faster and more effective. At least in principle, these models could serve: (i) To provide testable hypotheses on the nature of recovery; (ii) To predict the recovery of individual patients; (iii) To design patient-specific "optimal" therapy, by setting the treatment variables for maximizing the amount of recovery or for achieving a better generalization of the learned abilities across different tasks. Here we review the state of the art of computational models for neuromotor recovery through exercise, and their implications for treatment. We show that to properly account for the computational mechanisms of neuromotor recovery, multiple levels of description need to be taken into account. The review specifically covers models of recovery at central, functional and muscle synergy level. PMID- 23986690 TI - A micro-pool model for decision-related signals in visual cortical areas. AB - The study of sensory signaling in the visual cortex has been greatly advanced by the recording of neural activity simultaneously with the performance of a specific psychophysical task. Individual nerve cells may also increase their firing leading up to the particular choice or decision made on a single psychophysical trial. Understanding these signals is important because they have been taken as evidence that a particular nerve cell or group of nerve cells in the cortex is involved in the formation of the perceptual decision ultimately signaled by the organism. However, recent analyses show that the size of a decision-related change in firing in a particular neuron is not a secure basis for concluding anything about the contribution of a single neuron to the formation of a decision: rather the size of the decision-related firing is expected to be dominated by the extent to which the activation of a single neuron is correlated with the firing of the pool of neurons. The critical question becomes what defines membership of a population of neurons. This article presents the proposal that groups of neurons are naturally linked together by their connectivity, which in turn reflects the previous history of sensory stimulations. When a new psychophysical task is performed, a group of neurons relevant to the judgment becomes involved because the firing of some neurons in that group is strongly relevant to the task. This group of neurons is called a micro-pool. This article examines the consequences of such a proposal within the visual nervous system. The main focus is on the signals available from single neurons, but it argued that models of choice-related signals must scale up to larger numbers of neurons because MRI and MEG studies also show evidence of similar choice signals. PMID- 23986691 TI - Does "crisis-induced intermittency" explain bipolar disorder dynamics? PMID- 23986689 TI - Astrocytic and neuronal accumulation of elevated extracellular K(+) with a 2/3 K(+)/Na(+) flux ratio-consequences for energy metabolism, osmolarity and higher brain function. AB - Brain excitation increases neuronal Na(+) concentration by 2 major mechanisms: (i) Na(+) influx caused by glutamatergic synaptic activity; and (ii) action potential-mediated depolarization by Na(+) influx followed by repolarizating K(+) efflux, increasing extracellular K(+) concentration. This review deals mainly with the latter and it concludes that clearance of extracellular K(+) is initially mainly effectuated by Na(+),K(+)-ATPase-mediated K(+) uptake into astrocytes, at K(+) concentrations above ~10 mM aided by uptake of Na(+),K(+) and 2 Cl(-) by the cotransporter NKCC1. Since operation of the astrocytic Na(+),K(+) ATPase requires K(+)-dependent glycogenolysis for stimulation of the intracellular ATPase site, it ceases after normalization of extracellular K(+) concentration. This allows K(+) release via the inward rectifying K(+) channel Kir4.1, perhaps after trans-astrocytic connexin- and/or pannexin-mediated K(+) transfer, which would be a key candidate for determination by synchronization based computational analysis and may have signaling effects. Spatially dispersed K(+) release would have little effect on extracellular K(+) concentration and allow K(+) accumulation by the less powerful neuronal Na(+),K(+)-ATPase, which is not stimulated by increases in extracellular K(+). Since the Na(+),K(+)-ATPase exchanges 3 Na(+) with 2 K(+), it creates extracellular hypertonicity and cell shrinkage. Hypertonicity stimulates NKCC1, which, aided by beta-adrenergic stimulation of the Na(+),K(+)-ATPase, causes regulatory volume increase, furosemide-inhibited undershoot in [K(+)]e and perhaps facilitation of the termination of slow neuronal hyperpolarization (sAHP), with behavioral consequences. The ion transport processes involved minimize ionic disequilibria caused by the asymmetric Na(+),K(+)-ATPase fluxes. PMID- 23986692 TI - The situated HKB model: how sensorimotor spatial coupling can alter oscillatory brain dynamics. AB - Despite the increase of both dynamic and embodied/situated approaches in cognitive science, there is still little research on how coordination dynamics under a closed sensorimotor loop might induce qualitatively different patterns of neural oscillations compared to those found in isolated systems. We take as a departure point the Haken-Kelso-Bunz (HKB) model, a generic model for dynamic coordination between two oscillatory components, which has proven useful for a vast range of applications in cognitive science and whose dynamical properties are well understood. In order to explore the properties of this model under closed sensorimotor conditions we present what we call the situated HKB model: a robotic model that performs a gradient climbing task and whose "brain" is modeled by the HKB equation. We solve the differential equations that define the agent environment coupling for increasing values of the agent's sensitivity (sensor gain), finding different behavioral strategies. These results are compared with two different models: a decoupled HKB with no sensory input and a passively coupled HKB that is also decoupled but receives a structured input generated by a situated agent. We can precisely quantify and qualitatively describe how the properties of the system, when studied in coupled conditions, radically change in a manner that cannot be deduced from the decoupled HKB models alone. We also present the notion of neurodynamic signature as the dynamic pattern that correlates with a specific behavior and we show how only a situated agent can display this signature compared to an agent that simply receives the exact same sensory input. To our knowledge, this is the first analytical solution of the HKB equation in a sensorimotor loop and qualitative and quantitative analytic comparison of spatially coupled vs. decoupled oscillatory controllers. Finally, we discuss the limitations and possible generalization of our model to contemporary neuroscience and philosophy of mind. PMID- 23986693 TI - Learning from the value of your mistakes: evidence for a risk-sensitive process in movement adaptation. AB - Risk frames nearly every decision we make. Yet, remarkably little is known about whether risk influences how we learn new movements. Risk-sensitivity can emerge when there is a distortion between the absolute magnitude (actual value) and how much an individual values (subjective value) a given outcome. In movement, this translates to the difference between a given movement error and its consequences. Surprisingly, how movement learning can be influenced by the consequences associated with an error is not well-understood. It is traditionally assumed that all errors are created equal, i.e., that adaptation is proportional to an error experienced. However, not all movement errors of a given magnitude have the same subjective value. Here we examined whether the subjective value of error influenced how participants adapted their control from movement to movement. Seated human participants grasped the handle of a force-generating robotic arm and made horizontal reaching movements in two novel dynamic environments that penalized errors of the same magnitude differently, changing the subjective value of the errors. We expected that adaptation in response to errors of the same magnitude would differ between these environments. In the first environment, Stable, errors were not penalized. In the second environment, Unstable, rightward errors were penalized with the threat of unstable, cliff-like forces. We found that adaptation indeed differed. Specifically, in the Unstable environment, we observed reduced adaptation to leftward errors, an appropriate strategy that reduced the chance of a penalizing rightward error. These results demonstrate that adaptation is influenced by the subjective value of error, rather than solely the magnitude of error, and therefore is risk-sensitive. In other words, we may not simply learn from our mistakes, we may also learn from the value of our mistakes. PMID- 23986694 TI - Impact of functional MRI data preprocessing pipeline on default-mode network detectability in patients with disorders of consciousness. AB - An emerging application of resting-state functional MRI (rs-fMRI) is the study of patients with disorders of consciousness (DoC), where integrity of default-mode network (DMN) activity is associated to the clinical level of preservation of consciousness. Due to the inherent inability to follow verbal instructions, arousal induced by scanning noise and postural pain, these patients tend to exhibit substantial levels of movement. This results in spurious, non-neural fluctuations of the rs-fMRI signal, which impair the evaluation of residual functional connectivity. Here, the effect of data preprocessing choices on the detectability of the DMN was systematically evaluated in a representative cohort of 30 clinically and etiologically heterogeneous DoC patients and 33 healthy controls. Starting from a standard preprocessing pipeline, additional steps were gradually inserted, namely band-pass filtering (BPF), removal of co-variance with the movement vectors, removal of co-variance with the global brain parenchyma signal, rejection of realignment outlier volumes and ventricle masking. Both independent-component analysis (ICA) and seed-based analysis (SBA) were performed, and DMN detectability was assessed quantitatively as well as visually. The results of the present study strongly show that the detection of DMN activity in the sub-optimal fMRI series acquired on DoC patients is contingent on the use of adequate filtering steps. ICA and SBA are differently affected but give convergent findings for high-grade preprocessing. We propose that future studies in this area should adopt the described preprocessing procedures as a minimum standard to reduce the probability of wrongly inferring that DMN activity is absent. PMID- 23986695 TI - Growing a garden of neurons. PMID- 23986696 TI - Maturation and integration of adult born hippocampal neurons: signal convergence onto small Rho GTPases. AB - Adult neurogenesis, restricted to specific regions in the mammalian brain, represents one of the most interesting forms of plasticity in the mature nervous system. Adult-born hippocampal neurons play important roles in certain forms of learning and memory, and altered hippocampal neurogenesis has been associated with a number of neuropsychiatric diseases such as major depression and epilepsy. Newborn neurons go through distinct developmental steps, from a dividing neurogenic precursor to a synaptically integrated mature neuron. Previous studies have uncovered several molecular signaling pathways involved in distinct steps of this maturational process. In this context, the small Rho GTPases, Cdc42, Rac1, and RhoA have recently been shown to regulate the morphological and synaptic maturation of adult-born dentate granule cells in vivo. Distinct upstream regulators, including growth factors that modulate maturation and integration of newborn neurons have been shown to also recruit the small Rho GTPases. Here we review recent findings and highlight the possibility that small Rho GTPases may act as central assimilators, downstream of critical input onto adult-born hippocampal neurons contributing to their maturation and integration into the existing dentate gyrus (DG) circuitry. PMID- 23986697 TI - The temporoammonic input to the hippocampal CA1 region displays distinctly different synaptic plasticity compared to the Schaffer collateral input in vivo: significance for synaptic information processing. AB - In terms of its sub-regional differentiation, the hippocampal CA1 region receives cortical information directly via the perforant (temporoammonic) path (pp-CA1 synapse) and indirectly via the tri-synaptic pathway where the last relay station is the Schaffer collateral-CA1 synapse (Sc-CA1 synapse). Research to date on pp CA1 synapses has been conducted predominantly in vitro and never in awake animals, but these studies hint that information processing at this synapse might be distinct to processing at the Sc-CA1 synapse. Here, we characterized synaptic properties and synaptic plasticity at the pp-CA1 synapse of freely behaving adult rats. We observed that field excitatory postsynaptic potentials at the pp-CA1 synapse have longer onset latencies and a shorter time-to-peak compared to the Sc CA1 synapse. LTP (>24 h) was successfully evoked by tetanic afferent stimulation of pp-CA1 synapses. Low frequency stimulation evoked synaptic depression at Sc CA1 synapses, but did not elicit LTD at pp-CA1 synapses unless the Schaffer collateral afferents to the CA1 region had been severed. Paired-pulse responses also showed significant differences. Our data suggest that synaptic plasticity at the pp-CA1 synapse is distinct from the Sc-CA1 synapse and that this may reflect its specific role in hippocampal information processing. PMID- 23986698 TI - History of mild traumatic brain injury is associated with deficits in relational memory, reduced hippocampal volume, and less neural activity later in life. AB - Evidence suggests that a history of head trauma is associated with memory deficits later in life. The majority of previous research has focused on moderate to-severe traumatic brain injury (TBI), but recent evidence suggests that even a mild TBI (mTBI) can interact with the aging process and produce reductions in memory performance. This study examined the association of mTBI with memory and the brain by comparing young and middle-aged adults who have had mTBI in their recent (several years ago) and remote (several decades ago) past, respectively, with control subjects on a face-scene relational memory paradigm while they underwent functional magnetic resonance imaging (fMRI). Hippocampal volumes were also examined from high-resolution structural images. Results indicated middle aged adults with a head injury in their remote past had impaired memory compared to gender, age, and education matched control participants, consistent with previous results in the study of memory, aging, and TBI. The present findings extended previous results by demonstrating that these individuals also had smaller bilateral hippocampi, and had reduced neural activity during memory performance in cortical regions important for memory retrieval. These results indicate that a history of mTBI may be one of the many factors that negatively influence cognitive and brain health in aging. PMID- 23986699 TI - Of mice and men: neurogenesis, cognition and Alzheimer's disease. AB - Neural stem cells are maintained in the subgranular layer of the dentate gyrus and in the subventricular zone in the adult mammalian brain throughout life. Neurogenesis is continuous, but its extent is tightly regulated by environmental factors, behavior, hormonal state, age, and brain health. Increasing evidence supports a role for new neurons in cognitive function in rodents. Recent evidence delineates significant similarities and differences between adult neurogenesis in rodents and humans. Being context-dependent, neurogenesis in the human brain might be manifested differently than in the rodent brain. Decline in neurogenesis may play a role in cognitive deterioration, leading to the development of progressive learning and memory disorders, such as Alzheimer's disease. This review discusses the different observations concerning neurogenesis in the rodent and human brain, and their functional implications for the healthy and diseased brain. PMID- 23986702 TI - Antipsychotic treatments; focus on lurasidone. AB - The introduction of atypical antipsychotic drugs (AAPDs), or second-generation antipsychotics, with clozapine as the prototype, has largely changed the clinicians' attitudes toward the treatment of mental illnesses including, but not limited to schizophrenia. Initially, there was optimism that AAPDs would be superior over typical antipsychotic drugs (TAPDs), or first-generation antipsychotic drugs, in terms of efficacy in various phenomenological aspects, including cognitive impairment, and less likelihood of causing adverse events. However, these views have been partly challenged by results from recent meta analysis studies. Specifically, cardio-metabolic side effects of AAPDs, in spite of a relative paucity of extrapyramidal symptoms, may sometimes limit the use of these agents. Accordingly, attempts have been made to develop newer compounds, e.g., lurasidone, with the aim of increasing efficacy and tolerability. Further investigations are warranted to determine if a larger proportion of patients will be benefitted by treatment with AAPDs compared to TAPDs in terms of remission and recovery. PMID- 23986700 TI - Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis. AB - Over the past two decades there have been significant advances in our understanding of copper homeostasis and the pathological consequences of copper dysregulation. Cumulative evidence is revealing a complex regulatory network of proteins and pathways that maintain copper homeostasis. The recognition of copper dysregulation as a key pathological feature in prominent neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases has led to increased research focus on the mechanisms controlling copper homeostasis in the brain. The copper-transporting P-type ATPases (copper-ATPases), ATP7A and ATP7B, are critical components of the copper regulatory network. Our understanding of the biochemistry and cell biology of these complex proteins has grown significantly since their discovery in 1993. They are large polytopic transmembrane proteins with six copper-binding motifs within the cytoplasmic N terminal domain, eight transmembrane domains, and highly conserved catalytic domains. These proteins catalyze ATP-dependent copper transport across cell membranes for the metallation of many essential cuproenzymes, as well as for the removal of excess cellular copper to prevent copper toxicity. A key functional aspect of these copper transporters is their copper-responsive trafficking between the trans-Golgi network and the cell periphery. ATP7A- and ATP7B deficiency, due to genetic mutation, underlie the inherited copper transport disorders, Menkes and Wilson diseases, respectively. Their importance in maintaining brain copper homeostasis is underscored by the severe neuropathological deficits in these disorders. Herein we will review and update our current knowledge of these copper transporters in the brain and the central nervous system, their distribution and regulation, their role in normal brain copper homeostasis, and how their absence or dysfunction contributes to disturbances in copper homeostasis and neurodegeneration. PMID- 23986701 TI - Physiological and pharmacological aspects of the vas deferens-an update. AB - The vas deferens, a muscular conduit conveying spermatozoa from the epididymis to the urethra, has been used as a model tissue for smooth muscle pharmacological and physiological advancements. Many drugs, notably alpha-adrenergic antagonists, have effects on contractility and thus normal ejaculation, incurring significant side effects for patients that may interfere with compliance. A more thorough understanding of the innervation and neurotransmitter pharmacology of the vas has indicated that this is a highly complex structure and a model for co-transmission at the synapse. Recent models have shown clinical scenarios that alter the vas contraction. This review covers structure, receptors, neurotransmitters, smooth muscle physiology, and clinical implications of the vas deferens. PMID- 23986704 TI - Core competencies for pharmaceutical physicians and drug development scientists. AB - Professional groups, such as IFAPP (International Federation of Pharmaceutical Physicians and Pharmaceutical Medicine), are expected to produce the defined core competencies to orient the discipline and the academic programs for the development of future competent professionals and to advance the profession. On the other hand, PharmaTrain, an Innovative Medicines Initiative project, has become the largest public-private partnership in biomedicine in the European Continent and aims to provide postgraduate courses that are designed to meet the needs of professionals working in medicines development. A working group was formed within IFAPP including representatives from PharmaTrain, academic institutions and national member associations, with special interest and experience on Quality Improvement through education. The objectives were: to define a set of core competencies for pharmaceutical physicians and drug development scientists, to be summarized in a Statement of Competence and to benchmark and align these identified core competencies with the Learning Outcomes (LO) of the PharmaTrain Base Course. The objectives were successfully achieved. Seven domains and 60 core competencies were identified and aligned accordingly. The effective implementation of training programs using the competencies or the PharmaTrain LO anywhere in the world may transform the drug development process to an efficient and integrated process for better and safer medicines. The PharmaTrain Base Course might provide the cognitive framework to achieve the desired Statement of Competence for Pharmaceutical Physicians and Drug Development Scientists worldwide. PMID- 23986703 TI - Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognition in urban children. AB - Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA) children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-beta diffuse plaques (compared to 0% in low pollution control children). We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET 1) and/or inflammatory mediators in MCMA children. Thirty gram of dark cocoa with 680 mg of total flavonols were given daily for 10.11 +/- 3.4 days (range 9-24 days) to 18 children (10.55 years, SD = 1.45; 11F/7M). Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p = 0.0002). Fifteen children (83%) showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter (PM) and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimer's and Parkinson's diseases. PMID- 23986705 TI - An Escherichia coli strain for expression of the connexin45 carboxyl terminus attached to the 4th transmembrane domain. AB - A major problem for structural characterization of membrane proteins, such as connexins, by nuclear magnetic resonance (NMR) occurs at the initial step of the process, the production of sufficient amounts of protein. This occurs because proteins must be expressed in minimal based media. Here, we describe an expression system for membrane proteins that significantly improves yield by addressing two common problems, cell toxicity caused by protein translation and codon bias between genomes. This work provides researchers with a cost-effective tool for NMR and other biophysical studies, to use when faced with little-to-no expression of eukaryotic membrane proteins in Escherichia coli expression systems. PMID- 23986706 TI - Quantification of dendritic and axonal growth after injury to the auditory system of the adult cricket Gryllus bimaculatus. AB - Dendrite and axon growth and branching during development are regulated by a complex set of intracellular and external signals. However, the cues that maintain or influence adult neuronal morphology are less well understood. Injury and deafferentation tend to have negative effects on adult nervous systems. An interesting example of injury-induced compensatory growth is seen in the cricket, Gryllus bimaculatus. After unilateral loss of an ear in the adult cricket, auditory neurons within the central nervous system (CNS) sprout to compensate for the injury. Specifically, after being deafferented, ascending neurons (AN-1 and AN-2) send dendrites across the midline of the prothoracic ganglion where they receive input from auditory afferents that project through the contralateral auditory nerve (N5). Deafferentation also triggers contralateral N5 axonal growth. In this study, we quantified AN dendritic and N5 axonal growth at 30 h, as well as at 3, 5, 7, 14, and 20 days after deafferentation in adult crickets. Significant differences in the rates of dendritic growth between males and females were noted. In females, dendritic growth rates were non-linear; a rapid burst of dendritic extension in the first few days was followed by a plateau reached at 3 days after deafferentation. In males, however, dendritic growth rates were linear, with dendrites growing steadily over time and reaching lengths, on average, twice as long as in females. On the other hand, rates of N5 axonal growth showed no significant sexual dimorphism and were linear. Within each animal, the growth rates of dendrites and axons were not correlated, indicating that independent factors likely influence dendritic and axonal growth in response to injury in this system. Our findings provide a basis for future study of the cellular features that allow differing dendrite and axon growth patterns as well as sexually dimorphic dendritic growth in response to deafferentation. PMID- 23986707 TI - Glia-related circadian plasticity in the visual system of Diptera. AB - The circadian changes in morphology of the first visual neuropil or lamina of Diptera represent an example of the neuronal plasticity controlled by the circadian clock (circadian plasticity). It is observed in terminals of the compound eye photoreceptor cells, the peripheral oscillators expressing the clock genes. However, it has been found also in their postsynaptic partners, the L1 and L2 monopolar cells, in which the activity of the clock genes have not yet been detected. The circadian input that the L1 and L2 receive seems to originate not only from the retina photoreceptors and from the circadian pacemaker neurons located in the brain, but also from the glial cells that express the clock genes and thus contain circadian oscillators. This paper summarizes the morphological and biochemical rhythms in glia of the optic lobe, shows how they contribute to circadian plasticity, and discusses how glial clocks may modulate circadian rhythms in the lamina. PMID- 23986708 TI - Behavioral and neural plasticity caused by early social experiences: the case of the honeybee. AB - Cognitive experiences during the early stages of life play an important role in shaping future behavior. Behavioral and neural long-term changes after early sensory and associative experiences have been recently reported in the honeybee. This invertebrate is an excellent model for assessing the role of precocious experiences on later behavior due to its extraordinarily tuned division of labor based on age polyethism. These studies are mainly focused on the role and importance of experiences occurred during the first days of the adult lifespan, their impact on foraging decisions, and their contribution to coordinate food gathering. Odor-rewarded experiences during the first days of honeybee adulthood alter the responsiveness to sucrose, making young hive bees more sensitive to assess gustatory features about the nectar brought back to the hive and affecting the dynamic of the food transfers and the propagation of food-related information within the colony. Early olfactory experiences lead to stable and long-term associative memories that can be successfully recalled after many days, even at foraging ages. Also they improve memorizing of new associative learning events later in life. The establishment of early memories promotes stable reorganization of the olfactory circuits inducing structural and functional changes in the antennal lobe (AL). Early rewarded experiences have relevant consequences at the social level too, biasing dance and trophallaxis partner choice and affecting recruitment. Here, we revised recent results in bees' physiology, behavior, and sociobiology to depict how the early experiences affect their cognition abilities and neural-related circuits. PMID- 23986709 TI - Lesion-induced insights in the plasticity of the insect auditory system. AB - The auditory networks of Orthoptera offer a model system uniquely suited to the study of neuronal connectivity and lesion-dependent neural plasticity. Monaural animals, following the permanent removal of one ear in nymphs or adults, adjust their auditory pathways by collateral sprouting of afferents and deafferented interneurons which connect to neurons on the contralateral side. Transient lesion of the auditory nerve allows us to study regeneration as well as plasticity processes. After crushing the peripheral auditory nerve, the lesioned afferents regrow and re-establish new synaptic connections which are relevant for auditory behavior. During this process collateral sprouting occurs in the central nervous networks, too. Interestingly, after regeneration a changed neuronal network will be maintained. These paradigms are now been used to analyze molecular mechanism in neuronal plasticity on the level of single neurons and small networks. PMID- 23986710 TI - Trace conditioning in insects-keep the trace! AB - Trace conditioning is a form of associative learning that can be induced by presenting a conditioned stimulus (CS) and an unconditioned stimulus (US) following each other, but separated by a temporal gap. This gap distinguishes trace conditioning from classical delay conditioning, where the CS and US overlap. To bridge the temporal gap between both stimuli and to form an association between CS and US in trace conditioning, the brain must keep a neural representation of the CS after its termination-a stimulus trace. Behavioral and physiological studies on trace and delay conditioning revealed similarities between the two forms of learning, like similar memory decay and similar odor identity perception in invertebrates. On the other hand differences were reported also, like the requirement of distinct brain structures in vertebrates or disparities in molecular mechanisms in both vertebrates and invertebrates. For example, in commonly used vertebrate conditioning paradigms the hippocampus is necessary for trace but not for delay conditioning, and Drosophila delay conditioning requires the Rutabaga adenylyl cyclase (Rut-AC), which is dispensable in trace conditioning. It is still unknown how the brain encodes CS traces and how they are associated with a US in trace conditioning. Insects serve as powerful models to address the mechanisms underlying trace conditioning, due to their simple brain anatomy, behavioral accessibility and established methods of genetic interference. In this review we summarize the recent progress in insect trace conditioning on the behavioral and physiological level and emphasize similarities and differences compared to delay conditioning. Moreover, we examine proposed molecular and computational models and reassess different experimental approaches used for trace conditioning. PMID- 23986711 TI - Photoperiodic plasticity in circadian clock neurons in insects. AB - Since Bunning's observation of circadian rhythms and photoperiodism in the runner bean Phaseolus multiflorus in 1936, many studies have shown that photoperiodism is based on the circadian clock system. In insects, involvement of circadian clock genes or neurons has been recently shown in the photoperiodic control of developmental arrests, diapause. Photoperiod sets peaks of period (per) or timeless (tim) mRNA abundance at lights-off in Sarcophaga crassipalpis, Chymomyza costata and Protophormia terraenovae. Abundance of per and Clock mRNA changes by photoperiod in Pyrrhocoris apterus. Subcellular Per distribution in circadian clock neurons changes with photoperiod in P. terraenovae. Although photoperiodism is not known in Leucophaea maderae, under longer day length, more stomata and longer commissural fibers of circadian clock neurons have been found. These plastic changes in the circadian clock neurons could be an important constituent for photoperiodic clock mechanisms to integrate repetitive photoperiodic information and produce different outputs based on day length. PMID- 23986712 TI - Developmental and activity-dependent plasticity of filiform hair receptors in the locust. AB - A group of wind sensitive filiform hair receptors on the locust thorax and head makes contact onto a pair of identified interneuron, A4I1. The hair receptors' central nervous projections exhibit pronounced structural dynamics during nymphal development, for example, by gradually eliminating their ipsilateral dendritic field while maintaining the contralateral one. These changes are dependent not only on hormones controlling development but on neuronal activity as well. The hair-to-interneuron system has remarkably high gain (close to 1) and makes contact to flight steering muscles. During stationary flight in front of a wind tunnel, interneuron A4I1 is active in the wing beat rhythm, and in addition it responds strongly to stimulation of sensory hairs in its receptive field. A role of the hair-to-interneuron in flight steering is thus suggested. This system appears suitable for further study of developmental and activity-dependent plasticity in a sensorimotor context with known connectivity patterns. PMID- 23986714 TI - Interspecific acoustic recognition in two European bat communities. AB - Echolocating bats emit echolocation calls for spatial orientation and foraging. These calls are often species-specific and are emitted at high intensity and repetition rate. Therefore, these calls could potentially function in intra- and/or inter-specific bat communication. For example, bats in the field approach playbacks of conspecific feeding buzzes, probably because feeding buzzes indicate an available foraging patch. In captivity, some species of bats recognize and distinguish the echolocation calls of different sympatric species. However, it is still unknown if and how acoustic species-recognition mediates interspecific interactions in the field. Here we aim to understand eavesdropping on bat echolocation calls within and across species boundaries in wild bats. We presented playbacks of conspecific and heterospecific search calls and feeding buzzes to four bat species with different foraging ecologies. The bats were generally more attracted by feeding buzzes than search calls and more by the calls of conspecifics than their heterospecifics. Furthermore, bats showed differential reaction to the calls of the heterospecifics. In particular, Myotis capaccinii reacted equally to the feeding buzzes of conspecifics and to ecologically more similar heterospecifics. Our results confirm eavesdropping on feeding buzzes at the intraspecific level in wild bats and provide the first experimental quantification of potential eavesdropping in European bats at the interspecific level. Our data support the hypothesis that bat echolocation calls have a communicative potential that allows interspecific, and potentially intraspecific, eavesdropping in the wild. PMID- 23986713 TI - Mechanisms of plasticity in a Caenorhabditis elegans mechanosensory circuit. AB - Despite having a small nervous system (302 neurons) and relatively short lifespan (14-21 days), the nematode Caenorhabditis elegans has a substantial ability to change its behavior in response to experience. The behavior discussed here is the tap withdrawal response, whereby the worm crawls backwards a brief distance in response to a non-localized mechanosensory stimulus from a tap to the side of the Petri plate within which it lives. The neural circuit that underlies this behavior is primarily made up of five sensory neurons and four pairs of interneurons. In this review we describe two classes of mechanosensory plasticity: adult learning and memory and experience dependent changes during development. As worms develop through young adult and adult stages there is a shift toward deeper habituation of response probability that is likely the result of changes in sensitivity to stimulus intensity. Adult worms show short- intermediate- and long-term habituation as well as context dependent habituation. Short-term habituation requires glutamate signaling and auto-phosphorylation of voltage-dependent potassium channels and is modulated by dopamine signaling in the mechanosensory neurons. Long-term memory (LTM) for habituation is mediated by down-regulation of expression of an AMPA-type glutamate receptor subunit. Intermediate memory involves an increase in release of an inhibitory neuropeptide. Depriving larval worms of mechanosensory stimulation early in development leads to fewer synaptic vesicles in the mechanosensory neurons and lower levels of an AMPA-type glutamate receptor subunit in the interneurons. Overall, the mechanosensory system of C. elegans shows a great deal of experience dependent plasticity both during development and as an adult. The simplest form of learning, habituation, is not so simple and is mediated and/or modulated by a number of different processes, some of which we are beginning to understand. PMID- 23986715 TI - Temporal and morphological impact of pressure overload in transgenic FHC mice. AB - Although familial hypertrophic cardiomyopathy (FHC) is characterized as cardiac disease in the absence of overt stressors, disease penetrance, and pathological progression largely depend on modifying factors. Accordingly, pressure overload by transverse aortic constriction (TAC) was induced in 2-month-old, male mice with and without a FHC (R403Q) mutation in alpha-myosin heavy chain. A significantly greater number of FHC mice (n = 8) than wild-type (WT) mice (n = 5) died during the 9-week study period. TAC induced a significant increase in cardiac mass whether measured at 2 or 9 weeks post-TAC in both WT and FHC mice, albeit to a different extent. However, the temporal and morphological trajectory of ventricular remodeling was impacted by the FHC transgene. Both WT and FHC hearts responded to TAC with an early (2 weeks post-TAC) and significant augmentation of the relative wall thickness (RWT) indicative of concentric hypertrophy. By 9 weeks post-TAC, RWT decreased in WT hearts (eccentric hypertrophy) but remained elevated in FHC hearts. WT hearts following TAC demonstrated enhanced cardiac function as measured by the end-systolic pressure volume relationship, pre-load recruitable stroke work (PRSW), and myocardial relaxation indicative of compensatory hypertrophy. Similarly, TAC induced differential histological and cellular remodeling; TAC reduced expression of the sarcoplasmic reticulum Ca(2+)-ATPase (2a) (SERCA2a; 2 and 9 weeks) and phospholamban (PLN; 2 weeks) but increased PLN phosphorylation (2 weeks) and beta myosin heavy chain (beta-MyHC; 9 weeks) in WT hearts. FHC-TAC hearts showed increased beta-MyHC (2 and 9 weeks) and a late (9 weeks) decrease in PLN expression concomitant with a significant increase in PLN phosphorylation. We conclude that FHC hearts respond to TAC induced pressure overload with increased premature death, severe concentric hypertrophy, and a differential ability to undergo morphological, functional, or cellular remodeling compared to WT hearts. PMID- 23986716 TI - The effect of heart rate on the heart rate variability response to autonomic interventions. AB - Heart rate variability (HRV), the beat-to-beat variation in either heart rate (HR) or heart period (R-R interval), has become a popular clinical and investigational tool to quantify cardiac autonomic regulation. However, it is not widely appreciated that, due to the inverse curvilinear relationship between HR and R-R interval, HR per se can profoundly influence HRV. It is, therefore, critical to correct HRV for the prevailing HR particularly, as HR changes in response to autonomic neural activation or inhibition. The present study evaluated the effects of HR on the HRV response to autonomic interventions that either increased (submaximal exercise, n = 25 or baroreceptor reflex activation, n = 20) or reduced (pharmacological blockade: beta-adrenergic receptor, muscarinic receptor antagonists alone and in combination, n = 25, or bilateral cervical vagotomy, n = 9) autonomic neural activity in a canine model. Both total (RR interval standard deviation, RRSD) and the high frequency (HF) variability (HF, 0.24-1.04 Hz) were determined before and in response to an autonomic intervention. All interventions that reduced or abolished cardiac parasympathetic regulation provoked large reductions in HRV even after HR correction [division by mean RRsec or (mean RRsec)(2) for RRSD and HF, respectively] while interventions that reduced HR yielded mixed results. beta-adrenergic receptor blockade reduced HRV (RRSD but not HF) while both RRSD and HF increased in response to increases in arterial blood (baroreceptor reflex activation) even after HR correction. These data suggest that the physiological basis for HRV is revealed after correction for prevailing HR and, further, that cardiac parasympathetic activity is responsible for a major portion of the HRV in the dog. PMID- 23986718 TI - Neural control of the circulation during exercise in health and disease. PMID- 23986717 TI - Developing microRNA screening as a functional genomics tool for disease research. AB - Originally discovered as regulators of developmental timing in C. elegans, microRNAs (miRNAs) have emerged as modulators of nearly every cellular process, from normal development to pathogenesis. With the advent of whole genome libraries of miRNA mimics suitable for high throughput screening, it is possible to comprehensively evaluate the function of each member of the miRNAome in cell based assays. Since the relatively few microRNAs in the genome are thought to directly regulate a large portion of the proteome, miRNAome screening, coupled with the identification of the regulated proteins, might be a powerful new approach to gaining insight into complex biological processes. PMID- 23986720 TI - Plasticity in invertebrate sensory systems. PMID- 23986719 TI - Breast cancer stem cells. AB - Cancer metastasis, resistance to therapies and disease recurrence are significant hurdles to successful treatment of breast cancer. Identifying mechanisms by which cancer spreads, survives treatment regimes and regenerates more aggressive tumors are critical to improving patient survival. Substantial evidence gathered over the last 10 years suggests that breast cancer progression and recurrence is supported by cancer stem cells (CSCs). Understanding how CSCs form and how they contribute to the pathology of breast cancer will greatly aid the pursuit of novel therapies targeted at eliminating these cells. This review will summarize what is currently known about the origins of breast CSCs, their role in disease progression and ways in which they may be targeted therapeutically. PMID- 23986721 TI - Systems biology of platelet-vessel wall interactions. AB - Blood systems biology seeks to quantify outside-in signaling as platelets respond to numerous external stimuli, typically under flow conditions. Platelets can activate via GPVI collagen receptor and numerous G-protein coupled receptors (GPCRs) responsive to ADP, thromboxane, thrombin, and prostacyclin. A bottom-up ODE approach allowed prediction of platelet calcium and phosphoinositides following P2Y1 activation with ADP, either for a population average or single cell stochastic behavior. The homeostasis assumption (i.e., a resting platelet stays resting until activated) was particularly useful in finding global steady states for these large metabolic networks. Alternatively, a top-down approach involving Pairwise Agonist Scanning (PAS) allowed large data sets of measured calcium mobilization to predict an individual's platelet responses. The data was used to train neural network (NN) models of signaling to predict patient-specific responses to combinatorial stimulation. A kinetic description of platelet signaling then allows prediction of inside-out activation of platelets as they experience the complex biochemical milieu at the site of thrombosis. Multiscale lattice kinetic Monte Carlo (LKMC) utilizes these detailed descriptions of platelet signaling under flow conditions where released soluble species are solved by finite element method and the flow field around the growing thrombus is updated using computational fluid dynamics or lattice Boltzmann method. Since hemodynamic effects are included in a multiscale approach, thrombosis can then be predicted under arterial and venous thrombotic conditions for various anatomical geometries. Such systems biology approaches accommodate the effect of anti platelet pharmacological intervention where COX1 pathways or ADP signaling are modulated in a patient-specific manner. PMID- 23986722 TI - Challenges and opportunities of sensory plasticity after SCI. PMID- 23986723 TI - Basic disturbances of information processing in psychosis prediction. AB - The basic symptoms (BS) approach provides a valid instrument in predicting psychosis onset and represents moreover a significant heuristic framework for research. The term "basic symptoms" denotes subtle changes of cognition and perception in the earliest and prodromal stages of psychosis development. BS are thought to correspond to disturbances of neural information processing. Following the heuristic implications of the BS approach, the present paper aims at exploring disturbances of information processing, revealed by functional magnetic resonance imaging (fMRI) and electro-encephalographic as characteristics of the at-risk state of psychosis. Furthermore, since high-risk studies employing ultra high-risk criteria revealed non-conversion rates commonly exceeding 50%, thus warranting approaches that increase specificity, the potential contribution of neural information processing disturbances to psychosis prediction is reviewed. In summary, the at-risk state seems to be associated with information processing disturbances. Moreover, fMRI investigations suggested that disturbances of language processing domains might be a characteristic of the prodromal state. Neurophysiological studies revealed that disturbances of sensory processing may assist psychosis prediction in allowing for a quantification of risk in terms of magnitude and time. The latter finding represents a significant advancement since an estimation of the time to event has not yet been achieved by clinical approaches. Some evidence suggests a close relationship between self-experienced BS and neural information processing. With regard to future research, the relationship between neural information processing disturbances and different clinical risk concepts warrants further investigations. Thereby, a possible time sequence in the prodromal phase might be of particular interest. PMID- 23986725 TI - How robust is the language architecture? The case of mood. AB - In neurocognitive research on language, the processing principles of the system at hand are usually assumed to be relatively invariant. However, research on attention, memory, decision-making, and social judgment has shown that mood can substantially modulate how the brain processes information. For example, in a bad mood, people typically have a narrower focus of attention and rely less on heuristics. In the face of such pervasive mood effects elsewhere in the brain, it seems unlikely that language processing would remain untouched. In an EEG experiment, we manipulated the mood of participants just before they read texts that confirmed or disconfirmed verb-based expectations about who would be talked about next (e.g., that "David praised Linda because ... " would continue about Linda, not David), or that respected or violated a syntactic agreement rule (e.g., "The boys turns"). ERPs showed that mood had little effect on syntactic parsing, but did substantially affect referential anticipation: whereas readers anticipated information about a specific person when they were in a good mood, a bad mood completely abolished such anticipation. A behavioral follow-up experiment suggested that a bad mood did not interfere with verb-based expectations per se, but prevented readers from using that information rapidly enough to predict upcoming reference on the fly, as the sentence unfolds. In all, our results reveal that background mood, a rather unobtrusive affective state, selectively changes a crucial aspect of real-time language processing. This observation fits well with other observed interactions between language processing and affect (emotions, preferences, attitudes, mood), and more generally testifies to the importance of studying "cold" cognitive functions in relation to "hot" aspects of the brain. PMID- 23986726 TI - Causal Rasch models. AB - Rasch's unidimensional models for measurement show how to connect object measures (e.g., reader abilities), measurement mechanisms (e.g., machine-generated cloze reading items), and observational outcomes (e.g., counts correct on reading instruments). Substantive theory shows what interventions or manipulations to the measurement mechanism can be traded off against a change to the object measure to hold the observed outcome constant. A Rasch model integrated with a substantive theory dictates the form and substance of permissible interventions. Rasch analysis, absent construct theory and an associated specification equation, is a black box in which understanding may be more illusory than not. Finally, the quantitative hypothesis can be tested by comparing theory-based trade-off relations with observed trade-off relations. Only quantitative variables (as measured) support such trade-offs. Note that to test the quantitative hypothesis requires more than manipulation of the algebraic equivalencies in the Rasch model or descriptively fitting data to the model. A causal Rasch model involves experimental intervention/manipulation on either reader ability or text complexity or a conjoint intervention on both simultaneously to yield a successful prediction of the resultant observed outcome (count correct). We conjecture that when this type of manipulation is introduced for individual reader text encounters and model predictions are consistent with observations, the quantitative hypothesis is sustained. PMID- 23986724 TI - Electroconvulsive Treatment: Hypotheses about Mechanisms of Action. AB - No consensus has been reached on the mode of action of electroconvulsive treatment (ECT). We suggest that two features may aid in the delineation of the involved mechanisms. First, when effective, ECT would be likely to affect brain functions that are typically altered in its primary recipient group, people with severe depression. Central among these are the frontal and temporal lobes, the hypothalamus-pituitary-adrenal (HPA) stress axis, and the mesocorticolimbic dopamine system. Second, the involved mechanisms should be affected for a time period that matches the average endurance of clinical effects, which is indicated to be several days to a few weeks. To identify effects upon frontal and temporal lobe functioning we reviewed human studies using EEG, PET, SPECT, and fMRI. Effects upon the HPA axis and the dopamine system were assessed by reviewing both human and animal studies. The EEG studies indicate that ECT decelerates neural activity in the frontal and temporal lobes (increased delta and theta wave activity) for weeks to months. Comparable findings are reported from PET and SPECT studies, with reduced cerebral blood flow (functional deactivation) for weeks to months after treatment. The EEG deceleration and functional deactivation following ECT are statistically associated with reduced depression scores. FMRI studies indicate that ECT flattens the pattern of activation and deactivation that is associated with cognitive task performance and alters cortical functional connectivity in the ultra slow frequency range. A common finding from human and animal studies is that ECT acutely activates both the HPA axis and the dopamine system. In considering this evidence, we hypothesize that ECT affects the brain in a similar manner as severe stress or brain trauma which activates the HPA axis and the dopamine system and may compromise frontotemporal functions. PMID- 23986727 TI - Freedom of the mind. PMID- 23986728 TI - Global interference during early visual processing: ERP evidence from a rapid global/local selective task. AB - Visual perception depends on the integration of local elements of a visual scene into a global frame. Evidence from behavioral studies shows that (1) the detection of the global frame is faster than the detection of the local parts, a phenomenon called the global advantage, and that (2) an interference of the global shape is also present during local processing. Together, these effects are called the global precedence effect (GPE). Even if the global advantage appears to impact neural processing as early as the first 100 ms post-stimulus, previous studies failed to find a global interference effect before 200 ms post-stimulus. Using for the first time a rapid display of letter component stimuli during a global/local selective task in which conditions with perceptual conflict, congruent and incongruent conditions were considered, the present event-related potential (ERP) study shows a global interference effect occurring as early as the time range of the N1 component. In particular, only congruent stimuli elicited similar N1 amplitude during the global and local tasks, whereas an increased of the N1 amplitude during the global task was observed (as compared to the local task) for both stimuli with perceptual conflict and incongruent stimuli. This finding corroborates the recent neural models of human visual perception. PMID- 23986729 TI - Abnormal task modulation of oscillatory neural activity in schizophrenia. AB - Schizophrenia patients have deficits in cognitive function that are a core feature of the disorder. AX-CPT is commonly used to study cognition in schizophrenia, and patients have characteristic pattern of behavioral and ERP response. In AX-CPT subjects respond when a flashed cue "A" is followed by a target "X," ignoring other letter combinations. Patients show reduced hit rate to "go" trials, and increased false alarms to sequences that require inhibition of a prepotent response. EEG recordings show reduced sensory (P1/N1), as well as later cognitive components (N2, P3, CNV). Behavioral deficits correlate most strongly with sensory dysfunction. Oscillatory analyses provide critical information regarding sensory/cognitive processing over and above standard ERP analyses. Recent analyses of induced oscillatory activity in single trials during AX-CPT in healthy volunteers showed characteristic response patterns in theta, alpha, and beta frequencies tied to specific sensory and cognitive processes. Alpha and beta modulated during the trials and beta modulation over the frontal cortex correlated with reaction time. In this study, EEG data was obtained from 18 schizophrenia patients and 13 controls during AX-CPT performance, and single trial decomposition of the signal yielded power in the target wavelengths. Significant task-related event-related desynchronization (ERD) was observed in both alpha and beta frequency bands over parieto-occipital cortex related to sensory encoding of the cue. This modulation was reduced in patients for beta, but not for alpha. In addition, significant beta ERD was observed over motor cortex, related to motor preparation for the response, and was also reduced in patients. These findings demonstrate impaired dynamic modulation of beta frequency rhythms in schizophrenia, and suggest that failures of oscillatory activity may underlie impaired sensory information processing in schizophrenia that in turn contributes to cognitive deficits. PMID- 23986730 TI - Strategic modulation of response inhibition in task-switching. AB - Residual activations from previous task performance usually prime the system toward response repetition. However, when the task switches, the repetition of a response (RR) produces longer reaction times and higher error rates. Some researchers assumed that these RR costs reflect strategic inhibition of just executed responses and that this serves for preventing perseveration errors. We investigated whether the basic level of response inhibition is adapted to the overall risk of response perseveration. In a series of 3 experiments, we presented different proportions of stimuli that carry either a high or a low risk of perseveration. Additionally, the discriminability of high- and low-risk stimuli was varied. The results indicate that individuals apply several processing and control strategies, depending on the mixture of stimulus types. When discriminability was high, control was adapted on a trial-by trial basis, which presumably reduces mental effort (Experiment 1). When trial-based strategies were prevented, RR costs for low-risk stimuli varied with the overall proportion of high-risk stimuli (Experiments 2 and 3), indicating an adaptation of the basic level of response inhibition. PMID- 23986731 TI - Manipulations of word frequency reveal differences in the processing of morphologically complex and simple words in German. AB - We tested current models of morphological processing in reading with data from four visual lexical decision experiments using German compounds and monomorphemic words. Triplets of two semantically transparent noun-noun compounds and one monomorphemic noun were used in Experiments 1a and 1b. Stimuli within a triplet were matched for full-form frequency. The frequency of the compounds' constituents was varied. The compounds of a triplet shared one constituent, while the frequency of the unshared constituent was either high or low, but always higher than full-form frequency. Reactions were faster to compounds with high frequency constituents than to compounds with low-frequency constituents, while the latter did not differ from the monomorphemic words. This pattern was not influenced by task difficulty, induced by the type of pseudocompounds used. Pseudocompounds were either created by altering letters of an existing compound (easy pseudocompound, Experiment 1a) or by combining two free morphemes into a non-existing, but morphologically legal, compound (difficult pseudocompound, Experiment 1b). In Experiments 2a and 2b, frequency-matched pairs of semantically opaque noun-noun compounds and simple nouns were tested. In Experiment 2a, with easy pseudocompounds (of the same type as in Experiment 1a), a reaction-time advantage for compounds over monomorphemic words was again observed. This advantage disappeared in Experiment 2b, where difficult pseudocompounds were used. Although a dual-route might account for the data, the findings are best understood in terms of decomposition of low-frequency complex words prior to lexical access, followed by processing costs due to the recombination of morphemes for meaning access. These processing costs vary as a function of intrinsic factors such as semantic transparency, or external factors such as the difficulty of the experimental task. PMID- 23986732 TI - Sex, symptom, and premorbid social functioning associated with perceptual organization dysfunction in schizophrenia. AB - Impairments in visual perceptual organization abilities are a repeatedly observed cognitive deficit in schizophrenia. These impairments have been found to be most prominent among patients with histories of poor premorbid social functioning, disorganized symptoms, and poor clinical outcomes. Despite the demonstration of significant sex differences for these clinical factors in schizophrenia, the extent of sex differences for visual perceptual organization in schizophrenia is unknown. Therefore, we investigated the extent to which previously known correlates (premorbid social sexual functioning and disorganized symptoms) and a novel factor (participant sex) accounted for performance on two perceptual organization tasks (contour integration and Ebbinghaus illusion) that have previously demonstrated sensitivity to schizophrenia. We also determined the relative degree to which each of these factors predicted task scores over and above the others. Schizophrenia patients (N = 109, 43 females) from different levels of care were ascertained. Female patients demonstrated higher contour integration scores, but lower performance on the context sensitivity index of the Ebbinghaus illusion, compared to males. Contour integration performance was significantly associated with poorer premorbid adolescent social sexual functioning and higher levels of disorganized symptoms, supporting past results that indicate a relationship among poor premorbid social sexual functioning, disorganized symptoms, and visual perceptual abnormalities in schizophrenia. However, analyses of Ebbinghaus illusion performance suggests there is a complex relationship among patient sex, clinical factors and perceptual abilities with relatively intact bottom-up grouping processes in females, but greater problems, compared to males with more top-down mediated context sensitivity. Therefore, sex differences may be an important consideration for future studies of visual perceptual organization in schizophrenia. PMID- 23986733 TI - Coding task performance in early adolescence: a large-scale controlled study into boy-girl differences. AB - This study examined differences between boys and girls regarding efficiency of information processing in early adolescence. Three hundred and six healthy adolescents (50.3% boys) in grade 7 and 9 (aged 13 and 15, respectively) performed a coding task based on over-learned symbols. An age effect was revealed as subjects in grade 9 performed better than subjects in grade 7. Main effects for sex were found in the advantage of girls. The 25% best-performing students comprised twice as many girls as boys. The opposite pattern was found for the worst performing 25%. In addition, a main effect was found for educational track in favor of the highest track. No interaction effects were found. School grades did not explain additional variance in LDST performance. This indicates that cognitive performance is relatively independent from school performance. Student characteristics like age, sex, and education level were more important for efficiency of information processing than school performance. The findings imply that after age 13, efficiency of information processing is still developing and that girls outperform boys in this respect. The findings provide new information on the mechanisms underlying boy-girl differences in scholastic performance. PMID- 23986734 TI - Maternal representations in the dreams of pregnant women: a prospective comparative study. AB - Dreams are thought to respond to self- and socially-relevant situations that evoke strong emotions and require rapid adaptation. First pregnancy is such a situation during which maternal mental representations (MMR) of the unborn baby, the self and significant others undergo remodeling. Some studies suggest that dreams during pregnancy contain more MMR and are more dysphoric, but such studies contain important methodological flaws. We assessed whether dreamed MMR, like waking MMR, change from the 7th month of pregnancy to birth, and whether pregnancy-related themes and non-pregnancy characteristics are also transformed. Sixty non-pregnant and 59 pregnant women (37 early and 22 late 3rd trimester) completed demographic and psychological questionnaires and 14-day home dream logs. Dream reports were blindly rated according to four dream categories: (1) Dreamed MMR, (2) Quality of baby/child representations, (3) Pregnancy-related themes, (4) Non-pregnancy characteristics. Controlling for age, relationship and employment status, education level and state anxiety, women in both pregnant groups reported more dreams depicting themselves as a mother or with babies/children than did non-pregnant women (all p = 0.006). Baby/child representations were less specific in the late 3rd than in the early 3rd trimester (p = 0.005) and than in non-pregnant women (p = 0.01). Pregnant groups also had more pregnancy, childbirth and fetus themes (all p = 0.01). Childbirth content was higher in late than in early 3rd trimester (p = 0.01). Pregnant groups had more morbid elements than did the non-pregnant group (all p < 0.05). Dreaming during pregnancy appears to reflect daytime processes of remodeling MMR of the woman as a mother and of her unborn baby, and parallels a decline in the quality of baby/child representations in the last stage of pregnancy. More frequent morbid content in late pregnancy suggests that the psychological challenges of pregnancy are reflected in a generally more dysphoric emotional tone in dream content. PMID- 23986735 TI - Community structure in the phonological network. AB - Community structure, which refers to the presence of densely connected groups within a larger network, is a common feature of several real-world networks from a variety of domains such as the human brain, social networks of hunter-gatherers and business organizations, and the World Wide Web (Porter et al., 2009). Using a community detection technique known as the Louvain optimization method, 17 communities were extracted from the giant component of the phonological network described in Vitevitch (2008). Additional analyses comparing the lexical and phonological characteristics of words in these communities against words in randomly generated communities revealed several novel discoveries. Larger communities tend to consist of short, frequent words of high degree and low age of acquisition ratings, and smaller communities tend to consist of longer, less frequent words of low degree and high age of acquisition ratings. Real communities also contained fewer different phonological segments compared to random communities, although the number of occurrences of phonological segments found in real communities was much higher than that of the same phonological segments in random communities. Interestingly, the observation that relatively few biphones occur very frequently and a large number of biphones occur rarely within communities mirrors the pattern of the overall frequency of words in a language (Zipf, 1935). The present findings have important implications for understanding the dynamics of activation spread among words in the phonological network that are relevant to lexical processing, as well as understanding the mechanisms that underlie language acquisition and the evolution of language. PMID- 23986736 TI - Time in terms of space. PMID- 23986737 TI - Why we should talk about option generation in decision-making research. AB - Most empirical studies on decision-making start from a set of given options for action. However, in everyday life there is usually no one asking you to choose between A, B, and C. Recently, the question how people come up with options has been receiving growing attention. However, so far there has been neither a systematic attempt to define the construct of "option" nor an attempt to show why decision-making research really needs this construct. This paper aims to fill that void by developing definitions of "option" and "option generation" that can be used as a basis for decision-making research in a wide variety of decision making settings, while clarifying how these notions relate to familiar psychological constructs. We conclude our analysis by arguing that there are indeed reasons to believe that option generation is an important and distinct aspect of human decision-making. PMID- 23986738 TI - Measuring phonetic convergence in speech production. AB - Phonetic convergence is defined as an increase in the similarity of acoustic phonetic form between talkers. Previous research has demonstrated phonetic convergence both when a talker listens passively to speech and while talkers engage in social interaction. Much of this research has focused on a diverse array of acoustic-phonetic attributes, with fewer studies incorporating perceptual measures of phonetic convergence. The current paper reviews research on phonetic convergence in both non-interactive and conversational settings, and attempts to consolidate the diverse array of findings by proposing a paradigm that models perceptual and acoustic measures together. By modeling acoustic measures as predictors of perceived phonetic convergence, this paradigm has the potential to reconcile some of the diverse and inconsistent findings currently reported in the literature. PMID- 23986739 TI - Young and restless: validation of the Mind-Wandering Questionnaire (MWQ) reveals disruptive impact of mind-wandering for youth. AB - Mind-wandering is the focus of extensive investigation, yet until recently there has been no validated scale to directly measure trait levels of task-unrelated thought. Scales commonly used to assess mind-wandering lack face validity, measuring related constructs such as daydreaming or behavioral errors. Here we report four studies validating a Mind-Wandering Questionnaire (MWQ) across college, high school, and middle school samples. The 5-item scale showed high internal consistency, as well as convergent validity with existing measures of mind-wandering and related constructs. Trait levels of mind-wandering, as measured by the MWQ, were correlated with task-unrelated thought measured by thought sampling during a test of reading comprehension. In both middle school and high school samples, mind-wandering during testing was associated with worse reading comprehension. By contrast, elevated trait levels of mind-wandering predicted worse mood, less life-satisfaction, greater stress, and lower self esteem. By extending the use of thought sampling to measure mind-wandering among adolescents, our findings also validate the use of this methodology with younger populations. Both the MWQ and thought sampling indicate that mind-wandering is a pervasive-and problematic-influence on the performance and well-being of adolescents. PMID- 23986740 TI - German and Korean mothers' sensitivity and related parenting beliefs. AB - This study contributes to a differentiated understanding of maternal sensitivity in cultural and situational context. We investigated differences and similarities in German and Korean mothers' maternal sensitivity. We interviewed 92 German and 100 Korean mothers of first graders about their preference for proactive (anticipating children's needs) or reactive sensitivity (responding to children's direct cues) in different scenarios. Related parenting beliefs were assessed by asking the mothers to explain the reasons why they would prefer specific parenting behaviors. Results revealed significant cultural differences in reactive vs. proactive sensitivity preferences. Overall, German mothers were more likely to indicate that a mother should respond reactively and less likely to report that a mother should act proactively than were Korean mothers. Korean mothers gave preference to both reactive and proactive sensitivity depending on the scenario. With regard to parenting beliefs, analyses revealed that German and Korean mothers who preferred reactive sensitivity mainly explained their choices as attempts to encourage children's development of independence. In contrast, Korean and German mothers with a preference for proactive sensitivity were more likely to report that mothers would assist their children due to their immaturity in dealing with emotional distress. Results are discussed in the framework of the different meanings and functions of maternal sensitivity for socialization in different cultural contexts. PMID- 23986741 TI - Caveats for using shock tube in blast-induced traumatic brain injury research. PMID- 23986742 TI - Levetiracetam use in the critical care setting. AB - Intravenous (IV) levetiracetam (LEV) is currently approved as an alternative or replacement therapy for patients unable to take the oral form of this antiepileptic drug (AED). The oral form has Food and Drug Administration (FDA) indications for adjunctive therapy in the treatment of partial onset epilepsy ages 1 month or more, myoclonic seizures associated with juvenile myoclonic epilepsy starting with the age of 12 and primary generalized tonic-clonic seizures in people 6 years and older. Since the initial introduction, oral and IV LEV has been evaluated in various studies conducted in the critical care setting for the treatment of status epilepticus, stroke-related seizures, seizures following subarachnoid or intracerebral hemorrhage, post-traumatic seizures, tumor-related seizures, and seizures in critically ill patients. Additionally, studies evaluating rapid infusion of IV LEV and therapeutic monitoring of serum LEV levels in different patient populations have been performed. In this review we present the current state of knowledge on LEV use in the critical care setting focusing on the IV uses and discuss future research needs. PMID- 23986743 TI - An Intimate Relationship between Thyroid Hormone and Skin: Regulation of Gene Expression. AB - Skin is the largest organ of the human body and plays a key role in protecting the individual from external insults. The barrier function of the skin is performed primarily by the epidermis, a self-renewing stratified squamous epithelium composed of cells that undergo a well-characterized and finely tuned process of terminal differentiation. By binding to their receptors thyroid hormones (TH) regulate epidermal cell proliferation, differentiation, and homeostasis. Thyroid dysfunction has multiple classical manifestations at skin level. Several TH-responsive genes, as well as genes critical for TH metabolism and action, are expressed at epidermal level. The role of TH in skin is still controversial, although it is generally recognized that TH signaling is central for skin physiology and homeostasis. Here we review the data on the epidermis and its function in relation to TH metabolism and regulation of gene expression. An understanding of the cellular and molecular basis of TH action in epidermal cells may lead to the identification of putative therapeutical targets for treatment of skin disorders. PMID- 23986745 TI - Acculturation, Dietary Acceptability, and Diabetes Management among Chinese in North America. AB - Immigrants to a new country face many challenges when diagnosed with type 2 diabetes, a chronic disease with a complex treatment involving both medical and behavioral interventions. These challenges will depend upon the extent to which the patient has adapted to the new country's social and cultural norms, as well as individual factors such as age, education, and gender. This adaptation is termed acculturation. With respect to nutritional interventions for type 2 diabetes, uptake and adherence over the long term will depend upon overall health literacy, the cultural acceptability of the recommended diet. This review has focused on acculturation and its effects on diabetes management in ethnic Chinese in North America as an example of one populous minority and the challenges faced in adopting nutritional recommendations. Research directions and practical considerations are suggested. PMID- 23986747 TI - Retraction: Colonic flora, probiotics, obesity and diabetes. PMID- 23986746 TI - Intersectin: The Crossroad between Vesicle Exocytosis and Endocytosis. AB - Intersectins (ITSNs) are a family of highly conserved proteins with orthologs from nematodes to mammals. In vertebrates, ITSNs are encoded by two genes (itsn1 and itsn2), which act as scaffolds that were initially discovered as proteins involved in endocytosis. Further investigation demonstrated that ITSN1 is also implicated in several other processes including regulated exocytosis, thereby suggesting a role for ITSN1 in the coupling between exocytosis and endocytosis in excitatory cells. Despite a high degree of conservation amongst orthologs, ITSN function is not so well preserved as they have acquired new properties during evolution. In this review, we will discuss the role of ITSN1 and its orthologs in exo- and endocytosis, in particular in neurons and neuroendocrine cells. PMID- 23986744 TI - Bone vascularization in normal and disease conditions. AB - Bone vasculature is essential for many processes, such as skeletal development and growth, bone modeling and remodeling, and healing processes. Endothelium is an integral part of bone tissue, expressing a physiological paracrine function via growth factors and chemokines release, and interacting with several cellular lines. Alterations of the complex biochemical interactions between vasculature and bone cells may lead to various clinical manifestations. Two different types of pathologies result: a defect or an excess of bone vasculature or endothelium metabolism. Starting from the molecular basis of the interactions between endothelial and bone cells, the Authors present an overview of the recent acquisitions in the physiopathology of the most important clinical patterns, and the modern therapeutic strategies for their treatments. PMID- 23986748 TI - Dinitrogen fixation in aphotic oxygenated marine environments. AB - We measured N2 fixation rates from oceanic zones that have traditionally been ignored as sources of biological N2 fixation; the aphotic, fully oxygenated, nitrate (NO(-) 3)-rich, waters of the oligotrophic Levantine Basin (LB) and the Gulf of Aqaba (GA). N2 fixation rates measured from pelagic aphotic waters to depths up to 720 m, during the mixed and stratified periods, ranged from 0.01 nmol N L(-1) d(-1) to 0.38 nmol N L(-1) d(-1). N2 fixation rates correlated significantly with bacterial productivity and heterotrophic diazotrophs were identified from aphotic as well as photic depths. Dissolved free amino acid amendments to whole water from the GA enhanced bacterial productivity by 2-3.5 fold and N2 fixation rates by ~2-fold in samples collected from aphotic depths while in amendments to water from photic depths bacterial productivity increased 2-6 fold while N2 fixation rates increased by a factor of 2 to 4 illustrating that both BP and heterotrophic N2 fixation were carbon limited. Experimental manipulations of aphotic waters from the LB demonstrated a significant positive correlation between transparent exopolymeric particle (TEP) concentrations and N2 fixation rates. This suggests that sinking organic material and high carbon (C): nitrogen (N) micro-environments (such as TEP-based aggregates or marine snow) could support high heterotrophic N2 fixation rates in oxygenated surface waters and in the aphotic zones. Indeed, our calculations show that aphotic N2 fixation accounted for 37 to 75% of the total daily integrated N2 fixation rates at both locations in the Mediterranean and Red Seas with rates equal or greater to those measured from the photic layers. Moreover, our results indicate that that while N2 fixation may be limited in the surface waters, aphotic, pelagic N2 fixation may contribute significantly to new N inputs in other oligotrophic basins, yet it is currently not included in regional or global N budgets. PMID- 23986749 TI - Mechanisms of antimicrobial resistance in finfish aquaculture environments. AB - Consumer demand for affordable fish drives the ever-growing global aquaculture industry. The intensification and expansion of culture conditions in the production of several finfish species has been coupled with an increase in bacterial fish disease and the need for treatment with antimicrobials. Understanding the molecular mechanisms of antimicrobial resistance prevalent in aquaculture environments is important to design effective disease treatment strategies, to prioritize the use and registration of antimicrobials for aquaculture use, and to assess and minimize potential risks to public health. In this brief article we provide an overview of the molecular mechanisms of antimicrobial resistance in genes found in finfish aquaculture environments and highlight specific research that should provide the basis of sound, science-based policies for the use of antimicrobials in aquaculture. PMID- 23986751 TI - Effects of Spartina alterniflora invasion on the communities of methanogens and sulfate-reducing bacteria in estuarine marsh sediments. AB - The effect of plant invasion on the microorganisms of soil sediments is very important for estuary ecology. The community structures of methanogens and sulfate-reducing bacteria (SRB) as a function of Spartina alterniflora invasion in Phragmites australis-vegetated sediments of the Dongtan wetland in the Yangtze River estuary, China, were investigated using 454 pyrosequencing and quantitative real-time PCR (qPCR) of the methyl coenzyme M reductase A (mcrA) and dissimilatory sulfite-reductase (dsrB) genes. Sediment samples were collected from two replicate locations, and each location included three sampling stands each covered by monocultures of P. australis, S. alterniflora and both plants (transition stands), respectively. qPCR analysis revealed higher copy numbers of mcrA genes in sediments from S. alterniflora stands than P. australis stands (5- and 7.5-fold more in the spring and summer, respectively), which is consistent with the higher methane flux rates measured in the S. alterniflora stands (up to 8.01 +/- 5.61 mg m(-2) h(-1)). Similar trends were observed for SRB, and they were up to two orders of magnitude higher than the methanogens. Diversity indices indicated a lower diversity of methanogens in the S. alterniflora stands than the P. australis stands. In contrast, insignificant variations were observed in the diversity of SRB with the invasion. Although Methanomicrobiales and Methanococcales, the hydrogenotrophic methanogens, dominated in the salt marsh, Methanomicrobiales displayed a slight increase with the invasion and growth of S. alterniflora, whereas the later responded differently. Methanosarcina, the metabolically diverse methanogens, did not vary with the invasion of, but Methanosaeta, the exclusive acetate utilizers, appeared to increase with S. alterniflora invasion. In SRB, sequences closely related to the families Desulfobacteraceae and Desulfobulbaceae dominated in the salt marsh, although they displayed minimal changes with the S. alterniflora invasion. Approximately 11.3 +/- 5.1% of the dsrB gene sequences formed a novel cluster that was reduced upon the invasion. The results showed that in the sediments of tidal salt marsh where S. alterniflora displaced P. australis, the abundances of methanogens and SRB increased, but the community composition of methanogens appeared to be influenced more than did the SRB. PMID- 23986752 TI - Transcriptional regulation of the carbohydrate utilization network in Thermotoga maritima. AB - Hyperthermophilic bacteria from the Thermotogales lineage can produce hydrogen by fermenting a wide range of carbohydrates. Previous experimental studies identified a large fraction of genes committed to carbohydrate degradation and utilization in the model bacterium Thermotoga maritima. Knowledge of these genes enabled comprehensive reconstruction of biochemical pathways comprising the carbohydrate utilization network. However, transcriptional factors (TFs) and regulatory mechanisms driving this network remained largely unknown. Here, we used an integrated approach based on comparative analysis of genomic and transcriptomic data for the reconstruction of the carbohydrate utilization regulatory networks in 11 Thermotogales genomes. We identified DNA-binding motifs and regulons for 19 orthologous TFs in the Thermotogales. The inferred regulatory network in T. maritima contains 181 genes encoding TFs, sugar catabolic enzymes and ABC-family transporters. In contrast to many previously described bacteria, a transcriptional regulation strategy of Thermotoga does not employ global regulatory factors. The reconstructed regulatory network in T. maritima was validated by gene expression profiling on a panel of mono- and disaccharides and by in vitro DNA-binding assays. The observed upregulation of genes involved in catabolism of pectin, trehalose, cellobiose, arabinose, rhamnose, xylose, glucose, galactose, and ribose showed a strong correlation with the UxaR, TreR, BglR, CelR, AraR, RhaR, XylR, GluR, GalR, and RbsR regulons. Ultimately, this study elucidated the transcriptional regulatory network and mechanisms controlling expression of carbohydrate utilization genes in T. maritima. In addition to improving the functional annotations of associated transporters and catabolic enzymes, this research provides novel insights into the evolution of regulatory networks in Thermotogales. PMID- 23986750 TI - The MHC-II transactivator CIITA, a restriction factor against oncogenic HTLV-1 and HTLV-2 retroviruses: similarities and differences in the inhibition of Tax-1 and Tax-2 viral transactivators. AB - The activation of CD4(+) T helper cells is strictly dependent on the presentation of antigenic peptides by MHC class II (MHC-II) molecules. MHC-II expression is primarily regulated at the transcriptional level by the AIR-1 gene product CIITA (class II transactivator). Thus, CIITA plays a pivotal role in the triggering of the adaptive immune response against pathogens. Besides this well known function, we recently found that CIITA acts as an endogenous restriction factor against HTLV-1 (human T cell lymphotropic virus type 1) and HTLV-2 oncogenic retroviruses by targeting their viral transactivators Tax-1 and Tax-2, respectively. Here we review our findings on CIITA-mediated inhibition of viral replication and discuss similarities and differences in the molecular mechanisms by which CIITA specifically counteracts the function of Tax-1 and Tax-2 molecules. The dual function of CIITA as a key regulator of adaptive and intrinsic immunity represents a rather unique example of adaptation of host-derived factors against pathogen infections during evolution. PMID- 23986753 TI - Characterization of hospital-associated lineages of ampicillin-resistant Enterococcus faecium from clinical cases in dogs and humans. AB - Ampicillin-resistant Enterococcus faecium (ARE) has rapidly emerged worldwide and is one of the most important nosocomial pathogens. However, very few reports are available on ARE isolates from canine clinical cases. The objective of this study was to characterize ARE strains of canine clinical origin from a veterinary teaching hospital in Canada and to compare them with human strains. Ten ARE strains from dogs and humans were characterized by multilocus sequence typing (MLST), pulsed field gel electrophoresis (PFGE), antibiotic susceptibility and biofilm activities, presence of rep-families, CRISPR-cas and putative virulence genes. All ARE strains (n = 10) were resistant to ciprofloxacin and lincomycin. Resistances to tetracycline (n = 6), macrolides (n = 6), and to high concentrations of gentamicin, kanamycin and streptomycin (n = 5) were also observed. Canine ARE isolates were found to be susceptible to vancomycin whereas resistance to this antibiotic was observed in human strains. Ampicillin resistance was linked to PBP5 showing mutations at 25 amino acid positions. Fluoroquinolone resistance was attributable to ParC, GyrA, and GyrB mutations. Data demonstrated that all canine ARE were acm (collagen binding protein) positive and that most harbored the efaAfm gene, encoding for a cell wall adhesin. Biofilm formation was observed in two human strains but not in canine strains. Two to five rep-families were observed per strain but no CRISPR sequences were found. A total of six STs (1, 18, 65, 202, 205, and 803) were found with one belonging to a new ST (ST803). These STs were identical or closely related to human hospital-associated lineages. This report describes for the first time the characterization of canine ARE hospital-associated strains in Canada and also supports the importance of prudent antibiotic use in veterinary medicine to avoid zoonotic spread of canine ARE. PMID- 23986754 TI - Microbial colonization of basaltic glasses in hydrothermal organic-rich sediments at Guaymas Basin. AB - Oceanic basalts host diverse microbial communities with various metabolisms involved in C, N, S, and Fe biogeochemical cycles which may contribute to mineral and glass alteration processes at, and below the seafloor. In order to study the microbial colonization on basaltic glasses and their potential biotic/abiotic weathering products, two colonization modules called AISICS ("Autonomous in situ Instrumented Colonization System") were deployed in hydrothermal deep-sea sediments at the Guaymas Basin for 8 days and 22 days. Each AISICS module contained 18 colonizers (including sterile controls) filled with basaltic glasses of contrasting composition. Chemical analyses of ambient fluids sampled through the colonizers showed a greater contribution of hydrothermal fluids (maximum temperature 57.6 degrees C) for the module deployed during the longer time period. For each colonizer, the phylogenetic diversity and metabolic function of bacterial and archaeal communities were explored using a molecular approach by cloning and sequencing. Results showed large microbial diversity in all colonizers. The bacterial distribution was primarily linked to the deployment duration, as well as the depth for the short deployment time module. Some 16s rRNA sequences formed a new cluster of Epsilonproteobacteria. Within the Archaea the retrieved diversity could not be linked to either duration, depth or substrata. However, mcrA gene sequences belonging to the ANME-1 mcrA-guaymas cluster were found sometimes associated with their putative sulfate-reducers syntrophs depending on the colonizers. Although no specific glass alteration texture was identified, nano-crystals of barite and pyrite were observed in close association with organic matter, suggesting a possible biological mediation. This study gives new insights into the colonization steps of volcanic rock substrates and the capability of microbial communities to exploit new environmental conditions. PMID- 23986755 TI - HPV18 E1^E4 is assembled into aggresome-like compartment and involved in sequestration of viral oncoproteins. AB - Papillomavirus is the etiological agent for warts and several squamous carcinomas. Skin cancer induced by cottontail rabbit papillomavirus was the first animal model for virus-induced carcinogenesis. The target organ of the virus infection is stratified epithelium and virus replication is tightly regulated by the differentiation program of the host cell. E1^E4 protein is a viral gene product, and although it is considered to be involved in the control of virus replication, little is known about the biological role. We found that HPV18 E1^E4 was assembled into an aggresome-like compartment and was involved in sequestration of virus oncoproteins, which might contribute to the differentiation-dependent lifecycle of papillomavirus. PMID- 23986757 TI - The multiple roles of antibiotics and antibiotic resistance in nature. PMID- 23986756 TI - Cellular and humoral immunity of virus-induced asthma. AB - Asthma inception is associated with respiratory viral infection, especially infection with respiratory syncytial virus (RSV) and/or human rhinovirus (HRV), in the vast majority of cases. However, the reason why RSV and HRV induce the majority of bronchiolitis cases during early childhood and why only a small percentage of children with RSV- and HRV-induced bronchiolitis later develop asthma remains unclear. A genetic association study has revealed the important interaction between viral illness and genetic variants in patients with asthma. Severe RSV- and HRV-induced bronchiolitis may be associated with a deficiency in the innate immune response to RSV and HRV. RSV and HRV infections in infants with deficient innate immune response and the dysfunction of regulatory T cells are considered to be a risk factor for the development of asthma. Sensitization to aeroallergens, beginning in the first year of life, consistently predisposes children to HRV-induced wheezing illnesses, but the converse is not true. Some evidence of virus specificity exists, in that allergic sensitization specifically increased the risk of wheezing in individuals infected with HRV, but not RSV. Administration of Palivizumab, a humanized monoclonal antibody that targets the A antigenic site of the Fusion-protein of RSV, decreases the risk of hospitalization in high-risk infants and the risk of recurrent of wheezing. However, palivizumab did not have any effect on subsequent recurrent wheezing in children with a family history of atopy. These findings suggest that infection with RSV and infection with HRV might predispose individuals to recurrent wheezing through an atopy-independent and an atopy-dependent mechanism, respectively. Respiratory virus-induced wheezing illnesses may encompass multiple sub-phenotypes that relate to asthma in different ways. PMID- 23986758 TI - Activin a inhibits antigen-induced allergy in murine epicutaneous sensitization. AB - Activin A, a member of the TGFbeta superfamily, is involved in physiological processes such as cell differentiation, tissue homeostasis, wound healing, reproduction, and in pathological conditions, such as fibrosis, cancer, and asthma. Activin enhances mast cell maturation, as well as regulatory T-cell and Langerhans cell differentiation. In this study we investigated the potential role of activin in epicutaneous sensitization with ovalbumin (OVA), notably with respect to its effect on known Th2-polarization. For this purpose, transgenic mice overexpressing activin in keratinocytes and their wild-type (WT) controls were sensitized epicutaneously with OVA. Skin biopsies were analyzed with regard to histopathological features and mRNA expression of pro-inflammatory and Th1/Th2 cytokines, and Ig levels were measured in the serum. Unexpectedly, activin overexpressing animals were protected from Th2-cytokine expression and induction of OVA-specific IgE levels compared to WT animals. On the other hand, transgenic mice were more susceptible to inflammation compared to WT littermates after tape stripping and saline (vehicle) or OVA application, as shown by increased pro inflammatory cytokine mRNA levels and neutrophil accumulation at the site of the treatment. We conclude that activin protects from antigen-induced cutaneous Th2 polarization through modulation of the immune response. These findings highlight the role of activin in cutaneous sensitization, allergy, and in skin homeostasis. PMID- 23986759 TI - Convergences and divergences of thymus- and peripherally derived regulatory T cells in cancer. AB - The expansion of regulatory T cells (Treg) is a common event characterizing the vast majority of human and experimental tumors and it is now well established that Treg represent a crucial hurdle for a successful immunotherapy. Treg are currently classified, according to their origin, into thymus-derived Treg (tTreg) or peripherally induced Treg (pTreg) cells. Controversy exists over the prevalent mechanism accounting for Treg expansion in tumors, since both tTreg proliferation and de novo pTreg differentiation may occur. Since tTreg and pTreg are believed as preferentially self-specific or broadly directed to non-self and tumor specific antigens, respectively, the balance between tTreg and pTreg accumulation may impact on the repertoire of antigen specificities recognized by Treg in tumors. The prevalence of tTreg or pTreg may also affect the outcome of immunotherapies based on tumor-antigen vaccination or Treg depletion. The mechanisms dictating pTreg induction or tTreg expansion/stability are a matter of intense investigation and the most recent results depict a complex landscape. Indeed, selected Treg subsets may display peculiar characteristics in terms of stability, suppressive function, and cytokine production, depending on microenvironmental signals. These features may be differentially distributed between pTreg and tTreg and may significantly affect the possibility of manipulating Treg in cancer therapy. We propose here that innovative immunotherapeutic strategies may be directed at diverting unstable/uncommitted Treg, mostly enriched in the pTreg pool, into tumor-specific effectors, while preserving systemic immune tolerance ensured by self-specific tTreg. PMID- 23986760 TI - Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases. AB - Elimination of potential self-reactive T cells in the thymus is crucial for preventing the onset of autoimmune diseases. Epithelial cell subsets localized in thymic medulla [medullary thymic epithelial cells (mTECs)] contribute to this process by supplying a wide range of self-antigens that are otherwise expressed in a tissue-specific manner (TSAs). Expression of some TSAs in mTECs is controlled by the autoimmune regulator (AIRE) protein, of which dysfunctional mutations are the causative factor of autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy (APECED). In addition to the elimination of self-reactive T cells, recent studies indicated roles of mTECs in the development of Foxp3 positive regulatory T cells, which suppress autoimmunity and excess immune reactions in peripheral tissues. The TNF family cytokines, RANK ligand, CD40 ligand, and lymphotoxin were found to promote the differentiation of AIRE- and TSA-expressing mTECs. Furthermore, activation of NF-kappaB is essential for mTEC differentiation. In this mini-review, we focus on molecular mechanisms that regulate induction of AIRE and TSA expression and discuss possible contributions of these mechanisms to prevent the onset of autoimmune diseases. PMID- 23986761 TI - Genetic Adjuvantation of Recombinant MVA with CD40L Potentiates CD8 T Cell Mediated Immunity. AB - Modified vaccinia Ankara (MVA) is a safe and promising viral vaccine vector that is currently investigated in several clinical and pre-clinical trials. In contrast to inactivated or sub-unit vaccines, MVA is able to induce strong humoral as well as cellular immune responses. In order to further improve its CD8 T cell inducing capacity, we genetically adjuvanted MVA with the coding sequence of murine CD40L, a member of the tumor necrosis factor superfamily. Immunization of mice with this new vector led to strongly enhanced primary and memory CD8 T cell responses. Concordant with the enhanced CD8 T cell response, we could detect stronger activation of dendritic cells and higher systemic levels of innate cytokines (including IL-12p70) early after immunization. Interestingly, acquisition of memory characteristics (i.e., IL-7R expression) was accelerated after immunization with MVA-CD40L in comparison to non-adjuvanted MVA. Furthermore, the generated cytotoxic T-lymphocytes (CTLs) also showed improved functionality as demonstrated by intracellular cytokine staining and in vivo killing activity. Importantly, the superior CTL response after a single MVA-CD40L immunization was able to protect B cell deficient mice against a fatal infection with ectromelia virus. Taken together, we show that genetic adjuvantation of MVA can change strength, quality, and functionality of innate and adaptive immune responses. These data should facilitate a rational vaccine design with a focus on rapid induction of large numbers of CD8 T cells able to protect against specific diseases. PMID- 23986764 TI - Resolution of inflammation: leukocytes and molecular pathways as potential therapeutic targets. PMID- 23986762 TI - Peripheral and thymic foxp3(+) regulatory T cells in search of origin, distinction, and function. AB - Over the past decade, much has been learnt and much more to discover about Foxp3(+) regulatory T cells (Tregs). Initially, it was thought that Tregs were a unique entity that originates in the thymus. It is now recognized that there is a fraternal twin sibling that is generated in the periphery. The difficulty is in the distinction between these two subsets. The ability to detect, monitor, and analyze these two subsets in health and disease will provide invaluable insights into their functions and purposes. The plasticity and mechanisms of action can be unique and not overlapping within these subsets. Therefore, the therapeutic targeting of a particular subset of Tregs might be more efficacious. In the past couple of years, a vast amount of data have provided a better understanding of the cellular and molecular components essential for their development and stability. Many studies are implicating their preferential involvement in certain diseases and immunologic tolerance. However, it remains controversial as to whether any phenotypic markers have been identified that can differentiate thymic versus peripheral Tregs. This review will address the validity and controversy regarding Helios, Lap/Garp and Neuropilin-1 as markers of thymic Tregs. It also will discuss updated information on distinguishing features of these two subsets and their critical roles in maternal-fetal tolerance and transplantation. PMID- 23986763 TI - Tissue specific heterogeneity in effector immune cell response. AB - Post pathogen invasion, migration of effector T-cell subsets to specific tissue locations is of prime importance for generation of robust immune response. Effector T cells are imprinted with distinct "homing codes" (adhesion molecules and chemokine receptors) during activation which regulate their targeted trafficking to specific tissues. Internal cues in the lymph node microenvironment along with external stimuli from food (vitamin A) and sunlight (vitamin D3) prime dendritic cells, imprinting them to play centre stage in the induction of tissue tropism in effector T cells. B cells as well, in a manner similar to effector T cells, exhibit tissue-tropic migration. In this review, we have focused on the factors regulating the generation and migration of effector T cells to various tissues along with giving an overview of tissue tropism in B cells. PMID- 23986765 TI - Comparative sequence analysis of nitrogen fixation-related genes in six legumes. AB - Legumes play an important role as food and forage crops in international agriculture especially in developing countries. Legumes have a unique biological process called nitrogen fixation (NF) by which they convert atmospheric nitrogen to ammonia. Although legume genomes have undergone polyploidization, duplication and divergence, NF-related genes, because of their essential functional role for legumes, might have remained conserved. To understand the relationship of divergence and evolutionary processes in legumes, this study analyzes orthologs and paralogs for selected 20 NF-related genes by using comparative genomic approaches in six legumes i.e., Medicago truncatula (Mt), Cicer arietinum, Lotus japonicus, Cajanus cajan (Cc), Phaseolus vulgaris (Pv), and Glycine max (Gm). Subsequently, sequence distances, numbers of synonymous substitutions per synonymous site (Ks) and non-synonymous substitutions per non-synonymous site (Ka) between orthologs and paralogs were calculated and compared across legumes. These analyses suggest the closest relationship between Gm and Cc and the highest distance between Mt and Pv in six legumes. Ks proportional plots clearly showed ancient genome duplication in all legumes, whole genome duplication event in Gm and also speciation pattern in different legumes. This study also reports some interesting observations e.g., no peak at Ks 0.4 in Gm-Gm, location of two independent genes next to each other in Mt and low Ks values for outparalogs for three genes as compared to other 12 genes. In summary, this study underlines the importance of NF-related genes and provides important insights in genome organization and evolutionary aspects of six legume species analyzed. PMID- 23986767 TI - Flexible resource allocation during plant defense responses. AB - Plants are organisms composed of modules connected by xylem and phloem transport streams. Attack by both insects and pathogens elicits sometimes rapid defense responses in the attacked module. We have also known for some time that proteins are often reallocated away from pathogen-infected tissues, while the same infection sites may draw carbohydrates to them. This has been interpreted as a tug of war in which the plant withdraws critical resources to block microbial growth while the microbes attempt to acquire more resources. Sink-source regulated transport among modules of critical resources, particularly carbon and nitrogen, is also altered in response to attack. Insects and jasmonate can increase local sink strength, drawing carbohydrates that support defense production. Shortly after attack, carbohydrates may also be drawn to the root. The rate and direction of movement of photosynthate or signals in phloem in response to attack is subject to constraints that include branching, degree of connection among tissues, distance between sources and sinks, proximity, strength, and number of competing sinks, and phloem loading/unloading regulators. Movement of materials (e.g., amino acids, signals) to or from attack sites in xylem is less well understood but is partly driven by transpiration. The root is an influential sink and may regulate sink-source interactions and transport above and below ground as well as between the plant and the rhizosphere and nearby, connected plants. Research on resource translocation in response to pathogens or herbivores has focused on biochemical mechanisms; whole-plant research is needed to determine which, if any, of these plant behaviors actually influence plant fitness. PMID- 23986766 TI - Perspectives on deciphering mechanisms underlying plant heat stress response and thermotolerance. AB - Global warming is a major threat for agriculture and food safety and in many cases the negative effects are already apparent. The current challenge of basic and applied plant science is to decipher the molecular mechanisms of heat stress response (HSR) and thermotolerance in detail and use this information to identify genotypes that will withstand unfavorable environmental conditions. Nowadays X omics approaches complement the findings of previous targeted studies and highlight the complexity of HSR mechanisms giving information for so far unrecognized genes, proteins and metabolites as potential key players of thermotolerance. Even more, roles of epigenetic mechanisms and the involvement of small RNAs in thermotolerance are currently emerging and thus open new directions of yet unexplored areas of plant HSR. In parallel it is emerging that although the whole plant is vulnerable to heat, specific organs are particularly sensitive to elevated temperatures. This has redirected research from the vegetative to generative tissues. The sexual reproduction phase is considered as the most sensitive to heat and specifically pollen exhibits the highest sensitivity and frequently an elevation of the temperature just a few degrees above the optimum during pollen development can have detrimental effects for crop production. Compared to our knowledge on HSR of vegetative tissues, the information on pollen is still scarce. Nowadays, several techniques for high-throughput X-omics approaches provide major tools to explore the principles of pollen HSR and thermotolerance mechanisms in specific genotypes. The collection of such information will provide an excellent support for improvement of breeding programs to facilitate the development of tolerant cultivars. The review aims at describing the current knowledge of thermotolerance mechanisms and the technical advances which will foster new insights into this process. PMID- 23986768 TI - Fe deficiency differentially affects the vacuolar proton pumps in cucumber and soybean roots. AB - Iron uptake in dicots depends on their ability to induce a set of responses in root cells including rhizosphere acidification through H(+) extrusion and apoplastic Fe(III) reduction by Fe(III)-chelate reductase. These responses must be sustained by metabolic rearrangements aimed at providing the required NAD(P)H, ATP and H(+). Previous results in Fe-deficient cucumber roots showed that high H(+) extrusion is accompanied by increased phosphoenolpyruvate carboxylase (PEPC) activity, involved in the cytosol pH-stat; moreover (31)P-NMR analysis revealed increased vacuolar pH and decreased vacuolar [inorganic phosphate (Pi)]. The opposite was found in soybean: low rhizosphere acidification, decreased PEPC activity, vacuole acidification, and increased vacuolar [Pi]. These findings, highlighting a different impact of the Fe deficiency responses on cytosolic pH in the two species, lead to hypothesize different roles for H(+) and Pi movements across the tonoplast in pH homeostasis. The role of vacuole in cytosolic pH-stat involves the vacuolar H(+)-ATPase (V-ATPase) and vacuolar H(+)-pyrophosphatase (V PPase) activities, which generating the DeltapH and DeltaPsi, mediate the transport of solutes, among which Pi, across the tonoplast. Fluxes of Pi itself in its two ionic forms, H2PO4 (-) predominating in the vacuole and HPO4 (2-) in the cytosol, may be involved in pH homeostasis owing to its pH-dependent protonation/deprotonation reactions. Tonoplast enriched fractions were obtained from cucumber and soybean roots grown with or without Fe. Both V-ATPase and V PPase activities were analyzed and the enrichment and localization of the corresponding proteins in root tissues were determined by Western blot and immunolocalization. V-ATPase did not change its activity and expression level in response to Fe starvation in both species. V-PPase showed a different behavior: in cucumber roots its activity and abundance were decreased, while in Fe deficient soybean roots they were increased. The distinct role of the two H(+) pumps in Pi fluxes between cytoplasm and vacuole in Fe-deficient cucumber and soybean root cells is discussed. PMID- 23986769 TI - Desiccation stress and tolerance in green algae: consequences for ultrastructure, physiological and molecular mechanisms. AB - Although most green algae typically occur in aquatic ecosystems, many species also live partly or permanently under aeroterrestrial conditions, where the cells are exposed to the atmosphere and hence regularly experience dehydration. The ability of algal cells to survive in an air-dried state is termed desiccation tolerance. The mechanisms involved in desiccation tolerance of green algae are still poorly understood, and hence the aim of this review is to summarize recent findings on the effects of desiccation and osmotic water loss. Starting from structural changes, physiological, and biochemical consequences of desiccation will be addressed in different green-algal lineages. The available data clearly indicate a range of strategies, which are rather different in streptophycean and non-streptophycean green algae. While members of the Trebouxiophyceae exhibit effective water loss-prevention mechanisms based on the biosynthesis and accumulation of particular organic osmolytes such as polyols, these compounds are so far not reported in representatives of the Streptophyta. In members of the Streptophyta such as Klebsormidium, the most striking observation is the appearance of cross-walls in desiccated samples, which are strongly undulating, suggesting a high degree of mechanical flexibility. This aids in maintaining structural integrity in the dried state and allows the cell to maintain turgor pressure for a prolonged period of time during the dehydration process. Physiological strategies in aeroterrestrial green algae generally include a rapid reduction of photosynthesis during desiccation, but also a rather quick recovery after rewetting, whereas aquatic species are sensitive to drying. The underlying mechanisms such as the affected molecular components of the photosynthetic machinery are poorly understood in green algae. Therefore, modern approaches based on transcriptomics, proteomics, and/or metabolomics are urgently needed to better understand the molecular mechanisms involved in desiccation-stress physiology of these organisms. The very limited existing information is described in the present review. PMID- 23986770 TI - Phloem-specific expression of a melon Aux/IAA in tomato plants alters auxin sensitivity and plant development. AB - Phloem sap contains a large repertoire of macromolecules in addition to sugars, amino acids, growth substances and ions. The transcription profile of melon phloem sap contains over 1000 mRNA molecules, most of them associated with signal transduction, transcriptional control, and stress and defense responses. Heterografting experiments have established the long-distance trafficking of numerous mRNA molecules. Interestingly, several trafficking transcripts are involved in the auxin response, including two molecules coding for auxin/indole acetic acid (Aux/IAA). To further explore the biological role of the melon Aux/IAA transcript CmF-308 in the vascular tissue, a cassette containing the coding sequence of this gene under a phloem-specific promoter was introduced into tomato plants. The number of lateral roots was significantly higher in transgenic plants expressing CmF-308 under the AtSUC2 promoter than in controls. A similar effect on root development was obtained after transient expression of CmF-308 in source leaves of N. benthamiana plants. An auxin-response assay showed that CmF 308-transgenic roots are more sensitive to auxin than control roots. In addition to the altered root development, phloem-specific expression of CmF-308 resulted in shorter plants, a higher number of lateral shoots and delayed flowering, a phenotype resembling reduced apical dominance. In contrast to the root response, cotyledons of the transgenic plants were less sensitive to auxin than control cotyledons. The reduced auxin sensitivity in the shoot tissue was confirmed by lower relative expression of several Aux/IAA genes in leaves and an increase in the relative expression of a cytokinin-response regulator, TRR8/9b. The accumulated data suggest that expression of Aux/IAA in the phloem modifies auxin sensitivity in a tissue-specific manner, thereby altering plant development. PMID- 23986771 TI - Construction of a rice glycoside hydrolase phylogenomic database and identification of targets for biofuel research. AB - Glycoside hydrolases (GH) catalyze the hydrolysis of glycosidic bonds in cell wall polymers and can have major effects on cell wall architecture. Taking advantage of the massive datasets available in public databases, we have constructed a rice phylogenomic database of GHs (http://ricephylogenomics.ucdavis.edu/cellwalls/gh/). This database integrates multiple data types including the structural features, orthologous relationships, mutant availability, and gene expression patterns for each GH family in a phylogenomic context. The rice genome encodes 437 GH genes classified into 34 families. Based on pairwise comparison with eight dicot and four monocot genomes, we identified 138 GH genes that are highly diverged between monocots and dicots, 57 of which have diverged further in rice as compared with four monocot genomes scanned in this study. Chromosomal localization and expression analysis suggest a role for both whole-genome and localized gene duplications in expansion and diversification of GH families in rice. We examined the meta-profiles of expression patterns of GH genes in twenty different anatomical tissues of rice. Transcripts of 51 genes exhibit tissue or developmental stage-preferential expression, whereas, seventeen other genes preferentially accumulate in actively growing tissues. When queried in RiceNet, a probabilistic functional gene network that facilitates functional gene predictions, nine out of seventeen genes form a regulatory network with the well-characterized genes involved in biosynthesis of cell wall polymers including cellulose synthase and cellulose synthase-like genes of rice. Two-thirds of the GH genes in rice are up regulated in response to biotic and abiotic stress treatments indicating a role in stress adaptation. Our analyses identify potential GH targets for cell wall modification. PMID- 23986772 TI - Growing poplars for research with and without mycorrhizas. AB - During the last decades the importance of the genus Populus increased because the poplar genome has been sequenced and molecular tools for basic research have become available. Poplar species occur in different habitats and harbor large genetic variation, which can be exploited for economic applications and for increasing our knowledge on the basic molecular mechanisms of the woody life style. Poplars are, therefore, employed to unravel the molecular mechanisms of wood formation, stress tolerance, tree nutrition and interaction with other organisms such as pathogens or mycorrhiza. The basis of these investigations is the reproducible production of homogeneous plant material. In this method paper we describe techniques and growth conditions for the in vitro propagation of different poplar species (Populus * canescens, P. trichocarpa, P. tremula, and P. euphratica) and ectomycorrhizal fungi (Laccaria bicolor, Paxillus involutus) as well as for their co-cultivation for ectomycorrhizal synthesis. Maintenance and plant preparation require different multiplication and rooting media. Growth systems to cultivate poplars under axenic conditions in agar and sand cultures with and without mycorrhizal fungi are described. Transfer of the plants from in vitro to in situ conditions is critical and hardening is important to prevent high mortality. Growth and vitality of the trees in vitro and outdoors with and without ectomycorrhizas are reported. PMID- 23986773 TI - Epigenetic control of Epstein-Barr virus transcription - relevance to viral life cycle? AB - DNA methylation normally leads to silencing of gene expression but Epstein-Barr virus (EBV) provides an exception to the epigenetic paradigm. DNA methylation is absolutely required for the expression of many viral genes. Although the viral genome is initially un-methylated in newly infected cells, it becomes extensively methylated during the establishment of viral latency. One of the major regulators of EBV gene expression is a viral transcription factor called Zta (BZLF1, ZEBRA, Z) that resembles the cellular AP1 transcription factor. Zta recognizes at least 32 variants of a 7-nucleotide DNA sequence element, the Zta-response element (ZRE), some of which contain a CpG motif. Zta only binds to the latter class of ZREs in their DNA-methylated form, whether they occur in viral or cellular promoters and is functionally relevant for the activity of these promoters. The ability of Zta to interpret the differential DNA methylation of the viral genome is paramount for both the establishment of viral latency and the release from latency to initiate viral replication. PMID- 23986774 TI - Association between hTERT rs2736100 polymorphism and sensitivity to anti-cancer agents. AB - BACKGROUND: The rs2736100 single nucleotide polymorphism (SNP) is located in the intron 2 of human telomerase reverse transcriptase (hTERT) gene. Recent genome wide association studies (GWAS) have consistently supported the strong association between this SNP and risk for multiple cancers. Given the important role of the hTERT gene and this SNP in cancer biology, we hypothesize that rs2736100 may also confer susceptibility to anti-cancer drug sensitivity. In this study we aim to investigate the correlation between the rs2736100 genotype and the responsiveness to anti-cancer agents in the NCI-60 cancer cell panel. METHODS AND MATERIALS: The hTERT rs2736100 was genotyped in the NCI-60 cancer cell lines. The relative telomere length (RTL) of each cell line was quantified using real time PCR. The genotype was then correlated with publically available drug sensitivity data of two agents with telomerase-inhibition activity: Geldanamycin (HSP90 inhibitor) and RHPS4/BRACO19 (G-quadruplex stabilizer) as well as additional 110 commonly used agents with established mechanism of action. The association between rs2736100 and mutation status of TP53 gene was also tested. RESULTS: The C allele of the SNP was significantly correlated with increased sensitivity to RHPS4/BRACO19 with an additive effect (r = -0.35, p = 0.009) but not with Geldanamycin. The same allele was also significantly associated with sensitivity to antimitotic agents compared to other agents (p = 0.003). The highest correlation was observed between the SNP and paclitaxel (r = -0.36, p = 0.005). The telomere length was neither associated with rs2736100 nor with sensitivity to anti-cancer agents. The C allele of rs2736100 was significantly associated with increased mutation rate in TP53 gene (p = 0.004). CONCLUSION: Our data suggested that the cancer risk allele of hTERT rs2736100 polymorphism may also affect the cancer cell response to both TERT inhibitor and anti-mitotic agents, which might be attributed to the elevated telomerase-independent activity of hTERT, as well as the increased risk for TP53 gene mutagenesis conferred by the polymorphism. Detailed mechanisms need to be further investigated. PMID- 23986775 TI - Maternal Nodal inversely affects NODAL and STOX1 expression in the fetal placenta. AB - Nodal, a secreted signaling protein from the transforming growth factor beta (TGF beta)-super family plays a vital role during early embryonic development. Recently, it was found that maternal decidua-specific Nodal knockout mice show intrauterine growth restriction (IUGR) and preterm birth. The chromosomal location of NODAL is in the same linkage area as the placental (fetal) pre eclampsia (PE) susceptibility gene STOX1, which is associated with the familial form of early-onset, IUGR-complicated PE. As the STOX1 linkage was originally identified in women being born from a pre-eclamptic pregnancy as well as suffering from PE themselves, the linkage could in part be caused by NODAL, which is why the potential maternal-fetal interaction between STOX1 and NODAL was investigated. In the PE families with the STOX1 susceptibility allele carried by the children born from pre-eclamptic pregnancies, it was found that the pre eclamptic mothers themselves all carried the NODAL H165R SNP, which causes a 50% reduced activity. Surprisingly, in decidua-specific Nodal knockout mice the fetal placenta showed up-regulation of STOX1 and NODAL expression. Conditioned media of human first trimester decidua and a human endometrial stromal cell line (T-HESC) treated with siRNAs against NODAL or carrying the H165R SNP were also able to induce NODAL and STOX1 expression when added to SGHPL-5 first trimester extravillous trophoblast cells. Finally, a human TGF-beta/BMP signaling pathway PCR-array on decidua and the T-HESC cell line with Nodal knockdown revealed upregulation of Activin-A, which was confirmed in conditioned media by ELISA. We show that maternal decidua Nodal knockdown gives upregulation of NODAL and STOX1 mRNA expression in fetal extravillous trophoblast cells, potentially via upregulation of Activin-A in the maternal decidua. As both Activin-A and Nodal have been implicated in PE, being increased in serum of pre-eclamptic women and upregulated in pre-eclamptic placentas respectively, this interaction at the maternal-fetal interface might play a substantial role in the development of PE. PMID- 23986776 TI - The hippo-yes association protein pathway in liver cancer. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer mortality. Despite continuing development of new therapies, prognosis for patients with HCC remains extremely poor. In recent years, control of organ size becomes a hot topic in HCC development. The Hippo signaling pathway has been delineated and shown to be critical in controlling organ size in both Drosophila and mammals. The Hippo kinase cascade, a singling pathway that antagonizes the transcriptional coactivator Yes associated protein (YAP), plays an important role in animal organ size control by regulating cell proliferation and apoptosis rates. During HCC development, this pathway is likely inactivated in tumor initiated cells that escape suppressive constrain exerted by the surrounding normal tissue, thus allowing clonal expansion and tumor development. We have reviewed evolutionary changes in YAP as well as other components of the Hippo pathway and described the relationships between YAP genes and HCC. We also discuss regulation of transcription factors that are up- and downstream of YAP in liver cancer development. PMID- 23986777 TI - Vitamin d status in patients operated for primary hyperparathyroidism: comparison of patients from southern and northern europe. AB - Aim. The interaction between vitamin D deficiency and primary hyperparathyroidism (PHPT) is not fully understood. The aim of this study was to investigate whether patients with PHPT from Spain and Sweden differed in vitamin D status and PHPT disease activity before and after surgery. Methods. We compared two cohorts of postmenopausal women from Spain (n = 126) and Sweden (n = 128) that had first time surgery for sporadic, uniglandular PHPT. Biochemical variables reflecting bone metabolism and disease activity, including levels of 25-hydroxy vitamin D3 (25(OH)D) and bone mineral density, BMD, were measured pre- and one year postoperatively. Results. Median preoperative 25(OH)D levels were lower, and adenoma weight, PTH, and urinary calcium levels were higher in the Spanish cohort. The Spanish patients had higher preoperative levels of PTH (13.5 versus 11.0 pmol/L, P < 0.001), urinary calcium (7.3 versus 4.1 mmol/L, P < 0.001), and heavier adenomas (620 versus 500 g, P < 0.001). The mean increase in BMD was higher in patients from Spain and in patients with vitamin D deficiency one year after surgery. Conclusion. Postmenopasual women with PHPT from Spain had a more advanced disease and lower vitamin 25(OH)D levels. Improvement in bone density one year after surgery was higher in patients with preoperative vitamin D deficiency. PMID- 23986778 TI - Effect of a High Protein Weight Loss Diet on Weight, High-Sensitivity C-Reactive Protein, and Cardiovascular Risk among Overweight and Obese Women: A Parallel Clinical Trial. AB - Studies regarding the effects of high protein (HP) diets on cardiovascular (CVD) risk factors have reported contradictory results. We aimed to determine the effects of an HP diet on CVD risk factors and high-sensitivity C-reactive protein (hs-CRP) among overweight and obese women. In this randomized controlled trial, we recruited 60 overweight and obese women, aged 20-65, into an HP or energy restricted control diet for three months (protein, carbohydrate, and fat: 25%, 45%, and 30% versus 15%, 55%, and 30%, resp.). Total protein was divided between animal and plant sources in a 1 : 1 ratio, and animal sources were distributed equally between meats and dairy products. Fasting blood samples, hs-CRP, lipid profile, systolic and diastolic blood pressure, and anthropometric measurements were assessed using standard guidelines. Percent change was significantly different between the two diet groups for weight (standard protein (SP): -3.90 +/ 0.26 versus HP: -6.10 +/- 0.34%; P < 0.0001, resp.) and waist circumference (SP: -3.03 +/- 0.21 versus HP: -5.06 +/- 0.28%; P < 0.0001, resp.). Percent change of fasting blood glucose (FBG) substantially decreased in the control group compared to the HP group (-9.13 +/- 0.67 versus -4.93 +/- 1.4%; P = 0.01, resp.). Total cholesterol, systolic blood pressure (SBP), and diastolic blood pressure (DBP) decreased both in the HP and in the control diet groups (P = 0.06, P = 0.07, and P = 0.09, resp.); however, the results were marginally significant. Serum levels of hs-CRP were reduced both in the control (-0.08 +/- 0.11%, P = 0.06) and in the high protein groups (-0.04 +/- 0.09%, P = 0.06). The energy-restricted HP diet resulted in more beneficial effects on weight loss and reduction of waist circumference. CVD risk factors may improve with HP diets among overweight and obese women. When using isoenergetic weight loss diets, total cholesterol, hs CRP, and SBP were marginally significantly reduced, independent of dietary protein content. This trial is registered with ClinicalTrials.gov NCT01763528. PMID- 23986779 TI - What do resource-oriented approaches mean to general practitioners and how can they be facilitated in primary care? A qualitative study. AB - Although resource orientation, as a part of health promotion, should play a major role in general practice, the anchoring and realization of resource-oriented approaches remain small in Germany. The aim of this study was to analyze what resource orientation means to general practitioners (GPs) and develop strategies as to how this can be facilitated in GP practice. Within a qualitative research approach, 19 semi-structured telephone interviews were recorded, transcribed, and analyzed using qualitative content analysis. Within the interviews, the inclusion of the patients' individual resources is described as core competence of GPs. Supporting the patients' disease coping strategies and self-help were seen as important by GPs. However, perceptions as to which resources are considered to be fundamental ranged widely across the participant group. The results confirm the important role of resource-oriented approaches in general practice. However, a general definition of resource orientation is needed. In addition, working conditions for GPs need to be taken into account to ensure that these contribute to a healthy work-life balance. The need for GP training was identified to improve communication skills. Further integration of GPs in health promotion and communal structures would be beneficial. PMID- 23986780 TI - Tai chi for essential hypertension. AB - Objectives. To assess the current clinical evidence of Tai Chi for essential hypertension (EH). Search Strategy. 7 electronic databases were searched until 20 April, 2013. Inclusion Criteria. We included randomized trials testing Tai Chi versus routine care or antihypertensive drugs. Trials testing Tai Chi combined with antihypertensive drugs versus antihypertensive drugs were also included. Data Extraction and Analyses. Study selection, data extraction, quality assessment, and data analyses were conducted according to the Cochrane standards. Results. 18 trials were included. Methodological quality of the trials was low. 14 trials compared Tai Chi with routine care. 1 trial compared Tai Chi with antihypertensive drugs. Meta-analysis all showed significant effect of TaiChi in lowering blood pressure (BP). 3 trials compared Tai Chi plus antihypertensive drugs with antihypertensive drugs. Positive results in BP were found in the other 2 combination groups. Most of the trials did not report adverse events, and the safety of Tai Chi is still uncertain. Conclusions. There is some encouraging evidence of Tai Chi for EH. However, due to poor methodological quality of included studies, the evidence remains weak. Rigorously designed trials are needed to confirm the evidence. PMID- 23986781 TI - Gross morphological features of the organ surface primo-vascular system revealed by hemacolor staining. AB - The primo-vascular system (PVS), which consists of primo-vessels (PVs) and primo nodes (PNs), is a novel thread-like structure identified in many animal species. Various observational methods have been used to clarify its anatomical properties. Here, we used Hemacolor staining to examine the gross morphology of organ-surface PVS in rats. We observed a sinus structure (20-50 MU m) with a remarkably low cellularity within PNs and PVs and several lines of ductules (3-5 MU m) filled with single cells or granules (~1 MU m) in PV. Both sinuses and ductules were linearly aligned along the longitudinal axis of the PVS. Such morphology of the PVS was further confirmed by acridine orange staining. In PN slices, there was a honeycomb-like structure containing the granules with pentagonal lumens (~10 MU m). Both PVs and PNs were densely filled with WBCs, RBCs, and putative mast cells (MCs), which were 90.3%, 5.9%, and 3.8% of the cell population, respectively. Granules in putative MCs showed spontaneous vibrating movements. In conclusion, the results show that Hemacolor, a simple and rapid staining system, can reveal the gross morphological features reported previously. Our findings may help to elucidate the structure and function of the PVS in normal and disease states in future studies. PMID- 23986782 TI - Effects of laser acupuncture on longitudinal bone growth in adolescent rats. AB - Longitudinal bone growth is the results of chondrocyte proliferation and hypertrophy and subsequent endochondral ossification in the growth plate. Recently, laser acupuncture (LA), an intervention to stimulate acupoint with low level laser irradiation, has been suggested as an intervention to improve the longitudinal bone growth. This study investigated the effects of laser acupuncture on growth, particularly longitudinal bone growth in adolescent male rats. Laser acupuncture was performed once every other day for a total of 9 treatments over 18 days to adolescent male rats. Morphometry of the growth plate, longitudinal bone growth rate, and the protein expression of BMP-2 and IGF-1 in growth plate were observed. The bone growth rate and the heights of growth plates were significantly increased by laser acupuncture. BMP-2 but not IGF-1 immunostaining in growth plate was increased as well. In conclusion, LA promotes longitudinal bone growth in adolescent rats, suggesting that laser acupuncture may be a promising intervention for improving the growth potential for children and adolescents. PMID- 23986783 TI - Complementary and alternative medicine in cancer stem cells. PMID- 23986784 TI - Detoxification combining fasting with fluid therapy for refractory cases of severe atopic dermatitis. AB - To introduce and determine the clinical benefits of a detoxification program that combines fasting with fluid therapy for refractory cases of severe atopic dermatitis (AD), we performed a retrospective chart review of inpatients with AD from March 2010 to February 2012 at the Department of Ophthalmology, Otorhinolaryngology and Dermatology of Korean Medicine in the Kyung Hee Medical Center. Patients were treated with the detoxification program, which combined fasting with fluid therapy, and herbal medicine, herbal wet wrap dressings, or acupuncture treatment when clinically necessary. The primary outcome was the SCORAD total index. The secondary outcome was the pruritus visual analogue scale (VAS) score in SCORAD as evaluated by a trained dermatology specialist. Among the 130 inpatients that have done detoxification, 7 patients met the inclusion criteria. The mean total SCORAD scores significantly decreased from 64.67 +/- 11.72 to 26.26 +/- 11.01 (P = 0.018) after the detoxification program. There was also a significant decrease in VAS score for pruritus from 8.00 +/- 1.16 to 2.57 +/- 0.98 (P = 0.016) between admission and discharge. We suggest that fasting with fluid therapy as a complementary and alternative treatment method may provide some benefits for patients with refractory cases of severe atopic dermatitis. PMID- 23986785 TI - Wild animals used as food medicine in Brazil. AB - The connection between eating and healing is common in traditional folk medical systems, and the multiple possibilities resulting from the combination of biodiversity and culture confer a wealth and complexity in terms of knowledge of the flora and fauna as to their potential as food medicine. The growing awareness of the links between traditional therapeutic-alimentary uses of wildlife and conservation has drawn attention to the gaps in knowledge on the social, economic, and biological contexts in which different forms of traditional wildlife uses take place, particularly with regard to zootherapeutic resources. In this study we interviewed 124 merchants and 203 traditional users of animal derived remedies in Brazil, aiming at documenting the animal species used as foods and medicines in urban and rural areas of the country. At least 354 wild animal species are used in Brazilian traditional medicine, of which 157 are also used as food. The high degree of overlap between medicinal and alimentary uses of wild animals highlights the importance of understanding the socioeconomic, cultural, and ecological contexts in which those traditional uses take place for elucidating their potential impact on public health and biodiversity conservation. PMID- 23986786 TI - Who is Subjected to Coercive Measures as a Psychiatric Inpatient? A Multi-Level Analysis. AB - BACKGROUND: For a reduction in the use of coercive interventions it will be necessary to identify patients at risk. The aim of this study was to explore the impact of basic patient characteristics at admission, history within 24 hours before admission, and living conditions on the risk of experiencing coercive measures, controlling for ward characteristics in a multi-level approach. METHODS: Patient characteristics of 3389 patients (1920 women) who had received inpatient treatment in 2007, data relating to coercive measures, and ward characteristics were extracted from the clinical basic documentation. RESULTS: Patients with aggressive behaviour in the 24 hours prior to admission had a three times higher risk of coercive measures compared to non-aggressive patients. Severity of illness increased the risk of coercion markedly. With each level of severity, the risk of coercion was doubled. Voluntariness of stay appeared to be the best protective factor against coercive measures. If a patient stayed voluntarily, this reduced the risk of coercion by more than two thirds. No impact was found for living conditions. CONCLUSIONS: To identify patients at risk, it is most important to intensively monitor patients with aggressive behaviour prior to admission and patients with a greater severity of psychopathological symptoms. PMID- 23986787 TI - The Use of Antidepressants in the Long-Term Treatment Should not Improve the Impact of Fibromyalgia on Quality of Life. AB - BACKGROUND: Antidepressant (AD) drugs are effective in the short term treatment of fibromyalgia (FM). It may be useful to study the long-term impact of AD on patients with FM. METHODS: One-year follow-up study on 23 females with FM divided into groups on AD (ADg-N=7), and not taking AD (NADg-N=11). Evaluation at t1 and at the end (t2) with the Fibromyalgia Impact Questionnaire (FIQ); at t2 with: SCID-IV; Mood Disorder Questionnaire (MDQ); Short Form-12; Hamilton Depression Rating Scale (HAM-D); Functioning Assessment Short Test (FAST). RESULTS: After a year the AD group showed a worst impact of the disease by FIQ (p=0.017), worsened quality of life by SF-12 (p<0.01), and disability linked to bipolar symptoms by FAST (p=0.05). About 40% of the sample was screened positive at MDQ without difference in the two groups. The patients who recovered from a depressive episode did not differ between ADg and NADg (20% vs 33.3%), and were fewer than expected from the literature (40-60%). The HAM-D score at the end of the trial was worse in the ADg (p<0.03). LIMITATIONS: Observational research on few patients, not specifically designed to test the hypothesis. The results have a heuristic value only. DISCUSSION: The results should be read in the light of the high prevalence of patients screened positive for Bipolar Disorders and of the well-known poor response of the mood symptoms to antidepressants in Bipolar Depression. The deterioration in the long-term management of FM patients following AD treatments suggests the need for new and robust studies. PMID- 23986789 TI - Tracking lung tumors in orthogonal X-rays. AB - This paper presents a computationally very efficient, robust, automatic tracking method that does not require any implanted fiducials for low-contrast tumors. First, it generates a set of motion hypotheses and computes corresponding feature vectors in local windows within orthogonal-axis X-ray images. Then, it fits a regression model that maps features to 3D tumor motions by minimizing geodesic distances on motion manifold. These hypotheses can be jointly generated in 3D to learn a single 3D regression model or in 2D through back projection to learn two 2D models separately. Tumor is tracked by applying regression to the consecutive image pairs while selecting optimal window size at every time. Evaluations are performed on orthogonal X-ray videos of 10 patients. Comparative experimental results demonstrate superior accuracy (~1 pixel average error) and robustness to varying imaging artifacts and noise at the same time. PMID- 23986788 TI - Space constrained homology modelling: the paradigm of the RNA-dependent RNA polymerase of dengue (type II) virus. AB - Protein structure is more conserved than sequence in nature. In this direction we developed a novel methodology that significantly improves conventional homology modelling when sequence identity is low, by taking into consideration 3D structural features of the template, such as size and shape. Herein, our new homology modelling approach was applied to the homology modelling of the RNA dependent RNA polymerase (RdRp) of dengue (type II) virus. The RdRp of dengue was chosen due to the low sequence similarity shared between the dengue virus polymerase and the available templates, while purposely avoiding to use the actual X-ray structure that is available for the dengue RdRp. The novel approach takes advantage of 3D space corresponding to protein shape and size by creating a 3D scaffold of the template structure. The dengue polymerase model built by the novel approach exhibited all features of RNA-dependent RNA polymerases and was almost identical to the X-ray structure of the dengue RdRp, as opposed to the model built by conventional homology modelling. Therefore, we propose that the space-aided homology modelling approach can be of a more general use to homology modelling of enzymes sharing low sequence similarity with the template structures. PMID- 23986790 TI - Damage of collagen and elastic fibres by borrelia burgdorferi - known and new clinical and histopathological aspects. AB - Lyme Borreliosis, or Lyme's disease, manifests itself in numerous skin conditions. Therapeutic intervention should be initiated as soon as a clinical diagnosis of erythema migrans is made. The histopathology of some of the skin conditions associated with Lyme Borreliosis is characterised by structural changes to collagen, and sometimes also elastic fibres. These conditions include morphea, lichen sclerosus et atrophicus and acrodermatitis chronica atrophicans. More recently, further skin conditions have been identified by the new microscopic investigation technique of focus floating microscopy: granuloma annulare, necrobiosis lipoidica, necrobiotic xanthogranuloma, erythema annulare centrifugum, interstitial granulomatous dermatitis, cutaneous sarcoidosis and lymphocytic infiltration; these conditions also sometimes cause changes in the connective tissue. In the case of ligaments and tendons, collagen and elastic fibres predominate structurally. They are also the structures that are targeted by Borrelia. The resultant functional disorders have previously only rarely been associated with Borreliosis in clinical practice. Ligamentopathies and tendinopathies, spontaneous ruptures of tendons after slight strain, dislocation of vertebrae and an accumulation of prolapsed intervertebral discs as well as ossification of tendon insertions can be viewed in this light. PMID- 23986791 TI - Effect of food stimulated liquids and thermocycling on the monomer elution from a nanofilled composite. AB - The present study was aimed to evaluate the effects of food simulating liquids and thermocycling on the elution of monomers from a nanofilled resin composite in different immersion times. Five Specimen discs were made from a nano-hybrid composite (Supreme 3M) for each group (Total = 180) and immersed in distilled water (control), citric acid, lactic acid, and 75% aqueous ethanol solution. The discs were removed after 24 h, 48 h, 72 h, 1 wk, 4 wk, and 12 wk. Three groups of samples underwent thermocycling for 1000, 2000 and 3000 cycles. The solutes were analyzed with HPLC for detection of eluted monomers. The results showed that the amount of released TEGDMA was significantly higher than that of Bis-GMA; however, there were not any significant differences between the amount of released Bis-GMA and UDMA. Moreover, the highest amount of monomers was released from samples immersed in ethanol solution; samples immersed in citric acid and lactic acid significantly released more monomers than those immersed in distilled water. Furthermore, the immersion time in aqueous ethanol solution had an increasing effect on the release of monomers. In addition, the higher amounts of monomers were release from samples immersed in ethanol and citric acid which underwent a higher number of thermal cycles. In conclusion, food and drink stimulated liquids used in this study increased the amount of some of the monomers released from composite resin. Thermal shocks and storage time are other factors that increased the release of monomers from the composite resin. PMID- 23986792 TI - Effect of cementation technique of individually formed fiber-reinforced composite post on bond strength and microleakage. AB - OBJECTIVES: The aim of this study was to evaluate the effect of two different cementation techniques of individually formed E-glass fiber-reinforced composite (FRC) post on bond strength and microleakage. METHODS: The crowns of extracted third molars were removed and post preparation was carried out with parapost drills (diameter 1.5 mm). After application of bonding agents individually formed FRC posts (everStick POST, diameter 1.5 mm) were cemented into the post spaces with either ParaCem(r)Universal or self-adhesive RelyXTMUnicem, using two different cementation techniques: 1) an "indirect (traditional) technique" where the post was prepolymerized prior application of luting cement and insertion into the post space or 2) a "direct technique" where the uncured post was inserted to the post space with luting cement and light-polymerized in situ at the same time. After water storage of 48 hours, the roots (n = 10/group) were cut into discs of thickness of 2 mm. A push-out force was applied until specimen fracture or loosening of the post. A microleakage test was carried out on roots which were not subjected to the loading test (n= 32) to evaluate the sealing capacity of the post-canal interface. The microleakage was measured using dye penetration depth under a stereomicroscope. RESULTS: Higher bond strength values (p<0.05) and less microleakage (p<0.05) were obtained with the "direct technique" compared to the "indirect technique". None of the FRC posts revealed any dye penetration between the post and the cement. CONCLUSIONS: The "direct technique" seems to be beneficial when cementing individually formed FRC posts. PMID- 23986793 TI - Assessment of knowledge of dental staff at a saudi arabian university regarding the prophylaxis for infective endocarditis. AB - The use of prophylactic antibiotics for the prevention of infective endocarditis following dental procedures has long been debated and there is still confusion regarding its efficacy. As a result, the prophylactic treatment varies considerably amongst different countries across the world and amongst different dental practitioners. AIM: To evaluate the knowledge of dental staff regarding the guidelines for the prevention of infective endocarditis. METHODS: This was a cross sectional analytical study which included all staff members. A self administered questionnaire was used and responses were "graded" according to the American Heart Association (AHA) guidelines. RESULTS: The response rate was 87% (N=39) and 97% reported to use the AHA guidelines; 66% reported their knowledge was based on previous training and scientific journals. Of those cardiac conditions and dental procedures which required prophylaxis; 47% and 65% chose the correct option, respectively. Penicillin was prescribed as the drug of choice by the majority of respondents. CONCLUSIONS: Although almost all staff reported the use of the AHA guidelines, many were not following them. The study emphasizes the need for continuous education and evaluation of this critical aspect of dentistry. PMID- 23986794 TI - Attachment, proliferation, and chondroinduction of mesenchymal stem cells on porous chitosan-calcium phosphate scaffolds. AB - Symptomatic osteochondral lesions occur frequently, but relatively few treatment options are currently available. The purpose of this study was to conduct a preliminary investigation into a new tissue engineering approach to osteochondral regeneration. The concept is a biphasic construct consisting of a porous, osteoconductive chitosan-calcium phosphate scaffold supporting a layer of neocartilage formed by marrow-derived mesenchymal stem cells. Two experiments were conducted to assess the feasibility of this approach. The first experiment characterized the attachment efficiency and proliferation of primary human marrow derived mesenchymal stem cells seeded relatively sparely onto the scaffold's surface. The second experiment compared two different methods of creating a biphasic construct using a much higher density of primary porcine marrow stromal cells. About 40% of the sparsely seeded human cells attached and proliferated rapidly. Constructs formed by one of the two experimental techniques exhibited a layer of cartilaginous tissue which only partially covered the scaffold's surface due to inadequate adhesion between the cells and the scaffold. This study demonstrates some potential for the approach to yield an implantable biphasic construct, but further development is required to improve cell-scaffold adhesion. PMID- 23986796 TI - Diastolic heart failure: a concise review. AB - The concept of "diastolic" heart failure grew out of the observation that many patients who have the symptoms and signs of heart failure had an apparently normal left ventricular (LV) ejection fraction. Thus it was assumed that since systolic function was "preserved" the problem must lie in diastole, although it is not clear by whom or when this assumption was made. Nevertheless, many guidelines followed on how to diagnose "diastolic" heart failure backed up by indicators of diastolic dysfunction derived from Doppler echoardiography. Diastolic heart failure is associated with a lower annual mortality rate of approximately 8% as compared to annual mortality of 19% in heart failure with systolic dysfunction, however, morbidity rate can be substantial. Thus, diastolic heart failure is an important clinical disorder mainly seen in the elderly patients with hypertensive heart disease. Early recognition and appropriate therapy of diastolic dysfunction is advisable to prevent further progression to diastolic heart failure and death. There is no specific therapy to improve LV diastolic function directly. Medical therapy of diastolic dysfunction is often empirical and lacks clear-cut pathophysiologic concepts. Nevertheless, there is growing evidence that calcium channel blockers, beta-blockers, ACE-inhibitors and ARB as well as nitric oxide donors can be beneficial. Treatment of the underlying disease is currently the most important therapeutic approach. PMID- 23986797 TI - Peripheral corneal ulceration associated with rheumatoid arthritis. AB - PATIENT: Female, 60 FINAL DIAGNOSIS: Corneal ulceration Symptoms: Blurred vision Medication: Abatacept Clinical Procedure: - Specialty: Ophthalmology. OBJECTIVE: Management of emergency care. BACKGROUND: To report a case of a patient with rheumatoid arthritis (RA) and associated peripheral corneal ulceration. CASE REPORT: A 60-year-old woman with RA diagnosed 15 years ago, under immunosuppressive therapy (IV abatacept 250 mg/month), demonstrated blurring of vision in her RE (right eye). Visual acuity was 6/10 in the RE and 10/10 in the LE. Slit lamp examination revealed a paracentral superior corneal melt in the RE. Anterior chamber reaction was 2+. Laboratory investigations revealed positive anti-Ro and anti-La, anti-Extractable Nuclear Antigens (anti-ENA, ELISA), while anti-Sm, anti-Rnp, anti-Jo1 and anti-Scl70 were found negative. IgG and IgA serum immunoglobulins were found elevated, but IgE and IgM were within normal levels. Further evaluation for the underlying disease revealed highly elevated rheumatoid factor and C-reactive protein. The patient, who had been receiving anti-TNF during the last 6 months, underwent treatment with topical tobramycin and lubricants and oral prednisone 60 mg/day with tapering doses, to which methotrexate p.os. 15 mg/week was added. The condition improved within a few days after the initiation of prednisone treatment. Re-epithelization occurred 1 week after the onset of the immunosuppressive treatment. Only punctate fluorescein dye uptake was detected in the margins of the lesion. CONCLUSIONS: The effective control of the underlying disease and early diagnosis of the dry eye syndrome in RA patients may prevent serious corneal complications such as corneal ulceration. The initiation of treatment with steroids and immunosuppresants was found to halt the progression of keratolysis, and assisted re-epithelization. PMID- 23986798 TI - Histiocytic endometritis. AB - PATIENT: Female, 72 FINAL DIAGNOSIS: Histiocytic endometritis Symptoms: Vaginal discharge * fever * weakness MEDICATION: - Clinical Procedure: Endometrial and cervical biopsy Specialty: Pathology * Gynaecology. OBJECTIVE: Rare disease. BACKGROUND: Histiocytic or xanthogranulomatous endometritis, characterized by disappearance of endometrial mucosa and its replacement by sheets of lipid containing histiocytic cells, is very rare. Extensive internet and PubMed searches revealed only 19 cases reported to date. The pathogenesis of histiocytic endometritis seems to be inflammation due to post-menopausal cervical stenosis or as the result of cervical carcinoma. Histiocytic endometritis can infiltrate the myometrium and can mimic a malignancy. CASE REPORT: We report the case of a 78 year-old post-menopausal female with symptoms of vaginal discharge, fever, and weakness. Radiological investigation showed a mass lesion in the cervix, extending into the myometrium, suggestive of cervical carcinoma. The lesion was biopsied and histopathological examination led to the diagnosis of histiocytic endometritis with no evidence of malignancy. CONCLUSIONS: Histiocytic endometritis, an inflammatory pathology, can mimic malignancy clinically as well as radiologically. Histopathological examination with extensive sampling of tissue is essential because presence of endometritis does not rule out malignancy. PMID- 23986795 TI - T-Cell Signaling in HIV-1 Infection. AB - HIV exploits the T-cell signaling network to gain access to downstream cellular components, which serves as effective tools to break the cellular barriers. Multiple host factors and their interaction with viral proteins contribute to the complexity of HIV-1 pathogenesis and disease progression. HIV-1 proteins gp120, Nef, Tat and Vpr alter the T-cell signaling pathways by activating multiple transcription factors including NF-KB, Sp1 and AP-1. HIV-1 evades the immune system by developing a multi-pronged strategy. Additionally, HIV-1 encoded proteins influence the apoptosis in the host cell favoring or blocking T-cell apoptosis. Thus, T-cell signaling hijacked by viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection. Here, we summarize past and present studies on HIV-1 T-cell signaling with special focus on the possible role of T cells in facilitating viral infection and pathogenesis. PMID- 23986799 TI - Phosphoinositide 3-kinase at the crossroad between endocytosis and signaling of cytokine receptors. AB - Class I phosphoinositide 3-kinase (PI3K) is a lipid kinase playing key roles in many signaling pathways regulating cell survival and growth. Besides its important role in signal transduction, PI3K is also involved in actin and membrane reorganization such as protrusion, adhesion, phagocytosis and macropinocytosis. Receptor-mediated endocytosis is initiated by plasma membrane reorganization creating buds that then mature to small vesicles. Whereas most of endocytic mechanisms involve actin polymerization, PI3K requirement has not been clearly investigated. Our study identifies class I PI3K as a key player in clathrin-independent endocytosis of the interleukin 2 receptor (IL-2R) in contrast to the clathrin-dependent entry of transferrin (Tf). IL-2R is a cytokine receptor, inducing several signaling cascades such as PI3K, that are essential for the immune response. We have shown previously that IL-2R can be internalized with or without IL-2 and this process requires dynamin, actin and their regulators cortactin, N-WASP, Rac1 and the kinases Pak. Our recent work reveals that PI3K regulates Rac1 during IL-2R uptake in two ways: via its catalytic activity (p110) and via its regulatory factor (p85). Indeed, the catalytic activity of PI3K is required for both constitutive and IL-2 induced uptake of cytokine receptors, in lymphocytes as well as in epithelial cells. Interestingly, Vav2, a Rac1 GTPase exchange factor (GEF) induced upon PI3K activation, is specifically involved and recruited during IL-2R uptake. The second action of PI3K is via its regulatory subunit, p85, which binds activated Rac1 and IL-2R; this interaction being enhanced upon IL-2 treatment. Thus, PI3K regulates both the activation of Rac1 and its recruitment during IL-2R endocytosis. Finally, our results identify a link between cytokine receptors signaling and clathrin independent endocytosis. PMID- 23986800 TI - Ras GTPases' interaction with effector domains: Breaking the families' barrier. AB - THE RAS SUPERFAMILY OF PROTEINS CONSISTS OF FIVE BRANCHES: Ras, Rho, Arf, Rab and Ran subfamilies. These proteins are involved in a plethora of biological functions spanning cytoskeletal organization, cell proliferation, transcription and intracellular trafficking. Ras-Binding Domains (RBDs) have classically been identified as autonomous ubiquitin-like folded regions that bind certain activated Ras GTPases of the Ras subfamily. In general, RBDs in many proteins have been tagged with membrane-targeting functions as in the case of the well characterized c-Raf-RBD/Ras interaction. However, it is becoming apparent that the definition and functions of RBDs need to be revamped in order to reflect the new discoveries associated with this domain. Here, we discuss in more detail the recent advances associated with these RBDs. We highlight research identifying RBDs in formins, ELMOs and the RhoGEF, Syx and discuss the emerging role for RBDs in controlling autoinhibition relief and the newly recognized versatility of RBDs to interact with Rho and Arf family GTPases. In addition, these recent findings raise the exciting hypothesis that functional RBDs remain hidden in the proteome and are ready to be uncovered. PMID- 23986801 TI - Role of Rabex-5 in the sorting of ubiquitinated cargo at an early stage in the endocytic pathway. AB - The covalent modification of transmembrane receptors by ubiquitin (Ub) is a key biological mechanism controlling their internalization and endocytic sorting to recycling and degradative pathways to attenuate their signaling potential. In this Ub-dependent endocytic trafficking pathway, Ub-binding proteins (UBPs) play a critical role in the sorting of these ubiquitinated transmembrane proteins at the plasma membrane, early endosomes, and multivesicular bodies. We recently reported that Rabex-5, a UBP and guanine nucleotide exchange factor for Rab5, is translocated to the plasma membrane in an extracellular ligand-dependent manner to regulate the internalization of ligand-induced ubiquitinated transmembrane proteins upon stimulation with extracellular ligands. Here, we show that Rabex-5 predominantly localizes on Rab5- and syntaxin 13-positive endosomes, but not on Rab11-positive recycling endosomes before stimulation with extracellular ligands. We further discuss the significance of Rabex-5-mediated sorting of ubiquitinated transmembrane proteins as cargo at an early stage of the endocytic pathway. PMID- 23986802 TI - Let's play a game of chutes and ladders: Lysosome fusion with the epithelial plasma membrane. AB - In non-polarized cells, calcium-induced exocytosis of "conventional" lysosomes is important in diverse processes like membrane repair after exposure to pore forming toxins and clearance of cellular debris. Resealing of torn membranes is especially critical for barrier epithelia that directly interact with pathogens and toxins, which can result in membrane microdisruptions and lesions. However, whether lysosomes participate in membrane repair in polarized epithelia has been an open question. We recently reported that in polarized Madin-Darby canine kidney (MDCK) cells, localized influx of calcium induces lysosomes to fuse with the basolateral membrane. This spatial segregation of exocytosis depends on an intact actin cytoskeleton, membrane cholesterol and restricted distribution of fusion machinery such as the t-SNARE syntaxin 4. Our data show that the polarity of syntaxin 4 (which is regulated by the clathrin adaptor protein AP-1) dictates whether lysosomes parachute down to the basolateral membrane or take a ladder up to the apical membrane. Here, we speculate about additional machinery (such as the lysosomal calcium sensor synaptotagmin VII and the v-SNARE VAMP7) that could be involved in polarized fusion of lysosomes with the epithelial membrane. We also discuss the potential importance of lysosome exocytosis in maintaining membrane integrity in the retinal pigment epithelium, the primary tissue affected in blinding diseases such as age-related macular degeneration. PMID- 23986803 TI - Resting microglia respond to and regulate neuronal activity in vivo. AB - Microglia are the primary immune cells in the brain. Under pathological conditions, they become activated and participate in scavenging, inflammation and tissue repair in response to brain injury. While the function and underlying mechanism of activated microglia have been intensively studied in the past decades, physiological functions of resting microglia remain largely underestimated. In our recent work, by simultaneously monitoring both the motility of resting microglial processes and the activity of surrounding neurons in intact zebrafish optic tectum, we examined the interaction between resting microglia and neurons. Local increase in neuronal activity attracts resting microglial processes and drives them to contact neurons with high levels of activity. This process is mediated by neuronal release of "find-me" signals such as ATP via pannexin-1 hemichannels and requires small Rho GTPase Rac in microglia. Reciprocally, the microglia-neuron contact reduces both the spontaneous and visually evoked activities of contacted neurons. We here summarize and explain the key results in the context of our previous work. PMID- 23986804 TI - Parkin deficiency results in accumulation of abnormal mitochondria in aging myocytes. AB - Autophagy plays a critical role in cellular quality control and is involved in removing damaged or excess organelles. Dysfunctional mitochondria are quickly cleared from the cell by autophagosomes before they can cause damage to the cell. Parkin is an E3 ubiquitin ligase that selectively ubiquitinates proteins on dysfunctional mitochondria, thereby marking those mitochondria for degradation by autophagosomes. In our recent study, we investigated the functional role of Parkin in the myocardium and discovered that Parkin is dispensable in the adult heart under normal conditions. Instead, our findings suggest that Parkin plays an important role in clearing damaged mitochondria in myocytes during stress. Here, we report that Parkin deficiency results in the accumulation of abnormal mitochondria in myocytes with age. PMID- 23986805 TI - New perspectives on the functioning and evolution of photosymbiosis in plankton: Mutualism or parasitism? AB - Photosymbiosis is common and widely distributed in plankton and is considered to be beneficial for both partners (mutualism). Such intimate associations involving heterotrophic hosts and microalgal symbionts have been extensively studied in coral reefs, but in the planktonic realm, the ecology and evolution of photosymbioses remain poorly understood. Acantharia (Radiolaria) are ubiquitous and abundant heterotrophic marine protists, many of which host endosymbiotic microalgae. Two types of photosymbiosis involving acantharians have recently been described using molecular techniques: one found in a single acantharian species involving multiple microalgal partners (dinoflagellates and haptophytes), and the other observed in more than 25 acantharian species exclusively living with the haptophyte Phaeocystis. Contrary to most benthic and terrestrial mutualistic symbioses, these symbiotic associations share the common feature of involving symbionts that are abundant in their free-living stage. We propose a hypothetical framework that may explain this original mode of symbiosis, and discuss the ecological and evolutionary implications. We suggest that photosymbiosis in Acantharia, and probably in other planktonic hosts, may not be a mutualistic relationship but rather an "inverted parasitism," from which only hosts seem to benefit by sequestrating and exploiting microalgal cells. The relatively small population size of microalgae in hospite would prevent reciprocal evolution that can select uncooperative symbionts, therefore making this horizontally transmitted association stable over evolutionary time. The more we learn about the diversity of life and the structure of genomes, the more it appears that much of the evolution of biodiversity is about the manipulation of other species-to gain resources and, in turn, to avoid being manipulated (John Thompson, 1999). PMID- 23986806 TI - Physiological role of stalk lengthening in Caulobacter crescentus. AB - The Gram-negative bacterium Caulobacter crescentus forms a thin polar stalk, which mediates its attachment to solid surfaces. Whereas stalks remain short (1 um) in nutrient-rich conditions, they lengthen dramatically (up to 30 um) upon phosphate starvation. A long-standing hypothesis is that the Caulobacter stalk functions as a nutrient scavenging "antenna" that facilitates phosphate uptake and transport to the cell body. The mechanistic details of this model must be revisited, given our recent identification of a protein-mediated diffusion barrier, which prevents the exchange of both membrane and soluble proteins between the stalk extension and the cell body. In this report, we discuss the potential of stalks to facilitate nutrient uptake and propose additional physiological roles for stalk elongation in Caulobacter cells. PMID- 23986807 TI - Rapid and multiple-stage activation of the human amygdala for processing facial signals. AB - Human faces transmit multiple valuable signals, and neuroimaging studies have shown that the amygdala is active in response to facial stimuli. However, little has been known about the temporal profile of amygdala activation during facial signal processing until recently. Here we review three recent studies conducted by our group in which we recorded amygdala intracranial electroencephalography in humans. The subjects were engaged in tasks that required automatic processing of faces, eye gazes and emotional expressions. Time-frequency statistical parametric mapping analyses revealed that the amygdala showed gamma-band activation in response to emotional expressions, gazes and faces, with peak latencies at about 100 ms, 200 ms and 250 ms, respectively. These results suggest that: (1) the amygdala performs multiple-stage processing in response to these facial signals using different visual input routes, and (2) amygdala activation for processing all of these facial signals is rapid, which could be prior to or simultaneous with conscious awareness of faces. PMID- 23986808 TI - Natural-born con artists and counterfeiters: Who is being deceived here? AB - Deception is ubiquitous in plant and animal kingdoms and is widely thought to provide selective advantages to the individual and evolutionary success to the species. Mimicry, a form of deception whereby an individual imitates their model to advantage by closely resembling their behavior or appearance, is particularly well documented and represented by the peripheral eyespots seen on the wings of many butterfly species. The significance of butterfly eyespots has been convincingly demonstrated to serve as an anti-predatory function either by imitation of a predator's own dangerous enemies (intimidation hypothesis) or by deflecting predator strikes toward less-vital parts of the body (deflection hypothesis). A convincing and compelling explanation in butterflies, the functional role of eyespots as anti-predatory devices has become a widely held and firmly entrenched belief that has been freely adopted into other systems. Here we comment on a recent paper that demonstrates a vastly different role for eyespots, that of intra-specific male-male competition, and make the point that even long-held beliefs need to be tested and challenged under different contexts if we are not to be deceived ourselves. PMID- 23986809 TI - Staurosporine: A new tool for studying phosphatidylserine trafficking. AB - The Ras GTPases comprising three main isoforms H-, N- and K-Ras operate at the plasma membrane as molecular switches in essential signaling pathways. Active concentration of the minor phospholipid phosphatidylserine in the inner leaflet of the plasma membrane contributes to the electrostatic potential that is required for K-Ras anchoring to the plasma membrane. We recently observed that staurosporine and related analogs: 7-oxostaurosporine, UCN-01 and UCN-02, long known as relatively non-specific protein kinase inhibitors, block endosomal sorting and recycling of phosphatidylserine, resulting in redistribution of phosphatidylserine to endosomes and endomembranes with concomitant mislocalization of K-Ras. Staurosporines are therefore a new tool to study phosphatidylserine trafficking. We discuss whether the mechanism of action of UCN 01, an FDA-approved staurosporine analog used as an anti-cancer therapeutic, is related to effects on phosphatidylserine subcellular distribution. Given the high prevalence of expression of constitutively active K-Ras in human cancers, we ask whether inhibitors of phosphatidylserine trafficking may have important therapeutic applications. PMID- 23986810 TI - Ubiquitination within the membrane-proximal ezrin-radixin-moesin (ERM)-binding region of the L1 cell adhesion molecule. AB - The dynamic turnover of the L1 cell adhesion molecule to and from the plasma membrane that is mediated through exo-and endocytic trafficking is central to axon outgrowth. Although the ubiquitination of L1 in response to incubation with an L1 antibody that mimics L1-L1 homophilic binding has been previously shown, the endocytic trafficking pathway of the ubiquitinated L1 destined for degradation is yet unclear. I have recently shown that the ubiquitinated L1 is endocytosed by Rabex-5, which is an ubiquitin-binding protein and guanine nucleotide exchange factor for Rab5, into early endosomes from the plasma membrane. Here, I speculate on the putative ubiquitination site within the membrane-proximal ezrin-binding motif in the cytoplasmic domain of L1 and discuss the regulatory role of this motif in the competition between ubiquitination and the binding of ezrin prior to L1 internalization. PMID- 23986811 TI - Potential effects of anthropogenic noise on echolocation behavior in horseshoe bats. AB - We previously reported that band-pass filtered noise (BFN, bandwidth 20 kHz) affected the echolocation behavior of horseshoe bats in different ways depending on which frequencies within the bats' hearing range BFN was centered. We found that call amplitudes only increased when BFN was centered on the dominant frequency of the bats' calls. In contrast, call frequencies were shifted for all BFN stimuli centered on or below the dominant frequency of echolocation calls including when BFN was centered at 20 kHz (BFN20), which is far below the range of the bats' echolocation call frequencies. In the present study we focused on masking effects of BFN20 and used it as a model stimulus for anthropogenic noise to investigate how this noise affected call parameters of echolocation calls, such as their frequency, amplitude, duration and rate. We show that only call frequencies shifted in response to masking BFN20, whereas all other call parameters tested exhibited no noise-related changes. Our findings provide an empirical basis to quantitatively predict the impact of anthropogenic noise on echolocation behavior in bats. They also emphasize the need for a better understanding of the impact of anthropogenic noise on bioacoustic communication and orientation systems in general. PMID- 23986812 TI - How useful are olfactometer experiments in chemical ecology research? AB - Olfactometer experiments, in which arthropods are given the choice between two or more odor sources to test behavioral preferences, are commonly used in chemical ecology research. Results of such often lead to conclusions on behavior in an ecologically relevant setting. However, it is widely unknown how well these experiments reflect actual behavior in nature. Recently, we used natural insect herbivores of wild lima bean plants to evaluate their behavior in Y-tube olfactometer experiments compared with feeding experiments. We demonstrated that depending on volatile concentration, insect sex significantly determined preference, and that independent of sex, the actual feeding choice of insects depended on defensive short-distance cues, which did not correlate with volatile cues emitted by the plants. Thus, our study shows that olfactory decisions do not reflect actual feeding choice and that olfactometer experiments may only provide a limited and simplified picture of actual decision making by insects. PMID- 23986813 TI - Small-world networks of spontaneous Ca(2+) activity. AB - Synchronized network activity among groups of interconnected cells is essential for diverse functions in the brain. However, most studies have been made on cellular networks in the mature brain when chemical synapses have been formed. Much less is known about the situation earlier in development. When studying neural progenitors derived from embryonic stem cells and neural progenitors from mice embryos, we found networks of gap junction coupled cells with vivid spontaneous non-random calcium (Ca(2+)) activity driven by electrical depolarization that stimulated cell growth. Network activity was revealed by single-cell live Ca(2+) imaging and further analyzed for correlations and network topology. The analysis revealed the networks to have small-world characteristics with scale-free properties. Taken together, these results demonstrate that immature cells in the developing brain organize in small-world networks that critically regulate neural progenitor proliferation. PMID- 23986814 TI - Survival of the beautiful: A conversation with David Rothenberg about evolution and beauty. PMID- 23986815 TI - Chaperone-assisted proteostasis is essential for mechanotransduction in mammalian cells. AB - Maintaining the dynamic proteome of a living cell in the face of an ever-changing environment depends on a fine-tuned balance of protein synthesis and protein degradation. Molecular chaperones exert key functions during protein homeostasis (proteostasis). They associate with nonnative client proteins following synthesis or damage and facilitate client sorting and folding. When client proteins are terminally misfolded, chaperones cooperate with protein degradation systems to dispose of such clients. This dual proteostasis activity of chaperones is essential for maintaining cell function under normal growth conditions and becomes even more important under stress conditions such as heat and oxidative stress. The recent identification of chaperone-assisted selective autophagy (CASA) as a tension-induced autophagy pathway highlights the critical role of molecular chaperones in mechanically strained cells and tissues. The CASA complex, assembled by the cochaperone BAG3, coordinates protein degradation and protein synthesis in response to mechanical force. Here we describe the composition and function of this chaperone complex in mammals and discuss its relevance for tissue homeostasis and the regulation of cell adhesion, migration and proliferation. We provide a unifying concept for the function of BAG3, which integrates its involvement in muscle maintenance, tumor formation and virus infection. PMID- 23986816 TI - Randomized controlled trial of a brief dyadic cognitive-behavioral intervention designed to prevent PTSD. AB - BACKGROUND: There is a dearth of effective interventions to prevent the development of post-traumatic stress disorder (PTSD). METHOD: We evaluated the efficacy of a brief dyadic two-session cognitive-behavioral intervention through a controlled trial involving trauma-exposed individuals recruited at the hospital's emergency room. Participants were randomly assigned to either the dyadic intervention group (n=37) or to a waiting list (assessment only) group (n=37). RESULTS: In an intent-to-treat analysis, a time-by-group interaction was found, whereby the treated participants had less PTSD symptoms at the post treatment but not at the pre-treatment compared to controls. Controlling for the improvement observed in the control participants, the intervention yielded a net effect size of d=0.39. CONCLUSIONS: A brief, early, and effective intervention can be provided by nurses or social workers in hospital settings, at a fairly low cost to individuals presenting to the emergency room as the result of trauma exposure. PMID- 23986817 TI - Zolendronate may cause ONJ if periodontitis is present. PMID- 23986818 TI - Blocking FGF23 has positive and negative effects in renal failure. PMID- 23986819 TI - Bisphosphonates reduce fracture risk in women on glucocorticoids. PMID- 23986820 TI - Treatment with a BMP receptor blocker increases bone mass in mice. PMID- 23986821 TI - Bilateral multiple extraocular muscle metastasis from hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) rarely metastasizes to the extra ocular muscles (EOMs). We present a case of bilateral metastasis of HCC to the EOMs and focus on the magnetic resonance imaging (MRI) features. Orbital MRI revealed nodular enlargement of bilateral multiple EOMs, with isointensity on T1-weighted images and heterogeneous, intermediate-to-high signal intensity on T2-weighted images, and showed mild-to-significant heterogeneous contrast enhancement with gadolinium. Physicians should be aware of this rare cause of EOM enlargement, understand the radiologic characteristics of EOM metastasis, and thus make appropriate treatment strategy. PMID- 23986822 TI - Mixed epithelial and stromal tumor of the kidney with polypoid component extending into renal pelvis and ureter. AB - Mixed epithelial and stromal tumor (MEST) of the kidney is an unusual benign neoplasm that predominantly occurs in middle-aged females. It typically appears as a well-circumscribed multiseptate mass with solid components on computed tomography (CT) or magnetic resonance image (MRI), reflecting its characteristics of an admixture of stromal proliferation and epithelial cells consisting of multiple cysts. We present a rare case of 61-year-old woman with MEST, which manifested as a multilocular cystic mass with a polypoid component protruding into the renal pelvis and ureter. To our best knowledge, this is the first case of MEST extending into the ureter. PMID- 23986823 TI - A new diffusion metric, diffusion kurtosis imaging, used in the serial examination of a patient with stroke. AB - WE REPORT A CASE OF A PATIENT WHO DEVELOPED A CEREBRAL INFARCTION, WHICH WAS ASSESSED USING A NEW AND ADVANCED DIFFUSION TECHNIQUE: diffusional kurtosis (DK) imaging. The signal changes on DK images were different from those on apparent diffusion coefficient (ADC) maps, and they seem to be useful for the prediction of early-stage tissue infarction. Although diffusion-weighted imaging and its metric, the ADC, have been widely used in the evaluation of stroke, DK imaging will provide additional and useful information, including a more detailed evaluation of pathologic tissue changes. This information can be predictive of the prognosis. PMID- 23986824 TI - Urachal carcinoma: imaging findings. AB - Urachal carcinoma is a rare neoplasm, which accounts for only 0.5-2% of bladder malignancies, and arises from a remnant of the fetal genitourinary tract. A 46 year-old woman presented with a history of pelvic pain and frequent daytime urination. Ultrasound (US), computed tomography (CT), and magnetic resonance (MR) demonstrated a supravesical heterogeneous mass with calcifications. The patient underwent a partial cystectomy with en-bloc resection of the mass and histopathological examination revealed the diagnosis of urachal adenocarcinoma. Urachal carcinomas are usually associated with poor prognosis and early diagnosis is fundamental. CT and MR are useful to correctly diagnose and preoperatively staging. PMID- 23986825 TI - Bilateral thalamic infarction and DSA demonstrated AOP after thrombosis. AB - Bilateral paramedian thalamic stroke is a special ischemic pattern that results from occlusion of the artery of Percheron (AOP), a rare anatomic variant of the paramedian arteries. We report a case of bilateral thalamic infarctions, with a dramatic improvement after thrombolysis. DSA demonstrated recanalization of AOP with possible unreported variation. PMID- 23986826 TI - Unusual cause of neuropathy: extensive dural spread of primary cervical osteosarcoma. AB - We report a very rare case of a high grade osteosarcoma of the cervical spine in a 62-year-old woman. She presented with a relatively short history of a swelling in the posterior neck and cervical lymphadenopathy. This was associated with hoarseness of the voice, significant weight loss, and right upper arm radicular symptoms initially, progressing to paraplegia. Based on MR and CT imaging of the neck and an excision biopsy of an enlarged right supraclavicular lymph node, the histology revealed a high grade primary osteosarcoma of the cervical spine. PMID- 23986827 TI - Hepatic encephalopathy due to intrahepatic portosystemic venous shunt successfully treated by balloon occluded retrograde transvenous embolization with GDCs. AB - We report a 65-year-old man with hepatic encephalopathy due to an intrahepatic portosystemic venous shunt that was successfully occluded by balloon occluded retrograde transvenous embolization with Guglielmi and interlocking detachable coils as performed percutaneously. PMID- 23986828 TI - Transcatheter arterial embolization with trisacryl gelatin microspheres (Embosphere((r))) leads to life-threatening tumor lysis syndrome in a rectal carcinoid patient with hepatic metastases. AB - The incidence of gastrointestinal carcinoids appears to be increasing, and the rectum is the third most common location. Transcatheter arterial embolization (TAE) with trisacryl gelatin microspheres (Embosphere((r))) has been reported as an effective method for hepatic metastases of rectal carcinoids. Complications are uncommon and usually of minor consequence. We report an unusual case of a 34 year-old man with tumor lysis syndrome following TAE with Embosphere((r)) in a patient with multiple hepatic metastases of a rectal carcinoid. Early detection and effective treatment are essential for this rare but potentially catastrophic complication. PMID- 23986829 TI - Polyarteritis nodosa with uterine involvement. AB - Polyarteritis nodosa (PAN) is characterized by multisystem necrotizing vasculitis, primarily affecting small-to-medium-sized muscular arteries, and it is typically found in middle-aged men. PAN is rarely found in the female genital tract (including the uterus), and imaging of the uterus with PAN has not previously been reported. Reported is a case of a 78-year-old patient with uterus enlargement who was diagnosed with PAN through clinical findings and images. Computed tomography and magnetic resonance imaging findings of a uterus affected by PAN are presented and reviewed, and potential characteristic findings of the uterine with PAN are discussed. PMID- 23986830 TI - Embolization of pulmonary AVMs of feeding arteries less than 3 mm: reports of two cases and an 8-year follow-up without embolization. AB - Pulmonary arteriovenous malformations (PAVMs) with feeding arteries of 3 mm or more have been shown to be associated with paradoxical embolization and serious neurologic complications. Therefore it is generally recommended to occlude feeding arteries of this size, while smaller feeding arteries often are left untreated. However, neurologic complications have also been described in patients with small PAVMs, and it has not been possible to stratify risk by size of feeding artery and thus there is no evidence that 3 mm is the critical size of the feeding artery potentially giving complications. Further, it is well-known that with time PAVMs and their feeding arteries may enlarge. Also, embolization of small feeding arteries will minimize the risk of paradoxical emboli and reduce the need for CT follow-up controls in these patients. Two cases demonstrate the possibility to embolize small feeding arteries. PMID- 23986831 TI - Successful treatment of ruptured duodenal varices with dual balloon-occluded embolotherapy. AB - Duodenal varices are ectopic portosystemic shunts that do not tend to result in gastrointestinal bleeding. Balloon-occluded retrograde transvenous obliteration is an established treatment for gastric varices. We report a 60-year-old man with melena due to ruptured duodenal varices originating at an inferior pancreaticoduodenal vein; drainage was into a gonadal vein. His ruptured duodenal varices were successfully treated by dual balloon-occluded embolotherapy. PMID- 23986832 TI - Successful closure of intractable tracheoesophageal fistula using a combination of a modified silicon stent and metallic stents. AB - Although surgery is the usual management strategy for acquired benign tracheoesophageal fistula, sometimes this approach is contraindicated or the patient declines surgical management. In this report, we describe a case of a patient with tracheoesophageal fistula at the level of the carina due to bronchial arterial infusion chemotherapy. Closure could not be achieved in response to multiple treatment strategies, including airway stenting, esophageal stenting, occlusion with microcoils, or cyanoacrylate glue. We subsequently achieved closure of this fistula through the combination of a modified silicon stent and metallic stents. PMID- 23986833 TI - Dynamic alteration of regional cerebral blood flow during carotid compression and proof of reversibility. AB - BACKGROUND: It is difficult to non-invasively visualize changes in regional cerebral blood flow caused by manual compression of the carotid artery. PURPOSE: To visualize dynamic changes in regional cerebral blood flow during and after manual compression of the carotid artery. MATERIAL AND METHODS: Two healthy volunteers were recruited. Anatomic features and flow directions in the circle of Willis were evaluated with time-of-flight magnetic resonance angiography (MRA) and two-dimensional phase-contrast (2DPC) MRA, respectively. Regional cerebral blood flow was visualized with territorial arterial spin-labeling magnetic resonance imaging (TASL-MRI). TASL-MRI and 2DPC-MRA were performed in three states: at rest, during manual compression of the right carotid artery, and after decompression. In one volunteer, time-space labeling inversion pulse (Time-SLIP) MRA was performed to confirm collateral flow. RESULTS: During manual carotid compression, in one volunteer, the right thalamus changed to be fed only by the vertebrobasilar system, and the right basal ganglia changed to be fed by the left internal carotid artery. In the other volunteer, the right basal ganglia changed to be fed by the vertebrobasilar system. 2DPC-MRA showed that the flow direction changed in the right A1 segment of the anterior cerebral artery and the right posterior communicating artery. Perfusion patterns and flow directions recovered after decompression. Time-SLIP MRA showed pial vessels and dural collateral circulation when the right carotid artery was manually compressed. CONCLUSION: Use of TASL-MRI and 2DPC-MRA was successful for non-invasive visualization of the dynamic changes in regional cerebral blood flow during and after manual carotid compression. PMID- 23986834 TI - Massive retroperitoneal hemorrhage from a giant renal angiomyolipoma treated by selective arterial embolization with an Amplatzer Vascular Plug II. AB - We report on a 36-year-old Caucasian woman who presented to the emergency department with post-traumatic retroperitoneal bleeding diagnosed by computed tomography. After clinical stabilization of the patient, selective arterial embolization was performed. The angiomyolipoma's feeding artery was successfully treated with an 8-mm Amplatzer Vascular Plug Type II. The upper pole of the left kidney, which was supplied by a separate upper renal artery, was conserved. Consequently, the renal angiomyolipoma became necrotic and surgical resection of the entire renal angiomyolipoma was performed. This case illustrates a simple and effective application of an Amplatzer Vascular Plug occluder for vessel embolization, without additional coiling. PMID- 23986835 TI - FDG-PET/CT finding of benign metastasizing leiomyoma of the lung. AB - We report a case of multiple benign metastasizing leiomyoma (BML) lung nodules showing faint or non-avid uptake of F-18 fluorodeoxyglucose (FDG) (respective 1 hour early and 2-hour delayed maximum standardized uptake values; 1.3 or less and 1.2 or less) in a 50-year-old woman with a history of hysterectomy for uterine leiomyoma at the age of 38 years. When multiple lung nodules show faint or non avid FDG uptake in a patient with a history of hysterectomy for uterine leiomyoma, BML should be included in the differential diagnosis. PMID- 23986836 TI - A case of lymphatic malformation/lymphangioma of the scrotum. AB - Lymphatic malformation/lymphangioma of the scrotum is rare. It is caused by lymphatic abnormalities and the most common sites are the neck and axilla. The scrotum is one of the most uncommon sites. We report the case of a 12-year-old boy with pathologically confirmed cystic lymphangioma/lymphatic malformation in the scrotum. The diagnosis was suspected from ultrasonography and magnetic resonance imaging. The most common cause of a cystic mass in the scrotum is scrotal hydrocele, but cystic lymphangioma/lymphatic malformation should be considered as a differential diagnosis for multicystic scrotal mass. PMID- 23986837 TI - Hydrocele of the canal of Nuck: imaging findings. AB - The hydrocele of the canal of Nuck is quite a rare condition and results from the failure of obliteration of the distal portion of evaginated parietal peritoneum within the inguinal canal which forms a sac containing fluid. It generally presents with painless inguinal swelling. Ultrasonography and MRI is plays an important role to differentiate from the other conditions presenting with inguinal swelling. We present the imaging findings of a case in 5-year-old girl. PMID- 23986838 TI - Chronic post-traumatic high-flow priapism treated with temporary gelatin sponge embolization. AB - We report the case of a 26-year-old man who presented with a non-painful priapism with a history of 3 months permanent erection after suffering a perineal trauma. An arteriocorporal fistula with a turbulent flow between the right cavernosal artery and the corpus cavernosum, conclusive for a high-flow priapism was initially detected by colour Doppler ultrasound. A superselective embolization with Gelatin sponge was safe and effective to treat the high-flow priapism. The use of gelatin sponge resulted in a temporary embolization with long-term effect of penile detumescence and preservation of erectile function. PMID- 23986839 TI - Uterine cervical melanoma presenting with rapid progression detected by PET/CT. AB - Malignant melanoma of the uterine cervix is a rare extracutaneous melanoma which develops aggressively and is associated with a bleak prognosis. To our knowledge, no prior published reports have discussed the role of 18F-FDG positron emission tomography/computed tomography (PET/CT) in managing this disease. Our case study involved a 66-year-old woman with a malignant melanoma of the uterine cervix. The patient received PET/CT that identified metastases and lesions which had not been detected from her MRI. Serial PET/CT elucidated that the disease was initially limited to the pelvis, but then metastasized to the abdominal para-aortic lymph nodes, followed by extensive metastases to the brain, lungs, breast, supraclavicular, neck, and other abdominal lymph nodes, as observed at 6-month follow-up. PET/CT was used to complement conventional anatomic imaging modalities, and provided a novel modality for whole body screening. Visualization of the metabolic activity of indeterminate lesions may help in staging, re staging, treatment planning, and prognostic prediction for patients with this rare disease. PMID- 23986840 TI - Crouzon syndrome associated with acanthosis nigricans: prenatal 2D and 3D ultrasound findings and postnatal 3D CT findings. AB - Crouzon syndrome with acanthosis nigricans (CAN) is a very rare condition with an approximate prevalence of 1 per 1 million newborns. We add the first report on prenatal 2D and 3D ultrasound findings in CAN. In addition we present the postnatal 3D CT findings. The diagnosis was confirmed by molecular testing. PMID- 23986841 TI - CT evaluation of spontaneously ruptured renal angiomyolipomas with massive hemorrhage spreading into multi-retroperitoneal fascia and fascial spaces. AB - BACKGROUND: Renal angiomyolipomas (RAMLs) can spontaneously rupture and induce hemorrhage that is usually confined to the perirenal space (PS) but may spread beyond the PS into other retroperitoneal fascia and fascial spaces, including up to the subdiaphramatic and down to pelvic extra-peritoneal regions. PURPOSE: To evaluate the computed tomography (CT) manifestations of renal angiomyolipoma (RAML) associated with spontaneous rupture and massive hemorrhage spreading beyond the PS into other retroperitoneal fascia and fascial spaces, including up to the subdiaphramatic and down to pelvic extra-peritoneal regions. MATERIAL AND METHODS: The CT scans of seven patients with spontaneously ruptured of RAMLs and massive hemorrhage (surgically and pathologically confirmed) were retrospectively reviewed. We evaluated the CT signs of the RAML itself and the regions with extensive retroperitoneal spreading after RAML rupture. RESULTS: THE CT MANIFESTATIONS OF SEVEN CASES WITH RAML SPONTANEOUS RUPTURE AND MASSIVE HEMORRHAGE INCLUDED THE FOLLOWING: (a) RAML signs: size (>4.0 cm, five patients; <4.0 cm, two patients), location (periphery, six patients; central portion, one patient), component (fat tissue included, seven patients), and boundary (poorly revealed, seven patients); and (b) signs of extensive retroperitoneal spreading after RAML rupture: involving the PS and extending beyond the PS (seven patients); spread to the pelvic extraperitoneal space (seven patients); attached to the subdiaphragmatic extraperitoneal region (four patients); and extended to the contralateral retroperitoneal spaces (six patients). CONCLUSION: CT scans clearly depict both the primary tumor and complicated signs of a spontaneously ruptured RAML with massive hemorrhage, which can affect other fascial planes and retroperitoneal spaces and can extend upward to the subdiaphragmatic region and downward to the pelvic extraperitoneal region or communicate with the contralateral side. PMID- 23986842 TI - A case of postoperative pyopneumothorax following CT-guided radiofrequency ablation for lung cancer with interstitial pneumonia. AB - We report a case of serious complications following computed tomography (CT) guided radiofrequency ablation (RFA) performed for the treatment of lung cancer with interstitial pneumonia. The patient developed delayed-onset pyopneumothorax, which required 6 months of antibiotic treatment, drainage, and video-assisted thoracoscopic debridement. Although CT-guided RFA is a promising, effective procedure for difficult-to-treat lung cancer, the present case suggests a risk of complications for patients complicated with interstitial pneumonia and warrants caution. PMID- 23986843 TI - Solitary fibrous tumor of filum terminale. AB - Solitary fibrous tumor (SFT) is a mesenchymal neoplasm that most commonly arises from the visceral or parietal pleura. Solitary fibrous tumor with a primary site in the filum terminale has not been reported previously in the literature. Here we report a case of SFT occurring in the filum terminale. The characteristic imaging feature of this tumor is hypointensity on T2-weighted images. Even though rare, SFT should be considered in the differential diagnosis of tumors occurring intraspinally, even in the filum terminale. PMID- 23986844 TI - Macronodular hepatosplenic tuberculosis. AB - Hepatosplenic involvement is a rare manifestation of abdominal tuberculosis in children. We describe the case of a 7-year-old girl with persistent fever, cough, and hepatosplenomegaly. Typical lesions were shown in the liver and spleen by ultrasound and computed tomography. Colonoscopy showed a nodular, ulcerated mass that partially obstructed the cecum. Microbiological and histopathological findings of intestinal and liver biopsy confirmed the clinical suspicion of tuberculosis. PMID- 23986845 TI - Migration to the pulmonary artery of nine metallic coils placed in the internal iliac vein for treatment of giant rectal varices. AB - Transcatheter venous embolization with metallic coils is a safe and reliable method for the treatment of pelvic congestion syndrome and pelvic varicocele. While rare, coil migration to the pulmonary arteries is potentially fatal. We report the migration to the pulmonary artery of a cluster of nine metallic microcoils placed in the internal iliac vein to obliterate giant rectal varices. Our patient suffered no severe sequelae. To avoid coil migration to the pulmonary arteries, the coils chosen for placement must take into consideration the characteristics of the target vessels, particularly of larger veins. PMID- 23986846 TI - Littoral cell angioma mimicking hepatic tumor. AB - Littoral cell angioma is a rare vascular tumor of the spleen that was described by Falk et al. in 1991. Because of the limited number, untypical imaging manifestations, and lack of knowledge on this tumor type, these tumors are often misdiagnosed. In most cases, the tumor presents with multiple small hypoattenuating nodules in the spleen with delayed enhancement. However, solitary littoral cell angiomas have not been well described. We present the CT features of an unusual littoral cell angioma mimicking hepatic tumor. PMID- 23986847 TI - Osteochondritis dissecans of the humeral capitellum in identical twins. AB - Osteochondritis dissecans (OCD) of the humeral capitellum is a disorder affecting mainly boys between the ages of 12 and 15 years. The exact etiology of OCD is not clear, but it is believed that repetitive trauma is the primary cause. Genetic factors are thought to play a secondary role in the pathogenesis. We present 17 year-old identical twins with similar MRI and arthroscopic findings, suggesting that genetic components are involved in the etiology of OCD of the humeral capitellum. PMID- 23986848 TI - Selective embolization of the splenic vein for shunt-preserving disconnection of the portal and systemic circulation: report of two cases. AB - In carefully selected patients with portosystemic encephalopathy, it is possible to safely disconnect the portal and systemic circulation while preserving the shunt. We report two patients with chronic hepatitis and recurrent episodes of hepatic encephalopathy due to a portosystemic shunt who underwent successful selective embolization of the splenic vein for a shunt-preserving disconnection of the portal and systemic circulation via the percutaneous transhepatic route. PMID- 23986849 TI - Variation in urinary excretion of FDG, yet another uncertainty in quantitative PET. AB - BACKGROUND: The standardized uptake value (SUV) is the most common estimate of metabolic activity used in clinical positron emission tomography (PET). Several biological and technological factors influence the accurate SUV calculation. PURPOSE: To assess another potential source of variability of the SUV, the variations in urinary excretion of fluorodeoxyglucose (FDG). MATERIAL AND METHODS: Twenty patients with various malignancies scheduled for PET/CT with 18F FDG were included in the present study. The activity in urine voided immediately before image acquisition was measured and decay corrected. An estimation of FDG content in the urinary bladder was made during imaging, and the two components of urinary FDG were added. The urinary output of FDG, and the quantity of FDG divided by the time to measurements, was estimated. RESULTS: The excretion of FDG in urine was between 5.7% and 15.2% of injected dose (decay corrected), and from 0.06% to 0.3%/min after injection, a five-fold difference in clearance. CONCLUSION: About 10% of injected dose is excreted in urine at 70 min post injection, but the urinary FDG excretion was found to be highly variable, yet another uncertainty affecting the SUV measurements. PMID- 23986850 TI - Unusual imaging profile of a solitary splenic lymphangioma. AB - Splenic lymphangioma is a rare, benign lesion of the spleen that is characterized microscopically by a proliferation of thin-walled vascular channels filled by proteinacious material. Based on microscopic features, three types of lymphangiomas are described as simple capillary, cavernous, and cystic; however, the distinction between these types is not uniformly accepted. The cystic type is the most common type and has well described imaging characteristics. However, little is known about the less common cavernous and capillary forms of lymphangioma. Herein, we present a case of a patient with two synchronous colon cancers that presented with a concomitant splenic mass that was initially suspected to be metastatic disease. Despite the use of multiple imaging modalities including computed tomography (CT), magnetic resonance imaging (MRI), nuclear imaging, and contrast-enhanced ultrasound, the final diagnosis of cavernous lymphangioma was made following core needle biopsy of the lesion. A thorough review of literature and this case now demonstrate the difficulty in differentiating atypical forms of splenic lymphangiomas from other benign lesions such as hemangioma. PMID- 23986851 TI - Leiomyoma of the nipple diagnosed by MRI. AB - Leiomyoma of the nipple is a rare, benign, non-epithelial tumor that is thought to arise from smooth muscle fibers in the subareolar tissue of the breast. We report an unusual case of leiomyoma of the nipple in a 32-year-old woman in whom the diagnosis was made by ultrasound-guided core needle biopsy. She came to our hospital complaining of a recently enlarged nipple with discharge and erosion in the region of the left nipple-areolar complex. This mass was evaluated by mammography, ultrasonography, and magnetic resonance imaging (MRI). To the best of our knowledge, this is the first case of a leiomyoma of the nipple examined by MRI. MRI showed an oval mass with circumscribed margins that appeared as an intermediate signal intensity on both T1- and T2-weighted images. A dynamic MRI study showed a rim-enhancing oval mass with delayed persistent enhancement. Ultrasound-guided core needle biopsy revealed spindle cell proliferation consistent with leiomyoma of the nipple. PMID- 23986852 TI - Primary signet ring cell carcinoma of the appendix mimicking acute appendicitis. AB - Primary signet ring cell carcinoma of the appendix is a very rare neoplasm that usually presents with signs and symptoms of acute appendicitis and in particular with a right lower abdominal pain. Preoperative imaging detection of appendiceal adenocarcinoma has an important value because it may result in an appropriate surgical procedure. We report a rare case of primary signet ring cell carcinoma of the vermiform appendix in an 80-year-old man who was misdiagnosed on computed tomography (CT) scan as acute appendicitis. PMID- 23986853 TI - Iron deposits in the knee joints of a thalassemic patient. AB - The overall prognosis for patients with beta-thalassemia has improved considerably during the past decades mainly due to regular blood transfusions, improvements in chelation therapy, and enhanced surveillance with imaging studies examining iron overload and other clinical complications. However, the prolonged survival of these patients leads to the development of other health problems including degenerative diseases such as arthropathies, which require further attention since they have a significant impact on the quality of life. In the current case report, we present a 45-year-old white man with beta-thalassemia complaining of non-traumatic pain and restriction in the range of motion of both knees. Magnetic resonance imaging (MRI) revealed a tear in the medial meniscus of the left knee as well as iron deposits in both knees. Histological findings confirmed the presence of hemosiderin in both joints. To our knowledge, this is the first reported case of macroscopically documented iron deposits in the knee joints of a patient with beta-thalassemia using MRI. PMID- 23986854 TI - Right aortic arch and Kommerell's diverticulum associated with acute aortic dissection and pericardial tamponade. AB - The right-sided aorta associated with an aberrant left subclavian artery is a rare anomaly of the aortic branches in the upper mediastinum. We present a 62 year-old patient suffering from an acute dissection of the ascending aorta associated with hemopericardium. In this case, there was also aneurysmal dilatation of the origin of the left subclavian artery, known as diverticulum of Kommerell. PMID- 23986855 TI - Successful removal of a Gunther tulip vena cava filter with wall-embedded hook and migration during a retrieval attempt. AB - Retrieval of a Gunther tulip vena cava filter implanted in a patient with inferior vena cava and right common iliac vein thrombosis was attempted by the standard method. Because the filter was tilted, the hook became attached to the vena cava wall and could not be snared. During attempts at removal by an alternative method, the filter migrated toward the right atrium. However, it was finally successfully removed. PMID- 23986856 TI - Slow-growing primary marginal zone B-cell lymphoma arising in the chest wall in a patient without a history of tuberculosis. AB - A 57-year-old man with a 15-year history of a right chest wall mass lesion without follow-up for 5 years was admitted to our hospital without any symptoms or evidence of malignancy. On MRI, an additional small subcutaneous mass lesion was found. Histology of both lesions revealed marginal zone B-cell lymphomas. Primary chest wall marginal zone B-cell lymphomas are rare; this report discusses the case and the literature on chest wall lymphomas. PMID- 23986857 TI - Primary hepatic neuroendocrine tumor: gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging. AB - We present a case of a 71-year-old man with prostate cancer who had no prior underlying liver disease. During metastatic evaluation, a solid mass in the liver was identified by computed tomography and ultrasound. Gadoxetic acid (Gd-EOB DTPA)-enhanced magnetic resonance imaging demonstrated a well-defined, peripheral enhancing hepatic mass containing small cystic component. This lesion was diagnosed as hepatic neuroendocrine tumor. Primary neuroendocrine tumors of the liver are extremely rare. This case is interesting because of the rarity of this neoplasm and the unique radiologic findings despite its small size. Reviews of previously reported cases in the literature are also presented. PMID- 23986858 TI - Fatal intra-abdominal hemorrhage as a result of avulsion of the gallbladder: a postmortem case report. AB - Gallbladder injuries are extremely rare in blunt trauma, with a reported incidence of <2%. We report an autopsy case of fatal hemorrhagic shock due to intra-abdominal bleeding resulting from complete avulsion of the gallbladder associated with liver cirrhosis. Multiplanar images derived from multislice computed tomography (MSCT) performed as part of pre-autopsy screening showed complete avulsion of the gallbladder without any other associated intra-abdominal injuries, facilitating forensic autopsy planning. In this report, we discuss the role of MSCT in cases of fatal intra-abdominal bleeding caused by avulsion of the gallbladder and discuss the mechanism of this injury. PMID- 23986859 TI - Perfusion computed tomography relative threshold values in definition of acute stroke lesions. AB - BACKGROUND: Perfusion computed tomography (CT) is a relatively new technique that allows fast evaluation of cerebral hemodynamics by providing perfusion maps and gives confirmation of perfusion deficits in ischemic areas. Some controversies exist regarding accuracy of quantitative detection of tissue viability: penumbra (tissue at risk) or core (necrosis). PURPOSE: To define brain tissue viability grade on the basis of the perfusion CT parameters in acute stroke patients. MATERIAL AND METHODS: A multimodal CT imaging protocol; unenhanced CT of the brain, CT angiography of head and neck blood vessels, followed by brain perfusion CT and 24 h follow-up brain CT was performed. Perfusion deficits were detected first visually, with subsequent manual quantitative and relative measurements in affected and contra-lateral hemisphere in 87 acute stroke patients. RESULTS: Visual perfusion deficit on perfusion CT images was found in 78 cases (38 women, 40 men; mean age, 30-84 years). Penumbra lesions (n = 49) and core lesions (n = 42) were detected by increased mean transit time (MTT) on perfusion CT maps in comparison to contra-lateral hemispheres. Cerebral blood volume (CBV) mean values in the penumbra group were increased in the penumbra group and decreased in the core group. Cerebral blood flow (CBF) values were decreased in penumbra and markedly decreased in core lesion. CONCLUSION: Perfusion CT measurements are reliable in estimation of penumbra and core lesions in acute stroke patients, if relative threshold values are used. The most accurate parameter of hypoperfusion is increased MTT above 190%. Relative threshold values for irreversible lesion are CBF <30-40% and CBV <40% in comparison to contra-lateral hemisphere. Penumbra lesion is characterized by MTT increase and CBF decrease, while CBV shows variable values. PMID- 23986860 TI - Reuse of a previously transplanted kidney: does success come with a price? AB - Longer wait times for deceased donor kidney transplant have prompted newer initiatives to expedite the process. Reuse of a previously transplanted kidney might be appropriate in certain circumstances. However, one must also consider the unique issues that may arise after such transplants. We describe our experience in one such case where the donor kidney had lesions of focal and segmental glomerulosclerosis and signs of alloreactivity (positive C4d staining) prior to transplantation and the recipient developed ganciclovir-resistant cytomegalovirus (CMV) infection, which was perhaps transmitted from the donor. Despite the challenges, the allograft function remained stable 5 years after reuse. PMID- 23986861 TI - APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice. AB - ApoE, ApoE receptors and APP cooperate in the pathogenesis of Alzheimer's disease. Intriguingly, the ApoE receptor LRP4 and APP are also required for normal formation and function of the neuromuscular junction (NMJ). In this study, we show that APP interacts with LRP4, an obligate co-receptor for muscle-specific tyrosine kinase (MuSK). Agrin, a ligand for LRP4, also binds to APP and co operatively enhances the interaction of APP with LRP4. In cultured myotubes, APP synergistically increases agrin-induced acetylcholine receptor (AChR) clustering. Deletion of the transmembrane domain of LRP4 (LRP4 ECD) results in growth retardation of the NMJ, and these defects are markedly enhanced in APP(-/ );LRP4(ECD/ECD) mice. Double mutant NMJs are significantly reduced in size and number, resulting in perinatal lethality. Our findings reveal novel roles for APP in regulating neuromuscular synapse formation through hetero-oligomeric interaction with LRP4 and agrin and thereby provide new insights into the molecular mechanisms that govern NMJ formation and maintenance. DOI:http://dx.doi.org/10.7554/eLife.00220.001. PMID- 23986862 TI - ATP-dependent chromatin assembly is functionally distinct from chromatin remodeling. AB - Chromatin assembly involves the combined action of ATP-dependent motor proteins and histone chaperones. Because motor proteins in chromatin assembly also function as chromatin remodeling factors, we investigated the relationship between ATP-driven chromatin assembly and chromatin remodeling in the generation of periodic nucleosome arrays. We found that chromatin remodeling-defective Chd1 motor proteins are able to catalyze ATP-dependent chromatin assembly. The resulting nucleosomes are not, however, spaced in periodic arrays. Wild-type Chd1, but not chromatin remodeling-defective Chd1, can catalyze the conversion of randomly-distributed nucleosomes into periodic arrays. These results reveal a functional distinction between ATP-dependent nucleosome assembly and chromatin remodeling, and suggest a model for chromatin assembly in which randomly distributed nucleosomes are formed by the nucleosome assembly function of Chd1, and then regularly-spaced nucleosome arrays are generated by the chromatin remodeling activity of Chd1. These findings uncover an unforeseen level of specificity in the role of motor proteins in chromatin assembly. DOI:http://dx.doi.org/10.7554/eLife.00863.001. PMID- 23986863 TI - Endocytosis gets in tune with action potential bursts. AB - Neurons use a calcium-dependent mechanism to optimize the rate at which synaptic vesicles are recycled. PMID- 23986864 TI - Assembly, remodelled. AB - Biochemical assays reveal that nucleosome maturation and chromatin remodelling by the motor protein Chd1 are distinct, separable enzymatic activities. PMID- 23986865 TI - Comparison of Optical versus Ultrasonic Biometry in Keratoconic Eyes. AB - Purpose. To compare the measurements of optical versus ultrasonic biometry devices in keratoconic eyes. Materials and Methods. Forty-two eyes of 42 keratoconus (KC) patients enrolled in the study were examined. Clinical and demographic characteristics of the patients were noted, and detailed ophthalmological examination was performed. Following Pentacam measurements, central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), and axial length (AL) were obtained using the Lenstar and US biometer to determine the reproducibility of the measurements between the two devices in keratoconic eyes. The Bland-Altman method was used to describe the agreement between the two devices. Results. The Lenstar could not measure at least one of the biometric properties in one eye and did not automatically give the corrected ACD in 2/3 of our study population. The Lenstar measured CCT (average difference 5.4 +/- 19.6 um; ICC = 0.90; P < 0.001), LT (average difference 0.13 +/- 0.17 mm; ICC = 0.67; P < 0.001), and AL (average difference 0.10 +/- 0.76 mm; ICC = 0.75; P < 0.001) thinner than US biometer, whereas it measured ACD (average difference 0.18 +/- 0.17 mm; ICC = 0.85; P < 0.001) deeper than US biometer in keratoconic eyes. Conclusion. Although the difference between the measurements obtained using the two devices might be clinically acceptable, US biometry and Lenstar should not be used interchangeably for biometric measurements in KC patients. PMID- 23986866 TI - Bioactive peptides in cancer: therapeutic use and delivery strategies. PMID- 23986867 TI - Using social network analysis to identify key child care center staff for obesity prevention interventions: a pilot study. AB - INTRODUCTION: Interest has grown in how systems thinking could be used in obesity prevention. Relationships between key actors, represented by social networks, are an important focus for considering intervention in systems. METHOD: Two long day care centers were selected in which previous obesity prevention programs had been implemented. Measures showed ways in which physical activity and dietary policy are conversations and actions transacted through social networks (interrelationships) within centers, via an eight item closed-ended social network questionnaire. Questionnaire data were collected from (17/20; response rate 85%) long day care center staff. Social network density and centrality statistics were calculated, using UCINET social network software, to examine the role of networks in obesity prevention. RESULTS: "Degree" (influence) and "betweeness" (gatekeeper) centrality measures of staff inter-relationships about physical activity, dietary, and policy information identified key players in each center. Network density was similar and high on some relationship networks in both centers but markedly different in others, suggesting that the network tool identified unique center social dynamics. These differences could potentially be the focus of future team capacity building. CONCLUSION: Social network analysis is a feasible and useful method to identify existing obesity prevention networks and key personnel in long day care centers. PMID- 23986870 TI - Infuence of microstructure in drug release behavior of silica nanocapsules. AB - Meso- and nanoporous structures are adequate matrices for controlled drug delivery systems, due to their large surface areas and to their bioactive and biocompatibility properties. Mesoporous materials of type SBA-15, synthesized under different pH conditions, and zeolite beta were studied in order to compare the different intrinsic morphological characteristics as pore size, pore connectivity, and pore geometry on the drug loading and release process. These materials were characterized by X-ray diffraction, nitrogen adsorption, scanning and transmission electron microscopy, and calorimetric measurements. Ibuprofen (IBU) was chosen as a model drug for the formulation of controlled-release dosage forms; it was impregnated into these two types of materials by a soaking procedure during different periods. Drug loading and release studies were followed by UV-Vis spectrophotometry. All nano- and mesostructured materials showed a similar loading behavior. It was found that the pore size and Al content strongly influenced the release process. These results suggest that the framework structure and architecture affect the drug adsorption and release properties of these materials. Both materials offer a good potential for a controlled delivery system of ibuprofen. PMID- 23986868 TI - Preoperative localization and surgical margins in conservative breast surgery. AB - Breast-conserving surgery (BCS) is the treatment of choice for early breast cancer. The adequacy of surgical margins (SM) is a crucial issue for adjusting the volume of excision and for avoiding local recurrences, although the precise definition of an adequate margins width remains controversial. Moreover, other factors such as the biological behaviour of the tumor and subsequent proper systemic therapies may influence the local recurrence rate (LRR). However, a successful BCS requires preoperative localization techniques or margin assessment techniques. Carbon marking, wire-guided, biopsy clips, radio-guided, ultrasound guided, frozen section analysis, imprint cytology, and cavity shave margins are commonly used, but from the literature review, no single technique proved to be better among the various ones. Thus, an association of two or more methods could result in a decrease in rates of involved margins. Each institute should adopt its most congenial techniques, based on the senologic equipe experience, skills, and technologies. PMID- 23986869 TI - Takayasu arteritis: criteria for surgical intervention should not be ignored. AB - Takayasu aortoarteritis is a rare, chronic granulomatous panarteritis with significant morbidity amongst young patients. Current challenges include a lack of awareness about the condition, delays in diagnosis due to its varied presentation, and suboptimal methods for assessing disease activity. The development of noninvasive imaging including magnetic resonance angiography and positron emission tomography is aiding earlier diagnosis. Early initiation of immunosuppressive treatment is crucial to control active inflammation and minimize arterial injury. Recent studies investigating biological agents such as tumour necrosis factor- alpha antagonists are encouraging. Surgical revascularization should only be undertaken following careful consideration, as restenosis is common. The indications for considering intervention include uncontrolled hypertension due to renal artery stenosis, severe symptomatic coronary artery or cerebrovascular disease, severe aortic regurgitation, stenotic or occlusive lesions resulting in critical limb ischemia, and aneurysms at risk of rupture. In these cases, the risk benefit ratio for intervention is good. Open surgery, at present, has better outcomes compared to endovascular techniques. However, technological advances in endovascular treatment are continually improving. Controlling disease activity prior to and following revascularization is key to preventing complications. A multidisciplinary approach to the diagnosis and management of Takayasu arteritis is essential to achieve satisfactory patient outcomes. PMID- 23986871 TI - In vivo evaluation of the skin tensile strength by the suction method: pilot study coping with hysteresis and creep extension. AB - From an engineering standpoint, both the skin and subcutaneous tissue act as interconnected load-transmitting structures. They are subject to a variety of intrinsic and environmental influences. Changes in the cutaneous viscoelasticity represent an important aspect in a series of skin conditions. The aim of this work was to explore the methodology of biomechanical measurements in order to better appreciate the evolution and severity of some connective tissue diseases. The Cutometer MPA 580 (C+K electronic) was used in the steep and progressive suction procedures. Adapting measurement modalities was explored in order to mitigate any variability in data collection. The repeat steep suction procedure conveniently reveals the creep phenomenon. By contrast, the progressive suction procedure highlights the hysteresis phenomenon. These viscoelastic characteristics are presently described using the 2 and 4 mm probes on normal skin and in scleroderma, acromegaly, corticosteroid-induced dermatoporosis, and Ehlers-Danlos syndrome. The apposition of an additional outer contention on the skin altered differently the manifestations of the creep extension and hysteresis among the tested skin conditions. Any change in the mechanical test procedure affects the data. In clinical and experimental settings, it is mandatory to adhere to a strict and controlled protocol. PMID- 23986872 TI - A comparative study on diadochokinetic skill of dyslexic, stuttering, and normal children. AB - Objective. Previous studies have shown some motor deficits among stuttering and dyslexic children. While motor deficits in speech articulation of the stuttering children are among the controversial topics, no study on motor deficits of dyslexic children has been documented to date. Methods. 120 children (40 stuttering, 40 dyslexia, and 40 normal) 6-11 years old were matched and compared in terms of diadochokinetic skill. Dyslexia symptoms checklist, reading test, and diadochokinetic task were used as measurement instruments. Results. The data analysis showed that there are significant differences (P < 0.001) in reaction time and the number of syllables in accomplishing diadochokinetic tasks among stuttering children, dyslexics, and the control group. This indicates that stuttering children and dyslexics have poor performance in reaction time and in the number of monosyllable articulation and long syllable articulation. Furthermore, there are significant differences (P < 0.001) in these indices between stuttering children and dyslexics, so that the latter group have better performance than the former one. Conclusion. The findings indicate that stuttering children and dyslexics have deficits in diadochokinetic skill which suggests their low performance in the motor control of speech production and articulation. Such deficits might be due to the role of the tongue in the development of stuttering and dyslexia. PMID- 23986873 TI - Assessment of Knowledge of Breast Cancer and Screening Methods among Nurses in University Hospitals in Addis Ababa, Ethiopia, 2011. AB - Background. According to the American Cancer Society, about 1.3 million women will be diagnosed with breast cancer annually worldwide and about 465,000 will die from the disease. In Ethiopia breast cancer is the second most often occurring cancer among women. Early diagnosis is especially important for breast cancer because the disease responds best to treatment before it has spread. Objective. To assess knowledge of breast cancer and screening methods among nurses in university hospitals. Method. This cross-sectional descriptive study used simple random sampling on sample of 281 nurses. Structured questionnaires draw out responses about knowledge and screening method of nurses in regard to breast cancer. Bivariate analysis was used principally and variables were then entered to multiple logistic regressions model for controlling the possible effect of confounders and the variables which have significant association were identified on the basis of OR, with 95% CI and P value. Results. The findings of this study revealed that only 156 (57.8%) of them were knowledgeable about breast cancer and its screening and 114 (42.2%) were not. Knowledge of breast cancer was found to be significantly associated with regular course in nursing, family history of respondents, and unit of work. Conclusion and Recommendation. The results of this study indicate that the knowledge of nurses is not satisfying and highlight the need to improve the content in the nursing curriculum and to undergo more workplace training in the area of breast cancer and screening methods. PMID- 23986874 TI - Ocular vestibular evoked myogenic potential using different test stimuli. AB - Aim. Ocular Evoked Myogenic Potential (oVEMP) are short latency potentials evoked by higher acoustic stimulation. In this study, we aimed at comparing the click, 500 Hz mixed modulated, and 500 Hz short duration tone burst stimuli using oVEMP. Material. Click, 500 Hz mixed modulated and 500 Hz short duration tone burst stimuli were used for the study. Method. Conventional sampling and conveneint study design were used. Sixty healthy subjects underwent contralateral oVEMP testing maintaining 30 degrees upward gaze. Single channel electrode montage was applied to record oVEMP response. Results. On statistical analysis the three stimuli evoked equal response rates (100%), and when latency of n1 and p1 and peak-peak amplitude were compared, the click evoked showed significantly early latency and lower peak-peak amplitude than the 500 Hz stimuli. Five hundred Hz stimuli did not show significant difference in latency and peak-peak amplitude of n1-p1. Discussion. Thus, 500 Hz stimuli can evoke better latency and peak-peak amplitude. oVEMP has good clinical significance in diagnosing subjects with vestibular dysfunction. To add to the sensitivity of the oVEMP test, 500 Hz stimuli may also be used as it can evoke better oVEMP responses in clinical population with good morphology. PMID- 23986875 TI - Pancreatic Remnant Occlusion after Whipple's Procedure: An Alternative Oncologically Safe Method. AB - Introduction. To present our experience regarding the use of pancreatic stump occlusion technique as an alternative management of the pancreatic remnant after pancreatoduodenectomy (PD). Methods. Between 2002 and 2009, hospital records of 93 patients who had undergone a Whipple's procedure for either pancreatic periampullary cancer or chronic pancreatitis were retrospectively studied. In 37 patients the pancreatic duct was occluded by stapling and running suture without anastomosis of the pancreatic remnant, whereas in 56 patients a pancreaticojejunostomy was performed. Operative data, postoperative complications, oncological parameters, and survival rates were recorded. Results. 2/37 patients of the occlusion group and 9/56 patients of the anastomosis group were treated for chronic pancreatitis, whereas 35/37 and 47/56 patients for periampullary malignancies. The duration of surgery for the anastomosis group was significantly longer (mean time 220 versus 180 minutes). Mean hospitalization time was 6 days for both groups. The occlusion group had a lower morbidity rate (24% versus 32%). With regard to postoperative complications, a slightly higher incidence of pancreatic fistulas was observed in the anastomosis group. Conclusions. Pancreatic remnant occlusion is a safe, technically feasible, and reducing postoperative complications alternative approach of the pancreatic stump during Whipple's procedure. PMID- 23986876 TI - Nontargeted Identification of the Phenolic and Other Compounds of Saraca asoca by High Performance Liquid Chromatography-Positive Electrospray Ionization and Quadrupole Time-of-Flight Mass Spectrometry. AB - High performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer was used for separation and identification of phenolic and other compounds in the water extracts of Saraca asoca (Roxb.), De. Wilde. The aim of the study was to identify and evaluate the distribution of phenolic compounds in the different parts of the plant. The identity of compounds was established through the comparison with standards and characteristic base peaks as well as other daughter ions. In crude extracts, 34 catechin derivatives, 34 flavonoids, and 17 other compounds were identified. Interestingly, further analysis of compounds showed plant part specific unique pattern of metabolites; that is, regenerated bark is observed to be the best source for catechin/catechin derivative while flowers were found to be the source for wide variety of flavonoids. Moreover, these plant part specific compounds can be used as biomarkers for the identification of plant material or herbal drugs. Overall, the present study provides for the first time a comprehensive analysis of the phenolic components of this herb which may be helpful not only to understand their usage but also to contribute to quality control as well. PMID- 23986877 TI - Formulation Development and Evaluation of Drug Release Kinetics from Colon Targeted Ibuprofen Tablets Based on Eudragit RL 100-Chitosan Interpolyelectrolyte Complexes. AB - Colon-targeted drug delivery systems (CTDDSs) could be useful for local treatment of inflammatory bowel diseases (IBDs). In this study, various interpolyelectrolyte complexes (IPECs), formed between Eudragit RL100 (EL) and chitosan (CS), by nonstoichiometric method, and tablets based on the IPECs, prepared by wet granulation, were evaluated as potential oral CTDDSs for ibuprofen (IBF). Results obtained showed that the tablets conformed to compendial requirements for acceptance and that CS and EL formed IPECs that showed pH dependent swelling properties and prolonged the in vitro release of IBF from the tablets in the following descending order: 3 : 2 > 2 : 3 > 1 : 1 ratios of CS and EL. An electrostatic interaction between the carbonyl (-CO-) group of EL and amino (-NH3 (+)) group of CS of the tablets formulated with the IPECs was capable of preventing drug release in the stomach and small intestine and helped in delivering the drug to the colon. Kinetic analysis of drug release profiles showed that the systems predominantly released IBF in a zero-order manner. IPECs based on CS and EL could be exploited successfully for colon-targeted delivery of IBF in the treatment of IBDs. PMID- 23986878 TI - Validation of the dynamic direct exposure method for toxicity testing of diesel exhaust in vitro. AB - Diesel exhaust emission is a major health concern because of the complex nature of its gaseous content (e.g., NO2, NO, CO, and CO2) and high concentration of particulate matter (PM) less than 2.5 MU m which allows for deeper penetration into the human pulmonary system upon inhalation. The aim of this research was to elucidate the potential toxic effects of diesel exhaust on a human pulmonary based cellular system. Validation of a dynamic direct exposure method for both laboratory (230 hp Volvo truck engine) and field (Volkswagen Passat passenger car) diesel engines, at idle mode, was implemented. Human pulmonary type II epithelial cells (A549) grown on porous membranes were exposed to unmodified diesel exhaust at a low flow rate (37.5 mL/min). In parallel, diesel emission sampling was also conducted using real-time air monitoring techniques. Induced cellular effects were assessed using a range of in vitro cytotoxicity assays (MTS, ATP, and NRU). Reduction of cell viability was observed in a time-dependent manner following 30-60 mins of exposure with NRU as the most sensitive assay. The results suggest that the dynamic direct exposure method has the potential to be implemented for both laboratory- and field-based in vitro toxicity studies of diesel exhaust emissions. PMID- 23986879 TI - Evaluating the Polyphenol Profile in Three Segregating Grape (Vitis vinifera L.) Populations. AB - This paper explores the characteristics of the anthocyanin and flavonol composition and content in grapes from plants resulting from intraspecific crosses of Vitis vinifera varieties Monastrell * Cabernet Sauvignon, Monastrell * Syrah, and Monastrell * Barbera, in order to acquire information for future breeding programs. The anthocyanin and flavonol compositions of twenty-seven hybrids bearing red grapes and 15 hybrids bearing white grapes from Monastrell * Syrah, 32 red and 6 white from Monastrell * Cabernet Sauvignon, and 13 red from Monastrell * Barbera have been studied. Among the intraspecific crosses, plants with grapes presenting very high concentrations of anthocyanins and flavonols were found, indicating a transgressive segregation for this character, and this could lead to highly colored wines with an increased benefits for human health. As regards the qualitative composition of anthocyanins and flavonols, the hydroxylation pattern of the hybrids that also may influence wine color hue and stability presented intermediate values to those of the parentals, indicating that values higher than that showed by the best parental in this respect will be difficult to obtain. The results presented here can be helpful to acquire information for future breeding efforts, aimed at improving fruit quality through the effects of flavonoids. PMID- 23986880 TI - Positron Emission Tomography as a Method for Measuring Drug Delivery to Tumors in vivo: The Example of [(11)C]docetaxel. AB - Systemic anticancer treatments fail in a substantial number of patients. This may be caused by inadequate uptake and penetration of drugs in malignant tumors. Consequently, improvement of drug delivery to solid tumors may enhance its efficacy. Before evaluating strategies to enhance drug uptake in tumors, better understanding of drug delivery to human tumors is needed. Positron emission tomography (PET) is an imaging technique that can be used to monitor drug pharmacokinetics non-invasively in patients, based on radiolabeling these drugs with short-lived positron emitters. In this mini review, principles and potential applications of PET using radiolabeled anticancer drugs will be discussed with respect to personalized treatment planning in oncology. In particular, it will be discussed how these radiolabeled anticancer drugs could help to develop strategies for improved drug delivery to solid tumors. The development and clinical implementation of PET using radiolabeled anticancer drugs will be illustrated by validation studies of carbon-11 labeled docetaxel ([(11)C]docetaxel) in lung cancer patients. PMID- 23986881 TI - Bone marrow recovery and subsequent chemotherapy following radiolabeled anti prostate-specific membrane antigen monoclonal antibody j591 in men with metastatic castration-resistant prostate cancer. AB - Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin's lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate specific membrane antigen. Four phase I and II trials utilizing (177)Lu- or (90)Y J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT. PMID- 23986882 TI - Tumor-penetrating peptides. AB - Tumor-homing peptides can be used to deliver drugs into tumors. Phage library screening in live mice has recently identified homing peptides that specifically recognize the endothelium of tumor vessels, extravasate, and penetrate deep into the extravascular tumor tissue. The prototypic peptide of this class, iRGD (CRGDKGPDC), contains the integrin-binding RGD motif. RGD mediates tumor-homing through binding to alphav integrins, which are selectively expressed on various cells in tumors, including tumor endothelial cells. The tumor-penetrating properties of iRGD are mediated by a second sequence motif, R/KXXR/K. This C-end Rule (or CendR) motif is active only when the second basic residue is exposed at the C-terminus of the peptide. Proteolytic processing of iRGD in tumors activates the cryptic CendR motif, which then binds to neuropilin-1 activating an endocytic bulk transport pathway through tumor tissue. Phage screening has also yielded tumor-penetrating peptides that function like iRGD in activating the CendR pathway, but bind to a different primary receptor. Moreover, novel tumor-homing peptides can be constructed from tumor-homing motifs, CendR elements and protease cleavage sites. Pathologies other than tumors can be targeted with tissue penetrating peptides, and the primary receptor can also be a vascular "zip code" of a normal tissue. The CendR technology provides a solution to a major problem in tumor therapy, poor penetration of drugs into tumors. The tumor-penetrating peptides are capable of taking a payload deep into tumor tissue in mice, and they also penetrate into human tumors ex vivo. Targeting with these peptides specifically increases the accumulation in tumors of a variety of drugs and contrast agents, such as doxorubicin, antibodies, and nanoparticle-based compounds. Remarkably the drug to be targeted does not have to be coupled to the peptide; the bulk transport system activated by the peptide sweeps along any compound that is present in the blood. PMID- 23986884 TI - Challenges in conducting community-driven research created by differing ways of talking and thinking about science: a researcher's perspective. AB - Increasingly, health scientists are becoming aware that research collaborations that include community partnerships can be an effective way to broaden the scope and enhance the impact of research aimed at improving public health. Such collaborations extend the reach of academic scientists by integrating a variety of perspectives and thus strengthening the applicability of the research. Communication challenges can arise, however, when attempting to address specific research questions in these collaborations. In particular, inconsistencies can exist between scientists and community members in the use and interpretation of words and other language features, particularly when conducting research with a biomedical component. Additional challenges arise from differing perceptions of the investigative process. There may be divergent perceptions about how research questions should and can be answered, and in expectations about requirements of research institutions and research timelines. From these differences, misunderstandings can occur about how the results will ultimately impact the community. These communication issues are particularly challenging when scientists and community members are from different ethnic and linguistic backgrounds that may widen the gap between ways of talking and thinking about science, further complicating the interactions and exchanges that are essential for effective joint research efforts. Community-driven research that aims to describe the burden of disease associated with Helicobacter pylori infection is currently underway in northern Aboriginal communities located in the Yukon and Northwest Territories, Canada, with the goal of identifying effective public health strategies for reducing health risks from this infection. This research links community representatives, faculty from various disciplines at the University of Alberta, as well as territorial health care practitioners and officials. This highly collaborative work will be used to illustrate, from a researcher's perspective, some of the challenges of conducting public health research in teams comprising members with varying backgrounds. The consequences of these challenges will be outlined, and potential solutions will be offered. PMID- 23986883 TI - Modeling High-Grade Serous Carcinoma: How Converging Insights into Pathogenesis and Genetics are Driving Better Experimental Platforms. AB - Recent developments in the study of epithelial ovarian cancer have called into question the traditional views regarding the site of tumor initiation. Histopathologic studies and genomic analyses suggest that extra-ovarian sites, like the fallopian tube, may harbor the coveted cell of origin and could therefore contribute significantly to the development of high-grade serous ovarian carcinoma (HG-SOC). Our ability to validate these emerging genomic and pathologic observations and characterize the early transformation events of HG SOC hinges on the development of novel model systems. Currently, there are only a handful of new model systems that are addressing these concerns. This review will chronicle the convergent evolution of these ovarian cancer model systems in the context of the changing pathologic and genomic understanding of HG-SOC. PMID- 23986885 TI - The influence of social support on risk of acute cardiovascular diseases in female population aged 25-64 in Russia. AB - OBJECTIVE: To study the prevalence of social support (SS) and its influence on the relative risk (RR) of myocardial infarction (MI) and stroke in the female population aged 25-64 in Russia. MATERIALS AND METHODS: Under the third screening of the WHO "MONICA-psychosocial" programme, a random representative sample of women aged 25-64 (n=870) were surveyed in Novosibirsk. SS was measured according to the methods of the Berkman-Sym test [indices of close contacts (ICC) and index of social network (SNI)]. From 1995 to 2010, women were followed for 16 years to observe the incidence of MI and stroke. RESULTS: The prevalence of low levels of ICC and SNI in women aged 25-64 was 57.1 and 77.7%, respectively. Low levels of ICC and SNI were associated with poor self-rated health and awareness about their health, adverse behavioral habits, high job strain and family stress. Rates of MI and stroke development were higher in married women with low ICC and SNI who were being in class "hard manual work". Over a 16-year study period, the RR of MI in women with low ICC compared to those with high ICC was 4.9 times higher, and the risk of stroke was 4.1 times higher. Low level of SNI increased MI risk in 2.9 times, risk of stroke in 2.7 times. CONCLUSION: Majority of women aged 25-64 years in Russia have low social support which is associated with poor self-rated health, low awareness about the health that increases the risk of MI and stroke in 2.7-4.9 times in groups of "married" and "hard physical work". PMID- 23986887 TI - The ethnic differences of stroke in Yakutia. AB - BACKGROUND: In Yakutia, the morbidity and mortality from stroke increased in the past 2 decades. Stroke share in the total mortality structure increased significantly. According to the autopsies, haemorrhagic stroke (HS) was more common in indigenous patients. OBJECTIVE: The aim of the study was to examine ethnic features of stroke patients of indigenous and non-indigenous ethnicity admitted to Regional Vascular Center (RVC), Yakutsk. DESIGN: The study used data from a hospital stroke registry, which took into account the cases of acute stroke in 2011. Stroke type and aetiology were determined by clinical examination, computed tomography and magnetic resonance imaging studies, cerebral angiography and ultrasound of cerebral vessels. RESULTS: A total of 1,108 patients were hospitalized (51.4% male, n=569) in 2011. The mean age was 60.5 +/- 12.9 years, male: 59.1 +/- 12.8, female: 61.9 +/- 13.05. Five hundred and ninety two ischemic strokes (IS; 53.4%), 236 HS (21.3%), 280 transient ischemic attacks (TIA; 25.3%) were diagnosed. Patients who had a stroke were divided into 3 groups according to their ethnicity: native (n=411; 49.6%), Russians (n=347; 41.9%) and other nationalities (n=70; 8.5%). When comparing the incidence of HS in different ethnic groups, it was found that indigenous patients had more cases of HS than Russians (38% vs. 20.2%, p<0.05; adjusted odds ratio=2.42; 95% confidence interval: 1.72-3.41). Mean age of IS and HS indigenous patients had no significant differences compared with the average age of Russian ethnicity patients (p=0.69; p=0.201, respectively). CONCLUSIONS: The data from this study suggest that among the patients who suffered from stroke in the indigenous population, the share of a haemorrhagic form was higher than those of non indigenous Caucasians. At the same time, the average age of patients, both having IS and HS had no significant differences by ethnicity. Further studies are needed to establish the causes of ethnic differences of stroke in Yakutia. PMID- 23986886 TI - Abusive head trauma among children in Alaska: a population-based assessment. AB - BACKGROUND: Serious physical abuse resulting in a traumatic brain injury (TBI) has been implicated as an underreported cause of infant mortality. Nearly 80% of all abusive head trauma (AHT) occurs among children <2 years of age, with infants experiencing an incidence nearly 8 times that of 2-year olds. OBJECTIVE: This study describes the validation of the CDC Pediatric Abusive Head Trauma (PAHT) definitions when applied to a multi-source database at the state level and provides a robust annual incidence estimate of AHT among children <2 years of age in Alaska. DESIGN: AHT cases among children residing in Alaska during 2005-2010 were identified by applying the PAHT coding schema to a multi-source database which included vital death records, the Violent Death Reporting System (AK-VDRS), the Maternal Infant Mortality Review - Child Death Review (MIMR-CDR), the Alaska Trauma Registry (ATR), the inpatient Hospital Discharge Database (HDD) and Medicaid claims. Using these data, we calculated statewide AHT annual incidence rates. RESULTS: The databases with the highest case capture rates were the ATR and Medicaid systems, both at 51%, followed by HDD at 38%. Combined, the ATR, HDD and Medicaid systems captured 91% of all AHT cases. The linkage and use of the PAHT definitions yielded an estimated sensitivity of 91% and specificity of 98%. During the study period, we detected an annual average incidence of 34.4 cases per 100,000 children aged <2 years (95% CI 25.1, 46.1) and a case fatality proportion of 22% (10/45). Among the AHT cases, 82% were infants. Significant differences (p < 0.05) in AHT were noted by age and race, but not by sex. CONCLUSIONS: In Alaska, applying the CDC PAHT definition to the multi-source database enabled us to capture 49% more AHT cases than any of the individual database used in this analysis alone. PMID- 23986888 TI - Evaluation of serum procathepsin B, cystatin B and cystatin C as possible biomarkers of ovarian cancer. AB - OBJECTIVES: To evaluate procathepsin B, as well as endogenous inhibitors of cysteine proteases (cystatin B and cystatin C) in biological fluids as possible biomarkers of ovarian cancer. To observe levels of serum procathepsin B in different age groups. STUDY DESIGN: The sample (N=27) of women with gynaecological tumours included 18 patients with ovarian cancer (n=18) and 9 patients with benign ovarian tumours (n=9); 72 healthy women were in the control group. All patients were treated in Novosibirsk Regional Oncological Center, Russia. Serum samples of healthy women (n=40) aged 18-70 years were used as controls for common biomarker of ovarian cancer CA-125. In the Procathepsin B study, serum samples of healthy women (n=32) aged 18-40 years (n=14), 41-55 years (n=10) and 56-80 (n=8) years were used as controls. METHODS: Common biomarker of ovarian cancer, CA-125, was assayed by using a commercial kit (Vector, Koltsovo, Novosibirsk Region, Russia). Procathepsin B was measured by means of a commercial kit for human procathepsin B (R&D, USA); cystatin C was measured by commercial ELISA kits for human (BioVendor, Czechia); cystatin B was measured by ELISA kits for human (USCN Life Science Inc., Wuhan, China). Statistical analysis was performed by one-way ANOVA (Statistica 10 Program). RESULTS: In the control group, serum procathepsin B concentration did not reveal age dependency. In the ovarian cancer group, both levels of serum procathepsin B and standard biomarker CA-125 increased significantly (both p<0.001) compared with the control group. In the benign ovarian tumour group, serum procathepsin B (p<0.001) and CA-125 (p=0.004) increased about 2.5- and 8-fold compared to the control group. Serum cystatin B level increased up to 1.7-fold in the ovarian cancer group compared to the control group. The increase of serum CA-125 was about 3.5-fold higher (p=0.017) and procathepsin B was 1.8-fold higher (p<0.05) in the ovarian cancer group compared to the benign tumour group. Cystatin B in ascites fluid increased equally in both ovarian cancer (p<0.001) and benign ovarian tumours group (p<0.05). Cystatin C concentration in ascites fluid increased only in patients with ovarian cancer (p<0.05) and did not change in the benign tumours group. Large increases of procathepsin B level (about 13-fold, p<0.001) and to a lesser degree of cystatin C (1.8-fold, p<0.05) and cystatin B levels (1.4 fold, p<0.001) were revealed in ascites fluids of patients with ovarian cancer compared to the control serum. The significant difference in serum procathepsin B levels was noted between the ovarian cancer and benign tumour groups (p<0.05), which could be used in differential diagnostics between malignant and benign gynaecological tumours. CONCLUSION: Serum procathepsin B demonstrated significant promise as a new biomarker of ovarian cancer. PMID- 23986889 TI - "Double culturedness": the "capital" of Inuit nurses. AB - BACKGROUND: The health and educational systems in Greenland and Nunavut are reflections of those in Denmark and Southern Canada, with the language of instruction and practise being Danish and English. This places specific demands on Inuit studying nursing. OBJECTIVE: This paper discusses the experiences of Inuit who are educated in nursing programmes and practise in healthcare systems located in the Arctic but dominated by EuroCanadian and Danish culture and language. DESIGN: Research was qualitative and ethnographic. It was conducted through 12 months of fieldwork in 5 Greenlandic and 2 Nunavut communities. METHODS: Observation, participant observation, interviews, questionnaires and document review were used. The analytical framework involved Bourdieu's concepts of capital and habitus. RESULTS: Participants experienced degrees of success and well-being in the educational systems that are afforded to few other Canadian and Greenlandic Inuit. This success appeared to be based on nurses and students possessing, or having acquired, what I call "double culturedness"; this makes them able to communicate in at least 2 languages and cultures, including the ability to understand, negotiate and interact, using at least 2 ways of being in the world and 2 ways of learning and teaching. CONCLUSION: There continues to be a critical need for Inuit nurses with their special knowledge and abilities in the healthcare systems of the Arctic. Inuit nurses' experiences will help inform the education and healthcare systems and point to areas in need of support and change in order to increase recruitment and retention of nursing students and practitioners. PMID- 23986890 TI - Washeteria closures, infectious disease and community health in rural Alaska: a review of clinical data in Kivalina, Alaska. AB - BACKGROUND: Kivalina is a northwest Alaska barrier island village of 400 people vulnerable to storm surges exacerbated recently by delayed winter sea and shore ice formation. The village has no in-home piped water or sewage; the "washeteria" is the only structure providing public showers, laundry facilities and flush toilets. In October 2004, a storm damaged the washeteria septic system resulting in prolonged facility closures. We assessed rates of gastrointestinal, respiratory and skin infections potentially impacted by prolonged washeteria closures. METHODS: We obtained washeteria closure dates from 2003 to July 2009 and defined >7 day closure as prolonged. We received de-identified data on all Kivalina clinic visits from 2003 to 2009 and selected visits with ICD-9 diagnosis codes for respiratory, skin, or gastrointestinal infection; subsequent same patient/same illness-category visits within 14 days were excluded. We compared annual visit rates, for all ages combined, before (2003-2004) and after (2005 2009) the "2004" storm. RESULTS: The washeteria had prolonged closures for 34 days (4.7%) in the 2 years 2003-2004 and 864 days (51.7%) between January 2005 and July 2009. Closures ranged from 8 to 248 days. Respiratory infection rates declined significantly from 1.32 visits/person/year in the 2003-2004 period to 0.99 visits/person/year in the 2005-2009 period. There was a significant increase in skin infection rates after 2004, peaking at 0.28 visits/person/year in 2007 and then declining significantly to 0.15 visits/person/year in 2009. Gastrointestinal infection rates remained stable and low throughout (average: 0.05 visits/person/year). No temporal association was observed between respiratory, gastrointestinal or skin infection rates and prolonged washeteria closures. CONCLUSION: The Kivalina washeteria was closed frequently and for extended periods between 2005 and 2009. Initial closures possibly resulted in increased skin infection rates. No increase in respiratory or gastrointestinal infections was noted. Evaluation of community adaptations to closures and other factors (e.g. childhood pneumococcal vaccination) would expand understanding of these findings. PMID- 23986891 TI - Arctic passages: liminality, Inupiat Eskimo mothers and NW Alaska communities in transition. AB - BACKGROUND: While the primary goal of the NW Alaska Native maternal transport is safe deliveries for mothers from remote villages, little has been done to question the impact of transport on the mothers and communities involved. This study explores how presence of Inupiat values influences the desire of indigenous women of differing eras and NW Alaska villages to participate in biomedical birth, largely made available by a tribal health-sponsored transport system. OBJECTIVE: This paper portrays how important it is (and why) for Alaska Native families and women of different generations from various areas of Inupiat villages of NW Alaska to get to the hospital to give birth. This research asks: How does a community's presence of Inupiat values influence women of different eras and locations to participate in a more biomedical mode of birth? DESIGN: Theoretical frameworks of medical anthropology and maternal identity work are used to track the differences in regard to the maternal transport operation for Inupiat mothers of the area. Presence of Inupiat values in each of the communities is compared by birth era and location for each village. Content analysis is conducted to determine common themes in an inductive, recursive fashion. RESULTS: A connection is shown between a community's manifestation of Inupiat cultural expression and mothers' acceptance of maternal transport in this study. For this group of Inupiat Eskimo mothers, there is interplay between community expression of Inupiat values and desire and lengths gone to by women of different eras and locations. CONCLUSIONS: The more openly manifested the Inupiat values of the community, the more likely alternative birthing practices sought, lessening the reliance on the existing transport policy. Conversely, the more openly western values are manifested in the village of origin, the less likely alternative measures are sought. For this study group, mothers from study villages with openly manifested western values are more likely to easily acquiesce to policy, and "make the best" of their prenatal travel. PMID- 23986892 TI - The frequency of HLA alleles in a population of Inuit women of northern Quebec. AB - BACKGROUND: Human leukocyte antigen (HLA) alleles code for proteins that are involved in the recognition of foreign antigens and activation of the immune system. The frequency of HLA alleles varies across different populations. OBJECTIVE: To describe the frequency of HLA alleles in a population of Inuit women of Nunavik, Quebec, Canada. DESIGN: A cohort of women was recruited from 4 different communities between January 2002 and December 2007. HLA-B*07, HLA DQB1*03, DQB1*06:02, DRB1*13 and DRB1*15:01 alleles were typed by PCR sequence specific primers (PCR-SSP) and HLA-E and G alleles were type by DNA-sequencing procedures. RESULTS: We obtained data on 524 participants. The most frequent HLA alleles in this population were HLA-E*01:03, HLA-G*01:04:01 and HLA-DQB1*03, and they were found in 89, 75 and 94% of the population, respectively. CONCLUSIONS: The distribution of HLA alleles in Nunavik, Quebec is unique when compared to other populations in Canada or around the world. PMID- 23986893 TI - Assessing the social and physical determinants of circumpolar population health. AB - INTRODUCTION: Systematic reviews of the social and physical determinants of health provide metrics for evaluation of programs to mitigate health disparities. Previous meta-analyses of the population health literature have identified several proximate social and physical determinants of population health in the circumpolar north including addiction, environmental exposures, diet/nutrition and global climate change. Proximate health determinants are most amenable to early detection and modification or mitigation through disease prevention or health promotion interventions. DESIGN: There is a need for research to replicate these findings based on the latest science. This presentation describes a study applying Dahlgren and Whitehead's (1991) socio-ecological model of health determinants to identify the proximate social and physical determinants of health in the circumpolar north. METHODS: The study consisted of a systematic review of recent studies that link determinants of health with the leading causes of mortality and morbidity in Alaska. Our search strategy employed a keyword search using the Circumpolar Health Bibliographic Database (CHBD) and 4 databases within the Web of Knowledge (WoK) data gateway. Keywords included various terms for the arctic, all relevant nations and territories within the region, as well as leading health outcomes. RESULTS: Studies meeting the following inclusion criteria were reviewed: original research within a circumpolar population, published in English during 2011, and involving a rigorous demonstration of a link between a social determinant and selected health outcomes. CONCLUSIONS: Study conclusions includes a list of determinants identified, their associated outcomes and the study designs implemented to assess that association. PMID- 23986894 TI - Intimate partner violence in the Canadian territorial north: perspectives from a literature review and a media watch. AB - INTRODUCTION: Family violence is a complex, multidimensional and pervasive presence in many Aboriginal communities. Although practitioners acknowledge that intimate partner violence (IPV) is a grave concern in the North, as in other jurisdictions in Canada, there is a paucity of literature about IPV and the local response to that violence. OBJECTIVE: The purpose of this study is to report on a synthesis of Northern Territorial literature and a 3-year media watch conducted in the Canadian territories. DESIGN: This review is part of a multidisciplinary 5 year study occurring in the Northwest Territories (NT) and northern regions of the Prairie Provinces of Canada. The methods included a review of the literature through CINAHL, PubMed, Academic Search Complete, Social Sciences Index and JSTOR (1990-2012) combined with a media watch from 2009 to 2012. A thematic content analysis was completed. RESULTS: THEMES INCLUDED: colonization; alcohol and substance use; effects of residential schooling; housing inadequacies; help seeking behaviors; and gaps within the justice system. Identified themes from the media watch were: murders from IPV; reported assaults and criminal charges; emergency protection orders; and awareness campaigns and prevention measures. CONCLUSION: When synthesized, the results of the literature review and media surveillance depict a starting context and description of IPV in the Canadian territories. There are many questions left unanswered which build support for the necessity of the current research, outline the public outcry for action in local media and identify the current published knowledge about IPV. PMID- 23986895 TI - Prevalence and sensitization of atopic allergy and coeliac disease in the Northern Sweden Population Health Study. AB - BACKGROUND: Atopic allergy is effected by a number of environmental exposures, such as dry air and time spent outdoors, but there are few estimates of the prevalence in populations from sub-arctic areas. OBJECTIVE: To determine the prevalence and severity of symptoms of food, inhalation and skin-related allergens and coeliac disease (CD) in the sub-arctic region of Sweden. To study the correlation between self-reported allergy and allergy test results. To estimate the heritability of these estimates. STUDY DESIGN: The study was conducted in Karesuando and Soppero in Northern Sweden as part of the Northern Sweden Population Health Study (n=1,068). We used a questionnaire for self reported allergy and CD status and measured inhalation-related allergens using Phadiatop, food-related allergens using the F * 5 assay and IgA and IgG antibodies against tissue transglutaminase (anti-tTG) to indicate prevalence of CD. RESULTS: The prevalence of self-reported allergy was very high, with 42.3% reporting mild to severe allergy. Inhalation-related allergy was reported in 26.7%, food-related allergy in 24.9% and skin-related allergy in 2.4% of the participants. Of inhalation-related allergy, 11.0% reported reactions against fur and 14.6% against pollen/grass. Among food-related reactions, 14.9% reported milk (protein and lactose) as the cause. The IgE measurements showed that 18.4% had elevated values for inhalation allergens and 11.7% for food allergens. Self reported allergies and symptoms were positively correlated (p<0.01) with age- and sex-corrected inhalation allergens. Allergy prevalence was inversely correlated with age and number of hours spent outdoors. High levels of IgA and IgG anti-tTG antibodies, CD-related allergens, were found in 1.4 and 0.6% of participants, respectively. All allergens were found to be significantly (p<3 e-10) heritable, with estimated heritabilities ranging from 0.34 (F * 5) to 0.65 (IgA). CONCLUSIONS: Self-reported allergy correlated well with the antibody measurements. The prevalence of allergy was highest in the young and those working inside. Heritability of atopy and sensitization was high. The prevalence of CD-related autoantibodies was high and did not coincide with the self-reported allergy. PMID- 23986896 TI - Access and benefits sharing of genetic resources and associated traditional knowledge in northern Canada: understanding the legal environment and creating effective research agreements. AB - BACKGROUND: Research in northern Canada focused on Aboriginal peoples has historically benefited academia with little consideration for the people being researched or their traditional knowledge (TK). Although this attitude is changing, the complexity of TK makes it difficult to develop mechanisms to preserve and protect it. Protecting TK becomes even more important when outside groups become interested in using TK or materials with associated TK. In the latter category are genetic resources, which may have commercial value and are the focus of this article. OBJECTIVE: This article addresses access to and use of genetic resources and associated TK in the context of the historical power imbalances in research relationships in Canadian north. DESIGN: Review. RESULTS: Research involving genetic resources and TK is becoming increasingly relevant in northern Canada. The legal framework related to genetic resources and the cultural shift of universities towards commercial goals in research influence the environment for negotiating research agreements. Current guidelines for research agreements do not offer appropriate guidelines to achieve mutual benefit, reflect unequal bargaining power or take the relationship between parties into account. CONCLUSIONS: Relational contract theory may be a useful framework to address the social, cultural and legal hurdles inherent in creating research agreements. PMID- 23986897 TI - The influence of depression on risk development of acute cardiovascular diseases in the female population aged 25-64 in Russia. AB - BACKGROUND: Recent studies showed that depression was an independent predictor of mortality from cardio-vascular disease in healthy women. OBJECTIVE: To explore the effect of depression (D) on relative risk (RR) of myocardial infarction (MI) and stroke for 16 years (1995-2010) in the female population aged 25-64 years from Novosibirsk, Russia. MATERIALS AND METHODS: Under the third screening of the WHO "MONICA-psychosocial" (MOPSY) programme, a cohort of women aged 25-64 years (N=560) was surveyed. Women were followed for 16 years for the incidence of MI and stroke (1995-2010). D was measured at the baseline examination by means of test "MOPSY". Participants having stroke, MI, arterial hypertension, coronary artery diseases and diabetes in their medical history at the baseline were excluded from this analysis. RESULTS: The prevalence of D in women aged 25-64 years was 55.2%. With the growth of D levels, positive self-rated health reduced and almost 100% of those women have complaints about their health, but considered the care of their health insufficient. Women with major D significantly extended negative behavioral habits: smoking and unsuccessful attempts to give up, low physical activity, and less likely to follow a diet (healthy food). Major D associated with high job strain and family stress. Relative risk (RR) of MI development in women with D during 16 years of study was higher in 2.53 cases (p<0.05) and risk of stroke was higher in 4.63 cases (p<0.05). CONCLUSIONS: The prevalence of D in women aged 25-64 years was >50%. Women with D had a 2.53-fold risk of MI and 4.63-fold risk of stroke during the 16 years of follow-up. PMID- 23986898 TI - Resituating the ethical gaze: government morality and the local worlds of impoverished Indigenous women. AB - BACKGROUND: Over generations, government policies have impacted upon the lives of Indigenous peoples of Canada in unique and often devastating ways. In this context, Indigenous women who struggle with poverty, mental illness, trauma and substance abuse are among the most vulnerable, as are Indigenous children involved in child welfare systems. OBJECTIVE: By examining the life history of Wanda, a First Nations woman, this article examines the intergenerational role that government policies play in the lives of impoverished Indigenous women and their families. Questions of moral governance and responsibility and the need for ethical policies are raised. DESIGN: The life narrative presented in this article is part of a larger qualitative research programme that has collected over 100 life histories of Indigenous women with addictions and who have involvement with the child welfare system, as children or adults. Wanda's life story exemplifies the impact of government policies that is characteristic of vulnerable Indigenous women and draws attention to the lack of ethical standards in government policymaking in child welfare, public health and mental health/addictions. RESULTS: The path to recovery for Canadian Indigenous women in need of treatment for co-occurring mental disorders and substance addiction is too frequently characterized by an inadequate and ever shifting continuum of care. For those who feel intimidated, suspicious or have simply given up on seeking supports, a profound invisibility or forgetting of their struggle exists in areas of government policy and programming provision. Living outside the scope of mental health and addiction priorities, they become visible to the human service sector only if they become pregnant, their parenting draws the attention of child and family services (CFS), they need emergency health care, or are in trouble with the law. The intergenerational cycle of substance abuse, mental illness and poverty is commonly associated with child welfare involvement, specifically practices that place the health and well-being of Indigenous children at risk. In order to break this cycle, close attention to implementation of ethically based policies and best practice interventions is required. CONCLUSIONS: From an ethical policy perspective, the focus of government policies and the practices they generate must be first and foremost to ensure that individuals, families and groups are not left worse off than prior to a government policy impacting upon their life. Furthermore, the impact of living a life determined by multiple government policies should not be a story of individual and family devastation, and government policies should not be the most significant determinant of health for any group of people. PMID- 23986899 TI - Initial findings from the implementation of a community-based sentinel surveillance system to assess the health effects of climate change in Alaska. AB - BACKGROUND: This report describes the results of a study to determine whether a community-based sentinel surveillance system can be developed and implemented to assess the health effects of climate change, and to contribute to local discussions to mitigate these health effects. The purpose of this report is to describe the process and outcomes of this innovative approach to identifying priority areas for adaptation investment. This report can be used to assist local, state and federal governments in determining how to develop actions and policies to promote adaptation to climate change. OBJECTIVE: To evaluate the health effects of climate change in rural Alaska. DESIGN: We conducted an iterative and participatory process to develop metrics, an instrument and a protocol to collect sentinel surveillance data on the health effects of climate change in 3 ecologically distinct regions of the state. RESULTS: We collected surveillance data from 91 study participants over the course of 12 months. These data were analyzed and categorized by frequency and association between specific health outcomes or health-related factors (such as food security) and reported exposure to environmental effects of climate change. We found significant associations between several health outcomes and health outcome mediators and reported exposures. We presented these data to study participants in community settings and moderated discussions of likely causal factors for these measured associations, and helped community residents to identify specific adaption measures to mitigate those health effects. CONCLUSIONS: We conclude that community-based sentinel surveillance is an effective method for assessing health outcomes from exposure to environmental effects of climate change, and informing climate change health adaptation planning in Alaskan communities. We contend that it would be effective in other regions of the nation as well. PMID- 23986900 TI - Animistic pragmatism and native ways of knowing: adaptive strategies for overcoming the struggle for food in the sub-Arctic. AB - BACKGROUND: Subsistence norms are part of the "ecosophy" or ecological philosophy of Alaska Native Peoples in the sub-Arctic, such as the Inupiat of Seward Peninsula. This kind of animistic pragmatism is a special source of practical wisdom that spans over thousands of years and which has been instrumental in the Inupiat's struggle to survive and thrive in harsh and evolving environments. OBJECTIVE: I hope to show how narrative in relationship to the "ecosophy" of Alaska Native peoples can help to promote a more ecological orientation to address food insecurity in rural communities in Alaska. Alaska Native ecosophy recommends central values and virtues necessary to help address concerns in Alaska's rural communities. DESIGN: Here, I will tease out the nature of this "ecosophy" in terms of animistic pragmatism and then show why this form of pragmatism can be instrumental for problematizing multi-scalar, intergenerational, uncertain and complex environmental challenges like food security. RESULTS: Native elders have been the embodiment of trans-generational distributed cognition, for example, collective memory, norms, information, knowledge, technical skills and experimental adaptive strategies. They are human "supercomputers," historical epistemologists and moral philosophers of a sort who use narrative, a form of moral testimony, to help their communities face challenges and seize opportunities in the wake of an ever-changing landscape. CONCLUSIONS: The "ecosophy" of the Inupiat of Seward Peninsula offers examples of "focal practices", which are essential for environmental education. These focal practices instil key virtues, namely humility, gratitude, self-reliance, attentiveness, responsibility and responsiveness, that are necessary for subsistence living. PMID- 23986901 TI - Energy drink use, problem drinking and drinking motives in a diverse sample of Alaskan college students. AB - BACKGROUND: Recent research has identified the use of caffeinated energy drinks as a common, potentially risky behavior among college students that is linked to alcohol misuse and consequences. Research also suggests that energy drink consumption is related to other risky behaviors such as tobacco use, marijuana use and risky sexual activity. OBJECTIVE: This research sought to examine the associations between frequency of energy drink consumption and problematic alcohol use, alcohol-related consequences, symptoms of alcohol dependence and drinking motives in an ethnically diverse sample of college students in Alaska. We also sought to examine whether ethnic group moderated these associations in the present sample of White, Alaska Native/American Indian and other ethnic minority college students. DESIGN: A paper-and-pencil self-report questionnaire was completed by a sample of 298 college students. Analysis of covariance (ANCOVA) was used to examine the effects of energy drink use, ethnic group and energy drink by ethnic group interactions on alcohol outcomes after controlling for variance attributed to gender, age and frequency of binge drinking. RESULTS: Greater energy drink consumption was significantly associated with greater hazardous drinking, alcohol consequences, alcohol dependence symptoms, drinking for enhancement motives and drinking to cope. There were no main effects of ethnic group, and there were no significant energy drink by ethnic group interactions. CONCLUSION: These findings replicate those of other studies examining the associations between energy drink use and alcohol problems, but contrary to previous research we did not find ethnic minority status to be protective. It is possible that energy drink consumption may serve as a marker for other health risk behaviors among students of various ethnic groups. PMID- 23986902 TI - Vitamin D status in Greenland--dermal and dietary donations. AB - BACKGROUND: Vitamin D status influences skeletal health, the risk of falls and fractures, and muscle health, and it has been associated with inflammatory, infectious, cardiovascular and metabolic disorders in addition to some cancers. Prevailing intracellular infections such as tuberculosis are speculated to relate to vitamin D status. The vitamin D sources are dietary and dermal, the latter depending on UVB radiation exposure from the sun. Life in the Arctic influences vitamin D status because of dietary peculiarities, the polar night, waning of the ozone layer and maybe ethnic differences between Inuit and non-Inuit. OBJECTIVE AND DESIGN: Data on vitamin D status as estimated by plasma 25OHD in Inuit and non-Inuit in Greenland are reviewed. RESULTS: Decreasing intake of vitamin D-rich local food items associated with decreasing plasma 25OHD levels and insufficient vitamin D status is seen with low intake of traditional Inuit foods. Plasma 25OHD levels increase markedly during spring and summer in parallel with the high influx of sunlight while plasma 25OHD is not influenced by obesity in Greenland Inuit and no clear-cut association is seen between plasma 25OHD and the risk of tuberculosis. CONCLUSION: The frequency of vitamin D deficiency in populations in Greenland rises with the dietary transition and diseases related to low vitamin D status should be monitored. PMID- 23986903 TI - Migration of persons between households in rural Alaska: considerations for study design. AB - INTRODUCTION: Recent epidemiologic research studies in rural Alaska have examined risk factors for infectious diseases collected at the household level. Examples include the health effects of in-home piped water and household air quality. Because the exposure is measured at the household level, it is necessary to determine if participants remained in the same house throughout the course of follow-up. METHODS: We used data from a pneumococcal nasopharyngeal carriage study in 8 rural Alaska villages [3 regions; average number of persons: 642 (min 210, max 720 per village) to quantify changes in household membership and individual movements from 2008 to 2010. We define a household as a group of individuals living in a home together. Because the same households participated in carriage surveys over several years, we could determine changes on an annual basis. We calculated the percentage of households with a >= 1 person change in household members from year to year. Additionally, we present the percentage of individuals that changed households during consecutive years. RESULTS: In 3 regions of Alaska, the average household size was 5 persons. Between 2008 and 2009, 50% (250/497) of households had a change in their membership (>= 1 person in-migrated or out-migrated). Fifty-three percent of households experienced some migration of their members between 2009 and 2010. A total of 27 and 15% of households had a change of >= 2 and >= 3 persons, respectively. The percentage of households with movement was similar among the 3 rural regions and varied from 42 to 63% between villages. At the individual level, an average of 11% of persons changed households between years. The group with the most movement between houses was persons 18-29 years of age (19%), and least movement was in 5-10 and 50-64 years of age (6%). There was no difference in movement by gender. CONCLUSIONS: In rural Alaska, 52% of households experienced movement of members between years and 11% of individuals change households. These are important demographic figures to consider when planning and designing studies that measure an epidemiological exposure at the household level. Power and sample size calculations should account for the loss to follow-up associated with in- and out-migration of individuals from households. PMID- 23986904 TI - Raised BMI cut-off for overweight in Greenland Inuit--a review. AB - BACKGROUND: Obesity is associated with increased morbidity and premature death. Obesity rates have increased worldwide and the WHO recommends monitoring. A steep rise in body mass index (BMI), a measure of adiposity, was detected in Greenland from 1963 to 1998. Interestingly, the BMI starting point was in the overweight range. This is not conceivable in a disease-free, physically active, pre-western hunter population. OBJECTIVE: This led us to reconsider the cut-off point for overweight among Inuit in Greenland. DESIGN AND FINDINGS: We found 3 different approaches to defining the cut-off point of high BMI in Inuit. First, the contribution to the height by the torso compared to the legs is relatively high. This causes relatively more kilograms per centimetre of height that increases the BMI by approximately 10% compared to Caucasian whites. Second, defining the cut off by the upper 90-percentile of BMI from height and weight in healthy young Inuit surveyed in 1963 estimated the cut-off point to be around 10% higher compared to Caucasians. Third, if similar LDL-cholesterol and triglycerides are assumed for a certain BMI in Caucasians, the corresponding BMI in Inuit in both Greenland and Canada is around 10% higher. However, genetic admixture of Greenland Inuit and Caucasian Danes will influence this difference and hamper a clear distinction with time. CONCLUSION: Defining overweight according to the WHO cut-off of a BMI above 25 kg/m(2) in Greenland Inuit may overestimate the number of individuals with elevated BMI. PMID- 23986905 TI - DUSP1 Gene Polymorphisms Are Associated with Obesity-Related Metabolic Complications among Severely Obese Patients and Impact on Gene Methylation and Expression. AB - The DUSP1 gene encodes a member of the dual-specificity phosphatase family previously identified as being differentially expressed in visceral adipose tissue (VAT) of severely obese men with versus without the metabolic syndrome. Objective. To test the association between DUSP1 polymorphisms, obesity-related metabolic complications, gene methylation, and expression levels in VAT. Methods. The DUSP1 locus and promoter region were sequenced in 25 individuals. SNPs were tested for association with obesity-related complications in a cohort of more than 1900 severely obese individuals. The impact of SNPs on methylation levels of 36 CpG sites and correlations between DNA methylation and gene expression levels in VAT were computed in a subset of 14 samples. Results. Heterozygotes for rs881150 had lower HDL-cholesterol levels (HDL-C; P = 0.01), and homozygotes for the minor allele of rs13184134 and rs7702178 had increased fasting glucose levels (P = 0.04 and 0.01, resp.). rs881150 was associated with methylation levels of CpG sites located ~1250 bp upstream the transcription start site. Methylation levels of 4 CpG sites were inversely correlated with DUSP1 gene expression. Conclusion. These results suggest that DUSP1 polymorphisms modulate plasma glucose and HDL-C levels in obese patients possibly through alterations of DNA methylation and gene expression levels. PMID- 23986906 TI - Microbial adhesion and biofilm formation on microfiltration membranes: a detailed characterization using model organisms with increasing complexity. AB - Since many years, membrane biofouling has been described as the Achilles heel of membrane fouling. In the present study, an ecological assay was performed using model systems with increasing complexity: a monospecies assay using Pseudomonas aeruginosa or Escherichia coli separately, a duospecies assay using both microorganisms, and a multispecies assay using activated sludge with or without spiked P. aeruginosa. The microbial adhesion and biofilm formation were evaluated in terms of bacterial cell densities, species richness, and bacterial community composition on polyvinyldifluoride, polyethylene, and polysulfone membranes. The data show that biofouling formation was strongly influenced by the kind of microorganism, the interactions between the organisms, and the changes in environmental conditions whereas the membrane effect was less important. The findings obtained in this study suggest that more knowledge in species composition and microbial interactions is needed in order to understand the complex biofouling process. This is the first report describing the microbial interactions with a membrane during the biofouling development. PMID- 23986908 TI - Effect of low refocusing angle in T1-weighted spin echo and fast spin echo MRI on low-contrast detectability: a comparative phantom study at 1.5 and 3 Tesla. AB - MRI tissue contrast is not well preserved at high field. In this work, we used a phantom with known, intrinsic contrast (3.6%) for model tissue pairs to test the effects of low angle refocusing pulses and magnetization transfer from adjacent slices on intrinsic contrast at 1.5 and 3 Tesla. Only T1-weighted spin echo sequences were tested since for such sequences the contrast loss, tissue heating, and image quality degradation at high fields seem to present significant diagnostic and quality issues. We hypothesized that the sources of contrast loss could be attributed to low refocusing angles that do not fulfill the Hahn spin echo conditions or to magnetization transfer effects from adjacent slices in multislice imaging. At 1.5 T the measured contrast was 3.6% for 180 degrees refocusing pulses and 2% for 120 degrees pulses, while at 3 T, it was 4% for 180 degrees and only 1% for 120 degrees refocusing pulses. There was no significant difference between single slice and multislice imaging suggesting little or no role played by magnetization transfer in the phantom chosen. Hence, one may conclude that low angle refocusing pulses not fulfilling the Hahn spin echo conditions are primarily responsible for significant deterioration of T1-weighted spin echo image contrast in high-field MRI. PMID- 23986907 TI - The role of epidermal growth factor receptor in cancer metastasis and microenvironment. AB - Despite significant improvements in diagnosis, surgical techniques, and advancements in general patient care, the majority of deaths from cancer are caused by the metastases. There is an urgent need for an improved understanding of the cellular and molecular factors that promote cancer metastasis. The process of cancer metastasis depends on multiple interactions between cancer cells and host cells. Studies investigating the TGF alpha-EGFR signaling pathways that promote the growth and spread of cancer cells. Moreover, the signaling activates not only tumor cells, but also tumor-associated endothelial cells. TGF alpha-EGFR signaling in colon cancer cells creates a microenvironment that is conducive for metastasis, providing a rationale for efforts to inhibit EGFR signaling in TGF alpha-positive cancers. In this review, we describe the recent advances in our understanding of the molecular basis of cancer metastasis. PMID- 23986912 TI - [What was your diagnosis at first glance... livedoid vasculopathy]. PMID- 23986910 TI - Effects of a rehabilitation program on perceived environmental barriers in older patients recovering from hip fracture: a randomized controlled trial. AB - OBJECTIVES: To study effects of a one-year multicomponent intervention on perceived environmental barriers in hip fracture patients. DESIGN: Randomized controlled trial of a 12-month home-based rehabilitation aiming to improve mobility and function (ISRCTN53680197); secondary analyses. Subjects. Community dwelling hip fracture patients on average 70 days after trauma (n = 81). METHODS: Assessments at baseline, 3, 6, and 12 months later included perceived entrance related barriers (e.g., indoor/outdoor stairs, lighting, floor surfaces, and storage for mobility devices) and perceived barriers in the outdoor environment (poor street condition, hilly terrain, long-distances, and lack of resting places). Sum scores for entrance-related and outdoor barriers were analyzed using general estimating equation models. RESULTS: At baseline, 48% and 37% of the patients perceived at least one entrance-related barrier, and 62% and 60% perceived at least one outdoor barrier in the intervention and control group, respectively. Over time, (P = 0.003) the number of entrance-related barriers decreased in both groups (group P = 0.395; interaction P = 0.571). For outdoor barriers, time (P = 0.199), group (P = 0.911), and interaction effect (P = 0.430) were not significant. CONCLUSION: Our intervention had no additional benefit over standard care in hip fracture patients. Further study is warranted to determine whether perceived environmental barriers can be reduced by interventions targeted at the older individual. This trial is registered with ISRCTN53680197. PMID- 23986909 TI - The role of neuropeptides in suicidal behavior: a systematic review. AB - There is a growing evidence that neuropeptides may be involved in the pathophysiology of suicidal behavior. A critical review of the literature was conducted to investigate the association between neuropeptides and suicidal behavior. Only articles from peer-reviewed journals were selected for the inclusion in the present review. Twenty-six articles were assessed for eligibility but only 22 studies were included. Most studies have documented an association between suicidality and some neuropeptides such as corticotropin releasing factor (CRF), VGF, cholecystokinin, substance P, and neuropeptide Y (NPY), which have been demonstrated to act as key neuromodulators of emotional processing. Significant differences in neuropeptides levels have been found in those who have attempted or completed suicide compared with healthy controls or those dying from other causes. Despite cross-sectional associations between neuropeptides levels and suicidal behavior, causality may not be inferred. The implications of the mentioned studies were discussed in this review paper. PMID- 23986913 TI - [Disaster medicine: how do doctors cope?]. PMID- 23986911 TI - Metabolomics in plants and humans: applications in the prevention and diagnosis of diseases. AB - In the recent years, there has been an increase in the number of metabolomic approaches used, in parallel with proteomic and functional genomic studies. The wide variety of chemical types of metabolites available has also accelerated the use of different techniques in the investigation of the metabolome. At present, metabolomics is applied to investigate several human diseases, to improve their diagnosis and prevention, and to design better therapeutic strategies. In addition, metabolomic studies are also being carried out in areas such as toxicology and pharmacology, crop breeding, and plant biotechnology. In this review, we emphasize the use and application of metabolomics in human diseases and plant research to improve human health. PMID- 23986916 TI - Proteomic insights into seed germination in response to environmental factors. AB - Seed germination is a critical process in the life cycle of higher plants. During germination, the imbibed mature seed is highly sensitive to different environmental factors.However, knowledge about the molecular and physiological mechanisms underlying the environmental effects on germination has been lacking. Recent proteomic work has provided invaluable insight into the molecular processes in germinating seeds of Arabidopsis, rice (Oryza sativa), soybean (Glycine max), barley (Hordeum vulgare), maize (Zeamays), tea (Camellia sinensis), European beech (Fagus sylvatica), and Norway maple (Acer platanoides) under different treatments including metal ions (e.g. copper and cadmium), drought, low temperature, hormones, and chemicals (gibberellic acid, abscisic acid, salicylic acid, and alpha-amanitin), as well as Fusarium graminearum infection. A total of 561 environmental factor-responsive proteins have been identified with various expression patterns in germinating seeds. The data highlight diverse regulatory and metabolic mechanisms upon seed germination, including induction of environmental factor-responsive signaling pathways, seed storage reserve mobilization and utilization, enhancement of DNA repair and modification, regulation of gene expression and protein synthesis, modulation of cell structure, and cell defense. In this review, we summarize the interesting findings and discuss the relevance and significance for our understanding of environmental regulation of seed germination. PMID- 23986917 TI - Proteomics in the fruit tree science arena: new insights into fruit defense, development, and ripening. AB - Fruit tree crops are agricultural commodities of high economic importance, while fruits also represent one of the most vital components of the human diet. Therefore, a great effort has been made to understand the molecular mechanisms covering fundamental biological processes in fruit tree physiology and fruit biology. Thanks to the development of cutting-edge "omics" technologies such as proteomic analysis, scientists now have powerful tools to support traditional fruit tree research. Such proteomic analyses are establishing high-density 2DE reference maps and peptide mass fingerprint databases that can lead fruit science into a new postgenomic research era. Here, an overview of the application of proteomics in key aspects of fruit tree physiology as well as in fruit biology, including defense responses to abiotic and biotic stress factors, is presented. A panoramic view of ripening-related proteins is also discussed, as an example of proteomic application in fruit science. PMID- 23986918 TI - Retraction notice to "Transcriptional regulation of the AT1 receptor gene in immortalized human trophoblast cells."[Biochim. Biophys. Acta 1680 (2004) 158 170]. PMID- 23986919 TI - Retraction notice to "Human chromosome 21-derived miRNAs are over-expressed in down syndrome brains and hearts" [Biochem. Biophys. Res. Commun. 370 (2008) 473 477]. PMID- 23986920 TI - Authors' reply. PMID- 23986921 TI - Author's reply: To PMID 21660399. PMID- 23986922 TI - Opinion. PMID- 23986923 TI - Homer Richards Warner, 1922-2012. PMID- 23986924 TI - Errata. AB - Riadh et al. Afr J Tradit Complement Altern Med. 2011;8(3):322-327. DETECTION AND EXTRACTION OF ANTI-LISTERIAL COMPOUNDS FROM CALLIGONUM COMOSUM, A MEDICINAL PLANT FROM ARID REGIONS OF TUNISIA. Riadh H, Imen F, Abdelmajid Z, Sinda F. Should read Hammami et al. Afr J Tradit Complement Altern Med. 2011;8(3):322-327. DETECTION AND EXTRACTION OF ANTI-LISTERIAL COMPOUNDS FROM CALLIGONUM COMOSUM, A MEDICINAL PLANT FROM ARID REGIONS OF TUNISIA. Hammami R, Farhat I, Zouhir A, Fedhila S[This corrects the article on p. 322 in vol. 8, PMID: 22468012.]. PMID- 23986926 TI - A closer look at recertification candidate pass rates. PMID- 23986927 TI - [Management of employee health information]. PMID- 23986928 TI - [Current topics of epilepsy]. PMID- 23986929 TI - [Case of an employee returning to work despite being terminated by employer]. PMID- 23986930 TI - [Rectal cancer- current view of surgical resection radicality criteria]. PMID- 23986931 TI - Can a hospital be like a grocery store? PMID- 23986932 TI - Trends in healthcare and the changing role of radiology. AB - Change is sweeping the healthcare industry and the consensus of one group of radiology leaders is that they must not watch passively. Members of AHRA discussed this and several important topics during the inaugural AHRA-GE Healthcare Annual Summit. Attendees explored challenges facing healthcare: demographic shifts in patient and workforce populations, declining reimbursements, policy developments in Washington, DC, rising consumer choice, pricing pressure, and others. Attendees also discussed innovations in imaging technology that can improve patient care and advances in information technology that can help deliver the productivity improvements on which future prosperity depends. PMID- 23986933 TI - Roundtable: charting the way forward. AB - Radiology leaders met at the inaugural AHRA-GE Healthcare Annual Summit to discuss challenges facing the profession and opportunities to drive success in a fast changing care environment. Changes in the healthcare environment mean unprecedented challenges for the radiology profession. The Affordable Care Act, declining reimbursement, an aging population, growing consumer choice, and other trends are forcing radiology leaders to reexamine their ways of doing business and even the basic role of radiologists in patient care. Twelve members of AHRA shared their views on essential topics in a moderated roundtable discussion. That discussion is transcribed here. PMID- 23986934 TI - Why not?! PMID- 23986935 TI - ICD-10 artificial openings. PMID- 23986936 TI - Online documentation of equipment maintenance and performance. AB - A radiology department or imaging center relies on the proper operation of its equipment. This is accomplished through appropriate maintenance and independent medical physics monitoring. These activities represent an expensive but necessary effort to protect the original investment. Effective management requires accurate, timely, and useful documentation. The Georgia Regents Medical Center Department of Diagnostic, Therapeutic, and Interventional Radiology developed a comprehensive database encompassing both maintenance and monitoring activities associated with imaging equipment. This database is accessible throughout the facility via a website, providing a central hub for information distribution and access. The radiology engineering supervisor and quality control technologist make extensive use of this system and were key to its implementation and ongoing improvement. PMID- 23986938 TI - Imaging metrics. PMID- 23986937 TI - Increasing mobile radiography productivity. AB - Mobile radiography using computed radiography (CR) cassettes is a common equipment combination with a workflow bottleneck limited by location of CR readers. Advent of direct digital radiography (DDR) mobile x-ray machines removes this limitation by immediate image review and quality control. Through the use of key performance indicators (KPIs), the increase in efficiency can be quantified. PMID- 23986939 TI - Not another password... PMID- 23986940 TI - [Evaluation of the characteristics of tuberculosis patients in Ashikaga Red Cross Hospital, Tochigi Prefecture, Japan (2007-2011)]. AB - OBJECTIVE: To retrospectively evaluate the trends in tuberculosis characteristics among patients attending the Ashikaga Red Cross Hospital, Tochigi Prefecture, Japan, between January 2007 and December 2011, and to compare this trend with that observed globally. METHODS: In total, 273 newly reported tuberculosis patients attending the Ashikaga Red Cross Hospital were examined from January 2007 to December 2011 in terms of age, sex, mortality during tuberculosis treatment, race (Japanese or non-Japanese), nationality of non-Japanese patients, pulmonary (including sputum positivity and/or cavity formation in the lungs) or extrapulmonary tuberculosis, latent tuberculosis infection, residential areas of patients, and diseases coexisting with tuberculosis. RESULTS: Among the 255 Japanese tuberculosis patients, 202 patients were aged over 60 years, while the 18 non-Japanese patients were aged less than 50 years. Latent tuberculosis infections in 10 patients, including nurses and members of the patients' family, were treated. Among the 239 patients with pulmonary tuberculosis, 160 (67%) had Mycobacterium tuberculosis-positive sputum cultures and 99 patients (41%) had cavity formation in their lungs. Moreover, 1 multidrug-resistant, 2 isoniazid resistant, and 3 ethambutol-resistant strains of bacteria were isolated in the patients. Mortality during tuberculosis treatment, which increased with age, was observed in 41 patients. There were 66 cases of diabetes mellitus and/or chronic kidney dysfunction (or failure), which were the most common diseases that coexisted with tuberculosis. Disability, dementia, and/or residing in nursing home was also commonly observed (31 cases). Furthermore, 240 (88%) tuberculosis patients were transferred from other clinics or hospitals to our hospital, implying that people visiting nearby clinics or hospitals are cautious about interacting with tuberculosis patients. CONCLUSION: To a certain extent, tuberculosis is still prevalent among the elderly (more frequently in men than women) in Japan; however, in the younger generation, more than 30% of the patients are non-Japanese. The trends in tuberculosis observed in the Ashikaga Red Cross Hospital, Tochigi, Japan over a 5-year period were concordant with the global epidemiology of tuberculosis. PMID- 23986941 TI - [Extensive genetic analysis of clinical tuberculosis isolates and analysis of host factors to evaluate rapid development of multidrug resistance during initial treatment]. AB - INTRODUCTION: In this study, we aimed at determining the cause of resistance to tuberculosis treatment by performing genetic analyses of bacteria obtained from a patient who developed multidrug-resistant tuberculosis (MDR-TB) during the initial course of treatment for tuberculosis. METHODS: Specimens obtained before and after the development of MDR-TB were subjected to spoligotyping, drug resistance gene analysis, and variable-number tandem repeat (VNTR) typing. The patient's clinical background was also reviewed. RESULTS: After the development of resistance, the bacterial genome had changed with regard to only 1 mutation: S531L in the rpoB gene. Spoligotyping revealed that the genotype was that of the Beijing strain. VNTR typing confirmed all 35 loci. Review of the patient's clinical background showed that diabetes mellitus was present as a complication. DISCUSSION: There was no evidence of reinfection or polyclonal infection. The strain belonged to a sublineage of the Beijing genotype that is a common precipitating cause of MDR-TB due to this genotype. The patient had diabetes mellitus and was thus vulnerable to the development of resistance. Factors associated with both the host and bacteria, therefore, contributed to the development of resistance in this case, which seemed to result in the rapid development of MDR-TB. PMID- 23986942 TI - [Clinical factors of pulmonary tuberculosis in non-tuberculosis wards and its incidence among contact patients and healthcare workers in our hospital using QuantiFERON GOLD testing]. AB - OBJECTIVE AND METHODS: In our hospital, we analyzed the clinical factors of pulmonary tuberculosis (TB) diagnosed in non-TB wards and the incidence of TB infection among contact patients and healthcare workers (HCWs) using QuantiFERON TB GOLD (QFT) testing. MATERIAL: This study included 16 patients who were diagnosed with pulmonary TB in non-TB wards in our hospital from January 2008 to May 2011. Eight contact patients and 120 HCWs were also enrolled. RESULTS: The 16 TB patients comprised 11 men (77.7 years) and 5 women (74.4 years). Among them, only 9 patients exhibited positive results for Mycobacterium tuberculosis after the first acid-fast bacterial examination; the other 7 patients presented positive results only after the second or third examinations. Moreover, there were 3 cases of positive Mycobacterium avium samples in the first acid-fast bacterial examination. Among 16 pulmonary Mycobacterium tuberculosis cases, 8 were sputum smear and culture positive, 7 were sputum smear negative and culture positive, and 1 was sputum smear and culture negative. Moreover, 17 days had elapsed from the time of admission to the non-TB ward to diagnosis. TB contact examination revealed that QFT results for 2 HCWs changed from negative to positive. DISCUSSION: We suspected pulmonary aspergillosis or old TB when presented with cases with a history of TB. Moreover, we believe that the periods from admission to diagnosis were delayed when the first acid-fast bacterial sputum examination was negative or showed non-tuberculous mycobacteria. PMID- 23986943 TI - [Tuberculosis Annual Report 2011--(2) Childhood and elderly tuberculosis]. AB - In 2011, the number of newly notified childhood tuberculosis (TB) cases (tuberculosis patients aged 0-14 years) in Japan was 84, which corresponds to a notification rate of 0.50 per 100,000. The annual notified numbers and rates (per 100,000 population) of childhood TB cases decreased steadily until 2006, when the number became less than 100, after which the numbers have since remained stable. Among the 84 childhood TB patients who were notified in 2011, 33 (39.3%) were aged 0-4 years, 20 (23.8%) were aged 5-9 years, and 31 (36.9%) were aged 10-14 years. The proportion of TB patients aged 10-14 years was higher in 2011 than in previous years. In 2011, one TB meningitis case and two miliary TB cases were reported in children. Further, 23 symptomatic patients (27.4%) were identified at medical institutions and 45 patients (53.6%) were identified by contact investigation of household members. Together, these groups of patients accounted for nearly 80% of the cases of childhood TB that were detected, which was similar to the percentage in previous years. Since 1999, the notification rates of TB patients aged 85 years and above have been consistently higher among those aged 65 years and above in Japan. The annual rate of reduction in the notification rates of TB patients aged 65-79 years has accelerated from 12,625 in 2000 to 6,427 in 2011. The proportion of TB patients aged 65 years and above has consistently increased, reaching up to more than 60% in 2011; notably, the proportion of TB patients aged 80 years and above has increased to more than 30%. The proportion of bacteriologically positive TB cases among pulmonary TB (PTB) cases was higher in those aged 65 years and above than those aged 15-64 years. The proportion of PTB patients with only nonrespiratory symptoms increased with age, reaching 28.9% in those aged 85 years and above. The proportion of TB cases associated with a patient delay of two months or longer was much less in the patients aged 65 years and above than those aged 15-64 years (14.5% vs. 25.8%), whereas the proportion of TB cases associated with a doctor delay of one month or longer was slightly higher in the patients aged 65 years and above than those aged 15-64 years (24.2% vs. 20.0%). Of the newly notified TB patients in 2010 whose treatment outcomes are available as of writing, 28.5% died within a year after the initiation of TB treatment; of these, 16.3% died within three months. The proportion of deaths within three months after the initiation of the TB treatment among the patients aged 65 years and above showed substantial increase with age from 3.6% in 65-69 years old to 17.0% in 90 years and above. PMID- 23986944 TI - [Institute role in occupational health and industrial ecology scientific investigation development. International and national aspects]. AB - The analyses of Institute activity main directions are briefly presented as well as Institute role in preventive medicine development, occupational health and industrial ecology key problems solving, international collaboration development, and WHO Global Plan of Action on Workers' Health 2008-2017 realization in the Russian Federation. PMID- 23986945 TI - [Protecting health of workers and predictive preventive personified medicine]. AB - Industrial medicine is an integrated sphere of preventive medicine, aimed to regulate health of workers and concerned with scentific basis and practical application of means and methods to preserve and improve workers' health. The article covers major research trends in workers' health preservation, results of fundamental studies on pathogenetic mechanisms and developmental patterns of contemporary occupational and industrial pathologies, prospects of predictive personified trend development and its application in industrial medicine. PMID- 23986946 TI - [Development of social hygienic research in industrial medicine]. AB - The article covers history of establishment and development of social hygienic research in Industrial Medicine Research Institute with RAMSc over last 90 years. The materials deal with founders and leaders of Social Hygienic research laboratory in various periods, with history of occupational morbidity studies, with development and results of social hygienic studies, organization of occupational therapy service in Russia, studies concerning remote effects of occupational hazards through analytic epidemiology methods, with considerably restricted possibilities in studies of relationships (especially remote) between work conditions and workers' health nowadays due to implemented law on personal data and new approaches to evaluation of industrial hazards effects on health. PMID- 23986947 TI - [Labor physiology role in workers of different type labor activity workability and health. Progress and prospects]. AB - There are presented the data of workers overstrain and fatigue conditions mechanisms based on physiological, psychological and ergonomic aspects of work processes in different types of activities (mental, visual-strained, physical). 15-year historical analysis, current state and prospects of labor physiology methods development are shown. Complex physiological and ergonomic investigations have allowed developing the measures of work ability raise and diseases prevention for workers various professions. Obtained results provided the basis of development of regulatory documents in area of human organism strain physiological norms, consequences of psycho-emotional stress and overstrain prevention taking into account working conditions class. PMID- 23986948 TI - [Special industrial medicine as a basis for workers' health preservation]. AB - The article covers results and prospects of research in special industrial medicine on improving methodology of complex evaluation of work conditions in major economy branches including medical sphere workers. On the basis of ecologic epidemiologic research, remote effects of occupational and non-industrial hazards in workers and general population were studied, new technologic processes and equipment were assessed, principles for unifying methods to control chemicals in workplace air were defined, regulation methodical documents concordant with WHO, ILO and EC are specified. PMID- 23986949 TI - [Occupational microclimate. Results and prospects of research]. AB - The article covers results of studies conducted over last 15 years and aimed to elaboration of requirements to integral parameters of microclimate at workplace, its evaluation and regulation, prophylactic measures against body overcooling and overheating. The authors present methods to evaluate combined effects of physical factors (noise, vibration, microclimate) and to assess microclimate with consideration of factors determining body thermal load (energy expenditure, duration of stay at workplace, heat insulation of clothes and thermo-physical parameters of its materials). Mathematic models of forecasting cold and heat stress are presented, as well as requirements to heat insulation for individual protective means against cold and methods to calculate it. Regimens of work in heating and cooling conditions are specified. The authors set directions for further studies to define regulation requirements to microclimate on basis of studied patterns of body heat state formation, its evaluation criteria, epidemiologic studies results, specified prophylactic measures against overheating and overcooling with consideration of adaptation, sex, thermo physical characteristics of individual protective means (special clothes, footwear, gauntlets, headwear). PMID- 23986950 TI - [Problem of studying influence of electric and magnetic fields on human health. Results and prospects]. AB - The article presents results and prospects of studies on problem of unfavorable effects caused by electric and magnetic fields on human health, and working out hygienic regulation of the factor in occupational and ambient surroundings. PMID- 23986951 TI - [Prevention and protection of workers' reproductive health]. AB - The article mentiones issues of preserving and strengthening the reproductive health of women workers, dealed by researchers of the laboratory, established in 1974. It describes the developed concept of the reproductive health problems and scientific research areas, developed documents, including legislative fields, formulates main prospects of the laboratory to meet the requirements of the present moment. Noted the role of the Problem Commission "Scientific basis for the reproductive health of workers", in the work of the Scientific Council on medical and environmental issues of workers' health. PMID- 23986952 TI - [Research on radiation hygiene problems]. AB - The author presents brief historical reference on research in radiation hygiene problems, initiated by scientists in Central Institute for Occupational hygiene and Preventive hygiene (now--Federal State Budgetary Institution "Research Institute of Occupational Health" with Russian Academy of Medical Sciences). PMID- 23986953 TI - [Three kinds of speech evaluation in maxillectomy patients during the fabrication process of a hollow-type obturator]. AB - Speech evaluation is essential to the rehabilitation of maxillectomy patients. A speech intelligibility test has been frequently used for the evaluation because of its simplicity. However, the test needs human listeners and this has been a shortcoming of the test. Thus, objective evaluation methods have been discussed. One of them is formant analysis for vowel evaluation and another is psychoacoustic analysis for consonants. In this research, to evaluate the speech in five maxillectomy patients, the F2-range was examined as formant analysis and the sharpness of /sa/ was examined as psychoacoustic analysis, in addition to the speech intelligibility test, during the fabrication process of a hollow-type obturator. The objective evaluation of patients' speech was effectively performed using those three methods. The F2-range was larger, the sharpness of /sa/ was higher and the speech intelligibility was higher when patients wore an obturator compared to when patients did not wear an obturator. The difference in speech when changing the types of obturator was not clear. The method and the findings are important for future research in this field, since speech is one of the important factors in maxillofacial rehabilitation. PMID- 23986954 TI - [Relationship between oral health status and life behavior in junior and senior high school students in Japan]. AB - A survey of dental diseases carried out by the Ministry of Health, Labour and Welfare in 2003 revealed that more than 40% of people aged between 5 and 25 suffer from periodontal diseases and the average number of DMFT has been decreasing. The lifestyle of junior and senior high school students in particular has changed drastically. This study investigated the relationship between dietary habits and oral diseases in junior and senior high school students in Tokyo. Survey responses were received from 813 of 848 students. There was a significant correlation between the presence of untreated teeth and student's dietary habits, or the presence of periodontal diseases. These results suggest that dental hygienists need to consider providing advice on appropriate eating habits during dental hygiene instruction to students. PMID- 23986955 TI - [Influence of contributing factors in temporomandibular disorders in female college students]. AB - This study was performed to ascertain any relationship between temporomandibular disorders (TMD) and contributing factors such as tooth contacting habit (TCH) that influence the manifestation of TMD and TCH in graduate female college students. The subjects were 114 graduate female college students in Oral Health Care Sciences, Faculty of Dentistry, Tokyo Medical and Dental University. The subjects were assessed using a questionnaire and observation of tongue indentation and buccal mucosa ridging. Of these students, 89 (78.1%) answered the questionnaire. Statistical examinations were performed using t-tests and logistic regression analyses. A p value of less than 0.05 was considered to be a significant difference. The prevalence rate of TMD was 16 (19.3%) and the prevalence rate of TCH was 39 (47.0%). Logistic regression analyses indicated that unilateral chewing, presence of tongue indentation, and buccal mucosa ridging were significant contributors to the manifestation of TMD. In addition, these analyses indicated that sleep disorders and physical pain such as headaches and neck pain were significant contributors to the manifestation of TCH. This study suggested the following: unilateral chewing, presence of tongue indentation, and buccal mucosa ridging could correlate with the manifestation of TMD. In addition, sleep disorders, headaches, and neck pains could correlate with the manifestation of TCH. PMID- 23986956 TI - Computerized technology for restorative dentistry. AB - Computers have had a meaningful impact on the dental office and dental practice leading to significant changes in communication, financial accounting, and administrative functions. Computerized systems have more recently generated increasing diversity of application for the delivery of patient treatment. Digital impression systems and chairside CAD/CAM systems offer opportunities to integrate digital impressions and full contour restorations in the dental office. Systems rely on single image and video cameras to record the digital file that is the foundation for an accurate outcome. This article presents key aspects of computerized technology using the CAD/CAM process. PMID- 23986957 TI - Influence of dentin pretreatment with titanium tetrafluoride and self-etching adhesive systems on microtensile bond strength. AB - PURPOSE: To evaluate the effect of dentin pretreatment with 2.5% titanium tetrafluoride (TiF4) on microtensile bond strength (microTBS) of one- or two-step self-etching adhesive systems. METHODS: 24 human sound third molars were used. A flat dentin surface of each tooth was exposed. After planing, teeth were divided into groups so that dentin would be left untreated or treated with a 2.5% TiF4 solution for 1 minute. Specimens were then subdivided into two groups to receive one of the following adhesive systems: one-step self-etching Adper Easy One (ADP) or two-step self-etching adhesive Clearfil SE Bond (CLEAR). A block of composite measuring 5.0 mm high and 5.0 mm wide was made incrementally on the tooth. Specimens were taken to a metallographic cutter to fabricate sticks with a bond area of approximately 1 mm2. After 24 hours, specimens were submitted to microTBS testing and the failure mode was recorded by examining specimens under stereomicroscopy. Scanning electron microscope (SEM) photomicrographs were obtained of the tooth/restoration interface. RESULTS: Two-way ANOVA and Tukey's test demonstrated that pretreatment of dentin with a TiF4 solution did not affect the microTBS values of either of the adhesive systems (P = 0.675). CLEAR provided higher bond strength than ADP, regardless of whether dentin was or was not pretreated with the TiF4 solution. Failure mode showed mostly adhesive failures in all groups, except when only ADP was used, causing mostly cohesive fractures in resin. PMID- 23986958 TI - Effect of different bonding strategies on the marginal adaptation of class 1 silorane restorations. AB - PURPOSE: To evaluate the quality of marginal and internal adaptation of Filtek Silorane composite in standardized class 1 cavities before and after thermo mechanical loading using different application protocols of the Silorane System Adhesive (SSA). METHODS: Five groups (n = 10) of class 1 cavities were restored with Filtek Silorane using different SSA applications. Total bonding (TB): Group A (SSA), Group B (SSA without primer polymerization), Group C (enamel etching + SSA), Group D (enamel etching + SSA without primer polymerization) and Selective bonding (SB): Group E. Marginal adaptation was assessed on replicas in the SEM at x200 magnification before and after thermomechanical loading (3,000 x 5-55 degrees C, 1.2.10(6) x 49N; 1.7Hz) under simulated dentin fluid. After loading, the samples were sectioned and the internal adaptation was evaluated as well. RESULTS: The lowest scores of %CM (Continuous Margin) before/after thermo mechanical loading being 80.8 (+/- 8.2) / 32.1 (+/- 8.3) were observed in the control group A. Enamel phosphoric acid etching prior to the application of the SSA resulted in significantly higher %CM before and after loading in comparison with the "non-etched" groups (P > 0.05). When enamel etching was performed before the application of the adhesive system, no statistically significant differences (P > 0.05) were observed regardless of how the SSA was applied (total vs. selective bonding). Internal adaptation was negatively influenced by omitting the SSA-primer polymerization (P > 0.05). PMID- 23986959 TI - Recovery percentage of remineralization according to severity of early caries. AB - PURPOSE: To analyze the cutoff severity of early lesions according to recovery rate after fluoride treatment. METHODS: 100 specimens were demineralized over 3 to 40 days. Specimens were immersed in 2% sodium fluoride solution for 4 minutes, and then in artificial saliva for the rest of the total 24 hours. After 10-time repetition of this cycle, the deltaF recovery rates (R(deltaF,) %) were calculated from the deltaF values before (deltaF(base), %) and after (deltaF(tx), %) remineralization using the QLF-D system. For the discrimination of R(deltaF) based on deltaF(base), the sensitivities versus 1-specificities were analyzed in receiver operating characteristic (ROC) curves, the 95% confidence interval (CI) as well as the significance of differences. The histological features of lesions were observed and lesion depths were digitally measured by polarized light microscopy (PLM). A paired t-test was also performed to assess the differences in deltaF and lesion depth before and after applying fluoride. RESULTS: For a threshold recovery percentage of 40%, the suggested deltaF(base) cutoff value was -19.15%, whereas for a threshold recovery percentage of 50%, the suggested cutoff value was -14.60% (P < 0.0001). According to the QLF-D system and PLM analysis, recovery percentage was greater for shallower lesions. Based on fluoride treated recovery percentages, the findings suggested that it is possible for early caries lesions to make more than 50% recovery when the deltaF(base) value was greater than -14.60%. Visually and numerically, the relative recovery percentages were highest during the earlier stages of caries. PMID- 23986960 TI - Effect of a functional desensitizing paste containing 8% arginine and calcium carbonate on the microtensile bond strength of etch-and-rinse adhesives to human dentin. AB - PURPOSES: To evaluate (1) the effect of a desensitizing paste containing 8% arginine and calcium carbonate on the microtensile bond strength between dentin and etch-and-rinse adhesive systems; and (2) to examine the dentin tubules occlusion quantitatively. METHODS: 48 freshly extracted intact human mandibular third molars were divided randomly into three groups. The mid-coronal dentin of each tooth was exposed and treated. Group A: no treatment; Group B: specimens were polished with a desensitizing paste containing 8% arginine and calcium carbonate using a rotary cup operating at a low speed for 3 seconds, followed by an additional duration of 3 seconds (total operation time of 6 seconds), according to the manufacturer's instructions; Group C: specimens were handled in the same way with the exception of an increased operation time of 9 seconds, twice (total operation time of 18 seconds). Each group was randomly divided into two subgroups in order to evaluate the effectiveness of two different adhesive agents. A two-step etch-and-rinse adhesive agent (Adper SingleBond 2) and a three step etch-and-rinse adhesive agent (Adper ScotchBond Multi-purpose) were applied to dentin surfaces. Then, microtensile bond strengths of the six subgroups were tested. Dentin surfaces were analyzed using field-emission scanning electron microscopy (FESEM) and laser scanning confocal microscopy (LSCM). RESULTS: There was no significant difference in microtensile bond strength between the control group and the experimental groups treated with the 8% arginine and calcium carbonate desensitizing paste during the application of etch-and-rinse adhesives. Both FESEM and LSCM showed that the desensitizing paste occluded dentin tubules effectively. PMID- 23986961 TI - Clinical evaluation of the efficacy of fluoride adhesive tape (F-PVA) in reducing dentin hypersensitivity. AB - PURPOSE: To evaluate the in vivo effectiveness of an experimental 2.26% fluoride polyvinyl alcohol (F-PVA) tape in reducing dentin hypersensitivity. METHODS: 30 healthy men and women (total of 79 teeth) in their third decade of life with dentin hypersensitivity were enrolled in this study. The subjects were divided into four groups: three experimental groups were treated with fluoride agents (F PVA tape, Vanish varnish, and ClinPro XT varnish), and a control group was treated with gelatin as a placebo. Each fluoride agent was applied according to the manufacturer's instructions. Stimulation was applied to the subjects' teeth using compressed air and ice sticks before applying the agent, as well as at 3 days and 4, 8, and 12 weeks after applying the agent. The degree of pain was measured using a visual analogue scale (VAS). RESULTS: The VAS scores were significantly (P < 0.05) decreased at 3 days and at 4, 8, and 12 weeks from baseline in both the air stream and ice stick tests. The reduction in the VAS scores for the three fluoride agents was decreased 8 weeks after their application. The F-PVA tape was found to be more effective for dentin hypersensitivity than the Vanish varnish and ClinPro XT varnish at 4 and 8 weeks of the examination period. PMID- 23986962 TI - Long-term management of plaque and gingivitis using an alcohol-free essential oil containing mouthrinse: a 6-month randomized clinical trial. AB - PURPOSE: This 6-month, examiner-blind, single center, randomized, parallel group, controlled clinical trial compared the antiplaque/antigingivitis effects of an alcohol-free EO mouthrinse (LISTERINE Zero) to a negative control (5% flavored, colored hydroalcohol) and to an alcohol-free CPC-containing mouthrinse (Colgate Plax). METHODS: 337 gingivitis subjects were clinically examined to determine Modified Gingival Index (MGI) and Plaque Index (PI) at baseline, 3 and 6 months. The primary efficacy variables were mean MGI and mean PI at 6 months (statistically analyzed by ANCOVA). After professional dental prophylaxis, subjects were randomly assigned to 6-month twice daily unsupervised use of alcohol-free EO, alcohol-free CPC or a negative control rinse, in conjunction with normal brushing and flossing. Safety was monitored throughout the study. RESULTS: 311 subjects completed the study. After 6 months of use, EO significantly reduced plaque (31.6%) and gingivitis (24.0%) compared to negative control. At 6 months, CPC also significantly reduced plaque (6.4%) and gingivitis (4.4%) compared to negative control. EO provided a 26.9% decrease in plaque and a 20.5% decrease in gingivitis compared to CPC (P < 0.001). All rinses were well tolerated. The alcohol-free EO mouthrinse demonstrated superior efficacy in reducing plaque and gingivitis over 6 months compared to both negative control and alcohol-free CPC mouthrinse. PMID- 23986963 TI - Effects of two essential oil mouthrinses on 4-day supragingival plaque regrowth: a randomized cross-over study. AB - PURPOSE: To investigate the plaque inhibiting effects of two commercially available mouthrinses containing essential oils (EO). Both products contained the same concentration of EO, but one of them did not contain ethanol. METHODS: The study was an observer-masked, randomized, 4 x 4 Latin square cross-over design, balanced for carryover effects, involving 12 participants in a 4-day plaque regrowth model. A 0.12% chlorhexidine (CHX) rinse and a saline solution served as positive and negative controls, respectively. On Day 1, subjects received professional prophylaxis, suspended oral hygiene measures, and commenced rinsing with their allocated rinses. On Day 5, subjects were scored for disclosed plaque. RESULTS: Differences among treatments were highly significant (P < 0.0001), with greater plaque inhibition by CHX compared to EO rinse containing ethanol (P = 0.012), which, in turn, was significantly more effective than the rinse without ethanol and the saline (P < 0.001). The reduction in plaque regrowth seen with the EO rinse without ethanol was quite similar to that elicited by saline (P > 0.05). PMID- 23986964 TI - How to re-seal previously sealed dentin. AB - PURPOSE: To test different kinds of mechanical and chemical pre-treatments of previously sealed dentin before re-sealing. METHODS: 75 bovine dentin samples were precycled for 3 days (per day: 6 x 1 minute erosion (HCl; pH 2.3), and kept in artificial saliva in dwell time and overnight. Group 1 samples (n = 15) remained untreated (control). Remaining samples were sealed with Seal&Protect (S&P). After thermo-mechanical loading (5,000 cycles, 50/5 degrees C, 11,000 brushing strokes) a first measurement was performed to evaluate permeability of the sealant. Permeability was tested by storing the samples in HCl (pH 2.3; 24 hours) and measuring the calcium release into the acid by atomic absorption spectroscopy. Based on these calcium release values, the previously sealed samples were allocated to four groups (2-5) according to a stratified randomization. Samples of Groups 2-5 were re-sealed with S&P after either being treated with ethanol (Group 3), silane-coupling-agent (Group 4) or sandblasting (Group 5). After re-sealing, all samples had a second measurement of permeability. After another thermo-mechanical loading, a third evaluation of permeability was conducted. RESULTS: At all measurements, calcium release was significantly higher in the untreated control group than in the sealed Groups 2-5 with no significant differences among the sealed groups. Within Groups 2-5, calcium release at the first and third measurement was higher compared with that at the second measurement (P < 0.05). PMID- 23986965 TI - Fluoride uptake by human tooth enamel: topical application versus combined dielectrophoresis and AC electroosmosis. AB - PURPOSE: To compare fluoride uptake by enamel after applying 1.23% acidulated phosphate fluoride gel to human tooth enamel topically (n = 12) or with combined dielectrophoresis and AC electroosmosis (DEP/ACE) at frequencies of 10, 400 and 5,000 Hz (n = 12) for 20 minutes. METHODS: DEP/ACE induced nonuniform electrical fields with three alternating current frequencies to polarize, orient, and motivate fluoride particles. Fluoride concentrations were measured at various enamel depths using wavelength dispersive spectrometry. Data were analyzed by ANOVA/Student-Newman-Keuls post hoc tests (P < or = 0.05). RESULTS: Fluoride concentrations in the diffusion group were significantly higher than baseline readings at 10, 20 and 50 microm depths. Fluoride concentrations in DEP/ACE treated teeth were significantly higher than the diffusion group at 10, 20, 50, 100, 200 and 300 microm (ANOVA/Student-Newman-Keuls post hoc, P < 0.05). Fluoride uptake with DEP/ACE was substantially higher than diffusion at 10, 20, 50, 100, 200 and 300 microm depths (paired t test, P < 0.05). DEP/ACE transported fluoride up to 300 microm deep, whereas conventional fluoride application was comparatively ineffective beyond 20 microm depth (P < 0.05). Compared to passive diffusion, fluoride uptake in enamel was significantly higher in the DEP/ACE group at 10, 20, 50, 100, 200 and 300 microm depths (P < 0.05). DEP/ACE drove fluoride substantially deeper into human enamel with a difference in uptake 1,575 ppm higher than diffusion at 100 microm depth; 6 times higher at 50 microm depth; 5 times higher at 20 microm depth; and 7 times higher at 10 microm depth. Fluoride levels at 100 microm were equivalent to long-term prophylactic exposure. PMID- 23986966 TI - Optimal concentration of hyaluronan and plant protein in different culture systems for in vitro maturation of bovine oocytes. AB - With a view to search for optimal concentration of hyaluronan (HA) and plant protein (PP) in different culture systems for in vitro maturation of bovine oocytes, cumulus-oocyte complexes (COCs) were matured in vitro in 2 culture systems (first co-cultured with granulose cells and estrus calf serum (ECS) in 2 mL volume, second without co-culture where ECS was replaced by exogenous hormones and BSA or PP in 100 microL dose under mineral oil). Seven types of media were used; 3 in first system and 4 in second system. To evaluate HA and PP effect on oocytes after in vitro culture an estimation of meiosis stage and a level of DNA fragmentation was performed by TUNEL staining. The highest meiotic maturation (84%) was observed in oocytes cultured in medium enriched with ECS in co-culture with granulose cells (1st system). The lowest meiotic maturation was noted in medium with addition of BSA (43%). The addition of HA in the medium enriched with BSA significantly increased the rate of matured oocytes (67%) and also didn't affect the chromatin quality of individual oocytes. The addition of HA to the culture medium supplemented with a PP decreased the rate of matured oocytes to 54% but no statistical differences were noted. The results of the present study showed that HA supplementation didn't have a detrimental impact on oocyte chromatin integrity and improved bovine oocytes' meiotic maturation in medium supplemented only with BSA without co-culture of granulose cells. PMID- 23986967 TI - Effects of sodium dodecyl sulphate on enhancement of lipoxygenase activity of hemoglobin. AB - Lipoxygenases comprise a family of non-heme iron-containing enzymes that catalyze the stereospecific dioxygenation of polyunsaturated fatty acids with 1, 4-cis-cis pentadiene structure. Hemoglobin, a heme iron-containing protein has been reported to have lipoxygenase activity but the assay conditions that could enhance the activity remain obscure. Therefore, establishment of optimum assay conditions for lipoxygenase activity of hemoglobin could allow modeling of hemoglobin as lipoxygenase. Hemoglobin was extracted from blood of an identified individual of genotype AA. The hemoglobin was dialyzed at 4 degrees C for 24 h against 50 mM Tris-HCl buffers (pH 8.5 and 7.2) and effects of sodium dodecyl sulphate (SDS) and linoleic studied at pH 5.0 and 7.2 with UV-VIS Titration Spectrophotometry. The results show that 3.3, 8.6 and 88.1% concentrations of met hemoglobin were found in presence of 0.0 mM SDS at pH 5.0 and 7.2, 1.043 mM SDS at pH 7.2 and 0.404 mM SDS at pH 5.0 respectively. Also, the difference spectra of hemoglobin in presence of linoleic acid showed positive peak at 285 nm which suggest the presence of oxodienes--a reaction product of hydroperoxidase activity of lipoxygenase. Formation of met-hemoglobin/met-myoglobin is highly correlated with lipid oxidation. Since highest concentration of met-hemoglobin (88.1%) was observed in presence of 0.404 mM SDS at pH 5.0, lipoxygenase activity of hemoglobin was enhanced in presence of SDS under these conditions. PMID- 23986968 TI - Curcumin sensitizes lung adenocarcinoma cells to apoptosis via intracellular redox status mediated pathway. AB - The present study demonstrates that curcumin acts as pro-oxidant and sensitizes human lung adenocarcinoma epithelial cells (A549) to apoptosis via intracellular redox status mediated pathway. Results indicated that curcumin induced cell toxicity (light microscopy and MTT assay) and apoptosis (AnnexinV-FITC/PI labeling and caspase-3 activity) in these cells. These events seem to be mediated through generation of reactive oxygen species (ROS) and superoxide radicals (SOR) and enhanced levels of lipid peroxidation. These changes were accompanied by increase in oxidized glutathione (GSSG), reduced glutathione (GSH) and gamma glutamylcysteine synthetase (gamma-GCS) activity, but decrease in GSH/GSSG ratio. The induction of apoptosis and decrease in GSH/GSSG ratio was also accompanied by sustained phosphorylation and activation of p38 mitogen activated protein kinase (MAPK). On the other hand, addition of N-acetyl cysteine (NAC), an antioxidant, blocked the curcumin-induced ROS production and rescued malignant cells from curcumin-induced apoptosis through caspase-3 deactivation. However, L-buthionine sulfoximine (BSO), a GSH synthesis blocking agent, further enhanced curcumin induced ROS production and apoptosis in A549 cells. Decreased GSH/GSSG ratio seems to be a crucial factor for the activation of MAPK signaling cascade by curcumin. The study therefore, provides an insight into the molecular mechanism involved in sensitization of lung adenocarcinoma cells to apoptosis by curcumin. PMID- 23986969 TI - Neuropharmcological potential of methanolic extract and a triterpene isolated from Madhuca longifolia L leaves in mice. AB - The methanolic extract of M. longifolia (MLME) and a compound a triterpene, derivative of madhucic acid (dMA) isolated from the leaves of M. longifolia, were investigated for their possible neuropharmacological activities in mice using phenobarbitone induced sleeping time, spontaneous motor activity, marble burying test and Eddy's hot plate method. LD50 for MLME and dMA were 100 and 10 mg/kg of body weight, respectively. Both MLME and dMA (10 mg/kg and 2 mg/kg oral route respectively) exhibited significant increase in phenobarbitone induced sleeping time, greater reduction in spontaneous motor activity and marble burying activity, confirming their sedative nature. Both MLME and dMA also exhibited considerable antinociceptive activity in experimental animals. The results suggest that both MLME and dMA have CNS depressant activity in mice. PMID- 23986970 TI - Effect of long acting insulin supplementation on diabetic nephropathy in Wistar rats. AB - This study was designed to check whether insulin supplementation is crucial for inducing diabetic nephropathy (DNP) in Wistar rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin. The urinary biochemical parameters such as albumin, creatinine and urea nitrogen were monitored every two weeks. The histological changes in the kidney were observed at the end of both fifth and seventh month. Immunohistochemical analyses of VEGF, ERK-1 and NF kappaB expression were performed to demonstrate mesangial expansion and glomerulosclerosis, which are the defining histological features of nephropathy. A significant change in the urinary biochemistry was observed in diabetic animals at the end of four months, but the aforementioned quantitative changes were delayed in diabetic animals treated with insulin. At the end of seven months, the diabetic animals showed prominent histological changes such as glomerular basement membrane thickening, nodular glomerulosclerosis and mesangial expansion. However, these changes were not observed in diabetic animals treated with insulin even at the end of the study. From the results, it can be concluded that there is no need of insulin supplementation for inducing DNP, when the animals are induced with an optimal dose of 45 mg/kg body weight of streptozotocin. PMID- 23986971 TI - Protective effects of different extracts of Eucommia ulmoides Oliv. against thioacetamide-induced hepatotoxicity in mice. AB - A comparison of analysis in evaluating the hepatoprotective action of fractional ethanolic (F0), ethyl acetic (F1), n-butanol (F2) and aqueous (F3) extracts of E. ulmoides Oliv. (EUO) against thioacetamide (TAA) induced hepatic damage was studied in mice. The extract (453 mg/kg-F0, 104 mg/kg-F1, 95 mg/kg-F2 and 237 mg/kg-F3 body weight, po, once daily for 15 days) restored serum marker enzymes levels to normal in TAA treated mice. The biochemical biomarkers viz., total protein, albumin and total bilirubin were also restored forward normal level expression pattern of liver protein profile of mice by using sodium dodecyl sulfate polyacrylamide gel electrophoresis and two-dimensional gel electrophoresis showed 144 spots in TAA administered group which were significantly reduced in EUO extracts treated group. Among the four extracts ethyl acetate (F1) and n-butanol (F2) extracts showed more significant liver protection. TAA induced injury can be correlated with its high phenolic content in these extracts which may have hepatoprotective effects in regulating liver proteins by scavenging free radicals. PMID- 23986972 TI - Endothelium-dependent and independent vasorelaxant effects of aqueous extract of Tridax procumbens Lin. leaf in rat aortic rings. AB - Tridax procumbens leaf extract induced aortic relaxation in a concentration dependent manner, for both phenylephrine (PE) and KCl- induced contractions in isolated rat aortic rings. The relaxation effect of the extract on PE-induced contraction was 57% greater than that on KCl- induced contraction. The extract caused dose-dependent relaxations in precontracted isolated rat aorta with phenylephrine; the relaxation was attenuated by the removal of endothelium. However, the relaxation responses to sodium nitroprusside were not significantly abolished by the removal of endothelium. The vasorelaxatory effect of the extract was completely abolished in presence of L-NAME. The results indicate that the vasorelaxant effect of T. procumbens extract is probably mediated by both endothelium-dependent and-independent mechanisms. PMID- 23986973 TI - Microwave radiation induced oxidative stress, cognitive impairment and inflammation in brain of Fischer rats. AB - Public concerns over possible adverse effects of microwave radiation emitted by mobile phones on health are increasing. To evaluate the intensity of oxidative stress, cognitive impairment and inflammation in brain of Fischer rats exposed to microwave radiation, male Fischer-344 rats were exposed to 900 MHz microwave radiation (SAR = 5.953 x 10(-4) W/kg) and 1800 MHz microwave radiation (SAR = 5.835 x 10(-4) W/kg) for 30 days (2 h/day). Significant impairment in cognitive function and induction of oxidative stress in brain tissues of microwave exposed rats were observed in comparison with sham exposed groups. Further, significant increase in level of cytokines (IL-6 and TNF-alpha) was also observed following microwave exposure. Results of the present study indicated that increased oxidative stress due to microwave exposure may contribute to cognitive impairment and inflammation in brain. PMID- 23986974 TI - Protective effect of Spirulina and tamarind fruit pulp diet supplement in fish (Gambusia affinis Baird & Girard) exposed to sublethal concentration of fluoride, aluminum and aluminum fluoride. AB - Protective role of diet supplements (Spirulina, tamarind fruit pulp and their combination) on a freshwater fish G. affinis exposed at sublethal concentration of fluoride (F-) (10 ppm), Al(+3) (3 ppm) and aluminum fluoride (AlF3) (35.4 ppm) in the microcosms (15 L sized) for 30-60 days in winter (90 days in summer) has been reported. Toxic effects of chemicals were manifested as higher fish mortality (4-50%) and acid (approximately -30%) and alkaline phosphatase (25-50%) contents, but reduction in RBC counts (5-55%) and protein content (approximately 29%) compared with controls. Alterations in values of these parameters were found maximum in aluminum exposed fish suggesting it as the most toxic among the tested chemicals. Diet supplements reduced toxicity of tested chemicals, especially when Spirulina and tamarind were given together. PMID- 23986975 TI - Induction of somatic embryogenesis in endangered butterfly ginger Hedychium coronarium J. Koenig. AB - An efficient protocol has been developed for regeneration of complete plants through somatic embryogenesis in H. coronarium. Creamish white, pale yellow and brown calli were obtained on MS medium supplemented with different concentrations of auxins [2, 4-Dichlorophenoxy acetic acid (2, 4-D), Indole-3 acetic acid (IAA) and 1-Naphthylacetic acid (NAA)] after 4 weeks. Creamy white calli developed on 0.5 mg L(-1) 2, 4-D turned embryogenic when subcultured on basal medium and produced small globular somatic embryos after 6 weeks. Further growth of somatic embryos required their transfer to medium containing 6-benzylaminopurine (BAP) or kinetin (KN). BAP was more effective than KN in promoting shoot proliferation. Maximum shoot length was obtained with 0.5 mg L(-1) BAP whereas maximum shoot number was obtained with 1.0 mg L(-1) BAP. The plantlets thus formed were successfully hardened, and transferred to sand-soil and farm yard manure (1:1:1) with 95% survival. PMID- 23986976 TI - Direct and indirect method of plant regeneration from root explants of Caesalpinia bonduc (L.) Roxb.--a threatened medicinal plant of Western Ghats. AB - An in vitro regeneration protocol has been standardized via direct and indirect methods from excised root explants of C. bonduc, a threatened woody legume used for the treatment of contagious diseases, inflammation, leprosy, antiperiodic, febrifuge, anthelmenthic, urinary disorders, leucorrhoea, piles and to heal wounds. MS medium supplemented with 17.75 micromol BAP and 2.46 micromol IBA, induced a mean of 3.40 +/- 1.07 shoots directly from the surface of excised root explant. Subsequently, the shoots rooted readily on MS half strength medium with out growth regulators. In indirect organogenesis, callogenic frequency was optimized (96.66%) at the concentration of 9.04 micromol 2, 4-D and 0.88 micromol BAP. An average, 15.30 +/- 5.25 shoots were differentiated from the root callus at the concentration of 17.57 micromol BAP and 2.85 micromol IAA. Shoots regenerated through callus were rooted well on MS half strength medium with growth regulators at 2.95 micromol IBA. Rooted plantlets were transferred to the pots containing sterilized soil and were successfully hardened at greenhouse condition for three weeks then exposed to the natural environment. Survival rate was more (95%) in plantlets derived through direct organogenesis than (60%) the plantlets regenerated through root calli. PMID- 23986977 TI - Chinese elders' self-image and their perceived peer-image: possibility of self enhancement bias. AB - Decades of research with Western participants has documented that there is a pervasive motivation for people to view themselves as better off than others while evidence for the existence of such self-enhancement bias (SEB) among East Asians varies considerably across studies. Considering the traditional culture of Confucius on modesty, the present study hypothesizes that there should be no significant SEB among Chinese elders. Structured face-to-face interviews were conducted with 445 older people in China-Wuhan, in which the revised Chinese version of Image of Aging Scale (IAS-C) was filled out. SEB was calculated by subtracting participants' ratings of "Peer-Image" (P) from their ratings of Self Image (S). However, inconsistent with our hypothesis, a significant SEB was observed among the Chinese older participants and significant differences in the magnitude of SEB were discerned among older people in different characteristic groups. Possible explanations were further provided for the mismatch between Chinese values and the existence of SEB. PMID- 23986978 TI - The meaning of elder self-neglect: social workers' perspective. AB - AIMS: To explore the unique aspects of the elder self-neglect phenomenon and to achieve phenomenological understanding of self-neglect through the eyes of professional social workers. METHOD: A qualitative study based on a sample of 14 certified social workers. Data collection was performed through in-depth semi structured interviews, followed by content analysis. FINDINGS: Three major themes emerged from the participants: (1) "How can you live like that?" self-neglect as an unsolved riddle; (2) "It's very difficult for me, I go outside and immediately start thinking about myself": the personal burden; and (3) "I keep trying": seeking intervention strategies following the refusal to accept assistance. DISCUSSION & CONCLUSIONS: Social workers' direct involvement with the self neglecting elders poses a very significant ethical, personal, and professional challenge. In this context, there is a need to impart tools for "solving the riddle" to social workers through self-reflection, improvement of knowledge, theory, and empirical findings regarding the conceptualization and understanding of the self-neglect phenomenon. Moreover, it may be that adopting a clearer ethical "ideology," which is rooted in a discourse of human rights, could assist social workers to reconcile their tensions and difficulties in providing assistance to older, self-neglected persons. PMID- 23986979 TI - The old, old-old, and the oldest old: continuation or distinct categories? An examination of the relationship between age and changes in health, function, and wellbeing. AB - This study aims to examine whether old age, old-old age, and oldest-old age comprise distinct categories via comparing persons aged 75-84, 85-94, and 95+ on demographics, health, function, and wellbeing. The sample was drawn from a representative longitudinal cohort of older persons in Israel. Matched cohort comparisons found a significant decline in Activities of Daily Living (ADL), instrumental ADL, cognitive function, percent of participants who go outside their home, and physical activity, with an increase in physical and mobility difficulties, and no difference in depressed affect or loneliness. Longitudinal results showed increased widowhood, institutionalization, comorbidity, physical and mobility difficulties, loneliness, and depressed affect, as well as decreased subjective health and physical activity over time. In the absence of changes in social support as manifested by marital status and community living, there was no decline in wellbeing. Current evidence of various gradual quantitative differences suggest that in most respects old age may be better conceptualized as a single phase marked by a continual quality. PMID- 23986981 TI - A member wasteland? PMID- 23986980 TI - Undergraduate students' knowledge about aging and attitudes toward older adults in east and west: a socio-economic and cultural exploration. AB - Knowledge about aging and the attitudes toward older people were surveyed in undergraduate students (total number of subjects sampled is 1402) in four countries (Japan, China, Taiwan, and Vietnam) in eastern cultures and in two countries (United States and United Kingdom) in western cultures. All participants completed two questionnaires, FAQ1 (for knowledge) and ASD (for attitudes) in their own languages. It was found that within the undergraduate students sampled: (a) the level of knowledge about aging in the western countries is significantly higher than that in the eastern countries, and (b) attitudes toward aging are more positive in the western countries compared to the eastern countries. The data suggest that, within the limits of the sampling: (a) the tradition of respecting older adults in eastern cultures may have weakened gradually, and (b) the modernization theory that assumes industrialization devalues aging populations appears to be supported in eastern countries but not in western countries. An alternative non-linear theory is discussed for the relationship between modernization and the societal views on aging. Educational promotion of knowledge about aging is emphasized for the formation of positive attitudes toward older adults. PMID- 23986982 TI - CPHVA members split over support for uniforms. PMID- 23986983 TI - Unite visits the Greece Solidarity Campaign in Athens. PMID- 23986984 TI - School nurse 121 campaign. PMID- 23986985 TI - No smoke without fire? PMID- 23986986 TI - Telly health. Interview by Louise Naughton. PMID- 23986987 TI - Human milk science: what makes human milk's composition ideal for infants? PMID- 23986988 TI - Maintaining professional resilience through group restorative supervision. AB - Restorative clinical supervision has been delivered to over 2,500 professionals and has shown to be highly effective in reducing burnout, stress and increasing compassion satisfaction. Demand for the programme has shown that a sustainable model of implementation is needed for organisations who may not be able to invest in continued individual sessions. Following the initial six sessions, group restorative supervision has been developed and this paper reports on the programme's success in maintaining and continuing to improve compassion satisfaction, stress and burnout through the process of restorative group supervision. This means that organisations can continue to maintain the programme once the initial training has been completed and have confidence within the restorative group supervision to support professionals in managing the emotional demands of their role. The restorative groups have also had inadvertent positive benefits in workplace functioning. The paper outlines how professionals have been able to use this learning to support them in being more effective. PMID- 23986989 TI - A lecturer-practitioner's contribution to the Health Visitor Implementation Plan in East London. AB - Before 2011 the UK saw a decline in the number of nurses coming forward to undertake a postgraduate programme in specialist community practice. In addition to financial constraints and an aging nursing demographic, existing health visiting teams have struggled to meet the complex health and social needs of parents with pre-school children. The Health Visitor Implementation Plan published by the Department of Health in England in 2011 aimed to expand and strengthen health visiting services nationwide. This plan is in conjunction with developing new ways of working incorporating the Healthy Child Programme. This model of working was piloted in 26 areas around the UK, commencing in 2011 as an Early Implementer site. The Community Trust in Hackney in East London was one of three trusts within London chosen by the DH in recognition that the health visiting service demonstrated good practice and had the infrastructure to build further sustainable community links. My entry into the role of lecturer practitioner, on a two-year contract, coincided with this exciting and challenging time for health visiting in Hackney. The article describes the development of a Learning in Practice (LiP) series of workshops, under the umbrella of the Health Visitors Implementation Plan. The aim of the LiP was to support specialist community public health nursing students' transition into practice, whilst at the same time offering support to practice teachers who were managing complex caseloads with the demands of an increase in students. PMID- 23986990 TI - What support do health visitor mentors need? AB - This paper seeks to explore and understand the role of health visitor mentors undertaking a mentoring responsibility for specialist community public health nurses. During the unprecedented round of health visitor training, responsibility for the direct management of this role has been devolved from practice teachers to mentors. A qualitative approach using a purposive sample of eight participants and a semi-structured interview was the chosen method. Simple qualitative analysis was undertaken allowing data to be compared and themes identified. The overarching theme within this study was 'powerlessness'; mentors felt they had no say in adopting this role which was imposed upon them. Sub-themes included 'preparedness' relating to their perceived lack of appropriate training, and 'emotional support', which identified inadequate support from managers, while good levels of support were experienced by most mentors from their colleagues. Finally, 'compromising' related to difficulties associated with managing client care, student education and family responsibilities, achieved through prioritising and working overtime. In conclusion, the paper suggests that mentors need further support that acknowledges the pressure of the dual role, and standards for professional development of mentors need to be developed. PMID- 23986991 TI - Letter to my student health visitor. PMID- 23986992 TI - School nursing: the picture in Sweden. PMID- 23986993 TI - A guide to home visiting in child protection cases. PMID- 23986994 TI - Delivering Solihull Approach training in Pakistan. PMID- 23986995 TI - Nutritional requirements in pregnancy and use of dietary supplements. AB - A new British Nutrition Foundation (BNF) Task Force report has been published, which looks in detail at the impact of early life nutrition on health and the risk of diseases in later life, including obesity, diabetes, cardiovascular disease, cancer, bone health, allergic disease and cognitive function. One of the aspects that the report covers in detail is the health and nutrition of pregnant women and where improvements in the maternal diet could be made. This article focuses on the report's findings with regard to the essential nutrients folic acid and vitamin D, including current intakes and status, uptake of supplements and vulnerable groups that are falling short of dietary guidelines. PMID- 23986996 TI - [Dose effect of alcohol on sex differences in blood alcohol metabolism--cases where healthy subjects with ALDH2*1/1 genotype drunk beer with meal]. AB - It is said that blood alcohol concentrations (BAG) are higher in female than in male due to the smaller distribution volume of alcohol in female, whereas the rate of alcohol metabolism is faster in female than in males due to a higher activity of liver alcohol dehydrogenase (ADH) in female. However, it is also known that alcohol metabolism varies depending on drinking conditions. In this study, we evaluated the dose effect of alcohol on sex differences in alcohol metabolism in daily drinking conditions, where young adults (16 males, 15 females) with ALDH2*1/1 genotype drunk beer at a dose of 0.32g or 1.0g ethanol/kg body weight with a test meal (460kcal). This study was conducted using a randomized cross-over design. In the considerable drinking condition (1.0g/kg), BAG was significantly higher in females than in males, whereas the rate of alcohol metabolism (beta) was higher in female than in male. In the moderate drinking condition (0.32g/kg), however, no sex differences in alcohol metabolism including BAG were seen. These results suggest that an increased first pass metabolism through liver ADH in female, which may be caused by the reduction of gastric emptying rate due to the meal intake, contribute to the vanishing of sex difference in BAC in the moderate drinking condition. PMID- 23986997 TI - [Awareness of pre-alcoholics and changes process in their awareness--analysis of narratives by patients and their families]. AB - This study aimed to compare the process of changes in the recognition of pre alcoholism between alcoholic patients and their family members, and examine the timing and methods of intervention for patients and their families. We conducted semi-structured interviews with 15 patient-family pairs, consisting of inpatients on the alcoholism ward and their family members in the same household. Our analysis of interview data showed that the process of changes in the patients' drinking behavior, i.e., from healthy drinking to alcohol dependence, had the following 4 stages: "look to benefits of alcohol consumption", "escape reality that they found hard to bear", "manifest health-related impairment", and "have increasing difficulties in restraining themselves from drinking". Drinking problems became more serious when the patients went through several stages at one time, or when they moved back and forth between the stages. There was a time gap between patients and their families in recognizing drinking problems, which leads to the worsening of the problems. Behind this lied communication and emotional problems between patients and their family members. The findings suggest the need to take account of the pre-alcoholic stages, and adequately respond to and care for both patients and families from an early stage onward. PMID- 23986998 TI - [The effects of chronic alcohol exposure on progression of liver injury in spontaneously hypertensive rats; preliminary study]. AB - The association between alcohol intake and blood pressure is well known, and our previous studies indicate that the stimulus of sympathetic nervous system induce the progression of liver injury. In this study, we examined the effects of chronic ethanol treatment on the progression of liver injury using the spontaneously hypertensive rat (SHR). The advantage of using the present strain is to possess sympathetic facilitation without any treatment. Normotensive Wistar Kyoto rat (WKY) was used as control. 7-week-old male rats were pair-fed with either ethanol- or control-liquid-diet for 49 days and divided into four groups: control liquid-diet-fed WKY and SHR, continuous ethanol liquid diet-fed WKY and SHR. Plasma alanine aminotransferase (ALT) levels, and histological analyses based on Hematoxylin-Eosin (H-E), Oil red O and Sirius red stains of the liver sections were used to assess alcohol-induced liver injury. Chronic ethanol treatment induced the increases in plasma ALT, the accumulation of fatty droplets within hepatocytes and pericellular hepatic fibrosis, particularly in SHR. Between the control group rats of SHR and WKY, SHR showed the increases in accumulation of fatty droplets and pericellular hepatic fibrosis. No significant inflammatory cell infiltration was shown in all groups. These results suggested that chronic ethanol treatment in SHR could induce the more severe liver injuries when compared with WKY. In conclusion, chronic alcohol intake in rats with hypertension could deteriorate the ethanol-induced liver injury via the sympathetic overactivity. PMID- 23986999 TI - [The application of nasal CT scan in evaluating the function of nasal ventilation in patients with deviation of nasal septum]. AB - OBJECTIVE: To compare the CT scan results in patients with deviation of nasal septum and normal adults and to explore its values in evaluating the state of nasal ventilation. METHOD: Twenty-six patients with deviation of nasal septum and 15 normal people were recruited in the study. The nasal airway from anterior nostril to posterior nostril was evaluated with PhlipsTomos scan AV Expander Elspiral scanner. The indexes of nasal ventilation was measured with the image analysis software. The results of CT scan between patients with deviation of nasal septum and normal people was compared. RESULT: (1) There was obvious difference between patients with deviation of nasal septum and normal people in the NMCSA, IMCSA, DNCAT and DICAT. There was obvious difference between patients with deviation of nasal septum with obstruction in the opposite side and normal people in the ONMCSA and ODNCAT. There was obvious difference between patients with deviation of nasal septum without obstruction in the opposite side and normal people in the ODNCAT. (2) In the patients with deviation of nasal septum, between nasal minimal cross sectional area and inferior turbinate's maximum cross sectional area, there is obvious relation, r = -0.394, P < 0.05. CONCLUSION: CT is one kind of objective inspection method in evaluating the state of nasal ventilation. With the measurement of the nasal morphology and functional index, we can understand the state of nasal ventilation more comprehensively. And with this, the treatment and diagnosis of disease with nasal obstruction will be more scientific. PMID- 23987000 TI - [The clinical significance of 1,3-beta-D glucanase detection in plasma to the diagnosis of fungal rhinosinusitis]. AB - OBJECTIVE: To investigate the clinical significance of 1,3-beta-D glucanase detection in plasma to the diagnosis of fungal rhinosinusitis. METHOD: MB-80 rapid microorganism detection system was used to detect preoperative and postoperative 1,3-beta-D glucanase in plasma of 37 patients of fungal rhinosinusitis which were treated by endoscopic sinus surgery and confirmed by postoperative pathology. Blood samples of 47 patients who underwent endoscopic surgery(fungal rhinosinusitis excluded) were taken as control group. RESULT: 1,3 beta-D glucanase content is more than 10 pg/ml in 34 cases of the fungal rhinosinusitis group,and every 1,3-beta-D glucanase content of 47 control cases is less than 10 pg/ml. Significant difference is found between case and control groups(chi2 = 72.6, P < 0.01). CONCLUSION: 1,3-beta-D glucanase detection in plasma is a simple,rapid diagnostic method of fungal rhinosinusitis. PMID- 23987001 TI - [Clinical analysis of 23 patients with ossifying fibroma of paranasal sinuses]. AB - OBJECTIVE: To investigate the clinical features and treatment options of ossifying fibroma of paranasal sinuses. METHOD: A retrospective evaluation of twenty-three patients with ossifying fibroma of paranasal sinuses was presented. The choice of surgical operations on ossifying fibroma of paranasal sinuses was mainly decided by the location and area of ossifying fibroma. Radical operations were performed in twenty-one patients, ten of them through a lateral rhinotomy approach, eight through nasal endoscopic approach, four through Caldwell-Luc approach, one through coronal approach. RESULT: Two patients were performed partial resection by nasal endoscopic surgery. Diagnoses of all cases were confirmed by pathology. All patients outcomes were successful, no serious complication from the surgical technique occurred. Twenty cases were followed-up for six months to nineteen years. Two patients recurred. CONCLUSION: Earlier diagnosis, CT scan, proper surgery, and radical resection are the keys to the treatment of ossifying fibroma of paranasal sinuses. PMID- 23987002 TI - [The effect of plasma radiofrequency ablation on nasal mucosa provocative tests for allergic rhinitis]. AB - OBJECTIVE: In order to explore the effect of plasma radiofrequency ablation on nasal mucosa provocative tests for allergic rhinitis. METHOD: Eighty patients with allergic rhinitis were enrolled in this study. The nasal mucosa provocative tests and nasal airway resistance and subjective nasal patency feeling were studied before and after plasma radiofrequency ablation treatment. The correlation of subjective and objective nasal patency was evaluated. RESULT: The preoperative nasal mucosa provocative test of all the patients allergic to mites were positive. The nasal mucosa provocative tests were negative within 72 patients, while remained positive in eight patients after 3 months of operation. The nasal airway resistance decreased from (0.772 +/- 0.224) kPa x s/L to (0.221 +/- 0.112) kPa x s/L after surgery (P < 0.01); Visual analog scale decreased from 7.0 +/- 2.0 to 2.5 +/- 1.5 after 3 months of operation (P < 0.01). CONCLUSION: Due to its ability to reduce the sensitivity of the nasal mucosa, nasal airway resistance and improve subjective feeling of nasal patency, plasma radiofrequency ablation is effective for the treatment of patients with allergic rhinitis. PMID- 23987003 TI - [Meta analysis of the relationship between human papilloma virus and nasal inverted papilloma]. AB - OBJECTIVE: To evaluate the relationship between human papilloma virus (HPV) infection and the occurrence, recurrence and malignant transformation of nasal inverted papilloma (NIP). METHOD: With comprehensive retrieval of related literature that had been published in databases included Pubmed (1990--2011), Cochrane Library, CNKI (1979-2011), VIP (1989-2011), CBM (1990-2011) and WANFANG Meta-analysis software Rev-Man 5.0 was used to analyze the raw data and to calculate the value of combined odd ratio (OR) and 95% confidence interval (CI). RESULT: According to Meta-analysis, the occurrence group between HPV and NIP, the OR was 34.44 and 95% CI was 12.96-91.56; the recurrence group, the OR was 3.66 and 95% CI was 1.77-7.56, to the high-risk HPV, the OR was 1.94 and 95% CI was 0.30-12.58; the malignant transformation group, the OR was 1.79 and 95% CI was 0.94-3.40 to the high-risk HPV, the OR was 49.35 and 95% (CI was 0.45-11.23. CONCLUSION: HPV may play an important role in the occurrence and recurrence of NIP and high-risk HPV was closely related to the progress of NIP. PMID- 23987004 TI - [The effect of laryngoscopic surgery combined with nasal endoscopic system for the treatment of vocal cords benign lesions]. AB - OBJECTIVE: To investigate the effect of laryngoscopic surgery combined with nasal endoscopic system for the treatment of vocal cords benign lesions. METHOD: Fifty two patients admitted to our department with vocal cords benign lesions (including vocal polyps, vocal nodules, vocal cord cyst) underwent laryngoscopic surgery combined with nasal endoscopic system. RESULT: All patients were treated successfully once and for all without any significant postoperative complication. CONCLUSION: The laryngoscopic surgery combined with nasal endoscopic system is a safe, minimally invasive and simple method for the treatment of benign lesions of vocal cords. PMID- 23987005 TI - [Fast onset of action of sublingual immunotherapy in dust mite caused allergic rhinoconjunctivitis]. AB - OBJECTIVE: To investigate whether sublingual immunotherapy(SLIT) can take effect during the early phase in allergic rhinoconjunctivitis. METHOD: Sixty subjects diagnosed as allergic rhinoconjunctivitis were enrolled and divided into the SLIT group and the control group. The daily symptom and medication scores were recorded and analyzed. RESULT: After 4 weeks treatments, the daily symptoms score had significantly reduced in SLIT group(P<0. 05). After 6, 8, 10 weeks treatments, the daily symptoms scores of subjects in the SLIT group had all shown continuous reduction, with no consumption of medication. The comparison between daily symptom score at 4th week and those in 6th week or 8th week or 10th week in the SLIT group had shown no significant difference (all P > 0.05). Whereas, the daily symptoms score and daily medication score in control group had shown changes with fluctuations. The correlation analysis had indicated that the daily medication score in the control group had a significant negative correlation with the daily symptom score (F = 554.9, P < 0.01). No serious adverse events occurred in this study. CONCLUSION: SLIT could take effect in patients with allergic rhinoconjunctivitis sensitive to house dust mite as fast as the 4th week. PMID- 23987006 TI - [The study on the correlation between snoring and carotid artery plaques in the elderly population]. AB - OBJECTIVE: To explore the correlation between snoring and carotid artery plaques in the elderly population. METHOD: Sixty-seven patients with snoring and 61 healthy volunteers accepted questionnaire on sleep apnea were analyzed in the survey. Multivariate Logistic regression analysis was used to analyze the factors affecting carotid artery plaques. RESULT: Among the non-snorers (n = 61), mild snorer (n = 18), moderate snorers (n = 24) and severe snorers (n = 25) groups, the prevalence of carotid artery plaques in four groups were 19.7%, 44.4%, 62.5%, 84.0% respectively. There was statistically significant differences between groups. After multivariable adjustment, the moderate and severe snorers were still risk factors affecting carotid artery plaques, the OR (95% CI) values were 4.378 (1.181-16.225), and 19.572 (3.316-115.528) respectively. CONCLUSION: The moderate and severe snoring in the elderly population were relevant to the increased prevalence of carotid artery plaques, and was a risk factor on carotid artery plaques. PMID- 23987007 TI - [The application of expanded forehead flap in reconstructing defects around nasal tip]. AB - OBJECTIVE: To discuss using expanded forehead flap to repair defects around nasal tip and to find a standard and rational repairing method. METHOD: Three-staged operations were adopted. The first stage is to implant expander. The second stage is to reconstruct defects around nasal tip using the expanded forehead flap with the supra trochlear vessels as its pedicle. If necessary, the autogenous cartilage was harvested from ribs and used as a nasal framework, which reestablished the projection of the tip. The third stage is to conduct the pedicle resection and repairing. RESULT: Seventeen patients who suffered from defects around nasal tip were cured using the expanded forehead flap. These flaps survived well. The appearance of nasal tips and ventilation function were very nice. CONCLUSION: The expanded forehead flap is an ideal method to reconstruct defects around nasal tip. The advantages of this method are safety, good appearance, matched colour and luster, and covert scar of donor site. PMID- 23987008 TI - [Endoscope assisted coblation surgery for treating subglottic stenosis]. AB - OBJECTIVE: To introduce a new surgical treatment for subglottic stenosis. METHOD: Six patients with subglottic stenosis were retrospectively studied. Four cases had history of intubation or tracheostomy. Two cases were because of B cell lymphoma and Wegener granulomatosis. All cases underwent endoscope assisted coblation surgery. RESULT: All of the patients were discharged from hospital with no tube in one week after surgery. In a follow-up of 3-21 months, stenosis in 2 cases of B cell lymphoma and Wegener granulomatosis recurred 3 months after operation. These 2 patients were operated by coblation again and are still followed-up by now. CONCLUSION: The endoscope assisted coblation surgery is a new minimally invasive method for treating subglottic stenosis. Further more,it can be reused to whom has a relapse. PMID- 23987009 TI - [A retrospective analysis of 163 cases with intractable epistaxis managed by nasal endoscopic surgery]. AB - OBJECTIVE: To investigate the clinical characteristics of intractable epistaxis and the application of nasal endoscopic surgery as the treatment. METHOD: The clinical data of 163 patients with intractable epistaxis were retrospectively analyzed. RESULT: The bleeding points were found in the following different sites, superior wall of inferior nasal meatus (31.3%, 51/163), olfactory cleft area (21.5%, 35/163), postero-inferior wall of nasal septum (20.8%, 34/163), middle nasal meatus (10.4%, 17/163) and Little area (8.6%, 14/163). The results showed that the bleeding points had correlation with age. According to the frequency of nasal bleeding, patients under the age of forty in turn occurred in superior wall of inferior nasal meatus, olfactory cleft area, Little area, postero-inferior wall of nasal septum and middle nasal meatus; patients over the age of forty occurred in superior wall of inferior nasal meatus, postero-inferior wall of nasal septum, olfactory cleft area, middle nasal meatus and Little area. There was a significant difference between the two groups (P < 0.05). All cases stopped bleeding after 1 time of treatment, and there was no complication during a followed-up for 3 months after management. Seven cases reoccurred bleeding in half a year, but they were finally cured under nasal endoscopic surgery. CONCLUSION: The results indicate that we should pay attention to different bleeding points in different age groups. In addition, nasal endoscopic treatment is a reliable, convenient and effective method for intractable epistaxis and is the first choice after failed nasal packing. PMID- 23987010 TI - [FA-MNP-MMP-9-ASODN complex construction and the study of its FA molecular targeting ability]. AB - OBJECTIVE: To construct FA targeted magnetic nanocomplex (FA-MNP-MMP-9-ASODN) loading matrix metalloproteinase 9 (MMP-9) antisense oligonucleotide (ASODN) and evaluate its targeting capacity and efficiency of gene transfection to folate receptor (FR) positive NPC. METHOD: FA-MNP-MMP-9-ASODN was constructed by MMP-9 ASODN coupling with FA-MNP prepared by our research team through the aldehyde ammonia condensation reaction. To analyze the feasibility of ASODN coupling with nanocarrier agarose gel electrophoresis. Two kinds of HNE-1 and CNE-2 cells and implanted tumors phagocytosis of FA-MNP-MMP-9-ASODN were observed by MRI on tumor bearing nude mice, iron staining and TEM. To analyze gene transfection of the vector by observing FITC in the cell. RESULT: The electrophoresis results revealed ASODN successfully coupling with FA-MNP. HNE-1 cell can effectively ingest the nanocomposite,with more FITC in the cell, but CNE-2 cell had not uptake for the nanocomposite, with no FITC in the cell. By comparing with CNE-2 tumor, HNE-1 tumor also can efficiently swallow the nanocomposite. CONCLUSION: FA MNP-MMP-9-ASODN nanocomplex is constructed successfully with good FA targeting ability and gene transfection. PMID- 23987011 TI - [Comparison of tonsillar biofilms between patients with recurrent tonsillitis and a control group]. PMID- 23987012 TI - [Twenty-three cases of recurrent dacryocystitis treated with modified silicone mold implantation]. AB - OBJECTIVE: To observe the surgical therapeutic effects of dacryorhinocystotomy under nasal endoscope combined with the application of modified silicone mold implantation for postoperative recurrent dacryocystitis. METHOD: The research method is to conduct the dacryorhinocystotomy under nasal endoscope to 23 cases(24 eyes) of recurrent dacryocystitis, in the process of which modified silicone mold is implanted under the nasal mucosa. RESULT: During a follow-up of 6-12 months to the 23 cases (24 eyes), 18 eyes were cured, 6 eyes were getting setter and there was no recurrence. CONCLUSION: It's concluded that the modified silicone mold implantation can avoid the recurrent atresia of the aperture created by the dacryorhinocystotomy, which proves that the combination with the modified silicone mold implantation in dacryorhinocystotomy is an effective treatment method of curing recurrent dacryocystitis. PMID- 23987013 TI - [Application of autogenous bone pate for atticus reconstruction and mastoid cavity obliteration in tympanoplasty with mastoidectomy]. AB - OBJECTIVE: To observe the curative effect of autogenous bone pate for atticus reconstitution and mastoid cavity obliteration in canal wall down mastoidectomy with tympanoplasty. METHOD: The 60 patients (60 ears) of cholesteatomatous tympanitis were randomly divided into 2 groups. The experimental group underwent canal wall down mastoidectomy with tympanoplasty and using autogenous bone pate for atticus reconstitution and mastoid cavity obliteration. The control group only underwent canal wall down mastoidectomy with tympanoplasty. All patients were followed up for 0.5-2 years. Improvement of hearing and dry ear time in these two groups was retrospectively observed. RESULTS: There are significant difference between two groups in improvement of hearing and dry ear time, according to follow-up and analysis of therapeutic efficacy (P < 0.05). CONCLUSION: Hearing can be improved, dry ear time can be shorten and correlative complication can be decreased by atticus reconstruction and mastoid cavity obliteration with autogenous bone pate in canal wall down mastoidectomy with tympanoplasty, which guarantees the normal activity space of auditory bone chain. PMID- 23987014 TI - [The outcomes of endoscopic septorhinoplasty with three-line-tension-relaxing technique combined with nasal bone fracture correction for traumatic nasal septum deviation]. AB - OBJECTIVE: To investigate the feasibility and the efficacy of endoscopic three lines tension relaxing septorhinoplasty combined with nasal bone fracture correction for traumatic nasal septum deviation. METHOD: Clinical data of 45 cases with traumatic nasal septum deviation treated were retrospectively analysed. These patients were performed with three lines tension relaxing septorhinoplasty and nasal bone fracture correction under endoscopy 5 to 14 days after injury. RESULT: All patients were followed up for more than six months. They all achieved significant efficacy and no complications occurred. CONCLUSION: Endoscopic three lines tension relaxing septorhinoplasty combined with nasal bone fracture correction can achieve satisfactory curative effect and can effectively prevent the occurrence of complications. PMID- 23987015 TI - [Clinical value of carbon dioxide laser in treatment of epiglottic cysts]. PMID- 23987016 TI - [Selection of surgical approaches of parotid tumors for facial nerve protected]. PMID- 23987017 TI - [Clinical application of disposable double-lumen balloon catheter in the operative cavity packing after sinus surgery]. PMID- 23987018 TI - [Misdiagnosis of nasal sinus foreign body in adult]. PMID- 23987019 TI - [Mixed tumor of nasal septum]. PMID- 23987020 TI - [Unilateral nasal cavity and paranasal sinus neoplasm in adolescent]. AB - The clinical data of two adolescents with unilateral nasal cavity neoplasm were analyzed. Both were male, one was 14-year-old and the other was 17. Both were complained of unilateral nasal obstruction and nasal discharge; The course of disease of the former was one month ,and that of the latter was three month; both were found neoformation in unilateral nasal cavity in medical examination. Occupying lesion in unilateral nasal cavity and sinus were demonstrated in CT scan of two cases. Endoscopy surgery were operated in both cases, incisal opening in labiogingival groove was added in the latter. Pathology of the former was capillary hemangioma and the latter was rhabdomyosarcoma. No findings indicating recurrence has been observed in two cases under 6 months follow-up. Recognition at nasal cavity and paranasal sinus neoplasm in adolescent is essential so that proper management can be initiated. PMID- 23987021 TI - [Prophylaxis of injuries of biliary ducts in laparoscopic cholecystectomy: clinical recommendations of Ukrainian association of specialists for miniinvasive, endoscopic and laser technologies]. AB - Wide introduction of laparoscopic cholecystectomy (LCHE) caused during last 20 years a significant enhancement of rate of the biliary ducts injuries (BDI). Taking into account the experience gained in performing of more than 40,000 operations of LCHE in a leading clinics, including such in a technically complex situations, as well as experience of more than 500 operations performance for BDI, clinical recommendations, based on principles of a substantiality medicine were elaborated. More than 100 sources of foreign and domestic literature were analyzed, summarizing the results of more than 150,000 operations of LCHE, special attention was drawn to the sources I (meta-analysis and prospective randomized investigations) and II (systematic reviews, thoroughly planned prospective comparative investigations) levels of substantiality. Every paragraph is accompanied by a certain level of a recommendation strength (RS, A-C). It is necessary to follow these recommendations strictly today. PMID- 23987022 TI - [Prognosis of the hemorrhage recurrence in the patients suffering from acute gastroduodenal ulcer bleeding]. AB - The prognostication method for the hemorrhage recurrence, permitting to estimate the risk of its occurrence and to prescribe an adequate antirecurrence treatment, was proposed. Among numerous predictors of recurrence the most significant clinical, endoscopic and laboratory factors were selected to raise the prognostication precision. Depending on therisk degree of a recurrent hemorrhage, different methods of treatment were prescribed to the patients. The proposed method was applied in 112 patients, suffering ulcer gastroduodenal hemorrhage. The hemorrhage recurrence have had occurred in 45 (43.3%) of them, in 5 (4.46%)- operative intervention was conducted, using organpreserving methods. General lethality have had constituted 0.89%, postoperative one in a control group- 7.14%, and in the main all the patients were alive. The method proposed permits with a high precision to prognosticate and to determine effective tactics of treatment. Taking into account the additional factors of risk raises the prognosis precision and permits to prescribe antihelicobacter therapy and the proton pump inhibirors in a rational dosage soundly. PMID- 23987023 TI - [The results of surgical treatment of early gastric cancer patients obtained based on early determination of local spread zones and regional lymphatic metastasis process]. AB - Modern tendencies of surgical progress makes possible not only to improve technical aspects of operative interventions, but to determine their volume, the algorithms of preoperative diagnosis as well as to guarantee a high quality of life of the patients. Analysis of 559 retrospective and 64 prospectively followed up patients, operated on for gastric cancer in early stages of the disease, was conducted. The factors were established, which impact trustworthy the survival indices in patients, suffering early gastric cancer. PMID- 23987024 TI - [The impact of early gastric cancer diagnosis on indices of survival in patients after radical surgical intervention]. AB - Basing on the determined rate of early gastric cancer diagnosis it is possible to prognosticate the survival indices in patients, suffering gastric cancer after radical surgical intervention performance as well as the adjuvant chemotherapy efficacy. There were analyzed the data of their own, as well as such from Japan and Western Europe, concerning studying of the early gastric cancer incidence, the survival indices after conduction of D2 lymphodissection for gastric cancer and a rate of a synchronous macroscopically obvious remote metastases (SMVRM). There was established, that in gastric cancer patients the lesser is the early gastric cancer rate--the SMVRM rate is higher in any stage of the tumor; high rate of SMVRM in the patients, suffering gastric cancer coincide with a high rate of synchronous hided remote metastases in any stage of a tumor; the early gastric cancer rate correlates directly with a 5-year survival indices after radical surgical intervention for gastric cancer, in any resectable stage (I-III); the lesser early gastric cancer rate--the bigger necessity of adjuvant chemotherapy conduction for gastric cancer. PMID- 23987025 TI - [Surgical treatment of a solitary hepatic abscess]. AB - Retrospective analysis of the treatment results of 120 patients, suffering solitary hepatic abscess (SHA), was conducted. The sanation methods, in accordance to technology, the treatment impact intensity and aggressiveness, may be divided on three lines: aspirational, draining and resectional. The method of sanation is selected on the background of morphological peculiarities of abscess- its sizes, by presence of sequesters, divisioning septs, dense rigid capsule, grade of periprocess. Surgical access is determined by the abscess localization, the patient's state severity, instrumental equipment of the clinic. Differentiated approach, taking into account genesis, sizes, localization and stage of its formation, constitutes a background of successful treatment of SHA. In totally formatted acute SHA, as a rule, the methods of choice are aspirational and aspiration-draining methods of sanation under ultrasonographic control or laparoscopy. In the presence of chronic SHA or suppurated parasitic hepatic cyst it is mandatory to select the resectional methods. PMID- 23987026 TI - [Application of a hepasol neo preparation in the treatment of obturation jaundice patients]. AB - The results of treatment of 52 patients, suffering obturation jaundice (OJ), were analyzed. The causes of the OJ occurrence were studied up. A peculiar attention was drawn to the treatment of patients, suffering OJ on a hepatic cirrhosis background. On the first stage of surgical treatment various operative procedures were applied to eliminate OJ. The impact of the tactics proposed, consisting of detoxication and infusion therapy, on duration of postoperative rehabilitation of the patients was studied up. In postoperative period to all the patients Hepasol Neo was prescribed, what have promoted their general condition improvement, the bilirubin level normalization, as well as the cytolysis and cholestasis elimination. PMID- 23987027 TI - [Optimization of diagnosis and control of treatment of gastrointestinal paresis in the early postoperative period in extended peritonitis]. AB - The results of treatment of patients, operated on for extended peritonitis in reactive and toxic phases, presenting with prominent gastrointestinal paresis, using the impulse stimulation of their peristalsis and early enteral nutrition under guidance of electrogastroenterography, are analyzed. The method is simple in application, it may be used in surgical and reanimation stationaries of any level, it has not the current restrictions and special contraindications. PMID- 23987028 TI - [Peculiarities of performance of endoscopic transpapillary interventions in the early period after cholecystectomy]. AB - The peculiarities of performance of endoscopic transpapillary interventions (ETI) during the early period after cholecystectomy were studied up. There were examined 1788 patients, aged from 18 to 90 yrs old, in whom postcholecystectomy syndrome was diagnosed. Emergent interventions were performed in 780 (43.6%) patients (main group). Into the comparison group 1008 (56.4%) patients were included, who were admitted to the hospital in 0.5-552 (Me 36) months after cholecystectomy conduction. The indications to perform the urgent endoscopic intervention were excessive transdrainage biliary output (more than 350 ml a day) from a subhepatic indignation (in 442 patients) and the obturation jaundice presence (in 338). Using ETI the cause of biliary obstruction in the early postoperative period was established in 93.5% of patients. Miniinvasive methods were applied in 82.2% patients of the main group and in 93.4%--of the comparison group. PMID- 23987029 TI - [Thyroidectomy of completion and reoperations for thyroid cancer]. AB - In 1990--2010 yrs there were operated 159 patients for differentiated thyroid gland cancer (THGC) and 89 - for medullary thyroid gland cancer (MTHGC). The recurrence rate in application of radical tactics of surgical treatment in the first operation for differentiated THGC, comparing with such after reoperation, is lesser - (2.7 +/- 1.5) and (7.3 +/- 4.0)%, accordingly (P < 0.05). The results of diagnostic lymphadenectomy constitute a secure criterion for indication to perform a dissection of a lateral basin of the lymph nodes. The indices of survival in patients, suffering MTHGC, in whom a radical tactics was used in the first operation, are by 29.4% (P = 0.024) better, than in patients, to whom it was applied while subsequent operations, the disease-free survival - by 45.6% (P= .0001). Reoperation is indicated in occurrence of any local and regional recurrences of the THGC. In anaplastic THGC reoperations are performed rarely. PMID- 23987030 TI - [A coronary atherosclerosis course in patients after interventions on coronary arteries]. AB - Retrospective analysis of primary and secondary coronaroventriculography was conducted in 283 patients, to whom coronary stenting and coronary shunting were performed. Further course of coronary atherosclerosis was investigated in patients after intervention on coronary arteries. PMID- 23987031 TI - [Aneurysm of the unpaired visceral aortal branches]. AB - Clinical signs, data of additional methods of examination, results of surgical treatment of patients for aneurysm of unpaired visceral aortal branches were analyzed. Specific complaints and clinical signs are absent. Most informative and trustworthy method of investigation is a computer tomography. In the sizes of aneurysm more than 2 cm surgical treatment is indicated. PMID- 23987032 TI - [Impact of the combined application of elastic bandaging of the lower extremities and autohemotransfusion on biochemical indices of the blood and severity of endogenous intoxication in patients with concomitant cardiovascular insufficiency]. AB - Venous congestion in abdominal inner organs in surgical diseases in patients with heart insufficiency may additionally impact biochemical indices of the blood and severity of endogenous intoxication (EI). Basing on the data obtained in the investigations, th was established, that the lower extremities bandaging promotes exit of the blood from depot, where it resides in a concentrated state in cellular and biochemical aspects. It promotes more effective accomplishment of hemodilution as well as reduction of the EI severity in taking of the autologous blood. PMID- 23987033 TI - [Hemoperitoneum as a predictor of the traumatic process complications in the injured persons with severe combined trauma]. AB - Multifactorial analysis was conducted in 48 injured persons, who had suffered combined abdominal organs trauma, trauma severity score according to the AIS-90 scale more than 25 points, and died. There were elaborated theoretical aspects of prognostication of the injured person's death timing. There was established, that while hemoperitoneum volume enhancement by 200 ml (critical level of hemoperitoneum is considered 682 ml) the death timing becomes accelerated by 1.2 h. PMID- 23987034 TI - [Surgical treatment of the plexus brachialis injury using long-lasting electrostimulation]. AB - The results of surgical treatment were analyzed in 103 patients, suffering consequences of the plexus brachialis injury, using the system for long-lasting electrostimulation, called "Henci 3M". The system of a domestic manufacture is an individual one, permits to perform the direct electrostimulation seances in a home conditions several times a day for a long time. There were positive results noted: an enhancement in volume and strength of movements in upper extremity of various degree, restoration of sensitivity and disappearance or reduction of a pain syndrome intensity in 90.6% of patients. Long-lasting electrostimulation permits more effectively and valuably to restore a plexus brachialis function in its traumatic injury. PMID- 23987035 TI - [Syndrome of vena cava superior in the injured persons with traumatic instability of a sternocostal skeleton as a consequence of polytrauma]. AB - There were analyzed 8 clinical observations of treatment of syndrome of vena cava superior in the injured persons in traumatic instability of a sternocostal skeleton. Peculiarities of course of traumatic process, concerning the trauma severity objective prove, were established. PMID- 23987036 TI - [Caudal-epidural injection of adjuvants and local anaesthetics in the newborns undergoing surgery]. AB - In 45 newborns, operated on for the inborn failures of gut, the markers of stress and indices of central hemodynamics were studied up. General anaesthesia was applied together with caudal-epidural injection of local anaesthetics in 15 newborns, in 15--the adjuvants--klophelline and promedol--were added to local anaesthetics, in 15--a standard atharalgesia was used. The best and most durable effect was noted while application of anesthesia in combination with adjuvants. PMID- 23987037 TI - [The dynamics of the immune status indices in conditions of cranio-cerebral trauma on background of a streptozotocin-induced diabetes mellitus in experiment]. AB - Peculiarities of changes in the immune status in a cranio-cerebral trauma (CCT) on a background of a streptozotocin-induced diabetes mellitus (DM) were studied up. After CCT there are noted the inhibition of predominantly cellular link of immunity, accompanied by reduction of the CD3+ lymphocytes quantity, as well as lymphocytes of the main subpopulations CD4+ and CD8+, CD16+, reduction of the neutrophils phagocytic activity, a complement titer enhancement. Experimental CCT do not cause the essential changes in a CD19+ lymphocytes quantity. The CCT modelling on a background of a streptozotocin-induced DM causes the immune deficiency deepening, in a cellular and humoral links together, significant reduction of activity of a phagocytosis system and complement as well. PMID- 23987038 TI - [Towards universal nomenclature for urgent surgical care]. AB - In a modern professional literature the diseases, which undoubtedly threaten the patient's health and life, are called an urgent, special, emergent, fixed-date, etc. Not rare these terms are used simultaneously. Such a plurality of names of a quite dangerous state causes sometimes in these conditions uncertainty to seek help of a specialists and loss of a time. Modern dictionaries of a foreign languages words, of a foreign languages words in Ukrainian language, medical, big explanatory dictionary of a modern Ukrainian language definitely explains, that these terms are synonyms. All of them mean unconditional, timing. And every expression may be used in this context. The above mentioned suggestions and thoughts do not promote a secure fixing in the citizens consciousness the undoubtedness, the disease consequences danger, a threat to health and life. To deposit this in their awareness it is possible not by amorphous depiction, but using a singular, brief, firm term - an urgent. PMID- 23987039 TI - [Successful performance of laparoscopic cholecystectomy for chronic calculous cholecystitis in a woman patient, previously numerously operated on abdominal organs]. PMID- 23987040 TI - [Scrotal lipoma]. PMID- 23987041 TI - [The results of intestinoplasty of ureters]. AB - The article presents the immediate and long-term results of intestinoplasty of extensive uretral obstructions. From 2001 to 2012, 47 patients underwent intestinoplasty, and 3 patients--sigmoureteroplasty. 33 patients (66%) had unilateral lesions, and 17 (34%)--bilateral lesions. Postoperative complications occurred in 14% of cases. Early complications occurred in 6 (12%), late complications--in 1 (2%) patient. Complications requiring surgery occurred in 3 (6%) patients. The results of re-operations were successful. Deaths were not recorded. The observation period ranged from 3 months to 11 years. All patients achieved the restoration of urodynamics and normalization of kidney function. Intestinoplasty in extensive uretral obstruction is the operation of choice, as it allows to restore the flow of urine from the kidney, improves its function, arrests the chronic pyelonephritis and rescues patients from permanent renal and ureteral fistulas. PMID- 23987042 TI - [Extracorporeal shockwave lithotripsy of stones in lower calices of kidney]. AB - The article presents the results of the study aimed to evaluation of possible relationship between anatomical structure of the renal pelvis of the kidney, the size of the stone and the effectiveness of extracorporeal shockwave lithotripsy (ESWL) of stones in lower calices of kidney, defined as "stone-free state". ESWL was performed in 285 patients. Sizes of stones varied from 5 to 25 mm. With interval distribution of stone sizes, the greatest number of cases was detected with size of 5 to 12 mm. The destruction of stone required one ESWL session in 196 cases, and three sessions only in 12 cases. The total number of pulses per one stone did not exceed 9500, and more than 70% of the stones have been effectively destroyed with less than 3000 pulses. The result of treatment was assessed 3-4 months after the last ESWL session on the basis of ultrasound and X ray examination using nominal (dichotomous) scale. In addition, for verification of significant (expected and unexpected) correlations, exploratory analysis of the correlation matrices of factors possibly affecting the discharge of stone fragments was performed. Positive treatment outcome was recorded in 212 (74.4%) patients. Residual stone fragments (> or = 5 mm) were identified in 73 (25.6%) patients; in 69 patients fragments corresponded to the initial localization and 4 fragments were located in the pelvis and calices of middle and lower segments of the kidney. Statistical processing found no association between the size of the stone and the number of ESWL sessions required for its destruction (P = 0,4056). The analysis of relationship between the nature of the complications and size of stone revealed differences, but there were no significant differences in median test (p = 0.1067). Based on exploratory analysis and correlations identified, in depth evaluation was carried out on three factors: the size of the stone, length of lower calices neck, and pyelocaliceal corner. Width of lower calices neck as a statistically nonsignificant criterion was excluded from further analysis. A full scale statistical analysis resulted in a number of conclusions that reflect the dependence of the efficiency of ESWL of stones in lower calices of kidney on size of the stone and a number of anatomical features of the renal pelvis system. PMID- 23987043 TI - [Morphological and functional changes of organs of female and male reproductive systems at change of sex]. AB - The aim of the study was to identify the effects of virilizing and feminizing hormone replacement therapy on the morphology and function of the male and female reproductive systems in the application of technology for change of sex. The results of the pathomorphorogic examination of the uterus with appendages, testes, the corpora cavernosa, and biopsies of the prostate and mammary glands at different times of treatment in transsexual patients aged from 22 to 43 years are presented. It was found that prolonged exposure to high concentrations of exogenous hormones in the women and men significantly increases the risk of tumors and tumor-like processes, such as endocervicosis, cervical intraepithelial neoplasia, metaplasia of the endometrium, endocervical and endometrial polyps, endometrial hyperplasia, proliferative processes in tubular epithelium, ovarian polycystic disease, mammary tumors, hyperplasia and metaplasia of the ductal epithelium of the prostate gland. PMID- 23987044 TI - [The role of immunomodulating therapy in the treatment and prevention of exacerbations of chronic cystitis]. AB - The article presents the results of the examination and treatment of 60 women with chronic cystitis aged 20 to 80 years. The mean disease duration was 4,9 years (ranged from 6 months to 40 years). Immunomodulator Tilorone was included in the complex therapy of 30 patients of the main group. Besides the standard examination, immunological studies, including the definition of netrophil phagocytic rates in the patients were performed. It was revealed that the inclusion of immunomodulator in the treatment regimen of exacerbations of chronic cystitis contributes to an increase of index of activation of neutrophil phagocytic reserve, significant reduction in the frequency of exacerbations of the disease after the basic and preventive courses of treatment. PMID- 23987045 TI - [Combined treatment of patients with erectile dysfunction and urination disorders]. AB - The article presents the results of the study aimed to the evaluation the efficacy of combination therapy with alpha1-blocker (tamsulosin) and phosphodiesterase type 5 inhibitor (sildenafil) in patients with urination disorders and erectile dysfunction (ED). A pilot observational study involving 60 men aged from 50 and 80 years divided into 3 groups of 20 people was performed. Group 1 of patients received sildenafil 25 mg daily (dynamico), Group 2- tamsulosin 0.4 mg daily (Omnic-Ocas), and Group 3--tamsulosin 0.4 mg (Omnic-Ocas) and sildenafil 25 mg (dynamico) daily. The visits were carried out at the stage of screening, further--every 10 days (a total number--4 visits). Combination therapy of urination disorders and ED contributed to the significant improvement in uroflowmetry, the stopping of complaints according to the IPSS and IIEF-15 questionnaires, and improving the quality of life (according to the QoL questionnaire). Combination therapy significantly decreased obstructive and irritative symptoms, increased the maximum urine flow rate within the period of observation, as well as significantly decreased the residual urine volume, more pronounced when compared with monotherapy. Significant positive effect on erectile component and all components of the overall satisfaction in the sexual sphere were registered, that as a consequence led to the positive impact on the quality of life in patients treated with PDE5 inhibitor. Given the high prevalence of urinary disorders and erectile dysfunction, combined therapy with alpha1-blockers and PDE5 inhibitors in this case should be a promising area for drug therapy. PMID- 23987046 TI - [The evaluation of efficacy and safety of treatment with dalfaz SR in patients with prostatic adenoma]. AB - An open non-comparative multicenter study-observation according the program involving 190 patients (mean age--62.3 +/- 9.7 years) with benign prostatic hyperplasia (BPH) and severe urination disorders was performed. All of the patients received alfuzosin (dalfaz SR) 10 mg daily for 12 months. The primary criterion for evaluation of treatment effectiveness was the change of the total IPSS score. As secondary criteria, change of QoL score, total number of urination per day and subjective patient's satisfaction with the treatment results were registered. Safety was assessed by recording the adverse events. The treatment led to the progressive decrease in the total IPSS score--from 16.4 +/- 4.8 at baseline to 7.7 +/- 2.6 at the final visit (P < 0.001). The average QoL score has decreased by 67% - from 3.9 +/- 1.1 to 1.3 +/- 0.7 at the end of the study (P < 0.001). In general, 94.2% of respondents positively assessed the results of treatment. The frequency of urination at night has decreased by 56%. Adverse effects (dizziness and slight fatigue) were recorded only in 1 (0.5%) patient. The present study has demonstrated a high efficacy and a favorable safety profile of dalfaz SR at a dose of 10 mg in the treatment of patients with BPH. Of particular note is the high proportion of patients who continued to receive the drug for 12 months, showing a good tolerability ofdalfaz SR and high treatment compliance. PMID- 23987047 TI - [The role of endothelial dysfunction in the pathogenesis of non-inflammatory form of chronic abacterial prostatitis]. AB - The evaluation of some indicators of blood proteolytic systems and their role in the development of endothelial dysfunction in noninflammatory form of chronic prostatitis abacterial (CAP III B) was performed. The association between the activity of blood proteolytic systems and endothelial damage in patients with CAP III B was examined. Indicators of blood kallikrein-kinin system and renin angiotensin system (activity of kallikrein, alpha1-proteinase inhibitor, alpha2 macroglobulin, total argininesterase activity, activity of angiotensin converting enzyme, prekallikrein content) were evaluated in 32 patients with CAP III B before and after occlusive bronchial test. It was established that a violation of endothelium-dependent vasodilation is accompanied by an imbalance of pro- and antiproteolitic blood systems. PMID- 23987048 TI - [Morphological changes of testicular tissues in rats of different age groups, depending on the time of being in the abdominal cavity]. AB - Pathological changes in the testes of animals of different age groups with the experimentally simulated cryptorchidism were evaluated. Animals were divided into 3 groups according to the time of fixation of testes into the abdominal cavity for a term of 2, 3 and 4 weeks. The changes were recorded at the time of bringing down the testes into the scrotum and at 14th and 28th day after bringing down. An assessment of pathological changes and the dynamics of the reparative capacity of testicular tissue in animals of different age groups at different stages of the study was performed. Experimental cryptorchidism leads to marked degenerative changes in the testes, up to the destruction of the elements of the testicular tissue in both groups. Comparative analysis of reparative capabilities revealed that potential of recovery of testicular tissue in young group of animals is much higher than that of mature animals. PMID- 23987049 TI - [Efficiency of vibrothermomagnetic effects in the treatment of hemodynamic disorders of pelvic floor muscles of in patients with abacterial prostatitis]. PMID- 23987050 TI - [The epidemiology of renal cell carcinoma in the regions of Siberia and the Far East (1994-2008)]. AB - The article presents the results of an epidemiological study of territorial and temporal characteristics of incidence of renal cell carcinoma in population of Siberia and the Far East, taking into account age and gender. In the average, regional incidence of renal cell carcinoma in men was 10.6 +/- 0.1 per hundred thousand; in women--5.6 +/- 0.1 per hundred thousand. During the years 1994-2008, incidence increased by 1.4 times in male and female population. Based on the results of analysis, territories at-risk of renal cell carcinoma were identified- Omsk and Irkutsk regions. The incidence of renal cell carcinoma in child population was also evaluated. Peak incidence at the age of 4 years was revealed; in 2004-2008 it amounted to 1.72 +/- 0.32 per hundred thousand, which in turn has led to the fact that renal cell carcinoma took 2nd place (13.2%) in malignant tumors in this age group after hematological malignancies. The highest incidence and its high growth in infants during the study period were revealed in Kamchatka, Amur and Sakhalin regions. PMID- 23987051 TI - [Endoscopic methods for the correction of ureteral strictures]. AB - The comprehensive examination and treatment of 80 patients aged 19 to 63 years with strictures of the ureteropelvic junction (UPJ) and ureter obstruction was performed. 23 patients underwent probing with ureteral stenting, 30 patients underwent balloon dilation of strictures under fluoroscopic guidance, 18 patients -endoureteropielotomy with "cold" knife, 9 patients underwent endoureteropielotomy using holmium laser. Correction of ureteral stricture with the removal of the stone was performed in 6 patients. It was found that efficiency of the methods increases in the following order: balloon dilatation (73.3%), dissection using "cold" knife (77.8%), probing with ureteral stenting (82.6%), and laser endoureteropielotomy (100%). In general, endoscopic correction of ureteral contractions is a minimally invasive treatment option for restoring its continuity, without perfoming traumatic surgery in 80% of patients with UPJ and ureteral strictures, including complicated by stone formation. PMID- 23987052 TI - [Evaluation of different methods of hemostasis when performing laparoscopic partial nephrectomy]. AB - The experience of performing 44 partial nephrectomies using laparoscopic and lumboscopic approaches is presented. A comparative analysis of the effectiveness of different methods of hemostasis when performing nephron sparing interventions was conducted. It is shown that physical methods of hemostasis do not meet the necessary requirements, increasing warm ischemia time and the risk of intraoperative blood loss, and makes it difficult to visualize the boundaries of resection. Pilot study using histological assessment methods proved negative effects of high-frequency energy on parenchyma, which does not allow to recommend this method of hemostasis in nephron sparing surgery. We believe that currently ligature method in partial nephrectomy remains the only reliable and safe method for the achievement of final hemostasis. PMID- 23987053 TI - [Modern principles of diagnosis and prediction of course of chronic obstructive pyelonephritis in children]. AB - An assessment of changes in the levels of cytokines, cell adhesion molecules, acute phase proteins in serum, urine and biopsy using ELISA was performed. The evaluation was performed in 167 patients with various congenital urinary tract obstructions in the perioperative period. It is shown that serum C-reactive protein and IL-6, IL-8 urine levels have high diagnostic significance for determining the severity of inflammation in the urinary tract in the development of chronic obstructive pyelonephritis at different levels of obstruction. The calculation of the proposed index of inflammation activity based on IL-8 and IL 10 urine levels in children in the dynamics allows to estimate the phase of inflammation and efficacy of the treatment. PMID- 23987055 TI - [Obstructive complications of endoscopic treatment of vesicoureteral reflux in children]. AB - The study was aimed to the selection of patients, in which endoscopic treatment of vesicoureteral reflux (VUR) is contraindicated due to the high risk of the formation of obstructive hydroureteronephrosis (HUN). From June 1991 to December 2011, endoscopic treatment of I-V degree VUR was performed in more than 4,000 children aged 4 months to 17 years. In period of wide use of endoscopic technique, obstructive HUN occurred in average in 1 (0.5%) case of 200 VUR (5 cases in 5 children), only in IV degree reflux and in only in children with initial subcompensated obstruction of ureterovesical segment, which was manifested as flask-shaped extension of juxtavesical ureter on intravenous urograms. Ureterocystoneostomy allowed to resect the terminal ureter with encapsulated implants in 4 out of 5 children. The macroscopic and histological examination of biopsy specimens confirmed the correct position of the implant in all cases, which excluded the technical complications. Thus, persistent decompensation of urodynamics of upper urinary tract is the result of increased pressure profile of the terminal ureter, inevitable in the endoscopic treatment of UVR, in children with initial obstruction of ureterovesical segment. Therefore, endoscopic treatment is contraindicated for children with high-degree reflux and radiological signs of obstruction of the terminal ureter. PMID- 23987054 TI - [Balanoplasty in accordance with the normal anatomy--the key to successful correction of hypospadias]. AB - The features of the normal anatomy of the balanus and distal urethra were evaluated. It was found that there is a physiological mechanism of stretching of distal urethra during urination owing to the scaphoid fossa, bridle and hippocrepiform-located corpus spongiosum of balanus. Based on these data, modified balanoplasty was proposed, which consisted in mobilization and increase the length of corpus spongiosum of wings of balanus by longitudinal incisions, followed by suturing wings of balanus with separate inside sutures on a short distance not above 3-5 mm and their dipping at a depth not above 1-2 mm. Between 2005 and 2010, 410 patients aged 1 to 18 years underwent surgeries. 90 (22%) patients underwent reoperation. Boys with glandular and coronal hypospadias (n = 69) underwent MAGPI surgery. Patients with penile hypospadias (n = 243) underwent TIP-Snodgrass (n = 72), onlay (n = 23), Mathuie (n = 123), and GTIP (n = 25) surgeries. In children with scrotal and perineal hypospadias (n = 98), method of transverse tubularized foreskin flap was used. All patients were arbitrarily divided into two groups. The study group consisted of patients (n = 210) who underwent modified balanoplasty. The comparison group consisted of 200 patients who underwent conventional balanoplasty. Complication rate after hypospadias correction was reduced from 18 to 12% in penile hypospadias, and from 28 to 18% in scrotal and perineal hypospadias. It is shown that modified balanoplasty excludes formation of obstructive ring of corpus spongiosum in the distal urethra. The results of urodynamic examinations in follow-up period showed improvement of mean urinary flow rates. PMID- 23987056 TI - [Features of approach to the diagnosis and treatment of recurrent lower urinary tract infections]. PMID- 23987057 TI - [Laparoscopic heminephrureterectomy and bladder resection in urothelial carcinoma of horseshoe kidney]. PMID- 23987058 TI - [The giant foreign body of bladder of iatrogenic nature]. PMID- 23987059 TI - [Substitutive buccal urethroplasty of extended stricture in urethral amyloidosis]. PMID- 23987060 TI - [Modernity in the treatment of erectile dysfunction: Levitra (vardenafil) in the form of oral dispersible tablet]. AB - Due to high efficiency, prompt action and low incidence of side effects, phosphodiesterase type 5 inhibitors are the drugs of first choice in the treatment of erectile dysfunction (ED). One of the most widely used drugs in this group currently is vardenafil. Vardenafil has a number of properties that distinguish it from other drugs in this group: high selectivity and the highest inhibitory activity. Recently, new form of this drug, an oral-dispersible tablet (Levitra ODT) was developed. It dissolves in the mouth for a few seconds and does not required to drink water. This feature Levitra ODT enables easy administration of the drug, which provides the desired effect at any time and in any circumstances. Studies have shown that of simplicity of drug intake is one of the most important characteristics of the "ideal" treatment for erectile dysfunction from the point of view of patients. Currently, Levitra ODT is available at a dose of 10 mg. Two large, randomized, double-blind placebo-controlled studies, POTENT I and POTENT II, with participation of more than 700 patients with erectile dysfunction divided into 2 age groups, have shown a high efficacy and good tolerability of Levitra ODT in both groups. Thus, Levitra ODT is a new and promising form of the drug vardenafil, more convenient to use. There is no doubt that Levitra ODT will occupy an important place in the arsenal of modern methods of treatment of erectile dysfunction due to its high efficacy, good tolerability and usability. PMID- 23987061 TI - [Infectious complications after kidney transplantation]. AB - The review of literature presents the current view of domestic and foreign authors on the frequency of infectious complications after kidney transplantation, their etiology, timing of emergence, and the spectrum of bacterial pathogens. Data on the effects of bacterial complications on the function of renal transplant and recipient survival are also demonstrated. PMID- 23987062 TI - [Comparative analysis of antibacterial therapy for acute cystitis]. PMID- 23987063 TI - [Metasympathetic nervous system and its role in the function of the bladder]. PMID- 23987064 TI - [Integrins as a potential target for targeted anticancer therapy]. AB - The review briefly summarizes information of structure of integrins and their involvement in the development and malignant progression of tumors. Special attention is paid to approaches based on modification of functional properties of integrins that prevent/antagonize tumor growth and progression; these approaches developed in modem experimental biology have certain perspective in clinical application. PMID- 23987065 TI - [Imiquimod: the biochemical mechanisms of immunomodulatory and anti-inflammatory activity]. AB - Imidazoquinolins represent a new group of compounds that recently entered into clinical practice as anti-tumor and anti-viral immune modulators. They are low molecular weight synthetic guanosine-like molecules. Although imiquimod, the most widely used imidazoquinolin, is recommended for the treatment of several forms of skin cancer and papillomas, the molecular mechanisms of its action are not fully understood. In particular, imiquimod has been characterized as a specific agonist of Toll-like receptor 7 (TLR7) and is widely used in this capacity in a large number of experimental studies and clinical trials. However, detailed analysis of the published data with the use of imiquimod, suggests that its biological activity can not be explained only by interaction with TLR7. There are indications of a direct interaction of imiquimod with adenosine receptors and other molecules that regulate the synthesis of cyclic adenosine monophosphate. A detailed understanding of the biochemical basis of imiquimod immunomodulating and antitumor effect will increase its clinical effectiveness and accelerate the development of new drugs with similar but improved medical properties. This review summarizes the published data concerning the effects of imiquimod on a variety of intracellular biochemical processes and signaling pathways. PMID- 23987066 TI - [Conotoxins: from the biodiversity of gastropods to new drugs]. AB - A review describes general trends in research of conotoxins that are peptide toxins isolated from sea gastropods of the Conus genus, since the toxins were discovered in 1970th. There are disclosed a conotoxin classification, their structure diversity and different ways of action to their molecular targets, mainly, ion channels. In the applied aspect of conotoxin research, drug discovery and development is discussed, the drugs being based on conotoxin structure. A first exemplary drug is a ziconotide, which is an analgesic of new generation. PMID- 23987067 TI - [Potentiation of NO-dependent activation of soluble guanylyl cyclase by 5 nitroisatin and antiviral preparatation arbidol]. AB - Isatin (indole-dione) is an endogenous indole that exibits a wide range of biological and physiological activity. The influence of isatin derivatives 5 nitroisatin and arbidol (an antiviral preparatation) on spermine NONO-induced activation of human platelet soluble guanylyl cyclase was investigated. 5 nitroistnin and arbidol had no effect on basal activity, but synergistically increased in a concentration-dependent manner the spermine NONO-induced activation of this enzyme. 5-Nitroisatin and arbidol, like YC-1, sensitized guanylyl cyclase towards nitric oxide (NO) and produced a leftward shift of the spermine NONO concentration response curve. At the same time both compounds used did not influence the activation of guanylyl cyclase by YC-1 and did not change the synergistic increase of spermine NONO-induced activation of soluble guanylyl cyclase in the presence of YC-1. This suggests that 5-nitroisanin and arbidol did not compete with YC-1. Addition of isatin did not change the synergistic increase in the spermine NONO-induced guanylyl cyclase activation by 5-nitroisatin and arbidol and did not influence a leftward shift of spermine NONO concentration response curve produced by these compounds. These data suggest lack of competitive interaction between isatin and both its derivatives used. PMID- 23987068 TI - [Anticancer activity of oxovanadium compounds]. AB - Cytotoxic and antitumor activity of the biligand vanadyl derivative of L-malic acid (bis(L-malato)oxovanadium(IV) (VO(mal)2) was investigated in comparison with inorganic vanadium(IV) compound--vanadyl sulfate (VOSO4) and also with oxovanadium monocomplex with L-malic acid (VO(mal)) and vanadyl biscomplex with acetylacetonate. In this purpose the effect of vanadyl compounds on growth of normal human skin fibroblasts and tumor cells of different lines: mouse fibrosarcoma (L929), rat pheochromocytome (PC12), human liver carcinoma (HepG2), virus transformated mouse fibroblast (NIN 3T3), virus transformated cells of human kidney (293) were investigated. The results showed that VO(mal)2 was not toxic for normal human skin fibroblasts but considerably inhibited growth of cancer cells in culture. Cytotoxic antitumor effect of vanadium complexes was found to be dependent on incubation time and concentration and on type of cells and nature of ligands of the central group of the complex (VO2+). These studies provide evidence that VO(mal)2 may be considered as a potential antitumor agent due to its low toxicity in non-tumor cells and significant anticancer activity. PMID- 23987069 TI - [Molecular modeling of interaction of 17(20)Z- and 17(20)E-pregna-5,17(20)-dien 21-oyl amides with the nuclear receptor LXRbeta]. AB - Aiming the search of novel regulators of lipid metabolism and their potential targets, in this study we performed molecular modeling of eight isomeric 17(20)Z- and 17(20)E-pregna-5,17(20)-dien-21-oyl amides differing in structure of the amide moiety. Analysis of the low energy conformers revealed that all 17(20)E isomers had three main energy minima (corresponding to values of the dihedral angle theta20,21 (C17 = C20-C21 = 0) to approximately 0 degrees, to approximately 120 degrees and to approximately 240 degrees), the most occupied minimum was found to correspond to theta20,21 to approximately 0 degrees; while 17(20)Z isomers had either one or two pools of low energy conformations. Molecular docking of these compounds to the ligand-binding site of the nuclear receptor LXRbeta (a potential target) indicates high probability of binding for E-isomers and the absence of that for Z-isomers. Results of the molecular modeling were confirmed by an experiment in which stimulation of triglyceride biosynthesis in Hep G2 cells in the presence of 17(20)E-3beta-hydroxypregna-5,17(20)-dien-21-oyl (hydroxyethyl)amide was demonstrated. PMID- 23987070 TI - [Prooxidant and antioxidant activity of blood plasma and histology of internal organs of rats after intravenous administration of magnetite nanoparticles]. AB - The effect of a single and multiple intravenous injections of a nanosized magnetite suspension on total prooxidant and antioxidant activity of blood plasma has been investigated by the method of luminol-dependent chemoluminescence. Magnetite nanoparticles possess dose-dependent prooxidant properties due to their iron atoms and at the same time their trigger compensatory activation of antioxidant systems in the rat blood plasma. After a single intravenous administration of magnetite the studied parameters of blood plasma returned to the normal level by the end of the experiment as due to removal ofnanoparticles from the body. In the case of multiple administration of the magnetite suspension dose-dependent changes in the pro- and antioxidant plasma activity persist during the whole experiment. Accumulation of magnetite particles in the cells of the mononuclear phagocytic system in the rats' liver, lungs and kidneys is associated with hemodynamic damages, local dystrophic and necrotic changes of parenchyma in these organs. After a single intravenous injection magnetite nanoparticles are identified in the rat organs for 40 days, but their number decreases by the end of the experiment. PMID- 23987071 TI - [Identification of "side population" associated with cancer stem cells by flow cytometry with violet laser]. AB - The possibility of identification of cancer stem cells "side population" in solid tumors by using the flow cytometer equipped with 405 nm violet laser was investigated. Ovarian cancer (Skov-3) and colon cancer (Colo 320) cell lines formed the "side population" after vital staining with Hoechst 33342. Analysis of cells isolated from tumor tissue of malignant melanoma and colorectal cancer, also revealed "side population" that was a result of the fluorescent dye exclusion. The percentage of melanoma cells included in the "side population" was the same as that of cells co-expressing cancer stem cells markers--CD34 and CD44. In contrast, the colon cancer "side population" was significantly smaller than the minor populations of colon cancer cells identified by either CD133 expression or exclusion of Rhodamine 123. PMID- 23987072 TI - [Photo-activity of actinomycins]. AB - Using actinomycins as an example, the possibility of increasing the anti-tumor activity of heterocyclic antibiotics due to photo-activation, has been studied. In model experiments with solutions of actinomycins, it was showed that actinomycins have a significant photochemical activity (of its own), changing by the binding to DNA in solution or in tumor cells. Photo-destruction of HeLa cells and the release of the antibiotic were observed. PMID- 23987073 TI - [The value of low-molecular-weight DNA of blood plasma in the diagnostic of the patological processes of different genesis]. AB - The low-molecular-weight DNA appears in blood plasma of irradiated rats, and its content correlates directly with the irradiation dose. Cloning has shown, that enrichment of low-molecular-weight DNA with G+C content and features of its nucleotide sequences point to its ability to form rather stable nucleosomes. DNA obtained after irradiation of rats with principally different doses 8 and 100 Gy differed not only quantitatively, but also by content of the dinucleotides CpG and CpT; this suggests their origin from different sites of genome. For the first time it has been shown that exposure to low-frequency noise results in an increase of the contents of blood plasma low-molecular-weight DNA. In stroke patients blood concentrations of this DNA increased 3 days after the beginning of the acute period, and dynamics of its excretion differs in ischemic and hemorrhagic forms; in the case of ischemia low-molecular-weight DNA appears in cerebrospinal fluid. The chronic obstructive pulmonary disease in the state of remission is characterized by the decline of the level of low-molecular-weight DNA in the blood plasma unlike in the case of the chronic nonobstructive bronchitis. The clear dependence between formation and special features of the low-molecular-weight DNA fraction in blood plasma makes it possible to consider the low-molecular fraction as an universal index of apoptosis, which allows to distinguish basically different conditions of the body. PMID- 23987074 TI - Digestion and absorption of phenolic compounds assessed by in vitro simulation methods. A review. AB - Phenolic compounds are a group of key plant metabolites found abundantly in fruit and vegetables. Because of their antioxidant properties, they play a significant role in preventing various degenerative illnesses, tumours or cardiovascular disease. In nature, they are present in foods mainly as esters, glycosides and polymers which need to undergo enzymatic hydrolysis in the digestive tract or by the gut microflora before becoming absorbed. The biological properties of these phenolic compounds undergoing this degradation, are thus governed by their absorption as well as metabolism. Many methods are used to assess the rates and the degrees to which these substances are digested and absorbed, both in vivo and in vitro ones, where the former are the most reliable, although they suffer from various limitations. For this reason, many in vitro models have now arisen to simulate the function of human digestion in the attempt to faithfully re-create real-life conditions. Mechanisms of polyphenols absorption have been principally studied by intestinal epithelial cell models, in particular, those using the Caco 2 cell line. PMID- 23987075 TI - Optimisation and validation of the analytical procedure for the determination of acrylamide in coffee by LC-MS/MS with SPE clean up. AB - BACKGROUND: Numerous studies have demonstrated acrylamide to be both neurotoxic and carcinogenic. At present it is widely recognised that acrylamide is mainly formed through the Maillard reaction from free asparagine and reducing sugars. The major sources of dietary acrylamide are potato products, processed cereals and coffee. OBJECTIVE: To optimise and validate an analytical method for determining acrylamide in coffee by liquid chromatography and tandem mass spectrometry analysis (LC/MS/MS) using SPE clean-up. MATERIAL AND METHODS: Analytical separation of acrylamide from roasted coffee was performed by liquid chromatography using a Hypercarb column followed by LC/MS/MS analysis, with 2,3,3 d3 acrylamide as an internal standard. The method was based on two purification steps: the first with hexane and Carrez solutions in order to remove of fat and to precipitate proteins, respectively; and the second with a solid-phase extraction (SPE) column which proved to be efficient in the elimination of the main chromatographic interferences. RESULTS: Limit of quantification (LOQ) for measuring acrylamide in coffee was 50 microg/kg. The described method demonstrates satisfactory precision (RSD = 2.5%), repeatability (RSD = 9.2%) and accuracy (mean recovery - 97.4%). CONCLUSIONS: Our results confirm that LC-MS/MS with SPE clean-up is selective and suitable for determination of acrylamide in coffee. Indeed, this method meets the criteria of EU Commission Recommendations (No. 2007/331/EC and No. 2010/307/EU), on the monitoring of acrylamide levels in food. PMID- 23987076 TI - Determination of barium in natural waters by ICP-OES technique. Part II: Assessment of human exposure to barium in bottled mineral and spring waters produced in Poland. AB - BACKGROUND: A method of the classification of natural mineral and spring waters and maximum admissible concentration (MAC) levels of metals present in such types of waters are regulated by Commission Directive 2003/40/EC, Directive 2009/54/EC of the European Parliament and of the Council and Ordinance of Minister of Health of 30 March 2011 on the natural mineral waters, spring waters and potable waters. MAC of barium in natural mineral and spring waters was set at 1.0 mg/l, while World Health Organization determined the Ba guideline value in water intended for human consumption at the level of 0.7 mg/l. OBJECTIVE: The aims of the study were: the determination of barium in natural mineral and spring waters (carbonated, non-carbonated and medium-carbonated waters) produced and bottled on the area of Poland, and assessment of human exposure to this metal presents in the above-mentioned types of waters. MATERIAL AND METHOD: The study concerning barium determinations in 23 types of bottled natural mineral waters and 15 types of bottled spring waters (bought in Polish retail outlets) was conducted in 2010. The analyses were performed by validated method of determination of barium in water based on inductively coupled plasma optical emission spectrometry, using modern internal quality control scheme. RESULTS: Concentrations of barium determined in natural mineral and spring waters were in the ranges from 0.0136 mg/l to 1.12 mg/l and from 0.0044 mg/l to 0.43 mg/l, respectively. Only in the single case of natural mineral water the concentration of barium (1.12 mg/l), exceeded above-mentioned MAC for this metal, which is obligatory in Poland and the European Union - 1.0 mg/l. The long-term monitoring of barium concentration in another natural mineral water (2006 - 2010), in which incidental exceeding MAC was observed in 2006, was conducted. All measured barium concentrations in this water were lower than 1.0 mg/l and therefore, it is possible to state that the proper method of mixing waters taken from six independent groundwater intakes applied during production is actually used. The estimated Hazard Quotient indices were in the ranges: 0.0019 - 0.16 (natural mineral waters) and 0.00063 - 0.061 (natural spring waters), respectively. CONCLUSIONS: The natural mineral waters are usually characterized by higher Ba concentrations than those observed in the cases of natural spring waters. The presence of a high concentration of HCO3- in such types of natural waters ensures the existence of Ba2+ in solution as Ba(HCO3)2, which is a highly soluble salt. Taking into account the concentrations of barium determined in above-mentioned waters and the available toxicological data for this metal no long-term risk for human health could be expected (estimated Hazard Quotient indices < or = 0.16). PMID- 23987077 TI - Dietary intakes of iron and zinc assessed in a selected group of the elderly: are they adequate? AB - BACKGROUND: Many studies demonstrate that the elderly consume a nutritionally inadequate diet that includes deficiencies in macro- and microelements; iron and zinc being significant examples of the former. OBJECTIVES: To assess the adequacy of dietary iron and zinc intakes in the elderly. MATERIAL AND METHODS: The study was conducted on n = 102 elderly persons, participating in the PolSenior Project, aged over 65, of which 44 were women and 58 men. Consumption data were collected by using 3 day dietary record from which a usual intakes of energy, macroelements (iron and zinc) were calculated. The Estimated Average Requirement (EAR) cut point and z-scores methods were used to determine probabilities of whether iron and zinc uptake was adequate per subject. RESULTS: By using the EAR cut-point method it was stated that iron intake was inadequate for 5% of respondents, whereas 44% showed deficits in zinc (34% women and 52% men). The z-scores demonstrated that 3% of subjects had high probabilities of deficiencies in iron and 52% in zinc. Indeed, very high zinc deficiencies were observed in 20% of cases. CONCLUSIONS: The insufficient energy intake observed among respondents contributes to a high risk of zinc deficiency necessary to ensure health in the elderly. In most cases, the low risk of iron deficiency shows that there is no need to increase this nutrient uptake in the examined group of elderly. The study highlights the need for educating the elderly, especially focused on improving zinc intake without changing iron intake. It can be done through appropriate dietary choices so as to include products such as dairy products, wheat bran, pumpkin and sunflower seeds, beans, lentils and nuts. PMID- 23987078 TI - Estimated dietary intakes of nitrates in vegetarians compared to a traditional diet in Poland and acceptable daily intakes: is there a risk? AB - BACKGROUND: Vegetarian diets, by definition, are rich in vegetables and so may have high levels of nitrates, that can elicit both positive or negative effects on the human body. Exposure to nitrates can thus be potentially higher for this population group. OBJECTIVE: To estimate dietary nitrates intakes in Polish vegetarians and compare these with the Polish average. MATERIAL AND METHODS: A sample of 86 vegetarians were surveyed via a questionnaire to determine nitrate intake for those adopting a vegetarian diet. Nitrate intakes for the average Pole were obtained from the Central Statistical Office. RESULTS: The domestic intake of nitrate, per average person, during 2000-2009, ranged from 115.5 to 133.7 mg NaNO3 with a mean of 125 mg NaNO3 of which 35.4% constituted the Acceptable Daily Intake (ADI). For vegetarians, the corresponding levels ranged from 37.3 to 2054.3 mg NaNO3 with a mean intake of 340.1 mg NaNO3 of which 95.8% represented the ADI. This was almost twice more than values obtained from calculating nitrate intakes of a typical 7-day vegetarian menu; 104.5 to 277.6 mg NaNO3, with a mean 175.9 mg NaNO3 with the 49.1% making up the ADI. CONCLUSIONS: The nitrate intakes in the tested vegetarians were 140 to 270% higher than ones for the average Pole, however in both cases the ADI was not exceeded. Nevertheless, the higher intake of nitrates so observed in vegetarians can be hazardous to some from this population group. PMID- 23987079 TI - Reduction of the neutralisation time during antimicrobial activity testing of disinfectants according to European Standards. AB - BACKGROUND: Evaluation of the biocidal activity of chemical disinfectants and antiseptics according to European Standards (EN) is based on determination of the reduction of the number of viable test microorganisms under defined conditions. OBJECTIVE: The objective of this study was to investigate whether reducing the neutralization time required following declared product contact times for the tested microorganisms yields method validations. MATERIAL AND METHODS: This study was conducted on 14 products containing active substances from different chemical groups: alcohols, aldehydes, biguanides, quaternary ammonium compounds, phenols, amines derivatives, oxidizing agents. These products were tested according to phase 1 tests: EN 1040:2005 and EN 1275:2005 and then according to phase 2, step 1 tests: Draft EN 13727:2005 and EN 13624:2003. Biocidal activity was evaluated using the following test organisms: S. aureus ATCC 6538, P. aeruginosa ATCC 15442, E. coli NCTC 10538, E. coli ATCC 10536, E. hirae ATCC 10541, C. albicans ATCC 10231 and A. brasiliensis ATCC 16404. RESULTS: Validation C results for all products and tested microorganism strains were at least half of the density of the suspension for validation (Nvo) after only 10 s of neutralization. Furthermore, results from test procedures performed in parallel were also positive except 5 products toward A. brasiliensis. CONCLUSIONS: The results of our study confirm that the contact time described in the European Standards phase 1: EN 1040 and EN 1275, as well as phase 2, step 1: Draft EN 13727 and EN 13624 can be precisely determined in spite of reducing the neutralization time from 5 minutes to even 10 seconds. PMID- 23987080 TI - The influence of selenium compounds of different structure on morphology, blood biochemistry and phagocytic capability of granulocytes in rats. AB - BACKGROUND: Selenium belongs to important microelements. Numerous studies have revealed relationships between its deficiency and occurrence of diverse illnesses, but the question of the proper form and dose of Se-supplementation still remains unsolved. OBJECTIVE: In the present study the influence of different selenium compounds on blood morphology and biochemistry as well as on phagocytic capacity of granulocytes and NBT test in rats was investigated. MATERIAL AND METHODS: Adolescent male Wistar rats were divided into four groups (ten animals each): I--control, received saline; II--received sodium selenite Na2SeO3; III--received selenoorganic compound A of chain structure 4-(o-tolyl-) selenosemicarbazide of 2-chlorobenzoic acid; IV--received selenoorganic compound B of cyclic structure 3-(2-chlorobenzoylamino-)-2-(o-tolylimino-)-4-methyl-4 selenazoline. The administration was performed by stomach tube at a dose of 5 x 10(-4) mg Se g(-1) b.w. once a day for 10 days. RESULTS: Selenium compounds treatment decreased haematocrit. Erythrocytes number was unchanged in all groups receiving Se vs. control, whereas leucocytes number was depressed in groups II and IV. Haemoglobin was significantly decreased in group III. White blood count was altered in groups II and III, where all parameters were markedly decreased except for lymphocytes in group III and remained unchanged in group IV. The outcomes regarding selenium effect on biochemistry parameters of blood showed that urea remained unchanged, glucose was statistically decreased in groups II and III, whereas cholesterol was significantly diminished in group II and increased in group III vs. control. Results concerning phagocytosis and NBT test displayed that % of positive cells were decreased in groups II and III, whereas remained unaltered in group IV vs. control. CONCLUSIONS: As cyclic selenoorganic compound B did not cause many significant changes of the studied parameters it may be suggested that after further researches it could be taken into account as a possible selenium supplement. PMID- 23987081 TI - The effect of a Mediterranean diet model on serum beta-carotene concentration. A preliminary assessment. AB - BACKGROUND: Some of the main nutritional reasons for recommending a Mediterranean diet is to prevent metabolic diseases arising through free radical formation. A key constituent compound is beta-carotene which, amongst the carotenoids, displays the greatest provitamin A activity as well as possessing significant antioxidant properties. OBJECTIVES: Principally, to determine the relationship between serum beta-carotene levels and the effect of Mediterranean diet guidelines in a selected group of women. MATERIALS AND METHODS: The subject group consisted of 26 women aged 19-22 years. A nutritional assessment was performed using 3 day repeats of 24-hour recall interviews. A 9-point aMED (alternate Mediterranean Diet) score was used to study dietary habits. Serum beta-carotene was measured by liquid chromatography with photodiode array detection (HPLC-PDA). RESULTS: Beta-carotene dietary intake was highly variable, ranging from 734 to 14476 microg/day (median 3022 microg/day). Serum beta-carotene concentration ranged between 0.071-1.905 micromol/L (median 0.519 micromol/L) and was significantly associated with the Mediterranean Diet model (Spearman r = 0.633, p < 0.001). Out of the dietary sources of beta-carotene, consuming carrots had the most significant impact on its serum concentration. Other dietary factors positively affecting serum beta-carotene were: consumption of nuts and seeds, pulses, a favourable ratio of mono-unsaturated fatty acids to saturated fatty acids and eating fruit and wholegrain cereal products. CONCLUSIONS: Adopting a Mediterranean-based diet had a positive effect on increasing serum beta-carotene levels. PMID- 23987082 TI - Dietary habits and locus of control assessed in middle-school pupils from the Malopolska region of Poland. AB - BACKGROUND: The formative years of adolescence are a crucial time for developing eating habits which, amongst other factors, are determined by personality traits. OBJECTIVE: The aim of the study was to estimate eating behaviour in a group of middle school pupils according to gender and locus of control (LOC). MATERIALS AND METHODS: Subjects were n = 200 boys and n = 200 girls, aged 14-16 living in the Malopolska region of Poland who were surveyed by questionnaire about their eating habits. A standardised Delta questionnaire, by Drwal, was used to assess LOC. Based on the median from the raw LOC scale scores, groups of boys and girls were thereby identified as having high internal (below the median) or high external (above the median) loci of control. The Chi2 test assessed the dependence between LOC and eating habits using PQStat software ver. 1.4.2.324 adopting values of p < 0.05 as beingstatistically significant. RESULTS: Boys were found to consume dairy products significantly more frequently than girls (P < 0.001), and likewise for sugary fizzy drinks (P < 0.05). Dairy products were consumed daily by 51% girls and 70% boys (P < 0.001), whilst fizzy drinks by 32% girls and 43% boys (P < 0.05). Girls with an external LOC consumed breakfast (P < 0.01) and second breakfast (P < 0.001) less regularly, with a less frequent consumption of fruit (P < 0.001) and dairy products (P < 0.01). Boys having an external LOC consumed meals less frequently (P < 0.01), whereas sweets and confectionery products (P < 0.001) and fizzy drinks (P < 0.05) were consumed more often, compared to boys with an internal LOC. CONCLUSIONS: Numerous irregularities in diet and differences in certain eating behaviour have been found in middle school students that relate to their gender and LOC. The more rational and appropriate choices were taken by subjects with an internal LOC. PMID- 23987083 TI - The relation between selected health behaviour and body mass index amongst adolescents living in urban and rural areas in south-western Poland. AB - BACKGROUND: Changes to the body and its proportions, especially body mass, are frequently and critically assessed by the young according to peer pressure and opinions prevalent in their living and home surroundings, as well as through role models created by the media; particularly those promoting fashions for having a slim figures. The desire to achieve this ideal, is thus responsible for adolescents undertaking a variety of actions/behaviour to regulate their body weight. OBJECTIVE: To compare healthy lifestyle behaviour in secondary school pupils living in towns and the countryside who have variable weights and heights associated with a self-assessment of body mass. MATERIAL AND METHODS: Subjects were n = 1,279 pupils aged 13-15 years, attending secondary school. Those from the countryside environments were n = 273 (136 boys and 137 girls), whilst those from urban areas, (towns) were n = 1,006 (512 boys and 494 girls). Both weights and heights were measured and the Body Mass Index (BMI) determined. Threshold values for overweight, obesity and underweight, were used to assign BMI groups according to the procedure of Cole et al. Perceptions on how subjects assessed their body weight and remedial actions so arising, were surveyed using the Youth Risk Behaviour Survey (YRBS) questionnaire. The relationships between the factors studied were subjected to log-linear analysis and their significance evaluated by Chi2 test using a significance level of p < or = 0.05. RESULTS: No significant differences were found in the observed frequencies of overweight, obesity and underweight groups between students from the different environments studied. Pupils having a normal body mass constituted 68.9% of total subjects. There were also no differences seen in body weight perception between the various environments. Approximately 70% of subjects properly assessed their own body mass, however the methods of its assessment differed between boys and girls. The main ways adopted for regulating body mass was found to be exercise and diet in both student groups. Significantly more girl pupils living in towns, (54.9%) did physical exercises, aimed at weight reduction, compared to those living in the countryside (43.8%). CONCLUSIONS: Only small differences in observed frequencies of height-weight were seen between urban and rural dwelling pupils; the same being true for lifestyle behaviour in controlling weight. Irrespective of residence, two thirds of pupils, aged 13-16 years, correctly assessed their own body mass. In children and adolescents, improving self-awareness of body proportions can be achieved through educating on what the significance of having a healthy BMI is, effective ways of its estimation and safe methods for regulation. PMID- 23987084 TI - Estimation of energy and nutritional intake of young men practicing aerobic sports. AB - BACKGROUND: Keeping to a balanced diet plays a key role in maximizing the body's efficiency so that sports training becomes more effective. Previous studies have shown that an athletes' diet is often not properly balanced, and can thus negatively affect sporting performance. OBJECTIVES: To assess the energy and nutrient intake in young men practicing aerobic sport and compare them with those recommended. MATERIAL AND METHODS: Subjects were 25 male athletes, aged 19-25 years, practicing aerobic sports who were students at two Warsaw Universities; The Military University of Technology and University of Physical Education. The average body mass was 80.6 +/- 9.6 kg and average height was 187.0 +/- 7.6 cm, (BMI thus being 23.01 +/- 1.70 kg/m2). Dietary assessment was based on three-day dietary recalls consisting of two weekdays and one day of the weekend. The energy and macro/ micro-nutrient intake were evaluated using the Polish Software 'Energia' package and compared to recommendations and standards. Supplements were absent from the athletes' diets. RESULTS: The energy value of diets were too low in most instances; average %-age deficiency was 30.22 +/- 13.76%. Total protein intake, (mean 1.41 +/- 0.36 g per kg body weight) was inadequate in 40% of cases, whilst all showed appropriate intakes of animal protein. Most subjects' carbohydrate intake (84%) was deficient; median 3.28 g/kg body weight. Fibre intake, (median 17.17 g) was also insufficient in 76% cases. Total fat intake, (33.9% +/- 5.7 energy) was too high in 32% of cases. The %-age dietary energy obtained from saturated fatty acids was 12.18% +/- 2.53 and 5.72% +/- 1.43 from polyunsaturated fatty acids, where most subjects' diet (64%) was, as well, high in cholesterol. Furthermore, significant deficiencies were observed in the following: Vitamin A (44% of group below EAR), vitamin C (80% below EAR), vitamin D (92% below EAR), foliate (84% below EAR), calcium (52% below EAR) and magnesium (60% below EAR). Vitamin E intake was however higher than the AI level. Almost all subjects had adequate intakes of vitamins B1, B2, B6, B12, niacin and zinc. CONCLUSIONS: The energy value of diet and carbohydrate intake were inadequate to the athletes' requirements. Dietary deficiencies of folate, vitamins C and D, magnesium, calcium and potassium were also observed. There is therefore a need for sports nutrition counselling and education which would help athletes improve their eating habits and health, as well as for optimising their sports training performance. PMID- 23987085 TI - Assessing schoolchildren's ability to make proper use of a food and nutrition pyramid. AB - BACKGROUND: Being acquainted with nutritional recommendations does not necessarily imply that they are fully understood, nor on how they can be applied when correctly planning an adequate diet. OBJECTIVE: To determine whether children can recognise single portion sizes of various foodstuffs and to test their ability for planning a daily menu in accordance to the guidelines from a Food and Nutrition Pyramid. MATERIAL AND METHODS: Subjects under survey were n = 100 children aged 10-11 years, attending two elementary schools: in Warsaw and Piaseczno. The school in Warsaw participated in two national education programmes on food and nutrition (ie. 'Fruit at School' and 'A Glass of Milk') whilst the other did not participate in any such programmes. The study tool was a questionnaire consisting of closed questions together with practical exercises on planning a dietary balanced menu using the Food and Nutrition Pyramid recommendations. RESULTS: Children could easily recognise single portion sizes (73% correct replies), however they found it more difficult to plan a suitable menu, where 60% met the given specifications; ie. numbers of different food type portions, menu diversity, number of meals as well as taking physical activity into account. Girls were significantly better at planning menus. It was also found that, compared to the guidelines, wheat and dairy products, vegetables and fats were under-represented whereas meat and fruit were chosen in excess. Nearly 80% of menus were sufficiently diverse but only 48% were composed of a typical/normal selection of foodstuffs. CONCLUSIONS: Despite being provided with guidelines for preparing appropriate menus, most children failed this task. This was likely due to either not fully understanding the instructions or a lack of skills in adopting the Food and Nutrition Pyramid recommendations. Thus it is necessary to give more comprehensive explanations when teaching nutrition during school lessons as well as letting the children practice doing the practical aspects. PMID- 23987086 TI - How often are x-rays used as diagnostic tool by healthcare providers in the Mazovian province of Poland. AB - BACKGROUND: Within the medical facilities provided by state healthcare services, a universally applied technique for patient diagnosis and treatment relies on ionising radiation; for example in radiotherapy and X-ray (ie. examination). Human exposure to such radiation is not however entirely free of associated health risks. OBJECTIVES: To determine and estimate the numbers and types of X ray based medical procedures that are performed in general and dental radiography, mammography and computer tomography on patients from the Mazovian province in Poland, which included children, women and men subjects. MATERIAL AND METHODS: The numbers of patient subjects undergoing X-rays was estimated by surveying the patient intake in X-ray testing rooms within the healthcare facilities of the Mazovian province. Questionnaires were either dispatched by mail to such healthcare centres or were completed by the X-ray operating staff during the testing of quality control. Results so obtained from the latter, were compared to entries from the X-ray rooms' register RESULTS: During 2009, the number of X-rays performed were 7612046 equivalent to 1460 examinations per 1000 inhabitants. The majority were done on women ie. 3847961 (50.55%), followed by 3193781 (41.96%) on men and 570 304 (7.49%) for children. CONCLUSIONS: Results indicated that the predominating medical procedure used of this type, was for making general diagnoses; especially through using chest radiography. Others included, in descending order; dental X-ray (mainly intra-oral examination), computer tomography (mainly CT head examinations) and mammography procedures. It was also found that the annual numbers of having X-rays has increased compared to previous years. PMID- 23987087 TI - Conversion of iodide to hypoiodous acid and iodine in aqueous microdroplets exposed to ozone. AB - Halides are incorporated into aerosol sea spray, where they start the catalytic destruction of ozone (O3) over the oceans and affect the global troposphere. Two intriguing environmental problems undergoing continuous research are (1) to understand how reactive gas phase molecular halogens are directly produced from inorganic halides exposed to O3 and (2) to constrain the environmental factors that control this interfacial process. This paper presents a laboratory study of the reaction of O3 at variable iodide (I(-)) concentration (0.010-100 MUM) for solutions aerosolized at 25 degrees C, which reveal remarkable differences in the reaction intermediates and products expected in sea spray for low tropospheric [O3]. The ultrafast oxidation of I(-) by O3 at the air-water interface of microdroplets is evidenced by the appearance of hypoiodous acid (HIO), iodite (IO2(-)), iodate (IO3(-)), triiodide (I3(-)), and molecular iodine (I2). Mass spectrometry measurements reveal an enhancement (up to 28%) in the dissolution of gaseous O3 at the gas-liquid interface when increasing the concentration of NaI or NaBr from 0.010 to 100 MUM. The production of iodine species such as HIO and I2 from NaI aerosolized solutions exposed to 50 ppbv O3 can occur at the air-water interface of sea spray, followed by their transfer to the gas-phase, where they contribute to the loss of tropospheric ozone. PMID- 23987088 TI - A three-dimensional chemical phase pharmacophore mapping, QSAR modelling and electronic feature analysis of benzofuran salicylic acid derivatives as LYP inhibitors. AB - Lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has a critical negative regulatory role in T-cell antigen receptor (TCR) and emerged as a promising drug target for human autoimmune diseases. A five-point pharmacophore with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic ring features was generated for a series of benzofuran salicylic acid derivatives as LYP inhibitors in order to elucidate their anti-autoimmune activity. The generated pharmacophore yielded a significant 3D-QSAR model with r(2) of 0.9146 for a training set of 27 compounds. The model also showed excellent predictive power with Q(2) of 0.7068 for a test set of eight compounds. The investigation of the 3D-QSAR model has revealed the structural insights which could lead to more potent analogues. The most active and inactive compounds were further subjected to electronic structure analysis using density functional theory (DFT) at B3LYP/3 21(*)G level to support the 3D-QSAR predictions. The results obtained from this study are expected to be useful in the proficient design and development of benzofuran salicylic acid derivatives as inhibitors of LYP. PMID- 23987089 TI - Can all cause readmission policy improve quality or lower expenditures? A historical perspective on current initiatives. AB - All-cause readmission to inpatient care is of wide policy interest in the United States and a number of other countries (Centers for Medicare and Medicaid Services, in the United Kingdom by the National Centre for Health Outcomes Development, and in Australia by the Australian Institute of Health and Welfare). Contemporary policy efforts, including high powered incentives embedded in the current US Hospital Readmission Reduction Program, and the organizationally complex interventions derived in anticipation of this policy, have been touted based on potential cost savings. Strong incentives and resulting interventions may not enjoy the support of a strong theoretical model or the empirical research base that are typical of strong incentive schemes. We examine the historical broad literature on the issue, lay out a 'full' conceptual organizational model of patient transitions as they relate to the hospital, and discuss the strengths and weaknesses of previous and proposed policies. We use this to set out a research and policy agenda on this critical issue rather than attempt to conduct a comprehensive structured literature review. We assert that researchers and policy makers should consider more fundamental societal issues related to health, social support and health literacy if progress is going to be made in reducing readmissions. PMID- 23987090 TI - Organic anion-transporting polypeptides: a novel approach for cancer therapy. AB - Organic anion-transporting polypeptides (OATPs) encoded by the SLCO genes constitute an important transporter superfamily that mediates transmembrane transport of various clinical drugs and endogenous nutrients. Eleven human OATPs with different transport functions are expressed in various tissues. Bile acids, steroid hormone conjugates, prostaglandins, testosterone and thyroid hormones that promote cell proliferation are typical substrates of OATPs. Many important clinical drugs have been identified as substrates of OATP1B1, OATP1B3, OATP2B1 and OATP1A2. Liver-specific OATP1B1 and OATP1B3 as well as testis-specific OATP6A1 are expressed in malignancies and can act as biomarkers for many tumours. Various studies have shown the associations of genetic polymorphisms in OATP genes with the uptake pharmacokinetics of their substrates. Because of their abundant expression in tumours and their high transport activity for many cancer drugs, OATPs should be considered as important therapeutic targets in anti-cancer drug design. PMID- 23987091 TI - Big data. PMID- 23987092 TI - Stemless revision of a failed hemiarthroplasty: case report and surgical technique. PMID- 23987093 TI - Impact of secondary hard substrate on the distribution and abundance of Aurelia aurita in the western Baltic Sea. AB - This study assessed the impact of secondary hard substrate, as being introduced into marine ecosystems by the establishment of wind farm pillars, on the occurrence and distribution of the moon jelly Aurelia aurita in the southwestern Baltic Sea. A two-year data sampling was conducted with removable settlement plates to assess the distribution and population development of the scyphozoan polyps. The data collected from these samples were used to set up a model with Lagrangian particle technique. The results confirm that anthropogenic created hard substrate (e.g. offshore wind farms) has the potential to increase the abundance of the A. aurita population. The distribution of wind farm borne jellyfish along Danish, German and Polish coasts indicates conflicts with further sectors, mainly energy and tourism. PMID- 23987094 TI - Chlorine dioxide as a treatment for ballast water to control invasive species: shipboard testing. AB - The efficacy of chlorine dioxide (ClO2) in eliminating organisms present in estuarine ballast water of a containership was determined under actual operating conditions by comparing the survival of planktonic communities present in waters of treated and control ballast tanks. Sampling was via ballast-tank hatches. The treatment (5 mg L(-1)ClO2 without pre-filtration) delivered by a prototype ClO2 generating system was generally effective against planktonic assemblages, although bacterial communities rebounded after a few days. Regardless of temperature, ClO2 was very effective against phytoplankton; the effect was immediate, without resurgence. Some zooplankters in the >= 50-MUm fraction may survive the biocide, especially those able to find refuge within a protective coating (e.g., cysts, resting eggs, and shells) or in sediment. In order to boost efficacy, a pre-filtration step is recommended (now installed as standard equipment) to lower the intake of the >= 50-MUm fraction and lessen the challenge posed by this size class. PMID- 23987095 TI - In situ and in vitro impacts of the Deepwater Horizon oil spill on Vibrio parahaemolyticus. AB - Most established virulence genes in Vibrio parahaemolyticus (Vp), e.g., thermostable direct hemolysin (tdh), tdh-related hemolysin (trh), and type three secretion system 2 (TTSS2), are on the chromosome 2 pathogenicity island, which also possesses numerous uncharacterized genes. We hypothesized the 2010 Deepwater Horizon (DH) oil spill would cause an increase in populations of Vibrio parahaemolyticus carrying environmental adaptation genes. Vp isolated pre- and post-spill were analyzed for TTSS2 genes, and impacts of DH oil on Vp were examined in vitro. There was no change in TTSS2 in situ, but tdh and V. vulnificus levels were higher post-spill. In vitro exposure of water samples to DH oil produced no changes in Vp densities. Two years post-spill, total Vp remained low; tdh and trh increased. These results indicate the effects of the DH oil spill on potentially pathogenic Vp subpopulations were complex and difficult to discern from other concurrent anthropogenic and natural events. PMID- 23987096 TI - Targeting of eugenol-loaded solid lipid nanoparticles to the epidermal layer of human skin. AB - AIM: The purpose of this study was to formulate carbopol hydrogels containing eugenol-loaded solid lipid nanoparticles (EG-SLNs) for epidermal targeting to treat fungal infections in skin. MATERIALS & METHODS: EG-SLNs were incorporated into carbopol hydrogels and the physiochemical characteristics of EG-SLN in hydrogels were investigated by dynamic light scattering, transmission electron microscopy and atomic force microscopy. Rheological behavior and mechanical properties of hydrogels were also studied before and after incorporation of EG SLNs. The epidermal-targeting ability of EG-SLN-enriched hydrogels was evaluated by estimation of eugenol in the epidermis of human cadaver skin. An occlusion (hydration) study was also performed to elucidate the mechanism of epidermal targeting of EG-SLN-enriched hydrogels. RESULTS: The particle size (d90) and morphology of EG-SLNs were not significantly changed after incorporation into the hydrogel. EG-SLN of stearic acid-enriched hydrogels follow the Carreau model that describes pseudoplastic flow. The hydrogel containing EG-SLN of stearic acid and of Compritol((r)) (Gattefose, Mumbai, India) showed significantly greater accumulation of eugenol in the epidermis (62.65 +/- 4.35 and 52.86 +/- 3.76 ug/cm(2), respectively) than that of eugenol-hydroxypropyl-beta-cyclodextrin complex in hydrogel (9.77 +/- 1.16 ug/cm(2)) and almond oil solution of eugenol (3.45 +/- 0.6 ug/cm(2)). The occlusion study demonstrated greater hydration of human cadaver skin treated with EG-SLN-enriched hydrogel compared with that of hydrogel and intact skin. CONCLUSION: Hydrogels containing EG-SLNs could be a promising formulation for epidermal targeting to treat fungal infections in skin. PMID- 23987097 TI - Why does gaze enhance mimicry? Placing gaze-mimicry effects in relation to other gaze phenomena. AB - Eye gaze is a powerful signal, which exerts a mixture of arousal, attentional, and social effects on the observer. We recently found a behavioural interaction between eye contact and mimicry where direct gaze rapidly enhanced mimicry of hand movements ). Here, we report two detailed investigations of this effect. In Experiment 1, we compared the effects of "direct gaze", "averted gaze", and "gaze to the acting hand" on mimicry and manipulated the sequence of gaze events within a trial. Only direct gaze immediately before the hand action enhanced mimicry. In Experiment 2, we examined the enhancement of mimicry when direct gaze is followed by a "blink" or by "shut eyes", or by "occluded eyes". Enhanced mimicry relative to baseline was seen only in the blink condition. Together, these results suggest that ongoing social engagement is necessary for enhanced mimicry. These findings allow us to place the gaze-enhancement effect in the context of other reported gaze phenomena. We suggest that this effect is similar to previously reported audience effects, but is less similar to ostensive cueing effects. This has important implications for our theories of the relationships between social cues and imitation. PMID- 23987098 TI - beta-Oxygen effect in the Barton-McCombie deoxygenation reaction: further experimental and theoretical findings. AB - The chemistry of (S)-methyl xanthates derived from xylo- and ribo-furanose derivatives in the presence of the stannyl radical is investigated. Xanthate derived from beta-xylo-furanose affords exclusively a deoxygenated product; whereas, under the same reaction conditions, the alpha-ribo-furanose xanthate derivative produces quantitatively a hemithioacetal compound. We reasoned that in the case of the beta-xylo-furanose derivative, a favorable beta-oxygen effect in the Barton-McCombie deoxygenation reaction is operating where, according to theoretical calculations, unusual molecular orbital interactions (and not strain, as previously proposed) are present. These orbital interactions involve the SOMO (intermediary generated from the stannyl radical addition) with the sigma* orbital of the bond undergoing cleavage and this with the two C-O antibonding orbitals anti oriented. Such molecular orbital interactions are not present in the alpha-ribo-furanose; therefore, the beta-scission is highly delayed, and due to the reversibly nature of the stannyl radical addition, the ribo-furanose xanthate is forced to take an alternative route: the homolytic substitution (S(H)2) of the sulfide sulfur by stannyl radical. This radical addition gives the alkoxythiocarbonyl radical, which is trapped by Bu3SnH before the elimination of carbonyl sulfide; subsequently, radical stannyl addition followed by radical reduction produces the hemithioacetal. PMID- 23987100 TI - Cardiac angiogenesis directed by stable Hypoxia Inducible Factor-1. AB - BACKGROUND: The heterodimeric, oxygen-sensitive transcription factor Hypoxia Inducible Factor-1 (HIF-1) orchestrates angiogenesis and plays a key role in the response to ischemia and the growth of cancers. METHODS: We developed a transgenic mouse line in which expression of an oxygen-stable HIF-1alpha construct was controlled by a tetracycline-responsive promoter. HIF-1alpha expression was induced for up to 28 days in adult mouse heart, resulting in angiogenesis and progressive ventricular dysfunction. RESULTS: Gross inspection demonstrated enlarged hearts with large epicardial vessels with prominent side branches. Perfusion curves obtained by ultrasound contrast analysis demonstrated a significant increase in the myocardial red cell volume after 28 days of HIF 1alpha expression. Corrosion casts of cardiac vessels were made with a new low viscosity resin that can fill the vasculature down to the level of the capillaries. Scanning electron microscopy of these casts reveal "lakes" of capillaries forming off of larger vessels after HIF expression, and support the rapid formation of mature neovascularization. Pro-angiogenic factors DLL-4, Notch 1, and PDGF-beta, were evaluated by immunohistochemistry and Western blots, and support a pattern of progressive functional neoangiogenesis. CONCLUSIONS: This study demonstrates the structural characteristics of HIF-directed angiogenesis and supports the utility of manipulation of HIF signaling to enhance perfusion and treat ischemia. PMID- 23987099 TI - A novel helper-dependent adenovirus-based cell culture model for Hepatitis C virus replication and production. AB - BACKGROUND: By using the hepatitis C virus (HCV) genotype 2a JFH-1 or its chimeric strains, a HCV infection system has been previously developed through several methods- such as in vitro-transcribed JFH1-RNA transfection or stable transfection of the JFH1 cDNA into human hepatoma Huh-7 cell line or its derivatives. However, other reliable methods for delivery of the HCV genome into cells are still worth trying. The helper-dependent adenovirus (HDAd) is devoid of all viral coding sequences and has a package capacity of 37 kb, which is suitably large for the delivery of the HCV genome. Here we report a new method for delivery of the HCV genome into Huh-7 and HepG2 cells by using the HDAd vector. RESULTS: Our results demonstrated that the infection of Huh-7 cells with the HDAdJFH1 virus led to efficient HCV replication and virion production. We found that the HCV viral RNA levels could reach 107 copies per milliliter (ml) in the culture medium. HDAdJFH1-infected Huh-7 cells could be cultured for 8 passages with the culture medium remaining infectious for naive Huh-7 cells throughout this period. This infection system proved effective for evaluating the anti-HCV effects of IFN-alpha in Huh-7 cells. Co-infection of HepG2 cells with the HDAdJFH1 and HDAdmiR-122 virus also resulted in HCV expression and replication. CONCLUSION: This is the first report of an HDAd-based strategy for HCV replication and production in vitro. PMID- 23987101 TI - Ring-opening polymerization with Zn(C6F5)2-based Lewis pairs: original and efficient approach to cyclic polyesters. AB - Dual systems combining Zn(C6F5)2 with an organic base (an amine or a phosphine) promote the controlled ring-opening polymerization of lactide and epsilon caprolactone. The Lewis pairs cooperate to activate the monomers, affording well defined high molecular weight cyclic polyesters. Efficient chain-extension gives access to cyclic block copolymers. PMID- 23987102 TI - Life-style characteristics and cardiovascular risk factors in regular downhill skiers: an observational study. AB - BACKGROUND: Downhill skiing is part of active life style in many residents of Alpine regions. However, only very little information is available whether downhill skiing on a regular basis is associated with a healthier life style resulting in the reduction of major risk factors for cardiovascular diseases and memory deficits when compared to the general population. Thus, the aim of the study was to compare life-style characteristics and cardiovascular risk factors between regular downhill skiers and the general population. METHODS: Self reported health and life-style data were collected by questionnaire from 1259 long-term downhill skiers (971 males, aged 57.3 +/- 14.6 years; 288 females, aged 47.7 +/- 16.4 years) and compared with data from the general population. RESULTS: Long-term skiers showed more favourable life-style characteristics and a better health status than the general population. Prevalences of hypercholesterolemia, systemic hypertension, diabetes, the frequency of mental stress and the occurrence of memory deficits declined with increasing yearly skiing frequency. CONCLUSION: Long-term alpine skiing on a regular basis may contribute to healthy aging by its association with a healthier life style. PMID- 23987104 TI - Metal-free oxidative C(sp3)-H bond thiolation of ethers with disulfides. AB - A novel method for the preparation of alkyl aryl sulfides through direct oxidation thiolation of commercial ethers with diaryl disulfides using di-tert butyl peroxide (DTBP) as the oxidant without a metal catalyst was established. The C(sp(3))-H bond in various ethers was successfully converted into a C-S bond, and the corresponding sulfides were achieved with moderate to high yields. PMID- 23987105 TI - Geological and climatic changes in quaternary shaped the evolutionary history of Calibrachoa heterophylla, an endemic South-Atlantic species of petunia. AB - BACKGROUND: The glacial and interglacial cycles that characterized the Quaternary greatly affected the distribution and genetic diversity of plants. In the Neotropics, few phylogeographic studies have focused on coastal species outside of the Atlantic Rainforest. Climatic and sea level changes during the Quaternary played an important role in the evolutionary history of many organisms found in coastal regions. To contribute to a better understanding of plant evolution in this environment in Southern South America, we focused on Calibrachoa heterophylla (Solanaceae), an endemic and vulnerable wild petunia species from the South Atlantic Coastal Plain (SACP). RESULTS: We assessed DNA sequences from two cpDNA intergenic spacers and analyzed them using a phylogeographic approach. The present phylogeographic study reveals the influence of complex geologic and climatic events on patterns of genetic diversification. The results indicate that C. heterophylla originated inland and subsequently colonized the SACP; the data show that the inland haplogroup is more ancient than the coastal one and that the inland was not affected by sea level changes in the Quaternary. The major diversification of C. heterophylla that occurred after 0.4 Myr was linked to sea level oscillations in the Quaternary, and any diversification that occurred before this time was obscured by marine transgressions that occurred before the coastal sand barrier's formation. Results of the Bayesian skyline plot showed a recent population expansion detected in C. heterophylla seems to be related to an increase in temperature and humidity that occurred at the beginning of the Holocene. CONCLUSIONS: The geographic clades have been formed when the coastal plain was deeply dissected by paleochannels and these correlate very well with the distributional limits of the clades. The four major sea transgressions formed a series of four sand barriers parallel to the coast that progressively increased the availability of coastal areas after the regressions and that may have promoted the geographic structuring of genetic diversity observed today. The recent population expansion for the entire species may be linked with the event of marine regression after the most recent sea transgression at ~5 kya. PMID- 23987106 TI - Of mice, men and nanoparticle biocoronas: are in vitro to in vivo correlations and interspecies extrapolations realistic? PMID- 23987107 TI - Brain targeting with polymeric nanoparticles: which administration route should we take? PMID- 23987103 TI - Cancer risk in immune-mediated inflammatory diseases (IMID). AB - Inflammation and cancer have a profound yet ambiguous relationship. Inflammation especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86. PMID- 23987111 TI - Cerium oxide nanoparticles: applications and prospects in nanomedicine. AB - Promising results have been obtained using cerium (Ce) oxide nanoparticles (CNPs) as antioxidants in biological systems. CNPs have unique regenerative properties owing to their low reduction potential and the coexistence of both Ce(3+)/Ce(4+) on their surfaces. Defects in the crystal lattice due to the presence of Ce(3+) play an important role in tuning the redox activity of CNPs. The surface Ce(3+):Ce(4+) ratio is influenced by the microenvironment. Therefore, the microenvironment and synthesis method adopted also plays an important role in determining the biological activity and toxicity of CNPs. The presence of a mixed valance state plays an important role in scavenging reactive oxygen and nitrogen species. CNPs are found to be effective against pathologies associated with chronic oxidative stress and inflammation. CNPs are well tolerated in both in vitro and in vivo biological models, which makes CNPs well suited for applications in nanobiology and regenerative medicine. PMID- 23987112 TI - Liposomal drug products and recent advances in the synthesis of supercritical fluid-mediated liposomes. AB - Since the pioneering research of Bangham et al. in 1965, liposomes have attracted a large amount of interest as potential carriers of various bioactive molecules for clinical applications. However, scaling-up conventional methods of liposome preparation has been proven to be challenging. Compared with conventional methods, processes that use supercritical fluid (SCF)-CO2 require a reduced amount of organic solvent, are relatively fast and simple to perform, and yield stable and more uniform liposomes. A number of studies have demonstrated that SCF CO2 methods might be suitable for industrial-scale manufacturing of liposomes. In this review there are two topics being discussed. We provide an overview of liposomal drug products and aim to describe the physicochemical properties of liposomes prepared using various SCF methods. We review all of the available literature on SCF-CO2-based liposomes and focus on the future applications of these innovative technologies in industrial-scale liposome preparation. PMID- 23987110 TI - Rational design of nanofiber scaffolds for orthopedic tissue repair and regeneration. AB - This article reviews recent significant advances in the design of nanofiber scaffolds for orthopedic tissue repair and regeneration. It begins with a brief introduction on the limitations of current approaches for orthopedic tissue repair and regeneration. It then illustrates that rationally designed scaffolds made up of electrospun nanofibers could be a promising solution to overcome the problems that current approaches encounter. The article also discusses the intriguing properties of electrospun nanofibers, including control of composition, structures, orders, alignments and mechanical properties, use as carriers for topical drug and/or gene sustained delivery, and serving as substrates for the regulation of cell behaviors, which could benefit musculoskeletal tissue repair and regeneration. It further highlights a few of the many recent applications of electrospun nanofiber scaffolds in repairing and regenerating various orthopedic tissues. Finally, the article concludes with perspectives on the challenges and future directions for better design, fabrication and utilization of nanofiber scaffolds for orthopedic tissue engineering. PMID- 23987114 TI - Socioecological psychology. AB - Socioecological psychology investigates humans' cognitive, emotional, and behavioral adaption to physical, interpersonal, economic, and political environments. This article summarizes three types of socioecological psychology research: (a) association studies that link an aspect of social ecology (e.g., population density) with psychology (e.g., prosocial behavior), (b) process studies that clarify why there is an association between social ecology and psychology (e.g., residential mobility -> anxiety -> familiarity seeking), and (c) niche construction studies that illuminate how psychological states give rise to the creation and maintenance of a social ecology (e.g., familiarity seeking -> dominance of national chain stores). Socioecological psychology attempts to bring the objectivist perspective to psychological science, investigating how objective social and physical environments, not just perception and construal of the environments, affect one's thinking, feeling, and behaviors, as well as how people's thinking, feeling, and behaviors give rise to social and built environments. PMID- 23987115 TI - In vitro and ex vivo characterization of lectin-labeled Mycobacterium tuberculosis antigen-containing microspheres for enhanced oral delivery. AB - PURPOSE: Oral immunization for mucosal protection against Mycobacterium tuberculosis would be the best option for effective tuberculosis (TB) control. However, this route of vaccine delivery is limited due to the short residence time of the delivery system at the site of absorption. Cytoadhension has made it possible to optimize the targeted delivery of oral vaccine to lymphoid tissues. The purpose of this project was to evaluate the ability of human M-cell specific lectin-labeled microparticles to target the human M-cells of the Peyer's patches. METHOD: Albumin microspheres containing Mycobacterium tuberculosis cell lysate antigens were coupled with Wheat germ agglutinin and Aleuria aurantia lectins and their ability to bind to M cell models as well as their preferential distribution in the Peyer's patches were investigated. RESULTS: The study demonstrated an enhanced delivery of targeted polystyrene and BSA/Lysate microspheres to M cells. It was demonstrated that alpha-l-fucose sugar residue might be the target of these lectins. CONCLUSION: It can be concluded from the study that the lectin coupled microspheres had better affinity for M-cells and showed preferential binding to the Peyer's patches. This means that the coupling enhanced the targeted delivery of the antigens to the M cells. PMID- 23987116 TI - Pesticide-induced gene mutations and Parkinson disease risk: a meta-analysis. AB - AIMS: Increasing scientific evidence suggests that pesticide-induced gene mutations may contribute to increasing susceptibility to Parkinson disease (PD), but many existing studies have yielded inconclusive results. This meta-analysis aims at assessing the exact roles of pesticide-induced gene mutations in the development of PD. METHODS: An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude odds ratio with 95% confidence interval was calculated. RESULTS: Ten case-control studies were included with a total of 1248 PD patients and 1831 healthy controls. Our meta-analysis revealed that PD patients with pesticide exposure had higher gene mutation rates than those of healthy controls. Subgroup analysis by gene type indicated that the mutation rates in the GSTP1, SLC6A3, and MDR1 genes of PD patients with pesticide exposure were higher than those of healthy controls. No publication bias was detected in this meta-analysis. CONCLUSION: The current meta-analysis indicates that pesticide-induced gene mutations may contribute to increasing susceptibility to PD, especially in the GSTP1, SLC6A3, and MDR1 genes. PMID- 23987117 TI - "Double whammy": anomalous pulmonary and systemic venous drainage in a patient with scimitar syndrome. AB - Anomalously draining right pulmonary veins are expected with scimitar syndrome, but systemic venous abnormalities are rare. We present an unusual case of a female patient with scimitar and an interrupted inferior vena cava. PMID- 23987118 TI - Granulomatous tubercular myocarditis: a rare cause of heart failure in the young. AB - Granulomatous myocarditis is a rare disease of the heart. The present case highlights a potentially life-threatening and rare tubercular involvement of the myocardium in a young woman in the form of granulomas and abscess. PMID- 23987120 TI - Progress of basic research in Parkinson's disease in China: data mini-review from the National Natural Science Foundation. AB - This review is to analyze the role of National Natural Science Foundation of China (NSFC) on the development of basic research of Parkinson's disease from 1990 to 2012. Data on the total number of projects and funding of NSFC allocated to Parkinson's disease, as well as hotspots in western countries, papers published, awards, personnel training, subject construction were collected, and the role of NSFC on other sources of funding was evaluated. Over the past 23 years, a full range of continuous funding from NSFC has led to fruitful results and a strong impetus to the progress of basic research of Parkinson's disease. PMID- 23987119 TI - Poly(iohexol) nanoparticles as contrast agents for in vivo X-ray computed tomography imaging. AB - Biocompatible poly(iohexol) nanoparticles, prepared through cross-linking of iohexol and hexamethylene diisocyanate followed by coprecipitation of the resulting cross-linked polymer with mPEG-polylactide, were utilized as contrast agents for in vivo X-ray computed tomography (CT) imaging. Compared to conventional small-molecule contrast agents, poly(iohexol) nanoparticles exhibited substantially protracted retention within the tumor bed and a 36-fold increase in CT contrast 4 h post injection, which makes it possible to acquire CT images with improved diagnosis accuracy over a broad time frame without multiple administrations. PMID- 23987121 TI - PAH-CALUX, an optimized bioassay for AhR-mediated hazard identification of polycyclic aromatic hydrocarbons (PAHs) as individual compounds and in complex mixtures. AB - Polycyclic aromatic hydrocarbons (PAHs) represent a class of ubiquitously occurring environmental compounds that are implicated in a wide range of toxicological effects. Routine measurement of PAH contamination generally involves chemical analytical analysis of a selected group of representatives, for example, EPA-16, which may result in underestimation of the PAH-related toxicity of a sample. Many high molecular weight PAHs are known ligands of the aryl hydrocarbon receptor (AhR), a nuclear receptor that mediates toxic effects related to these compounds. Making use of this property we developed a PAH CALUX assay, a mammalian, H4IIe- cell-based reporter assay for the hazard identification of total PAH mixtures. The PAH CALUX reporter cell line allows for specific, rapid (4 h exposure time) and reliable quantification of AhR-induced luciferase induction relative to benzo[a]pyrene (BaP), which is used as a positive reference PAH congener. Full dose response relationships with inductions over 100-fold were reached within only 2 h of exposure to BaP. The PAH CALUX is highly sensitive, that is, using a 4 h exposure time, a limit of detection (LOD) of 5.2 * 10(-11) M BaP was achieved, and highly accurate, that is, a repeatability of 5.9% and a reproducibility of 6.6% were established. Screening of a selection of PAHs that were prioritized by the European Union and/or the U.S. Environmental Protection Agency showed that the PAH CALUX bioassay has a high predictability, particularly for carcinogenic PAHs. Experiments with synthetic mixtures and reference materials containing complex PAH mixtures show the suitability of the assay for these types of applications. Moreover, the presented results suggest that application of the PAH CALUX will result in a lower risk of underestimation of the toxicity of a sample than chemical analytical approaches that focus on a limited set of prioritized compounds. PMID- 23987122 TI - Robust magnetic/polymer hybrid nanoparticles designed for crude oil entrapment and recovery in aqueous environments. AB - Well-defined, magnetic shell cross-linked knedel-like nanoparticles (MSCKs) with hydrodynamic diameters ca. 70 nm were constructed through the co-assembly of amphiphilic block copolymers of PAA20-b-PS280 and oleic acid-stabilized magnetic iron oxide nanoparticles using tetrahydrofuran, N,N-dimethylformamide, and water, ultimately transitioning to a fully aqueous system. These hybrid nanomaterials were designed for application as sequestering agents for hydrocarbons present in crude oil, based upon their combination of amphiphilic organic domains, for aqueous solution dispersibility and capture of hydrophobic guest molecules, with inorganic core particles for magnetic responsivity. The employment of these MSCKs in a contaminated aqueous environment resulted in the successful removal of the hydrophobic contaminants at a ratio of 10 mg of oil per 1 mg of MSCK. Once loaded, the crude oil-sorbed nanoparticles were easily isolated via the introduction of an external magnetic field. The recovery and reusability of these MSCKs were also investigated. These results suggest that deployment of hybrid nanocomposites, such as these, could aid in environmental remediation efforts, including at oil spill sites, in particular, following the bulk recovery phase. PMID- 23987123 TI - Medical and psychosocial implications of adolescent extreme obesity - acceptance and effects of structured care, short: Youth with Extreme Obesity Study (YES). AB - BACKGROUND: Prevalence rates of overweight and obesity have increased in German children and adolescents in the last three decades. Adolescents with extreme obesity represent a distinct risk group. On the basis of data obtained by the German Child and Youth Survey (KiGGS) and the German district military offices we estimate that the group of extremely obese adolescents (BMI >= 35 kg/m2) currently encompasses approximately 200.000 adolescents aged 14 to 21 yrs. Conventional approaches focusing on weight reduction have largely proven futile for them. In addition, only a small percentage of adolescents with extreme obesity seek actively treatment for obesity while contributing disproportionately strong to health care costs. Because of somatic and psychiatric co-morbidities and social problems adolescents with extreme obesity require special attention within the medical care system. We have initiated the project "Medical and psychosocial implications of adolescents with extreme obesity--acceptance and effects of structured care, short: 'Youths with Extreme Obesity Study (YES)'", which aims at improving the medical care and social support structures for youths with extreme obesity in Germany. METHODS/DESIGN: We focus on identification of these subjects (baseline examination) and their acceptance of diagnostic and subsequent treatment procedures. In a randomized controlled trial (RCT) we will investigate the effectiveness of a low key group intervention not focusing on weight loss but aimed at the provision of obesity related information, alleviation of social isolation, school and vocational integration and improvement of self-esteem in comparison to a control group treated in a conventional way with focus on weight loss. Interested individuals who fulfill current recommended criteria for weight loss surgery will be provided with a structured preparation and follow-up programs. All subjects will be monitored within a long-term observational study to elucidate medical and psychosocial outcomes. Our aim is to evaluate realistic treatment options. Therefore inclusion and exclusion criteria are minimized. We will recruit adolescents (age range 14 21 years) with extreme obesity (BMI >= 35 kg/m2) (extreme group) within 24 months (120 per centre, 5 centres) as well as obese adolescents being at risk for developing extreme obesity (BMI >= 30-34.9 kg/m2) (at risk group). Follow-up evalutations will be performed biannually after inclusion for several years depending on additional funding. In sum, we aim at establishing evaluated health care structures for extremely obese adolescents. DISCUSSION: The results of YES will be of importance for a frequently neglected group of individuals, for whom current medicine has little to offer in terms of structured access to empirically evaluated therapeutic programs. Thus, the results will be both a help for the adolescents within the study and for others in the future given that the trial will lead to a positive finding. Moreover, it will help practitioners and therapists to deal with this neglected group of individuals. TRIAL REGISTRATION: Project registration numbers for each subproject: 1.) ClinicalTrials.gov: NCT01625325, NCT01703273, NCT01662271, NCT01632098; 2.) Germanctr.de: DRKS00004172, DRKS00004195, DRKS00004198, DRKS00004197. PMID- 23987124 TI - Applications and limitations of the I2-mediated carbamate annulation for the synthesis of piperidines: five- versus six-membered ring formation. AB - A protecting-group-free synthetic strategy for the synthesis of piperidines has been explored. Key in the synthesis is an I2-mediated carbamate annulation, which allows for the cyclization of hydroxy-substituted alkenylamines into piperidines, pyrrolidines, and furans. In this work, four chiral scaffolds were compared and contrasted, and it was observed that with both d-galactose and 2-deoxy-d galactose as starting materials, the transformations into the piperidines 1 deoxygalactonorjirimycin (DGJ) and 4-epi-fagomine, respectively, could be achieved in few steps and good overall yields. When d-glucose was used as a starting material, only the furan product was formed, whereas the use of 2-deoxy d-glucose resulted in reduced chemo- and stereoselectivity and the formation of four products. A mechanistic explanation for the formation of each annulation product could be provided, which has improved our understanding of the scope and limitations of the carbamate annulation for piperidine synthesis. PMID- 23987125 TI - Associations of genetic polymorphisms of SAA1 with cerebral infarction. AB - BACKGROUND: Serum amyloid A protein (SAA) is both an inflammatory factor and an apolipoprotein. However, the relation between genetic polymorphisms of SAA and cerebral infarction (CI) remains unclear. METHODS AND RESULTS: The previously reported 4 Single Nucleotide Polymorphisms (rs12218, rs4638289, rs7131332, and rs11603089) of SAA1 gene were genotyped by TaqMan method in a case-control study including 287 cerebral infarction patients and 376 control subjects. We found rs12218 CC genotype and rs7131332 AA genotype were more frequent among CI patients than among controls (9.76% versus 3.19%, P = 0.001; 32.75% versus 24.20%; p = 0.017; respectively). After adjustment of confounding factors such as sex, age, smoking, drinking, hypertension, diabetes, and lipids profile, the difference remained significant in rs12218 (P < 0.01, OR = 2.106, 95% CI: 1.811 7.121). CONCLUSION: Genetic polymorphism of SAA1 may be a genetic maker of cerebral infarction in Chinese. PMID- 23987126 TI - HIV prevention in favour of the choice-disabled in southern Africa: study protocol for a randomised controlled trial. AB - BACKGROUND: Most HIV prevention strategies assume beneficiaries can act on their prevention decisions. But some people are unable to do so. They are 'choice disabled'. Economic and educational interventions can reduce sexual violence, but there is less evidence that they can reduce HIV. There is little research on complex interventions in HIV prevention, yet all countries in southern Africa implement combination prevention programmes. METHODS/DESIGN: The primary objective is to reduce HIV infections among women aged 15 to 29 years. Secondary objectives are reduction in gender violence and improvement in HIV-related knowledge, attitudes and practices among youth aged 15 to 29 years.A random sample of 77 census enumeration areas in three countries (Botswana, Namibia and Swaziland) was allocated randomly to three interventions, alone or in combination, in a factorial design stratified by country, HIV rates (above or below average for country), and urban/rural location. A baseline survey of youth aged 15 to 29 years provided cluster specific rates of HIV. All clusters continue existing prevention efforts and have a baseline and follow-up survey. Cluster is the unit of allocation, intervention and analysis, using generalised estimating equations, on an intention-to-treat basis.One intervention discusses evidence about choice disability with local HIV prevention services, to help them to serve the choice-disabled. Another discusses an eight-episode audio-docudrama with community groups, of all ages and both sexes, to generate endogenous strategies to reduce gender violence and develop an enabling environment. A third supports groups of women aged 18 to 25 years to build self-esteem and life skills and to set up small enterprises to generate income.A survey in all clusters after 3 years will measure outcomes, with interviewers unaware of group assignment of the clusters. The primary outcome is HIV infection in women aged 15 to 29 years. Secondary outcomes in youth aged 15 to 29 years are gender violence and protective knowledge, attitudes, subjective norms, intention to change, agency, discussion of prevention and practices related to HIV and gender violence. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: ISRCTN28557578. PMID- 23987128 TI - Bio-inspired, melanin-like nanoparticles as a highly efficient contrast agent for T1-weighted magnetic resonance imaging. AB - The development of nontoxic and biocompatible imaging agents will create new opportunities for potential applications in clinical MRI diagnosis. Synthetic melanin-like nanoparticles (MelNPs), analogous to natural sepia melanin (a major component of the cuttlefish ink), can be used as contrast agent for MRI. MelNPs complexed with paramagnetic Fe(3+) ions show much higher relaxivity values than existing MRI T1 contrast agents based on gadolinium (Gd) or manganese (Mn); MelNP values at 3T were r1 = 17 and r2 = 18 mM(-1) s(-1) (r2/r1 value of 1.1). With significant enhancement to MRI contrast, this biomimetic approach using MelNPs functionalized with paramagnetic Fe(3+) ions and surface-modified with biocompatible poly(ethylene glycol) units, could provide new insight into how melanin-based bioresponsive and therapeutic imaging probes integrate with their various biological functions. PMID- 23987127 TI - Impact of microRNAs on regulatory networks and pathways in human colorectal carcinogenesis and development of metastasis. AB - BACKGROUND: Qualitative alterations or abnormal expression of microRNAs (miRNAs) in colon cancer have mainly been demonstrated in primary tumors. Poorly overlapping sets of oncomiRs, tumor suppressor miRNAs and metastamiRs have been linked with distinct stages in the progression of colorectal cancer. To identify changes in both miRNA and gene expression levels among normal colon mucosa, primary tumor and liver metastasis samples, and to classify miRNAs into functional networks, in this work miRNA and gene expression profiles in 158 samples from 46 patients were analysed. RESULTS: Most changes in miRNA and gene expression levels had already manifested in the primary tumors while these levels were almost stably maintained in the subsequent primary tumor-to-metastasis transition. In addition, comparing normal tissue, tumor and metastasis, we did not observe general impairment or any rise in miRNA biogenesis. While only few mRNAs were found to be differentially expressed between primary colorectal carcinoma and liver metastases, miRNA expression profiles can classify primary tumors and metastases well, including differential expression of miR-10b, miR-210 and miR-708. Of 82 miRNAs that were modulated during tumor progression, 22 were involved in EMT. qRT-PCR confirmed the down-regulation of miR-150 and miR-10b in both primary tumor and metastasis compared to normal mucosa and of miR-146a in metastases compared to primary tumor. The upregulation of miR-201 in metastasis compared both with normal and primary tumour was also confirmed. A preliminary survival analysis considering differentially expressed miRNAs suggested a possible link between miR-10b expression in metastasis and patient survival. By integrating miRNA and target gene expression data, we identified a combination of interconnected miRNAs, which are organized into sub-networks, including several regulatory relationships with differentially expressed genes. Key regulatory interactions were validated experimentally. Specific mixed circuits involving miRNAs and transcription factors were identified and deserve further investigation. The suppressor activity of miR-182 on ENTPD5 gene was identified for the first time and confirmed in an independent set of samples. CONCLUSIONS: Using a large dataset of CRC miRNA and gene expression profiles, we describe the interplay of miRNA groups in regulating gene expression, which in turn affects modulated pathways that are important for tumor development. PMID- 23987129 TI - Nanoparticle-stabilized liposomes for pH-responsive gastric drug delivery. AB - We report a novel pH-responsive gold nanoparticle-stabilized liposome system for gastric antimicrobial delivery. By adsorbing small chitosan-modified gold nanoparticles (diameter ~10 nm) onto the outer surface of negatively charged phospholipid liposomes (diameter ~75 nm), we show that at gastric pH the liposomes have excellent stability with limited fusion ability and negligible cargo releases. However, when the stabilized liposomes are present in an environment with neutral pH, the gold stabilizers detach from the liposomes, resulting in free liposomes that can actively fuse with bacterial membranes. Using Helicobacter pylori as a model bacterium and doxycycline as a model antibiotic, we demonstrate such pH-responsive fusion activity and drug release profile of the nanoparticle-stabilized liposomes. Particularly, at neutral pH the gold nanoparticles detach, and thus the doxycycline-loaded liposomes rapidly fuse with bacteria and cause superior bactericidal efficacy as compared to the free doxycycline counterpart. Our results suggest that the reported liposome system holds a substantial potential for gastric drug delivery; it remains inactive (stable) in the stomach lumen but actively interacts with bacteria once it reaches the mucus layer of the stomach where the bacteria may reside. PMID- 23987130 TI - A novel method for the quantification of adeno-associated virus vectors for RNA interference applications using quantitative polymerase chain reaction and purified genomic adeno-associated virus DNA as a standard. AB - Recombinant adeno-associated virus (rAAV) vectors are promising tools in gene therapy, but accurate quantification of the vector dose remains a critical issue for their successful application. We therefore aimed at the precise determination of the titer of self-complementary AAV (scAAV) vectors to improve the reliability of RNA interference (RNAi)-mediated knockdown approaches. Vector titers were initially determined by quantitative polymerase chain reaction (qPCR) using four primer sets targeting different regions within the AAV vector genome (VG) and either coiled or linearized plasmid standards. Despite very low variability between replicates in each assay, these quantification experiments revealed up to 20-fold variation in vector titers. Therefore, we developed a novel approach for the reproducible determination of titers of scAAV vectors based on the use of purified genomic vector DNA as a standard (scAAVStd). Consistent results were obtained in qPCR assays using the four primer sets mentioned above. RNAi-mediated silencing of human cyclophilin B (hCycB) by short hairpin RNA-expressing scAAV vectors was investigated in HeLa cells using two independent vector preparations. We found that the required vector titers for efficient knockdown differed by a factor of 3.5 between both preparations. Hence, we also investigated the number of internalized scAAV vectors, termed transduction units (TUs). TUs were determined by qPCR applying the scAAVStd. Very similar values for 80% hCycB knockdown were obtained for the two AAV vector preparations. Thus, only the determination of TUs, rather than vector concentration, allows for reproducible results in functional analyses using AAV vectors. PMID- 23987131 TI - A novel drug "copper acetylacetonate" loaded in folic acid-tagged chitosan nanoparticle for efficient cancer cell targeting. AB - Several copper compounds have proven anti-cancer activity. Similarly, curcumin a derivative of 1,3 diketone, which is not plenty in nature, has comparable anti cancer activity. In this work, we have explored the synergistic anti-cancer activity of copper ion and acetylacetone complex containing 1,3 diketone group. The cytotoxicity of the copper acetylacetonate (CuAA) complex was evaluated on various cancer cells and LD50 doses were determined. To investigate the mechanism, various biochemical assays were performed and reactive oxygen species as well as the glutathione level in the cell were found to be increased after the treatment with the above-mentioned complex. Further this reagent induced apoptosis and reduced mitochondrial membrane potential of the cells. Because of the poor solubility and reasonable cytotoxicity of CuAA, polymer nanoparticles (NPs) of chitosan derivatives were used for delivery in cancer cells. For the targeted delivery, folic acid-tagged hydrophobic-modified chitosan NPs were developed and the CuAA was encapsulated. Finally, these drug-encapsulated NPs were successfully delivered to folate receptor over-expressed cancer cells. Thus using nanotechnology, we developed an anti-cancer agent suitable for targeted delivery. PMID- 23987133 TI - Focus on the larynx. PMID- 23987132 TI - Gap junction communication and the propagation of bystander effects induced by microbeam irradiation in human fibroblast cultures: the impact of radiation quality. AB - Understanding the mechanisms underlying the bystander effects of low doses/low fluences of low- or high-linear energy transfer (LET) radiation is relevant to radiotherapy and radiation protection. Here, we investigated the role of gap junction intercellular communication (GJIC) in the propagation of stressful effects in confluent normal human fibroblast cultures wherein only 0.036-0.144% of cells in the population were traversed by primary radiation tracks. Confluent cells were exposed to graded doses from monochromatic 5.35 keV X ray (LET ~6 keV/MUm), 18.3 MeV/u carbon ion (LET ~103 keV/MUm), 13 MeV/u neon ion (LET ~380 keV/MUm) or 11.5 MeV/u argon ion (LET ~1,260 keV/MUm) microbeams in the presence or absence of 18-alpha-glycyrrhetinic acid (AGA), an inhibitor of GJIC. After 4 h incubation at 37 degrees C, the cells were subcultured and assayed for micronucleus (MN) formation. Micronuclei were induced in a greater fraction of cells than expected based on the fraction of cells targeted by primary radiation, and the effect occurred in a dose-dependent manner with any of the radiation sources. Interestingly, MN formation for the heavy-ion microbeam irradiation in the absence of AGA was higher than in its presence at high mean absorbed doses. In contrast, there were no significant differences in cell cultures exposed to X ray microbeam irradiation in presence or absence of AGA. This showed that the inhibition of GJIC depressed the enhancement of MN formation in bystander cells from cultures exposed to high-LET radiation but not low-LET radiation. Bystander cells recipient of growth medium harvested from 5.35 keV X-irradiated cultures experienced stress manifested in the form of excess micronucleus formation. Together, the results support the involvement of both junctional communication and secreted factor(s) in the propagation of radiation-induced stress to bystander cells. They highlight the important role of radiation quality and dose in the observed effects. PMID- 23987134 TI - Improved biocatalysts from a synthetic circular permutation library of the flavin dependent oxidoreductase old yellow enzyme. AB - Members of the old yellow enzyme (OYE) family are widely used, effective biocatalysts for the stereoselective trans-hydrogenation of activated alkenes. To further expand their substrate scope and improve catalytic performance, we have applied a protein engineering strategy called circular permutation (CP) to enhance the function of OYE1 from Saccharomyces pastorianus. CP can influence a biocatalyst's function by altering protein backbone flexibility and active site accessibility, both critical performance features because the catalytic cycle for OYE1 is thought to involve rate-limiting conformational changes. To explore the impact of CP throughout the OYE1 protein sequence, we implemented a highly efficient approach for cell-free cpOYE library preparation by combining whole gene synthesis with in vitro transcription/translation. The versatility of such an ex vivo system was further demonstrated by the rapid and reliable functional evaluation of library members under variable environmental conditions with three reference substrates ketoisophorone, cinnamaldehyde, and (S)-carvone. Library analysis identified over 70 functional OYE1 variants with several biocatalysts exhibiting over an order of magnitude improved catalytic activity. Although catalytic gains of individual cpOYE library members vary by substrate, the locations of new protein termini in functional variants for all tested substates fall within the same four distinct loop/lid regions near the active site. Our findings demonstrate the importance of these structural elements in enzyme function and support the hypothesis of conformational flexibility as a limiting factor for catalysis in wild type OYE. PMID- 23987135 TI - Rich crystal chemistry and magnetism of "114" stoichiometric LnBaFe4O7.0 ferrites. AB - Stoichiometric LnBaFe4O7.0 oxides with Ln = Dy to Lu have been synthesized and protected in order to prevent oxidation at room temperature. The structural study of these compounds, using laboratory and synchrotron X-ray as well as neutron powder diffraction, shows the extraordinary flexibility of the tetrahedral [Fe4] sublattice of these compounds, which exhibit various distortions. At room temperature they all are tetragonal (I4), and at higher temperature (T > 580 K) they exhibit a cubic symmetry (F43m). Moreover, the low-temperature structures of these oxides are dependent on the nature of the Ln(3+) cation. At 110 K, compounds with Ln = Dy and Ho adopt the same monoclinic (P12(1)1) structure as YBaFe4O7.0, whereas YbBaFe4O7.0 possesses a new centered monoclinic cell (I121), and members with Ln = Er and Lu keep the tetragonal (I4) symmetry. Neutron diffraction patterns evidence long-range magnetic ordering only for the most distorted structures (Ln = Dy and Ho), showing that the geometric frustration generated by the tetrahedral [Fe4]infinity sublattice can be lifted only with the most severe distortions. The other oxides (Ln = Er, Yb, and Lu) with weakly distorted [Fe4]infinity sublattices do not exhibit magnetic ordering down to 4 K, demonstrating the importance of magnetic frustration. The behavior of these "114" iron oxides is compared to the cobalt family, showing in both cases a striking underbonding of barium. PMID- 23987136 TI - Fed-batch production of MCL-PHA with elevated 3-hydroxynonanoate content. AB - With no inhibition of beta-oxidation, Pseudomonas putida KT2440 produces medium chain-length poly(3-hydroxyalkanoate) (MCL-PHA) with approximately 65 mol% 3 hydroxynonanoate (HN) from nonanoic acid. Production of PHA with higher HN content and an adjustable monomeric composition was obtained using acrylic acid, a fatty acid beta-oxidation inhibitor, together with nonanoic acid and glucose as co-substrates in fed-batch fermentations. Different monomeric compositions were obtained by varying the feeding conditions to impose different specific growth rates and inhibitor feed concentrations. At a nonanoic acid: glucose: acrylic acid feed mass ratio of 1.25: 1: 0.05 and a specific growth rate of 0.15 h-1, 71.4 g L-1 biomass was produced containing 75.5% PHA with 89 mol% HN at a cumulative PHA productivity of 1.8 g L-1 h-1. PMID- 23987137 TI - E-health: potential benefits and challenges in providing and accessing sexual health services. AB - BACKGROUND: E-health has become a burgeoning field in which health professionals and health consumers create and seek information. E-health refers to internet based health care and information delivery and seeks to improve health service locally, regionally and worldwide. E-sexual health presents new opportunities to provide online sexual health services irrespective of gender, age, sexual orientation and location. DISCUSSION: The paper used the dimensions of the RE-AIM model (reach, efficacy, adoption, implementation and maintenance) as a guiding principle to discuss potentials of E-health in providing and accessing sexual health services. There are important issues in relation to utilising and providing online sexual health services. For healthcare providers, e-health can act as an opportunity to enhance their clients' sexual health care by facilitating communication with full privacy and confidentiality, reducing administrative costs and improving efficiency and flexibility as well as market sexual health services and products. Sexual health is one of the common health topics which both younger and older people explore on the internet and they increasingly prefer sexual health education to be interactive, non-discriminate and anonymous. This commentary presents and discusses the benefits of e-sexual health and provides recommendations towards addressing some of the emerging challenges. FUTURE DIRECTIONS: The provision of sexual health services can be enhanced through E-health technology. Doing this can empower consumers to engage with information technology to enhance their sexual health knowledge and quality of life and address some of the stigma associated with diversity in sexualities and sexual health experiences. In addition, e-sexual health may better support and enhance the relationship between consumers and their health care providers across different locations. However, a systematic and focused approach to research and the application of findings in policy and practice is required to ensure that E-health benefits all population groups and the information is current and clinically valid and effective, including preventative approaches for various client groups with diverse needs. PMID- 23987138 TI - Charge trapping states at the SiO2-oligothiophene monolayer interface in field effect transistors studied by Kelvin probe force microscopy. AB - Using Kelvin probe force microscopy (KPFM) we studied the local charge trapping states at the SiO2-oligothiophene interface in a field effect transistor (FET), where SiO2 is the gate dielectric. KPFM reveals surface potential inhomogeneities within the oligothiophene monolayer, which correlate with its structure. A large peak of trap states with energies in the oligothiophene's band gap due to hydroxyl groups is present at the oxide surface. We show that these states are successfully eliminated by preadsorption of a layer of (3 aminopropyl)triethoxysilane (APTES). Time-resolved surface potential transient measurements further show that the charge carrier injection in the nonpassivated FET contains two exponential transients, due to the charge trapping on the oxide surface and in the bulk oxide, while the APTES-passivated FET has only a single exponential transient due to the bulk oxide. The results demonstrate that APTES is a good SiO2 surface passivation layer to reduce trap states while maintaining a hydrophilic surface, pointing out the importance of dielectric surface passivation to bridge the gap between soft materials and electronic devices. PMID- 23987140 TI - Cyclohexanones by Rh-mediated intramolecular C-H insertion. AB - Some long chain alpha-aryl alpha-diazo ketones under Rh catalysis cyclize efficiently to the corresponding cyclohexanones. This is in marked contrast to the cyclizations of alpha-diazo beta-ketoesters, which consistently deliver cyclopentanone products. PMID- 23987139 TI - Generation and characterization of feline arterial and venous endothelial cell lines for the study of the vascular endothelium. AB - BACKGROUND: The in vitro culture of endothelial cells (ECs) is an indispensable tool for studying the role of the endothelium in physical and pathological conditions. Primary ECs, however, have a restricted proliferative lifespan which hampers their use in long-term studies. The need for standardized experimental conditions to obtain relevant and reproducible results has increased the demand for well-characterized, continuous EC lines that retain the phenotypic and functional characteristics of their non-transformed counterparts. RESULTS: Primary feline ECs from aorta and vena cava were successfully immortalized through the successive introduction of simian virus 40 large T (SV40LT) antigen and the catalytic subunit of human telomerase (hTERT). In contrast to the parental ECs, the transformed cells were able to proliferate continuously in culture. Established cell lines exhibited several inherent endothelial properties, including typical cobblestone morphology, binding of endothelial cell specific lectins and internalization of acetylated low-density lipoprotein. In addition, the immortalization did not affect the functional phenotype as demonstrated by their capacity to rapidly form cord-like structures on matrigel and to express cell adhesion molecules following cytokine stimulation. CONCLUSION: The ability to immortalize feline ECs, and the fact that these cells maintain the EC phenotype will enable a greater understanding of fundamental mechanisms of EC biology and endothelial-related diseases. Furthermore, the use of cell lines is an effective implementation of the 3-R principles formulated by Russel and Burch. PMID- 23987141 TI - Physiological change under OsHV-1 contamination in Pacific oyster Crassostrea gigas through massive mortality events on fields. AB - BACKGROUND: Massive mortalities have been observed in France since 2008 on spat and juvenile Pacific oysters, Crassostrea gigas. A herpes virus called OsHV-1, easily detectable by PCR, has been implicated in the mortalities as demonstrated by the results of numerous field studies linking mortality with OsHV-1 prevalence. Moreover, experimental infections using viral particles have documented the pathogenicity of OsHV-1 but the physiological responses of host to pathogen are not well known. RESULTS: The aim of this study was to understand mechanisms brought into play against the virus during infection in the field. A microarray assay has been developed for a major part of the oyster genome and used for studying the host transcriptome across mortality on field. Spat with and without detectable OsHV-1 infection presenting or not mortality respectively were compared by microarray during mortality episodes. In this study, a number of genes are regulated in the response to pathogen infection on field and seems to argue to an implication of the virus in the observed mortality. The result allowed establishment of a hypothetic scheme of the host cell's infection by, and response to, the pathogen. CONCLUSIONS: This response shows a "sensu stricto" innate immunity through genic regulation of the virus OsHV-1 life cycle, but also others biological processes resulting to complex interactions between host and pathogens in general. PMID- 23987143 TI - Interaction of dipalmitoyl phosphatidylcholine monolayers with a particle-laden subphase. AB - Recent interest in using submicrometer particles for industrial and therapeutic purposes has led to concerns about their interactions with biological membranes. The mechanisms of particle-membrane interactions are not well understood resulting in contradictory reports on the effects of particles on membrane interfacial properties. In this study, the interactions between negatively charged polystyrene particles (200 nm) and monolayers of dipalmitoyl phosphatidylcholine (DPPC) were investigated. Surface pressure, surface potential, and surfactant microstructure studies were conducted to monitor the interfacial properties of DPPC monolayers spread on a subphase in which particles were dispersed. At a concentration of 0.1 g/L, particles caused a partial collapse of the monolayer. DPPC monolayers spread on a particle-laden subphase also exhibited higher surface potential and increased ratio of ordered domains supporting the presence of a more compact monolayer. These results suggest that particles penetrated the air-water interface thereby altering monolayer packing at the interface. These findings are contrary to our previous work where particles injected into the subphase beneath a DPPC monolayer did not penetrate the interface confirming that the sequence of particle and monolayer addition can alter particle-monolayer interactions. These studies may partially explain the varying results reported in previous studies. PMID- 23987142 TI - Visualization of multimodal polymer-shelled contrast agents using ultrasound contrast sequences: an experimental study in a tissue mimicking flow phantom. AB - BACKGROUND: A multimodal polymer-shelled contrast agent (CA) with target specific potential was recently developed and tested for its acoustic properties in a single element transducer setup. Since the developed polymeric CA has different chemical composition than the commercially available CAs, there is an interest to study its acoustic response when using clinical ultrasound systems. The aim of this study was therefore to investigate the acoustic response by studying the visualization capability and shadowing effect of three polymer-shelled CAs when using optimized sequences for contrast imaging. METHODS: The acoustic response of three types of the multimodal CA was evaluated in a tissue mimicking flow phantom setup by measuring contrast to tissue ratio (CTR) and acoustic shadowing using five image sequences optimized for contrast imaging. The measurements were performed over a mechanical index (MI) range of 0.2-1.2 at three CA concentrations (106, 105, 104 microbubbles/ml). RESULTS: The CTR-values were found to vary with the applied contrast sequence, MI and CA. The highest CTR values were obtained when a contrast sequence optimized for higher MI imaging was used. At a CA concentration of 106 microbubbles/ml, acoustic shadowing was observed for all contrast sequences and CAs. CONCLUSIONS: The CAs showed the potential to enhance ultrasound images generated by available contrast sequences. A CA concentration of 106 MBs/ml implies a non-linear relation between MB concentration and image intensity. PMID- 23987144 TI - Immunoglobulin G4-related retroperitoneal fibrosis: a new name for an old disease. PMID- 23987145 TI - Stone compositions in Turkey: an analysis according to gender and region. AB - OBJECTIVE: To evaluate the compositions of the kidney stones obtained from different regions of Turkey and to present the gender and regional differences. METHODS: The study included 6453 kidney stones obtained from patients from different parts of Turkey. All of the stones were obtained using ureterorenoscopy, percutaneous stone surgery, laparoscopic or open stone surgery, or extracorporeal shock wave lithotripsy. X-ray diffraction crystallography method was used for analysis. RESULTS: At the end of the analysis, 11 different stone types including calcium oxalate (Ca-ox) monohydrate (whewellite, COM), Ca ox dihydrate (weddellite, COD), uric acid, cystine, struvite, biurea, xanthine brushite, quartz, whitlockite, and dahlite were determined either in pure or mixed conditions. Of the stones, 80.4% were Ca-ox (55.7% COM, 5.9% COD, 18.8% COM + COD), 4.8% uric acid, 3.1% cystine, and 3.3% were phosphate stones (dahlite, brushite, struvite, whitlockite). The remaining 8.4% of the stones were in mixed form with different combinations. Of the patients, 4411 were men (68.3%) and 2042 were women (31.7%). CONCLUSION: Ca-ox was the most frequently encountered stone type in our country as it is worldwide. The distribution of the other stone types is different than the other countries. The information about the structure of the stone has significant contribution to the understanding of the stone formation etiology, programming of the treatment process, and prevention of the recurrences. The study is significant in presenting the stone profile of Turkey. PMID- 23987147 TI - Editorial comment. PMID- 23987149 TI - Editorial comment. PMID- 23987148 TI - Stone characteristics on noncontrast computed tomography: establishing definitive patterns to discriminate calcium and uric acid compositions. AB - OBJECTIVE: To evaluate if different stone compositions can be distinguished by variations in Hounsfield unit (HU) patterns from stone core to periphery. MATERIALS AND METHODS: We retrospectively reviewed our stone registry searching for pure uric acid (UA) and calcium oxalate (CaOx) stones. Inclusion criteria comprised: pure calculi; noncontrast computed tomography before stone analysis; and stone size >=4 mm. A single urologist reviewed all images (abdominal/bone windows). Absolute HU attenuation was measured in the center (core) and edges (periphery) of each stone. HU density (HU/size) and stone volume were calculated. Categorical variables were compared with Chi-square/Fisher exact test; continuous with analysis of variance/Student t test. Spearman's test was used correlate HU values and stone dimensions. A P <.05 was considered significant. RESULTS: Included were 47 UA and 36 CaOx stones. CaOx cohort had higher HU values for all parameters (P <.001). HU variation (core-periphery) was more homogeneous in the UA group (-25%) than in the CaOx group (-52%). Stone dimensions had a significant positive correlation with HU values in CaOx cohort. In the UA group, stone volume and periphery HU had significant positive correlation. On bone window, CaOx stones had a heterogeneous pattern with a higher attenuation core with decreasing attenuation toward the periphery; UA calculi had a more homogeneous constant frosted white cloudy appearance. CONCLUSION: Stone size does not affect HU for UA stone, but has a positive correlation with CaOx stone. UA stones can be differentiated from CaOx by evaluating variation in HU from core to periphery and by subjective evaluation of homogeneity in bone windows. PMID- 23987150 TI - Results of a national population-based study of outcomes of surgery for renal tumors associated with inferior vena cava thrombus. AB - OBJECTIVE: To determine whether surgeon or hospital volume effects in-hospital mortality or complications of radical nephrectomy with concomitant removal of inferior vena cava (IVC) thrombus, we examine a national population-based cohort. Radical nephrectomy with removal of IVC thrombus is a complex urologic operation, which, similar to other major surgical procedures, may have an association between provider volume and outcomes. METHODS: Canadian Institute for Health Information administrative codes were used to identify nephrectomies associated with IVC manipulation in Canada from 1998 to 2007. Canadian Institute for Health Information databases yielded information on in-hospital mortality and complications for the hospital admission at surgery. Multivariate regression analysis was performed to assess the effect of surgeon and hospital volume on in hospital mortality and complications, adjusting for age, sex, comorbidity, year of surgery, and region. RESULTS: During the study period, 816 radical nephrectomies with associated IVC thrombectomy were performed on 521 men and 295 women. The in-hospital mortality rate was 7%. Notably, 75% of deaths occurred in the first 2 cases of surgeon experience. Median length of stay was 10 days. Complications were noted in 633 patients (78%). Fifty-eight patients with concomitant cardiac bypass had increased in-hospital mortality and complications. Age, comorbidity, and cardiac bypass were the strongest predictors of in-hospital mortality. Increasing surgeon volume, but not hospital volume, was associated with lower in-hospital mortality on multivariate regression analysis; however, this was not statistically significant. CONCLUSION: Radical nephrectomy with associated IVC thrombectomy has significant complications and mortality. Surgeon but not hospital volume may affect outcomes. PMID- 23987151 TI - Editorial comment. PMID- 23987154 TI - Editorial comment. PMID- 23987153 TI - Effect of visceral obesity on minimally invasive partial nephrectomy. AB - OBJECTIVE: To assess the relationship between visceral obesity and perioperative parameters in patients undergoing laparoscopic or robotic-assisted partial nephrectomy. METHODS: We retrospectively reviewed the medical records of 118 patients who underwent minimally invasive partial nephrectomy. On preoperative imaging, perinephric, visceral, and subcutaneous fat were measured. Higher estimated blood loss, complications, and warm ischemia time were used as surrogates of increased operation difficulty. We examined the association between the 3 groups of patients (ie low, medium, and high fat) with demographic and clinical characteristics. Multivariate analysis was performed to determine whether various measurements of obesity adversely affected surgical outcomes and complexity. RESULTS: No statistically significant differences were found between perioperative parameters and either perinephric, visceral, or subcutaneous fat. There was no association between changes in renal function and different fat groups. Multivariate analysis for estimated blood loss, complication rates, and warm ischemia time adjusted for age, race, sex, nephrometry score, Charlson comorbidities score, and other fat types, failed to demonstrate any significant differences. Increasing perinephric fat content was associated with higher visceral (P <.0005), but not subcutaneous fat (P = .55). Hypertension was associated with perinephric (P = .02) and visceral (P = .04), but not subcutaneous obesity (P = .08). Neither Charlson comorbidity nor American Society of Anesthesiologists scores showed any significant association with different fat types. CONCLUSION: Individual patterns of obesity, namely subcutaneous, visceral, and perinephric, do not increase surgical complexity for minimally invasive partial nephrectomy by experienced surgeons. Furthermore, this operation can be performed safely with comparable complications and outcomes in moderately obese patients without compromising renal function. PMID- 23987156 TI - Dapoxetine treatment in patients with lifelong premature ejaculation: the reasons of a "Waterloo". AB - OBJECTIVE: To assess both the acceptance and the discontinuation rates from dapoxetine, the first oral pharmacological agent indicated for the treatment of premature ejaculation (PE). METHODS: One hundred twenty consecutive potent patients (mean age 40.3 years; range 18-63 years) seeking medical treatment for lifelong PE were enrolled in a prospective phase II study. Moreover, they were assessed regarding detailed medical and sexual history, intravaginal ejaculatory latency time (IELT), International Index of Erectile Function (IIEF), and complete physical examination. The patients received a dapoxetine prescription (30 mg on demand) and unresponded cases received increased dose (60 mg after 3 months). The patients were evaluated at 1, 3, 6, and 12 months, and requested to complete a multiple-choice global assessment questionnaire regarding specific reasons for eventual therapy discontinuation. RESULTS: Twenty-four of the patients (20%) decided not to start dapoxetine. Fear of using a "drug" was the most frequently reported reason for treatment nonacceptance (50%) and the cost of treatment was the reason for 25% of the patients. Ninety-six patients (80%) started the therapy. Twenty-six percent dropped out after 1 month, 42.7% dropped out after 3 months, 18.7% dropped out at 6 months, 2% dropped out at 12 months, and 10.4% are continuing the therapy after 1 year. The main reasons were effect below expectations 24.4%, costs 22.1%, side effects 19.8%, loss of interest in sex 19.8%, and no efficacy 13.9%. CONCLUSION: Twenty percent of lifelong PE patients seeking medical treatment for early ejaculation freely decided not to start treatment with dapoxetine, and roughly 90% of the patients who started therapy discontinued after 1 year. PMID- 23987157 TI - Second pathways in the pathophysiology of ischemic priapism and treatment alternatives. AB - OBJECTIVE: To evaluate the early therapeutic alternatives such as bosentan, an endothelin receptor blocker, theophylline, an adenosin receptor blocker, and a nonselective phosphodiesterase enzyme inhibitor, zinc protoporphyrin (ZnPP), a heme oxygenase 1 inhibitor, for the therapy of ischemic priapism in the rat models. METHODS: Twenty-four Sprague-Dawley rats were randomly divided into 4 equal groups: control group, ZnPP group, bosentan group, and theophylline group. Erection was provided by vacuum constriction method and maintained for 4 hours for achieving the priapism in all groups. The rats in the control group were administered 1 mL/kg saline intraperitoneally (ip). The rats in group 2 were administered 25 mg/kg ZnPP ip. The rats in group 3 were administered 0.25 mg/kg bosentan ip. The rats in group 4 were administered 100 mg/kg theophylline ip. Six rats from each group were decapitated after 6 hours of drug administration. Then endothelin 1, adenosine deaminase, heme oxygenase 1 enzymatic activity, and apoptosis index in the cavernous tissues were estimated. RESULTS: Cavernous tissue endothelin 1, adenosine deaminase, heme oxygenase 1 enzymatic activity levels, and apoptosis index were significantly decreased in bosentan, theophylline, and ZnPP-treated rats compared with the controls. CONCLUSION: Inhibition of priapism induced apoptosis with bosentan, theophylline, and ZnPP seems promising on preserving erectile function. PMID- 23987159 TI - Editorial comment. PMID- 23987158 TI - Anatomic extent of pelvic lymph node dissection: impact on long-term cancer specific outcomes in men with positive lymph nodes at time of radical prostatectomy. AB - OBJECTIVE: To evaluate the impact of an extended pelvic lymph node (LN) dissection (EPLND) on the oncologic outcomes of men with LN-positive prostate cancer. METHODS: Patients were identified who underwent an open radical prostatectomy by one of two surgeons at the Johns Hopkins Hospital between 1992 and 2003. The first surgeon routinely performed a limited pelvic LN dissection (LPLND), whereas the second performed an EPLND. Men with positive LNs from each cohort were compared for differences in oncologic outcomes. RESULTS: Positive LNs were found in 94 men (2.2%), 21 (22.3%) with an LPLND and 73 (77.7%) with an EPLND. On average, LPLND and EPLND yielded 11.4 and 14.6 nodes, respectively (P = .022). The two groups were similar in terms of the number of positive LNs (1.4 vs 1.8, P = .223) and the proportion of patients with <15% positive nodes (57.1% vs 69.9%, P = .300). At a median follow-up of 10.5 years, patients who underwent an EPLND had superior oncologic outcomes compared with the LPLND group: 5-year biochemical recurrence-free survival of 30.1% vs 7.1% (P = .018), 10-year metastasis-free survival of 62.2% vs 22.2% (P = .035), and 10-year cancer specific survival of 83.6% vs 52.6% (P = .199). This analysis demonstrated an augmented improvement in biochemical recurrence-free survival in men with <15% positive nodes. CONCLUSION: In addition to affording valuable staging information, an EPLND may confer a therapeutic benefit to patients found to have positive LNs at the time of radical prostatectomy. PMID- 23987161 TI - Beneficial influence of carvedilol on urologic indices in patients with hypertension and benign prostatic hyperplasia: results of a randomized, crossover study. AB - OBJECTIVE: To assess the influence of carvedilol, an alpha- and beta-blocker, on lower urinary tract symptoms (LUTS) and urine flow in hypertensive patients with benign prostatic hyperplasia (BPH). METHODS: Fifty men were included in this double blind crossover study with placebo. After initial screening, participants were randomized to the carvedilol or the enalapril group, with cross over after 3 months. Doses of both drugs were uptitrated or additional therapy was introduced to ensure normal control of blood pressure (BP). Urologic assessment included uroflowmetry (average [Qavg] and maximum urinary flow rate [Qmax]), postvoid residual urine volume (PVR), International Prostate Symptom Score (IPSS), and prostate-specific antigen (PSA). RESULTS: After carvedilol or enalapril administration, BP values were significantly reduced, whereas heart rate decreased only in the carvedilol group. Basal urologic values for carvedilol and enalapril were similar: Qavg, 7.8 +/- 0.9 and 8.1 +/- 0.6 mL/s; Qmax, 13.2 +/- 1.5 and 13.7 +/- 0.9 mL/s; PVR, 86.1 +/- 13.2 and 85.6 +/- 11.7 mL; and IPSS, 13.2 +/- 0.9 and 12.3 +/- 0.8 points, respectively. After treatment with carvedilol, PVR and IPSS significantly decreased (48.2 +/- 11.7 mL, 9.0 +/- 0.8 points, respectively; P <.001), whereas Qavg and Qmax increased (10.3 +/- 0.9 mL/s, 16.5 +/- 1.4 mL/s, respectively; P <.001). In the enalapril group, all of these values remained unchanged. CONCLUSION: Carvedilol, compared with enalapril, has a positive influence on LUTS related to BPH in patients with hypertension. Thus, therapy with carvedilol may be considered in hypertensive patients with BPH. Further studies on the urologic benefit from long-term use of the drug are warranted. PMID- 23987162 TI - Editorial comment. PMID- 23987164 TI - A retrospective review of office-based 532-nm GreenLight laser prostatectomy in men with symptomatic benign prostatic hyperplasia. AB - OBJECTIVE: To evaluate the feasibility, safety, and outcomes of men with symptomatic benign prostatic hyperplasia undergoing 532-nm GreenLight laser prostatectomy in the office-based setting. MATERIALS AND METHODS: From September 2007 to October 2011, 47 patients underwent office-based 532-nm GreenLight laser prostatectomy by a single surgeon. Patients were enrolled prospectively and preoperative, intraoperative, and postoperative parameters were then reviewed retrospectively. Statistical analysis was performed with Wilcoxon rank sum test with a P value <=.05 being considered statistically significant. RESULTS: The mean patient age was 66 (range, 49-89); 91% of men were on an alpha-blocker preoperatively; mean (standard deviation; SD) prostate volume by transrectal ultrasound was 35.8 mL (14.5); mean (SD) American Society of Anesthesiologists score was 2.33 (0.77); mean (SD) operative time was 36.73 minutes (18); mean (SD) lasing time was 19.1 minutes (8.31); mean (SD) total laser kiloJoules used was 85,387 kJ (38,885); and mean (SD) follow-up time was 8.48 months (8.24). The 1 year decrease in mean (SD) American Urologic Association Symptom Score and quality of life were 17.7 (8.3)-7 (7.3) and 4.1 (1.4)-2.27 (2) respectively. The maximal urinary flow increased from 8.1 (3.8) to 10.7 (6). Patients' postvoid residual improved from 130 mL (147) to 27 mL (55) over a 1-year period. (P <.01 for all). There were no reoperations for refractory lower urinary tract symptoms or hospital admissions. CONCLUSION: For men with small but symptomatic benign prostatic enlargement, office-based GreenLight laser prostatectomy is safe and feasible. PMID- 23987165 TI - Editorial comment. PMID- 23987167 TI - Editorial comment. PMID- 23987168 TI - Intravesical hemostatic gelatin matrix instillation in the management of intractable hematuria. AB - INTRODUCTION: The objective of the present study was to evaluate the safety and feasibility of a novel and minimally invasive approach, namely, intravesical instillation of a gelatin matrix hemostatic sealant (GMHS) in the management of intractable hematuria. TECHNICAL CONSIDERATIONS: Six consecutive patients with intractable hematuria not responding to standard treatment underwent intravesical instillation of a hemostatic bovine-derived gelatin matrix mixed with a human derived thrombin component. The technical aspects of this approach are described in detail. The mean age of the patients was 70 +/- 4 years (median 71, range 50 79). All patients had pelvic malignancy: 5 had prostate cancer, and 1, cervical cancer. Mean duration of hematuria before intervention was 6 +/- 1 days (median 6, range 2-9). Mean preoperative hemoglobin level was 9.2 +/- 0.5 g/dL (median 9.0, range 8.0-10.2). Complete control of bleeding was achieved in 5 patients (83%) and all 6 patients (100%) on day 1 and 7, respectively. At a mean follow-up of 10 +/- 6 months (median 13, range 1-15), permanent control of bleeding was achieved in 5 of 6 patients (83%). A second GMHS instillation was performed in 1 patient (17%) and it was successful. During the follow-up, there were no complications related to GMHS instillation. Two patients died because of their underlying malignant disease. CONCLUSION: Intravesical GMHS instillation appears to be a safe and feasible option in the management of intractable hematuria in the short-term. PMID- 23987169 TI - Novel use of indocyanine green for intraoperative, real-time localization of ureteral stenosis during robot-assisted ureteroureterostomy. AB - OBJECTIVE: To present a novel method to intraoperatively localize ureteral strictures during robot-assisted ureteroureterostomy via indocyanine green (ICG) visualization under near-infrared (NIR) light. MATERIALS AND METHODS: Seven patients underwent robot-assisted ureteroureterostomy for ureteral stricture by a single surgeon (D.D.E.). Intraoperative localization of ureteral stricture involved instilling ICG (25 mg in 10 mL distilled water) above and below the level of stenosis through a ureteral catheter or a percutaneous nephrostomy tube, or both. The fluorescent tracer was detected as a green color using the NIR modality on the da Vinci Si (Intuitive Surgical, Sunnyvale, CA). All patients consented to off-label use of ICG after full disclosure. RESULTS: Intraoperative ICG injection and visualization under NIR light assisted in the performance of a tension-free anastomosis in all patients. At the time of surgery, mean age was 55.7 +/- 12.4 years and mean body mass index was 30.3 +/- 5.8 kg/m(2). Mean operative time was 171.3 +/- 52.4 minutes, mean estimated blood loss was 175.0 +/ 146.5 mL, and mean length of ureteral excision on pathologic analysis was 1.6 +/ 0.7 cm. There were no immediate or delayed adverse effects attributable to intraureteral ICG administration. Mean hospital length of stay was 1.6 +/- 1.5 days, with no postoperative complications. Mean follow-up was 5.9 +/- 1.5 months, and all cases were clinically and radiographically successful at last follow-up. CONCLUSION: Intraureteral injection of ICG with visualization under NIR light allows for real-time delineation of the ureter. Additionally, ICG administration aids in discerning healthy ureter from diseased tissue, further assisting successful robotic ureteral repair. PMID- 23987170 TI - In vitro comparison of a novel facilitated ultrasound targeting technology vs standard technique for percutaneous renal biopsy. AB - OBJECTIVE: To improve the understanding of the epidemiology of renal cortical neoplasms through pretreatment biopsy, we evaluated a facilitated ultrasound targeting (FUT) technology. The technology allows a needle to be passed through the transducer probe and guided along a virtual dotted line on the monitor. We compared the FUT with standard percutaneous biopsy (PB) technique. MATERIALS AND METHODS: Forty-eight participants with various levels of training were recruited. Participants performed ultrasound-guided biopsies on phantom models using FUT and the standard biopsy technique in a randomized sequence. The phantom models consisted of pimento olives embedded in an opaque mold of Metamucil and Knox gelatin. Patients were given up to 10 attempts to achieve 3 complete specimens from the olives. Patients rated each biopsy technique. Results were stratified by level of experience. RESULTS: The mean time to obtain 3 complete biopsy specimens was significantly faster for FUT compared with the standard technique (140 seconds vs 246 seconds, P = .0001). The mean number of attempts needed to obtain 3 specimens was significantly less with FUT compared with the standard technique (4.3 vs 5.6 attempts, P = .0007). Patients reported that FUT was significantly easier to use compared with the standard technique (P = .0005). No significant order effect was observed. CONCLUSION: In this in vitro comparison, FUT increased the efficiency and efficacy of PB for users of all experience levels. FUT may allow urologists with limited PB experience to perform the procedure reliably and easily. Clinical evaluation of this technology is actively in progress. PMID- 23987171 TI - Re: Ben-Zvi et al.: GreenLight XPS 180W vs HPS 120W laser therapy for benign prostate hyperplasia: a prospective comparative analysis after 200 cases in a single-center study (Urology 2013;81:853-858). PMID- 23987172 TI - Reply by the authors. PMID- 23987173 TI - Re: Koraitim: predictors of erectile dysfunction post pelvic fracture urethral injuries: a multivariate analysis (Urology 2013;81:1081-1085). PMID- 23987174 TI - Reply by the authors. PMID- 23987175 TI - Re: Hsiao et al.: varicocelectomy is associated with increases in serum testosterone independent of clinical grade (Urology 2013;81:1213-1218). PMID- 23987176 TI - Re: Mistry et al.: a simple two-stage "bailout" technique for the removal of an unyielding ureteric stent (Urology 2013;81:242-244). PMID- 23987177 TI - Reply by the authors. PMID- 23987178 TI - Reply by the authors. PMID- 23987179 TI - Re: de Martino et al.: high-risk human papilloma virus infection of the foreskin in asymptomatic boys (Urology 2013;81:869-872). PMID- 23987180 TI - Urinary proteome analysis in patients with stable SFU grade 4 ureteropelvic junction obstruction differs from normal. AB - OBJECTIVE: To evaluate and analyze the urinary proteome in infants with stable grade 4 ureteropelvic junction obstruction (UPJO) and compare to age-matched normal controls. METHODS: Bladder urine specimens were obtained from 21 healthy infants with normal maternal/fetal ultrasound and 25 infants with grade 4 unilateral UPJO. All patients had >40% ipsilateral individual kidney function by renal scanning and the anteroposterior (AP) diameter of the hydronephrotic kidney ranged from 1.6-3.9 cms at presentation. Over a 5-year follow-up period, the disease progressed in 7 infants (28%), resolved in 4 (16%), and remains stable in the majority (56%). The urinary specimens were prepared using standard methods and subjected to LC/MS/MS analysis. The normalized data were annotated utilizing the Ingenuity Pathways Analysis (IPA; www.Ingenuity.com) knowledge platform. RESULTS: In the stable UPJO group, the urinary proteomes obtained in infancy differed significantly from the age-matched controls. Analysis revealed important differences in a number of biologic functions including inflammation, apoptosis, tubular injury and fibrosis, and reactive oxygen species response. CONCLUSION: The urinary proteomes from the bladder in patients with stable grade 4 UPJO (by imaging criteria) are significantly different at birth and during the first year of life and seem to indicate the presence of an ongoing active renal response to UPJO. The imminent discovery of surrogate urinary biomarkers may result in reconsideration of the watchful waiting strategy during this critical period of renal maturation and development in infancy. PMID- 23987181 TI - Multiple bilateral nonpapillary serous cystadenoma of the epididymis. AB - Epithelial cystic neoplasms of the epididymis are rare, the commonest is papillary serous cystadenoma. Recently, few cases of epididymal nonpapillary serous cystadenoma (NPSC) were reported. They have unique histomorphologic and immunohistochemical features that help distinguish them from other cystic lesions of the paratestis. All the reported cases presented as a single unilateral epididymal cyst. We report a unique example and, to our knowledge, the first case of multiple bilateral NPSC of the epididymis. Moreover, it showed a pigmented epithelium. PMID- 23987182 TI - Hydroureteronephrosis secondary to juxta-uretrovesical junction bladder diverticula. AB - Bladder diverticulum is rarely associated to hydroureteronephrosis. We present clinical images of an adult patient with a bladder diverticulum near the ureterovesical junction (UVJ) with secondary obstruction. An 84-year-old man presented with left hydroureteronephrosis and a presumed 25-mm left ureteral stone at UVJ on computed tomography. Cystoscopy revealed a stone located in a bladder diverticulum just cephalad and medial to left ureteral orifice; the patient successfully underwent endoscopic laser cystolithotripsy with resolution of his hydronephrosis. Juxta-UVJ bladder diverticula may cause obstruction of the ipsilateral upper urinary tract. PMID- 23987183 TI - Malignant ascites and small renal mass: an unusual presentation of advanced renal cell carcinoma. AB - Metastatic renal cell carcinoma (RCC) presenting with peritoneal involvement or ascites is rare and has been previously described clinically in the setting of large renal mass or other distant metastases. We report an unusual case of RCC presenting with ascites without large mass or other distant metastases. Advances in cytologic diagnosis of metastatic RCC in serous ascitic fluid is discussed, while a potential mechanism of tumor spread is presented. PMID- 23987184 TI - Temporal trends and molecular epidemiology of HIV type 1 infection in Rio de Janeiro, Brazil. AB - HIV-1 molecular epidemiology studies carried out in Rio de Janeiro, Brazil have identified the prevalence of subtypes B, F1 and BF1 recombinants. A high percentage of HIV-1 subtype B isolates in Rio de Janeiro harbor the GWG motif at the V3 tip (B'' variant) instead of the canonical GPG motif (B variant). To trace the dynamics of the HIV-1 variants over time in different exposure categories in Rio de Janeiro, the HIV-1 proviral DNA from heterosexual men (HET) and men who have sex with men (MSM) from two distinct time periods (1990-1992 and 2008-2010) were extracted, and the env-gp120 region was amplified. Neighbor-joining phylogenetic analysis was performed to determine the viral subtype, and Bayesian analysis was used to trace the HIV-1 transmission networks. A predominance of subtype B was observed in both study periods, independent of the exposure risk category. An increase of non-B subtypes was observed in the HET group, but these subtypes were maintained among the MSM group. The distribution of HIV-1 subtype B signatures in the first and second periods studied were, respectively, HET (GPG) [44.8-51.5%], (GWG) [13.8-33.3%], and (GXG) [41.4-15.2%] and MSM (GPG) [34-50%], (GWG) [55.3-30.6%], and (GXG) [10.7-19.4%]. In the first period, an association between GWG and MSM was verified while a significant reduction of this association was observed during the second period. The phylogenetic tree and the BaTS program detected the clustering of isolates only according to the B signatures but not by exposure risk category. Our findings indicate a stable prevalence of HIV-1 subtypes B and F over time in Rio de Janeiro and further suggest that the B'' subclade of subtype B was possibly introduced into the MSM group in this area of Brazil. PMID- 23987185 TI - Mesenchymal stem cell survival in the infarcted heart is enhanced by lentivirus vector-mediated heat shock protein 27 expression. AB - Mesenchymal stem cell (MSC) therapy offers the potential to promote recovery after myocardial infarction (MI). However, therapeutic efficacy may be limited by poor survival and retention of transplanted cells. A combination of gene and cell therapy has the capacity to prevent donor cell death and augment the reparative and regenerative effects of cell transfer. The present study investigates the effect of exogenous heat shock protein 27 (Hsp27) expression in MSCs in an in vitro model of ischemia and in an in vivo rat MI model and aims to determine if this could enhance the therapeutic benefit associated with cell delivery. Hsp27 overexpression by lentivirus vector modification resulted in increased MSC survival in vitro and in vivo. Furthermore, decreased apoptosis in the infarcted tissue and improved cardiac function was observed in the Hsp27 group, enhancing the therapeutic effect of MSCs. Together, these data demonstrate that ex vivo genetic modification-specifically Hsp27 overexpression-offers the possibility of enhancing the efficacy of MSC therapy in MI. PMID- 23987186 TI - Importance of establishing threshold levels for food allergens. PMID- 23987188 TI - Use of vaccines in the evaluation of presumed immunodeficiency. PMID- 23987189 TI - Management of the individual worker with occupational asthma. PMID- 23987187 TI - Lipid mediators and allergic diseases. AB - OBJECTIVE: To review the basic science and translational relevance of lipid mediators in the pathobiology of allergic diseases. DATA SOURCES: PubMed was searched for articles using the key terms lipid mediator, prostaglandin, prostanoid, leukotriene, thromboxane, asthma, and allergic inflammation. STUDY SELECTIONS: Articles were selected based on their relevance to the goals of this review. Articles with a particular focus on clinical and translational aspects of basic science discoveries were emphasized. RESULTS: Lipid mediators are bioactive molecules generated from cell membrane phospholipids. They play important roles in many disease states, particularly in inflammatory and immune responses. Lipid mediators and their receptors are potentially useful as diagnostic markers of disease and therapeutic targets. CONCLUSIONS: Several useful therapeutic agents have been developed based on a growing understanding of the lipid mediator pathways in allergic disease, notably the cysteinyl leukotriene receptor type 1 antagonists and the 5-lipoxygenase inhibitor, zileuton. Additional receptor agonists and antagonists relevant to these pathways are in development, and it is likely that future pharmacologic treatments for allergic disease will become available as our understanding of these molecules continues to evolve. PMID- 23987190 TI - Treatment of patients who present after an episode of anaphylaxis. PMID- 23987191 TI - Age dependent sex disproportion in US asthma hospitalization rates, 2000-2010. AB - BACKGROUND: Age-stratified sex differences in asthma hospitalizations rates have been reported to be most marked between the ages of 40 and 54 years in New York. It is not known whether age-dependent sex differences in asthma hospitalization rates also exist for the entire United States. OBJECTIVES: To compare sex specific hospitalization rates for asthma in adults in the United States and to describe the adjusted associations between female sex and age in the fifth to sixth decades of life. METHODS: The National Inpatient Sample databases for 2000 2010 were queried for a principal diagnosis of asthma to calculate the ratio of female to male hospitalization rates for different decades of adult life. Logistic regression modeling was used to determine whether age in the fifth to sixth decades of life had associations with female sex that remained significant after adjusting for comorbidities and demographic features. RESULTS: For all years of the study, there was a distinct peaking in female to male ratio most manifested in the fifth to sixth decades of life. This age grouping was significantly associated with female sex. Models revealed that female sex was significantly associated with this age grouping, even after adjustment for obesity, chronic obstructive pulmonary disease, race, insurance status, discharge year, and smoking. Excluding identifiable repeat admissions also did not abrogate the age grouping association. CONCLUSION: There is a striking propensity of women in their fifth to sixth decades of life to be admitted for asthma, which appears to be independent of many known comorbidities. PMID- 23987192 TI - Refractoriness to inhaled mannitol 3 hours after allergen challenge. AB - BACKGROUND: A positive response to indirect airway challenges (eg, mannitol) that cause release of mast cell mediators causes refractoriness to a repeat exposure to the same or different indirect stimulus that lasts for at least several hours. Allergen challenge causes increased response to methacholine measured at 3 hours. OBJECTIVE: To compare allergen-induced changes in airway response to methacholine and mannitol 3 hours after completion of an allergen challenge. METHODS: Ten atopic patients with asthma completed a randomized clinical trial. The provocation concentration of methacholine causing a 20% decrease in forced expiratory volume in 1 second (FEV1) was measured 24 hours before and 3 hours after a standard allergen challenge. The provocation dose of mannitol causing a 15% decrease in FEV1 was also measured 24 hours before and 3 hours after allergen challenge. The allergen challenges were separated by 7 to 14 days. RESULTS: The allergen-induced early responses, expressed as the maximum (SD) percent decrease in FEV1, were 29.7% (11.1%) and 27.8% (7.6%) on the methacholine and mannitol days, respectively. Airway response to methacholine increased significantly after allergen challenge (P = .02). By contrast, the airway response to mannitol was reduced by almost a doubling dose (P = .02) after allergen. CONCLUSION: Three hours after allergen challenge at a time when the airways are more responsive to methacholine, there is a significant refractoriness to the indirect stimulus mannitol. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01699594. PMID- 23987194 TI - Dissociation between sensitizing and colonizing fungi in patients with allergic bronchopulmonary aspergillosis. AB - BACKGROUND: Because allergic bronchopulmonary aspergillosis (ABPA) does not require the presence of Aspergillus fumigatus for diagnosis, serological and radiological findings without cultures usually confirm this condition. OBJECTIVE: To determine which fungi colonize the airways of patients with definitive ABPA. METHODS: We enrolled 11 patients (ages 57.5 +/- 17.1 years; male: female, 4:7) with ABPA diagnosed by serological and radiological criteria. Fungi colonizing the airway were identified from mucous plugs that were naturally expectorated or obtained by fiberoptic bronchoscopy. RESULTS: Aspergillus spp. (n = 8) was the most frequently isolated, followed by Schizophyllum commune (n = 4), Candida albicans (n = 2), Rhizopus oryzae (n = 1), and Penicillium spp. (n = 1). Among the Aspergillus spp., A. niger, A. terreus, and A. sydowii were more frequently isolated (total, n = 6) than A. fumigatus (n = 2). Many patients were sensitized with several fungi in addition to Aspergillus, which were dissociated with airway colonizing fungi. CONCLUSION: Multiple fungal species can colonize the airway, and dissociation between colonizing and sensitizing species frequently occurs in definitive ABPA. Considering the increased prevalence of azole-resistant Aspergillus spp., administering antifungal drugs that target A. fumigatus without identifying which fungal species colonize the airway might be problematic. PMID- 23987193 TI - Prescription fill patterns in underserved children with asthma receiving subspecialty care. AB - BACKGROUND: Children with asthma receiving specialty care have been found to have improved asthma outcomes. However, these outcomes can be adversely affected by poor adherence with controller medications. OBJECTIVE: To analyze pharmacy fill patterns as a measure of primary adherence in a group of underserved minority children receiving allergy subspecialty care. METHODS: As part of a larger 18 month nebulizer use study in underserved children (ages 2-8 years) with persistent asthma, 53 children were recruited from an urban allergy practice. Pharmacy records were compared with prescribing records for all asthma medications. RESULTS: Allergist controller prescriptions were written in 30-day quantities with refills and short-acting beta-agonists (SABAs) with no refills. Only 49.1% of inhaled corticosteroid (ICS), 49.5% of combination ICS and long acting beta-agonist, and 64.5% of leukotriene modifier (LTM) initial and refill prescriptions were ever filled during the 18-month period. A mean of 5.1 refills (range, 0-14) for SABAs were obtained during 18 months, although only 1.28 SABA prescriptions were prescribed by the allergist. Mean times between first asthma prescription and actual filling were 30 days (range, 0-177 days) for ICSs, 26.6 days (range, 0-156 days) for LTMs, and 16.8 days (range, 0-139 days) for SABAs. CONCLUSION: Underserved children with asthma receiving allergy subspecialty care suboptimally filled controller prescriptions, yet filled abundant rescue medications from other prescribers. Limiting albuterol prescriptions to one canister without additional refills may provide an opportunity to monitor fill rates of both rescue and controller medications and provide education to patients about appropriate use of medications to improve adherence. PMID- 23987195 TI - Factors associated with reported food allergy tolerance among US children. AB - BACKGROUND: Limited studies exist on predictors of food allergy tolerance. OBJECTIVE: To describe factors associated with tolerance to 9 common food allergens based on caregiver report in a nationally representative survey. METHODS: Data from children with current and outgrown food allergies were identified for analysis from a randomized, cross-sectional survey administered in US households with children from June 2009 through February 2010. Allergies were analyzed based on type of allergy, age at which allergies were outgrown, and reaction history. Adjusted models were formulated to examine the association of child and food allergy characteristics with odds of reporting an allergy as being outgrown. RESULTS: Of 40,104 children surveyed, 1,245 cases of outgrown food allergy were identified. The frequency of tolerance in children with food allergy was 26.6% at a mean age of 5.4 years. Children with milk (41.1%), egg (40.2%), or soy (35.7%) allergy had significantly higher frequencies of tolerance, whereas children with shellfish (13.0%), tree nut (14.3%), and peanut (15.6%) allergies had significantly lower frequencies (P < .05). Factors significantly associated with a report of outgrowing an allergy included a mild to moderate reaction history, being allergic to only 1 food, eczema as the sole allergy symptom, and white compared with black race (P < .05). Probability of tolerance also was significantly higher at younger ages of first reaction and decreased for first reactions occurring later in life, irrespective of allergen, severity, or presentation (P < .05). CONCLUSION: Multiple factors were associated with a report of outgrowing an allergy. Understanding factors associated with outgrowing an allergy can improve disease management and counseling. PMID- 23987196 TI - Longitudinal study of 954 patients with stinging insect anaphylaxis. AB - BACKGROUND: Stinging insect anaphylaxis (SIA) is a common cause of anaphylaxis and is potentially life-threatening. OBJECTIVES: To examine US patients with an emergency department (ED) visit or hospitalization for SIA to evaluate postdischarge follow-up care. METHODS: We identified all patients with an ED visit or hospitalization for SIA during 2002-2008 in the MarketScan Database using International Classification of Diseases, Ninth Revision, Clinical Modification codes (index date was the initial ED visit or hospitalization). Patients were required to have continuous full insurance coverage for 1 year or more before and after index. We examined patient factors during the preindex period, characteristics of the index event, and outcomes during the postindex period. Multivariable logistic regression was used to identify independent predictors of receiving preventive anaphylaxis care. RESULTS: We identified 954 patients with an ED visit or hospitalization for SIA (mean [SD] age, 46 [19] years; 41% female). A total of 85% of patients were discharged directly from the ED. For those hospitalized, the mean hospital stay was 1 day, and 50% spent time in the intensive care unit. Cardiorespiratory failure occurred in 27% of those hospitalized. During the postindex period, 69% filled 1 or more epinephrine autoinjector prescription, but only 14% had 1 or more allergist/immunologist visit. Independent factors associated with receiving preventive anaphylaxis care during the postindex period were higher household income, no ED visit (for any reason) in the preindex period, and no cardiorespiratory arrest or failure during the index event. CONCLUSION: Although two-thirds of patients filled a prescription for an epinephrine autoinjector after an ED visit or hospitalization for SIA, only 14% of patients received follow-up care by an allergist/immunologist. This missed opportunity to provide venom immunotherapy, an essentially curative therapy, unnecessarily places patients at risk for recurrent anaphylaxis. PMID- 23987197 TI - Expression of matrix metalloproteinase 2 and 9 and tissue inhibitor of metalloproteinase 1 in nonrecurrent vs recurrent nasal polyps. AB - BACKGROUND: Matrix metalloproteinases (MMPs) 2 and 9 are a group of Zn2+ dependent endopeptidases to remodel the extracellular matrix. The association of these 2 endopeptidases with the development of morphologic changes in nasal polyps was previously described. OBJECTIVE: To determine whether MMP-2, MMP-9, and tissue inhibitor of MMP-1 (TIMP-1) play a role in the recurrence of nasal polyps. METHODS: To compare MMP-2, MMP-9, and TIMP-1 expression in recurrent vs nonrecurrent polyps, nasal polyps (NPs) and recurrent nasal polyps (RNPs) were obtained from 15 NP patients with chronic rhinosinusitis (CRS) undergoing endoscopic sinus surgery (ESS) and 15 RNP patients with CRS undergoing revision ESS. Fifteen specimens of inferior turbinate mucosa from patients undergoing nasal septal surgery were used as control. Through real-time polymerase chain reaction and immunohistochemistry, MMP-2, MMP-9, and TIMP-1 expressions were measured among controls, NP patients, and RNP patients. RESULTS: Expression of MMP-9 messenger RNA in the NP patients was significantly higher than in the controls. In addition, expression of MMP-9 messenger RNA in the RNP patents was significantly increased compared with NP patients. With immunohistochemistry, a more increased expression of MMP-9 was observed in NP patients than controls. Expression of MMP-9 in RNP patients was also significantly high compared with NP patients, particularly in stroma. CONCLUSION: Expression of MMP-9 is increased in NP patients, and it is so more in the mucosa of RNP patients. Increased expression of MMP-9 is particularly found in the stoma of RNP patients, and it may contribute to the recurrence of NP. PMID- 23987198 TI - Effect of time to treatment on response to C1 esterase inhibitor concentrate for hereditary angioedema attacks. AB - BACKGROUND: C1 esterase inhibitor (C1-INH) concentrate is well established as effective therapy for hereditary angioedema (HAE). It is thought that treatment of an acute HAE attack with C1-INH as early as possible improves efficacy, but there are limited data from prospective studies supporting this recommendation. OBJECTIVE: To assess the effect of time to treatment (<6 vs >=6 hours after start of an attack) with 20 U/kg of C1-INH concentrate on efficacy. METHODS: A post hoc analysis of time to treatment after start of an attack was performed for 2 studies with C1-INH concentrate: International Multicenter Prospective Angioedema C1-INH Trial (IMPACT) 1 (randomized, placebo-controlled) and IMPACT 2 (open label, uncontrolled extension). Because of differences in study design, the data sets were analyzed separately. IMPACT 1 data were analyzed using Cox regression with hazard ratios (HRs). For IMPACT 2 data, linear regression was applied to evaluate whether earlier treatment leads to faster recovery. Descriptive statistics for treatment response were calculated for both studies. RESULTS: In IMPACT 1, treatment with C1-INH within less than 6 hours after start of an attack resulted in considerably shorter times to onset of symptom relief (HR, 3.36) and complete resolution (HR, 4.30) vs placebo. The benefit of C1-INH compared with placebo was reduced when administered after 6 or more hours (HRs, 1.18 for times to onset of symptom relief and 1.61 for complete resolution). Analysis of IMPACT 2 data indicated slower complete resolution of symptoms with later start of treatment. CONCLUSION: Early treatment with C1-INH (<6 hours) provides a better treatment response than late treatment (>=6 hours), supporting the international recommendation to treat HAE attacks as early as possible. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT00168103 and NCT00292981. PMID- 23987199 TI - Real-world effects of once vs greater daily inhaled corticosteroid dosing on medication adherence. AB - BACKGROUND: Nonadherence to inhaled corticosteroids (ICSs) for asthma maintenance therapy is common and is associated with poor asthma outcomes. Simplifying dosing regimens for some chronic disease conditions has resulted in better adherence; however, little is known regarding the effect of ICS dosing on adherence for the treatment of asthma. OBJECTIVE: To determine whether once daily dosing is associated with higher adherence to ICS therapy when compared with 2 or more times daily dosing among patients with asthma. METHODS: Six years of pharmacy claims data were linked with prescription information to estimate ICS therapy adherence for patients with asthma 12 to 56 years of age who were members of a large health maintenance organization. Patient follow-up continued from the initial ICS fill until one of the following: the last ICS fill in the observation period, a switch of ICS dosing regimen, or the initiation of ICS and long-acting beta-agonist combination therapy. Adherence was estimated by calculating a continuous multiple-interval measure of medication availability. Regression models were used to assess the relationship between adherence in patients treated with once daily vs 2 or more times daily ICS therapy. RESULTS: Among the 1,302 patients who met the inclusion criteria, 17% were prescribed once daily therapy, and 83% were prescribed 2 or more times daily therapy. Models comparing ICS adherence among individuals following once daily and 2 or more times daily ICS regimens suggested that once daily dosing was associated with an approximately 20% increase in adherence. This significant difference persisted among subgroups defined by sex, race/ethnicity, age, and asthma severity. CONCLUSION: Once daily dosing was associated with higher adherence to ICS therapy; this included clinically relevant subgroups. PMID- 23987200 TI - Neonatal B-cell suppression after in utero exposure to R-CHOP. PMID- 23987201 TI - A case of anaphylaxis to erythritol diagnosed by CD203c expression-based basophil activation test. PMID- 23987202 TI - Immunotherapy for mouse bite anaphylaxis and allergy. PMID- 23987203 TI - Resolution of an acute attack of idiopathic angioedema with ecallantide. PMID- 23987204 TI - A new phenotype of asthma: chest tightness as the sole presenting manifestation. PMID- 23987205 TI - Contact dermatitis to vitamin K1 in an eye cream. PMID- 23987206 TI - Measurement of immunoglobulin E interaction with allergen extracts by surface plasmon resonance biosensor analysis. PMID- 23987207 TI - Association of subclinical hypothalamic-pituitary-adrenal axis suppression with bone loss in patients with asthma taking inhaled corticosteroids. PMID- 23987208 TI - Pomegranate allergy and pathogenesis-related protein 4. PMID- 23987209 TI - FEF25-75: a marker for small airways and asthma control. PMID- 23987210 TI - Author response. PMID- 23987211 TI - Allergen of the month-harvester ant. PMID- 23987212 TI - Pd-catalyzed Semmler-Wolff reactions for the conversion of substituted cyclohexenone oximes to primary anilines. AB - Homogeneous Pd catalysts have been identified for the conversion of cyclohexenone and tetralone O-pivaloyl oximes to the corresponding primary anilines and 1 aminonaphthalenes. This method is inspired by the Semmler-Wolff reaction, a classic method that exhibits limited synthetic utility owing to its forcing conditions, narrow scope, and low product yields. The oxime N-O bond undergoes oxidative addition to Pd(0)(PCy3)2, and the product of this step has been characterized by X-ray crystallography and shown to undergo dehydrogenation to afford the aniline product. PMID- 23987215 TI - Synergy in photomagnetic/ferromagnetic sub-50 nm core-multishell nanoparticles. AB - Based on nickel hexacyanidochromate and cobalt hexacyanidoferrate Prussian blue analogues, two series of photomagnetic/ferromagnetic sub-50 nm core multishell coordination nanoparticles have been synthesized in a surfactant-free one-pot multistep procedure with good control over the dispersity (10% standard deviation) and good agreement with the targeted size at each step. The composition and the valence state of each shell have been probed by different techniques that have revealed the predominance of Co(II)-NC-Fe(III) pairs in a series synthesized without alkali while Co(III)-NC-Fe(II) photoswitchable pairs have been successfully obtained in the photoactive coordination nanoparticles by control of Cs(+) insertion. When compared, the photoinduced behavior of the latter compound is in good agreement with that of the model one. Exchange coupling favors a uniform reversal of the magnetization of the heterostructured nanoparticles, with a large magnetization brought by a soft ferromagnetic shell and a large coercivity due to a harder photomagnetic shell. Moreover, a persistent increase of the photoinduced magnetization is observed for the first time up to the ordering temperature (60 K) of the ferromagnetic component because of a unique synergy. PMID- 23987214 TI - Virmid: accurate detection of somatic mutations with sample impurity inference. AB - Detection of somatic variation using sequence from disease-control matched data sets is a critical first step. In many cases including cancer, however, it is hard to isolate pure disease tissue, and the impurity hinders accurate mutation analysis by disrupting overall allele frequencies. Here, we propose a new method, Virmid, that explicitly determines the level of impurity in the sample, and uses it for improved detection of somatic variation. Extensive tests on simulated and real sequencing data from breast cancer and hemimegalencephaly demonstrate the power of our model. A software implementation of our method is available at http://sourceforge.net/projects/virmid/. PMID- 23987213 TI - Chromatin changes in reprogramming of mammalian somatic cells. AB - Somatic cell nuclear transfer (SCNT), cell fusion, and induced pluripotent stem cells (iPSCs) technologies are three strategies that allow reprogramming somatic cells into the pluripotent state; however, the efficiency is low and the mechanisms are not fully clear. In addition, there are reports that changes in chromatin play a critical role in these reprogramming strategies by modulating binding of transcription factors to their targets. In this review, we mainly discuss inactivation of the X chromosome, chromatin decondensation and remodeling, histone modifications, and histone variants in the three strategies. This review will provide an insight for future nuclear reprogramming research. PMID- 23987216 TI - Cause-specific mortality by occupational skill level in Canada: a 16-year follow up study. AB - INTRODUCTION: Mortality data by occupation are not routinely available in Canada, so we analyzed census-linked data to examine cause-specific mortality rates across groups of occupations ranked by skill level. METHODS: A 15% sample of 1991 Canadian Census respondents aged 25 years or older was previously linked to 16 years of mortality data (1991-2006). The current analysis is based on 2.3 million people aged 25 to 64 years at cohort inception, among whom there were 164 332 deaths during the follow-up period. Occupations coded according to the National Occupation Classification were grouped into five skill levels. Age-standardized mortality rates (ASMRs), rate ratios (RRs), rate differences (RDs) and excess mortality were calculated by occupational skill level for various causes of death. RESULTS: ASMRs were clearly graded by skill level: they were highest among those employed in unskilled jobs (and those without an occupation) and lowest for those in professional occupations. All-cause RRs for men were 1.16, 1.40, 1.63 and 1.83 with decreasing occupational skill level compared with professionals. For women the gradient was less steep: 1.23, 1.24, 1.32 and 1.53. This gradient was present for most causes of death. Rate ratios comparing lowest to highest skill levels were greater than 2 for HIV/AIDS, diabetes mellitus, suicide and cancer of the cervix as well as for causes of death associated with tobacco use and excessive alcohol consumption. CONCLUSION: Mortality gradients by occupational skill level were evident for most causes of death. These results provide detailed cause-specific baseline indicators not previously available for Canada. PMID- 23987217 TI - Hospitalizations for unintentional injuries among Canadian adults in areas with a high percentage of Aboriginal-identity residents. AB - INTRODUCTION: Injuries are a leading cause of death and morbidity. While individual Aboriginal identifiers are not routinely available on national administrative databases, this study examines unintentional injury hospitalization, by cause, in areas with a high percentage of Aboriginal-identity residents. METHODS: Age-standardized hospitalization rates (ASHRs) and rate ratios were calculated based on 2004/2005-2009/2010 data from the Discharge Abstract Database. RESULTS: Falls were the most frequent cause of injury. For both sexes, ASHRs were highest in high-percentage First Nations-identity areas; high-percentage Metis-identity areas presented the highest overall ASHR among men aged 20-29 years, and high-percentage Inuit-identity areas presented the lowest ASHRs among men of all age groups. Some causes, such as falls, presented a high ASHR but a rate ratio similar to that for all causes combined; other causes, such as firearm injuries among men in high-percentage First Nations-identity areas, presented a relatively low ASHR but a high rate ratio. Residents of high percentage Aboriginal-identity areas have a higher ASHR for hospitalization for injuries than residents of low-percentage Aboriginal-identity areas. CONCLUSION: Residents of high-percentage Aboriginal-identity areas also live in areas of lower socio-economic conditions, suggesting that the causes for rate differences among areas require further investigation. PMID- 23987218 TI - Chronic bronchitis in Aboriginal people--prevalence and associated factors. AB - INTRODUCTION: Knowledge about chronic bronchitis (CB) among Aboriginal people in Canada is limited. The aim of this study was to determine the prevalence of CB and its associated factors among Aboriginal people aged 15 years plus. METHODS: Logistic regression analysis was used on data from the cross-sectional 2006 Aboriginal Peoples Survey to determine risk factors associated with CB. RESULTS: CB prevalence was 6.6% among First Nations, 6.2% among Metis and 2.4% among Inuit. Prevalence was higher among females than males (7.2% versus 5.0%). Individuals with CB were more likely to be older, living at a lower income, with a lower educational attainment and residing in rural areas. Smoking status and body mass index were also significantly associated with CB, but their effect differed by sex. Obesity was particularly significantly associated with CB among females compared with males, and current smoking and non-smoking status was significantly associated with CB among females but not males. CONCLUSION: These findings identify factors associated with CB among Aboriginal people. As such, they may represent potentially preventable risk factors that can inform health promotion and disease prevention practices. PMID- 23987219 TI - Changes in fall-related mortality in older adults in Quebec, 1981-2009. AB - INTRODUCTION: Our purpose was to evaluate changes in fall-related mortality in adults aged 65 years and over in Quebec and to propose a case definition based on all the causes entered on Return of Death forms. METHODS: The analysis covers deaths between 1981 and 2009 recorded in the Quebec vital statistics data. RESULTS: While the number of fall-related deaths increased between 1981 and 2009, the adjusted falls-related mortality rate remained relatively stable. Since the early 2000s, this stability has masked opposing trends. The mortality rate associated with certified falls (W00-W19) has increased while the rate for presumed falls (exposure to an unspecified factor causing a fracture) has decreased. CONCLUSION: For fall surveillance, analyses using indicators from the vital statistics data should include both certified falls and presumed falls. In addition, a possible shift in the coding of fall-related deaths toward secondary causes should be taken into account. PMID- 23987220 TI - Improved estimation of the health and economic burden of chronic disease risk factors in Manitoba. AB - INTRODUCTION: There are analytic challenges involved with estimating the aggregate burden of multiple risk factors (RFs) in a population. We describe a methodology to account for overlapping RFs in some sub-populations, a phenomenon that leads to "double-counting" the diseases and economic burden generated by those factors. METHODS: Our method uses an efficient approach to accurately analyze the aggregate economic burden of chronic disease across a multifactorial system. In addition, it involves considering the effect of body weight as a continuous or polytomous exposure that ranges from no excess weight through overweight to obesity. We then apply this method to smoking, physical inactivity and overweight/obesity in Manitoba, a province of Canada. RESULTS: The annual aggregate economic burden of the RFs in Manitoba in 2008 is about $1.6 billion ($557 million for smoking, $299 million for physical inactivity and $747 million for overweight/obesity). The total burden represents a 12.6% downward adjustment to account for the effect of multiple RFs in some individuals in the population. CONCLUSION: An improved estimate of the aggregate economic burden of multiple RFs in a given population can assist in prioritizing and gaining support for primary prevention initiatives. PMID- 23987221 TI - Estimating cancer risk in relation to tritium exposure from routine operation of a nuclear-generating station in Pickering, Ontario. AB - INTRODUCTION: Evidence suggests that current levels of tritium emissions from CANDU reactors in Canada are not related to adverse health effects. However, these studies lack tritium-specific dose data and have small numbers of cases. The purpose of our study was to determine whether tritium emitted from a nuclear generating station during routine operation is associated with risk of cancer in Pickering, Ontario. METHODS: A retrospective cohort was formed through linkage of Pickering and north Oshawa residents (1985) to incident cancer cases (1985-2005). We examined all sites combined, leukemia, lung, thyroid and childhood cancers (6 19 years) for males and females as well as female breast cancer. Tritium estimates were based on an atmospheric dispersion model, incorporating characteristics of annual tritium emissions and meteorology. Tritium concentration estimates were assigned to each cohort member based on exact location of residence. Person-years analysis was used to determine whether observed cancer cases were higher than expected. Cox proportional hazards regression was used to determine whether tritium was associated with radiation sensitive cancers in Pickering. RESULTS: Person-years analysis showed female childhood cancer cases to be significantly higher than expected (standardized incidence ratio [SIR] = 1.99, 95% confidence interval [CI]: 1.08-3.38). The issue of multiple comparisons is the most likely explanation for this finding. Cox models revealed that female lung cancer was significantly higher in Pickering versus north Oshawa (HR = 2.34, 95% CI: 1.23-4.46) and that tritium was not associated with increased risk. The improved methodology used in this study adds to our understanding of cancer risks associated with low-dose tritium exposure. CONCLUSION: Tritium estimates were not associated with increased risk of radiationsensitive cancers in Pickering. PMID- 23987222 TI - Knowledge exchange systems for youth health and chronic disease prevention: a tri provincial case study. AB - INTRODUCTION: The research teams undertook a case study design using a common analytical framework to investigate three provincial (Prince Edward Island, New Brunswick and Manitoba) knowledge exchange systems. These three knowledge exchange systems seek to generate and enhance the use of evidence in policy development, program planning and evaluation to improve youth health and chronic disease prevention. METHODS: We applied a case study design to explore the lessons learned, that is, key conditions or processes contributing to the development of knowledge exchange capacity, using a multi-data collection method to gain an in-depth understanding. Data management, synthesis and analysis activities were concurrent, iterative and ongoing. The lessons learned were organized into seven "clusters." RESULTS: Key findings demonstrated that knowledge exchange is a complex process requiring champions, collaborative partnerships, regional readiness and the adaptation of knowledge exchange to diverse stakeholders. DISCUSSION: Overall, knowledge exchange systems can increase the capacity to exchange and use evidence by moving beyond collecting and reporting data. Areas of influence included development of new partnerships, expanded knowledge-sharing activities, and refinement of policy and practice approaches related to youth health and chronic disease prevention. PMID- 23987223 TI - Methodology of the 2009 Survey on Living with Chronic Diseases in Canada- hypertension component. AB - INTRODUCTION: The Survey on Living with Chronic Diseases in Canada--hypertension component (SLCDC-H) is a 20-minute cross-sectional telephone survey on hypertension diagnosis and management. Sampled from the 2008 Canadian Community Health Survey (CCHS), the SLCDC-H includes Canadians (aged >= 20 years) with self reported hypertension from the ten provinces. METHODS: The questionnaire was developed by Delphi technique, externally reviewed and qualitatively tested. Statistics Canada performed sampling strategies, recruitment, data collection and processing. Proportions were weighted to represent the Canadian population, and 95% confidence intervals (CIs) were derived by bootstrap method. RESULTS: Compared with the CCHS population reporting hypertension, the SLCDC-H sample (n = 6142) is slightly younger (SLCDC-H mean age: 61.2 years, 95% CI: 60.8-61.6; CCHS mean age: 62.2 years, 95% CI: 61.8-62.5), has more post-secondary school graduates (SLCDC-H: 52.0%, 95% CI: 49.7%-54.2%; CCHS: 47.5%, 95% CI: 46.1%-48.9%) and has fewer respondents on hypertension medication (SLCDC-H: 82.5%, 95% CI: 80.9%-84.1%; CCHS: 88.6%, 95% CI: 87.7%-89.6%). CONCLUSION: Overall, the 2009 SLCDC-H represents its source population and provides novel, comprehensive data on the diagnosis and management of hypertension. The survey has been adapted to other chronic conditions--diabetes, asthma/chronic obstructive pulmonary disease and neurological conditions. The questionnaire is available on the Statistics Canada website; descriptive results have been disseminated by the Public Health Agency of Canada. PMID- 23987224 TI - How we identify and count Aboriginal people--does it make a difference in estimating their disease burden? AB - INTRODUCTION: We examined the concordance between the Canadian Community Health Survey (CCHS) "identity" and "ancestry" questions used to estimate the size of the Aboriginal population in Canada and whether the different definitions affect the prevalence of selected chronic diseases. METHODS: Based on responses to the "identity" and "ancestry" questions in the CCHS combined 2009-2010 microdata file, Aboriginal participants were divided into 4 groups: (A) identity only; (B) ancestry only; (C) either ancestry or identity; and (D) both ancestry and identity. Prevalence of diabetes, arthritis and hypertension was estimated based on participants reporting that a health professional had told them that they have the condition(s). RESULTS: Of participants who identified themselves as Aboriginal, only 63% reported having an Aboriginal ancestor; of those who claimed Aboriginal ancestry, only 57% identified themselves as Aboriginal. The lack of concordance also differs according to whether the individual was First Nation, Metis or Inuit. The different method of estimating the Aboriginal population, however, does not significantly affect the prevalence of the three selected chronic diseases. CONCLUSION: The lack of concordance requires further investigation by combining more cycles of CCHS to compare discrepancy across regions, genders and socio-economic status. Its impact on a broader list of health conditions should be examined. PMID- 23987228 TI - A carbohydrate-based approach for the total synthesis of (-)-dinemasone B, (+)-4a epi-dinemasone B, (-)-7-epi-dinemasone B, and (+)-4a,7-Di-epi-dinemasone B. AB - (-)-Dinemasone B was isolated by Krohn and co-workers from a culture of the endophytic fungus Dinemasporium strigosum and has shown promising antimicrobial activity. Described herein is the first total synthesis of (-)-dinemasone B, (+) 4a-epi-dinemasone B, (-)-7-epi-dinemasone B, and (+)-4a,7-di-epi-dinemasone B. Their absolute configurations were also determined. The developed synthesis features a stereoselective reduction of C-glycosidic ketone, lactonization, and E olefination of aldehyde starting from D-glucose. PMID- 23987229 TI - Dielectric breakdown strength of regenerated silk fibroin films as a function of protein conformation. AB - Derived from Bombyx mori cocoons, regenerated silk fibroin (RSF) exhibits excellent biocompatibility, high toughness, and tailorable biodegradability. Additionally, RSF materials are flexible, optically clear, easily patterned with nanoscale features, and may be doped with a variety bioactive species. This unique combination of properties has led to increased interest in the use of RSF in sustainable and biocompatible electronic devices. In order to explore the applicability of this biopolymer to the development of future bioelectronics, the dielectric breakdown strength (Ebd) of RSF thin films was quantified as a function of protein conformation. The application of processing conditions that increased beta-sheet content (as determined by FTIR analysis) and produced films in the silk II structure resulted in RSF materials with improved Ebd with values reaching up to 400 V/MUm. PMID- 23987230 TI - Preferred HIV testing services and programme characteristics among clients of a rapid HIV testing programme. AB - BACKGROUND: In the current context of diversity and coexistence of HIV testing approaches, limited information exists on test recipient's views of HIV testing services and programme attributes that could ease the testing process and make it more appealing for at risk individuals who don't know their HIV status. This study analyzed ratings given to different testing sites and programme characteristics that might facilitate testing. METHODS: We analyzed data from 3120 persons attending a mobile HIV testing programme located on a central street in the gay district of Madrid. RESULTS: 64% were men (of which, 55% had had sex with other men), 59.5% were <30 years, 35.4% foreigners, 50.6% had a university degree,71.7% a regular employment, 59.3% reported multiple partners and inconsistent condom use and 56.5% had been tested for HIV. Non Governmental Organizations and specific HIV/STI centres received the maximum rating from over 60% of participants, followed by self-testing (38.9%). Pharmacies (20.8%) and hospital emergency departments (14.2%) were the worst valued testing sites. Over 80% gave the highest rating to having immediate test results, not needing a previous appointment, and free testing, while less than 50% gave the maximum rating to privacy and anonymity. CONCLUSIONS: HIV testing services that don't require an appointment, based on free tests with rapid results are most valued by a young, not socially marginalized but high risk sexual exposure population. On the contrary, issues traditionally highly valued by health care providers or AIDS social organizations (privacy and anonymity) are much less valued. PMID- 23987232 TI - Course of COPD assessment test (CAT) and clinical COPD questionnaire (CCQ) scores during recovery from exacerbations of chronic obstructive pulmonary disease. AB - INTRODUCTION: COPD exacerbations have a negative impact on lung function, decrease quality of life (QoL) and increase the risk of death. The objective of this study was to assess the course of health status after an outpatient or inpatient exacerbation in patients with COPD. METHODS: This is an epidemiological, prospective, multicentre study that was conducted in 79 hospitals and primary care centres in Spain. Four hundred seventy-six COPD patients completed COPD assessment test (CAT) and Clinical COPD Questionnaire (CCQ) questionnaires during the 24 hours after presenting at hospital or primary care centres with symptoms of an exacerbation, and also at weeks 4-6. The scores from the CAT and CCQ were evaluated and compared at baseline and after recovery from the exacerbation. RESULTS: A total of 164 outpatients (33.7%) and 322 inpatients (66.3%) were included in the study. The majority were men (88.2%), the mean age was 69.4 years (SD = 9.5) and the mean FEV1 (%) was 47.7% (17.4%). During the exacerbation, patients presented high scores in the CAT: [mean: 22.0 (SD = 7.0)] and the CCQ: [mean: 4.4 (SD = 1.2)]. After recovery there was a significant reduction in the scores of both questionnaires [CAT: mean: -9.9 (SD = 5.1) and CCQ: mean: -3.1 (SD = 1.1)]. Both questionnaires showed a strong correlation during and after the exacerbation and the best predictor of the magnitude of improvement in the scores was the severity of each score at onset. CONCLUSIONS: Due to their good correlation, CAT and CCQ can be useful tools to measure health status during an exacerbation and to evaluate recovery. However, new studies are necessary in order to identify which factors are influencing the course of the recovery of health status after a COPD exacerbation. PMID- 23987231 TI - Aetiology of biliary atresia: what is actually known? AB - Biliary atresia (BA) is a rare disease of unknown etiology and unpredictable outcome, even when there has been timely diagnosis and exemplary surgery. It has been the commonest indication for liver transplantation during childhood for the past 20 years. Hence much clinical and basic research has been directed at elucidating the origin and pathology of BA. This review summarizes the current clinical variations of BA in humans, its occasional appearance in animals and its various manifestations in the laboratory as an experimental model. PMID- 23987233 TI - Spatial compartmentalization at the nuclear periphery characterized by genome wide mapping. AB - BACKGROUND: How gene positioning to the nuclear periphery regulates transcription remains largely unclear. By cell imaging, we have previously observed the differential compartmentalization of transcription factors and histone modifications at the nuclear periphery in mouse C2C12 myoblasts. Here, we aim to identify DNA sequences associated with the nuclear lamina (NL) and examine this compartmentalization at the genome-wide level. RESULTS: We have integrated high throughput DNA sequencing into the DNA adenine methyltransferase identification (DamID) assay, and have identified ~15, 000 sequencing-based Lamina-Associated Domains (sLADs) in mouse 3T3 fibroblasts and C2C12 myoblasts. These genomic regions range from a few kb to over 1 Mb and cover ~30% of the genome, and are spatially proximal to the NL. Active histone modifications such as H3K4me2/3, H3K9Ac and H3K36me3 are distributed predominantly out of sLADs, consistent with observations from cell imaging that they are localized away from the nuclear periphery. Genomic regions around transcription start sites of expressed sLAD genes display reduced association with the NL; additionally, expressed sLAD genes possess lower levels of active histone modifications than expressed non-sLAD genes. CONCLUSIONS: Our work has shown that genomic regions associated with the NL are characterized by the paucity of active histone modifications in mammalian cells, and has revealed novel connections between subnuclear gene positioning, histone modifications and gene expression. PMID- 23987234 TI - NMR investigations of the interaction between the azo-dye sunset yellow and fluorophenol. AB - The interaction of small molecules with larger noncovalent assemblies is important across a wide range of disciplines. Here, we apply two complementary NMR spectroscopic methods to investigate the interaction of various fluorophenol isomers with sunset yellow. This latter molecule is known to form noncovalent aggregates in isotropic solution, and form liquid crystals at high concentrations. We utilize the unique fluorine-19 nucleus of the fluorophenol as a reporter of the interactions via changes in both the observed chemical shift and diffusion coefficients. The data are interpreted in terms of the indefinite self-association model and simple modifications for the incorporation of a second species into an assembly. A change in association mode is tentatively assigned whereby the fluorophenol binds end-on with the sunset yellow aggregates at low concentration and inserts into the stacks at higher concentrations. PMID- 23987237 TI - Adiposity and the relationship between vitamin D and blood pressure. AB - OBJECTIVE: Circulating vitamin D (25OHD) concentrations are negatively associated with blood pressure (BP) but little is known about the mechanisms for this relationship. Adiposity is positively associated with BP and inversely with circulating 25OHD concentrations but no studies have assessed the relationship between plasma 25OHD and adiposity on BP. The goal of this study is to investigate if the association between plasma 25OHD and BP is mediated by adiposity. MATERIALS/METHODS: The relationship between plasma 25OHD, systolic and diastolic BP, and adiposity [BMI, waist circumference, visceral adipose tissue (VAT)] was assessed in a multi-ethnic cross-sectional study of Aboriginal (n=151), Chinese (n=190), European (n=170), and South Asian (n=176) participants by linear regression models. RESULTS: Plasma 25OHD concentrations were negatively associated with systolic (standardized B=-0.191, P<0.001) and diastolic BP (standardized B=-0.196, P<0.001) in models adjusted for age, sex, ethnicity, family history of CVD, smoking status, alcohol consumption, and physical activity. The negative relationship between plasma 25OHD concentrations and systolic and diastolic BP was attenuated after the addition of BMI, waist circumference, and VAT to the models, but the relationship remained significant. Plasma 25OHD concentrations accounted for 0.7% and 0.8% of the variance in systolic and diastolic BP, respectively. CONCLUSION: These findings suggest that the relationship between vitamin D and BP is independent of adiposity. Further studies are required to determine the mechanisms by which vitamin D affects BP. PMID- 23987236 TI - Circulating 25-hydroxyvitamin D is associated with insulin resistance cross sectionally but not longitudinally in older adults: The Cardiovascular Health Study. AB - BACKGROUND: Despite extensive study, the role of vitamin D in insulin resistance and secretion remains unclear. OBJECTIVE: To examine the cross-sectional and longitudinal relationships between 25-hydroxyvitamin D (25(OH)D) concentrations and indices of insulin resistance and secretion in older adults. METHODS AND RESULTS: Among 2134 participants of the Cardiovascular Health Study who were free from cardiovascular disease, we measured serum 25(OH)D concentrations in samples collected in 1992-1993. We examined insulin resistance and secretion using Homeostasis Model Assessment (HOMA) estimates cross-sectionally and among 1469 participants who had repeated HOMA measures four years later (1996-1997). In cross-sectional analysis, each 10 ng/mL increment in 25(OH)D concentration was associated with a 0.09 lower adjusted HOMA-IR [95% CI (-0.17, -0.02), p=0.01]. However, baseline 25(OH)D concentrations were not associated with change in HOMA IR over 4 years of follow up (p=0.48). 25(OH)D concentrations were not associated with insulin secretion, as determined by HOMA-beta, in either cross-sectional or longitudinal analysis. CONCLUSIONS: Circulating 25(OH)D concentrations are associated with lower insulin resistance in cross-sectional but not longitudinal analyses. Whether this reflects residual confounding in cross-sectional analyses or the short-term nature of the relationship between vitamin D and insulin sensitivity will require trials with repeated measures of these factors. PMID- 23987238 TI - Cochlear implantation for a child with cochlear nerve deficiency: parental perspectives explored through narrative. AB - OBJECTIVE: The objective of this study was to explore, from the parents' perspectives, decision-making regarding a cochlear implant (CI) for their child when a favourable outcome is less likely because of abnormal neurophysiology. DESIGN: The primary research method of this single case study was qualitative interviewing drawing on a narrative approach to elicit the parents' perspectives about their experiences over time. Each parent was interviewed separately, but thematic analyses were undertaken both within and across interviews in order to identify overlaps and differences. STUDY SAMPLE: Participants included the parents of a five-year old child with severe-profound hearing loss, cochlear nerve deficiency, and bilateral common cavities who had received a CI at the age of 18 months. RESULTS: Four themes were identified across the four narrative stages that emerged from the parents' accounts of their experiences regarding their daughter's CI. Themes included hope and despair, questioning professionals' motivations, does deafness need a cure, and bringing the child into the family. Although these themes emerged from both parents' accounts, each parent expressed different perspectives and insights within them. CONCLUSIONS: Findings highlight the central place of parental needs and perspectives in decision-making regarding a CI, particularly in the context of uncertain outcomes. PMID- 23987239 TI - Three-dimensional upper-airway assessment in patients with bronchial asthma. AB - Abstract Objective: To assess the upper airway (UAW) total volume (TV), the nasopharyngeal narrowest area (NNA), and the oropharyngeal narrowest area (ONA) in patients with bronchial asthma. Materials and Methods: The sample consisted of 52 patients divided into two groups: the control group (n = 26; mean age = 14.85 years), which consisted of patients not suffering from bronchial asthma; and the asthmatic group (n = 26; mean age = 16.65 years), which consisted of patients with bronchial asthma. To assess UAW-related variables (TV, NNA, and ONA), cone-beam computed tomography scans of the patients were evaluated by means of the Dolphin Imaging software 11.5. All measurements were repeated after 30 days, and the results were submitted to reliability tests by means of the intraclass correlation coefficient and the Bland-Altman agreement test. The values obtained for TV, NNA, and ONA for each group were compared by using Student's t-test for independent samples (5% level of significance). Results: The results showed that the groups were matched concerning gender, cephalometric characteristics, and type of malocclusion. The asthmatic group had significantly lower TV (P = .01) and ONA (P = .007) than the control group. However, no significant difference was observed for NNA between the groups (P = .54). Conclusions: Bronchial asthma may be a determining factor for the reduction of UAW dimensions, as patients with asthma showed significant reductions in TV and ONA dimensions. PMID- 23987235 TI - Impact of hematopoietic cyclooxygenase-1 deficiency on obesity-linked adipose tissue inflammation and metabolic disorders in mice. AB - OBJECTIVE: Adipose tissue (AT)-specific inflammation is considered to mediate the pathological consequences of obesity and macrophages are known to activate inflammatory pathways in obese AT. Because cyclooxygenases play a central role in regulating the inflammatory processes, we sought to determine the role of hematopoietic cyclooxygenase-1 (COX-1) in modulating AT inflammation in obesity. MATERIALS/METHODS: Bone marrow transplantation was performed to delete COX-1 in hematopoietic cells. Briefly, female wild type (wt) mice were lethally irradiated and injected with bone marrow (BM) cells collected from wild type (COX-1+/+) or COX-1 knock-out (COX-1-/-) donor mice. The mice were fed a high fat diet for 16 weeks. RESULTS: The mice that received COX-1-/- bone marrow (BM-COX-1-/-) exhibited a significant increase in fasting glucose, total cholesterol and triglycerides in the circulation compared to control (BM-COX-1+/+) mice. Markers of AT-inflammation were increased and were associated with increased leptin and decreased adiponectin in plasma. Hepatic inflammation was reduced with a concomitant reduction in TXB2 levels. The hepatic mRNA expression of genes involved in lipogenesis and lipid transport was increased while expression of genes involved in regulating hepatic glucose output was reduced in BM-COX-1-/- mice. Finally, renal inflammation and markers of renal glucose release were increased in BM-COX-1-/- mice. CONCLUSION: Hematopoietic COX-1 deletion results in impairments in metabolic homeostasis which may be partly due to increased AT inflammation and dysregulated adipokine profile. An increase in renal glucose release and hepatic lipogenesis/lipid transport may also play a role, at least in part, in mediating hyperglycemia and dyslipidemia, respectively. PMID- 23987240 TI - A prospective controlled evaluation of Class II division 1 malocclusions treated with fixed lingual mandibular growth modificator. AB - OBJECTIVE: To assess the net dentofacial effects of the fixed lingual mandibular growth modificator (FLMGM). MATERIALS AND METHODS: The study sample comprised 38 patients with Class II/1 malocclusion and retrognathic mandible. All were in the pubertal growth spurt. Whereas FLMGM was applied to the treatment group (n=21, mean age=13.2 years), no treatment was performed on the control group (n=17, mean age=12.5 years). Skeletal and dentoalveolar changes were assessed on digital lateral cephalograms obtained at the beginning and end of the treatment/observation period of 8 months. Paired and independent t-tests were used to assess the differences within and between groups. RESULTS: Maxillary growth was not affected by FLMGM treatment, which resulted in a significant overjet reduction of 4.1 mm, an increase in total mandibular length (Co-Gn) of 2.3 mm, chin advancement of 1.6 degrees , and upper incisor retroclination of 4.0 degrees . A reduction of 2.4 degrees in ANB was largely due to an increase of 1.8 degrees in SNB. Favorably, the lower incisors were obviously retroclined by 4.5 degrees . The changes in the vertical skeletal relationships were negligible. CONCLUSION: FLMGM was effective in treating growing Class II/1 patients and produced favorable dentofacial effects, with the matched untreated sample showing minimal changes. Lower incisor retroclination was a benefit of FLMGM treatment. PMID- 23987241 TI - Effects of fixed functional therapy on tongue and hyoid positions and posterior airway. AB - OBJECTIVE: To evaluate how therapy with a fixed functional appliance affects airway dimensions, dentoalveolar changes, and tongue and hyoid positions. MATERIALS AND METHODS: A retrospective study was carried out on 46 pre- and posttreatment lateral cephalometric radiographs of 23 post-peak Class II patients (12 girls, 11 boys) treated with a Forsus Fatigue Resistant Device (FRD) appliance. The radiographies were taken at the start and at the end of Forsus FRD appliance therapy when a Class I or overcorrected Class I canine and molar relationship was achieved. The process took an average of 5 months 13 days +/- 1 month 4 days. Skeletal and dental parameters were measured using Dolphin software, and the sagittal airway area was measured by AutoCAD software. RESULTS: Analyses of the pre- and posttreatment means revealed that there was no statistically significant skeletal correction of the sagittal malocclusion; increase of lower incisor inclination, decrease of upper incisor inclination, decrease of interincisal angle, and rotation of occlusal plane all contributed to the reduction of overjet. The tongue area and intermaxillary space area increased in response to these dentoalveolar changes; however, there was no statistically significant change in the hyoid position or the oropharyngeal area between the two time points. CONCLUSIONS: The dentoalveolar changes produced by Forsus FRD appliance did not cause any significant posterior airway changes in young adult patients. PMID- 23987242 TI - Expression of substance P, calcitonin gene-related peptide, beta-endorphin and methionine-enkephalin in human dental pulp tissue after orthodontic intrusion: a pilot study. AB - OBJECTIVE: To determine the levels of two sensory neuropeptides (substance P [SP] and calcitonin gene-related peptide [CGRP]) and two endogenous opioids (methionine-enkephalin [Met-Enk] and beta-endorphin [beta-End]) in dental pulp tissue samples subjected to controlled orthodontic intrusive forces. MATERIALS AND METHODS: Sixteen healthy premolars were selected from eight patients who were undergoing extraction for orthodontic purposes. Eight were randomly used as controls, and the other eight were assigned to an experimental group (controlled orthodontic intrusive forces applied for 24 hours). After this period, teeth were extracted, and pulp samples were obtained. All samples were processed to quantify the expression levels of SP, CGRP, Met-Enk, and beta-End using commercial radioimmunoassay kits. RESULTS: All samples exhibited basal levels of both neuropeptides and endogenous opioids. After 24 hours of the intrusive stimulus, all patients reported a tolerable discomfort localized at the involved premolar. Only SP was significantly increased (P<.05). For the other molecules, no statistically significant differences were observed (P>.05); however, they expressed important increasing trends. CONCLUSIONS: The expression levels of SP and CGRP in dental pulp samples from the experimental group support the positive correlation between the symptomatic clinical scenario and increased expression levels of neuropeptides, clarifying the role of neurogenic inflammation in early injury response. PMID- 23987243 TI - Effects of first- and second-order gable bends on the orthodontic load systems produced by T-loop archwires. AB - OBJECTIVE: To measure the effects of first- and second-order gable bends on the forces and moments produced by a commercially available closing T-loop archwire. MATERIALS AND METHODS: A dentoform-simulated space closure case was mounted on an orthodontic force tester. Sixteen gable bend combinations were placed in the archwires, which were then activated using standard clinical procedures. At each activation, the three force components and three moment components on the maxillary left lateral incisor and canine were simultaneously measured. RESULTS: The first- and second-order gable bends showed low load coupling effects when used independently, but the load systems became unpredictable when bends were combined. Gable bends affect the magnitudes and directions of the forces and moments that are applied to teeth. The resulting moment to force ratios are sensitive to the bends. CONCLUSION: Gable bends alter the orthodontic load systems; however, the three-dimensional interactions produce complex and unpredictable tradeoffs. PMID- 23987244 TI - Characterization of the cellular activity of PDE 4 inhibitors using two novel PDE 4 reporter cell lines. AB - We report here the generation and pharmacological characterization of two novel PDE 4B1 and PDE 4D3 reporter cell lines. Intracellular cAMP levels are monitored in these cells by a cAMP-sensitive biosensor. We used the recombinant PDE 4B1 and PDE 4D3 reporter cell lines to characterize the cellular effects of various competitive and allosteric PDE 4 inhibitors. In addition, we compared the cellular activity of these PDE 4 inhibitors with the in vitro inhibition of full length PDE 4D3 and a truncated enzyme comprising the PDE 4D3 catalytic domain. Two different groups of PDE 4 inhibitors could be identified. The first group, including competitive inhibitors like roflumilast, cilomilast and piclamilast, shows similar in vitro activity on full-length and truncated PDE 4D3 and comparably low cellular activity. The second group, including the allosteric inhibitors PMNPQ, D159153, and D159404, shows much better inhibition of full length versus truncated PDE 4D3. In addition, these compounds show high cellular activity. Our data obtained with the prototype PDE 4 inhibitor rolipram show that rolipram has properties intermediate between the two groups. The results imply that these novel PDE 4 reporter cell lines are well-suited for the characterization of the cellular activity of PDE 4 inhibitors and may also support a better understanding of the complex PDE 4 pharmacology. PMID- 23987245 TI - Laparoscopic radical prostatectomy monotherapy, a more aggressive yet less invasive option, is oncologically effective in selected men with high-risk prostate cancer having only one D'Amico risk factor: experience from an Asian tertiary referral center. AB - PURPOSE: To present oncologic results of laparoscopic radical prostatectomy (LRP) monotherapy for men with high-risk, localized prostate cancer, and to find factors associated with a good prognosis via surgery alone. PATIENTS AND METHODS: Between 2002 and 2009, 241 men underwent LRP at an Asian tertiary referral center. Among them, we retrospectively identified 85 (35.3%) men who met the D'Amico's high-risk criteria: Prostate-specific antigen level >20 ng/mL, Gleason score of 8 to 10, or clinical stage >=T2c. Perioperative parameters were analyzed against biochemical recurrence (BCR)-free survival. RESULTS: At a median follow up of 54 months, BCR developed in 28 (34.1%), with an actuarial BCR-free survival rate of 63.3% at 5 years. Pathologically, 37.6% of the men had organ-confined (OC) disease. Positive surgical margins (PSM) were identified in 49.4% of the patients. A favorable pathologic outcome, defined as OC(+)PSM(-), was observed in 24 patients and associated with a 5-year BCR-free survival rate of 87.0%, compared with 100%, 54.0%, and 46.4% in men with OC(+)PSM(+), OC(-)PSM(-) and OC( )PSM(+) disease (log-rank, P=0.008). The overall positive lymph node rate was 14.1%. Men (65.9%) with only one D'Amico risk factor had a 5-year BCR-free survival rate of 76.9%, compared with 34.6% in men (34.1%) with >=2 risk factors (log-rank, P<0.001). CONCLUSIONS: Radical prostatectomy monotherapy performed laparoscopically or robotically appears to be an option for high-risk prostate cancer, especially in men with a single D'Amico risk factor. Men with >=2 risk factors are more prone for BCR to develop after surgery and may need second-line therapy. PMID- 23987246 TI - Methotrexate analogues display enhanced inhibition of TNF-alpha production in whole blood from RA patients. AB - OBJECTIVES: Although methotrexate (MTX) is the anchor drug in the treatment of rheumatoid arthritis (RA), patients experience clinical resistance to MTX upon prolonged treatment. We explored whether new-generation antifolates elicit superior anti-inflammatory properties when compared to MTX, based on their capacity to inhibit tumour necrosis factor (TNF)-alpha production. METHOD: T cells in whole blood from 18 RA patients (including MTX-naive, MTX- responsive, and MTX non-responsive patients) and seven healthy volunteers were stimulated with alphaCD3/alphaCD28 antibodies and incubated ex vivo for 72 h with MTX and eight novel antifolate drugs with potentially favourable biochemical and pharmacological properties. Drug concentrations exerting 50% inhibition (IC-50) of TNF-alpha production (by enzyme-linked immunosorbent assay, ELISA) were determined as an estimate for their anti-inflammatory capacity. In addition, induction of T-cell apoptosis was evaluated by flow cytometry. RESULTS: The new generation antifolates PT523, PT644, raltitrexed, and GW1843 proved to be potent inhibitors of TNF-alpha production in activated T cells from all three groups of RA patients and from healthy volunteers. Based on IC-50 values, these antifolates were up to 10.3 times more potent than MTX. The anti-inflammatory effects were observed at drug concentrations that provoked suppression of T-cell activation and induction of apoptosis in 20-40% of activated T cells. CONCLUSION: In an ex vivo setting, novel antifolates elicited marked inhibition of TNF-alpha production in activated T cells from RA patients. Further clinical evaluation is warranted to investigate whether a low dosage of these antifolates can elicit immunosuppressive effects equivalent to MTX, and whether they are superior to MTX in patients who fail to respond to MTX. PMID- 23987247 TI - Mechanism of cobalt self-exchange electron transfer. AB - A heptanuclear cobalt cluster was synthesized in two different oxidation states, Co(II)7 and a mixed valence Co(III)Co(II)6, as a soluble model of a cobalt phosphate/borate (Co-OEC) water splitting catalyst. Crystallographic characterization indicates similar cluster cores, distinguished primarily at the central Co atom. An anion associates to the cluster cores via hydrogen bonding. Using an isotope exchange method, an anomalously slow self-exchange electron transfer rate constant (k(obs) = 1.53 * 10(-3) M(-1) s(-1) at 40 degrees C and 38 mM [OTf] in MeCN), as compared to that predicted from semiclassical Marcus theory, supports a charge transfer process that is accelerated by dissociation of the anion from the oxidized cluster. This mechanism sheds light on the inverse dependence of anions in the self-repair mechanism of Co-OECs. Moreover, because H2O cannot directly bridge cobalt centers, owing to the encapsulation of the central Co within the cluster core, the observed results address a long-standing controversy surrounding the Co(2+/3+) self-exchange electron transfer reaction of the hexaaqua complex. PMID- 23987248 TI - Systematic investigation of thorium(IV)- and uranium(IV)-ligand bonding in dithiophosphonate, thioselenophosphinate, and diselenophosphonate complexes. AB - Homoleptic soft-donor actinide complexes of the general form An[E2PROR']4 were synthesized from salt metathesis between ThCl4(DME)2 or UI4(1,4-dioxane)2 and M[E2PROR'], M = Na, K, to yield 2 (An = Th, E = S, R = 4-MeOC6H4, R' = Me), 3 (An = Th, E = S, R = 4-MeOC6H4, R' = (t)Bu), 4 (An = U, E = S, R = 4-MeOC6H4, R' = Me), 5 (An = Th, E = Se, R = C6H5, R' = Me), and 6 (An = U, E = Se, R = C6H5, R' = Me). In addition thorium and uranium thioselenophosphinate complexes 7 and 8 were produced from the reaction of ThCl4(DME)2 and UI4(1,4-dioxane)2 and Na[SSePPh2], respectively. All compounds were characterized using elemental analysis, (1)H and (31)P NMR, and IR spectroscopy, and the U(IV) compounds were also examined with UV-vis spectroscopy. The (77)Se NMR spectrum of 5 reveals the first reported resonance with a Th-Se bond. The solid-state structures of 2, 5, 7, and 8 were determined by X-ray crystallography. The actinide-ligand bonding was examined using density functional theory calculations in conjunction with quantum theory of atoms-in-molecules analysis and shows slightly increased covalency in actinide-selenium bonds than actinide-sulfur. PMID- 23987249 TI - Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells. AB - BACKGROUND: Ten-Eleven Translocation (TETs)proteins mediate the oxidation of 5 methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 is expressed at high levels in mouse embryonic stem cells (ESCs), where it mediates the induction of 5hmC decoration on gene-regulatory elements. While the function of Tet1 is known, the mechanisms of its specificity remain unclear. RESULTS: We perform a genome wide comparative analysis of 5hmC in pluripotent ESCs, as well as in differentiated embryonic and adult cells. We find that 5hmC co-localization with Polycomb repressive complex 2 (PRC2) is specific to ESCs and is absent in differentiated cells. Tet1 in ESCs is distributed on bivalent genes in two independent pools: one with Sin3a centered at non-hydroxymethylated transcription start sites and another centered downstream from these sites. This latter pool of Tet1 co-localizes with 5hmC and PRC2. Through co-immunoprecipitation experiments, we show that Tet1 forms a complex with PRC2 specifically in ESCs. Genome-wide analysis of 5hmC profiles in ESCs following knockdown of the PRC2 subunit Suz12 shows a reduction of 5hmC within promoter sequences, specifically at H3K27me3 positive regions of bivalent promoters. CONCLUSIONS: In ESCs, PRC2 recruits Tet1 to chromatin at H3K27me3 positive regions of the genome, with 5hmC enriched in a broad peak centered 455 bp after the transcription start site and dependent on the PRC2 component Suz12. These results suggest that PRC2-dependent recruitment of Tet1 contributes to epigenetic plasticity throughout cell differentiation. PMID- 23987250 TI - Childhood obesity task forces established by state legislatures, 2001-2010. AB - INTRODUCTION: States and communities are considering policy and environmental strategies, including enacting legislation, to reduce and prevent childhood obesity. One legislative approach has been to create task forces to understand key issues and develop a course of action. The goal of this study was to describe state-level, childhood obesity task forces in the United States created by legislation from 2001 through 2010. METHODS: We used the Center for Disease Control and Prevention's Division of Nutrition, Physical Activity, and Obesity database to identify state-level childhood obesity task forces created through legislation from 2001 through 2010. RESULTS: We identified 21 states that had enacted legislation creating childhood obesity task forces of which 6 had created more than one task force. Most task forces were charged with both gathering and reviewing information and making recommendations for obesity-prevention actions in the state. Most legislation required that task forces include representation from the state legislature, state agencies, community organizations, and community members. CONCLUSION: Evaluation of the effectiveness of obesity prevention task forces and the primary components that contribute to their success may help to determine the advantages of the use of such strategies in obesity prevention. PMID- 23987251 TI - Implementing a farmers' market incentive program: perspectives on the New York City Health Bucks Program. AB - INTRODUCTION: One strategy for lowering the prevalence of obesity is to increase access to and affordability of fruits and vegetables through farmers' markets. However, little has been documented in the literature on the implementation of such efforts. To address this gap, the Division of Nutrition, Physical Activity, and Obesity (DNPAO) sponsored an evaluation of the New York City Health Bucks program, a farmers' market coupon incentive program intended to increase access to fresh fruits and vegetables in underserved neighborhoods while supporting local farmers. METHODS: We conducted a process evaluation of Health Bucks program implementation. We interviewed 6 farmer/vendors, 3 market managers, and 4 program administrators, and collected data on site at 86 farmers' markets, including surveys of 81 managers and 141 farmer/vendors on their perspectives on promotion and redemption of the incentive coupons; knowledge and attitudes regarding the program; experiences with markets and products; and facilitators and barriers to program participation. RESULTS: Results indicate that respondents view Health Bucks as a positive program model. Farmers' market incentive coupon programs like Health Bucks are one strategy to address the problem of obesity and were associated with higher fruit and vegetable access and purchases in low-income communities. CONCLUSIONS: This evaluation identified some areas for improving implementation of the Health Bucks program. Farmers' market incentive programs like Health Bucks may be one avenue to increase access to and affordability of fruits and vegetables among low-income persons. Further research is needed to assess the potential effects of these programs on access and health outcomes. PMID- 23987252 TI - Intermediate outcomes of a chronic disease self-management program for Spanish speaking older adults in South Florida, 2008-2010. AB - INTRODUCTION: The prevalence and negative health effects of chronic diseases are disproportionately high among Hispanics, the largest minority group in the United States. Self-management of chronic conditions by older adults is a public health priority. The objective of this study was to examine 6-week differences in self efficacy, time spent performing physical activity, and perceived social and role activities limitations for participants in a chronic disease self-management program for Spanish-speaking older adults, Tomando Control de su Salud (TCDS). METHODS: Through the Healthy Aging Regional Collaborative, 8 area agencies delivered 82 workshops in 62 locations throughout South Florida. Spanish-speaking participants who attended workshops from October 1, 2008, through December 31, 2010, were aged 55 years or older, had at least 1 chronic condition, and completed baseline and post-test surveys were included in analysis (N=682). Workshops consisted of six, 2.5-hour sessions offered once per week for 6 weeks. A self-report survey was administered at baseline and again at the end of program instruction. To assess differences in outcomes, a repeated measures general linear model was used, controlling for agency and baseline general health. RESULTS: All outcomes showed improvement at 6 weeks. Outcomes that improved significantly were self-efficacy to manage disease, perceived social and role activities limitations, time spent walking, and time spent performing other aerobic activities. CONCLUSION: Implementation of TCDS significantly improved 4 of 8 health promotion skills and behaviors of Spanish-speaking older adults in South Florida. A community-based implementation of TCDS has the potential to improve health outcomes for a diverse, Spanish-speaking, older adult population. PMID- 23987253 TI - Building social networks for health promotion: Shout-out Health, New Jersey, 2011. AB - BACKGROUND: Building social networks for health promotion in high-poverty areas may reduce health disparities. Community involvement provides a mechanism to reach at-risk people with culturally tailored health information. Shout-out Health was a feasibility project to provide opportunity and support for women at risk for or living with human immunodeficiency virus infection to carry out health promotion within their informal social networks. COMMUNITY CONTEXT: The Shout-out Health project was designed by an academic-community agency team. During 3 months, health promotion topics were chosen, developed, and delivered to community members within informal social networks by participants living in Paterson and Jersey City, New Jersey. METHODS: We recruited women from our community agency partner's clients; 57 women participated in in-person or online meetings facilitated by our team. The participants identified and developed the health topics, and we discussed each topic and checked it for message accuracy before the participants provided health promotion within their informal social networks. The primary outcome for evaluating feasibility included the women's feedback about their experiences and the number of times they provided health promotion in the community. Other data collection included participant questionnaires and community-recipient evaluations. OUTCOME: More than half of the participants reported substantial life challenges, such as unemployment and housing problems, yet with technical support and a modest stipend, women in both groups successfully provided health promotion to 5,861 people within their informal social networks. INTERPRETATION: Shout-out Health was feasible and has implications for building social networks to disseminate health information and reduce health disparities in communities. PMID- 23987301 TI - Influence of the acetylenic substituent on the intramolecular carbolithiation of alkynes: a DFT theoretical study. AB - A theoretical study of the intramolecular 5-exo-dig carbolithiation of substituted propargyl o-lithioaryl ethers, leading to dihydrobenzofurans, has been performed. The results show that a DFT description of the reaction (B3P86, 6 31G**) matches the experimental data provided that an explicit solvation by two molecules of THF is considered. To take place, the cyclization also implies that the acetylenic chain adopts a conformation in which a significant interaction arises between the lithium and the C=C triple bond. Reaching the cyclization TS requires the passage of an activation barrier that should not be higher than 12 13 kcal mol(-1). From a thermodynamic point of view, the reaction is exothermic whatever the substituent R (from approximately -40 to -62 kcal mol(-1)). In the starting substrate, a supplementary interaction between the Li and a substituent at the propargylic position can develop, influencing the future double-bond configuration. Thus, derivatives exhibiting an R-Li interaction tend to provide E olefins. In contrast, when no coordination between the lithium cation and the terminal R occurs, syn carbolithiation takes place, and the configuration of the exocyclic olefin is likely to be Z. This hypothesis accounts for most of the experimental results published before. PMID- 23987300 TI - Photolithographic fabrication of microapertures with well-defined, three dimensional geometries for suspended lipid membrane studies. AB - Robust and high-density biosensors incorporating suspended lipid membranes require microfabricated apertures that can be readily integrated into complex analysis systems. Apertures with well-defined, three-dimensional geometries enable the formation of suspended lipid membranes and facilitate reduced aperture size compared to vertical-walled apertures. Unfortunately, existing methods of producing apertures with well-defined, three-dimensional geometries are based on complex and expensive fabrication procedures, some of which yield apertures in excessively fragile thin-film materials. Here, we describe a microfabrication method utilizing incline and rotate lithography that achieves sloped-wall microapertures in SU-8 polymer substrates with precision control of the aperture diameter, substrate thickness, and wall angle. This approach is simple, is of low cost, and is readily scaled up to allow highly reproducible parallel fabrication. The effect of the incident angle of UV exposure and the size of photomask features on the aperture geometry were investigated, yielding aperture diameters as small as 7 MUm and aperture wall angles ranging from 8 degrees to 36 degrees measured from the normal axis. Black lipid membranes were suspended across the apertures and showed normalized conductance values of 0.02-0.05 pS MUm(-2) and breakdown voltages of 400-600 mV. The functionality of the resulting sloped-wall microapertures was validated via measurement of reconstituted alpha-hemolysin activity and the voltage-gated channel activity of alamethicin. PMID- 23987302 TI - Kids Safe and Smokefree (KiSS): a randomized controlled trial of a multilevel intervention to reduce secondhand tobacco smoke exposure in children. AB - BACKGROUND: Secondhand smoke exposure (SHSe) harms children's health, yet effective interventions to reduce child SHSe in the home and car have proven difficult to operationalize in pediatric practice. A multilevel intervention combining pediatric healthcare providers' advice with behavioral counseling and navigation to pharmacological cessation aids may improve SHSe control in pediatric populations. METHODS/DESIGN: This trial uses a randomized, two-group design with three measurement periods: pre-intervention, end of treatment and 12 month follow-up. Smoking parents of children < 11-years-old are recruited from pediatric clinics. The clinic-level intervention includes integrating tobacco intervention guideline prompts into electronic health record screens. The prompts guide providers to ask all parents about child SHSe, advise about SHSe harms, and refer smokers to cessation resources. After receiving clinic intervention, eligible parents are randomized to receive: (a) a 3-month telephone-based behavioral counseling intervention designed to promote reduction in child SHSe, parent smoking cessation, and navigation to access nicotine replacement therapy or cessation medication or (b) an attention control nutrition education intervention. Healthcare providers and assessors are blind to group assignment. Cotinine is used to bioverify child SHSe (primary outcome) and parent quit status. DISCUSSION: This study tests an innovative multilevel approach to reducing child SHSe. The approach is sustainable, because clinics can easily integrate the tobacco intervention prompts related to "ask, advise, and refer" guidelines into electronic health records and refer smokers to free evidence based behavioral counseling interventions, such as state quitlines. TRIAL REGISTRATION: NCT01745393 (clinicaltrials.gov). PMID- 23987303 TI - From invisible structures of SWCNTs toward fluorescent and targeting architectures for cell imaging. AB - Single-walled carbon nanotubes (SWNTs) are unique nanostructures used as cargo systems for variety of diagnostic and therapeutic agents. For taking advantage of these structures in biological processes, they should be visible. Therefore, fluorescence labeling of SWCNTs with various probes is a significant issue. Herein, we demonstrate a simple approach for cell specific imaging and diagnosis by combining SWCNTs with a copolymer poly(para-phenylene) (PPP) containing polystyrene (PSt) and poly(epsilon-caprolactone) (PCL) side chains (PPP-g-PSt PCL). In this approach PPP-g-PSt-PCL is noncovalently attached on carboxyl functional SWCNTs. The obtained fluorescent probe is bound to folic acid (FA) for targeted imaging of folate receptor (FR) positive HeLa cells. In vitro studies demonstrate that this conjugate can specifically bind to HeLa cells and indicate great potential for targeting and imaging studies. PMID- 23987304 TI - GEMBASSY: an EMBOSS associated software package for comprehensive genome analyses. AB - The popular European Molecular Biology Open Software Suite (EMBOSS) currently contains over 400 tools used in various bioinformatics researches, equipped with sophisticated development frameworks for interoperability and tool discoverability as well as rich documentations and various user interfaces. In order to further strengthen EMBOSS in the fields of genomics, we here present a novel EMBOSS associated software (EMBASSY) package named GEMBASSY, which adds more than 50 analysis tools from the G-language Genome Analysis Environment and its Representational State Transfer (REST) and SOAP web services. GEMBASSY basically contains wrapper programs of G-language REST/SOAP web services to provide intuitive and easy access to various annotations within complete genome flatfiles, as well as tools for analyzing nucleic composition, calculating codon usage, and visualizing genomic information. For example, analysis methods such as for calculating distance between sequences by genomic signatures and for predicting gene expression levels from codon usage bias are effective in the interpretation of meta-genomic and meta-transcriptomic data. GEMBASSY tools can be used seamlessly with other EMBOSS tools and UNIX command line tools. The source code written in C is available from GitHub (https://github.com/celery kotone/GEMBASSY/) and the distribution package is freely available from the GEMBASSY web site (http://www.g-language.org/gembassy/). PMID- 23987306 TI - Condensed-phase effects on the structural properties of FCH2CN-BF3 and ClCH2CN BF3: a matrix-isolation and computational study. AB - We have measured several IR bands of FCH2CN-BF3 and ClCH2CN-BF3 in solid nitrogen, argon, and neon. These bands include the B-F asymmetric stretch (nuBF(a)), the B-F symmetric stretch (nuBF(s)), the BF3 symmetric deformation or "umbrella" mode (deltaBF(s)), and the CN stretch (nuCN). For both complexes, the frequencies of these modes shift across the various media, particularly the B-F asymmetric stretching band, and thus they indicate that the inert gas matrix environments significantly alter the structural properties of FCH2CN-BF3 and ClCH2CN-BF3. Furthermore, the frequencies shift in a manner that parallels the dielectric constant of these media, which suggests a progressive contraction of the B-N distances in these systems and also that it parallels the ability of the medium to stabilize the increase in polarity that accompanies the bond contraction. We have also mapped the B-N distance potentials for FCH2CN-BF3 and ClCH2CN-BF3 using several density functional and post-Hartree-Fock methods, all of which reveal a flat, shelflike region that extends from the gas-phase minimum (near 2.4 A) toward the inner wall (to about 1.7 A). Furthermore, we were able to rationalize the medium effects on the structure by constructing hybrid bond potentials composed of the electrostatic component of the solvation free energy and the gas-phase electronic energy. These curves indicate that the solvation energies are greatest at short B-N distances (at which the complex is more polar), and ultimately, the potential minima shift inward as the dielectric constant of the medium increases. PMID- 23987305 TI - Predictors of postoperative renal functional damage after nephron-sparing surgery. AB - BACKGROUND: Although nephron-sparing surgery has been reported not to affect total renal function, it is a non-negligible fact that functional damage of the operated kidney usually results, for various reasons. This study aimed to explore the effects of preoperative baseline characteristics, tumor characteristics, and function protection methods on postoperative renal damage. METHODS: This study was a retrospective review of 51 patients who underwent open nephron-sparing surgery. The mean age of the patients (39 men, 12 women) was 54.2 +/- 13.9 years, range 32 to 71 years. The glomerular filtration rate (GFR) was measured preoperatively and 6th months after the operation. Univariate analysis was used to screen indicators with significant differences in different levels of renal function damage. All variables found to be significant on univariate analysis were entered into a multiple logistic regression model to predict risk factors for renal function damage. RESULTS: Univariate analysis showed that there was a significant difference in age, GFR of operated kidney, tumor diameter, tumor depth, and ischemic protection type between patients with little damage and those with heavy damage (P < 0.05). Forward stepwise logistic regression analysis suggested that age (odds ratio, 3.08; 95% confidence interval 1.78 to 7.04; P = 0.037), preoperative GFR of operated kidney (odds ratio, 0.51; 95% confidence interval 0.11 to 0.73; P = 0.033), and tumor diameter (odds ratio, 5.49; 95% confidence interval 2.14 to 7.88; P = 0.012) and depth (odds ratio, 5.82; 95% confidence interval 2.66 to 8.06; P = 0.010) were independent risk factors for postoperative renal function damage. CONCLUSIONS: Patients with older age, poor renal function, and large tumor diameter and depth might be at higher risk of renal function damage after nephron-sparing surgery. PMID- 23987307 TI - Identification of a novel infection-enhancing epitope on dengue prM using a dengue cross-reacting monoclonal antibody. AB - BACKGROUND: Dengue virus (DENV) infection is the most important arthropod- borne viral disease in human, but antiviral therapy and approved vaccines remain unavailable due to antibody-dependent enhancement (ADE) phenomenon. Many studies showed that pre-membrane (prM)-specific antibodies do not efficiently neutralize DENV infection but potently promote ADE infection. However, most of the binding epitopes of these antibodies remain unknown. RESULTS: In the present study, we characterized a DENV cross-reactive monoclonal antibody (mAb), 4D10, that neutralized poorly but potently enhanced infection of four standard DENV serotypes and immature DENV (imDENV) over a broad range of concentration. In addition, the epitope of 4D10 was successfully mapped to amino acid residues 14 to18 of DENV1-4 prM protein using a phage-displayed peptide library and comprehensive bioinformatics analysis. We found that the epitope was DENV serocomplex cross-reactive and showed to be highly immunogenic in Balb/c mice. Furthermore, antibody against epitope peptide PL10, like 4D10, showed broad cross reactivity and weak neutralizing activtity with four standard DENV serotypes and imDENV but significantly promoted ADE infection. These results suggested 4D10 and anti-PL10 sera were infection-enhancing antibodies and PL10 was infection enhancing epitope. CONCLUSIONS: We mapped the epitope of 4D10 to amino acid residues 14 to18 of DENV1-4 prM and found that this epitope was infection enhancing. These findings may provide significant implications for future vaccine design and facilitate understanding the pathogenesis of DENV infection. PMID- 23987308 TI - Effects of Ankaferd on anastomotic healing of colon. AB - BACKGROUND: Ankaferd (Ankaferd blood stopper(r), ABS) is a recently developed topical hemostatic agent. ABS is a standardized mixture of the plants Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica. Through its effects on the endothelium, blood cells, angiogenesis, cellular proliferation, vascular dynamics, and cell mediators; Ankaferd plays a part in inflammation and hemostasis processes. The aim of this experimental study is to assess the effects of ABS on the left colonic anastomoses under normal, septic, and ischemic conditions. METHODS: Forty-eight Wistar Albino male rats were divided into six weight-matched equal groups: A, anastomosis in normal condition (n = 8); AA, anastomosis with ABS in normal condition (n = 8); AS, anastomosis in septic condition (n = 8); AAS, anastomosis with ABS in septic condition (n = 8); AI, anastomosis in ischemic condition (n = 8); and AAI, anastomosis with ABS in ischemic condition (n = 8). Blood and tissue samples were taken for the histopathological and biochemical studies after the anastomotic bursting pressures were measured. RESULTS: Higher hydroxyproline levels (p = .048) and angiogenesis (p = .038) were observed in the sepsis-induced rats compared to the control group. The inflammatory activity, fibrosis, and granulation were comparable in all experimental groups. Ankaferd improved the angiogenesis under septic conditions (AAS) when compared to the control group (AI; p = .038). CONCLUSIONS: ABS may support anastomotic healing in septic conditions. Topical ABS application controlling the mucosal bleeding at the cut ends of the colon may also improve the anastomotic wound healing by means of increasing mechanical strength and positively affecting angiogenesis. Further studies shall focus on the clinical importance of those findings. PMID- 23987309 TI - Histologic evidence of intrapulmonary anastomoses by three-dimensional reconstruction in severe bronchopulmonary dysplasia. AB - RATIONALE: Bronchopulmonary dysplasia (BPD) is the chronic lung disease of infancy that occurs in premature infants after oxygen and ventilator therapy for acute respiratory disease at birth. Despite improvement in current therapies, the clinical course of infants with BPD is often characterized by marked hypoxemia that can become refractory to therapy. Preacinar anatomic and functional communications between systemic and pulmonary vascular systems has been established in fetal lungs, but whether increased intrapulmonary anastomotic vessels or their failure to regress after birth contributes to hypoxemia in preterm infants with BPD is unknown. OBJECTIVES: We sought to find histologic evidence of intrapulmonary anastomotic vessels in lungs of patients who died of severe BPD. METHODS: We collected lung tissues from fatal BPD cases and performed histology, immunohistochemistry, and high-precision three-dimensional reconstruction techniques. MEASUREMENTS AND MAIN RESULTS: We report histologic evidence of intrapulmonary vessels that bridge pulmonary arteries and veins in the distal lungs of infants dying with severe BPD. These prominent vessels appear similar to "misaligned pulmonary veins" described in the lethal form of congenital lung disorder, alveolar capillary dysplasia. CONCLUSIONS: We found striking histological evidence of precapillary arteriovenous anastomotic vessels in the lungs of infants with severe bronchopulmonary dysplasia. We propose that persistence or expansion of these vessels after premature birth provides the anatomic basis for intrapulmonary shunt and hypoxemia in neonates with severe bronchopulmonary dysplasia and may play a significant role in the morbidity and mortality of BPD. PMID- 23987310 TI - Properties of aqueous solutions of lentinan in the absence and presence of zwitterionic surfactants. AB - Morphological and conformational transitions of lentinan (LT), a beta-glucan extracted from Shiitake mushrooms (Lentinula edodes), were investigated at different concentrations of aqueous NaOH, using Small Angle X-ray Scattering (SAXS) technique. At low NaOH(aq) concentration LT chains are self-associated and adopt the triple helix form where as at higher NaOH concentrations the polymer chains undergo a transition to random coil chains. Also, the presence of fractal dimensions was observed through analysis of the exponential decay of the scattering intensity as a function of the scattering angle. In addition, the lateral radius of gyration was determined for LT in different concentrations of NaOH solution, indicating a rigid triple helix present as a small rod-like structure. Interactions of LT with two zwitterionic surfactants were investigated by surface tension, fluorescence, and static light scattering measurements. Experimental data showed that the formation of LT-(surfactant) complexes occurred through a cooperative process. PMID- 23987311 TI - Characterization and hypoglycemic effect of a polysaccharide extracted from the fruit of Lycium barbarum L. AB - Diabetes mellitus is a group of complicated metabolic disorders characterized by high blood glucose level and inappropriate insulin secreting capacity due to decreased glucose metabolism and pancreatic beta cell mass or dysfunction of beta cells. Thus, improving glucose metabolism and preserving beta cell mass and function might be useful for the treatment of diabetes. In this study, a novel acidic polysaccharide LBP-s-1 extracted from Lycium barbarum L. was obtained by purification using macroporous resin and ion-exchanged column. Monosaccharide composition analysis indicated that LBP-s-1 was comprised of rhamnose, arabinose, xylose, mannose, glucose, galactose, galacturonic acid in the molar ratio of 1.00:8.34:1.25:1.26:1.91:7.05:15.28. The preliminary structure features of LBP-s 1 were investigated by FT-IR, (1)H NMR and (13)C NMR. In vitro and in vivo hypoglycemic experiments showed that LBP-s-1 had significant hypoglycemic effects and insulin-sensitizing activity through increasing glucose metabolism and insulin secretion and promoting pancreatic beta cell proliferation. Preliminary mechanisms were also elucidated. PMID- 23987312 TI - Encapsulation of volatiles in nanofibrous polysaccharide membranes for humidity triggered release. AB - A single-step electrospinning process will be applied to a blend of edible carbohydrate polymers (pullulan and beta-cyclodextrin) to encapsulate bioactive aroma compounds and allow a humidity-triggered release. The encapsulation is rapid and efficient and the final product is an active nanofibrous membrane that can be directly used for food or active packaging applications. The membrane hosts small and homogeneously dispersed crystals of cyclodextrin-aroma complexes which are formed during the electrospinning. With this type of structure, the release of aroma compound is negligible at ambient conditions (23 degrees C and 55% UR) even at high temperature (up to 230 degrees C), and it occurs beyond a given relative humidity threshold (90%), useful for food packaging applications. The mass fraction of free aroma released is directly related to the water activity of the system, namely, phi=aW(n)/(aW(n)+Kapp) explaining the observed key role played by the relative humidity on the release of the aroma compounds. PMID- 23987313 TI - Polysaccharide structure of tetrasporic red seaweed Tichocarpus crinitus. AB - Sulfated polysaccharide isolated from tetrasporic plants of Tichocarpus crinitus was investigated. The polysaccharide was isolated by two methods: with water extraction at 80 degrees C (HT) and with a mild alkaline extraction (AE). The extracted polysaccharides were presented by non-gelling ones only, while galactose and 3,6-AG were the main monosaccharides, at the same time amount of 3,6-AG in AE polysaccharides was the similar to that of HT. According to methods of spectroscopy and mass spectrometry, the polysaccharide from tetrasporic T. crinitus contains main blocks of 1,3-linked beta-D-galactopyranosyl-2,4 disulfates and 1,4-linked 3,6-anhydro-alpha-D-galactopyranosyl while 6-sulfated 4 linked galactopyranosyl resudies are randomly distributed along the polysaccharide chain. The alkaline treatment of HT polysaccharide results in obtaining polysaccharide with regular structure that composed of alternating 1,3 linked beta-D-galactopyranosyl-2,4-disulfates and 1,4-linked 3,6-anhydro-alpha-D galactopyranosyl residues. Native polysaccharide (HT) possessed both high anticoagulant and antiplatelet activity measured by fibrin clotting and platelet aggregation induced by collagen. This activity could be connected with peculiar chemical structure of HT polysaccharide which has high sulfation degree and contains also 3,6-anhydrogalactose in the polymer chain. PMID- 23987314 TI - Preparation, characterization, and in vitro efficacy of O-carboxymethyl chitosan conjugate of melphalan. AB - A series of melphalan-O-carboxymethyl chitosan (Mel-OCM-chitosan) conjugates with different spacers were prepared and structurally characterized. All conjugates showed satisfactory water-solubility (160-217 times of Mel solubility). In vitro drug release behaviors by both chemical and enzymatic hydrolysis were investigated. The prodrugs released Mel rapidly within papain and lysosomal enzymes of about 40-75%, while released only about 4-5% in buffer and plasma, which suggested that the conjugates have good plasma stability and the hydrolysis in both papain and lysosomes occurs mostly via enzymolysis. It was found that the spacers have important effect on the drug content, water solubility, drug release properties and cytotoxicity of Mel-OCM-chitosan conjugates. Cytotoxicity studies by MTT assay demonstrated that these conjugates had 52-70% of cytotoxicity against RPMI8226 cells in vitro as compared with free Mel, indicating the conjugates did not lose anti-cancer activity of Mel. Overall these studies indicated Mel-OCM-chitosan conjugates as potential prodrugs for cancer treatment. PMID- 23987315 TI - Hydrolysis of wheat B-starch and characterisation of acetylated maltodextrin. AB - Wheat B-starch was hydrolysed by alpha-amylase "Liquozyme supra" from Bacillus licheniformis at 90 degrees C and pH 7. After 2 h, the dextrose equivalent was 18; according to size exclusion chromatography, however, the hydrolysate contained not only dominant malto-oligosaccharides with the degree of polymerisation (DP)<10 but also more than 20% of components with DP higher than 40. The product was acetylated to a high degree as verified by FTIR and (1)H NMR (degree of substitution DS=3.1); nevertheless, detailed analysis of the MALDI-TOF mass spectra of the product showed that most of the malto-oligosaccharides molecules contained one or two residual hydroxyls. Size exclusion chromatography confirmed that the acetylated maltodextrin still contained a significant part with DP>40. This non-uniformity of acetylated maltodextrin, both with respect to DP and to DS, must be taken into account in the development of acetylated maltodextrin applications such as use as plasticisers or compatibilisers in biodegradable composites. PMID- 23987316 TI - Spinning of hydroalcoholic chitosan solutions. AB - We investigated the spinning of hydroalcoholic chitosan solutions. The dope composition was optimized in order to obtain a continuous alcogel fiber by water evaporation on heating the extruded hydroalcoholic solution. This alcogel fiber was then neutralized in aqueous alkali baths and washed in water to eliminate the residual alcohol and salts before final drying. Depending on the alcohol content in the filament at the neutralization step, on specific alcohol-chitosan interactions and on the nature and concentration of the coagulation base, the process yielded semicrystalline chitosan fibers with different proportions of anhydrous and hydrated allomorphs. Contrarily to the classical annealing method, the formation of mainly anhydrous crystals was obtained without significant molecular weight decrease by neutralizing the polymer in hydrophobic conditions. The control of allomorph content was shown to be related to the hydrophobicity of the solvent (alcohol fraction) at the neutralization step. PMID- 23987317 TI - Preparation and in vitro evaluation of xanthan gum facilitated superabsorbent polymeric microspheres. AB - Interpenetrating polymer network (IPN) hydrogel microspheres of xanthan gum (XG) based superabsorbent polymer (SAP) and poly(vinyl alcohol) (PVA) were prepared by water-in-oil (w/o) emulsion crosslinking method for sustained release of ciprofloxacin hydrochloride (CIPRO). The microspheres were prepared with various ratios of hydrolyzed SAP to PVA and extent of crosslinking density. The prepared microspheres with loose and rigid surfaces were evidenced by scanning electron microscope (SEM). Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis confirmed the IPN formation. Differential scanning calorimetry (DSC) study was performed to understand the dispersion nature of drug after encapsulation. The in vitro drug release study was extensively evaluated depending on the process variables in both acidic and alkaline media. All the formulations exhibited satisfactory physicochemical and in vitro release characteristics. Release data indicated a non-Fickian trend of drug release from the formulations. Based on the results, this study suggest that CIPRO loaded IPN microspheres were suitable for sustained release application. PMID- 23987318 TI - Developing hydroxypropyl methylcellulose/hydroxypropyl starch blends for use as capsule materials. AB - Blends of hydroxypropyl methylcellulose (HPMC) with up to 70% hydroxypropyl starch (HPS) were developed for use as hard capsule materials. Polyethylene glycol (PEG) was used as both a plasticizer and a compatibilizer in the blends. In order to prepare hard capsules for pharmaceutical application using the well established method of dipping stainless steel mold pins into solution then drying at certain temperature, equilibrated solutions with higher solids concentration (20%) were investigated and developed. The solutions, films and capsules of the different HPMC/HPS blends were characterized by viscosity, transparency, tensile testing, water contact angle, SEM, as well as FTIR. The results showed that the blend system is immiscible but compatible in certain degree, especially after adding PEG. The hydroxypropylene groups grafted onto both cellulose and starch improved the compatibility between the HPMC and the modified starch. The higher viscosity of starch at lower temperature improved the viscosity balance of the system, which enlarged the operation window for the dipping-drying technique. The PEG increased the transparency and toughness of the various blends. By optimizing temperature and incubation time to control viscosity, capsules of various blends were successfully developed. PMID- 23987319 TI - Synthesis of HPMC stabilized nickel nanoparticles and investigation of their magnetic and catalytic properties. AB - Nickel nanoparticles synthesized from NiCl2.6H2O by hydrazine hydrate in mixed solvent of ethanol and water in the presence of hydroxypropylmethylcellulose (HPMC) as protective and stabilizing agents. The morphology and sizes of synthesized Ni nanoparticles were studied by field-emission-scanning-electron microscopy (FESEM). Structural properties of nanoparticles were examined by X-ray diffraction (XRD). The polymer stabilized Ni nanoparticles were characterized by Fourier-transform infrared (FTIR) spectroscopy. The magnetic measurement showed that the resultant Ni nanoparticles were ferromagnetic. Also, the saturation magnetization (MS), remanent magnetization (MR) and coercivity (MR) were observed to increase with decreasing temperature. The results of magnetic characterization showed that the magnetic properties of the HPMC stabilized Ni nanoparticles are quite different from those of the bared Ni nanoparticles. All the observed magnetic properties essentially reflected the very typical nanoparticle type nature. Consequently, the resulting Ni nanoparticles were found to be highly active and recyclable catalyst for Suzuki coupling reactions. PMID- 23987321 TI - Preparation of carboxylic acid-bearing polysaccharide nanofiber made from euglenoid beta-1,3-glucans. AB - This paper introduces a new strategy for creating surface modified polysaccharide nanofibers. To demonstrate proof of principle, the synthesis, structure, and self assembly behavior of a carboxylic acid-bearing polysaccharide made from paramylon (beta-1,3-glucan) and succinic anhydride were investigated. Examination by a combination of NMR, FT-IR, and SEC-MALLS confirmed that successful preparation of the desired succinylated paramylon without significant depolymerization. NMR, SEC MALLS, visible absorption and CD spectroscopic analyses indicated that the paramylon derivative forms the triplex structure in solutions. SEM observation revealed that succinylated paramylon forms a nanofiber that has carboxylic acid on the surface. PMID- 23987320 TI - Preparation and characterization of mucilage polysaccharide for biomedical applications. AB - In the present investigation, the polysaccharide/mucilage from waste of Abelmoscus esculentus by modification in hot extraction using two different solvents (Acetone, Methanol) were extracted, characterized and further compared with seaweed polysaccharide for their potential applications. The percentage yield, emulsifying capacity and swelling index of this mucilage were determined. The macro algae and okra waste, gave high % yield (22.2% and 8.6% respectively) and good emulsifying capacity (EC%=52.38% and 54.76% respectively) with acetone, compared to methanol (11.3% and 0.28%; EC%=50%) (PH=7) while swelling index was greater with methanol than acetone extracts respectively. The infrared (I.R.) spectrum of the samples was recorded to investigate the chemical structure of mucilage. Thermal analysis of the mucilage was done with TGA (Thermal Gravimetric Analyzer) and DSC (Differential Scanning Calorimeter) which showed both okra and algal polysaccharide were thermostable hydrogels. PMID- 23987322 TI - Characterization of films made with chayote tuber and potato starches blending with cellulose nanoparticles. AB - The aim of this study was to characterize chayotextle starch films reinforced with cellulose (C) and cellulose nanoparticle (CN) (at concentrations of 0.3%, 0.5%, 0.8% and 1.2%), using thermal, mechanical, physicochemical, permeability, and water solubility tests. C was acid-treated to obtain CN. The films were prepared by casting; potato starch and C were used as the control. The solubility of the starch films decreased with the addition of C and CN compared with its respective film without C and CN. No statistical difference (alpha=0.05) was found in the films added with different concentrations of C and CN. In general, the mechanical properties were improved with the addition of C and CN, and higher values of tensile strength and elastic modulus were determined in the films reinforced with CN. The melting temperature and enthalpy increased with the addition of C and CN, and the values of both thermal parameters were higher in the films with CN than with C; the enthalpy value of the film decreased when the concentration of C or CN increased in the composite. Low concentration of C and CN is better distributed in the matrix film. The addition of C and CN in the starch films improved some mechanical, barrier, and functional properties. PMID- 23987323 TI - In vitro evaluation of antioxidant defense mechanism and hemocompatibility of mauran. AB - Mauran (MR), a highly polyanionic sulfated exopolysaccharide was extracted from moderately halophilic bacterium; Halomonas maura and characterized using X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. Purified MR was evaluated for antioxidant defense mechanisms under in vitro conditions using L929, mouse fibroblast cell line and mice liver homogenate. It was demonstrated that MR could impart protective effect against oxidative stress in both cells and tissue up to a concentration of 500 MUg, which is found to be safe under laboratory conditions. Various enzymatic and non-enzymatic parameters of antioxidant mechanisms were evaluated and concluded that MR has the tendency to maintain a balance of antioxidative enzymes with in the test systems studied. Also, hemocompatibility assay performed revealed that MR has a lesser hemolytic index and exhibited a prolonged clotting time, which shows both antihemolytic, and antithrombogenic nature respectively. Furthermore, absorption studies performed using fluorescent-labeled MR confirmed that MR accumulated within the cell cytoplasm neither induced cellular lysis nor affected the cell integrity. PMID- 23987324 TI - Anti-glycated activity prediction of polysaccharides from two guava fruits using artificial neural networks. AB - High-efficiency ultrasonic treatment was used to extract the polysaccharides of Psidium guajava (PPG) and Psidium littorale (PPL). The aims of this study were to compare polysaccharide activities from these two guavas, as well as to investigate the relationship between ultrasonic conditions and anti-glycated activity. A mathematical model of anti-glycated activity was constructed with the artificial neural network (ANN) toolbox of MATLAB software. Response surface plots showed the correlation between ultrasonic conditions and bioactivity. The optimal ultrasonic conditions of PPL for the highest anti-glycated activity were predicted to be 256 W, 60 degrees C, and 12 min, and the predicted activity was 42.2%. The predicted highest anti-glycated activity of PPG was 27.2% under its optimal predicted ultrasonic condition. The experimental result showed that PPG and PPL possessed anti-glycated and antioxidant activities, and those of PPL were greater. The experimental data also indicated that ANN had good prediction and optimization capability. PMID- 23987325 TI - Spray-dried voriconazole-cyclodextrin complexes: solubility, dissolution rate and chemical stability. AB - The present work investigates the effect of complexation with hydroxypropyl-beta cyclodextrin (HPBCD) and 2-O-methyl-beta-cyclodextrin (2-O-MBCD), on voriconazole solubility, dissolution rate and chemical stability. Drug-cyclodextrin complexes were prepared as aqueous solutions, which were spray-dried, and their properties were compared to wet ground samples and physical mixtures. DSC analysis revealed absence of crystalline voriconazole from spray-dried complexes. FTIR spectroscopy indicated changes in the H-bonding network of the hydroxyl groups of cyclodextrin following drug inclusion. Dissolution rate of voriconazole was significantly higher from spray-dried complexes with either cyclodextrin in comparison with free drug, physical mixtures, or wet ground mixtures. However, two degradation impurities were found in aged samples, with slightly higher impurity level with HPBCD. Performed solubility studies suggested that 2-O-MBCD is more efficient solubilizer. Molecular docking simulations showed a difference in the 1:1 binding affinities and sites, with HPBCD surprisingly forming complexes of much lower energy, thus suggesting a multiple rather than a 1:1 complexation. PMID- 23987326 TI - Uptake of perchlorate from aqueous solutions by amine-crosslinked cotton stalk. AB - Virgin cotton stalk was produced into an effective biosorbent for perchlorate adsorption. Surface analysis including BET surface area and SEM illustrated the reduction of porous structure in amine-crosslinked cotton stalk (AC-CS). Elemental and zeta potential analysis validated the graft of some positively charged amine groups on surface of AC-CS. Spectra analysis (XPS, FTIR and Raman spectra) suggested that interaction between AC-CS and ClO4(-) should be based on electrostatic attraction. The maximum adsorption capacity (qmax) of AC-CS for perchlorate at different pHs (3.0, 6.0, 9.0 and 11.0) were calculated as 29.6, 42.6, 41.0 and 33.0 mg/g, respectively. The saturated perchlorate uptakes in column were in range of 25.0-38.1 mg/g at different pHs. In addition, the exhausted AC-CS column was regenerated by 0.5 mol/L of NaCl solution, which was adequate for almost complete desorption of the perchlorate. PMID- 23987327 TI - Properties of polylactic acid composites reinforced with oil palm biomass microcrystalline cellulose. AB - In this work, polylactic acid (PLA) composites filled with microcrystalline cellulose (MCC) from oil palm biomass were successfully prepared through solution casting. Fourier transform infrared (FT-IR) spectroscopy indicates that there are no significant changes in the peak positions, suggesting that incorporation of MCC in PLA did not result in any significant change in chemical structure of PLA. Thermogravimetric analysis was conducted on the samples. The T50 decomposition temperature improved with addition of MCC, showing increase in thermal stability of the composites. The synthesized composites were characterized in terms of tensile properties. The Young's modulus increased by about 30%, while the tensile strength and elongation at break for composites decreased with addition of MCC. Scanning electron microscopy (SEM) of the composites fractured surface shows that the MCC remained as aggregates of crystalline cellulose. Atomic force microscopy (AFM) topographic image of the composite surfaces show clustering of MCC with uneven distribution. PMID- 23987328 TI - Sulfonated hierarchical H-USY zeolite for efficient hydrolysis of hemicellulose/cellulose. AB - Sulfonated hierarchical H-USY zeolite was prepared and characterized by X-ray diffraction, N2 physisorption, Fourier transform infrared spectroscopy, inductively coupled plasma atomic emission spectroscopy, temperature-programmed desorption of ammonia, and acid-base titration. It was proved that sulfonic group was successfully anchored onto the hierarchical H-USY zeolite. The acidity of the hierarchical H-USY was remarkably improved. Sulfonated hierarchical H-USY zeolite was efficient for the hydrolysis of hemicellulose and cellulose. The yield of TRS for hydrolysis of hemicellulose reached 78.0% at 140 degrees C for 9h. For hydrolysis of alpha-cellulose, 60.8% conversion with 22.4% yield of glucose was obtained. Even for microcrystalline cellulose, 43.7% conversion with 15.1% yield of glucose can be obtained. These results are much higher than those obtained over hierarchical H-USY zeolite, indicating that both the acidity and the pore structure determine the activity of zeolite as catalyst in the hydrolysis of biomass. PMID- 23987329 TI - Rheology and thermal degradation of isocyanate-functionalized methyl cellulose based oleogels. AB - The -NCO-functionalization of methyl cellulose with HMDI and its application to chemically gel the castor oil is explored in this work by analyzing the influence of functionalization degree on the rheological and thermogravimetric behavior of resulting chemical oleogels. With this aim, different methyl cellulose chemical modifications were achieved by limiting the proportion of HMDI and, subsequently, oleogels were obtained by dispersing these polymers in castor oil and promoting the reaction between those biopolymers and the hydroxyl groups located in the ricinoleic fatty acid chain. -NCO-functionalized methyl cellulose-based oleogels were characterized from themogravimetric and rheological points of view. Suitable thermal resistance and rheological characteristics were found in order to propose these oleogels as promising bio-based alternatives to traditional lubricating greases based on non-renewable resources. In general, -NCO-functionalized methyl cellulose thermally decomposed in three main steps whereas resulting oleogels thermal decomposition takes place in one main single stage which comprises the thermal degradation of both the polymer and the castor oil. Temperature range for thermal degradation is broadened when using highly -NCO-functionalized methyl cellulose. A cross-linked viscoelastic gel was obtained with methyl cellulose functionalized in a relatively low degree (around 6% -NCO molar content). The rheological properties of highly functionalized methyl cellulose-based oleogels evolve during several months of aging, but mainly during the first week, due to the progress of the reaction between -NCO functional groups and castor oil -OH groups. SAOS functions analyzed and oleogel relative elasticity increase with the functionalization degree. Oleogel linear viscoelastic response is also extremely dependent on NCO-functionalized methyl cellulose concentration. PMID- 23987330 TI - Preparation and characterization of bionanocomposite fiber based on cellulose and nano-SiO2 using ionic liquid. AB - Microcrystalline cellulose (MCC)/nano-SiO2 composite fibers were processed from solutions in 1-allyl-3-methylimidazolium chloride (AMIMCl) by the method of dry jet wet spinning. The oscillatory shear measurements demonstrated that the gel network formed above 10 wt% nano-SiO2 and the complex viscosity increased with increasing nano-SiO2. Remarkably, the shear viscosity of the nanofluids was even lower than solutions without nano-SiO2 under high shear rates. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images revealed that well-dispersed particles exhibit strong interfacial interactions with cellulose matrix. Measurements on wide-angle X-ray diffraction (WAXD) indicated that the regenerated cellulose and nanocomposite fibers were the typical cellulose II crystalline form, which was different from the native cellulose with the polymorph of Type I. The tensile strength of the nanocomposite fibers was larger than that of pure cellulose fiber and showed a tendency to increase and then decrease with increasing nano-SiO2. Furthermore, the nanocomposite fibers exhibited improved thermal stability. PMID- 23987331 TI - Environmentally friendly microwave ionic liquids synthesis of hybrids from cellulose and AgX (X=Cl, Br). AB - The purpose of this article was to explore an environmentally friendly strategy to synthesis of biomass-based hybrids. Herein, microwave-assisted ionic liquids method was applied to fabricate the hybrids from cellulose and AgX (X=Cl, Br) using cellulose and AgNO3. The ionic liquids act simultaneously as a solvent, a microwave absorber, and a reactant. Ionic liquids provided Cl(-) or Br(-) to the synthesis of AgCl or AgBr crystals; thus no additional reactant is needed. The products are characterized by X-ray powder diffraction (XRD), Fourier transform infrared spectrometry (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and differential thermal analysis (DTA). The cellulose-Ag/AgCl hybrid and cellulose-Ag/AgBr hybrid were also obtained by using cellulose-AgCl and cellulose-AgBr hybrids as precursors. This environmentally friendly microwave-assisted ionic liquids method is beneficial to the hybrids with high dispersion. PMID- 23987332 TI - Synthesis and characterization of N-(2-aminoethyl)-2-acetamidyl gellan gum with potential biomedical applications. AB - N-(2-aminoethyl)-2-acetamidyl gellan gum (GCM-EDA) was prepared by carboxymethylation (via nucleophilic substitution of primary hydroxyl groups of the beta-D-glucose unit of gellan gum, in the presence of alkali and chloroacetic acid) and reaction with tert-butyl N-(2-aminoethyl) carbamate (N-Boc-EDA) using 1 ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDAC) as an activator, followed by deprotection with trifluoroacetic acid. The structural confirmation and characterization of N-(2-aminoethyl)-2-acetamidyl gellan gum was performed by spectroscopic, rheological and thermogravimetric analysis, and in vitro tests showed a lack of cytotoxicity which is indicative of the potential of this material to be used in biomedical applications. PMID- 23987333 TI - Effect of Tween 80 on the production of curdlan by Alcaligenes faecalis ATCC 31749. AB - This study aims to investigate the effects of Tween 80 on curdlan production, cell growth, and glucosyltransferase activity. The addition of Tween 80 to the culture medium increased curdlan production. However, curdlan production did not increase further when excessive Tween 80 (>0.3% Tween 80) was added to the culture medium. The addition of Tween 80 to the culture medium did not affect cell growth. The glucosyltransferase activity involved in the curdlan synthesis increased with the increase of Tween 80 concentration. The glucosyltransferase activity did not increase further when excessive Tween 80 (>0.3% Tween 80) was added to the culture medium. Maximum curdlan was observed at day 5 and then levelled off. The biomass continued to increase until the end of the experimental period (6d). Maximum glucosyltransferase activity was also observed at day 5 and decreased thereafter. The results indicate that the enhanced curdlan production by Tween 80 is highly correlated with glucosyltransferase activity. PMID- 23987334 TI - Reduction/pH dual-sensitive PEGylated hyaluronan nanoparticles for targeted doxorubicin delivery. AB - To minimize the side effect of chemotherapy, a novel reduction/pH dual-sensitive drug nanocarrier, based on PEGylated dithiodipropionate dihydrazide (TPH) modified hyaluronic acid (PEG-SS-HA copolymer), was developed for targeted delivery of doxorubicin (DOX) to hepatocellular carcinoma. The copolymer was synthesized by reductive amination via Schiff's base formation between TPH modified HA and galactosamine-conjugated poly(ethylene glycol) aldehyde/methoxy poly(ethylene glycol) aldehyde. Conjugation of DOX to PEG-SS-HA copolymer was accomplished through the hydrazone linkage formed between DOX and PEG-SS-HA, and confirmed by FTIR and (1)H NMR spectra. The polymer-DOX conjugate could self assemble into spherical nanoparticles (~150 nm), as indicated by TEM and DLS. In vitro release studies showed that the DOX-loaded nanoparticles could release DOX rapidly under the intracellular levels of pH and glutathiose. Cellular uptake experiments demonstrated that the nanoparticles could be efficiently internalized by HepG2 cells. These results indicate that the PEG-SS-HA copolymer holds great potential for targeted intracellular delivery of DOX. PMID- 23987335 TI - Carbon nanotubes in blends of polycaprolactone/thermoplastic starch. AB - Despite the importance of polymer-polymer multiphase systems, very little work has been carried out on the preferred localization of solid inclusions in such multiphase systems. In this work, carbon nanotubes (CNT) are dispersed with polycaprolactone (PCL) and thermoplastic starch (TPS) at several CNT contents via a combined solution/twin-screw extrusion melt mixing method. A PCL/CNT masterbatch was first prepared and then blended with 20 wt% TPS. Transmission and scanning electron microscopy images reveal a CNT localization principally in the TPS phase and partly at the PCL/TPS interface, with no further change by annealing. This indicates a strong driving force for the CNTs toward TPS. Young's model predicts that the nanotubes should be located at the interface. X-ray photoelectron spectroscopy (XPS) of extracted CNTs quantitatively confirms an encapsulation by TPS and reveals a covalent bonding of CNTs with thermoplastic starch. It appears likely that the nanotubes migrate to the interface, react with TPS and then are subsequently drawn into the low viscosity TPS phase. In a low shear rate/low shear stress internal mixer the nanotubes are found both in the PCL phase and at the PCL/TPS interface and have not completed the transit to the TPS phase. This latter result indicates the importance of choosing appropriate processing conditions in order to minimize kinetic effects. The addition of CNTs to PCL results in an increase in the crystallization temperature and a decrease in the percent crystallinity confirming the heterogeneous nucleating effect of the nanotubes. Finally, DMA analysis reveals a dramatic decrease in the starch rich phase transition temperature (~26 degrees C), for the system with nanotubes located in the TPS phase. PMID- 23987336 TI - Dodonaea viscosa var. angustifolia leaf: new source of polysaccharide and its anti-oxidant activity. AB - Ultrasonic technology was applied for polysaccharide extraction from the leaves of Dodonaea viscosa and response surface methodology (RSM) was used to optimize the effects of processing parameters on polysaccharide extraction yield. Three independent variables were extraction time (X1), extraction temperature (X2) and ultrasonic power (X3), respectively. The statistical analysis indicated the independent variables (X1, X2, X3), the quadratic terms (X11 and X33) and the interaction terms (X1X2, X1X3, X2X3) had significant effects on the yield of polysaccharides (P<0.05). The optimal extraction conditions of D. viscosa leaf were determined as follows: extraction time 50.54 min, extraction temperature 85 degrees C and ultrasonic power 400 W. Under these conditions, the experimental yield of polysaccharides was 9.455+/-0.24%, which was agreed closely with the predicted value (9.398%). The evaluation of anti-oxidant activity suggested that the polysaccharide exhibited significant protection against DPPH and hydroxyl radicals and could be explored as a nutraceutical agent. PMID- 23987337 TI - Synthesis and properties of fatty acid starch esters. AB - Being completely bio-based, fatty acid starch esters (FASEs) are attractive materials that represent an alternative to crude oil-based plastics. In this study, two synthesis methods were compared in terms of their efficiency, toxicity and, especially, product solubility with starch laurate (C12) as model compound. Laurates (DS>2) were obtained through transesterification of fatty acid vinylesters in DMSO or reaction with fatty acid chlorides in pyridine. The latter lead to higher DS-values in a shorter reaction time. But due to the much better solubility of the products compared to lauroyl chloride esterified ones, vinylester-transesterification was preferred to optimize reaction parameters, where reaction time could be shortened to 2h. FASEs C6-C18 were also successfully prepared via transesterification. To determine the DS of the resulting starch laurates, the efficient ATR-IR method was compared with common methods (elementary analysis, (1)H NMR). Molar masses (Mw) of the highly soluble starch laurates were analyzed using SEC-MALLS (THF). High recovery rates (>80%) attest to the outstanding solubility of products obtained through transesterification, caused by a slight disintegration during synthesis. Particle size distributions (DLS) demonstrated stable dissolutions in CHCl3 of vinyl laurate esterified - contrary to lauroyl chloride esterified starch. For all highly soluble FASEs (C6 C18), formation of concentrated solutions (10 wt%) is feasible. PMID- 23987338 TI - Purification, characterization and immunostimulatory activity of polysaccharide from Cipangopaludina chinensis. AB - In this study, we investigated the purification, preliminary characterization and immunostimulatory activity in vivo of polysaccharide from Cipangopaludina chinensis (CCPS). Firstly, crude CCPS was prepared by hot water extraction. And the crude CCPS was sequentially purified by chromatography of DEAE-52 and Sephadex G-100, resulting in two purified fractions of CCPS-1 and CCPS-2. We found the two fractions were homogeneous heteropolysaccharides mainly composed of rhamnose and glucose with the average molecular weight of 226 and 235 kDa, respectively. CCPS-2 was quite different from CCPS-1. It had much higher content of uronic acid and sulfuric radical. For immunostimulatory activity in vivo, crude CCPS could significantly increase the thymus and spleen indices, enhance the macrophage function, and increase the level of serum hemolysin in cyclophosphamide-treated mice, suggesting CCPS had a potent immunostimulatory activity and could be explored as a potential natural immunomodulatory agent. PMID- 23987339 TI - Fucan effect on CHO cell proliferation and migration. AB - Fucan is a term used to denominate sulfated L-fucose rich polysaccharides. Here, a heterofucan, named fucan B, was extracted from the Spatoglossum schroederi seaweed. This 21.5 kDa galactofucan inhibited CHO-K1 proliferation and migration when fibronectin was the substrate. Fucan B derivatives revealed that such effects depend on their degree of sulfation. Fucan B did not induce cell death, but promoted G1 cell cycle arrest. Western blotting and flow cytometry analysis suggest that fucan B binds to fibronectin and activates integrin, mainly integrin alpha5beta1, which induces FAK/RAS/MEK/ERK activation. FAK activation inhibits CHO-K1 migration on fibronectin and ERK blocks cell cycle progression. This study indicates that fucan B could be applied in developing new antitumor drugs. PMID- 23987340 TI - Development of cesium phosphotungstate salt and chitosan composite membrane for direct methanol fuel cells. AB - A novel composite membrane has been developed by doping cesium phosphotungstate salt (CsxH3-xPW12O40 (0<=x<=3), Csx-PTA) into chitosan (CTS/Csx-PTA) for application in direct methanol fuel cells (DMFCs). Uniform distribution of Csx PTA nanoparticles has been achieved in the chitosan matrix. The proton conductivity of the composite membrane is significantly affected by the Csx-PTA content in the composite membrane as well as the Cs substitution in PTA. The highest proton conductivity for the CTS/Csx-PTA membranes was obtained with x=2 and Cs2-PTA content of 5 wt%. The value is 6*10(-3) S cm(-1) and 1.75*10(-2) S cm(-1) at 298 K and 353 K, respectively. The methanol permeability of CTS/Cs2-PTA membrane is about 5.6*10(-7), 90% lower than that of Nafion-212 membrane. The highest selectivity factor (phi) was obtained on CTS/Cs2-PTA-5 wt% composite membrane, 1.1*10(4)/Scm(-3)s. The present study indicates the promising potential of CTS/Csx-PTA composite membrane as alternative proton exchange membranes in direct methanol fuel cells. PMID- 23987341 TI - Changes in physicochemical properties of waxy corn starches at different stages of harvesting. AB - Starches were isolated from immature waxy corn kernels harvested at 0, 2, 4 and 6 days after optimum stage (DAO) and from mature kernels at 16 DAO. The starch contents showed varied according to genotypes and harvesting stages. The accumulation of starches showed an increasing trend in relation to delayed harvesting time, from the optimum stage until the physiological maturity stage. Among all harvesting stages, medium granules had the highest contribution to the total starch volume (60.8-81.5%), followed by large (5.7-30.1%), and small granules (9.1-15.3%). Average chain length distribution of amylopectin ranged from DP 14.7 to 16.9 for KKU-UB, DP 16.9 to 17.4 for KKU-JD, and DP 5.7 to 30.1 for Violet white. The pasting behaviors of starches were greatly affected by harvesting times. The peak viscosity of starches increased with delayed harvesting until physiological maturity and then decreased until dried kernels at 35 days after pollination. PMID- 23987342 TI - Effect of sucrose, stevia and xylitol on rheological properties of gels from blends of chestnut and rice flours. AB - The development of high quality gluten-free products requires the understanding of the phenomena that dictate the ingredient interactions commonly used in foodstuff. In this work, the main objective was to develop alternative gluten free gelled desserts from blends of chestnut flour (Cf) and whole (Rw), Agulha (Ra) or Carolino (Rc) rice flours. The impact of sucrose, stevia and xylitol on textural, rheological and structural properties of selected gels was investigated. Texture results indicated that studied gels in the presence of sucrose and xylitol decreased significantly the firmness. Rheological outcomes showed that the temperature ramps on heating of Cf/Rw gels were similar to those obtained for Cf/Ra, whereas Cf/Rc gels presented a particular pattern. The presence of sucrose resulted in a significant decrease in the values of storage and loss moduli. Confocal microscopic images showed that the sugar addition leads to a less aggregated structure with fracture lines well marked. PMID- 23987343 TI - Synthesis of interpenetrating network hydrogel from poly(acrylic acid-co hydroxyethyl methacrylate) and sodium alginate: modeling and kinetics study for removal of synthetic dyes from water. AB - Several interpenetrating network (IPN) hydrogels were made by free radical in situ crosslink copolymerization of acrylic acid (AA) and hydroxy ethyl methacrylate in aqueous solution of sodium alginate. N,N'-methylenebisacrylamide (MBA) was used as comonomer crosslinker for making these crosslink hydrogels. All of these hydrogels were characterized by carboxylic content, FTIR, SEM, XRD, DTA TGA and mechanical properties. Swelling, diffusion and network parameters of the hydrogels were studied. These hydrogels were used for adsorption of two important synthetic dyes, i.e. Congo red and methyl violet from water. Isotherms, kinetics and thermodynamics of dye adsorption by these hydrogels were also studied. PMID- 23987344 TI - Separation of lacquer polysaccharides and interaction with poly-L-lysine. AB - A naturally occurring acidic lacquer polysaccharide with glucuronic acid at the terminals of the complex branches has specific biological activities including promotion of blood coagulation and antitumor activities. The polysaccharide has two molecular weight fractions M-n=10*10(4) and M-n=3.0*10(4). In the present work, two pure fractions were isolated for the first time by Sephadex G-100 column chromatography. Then, each fraction was treated with diluted alkaline solution to decrease the molecular weights to M-n=3.0*10(4) and M-n=1.4*10(4), respectively. The NMR and IR spectra and specific rotations of the fractionated and original lacquer polysaccharides were almost identical, suggesting that the lacquer polysaccharides are an associated structure with several low molecular weight polysaccharides of M-n=1.4*10(4). Interactions between each lacquer polysaccharide and poly-L-lysine, a model compound of proteins and peptides with positively-charged amino groups, were investigated by surface plasmon resonance (SPR) to elucidate the biological mechanism. The apparent dissociation-rate (kd), association-rate (ka), and dissociation constant (KD) obtained by SPR indicate that the lacquer polysaccharides had weaker interactions with poly-L-lysine than sulfated polysaccharides and that the interaction depended on the molecular weight. These SPR results suggest that the specific biological activities of lacquer polysaccharides originate from electrostatic interaction. PMID- 23987345 TI - Hydroxypropyl methylcellulose substituent analysis and rheological properties. AB - The methyl and hydroxypropyl substituents in hydroxypropyl methylcellulose (HPMC) affect the resulting gel properties. These substituents in five HPMC gels were characterized using Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, small-amplitude oscillatory shear measurements, and differential scanning calorimetry (DSC). In FT-IR spectra, the most intense peak appeared at 1053 cm(-1), denoting the presence of the glucose ring. The ratio of peak intensities at 1452 cm(-1), which represents -C-H absorptions, and at 1053 cm(-1) (I1452/I1053) and percent methylation from gas chromatography exhibited a linear association (r(2)=0.6296). The broadening of the Raman spectra indicated that the relative crystallinity of HPMC decreases with increasing hydroxypropyl contents. DSC showed no linear relationship between the percent hydroxypropylation in HPMC and the percentage of free water in an HPMC gel. Small-amplitude oscillatory shear measurements revealed that the formation of an entanglements networks and/or weak gel depends on substituent contents. PMID- 23987346 TI - Heat insulation performance, mechanics and hydrophobic modification of cellulose SiO2 composite aerogels. AB - Cellulose-SiO2 composite hydrogel was prepared by combining the NaOH/thiourea/H2O solvent system and the immersion method with controlling the hydrolysis fasculation rate of tetraethyl orthosilicate (TEOS). The hydrophobic composite aerogels were obtained through the freeze-drying technology and the cold plasma modification technology. Composite SiO2 could obviously reduce the thermal conductivity of cellulose aerogel. The thermal conductivity could be as low as 0.026 W/(mK). The thermal insulation mechanism of the aerogel material was discussed. Composite SiO2 reduced hydrophilicity of cellulose aerogel, but environmental humidity had a significant influence on heat insulation performance. After hydrophobic modification using CCl4 as plasma was conducted, the surface of composite aerogel was changed from hydrophilic to hydrophobic and water contact angle was as high as 132 degrees . The modified composite aerogel still kept good heat insulation performance. This work provided a foundation for the possibility of applying cellulose-SiO2 composite aerogel in the insulating material field. PMID- 23987347 TI - Green synthesis of silver nanoparticles using cellulose extracted from an aquatic weed; water hyacinth. AB - As part of the desire to save the environment through "green" chemistry practices, we herein report an environmentally benign synthesis of silver nanoparticles (Ag-NPs) using cellulose extracted from an environmentally problematic aquatic weed, water hyacinth (WH), as both reducing and capping agent in an aqueous medium. By varying the pH of the solution and reaction time, the temporal evolutions of the optical and morphological properties of the as synthesised Ag-NPs were investigated. The as-synthesised cellulose capped silver nanoparticles (C-Ag-NPs) were characterised using Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-vis), transmission electron microscopy (TEM) and high resolution transmission electron microscopy (HRTEM). The maximum surface plasmon resonance (SPR) peak decreased as the pH increased indicating that an increase in the pH of the solution favoured the formation of smaller particles. In addition, instantaneous change in the colour of the solution from colourless to brown within 5 min at pH 11 showed that the rate of reduction is faster at this pH compared to those at lower pH. The TEM micrographs showed that the materials are small, highly monodispersed and spherical in shape. The average particle mean diameters were calculated to be 5.69+/-5.89 nm, 4.53+/-1.36 nm and 2.68+/-0.69 nm nm at pH 4, 8 and 11 respectively. The HRTEM confirmed the crystallinity of the material while the FTIR spectra confirmed the capping of the as-synthesised Ag-NPs by the cellulose. It has been shown therefore that based on this synthetic method, this aquatic plant can be used to the advantage of mankind. PMID- 23987348 TI - Preparation of crystalline starch nanoparticles using cold acid hydrolysis and ultrasonication. AB - Waxy maize starch in an aqueous sulfuric acid solution (3.16 M, 14.7% solids) was hydrolyzed for 2-6 days, either isothermally at 40 degrees C or 4 degrees C, or at cycled temperatures of 4 and 40 degrees C (1 day each). The starch hydrolyzates were recovered as precipitates after centrifuging the dispersion (10,000 rpm, 10 min). The yield of starch hydrolyzates depended on the hydrolysis temperature and time, which varied from 6.8% to 78%. The starch hydrolyzed at 40 degrees C or 4/40 degrees C exhibited increased crystallinity determined by X ray diffraction analysis, but melted in broader temperature range (from 60 degrees C to 110 degrees C). However, the starch hydrolyzed at 4 degrees C displayed the crystallinity and melting endotherm similar to those of native starch. The starch hydrolyzates recovered by centrifugation were re-dispersed in water (15% solids), and the dispersion was treated by an ultrasonic treatment (60% amplitude, 3min). The ultrasonication effectively fragmented the starch hydrolyzates to nanoparticles. The hydrolyzates obtained after 6 days of hydrolysis were more resistant to the ultrasonication than those after 2 or 4 days, regardless of hydrolysis temperatures. The starch nanoparticles could be prepared with high yield (78%) and crystallinity by 4 degrees C hydrolysis for 6 days followed by ultrasonication. Scanning electron microscopy revealed that the starch nanoparticles had globular shapes with diameters ranging from 50 to 90 nm. PMID- 23987349 TI - Effects of high temperature during grain filling under control conditions on the physicochemical properties of waxy maize flour. AB - The effects of high temperature during different grain filling stages (1-15 d and 16-30 d after pollination) on the physicochemical properties of four varieties of waxy maize grain were studied. Heat stress during grain filling decreased grain weight and starch deposition, while it increased protein content, starch granule size, abnormal granule numbers and iodine binding capacity. These effects were more severe when heat stress was introduced at early development stage than at late grain filling stage. The peak intensities and crystallinities were decreased when plants were exposed to high temperature at early development stage. By contrast, responses to high temperature at late development stage were variety dependent. High temperature during grain filling decreased the peak and breakdown viscosities and increased the gelatinization temperature and enthalpy, and retrogradation percentage of flours, especially during early development stage. In conclusion, high temperature during grain filling changed the grain proximate and starch structure, resulting in the deterioration of pasting and thermal properties. PMID- 23987350 TI - Influence of Aloe vera on water absorption and enzymatic in vitro degradation of alginate hydrogel films. AB - This study investigates the influence of Aloe vera on water absorption and the in vitro degradation rate of Aloe vera-Ca-alginate hydrogel films, for wound healing and drug delivery applications. The influence of A. vera content (5%, 15% and 25%, v/v) on water absorption was evaluated by the incubation of the films into a 0.1 M HCl solution (pH 1.0), acetate buffer (pH 5.5) and simulated body fluid solution (pH 7.4) during 24h. Results show that the water absorption is significantly higher for films containing high A. vera contents (15% and 25%), while no significant differences are observed between the alginate neat film and the film with 5% of A. vera. The in vitro enzymatic degradation tests indicate that an increase in the A. vera content significantly enhances the degradation rate of the films. Control films, incubated in a simulated body fluid solution without enzymes, are resistant to the hydrolytic degradation, exhibiting reduced weight loss and maintaining its structural integrity. Results also show that the water absorption and the in vitro degradation rate of the films can be tailored by changing the A. vera content. PMID- 23987351 TI - Rheology and dynamic light scattering of octa-ethyleneglycol monododecylether/chitosan solutions. AB - In this work we used rheometry and DLS to probe relaxation phenomena in solutions of chitosan and octa-ethyleneglycol-monododecylether. The dispersions had a marked pseudoplastic behavior, which became less evident, as surfactant concentration was increased. Arrhenius plots showed that systems with surfactant presented a characteristic temperature at which apparent enthalpy of activation (varying from 3 to 40 kJ mol(-1)) changed: this change was correlated to a possible transition of colloidal aggregates to a wormlike configuration. DLS intensity correlation functions were described by KWW equation: pure chitosan solutions had relaxation rate distributions centered at a characteristic relaxation rate around 4.6*10(-6) MUS(-1); as surfactant was added, a new component, with a faster characteristic relaxation rate with a magnitude order of 10(-3) MUs(-1), appeared. It was shown that the dependence between these relaxation rates and surfactant concentration could be used to describe DLS related relaxation phenomena as an Arrhenius-activated process, agreeing with results obtained using rheometry. PMID- 23987352 TI - Pectin-coated chitosan microgels crosslinked on superhydrophobic surfaces for 5 fluorouracil encapsulation. AB - 5-Fluorouracil (5-FU)-loaded chitosan microgels for oral and topical chemotherapy were prepared applying a superhydrophobic surface-based encapsulation technology. Drug-loaded chitosan dispersions were cross-linked and then coated with drug-free chitosan or pectin layers at the solid-air interface in a highly efficient and environment-friendly way. The size of the microgels (with diameters of ca. 280 and 557 MUm for the chitosan seeds and pectin-coated microgels respectively) was the lowest obtained until now using similar biomimetic methodologies. The microgels were characterized regarding 5-FU release profiles in vitro in aqueous media covering the pH range of the gastrointestinal tract, and cytotoxicity against two cancer cell lines sensitive to 5-FU. Owing to their control of 5-FU release in acidic medium, calcium pectinate-coated microgels can be considered as suitable for oral administration. Growth inhibition of cancer cells by 5-FU was greater when incorporated to chitosan microgels; these being potentially useful for treatment of skin and colorectal tumors. PMID- 23987353 TI - Optimization of isolation of cellulose from orange peel using sodium hydroxide and chelating agents. AB - Response surface methodology was used to optimize cellulose recovery from orange peel using sodium hydroxide (NaOH) as isolation reagent, and to minimize its ash content using ethylenediaminetetraacetic acid (EDTA) as chelating agent. The independent variables were NaOH charge, EDTA charge and cooking time. Other two constant parameters were cooking temperature (98 degrees C) and liquid-to-solid ratio (7.5). The dependent variables were cellulose yield and ash content. A second-order polynomial model was used for plotting response surfaces and for determining optimum cooking conditions. The analysis of coefficient values for independent variables in the regression equation showed that NaOH and EDTA charges were major factors influencing the cellulose yield and ash content, respectively. Optimum conditions were defined by: NaOH charge 38.2%, EDTA charge 9.56%, and cooking time 317 min. The predicted cellulose yield was 24.06% and ash content 0.69%. A good agreement between the experimental values and the predicted was observed. PMID- 23987354 TI - Simple organocatalytic route for the synthesis of starch esters. AB - Starch acetates and starch butyrates with degree of substitution (DS) in the range of 0.06-1.54 were prepared by a simple direct solvent-free organocatalytic methodology of starch acylation. The starch esters synthesized have important applications in the food and pharmaceutical industries, among others. The acylation methodology used involves a non-toxic biobased alpha-hydroxycarboxylic acid as catalyst, and proceeds with high efficiency in absence of solvents. The effect of reaction time on the advance of starch modification was studied as a simple way to control the level of substitution achieved, when all other reaction parameters were kept constant. Starch esters were characterized by means of Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and X-ray diffraction (XRD). FTIR spectroscopy qualitatively confirmed the esterification of starch by the appearance of bands which are associated with esters groups. Scanning electron microscopy showed that the granular structure of the polysaccharide was preserved upon acylation, although acylated granules had rougher surfaces; and wrinkles, grooves and deformed zones appeared in some granules at high DS. Thermogravimetric analysis showed a gradual reduction in the water content of acylated starches, as well as noticeable changes in their thermal properties at increasing DS. X-ray diffraction analysis showed that the acetylation treatment led to lower crystallinity at increasing DS, although characteristic corn starch A-type patterns could be identified even at the highest DS achieved (DS=1.23). Specific bands and weight losses derived from FTIR and TGA data could be very well correlated with the substitution degree achieved in acetylated starches at DS lower/equal than 0.6. The organocatalytic methodology described for the synthesis of starch acetates and butyrates has the potential to be easily extended to the synthesis of other starch esters using a variety of anhydrides or carboxylic acids as acylating agents. PMID- 23987355 TI - Synthesis of CarAlg/MMt nanocomposite hydrogels and adsorption of cationic crystal violet. AB - CarAlg/MMt nanocomposite hydrogels composed of kappa-carrageenan (Car) and sodium alginate (Alg) biopolymers were synthesized by incorporation of sodium montmorillonite (Na-MMt) nanoclay. Acrylamide (AAm), methylenebisacrylamide (MBA), and ammonium persulfate (APS) were used as monomer, crosslinker, and initiator, respectively. The structure and morphology of nanocomposites were characterized by XRD, SEM, and TEM techniques. The XRD results showed exfoliated MMt nanoclay and exfoliation of MMt was confirmed by TEM graph. The resulting nanocomposites were evaluated to remove cationic crystal violet (CV) dye from water. According to data, the adsorption capacity of nanocomposites was enhanced as the clay content was increased. The experimental data were analyzed according to both Langmuir and Freundlich models and experimental maximum adsorption capacity was obtained 88.8 mg g(-1). By studying the effect of pH on the dye adsorption capacity of nanocomposites, it was revealed that the adsorption capacity of nanocomposites was enhanced at acidic pHs as the Na-MMt nanoclay and kappa-carrageenan components were increased. PMID- 23987356 TI - Burdock fructooligosaccharide enhances biocontrol of Rhodotorula mucilaginosa to postharvest decay of peaches. AB - The influence of adding burdock fructooligosaccharide (BFO) in the culture media on the efficacy of Rhodotorula mucilaginosa in controlling postharvest decay of peaches and its possible mode of action were investigated. The antagonistic activity of R. mucilaginosa to Rhizopus decay and blue mold decay of peaches was greatly enhanced through cultivation in the nutrient yeast dextrose agar (NYDA) medium amended with BFO at the concentration of 0.32%, compared with that cultivated in NYDB without BFO. R. mucilaginosa at 1*10(8) cells/mL cultivation in the NYDB media did not reduce the natural decay incidence of peaches, compared with the control after 30 d at 4 degrees C followed by 7d at 20 degrees C. However, R. mucilaginosa cultivation in the NYDB media amended with BFO at the concentration of 0.32% reduced the natural decay incidence of peaches. The population of R. mucilaginosa harvested from NYDB amended with BFO at 0.32% increased rapidly in peach wounds compared to that harvested from NYDB without BFO no matter peaches were stored at 20 degrees C or 4 degrees C. The activities of chitinase and beta-1,3-glucanase of cell-free culture filtrate of R. mucilaginosa harvested from NYDB amended with BFO at 0.32% were higher than that at other concentrations and the control. PMID- 23987357 TI - Scanning probe acoustic microscopy of extruded starch materials: direct visual evidence of starch crystal. AB - Scanning probe acoustic microscopy (SPAM) has been successfully used to study inorganic and keratin biomaterials. However, few studies have attempted to apply SPAM to structural study of non-keratin organic materials such as starch based materials. This study investigated hardness and surface finish to establish sample preparation method suitable for SPAM imaging and acquired clear acoustic images of extruded starch materials. Acquired acoustic images directly exhibited certain structure of starch materials and provided visual evidence of starch material components and aggregates. In addition, through correlating acoustic images with X-ray diffraction data, crystal-structural information in nano-scale was obtained and acoustic image contrast showed a linear relationship with starch amylose content in extruded starch materials. PMID- 23987358 TI - Characterization, dissolution and in vivo evaluation of solid acetazolamide complexes. AB - The effects of binary and ternary systems of acetazolamide (ACZ) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) alone or with triethanolamine (TEA) on the crystalline properties, dissolution and intraocular pressure (IOP) lowering effect were investigated. It was found that the crystal structure of ACZ powder could be modified by the processing conditions. Freeze-drying ACZ powder affected not only the particle morphology but also its polymorphic form and the starting ACZ was converted to pure form A upon freeze-drying treatment. Results provided by DSC/TGA, XRPD, SEM and FT-IR suggested the formation of inclusion complexes between ACZ with HP-beta-CD alone or with TEA, obtained by the freeze drying method and the conversion of the drug into the amorphous state. Binary and ternary systems of ACZ obtained by freeze-drying exhibited significantly enhanced ACZ dissolution rates. The IOP-lowering effects of ACZ and its complexes with HP beta-CD alone or with TEA were studied in normotensive rabbits. Whereas the maximum IOP-lowering effect (~4 mmHg, ~33%), obtained with these binary and ternary lyophilized ACZ systems occurred at around 90 min, the ternary system exhibited a longer maximum IOP-lowering effect peak compared with that of the binary system. These results are in line with those obtained from the dissolution studies, where the ternary system exhibited longer dissolution times compared to the lyophilized binary one. Results obtained from the dissolution studies, also showed that freeze-drying the native crystalline form of ACZ significantly increased the dissolution rate of ACZ, thus improving the IOP-lowering effect of this drug. PMID- 23987359 TI - Effect of montmorillonite on morphology, glass transition and crystallinity of the xylitol-plasticized bionanocomposites. AB - High amylose based nanocomposites plasticized by xylitol were prepared via twin screw extrusion. The synergistic interaction in the xylitol-plasticized nanocomposite was studied via various characterization methods and the unique behavior of the xylitol-plasticized nanocomposite had been discussed. As revealed in the XRD and TEM results, good intercalated/exfoliated morphology had been achieved in all the nanocomposites. Furthermore, the expansion of nanoclay basal spacing was related to the xylitol/nanoclay ratio. DSC analysis clearly proved the unique crystallization process of xylitol-plasticized samples. Moreover, in the crystallization domain results, two domains sized at approximately 93.7 A and 346 A were found. This observation points to a two-level complex effect from two aggregate domains; one, the re-aggregation of certain number of silicate layers into domains which trap some of the amylose polymer chains, and two, the bulk drying process which combines smaller amylose crystalline domains within a larger amorphous high amylose matrix. PMID- 23987361 TI - Acetone-soluble cellulose acetate extracted from waste blended fabrics via ionic liquid catalyzed acetylation. AB - Isolation of cellulose from waste polyester/cotton blended fabrics (WBFs) is a bottleneck for recycling and exploiting waste textiles. The objective of this study was to provide a new environmental-friendly and efficient approach for extracting cellulose derivatives and polyester from WBFs. A Bronsted acidic ionic liquid (IL) N-methyl-imidazolium bisulfate, [Hmim]HSO4, was used as a novel catalyst for acetylation of cellulose rather than a solvent with the aim to overcome low isolation efficiency associated with the very high viscosity and relatively high costs of ILs. The extraction yield of acetone-soluble cellulose acetate (CA) was 49.3%, which corresponded to a conversion of 84.5% of the cellulose in the original WBFs; meanwhile, 96.2% of the original poly(ethylene terephthalate) (PET) was recovered. The extracted CA was characterized by (1)H NMR, FTIR, XRD and TGA analysis, and the results indicated that high purity acetone-soluble CA and carbohydrate-free PET could be isolated in this manner from WBFs. PMID- 23987360 TI - Preparation of poly(acrylamide-co-acrylic acid)-grafted gum and its flocculation and biodegradation studies. AB - Biodegradation studies of Gum ghatti (Gg) and acrylamide-co-acrylic acid based flocculants [Gg-cl-poly(AAm-co-AA)] have been reported using the soil composting method. Gg-cl-poly(AAm-co-AA) was found to degrade 89.76% within 60 days. The progress of biodegradation at each stage was monitored through FT-IR and SEM. Polymer was synthesized under pressure using potassium persulphate-ascorbic acid as a redox initiator and N,N'-methylene-bis-acrylamide as a crosslinker. Synthesized polymer was found to show pH, temperature and ionic strength of the cations dependent swelling behavior. Gg-cl-poly(AAm-co-AA) was utilized for the selective absorption of saline from different petroleum fraction-saline emulsions. The flocculation efficiency of the polymer was studied as a function of polymer dose, temperature and pH of the solution. Gg-cl-poly(AAm-co-AA) showed maximum flocculation efficiency with 20 mol L(-1) polymer dose in acidic medium at 50 degrees C. PMID- 23987362 TI - Dissolution of cellulose from AFEX-pretreated Zoysia japonica in AMIMCl with ultrasonic vibration. AB - In this study, 1-allyl-3-methylimidazolium chloride (AMIMCl), an ionic liquid, was synthesized and characterized by a series of test methods. Pretreatment of Zoysia japonica by ammonia fiber expansion (AFEX) was shown to reduce significantly the mass of hemicellulose and lignin in biomass, thereby breaking the lignocellulosic structure. Z. japonica samples pretreated with AFEX showed reasonable solubility in AMIMCl upon ultrasonic treatment. The rate of cellulose regeneration from Z. japonica samples pretreated with AFEX increased with increase in applied power of ultrasonication within a certain power range from 0 to 110 W. The regeneration rate of cellulose from AFEX-pretreated Z. japonica reached a maximum of 97% when the ultrasonic power was 110 W. Fourier transform infrared spectroscopy and nuclear magnetic resonance analyses indicated that the regenerated cellulose was similar to microcrystalline cellulose. PMID- 23987363 TI - Particle size distribution of rice flour affecting the starch enzymatic hydrolysis and hydration properties. AB - Rice flour is becoming very attractive as raw material, but there is lack of information about the influence of particle size on its functional properties and starch digestibility. This study evaluates the degree of dependence of the rice flour functional properties, mainly derived from starch behavior, with the particle size distribution. Hydration properties of flours and gels and starch enzymatic hydrolysis of individual fractions were assessed. Particle size heterogeneity on rice flour significantly affected functional properties and starch features, at room temperature and also after gelatinization; and the extent of that effect was grain type dependent. Particle size heterogeneity on rice flour induces different pattern in starch enzymatic hydrolysis, with the long grain having slower hydrolysis as indicated the rate constant (k). No correlation between starch digestibility and hydration properties or the protein content was observed. It seems that in intact granules interactions with other grain components must be taken into account. Overall, particle size fractionation of rice flour might be advisable for selecting specific physico-chemical properties. PMID- 23987364 TI - Chemical modification, antioxidant and alpha-amylase inhibitory activities of corn silk polysaccharides. AB - Water-soluble corn silk polysaccharides (CSPS) were chemically modified to obtain their sulfated, acetylated and carboxymethylated derivatives. Chemical characterization and bioactivities of CSPS and its derivatives were comparatively investigated by chemical methods, gas chromatography, gel filtration chromatography, scanning electron microscope, infrared spectroscopy and circular dichroism spectroscopy, scavenging DPPH free radical assay, scavenging hydroxyl radical assay, ferric reducing power assay, lipid peroxidation inhibition assay and alpha-amylase activity inhibitory assay, respectively. Among the three derivatives, carboxylmethylated polysaccharide (C-CSPS) demonstrated higher solubility, narrower molecular weight distribution, lower intrinsic viscosity, a hyperbranched conformation, significantly higher antioxidant and alpha-amylase inhibitory abilities compared with the native polysaccharide and other derivatives. C-CSPS might be used as a novel nutraceutical agent for human consumption. PMID- 23987365 TI - The comparison of immune-enhancing activity of sulfated polysaccharidses from Tremella and Condonpsis pilosula. AB - Based on our previous research, four sulfated polysaccharide (sPSs) from Tremella and Condonpsis pilosula, sTPStp, sTPS70c, sCPPStp and sCPPS50c, were prepared and their effects on splenic lymphocytes proliferation in vitro and the immune response of ND vaccine in chicken were compared taking the unmodified polysaccharide (uPS) TPStp as control. The results showed that four sPSs could significantly or numerically stimulate splenic lymphocyte proliferation singly or synergistically with LPS in vitro, sTPS70c and sCPPStp demonstrated better effect; promote peripheral lymphocytes proliferation and enhance serum HI antibody titer in chickens vaccinated with ND vaccine, the actions of sPSs were stronger than that of uPS, and sTPS70c at medium dosage presented the best efficacy. These indicated that sulfation modification could improve the immune enhancing activity of TPS and CPPS, sTPS70c possessed the strongest activity and would be expected as a component of new-type immunopotentiator. PMID- 23987366 TI - Molecular weight distribution and functional group profiles of TEMPO-oxidized lyocell fibers. AB - The effects of TEMPO-mediated oxidation, performed with NaClO, a catalytic amount of NaBr, and 2,2',6,6'-tetramethylpiperidine-1-oxy radical (TEMPO), were studied on lyocell fibers by means of GPC using multiple detection and group-selective fluorescence labeling according to the CCOA and FDAM methodology. The applied method determines functional group content as a sum parameter, as well as functional group profiles in relation to the molecular weight of the cellulose fibers. Both the CHO and COOH profiles, as well as molecular weight alterations, were analyzed. A significant decrease in the average molecular weight was obtained during the first hour of TEMPO-mediated oxidation, but prolonged oxidation time resulted in no strong additional chain scission. Significant amounts of COOH groups were introduced in the high molecular weight fractions by the oxidation with higher concentrations of NaClO (2.42-9.67 mmol NaClO/g fiber) after modification times of 1h or longer. PMID- 23987367 TI - Obtaining of new magnetic nanocomposites based on modified polysaccharide. AB - The study presents the preparation of some composite materials with magnetic properties by two different encapsulation methods of magnetite (Fe3O4) in a polymer matrix based on carboxymethyl starch-g-polylactic acid (CMS-g-PLA). The copolymer matrix used to obtain the magnetic nanocomposites was synthesized by grafting reaction of carboxymethyl starch (CMS) with D,L-lactic acid (DLLA), in the presence of Sn octanoate [Sn(Oct)2] as catalyst. Magnetite was obtained by co precipitation from aqueous salt solutions FeCl2/FeCl3 (molar ratio 1/2). The magnetic composites were prepared by precipitation method in acetone (non solvent) of the DMSO solutions of magnetite and copolymer, and synthesis in situ of the nanocomposites. In the first case, the particle size measured by DLS technique was 168 nm, and the magnetization was 46.82 emu/g, while after in situ synthesis, the composite materials showed smaller size (141 nm), but the magnetization was reduced (3.04 emu/g). The higher magnetization in the first case is due to the great degree of encapsulation of the magnetite, which was about 43.4 wt.%, compared to 4.37 wt.% for the in situ synthesis (determined by thermogravimetry). The CMS-g-PLA copolymer, magnetite, and the nanocomposites were characterized by infrared spectroscopy (FTIR), near infrared chemical imagistic (NIR-CI), dynamic light scattering (DLS) technique, X-ray diffraction (WAXD), scanning electron microscopy (SEM), vibrating sample magnetometer (VSM) and thermal analyses. Since the polymer matrix and magnetite are biodegradable and biocompatible, the magnetic nanocomposites can be used for conjugation of some drugs. The polymer matrix CMS-g-PLA acts as a shell, and vehicle for the active component, whereas magnetite is the component which makes targeting possible by external magnetic field manipulation. PMID- 23987368 TI - Free radical grafting kinetics of acrylamide onto a blend of starch/chitosan/alginate. AB - Grafting of monomer onto polymer backbone is one of the effective and accessible methods for the chemical modification of polysaccharides. Grafting of acrylamide (AAm) onto polysaccharides blend (PsB) composed of starch, chitosan and alginate has been carried out using potassium persulfate (KPS) as an initiator. The kinetics of the grafting polymerization also has been studied. The grafting parameters have been evaluated by changing the initial concentrations of AAm from 8 to 16 g, PsB from 6 to 14 g and KPS from 0.2 to 1 g. Evidence of grafting has been obtained from FTIR, XRD and TGA. The kinetics of the grafting polymerization also has been studied. The grafting rate equation of the produced hydrogel (PsB-g AAm) hydrogel has been expressed by: Rg=k[AAm] [PsB](0.5) [KPS](0.5). The grafting rate is a first order dependence to [AAm] initial concentration and square root to [PsB] and [KPS] initial concentrations in the used concentrations range. PMID- 23987369 TI - Nanocrystalline cellulose with various contents of sulfate groups. AB - Properties of films derived from aqueous nanocrystalline cellulose dispersions by water evaporation depend on concentration of sulfate groups. Namely type of thermodestruction and surface morphology change as a function of contents of sulfate groups. Surface roughness increases and water adsorption enhances with increasing sulfate groups content particularly at high relative pressure. PMID- 23987370 TI - Phosphorylated multiwalled carbon nanotube-cyclodextrin polymer: synthesis, characterisation and potential application in water purification. AB - Multiwalled carbon nanotubes were synthesised by the nebulised spray pyrolysis method and purified to remove amorphous carbon and fullerenes. The purified multiwalled carbon nanotubes were oxidised using a 3:1 H2SO4/HNO3 mixture to introduce carboxylic groups and to a smaller extent hydroxyl groups on the walls of the carbon nanotubes. Subsequently, the oxidised carbon nanotubes were chlorinated using oxalyl chloride to generate acyl chloride groups through which phosphorylation took place. 4-Aminophenyl methylphosphonate was attached to the multiwalled carbon nanotubes via an amidation reaction. FT-IR and XPS confirmed the presence of PO, PO and PCP functional groups in the phosphorylated carbon nanotubes. Polymerisation of the phosphorylated carbon nanotubes with cyclodextrins was achieved using hexamethylene diisocyanate as a bifunctional linker. Surface morphology of the polymer was investigated by SEM while FT-IR was used to confirm the polymerisation reaction. Moreover, the thermal stability of the polymer was probed using TGA while BET was employed to determine the surface area and pore volume of the polymer. Furthermore, the polymer was tested for the removal of cobalt and 4-chlorophenol from synthetic aqueous solutions of the pollutants. The polymer displayed potential as an adsorbent for both cobalt and 4 chlorophenol. PMID- 23987371 TI - The structure and properties of different types of starch exposed to UV radiation: a comparative study. AB - The effect of UV-irradiation on four different types of native starch (corn, waxy corn, wheat and potato) have been investigated. Although the changes in the chemical structure of starch specimens were small, indicating good photostability, the samples lost adsorbed water and their crystallinity degree decreased after irradiation. Moreover, a drop in average molecular weight occurred in samples (with the exception of potato starch) as a result of main chain scission. The variations in the properties of investigated specimens of various origin were related to the differences in their structure and macromolecular arrangement. The lowest photostability among the four starches was exhibited by potato starch. PMID- 23987372 TI - Chitin nanofibrils for rapid and efficient removal of metal ions from water system. AB - Joint mechanical defibrillation was successfully used to downsize chitin micro particles (CMP) into nanofibrils without changing its chemical or crystalline structure. The fine chitin nanofibrils (CNF) bearing width of about 50 nm and length of more than 1 MUm were then developed as heavy metal ion sorbents. The uptake performance of CNF dependent on pH, ionic concentration, time, and temperature was investigated. Results show that fixation amount of Cd(II), Ni(II), Cu(II), Zn(II), Pb(II), Cr(III) on CNF was up to 2.94, 2.30, 2.22, 2.06, 1.46, and 0.31 mmol/g, respectively, much higher than CMP due to high specific surface area and widely distributed pores of CNF. Adsorption kinetics of CMP and CNF followed pseudo-second-order model and Freundlich isotherm although CNF exhibited higher rate constant and sorption capacity than that of CMP. The defibrillated CNF is renewable, feasible, easily recyclable, and is thought as good candidate for heavy metal ion treatment due to their low sorption energy, rapid and efficient uptake capacity. PMID- 23987373 TI - Characterization of ligno-cellulosic materials bleached with oxo-diperoxo molybdates. AB - A newly effective system was used to bleach ligno-cellulosic textile materials. This system is based on two different newly synthesized natrium oxo-diperoxo molybdates, Na2[MoO (O2)2(C2O4)] and Na2[MoO (O2)2(C6H6O7)]. These two compounds were characterized by means of cyclic voltammetry, and the bleached fabrics were fully characterized by measuring their whiteness index, percent loss in fabric weight and the content of lignin in the fabric. The obtained results revealed that good whiteness index of the bleached linen-cotton fabrics (50% linen and 50% cotton) and low content of lignin could be obtained by soaking the fabric for 55 min at 90 degrees C in a solution containing 3.5% of molybdate complex and 3.5% H2O2. PMID- 23987374 TI - PAMAM conjugated chitosan through naphthalimide moiety for enhanced gene transfection efficiency. AB - Development of efficient and safe gene carrier is the main hurdle for successful gene therapy till date. Poor water solubility and low transfection efficiency of chitosan are the main drawbacks to be efficient gene carrier for successful gene therapy. In this work, PAMAM conjugated chitosan was prepared through naphthalimide moiety by simple substitution reaction. The synthesis of the chitosan conjugates was confirmed by FTIR, (1)H NMR and XRD analyses. The conjugates showed enhanced DNA binding capability compared to that of unmodified chitosan. Moreover, the conjugates showed minimal cytotoxicity compared to that of polyethyleneimine (PEI, 25 kDa) and also showed good blood compatibility with negligible haemolysis. The transfection efficiency of the conjugate was significantly increased compared to that of unmodified chitosan and it also surpassed the transfection efficiency by PEI. Therefore, PAMAM conjugated chitosan can be used safely as alternate efficient gene delivery vector in gene therapy. PMID- 23987375 TI - Adsorption of Victoria blue by carbon/Ba/alginate beads: kinetics, thermodynamics and isotherm studies. AB - The kinetic, thermodynamic and isotherm modeling studies were carried out on adsorptive removal of Victoria blue (VB) dye using activated carbon, Ba/alginate and modified carbon/Ba/alginate polymer beads. The feasibility of sorption process was determined by varying the experimental parameters viz., dye concentration (4-20 mg L(-1)), contact time (10-90 min), pH (3-10), adsorbent dose (0.5-2.5 g) and temperature (303-343 K). Freundlich and Langmuir isotherms were determined and ascertained with the dimensionless separation factor (RL). Lagergren's pseudo-first order, pseudo-second order and intraparticle diffusion model equations were used to analyze the kinetics of the adsorption process. The thermodynamic consistency of adsorption was found with Gibbs free energy (DeltaG degrees ), changes in enthalpy (DeltaH degrees ) and entropy (DeltaS degrees ) were calculated using the Van't Hoff plot. The polymer beads were characterized using Fourier Transform Infrared Spectroscopy (FTIR) and their morphology was determined by scanning electron microscopy (SEM). PMID- 23987376 TI - TG-MS analysis for thermal decomposition of cellulose under different atmospheres. AB - Cellulose degradation under inert (He) and oxidative atmospheres (7% O2, 20% O2 and 60% O2) was investigated through thermogravimetric (TG) equipped with mass spectroscopy (MS) system. Two mass loss stages were observed for cellulose degraded under oxidative atmosphere, where the first mass loss stage is close to that under inert atmosphere, and the second one designated to char oxidation was enhanced by the increased oxygen concentration. The evolution of prominent volatiles including furfural, acetone, 2/5-hydromethyl furfural, formaldehyde, CO and CO2 was examined considering the influence of oxygen concentration. The plateau for mass loss and evolution of some volatiles leads to the difficulty to determine the division-point for the two stages. However, the fitting parameter (Dev%) around 5% confirms the applicability of the proposed two-stage kinetic model accounting for partial pressure of oxygen. PMID- 23987377 TI - Arabinogalactan protein cluster from Jatropha curcas seed embryo contains fasciclin, xylogen and LysM proteins. AB - An non-GPI-anchored AGP cluster (Y2) was isolated from the seeds of Jatropha curcas L. (Euphorbiaceae) composed of 4.8% polypeptides (mainly Ala, Ser, Gly, Hyp, Glu) and a carbohydrate moiety composed of Gal, Ara, GlcA, Rha, Man and GlcN. Besides the typical structural features of arabinogalactan proteins, typical N-glycan linker of the complex type (GlcNAc4Man3Gal2Fuc1Xyl1) were identified. O-glycosylation occurred mainly via Hyp and to a lesser extent via Thr and Ser. N-glycans from the complex type, carrying at the innermost GlcNAc at position O-3 one alpha-Fuc-residue, were also present. MS analysis of the tryptic digest assigned peptides of three major protein groups: fasciclin-like arabinogalactan proteins, xylogen-like proteins and LysM domain-containing proteins. They could not be separated further and it is indicated that various homologous protein forms co-exist. Histological investigation of J. curcas seeds revealed the presence of AGPs in the vessels of cotyledons and in the procambium ring of the embryo. PMID- 23987378 TI - Blend miscibility of cellulose propionate with poly(N-vinyl pyrrolidone-co-methyl methacrylate). AB - The blend miscibility of cellulose propionate (CP) with poly(N-vinyl pyrrolidone co-methyl methacrylate) (P(VP-co-MMA)) was investigated. The degree of substitution (DS) of CP used ranged from 1.6 to >2.9, and samples for the vinyl polymer component were prepared in a full range of VP:MMA compositions. Through DSC analysis and solid-state (13)C NMR and FT-IR measurements, we revealed that CPs of DS<2.7 were miscible with P(VP-co-MMA)s of VP>=~10mol% on a scale within a few nanometers, in virtue of hydrogen-bonding interactions between CP-hydroxyls and VP-carbonyls. When the DS of CP exceeded 2.7, the miscibility was restricted to the polymer pairs using P(VP-co-MMA)s of VP=ca. 10-40 mol%; the scale of mixing in the blends concerned was somewhat larger (ca. 5-20 nm), however. The appearance of such a "miscibility window" was interpretable as an effect of intramolecular repulsion in the copolymer component. Results of DMA and birefringence measurements indicated that the miscible blending of CP with the vinyl polymer invited synergistic improvements in thermomechanical and optical properties of the respective constituent polymers. Additionally, it was found that the VP:MMA composition range corresponding to the miscibility window was expanded by modification of the CP component into cellulose acetate propionate. PMID- 23987379 TI - Effects of sucrose and urea on soy hull pectic polysaccharide gel induced by D glucono-1,5-lactone. AB - Gelation properties of pectic polysaccharide extracted with ammonium oxalate from soybean hulls assisted by microwave were seldom studied. Water mobility in soy hull pectic polysaccharide (SHPP) was firstly studied by low field NMR. D-Glucono 1,5-lactone (GDL) and sucrose both could decrease spin-spin relaxation times (T2) of SHPP solutions which indicated the SHPP network formed. Rheological analysis conformed that SHPP gel was formed induced by GDL and enhanced by sucrose. Urea can increase T2 and collapse the network of SHPP. TGA was used to draw the profiles of water desorption from SHPP solutions or gels, during heating at a controlled rate. It was found that sucrose increased the bound water content and urea acted a conversely role. Hydrogen bond is the main force to maintain SHPP gel network. PMID- 23987380 TI - The effect of titanium with heparin/BMP-2 complex for improving osteoblast activity. AB - The objective of this study was to investigate the enhanced osteoblast activity of MG-63 cells cultured on titanium (Ti) with a heparin/BMP-2 (Hep/BMP-2) complex. The Ti substrates were initially modified by chemical grafting poly-L lysine (PLL) using condensing agent, followed by immobilizing the heparin/BMP-2 complex to the PLL-grafted Ti substrate via electrostatic interactions. The surface modification of Ti substrates with PLL and/or Hep/BMP-2 complex were confirmed with scanning electron microscopy, contact angle measurements, and X ray photoelectron spectroscopy. Immobilized BMP-2 was released from the Hep/BMP 2/Ti substrate in a sustained manner. In vitro studies revealed that osteoblasts grown on Hep/BMP-2/Ti substrate increased ALP activity, calcium deposition, ALP and osteocalcin levels as compared to those grown on pristine Ti or PLL-Ti. These results indicated that heparin/BMP-2 complex immobilized Ti substrate can be useful to effectively improve osteoblast activity. PMID- 23987381 TI - Preparation and properties of amylose complexes prepared from hexadecylamine and its hydrochloride salt. AB - Amylose inclusion complexes were prepared from jet-cooked aqueous mixtures of high amylose corn starch and 1-hexadecylamine (HDA). Slow-cooling produced torus/disc-shaped spherulites, whereas aggregates of smaller spherulites were obtained by rapid-cooling in ice. The morphologies and 61V X-ray diffraction patterns of these spherulites were similar to those of spherulites obtained previously with palmitic acid, indicating that spherulite morphology is influenced largely by the hydrophobic structure of the carbon chain of the complex-forming ligand and to a lesser extent by the nature of the more polar head group. Water soluble, cationic amylose inclusion complexes were prepared by adding an aqueous solution of the HCl salt of HDA to a jet-cooked dispersion of high amylose starch. The cationic nature of these HDA.HCl complexes suggests possible applications as flocculating agents for water purification and as retention aids in papermaking. PMID- 23987382 TI - Preparation and characterization of nano-cellulose with new shape from different precursor. AB - Three different precursor materials - 1. China cotton, 2. South African cotton, 3. Waste tissue papers were used to produce nano-cellulose by acid hydrolysis route. No chemical pretreatment has been done for the production of nano cellulose from these precursors. Prepared nano-cellulose and their corresponding precursor materials were characterized by transmission electron microscopy (TEM), particle size analysis, X-ray diffraction (XRD) study, thermo gravimetric analysis (TGA), differential scanning calorimetric (DSC) analysis and Fourier transformed infra red (FTIR) spectroscopy. A comparative study of the characteristics was done with the properties of raw materials and with that of nano-cellulose. Shape and size of the nano cellulose generally depends on nature of the precursor and hydrolysis condition. Morphology study of nano-cellulose from different sources revealed range of length from 50 to 200 nm and diameter from 10 to 90 nm. Higher thermal stability and crystallinity of nano-cellulose were observed compared to that of precursor from TGA/DSC study. PMID- 23987383 TI - Formation of nanometal particles in the dialdehyde starch matrix. AB - Environmentally friendly method of the preparation of dialdehyde starch (DAS) based composites containing nanosilver (DAS/Ag) and nanogold (DAS/Au) as reducing and protecting agents was developed. UV-vis spectroscopy, transmission electron microscopy (TEM) and X-ray diffraction (XRD) confirmed formation of about 10nm ball shaped Ag and Au nanoparticles situated within the polysaccharide template. Thermal properties of the composites were characterized involving differential scanning calorimetry (DSC), whereas molecular weights of polysaccharide chains of the matrix were estimated with the size exclusion chromatography coupled with multiangle laser light scattering and refractometric detectors (HPSEC-MALLS-RI). Formation of nanosilver and nanogold containing composites led to induction of the polymerization and/or crosslinking reactions of DAS molecules, resulting in a significant rise of molecular weight of polysaccharide chains constituting DAS/Ag and DAS/Au composite templates. PMID- 23987384 TI - Cell culture and characterization of cross-linked poly(vinyl alcohol)-g-starch 3D scaffold for tissue engineering. AB - The research goal of this experiment is chemically to cross-link poly(vinyl alcohol) (PVA) and starch to form a 3D scaffold that is effective water absorbent, has a stable structure, and supports cell growth. PVA and starch can be chemically cross-linked to form a PVA-g-starch 3D scaffold polymer, as observed by Fourier transform infrared spectroscopy (FTIR), with an absorbency of up to 800%. Tensile testing reveals that, as the amount of starch increases, the strength of the 3D scaffold strength reaches 4*10(-2) MPa. Scanning electron microscope (SEM) observations of the material reveal that the 3D scaffold is highly porous formed using a homogenizer at 500 rpm. In an enzymatic degradation, the 3D scaffold was degraded by various enzymes at a rate of up to approximately 30-60% in 28 days. In vitro tests revealed that cells proliferate and grow in the 3D scaffold material. Energy dispersive spectrometer (EDS) analysis further verified that the bio-compatibility of this scaffold. PMID- 23987385 TI - Effect of crosslinking in chitosan/aloe vera-based membranes for biomedical applications. AB - The positive interaction between polysaccharides with active phytochemicals found in medicinal plants may represent a strategy to create active wound dressing materials useful for skin repair. In the present work, blended membranes composed of chitosan (Cht) and aloe vera gel were prepared through the solvent casting, and were crosslinked with genipin to improve their properties. Topography, swelling, wettability, mechanical properties and in vitro cellular response of the membranes were investigated. With the incorporation of aloe vera gel into chitosan solution, the developed chitosan/aloe-based membranes displayed increased roughness and wettability; while the genipin crosslinking promoted the formation of stiffer membranes in comparison to those of the non-modified membranes. Moreover, in vitro cell culture studies evidenced that the L929 cells have high cell viability, confirmed by MTS test and calcein-AM staining. The findings suggested that both blend compositions and crosslinking affected the physico-chemical properties and cellular behavior of the developed membranes. PMID- 23987386 TI - A facile one-pot synthesis of a fluorescent agarose-O-naphthylacetyl adduct with slow release properties. AB - A microwave assisted facile synthesis of a fluorescent 6-O-naphthylacetyl agarose (NA-agarose) employing carbodiimide chemistry (dicyclohexylcarbodiimide/4 dimethylaminopyridine) has been described. NA-agarose was characterized by TGA, GPC, UV spectrophotometry, fluorescence spectroscopy, FT-IR, (1)H and (13)C NMR spectra, exhibiting that in NA-agarose the naphthylacetyl group was attached to the backbone of the agarose polymer. The hydrolysis of NA-agarose in heterogeneous aqueous phase showed that the 1-naphthyl acetic acid (NAA), a plant growth regulator, got released in a controlled manner, the release rate being dependent on the hydrophilicity of the polymer adduct as well as on pH and temperature. The fluorescence emission (lambdamax 332 nm) of NA-agarose (1*10(-3) M) in ethylene glycol was significantly higher (ca. 82%) than that of the molar equivalent of NAA content in the product i.e. 0.08 mg in 1*10(-3) M solution. The resulting polymer would be of potential utility as a sustained release plant growth regulator and sensory applications. PMID- 23987388 TI - Enzyme assisted extraction of polysaccharides from the fruit of Cornus officinalis. AB - Process of enzyme assisted extraction (EAE) of polysaccharides from Cornus officinalis was optimized by response surface methodology (RSM). The influence of four different factors on the yield of C. officinalis polysaccharides (COP) was studied. Results showed that the optimal conditions were compound enzyme amount of 2.15%, extraction pH of 4.2, extraction temperature of 55 degrees C and extraction time of 97 min. Under these conditions, the COP yield was 9.29+/ 0.31%, which was well in agreement with the value predicted by the model. The three methods, EAE, hot water extraction (HWE), ultrasound-assisted extraction (UAE) for extracting COP by RSM were further compared. Results showed that EAE had the largest yield of polysaccharides with lower equipment cost. PMID- 23987387 TI - Blood compatible N-maleyl chitosan-graft-PAMAM copolymer for enhanced gene transfection. AB - To improve transfection efficiency, we prepared N-maleyl chitosan-graft polyamidoamine (NMCTS-graft-PAMAM) copolymer. Self-assembled NMCTS-graft PAMAM/pDNA complexes were prepared by complex coacervation method at different N/P (nitrogen to phosphate ratio) ratios. The copolymer effectively formed complexes with pDNA at lower N/P ratio (N/P ratio 1.0) than that of unmodified chitosan (N/P ratio 2.0) and the complexes were spherical with particle size of 100-150 nm. The copolymer showed significant protection of DNA from nuclease attack with lower toxicity against HeLa cell. The copolymer also showed no noticeable hemolytic effects up to 10mg/mL indicating no detectable disturbance of the red blood cell membranes. The transfection efficiency of the copolymer was increased significantly compared to that of chitosan and reached up to 36+/-2% at N/P ratio 7.0 which was higher than that of PEI (30+/-3% at N/P ratio 10). Therefore, the copolymer may be a strong alternative candidate as effective nonviral vector. PMID- 23987389 TI - Preparation of polysaccharide supramolecular films by vine-twining polymerization approach. AB - In this study, we investigated the preparation of polysaccharide supramolecular films through the formation of inclusion complexes by amylose in vine-twining polymerization using carboxymethyl cellulose-graft-poly(epsilon-caprolactone) (CMC-g-PCL) as a new guest polymer. First, hydrogels were prepared by phosphorylase-catalyzed enzymatic polymerization in the presence of CMC-g-PCL according to the vine-twining polymerization manner. The XRD result of a powdered sample obtained by lyophilization of the resulting hydrogel indicated the presence of inclusion complexes of amylose with the PCL graft-chains between intermolecular (CMC-g-PCL)s, which acted as supramolecular cross-linking points for the hydrogelation. Then, the supramolecular films were obtained by adding water to the powdered samples, followed by drying. The mechanical properties of the selected films examined by tensile testing were superior to those of a CMC film. The effect of the supramolecular cross-linking structures on the mechanical properties of the films was evaluated further by several investigations. PMID- 23987390 TI - Fractal kinetic analysis of the enzymatic saccharification of CO2 laser pretreated corn stover. AB - The enzymatic hydrolyses of laser pretreated corn stover as a novel pretreatment method were examined to establish a simplified kinetic model for the complicated hydrolysis process. The time dependence of the total reducing sugars amount was closely related to the amounts of cellulosic materials and amounts of cellulase. The evaluated model fitted very well with the experimental data of enzymatic hydrolysis of laser pretreated corn stover under different conditions, including cellulase loading, nature of substrate, substrate loading in the reaction medium. The results indicated that the complex kinetics of cellulase enzymatic saccharification could be assessed with the fractal kinetic model. The cellulase enzymatic reaction process was effectively predicted and controlled with the kinetic model. The result showed that the model could effectively reflect dynamic process of enzyme hydrolysis. PMID- 23987391 TI - Multifunctional finishing of wool fabrics by chitosan UV-grafting: an approach. AB - The aim of this study was the surface modification of wool fibers to confer a multifunctional finishing to the fabrics, improving the textile value and its applications without damage of comfort properties. The attention was focused on an economical and environmental friendly process to obtain an effective treatment with good durability to washing. Chitosan in acetic acid solution was applied by padding, and grafted by ultraviolet radiation, through radical reactions promoted by a photoinitiator. 2% chitosan grafted was enough to confer satisfactory antimicrobial activity (67% reduction of Escherichia coli) after an oxidative wool pre-treatment and 1h impregnation at 50 degrees C. Moreover treated wool fabrics showed a strong dyeability increase toward acid dye. However the evaluation of the treatment durability to laundering showed different behavior depending on the nature of the surfactants. Finally, anti-felting properties with respect to untreated fabrics were revealed, while no effect was shown toward anti pilling properties. PMID- 23987392 TI - Mechanical, barrier and morphological properties of pea starch and peanut protein isolate blend films. AB - Mechanical, barrier and morphological properties of edible films based on blends of Pea starch (PS) and Peanut protein isolate (PPI) plasticized with glycerol (30%, w/w) were investigated. As PPI ratio in PS/PPI blends increased, the thickness of films decreased, the opacity slightly elevated and color intensified. The addition of PPI to the PS film significantly reduced tensile strength from 5.44 MPa to 3.06 MPa, but increased elongation from 28.56% to 98.12% with the incorporation of PPI into PS at 50% level. Film solubility value fell from 22.31% to 9.78% upon the incorporation of PPI ranged from 0 to 50% level. When PPI was added into PS film at 40% level, the WVP and WVTR of the films markedly dropped from 11.18% to 4.19% and 6.16 to 1.95%, respectively. Scanning electron microscopy (SEM) of the surface of films showed that many swollen starch granules were presented in the 100% PS film, while 100% PPI film was observed to have rougher surfaces with presence of pores or cavities. The PS/PPI blend films upon the incorporation of PPI at 20% and 50% level were not homogeneous. However, the smoother film surface was observed in PS/PPI blend films with the addition of PPI at 40% level. SEM image of the cross-sections of the films revealed that the 100% PS film showed a uniform and compact matrix without disruption, and pore formation and 100% PPI film displayed a smooth structure. Rougher and flexible network was shown in blend film with the addition of PPI reaching 40% level. PMID- 23987393 TI - Development of inclusion complex of brinzolamide with hydroxypropyl-beta cyclodextrin. AB - Glaucoma is an accumulative optic neuropathy resulted from increasing intraocular pressure. Brinzolamide (BRZ) is a kind of carbonic anhydrase inhibitors for glaucoma treatment. In this study, brinzolamide-hydroxypropyl-beta-cyclodextrin (BRZ-HP-beta-CD) inclusion complex was prepared by solvent evaporation method to improve the solubility of BRZ and enhance the therapeutic effect of BRZ. The formation of the inclusion complex was confirmed by Fourier transform infrared spectroscopy, differential scanning calorimeter and nuclear magnetic resonance spectroscopy. The solubility of BRZ increased about 10-fold after the formation of the BRZ-HP-beta-CD inclusion complex. The in vitro corneal accumulative permeability of the inclusion complex increased 2.91-fold compared to the commercial available formulation (AZOPT((r))). In addition, BRZ-HP-beta-CD inclusion complex (0.5% BRZ) had an equivalent efficiency of lowering intraocular pressure with AZOPT((r)) (1% BRZ) in vivo. These results identified the BRZ-HP beta-CD inclusion complex might have a promising future as a novel formulation of BRZ for glaucoma treatment. PMID- 23987394 TI - On the weak dependence of water diffusivity on the degree of hydrophobicity of acetylated hydroxypropyl xylan. AB - We used molecular dynamics (MD) simulation to study the diffusion of water at low concentrations in a series of chemically modified xylans, a major hemicellulose, including hydroxypropyl xylan (HPX) and acetoxypropyl xylan (APX) which is essentially acetylated HPX, with different degrees of acetylation (i.e., different degrees of hydrophobicity) at 400 K, a temperature well above the glass transition temperatures of the materials. We used one HPX and three APX models. The three APX models were constructed using the HPX model by substituting 1, 2 or 3 hydroxyl moieties on its repeating units, respectively. The simulation results showed that the diffusivity of water at low concentrations in the chemically modified xylans decreased slightly (~20%) from HPX to APX with 3 acetylated hydroxyl moieties, a trend that has been experimentally observed for xylans and other cellulosic type materials. Further data analysis shows that acetylation decreases the ability of the xylan to form hydrogen bonds with water and its degree of swelling. And these two factors exert opposite effects on the diffusivity of water. In particular, the first factor increases the mobility (lower activation energy) of the water molecules, while the second factor reduces the free volumes available for diffusion, thereby decreasing the water mobility. This finding implies that it is not likely to obtain orders of magnitude change to the water diffusivity simply by the acetylation of all hydroxyl moieties on xylan. The high degree of swelling observed for HPX compared to those of APXs is attributed to the fact that many hydrogen bonds in HPX are broken by water. It is interesting to note that water in most of the hydrogen bonds formed between water and xylans acted as hydrogen bond acceptors rather than donors. PMID- 23987395 TI - Isolated starches from yams (Dioscorea sp) grown at the Venezuelan Amazons: structure and functional properties. AB - This work aimed to characterize the molecular structure and functional properties of starches isolated from wild Dioscorea yams grown at the Amazons, using conventional and up-to-date methodologies. Among the high purity starches isolated (>=99%), the chain lengths were similar, whereas variations in gelatinization profile were observed. Starches have shown varied-shaped granules with monomodal distribution, and B-type crystallinity. Variations in amylose contents found by three analyses were hypothesized being related to intermediate material. Linear chain lengths were similar, and their amylopectins showed a dense, spherical conformation and similar molecular characteristics. The average molar mass and the radius of gyration of the chromatograms of the yam amylopectin, M-W and R-G were ranging between 174*10(6) g mol(-1) and 237*10(6) g mol(-1), and 201 nm and 233 nm, respectively. The white yams starches were more sensible to enzymes than the other two. All starches have shown a wide range of functional and nutritional properties. PMID- 23987396 TI - Anti-plasticization of cassava starch by complexing fatty acids. AB - The effect of adding 1-8% amylose complexing fatty acids (CFA), such as linoleic and oleic acids, on the glass transition temperature (Tg) of cassava starch (CS) with moisture content varying from 5 to 35% (dry basis) was studied. The main relaxation temperature (Talpha), associated with the glass transition temperature of the samples (Tg), was determined by dynamic-mechanical-thermal analysis. The plasticizing behavior of water in the blends was evidenced by a decrease of Talpha values with moisture content. The effect of CFA on CS was found to be a function of moisture content. At low moisture (<11%) it caused an anti plasticization effect, while at higher moisture contents it produced plasticization. The anti-plasticizing effect of CFA on CS was attributed to amylose-lipid complex formation. PMID- 23987397 TI - Chitosan stabilizes platelet growth factors and modulates stem cell differentiation toward tissue regeneration. AB - The idea of using chitosan as a functional delivery aid to support simultaneously PRP, stem cells and growth factors (GF) is associated with the intention to use morphogenic biomaterials to modulate the natural healing sequence in bone and other tissues. For example, chitosan-chondroitin sulfate loaded with platelet lysate was included in a poly(D,L-lactate) foam that was then seeded with human adipose-derived stem cells and cultured in vitro under osteogenic stimulus: the platelet lysate provided to the bone tissue the most suitable assortment of GF which induces the osteogenic differentiation of the mesenchymal stem cells. PDGF, FGF, IGF and TGF-beta were protagonists in the repair of callus fractures. The release of GF from the composites of chitosan-PRP and either nano-hydroxyapatite or tricalcium phosphate was highly beneficial for enhancing MSC proliferation and differentiation, thus qualifying chitosan as an excellent vehicle. A number of biochemical characteristics of chitosan exert synergism with stem cells in the regeneration of soft tissues. PMID- 23987398 TI - Synthesis and properties of carrageenan grafted copolymer with poly(vinyl alcohol). AB - The aim of this work was to prepare a carrageenan-g-poly(vinyl alcohol) (CG-g PVA) polymer using potassium persulphate as an initiator. The effect of different ratios of the polymer blends on the parameters of the grafted polymer was investigated. The grafting ratio decreased with an increase of the CG content in the graft copolymer. The resulting CG-g-PVA was characterized by ATR-FTIR, tensile strength, elongation at break, swelling ratio, contact angle and biodegradation in soil. From the ATR-FTIR the 3,6-anhydride-galactose of the CG showed a peak at 927 cm(-1) that was absent in the CG-g-PVA and the ether linkage of PVA-g-CG between the hydroxyl group of PVA and the 3,6-anhydride-galactose of CG showed a peak at 1089 cm(-1) in the graft copolymer. The tensile strength and elongation at break decreased with an increase of the CG due to its phase separation. The highest tensile strength was observed at 2:8 CG/PVA. In addition, the swelling ratio decreased and the contact angle increased as a function of the increase of the CG in the grafted copolymer. The best ratio of CG-g-PVA was 2:8 CG/PVA. This graft copolymer was easily biodegraded in natural soil. PMID- 23987399 TI - Effect of acetylation on antioxidant and cytoprotective activity of polysaccharides isolated from pumpkin (Cucurbita pepo, lady godiva). AB - Acetylation of pumpkin (Cucurbita pepo, lady godiva variety) polysaccharide using acetic anhydride with pyridines as catalyst under different conditions was conducted to obtain different degrees of acetylation on a laboratory scale. Furthermore, antioxidant activities and cytoprotective effects of pumpkin polysaccharide and its acetylated derivatives were investigated employing various established in vitro systems. Results showed that addition of pyridine as catalyst could increase the degree of substitution, whereas volume of acetic anhydride had little effect. The acetylated polysaccharides in DPPH scavenging radical activity assay, superoxide anion radical activity assay and reducing power assay exhibited higher antioxidant activity than that of unmodified polysaccharide. H2O2-induced oxidative damages on rat thymic lymphocyte were also prevented by pumpkin polysaccharide and its acetylated derivatives and the derivatives presented higher protective effects. On the whole, acetylated polysaccharide showed relevant antioxidant activity both in vitro and in a cell system. PMID- 23987400 TI - TBAF-catalyzed deacylation of cellulose esters: reaction scope and influence of reaction parameters. AB - In order to expand its utility and understand how to carry it out most efficiently, the scope of the highly regioselective, tetrabutylammonium fluoride (TBAF) catalyzed deacylation of cellulose acetates has been investigated, including the influence of key process parameters: solvent, temperature, and water content. Reactions in DMSO, THF, MEK and acetone afforded similar extents of deacylation and regioselectivity. Reaction with TBAF in DMSO at 50 degrees C for 18 h was the most efficient process providing regioselective deacylation at O 2/3. All results were consistent with our previous mechanistic proposals. Furthermore, we demonstrate that TBAF-catalyzed deacylation is also effective and regioselective with cellulose acetate, butyrate, and hexanoate triesters, and even with a cellulose ester devoid of alpha protons, cellulose tribenzoate. These reactions displayed regioselectivity for deacylation at O-2/3 similar to that observed earlier with cellulose acetate (DS 2.4). PMID- 23987401 TI - Phase separation induced molecular fractionation of gum arabic--sugar beet pectin systems. AB - This paper investigates the phase separation and phase separation-induced fractionation of gum arabic (GA)/sugar beet pectin (SBP) mixed solutions. A phase diagram, including cloud and binodal curves, was established by visual observation and phase composition analysis. The deviation of the binodal curve from the cloud curve was a result of phase separation-induced fractionation of polydisperse GA and SBP molecules. Fractionation of GA increased the content of arabinogalactan-protein complex (AGP) from ca. 13% to 27%. The fractionated GA (FGA) showed improved emulsifying functionality, whereas the fractionated SBP (FSBP) had a reduced emulsifying functionality. The changes in emulsifying efficiency can be explained by interfacial adsorption behaviors at the oil-water interface as indicated by interfacial tension measurements. PMID- 23987402 TI - Flame retardant finishing of cotton fabric based on synergistic compounds containing boron and nitrogen. AB - Boric acid and compound containing nitrogen, 2,4,6-tri[(2-hydroxy-3-trimethyl ammonium)propyl]-1,3,5-triazine chloride (Tri-HTAC) were used to finish cotton fabric. The flame retardant properties of the finished cotton fabrics and the synergetic effects of boron and nitrogen elements were investigated and evaluated by limited oxygen index (LOI) method. The mechanism of cross-linking reaction among cotton fiber, Tri-HTAC, and boric acid was discussed by FTIR and element analysis. The thermal stability and surface morphology of the finished cotton fabrics were investigated by thermogravimetric analysis (TGA) and scanning electron microscope (SEM), respectively. The finishing system of the mixture containing boron and nitrogen showed excellent synergistic flame retardancy for cotton fabric. The cotton fabric finished with mixture system had excellent flame retardancy. The LOI value of the treated cotton fabric increased over 27.5. Tri HTAC could form covalent bonds with cellulose fiber and boric acid. The flame retardant cotton fabric showed a slight decrease in tensile strength and whiteness. The surface morphology of flame retardant cotton fiber was smooth. PMID- 23987403 TI - Starch-based microspheres for sustained-release of curcumin: preparation and cytotoxic effect on tumor cells. AB - Curcumin (CUR) has been proved to be highly cytotoxic against different tumor cell lines. However, its poor solubility in aqueous medium and fast degradation in physiological pH are the common drawbacks preventing its efficient practical use. Herein, we report the development of original microspheres based on the biopolymer starch crosslinked with N,N-methylenebisacrylamide (MBA) to be applied as an efficient delivering system for CUR. The starch-based microspheres showed high loading efficiency even in loading solution with different CUR concentrations. In vitro release assays data showed that the CUR release is governed by anomalous transport (n=0.73) and it is pH-dependent. Cytotoxicity assays showed that starch microspheres could improve the cytotoxicity of CUR toward Caco-2 and HCT-116 tumor cell lines up to 40 times than that found for pure CUR. This behavior was attributed to the slowly and sustained release of CUR from the microspheres. PMID- 23987404 TI - The effect of pulping concentration treatment on the properties of microcrystalline cellulose powder obtained from waste paper. AB - Microcrystalline cellulose (MCC) powder was isolated from three grades of waste paper: book, Groundwood/Newsprint and paperboard, through the processes of pulping and hydrolysis. Pulping treatment on these grades of waste paper was done using varying concentrations of caustic soda. Effects of the concentration of the pulping medium on the thermal and kinetic properties were investigated. Also determined were the effects of this on the physico-chemical properties. The chemical structure was characterized using an infrared spectroscopy (FTIR). Results showed these properties to be affected by the concentration of the pulping medium. PMID- 23987405 TI - Multiple complexation of cyclodextrin with soy isoflavones present in an enriched fraction. AB - In the present study we evaluated the complexation of daidzein/genistein/glycitein, present in an isoflavone enriched fraction (IEF), with beta-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). Based on the increased solubility and higher complexation efficiency, IEF and HPbetaCD solid complexes were prepared by kneading, freeze-drying, co-evaporation, spray drying and microwave. The solid complexes were characterized using Fourier transformed-infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, scanning electron microscopy, and nuclear magnetic resonance spectroscopy, and the isoflavone content and solubility were determined by liquid chromatography. The results suggest that the isoflavones daidzein, genistein and glycitein may be externally associated to HPbetaCD as well as that isoflavones/HPbetaCD inclusion complexes are formed through the insertion of B ring into the cyclodextrin cavity. Except for the freeze-dried IEF/HPbetaCD solid complex, all complexes showed similar content and solubility. In conclusion, the three isoflavones showed to be able to simultaneously complex with HPbetaCD. PMID- 23987406 TI - Collagen/cellulose hydrogel beads reconstituted from ionic liquid solution for Cu(II) adsorption. AB - A novel adsorbent, biodegradable collagen/cellulose hydrogel beads (CCHBs), was prepared by reconstitution from a 1-butyl, 3-methylimidazolium chloride ([C4mim]Cl) solution. The adsorption properties of the CCHBs for Cu(II) ion removal from aqueous solutions were investigated and compared with those of cellulose hydrogel beads (CHBs). The CCHBs have a three-dimensional macroporous structure whose amino groups are believed to be the main active binding sites of Cu(II) ions. The equilibrium adsorption capacity (qe) of the CCHBs is greatly influenced by the collagen/cellulose mass ratio, and steeply increases until the collagen/cellulose mass ratio exceeds 2/1. The maximum adsorption is obtained at pH 6. The qe of Cu(II) ions increases with increased initial concentration of the solution. Based on Langmuir isotherms, the maximum adsorption capacity (qm) of CCHB3 (collagen/cellulose mass ratio of 3/1) is 1.06 mmol/g. The CCHBs maintain good adsorption properties after the fourth cycle of adsorption-desorption. PMID- 23987407 TI - The effect of degradation on kappa-carrageenan/locust bean gum/konjac glucomannan gels at acidic pH. AB - The feasibility of textural and rheological modification of gels containing kappa carrageenan (KC) and locust bean gum (LBG) by addition of konjac glucomannan (KGM) was investigated. Special attention was paid to the effect of polysaccharide degradation during heating at acidic pH. The general effect of polysaccharide degradation was to decrease the Young's modulus, while the fracture strain in extension was scarcely affected unless the degradation was very severe. Differential scanning calorimetry showed that the melting peak corresponding to dissociation of KC-KGM bonds decreased faster than the melting peak of KC-only bonds with increasing degree of polysaccharide degradation. The implication is that as degradation proceeds, fewer KGM molecules can interact with KC to form elastic bonds, and the excess of KGM which reinforces the existing elastic network and increases the fracture strain actually increases. For this reason, the fracture strain remains nearly unchanged with increasing degradation levels. A decrease in fracture strain is thus observed only at very severe degradations, where KC no longer forms a self-supporting gel by itself. PMID- 23987408 TI - Extraction, characterization and spontaneous emulsifying properties of pectin from sugar beet pulp. AB - The effects of organic acid extractants on the yield and characteristics of pectin from sugar beet pulp were investigated with citric acid, malic acid and lactic acid at different pH (1.5 and 2.0) and time (1 h and 2 h). The results demonstrated that the yields of pectins were directly correlated with the decrease of pH and reaction time, and the optimum yield of 17.2% was obtained at pH 1.5 and 2 h. Furthermore, the acid type also affected the physicochemical characteristics of pectin, especially on the esterification degree (42-71), galacturonic acid content (60.2-77.8%), emulsion activity (35.2-40.1%) and emulsion stability (62.1-79.4%), and a relatively single pectin mainly consisted of homogalacturonan could be obtained under a suitable reaction condition, which was an excellent crude material for the production of emulsion activity. PMID- 23987409 TI - Rheology and synergy of kappa-carrageenan/locust bean gum/konjac glucomannan gels. AB - The rheology and melting of mixed polysaccharide gels containing konjac glucomannan (KGM), locust bean gum (LBG) and kappa-carrageenan (KC) were studied. Synergy-type peaks in the Young's modulus at optimal mixing ratios were found for both KC/LBG and KC/KGM binary gels at a fixed total polysaccharide content (1:5.5 for LBG:KC and 1:7 for KGM:KC). The Young's modulus peak for KC/KGM was higher than for KC/LBG gels. The same stoichiometric mixing ratios were found when either LBG or KGM was added to KC at a fixed KC concentration, where the Young's modulus increased up to additions at the stoichiometric ratio, but leveled off at higher LBG or KGM additions. Addition of KGM or LBG to the 2-component gels beyond the stoichiometric (optimal) mixing ratio at a fixed total polysaccharide content led to a decrease in the Young's modulus and an increase in the rupture strain and stress in extension, and both trends were stronger for KGM than for LBG. Differential scanning calorimetry of the gels revealed the development of a second melting peak for the KC/KGM gels that increased with KGM addition up to higher KGM contents than the stoichiometric ratio. For the KC/LBG gels, only a slight broadening and shift to a higher temperature were observed. When the three polysaccharides were mixed, the DSC endotherms reflected only the main features of the interaction between KC and KGM, and the same was true for the fracture in extension. The different trends led to higher Young's moduli at intermediate KC concentrations when a 1:1 addition of LBG:KGM was used than when either only KGM or LBG was added at a fixed total polysaccharide concentration. This suggests that no special interactions arise when the three polysaccharides are mixed and the binding mechanisms are simply a sum of the bindings observed for KC/KGM and KC/LBG two-component gels. PMID- 23987410 TI - Fucomannogalactan and glucan from mushroom Amanita muscaria: structure and inflammatory pain inhibition. AB - A fucomannogalactan (FMG-Am) and a (1->3), (1->6)-linked beta-D-glucan (betaGLC Am) were isolated from Amanita muscaria fruiting bodies. These compounds' structures were determined using mono- and bi-dimensional NMR spectroscopy, methylation analysis, and controlled Smith degradation. FMG-Am was shown to be a heterogalactan formed by a (1->6)-linked alpha-D-galactopyranosyl main chain partially substituted at O-2 mainly by alpha-L-fucopyranose and a minor proportion of beta-D-mannopyranose non-reducing end units. betaGLC-Am was identified as a (1->3)-linked beta-D-glucan partially substituted at O-6 by mono- and a few oligosaccharide side chains, which was confirmed after controlled Smith degradation. Both the homo- and heteropolysaccharide were evaluated for their anti-inflammatory and antinociceptive potential, and they produced potent inhibition of inflammatory pain, specifically, 91+/-8% (30 mg kg(-1)) and 88+/-7% (10 mg kg(-1)), respectively. PMID- 23987411 TI - Access to tetra-N-acetyl-chitopentaose by chemical N-acetylation of glucosamine pentamer. AB - Nowadays, the easy access of tetra-N-acetyl-chitopentaose and its counterparts is highly interesting since such chemical compounds are precursors of biological signal molecules with a strong agro-economic impact. The chemical synthesis of tetra-N-acetyl-chitopentaose by controlled N-acetylation of the glucosamine pentamer hydrochloride under mild conditions is described herein. A systematic study on the influence of the different parameters involved in this reaction, such as the solvent, the acetylating agent, and the base used for the deprotonation of ammonium groups of the starting material was carried out. The characterization of final reaction products by HPLC and MALDI-TOF mass spectrometry showed that each of these parameters affects differently the acetylation reaction. Whereas the solvent plays an important role in the N- or O acetylation selectivity, the acetylating agent and the base were found to influence both the degree of N-acetylation and the distribution of the partially N-acetylated derivatives in the product mixtures. Based on these results, optimized reaction conditions have been established allowing tetra-N-acetyl chitopentaose to be synthesized in a one-pot deprotonation/N-acetylation of the glucosamine pentamer hydrochloride in a moderate yield (ca 30%). PMID- 23987412 TI - Iodine binding to explore the conformational state of internal chains of amylopectin. AB - Previous studies have found that the proportion of long chains of amylopectin correlates to its functional and nutritional properties. As a possible explanation of this correlation, the iodine binding property of amylopectin internal chains was investigated as an indirect evidence of their ability to form helices for intra- or inter-molecular interactions. Waxy and amylose-extender waxy corn starches were hydrolyzed by beta-amylase for varying periods of time to incrementally remove the external chains, and the absorbance and the wavelength of maximum absorbance of iodine binding were examined. Experimental results suggest that iodine can bind with both external and internal chains; a significant amount of absorption comes from the latter, as stepwise removal of external chains only somewhat reduced absorption. Internal amylopectin chains, thus, were concluded to likely pre-exist in helical form, as opposed to a conformational change into helices facilitating iodine binding in the absence of external chains. Such internal chain helical structures possibly drive intermolecular interactions that would explain why amylopectin with high proportion of internal chains form harder gels, create pastes less prone to shear breakdown, and are more slowly digesting. PMID- 23987413 TI - Characterization and bisphenol A adsorption capacity of beta-cyclodextrin carboxymethylcellulose-based hydrogels. AB - Novel hydrogel beads having molecular adsorption abilities were prepared from carboxymethylcellulose sodium salt (CMC) and beta-cyclodextrin (beta-CD) by suspension crosslinking, using ethylene glycol diglycidyl ether (EGDE) in basic medium as a crosslinking agent. FTIR and solid-state NMR spectroscopic analysis revealed that the amount of incorporated beta-CD and crosslinking densities within the hydrogel bead structures are strongly dependent on the molar feed ratio of beta-CD to CMC during preparation. The hydrogel beads showed water swelling capacities of 70-200 mL/g-polymer, with decreases in capacity associated with increased amounts of beta-CD incorporated in the gel structure. The hydrogel beads also showed a high adsorption capacity toward bisphenol A (BPA) in water. Batch BPA-adsorption experiments were analyzed employing Langmuir isotherm models; hydrogel bead adsorption isotherms for BPA could be fitted to the Langmuir model. The maximum BPA-adsorption among the prepared series of hydrogel beads amounted to 167 MUmol g(-1). PMID- 23987414 TI - Statistical modeling of process parameters for the recovery of polysaccharide from Morus alba leaf. AB - A central composite rotatable design (CCRD) was used to evaluate the effects of extraction time, extraction temperature, particle size of mulberry leaf, number of extraction and water to the mulberry leaf ratio on extraction yield of mulberry leaf crude polysaccharides (MLCP). The response surface methodology (RSM) showed that the significant quadratic regression equation with high R(2) (=0.9782) was successfully fitted for extraction yield of MLCP as function of independent variables. The overall optimum region was found to be at the combined level of extraction time 5h, extraction temperature 85 degrees C, particle size of mulberry leaf (mesh) 40, number of extraction 4 and water to mulberry leaf ratio 18. At this optimum point, extraction yield of MLCP was 12.0017+/-0.42%. No significant (p>0.05) difference was found between the actual and predicted (11.6286+/-0.19) values. The results demonstrated that MLCP had strong scavenging activities on DPPH and hydroxyl radicals. Overall, MLCP may have potential applications in the medical and food industries. PMID- 23987415 TI - Synthesis of beta-1,3-glucan esters showing nanosphere formation. AB - Polysaccharide nanoparticles are versatile functional materials used in drug delivery applications. Here we describe a method for the synthesis of beta-1,3 glucan esters which show the formation of nanoparticles. Pyridine-soluble beta 1,3-glucan formate was first synthesized as an intermediate and then reacted with various anhydrates to yield beta-1,3-glucan acetate and hexaonate. The resultant esters were soluble in common organic solvents like acetone, pyridine and dimethylacetamide. By using a simple dialysis process, homogeneous hollow or solid nanospheres with diameter from 132 to 487 nm were prepared. The chemical structures of the obtained beta-1,3-glucan esters were characterized and the morphologies of the beta-1,3-glucan based nanoparticles were evaluated. These new types of nanoparticles could be potentially used for the encapsulation of hydrophobic drugs targeting immune cells. PMID- 23987416 TI - Chitosan-glycerol-phosphate (GP) gels release freely diffusible GP and possess titratable fixed charge. AB - Chitosan-glycerol-phosphate (GP) solutions undergo a sol-gel transition upon heating. A model of heat-induced transfer of protons from chitosan to GP in solution has been proposed to explain this sol-gel transition. This model suggests that reduced inter-chain electrostatic repulsion by a decreased protonation of positively charged amino groups - via proton transfer to GP(2-) thereby reduced to GP(-) - would allow chitosan polymer chains to precipitate together and form a solid hydrogel structure. The hypothesis that GP has the single role of acting as a proton acceptor and not as a divalent electrostatic cross-linker of chitosan amine groups suggests that it should freely diffuse out of the gel after the gel formation. We found indeed that GP is free to diffuse and the experimental diffusion profile corresponds to a free diffusion model indicating that it plays no role in electrostatic cross-linking. Finally since chitosan amine groups in the gel are not bound to GP, we examined whether they are titratable in the gel. We show that chitosan in the hydrogel indeed possesses titratable amine groups with significant fixed charge up to +80 mM and follows the same ionization behavior as chitosan in solution. The results of these studies are significant in light of the current and future biomedical applications of this system, including its recent clinical approval as a biomaterial for cartilage repair. PMID- 23987417 TI - Rapid synthesis of graft copolymers from natural cellulose fibers. AB - Cellulose is the most abundant natural polysaccharide polymer, which is used as such or its derivatives in a number of advanced applications, such as in paper, packaging, biosorption, and biomedical. In present communication, in an effort to develop a proficient way to rapidly synthesize poly(methyl acrylate)-graft cellulose (PMA-g-cellulose) copolymers, rapid graft copolymerization synthesis was carried out under microwave conditions using ferrous ammonium sulfate potassium per sulfate (FAS-KPS) as redox initiator. Different reaction parameters such as microwave radiation power, ratio of monomer, solvent and initiator concentrations were optimized to get the highest percentage of grafting. Grafting percentage was found to increase with increase in microwave power up to 70%, and maximum 36.73% grafting was obtained after optimization of all parameters. Fourier transforms infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA/DTA/DTG) analysis were used to confirm the graft copolymerization of poly(methyl acrylate) (PMA) onto the mercerized cellulose. The grafted cellulosic polymers were subsequently subjected to the evaluation of different physico-chemical properties in order to access their application in everyday life, in a direction toward green environment. The grafted copolymers demonstrated increased chemical resistance, and higher thermal stability. PMID- 23987418 TI - A new strategy to enhance gellan production by two-stage culture in Sphingomonas paucimobilis. AB - The effects of different initial sucrose concentrations and temperatures on gellan biosynthesis by Sphingomonas paucimobilis ATCC 31461 were investigated. Lower sucrose concentrations and higher temperatures were favorable for cell growth. Higher sucrose concentrations and lower temperatures promoted gellan production but retarded cell growth. Based on these results, a two-stage culture strategy was developed to improve gellan production. During the first 24 h, S. paucimobilis was cultured in a pulse fed-batch mode with an initial sucrose concentration 10 g/L. Ten grams per liter of sucrose were added at 12 h and 24 h, and the temperature was controlled at 33 degrees C. Batch culture was performed, and the temperature was reduced to 28 degrees C to achieve a high gellan accumulation. The two-stage culture strategy achieved the highest gellan production (22.61 g/L) at 60 h that was 35.71% higher than the result of the best conventional batch operation (16.66 g/L). Meanwhile, high gellan yield was related to high UDPG-pyrophosphorylase activity and glucosyltransferase activity. PMID- 23987419 TI - Maillard reaction products from chitosan-xylan ionic liquid solution. AB - A facile method is reported to prepare Maillard reaction products (MRPs) from chitosan and xylan in co-solvent ionic liquid. UV absorbance and fluorescence changes were regarded as indicators of the occurrence of Maillard reaction. FT IR, NMR, XRD and TG were used to investigate the structure of chitosan-xylan conjugate. The results revealed that when chitosan reacted with xylan in ionic liquid, the hydrogen bonds in chitosan were destroyed, the facts resulted in the formation of chitosan-xylan MRPs. Moreover, when the mass ratio of chitosan to xylan was 1:1, the Maillard reaction proceeded easily. In addition, relatively high antioxidant property was also noted for the chitosan-xylan conjugate with mass ratio 1:1. So the obtained chitosan-xylan MRP is a promising antioxidant agent for food industry. PMID- 23987420 TI - Starch-based extruded cereals enriched in fibers: a behavior of composite solid foams. AB - Extruded cereals mainly composed of starch and enriched in fibers were produced with two types of base recipes: (i) one recipe mainly composed of wheat flour and (ii) one recipe mainly composed of corn and soya flours. The addition of fibers was performed through the use of oat bran concentrate or wheat bran, up to 32% of the recipe. The structure of the extrudates, assessed by X-ray tomography, pointed out the decrease of porosity and of mean cells size with the increase of the total dietary fibers content of the recipe. The hardness of the products, i.e. the maximum stress determined by a compression test, was linked to their porosity. The Gibson-Ashby relationship could be applied and the fit was even improved when considering the walls of the solid foam as composite materials. Fibers and proteins can be indeed considered as particles dispersed in the starchy phase. This work thus shows the impact of the structure of the extrudates on their mechanical properties. The structure is taken into account at different length scales; at the level of the porous structure and at the level of the phase of the main biopolymers present in the recipe (starch, proteins and fibers). The mechanical behavior of these products is then discussed according to their characteristics of composite solid foams. PMID- 23987421 TI - Statistical studies on high molecular weight pullulan production in solid state fermentation using jack fruit seed. AB - The purpose of the work was to optimize the medium variables for maximizing pullulan production using jack fruit seed as a low cost substrate by Aureobasidium pullulans in solid state fermentation. Effects of K2HPO4, KH2PO4, ZnSO4.5H2O, MgSO4.7H2O, NaCl, (NH4)2SO4.5H2O, yeast extract, moisture content (%, w/w) in the production medium on pullulan production were studied using Plackett Burman design. Production of pullulan was significantly affected by the medium variables namely KH2PO4, ZnSO4.5H2O, NaCl and moisture content (%, w/w). Then screened variables were optimized by Box Behnken experiment design. The pullulan obtained was characterized and confirmed by FTIR, (1)H NMR and (13)C NMR. Molecular weight of pullulan was found to be 1.733*10(6) g/mol by gel permeation chromatography (GPC). PMID- 23987422 TI - Preparation and characterization of inclusion complexes of naringenin with beta cyclodextrin or its derivative. AB - The inclusion complexation behavior, characterization and binding ability of naringenin with beta-cyclodextrin and its derivatives were investigated in both solution and the solid state by means of XRD, DSC, SEM, (1)H and 2D NMR and UV vis spectroscopy. The results showed that the water solubility and thermal stability of naringenin were obviously increased in the inclusion complex with cyclodextrins. This satisfactory water solubility and high thermal stability of the naringenin/CD complexes will be potentially useful for their application as herbal medicines or healthcare products. PMID- 23987423 TI - Development of chitosan-based nanoparticles through inter-polymeric complexation for oral drug delivery. AB - The possibility of inter-polymeric complexation of cationic chitosan and anionic egg albumin stabilized with PEG 400 to develop novel nanoparticles for oral delivery of alprazolam by heat coagulation method at pH 5.4 and 80 degrees C. Nine formulations were prepared by changing the concentration of chitosan, PEG 400 and heating time. The alprazolam entrapment efficiency of these nanoparticles was in the range of 68.12+/-1.27 to 99.37+/-4.86%. These nanoparticles were characterized by FTIR, DSC, P-XRD and FE-SEM analysis. Average particle diameter, poly-dispersity index and zeta potential of these nanoparticles were found 259.60 nm, 0.501, and -9.00 mV, respectively. The in vitro drug release from these alprazolam-loaded nanoparticles showed sustained drug release over a period of 24h. In conclusion, these newly developed chitosan-egg albumin-PEG nanoparticles were found to be a promising vehicle for sustained release delivery of lipophilic drugs. PMID- 23987424 TI - Pectin/carboxymethyl cellulose/microfibrillated cellulose composite scaffolds for tissue engineering. AB - Highly porous three-dimensional scaffolds made of biopolymers are of great interest in tissue engineering applications. A novel scaffold composed of pectin, carboxymethyl cellulose (CMC) and microfibrillated cellulose (MFC) were synthesised using lyophilisation technique. The optimised scaffold with 0.1% MFC, C(0.1%), showed highest compression modulus (~3.987 MPa) and glass transition temperature (~103 degrees C). The pore size for the control scaffold, C(0%), was in the range of 30-300 MUm while it was significantly reduced to 10-250 MUm in case of C(0.1%). Using micro computed tomography, the porosity of C(0.1%) was estimated to be 88%. C(0.1%) showed excellent thermal stability and lower degradation rate compared to C(0%). The prepared samples were also characterised using XRD and FTIR. C(0.1%) showed controlled water uptake ability and in vitro degradation in PBS. It exhibited highest cell viability on NIH3T3 fibroblast cell line. These results suggest that these biocompatible composite scaffolds can be used for tissue engineering applications. PMID- 23987425 TI - Structural characterization and antitumor activity of a pectic polysaccharide from Codonopsis pilosula. AB - A pectic polysaccharide (CPP1b) was at first isolated from Codonopsis pilosula. Sugar analysis revealed that CPP1b is composed of rhamnose (Rha), arabinose (Ara), galactose (Gal) and galacturonic acid (GalA) with a molar ratio of 0.25:0.12:0.13:2.51. The result of esterification assay showed that about 46.7+/ 0.4% of carboxylic groups in GalA residues existed as methyl ester. Combined with chemical and spectroscopic analyses, a preliminary structure of CPP1b was proposed as follows: 1,4-linked alpha-D-GalpA and 1,4-linked alpha-D-GalpA6Me interspersed with rare 1,2-linked beta-L-Rhap, 1,2,6-linked alpha-D-Galp and terminal alpha-L-Arap. CPP1b had an average molar mass and root-mean square radius (RMS) of 1.45*10(5) Da and 29.7 nm, respectively, and presented a linear random coil conformation in 0.9% NaCl. The ultrastructure of CPP1b was further investigated by transmission electron microscope (TEM) and scanning electron microscope (SEM). CPP1b exhibited obvious cytotoxicity to human lung adenocarcinoma A549 cells in a dose- and time-dependent manner. PMID- 23987426 TI - Novel phosphorus-containing cyclodextrin polymers and their affinity for calcium cations and hydroxyapatite. AB - Novel phosphorous-containing beta-cyclodextrin (betaCD) polymers (CDP) were synthesized easily under "green chemistry" conditions. A simple polycondensation between the hydroxyl groups of betaCD and non-toxic sodium trimetaphosphate (STMP) under basic conditions led to soluble, non-reticulated CDPs with molecular weights (Mw) higher than 10(4) g mol(-1), the actual value depending on the NaOH:betaCD and STMP:betaCD weight ratios. The presence of both betaCD and phosphate groups in the polymer allows for strong interactions with amphiphilic probes, such as 1-adamantyl acetic acid, or with divalent cations, such as Ca(2+), whose strengths were characterized by isothermal titration microcalorimetry. The obtained phosphated compounds also display high affinity towards hydroxyapatite (HA), leading to HA nanoparticles that could easily be recovered by CDPs, as demonstrated by transmission electron microscopy and quantitative determination of the total amount of phosphated molecules fixed on HA. PMID- 23987427 TI - One-step synthesis of amphiphilic hyperbranched amylopectin derivatives, characterization and use as functional nanovehicles. AB - Amylopectin is a naturally hyperbranched biopolymer with an extremely high molecular weight. Furthermore, this material is non-toxic in nature, and exhibits good biocompatibility and biodegradability properties. Herein, we describe the development of a one-step reaction strategy for the synthesis of amphiphilic high molecular-weight hyperbranched amylopectin derivatives with hydrophobic shells and large hydrophilic cores. The chemical structures of the resulting materials were characterized using FTIR spectroscopy, solid-state (13)C cross polarization/magic angle spinning NMR spectroscopy and gas chromatography. The results from transmission electron microscopy, fluorescence spectroscopy, and UV vis analysis confirmed that the hyperbranched amylopectin derivatives were composed of hydrophobic shells with cholesteryl residues and hydrophilic amylopectin cores. These amylopectin derivatives exhibited high encapsulation capabilities toward water-soluble molecules, and could be used as functional nanovehicles for the controlled release of water-soluble molecules, and the in situ synthesis of metallic nanoparticles. PMID- 23987428 TI - Comparison of xanthans by the relative abundance of its six constituent repeating units. AB - Five xanthans were hydrolyzed to their repeating units using cellulases. Hydrophilic interaction chromatography with online electrospray ionization ion trap mass spectrometry and evaporative light scattering detection was used to analyze the oligomers released. It was concluded that six different pentamer repeating units (RUs) exists within a xanthan sample. The most abundant RU shows acetylation on the inner mannose and pyruvylation on the outer mannose. The second most abundant RU shows acetylation on both the inner and the outer mannose. It becomes clear that more variations in the xanthan structure exist than generally recognized. Comparison of five different xanthan samples revealed that, although the molecular composition of xanthan samples can be exactly the same, the ratio in which the RUs occur can differ significantly. It is, therefore, concluded that xanthan samples should be characterized for both, their molecular composition and the relative abundance of the RUs present. PMID- 23987429 TI - Purification, structure, lipid lowering and liver protecting effects of polysaccharide from Lachnum YM281. AB - The extracellular polysaccharide (LEP) produced by Lachnum YM281 was obtained from the fermentation broth, and LEP-1b with molecular weight of 4.02*10(4) Da was separated and sequentially purified through DEAE-cellulose 52 column chromatography and Sepharose CL-6B column chromatography. GC-MS, IR and NMR ((1)H, (13)C) spectroscopy analysis indicated that the repeat unit of LEP-1b was: [formula; see text] The effects of LEP-1b on the serum lipids, liver lipids levels and aminotransferase activities of model mice with hyperlipidemic fatty live were studied, and the results showed that LEP-1b had strong lipid lowering and liver protecting effects on mice with hyperlipidemic fatty live. PMID- 23987430 TI - Filler modification for papermaking with starch/oleic acid complexes with the aid of calcium ions. AB - To mitigate the negative effect of filler addition on paper strength and improve filler retention, filler modification with hydrogen bonding polymers (e.g., starch) or their composites is an interesting research topic. Differing from previous reports, the concept related to the deposition of starch/oleic acid complexes on precipitated calcium carbonate (PCC) with the aid of calcium ions was demonstrated. The introduction of calcium ions resulted in effective starch deposition. As a result of filler modification, filler retention and the tensile strength of the filled paper were simultaneously improved essentially due to the aggregation of PCC particles in filler modification process as well as improved filler bondability. The concept demonstrated in this brief study may provide an alternative approach to filler bondability enhancement for improved papermaking performances. PMID- 23987431 TI - Functional cell-laden alginate scaffolds consisting of core/shell struts for tissue regeneration. AB - We report an innovative cell-dispensing process using a three-axis robot system coupled with a micro-core/shell nozzle and an aerosol cross-linking process to achieve controlled mechanical properties and high cell viability of porous cell laden alginate scaffolds. The scaffolds were fabricated into layer-by-layer struts, which were used to design the pore structure. The struts consisted of a core/shell region; a low weight fraction of alginate and cells (MC3T3-E1) was injected in the shell region to efficiently exchange nutrients and metabolic wastes, while a high weight fraction of alginate without cells was deposited in the core region to improve the mechanical properties of the cell-laden scaffold. After 10 days of cell culture, the cell viability (95%) in the shell region improved significantly compared to 70% for the cells homogeneously distributed in the struts, and the mechanical properties were enhanced from 1.4 to 15.7 kPa. Stained nuclei and F-actin images showed that the laden cells proliferated well on the functional hydrogel scaffold after 20 days of cell culture, indicating that the cells concentrated in the shell region of the struts survived and increased their metabolic functions during several incubation periods compared to the standard cell-laden scaffold. This innovative cell-dispensing technique represents a promising fabrication tool for obtaining bottom-up scaffolds for various tissue regenerations. PMID- 23987432 TI - Determination of the DS distribution of non-degraded sodium carboxymethyl cellulose by gradient chromatography. AB - Two series of sodium carboxymethyl celluloses (NaCMCs) derived from microcrystalline cellulose (Avicel samples, DP~160) and cotton linters (BWL samples, DP~1400) with average degrees of substitution in the range DS=0.45-1.55 were analyzed by gradient liquid adsorption chromatography (gradient LAC) in order to determine their chemical composition distributions (DS distributions or 1st order heterogeneities). Clear separations of samples having different average DS values were achieved for both sample series, allowing determination of the DS distributions of the samples. A slight molar mass influence on the eluent composition at elution was observed. From the DS distributions the DS standard deviations were calculated and taken as a measure for the extent of chemical heterogeneity of the single samples. While no noticeable dependence of the chemical heterogeneity on average DS was observed for Avicels, the heterogeneity decreases with increasing average DS for BWLs. PMID- 23987433 TI - Formation and characterization of chitosan-polylacticacid-polyethylene glycol gelatin nanoparticles: a novel biosystem for controlled drug delivery. AB - Chitosan (CS)-polylacticacid (PLA)-polyethylene glycol (PEG)-gelatin (G) nanoparticles, a novel drug vehicle for the controlled release of an antitubercluosis drug, rifampicin (RIF) was developed and its chemical and biochemical activities were studied by various standard methods. The designed carriers CS, PEG and G nanoparticles were prepared by emulsion solvent evaporation technique, and then used for entrapping RIF. Linking was confirmed by FTIR spectroscopy. The surface morphology of the nanoparticles was studied using scanning electron microscope and polarizing microscope. The influence of process variables, on particle size, zeta potential and matrix entrapment of RIF was studied. The encapsulation and loading capacity were evaluated, and an in vitro release of RIF was assessed using the dialysis method. The effect of nanoencapsulation of RIF on the antibacterial activity of RIF against Mycobacterium strains was evaluated. The preliminary results clearly suggested that the cross linked CS-PLA-PEG-G matrix may be a potential polymeric carrier for controlled delivery of RIF. PMID- 23987434 TI - The properties of antimicrobial films derived from poly(lactic acid)/starch/chitosan blended matrix. AB - An antimicrobial material with a slow release property was developed based on poly(lactic acid)/starch/chitosan blends, in which chitosan acted as an antimicrobial agent while PLA and starch together were used as a slow-releasing device. An increase in the starch content drastically improved the hydrophilicity of the blends, which was favorable for the diffusion of the embedded chitosan. Moreover, the release of chitosan was observed to occur in two stages, with a very fast release stage initially and a slow but durable release stage as the latter. These two stages exhibited the effectiveness and long residual action of antimicrobial property of the blends respectively, demonstrating the suitability to be used for foods with high water activity, such as fresh meat. The tensile and thermal properties further verified the promising use of the blend material in packaging. PMID- 23987435 TI - Purification and biochemical characterization of a novel thermostable lichenase from Aspergillus niger US368. AB - New beta-1,3;1,4-glucanase was purified from Aspergillus niger US368. The pure glucanase has a molecular mass of about 32 kDa. The N-terminal sequence of the purified enzyme (A-G-T-N-P-P-I-G-V) was determined. The optimum pH and temperature recorded for enzyme activity were 5 and 60 degrees C, respectively. It also displayed marked thermostability with a half-life of 30 min at 70 degrees C. At 37 degrees C, the enzyme showed 100% stability from pH 3 to 10. The Km and Vmax values exhibited by the enzyme on barley beta-glucan were 0.62 mg ml(-1) and 34.46 U ml(-1), respectively. The enzyme is a retaining-one and was only active toward glucan containing beta-1,3;1,4-linkages. The production of beta-glucanase with barley flour as the sole carbon source was optimized. This is the first report on the purification and characterization of a beta-1,3;1,4 glucanase from A. niger. This lichenase could be considered as a candidate for future application particularly in the animal feed industry. PMID- 23987436 TI - Analysis of monosaccharide composition of Cyclocarya paliurus polysaccharide with anion exchange chromatography. AB - A simple, rapid and sensitive analytical method for the determination of monosaccharide composition in Cyclocarya paliurus polysaccharide was developed and validated. This method was based on hydrolysis of the polysaccharides followed by high-performance anion-exchange chromatography analysis. The effects of sodium hydroxide concentration and column temperature on retention and separation of the monosaccharide were investigated with Carbo PACTM PA10 analytical column. The established method was validated and the results showed that this method had good linearity (R(2), 0.9987-0.9999), adequate accuracy (98.53-102.13% recovery), high precision (relative standard deviation <3.8%) and sensitive detection limits (2.57-7.86 nM), with a simple preparation of the samples (no need to derivatize the samples) and short run time (20 min). The results showed that the C. paliurus polysaccharide consisted of rhamnose, arabinose, galactose, glucose, mannose and xylose in the molar ratio of 1.00:1.85:3.26:3.12:0.85:0.29. PMID- 23987437 TI - Host-guest chemistry of cyclodextrin carbamates and cellulose derivatives in aqueous solution. AB - Supramolecular polymer micelles were prepared on basis of the inclusion complexation between cyclodextrin carbamates and cellulose derivatives in aqueous media. Cyclodextrin carbamates were synthesized by microwave-assisted method from cyclodextrin and urea. The urea modified cyclodextrin shows the higher yield than the physical mixture of urea/cyclodextrin in the micellization with cellulose derivatives. The supramolecular structure of the core-shell micelles was demonstrated by (1)H NMR spectra, TEM images, and fluorescence spectra. The drug release behavior of the supramolecular polymer micelles was evaluated using prednisone acetate as a model drug. The drug loaded micelles showed steady and long time drug release behavior. With these properties, the supramolecular polymer micelles are attractive as drug carriers for pharmaceutical applications. PMID- 23987438 TI - Production of enzymes by Alteromonas sp. A321 to degrade polysaccharides from Enteromorpha prolifera. AB - Polysaccharides from Enteromorpha prolifera (PE) are becoming increasingly popular due to its bioactivity and abundant source. Screening novel microorganisms which could secrete enzymes to degrade PE efficiently for oligosaccharides production is a promising solution to improve its application. In this study, a marine bacterium that can produce enzymes to degrade PE specifically was selected. It was identified as Alteromonas sp. A321, based on the biochemical properties and 16S rDNA gene sequencing. In order to maximize the activity of degradase for polysaccharides from E. prolifera (DPE), the effects of medium composition and culture conditions were investigated. The highest DPE production was obtained in the medium consisting of K2HPO4 0.15%, PE 0.9%, NaNO3 0.4%, NaCl 1.0% and MgSO4 0.05%. The degradase activity was enhanced from original 0.391 U/ml to 0.744 U/ml. DPE show high efficiency and substrate specificity to PE with 63.53% of reducing sugar production in the 7 h hydrolysis. PMID- 23987439 TI - RETRACTED: Evaluation of amorphous debranched starch as extended-release matrices in tablets. AB - This study aims to investigate the physicochemical and extended-release properties of amorphous debranched starch (ADBS) that is a linear short chain amylose derived from pullulanase enzymatic modification. The results show the completely amorphous ADBS was soluble in cold water, which developed into a disordered gel network at 25 degrees C. ADBS based tablets were able to extend drug release in different media. Drug release, which was accelerated by decreased pH and pancreatin, was barely affected by ionic strength. The kinetics of the drug release process that was dominated by Fickian diffusion was best fitted and interpreted by the Higuchi equation. The results indicate ADBS is an ideal hydrophilic excipient which extends the in vitro release of water-soluble drugs for 24 h. PMID- 23987440 TI - Fabrication of borassus fruit lignocellulose fiber/PP composites and comparison with jute, sisal and coir fibers. AB - Novel composites based on borassus fruit fine fiber (BFF) and polypropylene (PP) were fabricated with variable fiber composition (5, 10, 15 and 20 wt%) by injection molding. Maleated PP (MAPP) was also used as compatibilizer at 5 wt% for effective fiber-matrix adhesion. FTIR analysis confirms the evidence of a chemical bonding between the fiber and polymeric matrix through esterification in presence of MAPP. The tensile and flexural properties were found to increase with 15 and 10 wt% fiber loadings respectively, and decreased thereafter. Coir, jute and sisal fiber composites were also fabricated with 15 wt% fiber loading under the same conditions as used for BFF/PP composites. It was found that the mechanical properties of BFF (15 wt%)/PP composites were equivalent to jute/PP, sisal/PP and superior to coir/PP composites. Jute/PP and sisal/PP composites showed higher water absorption than BFF/PP and coir/PP composites. These results have demonstrated that the BFF/PP composites can also be an alternative material for composites applications. PMID- 23987441 TI - Microencapsulation of Lactobacillus helveticus and Lactobacillus delbrueckii using alginate and gellan gum. AB - Sodium alginate (SA) at 2% (w/v) and low acylated gellan gum (LAG) at 0.2% (w/v) were used to microencapsulate Lactobacillus helveticus and Lactobacillus delbrueckii spp lactis by employing the internal ionic gelation technique through water-oil emulsions at three different stirring rates: 480, 800 and 1200 rpm. The flow behavior of the biopolymer dispersions, the activation energy of the emulsion, the microencapsulation efficiency, the size distribution, the microcapsules morphology and the effect of the stirring rate on the culture viability were analyzed. All of the dispersions exhibited a non-Newtonian shear thinning flow behavior because the apparent viscosity decreased in value when the shear rate was increased. The activation energy was calculated using the Arrhenius-like equation; the value obtained for the emulsion was 32.59 kJ/mol. It was observed that at 400 rpm, the microencapsulation efficiency was 92.83%, whereas at 800 and 1200 rpm, the stirring rates reduced the efficiency to 15.83% and 4.56%, respectively, evidencing the sensitivity of the microorganisms to the shear rate (13.36 and 20.05 s(-1)). Both optical and scanning electron microscopy (SEM) showed spherical microcapsules with irregular topography due to the presence of holes on its surface. The obtained size distribution range was modified when the stirring rate was increased. At 400 rpm, bimodal behavior was observed in the range of 20-420 MUm; at 800 and 1200 rpm, the behavior became unimodal and the range was from 20 to 200 MUm and 20 to 160 MUm, respectively. PMID- 23987442 TI - Using high pressure processing (HPP) to pretreat sugarcane bagasse. AB - High pressure processing (HPP) technology was used to modify the structural composition of sugarcane bagasse. The effect of pressure (0, 150 and 250 MPa), time (5 and 10 min) and temperature (25 and 50 degrees C) as well as the addition of phosphoric acid, sulfuric acid and NaOH during the HPP treatment were assessed in terms of compositional analysis of the lignocellulosic fraction, structural changes and crystallinity of the bagasse. The effect of HPP pretreatment on the bagasse structure was also evaluated on the efficiency of the enzymatic hydrolysis of bagasse. Results showed that 68.62 and 45.84% of the hemicellulose fraction was degraded by pretreating at 250 MPa with sulfuric and phosphoric acids, respectively. The removal of lignin (54.10%) was higher with the HPP-NaOH treatment. The compacted lignocellulosic structure of the raw bagasse was modified by the HPP treatments and showed few cracks, tiny holes and some fragments flaked off from the surface. Structural changes were higher at 250 MPa and 50 degrees C. The X ray diffraction (XRD) patterns of the raw bagasse showed a major diffraction peak of the cellulose crystallographic 2theta planes ranging between 22 and 23 degrees . The distribution of the crystalline structure of cellulose was affected by increasing the pressure level. The HPP treatment combined with NaOH 2% led to the higher glucose yield (25 g/L) compared to the combination of HPP with water and acids (>5 g/L). Results from this work suggest that HPP technology may be used to pretreat sugarcane bagasse. PMID- 23987443 TI - Self-healing guar gum and guar gum-multiwalled carbon nanotubes nanocomposite gels prepared in an ionic liquid. AB - Guar gum is a galactomannan extracted from the seed of the leguminous shrub Cyamopsis tetragonoloba. It was found to form a soft viscoelastic gel in 1-butyl 3-methylimidazolium chloride, an ionic liquid at an optimized concentration of 10%w/v. A nanocomposite gel of the gum with enhanced strength could be prepared with 0.2%w/v of multiwalled carbon nanotubes (MWCNTs) in the ionic liquid. When the gels thus prepared were subjected to surface fractures or bisected completely, they found to self-heal at room temperature without any external interventions. The self-healing process could be repeated several times. These viscoelastic gel systems showed thixotropic nature and recovery of the storage modulus with time for several cycles was observed upon rheological investigations. The interaction took place between ionic liquid, guar gum and MWCNT was studied by SEM, TEM, FT-IR, powder XRD and rheometry. The results suggested that, upon standing at room temperature development of electrostatic interactions and the van der Waals interactions among the ionic liquid molecules facilitated the formation of reversible noncovalent bonds and eventually activated the self-healing in the gel systems through appropriate chain entanglements. PMID- 23987445 TI - The influence of quarternary salt on hyaluronan conformation and particle size in solution. AB - Interaction of hyaluronan (NaHy) with the quaternary salt, benzalkonium chloride (BAC), was studied. Based on the DLS experiments, viscometry and surface tension measurements executed on hyaluronan samples with two molecular weights of Mw=1.8 MDa and Mw=0.35 MDa, the hypothesis was proposed suggesting that at certain BAC concentrations, hyaluronan can form aggregates, which lead to increase of the polymer coil size measured as z-average diameter. Moreover, it was confirmed that within the whole range of BAC concentrations, repeated variations in size and conformations of polymer coils occur, being connected with the critical micellar concentration of BAC and with hydrophobic interactions of non-polar segments of BAC with hyaluronan hydrophobic domains. Tensiometry, DLS and viscometry data support the assumption that variations of thermodynamical "favourability" of BAC BAC or NaHy-BAC interactions take place in hyaluronan solutions, based on the BAC concentration. PMID- 23987444 TI - Structure and properties of novel regenerated cellulose fibers prepared in NaOH complex solution. AB - Novel spinning solution, prepared by dissolving hydroxyethyl cellulose (HEC) owning a low molar substitution (MS) into NaOH/urea/thiouea aqueous solution with a specific weight ratio of 8:8:6.5, was employed to fabricate a new type of regenerated fibers by wet-spun method. The structure and properties of the resultant HEC fibers were characterized by (13)C NMR, FTIR, synchrotron WAXS, SEM, and tensile tester. The results showed that HEC fibers exhibited structure identical with HEC because of the physical dissolution and coagulation processes, but quite different from native cellulose due to partial breakage of hydrogen bonds and crystal transformation from cellulose I to cellulose II during cellulose modification. The resultant HEC fibers with relatively dense and homogenous structure displayed good moisture related properties and stayed stable in alkali solution with low concentration. Moreover, the novel fibers owned good dry mechanical properties in spit of their slightly poor wet mechanical properties comparable to viscose rayon, showing great potential in substituting the traditional viscose fibers. PMID- 23987446 TI - Impact on molecular organization of amylopectin in starch granules upon annealing. AB - This study investigated the influence of the internal structure of amylopectin on annealing (3h, 24h) of starches from four different types of amylopectin (Bertoft, Koch, & Aman, 2012; Bertoft, Piyachomkwan, Chatakanonda, & Sriroth, 2008). Regardless of the starch source and incubation time, annealing significantly increased the onset gelatinization temperature (To) and narrowed and deepened the amylopectin endotherm. However, the extent of the change in the melting temperature (Tm) and the enthalpy of gelatinization (DeltaH) differed among the types. In terms of the To and Tm, starches from type 1 (oat, rye, barley, and waxy barley) showed the most significant response to annealing. The Tm of starches belonging to type 2 (waxy maize, rice, waxy rice, and sago) remained unchanged after 3h of annealing. Type 1 and type 2 starches with the lowest gelatinization temperatures showed the greatest increase in melting temperature after annealing. However, type 3 (tapioca, mung bean, and arrowroot) and type 4 (potato, waxy potato, canna, and yam) starches were not in line with these observations. Instead, starches from type 3 and type 4 showed a pronounced increase in the DeltaH. The inter-block chain length (IB-CL) (distance between tightly branched units within a cluster) correlated positively (r=0.93, p<0.01) with the change in enthalpy after 24h of annealing. These data indicate that a short IB-CL affects the optimum registration of double helices within the crystalline lamellae. The relationship between the gelatinization parameters before and after annealing suggests that type 1 and 2 starches might possess a high number of unpacked double helices (type 1>type 2) compared to other types. Longer IB-CLs, which facilitate the parallel packing of splayed double helices, and the lengthening of double helices likely increased the DeltaH in type 3 and type 4 starches. It is concluded that annealing can be used as a probe for visualizing the organization of glucan chains (alignment of double helices/degree of perfection) within crystalline lamellae. PMID- 23987447 TI - Synthesis and properties of silane-fluoroacrylate grafted starch. AB - The latex of silane-fluoroacrylate grafted starch for coating materials, VTMS starch/P(MMA/BA/3FMA), is obtained by two step grafting reactions. Vinyltrimethoxysilane (VTMS) is primarily grafted onto starch by condensation between Si-OH and C-OH at 120 degrees C, and then the copolymer of methyl methacrylate (MMA), butyl acrylate (BA) and 2,2,2-trifluoroethyl methacrylate (3FMA) is grafted onto the VTMS-starch by emulsion polymerization. Fourier transform infrared spectrometry (FTIR) and X-ray photoelectron spectroscopy (XPS) have been used to confirm the chemically grafting reactions in every step. The conversion percent, grafting percent and grafting efficiency for VTMS starch/p(MMA/BA/3FMA) latex indicate that the optimum conditions should be controlled at 75 degrees C for 1h as VTMS-starch/P(MMA/BA/3FMA) in 1/3 weight ratio. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis have revealed that the latexes exhibit the uniform spherical particles of 40-60 nm in a narrow size distribution. The latex films perform the obvious hydrophobic (107 degrees ) property, lower surface free energy (25-35 mN/m) and the higher thermostability (330-440 degrees C) than starch (51 degrees , 51.32 mN/m, 100-330 degrees C). Dynamic thermomechanical analysis (DMA) shows that the latex film could gain considerable toughness and strength with an elongation at break of 39.45% and a tensile strength of 11.97 MPa. PMID- 23987448 TI - Assessment of the changes in the cellulosic surface of micro and nano banana fibres due to saponin treatment. AB - The effect of saponin on the surface properties of banana fibres was studied by Inverse Gas Chromatography (IGC). Parameters including the dispersive component of the surface energy, surface heterogeneity, surface area, as well as acid-base surface properties were determined for saponin modified banana micro and nanofibres. These parameters show a more extensive saponin coating on the nanofibres with a network formation which is explained by the higher reactivity of nanofibres due to the higher surface energy, specific interaction and higher surface area presented by the nanofibres. The energetic profile indicates that both micro and nanofibres coated with saponin interact with the same, or similar, energy active sites. Saponin treatment reduces considerably the surface area of the fibres, with the consequent decrease in the monolayer capacity. The interaction with the polar probes clearly indicates that saponin treatment creates new polar active sites for specific interactions in both samples. However, the treatment increases predominately the basicity of the fibre surface with more relevance to the nanofibres. This behaviour will lead to better polymer/fibre interaction during composite preparation. PMID- 23987449 TI - High-barrier coated bacterial cellulose nanowhiskers films with reduced moisture sensitivity. AB - This study reports on the development and characterization of bacterial cellulose (BCNW) films coated with hydrophobic layers, presenting enhanced barrier properties. Pure BCNW films showed good transparency and thermal stability, high rigidity and extremely low oxygen permeability at 0%RH. The dramatic increase in oxygen permeability at 80%RH, due to the hydrophilic character of BCNW, was counteracted through coating the films with annealed PLA electrospun nanostructured fibres or hydrophobic silanes. The use of electrospinning was crucial to attain a good adhesion between the hydrophilic BCNW and the hydrophobic PLA layer. After electrospinning, the fibres were homogenised by annealing, thus obtaining a uniform and continuous coating. Coated systems showed a hydrophobic surface and protected the BCNW from moisture, thus reducing ca. 70% the water permeability and up to 97% the oxygen permeability at 80%RH. Furthermore, this novel approach was seen to protect BCNW films from moisture more efficiently than coating with hydrophobic silanes. PMID- 23987451 TI - Supercritical carbon dioxide assisted silicon based finishing of cellulosic fabric: a novel approach. AB - Usage of supercritical carbon dioxide as a medium for finishing cotton fabrics with modified dimethylsiloxane polymers terminated with silanol groups was investigated, different cross-linkers namely 3-isocyanatepropyltriethoxysilane (IPES) and tetraethylorthosilicate (TEOS) were used for covalently bonding between silicon and cellulose. The presence and the amount of PDMS compounds on the treated fabrics were characterized by FT-IR. Qualitative and quantitative information on the distribution of the silicon molecules across the fibre cross section was provided by SEM/EDX analysis and Confocal Raman microscopy (CRM) respectively. The results confirm that all fibres treated with PDMS and IPES have larger silicon amounts than those treated with TEOS. SC-CO2 medium provides good coating of cotton surface with a 3D network of DMS compound and cross linker, and leads to forming highest DMS concentration in a layer between 1 and 2MU under the surface of cotton fabrics. PMID- 23987450 TI - Microwave assisted synthesis of acrylamide grafted locust bean gum and its application in drug delivery. AB - Acrylamide grafted copolymer of locust bean gum was prepared by microwave irradiation using ceric ammonium nitrate as redox initiator. The grafting process was optimized in terms of irradiation time, amount of initiator and acrylamide by using constant amount of native locust bean gum. The grafted gum was characterized by Fourier transform infrared spectroscopy (FT-IR), (13)C nuclear magnetic resonance (NMR), scanning electron microscopy (SEM), X-ray diffraction study (XRD), differential scanning calorimetry (DSC), elemental analysis, contact angle, viscosity, molecular weight, swelling and biodegradability studies. The grafted gum was found to be biodegradable and non-toxic. It was further used to prepare controlled-release matrix tablet of buflomedil hydrochloride. The in vitro release profile of the tablet showed the rate controlling property of acrylamide grafted locust bean gum was similar to that of hydroxypropyl methylcellulose (HPMC-K15M). PMID- 23987452 TI - Both solubility and chemical stability of curcumin are enhanced by solid dispersion in cellulose derivative matrices. AB - Amorphous solid dispersions (ASD) of curcumin (Cur) in cellulose derivative matrices, hydroxypropylmethylcellulose acetate succinate (HPMCAS), carboxymethylcellulose acetate butyrate (CMCAB), and cellulose acetate adipate propionate (CAAdP) were prepared in order to investigate the structure-property relationship and identify polymer properties necessary to effectively increase Cur aqueous solution concentration. XRD results indicated that all investigated solid dispersions were amorphous, even at a 9:1 Cur:polymer ratio. Both stability against crystallization and Cur solution concentration from these ASDs were significantly higher than those from physical mixtures and crystalline Cur. Remarkably, curcumin was also stabilized against chemical degradation in solution. Chemical stabilization was polymer-dependent, with stabilization in CAAdP>CMCAB>HPMCAS>PVP, while matrices enhanced solution concentration as PVP>HPMCAS>>CMCAB~CAAdP. HPMCAS/Cur dispersions have useful combinations of pH triggered release profile, chemical stabilization, and strong enhancement of Cur solution concentration. PMID- 23987453 TI - Physical, mechanical and barrier properties of corn starch films incorporated with plant essential oils. AB - Corn starch-based films are inherently brittle and lack the necessary mechanical integrity for conventional packaging. However, the incorporation of additives can potentially improve the mechanical properties and processability of starch films. In this work two essential oils, Zataria multiflora Boiss (ZEO) or Mentha pulegium (MEO) at three levels (1%, 2% and 3% (v/v)), were incorporated into starch films using a solution casting method to improve the mechanical and water vapor permeability (WVP) properties and to impart antimicrobial activity. Increasing the content of ZEO or MEO from 2% to 3% (v/v) increased values for elongation at break from 94.38% to 162.45% and from 53.34% to 107.71% respectively, but did not significantly change tensile strength values of the films. The WVP properties of the films decreased from 7.79 to 3.37 or 3.19 g mm m(-2) d(-1) kPa(-1) after 3% (v/v) ZEO or MEO incorporation respectively. The oxygen barrier properties were unaffected at the 1% and 2% (v/v) oil concentration used but oxygen transmission increased with 3% (v/v) for both formulations. The films' color became slightly yellow as the levels of ZEO or MEO were increased although transparency was maintained. Both films demonstrated antimicrobial activity with films containing ZEO more effective against Escherichia coli and Staphylococcus aureus than those containing MEO. These results suggest that ZEO and MEO have the potential to be directly incorporated into corn starch to prepare antimicrobial biodegradable films for various food packaging applications. PMID- 23987454 TI - Characterization of soluble soybean polysaccharide film incorporated essential oil intended for food packaging. AB - This study examines the development of new bio-active polysaccharide-based bioplastics through casting and solvent-evaporation. Soluble soybean polysaccharide (SSPS) films incorporated with Zataria multiflora Boiss (ZEO) or Mentha pulegium (MEO) at various concentrations were prepared and characterized. The presence of ZEO and MEO improved polysaccharide interactions, reducing the films' water solubility and water vapor barrier properties, but did not markedly modify their moisture content or thickness. Differing amounts of ZEO or MEO had no significant effect on mechanical behavior, with the exception of 3% oil concentration, which decreased tensile strength and significantly increased elongation at break. DMTA curves revealed a single Tg, which may indicate the compatibility of essential oil and SSPS. The electron scanning micrograph for the composite film was homogeneous, without signs of phase separation between the components. These results suggest that ZEO and MEO can potentially be directly incorporated into SSPS to prepare active biodegradable films for food-packaging applications. PMID- 23987455 TI - Combined effect of fermentation, sun-drying and genotype on breadmaking ability of sour cassava starch. AB - The influence of genotype and post-harvest treatments on expansion ability of sour cassava starch was investigated using 13 cassava genotypes from Colombia. Starches from cassava grown at 1000 m and 1700 m.a.s.l (3 lowland and 10 highland clones respectively) were modified by fermentation (0 or 30 days) and drying (oven or sun) treatments. RVA average peak viscosity decreased regularly from 952 cP in native starch to 699 cP in fermented and sun-dried starch. Granule size analysis revealed that fermentation hydrolysed lowland and highland granules by exocorrosion and endocorrosion respectively. This result was corroborated by significantly higher RVA breakdown and lower intrinsic viscosity in highland clones, reflecting different sensitivity to fermentation. For the first time, amylose contents ranging from 15.7 to 21.7% were correlated with expansion ability (3.0-8.6 mL/g) of sour cassava starch. Therefore the combination of cassava genotypes (mainly amylose content) and post-harvest treatments is key for expansion ability. Supra-molecular granule structure influenced sensitivity to fermentation. PMID- 23987456 TI - Exopolysaccharide from Lactobacillus planterum LP6: antioxidation and the effect on oxidative stress. AB - An exopolysaccharide (EPS-3) was isolated from the culture of Lactobacillus planterum LP6 and purified by ion exchange and gel chromatography. The concentrations required to scavenge 50% of the initial radical for DPPH., OH. and O2(.-) radicals were 1.38, 3.43 and 0.11 mg/mL, respectively. The reducing power (A700 nm) was 0.632 at 5mg/mL. The cell viability of PC12 was improved by 21.67% at 200 MUg/mL of EPS-3. Compared with the H2O2 group, the total-antioxidant capacity, activities of superoxide dismutase and catalase were enhanced by 65.81%, 41.34% and 59.05%, respectively. Meanwhile, the level of malondialdehyde and lactate dehydrogenase were decreased by 52.80% and 30.24%. The result indicated that EPS-3 had a notable protective effect against oxidative damage on PC12 cells. The study might lay a theoretical foundation for the comprehensive utilization of lactic acid bacteria source which could result in its application in food systems. PMID- 23987457 TI - Structural studies of an exopolysaccharide produced by Gluconacetobacter diazotrophicus Pal5. AB - Gluconacetobacter diazotrophicus is a nitrogen-fixing bacterium that has been found colonizing several plants. This acid-tolerant bacterium produces phytohormones that promote plant growth and is also able to grow in high-sugar concentrations. It has been demonstrated that exopolysaccharides (EPS), which are produced by strain Pal5 of G. diazotrophicus, play an important role in plant infection. We have investigated the structure of the EPS, which was produced by a strain of Pal5 grown in liquid medium containing mannitol as the sole carbon source. The results reveal an EPS with Glc, Gal, Man in a molar ratio of 6:3:1, respectively. NMR spectroscopy and chemical derivatization have revealed that the EPS structure has 4-O-substituted units of beta-glucose, 3-O-substituted units of beta-galactose and 2-O-substituted units of alpha-mannose. Glucose and galactose units linked at C6 were also found. The structure proposed herein is different from EPS produced by other species of Gluconacetobacter published to date. PMID- 23987458 TI - Functionalization of pectin by periodate oxidation. AB - High methoxy citrus pectin was oxidized by periodic acid to prepare a dialdehyde functionalized material. The effect of various reaction conditions, viz., reaction time, reaction temperature, pH of the medium, periodic acid concentration and solvent composition on the oxidation process was investigated. With an increase in the reaction time, the aldehyde content increased. However, the intrinsic viscosity of the system decreased indicating that degradation takes place simultaneously with oxidation. The amount of aldehyde generated also increased with an increase in reaction temperature and the concentration of periodic acid. Due to the polyanionic behaviour of pectin, greater aldehyde contents were obtained at lower pH. Keeping all other reaction conditions constant, greater aldehyde contents were obtained in water-ethanol system than in pure aqueous medium. Increase in the ethanol content increased the amount of aldehyde generated. FTIR spectra of oxidized pectin systems show a carbonyl peak at 1734 cm(-1). They further reveal that partial ionisation of-COOH groups takes place leading to a peak at 1614 cm(-1). PMID- 23987459 TI - Morphological and antibacterial properties of modified paper by PS nanocomposites for packaging applications. AB - With the increasing sustainability trend with packaging materials, paper and polymer nanocomposites represent a novel class of packaging materials. This study evaluates the potential achievement of alternative sustainable materials as antibacterial packaging application. Paper sheet from rice straw coated with 5 or 10% polystyrene (PS) nanocomposites using titanium dioxide nanoparticles (TiO2 NPs) doped or undoped with sliver nanoparticles (Ag-NPs) were prepared. The morphology of the uncoated and coated paper sheets was studied by SEM. The treated paper sheets were analyzed for their elemental composition using EDAX. The Barrier, air permeability, cob test, as well as mechanical properties and tensile strength were also evaluated. The inhibitory effect of modified paper sheets against Pseudomonas, Staphylococcus aureus, Candida, and Staphylococcus were investigated. PMID- 23987460 TI - Polyamidoamine dendrimer conjugated chitosan nanoparticles for the delivery of methotrexate. AB - Encapsulating anticancer drugs to synthetic polymer is a promising approach to improve the efficiency and reduce the side effects of anticancer drugs. In this study, novel chitosan derivatives with polyamidoamine moieties (CS-PAMAM) were synthesized and characterized by morphology, particle size, and zeta potential. Then the anticancer drug-methotrexate-encapsulated CS-PAMAM was prepared by hydrophobic-hydrophilic interactions. The drug release assay showed that the amount of the methotrexate release from CS-PAMAM was pH depended. Meanwhile, the cell viability assay illustrated that CS-PAMAM was suitable for the drug delivery because of its low cytotoxicity on cells. Moreover, our results showed that the CS-PAMAM could significantly improve the cytotoxicity of free methotrexate on A549 cells. These results demonstrate that CS-PAMAM may provide a suitable platform for the water-insoluble drug delivery. PMID- 23987461 TI - Effect of methylcellulose on the formation and drug release behavior of silk fibroin hydrogel. AB - In this study, methylcellulose (MC) was used to control the gelation time of silk fibroin (SF) aqueous solution. The gelation time was measured using a Vibro Viscometer at 50 degrees C. Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and a texture meter were used to investigate the effect of MC on the hydrogelation of SF solution. SF/MC hydrogels could be formed by the addition of MC, although their gelation time was increased with MC content. To examine the conformational change of SF/MC hydrogels, time-resolved FT-IR spectra were obtained at constant temperature using a custom-made IR chamber. From FT-IR spectra focused on the amide I peak position, the transition of SF molecules in SF/MC solution from a random coil to a beta-sheet structure was inhibited in the presence of MC molecules. In addition, the drug release of SF/MC hydrogels loaded with 5-aminosalicylic acid was studied in 2-dimensional (2 D) and 3-dimensional (3-D) conditions in vitro. The drug release behavior of SF or SF/MC hydrogels was measured using UV-Vis spectroscopy. The release rate of 5 aminosalicylic acid in SF/MC hydrogel was lower than that of SF hydrogel, which may be closely associated with the hydrophilic interaction between MC and 5 aminosalicylic acid. This approach to controlling the sol-gel transition and the drug release of SF hydrogels by the addition of MC will be useful in the design and tailoring of novel materials for biomedical applications. PMID- 23987462 TI - Tumoricidal effects of a selenium (Se)-polysaccharide from Ziyang green tea on human osteosarcoma U-2 OS cells. AB - Selenium(Se)-enriched green tea consumption in human diets is well-known to reduce the risk of a variety of diseases. Here, we isolated a Se-polysaccharide (Se-ZYTP) from Se-enriched Ziyang green tea and investigated its antitumor activity on human osteosarcoma U-2 OS cells in vitro and in vivo. Se-ZYTP contained 94.5% of carbohydrate and 2.1% of uronic acid, as well as 2.14 MUg/g Se, revealing that Se-ZYTP was an acidic Se-conjugated polysaccharide. Monosaccharide composition analysis indicated that Se-ZYTP consisted of mannose, rhamnose and fucose in molar ratios of 2.4:1.5:1.2:0.2:0.1:0.3:0.3. In vitro, both MTT and LTH assays proved that Se-ZYTP (25, 50, 100 and 200 MUg/ml) could significantly inhibit the proliferation of human osteosarcoma U-2 OS cells in a concentration-dependent fashion (P<0.05 or P<0.01). In U-2 OS cancer xenograft model in BALB/c athymic mice, Se-ZYTP oral administration at three doses of 100, 200 and 400mg/kg body weight (B.W.) daily for 28 days resulted in obvious tumor regression as compared to model control (P<0.05 or P<0.01). In addition, body weights of mice in control or Se-ZYTP treated groups did not differ significantly and no mice died during experiment, suggesting the safety of Se-ZYTP. Therefore, we postulate that Se-ZYTP might have cancer-preventive and cancer-therapeutic benefit for human osteosarcoma. PMID- 23987463 TI - Co-conjugation vis-a-vis individual conjugation of alpha-amylase and glucoamylase for hydrolysis of starch. AB - Two enzymes, alpha-amylase and glucoamylase have been individually and co conjugated to pectin by covalent binding. Both the enzyme systems showed better thermal and pH stability over the free enzyme system with the complete retention of original activities. Mixture of individually conjugated enzymes showed lower inactivation rate constant with longer half life than the co-conjugated enzyme system. Individually conjugated enzymes showed an increase of 56.48 kJ/mole and 38.22 kJ/mole in activation energy for denaturation than the free enzymes and co conjugated enzymes, respectively. Km as well as Vmax of individually and co conjugated enzymes was found to be higher than the free enzymes. SDS polyacrylamide gel electrophoresis confirmed the formation of conjugate and co conjugate as evident by increased molecular weight. Both the enzyme systems were used for starch hydrolysis where individually conjugated enzymes showed highest release of glucose at 60 degrees C and pH 5.0 as compared to free and co conjugated enzyme. PMID- 23987464 TI - Preparation of high-strength transparent chitosan film reinforced with surface deacetylated chitin nanofibers. AB - Surface-deacetylated chitin nanofiber reinforced chitosan films were prepared. The nano-composite films were highly transparent of approximately 84% at 600 nm due to the nanometer-sized fillers and chitosan matrix, which were embedded in the cavities and on the rough surface of the nanofiber networks. Due to the extended crystalline structure, the nanofibers worked effectively as reinforcement filler to improve the Young's modulus and the tensile strength of the chitosan film. After 10% blending of nanofiber, these properties were increased by 65% and 94%, respectively. Moreover, thermal expansion was also significantly decreased from 35.3 to 26.1 ppm K(-1) after 10% addition of nanofibers. Surface-deacetylated chitin nanofiber and the nano-composite films showed antifungal activity against A. alternata. PMID- 23987465 TI - Analysis of xyloglucans by ambient chloride attachment ionization tandem mass spectrometry. AB - Xyloglucan oligomers obtained upon enzyme digestion from Hymenaea courbaril, Arabidopsis Columbia-0 and mur3 were ionized and analyzed by using chloride anion attachment electrospray ionization (ESI) and tandem mass spectrometry. MW determination and structural elucidation of several xyloglucan oligomers was performed directly from the mixture solutions without sample pretreatment or derivatization. Sodium cation attachment was used to determine the number of xyloglucans present in the mixtures and their MWs. However, tandem mass spectrometry results showed that structure elucidation based on the sodium adducts is ambiguous. Chloride anion also forms stable adducts with these xyloglucans upon ESI. These adducts can be readily identified due to the chlorine isotope pattern. The mass spectral profile of xyloglucans obtained for the mixtures matches the HPAEC results, thus validating this methodology for the determination of the xyloglucan composition and the MW of each xyloglucan. Upon collisional activation in MS(2) experiments, the chloride anion adducts readily lose HCl, which helps verify the molecular weight of each xyloglucan. Isolating the resulting anion (deprotonated oligomer) and subjecting it to further collision-activated dissociation experiments (MS(n); n=3-4) yields useful structural information that allows the differentiation between isomeric anions and hence determination of the sequence of the xyloglucan oligomers. The deprotonated oligomers fragment by a stepwise loss of sugar units from the reducing end. PMID- 23987466 TI - Acrylic acid grafted cellulosic Luffa cylindrical fiber for the removal of dye and metal ions. AB - Acrylic acid grafted cellulosic Luffa cylindrical fiber was utilized for the removal of methylene blue and metal ions from the water system using batch process. The grafted sample used was found to demonstrate a maximum grafting efficiency of 90.8% under concentrations of 0.432*10(-3) mol/L, temperature of 35 degrees C, time of 60 min and pH of 7.0 respectively. The remarkable improvement in thermal properties of the grafted sample was observed. The formation of new bands in FTIR spectra of grafted sample confirmed the grafting of acrylic acid onto the cellulosic fiber. The maximum adsorption capacity of dye onto adsorbent was observed to be 62.15 mg g(-1) at 175 min. A maximum removal of 45.8% was observed for Mg(2+) as compared to other metal ions. High values of correlation coefficient for methylene blue (0.995) and metal ions such as Mg(2+) (0.996), Ni(2+) (0.995), Zn(2+) (0.996) confirmed the applicability of Langmuir isotherm that assumed a monolayer coverage and uniform activity distribution on the adsorbent surface. PMID- 23987467 TI - Adsorption behavior of Hg2+ in aqueous solutions on a novel chelating cross linked chitosan microsphere. AB - In this study, cross-linked chitosan microspheres (CCTS) was synthesized from chitosan and epichlorohydrin (ECH), then, 2-(chloromethyl) benzimidazole (CBM) was introduced to modify CCTS as the ligand. The resulting CBM-chitosan was characterized by EA, FTIR and TGA, and tested for metal adsorption. Results showed that CBM-chitosan has a relatively high selectivity toward Hg(2+). Equilibrium data were fitted well with Langmuir isotherms with the maximum adsorption capacity of 257.8 mg/g for Hg(2+). Both kinetics and thermodynamic parameters of the adsorption process were obtained. The data indicated that adsorption process was exothermic spontaneous reaction and kinetically proceeded according to Second-order kinetics model. CBM-chitosan can be eluted effectively using 1.0 mol/L HCl solution and it has a potential use for separation and preconcentration of Hg(2+) ions from contaminated natural waters. PMID- 23987468 TI - Development of chitosan-based antimicrobial leather coatings. AB - The development of antimicrobial coatings for footwear components is of great interest both from industry and consumer's point of view. In this work, antimicrobial leather materials were developed taking advantage of chitosan intrinsic antimicrobial activity and film forming capacity. Considering the specificities of the leather tanning industry, different coating technologies, namely drum, calender and spray, were tested, being the best results achieved with the drum. This last approach was further investigated to assess the effect of chitosan content, type of solubilizing acid, and impregnation time on the achieved antimicrobial capacity. Considering chitosan price (economic reasons) and the obtained results (antimicrobial activity and coating effectiveness, as inspected by SEM), the impregnation in the drum using a chitosan content of 1% (w/v) in a formic acid solution during 2h, is proposed as the best option for obtaining leather with antimicrobial capacity. PMID- 23987469 TI - Antitumor and immunomodulatory activities of a polysaccharide from Artemisia argyi. AB - A water-soluble polysaccharide (FAAP-02), composed of N-acetyl-D-glucosamine, glucose, mannose, galactose, rhamnose, arabinose, xylose and ribose, with an average molecular weight of 5169 Da, was isolated from Artemisia argyi. The antitumor and immunomodulatory activities of FAAP-02 were evaluated in Sarcoma 180 (S180) tumor-bearing mice by intraperitoneal administration. As a result, FAAP-02 significantly inhibited the growth of the S180 transplanted tumors and prolonged the survival time of the tumor-bearing mice. Moreover, FAAP-02 could obviously increase the thymus and spleen indices, the levels of serum Interleukin 2 (IL-2), Interleukin 6 (IL-6), Interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-alpha), and the expression of CD4+ and CD8+ splenic T lymphocytes which were suppressed by the transplanted tumor or/and 5-fluorouracil (5-FU) in the mice. These results indicated that the antitumor activity of FAAP-02 might be associated with its immunostimulatory effects. PMID- 23987471 TI - A Ru(II) bis-terpyridine-like complex that catalyzes water oxidation: the influence of steric strain. AB - The complexation of 2,9-dicarboxy-1,10-phenanthroline (DPA) with [Ru(tpy)Cl3] (tpy = 2,2';6,2"-terpyridine) provides a six-coordinate species in which one carboxyl group of DPA is not bound to the Ru(II) center. A more soluble tri-t butyl tpy analogue is also prepared. Upon oxidation, neither species shows evidence for intramolecular trapping of a seven-coordinate intermediate. The role of the tpy ligand is revealed by the preparation of [Ru(tpy)(phenq)](2+) (phenq = 2-(quinol-8'-yl)-1,10-phenanthroline) that behaves as an active water oxidation catalyst (TON = 334). This activity is explained by the expanded coordination geometry of the phenq ligand that can form a six-membered chelate ring that better accommodates the linear arrangement of axial ligands required for optimal pentagonal bipyramid geometry. When a 1,8-naphthyidine ring is substituted for each of the two peripheral pyridine rings on tpy, increased crowding in the vicinity of the metal center impedes acquisition of the prerequisite reaction geometry. PMID- 23987470 TI - Endoscopic combined intrarenal surgery for large calculi: simultaneous use of flexible ureteroscopy and mini-percutaneous nephrolithotomy overcomes the disadvantageous of percutaneous nephrolithotomy monotherapy. AB - BACKGROUND AND PURPOSE: Percutaneous nephrolithotomy (PCNL) is considered the standard procedure for the removal of large renal calculi. The development of the "minimally invasive PCNL" (mini-PCNL) has reduced the complications of the surgery; it also appears to be associated with less morbidity than the conventional PCNL (con-PCNL). This study aimed at evaluating the efficacy of endoscopic intrarenal surgery, using the prone-split leg position, using flexible ureteroscopy and mini-PCNL (mini- endoscopic combined intrarenal surgery [ECIRS]) by retrospectively comparing this technique with mini-PCNL and con-PCNL. PATIENTS AND METHODS: In total, 161 consecutive patients who were observed for the follow up of large renal calculi between February 2004 and January 2013 were selected for mini-ECIRS (60), mini-PCNL (19), or con-PCNL (82). Mini-ECIRS was performed with patients in the prone split-leg position via 18F minipercutaneous tract and 14F ureteral access sheath. The mini-PCNL was performed via 18F percutaneous tract and con-PCNL performed via the 30F tract. Mean size of the renal calculi removed via mini-ECIRS, mini-PCNL, and con-PCNL were 39.2, 38.4, and 34.6 mm, respectively. RESULTS: Average surgical time for mini-ECIRS was shorter than that for mini-PCNL and con-PCNL (120.5 vs. 181.9 vs 134.1 min, respectively; P<0.001). The stone-free rate for mini-ECIRS was significantly higher than that of the other procedures (initial rates 81.7% vs. 38.9% vs. 45.1%, respectively; P<0.001; rates after further treatment 86.7% vs. 61.1% vs. 61.0%, respectively; P=0.002). Only one patient in the mini-ECIRS group needed blood transfusions. The decrease in hemoglobin during mini-ECIRS and mini-PCNL was significantly lower than that during con-PCNL (P=0.011). CONCLUSION: Mini-ECIRS is better than monotherapy with mini-PCNL or con-PCNL. The study results show that mini-ECIRS is a safe, efficient, and versatile procedure that can be effective for the management of renal calculi. PMID- 23987472 TI - Inhibition of mucin-type O-glycosylation through metabolic processing and incorporation of N-thioglycolyl-D-galactosamine peracetate (Ac5GalNTGc). AB - Mucin-type O-glycans form one of the most abundant and complex post-translational modifications (PTM) on cell surface proteins that govern adhesion, migration, and trafficking of hematopoietic cells. Development of targeted approaches to probe functions of O-glycans is at an early stage. Among several approaches, small molecules with unique chemical functional groups that could modulate glycan biosynthesis form a critical tool. Herein, we show that metabolism of peracetyl N acyl-D-galactosamine derivatives carrying an N-thioglycolyl (Ac5GalNTGc, 1) moiety-but not N-glycolyl (Ac5GalNGc, 2) and N-acetyl (Ac4GalNAc, 3)-through the N-acetyl-D-galactosamine (GalNAc) salvage pathway induced abrogation of MAL-II and PNA epitopes in Jurkat cells. Mass spectrometry of permethylated O-glycans from Jurkat cells confirmed the presence of significant amounts of elaborated O glycans (sialyl-T and disialyl-T) which were inhibited upon treatment with 1. O Glycosylation of CD43, a cell surface antigen rich in O-glycans, was drastically reduced by 1 in a thiol-dependent manner. By contrast, only mild effects were observed for CD45 glycoforms. Direct metabolic incorporation of 1 was confirmed by thiol-selective Michael addition reaction of immunoprecipitated CD43-myc/FLAG. Mechanistically, CD43 glycoforms were unperturbed by peracetylated N-(3 acetylthiopropanoyl) (4), N-(4-acetylthiobutanoyl) (5), and N-methylthioacetyl (6) galactosamine derivatives, N-thioglycolyl-D-glucosamine (7, C-4 epimer of 1), and alpha-O-benzyl 2-acetamido-2-deoxy-D-galactopyranoside (8), confirming the critical requirement of both free sulfhydryl and galactosamine moieties for inhibition of mucin-type O-glycans. Similar, yet differential, effects of 1 were observed for CD43 glycoforms in multiple hematopoietic cells. Development of small molecules that could alter glycan patterns in an antigen-selective and cell type selective manner might provide avenues for understanding biological functions of glycans. PMID- 23987473 TI - Epidemiology of Plasmodium relictum infection in the house sparrow. AB - In vertebrates, multiple host characteristics and environmental factors are known to influence infectious disease dynamics. Here, we investigated variability in prevalence and parasitemia of Plasmodium relictum in the house sparrow ( Passer domesticus ) across a large number of rural and urban populations (n = 16). We found that prevalence was not predicted by any of the host traits investigated (age, sex, body mass, or wing length). However, parasitemia was significantly higher in females when compared to males and in 1-yr-olds as compared to older individuals. Neither prevalence nor parasitemia differed according to habitat type (urban vs. rural). These results suggest that inter-population variation in parasitemia depends on host intrinsic factors whereas variation in prevalence could be due to environmental differences between populations, such as climatic variables that might affect the abundance of vectors. This large-scale study gives us a better understanding of the key factors involved in the epidemiology of avian malaria. PMID- 23987474 TI - Influence of dimethylsulfoxide on RNA structure and ligand binding. AB - Dimethyl sulfoxide (DMSO) is widely used as a cosolvent to solubilize hydrophobic compounds in RNA-ligand binding assays. Although it is known that high concentrations of DMSO (>75%) can significantly affect RNA structure and folding energetics, a thorough analysis of how lower concentrations (<10%) of DMSO typically used in binding assays affects RNA structure and ligand binding has not been undertaken. Here, we use NMR and 2-aminopurine fluorescence spectroscopy to examine how DMSO affects the structure, dynamics, and ligand binding properties of two flexible hairpin RNAs: the transactivation response element from HIV-1 and bacterial ribosomal A-site. In both cases, 5-10% DMSO decreased stacking interactions and increased local disorder in noncanonical residues within bulges and loops and resulted in 0.3-4-fold reduction in the measured binding affinities for different small molecules, with the greatest reduction observed for an intercalating compound that binds RNA nonspecifically. Our results suggest that, by competing for hydrophobic interactions, DMSO can have a small but significant effect on RNA structure and ligand binding. These effects should be considered when developing ligand binding assays and high throughput screens. PMID- 23987477 TI - One and two-electron investigation of electronic structure for Ba(+)Xe and BaXe van der Waals molecules in a pseudopotential approach. AB - The potential energy curves, vibrational energy levels, spectroscopic constants, and dipole moment curves for the ground and excited states of BaXe and its ion Ba(+)Xe molecules are calculated with an ab initio method using pseudopotential techniques and core polarization potentials. The molecules are treated as two (BaXe) or one (Ba(+)Xe) active electrons systems taking benefit of the zero pseudopotential approach for Xe. The vibrational levels and their energy spacing have been also determined for Sigma(+), Pi, and Delta states. The permanent and transition dipole moment curves are investigated for the (1,3)Sigma(+) states of the BaXe neutral molecule and (2)Sigma(+) states of the Ba(+)Xe ion. The analysis of these numerous results shows interesting behavior in potential energy curves imprinted by the strong repulsive interactions between electron and Xe and also indicates an intense transition dipole moment for both Ba(+)Xe and BaXe. PMID- 23987476 TI - Phenylpyrazolo[1,5-a]quinazolin-5(4H)-one: a suitable scaffold for the development of noncamptothecin topoisomerase I (Top1) inhibitors. AB - In search for a novel chemotype to develop topoisomerase I (Top1) inhibitors, the pyrazolo[1,5-a]quinazoline nucleus, structurally related to the indenoisoquinoline system precursor of well-known Top1 poisons, was variously decorated (i.e., a substituted phenyl ring at 2- or 3-position, a protonable side chain at 4- or 5-position), affording a number of Top1 inhibitors with cleavage patterns common to CPT and MJ-III-65. SARs data were rationalized by means of an advanced docking protocol. PMID- 23987478 TI - A rapid and efficient way to manage hyponatremia in patients with SIADH and small cell lung cancer: treatment with tolvaptan. AB - BACKGROUND: Hyponatremia based on syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH) is observed in up to 15% of patients with small cell lung cancer (SCLC). The electrolyte imbalance is associated with a high morbidity and mortality and often delays appropriate treatment. Management of hyponatremia proved to be challenging until new vasopressin-2 receptor antagonists such as tolvaptan became available. This is the first report which presents a prospective case series with an efficient management of hyponatremia including tolvaptan in ten patients with SCLC and severe SIADH (plasma sodium < 125 mmol/l). METHODS: Ten patients with SCLC and severe SIADH were followed after the onset of clinical symptoms of SIADH. Patients were chosen on the basis of histological proven diagnosis of SCLC and the clinical picture of a neurocognitive deficit caused by SIADH-related hyponatremia. All patient data were monitored for clinical improvement based on ECOG status, commencement of chemotherapy and correction of sodium levels. RESULTS: The treatment followed a diagnostic and treatment algorithm and lead to a rapid and efficient correction of both clinical symptoms and plasma sodium level. CONCLUSIONS: Based on this algorithm all patients started chemotherapy in time. Subsequently, the treatment with tolvaptan lead to an improvement of the ECOG-performance status. In addition, all patients benefit from the effective management of SIADH which omitted prolonged hospital stays and non-elective hospitalizations due to an unstable clinical condition due to severe hyponatremia. These observations add new insight to management of SIADH in thoracic oncology and are of interest for specialists in oncology, endocrinology and pulmonary medicine. PMID- 23987479 TI - [Iodine nutrition and thyroid diseases]. AB - Iodine, an essential component of the hormones produced by the thyroid gland, is widely but unevenly distributed in the earth's environment. Great difference exists in the iodine nutritional status of populations residing in different region. Both iodine deficiency and iodine excess can injure the thyroid gland. Iodine deficiency tigers endemic goiter, cretinism, and hyperthyroidism, while iodine excess can result in high iodine goiter, chronic lymphocytic thyroiditis, iodine-induced hyperthyroidism, and hypothyroidism; also, iodine deficiency or excess may affect the histological type of thyroid cancer. In 1996, China began to implement the universal salt iodization policy, which has basically eliminated the iodine deficiency disorders nationwide; however, it also caused the changes in the spectra of other thyroid diseases including iodine-induced hyperthyroidism, autoimmune thyroid disease, and papillary thyroid carcinoma. Individualized iodine nutritional status assessment for the populations, particularly those with thyroid diseases, will be beneficial. PMID- 23987480 TI - [Application of iodine metabolism analysis methods in thyroid diseases]. AB - The main physiological role of iodine in the body is to synthesize thyroid hormone. Both iodine deficiency and iodine excess can lead to severe thyroid diseases. While its role in thyroid diseases has increasingly been recognized, few relevant platforms and techniques for iodine detection have been available in China. This paper summarizes the advantages and disadvantages of currently iodine detection methods including direct titration, arsenic cerium catalytic spectrophotometry, chromatography with pulsed amperometry, colorimetry based on automatic biochemistry, inductively coupled plasma mass spectrometry, so as to optimize the iodine nutrition for patients with thyroid diseases. PMID- 23987481 TI - [Surgical therapy of thyroid cancer]. AB - The prevalence of thyroid cancer has shown an upward trend in China in recent years. Advances in thyroid ultrasound and fine needle puncture cytology have improved the accuracy of the preoperative diagnosis of thyroid cancer. Also,the application of endoscopy-assisted techniques and intraoperative nerve monitoring technology and the further understanding of thyroid lymph node metastasis have made the thyroid surgeries safer and less invasive. This article summarizes the recent advances in the surgical therapy of thyroid cancer. PMID- 23987482 TI - [Postoperative treatment of differentiated thyroid carcinoma with intermediate recurrence risk]. AB - The three-level recurrence stratification of differentiated thyroid carcinoma (DTC) has attracted wide attention since its introduction in 2009 American Thyroid Association guidelines. Among these three levels, the postoperative treatment of DTC with intermediate recurrence risk is highly controversial. This article summarizes the relevant advances and controversies in this field. PMID- 23987483 TI - [Research advances in molecular pathogenesis of thyroid cancer]. AB - Thyroid cancer is the one of the most common endocrine tumors. The biological behaviors and prognoses of the thyroid cancer of different histological types remarkably differ. The highly invasive thyroid cancer responds poorly to traditional therapies. Recent research advances in the molecular mechanisms of the pathogenesis of thyroid cancer have revealed the roles of many genetic and epigenetic variations such as gene mutation, abnormal gene amplification, and abnormal gene methylation in the development of thyroid cancer, which provides new insights in the molecular diagnosis, prognosis, and target therapy of the thyroid cancer. PMID- 23987484 TI - [Retrospective analysis of clinical data of patients received thyroid surgery in Peking Union Medical College Hospital from 1986 to 2012]. AB - OBJECTIVE: To study the changes in the constituent ratio of patients received surgical therapy for their thyroid diseases in Peking Union Medical College Hospital from 1986 to 2012. METHODS: The clinical data of patients received surgical therapy with pathologically confirmed findings from 1986 to 2012 were collected, and a corresponding database was established. The constituent ratios of thyroid diseases and thyroid malignant tumor among different population groups in different years were analyzed. RESULTS: The number of patients with thyroid diseases admitted to our hospital had significantly increased in the past 27 years, particularly those with nodular goiter or thyroid cancer. The composition ratios of thyroid cancer and nodular goiter increased significantly, and among malignancies the papillary thyroid carcinoma increased obviously. The detection rate of papillary thyroid micro-carcinoma had continuously increased since 2008. CONCLUSION: Thyroid diseases and malignant tumor pathological types had dramatically changed in hospitalized patients in our hospital in the past 27 years. PMID- 23987485 TI - [Diagnostic values of ultrasound and (18)F-fluoro-2-deoxy-D-glucose-positron emission tomography/computerized tomography for patients with suspected thyroid carcinoma and lymph node metastasis]. AB - OBJECTIVE: To evaluate the diagnostic values of ultrasound (US) and (18)F-fluoro 2-deoxy-D-glucose-positron emission tomography (FDG PET)/computerized tomography (CT) in diagnosing suspected thyroid carcinoma and lymph node metastasis. METHODS: The clinical data of 28 patients who had undergone total or subtotal thyroidectomy with or without neck dissection from December 2011 to December 2012 in PUMC Hospital and had undergone US and FDG PET/CT before surgery were retrospectively analyzed. In each patient, US and FDG PET/CT images were retrospectively reviewed to determine the presence of carcinoma with or without loco-regional metastasis by level-by-level analysis. The potential correlation between imaging results and histopathology were analyzed. RESULTS: There were 11 benign lesions,15 papillary carcinomas, one follicular carcinoma, and one medullary carcinoma. For thyroid carcinoma,the sensitivity and specificity were 88.2% and 63.6% for US and 76.5% and 54.5% for FDG PET/CT(P>0.05). For lymph node metastasis, the sensitivity was 68.0% for US and 60.0% for FDG PET/CT (P>0.05), and the specificity was 96.7% for US and FDG PET/CT.FDG PET/CT could provide more diagnostic information than US for patients with level 2 or 5 metastasis. CONCLUSIONS: Combination of US and FDG PET/CT is typically not needed for differentiating thyroid lesions.However, for patients with suspected lymph node metastasis of infrequently involved levels, the combination of US and FDG PET/CT may be a good choice. PMID- 23987486 TI - [Invasiveness of papillary thyroid microcarcinoma with BRAF mutation]. AB - OBJECTIVE: To explore the invasiveness of papillary thyroid microcarcinoma(PTMC)with BRAF mutation. METHODS: Totally 99 patients with PTMC with BRAF mutation were enrolled in this study, meanwhile another 97 patients with papillary thyroid carcinoma (PTC) (tumor size>1 cm)with BRAF mutation were included as controls. The clinicopathologic factors including extrathyroidal invasion, multifocality, and distant metastasis were analyzed. RESULTS: The rates of extrathyroidal invasion and nodal metastasis in PTMC group were as high as 16.10% and 71.74%, respectively. In the PTMC group and PTC group,the extrathyroidal invasion rate was 16.10% and 39.18%, cervical lymph node metastasis rate was 71.74% and 91.75%, and distant metastasis rate was 1.01% and 9.28%, respectively. In the PTMC subgroups with tumor sizes <=0.3 cm, 0.3-0.6 cm, and 0.6-1.0 cm, the cervical lymph node invasion rate was 60.00%, 72.50%, and 73.81%, the extrathyroidal invasion rate was 10.00%, 9.09%, and 24.44%, and the multifocality rate was 60.00%, 38.64%, and 57.78%, respectively. Univariate analysis showed that the tumor size was not significantly correlated with multifocality (Chi (2)=3.752, P=0.153), cervical lymph node metastasis (Chi (2) = 0.780,P = 0.677), extrathyroidal invasion (Chi (2) = 4.182, P = 0.124), and distant metastasis (Chi (2)=1.212, P = 0.545). While the BRAF group and PTC group were not significantly different in multifocality (Chi (2) = 1.742, P=0.187), they were significantly different in terms of extrathyroidal invasion (Chi (2) = 13.000, P = 0.000), nodal involvement (Chi (2) = 12.819, P = 0.000), and distant metastasis (Chi (2) = 5.316, P = 0.021). Multivariate analysis showed that nodal metastasis was independently associated with size>1 cm (P=0.001) and extrathyroidal invasion (P=0.003). CONCLUSIONS: BRAF mutant PTMC manifests relative high extrathyroidal involvement and nodal metastasis, and the similar multifocality as BRAF mutant PTC. Radioactive iodine should be considered in PTMC with the presence of BRAF mutation combined with extrathyroidal invasion or nodal metastasis. PMID- 23987487 TI - [Efficacy of cyclosporine A-nanoparticles emulsion combined with stem cell transplantation therapy for acute myocardial infarction]. AB - OBJECTIVE: To evaluate the efficacy of cyclosporine A-nanoparticles emulsion (CsA NP) combined with adipose tissue-derived stem cells (ASCs)transplantation therapy for acute myocardial infarction (AMI) in a miniswine model. METHODS: CsA-NP emulsion was prepared by the high-pressure homogenization method. Models were performed by coronary angioplasty for percutaneous balloon occlusion of left anterior descending artery (LAD). A total of 17 miniswines survived after AMI were divided into four groups: control group (n=5), CsA-NP group (n=4), ASCs group (n=4), and CsA-NP+ASCs group (n=4). ASCs or saline were delivered by intracoronary injection one week after AMI.Before cell transplantation and 8 weeks after cell transplantation, delayed-enhanced magnetic resonance imaging (DE MRI) was performed to evaluate cardiac function and viability. The infarcted myocardium and implanted cells were histologically studied. RESULTS: Eight weeks after treatment, the left ventricular ejection fraction (LVEF)significantly increased in the CsA-NP+ASCs group when compared with the ASCs group [(53.6 +/- 2.4)% vs. (48.3 +/- 1.8)%, P<0.05]; meanwhile, the infarct size significantly decreased [(6.2 +/- 1.7)cm(3) vs.(7.5 +/- 0.6) cm(3), P<0.05] and the thickness of the ventricular wall significantly increased (P<0.05). Histology showed that the number of surviving cells increased nearly by three times in the CsA-NP+ASCs group, and the expressions of the cardiomyocyte specific markers (cTnT and alpha actin) were detected. Histological samples also showed that CsA-NP+ASCs group reduced fibrotic tissue, and down-regulated the activation of Caspase-3. CONCLUSION: The CsA-NP+ASCs combination therapy can enhance the viability of ASCs by improving LVEF and preventing LV expansion, which may be explained that CsA-NP has the anti-apoptotic effect and can promote the survivals and proliferation of ASCs. PMID- 23987488 TI - [Self-made ultrasound/fluorescent bi-functional contrast agent for rabbit's normal lymph node imaging]. AB - OBJECTIVE: To prepare a lymph node-targeted ultrasound/fluorescence bi-functional imaging contrast agents, and observe its effectiveness both on contrast-enhanced ultrasound (CEUS) and vivo near infrared fluorescence (NIR) imaging through animal experiments. METHODS: The chimeric lymph node-targeted ligand (phosphatidylserine) and near-infrared fluorescent substance were assembled to form bi-functional contrast microbubbles. The morphology and size distribution were detected by optical microscope and Malvern potential tests. Five normal New Zealand white rabbits were subcutaneously injected with the prepared contrast agent in bilateral footpads, and the imaging effectiveness of lymph nodes and lymphatic vessel were observed by CEUS and NIR technique. Then blue dye was subcutaneously injected at the same site, and the rabbits were sacrificed for lymph nodes pathological examination. RESULTS: Lipid ultrasound microbubbles,with a mean size of 3-5 MUm in diameter, appeared to be uniform in distribution and regular in configuration. The images of inflow lymphatic vessel and relevant lymph node were quickly showed up after the subcutaneous injection by CEUS, which was identical to the result detected by NIR. Biopsy confirmed that all the blue stained lymph nodes could be displayed by NIR. CONCLUSIONS: The self-made bi functional contrast agent has a good imaging ability in CEUS and NIR imaging. It may be a better agent as lymph node tracer. PMID- 23987489 TI - [Differentiation between glioma recurrence and radiation-induced brain injuries using perfusion-weighted magnetic resonance imaging]. AB - OBJECTIVE: To evaluate the role of perfusion weighted imaging (PWI) in the differentiation between recurrent glioma and radiation-induced brain injuries. METHODS: Twenty-three patients with previously resected and irradiated glioma, presenting newly developed abnormal enhancement, were included in the study. The final diagnosis was determined either histologically or clinicoradiologically. PWI was obtained with a gradient echo echo-planar-imaging (GRE-EPI)technique. The normalized relative cerebral blood volume (rCBV) ratio [rCBV (abnormal enhancement)/rCBV (contralateral tissue)], relative cerebral blood flow (rCBF) ratio [rCBF (abnormal enhancement)/rCBF(contralateral tissue)], mean transit time(MTT) ratio [MTT (abnormal enhancement)/MTT(contralateral tissue)],time to peak(TTP)ratio[TTP(abnormal enhancement)/TTP(contralateral tissue)],and bolus arrive time(BAT)ratio[BAT(abnormal enhancement)/BAT(contralateral tissue)] were calculated. The regions of interest (ROIs) consisting of 20-40mm(2) were placed in the abnormal enhanced areas on postcontrast T1-weighted images.Ten ROIs measurements were performed in each lesion.T test was used to determine whether there was a difference in the rCBV/rCBF/rMTT/rTTP/rBAT ratios between recurrent glioma and irradiated injuries.Significance was set to a P value <0.05. RESULTS: Thirteen of the 23 patients were proved recurrent glioma and 10 were proved radiation-induced brain injuries. The rCBV ratio (3.60+/-3.86 vs. 0.82 +/- 0.74, P = 0.000)and rCBF ratio (2.88 +/- 2.27 vs. 0.84 +/- 0.80, P = 0.000) in glioma recurrence were markedly higher than those in radiation injuries. The areas under rCBV and rCBF ROC curve were both 0.8763. rMTT (P=0.204), rTTP (P=0.260), and rBAT (P=0.071) ratios showed no statistical difference between the two groups. CONCLUSION: PWI is an effective technique in distinguishing glioma recurrence from radiation injuries,and the ratios of rCBV and rCBF ratio differential diagnosis of critical value to 1.3088 and 1.1235, respectively, can be used as a reliable clinical indicator. PMID- 23987490 TI - [Relationship between female menopause and hypertension/isolated systolic hypertension in rural districts of Hanzhong in Shaanxi province]. AB - OBJECTIVE: To analyze the associations between menopause and hypertension/isolated systolic hypertension (ISH) among rural females in Hanzhong, Shaanxi Province, China. METHODS: In this cross-sectional study, 3030 residents were selected by stratified random sampling and investigated by questionnaire survey and physical examinations. Data of the females were analyzed to explore the impact of menopause on blood pressure by quantile regression and to investigate the associations between menopause and hypertension, ISH, and isolated distolic hypertension (IDH) by logistic regression. RESULTS: The number of premenopausal and postmenopausal women was 965 and 998. The average age was (41.0 +/- 8.07) years in the premenopausal group and (58.0+/-7.12) years in the postmenopausal group (P<0.001). The prevalence of hypertension among the premenopausal group and postmenopausal group was 21.9% and 49.3%, respectively. Quantiles regression analysis showed that the impact of menopause on systolic blood pressure increased as the percentile increased. The diastolic blood pressure (DBP) of the premenopausal group was significantly lower than that in the postmenopausal at q >= 0.40(DBP = 84 mmHg,1 mmHg = 0.133 kPa) percentile points (P<0.05), while the difference was not significant at q<= 0.30 (DBP=80 mmHg) percentile points(P>0.05). After the potential confounders including age, education level, marriage, occupational, hyperlipidemia, family history, exercise, sleep, watching TV, smoking, passive smoking, alcohol consumption, body mass index, wealth index, waist circumference were controlled, positive associations were observed between menopause and hypertension/ISH in logistic regression models. CONCLUSIONS: Menopause is positively related with hypertension/ISH. More effective interventions should be taken to prevent hypertension and ISH among rural women. PMID- 23987491 TI - [Relationship between maternal milk and serum thyroid hormones in patients with thyroid related diseases]. AB - OBJECTIVE: To explore the relationship between maternal milk and serum thyroid hormones in patients with thyroid-related diseases. METHODS: Serum and breast milk samples were collected from 56 breastfeeding mothers. Milk and serum free triiodothyronine (FT3), free thyroxine (FT4), triiodothyronine(T3), thyroxine (T4), and thyrotrophin (TSH) were determined, and T3/T4 was calculated. Using the serum thyroid hormones as the independent variables and milk thyroid hormones as the dependent variables, we performed linear regression analysis. RESULTS: The milk FT3, FT4, T3, T4, TSH, and T3/T4 were (2.30 +/- 0.82) pg/ml ,(0.45 +/- 0.26) ng/dl, (0.35 +/- 0.20) ng/ml, (2.96 +/- 1.55) MUg/dl, (0.12 +/- 0.08) MUU/ml, and 0.12 +/- 0.04, respectively. Milk FT3 (r = 0.778, P = 0.000), T3 (r = 0.603, P = 0.000), T4 (r = 0.485, P = 0.004), and TSH (r = 0.605, P = 0.000) concentrations were positively correlated with those in serum. CONCLUSION: Thyroid hormones are present in human milk and are positively correlated with those in serum. PMID- 23987492 TI - [Mechanisms of icariin in regulating bone formation of osteoblasts and bone resorption of osteoclasts]. AB - OBJECTIVE: To investigate the molecular mechanisms of icariin (ICA) in regulating the bone formation of osteoblasts and the bone resorption of osteoclasts. METHODS: Primary osteoblast cell cultures were obtained from newborn rat calvarial. Calcified nodules were stained by alizarin red. The mRNA levels of osterix (OSX), runt-related transcription factor 2 (Runx-2), alkaline phosphatase (ALP), Collagen1, osteoprotegerin (OPG), and receptor activator of nuclear factor KappaB ligand (RANKL) were analyzed by quantitative real-time RT-PCR, the protein levels of OPG, RANKL, and Collagen1 were examined by Western blotting, and the intracellular Ca(2+) concentration of osteoblasts was measured on a flow cytometer using the Cellquest program. RESULTS: Compared with control group, ICA markedly promoted bone formation by significant up-regulating the gene expressions of OSX, Runx-2,ALP, and Collagen1, the protein expression of Collagen1(all P<0.01), and the Ca(2+) concentration. Furthermore, ICA remarkably inhibited bone resorption by significant up-regulating the mRNA and protein expressions of OPG as well as the OPG/RANKL ratio. CONCLUSIONS: ICA could promote bone formation of osteoblasts through inducting the gene expressions of OSX,Runx 2, ALP and Collagen1, and the protein expressions of Collagen1, and by increasing the Ca (2+) concentration. Moreover, ICA could inhibit bone resorption of osteoclasts through regulating OPG/RANKL signal pathway. PMID- 23987493 TI - [Impact of 36-hour sleep deprivation on visuo-motor coupling mechanism in young soldiers]. AB - OBJECTIVE: To explore the impact of 36-hour sleep deprivation (SD) on the brain electrophysiological indicators of visuo-motor coupling in young soldiers. METHODS: During the 36-hour SD, 10 healthy young soldiers were tested on visuospatial rotation tasks by event-related potentials system before and after SD. The incubation period and amplitude of P500 as well as their error number and reaction time were measured. RESULTS: Compared with subjects in SD 0 hour,subjects in SD 36-hour had significantly increased error rate [(9.7 +/- 3.9)% vs. (18.3 +/- 4.5)%, P<0.05] and significantly increased reaction time [(632.5 +/- 53.6) ms vs. (693.6 +/- 65.7) ms, P < 0.05]. Subjects in SD 36-hour showed significantly reduced amplitudes than those in SD 0-hour [(8.7 +/- 2.3) MUV vs. (5.2 +/- 1.6) MUV, P < 0.05]. Additionally, subjects in SD 36-hour showed significantly increased P500 latencies than did those in SD 0-hour [(489.6 +/- 42.6) ms vs .(530.2 +/- 51.9) ms, P < 0.05]. Compared with subjects in SD 0-hour, the deficit was an absence of a mental rotation function SD 36-hour in subjects. CONCLUSIONS: The 36-hour SD in young soldiers can harm the processing mechanism of visuo-motor coupling in a certain extent. SD can affect the fixed position ability of visual space cognition in young soldiers. PMID- 23987494 TI - [Drug-resistant genes at hepatitis B virus polymerase region during entecavir treatment]. AB - OBJECTIVE: To investigate the drug-resistant genes at hepatitis B virus (HBV) polymerase region during entecavir (ETV) treatment. METHODS: Serum samples from chronic hepatitis B patients with virologic breakthrough during enticavir therapy were studied. The resistant mutation patterns in the polymerase gene of hepatitis B virus were analyzed using the polymerase chain reaction (PCR)-sequencing method. RESULTS: ETV resistance was detected from 19 out of 29 ETV-refractory patients, among whom 16 (84.2%) had a history of lamivudine-refractory. The mutation patterns were diverse, while rtL180 + rtM204 + rtT184 (58.6%, 17/29) was most common in patients with ETV genotype resistance. Four of 7 patients (7/29, 24.1%) with genotype B were detected to have ETV genotype resistance, while 15 of 22 patients (22/29, 75.9%) with genotype C were detected to have ETV genotype resistance. The rate of ETV genotype resistance was 57.1% (4/7) and 68.2% (15/22) in patients with genotype B and genotype C,while no statistical difference was found(P = 0.665). CONCLUSIONS: ETV genotype resistance is more common in patients who have been refractory to ETV and lamivudine sequential treatment. rtM204+rtL180+rtT184 mutation is common in genotype B and C ETV resistance patients. PMID- 23987495 TI - [Inhibitory effects of celecoxib combined with capecitabine on H22 hepatoma mice and its mechanism]. AB - OBJECTIVE: To evaluate the inhibitory effect and its mechanism of celecoxib combined with capecitabine on the growth of implanted H22 hepatoma in mice. METHODS: Tumor model was established by hypodermical injection of H22 cells in BALB/c nude mice. Forty mice were equally randomly divided into 4 groups: control group, celecoxib group (receiving 100 mg/kg celecoxib), capecitabine group (receiving 755 mg/kg capecitabine), and combined treatment group (receiving 100 mg/kg of celecoxib and 755 mg/kg of capecitabine). From the third post implantation day, each mouse was given relevant drug (or normal saline) by oral gavage. Fifteen days later, all mice were sacrificed and the tumor tissues were measured. The mRNA and protein levels of nuclear factor kappa-B (NF-KappaB) p65 and cyclooxygenase (COX)-2 in tumor tissues were detected by the quantitative polymerase chain reaction (qPCR)and Western blotting, respectively. RESULTS: The tumor inhibition rate was 30.2% in celecoxib group and 49.9% in capecitabine group, which was significantly lower than that (75.4%) in the combined treatment group (P<0.01,P<0.05, respectively). qPCR showed a significant decrease of the mRNA expression of COX-2 in celecoxib group and combined treatment group when compared with control group (P<0.001), but no significant change in NF-KappaB p65.Capecitabine had no significant effects on the mRNA expression of COX-2 and NF-KappaB p65. Western blotting showed that celecoxib and combined treatment significantly inhibited the protein expression of COX-2 and NF-KappaB p65(P<0.05), but not capecitabine. CONCLUSION: Celecoxib can enhance the antitumor effect of capecitabine by inhibiting the expressions of COX-2 and NF KappaB p65 in mice bearing H22 implanted tumor. PMID- 23987496 TI - [Effect of subanaesthetic dose of ketamine on mechanical stimulus on brain regions]. AB - OBJECTIVE: To investigate the effect of subanaesthetic dose of ketamine on mechanical stimulus on brain regions. METHODS: Totally 13 healthy male volunteers were enrolled in this study, in whom 0 and 100 ng/ml ketamine were administrated by target controlled infusion system in pilot study. After von Frey filaments (vFFs) 300 g were used as mechanical stimuli, Visual Analogue Scale scores were evaluated. Functional magnetic resonance imaging (fMRI)was taken 1 week after pilot study at the following sequences: structure imaging + functional imaging (stimulus sequence with 300 g vFFs, ketamine sequence); stimulus sequence = 6*(20s on + 20s off), with target concentration of ketamine at 0,100 ng/ml.fMRI result was processed by SPM2 and Metlab 7.01 software package. RESULTS: Posterior cerebellum lobe and corpus callosum were inhibited at 100 ng/ml under vFFs stimulus, whereas cingulate gyrus, middle frontal gyrus, inferior parietal lobule, occipital lobe, and posterior cerebellum lobe were activated at 100 ng/ml under vFFs stimulus. CONCLUSIONS: Ketamine 100 ng/ml exerts its effect on pain related brain regions. It can both activate and inhibit these brain regions, with the activating effect being the primary effect. PMID- 23987497 TI - [Advances in minimally invasive spine surgery in treatment of adolescent idiopathic scoliosis and adult scoliosis]. AB - The traditional treatment of scoliosis is mainly based on open surgeries that use the anterior approach, the posterior approach, or both. These surgical procedures often lead to complications including massive blood loss, infections, and pain of incision.The minimally invasive spine surgery (MISS) was introduced in the 1990s and has shown many advantages including less blood loss, less pain, and lower infection incidences.Today MISS is mainly used in the treatment of adolescent idiopathic scoliosis and adult scoliosis. However, due to some inevitable complications, it still can not be routinely applied.This review will briefly summarize the advances in the application of MISS in surgical treatment of adolescent idiopathic scoliosis and adult scoliosis. PMID- 23987498 TI - [Research advances in the gut microbiota and inflammation in obesity]. AB - Human gut microbiota plays a key role in the development of obesity. Intestinal flora can regulate energy absorption and nutrition metabolism, increasing the energy harvesting from diet. Alteration of gut flora produces excessive lipopolysaccharide, which, when absorbed into the blood, can induce inflammatory reactions and promote the high-fat diet-associated obesity and metabolic syndrome. Intestinal flora increase visceral fat deposition by lowering the expression of Fiaf in intestinal mucosa. Different immune status also affects the intestinal flora.The gut microbiota is hypothesized to be an environmental factor that contributes to obesity; by interacting with factors such as host and diet, it adjusts the energy metabolism. Antibiotics or probiotics may alter the composition of intestinal microflora and improve the metabolic syndrome, and thus provides new treatment options. PMID- 23987499 TI - [Research advance in antitumor activities of artemisinin and its derivatives]. AB - Artemisinin and its derivatives are highly effective in fighting against malaria. Notably, these drugs have shown potent anti-timor activities by arresting cellular growth, enhancing apoptosis, inhibiting angiogenesis, and regulating the expression of tumor-associated genes, although the underlying mechanisms remain unclear. PMID- 23987501 TI - Insight into organometallic intermediate and its evolution to covalent bonding in surface-confined ullmann polymerization. AB - We provide insight into surface-catalyzed dehalogenative polymerization, analyzing the organometallic intermediate and its evolution into planar polymeric structures. A combined study using scanning tunneling microscopy (STM), X-ray photoelectron spectroscopy (XPS), low energy electron diffraction (LEED), near edge X-ray absorption fine structure (NEXAFS) spectroscopy and first-principles calculations unveils the structural conformation of substrate-bound phenylene intermediates generated from 1,4-dibromobenzene precursors on Cu(110), showing the stabilizing role of the halogen. The appearance of covalently bonded conjugated structures is followed in real time by fast-XPS measurements (with an acquisition time of 2 s per spectrum and heating rate of 2 K/s), showing that the detaching of phenylene units from the copper substrate and subsequent polymerization occur upon annealing above 460 +/- 10 K. PMID- 23987502 TI - A novel exploratory chemometric approach to environmental monitorring by combining block clustering with Partial Least Square (PLS) analysis. AB - BACKGROUND: Given the serious threats posed to terrestrial ecosystems by industrial contamination, environmental monitoring is a standard procedure used for assessing the current status of an environment or trends in environmental parameters. Measurement of metal concentrations at different trophic levels followed by their statistical analysis using exploratory multivariate methods can provide meaningful information on the status of environmental quality. In this context, the present paper proposes a novel chemometric approach to standard statistical methods by combining the Block clustering with Partial least square (PLS) analysis to investigate the accumulation patterns of metals in anthropized terrestrial ecosystems. The present study focused on copper, zinc, manganese, iron, cobalt, cadmium, nickel, and lead transfer along a soil-plant-snai food chain, and the hepatopancreas of the Roman snail (Helix pomatia) was used as a biological end-point of metal accumulation. RESULTS: Block clustering deliniates between the areas exposed to industrial and vehicular contamination. The toxic metals have similar distributions in the nettle leaves and snail hepatopancreas. PLS analysis showed that (1) zinc and copper concentrations at the lower trophic levels are the most important latent factors that contribute to metal accumulation in land snails; (2) cadmium and lead are the main determinants of pollution pattern in areas exposed to industrial contamination; (3) at the sites located near roads lead is the most threatfull metal for terrestrial ecosystems. CONCLUSION: There were three major benefits by applying block clustering with PLS for processing the obtained data: firstly, it helped in grouping sites depending on the type of contamination. Secondly, it was valuable for identifying the latent factors that contribute the most to metal accumulation in land snails. Finally, it optimized the number and type of data that are best for monitoring the status of metallic contamination in terrestrial ecosystems exposed to different kinds of anthropic polution. PMID- 23987500 TI - Computational simulation strategies for analysis of multisubunit RNA polymerases. PMID- 23987503 TI - Control of expression of the ICE R391 encoded UV-inducible cell-sensitising function. AB - BACKGROUND: Many SXT/R391-like enterobacterial Integrative Conjugative Elements (ICEs) have been found to express an atypical, recA-dependent, UV-inducible, cell sensitising phenotype observed as a reduction in post-irradiation cell survival rates in host cells. Characterisation of a complete deletion library of the prototype ICE R391 identified the involvement of three core ICE genes, orfs90/91 encoding a putative transcriptional enhancer complex, and orf43, encoding a putative type IV secretion system, outer membrane-associated, conjugative transfer protein. RESULTS: In this study, expression analysis of orf43 indicated that it was up-regulated as a result of UV irradiation in an orfs90/91-dependent manner. Induced expression was found to be controlled from a site preceding the gene which required functional orfs90/91. Expression of orfs90/91 was in turn found to be regulated by orf96, a lambda cI-like regulator. Targeted construction of ICE R391 deletions, RT-PCR and qRT-PCR analysis confirmed a regulatory link between orfs90/91 and orf43 while site-directed mutagenesis of orf43 suggested an association with the cell membrane was a prerequisite for the cytotoxic effect. CONCLUSIONS: Because of the recA-dependence of the effect, we hypothesise that UV induction of RecA results in cleavage of the cI-like ICE-encoded repressor protein, the product of orf96. This in turn allows expression of the transcriptional enhancer complex encoded by orfs90/91, which we conclude stimulates transcription of orf43, whose product is directly responsible for the effect. PMID- 23987504 TI - Translocation of a charged nanoparticle through a fluidic nanochannel: the interplay of nanoparticle and ions. AB - Inspired by the importance of charged nanoparticles (NPs) in biomedicine and their potential applications in nanofluids, we analyze the translocation of cationic and anionic nanoparticles through a nanochannel by explicit solvent molecular dynamics simulations. We focus on the interplay of NPs and ions. The cations bind to the anionic NPs much more than the anions to the cationic NPs, which in turn affects the flux behavior. In particular, the nanochannel enhances the difference between cationic and anionic NPs during the translocation process. With the increase of salt concentration, the ion flux increases nonlinearly with external field strength, in agreement with recent experimental observations, while the NP flux decreases, which suggests a nontrivial competition between the translocation of ions and NPs. Our results revealed the important role of ions during the NP translocation and may have implications in the detection, separation, and filtration of charged NPs. PMID- 23987505 TI - Type 2 diabetes mellitus coincident with pulmonary tuberculosis is associated with heightened systemic type 1, type 17, and other proinflammatory cytokines. AB - RATIONALE: Type 2 diabetes mellitus is a major risk factor for the development of active tuberculosis, although the biological basis underlying this susceptibility remains poorly characterized. OBJECTIVES AND METHODS: To identify the influence of coincident diabetes mellitus on cytokine levels in pulmonary tuberculosis, we examined circulating levels of a panel of cytokines and chemokines in the plasma of individuals with tuberculosis with diabetes and compared them with those of individuals without diabetes. MEASUREMENTS AND MAIN RESULTS: Tuberculosis with diabetes is characterized by elevated circulating levels of type 1 (IFN-gamma, tumor necrosis factor-alpha, and IL-2), type 2 (IL-5), and type 17 (IL-17A) cytokines but decreased circulating levels of IL-22. This was associated with increased systemic levels of other proinflammatory cytokines (IL-1beta, IL-6, and IL-18) and an antiinflammatory cytokine (IL-10) but not type 1 IFNs. Moreover, tuberculosis antigen-stimulated whole blood also showed increased levels of proinflammatory cytokines. Finally, type 1 and type 17 cytokines in plasma exhibit a significant positive correlation with hemoglobin A1C levels, indicating that impaired control of diabetes is associated with this proinflammatory milieu. Multivariate analysis revealed that the association of proinflammatory cytokines with diabetes mellitus was not influenced by age, sex, or other metabolic parameters. CONCLUSIONS: Our data reveal that tuberculosis with diabetes is characterized by heightened cytokine responsiveness, indicating that chronic inflammation underlying type 2 diabetes potentially contributes to increased immune pathology and poor control in tuberculosis infection. PMID- 23987507 TI - Centrosomes tune in to metabolic state and turn on to oxygen. AB - Events required for cell-cycle progression, including centriole duplication and mitotic spindle formation, are obligatorily linked to the metabolic state of a cell. In this issue of Developmental Cell, Moser et al. (2013) show that PHD1 can act as such a sensor through proline hydroxylation of the centrosomal protein Cep192. PMID- 23987506 TI - Hierarchical scaffolding of an ERK1/2 activation pathway. AB - BACKGROUND: Scaffold proteins modulate cellular signaling by facilitating assembly of specific signaling pathways. However, there is at present little information if and how scaffold proteins functionally interact with each other. RESULTS: Here, we show that two scaffold proteins, caveolin-1 and IQGAP1, are required for phosphorylation of the actin associated pool of extracellular signal regulated kinase 1 and 2 (ERK1/2) in response to protein kinase C activation. We show by immunofluorescence and proximity ligation assays, that IQGAP1 tethers ERK1/2 to actin filaments. Moreover, siRNA experiments demonstrate that IQGAP1 is required for activation of actin-bound ERK1/2. Caveolin-1 is also necessary for phosphorylation of actin-bound ERK1/2 in response to protein kinase C, but is dispensible for ERK1/2 association with actin. Simultaneous knock down of caveolin-1 and IQGAP1 decreases total phorbol ester-induced ERK1/2 phosphorylation to the same degree as single knock down of either caveolin-1 or IQGAP1, indicating that caveolin-1 and IQGAP1 operate in the same ERK activation pathway. We further show that caveolin-1 knock down, but not IQGAP1 knock down, reduces C-Raf phosphorylation in response to phorbol ester stimulation. CONCLUSIONS: Based on our data, we suggest that caveolin-1 and IQGAP1 assemble distinct signaling modules, which are then linked in a hierarchical arrangement to generate a functional ERK1/2 activation pathway. PMID- 23987508 TI - Slide to the left and slide to the right: motor coordination in neurons. AB - Molecular motors employ specific adaptor proteins to dock on transport cargos. Reporting in The Journal of Cell Biology, Fu and Holzbaur (2013) show that the adaptor JNK interacting protein 1 (JIP1) binds kinesin-1 and dynactin and controls bidirectional axonal amyloid precursor protein trafficking, suggesting a regulatory role for adaptors during cargo transport. PMID- 23987509 TI - PRC2 goes solo in the Drosophila female germline. AB - Polycomb-group proteins silence gene expression through epigenetic modification of chromatin. In this issue of Developmental Cell, Iovino et al. (2013) demonstrate that Polycomb repressive complex 2 (PRC2) is required for maintenance of oocyte fate by repressing expression of two critical targets, Cyclin E and dacapo, during the early meiotic cycle. PMID- 23987510 TI - Lypd6 enhances Wnt/beta-catenin signaling by promoting Lrp6 phosphorylation in raft plasma membrane domains. AB - Wnt/beta-catenin signaling plays critical roles during embryogenesis, tissue homeostasis, and regeneration. How Wnt-receptor complex activity is regulated is not yet fully understood. Here, we identify the Ly6 family protein LY6/PLAUR domain-containing 6 (Lypd6) as a positive feedback regulator of Wnt/beta-catenin signaling. lypd6 enhances Wnt signaling in zebrafish and Xenopus embryos and in mammalian cells, and it is required for wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Lypd6 is GPI anchored to the plasma membrane and physically interacts with the Wnt receptor Frizzled8 and the coreceptor Lrp6. Biophysical and biochemical evidence indicates that Lypd6 preferentially localizes to raft membrane domains, where Lrp6 is phosphorylated upon Wnt stimulation. lypd6 knockdown or mislocalization of the Lypd6 protein to nonraft membrane domains shifts Lrp6 phosphorylation to these domains and inhibits Wnt signaling. Thus, Lypd6 appears to control Lrp6 activation specifically in membrane rafts, which is essential for downstream signaling. PMID- 23987511 TI - A NudE/14-3-3 pathway coordinates dynein and the kinesin Khc73 to position the mitotic spindle. AB - Mitotic spindle position is controlled by interactions of cortical molecular motors with astral microtubules. In animal cells, Partner of Inscuteable (Pins) acts at the cortex to coordinate the activity of Dynein and Kinesin-73 (Khc73; KIF13B in mammals) to orient the spindle. Though the two motors move in opposite directions, their synergistic activity is required for robust Pins-mediated spindle orientation. Here, we identify a physical connection between Dynein and Khc73 that mediates cooperative spindle positioning. Khc73's motor and MBS domains link Pins to microtubule plus ends, while its stalk domain is necessary for Dynein activation and precise positioning of the spindle. A motif in the stalk domain binds, in a phospho-dependent manner, 14-3-3zeta, which dimerizes with 14-3-3epsilon. The 14-3-3zeta/epsilon heterodimer binds the Dynein adaptor NudE to complete the Dynein connection. The Khc73 stalk/14-3-3/NudE pathway defines a physical connection that coordinates the activities of multiple motor proteins to precisely position the spindle. PMID- 23987512 TI - A multifunctional protein, EWS, is essential for early brown fat lineage determination. AB - The recent surge in obesity has provided an impetus to better understand the mechanisms of adipogenesis, particularly in brown adipose tissue (BAT) because of its potential utilization for antiobesity therapy. Postnatal brown adipocytes arise from early muscle progenitors, but how brown fat lineage is determined is not completely understood. Here, we show that a multifunctional protein, Ewing Sarcoma (EWS), is essential for determining brown fat lineage during development. BATs from Ews null embryos and newborns are developmentally arrested. Ews mutant brown preadipocytes fail to differentiate due to loss of Bmp7 expression, a critical early brown adipogenic factor. We demonstrate that EWS, along with its binding partner Y-box binding protein 1 (YBX1), activates Bmp7 transcription. Depletion of either Ews or Ybx1 leads to loss of Bmp7 expression and brown adipogenesis. Remarkably, Ews null BATs and brown preadipocytes ectopically express myogenic genes. These results demonstrate that EWS is essential for early brown fat lineage determination. PMID- 23987514 TI - Homeoproteins Six1 and Six4 regulate male sex determination and mouse gonadal development. AB - The Y-linked gene Sry regulates mammalian sex determination in bipotential embryonic gonads. Here, we report that the transcription factors Six1 and Six4 are required for male gonadal differentiation. Loss of Six1 and Six4 together, but neither alone, resulted in a male-to-female sex-reversal phenotype in XY mutant gonads accompanied by a failure in Sry activation. Decreased gonadal precursor cell formation at the onset of Sry expression and a gonadal size reduction in both sexes were also found in mutant embryos. Forced Sry transgene expression in XY mutant gonads rescued testicular development but not the initial disruption to precursor growth. Furthermore, we identified two downstream targets of Six1/Six4 in gonadal development, Fog2 (Zfpm2) and Nr5a1 (Ad4BP/Sf1). These two distinct Six1/Six4-regulated pathways are considered to be crucial for gonadal development. The regulation of Fog2 induces Sry expression in male sex determination, and the regulation of Nr5a1 in gonadal precursor formation determines gonadal size. PMID- 23987513 TI - Spatial coordination between stem cell activity and cell differentiation in the root meristem. AB - A critical issue in development is the coordination of the activity of stem cell niches with differentiation of their progeny to ensure coherent organ growth. In the plant root, these processes take place at opposite ends of the meristem and must be coordinated with each other at a distance. Here, we show that in Arabidopsis, the gene SCR presides over this spatial coordination. In the organizing center of the root stem cell niche, SCR directly represses the expression of the cytokinin-response transcription factor ARR1, which promotes cell differentiation, controlling auxin production via the ASB1 gene and sustaining stem cell activity. This allows SCR to regulate, via auxin, the level of ARR1 expression in the transition zone where the stem cell progeny leaves the meristem, thus controlling the rate of differentiation. In this way, SCR simultaneously controls stem cell division and differentiation, ensuring coherent root growth. PMID- 23987515 TI - Second try: who returns for additional assisted reproductive technology treatment and the effect of a prior assisted reproductive technology birth. AB - OBJECTIVE: To evaluate the effect of a prior assisted reproductive technology (ART) live birth on subsequent live-birth rates. DESIGN: Historical cohort study. SETTING: Clinic-based data. PATIENT(S): The study population included 297,635 women with 549,278 cycles from 2004 to 2010 from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System. Try 1 refers to ART cycles up to and including the first live birth, try 2 to ART cycles after a first live birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rates by cycle number, try number, and oocyte source. RESULT(S): Younger women at try 1 are more likely to return for try 2. Women returning for try 2 were more likely to have had an ART singleton versus multiple birth (33.2% after a try 1 singleton versus 8.1% after twins and 4.9% after triplets) and were less likely to have a diagnosis of diminished ovarian reserve or tubal factors. Live-birth rates were significantly higher for try 2 compared with try 1 for autologous fresh cycles, averaging 7.7 percentage points higher over five cycles. Live-birth rates were not significantly different for try 2 versus try 1 with thawed autologous cycles or either fresh or thawed donor cycles. CONCLUSION(S): These results indicate that when fresh autologous oocytes can be used, live-birth rates per cycle are significantly greater after a prior history of an ART live birth. PMID- 23987516 TI - Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. AB - OBJECTIVE: To determine whether random-start controlled ovarian stimulation (COS), in which a patient is stimulated on presentation regardless of her menstrual-cycle phase, has outcomes similar to conventional early follicular phase-start COS for fertility preservation in cancer patients. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENT(S): Women recently diagnosed with cancer and in preparation for gonadotoxic therapy. INTERVENTION(S): Random- versus conventional-start COS. MAIN OUTCOME MEASURE(S): PRIMARY OUTCOME: number of mature oocytes retrieved; secondary outcomes: pattern of follicular development, oocyte yield, and fertilization rate. RESULT(S): The number of total and mature oocytes retrieved, oocyte maturity rate, mature oocyte yield, and fertilization rates were similar in random- (n = 35) and conventional start (n = 93) COS cycles. No superiority was noted when comparing COS started in the late follicular (n = 13) or luteal phase (n = 22). The addition of letrozole, in the case of estrogen-sensitive cancers, did not adversely affect COS outcomes or oocyte maturity and competence in either random- or conventional-start protocols. CONCLUSION(S): Random-start COS is as effective as conventional-start COS in fertility preservation. This protocol would minimize delays and allow more patients to undergo fertility preservation and still proceed with cancer treatment within 2-3 weeks. PMID- 23987517 TI - Metformin reduces the expression of corticotropin-releasing hormone and urocortin in the endometrium of healthy women. AB - OBJECTIVE: To investigate the effect of metformin administration on the expression of endometrial corticotrophin-releasing hormone (CRH) and urocortin (UCN) in the midluteal phase of the cycle. DESIGN: Experimental study, performed in 2010-2011. SETTING: University hospital. PATIENT(S): Eight healthy, normally cycling and parous women volunteered for the study. INTERVENTION(S): All women were investigated in two nonconsecutive cycles (control cycle, untreated and after one cycle break; trial cycle, oral administration of metformin [850 mg * 2]). Endometrial pipelle biopsies were obtained on day LH+7. MAIN OUTCOME MEASURE(S): The endometrial biopsies were immunohistochemically assessed for CRH and UCN expression. Evaluation of positivity was performed by applying the immunoreactive score. RESULT(S): Compared with samples from control cycles, CRH and UCN were significantly reduced in endometrial samples obtained during metformin treatment. This down-regulation was significant both in the endometrial cells and in the endometrial stroma. CONCLUSION(S): This is the first study showing that during the midluteal phase of the cycle, metformin may decrease the production of CRH and UCN in the endometrium. Metformin interference to decidualization could happen by CRH/UCN modification. PMID- 23987518 TI - Fresh semen quality in ejaculates produced by nocturnal emission in men with idiopathic anejaculation. AB - OBJECTIVE: To compare the quality of fresh semen samples collected by nocturnal emission (NE), penile vibratory stimulation (PVS), or electroejaculation (EEJ) from idiopathic anejaculation patients with those collected by masturbation from healthy control subjects. DESIGN: Retrospective clinical study. SETTING: University medical center. PATIENT(S): Ninety-one men with idiopathic anejaculation. INTERVENTION(S): NE, PVS, EEJ, computer-assisted semen analysis system. MAIN OUTCOME MEASURE(S): Sperm volume, concentration, motility, and morphology. RESULT(S): The mean percentage of motile sperm in the NE group was 30.6% +/- 3.5% (range 11.2%-50.9%), which is 1.5- and 1.9-fold higher than that of the PVS (20.5% +/- 1.3%, range 6.9%-40.2%) and EEJ (16.1% +/- 0.9%, range 3.7% 27.3%) groups, respectively. The percentage of sperm that have normal morphology in the NE group was 61.4% +/- 4.8%, which is significantly higher than that in the PVS (38.4% +/- 2.8%) and EEJ groups (29.5% +/- 1.7%), respectively. However, compared with the healthy control group, the sperm motility and normal morphology in the NE, PVS, and EEJ groups were significantly lower. The sperm concentration in the NE group (149.4 +/- 16.3 * 10(6) mL(-1)) was similar to that of the PVS group (143.8 +/- 13.1 * 10(6) mL(-1)) but was higher than in the EEJ group (96.3 +/- 8.6 * 10(6) mL(-1)) and lower than in the control group (225.0 +/- 15.0 * 10(6) mL(-1)). Furthermore, the semen volume in the NE group (2.6 +/- 0.2 mL) was lower than that of the control group (3.0 +/- 0.1 mL). CONCLUSION(S): This study is the first to report on the quality of fresh semen obtained by NE in patients with idiopathic anejaculation. Sperm motility and normal morphology were higher in patients who collected sperm by NE than in those who collected sperm by PVS and EEJ. PMID- 23987520 TI - New layered fluorosulfide SrFBiS2. AB - We have synthesized a new layered BiS2-based compound, SrFBiS2. This compound has a similar structure to LaOBiS2. It is built up by stacking up SrF layers and NaCl type BiS2 layers alternatively along the c axis. Electric transport measurement indicates that SrFBiS2 is a semiconductor. Thermal transport measurement shows that SrFBiS2 has a small thermal conductivity and large Seebeck coefficient. First principle calculations are in agreement with experimental results and show that SrFBiS2 is very similar to LaOBiS2, which becomes a superconductor with F doping. Therefore, SrFBiS2 may be a parent compound of new superconductors. PMID- 23987519 TI - Cysteine-rich secretory protein 1 in seminal plasma: potential biomarker for the distinction between obstructive and nonobstructive azoospermia. AB - OBJECTIVE: To investigate the presence of cysteine-rich secretory protein 1 (CRISP1) in seminal plasma as a means of distinguishing between obstructive azoospermia (OA) and nonobstructive azoospermia (NOA). DESIGN: Seminal plasma from normospermic donors (n = 45) and azoospermic donors (n = 80) was examined to determine CRISP1 levels. Neutral alpha-glucosidase (NAG) enzymatic activity was measured for comparison with CRISP1 levels. SETTING: Research unit of an academic medical center. PATIENT(S): Normospermic and azoospermic donors from the clinical andrology laboratory of the centre hospitalier universitaire de Quebec and from Mount Sinai Hospital. INTERVENTION(S): Seminal CRISP1 measurement by Western blot analysis. Neutral alpha-glucosidase activity was evaluated by a photometric method. MAIN OUTCOME MEASURE(S): Seminal plasma CRISP1 levels, NAG activity, cutoff value, sensitivity, and specificity. RESULT(S): All seminal plasma samples from normospermic and nonobstructive azoospermic donors were CRISP1 positive, whereas CRISP1 was absent or present at low levels in samples from patients with OA. A significant correlation between seminal CRISP1 levels and NAG activity was found in azoospermic semen samples. The cutoff point to distinguish between donors with NOA or OA was established at 0.655 (relative intensity). At this threshold, specificity was 85% and sensitivity was 92%. CONCLUSION(S): Seminal CRISP1 combined with NAG activity can potentially distinguish between OA and NOA. PMID- 23987521 TI - Comprehensive analysis of sexual function outcome in prostate cancer patients after robot-assisted radical prostatectomy. AB - PURPOSE: The recovery of potency following radical prostatectomy is complex and has a very wide range. In this study, we analyzed in detail the precise pattern of recovery of potency following robot-assisted radical prostatectomy (RARP). MATERIALS AND METHODS: Prospectively collected database of patients with a minimum follow-up of 1 year after RARP were evaluated retrospectively. Of 503 patients identified, 483 patients completed the sexual health inventory for men (SHIM) preoperatively and postoperatively every 3 months for the first 12 months. Overall potency, usage of phosphodiesterase type-5 (PDE-5) inhibitors, and return to baseline erectile function were evaluated. Potency was defined as having erection that is sufficient for sexual intercourse more than 50% of attempts, while quality potency was defined as being potent without the use of PDE-5 inhibitors. RESULTS: Preoperatively, the overall potency and quality potency rate were 67.1% and 48.1%, respectively. Postoperatively, the overall potency rate was 61.4%, while the quality potency rate was 37.2%. In multivariate regression analysis, independent predictors of potency recovery were young age (<60), preoperative potency status, and bilateral preservation of neurovascular bundles (NVBs). In men with SHIM>21, the overall potency and quality potency rate were 79.7% and 41.2%, respectively. More importantly, only 21.4% of the men with normal erection preoperatively (SHIM>21) returned to baseline erectile function (SHIM>21) 12 months after surgery. CONCLUSIONS: This study indicates that young age (<60), preoperative potency, and bilateral preservation of NVBs were positive predictors of potency recovery following RARP. However, an overwhelming majority of men experience a deterioration in the overall quality of erection after RARP. PMID- 23987522 TI - Targeted metabolomic approach for assessing human synthetic cannabinoid exposure and pharmacology. AB - Designer synthetic cannabinoids like JWH-018 and AM2201 have unique clinical toxicity. Cytochrome-P450-mediated metabolism of each leads to the generation of pharmacologically active (omega)- and (omega-1)-monohydroxyl metabolites that retain high affinity for cannabinoid type-1 receptors, exhibit Delta(9)-THC-like effects in rodents, and are conjugated with glucuronic acid prior to excretion in human urine. Previous studies have not measured the contribution of the specific (omega-1)-monohydroxyl enantiomers in human metabolism and toxicity. This study uses a chiral liquid chromatography-tandem mass spectroscopy approach (LC-MS/MS) to quantify each specific enantiomer and other nonchiral, human metabolites of JWH-018 and AM2201 in human urine. The accuracy (average % RE = 18.6) and reproducibility (average CV = 15.8%) of the method resulted in low-level quantification (average LLQ = 0.99 ng/mL) of each metabolite. Comparisons with a previously validated nonchiral method showed strong correlation between the two approaches (average r(2) = 0.89). Pilot data from human urine samples demonstrate enantiospecific excretion patterns. The (S)-isomer of the JWH-018-(omega-1) monohydroxyl metabolite was predominantly excreted (>87%) in human urine as the glucuronic acid conjugate, whereas the relative abundance of the corresponding AM2201-(omega-1)-metabolite was low (<5%) and did not demonstrate enantiospecificity (approximate 50:50 ratio of each enantiomer). The new chiral method provides a comprehensive, targeted metabolomic approach for studying the human metabolism of JWH-018 and AM2201. Preliminary evaluations of specific enantiomeric contributions support the use of this approach in future studies designed to understand the pharmacokinetic properties of JWH-018 and/or AM2201. PMID- 23987523 TI - Substrate-triggered addition of dioxygen to the diferrous cofactor of aldehyde deformylating oxygenase to form a diferric-peroxide intermediate. AB - Cyanobacterial aldehyde-deformylating oxygenases (ADOs) belong to the ferritin like diiron-carboxylate superfamily of dioxygen-activating proteins. They catalyze conversion of saturated or monounsaturated C(n) fatty aldehydes to formate and the corresponding C(n-1) alkanes or alkenes, respectively. This unusual, apparently redox-neutral transformation actually requires four electrons per turnover to reduce the O2 cosubstrate to the oxidation state of water and incorporates one O-atom from O2 into the formate coproduct. We show here that the complex of the diiron(II/II) form of ADO from Nostoc punctiforme (Np) with an aldehyde substrate reacts with O2 to form a colored intermediate with spectroscopic properties suggestive of a Fe2(III/III) complex with a bound peroxide. Its Mossbauer spectra reveal that the intermediate possesses an antiferromagnetically (AF) coupled Fe2(III/III) center with resolved subsites. The intermediate is long-lived in the absence of a reducing system, decaying slowly (t(1/2) ~ 400 s at 5 degrees C) to produce a very modest yield of formate (<0.15 enzyme equivalents), but reacts rapidly with the fully reduced form of 1 methoxy-5-methylphenazinium methylsulfate ((MeO)PMS) to yield product, albeit at only ~50% of the maximum theoretical yield (owing to competition from one or more unproductive pathway). The results represent the most definitive evidence to date that ADO can use a diiron cofactor (rather than a homo- or heterodinuclear cluster involving another transition metal) and provide support for a mechanism involving attack on the carbonyl of the bound substrate by the reduced O2 moiety to form a Fe2(III/III)-peroxyhemiacetal complex, which undergoes reductive O-O bond cleavage, leading to C1-C2 radical fragmentation and formation of the alk(a/e)ne and formate products. PMID- 23987562 TI - Development of an enzyme immunoassay using a monoclonal antibody against the psychoactive diterpenoid salvinorin A. AB - Salvinorin A (1), the main active constituent in Salvia divinorum, is a highly selective kappa-opioid receptor agonist with hallucinogenic effects, which is regulated in several countries. In the present study, a monoclonal antibody (mAb) against 1 was prepared, and an indirect competitive enzyme-linked immunosorbent assay (icELISA) system was developed for the detection of salvinorins. To raise mAbs against 1, salvinorin B (2) hemisuccinate was synthesized and used to prepare the immunogen 2-bovine serum albumin conjugate. This technique was used to prepare a hybridoma cell line, 3D5, which secreted a mAb that recognized 1. The mAb was shown to have specificity for 1 and other salvinorins in cross reactivity tests. The intra-assay calibration range by icELISA using the mAb against 1 was 0.0195-0.625 MUg/mL. After validating the icELISA using intra- and interassays, a recovery experiment and analysis of several plants in the family Lamiaceae, including S. divinorum, confirmed that the analytical method based on ELISA is not only simple but also precise, accurate, sensitive, and sufficiently reliable. The results indicate that icELISA is a useful tool in the identification of S. divinorum. PMID- 23987561 TI - Effects of eye movement desensitization and reprocessing (EMDR) on non-specific chronic back pain: a randomized controlled trial with additional exploration of the underlying mechanisms. AB - BACKGROUND: Non-specific chronic back pain (CBP) is often accompanied by psychological trauma, but treatment for this associated condition is often insufficient.Nevertheless, despite the common co-occurrence of pain and psychological trauma, a specific trauma-focused approach for treating CBP has been neglected to date. Accordingly, eye movement desensitization and reprocessing (EMDR), originally developed as a treatment approach for posttraumatic stress disorders, is a promising approach for treating CBP in patients who have experienced psychological trauma.Thus, the aim of this study is to determine whether a standardized, short-term EMDR intervention added to treatment as usual (TAU) reduces pain intensity in CBP patients with psychological trauma vs. TAU alone. METHODS/DESIGN: The study will recruit 40 non specific CBP patients who have experienced psychological trauma. After a baseline assessment, the patients will be randomized to either an intervention group (n = 20) or a control group (n = 20). Individuals in the EMDR group will receive ten 90-minute sessions of EMDR fortnightly in addition to TAU. The control group will receive TAU alone. The post-treatment assessments will take place two weeks after the last EMDR session and six months later.The primary outcome will be the change in the intensity of CBP within the last four weeks (numeric rating scale 0-10) from the pre-treatment assessment to the post-treatment assessment two weeks after the completion of treatment.In addition, the patients will undergo a thorough assessment of the change in the experience of pain, disability, trauma associated distress, mental co-morbidities, resilience, and quality of life to explore distinct treatment effects. To explore the mechanisms of action that are involved, changes in pain perception and pain processing (quantitative sensory testing, conditioned pain modulation) will also be assessed.The statistical analysis of the primary outcome will be performed on an intention-to-treat basis. The secondary outcomes will be analyzed in an explorative, descriptive manner. DISCUSSION: This study adapts the standard EMDR treatment for traumatized patients to patients with CBP who have experienced psychological trauma. This specific, mechanism-based approach might benefit patients. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov (NCT01850875). PMID- 23987563 TI - Robustly passivated, gold nanoaperture arrays for single-molecule fluorescence microscopy. AB - The optical confinement generated by metal-based nanoapertures fabricated on a silica substrate has recently enabled single-molecule fluorescence measurements to be performed at physiologically relevant background concentrations of fluorophore-labeled biomolecules. Nonspecific adsorption of fluorophore-labeled biomolecules to the metallic cladding and silica bottoms of nanoapertures, however, remains a critical limitation. To overcome this limitation, we have developed a selective functionalization chemistry whereby the metallic cladding of gold nanoaperture arrays is passivated with methoxy-terminated, thiol derivatized polyethylene glycol (PEG), and the silica bottoms of those arrays are functionalized with a binary mixture of methoxy- and biotin-terminated, silane derivatized PEG. This functionalization scheme enables biotinylated target biomolecules to be selectively tethered to the silica nanoaperture bottoms via biotin-streptavidin interactions and reduces the nonspecific adsorption of fluorophore-labeled ligand biomolecules. This, in turn, enables the observation of ligand biomolecules binding to their target biomolecules even under greater than 1 MUM background concentrations of ligand biomolecules, thereby rendering previously impracticable biological systems accessible to single-molecule fluorescence investigations. PMID- 23987565 TI - Factors associated with changes into public or private maternity care for a second pregnancy. AB - OBJECTIVE: The aim of this study was to determine whether outcomes in a first pregnancy were associated with changes into and out of public maternity care. METHODS: The study population included 155492 women with first and second sequential singleton births, 2000-09 in New South Wales. Analyses were stratified by whether obstetric care for the first birth involved private or public maternity care. Interventions, infant and maternal outcomes were assessed as predictors of a change in care. Adjusted odds ratios for changing care were obtained from logistic regression using backwards elimination. RESULTS: Similar proportions of women changed from private to public care between first and second births (9.6% compared with 9.4% public to private, P-value=0.10). Although interventions (operative delivery, epidural) and outcomes (low Apgar, preterm birth, perinatal death, postpartum haemorrhage, perineal tear and severe maternal morbidity) were all associated with changes from public to private care, only poor infant condition (adjusted odds ratio 1.39, 95% confidence interval 1.15 1.68) was associated with a change from private to public care. CONCLUSIONS: The majority of women had consistent care type for both births. This may indicate that women are generally satisfied with care, they rationalise that their first birth care was optimal or they value continuity of carer across pregnancies. PMID- 23987564 TI - Properties and reactivity of gaseous distonic radical ions with aryl radical sites. PMID- 23987567 TI - Prevalence of bronchoconstriction induced by eucapnic voluntary hyperpnoea in recreationally active individuals. AB - OBJECTIVE: Exercise-induced bronchoconstriction (EIB) is more prevalent in elite athletes than in the general population. Many of these athletes provide a positive eucapnic voluntary hyperpnoea (EVH) challenge without previous diagnosis of EIB. It is unknown whether this is specific to elite athletes or whether the same risk applies to recreationally active individuals. The purpose of this study was to investigate the prevalence of a positive EVH challenge in a population of recreationally active individuals. METHODS: 136 recreationally active individuals (Age: 21.9 +/- 3.7 years; Height: 175 +/- 9 cm; Weight: 70.9 +/- 10.0 kg) without previous history of asthma or EIB, volunteered to take part in the study. All participants completed an EVH challenge, which was deemed positive if FEV1 fell >=10% from baseline at two consecutive time points, and was reversible following inhalation of a short acting beta2-agonist. RESULTS: 18 of 136 (13.2%) participants had a positive EVH challenge. Of the 18 individuals, the fall in FEV1 from baseline ranged from -12% to -50%. At baseline, percentage predicted FEV1 (97.5 +/- 12.5% versus 104.9 +/- 10%; p < 0.01), FEV1/FVC ratio (79.5 +/- 6.9% versus 87.8 +/- 5.5%; p < 0.01), FEF25-75 (3.73 +/- 1.00 versus 4.73 +/- 1.00 l/s; p < 0.01) and predicted PEF (89.4 +/- 8.8% versus 97.5 +/- 13.6%; p < 0.05) values for EVH positive participants were significantly lower than EVH negative participants respectively. CONCLUSIONS: Overall, 13.2% of recreationally active individuals with no previous history of asthma presented with a positive EVH challenge. Individuals who are recreationally active may benefit from an objective bronchial provocation challenge, given that self-reported symptoms alone only provide a supportive role towards a valid EIB diagnosis. PMID- 23987566 TI - Nitric oxide modulates the hyperalgesic response to mechanical noxious stimuli in sleep-deprived rats. AB - BACKGROUND: Sleep restriction alters pain perception in animals and humans, and many studies have indicated that paradoxical sleep deprivation (PSD) promotes hyperalgesia. The hyperalgesia observed after mechanical nociceptive stimulus is reversed through nitric oxide synthase (NOS) inhibition. Both nitric oxide (NO) and the dorsolateral periaqueductal gray matter (dlPAG) area of the brainstem are involved in hyperalgesia. Thus, in this work, we investigated the pain-related behavior response after mechanical noxious stimuli (electronic von Frey test), and the activity of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH d), an indicator of NOS activity, within the dlPAG of paradoxical sleep-deprived rats. We also evaluated the effects of pre-treatment with L-NAME on these parameters. RESULTS: These data revealed that PSD reduced the hindpaw withdrawal threshold (-47%, p < 0.0001) confirming the hyperalgesic effect of this condition. In addition, there were more NADPH-d positive cells in dlPAG after PSD than in control rats (+ 59%, p < 0.0001). L-NAME treatment prevented the reduction in the hindpaw withdrawal threshold (+ 93%, p < 0.0001) and the increase in the NADPH-d positive cells number in the dlPAG of PSD-treated rats ( 36%, p < 0.0001). CONCLUSION: These data suggest that the hyperalgesic response to mechanical noxious stimuli in paradoxical sleep-deprived rats is associated with increased NOS activity in the dlPAG, which presumably influences the descending antinociceptive pathway. PMID- 23987568 TI - Asthma and severity of the 2009 novel H1N1 influenza: a case-control study. AB - OBJECTIVE: Previous studies reported that the most common chronic condition found among hospitalized patients due to the novel 2009 H1N1 influenza was asthma. However, these studies did not include a concurrent control group. Thus, we investigated the association of asthma status and severity of H1N1 influenza in adults. METHODS: The study was designed as a multi-site case-control study. Cases were patients who had positive PCR for H1N1 influenza and were admitted to the ICU or general ward with a diagnosis of H1N1 influenza from 1 January 2009 to 31 December 2009. Controls were patients who had positive PCR for H1N1 influenza, but were not admitted to hospitals. RESULTS: There were 91 H1N1 cases admitted to either ICU (n = 41) or general hospital ward (n = 50), and 56 controls who met the matching criteria were available. Of the 91 cases, the mean age was 47.3 years, 59% were female, and 38% had comorbid conditions. Of the 91 cases, 12 (13%) had asthma. Stratified analysis by comorbid conditions showed that among those without any comorbid conditions, 8 of 56 cases (14%) and 2 of 49 controls (4%) had asthma, (OR: 3.92, 95% CI: 0.79-19.42, p = 0.095) whereas, among the 39 subjects with one or more comorbid conditions, one of 7 controls (14%) had asthma and 4 of 35 (11%) cases had asthma (p = 0.83). CONCLUSIONS: Asthma may be associated with severity of H1N1 influenza among those without any non-asthma comorbid conditions. However, the limited sample size did not allow this study to fully establish statistical significance. We still recommend asthmatics as a priority group for influenza vaccination and treatment. PMID- 23987569 TI - Carbon dioxide fixation by Calvin-Cycle enzymes improves ethanol yield in yeast. AB - BACKGROUND: Redox-cofactor balancing constrains product yields in anaerobic fermentation processes. This challenge is exemplified by the formation of glycerol as major by-product in yeast-based bioethanol production, which is a direct consequence of the need to reoxidize excess NADH and causes a loss of conversion efficiency. Enabling the use of CO2 as electron acceptor for NADH oxidation in heterotrophic microorganisms would increase product yields in industrial biotechnology. RESULTS: A hitherto unexplored strategy to address this redox challenge is the functional expression in yeast of enzymes from autotrophs, thereby enabling the use of CO2 as electron acceptor for NADH reoxidation. Functional expression of the Calvin cycle enzymes phosphoribulokinase (PRK) and ribulose-1,5-bisphosphate carboxylase (Rubisco) in Saccharomyces cerevisiae led to a 90% reduction of the by-product glycerol and a 10% increase in ethanol production in sugar-limited chemostat cultures on a mixture of glucose and galactose. Co-expression of the Escherichia coli chaperones GroEL and GroES was key to successful expression of CbbM, a form-II Rubisco from the chemolithoautotrophic bacterium Thiobacillus denitrificans in yeast. CONCLUSIONS: Our results demonstrate functional expression of Rubisco in a heterotrophic eukaryote and demonstrate how incorporation of CO2 as a co-substrate in metabolic engineering of heterotrophic industrial microorganisms can be used to improve product yields. Rapid advances in molecular biology should allow for rapid insertion of this 4-gene expression cassette in industrial yeast strains to improve production, not only of 1st and 2nd generation ethanol production, but also of other renewable fuels or chemicals. PMID- 23987570 TI - Behavior of human cytochromes P450 on lipid membranes. AB - Human cytochromes P450 (CYPs) are membrane-anchored enzymes involved in biotransformation of many marketed drugs. We constructed atomic models of six human CYPs (CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4) anchored to a lipid bilayer to investigate the positions and orientations of CYPs on a membrane. We equilibrated the models by molecular dynamics simulations on a 100+ ns time scale. Catalytic domains of all studied CYPs were found to be partially immersed in the lipid bilayer, whereas the N-terminal part and F'/G' loop are deeply immersed. The proximal side of the enzyme faces the cytosol, whereas the distal side, where openings of substrate access and product release channels to the active site are primarily located, points toward the lipid bilayer. Access channels with openings in the vicinity of the B/C and F/G loops are typically positioned below the lipid head groups, whereas the solvent channel points toward the membrane-water interface. We found that the access channel opening positions match the preferred substrate positions, whereas the product release channel exit positions correspond closely with the positions of the products. This may indicate that membrane-anchored CYPs have evolutionarily adapted to facilitate uptake of nonpolar substrates from the membrane and uptake/release of polar substrates or products from/to the membrane-water interface. PMID- 23987571 TI - Using ClinicalTrials.gov to understand the state of clinical research in pulmonary, critical care, and sleep medicine. AB - RATIONALE: ClinicalTrials.gov is the largest trial registry in the world. Strengthened registration requirements, including federal mandates in 2007, have increased study representation. A systematic evaluation of all registered studies has been limited by the absence of an aggregate data set and specialty-specific search terms. OBJECTIVES: We leveraged a newly transformed database containing annotated data from ClinicalTrials.gov to define the portfolio of interventional clinical research in pulmonary, critical care, and sleep medicine. METHODS: Analysis was restricted to studies registered after September 2007 through September 2010 and defined as "interventional" (n = 40,970). A specialty-specific study data set (n = 2,226) was created using disease condition terms provided by data submitters and medical subject heading terms generated by a National Library of Medicine algorithm. Trial characteristics were extracted and summarized using descriptive statistics. MEASUREMENTS AND MAIN RESULTS: Pulmonary, critical care, and sleep medicine trials composed 5.4% of all interventional studies registered over the 3-year period. In contrast, oncology and cardiovascular disease composed 21.9 and 8.4% of trials, respectively. Within pulmonary trials, asthma and chronic obstructive pulmonary disease were the most studied conditions (27.4 and 21.8% of studies, respectively), and measures of lung function or safety were the most frequent primary outcomes. Nearly two-thirds of trials indicated enrollment of 100 patients or fewer, and a majority of studies were phase II or III trials. The single largest funding source (43.5%) was industry, and study characteristics varied by funding source. CONCLUSIONS: We applied a novel approach to describe the portfolio of interventional clinical research in pulmonary medicine. Our results indicate a disparity between trial representation and the burden of respiratory disease. Resources should be targeted across the spectrum of pulmonary research to address this discrepancy. PMID- 23987572 TI - Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma. AB - BACKGROUND: Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population. METHODS: Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening. RESULTS: Overall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients' geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases. CONCLUSIONS: Our findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease. PMID- 23987573 TI - Severe laceration in a percutaneous endoscopic jejunostomy placement resolved with over-the-scope clips. PMID- 23987575 TI - En bloc resection of large gastric submucosal tumor with endoscopic submucosal dissection. PMID- 23987574 TI - Alternative endoscopic treatment of Zenker's diverticulum: a case series (with video). PMID- 23987576 TI - Fascioliasis diagnosed by EUS and ERCP. PMID- 23987577 TI - Polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) in seven different marine bird species from Iceland. AB - Data on distribution, concentration and trends of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs) is scarce in biota from the sub Arctic region of the Atlantic. The present study is an investigation on PBDE and HBCD concentrations in eggs from seven marine bird species from Iceland, i.e. common eider (Somateria mollissima), arctic tern (Sterna paradisaea), guillemot (Uria aalge), fulmar (Fulmarus glacialis), lesser black-backed gull (Larus fuscus), great black-backed gull (Larus marinus) and great skua (Stercorarius skua). Concentrations of sum PBDEs ranged from 44 ng g(-1)fat in eider eggs to 2400 ng g(-1)fat in great skua eggs. The contribution of different PBDE congeners to the sum concentration differed between species. Concentration of HBCDs (sum of alpha-,beta(-) and gamma-HBCD) ranged from 1.3 ng g(-1)fat in arctic tern eggs to 41 ng g(-1)fat in great black-backed gull. PCA on PBDE and HBCD shows different trends between the two BFR groups, further indicating different sources/usage. Investigations on any potential health or population effects of environmental pollutants on the great skua are advised since both the PBDE and HBCD concentrations are high. PMID- 23987578 TI - Oxidative stress on land snail Helix aspersa as a sentinel organism for ecotoxicological effects of urban pollution with heavy metals. AB - The oxidative stress in the digestive gland of the land snail Helix aspersa was considered as a bioindicator for atmospheric pollution with heavy metals from several industries and vehicular traffic in Kafr El-Zayat city. Regional means of heavy metals concentration of all sites were 0.71, 7.09, 0.71, 2.68, 41.44 and 18.01 mg kg(-1) wet mass for Cd, Mn, Ni, Pb, Zn and Cu, respectively. In addition, the highest values of Cd concentrations were found 1.22 and 1.73 mg kg( 1) wet mass in S1 (Potato International Center) and S4 (The Nile bank), respectively. Lactate dehydrogenase (D-LDH(and recorded lipid peroxidation (LPO) levels were significantly high in S1 and S2 (Traffic station). On the other hand, the highest activity of catalase (CAT) was found in S2 (194.04% of control), while the activity of glutathione peroxidase (GPx) reached the highest significant value in S1. As a matter of fact, glutathione-S-transferase (GST) and glutathione reductase (GR) activities were significantly higher in polluted sites than in reference zone. In contrast, the glutathione (GSH) concentration of exposed animals showed significant decrease in all sites, with the lowest value in S1 (57.61% of control). However, metallothioneins concentration (MT) showed no significant difference in all sites except in S1 which accounted for 127.81% of control. Therefore, the overall results of this study showed the importance of H. aspersa as a sentinel organism for biomonitoring the biologic impact of atmospheric pollution in urban areas. PMID- 23987579 TI - Synthesis and structural characterization of bis(2-oxoimidazolyl)hydroborato complexes: a new class of bidentate oxygen-donor ligands. AB - A new class of bidentate ligands that feature oxygen donors, namely, the bis(2 oxo-1-tert-butylimidazolyl)hydroborato and bis(2-oxo-1 methylbenzimidazolyl)hydroborato ligands, [Bo(Bu(t))] and [Bo(MeBenz)], have been synthesized via the reactions of MBH4 with 2 equiv of the respective 2 imidazolone. Chelation of [Bo(Bu(t))] and [Bo(MeBenz)] to a metal center results in a flexible eight-membered ring that is capable of adopting a "boatlike" conformation that allows for secondary M...H-B interactions. PMID- 23987581 TI - Response to comment on "High-active anatase TiO2 nanosheets exposed with 95% {100} facets toward efficient H2 evolution and CO2 photoreduction". PMID- 23987582 TI - Ruthenium-catalyzed hydroformylation/reduction of olefins to alcohols: extending the scope to internal alkenes. AB - In the presence of 2-phosphino-substituted imidazole ligands and Ru3(CO)12 or Ru(methylallyl)2(COD) direct hydroformylation and hydrogenation of alkenes to alcohols takes place. In addition to terminal alkenes, also more challenging internal olefins are converted preferentially to industrially important linear alcohols in high yield (up to 88%) and regioselectivity (n:iso up to 99:1). PMID- 23987583 TI - Coherent anti-Stokes Raman scattering microspectroscopic kinetic study of fast hydrogen bond formation in microfluidic devices. AB - The kinetics of a key noncovalent, hydrogen bonding interaction was studied in situ using coherent anti-stokes Raman scattering (CARS) microspectroscopy in a microfluidic device. The association of model compounds, pyridine and hexafluoroisopropanol, was quantitatively monitored with submicrometer resolution. Lower limits for the very high formation and dissociation rate constants of the model 1:1 pyridine-hexafluoroisopropanol hydrogen bonded complex in dichloromethane-d2 were determined to be k1 > 10(5) M(-1)s(-1) and k-1 > 333.3 s(-1), respectively. PMID- 23987586 TI - Evaluation of a website that promotes social connectedness: lessons for equitable e-health promotion. AB - The online provision of health information and services has been viewed as having the potential to inform and empower health consumers and, ultimately, to promote better health. The Internet can be an innovative tool to deliver services to 'hard-to-reach' population groups, including geographically isolated populations. However, the online platform raises questions regarding the equitable distribution of health services. In this paper we examine a case study of a website that aims to promote health by fostering social connectedness. The website provides information to connect people to locally based community events across Australia. We draw on evaluation findings to examine the socioeconomic and geographical distribution of website usage. A descriptive analysis of web usage statistics revealed a gradient whereby more information is listed and viewed about events in affluent socioeconomic areas. Furthermore, the analysis showed that a greater proportion of information listed and viewed related to urban areas. These results are consistent with broader gradients of Internet access and usage. Drawing on these findings, we identify implications for online health promotion across different population groups, particularly for interventions that do not incorporate an explicit equity focus. PMID- 23987585 TI - Farnesides A and B, sesquiterpenoid nucleoside ethers from a marine-derived Streptomyces sp., strain CNT-372 from Fiji. AB - Farnesides A and B (1, 2), linear sesquiterpenoids connected by ether links to a ribose dihydrouracil nucleoside, were isolated from a marine-derived Streptomyces sp., strain CNT-372, grown in saline liquid culture. The structures of the new compounds were assigned by comprehensive spectroscopic analysis primarily involving 1D and 2D NMR analysis and by comparison of spectroscopic data to the recently reported ribose nucleoside JBIR-68 (3). The farnesides are only the second example of this exceedingly rare class of microbial terpenoid nucleoside metabolites. Farneside A (1) was found to have modest antimalarial activity against the parasite Plasmodium falciparum. PMID- 23987584 TI - The pathogenesis of chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5(+)CD23(+) B cells in blood, marrow, and second lymphoid tissues. Gene expression profiling and phenotypic studies suggest that CLL is probably derived from CD5(+) B cells similar to those found in the blood of healthy adults. Next generation sequencing has revealed recurrent genetic lesions that are implicated in CLL pathogenesis and/or disease progression. The biology of CLL is entwined with its microenvironment, in which accessory cells can promote leukemia cell growth and/or survival. Recently, much attention has been focused on the CLL B cell receptor (BCR) and on chemokine receptors that enable CLL cells to home to lymphoid tissues and to establish the leukemia microenvironment. Agents that can interfere with BCR signaling or chemokine-receptor signaling, or that target surface antigens selectively expressed on CLL cells, promise to have significant therapeutic benefit in patients with this disease. PMID- 23987587 TI - Pneumonia during remission induction chemotherapy in patients with acute leukemia. AB - BACKGROUND: Pneumonia is a major cause of death during induction chemotherapy for acute leukemia. The purpose of this study was to quantify the incidence, risk factors, and outcomes of pneumonia in patients with acute leukemia. METHODS: We conducted a retrospective cohort study of 801 patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or acute lymphocytic leukemia (ALL) who underwent induction chemotherapy. MEASUREMENTS AND MAIN RESULTS: Pneumonia was present at induction start in 85 patients (11%). Of the 716 remaining patients, 148 (21%) developed pneumonia. The incidence rate of pneumonia was higher in MDS and AML than in ALL (0.013 vs. 0.008 vs. 0.003 pneumonias per day, respectively; P < 0.001). In multivariate analysis, age greater than or equal to 60 years, AML, low platelet count, low albumin level, neutropenia, and neutrophil count greater than 7,300 were risk factors. The case fatality rate of pneumonia was 17% (40 of 233). Competing risk analysis demonstrated that in the absence of pneumonia, death was rare: 28-day mortality was 6.2% for all patients but only 1.26% in those without pneumonia. Compared with patients without pneumonia, patients with pneumonia had more intensive care unit days, longer hospital stays, and 49% higher costs (P < 0.001). CONCLUSIONS: Pneumonia after induction chemotherapy for acute leukemia continues to be common, and it is the most important determinant of early mortality after induction chemotherapy. Given the high incidence, morbidity, mortality, and cost of pneumonia, interventions aimed at prevention are warranted in patients with acute leukemia. PMID- 23987588 TI - Improving activity of minicellulosomes by integration of intra- and intermolecular synergies. AB - BACKGROUND: Complete hydrolysis of cellulose to glucose requires the synergistic action of three general types of glycoside hydrolases; endoglucanases, exoglucanases, and cellobiases. Cellulases that are found in Nature vary considerably in their modular diversity and architecture. They include: non complexed enzymes with single catalytic domains, independent single peptide chains incorporating multiple catalytic modules, and complexed, scaffolded structures, such as the cellulosome. The discovery of the latter two enzyme architectures has led to a generally held hypothesis that these systems take advantage of intramolecular and intermolecular proximity synergies, respectively, to enhance cellulose degradation. We use domain engineering to exploit both of these concepts to improve cellulase activity relative to the activity of mixtures of the separate catalytic domains. RESULTS: We show that engineered minicellulosomes can achieve high levels of cellulose conversion on crystalline cellulose by taking advantage of three types of synergism; (1) a complementary synergy produced by interaction of endo- and exo-cellulases, (2) an intramolecular synergy of multiple catalytic modules in a single gene product (this type of synergism being introduced for the first time to minicellulosomes targeting crystalline cellulose), and (3) an intermolecular proximity synergy from the assembly of these cellulases into larger multi-molecular structures called minicellulosomes. The binary minicellulosome constructed in this study consists of an artificial multicatalytic cellulase (CBM4-Ig-GH9-X11-X12-GH8-Doc) and one cellulase with a single catalytic domain (a modified Cel48S with the structure CBM4-Ig-GH48-Doc), connected by a non-catalytic scaffoldin protein. The high level endo-exo synergy and intramolecular synergies within the artificial multifunctional cellulase have been combined with an additional proximity dependent synergy produced by incorporation into a minicellulosome demonstrating high conversion of crystalline cellulose (Avicel). Our minicellulosome is the first engineered enzyme system confirmed by test to be capable of both operating at temperatures as high as 60 degrees C and converting over 60% of crystalline cellulose to fermentable sugars. CONCLUSION: When compared to previously reported minicellulosomes assembled from cellulases containing only one catalytic module each, our novel minicellulosome demonstrates a method for substantial reduction in the number of peptide chains required, permitting improved heterologous expression of minicellulosomes in microbial hosts. In addition, it has been shown to be capable of substantial conversion of actual crystalline cellulose, as well as of the less-well-ordered and more easily digestible fraction of nominally crystalline cellulose. PMID- 23987589 TI - A systematic review of the diagnostic performance of orthopedic physical examination tests of the hip. AB - BACKGROUND: Previous reviews of the diagnostic performances of physical tests of the hip in orthopedics have drawn limited conclusions because of the low to moderate quality of primary studies published in the literature. This systematic review aims to build on these reviews by assessing a broad range of hip pathologies, and employing a more selective approach to the inclusion of studies in order to accurately gauge diagnostic performance for the purposes of making recommendations for clinical practice and future research. It specifically identifies tests which demonstrate strong and moderate diagnostic performance. METHODS: A systematic search of Medline, Embase, Embase Classic and CINAHL was conducted to identify studies of hip tests. Our selection criteria included an analysis of internal and external validity. We reported diagnostic performance in terms of sensitivity, specificity, predictive values and likelihood ratios. Likelihood ratios were used to identify tests with strong and moderate diagnostic utility. RESULTS: Only a small proportion of tests reported in the literature have been assessed in methodologically valid primary studies. 16 studies were included in our review, producing 56 independent test-pathology combinations. Two tests demonstrated strong clinical utility, the patellar-pubic percussion test for excluding radiologically occult hip fractures (negative LR 0.05, 95% Confidence Interval [CI] 0.03-0.08) and the hip abduction sign for diagnosing sarcoglycanopathies in patients with known muscular dystrophies (positive LR 34.29, 95% CI 10.97-122.30). Fifteen tests demonstrated moderate diagnostic utility for diagnosing and/or excluding hip fractures, symptomatic osteoarthritis and loosening of components post-total hip arthroplasty. CONCLUSIONS: We have identified a number of tests demonstrating strong and moderate diagnostic performance. These findings must be viewed with caution as there are concerns over the methodological quality of the primary studies from which we have extracted our data. Future studies should recruit larger, representative populations and allow for the construction of complete 2*2 contingency tables. PMID- 23987636 TI - The independent, unfavorable prognostic factors endothelin A receptor and chemokine receptor 4 have a close relationship in promoting the motility of nasopharyngeal carcinoma cells via the activation of AKT and MAPK pathways. AB - BACKGROUND: Recent studies have indicated that the expression of endothelin A receptor (ETAR) and chemokine receptor 4 (CXCR4) could be used as an indicator of the metastatic potential of nasopharyngeal carcinoma (NPC). The aim of this study was to determine the prognostic value of ETAR and CXCR4 in NPC patients and to reveal the interplay of the endothelin-1 (ET-1)/ETAR and stromal-derived factor 1(SDF-1)/CXCR4 pathways in promoting NPC cell motility. METHODS: Survival analysis was used to analyze the prognostic value of ETAR and CXCR4 expression in 153 cases of NPC. Chemotaxis assays were used to evaluate alterations in the migration ability of non-metastatic 6-10B and metastatic 5-8F NPC cells. Real time PCR, immunoblotting, and flow cytometric analyses were used to evaluate changes in the expression levels of CXCR4 mRNA and protein induced by ET-1. RESULTS: The expression levels of ETAR and CXCR4 were closely related to each other and both correlated with a poor prognosis. A multivariate analysis showed that the expression levels of both ETAR and CXCR4 were independent prognostic factors for overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The migration of 6-10B and 5-8F cells was elevated by ET-1 in combination with SDF-1alpha. The knockdown of ETAR protein expression by siRNA reduced CXCR4 protein expression in addition to ETAR protein expression, leading to a decrease in the metastatic potential of the 5-8F cells. ET-1 induced CXCR4 mRNA and protein expression in the 6-10B NPC cells in a time- and concentration-dependent fashion and was inhibited by an ETAR antagonist and PI3K/AKT/mTOR and MAPK/ERK1/2 pathway inhibitors. CONCLUSIONS: ETAR and CXCR4 expression levels are potential prognostic biomarkers in NPC patients. ETAR activation partially promoted NPC cell migration via a mechanism that enhanced functional CXCR4 expression. PMID- 23987649 TI - Uranium(III) complexes with bulky aryloxide ligands featuring metal-arene interactions and their reactivity toward nitrous oxide. AB - We report the synthesis and use of an easy-to-prepare, bulky, and robust aryloxide ligand starting from inexpensive precursor materials. Based on this aryloxide ligand, two reactive, coordinatively unsaturated U(III) complexes were prepared that are masked by a metal-arene interaction via delta-backbonding. Depending on solvent and uranium starting material, both a tetrahydrofuran (THF) bound and Lewis-base-free U(III) precursor can easily be prepared on the multigram scale. The reaction of these trivalent uranium species with nitrous oxide, N2O, was studied and an X-ray diffraction (XRD) study on single crystals of the product revealed the formation of a five-coordinate U(V) oxo complex with two different molecular geometries, namely, square pyramidal and trigonal bipyramidal. PMID- 23987648 TI - Clinical translation of human neural stem cells. AB - Human neural stem cell transplants have potential as therapeutic candidates to treat a vast number of disorders of the central nervous system (CNS). StemCells, Inc. has purified human neural stem cells and developed culture conditions for expansion and banking that preserve their unique biological properties. The biological activity of these human central nervous system stem cells (HuCNS SC(r)) has been analyzed extensively in vitro and in vivo. When formulated for transplantation, the expanded and cryopreserved banked cells maintain their stem cell phenotype, self-renew and generate mature oligodendrocytes, neurons and astrocytes, cells normally found in the CNS. In this overview, the rationale and supporting data for pursuing neuroprotective strategies and clinical translation in the three components of the CNS (brain, spinal cord and eye) are described. A phase I trial for a rare myelin disorder and phase I/II trial for spinal cord injury are providing intriguing data relevant to the biological properties of neural stem cells, and the early clinical outcomes compel further development. PMID- 23987650 TI - Global adaptive output feedback control for a class of nonlinear time-delay systems. AB - This paper addresses the problem of global output feedback control for a class of nonlinear time-delay systems. The nonlinearities are dominated by a triangular form satisfying linear growth condition in the unmeasurable states with an unknown growth rate. With a change of coordinates, a linear-like controller is constructed, which avoids the repeated derivatives of the nonlinearities depending on the observer states and the dynamic gain in backstepping approach and therefore, simplifies the design procedure. Using the idea of universal control, we explicitly construct a universal-type adaptive output feedback controller which globally regulates all the states of the nonlinear time-delay systems. PMID- 23987651 TI - Ordering high-cost medical imaging: a right or a privilege? PMID- 23987652 TI - Milestones: direct observation may be the key to accelerated training. PMID- 23987653 TI - P-TRAP: a Panicle TRAit Phenotyping tool. AB - BACKGROUND: In crops, inflorescence complexity and the shape and size of the seed are among the most important characters that influence yield. For example, rice panicles vary considerably in the number and order of branches, elongation of the axis, and the shape and size of the seed. Manual low-throughput phenotyping methods are time consuming, and the results are unreliable. However, high throughput image analysis of the qualitative and quantitative traits of rice panicles is essential for understanding the diversity of the panicle as well as for breeding programs. RESULTS: This paper presents P-TRAP software (Panicle TRAit Phenotyping), a free open source application for high-throughput measurements of panicle architecture and seed-related traits. The software is written in Java and can be used with different platforms (the user-friendly Graphical User Interface (GUI) uses Netbeans Platform 7.3). The application offers three main tools: a tool for the analysis of panicle structure, a spikelet/grain counting tool, and a tool for the analysis of seed shape. The three tools can be used independently or simultaneously for analysis of the same image. Results are then reported in the Extensible Markup Language (XML) and Comma Separated Values (CSV) file formats. Images of rice panicles were used to evaluate the efficiency and robustness of the software. Compared to data obtained by manual processing, P-TRAP produced reliable results in a much shorter time. In addition, manual processing is not repeatable because dry panicles are vulnerable to damage. The software is very useful, practical and collects much more data than human operators. CONCLUSIONS: P-TRAP is a new open source software that automatically recognizes the structure of a panicle and the seeds on the panicle in numeric images. The software processes and quantifies several traits related to panicle structure, detects and counts the grains, and measures their shape parameters. In short, P-TRAP offers both efficient results and a user-friendly environment for experiments. The experimental results showed very good accuracy compared to field operator, expert verification and well-known academic methods. PMID- 23987654 TI - Direct observation of amyloid nucleation under nanomechanical stretching. AB - Self-assembly of amyloid nanofiber is associated with both functional biological and pathological processes such as those in neurodegenerative diseases. Despite intensive studies, the stochastic nature of the process has made it difficult to elucidate a molecular mechanism for the key amyloid nucleation event. Here we investigated nucleation of the silk-elastin-like peptide (SELP) amyloid using time-lapse lateral force microscopy (LFM). By repeated scanning of a single line on a SELP-coated mica surface, we observed a sudden stepwise height increase. This corresponds to nucleation of an amyloid fiber, which subsequently grew perpendicular to the scanning direction. The lateral force profiles followed either a worm-like chain model or an exponential function, suggesting that the atomic force microscopy (AFM) tip stretches a single or multiple SELP molecules along the scanning direction. The probability of nucleation correlated with the maximum stretching force and extension, implying that stretching of SELP molecules is a key molecular event for amyloid nucleation. The mechanically induced nucleation allows for positional and directional control of amyloid assembly in vitro, which we demonstrate by generating single nanofibers at predetermined nucleation sites. PMID- 23987657 TI - Clinical effectiveness of online training in palliative care of primary care physicians. AB - BACKGROUND: Primary care physicians (PCPs) have a major responsibility in the management of palliative patients. Online palliative care (PC) education has not been shown to have a clinical impact on patients that is equal or different to traditional training. OBJECTIVE: This study tested the clinical effectiveness of online PC education of physicians through impact on symptom control, quality of life (QOL), caregiver satisfaction, and knowledge-attitude of physicians at 18 months of the intervention. METHODS: We conducted a randomized clinical trial. Subjects were 169 physicians randomly assigned to receive the online model or traditional training. Consecutive patients with advanced cancer requiring PC were included. Physicians and patients completed the Palliative Care Outcome Scale (POS), and patients the Brief Pain Inventory (BPI) and the Rotterdam Symptom Checklist (RSCL) twice, 7 to 10 days apart. Caregivers completed the SERVQUAL. Physicians' level of knowledge-attitude was measured at 18 months. RESULTS: Sixty seven physicians enrolled 117 patients. The intervention group had reduced scores for pain, symptoms, and family anxiety. The global RSCL scale showed a difference between groups. There was no significant difference in the questionnaires used. Caregiver satisfaction was comparable between groups. Physicians in the intervention group significantly increased their knowledge without any differences in attitude. Online training was completed by 86.6% in the intervention group, whereas 13.4% in the control group accessed traditional training. CONCLUSIONS: Participation in an online PC education program by PCPs improved patient scores for some symptoms and family anxiety on the POS and also showed improved global QOL. Significant differences were found in physicians' knowledge at short and long term. PMID- 23987658 TI - Very-low-dose methadone for the prevention of opioid hyperalgesia. PMID- 23987659 TI - Transformation of biomass into commodity chemicals using enzymes or cells. PMID- 23987660 TI - Effect of internal cavities on folding rates and routes revealed by real-time pressure-jump NMR spectroscopy. AB - The time required to fold proteins usually increases significantly under conditions of high pressure. Taking advantage of this general property of proteins, we combined P-jump experiments with NMR spectroscopy to examine in detail the folding reaction of staphylococcal nuclease (SNase) and of some of its cavity-containing variants. The nearly 100 observables that could be measured simultaneously collectively describe the kinetics of folding as a function of pressure and denaturant concentration with exquisite site-specific resolution. SNase variants with cavities in the central core of the protein exhibit a highly heterogeneous transition-state ensemble (TSE) with a smaller solvent-excluded void volume than the TSE of the parent SNase. This heterogeneous TSE experiences Hammond behavior, becoming more native-like (higher molar volume) with increasing denaturant concentration. In contrast, the TSE of the L125A variant, which has a cavity at the secondary core, is only slightly different from that of the parent SNase. Because pressure acts mainly to eliminate solvent-excluded voids, which are heterogeneously distributed throughout structures, it perturbs the protein more selectively than chemical denaturants, thereby facilitating the characterization of intermediates and the consequences of packing on folding mechanisms. Besides demonstrating how internal cavities can affect the routes and rates of folding of a protein, this study illustrates how the combination of P jump and NMR spectroscopy can yield detailed mechanistic insight into protein folding reactions with exquisite site-specific temporal information. PMID- 23987661 TI - Commentary on: Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement. PMID- 23987663 TI - The ameliorative effect of Cetraria islandica against diabetes-induced genetic and oxidative damage in human blood. AB - CONTEXT: The aqueous extracts of Cetraria islandica (L.) Ach. (Parmeliaceae) is traditionally used in many countries against a number of conditions, including inflammatory conditions. OBJECTIVE: The present study aimed to assess, for the first time, the effectiveness of C. islandica in cultured primary blood cells of Type 1 diabetes subjects. MATERIALS AND METHODS: Diabetic and control blood samples were treated with or without aqueous lichen extract (5 and 10 MUg mL(-1)) for 48 h. The activity of antioxidant enzymes in erythrocytes and also malondialdehyde levels in plasma were determined to evaluate the oxidative status. DNA damages were analyzed by SCE, MN and comet assays in cultured human lymphocytes. Additionally, proliferation index (PI) was evaluated in peripheral blood lymphocytes. RESULTS: There were significant increases in observed total DNA damage (comet assay) (240.2%) and SCE (168.8%), but not in MN frequencies of cultures with diabetes as compared (p > 0.05) to controls. Whereas, the significant reductions of total DNA damage (69.2 and 65.3%) and SCE frequencies (17.7 and 12.3%) were determined when the 5 and 10 mg mL(-1) lichen extract was added to the cell culture medium, respectively. However, lichen extract did not completely inhibit the induction of SCEs in lymphocytes of patients with diabetes. C. islandica extract was also useful on PI rates. DISCUSSION: In conclusion, the antioxidant role of C. islandica in alleviating diabetes-induced genomic instability and for increasing cell viability was firstly indicated in the present study. PMID- 23987662 TI - Synthesis and antibacterial activity of doxycycline neoglycosides. AB - A set of 37 doxycycline neoglycosides were prepared, mediated via a C-9 alkoxyamino-glycyl-based spacer reminiscent of that of tigecycline. Subsequent in vitro antibacterial assays against representative drug-resistant Gram negative and Gram positive strains revealed a sugar-dependent activity profile and one doxycycline neoglycoside, the 2'-amino-alpha-D-glucoside conjugate, to rival that of the parent pharmacophore. In contrast, the representative tetracycline susceptible strain E. coli 25922 was found to be relatively responsive to a range of doxycycline neoglycosides. This study also extends the use of aminosugars in the context of neoglycosylation via a simple two-step strategy anticipated to be broadly applicable for neoglycorandomization. PMID- 23987664 TI - MicroRNA profiling implicates the insulin-like growth factor pathway in bleomycin induced pulmonary fibrosis in mice. AB - BACKGROUND: Idiopathic pulmonary fibrosis is a disease characterized by alveolar epithelial cell injury, inflammatory cell infiltration and deposition of extracellular matrix in lung tissue. As mouse models of bleomycin-induced pulmonary fibrosis display many of the same phenotypes observed in patients with idiopathic pulmonary fibrosis, they have been used to study various aspects of the disease, including altered expression of microRNAs. RESULTS: In this work, microRNA expression profiling of the lungs from treated C57BL/6J mice, relative to that of untreated controls, was undertaken to determine which alterations in microRNAs could in part regulate the fibrosis phenotype induced by bleomycin delivered through mini-osmotic pumps. We identified 11 microRNAs, including miR 21 and miR-34a, to be significantly differentially expressed (P < 0.01) in lungs of bleomycin treated mice and confirmed these data with real time PCR measurements. In situ hybridization of both miR-21 and miR-34a indicated that they were expressed in alveolar macrophages. Using a previously reported gene expression profile, we identified 195 genes to be both predicted targets of the 11 microRNAs and of altered expression in bleomycin-induced lung disease of C57BL/6J mice. Pathway analysis with these 195 genes indicated that altered microRNA expression may be associated with hepatocyte growth factor signaling, cholecystokinin/gastrin-mediated signaling, and insulin-like growth factor (IGF 1) signaling, among others, in fibrotic lung disease. The relevance of the IGF-1 pathway in this model was then demonstrated by showing lung tissue of bleomycin treated C57BL/6J mice had increased expression of Igf1 and that increased numbers of Igf-1 positive cells, predominantly in macrophages, were detected in the lungs. CONCLUSIONS: We conclude that altered microRNA expression in macrophages is a feature which putatively influences the insulin-like growth factor signaling component of bleomycin-induced pulmonary fibrosis. PMID- 23987665 TI - In-hospital acute stress symptoms are associated with impairment in cognition 1 year after intensive care unit admission. AB - RATIONALE: Prior studies have found that cognitive dysfunction is common in intensive care unit (ICU) survivors. Yet, relatively little is known about potentially modifiable risk factors for longer-term post-ICU cognitive impairment. OBJECTIVES: To determine if in-hospital acute stress symptoms were associated with impaired 12-month cognitive functioning among ICU survivors. METHODS: We prospectively enrolled 150 nontrauma patients without cognitive impairment or a dementia diagnosis who were admitted to an ICU for more than 24 hours. Patients were interviewed before hospital discharge and again via telephone at 12 months post-ICU. MEASUREMENTS AND MAIN RESULTS: Demographics and clinical information were obtained through medical record reviews and in-person interviews. In-hospital acute stress symptoms were assessed with the Posttraumatic Stress Disorder Checklist-Civilian Version. Twelve-month post-ICU cognition was assessed with the modified Telephone Interview for Cognitive Status. Follow-up interviews were completed with 120 (80%) patients. Patients' mean age at hospitalization was 48.2 years (SD, 13.7). In unadjusted analyses, a greater number of in-hospital acute stress symptoms was associated with significantly greater impairment in 12-month cognitive functioning (beta, -0.1; 95% confidence interval, -0.2 to -0.004; P = 0.04). After adjusting for patient and clinical factors, in-hospital acute stress symptoms were independently associated with greater impairment in 12-month cognitive functioning (beta, -0.1; 95% CI, -0.2 to -0.01; P = 0.03). CONCLUSIONS: In-hospital acute stress symptoms may be a potentially modifiable risk factor for greater impairment in cognitive functioning post-ICU. Early interventions for at-risk ICU survivors may improve longer-term outcomes. PMID- 23987667 TI - Measuring atomic emission from beacons for long-distance chemical signaling. AB - In an effort to exploit chemistry for information science, we have constructed a system to send a message powered by a combustion reaction. Our system uses the thermal excitation of alkali metals to transmit an encoded signal over long distances. A message is transmitted by burning a methanol-soaked cotton string embedded with combinations of high, low, or zero levels of potassium, rubidium, and/or cesium ions. By measuring the intensities at the characteristic emission wavelengths of each metal in the near-infrared, 19 unique signals can be distinguished. We have built a custom telescope to detect these signals from 1 km away for nearly 10 min. The signal is isotropic, is self-powered, and has a low background. A potential application of this platform is for search and rescue signaling where another layer of information can be transmitted, in addition to the location of the beacon. This work, which seeks to encode and transmit information using chemistry instead of electronics, is part of the new field of "infochemistry". PMID- 23987668 TI - The government can't have it both ways. PMID- 23987666 TI - 2'-hydroxy C16-ceramide induces apoptosis-associated proteomic changes in C6 glioma cells. AB - Ceramide is a bioactive sphingolipid involved in regulation of numerous cell signaling pathways. Evidence is accumulating that differences in ceramide structure, such as N-acyl chain length and desaturation of sphingoid base, determine the biological activities of ceramide. Using synthetic (R)-2'-hydroxy C16-ceramide, which is the naturally occurring stereoisomer, we demonstrate that this ceramide has more potent pro-apoptotic activity compared to its (S) isomer or non-hydroxylated C16-ceramide. Upon exposure to (R)-2'-hydroxy-ceramide, C6 glioma cells rapidly underwent apoptosis as indicated by caspase-3 activation, PARP cleavage, chromatin condensation, and annexin V stain. A 2D gel proteomics analysis identified 28 proteins whose levels were altered during the initial 3 h of exposure. Using the list of 28 proteins, we performed a software-assisted pathway analysis to identify possible signaling events that would result in the observed changes. The result indicated that Akt and MAP kinase pathways are among the possible pathways regulated by (R)-2'-hydroxy-ceramide. Experimental validation confirmed that 2'-hydroxy-ceramide significantly altered phosphorylation status of Akt and its downstream effector GSK3beta, as well as p38, ERK1/2, and JNK1/2 MAP kinases. Unexpectedly, robust phosphorylation of Akt was observed within 1 h of exposure to 2'-hydroxy-ceramide, followed by dephosphorylation. Phosphorylation status of MAPKs showed a complex pattern, in which rapid phosphorylation of ERK1/2 was followed by dephosphorylation of p38 and ERK1/2 and phosphorylation of the 46 kDa isoform of JNK1/2. These data indicate that (R)-2'-hydroxy-ceramide regulates multiple signaling pathways by affecting protein kinases and phosphatases with kinetics distinct from that of the extensively studied non-hydroxy-ceramide or its unnatural stereoisomer. PMID- 23987669 TI - Trust displays nurses' names above beds to show who is responsible. PMID- 23987671 TI - Unions ready to fight expected attack on incremental pay. PMID- 23987674 TI - Essential staffing levels for safe children's care updated by RCN. PMID- 23987678 TI - Change in approach to governance of nurse education programmes. PMID- 23987682 TI - Report reveals staff uncertainties over the use of physical restraint. PMID- 23987685 TI - Demands on NHS nurses may be too great to stop exodus of over-50s. PMID- 23987687 TI - Hospitals prepare for clampdown on unacceptable care standards. PMID- 23987693 TI - Rescuing the vulnerable. AB - Human trafficking, such as forced prostitution and labour, affects men, women and children in the UK. Many have been brought into the country from eastern Europe and Africa. This article describes new guidance from the Department of Health that is designed to help healthcare professionals identify and support trafficked people. PMID- 23987694 TI - Too painful to be trivialised. AB - Known as the 'disease of kings' and often trivialised as a self-inflicted condition, gout is in fact the most common type of inflammatory arthritis, affecting 1.4 per cent of the UK population. A wide range of risk factors, including genetics, play a part in its development. Early detection and treatment are important, as it is often extremely painful. PMID- 23987695 TI - Evidence shows staff ratios can work. AB - Supporters of mandatory staffing ratios argue that they are essential to ensure safe patient care, and can point to states in the United States and Australia where they have been implemented successfully. Ratios are complex and are likely to face political resistance in the UK. PMID- 23987708 TI - Whistleblowers are heroes who should be rewarded for bravery. PMID- 23987710 TI - Long-standing concerns over the former head of the CQC. PMID- 23987709 TI - Reports of poor care are still dismissed or handled clumsily. PMID- 23987711 TI - There are no simple answers in forensic mental health. PMID- 23987712 TI - Nurses should not be obliged to force-feed political prisoners. PMID- 23987714 TI - It is time to accept that health care is a round-the-clock job. PMID- 23987715 TI - Placement of nasogastric tubes must be checked thoroughly. PMID- 23987716 TI - It is okay to cry at work but only when well away from patients. PMID- 23987717 TI - Don a pair of gloves to raise awareness of scleroderma. PMID- 23987720 TI - National audit of bedside transfusion practice. AB - AIM: To measure clinical bedside practice and promote best practice for the administration of blood. METHOD: Data were collected on patient identification and the monitoring of patients receiving a transfusion. RESULTS: The majority of patients received safe transfusion, with adequate identity checks and careful monitoring. Some patients, however, were at risk of misidentification or an unobserved transfusion reaction because of the absence of a patient identity wristband or lack of monitoring during transfusion. CONCLUSION: The results of the audit are largely positive, with a continual comparative trend from previous audits of improvement in patient safety during transfusion. Healthcare professionals appear to recognise the importance of the final bedside check and monitoring of transfused patients, contributing to safe practice. However, a minority of patients were put at risk because procedures were not followed. The findings of this audit, particularly those relating to patient identification and monitoring, are relevant to many other aspects of clinical care, not only safe transfusion practice. PMID- 23987719 TI - Quality control in urodynamics. AB - AIM: To review the quality and consistency of urodynamic traces collected as part of the Bladder Ultrasound Study (BUS). METHOD: A total of 64 urodynamic traces were randomly selected and assessed for adherence to the BUS standard operating procedure based on good urodynamic practice guidelines. Assessments were undertaken of the patient's position during the filling phase, filling cystometry rate, presence of one cough per minute, presence of cough pre and post void, reliability of initial diagnosis and whether there was adequate zeroing pressures before starting the urodynamic studies. RESULTS: Eight traces complied fully with the BUS standard operating procedure. In 52 traces, women were in the recommended filling position and 34 traces were performed at the recommended cystometry rate. In 58 traces, initial diagnoses were re-confirmed by the reviewers. CONCLUSION: There was good consistency and adherence to urodynamic practice guidelines. Areas for improvement include adhering to the recommended filling cystometry rate and initiating cough post void. PMID- 23987721 TI - The effect of organisational culture on patient safety. AB - This article explores the links between organisational culture and patient safety. The key elements associated with a safety culture, most notably effective leadership, good teamwork, a culture of learning and fairness, and fostering patient-centred care, are discussed. The broader aspects of a systems approach to promoting quality and safety, with specific reference to clinical governance, human factors, and ergonomics principles and methods, are also briefly explored, particularly in light of the report of the public inquiry into care failings at Mid Staffordshire NHS Foundation Trust. PMID- 23987722 TI - Quantitative research. PMID- 23987723 TI - We're here to help you. PMID- 23987725 TI - Map your work to prove your worth. PMID- 23987727 TI - Combined expertise. PMID- 23987728 TI - Violent crime rates as a proxy for the social determinants of sexually transmissible infection rates: the consistent state-level correlation between violent crime and reported sexually transmissible infections in the United States, 1981-2010. AB - BACKGROUND: Numerous social determinants of health are associated with violent crime rates and sexually transmissible infection (STI) rates. This report aims to illustrate the potential usefulness of violent crime rates as a proxy for the social determinants of STI rates. METHODS: For each year from 1981 to 2010, we assessed the strength of the association between the violent crime rate and the gonorrhoea (Neisseria gonorrhoeae) rate (number of total reported cases per 100?000) at the state level. Specifically, for each year, we calculated Pearson correlation coefficients (and P-values) between two variables (the violent crime rate and the natural log of the gonorrhoea rate) for all 50 states and Washington, DC. For comparison, we also examined the correlation between gonorrhoea rates, and rates of poverty and unemployment. We repeated the analysis using overall syphilis rates instead of overall gonorrhoea rates. RESULTS: The correlation between gonorrhoea and violent crime was significant at the P<0.001 level for every year from 1981 to 2010. Syphilis rates were also consistently correlated with violent crime rates. In contrast, the P-value for the correlation coefficient exceeded 0.05 in 9 of the 30 years for the association between gonorrhoea and poverty, and in 17 of the 30 years for that between gonorrhoea and unemployment. CONCLUSIONS: Because violent crime is associated with many social determinants of STIs and because it is consistently associated with STI rates, violent crime rates can be a useful proxy for the social determinants of health in statistical analyses of STI rates. PMID- 23987729 TI - Shifting perceptions: a pre-post study to assess the impact of a senior resident rotation bundle. AB - BACKGROUND: Extended duty hours for residents are associated with negative consequences. Strategies to accommodate duty hour restrictions may also have unintended impacts. To eliminate extended duty hours and potentially lessen these impacts, we developed a senior resident rotation bundle that integrates a night float system, educational sessions on sleep hygiene, an electronic handover tool, and a simulation-based medical education curriculum. The aim of this study was to assess internal medicine residents' perceptions of the impact of the bundle on three domains: the senior residents' wellness, ability to deliver quality health care, and medical education experience. METHODS: This prospective study compared eligible residents' experiences (N = 67) before and after a six-month trial of the bundle at a training program in western Canada. Data was collected using an on-line survey. Pre- and post-intervention scores for the final sample (N = 50) were presented as means and compared using the t-test for paired samples. RESULTS: Participants felt that most aspects of the three domains were unaffected by the introduction of the bundle. Four improved and two worsened perception shifts emerged post-intervention: less exposure to personal harm, reduced potential for medical error, more successful teaching, fewer disruptions to other rotations, increased conflicting role demands and less staff physician supervision. CONCLUSIONS: The rotation bundle integrates components that potentially ease some of the perceived negative consequences of night float rotations and duty hour restrictions. Future areas of study should include objective measures of the three domains to validate our study participants' perceptions. PMID- 23987730 TI - Indirect nuclear 15N-15N scalar coupling through a hydrogen bond: dependence on structural parameters studied by quantum chemistry tools. AB - NMR spin-spin couplings through a hydrogen bond in the free-base and protonated forms of the complete series of [(15)N2]-N-methylated 1,8-diaminonaphthalenes have been analyzed using quantum chemistry tools. The dominating role of the overlap of the coupling pathway orbitals has been demonstrated. The correlation of the sum of the (13)C NMR shifts of the naphthalene ring C(1,8) carbons directly attached to the interacting nitrogens with the J(N-N) values and the degree of methylation found earlier by G. C. Lloyd-Jones et al. [Chem.-Eur. J. 2003, 9, 4523] have been reexamined. It has been found that the correlations of J(N-N) and [DeltaSigmaC(1,8)] with the degree of methylation have different reasons. While the former is mostly connected with the structural changes due to the solvent effect, the latter is attributed to the changes in the paramagnetic contributions from the C-N and C-C bonds caused by the replacement of a hydrogen by a methyl group. PMID- 23987731 TI - Evaluation of anti-citrullinated type II collagen and anti-citrullinated vimentin antibodies in patients with juvenile idiopathic arthritis. AB - BACKGROUND: To determine the prevalence and significance of anti-citrullinated vimentin and anti-citrullinated type II collagen antibodies and elucidate their role in the disease process of juvenile idiopathic arthritis (JIA). METHODS: Sera were obtained from 95 patients with various subtypes of JIA, 19 systemic lupus erythematosus (SLE) patients, and 10 healthy children. Antibodies were measured in the sera against citrullinated and native type II collagen and vimentin (vim1 16 and vim 59-74) by enzyme-linked immunosorbent assay. Samples were compared to anti-cyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor (RF) isotypes, and our previously measured anti-citrullinated fibrinogen and alpha enolase antibodies on the same patient population, in addition to erythrocyte sedimentation rate and C-reactive protein. The relationship between the anti citrullinated antibody profile and disease activity and joint damage were also investigated. RESULTS: Twenty-three JIA patients (24%) demonstrated reactivity to anti-citrullinated type II collagen. Ten JIA patients (10.5%) demonstrated reactivity to anti-citrullinated vimentin 1-16 antibodies and 7 (7.4%) to anti citrullinated vimentin 59-74 antibodies. One IgM RF-positive polyarticular patient was positive for all 5 of the citrullinated autoantibodies tested. Thirty seven different subsets of patients were identified based on their anti citrullinated autoantibody and RF isotype profile. No significant associations were noted with anti-citrullinated type II collagen and anti-citrullinated vimentin antibodies with joint damage or disease activity. Anti-citrullinated vimentin 59-74 antibodies demonstrated the highest overall specificity at 89.7%, with anti-citrullinated vimentin 1-16 and anti-citrullinated type II collagen antibodies at 86.2%. CONCLUSION: This study demonstrates that antibodies to multiple citrullinated epitopes are present in the sera of patients with various subtypes of JIA. It also demonstrates the frequent occurrence of anti citrullinated type II collagen and anti-citrullinated fibrinogen antibodies. The presence of autoantibodies to citrullinated antigens in JIA patients is highly diverse. PMID- 23987732 TI - Congenital toxoplasmosis. AB - INTRODUCTION: Infection with Toxoplasma gondii is asymptomatic or mild in immunocompetent people and leads to lifelong immunity, but it can have serious consequences in pregnancy. About five per 1000 non-immune pregnant women may acquire toxoplasma infection, with a 10% to 100% risk of transmission to the baby. Risks of transmission to the baby are higher later in pregnancy, but risks of infection causing harm to the baby are greater earlier in pregnancy. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects on mother and baby of treating toxoplasmosis during pregnancy to reduce risk of vertical transmission and treat fetal infection? What are the effects of treating toxoplasmosis in neonates infected with toxoplasmosis prenatally? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found six systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiparasitic drugs in pregnancy, and antiparasitic drugs in neonates. PMID- 23987733 TI - Medical and ethical considerations in uterus transplantation. AB - Transplanting a uterus has unique characteristics, since a successful outcome is represented only by the birth of a viable healthy child. For this reason, critical issues in this type of transplantation differ profoundly from those of other solid organs and, beside a functioning uterus, involve 3 additional steps. First, at the time of implantation, the quality of embryo is tested by specialized decidual cells surrounding the implanting embryo; such testing is aimed at allowing the development of a normal embryo. Second, from early gestation onward, blood supply to the uterus increases from 45 to 750mL per minute. Vascular anastomoses should support such a marked increase in blood flow. Third, full transformation of spiral arterioles in the placental bed is required to direct 75% of the uterine blood flow to the intervillous space. Unfortunately, no suitable animal model is available for experimentation. Three overarching ethical issues must be considered. Should organ transplant be conducted when it is not absolutely necessary as a life-saving or quality-of-life-saving measure? To what extent should medicine delimit its potential in spite of societal desires? Should society demand from medicine the application of whichever technology can be developed and, if so, to what extent? PMID- 23987734 TI - Religious leaders gain ground in the Jordanian family-planning movement. AB - OBJECTIVE: To assess the effect of a training program designed to enhance the role of Muslim religious leaders (RLs) in promoting family welfare, including reproductive health generally and family planning more specifically. METHODS: A panel study design was utilized; 136 and 115 RLs completed the self-administered questionnaires at baseline (pre-training) and endline (6 months post-training), respectively. Scales were generated to assess RLs' knowledge of the number of family-planning methods deemed to be acceptable according to Islamic teachings (9 methods, Cronbach alpha=0.85), attitudes toward family planning (7 statements, Cronbach alpha=0.67), and preaching and/or counseling on family-planning topics (7 topics, Cronbach alpha=0.85). RESULTS: Linear regressions controlling for sex, age, and educational attainment showed that, on average, RLs cited more methods deemed acceptable according to Islamic teachings (beta=1.381; P<0.001), expressed more positive attitudes toward family planning (beta=0.514; P<0.05), and preached and/or counseled on family-planning topics more frequently at endline compared with baseline (beta=0.965; P<0.01). CONCLUSION: Culturally appropriate training for RLs can lead to a deeper understanding of, and appreciation for, reproductive health and family planning, with the effects manifesting as increased preaching and/or counseling about these important topics. PMID- 23987735 TI - Gynecologic implications of Gorlin-Goltz syndrome. PMID- 23987736 TI - Hoop-strong nanotubes for battery electrodes. AB - The engineering of hollow nanostructures is a promising approach to addressing instabilities in silicon-based electrodes for lithium-ion batteries. Previous studies showed that a SiOx coating on silicon nanotubes (SiNTs) could function as a constraining layer and enhance capacity retention in electrodes with low mass loading, but we show here that similarly produced electrodes having negligible SiOx coating and significantly higher mass loading show relatively low capacity retention, fading quickly within the early cycles. We find that the SiNT performance can still be enhanced, even in electrodes with high mass loading, by the use of Ni functional coatings on the outer surface, leading to greatly enhanced capacity retention in a manner that could scale better to industrially relevant battery capacities. In situ transmission electron microscopy studies reveal that the Ni coatings suppress the Si wall from expanding outward, instead carrying the large hoop stress and forcing the Si to expand inward toward the hollow inner core. Evidence shows that these controlled volume changes in Ni coated SiNTs, accompanied by the electrochemically inert nature of Ni coatings, unlike SiOx, may enhance the stability of the electrolyte at the outer surface against forming a thick solid electrolyte interphase (SEI) layer. These results provide useful guidelines for designing nanostructured silicon electrodes for viable lithium-ion battery applications. PMID- 23987737 TI - Conducting nanosponge electroporation for affordable and high-efficiency disinfection of bacteria and viruses in water. AB - High-efficiency, affordable, and low energy water disinfection methods are in great need to prevent diarrheal illness, which is one of the top five leading causes of death over the world. Traditional water disinfection methods have drawbacks including carcinogenic disinfection byproducts formation, energy and time intensiveness, and pathogen recovery. Here, we report an innovative method that achieves high-efficiency water disinfection by introducing nanomaterial assisted electroporation implemented by a conducting nanosponge filtration device. The use of one-dimensional (1D) nanomaterials allows electroporation to occur at only several volts, which is 2 to 3 orders of magnitude lower than that in traditional electroporation applications. The disinfection mechanism of electroporation prevents harmful byproduct formation and ensures a fast treatment speed of 15,000 L/(h.m(2)), which is equal to a contact time of 1 s. The conducting nanosponge made from low-cost polyurethane sponge coated with carbon nanotubes and silver nanowires ensures the device's affordability. This method achieves more than 6 log (99.9999%) removal of four model bacteria, including Escherichia coli, Salmonella enterica Typhimirium, Enterococcus faecalis, and Bacillus subtilis, and more than 2 log (99%) removal of one model virus, bacteriophage MS2, with a low energy consumption of only 100 J/L. PMID- 23987738 TI - Transcriptomic analysis highlights epigenetic and transcriptional regulation during zygotic embryo development of Pinus pinaster. AB - BACKGROUND: It is during embryogenesis that the plant body plan is established and the meristems responsible for all post-embryonic growth are specified. The molecular mechanisms governing conifer embryogenesis are still largely unknown. Their elucidation may contribute valuable information to clarify if the distinct features of embryo development in angiosperms and gymnosperms result from differential gene regulation. To address this issue, we have performed the first transcriptomic analysis of zygotic embryo development in a conifer species (Pinus pinaster) focusing our study in particular on regulatory genes playing important roles during plant embryo development, namely epigenetic regulators and transcription factors. RESULTS: Microarray analysis of P. pinaster zygotic embryogenesis was performed at five periods of embryo development from early developing to mature embryos. Our results show that most changes in transcript levels occurred in the first and the last embryo stage-to-stage transitions, namely early to pre-cotyledonary embryo and cotyledonary to mature embryo. An analysis of functional categories for genes that were differentially expressed through embryogenesis highlighted several epigenetic regulation mechanisms. While putative orthologs of transcripts associated with mechanisms that target transposable elements and repetitive sequences were strongly expressed in early embryogenesis, PRC2-mediated repression of genes seemed more relevant during late embryogenesis. On the other hand, functions related to sRNA pathways appeared differentially regulated across all stages of embryo development with a prevalence of miRNA functions in mid to late embryogenesis. Identification of putative transcription factor genes differentially regulated between consecutive embryo stages was strongly suggestive of the relevance of auxin responses and regulation of auxin carriers during early embryogenesis. Such responses could be involved in establishing embryo patterning. Later in development, transcripts with homology to genes acting on modulation of auxin flow and determination of adaxial-abaxial polarity were up-regulated, as were putative orthologs of genes required for meristem formation and function as well as establishment of organ boundaries. Comparative analysis with A. thaliana embryogenesis also highlighted genes involved in auxin-mediated responses, as well as epigenetic regulation, indicating highly correlated transcript profiles between the two species. CONCLUSIONS: This is the first report of a time-course transcriptomic analysis of zygotic embryogenesis in a conifer. Taken together our results show that epigenetic regulation and transcriptional control related to auxin transport and response are critical during early to mid stages of pine embryogenesis and that important events during embryogenesis seem to be coordinated by putative orthologs of major developmental regulators in angiosperms. PMID- 23987740 TI - Contribution of cytochrome P450 isoforms to gliquidone metabolism in rats and human. AB - 1. Gliquidone, a second generation sulfonylurea, is a widely used oral antidiabetic drug. Due to the differences in its rate of metabolism, gliquidone shows inter-subject variability in pharmacokinetic and pharmacodynamic profiles. 2. Cytochrome P450 (CYP450) isoforms are involved in the metabolism of a majority of drugs in clinical use and plays a significant role in reducing possible drug interactions. This research aimed to systematically study the contribution of various human CYP450 isoforms to gliquidone metabolism in vitro in rats and human. 3. In rat liver microsomes, gliquidone was metabolized mainly by the most abundant CYP2C. The other isoforms involved in the metabolism included CYP3A, CYP2D, CYP1A and CYP2E. 4. Further investigation of rat recombinant enzymes showed that CYP3A1 and CYP2C11 played a major role in gliquidone metabolism in vitro, while CYP2D1, CYP1A2 and CYP2E1 were also involved. 5. But the metabolism of gliquidone in the human liver microsomes was mainly mediated by CYP3A4. The other isoforms involved in this process were CYP2C9, CYP2C19 and CYP2D6. 6. The further study of human recombinant enzymes demonstrated that CYP3A4 was the principal isoform enzyme for the metabolism of gliquidone. The intrinsic clearance (Vmax/Km) of CYP3A4 during gliquidone metabolism was 3-12 times greater than that of other CYP450 isoforms including CYP2C9, CYP2D6 and CYP2C19. 7. These findings may assist in valuable prediction of potential interactions of gliquidone with other drugs that are CYP3A4 inhibitors or inducers and help to design more efficacious and safer pharmacotherapy for patients of diabetes mellitus. PMID- 23987741 TI - ent-Labdane diterpenes from the stems of Mallotus japonicus. AB - Eight new ent-labdane diterpenoids, mallonicusins A-H (1-8), were isolated from the stems of Mallotus japonicus. Their structures, including the absolute configurations, were determined by extensive analyses of spectroscopic data and the ECD spectra of the Pr(FOD)3 complex of substrates in CCl4. The absolute configuration of compound 1 was confirmed by single-crystal X-ray crystallography using Cu Kalpha radiation. PMID- 23987739 TI - Challenging and complex decisions in the management of the BRCA mutation carrier. AB - Women afflicted by the hereditary breast and ovarian cancer syndrome face complex decisions regarding medical interventions aimed at reducing their risk of ovarian and breast cancer, interventions which in turn may interfere with their fertility and cause early menopause. This review addresses selected topics of importance and controversy in the management of the BRCA mutation carrier, such as psychological well-being and quality of life, breast and ovarian cancer screening, risk-reducing interventions for breast cancer and ovarian cancer, the issue of hysterectomy at the time of the risk-reducing salpingo-oophorectomy, health consequences of early surgical menopause, and safety of hormonal therapy after oophorectomy. The information presented is based on an extensive review of the literature on the selected topics and on the expertise of our multidisciplinary team. PMID- 23987742 TI - Effects of Japanese traditional herbal medicines (Kampo) on growth and virulence properties of Porphyromonas gingivalis and viability of oral epithelial cells. AB - CONTEXT: Kampos, commonly used in Japanese traditional medicine, are standardized herbal mixtures that have been used for centuries to treat a variety of ailments. We hypothesized that Kampos may have unidentified properties that may be beneficial in periodontitis, an inflammatory disease affecting the tooth supporting tissues. OBJECTIVE: The aim of our study was to investigate various Kampos and their natural ingredients for their effects on Porphyromonas gingivalis growth, adherence to epithelial cells and proteinase activity. In addition, their effects on oral epithelial cell viability were evaluated. MATERIALS AND METHODS: Growth inhibition of P. gingivalis by various Kampos and their natural ingredients was evaluated by a microdilution broth assay method. Their effects on P. gingivalis proteinase activity and adherence to oral epithelial cells were determined by fluorometric assays. The cytotoxicity of test compounds towards oral epithelial cells was evaluated by MTT [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] test. RESULTS: Of the 27 Kampos tested, 7 were found to inhibit the growth of P. gingivalis. The lowest minimal inhibitory concentration (MIC) (250 ug/ml) was obtained with TJ-113. Analysis of the composition of the seven active Kampos showed that they contain Chinese rhubarb as a common ingredient. Therefore, additional growth inhibitory assays on P. gingivalis were carried out with purified anthraquinones known to be present in rhubarb. Aloe-emodin and rhein possessed the strongest antibacterial effects towards P. gingivalis with an MIC of 0.78 ug/ml. The seven Kampos containing rhubarb and purified anthraquinones also exhibited the capacity to decrease the adherence of P. gingivalis to oral epithelial cells and to reduce its proteinase activity. The most important anti-adherence effect of Kampo was obtained with TJ-126; at 250 ug/ml it reduced adherence of P. gingivalis to epithelial cells by 83%. Purified anthraquinones were found to be less active than Kampos. Kampo TJ-113 was found to be the most effective for inhibition of gelatin degradation (49% inhibition at 62.5 ug/ml). Again, purified anthraquinones inhibited gelatin degradation to a lesser extent. Lastly, none of the tested compounds showed cytotoxicity towards oral epithelial cells at the effective concentrations. CONCLUSION: Kampos containing rhubarb and its anthraquinone derivatives may represent promising molecules for controlling periodontal diseases through their capacity to inhibit P. gingivalis growth and virulence properties. PMID- 23987743 TI - High burden of palliative needs among older intensive care unit survivors transferred to post-acute care facilities. a single-center study. AB - RATIONALE: Adults with chronic critical illness (tracheostomy after >= 10 d of mechanical ventilation) have a high burden of palliative needs, but little is known about the actual use and potential need of palliative care services for the larger population of older intensive care unit (ICU) survivors discharged to post acute care facilities. OBJECTIVES: To determine whether older ICU survivors discharged to post-acute care facilities have potentially unmet palliative care needs. METHODS: We examined electronic records from a 1-year cohort of 228 consecutive adults >= 65 years of age who had their first medical-ICU admission in 2009 at a single tertiary-care medical center and survived to discharge to a post-acute care facility (excluding hospice). Use of palliative care services was defined as having received a palliative care consultation. Potential palliative care needs were defined as patient characteristics suggestive of physical or psychological symptom distress or anticipated poor prognosis. We examined the prevalence of potential palliative needs and 6-month mortality. MEASUREMENTS AND MAIN RESULTS: The median age was 78 years (interquartile range, 71-84 yr), and 54% received mechanical ventilation for a median of 7 days (interquartile range, 3-16 d). Six subjects (2.6%) received a palliative care consultation during the hospitalization. However, 88% had at least one potential palliative care need; 22% had chronic wounds, 37% were discharged on supplemental oxygen, 17% received chaplaincy services, 23% preferred to not be resuscitated, and 8% were designated "comfort care." The 6-month mortality was 40%. CONCLUSIONS: Older ICU survivors from a single center who required postacute facility care had a high burden of palliative care needs and a high 6-month mortality. The in-hospital postcritical acute care period should be targeted for palliative care assessment and intervention. PMID- 23987744 TI - Understanding of latent tuberculosis, its treatment and treatment side effects in immigrant and refugee patients. AB - BACKGROUND: Isoniazid treatment of latent tuberculosis infection (LTBI) is commonly prescribed in refugees and immigrants. We aimed to assess understanding of information provided about LTBI, its treatment and potential side effects. METHODS: A questionnaire was administered in clinics at a tertiary hospital. Total Knowledge (TKS) and Total Side Effect Scores (TSES) were derived. Logistic regression analyses were employed to correlate socio-demographic factors with knowledge. RESULTS: Fifty-two participants were recruited, 20 at isoniazid commencement and 32 already on isoniazid. The average TKS were 5.04/9 and 6.23/9 respectively and were significantly associated with interpreter use. Approximately half did not know how tuberculosis was transmitted. The average TSES were 5.0/7 and 3.5/7 respectively, but were not influenced by socio demographic factors. CONCLUSIONS: There was suboptimal knowledge about LTBI. Improvements in health messages delivered via interpreters and additional methods of distributing information need to be developed for this patient population. PMID- 23987745 TI - Detection of cellular glutathione and oxidized glutathione using magnetic plasmonic nanocomposite-based "turn-off" surface enhanced Raman scattering. AB - Glutathione (GSH) and oxidized glutathione (GSSG) control cellular function and efficiency of anticancer therapy. Reliable detection of cellular GSH/GSSG is challenging due to their ultralow concentration (typically femtomolar concentrations) and interference by other thiol-based molecules. Here, we report a "turn-off" surface enhanced Raman scattering (SERS)-based approach for reliable detection of cellular GSH and GSSG. This approach exploits GSH-induced replacement of a Raman probe from the surface of gamma-Fe2O3-Au followed by Ag growth around gamma-Fe2O3-Au that generates electromagnetic hot spots at the junction between Au and Ag where the Raman probe is localized. The magnetic component of the hybrid nanoparticle concentrates the cellular GSH, and the Au/Ag based plasmonic component provides electromagnetic hot spots for sensitive SERS. This approach is able to monitor GSH level during photothermal cancer therapy. PMID- 23987746 TI - Productivity costs of nonviral sexually transmissible infections among patients who miss work to seek medical care: evidence from claims data. AB - BACKGROUND: Productivity losses can arise when employees miss work to seek care for sexually transmissible infections (STIs). We estimated the average productivity loss per acute case of four nonviral STIs: chlamydia, gonorrhoea, syphilis and trichomoniasis. METHODS: We extracted outpatient claims from 2001 2005 MarketScan databases using International Classification Disease ver. 9 (ICD 9) codes. We linked claims with their absence records in the Health and Productivity Management database by matching enrolee identifiers and the service dates from the claims such that our final data included only those who were absent because they were sick and were diagnosed with an STI on the day of their visit. To ensure that the visit was for the STIs being examined, we restricted the criteria to records with the specified ICD-9 codes only, excluding claims with other codes. We estimated the average number of hours absent and multiplied it by the mean hourly wage rate including benefits ($29.72 in 2011 United States dollars) to estimate the average productivity loss per case. RESULTS: The average productivity losses per case were: $262 for chlamydia, $197 for gonorrhoea, $419 for syphilis and $289 for trichomoniasis. There were no significant differences between males and females. CONCLUSIONS: Among those who take sick leave to seek care, productivity losses associated with treating nonviral STIs may be higher than their estimated direct medical costs. These productivity cost estimates can help to quantify the overall STI burden, and inform cost-effectiveness analyses of prevention and control efforts. PMID- 23987790 TI - Who are the key players in a new translational research network? AB - BACKGROUND: Professional networks are used increasingly in health care to bring together members from different sites and professions to work collaboratively. Key players within these networks are known to affect network function through their central or brokerage position and are therefore of interest to those who seek to optimise network efficiency. However, their identity may not be apparent. This study using social network analysis to ask: (1) Who are the key players of a new translational research network (TRN)? (2) Do they have characteristics in common? (3) Are they recognisable as powerful, influential or well connected individuals? METHODS: TRN members were asked to complete an on-line, whole network survey which collected demographic information expected to be associated with key player roles, and social network questions about collaboration in current TRN projects. Three questions asked who they perceived as powerful, influential and well connected. Indegree and betweenness centrality values were used to determine key player status in the actual and perceived networks and tested for association with demographic and descriptive variables using chi square analyses. RESULTS: Response rate for the online survey was 76.4% (52/68). The TRN director and manager were identified as key players along with six other members. Only two of nine variables were associated with actual key player status; none with perceived. The main finding was the mismatch between actual and perceived brokers. Members correctly identified two of the three central actors (the two mandated key roles director and manager) but there were only three correctly identified actual brokers among the 19 perceived brokers. Possible reasons for the mismatch include overlapping structures and weak knowledge of members. CONCLUSIONS: The importance of correctly identifying these key players is discussed in terms of network interventions to improve efficiency. PMID- 23987791 TI - Analysis of aprepitant for prevention of chemotherapy-induced nausea and vomiting with moderately and highly emetogenic chemotherapy. AB - AIM: This study aimed to determine how aprepitant affects the impact of chemotherapy-induced nausea and vomiting (CINV) on daily activities during highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). PATIENTS & METHODS: Patients received aprepitant plus standard antiemetic therapy (ondansetron plus dexamethasone) or standard antiemetic therapy alone. Data were analyzed from pooled data of two Phase III randomized, double-blind HEC trials and one MEC trial. Patients completed the Functional Living Index-Emesis questionnaire. RESULTS: A significantly greater percentage of patients receiving aprepitant reported no or minimal CINV impact on daily life (overall total Functional Living Index-Emesis score >6) compared with those receiving standard therapy alone (HEC: 74.4 vs 63.9%, respectively; p < 0.01; MEC: 73.4 vs 66.3%; p < 0.05). In HEC, favorable responses to aprepitant treatment persisted in nausea (70.2 vs 60.9%) and vomiting domains (84.6 vs 68.7%; both p < 0.01). Similar results were seen in MEC. CONCLUSION: Addition of aprepitant reduced CINV impact on daily life compared with standard antiemetic therapy. PMID- 23987792 TI - Tautomerism and behavior of 3-hydroxy-2-phenyl-4H-chromen-4-ones (flavonols) and 3,7-dihydroxy-2,8-diphenyl-4H,6H-pyrano[3,2-g]chromene-4,6-diones (diflavonols) in basic media: spectroscopic and computational investigations. AB - Absorption and emission spectroscopic investigations and computational predictions have shown that neutral molecules of flavonols and diflavonols can exist in the ground and excited states in one or two tautomeric forms stabilized by intramolecular (in aprotic media) or intermolecular (with solvent molecule(s), in protic media) hydrogen bonds. Electronic excitation creates conditions for the transformation of tautomeric forms, accompanied by proton transfer, reflected in fluorescence spectra. Proton transfer is also probable in monoanions of diflavonols in protic media. The OH groups involved in hydrogen bonds exhibit a proton-donating ability characterized by the respective acidity constants. The electronically excited diflavonols are relatively strong acids if they lose one proton. With increasing basicity of the medium, anionic forms occur, which exhibit spectral characteristics and emission abilities different from those of neutral molecules. These features open up possibilities for the analytical use of these compounds as spectral probes sensitive to the properties of liquid phases- from neutral to strongly basic. The less intensively studied diflavonols seem to be more promising than flavonols for these purposes, since they are more lipophilic, polarizable, polar, and sensitive to basic features of the environment. PMID- 23987793 TI - Become a farmer and avoid new allergic sensitization: adult farming exposures protect against new-onset atopic sensitization. PMID- 23987794 TI - National burden of antibiotic use for adult rhinosinusitis. PMID- 23987795 TI - Predicting asthma in preschool children with asthma-like symptoms: validating and updating the PIAMA risk score. AB - BACKGROUND: The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) risk score predicts the probability of having asthma at school age among preschool children with suggestive symptoms. OBJECTIVE: We sought to externally validate the PIAMA risk score at different ages and in ethnic and socioeconomic subgroups of children in addition to updating it. METHODS: We studied 2877 children with preschool asthma-like symptoms participating in the multiethnic, prospective, population-based cohort study Generation R. The PIAMA risk score was assessed at preschool age, and asthma was predicted at age 6 years. Discrimination (concordance index [C-index]) and calibration were calculated. The PIAMA risk score was updated, and its performance was similarly analyzed. RESULTS: At age 6 years, 6% (168/2877) of the children had asthma. The discriminative ability of the original PIAMA risk score to predict asthma in Generation R was similar compared with that in the PIAMA cohort (C-index = 0.74 vs 0.71). The predicted risks by using the original PIAMA risk score for having asthma at the age of 6 years tended to be slightly higher than the observed risks (8% vs 6%). No differences in discriminative ability were found at different ages or in ethnic and socioeconomic subgroups (P > .05). The updated PIAMA risk score had a C-index of 0.75. CONCLUSIONS: The PIAMA risk score showed good external validity. The discriminative ability was similar at different ages and in ethnic and socioeconomic subgroups of preschool children, which suggests good generalizability. Further studies are needed to reproduce the predictive performance of the updated PIAMA risk score in other populations and settings and to assess its clinical relevance. PMID- 23987796 TI - Allergen reference doses for precautionary labeling (VITAL 2.0): clinical implications. AB - BACKGROUND: There has been a dramatic proliferation of precautionary labeling by manufacturers to mitigate the perceived risk from low-level contamination from allergens in food. This has resulted in a significant reduction in choice of potentially safe foods for allergic consumers. OBJECTIVES: We aimed to establish reference doses for 11 commonly allergenic foods to guide a rational approach by manufacturers based on all publically available valid oral food challenge data. METHODS: Reference doses were developed from statistical dose-distribution modeling of individual thresholds of patients in a dataset of more than 55 studies of clinical oral food challenges. Sufficient valid data were available for peanut, milk, egg, and hazelnut to allow assessment of the representativeness of the data used. RESULTS: The data were not significantly affected by the heterogeneity of the study methodology, including little effect of age on results for those foods for which sufficient numbers of adult challenge data were available (peanut and hazelnut). Thus by combining data from all studies, the eliciting dose for an allergic reaction in 1% of the population estimated for the following were 0.2 mg of protein for peanut, 0.1 mg for cow's milk, 0.03 mg for egg, and 0.1 mg for hazelnut. CONCLUSIONS: These reference doses will form the basis of the revised Voluntary Incidental Trace Allergen Labeling (VITAL) 2.0 thresholds now recommended in Australia. These new levels will enable manufacturers to apply credible precautionary labeling and provide increased consumer confidence in their validity and reliability, as well as improving consumer safety. PMID- 23987797 TI - Cognitive and psychosocial function post hematopoietic stem cell transplantation in children with hemophagocytic lymphohistiocytosis. AB - OBJECTIVES: This study investigated the cognitive and psychosocial outcomes in childhood survivors of hemophagocytic lymphohistiocytosis after hematopoietic stem cell transplantation. METHODS: Twenty-one children were assessed on standardized measures of cognitive and psychosocial functioning and compared with an unaffected sibling control group (n = 14). Parent and teacher reports were obtained to provide additional information. RESULTS: The average full-scale intelligence quotient for the patient cohort was 81 (95% CI, 72-90), which was significantly lower than both the population average of 100 (P = .001) and the average for the unaffected sibling control group (99.2, P = .002). Fifty-six percent of school-aged children were receiving additional support at school, with the majority needing high levels of support. These children also experienced significant psychosocial difficulties. Lower socioeconomic status was associated with poorer cognitive outcomes, but age at transplantation, time to transplantation, type of conditioning, and presence of mixed chimerism were not. Ten (48%) of 21 children had evidence of neurologic involvement at diagnosis, but surprisingly, this was not significantly associated with adverse neurologic outcomes, and some children who did not have any apparent neurologic involvement at diagnosis had severe learning difficulties at follow-up. CONCLUSIONS: In summary, childhood survivors of hemophagocytic lymphohistiocytosis are at risk of long-term cognitive and psychosocial difficulties. Prospective and systematic long-term follow-up of these patients is essential for early identification and effective management of these problems. PMID- 23987799 TI - Low-dose radiation, scientific scrutiny, and requirements for demonstrating effects. AB - Recent nuclear accidents have prompted renewed interest in the fitness consequences of low-dose radiation. Hiyama et al. provided information on such effects in the Japanese pale grass blue butterfly in a paper that has been viewed more than 300,000 times, prompting a barrage of criticism. These exchanges highlight the role of scrutiny in studies with potential effects on humans, but also raise questions about minimum requirements for demonstrating biological effects. PMID- 23987798 TI - Marked and persistent eosinophilia in the absence of clinical manifestations. AB - BACKGROUND: Although most patients with hypereosinophilic syndromes (HES) present with clinical signs and symptoms attributable to eosinophilic tissue infiltration, some untreated patients remain asymptomatic or have signs and symptoms, such as allergic rhinitis, for which the relationship to peripheral eosinophilia is unclear (hypereosinophilia of unknown significance [HEUS]). OBJECTIVE: To identify and characterize subjects with HEUS of 5 years duration or more as compared to untreated patients with symptomatic HES and healthy normal volunteers. METHODS: All subjects with eosinophilia underwent yearly evaluation, including a standardized clinical evaluation, whole blood flow cytometry to assess lymphocyte subsets and eosinophil activation, and serum collection. Peripheral blood mononuclear cells were cultured overnight with and without phorbol 12-myristate 13-acetate/ionomycin. Cytokines and chemokines were measured in serum and cell supernatants, and mRNA expression was assessed by using quantitative real-time PCR. RESULTS: Eight of the 210 subjects referred for the evaluation of eosinophilia (absolute eosinophil count [AEC] > 1500/MUL) met the criteria for HEUS of 5 years duration or more (range, 7-29 years). Peak eosinophil count and surface expression of eosinophil activation markers were similar in subjects with HEUS and in untreated subjects with platelet-derived growth factor alpha-negative HES (n = 28). Aberrant or clonal T-cell populations were identified in 50% of the subjects with HEUS as compared to 29% of the subjects with HES (P = .12). Increased levels of IL-5, GM-CSF, IL-9, and IL-17A were also comparable in subjects with HEUS and HES. Serum levels of IgE and IL-13 were significantly increased only in subjects with HES. CONCLUSIONS: A small number of patients with persistent peripheral eosinophilia (AEC > 1500/MUL) appear to have clinically benign disease. PMID- 23987800 TI - Percutaneous revascularization strategies in small-vessel disease. AB - Percutaneous coronary intervention (PCI) of small coronary vessels represents a real challenge for myocardial revascularization because of the high risk of stent restenosis and increased risk of adverse clinical events. Moreover, small coronary arteries supply small myocardial territories therefore questioning the clinical significance of small-vessel stenoses. The definition of small-vessel disease and PCI-strategies used are very heterogeneous across studies. The present review will focus on percutaneous coronary revascularization in patients with small vessel coronary artery disease. PMID- 23987801 TI - Representative taxa in field trials for environmental risk assessment of genetically modified maize. AB - When assessing the benefits and risks of transgenic crops, one consideration is their relative effects on non-target arthropod (NTA) abundance and functions within agroecosystems. Several laboratory and field trials have been conducted in Spain since the late 1990s to assess this issue. A consideration in the design of field trials is whether it is necessary to sample most NTAs living in the crop or only representative taxa that perform main ecological functions and have a good capacity to detect small changes in their abundance. Small changes in the field abundance of an effective representative taxon should be detectable using standard experimental protocols. The ability of a species to reveal differences across treatments may be analysed by examining the detectable treatment effects for surveyed non-target organisms. Analysis of data from several NTAs recorded in 14 field trials conducted over 10 years using complete block designs allowed us to select a number of representative taxa capable of detecting changes in the density or activity of arthropod herbivores, predators, parasitoids and decomposers in transgenic and non-transgenic maize varieties. The most suitable NTA as representative taxa (with detectable treatment effects below 50%) included leafhoppers among arthropod herbivores, Orius spp., Araneae, and Carabidae among predators, chalcidids, particularly the family Mymaridae, among parasitoids and Chloropidae as decomposer. Details of sampling techniques for each sampled taxa and their advantages and disadvantages are discussed. It is concluded that abundance of taxa is the most influential factor determining their capacity to detect changes caused by genetically modified varieties. PMID- 23987802 TI - An evaluation of instruments for scoring physiological and behavioral cues of pain, non-pain related distress, and adequacy of analgesia and sedation in pediatric mechanically ventilated patients: A systematic review. AB - OBJECTIVES: Advancing technology allows for successful treatment of children with life-threatening illnesses. Effectively assessing and optimally treating a child's distress during their stay in the Pediatric Intensive Care Unit (PICU) is paramount. Objective measures of distress in mechanically ventilated pediatric patients are increasingly available but few have been evaluated. The objectives of this systematic review were to identify available instruments appropriate for measuring physiological and behavioral cues of pain, non-pain related distress, and adequacy of analgesia and sedation in mechanically ventilated pediatric patients, and evaluate these instruments in terms of their psychometric properties. DESIGN: A systematic review of original and validation reports of objective instruments to measure pain and non-pain related distress, and adequacy of analgesia and sedation in mechanically ventilated PICU patients was undertaken. DATA SOURCES: A comprehensive search was conducted in 10 databases from January 1970 to June 2011. Reference lists of relevant articles were reviewed to identify additional articles. REVIEW METHODS: Studies were included in the review if they met pre-established eligibility criteria. Two independent reviewers reviewed studies for inclusion, assessed quality, and extracted data. RESULTS: Twenty-five articles were included, identifying 15 instruments. The instruments had different foci including: assessing pain, non-pain related distress, and sedation (n=2); assessing pain exclusively (n=4); assessing sedation exclusively (n=7), assessing sedation in mechanically ventilated muscle relaxed PICU patients (n=1); and assessing delirium in mechanically ventilated PICU patients (n=1). The Comfort Scale demonstrated the greatest clinical utility in the assessment of pain, non-pain related distress, and sedation in mechanically ventilated pediatric patients. Modified FLACC and the MAPS are more appropriate, however, for the assessment of procedural pain and other brief painful events. More work is required on instruments for the assessment of distress in mechanically ventilated muscle relaxed PICU patients, and the assessment of delirium in PICU patients. CONCLUSIONS: This review provides essential information to guide PICU clinicians in choosing instruments to assess pain, non-pain related distress, and adequacy of analgesia and sedation in mechanically ventilated pediatric patients. Effective knowledge translation is essential in the implementation, adoption, and successful use of these instruments. PMID- 23987803 TI - Coupling strength can control the polarization twist of a plasmonic antenna. AB - The far-field polarization of the optical response of a plasmonic antenna can be tuned by subtly engineering of its geometry. In this paper, we develop design rules for nano antennas which enable the generation of circular polarized light via the excitation of circular plasmonic modes in the structure. Two initially orthogonal plasmonic modes are coupled in such a way that a rotational current is excited in the structure. Modifying this coupling strength from a weak to a strong regime controls the helicity of the scattered field. Finally, we introduce an original sensing approach that relies on the rotation of the incident polarization and demonstrates a sensitivity of 0.23 deg.nm(-1) or 33 deg.RIU(-1), related to changes of mechanical dimensions and the refractive index, respectively. PMID- 23987804 TI - Physical activity on prescription (PAP) from the general practitioner's perspective - a qualitative study. AB - BACKGROUND: Physical activity on prescription (PAP) is a successful intervention for increasing physical activity among patients with a sedentary lifestyle. The method seems to be sparsely used by general practitioners (GPs) and there is limited information about GPs' attitudes to counselling using PAP as a tool. The aim of the study was to explore and understand the meaning of prescribing physical activity from the general practitioner's perspective. METHODS: Three focus group interviews were conducted with a purposive sample of 15 Swedish GPs in the south of Sweden. Participants were invited to talk about their experience of using PAP. The interviews were transcribed verbatim, analysed using qualitative content analysis. RESULTS: The analysis resulted in four categories: The tradition makes it hard to change attitude, Shared responsibility is necessary, PAP has low status and is regarded with distrust and Lack of procedures and clear guidelines. Traditionally GPs talk with patients about the importance of an increased level of physical activity but they do not prescribe physical activity as a treatment. Physician's education focuses on the use of pharmaceuticals. The responsibility for patients' physical activity level is shared with other health professionals, the patient and society. The GPs express reservations about prescribing physical activity. A heavy workload is a source of frustration. PAP is regarded with distrust and considered to be a task of less value and status. Using a prescription to emphasize an increased level is considered to be redundant and the GPs think it should be administered by someone else in the health care system. Scepticism about the result of the method was also expressed. CONCLUSIONS: There is uncertainty about using PAP as a treatment since physicians lack education in non-pharmaceutical methods. The GPs do not regard the written referral as a prioritized task and rather refer to other professionals in the health care system to prescribe PAP. GPs pointed out a need to create routines and arrangements for the method to gain credibility and become everyday practice among GPs. PMID- 23987805 TI - QTL validation and stability for volatile organic compounds (VOCs) in apple. AB - The aroma trait in apple is a key factor for fruit quality strongly affecting the consumer appreciation, and its detection and analysis is often an extremely laborious and time consuming procedure. Molecular markers associated to this trait can to date represent a valuable selection tool to overcome these limitations. QTL mapping is the first step in the process of targeting valuable molecular markers to be employed in marker-assisted breeding programmes (MAB). However, a validation step is usually required before a newly identified molecular marker can be implemented in marker-assisted selection. In this work the position of a set of QTLs associated to volatile organic compounds (VOCs) was confirmed and validated in three different environments in Switzerland, namely Wadenswil, Conthey and Cadenazzo, where the progeny 'Fiesta*Discovery' was replicated. For both QTL identification and validation, the phenotypic data were represented by VOCs produced by mature apple fruit and assessed with a Proton Transfer Reaction-Mass Spectrometer (PTR-MS) instrument. The QTL-VOC combined analysis performed among these three locations validated the presence of important QTLs in three specific genomic regions, two located in the linkage group 2 and one in linkage group 15, respectively, for compounds related to esters (m/z 43, 61 and 131) and to the hormone ethylene (m/z 28). The QTL set presented here confirmed that in apple some compounds are highly genetically regulated and stable across environments. PMID- 23987807 TI - Expression of soybean lectin in transgenic tobacco results in enhanced resistance to pathogens and pests. AB - Lectins are proteins of non-immune origin that specifically interact with carbohydrates, known to play important roles in the defense system of plants. In this study, in order to study the function of a new soybean lectin (SBL), the corresponding encoding gene lec-s was introduced into tobacco plants via Agrobacterium-mediated transformation. Southern blot analyses had revealed that the lec-s gene was stable integrated into the chromosome of the tobacco. The results of the reverse transcription polymerase chain reaction (RT-PCR) also indicated that the lec-s gene in the transgenic tobacco plants could be expressed under the control of the constitutive CaMV35S promoter. Evaluation agronomic of the performance had showed that the transgenic plants could resist to the infection of Phytophthora nicotianae. Insect bioassays using detached leaves from transgenic tobacco plants demonstrated that the ectopically expressed SBL significantly (P.0.05) reduced the weight gain of larvae of the beet armyworm (Spodoptera exigua). Further on, the lectins retarded the development of the larvae and their metamorphosis. These findings suggest that soybean lectins have potential as a protective agent against pathogens and insect pests through a transgenic approach. PMID- 23987806 TI - Alterations in lignin content and phenylpropanoids pathway in date palm (Phoenix dactylifera L.) tissues affected by brittle leaf disease. AB - Brittle leaf disease or Maladie de la Feuille Cassante (MFC) is a lethal disorder of date palm that has assumed epidemic proportions in the oases of Tunisia and Algeria. No pathogen could ever be associated with the disease, while leaflets of affected palms have been previously shown to be deficient in manganese. The work reported here aims to understand the biochemical basis of the date palm response to this disorder. Since the typical disease symptom is the leaf fragility, we have investigated lignin content in leaves and roots. Strong decrease in total lignin content was observed in affected leaves, while lignin content increased in affected roots. Histochemical analyses showed hyperlignification thicker suberin layer in roots cortical cells. The phenylpropanoids pathway was also disrupted in leaves and roots, cinnamoyl-CoA reductase and cinnamyl-alcohol dehydrogenase gene expression was affected by the disease which severely affects the cell wall integrity. PMID- 23987808 TI - Normoergic NO-dependent changes, triggered by a SAR inducer in potato, create more potent defense responses to Phytophthora infestans. AB - In our experimental approach we examined how potato leaves exposed to a chemical agent might induce nitric oxide (NO) dependent biochemical modifications for future mobilization of an effective resistance to Phytophthora infestans. After potato leaf treatment with one of the following SAR inducers, i.e. beta aminobutyric acid (BABA), 2,6-dichloroisonicotinic acid (INA) or Laminarin, we observed enhanced NO generation concomitant with biochemical changes related to a slight superoxide anion (O2(-)) and hydrogen peroxide (H2O2) accumulation dependent on minimal NADPH oxidase and peroxidase activities, respectively. These rather normoergic changes, linked to the NO message, were mediated by the temporary down-regulation of S-nitrosoglutathione reductase (GSNOR). In turn, after challenge inoculation signal amplification promoted potato resistance manifested in the up-regulation of GSNOR activity tuned with the depletion of the SNO pool, which was observed by our team earlier (Floryszak-Wieczorek et al., 2012). Moreover, hyperergic defense responses related to an early and rapid O2( )and H2O2 overproduction together with a temporary increase in NADPH oxidase and peroxidase activities were noted. BABA treatment was the most effective against P. infestans resulting in the enhanced activity of beta-1,3-glucanase and callose deposition. Our results indicate that NO-mediated biochemical modifications might play an important role in creating more potent defense responses of potato to a subsequent P. infestans attack. PMID- 23987809 TI - Hemoglobins, programmed cell death and somatic embryogenesis. AB - Programmed cell death (PCD) is a universal process in all multicellular organisms. It is a critical component in a diverse number of processes ranging from growth and differentiation to response to stress. Somatic embryogenesis is one such process where PCD is significantly involved. Nitric oxide is increasingly being recognized as playing a significant role in regulating PCD in both mammalian and plant systems. Plant hemoglobins scavenge NO, and evidence is accumulating that events that modify NO levels in plants also affect hemoglobin expression. Here, we review the process of PCD, describing the involvement of NO and plant hemoglobins in the process. NO is an effector of cell death in both plants and vertebrates, triggering the cascade of events leading to targeted cell death that is a part of an organism's response to stress or to tissue differentiation and development. Expression of specific hemoglobins can alter this response in plants by scavenging the NO, thus, interrupting the death process. Somatic embryogenesis is used as a model system to demonstrate how cell specific expression of different classes of hemoglobins can alter the embryogenic process, affecting hormone synthesis, cell metabolite levels and genes associated with PCD and embryogenic competence. We propose that plant hemoglobins influence somatic embryogenesis and PCD through cell-specific expression of a distinct plant hemoglobin. It is based on the premise that both embryogenic competence and PCD are strongly influenced by cellular NO levels. Increases in cellular NO levels result in elevated Zn(2+) and reactive-oxygen species associated with PCD, but they also result in decreased expression of MYC2, a transcription factor that is a negative effector of indoleacetic acid synthesis, a hormone that positively influences embryogenic competence. Cell-specific hemoglobin expression reduces NO levels as a result of NO scavenging, resulting in cell survival. PMID- 23987810 TI - Consequences of gene flow between oilseed rape (Brassica napus) and its relatives. AB - Numerous studies have focused on the probability of occurrence of gene flow between transgenic crops and their wild relatives and the likelihood of transgene escape, which should be assessed before the commercial release of transgenic crops. This review paper focuses on this issue for oilseed rape, Brassica napus L., a species that produces huge numbers of pollen grains and seeds. We analyze separately the distinct steps of gene flow: (1) pollen and seeds as vectors of gene flow; (2) spontaneous hybridization; (3) hybrid behavior, fitness cost due to hybridization and mechanisms of introgression; (4) and fitness benefit due to transgenes (e.g. herbicide resistance and Bt toxin). Some physical, biological and molecular means of transgene containment are also described. Although hybrids and first generation progeny are difficult to identify in fields and non-crop habitats, the literature shows that transgenes could readily introgress into Brassica rapa, Brassica juncea and Brassica oleracea, while introgression is expected to be rare with Brassica nigra, Hirschfeldia incana and Raphanus raphanistrum. The hybrids grow well but produce less seed than their wild parent. The difference declines with increasing generations. However, there is large uncertainty about the evolution of chromosome numbers and recombination, and many parameters of life history traits of hybrids and progeny are not determined with satisfactory confidence to build generic models capable to really cover the wide diversity of situations. We show that more studies are needed to strengthen and organize biological knowledge, which is a necessary prerequisite for model simulations to assess the practical and evolutionary outputs of introgression, and to provide guidelines for gene flow management. PMID- 23987811 TI - Improving starch yield in cereals by over-expression of ADPglucose pyrophosphorylase: expectations and unanticipated outcomes. AB - Significant improvements in crop productivity are required to meet the nutritional requirements of a growing world population. This challenge is magnified by an increased demand for bioenergy as a means to mitigate carbon inputs into the environment. Starch is a major component of the harvestable organs of many crop plants, and various endeavors have been taken to improve the yields of starchy organs through the manipulation of starch synthesis. Substantial efforts have centered on the starch regulatory enzyme ADPglucose pyrophosphorylase (AGPase) due to its pivotal role in starch biosynthesis. These efforts include over-expression of this enzyme in cereal plants such as maize, rice and wheat as well as potato and cassava, as they supply the bulk of the staple food worldwide. In this perspective, we describe efforts to increase starch yields in cereal grains by first providing an introduction about the importance of source-sink relationship and the motives behind the efforts to alter starch biosynthesis and turnover in leaves. We then discuss the catalytic and regulatory properties of AGPase and the molecular approaches used to enhance starch synthesis by manipulation of this process during grain filling using seed specific promoters. Several studies have demonstrated increases in starch content per seed using endosperm-specific promoters, but other studies have demonstrated an increase in seed number with only marginal impact on seed weight. Potential mechanisms that may be responsible for this paradoxical increase in seed number will also be discussed. Finally, we describe current efforts and future prospects to improve starch yield in cereals. These efforts include further enhancement of starch yield in rice by augmenting the process of ADPglucose transport into amyloplast as well as other enzymes involved in photoassimilate partitioning in seeds. PMID- 23987813 TI - The rice REDUCED CULM NUMBER11 gene controls vegetative growth under low temperature conditions in paddy fields independent of RCN1/OsABCG5. AB - Low temperature tolerance during vegetative growth is an important objective in rice (Oryza sativa L.) breeding programs. We isolated a novel reduced culm number mutant, designated reduced culm number11 (rcn11), by screening under low temperature condition in a paddy fields. Since the shoot architecture of the rcn11 was very similar to that of the rcn1, we examined whether RCN11 is involved in RCN1/OsABCG5-associated vegetative growth control. The rcn11 mutant has no mutation in the RCN1/OsABCG5 gene and rcn11 has no effect on RCN1/OsABCG5 gene expression. In the rcn1 mutant, RCN1/OsABCG5 was upregulated showing that RCN1/OsABCG5 is controlled by negative feedback regulation. Absence of an effect of rcn11 on RCN1/OsABCG5 feedback regulation supported that RCN11 is not involved in the RCN1/OsABCG5-associated transport system. A genetic allelism test and molecular mapping study showed that rcn11 is independent of rcn1 on rice chromosome 3 and located on chromosome 8. The rcn1 rcn11 phenotype suggests that RCN11 acts on vegetative growth independent of RCN1/OsABCG5. A root development comparison between rcn1 and rcn11 in young seedlings represented that rcn11 reduced crown root number and elongation, whereas rcn1 reduced lateral root density and elongation. Thus, rcn11 will shed new light on vegetative growth control under low temperature. PMID- 23987812 TI - Purification and characterization of a betanidin glucosyltransferase from Amaranthus tricolor L catalyzing non-specific biotransformation of flavonoids. AB - Betacyanins are the major pigments present in Amaranthus tricolor, a leafy vegetable consumed globally. The terminal glycosylation of the aglycone betanidin is an important step in the biosynthesis of this natural red antioxidant pigment. A betanidin 5-O-glucosyltransferase (BGT) was fully purified to 134 folds (specific activity, 265.2 nkat mg(-1)) from the red amaranth by ammonium sulfate precipitation followed by hydrophobic interaction, anion exchange and size exclusion chromatography. Homogeneity of the purified protein was confirmed by 2 dimensional polyacrylamide gel electrophoresis (2D PAGE). The molecular weight of the enzyme determined by liquid chromatography-mass spectrometry (LC-MS) was found to be 62.8 kDa. Furthermore, the enzyme glycosylated flavonoids (kaempferol and quercetin) but not anthocyanidins, presence of which is mutually exclusive to betacyanin accumulating plants. The apparent Km (344+/-2.34 MUM) and Vmax (17.24 MUM min(-1)) of the enzyme were determined by LC-MS/MS. Peptide mass fingerprinting of the purified protein showed 38.4% coverage of peptide masses with anthocyanidin 3-O-glucosyltransferase from Zea mays. Study on this purified enzyme, for the first time, revealed its role of glycosylation in biosynthesis of betacyanin in A. tricolor and indicates promiscuous substrate-specificity. PMID- 23987814 TI - Redox control of plant growth and development. AB - Redox changes determined by genetic and environmental factors display well organized interactions in the control of plant growth and development. Diurnal and seasonal changes in the environmental conditions are important for the normal course of these physiological processes and, similarly to their mild irregular alterations, for stress adaptation. However, fast or large-scale environmental changes may lead to damage or death of sensitive plants. The spatial and temporal redox changes influence growth and development due to the reprogramming of metabolism. In this process reactive oxygen and nitrogen species and antioxidants are involved as components of signalling networks. The control of growth, development and flowering by reactive oxygen and nitrogen species and antioxidants in interaction with hormones at organ, tissue, cellular and subcellular level will be discussed in the present review. Unsolved problems of the field, among others the need for identification of new components and interactions in the redox regulatory network at various organization levels using systems biology approaches will be also indicated. PMID- 23987815 TI - Homeostasis: an underestimated focal point of ecology and evolution. AB - BACKGROUND: The concept of homeostasis is often ill-defined, in the scientific literature. The word "homeostasis", literally, indicates the absence of changes and an absolute maintenance of the status quo. The multiplicity of possible examples of homeostasis suggests that it is essentially impossible that all aspects of the composition of the organism and the rate of processes carried out by the organism are simultaneously held constant, when the environment changes are in the non-lethal range. SCOPE: In attempting to clarify the usage of the term homeostasis, I emphasize the probable contributions to evolutionary fitness of homeostasis main attributes: rate processes and compositions. I also attempted to identify the aspects of homeostasis that are most likely to be subject to natural selection. CONCLUSIONS: The tendency to retain the status quo derives from the interplay of functions (among which growth), metabolic pools and elemental stoichiometry. The set points around which oscillations occur in biological system and their control mechanisms are determined by evolutionary processes; consequently, also the tendency of a cell to be homeostatic with respect to a given set point is selectable. A homeostatic response to external perturbations may be selectively favored when the potential reproductive advantage offered by a reorganization of cell resources cannot be exploited. This is most likely to occur in the case of environmental perturbations of moderate intensity and short duration relative to the growth rate. Under these circumstances, homeostasis may be an energetically and competitively preferable option, because it requires no alteration of the expressed proteome and eliminates the requirement for reverse acclimation, upon cessation of the perturbation. This review also intends to be a stimulus to "ad hoc" experiments to assess the ecological and evolutionary relevance of homeostasis. PMID- 23987816 TI - Cross-talk interactions of exogenous nitric oxide and sucrose modulates phenylpropanoid metabolism in yellow lupine embryo axes infected with Fusarium oxysporum. AB - The aim of the study was to examine cross-talk of exogenous nitric oxide (NO) and sucrose in the mechanisms of synthesis and accumulation of isoflavonoids in embryo axes of Lupinus luteus L. cv. Juno. It was verified whether the interaction of these molecules can modulate the defense response of axes to infection and development of the pathogenic fungus Fusarium oxysporum f. sp. lupini. Sucrose alone strongly stimulated a high level of genistein glucoside in axes pretreated with exogenous nitric oxide (SNP or GSNO) and non-pretreated axes. As a result of amplification of the signal coming from sucrose and GSNO, high isoflavonoids accumulation was observed (+Sn+GSNO). It needs to be stressed that infection in tissues pretreated with SNP/GSNO and cultured on the medium with sucrose (+Si+SNP/+Si+GSNO) very strongly enhances the accumulation of free isoflavone aglycones. In +Si+SNP axes phenylalanine ammonia-lyase activity was high up to 72h. As early as at 12h in +Si+SNP axes an increase was recorded in gene expression level of the specific isoflavonoid synthesis pathway. At 24h in +Si+SNP axes a very high total antioxidant capacity dependent on the pool of fast antioxidants was noted. Post-infection generation of semiquinone radicals was lower in axes with a high level of sucrose than with a deficit. PMID- 23987817 TI - Identification of cold-responsive genes in energycane for their use in genetic diversity analysis and future functional marker development. AB - Breeding for cold tolerance in sugarcane will allow its cultivation as a dedicated biomass crop in cold environments. Development of functional markers to facilitate marker-assisted breeding requires identification of cold stress tolerance genes. Using suppression subtractive hybridization, 465 cold-responsive genes were isolated from the cold-tolerant energycane Ho02-144. Predicted gene interactions network indicated several associated pathways that may coordinately regulate cold tolerance responses in energycane. Expression analysis of a select set of genes, representing signaling and transcription factors, genes involved in polyamine and antioxidant biosynthesis, protein degradation and in the repair of damaged proteins in the cytosol, showed their time-dependent regulation under cold-stress. Comparative expression profiles of these genes between Ho02-144 and a cold-sensitive clone (L79-1002) showed that almost all genes were induced immediately upon imposition of cold stress and maintained their expression in Ho02-144 whereas they were either downregulated or their upregulation was very low in L79-1002. Simple sequence repeat markers derived from 260 cold-responsive genes showed allelic diversity among the cold-sensitive commercial hybrids that were distinct from the Saccharum spontaneum clones. Future efforts will target sequence polymorphism information of these genes in our ongoing QTL and association mapping studies to identify functional markers associated with cold tolerance in sugar/energycane. PMID- 23987818 TI - Targeting of tonoplast proteins to the vacuole. AB - Vacuoles are essential for plant growth and development, and are dynamic compartments that require constant deposition of integral membrane proteins. These membrane proteins carry out many critical functions of the vacuole such as transporting ions and metabolites for vacuolar storage. Understanding the mechanisms for targeting proteins to the vacuolar membrane, or tonoplast, is important for developing novel applications for biotechnology. The mechanisms to target tonoplast proteins to the vacuole are quite complex. Multiple routes, including both Golgi-dependent and Golgi-independent mechanisms, have been implicated in tonoplast protein trafficking. A few endomembrane proteins that regulate this traffic at the level of the endoplasmic reticulum, the pre-vacuolar compartment and the tonoplast are now known. Recent reports indicate that the Golgi-dependent and independent pathways may merge at the level of the pre vacuolar compartment. Finally, the small GTP-binding protein Rab7 and the SNARE protein SYP21 have been implicated in the traffic of tonoplast proteins from the pre-vacuolar compartment to the tonoplast. With multiple cargo proteins being analyzed under a variety of experimental systems, a clearer picture for targeting mechanisms for tonoplast proteins is starting to emerge. PMID- 23987819 TI - Understanding the chromatin remodeling code. AB - Remodeling a chromatin structure enables the genetic elements stored in a genome to function in a condition-specific manner and predisposes the interactions between cis-regulatory elements and trans-acting factors. A chromatin signature can be an indicator of the activity of the underlying genetic elements. This paper reviews recent studies showing that the combination and arrangements of chromatin remodeling marks play roles as chromatin code affecting the activity of genetic elements. This paper also reviews recent studies inferring the primary DNA sequence contexts associated with chromatin remodeling that suggest interactions between genetic and epigenetic factors. We conclude that chromatin remodeling, which provides accurate models of gene expression and morphological variations, may help to find the biological marks that cannot be detected by genome-wide association study or genetic study. PMID- 23987820 TI - Interaction between myelomonocytic and lymphoid cells in a patient with acute myelomonocytic leukemia and chronic lymphocytic leukemia. PMID- 23987821 TI - The safety of bendamustine in patients with chronic lymphocytic leukemia or non Hodgkin lymphoma and concomitant renal impairment: a retrospective electronic medical record database analysis. AB - Abstract This retrospective study compared adverse-event rates in patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), with and without renal impairment, receiving bendamustine alone or with rituximab. Patients (n = 940) were stratified into a renally impaired group (creatinine clearance [CrCL] < 40 mL/min) and two comparator groups (CrCL >= 40 mL/min and CrCL >= 60 mL/min). Renally impaired patients with NHL had a significantly greater incidence of grade 3-4 thrombocytopenia compared with the CrCL >= 60 mL/min group (hazard ratio [HR], 2.57; p = 0.025). For CLL and NHL together, grade 3-4 increased blood urea nitrogen was significantly higher in the renally impaired group than in the CrCL >= 40 mL/min (HR, 2.36; p = 0.02) and CrCL >= 60 mL/min (HR, 4.46; p = 0.001) groups. Based on these results, monitoring blood counts (including platelets) and renal function would be prudent in the management of patients with renal dysfunction and NHL or CLL who receive bendamustine-based regimens. PMID- 23987822 TI - Seven-year follow-up of allogeneic transplant using BCNU, etoposide, cytarabine and melphalan chemotherapy in patients with Hodgkin lymphoma after autograft failure: importance of minimal residual disease. AB - Abstract Allogeneic transplant using reduced intensity conditioning is a therapeutic option for patients with Hodgkin lymphoma (HL) who relapse after an autograft. This was a prospective study of 31 consecutive eligible patients with HL who relapsed after an autograft and underwent an allograft using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning. At a median follow-up of 7 years the progression-free survival (PFS) was 36% (95% confidence interval [CI] 19-54%) and overall survival (OS) was 42% (95% CI 23-59%). In multivariate analysis only residual disease at the time of transplant predicted outcome, with a 4-year PFS and OS of 62% and 75% for patients with minimal residual disease versus 8% and 8% for patients with gross residual disease, respectively (p = 0.005 and p = 0.001, respectively). This benefit seemed to be irrespective of chemosensitivity, with an OS for patients with chemorefractory yet minimal disease of 71% at 4 years. BEAM allogeneic transplant is effective in producing long-term remissions after autograft failure. Regardless of chemosensitivity, minimizing tumor burden pre transplant may improve long-term outcome. PMID- 23987823 TI - Symptomatic BK virus reactivation following fludarabine, cyclophosphamide and rituximab chemotherapy for chronic lymphocytic leukemia/small lymphocytic lymphoma. PMID- 23987825 TI - Cystatin C, Beta2 Microglobulin, N-Acetyl-beta-D-glucosaminidase, Retinol-Binding Protein, and Endothelin 1 Levels in the Evaluation of Sickle Cell Disease Nephropathy. AB - OBJECTIVES: Renal involvement is common in sickle cell disease (SCD). Early demonstration of renal injury and commencement of appropriate treatment will increase survival and quality of life in these patients. We investigated renal manifestations in our pediatric and adult SCD patients and evaluated the role of cystatin C, Beta2 microglobulin (B2M), retinol-binding protein (RBP), N-acetyl beta-D-glucosaminidase (NAG), and endothelin-1 (ET-1) to indicate renal damage. METHODS: The study involved 45 pediatric and 10 adult patients with SCD and 20 healthy children and 10 healthy adults as a control. All the patients were questioned for possible renal manifestations. 24-hour urine samples were collected and glomerular filtration rates (GFRs) were calculated by using creatinine (GFR(creatinine)), Schwartz formula (GFR(Schwartz)), and cystatin C (GFR(cystatin C)). Blood and urine samples were collected and serum cystatin C, urine B2M, RBP, NAG, and ET-1 levels were measured. RESULTS: Nocturnal enuresis and proteinuria were the most common renal manifestations in SCD patients. When the groups were compared in terms of GFR, GFR(creatinine) and GFR(Schwartz) levels were higher in group 1 and 2 patients than in control 1 and 2 patients (P < .05). Cystatin C, B2M, RBP, NAG, and ET-1 values were normal in both the patient and the control groups. However, B2M/creatinine levels were higher than 160 MUg/mg creatinine levels in 10 patients. CONCLUSIONS: Serum cystatin C, urine NAG, RBP, and ET-1 levels were found to be insufficient for the evaluation of SCD nephropathy. Increased B2M/creatinie levels can be valuable in estimating possible glomerular and tubular damage in SCD. PMID- 23987826 TI - Ventilator-dependent children and the health services system. Unmet needs and coordination of care. AB - RATIONALE: Children dependent on mechanical ventilation are a vulnerable population by virtue of their chronic disability and are therefore at increased risk for health disparities and access barriers. The present study is the first, to our knowledge, to conduct a large-scale survey of caregivers of ventilator dependent children to develop a comprehensive socio-demographic profile. OBJECTIVES: To describe the demographic and health status profile of ventilator dependent children, to identify the types of unmet needs families caring for a child on a ventilator face, and to determine the correlates of access to care coordination. METHODS: A survey was administered to 122 parents whose children attended a pediatric home ventilator clinic at a large tertiary Midwestern medical center (84% of the clinic population). MEASUREMENTS AND MAIN RESULTS: Half of the patient population had severe functional limitations, and 70% had one or more comorbidities. One quarter of caregivers reported current financial struggles, and 16% screened positive for a probable depressive disorder. More than half of families reported unmet needs for care, most frequently therapeutic services and skilled nursing care. Of those reporting an unmet need for skilled nursing care, lack of adequate staffing was the main barrier (71.1%). Financial struggles and a probable caregiver depressive disorder were significantly associated with an unmet need for care coordination. CONCLUSIONS: This is the first large-scale quantitative study to investigate the themes of unmet need and care coordination within this vulnerable population. The results suggest these families face barriers accessing therapeutic and skilled nursing services, and caregiver mental health and financial struggles may be important points of intervention for service providers through the inclusion of multidisciplinary care teams and the strengthening of social services referral networks. PMID- 23987824 TI - Ultrathin gold nanowire-functionalized carbon nanotubes for hybrid molecular sensing. AB - Carbon nanotubes (CNTs) have shown great potential as sensing component in the electrochemical field effect transistor and optical sensors, because of their extraordinary one-dimensional electronic structure, thermal conductivity, and tunable and stable near-infrared emission. However, the insolubility of CNTs due to strong van der Waals interactions limits their use in the field of nanotechnology. In this study, we demonstrate that noncovalent ultrathin gold nanowires functionalized multiwalled carbon nanotube (GNW-CNT) hybrid sensing agents show highly efficient and selective immune molecular sensing in electrochemical and near-infrared photoacoustic imaging methods. A detection limit of 0.01 ng/mL for the alpha-fetoprotein (AFP) antigen with high selectivity is shown. The extraordinary optical absorption, thermal, and electric conductivity of hybrid GNW-CNTs presented in this study could be an effective tactic to integrate imaging, sensing, and treatment functionalities. PMID- 23987827 TI - Idiopathic Parkinson's disease phenotype related to C9ORF72 repeat expansions: contribution of the neuropsychological assessment. AB - BACKGROUND: Expanded GGGGCC hexanucleotide repeats in the non-coding region of the C9ORF72 gene was recently identified as being responsible for over 40% of the cases of amyotrophic lateral sclerosis associated with frontotemporal lobar degeneration, in various extrapyramidal syndromes including supranuclear gaze palsy and corticobasal degeneration, and in addition, has been found to be a rare genetic cause of isolated Parkinsonism. To our knowledge, there is no published data concerning the neuropsychological evaluation of patients diagnosed with idiopathic Parkinson's disease related with C9ORF72 repeat expansions. CASE PRESENTATION: We report the results of the comprehensive neuropsychological evaluation in a newly described case in the literature (the sixth) of a patient presenting isolated idiopathic Parkinson's disease associated with C9ORF72 repeat expansions.The decrease in the patient's prefrontal functions resulted in a slight decrease in global efficiency. These abnormalities did not appear to be different, with respect to the deficit observed and the intensity of the cognitive impairment, from those classically observed in cases of sporadic idiopathic Parkinson's disease. Our patient also exhibited a significant impairment in visual gnosis. CONCLUSIONS: If confirmed in other patients, visuoperceptive deficits in idiopathic Parkinson's disease could represent a red flag that should prompt the clinician to perform addition diagnostic procedures. A thorough neuropsychological assessment may prove to be useful for detecting idiopathic Parkinson's disease in patients who are suspected of having repeat abnormalities of C9ORF72 expansions. PMID- 23987828 TI - Stepwise orthogonal click chemistry toward fabrication of paclitaxel/galactose functionalized fluorescent nanoparticles for HepG2 cell targeting and delivery. AB - In this report, we used stepwise orthogonal click chemistry (SOCC) involving strain-promoted azide-alkyne cycloaddition (SPAAC) and microwave-assisted Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC) to assemble an anticancer drug (paclitaxel, PTX) and a targeting ligand (trivalent galactoside, TGal) on a fluorescent silicon oxide nanoparticle (NP) by using dialkyne linker 8 as a bridge. The fluorescent NH2@Cy3SiO2NP was fabricated using a competition method to incorporate Cy3 without loss of the original surface amine density on the NPs. The concept of SOCC was first investigated in a solution-phase model study that showed quantitative reaction yield. In the fabrication of TGal-PTX@Cy3SiO2NP, the expensive compound azido-functionalized PTX 12 used in SPAAC can be easily recovered due to the absence of other reagents in the reaction mixture. High loading of the sugar ligand on the NP surface serves a targeting function and also overcomes the low water solubility of PTX. Confocal fluorescence microscopy and cytotoxicity assay showed that TGal-PTX@Cy3SiO2NP was taken up by HepG2 cells and was affected by the microtubule skeleton in these cells and inhibited the proliferation of these cells in a dose-dependent manner. The presence of a fluorescent probe, a targeting ligand, and an anticancer drug on the multifunctional TGal-PTX@Cy3SiO2NP allows for real-time imaging, specific cancer cell targeting, and the cell-killing effect which is better than free PTX. PMID- 23987829 TI - Investigation of an imported case of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection in Florence, Italy, May to June 2013. AB - On 31 May 2013, the first case of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection in Italy was laboratory confirmed in a previously healthy adult man, who developed pneumonia with moderate respiratory distress after returning from a holiday in Jordan. Two secondary cases were identified through contact tracing, among family members and colleagues who had not previously travelled abroad. Both secondary cases developed mild illness. All three patients recovered fully. PMID- 23987830 TI - Acute hepatitis E complicated by Guillain-Barre syndrome in Portugal, December 2012--a case report. AB - Autochthonous hepatitis E virus (HEV) infection has been increasingly reported in Europe and the United States, mostly arising from genotype 3 and less frequently genotype 4. We report here on a patient with HEV genotype 3a infection complicated by Guillain-Barre syndrome in Portugal in December 2012. We draw attention to the diagnosis of autochthonous HEV infection and to its rare, but important, neurological complications. PMID- 23987831 TI - Lymphogranuloma venereum among men who have sex with men in the Netherlands: regional differences in testing rates lead to underestimation of the incidence, 2006-2012. AB - Since 2003, an epidemic of lymphogranuloma venereum (LGV) has been ongoing in men who have sex with men (MSM) in Europe. Of 92,271 MSM consulting sexually transmitted disease (STI) clinics in the Netherlands between 2006 and 2011, 63,228 (68%) were tested for anorectal Chlamydia infection, with 6,343 (10%) positive diagnoses. In 4,776 of those (75%), LGV testing was performed, with regional variation from 7% to 97%. In total 414 LGV cases were diagnosed, a mean annual positivity rate of 8.7%, decreasing from 14% in 2007 to 6% in 2011, but increasing to 13.1% during 2012 (184 new cases). Risk factors for LGV were human immunodeficiency virus (HIV) positivity (odds ratio (OR)=4.1; 95% confidence interval (CI): 3.2-5.3), STI symptoms (OR=4.1; 95% CI: 3.1-5.4), more than 50 sex partners in the past six months (OR=3.7; 95% CI: 1.1-12.4), older age (40-44 years: OR=2.1; 95% CI: 1.5-2.8), no condom use (OR=2.2; 95% CI: 1.2-3.9) and homosexuality (as opposed to bisexuality; OR=2.2; 95% CI: 1.1-4.2). Regional differences in LGV testing rates limit national LGV surveillance, leading to an underestimation of the real incidence. Characteristics of MSM with LGV did not change over time, so existing prevention strategies should be intensified. PMID- 23987832 TI - Risk factors for Chlamydia trachomatis infection in adolescents: results from a representative population-based survey in Germany, 2003-2006. AB - Infections with Chlamydia trachomatis (CT) can lead to severe sequelae; however, they are not notifiable in Germany. We tested urine samples from participants of KiGGS (German Health Interview and Examination Survey for Children and Adolescents) for CT infections and linked the results to demographic and behavioural data from 1,925 participants (girls aged 15-17 years and boys aged 16 17 years) to determine a representative prevalence of CT infection in adolescents in Germany and to assess associated risk factors. Prevalence of CT infection was 2.2% (95% CI: 1.4-3.5) in girls and 0.2% (95% CI: 0.1-0.7) in boys. CT infection in girls was associated with higher use of alcohol, marijuana and cigarettes, lower social status, oral contraceptive use, pregnancy, repeated lower abdominal pain and higher rates of doctors' consultations within the preceding three months and consultation of gynaecologists within the last 12 months. In multiple logistic regression, we identified two predictors for CT infection: marijuana consumption often or several times within the last 12 months (F(1,164)=7.56; p<0.05) and general health status less than 'very good' (F(1,164)=3.83; p=0.052). Given our findings, we recommend enhancing sex education before sexual debut and promoting safe sex practices regardless of the contraceptive method used. Well informed consumption of alcohol should be promoted, the risky behaviour of people intoxicated through consumption of marijuana highlighted and doctors' awareness of CT screening enhanced. PMID- 23987833 TI - Efficacy and safety of trabectedin as an early treatment for advanced or metastatic liposarcoma and leiomyosarcoma. AB - AIMS: We aimed to evaluate the effect of prior chemotherapies on the outcomes of patients with liposarcoma and leiomyosarcoma treated with trabectedin as a 24-h infusion every 3 weeks. PATIENTS & METHODS: Data from 129 patients who received trabectedin as second-line treatment following failure with an anthracycline/ifosfamide and those who had received at least two lines of prior chemotherapy were analyzed. RESULTS: Forty seven patients received one prior regimen (group A) and 82 patients received at least two lines of chemotherapy (group B). A favorable trend in median time to progression (4.4 vs 3.0 months), progression-free survival (4.4 vs 2.6 months) and overall survival (17.4 vs 13.3 months) was found in group A. A trend toward higher overall response rate (6.4 vs 4.9%) and disease control rate (34.0 vs 26.8%) also favored group A. Both groups had equivalent safety profiles. CONCLUSION: All efficacy outcomes were better in patients who received trabectedin as second-line treatment compared with patients with more extensive prior therapy. PMID- 23987834 TI - Interleukin-6 and activin A are independently associated with cardiovascular events and mortality in type 2 diabetes: the prospective Asker and Baerum Cardiovascular Diabetes (ABCD) cohort study. AB - BACKGROUND: Novel and robust cardiovascular (CV) markers are needed to improve CV morbidity and mortality risk prediction in type 2 diabetes (T2D). We assessed the long term predictive value of 4 novel CV risk markers for major CV events and mortality. METHODS: We included patients with T2D who had cytokines (interleukin [IL]-6 and activin A [actA]), a maximum stress ECG test (evaluated by the normalization pattern in early recovery phase) and echocardiography (evaluated by a measure of the left ventricular filling pressure - E/Em) assessed at baseline. The primary endpoint was time to first of any of the following events: myocardial infarction, stroke, hospitalization for unstable angina pectoris and death. All outcomes were adjudicated by independent experts. We used Cox proportional hazard modeling, Harrell C-statistic and the net reclassification improvement (NRI) to assess the additional value beyond conventional markers (age, gender, prior CV disease, HDL, creatinine, diastolic BP, microalbuminuria). RESULTS: At baseline the study cohort (n = 135, mean age/diabetes duration/HbA1c: 59 yrs/7 yrs/7.6% [59 mmol/mol], 26% females) had moderate elevated CV risk (42% microalbuminuria, mean Framingham 10 year CV-risk 9.6%). During 8.6 yrs/1153.7 person years, 26 patients experienced 36 events. All 4 novel risk markers were significantly associated with increased risk of the primary endpoint, however, only IL-6 and actA improved C-statistic and NRI (+0.119/43.2%, +0.065/20.3% respectively) compared with the conventional CV risk factors. CONCLUSIONS: IL-6 and actA may provide prognostic information on CV events and mortality in T2D beyond conventional CV risk factors. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00133718. PMID- 23987835 TI - Sometimes only the law will guarantee quality. PMID- 23987837 TI - Nurses could be struck off by NMC for failing to show compassion. PMID- 23987838 TI - Liverpool care pathway too prescriptive. PMID- 23987839 TI - Values-based recruitment and robust training cuts trust's HCA turnover. PMID- 23987840 TI - NHS in Wales to recruit 300 extra nurses. PMID- 23987841 TI - Experience should count as credit for degrees, concludes HCA review. PMID- 23987844 TI - Dementia audit highlights need for increased awareness training. PMID- 23987843 TI - Three-year review of staffing levels. PMID- 23987846 TI - Draft curriculum finds room for two nurse icons, but omits Nightingale. PMID- 23987847 TI - CBT delivered by nurses proves effective in reducing anxiety. PMID- 23987850 TI - World in brief. PMID- 23987848 TI - People taking 'easy option' could be behind surge in nursing applications. PMID- 23987852 TI - RCN helps to drive improvements at hospitals probed over death rates. PMID- 23987853 TI - RCN answers for the past and sets out lessons to learn from Mid Staffs. AB - Only time will tell whether the publication of Robert Francis QC's report into poor care at Mid Staffordshire NHS Foundation Trust was a defining moment in the history of the NHS. PMID- 23987854 TI - 'It's not a comfortable time to be a nurse,' says England's deputy CNO. AB - By the time Liz Redfern was announced as deputy to England's chief nursing officer Jane Cummings last month, she had already been working in the role unofficially for a couple of months. PMID- 23987860 TI - Listen to us before changing services. AB - The health service is in the midst of unprecedented change as services shift towards the community, hospital departments and beds are closed, and some specialist services are centralised in units serving a larger population. PMID- 23987861 TI - A place to say goodbye. AB - When Julia Shirtliffe became service manager at East Anglia's Children's Hospices ten years ago, virtually every neonatal death in the area occurred in hospital. PMID- 23987862 TI - 6Cs + principles = care. AB - Every nurse needs to be mindful of their personal contribution to the quality of care delivery. Crucially, this involves the everyday nursing interacations and activities that make up a patient's direct experience of care. PMID- 23987875 TI - Jane Bates is right: it is natural for nurses to meddle in health matters. PMID- 23987876 TI - Denying migrants access to the NHS will cause long-term harm. PMID- 23987877 TI - The government is shirking its humanitarian obligations. PMID- 23987878 TI - There is no such thing as a national health service. PMID- 23987879 TI - Paul Lloyd was ahead of his time as occupational health adviser. PMID- 23987882 TI - Vitamin D deficiency: identifying gaps in the evidence base. AB - Vitamin D deficiency is a global health problem. Vitamin D has attracted attention since evidence emerged that it may have functions beyond the control of serum calcium, for example immune system functioning and protection against damage to blood vessels. Gaps in the evidence base relating to vitamin D are also acknowledged. In this article, the production and functions of vitamin D are described, and the effects of vitamin D deficiency on pregnant women, infants, older people and other at-risk individuals are outlined. The management of vitamin D deficiency and the benefits of vitamin D supplementation are also identified. PMID- 23987883 TI - Common skin infections in children. AB - There are many common skin infections that may affect children at any time. Certain conditions may be recurrent, while others tend to result in the child developing immunity and do not recur. Skin infections may be bacterial, fungal or viral in origin, and the article outlines some of the most common of these and the management options available. PMID- 23987884 TI - Parenteral nutrition: indications, risks and nursing care. AB - Parenteral nutrition is a recognised method of feeding patients with specific clinical conditions, most notably those with various forms of intestinal failure who cannot be fed enterally. However, it has several associated risks including sepsis, and metabolic and electrolyte imbalances. The aim of this article is to enhance nurses' understanding of parenteral nutrition and how this differs from oral or enteral nutrition, indications for use and the potential risks involved. Appropriate vascular access is discussed as well as the clinical monitoring that is required to ensure complications of therapy are detected quickly. A greater understanding of the issues associated with parenteral nutrition allows nurses caring for patients receiving parenteral nutrition to ensure safe and effective care. PMID- 23987885 TI - Atrial fibrillation. AB - My first placement as a nursing student was on a cardio-thoracic surgical ward, where patients frequently present with atrial fibrillation (AF). The learning zone article has helped to improve my knowledge and understanding of AF, including symptoms, risk factors, diagnosis and treatment. PMID- 23987886 TI - Where's the evidence? AB - The main difference between the diploma and graduate-level undergraduate nurse training is the latter's emphasis on the application of research evidence in practice. PMID- 23987887 TI - Work passports offer ease of access. AB - European Union (EU) member countries are negotiating the final practical details for the introduction of an electronic professional card, with a decision expected to be adopted by the relevant European Commission committee this month. PMID- 23987890 TI - Student life - a productive get-together. AB - The University of Manchester is the national centre for peer-assisted study sessions (PASS), which were developed in 2009 to enable extra-curricular learning in an informal environment. PMID- 23987891 TI - Rapid diagnostics of tuberculosis and drug resistance in the industrialized world: clinical and public health benefits and barriers to implementation. AB - In this article, we give an overview of new technologies for the diagnosis of tuberculosis (TB) and drug resistance, consider their advantages over existing methodologies, broad issues of cost, cost-effectiveness and programmatic implementation, and their clinical as well as public health impact, focusing on the industrialized world. Molecular nucleic-acid amplification diagnostic systems have high specificity for TB diagnosis (and rifampicin resistance) but sensitivity for TB detection is more variable. Nevertheless, it is possible to diagnose TB and rifampicin resistance within a day and commercial automated systems make this possible with minimal training. Although studies are limited, these systems appear to be cost-effective. Most of these tools are of value clinically and for public health use. For example, whole genome sequencing of Mycobacterium tuberculosis offers a powerful new approach to the identification of drug resistance and to map transmission at a community and population level. PMID- 23987892 TI - Preoperative predictors of successful surgical treatment in the management of parapneumonic empyema. AB - BACKGROUND: Video-assisted thoracoscopic surgery (VATS) and thoracotomy are the main surgical options for treating parapneumonic empyema. The choice of either operation depends on many preoperative features, including the patient's condition, clinical and radiologic findings, and pleural fluid characteristics. The identification of the combination of those preoperative findings that will allow surgeons to select the appropriate approach for a successful operation (VATS or thoracotomy) could be of great interest in clinical settings. METHODS: We retrospectively reviewed a series of 97 patients who had undergone successful VATS or thoracotomy for parapneumonic empyema; in all cases, the operation had begun through VATS and was changed to a thoracotomy if a complete decortication was needed. Preoperative clinical, radiologic, and laboratory features were compared between the two groups to search for differences that might serve as predictive factors for either operation. Perioperative findings were also analyzed. RESULTS: The operation was accomplished by VATS in 40 patients (41%), and conversion to thoracotomy was necessary in 57 (59%). Significant predictive factors for conversion were a prolonged delay from diagnosis to operation, the presence of fever and of pleural thickness on computed tomography (CT) images. The 25 patients who presented with these three features were cured by thoracotomy. The operative time and postoperative complication rate were significantly higher for the thoracotomy patients. CONCLUSIONS: Some preoperative features can help the surgeon to better select patients for the appropriate operation. Delayed operation, fever, and pleural thickness can be used to predict the likelihood of conversion to thoracotomy. PMID- 23987893 TI - A novel approach to treat women patients with palmar hyperhidrosis: transumbilical thoracic sympathectomy with an ultrathin gastroscope. AB - BACKGROUND: Primary palmar hyperhidrosis is very common in women. Video-assisted thoracic sympathectomy is recognized as an effective treatment for patients with severe hyperhidrosis, which has usually been performed with more than 2 skin incisions. We developed a novel approach for thoracic sympathectomy in women with palmar hyperhidrosis through the umbilicus using an ultrathin gastroscope. The approach requires only 1 tiny incision, which is hidden in the umbilicus. METHODS: Under general anesthesia, patients were intubated with a dual-lumen endotracheal tube. Through the incision in the umbilicus, a newly developed long trocar was inserted into the abdominal cavity. After insertion of the ultrathin gastroscope through this trocar, a small incision was created on the both sides of diaphragm by a needle knife. The endoscope was introduced into the thoracic cavity through the incision made in the left or right diaphragm. The sympathetic chain was identified at the desired thoracic level and ablated. RESULTS: From January 10, 2010, to November 30, 2011, 25 women underwent transumbilical diaphragmatic thoracic sympathectomy. The mean operating room time for the entire bilateral procedure was 56.9 +/- 6.9 minutes. There were no significant postoperative complications. The symptoms disappeared in all patients. Compensatory sweating was reported in 56%. All of the patients were satisfied with the surgical results and the cosmetic outcome of the incision. CONCLUSIONS: Transumbilical thoracic sympathectomy with the ultrathin flexible endoscope was a safe and effective option for women with severe palmar hyperhidrosis that provided excellent cosmetic outcomes. PMID- 23987894 TI - Minimally invasive mitral valve surgery can be performed with optimal outcomes in the presence of left ventricular dysfunction. AB - BACKGROUND: Minimally invasive approaches to mitral valve repair have demonstrated equivalent technical outcomes and more rapid recovery when compared with traditional sternotomy. These techniques have been widely accepted for mitral insufficiency and stenosis. The utilization of minimally invasive techniques in the presence of left ventricular (LV) dysfunction has been controversial. We hypothesized that minimally invasive mitral valve surgery could be safely performed in the presence of compromised myocardial function, thereby minimizing recovery time. METHODS: All patients undergoing minimally invasive mitral valve surgery at our center from November 1998 through June 2012 were analyzed. During this time 1,103 patients underwent minimally invasive, port access, mitral valve surgery utilizing a video-assisted limited right thoracotomy approach. Patients with LV dysfunction (ejection fraction <= 0.40, n = 140) were compared with patients with normal ventricular function (n = 963). Preoperative, intraoperative, and postoperative variables were compared between cohorts. RESULTS: Patients with LV dysfunction were able to undergo mitral valve surgery with minimal mortality (2.1% vs 1.7%, p = 0.7) and morbidity, that was comparable with patients with normal ventricular function. Postoperative recovery was only slightly longer compared with patients with normal LV function as noted by time to extubation (6.0 vs 7.0 hours, p = 0.005) and hospital length of stay (7.0 vs 6.0 days, p < 0.001). A significant percentage of patients with LV dysfunction underwent redo cardiac surgery (40.0%) through minimally invasive approaches. CONCLUSIONS: Minimally invasive, port-access, mitral valve surgery can be safely performed with minimal morbidity and mortality in the presence of cardiomyopathy. This approach may be considered in patients with isolated mitral valve pathology and LV dysfunction in an experienced center. PMID- 23987895 TI - A comparison of length of stay, readmission rate, and facility reimbursement after lobectomy of the lung. AB - BACKGROUND: Readmission to the hospital has become a focus for payers with the threat of nonpayment for preventable readmissions and a global penalty for excessive readmissions rates. This study compares readmission rates with lengths of stay (LOS) for patients undergoing lobectomy of the lung and the potential impact on reimbursement. METHODS: The Premier database for a single health system's hospitals was used to identify patients undergoing lobectomy for non small cell lung cancer by cardiothoracic surgeons over a 5-year period. Charlson comorbidity scores were also calculated. Regression analysis was used to study the relationship between length of stay and readmission rates. A comparison of the effects of LOS and readmission on reimbursement was also performed. RESULTS: During the study period, 4,296 lobectomies were performed in 61 hospitals within the healthcare system that met the study's inclusion criteria. A readmission was recorded for 289 patients (7%). Factors associated with readmission were length of stay less than 5 days or more than 16 days and age more than 78 years (p = 0.001). An analysis of the effects of LOS and readmission on reimbursement found an extension of LOS was more cost effective than a readmission. CONCLUSIONS: This review found that mean LOS after lobectomy is negatively associated with readmission rates, with the maximal effect being before postoperative day 5. Furthermore, facility reimbursement was optimized when LOS was extended to minimize the risk of readmission. PMID- 23987896 TI - Comparative effects of ventricular assist device and extracorporeal membrane oxygenation on renal function in pediatric heart failure. AB - BACKGROUND: Effects of mechanical cardiac support on renal function in children with end-stage heart failure are unknown. The objective of this study was to investigate the impact of ventricular assist device (VAD) and extracorporeal membrane oxygenation (ECMO) on renal function in children. METHODS: We performed a single center retrospective observational study in children with end-stage heart failure supported on pediatric mechanical cardiac support. The patient population was divided into three groups: the VAD group included patients receiving ventricular assist device support; the ECMO group included patients receiving extracorporeal membrane oxygenation membrane support for more than 14 days; and the ECMO+VAD group included patients receiving ECMO followed by VAD support. Comparison of baseline characteristics, duration of mechanical cardiac support, and renal function was made between the three groups. RESULTS: During the study period, there were 23 patients in the VAD group, 16 patients in the ECMO+VAD group, and 37 patients in the ECMO group. The patients in the ECMO group were significantly younger and smaller than the patients in the VAD and ECMO+VAD groups. There was a steady improvement in eGFR in the VAD group and the ECMO+VAD group until day 7 after which there was a decline in renal function. In the ECMO group, the improvement in eGFR continued until day 28 after which there was a steady decline in eGFR. Improvement in eGFR in the VAD group and the ECMO+VAD group was much higher than in the ECMO group in the first 7 days. CONCLUSIONS: On the basis of these data, we demonstrate that renal dysfunction improves early after mechanical cardiac support. PMID- 23987897 TI - The model for end-stage liver disease (MELD) predicts early and late outcomes of cardiovascular operations in patients with liver cirrhosis. AB - BACKGROUND: We aimed to evaluate the severity of cirrhosis as a predictor of early and late outcomes after cardiovascular operations. METHODS: We retrospectively reviewed patients who underwent cardiovascular operations in our institute between October 1999 and April 2009. The severity of liver cirrhosis was assessed using the Child-Pugh classification and the Model for End-stage Liver Disease (MELD) score. RESULTS: Liver cirrhosis was identified in 32 consecutive patients. Averages of Child-Pugh and MELD scores were 7.2 +/- 1.9 and 11.5 +/- 5.1, respectively: 14 patients were classified as Child-Pugh class A, 14 as class B, and 4 as class C. The MELD score was less than 10 (category 1) in 10 patients, between 10 and 14.9 (category 2) in 14, and 15 or higher (category 3) in 8. The hospital mortality rate was 16% (5 of 32). Hospital mortality increased significantly as the MELD score category increased: category 1, 0%; category 2, 7%; and category 3, 50% (p = 0.005). There was no significant association between hospital mortality and Child-Pugh classification: class A, 7%; class B, 21%; and class C, 0% (p = 0.60). Overall survival was 72% +/- 8% at 5 years and 47% +/- 13% at 10 years. The survival rate decreased significantly as the MELD score category increased (p = 0.004). No relationship was found between the Child-Pugh classification and long-term survival. CONCLUSIONS: Our results suggest that the MELD score is useful to predict hospital death and long-term survival after cardiac operations for patients with liver cirrhosis. PMID- 23987898 TI - Adenocarcinoma of the esophagus with signet ring cell features portends a poor prognosis. AB - BACKGROUND: Adenocarcinoma with signet ring cell (SRC) features has been reported to be a poor prognostic marker in gastric and colorectal carcinomas. Although uncommon in the esophagus, SRC histology, interestingly, has been correlated with improved survival. Our impression has been that the incidence of esophageal adenocarcinomas with SRC features is increasing and is associated with worse outcomes. We hypothesize that patients with SRC histology present with more advanced disease, respond less well to induction therapy, and have decreased survival after resection compared with patients with non-SRC adenocarcinoma. METHODS: The medical records of 151 consecutive patients who underwent resection for adenocarcinoma of the esophagus or gastroesophageal junction in a prospectively maintained database from 1998 to 2011 were reviewed. Outcomes of 23 patients (15%) with SRC histology (21 men, 2 women; average age, 66 years) were compared with 128 patients (85%) with non-SRC adenocarcinoma (116 men, 12 women; average age, 63 years). Overall survival, stage-specific survival, and response to induction therapy were evaluated. Cox regression multivariate analysis was used to identify independent predictors of 3-year survival. RESULTS: SRC and non SRC patients were evenly matched for clinical and tumor characteristics. Downstaging achieved with induction therapy was 13.3% (2 of 15) in SRC histology patients vs 67.1% (53 of 79) in non-SRC patients (p <= 0.001). Patients with SRC histology who did not respond well to induction treatment demonstrated strong trends toward a worse 3-year survival than patients with non-SRC adenocarcinoma (p = 0.084). The overall 3-year survival was 65.6% in patients without SRC histology vs 34.8% in those with SRC (p = 0.006). Patients with pathologic stage II or III and SRC histology had a 3-year survival of 27.3% compared with 57.4% in patients with non-SRC adenocarcinoma (p = 0.01). Multivariate analysis showed SRC histology trended toward significance as an independent risk factor for poor survival (p = 0.060). CONCLUSIONS: Patients with adenocarcinoma of the esophagus or gastroesophageal junction and SRC histology respond less well to induction therapy and have decreased overall survival compared with patients with non-SRC histology. PMID- 23987899 TI - Heart transplantation for the failing Fontan. AB - BACKGROUND: Patients with failing Fontan circulation are at high risk for complications after heart transplantation (HTx) because of multiple prior operations, elevated panel reactive antibody, hepatic dysfunction, coagulopathy, protein-losing enteropathy (PLE), and poor nutrition. The purpose of this review was to evaluate the outcome of HTx for these patients, including those who are status post-Fontan conversion. METHODS: Of 206 heart transplants at Ann & Robert H. Lurie Children's Hospital of Chicago from 1990 to 2012, 22 patients had a failing Fontan. Median age at HTx was 12.2 years, median interval from initial Fontan to HTx was 7.1 years. Potential preoperative risk factors included PLE (n = 15), mechanical ventilation (n = 8), prior Fontan conversion (n = 7), renal failure (n = 3), and plastic bronchitis (n = 2) Median number of prior operations was 3. Donor branch pulmonary arteries were used in 17 patients. RESULTS: There were 5 early deaths (23%), due to graft failure (1), pulmonary hypertension (1), and infection (3). There were 3 late deaths (13%) at 1, 5, and 8 years. Two of 3 patients with preoperative renal failure died. Survivors who had preoperative PLE (n = 11) and preoperative plastic bronchitis (n = 2) experienced complete resolution of these pathological conditions after heart transplantation. Median length of stay was 30 days. Five of 7 Fontan conversion patients survived, and 6 of 8 preoperative ventilator-dependent patients survived. One-, 5-, and 10-year survival was 77%, 66%, and 45%, respectively. CONCLUSIONS: The operative mortality of HTx for patients with a failing Fontan is high. Using the donor branch pulmonary arteries greatly facilitated the transplant. Because infection caused the majority of early deaths, lower intensity initial immunosuppression may be warranted. Transplantation was successful in treating PLE in all survivors. Prior Fontan conversion was not a risk factor. Preoperative mechanical ventilation was not a risk factor. Preoperative renal failure may be a relative contraindication. Earlier referral of failing Fontan patients may improve results. PMID- 23987900 TI - Chest tube tip culture as a predictor of postoperative infection in lung cancer operations. AB - BACKGROUND: Postoperative infection is one of the most frequently observed complications after lung resection and should be addressed in perioperative management. This study evaluated the clinical significance of chest tube tip culture relevant to postoperative infection. METHODS: From September 2002 to December 2011, 1,438 patients who underwent lung cancer operations in Shizuoka Cancer Center Hospital were evaluated. Postoperative infections, including surgical site infection, postoperative pneumonia, and postoperative empyema without fistula, were defined as those occurring within 30 days of thoracotomy. RESULTS: Postoperative infections developed in 84 of the 1,438 patients (5.8%), including 42 (2.9%) with surgical site infection, 36 (2.5%) with pneumonia, and 13 (0.9%) with empyema. The sensitivity, specificity, and positive predictive value of chest tube tip culture were 23%, 98%, and 41.3%, respectively. Multivariate analysis demonstrated that the independent risk factors associated with the development of postoperative infections were coexisting diabetes mellitus and positive chest tube tip culture. Positive chest tube tip culture was the only independent risk factor associated with surgical site infection. The independent risk factors associated with postoperative pneumonia were age 70 years or older, coexisting diabetes mellitus, and positive chest tube tip culture. Finally, positive chest tube tip culture was the only independent risk factor associated with postoperative empyema. CONCLUSIONS: Positive chest tube tip culture strongly predicts postoperative infections in lung cancer surgery and necessitates careful observation in the perioperative period. PMID- 23987901 TI - Robotic totally endoscopic coronary artery bypass grafting in men and women: are there sex differences in outcome? AB - BACKGROUND: According to several studies, women are at higher risk for mortality and experience less relief of angina after coronary artery bypass graft surgery (CABG) than men. Sex-related differences in patients undergoing totally endoscopic coronary bypass grafting (TECABG) have not been investigated thus far. The aim of the present study was to evaluate the impact of sex on the outcome of patients undergoing TECABG. METHODS: The data of 500 consecutive patients (364 male, 136 female) undergoing TECABG using the da Vinci telemanipulation system (Intuitive Surgical, Sunnyvale, CA) from 2001 to 2011 at two institutions were investigated regarding sex-related differences in short-term and long-term outcome. RESULTS: In all, 334 single, 150 double, 15 triple, and 1 quadruple TECABG procedures were carried out. Female patients were significantly older (63 years [range, 26 to 90] versus 59 years [range, 31 to 85], p = 0.001) and had higher European System for Cardiac Operative Risk Evaluation score levels (3 [range, 0 to 11] versus 2 [range, 0 to 13], p < 0.001). Male patients received slightly more grafts (1 [range, 1 to 4] versus 1 [range, 1 to 3], p = 0.028), female patients were more likely to undergo beating heart surgery (20% versus 28%, p = 0.042). In-hospital mortality was 3 of 364 men (0.8%) and 2 of 136 women (1.5%; p = 0.513). Comparison of long-term-survival revealed 1-, 3- and 5-year survival rates of 96%, 96%, and 95% in men and 96%, 96%, and 96% in women, respectively, without any significant difference. Analysis of freedom from major adverse cardiac and cerebrovascular events revealed 1-, 3-, and 5-year rates of 86%, 84%, and 82% in men and 85%, 81%, and 81% in women, respectively, without any significant difference. CONCLUSIONS: Our data show that women undergoing TECABG have outcomes similar to those of men. PMID- 23987902 TI - pT2 Adenocarcinoma of the esophagus: early or advanced cancer? AB - BACKGROUND: There is an increasing trend to include patients with esophageal carcinoma invading the muscularis propria (pT2) in neoadjuvant therapy regimens. But it is unclear which patients have prognostic benefit from this strategy. The aim of this study was to assess the prognosis and prognostic factors in patients with pT2 esophageal adenocarcinoma to further optimize treatment strategies. METHODS: Included were patients with pT2 esophageal adenocarcinoma treated operatively at three centers specializing in upper gastrointestinal surgery. There were 159 patients (139 male) without induction therapy; median age was 64.5 years. Survival was analyzed by univariate and multivariate analysis. RESULTS: In 37% of patients (n = 59), no lymph node involvement (pN0) was detected. Overall 5 year survival rate for all patients was 37%; for pN0 patients it was 62%, and for patients with lymph node metastases (pN+) it was 24%. Median number of examined lymph nodes was 26. Extracapsular lymph node involvement (ELNI) was evident in 55 of 100 pN+ patients with a 5-year survival rate of 14%. Patients without ELNI had a 5-year survival rate of 36% (p = 0.041). Results were comparable in all participating hospitals. Thirty-day and 90-day mortality rates of the entire collective were 2.6% and 3.8%, respectively. Multivariate analysis of prognosis revealed the lymph node ratio (p < 0.001) and the pN-ELNI category (p = 0.005) as significant parameters (pN0 hazard ratio 1 [reference]; pN+ without ELNI hazard ratio 2.2, 95% confidence interval: 1.2 to 3.8); pN+ with ELNI hazard ratio 2.5, 95% confidence interval: 1.5 to 4.5). CONCLUSIONS: The prognosis of patients with esophageal adenocarcinoma invading the muscularis propria without lymph node metastasis is very good. However, in this study, about 30% had extracapsular lymph node involvement, which reflects particularly aggressive biological tumor behavior. PMID- 23987903 TI - The short-term outcome of three-field minimally invasive esophagectomy for Siewert type I esophagogastric junctional adenocarcinoma. AB - BACKGROUND: The incidence of esophagogastric junctional adenocarcinoma is increasing, and the surgery is associated with high mortality and morbidity rates. This study aims to evaluate whether three-field minimally invasive surgery promotes outcome as compared with three-incision open surgery. METHODS: From January 1, 2009, to March 1, 2012, 114 consecutive patients with Siewert type I esophagogastric junctional adenocarcinoma were involved in this retrospective study. Patients were randomly assigned by a computer-generated randomization sequence to receive either three-incision open esophagectomy or minimally invasive esophagectomy. Details concerning patients and tumor characteristics, surgical procedures, and postoperative outcomes were collected and compared. RESULTS: Totally, 59 patients were involved in the open esophagectomy group and 55 in the minimally invasive esophagectomy group. The incidence of pulmonary morbidity (9.09% versus 28.81%) and vocal cord paralysis (0% versus 15.25%) in the minimally invasive group was significantly less than that in the open esophagectomy group. Furthermore, the postoperative life quality in the minimally invasive group was better than that in the open group. Survival at 2 years was 83.6% for the minimally invasive group (46 of 55 patients) and 79.7% for the open esophagectomy group (47 of 59 patients). CONCLUSIONS: Minimally invasive esophagectomy could lead to a significant improvement of the short-term benefits for patients with Siewert type I esophagogastric junctional adenocarcinoma. PMID- 23987904 TI - Severe thrombocytopenia and its clinical impact after implant of the stentless Freedom Solo bioprosthesis. AB - BACKGROUND: This single-center study analyzed the occurrence of severe thrombocytopenia and its clinical effect after concomitant and isolated aortic valve replacement (AVR) with the stentless Freedom Solo (FS) prosthetic valve (Sorin Group, Saluggia, Italy). METHODS: Between October 2009 and February 2012, 151 consecutive patients underwent AVR with a FS, either isolated (lone-FS group) or concomitant with another procedure (all-FS group). These groups were compared with 152 consecutive patients implanted with a stented Edwards Lifesciences Perimount (EP) bioprosthesis (Edwards Lifesciences, Irvine, CA). Primary end point was the incidence of severe thrombocytopenia (platelet count < 50 * 10(9)/L). Secondary end points were clinical outcomes, administered transfusions (red blood cells, thrombocytes, frozen plasma), and adverse events. Rinsing the FS before implantation with saline solution was also evaluated. RESULTS: Platelet counts were significantly lower in the all-FS and lone-FS groups than in the EP group during the first 5 days (p < 0.001). Average nadir was 102 +/- 50 in lone FS group and 130 +/- 35 in lone-EP group (p < 0.001). Independent predictors for severe thrombocytopenia were FS, body surface area, and preoperative platelet count. No significant difference was found in transfusions or adverse events. Intensive care unit stay was slightly increased in the lone-FS group (p = 0.04). Rinsing the FS did not prevent thrombocytopenia. CONCLUSIONS: AVR with FS was associated with severe thrombocytopenia during the first postoperative days. Besides a slightly longer hospitalization in the intensive care unit in the FS group, the clinical outcome did not differ significantly, indicating thrombocytopenia was a transient and self-recovering phenomenon, not affecting clinical outcome. Rinsing the FS did not prevent thrombocytopenia. PMID- 23987905 TI - Midterm results of different surgical techniques to replace dilated ascending aorta associated with bicuspid aortic valve disease. AB - BACKGROUND: This study evaluated effectiveness of three different surgical strategies for treating ascending aorta aneurysm, with or without involvement of the aortic root, associated with bicuspid aortic valve (BAV). METHODS: Between 2005 and 2011, 150 consecutive patients underwent a Bentall operation in the presence of ascending aorta and aortic root dilation exceeding 45 mm in diameter and malfunctioning BAV (n = 46, group 1); separate aortic valve and ascending aorta replacement in presence of ascending aorta dilation exceeding 45 mm, aortic root of less than 45 mm, and malfunctioning BAV (n = 77, group 2); or ascending aorta replacement, with or without BAV repair, in the presence of ascending aorta dilation exceeding 45 mm, aortic root of less than 45 mm, and normally functioning or mildly insufficient BAV (n = 27, group 3). RESULTS: Compared with groups 2 and 3, group 1 patients were younger and affected by more severe BAV insufficiency and worse left ventricular function. In groups 1, 2, and 3, respectively, operative mortality was 2.1%, 1.3%, and 0%, and 5-year survival was 94% +/- 4%, 92% +/- 3.4%, and 100%. At 5 years, no patient in any group required reoperation on the ascending aorta or experienced aortic complications. In groups 2 and 3, root dimensions did not increase and were also significantly smaller compared with preoperative measurements (p < 0.05). Aortic regurgitation grade in group 3 (0.5 +/- 0.8/4+) did not increase compared with the preoperative grade (0.8 +/- 0.9/4+). CONCLUSIONS: At midterm follow-up, the Bentall operation remains associated with optimal results for the treatment of BAV, despite a worse preoperative presentation. In presence of a mildly diseased or normal aortic root and normal BAV function at the time of operation, less invasive surgical procedures, BAV-sparing, or repair procedures, appear to offer gratifying results. PMID- 23987907 TI - Descending necrotizing mediastinitis associated with Lactobacillus plantarum. AB - BACKGROUND: Descending necrotizing mediastinitis (DNM), a severe infection with a high fatality rate, develops in mediastinal spaces due mainly to deep cervical abscesses. The majority of causative microbes of DNM are Streptococci and oral anaerobes. DNM associated with Lactobacillus-infection is rather rare. CASE PRESENTATION: A 69-year-old male with an unremarkable past medical history was referred to our hospital for surgical resection of advanced laryngeal cancer. Full examination revealed a neck abscess and DNM with a background of untreated diabetes mellitus. Initially, he was treated with meropenem. However, Lactobacillus plantarum was isolated from surgical drainage of a mediastinal abscess. Despite using antibiotics capable of eradicating all isolates with susceptibilities not differing significantly from those of the neck and mediastinal abscesses, we attributed DNM to the L. plantarum detected only in the mediastinal abscess. After DNM treatment, he underwent total pharyngolaryngectomy with bilateral neck dissection followed by reconstruction using free jejunum. He was discharged fully recovered. CONCLUSION: We concluded that L. plantarum as the sole cause of the mediastinal abscess in the present case cannot be ruled out. As the number of immunocompromised patients increases, we should be cautious regarding this "familiar" microbe. PMID- 23987908 TI - Computational modelling of hydrocephalus. PMID- 23987909 TI - Physical activity, sedentary behaviours and dietary habits among Kuwaiti adolescents: gender differences. AB - OBJECTIVE: The present study was designed to assess physical activity, sedentary behaviours and dietary habits among adolescents in Kuwait and to compare the differences between genders. DESIGN: A cross-sectional study was conducted among secondary-school children who participated in the Arab Teens Lifestyle Study (ATLS), a multi-centre collaborative project. SETTING: Secondary schools in Kuwait. SUBJECTS: Adolescents (463 boys and 443 girls), aged 14-19 years. RESULTS: Nearly half (44.6 %) of the boys and three-quarters (76.0 %) of the girls did not meet the recommended daily physical activity levels (>=2520 MET min/week, moderate to vigorous intensity). Nearly all (96.3 % of boys and 96.7 % of girls) adolescents reported spending >2 h/d on screen time, with girls found to spend more time per day watching television (P = 0.02) and using a computer (P < 0.001). The large majority of the adolescents reported skipping breakfast and not having milk and milk products, vegetables and fruit daily, while nearly two thirds of the boys and girls had sugar-sweetened drinks on more than 3 d/week. Compared with girls, boys reported consuming more fruit (3.4 v. 2.8 times/week, P = 0.001), dairy products (4.5 v. 3.6 times/week, P = 0.001) and energy drinks (1.3 v. 1.1 times/week, P = 0.003). CONCLUSIONS: The majority of the Kuwaiti adolescents, especially girls, do not perform adequate physical activity, spend more time on sedentary activities and have unhealthy dietary practices. The findings emphasize an urgent need for implementing an appropriate intervention for promoting physical activity, healthy eating and reducing sedentary behaviours among these children. PMID- 23987910 TI - Leveraging crystal anisotropy for deterministic growth of InAs quantum dots with narrow optical linewidths. AB - Crystal growth anisotropy in molecular beam epitaxy usually prevents deterministic nucleation of individual quantum dots when a thick GaAs buffer is grown over a nanopatterned substrate. Here, we demonstrate how this anisotropy can actually be used to mold nucleation sites for single dots on a much thicker buffer than has been achieved by conventional techniques. This approach greatly suppresses the problem of defect-induced line broadening for single quantum dots in a charge-tunable device, giving state-of-the-art optical linewidths for a system widely studied as a spin qubit for quantum information. PMID- 23987911 TI - Acoustic vibrations of Au nano-bipyramids and their modification under Ag deposition: a perspective for the development of nanobalances. AB - We investigated the acoustic vibrations of gold nanobipyramids and bimetallic gold-silver core-shell bipyramids, synthesized by wet chemistry techniques, using a high-sensitivity pump-probe femtosecond setup. Three modes were observed and characterized in the gold core particles for lengths varying from 49 to 170 nm and diameters varying from 20 to 40 nm. The two strongest modes have been associated with the fundamental extensional and its first harmonic, and a weak mode has been associated with the fundamental radial mode, in very good agreement with numerical simulations. We then derived linear laws linking the periods to the dimensions both experimentally and numerically. To go further, we investigated the evolution of these modes under silver deposition on gold core bipyramids. We studied the evolution of the periods of the extensional modes, which were found to be in good qualitative agreement with numerical simulations. Moreover, we observed a strong enhancement of the radial mode amplitude when silver is deposited: we are typically sensitive to the deposition of 40 attograms of silver per gold core particle. This opens up possible applications in the field of mass sensing, where metallic nanobalances have an important role to play, taking advantage of their robustness and versatility. PMID- 23987912 TI - Ocean acidification in the coastal zone from an organism's perspective: multiple system parameters, frequency domains, and habitats. AB - Multiple natural and anthropogenic processes alter the carbonate chemistry of the coastal zone in ways that either exacerbate or mitigate ocean acidification effects. Freshwater inputs and multiple acid-base reactions change carbonate chemistry conditions, sometimes synergistically. The shallow nature of these systems results in strong benthic-pelagic coupling, and marine invertebrates at different life history stages rely on both benthic and pelagic habitats. Carbonate chemistry in coastal systems can be highly variable, responding to processes with temporal modes ranging from seconds to centuries. Identifying scales of variability relevant to levels of biological organization requires a fuller characterization of both the frequency and magnitude domains of processes contributing to or reducing acidification in pelagic and benthic habitats. We review the processes that contribute to coastal acidification with attention to timescales of variability and habitats relevant to marine bivalves. PMID- 23987913 TI - Antagonistic coevolution of marine planktonic viruses and their hosts. AB - The potential for antagonistic coevolution between marine viruses and their (primarily bacterial) hosts is well documented, but our understanding of the consequences of this rapid evolution is in its infancy. Acquisition of resistance against co-occurring viruses and the subsequent evolution of virus host range in response have implications for bacterial mortality rates as well as for community composition and diversity. Drawing on examples from a range of environments, we consider the potential dynamics, underlying genetic mechanisms and fitness costs, and ecological impacts of virus-host coevolution in marine waters. Given that much of our knowledge is derived from laboratory experiments, we also discuss potential challenges and approaches in scaling up to diverse, complex networks of virus-host interactions. Finally, we note that a variety of novel approaches for characterizing virus-host interactions offer new hope for a mechanistic understanding of antagonistic coevolution in marine plankton. PMID- 23987914 TI - The oceanography and ecology of the Ross Sea. AB - The continental shelf of the Ross Sea exhibits substantial variations in physical forcing, ice cover, and biological processes on a variety of time and space scales. Its circulation is characterized by advective inputs from the east and exchanges with off-shelf regions via the troughs along the northern portions. Phytoplankton biomass is greater there than anywhere else in the Antarctic, although nitrate is rarely reduced to levels below 10 MUmol L(-1). Overall growth is regulated by irradiance (via ice at the surface and by the depths of the mixed layers) and iron concentrations. Apex predators reach exceptional abundances, and the world's largest colonies of Adelie and emperor penguins are found there. Krill are represented by two species (Euphausia superba near the shelf break and Euphausia crystallorophias throughout the continental shelf region). Equally important and poorly known is the Antarctic silverfish (Pleuragramma antarcticum), which is also consumed by most upper-trophic-level predators. Future changes in the Ross Sea environment will have profound and unpredictable effects on the food web. PMID- 23987915 TI - Hide and seek in the open sea: pelagic camouflage and visual countermeasures. AB - Camouflage is exceptionally challenging in pelagic environments because of their featureless nature. Thus, it is perhaps no surprise that pelagic species have evolved highly sophisticated cryptic strategies, three of which-transparency, mirrors, and counter illumination-are rare or absent in other habitats. Pelagic visual systems are equally complex, and several visual capabilities, including UV and polarization sensitivity and intraocular filters, are thought to facilitate detection of camouflaged animals. This article reviews the optical nature of the pelagic realm and both the camouflage and camouflage-breaking strategies of its inhabitants, focusing primarily on underlying principles and what remains to be discovered. A theme throughout is that far more is known about the structures of the optical and visual systems involved than about their function, an imbalance that is due primarily to the rarity of observations of undisturbed behavior. PMID- 23987916 TI - Benthic exchange and biogeochemical cycling in permeable sediments. AB - The sandy sediments that blanket the inner shelf are situated in a zone where nutrient input from land and strong mixing produce maximum primary production and tight coupling between water column and sedimentary processes. The high permeability of the shelf sands renders them susceptible to pressure gradients generated by hydrodynamic and biological forces that modulate spatial and temporal patterns of water circulation through these sediments. The resulting dynamic three-dimensional patterns of particle and solute distribution generate a broad spectrum of biogeochemical reaction zones that facilitate effective decomposition of the pelagic and benthic primary production products. The intricate coupling between the water column and sediment makes it challenging to quantify the production and decomposition processes and the resultant fluxes in permeable shelf sands. Recent technical developments have led to insights into the high biogeochemical and biological activity of these permeable sediments and their role in the global cycles of matter. PMID- 23987917 TI - Hematologic and bone marrow changes in children with protein-energy malnutrition. AB - BACKGROUND: All systems in an organism are affected by protein-energy malnutrition (PEM), but one of the worst affected is the hematopoietic system. Today PEM remains a very serious problem in developing countries. We examined the relationships between clinical features, hematological, and bone marrow changes with severe PEM from Turkey. METHOD: We evaluated 34 (11 females and 23 males) consecutive cases of severe PEM, with no underlying diseases aged 3-20 months. The clinical nutritional conditions of the patients were determined using the Wellcome-Trust PEM classification. Ten of the patients were in the Marasmic Kwashiorkor (M-K) group, 10 were in the Kwashiorkor (KW) group, and 14 were in the Marasmic (M) group. Full blood count, protein, albumin, serum iron (SI), iron binding capacity (TIBC), ferritin, vitamin B12, folic acid, complement-3 (C3), complement-4 (C4), and bone marrow were investigated in all groups. RESULTS: Anemia was detected in 97% of patients. We determined serum iron levels were low in 67.6% of the patients, TS levels were low in 76.4% of the patients and ferritin levels were low in 20.5%. The level of vitamin B12 was normal in all patients. Bone marrow analysis showed erythroid series hypoplasia in 28.5% of patients in the M group, 50% in the KW group, and 30% in the M-K group. Marrow iron was absent in 58.8% of patients. CONCLUSION: The most common hematologic change in the children with PEM was anemia and major cause of anemia was iron deficiency in this study. Patients with severe PEM have normal Vit B12 and serum folate levels. Most of the patients with severe PEM had normal cellularity with megaloblastic and dysplastic changes in bone marrow due to the inadequate and imbalanced intake of protein and energy. PMID- 23987918 TI - Prevalence of schistosome antibodies with hepatosplenic signs and symptoms among patients from Kaoma, Western Province, Zambia. AB - BACKGROUND: Schistosomiasis is a major cause of morbidity and mortality, with over 200 million people infected worldwide. Eighty-five percent of cases are in Africa. The hepatosplenic form develops over time by an immune reaction to trapped Schistosoma mansoni eggs in the portal system leading to liver fibrosis, portal hypertension and oesophageal varices. Most patients presenting to the University Teaching Hospital in Lusaka with oesophageal varices, come from Western province, but no formal studies have been carried out in this area assessing the burden of hepatosplenic pathology. We aimed to define the extent of the problem in Kaoma district, western Zambia, and to correlate signs and symptoms with serology. FINDINGS: A symptom questionnaire, demographic survey and physical examination was conducted amongst patients presenting to Kaoma district outpatient clinics. To assess the prevalence of Schistosoma mansoni infections, blood was collected and screened for the presence of Schistosoma antibodies using Enzyme linked immunosorbent assay (ELISA). Of the 110 patients screened, 97 (88%) were ELISA positive. Forty-six percent (51/110) reported haematochezia and 7% experienced haematemesis (8/110). On physical examination 27% (30/110) hepatomegaly and 17% (30/110) splenomegaly was observed amongst participants but there were few correlations between serology and signs/symptoms. On questioning 68% (75/110) of participants knew nothing about schistosomiasis transmission. CONCLUSIONS: Our serological and clinical data indicate a very heavy burden of schistosomiasis-related portal hypertension. Our evidence highlights a need for mass treatment in Kaoma to address and prevent extensive pathology of hepatosplenic schistosomiasis. Safe water and health education throughout Western Province are clearly also important. PMID- 23987919 TI - An examination of adverse asthma outcomes in U.S. Adults with multiple morbidities. AB - RATIONALE: More Americans are managing multiple chronic conditions. Little is known regarding combinations of multiple chronic conditions with asthma. OBJECTIVES: To examine the prevalence and demographic distribution of five common chronic conditions (arthritis, heart disease, cancer, diabetes, and hypertension) in adults with and without asthma and the adverse asthma outcomes associated with multiple chronic conditions. METHODS: Cross-sectional interview data from the National Health and Nutrition Examination Survey were analyzed (n = 22,172) between 2003 and 2010. Bivariate analysis methods and multivariate generalized linear regression were used to examine associations. MEASUREMENTS AND MAIN RESULTS: Of the 10% of subjects with asthma, 54% had one or more coexisting health condition(s). The prevalence of two or three or more other chronic conditions was greater among those with asthma compared with those without (P < 0.001). Common comorbidities with asthma were hypertension (34%) and arthritis (31%). For every additional comorbid chronic condition, there was an increase in the prevalence of reported asthma symptom episodes (prevalence ratio [PR], 1.06; 95% confidence interval [CI], 1.00-1.13), frequent activity limitation (PR, 1.14; 95% CI, 1.04-1.25), sleep disturbances (PR, 1.22; 95% CI, 1.04-1.43), and emergency department visit for asthma (PR, 1.45; 95% CI, 1.19-1.76) when adjusted for socioeconomic and demographic factors and body mass index. The population attributable risk for emergency department visits for asthma among individuals with asthma who have other chronic comorbidities was 19.5%. CONCLUSIONS: Half of the adult population with asthma in the United States suffers from comorbid conditions, which are associated with adverse asthma-related outcomes and account for up to 20% of emergency room visits for asthma. PMID- 23987920 TI - Sparing functional anatomical structures during intensity-modulated radiotherapy: an old problem, a new solution. AB - During intensity-modulated radiotherapy, an organ is usually assumed to be functionally homogeneous and, generally, its anatomical and spatial heterogeneity with respect to radiation response are not taken into consideration. However, advances in imaging and radiation techniques as well as an improved understanding of the radiobiological response of organs have raised the possibility of sparing the critical functional structures within various organs at risk during intensity modulated radiotherapy. Here, we discuss these structures, which include the critical brain structure, or neural nuclei, and the nerve fiber tracts in the CNS, head and neck structures related to radiation-induced salivary and swallowing dysfunction, and functional structures in the heart and lung. We suggest that these structures can be used as potential surrogate organs at risk in order to minimize their radiation dose and/or irradiated volume without compromising the dose coverage of the target volume during radiation treatment. PMID- 23987921 TI - First report of a phylogenetic analysis of an autochthonous Plasmodium vivax strain isolated from a malaria case in East Attica, Greece. AB - Malaria has become an emerging infection in Greece, which is the doorstep to Europe for thousands of immigrants. With increasing immigration, cases with evidence of domestic transmission (autochthonous) are being reported. In the present study, an isolate of Plasmodium vivax from an autochthonous clinical case was subjected to phylogenetic analysis of the genes encoding the merozoite surface protein 1 (MSP-1) and the circumsporozoite protein (CSP). In the MSP region, the strain was related with strains from Brazil, South Korea, Turkey and Thailand, whereas in the CSP region, with strains from Brazil, Colombia and New Guinea. The present study establishes for the first time in Greece the basis for the creation of a database comprising genotypic and phylogenetic characteristics of Plasmodium spp. PMID- 23987922 TI - Systematic review of clinical practice guidelines in the diagnosis and management of thyroid nodules and cancer. AB - BACKGROUND: Given the uncertainties regarding thyroid nodule assessment and management, physicians require systematically and transparently developed recommendations. This systematic review assesses the quality and consistency of the recommendations of international clinical practice guidelines (CPGs) for the diagnosis and management of thyroid nodules and cancer to assist physicians in making appropriate recommendations. METHODS: The CPGs on the management of thyroid nodules and cancer published before June 2013 were retrieved. All the reviewed guidelines were in English. Four reviewers independently assessed the rigor of guideline development by using the Appraisal of Guidelines Research and Evaluation II (AGREE-II) instrument, and their reported evidence was evaluated. RESULTS: Ten eligible guidelines were included: nine had been developed by professional organizations, and the remaining guideline was endorsed by an independent regional body. Three guidelines achieved a score of greater than 50% in all six AGREE-II domains. Guidelines scored highest on the measurement of 'scope and purpose' (>=61.1% for eight CPGs) and lowest on the measurement of 'applicability' (<=38.5% for five CPGs). The overall quality ranged from 3.0 to 6.25 on a seven-point scale on the AGREE-II tool. Most CPG recommendations on the management of thyroid cancer were relatively consistent. Guidelines varied regarding the indication of fine-needle aspiration for thyroid nodules, as well as in their suggestions for postoperative radioiodine ablation. CONCLUSIONS: Our analysis showed that the current CPGs varied in methodological quality. More effort is needed to improve the quality of recommendations on the diagnosis and management of thyroid nodules and cancer. PMID- 23987923 TI - Nursing students' fresh outlook could save NHS. AB - Sir Bruce Keogh has rightly been praised for his review of 14 troubled NHS trusts. His concise report contained 48 pages of sage advice on how managers can turn around their organisations, and how others can avoid getting into difficulties in the first place. PMID- 23987924 TI - Burnout may be responsible for referrals of older nurses to NMC. PMID- 23987926 TI - Trusts launch recruitment drives in bid to tackle death rate anomalies. PMID- 23987929 TI - Senior nurse calls for 'essential standards' on staffing levels. PMID- 23987940 TI - NMC unveils support mechanisms to help witnesses in FtP hearings. PMID- 23987934 TI - Experts warn of excessive heat risks as weather triggers rise in A&E visits. AB - Hospital emergency departments across the country are dealing with the effects of Britain's longest heatwave for seven years. PMID- 23987942 TI - End of pathway leaves questions about what will take its place. PMID- 23987943 TI - Wright Angle: beware the dismantlers who distract and destroy. PMID- 23987949 TI - Putting patients first. AB - Care home manager Geraldine Browne has improved the quality of care for her patients and reduced the number of hospital admissions. The changes, enthusiastically implemented by staff, have won her the RCN Northern Ireland nurse of the year award. PMID- 23987951 TI - League of friends. AB - Nurses' leagues are egalitarian organisations attached to training hospitals that promote high standards in the nursing profession and offer social and educational support to their members. Most members are older nurses but younger nurses from the university system are also proud of their participation. PMID- 23987952 TI - A manager's workout. AB - A Management Masterclass course run by the company Mind Gym is helping nurse Jessica Higson to learn new strategies for leading her ward team and to understand financial realities. The big message from the course, she says, is that thinking optimistically gets results. PMID- 23987953 TI - Caring for a killer. AB - People suspected or convicted of terrible crimes often need nursing care, either for injuries received while committing their crime, being apprehended or as part of their ongoing care. Nurses need support to set their personal feelings to one side and behave with professionalism. PMID- 23987958 TI - Starting out - I aim to teach mental health patients about the dangers of illicit drugs. AB - While on placement on an acute admissions mental health ward, a male patient, who I will call Mr Smith, returned after weekend leave. PMID- 23987966 TI - As a profession, we need to grow up and win back public confidence. PMID- 23987967 TI - Education is power, and to many this is undesirable in nurses. AB - Stella Backhouse (Reflections July 17) highlights the age-old fear of the educated woman. Girls and women are oppressed in many countries by being denied access to education. PMID- 23987968 TI - Commissioning changes may lead to a leadership vacuum. PMID- 23987969 TI - Experience of walk-in centre and NHS 111 made me hanker after A&E. PMID- 23987970 TI - Higher taxes or charges are needed to pay for 24-hour care. PMID- 23987974 TI - Preventing acute hypercapnic respiratory failure in COPD patients. AB - Patients with chronic obstructive pulmonary disease (COPD) are at risk of developing acute hypercapnic respiratory failure (AHRF) if given high concentration uncontrolled oxygen inappropriately. This article analyses a critical incident involving a patient who developed AHRF, and identifies areas for improvement in clinical practice that would improve the standard of care for patients with COPD. PMID- 23987975 TI - Management of poisoning in adults. AB - Nurses play a key role in the care of patients presenting with poisoning. Assessment and management of such patients can be challenging, especially if they are intoxicated, have co-ingested other agents or their mental health is compromised. In addition, some nurses may be unfamiliar with current management guidelines. This article outlines a number of protocols and initiatives aimed at improving consistency in the management of patients following an overdose. The article focuses on paracetamol poisoning, the most common overdose presentation in the UK. This article was updated on May 7 2013 to include current UK guidelines for management of paracetamol overdose, which changed in September 2012 following a review by the Commission on Human Medicines. In addition, the authors published recently an article in this journal that discussed the assessment and management of patients who present to hospital following a paracetamol overdose ( Pettie and Dow 2013 ). PMID- 23987976 TI - Promoting mental and physical health in adults with psychosis. AB - Psychosis is an umbrella term for a range of mental health problems characterised by hallucinations, delusions, and/or becoming inactive or withdrawn. This article explores developments in understanding psychosis and reports on progress in finding effective treatments for psychotic symptoms. While such advances offer new opportunities to promote mental wellbeing, it is recognised that people with severe mental illnesses, such as psychosis, die up to 20 years earlier than the general population. Mortality rates from unnatural causes such as suicide are elevated in this group, but premature deaths are primarily the result of treatable physical health problems such as cardiovascular disease. Therefore, the poor physical health of adults with psychosis and the need to focus on interventions to enhance the mental and physical health of this often neglected population are considered. PMID- 23987977 TI - Diabetic foot ulcers. PMID- 23987978 TI - Older people need expert carers. PMID- 23987980 TI - An underrated leadership skill. PMID- 23987981 TI - Student life - inspiration from the top. PMID- 23987982 TI - Preference for newspaper size. AB - The past few years has seen a change in the size of newspapers, with publishers moving to a smaller size format. Five 'standard' newspaper sizes are used in different countries: Broadsheet, Rhensch, Tabloid, Tall Tabloid and Berliner. These papers vary in both width and height of pages and hence there are implications for human reading comfort, which may be dependent on reading location such as on a lounge chair or on a train. Experiments were carried out to determine preferences for the different sizes and to relate these preferences to the geometric characteristics of the newspapers. For both comfortable and cramped/uncomfortable reading conditions, the rank order of preference for paper types was, from least to most-preferred, Broadsheet, Rhensch, Berliner, Tall Tabloid and Tabloid. Preferences were much stronger when determined in cramped/uncomfortable reading conditions, where most comparisons were significantly different. There was good correlation between participant ratings on several scales and preference, where most factors were related to comfort of holding and controlling the paper. PMID- 23987983 TI - All-semiconductor plasmonic nanoantennas for infrared sensing. AB - Infrared absorption spectroscopy of vibro-rotational molecular resonances provides a powerful method for investigation of a wide range of molecules and molecular compounds. However, the wavelength of light required to excite these resonances is often orders of magnitude larger than the absorption cross sections of the molecules under investigation. This mismatch makes infrared detection and identification of nanoscale volumes of material challenging. Here we demonstrate a new type of infrared plasmonic antenna for long-wavelength nanoscale enhanced sensing. The plasmonic materials utilized are epitaxially grown semiconductor engineered metals, which results in high-quality, low-loss infrared plasmonic metals with tunable optical properties. Nanoantennas are fabricated using nanosphere lithography, allowing for cost-effective and large-area fabrication of nanoscale structures. Antenna arrays are optically characterized as a function of both the antenna geometry and the optical properties of the plasmonic semiconductor metals. Thin, weakly absorbing polymer layers are deposited upon the antenna arrays, and we are able to observe very weak molecular absorption signatures when these signatures are in spectral proximity to the antenna resonance. Experimental results are supported with finite element modeling with strong agreement. PMID- 23987984 TI - Use of single-layer centrifugation with Androcoll-C to enhance sperm quality in frozen-thawed dog semen. AB - The aim of this study was to investigate whether single-layer centrifugation (SLC) with Androcoll-C could select good quality spermatozoa, including those with specific motility patterns, from doses of frozen dog semen. Semen from five dogs was collected and cryopreserved following a standard protocol. After thawing, the semen samples were divided in two aliquots, one of which was used as a control and the other one processed by SLC. Assessment of sperm motility (assessed by computer-assisted semen analysis), morphology (Diff-Quick staining), viability (dual staining with propidium iodine/acridine orange), and acrosome integrity (dual staining with propidium iodine/isothiocyanate-labeled peanut [Arachis hypogaea] agglutinin) were performed on aliquots of fresh semen, frozen thawed control samples, and frozen-thawed SLC-treated preparations. A multivariate clustering procedure separated 57,577 motile spermatozoa into three subpopulations (sP): sP1 consisted of poorly active and nonprogressive spermatozoa (48.8%), sP2 consisted of moderately slow but progressive spermatozoa (13.3%), and sP3 consisted of highly active and/or progressive spermatozoa (37.8%). SLC with Androcoll-C yielded sperm suspensions with improved motility, viability, and acrosome integrity (P < 0.01). The frozen-thawed SLC-treated samples were enriched in sP3, representing 38.5% of the sperm population. Likewise, sP2 was more frequently observed after SLC, but not significantly so. From these results, we concluded that for dog semen samples selected by SLC with Androcoll-C after thawing, the sperm quality parameters, including motility patterns, are better than in frozen-thawed control samples. PMID- 23987985 TI - THY1 as a reliable marker for enrichment of undifferentiated spermatogonia in the goat. AB - Spermatogonial stem cells are unique cells of testes that can restore fertility upon transplantation into recipient testes. However, use of suitable markers for enrichment of these cells have important potential application. THY1, is an established conserved marker of spermatogonial stem cells in bovine, rodents, and primates, but there is no information available in goats. After three rounds of enzymatic digestion of prepubertal goat testicular tissues, undifferentiated spermatogonia positive for THY1 were isolated by magnetic-activated cell sorting and were used for immunocytochemistry, real-time polymerase chain reaction analysis for gene expression, protein expression, and transplantation into recipient mice. Immunocytochemical analyses showed that significantly higher percentage of THY1(+) cells were positive for PLZF and VASA when compared with unselected population. This result for PLZF was further confirmed at the protein level. Real-time polymerase chain reaction analysis revealed that expression of THY1, PLZF, VASA, BCL6B, and UCHL1 as SCCs characteristic genes in THY1(+) cells was significantly higher than in the initial population. Finally, transplantation of PKH26-labeled cells revealed that THY1(+) cells had higher capacity for colony formation when compared with unselected cells. In conclusion, the results provide indications that THY1 surface marker can be reliably used for enrichment of undifferentiated spermatogonial in the goats. PMID- 23987986 TI - Effect of a GnRH analogue (Maprelin) on the reproductive performance of gilts and sows. AB - The ability of peforelin (l-GnRH-III) to stimulate follicular growth, FSH release, and estrus in gilts after altrenogest treatment and in sows after weaning was investigated. In three farrow-to-wean herds, with at least 600 sows and average production performance, 216 gilts, 335 primiparous, and 1299 pluriparous sows were randomly allocated to three treatments: peforelin (M group: Maprelin), eCG (F group: Folligon), and physiological saline solution (C group). Animals were treated 48 hours after their last altrenogest treatment (gilts) or 24 hours after weaning (sows). The weaning-to-estrus interval, estrus duration, estrus rate (ER), pregnancy rate, and total born (TB), live born, and stillborn (SB) numbers were recorded and compared between treatments for the different parity groups (gilts and primiparous and pluriparous sows). Follicle sizes were measured in representative animals from each group on the occasion of their last altrenogest treatment or at weaning, and also on the occasions of their first (FS1) and second (FS2) attempted inseminations. Blood samples were taken to determine FSH concentrations at weaning and 2 hours after injection, and progesterone concentrations 10 days after the first insemination attempt. The relative change in FSH concentrations was calculated. Significant differences were found for ER within 7 days of weaning in pluriparous sows (95%, 91%, and 90% for the M, F, and C groups, respectively, P = 0.005). Gilts in the F-group had high TB numbers, and pluriparous sows in the M group had high SB numbers (TB gilts = 13.6, 15.4, and 14.9 [P = 0.02] and SB pluriparous sows = 1.8, 1.4, and 1.7 [P = 0.05] for the M, F, and C groups, respectively). The M group had the highest FS1 (for gilts) and FS2 (for pluriparous sows) values: FS1 = 5.4, 4.9, and 4.9 mm [P = 0.02] and FS2 = 6.8, 5.3, and 6.3 mm [P = 0.03] for the M, F, and C groups, respectively. There were no significant differences between the different treatments within each parity group with respect to any of the other variables. Overall, peforelin treatment had small but positive effects on the ER and follicle growth in certain parity groups but did not seem to affect litter sizes or FSH and progesterone levels in sows on the occasions of the corresponding examinations. PMID- 23987987 TI - Collection of field reproductive data from carcasses of the female Eurasian lynx (Lynx lynx). AB - Information about reproductive physiology in the Eurasian lynx (Lynx lynx) would generate knowledge that could be useful in the management of the Swedish lynx population based on the knowledge about their reproductive potential and population development. Age-related differences in ovulation and implantation rates would affect the reproductive output and the development of the population. The aims of this study were to evaluate a protocol for collection of reproductive data from carcasses by comparisons with published field data and to generate data about reproduction in the Swedish lynx. Reproductive organs from 120 females that were harvested between March 1 and April 9 from 2009 to 2011 were collected and evaluated macroscopically for placental scars. Females had their first estrus as yearlings but did not have their first litter until the next season. Pregnancy rates were lower in 2-year-old females than in females aged 3 to 7 years but did not differ significantly from females aged 8 to 13 years (54.5%, 95.6%, and 75.0%, respectively). CL from the present season were morphologically distinctly different from luteal bodies from previous cycles (LBPC). All females >=3 years had macroscopically visible LBPC, whereas only 67% of 22 to 23 months old females had one to three LBPC and no females <1 year of age had LBPC. Females aged 34 to 35 months had up to eight LPBC, whereas the highest number of LBPC counted in females >=3 years of age was 11. These data would be in agreement with only one estrus per season and LBPC from at least three previous reproductive seasons in older females. The number of LBPC was significantly correlated with the weight of the ovaries rs = 0.648, P < 0.001) and the age of the animals (rs = 0.572, P < 0.001). Uterine weight differed significantly with the stage of the reproductive cycle and was highest for mature females in the luteal phase of the cycle. The estrous period, defined as occurrence of ovarian follicles lasted from March 5 to April 1 in this material. In conclusion, this study confirms that useful information about lynx reproduction can be collected from reproductive organs retrieved after the death of the animals. Continuous monitoring of lynx reproductive organs would therefore make a valuable contribution to collection of field data, gathering information that can be useful for the management of lynx populations and potentially for the lynx as an indicator of environmental disturbances. PMID- 23987988 TI - Development competence and relative transcript abundance of oocytes derived from small and medium follicles of prepubertal gilts. AB - The objective of this study was to examine the competence of mature oocytes aspirated from small follicles (SF, <2 mm in diameter) and medium follicles (MF, 3-6 mm) of abattoir-derived prepubertal gilt ovaries. Oocytes were selected by the presence of the first polar body (1pb) after IVM in a chemically defined medium, for sperm penetration, pronuclear formation, cleavage rate, and development to the blastocyst stage. Relative transcript abundance of genes associated with regulation of oocyte maturation (AURKA, AURKB, and MOS), fertilization (ZP3 and ZP4), maternal effect (NALP9 and HSF1), and anti-apoptosis (BCL2) were also examined in oocytes at germinal vesicle (GV) and metaphase-II (MII) stages. In SF, compared with MF, the maturation rate post-IVM was lower (P < 0.05), but there were no differences in sperm penetration rate (78.2% and 68.5% at 6 hours after insemination and 90.8% and 91.9% at 9 hours after insemination, P = 0.51 and P = 0.67, respectively), the percentage of oocytes that formed both female and male pronuclei (27.9% and 25.8% at 6 hours after insemination and 79.4% and 76.1% at 9 hours after insemination), or cleavage rate at 48 hours after insemination (85.9% and 89.7%, respectively, P = 0.46), whereas blastocyst formation rate was lower (P < 0.05) in oocytes from SF versus MF (14.7% and 31.0%). Transcript abundances decreased (P < 0.05) in all genes examined between the GV and MII stages, although only transcript abundance for MOS was lower (P < 0.05) in GV oocytes from SF versus MF. In conclusion, mature oocytes from SF and MF of prepubertal gilts with a visible 1pb had similar fertilizability in vitro and relative transcript abundance of nine genes. However, follicle size affected meiotic competence, early embryonic development to the blastocyst stage, and transcript abundance of the MOS gene. PMID- 23987989 TI - Temperature management during semen processing: Impact on boar sperm quality under laboratory and field conditions. AB - Freshly collected boar spermatozoa are sensitive to a fast reduction in temperature because of lipid phase transition and phase separation processes. Temperature management during semen processing may determine the quality of stored samples. The aim of this study was to evaluate the influence of isothermic and hypothermic semen processing protocols on boar sperm quality under laboratory and field conditions. In the laboratory study, ejaculates (n = 12) were first diluted (1:1) with Beltsville Thawing Solution (BTS) at 32 degrees C, then processed either with isothermic (32 degrees C) or hypothermic (21 degrees C) BTS, stored at 17 degrees C, and assessed on days 1, 3, and 6. Temperature curves showed that 150 minutes after the first dilution, semen doses of both groups reached the same temperature. Two-step hypothermic processing resulted in lower sperm motility on days 1 and 6 (P < 0.05). Concomitantly, hypothermally processed samples contained less membrane intact sperm on days 3 and 6 (P < 0.05). Using AndroStar Plus extender instead of BTS reduced the negative effect of hypothermic processing. In the field study, 15 semen samples from each of 23 European artificial insemination studs were evaluated as part of an external quality control program. Semen quality based on motility, membrane integrity, mitochondrial activity, and a thermoresistance test was higher for stations using one-step isothermic dilutions (n = 7) compared with artificial insemination centers using two-step hypothermic protocols (n = 16). Both studies show that chilling injury associated with hypothermic dilution results in lower quality of stored boar semen compared with isothermic dilution and that the type of semen extender affects the outcomes. PMID- 23987990 TI - Vegetable and fruit consumption, education and plasma vitamin C concentration in Russian and Finnish Karelia, 1992-2002. AB - OBJECTIVE: To examine (i) whether the consumption of fresh vegetables, fruit and berries is associated with plasma vitamin C concentration and (ii) educational differences in plasma vitamin C concentration in two neighbouring areas in Russia and Finland. DESIGN: Cross-sectional risk factor surveys in 1992, 1997 and 2002. Logistic regression analysis was applied to examine the associations of consumption of selected foods and education with plasma vitamin C concentration. SETTING: District of Pitkaranta in the Republic of Karelia, Russia and North Karelia, Finland. SUBJECTS: Adults aged 25-64 years: 579 men and 612 women in Pitkaranta; 974 men and 642 women in North Karelia. RESULTS: The plasma vitamin C concentration was strikingly low in Pitkaranta, Russia across the study years. During the 10 years of monitoring, the mean plasma vitamin C concentration among men ranged from 2.5 to 8.0 MUmol/l in Pitkaranta, Russia and from 27.1 to 53.9 MUmol/l in North Karelia, Finland. In both areas, daily consumption of fruit was most strongly associated with plasma vitamin C, while the association of fresh vegetable consumption with plasma vitamin C was less consistent. Consumption of berries was less important in explaining plasma vitamin C. In Pitkaranta, the plasma vitamin C concentration was lower among respondents in the lowest education group. CONCLUSIONS: Differences in the consumption of fresh vegetables and fruit resulted in notable differences in vitamin C status between Pitkaranta and North Karelia in spring. In comparative settings, knowledge of local food culture and validation pilots are important before conducting large population surveys. PMID- 23987991 TI - Resistant mechanism study of benzalkonium chloride selected Salmonella Typhimurium mutants. AB - Benzalkonium chloride is one of the invaluable biocides that is extensively used in healthcare settings as well as in the food processing industry. After exposing wild-type Salmonella Typhimurium 14028s or its AcrAB inactivation mutant to gradually increasing levels of benzalkonium chloride, resistance mutants S-41, S 150, S-AB-23, S-AB-38, and S-AB-73 were selected and these mutants also showed a 2-64-fold stable minimum inhibitory concentration (MIC) increase to chloramphenicol, ciprofloxacin, nalidixic acid, and tetracycline. In S-41 and S 150, the expression of acrB was increased 2.7- and 7.6-fold, and DeltatolC or DeltaacrAB mutants of S-41 and S-150 showed the same MICs to all tested antimicrobials as the equivalent Salmonella Typhimurium 14028s mutants. However, in S-AB-23, S-AB-38, and S-AB-73, the expression of acrF was increased 96-, 230-, and 267-fold, respectively, and DeltatolC or DeltaacrEF mutants of S-AB-23, S-AB 38, and S-AB-73 showed the similar MICs to all tested antimicrobials as the DeltatolC mutant of Salmonella Typhimurium 14028s. Our data showed that constitutively over-expressed AcrAB working through TolC was the main resistance mechanism in ST14028s benzalkonium chloride resistance mutants. However, after AcrAB had been inactivated, benzalkonium chloride-resistant mutants could still be selected and constitutively over-expressed, AcrEF became the dominant efflux pump working through TolC and being responsible for the increasing antimicrobial resistance. These data indicated that different mechanisms existed for acrB and acrF constitutive over-expression. Since exposure to benzalkonium chloride may lead to Salmonella mutants with a decreased susceptibility to quinolones, which is currently one of the drugs of choice for the treatment of life-threatening salmonelosis, research into the pathogenesis and epidemiology of the benzalkonium chloride resistance mutants will be of increasing importance. PMID- 23987992 TI - Emergence and long-lasting persistence of linezolid-resistant Enterococcus faecium-ST117 in an oncohematologic patient after a nine-day course of linezolid. AB - We report the emergence and long-lasting persistence of linezolid resistance in an ampicillin-resistant Enterococcus faecium strain in the intestine of a neutropenic oncohematologic patient receiving chemotherapy. The patient was first colonized by an epidemic ampicillin-resistant E. faecium (ARE)-ST117 clustering into lineage 78. This clone exhibited resistance to levofloxacin, erythromycin and high-level resistance to streptomycin and gentamicin. After receiving treatment with several broad spectrum antibiotics for febrile neutropenia, a 9 day course of oral linezolid was administered once the patient developed bacteraemia by the same ARE colonizing clone. Linezolid-resistant ARE was detected 17 days later in the follow-up fecal samples and persisted 41 days after suppression of linezolid therapy. Resistance to linezolid was associated with G2576T transversion in the 23S rRNA and the presence of cfr gene was not detected. The persistence of G2576T-ARE strains, especially in oncohematologic patients with injured intestinal membranes, could increase the risk of bacteraemia. PMID- 23987994 TI - Twinning superlattice formation in GaAs nanowires. AB - Semiconductor nanowires have proven a versatile platform for the realization of novel structures unachievable by traditional planar epitaxy techniques. Among these, the periodic arrangement of twin planes to form twinning superlattice structures has generated particular interest. Here we demonstrate twinning superlattice formation in GaAs nanowires and investigate the diameter dependence of both morphology and twin plane spacing. An approximately linear relationship is found between plane spacing and nanowire diameter, which contrasts with previous results reported for both InP and GaP. Through modeling, we relate this to both the higher twin plane surface energy of GaAs coupled with the lower supersaturation relevant to Au seeded GaAs nanowire growth. Understanding and modeling the mechanism of twinning superlattice formation in III-V nanowires not only provides fundamental insight into the growth process, but also opens the door to the possibility of tailoring twin spacing for various electronic and mechanical applications. PMID- 23987993 TI - Human immunodeficiency virus, hepatitis C, and inflammatory biomarkers in individuals with alcohol problems: a cross-sectional study. AB - BACKGROUND: Assessing whether hepatitis C (HCV) co-infection with human immunodeficiency virus (HIV) is associated with increased inflammation is complex. The liver, integral to inflammatory biomarker synthesis, is compromised by HCV and alcohol abuse. Using single liver-synthesized biomarkers (e.g. C reactive protein) to represent inflammation may not be appropriate in HIV/HCV co infection. We hypothesized that 1) detectable HIV/HCV RNA was independently associated with increased inflammation; 2) a composite inflammation measure describes inflammation differently from single inflammatory biomarkers. METHODS: We compared inflammation by HIV/HCV group in a cohort of 361 HIV infected participants from the HIV-Longitudinal Interrelationships of Viruses and Ethanol study. Inflammatory biomarkers >75th percentile were considered elevated. Associations between HIV/HCV group and elevated biomarkers were analyzed as a composite measure (inflammatory burden) or individually. We defined inflammatory burden as number of concurrently elevated biomarkers. Biomarkers included interleukin-6 (IL-6), C-reactive protein (CRP), cystatin C, serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10). Covariates: alcohol, liver fibrosis, comorbidities, CD4 count, antiretroviral therapy, substance use. RESULTS: Detectable HIV and HCV RNA (OR = 2.49; 95% CI = 1.05-5.89) and detectable HCV RNA alone (2.95; 1.08-8.01) were independently associated with increased odds of having a greater inflammatory burden compared to undetectable viremia. Elevated IL-10 (7.79; 1.90-31.97) and TNF-alpha (7.70; 1.42-41.83) were independently associated with detectable HIV and HCV RNA. Elevated IL-10 was also associated with detectable HCV RNA alone (5.51; 1.17, 25.84). CONCLUSIONS: Detectable HIV and HCV replication versus undetectable replication was associated with inflammatory burden and certain inflammatory biomarkers independently of alcohol consumption, liver fibrosis and other comorbidities. PMID- 23987995 TI - Recognizing the limitations of performance reference compound (PRC)-calibration technique in passive water sampling. PMID- 23987996 TI - Serpins as therapeutics--a potential biologic source for unique protein-based therapeutics. PMID- 23987997 TI - Augmentation therapy with alpha1-antitrypsin: novel perspectives. AB - SERPINA1, alpha-antitrypsin (AAT) is an acute phase protein, a member of the serpin (serine protease inhibitor) super family and one of the most abundant protease inhibitors in the circulation. The clinical importance of AAT is emphasized in persons with inherited AAT deficiency who exhibit high risk of developing early onset pulmonary emphysema, neonatal hepatitis, liver cirrhosis, which may appear at any age, and in rare cases panniculitis and vasculitis. The most common and severe AAT deficiency is associated with the Z (Glu342 to Lys) mutation. It is also well established that Z AAT deficiency results from the polymerization and accumulation of the misfolded AAT protein. Consequently, low levels of circulating Z AAT are assumed to be inadequate to neutralize elastolytic activity and to prevent lung tissue damage. Novel studies, however, are expanding the link between AAT and human diseases. Associations are shown between reduced AAT levels and HIV type 1 infection, hepatitis C infection, diabetes mellitus, vasculitis, panniculitis and other diseases. Given the importance of the protease/antiprotease imbalance in causing emphysema, augmentation of circulating AAT is used as a specific therapy for patients with AAT deficiency-related emphysema but not for those with liver diseases. According to the novel findings, therapy with AAT possesses antiinflammatory and immuno modulatory effects across a broad spectrum of experimental models of systemic and local inflammation. Hence, in this article we will discuss putative new directions for the clinical use of therapy with AAT. PMID- 23987998 TI - The serpin solution; targeting thrombotic and thrombolytic serine proteases in inflammation. AB - Serpins in the mammalian body are highly potent serine protease inhibitors which modulate both thrombotic and thrombolytic pathway activation, with direct and indirect crosstalk with immune and inflammatory pathways. In this review, we discuss mammalian and viral serpins as regulators of coagulation and inflammation. We focus first on the thrombotic and thrombolytic serine proteases and known interactions between these protease cascades and elements of the innate immune response. Serpin-mediated regulation of the thrombotic pathway is then discussed, with emphasis on those serpins that have been evaluated as potential new drugs. Finally the potential of viral serpins that target the coagulation and thrombolytic cascades as potential therapeutics for anti-inflammatory properties is discussed from basic molecular activity to studies in animal models. The studies discussed range from thrombosis and hemorrhage to vascular disease and transplant rejection and finally to sepsis and clinical studies in humans. In conclusion, these unique proteins, the serpin family, now have demonstrated therapeutic potential for a wide variety of inflammatory diseases in both animal and human studies and represent a new approach for drug development. PMID- 23987999 TI - Anti-apoptotic serpins as therapeutics in cardiovascular diseases. AB - Acute cardiovascular syndromes such as myocardial infarction and stroke are a major cause of death in the Western society and are generally caused by rupture of an atherosclerotic plaque. Treatment of atherosclerosis, the main underlying cause of acute cardiovascular syndromes, is still inadequate for most of the patients. Therefore, there is a need for new therapeutic strategies in addition to the existing lipid-lowering drugs such as statins. Lipid accumulation, inflammation and matrix degradation are generally considered key processes in the pathogenesis of atherosclerosis and that of plaque rupture. Furthermore, apoptosis or programmed cell death of plaque cells, depending on the disease stage, is thought to be of importance in the development and progression of atherosclerosis and the incidence of acute cardiovascular syndromes. Serine protease inhibitors or so-called serpins have been demonstrated to be involved in both the induction and inhibition of apoptosis and may thus be of interest as therapeutics in cardiovascular diseases such as atherosclerosis. In this review, we will discuss the current knowledge on the role of serpins in cardiovascular diseases with particular emphasis on apoptotic cell death and the potential therapeutic applications. PMID- 23988000 TI - Serpins for diagnosis and therapy in cancer. AB - Serine protease inhibitors (Serpins) play an important role in regulating a wide array of diverse biological activities, representing up to 2-10% of circulating plasma proteins. The serpin suicide inhibitors regulate coagulation (thrombosis and thrombolysis), neurotrophic factors, hormone transport, complement and inflammation, angiogenesis, hormone transport, and blood pressure among many other biological reactions. Select serpins have been associated with progression or remission of selected cancers, making them valuable for therapeutic or diagnostic use. Plasminogen activator inhibitor-1 (PAI-1), the main regulator of thrombolysis, has the potential to either reduce or accelerate tumor growth but blockade of PAI-1 has recently been reported to reduce cancer cell migration, proliferation and survival through modulating the function of urokinase-type plasminogen activator receptor. Maspin is a non-inhibitory serpin, that increases cancer cell sensitivity to apoptosis and inhibits cancer cell migration thus providing a serpin that blocks tumor gorwth. Pigment epithelium derived factor (PEDF) has potent anti-angiogenesis activity and also promotes cancer cell apoptosis. Among other serpins, the mammalian serpin, neuroserpin, and the myxomavirus derived serpin, Serp-1 are under investigation in our lab for their potential tumor-suppressive functions. Further study on the efficacy and mechanisms of serpin mediated anti-cancer activity is warranted in order to develop new serpin-based approaches in cancer therapy. PMID- 23988001 TI - Evaluation of B lymphocyte deficiencies. AB - The most common of the primary immunodeficiency diseases are those that involve inadequate antibody production. The characteristic presentation of these disorders is recurrent sinopulmonary infections. An arrest in B cell development at the pre-B cell stage leads to agammaglobulinemia and an insignificant number of B cells. X-linked agammaglobulinemia is the most common of these developmental arrests while the autosomal recessive agammaglobulinemias comprise a small minority of the total cases. Likewise, the most common form of the hyper-IgM syndromes (CD40 ligand deficiency) is X-linked. Of the autosomal recessive forms, CD40 deficiency is basically identical to the X-linked form in its clinical phenotype where, in addition to inadequate antibody production, there is defective T cell signaling through the CD40-CD40L interaction. Aside from CD40 deficiency, the other recessive forms of hyper-IgM syndrome have adequate T cell function. IgA deficiency is the most common and the most benign of the B cell disorders. Common variable immunodeficiency is diverse in its presentation and clinical course. The pathophysiology of this disease is multifactorial and frequently ill defined, often making it a diagnosis of exclusion. A working knowledge of identifiable PIDDs is essential in both recognizing when to suspect immunodeficiency and making a diagnosis. PMID- 23988002 TI - Plasminogen activator inhibitor with very long half-life (VLHL PAI-1) can reduce bleeding in PAI-1-deficient patients. AB - This review summarizes our current knowledge of plasminogen activator inhibitor (PAI-1) deficiency and proposes some novel treatments for this condition. PAI-1 is a fast acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA). PAI-1 controls/slows clot lysis triggered by tPA activated plasminogen. PAI-1 deficiency was once considered to be an extremely rare disorder characterized by frequent and prolonged bleeding episodes. PAI-1 deficiency is now thought to be more frequent than initially reported and is known to be caused by mutations in the PAI-1 gene that produce a dysfunctional PAI-1 protein or slow the secretion of PAI-1 into the circulation. PAI-1 deficiency is characterized by hyperfibrinolysis that results in frequent bleeding episodes. Patients with this condition form normal blood clots that are quickly lysed by unopposed tPA activated plasmin. Spontaneous bleeding is rare in PAI-1 deficient patients, but moderate hemorrhaging of the knees, elbows, nose, and gums can be triggered by mild trauma. Additionally, prolonged bleeding after surgery is common and menstrual bleeding may be severe. Moderate PAI-1 deficiency is associated with a lifelong bleeding tendency, but severe deficiencies can be life-threatening. The diagnosis of this disorder remains challenging due to the lack of a clear definition of PAI-1 deficiency as well as a lack of standardized tests. Patients with mild PAI-1 deficiency may be treated with antifibrinolytic agents (epsilon aminocaproic acid or tranexamic acid); however, not all patients respond well to these treatments. These patients may be treated with wild-type PAI-1; however, this molecule quickly converts into its inactive form. We propose to use PAI-1 with an extended half-life to treat these patients. PMID- 23988003 TI - The development and progression of atherosclerosis: evidence supporting a role for endoplasmic reticulum (ER) stress signaling. AB - Cardiovascular disease is the number one cause of death worldwide. A major underlying cause of cardiovascular disease is atherosclerosis--a chronic inflammatory disease of the large arteries. Despite substantial advances over the past few decades, our understanding of the molecular mechanisms that link cardiovascular risk factors to the development and progression of atherosclerosis is incomplete. The endoplasmic reticulum (ER) is a membranous organelle found in all eukaryotic cells that is responsible for protein processing and lipid biosynthesis. In recent years it has become evident that disruptions in ER function are associated with a number of human diseases including atherosclerosis. In this review we examine the potential role of endoplasmic reticulum stress in the initiation and progression of atherosclerosis and discuss possible strategies to target this pathway toward the development of new anti atherogenic therapies. PMID- 23988004 TI - Oxidative stress and transforming growth factor-beta1-induced cardiac fibrosis. AB - A chronic increase in reactive oxygen species (ROS) plays a critical role in the development and progression of cardiac remodeling associated with heart failure. Oxidative stress is indeed increased in heart failure, hypertension, cardiac fibrosis and hypertrophy. In vitro exposure of cardiac fibroblasts to superoxide anion stimulates their proliferation by increasing the production of transforming growth factor-beta1 (TGF-beta1), a potent fibrogenic cytokine. TGF-beta1 plays an important role in cardiac development, cardiac hypertrophy, ventricular remodeling and the early response to myocardial infarction. In this review the role of TGF-beta1 and ROS in the production and deposition of collagens by cardiac fibroblasts and in the induction of gene expression in relation to the development of myocardial fibrosis and to myocardial tissue repair will be discussed. PMID- 23988005 TI - Donor-recipient size matching and survival after lung transplantation. A cohort study. AB - RATIONALE: The association between a high predicted total lung capacity (pTLC) ratio (equal to pTLC(donor)/pTLC(recipient)), suggestive of an oversized allograft, with improved survival after lung transplantation (LTx) remains controversial. OBJECTIVES: To characterize donor-recipient lung size matching based on the pTLC ratio and to investigate the relationship of the pTLC ratio with post-LTx survival. METHODS: All subjects in the Scientific Registry of Transplant Recipients, who underwent first-time LTx in the lung allocation score based system between May 4, 2005 and March 31, 2012, were studied, and the pTLC ratio was calculated on the basis of sex, height, and age. Risk of death after LTx was analyzed using Cox proportional hazards models. MEASUREMENTS AND MAIN RESULTS: The pTLC ratio was available for 10,289 of the 10,318 study subjects (99.7%). The mean pTLC ratio was 1.015 +/- 0.175 (interquartile range, 0.918 1.119). Univariate analysis showed that the pTLC ratio was strongly associated with death in the first LTx year (P < 0.0001). With the pTLC ratio entered as a spline there was a nonlinear association with declining risk of death with higher pTLC ratio from 0.5 to about 1.3, where an inflection occurred with rising risk at higher values. Accounting for the pTLC ratio, recipient and donor sex were not independently associated with death after LTx. A change of pTLC ratio from 0.918 to 1.119 (the interquartile range) was associated with similar point estimates of reduced risk of death at 1 year in univariate (hazard ratio, 0.78) and comprehensive risk-adjusted multivariate models (hazard ratio, 0.86). CONCLUSIONS: The pTLC ratio is an independent predictor of death in the first year after LTx and explains the association of sex with survival after LTx. Incorporating the pTLC ratio in the lung allocation mechanism could improve outcomes after LTx. PMID- 23988006 TI - Passivated iodine pentoxide oxidizer for potential biocidal nanoenergetic applications. AB - Iodine pentoxide (I2O5), also known as diiodine pentoxide, is a strong oxidizer which has been recently proposed as an iodine-rich oxidizer in nanoenergetic formulations, whose combustion products lead to molecular iodine as a biocidal agent. However, its highly hygroscopic nature hinders its performance as a strong oxidizer and an iodine releasing agent and prevents its implementation. In this work, we developed a gas phase assisted aerosol spray pyrolysis which enables creation of iron oxide passivated I2O5. Transmission electron microscopy elemental imaging as well as temperature-jump mass spectrometry confirmed the core shell nature of the material and the fact that I2O5 could be encapsulated in pure unhydrated form. Combustion performance finds an optimal coating thickness that enables combustion performance similar to a high performing CuO based thermite. PMID- 23988007 TI - Synthesis of phytosteryl ester containing pinolenic acid in a solvent-free system using immobilized Candida rugosa lipase. AB - Phytosteryl ester synthesized with pinolenic acid (PLA) from pine nut oil is expected to have features of both phytosterol and PLA. In this study, lipase from Candida rugosa (CRL) was immobilized and then used to optimize conditions for synthesis of phytosteryl ester containing PLA. Lewatit VP OC 1600, a macroporous hydrophobic resin, was selected as the best carrier, and the optimum condition for the immobilization of CRL was established. With immobilized CRL prepared, synthesis of phytosteryl ester with fatty acid from pine nut oil was carried out. Parameters investigated were temperature, molar ratio (phytosterol to fatty acid), enzyme loading, and vacuum. Optimum conditions for synthesis of phytosteryl ester were a temperature of 60 degrees C, molar ratio of 1:4, enzyme loading of 10% (based on the total weight of the substrate), and pressure of 80 kPa. The maximum conversion of phytosteryl ester was ca. 93 mol % at the optimum condition. PMID- 23988008 TI - Cancer incidence and survival among infants in Israel, 1998-2007. AB - Cancer during the first year of life is relatively rare and often has clinical and biological properties different from those of the same histologic type of cancer occurring in older children. The aim of this study was to find differences in epidemiology and survival between infants and older children and to compare the percentage of distribution of infant cancer types in Israel with that reported in the United States. We collected infant <1 year of age cases diagnosed between 1998 and 2007 as having cancer from the database of the Israel National Cancer Registry, a total of 309 cases with an incidence rate of 228.5 cases per million. The largest group was diagnosed with neuroblastoma (35%) with an incident rate of 80 per million, followed by leukemia (15.9%), with acute lymphoid leukemia and acute myeloid leukemia accounting for most of this group and central nervous system malignancies comprised 10.7% of infant cancer. One hundred and fifty four new cases of infant girls was diagnosed compared to 155 infant boys with an incidence rates of 234 cases per million for girls and 224.7 for boys, not statistically significant (F:M rate ratio of 1.04). The 5-year survival rates seen in the different groups were leukemia: 55.3%, lymphoma: 71%, CNS tumors: 53.3%, neuroblastoma: 93.4%, retinoblastoma: 94.7% renal tumors: 90.9%, hepatic tumors: 63.3%, soft tissue sarcoma: 76.2%, germ cell neoplasms: 83.3%, and other epithelial neoplasms: 100%. Our study did not find survival differences with statistical significance upon comparing survival rates between different genders and ethnic groups. PMID- 23988009 TI - Description, microhabitat selection and infection patterns of sealworm larvae (Pseudoterranova decipiens species complex, nematoda: ascaridoidea) in fishes from Patagonia, Argentina. AB - BACKGROUND: Third-stage larvae of the Pseudoterranova decipiens species complex (also known as sealworms) have been reported in at least 40 marine fish species belonging to 21 families and 10 orders along the South American coast. Sealworms are a cause for concern because they can infect humans who consume raw or undercooked fish. However, despite their economic and zoonotic importance, morphological and molecular characterization of species of Pseudoterranova in South America is still scarce. METHODS: A total of 542 individual fish from 20 species from the Patagonian coast of Argentina were examined for sealworms. The body cavity, the muscles, internal organs, and the mesenteries were examined to detect nematodes. Sealworm larvae were removed from their capsules and fixed in 70% ethanol. For molecular identification, partial fragments of the mitochondrial cytochrome c oxidase subunit 1 gene (cox1) were amplified for 10 isolates from 4 fish species. Morphological and morphometric data of sealworms were also obtained. RESULTS: A total of 635 larvae were collected from 12 fish species. The most infected fish was Prionotus nudigula, followed by Percophis brasiliensis, Acanthistius patachonicus, Paralichthys isosceles, and Pseudopercis semifasciata. Sequences obtained for the cox1 of sealworms from A. patachonicus, P. isosceles, P. brasiliensis and P. nudigula formed a reciprocally monophyletic lineage with published sequences of adult specimens of Pseudoterranova cattani from the South American sea lion Otaria flavescens, and distinct from the remaining 5 species of Pseudoterranova. A morphological description, including drawings and scanning electron microscopy photomicrographs of these larvae is provided. Sealworms collected from Argentinean fishes did not differ in their diagnostic traits from the previously described larvae of P. cattani. However a discriminant analysis suggests that specimens from P. nudigula were significantly larger than those from other fishes. Most of the sealworms were collected encapsulated from the muscles and, to a lesser degree, from the mesenteries and the liver. CONCLUSIONS: We provided the first molecular identification, morphological description and microhabitat characterization of sealworm larvae from the Argentinean Patagonian coast. We also reported the infection levels of sealworms on 20 fish species in order to elucidate the life cycle of these nematodes in this area. PMID- 23988012 TI - Phosphopeptidomimetic substance libraries from multicomponent reaction: enantioseparation on quinidine carbamate stationary phase. AB - In the present contribution we report a HPLC enantioseparation method for a library of amido-aminophosphonate structures generated by a novel Ugi multicomponent reaction. The enantioseparation of these novel potentially bioactive molecules was achieved by means of HPLC on cinchona-carbamate based chiral anion-exchangers under polar organic elution conditions. The compounds were synthesized with the aim of offering a wide degree of heterogeneity in terms of structural elements to evaluate the influence of various structural motifs on enantioselectivity. The resultant compound library allows to derive structure enantioselectivity relationships useful for understanding the chiral recognition process. As part of the study mobile phase characteristics such as concentration and type of counterion, mobile phase composition, apparent pH and temperature were investigated with regards to their effect on the separation performances. Employing a single mass spectrometry-compatible mobile phase, 23 compounds out of a pool of 42 racemic amido-aminophosphonate structures reached full baseline separation (Rs>1.5) and 5 were almost baseline separated (1SO4(2-)>NO3(-)>Cl(-). Saturated CR20-Cu can be regenerated using 4% NaCl at pH 7. More than 95% of the phosphate from CR20-Cu was recovered, and the phosphate uptake capacity for CR20-Cu was not reduced after 7 regeneration cycles. PMID- 23988082 TI - The effect of geometrical confinement on coalescence efficiency of droplet pairs in shear flow. AB - Droplet coalescence is determined by the combined effect of the collision frequency and the coalescence efficiency of colliding droplets. In the present work, the effect of geometrical confinement on coalescence efficiency in shear flow is experimentally investigated by means of a counter rotating parallel plate device, equipped with a microscope. The model system consisted of Newtonian droplets in a Newtonian matrix. The ratio of droplet diameter to plate spacing (2R/H) is varied between 0.06 and 0.42, thus covering bulk as well as confined conditions. Droplet interactions are investigated for the complete range of offsets between the droplet centers in the velocity gradient direction. It is observed that due to confinement, coalescence is possible up to higher initial offsets. On the other hand, confinement also induces a lower boundary for the initial offset, below which the droplets reverse during their interaction, thus rendering coalescence impossible. Numerical simulations in 2D show that the latter phenomenon is caused by recirculation flows at the front and rear of confined droplet pairs. The lower boundary is independent of Ca, but increases with increasing confinement ratio 2R/H and droplet size. The overall coalescence efficiency is significantly larger in confined conditions as compared to bulk conditions. PMID- 23988083 TI - Multilayer films made from poly(allylamine) and phosphorous containing polyoxometalates: focus on the zeta potential. AB - The physicochemical characterization of coatings deposited in a step-by-step (SBS) manner relies most often on thickness and homogeneity measurements by means of atomic force microscopy. In the case of coatings produced from oppositely charged species, their surface potential, estimated through their zeta potential, was for a long time expected to change alternatively as a prerequisite for the film deposition. However, some counterexamples appeared in the literature where the growth of the coating was observed when the number of deposition steps was increased but without a regular change in the sign of the surface potential. These data showed that the interpretation of the zeta potential of SBS deposited films should be subjected to more attention. In this article, we show the occurrence of ionic strength dependent instability of the surface potential of films made from the alternated deposition of poly(allylamine hydrochloride) and polyoxoanions. This instability may be due to a structural change in the coating, but we cannot exclude some shear induced desorption during the zeta potential measurement. In addition, a change in ionic strength between the deposition of the coating and the measurement of its streaming potential can have a huge importance on the result. PMID- 23988084 TI - Linking neuronal brain activity to the glucose metabolism. AB - BACKGROUND: Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. METHODS: First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. RESULTS: Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. CONCLUSIONS: The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported. PMID- 23988085 TI - Childhood neglect and increased withdrawal and depressive severity in crack cocaine users during early abstinence. AB - Studies have shown that environmental factors, such as exposure to childhood maltreatment, might shift the course of addiction. Little is known, however, about whether childhood physical neglect (PN) influences the severity of withdrawal and depressive symptoms during the detoxification period. This is a 3 weeks follow-up study. The participants were divided into 2 groups: those with a history of PN (PN+) (n=32) and those without a history of PN (PN-) (n=48). Clinical variables were assessed with the SCID-I, BDI-II, Childhood Trauma Questionnaire, Addiction Severity Index and Cocaine Selective Severity Assessment. Depressive symptom assessments were repeated at three time points. Withdrawal symptom assessments were repeated at five different points following detoxification. A repeated measures analysis of covariance indicated that the PN+ group exhibited a significantly lower reduction in the severity of withdrawal symptoms compared to the PN- group (p<0.05). Post hoc analyses showed that after 12 days of treatment, the severity of withdrawal symptoms in the PN+ group did not decrease in the same level as was observed in the PN- group. Moreover, a strong correlation was found between the severity of depression and the intensity of the abstinence symptoms during treatment. Patients who reported more depressive symptoms also exhibited more severe withdrawal symptoms. The ASI-6 indicated higher severity problems related to alcohol and psychiatric disorders in the PN+ groups. Our data support the role of childhood PN in the contingencies of the detoxification process of crack cocaine-dependent women. PMID- 23988086 TI - Isocitrate dehydrogenase 1 (IDH1) mutation-specific microRNA signature predicts favorable prognosis in glioblastoma patients with IDH1 wild type. AB - BACKGROUND: To date, no prognostic microRNAs (miRNAs) for isocitrate dehydrogenase 1 (IDH1) wild-type glioblastoma multiformes (GBM) have been reported. The aim of the present study was to identify a miRNA signature of prognostic value for IDH1 wild-type GBM patients using miRNA expression dataset from the The Cancer Genome Atlas (TCGA). METHODS: Differential expression profiling analysis of miRNAs was performed on samples from 187 GBM patients, comprising 17 mutant-type IDH1 and 170 wild-type IDH1 samples. RESULTS: A 23 micoRNA signature which was specific to the IDH1 mutation was revealed. Survival data was available for 140 of the GBM patients with wild-type IDH1. Using these data, the samples were characterized as high-risk or low-risk group according to the ranked protective scores for each of the 23 miRNAs in the 23-miRNA signature. Then, the 23 IDH1 mutation-specific miRNAs were classified as risky group and protective group miRNAs based on the significance analysis of microarrays d-score (SAM d-value) (positive value or negative value). The risky group miRNAs were found to be expressed more in the high-risk samples while the protective group miRNAs were expressed more in the low-risk samples. Patients with high protective scores had longer survival times than those with low protective scores. CONCLUSION: These findings show that IDH1 mutation-specific miRNA signature is a marker for favorable prognosis in primary GBM patients with the IDH1 wild type. PMID- 23988087 TI - Improvement of the efficacy of dihydroartemisinin with atorvastatin in an experimental cerebral malaria murine model. AB - BACKGROUND: The medical care of malaria is a clinical emergency because it may develop into severe malaria, which has a high risk of complications and death. One of the major complications of Plasmodium falciparum infections is cerebral malaria (CM), which is responsible for at least 175,000 deaths worldwide each year and has long-term neurological sequelae. Moreover, treatment for CM is only partially effective. Statins are now known to have anti-inflammatory action, to attenuate sepsis and to have neuroprotective effects. In vitro, atorvastatin (AVA) has an anti-malarial activity and has improved the activity of quinine (QN), mefloquine (MQ), and dihydroartemisinin (DHA). OBJECTIVES: This study had two objectives. First, the ability of AVA to enhance DHA efficacy by improving the survival rate for CM and also decreasing signs of CM was evaluated in a murine model of experimental cerebral malaria (ECM), which was designed in C57BL6/N mice. Second, the inflammatory biomarkers were assessed at D6 and D10 in mice treated by DHA and in untreated mice in which clinical signs of CM appear rapidly and death occurs before D12. Both experiments were designed with seven days of treatment with 40 mg/kg AVA combined with five days of 3 mg/kg DHA administered intraperitoneally. RESULTS: AVA in combination with DHA in a therapeutic scheme leads to a significant delay in mouse death, and it has an effect on the onset of CM symptoms and on the level of parasitaemia. Evaluation of the biomarkers highlights the significant difference between treated and control mice for five cytokines and chemokines (Eotaxin-CCL11, IL-13, LIX-CXCL5, MIP1b-CCL4 and MIP2) that are known to have a role in chemotaxis. CONCLUSIONS: The combination of DHA and AVA seems to be effective as a therapeutic scheme for improving mouse survival but less effective for cytokine modulation, which is associated with protection against CM. These results call for clinical trials of AVA as an adjuvant with anti-malarial therapy, especially with artemisinin-based combination therapy, in CM treatment or prevention. PMID- 23988088 TI - Localized permeabilization of E. coli membranes by the antimicrobial peptide Cecropin A. AB - Fluorescence microscopy enables detailed observation of the effects of the antimicrobial peptide Cecropin A on the outer membrane (OM) and cytoplasmic membrane (CM) of single E. coli cells with subsecond time resolution. Fluorescence from periplasmic GFP decays and cell growth halts when the OM is permeabilized. Fluorescence from the DNA stain Sytox Green rises when the CM is permeabilized and the stain enters the cytoplasm. The initial membrane disruptions are localized and stable. Septating cells are attacked earlier than nonseptating cells, and curved membrane surfaces are attacked in preference to cylindrical surfaces. Below a threshold bulk Cecropin A concentration, permeabilization is not observed over 30 min. Above this threshold, we observe a lag time of several minutes between Cecropin A addition and OM permeabilization and ~30 s between OM and CM permeabilization. The long lag times and the existence of a threshold concentration for permeabilization suggest a nucleation mechanism. However, the roughly linear dependence of mean lag time on bulk peptide concentration is not easily reconciled with a nucleation step involving simultaneous insertion of multiple peptides into the bilayer. Monte Carlo simulations suggest that within seconds, the OM permeability becomes comparable to that of a pore of 100 nm diameter or of numerous small pores distributed over a similarly large area. PMID- 23988089 TI - PKCdelta as a regulator for TGF-beta-stimulated connective tissue growth factor production in human hepatocarcinoma (HepG2) cells. AB - CTGF (connective tissue growth factor) is widely regarded as an important amplifier of the profibrogenic action of TGF-beta (transforming growth factor beta) in a variety of tissues, although the precise mechanism of how the TGF-beta signalling pathways modulate CTGF expression remains unclear. In the present study, the role of PKCdelta (protein kinase Cdelta) in TGF-beta1-mediated CTGF expression was investigated using HepG2 cells. TGF-beta1 treatment specifically elevated PKCdelta activation and CTGF expression. In contrast, blockade of PKCdelta by the selective inhibitor Rottlerin or by siRNA knockdown significantly reduced TGF-beta1-induced CTGF production. The regulatory mechanism was further demonstrated in HepG2 cells whereby TGF-beta1-induced PKCdelta activation negatively regulated the nuclear levels of PPM1A (protein phosphatase, Mg2+/Mn2+ dependent, 1A) through the RhoA/ROCK (Rho-associated kinase) pathway. Moreover, we showed that both Smad signalling and the PKCdelta pathway appeared to be stimulated by TGF-beta1 in parallel. Time course assessments indicated that PKCdelta signalling may have a function in maintaining nuclear phospho-Smads at a maximal level. The collective results of the present study demonstrated that PKCdelta-stimulated RhoA/ROCK activation resulted in a reduction in PPM1A, thereby up-regulating Smad-dependent gene induction for extended periods. These findings indicated that PKCdelta plays a critical role in TGF-beta1-induced CTGF production in HepG2 cells. PMID- 23988090 TI - Evaluation of patients with intracranial tumors and central diabetes insipidus. AB - The aim of the study is to evaluate the etiologic and clinical characteristics, treatment regimens, and outcome of the patients with intracranial tumors presenting with central diabetes insipidus (DI). Sixty-nine patients with intracranial tumors presenting with central DI between 1972 and 2012 were retrospectively evaluated. Fifty-three out of 69 patients were included in the analysis. Male/female ratio was 1.52, median age was 7.6 years. Of 53 patients, 37 patients (69.8%) were diagnosed with Langerhans cell histiocytosis, 14 patients (26.4%) with germinoma, 1 (1.9%) with astrocytoma, and 1 (1.9%) with optic glioma. 10-year overall survival (OS) rate and disease-free survival rate for all patients were 91.7% and 52%. 10-year OS rate according to diagnostic criteria was 91% for Langerhans cell histiocytosis (LCH) cases, 79% for intracranial germinoma, which was statistically significant (P = .0001). Central DI may be very important clinical presentation of serious underlying disease in children. Intracranial tumors are the most frequent cause of DI. Most frequent diagnosis were LCH and germ cell tumors in our series. PMID- 23988091 TI - Dual-energy CT for the evaluation of urinary calculi: image interpretation, pitfalls and stone mimics. AB - Urolithiasis is a common disease with a reported prevalence between 4% and 20% in developed countries. Determination of urinary calculi composition is a key factor in preoperative evaluation, treatment, and stone recurrence prevention. Prior to the introduction of dual-energy computed tomography (DECT), available methods for determining urinary stone composition were only available after stone extraction, and thereby unable to aid in optimized stone management prior to intervention. DECT utilizes the attenuation difference produced by two different x-ray energy spectra to quantify urinary calculi composition as uric acid or non-uric acid (with likely further classification in the future) while still providing the information attained with a conventional CT. Knowledge of DECT imaging pitfalls and stone mimics is important, as the added benefit of dual-energy analysis is the determination of stone composition, which in turn affects all aspects of stone management. This review briefly describes DECT principles, scanner types and acquisition protocols for the evaluation of urinary calculi as they relate to imaging pitfalls (inconsistent characterization of small stones, small dual energy field of view, and mischaracterization from surrounding material) and stone mimics (drainage devices) that may adversely impact clinical decisions. We utilize our clinical experience from scanning over 1200 patients with this new imaging technique to present clinically relevant examples of imaging pitfalls and possible mechanisms for resolution. PMID- 23988092 TI - Assessment and source identification of trace metals in the soils of greenhouse vegetable production in eastern China. AB - Worldwide concern about the occurrence of trace metals in greenhouse vegetable production soils (GVPS) is growing. In this study, a total of 385 surface GVPS samples were collected in Shouguang and four vegetable production bases in Nanjing, Eastern China, for the determination of As and Hg using atomic fluorescence spectrometry and Pb, Cu, Cd, and Zn using inductively coupled plasma mass spectrometry. Geo-accumulation indices and factor analysis were used to investigate the accumulation and sources of the trace metals in soils in Eastern China. The results revealed that greenhouse production practices increased accumulation of the trace metals, particularly Cd, Zn, and Cu in soils and their accumulation became significant with increasing years of cultivation. Accumulation of Cd and Zn was also found in soils from organic greenhouses. The GVPS was generally less polluted or moderately polluted by As, Cu, Zn, and Pb but heavily polluted by Cd and Hg in some locations. Overall, accumulation of Cd, Zn, and Cu in GVPS was primarily associated with anthropogenic activities, particularly, application of manure. The high level of Hg found in some sites was related to historical heavy application of Hg containing pesticides. However, further identification of Hg sources is needed. To reduce accumulation of the trace metals in GVPS, organic fertilizer application should be suggested through development and implementation of reasonable and sustainable strategies. PMID- 23988093 TI - Reverse osmosis pretreatment method for toxicity assessment of domestic wastewater using Vibrio qinghaiensis sp.-Q67. AB - Luminescent bacterial test is a fast and sensitive method for acute toxicity assessment of water and wastewater. In this study, an improved toxicity testing method was developed using the freshwater luminescent bacteria Vibrio qinghaiensis sp.-Q67 that involved pretreatment of water samples with reverse osmosis (RO) to eliminate the interferences caused by nutrients in concentrated samples and to improve the reliability and sensitivity of the analysis. Because water samples contain low concentrations of several target toxic substances, rapid acute toxicity testing method that is commonly employed does not achieve enough sensitivity. The proposed RO pretreatment could effectively enrich organic and inorganic substances in water samples to enable a more effective and sensitive toxicity evaluation. The kinetic characteristics of toxicity of raw sewage and secondary effluent were evaluated based on the relative luminescence unit (RLU) curves and time-concentration-effect surfaces. It was observed that when the exposure time was prolonged to 8-h or longer, the bacteria reached the logarithmic growth stage. Hence, the stimulating effects of the coexisting ions (such as Na(+), K(+), NO3(-)) in the concentrated samples could be well eliminated. A 10-h exposure time in proposed Q67 test was found to quantitatively evaluate the toxicity of the organic and inorganic pollutants in the RO concentrated samples. PMID- 23988110 TI - Short- and long-term effects of a novel on connectivity in the brain. AB - We sought to determine whether reading a novel causes measurable changes in resting-state connectivity of the brain and how long these changes persist. Incorporating a within-subjects design, participants received resting-state functional magnetic resonance imaging scans on 19 consecutive days. First, baseline resting state data for a "washin" period were taken for each participant for 5 days. For the next 9 days, participants read 1/9th of a novel during the evening and resting-state data were taken the next morning. Finally, resting state data for a "wash-out" period were taken for 5 days after the conclusion of the novel. On the days after the reading, significant increases in connectivity were centered on hubs in the left angular/supramarginal gyri and right posterior temporal gyri. These hubs corresponded to regions previously associated with perspective taking and story comprehension, and the changes exhibited a timecourse that decayed rapidly after the completion of the novel. Long-term changes in connectivity, which persisted for several days after the reading, were observed in bilateral somatosensory cortex, suggesting a potential mechanism for "embodied semantics." PMID- 23988111 TI - Differential binding of latrunculins to G-actin: a molecular dynamics study. AB - Latrunculins are unique macrolides containing a thiazolidinone moiety. Latrunculin A (1), latrunculin B (2), 16-epi-latrunculin B (3), and latrunculin T (4) were isolated from the Red Sea sponge Negombata magnifica. In the present study, after testing compounds 2-4 for cytotoxic activity, they were docked into the crystal structure of G-actin and subjected to binding energy calculation and a 20 ns MD simulation. The modeling study shows that latrunculins binding depends on both hydrophobic interaction of the macrocycle as well as H bonding of the thiazolidinone ring with Asp157 and Thr186. It was noticed that epimerization at C16 of latrunculin B was well tolerated as it could form an alternative H bonding network. However, opening of the macrocyclic ring deteriorates the actin binding due to reduced hydrophobicity. MD simulation showed that latrunculin B (2) possesses a more significant stabilizing effect on G-actin than latrunculin T (4) and could efficiently hinder the flattening transition of G-actin into F-actin. These findings could explain, at the molecular level, the impact of epimerization and macrolide ring-opening on latrunculins activity, an issue that has not been addressed before. Also, the study gives insights into the mechanism of cytotoxicity of diverse latrunculins and provides direction for future lead optimization studies. PMID- 23988112 TI - Crystal structure of Psb31, a novel extrinsic protein of photosystem II from a marine centric diatom and implications for its binding and function. AB - Psb31 is a fifth extrinsic protein found in photosystem II (PSII) of a centric diatom, Chaetoceros gracilis . The protein has been shown to bind directly to PSII in the absence of other extrinsic proteins and serves in part as a substitute for PsbO in supporting oxygen evolution. We report here the crystal structure of Psb31 at a resolution of 1.55 A. The structure of Psb31 was composed of two domains, one major, N-terminal four helical domain and one minor, flexible C-terminal domain. The four helices in the N-terminal domain were arranged in an up-down-up-down fold, which appeared unexpectedly to be similar to the structure of spinach PsbQ, in spite of their low sequence homology. This suggests that the centric diatom PSII contains another PsbQ-type extrinsic protein in addition to the original PsbQ protein found in the organism. On the other hand, the C terminal domain of Psb31 has a unique structure composed of one loop and one short helix. Based on these structural analysis and chemical cross-linking experiments, residues responsible for the binding of Psb31 to PSII intrinsic proteins were suggested. The results are discussed in relation to the copy number of extrinsic proteins in higher plant PSII. PMID- 23988113 TI - The British Columbia Nephrologists' Access Study (BCNAS) - a prospective, health services interventional study to develop waiting time benchmarks and reduce wait times for out-patient nephrology consultations. AB - BACKGROUND: Early referral and management of high-risk chronic kidney disease may prevent or delay the need for dialysis. Automatic eGFR reporting has increased demand for out-patient nephrology consultations and in some cases, prolonged queues. In Canada, a national task force suggested the development of waiting time targets, which has not been done for nephrology. METHODS: We sought to describe waiting time for outpatient nephrology consultations in British Columbia (BC). Data collection occurred in 2 phases: 1) Baseline Description (Jan 18-28, 2010) and 2) Post Waiting Time Benchmark-Introduction (Jan 16-27, 2012). Waiting time was defined as the interval from receipt of referral letters to assessment. Using a modified Delphi process, Nephrologists and Family Physicians (FP) developed waiting time targets for commonly referred conditions through meetings and surveys. Rules were developed to weigh-in nephrologists', FPs', and patients' perspectives in order to generate waiting time benchmarks. Targets consider comorbidities, eGFR, BP and albuminuria. Referred conditions were assigned a priority score between 1-4. BC nephrologists were encouraged to centrally triage referrals to see the first available nephrologist. Waiting time benchmarks were simultaneously introduced to guide patient scheduling. A post-intervention waiting time evaluation was then repeated. RESULTS: In 2010 and 2012, 43/52 (83%) and 46/57 (81%) of BC nephrologists participated. Waiting time decreased from 98(IQR44,157) to 64(IQR21,120) days from 2010 to 2012 (p = <.001), despite no change in referral eGFR, demographics, nor number of office hrs/wk. Waiting time improved most for high priority patients. CONCLUSIONS: An integrated, Provincial initiative to measure wait times, develop waiting benchmarks, and engage physicians in active waiting time management associated with improved access to nephrologists in BC. Improvements in waiting time was most marked for the highest priority patients, which suggests that benchmarks had an influence on triaging behavior. Further research is needed to determine whether this effect is sustainable. PMID- 23988115 TI - Understanding the ways in which health visitors manage anxiety in cross-cultural work: a qualitative study. AB - AIM: This paper is a report of part of a study that explored the ways in which health visitors manage uncertainty and anxiety when working with clients across cultures. BACKGROUND: Internationally health care professionals are required to deliver a high standard of culturally appropriate care to increasingly diverse communities and yet problems persist. Research evidence informing cultural 'competence' is focused largely around student experience and consequently little is known about the day-to-day experiences of health professionals in diverse community settings. Anxiety and uncertainty are increasingly recognised as important emotions experienced by a variety of health care professionals when working across cultures and yet the ways in which anxiety and uncertainty is managed in practice is less well understood. DESIGN: Grounded theory methodology was used and 21 semi-structured interviews were conducted with participating health visitors in the North East of England between May 2008 and September 2009. All participants described themselves as white. FINDINGS: This study identified three different positions adopted by the health visitors to manage uncertainty and anxiety in their work across cultures. Identified as, 'Fixing a culture', 'Reworking the equality agenda' and 'Asserting the professional self', these strategies identify the ways in which health visitors try to manage the uncertainty and anxiety they feel when working in diverse communities. All of these strategies attempt in different ways to negate cultural difference and to render culture as static and known. CONCLUSION: Given that health professionals report anxiety and uncertainty when working across diverse community settings, identification of the strategies used by health visitors to manage that anxiety is important for both policy and practice. New strategies need to be developed to help health professionals to manage uncertainty and anxiety in ways that promote both cultural safe care and health equity. PMID- 23988114 TI - Interactions between HIV-1 Vif and human ElonginB-ElonginC are important for CBF beta binding to Vif. AB - BACKGROUND: The HIV-1 accessory factor Vif is necessary for efficient viral infection in non-permissive cells. Vif antagonizes the antiviral activity of human cytidine deaminase APOBEC3 proteins that confer the non-permissive phenotype by tethering them (APOBEC3DE/3F/3G) to the Vif-CBF-beta-ElonginB ElonginC-Cullin5-Rbx (Vif-CBF-beta-EloB-EloC-Cul5-Rbx) E3 complex to induce their proteasomal degradation. EloB and EloC were initially reported as positive regulatory subunits of the Elongin (SIII) complex. Thereafter, EloB and EloC were found to be components of Cul-E3 complexes, contributing to proteasomal degradation of specific substrates. CBF-beta is a newly identified key regulator of Vif function, and more information is needed to further clarify its regulatory mechanism. Here, we comprehensively investigated the functions of EloB (together with EloC) in the Vif-CBF-beta-Cul5 E3 ligase complex. RESULTS: The results revealed that: (1) EloB (and EloC) positively affected the recruitment of CBF beta to Vif. Both knockdown of endogenous EloB and over-expression of its mutant with a 34-residue deletion in the COOH-terminal tail (EloBDeltaC34/EBDeltaC34) impaired the Vif-CBF-beta interaction. (2) Introduction of both the Vif SLQ -> AAA mutant (VifDeltaSLQ, which dramatically impairs Vif-EloB-EloC binding) and the Vif PPL -> AAA mutant (VifDeltaPPL, which is thought to reduce Vif-EloB binding) could reduce CBF-beta binding. (3) EloB-EloC but not CBF-beta could greatly enhance the folding of full-length Vif in Escherichia coli. (4) The over expression of EloB or the N-terminal ubiquitin-like (UbL) domain of EloB could significantly improve the stability of Vif/VifDeltaSLQ/VifDeltaPPL through the region between residues 9 and 14. CONCLUSION: Our results indicate that the Vif interaction with EloB-EloC may contribute to recruitment of CBF-beta to Vif, demonstrating that the EloB C-teminus may play a role in improving Vif function and that the over-expression of EloB results in Vif stabilization. PMID- 23988116 TI - Balance and knee extensibility evaluation of hemiplegic gait using an inertial body sensor network. AB - BACKGROUND: Most hemiplegic patients have difficulties in their balance and posture control while walking because of the asymmetrical posture and the abnormal body balance. The assessment of rehabilitation of hemiplegic gait is usually made by doctors using clinical scale, but it is difficult and could not be used frequently. It is therefore needed to quantitatively analyze the characteristics of hemiplegic gait. Thus the assessment would be simple, and real time evaluation of rehabilitation could be carried out. METHODS: Twenty subjects (ten hemiplegic patients, ten normal subjects) were recruited. The subjects walked straight for five meters at their self-selected comfortable speed towards a target line on the floor.Xsens MTx motion trackers were used for acquiring gestures of body segments to estimate knee joint angles and identify gait cycles. A practical method for data acquisition that does not need to obtain accurate distances between a knee joint and its corresponding sensors is presented. RESULTS: The results showed that there were significant differences between the two groups in the three nominated angle amplitudes. The mean values of balance level of each parameter in hemiplegic gait and normal gait were: 0.21 versus 0.01, 0.18 versus 0.03, and 0.92 versus 0.03, respectively. The mean values of added angles of each parameter in hemiplegic gait and normal gait were: 74.64 versus 91.31, -76.48 versus -132.4, and 6.77 versus 35.74. CONCLUSIONS: It was concluded that the wearable bio-motion acquisition platform provided a practical approach that was effective in discriminating gait symptoms between hemiplegic and asymptomatic subjects. The extensibility of hemiplegic patients' lower limbs was significantly lower than that of normal subjects, and the hemiplegic gait had worse balance level compared with normal gait. The effect of rehabilitation training of hemiplegic gait could be quantitatively analyzed. PMID- 23988117 TI - Adaptive translation as a mechanism of stress response and adaptation. AB - The composition of the cellular proteome is commonly thought to strictly adhere to the genetic code. However, accumulating evidence indicates that cells also regulate the synthesis of mutant protein molecules that deviate from the genetic code. Production of mutant proteins generally occurs when cells are stressed or when they undergo environmental adaptation, but production varies in amounts and specificity. The deliberate synthesis of mutant proteins suggests that some of these proteins can be useful in cellular stress response and adaptation. This review describes the occurrence of, the translation mechanisms for, and the functional hypotheses on regulated synthesis of mutant proteins. PMID- 23988118 TI - Estimation and partition of heritability in human populations using whole-genome analysis methods. AB - Understanding genetic variation of complex traits in human populations has moved from the quantification of the resemblance between close relatives to the dissection of genetic variation into the contributions of individual genomic loci. However, major questions remain unanswered: How much phenotypic variation is genetic; how much of the genetic variation is additive and can be explained by fitting all genetic variants simultaneously in one model, and what is the joint distribution of effect size and allele frequency at causal variants? We review and compare three whole-genome analysis methods that use mixed linear models (MLMs) to estimate genetic variation. In all methods, genetic variation is estimated from the relationship between close or distant relatives on the basis of pedigree information and/or single nucleotide polymorphisms (SNPs). We discuss theory, estimation procedures, bias, and precision of each method and review recent advances in the dissection of genetic variation of complex traits in human populations. By using genome-wide data, it is now established that SNPs in total account for far more of the genetic variation than the statistically highly significant SNPs that have been detected in genome-wide association studies. All SNPs together, however, do not account for all of the genetic variance estimated by pedigree-based methods. We explain possible reasons for this remaining "missing heritability." PMID- 23988120 TI - Radiation effects on human heredity. AB - In experimental organisms such as fruit flies and mice, increased frequencies in germ cell mutations have been detected following exposure to ionizing radiation. In contrast, there has been no clear evidence for radiation-induced germ cell mutations in humans that lead to birth defects, chromosome aberrations, Mendelian disorders, etc. This situation exists partly because no sensitive and practical genetic marker is available for human studies and also because the number of people exposed to large doses of radiation and subsequently having offspring was small until childhood cancer survivors became an important study population. In addition, the genome of apparently normal individuals seems to contain large numbers of alterations, including dozens to hundreds of nonfunctional alleles. With the number of mutational events in protein-coding genes estimated as less than one per genome after 1 gray (Gy) exposure, it is unsurprising that genetic effects from radiation have not yet been detected conclusively in humans. PMID- 23988121 TI - Expression of deleted in liver cancer 1 and plasminogen activator inhibitor 1 protein in ovarian carcinoma and their clinical significance. AB - BACKGROUND: The deleted in liver cancer 1 (DLC1) and plasminogen activator inhibitor 1 (PAI-1) are known to be closely associated with tumor growth and metastasis in several kinds of human tumors. The aim of this study was to investigate the expression of DLC1 and PAI-1 in ovarian carcinoma, and evaluate their relations with the prognosis of ovarian carcinoma. METHODS: Immunohistochemical staining and Western blot were used to examine the expressions of DLC1 and PAI-1 protein in 25 specimens normal ovarian tissues, 52 specimens of serous cystadenocarcinoma tissues and 23 specimens of mucinous cystadenocarcinoma tissues. Chi-square test, Logistic regression and Partial Correlate analysis were performed to evaluate the association between DLC1 and PAI-1 with clinicopathological characteristics. Overall survival was estimated by Kaplan-Meier curves and multivariate Cox analysis. The relationships between DLC1 and PAI-1 protein expression were analyzed by Pearson's correlation coefficient. RESULTS: The expression of DLC1 protein in ovarian carcinoma tissues was significantly lower than that in normal ovarian tissues, but it was converse for PAI-1. In ovarian carcinoma, the expression of DLC1 was significantly associated with advanced FIGO stage, ascites and positive lymph node metastasis, whereas PAI 1 protein was closely related with advanced FIGO stage, poor histological differentiation and lymph node metastasis. The expression of DLC1 was negatively correlated with PAI-1 in ovarian carcinoma. Ovarian cancer patients with negative expression of DLC1 and positive expression of PAI-1 had the worst overall survival time compared to other patients. CONCLUSIONS: The expression of DLC1 and PAI-1 were closely related with the metastasis and invasion of ovarian carcinoma, only the combination of DLC1 and PAI-1 could serve as an independent prognostic factor of ovarian carcinoma. PMID- 23988122 TI - Modulation of aldose reductase inhibition by halogen bond tuning. AB - In this paper, we studied a designed series of aldose reductase (AR) inhibitors. The series was derived from a known AR binder, which had previously been shown to form a halogen bond between its bromine atom and the oxygen atom of the Thr-113 side chain of AR. In the series, the strength of the halogen bond was modulated by two factors, namely bromine-iodine substitution and the fluorination of the aromatic ring in several positions. The role of the single halogen bond in AR ligand binding was elucidated by advanced binding free energy calculations involving the semiempirical quantum chemical Hamiltonian. The results were complemented with ultrahigh-resolution X-ray crystallography and IC50 measurements. All of the AR inhibitors studied were shown by X-ray crystallography to bind in an identical manner. Further, it was demonstrated that it was possible to decrease the IC50 value by about 1 order of magnitude by tuning the strength of the halogen bond by a monoatomic substitution. The calculations revealed that the protein-ligand interaction energy increased upon the substitution of iodine for bromine or upon the addition of electron withdrawing fluorine atoms to the ring. However, the effect on the binding affinity was found to be more complex due to the change of the solvation/desolvation properties within the ligand series. The study shows that it is possible to modulate the strength of a halogen bond in a protein-ligand complex as was designed based on the previous studies of low-molecular-weight complexes. PMID- 23988119 TI - Dissecting social cell biology and tumors using Drosophila genetics. AB - Cancer was seen for a long time as a strictly cell-autonomous process in which oncogenes and tumor-suppressor mutations drive clonal cell expansions. Research in the past decade, however, paints a more integrative picture of communication and interplay between neighboring cells in tissues. It is increasingly clear as well that tumors, far from being homogenous lumps of cells, consist of different cell types that function together as complex tissue-level communities. The repertoire of interactive cell behaviors and the quantity of cellular players involved call for a social cell biology that investigates these interactions. Research into this social cell biology is critical for understanding development of normal and tumoral tissues. Such complex social cell biology interactions can be parsed in Drosophila. Techniques in Drosophila for analysis of gene function and clonal behavior allow us to generate tumors and dissect their complex interactive biology with cellular resolution. Here, we review recent Drosophila research aimed at understanding tissue-level biology and social cell interactions in tumors, highlighting the principles these studies reveal. PMID- 23988123 TI - Structural requirements of 2-oxoglutaric acid analogues to mimic its signaling function. AB - A 2-oxoglutaric acid (2-OG) probe bearing a methylene group introduced at the C4 position and a vinyl group to replace the carbonyl group at the C2 position elicited characteristic affinity for NtcA, the 2-OG receptor, while maintaining the signaling function of the parent natural metabolite 2-OG. This discovery opens new perspectives in the design, synthesis, and implementation of specific 2 OG analogues as molecular probes for investigating the complex 2-OG signaling pathways. PMID- 23988124 TI - Promiscuity as a functional trait: intrinsically disordered regions as central players of interactomes. AB - Because of their pervasiveness in eukaryotic genomes and their unique properties, understanding the role that ID (intrinsically disordered) regions in proteins play in the interactome is essential for gaining a better understanding of the network. Especially critical in determining this role is their ability to bind more than one partner using the same region. Studies have revealed that proteins containing ID regions tend to take a central role in protein interaction networks; specifically, they act as hubs, interacting with multiple different partners across time and space, allowing for the co-ordination of many cellular activities. There appear to be three different modules within ID regions responsible for their functionally promiscuous behaviour: MoRFs (molecular recognition features), SLiMs (small linear motifs) and LCRs (low complexity regions). These regions allow for functionality such as engaging in the formation of dynamic heteromeric structures which can serve to increase local activity of an enzyme or store a collection of functionally related molecules for later use. However, the use of promiscuity does not come without a cost: a number of diseases that have been associated with ID-containing proteins seem to be caused by undesirable interactions occurring upon altered expression of the ID containing protein. PMID- 23988129 TI - Preoperative atrial fibrillation and long-term survival after open heart surgery in a rural tertiary heart institute. AB - BACKGROUND: Preoperative atrial fibrillation (AF) is associated with increased morbidity and mortality after open heart surgery. However, the impact of preoperative AF on long-term survival after open heart surgery has not been widely examined in rural populations. Patients from rural regions are less likely to receive treatment for cardiac conditions and to have adequate medical insurance coverage. OBJECTIVE: To examine the influence of preoperative AF on long-term survival following open heart surgery in rural eastern North Carolina. METHODS: Long-term survival was compared in patients with and without preoperative AF after coronary artery bypass grafting (CABG) and CABG plus valve (CABG + V) surgery between 2002 and 2011. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. RESULTS: The study population consisted of 5438 patients. A total of 263 (5%) patients had preoperative AF. Preoperative AF was an independent predictor of long-term survival (open heart surgery: adjusted HR = 1.6, 95% CI = 1.3-2.0; CABG: adjusted HR = 1.6, 95% CI = 1.3-2.1; CABG + V: adjusted HR = 1.6, 95% CI = 1.1-2.3). CONCLUSION: Preoperative AF is an important predictor of long-term survival after open heart surgery in this rural population. PMID- 23988130 TI - Leukapheresis in childhood acute leukemias: single-center experience. AB - Hyperleukocytosis in patients with leukemia is associated with early mortality, especially due to the pulmonary and neurological complications of leukostasis. The prompt use of leukapheresis may improve patients' survival in the initial treatment period. The medical records of all previously untreated acute leukemia patients were reviewed to determine whether there was hyperleukocytosis at presentation. This study summarizes a single-center experience of leukapheresis that was applied to 12 children with acute leukemia and hyperleukocytosis. The median leukocyte count at diagnosis was 589,000/mm(3) (range: 389,000 942,000/mm(3)) for ALL patients and 232,000/mm(3) (range: 200,000-282,000/mm(3)) for AML patients. A central venous catheter (CVC) was inserted, and leukapheresis procedures were repeated at 12-hour intervals. A total of 29 leukapheresis cycles were performed on 12 children. The median number of cycles of leukapheresis required by each patient was two (range: 1-4). The median absolute and percentage reductions in white blood cell (WBC) count after the first cycle of leukapheresis were 113,000/mm(3) (range: 55,000-442,000/mm(3)) and 36% (range: 16-57.4%), respectively. As a laboratory finding, mild hypocalcemia was the most frequently observed complication. No patients developed any other problem related to the procedure. Our results showed that leukapheresis is a safe and effective procedure if performed by experienced staff. PMID- 23988131 TI - Transcranial direct current stimulation over multiple days improves learning and maintenance of a novel vocabulary. AB - INTRODUCTION: Recently, growing interest emerged in the enhancement of human potential by means of non-invasive brain stimulation. In particular, anodal transcranial direct current stimulation (atDCS) has been shown to exert beneficial effects on motor and higher cognitive functions. However, the majority of transcranial direct current stimulation (tDCS) studies have assessed effects of single stimulation sessions that are mediated by transient neural modulation. Studies assessing the impact of multiple stimulation sessions on learning that may induce long-lasting behavioural and neural changes are scarce and have not yet been accomplished in the language domain in healthy individuals. METHOD: The present study probed the potential of atDCS to enhance language learning over multiple days by employing an explicit word learning paradigm. Forty healthy young participants were randomized to learning with either simultaneous atDCS or sham stimulation (N = 20/group; comparable regarding demographic variables and neurocognitive status). All participants acquired a novel vocabulary (familiar and novel object picture - non-word pairs) over five consecutive days. Two memory tasks (free recall; forced choice recognition tasks) were administered immediately after each training session. A one week follow-up tested the maintenance of learning success. RESULTS: Linear mixed effects model analysis revealed superior learning during atDCS compared to sham stimulation for both familiar and novel objects. atDCS yielded a steeper learning curve and significantly more pronounced learning at the end of the training during the recall task. During the recognition task, the atDCS group reached ceiling levels earlier and overall learning success was greater. For both tasks, beneficial atDCS effects were maintained during the follow-up assessment. CONCLUSIONS: The present study provides direct evidence that atDCS administered during multiple learning sessions facilitates language learning and that effects are maintained over time. This study contributes important novel information about the extent of stimulation effects in the healthy brain, thereby highlighting the potential of atDCS to enhance language recovery after stroke. PMID- 23988125 TI - Physiological and pathological roles of mitochondrial SLC25 carriers. AB - The mitochondrion relies on compartmentalization of certain enzymes, ions and metabolites for the sake of efficient metabolism. In order to fulfil its activities, a myriad of carriers are properly expressed, targeted and folded in the inner mitochondrial membrane. Among these carriers, the six-transmembrane helix mitochondrial SLC25 (solute carrier family 25) proteins facilitate transport of solutes with disparate chemical identities across the inner mitochondrial membrane. Although their proper function replenishes building blocks needed for metabolic reactions, dysfunctional SLC25 proteins are involved in pathological states. It is the purpose of the present review to cover the current knowledge on the role of SLC25 transporters in health and disease. PMID- 23988133 TI - A comparison of the electrosensory morphology of a euryhaline and a marine stingray. AB - The electrosensory system is found in all chondrichthyan fishes and is used for several biological functions, most notably prey detection. Variation in the physical parameters of a habitat type, i.e. water conductivity, may influence the morphology of the electrosensory system. Thus, the electrosensory systems of freshwater rays are considerably different from those of fully marine species; however, little research has so far examined the morphology and distribution of these systems in euryhaline elasmobranchs. The present study investigates and compares the morphology and distribution of electrosensory organs in two sympatric stingray species: the (euryhaline) estuary stingray, Dasyatis fluviorum, and the (marine) blue-spotted maskray, Neotrygon kuhlii. Both species possess a significantly higher number of ventral electrosensory pores than previously assessed elasmobranchs. This correlates with a diet consisting of benthic infaunal and epifaunal prey, where the electrosensory pore distribution patterns are likely to be a function of both ecology and phylogeny. The gross morphology of the electrosensory system in D. fluviorum is more similar to that of other marine elasmobranch species, rather than that of freshwater species. Both D. fluviorum and N. kuhlii possess 'macro-ampullae' with branching canals leading to several alveoli. The size of the pores and the length of the canals in D. fluviorum are smaller than in N. kuhlii, which is likely to be an adaptation to habitats with lower conductivity. This study indicates that the morphology of the electrosensory system in a euryhaline elasmobranch species seems very similar to that of their fully marine counterparts. However, some morphological differences are present between these two sympatric species, which are thought to be linked to their habitat type. PMID- 23988132 TI - People-selectivity, audiovisual integration and heteromodality in the superior temporal sulcus. AB - The functional role of the superior temporal sulcus (STS) has been implicated in a number of studies, including those investigating face perception, voice perception, and face-voice integration. However, the nature of the STS preference for these 'social stimuli' remains unclear, as does the location within the STS for specific types of information processing. The aim of this study was to directly examine properties of the STS in terms of selective response to social stimuli. We used functional magnetic resonance imaging (fMRI) to scan participants whilst they were presented with auditory, visual, or audiovisual stimuli of people or objects, with the intention of localising areas preferring both faces and voices (i.e., 'people-selective' regions) and audiovisual regions designed to specifically integrate person-related information. Results highlighted a 'people-selective, heteromodal' region in the trunk of the right STS which was activated by both faces and voices, and a restricted portion of the right posterior STS (pSTS) with an integrative preference for information from people, as compared to objects. These results point towards the dedicated role of the STS as a 'social-information processing' centre. PMID- 23988134 TI - Comorbidity of schizotypy and psychopathy: skin conductance to affective pictures. AB - Prior research indicates a relationship between psychopathy and schizophrenia, elucidating a specific trajectory toward violence. Recent research has suggested that this relationship exists at the nonclinical trait level of schizotypy; however, this finding has not been examined objectively. To explore this relationship using both subjective and objective measures, 54 undergraduates (50% male; mean age 20.41) who endorsed a wide range of schizotypy on the Schizotypal Personality Questionnaire (SPQ) completed a laboratory-based protocol. Participants viewed 15 pictures (five neutral, five threatening, and five of others in distress) from the International Affective Pictures System while electrodermal activity was recorded. As expected, all participants exhibited increased skin conductance levels (SCL) to threat and distress pictures compared to neutral pictures; however, no difference in SCL was found between threat and distress pictures. A unique relationship between psychopathy and schizotypy was found (i.e., schizotypy was related to higher Self-Centered Impulsivity and lower Fearless Dominance); however, schizotypy was related to increased SCL in response to emotional and neutral pictures. Although results do not support autonomic hyporesponsiveness often found in clinical psychopathy, a positive relationship was found between schizotypy and self-reported physical aggression. Findings highlight the need to examine other trajectories of violence within the schizophrenia spectrum disorders. PMID- 23988136 TI - Short bowel syndrome/intestinal failure. PMID- 23988135 TI - Cortical folding is altered before surgery in infants with congenital heart disease. AB - Infants with congenital heart disease have altered brain development. We characterized cortical folding, a critical part of brain development, in congenital heart disease infants and demonstrated an overall decrease in cortical surface area and cortical folding with regional alterations in the right lateral sulcus and left orbitofrontal region, cingulate region, and central sulcus. These abnormalities were present prior to surgery. PMID- 23988137 TI - Bedside ultrasound diagnosis of acute embolic femoral artery occlusion. AB - BACKGROUND: Acute limb ischemia is both a limb-threatening and life-threatening disease process. Nontraumatic acute peripheral arterial occlusion is most commonly caused by a thrombosis or an embolism. OBJECTIVES: There is limited evidence on the use of bedside ultrasound for the detection of acute limb ischemia, but duplex ultrasonography is standard in the diagnosis and operative planning in chronic limb ischemia. Emergency physicians may use bedside ultrasound in the evaluation of patients with symptoms and signs suggestive of this disease entity. CASE REPORT: A 64-year-old man with a past medical history of hypertension and an ischemic stroke presented to the Emergency Department with <2 h of severe upper left leg pain that radiated down to his foot. A bedside ultrasound of the left lower extremity was emergently performed. On B-mode ultrasound evaluation, echogenic material was visualized in the left common femoral artery, the artery was noncompressible, and there was an absence of Doppler flow signal. He was then directly taken to the operating room for an emergent limb-saving procedure. CONCLUSION: A focused examination of the aorta, iliac vessels, and femoral artery bifurcation with bedside ultrasonography may help to localize peripheral arterial occlusions and can assist the emergency physician in seeking timely surgical consultation and management. PMID- 23988138 TI - Acute nontraumatic spinal intradural hematoma in a patient on warfarin. AB - BACKGROUND: Nontraumatic spinal intradural extramedullary hematomas are extremely rare. When they occur, they can rapidly lead to spinal cord or cauda equina compression and have devastating consequences. OBJECTIVE: The aim here was to report a case of this rare phenomenon and discuss the etiology, imaging, management, and outcome of intradural hematomas. CASE REPORT: We describe the case of a 76-year-old man on warfarin therapy who presented with severe lower back pain and flaccid paraparesis. Blood tests revealed an international normalized ratio of 6.0. A magnetic resonance imaging result suggested an intradural hematoma extending from L1 to L4 and compressing the spinal cord and cauda equina. Emergency surgical decompression revealed an extensive intradural extramedullary hematoma, which was evacuated. The patient showed only minor neurologic improvement 6 months postoperatively. CONCLUSIONS: Coagulopathy induced spinal hemorrhage should be included in the differential diagnosis for patients presenting with signs of acute spinal cord compression. PMID- 23988139 TI - Repeated episodes of respiratory failure due to bilateral vocal cord paralysis. AB - BACKGROUND: Bilateral vocal cord paralysis can produce severe airway obstruction, leading to acute respiratory failure. Discriminating the pathology of the upper airway from chronic obstructive diseases of the lower airways often presents a challenge for clinicians in the Emergency Department. OBJECTIVES: To underlie the value of clinical examination and flow-volume loops in the establishment of diagnosis of upper airway obstruction. CASE REPORT: We describe the case of a 55 year-old female ex-smoker who presented with a long history of hoarseness and progressive exertional dyspnea. The patient developed repeated episodes of acute respiratory failure and was supported with noninvasive ventilation. The diagnosis of bilateral vocal cord paralysis was finally established by patient's symptoms and flow-volume loops demonstrating variable extrathoracic obstruction. CONCLUSION: Vocal cord paralysis is a rare and often neglected condition, contributing to repeated episodes of acute respiratory failure. Flow-volume loop is a useful tool when symptoms are suggestive of upper airway obstruction. PMID- 23988140 TI - Cardiovocal syndrome arising from gas-forming mycotic aneurysm of the thoracic aorta. PMID- 23988141 TI - Emergency department management of patients with ACE-inhibitor angioedema. AB - BACKGROUND: Angiotensin-converting-enzyme inhibitors (ACEI) are one of the most prescribed medications worldwide. Angioedema is a well-recognized adverse effect of this class of medications, with a reported incidence of ACEI angioedema of up to 1.0%. Of importance to note, ACEI angioedema is a class effect and is not dose dependent. The primary goal of this literature search was to determine the appropriate Emergency Department management of patients with ACEI angioedema. METHODS: A MEDLINE literature search from January 1990 to August 2012 and limited to human studies written in English for articles with keywords of ACEI angioedema. Guideline statements and non-systematic reviews were excluded. Studies identified then underwent a structured review from which results could be evaluated. RESULTS: Five hundred sixty-two papers on ACEI angioedema were screened and 27 appropriate articles were rigorously reviewed in detail and recommendations given. CONCLUSION: The literature search did not support any specific treatment protocol with a high level of evidence due to the limited--and limitations of the--available studies. PMID- 23988142 TI - Shock one week after abdominal surgery. PMID- 23988143 TI - Ultrasound-guided arthrocentesis of the elbow: a posterior approach. AB - BACKGROUND: Identification of fluid in the elbow joint by physical examination alone can be challenging. Ultrasound can assist in the diagnosis of elbow effusion, and guide aspiration of the effusion. OBJECTIVES: We illustrate the anatomy and ultrasound guidance technique of a posterior approach to elbow arthrocentesis using examples of normal and pathologic elbow joint ultrasound images. DISCUSSION: The posterior distal humerus at the level of the olecranon fossa provides an excellent acoustic window into the joint space. This location also provides a safe path for the performance of ultrasound-guided arthrocentesis. CONCLUSION: Ultrasound-guided arthrocentesis of the elbow from a posterior approach is a helpful technique to guide the aspiration of the painful swollen elbow. PMID- 23988144 TI - In memoriam: to Ron Krome, my hero and my friend. PMID- 23988145 TI - Virtual surgical planning for treatment of severe mandibular retrognathia with collapsed occlusion using contemporary surgical and prosthodontic protocols. AB - PURPOSE: To meet functional and esthetic needs in an older adult for treatment of complex skeletal and dentoalveolar deformities using contemporary surgical and prosthodontic protocols. METHODS: An older adult with dentoalveolar complex and skeletal deformity (mandibular retrognathia) was treated by a combination of virtual planning and current surgical and prosthodontic protocols. Treatment planning steps and sequencing are presented. RESULTS: Skeletal, soft tissue, and dental harmonies were attained without biological or mechanical complications. Definitive oral rehabilitation was completed with a maxillary complete denture and a mandibular metal ceramic fixed implant-retained prosthesis. CONCLUSIONS: A surgical and prosthodontic team approach in combination with technologic advances can predictably optimize esthetic and functional outcomes for patients with complex skeletal and dentoalveolar deformities. PMID- 23988146 TI - Postsurgical stability after mandibular setback surgery with minimal orthodontic preparation following upper premolar extraction. AB - PURPOSE: To compare patterns of surgical change and postsurgical relapse between patients with mandibular setback surgery with minimal orthodontic preparation (MS MO) and those with sufficient orthodontic preparation (MS-SO) after upper premolar extraction (UPE). MATERIALS AND METHODS: Twenty-six patients were allocated to 2 groups based on the duration of presurgical orthodontic preparation: MS-MO/UPE (n = 15; 5.53 +/- 3.14 months) and MS-SO/UPE (n = 11; 13.00 +/- 5.33 months). Lateral cephalograms were taken during the initial examination (T0), at splint removal (4 weeks after surgery; T1), and immediately after debonding (T2). To evaluate the surgical changes (T1 vs. T0) and relapse (T2 vs. T1), linear, angular, and dental measurements were used and analyzed using paired t test and independent t test. RESULTS: Although there was no significant difference in skeletodental patterns at T0 between the 2 groups, the MS-MO/UPE group showed a significantly larger amount of mandibular setback than the MS-SO/UPE group from T0 to T1. The 2 groups exhibited significant anterior and superior movement of the mandible from T1 to T2. However, the MS-MO/UPE group manifested greater counterclockwise rotation and forward movement of the mandible than the MS-SO/UPE group. Owing to such relapse of the mandible, the MS-MO/UPE group exhibited limited retraction of the upper incisors, whereas the MS-SO/UPE group showed slight labioversion of the upper incisors. CONCLUSION: Compared with the MS-SO/UPE group, the MS-MO/UPE group showed a larger amount of surgical setback and greater postsurgical counterclockwise rotation and forward movement of the mandible. PMID- 23988147 TI - Temporal-order judgment of audiovisual events involves network activity between parietal and prefrontal cortices. AB - Our perception of the temporal order of everyday external events depends on the integrated sensory information in the brain. Our understanding of the brain mechanism for temporal-order judgment (TOJ) of unisensory events, particularly in the visual domain, is advanced. In case of multisensory events, however, there are unanswered questions. Here, by using physically synchronous and asynchronous auditory-visual events in functional magnetic resonance imaging (fMRI) experiments, we identified the brain network that is associated with the perception of the temporal order of multisensory events. The activation in the right temporo-parietal junction was modulated by the perception of asynchronous audiovisual events. During this perception of temporal order, the right dorsolateral prefrontal cortex coordinated activity with the right temporo parietal and the left inferior parietal cortices. These results suggest that the TOJ in the multisensory domain underlies a network activity between parietal and prefrontal cortices unlike the regional activity in the right temporo-parietal junction in the unisensory visual domain. PMID- 23988149 TI - Cell metabolomics. AB - Abstract Metabolomics technologies enable the examination and identification of endogenous biochemical reaction products, revealing information on the precise metabolic pathways and processes within a living cell. Metabolism is either directly or indirectly involved with every aspect of cell function, and metabolomics is thus believed to be a reflection of the phenotype of any cell. Metabolomics analysis of cells has many potential applications and advantages compared to currently used methods in the postgenomics era. Cell metabolomics is an emerging field that addresses fundamental biological questions and allows one to observe metabolic phenomena in cells. Cell metabolomics consists of four sequential steps: (a) sample preparation and extraction, (b) metabolic profiles of low-weight metabolites based on MS or NMR spectroscopy techniques, (c) pattern recognition approaches and bioinformatics data analysis, (d) metabolites identification resulting in putative biomarkers and molecular targets. The biomarkers are eventually placed in metabolic networks to provide insight on the cellular biochemical phenomena. This article analyzes the recent developments in use of metabolomics to characterize and interpret the cellular metabolome in a wide range of pathophysiological and clinical contexts, and the putative roles of the endogenous small molecule metabolites in this new frontier of postgenomics biology and systems medicine. PMID- 23988150 TI - Multi-locus candidate gene analyses of lipid levels in a pediatric Turkish cohort: lessons learned on LPL, CETP, LIPC, ABCA1, and SHBG. AB - Cardiovascular risk factors and atherosclerosis precursors were examined in 365 Turkish children and adolescents. Study participants were recruited at five different state schools. We tested single and multi-locus effects of six polymorphisms from five candidate genes, chosen based on prior known association with lipid levels in adults, for association with low (<=10th percentile) high density lipoprotein cholesterol (HDL-C) and high (>=90th percentile) triglycerides (TG), and the related continuous outcomes. We observed an association between CETP variant rs708272 and low HDL-C (allelic p=0.020, genotypic p=0.046), which was supported by an independent analysis, PRAT (PRAT control p=0.027). Sex-stratified logistic regression analysis showed that the B2 allele of rs708272 decreased odds of being in the lower tenth percentile of HDL-C measurements (OR=0.36, p=0.02) in girls; this direction of effect was also seen in boys but was not significant (OR=0.64, p=0.21). Logistic regression analysis also revealed that the T allele of rs6257 (SHBG) decreased odds of being in the top tenth percentile of TG measurements in boys (OR=0.43, p=0.03). Analysis of lipid levels as a continuous trait revealed a significant association between rs708272 (CETP) and LDL-C levels in males (p=0.02) with the B2B2 genotype group having the lowest mean LDL-C; the same direction of effect was also seen in females (p=0.05). An effect was also seen between rs708272 and HDL-C levels in girls (p=0.01), with the B2B2 genotype having the highest mean HDL-C levels. Multi-locus analysis, using quantitative multifactor dimensionality reduction (qMDR) identified the previously mentioned CETP variant as the best single locus model, and overall model, for predicting HDL-C levels in children. This study provides evidence for association between CETP and low HDL-C phenotype in children, but the results appear to be weaker in children than previous results in adults and may also be subject to gender effects. PMID- 23988151 TI - MMGBSA as a tool to understand the binding affinities of filamin-peptide interactions. AB - Filamins (FLN) are large dimeric proteins that cross-link actin and work as important scaffolds in human cells. FLNs consist of an N-terminal actin-binding domain followed by 24 immunoglobulin-like domains (FLN1-24). FLN domains are divided into four subgroups based on their amino acid sequences. One of these subgroups, including domains 4, 9, 12, 17, 19, 21, and 23, shares a similar ligand-binding site between the beta strands C and D. Several proteins, such as integrins beta2 and beta7, glycoprotein Ibalpha (GPIbalpha), and migfilin, have been shown to bind to this site. Here, we computationally estimated the binding free energies of filamin A (FLNa) subunits with bound peptides using the molecular mechanics-generalized Born surface area (MMGBSA) method. The obtained computational results correlated well with the experimental data, and they ranked efficiently both the binding of one ligand to all used FLNa-domains and the binding of all used ligands to FLNa21. Furthermore, the steered molecular dynamics (SMD) simulations pinpointed the binding hot spots for these complexes. These results demonstrate that molecular dynamics combined with free energy calculations are applicable to estimating the energetics of protein-protein interactions and can be used to direct the development of novel FLN function modulators. PMID- 23988152 TI - Structure and dynamics of the N-terminal domain of the Cu(I) binding protein CusB. AB - CusCFBA is one of the metal efflux systems in Escherichia coli that is highly specific for its substrates, Cu(I) and Ag(I). It serves to protect the bacteria in environments that have lethal concentrations of these metals. The membrane fusion protein CusB is the periplasmic piece of CusCFBA, which has not been fully characterized by crystallography because of its extremely disordered N-terminal region. This region has both structural and functional importance because it has been experimentally proven to transfer the metal by itself from the metallochaperone CusF and to induce a structural change in the rest of CusB to increase Cu(I)/Ag(I) resistance. Understanding metal uptake from the periplasm is critical to gain insight into the mechanism of the whole CusCFBA pump, which makes resolving a structure for the N-terminal region necessary because it contains the metal binding site. We ran extensive molecular dynamics simulations to reveal the structural and dynamic properties of both the apo and Cu(I)-bound versions of the CusB N-terminal region. In contrast to its functional companion CusF, Cu(I) binding to the N-terminus of CusB causes only a slight, local stabilization around the metal site. The trajectories were analyzed in detail, revealing extensive structural disorder in both the apo and holo forms of the protein. CusB was further analyzed by breaking the protein up into three subdomains according to the extent of the observed disorder: the N- and C terminal tails, the central beta strand motif, and the M21-M36 loop connecting the two metal-coordinating methionine residues. Most of the observed disorder was traced back to the tail regions, leading us to hypothesize that the latter two subdomains (residues 13-45) may form a functionally competent metal-binding domain because the tail regions appear to play no role in metal binding. PMID- 23988153 TI - Recurrence of perinatal death in Northern Tanzania: a registry based cohort study. AB - BACKGROUND: Perinatal mortality is known to be high in Sub-Saharan Africa. Some women may carry a particularly high risk which would be reflected in a high recurrence risk. We aim to estimate the recurrence risk of perinatal death using data from a hospital in Northern Tanzania. METHODS: We constructed a cohort study using data from the hospital based KCMC Medical Birth Registry. Women who delivered a singleton for the first time at the hospital between 2000 and 2008 were followed in the registry for subsequent deliveries up to 2010 and 3,909 women were identified with at least one more delivery within the follow-up period. Recurrence risk of perinatal death was estimated in multivariate models analysis while adjusting for confounders and accounting for correlation between births from the same mother. RESULTS: The recurrence risk of perinatal death for women who had lost a previous baby was 9.1%. This amounted to a relative risk of 3.2 (95% CI: 2.2 - 4.7) compared to the much lower risk of 2.8% for women who had had a surviving baby. Recurrence contributed 21.2% (31/146) of perinatal deaths in subsequent pregnancies. Preeclampsia, placental abruption, placenta previa, induced labor, preterm delivery and low birth weight in a previous delivery with a surviving baby were also associated with increased perinatal mortality in the next pregnancy. CONCLUSIONS: Some women in Tanzanian who suffer a perinatal loss in one pregnancy are at a particularly high risk of also losing the baby of a subsequent pregnancy. Strategies of perinatal death prevention that target pregnant women who are particularly vulnerable or already have experienced a perinatal loss should be considered in future research. PMID- 23988155 TI - Manufacturing conditioned roughness and wear of biomedical oxide ceramics for all ceramic knee implants. AB - BACKGROUND: Ceramic materials are used in a growing proportion of hip joint prostheses due to their wear resistance and biocompatibility properties. However, ceramics have not been applied successfully in total knee joint endoprostheses to date. One reason for this is that with strict surface quality requirements, there are significant challenges with regard to machining. High-toughness bioceramics can only be machined by grinding and polishing processes. The aim of this study was to develop an automated process chain for the manufacturing of an all-ceramic knee implant. METHODS: A five-axis machining process was developed for all ceramic implant components. These components were used in an investigation of the influence of surface conformity on wear behavior under simplified knee joint motion. RESULTS: The implant components showed considerably reduced wear compared to conventional material combinations. Contact area resulting from a variety of component surface shapes, with a variety of levels of surface conformity, greatly influenced wear rate. CONCLUSIONS: It is possible to realize an all-ceramic knee endoprosthesis device, with a precise and affordable manufacturing process. The shape accuracy of the component surfaces, as specified by the design and achieved during the manufacturing process, has a substantial influence on the wear behavior of the prosthesis. This result, if corroborated by results with a greater sample size, is likely to influence the design parameters of such devices. PMID- 23988156 TI - Introduction: special issue on animal health and climate change. PMID- 23988154 TI - SIV replication is directly downregulated by four antiviral miRNAs. AB - BACKGROUND: Host cell microRNAs (miRNAs) have been shown to regulate the expression of both cellular and viral RNAs, in particular impacting both Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). To investigate the role of miRNAs in regulating replication of the simian immunodeficiency virus (SIV) in macrophage lineage cells, we used primary macrophages to study targeting of SIV RNA by miRNAs. We examined whether specific host miRNAs directly target SIV RNA early in infection and might be induced via type I interferon pathways. RESULTS: miRNA target prediction programs identified miRNA binding sites within SIV RNA. Predicted binding sites for miRs-29a, -29b, -9 and -146a were identified in the SIV Nef/U3 and R regions, and all four miRNAs decreased virus production and viral RNA expression in primary macrophages. To determine whether levels of these miRNAs were affected by SIV infection, IFNbeta or TNFalpha treatments, miRNA RT-qPCR assays measured miRNA levels after infection or treatment of macrophages. SIV RNA levels as well as virus production was downregulated by direct targeting of the SIV Nef/U3 and R regions by four miRNAs. miRs-29a, -29b, 9 and -146a were induced in primary macrophages after SIV infection. Each of these miRNAs was regulated by innate immune signaling through TNFalpha and/or the type I IFN, IFNbeta. CONCLUSIONS: The effects on miRNAs caused by HIV/SIV infection are illustrated by changes in their cellular expression throughout the course of disease, and in different patient populations. Our data demonstrate that levels of primary transcripts and mature miRs-29a, -29b, -9 and -146a are modulated by SIV infection. We show that the SIV 3' UTR contains functional miRNA response elements (MREs) for all four miRNAs. Notably, these miRNAs regulate virus production and viral RNA levels in macrophages, the primary cells infected in the CNS that drive inflammation leading to HIV-associated neurocognitive disorders. This report may aid in identification miRNAs that target viral RNAs and HIV/SIV specifically, as well as in identification of miRNAs that may be targets of new therapies to treat HIV. PMID- 23988157 TI - Cu(TFA)2-catalyzed oxidative tandem cyclization/1,2-alkyl migration of enamino amides for synthesis of pyrrolin-4-ones. AB - A novel Cu(TFA)2-catalyzed oxidative tandem cyclization/1,2-alkyl migration of readily available enamino amides for the synthesis of pyrrolin-4-ones has been developed. The reaction tolerates a wide range of functional groups and is a reliable method for the rapid synthesis of substituted pyrrolin-4-ones in high yields under mild conditions. PMID- 23988159 TI - Protein conformational populations and functionally relevant substates. AB - Functioning proteins do not remain fixed in a unique structure, but instead they sample a range of conformations facilitated by motions within the protein. Even in the native state, a protein exists as a collection of interconverting conformations driven by thermodynamic fluctuations. Motions on the fast time scale allow a protein to sample conformations in the nearby area of its conformational landscape, while motions on slower time scales give it access to conformations in distal areas of the landscape. Emerging evidence indicates that protein landscapes contain conformational substates with dynamic and structural features that support the designated function of the protein. Nuclear magnetic resonance (NMR) experiments provide information about conformational ensembles of proteins. X-ray crystallography allows researchers to identify the most populated states along the landscape, and computational simulations give atom-level information about the conformational substates of different proteins. This ability to characterize and obtain quantitative information about the conformational substates and the populations of proteins within them is allowing researchers to better understand the relationship between protein structure and dynamics and the mechanisms of protein function. In this Account, we discuss recent developments and challenges in the characterization of functionally relevant conformational populations and substates of proteins. In some enzymes, the sampling of functionally relevant conformational substates is connected to promoting the overall mechanism of catalysis. For example, the conformational landscape of the enzyme dihydrofolate reductase has multiple substates, which facilitate the binding and the release of the cofactor and substrate and catalyze the hydride transfer. For the enzyme cyclophilin A, computational simulations reveal that the long time scale conformational fluctuations enable the enzyme to access conformational substates that allow it to attain the transition state, therefore promoting the reaction mechanism. In the long term, this emerging view of proteins with conformational substates has broad implications for improving our understanding of enzymes, enzyme engineering, and better drug design. Researchers have already used photoactivation to modulate protein conformations as a strategy to develop a hypercatalytic enzyme. In addition, the alteration of the conformational substates through binding of ligands at locations other than the active site provides the basis for the design of new medicines through allosteric modulation. PMID- 23988158 TI - Experimental verification of structural alerts for the protein binding of cyclic compounds acting as Michael acceptors. AB - This study outlines how a combination of and in vitro data can be used to define the applicability domain of selected structural alerts within the protein binding profilers of the Organisation for Economic Co-operation (OECD) Quantitative Structure-Activity Relationship (QSAR) Toolbox. Thirty chemicals containing a cyclic moiety were profiled for reactivity using the OECD and Optimised Approach based on Structural Indices Set (OASIS) protein binding profilers. The profiling results identified 22 of the chemicals as being reactive towards proteins. Analysis of the experimentally data showed 19 of these chemicals to be reactive. Subsequent analysis allowed refinements to be suggested to improve the applicability domain of the structural alerts investigated. The accurate definition of the applicability domain for structural alerts within in silico profilers is important due to their use in chemical category in predictive and regulatory toxicology. PMID- 23988160 TI - Geological sequestration of biomass char to mitigate climate change. PMID- 23988161 TI - LeView: automatic and interactive generation of 2D diagrams for biomacromolecule/ligand interactions. AB - : 2D diagrams are widely used in the scientific literature to represent interactions between ligands and biomacromolecules. Such schematic diagrams are very helpful to better understand the chemical interactions and biological processes in which ligands are involved. Here, a new tool for automatic and interactive generation of 2D diagrams for biomacromolecule/ligand interactions is presented. LeView (Ligand-Environment Viewer) produces customised and high quality figures, with a good compromise between a faithful representation of the 3D data (structures and interactions) and aesthetic criteria. LeView can be freely downloaded at http://www.pegase-biosciences.com/tools/leview/. PMID- 23988162 TI - Expanded porphyrin-like structures based on twinned triphenylenes. AB - Triphenylene twins are intriguing structures, and those bridged through their 3,6 positions by dipyrromethene units give a new class of macrocycles that can be viewed as rigid, expanded porphyrin derivatives in which coplanarity is enforced in a formally antiaromatic pi system. Somewhat surprisingly, however, macrocyclization leads to significant overall stabilization of the dipyrromethene chromophores. PMID- 23988163 TI - Effect of co-administration of morphine and nicotine on cardiovascular function in two-kidney one clip hypertensive (2K1C) rats. AB - Cardiovascular morbidity and mortality are potentiated with smoking and hypertension. The aim of this study was to investigate the effects of morphine and nicotine co-administration on cardiovascular function in two-kidney one-clip hypertensive (2K1C) rats. Thirty-two male rats were divided into four groups as follow: Vehicle, morphine, nicotine and nicotine + morphine. All drugs were administered for 8 weeks. Baroreflex sensitivity (BRS), heart rate and blood pressure were measured using a Power Lab data acquisition. Plasma rennin activity (PRA) and serum concentration of nitric oxide (NO) were measured using Elisa method. To induce hypertension, the renal artery of left kidney was clipped for 8 weeks. A significant decrease in systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) was observed in nicotine + morphine group compared to vehicle and nicotine groups (p<0.05). Serum concentration of NO was lower in nicotine + morphine group compared to morphine group and significantly higher than nicotine group. The BRS was lower in the nicotine + morphine group compared to other groups. The PRA level was higher in nicotine + morphine compared to morphine group but it was higher than nicotine group. This study demonstrated that prolonged co-consumption of morphine and nicotinedecreased PRA and blood pressure and increased the serum concentration of NO in hypertensive rats. Co-administration of morphine and nicotine decreased BRS in 2k1c hypertensive rats probably via central nervous system. PMID- 23988164 TI - Activation of M1 mAChRs by lesatropane rescues glutamate neurotoxicity in PC12 cells via PKC-mediated phosphorylation of ERK1/2. AB - Lesatropane, a synthesized chiral tropane (3S, 6S-isomer of satropane), is a novel muscarinic agonist, and is being under preclinical development in China for the treatment of primary glaucoma. The reports concerning that activation of muscarinic acetylcholine receptors (mAChRs) could protect cells against apoptosis prompted us to study the neuroprotective effects of lesatropane and the mechanism. We found that lesatropane could protect PC12 cells from glutamate induced neurotoxicity and reverse the decreased ERK1/2 activation caused by glutamate. Atropine or pirenzepine, antagonist of mAChR or M1 mAChR, antagonized the protective effects of lesatropane respectively and suppressed the lesatropane's effects on ERK1/2. Furthermore, chelerythrine, a PKC inhibitor, partially suppressed ERK1/2 activation induced by lesatropane. The results indicated that the specific M1 mAChR via PKC-ERK1/2 pathway might be involved in the neuroprotective effects of lesatropane. While M1 mAChR is a therapeutic target of Alzheimer's disease (AD), the results of this paper contribute to further information concerning the activation of M1 mAChR as a therapeutic target in AD. PMID- 23988165 TI - Pathologic morphology of acute experimental osteomyelitis. AB - The goal of our work was to study the changes in the bone tissue, bone marrow and surrounding tissues in animals during early stages of experimental osteomyelitis. Osteomyelitis was simulated in 30 infants rabbits aged 3-4 months whose body weight accounted 1200-1600 grams through the insertion of 5-6 million of aurococcus into the marrow channel of a shinbone. The study of bone marrow, bone tissue and surrounding tissue was conducted 30 minutes, 6, 12, 24, 48 and 60 hours after the contamination with the help of light and electronic (transmission and scanning) microscopy. It was proved that the first changes are characterized by the evident changes in the vessel's walls which cause the swelling of bone marrow and suppurative inflammation in the bone tissue occurs only in the end of the 3d day of the experiment. These data confirm the necessity of osteoperfortation during the first 24 hours of contamination in order to remove the swelling and to correct vessel disorders. PMID- 23988166 TI - Association of dopamine receptor gene polymorphism and psychological personality traits in liability for opioid addiction. AB - There is a clear evidence that same psychoactive substance may cause various individual physiological reactions in same environmental conditions. Although there is a general attitude on equal liability to opioid addiction, latest genetic analysis findings imply there are certain quantifiable factors that could lead to elevated individual liability towards development of opioid addiction. The goal of this study was to investigate association of certain personality traits and genetic factors (separately and in combination) with heroin addiction. Total of 200 individuals participated in the study: 100 patients on Metadone Maintenance Treatment (MMT) and 100 age and sex matched healthy volunteers. All were medically examined, interviewed and psychologically evaluated using Eysenck personality questionnaire (EPQ) and genotyped for DRD2 (rs1800497) using PCR-RFLP method. Overrepresentation of certain personality traits (neuroticism, psychoticism and extraversion/ intraversion), together with environemental risk factors such as: upbringing within incomplete families and familial history of psychotropic substances abuse, are associated with high-risk development of opioid addiction. PMID- 23988167 TI - Evaluation of emm gene types, toxin gene profiles and clonal relatedness of group A streptococci. AB - The aim of this study is to evaluate antibiotic susceptibilities, emm gene types, toxin gene profiles and clonal relatedness of group A streptococci (GAS) isolates obtained from patients and carriers. A total of 79 clinical isolates from patients and 60 isolates from carriers were included in the study. Emm typing, toxin gene detection for speA, speB, speC, speG and smeZ genes and pulsed-field gel electrophoresis (PFGE) was performed. Twenty-one distinct emm types were detected; the most common types were emm12, emm89, emm1, emm77, emm4 and emm3. The detection rates of both emm types and the toxin genes didn't differ significantly between patients and carriers. The presence of speA and smeZ was significantly higher in emm1 and speG was significantly lower in emm4 when compared to the other emm types. The rate of clustering obtained with PFGE wasn't significantly different in patients and carriers. As a result, twelve of the 21 emm types detected in this study were covered by the 26-valent vaccine, constituting 77.7% of the emm typeable isolates; however the emm4 type which is one of the most common types in the present study is not among this coverage. PMID- 23988168 TI - Kidney injury molecule-1 expression is closely associated with renal allograft damage. AB - The aim of our study was to investigate the expression of kidney injury molecule 1 (KIM-1) in renal allograft biopsy samples and assess the clinical significance of its use as a biomarker for tissue damage. A total of 69 renal allograft biopsy samples from 17 patients with normal serum creatinine and 52 cases of increased serum creatinine were collected. They were divided into different groups according to the Banff 2007 diagnostic criteria. KIM-1 expression was detected by immunohistochemical methods and the association of KIM-1 and blood biochemical indexes was analyzed. KIM-1 expression increased as Banff 2007 classification grade increased and was positively correlated with tubular inflammation severity in the acute T-cell rejection group. Moreover, KIM-1 expression was strongly positive in the chronic active antibody-mediated rejection group. Interestingly, KIM-1 was weakly positive in the normal group without obvious acute rejection and injury of immunosuppressant toxicity. In this group, 27.3% (3/11) of the cases with normal serum creatinine level showed weakly positive KIM-1 expression in their renal tissues. KIM-1 expression level is positively correlated with renal allograft damage and tubular cell injury. KIM-1 is expressed in tubular epithelial cells before blood biochemical indexes become elevated and morphological changes occur. KIM-1 expression is an early, sensitive, and specific biomarker to determine renal tubular epithelial cell injury in renal allograft tissue. PMID- 23988169 TI - Electrophysiological effects of bosentan in rats with induced cerebral ischemia reperfusion. AB - We examined the effect of bosentan, an ETA and ETB receptor antagonist, on EEG, an indicator of neuronal activity, in rats with experimentally induced cerebral ischemia-reperfusion. The rats were divided into three groups with seven rats in each group. Before the procedures, the EEGs of all rats were recorded for ten minutes. 30 mg/kg bosentan in 2 cc physiological serum was administered to the first group, and the second and third groups were injected with 2 cc physiological serum intraperitoneally. After the administration, the right and the left common carotid arteries of the animals in Groups 1 and 2 were clipped for 10 minutes using aneurysm clippings. The rats in the third group received only a subcutaneous incision. Ten minutes after the clips were removed in the first and second groups and after the incision in the third group, EEG recordings were repeated for 10 minutes. All the rats were decapitated and MDA values in the brain tissue were measured for evaluation of the efficiency of induced cerebral ischemia. Induced cerebral ischemia was performed effectively because the MDA levels in Groups 1 and 2 were elevated, compared to the levels in Group 3 (p<0.05). After the application of the Cerebral Ischemia-Reperfusion Technique, the EEG showed minimal slowing in the rats in Group 1, and generalized diffuse slowing in the rats in Group 2 compared to pre-ischemic findings. Bosentan may reduce the damage induced by ischemia on neuronal electrophysiology, likely through its vasodilation effect on cerebral vessels. PMID- 23988170 TI - Evaluation of endocrine changes in women with the polycystic ovary syndrome during metformin treatment. AB - The aim of study was to evaluate endocrine changes in PCOS women during metformin treatment. One hundred women with PCOS, aged 20-40 years were included. A complete hormonal and metabolic pattern was recorded for each subject every 6 months. Metformin treatment after 6 and 12 months significantly reduced weight, BMI, waist circumference, insulin and HOMA-IR (p=0.000) with high differences of variances within repeated measurements. There was significant reduction of PRL, testosterone and estradiol (p=0.000) with small differences within repeated measurements. Metformin did not have effect on TSH. However, results showed important reduction of CRP, LH, LH/FSH, androstendione, DHEA-S and progesterone (p=0.000) with moderate differences within measures. Metformin restored menstrual cyclicity in most participants. At baseline in study group was 69% women with oligomenorrhoea, amenorrhoea or polymenorrhoea. After 12 months of treatment, only 20% PCOS women had irregular menstrual cycle (p=0.000). Hirsutism was also reduced. Intriguingly, during first 6 months of treatment in PCOS women 9 pregnancies occurred (p=0.000), while during last 6 months treatment were 2 pregnancies (p=0.317), in total 11(13%). Multiple regression model revealed that the presence of anovulation in PCOS women was strongly associated with BMI, waist, FSH and age. Insulin resistance was significantly predicted by BMI, cholesterol, progesterone and presence of hirsutism. The metformin therapy significantly improved insulin resistance, imbalance of endocrine hormones, hirsutism and menstrual cyclicity in women with PCOS. The most important predictors for duration of metformin treatment in PCOS women were testosterone, progesterone, FSH, CRP and presence of anovulation. PMID- 23988171 TI - Induction of apoptosis by grape seed extract (Vitis vinifera) in oral squamous cell carcinoma. AB - Development of novel therapeutic modalities is crucial for the treatment of oral squamous cell carcinoma (OSCC). Recent scientific studies have been focused on herbal medicines as potent anti-cancer drug candidates. This study is the first to investigate the cytotoxic effects and the mechanism of cell death induced by grape seed extract (GSE) in oral squamous cell carcinoma (KB cells). MTT (3-(4,5 dimetylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) and trypan blue assays were performed in KB cells as well as human umbilical vein endothelial cells (HUVEC) were used to analyze the cytotoxic activity of GSE. Furthermore, the apoptosis inducing action of the extract was determined by TUNEL, DNA fragmentation and cell death analysis. Statistical significance was determined by analysis of variance (ANOVA), followed by Duncan's test at a significance level of P<=0.05. The results showed apoptotic potential of GSE, confirmed by significant inhibition of cell growth and viability in a dose- and time- dependent manner without inducing damage to non-cancerous cell line HUVEC. The results of this study suggest that this plant contains potential bioactive compound(s) for the treatment of oral squamous cell carcinoma. PMID- 23988172 TI - Plasma leptin values in postmenopausal women with osteoporosis. AB - Obesity has a protective effect against osteoporosis and this effect has been attributed to a high body fat content. It has been shown that the leptin concentration is higher in obese patients. Leptin, the protein product of obesity gene, is a hormone produced in adipose tissue. Some studies suggest that endogenous leptin might influence bone metabolism in postmenopausal women. In this study, we investigated plasma leptin concentrations in postmenopausal women with osteoporosis and also analyzed the relationship between plasma leptin levels and bone mineral density (BMD) in order to understand the potential role of leptin in maintaining bone mass. Forty-two postmenopausal women with osteoporosis and thirty seven age and BMI-matched healthy postmenopausal women were included in the study. The mean femoral neck BMD value in the patient group was significantly lower than that in the control group (0.691+/-0.1 g/cm2 and 0.863+/ 0.1 g/cm2, respectively; p<0.001). The mean plasma leptin concentration in the patient group was not significantly different from that in the control group (p>0.05). Plasma leptin levels were correlated with BMI in both groups (p<0.001 in the patient group and p=0.001 in controls). There was also a strong positive correlation between plasma leptin levels and %fat in both groups (p<0.001 in the patient group and p<0.001 in controls). But there was no correlation between plasma leptin levels and femoral neck BMD values in both groups. Our results do not support the hypothesis that leptin itself plays an important role in maintaining bone mass in postmenopausal women. PMID- 23988173 TI - In vitro fluoride release from a different kind of conventional and resin modified glass-ionomer cements. AB - Fluoride release is important characteristic of glass-ionomer cements. Quantity of fluoride ions released from the glass-ionomer cements has major importance in definition of their biological activity. The objectives of this study were to define the quantity of fluoride ions released from the experimental glass-ionomer cements and to define the effect of fluoride ions released from the experimental glass-ionomer cements on their cytotoxicity. Concentrations of the fluoride ions released in the evaluated glass-ionomer cements were measured indirectly, by the fluoride-selective WTW, F500 electrode potential, combined with reference R503/D electrode. Statistical analyses of F-ion concentrations released by all glass ionomers evaluated at two time points, after 8 and after 24 hours, show statistically higher fluoride releases from RMGICs: Vitrebond, Fuji II LC and Fuji Plus, when compared to conventional glass-ionomer cements: Fuji Triage, Fuji IX GP Fast and Ketac Silver, both after 8 and after 24 hours. Correlation coefficient between concentrations of fluoride ion released by evaluated glass ionomer cements and cytotoxic response of UMR-106 osteoblast cell-line are relatively high, but do not reach levels of biological significance. Correlation between concentrations of fluoride ion released and cytotoxic response of NIH3T3 mouse fibroblast cell line after 8 hours is high, positive and statistically significant for conventional GICs, Fuji Triage and Fuji IX GP Fast, and RMGIC, Fuji II LC. Statistically significant Correlation coefficient between concentrations of fluoride ion released and cytotoxic response of NIH3T3 cell line after 24 hours is defined for RMGIC Fuji II LC only. PMID- 23988174 TI - Clinics related to acute pancreatitis wonder whether IFN-gamma can attenuate pancreatic injury or not. PMID- 23988175 TI - Mammalian pheromones. AB - Mammalian pheromones control a myriad of innate social behaviors and acutely regulate hormone levels. Responses to pheromones are highly robust, reproducible, and stereotyped and likely involve developmentally predetermined neural circuits. Here, I review several facets of pheromone transduction in mammals, including (a) chemosensory receptors and signaling components of the main olfactory epithelium and vomeronasal organ involved in pheromone detection; (b) pheromone-activated neural circuits subject to sex-specific and state-dependent modulation; and (c) the striking chemical diversity of mammalian pheromones, which range from small, volatile molecules and sulfated steroids to large families of proteins. Finally, I review (d) molecular mechanisms underlying various behavioral and endocrine responses, including modulation of puberty and estrous; control of reproduction, aggression, suckling, and parental behaviors; individual recognition; and distinguishing of own species from predators, competitors, and prey. Deconstruction of pheromone transduction mechanisms provides a critical foundation for understanding how odor response pathways generate instinctive behaviors. PMID- 23988178 TI - Toxicity of daphnane-type diterpenoids from Genkwa Flos and their pharmacokinetic profile in rat. AB - Daphnane-type diterpenoids (DDs) are the main types of plant diterpene orthoesters known and have remarkable biological activities. However, the in vivo toxicity and pharmacokinetic profile of DDs remains unkonwn. The aim of this study was to investigate the toxicity and pharmacokinetic profile of DDs from Genkwa Flos (Thymelaeaceae). The toxicity of diterpenoids was evaluated after oral administration of total diterpenoids extract from Genkwa Flos to rats, and the blood concentration of diterpenoids was analyzed by ultra performance liquid chromatography tandem triple-quadrupole mass spectrometry (UPLC-TQ-MS). The diterpenoids were confirmed to be the toxic components of Genkwa Flos. The pharmacokinetic profile of these diterpenoids was quite different due to their different structures. Although the contents of yuanhuafine and yuanhuapine were low in the extract, the blood concentrations were extremely high. In contrary, the contents of genkwanine F and Wikstroemia factor M1 in the extract were much higher, but they could not be detected in the blood. This result implied that yuanhuafine and yuanhuapine but not genkwanine F and Wikstroemia factor M1 were the potentail toxic components of Genkwa Flos in vivo. This paper shows for the first time the toxicity of diterpenoids from Genkwa Flos was correlated with their blood concentration and when DDs were used for medicinal purposes, their contents in herb as well as their blood concentrations should be considered. PMID- 23988176 TI - Hypoxia-inducible factor 1 and cardiovascular disease. AB - Cardiac function is required for blood circulation and systemic oxygen delivery. However, the heart has intrinsic oxygen demands that must be met to maintain effective contractility. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis in all metazoan species. HIF-1 controls oxygen delivery, by regulating angiogenesis and vascular remodeling, and oxygen utilization, by regulating glucose metabolism and redox homeostasis. Analysis of animal models suggests that by activation of these homeostatic mechanisms, HIF-1 plays a critical protective role in the pathophysiology of ischemic heart disease and pressure-overload heart failure. PMID- 23988177 TI - Early inflammatory response to the saponin adjuvant Matrix-M in the pig. AB - The early inflammatory response to Matrix-M was evaluated in pigs. Adverse reactions measured as body temperature, appetite, activity level and reaction at the site of injection were not observed after s.c. injection with three doses of the adjuvant (75, 100 or 150MUg) into one week old piglets. Analyses of the immediate cytokine response of PBMC after in vitro exposure to Matrix-M (AbISCO 100((r))) revealed only a low expression of mRNA for tumour necrosis factor-alpha (p<0.05) after 6h incubation. Histological examination revealed an infiltration of leukocytes, haemorrhage and necrosis in muscle 24h after i.m. injection of 150MUg Matrix-M in pigs aged eleven weeks. At this time, different grades of reactive lymphoid hyperplasia were recorded in the draining lymph node that was enlarged in three of these six pigs injected with Matrix-M. The global transcriptional response at the site of injection and in the draining lymph node was analyzed using Affymetrix GeneChip Porcine Genome Array. A significant enrichment of gene signatures for the cell types described as "myeloid cells" and "plasmacytoid dendritic cells" was observed at the site of injection in Matrix-M injected pigs compared with pigs injected with saline. A number of genes encoding cytokines/chemokines or their receptors were upregulated at the injection site as well as in the draining lymph node. In the draining lymph node, a majority of the upregulated genes were interferon-regulated genes (IRGs). The expression of IFN beta, but not IFN-alpha, was increased in the draining lymph nodes of a majority of the pigs exposed to Matrix-M. These IFN-beta expressing pigs also expressed increased levels of osteopontin (OPN) or stimulator of interferon genes (STING), two factors known to facilitate the expression of type I IFNs in response to viral infection. Thus, Matrix-M does not appear to induce any harmful inflammatory response in piglets whilst contributing to the innate immunity by activating the type I IFN system, possibly through several alternative signalling pathways. PMID- 23988179 TI - Cognitive-coping therapy for obsessive-compulsive disorder: a randomized controlled trial. AB - Pharmacotherapy and cognitive-behavioral therapy (CBT) are widely used to treat obsessive-compulsive disorder (OCD). These treatments have helped many patients with OCD, but there still is room for improvement. Recently, a promising psychotherapy for OCD, cognitive-coping therapy (CCT), has been developed. Pharmacotherapy plus CCT (PCCT) demonstrates higher efficacy in a shorter period of time and lower relapses than pharmacotherapy or pharmacotherapy plus CBT. In this randomized controlled trial, we investigated the efficacy of CCT for OCD treatment. One hundred and forty-five OCD patients were randomly assigned into two groups: pharmacotherapy (N = 72) and PCCT (N = 73). In each group, drug resistant (DR) and non-drug-resistant (NDR) OCD were further analyzed to examine the efficacy of CCT. Some clinical features and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) were blindly assessed pre-treatment and post-treatment at week 1, 2, 3, 4, and 12. The Y-BOCS scores were significantly lower in PCCT than in the pharmacotherapy group at any post-treatment time-point (P < 0.001). Compared with pre-treatment, the Y-BOCS scores were significantly reduced at any time-point (P < 0.001) in PCCT group, but only at week 12 (P < 0.001) in the pharmacotherapy group. In the PCCT group, there were no differences between DR and NDR groups' Y-BOCS scores at any post-treatment time-point. The response rates and remission rates were higher in PCCT than in the pharmacotherapy group. Three variables, the number of weeks of treatment, insight, and disregarding of obsessions, were significantly correlated with the Y-BOCS score. Therefore, CCT might be a potential treatment for OCD. PMID- 23988180 TI - Effect of blood handling conditions on progesterone assay results obtained by chemiluminescence in the bitch. AB - Assay of blood progesterone (P4) is commonly practiced to determine the time of ovulation, diagnose luteal insufficiency, and predict time of parturition in bitches. Because of practical constraints, most blood samples cannot be assayed on site immediately after collection. The aim of this work was to evaluate the effects of various sampling and storage conditions on concentrations of P4 as determined by chemiluminescence immunoassay. The blood of 5 Beagle bitches was collected from the jugular vein to study the effect of the type of collection tube (silicone, lithium heparin, EDTA), the storage time of unseparated or separated plasma (2 h to 14 d), and the number of freeze-thaw cycles (1-10) on P4. The effect of each factor was tested within one assay session. None of the factors significantly affected P4. Thus, P4 appears to remain relatively stable in canine blood samples exposed to various processing and storage conditions. PMID- 23988182 TI - Psychometric validation of a German version of the compulsive Internet use scale. AB - Excessive Internet use and Internet addiction are currently increasing in many industrial nations. Verified and validated measuring instruments could contribute to a better understanding of this still quite recent development. The aim of this survey was to investigate the psychometric properties of a German version of the Compulsive Internet Use Scale (CIUS). We surveyed a representative German quota sample of 1,723 adolescents aged between 14 and 17 years, as well as one parent each, with standardized questionnaires. In addition, adolescents and parents were asked whether the media use by the youth was considered problematic or excessive, and whether it led to arguments at home. We conducted confirmatory factor analyses (CFA) with maximum likelihood estimation to examine the factorial validity of the German CIUS, as well as reliability and correlation analyses. The results of the CFA indicate good psychometric properties for the German version of the CIUS. They appear in line with the findings for the original version of the questionnaire. Furthermore, the CIUS showed high internal consistency, and we found significant correlations between the "CIUS-summary score" and different ratings of problems with the media usage by the youth and the parents. The German version of the CIUS seems to be a valid and suitable diagnostic tool for measuring problematic to pathological Internet use. PMID- 23988183 TI - Induction of hypoxia by vascular disrupting agents and the significance for their combination with radiation therapy. AB - PURPOSE: This pre-clinical study was designed to investigate the effect of various vascular disrupting agents (VDAs) that have undergone or are in clinical evaluation, had on the oxygenation status of tumours and what effects that could have on the combination with radiation. MATERIAL AND METHODS: The tumour model was a C3H mammary carcinoma grown in the right rear foot of female CDF1 mice and treated when at 200 mm(3) in size. The VDAs were the flavenoid compounds flavone acetic acid (FAA) and its more recent derivative 5,6-dimethylxanthenone-4-acetic acid (DMXAA), and the leading tubulin binding agent combretastatin A-4 phosphate (CA4P) and the A-1 analogue OXi4503. Oxygenation status was estimated using the Eppendorf oxygen electrode three hours after drug injection. Radiation response was determined following single or fractionated (10 fractions in 12 days) irradiations with a 240 kV x-ray machine using either a tumour re-growth or local tumour control assay. RESULTS: All VDAs significantly reduced the oxygenation status of the tumours. They also influenced radiation response, but the affect was time and sequence dependent using single radiation schedules; an enhanced effect when the VDAs were injected at the same time or after irradiating, but no or even a reduced effect when given prior to irradiation. Only OXi4503 showed an increased response when given before the radiation. CA4P and OXi4503 also enhanced a fractionated radiation treatment if the drugs were administered after fractions 5 and 10. CONCLUSIONS: VDAs clearly induced tumour hypoxia. This had the potential to decrease the efficacy of radiation. However, if the appropriate timing and scheduling were used an enhanced effect was observed using both single and fractionated radiation treatments. PMID- 23988184 TI - Development in a naturally acidified environment: Na+/H+-exchanger 3-based proton secretion leads to CO2 tolerance in cephalopod embryos. AB - BACKGROUND: Regulation of pH homeostasis is a central feature of all animals to cope with acid-base disturbances caused by respiratory CO2. Although a large body of knowledge is available for vertebrate and mammalian pH regulatory systems, the mechanisms of pH regulation in marine invertebrates remain largely unexplored. RESULTS: We used squid (Sepioteuthis lessoniana), which are known as powerful acid-base regulators to investigate the pH regulatory machinery with a special focus on proton secretion pathways during environmental hypercapnia. We cloned a Rhesus protein (slRhP), V-type H+-ATPase (slVHA) and the Na+/H+ exchanger 3 (slNHE3) from S. lessoniana, which are hypothesized to represent key players in proton secretion pathways among different animal taxa. Specifically designed antibodies for S. lessoniana demonstrated the sub-cellular localization of NKA, VHA (basolateral) and NHE3 (apical) in epidermal ionocytes of early life stages. Gene expression analyses demonstrated that slNHE3, slVHA and slRhP are up regulated in response to environmental hypercapnia (pH 7.31; 0.46 kPa pCO2) in body and yolk tissues compared to control conditions (pH 8.1; 0.045 kPa pCO2). This observation is supported by H+ selective electrode measurements, which detected increased proton gradients in CO2 treated embryos. This compensatory proton secretion is EIPA sensitive and thus confirms the central role of NHE based proton secretion in cephalopods. CONCLUSION: The present work shows that in convergence to teleosts and mammalian pH regulatory systems, cephalopod early life stages have evolved a unique acid-base regulatory machinery located in epidermal ionocytes. Using cephalopod molluscs as an invertebrate model this work provides important insights regarding the unifying evolutionary principles of pH regulation in different animal taxa that enables them to cope with CO2 induced acid-base disturbances. PMID- 23988185 TI - Aberrant septin 9 DNA methylation in colorectal cancer is restricted to a single CpG island. AB - BACKGROUND: The septin 9 gene (SEPT9) codes for a GTP-binding protein associated with filamentous structures and cytoskeleton formation. SEPT9 plays a role in multiple cancers as either an oncogene or a tumor suppressor gene. Regulation of SEPT9 expression is complex and not well understood; however, hypermethylation of the gene was recently introduced as a biomarker for early detection of colorectal cancer (CRC) and has been linked to cancer of the breast and of the head and neck. Because the DNA methylation landscape of different regions of SEPT9 is poorly understood in cancer, we analyzed the methylation patterns of this gene in distinct cell populations from normal and diseased colon mucosa. METHODS: Laser capture microdissection was performed to obtain homogeneous populations of epithelial and stromal cells from normal, adenomatous, and tumorous colon mucosa. Microdissected samples were analyzed using direct bisulfite sequencing to determine the DNA methylation status of eight regions within and near the SEPT9 gene. Septin-9 protein expression was assessed using immunohistochemistry (IHC). RESULTS: Regions analyzed in SEPT9 were unmethylated in normal tissue except for a methylation boundary detected downstream of the largest CpG island. In adenoma and tumor tissues, epithelial cells displayed markedly increased DNA methylation levels (>80%, p <0.0001) in only one of the CpG islands investigated. SEPT9 methylation in stromal cells increased in adenomatous and tumor tissues (<=50%, p <0.0001); however, methylation did not increase in stromal cells of normal tissue close to the tumor. IHC data indicated a significant decrease (p <0.01) in Septin 9 protein levels in epithelial cells derived from adenoma and tumor tissues; Septin-9 protein levels in stromal cells were low in all tissues. CONCLUSIONS: Hypermethylation of SEPT9 in adenoma and CRC specimens is confined to one of several CpG islands of this gene. Tumor-associated aberrant methylation originates in epithelial cells; stromal cells appear to acquire hypermethylation subsequent to epithelial cells, possibly through field effects. The region in SEPT9 with disease-related hypermethylation also contains the CpGs targeted by a novel blood-based screening test (Epi proColon(r)), providing further support for the clinical relevance of this biomarker. PMID- 23988186 TI - Docking-based CoMFA and CoMSIA study of azaindole carboxylic acid derivatives as promising HIV-1 integrase inhibitors. AB - Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed based on a series of azaindole carboxylic acid derivatives that had previously been reported as promising HIV-1 integrase inhibitors. Docking studies to explore the binding mode were performed based on the highly active molecule 36. The best docked conformation of molecule 36 was used as template for alignment. The comparative molecular field analysis (CoMFA) model (including steric and electrostatic fields) yielded the cross validation q (2) = 0.655, non cross validation r (2) = 0.989 and predictive r (2) pred = 0.979. The best comparative molecular similarity indices analysis (CoMSIA) model (including steric, electrostatic, hydrophobic and hydrogen-bond acceptor fields) yielded the cross validation q (2) = 0.719, non-cross validation r (2) = 0.992 and predictive r (2) pred = 0.953. A series of new azaindole carboxylic acid derivatives were designed and the HIV-1 integrase inhibitory activities of these designed compounds were predicted based on the CoMFA and CoMSIA models. PMID- 23988188 TI - Substitution of aromatics by amines at room temperature with negative energy of activation: amino peri-arylenes as metal-free components for dye-sensitized solar cells. AB - Substitution reactions of the chemically and photochemically unusually stable perylenetetracarboxylic bisimides proceed with neat amines even below room temperature where negative effective energies of activation were found. Analogous reactions proceed with naphthalenecarboximides as the lower homologues and terrylene and quaterrylene carboximides as the higher homologues. Bathochromically absorbing dyes with a novel pattern of substitution were obtained suitable as efficient metal-free light-absorbers for dye-sensitized solar cells. PMID- 23988187 TI - A computer model of lens structure and function predicts experimental changes to steady state properties and circulating currents. AB - BACKGROUND: In a previous study (Vaghefi et al. 2012) we described a 3D computer model that used finite element modeling to capture the structure and function of the ocular lens. This model accurately predicted the steady state properties of the lens including the circulating ionic and fluid fluxes that are believed to underpin the lens internal microcirculation system. In the absence of a blood supply, this system brings nutrients to the core of the lens and removes waste products faster than would be achieved by passive diffusion alone. Here we test the predictive properties of our model by investigating whether it can accurately mimic the experimentally measured changes to lens steady-state properties induced by either depolarising the lens potential or reducing Na+ pump rate. METHODS: To mimic experimental manipulations reported in the literature, the boundary conditions of the model were progressively altered and the model resolved for each new set of conditions. Depolarisation of lens potential was implemented by increasing the extracellular [K+], while inhibition of the Na+ pump was stimulated by utilising the inherent temperature sensitivity of the pump and changing the temperature at which the model was solved. RESULTS: Our model correctly predicted that increasing extracellular [K+] depolarizes the lens potential, reducing and then reversing the magnitude of net current densities around the lens. While lowering the temperature reduced Na+ pump activity and caused a reduction in circulating current, it had a minimal effect on the lens potential, a result consistent with published experimental data. CONCLUSION: We have shown that our model is capable of accurately simulating the effects of two known experimental manipulations on lens steady-state properties. Our results suggest that the model will be a valuable predictive tool to support ongoing studies of lens structure and function. PMID- 23988189 TI - Direct cardiovascular effects of glucagon like peptide-1. AB - Current gold standard therapeutic strategies for T2DM target insulin resistance or beta cell dysfunction as their core mechanisms of action. However, the use of traditional anti-diabetic drugs, in most cases, does not significantly reduce macrovascular morbidity and mortality. Among emerging anti-diabetic candidates, glucagon like peptide-1 (GLP-1) based therapies carry special cardiovascular implications, exerting both direct as well as indirect effects. The direct cardiovascular effects of GLP-1 and its analogs remain the focus of this review. PMID- 23988190 TI - Substance abuse treatment for HIV infected young people: an open pilot trial. AB - The purpose of this study was to test an integrated cognitive behavioral and contingency management (CBT/CM) intervention for young people living with HIV (YPLH) with an alcohol and/or cannabis use disorder in an open pilot trial. Seventeen participants (ages 18-24) were recruited from three HIV community clinics. Assessments were completed at pre-and post-treatment as well as 3 month follow-up. Eighty percent of participants were retained in the study. Results suggest that the CBT/CM intervention was acceptable, feasible, and could be delivered with fidelity. Further, participants reported significant reductions in alcohol use, withdrawal symptoms, dependence symptoms and related problems, as well as co-occurring depressive symptoms and delinquent behavior across assessment periods. A trend was evident for reductions in marijuana use and related problems. Overall, these preliminary results suggest that a substance abuse CBT/CM intervention tailored to YPLH is acceptable, feasible, and holds promise for symptomatic improvement. Further testing of this type of protocol is warranted. PMID- 23988193 TI - Recent advancements in mechanical reduction methods: particulate systems. AB - The screening of new active pharmaceutical ingredients (APIs) has become more streamlined and as a result the number of new drugs in the pipeline is steadily increasing. However, a major limiting factor of new API approval and market introduction is the low solubility associated with a large percentage of these new drugs. While many modification strategies have been studied to improve solubility such as salt formation and addition of cosolvents, most provide only marginal success and have severe disadvantages. One of the most successful methods to date is the mechanical reduction of drug particle size, inherently increasing the surface area of the particles and, as described by the Noyes Whitney equation, the dissolution rate. Drug micronization has been the gold standard to achieve these improvements; however, the extremely low solubility of some new chemical entities is not significantly affected by size reduction in this range. A reduction in size to the nanometric scale is necessary. Bottom-up and top-down techniques are utilized to produce drug crystals in this size range; however, as discussed in this review, top-down approaches have provided greater enhancements in drug usability on the industrial scale. The six FDA approved products that all exploit top-down approaches confirm this. In this review, the advantages and disadvantages of both approaches will be discussed in addition to specific top-down techniques and the improvements they contribute to the pharmaceutical field. PMID- 23988194 TI - Stereoselective synthesis of 2,3-dihydropyrroles from terminal alkynes, azides, and alpha,beta-unsaturated aldehydes via N-sulfonyl-1,2,3-triazoles. AB - A stereoselective method for synthesis of trans-2,3-disubstituted 2,3 dihydropyrroles is reported. N-Sulfonyl-1,2,3-triazoles prepared from terminal alkynes generate alpha-imino rhodium carbene complexes, which when combined with alpha,beta-unsaturated aldehydes produce trans-2,3-disubstituted dihydropyrroles. The method can be successfully applied to a one-pot process starting from terminal alkynes. PMID- 23988191 TI - Assessing the generalizability of the CSAT-sponsored GAIN dataset: are the CSAT sites representative of adolescent treatment programs in the U.S.? AB - The CSAT-sponsored GAIN dataset represents one of the largest longitudinal datasets of adolescent substance use treatment currently available. Understanding the characteristics of the included treatment programs is needed to help inform whether the data are generalizable to adolescent treatment more broadly. Data from a national sample of adolescent treatment programs were compared to the CSAT funded programs to assess generalizability and understand trends over time in quality service provision. The results indicated that CSAT-funded programs had higher rates of comprehensive mental health assessments, discharge planning, HIV, STD and TB testing, and HIV/AIDS education and support. Conversely, CSAT and non CSAT-funded programs had similar rates of comprehensive substance use screening and assessment, family and aftercare counseling, drug and alcohol urine screening, case management support, and licensing. The results also showed that service provision has not changed much over the past decade and is in critical need of improvement to reflect expert-informed quality standards. PMID- 23988192 TI - Characterizing smoking, cessation services, and quit interest across outpatient substance abuse treatment modalities. AB - The majority of individuals seeking treatment for substance use disorders are cigarette smokers, yet smoking cessation is rarely addressed during treatment. Conducting a detailed smoking-related characterization of substance abuse treatment patients across treatment modalities may facilitate the development of tailored treatment strategies. This study administered a battery of self-report instruments to compare tobacco use, quit attempts, smoking knowledge and attitudes, program services, and interest in quitting among smoking patients enrolled in opioid replacement therapy (ORT) versus non-opioid replacement (non ORT). ORT compared with non-ORT participants smoked more heavily, had greater tobacco dependence, and endorsed greater exposure to smoking cessation services at their treatment programs. Favorable attitudes towards cessation during treatment were found within both groups. These data identify several potential clinical targets, most notably including confidence in abstaining and attitudes toward cessation pharmacotherapies that may be addressed by substance abuse treatment clinics. PMID- 23988195 TI - How do incorrect results change the processing of arithmetic information? Evidence from a divided visual field experiment. AB - Despite several recent important developments in understanding numerical processing of both isolated numbers and numbers in the context of arithmetic equations, the relative impact of congruency on high-level compared to low-level processing remains unclear. The current study investigated hemispheric differences in the processing of arithmetic material, as a function of semantic and perceptual congruency, using a delayed answer verification task and divided visual field paradigm. A total of 37 participants (22 females and 15 males, mean age 30.06, SD 9.78) were presented unilaterally or bilaterally with equation results that were either correct or incorrect and had a consistent or inconsistent numerical notation. Statistical analyses showed no visual field differences in a notation consistency task, whereas when judgements had to be made on mathematical accuracy there was a right visual field advantage for incorrect equations that were notation consistent. These results reveal a clear differential processing of arithmetic information by the two cerebral hemispheres with a special emphasis on erroneous calculations. Faced with incorrect results and with a consistent numerical notation, the left hemisphere outperforms its right counterpart in making mathematical accuracy decisions. PMID- 23988196 TI - Preventive effect of phosphodiesterase 5 inhibitor tadalafil on experimental post pyelonephritic renal injury in rats. AB - BACKGROUND: To evaluate the effects of Tadalafil, a phosphodiesterase 5 enzyme inhibitor, on Escherichia coli-induced renal damage in an acute pyelonephritis (PN) rat model. METHODS: Experimental PN was induced in 32 Wistar rats, and four groups were formed: group 1 (no treatment), group 2 (antibiotic), group 3 (Tadalafil), and group 4 (antibiotic + Tadalafil). Antibiotic was given on days 3 to 8, and Tadalafil was administered between days 0 and 28 of bacterial inoculation. Half of the rats were killed on the ninth day (early period) and histopathological parameters, immunohistochemical renal fibrosis markers, and oxidant/antioxidant system activities were evaluated. The rest of the rats were killed at the sixth week of the study and evaluated for histopathological parameters and renal fibrosis markers. RESULTS: Inflammatory activity was significantly milder in rats treated with antibiotic + Tadalafil versus no treatment group both in the early and late periods. In the late period, interstitial fibrosis or tubular atrophy was lower in the antibiotic + Tadalafil group versus the no treatment and antibiotic groups, and in Tadalafil versus antibiotic group. Tadalafil administration significantly reduced renal malondialdehyde and nitric oxide levels and enhanced superoxide dismutase and catalase activities. In addition, circulating tumor necrosis factor alpha, interleukin 1beta was greatly reduced in Tadalafil group versus the no treatment group. CONCLUSIONS: We have provided the first evidence that phosphodiesterase 5 enzyme inhibitor Tadalafil ameliorates circulating inflammatory cytokines, reverses oxidant/antioxidant dysfunction and eventually possesses an overall protective effect on renal tissue from Escherichia coli-induced PN-related kidney injury. Phophodieterase 5 inhibitor might be a novel therapeutic target for PN. PMID- 23988197 TI - Food for thought: food systems, livestock futures and animal health. AB - Global food security, livestock production and animal health are inextricably bound. However, our focus on the future tends to disaggregate food and health into largely separate domains. Indeed, much foresight work is either food systems or health-based with little overlap in terms of predictions or narratives. Work on animal health is no exception. Part of the problem is the fundamental misunderstanding of the role, nature and impact of the modern futures tool kit. Here, I outline three key issues in futures research ranging from methodological confusion over the application of scenarios to the failure to effectively integrate multiple methodologies to the gap between the need for more evidence and power and control over futures processes. At its core, however, a better understanding of the narrative and worldview framing much of the futures work in animal health is required to enhance the value and impact of such exercises. PMID- 23988198 TI - Therapeutic potential of the peptide leucine arginine as a new nonplant bowman birk-like serine protease inhibitor. AB - The peptide leucine arginine (pLR) belongs to a new class of cyclic peptides isolated from frog skin. Its primary sequence is similar to the reactive loop of plant Bowman-Birk inhibitors (BBI), and the recently discovered circular sunflower trypsin inhibitor-1 (SFTI-1). The conformational properties of pLR in solution were determined by NMR spectroscopy and revealed excellent structural similarity to BBI and SFTI-1. Moreover, pLR is a highly potent trypsin inhibitor, with Ki values in the nanomolar range, and, due to its small size, a potential inhibitor of the serine protease tryptase. Since tryptase plays a crucial role in the development of allergic airway inflammation, the therapeutic potential of pLR in a murine asthma model was investigated. Treatment of ovalbumin-sensitized mice with pLR during allergen challenge reduced the acute asthma phenotype. Most importantly, application even at the end of a long-lasting chronic asthma model decreased the development of chronic airway inflammation and tissue remodeling. PMID- 23988201 TI - Redox-responsive complexation between a pillar[5]arene with mono(ethylene oxide) substituents and paraquat. AB - Host-guest complexation between a pillar[5]arene with mono(ethylene oxide) substituents and paraquat was studied. We demonstrated that this pillar[5]arene can form a 1:1 complex with paraquat in solution and in the solid state. The formation of this complex was confirmed by proton NMR spectroscopy, electrospray ionization mass spectrometry, and single crystal X-ray analysis. Furthermore, this complexation can be reversibly controlled through the sequential addition and removal of Zn powder. The host substituent effect on the complexation ability was also addressed. PMID- 23988199 TI - Cigarette smoke enhances human rhinovirus-induced CXCL8 production via HuR mediated mRNA stabilization in human airway epithelial cells. AB - BACKGROUND: Human rhinovirus (HRV) triggers exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Cigarette smoking is the leading risk factor for the development of COPD and 25% of asthmatics smoke. Smoking asthmatics have worse symptoms and more frequent hospitalizations compared to non smoking asthmatics. The degree of neutrophil recruitment to the airways correlates with disease severity in COPD and during viral exacerbations of asthma. We have previously shown that HRV and cigarette smoke, in the form of cigarette smoke extract (CSE), each induce expression of the neutrophil chemoattractant and activator, CXCL8, in human airway epithelial cells. Additionally, we demonstrated that the combination of HRV and CSE induces expression of levels of CXCL8 that are at least additive relative to induction by each stimulus alone, and that enhancement of CXCL8 expression by HRV+CSE is regulated, at least in part, via mRNA stabilization. Here we further investigate the mechanisms by which HRV+CSE enhances CXCL8 expression. METHODS: Primary human bronchial epithelial cells were cultured and treated with CSE alone, HRV alone or the combination of the two stimuli. Stabilizing/destabilizing proteins adenine/uridine-rich factor-1 (AUF-1), KH-type splicing regulatory protein (KHSRP) and human antigen R (HuR) were measured in cell lysates to determine expression levels following treatment. siRNA knockdown of each protein was used to assess their contribution to the induction of CXCL8 expression following treatment of cells with HRV and CSE. RESULTS: We show that total expression of stabilizing/de-stabilizing proteins linked to CXCL8 regulation, including AUF-1, KHSRP and HuR, are not altered by CSE, HRV or the combination of the two stimuli. Importantly, however, siRNA-mediated knock-down of HuR, but not AUF-1 or KHSRP, abolishes the enhancement of CXCL8 by HRV+CSE. Data were analyzed using one-way ANOVA with student Newman-Keuls post hoc analysis and values of p<= 0.05 were considered significant. CONCLUSIONS: Induction of CXCL8 by the combination of HRV and CSE is regulated by mRNA stabilization involving HuR. Thus, targeting the HuR pathway may be an effective method of dampening CXCL8 production during HRV induced exacerbations of lower airway disease, particularly in COPD patients and asthmatic patients who smoke. PMID- 23988200 TI - Uveal metastasis from lung cancer: clinical features, treatment, and outcome in 194 patients. AB - PURPOSE: To evaluate the clinical features, treatment, and prognosis of patients with uveal metastasis from lung cancer. DESIGN: Retrospective chart review. PARTICIPANTS: There were 194 patients with a diagnosis of uveal metastasis from lung cancer. INTERVENTION: Radiotherapy, chemotherapy, enucleation, or observation. MAIN OUTCOME MEASURES: Ocular tumor control, final visual acuity, and tumor-related death. RESULTS: There were 374 uveal metastatic tumors originating from primary lung cancer in 229 eyes of 194 patients. Tumor location included choroid (88%), ciliary body (2%), and iris (10%), with bilateral involvement in 18%. Diagnosis of uveal metastasis preceded the diagnosis of primary lung cancer in 44% of patients. The choroidal metastatic focus had a mean basal diameter of 8 mm and mean thickness of 3 mm, and were mostly located posterior to the equator (91%). The choroidal metastasis commonly had yellow or orange color (98%), had plateau (61%) or dome (38%) configuration, and displayed associated subretinal fluid (85%). Choroidal tumors were multifocal in 49 cases (23%). Ciliary body tumors were commonly dome shaped (75%) with an episcleral sentinel vessel (75%). Iris tumors were multifocal in 2 cases (13%), had visible intrinsic vessels (97%), and were associated with tumor seeding in the angle (38%) or on the iris stroma (25%). The uveal metastases were treated with teletherapy (31%), chemotherapy (18%), brachytherapy (9%), chemotherapy combined with teletherapy or brachytherapy (14%), enucleation (3%), or observation (21%). At last visit, eyes with follow-up showed tumor regression (66%), stability (12%), growth (14%), recurrence (3%), or new metastasis (5%). Visual acuity improved or remained stable in 59% eyes. One-year mortality from the time of detection of uveal metastasis was 54%. CONCLUSIONS: Of 194 patients with uveal metastasis from lung cancer, 44% did not have a history of known lung cancer. Current methods of ocular treatment allow globe salvage in 92% of patients and improved/stable vision in 59% of patients. Systemic prognosis remains poor with tumor-related death in 54% of patients at 1 year. PMID- 23988202 TI - Genotyping and pathobiologic characterization of canine parvovirus circulating in Nanjing, China. AB - BACKGROUND: Canine parvovirus (CPV) is an important pathogen that causes acute enteric disease in dogs. It has mutated and spread throughout the world in dog populations. We provide an update on the molecular characterization of CPV that circulated in Nanjing, a provincial capital in China between 2009 and 2012. RESULTS: Seventy rectal swab samples were collected from the dogs diagnosed with CPV infection in 8 animal hospitals of Nanjing. Sequence analysis of VP2 genes of 31 samples revealed that 29 viral strains belonged to CPV-2a subtype, while other two strains were classified into CPV-2b. To investigate the pathogenicity of the prevalent virus, we isolated CPV-2a and performed the animal experiment. Nine beagles were inoculated with 105.86 of 50% tissue culture infectious doses (TCID50) of the virus. All the experimentally infected beagles exhibited mild to moderate mucoid or watery diarrhea on day 4 post-infection (p.i.). On day 9 p.i., characteristic histopathological lesions were clearly observed in multiple organs of infected dogs, including liver, spleen, kidney, brain and all segments of the small and large intestines, while viral DNA and antigen staining could be detected in the sampled tissues. It is notable that canine parvovirus was isolated in one from two brain samples processed. CONCLUSION: Our results indicated that CPV-2a is the predominant subtype in Nanjing of China. And this virus caused extensive lesions in a variety of tissues, including the brain. PMID- 23988218 TI - Eye care use among rural adults in China: the Handan Eye Study. AB - PURPOSE: To assess the use of eye care services in a rural population in North China and to analyze the factors associated with underuse of these services. METHODS: In a cross-sectional population-based study, demographic, health and vision-related information including use of eye care services were determined during a face-to-face interview. A single visit to an eye care provider qualified as "use" of eye care services. RESULTS: Of 6612 participants, 754 (11.4%, 95% confidence interval, CI, 8.7-14.1%) had used eye care services. The most common reason cited for not seeing an eye care provider was "no need" (n = 5754). Of the 5754 who thought that there was no need to see an ophthalmologist, 3458 (60.1%) were found to have one or more type of eye disease, including glaucoma (56, 1.0%), cataract (1056, 18.4%), age-related macular degeneration (AMD; 164, 2.9%) and refractive error (3048, 53.0%). Also, 74 (1.3%) and 409 (7.1%) of the 5754 participants had visual impairment (<20/60) according to best-corrected visual acuity and presenting visual acuity, respectively. In a multiple regression model, participants who had glaucoma (adjusted odds ratio, OR, 4.0, 95% CI 3.0 5.4), AMD (adjusted OR 1.6, 95% CI 1.2-2.3) or refractive error (adjusted OR 1.4, 95% CI 1.1-1.8), were more likely to visit an eye care provider. CONCLUSION: A high proportion of the Chinese rural population had never used eye care services although three fifths had eye diseases. Further efforts towards better education of the general population about common eye problems as well as increasing the number of ocular health providers would be necessary in future. PMID- 23988219 TI - Fetal cystic hygroma: the importance of natural history. AB - OBJECTIVES: To evaluate the natural history of cystic hygroma (CH) in fetal and neonatal periods to enrich parental counselling. Ultrasonographic characteristics, associated syndromes, chromosomal anomalies, fetal cardiac pathology and life after birth were considered. STUDY DESIGN: From May 1985 to September 2010, 207 pregnancies were seen the authors' centre with suspected vascular-lymphatic fetal malformation: 156 of them had CH. Cases were followed up by telephone interview to determine fetal and neonatal outcomes. Chi-squared test was used for statistical analysis. RESULTS: Among the 156 cases of CH, the condition was septated in 75% of cases, associated with other pathologies in 74%, and retronuchal in 88%. Intrauterine regression was seen in 36% of cases, with complete disappearance in 77%. The karyotype was normal in 55% of cases. Follow up was completed in 85 cases and revealed 54 spontaneous abortions (63%) and 31 live births (37%). Amongst these, 21 out of 31 children had a favourable outcome (68%). A negative embryo-fetal outcome was significantly associated with CH being associated with other pathologies, such as hydrops, retronuchal position and altered karyotype. Spontaneous regression or resolution of CH was associated with live births. CONCLUSIONS: The management of pregnancies with a diagnosis of fetal CH requires knowledge of natural history of the malformation for appropriate parental counselling. PMID- 23988220 TI - Sexuality in German urogynecological patients and healthy controls: is there a difference with respect to the diagnosis? AB - OBJECTIVE: To evaluate sexual function among German urogynecological patients compared to a control group without urogynecological symptoms, using the validated German version of the Australian pelvic floor questionnaire. STUDY DESIGN: Retrospective study including 313 women divided into five subgroups: women with stress urinary incontinence (SUI), overactive bladder (OAB), mixed incontinence (MI), pelvic organ prolapse (POP) and healthy controls. The self administered questionnaire is divided into three domains: bladder, pelvic organ prolapse, and sexual function. It also includes severity, bothersomeness and condition-specific quality of life. Only completely filled out questionnaires were included. The Mann-Whitney U-test was used as a non-parametric test to calculate significances for ordinal data. A p-value <.05 was taken as significant. RESULTS: 16/59 (27.1%) women in the control group were not sexually active compared to 19/60 (31.7%) in the SUI group, 51/98 (52.0%) in the mixed incontinence group, 19/43 (44.2%) in the OAB group, and 24/53 (45.3%) in the prolapse group. Coital incontinence was present significantly more often in women with SUI (15/41, 36.6%) or mixed incontinence (20/44, 45.5%) than among the controls (1/49, 2.1%). Hence, concerning sexuality, women with urogynecological symptoms were all significantly more affected than the healthy controls. CONCLUSION: The German version of the Australian pelvic floor questionnaire is a feasible tool to evaluate not only symptoms of urinary incontinence and pelvic organ prolapse but also sexual dysfunction. A substantial proportion of our urogynecological patients suffer immensely from problems with their sexuality, and it is therefore our responsibility as physicians to provide assistance and improve our education in this field. PMID- 23988222 TI - Perceived humiliation during admission to a psychiatric emergency service and its relation to socio-demography and psychopathology. AB - BACKGROUND: There is a lack of empirical studies of patients' level of humiliation during the hospital admission process and its implications for the clinical setting. We wanted to explore associations between self-rated humiliation and socio-demography and psychopathology in relation to admission to a psychiatric emergency unit. METHODS: Consecutively admitted patients (N = 186) were interviewed with several validated instruments. The patients self-rated humiliation by The Cantril Ladder, and 35% of the sample was defined as the high humiliation group. RESULTS: Final multivariate analysis found significant associations between compulsory admission, not being in paid work, high scores on hostility, and on entitlement, and high levels of humiliation. No significant interactions were observed between these variables, and the narcissism score was not a confounder concerning humiliation. CONCLUSIONS: High level of humiliation during the admission process was mainly related to patient factors, but also to compulsory admission which should be avoided as much as possible protecting the self-esteem of the patients. PMID- 23988223 TI - Glyceraldehyde-3-phosphate dehydrogenase gene over expression correlates with poor prognosis in non small cell lung cancer patients. AB - BACKGROUND: Glycolysis in presence of oxygen with high glucose consumption is known to be the metabolism of choice in many tumors. In lung cancer this phenomenon is routinely exploited in diagnostic PET imaging of fluorodeoxyglucose uptake, but not much is known about the prognostic capabilities of glycolysis level assessment in resected lung tumor samples. METHODS: In this retrospective study, we used real time polymerase chain reaction(RQ-PCR) to assess the expression level of the gene for Glyceraldehyde 3-phosphate dehydrogenase(GAPDH), key enzyme for glucose breakdown, in tumor samples from 82 consecutive early stages resected non small cell lung cancer(NSCLC) patients. We then compared our results in six large publicly available NSCLC microarray datasets collecting data from over 1250 total patients. RESULTS: In our study GAPDH gene over expression was found to be an adverse prognostic factor in early stages NSCLC (n = 82 HR = 1.30 p = 0.050). This result was confirmed in 5 of 6 public datasets analyzed: Shedden et al. 2008: n = 442 HR = 1.54 p < 0.0001; Lee et al. 2008: n = 138 HR = 1.31 p = 0.043; Tomida et al. 2009: n = 117 HR = 1.59 p = 0.004; Roepman et al. 2009: n = 172 (TPI1 gene) HR = 1.51 p = 0.009; Okayama et al. 2012: n = 226 HR = 3.19 p < 0.0001; Botling et al. 2013: n = 196 HR = 1.00 p = 0.97). Furthermore, in the large and clinically well annotated Shedden et al. microarray dataset, GAPDH hazard ratio did not change whether calculated for the whole dataset or for the subgroup of adjuvant naive patients only (n = 330 HR = 1.49 p < 0.0001). CONCLUSION: GAPDH gene over expression in resected tumor samples is an adverse prognostic factor in NSCLC. Our results confirm the prognostic value of glucose metabolism assessment in NSCLC. PMID- 23988224 TI - Development and validation of regression-based QSAR models for quantification of contributions of molecular fragments to skin sensitization potency of diverse organic chemicals. AB - In our present work, we have developed regression-based QSAR models for skin sensitization potential of 51 diverse organic chemicals. The objective behind the present work is to determine the influence of different molecular features on the skin sensitizing potential of chemicals. Among several models developed, the two best ones are discussed to unveil specific information regarding the contribution of different structural and physicochemical features towards the property of skin sensitization. The QSAR models suggested that aromatic compounds are more skin sensitizing than aliphatic ones, but in the case of carbonyl compounds, aliphatic ones are more skin sensitizing than aromatic ones. Other descriptors such as LUMO and <2-Atype_H-47> signify the importance of the electrophilic and hydrophilic character respectively of the molecules for showing skin sensitizing property. Another two descriptors, and (3)chiC also exert significant contributions towards the skin sensitization potential of the chemicals. Further, it is observed that the nitrogen atoms (nN), triple bonds (nTB) and also the fragment Al-C(=X)-Al (Atype_C38) are responsible for skin sensitizing property. All the above information provides additional support for further research involving identification of the skin sensitization potential of new chemicals. PMID- 23988221 TI - Towards a 'systems'-level understanding of the nervous system and its disorders. AB - It is becoming clear that nervous system development and adult functioning are highly coupled with other physiological systems. Accordingly, neurological and psychiatric disorders are increasingly being associated with a range of systemic comorbidities including, most prominently, impairments in immunological and bioenergetic parameters as well as in the gut microbiome. Here, we discuss various aspects of the dynamic crosstalk between these systems that underlies nervous system development, homeostasis, and plasticity. We believe a better definition of this underappreciated systems physiology will yield important insights into how nervous system diseases with systemic comorbidities arise and potentially identify novel diagnostic and therapeutic strategies. PMID- 23988225 TI - Size-dependent effects of micro polystyrene particles in the marine copepod Tigriopus japonicus. AB - We investigated the effects of three sizes of polystyrene (PS) microbeads (0.05, 0.5, and 6-MUm diameter) on the survival, development, and fecundity of the copepod Tigriopus japonicus using acute and chronic toxicity tests. T. japonicus ingested and egested all three sizes of PS beads used and exhibited no selective feeding when phytoplankton were added. The copepods (nauplius and adult females) survived all sizes of PS beads and the various concentrations tested in the acute toxicity test for 96 h. In the two-generation chronic toxicity test, 0.05-MUm PS beads at a concentration greater than 12.5 MUg/mL caused the mortality of nauplii and copepodites in the F0 generation and even triggered mortality at a concentration of 1.25 MUg/mL in the next generation. In the 0.5-MUm PS bead treatment, despite there being no significant effect on the F0 generation, the highest concentration (25 MUg/mL) induced a significant decrease in survival compared with the control population in the F1 generation. The 6-MUm PS beads did not affect the survival of T. japonicus over two generations. The 0.5- and 6-MUm PS beads caused a significant decrease in fecundity at all concentrations. These results suggest that microplastics such as micro- or nanosized PS beads may have negative impacts on marine copepods. PMID- 23988226 TI - Think modular: a simple apoferritin-based platform for the multifaceted detection of pancreatic cancer. AB - The generation of nanosized probes often requires time-intensive and application specific optimization processes that involve conjugating a nanoconstruct to a targeting moiety. Herein, we genetically modify apoferritin and generate a universal interface system composed of protein G and 6*His-tag. The resulting construct, conferred with modularity and high targeting efficiency, is applied toward two distinct applications in the detection of a pancreatic cancer biomarker and used to demonstrate its potential in the facile exchange of nanoprobe components. PMID- 23988227 TI - Higher levels of coated-platelets are observed in patients with subarachnoid hemorrhage but lower levels are associated with increased mortality at 30 days. AB - BACKGROUND: Coated-platelets are procoagulant platelets observed upon dual agonist stimulation with collagen and thrombin. Coated-platelet levels are elevated in non-lacunar ischemic stroke compared to either lacunar stroke or controls. In contrast, coated-platelet levels are decreased in spontaneous intracerebral hemorrhage (ICH) and inversely correlated with bleed size. We now report the first investigation of coated-platelets in patients with subarachnoid hemorrhage (SAH). METHODS: Coated-platelet levels were determined in 40 consecutive patients with spontaneous SAH and in 40 controls. Results are reported as percent of cells converted to coated-platelets. Mortality at one month was recorded for all patients. RESULTS: Coated-platelet levels (mean +/- SD) were significantly higher in SAH patients compared to controls (41.8 +/- 11.4% vs. 30.7 +/- 12.2%, p<0.0001). Among all patients, mortality at 1 month was 20% (8 deaths). Patients were analyzed according to tertiles of coated-platelet levels (split at <36.7%, 36.7-46.2%, >46.2%). The 1-month mortality differed significantly between the coated-platelet tertiles (p=0.01) with 46% mortality (6/13) among patients in the lowest tertile (lowest levels) compared to 14.3% (2/14) among those in the middle tertile and 0% in the highest tertile. CONCLUSIONS: Coated-platelet levels are higher in SAH patients compared to controls. However, lower coated-platelet levels are associated with increased 1 month mortality in SAH patients, a finding compatible with prior observations of an inverse relationship between coated-platelet levels and bleed volume in ICH. The current data support the role played by these prothrombotic platelets in thrombosis or hemorrhage and suggest a potential place for coated-platelet levels in predicting prognosis after SAH. PMID- 23988228 TI - Microbleeds in ischemic stroke are associated with lower serum adiponectin and higher soluble E-selectin levels. AB - BACKGROUND: Cerebral microbleeds (CMBs) are the important indicators of cerebral small vessel disease. However, it is still unclear whether endothelial dysfunction is involved in CMBs. In this study, we performed a prospective study to investigate the correlation between sE-selectin (soluble E-selectin) or adiponectin and the prevalence of CMBs. METHODS: We recruited 133 consecutive patients with first-ever ischemic stroke for this study. Finally, 126 patients were analyzed. The number and presence of CMBs were detected and evaluated on susceptibility-weighted magnetic resonance imaging within two weeks after symptom onset. We assessed the serum levels of adiponectin and sE-selectin for patients. RESULTS: CMBs were detected in 63 subjects (50%) within 126 patients and more prevalent in mixed brain regions (55.6%). In binary logistic regression analysis, each 1SD-increase in adiponectin level was significantly conversely associated with the prevalence of CMBs after adjusting for age, sex and cardiovascular risk factors (OR = 0.55; 95% CI: 0.36-0.84); but sE-selectin was significantly positively associated with the prevalence of CMBs (OR = 1.09; 95% CI: 1.02-1.15). Furthermore, partial correlation analyses showed that sE-selectin remained significantly associated with and correlated conversely to adiponectin (r = 0.452, p = 0.001). CONCLUSIONS: Endothelial injury may play a role in the pathogenesis of CMBs, and serum levels of adiponectin and sE-selectin were closely related to CMBs. Adiponectin might be protective for the prevalence of CMBs. PMID- 23988229 TI - Atypical clinical and radiological presentation of cryptococcal choroid plexitis in an immunocompetent woman. AB - Central nervous system cryptococcal infections usually manifests as meningitis, meningoencephalitis, encephalitis or ventriculitis. Cryptococcal choroid plexus inflammation is a particularly rare entity most often presenting with signs and symptoms of intracranial hypertension, hydrocephalus or meningitis due to a delayed diagnosis. Herein we reported the case of a 63-year-old immunocompetent woman with a history of temporal lobe epilepsy and behavioral disorders. Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomographic (FDG PET) images revealed atypical cryptococcal choroid plexitis with surrounding bitemporal edema without features of meningitis, intraparenchymal cryptococcoma or hydrocephalus. The patient underwent serial MRI and FDG-PET images performed before and after antifungal therapy that caused a marked clinical improvement. Our case also suggests a potential role of FDG-PET in the monitoring antifungal therapeutic efficacy. PMID- 23988230 TI - Use of boost radiotherapy in oncoplastic breast-conserving surgery - a systematic review. AB - BACKGROUND: The use of local boost radiotherapy to the tumour bed has been demonstrated in randomised-controlled trials to reduce local recurrence rates following breast-conserving surgery (BCS) and is the standard of care. Oncoplastic BCS techniques with parenchymal rearrangement present new challenges to the localisation of the tumour bed and therefore delivery of local boost radiotherapy. The aim of this review was to evaluate the reporting of boost radiotherapy in the oncoplastic BCS literature. METHODS: Pubmed, Ovid MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews were searched for studies reporting oncoplastic BCS using volume displacement techniques. RESULTS: 24 studies met the inclusion criteria (n = 1933 patients). Use of boost radiotherapy was reported in 11 studies, in 2 of which it was for the treatment of incomplete or close margins, and marking of the tumour bed was only reported in 8 studies. None of the studies reported the number of patients where the tumour bed could not be localised. CONCLUSIONS: The use of local boost radiotherapy and tumour bed marking was not reported in the majority of studies of oncoplastic BCS. Future studies need to provide detailed information regarding the use of boost radiotherapy and difficulties determining the target volume so that current radiotherapy approaches can be reviewed and improved for these advanced techniques. PMID- 23988231 TI - Is Balamuthia mandrillaris a public health concern worldwide? AB - Balamuthia mandrillaris is an opportunistic, free-living amoeba that can cause skin lesions and the typically fatal Balamuthia amoebic encephalitis (BAE) both in immunocompromised and immunocompetent individuals. Available data for BAE cases indicate that this disease is difficult to detect because knowledge of predisposing factors is lacking, causing a challenge for diagnosing BAE. The number of reported BAE cases is increasing worldwide, and this is a major concern because little is known about the pathogen, no standardized detection tools are available, and most of the treatments are almost empirical. The recently reported cases, novel diagnostics tools, and successful therapeutic approaches against BAE infections are reviewed here. PMID- 23988232 TI - Functional near infrared-emitting Cr3+/Pr3+ co-doped zinc gallogermanate persistent luminescent nanoparticles with superlong afterglow for in vivo targeted bioimaging. AB - Near infrared (NIR)-emitting persistent luminescent nanoparticles (PLNPs) have great potential for in vivo bioimaging with the advantages of no need for in situ excitation, high signal-to-noise ratio, and deep tissue penetration. However, functional NIR-emitting PLNPs with long afterglow for long-term in vivo imaging are lacking. Here, we show the synthesis of NIR-emitting long-persistent luminescent nanoparticles (LPLNPs) Zn2.94Ga1.96Ge2O10:Cr(3+),Pr(3+) by a citrate sol-gel method in combination with a subsequent reducing atmosphere-free calcination. The persistent luminescence of the LPLNPs is significantly improved via codoping Pr(3+)/Cr(3+) and creating suitable Zn deficiency in zinc gallogermanate. The LPLNP powder exhibits bright NIR luminescence in the biological transparency window with a superlong afterglow time of over 15 days. A persistent energy transfer between host and Cr(3+) ion in the LPLNPs is observed and its mechanism is discussed. PEGylation greatly improves the biocompatibility and water solubility of the LPLNPs. Further bioconjugation with c(RGDyK) peptide makes the LPLNPs promising for long-term in vivo targeted tumor imaging with low toxicity. PMID- 23988233 TI - Metal-free, mild, nonepimerizing, chemo- and enantio- or diastereoselective N alkylation of amines by alcohols via oxidation/imine-iminium formation/reductive amination: a pragmatic synthesis of octahydropyrazinopyridoindoles and higher ring analogues. AB - A mild step and atom-economical nonepimerizing chemo- and enantioselective N alkylating procedure has been developed via oxidation/imine-iminium formation/reduction cascade using TEMPO-BAIB-HEH-Bronsted acid catalysis in DMPU as solvent and a stoichiometric amount of amine. The optimized conditions were further extended for the nonenzymatic kinetic resolution of the chiral amine thus formed under nonenzymatic in situ hydrogen-transfer conditions using VAPOL derived phosphoric acid (VAPOL-PA) as the Bronsted acid catalyst. The enantioselective cascade of the presented reaction was successfully utilized in the synthesis of octahydropyrazinopyridoindole and its higher ring analogues. PMID- 23988234 TI - Admixture analysis of age at onset in schizophrenia: evidence of three subgroups in a first-episode sample. AB - OBJECTIVE: The objective was to assess the presence of different subgroups, via age-at-onset (AAO) analysis, in a schizophrenia population consecutively recruited through an Early Psychosis Service in London, Canada. METHOD: Admixture analysis was applied in order to identify a model of separate normal distribution of AAO characterized by different means, variances and population proportions to allow for evaluation of different subgroups in a sample of 187 unrelated patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia. RESULTS: The best-fitting model suggested three subgroups with means and standard deviations of 16.8 +/- 1.9, 22.3 +/- 2.1 and 32.7 +/- 5.9 years comprising 41%, 30% and 29% of the schizophrenia sample, respectively. These three subgroups were categorized as early, intermediate and late onset with cutoffs determined by admixture analysis to be 19 and 26 years of age, respectively. In our investigation, the definition of early-onset schizophrenia is the main outcome. We considered the clinical variables mainly related to the heritability and neurobiology of schizophrenia. Single status was strongly associated with early onset (P<.001). The male gender (P=.023), as well as a history of drug abuse (P=.004), was significantly associated with early onset. Interestingly, lower academic achievement was also associated with early onset schizophrenia (P<.001). CONCLUSION: Overall, our study showed that a typical early-onset schizophrenia patient is more likely to be a single male, with a history of drug abuse and birth complications, and lower academic achievement as compared to the late-onset subgroup. PMID- 23988236 TI - Randomized controlled trial quality in pediatric physical therapy. AB - The aim of this study is to describe the reported quality of randomized controlled trials (RCTs) in pediatric physical therapy (PPT) and changes with time. All RCTs sourced from PEDro database and scored using the PEDro scale were included. RCTs were classified as high- or low quality both with the original cut off of 6 and a modified cut-off of 5. The relationship between PEDro scores and year of publication was also investigated. One thousand three hundred sixty-seven articles were analyzed. According to the PEDro scale original and modified cut off, 29% and 56% of the articles were classified as high-quality studies, respectively. The number of RCTs and the average PEDro score increased between 1962 and 2012. However, since some items of the scale could be more frequently satisfied, a further improvement of the quality of RCTs in PPT is recommended. PMID- 23988235 TI - Pesticides that inhibit the ubiquitin-proteasome system: effect measure modification by genetic variation in SKP1 in Parkinson's disease. AB - Cytoplasmic inclusions known as Lewy bodies, a hallmark of Parkinson's disease (PD) pathology, may protect against cytotoxic proteins. Since the ubiquitin proteasome system (UPS) degrades cytotoxic proteins, dysfunction in the UPS may contribute to PD etiology. Our goal in this study was to screen pesticides for proteasome inhibition and investigate (i) whether ambient exposures to pesticides that inhibit the UPS increase PD risk and (ii) whether genetic variation in candidate genes of the UPS pathway modify those increased risks. We assessed 26S UPS activity in SK-N-MC(u) cells by fluorescence. We recruited idiopathic PD cases (n=360) and population-based controls (n=816) from three counties in California with considerable commercial agriculture. We determined ambient pesticide exposure by our validated GIS-based model utilizing residential and workplace address histories. We limited effect measure modification assessment to Caucasians (287 cases, 453 controls). Eleven of 28 pesticides we screened inhibited 26S UPS activity at 10 uM. Benomyl, cyanazine, dieldrin, endosulfan, metam, propargite, triflumizole, and ziram were associated with increased PD risk. We estimated an odds ratio of 2.14 (95% CI: 1.42, 3.22) for subjects with ambient exposure to any UPS-inhibiting pesticide at both residential and workplace addresses; this association was modified by genetic variation in the s phase kinase-associated protein 1 gene (SKP1; interaction p-value=0.005). Our results provide evidence that UPS-inhibiting pesticides play a role in the etiology of PD and suggest that genetic variation in candidate genes involved in the UPS pathway might exacerbate the toxic effects of pesticide exposures. PMID- 23988238 TI - Outcomes and projected impact on vision restoration of the China Million Cataract Surgeries Program. AB - PURPOSE: The recently completed Chinese "Million Cataract Surgeries Program" (MCSP) is among the largest such campaigns ever, providing 1.05 million operations. We report MCSP outcomes for the first time, in Jiangxi, the province with the greatest program output. METHODS: Ten county hospitals participating in MCSP were selected in Jiangxi (range of gross domestic product per capita US$743 2998). Each hospital sought to enroll 75 consecutive MCSP patients aged >= 50 years. Data recorded included type of cataract procedure, bilateral uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA), and refractive error pre- and >= 50 days postoperatively. RESULTS: Among 715 patients (mean age 72.3 +/- 9.1 years, 55.5% female), preoperative UCVA was <3/60 (legally blind) bilaterally in 13.3% and unilaterally in the operated eye in 50.9%. No subjects had UCVA >6/18 preoperatively. Small incision cataract surgery was performed in 92.3% patients. Among 662 patients (92.6%) completing follow-up was >= 40 days after surgery, BCVA was >= 6/18 in 80.1%, UCVA was >= 6/18 in 57.1% and UCVA was <3/60 in 2.1%. Older age (p < 0.001), female sex (p = 0.04), worse refractive error (p = 0.02) and presence of intra- (p = 0.002) and postoperative surgical complications (p < 0.001), were independently associated with worse postoperative UCVA. Based on these results, the MCSP cured an estimated 124,950 cases (13.3% * [100-2.1%] * 1.05 million) of bilateral and 502,500 (50.9% * [100-2.1%] * 1.05 million) of unilateral blindness. CONCLUSIONS: Due to relatively good outcomes and the large number of surgeries performed on blind persons, the sight-restoring impact of the MCSP was probably substantial. PMID- 23988239 TI - Evolution of femtosecond-laser technology for lens-based surgery-continued. PMID- 23988237 TI - Developmental maturation of astrocytes and pathogenesis of neurodevelopmental disorders. AB - Recent studies have implicated potentially significant roles for astrocytes in the pathogenesis of neurodevelopmental disorders. Astrocytes undergo a dramatic maturation process following early differentiation from which typical morphology and important functions are acquired. Despite significant progress in understanding their early differentiation, very little is known about how astrocytes become functionally mature. In addition, whether functional maturation of astrocytes is disrupted in neurodevelopmental disorders and the consequences of this disruption remains essentially unknown. In this review, we discuss our perspectives about how astrocyte developmental maturation is regulated, and how disruption of the astrocyte functional maturation process, especially alterations in their ability to regulate glutamate homeostasis, may alter synaptic physiology and contribute to the pathogenesis of neurodevelopmental disorders. PMID- 23988240 TI - Femtosecond laser-assisted technique for performing bag-in-the-lens intraocular lens implantation. AB - We describe a technique for femtosecond laser-assisted bag-in-the-lens (BIL) intraocular lens (IOL) implantation. Anterior capsulotomy and lens division into small pieces are performed by the laser. A fluid-filled interface makes it possible to re-dock the laser to the eye for posterior capsulotomy after the eye has been opened for lens aspiration without complications. The integrated optical coherence tomography also visualizes the posterior capsule, allowing a centered central posterior capsulotomy for uncomplicated IOL positioning. In 31 patients, no complications were observed within a 1-month follow-up. Femtosecond laser assisted cataract surgery facilitated the BIL technique. PMID- 23988241 TI - Modified ab externo method for introducing 2 polypropylene loops for scleral suture fixation of intraocular lenses. AB - We describe a method that enables the introduction of 2 suture loops for scleral fixation of an intraocular lens (IOL) by a single ab externo procedure. A long needle carrying a polypropylene suture loop is inserted through the scleral fixation site and docked with a hollow needle inserted through the opposite fixation site. The hollow needle pulls the suture needle out, but the suture loop end is left external. Another polypropylene suture loop is placed through the first loop. As the first (leading) suture is pulled, the second (trailing) suture is drawn into the eye. The suture loops are retrieved through the main incision. The IOL haptics are secured with a polypropylene loop by cow hitches. After the IOL is placed in the eye, the sutures are fixated to the sclera. This technique enhances efficiency and control during the introduction of suture loops for scleral fixation of IOLs. PMID- 23988242 TI - Effectiveness and safety of femtosecond laser-assisted lens fragmentation and anterior capsulotomy versus the manual technique in cataract surgery. AB - PURPOSE: To evaluate the effectiveness and safety of cataract surgery using femtosecond laser-assisted lens fragmentation and anterior capsulotomy versus manual cataract surgery. SETTING: MaxiVision Eye Hospital, Begumpet, Hyderabad, India. DESIGN: Randomized controlled open-label multisurgeon prospective trial. METHODS: Patients (at least 18 years old) were randomized to femtosecond laser assisted lens prefragmentation and capsulotomy or manual capsulorhexis and standard phacoemulsification. Measured outcomes were effective phacoemulsification time (EPT), surgeon-assessed ease of phacoemulsification, mean phaco energy, mean phaco time, balanced salt solution volume, capsulotomy precision, and adverse event rates. RESULTS: Fifty-six eyes had the femtosecond laser procedure, and 63 had manual cataract surgery. The mean EPT was significantly lower in the laser group (5.2 seconds +/- 5.7 [SD]) than in the manual group (7.7 +/- 6.0 seconds) (P=.025). There was a significant difference in the mean phaco energy between the 2 groups (13.8% +/- 10.3% in laser group; 20.3% +/- 8.1% in manual group) (P<.001). There were no significant between-group differences in the ease of phacoemulsification, mean phaco time, or balanced salt solution volume. Laser-assisted capsulotomies were significantly more accurate and precise (intended diameter, circularity, centration) (P<.01). The safety profiles of the procedures were equivalent, with no adverse events at the 1-day follow-up. CONCLUSION: The femtosecond laser platform was effective and safe in cataract surgery, reducing EPT and the mean phaco energy during lens fragmentation and providing precise and reproducible capsulotomies. PMID- 23988243 TI - Femtosecond laser-assisted cataract surgery in eyes with a small pupil. AB - PURPOSE: To evaluate the efficacy of different treatment modalities in eyes with small pupils before femtosecond laser-assisted cataract surgery. SETTING: Ruhr University Eye Clinic, Bochum, Germany. DESIGN: Prospective clinical trial. METHODS: Eyes with an intraoperative pupil size smaller than 5.5 mm received sequential treatments to achieve a pupil larger than 5.5 mm in 3 steps: (1) intracameral administration of epinephrine solution, (2) additional viscomydriasis, and (3) implantation of a Malyugin ring pupil expander. When a step enlarged the pupil to at least 5.5 mm, femtosecond laser-assisted cataract surgery with an anterior capsulotomy diameter of at least 4.5 mm and 350 MUm nuclear fragmentation grids, ultrasound phacoemulsification, and intraocular lens implantation were performed. Main outcome measures were achieved preoperative pupil size in each sequential treatment group and analysis of intraoperative complications. RESULTS: Of 850 eyes scheduled for cataract surgery, 40 received sequential treatments. To achieve a pupil larger than 5.5 mm, epinephrine was sufficient in 7% of the eyes; additional viscomydriasis was necessary in 25%, and the pupil expander was implanted in 68%. The most frequent comorbidities were pseudoexfoliation of the lens capsule (30.0%) and intraoperative floppy-iris syndrome (12.5%). Tongue-like lesions of the capsulotomies were detected in 5 eyes. CONCLUSIONS: The 3-step treatment allowed the surgeon to increase the efficiency and safety of femtosecond-assisted cataract surgery in eyes with a small preoperative pupil, providing good safety margins at the pupil boundary for the capsulotomy and the softened nuclear volume. PMID- 23988244 TI - Endophthalmitis prophylaxis in cataract surgery: overview of current practice patterns in 9 European countries. AB - Data on practice patterns for prophylaxis against infectious postoperative endophthalmitis (IPOE) during cataract surgery in 9 European countries were searched in national registers and reviews of published surveys. Summary reports assessed each nation's IPOE rates, nonantibiotic prophylactic routines, topical and intracameral antibiotic use, and coherence to the European Society of Cataract & Refractive Surgeons (ESCRS) 2007 guidelines. Although the reliability and completeness of available data vary between countries, the results show that IPOE rates differ significantly. Asepsis routines with povidone-iodine and postoperative topical antibiotics are generally adopted. Use of preoperative and perioperative topical antibiotics as well as intracameral cefuroxime varies widely between and within countries. Five years after publication of the ESCRS guidelines, there is no consensus on intracameral cefuroxime use. Major obstacles include legal barriers or persisting controversy about the scientific rationale for systematic intracameral cefuroxime use in some countries and, until recently, lack of a commercially available preparation. PMID- 23988245 TI - Refractive Surgical Problem: September consultation #1. PMID- 23988246 TI - September consultation #2. PMID- 23988247 TI - September consultation #3. PMID- 23988248 TI - September consultation #5. PMID- 23988249 TI - September consultation #4. PMID- 23988250 TI - September consultation #6. PMID- 23988251 TI - September consultation #7. PMID- 23988252 TI - Simulation of eye rubbing. PMID- 23988253 TI - Reply: simulation of eye rubbing. PMID- 23988254 TI - Intraocular lens power calculation after photorefractive surgery: modified double K method. PMID- 23988255 TI - Refractive outcomes in pseudoexfoliation syndrome. PMID- 23988256 TI - Reply: intraocular lens power calculation after photorefractive surgery: modified double-K method. PMID- 23988257 TI - Endophthalmitis in Cape Town, South Africa: are the data real? PMID- 23988258 TI - Safety of intracameral preservative-free triamcinolone acetonide during anterior vitrectomy. PMID- 23988259 TI - In vitro morphine metabolism by rat microglia. AB - Morphine is mainly transformed to morphine-3-glucuronide (M3G) and morphine-6 glucuronide (M6G) in the liver. Glucuronidation is also performed by rat brain homogenates and UDP-glucuronosyltransferases (UGTs) are present in the brain. Here we investigated the possibility that microglia transforms morphine into its metabolites M3G and M6G. Primary cultures of neonatal rat microglia were incubated for different intervals of time in basal conditions or with different concentrations of morphine. The following measures were performed on these cultures and/or in the medium: (i) morphine as well as M3G and M6G concentrations; (ii) levels of mRNA coding for UGT1A1, UGT1A6, UGT1A7, and UGT2B1 as well as their protein levels; (iii) released prostaglandin (PG)E2 and nitrite concentrations. Results show that in basal conditions morphine and M3G are produced by microglia; accordingly, these cells expressed UGT1A1, UGT1A6 and UGT1A7, but not UGT2B1. When cultures were exposed to different concentrations of exogenous morphine, M6G was also synthesized. This shift in the glucuronidation was associated with variations in the expression of UGT isozymes. In particular, UGT1A7 expression was rapidly upregulated and this event was translated into enhanced protein levels of UGT1A7; lesser effects were exerted on UGT1A1 and UGT1A6. Upon prolonged exposure to morphine, microglial cell UGT expression returned to baseline conditions or even to reduced levels of expression. Morphine exposure did not affect the synthesis of both PGE2 and nitrites, ruling out a generalized priming of microglia by morphine. In conclusion, this study suggests that morphine glucuronides found in the cerebrospinal liquor upon peripheral morphine administration may at least in part be brain-born, reconciling the conceptual gap between the high hydrophilic features of morphine glucuronides and their presence beyond the blood-brain barrier. PMID- 23988260 TI - Sweet anion receptors: recognition of chiral carboxylate anions by D-glucuronic acid-decorated diindolylmethane. AB - Anion receptors containing glucuronic acid were synthesized, and their anion binding ability studied. Chirality of anionic guests derived from mandelic acid and amino acids can be distinguished not only in terms of stability constants but also by significant differences in chemical shift changes for sugar moiety protons. PMID- 23988261 TI - Risk factors for 28-day mortality in elderly patients with extended-spectrum beta lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bacteremia. AB - Gram-negative bacteremia is common in elderly patients and, compared with younger patients, mortality rates in bacteremic elderly patients are high. ESBL-producing organisms were one of the most important risk factors associated with mortality. In addition, older age is one of risk factors for colonization or infection with ESBL-producing organisms. We conducted a retrospective cohort study to evaluate risk factors of all-cause 28-day mortality in elderly patients with ESBL producing Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) bacteremia. Patients aged 65 years or older, who had one or more blood cultures positive for E. coli and K. pneumoniae and who were hospitalized between January 2006 and December 2010 at a tertiary-care teaching hospital, were included. 191 bacteremic elderly patients were eligible for the study. The all-cause 28-day mortality rate was 24.6% (47/191). In multivariate analysis, prior antimicrobial therapy (p=0.014) and an elevated SOFA score (p<0.001) were independent risk factors for increased mortality, while urinary tract infection (UTI) was an independent determinant for non-mortality (p=0.011). In the current study, prior antimicrobial therapy within 30 days, an elevated SOFA score and nonurinary source of infection were significantly associated with adverse outcomes in elderly patients with ESBL-producing gram-negative bacteremia. PMID- 23988262 TI - The genotype C could play a key role in hepatitis B virus associated nephritis among the northwest Chinese children. AB - BACKGROUND: Hepatitis B virus-associated glomerulonephritis (HBV-GN) is a kind of immune complex-induced glomerulonephritis. The present study was designed to determine whether Hepatitis B virus (HBV) genotype is associated with glomerulonephritis in north-west Chinese children. METHODS: A total of 296 HBV infected patients were enrolled in this study. The serum of patients was subjected to DNA extraction and the HBV genotypes were determined by PCR. RESULTS: The results showed that genotype C (49%) was predominant within the subjects, compared to HBV/B (38.5%), B/C recombinant (7.4%) and none B/C (5.1%). The serum tests showed that the changes of Complement 3 (C3) and alanine amino transferase (ALT) levels in the genotype C patients were significantly greater than those in the genotype B patients. The frequency of genotype C in HBV-GN patients was higher than that in non HBV-GN patients (chi2 value=30.239, P<0.001). But, it was not associated with renal dysfunction. Furthermore, The genotype C was associated with high HBV-DNA load (82.9% vs 17.1%, P<0.001), which is seen more frequently in the HBV-GN children (86.3% vs 13.3%, P=0.004). CONCLUSIONS: The genotype C may play a role in HBV-GN children, via favoring HBV replication. PMID- 23988263 TI - Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. AB - Anemia of chronic disease (ACD) is frequently observed in patients with chronic diseases as a significant contributor to morbidity and mortality, which can aggravate the severity of symptoms of the underlying inflammatory status. The pathophysiology of ACD is multifactorial, including three mechanisms: shortened erythrocyte survival, impaired proliferation of erythroid progenitor cells, and abnormalities of iron metabolism. These mechanisms are "immune and inflammation" driven, but several other factors, including chronic blood loss, hemolysis, or vitamin deficiencies, can aggravate anemia. All the abnormalities of iron metabolism observed in ACD can be explained by the effect of hepcidin upregulation. Hepcidin is a small liver peptide, that inhibits the cellular macrophage efflux of iron and intestinal iron absorption, binding to ferroportin and inducing its internalization and degradation. In ACD the synthesis of hepcidin is upregulated by increased inflammatory cytokines, causing the two main principal features: the macrophage iron sequestration and the iron-restricted erythropoiesis. ACD is the most complex anemia to treat. The recommended approach is the treatment of the underlying disease, which can lead to a major improvement or even resolution of ACD. Currently available treatments (transfusion, iron, and erythropoiesis-stimulating agents) can ameliorate anemia, but a considerable percentage of non-responders exist. On this evidence new treatment strategies might arise from the knowledge of the pathophysiology of ACD, in which hepcidin plays the central role. Prospective studies are needed to evaluate the safety and the efficacy of the new emerging treatments, which modulate hepcidin expression through different mechanisms. PMID- 23988264 TI - Epidemiology and molecular analysis of hepatitis A, B and C in a semi-urban and rural area of Crete. AB - AIM: An observational seroepidemiological study was carried out in a well-defined primary-care district on the island of Crete in order to determine the recent endemicity of viral hepatitis in Cretan-population. SETTING AND PARTICIPANTS: The setting consisted of a semi-urban group and a remote & rural group. Serum samples were collected from 876 subjects (437 males, 439 females) aged 15 years or above. Subjects were randomly selected from the permanent population of the area that consisted of 5705 individuals. The aim was to measure the prevalence of selected viral-hepatitis markers. RESULTS: Hepatitis B surface-antigen (HBsAg) was found positive in twenty-nine individuals, (3.3%). Antibodies to hepatitis B virus core antigen (HBcAb) were detected in 287 subjects (32.8%) and antibodies to hepatitis C virus (anti-HCV) were detected in nineteen subjects (2.2%). Seropositivities for the semi-urban group were: 3.4%, 19.1%, 2.1% and 3.2%, 48.8%, 2.2% in remote & rural group respectively. Virtually, all subjects >45 years old were seropositive for antibodies to hepatitis A, whereas approximately 80% of those in the 15-44 age-group were found to be seropositive. CONCLUSION: A threefold increase in the HBV exposure and carrier proportion was found in Cretan native population and in rural-areas compared to older studies carried out in other rural-populations of the island. It is still unknown whether the recent economic crisis or the demographic changes in Cretan-population contributed to these findings. HCV endemicity remains relatively constant, however an alteration of hepatitis C genotypes was observed. Exposure to HAV was found to be higher in remote and rural areas compared to semi-urban areas. PMID- 23988265 TI - Fetal aortic distensibility, compliance and pulse pressure assessment during the second half of pregnancy. AB - The objective of the study was to measure fetal aortic pulse wave velocity and lumen diameter waveforms and subsequently calculate local distensibility, compliance and pulse pressure. A dedicated algorithm for optimizing lumen diameter assessment from radiofrequency ultrasound data is described. Biplane raw data were obtained from a matrix array transducer. We evaluated 83 confirmed, normally developing pregnancies at 22-38 wk. Fetal aortic pulse wave velocity (PWV, m/s) = 0.047 * gestational age (wk) + 1.241, and the distensibility coefficient (1/kPa) = 1/(1.04 * PWV(2)). The logarithm of the local compliance index (mm(2)/kPa) and the pulse pressure (kPa) were both linearly related to gestational age as 0.022 * GA (wk) - 0.343 and 0.012 * GA (wk) + 0.931, respectively. In conclusion, fetal aortic elastic properties can be derived from phase-sensitive radiofrequency data and multiline diameter assessment. Future studies may shed further light on the developmental origins of vascular health and disease. PMID- 23988266 TI - Examining the cost effectiveness of interventions to promote the physical health of people with mental health problems: a systematic review. AB - BACKGROUND: Recently attention has begun to focus not only on assessing the effectiveness of interventions to tackle mental health problems, but also on measures to prevent physical co-morbidity. Individuals with mental health problems are at significantly increased risk of chronic physical health problems, such as cardiovascular disease or diabetes, as well as reduced life expectancy. The excess costs of co-morbid physical and mental health problems are substantial. Potentially, measures to reduce the risk of co-morbid physical health problems may represent excellent value for money. METHODS: To conduct a systematic review to determine what is known about economic evaluations of actions to promote better physical health in individuals identified as having a clinically diagnosed mental disorder, but no physical co-morbidity. Systematic searches of databases were supplemented by hand searches of relevant journals and websites. RESULTS: Of 1970 studies originally assessed, 11 met our inclusion criteria. In addition, five protocols for other studies were also identified. Studies looked at exercise programmes, nutritional advice, smoking, alcohol and drug cessation, and reducing the risk of blood borne infectious diseases such as HIV/AIDS and hepatitis. All of the lifestyle and smoking cessation studies focused on people with depression and anxiety disorders. Substance abuse and infectious disease prevention studies focused on people with psychoses and bipolar disorder. CONCLUSIONS: There is a very small, albeit growing, literature on the cost effectiveness of interventions to promote the physical health of people with mental health problems. Most studies suggest that value for money actions in specific contexts and settings are available. Given that the success or failure of health promoting interventions can be very context specific, more studies are needed in more settings, focused on different population groups with different mental health problems and reporting intermediate and long term outcomes. There is a need to better distinguish between resource use and costs in a transparent manner, including impacts outside of the health care system. Issues such as programme fidelity, uptake and adherence should also be accounted for in economic analysis. The role of behavioural psychological techniques to influence health behaviours might also be considered. PMID- 23988268 TI - The role played by the microenvironment in site-specific metastasis. AB - Cancer cells that disseminate to metastatic sites may progress to frank metastasis or persist as dormant micrometastasis. Significant progress has been made in defining the genetic and phenotypic cancer-cell-autonomous determinants of metastasis and in the understanding of the cross-talk between metastasizing tumor cells and the metastatic microenvironment. However several questions remain open, in particular the identity of microenvironmental factors that keep micrometastatic cells in a state of dormancy and those that promote survival, proliferation and progression of such cells. Significantly more information is available on the latter factors than on microenvironmental cells and molecules that restrain micrometastasis. This mini-review summarizes findings suggesting that: In view of the above, it is not unlikely that metastases residing in different microenvironments may require "individualized" treatment modalities. PMID- 23988269 TI - Direct determination of the NaF/AlF3 molar ratio by Raman spectroscopy in NaF AlF3-CaF2 melts at 1000 degrees C. AB - For the last 40 years, Raman spectroscopy has been very useful in investigating the structure of corrosive molten salts, such as the cryolite-based melts widely used as electrolyte in the Hall-Heroult process. Even if this process remains the most economically efficient for metallic aluminum electro-production, it suffers from a high energy loss, which is dependent on the melt composition. Therefore, controlling the chemical composition of the electrolyte is essential. The present paper proposes to apply Raman spectroscopy for the direct determination of the NaF-AlF3 molar ratio in NaF-AlF3-CaF2-based melts. Despite the experimental difficulties, a calibration curve based on equilibria taking place in the melt has been developed and the procedure has been successfully compared to industrial samples of known compositions. The possible exportation of the laboratory scale procedure to an industrial environment application for the control of the Hall Heroult process is finally discussed. PMID- 23988267 TI - Molecular mechanisms underlying chronic inflammation-associated cancers. AB - Although it is now accepted that chronic inflammation plays an essential role in tumorigenesis, the underlying molecular mechanisms linking inflammation and cancer remain to be fully explored. Inflammatory mediators present in the tumor microenvironment, including cytokines and growth factors, as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS), have been implicated in the etiology of inflammation-associated cancers. Epithelial NADPH oxidase (Nox) family proteins, which generate ROS regulated by cytokines, are upregulated during chronic inflammation and cancer. ROS serve as effector molecules participating in host defense or as chemo-attractants recruiting leukocytes to wounds, thereby influencing the inflammatory reaction in damaged tissues. ROS can alter chromosomal DNA, leading to genomic instability, and may serve as signaling molecules that affect tumor cell proliferation, survival, metabolism, angiogenesis, and metastasis. Targeting Noxs and their downstream signaling components may be a promising approach to pre-empting inflammation-related malignancies. PMID- 23988270 TI - Brain resting-state functional MRI connectivity: morphological foundation and plasticity. AB - Despite the immense ongoing efforts to map brain functional connections and organizations with resting-state functional MRI (rsfMRI), the mechanisms governing the temporally coherent rsfMRI signals remain unclear. In particular, there is a lack of direct evidence regarding the morphological foundation and plasticity of these rsfMRI derived connections. In this study, we investigated the role of axonal projections in rsfMRI connectivity and its plasticity. Well controlled rodent models of complete and posterior corpus callosotomy were longitudinally examined with rsfMRI at 7T in conjunction with intracortical EEG recording and functional MRI tracing of interhemispheric neuronal pathways by manganese (Mn(2+)). At post-callosotomy day 7, significantly decreased interhemispheric rsfMRI connectivity was observed in both groups in the specific cortical areas whose callosal connections were severed. At day 28, the disrupted connectivity was restored in the partial callosotomy group but not in the complete callosotomy group, likely due to the compensation that occurred through the remaining interhemispheric axonal pathways. This restoration - along with the increased intrahemispheric functional connectivity observed in both groups at day 28 - highlights the remarkable adaptation and plasticity in brain rsfMRI connections. These rsfMRI findings were paralleled by the intracortical EEG recording and Mn(2+) tracing results. Taken together, our experimental results directly demonstrate that axonal connections are the indispensable foundation for rsfMRI connectivity and that such functional connectivity can be plastic and dynamically reorganized atop the morphological connections. PMID- 23988271 TI - Revisiting multi-subject random effects in fMRI: advocating prevalence estimation. AB - Random effect analysis has been introduced into fMRI research in order to generalize findings from the study group to the whole population. Generalizing findings is obviously harder than detecting activation within the study group since in order to be significant, an activation has to be larger than the inter subject variability. Indeed, detected regions are smaller when using random effect analysis versus fixed effects. The statistical assumptions behind the classic random effect model are that the effect in each location is normally distributed over subjects, and "activation" refers to a non-null mean effect. We argue that this model is unrealistic compared to the true population variability, where due to function-anatomy inconsistencies and registration anomalies, some of the subjects are active and some are not at each brain location. We propose a Gaussian-mixture-random-effect that amortizes between-subject spatial disagreement and quantifies it using the prevalence of activation at each location. We present a formal definition and an estimation procedure of this prevalence. The end result of the proposed analysis is a map of the prevalence at locations with significant activation, highlighting activation regions that are common over many brains. Prevalence estimation has several desirable properties: (a) It is more informative than the typical active/inactive paradigm. (b) In contrast to the usual display of p-values in activated regions - which trivially converge to 0 for large sample sizes - prevalence estimates converge to the true prevalence. PMID- 23988272 TI - Bi-level multi-source learning for heterogeneous block-wise missing data. AB - Bio-imaging technologies allow scientists to collect large amounts of high dimensional data from multiple heterogeneous sources for many biomedical applications. In the study of Alzheimer's Disease (AD), neuroimaging data, gene/protein expression data, etc., are often analyzed together to improve predictive power. Joint learning from multiple complementary data sources is advantageous, but feature-pruning and data source selection are critical to learn interpretable models from high-dimensional data. Often, the data collected has block-wise missing entries. In the Alzheimer's Disease Neuroimaging Initiative (ADNI), most subjects have MRI and genetic information, but only half have cerebrospinal fluid (CSF) measures, a different half has FDG-PET; only some have proteomic data. Here we propose how to effectively integrate information from multiple heterogeneous data sources when data is block-wise missing. We present a unified "bi-level" learning model for complete multi-source data, and extend it to incomplete data. Our major contributions are: (1) our proposed models unify feature-level and source-level analysis, including several existing feature learning approaches as special cases; (2) the model for incomplete data avoids imputing missing data and offers superior performance; it generalizes to other applications with block-wise missing data sources; (3) we present efficient optimization algorithms for modeling complete and incomplete data. We comprehensively evaluate the proposed models including all ADNI subjects with at least one of four data types at baseline: MRI, FDG-PET, CSF and proteomics. Our proposed models compare favorably with existing approaches. PMID- 23988273 TI - Gray matter and intrinsic network changes in the posterior cingulate cortex after selective serotonin reuptake inhibitor intake. AB - Preclinical studies have demonstrated that serotonin (5-HT) challenge changes neuronal circuitries and microarchitecture. However, evidence in human subjects is missing. Pharmacologic magnetic resonance imaging (phMRI) applying selective 5 HT reuptake inhibitors (SSRIs) and high-resolution structural and functional brain assessment is able to demonstrate the impact of 5-HT challenge on neuronal network morphology and functional activity. To determine how SSRIs induce changes in gray matter and neuronal activity, we conducted a longitudinal study using citalopram and escitalopram. Seventeen healthy subjects completed a structural and functional phMRI study with randomized, cross-over, placebo-controlled, double-blind design. Significant gray matter increases were observed (among other regions) in the posterior cingulate cortex (PCC) and the ventral precuneus after SSRI intake of 10days, while decreases were observed within the pre- and postcentral gyri (all P<0.05, family-wise error [FWE] corrected). Furthermore, enhanced resting functional connectivity (rFC) within the ventral precuneus and PCC was associated with gray matter increases in the PCC (all FWE Pcorr<0.05). Corroborating these results, whole-brain connectivity density, measuring the brain's functional network hubs, was significantly increased after SSRI-intake in the ventral precuneus and PCC (all FWE Pcorr<0.05). Short-term administration of SSRIs changes gray matter structures, consistent with previous work reporting enhancement of neuroplasticity by serotonergic neurotransmission. Furthermore, increased gray matter in the PCC is associated with increased functional connectivity in one of the brain's metabolically most active regions. Our novel findings provide convergent evidence for dynamic alterations of brain structure and function associated with SSRI pharmacotherapy. PMID- 23988274 TI - Functional MRI reveals frequency-dependent responses during deep brain stimulation at the subthalamic nucleus or internal globus pallidus. AB - Deep brain stimulation (DBS) represents a widely used therapeutic tool for the symptomatic treatment of movement disorders, most commonly Parkinson's disease (PD). High frequency stimulation at both the subthalamic nucleus (STN) and internal globus pallidus (GPi) has been used with great success for the symptomatic treatment of PD, although the therapeutic mechanisms of action remain elusive. To better understand how DBS at these target sites modulates neural circuitry, the present study used functional blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to map global brain responses to DBS at the STN and GPi of the rat. Robust activation centered in the ipsilateral motor cortex was observed during high frequency stimulation at either target site, with peak responses observed at a stimulation frequency of 100Hz. Of note, frequency tuning curves were generated, demonstrating that cortical activation was maximal at clinically-relevant stimulation frequencies. Divergent responses to stimulation were noted in the contralateral hemisphere, with strong cortical and striatal negative BOLD signal during stimulation of the GPi, but not STN. The frequency-dependence of the observed motor cortex activation at both targets suggests a relationship with the therapeutic effects of STN and GPi DBS, with both DBS targets being functionally connected with motor cortex at therapeutic stimulation frequencies. PMID- 23988276 TI - [Proceedings of the 27th meeting of Anaesthesia Club ENT (Carorl)]. PMID- 23988275 TI - Anti-resorptive agents reduce the size of resorption cavities: a three dimensional dynamic bone histomorphometry study. AB - Alterations in resorption cavities and bone remodeling events during anti resorptive treatment are believed to contribute to reductions in fracture risk. Here, we examine changes in the size of individual remodeling events associated with treatment with a selective estrogen receptor modulator (raloxifene) or a bisphosphonate (risedronate). Adult female rats (6months of age) were submitted to ovariectomy (n=17) or sham surgery (SHAM, n=5). One month after surgery, the ovariectomized animals were separated into three groups: untreated (OVX, n=5), raloxifene treated (OVX+Ral, n=6) and risedronate treated (OVX+Ris, n=6). At 10months of age, the lumbar vertebrae were submitted to three-dimensional dynamic bone histomorphometry to examine the size (depth, breadth and volume) of individual resorption cavities and formation events. Maximum resorption cavity depth did not differ between the SHAM (23.66+/-1.87MUm, mean+/-SD) and OVX (22.88+/-3.69MUm) groups but was smaller in the OVX+Ral (14.96+/-2.30MUm) and OVX+Ris (14.94+/-2.70MUm) groups (p<0.01). Anti-resorptive treatment was associated with reductions in the surface area of resorption cavities and the volume occupied by each resorption cavity (p<0.01 each). The surface area and volume of individual formation events (double-labeled events) in the OVX+Ris group were reduced as compared to other groups (p<0.02). Raloxifene treated animals showed similar amounts of bone remodeling (ES/BS and dLS/BS) compared to sham-operated controls but smaller cavity size (depth, breadth and volume). The current study shows that anti-resorptive agents influence the size of resorption cavities and individual remodeling events and that the effect of anti-resorptives on individual remodeling events may not always be directly related to the degree of suppression of bone remodeling. PMID- 23988277 TI - Estimating the carbon sequestration capacity of shale formations using methane production rates. AB - Hydraulically fractured shale formations are being developed widely for oil and gas production. They could also represent an attractive repository for permanent geologic carbon sequestration. Shales have a low permeability, but they can adsorb an appreciable amount of CO2 on fracture surfaces. Here, a computational method is proposed for estimating the CO2 sequestration capacity of a fractured shale formation and it is applied to the Marcellus shale in the eastern United States. The model is based on historical and projected CH4 production along with published data and models for CH4/CO2 sorption equilibria and kinetics. The results suggest that the Marcellus shale alone could store between 10.4 and 18.4 Gt of CO2 between now and 2030, which represents more than 50% of total U.S. CO2 emissions from stationary sources over the same period. Other shale formations with comparable pressure-temperature conditions, such as Haynesville and Barnett, could provide significant additional storage capacity. The mass transfer kinetic results indicate that injection of CO2 would proceed several times faster than production of CH4. Additional considerations not included in this model could either reinforce (e.g., leveraging of existing extraction and monitoring infrastructure) or undermine (e.g., leakage or seismicity potential) this approach, but the sequestration capacity estimated here supports continued exploration into this pathway for producing carbon neutral energy. PMID- 23988278 TI - Investigation of the effect of Mycobacterium bovis infection on bovine neutrophils functions. AB - Bovine tuberculosis is a disease in cattle caused by infection with Mycobacterium bovis. The disease has posed significant economic losses and remains a public health hazard worldwide. Interactions between M. bovis and bovine macrophages have been extensively characterized in various studies, while similar analyses in neutrophils, which are one of the other types of white blood cells in mammals, were often overlooked. Neutrophils provide defense against all microbes and can present a diverse collection of antimicrobial molecules, which play an important role in the control of tuberculosis progression. Much of the available data about the involvement of neutrophils in the killing M. bovis is controversial. In this study, we assessed the effect of in vitro infection with M. bovis on some parameters of neutrophils functions including phenotypic changes, apoptosis rate and inflammatory cytokines production. Our results demonstrated that phagocytosis of M. bovis activated and enhanced bovine neutrophils functions as well as initialed their defense mechanism, but failed to eliminate the mycobacteria. Moreover, autophagy might get involved in the defense infection process functioning as a protective mechanism, and inducible-autophagy by lipopolysaccharides stimulation and starvation treatment could efficiently reverse the inability of neutrophils for killing M. bovis, suggesting a potential target for anti-mycobacterial drug-therapy. PMID- 23988279 TI - Simultaneous detection of Mycobacterium tuberculosis complex and nontuberculous mycobacteria in respiratory specimens. AB - Many nontuberculous mycobacteria (NTM) species have clinical significance, and the rapid and reliable identification of Mycobacterium tuberculosis complex (MTBC) and NTM species is important. We evaluated the simultaneous detection of MTBC and NTM in respiratory specimens. MTBC and NTM were simultaneously detected and identified by laboratory-developed (LDT) real-time PCR, multiplex real-time PCR/melting curve analysis, rpoB PCR restriction fragment length polymorphisms and the AdvanSure Mycobacteria GenoBlot assay (LG Life Sciences). Eighty-five respiratory specimens from 69 patients showed simultaneous detection of MTBC and NTM. A line probe assay showed 70.6% concordance with LDT. Ten patients (14.5%) had a history of tuberculosis, and eight patients (11.6%) had been previously diagnosed with bronchiectasis. Mixed cultures were present one time in 57 patients (82.6%) and repeatedly in 12 patients (17.4%). MTBC was more frequent in 44 patients (63.8%), and NTM was isolated in seven patients (10.1%). The commonly detected NTM species in the mixed cultures were Mycobacterium intracellulare (29.0%) and Mycobacterium abscessus (29.0%). Co-isolation caused a failure of antitubercular drug susceptibility testing in 2 patients (2.9%). Molecular methods allow MTBC and NTM species to be simultaneously identified in respiratory specimens. NTM isolated with MTBC has clinical significance in some patients and should not be ignored. PMID- 23988280 TI - Levels of inflammatory cytokines, adrenal steroids, and mRNA for GRalpha, GRbeta and 11betaHSD1 in TB pleurisy. AB - Our previous work on the immune-endocrine features of patients with pulmonary tuberculosis (TB) showed markedly decreased plasma levels of dehydroepiandrosterone (DHEA) together with augmented concentrations of Cortisol and pro- and anti-inflammatory cytokines. Studies in peripheral blood mononuclear cells (PBMC) indicated a lower mRNA alpha/beta ratio of glucocorticoid receptors GR- together with a higher 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) mRNA expression in cases with severe pulmonary TB. Since Pleural TB (PLTB) is a rather benign manifestation of TB, we now analyzed the systemic and local immune-endocrine profile as well as the GRalpha, GRbeta, 11betaHSD1 and 11betaHSD2 transcripts in PBMC and pleural effusion mononuclear cells (PEMC) of patients with PLTB. PLTB patients had increased levels of IL-1beta, IL-6 and IFNgamma together with reduced Cortisol and DHEA concentrations in pleural fluids. Also, a significantly increased expression of 11betaHSD1 and GRalpha was found in PEMC compared to PBMC. Findings point out to an appropriate immune response and a substantial inflammatory reaction, wherein the low Cortisol concentrations may be equally effective, because of the increased expression of GRalpha and 11betaHSD1 transcripts which may optimize the immunomodulatory properties of Cortisol. PMID- 23988281 TI - Comorbidity of late-life depression in the United States: a population-based study. AB - OBJECTIVES: This study sought to determine the clinical and sociodemographic correlates and the treatment-seeking rate of major depressive disorder (MDD), diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, among older adults and its association with comorbid psychiatric disorders and perceived health status. METHODS: Data were drawn from the 2001 2002 National Epidemiologic Survey on Alcohol and Related Conditions, a large cross-sectional survey (N = 43,093) representative of the US population. RESULTS: Compared with participants aged 65 years and older without a 12-month diagnosis of MDD, those with MDD were more likely to have lifetime and 12-month comorbid psychiatric disorders. Except for lifetime dysthymia, we found no significant interaction between rates of current somatic comorbidity, lifetime and 12-month psychiatric comorbidity, and age groups. Compared with younger participants with a 12-month MDD, they had an older age at onset, reported a similar number of lifetime major depressive episodes and perceived health status, and had lower mental health service utilization rates. CONCLUSIONS: Current major depression in the elderly seems to be as disabling as in younger adults in terms of comorbid psychiatric disorders and impaired quality of life. Poorer prognosis of MDD in older adults might be explained by a lower perceived need of treatment, resulting in a lower rate of treatment-seeking behavior. PMID- 23988282 TI - Timing of neonatal cardiac surgery is not associated with perioperative outcomes. AB - OBJECTIVE: The optimal timing for neonatal cardiac surgery is unknown. We aimed to determine the relationship between age at surgery and perioperative outcomes, hypothesizing that earlier intervention would be associated with lower morbidity and mortality. METHODS: A retrospective review was performed of neonates who had undergone an arterial switch operation, stage 1 palliation for functional single ventricle, or systemic-to-pulmonary shunt for obstructed pulmonary blood flow from January 1, 2005, to December 31, 2010. The subjects with clinical indications for delayed surgery or prematurity were excluded. Age at surgery was evaluated as both a continuous and a categorical variable. The primary outcome was a composite endpoint of mortality or prolonged intensive care stay. RESULTS: Of 344 subjects, 286 (77 arterial switch operation, 124 stage 1 palliation, 85 systemic-to-pulmonary shunt) met the inclusion criteria. In each group, age at surgery was not associated with the primary composite endpoint. The patients who died after systemic-to-pulmonary shunt had a median age at surgery of 3 days versus 6 days for the survivors (P = .04). A similar, but nonsignificant, pattern was seen for patients undergoing arterial switch operations (4.5 vs 7 days; P = .09). Earlier surgery was not associated with a reduced duration of vasoactive support, mechanical ventilation, or intensive care unit length of stay in any group. Stage 1 palliation subjects in the upper age quartile (>=8 days) at surgery were less likely to require prolonged mechanical ventilation (P = .03). CONCLUSIONS: Younger age at intervention in the neonatal period was not associated with reduced morbidity or mortality in any procedural subgroup studied. In our cohort, earlier systemic-to-pulmonary shunt for obstructed pulmonary blood flow was associated with a greater likelihood of a poor outcome. PMID- 23988283 TI - Hybrid repair of aortic aneurysm in patients with previous coarctation. AB - OBJECTIVES: Hybrid operations combining open and endovascular techniques have evolved for patients with complex aortic and coexisting cardiovascular disease. Our objectives were to describe the repair techniques and assess the outcomes in patients undergoing hybrid repair for aneurysm associated with previous aortic coarctation. METHODS: From 2004 to 2012, 14 patients underwent hybrid repair by elephant trunk with endovascular completion (n = 5), frozen elephant trunk (n = 8), or antegrade stent grafting (n = 1). The mean age at surgery was 45 +/- 13.5 years. Of the 14 patients, 8 underwent supra-aortic arterial revascularization (ascending to subclavian bypass in 5, carotid-subclavian bypass in 2, or ascending to carotid and subclavian bypass in 1). Ten patients had a bicuspid aortic valve, 5 underwent concomitant aortic valve replacement, and 1 underwent valve repair. Six had a hypoplastic arch. Other procedures included ascending aortic repair (n = 4), coronary artery bypass grafting (n = 1), ascending to descending bypass (n = 1), and subclavian aneurysm repair (n = 1). One operation was an emergency, the others were elective. The mean maximum aneurysm diameter was 5.9 +/- 1.5 cm. Data were obtained from a prospective database and chart review. RESULTS: No perioperative mortality, stroke, renal failure, or paraplegia occurred. One patient required prolonged intubation, another required reoperation for postoperative bleeding. Two endoleaks required repeat intervention. The mean length of stay was 9 +/- 5.5 days. One late death occurred from hypertensive crisis and associated disseminated intravascular coagulation. At a mean follow-up of 26 months, no aortic growth was found. CONCLUSIONS: Hybrid repair of postcoarctation repair aneurysm is a safe and effective, less-invasive treatment option for patients with complex anatomy and/or concomitant cardiac disease. PMID- 23988284 TI - Medium-term outcome after anomalous aortic origin of a coronary artery repair in a pediatric cohort. AB - BACKGROUND: Anomalous aortic origin of a coronary artery with an interarterial and intramural course (AAOCA) is a rare anomaly with increased risk of sudden cardiac death during or just after exercise among otherwise healthy youth. Risk stratification and management remain controversial, especially for the asymptomatic child with an anomalous right coronary artery from the left coronary sinus (ARCA). Medium-term surgical and quality-of-life (QOL) outcome data are lacking in this population. METHODS: We performed medical record review on 24 subjects who underwent AAOCA repair between 2001 and 2007 at The Children's Hospital of Philadelphia. QOL was prospectively assessed with age-appropriate questionnaires. RESULTS: Median age at follow-up was 18 (range, 11-25) years, median follow-up from surgery was 63 (range, 12-110) months, and 16 (67%) had ARCA. All were alive without exercise restriction. Thirteen (54%) complained of cardiac-type symptoms postoperatively, most commonly chest pain, none correlating with evidence of ischemia on testing. Of the 13 patients, 7 (54%) reported the same symptoms preoperatively; and of these, 5 had ARCA. Postoperative morbidity occurred in 16 (67%), including pericardial effusion (n = 11), wound infection (n = 2), and development of mild aortic insufficiency (n = 4). QOL questionnaires were sent to 21 subjects; 12 (57%) were returned. Average QOL was normal for all subjects. CONCLUSIONS: In the medium-term after AAOCA repair, cardiac-type symptoms frequently persist and morbidity is common, but these do not impair QOL. The significance of these findings in the long-term is unknown and warrants continued follow-up. PMID- 23988285 TI - Prevalence of lymph node metastases in superficial esophageal squamous cell carcinoma. AB - OBJECTIVE: Endoscopic treatment of superficial esophageal carcinoma has been increasingly conducted around the world. Because no lymph nodes are removed in such a procedure, the risk of lymph node metastases (LNMs) should be clearly understood. The aim of the present study was to accurately clarify the pattern of lymphatic spread in patients with superficial esophageal squamous cell carcinoma and analyze the factors potentially related to LNMs. METHODS: The pattern of lymphatic spread was studied in 189 patients who had undergone radical lymphadenectomy from 2006 to 2011. The risk factors associated with LNMs were determined by multivariate logistic regression analysis. According to the depth of tumor invasion, mucosal tumors were classified as M1, M2, and M3 and submucosal tumors as SM1, SM2, and SM3. RESULTS: A total of 4252 lymph nodes were resected (average, 23 +/- 9; range, 12-68). LNMs occurred in 49 patients (25.9%). The frequency of LNMs was 4.3% in those with mucosal and 33.1% in those with submucosal cancer. LNMs were found in 0%, 0%, 11.8%, 24.0%, 20.5%, and 43.8% of the M1, M2, M3, SM1, SM2, and SM3 cancer, respectively. For submucosal cancer, SM3 cancer (P = .006) and lymphovascular invasion (P = .001) were significant independent risk factors for LNMs. Paratracheal nodes were the most frequently involved. "Skip" metastases occurred in 20 of 49 patients (40.8%). CONCLUSIONS: Endoscopic treatment can be attempted when the tumor is limited to the lamina propria mucosa. However, 2-field radical lymphadenectomy with careful upper mediastinal lymph node resection should be conducted for submucosal squamous cell carcinoma. PMID- 23988286 TI - Reconstructive options for gastroesophageal junction adenocarcinoma after Roux-en Y gastric bypass. PMID- 23988287 TI - European experience of the convergent atrial fibrillation procedure: multicenter outcomes in consecutive patients. AB - BACKGROUND: The objective of this collaborative, multicenter, European effort was to evaluate the outcomes of the convergent procedure for the treatment of persistent and long-standing persistent atrial fibrillation (AF) in consecutive patients at 4 European centers. METHODS: Outcomes of consecutive patients, undergoing the convergent procedure at 4 European centers, were evaluated in this study. Epicardial ablation was performed before endocardial ablation. Convergent procedure outcomes were recorded by interrogation of implanted loop recorders or Holter monitors. Rhythm status and required interventions (antiarrhythmic drugs, cardioversions, and repeat ablations) were quantified 6 and 12 months after the procedure. Outcomes, monitoring type, and patient baseline characteristics were analyzed and reported. RESULTS: Seventy-three consecutive patients presenting with persistent AF (30.1%) or long-standing persistent AF (69.9%) underwent the convergent procedure between January 2010 and December 2011. At 6 months, 82% (56/68) were in sinus rhythm. At 12 months, 80% (53/66) were in sinus rhythm; single-procedure maintenance of sinus rhythm without postblanking period interventions was 76% (50/66); 52% (34/66) were in sinus rhythm and not receiving antiarrhythmic drugs. CONCLUSIONS: This multicenter European collaborative effort demonstrated that the convergent procedure is a safe and efficacious treatment option for persistent and long-standing persistent AF. PMID- 23988288 TI - Long-term results of the Medtronic Mosaic porcine bioprosthesis in the aortic position. AB - OBJECTIVE: We addressed the long-term results of the Medtronic Mosaic porcine prosthesis in the aortic position. METHODS: From 1994 to 2004, 1007 Mosaic valves were used for aortic valve replacement. The data were prospectively collected, retrospectively analyzed, and stratified according to patient age at surgery (group 1, <70 years; group 2, 70-75 years; group 3, 76-80 years; and group 4, >80 years), using both actual (cumulative risks) and actuarial methods. RESULTS: Operative mortality was 5% (valve related in 14%). Globally, 8122.17 patient years were available (average follow-up, 8.5 +/- 3.9 years; 99.8% complete). Overall, survival at 15 years was lower among the elderly strata (P < .0001). Freedom from structural valve deterioration (SVD) was 95.1% (actual) and 86.3% (actuarial; 24 SVD events). Survival free from SVD was lower in group 1 (P = .003) but comparable among the other groups. Overall freedom at 15 years from the composite endpoint (any valve-related adverse events) was 82% (actual) and 71.3% (actuarial). No meaningful intergroup differences were found in survival free from the composite endpoint (P = .9) or freedom from valve-related mortality (P = .8). Younger patients at surgery did not show accelerated degeneration. No relationship could be established between prosthetic size and SVD. CONCLUSIONS: The implantation of a bioprosthesis in patients aged 70 years or older remains fully justified. The rate of SVD was higher in younger patients, mainly owing to their greater life expectancy. Patients younger than 70 can receive a bioprosthesis, provided that the correct information regarding the expected durability has been provided. This might be better accomplished through the actual methodology. PMID- 23988289 TI - Knowledge, attitudes, and practice patterns in surgical management of bicuspid aortopathy: a survey of 100 cardiac surgeons. AB - OBJECTIVE: Clinical practice guidelines have been established for surgical management of the aorta in bicuspid aortic valve disease. We hypothesized that surgeons' knowledge of and attitudes toward bicuspid aortic valve aortopathy influence their surgical approaches. METHODS: We surveyed cardiac surgeons to probe the knowledge of, attitudes toward, and surgical management of bicuspid aortopathy. A total of 100 Canadian adult cardiac surgeons participated. RESULTS: Fifty-two percent of surgeons believed that the mechanism underlying aortic dilation in those with bicuspid aortic valve was due to an inherent genetic abnormality of the aorta, whereas only 2% believed that altered valve-related processes were involved in this process. Only a minority (15%) believed that bicuspid valve leaflet fusion type is associated with a unique pattern of aortic dilatation aortic phenotype. Sixty-five percent of surgeons recommended echocardiographic screening of first-degree relatives of patients with bicuspid aortic valve. Most surgeons (61%) elected to replace the aorta when the diameter is 45 mm or greater at the time of valve surgery. Fifty-five percent of surgeons surveyed suggested that in the absence of concomitant valvular disease, they would recommend ascending aortic replacement at a threshold of 50 mm or greater. Approximately one third of surgeons suggested that they would elect to replace a mildly dilated ascending aorta (40 mm) at the time of valve surgery. The most common surgical approach (61%) for combined valve and aortic surgery was aortic valve replacement and supracoronary replacement of the ascending aorta, and only a minority suggested the use of deep hypothermic circulatory arrest and open distal anastomosis. More aggressive approaches were favored with greater surgeon experience, and when circulatory arrest was chosen, the majority (68%) suggested they would use antegrade cerebral perfusion. In the setting of aortic insufficiency and a dilated aorta, 42% of surgeons suggested that they would perform valve-sparing surgery. Of note, 40% of respondents used an index measure of aortic size to body surface area in addition to absolute aortic diameter in assessing the threshold for intervention. CONCLUSIONS: This large survey uncovered significant gaps in the knowledge and attitudes of surgeons toward the diagnosis and management of bicuspid aortopathy, many of which were at odds with current guideline recommendations. Efforts to promote knowledge translation in this area are strongly encouraged. PMID- 23988290 TI - Myectomy and mitral repair through the left atrium in hypertrophic obstructive cardiomyopathy: the preferred approach for contemporary surgical candidates? AB - OBJECTIVE: Patients with hypertrophic obstructive cardiomyopathy due to diffuse hypertrophy extending to or below the papillary muscles are poor candidates for alcohol septal ablation and suboptimal candidates for transaortic septal myectomy. In addition, the outflow obstruction is often aggravated by an abnormal mitral valve and subvalvular apparatus. METHODS: We performed transatrial myectomy in 12 patients with diffuse hypertrophy, who were highly symptomatic despite maximal medical therapy. All had at least moderate mitral regurgitation and systolic anterior motion. The anterior mitral leaflet (AML) was detached from commissure to commissure, allowing an easy myectomy through this AML toward the base of the anterior papillary muscle, with mobility fully restored. The abnormal chordae from the septum to the anterior papillary muscle and AML were divided. The continuity of this AML was restored with augmentation using an autologous pericardial patch. The height of the posterior mitral leaflet was reduced and the repair completed using an oversized annuloplasty ring. RESULTS: The peak intraventricular gradients decreased spectacularly from 98.8 +/- 6.29 to 19.2 +/- 13.4 mm Hg (P < .001), and the systolic anterior motion and mitral regurgitation disappeared. One patient died of left ventricular diastolic dysfunction. All other patients left the hospital in New York Heart Association class I or II. CONCLUSIONS: We believe that this technique is preferable for patients with hypertrophic obstructive cardiomyopathy and diffuse hypertrophy extending to the midportion of the left ventricle or beyond. It results in disappearance of outflow tract gradients and allows correction of the mitral valve abnormality. PMID- 23988291 TI - Correction of pectus excavatum through a minimally invasive approach with subxyphoid incision and 3-point fixation. PMID- 23988292 TI - Is commissural closure associated with mitral annuloplasty a durable technique for the treatment of mitral regurgitation? A long-term (<=15 years) clinical and echocardiographic study. AB - OBJECTIVE: Mitral regurgitation (MR) due to commissural prolapse/flail can be corrected by suturing the margins of the anterior and posterior leaflets in the commissural area (commissural closure). The long-term results of this type of repair are unknown. Our aim was to assess the clinical and echocardiographic outcomes of this technique up to 15 years after surgery. METHODS: From 1997 to 2007, 125 patients (age, 56.8 +/- 15.7 years; left ventricular ejection fraction, 58.1% +/- 7.1%) with MR due to pure commissural prolapse/flail of 1 or both leaflets underwent commissural closure combined with annuloplasty. The etiology of the disease was degenerative in 88.8% and endocarditis in 11.2%. The commissural region involved was posteromedial in 96 patients (76.8%) and anterolateral in 29 (23.2%). RESULTS: Hospital mortality was 1.6%. At discharge, MR was absent or mild in 120 patients (97.5%) and moderate (2+/4+) in 3 (2.4%). Clinical and echocardiographic follow-up was 98.4% complete (mean length, 7.1 +/- 3.0 years; median, 6.7; longest follow-up, 15). At 11 years, the actuarial survival, freedom from cardiac death, and freedom from reoperation was 78.8% +/- 6.2%, 95.2% +/- 3.3%, and 97.4% +/- 1.4%, respectively. At the last echocardiographic examination, MR 3+ or greater was demonstrated in 4 patients (3.3%). Freedom from MR 3+ or greater at 11 years was 96.3% +/- 1.7%. No predictors for recurrence of MR 3+ or greater were identified. The mean mitral valve area and gradient was 2.9 +/- 0.4 cm(2) and 3.4 +/- 1.1 mm Hg, respectively. New York Heart Association class I to II was documented in all cases. CONCLUSIONS: Commissural closure repair combined with annuloplasty provides excellent clinical and echocardiographic long-term results in patients with MR due to commissural lesions. PMID- 23988293 TI - High incidence of Dacron conduit stenosis for extracardiac Fontan procedure. AB - OBJECTIVES: Extracardiac conduits are widely used to complete a Fontan circulation in patients with univentricular hearts. Although polytetrafluoroethylene conduits have proven good long-term patency, Dacron (polyethylene terephthalate) prostheses are still infrequently applied, with, as yet, no information on the long-term patency. METHODS: All patients who received an extracardiac Dacron conduit (n = 12) were retrospectively studied. The initial conduit size was 16 mm in all recipients. The mean age at Fontan completion was 3.1 +/- 0.7 years. Patients with clinical symptoms and/or significant conduit stenosis (>50% of diameter) underwent reoperation. RESULTS: Of the 12 patients, 8 underwent reoperation (75%) at a mean interval of 6.5 +/- 1.8 years after the Fontan operation. All conduits were replaced by an 18-mm polytetrafluoroethylene graft. The explants showed ubiquitous tissue deposits on the inner surface, with a residual internal diameter from 8 to 11 mm. All patients survived the extracardiac conduit replacement. Recovery was uneventful, except that 1 patient experienced long-lasting pleural fluid drainage. The mean hospital stay was 10.6 +/- 12.0 days. CONCLUSIONS: The incidence of extracardiac Dacron conduit stenosis in total cavopulmonary connection patients is high. These data indicate that the use of this type of conduit should be avoided. Vigilant follow-up is advised for those patients who have undergone Fontan completion with a Dacron extracardiac conduit. PMID- 23988294 TI - H7N3 live attenuated influenza vaccine has a potential to protect against new H7N9 avian influenza virus. AB - After recent emergence of new avian influenza A(H7N9) viruses in humans many people and Governments are asking about H7 influenza vaccine which could provide cross-protection against new viruses, until H7N9 vaccine is prepared from a relevant strain. Here we scientifically justify that available H7N3 live attenuated influenza vaccine (LAIV) can be protective against H7N9 viruses due to the presence of conserved immune epitopes in its hemagglutinin. We used Immune Epitope Database analysis resource to predict B-cell and CTL epitopes distributed across H7N3 HA molecule and assessed their identity with new H7N9 viruses at near 70% and 60% of the epitopes, respectively. In addition, we tested serum samples of volunteers participated in phase I clinical trial of H7N3 LAIV for the presence of anti-H7N9 hemagglutination-inhibition and neutralizing antibodies and found seroconversions in 44.8% of vaccinated persons, which suggests the potential of H7N3 LAIV to protect against new H7N9 avian influenza viruses. PMID- 23988295 TI - Shared body representations and the 'Whose' system. AB - Mirroring has been almost exclusively analysed in motor terms with no reference to the body that carries the action. According to the standard view, one activates motor representations upon seeing other people moving. However, one does not only see movements, one also sees another individual's body. The following questions then arise. To what extent does one recruit body representations in social context? And does it imply that body representations are shared between self and others? This latter question is all the more legitimate since recent evidence indicates the existence of shared cortical networks for bodily sensations, including pain (e.g., Singer et al., 2004) and touch (e.g., Keysers et al., 2004; Blakemore, Bristow, Bird, Frith, & Ward, 2005). But if body representations are shared, then it seems that their activation cannot suffice to discriminate between one's body and other people's bodies. Does one then need a 'Whose' system to recognise one's body as one's own, in the same way that Jeannerod argues that one needs a 'Who' system to recognise one's actions as one's own? PMID- 23988296 TI - Limited use of price and quality advertising among American hospitals. AB - BACKGROUND: Consumer-directed policies, including health savings accounts, have been proposed and implemented to involve individuals more directly with the cost of their health care. The hope is this will ultimately encourage providers to compete for patients based on price or quality, resulting in lower health care costs and better health outcomes. OBJECTIVE: To evaluate American hospital websites to learn whether hospitals advertise directly to consumers using price or quality data. METHODS: Structured review of websites of 10% of American hospitals (N=474) to evaluate whether price or quality information is available to consumers and identify what hospitals advertise about to attract consumers. RESULTS: On their websites, 1.3% (6/474) of hospitals advertised about price and 19.0% (90/474) had some price information available; 5.7% (27/474) of hospitals advertised about quality outcomes information and 40.9% (194/474) had some quality outcome data available. Price and quality information that was available was limited and of minimal use to compare hospitals. Hospitals were more likely to advertise about service lines (56.5%, 268/474), access (49.6%, 235/474), awards (34.0%, 161/474), and amenities (30.8%, 146/474). CONCLUSIONS: Insufficient information currently exists for consumers to choose hospitals on the basis of price or quality, making current consumer-directed policies unlikely to realize improved quality or lower costs. Consumers may be more interested in information not related to cost or clinical factors when choosing a hospital, so consumer-directed strategies may be better served before choosing a provider, such as when choosing a health plan. PMID- 23988297 TI - Characterization of HbWRKY1, a WRKY transcription factor from Hevea brasiliensis that negatively regulates HbSRPP. AB - Small rubber particle protein (SRPP) is a major component of Hevea brasiliensis (H. brasiliensis) latex, which is involved in natural rubber (NR) biosynthesis. However, little information is available on the regulation of SRPP gene (HbSRPP) expression. To study the transcriptional regulation of HbSRPP, the yeast one hybrid experiment was performed to screen the latex cDNA library using the HbSRPP promoter as bait. One cDNA that encodes the WRKY transcription factor, designated as HbWRKY1, was isolated from H. brasiliensis. HbWRKY1 contains a 1437 bp open reading frame that encodes 478 amino acids. The deduced HbWRKY1 protein was predicted to possess two conserved WRKY domains and a C2H2 zinc-finger motif. HbWRKY1 was expressed at different levels, with the highest transcription in the flower, followed by the bark, latex, and leaf. Furthermore, the co-expression of pHbSRP::GUS with CaMV35S::HbWRKY1 significantly decreased the GUS activity in transgenic tobacco, indicating that HbWRKY1 significantly suppressed the HbSRPP promoter. These results suggested that HbWRKY1 maybe a negative transcription regulator of HbSRPP involved in NR biosynthesis in H. brasiliensis. PMID- 23988298 TI - Comparison of first-order-decay modeled and actual field measured municipal solid waste landfill methane data. AB - The first-order decay (FOD) model is widely used to estimate landfill gas generation for emissions inventories, life cycle assessments, and regulation. The FOD model has inherent uncertainty due to underlying uncertainty in model parameters and a lack of opportunities to validate it with complete field-scale landfill data sets. The objectives of this paper were to estimate methane generation, fugitive methane emissions, and aggregated collection efficiency for landfills through a mass balance approach using the FOD model for gas generation coupled with literature values for cover-specific collection efficiency and methane oxidation. This study is unique and valuable because actual field data were used in comparison with modeled data. The magnitude and variation of emissions were estimated for three landfills using site-specific model parameters and gas collection data, and compared to vertical radial plume mapping emissions measurements. For the three landfills, the modeling approach slightly under predicted measured emissions and over-estimated aggregated collection efficiency, but the two approaches yielded statistically equivalent uncertainties expressed as coefficients of variation. Sources of uncertainty include challenges in large scale field measurement of emissions and spatial and temporal fluctuations in methane flow balance components (generated, collected, oxidized, and emitted methane). Additional publication of sets of field-scale measurement data and methane flow balance components will reduce the uncertainty in future estimates of fugitive emissions. PMID- 23988300 TI - Predicted altitudinal shifts and reduced spatial distribution of Leishmania infantum vector species under climate change scenarios in Colombia. AB - Visceral leishmaniasis (VL) is caused by the trypanosomatid parasite Leishmania infantum (=Leishmania chagasi), and is epidemiologically relevant due to its wide geographic distribution, the number of annual cases reported and the increase in its co-infection with HIV. Two vector species have been incriminated in the Americas: Lutzomyia longipalpis and Lutzomyia evansi. In Colombia, L. longipalpis is distributed along the Magdalena River Valley while L. evansi is only found in the northern part of the Country. Regarding the epidemiology of the disease, in Colombia the incidence of VL has decreased over the last few years without any intervention being implemented. Additionally, changes in transmission cycles have been reported with urban transmission occurring in the Caribbean Coast. In Europe and North America climate change seems to be driving a latitudinal shift of leishmaniasis transmission. Here, we explored the spatial distribution of the two known vector species of L. infantum in Colombia and projected its future distribution into climate change scenarios to establish the expansion potential of the disease. An updated database including L. longipalpis and L. evansi collection records from Colombia was compiled. Ecological niche models were performed for each species using the Maxent software and 13 Worldclim bioclimatic coverages. Projections were made for the pessimistic CSIRO A2 scenario, which predicts the higher increase in temperature due to non-emission reduction, and the optimistic Hadley B2 Scenario predicting the minimum increase in temperature. The database contained 23 records for L. evansi and 39 records for L. longipalpis, distributed along the Magdalena River Valley and the Caribbean Coast, where the potential distribution areas of both species were also predicted by Maxent. Climate change projections showed a general overall reduction in the spatial distribution of the two vector species, promoting a shift in altitudinal distribution for L. longipalpis and confining L. evansi to certain regions in the Caribbean Coast. Altitudinal shifts have been reported for cutaneous leishmaniasis vectors in Colombia and Peru. Here, we predict the same outcome for VL vectors in Colombia. Changes in spatial distribution patterns could be affecting local abundances due to climatic pressures on vector populations thus reducing the incidence of human cases. PMID- 23988301 TI - Impact of inflammatory process on left ventricular recovery after Transcatheter Aortic Valve Implantation. PMID- 23988299 TI - Differential expression and localization of saposin-like protein 2 of Fasciola hepatica. AB - FhSAP2 is a novel antigen isolated from the adult fluke of Fasciola hepatica. Based on sequence similarity with amoebapores and other related proteins, it belongs to the saposin-like protein (SAPLIP) family. FhSAP2 has been shown to be highly immunogenic and capable of inducing protective immune responses in mice and rabbits challenged with F. hepatica. Moreover, FhSAP2 is also reactive with sera from humans with chronic fascioliasis. In the present study, we investigated the expression of FhSAP2 in various developmental stages of F. hepatica by qPCR and demonstrated that FhSAP2-mRNA species are up-regulated in undeveloped eggs, newly excysted juveniles, and adults, but down-regulated in the miracidium stage. Monoclonal antibodies against FhSAP2 were produced, and two clones that are positive to F. hepatica whole-body extract, but not reactive with extracts from other trematodes, were selected, expanded and used for histolocalization studies. Confocal immunofluorescence revealed the presence of native FhSAP2 in epithelial cells surrounding the gut, toward the outermost part of the tegument, and toward the tegumental cells of both adults and newly excysted juveniles. PMID- 23988302 TI - Ablation of atrial fibrillation in Brugada syndrome patients with an implantable cardioverter defibrillator to prevent inappropriate shocks resulting from rapid atrial fibrillation. AB - BACKGROUND: Inappropriate shocks resulting from atrial tachyarrhythmias are highly problematic for patients with an implantable cardioverter defibrillator (ICD). We aimed to determine the effectiveness of catheter ablation of atrial fibrillation (AF) in preventing inappropriate shocks due to rapid AF in patients diagnosed with Brugada syndrome (BS) who were implanted with an ICD. METHODS: We performed AF ablation in 5 BS patients with ICDs who experienced inappropriate shocks caused by rapid paroxysmal AF and in a BS patient scheduled to determine an indication of an ICD implantation who frequently experienced rapid AF. RESULTS: Although 2 patients underwent a 2nd ablation procedure because of AF recurrences, 5 of the 6 patients were finally free from AF after their last procedure during a median follow-up period of 43.2 months. No further inappropriate shocks caused by rapid AF occurred after the 1st ablation session in any of the patients. A patient developed a ventricular fibrillation storm during his electrophysiological study following the ablation procedure, and then was implanted with an ICD. CONCLUSIONS: AF ablation in BS patients may be reasonable to prevent inappropriate ICD shocks resulting from rapid AF. However, ventricular extrastimuli just after the ablation had better be avoided in them. PMID- 23988303 TI - Recurrent very late drug-eluting stent thrombosis. PMID- 23988305 TI - Minimally invasive direct coronary artery bypass reduces the need for repeated revascularization at long-term follow-up compared with stenting: a meta-analysis. PMID- 23988304 TI - Personalized assessment of radiation risks from the one-stop-shop myocardial 256 slice CT examination. AB - BACKGROUND: This study provides data on the cumulative life attributable risk (LAR) of radiation-induced cancer from the combination of coronary CT angiography (CCTA), dynamic CT perfusion (CTP) and delayed enhancement (DE) CT scans, required for reliable risk-benefit analysis of the one-stop-shop CCTA + CTP + DECT cardiac examination. METHODS: Monte Carlo simulation of the dynamic CTP and DECT exposures on 62 adult individuals was employed to determine radiation absorbed dose to exposed radiosensitive organs. Corresponding data for CCTA were derived using patient chest circumference and previously published data. Individual-specific LARs of cancer were estimated using organ/tissue-specific radiogenic cancer risk factors. Total LAR from CCTA + CTP + DECT scans' sequence were estimated and compared to nominal intrinsic risk of cancer. RESULTS: The main contribution, up to 80%, to cumulative radiation burden from CCTA + CTP + DECT scan-sequence was found to originate from the CTP scan. The total LAR from CCTA + CTP + DECT for females was found 4-6 times higher, compared to males. The mean cumulative risk of radiogenic cancer associated with the complete CCTA + CTP + DECT scan sequence was found to marginally increase the intrinsic risk for cancer induction by less than 0.6% and 0.1% for females and males, respectively. CONCLUSIONS: The radiation risk from the 256-slice CCTA + CTP + DECT scan sequence may be considered low and should not constitute an obstacle for the clinical endorsement of the one-stop-shop cardiac CT examination, given that its clinical value has been well verified. Nevertheless, every effort should be made towards optimization of the dynamic CTP component which is the main contributor to patient radiation burden. PMID- 23988306 TI - Phylogenetic relationships among Perissodactyla: secretoglobin 1A1 gene duplication and triplication in the Equidae family. AB - Secretoglobin family 1A member 1 (SCGB 1A1) is a small anti-inflammatory and immunomodulatory protein that is abundantly secreted in airway surface fluids. We recently reported the existence of three distinct SCGB1A1 genes in the domestic horse genome as opposed to the single gene copy consensus present in other mammals. The origin of SCGB1A1 gene triplication and the evolutionary relationship of the three genes amongst Equidae family members are unknown. For this study, SCGB1A1 genomic data were collected from various Equus individuals including E. caballus, E. przewalskii, E. asinus, E. grevyi, and E. quagga. Three SCGB1A1 genes in E. przewalskii, two SCGB1A1 genes in E. asinus, and a single SCGB1A1 gene in E. grevyi and E. quagga were identified. Sequence analysis revealed that the non-synonymous nucleotide substitutions between the different equid genes coded for 17 amino acid changes. Most of these changes localized to the SCGB 1A1 central cavity that binds hydrophobic ligands, suggesting that this area of SCGB 1A1 evolved to accommodate diverse molecular interactions. Three dimensional modeling of the proteins revealed that the size of the SCGB 1A1 central cavity is larger than that of SCGB 1A1A. Altogether, these findings suggest that evolution of the SCGB1A1 gene may parallel the separation of caballine and non-caballine species amongst Equidae, and may indicate an expansion of function for SCGB1A1 gene products. PMID- 23988307 TI - Molecular phylogenetic reconstructions identify East Asia as the cradle for the evolution of the cosmopolitan genus Myotis (Mammalia, Chiroptera). AB - Sequences of the mitochondrial cytochrome b (1140 bp) and nuclear Rag 2 (1148 bp) genes were used to assess the evolutionary history of the cosmopolitan bat genus Myotis, based on a worldwide sampling of over 88 named species plus 7 species with uncertain nomenclature. Phylogenetic reconstructions of this comprehensive taxon sampling show that most radiation of species occurred independently within each biogeographic region. Our molecular study supports an early divergence of species from the New World, where all Nearctic and Neotropical species plus a lineage from the Palaearctic constitute a monophyletic clade, sister to the remaining Old World taxa. The major Old World clade includes all remaining Eurasian taxa, most Oriental species, one Oceanian, and all Ethiopian species. Another lineage, including M. latirostris from Taiwan, appears at the base of these two major biogeographic clades and, because it bears nyctalodont molars, could be considered as a distinct genus. However, this molar configuration is also found in crown-group species, indicating that these dental characters are variable in the genus Myotis and may confound interpretation of the fossil record. Molecular datings suggest an origin of all recent Myotis in the early Miocene (about 21MYA with 95% highest posterior density interval 23-20MYA). This period was characterized by a global climatic cooling that reduced the availability of tropical habitats and favoured the development of more temperate vegetation. This sharp climatic change might have triggered the evolution of Myotis in the Northern continents, because Myotis ancestors seem to have been well adapted and successful in such temperate habitats. Ancestral area reconstructions based on the molecular phylogeny suggest that the eastern portion of the Asian continent was an important center of origin for the early diversification of all Myotis lineages, and involved relatively few subsequent transcontinental range expansions. PMID- 23988309 TI - Latex allergy: a brief summary. PMID- 23988308 TI - Gray matter correlates of dispositional optimism: a voxel-based morphometry study. AB - Dispositional optimism is an important product of human evolution. This individual difference variable plays a core role in human experience. Dispositional optimism is beneficial to physical and psychological wellbeing. Previous task-related neuroimaging studies on dispositional optimism were limited by small sample sizes, and did not examine individual differences in dispositional optimism related to brain structure. Thus, the current study used voxel-based morphometry and the revised Life Orientation Test to investigate individual dispositional optimism and its association with brain structure in 361 healthy participants. The results showed that individual dispositional optimism was associated with larger gray matter volume of a cluster of areas that included the left thalamus/left pulvinar that extended to the left parahippocampal gyrus. These findings suggest a biological basis for individual dispositional optimism, distributed across different gray matter regions of the brain. PMID- 23988310 TI - Alternatives for the lactose-intolerant patient. PMID- 23988311 TI - Minimizing the risk of teratogenic substance exposure for pregnant compounding pharmacists. PMID- 23988312 TI - Veterinary Considerations: COPD in Horses. PMID- 23988313 TI - Treating patients allergic to poison ivy. PMID- 23988314 TI - Introduction to nuclear pharmacy. PMID- 23988315 TI - Physical requirements for a nuclear pharmacy. PMID- 23988316 TI - Nuclear pharmacist training and certification. PMID- 23988318 TI - Prescription preparation in a nuclear pharmacy: three case studies. PMID- 23988317 TI - Typical day in a nuclear pharmacy. PMID- 23988319 TI - A Post-sclerotherapy Discoloration Treatment. PMID- 23988320 TI - Topical ketoprofen for fibromyalgia. PMID- 23988321 TI - Comparison of job satisfaction for compounders and noncompounders. AB - Job satisfaction among independent community pharmacists who were classified as compounders and noncompounders was measured using a mail questionnaire. Two previously validated survey instruments that measured job satisfaction were adapted for use in this study. Additional questions determined the volume of compounded prescriptions the respondents dispensed. Questionnaires were mailed to randomly selected independent community pharmacists in the United States and Canada. The response rate was 53.4%(n=391). The researcher classified independent community pharmacists who dispensed greater than or equal to five compounded prescriptions daily as compounders and those who dispensed less than or equal to four compounded prescriptions daily as non-compounders. Fifty-four percent (n=200) of all respondents were classified as compounders. Of the six satisfaction dimensions measured, responses to five of the dimensions were significantly different for compounders versus noncompounders. The results indicate that pharmacists' job satisfaction levels may be improved if intrinsic factors are satisfied in their job role. Since prescription compounding provides satisfaction with several intrinsic factors such as variety, challenge and use of skills, independent community pharmacists may improve their job satisfaction levels by providing prescription compounding services. PMID- 23988322 TI - Chemical stability of meperidine hydrochloride in polypropylene syringes. AB - The physical and chemical stability of preservative-free meperidine hydrochloride solutions in polypropylene syringes was studied. Solutions of meperidine hydrochloride were diluted in dextrose 5% and normal saline to 0.25, 1, 10, 20, and 30mg/mL, repectively, and stored at either 22 deg C or 4 deg C for 28 days. All solutions were protected from light druing storage. Triplicate samples were taken from each syringe on days zero, one, three, seven, 14 and 28 and frozen at 72 deg C. Samples were analyzed in duplicate using a stability-indiicating high pressure liquid chromatography assay. All samples remained colorless and free of precipitate throughout the course of the study. The concentration of meperidine remaining after the 28-day storage period was greater than 90% of the initial concentration for all the concentrations, diluents and temperatures studied. PMID- 23988323 TI - Stability of Sufentanil in a Syringe Pump under Simulated Epidural Infusion. AB - Sufentanil is a potent micro-opioid and centrally acting analgesic. In the management of acute postoperative pain, sufentanil is often administered epidurally using a standard syringe pump. For epidural administration, sufentanil is diluted to a concentration of 1 to 2 micrograms/mL with 0.9% sodium chloride injection. The stability of sufentanil in a syringe pump under simulated epidural infusion was studied using a stability-indicating high-performance liquid chromatography method. The concentration of sufentanil was determined in polypropylene syringes connected with a polyethlyene or polyvinyl chloride (PVC) tubing, filter and epidural catheter. Sufentanil concentrations remained constant in polypropylene syringes connected to epidural catheters and in the whole epidural infusion system using polyethylene tubing. Sufentanil concentrations decreased 7% to 15% in syringes connected to PVC tubing, polyethylene tubing and the whole epidural infusion system using PVC tubing. Adsorption of 17% of the sufentanil onto an epidural filter occurred during the first hour of the infusion; thereafter, sufentanil concentration remained stable at levels that were 5% to 15% below the theoretical concentration. In conclusion, adsorption of sufentanil should be considered when a new filter and tubing of different materials are used. PMID- 23988324 TI - Participation and social participation: are they distinct concepts? AB - INTRODUCTION: The concept of participation has been extensively used in health and social care literature since the World Health Organization introduced its description in the International Classification of Functioning, Disability and Health (ICF) in 2001. More recently, the concept of social participation is frequently used in research articles and policy reports. However, in the ICF, no specific definition exists for social participation, and an explanation of differences between the concepts is not available. AIM: The central question in this discussion article is whether participation, as defined by the ICF, and social participation are distinct concepts. This article illustrates the concepts of participation and social participation, presents a critical discussion of their definitions, followed by implications for rehabilitation and possible future directions. DISCUSSION: A clear definition for participation or social participation does not yet exist. Definitions for social participation differ from each other and are not sufficiently distinct from the ICF definition of participation. Although the ICF is regarded an important conceptual framework, it is criticised for not being comprehensive. The relevance of societal involvement of clients is evident for rehabilitation, but the current ICF definition of participation does not sufficiently capture societal involvement. CONCLUSION: Changing the ICF's definition of participation towards social roles would overcome a number of its shortcomings. Societal involvement would then be understood in the light of social roles. Consequently, there would be no need to make a distinction between social participation and participation. PMID- 23988325 TI - Dead-baby dreams, transfiguration and recovery from infant death trauma in northeast Brazil. AB - Maternal reactions to infant death in Northeast Brazil have been at the epicenter of anthropological debate since the 1980s. This ethnographic study of 45 death narratives by bereaved mothers collected from 1979-1989 in Pacatuba, Ceara, Brazil, refutes existing claims of mothers' "selective neglect" and "indifference" towards sick babies and emotionally empty grief response. I argue that through dead-baby dreams--and their imaginary transfiguration-grieving mothers alleviate infant death trauma. Feelings of hopelessness, helplessness, definitive loss, and personal guilt-the social seeds of depression--are reframed to deny death's finality and exonerate mothers from crippling self-blame. By transfiguring lingering mental images of the tiny cold corpse, mothers remold the irreversibility and definitiveness of death, gaining a sense of control over its unpredictable "jolt." In the politically oppressive Northeast Brazil--where social justice remains "an illusion"--mothers dream to preserve their own mental sanity and to recover from death's cruel aftermath. Any interpretation of mourning behavior must be contextualized within the local moral world and its "assumed structure of reality" to avoid demoralizing grieving Brazilian mothers and compounding their suffering. "You see, the only thing a poor woman truly owns that no one can borrow, cheat, steal or rob from her ... is her imagination!" (Dona Chiquinha grieving death of her 10 children, Pacatuba, Ceara, Brazil). PMID- 23988326 TI - Three-dimensional contrast echocardiography-guided alcohol septal ablation in hypertrophic obstructive cardiomyopathy. PMID- 23988327 TI - Left ventricular partitioning device ('Parachute'): a multi-modality imaging perspective. PMID- 23988328 TI - Jahn-Teller distortion relaxation across the LaMnO3+Delta phase diagram. AB - The evolution of the local Jahn-Teller distortion across the LaMnO3+Delta phase diagram was obtained using the perturbed angular correlation local probe technique. We found that upon doping, the local distortion decreases continuously with increasing doping and that no fully Jahn-Teller distorted Mn(3+)O6 octahedra are observed within the orthorhombic insulating phase. A local single-phase scenario is established for the orbital disordered orthorhombic crystallographic structure. We also show that the continuous weakening of the Jahn-Teller distortions is not limited to a single-phase environment and occurs in a similar manner within an undistorted rhombohedric matrix upon lowering the temperature. PMID- 23988329 TI - Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum associated protein degradation. AB - Quality control and degradation of misfolded proteins are essential processes of all cells. The endoplasmic reticulum (ER) is the entry site of proteins into the secretory pathway in which protein folding occurs and terminally misfolded proteins are recognized and retrotranslocated across the ER membrane into the cytosol. Here, proteins undergo polyubiquitination by one of the membrane embedded ubiquitin ligases, in yeast Hrd1/Der3 (HMG-CoA reductase degradation/degradation of the ER) and Doa10 (degradation of alpha), and are degraded by the proteasome. In this study, we identify cytosolic Ubr1 (E3 ubiquitin ligase, N-recognin) as an additional ubiquitin ligase that can participate in ER-associated protein degradation (ERAD) in yeast. We show that two polytopic ERAD substrates, mutated transporter of the mating type a pheromone, Ste6* (sterile), and cystic fibrosis transmembrane conductance regulator, undergo Ubr1-dependent degradation in the presence and absence of the canonical ER ubiquitin ligases. Whereas in the case of Ste6* Ubr1 is specifically required under stress conditions such as heat or ethanol or in the absence of the canonical ER ligases, efficient degradation of human cystic fibrosis transmembrane conductance regulator requires function of Ubr1 already in wild type cells under standard growth conditions. Together with the Hsp70 (heat shock protein) chaperone Ssa1 (stress-seventy subfamily A) and the AAA-type ATPase Cdc48 (cell division cycle), Ubr1 directs the substrate to proteasomal degradation. These data unravel another layer of complexity in ERAD. PMID- 23988330 TI - Safety mechanism assisted by the repressor of tetracycline (SMART) vaccinia virus vectors for vaccines and therapeutics. AB - Replication-competent viruses, such as Vaccinia virus (VACV), are powerful tools for the development of oncolytic viral therapies and elicit superior immune responses when used as vaccine and immunotherapeutic vectors. However, severe complications from uncontrolled viral replication can occur, particularly in immunocompromised individuals or in those with other predisposing conditions. VACVs constitutively expressing interferon-gamma (IFN-gamma) replicate in cell culture indistinguishably from control viruses; however, they replicate in vivo to low or undetectable levels, and are rapidly cleared even in immunodeficient animals. In an effort to develop safe and highly effective replication-competent VACV vectors, we established a system to inducibly express IFN-gamma. Our SMART (safety mechanism assisted by the repressor of tetracycline) vectors are designed to express the tetracycline repressor under a constitutive VACV promoter and IFN gamma under engineered tetracycline-inducible promoters. Immunodeficient SCID mice inoculated with VACVs not expressing IFN-gamma demonstrated severe weight loss, whereas those given VACVs expressing IFN-gamma under constitutive VACV promoters showed no signs of infection. Most importantly, mice inoculated with a VACV expressing the IFN-gamma gene under an inducible promoter remained healthy in the presence of doxycycline, but exhibited severe weight loss in the absence of doxycycline. In this study, we developed a safety mechanism for VACV based on the conditional expression of IFN-gamma under a tightly controlled tetracycline inducible VACV promoter for use in vaccines and oncolytic cancer therapies. PMID- 23988331 TI - Cross-sectional assessment of the relationships between dyspnea domains and lung function in diffuse parenchymal lung disease. AB - BACKGROUND: Activity-related dyspnea is the main contributor to the altered quality of life in diffuse parenchymal lung diseases (DPLD). Instruments pertaining to dyspnea are classified as pertaining to domains of sensory perceptual experience, affective distress or symptom/disease impact; whether these domains are equally related to lung function impairments remains to be established. OBJECTIVES: They were to assess the relationships between two domains of dyspnea (sensory-perceptual experience and symptom impact) and pulmonary function tests according to their evaluation of ventilatory demand, capacity and drive in patients suffering from DPLD. METHODS: Fifty patients were prospectively enrolled (median age, 58 years; 25 women) and underwent spirometry, body plethysmography, measurements of lung diffusion for carbon monoxide (DLCO) and nitric oxide, maximal airway pressures (capacity and demand assessments), mouth occlusion pressure at 0.1 s (P0.1: respiratory drive assessment) and a 6 min walk test with Borg score assessment (dyspnea: sensory domain). The impact domain of dyspnea was evaluated using the baseline dyspnea index. RESULTS: The sensory domain of dyspnea was linked to demand (CO transfer coefficient, kCO) only, while the impact domain was independently linked to demand and capacity (kCO and forced vital capacity, respectively). Among resting pulmonary function tests, both P0.1 and DLCO allowed the assessment of these two domains of dyspnea. CONCLUSIONS: In DPLD, the sensory-perceptual domain of dyspnea is mainly linked to alterations in ventilatory demand while the impact domain is related to both demand and capacity. DLCO that assesses both demand and capacity and P0.1 were the strongest correlates of dyspnea. PMID- 23988332 TI - Immunohistochemical expression of Bax and Bak in canine non-neoplastic tissues. AB - Apoptosis is critical for embryonic development, maintenance of tissue homeostasis and protection against malignant transformation. The Bcl-2 family of proteins plays a key role in intrinsic apoptosis by controlling the integrity of the outer mitochondrial membrane, and the multidomain pro-apoptotic Bcl-2 family members Bax and Bak are essential components of this pathway. The aim of this study was to provide data on the expression of these proteins in normal canine tissues. Two antibodies against Bax recognising different conformations of the protein and one antibody against Bak were validated by immunohistochemistry and immunoblotting using canine recombinant proteins and keratinocytes treated with ultraviolet light. The antibodies were used immunohistochemically to label a wide panel of histologically normal tissues assembled on tissue microarrays. In addition, a subset of the tissues was evaluated by Western blot analysis. Immunohistochemical and Western blot analyses revealed that both Bax and Bak are widely expressed in non-neoplastic tissues from adult dogs. Immunohistochemistry showed almost exclusively cytoplasmic labelling and prominent labelling of epithelial cells. In lymph nodes, immunohistochemical labelling was diffuse for both proteins and showed enhanced intensities in the mantle zones for Bax and the germinal centres for Bak. Strong reactivity for the active conformation of Bax was detected only in enterocytes and Leydig cells and in scattered lymphocytes. These data indicate widespread expression of Bax and Bak in normal canine tissues. Knowledge of the expression of Bax and Bak in normal tissues is a prerequisite in assessing the role of these proteins in canine neoplastic disease. PMID- 23988333 TI - Acetylcholinesterase activity in the cerebrospinal fluid of dogs with seizures. AB - Recent studies in animal models have focused on the role of cholinergic elements, mainly acetylcholinesterase (AChE) and the 'readthrough' acetylcholinesterase isoform (AChE-R), in seizures. A prospective double-masked study was conducted to assess the activity of AChE and AChE-R in cerebrospinal fluid (CSF) of 26 dogs post-seizure, 28 dogs with intervertebral disc disease (IVDD) and 16 healthy dogs. AChE was also measured in the serum in the post-seizure and IVDD groups. The results showed no significant differences in CSF AChE among the three groups. AChE-R was not detected in any dog and AChE in the serum was similar between groups. This preliminary study provides new information on AChE and AChE-R in the CSF and sera of dogs following naturally-occurring seizures. PMID- 23988334 TI - Effect of age and severity of cognitive dysfunction on two simple tasks in pet dogs. AB - Dogs exhibit age-dependent losses in learning and memory as well as a progressive accumulation of neuropathology that parallels that observed in normal human aging and early Alzheimer's disease. These deficits have been extensively studied using a number of standard cognitive tasks in the laboratory; however, appropriate tools for their assessment in veterinary clinics are still lacking. The aim of this study was to evaluate the effect of age and the severity of cognitive dysfunction syndrome (CDS) on two simple tests conducted in a clinical setting. A food searching (FS) task and a problem-solving (PS) task were administered to young (1-4 years, n=9), middle-aged (5-8 years, n=10), cognitively unimpaired aged (>=9 years, n=31), and cognitively impaired aged (>= 9 years, n=37) dogs. Cognitive status was classified using an owner-based questionnaire, and in the impaired group, dogs were categorized as having either mild or severe CDS. During the FS task, younger dogs (<9 years) were able to locate the food more quickly and with more success than the aged groups (>=9 years). Dogs with severe CDS exhibited poorer performance than those with mild CDS or their healthy counterparts. In the PS task, younger dogs performed better than the aged dogs in obtaining food, but there were no differences related to CDS severity. The FS task might help to better characterize cognitively affected dogs in the clinical setting than the PS task. These and similar tasks require further investigations in the field. PMID- 23988336 TI - Challenges of multidisciplinary care in Parkinson's disease. PMID- 23988335 TI - The stability of silver nanoparticles in a model of pulmonary surfactant. AB - The growing use of silver nanoparticles (AgNPs) in consumer products has raised concerns about their potential impact on the environment and human health. Whether AgNPs dissolve and release Ag(+) ions, or coarsen to form large aggregates, is critical in determining their potential toxicity. In this work, the stability of AgNPs in dipalmitoylphosphatidylcholine (DPPC), the major component of pulmonary surfactant, was investigated as a function of pH. Spherical, citrate-capped AgNPs with average diameters of 14 +/- 1.6 nm (n = 200) were prepared by a chemical bath reduction. The kinetics of Ag(+) ion release was strongly pH-dependent. After 14 days of incubation in sodium perchlorate (NaClO4) or perchloric acid (HClO4) solutions, the total fraction of AgNPs dissolved varied from ~10% at pH 3, to ~2% at pH 5, with negligible dissolution at pH 7. A decrease in pH from 7 to 3 also promoted particle aggregation and coarsening. DPPC (100 mg.L(-1)) delayed the release of Ag(+) ions, but did not significantly alter the total amount of Ag(+) released after two weeks. In addition, DPPC improved the dispersion of the AgNPs and inhibited aggregation and coarsening. TEM images revealed that the AgNPs were coated with a DPPC layer serving as a semipermeable layer. Hence, lung lining fluid, particularly DPPC, can modify the aggregation state and kinetics of Ag(+) ion release of inhaled AgNPs in the lung. These observations have important implications for predicting the potential reactivity of AgNPs in the lung and the environment. PMID- 23988338 TI - Management of atrial fibrillation in the year 2033: new concepts, tools, and applications leading to personalized medicine. PMID- 23988337 TI - Integrated multidisciplinary care in Parkinson's disease: a non-randomised, controlled trial (IMPACT). AB - BACKGROUND: A multidisciplinary approach is thought to be the best way to manage the motor and non-motor symptoms of Parkinson's disease, but how such care should be delivered is unknown. To address this gap in knowledge, we assessed the effectiveness of an integrated multidisciplinary approach compared with usual care. METHODS: We recruited patients for our non-randomised controlled trial from six community hospitals in the Netherlands (two in regions where the integrated care intervention was available and four in control regions that administered usual care). Eligible patients were those with Parkinson's disease, aged 20-80 years, and without severe cognitive impairment or comorbidity. Patients in the intervention group were offered an individually tailored comprehensive assessment in an expert tertiary referral centre and subsequent referrals to a regional network of allied health professionals specialised in Parkinson's disease. Primary outcomes were activities of daily living (Academic Medical Center linear disability score [ALDS]) and quality of life (Parkinson's disease quality of life questionnaire [PDQL]) measured at 4, 6, and 8 months. Secondary outcomes included motor functioning (unified Parkinson's disease rating scale, part III [UPDRS III], at 4 months), caregiver burden (belastungsfragebogen Parkinson angehorigen kurzversion [BELA-A-k] at 4 and 8 months), and costs (during whole study period). Primary analysis was by intention to treat and included scores over 4, 6, and 8 months, with correction for baseline score. The trial is registered at Clinicaltrials.gov, number NCT00518791. FINDINGS: We recruited 301 patients (150 patients in the intervention group and 151 in the control group) between August, 2007, and December, 2009, of whom 285 completed follow-up (last follow-up was July, 2010). 101 (67%) patients in the intervention group visited the expert centre; 49 (33%) opted not to visit the expert centre. The average ALDS score from months 4, 6, and 8, with correction for baseline score, was greater in the intervention group than in the control group (difference 1.3 points, 95% CI -2.1 to 2.8; corresponding raw logit score difference 0.1, 95% CI 0.003 to 0.2) as was the average PDQL score (difference 3.0 points, 0.4 to 5.6). Secondary analysis with correction for baseline disease severity showed no differences between groups for ALDS (difference 0.9 points, 95% CI -0.6 to 2.4; corresponding raw logit score difference 0.1, -0.02 to 0.3) or PDQL (difference 1.7 points, -1.2 to 4.6). Secondary outcomes did not differ between groups (UPDRS III score difference 0.6 points, 95% CI -1.4 to 2.6; BELA-A-k score difference 0.8 points, 0.2 to 1.8; cost difference ?742, -?489 to ?1950). INTERPRETATION: This integrated care approach offered only small benefits to patients with Parkinson's disease, and these disappeared after correction for baseline disease severity. These results suggest that different approaches are needed to achieve more substantial health benefits. FUNDING: NutsOhra Foundation, Stichting Parkinson Nederland, National Parkinson Foundation. PMID- 23988339 TI - Percutaneous management of lower limb ischemia after the use of vascular closure devices. AB - BACKGROUND: Lower extremity ischemia after the use of vascular closure devices (VCDs) after transfemoral percutaneous coronary and peripheral interventions is an infrequent though relevant clinical entity. We aimed to assess immediate and midterm outcomes of a systematic endovascular approach for the treatment of VCD related lower limb ischemia. METHODS: Between 2006 and 2008, all the patients who developed lower limb ischemia after the use of a VCD in a high volume French institution were systematically managed percutaneously and constituted the study population. Clinical characteristics, immediate, and midterm outcomes are reported. RESULTS: Of 2944 consecutive patients undergoing VCD placement after femoral access, 18 (3 men and 15 women) had VCD-related lower limb ischemia and were all managed percutaneously. Median age was 66.5 years. Devices were Angio Seal (St Jude Medical) in 12 cases, StarClose (Abbott Vascular Devices) in 3 cases, and Perclose (Abbott Vascular Devices) in 3 cases. Limb ischemia occurred with a median delay of 2 days after device placement. Index procedures were coronary interventions in 14 cases and peripheral in 4 cases. The occlusion site was successfully crossed in all cases. Twelve patients were treated with balloon angioplasty and 6 with stent implantation. Angiographic success was obtained in all cases. After a median 32-month follow-up, only 2 patients initially treated using percutaneous transluminal angioplasty needed reintervention consisting of a balloon angioplasty in 1 case and stent implantation in the second case. At final follow-up, all the patients were asymptomatic. CONCLUSIONS: Endovascular treatment for VCD-related limb ischemia is a feasible and effective approach resulting in excellent immediate and midterm outcomes. PMID- 23988340 TI - Incidence, secular trends, and outcomes of cardiac surgery in Aboriginal peoples. AB - BACKGROUND: Canada's Aboriginal people experience a disproportionate burden of comorbid illnesses predisposing them to higher rates of atherosclerotic disease. We set out to investigate secular rates of cardiovascular surgery (CVSx) and postsurgical outcomes in Aboriginals compared with non-Aboriginals. METHODS: All patients undergoing CVSx in Manitoba, Canada from 1995-2007 (N =12,170 [Aboriginal, 574, 4.7%; non-Aboriginal, 11,596, 95.3%]) were included in our study cohort. Race was self-identified. Age- and sex-adjusted incidence were determined using 2001 and 2006 census data. Multivariable logistic regression models were constructed to determine the association between race and the outcomes of death, infections, and a composite of adverse events. RESULTS: CVSx rates were significantly lower in Aboriginals compared with non-Aboriginals (all CVSx, 63.6 vs 97.7 per 10,000 population; coronary artery bypass grafting only, 46.2 vs 71.9 per 10,000 population, respectively). The lower CVSx rates were most pronounced among Aboriginals residing in urban areas (21.0 vs 78.0 per 10,000). Postoperatively, Aboriginals experienced significantly higher odds of infections (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.13-2.34; P = 0.008), in particular pneumonia (OR, 2.24; 95% CI, 1.58-3.19; P < 0.0001). There was no increase in risk of death after surgery (OR, 1.15; 95% CI, 0.63-2.08; P = 0.6) or the composite outcome (OR, 1.0; 95% CI, 0.66-1.52; P = 1.0) compared with non Aboriginals. CONCLUSIONS: Aboriginal peoples, particularly in the urban setting, are considerably less likely to undergo CVSx. When they do, they have postoperative mortality similar to that of non-Aboriginals. Our findings suggest an urban racial disparity in access to CVSx. PMID- 23988341 TI - Relationship of quality of life with procedural success of atrial fibrillation (AF) ablation and postablation AF burden: substudy of the STAR AF randomized trial. AB - BACKGROUND: The Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF) trial compared 3 strategies for ablation of high-burden paroxysmal/persistent atrial fibrillation (AF): complex fractionated electrogram ablation (CFE), pulmonary vein isolation (PVI), or a combined approach (PVI with CFE). This subanalysis aimed to identify the effect on quality of life (QOL) conferred by ablation strategy, AF recurrence, and type of AF. METHODS: The STAR AF study (n = 100) found 88%, 68%, and 38% freedom from AF > 30 seconds at 12 months for PVI with CFE, PVI, and CFE approaches, respectively (P = 0.001). QOL was measured before ablation and at 12 months after ablation using the Short-Form Health Survey (SF-36) scale. Transformed scores were calculated for each of the 8 subscales of the SF-36, and also converted to physical health and mental health component scores. RESULTS: There was a significant improvement in physical health (24%) and mental health (19%) component scores from baseline to 12 months after ablation (P < 0.05 for both). Significant QOL improvements were seen for all 3 ablation strategies despite differences in outcome. QOL measurements also improved regardless of AF recurrence, except in patients with an AF burden in the highest quartile (median 27.2 hours per month). AF recurrence independently predicted aggregate QOL score. CONCLUSIONS: QOL after AF ablation improves regardless of procedural outcome. QOL scores were only negatively affected in patients with a high symptomatic burden of arrhythmia recurrence suggesting that significant reduction in AF burden can improve QOL without total elimination of AF. PMID- 23988342 TI - Male breast cancer metastasis to the oral mucosa and face. PMID- 23988343 TI - Toe digital artery perforator flap for coverage of defects on the toe. PMID- 23988344 TI - Treatment of disseminated granuloma annulare with oral vitamin E: 'primum nil nocere'. AB - BACKGROUND: Disseminated granuloma annulare (DGA) is a benign and usually asymptomatic skin disease. However, many patients feel aesthetically disfigured and ask for treatment. Until today, no standard therapy is recommended. OBJECTIVE: To evaluate the safety and efficacy of oral vitamin E treatment compared to the natural course of DGA. METHODS: This single-centre observational cohort study included 38 consecutive patients with histologically confirmed DGA. 21 patients underwent treatment with oral vitamin E, whereas 17 patients preferred a wait-and-see approach. RESULTS: Complete healing (40%) and improvement (30%) were frequently seen under oral vitamin E therapy. However, DGA also spontaneously disappeared in 31% and improved in 25% of untreated control patients. Vitamin E therapy was very well tolerated. CONCLUSIONS: Oral vitamin E treatment is a safe and probably effective therapy for DGA. As the natural course of DGA leads to complete healing or significant improvement in many cases, 'primum nil nocere' should be the maxim. PMID- 23988345 TI - CCK response in bulimia nervosa and following remission. AB - The core defining features of bulimia nervosa (BN) are repeated binge eating episodes and inappropriate compensatory (e.g., purging) behavior. Previous studies suggest an abnormal post-prandial response in the satiety-signaling peptide cholecystokinin (CCK) in persons with BN. It is unknown whether this altered response persists following remission or if it may be a potential target for the development of clinical treatment strategies. To examine the nature of this altered response, this study assessed whether CCK normalizes following remission from BN (RBN). This study prospectively evaluated the plasma CCK response and corresponding eating behavior-related ratings (e.g., satiety, fullness, hunger, urge to binge and vomit) in individuals with BN-purging subtype (n=10), RBN-purging subtype (n=14), and healthy controls (CON, n=13) at baseline, +15, +30, and +60 min following the ingestion of a standardized liquid test meal. Subject groups did not significantly differ in CCK response to the test meal. A significant relationship between CCK response and satiety ratings was observed in the RBN group (r=.59, p<.05 two-tailed). A new and unanticipated finding in the BN group was a significant relationship between CCK response and ratings of "urge to vomit" (r=.86, p<.01, two-tailed). Unlike previous investigations, CCK response did not differ in BN and CON groups. Thus the role of symptom severity remains an area of further investigation. Additionally, findings suggest that in this sample, CCK functioning following remission from BN-purging subtype is not different from controls. It remains unknown whether or not CCK functioning may be a protective or liability factor in the stabilization and recovery process. Replication studies utilizing a larger sample size are needed to further elucidate the role of CCK in recovery from BN and its potential target of related novel treatment strategies. PMID- 23988347 TI - Management and outcome of primary spinal ependymomas: a single center experience from Taiwan. AB - BACKGROUND: Surgical treatment of spinal ependymomas requires careful consideration of the relative risks of neurological worsening from surgery. Our aim was to determine the risk factors of neurological deterioration after surgery for spinal ependymomas. MATERIAL AND METHODS: This 20-year study included 17 patients (seven men and 10 women; 44.65+/-13.62 years) with histologically confirmed spinal ependymomas. The basic features were reviewed and the functional status was assessed by using the modified McCormick classification. We subdivided the patient population into two groups according to whether neurological deterioration occurred after primary tumor resection (N=5) or not (N=12), and compared their clinical characteristics. RESULTS: The average duration of presenting symptoms in the 17 patients was 23.53+/-21.45 months. Three (17.6%) patients underwent subtotal or partial resection and 14 (82.4%) patients underwent gross total resection. The incidence of neurological deterioration after primary resection of spinal ependymomas was 29.4%. There were five (100%) and two (16.7%) male patients in the neurological-deterioration and no deterioration groups, respectively (p=0.003). The duration of presenting symptoms was 24 months or over in all the patients with neurological deterioration and five of the 12 patients with improved or stabilized function (p=0.044). CONCLUSION: The risk associated with surgical resection of spinal ependymomas should not be overlooked because of the significant incidence of neurological deterioration. The male gender and long-standing symptom (>=24 months) are risk factors of postoperative neurological worsening. Early diagnosis and surgery are therefore critical for successful treatment of spinal ependymomas. PMID- 23988346 TI - Hypothalamic malonyl-CoA and the control of food intake. AB - Fatty acid metabolism is implicated in the hypothalamic control of food intake. In this regard, malonyl-CoA, an intermediate in fatty acid synthesis, is emerging as a key player. Malonyl-CoA in the hypothalamus has been proposed as an anorectic mediator in the central control of feeding. A large body of evidence demonstrates that modulating hypothalamic activities of malonyl-CoA metabolic enzymes impacts food intake. Malonyl-CoA action appears to play a significant role in the intracellular signaling pathways underlying leptin anorectic effect in the arcuate nucleus. Ghrelin's hypothalamic effect on feeding may also involve the change in malonyl-CoA metabolism. Hypothalamic malonyl-CoA levels are altered in response to fasting and refeeding, suggesting physiological relevance of the changes in malonyl-CoA level in the controls of feeding and energy balance. Malonyl-CoA inhibits the acyltransferase activity of carnitine palmitoyltransferase-1 (CPT-1), and CPT-1 was considered as a downstream effector in hypothalamic malonyl-CoA effect on feeding. However, recent evidence has not been entirely consistent with this notion. In the arcuate nucleus, the inhibition of CPT-1 acyltransferase activity does not play an important role in the feeding effect of either leptin or cerulenin (a fatty acid synthase inhibitor) that requires the increase in malonyl-CoA level. Alternatively, the brain isoform of CPT-1 (CPT-1c) may act as a downstream target in the malonyl-CoA signaling pathways. CPT-1c does not possess a typical acyltransferase activity, and the exact molecular function of this protein is currently unknown. Recent data indicate it is involved in ceramide metabolism. Of relevance, in the arcuate nucleus, CPT-1c may link malonyl-CoA to ceramide metabolism to affect food intake. PMID- 23988349 TI - Biochemical characterization of recombinant nucleoside hydrolase from Mycobacterium tuberculosis H37Rv. AB - Tuberculosis (TB) is a major global health threat. There is a need for the development of more efficient drugs for the sterilization of the disease's causative agent, Mycobacterium tuberculosis (MTB). A more comprehensive understanding of the bacilli's nucleotide metabolic pathways could aid in the development of new anti-mycobacterial drugs. Here we describe expression and purification of recombinant iunH-encoded nucleoside hydrolase from MTB (MtIAGU NH). Glutaraldehyde cross-linking results indicate that MtIAGU-NH predominates as a monomer, presenting varied oligomeric states depending upon binding of ligands. Steady-state kinetics results show that MtIAGU-NH has broad substrate specificity, accepting inosine, adenosine, guanosine, and uridine as substrates. Inosine and adenosine displayed positive homotropic cooperativity kinetics, whereas guanosine and uridine displayed hyperbolic saturation curves. Measurements of kinetics of ribose binding to MtIAGU-NH by fluorescence spectroscopy suggest two pre-existing forms of enzyme prior to ligand association. The intracellular concentrations of inosine, uridine, hypoxanthine, and uracil were determined and thermodynamic parameters estimated. Thermodynamic activation parameters (Ea, DeltaG(#), DeltaS(#), DeltaH(#)) for MtIAGU-NH catalyzed chemical reaction are presented. Results from mass spectrometry, isothermal titration calorimetry (ITC), pH-rate profile experiment, multiple sequence alignment, and molecular docking experiments are also presented. These data should contribute to our understanding of the biological role played by MtIAGU-NH. PMID- 23988348 TI - The effects of nitroxyl (HNO) on H2O2 metabolism and possible mechanisms of HNO signaling. AB - Nitroxyl (HNO) possesses unique and potentially important biological/physiological activity that is currently mechanistically ill-defined. Previous work has shown that the likely biological targets for HNO are thiol proteins, oxidized metalloproteins (i.e. ferric heme proteins) and, most likely, selenoproteins. Interestingly, these are the same classes of proteins that interact with H2O2. In fact, these classes of proteins not only react with H2O2, and thus potentially responsible for the signaling actions of H2O2, but are also responsible for the degradation of H2O2. Therefore, it is not unreasonable to speculate that HNO can affect H2O2 degradation by interacting with H2O2-degrading proteins possibly leading to an increase in H2O2-mediated signaling. Moreover, considering the commonality between HNO and H2O2 biological targets, it also seems likely that HNO-mediated signaling can also be due to reactivity at otherwise H2O2-reactive sites. Herein, it is found that HNO does indeed inhibit H2O2 degradation via inhibition of H2O2-metaboilizing proteins. Also, it is found that in a system known to be regulated by H2O2 (T cell activation), HNO behaves similarly to H2O2, indicating that HNO- and H2O2-signaling may be similar and/or intimately related. PMID- 23988350 TI - The membrane potential modulates thrombin-stimulated Ca2+ mobilization and platelet aggregation. AB - G protein-coupled receptors can be directly modulated by changes in transmembrane voltage in a variety of cell types. Here we show that, while changes in the membrane voltage itself do not induce detectable modifications in the cytosolic Ca(2+) concentration, platelet stimulation with thrombin or the PAR-1 and PAR-4 agonist peptides SFLLRN and AYPGKF, respectively, results in Ca(2+) release from intracellular stores that is sensitive to the membrane depolarisation. Direct activation of G proteins or phospholipase C by AlF4(-) and m-3M3FBS, respectively, leads to Ca(2+) release that is insensitive to changes in the membrane potential. Thapsigargin-, as well as OAG-induced Ca(2+) entry are affected by the membrane voltage, probably as a result of the modification in the driving force for Ca(2+) influx; however, hyperpolarisation does not enhance thrombin- or OAG-evoked Ca(2+) entry probably revealing the presence of a voltage sensitive regulatory mechanism. Transmembrane voltage also modulates the activity of the plasma membrane Ca(2+)-ATPase (PMCA) most likely due to a decrease in the phosphotyrosine content of the pump. Thrombin-stimulated platelet aggregation is modulated by membrane depolarisation by a mechanism that is, at least partially, independent of Ca(2+). These observations indicate that PAR-1 and PAR-4 receptors are modulated by the membrane voltage in human platelets. PMID- 23988351 TI - Synthesis and antiproliferative activity of new cytotoxic tri- and tetraazabenzo[3,2-a]fluorene-5,6-dione derivatives. AB - A new series of substituted tri-/tetraazabenzo[3,2-a]fluorene-5,6-diones and their corresponding oxime derivatives have been synthesized and spectroscopically characterized. The antiproliferative activities of all compounds were evaluated on at least three different cell lines. PMID- 23988353 TI - Evaluation of the Influence of thiosemicarbazone-triazole hybrids on genes implicated in lipid oxidation and accumulation as potential anti-obesity agents. AB - A series of thiosemicarbazone-triazole hybrids 1a-h are efficiently synthesised and evaluated for their influence on the expression of genes, cpt-1, acc-1 and pgc-1, which are essential in lipid metabolism. The test results show that hybrids 1c and 1g exhibited relatively high influence on the expression of cpt-1 and pgc-1 and suppression of acc-1 as desired. PMID- 23988352 TI - Systematic replacement of amides by 1,4-disubstituted[1,2,3]triazoles in Leu enkephalin and the impact on the delta opioid receptor activity. AB - Using Cu(I)-catalyzed azide-alkyne cycloaddition in a mixed classical organic phase and solid phase peptide synthesis approach, we synthesized four analogs of Leu-enkephalin to systematically replace amides by 1,4 disubstituted[1,2,3]triazoles. The peptidomimetics obtained were characterized by competitive binding, contractility assays and ERK1/2 phosphorylation. The present study reveals that the analog bearing a triazole between Phe and Leu retains some potency, more than all the others, suggesting that the hydrogen bond acceptor capacity of the last amide of Leu-enkephalin is essential for the biological activity of the peptide. PMID- 23988354 TI - Long-lasting inhibition of EGFR autophosphorylation in A549 tumor cells by intracellular accumulation of non-covalent inhibitors. AB - In the present study, a small set of reversible or irreversible 4 anilinoquinazoline EGFR inhibitors was tested in A549 cells at early (1h) and late (8h) time points after inhibitor removal from culture medium. A combination of assays was employed to explain the observed long-lasting inhibition of EGFR autophosphorylation. We found that EGFR inhibition at 8h can be due, besides to the covalent interaction of the inhibitor with Cys797, as for PD168393 (2) and its prodrug 4, to the intracellular accumulation of non-covalent inhibitors by means of an active cell uptake, as for 5 and 6. Compounds 5-6 showed similar potency and duration of inhibition of EGFR autophosphorylation as the covalent inhibitor 2, while being devoid of reactive groups forming covalent bonds with protein thiols. PMID- 23988355 TI - Solid-phase synthesis of Biotin-S-Farnesyl-L-Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT). AB - Inhibition of isoprenylcysteine Carboxylmethyltransferase (ICMT) is of particular interest as a potential target for the development of cancer chemotherapeutic agents. Screening for inhibitors of ICMT utilises a scintillation proximity assay (SPA) in which Biotin-S-Farnesyl-L-Cysteine (BFC) acts as a surrogate substrate. A solid-phase synthesis protocol for the preparation of BFC using 2-chlorotrityl chloride resin as a solid support has been developed to provide sufficient supply of BFC for high throughput screening (HTS) and subsequent chemistry campaigns to target inhibitors of ICMT. The BFC prepared by this method can be produced quickly on large scale and is stable when stored at -20 degrees C as a solid, in solution, or on the resin. PMID- 23988356 TI - Phosphodiesterase inhibitors. Part 6: design, synthesis, and structure-activity relationships of PDE4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory activity. AB - We previously identified KCA-1490 [(-)-6-(7-methoxy-2-trifluoromethyl pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5 dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4 carboxamide (2a) had good anti-inflammatory effects in an animal model. PMID- 23988357 TI - Synthesis and antitumor activities of novel alpha-aminophosphonates dehydroabietic acid derivatives. AB - A series of novel alpha-aminophosphonate derivatives containing DHA structure were designed and synthesized as antitumor agents. In vitro antitumor activities of these compounds against the NCI-H460 (human lung cancer cell), A549 (human lung adenocarcinoma cell), HepG2 (human liver cancer cell) and SKOV3 (human ovarian cancer cell) human cancer cell lines were evaluated and compared with commercial anticancer drug 5-fluorouracil (5-FU), employing standard MTT assay. The pharmacological screening results revealed that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most demonstrated more potent inhibitory activities compared with the commercial anticancer drug 5-FU. The action mechanism of representative compound 7c was preliminarily investigated by acridine orange/ethidium bromide staining, Hoechst 33258 staining, JC-1 mitochondrial membrane potential staining and flow cytometry, which indicated that the compound can induce cell apoptosis in NCI-H460 cells. Cell cycle analysis showed that compound 7c mainly arrested NCI-H460 cells in G1 stage. PMID- 23988358 TI - Solid-phase synthesis, characterization and RNAi activity of branch and hyperbranch siRNAs. AB - Linear, branch and hyperbranch siRNAs were effectively prepared for down regulating GRP78 expression and inducing cell death in HepG2 liver cancer cells. Branch and hyperbranch GRP78 siRNAs were synthesized by automated solid-phase synthesis in good yields (44-78%) and isolated in excellent purities (>99%) following HPLC purification. Moreover, siRNAs adopted stable intramolecular hybrids as discerned by native PAGE and thermal denaturation studies. These sequences also exhibited the pre-requisite A-type helical trajectory for triggering RNAi activity as determined by CD spectroscopy. Biological studies confirmed potent suppression of GRP78 expression (50-60%) while compromising cancer cell viability by ~20%. Thus, branch and hyperbranch siRNAs may serve as potent siRNA candidates in cancer gene therapy applications. PMID- 23988359 TI - Effect of administration of bifidobacteria on intestinal microbiota in low-birth weight infants and transition of administered bifidobacteria: a comparison between one-species and three-species administration. AB - The effects of administration of bifidobacteria on the intestinal microbiota in low-birth-weight infants, and the transition of each strain of administered bifidobacteria were investigated. A single strain of Bifidobacterium breve M-16V (5 * 10(8); one-species group) or a mixture of three species composed of B. breve M-16V, Bifidobacterium longum subsp. infantis M-63 and B. longum subsp. longum BB536 (5 * 10(8) of each strain; three-species group) were administered daily for 6 weeks. Bifidobacterial administration significantly increased the detection rates and cell numbers of bifidobacteria in the feces (weeks 1-6). The proportion of bifidobacteria was significantly higher in the one-species group at weeks 1-4, and in the three-species group at weeks 1-6 compared with the control group. Furthermore, the proportion of bifidobacteria in the three-species group was significantly higher than that in the one-species group at weeks 1 and 6. The proportion of infants with bifidobacteria-predominant microbiota was significantly higher in the three-species group than in the control group during the test period. The detection rates of Clostridium were lower in the bifidobacteria-administered groups. The proportions of Enterobacteriaceae were significantly lower in the three-species group compared to the other groups (weeks 4 and 6). Among the three strains administered, B. breve M-16V and Bifidobacterium infantis M-63 were detected in 85% or more of the infants during the administration period, while B. longum BB536 was detected in 40% or less. Compared with administration of one species, administration of three species of bifidobacteria resulted in earlier formation of a bifidobacteria-predominant fecal microbiota and maintenance of this microbiota. PMID- 23988360 TI - Design of an ecological momentary assessment study of exposure to radiofrequency electromagnetic fields and non-specific physical symptoms. AB - INTRODUCTION: Idiopathic Environmental Intolerance (IEI) attributed to electromagnetic fields (EMF) refers to self-reported sensitivity mainly characterised by the attribution of non-specific physical symptoms to low-level EMF exposure emitted from sources such as mobile phones. Scientific studies have not provided evidence for the existence of IEI-EMF, but these studies did not resemble the real-life situation or suffered from poor exposure characterisation and biased recall of health symptoms. To improve existing methods for the study of IEI-EMF, an Ecological Momentary Assessment (EMA) study is designed. METHODS AND ANALYSIS: The study is an EMA study in which respondents carry personal exposure metres (exposimeters) that measure radiofrequency (RF) EMF, with frequent assessment of health symptoms and perceived EMF exposure through electronic diary registration during five consecutive days. Participants will be a selection from an epidemiological study who report to be sensitive to RF EMF. The exposimeters measure electric field strength in 12 frequency bands. Diary questions include the occurrence and severity of 10 non-specific physical symptoms, mood states and perceived exposure to (sources of) EMF. The relationship of actual and perceived EMF exposure and mood with non-specific physical symptoms will be analysed using multilevel regression analysis with time shift models. DISCUSSION: The study has several advantages over previous studies, including assessment of personal EMF exposure and non-specific physical symptoms by an ecological method with a minimised chance of recall bias. The within-person design reduces confounding by time-stable factors (eg, personal characteristics). In the conduct of the study and the analysis and interpretation of its outcomes, some methodological issues including a high participant burden, reactivity, compliance to the study protocol and the potential of chance findings due to multiple statistical testing will be accounted for and limited as much as possible. PMID- 23988361 TI - Health-related quality of life after catheter-directed thrombolysis for deep vein thrombosis: secondary outcomes of the randomised, non-blinded, parallel-group CaVenT study. AB - OBJECTIVES: To investigate whether additional catheter-directed thrombolysis (CDT) improves long-term quality of life (QOL) compared with standard treatment with anticoagulation and compression stockings alone in patients with proximal deep vein thrombosis (DVT). DESIGN: Open-label randomised controlled trial. SETTING: 19 Hospitals in the Norwegian southeastern health region. PARTICIPANTS: Patients (18-75 years) with a high proximal DVT, symptoms <21 days and no increased risk of bleeding were eligible. 189 of 209 recruited patients completed 24 months of follow-up. INTERVENTIONS: Participants were randomised to additional CDT with alteplase for 1-4 days or to standard treatment only with 6 months of anticoagulation and 24 months of compression stockings. PRIMARY AND SECONDARY OUTCOME MEASURES: Planned secondary outcome measures included QOL as assessed with the generic instrument EQ-5D and the disease-specific instrument VEINES QOL/Sym. Primary outcome measure was post-thrombotic syndrome (PTS) after 24 months. RESULTS: After 24 months there were no differences in QOL between the additional CDT and standard treatment arms; mean difference for the EQ-5D index was 0.04 (95% CI -0.10 to 0.17), for the VEINES-QOL score 0.2 (95% CI -2.8 to 3.0) and for the VEINES-Sym score 0.5 (95% CI -2.4 to 3.4; p values>0.37). Independent of treatment arms, patients with PTS had poorer outcomes than patient without PTS; mean difference for EQ-5D was 0.09 (95% CI 0.03 to 0.15), for VEINES QOL score 8.6 (95% CI 5.9 to 11.2) and for VEINES-Sym score 9.8 (95% CI 7.3 to 12.3; p values<0.001). CONCLUSIONS: QOL did not differ between patients treated with additional CDT compared with standard treatment alone. Patients who developed PTS reported poorer QOL and more symptoms than patients without PTS. QOL should be included as an outcome measure in clinical studies on patients at risk of PTS. TRIAL REGISTRATION: NCT00251771. PMID- 23988362 TI - Playing board games, cognitive decline and dementia: a French population-based cohort study. AB - OBJECTIVES: To study the relationship between board game playing and risk of subsequent dementia in the Paquid cohort. DESIGN: A prospective population-based study. SETTING: In the Bordeaux area in South Western France. PARTICIPANTS: 3675 non-demented participants at baseline. PRIMARY OUTCOME MEASURE: The risk of dementia during the 20 years of follow-up. RESULTS: Among 3675 non-demented participants at baseline, 32.2% reported regular board game playing. Eight hundred and forty participants developed dementia during the 20 years of follow up. The risk of dementia was 15% lower in board game players than in non-players (HR=0.85, 95% CI 0.74 to 0.99; p=0.04) after adjustment on age, gender, education and other confounders. The statistical significance disappeared after supplementary adjustment on baseline mini-mental state examination (MMSE) and depression (HR=0.96, 95% CI 0.82 to 1.12; p=0.61). However, board game players had less decline in their MMSE score during the follow-up of the cohort (beta=0.011, p=0.03) and less incident depression than non-players (HR=0.84; 95% CI 0.72 to 0.98; p<0.03). CONCLUSIONS: A possible beneficial effect of board game playing on the risk of dementia could be mediated by less cognitive decline and less depression in elderly board game players. PMID- 23988363 TI - A population-based study on chronic pain and the use of opioids in Portugal. AB - Although increasing doubts exist regarding the long-term effectiveness and safety of opioids in patients with chronic pain (CP), most guidelines still recognize opioids as an option in effective management of CP. We aimed to describe the prevalence and factors associated with opioid use in subjects with CP in Portugal and to evaluate satisfaction and self-assessed treatment effectiveness. A nationwide study was conducted in a representative sample of the adult Portuguese population. The 5094 participants were selected using random digit dialing and estimates were adequately weighted for the population. The prevalence of opioid use by subjects with CP was 4.37% (95% confidence interval [CI] 3.4-5.5); and in subjects experiencing CP with and without cancer, it was 10.13% and 4.24%, respectively. Use of strong opioids was reported by only 0.17% of CP subjects. Sex, pain severity and symptoms of depression and anxiety were significantly associated with opioid use; however, in multivariate modeling, only pain-related disability remained significant. No significant differences among users and nonusers of opioids were observed regarding treatment satisfaction and self assessed effectiveness. Although extremely high rates of use of opioids exist in a few countries, it should not be seen as a ubiquitous problem. Indeed, we showed that in Portugal, as in many other regions in the world, opioids are used much less frequently than in those few countries. Moreover, we did not find significant differences among users and nonusers of opioids regarding satisfaction and self-assessed effectiveness, eventually showing the results to be in line with reports that show doubt about opioids' effectiveness. Further research and particular attention to and continuous monitoring of the trends of use and abuse of opioids worldwide are recommended. PMID- 23988364 TI - 'Effects of motion style acupuncture treatment in acute low back pain patients with severe disability' by Shin et al. PMID- 23988365 TI - Astrocytes are involved in long-term facilitation of neuronal excitation in the anterior cingulate cortex of mice with inflammatory pain. AB - Neuronal plasticity in the pain-processing pathway is thought to be a mechanism underlying pain hypersensitivity and negative emotions occurring during a pain state. Recent evidence suggests that the activation of astrocytes in the anterior cingulate cortex (ACC) contributes to the development of negative emotions during pain hypersensitivity after peripheral inflammation. However, it is unknown whether these activated astrocytes contribute to neuronal plasticity in the ACC. In this study, by using optical imaging with voltage- and Ca(2+)-sensitive dyes, we examined the long-term facilitation of neuronal excitation induced by high frequency conditioning stimulation (HFS) in ACC slices of control mice and mice with peripheral inflammation induced by the injection of complete Freund adjuvant (CFA) to the hind paw. Immunoreactivity of glial fibrillary acidic protein in laminae II-III of the ACC in the CFA-injected mice was higher than in the control mice. Neuronal excitation in ACC slices from the CFA-injected mice was gradually increased by HFS, and the magnitude of this long-term facilitation was greater than in the control mice. The long-term facilitation in the CFA-injected mice was inhibited by the astroglial toxin, the N-methyl-d-aspartate (NMDA) receptor antagonist and NMDA receptor glycine binding site antagonist. The increase of intracellular Ca(2+) concentration in astrocytes during HFS was higher in the CFA injected mice than in the control mice and was inhibited by l-alpha-aminoadipate (l-alpha-AA). These results suggest that the activation of astrocytes in the ACC plays a crucial role in the development of negative emotions and LTP during pain hypersensitivity after peripheral inflammation. PMID- 23988366 TI - Response to letter by Wu and Guo. PMID- 23988367 TI - Ewing sarcoma and its many faces: are we close to a cure? PMID- 23988369 TI - Systemic mastocytosis in children - therapeutic problems. AB - Systemic mastocytosis is a myeloproliferative disorder characterized by growth and accumulation of abnormal mast cells in one or more organs. The symptoms of the disease are due both to the mast cells infiltrating the organs and to the action of its degranulation products. Over 85% of adult patients exhibit point mutations of KIT at position 816 (D816V). Systemic mastocytosis is rare in both adults and children, so treatment is highly individualized; therapy and further treatment is adjusted to each patient's needs. The aim of this study was to present the case of a 14-year old female with systemic mastocytosis and the problems with her treatment. Multidisciplinary management is recommended in systemic mastocytosis. PMID- 23988368 TI - [Chemotherapy in patients with refractory Ewing sarcoma]. AB - BACKGROUND: Patients with metastatic, progressive or recurrent Ewing sarcoma have a poor prognosis. In addition to increasing the intensity of conventional chemotherapy, the combination of irinotecan and temozolomide has been proposed as an effective salvage regimen for some pediatric malignancies. AIM: To evaluate the effect of two different salvage regimens on the final outcome of patients with refractory Ewing sarcoma. MATERIAL AND METHODS: During the period 2008-2012, twenty-two patients (age between 2.9 -19.3 years) with recurrent or refractory Ewing sarcoma were treated with the combination of vincristine, irinotecan and temozolomide (VIT regimen), and twenty patients were treated with the combination of cisplatin, doxorubicin, cyclophosphamide and teniposide (PACE regimen). All patients had standard tumour imaging and laboratory evaluation. All toxicities were documented. The WHO criteria were used to evaluate response. Statistical analysis was performed using STATA 10.0 for Windows. Results distributions were estimated using the method of Kaplan-Meier. The log-rang test was used to compare the groups. RESULTS: A total of 91 cycles of VIT and 65 cycles of PACE were administered. For VIT therapy the overall response rate was 68.1%. Median time to progression was 3.0 months. Five patients are alive with no evidence of disease with a median follow-up of 10.3 months. For PACE therapy the overall response rate was 75%. Median time to progression was 3.5 months. Four patients are alive with no symptoms of disease with a median follow-up of 17.6 months. The 2 years overall survival probability after recurrence was 29.94%; no differences were detected between therapy groups. Toxicity for PACE was significantly higher. CONCLUSIONS: The effectiveness of VIT regimen in refractory Ewing Sarcoma is comparable to conventional chemotherapy. The VIT regimen has less associated toxicities than the PACE regimen. PMID- 23988370 TI - [Late effects of treatment of childhood cancer - on the basis of the literature and own experience]. AB - This review summarizes the different late effects of childhood cancer treatment: the epidemiology, risk factors, symptoms and monitoring of cardiovascular disease, pulmonary dysfunction, endocrinopathies, growth disorders, hypogonadism and infertility, as well as the second cancers which can develop after chemo and radiotherapy. PMID- 23988371 TI - [Value of ultrasound of lymph nodes in children and adolescents in the family doctor's office and in pediatric practice - own investigations]. AB - Sonography is a very useful imaging tool, commonly used in clinical practice in the evaluation of lymph nodes. It is widely available, safe and patient-friendly imaging technique. This article describes the common sonographic features of lymph nodes in children. Gray scale, colour and power Doppler sonographic features of normal and abnormal lymph nodes are described. It also presents new ultrasound imaging techniques such as elastography and contrast-enhanced ultrasonography of lymph nodes. PMID- 23988372 TI - Infections reported in newborns with very low birth weight who required surgical treatment. Data from the Polish Neonatology Surveillance Network. AB - AIM: To determine the risk of various forms of infections appearing in very low birth weight newborns (VLBW) during the period of 30 days after surgical treatment in hospitals which have perinatal care departments with neonatal intensive care units that form the Polish Neonatology Surveillance Network (PNSN). MATERIAL AND METHODS: Continuous prospective monitoring of infections was carried out from January 1st to December 31st 2009 in six neonatal intensive care units which form the Polish Neonatal Surveillance Network. (PNSN). 910 newborns with very low birth weight (VLBW) were included in the study programme. 91 (10%) of this group underwent 118 surgical interventions. 12 newborns needed two or more surgeries. The most common procedure was the closure of persistent ductus artesiosus (PDA) and photocoagulation of vascular damage in the eye fundus. RESULTS: In the period of 30 days after surgery the following were diagnosed: in 3 newborns - necrotizing enterocolitis (NEC), in 22 newborns - sepsis (BSI) and in 54 newborns - pneumonia (PNEU). Symptoms of BSI and PNEU were on average observed on the 10th day after surgical intervention, while in the case of NEC on the 17th day. The highest incidence of infection (148.4%) was observed after PDA closure and in connection with introducing a drain into the pleural cavity through the intercostal space. The incidence of PN EU (37.3%) was twice as high as the incidence of BSI (18.6%). Surgical procedure was a factor significantly increasing the risk of infection and morbidity (RR 2.1, P<001) In our investigations there was no case of the local infection of a surgical site. 11 newborns died (mortality was 12.1%). The most common bacterial strains found in our investigation were coagulase-negative Staphylococcus and Escherichia Coli. CONCLUSIONS: Taking into consideration the fact that surgical procedure in VLBW newborns significantly increases the risk of pneumonia and to a minor degree the risk of NEC and BSI, further detailed investigation in the field of perisurgical epidemiology is needed in order to elaborate a more deeply oriented and more effective strategy of infection prevention in the group of VLBW newborns. PMID- 23988373 TI - Sonic hedgehog stimulates the recruitment of endothelial progenitor cells. AB - AIM: The present work focused on the Sonic hedgehog (SHH) gene that stimulates angiogenesis in the skin. It is postulated that endothelial progenitor cells (EPCs) are responsible for skin angiogenesis. The recruitment of endothelial progenitor cells was verified in the mouse skin transfected with the pSHH gene construct using the quantitative PCR method. MATERIAL AND METHODS: The tests were performed on male Balb/c mice. The SHH gene preparation was administered intradermally and/or intramuscularly. The assessment of the expression of EPCs angiogenic genes was performed using the qPCR method. The statistical analysis of the selected results was performed using the t-Student test. Differences were considered statistically significant when p<0.05. RESULTS: Studies indicate that the SHH gene administered to mouse skin as pSHH, pSHH/PEI/NaCl and pSHH/PEI/H20 formulations recruits endothelial progenitor cells to the sites of injection. The increased expression of genes specific to endothelial progenitor cells as CD34, CD44, CD133, KDR and others was observed. CONCLUSIONS: The sonic hedgehog gene stimulates the recruitment to the skin the cells expressing EPCs markers. The mechanism of proangiogenic activity of SHH is linked to EPCs mobilization. SHH gene seems to be a potential gene-candidate to proangiogenic gene therapy applications. PMID- 23988374 TI - Burden of chronic health conditions in adolescence measured by school surveys. AB - The Chronic Conditions Short Questionnaire (CCSQ) included as an optional package in the Health Behaviour in School-aged Children (HBSC) study protocol identifies adolescents with chronic conditions, and helps to understand the psychosocial impact of such illnesses. However, reliability of the results depends on the proper definition of the group with chronic conditions. THE AIM: of this paper is to report on the validity of self-reported data on chronic conditions obtained from the CCSQ questionnaire used in a large school-based population study. MATERIAL AND METHODS: The data was obtained from the 2010 HBSC study conducted in Poland in a group of 4570 pupils aged 13-17. The CCSQ includes three questions about chronic illness or disabilities occurrence diagnosed by a physician, and its selected consequences (missing school classes, medication). Four complex continuous scales were used as validation modules: the subjective complaints checklist and three sub-scales from the abbreviated Child Health and Illness Profile (CHIP-AE) questionnaire. The oldest age group was additionally asked about functional difficulties in: seeing, hearing, speaking, moving and breathing. Analysis of Variance with the post hoc test was used to compare subgroups of students defined according to CCSQ and functional difficulties. RESULTS: Chronic conditions were reported by 20.3% of young respondents (95% confidence interval 19.2-21.5%). A statistically significant difference was found between the mean indexes of all validation scales when comparing healthy and chronically-ill students meeting criteria of CCSQ. The difference increases in comparison with chronically-ill students with functional difficulties, missing classes or taking medication. CONCLUSIONS: The CCSQ questionnaire is an appropriate tool for assessing the occurrence of long-term health problems from the perspective of adolescents. The instrument also importantly allows for an assessment of the impact of chronic and long-term conditions on medication usage and hindered access to education. Occurrence of long-term health problems is a significant confounding variable that should be routinely included in school surveys on health and health behaviours. PMID- 23988375 TI - [Sedentary behaviour 13-years-olds and its association with selected health behaviours, parenting practices and body mass]. AB - OBJECTIVE: 1. To estimate the time spent in sedentary behaviour (watching TV, using the computer, doing homework). 2. To assess the link between the total time spent on watching TV, using the computer, doing homework and dietary habits, physical activity, parental practices and body mass. MATERIAL AND METHODS: Cross sectional study was conducted in Poland in 2008 among 13-year olds (n=600). They self-reported their time of TV viewing, computer use and homework. Their dietary behaviours, physical activity (MVPA) and parenting practices were also self reported. Height and weight were measured by school nurses. Descriptive statistics and correlation were used in this analysis. RESULTS: The mean time spent watching television in school days was 2.3 hours for girls and 2.2 for boys. Boys spent significantly more time using the computer than girls - respectively 1.8 and 1.5 hours, while girls took longer doing homework - respectively 1.7 and 1.3 hours. Mean screen time was about 4 hours in school days and about 6 hours during weekend, statistically longer for boys in weekdays. Screen time was positively associated with intake of sweets, chips, soft drinks, "fast food" and meals consumption during TV, and negatively with regularity of meals and parental supervision. There was no correlation between screen time with physical activity and body mass. CONCLUSION: Sedentary behaviours and physical activity are not competing behaviours in Polish teenagers, but their relationship with unhealthy dietary patterns may lead to development of obesity. Good parental practices, both mother's and father's supervision seems to be crucial for screen time limitation in their children. Parents should become aware that relevant lifestyle monitoring of their children is a crucial element of health education in prevention of civilization diseases. This is a task for both healthcare workers and educational staff. PMID- 23988376 TI - [Congenital laryngeal stridor - an interdisciplinary problem]. AB - The most common causes of laryngeal stridor are laryngomalacia (60%), vocal cord paralysis (VCP) (10 %) and subglottic laryngeal stenosis. Majority of cases of VCP are idiopathic, less frequently it is the effect of abnormalities in central nervous system (Arnold - Chiari syndrome, hydrocephalus, neonatal hypoxia). Differential diagnosis should also include anomalies of aortic arch and its branches (vascular rings). The authors present two cases of neonatal congenital laryngeal stridor. In the first case the girl presented with VCP of unknown etiology. The perinatal period was normal, ultrasound of central nervous system and neurologic examination revealed no abnormalities. Due to sustained VCP in control laryngeal ultrasound examinations, tracheostomy was performed in the third month of life. In the second case, stridor was caused by laryngomalacia and subglottic laryngeal stenosis of first grade according to Meyer-Cotton scale (larynx lumen diameter <4 mm). The diagnosis was established by laryngotracheobronchoscopy. In both children angiotomography was performed and vascular ring was diagnosed (aberrant right subclavian artery). Vascular anomaly was suspected in barium X-ray. In both cases echocardiographic examination did not visualize the fourth vessel of the aortic arch. Chest X- rays were normal. Both children had no symptoms caused by vascular ring. CONCLUSION: Diagnosis of congenital laryngeal stridor is an indication for complete evaluation to establish the cause of the airway obstruction. The differential diagnosis should include laryngomalacia, vocal cord paralysis, subglottic laryngeal stenosis, congenital anomalies of large vessels and abnormalities of the central nervous system. PMID- 23988377 TI - Phase diagram and annealing effect for Fe1+deltaTe1-xSx single crystals. AB - The excess Fe atoms which unavoidably exist in the Fe(Te, Se, S) crystal lattice result in a complicated antiferromagnetic ground state as well as the suppression of superconductivity. As a result, there are still discrepancies on their phase diagrams. In this paper, we report the synthesis of Fe1+deltaTe1-xSx (0 <= x <= 0.12) single crystals by a melting method. Superconductivity was greatly improved after air annealing by which we partially removed the excess Fe atoms. Based on the resistivity and susceptibility measurements, we concluded a phase diagram of the Fe1+deltaTe1-xSx (0 <= x <= 0.12) system with fewer excess iron atoms. We found a coexisting region (0.07 <= x <= 0.11) of antiferromagnetic order and bulk superconductivity. This phase diagram is similar to that of the K- or Co-doped BaFe2As2 system, as well as the Fe(Te, Se) system, implying a commonality of the iron-based superconductors. PMID- 23988378 TI - Telomeres in fishes. AB - In fishes, as in other vertebrate species, the DNA component of the telomeres consists of the tandemly repeated TTAGGG motif. The length of the telomeric arrays in fishes ranges from 2 to 25 kb and shortens with age in some of the species. To date, chromosomal distribution of the telomeric DNA sequences has been examined in approximately 80 fish species of which about 42% show additional telomeric hybridization signals far from the chromosomal termini. Based on the chromosomal location, such internally located telomeric repeats may be classified into 4 categories: (1) telomeric DNA sequences located at the pericentromeric regions, (2) interstitial telomeric sites observed between centromeres and the bona fide telomeres, (3) telomeric DNA sequences that scatter along the nucleolus organizer regions, and (4) telomeric DNA repeats interspersed with the entire chromosomes. Most of the pericentromeric and interstitial telomeric sequences in fish are possible relicts of chromosome fusion events. The origin of the telomeric sequences co- localizing with the major rDNA sequences or scattered along the whole chromosomes is not clear. Internally located telomeric repeats are considered as 'hot spots' for recombination and thus may potentially increase the rates of chromosome breaks and rearrangements leading to the various chromosomal polymorphisms in fishes. FISH with telomeric probe applied to metaphase spreads of androgenetic specimens that hatched from eggs exposed to ionizing radiation before insemination enabled the detection of small radiation induced fragments of maternal chromosomes. Remnants of the irradiated chromosomes were found to be ring chromosomes with the interstitial telomeric signals, telomerless rings, fragments with fused sister chromatids, and linear fragments with telomeres detected at both of their ends. The increasing availability of techniques enabling the study of fish telomeres and telomerase and the easy access to numerous fish species strongly confirm that these animals are promising models in research concerning the role of telomeres and telomerase in vertebrate aging, repair of ionizing radiation-induced DNA double strand breaks, and chromosomal rearrangements. PMID- 23988380 TI - C-reactive protein is elevated in heart failure patients with central sleep apnea and Cheyne-Stokes respiration. AB - BACKGROUND: Manifestation of central sleep apnea (CSA) with Cheyne-Stokes respiration is of major prognostic impact in chronic heart failure (CHF). Inflammatory processes have been linked to a progression of cardiovascular diseases, including heart failure. While an association of C-reactive protein (CRP) levels to obstructive sleep apnea has been documented before, there is a lack of information regarding variation of CRP levels in patients with CSA. OBJECTIVES: The objective of this study was to investigate a potential association of CRP levels to CSA severity in CHF patients. METHODS: High sensitivity CRP levels were analyzed in 966 patients with CHF (BMI 26.3 +/- 4.6, New York Heart Association class 2.6 +/- 0.5, left ventricular ejection fraction 29.4 +/- 7.9%, N-terminal pro-brain natriuretic peptide, NT-proBNP, level 2,209 +/- 3,315 pg/ml) without sleep-disordered breathing (SDB; Apnea-Hypopnea Index, AHI, <5/h) or various degrees of CSA, documented by in-hospital cardiorespiratory polygraphy or polysomnography. RESULTS: The CRP concentration in CHF patients was 0.550 +/- 0.794 mg/dl in patients without SDB (AHI 0-4/h, n = 403) versus 0.488 +/- 0.708 mg/dl in patients with mild CSA (AHI 5-14/h, n = 123, p = n.s.) and 0.660 +/- 0.963 mg/dl in patients with moderate CSA (AHI 15-29/h, n = 160, p = n.s.). In patients with severe CSA (AHI >= 30/h, n = 280), significantly higher CRP concentrations were documented (0.893 +/- 1.384 mg/dl, p < 0.05). Stepwise regression analysis revealed AHI, NT-proBNP and heart rate to be independently associated with elevated CRP levels. CONCLUSION: Severe CSA in CHF patients is associated with elevated levels of CRP, a systemic marker of inflammation and cardiovascular risk. This might explain in part the negative prognostic impact of CSA in these patients. PMID- 23988379 TI - The relationship between anti-idursulfase antibody status and safety and efficacy outcomes in attenuated mucopolysaccharidosis II patients aged 5 years and older treated with intravenous idursulfase. AB - In the pivotal phase II/III trial of idursulfase administered intravenously to treat mucopolysaccharidosis II, approximately half of the patients developed antibodies to idursulfase. This post-hoc analysis of data from the phase II/III trial and extension study examined the relationship between antibody status and outcomes. A total of 63 treatment-naive patients received 0.5 mg/kg of intravenous idursulfase weekly for two years. Thirty-two patients (51%) were positive for anti-idursulfase IgG antibodies, 23 of whom (37%) became persistently positive. All patients who developed an antibody response did so by their scheduled Week 27 study visit. Positive antibody status appeared to have no statistically significant effect upon changes in six-minute walk test distance, percent predicted forced vital capacity, or liver and spleen volume. All patients showed significant decreases in urinary GAG levels, although the antibody positive group maintained somewhat higher urinary GAG levels than their antibody negative counterparts at the end of study (138.7 vs. 94.7 MUg/mg creatinine, p = 0.001). Antibody positivity was not associated with a higher event rate for serious adverse events. Among patients who had no prior infusion-related reactions, antibody positive patients were 2.3 times more likely to have a first infusion-related reaction than those who would remain negative (p = 0.017); the risk increased to 2.5 times more likely for those who were persistently positive (p = 0.009). These differences in risk disappeared among patients with a previous infusion-related reaction, likely because of preventive measures. A genotype analysis for the 36 patients with available data found that patients with nonsense or frameshift mutations may be more likely to develop antibodies, to experience infusion-related reactions, and to have a reduced uGAG response than those with missense mutations, suggesting the possibility that antibodies are not a driver of clinical outcomes but rather a marker for genotype. PMID- 23988381 TI - Establishment of a patient-derived Wilms' tumor xenograft model: a promising tool for individualized cancer therapy. AB - OBJECTIVE: Lack of appropriate approaches that reliably predict response of Wilms' tumor (WT) to anticancer agents remains a major deficiency in clinical practice of individualized cancer therapy. The aim of this study was to establish a patient-derived tumor tissue (PDTT) xenograft model of WT for individualized chemotherapeutic regimen selection in accordance with the patient's tumor nature. MATERIAL AND METHODS: Tumor specimens of a primary WT were orthotopically implanted into three nude mice, and after 4 weeks xenografts were harvested for serial heterotopic transplantation in 20 nude mice that were divided into three experimental groups and one control group. In vitro and in vivo chemosensitivity to doxorubicin, actinomycin-D, and vincristine were evaluated. Hematoxylin and eosin (H&E) staining and immunohistochemical examination with desmin, vimentin, myogenin, and neuron-specific enolase (NSE) were also applied to determine histological stability of the xenograft during serial transplantation compared with the original tumor tissue. RESULTS: The xenograft model was successfully established. Histopathologic characteristics of the xenograft tumors were similar to the patient's tumor. Early passage of the PDTT showed a similar chemosensitivity pattern to the original tumor tissue. CONCLUSIONS: PDTT xenograft of WT provides an appropriate model for individualized cancer therapeutic regimen selection by means of its biological stability compared with original patient's tumor. PMID- 23988382 TI - Progesterone negatively regulates BCRP in progesterone receptor-positive human breast cancer cells. AB - BACKGROUND/AIMS: Breast cancer resistance protein (BCRP) plays a crucial role in multidrug resistance (MDR). Previous studies have shown that steroid hormones, like progesterone (PROG), regulate BCRP expression. The presence of a progesterone response element (PRE) in the BCRP promoter, suggests that PROG may regulate transcription of BCRP. METHODS: To investigate the role of PROG in the regulation of BCRP expression, two constructs encoding full-length BCRP driven by either an endogenous PRE promoter or a constitutive CMV promoter, were transfected into T47D cells that express the progesterone receptor (PR) or into PR-negative MDA-MB-231 cells. RESULTS: After treatment with PROG, qPCR and Western blotting analyses indicated that BCRP mRNA and BCRP protein levels were significantly reduced in a dose-dependent manner in PR-positive cells, but PROG had no significant effect on BCRP levels in the PR-negative cells. The effect observed in PR-positive cells was reversed by co-treatment with RU-486, a specific PROG inhibitor. Cytometric analysis confirmed that BCRP-mediated drug efflux was inhibited and chemosensitivity to mitoxantrone was markedly increased by PROG treatment. CONCLUSION: These results suggest that PROG reverses BCRP mediated MDR by down-regulating BCRP expression in breast cancer cells by affecting transcription from the PRE-containing BCRP promoter. Our studies suggest that breast cancer patients with BCRP-mediated MDR may be successfully treated with PROG. PMID- 23988383 TI - Women from refugee backgrounds and their experiences of attending a specialist antenatal clinic. Narratives from an Australian setting. AB - PROBLEM: In response to an identified need, a specialist antenatal clinic for women from refugee backgrounds was introduced in 2008, with an evaluation planned and completed in 2010. QUESTION: Can maternity care experiences for women from refugee backgrounds, attending a specialist antenatal clinic in a tertiary Australian public hospital, be improved? METHODS: The evaluation employed mixed methods, generating qualitative and quantitative data from two hospital databases, a chart audit, surveys and interviews with service users, providers and stakeholders. Contributions were received from 202 participants. FINDINGS: The clinic was highly regarded by all participants. Continuity of care throughout the antenatal period was particularly valued by newly arrived women as it afforded them security and support to negotiate an unfamiliar Western maternity system. Positive experiences decreased however; as women transitioned from the clinic to labour and postnatal wards where they reported that their traditional birthing and recuperative practices were often interrupted by the imposition of Western biomedical notions of appropriate care. The centrally located clinic was problematic, frequently requiring complex travel arrangements. Appointment schedules often impacted negatively on traditional spousal and family obligations. CONCLUSIONS: Providing comprehensive and culturally responsive maternity care for women from refugee backgrounds is achievable, however it is also resource intensive. The production of translated information which is high quality in terms of production and content, whilst also taking account of languages which are only rarely encountered, is problematic. Cultural competency programmes for staff, ideally online, require regular updating in light of new knowledge and changing political sensitivities. PMID- 23988384 TI - Objects do not predict fixations better than early saliency: a re-analysis of Einhauser et al.'s data. AB - Einhauser, Spain, and Perona (2008) explored an alternative hypothesis to saliency maps (i.e., spatial image outliers) and claimed that "objects predict fixations better than early saliency." To test their hypothesis, they measured eye movements of human observers while they inspected 93 photographs of common natural scenes (Uncommon Places dataset by Shore, Tillman, & Schmidt-Wulen 2004; Supplement Figure S4). Subjects were asked to observe an image and, immediately afterwards, to name objects they saw (remembered). Einhauser et al. showed that a map made of manually drawn object regions, each object weighted by its recall frequency, predicts fixations in individual images better than early saliency. Due to important implications of this hypothesis, we investigate it further. The core of our analysis is explained here. Please refer to the Supplement for details. PMID- 23988385 TI - Does spatio-temporal filtering account for nonretinotopic motion perception? Comment on Pooresmaeili, Cicchini, Morrone, and Burr (2012). PMID- 23988386 TI - Objects and saliency: reply to Borji et al. PMID- 23988387 TI - Spatiotemporal filtering and motion illusions. PMID- 23988388 TI - How the unstable eye sees a stable and moving world. AB - Eye motion, even during fixation, results in constant motion of the image of the world on our retinas. Vision scientists have long sought to understand the process by which we perceive the stable parts of the world as unmoving despite this instability and perceive the moving parts with realistic motion. We used an instrument capable of delivering visual stimuli with controlled motion relative to the retina at cone-level precision while capturing the subjects' percepts of stimulus motion with a matching task. We found that the percept of stimulus motion is more complex than conventionally thought. Retinal stimuli that move in a direction that is consistent with eye motion (i.e., opposite eye motion) appear stable even if the magnitude of that motion is amplified. The apparent stabilization diminishes for stimulus motions increasingly inconsistent with eye motion direction. Remarkably, we found that this perceived direction-contingent stabilization occurs separately for each separately moving pattern on the retina rather than for the image as a whole. One consequence is that multiple patterns that move at different rates relative to each other in the visual input are perceived as immobile with respect to each other, thereby disrupting our hyperacute sensitivity to target motion against a frame of reference. This illusion of relative stability has profound implications regarding the underlying visual mechanisms. Functionally, the system compensates retinal slip induced by eye motion without requiring an extremely precise optomotor signal and, at the same time, retains an exquisite sensitivity to an object's true motion in the world. PMID- 23988389 TI - Optic flow asymmetries bias high-speed steering along roads. AB - How do animals and insects use visual information to move through the world successfully? Optic flow, the pattern of motion at the eye, is a powerful source of information about self-motion. Insects and humans are sensitive to the global pattern of optic flow and try to maintain flow symmetry when flying or walking. The environments humans encounter, however, often contain demarcated paths that constrain future trajectories (e.g., roads), and steering has been successfully modeled using only road edge information. Here we examine whether flow asymmetries from a textured ground plane influences humans steering along demarcated paths. Using a virtual reality simulator we observed that different textures on either side of the path caused predictable biases to steering trajectories, consistent with participants reducing flow asymmetries. We also generated conditions where one textured region had no flow (either the texture was removed or the textured region was static). Despite the presence of visible path information, participants were biased toward the no-flow region consistent with reducing flow asymmetries. We conclude that optic flow asymmetries can lead to biased locomotor steering even when traveling along demarcated paths. PMID- 23988390 TI - Collinear integration affects visual search at V1. AB - Perceptual grouping plays an indispensable role in figure-ground segregation and attention distribution. For example, a column pops out if it contains element bars orthogonal to uniformly oriented element bars. Jingling and Tseng (2013) have reported that contextual grouping in a column matters to visual search behavior: When a column is grouped into a collinear (snakelike) structure, a target positioned on it became harder to detect than on other noncollinear (ladderlike) columns. How and where perceptual grouping interferes with selective attention is still largely unknown. This article contributes to this little studied area by asking whether collinear contour integration interacts with visual search before or after binocular fusion. We first identified that the previously mentioned search impairment occurs with a distractor of five or nine elements but not one element in a 9 * 9 search display. To pinpoint the site of this effect, we presented the search display with a short collinear bar (one element) to one eye and the extending collinear bars to the other eye, such that when properly fused, the combined binocular collinear length (nine elements) exceeded the critical length. No collinear search impairment was observed, implying that collinear information before binocular fusion shaped participants' search behavior, although contour extension from the other eye after binocular fusion enhanced the effect of collinearity on attention. Our results suggest that attention interacts with perceptual grouping as early as V1. PMID- 23988391 TI - Oral exposure to cylindrospermopsin in pregnant rats: reproduction and foetal toxicity studies. AB - Cylindrospermopsin (CYN) induces toxicity in pregnant mice when administered intraperitoneally. This study investigated whether oral exposure to CYN (0.03, 0.3 and 3 MUg/kg) during pregnancy causes toxic effects and impairs gestation in rats. The results of reproductive performance and teratology studies were similar between the control and experimental dams. Our findings suggest that CYN consumption within the guideline values for drinking water is not able to promote foetal toxicity or alterations in rat reproductive performance. PMID- 23988393 TI - Future socioeconomic model of academic rehabilitation medicine: is it time for a revolution? PMID- 23988392 TI - Essential role of amino acids in alphaD-beta4 loop of a Bacillus thuringiensis Cyt2Aa2 toxin in binding and complex formation on lipid membrane. AB - Bacillus thuringiensis subsp. darmstadiensis produces Cyt2Aa2 toxin that shows in vivo specific toxicity against Dipteran insect larvae but exhibits in vitro cytolytic activity to a broad-spectrum of cells including red blood cells. Two mutant toxins have been generated by introducing a small hydrophobic alanine into positions Thr-144 and Asn-145 in alphaD-beta4 loop. Both mutants were highly expressed as crystalline inclusions that were solubilized in alkaline conditions and processed by chymotrypsin to yield activated products similar to that of the wild type protein. The T144A mutant shows lower hemolytic activity but exhibits larvicidal activity against Aedes aegypti and Culex quinquefasciatus larvae comparable to the wild type. In contrast, loss of mosquito-larvicidal and hemolytic activities was observed for the N145A mutant. Membrane interaction assays shows that the T144A mutant binds and forms complexes on liposomes, sheep red blood cells and brush border membrane fractions (BBMF) from A. aegypti larvae whereas the N145A mutant did not bind to these membranes. Our data suggested that amino acids in alphaD-beta4 loop are important for specific binding and play a key role during toxin complex formation to lyse the targeted cell membranes. PMID- 23988394 TI - Symptom burden and comorbidities impact the consistency of responses on patient reported functional outcomes. AB - OBJECTIVE: To assess the influence of symptom intensity, mood, and comorbidities on patient-clinician agreement and the consistency of responses to functional patient-reported outcomes (PROs). DESIGN: Two data sources were used. The first, a cross-sectional database of patients with breast cancer who completed functional PROs and were administered the FIM, was used to examine whether average pain intensity (as measured with an 11-point numeric rating scale [NRS]) and Rand Mental Health inventory scores differed among those rating their functional independence as different than clinicians. The second, a longitudinal database of 311 adults with late-stage lung cancer who completed the Activity Measure for Post Acute Care Computer Adaptive Test (AM PAC CAT) with differences between their expected and actual responses as reflected in their AM PAC CAT SEs. SETTING: Two tertiary medical centers. PARTICIPANTS: Data source #1, 163 women with stage IV breast cancer; data source #2, 311 adults with late-stage lung cancer. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Data source #1, FIM, pain NRS, Older Americans Resource Study activities of daily living subscale, Physical Function-10, Mental Health Inventory-17. Data source #2, AM PAC CAT and NRS symptom ratings. RESULTS: Pain intensity was significantly higher when clinicians and patients disagreed regarding a patient's independence in the ability to transfer (NRS pain severity, 3.78 vs 2.40; P=.014), groom (3.71 vs 2.36, P=.009), bathe (3.76 vs 2.40, P=.016), and dress (3.09 vs 2.44, P=.034). The magnitude of AM PAC CAT SEs was significantly associated with the severity of participants' pain, dyspnea, and fatigue, as well as the presence of musculoskeletal disorders and coronary artery disease. Neither mood nor emotional distress was associated with clinician-patient agreement or AM PAC CAT SE. CONCLUSIONS: Pain intensity is associated with disagreement between patients and clinicians about the patient's level of functioning. Moreover, physical symptoms (pain, dyspnea, fatigue) as well as specific medical comorbidities (musculoskeletal disorders, coronary artery disease), but not mood, are associated with inconsistency in patients' assessment of their functional abilities. PMID- 23988395 TI - Evaluation of the short-term executive plus intervention for executive dysfunction after traumatic brain injury: a randomized controlled trial with minimization. AB - OBJECTIVE: To determine whether the Short-Term Executive Plus (STEP) cognitive rehabilitation program improves executive dysfunction after traumatic brain injury (TBI). DESIGN: Randomized, waitlist controlled trial with minimization and blinded outcome assessment. SETTING: Community. PARTICIPANTS: Participants with TBI and executive dysfunction (N=98; TBI severity 50% moderate/severe; mean time since injury +/- SD, 12+/-14y; mean age +/- SD, 45+/-14y; 62% women; 76% white). INTERVENTION: STEP program: 12 weeks (9h/wk) of group training in problem solving and emotional regulation and individual sessions of attention and compensatory strategies training. MAIN OUTCOME MEASURES: Factor analysis was used to create a composite executive function measure using the Problem Solving Inventory, Frontal Systems Behavior Scale, Behavioral Assessment of the Dysexecutive Syndrome, and Self-Awareness of Deficits Interview. Emotional regulation was assessed with the Difficulties in Emotion Regulation Scale. The primary attention measure was the Attention Rating and Monitoring Scale. Secondary measures included neuropsychological measures of executive function, attention, and memory and measures of affective distress, self-efficacy, social participation, and quality of life. RESULTS: Intention-to-treat mixed-effects analyses revealed significant treatment effects for the composite executive function measure (P=.008) and the Frontal Systems Behavior Scale (P=.049) and Problem Solving Inventory (P=.016). We found no between-group differences on the neuropsychological measures or on measures of attention, emotional regulation, self-awareness, affective distress, self-efficacy, participation, or quality of life. CONCLUSIONS: The STEP program is efficacious in improving self-reported post-TBI executive function and problem solving. Further research is needed to identify the roles of the different components of the intervention and its effectiveness with different TBI populations. PMID- 23988396 TI - Life beyond Z11. AB - The ACOSOG Z0011 (Z11) trial demonstrated the presence of a group of breast cancer patients with some residual axillary disease who did not benefit from axillary lymph node dissection (ALND) in the presence of whole breast radiotherapy and systemic therapy at short term follow-up. It is important that further long-term follow-up of this cohort continues. The outcomes of those patients fitting Z11 criteria who do not undergo ALND should be recorded on a prospective register to ensure close observation should any late divergence in overall survival develop. It is also essential that future studies are inclusive of groups excluded from Z11 rather than simply a re-hash of the trial. PMID- 23988397 TI - Bias in breast cancer research in the screening era. AB - Screening aims to detect breast cancer at an earlier stage than would occur if symptoms developed. The characteristics of breast cancer that are detectable at screening depend on both the physical properties of the screening test and specific anatomical features of breast cancer. As a result, breast cancer detected by screening is a select subset of all breast cancer existing in the population. Therefore, biomedical, clinical and epidemiological research into breast cancer using populations with access to screening can result in major bias. The biases, with examples, are explained. PMID- 23988398 TI - Prediction of unsuccessful treatment in patients with severe acute asthma. AB - BACKGROUND: Clinical assessment can be used to identify which patients with acute asthma are at risk of unsuccessful initial treatment. OBJECTIVE: To determine which elements of clinical assessment predict unsuccessful treatment, defined as needing critical care or any unplanned additional treatment. METHODS: We analysed data from a large multicentre trial (the 3Mg trial). Adults with severe acute asthma underwent standardised clinical assessment, including peak expiratory flow rate (PEFR), up to 2 h after initiation of treatment. Standard care was provided other than blinded random allocation to trial treatment or placebo. Patients were followed up by record review up to 30 days. Unsuccessful treatment was defined as needing (1) critical care or (2) critical care or any unplanned additional treatment within 7 days of presentation. Logistic regression was used to identify predictors and derive a prediction model for each outcome. RESULTS: Out of 1084 patients analysed, 81 (7%) received critical care and 157 (14%) received critical care or unplanned additional treatment. Baseline PEFR (p=0.017), baseline heart rate (p<0.001), other serious illness (p=0.019), PEFR change (p=0.015) and heart rate change (p<0.001) predicted need for critical care. Baseline PEFR (p=0.010), baseline heart rate (p<0.001), baseline respiratory rate (p=0.017), other serious illness (p=0.023), PEFR change (p=0.003) and heart rate change (p=0.001) predicted critical care or additional treatment. Models based on these characteristics had c-statistics of 0.77 and 0.69, respectively. CONCLUSIONS: PEFR, heart rate and other serious illnesses are the best predictors of unsuccessful treatment, but models based on these variables provide modest predictive value. PMID- 23988399 TI - Fatal arrhythmogenic right ventricular cardiomyopathy in 2 related subadult chimpanzees (Pan troglodytes). AB - Cardiovascular disease is increasingly recognized as an important cause of morbidity and mortality in captive chimpanzees (Pan troglodytes). This report records 2 cases of sudden cardiac death in closely related subadult captive chimpanzees with marked replacement fibrosis and adipocyte infiltration of the myocardium, which resemble specific atypical forms of the familial human disease arrhythmogenic right ventricular cardiomyopathy. Changes were consistent with left-dominant and biventricular subtypes, which are both phenotypic variants found within human families with familial arrhythmogenic right ventricular cardiomyopathy. Previously reported fibrosing cardiomyopathies in chimpanzees were characterized by nonspecific interstitial fibrosis, in contrast to the replacement fibrofatty infiltration with predilection for the outer myocardium seen in these 2 cases. To the authors' knowledge, this case report is the first to describe cardiomyopathy resembling arrhythmogenic right ventricular cardiomyopathy in nonhuman primates and the first to describe left-dominant arrhythmogenic cardiomyopathy-type lesions in an animal. PMID- 23988400 TI - A new manual retinal thickness measurement protocol to evaluate high myopia patients. AB - PURPOSE: To validate a manual measurement protocol for quantifying retinal thickness (RT) using an optical coherence tomography (OCT) device in pathologic myopia patients. METHODS: The macular Cross Hair protocol of Stratus OCT3 (Carl Zeiss Meditec, Inc., Dublin, Calif., USA) was applied and manual RT gauging was performed using the caliper tool. Foveal and paramacular RT, located at 1 and 2 mm distances from the fovea in both vertical and horizontal scans, were measured. Three consecutive RT measurements were taken to assess measurement reliability. The within-subject coefficient of variation (CVw) and intraclass correlation coefficients (ICC) were calculated to validate the manual method. RESULTS: The mean axial length of the 29 eyes assessed was 28.28 +/- 2.72 mm and the mean spherical refraction was -13.61 +/- 6.68 diopters. CVw ranged from 0.86 to 8.73% and ICC varied from 0.81 to 0.98. CONCLUSION: A manual RT measurement protocol could reliably be used in the daily clinic for assessing pathologic myopic patients when OCT software segmentation fails. PMID- 23988401 TI - Very long-standing Parkinson's disease. PMID- 23988402 TI - Detection of S-nitrosothiols. AB - BACKGROUND: S-nitrosothiols have been recognized as biologically-relevant products of nitric oxide that are involved in many of the diverse activities of this free radical. SCOPE OF REVIEW: This review serves to discuss current methods for the detection and analysis of protein S-nitrosothiols. The major methods of S nitrosothiol detection include chemiluminescence-based methods and switch-based methods, each of which comes in various flavors with advantages and caveats. MAJOR CONCLUSIONS: The detection of S-nitrosothiols is challenging and prone to many artifacts. Accurate measurements require an understanding of the underlying chemistry of the methods involved and the use of appropriate controls. GENERAL SIGNIFICANCE: Nothing is more important to a field of research than robust methodology that is generally trusted. The field of S-nitrosation has developed such methods but, as S-nitrosothiols are easy to introduce as artifacts, it is vital that current users learn from the lessons of the past. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23988403 TI - Individual quality assessment of autografting by probability estimation for clinical endpoints: a prospective validation study from the European group for blood and marrow transplantation. AB - The aim of supportive autografting is to reduce the side effects from stem cell transplantation and avoid procedure-related health disadvantages for patients at the lowest possible cost and resource expenditure. Economic evaluation of health care is becoming increasingly important. We report clinical and laboratory data collected from 397 consecutive adult patients (173 non-Hodgkin lymphoma, 30 Hodgkin lymphoma, 160 multiple myeloma, 7 autoimmune diseases, and 28 acute leukemia) who underwent their first autologous peripheral blood stem cell transplantation (PBSCT). We considered primary endpoints evaluating health economic efficacy (eg, antibiotic administration, transfusion of blood components, and time in hospital), secondary endpoints evaluating toxicity (in accordance with Common Toxicity Criteria), and tertiary endpoints evaluating safety (ie, the risk of regimen-related death or disease progression within the first year after PBSCT). A time-dependent grading of efficacy is proposed with day 21 for multiple myeloma and day 25 for the other disease categories (depending on the length of the conditioning regimen) as the acceptable maximum time in hospital, which together with antibiotics, antifungal, or transfusion therapy delineates four groups: favorable (<=7 days on antibiotics and no transfusions; <=21 [25] days in hospital), intermediate (from 7 to 10 days on antibiotics and <3 transfusions, <=21 to 25 days in hospital or >=7 days on antibiotics and no transfusions; from 21 to 30 days [25 to 34] in hospital), unfavorable (>7 days on antibiotics, >3 but <6 transfusions; >30/34 days in hospital after transplantation), and very unfavorable (>10 days on antibiotics, >6 transfusions; >30 to 34 days in hospital). The multivariate analysis showed that (1) PBSC harvests of >=4 * 10(6)/kg CD34 + cells in 1 apheresis procedure were associated with a favorable outcome in all patient categories except acute myelogenous leukemia and acute lymphoblastic leukemia (P = .001), (2) >=5 * 10(6)/kg CD34 + cells infused predicted better transplantation outcome in all patient categories (P < .0001) except acute myelogenous leukemia and acute lymphoblastic leukemia, (3) 1 or 2 aphereses (P = .001) predicted good outcome, (4) toxicity increased with higher graft volume reinfused (>500 mL) (P = .002), and (5) patients with a central venous catheter during both collection and infusion of PBSC had a more favorable outcome post-PBSCT than peripheral access (P = .007). The type of mobilization regimen did not affect the outcome of auto PBSCT. The present study identified predictive variables, which may be useful in future individual pretransplantation probability evaluations with the goal to improve supportive care. PMID- 23988404 TI - [Dermatophytosis diagnosed at the laboratory of parasitology and mycology of Le Dantec Hospital in Dakar between 2007 and 2011]. AB - INTRODUCTION: Dermatophytosis is a disease caused by dermatophytes, filamentous fungi adapted to human and animal keratin, colonizing and infecting human skin. The goal of this study was to identify dermatophytes responsible for dermatophytosis among patients, seeking for care in Dakar. Material and methods This study was carried out at the laboratory of parasitology and mycology at Le Dantec Hospital, in Senegal between June 2007 and December 2011, and included 2026 patients. RESULTS: Among these 2026 patients, 796 patients presented a dermatophytosis, confirmed after direct examination and/or culture in 1044 specimens. Patients' age varied between 3months to 89years with 25.5 years of age average; the infestation index was 39.3%. Patients between 20-29years were more infested with 15.3%, followed by 10-19years (9.1%), 0-9years (8.7%), 30-39years (2.7%), 40-49years (1.5%), 50-59years (1.3%), 60-69years (0.4%), 70-79years (0.2%), and 80-89years (0.1%). Women were more infected (77%) than men 23%. The main species isolated were Trichophyton soudanense (52.78%), Trichophyton rubrum (30.94%), Microsporum canis (4.89%), Trichophyton mentagrophytes var. interdigitale (4.50%), Microsporum langeronii (3.54%), Trichophyton mentagrophytes var. mentagrophytes (1.82%). CONCLUSION: This study shows that dermatophytes and dermatophytosis are endemic to Senegal. PMID- 23988405 TI - Analysis of Turner syndrome patients within the Jordanian population, with a focus on four patients with Y chromosome abnormalities. AB - This study presents findings in Turner syndrome (TS) patients from the Jordanian population, with focus on 4 patients with Y chromosomal abnormalities. From 1989 to 2011, 504 patients with TS stigmata were referred to our institute for karyotyping, resulting in 142 positive TS cases. Of these, 62 (43.7%) had the typical 45,X karyotype and the remaining individuals (56.3%) were found to be mosaics. Fifteen TS patients (10.5%) carried a structural abnormality of the Y chromosome and presented with the mosaic 45,X/46,XY karyotype. From these, 4 TS cases were investigated further. Karyotyping revealed that 1 patient carried a small supernumerary marker chromosome, whereas cytogenetic and molecular analyses showed that 3 patients carried 2 copies of the SRY gene. Further analysis by SRY sequencing revealed no mutations within the gene. The analyzed patients were found to be phenotypically either females or males, depending on the predominance of the cell line carrying the Y chromosome. This study demonstrates the importance of detailed cytogenetic analysis (such as FISH) in TS patients, and it also emphasizes the need for molecular analysis (such as PCR and sequencing) when fragments of the Y chromosome are present. PMID- 23988406 TI - Prevalence and disease burden of hyperhidrosis in the adult population. AB - BACKGROUND: Although hyperhidrosis is a common and burdensome condition, little is known about the population-based prevalence. OBJECTIVE: To evaluate the epidemiology, disease burden and medical care of hyperhidrosis in German adults. METHODS: Employees of fifty-two companies underwent skin screenings and interviews including hyperhidrosis questions. RESULTS: 14,336 individuals were investigated (36% women, mean age 42 years) of whom 2,340 (16.3%) reported hyperhidrosis, including 869 (6.1%) with frequent or continuous disturbing sweating. 28% showed focal hyperhidrosis, whilst 68% had a generalized condition. Predictors of hyperhidrosis were male gender and concomitant drug medication. Moreover, persons with psoriasis and with metabolic comorbidity were at increased risk. Only 27% of those with focal hyperhidrosis had consulted a physician, and only 28% used prescribed medication or self-medication. CONCLUSION: Hyperhidrosis is a frequent skin condition predicted by medical and personal factors. In spite of the disease burden, few individuals utilize medical care. Affected individuals should be encouraged to refer to a dermatologist. PMID- 23988407 TI - Influence of lone pair doping on the multiferroic property of orthorhombic HoMnO3: ab initio prediction. AB - Using first principles density functional theory, we predict new multiferroic compounds Ho1/2A1/2MnO3 (A = As, Sb, Bi) with enhanced polarization. We find that doping of lone pair cations with different ionic radii, at the A-site of orthorhombic HoMnO3, results in a marked increase of the electronic polarization and its development along the b-axis. This development of electronic polarization along the b-axis is attributed to the breaking of the two-fold rotational symmetry which leads to the emergence of a polar b-axis. Furthermore, this symmetry breaking leads to the emergence of two inequivalent Mn ions (Mn(0) and Mn(1)) and the variance in their octahedral (Mn(0)O6 and Mn(1)O6) distortions. We rationalize the observed trends in the total polarization in terms of disparate eg electron hopping along the two different Mn(0) and Mn(1) chains. We expect large ionic polarization in the doped compounds due to the presence of 4s(2) As, 5s(2) Sb and 6s(2) Bi lone pairs, but surprisingly the effect of the lone pairs seems to be inactive. This is attributed to the strong GdFeO3 distortions exhibited by the MnO6 octahedron which hinders polar displacement of the lone pair cations. PMID- 23988410 TI - Discovery of pyrazole as C-terminus of selective BACE1 inhibitors. AB - We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for BACE1, and could reduce endogenous Abeta1-40 production in APP transgenic mice. In present work, we rapidly identified substituted triazole as the C-terminus of compound 5 by replacing the benzylpiperidine ethyl group with click chemistry and tested these synthesized compounds by in situ screening assay. As revealed by the crystal structures of BACE1 in complex with our triazole compound 12, we found that Pro70 and Thr72 located in the flap region were the critical components for binding with these inhibitors. With the aid of the crystal structure, a new series of five-membered heterocyclic compounds was prepared in order to explore the structure-activity relationship (SAR) of this class of molecules. From these efforts, pyrazole was discovered as a novel C terminus of BACE1 inhibitors. After further modification of pyrazole with variable substituents, compound 37 exhibited good potency in enzyme inhibition assay (IC50=0.025 MUM) and compound 33 showed moderate inhibition effects on Abeta production of APP transfected HEK293 cells. Moreover, these pyrazole derivatives demonstrated good selectivity versus cathepsin D. Our results indicated that the vicinity of Pro70 and Thr72 might be utilized as a subsite, and the discovered pyrazole derivatives might provide useful hints for developing novel BACE1 inhibitors as anti-AD drugs. PMID- 23988409 TI - Design, synthesis, biological evaluation and docking study of 5-oxo-4,5 dihydropyrano[3,2-c]chromene derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors. AB - A series of fused coumarins namely 5-oxo-4,5-dihydropyrano[3,2-c]chromenes linked to N-benzylpyridinium scaffold were synthesized and evaluated as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. The 1 (4-fluorobenzyl)pyridinium derivative 6g showed the most potent anti-AChE activity (IC50 value=0.038 MUM) and the highest AChE/BuChE selectivity (SI>48). The docking study permitted us to rationalize the observed structure-affinity relationships and to detect possible binding modes. PMID- 23988408 TI - Accumulation of autophagosomes in breast cancer cells induces TRAIL resistance through downregulation of surface expression of death receptors 4 and 5. AB - TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis through death receptors (DRs) 4 and/or 5 expressed on the surface of target cells. We have previously shown that deficiency of DR4 and DR5 on the surface membrane is a critical mechanism of cancer cell resistance to the recombinant human TRAIL and its receptor agonistic antibodies, which are being evaluated clinically for treating cancers. In certain cancer cells, DR4 and DR5 were found to be mislocalized in intracellular compartments yet to be characterized. Here, we report a novel role of autophagy in the regulation of dynamics of TRAIL death receptors. We first assessed basal levels of autophagosomes in a panel of 11 breast cancer cell lines using complementary approaches (LC3 immunoblotting, RFP LC3 fluorescence microscopy, and electron microscopy). We found high levels of basal autophagosomes in TRAIL resistant breast cancer cell lines (e.g. BT474 and AU565) and relevant mouse xenograft models under nutrition-rich conditions. Notably, DR4 and DR5 co-localized with LC3-II in the autophagosomes of TRAIL resistant cells. Disruption of basal autophagosomes successfully restored the surface expression of the death receptors which was accompanied by sensitization of TRAIL-resistant cells to TRAIL induced apoptosis. By contrast, TRAIL-sensitive cell lines (MDA-MB-231) are characterized by high levels of surface DR4/DR5 and an absence of basal autophagosomes. Inhibition of lysosomal activity induced an accumulation of autophagosomes and a decrease in surface DR4 and DR5, and the cells became less sensitive to TRAIL-induced apoptosis. These findings demonstrate a novel role for the basal autophagosomes in the regulation of TRAIL death receptors. Further studies are warranted to explore the possibility of using autophagosome markers such as LC3-II/LC3-I ratios for prediction of tumor resistance to TRAIL related therapies. The results also provide a rationale for future non-clinical and clinical studies testing TRAIL agonists in combination with agents that directly inhibit autophagosome assembly. PMID- 23988411 TI - Helicobacter pylori inactivation and virulence gene damage using a supported sensitiser for photodynamic therapy. AB - About half of the world's population is currently infected with Helicobacter pylori, which is involved in the development of several gastro-duodenal pathologies. The increasing number of antibiotic resistance reduces the effectiveness of the first-line therapy, so new strategies to improve the H. pylori eradication rates are needed. Antimicrobial Photodynamic Therapy (APDT) benefits from photogenerated reactive oxygen species, such as singlet oxygen, which inactivate microorganisms by means of photosensitising dyes and visible light. Therefore, it could be a suitable alternative for H. pylori eradication in the gastro-duodenal tract, particularly in patients infected with antibiotic resistant strains. We evaluated APDT against H. pylori, in vitro, using a new photosensitising material (PSM) based on a ruthenium(II) complex covalently bound to micrometric glass beads. Five H. pylori isolates (classified according to cagA genotype, and metronidazole-clarithromycin resistance) were used. Bacteria were mixed with the PSM and incubated in the dark or illuminated by blue light. Aliquots (min 1', 2', 5', 15' and 30') were cultured and colonies were counted after 2-3 days. A 99.99999% decrease was detected in the number of colonies in the irradiated wells where the bacterium was mixed with the PSM, compared to non illuminated wells or with irradiated wells without PSM. It was also confirmed that DNA is a molecular target for oxidant species released during APDT (evaluated by alkaline gel electrophoresis after endonuclease III incubation, ureC and cagA RT-PCR, and bacterial fingerprint). Results were independent of cagA gene and antibiotic resistances. PMID- 23988412 TI - Design, synthesis, docking study and biological evaluation of some novel tetrahydrochromeno [3',4':5,6]pyrano[2,3-b]quinolin-6(7H)-one derivatives against acetyl- and butyrylcholinesterase. AB - Novel hybrid derivatives of two known scaffolds; tetrahydroaminoquinoline and coumarin were synthesized and evaluated for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. By means of an efficient nanocatalyst, the reaction time for the syntheses of the target compounds was reduced. Subsequently, Ellman's modified method was used to evaluate the enzyme inhibitory activity of the synthesized structures. It was observed that most hybrid structures were moderate to potent inhibitors of AChE compared to Tacrine as the reference drug among which 7f with 4-fluorophenyl substituent was the most active compound (IC50=5 nM). PMID- 23988414 TI - Detection of nodal metastases by 18F-FDG PET/CT in apparent early stage ovarian cancer: a prospective study. AB - BACKGROUND: The rate of nodal metastases in ovarian cancer macroscopically confined to the pelvis is about 15%-20%. Systematic pelvic and aortic lymphadenectomy improves staging but it is associated with increased morbidity and costs. The purpose of this study was to evaluate the role of 18F-FDG PET/CT in the pre-operative nodal metastases detection in ovarian cancer grossly confined to the pelvis. METHODS: From 2006 to 2012, 68 consecutive women with epithelial ovarian cancer confined to the pelvis underwent 18F-FDG PET/CT followed by surgery inclusive of systematic pelvic and aortic lymphadenectomy (SAPL). 18F-FDG PET/CT images were analyzed and correlated to histological examination. RESULTS: Twenty-six women underwent bilateral and 42 unilateral SAPL with 3165 nodes removed and analyzed. Median number of dissected nodes was 42 (range 16-91). Twelve women (17.6%) had nodal metastases. 18F-FDG PET/CT correctly identified 10 patients with nodal involvement. Sensitivity, specificity, accuracy, positive and negative-predictive value of 18F-FDG PET/CT in detecting nodal metastases were 83.3%, 98.2%, 95.6%, 90.9% and 96.5%, respectively, on overall patient-based, and 75.5%, 99.4%, 98.1%, 87.5% and 98.6%, respectively, on nodal lesion site-based analysis. CONCLUSION: 18F-FDG PET/CT is an accurate tool for the detection of nodal metastases. Metabolic imaging could be used to select women who could benefit from systematic lymphadenectomy. The high negative predictive value allows avoidance of SAPL in the vast majority of women, minimizing operative and post surgical complications. Further larger prospective investigation is required to confirm our data. PMID- 23988413 TI - Development and pilot of an advance care planning website for women with ovarian cancer: a randomized controlled trial. AB - OBJECTIVE: Few available tools facilitate cancer patients and physicians' discussions of quality of life and end-of-life. Our objective was to develop a web-based tool to promote advance care planning for women with ovarian cancer. METHODS: Women with ovarian cancer, their families, clinicians and researchers met to identify ways to improve cancer care. A prototype website was created to address advance care planning, focusing on advance healthcare directives (AHD) and palliative care consultation. Patients were recruited from a gynecologic oncology clinic for a pilot randomized controlled trial. Primary outcomes included completion of an AHD and palliative care consultation. RESULTS: At study completion, 53 women with ovarian cancer were enrolled and 35 completed the study. The mean age at enrollment was 57.9 +/- 9.5 years; most were newly diagnosed or at first recurrence. There were no statistical differences in completion of AHD (p=0.220) or palliative care consultation (p=0.440) between intervention and control groups. However, women in the intervention group showed evidence of moving toward decision making regarding AHD and palliative care and lower decisional conflict. Women assigned to the intervention, compared to control website, were highly satisfied with the amount (p=0.054) and quality (p=0.119) of information and when they accessed the website, used it longer (p=0.049). Overall website use was lower than expected, resulting from several patient-related and design barriers. CONCLUSIONS: A website providing information and decisional support for women with ovarian cancer is feasible. Increasing frequency of website use requires future research. PMID- 23988415 TI - Tracer injection sites and combinations for sentinel lymph node detection in patients with endometrial cancer. AB - OBJECTIVE: The aim of the present study was to clarify the most effective combination of injected tracer types and injection sites in order to detect sentinel lymph nodes (SLNs) in early endometrial cancer. PATIENTS AND METHODS: The study included 100 consecutive patients with endometrial cancer treated at Tohoku University Hospital between June 2001 and December 2012. The procedure for SLN identification entailed either radioisotope (RI) injection into the endometrium during hysteroscopy (55 cases) or direct RI injection into the uterine cervix (45 cases). A combination of blue dye injected into the uterine cervix or uterine body intraoperatively in addition to preoperative RI injection occurred in 69 of 100 cases. All detected SLNs were recorded according to the individual tracer and the resultant staging from this method was compared to the final pathology of lymph node metastases including para-aortic nodes. RESULTS: SLN detection rate was highest (96%) by cervical RI injection; however, no SLNs were detected in para-aortic area. Para-aortic SLNs were detected only by hysteroscopic RI injection (56%). All cases with pelvic lymph node metastases were detected by pelvic SLN biopsy. Isolated positive para-aortic lymph nodes were detected in 3 patients. Bilateral SLN detection rate was high (96%; 26 of 27 cases) by cervical RI injection combined with dye. CONCLUSION: RI injection into the uterine cervix is highly sensitive in detection of SLN metastasis in early stage endometrial cancer. It is a useful and safe modality when combined with blue dye injection into the uterine body. PMID- 23988416 TI - Incidence of trocar site herniation following robotic gynecologic surgery. AB - OBJECTIVE: Trocar site herniation is a recognized complication of minimally invasive surgery, but published data on trocar site herniation after robotic surgery are scarce. We sought to determine the incidence of trocar site herniation in women undergoing robotic surgery for gynecologic disease. METHODS: A retrospective review of robotic surgeries performed from January 1, 2006, through December 31, 2012, was conducted. Postoperative trocar site herniations were identified, along with time to presentation, location of herniation, and management. Patients were excluded if surgery was converted to laparotomy or traditional laparoscopy. The Wilcoxon rank-sum test was used to compare patients with and without herniation with respect to continuous variables, and Fisher's exact test was used to compare these 2 groups with respect to categorical variables. RESULTS: The study included 500 patients, 3 of whom experienced herniation at a single trocar site. The patients with and without herniation did not differ with respect to age, body mass index, smoking status, medical comorbidities, operating time, or estimated blood loss. All 3 herniations occurred at 12-mm trocar sites. Two herniations occurred at assistant port sites, and 1 occurred at the umbilical camera port site. The median time to herniation was 21 days (range, 8-38 days). One patient required immediate surgical intervention; the other 2 patients had conservative management. CONCLUSIONS: Trocar site herniation is a rare complication following robotic surgery. The most important risk factor for trocar site herniation appears to be larger trocar size, as all herniations occurred at 12-mm port sites. PMID- 23988417 TI - PET/CT in the staging of patients with a pelvic mass suspicious for ovarian cancer. AB - OBJECTIVE: To prospectively assess the value of PET/CT for staging, diagnosis and operability of ovarian cancer, with special attention to the peritoneal spread. METHODS: From June 2009 to March 2011, 69 patients with suspicion of having an ovarian cancer underwent an (18)F-FDG PET/CT. To identify the diagnostic value of PET/CT, the results were compared with the findings at diagnostic laparoscopy and/or debulking surgery. RESULTS: There were 56 patients with malignant tumors and 13 with benign tumors. We observed a sensitivity and specificity of 93% and 77%, respectively for malignant tumors with PET/CT. CT alone had a sensitivity and specificity of 96% and 38%, respectively. The overall FIGO classification evaluation for PET/CT and CT were the same. For the evaluation of metastases, the sensitivity of PET/CT was worse, while the specificity was better than CT. Retroperitoneal lymph node metastases were diagnosed better with PET/CT, while there was no difference for peritoneal spread and for the intestines. PET/CT detected another unknown primary tumor in 3 (4.3%) cases. CONCLUSION: PET/CT is better than CT in detecting retroperitoneal lymph node metastases, but not for peritoneal metastases. PMID- 23988418 TI - A two-stage, single-arm, phase II study of EGCG-enriched green tea drink as a maintenance therapy in women with advanced stage ovarian cancer. AB - OBJECTIVES: A two-stage, single-arm, phase II study was conducted to assess the effectiveness and safety of an epigallocatechin gallate (EGCG)-enriched tea drink, the double-brewed green tea (DBGT), as a maintenance treatment in women with advanced stage serous or endometrioid ovarian cancer (clinicaltrials.gov, NCT00721890). METHODS: Eligible women had FIGO stage III-IV serous or endometrioid ovarian cancer. They had to undergo complete response after debulking surgery followed by 6 to 8 cycles of platinum/taxane chemotherapy at the Centre Hospitalier Universitaire de Quebec. They all had to drink the DBGT, 500 mL daily until recurrence or during a follow-up of 18 months. The primary endpoint was the absence of recurrence at 18 months. Statistical analyses were done according to the principle of intention to treat. Using a two-stage design, the first stage consisted of 16 enrolled patients. At the end of the follow-up, if 7 or fewer patients were free of recurrence, the trial stopped. Otherwise, accrual would continue to a total of 46 patients. RESULTS: During the first stage of the study, only 5 of the 16 women remained free of recurrence 18 months after complete response. Accordingly, the clinical trial was terminated. Women's adherence to DBGT was high (median daily intake during intervention, 98.1%, interquartile range: 89.7-100%), but 6 women discontinued the intervention before the end of their follow-up. No severe toxicity was reported. CONCLUSIONS: DBGT supplementation does not appear to be a promising maintenance intervention in women with advanced stage ovarian cancer after standard treatment. PMID- 23988419 TI - Outcomes of 447 SCORE(r) highly congruent mobile-bearing total knee arthroplasties after 5-10 years follow-up. AB - INTRODUCTION: The goal of mobile-bearing total knee arthroplasties (TKA) with an anatomical trochlea is to reduce polyethylene wear, the risk of loosening, and patellofemoral complications. Rotating mobile-bearing SCORE((r)) TKA was designed according to these principles with standard instrumentation for component placement and a specific computer navigation system, Amplivision((r)). HYPOTHESIS: We hypothesized that the results of SCORE((r)) TKA would be satisfactory and better using computer navigation with or without patellar resurfacing and that there would be no specific patellofemoral complications associated with this trochlear design. MATERIALS AND METHODS: Four hundred and forty-seven SCORE((r)) TKA were performed. Outcome assessment was based on the IKS score, and component survival calculated by Kaplan-Meier analysis. RESULTS: Mean follow-up was 6.6 years (maximum 10.6 years). Six percent of patients were lost to follow-up. Ninety-eight percent of the patients were satisfied or very satisfied. The IKS knee score was 89 points and the function score was 86. The mechanical axis was 180 degrees (174-186), and it was significantly improved if the initial deformity was severe and TKA was computer navigated. There were nine revisions (one for fracture, two for pain, two for stiffness, four for infection). DISCUSSION: This study confirmed our hypothesis: the results of SCORE((r)) TKA were very satisfying after at least 5 years of follow-up because there was no mechanical loosening, no bearing dislocation and no patellofemoral complications with or without patellar resurfacing. Results were identical whether patellar resurfacing was performed or not. Although clinical results were not better for computer- navigated TKA, radiological results were. At 98 months of follow-up, component survival in relation to the risk of aseptic loosening or patellofemoral complications was 100%. LEVEL OF EVIDENCE: Level IV continuous retrospective study. PMID- 23988420 TI - Reduction plasty for hypertrophic anterior cruciate ligament mucoid degeneration: clinical and knee laxity outcomes in 23 cases. AB - INTRODUCTION: The best treatment for anterior cruciate ligament (ACL) mucoid degeneration remains open to debate. Current options are total or partial ACL resection, or a more conservative strategy, reduction plasty. The goal of this study was to retrospectively evaluate the effects of reduction plasty for ACL hypertrophy due to mucoid degeneration from clinical outcome and knee laxity points of view. MATERIALS AND METHODS: Arthroscopy was carried out on 23 knees (21 patients) to perform a circular volume reduction plasty of the ACL, while preserving the greatest number of ligament fibers. Notchplasty was not performed. All the patients were seen again with an average follow-up of 32 months (range 8 70). RESULTS: All the knees except three had symmetric postoperative flexion. Three patients still had pain. No patient reported having subjective feelings of instability. Among the 20 knees tested with the GNRB(TM) knee laxity measurement device, one knee had a 2.4mm difference in laxity and three had between 3 and 4mm of difference; 16 knees had no residual laxity. DISCUSSION: Treatment of ACL mucoid degeneration by reduction plasty leads to complete pain relief in 80% of cases while maintaining good postoperative knee stability. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 23988421 TI - Response to the letter by A.A. Ferreira Neto. PMID- 23988422 TI - Bacterial epidemiology of osteoarticular infections in a referent center: 10-year study. AB - INTRODUCTION: Management of osteoarticular infections combines surgical treatment with antibiotic therapy. For some teams the immediate postoperative regimen requires at least partly wide-spectrum probabilistic treatment while waiting for the microbiological results. This protocol exposes the patient to the selection of resistant bacteria and the hospital unit to a modification of its bacterial ecology. The objective of this study was to retrospectively describe the microbial epidemiology of the Traumatology and Orthopaedics Department of the Lille University Hospital over 10 years (2002-2011). MATERIALS AND METHODS: The bacterial species isolated in culture of osteoarticular samples were listed, after removing any duplicates. The antibiotics retained for follow-up were those used in treatment of these infections as well as those recognized as markers of resistance. For Gram-positive species, the antibiotics considered were methicillin, rifampicin, fluoroquinolones, glycopeptides, and linezolid; for the Gram-negative species, cefotaxime, cefepime, imipenem, and fluoroquinolones were considered. RESULTS: Of the 5006 strains isolated between 2002 and 2011, Gram positive cocci accounted for more than 71%; Staphylococcus aureus 27%, and coagulase-negative staphylococci (CoNS) 54%. Contrary to S. aureus, resistance to methicillin, fluoroquinolones, and teicoplanin significantly increased in CoNS, reaching 44%, 34%, and 22%, respectively, of the strains in 2011. The proportion of streptococcal and enterococcal infections remained stable, a mean 7.4% and 5.3%, respectively, per year. Enterobacteria (12.5% of the isolates) were producers of extended-spectrum beta-lactamase in 7.8% of the cases. Pseudomonas aeruginosa was involved in 3.6% of the infections, and 12% of the strains remained resistant to ceftazidime. Propionibacterium acnes accounted for 5.8% of the bacteria isolated and showed few antibiotic resistance problems. DISCUSSION: Stability in the distribution and the susceptibility of different bacterial species was noted over this 10-year period. Although the evolution of S. aureus resistance was favourable, the resistance of CoNS specially to methicillin and glycopeptides increased. LEVEL OF EVIDENCE: Level IV. Retrospective cohort study. PMID- 23988423 TI - Comments on: "Centering osteotomy for treatment of posterior shoulder dislocation in obstetrical palsy" by PR Vilaca, MK Uezami, A Zoppi Filho published in Orthop Tramatol Surg Res 2012; 98: 199-205. PMID- 23988424 TI - Peroneal nerve entrapment at the fibular head: outcomes of neurolysis. AB - BACKGROUND: Common peroneal nerve (CPN) entrapment at the fibular head is the most common nerve entrapment syndrome at the lower limbs. Motor deficits predominate and the risk of persistent functional impairment is the main concern. The objective was to evaluate outcomes of neurolysis and to evaluate the benefits of performing surgery early. MATERIALS AND METHODS: We retrospectively reviewed the medical charts of 15 patients (mean age, 32 years) treated with neurolysis. The diagnosis was idiopathic CPN entrapment in ten patients, indirect nerve injury with CPN paralysis due to an ankle injury in three patients, and postural CPN compression in two patients. Mean time to management was 7 months (range, 2 18 months). RESULTS: Mean follow-up after neurolysis was 42 months (range, 25 to 62 months). The outcome was considered excellent in seven cases, good in five cases, and fair in three cases. Mean time to functional recovery was 2.5 months (range, 2 weeks to 6 months). Of the ten patients with idiopathic CPN entrapment syndrome, nine had excellent or good outcomes. The three patients with fair outcomes had ankle injuries or polyneuropathy. DISCUSSION: Spontaneous recovery can take time and remain incomplete. We prefer to perform surgery between the third and fourth months in patients with persistent symptoms or incomplete recovery, even in forms confined to sensory dysfunction documented by electrophysiological testing. Time to recovery is shorter after surgical decompression than with rehabilitation therapy. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 23988425 TI - Regulation of ecto-5'-nucleotidase by docosahexaenoic acid in human endothelial cells. AB - BACKGROUND/AIMS: Modulation of extracellular adenine nucleotide and adenosine concentrations is one potential mechanism by which docosahexaenoic acid (DHA) may exert beneficial effects in critically ill patients. This study assessed DHA effects on extracellular adenine purines. METHODS: Experiments used human pulmonary endothelial cells (HPMEC) and umbilical vein endothelial cells (HUVEC) treated with DHA (48 h). mRNA level (real-time PCR), expression (western blot, flow cytometry) and activities (hydrolysis of etheno(epsilon)-purines and fluorescence HPLC) of CD73 (ecto-5'-nucleotidase) and CD39 (ecto-NTPDase-1) were quantified. RESULTS: DHA elevated total CD73 membrane protein expression concentration-dependently but CD73 mRNA level did not change. Increased expression was paralleled by increased enzyme activity. Effects observed on membrane level were reversed in intact cells, in which epsilon-AMP hydrolysis decreased after DHA. In intact endothelial cells ATP release was enhanced and CD39 activity blunted following DHA treatment. Hence, extracellular ATP and ADP concentrations increased and this inhibited epsilon-AMP hydrolysis. CONCLUSION: In human endothelial cells DHA caused 1) up-regulation of CD73 protein content and increased AMP hydrolysis at the cell membrane level, 2) increased cellular ATP release, and 3) decreased extracellular ATP/ADP hydrolysis. Thus, reorganization of the extracellular adenine-nucleotide-adenosine axis in response to DHA resulted in an increased extracellular ATP/adenosine ratio. PMID- 23988426 TI - Neurological disorders. AB - Neurological conditions during pregnancy can be pregnancy related or can be caused by exacerbation of pre-existing neurological disorders. Knowledge of pre existing epilepsy or myasthenia gravis in women of childbearing age requires preconception counselling by neurologist and planned pregnancy. Possible adverse effects of medication on the foetus should be balanced with the risk of uncontrolled symptoms. Interdisciplinary management before, during and after pregnancy is recommended. New acute neurological symptoms in pregnant or postpartum women should lead to an urgent neurological review. Patients need a thorough diagnostic evaluation that targets a range of serious pathological conditions that are either unique to (e.g. eclampsia) or arise more frequently (e.g. cerebral venous thrombosis) in this population. Most of these conditions are infrequent and require a specialized and multidisciplinary management. Treatment is challenging due to risks to the unborn child. PMID- 23988428 TI - Response to letter by Insall. PMID- 23988427 TI - Oligodendroglia: metabolic supporters of axons. AB - Axons are specialized extensions of neurons that are critical for the organization of the nervous system. To maintain function in axons that often extend some distance from the cell body, specialized mechanisms of energy delivery are likely to be necessary. Over the past decade, greater understanding of human demyelinating diseases and the development of animal models have suggested that oligodendroglia are critical for maintaining the function of axons. In this review, we discuss evidence for the vulnerability of neurons to energy deprivation, the importance of oligodendrocytes for axon function and survival, and recent data suggesting that transfer of energy metabolites from oligodendroglia to axons through monocarboxylate transporter 1 (MCT1) may be critical for the survival of axons. This pathway has important implications both for the basic biology of the nervous system and for human neurological disease. New insights into the role of oligodendroglial biology provide an exciting opportunity for revisions in nervous system biology, understanding myelin-based disorders, and therapeutics development. PMID- 23988429 TI - Do we need three players in COPD treatment? PMID- 23988430 TI - The sodium/iodide symporter: state of the art of its molecular characterization. AB - The sodium/iodide symporter (NIS or SLC5A5) is an intrinsic membrane protein implicated in iodide uptake into thyroid follicular cells. It plays a crucial role in iodine metabolism and thyroid regulation and its function is widely exploited in the diagnosis and treatment of benign and malignant thyroid diseases. A great effort is currently being made to develop a NIS-based gene therapy also allowing the radiotreatment of nonthyroidal tumors. NIS is also expressed in other tissues, such as salivary gland, stomach and mammary gland during lactation, where its physiological role remains unclear. The molecular identity of the thyroid iodide transporter was elucidated approximately fifteen years ago. It belongs to the superfamily of sodium/solute symporters, SSS (and to the human transporter family, SLC5), and is composed of 13 transmembrane helices and 643 amino acid residues in humans. Knowledge concerning NIS structure/function relationship has been obtained by taking advantage of the high resolution structure of one member of the SSS family, the Vibrio parahaemolyticus sodium/galactose symporter (vSGLT), and from studies of gene mutations leading to congenital iodine transport defects (ITD). This review will summarize current knowledge regarding the molecular characterization of NIS. PMID- 23988431 TI - Improved PHIP polarization using a precision, low noise, voltage controlled current source. AB - Existing para-hydrogen induced polarization (PHIP) instrumentation relies on magnetic fields to hyperpolarize substances. These hyperpolarized substances have enhanced magnetic resonance imaging (MRI) signals over 10,000 fold, allowing for MRI at the molecular level. Required magnetic fields are generated by energizing a solenoid coil with current produced by a voltage controlled voltage source (VCVS), also known as a power supply. A VCVS lacks the current regulation necessary to keep magnetic field fluctuations to a minimum, which results in low PHIP polarization. A voltage controlled current source (VCCS) is an electric circuit that generates a steady flow of electrons proportional to an input voltage. A low noise VCCS provides the solenoid current flow regulation necessary to generate a stable static magnetic field (Bo). We discuss the design and implementation of a low noise, high stability, VCCS for magnetic field generation with minimum variations. We show that a precision, low noise, voltage reference driving a metal oxide semiconductor field effect transistor (MOSFET) based current sink, results in the current flow control necessary for generating a low noise and high stability Bo. In addition, this work: (1) compares current stability for ideal VCVS and VCCS models using transfer functions (TF), (2) develops our VCCS design's TF, (3) measures our VCCS design's thermal & 1/f noise, and (4) measures and compares hydroxyethyl-propionate (HEP) polarization obtained using a VCVS and our VCCS. The hyperpolarization of HEP was done using a PHIP instrument developed in our lab. Using our VCCS design, HEP polarization magnitude data show a statistically significant increase in polarization over using a VCVS. Circuit schematic, bill of materials, board layout, TF derivation, and Matlab simulations code are included as supplemental files. PMID- 23988432 TI - Mitochondrial dysfunction in the hippocampus of rats caused by chronic oxidative stress. AB - The aim of this study was to analyze the effects of chronic oxidative stress on mitochondrial function and its relationship to progressive neurodegeneration in the hippocampus of rats chronically exposed to ozone. Animals were exposed to 0.25 ppm ozone for 7, 15, 30, or 60 days. Each group was tested for (1) protein oxidation and, manganese superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx) and succinate dehydrogenase (SDH) activity using spectrophotometric techniques, (2) oxygen consumption, (3) cytochrome c, inducible nitric oxide synthase (iNOS), peroxisome proliferator-activated receptor gamma Co-activator 1alpha (PGC-1alpha), B-cell lymphoma (Bcl-2), and Bax expression using Western blotting, (4) histology using hematoxylin and eosin staining, and (5) mitochondrial structure using electron microscopy. Our results showed increased levels of carbonyl protein and Mn-SOD activity after 30 days of ozone exposure and decreased GPx activity. The SDH activity decreased from 7 to 60 days of exposure. The oxygen consumption decreased at 60 days. Western blotting showed an increase in cytochrome c at 60 days of ozone exposure and an increase in iNOS up to 60 days of ozone exposure. The expression of PGC-1alpha was decreased after 15, 30, and 60 days compared to the earlier time Bcl-2 was increased at 60 days compared to earlier time points, and Bax was increased after 30 and 60 days of exposure compared to earlier time points. We observed cellular damage, and mitochondrial swelling with a loss of mitochondrial cristae after 60 days of exposure. These changes suggest that low doses of ozone caused mitochondrial abnormalities that may lead to cell damage. PMID- 23988433 TI - Spinal interleukin-33 and its receptor ST2 contribute to bone cancer-induced pain in mice. AB - Cancer pain, particularly bone cancer pain, affects the quality of life of cancer patients, and current treatments are limited. Interleukin (IL)-33, a new member of the IL-1 super family, has been reported to be involved in the modulation of inflammatory pain. However, studies focused on its role in the modulation of cancer pain have been rare. The present study was designed to investigate whether spinal IL-33/ST2 signaling was involved in bone cancer-induced pain in mice. Bone cancer was induced via intra-femoral inoculation of 4T1 mammary carcinoma cells. The mice inoculated with carcinoma cells showed mechanical allodynia, heat hyperalgesia and a reduction in limb use, whereas phosphate-buffered saline or heat-killed cells-injected mice showed no significant difference compared to non treated mice. The pain hypersensitive behaviors worsened over time and with bone destruction. Both the mRNA and the protein levels of IL-33 and relative cytokines (IL-1beta, IL-6, TNF-a) were significantly increased in the spinal cord after the inoculation of carcinoma cells. Intrathecal administration of ST2 antibody to block IL-33/ST2 signaling alleviated pain behaviors in a dose-dependent manner in bone cancer pain mice compared with vehicle-injected mice. Moreover, the ST2(-/-) mice showed a significant amelioration of limb use and heat hyperalgesia compared to wild-type mice. Meanwhile, concentrations of spinal IL-1beta, IL-6 and TNF-a in the cancer-bearing ST2(-/-) mice had no significant changes. These data further suggested that IL-33/ST2 signaling played a vital role in cancer pain. Our results provided evidence that IL-33 and its receptor ST2 may be a potential therapeutic target for the treatment of pain in bone cancer patients. PMID- 23988434 TI - Dihydropyrimidinase-like 3 regulates the inflammatory response of activated microglia. AB - Microglia, the resident immune cells of the CNS, are known to respond to injuries, infection and inflammation in the CNS by producing proinflammatory cytokines and phagocytosing cell debris and pathogens. In this study, we investigated the expression pattern and role of dihydropyrimidinase-like 3 (Dpysl3), a member of collapsin response mediator protein family, on the inflammatory reaction of microglia. Microarray analysis comparing the global gene expression profile of ameboid and ramified microglia has shown that Dpysl3 is mainly expressed in ameboid microglia in the 5-day postnatal rat brain. Immunohistochemical analysis revealed that Dpysl3 was intensely expressed in ameboid microglial cells in the rat brain till postnatal 7th day and then gradually diminished in ramified microglia of 2 weeks postnatal rat brain. Further, in vitro analysis confirmed that Dpysl3 expression was induced in activated BV-2 microglia treated with lipopolysaccharide (LPS). It is well documented that microglial activation by LPS increased the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines through the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF kappaB) activity in BV-2 microglia. However, siRNA-mediated knockdown of Dpysl3 prevented the LPS-induced expression of iNOS and cytokines including interleukin 1 beta, and tumor necrosis factor-alpha as well as nuclear translocation of NF kappaB in microglia. Remarkably, knockdown of Dpysl3 inhibited the migration of activated microglia coupled with deranged actin filament configuration (as revealed by F-actin cytoskeleton expression) in lamellipodia projecting from the cells. Knockdown of Dpysl3 also inhibited the phagocytic ability of activated microglia. These findings suggest that knockdown of Dpysl3 can inhibit activation, migration and phagocytic capability of microglia and consequently reduce neuroinflammation. PMID- 23988435 TI - Characterization of progression of pelvic osteolysis after cementless total hip arthroplasty: computed tomographic study. AB - A retrospective analysis of 63 primary total hip arthroplasty cases was done using repeated computed tomography scans to evaluate the pelvic osteolytic lesions in early stage. The progression rate of osteolysis of hips with small osteolytic volume less than 766.97 mm(3) in initial CT was 85.82 mm(3)/year, and that of hips with osteolysis more than 766.97 mm(3) was 456.3 mm(3)/year (P < 0.001). Younger patients less than 52 years old with good Harris Hip Scores (more than 80) frequently showed much faster progression in volume of osteolytic lesions. The rate of osteolysis was accelerated when the amount of osteolysis reached a certain threshold volume in active young patients in a cascade manner even in early stage. PMID- 23988436 TI - Comparison of postoperative morbidity between simultaneous bilateral and staged bilateral total knee arthroplasties: serological perspective and clinical consequences. AB - The present study compared simultaneous and two-staged (stages 1 and 2 with 8 month interval on average) bilateral TKAs in terms of postoperative serological status and clinical consequences. The decrease in hemoglobin over 2 weeks postoperatively was similar between groups. C-reactive protein levels and creatine phosphokinase index peaking on day 2 were significantly higher in the simultaneous group than in either staged group (P<0.05). Incidence of DVT on day 7 tended to be higher in the simultaneous group, but the difference was not significant. Considering the approximately 8-month interval and 2-month earlier functional recovery with stage 2 TKAs, 6 months were saved with the simultaneous bilateral TKA group. Collectively, simultaneous bilateral TKA is likely to offer a safe and effective procedure in appropriate clinical settings involving anti bleeding and anti-venous thromboembolism prophylaxis. PMID- 23988437 TI - [Target volume margins for lung cancer: internal target volume/clinical target volume]. AB - The aim of this study was to carry out a review of margins that should be used for the delineation of target volumes in lung cancer, with a focus on margins from gross tumour volume (GTV) to clinical target volume (CTV) and internal target volume (ITV) delineation. Our review was based on a PubMed literature search with, as a cornerstone, the 2010 European Organisation for Research and Treatment of Cancer (EORTC) recommandations by De Ruysscher et al. The keywords used for the search were: radiotherapy, lung cancer, clinical target volume, internal target volume. The relevant information was categorized under the following headings: gross tumour volume definition (GTV), CTV-GTV margin (first tumoural CTV then nodal CTV definition), in field versus elective nodal irradiation, metabolic imaging role through the input of the PET scanner for tumour target volume and limitations of PET-CT imaging for nodal target volume definition, postoperative radiotherapy target volume definition, delineation of target volumes after induction chemotherapy; then the internal target volume is specified as well as tumoural mobility for lung cancer and respiratory gating techniques. Finally, a chapter is dedicated to planning target volume definition and another to small cell lung cancer. For each heading, the most relevant and recent clinical trials and publications are mentioned. PMID- 23988438 TI - Detection of the dynamic magnetic behavior of the antiferromagnet in exchange coupled NiFe/IrMn bilayers. AB - The magnetothermal behavior of antiferromagnetic IrMn layers of different thickness (3, 6, 10 nm) has been studied by exploiting the exchange coupling with a ferromagnetic 5 nm-thick NiFe layer. A procedure has been devised for the measurement of the magnetization of the NiFe/IrMn bilayers as a function of temperature and time at different values of an external magnetic field, Hinv, antiparallel to the unidirectional exchange anisotropy. This analysis allows one to probe the effective distribution of anisotropy energy barriers of the antiferromagnetic phase, as sensed by the ferromagnetic layer. Two magnetic regimes have been distinguished. At temperature T < 100 K, the interfacial IrMn spins are frozen in a glassy state and are collectively involved in the exchange coupling with the NiFe spins. At T ~ 100 K the collective state breaks up; thus, above this temperature, only the interfacial IrMn spins which are tightly polarized by the IrMn nanograins, forming the bulk of the layer, are effectively involved in the exchange coupling mechanism. Due to that, for T > 100 K the exchange coupling is ruled by the anisotropy energy barriers of the bulk IrMn nanograins, namely by the layer thickness. The thermal evolution of the exchange field and of the coercivity in the three samples is coherently explained in the framework of this description of the dynamic magnetic behavior of the IrMn phase. PMID- 23988439 TI - Brain natriuretic peptide on admission as a biological marker of long-term mortality in ischemic stroke survivors. AB - BACKGROUND AND PURPOSE: We investigated whether brain natriuretic peptide (BNP) can serve as a biological marker of long-term mortality in ischemic stroke survivors. METHODS: Consecutive patients with ischemic stroke within 24 h of onset from April 2007 to December 2010 were prospectively enrolled, and admission plasma BNP levels were measured. Survivors were followed up until 1 year after stroke onset. Patients were divided into two groups: the deceased group and the surviving group. The factors associated with long-term mortality were investigated by multiple logistic regression analysis. RESULTS: A total of 736 patients who were alive at hospital discharge were included; 130 (17.7%) patients died. On multivariate analysis, age>75 years (odds ratio, OR, 2.83; 95% CI, 1.74 4.60, p=0.0001), dialysis-dependent chronic renal failure (OR, 5.99; 95% CI, 2.18 16.47, p=0.0005), modified Rankin Scale score>3 at discharge (OR, 4.41; 95% CI, 2.76-7.05, p<0.0001), and plasma BNP>100.0 pg/ml (OR, 3.94; 95% CI, 2.31-6.73, p<0.0001) were found to be independently associated with long-term mortality. We developed a risk score from 4 variables (each variable: 1 point, total score: 0-4 points). The mortality rates were 2% with a score of 0, 9% with a score of 1, 27% with a score of 2 and 50% with a score>=3. CONCLUSIONS: The risk score, composed of clinical parameters and BNP, may predict long-term mortality in ischemic stroke survivors. PMID- 23988440 TI - CHOP/ORP150 ratio in endoplasmic reticulum stress: a new mechanism for diabetic peripheral neuropathy. AB - BACKGROUND/AIMS: Peripheral neuropathy is a frequent and severe diabetic complication characterized by progressive loss of peripheral nerve axons and manifested by pain and eventually complete loss of sensation. Effective therapy for diabetic peripheral neuropathy (DPN) is still lacking due to our limited understanding of the mechanisms for nerve injury. METHODS: Here we tested the roles of endoplasmic reticulum (ER) stress and the ER stress-activated pro apoptotic protein CHOP and anti-apoptotic protein ORP150 in DPN in a rat model of high-fat/streptozotocin diabetes and in cultured Schwann cells (SCs). RESULTS: No significant DPN was seen in the early stage of diabetes (4 weeks following verification of diabetes). However, after prolonged diabetes (16 weeks following verification of diabetes), DPN was severely developed as reflected by slowed motor and sensory nerve conduction velocity, blunted thermal nociception, and decreased intraepidermal nerve fiber profiles in the hindpaw. Meanwhile, while it was not noticed in sciatic nerves of early diabetes, ER stress in prolonged diabetic rats was indicated by robust increases in H2O2 production and expression of the ER chaperon glucose-regulated protein 78 (GRP78). ORP150 expression was substantially upregulated, accompanied by mild increase in CHOP expression, resulting in a low CHOP/ORP150 ratio, in early diabetes. In contrast, with prolonged diabetes, CHOP expression exceeded ORP150 expression, resulting in an increased CHOP/ORP150 ratio. In vivo knockdown of ORP150 induced DPN in early diabetes and exacerbated the DPN after prolonged diabetes, whereas knockdown of CHOP ameliorated DPN in rats with prolonged diabetic. On the other hand, in vitro knockdown of ORP150 promoted high glucose-induced SC apoptosis, whereas knockdown of CHOP protected SCs from apoptosis. CONCLUSION: Taken together, we have provided evidence for the critical role of ER stress in the development of DN and also uncovered CHOP/ORP150 ratio as an important mechanism for determining neuronal apoptosis during ER stress. In the early stage of diabetes, CHOP/ORP150 ratio was relatively low favoring neuronal cell survival, whereas after prolonged diabetes, CHOP/ORP150 ratio increased resulting in apoptotic cell death leading to accelerated DPN. PMID- 23988441 TI - Gender differences of postdeployment post-traumatic stress disorder among service members and veterans of the Iraq and Afghanistan conflicts. AB - Despite the marked expansion of roles for women in the US military over the last decade, whether differences by gender exist in regard to the development of mental health conditions postdeployment is unclear. This comprehensive review of the literature (2001-2012) examined whether US servicewomen were more likely than men to experience post-traumatic stress disorder (PTSD) after returning from deployments to the Iraq and Afghanistan conflicts. Findings from 18 studies from 8 unique study populations were reviewed. Seven studies found that women had a higher risk for screening positive for PTSD compared with men, including prospectively designed studies that evaluated new-onset PTSD among members from all service branches. Although results from studies with Veterans Affairs samples found women at decreased risk in 4 analyses, these studies used the same source databases, were conducted in treatment-seeking populations, and were mostly unable to account for combat experience. Seven studies detected no differences by gender. In summary, women appeared to have a moderately higher risk for postdeployment PTSD, although there was a lack of consensus among the studies, and even those with the most rigorous methods were not designed specifically to evaluate potential gender differences. Given the limitations of the published literature, further research should use longitudinal study designs and comprehensive evaluations of deployment experiences while adjusting for predeployment factors to confirm that gender differences exist with regard to postdeployment PTSD. PMID- 23988442 TI - Antagonists to the Wnt cascade exhibit sex-specific expression in gonads of sexually mature shovelnose sturgeon. AB - Little is known regarding molecular mechanisms involved in sex determination and differentiation in sturgeon species. We addressed this knowledge gap by using next generation pyrosequencing technology to provide transcript libraries and species-specific sequences for mature gonads of shovelnose sturgeon, Scaphirhynchus platorynchus. We then mined these libraries to identify gender specific transcripts and quantified relative transcript abundance using quantitative real-time polymerase chain reaction (qPCR). We detected a limited number of genes known to play a role in sex differentiation in other species. The sequence for dmrt1 was found only in the testes library. The abundance of dmrt1 differed slightly between the sexes, but the melt curve suggests that there may be different isoforms of dmrt1 in ovaries and testes of shovelnose sturgeon. The transcription factor foxl2 was 5.3-fold greater in ovaries than in testes. Two antagonists to the Wnt cascade, dickkopf-1 (dkk1) and dapper-1 (dact1), were found only in the ovary library. Results from qPCR indicated that dkk1 and dact1 were upregulated 1,819.1- and 207.5-fold, respectively, in ovaries compared with testes. These results suggest that antagonists to the Wnt cascade may play significant roles in sex differentiation and gonadal development in sturgeon and could serve as sex markers in this group of ancient fish. PMID- 23988443 TI - Effectiveness of 0.05% oxymetazoline (Vicks Sinex Micromist(r)) nasal spray in the treatment of objective nasal congestion demonstrated to 12 h post administration by magnetic resonance imaging. AB - INTRODUCTION: This study aimed to assess the qualitative and quantitative utility of MRI imaging to illustrate the magnitude and duration of the effect of a standard 100 MUg dose of oxymetazoline in a commercially available formulation that also contains aromatic oils. METHODS: This was a randomized, open label, single dose, parallel group study in 21 adult male and female subjects who reported moderate to severe nasal congestion due to acute upper respiratory tract infection or hay fever. MRI scans were acquired using a 3T Philips Achieva scanner with a 16 channel head receive coil. High resolution MRI scans of the nasal turbinates were obtained immediately prior to dosing (baseline) and at approximately 1, 8, 10, 11, and 12 h after dosing. The efficacy variables of primary interest were inferior turbinate total volume at 8 and 12 h post-dosing. The secondary efficacy variables analysed were inferior turbinate total volume at 1, 10, and 11 h post-dosing, middle turbinate total volume at 1, 8, 10, 11, and 12 h post-dosing. RESULTS: Changes from baseline volumes measured for the inferior and middle turbinates of subjects receiving the oxymetazoline formulation showed significant (P < 0.05) decreases at all times up to and including 12 h post-administration. No significant decreases from baseline were detected in subjects receiving a sham 'spray' (untreated control - spray bottles with no spray solution). Statistical ANCOVA results of inferior and middle turbinate volume indicated significant differences (P < 0.05) at all measurement points up to and including 12 h post-administration between the oxymetazoline treatment group and the untreated control with the only exception the middle turbinate volume at 10 h (P = 0.0896). The significant changes were likely to be clinically relevant though this was not measured in the study. No AEs were reported during this study and no other safety evaluations were made. CONCLUSIONS: This study showed that MRI assessment of nasal congestion in human volunteers is a robust, repeatable and viable measurement technique. The application of a 100 MUg Vicks Sinex Micromist((r)) nasal decongestant (0.05% oxymetazoline solution) delivered a highly significant reduction in inferior and middle turbinate volumes compared with the application of a control, measurable by the MRI method up to and including a 12 h post-dose scan. PMID- 23988444 TI - Developing an adaptive radiation therapy strategy for nasopharyngeal carcinoma. AB - Adaptive radiotherapy (ART) has recently been introduced to restore the planned dose distribution by accounting for the anatomic changes during treatment. By quantifying the anatomic changes in nasopharyngeal carcinoma (NPC) patients, this study aimed to establish an ART strategy for NPC cases. A total of 30 NPC patients treated with helical tomotherapy were recruited. In the pretreatment megavoltage CT images, the anatomic changes of the posterolateral wall of nasopharynx (P-NP), neck region and parotid glands were measured and assessed. One-way repeated measure ANOVA was employed to define threshold(s) at any time point. The presence of a threshold(s) would indicate significant anatomical change(s) such that replanning should be suggested. A pragmatic schedule for ART was established by evaluating the threshold for each parameter. Results showed the P-NP, parotid gland and neck volumes demonstrated significant regressions over time. Respectively, the mean loss rates were 0.99, 1.35, and 0.39 %/day, and the mean volume losses were 35.70, 47.54 and 11.91% (all P < 0.001). The parotid gland shifted medially and superiorly over time by a mean of 0.34 and 0.24 cm, respectively (all P < 0.001). The neck region showed non-rigid posterior displacement, which increased from upper to lower neck. According to the threshold occurrences, three replans at 9th, 19th and 29th fractions were proposed. This ART strategy was able to accommodate the dosimetric consequences due to anatomic deviation over the treatment course. It is clinically feasible and would be recommended for centers where an adaptive planning system was not yet available. PMID- 23988445 TI - Fast track surgery to reduce short-term complications following radical cystectomy and intestinal urinary diversion with Vescica Ileale Padovana neobladder: proposal for a tailored enhanced recovery protocol and preliminary report from a pilot study. AB - OBJECTIVE: Different fast track programs for patients undergoing radical cystectomy (RC) can be found in the current literature. The aim of this work was to develop a new enhanced recovery protocol (ERP). PATIENTS AND METHODS: The ERP was designed after a structured literature review focusing on reduced bowel preparation, standardized feeding, postoperative nausea, vomiting and pain control. In order to test the ERP, a pilot observational prospective cohort study was planned, enrolling all patients consecutively undergoing RC and Vescica Ileale Padovana (VIP) neobladder. These patients were compared with a matched group of subjects who had undergone RC and VIP neobladder before implementation of the ERP. To achieve good comparability, a propensity score-matching was performed. The primary aim was to assess the ERP's feasibility; the secondary outcome measures were early morbidity and mortality. RESULTS AND LIMITATIONS: After an exhaustive literature search and a multidisciplinary consultation, an ERP was designed. Nine consecutive patients participated in the pilot study and were compared to 13 patients treated before implementation of the ERP. We did not find any statistically significant difference in terms of mortality rate (none died peri- or postoperatively in both groups). The complication rate, according to the modified Clavien classification, was significantly lower in the ERP group (22.22 vs. 84.61%, p < 0.004). The major limitations are the low number of patients enrolled to test the protocol and the lack of randomization for the comparative evaluations. CONCLUSION: The introduction of our ERP was proven to be feasible in the management of patients undergoing RC and intestinal urinary diversion with VIP neobladder. The postoperative course was enhanced by a significant reduction in both nasogastric tube insertion and parenteral nutrition support, with early postoperative feeding. All these findings were associated with no deleterious effect on morbidity or mortality, indeed there was a reduced occurrence of postoperative complication rates. PMID- 23988446 TI - EpCAM associates with endoplasmic reticulum aminopeptidase 2 (ERAP2) in breast cancer cells. AB - Epithelial cell adhesion molecule (EpCAM) is an epithelial and cancer cell "marker" and there is a cumulative and growing evidence of its signaling role. Its importance has been recognized as part of the breast cancer stem cell phenotype, the tumorigenic breast cancer stem cell is EpCAM(+). In spite of its complex functions in normal cell development and cancer, relatively little is known about EpCAM-interacting proteins. We used breast cancer cell lines and performed EpCAM co-immunoprecipitation followed by mass spectrometry in search for novel potentially interacting proteins. The endoplasmic reticulum aminopeptidase 2 (ERAP2) was found to co-precipitate with EpCAM and to co localize in the cytoplasm/ER and the plasma membrane. ERAP2 is a proteolytic enzyme set in the endoplasmic reticulum (ER) where it plays a central role in the trimming of peptides for presentation by MHC class I molecules. Expression of EpCAM and ERAP2 in vitro in the presence of dog pancreas rough microsomes (ER vesicles) confirmed N-linked glycosylation, processing in ER and the size of EpCAM. The association between ERAP2 and EpCAM is a unique and novel finding that provides new ideas on EpCAM processing and on how antigen presentation may be regulated in cancer. PMID- 23988447 TI - Raddeanin A induces human gastric cancer cells apoptosis and inhibits their invasion in vitro. AB - Raddeanin A is one of the triterpenoid saponins in herbal medicine Anemone raddeana Regel which was reported to suppress the growth of liver and lung cancer cells. However, little was known about its effect on gastric cancer (GC) cells. This study aimed to investigate its inhibitory effect on three kinds of different differentiation stage GC cells (BGC-823, SGC-7901 and MKN-28) in vitro and the possible mechanisms. Proliferation assay and flow cytometry demonstrated Raddeanin A's dose-dependent inhibitory effect and determined its induction of cells apoptosis, respectively. Transwell assay, wounding heal assay and cell matrix adhesion assay showed that Raddeanin A significantly inhibited the abilities of the invasion, migration and adhesion of the BGC-823 cells. Moreover, quantitative real time PCR and Western blot analysis found that Raddeanin A increased Bax expression while reduced Bcl-2, Bcl-xL and Survivin expressions and significantly activated caspase-3, caspase-8, caspase-9 and poly-ADP ribose polymerase (PARP). Besides, Raddeanin A could also up-regulate the expression of reversion inducing cysteine rich protein with Kazal motifs (RECK), E-cadherin (E cad) and down-regulate the expression of matrix metalloproteinases-2 (MMP-2), MMP 9, MMP-14 and Rhoc. In conclusion, Raddeanin A inhibits proliferation of human GC cells, induces their apoptosis and inhibits the abilities of invasion, migration and adhesion, exhibiting potential to become antitumor drug. PMID- 23988449 TI - Sigma 1 Receptor plays a prominent role in IL-24-induced cancer-specific apoptosis. AB - Interleukin-24 (IL-24), a member of the IL-10 cytokine family, is an immunomodulatory cytokine that also displays broad cancer-specific suppressor effects. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and cancer-specific apoptosis. We show that Sigma 1 Receptor (S1R), a ligand-regulated protein chaperone contributes to IL-24 induction of apoptosis. IL-24 generated from an adenovirus expressing IL-24 (Ad.IL-24) induces cancer-specific apoptosis by inducing an endoplasmic reticulum (ER) stress, reactive oxygen species production, and calcium mobilization. The present studies reveals that S1R is required for Ad.IL 24-induced cell death. We provide several lines of evidence to confirm a physical and functional interaction between IL-24 and S1R including: (a) S1R and IL-24 co localize, as judged by immunocytochemical analysis studies; (b) S1R and IL-24 co immunoprecipitate using either S1R or IL-24 antibody; (c) S1R agonist (+) SKF10047 inhibits apoptosis by Ad.IL-24; (d) (+)-SKF10047-mediated inhibition of Ad.IL-24 results in: diminished ER stress protein expression; (e) Calcium mobilization; and (f) ROS production. Collectively, these data demonstrate that S1R interacts with IL-24 and suggest that IL-24:S1R interaction determines apoptosis induction by Ad.IL-24. These studies define Sigma 1 Receptor as a key initial mediator of IL-24 induction of cancer-specific killing. These findings have important implications for our understanding of IL-24 as a tumor suppressor protein as well as an immune modulating cytokine. PMID- 23988448 TI - MicroRNA-133a-1 regulates inflammasome activation through uncoupling protein-2. AB - Inflammasomes are multimeric protein complexes involved in the processing of IL 1beta through Caspase-1 cleavage. NLRP3 is the most widely studied inflammasome, which has been shown to respond to a large number of both endogenous and exogenous stimuli. Although studies have begun to define basic pathways for the activation of inflammasome and have been instrumental in identifying therapeutics for inflammasome related disorders; understanding the inflammasome activation at the molecular level is still incomplete. Recent functional studies indicate that microRNAs (miRs) regulate molecular pathways and can lead to diseased states when hampered or overexpressed. Mechanisms involving the miRNA regulatory network in the activation of inflammasome and IL-1beta processing is yet unknown. This report investigates the involvement of miR-133a-1 in the activation of inflammasome (NLRP3) and IL-1beta production. miR-133a-1 is known to target the mitochondrial uncoupling protein 2 (UCP2). The role of UCP2 in inflammasome activation has remained elusive. To understand the role of miR-133a-1 in regulating inflammasome activation, we either overexpressed or suppressed miR 133a-1 in differentiated THP1 cells that express the NLRP3 inflammasome. Levels of Caspase-1 and IL-1beta were analyzed by Western blot analysis. For the first time, we showed that overexpression of miR-133a-1 increases Caspase-1 p10 and IL 1beta p17 cleavage, concurrently suppressing mitochondrial uncoupling protein 2 (UCP2). Surprisingly, our results demonstrated that miR-133A-1 controls inflammasome activation without affecting the basal expression of the individual inflammasome components NLRP3 and ASC or its immediate downstream targets proIL 1beta and pro-Caspase-1. To confirm the involvement of UCP2 in the regulation of inflammasome activation, Caspase-1 p10 and IL-1beta p17 cleavage in UCP2 of overexpressed and silenced THP1 cells were studied. Suppression of UCP2 by siRNA enhanced the inflammasome activity stimulated by H2O2 and, conversely, overexpression of UCP2 decreased the inflammasome activation. Collectively, these studies suggest that miR-133a-1 suppresses inflammasome activation via the suppression of UCP2. PMID- 23988450 TI - A compound CP-31398 suppresses excitotoxicity-induced neurodegeneration. AB - Neurodegeneration causes dysfunction and degeneration of neurons and is triggered by various factors including genetic defects, free radicals, injury, and glutamate excitotoxicity. Among those, glutamate excitotoxicity is implicated in chronic disorders including AD and ALS, and in acute insults in the CNS including traumatic brain injury. Neurological disorders show hallmark morphological abnormalities such as axon degeneration and cell body death. The molecular mechanisms underlying excitotoxicity-induced neurodegeneration are complex and deciphering a molecular mechanism from one angle is beneficial to understand the process, however, still difficult to develop strategies to suppress excitotoxicity-induced degeneration due to existence of other mechanisms. Thus, directly identifying compounds that can modulate excitotoxicity-induced neurodegeneration and subsequently clarifiying the molecular mechanism is a valid approach to develop effective strategies to suppress neurodegeneration. We searched for compounds that can suppress excitotoxicity-induced neurodegeneration and found that CP-31398, a known compound that can rescue the structure and function of the tumor suppressor protein p53 mutant form and stabilize the active conformation of the p53 wild-type form, suppresses excitotoxicity-induced axon degeneration and cell body death. Moreover, CP-31398 suppresses mitochondrial dysfunction which has a strong correlation with excitotoxicity. Thus, our findings identify a compound that can serve as a novel modulator of neurodegeneration induced by glutamate excitotoxicity. PMID- 23988451 TI - Biological effects of the Pim kinase inhibitor, SGI-1776, in multiple myeloma. AB - BACKGROUND: Pim kinases are constitutively active serine/threonine/tyrosine kinases that are overexpressed in hematological malignancies such as multiple myeloma. Pim kinase substrates are involved in transcription, protein translation, cell proliferation, and apoptosis. SGI-1776 is a potent Pim kinase inhibitor that has proven to be cytotoxic to leukemia and lymphoma cells. Based on this background, we hypothesized that SGI-1776 treatment would result in myeloma cytotoxicity. MATERIALS AND METHODS: To test this, myeloma cell lines and primary CD138(+) cells from myeloma patients were treated with SGI-1776 in a dose and time-dependent manner, and effect on cell death and proliferation, induction of autophagy, and changes in cell cycle profile were measured. RESULTS: SGI-1776 treatment resulted in limited apoptosis in cell lines (mean 30%) and CD138(+) cells (< 10%) assessed using Annexin-V/propidium iodide. Limited effect was observed in cell cycle profile or growth in cell lines. However, DNA synthesis was decreased by 70% at 3 MUM (all time points) in U266 though this was not observed in MM.1S. In accordance, immunoblot analyses revealed no change in transcription (c-Myc and H3), or apoptotic (Bad) proteins that are substrates of Pim kinases. In contrast, autophagy, assessed using acridine orange staining, was induced with SGI-1776 treatment in both cell lines (U266, 25%-70%; MM.1S, 8%-52%) and CD138(+) cells (19%-21%). Immunoblot analyses of the autophagy LC3b marker and translation initiation proteins (phospho-p70S6K and 4E-BP1) corroborated autophagy induction. CONCLUSION: These data indicate that SGI-1776 treatment in myeloma cell lines and CD138(+) myeloma cells elicits its deleterious effects through inhibition of translation and induction of autophagy. PMID- 23988453 TI - Understanding the impact of political violence in childhood: a theoretical review using a social identity approach. AB - The present paper reviews the literature that has assessed the psychological impact of political violence on children. Concern for those growing up in situations of political violence has resulted in two areas of research within psychology: the first considers children as victims of conflict and considers the mental health consequences of political violence. The second considers children as protagonists or aggressors in conflict and considers related moral and attitudinal consequences of exposure to political violence. These two literatures are most often considered separately. Here the two strands of research are brought together using a social identity framework, allowing apparently divergent findings to be integrated into a more coherent understanding of the totality of consequences for children and young people growing up in situations of armed conflict. PMID- 23988454 TI - The TEACCH program for children and adults with autism: a meta-analysis of intervention studies. AB - The intervention program for autism known as Treatment and Education of Autistic and Related Communication Handicapped Children (TEACCH) is considered an emerging practice for autism. In the present study we used state-of-the-art meta analytical procedures to examine the pooled clinical effects of TEACCH in a variety of outcomes. A total of 13 studies were selected for meta-analysis totaling 172 individuals with autism exposed to TEACCH. Standardized measures of perceptual, motor, adaptive, verbal and cognitive skills were identified as treatment outcomes. We used inverse-variance weighted random effects meta analysis supplemented with quality assessment, sensitivity analysis, meta regression, and heterogeneity and publication bias tests. The results suggested that TEACCH effects on perceptual, motor, verbal and cognitive skills were of small magnitude in the meta-analyzed studies. Effects over adaptive behavioral repertoires including communication, activities of daily living, and motor functioning were within the negligible to small range. There were moderate to large gains in social behavior and maladaptive behavior. The effects of the TEACCH program were not moderated by aspects of the intervention such as duration (total weeks), intensity (hours per week), and setting (home-based vs. center based). While the present meta-analysis provided limited support for the TEACCH program as a comprehensive intervention, our results should be considered exploratory owing to the limited pool of studies available. PMID- 23988452 TI - Psychosocial treatments for negative symptoms in schizophrenia: current practices and future directions. AB - Schizophrenia can be a chronic and debilitating psychiatric disorder. Though advancements have been made in the psychosocial treatment of some symptoms of schizophrenia, people with schizophrenia often continue to experience some level of symptoms, particularly negative symptoms, throughout their lives. Because negative symptoms are associated with poor functioning and quality of life, the treatment of negative symptoms is a high priority for intervention development. However, current psychosocial treatments primarily focus on the reduction of positive symptoms with comparatively few studies investigating the efficacy of psychosocial treatments for negative symptoms. In this article, we review and evaluate the existing literature on three categories of psychosocial treatments- cognitive behavioral therapy (CBT), social skills training (SST), and combined treatment interventions--and their impact on the negative symptoms of schizophrenia. Of the interventions reviewed, CBT and SST appear to have the most empirical support, with some evidence suggesting that CBT is associated with maintenance of negative symptom improvement beyond six months after treatment. It remains unclear if a combined treatment approach provides improvements above and beyond those associated with each individual treatment modality. Although psychosocial treatments show promise for the treatment of negative symptoms, there are many unanswered questions about how best to intervene. We conclude with a general discussion of these unanswered questions, future directions and methodological considerations, and suggestions for the further development of negative symptom interventions. PMID- 23988455 TI - A meta-analysis of nonrandomized effectiveness studies on outpatient cognitive behavioral therapy for adult anxiety disorders. AB - OBJECTIVE: The primary aim of this study was to assess the overall effectiveness of individual and group outpatient cognitive behavioral therapy (CBT) for adults with a primary anxiety disorder in routine clinical practice. METHOD: We conducted a random effects meta-analysis of 71 nonrandomized effectiveness studies on outpatient individual and group CBT for adult anxiety disorders. Standardized mean gain effect sizes pre- to posttreatment, and posttreatment to follow-up are reported for disorder-specific symptoms, depression, and general anxiety. The mean dropout from CBT is reported. RESULTS: Outpatient CBT was effective in reducing disorder-specific symptoms in completer (d=0.90-1.91) and intention-to-treat samples (d=0.67-1.45). Moderate to large (d=0.54-1.09) and small to large effect sizes (d=0.42-0.97) were found for depressive and general anxiety symptoms posttreatment. Across all anxiety disorders, the weighted mean dropout rate was 15.06%. Posttreatment gains for disorder-specific anxiety were maintained 12months after completion of therapy. CONCLUSIONS: CBT for adult anxiety disorders is very effective and widely accepted in routine practice settings. However, the methodological and reporting quality of nonrandomized effectiveness studies must be improved. PMID- 23988456 TI - Management of pleural empyema: don't miss the point! PMID- 23988458 TI - Volumetric changes in cerebellar regions in adolescent idiopathic scoliosis compared with healthy controls. AB - BACKGROUND CONTEXT: Adolescent idiopathic scoliosis (AIS) is a three-dimensional spinal deformation that affects adolescents, especially girls. The etiopathogenesis of this disease remains uncertain, and studies have been carried out to understand its cause and related organs. Previous studies suggest that AIS is probably related to the cerebellum dysfunction, which could also be related to the abnormality in morphology of the cerebellum. PURPOSE: The purpose of the study is to investigate the relationship between AIS and the volume and morphology of cerebellum. STUDY DESIGN/SETTING: The study design of the cerebellum segmentation and volume quantification involved the following four steps: whole-brain normalization, cerebellum isolation, mapping with the statistical cerebellum template, and cerebellum regional volume correction. PATIENT SAMPLE: In particular, high-resolution T1-weighted magnetic resonance images of 50 AIS patients with the right-thoracic curves (ie, Cobb angle >=20 degrees ) and 40 age-matched normal controls were acquired. The exclusion criteria included history of head injury, back injury, severe headache, weakness or numbness in any limbs, urinary incontinence, nocturnal enuresis, and any space occupying lesion found on magnetic resonance (MR) images. OUTCOME MEASURES: The AIS subjects were all with moderate-to-severe curves (ie, Cobb angle >=20 degrees ) (9 moderate and 41 severe; mean Cobb angle 48.7 degrees , range 20 degrees -90 degrees ). METHODS: The cerebellum was parcellated to 28 regions by mapping with a well-recognized probabilistic MR cerebellum atlas. Student t test of each cerebellar region and the correction for multiple comparisons were performed. RESULTS: The volumes of four regions, namely right VIIIa, right VIIIb, left X, and right X, were significantly increased by approximately 7.43% to 8.25% in the AIS compared with the control group. Statistically, the results suggested that the cerebellar volume in AIS patients was larger compared with normal controls in the cerebellum regions of prepyramidal-prebiventer and intrabiventer fissures, intrabiventer and secondary fissures, and floccular-nodular (X)-posterolateral fissure to the inferior hemispheric margin. CONCLUSIONS: The functions of the affected regions involve motor control, somatosensory, working memory, language, and response to visual stimulation. We conclude that the volume difference could be compensatory consequences in the central nervous system because of the persistent effort in AIS patients to maintain the body balance given the asymmetric spine. PMID- 23988457 TI - CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia. AB - The retinoid-responsive gene CXXC5 localizes to the 5q31.2 chromosomal region and encodes a retinoid-inducible nuclear factor (RINF) that seems important during normal myelopoiesis. We investigated CXXC5/RINF expression in primary human acute myeloid leukemia (AML) cells derived from 594 patients, and a wide variation in CXXC5/RINF mRNA levels was observed both in the immature leukemic myeloblasts and in immature acute lymphoblastic leukemia cells. Furthermore, patients with low risk cytogenetic abnormalities showed significantly lower levels compared to patients with high-risk abnormalities, and high RINF/CXXC5/ mRNA levels were associated with decreased overall survival for patients receiving intensive chemotherapy for newly diagnosed AML. This association with prognosis was seen both when investigating (i) an unselected patient population as well as for patients with (ii) normal cytogenetic and (iii) core-binding factor AML. CXXC5/RINF knockdown in AML cell lines caused increased susceptibility to chemotherapy-induced apoptosis, and regulation of apoptosis also seemed to differ between primary human AML cells with high and low RINF expression. The association with adverse prognosis together with the antiapoptotic effect of CXXC5/RINF suggests that targeting of CXXC5/RINF should be considered as a possible therapeutic strategy, especially in high-risk patients who show increased expression in AML cells compared with normal hematopoietic cells. PMID- 23988459 TI - Influence of an auxiliary facet system on intervertebral discs and adjacent facet joints. AB - BACKGROUND CONTEXT: Facet supplementation stabilizes after facetectomy and undercutting laminectomy. It is indicated in degenerative spondylolisthesis with moderate disc degeneration and dynamic stenosis. PURPOSE: To determine the influence of an auxiliary facet system (AFS) on the instrumented disc, adjacent levels' discs, and facet joints and to compare it with fusion. STUDY DESIGN: Finite element study. METHODS: L3-L4, L4-L5, and L5-S1 were studied using a validated finite element model with prescribed displacements for an intact spine, lesion by facetectomy and undercutting laminectomy, AFS, and fusion at L4-L5. The distribution of segmental range of motion (ROM) and applied moments, von Mises stress at the annulus, and facet joint contact forces were calculated with rotations in all planes. Institutional support for implant evaluation and modeling was received by Clariance. RESULTS: In flexion-extension and lateral bending, fusion decreased L4-L5 ROM and increased adjacent levels' ROM. Range of motion was similarly distributed with intact lesion and AFS. In axial rotation, L4-L5 ROM represented 33% with intact, 55% after lesion, 25% with AFS, and 21% with fusion. Fusion increased annulus stress at adjacent levels in flexion extension and lateral bending, but decreased stress at L4-L5 compared with AFS. In axial rotation, von Mises stress was similar with fusion and AFS. Facet loading increased in extension and lateral bending with fusion. It was comparable for fusion and AFS in axial rotation. CONCLUSIONS: This study suggests that the AFS stabilizes L4-L5 in axial rotation after facetectomy and undercutting laminectomy as fusion does. This is because of the cross-link that generates an increased annulus stress in axial rotation at adjacent levels. With imposed displacements, without in vivo compensation of the hips, the solicitation at adjacent levels' discs and facet joints is higher with fusion compared with AFS. Fusion decreases intradiscal stress at the instrumented level. PMID- 23988460 TI - Multiple primary intramedullary ependymomas: a case report and review of the literature. AB - BACKGROUND CONTEXT: Intramedullary ependymomas constitute the most frequent type of intramedullary tumor. In patients with neurofibromatosis type 2 (NF2), multiple intramedullary ependymomas are known to occur. In the non-NF2 population, however, the presence of multiple synchronous intramedullary ependymomas is exceedingly rare. PURPOSE: In this article, the authors report the second case in the literature of multiple primary synchronous intramedullary ependymomas. To the best of the authors knowledge, this report represents the first to provide a detailed pathology of all lesions, thereby giving an added level of confidence on the primary synchronous nature of the lesions. The authors have also performed a review of the literature regarding multifocal intramedullary ependymomas. STUDY DESIGN: A review article and case report. CONCLUSIONS: The concomitant localization of two primary intramedullary spinal cord ependymomas in the setting of nongenetic predisposition is an uncommon phenomenon. In this article, the authors present the second report of multiple, synchronous intramedullary ependymomas. A detailed review of the literature reveals that the presence of multiple intramedullary lesions in non-NF2 patients is both rare and deserving of further study. PMID- 23988461 TI - An evidence-based clinical guideline for antibiotic prophylaxis in spine surgery. AB - BACKGROUND CONTEXT: The North American Spine Society's (NASS) Evidence-Based Clinical Guideline on Antibiotic Prophylaxis in Spine Surgery provides evidence based recommendations to address key clinical questions regarding the efficacy and the appropriate antibiotic prophylaxis protocol to prevent surgical site infections in patients undergoing spine surgery. The guideline is intended to address these questions based on the highest quality clinical literature available on this subject as of June 2011. PURPOSE: Provide an evidence-based educational tool to assist spine surgeons in preventing surgical site infections. STUDY DESIGN: Systematic review and evidence-based clinical guideline. METHODS: This guideline is a product of the Antibiotic Prophylaxis in Spine Surgery Work Group of NASS Evidence-Based Guideline Development Committee. The work group consisted of neurosurgeons and orthopedic surgeons who specialize in spine surgery and are trained in the principles of evidence-based analysis. A literature search addressing each question and using a specific search protocol was performed on English language references found in MEDLINE (PubMed), ACP Journal Club, Cochrane Database of Systematic Reviews Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, EMBASE (Drugs and Pharmacology), and Web of Science to identify articles published since the search performed for the original guideline. The relevant literature was then independently rated using the NASS-adopted standardized levels of evidence. An evidentiary table was created for each of the questions. Final recommendations to answer each clinical question were developed via work group discussion, and grades were assigned to the recommendations using standardized grades of recommendation. In the absence of Levels I to IV evidence, work group consensus statements have been developed using a modified nominal group technique, and these statements are clearly identified as such in the guideline. RESULTS: Sixteen clinical questions were formulated and addressed, and the answers are summarized in this article. The respective recommendations were graded by the strength of the supporting literature, which was stratified by levels of evidence. CONCLUSIONS: The clinical guideline for antibiotic prophylaxis in spine surgery has been created using the techniques of evidence-based medicine and best available evidence to aid practitioners in the care of patients undergoing spine surgery. The entire guideline document, including the evidentiary tables, suggestions for future research, and all the references, is available electronically on the NASS Web site at http://www.spine.org/Pages/PracticePolicy/ClinicalCare/ClinicalGuidlines/Default. spx and will remain updated on a timely schedule. PMID- 23988462 TI - The influence of steroid sex hormones on the cognitive and emotional processing of visual stimuli in humans. AB - Steroid sex hormones are responsible for some of the differences between men and women. In this article, I review evidence that steroid sex hormones impact on visual processing. Given prominent sex-differences, I focus on three topics for sex hormone effects for which there is most research available: 1. Preference and mate choice, 2. Emotion and recognition, and 3. Cerebral/perceptual asymmetries and visual-spatial abilities. For each topic, researchers have examined sex hormones and visual processing using various methods. I review indirect evidence addressing variation according to: menstrual cycle phase, pregnancy, puberty, and menopause. I further address studies of variation in testosterone and a measure of prenatal testosterone, 2D:4D, on visual processing. The most conclusive evidence, however, comes from experiments. Studies in which hormones are administrated are discussed. Overall, many studies demonstrate that sex steroids are associated with visual processing. However, findings are sometimes inconsistent, differences in methodology make strong comparisons between studies difficult, and we generally know more about activational than organizational effects. PMID- 23988463 TI - Life cycle comparison of waste-to-energy alternatives for municipal waste treatment in Chilean Patagonia. AB - The energy system in the Region of Aysen, Chile, is characterized by a strong dependence on fossil fuels, which account for up to 51% of the installed capacity. Although the implementation of waste-to-energy concepts in municipal waste management systems could support the establishment of a more fossil independent energy system for the region, previous studies have concluded that energy recovery systems are not suitable from an economic perspective in Chile. Therefore, this work intends to evaluate these technical options from an environmental perspective, using life cycle assessment as a tool for a comparative analysis, considering Coyhaique city as a case study. Three technical alternatives were evaluated: (i) landfill gas recovery and flaring without energy recovery; (ii) landfill gas recovery and energy use; and (iii) the implementation of an anaerobic digestion system for the organic waste fraction coupled with energy recovery from the biogas produced. Mass and energy balances of the three analyzed alternatives have been modeled. The comparative LCA considered global warming potential, abiotic depletion and ozone layer depletion as impact categories, as well as required raw energy and produced energy as comparative regional-specific indicators. According to the results, the use of the recovered landfill gas as an energy source can be identified as the most environmentally appropriate solution for Coyhaique, especially when taking into consideration the global impact categories. PMID- 23988464 TI - Ascertaining cause of death among men in the prostate cancer intervention versus observation trial. AB - BACKGROUND: The Prostate Cancer Intervention Versus Observation Trial (PIVOT) randomized 731 men with localized prostate cancer to radical prostatectomy or observation. PURPOSE: We describe the methods and results for cause-of-death assignments in PIVOT, and compare them to alternative strategies for ascertaining prostate cancer-specific mortality, as well as to the methods and results in the similar Scandinavian Prostate Cancer Group Study 4 (SPCG-4) trial. METHODS: Three PIVOT Endpoints Committee members, blinded to randomized treatment assignments, reviewed medical records and death certificates when available to assign a cause of death using a primary and a secondary adjudication question. Initial disagreements were resolved through discussion. The level of initial agreement among committee members was examined, as well as guesses at randomized treatment assignments for a convenience sample of cases. Final cause of death determinations were compared to death certificates. RESULTS: Complete agreement on cause of death by all three committee members before any discussion was achieved in 200/354 (56%) cases on the primary and 209/354 (59%) cases on the secondary. However, complete agreement on the primary rose to 306/354 (86%) when 'definite' and 'probably' categories were collapsed, as planned a priori. The three committee members' proportions of correct guesses of randomized treatment assignment were 82/121 (68%), 113/148 (76%), and 99/134 (74%). Using the committee's final adjudications as a gold standard, death certificates had suboptimal sensitivities, specificities, or predictive values depending on how they were used to determine cause of death. LIMITATIONS: There was no separate 'gold standard' by which to judge the accuracy of the final endpoints committee adjudications, and useful death certificates could not be obtained on about a third of PIVOT participants who died. CONCLUSIONS: The low level of initial agreement on cause of death among endpoint committee members and the potential for biased determinations due to partial unblinding to treatment assignment raise methodologic concerns about using prostate cancer mortality as an endpoint in clinical trials like PIVOT. PMID- 23988465 TI - Statistical evaluation of surrogate markers: validity, efficiency, and sensitivity. AB - Identification of surrogate markers for a marketed drug is important in monitoring the efficacy or safety after a patient uses the drug. In this article, we clarify the statistical definitions of the surrogate endpoint and surrogate marker and introduce the concept of the validity and efficiency of a surrogate marker. We also review some existing methods and suggest the proportion of information gain is appropriate to be used to evaluate the validity of a surrogate marker. PMID- 23988466 TI - University of Pennsylvania 5th annual conference on statistical issues in clinical trials: emerging statistical issues in biomarker validation (afternoon session). PMID- 23988467 TI - Novel de novo SCN2A mutation in a child with migrating focal seizures of infancy. AB - BACKGROUND: Migrating focal seizures of infancy are characterized by seizure onset within 7 months of age, migrating focal motor seizures with multifocal ictal electroencephalography discharges intractable to conventional antiepileptic drugs, and poor prognosis. Reported genetic etiologies include SCN1A and KCNT1 mutations and homozygous deletion of the PLCB1 gene. Here we report a novel SCN2A mutation in a child with this syndrome. PATIENT: A 7-week-old girl was admitted to our hospital for management of status epilepticus. She was the product of a full-term unremarkable pregnancy. Seizures started around 5 weeks of age and remained medically refractory. Electroencephalography showed multifocal epileptiform discharges as well as seizures arising from multifocal regions in both cerebral hemispheres. Based on her phenotype, a diagnosis of migrating focal seizures of infancy was made. RESULT: A novel de novo missense mutation was identified in the SCN2A gene, exon 22 (coding for voltage-gated sodium channel type II): c.3977T>A (p.V1326D). This mutation affects a highly evolutionarily conserved area of the gene and replaces hydrophobic nonpolar valine with polar aspartic acid; thus, it is predicted to affect protein function and is presumed pathogenic. DISCUSSION: This report expands our knowledge of the genetic basis of migrating focal seizures of infancy to include mutations in SCN2A gene. PMID- 23988469 TI - Atorvastatin improves microenvironment to enhance the beneficial effects of BMSCs therapy in a rabbit model of acute myocardial infarction. AB - BACKGROUND/AIMS: To investigate the beneficial effects of atorvastatin added to the cell therapy with bone marrow-derived mesenchymal stromal cells (BMSCs) in a rabbit model of acute myocardial infarction (AMI). METHODS: Rabbits were randomly divided into control group (n=10), bone marrow stem cells transplantation group (n=10), and BMSCs + atorvastatin group (n=10). AMI was established by ligating the left descending coronary artery. The left ventricular (LV) function was evaluated by echocardiography. H&E staining and Masson's Trichrome staining were performed to evaluate inflammatory cell infiltration and cardiac fibrosis. Immunohistochemistry and TUNEL were conducted to assess survival, differentiation, and apoptosis of transplanted cells and cardiomyocytes. RESULTS: BMSCs decreased LV systolic and diastolic diameters and increased LV ejection fractions, LV fractional shortening, LV systolic pressure and LV end-diastolic pressure. Atorvastatin synergistically enhanced the BMSCs-induced improvements of ischemic cardiac dysfunction. Atorvastatin reduced inflammatory cell infiltration, cardiac fibrosis, and derangement of myocardial morphology/structure. Atorvastatin added a protective effect to cardiomyocytes against apoptotic cell death in infarct and peri-infarct areas, and also increased the survival rate of implanted BMSCs in acute myocardial ischemia. Atorvastatin also promoted cardiac differentiation of implanted BMSCs in infarct myocardium. CONCLUSION: Atorvastatin acts to improve the microenvironment both by synergistically enhancing the existing effects of BMSCs and by adding new therapeutic effects to BMSCs transplantation, and this combinational therapy is a superior cell/pharmacological therapeutic approach that merits future preclinical and clinical studies. PMID- 23988470 TI - Crystal shape-dependent magnetic susceptibility and Curie law crossover in the spin ices Dy2Ti2O7 and Ho2Ti2O7. AB - We present an experimental determination of the isothermal magnetic susceptibility of the spin ice materials Dy2Ti2O7 and Ho2Ti2O7 in the temperature range 1.8-300 K. The use of spherical crystals has allowed accurate correction for demagnetizing fields and allowed the true bulk isothermal susceptibility chiT(T) to be estimated. This has been compared against a theoretical expression based on a Husimi tree approximation to the spin ice model. Agreement between experiment and theory is excellent at T > 10 K, but systematic deviations occur below that temperature. Our results largely resolve an apparent disagreement between neutron scattering and bulk measurements that has been previously noted. They also show that the use of non-spherical crystals in magnetization studies of spin ice may introduce very significant systematic errors, although we note some interesting--and possibly new--systematics concerning the demagnetizing factor in cuboidal samples. Finally, our results show how experimental susceptibility measurements on spin ices may be used to extract the characteristic energy scale of the system and the corresponding chemical potential for emergent magnetic monopoles. PMID- 23988471 TI - [About Australopithecus afarensis Lucy]. PMID- 23988472 TI - [Diagnosis of neonatal metabolic acidosis by eucapnic pH determination]. AB - The identification of a metabolic acidosis is a key criterion for establishing a causal relationship between fetal perpartum asphyxia and neonatal encephalopathy and/or cerebral palsy. The diagnostic criteria currently used (pH and base deficit or lactatemia) are imprecise and non-specific. OBJECTIVE: The study aimed to determine among a low-risk cohort of infants born at term (n = 867), the best diagnostic tool of metabolic acidosis in the cordonal from the following parameters: pH, blood gases and lactate values at birth. MATERIALS AND METHODS: The data were obtained from arterial blood of the umbilical cord by a blood gas analyser. The parameter best predicting metabolic analysis was estimated from the partial correlations established between the most relevant parameters. RESULTS: The results showed a slight change in all parameters compared to adult values: acidemia (pH: 7.28 +/- 0.01), hypercapnia (56.5 +/- 1.59 mmHg) and hyperlactatemia (3.4 +/- 0.05 mmol/L). From partial correlation analysis, pCO(2) emerged to be the main contributor of acidemia, while lactatemia was shown to be non-specific for metabolic acidosis. Seven cases (0.81 %) showed a pH less than 7.00 with marked hypercapnia. The correction of this respiratory component by EISENBERG's method led to the eucapnic pH, classifying six out of seven cases as exclusive respiratory acidosis. DISCUSSION AND CONCLUSION: It has been demonstrated that the criteria from ACOG-AAP for defining a metabolic acidosis are incomplete, imprecise and generating errors in excess. The same is true for lactatemia, whose physiological significance has been completely revised, challenging the misconception of lactic acidosis as a specific marker of hypoxia. It appeared that eucapnic pH was the best way for obtaining a reliable diagnosis of metabolic acidosis. We proposed to adopt a simple decision scheme for determining whether a metabolic acidosis has occurred in case of acidemia less than 7.00. PMID- 23988473 TI - [Lucy's parturition, a way towards extinction?]. AB - OBJECTIVES: To compare pelvic cavities in australopithecines, modern humans and non-hominid primates in order to discuss the obstetrical mechanisms in australopithecines MATERIAL AND METHODS: Bony pelves from fossil material (Australopithecus afarensis AL 288-1, Australopithecus africanus Sts14, Australopithecus Stw 431 and Mh2), 133 modern humans (82 adult females and 51 adult males) and 67 anthropoid primates (36 gorilla, 26 Pan troglodytes, 5 Pongo pygmaeus) were reconstructed and compared (shape and morphometric analysis) using 16 pelvimetric mesasurements. RESULTS: Pelves of australopithecines were characterized by lower anteroposterior (AP) and transverse (TRV) diameters in inlet pelvis than in other species. Index (AP/TRV) of pelvic inlet, midpelvis and pelvic outlet in the australopithecines were the lowest (<100) and the pelvic shape was platypelloid. A logarithmic factorial analysis showed that the pelvic morphology of australopithecines was different from humans and non-hominid primates but nearer the humans. DISCUSSION AND CONCLUSION: In contrast with apes where obstetrical mechanics seem to be easier, and because of platypelloidy, mechanism of birth in australopithecines was as difficult as in modern homo sapiens. Birth without cesarean was probably possible in an asynclitic TRV orientation. PMID- 23988474 TI - [Is there any place for oocyte cryopreservation after cancer treatment?]. AB - The number of young cancer women theoretically eligible for fertility preservation before chemotherapy is steadily increasing. Nevertheless, the number of patients who can really benefit from complex ART techniques such as ovarian tissue or oocyte/embryo cryopreservation remains very low mainly because of a too short time-interval between the cancer diagnosis and its treatment. Lack of adequate information regarding post treatment infertility risk and logistical difficulties to access to a highly specialized cryopreservation centre are also reasons of importance. It is now well-established that these patients are at high risk of infertility even if they return to a normal ovarian function. Therefore, for patients who could not benefit from fertility preservation before cancer treatment, and who have recovered spontaneous menstrual cycle, one might raise the question of oocyte freezing once the cancer cured. PMID- 23988475 TI - Robot-assisted ramicotomy: evaluation in a swine model. AB - BACKGROUND: To evaluate the feasibility of robot-assisted thoracoscopic T2-T5 ramicotomy. METHODS: In 5 pigs, a robot-assisted thoracoscopic T2-T5 ramicotomy was performed, followed by T2-T5 sympathectomy 10 min later. Ramicotomy and sympathectomy times, and core (esophageal) and surface (left front foot) temperatures, were monitored and recorded. RESULTS: The procedure was successfully completed in all 5 animals. In all cases, the sympathetic chain remained intact. No major hemorrhage occurred. The mean operating time for T2-T5 ramicotomy from incision until transsection of the last efferent ramus was 34 min (32-40). After completion of the ramicotomy, a total T2-T5 sympathectomy was performed, with a mean duration of 7 min (4-12). Mean core temperature before the operation was 37.6 degrees C (36.7-38.0). Mean surface temperature before the operation was 34.2 degrees C (33.3-35.5). Ten minutes after completion of the ramicotomy, temperatures stabilized. Mean postramicotomy core temperature was 37.4 degrees C (36.3-38) and mean postramicotomy surface temperature was 35.4 degrees C (33.9-37). Mean postsympathectomy temperatures were: core 37.3 degrees C (36.1-38) and surface 35.8 degrees C (33.8-37.1). CONCLUSION: Robot-assisted thoracoscopic T2-T5 ramicotomy is feasible and effective in a porcine model. PMID- 23988476 TI - Situation and context impacts the expression of personality: the influence of breeding season and test context. AB - Non-human animal personality is defined as consistent behavioural differences across time and situations/contexts. Behaviours are, however, often plastic and to explain how plasticity and personality may coexist an adaptive framework has been developed. Still, there is little information on how personality is impacted by situations and contexts on an individual level. We investigated this in the European mink (Mustela lutreola) by performing a set of five experiments in two situations consisting of non-breeding and breeding season, and by using different test contexts. Three personality trait domains were identified; boldness, exploration and sociability. The levels of boldness and exploration changed between seasons but remained repeatable, which implies behavioural reaction norms and supports that the concept of personality remained applicable despite plasticity. Whilst males became bolder and more explorative in the breeding season females became shyer, which reflects European mink breeding behaviour. Furthermore, behaviours performed in mirror stimulus tests fell into different domains depending on whether, the test was conducted in the own territory or not, suggesting plasticity in the response towards conspecifics. To conclude, our results highlight the importance of situation and context for the expression of personality, and the significance of measuring multiple personality trait domains with several methods. PMID- 23988477 TI - Molecular modeling and simulation of FabG, an enzyme involved in the fatty acid pathway of Streptococcus pyogenes. AB - Streptococcus pyogenes (SP) is the major cause of pharyngitis accompanied by strep throat infections in humans. 3-keto acyl reductase (FabG), an important enzyme involved in the elongation cycle of the fatty acid pathway of S. pyogenes, is essential for synthesis of the cell-membrane, virulence factors and quorum sensing-related mechanisms. Targeting SPFabG may provide an important aid for the development of drugs against S. pyogenes. However, the absence of a crystal structure for FabG of S. pyogenes limits the development of structure-based drug designs. Hence, in the present study, a homology model of FabG was generated using the X-ray crystallographic structure of Aquifex aeolicus (PDB ID: 2PNF). The modeled structure was refined using energy minimization. Furthermore, active sites were predicted, and a large dataset of compounds was screened against SPFabG. The ligands were docked using the LigandFit module that is available from Discovery Studio version 2.5. From this list, 13 best hit ligands were chosen based on the docking score and binding energy. All of the 13 ligands were screened for Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties. From this, the two best descriptors, along with one descriptor that lay outside the ADMET plot, were selected for molecular dynamic (MD) simulation. In vitro testing of the ligands using biological assays further substantiated the efficacy of the ligands that were screened based on the in silico methods. PMID- 23988478 TI - Sex-specific effects of mindfulness on romantic partners' cortisol responses to conflict and relations with psychological adjustment. AB - Mindfulness is known to improve individuals' and couples' subjective stress regulation, but little is known about how it impacts hypothalamic-pituitary adrenal (HPA) axis responses to acute psychosocial stress. The current study tested effects of dispositional mindfulness facets on young adult couples' cortisol responses to a conflict discussion stressor, as well as associations with psychological adjustment. One hundred heterosexual couples completed the five facet mindfulness questionnaire one week before engaging in a conflict discussion task. Each partner provided five saliva samples from pre- to post conflict, which were assayed for cortisol. Measures of adjustment - depression and anxiety symptoms and global well-being - were also completed at this session. Hierarchical linear modeling of cortisol trajectories revealed sex-specific effects; whereas women's mindfulness (nonreactivity facet) predicted higher conflict stress cortisol levels, men's mindfulness (describing facet) predicted less pronounced cortisol reactivity/recovery curves. These patterns were related to better adjustment-lower depression symptoms for women and greater well-being for men. Implications for sex differences in mindfulness benefits are discussed. PMID- 23988479 TI - Clinical outcome of coronary stenting in patients with variant angina refractory to medical treatment: a consecutive single-center analysis. AB - OBJECTIVE: To investigate the efficacy of coronary stenting in patients with variant angina refractory to medical treatment. SUBJECTS AND METHODS: Variant angina was diagnosed in 81 patients admitted to the Department of Cardiology between January 2003 and June 2011. However, coronary stenting was performed in 21 patients refractory to medical treatment, but coronary angiography and intravascular ultrasound were performed in all patients, and acetylcholine provocative test was performed in 11 of the 21 patients refractory to medical treatment. Coronary angiography was repeated after 9-12 months in the 21 patients with coronary stents. Clinical follow-up time was 2.5 +/- 3.1 years (range 1-8). RESULTS: Of the 81 patients, coronary angiography and intravascular ultrasound did not reveal significant stenosis in 13 (16.0%), but revealed 20-75% fixed stenosis in the remaining 68 (84.0%) patients. The acetylcholine provocative test was positive in the 11 patients. Of the 21 patients with coronary stents, the spasm site was located in the right coronary artery in 16 (76.2%) and in the left anterior descending artery in the remaining 5 (23.8%) patients. During the 1- to 8-year follow-up period, 1 of the 21 patients with stents developed recurrent episodes of variant angina, 5 patients had occasional chest pain, and the other 15 were asymptomatic. Coronary angiography at 9-12 months after initial evaluation demonstrated no stenosis in 3 patients, 20-40% in-stent mild intimal hyperplasia in 15 patients, and 50-80% in-stent restenosis in 3 patients. Coronary stenting was performed again in 2 patients. CONCLUSIONS: The present study showed that coronary stenting for severe refractory coronary vasospasm was effective and without serious complications. It can be an alternative and viable option for some patients who are refractory to medical therapy and at a high risk of acute coronary syndrome recurrence. PMID- 23988480 TI - Targeted 13C enrichment of lipid and protein pools in the body reveals circadian changes in oxidative fuel mixture during prolonged fasting: a case study using Japanese quail. AB - Many animals undergo extended periods of fasting. During these fasts, animals oxidize a ratio of macronutrients dependent on the nutritional, energetic, and hydric requirements of the fasting period. In this study, we use Japanese quail (Coturnix coturnix japonica), a bird with natural intermediate fasting periods, to examine macronutrient use during a 6d fast. We raised groups of quail on isotopically labeled materials ((13)C-1-leucine, (13)C-U-glucose, or (13)C-1 palmitic acid) with the intent of labeling specific macronutrient/tissue pools in each treatment, and then traced their use as fuels by measuring the delta(13)C values of breath CO2. Based on changes in delta(13)C values during the fast, it appears that the carbohydrate label,(13)C-U-glucose, was largely incorporated into the lipid pool and thus breath samples ultimately reflected lipid use rather than carbohydrate use. In the lipid treatment, the (13)C-1-palmitic acid faithfully labeled the lipid pool and was reflected in the kinetics delta(13)C values in breath CO2 during the fast. Endogenous lipid oxidation peaked after 24h of fasting and remained constantly elevated thereafter. The protein label,(13)C-1 leucine, showed clear diurnal periods of protein sparing and degradation, with maximal rates of protein oxidation occurring at night and the lowest rates occurring during the day time. This stable isotope tracer method provides a noninvasive approach to study the nutrient dynamics of fasting animals and should provide new insights into how different types of animals use specific nutrient pools during fasting and possibly other non-steady physiological states. PMID- 23988481 TI - An examination of racial differences in process and outcome of colorectal cancer care quality among users of the veterans affairs health care system. AB - BACKGROUND: Veterans Affairs (VA) manages the largest US integrated health care system. Although quality of VA colorectal cancer (CRC) care is well chronicled, there is a paucity of research examining racial differences in this care. This study examines racial differences in 2 dimensions of quality of VA CRC care: processes (time to treatment) and outcomes (survival). PATIENTS AND METHODS: Retrospective data were from the VA External Peer Review Program (EPRP), a nationwide VA quality-monitoring program. Study patients were white and African American men diagnosed with nonmetastatic CRC between 2003 and 2006 who received definitive CRC surgery. We examined 3 quality indicators: time from (1) surgery to initiation of adjuvant chemotherapy (stages II-III disease), (2) surgery to surveillance colonoscopy (stages I-III disease), and (3) surgery to death (stages I-III disease). Unadjusted analyses used log-rank and Wilcoxon tests. Adjusted analyses used Cox proportional hazard models. RESULTS: In unadjusted analyses, there was no evidence of racial differences across the 3 quality measures. In adjusted Cox regression, there were no racial differences in time to initiation of chemotherapy (hazard ratio [HR], 0.82; P = .61) or surgery to death (HR, 0.94; P = .49). In adjusted Cox regression, among those receiving colonoscopy within 7 to 18 months after surgery, white patients experienced slightly shorter median times to surveillance colonoscopy than did African American patients (367 vs. 383 days; HR, 0.63; P = .02). CONCLUSION: Other than a small racial difference in timing of surveillance colonoscopy, there was little evidence of racial differences in quality of CRC care among VA health care system users. PMID- 23988483 TI - Standard dose versus low-dose abdominal and pelvic CT: comparison between filtered back projection versus adaptive iterative dose reduction 3D. AB - PURPOSE: To compare the dose and image quality of a standard dose abdominal and pelvic CT with Filtered Back Projection (FBP) to low-dose CT with Adaptive Iterative Dose Reduction 3D (AIDR 3D). MATERIALS AND METHODS: We retrospectively examined the images of 21 patients in the portal phase of an abdominal and pelvic CT scan before and after implementation of AIDR 3D iterative reconstruction. The acquisition length, dose and evaluations of the image quality were compared between standard dose FBP images and low-dose images reconstructed with AIDR 3D and FBP using the Wilcoxon test. RESULTS: The mean acquisition length was similar for both CT scans. There was a significant dose reduction of 49.5% with low-dose CT compared to standard dose CT (mean DLP of 451mGy.cm versus 892mGy.cm, P<0.001). There were no differences in image quality scores between standard dose FBP and low-dose AIDR 3D images (4.6+/-0.6 versus 4.4+/-0.6 respectively, P=0.147). CONCLUSION: AIDR 3D iterative reconstruction enables a significant reduction in dose of 49.5% to be achieved with abdominal CT scan compared to FBP, whilst maintaining equivalent image quality. PMID- 23988484 TI - Determination of viral load by quantitative real-time PCR in herpes simplex encephalitis patients. AB - OBJECTIVE: Human herpesviruses cause various acute, subacute, and chronic disorders of the central nervous system and peripheral nervous systems in adults and children. The objective of the present study is to summarize the experience gained with the estimation of viral load in the central nervous system of children and adults with herpes simplex encephalitis (HSE) admitted to a neurological institute at Nagpur, India, by quantitative real-time PCR (qPCR) assay within the past 4 years. METHODS: The qPCR assay was evaluated retrospectively in 242 cerebrospinal fluid (CSF) samples from patients. Evaluation of possible relationships was done between the herpes simplex virus (HSV) DNA concentration in CSF with that of patients' clinical and laboratory manifestations. The prevalence of the type of HSV in the study population was also determined using type-specific real-time PCR analysis. RESULTS AND CONCLUSIONS: Real-time analysis using type-specific primers revealed the presence of predominantly HSV-1 genotype in the study population. The qPCR results show that in patients with higher viral loads in their CSF, a greater number of cases were associated with the presence of lesions in the brain as revealed by computed tomography/magnetic resonance imaging scan. They required acyclovir therapy for a longer duration and had a poorer clinical outcome than the patients with lower viral loads in their CSF. PMID- 23988482 TI - The Anopheles innate immune system in the defense against malaria infection. AB - The multifaceted innate immune system of insects is capable of fighting infection by a variety of pathogens including those causing human malaria. Malaria transmission by the Anopheles mosquito depends on the Plasmodium parasite's successful completion of its lifecycle in the insect vector, a process that involves interactions with several tissues and cell types as well as with the mosquito's innate immune system. This review will discuss our current understanding of the Anopheles mosquito's innate immune responses against the malaria parasite Plasmodium and the influence of the insect's intestinal microbiota on parasite infection. PMID- 23988485 TI - Synthesis and enzymatic evaluation of phosphoramidon and its beta anomer: Anomerization of alpha-l-rhamnose triacetate upon phosphitylation. AB - A novel and efficient strategy for the synthesis of phosphoramidon and its beta anomer has been developed by manipulating the anomerization of alpha-l-rhamnose triacetate upon phosphitylation. The experimental results suggest that proton transfer, bond rotation, and N atom are the key factors for the anomerization. The determined Ki and Kd values establish that phosphoramidon prepared by this method possesses excellent biological activity, and indicate that the contacts of rhamnose moiety with the enzyme have limited contribution to the binding. PMID- 23988486 TI - Phylogenetic and forensic studies of the Southeast Florida Hispanic population using the next-generation forensic PowerPlex(r) Y23 STR marker system. AB - The purpose of this study is to examine the robustness and sensitivity of the newly available Y-STR multiplex kit, the PowerPlex(r) Y23 System, by comparing our data at the 23-loci level to the routinely used 17 loci provided by the AmpFlSTR(r) Yfiler(r) PCR Amplification kit. For the first time, allelic and genotypic frequencies for the 23 Y-STR loci included in the PowerPlex(r) Y23 System are provided for the Southeast Florida Hispanic (SFH) population. In addition, we have characterized the SFH population in terms of intra-population and inter-population parameters. We also compared these indices of forensic and population genetics interest in the SFH population to comparable data of previously published populations to assess their phylogenetic relationships. Our 23-loci data was shown to provide more discriminatory values as compared to the data when using only 17 loci. Also, the RST distance values demonstrate the superior capacity of the PowerPlex(r) Y23 system to discriminate among populations. PMID- 23988488 TI - Studies on the in vivo contribution of human cytochrome P450s to the hepatic metabolism of glaucine, a new drug of abuse. AB - Glaucine ((S)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-6-methyl-4H-dibenzo [de,g]quinoline), main isoquinoline alkaloid of Glaucium flavum (Papaveraceae), is used as antitussive, but also as recreational drug of abuse. Glaucine was mainly metabolized by O- and N-demethylation to four isomers in rats. So far, only scarce pharmacokinetic data were available. Therefore, the aim of the presented study was to assess the involvement of the ten most important cytochrome P450 (P450) isoforms in the main metabolic steps and determination of their kinetic parameters using the metabolite formation approach. Reference standards of investigated metabolites were synthesized for quantification. In addition, the impact of isomeric standards was tested for calibration and the use of simple peak area ratios on the kinetic constants and resulting contribution of P450 isoforms on estimated hepatic clearance. Kinetic profiles of all metabolite formations followed classic Michaelis-Menten behavior. Km values were between 25 and 140MUM, Vmax between 0.10 and 1.92pmol/min/pmol. Using the relative activity factor approach, the hepatic clearance was calculated to be 27 and 73% for 2-O demethylation by CYP1A2 and CYP3A4, 82, 3, and 15% for 9-O-demethylation by CYP1A2, CYP2C19, and CYP2D6, and finally <1 and 99% for N-demethylation by CYP2D6 and CYP3A4. These data were confirmed by inhibition tests. The calibration mode for determination of the metabolite concentrations had no relevant impact on the estimation of in vivo hepatic clearance of glaucine. As glaucine was metabolized via three initial steps and different P450 isoforms were involved in the hepatic clearance of glaucine, a clinically relevant interaction with single inhibitors should not be expected. PMID- 23988487 TI - Bile acid receptors in non-alcoholic fatty liver disease. AB - Accumulating data have shown that bile acids are important cell signaling molecules, which may activate several signaling pathways to regulate biological processes. Bile acids are endogenous ligands for the farnesoid X receptor (FXR) and TGR5, a G-protein coupled receptor. Gain- and loss-of-function studies have demonstrated that both FXR and TGR5 play important roles in regulating lipid and carbohydrate metabolism and inflammatory responses. Importantly, activation of FXR or TGR5 lowers hepatic triglyceride levels and inhibits inflammation. Such properties of FXR or TGR5 have indicated that these two bile acid receptors are ideal targets for treatment of non-alcoholic fatty liver disease, one of the major health concerns worldwide. In this article, we will focus on recent advances on the role of both FXR and TGR5 in regulating hepatic triglyceride metabolism and inflammatory responses under normal and disease conditions. PMID- 23988489 TI - Effect of antiasthmatic medication on the surface roughness and color stability of dental restorative materials. AB - OBJECTIVE: This study evaluated the effect of antiasthmatic medication on the surface roughness and color stability of dental restorative materials. MATERIALS AND METHODS: A total of 60 disc-shaped specimens were fabricated from glass ionomer (n = 20), composite resin (n = 20) and feldspathic porcelain (n = 20). Each material group was randomly divided into two subgroups (n = 10): (1) control group and (2) test group. Control groups of the specimens were kept in artificial saliva. Test groups were exposed to salbutamol sulfate (Ventolin Nebules) using an inhaler machine. Surface roughness measurements were done using a profilometry and color measurements were done with digital colorimetry at baseline and after inhalation and storing in artificial saliva. A two-way analysis of variance (ANOVA) and post-hoc Fisher's least significant difference test were used to compare the change in surface roughness and color. The confidence level was set at 95%. RESULTS: Inhaler treatment significantly increased the surface roughness and color change of glass ionomer and composite resin materials (p < 0.05), while the surface roughness and color of feldspathic porcelain was not changed after inhaler treatment (p > 0.05). CONCLUSION: The antiasthmatic inhaler medication (salbutamol sulfate) affected the surface roughness and color of composite resin and glass ionomer restorative materials. PMID- 23988490 TI - Magnetism and magnetic structures of PrMn2Ge2-xSix. AB - The structural and magnetic properties of seven PrMn2Ge2-xSix compounds with Si concentrations in the range x = 0.0-2.0 have been investigated by x-ray diffraction, magnetic (5-350 K), differential scanning calorimetry (300-500 K) and neutron diffraction (3-480 K) measurements. Replacement of Ge by Si leads to a contraction of the unit cell and significant modifications to the magnetic states--a crossover from ferromagnetism at room temperature for Ge-rich compounds to antiferromagnetism for Si-rich compounds. The compositional dependence of the room temperature lattice parameters exhibits non-linear behaviour around x = 1.2, reflecting the presence of magnetovolume effects. Re-entrant ferromagnetism has been observed in both PrMn2Ge1.0Si1.0 and PrMn2Ge0.8Si1.2 compounds with co existence of canted ferromagnetism and canted antiferromagnetism detected, with both compounds exhibiting a larger unit cell volume in the canted Fmc state than in the canted AFmc. Combined with earlier studies of this system, the magnetic phase diagram has been constructed over the full range of PrMn2Ge2-xSix compositions (x = 0.0-2.0) and over the temperature range of interest (T = 3-480 K). In common with other systems in the RMn2X2 series, the overall magnetic behaviour of PrMn2Ge2-xSix compounds is governed by the strong dependence of the magnetic couplings on the Mn-Mn spacing within the ab-plane. Both total manganese moment u(Mn)(tot) and in-plane manganese moment u(Mn)(ab) at 5 K are found to decrease with increasing Si content, which can be ascribed to the reduction of Mn Mn separation distance and stronger Si-Mn hybridization compared with Ge-Mn hybridization. Pr site ferromagnetic ordering occurs for x < 1.6 below T(Pr)(C). PMID- 23988491 TI - Lipopolysaccharides shapes the human Wharton's jelly-derived mesenchymal stem cells in vitro. AB - BACKGROUND: Although the expression of toll-like receptors (TLRs) on different types of human mesenchymal stem cells (hMSCs) has recently been reported, controversy remains regarding the presence of TLR4 as well as its engagement and impact on human Wharton's jelly-derived MSCs (hWJ-MSCs). METHODS: In the present study, the expression and role of TLR4 in hWJ-MSCs was investigated using a model of lipopolysaccharide (LPS). Proliferation, apoptosis, and the expression of paracrine factors in hWJ-MSCs primed with LPS were analysed. RESULTS: The expression of TLR4 was high at the RNA level but very low at the protein level. hWJ-MSCs responded to LPS stimulation and initiated a marked up-regulation of inflammatory cytokine (IL-1alpha, IL-1beta, IL-6, and IL-8) production. Moreover, hWJ-MSCs LPS stimulation resulted in the up-regulation of indoleamine 2,3 dioxygenase [IDO]-1, Cox2, interferon [IFN]-beta, and matrix metalloproteinase (MMP)-2 but a down-regulation of MMP-9, which affect the immunosuppressive potential of hWJ-MSCs. CONCLUSIONS: These data suggest that LPS engagement shapes hWJ-MSCs and results in the production of pro-inflammatory cytokines and inhibitory immune mediators, showing TLR4 agonist induces the hWJ-MSCs polarization to a pro-inflammatory and immunosuppressive state, which may be beneficial for the exploration of the clinical potential of hWJ-MSCs. PMID- 23988492 TI - Novel approach to engineer strains for simultaneous sugar utilization. AB - Use of lignocellulosic biomass as a second generation feedstock in the biofuels industry is a pressing challenge. Among other difficulties in using lignocellulosic biomass, one major challenge is the optimal utilization of both 6 carbon (glucose) and 5-carbon (xylose) sugars by industrial microorganisms. Most industrial microorganisms preferentially utilize glucose over xylose owing to the regulatory phenomenon of carbon catabolite repression (CCR). Microorganisms that can co-utilize glucose and xylose are of considerable interest to the biofuels industry due to their ability to simplify the fermentation processes. However, elimination of CCR in microorganisms is challenging due to the multiple coordinating mechanisms involved. We report a novel algorithm, SIMUP, which finds metabolic engineering strategies to force co-utilization of two sugars, without targeting the regulatory pathways of CCR. Mutants of Escherichia coli based on SIMUP algorithm showed predicted growth phenotypes and co-utilized glucose and xylose; however, consumed the sugars slower than the wild-type. Some solutions identified by the algorithm were based on stoichiometric imbalance and were not obvious from the metabolic network topology. Furthermore, sequencing studies on the genes involved in CCR showed that the mechanism for co-utilization of the sugars could be different from previously known mechanisms. PMID- 23988493 TI - The association of perceived stress with depressive symptoms in older Taiwanese Result of a longitudinal national cohort study. AB - OBJECTIVE: To determine the impact of perceived-stress over one's own health, financial condition, job, and conflict with family members, and family members' problems on depressive symptoms in older adults. METHODS: We analyzed datasets of the Taiwan Longitudinal Survey on Aging, and used self-reported stress in 2003 and 2007 to represent long-term stress conditions in 4854 >= 50-year old persons. The impact of long-term stress on depressive status (evaluated with CES-D10, score range 0-30) was determined with multivariate logistic regression analysis. Persons with proxy interviews, incomplete CES-D data, or cognitive impairment were excluded. RESULTS: Perceived-health stress had stronger impacts on depressive symptoms than most other stress situations. Job-related stress showed no impact. Other stress situations showed modest associations in the middle-aged and young-olds. Ongoing stress had stronger impacts than past stress. Excluding health and job stresses, the impact generally decreased with aging. The association with clinically relevant depression generally followed that with depressive symptoms. CONCLUSION: All perceived stresses are not equal in their impacts on subsequent depressive symptoms. Perceived-health stress has stronger impacts under most conditions. Better understanding of the associations of various stressors with depressive symptoms could enhance planning of effective strategies to reduce the risk of depression in older persons. PMID- 23988494 TI - An overview of national clinical guidelines for the management of childhood obesity in primary care. AB - STUDY DESIGN: Review of clinical guidelines. BACKGROUND: Most national clinical guidelines for the management of childhood obesity in primary care were published since 2003. It is unknown whether there is international consensus concerning the diagnosis and management of childhood obesity. OBJECTIVE: To present an overview of available guidelines for the management of childhood obesity in primary care METHODS: Guidelines were included if they met the following criteria: (1) the guideline makes recommendations concerning the management of childhood obesity, (2) the target group consists of primary care health practitioners, (3) the guideline is available in English or Dutch. RESULTS: Clinical guidelines from six different countries published from 2003 until 2010 met the selection criteria and were included in this review. The recommendations of the guidelines regarding the management of childhood obesity appeared to be quite similar. A consistent feature was the recommended combined intervention, with diet, physical activity and counselling being the three most important elements. There were discrepancies between the guidelines for recommendations regarding diagnostic classification criteria for childhood obesity. CONCLUSION: The present review shows that there is international consensus regarding the recommendations for management of childhood obesity. There is less international consensus regarding the diagnostic classification of childhood obesity. PMID- 23988495 TI - Obesity in red and blue: understanding the associations between politics and obesity. PMID- 23988496 TI - Maternal educational level and preschool children's consumption of high-calorie snacks and sugar-containing beverages: mediation by the family food environment. AB - OBJECTIVE: To examine the associations between maternal educational level and preschoolers' consumption of high-calorie snacks and sugar-containing beverages, and to assess the mediating effects of variables relating to the family food environment. METHODS: We analyzed data from 2814 native Dutch preschoolers enrolled in a birth cohort study in Rotterdam (the Netherlands), between 2002 and 2006. Logistic regression models were used to calculate odds ratios of snacking >= 2 times/day and consuming sugar-containing beverages >= 3 glasses/day for children of mothers with low, mid-low, and mid-high educational levels (reference group: high educational level), before and after adjustment for mediators. RESULTS: Children of low and mid-low educated mothers were significantly more likely to consume excessive amounts of high-calorie snacks and sugar-containing beverages compared with children of high educated mothers, with the highest odds in children of low educated mothers (OR: 2.44; 95% CI: 1.84, 3.23 and OR: 2.46; 95% CI: 1.87, 3.24 respectively). Parental feeding practices, parental consumption of sugar-containing beverages, and children's television time partly explained these associations. CONCLUSION: Maternal educational level is inversely related to preschoolers' consumption of high-calorie snacks and sugar-containing beverages. Targeting the family food environment may be an effective way of reducing educational inequalities in children's unhealthy dietary behaviors. PMID- 23988497 TI - Which newborns missed the hepatitis B birth dose vaccination among U.S. children? AB - OBJECTIVES: Hepatitis B birth dose vaccination is a critical step in preventing perinatal hepatitis B virus infection. This study assesses the prevalence of children who missed the birth dose of hepatitis B vaccination and identifies socio-demographic factors associated with non-receipt of the birth dose among children in the United States. METHODS: A survey observation study was conducted with the national representative sample of 17,053 U.S. children aged 19-35 months obtained from the 2009 National Immunization Survey. Categorical data analysis and multivariable logistic regression in the context of complex sample survey were applied to evaluate the prevalence and determine the independent risk factors. RESULTS: 39.2% of children missed the birth dose of hepatitis B vaccination. Children who reside in states without a universal hepatitis B vaccine supply policy, are not covered by health insurance, and have only 1 vaccination provider are significantly associated with non-receipt of the birth dose hepatitis B vaccination. CONCLUSIONS: Children who reside in states without a universal hepatitis B vaccine supply policy, and who are not covered by health insurance are two important modifiable risk factors for not receiving the birth dose hepatitis B vaccination. Future intervention studies could be needed to help control those modifiable risk factors. PMID- 23988498 TI - A material-independent cell-environment niche based on microreciprocating motion for cell growth enhancement. AB - In tissue engineering, cell-cell, cell-scaffold and cell-environment communication balances regulate how cell populations participate in tissue generation, maintenance and repair. These communication balances are called niches. In this study, an easily implemented and material-independent cell environment niche based on microreciprocating motions is developed to enhance cell growth. A micropositioning piezoelectric lead zirconate titanate stage is used to provide precise microreciprocating shear stress motions. Various shear stresses were applied to bovine endothelial cells (BECs) that were cultured on the artificially synthesized materials to obtain the suitable shear stress for growth enhancement. It was found that the suitable shear stress for apparent enhancement of BEC growth ranges from 1.8 to 2.2 N m(-2). Biopolymers were further used to verify the feasibility of the proposed approach using the optimized shear stress obtained from the culture on artificially synthesized polymers. The results further confirmed that the growth of BECs was enhanced as expected under the calculated reciprocating frequencies based on the suitable shear stress. It is hoped that the proposed microshear-stress-based niche could be a more cost- and time-effective solution for the enhancement of cell growth in tissue engineering applications. PMID- 23988499 TI - Association of small foci of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) with adenocarcinoma of the lung. AB - DIPNECH is regarded as a precursor lesion of neuroendocrine lung tumors, specifically carcinoids. A relationship with lung adenocarcinomas has not been clearly established so far. We present a series of four cases with a concomitant presence of adenocarcinoma and DIPNECH in the lung. The cases were retrieved from the archives of the Institutes of Pathology of the Jena University Hospital and the Charite, Berlin. The clinical data were collected from the hospital information system. The microscopic findings of adenocarcinoma and DIPNECH were reviewed. A panel of neuroendocrine and epithelial markers was analyzed immunohistochemically. In addition, the H&E slides of a series of 82 lung carcinomas were reevaluated for the presence of DIPNECH foci and the parameters of the IASLC/ATS/ERS classification for lung adenocarcinoma. DIPNECH foci were composed of small intramucosal nests of proliferating pulmonary neuroendocrine cells alongside or at the periphery of terminal airways. All detected foci measured less than 5mm in maximal diameter and showed a consistent reactivity against Synaptophysin. They did not express epithelial markers of squamous cell carcinoma and adenocarcinoma. In three cases, the DIPNECH foci were clearly associated with the adenocarcinoma, while in one case, they were observed in the non-neoplastic lung tissue. The adenocarcinoma with DIPNECH inside mainly showed low grade histology, while the fourth case was intermediate to high grade. The histologic evaluation of the HE slides of the other 82 lung cancer cases showed no suspected or definite DIPNECH foci. Within this series, we could confirm the prognostic significance of the IASLC/ATS/ERS classification of lung adenocarcinoma. Our series suggest that a subset of lung adenocarcinoma is characterized by the concomitant presence of DIPNECH within the tumor, suggesting a causal relationship. These adenocarcinomas seem to be low grade ones, and may have a particular tumorigenesis and clinical behavior. These observations need to be confirmed in larger tumor collectives. We could confirm the prognostic relevance of the new adenocarcinoma classification. PMID- 23988500 TI - Association between 5-HT2A receptor polymorphisms and risk of obstructive sleep apnea and hypopnea syndrome: a systematic review and meta-analysis. AB - Obstructive sleep apnea and hypopnea syndrome (OSAHS) is a common disorder with several predisposing factors, which may include genetic causes. Studies of the association of susceptibility to and severity of OSAHS with the polymorphisms of the 5-HTR 2A/2C genes have had low statistical power and have yielded inconsistent results. To clarify the association we perform a meta-analysis that combines the genotyping data from all eligible published studies. We quantitatively analyzed five publications, which included a pool of 633 cases and 512 controls, addressing the 5-HT receptor polymorphism and the risk of OSAHS. Hardy-Weinberg equilibrium (HWE) and the minor allele frequency of genetic frequency distributions for the controls were calculated. Differences in the distribution of genotypes between cases and controls were compared by odds ratios (ORs) with their 95% confidence intervals (CIs). For each genetic model, data were pooled using fixed- or random-effects models, depending on the inter publication heterogeneity. Our results from pooled data showed that individuals carrying the 5-HTR 2A -1438G/A AA genotype had an increased risk of OSAHS (OR=3.69, 95% CI=1.92-7.08) compared with those carrying the GG genotype. Significant results were also reached under a recessive model (OR=3.16, 95% CI=2.33-4.30, p<0.01). However, the results declined to an OR of 2.16 (95% CI=0.9 5.21) in a homozygote model when the studies were restricted to HWE. No statistically significant results concerning an association of the 102C/T polymorphism of the 5-HTR 2A gene with OSAHS were reached (p>0.05 for each genetic model). This meta-analysis suggested that the 5-HTR 2A -1438G/A genotype might modulate an elevated risk of OSAHS. No association of the 5-HTR 2A 102C/T genotype polymorphism with OSAHS was established. However, some publications exhibited HWE bias, which might influence the reliability of pooled data. Further studies in this field, using larger samples, better designs and additional ethnicities, are warranted. PMID- 23988501 TI - Novel UMOD mutations in familial juvenile hyperuricemic nephropathy lead to abnormal uromodulin intracellular trafficking. AB - BACKGROUND: Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal dominant disorder characterized by hyperuricemia and progressive chronic kidney disease. Uromodulin gene (UMOD) mutations, leading to abnormalities of uromodulin intracellular trafficking contribute to the progress of the disease. METHODS: We did UMOD screening in three Chinese FJHN families. We thus constructed mutant uromodulin express plasmids by site-mutagenesis from wild type uromodulin vector and transfected them into HEK293 (human embryonic kidney) cells. And then we detected uromodulin expression by western blot and observed intracellular distribution by immunofluorescence. RESULTS: We found three heterozygous mutations. Mutation Val109Glu (c.326T/A; p.Val109Glu) and mutation Pro236Gln (c.707C/A; p.Pro236Gln) were newly indentified mutations in two distinct families (family F1 and family F3). Another previously reported UMOD mutation Cys248Trp (c.744C/G; p.Cys248Trp) was detected in family F2. Phenotypes varied both within the same family and between different families. Uromodulin expression is abnormal in the patient biopsy. Functional analysis of mutation showed that mutant types of uromodulin were secreted into the supernatant medium much less when compared with wild type. In mutant type uromodulin transfected cells, intracellular uromodulin localized less in the Golgi apparatus and more in endoplasmic reticulum(ER). CONCLUSIONS: Our results suggested that the novel uromodulin mutations found in the Chinese families lead to misfolded protein, which was retained in the endoplasmic reticulum, finally contributed to the phenotype of FJHN. PMID- 23988502 TI - Molecular cloning and expression pattern of 11 genes involved in lipid metabolism in yellow catfish Pelteobagrus fulvidraco. AB - 11 genes involved in lipid metabolism were cloned from liver of yellow catfish Pelteobagrus fulvidraco, including CPT 1A, CPT 1B, PPARalpha, PPARgamma, SREBP-1, G6PD, 6PGD, FAS, acetyl-CoA ACCa, ACCb, and LPL. Phylogenetic analysis further identified these genes, and confirmed the classification and evolutionary status of yellow catfish. mRNA of all eleven genes was present in liver, muscle, mesenteric adipose, ovary and heart, but at varying levels. The present study will facilitate further studies on the regulation of lipid metabolism at the molecular level for the fish species. PMID- 23988503 TI - PSCA gene variants (rs2294008 and rs2978974) confer increased susceptibility of gallbladder carcinoma in females. AB - BACKGROUND AND AIM: PSCA is a tissue specific tumor suppressor or oncogene which has been found to be associated with several human tumors including gallbladder cancer. It is considered to be involved in the cell-proliferation inhibition and/or cell-death induction activity. Therefore, we aimed to investigate the role of PSCA gene polymorphisms in gallbladder cancer risk in North Indian population. METHODOLOGY: A total of 405 gallbladder cancer patients and 247 healthy controls were included in the case-control study for risk prediction. We examined the association of two functional SNPs, rs2294008 and rs2978974 in PSCA gene by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. Linkage disequilibrium and haplotype analysis was done with the help of SNPstats software. FDR test was used to correct for multiple comparisons. RESULTS: No significant associations of rs2294008 and rs2978974 genetic variants of the PSCA gene were found with GBC risk at allele, genotype or haplotype levels. Stratifying the subjects on the basis of gallstone also did not show any significant result. However, on gender stratification, we found a significant association of Trs2294008-Grs2978974 haplotype with higher risk of GBC in females (FDR Pcorr=0.021, OR=1.6). In contrary, Trs2294008-A rs2978974 haplotype conferred significant lower risk in males (FDR Pcorr=0.013; OR=0.25). CONCLUSIONS: These findings suggest that PSCA genetic variants may have a significant effect on GBC susceptibility in a gender specific manner. PMID- 23988504 TI - BBX proteins in green plants: insights into their evolution, structure, feature and functional diversification. AB - The B-box domain is conserved in a large number of proteins involved in cell growth control, differentiation and transcriptional regulation among animal and plant species. In Arabidopsis thaliana, some works have found that B-box proteins (BBX) play central developmental functions in flowering, light and abiotic stress signaling. Despite the functional importance of this protein family, evolutionary and structural relationships of BBX proteins have not been extensively investigated in the plant kingdom. Using a phylogenetic approach, we conducted a comprehensive evolutionary analysis of the BBX protein family in twelve plant species (four green algae, one moss, one lycophyte, three monocots and three dicots). The analysis classified 214 BBX proteins into five structure groups, which evolved independently at early stages of green plant evolution. We showed that the B-box consensus sequences of each structure groups retained a common and conserved domain topology. Furthermore, we identified seven novel motifs specific to each structure group and a valine-proline (VP) pair conserved at the C terminus domain in some BBX proteins suggesting that they are required for protein-protein interactions. As it has been documented in mammalian systems, we also found monopartite and bipartite amino acid sequences at the C-terminus domain that could function as nuclear localization signals (NLSs). The five BBX structure groups evolved constrained by the conservation of amino acid sequences in the two B-boxes, but radiating variation into NLSs and novel motifs of each structural group. We suggest that these features are the functional basis for the BBX protein diversity in green plants. PMID- 23988505 TI - PMM2-CDG: phenotype and genotype in four affected family members. AB - Congenital disorders of glycosylation (CDG) are genetic defects in protein and lipid glycosylation. PMM2-CDG is the most prevalent protein N-glycosylation disorder with more than 700 reported patients. Here we report on a large Italian family with four affected members and three mutations. Two young sisters are compound heterozygous for mutations p.Leu32Arg and p.Arg141His, while two paternal great-aunts are compound heterozygosity for p.Leu32Arg and p.Thr237Met. The latter association has not been reported before. The most severely affected member had in addition an ALG6 mutation known to exacerbate the phenotype of patients with PMM2-CDG. PMID- 23988506 TI - Point: There is a need for supplemental XRT with brachytherapy in the treatment of intermediate-risk prostate cancer patients. PMID- 23988507 TI - Long-term outcomes with high-dose-rate brachytherapy for the management of base of tongue cancer. AB - PURPOSE: To report the long-term results of a prospective, nonrandomized clinical trial using high-dose-rate (HDR) brachytherapy (BT) for the management of base of the tongue (BOT) tumors. METHODS AND MATERIALS: Between January 1992 and June 2011, 60 patients (mean age, 57 years; range, 36-78 years) with T1-T4 and N0-3 carcinoma of BOT were treated. Fifty-six patients (93%) had advanced (Stage III IV) disease. HDR BT boost (mean dose, 17 Gy; range, 12-30 Gy) was delivered after 50-70 Gy (mean 62 Gy) locoregional external beam irradiation. Seventeen patients (28%) received radiochemotherapy (RCT) with cisplatin. RESULTS: The 5-year actuarial rate of local tumor control, locoregional tumor control, overall survival (OS), and cancer-specific survival (CSS) was 57%, 50%, 47%, and 61%, respectively. OS was significantly better in patients (n=17) receiving RCT (69% vs. 39%; p=0.005). Delayed soft-tissue ulceration occurred in seven patients (12%). Only one patient (<2%) developed osteoradionecrosis. In univariate analysis, the tumor size (T1-T2-T3 vs. T4) was found to have a significant effect on CSS (p=0.043), whereas the nodal status (N0 vs. N+) affected locoregional tumor control (p=0.042), OS (p=0.002), and CSS (p=0.015). Low histologic grade (1 2) was associated with better CSS (p=0.020), whereas RCT significantly improved OS (p=0.012). CONCLUSIONS: External beam irradiation combined with interstitial HDR BT boost results in good local tumor control with an acceptable rate of late side effects in patients with BOT carcinoma. RCT improves OS. Our results are similar to those reported with traditional low-dose-rate BT implants. PMID- 23988508 TI - Rebuttal to Dr. Stone. PMID- 23988509 TI - The speed of learning instructed stimulus-response association rules in human: experimental data and model. AB - Humans can learn associations between visual stimuli and motor responses from just a single instruction. This is known to be a fast process, but how fast is it? To answer this question, we asked participants to learn a briefly presented (200ms) stimulus-response rule, which they then had to rapidly apply after a variable delay of between 50 and 1300ms. Participants showed a longer response time with increased variability for short delays. The error rate was low and did not vary with the delay, showing that participants were able to encode the rule correctly in less than 250ms. This time is close to the fastest synaptic learning speed deemed possible by diffusive influx of AMPA receptors. Learning continued at a slower pace in the delay period and was fully completed in average 900ms after rule presentation onset, when response latencies dropped to levels consistent with basic reaction times. A neural model was proposed that explains the reduction of response times and of their variability with the delay by (i) a random synaptic learning process that generates weights of average values increasing with the learning time, followed by (ii) random crossing of the firing threshold by a leaky integrate-and-fire neuron model, and (iii) assuming that the behavioural response is initiated when all neurons in a pool of m neurons have fired their first spike after input onset. Values of m=2 or 3 were consistent with the experimental data. The proposed model is the simplest solution consistent with neurophysiological knowledge. Additional experiments are suggested to test the hypothesis underlying the model and also to explore forgetting effects for which there were indications for the longer delay conditions. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23988510 TI - Conscientious objection and its social context. PMID- 23988512 TI - Adoption of American Heart Association 2020 ideal healthy diet recommendations prevents weight gain in young adults. AB - In 2010, the American Heart Association established the concept of ideal cardiovascular health. Nationally representative data estimated that <1% of Americans meet the seven health metrics required for achieving ideal cardiovascular health, with the main challenge residing in meeting the criteria for an ideal Healthy Diet Score. In a cohort of young adults (N=196), we aimed to investigate the prevalence of ideal cardiovascular health and ideal Healthy Diet Score and its association to weight gain over a 4-year follow-up period. Anthropometric measures, blood pressure, and blood samples were taken according to standardized procedures. Dietary intake was measured by a 3-day food diary and verified by a registered dietitian. We observed that only 0.5% of our sample met the criteria for ideal cardiovascular health and only 4.1% met the criteria for an ideal Healthy Diet Score. The components of the Healthy Diet Score with the lowest observance were consumption of fruits and vegetables (9.7%) and whole grains (14.8%). Meeting zero or one out of five of the Healthy Diet Score components was associated with increased risk of weight gain over 4 years compared with meeting at least two components (P=0.03). With the exception of dietary criteria, prevalence was high for achieving ideal levels of the remaining six cardiovascular health metrics. In conclusion, in this sample of young adults, a very low prevalence of ideal overall cardiovascular health was observed, mainly driven by poor dietary habits, and a poor Healthy Diet Score was associated with increased weight gain. PMID- 23988511 TI - Nutrient profiles of vegetarian and nonvegetarian dietary patterns. AB - BACKGROUND: Differences in nutrient profiles between vegetarian and nonvegetarian dietary patterns reflect nutritional differences that can contribute to the development of disease. OBJECTIVE: Our aim was to compare nutrient intakes between dietary patterns characterized by consumption or exclusion of meat and dairy products. DESIGN: We conducted a cross-sectional study of 71,751 subjects (mean age=59 years) from the Adventist Health Study 2. Data were collected between 2002 and 2007. Participants completed a 204-item validated semi quantitative food frequency questionnaire. Dietary patterns compared were nonvegetarian, semi-vegetarian, pesco vegetarian, lacto-ovo vegetarian, and strict vegetarian. Analysis of covariance was used to analyze differences in nutrient intakes by dietary patterns and was adjusted for age, sex, and race. Body mass index and other relevant demographic data were reported and compared by dietary pattern using chi(2) tests and analysis of variance. RESULTS: Many nutrient intakes varied significantly between dietary patterns. Nonvegetarians had the lowest intakes of plant proteins, fiber, beta carotene, and magnesium compared with those following vegetarian dietary patterns, and the highest intakes of saturated, trans, arachidonic, and docosahexaenoic fatty acids. The lower tails of some nutrient distributions in strict vegetarians suggested inadequate intakes by a portion of the subjects. Energy intake was similar among dietary patterns at close to 2,000 kcal/day, with the exception of semi vegetarians, who had an intake of 1,707 kcal/day. Mean body mass index was highest in nonvegetarians (mean=28.7 [standard deviation=6.4]) and lowest in strict vegetarians (mean=24.0 [standard deviation=4.8]). CONCLUSIONS: Nutrient profiles varied markedly among dietary patterns that were defined by meat and dairy intakes. These differences are of interest in the etiology of obesity and chronic diseases. PMID- 23988513 TI - The public health journey: the meaning and the moment. AB - The public health journey is a remarkable one, filled with twists and turns as well as risks and rewards. Because promoting the health of others represents a mission brimming with meaning, our professional work is also profoundly personal. At this extraordinary moment in our nation's public health history, I reflect on the purpose of the journey and comment on the opportunities before us to become a healthier nation in the future. PMID- 23988514 TI - Results of laparoscopic colorectal surgery from a national training center. AB - BACKGROUND/PURPOSE: Trials have shown laparoscopic colorectal surgery to be safe. We aim to analyze the long-term results from a single national training center for laparoscopic surgery, especially in patients with high predicted mortality scores as well as in octogenarians. We also aim to explore the trend in the length of the learning curve among consultants and colorectal trainees, and determine whether or not laparoscopic colorectal surgery is amenable to surgical training. METHODS: All patients between July 2003 and July 2011 having laparoscopic colorectal surgery were included in a prospectively maintained database and analyzed retrospectively. We collected operative data (operation time, conversion), postoperative 30-day morbidity/mortality, cancer survival (including local/distant recurrences), postoperative incisional/port site hernia rates, and rates of reoperation. RESULTS: A total of 508 patients (258 males and 250 females) were enrolled in the study. The mean age of patients was 65.5 years and median body mass index (BMI) 27 kg/m(2); 70% of cases were malignant. Conversion rate was 15%, mean operation time was 175 minutes, and mean blood loss was 220 mL. The mean postoperative length of stay was 5.8 days, 30-day morbidity 23% (leak rate 1.38%), and 30-day mortality 1.57%. Operating time and conversion rates were significantly lower in right-sided resections compared to left-sided and rectal resections, and lymph node retrieval was significantly higher. Readmission and reoperation rates were 4.9% and 2.8%, respectively. The overall mean follow-up period was 1.8 years, rate of incisional/port site/parastomal hernia was 5.7% (n = 30), and readmission secondary to adhesions was <1% (n = 4). Readmission rates and 30-day surgical morbidity were significantly higher in patients with non-neoplastic disease compared to those with benign or malignant lesions. The mean follow-up period for cancer patients was 2.3 years. Local and distant recurrence rates were 4.2% and 13.2%, respectively. Overall death from cancer was 10.4%. Among the study participants, 74 were octogenarians and 23 had a predicted mortality of >5% (P-Possum tool). No statistically significant increases were observed in conversion, morbidity, or mortality rates in these groups (p > 0.05), but length of stay was statistically longer-7 days for octogenarians and 8 days for patients with >5% predicted mortality (p < 0.05). In 2003, two consultants operated on all cases; currently, twice as many procedures are performed by supervised trainees instead of consultants, with no change in outcome. Operating time was significantly higher in the consultant-led cases, but no other differences were noted in short- or long-term outcomes between consultant- and junior/senior trainee-led cases. CONCLUSION: We conclude that laparoscopic colorectal surgery should be the standard treatment option offered to all patients regardless of age and comorbidities and it is amenable to training. PMID- 23988515 TI - Leukotriene B4, an endogenous stimulator of the innate immune response against pathogens. AB - Leukotriene B4 (LTB4) is an endogenous lipid mediator of inflammation derived from arachidonic acid by the sequential action of cytosolic phospholipase A2 and 5-lipoxygenase. This mediator was initially recognized for its involvement in the recruitment of neutrophils. However, in the last decade, LTB4 has been clearly demonstrated to play a significant role in the control of microbial infections through its ability to activate host innate defenses. In this review, we will focus on the modulator effects of LTB4 on the innate defenses and discuss its therapeutic potential against viral pathogens. PMID- 23988516 TI - Pulmonary hemorrhage due to pulmonary venous occlusion after radiofrequency catheter ablation for atrial fibrillation. PMID- 23988517 TI - Structure and magnetism in Fe/FexPd1-x core/shell nanoparticles formed by alloying in Pd-embedded Fe nanoparticles. AB - We have investigated atomic structure and magnetism in Fe nanoparticles with a diameter of 2 nm embedded in a Pd matrix. The samples for these studies were prepared directly from the gas phase by co-deposition, using a gas aggregation source and an MBE-type source for the Fe nanoparticles and Pd matrix respectively. Extended absorption fine structure (EXAFS) measurements indicate that there is an appreciable degree of alloying at the nanoparticle/matrix interface; at dilute nanoparticle concentrations, more than half of the Fe atoms are alloyed with Pd. This leads to a core/shell structure in the embedded nanoparticles, with an FexPd1-x shell surrounding a reduced pure Fe core. Magnetism in the nanocomposite samples was probed by means of magnetometry measurements, which were interpreted in the light of their atomic structure. These point to a magnetized cloud of Pd atoms surrounding the embedded nanoparticles which is significantly larger than around single Fe atoms in Pd. The coercivities in the Fe/Pd nanocomposite samples are larger than in FexPd1-x atomic alloys of corresponding composition, which is consistent with exchange coupling between the magnetically harder and softer regions in the nanocomposite samples. PMID- 23988519 TI - Ground night nesting in chimpanzees: new insights from central chimpanzees (Pan troglodytes troglodytes) in South-East Cameroon. AB - Some chimpanzee populations exhibit ground night nesting, which occurs in different habitat types, is driven by a variety of interconnected factors, and may reflect cultural or social differences. This has important implications for ape conservation management, given that accurate nest builder identification is required to estimate density, crucial in monitoring, and allows inferences about environmental and social factors that may have contributed to the transition from tree to ground sleeping in early hominins. We conducted a 24-month marked nest count survey in La Belgique, Cameroon, and recorded the occurrence of chimpanzee tree and ground night nests, temperature and rainfall, predator and large mammal abundance, human activities, nesting tree species, and Uapaca spp. consumption. Ground night nesting occurred at a rate of 3.47% (n = 1,008), with more in swamps, in the dry season and with increasing human activities. We found no influence of leopard/elephant presence, but a possible influence of lack of nesting trees. We suggest chimpanzees visit swamps in the dry season (low water levels) for relief from hunting pressure and to consume Uapaca spp. fruits. Ground nesting may be enabled due to high abundance of terrestrial herbaceous vegetation, and may be favoured for inconspicuousness and safety from gun hunters. PMID- 23988518 TI - Developing top down proteomics to maximize proteome and sequence coverage from cells and tissues. AB - Mass spectrometry based proteomics generally seeks to identify and characterize protein molecules with high accuracy and throughput. Recent speed and quality improvements to the independent steps of integrated platforms have removed many limitations to the robust implementation of top down proteomics (TDP) for proteins below 70 kDa. Improved intact protein separations coupled to high performance instruments have increased the quality and number of protein and proteoform identifications. To date, TDP applications have shown >1000 protein identifications, expanding to an average of ~3-4 more proteoforms for each protein detected. In the near future, increased fractionation power, new mass spectrometers and improvements in proteoform scoring will combine to accelerate the application and impact of TDP to this century's biomedical problems. PMID- 23988520 TI - Mice lacking inducible nitric oxide synthase develop exacerbated hepatic inflammatory responses induced by Plasmodium berghei NK65 infection. AB - Infection of mice with Plasmodium berghei NK65 represents a well-recognized malaria model in which infection is accompanied by an intense hepatic inflammatory response. Enzyme-inducible nitric oxide synthase is an important regulator of inflammation and leukocyte recruitment in microvessels, but these functions have yet to be evaluated in experimental malaria. In this study, we assessed the involvement of inducible nitric oxide synthase in inflammatory responses to murine experimental malaria induced by P. berghei NK65. We observed that wild type (WT) and nitric oxide synthase (iNOS)-deficient mice (iNOS(-/-)) mice showed similar levels of parasitemia following P. berghei NK65 infection, although infected iNOS(-/-) mice presented early mortality. Inducible nitric oxide synthase deficiency led to increased leukocyte rolling and adhesion to the liver in iNOS(-/-) mice relative to the WT animals, as observed via intravital microscopy. Infected iNOS(-/-) mice also exhibited increased hepatic leukocyte migration and subsequent liver damage, which was associated with high serum levels of the cytokines TNF-alpha, IL-6 and IL-10. Our data suggest potential role for the iNOS enzyme as a regulator of hepatic inflammatory response induced by P. berghei NK65-infection, and its absence leads to exacerbated inflammation and sequential associated-hepatic damage in the animals. PMID- 23988521 TI - Improvement of methane generation capacity by aerobic pre-treatment of organic waste with a cellulolytic Trichoderma viride culture. AB - Trichoderma viride is known as a potent cellulose decomposer and was successfully used to improve and accelerate the decomposition process of aerobic composting. In contrast, the role of fungi as pre-treatment organisms for anaerobic digestion is not clear, since the fast aerobic decomposition is thought to be responsible for a rapid depletion of easily available nutrients, leading to a lack of these for the anaerobic community. In the present study carried out in lab-scale, the application of T. viride for the aerobic pre-incubation of organic matter derived from the inlet port of a 750,000 L anaerobic digester led to an increase in total gas and methane production in a subsequent anaerobic digestion step. A high cellulase activity caused by the addition of T. viride seemed to be responsible for a better nutrient availability for anaerobic microorganisms. Therefore, aerobic pre-incubation of organic residues with T. viride for subsequent anaerobic digestion is a promising approach in order to increase methane yields. PMID- 23988522 TI - Identification of minuscule inward currents as precursors to membrane electroporation-induced currents: real-time prediction of pore appearance. AB - BACKGROUND/AIMS: The objective of this study is to examine the current signals in response to large hyperpolarizations with the aid of principal component analysis (PCA) to search for or even predict current fluctuations related to membrane electroporation-induced current (I(MEP)). METHODS: The characteristics of principal eigenvalues generated for I(MEP) and the current signals at 10 sec prior to the start of initial I(MEP) (I(Pre)) were examined. As membrane hyperpolarizations were applied at 0.1 Hz, the appearance of I(MEP) coincided with the higher principal eigenvalues extracted in PCA. RESULTS: Subsequent addition of LaCl3 (100 uM) greatly reduced I(MEP) and associated principal eigenvalues. In real-time analysis for a single frame (i.e, 300 msec), in response to large hyperpolarization, multiple runs of heralded minuscule inward currents (Imin) occurring before large rise in current amplitudes were detected. With PCA, such heralded Imin was noted to coincide with the extreme principal eigenvalues. The duration of Imin together with large principal eigenvalues was influenced by different levels of membrane hyperpolarization. In GH3 cells, palmitoyl-L-carnitine (PALCAR), a long-chain acylcarnitine, effectively increased the I(MEP) amplitude with an EC50 value of 2.4 uM. However, in PALCAR-treated cells, the Imin together with higher principal eigenvalues disappeared, while in isoflurane-treated cells, Imin occurring before large rise of current amplitude remained intact. Similarly, the PCA analysis from I(Pre) in RAW 264.6 macrophages showed the presence of herald Imin accompanied by the extreme principal eigenvalues. CONCLUSION: It is clear from this study that these large principal eigenvalues are representative of MEP-associated formation of electropores. Therefore, different compositions around the surface membrane of cells may alter the appearance of Imin followed by I(MEP) emergence. PMID- 23988523 TI - Current opinion: mean platelet volume is one of the most important parameters at the first glance. PMID- 23988524 TI - Ground and excited states of the diatomic dianion Cl2(2-). AB - The QCISD(T)/aug-cc-pVQZ and CIS/aug-cc-pVQZ calculations have been carried out to obtain potential energy curves (PECs) of the Cl2(2-) diatomic dianion in order to address possibility of its formation in the merged beam fragmentation of Cl2( ) questioned based on the observation of the Cl(-)+Cl+e(-) channel. Results show that two of the excited states, namely A(1)Sigmag and a(3)Sigmag are metastable with PECs having wells deep enough to suite several bound states, with minima located at Re=2.8280 A and Re=2.5972 A, and Coulomb barriers of 1648.288 and 1403.835 cm(-1) heights located at 4.0320 and 3.6130 A, respectively. Transition probabilities and tunneling predissociation lifetimes corresponding to these metastable states are also calculated and analyzed. Ground state X(1)Sigmag and excited states B(1)Sigmau, C(1)Pig and D(1)Piu calculated for this dianion are all repulsive. Calculated Franck-Condon factors suggest that Cl2(2-) can be produced in its excited states via an electron impact process initiating from the ground states of Cl2 and Cl2(-) . PMID- 23988525 TI - Spectroscopic, microscopic and catalytic properties of silver nanoparticles synthesized using Saraca indica flower. AB - The bioprospective field is dynamic area of research in the recent years. The present article reports a green synthetic route for the production of highly stable, bio-inspired silver nanoparticles using dried Saraca indica flower. The method is facile, cost effective, simple and reproducible. The reduction of silver ions and the formation of silver nanoparticles has been monitored using UV visible spectroscopy. The TEM, SAED and XRD result reveal that the silver nanoparticles are crystalline in nature. FTIR spectra are used to identify the biomolecules that bind on the surface of silver nanoparticles, which increased the stability of the particles. S. indica flower extract plays its role as an excellent reducing agent of silver ions and the biosynthesized silver nanoparticles are safer to environment. Also the size dependent catalytic activity of silver nanoparticles in the reduction of cationic dye, Methylene blue by NaBH4 is studied by UV-visible spectroscopy. The efficiency of synthesized nanoparticles as an excellent catalyst is proved by the reduction of Methylene blue which is confirmed by the decrease in the absorbance with time and is attributed to electron relay effect. PMID- 23988526 TI - Accurate calculations on 9 Lambda-S and 28 Omega states of NSe radical in the gas phase: potential energy curves, spectroscopic parameters and spin-orbit couplings. AB - The potential energy curves (PECs) of 28 Omega states generated from 9 Lambda-S states (X(2)Pi, 1(4)Pi, 1(6)Pi, 1(2)Sigma(+), 1(4)Sigma(+), 1(6)Sigma(+), 1(4)Sigma(-), 2(4)Pi and 1(4)Delta) are studied for the first time using an ab initio quantum chemical method. All the 9 Lambda-S states correlate to the first two dissociation limits, N((4)Su)+Se((3)Pg) and N((4)Su)+Se((3)Dg), of NSe radical. Of these Lambda-S states, the 1(6)Sigma(+), 1(4)Sigma(+), 1(6)Pi, 2(4)Pi and 1(4)Delta are found to be rather weakly bound states. The 1(2)Sigma(+) is found to be unstable and has double wells. And the 1(6)Sigma(+), 1(4)Sigma(+), 1(4)Pi and 1(6)Pi are found to be the inverted ones with the SO coupling included. The PEC calculations are made by the complete active space self consistent field method, which is followed by the internally contracted multireference configuration interaction approach with the Davidson modification. The spin-orbit coupling is accounted for by the state interaction approach with the Breit-Pauli Hamiltonian. The convergence of the present calculations is discussed with respect to the basis set and the level of theory. Core-valence correlation corrections are included with a cc-pCVTZ basis set. Scalar relativistic corrections are calculated by the third-order Douglas-Kroll Hamiltonian approximation at the level of a cc-pV5Z basis set. All the PECs are extrapolated to the complete basis set limit. The variation with internuclear separation of spin-orbit coupling constants is discussed in brief for some Lambda S states with one shallow well on each PEC. The spectroscopic parameters of 9 Lambda-S and 28 Omega states are determined by fitting the first ten vibrational levels whenever available, which are calculated by solving the rovibrational Schrodinger equation with Numerov's method. The splitting energy in the X(2)Pi Lambda-S state is determined to be about 864.92 cm(-1), which agrees favorably with the measurements of 891.80 cm(-1). Moreover, other spectroscopic parameters of Lambda-S and Omega states involved here are also in fair agreement with available measurements. It demonstrates that the spectroscopic parameters reported here can be expected to be reliable predicted ones. PMID- 23988527 TI - Synthesis, spectroscopic characterization and antimicrobial activity of binuclear metal complexes of a new asymmetrical Schiff base ligand: DNA binding affinity of copper(II) complexes. AB - The 1:1 condensation of o-acetoacetylphenol and 1,2-diaminopropane under condition of high dilution gives the mono-condensed Schiff base, (E)-3-(1 aminopropan-2-ylimino)-1-(2-hydroxyphenyl)butan-1-one. The mono-condensed Schiff base has been used for further condensation with isatin to obtain the new asymmetrical dicompartmental Schiff base ligand, (E)-3-(2-((E)-4-(2 hydroxyphenyl)-4-oxobutan-2-ylideneamino) propylimino)indolin-2-one (H3L) with a N2O3 donor set. Reactions of the ligand with metal salts give a series of new binuclear complexes. The ligand and its metal complexes were characterized by elemental analyses, IR, (1)H and (13)C NMR, electronic, ESR and mass spectra, conductivity and magnetic susceptibility measurements as well as thermal analyses. The analytical and spectroscopic tools showed that the complexes can be formulated as: [(HL)(VO)2(SO4)(H2O)].4H2O, [(HL)Fe2Cl4(H2O)3].EtOH, [(HL)Fe2(ox)Cl2(H2O)3].2H2O, [(L)M2(OAc)(H2O)m].nH2O; M=Co, Ni or Cu, m=4, 0 and n=2, 3, [(HL)Cu2Cl]Cl.6H2O and [(L)(UO2)2(OAc)(H2O)3].6H2O. The metal complexes exhibited octahedral geometrical arrangements except copper complexes that exhibited tetrahedral geometries and uranyl complex in which the metal ion is octa-coordinated. The Schiff base and its metal complexes were evaluated for antimicrobial activity against Gram positive bacteria (Staphylococcus aureus), Gram negative bacteria (Escherichia coli) and fungi (Candida albicans and Aspergillus flavus). The ligand and some of its complexes were found to be biologically active. The DNA-binding properties of the copper complexes (6 and 7) have been investigated by electronic absorption, fluorescence and viscosity measurements. The results obtained indicate that these complexes bind to DNA via an intercalation binding mode with an intrinsic binding constant, Kb of 1.34*10(4) and 2.5*10(4) M(-1), respectively. PMID- 23988528 TI - Synthesis, spectral and electrochemical studies of binuclear Ru(III) complexes containing dithiosemicarbazone ligand. AB - Synthesis of several new octahedral binuclear ruthenium(III) complexes of the general composition [(EPh3)2(X)Ru-L-Ru(X)(EPh3)2] containing benzene dithiosemicarbazone ligands (where E=P or As; X=Cl or Br; L=binucleating ligands) is presented. All the complexes have been fully characterized by elemental analysis, FT-IR, UV-vis and EPR spectroscopy together with magnetic susceptibility measurements. IR study shows that the dithiosemicarbazone ligands behave as dianionic tridentate ligands coordinating through the oxygen atom of the deprotonated phenolic group, nitrogen atom of the azomethine group and thiolate sulphur. In DMF solution, all the complexes exhibit intense d-d transition and ligand-to-metal charge transfer (LMCT) transition in the visible region. The magnetic moment values of the complexes are in the range 1.78-1.82 BM, which reveals the presence of one unpaired electron on each metal ion. The EPR spectra of the liquid samples at LNT show the presence of three different 'g' values (gx?gy?gz) indicate a rhombic distortion around the ruthenium ion. All the complexes exhibit two quasi-reversible one electron oxidation responses (Ru(III) Ru(III)/Ru(III)-Ru(IV); Ru(III)-Ru(IV)/Ru(IV)-Ru(IV)) within the E1/2 range of 0.61-0.74 V and 0.93-0.98 V respectively, versus Ag/AgCl. PMID- 23988529 TI - Experimental and DFT studies on the vibrational and electronic spectra of 2-(1H Imidazo [4,5-f][1,10]phenanthrolin-2-yl)phenol. AB - The compound 2-(1H-Imidazo [4,5-f][1,10] phenanthrolin-2-yl) phenol (IPP) was synthesized, followed by structure determination by X-ray diffraction, the results of which agree well with the calculated optimized, lowest energy geometrical structure. Vibrational information was obtained by FT-IR and Raman spectroscopy which also agree well with calculations (of harmonic vibration frequencies). The calculations were carried out with density functional theory B3LYP methods using 6-311G(**) and LANL2DZ basis sets. Absorption UV-Vis experiments of IPP in CH3OH solution reveal three maximum peaks at 237.0, 274.0 and 335.0 nm, which are in agreement with calculated electronic transitions using TD-B3LYP/6-311G(**) in CH3OH solution, and agree to a lesser extent with gas phase calculations. PMID- 23988530 TI - Optical properties of unsymmetrical azomethines with one imine bonds. AB - We have explored the photoluminescence (PL) and electronic properties, that is, orbital energies and resulting energy gap calculated theoretically by density functional theory (DFT) of four unsymmetrical (UAz1-UAz4) azomethines. All of the investigated compounds exhibited mesomorphic behavior. The photoluminescence studies have shown that molecular structure of the imines influenced both the PL properties and HOMO-LUMO levels of azomethines. Azomethines emitted violet, blue or green light. The effect of excitation wavelength and concentration on the PL properties has been detected as well. Unsymmetrical imine UAz3 posses carbazole unit exhibited lower both HOMO and LUMO energies compare to others investigated azomethines. Additionally, azomethines were investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Two unsymmetrical imines (UAz2 and UAz3) exhibited irreversible oxidation behavior. The HOMO level of the compound with ethylcarbazole (UAz2) moiety was observed at -5.22 eV, while for the UAz3 with phenoxybiphenyl unit was found at -5.64 eV. The data obtained by theoretical calculation using DFT method was very similar to the results obtained by electrochemical measurements. PMID- 23988531 TI - A Raman spectroscopic comparison of calcite and dolomite. AB - Raman spectroscopy was used to characterize and differentiate the two minerals calcite and dolomite and the bands related to the mineral structure. The (CO3)(2 ) group is characterized by four prominent Raman vibrational modes: (a) the symmetric stretching, (b) the asymmetric deformation, (c) asymmetric stretching and (d) symmetric deformation. These vibrational modes of the calcite and dolomite were observed at 1440, 1088, 715 and 278 cm(-1). The significant differences between the minerals calcite and dolomite are observed by Raman spectroscopy. Calcite shows the typical bands observed at 1361, 1047, 715 and 157 cm(-1), and the special bands at 1393, 1098, 1069, 1019, 299, 258 and 176 cm(-1) for dolomite are observed. The difference is explained on the basis of the structure variation of the two minerals. Calcite has a trigonal structure with two molecules per unit cell, and dolomite has a hexagonal structure. This is more likely to cause the splitting and distorting of the carbonate groups. Another cause for the difference is the cation substituting for Mg in the dolomite mineral. PMID- 23988532 TI - Exploring the site-selective binding of jatrorrhizine to human serum albumin: spectroscopic and molecular modeling approaches. AB - This paper exploring the site-selective binding of jatrorrhizine to human serum albumin (HSA) under physiological conditions (pH=7.4). The investigation was carried out using fluorescence spectroscopy, UV-vis spectroscopy, and molecular modeling. The results of fluorescence quenching and UV-vis absorption spectra experiments indicated the formation of the complex of HSA-jatrorrhizine. Binding parameters calculating from Stern-Volmer method and Scatchard method were calculated at 298, 304 and 310 K, with the corresponding thermodynamic parameters DeltaG, DeltaH and DeltaS as well. Binding parameters calculating from Stern Volmer method and Scatchard method showed that jatrorrhizine bind to HSA with the binding affinities of the order 10(4) L mol(-1). The thermodynamic parameters studies revealed that the binding was characterized by negative enthalpy and positive entropy changes and the electrostatic interactions play a major role for jatrorrhizine-HSA association. Site marker competitive displacement experiments and molecular modeling calculation demonstrating that jatrorrhizine is mainly located within the hydrophobic pocket of the subdomain IIIA of HSA. Furthermore, the synchronous fluorescence spectra suggested that the association between jatrorrhizine and HSA changed molecular conformation of HSA. PMID- 23988533 TI - A new resonance Rayleigh scattering spectral method for determination of O3 with victoria blue B. AB - Ozone (O3) could be absorbed by boric acid-potassium iodide (BKI) absorbent solution to produce tri-iodine ion (I3(-)) that react with victoria blue B (VBB) to form the associated particle (VBB-I3)n and exhibited a strong resonance Rayleigh scattering (RRS) peak at 722 nm. Under the chosen conditions, the RRS peak intensity was linear with O3 concentration in the range of 0.2-50 MUmol/L, with a linear regression equation of DeltaI722=17.9c-45.4 and detection limit of 0.057 MUmol/L. Accordingly, a simple, rapid and sensitive RRS spectral method was set up for determination of trace O3 in air, with satisfactory results. PMID- 23988534 TI - Four coordinate tin complexes: synthesis, characterization, thermodynamic and theoretical calculations. AB - In this work, two new Sn(IV) complexes, [SnL(x)]Cl2 where (L(x))(2-) is the deprotonated form of 5-A-salabza-H2=N,N'-bis(salicylidene)-2-aminobenzylamine and A=5-OMe, 5-H, 5-NO2, 5-Br, were synthesized and fully characterized by UV-Vis, FT IR, (1)H NMR, (13)C NMR, (119)Sn NMR spectroscopies, mass spectrometry and elemental analysis. The thermodynamic formation constants of the complexes were determined spectrophotometrically at 25 degrees C in acetonitrile. The trend of formation constants of the complexes are as: 5-OMe>5-H>5-NO2>5-Br and Ph2SnCl2>Me2SnCl2>n-Bu2SnCl2. DFT/B3LYP molecular orbital calculations were carried out for the 5-H substituent isomer, [SnL(2)](2+), in an attempt to explain the structure of complexes. The optimized resulting geometries, vibrational frequencies and the NMR resonances of the complexes are discussed. PMID- 23988535 TI - Effect of donor (tetradecyloxy) and acceptor (carboxamide) groups in trans stilbene for DSSCs: quantum chemical investigations. AB - Incorporation of tetradecyloxy and carboxamide groups in trans-stilbene molecule (dye) has been investigated first time for Dye Sensitized Solar Cells (DSSCs) applications. To understand the changes in electronic structure, geometry, dipole moment and polarizability of the mentioned dye architecture has been carried out by using density functional theory (DFT) and time dependent DFT calculations using hybrid functional B3LYP method. Further, the semiconductor TiO2 is also used as a model to evaluate the photo conversion efficiency of the chosen dye architecture. Results reveal that tetradecyloxy and carboxamide groups act as an excellent donor and acceptor groups respectively which give rise to larger difference in excited state dipole moment than the ground state. This kind of stilbene based metal free organic dyes are act as a promising sensitizer for practical DSSCs applications. PMID- 23988536 TI - Spectral and computational studies in substituted pyrrolyl styryl ketones- assessment of substituent effects. AB - A series of newly synthesized potent bioactive 2-pyrrolyl styryl ketone derivatives were characterized by spectral techniques. The effect of substituent on the absorption maximum, IR stretching frequencies and NMR chemical shifts were investigated. DFT calculations were made to calculate HOMO-LUMO energies and natural bond orbital analysis [NBO]. The electric dipole moment (MU) and the hyperpolarisability (beta) of the investigated molecules have also been studied and found that these synthesized molecules exhibits microscopic non-linear optical (NLO) behavior with non-zero tensor components. PMID- 23988537 TI - Facile synthesis of N-acetyl-L-cysteine capped CdHgSe quantum dots and selective determination of hemoglobin. AB - Using N-acetyl-L-cysteine (NAC) as a stabilizer, well water-dispersed, high quality and stable CdHgSe quantum dots were facilely synthesized via a simple aqueous phase method. The as-prepared NAC capped CdHgSe quantum dots were thoroughly characterized by fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, energy dispersive X-ray spectroscopy and transmission electron microscopy. A novel method for the selective determination of hemoglobin (Hb) was developed based on fluorescence quenching of the NAC capped CdHgSe quantum dots. A number of key factors including pH value of phosphate buffer solution, quantum dots concentration, the adding sequence of reagents and reaction time that influence the analytical performance of the NAC capped CdHgSe quantum dots in Hb determination were investigated. Under the optimal experimental conditions, the change of fluorescence intensity (DeltaI) was linearly proportional to the concentration of Hb in the range of 4.0*10(-9) 4.4*10(-7) mol L(-1) with a detection limit of 2.0*10(-9) mol L(-1). The developed method has been successfully employed to determine Hb in human urine samples. PMID- 23988538 TI - Hypothenar hammer syndrome from ice hockey stick-handling. AB - Ulnar artery thrombosis and hypothenar hammer syndrome are rare vascular complications that could potentially occur with repeated blows or trauma to the hand. Although initially reported as an occupational hazard among laborers and craftsmen, it has been observed more recently among recreationalists and athletes. Until now, it has never been reported as a complication in ice hockey players. In this case report, a 26-year-old Canadian professional ice hockey player presented with acute dominant right hand paleness, coolness, and pain with hand use. The patient used a wooden hockey stick with a large knob of tape at the end of the handle, which he regularly gripped in the palm of his right hand to help with face-offs and general stick-handling. Sonographic evaluation demonstrated no arterial flow in the distal right ulnar artery distribution, and ulnar artery occlusion with no aneurysmal degeneration was confirmed by magnetic resonance angiogram. Intraarterial thrombolytic therapy was initiated, and subsequent serial angiograms demonstrated significant improvement in distal ulnar artery flow as well as recanalization of right hand deep palmar arch and digital arteries. The patient's symptoms resolved, and he was maintained on therapeutic anticoagulation for 3 months prior to returning to playing ice hockey professionally, but with a padded glove and no tape knob at the handle tip. This case highlights a unique presentation of hockey stick-handling causing ulnar artery thrombosis that was likely from repeated palmar hypothenar trauma. Appropriate diagnostic imaging, early intraarterial thrombolysis, and postoperative surveillance and follow-up were crucial for the successful outcome in this patient. PMID- 23988539 TI - Delayed presentations of popliteal artery entrapment syndrome in a middle-aged military population. AB - Popliteal artery entrapment syndrome (PAES) is a rare but significant cause of disability usually diagnosed in young, healthy adults. Advancements in diagnostic imaging modalities have prompted a current report of our recent experience with PAES in a middle-aged military population at the Walter Reed National Military Medical Center. The addition of computed tomographic angiography (CTA) and magnetic resonance angiography (MRA) permit accurate and facile diagnosis of this complex syndrome. PMID- 23988540 TI - External iliac artery fibrosis in endurance athletes successfully treated with bypass grafting. AB - Endofibrosis of the external iliac artery is a rare cause of performance-limiting claudication in elite athletes. We describe a 47-year-old male competitive cyclist and a 52-year-old female former international triathlete, with unilateral and bilateral external artery occlusions, respectively, who presented with disabling claudication and an inability to cycle or run. Due to a long-segment occlusion, both were treated with Dacron bypass grafting. Both were able to return to competitive racing postoperatively. PMID- 23988541 TI - Male breast cancer manifesting as cephalic vein thrombosis. AB - Male breast cancer is an uncommon disease with a low annual prevalence in Western countries. Venous thromboembolism may be associated during malignancy of the breast. We report a 70-year-old man who presented with superficial vein thrombosis of right upper limb that predicted the diagnosis of breast invasive ductal carcinoma. Key issues surrounding the diagnosis, treatment, and relationship between breast cancer and venous disorders are discussed. Breast cancer and venous thromboembolism are 2 conditions that are often correlated more than expected, and attention to the combination of these clinical presentations is required. PMID- 23988542 TI - Retropharyngeal internal carotid artery: a rare presentation with significant clinical implications. AB - A retropharyngeal internal carotid artery is considered a rare anatomic variant with clinical implications. We present a 73-year-old woman with asymptomatic left carotid stenosis, in whom we elected to proceed with medical treatment. An evaluation of her computed tomography angiography scan revealed a retropharyngeal internal carotid artery. This case report outlines this rare entity and highlights its clinical significance. PMID- 23988543 TI - Symptomatic varix of the facial vein. AB - Varices of the facial and neck region are extremely rare, and the most prevalent varices in this region affect the orbital vein. To date, no report on a patent and symptomatic varix of the facial vein has been published, because these varices are particularly rare and most often thrombosed at the time of diagnosis. We present a patient with a prominent patent varix of the right facial vein. After a magnetic resonance imaging scan and duplex ultrasonography, the lesion was treated via surgical exploration, ligation, and complete excision. At 6 months of follow-up, no signs of recurrence were noted. PMID- 23988544 TI - Systematic review on health-related quality of life after revascularization and primary amputation in patients with critical limb ischemia. AB - BACKGROUND: The purpose of this study was to assess the effect of revascularization (bypass surgery, angioplasty) and primary amputation on health related quality of life (QoL) in patients with critical limb ischemia (CLI; resting pain or tissue loss). METHODS: A systematic review of the literature was performed through an electronic search of PubMed (from 1985 to 2012) and Embase (from 1985 to 2012) by two independent investigators to identify English-language articles investigating health-related QoL in regard to CLI. RESULTS: Three observational studies were identified describing a comparison between primary amputation and revascularization and their effects on QoL in patients with CLI, all concluding that revascularization should be attempted. Data pooling was omitted due to the impossibility of combining outcome parameters. A separate analysis of each article is presented. CONCLUSIONS: Patients with CLI have poor health prospects and life expectancy, irrespective of treatment administered. Randomized trials of health-related QoL after revascularization versus primary amputation are nonexistent. Also, the available observational studies do not allow sound conclusions, due to small numbers and methodologic imperfections. Therefore, no recommendations of either therapy in patients with CLI can be made with respect to an anticipated improvement in QoL. PMID- 23988545 TI - One-stage hybrid repair to thoracoabdominal aortic aneurysm. AB - BACKGROUND: Open repair of a thoracoabdominal aortic aneurysm (TAAA) is associated with high rates of morbidity and mortality. This study reviewed the midterm outcomes of hybrid TAAA repair in high-risk patients at our institution. METHODS: The clinical data of patients undergoing 1-stage hybrid repair of a TAAA between June 2007 and June 2011 were retrospectively analyzed. This study represents our experience with 10 patients at a single center who underwent 1 stage visceral hybrid procedures for complex thoracoabdominal aortic pathologies. There were 9 men and 1 woman with a median age of 65.7 years. The average preoperative European System for Cardiac Operative Risk Evaluation II score was 34.1%. RESULTS: The technical success rate with completion was 100%. No procedure was abandoned because of any aortic event. The 30-day mortality rate in this study was 10%. Overall major perioperative complication rates were 20%. Major complications included renal impairment requiring permanent support in 1 patient (10%) and paraplegia in 1 patient (10%). At a median follow-up of 20.1 months (range, 0.3-39 months), the overall survival rate was 70%. The primary graft patency rate was 96.8% (32/33). Only 1 renal artery graft was occluded. CONCLUSIONS: The midterm results in selected high-risk patients with TAAA undergoing 1-stage hybrid repair were encouraging. When open repair is hazardous and branched stent grafting is not an option, hybrid repair is a viable treatment alternative. However, larger study cohorts and longer durations of follow-up are necessary to provide data on the durability of aortic stent grafts and visceral artery reconstruction. PMID- 23988546 TI - Coagulopathy associated with sac reperfusion for reversing paraplegia after endovascular repair of type II thoracoabdominal aneurysm. AB - Sac perfusion may be helpful in preventing or reversing spinal cord injury after endovascular repair of thoracoabdominal aneurysms and it has been used as an adjunct to the standard physiologic measures of sustained hypertension and cerebrospinal fluid drainage. Coagulopathy as a result of endoleak after endovascular aneurysm repair has been reported, and very rare cases of treatment after repair of these endoleaks have been described. We report a 73-year-old man who had endovascular repair of a type II thoracoabdominal aneurysm with a branched stent graft. Sac reperfusion was initiated to manage postoperative paraplegia. The paraplegia partially resolved but severe hemorrhagic complications developed that were attributed to sac perfusion-related hyperfibrinolysis. Discontinuation of sac perfusion resolved the coagulopathy but resulted in paraplegia. PMID- 23988547 TI - Percutaneous femoral vein access for inferior vena cava filter placement does not cause insertion-site thrombosis. AB - BACKGROUND: The efficacy of inferior vena cava (IVC) filters in the prevention of pulmonary embolism in patients with lower extremity deep venous thrombosis (DVT) has been well described. What remains uncertain is the risk of insertion-site thrombosis of the femoral vein after filter placement. Historically, the risk was relatively high, most likely due to large delivery systems and therefore a need for longer compression at the insertion site to provide hemostasis. The purpose of this prospective study was to determine the incidence of thrombus formation at the femoral vein puncture site after percutaneous insertion of contemporary IVC filters. METHODS: From October 2010 to November 2011, 61 consecutive patients underwent placement of an IVC filter by 3 vascular surgeons and 3 interventional radiologists at our tertiary-care Level I trauma center. All filters were inserted through the right or left common femoral vein. Duplex ultrasound studies (DUS) were performed within 24 hours before filter placement and 24-72 hours after filter placement. RESULTS: Fifty-six patients completed the study, including 46 men and 10 women. They ranged in age from 19 to 90 (mean 50) years. Forty-one filters (73%) were placed for prophylaxis: 39 of the patients were trauma victims with immobility and/or contraindications to anticoagulation, 1 had an intracranial hemorrhage with an underlying malignancy, and 1 had very limited mobility. The remaining 15 filters (27%) were placed because of an acute DVT with a contraindication to or a complication from anticoagulation. The filters utilized were: Boston Scientific-Greenfield (n=25); Cook-Celect (n=18); Bard-G2X (n=2); Bard-Eclipse (n=6); and Cordis-TrapEase (n=5). Sheath diameters ranged from 6- to 12-French. None of the 56 patients had thrombus formation at the insertion site on follow-up DUS. CONCLUSIONS: Based on our study findings, the risk of femoral insertion-site thrombosis after percutaneous placement of contemporary IVC filters is negligible. Concern for femoral vein thrombosis should not be a reason for using the internal jugular vein to deploy IVC filters. PMID- 23988548 TI - Stent-assisted coil embolization of a complex wide-neck splenic artery aneurysm. AB - We describe the endovascular treatment of a wide-neck splenic artery aneurysm (SAA) using a stent-assisted coil embolization technique. A 55-year-old woman who was admitted for intermittent epigastric pain was diagnosed with a wide-neck aneurysm of the intermediate splenic artery. The SAA had a maximum diameter of 2.2 cm and originated from a tortuous vessel. After percutaneous access through the left brachial artery, a self-expandable stent was initially deployed across the origin of the aneurysm using a 4-French platform. The aneurysm sac was subsequently filled with coils through a microcatheter. The procedure was successful with no postoperative clinical complications. Patency of splenic artery and complete exclusion of the aneurysm were confirmed by follow-up computed tomographic angiography 1 year after treatment. In challenging anatomic situations, stent-assisted coil embolization may represent a first-choice endovascular treatment option for the exclusion of SAAs. PMID- 23988550 TI - Single-stage repair of a complex type B aortic dissection associated with a pressurized infrarenal abdominal aortic aneurysm. AB - The decision-making involved in managing type 2 aortic dissections remains challenging despite the advances in endovascular technology. We report a challenging case of a patient presenting with a type 2 aortic dissection and false lumen extension into an infrarenal abdominal aortic aneurysm (AAA). Severe back pain and hypertension were the patient's initial complaints, and dynamic magnetic resonance angiography revealed 1-way pulsatile flow into the AAA sac from the false lumen. This patient underwent endovascular repair with a thoracic and infrarenal aortic endograft, successfully excluding the false lumen and decompressing the infrarenal aneursymal sac. This is a unique presentation of total endovascular repair of a symptomatic type B aortic dissection with a pressurized infrarenal AAA sac from false lumen flow into the sac. PMID- 23988549 TI - Increased plasma levels of metalloproteinase-9 and neutrophil gelatinase associated lipocalin in a rare case of multiple artery aneurysm. AB - Matrix metalloproteinase-9 (MMP-9) is involved in the remodeling process by degrading extracellular matrix, which is fundamental in maintaining structural integrity and favorable mechanical properties of the artery vascular wall. Neutrophil gelatinase-associated lipocalin (NGAL) seems to enhance MMP-9 activity. ELISA test was used to evaluate plasma MMP-9 and NGAL values. Moreover, Western blot analysis and RT-PCR were used to evaluate expression of MMP-9 and NGAL in aneurysmatic tissue with respect to healthy endothelial tissue of the same patient. In this rare case of abdominal aortic aneurysm associated with multiple peripheral aneurysms, both plasma and tissue levels of MMP-9 and NGAL seemed to correlate with disease progression. More studies and clinical trials are necessary to confirm our findings. PMID- 23988551 TI - Compressive pancreaticoduodenal artery aneurysm associated with celiac artery stenosis. AB - Peripancreatic artery aneurysms are a rare condition, representing <2% of all splanchnic artery aneurysms, and have been significantly related to celiac axis stenosis. While they are most often asymptomatic, those aneurysms have a strong tendency to rupture (52% rupture rate at the initial presentation) and, in this case, the outcome is often dramatic. Given that reports of this disease are rare, appropriate guidelines are difficult to formulate and different treatment strategies have been proposed. Endovascular management seems to be efficient in the large majority of most recent reports, but open surgery still remains necessary for complex cases, especially when associated with celiac axis stenosis. We report a new occurrence of a symptomatic compressive aneurysm related to common bile duct compression that we treated using a hybrid procedure. PMID- 23988552 TI - Endovascular management of aortoduodenal fistula arising from recurrent mycotic aneurysm in an aortic stump. AB - BACKGROUND: We present a case of successful endovascular exclusion of an aortoduodenal fistula using an endovascular graft iliac plug. This treatment modality of aortoduodenal fistula arising from a recurrent mycotic aortic aneurysm stump has not yet been described in the literature. CASE REPORT: An 80 year-old man underwent emergency repair of a ruptured infrarenal mycotic aortic aneurysm with an axillobifemoral vascular bypass. Four months after the operation, a pseudoaneurysm arising from the aortic stump invaded the third part of the duodenum, forming an aortoduodenal fistula. An endovascular graft iliac plug and a chimney stent were used to achieve endovascular exclusion of the aortoduodenal fistula. CONCLUSION: The management of aortoduodenal fistula arising from recurrent mycotic aortic aneurysm stump with an endovascular graft iliac plug is successful, especially in patients with a previous history of abdominal aortic surgeries. This procedure reduces the mortality and morbidity associated with open surgery. Further validation with a greater number of cases and longer follow-up times would be required to prove that this is a viable definitive treatment modality. PMID- 23988553 TI - Segmental arterial mediolysis: a systematic review of 85 cases. AB - BACKGROUND: Segmental arterial mediolysis (SAM) is a nonatherosclerotic, noninflammatory arteriopathy of unknown etiology with life-threatening manifestations. With advances in endovascular techniques, SAM is increasingly being managed without the need for major surgery. METHODS: A systematic review of the literature published on SAM between 1976 and 2012 was performed, focusing on arterial involvement, diagnostic imaging modalities, mortality and morbidity rates, and in particular treatment outcomes with open versus endovascular intervention. RESULTS: Sixty-two studies reporting on 85 cases of SAM were reviewed. Sixty-nine percent of cases were diagnosed histologically (24% on autopsy). Angiography was the most common form of diagnostic imaging modality (56% of cases). Arterial involvement was largely abdominal or cranial, with splenic arterial involvement being the most prevalent (29% of cases). There was a total SAM-related mortality of 26%. Endovascular intervention, most commonly in the form of coil embolization of aneurysmal vessel(s), was successful in 88% of cases where attempted, with no reported mortality. There was a mortality rate of 9% where open surgery was attempted. CONCLUSIONS: Catheter-based endovascular techniques can be a successful, minimally invasive treatment option in the management of this potentially life-threatening condition, and may also provide a temporary bailout measure in the acute phase before definitive surgical treatment at a later stage. PMID- 23988554 TI - Applicability and mid-term results of endovascular treatment for descending thoracic acute aortic syndromes. AB - BACKGROUND: Descending thoracic acute aortic syndromes (DTAASs) are life threatening pathologies in which thoracic endovascular aortic repair (TEVAR) is an attractive therapeutic option. There are few data in the literature on the survival and morbidity rates of TEVAR in such indications. We provide the results of TEVAR from our single-center cohort of DTAASs: ruptured aneurysms (RAs), acute symptomatic dissections (ADs), and traumatic ruptures (TRs). METHODS: Between 2004 and 2011, data from all patients treated by TEVAR for DTAAS in our university center were collected prospectively. Primary end points were rates of 30-day mortality and morbidity. Secondary end points were mid-term outcomes and reinterventions. RESULTS: Forty-eight patients underwent TEVAR for DTAASs: 19 RAs (39.6%), 12 ADs (25.0%), and 17 TRs (35.4%). The cumulative 30-day mortality and morbidity rate was 33%. There were 10 deaths (6 RAs, 1 AD, and 3 TRs), 2 cases of paraplegia (0 postoperative and 2 preoperative cases (2 TRs), and no major reinterventions and 4 minor reinterventions (embolization for endoleak exclusion). Long-term outcomes were known in 33 patients (5 patients were lost to follow-up), with a mean duration follow-up of 27 months. The cumulative mortality and morbidity rate was 9%: no deaths were reported, and 2 major reinterventions (open aneurysm repair) and 1 minor reintervention (endoleak exclusion) were required. CONCLUSIONS: Our results confirm that TEVAR, as an emergency therapeutic option, is suited to DTAASs. The 21% perioperative mortality rate for such dramatic lesions remains high but is lower than medical or open repair therapeutic options previously reported. No additional deaths occurred during the 2-year follow-up period, and a low incidence of endograft-related reinterventions was observed. Nevertheless, scheduled follow-up visits with computed tomodensitometry scans on a regular basis are mandatory. PMID- 23988555 TI - [Pregnancy management among teenagers under 15 years old: a multidisciplinary challenge]. AB - OBJECTIVE: Pregnancy before 15 years old remains a troublesome issue for medical teams which are not used to working with adolescents. The aim of this work is to study the outcome of the pregnancies among very young adolescents, the psycho social context, the medical management, the professionals involved in it and the follow-up after pregnancy. MATERIALS AND METHODS: Retrospective analysis from four cases, in the university hospital of Rennes, during the year 2011. RESULTS: All the pregnancies were terminated, half of them on a psychological indication. Three adolescents showed evidence of major psychological distress and two of them had a history of sexual abuse. The medical care was heterogeneous, from the first meet until the follow-up after pregnancy, including the medical abortion. A multidisciplinary teamwork was found in three of the four cases. CONCLUSION: Pregnancy before the age of 15 years old is a rare event and often ends with a medical abortion. The medical management of those vulnerable adolescents is complex and requires a multidisciplinary team approach all along the follow-up. A national evaluation of clinical practice in this area seems to be needed. PMID- 23988556 TI - Effect of xanthan gum and guar gum on in situ gelling ophthalmic drug delivery system based on poloxamer-407. AB - The aim of this investigation was to develop a novel in situ gelling formulation based on poloxamer-407 (PM) for the sustained release of an ophthalmic drug. In an attempt to reduce the concentration of PM without compromising the in situ gelling capability and also to increase the drug release time, xanthan gum (XG) and guar gum (GG) were added into PM to develop different formulations. At concentrations of 18% and above, the PM was able to undergo sol-gel transition below body temperature. It was found that XG and GG at a weight ratio of 3:7 were able to convert PM solution into gel below body temperature at PM concentrations below 18%. Both the in vitro and in vivo studies indicated that the PM with an XG GG combination had a better ability to retain the drug than PM itself. The results indicated that the developed in situ gelling formulations containing PM with XG-GG may be a better alternative than a conventional eye drop. PMID- 23988557 TI - Mineralized self-assembled peptides on 3D laser-made scaffolds: a new route toward 'scaffold on scaffold' hard tissue engineering. AB - In this study, we propose a new approach to hard tissue regeneration based on the mineralization of 3D scaffolds made using lasers. To this end, we report the rational design of aspartate-containing self-assembling peptides targeted for calcium binding. We further investigate the suitability of these peptides to support cell attachment and proliferation when coupled on a hybrid organic inorganic structurable material, and evaluate the response of pre-osteoblastic cells on functionalized 3D scaffolds and material surfaces. Our results show that the mineralized peptide, when immobilized on a hybrid photo-structurable material strongly supports cell adhesion, a proliferation increase after three and seven days in culture, and exhibits a statistically significant increase of biomineralization. We propose this strategy as a 'scaffold on scaffold' approach for hard tissue regeneration. PMID- 23988558 TI - Evaluation of the Cryotech Vitrification Kit for bovine embryos. AB - The purpose of this work was to assess commercially available Cryotech Vitrification Kit, in terms of survival, in vitro development and pregnancy rate for bovine embryos. Cumulus-oocyte complexes (COCs) were recovered from ovaries obtained from slaughtered cows and then matured in vitro for 22 h. COCs were fertilized by sex-sorted sperm in IVF-mSOF and cultured in IVC-mSOF for 7 days to the blastocyst stage. Blastocysts were vitrified with the Cryotech Vitrification Kit((r)) and then either warmed to check viability or transferred to synchronized heifers. We observed 100% survival of the in vitro produced blastocysts and obtained the same pregnancy rate (46.8%) as that obtained using fresh in vitro produced blastocysts. We thus conclude that the Cryotech vitrification method is a valid alternative to other vitrification or slow-cooling methods in the bovine species and that it is ready for livestock production. PMID- 23988559 TI - The effects of preservation procedures on antibacterial property of amniotic membrane. AB - Amniotic membrane (AM), the innermost layer of the fetal membranes, has been widely employed in the surgical reconstruction and tissue engineering. Expression of the antimicrobial peptides such as defensins, elafin and SLPI which are essential elements of the innate immune system results in antibacterial properties of the AM. Preservation is necessary to reach a ready-to-use source of the AM. However, these methods might change the properties of the AM. The aim of this study was to evaluate antibacterial properties of the AM after preservation. Antibacterial property of the fresh AM was compared with cryopreserved and freeze dried AM by modified disk diffusion method. Staphylococcus aureus ATCC 25923, Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922 and two clinical isolated strains of E. coli were cultured in Mueller Hinton agar and a piece of the AM was placed on agar surface. After 24h incubation, the inhibition zone was measured. In addition, one of the most important antibacterial peptides, elafin, was measured by ELISA assay before and after preservations procedures. Antibacterial properties of the AM were maintained after cryopreservation and freeze-drying. However, the inhibition zone was depending on the bacterial strains. The cryopreservation and freeze-drying procedures significantly decreased elafin which shows that antibacterial property is not limited to the effects of amniotic cells and the other components such as extracellular matrix may contribute in antibacterial effects. The promising results of this study show that the preserved AM is a proper substitute of the fresh AM to be employed in clinical situations. PMID- 23988560 TI - Phospholipids profile in chloroplasts of Coffea spp. genotypes differing in cold acclimation ability. AB - Environmental temperature change may induce modifications in membrane lipid properties and composition, which account for different physiological responses among plant species. Coffee plants, as many tropical species, are particularly sensitive to cold, but genotypes can present differences that can be exploited to improve crop management and breeding. This work intended to highlight the changes promoted by low non-freezing temperatures (chilling) in phospholipid (PL) composition of chloroplast membranes of genotypes from two Coffea species, Coffea arabica cv. Catuai (moderately tolerant) and Coffea canephora cv. Conilon (Clone 153, more susceptible), and relate them with cold sensitivity differences. Such evaluation was performed considering a gradual temperature decrease, chilling (4 degrees C) exposure and a recovery period under rewarming conditions. Catuai presented an earlier acclimation response than Clone 153 (CL 153). It displayed a higher metabolic activity during acclimation (total fatty acids and total PL increases) and chilling (phosphatidylglycerol increases), and an overall better recovery. Catuai also showed the highest phosphatidylglycerol unsaturation (higher double bond index) after chilling, in contrast with CL 153 (gradual unsaturation decrease). Higher unsaturation degree in Catuai than in CL 153 was also observed for phosphatidylcholine and phosphatidylinositol, resulting, mainly, from raises in unsaturated C18:2 and C18:3. It is suggested that an enhanced PL synthesis and turnover induced by a gradual cold exposure, as well as unsaturation increases in major PL classes, is related to decreased Catuai susceptibility to low temperatures and strongly contributes to sustain photosynthetic activity in this genotype under chilling conditions, as reported in previous work by this team. PMID- 23988561 TI - Proteomic analysis of Arabidopsis thaliana leaves in response to acute boron deficiency and toxicity reveals effects on photosynthesis, carbohydrate metabolism, and protein synthesis. AB - Boron (B) stress (deficiency and toxicity) is common in plants, but as the functions of this essential micronutrient are incompletely understood, so too are the effects of B stress. To investigate mechanisms underlying B stress, we examined protein profiles in leaves of Arabidopsis thaliana plants grown under normal B (30 MUM), compared to plants transferred for 60 and 84 h (i.e., before and after initial visible symptoms) in deficient (0 MUM) or toxic (3 mM) levels of B. B-responsive polypeptides were sequenced by mass spectrometry, following 2D gel electrophoresis, and 1D gels and immunoblotting were used to confirm the B responsiveness of some of these proteins. Fourteen B-responsive proteins were identified, including: 9 chloroplast proteins, 6 proteins of photosynthetic/carbohydrate metabolism (rubisco activase, OEC23, photosystem I reaction center subunit II-1, ATPase delta-subunit, glycolate oxidase, fructose bisphosphate aldolase), 6 stress proteins, and 3 proteins involved in protein synthesis (note that the 14 proteins may fall into multiple categories). Most (8) of the B-responsive proteins decreased under both B deficiency and toxicity; only 3 increased with B stress. Boron stress decreased, or had no effect on, 3 of 4 oxidative stress proteins examined, and did not affect total protein. Hence, our results indicate relatively early specific effects of B stress on chloroplasts and protein synthesis. PMID- 23988562 TI - Expression of the 1-SST and 1-FFT genes and consequent fructan accumulation in Agave tequilana and A. inaequidens is differentially induced by diverse (a)biotic stress related elicitors. AB - The expression of genes coding for sucrose:sucrose 1-fructosyltransferase (1-SST; EC 2.4.1.99) and fructan:fructan 1-fructosyltransferase (1-FFT; EC 2.4.1.100), both fructan biosynthesizing enzymes, characterization by TLC and HPAEC-PAD, as well as the quantification of the fructo-oligosaccharides (FOS) accumulating in response to the exogenous application of sucrose, kinetin (cytokinin) or other plant hormones associated with (a)biotic stress responses were determined in two Agave species grown in vitro, domesticated Agave tequilana var. azul and wild A. inaequidens. It was found that elicitors such as salicylic acid (SA), and jasmonic acid methyl ester (MeJA) had the strongest effect on fructo oligosaccharide (FOS) accumulation. The exogenous application of 1mM SA induced a 36-fold accumulation of FOS of various degrees of polymerization (DP) in stems of A. tequilana. Other treatments, such as 50mM abscisic acid (ABA), 8% Sucrose (Suc), and 1.0 mg L(-1) kinetin (KIN) also led to a significant accumulation of low and high DP FOS in this species. Conversely, treatment with 200 MUM MeJA, which was toxic to A. tequilana, induced an 85-fold accumulation of FOS in the stems of A. inaequidens. Significant FOS accumulation in this species also occurred in response to treatments with 1mM SA, 8% Suc, and 10% polyethylene glycol (PEG). Maximum yields of 13.6 and 8.9 mg FOS per g FW were obtained in stems of A. tequilana and A. inaequidens, respectively. FOS accumulation in the above treatments was tightly associated with increased expression levels of either the 1-FFT or the 1-SST gene in tissues of both Agave species. PMID- 23988563 TI - The spectre of race in American medicine. AB - Controversies and debates surrounding race have long been a fixture in American medicine. In the past, the biological concept of race-the idea that race is biologically determined and meaningful-has served to justify the institution of slavery and the conduct of unethical research trials. Although these days may seem far behind, contemporary debates over the race-specific approval of drugs and the significance of genetic differences are evidence that race still yields tremendous influence on medical research and clinical practice. In many ways, the use of race in medicine today reflects the internalisation of racial hierarchies borne out of the history of slavery and state-mandated segregation, and there is still much uncertainty over its benefits and harms. Although using race in research can help elucidate disparities, the reflexive use of race as a variable runs the risk of reifying the biological concept of race and blinding researchers to important underlying factors such as socioeconomic status. Similarly, in clinical practice, the use of race in assessing a patient's risk of certain conditions (eg, sickle cell) turns harmful when the heuristic becomes a rule. Through selected historical and contemporary examples, I aim to show how the biological concept of race that gave rise to past abuses remains alive and harmful, and propose changes in medical education as a potential solution. By learning from the past, today's physicians will be better armed to discern-and correct-the ways in which contemporary medicine perpetuates historical injustices. PMID- 23988564 TI - Mathematical modeling of the coating process. AB - Coating of tablets is a common unit operation in the pharmaceutical industry. In most cases, the final product must meet strict quality requirements; to meet them, a detailed understanding of the coating process is required. To this end, numerous experiment studies have been performed. However, to acquire a mechanistic understanding, experimental data must be interpreted in the light of mathematical models. In recent years, a combination of analytical modeling and computational simulations enabled deeper insights into the nature of the coating process. This paper presents an overview of modeling and simulation approaches of the coating process, covering various relevant aspects from scale-up considerations to coating mass uniformity investigations and models for drop atomization. The most important analytical and computational concepts are presented and the findings are compared. PMID- 23988565 TI - Microfluidic one-step synthesis of Fe3O4-chitosan composite particles and their applications. AB - This paper demonstrates a simple and easy approach for the one-step synthesis of Fe3O4-chitosan composite particles with tadpole-like shape. The length and diameter of the particles were adjustable from 638.3 MUm to ca. 798 MUm (length), and from 290 MUm to 412 MUm (diameter) by varying the flow rate of the dispersed phase. Mitoxantrone was used as the model drug in the drug release study. The encapsulation rate of the drug was 71% for chitosan particles, and 69% for magnetic iron oxide-chitosan particles, respectively. The iron oxide-chitosan composite particles had a faster release rate (up to 41.6% at the third hour) than the chitosan particles (about 24.6%). These iron oxide-chitosan composite particles are potentially useful for biomedical applications, such as magnetic responsive drug carriers, magnetic resonance imaging (MRI) enhancers, in the future. PMID- 23988566 TI - Management of fractures of the condyle, condylar neck, and coronoid process. AB - Proper anatomic reduction of the fracture and accelerated complete recovery are desirable goals after trauma reconstruction. Over the recent decades, significant headway in craniomaxillofacial trauma care has been achieved and advancements in the management for the injuries of the mandibular condyle have also proved to be no exception. A trend in operative and reconstructive options for proper anatomic reduction and internal fixation has become notable as a result of newly introduced technology, surgical techniques, and operative expertise. PMID- 23988567 TI - Panfacial fractures: an approach to management. AB - Panfacial fractures are defined as fractures involving the lower, middle, and upper face. Treatment can be challenging and requires an individualized treatment plan. A firm understanding of the treatment principles of each individual fracture is necessary before attempting to tackle the patient with panfacial fractures. Advances in rigid fixation, wide exposure, primary bone grafting, and attention to soft tissue reattachment have significantly improved the treatment of the patient with panfacial fractures. PMID- 23988568 TI - Early squamous cell carcinoma of the oral tongue: comparing margins obtained from the glossectomy specimen to margins from the tumor bed. AB - OBJECTIVES: To evaluate the impact of margin sampling on local recurrence in patients with pT1-2 pN0 conventional squamous cell carcinoma of the oral tongue. MATERIALS AND METHODS: Based on margin sampling, 126 cases were divided into group 1 (margins sampled from the glossectomy specimen only), group 2 (with revision of glossectomy margins), and group 3 (margins primarily sampled from the tumor bed). RESULTS: The probability of local progression-free survival at 3years was .90, .76 and .73 (p=.0389) in groups 1, 2, and 3, respectively. Groups differed by frequency of positive glossectomy specimen margins (p=<.0001) and by the average distance from carcinoma to the closest margin (4.5, 2.4, and 3.0mm for Groups 1, 2, and 3, respectively; p=.0009). Tumor bed margin status (positive vs. negative) and other parameters (e.g., pattern and depth of invasion) did not correlate with local recurrence. Status of the glossectomy specimen margins did correlate with outcome. A positive glossectomy margin conferred a relative risk of 2.5 (95% confidence interval, CI, 1 - 6.3) for local recurrence. A proportional hazards regression model for margin width found a hazard ratio of 0.67 (95% CI=.57-.98) comparable to a 33% decrease in risk of local recurrence for an increase of 1mm of margin width (p=.0271). CONCLUSIONS: Status of the glossectomy specimen margins rather than that of tumor bed margins was prognostically relevant. Reliance on tumor bed margins appears to be associated with worse local control, perhaps due to the narrower initial resection. PMID- 23988571 TI - Alveolar epithelial cells: master regulators of lung homeostasis. AB - The lung interfaces with the environment across a continuous epithelium composed of various cell types along the proximal and distal airways. At the alveolar structure level, the epithelium, which is composed of type I and type II alveolar epithelial cells, represents a critical component of lung homeostasis. Indeed, its fundamental role is to provide an extensive surface for gas exchange. Additional functions that act to preserve the capacity for such unique gas transfer have been progressively identified. The alveolar epithelium represents a physical barrier that protects from environmental insults by segregating inhaled foreign agents and regulating water and ions transport, thereby contributing to the maintenance of alveolar surface fluid balance. The homeostatic role of alveolar epithelium relies on the regulated/controlled production of the pulmonary surfactant, which is not only a key determinant of alveolar mechanical stability but also a complex structure that participates in the cross-talk between local cells and the lung immune and inflammatory response. In regard to these critical functions, a major point is the maintenance of alveolar surface integrity, which relies on the renewal capacity of type II alveolar epithelial cells, and the contribution of progenitor populations within the lung. PMID- 23988569 TI - Study of functional infrared imaging for early detection of mucositis in locally advanced head and neck cancer treated with chemoradiotherapy. AB - BACKGROUND AND PURPOSE: Chemoradiotherapy (CRT) has led to improved efficacy in treating locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) but has led to almost universal in-field mucositis. Patients treated with the same regimen often have differences in mucositis occurrence and severity. Mucositis induced via radiation is known to represent an intense inflammatory response histologically. We hypothesized that patients destined to display severe mucocutaneous toxicity would demonstrate greater alterations in thermal intensity early in therapy than identically treated counterparts. This will allow identification of patients that will require more intensive supportive care using thermal imaging technology. MATERIALS AND METHODS: Subjects with LA-SCCHN (oral cavity or oropharynx) being treated with the identical chemoradiotherapy regimen underwent baseline and weekly thermal imaging. Changes in skin temperature caused by mucositis and dermatitis compared with a reference area (DeltaT were calculated and correlated to grade of mucositis based on NCI-CTCAE 3.0. RESULTS: Thirty-four subjects were enrolled. Grade 3 mucositis and dermatitis was observed in 53% and 21%, respectively. We observed a statistically significant positive association between an early rise in DeltaT and mucositis grade (p value=0.03). CONCLUSIONS: Thermal imaging is able to detect small and early changes in skin surface temperature that may be associated with development of mucositis in patients being treated with chemoradiotherapy. PMID- 23988570 TI - Dicarbonyl/l-xylulose reductase (DCXR): The multifunctional pentosuria enzyme. AB - Dicarbonyl/L-xylulose reductase (DCXR) is a highly conserved and phylogenetically widespread enzyme converting L-xylulose into xylitol. It also reduces highly reactive alpha-dicarbonyl compounds, thus performing a dual role in carbohydrate metabolism and detoxification. Enzymatic properties of DCXR from yeast, fungi and mammalian tissue extracts are extensively studied. Deficiency of the DCXR gene causes a human clinical condition called pentosuria and low DCXR activity is implicated in age-related diseases including cancers, diabetes, and human male infertility. While mice provide a model to study clinical condition of these diseases, it is necessary to adopt a physiologically tractable model in which genetic manipulations can be readily achieved to allow the fast genetic analysis of an enzyme with multiple biological roles. Caenorhabditis elegans has been successfully utilized as a model to study DCXR. Here, we discuss the biochemical properties and significance of DCXR activity in various human diseases, and the utility of C. elegans as a research platform to investigate the molecular and cellular mechanism of the DCXR biology. PMID- 23988572 TI - Concentration- and thickness-dependent magnetic properties of NixMn100-x in epitaxially grown NixMn100-x/Ni/(Co/)Cu3Au(001). AB - Magnetic proximity effects in single-crystalline NixMn100-x/Ni(/Co) bilayers on Cu3Au(001) are investigated for in-plane (IP) and out-of-plane (OoP) magnetization by means of the longitudinal and polar magneto-optical Kerr effect. Attention is paid to the influence on concentration- and thickness-dependent antiferromagnetic ordering (TAFM) and blocking (Tb) temperatures as well as the exchange bias field (Heb). For all the NixMn100-x films under study in contact with IP Ni, increasing TAFM is observed with decreasing Ni concentration from ~50 to ~20%, whereas only a slight change in TAFM is observed for the OoP case. Between ~28% and ~35% Ni concentration, a crossover temperature exists below which TAFM for the IP samples is higher than for the OoP samples and vice versa. Tb is higher for the IP case than for OoP, except for an equi-atomic NiMn film, while Heb increases significantly for both magnetization directions with decreasing x. These results are attributed to: (i) a rotation of the non collinear 3Q-like spin structure of NixMn100-x from the more-OoP to the more-IP direction for decreasing Ni concentration x, along with an associated increased magnetic anisotropy, and (ii) a smaller domain wall width within the NixMn100-x films at smaller x, leading to a smaller thickness required to establish exchange bias at a fixed temperature. PMID- 23988573 TI - Genome-wide transcriptional analysis of Drosophila larvae infected by entomopathogenic nematodes shows involvement of complement, recognition and extracellular matrix proteins. AB - Heterorhabditis bacteriophora is an entomopathogenic nematode (EPN) which infects its host by accessing the hemolymph where it releases endosymbiotic bacteria of the species Photorhabdus luminescens. We performed a genome-wide transcriptional analysis of the Drosophila response to EPN infection at the time point at which the nematodes reached the hemolymph either via the cuticle or the gut and the bacteria had started to multiply. Many of the most strongly induced genes have been implicated in immune responses in other infection models. Mapping of the complete set of differentially regulated genes showed the hallmarks of a wound response, but also identified a large fraction of EPN-specific transcripts. Several genes identified by transcriptome profiling or their homologues play protective roles during nematode infections. Genes that positively contribute to controlling nematobacterial infections encode: a homolog of thioester-containing complement protein 3, a basement membrane component (glutactin), a recognition protein (GNBP-like 3) and possibly several small peptides. Of note is that several of these genes have not previously been implicated in immune responses. PMID- 23988574 TI - Effects of indocyanine green staining on the recovery of visual acuity and macular morphology after macular hole surgery. AB - PURPOSE: To evaluate whether indocyanine green (ICG)-assisted internal limiting membrane peeling affects visual outcome and macular morphologic changes in spectral-domain optical coherence tomography images after macular hole (MH) surgery. METHODS: A retrospective analysis was performed of 34 eyes in 34 patients who had undergone surgical treatment for MH. Best-corrected visual acuity (BCVA) and optical coherence tomography parameters including central foveal thickness, length of the external limiting membrane (ELM) defect, and length of the inner segment and outer segment (IS/OS) defect were analyzed pre- and postoperatively. RESULTS: The eyes were divided into 2 groups based on ICG use (ICG+/-). The changes in BCVA did not differ significantly between the 2 groups at 6 months. However, the ICG+ group had poorer changes compared with the ICG- group at 1 and 3 months (p = 0.038, p = 0.012, respectively). Central foveal thickness and ELM defect did not differ between the 2 groups at each period. The IS/OS defect in the ICG+ group was significantly greater at 1 and 3 months than that in the ICG- group (p = 0.026, p = 0.048, respectively). CONCLUSIONS: ICG staining may affect the recovery process of macular morphology and visual acuity in the first several months after MH surgery. PMID- 23988575 TI - Photo-Fenton effect of 4-chlorophenol in ice. AB - The photoconversion of 4-chlorophenol (4-CP) in a simulated sunlight-Fenton system was investigated in ice and aqueous solution. It was found that the hydroxyl radical (OH) had an important effect on the photoconversion of 4-CP in both phases, but the effects of Cl(-), SO4(2-), NO3(-), and HCO3(-) were different. In aqueous solution, the photoconversion efficiency of 4-CP was proportional to the OH concentration, and hence, Cl(-) and HCO3(-) as OH scavengers prohibited the photoconversion; SO4(2-) had little effect; NO3(-) promoted the process under certain conditions owing to OH being generated by the photolysis of NO3(-). In ice, however, the photoconversion efficiency of 4-CP was not proportional to the concentration of OH. The photoconversion efficiency of 4 CP increased with increasing concentrations of all ions, although the OH remained almost constant, only increasing or decreasing slightly. This provides new evidence for the presence of a quasi-liquid layer (QLL). Hydroxylation products were detected in both phases. All photoproducts in aqueous solution contained only a single benzene ring, whereas in ice, dimers were also detected. PMID- 23988576 TI - Prognostic factors and long-term outcome of pancreatic neuroendocrine neoplasms: Ki-67 index shows a greater impact on survival than disease stage. The large experience of the Spanish National Tumor Registry (RGETNE). AB - INTRODUCTION: Pancreatic neuroendocrine neoplasms (PNENs) are uncommon neoplasms with a wide spectrum of clinical behavior. The objective of this study was to assess in a large cohort of patients the relative impact of prognostic factors on survival. METHODS: From June 2001 through October 2010, 1,271 patients were prospectively registered online (www.getne.org) at the Spanish National Cancer Registry for Gastroenteropancreatic Neuroendocrine Tumors (RGETNE) by participating centers. Clinical and histopathological features were assessed as potential prognostic factors by uni- and multivariate analyses. RESULTS: Of 483 PNENs, 171 (35%) were functional (F) and 312 (65%) non-functional (NF). NF-PNENs were associated with a higher incidence of histological features denoting more aggressive disease, such as poor tumor differentiation, Ki-67 >20%, or vascular invasion (NF- vs. F-PNENs, respectively, p < 0.05). Nevertheless, functionality was not a significant predictor of survival (p = 0.19). Stage at diagnosis, Ki-67 index, tumor differentiation and surgical resection of the primary tumor were all significant prognostic factors in univariate analysis. However, Ki-67 (>20 vs. <=2%) (hazard ratio (HR) 2.21, p = 0.01) and surgical resection (yes vs. no) (HR 0.92, p = 0.001) were the only independent predictors of survival in multivariate analysis. Among patients who underwent surgery, high Ki-67 index (HR 10.37, p = 0.02) and poor differentiation (HR 8.16, p = 0.03) were the only independent predictors of clinical outcome. CONCLUSION: Ki-67 index and tumor differentiation are key prognostic factors influencing survival of patients with PNENs and, in contrast to what it is observed for other solid malignancies, they seem to have a greater impact on survival than the extent of disease. This should be borne in mind by physicians in order to appropriately tailor therapeutic strategies and surveillance of these patients. PMID- 23988577 TI - Fibronectin is deposited by injury-activated epicardial cells and is necessary for zebrafish heart regeneration. AB - Unlike adult mammals, adult zebrafish vigorously regenerate lost heart muscle in response to injury. The epicardium, a mesothelial cell layer enveloping the myocardium, is activated to proliferate after cardiac injury and can contribute vascular support cells or provide mitogens to regenerating muscle. Here, we applied proteomics to identify secreted proteins that are associated with heart regeneration. We found that Fibronectin, a main component of the extracellular matrix, is induced and deposited after cardiac damage. In situ hybridization and transgenic reporter analyses indicated that expression of two fibronectin paralogues, fn1 and fn1b, are induced by injury in epicardial cells, while the itgb3 receptor is induced in cardiomyocytes near the injury site. fn1, the more dynamic of these paralogs, is induced chamber-wide within one day of injury before localizing epicardial Fn1 synthesis to the injury site. fn1 loss-of function mutations disrupted zebrafish heart regeneration, as did induced expression of a dominant-negative Fibronectin cassette, defects that were not attributable to direct inhibition of cardiomyocyte proliferation. These findings reveal a new role for the epicardium in establishing an extracellular environment that supports heart regeneration. PMID- 23988580 TI - The quasiparticle band dispersion in epitaxial multilayer silicene. AB - The growth of multilayer silicene is an exciting challenge for the future of silicon nano-electronics. Here, we use angle-resolved photoemission spectroscopy to map the entire Brillouin zone (BZ) of (?3 * ?3)R30 degrees reconstructed epitaxial multilayer silicene islands, growing on top of the first (3 * 3) reconstructed silicene wetting layer, on Ag(111) substrates. We found Lambda- and V-shape linear dispersions, which we relate to the pi and pi* bands of massless quasiparticles in multilayer silicene, at the BZ centre [Formula: see text] and at all the [Formula: see text] centres of the (?3 * ?3)R30 degrees Brillouin zones in the extended scheme, due to folding of the Dirac cones at the [Formula: see text] and [Formula: see text] points of the (1 * 1) silicene BZ. The Fermi velocity of ~0.3 * 10(6) m s(-1) obtained is highly promising for potential silicene-based devices. PMID- 23988578 TI - The PCP protein Vangl2 regulates migration of hindbrain motor neurons by acting in floor plate cells, and independently of cilia function. AB - Vangl2, a core component of the Planar Cell Polarity pathway, is necessary for the caudal migration of Facial Branchiomotor (FBM) neurons in the vertebrate hindbrain. Studies in zebrafish suggest that vangl2 functions largely non-cell autonomously to regulate FBM neuron migration out of rhombomere 4 (r4), but the cell-type within which it acts is not known. Here, we demonstrate that vangl2 functions largely in floor plate cells to regulate caudal neuronal migration. Furthermore, FBM neurons fail to migrate caudally in the mouse Gli2 mutant that lacks the floor plate, suggesting an evolutionarily conserved role for this cell type in neuronal migration. Although hindbrain floor plate cilia are disorganized in vangl2 mutant embryos, cilia appear to be dispensable for neuronal migration. Notably, Vangl2 is enriched in the basolateral, but not apical, membranes of floor plate cells. Taken together, our data suggest strongly that Vangl2 regulates FBM neuron migration by acting in floor plate cells, independently of cilia function. PMID- 23988579 TI - Smurf-mediated differential proteolysis generates dynamic BMP signaling in germline stem cells during Drosophila testis development. AB - Germline stem cells (GSCs) produce gametes throughout the reproductive life of many animals, and intensive studies have revealed critical roles of BMP signaling to maintain GSC self-renewal in Drospophila adult gonads. Here, we show that BMP signaling is downregulated as testes develop and this regulation controls testis growth, stem cell number, and the number of spermatogonia divisions. Phosphorylated Mad (pMad), the activated Drosophila Smad in germ cells, was restricted from anterior germ cells to GSCs and hub-proximal cells during early larval development. pMad levels in GSCs were then dramatically downregulated from early third larval instar (L3) to late L3, and maintained at low levels in pupal and adult GSCs. The spatial restriction and temporal down-regulation of pMad, reflecting the germ cell response to BMP signaling activity, required action in germ cells of E3 ligase activity of HECT domain protein Smurf. Analyses of Smurf mutant testes and dosage-dependent genetic interaction between Smurf and mad indicated that pMad downregulation was required for both the normal decrease in stem cell number during testis maturation in the pupal stage, and for normal limit of four rounds of spermatogonia cell division for control of germ cell numbers and testis size. Smurf protein was expressed at a constant low level in GSCs and spermatogonia during development. Rescue experiments showed that expression of exogenous Smurf protein in early germ cells promoted pMad downregulation in GSCs in a stage-dependent but concentration-independent manner, suggesting that the competence of Smurf to attenuate response to BMP signaling may be regulated during development. Taken together, our work reveals a critical role for differential attenuation of the response to BMP signaling in GSCs and early germ cells for control of germ cell number and gonad growth during development. PMID- 23988581 TI - Effects of nitric oxide and reactive oxygen species on HIF-1alpha stabilization following clostridium difficile toxin exposure of the Caco-2 epithelial cell line. AB - BACKGROUND/AIMS: Stabilization of the hypoxia-inducible factor (HIF-1alpha) is proposed to provide a protective host-response to C. difficile intoxication. Here, we aimed to elucidate whether nitric oxide and/or reactive oxygen species produced during C. difficile toxin exposure could influence HIF-1alpha stability and initiate protection against epithelial cell damage. METHODS/RESULTS: HIF 1alpha and inducible nitric oxide synthase (iNOS) proteins were up-regulated whereas factor-inhibiting HIF-1 (FIH-1) protein was down-regulated in Caco-2 epithelial cell monolayers with in vitro toxin exposure. We demonstrate using the biotin-switch assay that the stabilization of HIF-1alpha protein occurred via iNOS-dependent nitrosylation. Inhibition of iNOS activity by selective inhibitor (1400W) attenuated HIF-1alpha stabilization and exacerbated toxin-dependent disruptions in Caco-2 monolayer morphology and tight junctional integrity in vitro. Treatment of Caco-2 cell monolayers with N-actylcysteine (NAC), a scavenger of reactive oxygen species (ROS), attenuated toxin-dependent increases in iNOS and HIF-1alpha protein levels but had no effect on FIH-1 responses. In addition, mice that were exposed to C. difficile toxin in vivo also demonstrated a significant increase in HIF-1alpha protein and nitrosylation levels. CONCLUSION: Taken together, these data suggest that important synergistic actions exist between nitric oxide and ROS to stabilize HIF-1alpha and its innate, protective actions in the context of C. difficile toxin-mediated epithelial injury. PMID- 23988585 TI - Variability in CT protocols. PMID- 23988586 TI - Dynamics of skeletal muscle lipid pools. AB - Intramyocellular triacylglycerol (IMTG) is emerging as an important energy fuel source during muscle contraction and are adaptively increased in response to exercise, without adverse physiological effects. Paradoxically, elevated IMTG content in obese and type 2 diabetics has been linked to insulin resistance, highlighting the importance of IMTG pools in physiology and pathology. Two separate views suggest that IMTG dynamics are determinant for skeletal muscle fat oxidation, and that disruption of IMTG dynamics facilitates the accumulation of lipotoxic intermediates such as diacylglycerols and ceramides that interfere with insulin signaling. Thus, understanding the factors that control IMTG dynamics is crucial. Here we discuss recent literature describing the regulation of IMTG pools with a particular emphasis on lipases and lipid droplet (LD)-associated proteins. PMID- 23988582 TI - The downward spiral of chronic pain, prescription opioid misuse, and addiction: cognitive, affective, and neuropsychopharmacologic pathways. AB - Prescription opioid misuse and addiction among chronic pain patients are emerging public health concerns of considerable significance. Estimates suggest that more than 10% of chronic pain patients misuse opioid analgesics, and the number of fatalities related to nonmedical or inappropriate use of prescription opioids is climbing. Because the prevalence and adverse consequences of this threat are increasing, there is a pressing need for research that identifies the biobehavioral risk chain linking chronic pain, opioid analgesia, and addictive behaviors. To that end, the current manuscript draws upon current neuropsychopharmacologic research to provide a conceptual framework of the downward spiral leading to prescription opioid misuse and addiction among chronic pain patients receiving opioid analgesic pharmacotherapy. Addictive use of opioids is described as the outcome of a cycle initiated by chronic pain and negative affect and reinforced by opioidergic-dopamingeric interactions, leading to attentional hypervigilance for pain and drug cues, dysfunctional connectivity between self-referential and cognitive control networks in the brain, and allostatic dysregulation of stress and reward circuitry. Implications for clinical practice are discussed; multimodal, mindfulness-oriented treatment is introduced as a potentially effective approach to disrupting the downward spiral and facilitating recovery from chronic pain and opioid addiction. PMID- 23988587 TI - Potential use of optical coherence tomography and high-frequency ultrasound for the assessment of nail disease in psoriasis and psoriatic arthritis. AB - BACKGROUND/OBJECTIVE: Psoriatic nail disease is increasingly recognised to be of major clinical and research relevance. Clinical assessment remains the current gold standard for its evaluation. OBJECTIVE: We compared optical coherence tomography (OCT) and ultrasound (US) for nail disease assessment in psoriatic disease. METHODS: 18 patients with at least one involved nail and 12 healthy controls were scanned using OCT; psoriatic patients also had an US scan (using a linear probe at 9-14 MHz). Nail and contour abnormalities were documented. Clinical onychopathy was scored independently using the modified Nail Psoriasis Severity Index. RESULTS: Among 180 nails, 67.8% had clinical findings whereas 33.9% were abnormal by US and 44.4% had abnormalities on OCT. A positive OCT had a sensitivity and specificity of 44.4 and 95.8%, respectively, with a positive likelihood ratio of 10.7 for nail disease. OCT demonstrated 76.3% absolute agreement compared with clinical assessment and 65% with US. OCT detected subtle abnormalities in 12 clinically normal nails and in 41 nails with normal US findings. CONCLUSION: These findings show that OCT has a potential for the systematic characterisation of psoriatic nail changes and could be useful in diagnosis and more objective assessment of treatment response. PMID- 23988583 TI - Biological impact of auditory expertise across the life span: musicians as a model of auditory learning. AB - Experience-dependent characteristics of auditory function, especially with regard to speech-evoked auditory neurophysiology, have garnered increasing attention in recent years. This interest stems from both pragmatic and theoretical concerns as it bears implications for the prevention and remediation of language-based learning impairment in addition to providing insight into mechanisms engendering experience-dependent changes in human sensory function. Musicians provide an attractive model for studying the experience-dependency of auditory processing in humans due to their distinctive neural enhancements compared to nonmusicians. We have only recently begun to address whether these enhancements are observable early in life, during the initial years of music training when the auditory system is under rapid development, as well as later in life, after the onset of the aging process. Here we review neural enhancements in musically trained individuals across the life span in the context of cellular mechanisms that underlie learning, identified in animal models. Musicians' subcortical physiologic enhancements are interpreted according to a cognitive framework for auditory learning, providing a model in which to study mechanisms of experience dependent changes in human auditory function. PMID- 23988588 TI - The reconstructed skin micronucleus assay in EpiDermTM: reduction of false positive results - a mechanistic study with epigallocatechin gallate. AB - The high rate of false-positive or misleading results in in vitro mammalian genotoxicity testing is a hurdle in the development of valuable chemicals, especially those used in cosmetics, for which in vivo testing is banned in the European Union. The reconstructed skin micronucleus (RSMN) assay in EpiDermTM (MatTek Corporation, USA) has shown promise as a follow-up for positive in vitro mammalian genotoxicity tests. However, few studies have explored its better predictive performance compared with existing in vitro assays. In the present study, we followed the protocol of the RSMN assay and used eight chemicals to compare micronucleus (MN) induction with EpiDermTM with that in normal human epidermal keratinocytes (NHEKs), both derived from human skin. The assessments of EpiDermTM conformed to those of in vivo MN assay, whereas those of NHEKs did not. The effect of cell differentiation status on MN induction was further addressed using a model compound, epigallocatechin gallate (EGCG), which is a major component of green tea extract that shows positive results in in vitro mammalian genotoxicity assays via oxidative stress and negative results in in vivo MN studies. RSMN assay in an underdeveloped epidermal model, EpiDerm-201TM (MatTek Corporation), showed a negative result identical to that in EpiDermTM, indicating that the barrier function of keratinocytes has limited impact. Analysis of the gene expression profile of both EpiDermTM and NHEKs after EGCG treatment for 12h revealed that the expression of genes related to genotoxic response was significantly induced only in NHEKs. Conversely, antioxidative enzyme activities (catalase and glutathione peroxidase) in EpiDermTM were higher than those in NHEKs. These results indicate that EpiDermTM has antioxidant properties similar to those of a living body and is capable of eliminating oxidative stress that may be caused by EGCG under in vitro experimental conditions. PMID- 23988589 TI - Assessment of the in vitro gammaH2AX assay by High Content Screening as a novel genotoxicity test. AB - The gammaH2AX assay is widely used as a marker of DNA damage in multiple scientific fields such as cancer biomarker, clinical studies and radiation biology. In particular, the in vitro gammaH2AX assay has been suggested as a novel in vitro genotoxicity test with potential as a pre-screening tool. However, to date, limited assessments have been carried out to evaluate the sensitivity, specificity and accuracy of the in vitro gammaH2AX assay. In this study, the microscopy-based system combining automated cellular image acquisition with software quantification for High Content Screening (HCS) has been used for the first time to evaluate the in vitro gammaH2AX assay. A panel of well characterised genotoxic and non-genotoxic compounds was selected to assess the performance of the in vitro gammaH2AX assay in the human bronchial epithelial cell line BEAS-2B. The results obtained during this preliminary assessment indicate that the in vitro gammaH2AX assay has a high accuracy (86%) as a result of high sensitivity and specificity (86-92% and 80-88% respectively). Our data highlight the potential for gammaH2AX detection in HCS as a complement to the current regulatory genotoxicity battery of in vitro assays. We therefore recommend more comprehensive assessments to confirm the performance of the in vitro gammaH2AX assay by HCS with a more extensive set of compounds. PMID- 23988590 TI - Pubertal growth and serum testosterone and estradiol levels in boys. AB - BACKGROUND/AIMS: To study serum testosterone and estradiol in healthy boys in relation to growth during puberty up to peak height velocity (PHV). METHODS: Growth velocity was analyzed through testosterone (n = 41) and 17beta-estradiol (n = 37) 24-hour profiles in a dose-response model. Participants were 26 healthy boys admitted for short or tall stature or participating as healthy volunteers at the Queen Silvia Children's Hospital. Other inclusion criteria included the following: gestational age 37-42 weeks, birth weight and length >-2 standard deviation score (SDS) and prepubertal height and weight within +/- 3 SDS. Testosterone was measured using a modified radioimmunoassay (RIA) with a detection limit of 0.03 nmol/l. Estradiol was determined using an ultrasensitive extraction RIA with a detection limit 4 pmol/l. A sixth-grade polynomial was fitted to each child's growth data, giving growth velocity and age at PHV. RESULTS: Growth velocity increased by 50% from prepubertal growth to PHV at a morning testosterone level of 3.1 nmol/l (95% confidence interval 2.4-4.2), EC50. The corresponding EC50 of 17beta-estradiol was 6.5 pmol/l (3.2-13). Boys approaching PHV (<4% remaining) had morning testosterone levels >10 nmol/l and 17beta-estradiol >9 pmol/l. CONCLUSION: Observed early puberty/initial mid puberty morning testosterone levels of 2.4-4.2 nmol/l are associated with a 50% increase in growth velocity from prepubertal growth to PHV in healthy boys. PMID- 23988591 TI - Thyroid surgery in the elderly. AB - BACKGROUND: The increase in life expectancy combined with the relatively high incidence of thyroid disease requiring surgery in the elderly has raised questions concerning the appropriate management of the older patient. AIM: Evaluation of the surgical management and outcome of thyroid disease requiring surgery in elderly patients. METHODS: We performed a retrospective cohort study, in which the medical charts of 2,239 patients who underwent total thyroidectomy or hemithyroidectomy between 1995 and 2011 in a tertiary medical center were reviewed for clinical, disease-related, operative and outcome measures. Findings were analyzed between the patients aged more than 75 years for whom complete information was available (n = 255) and a control group of 100 patients aged 40 60 years matched for sex and extent of surgery. RESULTS: The prevalence of comorbidities was significantly higher in the elderly. Presenting symptoms were similar in the two groups; in approximately 25% of both groups thyroid cancer was an incidental finding. There were no between-group differences in surgery duration, time to anesthesia induction, recovery time from anesthesia, or rate of postoperative complications. Hospitalization was 3 days longer on average in the older group. Malignancy rates and distribution of histologic subtypes were similar in the two groups, although the older group presented with significantly higher rates of advanced disease stage and larger tumors. There were no differences in recurrence rate both locoregional and distant metastases. However, a higher proportion of older patients failed to achieve cure. CONCLUSION: Although older patients with thyroid disease have more comorbidities and advanced disease, there is no practical difference in their operative management and surgical outcome compared to younger patients. Surgery should not be deferred solely on the basis of age in the presence of compelling indications; rather, the decision should be based on individual risk-benefit analysis. PMID- 23988593 TI - New regulations for Medicare's inpatient PPS introduce another reduction program. PMID- 23988594 TI - Pharmacogenomics resources support pharmacists' need to know. PMID- 23988596 TI - Awareness of orphan therapies offer opportunities for pharmacists. PMID- 23988597 TI - Development and implementation of a hyperglycemic emergency protocol. PMID- 23988598 TI - Pertuzumab for the treatment of human epidermal growth factor receptor type 2 positive metastatic breast cancer. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, and administration of pertuzumab in patients with metastatic human epidermal growth factor receptor type 2 (HER2)-positive breast cancer are reviewed. SUMMARY: Disease progression in HER2-positive breast cancer is often due to resistance to or a lack of efficacy of trastuzumab-based anti-HER2 therapy. Pertuzumab is the first humanized monoclonal antibody in a new class of drugs, the HER dimerization inhibitors, approved by the Food and Drug Administration for the first-line treatment of patients with metastatic HER2-positive breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Since pertuzumab binds to a different epitope than trastuzumab, combination therapy with pertuzumab and trastuzumab results in a more complete blockade of HER2 signaling than trastuzumab monotherapy. The efficacy of adding pertuzumab to trastuzumab-docetaxel dual therapy was demonstrated in a pivotal randomized multicenter Phase III trial, which showed a significant benefit in terms of progression-free survival, with improved overall survival, in favor of the triple therapy as an initial regimen in treatment-naive patients with metastatic HER2 positive breast cancer. The combination of pertuzumab and trastuzumab has been found to have a tolerable toxicity profile. As clinical trials of pertuzumab for adjuvant, neoadjuvant, and metastatic-disease treatment continue, its role in the treatment of HER2-positive breast cancer will continue to evolve. CONCLUSION: Pertuzumab, a novel HER2 dimerization inhibitor, has been shown to be effective in the treatment of metastatic HER2-positive breast cancer when used in combination with trastuzumab and docetaxel and is recommended for first-line therapy. PMID- 23988599 TI - Acute hypokalemic periodic paralysis possibly precipitated by albuterol. AB - PURPOSE: An episode of acute hypokalemic paralysis associated with the use of inhaled albuterol is described. SUMMARY: A 34-year-old woman admitted to the emergency department reported the development of pain and diffuse paralysis of the extremities and torso shortly after using an albuterol inhaler. At age 18, she had been diagnosed with hyokalemic periodic paralysis (HPP), a disorder of muscle membrane excitability caused by serum potassium depletion that can lead to life-threatening neuromuscular and cardiovascular complications. After a 15-year period of episodically recurring HPP symptoms despite long-term acetazolamide use, she was switched to spironolactone therapy and had experienced no HPP exacerbations for about 1 year. On her arrival in the emergency department, the patient's serum potassium concentration was 1.8 meq/L and she was mildly tachycardic (heart rate of 125 beats/min). After careful supplementation to gradually increase the serum potassium concentration to 5.4 meq/L, the patient slowly regained movement and strength in her extremities. Application of the adverse drug reaction probability scale of Naranjo et al. to this case yielded a score of 3, indicating that albuterol was possibly the cause of the patient's HPP exacerbation. Beta-2-adrenergic agonists and several other medications can affect serum potassium levels; although the potential risks posed by the use of such drugs in patients with a history of HPP are unclear, cautious use in the context of known HPP is advised. CONCLUSION: A patient previously diagnosed with HPP experienced an exacerbation of HPP possibly induced by inhaled albuterol treatment. PMID- 23988601 TI - Transform health care: a call to action for pharmacy. PMID- 23988600 TI - Underutilization of cardiovascular medications: effect of a continuity-of-care program. AB - PURPOSE: The effect of hospital pharmacists' enhanced communication with patients and community providers on the underutilization of key cardiovascular medications was studied. METHODS: Patients enrolled in the Iowa Continuity of Care study were eligible for inclusion in this study if they had a diagnosis of hypertension, hyperlipidemia, heart failure, coronary artery disease, or a combination of these diagnoses. Eligible patients also had to be admitted to the internal medicine, family medicine, cardiology, or orthopedics services and receive their usual medical care in the community and their prescriptions from a community pharmacy. Patients were randomized to receive minimal intervention, enhanced intervention, or usual care. For the minimal- and enhanced-intervention groups, pharmacy case managers (PCMs) performed comprehensive medication reconciliations and identified drug-related problems within 24 hours of admission. The PCMs made recommendations to the inpatient care team and to patients' community physicians. For patients in the enhanced-intervention group, the PCM developed a discharge care plan containing the patient's discharge medication list. PCMs made specific recommendations to optimize regimens that did not meet current guidelines or medications that were underutilized. Medication underutilization was assessed at admission, discharge, 30 days after discharge, and 90 days after discharge. RESULTS: A total of 732 patients were enrolled in this study. There were no significant differences among the three study groups. Overall, the rate of underutilization remained constant among all three groups, despite enhanced pharmacist involvement in both intervention groups. CONCLUSION: Enhanced interventions by PCMs had no effect on the underutilization of key cardiovascular drugs during hospitalization or after hospital discharge. PMID- 23988602 TI - Residency preceptor development and evaluation: a new approach. AB - PURPOSE: The design and implementation of a preceptor development program involving close collaboration by the pharmacy residency program director (RPD) and members of a residency advisory committee (RAC) are described. SUMMARY: In 2011 the Nebraska Medical Center (NMC) implemented a program to foster the development of preceptors' teaching and clinical skills, as required by accreditation standards of the American Society of Health-System Pharmacists (ASHP). The RPD and RAC worked closely to define expectations of resident preceptors and a pathway for their transition from "conditional" to "primary" status. Among other program requirements, prospective (and new incoming) preceptors must (1) submit to the RAC a letter of interest in becoming a resident preceptor accompanied by an academic and professional record, (2) complete a new preceptor orientation session in which teaching concepts and principles are presented and discussed, and (3) obtain 10 preceptor education (PE) credits every two years. PE credits are earned through defined preceptor development opportunities including a teaching core and a clinical core focused on enhancing skills such as the application of therapeutic knowledge and conduct of clinical research. All preceptors are required to submit updated academic and professional records to the RAC every two years. The RAC audits 25% of preceptors to document attainment of PE credits and also conducts annual reviews of ASHP Resi-Trak summary evaluations of all preceptors and learning experiences. CONCLUSION: The NMC program may serve as a model for other institutions in planning and evaluating professional development programs to ensure that preceptors maintain the skills and knowledge necessary to provide high-quality resident training. PMID- 23988603 TI - Practical pearls for a successful residency project. PMID- 23988604 TI - A foundational document: the ASHP minimum standard for pharmacies in hospitals. PMID- 23988605 TI - ASHP guidelines: minimum standard for pharmacies in hospitals. PMID- 23988606 TI - CCN2 promotes keratinocyte adhesion and migration via integrin alpha5beta1. AB - BACKGROUND: CCN2, (a.k.a. connective tissue growth factor and CTGF) has emerged as a regulator of cell migration. While the importance of CCN2 for the fibrotic process in wound healing has been well studied, the effect of CCN2 on keratinocyte function is not well understood. In this study, we investigated the mechanism behind CCN2-driven keratinocyte adhesion and migration. MATERIALS AND METHODS: Adhesion assays were performed by coating wells with 10 MUg/ml fibronectin (FN) or phosphate-buffered saline (PBS). Keratinocytes were seeded in the presence or absence of 200 ng/ml CCN2, 5 mmol/l ethylenediaminetetraacetic acid, 10 mmol/l cations, 500 MUl arginine-glycine-aspartic acid (RGD), 500 MUM arginine-glycine-glutamate-serine (RGES), and 10 MUg/ml anti-integrin blocking antibodies. Migration studies were performed using a modified Boyden chamber assay. Quantitative PCR was used to study the effect of CCN2 on integrin subunit mRNA expression. To block intracellular pathways, keratinocytes were pretreated with 20 MUM PD98059 (MEK-1 inhibitor) or 20 MUM PF573228 (FAK inhibitor) for 60 min prior the addition of CCN2. Western blot was used to measure CCN2, p-ERK1/2, and ERK1/2. RESULTS: CCN2 enhanced keratinocyte adhesion to fibronectin via integrin alpha5beta1. The addition of anti-integrin alpha5beta1 antibodies reduced CCN2-mediated keratinocyte migration. In addition, CCN2 regulated mRNA and protein expression of integrin subunits alpha5 and beta1. CCN2 activated the FAK-MAPK signaling pathway, and pretreatment with MEK1-specific inhibitor PD98059 markedly reduced CCN2-induced keratinocyte migration. CONCLUSIONS: Our results demonstrate that CCN2 enhances keratinocyte adhesion and migration through integrin alpha5beta1 and activation of the FAK-MAPK signaling cascade. PMID- 23988607 TI - Impact of bacteria and bacterial components on osteogenic and adipogenic differentiation of adipose-derived mesenchymal stem cells. AB - Adult mesenchymal stem cells (MSC) are present in several tissues, e.g. bone marrow, heart muscle, brain and subcutaneous adipose tissue. In invasive infections MSC get in contact with bacteria and bacterial components. Not much is known about how bacterial pathogens interact with MSC and how contact to bacteria influences MSC viability and differentiation potential. In this study we investigated the impact of three different wound infection relevant bacteria, Escherichia coli, Staphylococcus aureus, and Streptococcus pyogenes, and the cell wall components lipopolysaccharide (LPS; Gram-negative bacteria) and lipoteichoic acid (LTA; Gram-positive bacteria) on viability, proliferation, and osteogenic as well as adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells (adMSC). We show that all three tested species were able to attach to and internalize into adMSC. The heat-inactivated Gram-negative E. coli as well as LPS were able to induce proliferation and osteogenic differentiation but reduce adipogenic differentiation of adMSC. Conspicuously, the heat-inactivated Gram positive species showed the same effects on proliferation and adipogenic differentiation, while its cell wall component LTA exhibited no significant impact on adMSC. Therefore, our data demonstrate that osteogenic and adipogenic differentiation of adMSC is influenced in an oppositional fashion by bacterial antigens and that MSC-governed regeneration is not necessarily reduced under infectious conditions. PMID- 23988608 TI - Magnetism and phase transitions in LaCoO3. AB - Neutron scattering and magnetometry measurements have been used to study phase transitions in LaCoO3 (LCO). For H <= 100 Oe, evidence for a ferromagnetic (FM) transition is observed at Tc ~ 87 K. For 1 kOe <= H <= 60 kOe, no transition is apparent. For all H, Curie-Weiss analysis shows predominantly antiferromagnetic (AFM) interactions for T > Tc, but the lack of long-range AFM order indicates magnetic frustration. We argue that the weak ferromagnetism in bulk LCO is induced by lattice strain, as is the case with thin films and nanoparticles. The lattice strain is present at the bulk surfaces and at the interfaces between the LCO and a trace cobalt oxide phase. The ferromagnetic ordering in the LCO bulk is strongly affected by the Co-O-Co angle (gamma), in agreement with recent band calculations which predict that ferromagnetic long-range order can only take place above a critical value, gammaC. Consistent with recent thin film estimations, we find gammaC = 162.8 degrees . For gamma > gammaC, we observe power-law behavior in the structural parameters. gamma decreases with T until the critical temperature, To ~ 37 K; below To the rate of change becomes very small. For T < To, FM order appears to be confined to regions close to the surfaces, likely due to the lattice strain keeping the local Co-O-Co angle above gammaC. PMID- 23988609 TI - Acetaminophen changes intestinal epithelial cell membrane properties, subsequently affecting absorption processes. AB - BACKGROUND/AIMS: Acetaminophen (APAP) effects on intestinal barrier properties are less investigated. APAP may lead to a changed bioavailability of a subsequently administered drug or diet in the body. We investigated the influence of APAP on enterocytic cell membrane properties that are able to modify the net intestinal absorption of administered substances across the Caco-2 barrier model. METHODS: The effect of APAP on cytotoxicity was measured by LDH assay, TER value and cell capacitance label-free using impedance monitoring, membrane permeability by FITC-dextrans, and efflux transporter MDR1 activity by Rh123. APAP levels were determined by HPLC analysis. Cell membrane topography and microvilli were investigated using SEM and intestinal alkaline phosphatase (Alpi) and tight junction protein 1 (TJP1) expression by western blot analysis. RESULTS: APAP changed the apical cell surface, reduced the number of microvilli and protein expression of Alpi as a brush border marker and TJP1, increased the membrane integrity and concurrently decreased cell capacitance over time. In addition, APAP decreased the permeability to small molecules and increased the efflux transporter activity, MDR1. CONCLUSION: APAP alters the Caco-2 cell membrane properties by different mechanisms and reduces the permeability to administered substances. These findings may help to optimize therapeutic implications. PMID- 23988610 TI - Juvenile fibromyalgia syndrome and improved recognition by pediatric primary care providers. AB - INTRODUCTION: Juvenile fibromyalgia syndrome (JFS) is a medically unexplained illness that can cause persistent, diffuse pain in a child or adolescent. This pain can lead to anxiety or depression and absence from school or work, and it can adversely affect a child's quality of life and family relationships. Prompt recognition of JFS may decrease problems for pediatric patients with chronic pain, but pediatric primary care providers' lack of familiarity with JFS can cause a delay in diagnosis. METHOD: A project using a developed screening tool, the SORE Scoresheet, was implemented in the pediatric clinic at Kaiser Permanente Fontana from September 2011 to January 2012. Pediatric providers were educated about the tool before the project began. RESULTS: Twenty-two patients with JFS were referred with use of the SORE Scoresheet. Symptoms of JFS matched at a rate of 93% between the providers and the rheumatologist, and a reduction in the number of weeks to referral and the number of visits before referral was found compared with a sample of patients with JFS from 2010. CONCLUSION: Pediatric provider education and development of a screening tool assists with the recognition of JFS. PMID- 23988611 TI - Attributes of advanced practice registered nurse care coordination for children with medical complexity. AB - Care coordination is an essential component of the pediatric health care home. This study investigated the attributes of relationship-based advanced practice registered nurse care coordination for children with medical complexity enrolled in a tertiary hospital-based health care home. Retrospective review of 2,628 care coordination episodes conducted by telehealth over a consecutive 3-year time period for 27 children indicated that parents initiated the majority of episodes and the most frequent reason was acute and chronic condition management. During this period, care coordination episodes tripled, with a significant increase (p < .001) between years 1 and 2. The increased episodes could explain previously reported reductions in hospitalizations for this group of children. Descriptive analysis of a program-specific survey showed that parents valued having a single place to call and assistance in managing their child's complex needs. The advanced practice registered nurse care coordination model has potential for changing the health management processes for children with medical complexity. PMID- 23988612 TI - Targeted therapy for breast cancer. AB - Breast cancer is a heterogeneous group of diseases that are clinically subdivided as hormone receptor-positive, human epidermal growth factor receptor 2-positive (HER2(+)), and triple-negative breast cancer, to guide therapeutic interventions. Agents that target estrogen receptor (ER) and HER2 are among the most successful cancer therapeutics. However, de novo or acquired resistance is common, despite the development of newer agents against these pathways. As our understanding of tumor biology improves, novel targets are being identified. Notably, inhibitors against several pathways [including, among others, the phosphoinositide 3 kinase/mammalian target of rapamycin (PI3K/mTOR), cell-cycle regulation, heat shock protein, and epigenetic pathways] have demonstrated promising activity in clinical trials, and the mTOR-inhibitor everolimus has been approved for advanced or metastatic aromatase inhibitor-resistant ER(+) breast cancer. At present, there are no established targeted agents for triple-negative breast cancer (negative ER, progesterone receptor, and HER2). Although poly(ADP-ribose) polymerase inhibitors have shown promising activity in BRCA-related cancers, its value in the treatment of triple-negative breast cancers remains to be demonstrated. In this Review, we present a basic understanding of the major targeted agents in current practice and under development for the treatment of breast cancer in the context of the three clinical subgroups. PMID- 23988614 TI - Convection-enhanced delivery of AAV2 in white matter--a novel method for gene delivery to cerebral cortex. AB - BACKGROUND: Convection-enhanced delivery (CED) is currently under investigation for delivering therapeutic agents to subcortical targets in the brain. Direct delivery of therapies to the cerebral cortex, however, remains a significant challenge. NEW METHOD: We describe a novel method of targeting adeno-associated viral vector (AAV) mediated gene therapies to specific cerebral cortical regions by performing high volume, high flow rate infusions into underlying white matter in a large animal (porcine) model. RESULTS: Infusion volumes of up to 700 MUl at flow rates as high as 10 MUl/min were successfully performed in white matter without adverse neurological sequelae. Co-infusion of AAV2/5-GFP with 0.2% Gadolinium in artificial CSF confirmed transgene expression in the deep layers of cerebral cortex overlying the infused areas of white matter. COMPARISON WITH EXISTING METHODS: AAV-mediated gene therapies have been previously targeted to the cerebral cortex by performing intrathalamic CED and exploiting axonal transport. The novel method described in this study facilitates delivery of gene therapies to specific regions of the cerebral cortex without targeting deep brain structures. CONCLUSIONS: AAV-mediated gene therapies can be targeted to specific cortical regions by performing CED into underlying white matter. This technique could be applied to the treatment of neurological disorders characterised by cerebral cortical degeneration. PMID- 23988615 TI - Removal of myeloid cytokines from the cellular environment enhances T-cell development in vitro. AB - The majority of T-cell development occurs in the thymus. Thymic epithelial cells are specialized cells that express NOTCH ligands and secrete specific cytokines required for normal T-cell lymphopoiesis. It has been demonstrated that OP9 cells derived from macrophage colony-stimulating factor (M-CSF)-deficient mice can support T-cell development when transduced with a NOTCH ligand, Delta-like 1 (Dll1). In this report, we have tested CSF-deficient mouse fibroblasts transduced with Dll1 for their ability to support T-cell differentiation. The data provided here demonstrate that CSF-deficient fibroblasts expressing DLL1 can support T cell development. Indeed, co-cultures with these fibroblasts produced more T-cell progenitors compared with OP9-DL1 cultures. Addition of myeloid cytokines to OP9 DL1 co-cultures significantly inhibited T-cell development while CSF-deficient DLL1(+) fibroblasts retained partial T-cell differentiation. Taken together, these data imply that their lack of myeloid cytokines allows DLL1(+) fibroblasts to more efficiently generate T-cells. Development of this fibroblast system suggests that there is potential for generating human T-cell precursors via co culture with human fibroblasts expressing DLL1 or DLL4. These T-cell precursors could be used for treating immunodeficient patients. PMID- 23988616 TI - Induction of T-cell development by Delta-like 4-expressing fibroblasts. AB - The thymus provides a unique environment for the induction of T-cell lineage commitment and differentiation, which is predicted by specific Notch ligand receptor interactions on epithelial cells and lymphoid progenitors, respectively. Accordingly, a bone marrow-derived stromal cell line (OP9) ectopically expressing the Notch ligand Delta-like 1 (Dll1) or Dll4 (OP9-DL1 and OP9-DL4, respectively) gains the ability to recapitulate thymus-like function, supporting T-cell differentiation of both mouse and human progenitors. In this study, we extend these findings by demonstrating that, unlike the NIH3T3 cell line, mouse primary fibroblasts made to express Dll4 (mFibro-DL4) acquire the capacity to promote and support T-cell development from hematopoietic stem cells (HSCs) into TCRalphabeta(+), CD4(+) and CD8(+) T-lineage cells. However, mFibro-DL4 cells showed a lower efficiency of T-cell generation than OP9-DL4 cells did. Nevertheless, progenitor T-cells (CD117(+) CD44(+) CD25(+)) generated in HSC/mFibro-DL4 co-cultures, when intravenously transferred into immunodeficient (Rag2(-/-) gammac(-/-)) mice, home to the thymus, undergo differentiation, and give rise to mature T-cells that go on to populate the periphery. Surprisingly, primary human fibroblast cells expressing Dll4 showed very low efficiency in supporting human T-lineage differentiation, which could not be improved by blocking myelopoiesis. Nevertheless, mFibro-DL4 cells could support human T-cell lineage differentiation. Our results provide a functional framework for the induction of T-cell development using easily accessible fibroblasts made to express Dll4. These cells, which are amenable for in vitro applications, can be further utilized in the design of individualized systems for T-cell production, with implications for the treatment of immunodeficiencies. PMID- 23988617 TI - Cigarette smoke impairs phagocytosis of apoptotic neutrophils by alveolar macrophages via inhibition of the histone deacetylase/Rac/CD9 pathways. AB - Efferocytosis, which is the homeostatic phagocytosis of apoptotic cells, prevents the release of toxic intracellular contents and subsequent tissue damage. Impairment of efferocytosis was reported in alveolar macrophages (AMs) of patients with chronic obstructive pulmonary disease (COPD), a common disease caused by smoking. In COPD, histone deacetylase (HDAC) activity is reduced in AMs. We investigated whether the reduction of HDAC activity is associated with the impairment of efferocytosis. Murine AMs were collected by bronchoalveolar lavage and their ability to efferocytose apoptotic human polymorphonuclear leukocytes was assessed. Pre-treatment of AMs with cigarette smoke extract (CSE) or trichostatin A (TSA), an HDAC inhibitor, suppressed efferocytosis and CSE reduced HDAC activity. TSA inhibited the activity of Rac, a key mediator of efferocytosis. These TSA-induced impairments were restored by treatment of AMs with aminophylline, a potent activator of HDAC. To further elucidate the underlying mechanism, we explored a role of CD9 in TSA-induced impairment of efferocytosis. CD9 is a transmembrane protein of the tetraspanin family that facilitates the uptake of several pathogens and other material. TSA profoundly down-regulated the expression of CD9 on AMs. The expression of CD9 was partly down-regulated by the Rac inhibitor. Pretreatment with an anti-CD9 mAb or CD9 small interfering RNA inhibited efferocytosis, which was attributable to the reduced binding of AMs to apoptotic cells. These results suggest that smoking impairs efferocytosis via inhibition of HDAC/Rac/CD9 pathways. Aminophylline/theophylline is effective in restoring the impairment of efferocytosis and might have benefit for the treatment of patients with COPD. PMID- 23988618 TI - Fall 2013: Another year, another DNP....Are we doing it right? PMID- 23988619 TI - Relaxant effect of 1-butanol fraction from Elaeagnus pungens leaf through inhibiting L-type Ca2+ channel on guinea pig tracheal smooth muscle. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaf of Elaeagnus pungens thunb. (Family Elaeagnaceae) has been documented as an effective herb for the treatment of asthma and chronic bronchitis in traditional Chinese medicine. In the past years, only a few of preliminary studies reported the chemical constituents and pharmacology effects of the herb, but their action on the tracheal relaxation has not been investigated. AIM OF THE STUDY: To investigate the relaxing effect and mechanism of the extracts from Elaeagnus pungens leaves on guinea pig tracheal smooth muscle and bronchi smooth muscle cells. MATERIALS AND METHODS: Four fractions of different polarities from Elaeagnus pungens leaves were tested to the tracheal strips on the resting tension or pre-contracted by histamine (20 MUM) and acetylcholine (20 MUM). Inhibitory effects of the 1-butanol fraction (400mg/ml) on cumulative histamine and acetylcholine (0.2-20 MUM) induced contraction were measured. In order to determine the mediators on the 1-butanol fraction effect, the relaxing effect of the 1-butanol fraction was evaluated in the absence and presence of beta-adrenoceptor antagonists (1 MUM propranolol), K(+) channels-blockers (4-aminopyridine (2mM), tetraethylammonium chloride (5mM) or glibenclamide (10 MUM)), the cyclooxygenase inhibitor (indomethacin, 10 MUM), nitric oxide synthase inhibitor (Nomega-nitro-L-arginine methyl ester, 100 MUM) or L-type Ca(2+) channel inhibitor (nifedipine, 1 MUM). Moreover, [Ca(2+)]i in bronchi smooth muscle cells was analyzed by measuring the fluorescence intensity with confocal system. RESULTS: 1-Butanol fraction induced the highest relaxant effect among four fractions of different polarities from Elaeagnus pungens leaves, and significantly relaxed the tracheal strip in the concentration dependent manner on the resting tension and pre-contracted by histamine phosphate and acetylcholine. It also produced an unparallel rightward shift of the cumulative concentration-response curve of histamine or acetylcholine. Furthermore, the relaxant effect of 1-butanol fraction was not affected by propranolol, glibenclamide, tetraethylammonium chloride, 4-aminopyridine, indomethacin and Nomega-nitro-L-arginine methyl ester. However, 1-butanol fraction-induced relaxation decreased after adding nifedipine. It also concentration-dependently inhibited CaCl2-induced contraction in the Ca(2+)-free, 60mM K(+)-containing solution. Additionally, [Ca(2+)]i in the BSMCs significantly reduced after administration of the 1-butanol fraction. CONCLUSIONS: The 1 butanol fraction from Elaeagnus pungens leaves resulted in a relaxation in the non-precontracted and pre-contracted tracheal strips. The relaxant effect was not related to K(+) channels, NO, cGMP or beta-adrenoceptors, but related to the inhibition of Ca(2+) influx through L-type Ca(2+) channels. PMID- 23988620 TI - Quantification of circulating miRNAs in plasma: effect of preanalytical and analytical parameters on their isolation and stability. AB - Circulating miRNAs are intensively evaluated as promising blood-based biomarkers. This growing interest in developing assays for circulating miRNAs necessitates careful consideration of the effects of preanalytical and analytical parameters on the isolation, stability, and quantification of circulating miRNAs. By using quantitative stem-loop RT-PCR, we compared the relative efficiencies of four miRNA isolation systems and different storage conditions. The effect of the data normalization procedure on the quantification of circulating miRNA levels in plasma from 30 healthy individuals and 30 patients with non-small cell lung carcinoma was estimated by measuring endogenous hsa-miR-21 and hsa-miR-16 and exogenous cel-miR-39 that was spiked in all samples at the same concentration. Silica column-based RNA extraction methods are more effective and reliable with respect to TRIzol LS. Endogenous circulating miRNA levels are unstable when plasma is stored at 4 degrees C, and samples should be kept at -70 degrees C, where the extracted miRNAs remain stable for up to 1 year. When normalization is based on combined endogenous and exogenous control miRNAs, differences in miRNA recovery and differences in cDNA synthesis between samples are compensated. Using this normalization procedure and hsa-miR-21 as a biomarker, we could clearly discriminate healthy individuals from patients with cancer. Experimental handling and the use of exogenous and endogenous controls for normalization are critical for the reliable quantification of circulating miRNA levels in plasma. PMID- 23988621 TI - Rapid identification of pathogens with the hemoFISH test applying a novel beacon based fluorescence in situ hybridization (bbFISH) technology in positive blood culture bottles. AB - Rapid and accurate identification of pathogens responsible for sepsis is essential for early and targeted antimicrobial therapy. Blood cultures are the current reference standard for detection of pathogens in blood, but culture-based identification methods are time consuming. We evaluated the hemoFISH assay by using the novel bbFISH technology for rapid and accurate identification of a broad range of microorganisms in positive blood cultures. A total of 103 positive blood culture bottles were investigated. In total, 106 bacterial species were detected in the blood cultures and subsequently identified with conventional methods. The Gram-staining indicated monomicrobial growth in 95.1% (98/103) and polymicrobial growth in 4.9% (5/103) blood cultures. In 65.0% (67/103) cultures Gram-positive, 32.0% (33/103) Gram-negative, and 3.0% (3/103) both Gram-positive and Gram-negative bacteria were identified. Depending on the Gram-staining results, either the hemoFISH Gram-positive or the hemoFISH Gram-negative panel was used. In case of a polymicrobial infection, both panels were applied. The hemoFISH assay showed a sensitivity and specificity of 100% (95% CIs of 96.34% to 100% and 30.48% to 100%, respectively). Of the 106 bacterial species, the hemoFISH assay correctly identified 55.7% (n = 59) to species level, 34.0% (n = 36) to genus level, and 7.5% (n = 8) to family level. The novel hemoFISH using bbFISH technology appears to be a valuable rapid tool for the identification of a broad range of microorganisms in positive blood cultures. PMID- 23988622 TI - Comparison of EGFR signaling pathway somatic DNA mutations derived from peripheral blood and corresponding tumor tissue of patients with advanced non small-cell lung cancer using liquidchip technology. AB - Somatic DNA mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway are known to predict responsiveness to EGFR-tyrosine kinase inhibitor drugs in patients with advanced non-small-cell lung cancers. We evaluated a sensitive liquidchip platform for detecting EGFR, KRAS (alias Ki ras), proto-oncogene B-Raf, and phosphatidylinositol 3-kinase CA mutations in plasma samples, which were highly correlated with matched tumor tissues from 86 patients with advanced non-small-cell lung cancers. Either EGFR exon 19 or 21 mutations were detected in 36 patients: 23 of whom had identical mutations in both their blood and tissue samples; whereas mutations in the remaining 13 were found only in their tumor samples. These EGFR mutations occurred at a significantly higher frequency in females, never-smokers, and in patients with adenocarcinomas (P <= 0.001). The EGFR exon 20 T790M mutation was detected in only one of the paired samples [100% (95% CI, 96% to 100%) agreement]. For KRAS, proto-oncogene B-Raf, and phosphatidylinositol 3-kinase CA mutations, the overall agreements were 97% (95% CI, 90% to 99%), 98% (95% CI, 92% to 99%), and 97% (95% CI, 90% to 99%), respectively, and these were not associated with age, sex, smoking history, or histopathologic type. In conclusion, mutations detected in plasma correlated strongly with mutation profiles in each respective tumor sample, suggesting that this liquidchip platform may offer a rapid and noninvasive method for predicting tumor responsiveness to EGFR-tyrosine kinase inhibitor drugs in patients with advanced non-small-cell lung cancers. PMID- 23988625 TI - Protection of renal function by green tea extract during Plasmodium berghei infection. AB - Impairment of renal function from oxidative stress during malaria infection is one of the leading causes of death in endemic areas. Since blood urea nitrogen and creatinine levels in plasma can be used as markers for monitoring renal damage, this study investigated the effect of green tea extract on reduction of blood urea nitrogen and creatinine levels during malaria infection using Plasmodium berghei ANKA infected mice as in vivo model. For in vivo testing, ICR mice were infected with 1 * 10(7) parasitized erythrocytes and green tea extract was subsequently administered orally twice a day for 10 consecutive days. Parasitemia was estimated by standard microscopy, and blood urea nitrogen and creatinine levels in plasma were also measured. It was found that parasitemia kept increasing until animal death, and is strongly correlated with high blood urea nitrogen and creatinine. The highest levels of blood urea nitrogen and creatinine in plasma were found on day 10 after infection. However, blood urea nitrogen and creatinine levels in plasma were reduced and decreased significantly (p<0.01) in green tea extract treated mice, compared with untreated group. It can be concluded that green tea extract can protect and maintain renal function during malaria infection, and this extract can be developed for use as a supplement and combination therapy. PMID- 23988623 TI - Interleukin-6 expands homeostatic space for peripheral T cells. AB - T cell homeostasis and survival is dependent on interleukin-7 (IL-7). Immune activation, however, downregulates IL-7 receptor expression on T cells so that T cell survival during activation must be maintained independently of IL-7. The pro inflammatory cytokine IL-6 shares common signaling pathways with IL-7 and can promote T cell survival in vitro. But whether IL-6 promotes T cell survival and homeostasis in vivo is not clear. Notably, IL-6 overexpression results in massive plasmacytosis and autoimmunity so that an IL-6 effect on in vivo T cell survival has remained untested. To overcome this limitation, here we generated IL-6 transgenic mice on an immunoglobulin heavy chain (IgH) deficient background which rendered them B cell deficient. Notably, such IgH(KO)IL6(Tg) mice were free of any signs of inflammation or autoimmunity and remained healthy throughout the course of analysis. In these mice, we found that IL-6 overexpression significantly increased peripheral T cell numbers, but importantly without increasing thymopoiesis. Moreover, IL-6 signaled T cells maintained their naive phenotype and did not express activation/memory markers, suggesting that increased T cell numbers were due to increased T cell survival and not because of expansion of activated T cells. Mechanistically, we found that IL-6 signaling induced expression of pro-survival factors Mcl-1 and Pim-1/-2 but not Bcl-2. Thus, IL-6 is a T cell homeostatic cytokine that expands T cell space and can maintain the naive T cell pool. PMID- 23988626 TI - Enzyme-linked immunosorbent assay for the diagnosis of Wuchereria bancrofti infection using urine samples and its application in Bangladesh. AB - In Sri Lanka, urine ELISA showed high sensitivity and specificity in detecting filaria-specific IgG4. It also produced much higher positive rates than antigen tests in prevalence studies with young children. In this study, we have confirmed the usefulness of urine ELISA in the field of Bangladesh. The ELISA detected 89 of 105 (85%) ICT antigen test positive subjects in endemic areas. With both ICT and microfilaria positives, the sensitivity was 97% (30/31). All of 104 ICT negative people in a non-endemic area were ELISA negative (100% specificity). In a prevalence study with 319 young children (5-10 years) from a low endemic area after five rounds of MDA, seven (2.2%) were detected by the present urine test, but only one (0.3%) by ICT (P=0.075). The satisfactorily high sensitivity, 100% specificity and effective case detection among young ages along with scope for analyzing the titers will indicate urine ELISA to be an effective tool in the post-MDA surveys to confirm elimination or to detect resurgence in Bangladesh. PMID- 23988627 TI - Inverted follicular keratosis: dermoscopic and reflectance confocal microscopic features. AB - Inverted follicular keratosis (IFK) is a rare benign tumor which usually appears as a firm papule on the face. The diagnosis is generally made by histopathology because the clinical appearance is difficult to differentiate from other lesions. Dermoscopic features of IFK have not been established to date. Herein we describe the dermoscopic findings of 4 cases of IFK. Radial peripheral hairpin vessels surrounded by a whitish halo arranged around a central white-yellowish amorphous area were observed in 3 cases, and glomerular vessels were present in the central area of one of them. The fourth case also presented a central white amorphous area but showed arborizing vessels. Reflectance confocal microscopy (available in 1 case) revealed a broadened honeycomb pattern, epidermal projections and hairpin and glomerular vessels. To our knowledge this is the first case series describing the dermoscopic features of inverted follicular keratosis and the first confocal microscopy description of this entity. PMID- 23988628 TI - Absence of high molecular weight proteins 1 and/or 2 is associated with decreased adherence among non-typeable Haemophilus influenzae clinical isolates. AB - High molecular weight (Hmw) proteins 1 and 2, type IV pilin protein (PilA), outer membrane protein P5 (OmpP5), Haemophilus protein D (Hpd) and Haemophilus adhesive protein (Hap) are surface proteins involved in the adherence of non-typeable Haemophilus influenzae. One hundred clinical isolates were evaluated for the presence of the genes encoding these proteins by PCR and for their adherence capacity (AC) to Detroit 562 nasopharyngeal cells (D562). The majority of isolates were from blood (77/100); other sites were also represented. Confluent D562 monolayers (1.2*10(5) cells per well) were inoculated with standardized minimal infective doses (m.o.i.) of 10(2), 10(3) or 10(4) c.f.u. per well. The AC was categorized as low (<10 %) or high (>=10 %) depending on the percentage of c.f.u. adhering per well. All the isolates evaluated showed adherence: 69/100 (69 %) demonstrated high adherence, while 31/100 (31 %) showed low adherence. Of all the genes evaluated, hmw1A and/or hmw2A were detected in 69/100 (69 %) of isolates. The presence of hmw1A and/or hmw2A was associated with increased adherence to D562 cells (P<=0.001). Dot immunoblots were performed to detect protein expression using mAbs 3D6, AD6 and 10C5. Among the high-adherence isolates (n = 69), 72 % reacted with 3D6 and 21 % with 10C5. Our data indicate that the absence of Hmw1 and/or Hmw2 was associated with decreased adherence to D562 cells. PMID- 23988629 TI - Stenotrophomonas maltophilia: pathogenesis model using Caenorhabditis elegans. PMID- 23988630 TI - Prevalence and molecular epidemiology of plasmid-mediated fosfomycin resistance genes among blood and urinary Escherichia coli isolates. AB - A total of 1878 non-duplicate clinical Escherichia coli isolates (comprising 1711 urinary isolates and 167 blood-culture isolates), which were collected from multiple centres in Hong Kong during 1996-2008, were used to investigate the prevalence and molecular epidemiology of plasmid-mediated fosfomycin (fos) resistance genes. Eighteen of the 1878 clinical E. coli isolates were fosfomycin resistant, of which six were fosA3 positive and two were positive for another fosA variant (designated fosKP96). No isolates had the fosC2 gene. The clones of the eight isolates were diverse: sequence type (ST) 95 (n = 2), ST118 (n = 1), ST131 (n = 1), ST617 (n = 1), ST648 (n = 1), ST1488 (n = 1) and ST2847 (n = 1). In the isolates, fosA3 and blaCTX-M genes were co-harboured on conjugative plasmids with F2:A-:B- (n = 2), N (n = 1), F-:A-:B1 and N (n = 1) and untypable (n = 2) replicons. Both fosKP96-carrying plasmids belonged to replicon N. RFLP analysis showed that the two F2:A-:B- plasmids carrying fosA3 and blaCTX-M-3 genes shared the same pattern. Complete sequencing of one of the two F2:A-:B- plasmids, pFOS-HK151325 (69 768 bp) demonstrated it to be >99 % identical to the previously sequenced plasmid pHK23a originating from a pig E. coli isolate in the same region. This study demonstrated the dissemination of fosA3 genes in diverse E. coli clones on multiple blaCTX-M-carrying plasmid types, of which F2:A-:B- plasmids closely related to pHK23a were shared by isolates from human and animal sources. PMID- 23988631 TI - Subdural haematoma in Plasmodium falciparum and Plasmodium vivax mixed infection presenting multiple clinical complications. AB - A 40-year-old man was admitted to hospital with a 5 day history of fever, restlessness and altered sensorium. Peripheral blood smears showed a Plasmodium vivax and Plasmodium falciparum mixed infection as revealed by the presence of rings, schizonts and gametocyte forms of the parasites. The patient soon became unconscious due to subdural haematoma (SDH) associated with disseminated intravascular coagulation and thrombocytopenia. Immediate intervention with a right fronto-parieto temporal craniectomy, evacuation of the SDH and intravenous quinine administration resulted in the patient's complete recovery within 8 days of admission, and he was discharged in good clinical condition. PMID- 23988632 TI - Trainee report dashboard: tool for enhancing feedback to radiology trainees about their reports. AB - During their radiology residency, trainees must learn multiple facets of radiology practice, including the writing of radiology reports. An important factor in the trainee's development of reporting skills is feedback from the attending radiologist on the trainee's preliminary reports. The quality and quantity of feedback may vary and are not typically documented. As radiology department workloads have increased and stricter limitations have been imposed on trainee work hours, less time is available for attending radiologists and trainees to perform a joint retrospective review of radiology reports. To compensate, the authors have developed a Web-based dashboard that provides trainees with case-specific feedback about their reports. Components include an attending radiologist-trainee report discrepancy logging and communication system that is integrated with the institutional picture archiving and communication system, an automated preliminary report-final report comparator, modules showing statistics related to the discrepancy logger and report comparator components, and a Web page that unifies these components with image and report display capabilities. Both the actual report feedback and the trainee's use of the system are documented, and the resultant data may be used for evaluating trainee competence in written communication, as mandated by the Accreditation Council for Graduate Medical Education. With these tools, trainees can obtain near-real-time feedback, which may pinpoint issues that can be corrected to improve the quality of their radiology reporting. This system, although it does not supplant face-to face training sessions with attending radiologists, can augment traditional methods of learning. PMID- 23988633 TI - Practice policy and quality initiatives quality improvement and confirmation projects: facilitating rapid, measurable performance improvement. AB - As radiology departments continue to increase in size and complexity, the process of improving and maintaining excellent performance is becoming increasingly challenging. In response, a systematic process for efficiently implementing and sustaining measurable improvement in our radiology department has been developed, which targets focused aspects of individual performance that contribute to overall departmental quality. Projects designed to achieve such improvements have been called quality improvement and confirmation (QuIC) projects. The QuIC project process involves a project champion, medical expert, technical expert, quality improvement technologist specialist, and appropriate leaders, managers, and support personnel. The project champion conducts a preliminary investigation and organizes team members, who define the desired performance through consensus, establish data collection and analysis procedures, and prepare to launch the project. Once launched, the QuIC project process follows an execution period that is divided into four phases: (a) project launch phase, (b) support phase, (c) transition phase, and (d) maintenance phase. The first three phases focus on education, group-level feedback, and individual feedback, respectively. Weekly audits are performed to track performance improvement. Data collection, analysis, and dissemination processes are automated to the extent possible. To date, four such projects have been successfully conducted. The QuIC project concept is an attempt to apply the principles of process improvement to the process of process improvement by enabling any member of a radiology department to efficiently and reliably spearhead a quality improvement project. We consider this to be a work in progress and continue to refine the process with the goal of eventually being able to conduct many projects simultaneously. PMID- 23988634 TI - Long-term efficacy of entecavir plus adefovir combination therapy versus entecavir monotherapy in adefovir refractory chronic hepatitis B patients with prior lamivudine resistance. AB - OBJECTIVES: We investigated the long-term efficacy of entecavir (ETV) + adefovir (ADV) combination therapy versus ETV monotherapy in lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients who failed to respond to ADV rescue therapy. METHODS: A total of 91 ADV refractory patients with prior LAM resistance received ETV (1.0 mg/day) + ADV (10 mg/day) combination therapy (group A, n = 45) or ETV (1.0 mg/day) monotherapy (group B, n = 46) for more than 48 weeks. RESULTS: The rates of undetectable serum hepatitis B virus DNA levels (<=20 IU/ml) at weeks 48 and 96 were not significantly different between group A and group B (31.1 vs. 23.9% at week 48, p = 0.442, and 44.7 vs. 34.5% at week 96, p = 0.457). However, the incidence of virological breakthrough in group A was significantly lower than that in group B (0 vs. 17.4% at week 48, p = 0.006, and 2.6 vs. 44.8% at week 96, p < 0.001). ETV monotherapy was the only independent factor significantly associated with virologic breakthrough (p = 0.015). CONCLUSIONS: ETV + ADV combination therapy is a better therapeutic option than ETV monotherapy for ADV refractory CHB patients with prior LAM resistance. PMID- 23988636 TI - A generic three-dimensional static force distribution basis for a medical needle inserted into soft tissue. AB - In this paper, the static interaction forces between a medical needle and soft tissue during CT (Computerized Tomography) guided insertion are studied. More precisely a set of linearly independent elements describing the forces (a basis) is identified. This forms a generic basis from which any forces that act on a static needle (that is not fixed at its base and that is inserted into human tissue) can be described accurately. To achieve this purpose, the same needle was inserted 62 times into fresh porcine shoulder tissue and CT scans were acquired after each push to determine the final trajectory of the needle. From this set of trajectories, a generic static force basis was determined by using static Beam, B spline theories and Principal Component Analysis (PCA). This generic basis was first validated on theoretical simulations and then on 20 different needles inserted into in vivo human tissues during real clinical interventions. Such a basis could be of use to highlight the forces acting all along the length of a needle inserted into a complex tissue and enables models of needle deflection to be developed. These models could be used in the development of automated robot assisted and/or image guided strategies for needle steering. PMID- 23988635 TI - The structural role of radial glial endfeet in confining spinal motor neuron somata is controlled by the Reelin and Notch pathways. AB - Neuronal migration is a fundamental biological process that enables the precise positioning of neurons to form functional circuits. Cortical neurons migrate along glial scaffolds formed by radial glia guided by Reelin ligand. However, it is unclear whether the Reelin-directed behavior of radial glia is also critical for positioning the spinal neurons. Here we demonstrate a novel role of radial glia that confines motor neurons within the neural tube and is promoted by Reelin and Notch signaling. Spinal radial glia express the Dab1 adaptor for Reelin signaling and are surrounded by Reelin. In reeler mice, in which Reelin is absent, ectopic motor neurons are found outside the neural tube, although they appear to maintain their identity. Boundary cap (BC) cells, Schwann cell precursors and the basal lamina at motor exit points are intact, whereas the glia limitans of radial glia are disorganized and detached from the basement membrane. The sparse and irregular radial scaffold is wide enough to allow motor somata to pass. Forced activation of Notch signaling rescued the structural defects in radial glia in reeler mice and the appearance of extraspinal neurons. In the absence of Reelin, Notch intracellular domain (NICD) protein level was reduced. In addition, disrupting the radial glia scaffold by destroying its polarity induced ectopic motor neurons in chick embryos. These findings suggest that activation of the Notch pathways by Reelin is required to establish the radial glial scaffold, a structure that actively constrains motor neuron somata and specifies the CNS-PNS boundary. PMID- 23988637 TI - Phase-sensitivity of Li intercalation into Sn. AB - Using density functional theory, we investigate Li intercalation into Sn and find a strong phase-sensitivity in the energy barriers. The rate determining steps of this process are bulk diffusion and surface penetration in alpha-Sn and beta-Sn, respectively. Although the energy barrier for bulk diffusion is lower in beta-Sn, the energy barrier for surface intercalation is much higher in beta-Sn than in alpha-Sn. Our calculations suggest that Li intercalation into alpha-Sn nanoparticles is kinetically more favorable than beta-Sn nanoparticles. PMID- 23988638 TI - Interactions within stroke systems of care: a policy statement from the American Heart Association/American Stroke Association. PMID- 23988639 TI - Low glomerular filtration rate, recurrent stroke risk, and effect of renin angiotensin system modulation. AB - BACKGROUND AND PURPOSE: To investigate the association of low estimated glomerular filtration rate (eGFR) <60 mL/min with recurrent stroke risk and to evaluate whether add-on renin-angiotensin system modulator therapy is associated with lower recurrent stroke risk in patients with low eGFR. METHODS: We analyzed the database of a multicenter trial involving 18,666 patients with recent ischemic stroke followed for 2.5 years. Primary outcome was time to first recurrent stroke. Independent associations of low eGFR with outcome in the entire cohort and add-on telmisartan treatment with outcome among those with low eGFR were evaluated. RESULTS: Low eGFR was observed in 3630 (20.1%) patients. Patients with low eGFR were older, more likely women, with a known history of hypertension. In unadjusted analyses, patients with low eGFR were more likely to experience a recurrent stroke (hazard ratio, 1.34; 95% confidence interval, 1.20 1.49). After adjusting for confounders, low eGFR was still associated with recurrent stroke but to a lesser extent (hazard ratio, 1.16; 95% confidence interval, 1.04-1.31). Telmisartan treatment among patients with low eGFR was not independently associated with recurrent stroke (hazard ratio, 1.08; 95% confidence interval, 0.89-1.31). CONCLUSIONS: Low eGFR is independently associated with a higher risk of recurrent stroke, but short-term add-on telmisartan therapy does not seem to mitigate this risk. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153062. PMID- 23988640 TI - Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: MRI characterization of carotid plaque has been studied recently as a potential tool to predict stroke caused by carotid atherosclerosis. We performed a systematic review and meta-analysis to summarize the association of MRI-determined intraplaque hemorrhage, lipid-rich necrotic core, and thinning/rupture of the fibrous cap with subsequent ischemic events. METHODS: We performed a comprehensive literature search evaluating the association of carotid plaque composition on MRI with ischemic outcomes. We included cohort studies examining intraplaque hemorrhage, lipid-rich necrotic core, or thinning/rupture of the fibrous cap with mean follow-up of >=1 month and an outcome measure of ipsilateral stroke or transient ischemic attack. A meta-analysis using a random effects model with assessment of study heterogeneity and publication bias was performed. RESULTS: Of the 3436 articles screened, 9 studies with a total of 779 subjects met eligibility for systematic review. The hazard ratios for intraplaque hemorrhage, lipid-rich necrotic core, and thinning/rupture of the fibrous cap as predictors of subsequent stroke/transient ischemic attack were 4.59 (95% confidence interval, 2.91-7.24), 3.00 (95% confidence interval, 1.51-5.95), and 5.93 (95% confidence interval, 2.65-13.20), respectively. No statistically significant heterogeneity or publication bias was present in the 3 main meta analyses performed. CONCLUSIONS: The presence of intraplaque hemorrhage, lipid rich necrotic core, and thinning/rupture of the fibrous cap on MRI of carotid plaque is associated with increased risk of future stroke or transient ischemic attack in patients with carotid atherosclerotic disease. Dedicated MRI of plaque composition offers stroke risk information beyond measurement of luminal stenosis in carotid atherosclerotic disease. PMID- 23988641 TI - Test accuracy of short screening tests for diagnosis of delirium or cognitive impairment in an acute stroke unit setting. AB - BACKGROUND AND PURPOSE: Guidelines recommend cognitive screening in acute stroke. Various instruments are available, with no consensus on a preferred tool. We aimed to describe test accuracy of brief screening tools for diagnosis of cognitive impairment and delirium in acute stroke. METHODS: We collected data on sequential stroke unit admission in a single center. Four assessors trained in cognitive testing independently performed screening and reference tests. Brief assessments comprised the following: 10- and 4-point Abbreviated Mental Test (AMT 10; AMT-4); 4-A Test (4AT); Clock Drawing Test (CDT); Cog-4; and Glasgow Coma Scale (GCS). We also recorded the multidisciplinary team's informal review using single question (SQ). We compared against reference standards of Montreal Cognitive Assessment (MoCA) and Confusion Assessment Method for delirium using usual diagnostic cutpoints. For MoCA, we described effects of lowering the diagnostic threshold to MoCA <24 and MoCA <20. We described sensitivity, specificity, and positive and negative predictive values. RESULTS: Over a 10-week period, 111 subjects had cognitive assessment data. Subjects were 50% male (n=55), and median age was 74 years (interquartile range, 64-85). AMT-4, AMT-10, and SQ all had excellent (1.00) specificity for detection of cognitive impairment, although sensitivity was poor (all <0.60). The 4AT had greatest sensitivity for detecting delirium (1.00 [confidence interval [CI], 0.74-1.00]) and reasonable specificity (0.82 [CI, 0.72-0.89]). Properties of 4AT for detection of cognitive impairment, at the traditional MoCA threshold, were also good (sensitivity, 0.86; specificity, 0.78). Using diagnostic thresholds of MoCA <=26, <24, and <20 gave proportions with cognitive impairments of 86%, 61%, and 49%, respectively, with resulting changes in screening test properties. At lower MoCA thresholds, CDT had favorable sensitivity and specificity (MoCA <20: sensitivity, 0.93, specificity, 0.66; MoCA <24: sensitivity, 0.85, specificity, 0.77). CONCLUSIONS: Many brief screening assessments are specific but not sensitive for detection of cognitive impairment in acute stroke. Our primary analysis suggests that 4AT is a reasonable choice for delirium and cognitive screening in this setting. However, these data are based on standard MoCA diagnostic threshold and may not be suited for an acute stroke population. PMID- 23988642 TI - Deficient eNOS phosphorylation is a mechanism for diabetic vascular dysfunction contributing to increased stroke size. AB - BACKGROUND AND PURPOSE: Phosphorylation of eNOS, an important post-translational modulator of its enzymatic activity, is reduced in diabetes mellitus. We hypothesized that modulation of eNOS phosphorylation could overcome diabetic vascular dysfunction and improves the outcome to stroke. METHODS: We used the db/db mouse model of type 2 diabetes mellitus. We mated db/db mice with eNOS knock-in mice that carry single amino acid mutations at the S1176 phosphorylation site; the phosphomimetic SD mutation (serine replaced by aspartate) shows increased eNOS enzymatic activity, whereas the unphosphorylatable SA mutation (serine replaced by alanine) shows decreased eNOS activity. We characterized the vascular anatomy, baseline physiological parameters, and vascular reactivity. We used the middle cerebral artery occlusion model of stroke and measured infarct volume and neurological deficits. RESULTS: db/db mice showed diminished eNOS phosphorylation at S1176. eNOS SD and SA mutations do not change the vascular anatomy at the Circle of Willis, brain capillary density, heart rate, or arterial blood gases of db/db mice. The eNOS SD mutation, but not the SA mutation, lowers blood pressure and improves vascular reactivity to acetylcholine in db/db mice. The eNOS SD mutation reduces stroke size and neurological deficit after middle cerebral artery occlusion. CONCLUSIONS: Diminished eNOS phosphorylation is a mechanism of vascular dysfunction in db/db mice. We show here that modulation of the eNOS S1176 phosphorylation site in db/db mice is associated with improved vascular reactivity and improved outcome to stroke after middle cerebral artery occlusion. PMID- 23988644 TI - INTERACT-2: should blood pressure be aggressively lowered acutely after intracerebral hemorrhage? PMID- 23988643 TI - Admission insular infarction >25% is the strongest predictor of large mismatch loss in proximal middle cerebral artery stroke. AB - BACKGROUND AND PURPOSE: Previous univariate analyses have suggested that proximal middle cerebral artery infarcts with insular involvement have greater severity and are more likely to progress into surrounding penumbral tissue at risk. We hypothesized that a practical, simple scoring method to assess percent insular ribbon infarction (PIRI score) would improve prediction of penumbral loss over other common imaging biomarkers. METHODS: Of consecutive acute stroke patients from 2003 to 2008, 45 with proximal middle cerebral artery-only occlusion met inclusion criteria, including available penumbral imaging. Infarct (diffusion weighted imaging), tissue at risk (magnetic resonance mean transit time), and final infarct volume (magnetic resonance/computed tomography) were manually segmented. Diffusion-weighted imaging images were rated according to the 5-point PIRI score (0, normal; 1, <25%; 2, 25%-49%; 3, 50%-74%; 4, >=75% insula involvement). Percent mismatch loss was calculated as an outcome measure of infarct progression. Receiver operating characteristic curve and multivariate analyses were performed. RESULTS: Mean admission diffusion-weighted imaging infarct volume was 30.9 (+/-38.8) mL and median (interquartile range) PIRI score was 3 (0.75-4). PIRI score was significantly correlated with percent mismatch loss (P<0.0001). When percent mismatch loss was dichotomized based on its median value (30.0%), receiver operating characteristic curve area under curve was 0.89 (P=0.0001) with a 25% insula infarction optimal threshold. After adjusting for time to imaging and treatment, binary logistic regression, including dichotomized PIRI (25% threshold), age, National Institutes of Health Stroke Scale score, diffusion-weighted imaging infarct volume, and computed tomography angiography collateral score as covariates, revealed that only dichotomized insula score (P=0.03) and age (P=0.02) were independent predictors of large (68.2%) versus small (8.1%) mismatch loss. There was excellent interobserver agreement for dichotomized PIRI scoring (kappa=0.91). CONCLUSIONS: Admission insular infarction >25% is the strongest predictor of large mismatch loss in this cohort of proximal middle cerebral artery occlusive stroke. This outcome marker may help to identify treatment-eligible patients who are in greatest need of rapid reperfusion therapy. PMID- 23988645 TI - Stroke care units versus general medical wards for acute management of stroke in Japan. AB - BACKGROUND AND PURPOSE: The Japanese stroke guideline recommends the use of stroke care units (SCUs) for acute stroke treatment, but few SCUs have been established and the evidence supporting their use is limited. The aim of this study was to evaluate the efficacy of SCUs compared with general medical wards (GMWs). METHODS: A multicenter observational study was conducted using a large administrative database involving 52 hospitals; patients with either intracerebral hemorrhage or cerebral infarction were included. In-hospital mortality was the primary end point, and this parameter as well as the proportion of patients with a modified Rankin Scale score of <=2 at discharge were compared between patients who were treated at SCUs and GMWs. Propensity score matching was performed to correct for selection bias. RESULTS: A total of 6977 patients were identified, of which 4527 patients were admitted to SCUs and 2450 patients were admitted to GMWs. The in-hospital mortality of patients with intracerebral hemorrhage was 14.8% and 24.1% in SCUs and GMWs, respectively (P=0.0004); the mortality of patients with cerebral infarction was 3.6% and 5.7%, respectively (P=0.003). Multivariate analysis in propensity score-matched pairs indicated significantly lower risk of death in the SCU group among patients with both intracerebral hemorrhage (odds ratio, 0.36; P=0.0007) and cerebral infarction (odds ratio, 0.60; P=0.02). However, the proportions of patients with a modified Rankin Scale score of <=2 were not significantly different between SCUs and GMWs. CONCLUSIONS: SCUs were associated with a reduced risk of in-hospital mortality of stroke patients compared with GMWs alone. PMID- 23988646 TI - Quantitative analysis of hypoperfusion in acute stroke: arterial spin labeling versus dynamic susceptibility contrast. AB - BACKGROUND AND PURPOSE: This study compares the concordance between arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) for the identification of regional hypoperfusion and diffusion-perfusion mismatch tissue classification using a quantitative method. METHODS: The inclusion criteria for this retrospective study were as follows: patients with acute ischemic syndrome with symptom onset <24 hours and acquisition of both ASL and DSC MR perfusion. The volumes of infarction and hypoperfused lesions were calculated on ASL and DSC multi-parametric maps. Patients were classified into reperfused, matched, or mismatch groups using time to maximum >6 sec as the reference. In a subset of patients who were successfully recanalized, the identical analysis was performed and the infarction and hypoperfused lesion volumes were used for paired pre- and posttreatment comparisons. RESULTS: Forty-one patients met our inclusion criteria. Twenty patients underwent successful endovascular revascularization (TICI>2a), resulting in a total of 61 ASL-DSC data pairs for comparison. The hypoperfusion volume on ASL-cerebral blood flow best approximated the DSC-time to peak volume (r=0.83) in pretreatment group and time to maximum (r=0.46) after recanalization. Both ASL-cerebral blood flow and DSC-TTP overestimated the hypoperfusion volume compared with time to maximum volume in pretreatment (F=27.41, P<0.0001) and recanalized patients (F=8.78, P<0.0001). CONCLUSIONS: ASL cerebral blood flow overestimates the DSC time to maximum hypoperfusion volume and mismatch classification in patients with acute ischemic syndrome. Continued overestimation of hypoperfused volume after recanalization suggests flow pattern and velocity changes in addition to arterial transit delay can affects the performance of ASL. PMID- 23988647 TI - Occupational noise exposure and the risk of stroke. AB - BACKGROUND AND PURPOSE: Traffic noise <60 dB(A) has been associated with an increased risk of stroke. We investigated this relationship for 80 to 86 dB(A) occupational noise. METHODS: We followed 116,568 industrial and 47,679 financial workers by linkage to Danish registries 2001 through 2007. Full-shift noise levels were estimated from subsets of workers at baseline and end of follow-up. RESULTS: We identified 981 stroke patients and observed a 27% increased confounder-adjusted risk of stroke for industrial compared with financial workers. However, longer duration or higher noise level within the industrial workers were unrelated to the risk of stroke. CONCLUSIONS: Our study did not support an association between occupational noise exposure and stroke, and the higher risk among industrial workers may reflect lifestyle differences. PMID- 23988648 TI - miR-224 is critical for celastrol-induced inhibition of migration and invasion of hepatocellular carcinoma cells. AB - BACKGROUND/AIMS: The molecular mechanisms of celastrol on hepatocellular carcinoma (HCC) cells migration and invasion ability is the major problem that prompted the study. METHODS: We first evaluated the effect of celastrol on migration and invasion ability of HepG2 cells using transwell migration and matrigel invasion assays. Next, we assessed the effect of celastrol on NF-kappaB transcriptional activity in hepatocellular carcinoma cells using western blot and luciferase reporter assay. We also performed real-time PCR to measure miR-224, MMP-2 and MMP-9 expression. Western blot was used to measure protein expression of MMP-2 and MMP-9. Furthermore, we used miR-224 inhibitor to evaluate whether down-regulation of miR-224 expression can affect MMP-2 and MMP-9 expression. The binding ability of p65/NF-kappaB on the miR-224 promote has been assessed by chromatin immunoprecipitation and quantitative real-time PCR (ChIP-qPCR). Finally, we evaluated the effect of miR-224 on celastrol-induced anti-tumor activity using miR-224 precursor. RESULTS: Celastrol significantly impaired migration and invasion of HepG2 cells and inhibited the activation of NF-kappaB and Akt in dose-dependent manner. IGF (the strong stimulator of Akt) inhibited the transcriptional activity of NF-kappaB in cells treated with celastrol. Besides, celastrol efficiently decreased the expression of miR-224 and protein expression of MMP-2 and MMP-9. ChIP-qPCR showed that p65/NF-kappaB binding to the miR-224 promoter sharply decreased after exposure to celastrol in time-dependent manner. Furthermore, inhibition of miR-224 expression can decrease MMP-9 protein level. Most importantly, miR-224 precursor can reverse the effect of celastrol on impairment of migration and invasion in HepG2 and Huh7 cells. CONCLUSION: Celastrol treatment inhibits migration and invasion of HCC cell and that the effect is partly due to NF-kappaB regulating miR-224 expression. PMID- 23988649 TI - On the estimation and correction of bias in local atrophy estimations using example atrophy simulations. AB - Brain atrophy is considered an important marker of disease progression in many chronic neuro-degenerative diseases such as multiple sclerosis (MS). A great deal of attention is being paid toward developing tools that manipulate magnetic resonance (MR) images for obtaining an accurate estimate of atrophy. Nevertheless, artifacts in MR images, inaccuracies of intermediate steps and inadequacies of the mathematical model representing the physical brain volume change, make it rather difficult to obtain a precise and unbiased estimate. This work revolves around the nature and magnitude of bias in atrophy estimations as well as a potential way of correcting them. First, we demonstrate that for different atrophy estimation methods, bias estimates exhibit varying relations to the expected atrophy and these bias estimates are of the order of the expected atrophies for standard algorithms, stressing the need for bias correction procedures. Next, a framework for estimating uncertainty in longitudinal brain atrophy by means of constructing confidence intervals is developed. Errors arising from MRI artifacts and bias in estimations are learned from example atrophy simulations and anatomies. Results are discussed for three popular non rigid registration approaches with the help of simulated localized brain atrophy in real MR images. PMID- 23988650 TI - [Fluid therapy in acute pancreatitis]. AB - Severe acute pancreatitis (AP) is associated with an increased need for fluids due to fluid sequestration and, in the most severe cases, with decreased peripheral vascular tone. For several decades, clinical practice guidelines have recommended aggressive fluid therapy to improve the prognosis of AP. This recommendation is based on theoretical models, animal studies, and retrospective studies in humans. Recent studies suggest that aggressive fluid administration in all patients with AP could have a neutral or harmful effect. Fluid therapy based on Ringer's lactate could improve the course of the disease, although further studies are needed to confirm this possibility. Most patients with AP do not require invasive monitoring of hemodynamic parameters to guide fluid therapy administration. Moreover, the ability of these parameters to improve prognosis has not been demonstrated. PMID- 23988651 TI - Dendritic cells from the elderly display an intrinsic defect in the production of IL-10 in response to lithium chloride. AB - Chronic, low grade inflammation is a characteristic of old age. Innate immune system cells such as dendritic cells (DCs) from the elderly display a pro inflammatory phenotype associated with increased reactivity to self. Lithium is a well-established anti-inflammatory agent used in the treatment of bipolar disorders. It has also been reported to reduce inflammation in DCs. Here, we investigated whether Lithium is effective in reducing the inflammatory responses in DCs from the elderly. The effect of Lithium Chloride (LiCl) was compared on the response of TLR4 agonist, LPS and TLR2 agonist, PAM3CSK4 stimulated aged and young DCs. LiCl enhanced the production of IL-10 in LPS stimulated young DCs. However, it did not affect TNF-alpha and IL-6 production. In contrast, in aged DCs, LiCl reduced the secretion of TNF-alpha and IL-6 in LPS stimulated DCs but did not increase IL-10. LiCl had no significant effect on PAM3CSK4 responses in aged and young DCs. LiCl treated DCs also displayed differences at the level of CD4 T cell priming and polarization. LPS-stimulated young DCs reduced IFN-gamma secretion and biased the Th cell response towards Th2/Treg while LiCl treated aged DCs only reduced IFN-gamma secretion but did not bias the response towards Th2/Treg. In summary, our data suggests that LiCl reduces inflammation in aged and young DCs via different mechanisms. Furthermore, the effect of LiCl is different on LPS and PAM3CSK4 responses. PMID- 23988652 TI - Short-term starvation for cancer control in humans. PMID- 23988654 TI - Ceramide synthesis in the epidermis. AB - The epidermis and in particular its outermost layer the stratum corneum provides terrestrial vertebrates with a pivotal defensive barrier against water loss, xenobiotics and harmful pathogens. A vital demand for this epidermal permeability barrier is the lipid-enriched lamellar matrix that embeds the enucleated corneocytes. Ceramides are the major components of these highly ordered intercellular lamellar structures, in which linoleic acid- and protein-esterified ceramides are crucial for structuring and maintaining skin barrier integrity. In this review, we describe the fascinating diversity of epidermal ceramides including 1-O-acylceramides. We focus on epidermal ceramide biosynthesis emphasizing its metabolic and topological requirements and discuss enzymes that may be involved in alpha- and omega-hydroxylation. Finally, we turn to epidermal ceramide regulation, highlighting transcription factors and liposensors recently described to play crucial roles in modulating skin lipid metabolism and epidermal barrier homeostasis. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. PMID- 23988653 TI - Longer leukocyte telomere length in Costa Rica's Nicoya Peninsula: a population based study. AB - Studies in humans suggest that leukocyte telomere length may act as a marker of biological aging. We investigated whether individuals in the Nicoya region of Costa Rica, known for exceptional longevity, had longer telomere length than those in other parts of the country. After controlling for age, age squared, rurality, rainy season and gender, the mean leukocyte telomere length in Nicoya was substantially longer (81 base pairs, p<0.05) than in other areas of Costa Rica, providing evidence of a biological pathway to which this notable longevity may be related. This relationship remains unchanged (79 base pairs, p<0.05) after statistically controlling for nineteen potential biological, dietary and social and demographic mediators. Thus the difference in the mean leukocyte telomere length that characterizes this unique region does not appear to be explainable by traditional behavioral and biological risk factors. More detailed examination of mean leukocyte telomere length by age shows that the regional telomere length difference declines at older ages. PMID- 23988656 TI - A multiplex RT-PCR assay for rapid and differential diagnosis of four porcine diarrhea associated viruses in field samples from pig farms in East China from 2010 to 2012. AB - Since October 2010, clinical outbreaks of diarrhea in suckling piglets have reemerged in pig-producing areas of China, causing an acute increase in the morbidity and mortality in young piglets. Four viruses, porcine epidemic diarrhea virus (PEDV), transmissible gastroenteritis virus (TGEV), porcine group A rotaviruses (GAR), and porcine circovirus 2 (PCV2), are the major causative agents of enteric disease in piglets. A novel multiplex reverse transcription polymerase chain reaction (mRT-PCR) was developed for simultaneous detection of the four viruses in field samples from piglets. A mixture of four previously published pairs of primers were used for amplification of viral gene, yielding four different amplicons with sizes of 481 bp for PCV2, 651 bp for PEDV, 859 bp for TGEV, and 309 bp for GAR, respectively. The sensitivity of the mRT-PCR using plasmids containing the specific viral target fragments was 2.17 * 10(3), 2.1 * 10(3), 1.74 * 10(4) and 1.26 * 10(4)copies for the four viruses, respectively. A total of 378 field samples were collected from suckling piglets with diarrhea in East China from October 2010 to December 2012, and detected by mRT-PCR. The PEDV positive rates of the three years were 69.2%, 62.8% and 54.9%, respectively, suggesting that PEDV was a major pathogen in these diarrheal outbreaks. Taken together, all data indicated that this mRT-PCR assay was a simple, rapid, sensitive, and cost-effective detection method for clinical diagnosis of mixed infections of porcine diarrhea associated viruses. PMID- 23988658 TI - Enhanced production of a self-toxic antibiotic xinghaiamine A from the novel marine-derived species Streptomyces xinghaiensis by resin addition. AB - An addition of 3% (w/v) adsorbent resin HP-20 at 3 days post-inoculation significantly improved xinghaiamine A production from 0.35 to 3.4 mg/L and shortened fermentation time from 18 to 9 days. Self-cytotoxicity of xinghaiamine A was verified and the minimal inhibitor concentration was estimated to be 8 MUg/mL. PMID- 23988655 TI - Loss of beta-carotene 15,15'-oxygenase in developing mouse tissues alters esterification of retinol, cholesterol and diacylglycerols. AB - We provide novel insights into the function(s) of beta-carotene-15,15'-oxygenase (CMOI) during embryogenesis. By performing in vivo and in vitro experiments, we showed that CMOI influences not only lecithin:retinol acyltransferase but also acyl CoA:retinol acyltransferase reaction in the developing tissues at mid gestation. In addition, LC/MS lipidomics analysis of the CMOI-/- embryos showed reduced levels of four phosphatidylcholine and three phosphatidylethanolamine acyl chain species, and of eight triacylglycerol species with four or more unsaturations and fifty-two or more carbons in the acyl chains. Cholesteryl esters of arachidonate, palmitate, linoleate, and DHA were also reduced to less than 30% of control. Analysis of the fatty acyl CoA species ruled out a loss in fatty acyl CoA synthetase capability. Comparison of acyl species suggested significantly decreased 18:2, 18:3, 20:1, 20:4, or 22:6 acyl chains within the above lipids in CMOI-null embryos. Furthermore, LCAT, ACAT1 and DGAT2 mRNA levels were also downregulated in CMOI-/- embryos. These data strongly support the notion that, in addition to cleaving beta-carotene to generate retinoids, CMOI serves an additional function(s) in retinoid and lipid metabolism and point to its role in the formation of specific lipids, possibly for use in nervous system tissue. PMID- 23988659 TI - In vivo effect of insulin to decrease matrix metalloproteinase-2 and -9 activity after arterial injury. AB - In vitro, insulin has both growth-promoting and vasculoprotective effects. In vivo, the effect of insulin is mainly protective. Insulin treatment (3 U/day) decreases smooth muscle cell (SMC) migration and neointimal growth after carotid angioplasty in normal rats maintained at normoglycemia by oral glucose. SMC migration requires limited proteolysis of the extracellular matrix, which is mediated by matrix metalloproteinases (MMPs). In this study, we investigated the effects of normoglycemic hyperinsulinemia on MMP activity after balloon angioplasty. Rats were divided into three groups: (1) control implants and tap water; (2) control implants and oral glucose, and (3) insulin implants (3 U/day) and oral glucose. RESULTS: Gelatin zymography revealed that insulin reduced the gelatinolytic activity of pro-MMP-2 by 46% (p < 0.05), MMP-2 by 44% (p < 0.05) and MMP-9 by 51% (p < 0.05) compared to controls after arterial injury. Insulin also reduced mRNA levels of MMP-2 (p < 0.05) and MMP-9 (p < 0.05) and protein levels of MMP-2 (p < 0.05). In contrast, there were no significant changes in membrane-type 1 MMP protein and tissue inhibitors of MMP activity after insulin treatment. Thus, these results suggest a mechanism by which insulin inhibits SMC migration and supports a vasculoprotective role for insulin in vivo. PMID- 23988662 TI - CXCR4 expression in bladder transitional cell carcinoma and its relationship with clinicopathological features. AB - OBJECTIVE: To elucidate the role of CXCR4 in the metastasis of bladder transitional cell carcinoma (BTCC) by examining CXCR4 expression in BTCC tissue and its correlation with clinicopathological features. METHODS: The expression of CXCR4 was assessed in bladder tissues from 70 BTCC patients and 18 normal controls, respectively, using immunohistochemistry. The correlation of CXCR4 expression with lymph node metastasis was also examined by determining the lymphatic vessel density (LVD). RESULTS: Overexpression of CXCR4 was detected in 58/70 (82.9%) BTCC tissues, whereas only in 3/18 (16.7%) normal bladder tissues. The expression was significantly higher in BTCC than that in normal controls (p < 0.01). CXCR4 expression level was closely associated with tumor size, pathological grades, clinical stages, and pelvic lymph node metastasis (p < 0.05). Multivariate analysis indicated that CXCR4 expression and lymph node metastasis were independent predictors for disease-free survival (both p < 0.05). The disease-free survival rate among the patients with high CXCR4 expression level was remarkably lower than that among the patients with no or low level expression (p < 0.01). CONCLUSION: Highly expressed in BTCC tissues, CXCR4 may play a critical role in the metastasis of BTCC, and the expression level in biopsy specimens might be a good indicator of lymph node metastasis. PMID- 23988663 TI - alpha2-3 Sialic acid glycoconjugate loss and its effect on infection with Toxoplasma parasites. AB - Recognition of sialylated glycoconjugates is important for host cell invasion by Apicomplexan parasites. Toxoplasma gondii parasites penetrate host cells via interactions between their microneme proteins and sialylated glycoconjugates on the surface of host cells. However, the role played by sialic acids during infection with T. gondii is not well understood. Here, we focused on the role of alpha2-3 sialic acid linkages as they appear to be widely expressed in vertebrates. Removal of alpha2-3 sialic acid linkages on macrophages by neuraminidase treatment did not influence the rate of infection or growth of T. gondii, nor did it affect phagocytosis in vitro. Sialyltransferase ST3Gal-I deficient mice (ST3Gal-I(-/-) mice) lost alpha2-3 sialic acid linkages in macrophages and spleen cells. The numbers of T. gondii-infected CD11b(+) cells in peritoneal cavities of the infected ST3Gal-I(-/-) mice were relatively lower than those of the infected wild type animals. In addition, CD8(+) T cell populations and numbers in the spleens and peritoneal cavities of the ST3Gal-I(-/-) mice were significantly lower than those in the wild type animals before and after the T. gondii infection. ST3Gal-I(-/-) mice had severe liver damage and reduced survival rates following peritoneal infection with T. gondii. Furthermore, adoptive transfer of immune CD8(+) cells from wild type mice to ST3Gal-I(-/-) mice increased their survival during infection with T. gondii. Our data show that parasite invasion via alpha2-3 sialic acid linkages might not contribute on host survival and indicate the impact that loss of alpha2-3 sialic acid linkages has on CD8(+) T cell populations, which are necessary for effective immune responses against infection with T. gondii. PMID- 23988664 TI - A circular analysis of chronobiology of Schistosoma japonicum cercarial emergence from hilly areas of Anhui, China. AB - About 46 mammal species have been suspected as reservoir hosts for Schistosoma japonicum and therefore the track of the target parasites, in relation to definitive host species, may be of great importance in terms of theoretical and practical implications. The circadian rhythm of cercariae emergence, a genetically controlled behavior for parasites to adapt to their definitive hosts, may seem to be a perfect biological marker for S. japonicum. In this study, a late (or nocturnal) cercarial emergence pattern was observed on the parasites from one hilly region in Anhui of China, where rodents serve as reservoirs, and on the first generation of the parasites. Moreover, by using the circular statistics, the homogeneity of parasites in such trait was also demonstrated. All these provide evidence for the genetically controlled biological trait, which seems essential in the investigation of macro- or micro-dynamics of parasite transmission of interest. This is particularly true in the case of S. japonicum when multiple parasite isolates or strains are more likely to exist. PMID- 23988665 TI - Epidemiological characteristics of norovirus associated with sporadic gastroenteritis among children from the 2006/2007 to 2011/2012 season in Nara Prefecture, Japan. AB - The present study aimed to describe the epidemiological characteristics of norovirus (NoV) associated with sporadic gastroenteritis in regional populations of Nara Prefecture, Japan, from the 2006/2007 to 2011/2012 epidemic season. Fecal specimens of sporadic gastroenteritis collected between September 2006 and August 2012 in Nara Prefecture were examined for the presence of NoV by reverse transcription-polymerase chain reaction. The NoV genotype was determined by nucleotide sequence analysis. In total, 274 NoVs associated with sporadic gastroenteritis were identified. We detected 10 different NoV genotypes: GI/3, GI/4, GI/8, GII/2, GII/3, GII/4, GII/6, GII/7, GII/12, and GII/13. A high NoV detection rate of 35.9% was identified in 1-year-old children. Among the 274 NoV isolates, 142 were obtained from males and 131 were obtained from females (the source of one was unknown). The most prevalent genotype was GII/4, accounting for 117 of the 192 different NoVs identified by sequencing. More epidemiological data will be required to determine the epidemiological characteristics of NoVs in other areas of Japan. PMID- 23988666 TI - Most regions of mouse epididymis are able to phagocytose immature germ cells. AB - The role of the epididymis as a quality control organ in preventing infertile gametes entering the ejaculate has been extensively explored, and it has been suggested that a specific region of mammalian epididymis is able to phagocytose abnormal germ cells. This study examines whether the epithelium of certain zones of the mouse epididymis can act as a selection barrier by removing immature germ cells from the lumen by phagocytosis. To detect the presence of immature germ cells in the epididymis, we generated transgenic mice expressing enhanced green fluorescent protein under the deleted in azoospermia-like (mDazl) promoter to easily identify immature germ cells under fluorescence microscopy. Using this technique, we observed that during the first stage of spermatogenesis in prepuberal mice, a wave of immature germ cells is released into the epididymis and that the immature epididymis is not able to react to this abnormal situation. By contrast, when immature germ cells were artificially released into the epididymis in adult mice, a phagocytic response was observed. Phagosomes appeared inside principal cells of the epididymal epithelium and were observed to contain immature germ cells at different degradation stages in different zones of the epididymis, following the main wave of immature germ cells. In this paper, we describe how the epididymal epithelium controls sperm quality by clearing immature germ cells in response to their artificially induced massive shedding into the epididymal lumen. Our observations indicate that this phenomenon is not restricted to a given epididymis region and that phagocytic capacity is gradually acquired during epididymal development. PMID- 23988667 TI - Consumer evaluation of palatability characteristics of a beef value-added cut compared to common retail cuts. AB - The objectives of this study were to educate consumers about value-added beef cuts and evaluate their palatability responses of a value cut and three traditional cuts. Three hundred and twenty-two individuals participated in the beef value cut education seminar series presented by trained beef industry educators. Seminar participants evaluated tenderness, juiciness, flavor, and overall like of four samples, bottom round, top sirloin, ribeye, and a value cut (Delmonico or Denver), on a 9-point scale. The ribeye and the value cut were found to be similar in all four attributes and differed from the top sirloin and bottom round. Correlations and regression analysis found that flavor was the largest influencing factor for overall like for the ribeye, value cut, and top sirloin. The value cut is comparable to the ribeye and can be a less expensive replacement. PMID- 23988668 TI - Differentiation of glutamatergic neurons from mouse embryonic stem cells requires raptor S6K signaling. AB - Although the mammalian target of rapamycin complex 1 (mTORC1) functions as an important signaling complex in many cellular processes, the role of mTORC1 in neurons derived from embryonic stem cells (ESCs) has been less explored. Here, using a modified protocol to differentiate mouse ESCs (mESCs) into almost uniform glutamatergic neurons, we explored the importance of raptor/mTORC1 in the differentiation of mESCs. Raptor gene-trap mESCs, and raptor-knockdown mESCs formed smaller-sized embryonic bodies than the wild type and failed to undergo neuronal differentiation. Treatment with 1MUM rapamycin starting at the point when neuronal precursors began to differentiate from mESCs caused the gradual loss of neurites, shrinkage of soma, and a decreased ratio of neurite length to cell number over 48 to 72h of treatment. This change was accompanied by activation of caspase-3 and S6 kinase (S6K), but not 4E-binding protein 1 (4EBP1). Knockdown of raptor during neuronal differentiation from mESCs also resulted in gradual loss of neurites and shrinkage of cell bodies. Loss of neurite density resulting from rapamycin treatment could be reversed by overexpression of S6K T389E. Taken together, these data demonstrate that raptor/mTORC1/S6K plays a critical role in the differentiation and survival of neurons derived from mESCs. PMID- 23988669 TI - Everything SAXS: small-angle scattering pattern collection and correction. AB - For obtaining reliable nanostructural details of large amounts of sample--and if it is applicable--small-angle scattering (SAS) is a prime technique to use. It promises to obtain bulk-scale, statistically sound information on the morphological details of the nanostructure, and has thus led to many a researcher investing their time in it over the last eight decades of development. Due to pressure from scientists requesting more details on increasingly complex nanostructures, as well as the ever improving instrumentation leaving less margin for ambiguity, small-angle scattering methodologies have been evolving at a high pace over the past few decades. As the quality of any results can only be as good as the data that go into these methodologies, the improvements in data collection and all imaginable data correction steps are reviewed here. This work is intended to provide a comprehensive overview of all data corrections, to aid the small angle scatterer to decide which are relevant for their measurement and how these corrections are performed. Clear mathematical descriptions of the corrections are provided where feasible. Furthermore, as no quality data exist without a decent estimate of their precision, the error estimation and propagation through all these steps are provided alongside the corrections. With these data corrections, the collected small-angle scattering pattern can be made of the highest standard, allowing for authoritative nanostructural characterization through its analysis. A brief background of small-angle scattering, the instrumentation developments over the years, and pitfalls that may be encountered upon data interpretation are provided as well. PMID- 23988670 TI - Comorbidities and kidney transplant evaluation in the elderly. AB - BACKGROUND/AIMS: The elderly are the fastest growing subpopulation with end-stage renal disease. The goal of our study was to define characteristics of elderly patients who were considered ineligible for transplantation compared to those who were listed. METHODS: 984 patients were referred for evaluation during a 2-year period. Records of patients >=65 years of age (n = 123) were reviewed. Patients who were listed versus not listed were characterized. Factors associated with waitlisting were determined using standard statistical tools. RESULTS: Half of elderly transplant candidates were accepted for listing compared to 75.4% of those aged <65 years. In multivariable logistic regression, older age (OR 1.29 per year >=65, 95% CI 1.14-1.45), coronary artery disease (OR 8.57, 95% CI 2.41 30.53), and poor mobility (OR 13.97, 95% CI 4.76-41.00) were independently associated with denial of listing. The receiver operating characteristic curve showed good discrimination for denial of listing (area under the receiver operating characteristic curve of 0.88). CONCLUSION: Elderly candidates carry a heavy burden of comorbidities and over half of those evaluated are deemed unsuitable for waitlisting. Better delineation of characteristics associated with suitability for transplant candidacy in the elderly is warranted to facilitate appropriate referrals by physicians and management of expectations in potential candidates. PMID- 23988671 TI - Teambuilding across healthcare professions: the ELDER project. AB - BACKGROUND: The key to ensuring quality care for older adults is a nursing workforce that collaborates across professions and provider levels (Wright M.C., Phillips-Bute, B.G., Petrusa, E.R., Griffin, K.L., Hobbs, G.W., & Taekman, J.M. (2008). Assessing teamwork in medical education and practice: Relating behavioural teamwork ratings and clinical performance. Med Teach, 29, 1-9). PURPOSE: To improve communication and teamwork among interprofessional health care providers (HCPs) by using innovative teambuilding activities over three years. METHODS: PARTICIPANTS: 97 multi-disciplinary HCPs from five long term or home care agencies in an underserved region of New England. PARTICIPANTS attended six interactive sessions focused on teambuilding skills through the use of role play, case studies, games, exercises and teambuilding strategies. The J. A. Hartford Foundation's (John A. Hartford Foundation. (2001). The John A. Hartford Foundation Geriatric Interdisciplinary Team Training (GITT) Program. Available at: http://www.nygec.org/index.cfm?section_id=26&sub_section_id=18&page_id=98) Geriatric Interdisciplinary Team Training (GITT) instrument and Interdisciplinary Teamwork IQ test were used to measure changes in knowledge and attitudes. RESULTS: T tests performed on matched pre/post GITT instruments (n=26) revealed no significant change, although scores improved slightly from pre: (71%) to post test (73.3%) (p=.39). Teamwork IQ scores also improved slightly though not significantly. Qualitative data gathered suggest that teambuilding exercises were helpful in practice and allowed for better understanding of other provider roles. CONCLUSIONS: Rarely is a variety of health care disciplines invited to participate in educational opportunities together. The interprofessional small group methodology used is a replicable model with potential to overcome barriers in communication and teamwork skills. PMID- 23988672 TI - [Bilateral adrenal hemorrhage revealing hyperhomocysteinemia]. AB - INTRODUCTION: Bilateral adrenal hemorrhage remains a rare disease. It has several etiologies, and clinical presentation is not specific. CASE REPORT: We report a 45-year old man without known prothrombotic factor who presented with acute left sided abdominal pain left revealing a bilateral adrenal hemorrhage. The diagnostic work-up identified a significant hyperhomocysteinemia associated with a previously undiagnosed homozygous mutation of the 5,10 methylene tetrahydrofolate reductase gene. The outcome was associated with the occurrence of an adrenal insufficiency. PMID- 23988673 TI - AICAR sustains J1 mouse embryonic stem cell self-renewal and pluripotency by regulating transcription factor and epigenetic modulator expression. AB - BACKGROUND/AIMS: [corrected] Embryonic stem cells (ES cells) have the capacity to propagate indefinitely, maintain pluripotency, and differentiate into any cell type under defined conditions. As a result, they are considered to be the best model system for research into early embryonic development. AICA ribonucleotide (AICAR) is an activator of AMP-activated protein kinase (AMPK) that is thought to affect ES cell function, but its role in ES cell fate decision is unclear. METHODS: In this study, we performed microarray analysis to investigate AICAR downstream targets and further understand its effect on ES cells. RESULTS: Our microarray data demonstrated that AICAR can significantly up-regulate pluripotency-associated genes and down-regulate differentiation-associated transcription factors. Although AICAR cannot maintain ES cell identity without LIF, it can antagonize the action of RA-induced differentiation. Using those differentially expressed genes identified, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis with the Database for Annotation, Visualization and Integrated Discovery (DAVID) online system. AICAR was not only shown to influence the AMPK pathway, but also act on other signaling pathways such as BMP, MAPK and TGF-beta, to maintain the stemness of J1 ES cells. Furthermore, AICAR modulated ES cell epigenetic modification by altering the expression of epigenetic-associated proteins, including Dnmt3a, Dnmt3b, Smarca2, Mbd3, and Arid1a, or through regulating the transcription of long intervening non-coding RNA (lincRNA). CONCLUSION: Taken together, our work suggests that AICAR is capable of maintaining ES cell self-renewal and pluripotency, which could be useful in future medical treatment. PMID- 23988674 TI - Robustness to divergence time underestimation when inferring species trees from estimated gene trees. AB - To infer species trees from gene trees estimated from phylogenomic data sets, tractable methods are needed that can handle dozens to hundreds of loci. We examine several computationally efficient approaches-MP-EST, STAR, STEAC, STELLS, and STEM-for inferring species trees from gene trees estimated using maximum likelihood (ML) and Bayesian approaches. Among the methods examined, we found that topology-based methods often performed better using ML gene trees and methods employing coalescent times typically performed better using Bayesian gene trees, with MP-EST, STAR, STEAC, and STELLS outperforming STEM under most conditions. We examine why the STEM tree (also called GLASS or Maximum Tree) is less accurate on estimated gene trees by comparing estimated and true coalescence times, performing species tree inference using simulations, and analyzing a great ape data set keeping track of false positive and false negative rates for inferred clades. We find that although true coalescence times are more ancient than speciation times under the multispecies coalescent model, estimated coalescence times are often more recent than speciation times. This underestimation can lead to increased bias and lack of resolution with increased sampling (either alleles or loci) when gene trees are estimated with ML. The problem appears to be less severe using Bayesian gene-tree estimates. PMID- 23988675 TI - Epidemiology and prevention of surgical site infections after cardiac surgery. AB - Deep sternal wound infection is the major infectious complication in patients undergoing cardiac surgery, associated with a high morbidity and mortality rate, and a longer hospital stay. The most common causative pathogen involved is Staphylococcus spp. The management of post sternotomy mediastinitis associates surgical revision and antimicrobial therapy with bactericidal activity in blood, soft tissues, and the sternum. The pre-, per-, and postoperative prevention strategies associate controlling the patient's risk factors (diabetes, obesity, respiratory insufficiency), preparing the patient's skin (body hair, preoperative showering, operating site antiseptic treatment), antimicrobial prophylaxis, environmental control of the operating room and medical devices, indications and adequacy of surgical techniques. Recently published scientific data prove the significant impact of decolonization in patients carrying nasal Staphylococcus aureus, on surgical site infection rate, after cardiac surgery. PMID- 23988676 TI - Molecular tools for functional genomics in filamentous fungi: recent advances and new strategies. AB - Advances in genetic transformation techniques have made important contributions to molecular genetics. Various molecular tools and strategies have been developed for functional genomic analysis of filamentous fungi since the first DNA transformation was successfully achieved in Neurospora crassa in 1973. Increasing amounts of genomic data regarding filamentous fungi are continuously reported and large-scale functional studies have become common in a wide range of fungal species. In this review, various molecular tools used in filamentous fungi are compared and discussed, including methods for genetic transformation (e.g., protoplast transformation, electroporation, and microinjection), the construction of random mutant libraries (e.g., restriction enzyme mediated integration, transposon arrayed gene knockout, and Agrobacterium tumefaciens mediated transformation), and the analysis of gene function (e.g., RNA interference and transcription activator-like effector nucleases). We also focused on practical strategies that could enhance the efficiency of genetic manipulation in filamentous fungi, such as choosing a proper screening system and marker genes, assembling target-cassettes or vectors effectively, and transforming into strains that are deficient in the nonhomologous end joining pathway. In summary, we present an up-to-date review on the different molecular tools and latest strategies that have been successfully used in functional genomics in filamentous fungi. PMID- 23988677 TI - Do depressive symptoms predict the incidence of myocardial infarction independent of hopelessness? AB - Depression and hopelessness predict myocardial infarction, but it is unclear whether depression and hopelessness are independent predictors of myocardial infarction incidents. Hopelessness, depression, and myocardial infarction incidence rate 18 years later were measured in 2005 men. Cox regressions were conducted with hopelessness and depression serving as individual predictors of myocardial infarction. Another Cox model examined whether the two predictors predict myocardial infarction when adjusting for each other. Depression and hopelessness predicted myocardial infarction in independent regressions, but when adjusting for each other, hopelessness, but not depression, predicted myocardial infarction incidents. Thus, these results suggest that depression and hopelessness are not independent predictors of myocardial infarction. PMID- 23988678 TI - Are the Male Body Dissatisfaction and Drive for Muscularity Scales reliable and valid instruments? AB - The Drive for Muscularity Scale and Male Body Dissatisfaction Scale were developed for use with men and correspond to measures of drive for thinness and body dissatisfaction in women. The psychometric properties of these measures were evaluated in a sample of 655 Italian men, who completed other 11 measures also. Both scales demonstrated excellent internal consistency and temporal stability as well as criterion-related and concurrent validity. Both measures distinguished between men with high and low levels of disordered eating. Confirmatory factor analysis replicated the unidimensional factor structure of both scales. Directions for future research are discussed. PMID- 23988679 TI - The making of expert patients: the role of online health communities in arthritis self-management. AB - Chronic disease is an epidemic, one that requires patients to play an active role in managing symptoms and disease affect. This study used ethnomethodology (N = 8231) to understand how patients with arthritis use online health communities to exchange disease-related information to better manage their chronic disease. The findings show that online health communities facilitate self-management behaviors through the exchange of health information and disease experience. These online health communities act as self-management programs led by peers with the same chronic disease through the exchange of health information based on experience, working to improve members' health literacy related to arthritis. PMID- 23988680 TI - Psychological therapies for the management of co-morbid depression following a spinal cord injury: a systematic review. AB - The evidence about psychological therapies used to manage co-morbid depression after a spinal cord injury is presented here. A comprehensive search of five electronic databases identified nine studies (participants, n = 591) meeting inclusion criteria. Pooled statistical analyses were conducted in combination with narrative synthesis. Overall, multimodal cognitive behavioural therapy was found to be moderately effective (standardised mean difference = -0.52; 95% confidence interval = -0.85, -0.19). Activity scheduling, psychoeducation, problem solving and cognitive therapy may be particularly beneficial therapies within cognitive behavioural therapy. Further high-quality randomised controlled trials are needed to better substantiate these findings. PMID- 23988681 TI - How does a risk-oriented "future-self" influence behavior? A structural-equation modeling approach with marijuana-related outcomes. AB - A study was conducted to examine the influence of a risk-oriented future self on self-reported marijuana use among college students. Drawing on theoretical work on possible selves, it was hypothesized that the extent to which a future self is viewed as risk-oriented will be associated with reported marijuana use and that effects of a risk-oriented future self on use would be partially mediated by risk oriented attitudes and perceived attractiveness of users. Analysis of data from an online survey of college students supported hypotheses, with the additional finding that the effect of user attractiveness on use is mediated by attitudes. PMID- 23988682 TI - Testing the invariance of adolescent survey-based smoking-related behaviors across ethnic groups and gender. AB - The present study examined the factor structure of 3 smoking-related items administered as part of the California Health Interview Survey. Factorial invariance was examined across Asian Americans (N = 377), Caucasians (N = 1739), African Americans (N = 115), and Latin Americans (N = 814), and across young men (N = 1612) and women (N = 1767). Factorial invariance analyses revealed all minority ethnic groups to be significantly different (p < .05) from Caucasians, and men to differ significantly from women. These findings suggest that the types of smoking behaviors assessed in the California Health Interview Survey do not predict behaviors uniformly across groups. PMID- 23988683 TI - Male body dissatisfaction and eating disorder symptomatology: moderating variables among men. AB - Body dissatisfaction is recognized as a robust risk factor for eating disorders. Despite over 80% of college men being body dissatisfied, not all men report several levels of eating disorder symptoms. In this study, we examined poor impulse control, social anxiety and internalization of media ideals as potential moderators. Data collected from 405 college-aged men were analysed, using latent variable structural equation modelling approach. All variables investigated have been found to moderate the body dissatisfaction-eating disorder symptomatology, such that male body dissatisfaction was strongly related to men's eating disorder symptomatology when each moderator was at its highest level. Practical implications are discussed. PMID- 23988684 TI - 'Soft and fluffy': medical students' attitudes towards psychology in medical education. AB - Psychology is viewed by medical students in a negative light. In order to understand this phenomenon, we interviewed 19 medical students about their experiences of psychology in medical education. Interviews were transcribed verbatim and analysed using thematic analysis. Four main themes were generated: attitudes, teaching culture, curriculum factors and future career path; negative attitudes were transmitted by teachers to students and psychology was associated with students opting for a career in general practice. In summary, appreciation of psychology in medical education will only happen if all educators involved in medical education value and respect each other's speciality and expertise. PMID- 23988685 TI - Beyond the barricades: social movements as participatory practice in health promotion. AB - Community-based health promotion has focussed on empowering disadvantaged groups, but there is growing awareness of the need to address everyday practices used to maintain power and privilege across social divisions. Participatory Action Research projects have proved subject to problems of resistance from dominant social groups. Social movements seeking to reshape power relations, give voice to excluded people and promote a social environment in which their problems are understood have been suggested as an alternative approach. A model of social movements based on theories and observations of social movement dynamics offers a practical framework for initiating such social change. PMID- 23988687 TI - EU electromagnetic fields Directive. PMID- 23988686 TI - Association between Helicobacter pylori and Barrett's esophagus, erosive esophagitis, and gastroesophageal reflux symptoms. AB - BACKGROUND & AIMS: Infection with Helicobacter pylori, particularly the cytotoxin associated gene A (cagA)+ strain, is believed to protect against Barrett's esophagus, but it is not clear if it protects against gastroesophageal reflux disease (GERD). We aimed to determine whether H pylori infection is associated with GERD symptoms, erosive esophagitis, and Barrett's esophagus within the same cohort. METHODS: We analyzed data from a case-control study of 533 men (ages, 50 79 y) who underwent colorectal cancer screening at 2 tertiary medical centers in Michigan between 2008 and 2011 and who also were recruited to undergo upper endoscopy. We assessed 80 additional men found to have Barrett's esophagus during clinically indicated upper-endoscopy examinations. Logistic regression was used to estimate the associations between serum antibodies against H pylori or cagA and GERD symptoms, esophagitis, and Barrett's esophagus, compared with randomly selected men undergoing colorectal cancer screens (n = 177). RESULTS: H pylori infection was associated inversely with Barrett's esophagus (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.29-0.97), particularly the cagA+ strain (OR, 0.36; 95% CI, 0.14-0.90). There was a trend toward an inverse association with erosive esophagitis (H pylori OR, 0.63; 95% CI, 0.37-1.08; and cagA+ OR, 0.47; 95% CI, 0.21-1.03). However, GERD symptoms were not associated with H pylori infection (OR, 0.948; 95% CI, 0.548-1.64; and cagA+ OR, 0.967; 95% CI, 0.461-2.03). CONCLUSIONS: Based on a case-control study, infection with H pylori, particularly the cagA+ strain, is associated inversely with Barrett's esophagus. We observed a trend toward an inverse association with esophagitis, but not with GERD symptoms. PMID- 23988688 TI - Quantifying lead-time bias in risk factor studies of cancer through simulation. AB - PURPOSE: Lead-time is inherent in early detection and creates bias in observational studies of screening efficacy, but its potential to bias effect estimates in risk factor studies is not always recognized. We describe a form of this bias that conventional analyses cannot address and develop a model to quantify it. METHODS: Surveillance Epidemiology and End Results (SEER) data form the basis for estimates of age-specific preclinical incidence, and log-normal distributions describe the preclinical duration distribution. Simulations assume a joint null hypothesis of no effect of either the risk factor or screening on the preclinical incidence of cancer, and then quantify the bias as the risk factor odds ratio (OR) from this null study. This bias can be used as a factor to adjust observed OR in the actual study. RESULTS: For this particular study design, as average preclinical duration increased, the bias in the total-physical activity OR monotonically increased from 1% to 22% above the null, but the smoking OR monotonically decreased from 1% above the null to 5% below the null. CONCLUSIONS: The finding of nontrivial bias in fixed risk-factor effect estimates demonstrates the importance of quantitatively evaluating it in susceptible studies. PMID- 23988689 TI - Clinical application of qualitative assessment for breast masses in shear-wave elastography. AB - PURPOSE: To evaluate the interobserver agreement and the diagnostic performance of various qualitative features in shear-wave elastography (SWE) for breast masses. MATERIALS AND METHODS: A total of 153 breast lesions in 152 women who underwent B-mode ultrasound and SWE before biopsy were included. Qualitative analysis in SWE was performed using two different classifications: E values (Ecol; 6-point color score, Ehomo; homogeneity score and Esha; shape score) and a four-color pattern classification. Two radiologists reviewed five data sets: B mode ultrasound, SWE, and combination of both for E values and four-color pattern. The BI-RADS categories were assessed B-mode and combined sets. Interobserver agreement was assessed using weighted kappa statistics. Areas under the receiver operating characteristic curve (AUC), sensitivity, and specificity were analyzed. RESULTS: Interobserver agreement was substantial for Ecol (kappa=0.79), Ehomo (kappa=0.77) and four-color pattern (kappa=0.64), and moderate for Esha (kappa=0.56). Better-performing qualitative features were Ecol and four-color pattern (AUCs, 0.932 and 0.925) compared with Ehomo and Esha (AUCs, 0.857 and 0.864; P<0.05). The diagnostic performance of B-mode ultrasound (AUC, 0.950) was not significantly different from combined sets with E value and with four color pattern (AUCs, 0.962 and 0.954). When all qualitative values were negative, leading to downgrade the BI-RADS category, the specificity increased significantly from 16.5% to 56.1% (E value) and 57.0% (four-color pattern) (P<0.001) without improvement in sensitivity. CONCLUSION: The qualitative SWE features were highly reproducible and showed good diagnostic performance in suspicious breast masses. Adding qualitative SWE to B-mode ultrasound increased specificity in decision making for biopsy recommendation. PMID- 23988690 TI - 18F-fluorodeoxyglucose uptake on positron emission tomography in mucinous adenocarcinoma. AB - BACKGROUND: The prognostic value of maximum standardized uptake value (maxSUV) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is known for localized pulmonary adenocarcinoma, which is most commonly non-mucinous adenocarcinoma. We examined the validity of thin-section computed tomography (TS CT) and FDG-PET findings in mucinous adenocarcinoma. MATERIALS AND METHODS: TS-CT and FDG-PET were performed on 25 patients with mucinous lung adenocarcinoma that was subsequently resected between January 2009 and March 2013. Based on the percentage reduction of maximum tumor diameter on the mediastinal window image compared with the diameter on the lung window image on TS-CT, tumors were classified as air-type (>=50%) or solid-type (<50%). All resected specimens were pathologically diagnosed according to the International Association for the Study of Lung Cancer (IASLC) classification, and the diameter of the pathological invasive area was assessed. RESULTS: Most mucinous adenocarcinomas were located in the lower lobe. All except two were classified as solid-type tumor on TS-CT. Multiple regression analysis revealed the correlation of maxSUV with pathological tumor size and diameter of pathological invasive area; these two parameters showed no significant correlation with each other (r=0.354, p=0.083). maxSUV was significantly lower for tumors with invasive area <=5 mm than for tumors with invasive area >5mm (1.62 vs. 3.77, p=0.01), but no statistically significant difference was found in terms of other pathological invasive findings such as the presence of lymphatic or vascular invasion, pleural involvement, or predominant histological subtype. CONCLUSIONS: Most mucinous adenocarcinomas had appearances of solid-type tumor on TS-CT. maxSUV on FDG-PET indicates the pathological invasive area in mucinous adenocarcinoma as well as non-mucinous adenocarcinoma. PMID- 23988691 TI - Acute stress during ontogeny suppresses innate, but not acquired immunity in a semi-precocial bird (Larus delawarensis). AB - Wild animals often encounter adverse conditions, and in response, activate their hypothalamic-pituitary-adrenal (HPA) axis. To date, work examining the development of the stress response has focused on altricial species, with little work focusing on species with other developmental patterns. Additionally, the effects of acute stress on indices of innate and adaptive immunity have been little studied in birds, particularly during development. We examined the ontogeny of the stress response in the semi-precocial ring-billed gull (Larus delawarensis). At hatch, 10, and 20days post-hatching, chicks underwent a standardized handling stress protocol, with blood samples taken within 3min of, and 30min after, initial disturbance. Levels of corticosterone (CORT), natural antibodies (NAb), complement activity, and immunoglobulins (IgY) were assessed in plasma samples. In contrast with altricial species, ring-billed gull chicks had detectible CORT levels at hatch, and were able to mount a stress response. At all ages, acute handling stress depressed NAb levels and complement-mediated lysis, but not IgY levels. IgY levels were higher in two chick broods than three chick broods, suggesting levels are determined in part by resource dependence. Our data provide insight into the development of the stress response and immune function in a colonial waterbird species, in which chicks are mobile shortly post hatch, and subject to aggression and possible injury from nearby adults. PMID- 23988692 TI - Why chronic obstructive pulmonary disease patients get so short of breath with limited activity. PMID- 23988693 TI - Twisted-light-induced intersubband transitions in quantum wells at normal incidence. AB - We examine theoretically the intersubband transitions induced by laser beams of light with orbital angular momentum (twisted light) in semiconductor quantum wells at normal incidence. These transitions become possible in the absence of gratings thanks to the fact that collimated laser beams present a component of the light's electric field in the propagation direction. We derive the matrix elements of the light-matter interaction for a Bessel type twisted light beam represented by its vector potential in the paraxial approximation. Then, we consider the dynamics of photoexcited electrons making intersubband transitions between the first and second subbands of a standard semiconductor quantum well. Finally, we analyze the light-matter matrix elements in order to evaluate which transitions are more favorable for a given orbital angular momentum of the light beam in the case of small semiconductor structures. PMID- 23988694 TI - The role of satisfaction and switching costs in Medicare Part D choices. AB - BACKGROUND: Most U.S. states had over 50 Medicare Prescription Drug Plans (PDPs) in 2007. Medicare beneficiaries are expected to switch Part D plans based on their health and financial needs; however, the switching rate has been low. Such consumer inertia potentially has negative effects on both beneficiaries and the insurance market, resulting in a critical need to investigate its cause. OBJECTIVES: To 1) describe how Medicare beneficiaries who were satisfied with their current Part D plan differed from those who were not satisfied; 2) examine the effect of switching costs on consideration of switching among Medicare beneficiaries who were dissatisfied with their current Part D plan. METHODS: Data from the 2007 Prescription Drug Study supplement to the Health and Retirement Study (HRS) survey were used in this study. The satisfied and dissatisfied groups were compared in terms of cost variables, switching costs, and perception of Part D complexity. Structural equation modeling was used to examine relationships among switching costs, Part D complexity, cost variables, and consideration of switching for beneficiaries who were dissatisfied with their current Part D coverage. RESULTS: Out of 467 participants, a total of 255 (54.6%) were satisfied with their current Part D plan. The satisfied group paid lower out-of-pocket costs ($50.63 vs. $114.60) and premiums ($30.88 vs. $40.77) than the dissatisfied group. They also had lower switching costs. Only 11.3% of the dissatisfied beneficiaries switched plans. Among respondents who were dissatisfied with their current plan, those who perceived Part D as complex had high switching costs and were less likely to consider switching plans. Out-of-pocket cost did not have a statistically significant association with consideration of switching. CONCLUSIONS: Medicare beneficiaries who were satisfied with their current Part D plans had lower out-of-pocket costs and premiums as well as higher switching costs. Among beneficiaries who were dissatisfied with their current Part D plan, those who had higher switching costs were less likely to consider switching Part D plans. PMID- 23988695 TI - Flecainide in CASQ2-mediated catecholaminergic polymorphic ventricular tachycardia: the gift that keeps on giving. PMID- 23988696 TI - TRPM4 modulates sinus node diastolic depolarization. PMID- 23988697 TI - Artificial microRNAs can effectively inhibit replication of Venezuelan equine encephalitis virus. AB - Venezuelan equine encephalitis virus is a member of the alphavirus family and genus togaviridae. VEEV is highly infectious in aerosol form and has been weaponized in the past making it a potential biothreat agent. At present, there are no FDA approved antiviral treatments or vaccines for VEEV. Artificial microRNAs are small molecules which are expressed through endogenous microRNA machinery by RNA polymerase II. These artificial microRNAs effectively inhibit gene expression and are non-toxic to the host cell. VEEV RNA dependent RNA polymerase (RdRp) is central to VEEV replication. Therefore, we hypothesize that targeted inhibition of VEEV RdRp using artificial microRNAs may efficiently inhibit VEEV replication. Five artificial microRNAs were tested in vitro in BHK cells. Three of these artificial miRNAs showed significant inhibition of VEEV replication. Further, these microRNAs were cloned into the expression vector in combination to see the synergistic effect on VEEV replication. Combination of more than one miRNA did not result in significant inhibition of virus replication. In conclusion, we have shown that RNAi through artificial microRNAs effectively inhibits VEEV replication and is significantly less toxic in comparison to siRNAs. PMID- 23988699 TI - Superhuman? Perceptions of accelerated students and graduates working in health care. AB - BACKGROUND: Accelerated university courses were developed in response to consumer demand and educational advances, yet a lack of research exists related to the impact of accelerated health care courses in the United Kingdom. OBJECTIVES: This study explored clinicians' perceptions of accelerated pre-registration courses in physiotherapy. METHOD: Senior clinicians were recruited by purposive sampling from several National Health Service hospitals across northeast England. Data from face-to-face semi-structured interviews were recorded, transcribed verbatim and analysed using Interpretive Phenomenological Analysis. FINDINGS: Findings from fourteen participants indicated their admiration of accelerated students' attributes to complete what they considered to be an intense and in-depth course. Such graduates were described as 'superhuman.' Participants noted that accelerated graduates were likely to 'hit the ground running' in clinical settings. However, concerns were raised that some accelerated graduates' over confidence affected team dynamics and/or affected some aspects of clinical reasoning. CONCLUSIONS: Participants valued the varied routes to graduation while recognising their strengths and limitations. Findings from the study suggested the need for different types of clinical supervision to support each route. PMID- 23988698 TI - Changes in biomarkers associated with living kidney donation. AB - Living donor kidneys have been associated with better graft and overall survival in kidney transplant recipients. Although a living kidney donation is generally considered safe in carefully selected living donors, concerns of possible adverse effects related to kidney donation remain, especially in younger and high-risk donors. In this study, we examined the changes in a panel of traditional and novel serum biomarkers linked with cardiovascular conditions in a cohort of 34 healthy living kidney donors with a mean age +/- SD of 40 +/- 10 years and estimated predonation glomerular filtration rate (GFR) of 86 +/- 10 ml/min/1.73 m(2). At 6 months after donation, there were no significant changes in the clinical parameters including body mass index and blood pressure despite a significant decline in the mean estimated GFR to 60 ml/min/1.73 m(2). Among the panel of markers, the levels of symmetric dimethylarginine and fibroblast growth factor 23 increased significantly compared to baseline, suggesting that living kidney donation may result in changes in biomarkers that are associated with cardiovascular risk in other cohorts. PMID- 23988700 TI - Quantification of survival gain from cardiac resynchronization therapy: nonlinear growth with time, and greater gain in low-risk patients, make raw trial data an underestimate of real-world behavior. AB - OBJECTIVES: The goal of this study was to examine the impact of calculation window duration on lifespan gain (as observed in trials) and on who gains most. BACKGROUND: The landmark trials of biventricular pacing (cardiac resynchronization therapy [CRT]) typically ran for <1 device battery life, and they may therefore underestimate lifespan benefit over longer durations. METHODS: We conducted a meta-analysis of biventricular pacing trials to calculate lifespan gained: first, within the duration of randomized controlled trial data up to 2 years; second, over a 5-year typical battery life; and third, over >1 battery life. Importantly, we applied the Gompertz method for age-related increase in mortality from non-CRT-preventable causes. RESULTS: Five landmark trials (COMPANION [Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure], CARE-HF (CArdiac REsynchronization-Heart Failure), MADIT-CRT [Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy], REVERSE [Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction], RAFT (Resynchronization-Defibrillation for Ambulatory Heart Failure)) provided data for 2 years (6,561 patients), with an average hazard ratio of 0.71. Lifespan gained across all trials increased nonlinearly with time from 0.1 month at 1 year, to 0.5 month at 2 years, and a projected 6.5 months at 5 years (65 times more than at 1 year). After multiple devices, it reached 14 months, involving on average 1.6 devices (i.e., 8.8 months per device implanted). Moreover, while over a short window (e.g., 2 years), lower mortality patients may gain less than higher-mortality patients (1.4 vs. 2.3 months), their positions reverse by 15 years (16.0 vs. 13.7 months). CONCLUSIONS: Lifespan gain from biventricular pacing rises nonlinearly with time. Early on, higher-risk patients exhibit more gain, but later, lower-risk patients exhibit more gain. Quantifying gain over less than a patient's lifetime underestimates lifespan gain. Over the first 1 or 2 years, lower-risk patients may seem to gain less, although they may ultimately be the ones who gain the most. PMID- 23988701 TI - Down-regulation of miR-30c promotes the invasion of non-small cell lung cancer by targeting MTA1. AB - BACKGROUND: The connection between microRNA expression and lung cancer development has been identified in recent literature. However, the mechanism of microRNA has been poorly elucidated in non-small-cell lung cancer (NSCLC). METHODS AND RESULTS: Comparing with adjacent tissues (n=75), miR-30c has a lower expression in lung cancer specimens (n=75). The knockdown of miR-30c enhanced the invasion of A549 cells; meanwhile, the overexpression of miR-30c could reverse the effect of the knockdown of miR-30c in vitro. A luciferase assay revealed that miR-30c was directly bound to the 3'-untranslated regions (3'-UTR) of MTA1. QRT PCR and western blot shows MTA1 was up-regulated in mRNA and protein levels. The effect taken on the invasion of NSCLC by overexpression of MTA1 works the same as down-regulated miR-30c. CONCLUSION: miR-30c may play a pivotal role in controlling lung cancer invasion through regulating MTA1in NSCLC. PMID- 23988702 TI - Activation of extracellular transglutaminase 2 by mechanical force in the arterial wall. AB - Inward remodeling of small arteries occurs after prolonged vasoconstriction, low blood flow, and in several models of hypertension. The cross-linking enzyme, transglutaminases 2 (TG2), is able to induce inward remodeling and stiffening of arteries. The activity of TG2 is dependent on its conformation, which can be open or closed, and on its redox state. Several factors have been shown to be involved in modulating TG2 activity, including Ca(2+) and GTP/GDP concentrations, as well as the redox state of the environment. This review introduces the hypothesis that mechanical force could be involved in regulating the activity of TG2 during inward remodeling by promoting its open and reduced active state. Several aspects of TG2, such as its structure and localization, are assessed in order to provide arguments that support the hypothesis. We conclude that a direct activation of TG2 by mechanical force exerted by smooth muscle cells may explain the link between smooth muscle activation and inward remodeling, as observed in several physiological and pathological conditions. PMID- 23988703 TI - Airway remodeling in asthma: tumor of the airway? PMID- 23988704 TI - A FEM based endosteal implant simulation to determine the effect of peri-implant bone resorption on stress induced implant failure. AB - Although dental implants exhibit only limited failure rates, their fracture is associated to major modifications of the prosthetic treatment and complex surgery for the removal of the remaining embedded implant part. This investigation aims to assess the developing stress fields in the bone-implant interface during mastication and asses the failure modes of oral implants.In order to achieve this, a FEM model of an implant was reverse engineered and virtually loaded at the top of the crown for a force spectrum ranging from 75-225 N in a vertical, horizontal and oblique occlusal direction. The calculated stress fields were compared with clinically retrieved fractured implants with identical geometrical characteristics and the fracture modes of both cases were correlated. The developing stress patterns facilitated the interpretation of the implant failure as the maximum stresses, indicated critical values in both, lingual and buccal sides of the implant-bone interface at a certain critical level of bone resorption, in which failure occurs. PMID- 23988705 TI - Evaluation of the clinical performance of ultrahigh molecular weight polyethylene fiber cable using a dog osteosynthesis model. AB - The purpose of this study was to assess the removability and biological reactivity of an ultrahigh molecular weight polyethylene (UHMWPE) fiber cable as a new biomaterial for osteosynthesis. We used a pull-out test and an implantation test to analyze the performance of the UHMWPE fiber cable using a dog model, and compared its characteristics with those of a wire cable and a soft wire. In the pull-out test, the UHMWPE fiber cable was as easy to remove as the soft wire, and both the UHMWPE fiber cable and the soft wire were significantly easier to remove than the wire cable. The fixation capability and the biological reactivity of the UHMWPE fiber cable were examined in an osteosynthesis model of the dog greater trochanter, and were compared with those of the soft wire. The bone union rate, assessed radiographically, was very similar when using the UHMWPE fiber cable and the soft wire. However, in the soft wire group, both the surface of the greater trochanter under the fixation material and the penetration area around the fixation material showed an increased tendency toward a biological reaction, including inflammation and granulation tissue formation, as compared to the UHMWPE fiber cable group. The UHMWPE fiber cable was as easily removed from the bone tissue as the soft wire, and was easier to remove than the wire cable. Additionally, the UHMWPE fiber cable caused reduced biological reactivity with the surrounding tissue, as compared with the soft wire. In conclusion, the UHMWPE fiber cable appeared to be a suitable fixation material for osteosynthesis. PMID- 23988706 TI - Apatite mineralization behavior on polyglutamic acid hydrogels in aqueous condition: effects of molecular weight. AB - Apatite-polymer composites mimicking specific structure of natural bone are promised as bone substitutes with moderate flexibility able to be fabricated into desired shapes as well as bone-bonding bioactivity. In order to precipitate the apatite on polymer surfaces, aqueous processing using solution supersaturated to the apatite has been attracting as much attention. Polyglutamic acid (PGA) is a promised candidate of the polymer, since it has high apatite-forming ability owing to abundant carboxyl groups able to trigger the heterogeneous apatite nucleation. Although combination of PGA with different molecular weight is expected to provide design of organic-inorganic composites with moderate bioresorbability, precise relationship between the molecular weight of the PGA and its apatite-forming ability has been remained unclear. In the present study, PGA hydrogels with different molecular weight were prepared by covalent cross linking using ethylenediamine. Difference in apatite formation in simulated body fluid (SBF) was interpreted in terms of their chemical structure. It was found that hydrogels prepared from PGA with higher molecular weight showed tendency to have higher apatite-forming ability. It was attributed to high content of the carboxyl group remaining on the hydrogel due to low degree of the cross-linking. PMID- 23988707 TI - Synthesis and characterization of noncytotoxic and biodegradable polymethacrylates-grafted chitosan gels. AB - Poly(methacrylates), namely 2-hydroxy ethyl methacrylate (HEMA), ethylene glycol dimethacrylate (EGDMA) and triethylene glycol dimethacrylate (TEGDMA) were grafted onto chitosan by using ceric ammonium nitrate as a redox initiator. Semi IPN gels of chitosan-graft-poly(HEMA)-graft-poly(EGDMA) and chitosan-graft poly(HEMA)-graft-poly(TEGDMA) were obtained. The grafting conditions were optimized with respect to monomer concentrations. The products were characterized by TGA, FTIR, XRD and SEM techniques. The solubility of the grafted products in aqueous medium decreased with increasing grafting percentage. The insoluble gels exhibited a highly pH sensitive swelling behaviour. TGA thermograms showed that poly(HEMA)/poly(TEGDMA)-grafted product is much more stable than poly(HEMA)/poly(EGDMA)-grafted product showing that TEGDMA is a more effective crosslinker than EGDMA. According to XRD analysis TEGDMA has a higher tendency to form ordered structures than EGDMA as it is capable of chain folding. The results of cytotoxicity studies revealed that the methacrylate-grafted chitosans were noncytotoxic and good candidates for biomedical applications. PMID- 23988708 TI - Micro-environmentally restricted hybridoma cell growth within polysaccharide hydrogel microbeads. AB - The mechanism of micro-environmentally restricted hybridoma cell growth caused by action of local mechanical compression stress generated within various polysaccharide hydrogel matrixes is estimated by comparing the growth of hybridoma cells within (1) 1.5% Ca-alginate microbeads from Bugarski et al. [in: Fundamentals of Animal Cells Immobilization and Microencapsulation, M.F.A. Goosen, ed., CRC Press, Boca Raton, FL, 1993, p. 267] and (2) 1.3% alginate agarose microbeads from Shen et al. [Animal Cell Technology: Basic & Applied Aspects, H. Murakami ed., Kluwer Academic Publishers, The Netherlands, 1992, p. 173].Consideration of restricted cell growth dynamics based on developed kinetic model and kinetic 3D Monte Carlo simulation include: (1) changes the fraction of active proliferating cells in the exponential phase and (2) changes of non proliferating cell concentration in the plateau phase.Higher value of the specific decrease of active fraction of proliferating cells kappa is obtained for 1.3% alginate-agarose compared to 1.5% alginate microbeads. It corresponds to higher compression stress generated within hydrogel matrix during cell growth obtained for 1.3% alginate-agarose microbeads. PMID- 23988710 TI - Experimental evaluation and theoretical modeling of oxygen transfer rate for the newly developed hollow fiber bioreactor with three compartments. AB - Bioartificial liver support provides a bridge to transplantation which is at present the only proven specific treatment for acute liver failure. In this paper, a novel multi-coaxial hollow fiber bioreactor so-called "Fibre-in-Fibre FIF Bioartificial liver device" with three compartments is experimentally and mathematically studied. The mathematical model in this paper is an extension of Krogh cylinder model for hollow fibre devices by including one more zone for oxygen transfer, i.e. oxygenation compartment. Three simultaneous linear differential equations were derived for pressure in plasma and cell compartments and flow rate in cell compartment. To validate the model, Oxygen Transfer Rate and hydrostatic pressure experimental measurements for different flow rates, 17 400 ml/min, and different number of hollow fibres pairs are used. Several important parameters of the Michaelis-Menten was investigated, namely, constant Vmax (the maximum oxygen consumption per unit volume of the cell mass), the oxygen partial pressure, the flow rate of the perfusate at device inlet. The results showed that the oxygenation compartment should easily secure Oxygen to the cells in compartment B. PMID- 23988709 TI - Adhesion, proliferation and differentiation of osteoblasts on zirconia films prepared by cathodic arc deposition. AB - Zirconia films were prepared on titanium by cathodic arc deposition technique. The surface topography and element composition of the films were characterized by scanning electron microscopy and X-ray photoelectron spectroscopy, respectively. Osteoblast-like MG63 cells were cultured on the surface of the zirconia films in vitro, and cell behaviour was investigated, with titanium as control. The results obtained from scanning electron microscopy and immunofluorescence studies showed that the MG63 cells on ZrO2 films spread better than those on Ti. The CCK8 assay indicated that the zirconia films promoted the proliferation of MG63 cells. The results of alkaline phosphatase (ALP) activity test and the expression of osteogenic marker genes, such as ALP, collagen I and osteocalcin, demonstrated that the differentiation of MG63 cells might be enhanced by zirconia films. In addition, the zirconia films possibly regulated osteoclastogenic gene expression by stimulating the expression of osteoprotegerin and reducing the expression of receptor activator of nuclear factor-kappaB ligand. The present work suggests that the ZrO2 film is worth further consideration for orthopedic implant applications. PMID- 23988711 TI - Agar-based bridges as biocompatible candidates to provide guide cues in spinal cord injury repair. AB - BACKGROUND: Spinal bridge implants are strategic to provide growth surfaces for axonal regeneration after spinal cord injuries. The design of an appropriate substrate, one that is suitable for implantation, must involve careful testing of the biomaterial properties both in vitro and in vivo. OBJECTIVE: The goal of this work was to test the structure, stability and biological response after spinal bridges implantation of several biopolymers, composed of mixtures of agar (AG), as structural matrix scaffold, with kappa-carrageenan (Kc), gelatin (G), xanthan gum (Xn) and polysulfone (PS). METHODS: Biopolymer structures were studied by environmental scanning electron microscopy, whereas the stability of gels was analyzed by in vitro degradation and swelling tests. The biocompatibility of these materials and their ability to promote cell growth and axonal regeneration were studied by implantation of spinal bridges containing empty linear channels in an acute rat spinal cord transection model at thoracic level (T8). RESULTS AND CONCLUSIONS: All gel mixtures gave rise to porous structures and they were stables to degradation, excepting the AG+G mixture. Spinal bridges constructed from all mixtures were implanted during a month in adult rats. After this time a low host reaction occurred to all bridge materials as well as neurite and cell ingrowths through the empty channels. Neurites within the bridges were mostly peripheral sensory fibers such as those positive for CGRP, whereas there was a lack of regeneration of central axons crossing from the spinal tissue to bridges. Many of these neurites established closed contacts with non-myelin Schwann cells. The histological analysis revealed a high accumulation of collagen fibers within the channels. Unexpected was the apparent loss of channels linearity which affected the growth of neurites and cells, indicating the need for additional regeneration strategies and vertebrae bridge fixing. PMID- 23988712 TI - Artery cross-clamping during laparoscopic vascular surgeries; a computational tactile sensing approach. AB - Artificial palpation is one of the most valuable achievements of artificial tactile sensing approach that can be used in various fields of medicine and more specifically in surgery. These techniques cause different surgical maneuvers to be done more precisely and noninvasively. In this study, considering the present problems and limitations of cross-clamping an artery during laparoscopic vascular surgeries, a new tactile sensory system will be introduced.Having imitated surgeon's palpation during open vascular surgeries and modeled it conceptually, the optimal amount of the total angular displacement of each robot joint in order to cross-clamping an artery without damaging to the artery surrounding tissues will be calculated. The elastic governing equation of contact occurred between the tactile sensor placed on the first link of the robot and the surrounding tissues around the artery were developed. A finite element model is coupled with genetic algorithm optimization method so that the normal stress and displacements in contact surface of the robot and artery's surrounding tissues would be minimized. Thus, reliability and accuracy of artificial tactile sensing method in artery cross-clamping will be demonstrated. Finally, the functional principles of the new tactile system capable of cross-clamping an artery during laparoscopic surgeries will be presented. PMID- 23988713 TI - An integrated approach of topology optimized design and selective laser melting process for titanium implants materials. AB - The load-bearing bone implants materials should have sufficient stiffness and large porosity, which are interacted since larger porosity causes lower mechanical properties. This paper is to seek the maximum stiffness architecture with the constraint of specific volume fraction by topology optimization approach, that is, maximum porosity can be achieved with predefine stiffness properties. The effective elastic modulus of conventional cubic and topology optimized scaffolds were calculated using finite element analysis (FEA) method; also, some specimens with different porosities of 41.1%, 50.3%, 60.2% and 70.7% respectively were fabricated by Selective Laser Melting (SLM) process and were tested by compression test. Results showed that the computational effective elastic modulus of optimized scaffolds was approximately 13% higher than cubic scaffolds, the experimental stiffness values were reduced by 76% than the computational ones. The combination of topology optimization approach and SLM process would be available for development of titanium implants materials in consideration of both porosity and mechanical stiffness. PMID- 23988715 TI - Nanoclusters self-assembled from conformation-stabilized influenza M2e as broadly cross-protective influenza vaccines. AB - Influenza vaccines with broad cross-protection are urgently needed. The highly conserved ectodomain of the influenza matrix protein 2 (M2e) can be a promising candidate if its low immunogenicity was overcome. In this study, we generated protein nanoclusters self-assembled from conformation-stabilized M2e tetramers (tM2e) to improve its immunogenicity. The resulting nanoclusters showed an average hydrodynamic diameter of 227 nm. Vaccination with the nanoclusters by an intranasal route elicited high levels of serum antigen-specific IgG in mice (approximately 100-fold higher than that obtained with soluble tM2e), as well as antigen-specific T cell and mucosal antibody responses. The immunity conferred complete protection against lethal challenge with homo- as well as heterosubtypic viruses. These results demonstrate that nanoclusters assembled from conformation stabilized M2e are promising as a potential universal influenza A vaccine. Self assembly into nanoclusters represents a novel approach for increasing the immunogenicity of vaccine antigens. FROM THE CLINICAL EDITOR: In order to develop more effective influenza vaccination, the highly conserved ectodomain of M2e could be a promising candidate. Unfortunately, it is a weak antigen for vaccination purposes. In this study, self-assembled protein nanoclusters of tM2e were generated and tested. The nanoclusters demonstrated superior vaccination properties, with complete protection against lethal challenge in the studied rodent model, raising hope for the introduction of similar vaccines to challenge human influenza outbreaks. PMID- 23988716 TI - Plasma exposure of free linezolid and its ratio to minimum inhibitory concentration varies in critically ill patients. AB - The clinical implications of free linezolid monitoring have not been fully clarified in critically ill patients. The aim of this study was to evaluate the variability in pharmacokinetics of free linezolid and its relationship with susceptibility to meticillin-resistant Staphylococcus aureus (MRSA) in critically ill patients. Twenty critically ill MRSA-infected patients receiving intravenous linezolid were enrolled. Blood specimens were collected by 12-h sampling after dosing at Day 7. The medians (interquartile range) of the minimum free concentration, area under the concentration-time curve of total and free linezolid from 0 to 24 h (AUC(0-24) and fAUC(0-24), respectively) and percentage bound were 9.9 MUg/mL (5.2-15 MUg/mL), 495 MUgh/mL (291-695 MUgh/mL), 385 MUgh/mL (242-528 MUgh/mL) and 23% (15-28%), respectively. The medians of the AUC(0-24) and fAUC(0-24) to minimum inhibitory concentration ratios (AUC/MIC and fAUC/MIC) were 248 (144-347) and 192 (109-264), respectively. Two patients failed to achieve adequate levels of AUC/MIC and fAUC/MIC for linezolid. The percentage bound of linezolid in hypoalbuminaemic patients was significantly lower than in non-hypoalbuminaemic patients. A significant correlation was observed between fAUC(0-24) and creatinine clearance. In addition, the fAUC(0-24) was correlated with the minimum free concentration. In conclusion, the plasma level of free linezolid was variable in critically ill patients with renal dysfunction and hypoalbuminaemia. This finding suggests that the monitoring of free linezolid is necessary in critically ill patients. PMID- 23988714 TI - Non-covalent assembly of meso-tetra-4-pyridyl porphine with single-stranded DNA to form nano-sized complexes with hydrophobicity-dependent DNA release and anti tumor activity. AB - DNA and porphyrin based therapeutics are important for anti-cancer treatment. The present studies demonstrate single-stranded DNA (ssDNA) assembles with meso-tetra 4-pyridyl porphine (MTP) forming porphyrin:DNA nano-complexes (PDN) that are stable in aqueous solution under physiologically relevant conditions and undergo dissociation with DNA release in hydrophobic environments, including cell membranes. PDN formation is DNA-dependent with the ratio of porphyrin:DNA being approximately two DNA nucleobases per porphyrin. PDN produce reactive oxygen species (ROS) in a light-dependent manner under conditions that favor nano complex dissociation in the presence of hydrophobic solvents. PDN induce light dependent cytotoxicity in vitro and anti-tumor activity towards bladder cancer xenografts in vivo. Light-dependent, PDN-mediated cell death results from ROS mediated localized membrane damage due to lipid peroxidation with mass spectrometry indicating the generation of the lipid peroxidation products 9- and 13-hydroxy octadecanoic acid. Our results demonstrate that PDN have properties useful for therapeutic applications, including cancer treatment. FROM THE CLINICAL EDITOR: In this study, porphyrin-DNA nanocomplexes were investigated as anti-cancer therapeutics inducing ROS production in a light-dependent manner. Efficacy is demonstrated in vitro as well as a in a bladder cancer xenograft model. PMID- 23988717 TI - Inhibition of Pseudomonas aeruginosa biofilm formation by LecA-binding polysaccharides. PMID- 23988718 TI - Utility of a novel multiplex TaqMan PCR assay for metallo-beta-lactamase genes plus other TaqMan assays in detecting genes encoding serine carbapenemases and clinically significant extended-spectrum beta-lactamases. AB - Prompt detection of infections caused by Enterobacteriaceae that produce therapeutically important beta-lactamases [metallo-beta-lactamases (MBLs), serine carbapenemases, acquired AmpC and CTX-M extended-spectrum beta-lactamases (ESBLs)] is crucial for infection prevention and control and surveillance purposes, and, more contentiously, also for effective patient management. A novel TaqMan PCR assay was developed to detect genes encoding IMP, VIM, NDM, SPM, SIM and GIM MBLs. Published PCR assays for acquired genes encoding CTX-M ESBLs and AmpC beta-lactamases were updated and adapted to the TaqMan format, respectively. A published TaqMan assay for serine carbapenemase genes was used. Assay specificity was tested using a panel of 59 isolates with known acquired genes from the four different beta-lactamase groupings. The four TaqMan assays correctly identified the most clinically relevant acquired beta-lactamase genes in the panel of 59 resistant Enterobacteriaceae, which included 3 VIM-, 7 NDM- and 12 IMP-producers. Consecutive, non-duplicate isolates of Enterobacteriaceae from 965 urinary and 343 blood cultures during 2010 were then screened for beta lactamase genes using these TaqMan assays. Amongst the urinary and blood culture isolates tested, 69 CTX-M-producers and 21 acquired AmpC beta-lactamase-producers were identified; the CTX-M rate amongst blood culture isolates (9.3%) broadly reflects the UK national average. During the study period, one Klebsiella pneumoniae isolate producing an NDM carbapenemase was identified from a wound sample. The assays developed and/or used will enable the future surveillance and the rapid detection and appropriate early treatment of infections caused by Gram negative bacteria producing clinically important beta-lactamases, including carbapenemases. PMID- 23988719 TI - Associations of macrolide and fluoroquinolone resistance with molecular typing in Streptococcus pyogenes from invasive infections, 2010-2012. AB - In this study, the relationship between emm type and antibiotic resistance in 283 invasive group A streptococcal strains collected during surveillance from 2010 to 2012 was analysed. Strains were characterised by emm typing, multilocus sequence typing and antimicrobial susceptibility. Resistance rates for macrolide antibiotics conferred by mef(A), erm(A) or erm(B) were high (54.4%). The most prevalent (40.3%) macrolide resistance mediated by mef(A) was present in 92.2% of emm1 strains. It was found that 53.3% of emm12 strains and 91.7% of emm28 strains had erm(A) or erm(B) genes. Intermediate resistance to fluoroquinolones caused by a mutation in parC was found in 14.1% of strains. Furthermore, three strains (1.1%) with high resistance caused by mutations in both parC and gyrA were detected. Fluoroquinolone resistance was present in various emm types. PMID- 23988720 TI - Wide distribution of CC92 carbapenem-resistant and OXA-23-producing Acinetobacter baumannii in multiple provinces of China. AB - Carbapenem-resistant Acinetobacter baumannii has spread rapidly across China and is currently reported to be a worldwide nosocomial menace. In light of its increasing clinical significance, this study aimed to investigate the molecular epidemiology of carbapenem-resistant and carbapenem-susceptible isolates obtained from multiple provinces of China. Antimicrobial susceptibility was determined by disk diffusion assay according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Multilocus sequence typing (MLST) was used to investigate the molecular epidemiology of the isolates. In addition, a minimum spanning tree algorithm was applied to cluster sequence types (STs) into clonal complexes (CCs) in order to analyse their evolutionary relatedness. Generally, the average rate of resistance to most antibiotics in carbapenem-resistant isolates was extremely high (>85%), except for minocycline (20.45%). Analysis of MLST data confirmed that the genetic background of carbapenem-resistant isolates was relatively simple, with ST92 being the most prevalent clone, occurring in every province, followed by ST138, ST75 and ST381. In contrast, carbapenem-susceptible isolates had a more diverse genetic background. Furthermore, the most widely distributed CC of carbapenem-resistant isolates was bla(OXA-23)-like-producing and predominantly CC92, which incorporate ST136 and its several single-locus variants. Interestingly, isolates belonging to CC92 possessed higher antibiotic resistance rates compared with other STs. Overall, these observations suggest a wide distribution of carbapenem-resistant and bla(OXA-23)-like-producing clone CC92, especially ST92, ST75 and ST138, as the principal reason for the rapidly increasing carbapenem resistance rate in China. PMID- 23988721 TI - Prognostic implications of percutaneous coronary interventions performed according to the appropriate use criteria for coronary revascularization. AB - OBJECTIVES: To assess the prognostic implication of the ACCF/AHA/SCAI appropriate use criteria (AUC) for coronary revascularization in a cohort of non-acute coronary syndrome patients. BACKGROUND: The AUC for coronary revascularization were developed in order to deliver high-quality care; however, the prognostic impact of these criteria remains undefined. METHODS: Consecutive patients (n=3817) undergoing elective percutaneous coronary intervention (PCI) at MedStar Washington Hospital Center since the 2009 AUC publication were retrospectively grouped according to AUC as an "Appropriate," "Inappropriate," or "Undetermined" indication for PCI. Outcomes to 1 year were compared. RESULTS: PCI was categorized as "Appropriate" in 47%, "Inappropriate" in 1.8% and as "Uncertain" in 51% of patients. "Appropriate" PCI patients had a higher prevalence of hypertension and diabetes but a lower prevalence of smoking. "Inappropriate" PCI involved the treatment of more complicated lesions, with lower rates of drug eluting stent utilization. While there were no differences in procedural complications among the 3 groups, in-hospital major complications and outcomes were worse for "Inappropriate" PCI patients. The 30-day (3.2% vs. 7% vs. 4.1%, p=0.32) and 1-year (13.1% vs. 11.8% vs. 15.3%, p=0.43) major adverse cardiac event rates of the "Appropriate," "Inappropriate," and "Uncertain" PCI patients, respectively, were comparable. In multivariable analysis, the procedural appropriateness was not associated with either in-hospital or 1-year outcome. CONCLUSIONS: At large, physicians practicing in tertiary centers adhere to the AUC when subjecting patients with non-acute coronary syndrome to revascularization. The present analysis did not demonstrate association between long-term outcome and procedure appropriateness according to the AUC. PMID- 23988722 TI - The two hit hypothesis: an improved method for siRNA-mediated gene silencing in stimulated primary human T cells. AB - Small interfering RNAs (siRNAs) have revolutionised cellular and molecular biology by uncovering new roles for genes in various biological processes and by providing new opportunities to silence gene expression for therapeutic purposes. A limiting factor of siRNA-mediated gene silencing, however, is the ability to efficiently deliver these molecules into hard-to-transfect cell types such as primary T cells. Nucleofection(r) technology, marketed by Lonza (Amaxa(r)), is an electroporation-based method that is commonly used for the delivery of siRNAs and plasmids into primary T cells. In this study we found that the recommended programs for nucleofection of stimulated primary human T cells with siRNAs inhibited cellular proliferation and were associated with a significant loss of cell viability. Furthermore, viable cells that survived the nucleofection procedure were perturbed in their ability to polarise in response to chemokine stimulation in comparison to mock nucleofections. We therefore evaluated other nucleofection programs and highlight one that resulted in significant silencing at the protein level following nucleofection with siRNAs, while maintaining cell viability and responsiveness to chemokine stimulation. Further optimisation of this method revealed that a second nucleofection with siRNAs after 72 h significantly increased silencing compared to a single nucleofection. This new and improved two-hit nucleofection method for siRNA-mediated gene silencing in stimulated primary human T cells will therefore permit the investigation of genes and signalling pathways in the T cell immune response. PMID- 23988723 TI - Inhibition of histone deacetylases potentiates BMP9-induced osteogenic signaling in mouse mesenchymal stem cells. AB - BACKGROUND/AIMS: We have demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent BMPs in regulating osteoblast differentiation of mesenchymal stem cells (MSCs) although the molecular mechanism underlying BMP9 induced osteogenesis remains to be fully elucidated. It is known that epigenetic regulations play an important role in regulating the stem cell potency and lineage commitment. Here, we investigate if the inhibition of histone deacetylases (Hdacs) affects BMP9-induced osteogenic differentiation of MSCs. METHODS: Using the Hdac inhibitor trichostatin A (TSA), we assess that TSA enhances BMP9-mediated osteogenic markers and matrix mineralization in MSCs, and bone formation in mouse embryonic limb explants. RESULTS: We find that the endogenous expression of most of the 11 Hdacs is readily detectable in MSCs. BMP9 is shown to induce most Hdacs in MSCs. We demonstrate that TSA potentiates BMP9 induced early osteogenic marker alkaline phosphatase (ALP) activity in MSCs, as well as late osteogenic markers osteopontin (OPN) and osteocalcin (OCN) and matrix mineralization. Fetal limb explant culture studies reveal that TSA potentiates BMP9-induced endochondral bone formation, possibly by expanding hypertrophic chondrocyte zone of growth plate. CONCLUSION: Our findings strongly suggest histone deacetylases may play an important role in fine-tuning BMP9 mediated osteogenic signaling through a negative feedback network in MSCs. Thus, Hdac inhibitors may be used as novel therapeutics for bone fracture healing. PMID- 23988724 TI - Plasmonic control of nonlinear two-photon absorption in graphene nanocomposites. AB - Nonlinear two-photon absorption in a quantum dot-graphene nanoflake nanocomposite system has been investigated. An external laser field is applied to the nanocomposite to simultaneously observe two-photon processes in the quantum dot and excite localized surface plasmons in the graphene nanodisk. This resonance condition can be achieved by tuning the plasmon resonance frequency in the graphene nanoflake via electrostatic gating. It is found that the strong local field of the graphene plasmons can enhance and control nonlinear optical processes in the quantum dot. Specifically, we show that the two-photon absorption coefficient in the quantum dot can be switched between single- and double-peaked spectra by modifying the graphene-quantum dot separation. Two photon processes in the quantum dot can also be switched on or off by slightly changing the gate voltage applied to the graphene. Our findings indicate that this system can be used for nonlinear optical applications such as all-optical switching, biosensing and signal processing. PMID- 23988725 TI - A link between the intrarenal renin angiotensin system and hypertension in autosomal dominant polycystic kidney disease. AB - BACKGROUND/AIMS: Early onset of hypertension and its consequences account for the great majority of deaths in patients with autosomal dominant polycystic kidney disease (ADPKD). Renin-angiotensin system (RAS) components have been shown in ADPKD kidneys independent of systemic RAS. Thus, we examined the urinary angiotensinogen (UAGT) levels as a biomarker of intrarenal RAS status in ADPKD patients with/without hypertension and healthy subjects. METHODS: Eighty-four ADPKD patients (43 with hypertension and 41 without hypertension) and 40 healthy controls were studied cross-sectionally. Patients with glomerular filtration rate <60 ml/min were excluded from the study. Hypertension was diagnosed with ambulatory blood pressure monitoring. Urinary and plasma concentration of angiotensinogen, spot urine microprotein and creatinine (UCre) levels were recorded for each participant. RESULTS: UAGT/UCre levels were higher in hypertensive ADPKD patients (23.7 +/- 8.4) compared with normotensive ADPKD patients (16.6 +/- 5.2) and healthy controls (6.9 +/- 3.3; p < 0.001). In univariate analysis, UAGT correlated with systolic blood pressure, diastolic blood pressure (DBP) and proteinuria. The independence of these correlations was analyzed in a regression model, and UAGT was shown to be significantly predicted by proteinuria and DBP. CONCLUSION: Intrarenal RAS activation which is monitored by UAGT levels clinically may be a harbinger of hypertension and kidney disease in ADPKD patients. PMID- 23988726 TI - Interdigital psoriasis of the feet (psoriasis alba): not a distinct form of psoriasis. AB - BACKGROUND: Interdigital psoriasis (IP) of the feet is often missed and is commonly mistaken for interdigital fungal infection. OBJECTIVE: To assess the characteristics and the clinical presentation of IP, in order to better understand if IP should be considered a distinct form of psoriasis or not. METHODS: We performed a 1-year observational study on 164 psoriatic patients, affected by moderate to severe cutaneous psoriasis and undergoing systemic therapy, examining each patient between the digits of both feet. In every suspected case of IP, differential diagnosis with interdigital fungal infection was excluded by direct microscopic examination of skin scrapings, by culture and by skin biopsy. RESULTS: We suspected IP in 7 of the 164 patients. IP was confirmed in 6 patients and in the other one a diagnosis of tinea pedis was made. CONCLUSION: IP proved to be not rare or atypical since IP localized between the toes usually presents as characteristic whitish and sodden plaques or patches. Such a diagnosis should be considered in all patients presenting characteristic lesions especially if these have a negative fungal culture, are resistant to antimycotic treatment and involve patients with a history of psoriasis. PMID- 23988727 TI - Educational differences in healthy behavior changes and adherence among middle aged Americans. AB - Although the better-educated are more likely to practice healthy behaviors when measured at one point in time, there is no clear evidence regarding whether more educated people are more likely to initiate healthy behavior changes in the face of new chronic conditions and whether they are better able to adhere to these healthy changes, once made. I use data from the Health and Retirement Study (HRS) (1992-2010) to examine smoking cessation and starting physical activity by educational attainment over an 18-year period among 16,606 respondents ages 50 to 75. The more-educated are the least likely to smoke and most likely to be physically active in middle age. They are also most likely to make healthy changes overall and better adhere to them. Education also shapes behavior change after a new diagnosis, which likely contributes to socioeconomic status differences in chronic disease management and health outcomes. PMID- 23988728 TI - Association between lean and fat mass and indicators of bone health in prepubertal caucasian children. AB - BACKGROUND/AIMS: Childhood and adolescence are critical periods for bone growth. The independent association between lean and fat mass and indicators of bone health in children is not yet known. We aim to examine the association between each of lean and fat mass and indicators of bone health in 8- to 10-year-old prepubertal Caucasian children. METHODS: We present a cross-sectional analysis of baseline data from the QUebec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort which study the natural history of obesity. Study participants (n = 483) included prepubertal children aged 8-10 years and their biological parents. Whole-body bone mineral content (BMC, g), bone area (cm2), bone mineral density (BMD, g/cm2), lean mass (kg), and fat mass (kg) were measured by dual energy X-ray absorptiometry. Data analyses include multiple linear regressions adjusted for potential confounding variables. RESULTS: A 1-kg increase in lean mass was associated with 28.42 g, 19.88 cm2, and 0.007 g/cm2 increase in whole body BMC, bone area and BMD respectively. A 1-kg increase in fat mass was associated with 9.32 g, 8.02 cm2, and 0.002 g/cm2 increase in whole-body BMC, bone area and BMD, respectively. CONCLUSION: Increasing lean mass in children may help optimize bone acquisition and prevent future osteoporosis. PMID- 23988729 TI - Molecular characterization of the African orthobunyavirus Ilesha virus. AB - Ilesha virus is an arthropod-borne virus belonging to the genus Orthobunyavirus of the Bunyaviridae family. Ilesha virus has been isolated from humans in several African countries, mostly in relation with febrile illness and erythema, though there are reported cases of fatal meningoencephalitis and hemorrhagic fever. In the present study, we report the complete genomic sequence of all three Ilesha virus segments (S, M, L) and characterize the open reading frames. The nucleoprotein encoded by segment S contains 59 conserved orthobunyavirus amino acids putatively critical for protein function. For the polyprotein encoded by segment M, potential proteolytic cleavage sites and N-glycosylation sites as well as conserved cysteines are described in reference to other orthobunyaviruses. Within the C terminal glycoprotein Gc a putative fusion peptide could be localized. In the RNA-dependent RNA polymerase encoded by segment L, all strictly conserved amino acids within the four conserved regions known to be catalytically active are present. Phylogenetic analyses conducted for each Ilesha virus genomic segment confirm the classification of Ilesha virus within the Bunyamwera serogroup of orthobunyaviruses. Ilesha virus segments S and L exhibit highest genetic conservation with Bunyamwera virus and Ngari virus, with maximum sequence identities of 88% for segment S and 82% for segment L. However, the M segment was found to be more diverse with a maximum nucleotide identity of 72% to Bunyamwera serogroup viruses. PMID- 23988730 TI - Determinants of inadequate parental sun protection behaviour in their children- results of a cross-sectional study in Germany. AB - OBJECTIVE: Unprotected sun exposure especially during childhood is a risk factor for skin cancer. A combined use of sun protection measures is recommended to protect children. However, the prevalence and determinants for combined use have been scarcely studied in children. The objective of this study was to identify determinants of parental sun protection behaviour. METHODS: A cross-sectional survey was performed in five regions in Bavaria (Germany) during school entrance health examination (2010/2011). Parents of 4579 children (47% female, aged 5-6 years) completed a self-administered questionnaire (response 61%). RESULTS: Most children were regularly protected with single measures (shade (69%), clothes (80%), hat (83%), sunscreen (89%), sunglasses (20%)). However, regarding regular and combined use, >50% of children were inadequately protected. Larger family size, lower household equivalent income, darker skin and sunburn history were associated with inadequate use of different sun protection measures. The less frequent use of one sun protection measure was associated with less frequent use of the others. Child's sex, migration background, parental education and sun exposure showed inconsistent results regarding the different sun protection outcomes. CONCLUSION: Based on our results a regular, combined and correct use of multiple sun protection for children should be promoted independent of sociodemographic characteristics. Priority of shade, clothes and hat before sunscreen should be clarified. PMID- 23988731 TI - An electrochemiluminescence (ECL)-based assay for the specific detection of anti drug antibodies of the IgE isotype. AB - To address a possible linkage between the occurrence of the hypersensitivity reactions and the induction of IgE anti-drug-antibodies (ADA), a drug specific IgE ADA assay was developed using electrochemiluminescence (ECL) technology. In the assay a drug-specific IgE isotype chimeric antibody was generated and used as an ADA positive control. The biotinylated drug X (an antibody) and ruthenium labeled omalizumab (an anti-human IgE antibody) were used as capture and detection reagents, respectively. The binding affinities of the chimeric IgE isotype positive control have been shown to be highly comparable to drug X and drug Y (drug X is the 2nd generation of drug Y), indicating that it could serve as a highly useful control to compare and contrast the relative ability of the two generations of drug to elicit IgE ADA responses. The assay cut point factor (CPF) was estimated to be 1.13. The cut point factor derived from normal human serum samples was statistically equivalent to the cut point factor determined from targeted population samples. The assay could detect less than 250ng/mL of IgE antibodies in the presence of 300MUg/mL drug X. The assay sensitivity was <0.2ng/mL. A minimal prozone was observed at 100MUg/mL IgE ADA, but the sample remained highly detectable. The inter-assay precision was within 12%. The assay was not susceptible to non-specific matrix effects. The performance specifications ensured that the assay was suitable for validation. The combination of the chimeric IgE positive control and the detection antibody (ruthenium-labeled omalizumab) used for the assay could potentially provide a general bioanalytical approach for other biopharmaceuticals for the detection of IgE ADA responses. PMID- 23988732 TI - Cytotoxic effect of amphotericin B in a myofibroblast cell line. AB - In this study we investigate whether Amphotericin B (AmB), a widely used antifungal agent, could decrease the proliferation of a myofibroblast cell line - GRX, a model of activated hepatic stellate cells (HSC). Three different hepatic cell lines (GRX, Hep G2 and ARL-6) were treated with two concentrations of AmB (1.25 MUg/mL or 2.50 MUg/mL). Cytotoxicity was assessed by MTT assay. The effects of AmB on GRX migration was evaluated by Wound-healing Assay. Cell cycle arrest was investigated by flow cytometry. Apoptosis and autophagy were analyzed by Caspase 3 and LC3 immunostaining, respectively. Treatment with AmB 1.25 or 2.50 MUg/mL showed a decrease in viability of GRX cells. This decrease was not observed for Hep G2 or ARL-6 in any of the two AmB concentrations tested. GRX cells treated with 1.25 MUg/mL AmB were unable to close the wound after 96 h. Cell cycle analysis showed an increase in sub-G1 population and a decrease in G2/M population in AmB-treated cells. In addition, AmB-treated GRX cells showed increased expression of LC-3 and Caspase-3 by immunohistochemistry, suggesting an increase in both autophagy and apoptosis. Here we show that AmB is cytotoxic for GRX cells, a model of activated HSC, but not for hepatic lineages HepG2 and ARL6. PMID- 23988733 TI - Increased whole blood viscosity is associated with silent cerebral infarction. AB - BACKGROUND: The presence of silent cerebral infarction (SCI) increases the risk of transient ischemia attack, symptomatic stroke, cardiovascular disease and dementia. Increased viscosity is associated with aging, obesity, carotid intima media thickness, metabolic syndrome, hypertension, diabetes, ischemic heart disease, and stroke. AIMS: The purpose of the study was to assess the hemorheological parameters levels in SCI patients. METHODS: A cross-sectional study was conducted to evaluate the association between hemorheological parameters and SCI in 1487 subjects (868 men and 619 women) undergoing medical check-up. RESULTS: The participants with SCI had higher whole blood viscosity (WBV) levels at low shear rate than those without SCI (10.34 +/- 1.77 mPa.s vs. 8.98 +/- 0.88 mPa.s; P < 0.001). Moreover, the subjects with a high WBV had a higher prevalence of SCI. Logistic regression analysis revealed that a significant association of WBV levels with the risk of SCI after adjustment for confounding factors (OR: 2.025; 95% CI: 1.750-2.343; P < 0.001). CONCLUSIONS: Whole blood viscosity at low shear rate is a novel indicator for SCI regardless of classical cardiovascular risk factors. Early measurement of whole blood viscosity may be helpful to assess the risk of stroke. PMID- 23988734 TI - Temperament, character and personality disorders. AB - OBJECTIVE: To study, whether temperament and character remain stable over time and whether they differ between patients with and without personality disorder (PD) and between patients with specific PDs. METHODS: Patients with (n=225) or without (n=285) PD from Jorvi Bipolar Study, Vantaa Depression Study (VDS) and Vantaa Primary Care Depression Study were interviewed at baseline and at 18 months, and in the VDS also at 5 years. A general population comparison group (n=264) was surveyed by mail. RESULTS: Compared with non-PD patients, PD patients scored lower on self-directedness and cooperativeness. Cluster B and C PDs associated with high Novelty Seeking and Harm Avoidance, respectively. In logistic regression models, sensitivity and specificity of Temperament and Character Inventory (TCI) dimensions for presence of any PD were 53% and 75%, and for specific PDs from 11% to 41% and from 92% to 100%, respectively. The 18-month test-retest correlations of TCI-R dimensions ranged from 0.58 to 0.82. CONCLUSIONS: Medium-term temporal stability of TCI in a clinical population appears good. Character scores differ markedly between PD and non-PD patients, whereas temperament scores differ only somewhat between the specific PDs. However, the TCI dimensions capture only a portion of the differences between PD and non-PD patients. PMID- 23988735 TI - Self-harm induced somatic admission after discharge from psychiatric hospital - a prospective cohort study. AB - BACKGROUND: Few studies have examined rate and predictors of self-harm in discharged psychiatric patients. AIMS: To investigate the rate, coding, timing, predictors and characteristics of self-harm induced somatic admission after discharge from psychiatric acute admission. METHOD: Cohort study of 2827 unselected patients consecutively admitted to a psychiatric acute ward during three years. Mean observation period was 2.3 years. Combined register linkage and manual data examination. Cox regression was used to investigate covariates for time to somatic admission due to self-harm, with covariates changing during follow-up entered time dependently. RESULTS: During the observation period, 10.5% of the patients had 792 somatic self-harm admissions. Strongest risk factors were psychiatric admission due to non-suicidal self-harm, suicide attempt and suicide ideation. The risk was increased throughout the first year of follow-up, during readmission, with increasing outpatient consultations and in patients diagnosed with recurrent depression, personality disorders, substance use disorders and anxiety/stress-related disorders. Only 49% of the somatic self-harm admissions were given hospital self-harm diagnosis. CONCLUSIONS: Self-harm induced somatic admissions were highly prevalent during the first year after discharge from acute psychiatric admission. Underdiagnosing of self-harm in relation to somatic self harm admissions may cause incorrect follow-up treatments and unreliable register data. PMID- 23988736 TI - The choice of nucleotide inserted opposite abasic sites formed within chromosomal DNA reveals the polymerase activities participating in translesion DNA synthesis. AB - Abasic sites in genomic DNA can be a significant source of mutagenesis in biological systems, including human cancers. Such mutagenesis requires translesion DNA synthesis (TLS) bypass of the abasic site by specialized DNA polymerases. The abasic site bypass specificity of TLS proteins had been studied by multiple means in vivo and in vitro, although the generality of the conclusions reached have been uncertain. Here, we introduce a set of yeast reporter strains for investigating the in vivo specificity of abasic site bypass at numerous random positions within chromosomal DNA. When shifted to 37 degrees C, these strains underwent telomere uncapping and resection that exposed reporter genes within a long 3' ssDNA overhang. Human APOBEC3G cytosine deaminase was expressed to create uracils in ssDNA, which were excised by uracil-DNA N glycosylase. During repair synthesis, error-prone TLS bypassed the resulting abasic sites. Because of APOBEC3G's strict motif specificity and the restriction of abasic site formation to only one DNA strand, this system provides complete information about the location of abasic sites that led to mutations. We recapitulated previous findings on the roles of REV1 and REV3. Further, we found that sequence context can strongly influence the relative frequency of A or C insertion. We also found that deletion of Pol32, a non-essential common subunit of Pols delta and zeta, resulted in residual low-frequency C insertion dependent on Rev1 catalysis. We summarize our results in a detailed model of the interplay between TLS components leading to error-prone bypass of abasic sites. Our results underscore the utility of this system for studying TLS bypass of many types of lesions within genomic DNA. PMID- 23988737 TI - Dehydroepiandrosterone sulfate mediates activation of transcription factors CREB and ATF-1 via a Galpha11-coupled receptor in the spermatogenic cell line GC-2. AB - Dehydroepiandrosterone sulfate (DHEAS) is a circulating steroid produced in the adrenal cortex, brain, and gonads. Whereas a series of investigations attest to neuroprotective effects of the steroid in the brain, surprisingly little is known about the physiological effects of DHEAS on cells of the reproductive system. Here we demonstrate that DHEAS acting on the spermatogenic cell line GC-2 induces a time- and concentration-dependent phosphorylation of c-Src and Erk1/2 and activates the transcription factors activating transforming factor-1 (ATF-1) and cyclic AMP-responsive element binding protein (CREB). These actions are consistent with the non-classical signaling pathway of testosterone and suggest that DHEAS is a pro-androgen that is converted into testosterone in order to exert its biological activity. The fact, however, that steroid sulfatase mRNA was not detected in the GC-2 cells and the clear demonstration of DHEAS-induced activation of Erk1/2, ATF-1 and CREB after silencing the androgen receptor by small interfering RNA (siRNA) clearly contradict this assumption and make it appear unlikely that DHEAS has to be converted in the cytosol into a different steroid in order to activate the kinases and transcription factors mentioned. Instead, it is likely that the DHEAS-induced signaling is mediated through the interaction of the steroid with a membrane-bound G-protein-coupled receptor, since silencing of Guanine nucleotide-binding protein subunit alpha-11 (Gnalpha11) leads to the abolition of the DHEAS-induced stimulation of Erk1/2, ATF-1, and CREB. The investigation presented here shows a hormone-like activity of DHEAS on a spermatogenic cell line. Since DHEAS is produced in male and female reproductive organs, these findings could help to define new roles for DHEAS in the physiology of reproduction. PMID- 23988738 TI - When ER stress reaches a dead end. AB - Endoplasmic reticulum (ER) stress is a common feature of several physiological and pathological conditions affecting the function of the secretory pathway. To restore ER homeostasis, an orchestrated signaling pathway is engaged that is known as the unfolded protein response (UPR). The UPR has a primary function in stress adaptation and cell survival; however, under irreversible ER stress a switch to pro-apoptotic signaling events induces apoptosis of damaged cells. The mechanisms that initiate ER stress-dependent apoptosis are not fully understood. Several pathways have been described where we highlight the participation of the BCL-2 family of proteins and ER calcium release. In addition, recent findings also suggest that microRNAs and oxidative stress are relevant players on the transition from adaptive to cell death programs. Here we provide a global and integrated overview of the signaling networks that may determine the elimination of a cell under chronic ER stress. This article is part of a Special Section entitled: Cell Death Pathways. PMID- 23988740 TI - Anomalous compression and new high-pressure phases of vanadium sesquioxide, V2O3. AB - We report results of a powder x-ray diffraction (XRD) study of vanadium sesquioxide, V2O3, under pressurization in a neon pressure-transmitting medium up to 57 GPa. We have established a bulk modulus value for corundum-type V2O3 of B0 = 150 GPa at B' = 4. This bulk modulus value is the lowest among those known for the corundum-type-structured oxides, e.g. Al2O3, alpha-Fe2O3, Cr2O3, Ti2O3, and alpha-Ga2O3. We have proposed that this might be related to the difference in the electronic band structures: at room temperature V2O3 is metallic, but the above corundum-structured sesquioxides are semiconducting or insulating. Around ~21-27 and ~50 GPa we registered changes in the XRD patterns that might be addressed to phase transitions. These transitions were sluggish upon room-temperature compression, and hence we additionally facilitated them by the laser heating of one sample. We have refined the XRD patterns of only the first high-pressure phase in an orthorhombic lattice of a Rh2O3(II)-type. Our findings significantly extend the knowledge of the P-T phase diagram of V2O3 and advance the understanding of its properties. We speculate that the elastic properties of V2O3 can be closely linked to its electronic band structure and, consequently, we propose that slightly doped V2O3 (e.g. with Cr) could be a potential candidate for systems in which the bulk modulus value may be remarkably switched by moderate pressure or temperature. PMID- 23988739 TI - Cyclic nucleotide phosphodiesterase 3A1 protects the heart against ischemia reperfusion injury. AB - Phosphodiesterase 3A (PDE3A) is a major regulator of cAMP in cardiomyocytes. PDE3 inhibitors are used for acute treatment of congestive heart failure, but are associated with increased incidence of arrhythmias and sudden death with long term use. We previously reported that chronic PDE3A downregulation or inhibition induced myocyte apoptosis in vitro. However, the cardiac protective effect of PDE3A has not been demonstrated in vivo in disease models. In this study, we examined the role of PDE3A in regulating myocardial function and survival in vivo using genetically engineered transgenic mice with myocardial overexpression of the PDE3A1 isozyme (TG). TG mice have reduced cardiac function characterized by reduced heart rate and ejection fraction (52.5+/-7.8% vs. 83.9+/-4.7%) as well as compensatory expansion of left ventricular diameter (4.19+/-0.19mm vs. 3.10+/ 0.18mm). However, there was no maladaptive increase of fibrosis and apoptosis in TG hearts compared to wild type (WT) hearts, and the survival rates also remained the same. The diminution of cardiac contractile function is very likely attributed to a decrease in beta-adrenergic receptor (beta-AR) response in TG mice. Importantly, the myocardial infarct size (4.0+/-1.8% vs. 24.6+/-3.8%) and apoptotic cell number (1.3+/-1.0% vs. 5.6+/-1.5%) induced by ischemia/reperfusion (I/R) injury were significantly attenuated in TG mice. This was associated with decreased expression of inducible cAMP early repressor (ICER) and increased expression of anti-apoptotic protein BCL-2. To further verify the anti-apoptotic effects of PDE3A1, we performed in vitro apoptosis study in isolated adult TG and WT cardiomyocytes. We found that the apoptotic rates stimulated by hypoxia/reoxygenation or H2O2 were indeed significantly reduced in TG myocytes, and the differences between TG and WT myocytes were completely reversed in the presence of the PDE3 inhibitor milrinone. These together indicate that PDE3A1 negatively regulates beta-AR signaling and protects against I/R injury by inhibiting cardiomyocyte apoptosis. PMID- 23988741 TI - Permanent distal occlusion of middle cerebral artery in rat causes local increased ETB, 5-HT1B and AT1 receptor-mediated contractility downstream of occlusion. AB - BACKGROUND/AIMS: In response to experimental stroke, a characteristic functional and expressional upregulation of contractile G-protein-coupled receptors has been uncovered in the affected cerebral vasculature; however, the mechanism initiating this phenomenon remains unknown. METHODS: Using a model of permanent distal occlusion of rat middle cerebral arteries, we investigated whether there was a regional difference in receptor-mediated contractility of segments located upstream and downstream of the occlusion site. The contractile response to endothelin, angiotensin and 5-hydroxytryptamine receptor stimulation was studied by sensitive wire myograph. RESULTS: Only downstream segments exhibited an augmented contractile response to stimulation with each of the three ligands, with the response towards sarafotoxin 6c being especially augmented compared to sham, upstream and contralateral controls. This functional increase did not seem to relate to ischemic tissue damage, inflammatory cell infiltration or the element of reperfusion. Interestingly, immunohistochemistry did not show any difference in the level of immunoreactivity towards endothelin B (ETB) receptors between groups. CONCLUSION: Single artery occlusion without significant visible infarct resulted in locally increased ETB, angiotensin type 1 and 5 hydroxytryptamine 1B receptor-mediated contractile responses only in segments located downstream of the occlusion site. This suggests lack of wall stress as an initiating trigger leading to regulation of contractile response after cerebral stroke. PMID- 23988742 TI - Spatiotemporal statistical modelling of long-term change in river nutrient concentrations in England & Wales. AB - Concentrations of nutrient nitrogen (N) and phosphorus (P) are elevated in rivers across large areas of Europe (European Nitrogen Assessment (ENA), Sutton et al., 2011). Environmental policies have been implemented over the past 20 years with the aim of reducing nitrogen inputs to surface waters. However, environmental and ecological status is still below set targets (ENA, Sutton et al., 2011). Identification of patterns in long-term change for nutrient trends in hydrological catchments in England & Wales is required to assess impacts of nutrient management policy and provide better evidence for future policy. Such information could provide essential evidence for supporting policy by combining information from the wider catchment, rather than relying on the analysis of data from individual sites. Surface water quality is subject to considerable spatial and short-period temporal variability, reflecting variability in loading and dilution. This makes it difficult to determine temporal trends at individual monitoring sites with relatively sparse sampling. Here we apply spatiotemporal statistical additive models for both nitrogen and phosphorus in river networks across England & Wales to investigate the overall pattern of nutrient concentrations in these river surface waters over the past 20-40 years. Concentrations of Orthophosphate (OP) have generally decreased over time for many of the Large Hydrological Areas with a seasonal pattern highlighting one peak in the summer months. Over the past ten years, Total Oxidised Nitrogen (Nitrate+Nitrite, TON) concentrations have generally been slowly decreasing or fairly constant. However, prior to 2000, concentrations were generally on an upward trend. The seasonal pattern highlights one trough in the summer months. The highest levels for OP and TON broadly occur in the same general areas across England & Wales. On average, over time, the lowest values are evident in the north-west and south-west (particularly for OP) and highest values are evident in the Midlands, Anglian and Southern regions. PMID- 23988743 TI - Ozonation of ibuprofen: a degradation and toxicity study. AB - This paper presents the results obtained in the degradation of ibuprofen by ozonation. This study aims to evaluate the degradation of ibuprofen by ozonation once the operating variables have been optimized, investigating the degradation and degradation efficiency of the compound and assessing the toxic effect of ibuprofen and of the intermediate compounds generated during oxidative treatment. Work was carried out to optimize the four operating variables: pH, conductivity, hydraulic retention time and the use of a maze of pipes to enhance contact between the ozone and the drug. All the trials were conducted in a purpose-built pilot-scale reactor. Analyses of the compound were carried out after solid-liquid phase extraction on high resolution liquid chromatography (HPLC). Working under optimal operating conditions (pH=9, HRT=20 min and 12 +/- 2 gN/m(3)), a degradation value of 99% was obtained, although degradation efficiency or mineralization of the compound was not achieved. The toxicity of ibuprofen and its intermediate compounds formed during the oxidative process was likewise studied. This toxicity was found to increase with increasing initial concentrations of the compound, with the intermediate compounds thus formed being more toxic than the starting compound. PMID- 23988744 TI - Sediment desiccation as a driver of phosphate availability in the water column of Mediterranean wetlands. AB - Sediment desiccation is expected to drastically affect nutrient cycling in Mediterranean wetlands as global climate change models predict that many areas will become significantly drier than they currently are. In this study, we selected two Mediterranean wetlands that clearly differ in their water chemical composition (Honda and Hituelo wetlands) in order to determine the impact of sediment desiccation on phosphate (PO4(3-)) adsorption and desorption properties. A decrease in PO4(3-) sorption properties was observed in transects from the littoral zone to dry land in both lakes concomitantly with a reduction in organic matter content, revealing a critical role of organic matter for sequestering P in the lake sediment. Our experiments designed to determine if drying events would lead to an enhanced P release upon re-wetting have shown that, simulating natural conditions of re-flooding (that is without adding sodium azide), PO4(3-) concentrations were notably higher in the overlying water than those initially measured in the lake water. These results highlight the impact of drying sediment and the subsequent re-wetting on increasing P concentrations in lake water and accordingly, affecting to lake trophic state. Finally, we aimed on determining the overall effect of biotic versus abiotic activity on P release patterns observed upon re-wetting. Our results have evidenced that while in Honda, biotic processes upon re-wetting are crucial for increasing P retention in the sediment; P exchange across sediment and water upon dry sediment re-wetting is basically mediated by abiotic processes in Hituelo. PMID- 23988745 TI - Comparison of contaminants of emerging concern removal, discharge, and water quality hazards among centralized and on-site wastewater treatment system effluents receiving common wastewater influent. AB - A comparative understanding of effluent quality of decentralized on-site wastewater treatment systems, particularly for contaminants of emerging concern (CECs), remains less understood than effluent quality from centralized municipal wastewater treatment plants. Using a novel experimental facility with common influent wastewater, effluent water quality from a decentralized advanced aerobic treatment system (ATS) and a typical septic treatment system (STS) coupled to a subsurface flow constructed wetland (WET) were compared to effluent from a centralized municipal treatment plant (MTP). The STS did not include soil treatment, which may represent a system not functioning properly. Occurrence and discharge of a range of CECs were examined using isotope dilution liquid chromatography-tandem mass spectrometry during fall and winter seasons. Conventional parameters, including total suspended solids, carbonaceous biochemical oxygen demand and nutrients were also evaluated from each treatment system. Water quality of these effluents was further examined using a therapeutic hazard modeling approach. Of 19 CECs targeted for study, the benzodiazepine pharmaceutical diazepam was the only CEC not detected in all wastewater influent and effluent samples over two sampling seasons. Diphenhydramine, codeine, diltiazem, atenolol, and diclofenac exhibited significant (p<0.05) seasonal differences in wastewater influent concentrations. Removal of CECs by these wastewater treatment systems was generally not influenced by season. However, significant differences (p<0.05) for a range of water quality indicators were observed among the various treatment technologies. For example, removal of most CECs by ATS was generally comparable to MTP. Lowest removal of most CECs was observed for STS; however, removal was improved when coupling the STS to a WET. Across the treatment systems examined, the majority of pharmaceuticals observed in on-site and municipal effluent discharges were predicted to potentially present therapeutic hazards to fish. PMID- 23988746 TI - Reduced risk estimations after remediation of lead (Pb) in drinking water at two US school districts. AB - The risk of students to develop elevated blood lead from drinking water consumption at schools was assessed, which is a different approach from predictions of geometric mean blood lead levels. Measured water lead levels (WLLs) from 63 elementary schools in Seattle and 601 elementary schools in Los Angeles were acquired before and after voluntary remediation of water lead contamination problems. Combined exposures to measured school WLLs (first-draw and flushed, 50% of water consumption) and home WLLs (50% of water consumption) were used as inputs to the Integrated Exposure Uptake Biokinetic (IEUBK) model for each school. In Seattle an average 11.2% of students were predicted to exceed a blood lead threshold of 5 MUg/dL across 63 schools pre-remediation, but predicted risks at individual schools varied (7% risk of exceedance at a "low exposure school", 11% risk at a "typical exposure school", and 31% risk at a "high exposure school"). Addition of water filters and removal of lead plumbing lowered school WLL inputs to the model, and reduced the predicted risk output to 4.8% on average for Seattle elementary students across all 63 schools. The remnant post-remediation risk was attributable to other assumed background lead sources in the model (air, soil, dust, diet and home WLLs), with school WLLs practically eliminated as a health threat. Los Angeles schools instead instituted a flushing program which was assumed to eliminate first-draw WLLs as inputs to the model. With assumed benefits of remedial flushing, the predicted average risk of students to exceed a BLL threshold of 5 MUg/dL dropped from 8.6% to 6.0% across 601 schools. In an era with increasingly stringent public health goals (e.g., reduction of blood lead safety threshold from 10 to 5 MUg/dL), quantifiable health benefits to students were predicted after water lead remediation at two large US school systems. PMID- 23988747 TI - Atmospheric polychlorinated naphthalenes (PCNs) in India and Pakistan. AB - Polychlorinated naphthalenes (PCNs) are now under review by the Stockholm Convention as candidates for persistent organic pollutants (POPs) due to their persistence, toxicity, bioaccumulation, and long-range atmospheric transport. Data on PCN levels are sparse in South Asia. Atmospheric PCNs in India and Pakistan were monitored during the winter by polyurethane foam disk passive air samplers (PUF-PAS). The average concentrations were 29 pg/m(3) and 7.7 pg/m(3) in the Indian and Pakistani samples, respectively. Those concentration levels were relatively lower than the previously reported values in other Asian countries, but still considerably higher than in other sites in the world. Tri-CNs and tetra CNs were the dominant homologues in the air, especially in India. Spatially, the PCNs were ubiquitous in the target areas, and local distribution was generally impacted by the proximity to potential sources. Major sources of PCNs in this study were the re-emission of Halowax and industrial thermal processes. Biomass burning influenced some sites in Pakistan. However, the enrichment of tri-CNs in Indian cities cannot be ascribed to either the signature of a specific source or the preferential volatilization and/or photodegradation in tropical areas. Despite this unclear issue in South Asia, the present study indicates that the potential health impact was generally comparable to that in non-urban sites worldwide. PMID- 23988749 TI - The RENAL nephrometry score and the PADUA classification for the prediction of perioperative outcomes in patients receiving nephron-sparing surgery: feasible tools to predict intraoperative conversion to nephrectomy. AB - OBJECTIVE: To evaluate the potential of the RENAL nephrometry score and the PADUA classification in the prediction of perioperative outcomes represented by intraoperative conversion to nephrectomy in patients with renal tumors for which nephron-sparing surgery (NSS) was attempted. METHODS: Recent 100 open NSSs attempted for cT1 renal tumors at a single institution were studied retrospectively. RESULTS: With the RENAL, the operation time and ischemia time were longer in the high complexity group (p = 0.01 and p = 0.03, respectively), and blood loss was seemingly greater in this group (394 vs. 220 and 167 ml, p = 0.09). Conversion to nephrectomy was more frequent in the high complexity (4 procedures, 33.3%) than in the low (0%) and moderate (1 procedures, 1.5%) groups (p < 0.01). Regarding the PADUA, the operation time, blood loss and ischemia time increased according to the complexity (p = 0.04, p = 0.02, and p = 0.02, respectively). Conversion to nephrectomy was more frequent in the high complexity (4 procedures, 22.2%) than in the low (0%) and moderate (1 procedure, 1.8%) groups (p < 0.01). In patients with achieved NSS, postoperative estimated glomerular filtration rate was more impaired in the high complexity group in the PADUA (p = 0.02), although not significant in the RENAL (p = 0.11). CONCLUSIONS: Both the RENAL and PADUA are useful in the prediction of conversion to nephrectomy in addition to NSS-associated perioperative outcomes. PMID- 23988748 TI - Role of p66shc in renal toxicity of oleic acid. AB - BACKGROUND/AIMS: Adult and childhood obesity is an independent risk factor in development of chronic kidney disease (CKD) and its progression to end-stage kidney disease. Pathologic consequences of obesity include non-esterified fatty acid-induced oxidative stress and consequent injury. Since the serine36 phosphorylated p66shc is a newly recognized mediator of oxidative stress and kidney injury, we studied its role in oleic acid (OA)-induced production of reactive oxygen species (ROS), mitochondrial depolarization and injury in cultured renal proximal tubule cells. METHODS: Renal proximal tubule cells were used and treated with OA: ROS production, mitochondrial depolarization as well as injury were determined. Transcriptional effects of OA on the p66shc gene were determined in a reporter luciferase assay. The role of p66shc in adverse effects of OA was determined using knockdown, p66shc serine36 phosphorylation and cytochrome c binding-deficient cells. RESULTS: We found that OA increased ROS production via the mitochondria - and to a less extent via the NADPH oxidase - resulting in ROS-dependent mitochondrial depolarization and consequent injury. Interestingly, OA also stimulated the promoter of p66shc. Hence, knockdown of p66shc, impairment its Ser36 phosphorylation (mutation of Ser36 residue to alanine) or cytochrome c binding (W134F mutation) significantly attenuated OA dependent lipotoxicity. CONCLUSION: These results offer a novel mechanism by which obesity may lead to renal tubular injury and consequently development of CKD. Manipulation of this pathway may offer therapeutic means to ameliorate obesity-dependent renal lipotoxicity. PMID- 23988750 TI - Mesenchymal cystic hamartoma? A revised diagnosis after 23 years. PMID- 23988751 TI - Reasons for heterogeneous change in LCI in children with cystic fibrosis after antibiotic treatment. PMID- 23988752 TI - Stretch-resistant coils for intracranial aneurysms: one step forward or two steps back? PMID- 23988753 TI - Evaluation of common structural brain changes in aging and Alzheimer disease with the use of an MRI-based brain atrophy and lesion index: a comparison between T1WI and T2WI at 1.5T and 3T. AB - BACKGROUND AND PURPOSE: The Brain Atrophy and Lesion Index combines several common, aging-related structural brain changes and has been validated for high field MR imaging. In this study, we evaluated measurement properties of the Brain Atrophy and Lesion Index by use of T1WI and T2WI at 1.5T and 3T MR imaging to comprehensively assess the usefulness of the lower field-strength testing. MATERIALS AND METHODS: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative. Images of subjects (n = 127) who had T1WI and T2WI at both 3T and 1.5T on the same day were evaluated, applying the Brain Atrophy and Lesion Index rating. Criterion and construct validity and interrater agreement were tested for each field strength and image type. RESULTS: Regarding reliability, the intraclass correlation coefficients for the Brain Atrophy and Lesion Index score were consistently high (>0.81) across image type and field strength. Regarding construct validity, the Brain Atrophy and Lesion Index score differed among diagnostic groups, being lowest in people without cognitive impairment and highest in those with Alzheimer disease (F > 5.14; P < .007). Brain Atrophy and Lesion Index scores correlated with age (r > 0.37, P < .001) and cognitive performance (r > 0.38, P < .001) and were associated with positive amyloid-beta test (F > 3.96, P < .050). The T1WI and T2WI Brain Atrophy and Lesion Index scores were correlated (r > 0.93, P < .001), with the T2WI scores slightly greater than the T1WI scores (F > 4.25, P < .041). Regarding criterion validation of the 1.5T images, the 1.5T scores were highly correlated with the 3T Brain Atrophy and Lesion Index scores (r > 0.93, P < .001). CONCLUSIONS: The higher field and T2WI more sensitively detect subtle changes in the deep white matter and perivascular spaces in particular. Even so, 1.5T Brain Atrophy and Lesion Index scores are similar to those obtained by use of 3T images. The Brain Atrophy and Lesion Index may have use in quantifying the impact of dementia on brain structures. PMID- 23988754 TI - Guidelines for the ethical use of neuroimages in medical testimony: report of a multidisciplinary consensus conference. AB - SUMMARY: With rapid advances in neuroimaging technology, there is growing concern over potential misuse of neuroradiologic imaging data in legal matters. On December 7 and 8, 2012, a multidisciplinary consensus conference, Use and Abuse of Neuroimaging in the Courtroom, was held at Emory University in Atlanta, Georgia. Through this interactive forum, a highly select group of experts including neuroradiologists, neurologists, forensic psychiatrists, neuropsychologists, neuroscientists, legal scholars, imaging statisticians, judges, practicing attorneys, and neuroethicists-discussed the complex issues involved in the use of neuroimaging data entered into legal evidence and for associated expert testimony. The specific contexts of criminal cases, child abuse, and head trauma were especially considered. The purpose of the conference was to inform the development of guidelines on expert testimony for the American Society of Neuroradiology and to provide principles for courts on the ethical use of neuroimaging data as evidence. This report summarizes the conference and resulting recommendations. PMID- 23988755 TI - Brain MRI measurements at a term-equivalent age and their relationship to neurodevelopmental outcomes. AB - BACKGROUND AND PURPOSE: An increased prevalence of disabilities is being observed as more preterm infants survive. This study was conducted to evaluate correlations between brain MR imaging measurements taken at a term-equivalent age and neurodevelopmental outcome at 2 years' corrected age among very low-birth weight infants. MATERIALS AND METHODS: Of the various brain MR imaging measurements obtained at term-equivalent ages, reproducible measurements of the transcerebellar diameter and anteroposterior length of the corpus callosum on sagittal images were compared with neurodevelopmental outcomes evaluated by the Bayley Scales of Infant Development (II) at 2 years' corrected age (mean +/- standard deviation, 16.1 +/- 6.4 months of age). RESULTS: Ninety infants were enrolled. The mean gestational age at birth was 27 weeks and the mean birth weight was 805.5 g. A short corpus callosal length was associated with a Mental Developmental Index <70 (P = .047) and high-risk or diagnosed cerebral palsy (P = .049). A small transcerebellar diameter was associated with a Psychomotor Developmental Index <70 (P = .003), Mental Developmental Index <70 (P = .004), and major neurologic disability (P = .006). CONCLUSIONS: A small transcerebellar diameter and short corpus callosal length on brain MR imaging at a term equivalent age are related to adverse neurodevelopmental outcomes at a corrected age of 2 years and could be a useful adjunctive tool for counseling parents about future developmental outcomes. PMID- 23988756 TI - Semiautomated volumetric measurement on postcontrast MR imaging for analysis of recurrent and residual disease in glioblastoma multiforme. AB - BACKGROUND AND PURPOSE: A limitation in postoperative monitoring of patients with glioblastoma is the lack of objective measures to quantify residual and recurrent disease. Automated computer-assisted volumetric analysis of contrast-enhancing tissue represents a potential tool to aid the radiologist in following these patients. In this study, we hypothesize that computer-assisted volumetry will show increased precision and speed over conventional 1D and 2D techniques in assessing residual and/or recurrent tumor. MATERIALS AND METHODS: This retrospective study included patients with native glioblastomas with MR imaging performed at 24-48 hours following resection and 2-4 months postoperatively. 1D and 2D measurements were performed by 2 neuroradiologists with Certificates of Added Qualification. Volumetry was performed by using manual segmentation and computer-assisted volumetry, which combines region-based active contours and a level set approach. Tumor response was assessed by using established 1D, 2D, and volumetric standards. Manual and computer-assisted volumetry segmentation times were compared. Interobserver correlation was determined among 1D, 2D, and volumetric techniques. RESULTS: Twenty-nine patients were analyzed. Discrepancy in disease status between 1D and 2D compared with computer-assisted volumetry was 10.3% (3/29) and 17.2% (5/29), respectively. The mean time for segmentation between manual and computer-assisted volumetry techniques was 9.7 minutes and <1 minute, respectively (P < .01). Interobserver correlation was highest for volumetric measurements (0.995; 95% CI, 0.990-0.997) compared with 1D (0.826; 95% CI, 0.695-0.904) and 2D (0.905; 95% CI, 0.828-0.948) measurements. CONCLUSIONS: Computer-assisted volumetry provides a reproducible and faster volumetric assessment of enhancing tumor burden, which has implications for monitoring disease progression and quantification of tumor burden in treatment trials. PMID- 23988757 TI - Patient-reported outcomes in clinical trials of CKD-related therapies: report of a symposium sponsored by the national kidney foundation and the U.S. Food and Drug Administration. AB - The National Kidney Foundation and the U.S. Food and Drug Administration (FDA) convened a symposium in September 2010, bringing together more than 70 experts, including representatives from the FDA, the National Institutes of Health, the Critical Path Institute, nephrologists, patients, and the pharmaceutical industry to discuss the feasibility and process of developing patient-reported outcome (PRO) measures to access how patients feel or function to be used in clinical trials for regulatory review of treatment benefit. Three disease areas were evaluated for development of end point models in which PRO measures may be useful: anemia secondary to chronic kidney disease, autosomal dominant polycystic kidney disease (ADPKD), and nephrotic syndrome. The participants thought it valuable to use observational data to generate hypotheses regarding patient baseline characteristics that are likely to predict clinically important changes in PROs in response to anemia treatment and to design adequately powered blinded randomized controlled trials of anemia treatment using PROs as primary rather than secondary end points. Validated PRO instruments that reflect the patient experience in ADPKD and nephrotic syndrome are essential to incorporate into clinical trials of new therapeutic interventions because glomerular filtration rate decline may occur late in the disease course, at which point therapeutic benefit is less likely. Conference attendees addressed how PRO measures could be used to evaluate, monitor, provide care, and facilitate the introduction of treatments for patients with these challenging conditions. PMID- 23988758 TI - Research amongst physical therapists in the state of Kuwait: participation, perception, attitude and barriers. AB - OBJECTIVES: The objectives of this descriptive study were to investigate the attitudes and perceptions of physical therapists regarding research, the intention to engage in research and the barriers to participating in research amongst physical therapists in the State of Kuwait. SUBJECTS AND METHODS: A previously validated questionnaire was distributed to 200 non-randomly selected physical therapists. The questionnaire gathered demographic data as well as information regarding research-related activities. Descriptive statistics, frequency and chi(2) analyses were used in this study. RESULTS: Of the 200 questionnaires distributed to physical therapists 122 (61%) were completed and returned. The physical therapists had a positive attitude towards reading these findings in order to update their knowledge. However, only 16 (17%) of the physical therapists participated in clinical research. The common reasons given were: minimal role and reduced ability, intention and level of engagement in initiating research, probably due to work overload, time constraints and limited access to resources. CONCLUSIONS: Physical therapists in Kuwait had a positive attitude towards the application of research findings to their practice. However, they were not confident in initiating research due to work overload and lack of time as well as limited access to library resources. Therefore, we recommend stimulation to engage in research activities to be a requirement and to develop a system to improve the skills and knowledge of doing research. PMID- 23988759 TI - A neuroimaging investigation of attribute framing and individual differences. AB - Functional magnetic resonance imaging was used to evaluate the neural basis of framing effects. We tested the reflexive and reflective systems model of social cognition as it relates to framing. We also examined the relationships among frame susceptibility, intelligence and personality measures. Participants evaluated whether personal attributes applied to themselves from multiple perspectives and in positive and negative frames. Participants rated whether each statement was descriptive or not and endorsed positive frames more than negative frames. Individual differences on frame decisions enabled us to form high and low frame susceptibility groups. Endorsement of frame-consistent attributes was associated with personality factors, cognitive reflection and intelligence. Reflexive brain regions were associated with positive frames while reflective areas were associated with negative frames. Region of Interest analyses showed that frame-inconsistent responses were associated with increased activation within reflective cognitive control regions including the left dorsolateral prefrontal cortex (PFC), dorsomedial PFC and left ventrolateral PFC. Frame consistent responses were associated with increased activation in the right orbitofrontal cortex. These results demonstrate that individual differences in frame susceptibility influence personal attribute evaluations. Overall, this study clarifies the neural correlates of the reflective and reflexive systems of social cognition as applied to decisions about social attributions. PMID- 23988760 TI - Time course of emotion-related responding during distraction and reappraisal. AB - Theoretical accounts of emotion regulation (ER) discriminate various cognitive strategies to voluntarily modify emotional states. Amongst these, attentional deployment (i.e. distraction) and cognitive change (i.e. reappraisal), have been shown to successfully down-regulate emotions. Neuroimaging studies found that both strategies differentially engage neural structures associated with selective attention, working memory and cognitive control. The aim of this study was to further delineate similarities and differences between the ER strategies reappraisal and distraction by investigating their temporal brain dynamics using event-related potentials (ERPs) and their patterns of facial expressive behavior. Twenty-one participants completed an ER experiment in which they had to either passively view positive, neutral and negative pictures, reinterpret them to down regulate affective responses (reappraisal), or solve a concurrently presented mathematical equation (distraction). Results demonstrate the efficacy of both strategies in the subjective control of emotion, accompanied by reductions of facial expressive activity (Corrugator supercilii and Zygomaticus major). ERP results indicated that distraction, compared with reappraisal, yielded a stronger and earlier attenuation of the late positive potential (LPP) magnitude for negative pictures. For positive pictures, only distraction but not reappraisal had significant effect on LPP attenuation. The results support the process model of ER, separating subtypes of cognitive strategies based on their specific time course. PMID- 23988761 TI - Dopamine beta-hydroxylase gene modulates individuals' empathic ability. AB - Dopamine beta-hydroxylase (DBH), an enzyme that converts dopamine to norepinephrine, has broad influences on social functions. In this study, we examined to what extent two polymorphisms (-1021C/T and a 19 bp insertion/deletion) in DBH gene modulate individuals' empathic perception and response, which were measured, respectively, by reading the mind in the eyes test and the empathic concern subscale of interpersonal reactivity index. Results showed that polymorphism at -1021C/T, but not the 19 bp insertion/deletion, accounts for 2.3% variance of empathic perception and 1.4% variance of empathic response. Individuals with the CC genotype, which is associated with higher DBH activity, manifested greater empathic ability than those with CT/TT genotypes. These findings demonstrate the importance of DBH -1021C/T as a genetic basis of empathy and in predicting individual differences in social and affective processing. PMID- 23988762 TI - Asthma increases pulmonary thromboembolism risk: a nationwide population cohort study. AB - Studies on the association between asthma and pulmonary thromboembolism are considerably limited. We investigated whether pulmonary embolism is associated with asthma using a nationwide cohort study. We identified 31,356 patients with newly diagnosed asthma in 2002-2008 and 125,157 individuals without asthma randomly selected from the general population, frequency matched by age, sex and index year using the National Health Insurance Research Database. Both cohorts were followed-up until the end of 2010 to measure the incidence of pulmonary embolism. Cox proportional hazards regression analysis was used to measure the hazard ratio of pulmonary embolism for the asthmatic cohort, compared with the nonasthmatic cohort. We followed 186,182 person-years for asthmatic patients and 743,374 person-years for nonasthmatic subjects. The hazard ratio of pulmonary embolism was 3.24 for the asthmatic cohort, compared with the nonasthmatic cohort after adjusting for sex, age, comorbidities and oestrogen supplementation. The risk of developing pulmonary embolism significantly increased with the increased frequency of asthma exacerbation and hospitalisation. This nationwide cohort study suggests that the risk of developing pulmonary embolism is significantly increased in asthmatic patients compared to the general population. Frequent asthma exacerbation and hospitalisation are significantly associated with pulmonary embolism risk. PMID- 23988763 TI - The PCDH1 gene and asthma in early childhood. AB - Previous studies have suggested that variants in the protocadherin-1 (PCDH1) gene, which is important for cell-cell adhesion, are associated with asthma, bronchial, hyperresponsiveness and atopic dermatitis in school children. Our aim was to associate common variants of the PCDH1 gene with longitudinally assessed asthma phenotypes and atopic dermatitis in early childhood. We analysed eight single-nucleotide polymorphisms in PCDH1 from 411 children born to asthmatic mothers from the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. Asthma and atopic dermatitis were diagnosed prospectively to the age of 7 years and asthma was categorised by temporal pattern: transient early respiratory symptoms, persistent symptoms and late-onset symptoms. Bronchial responsiveness was measured at age 6 years. We used additive genetic models. Kaplan-Meier plots revealed early onset in hetero- and homozygotes for the rs10063472-T allele. Significant association was observed between the transient early phenotype and rs10063472-T (transient early versus all: OR 1.91, 95% CI 1.21-3.01, p=0.0058; transient early versus asymptomatic: OR 2.00, 95% CI 1.23-3.25, p=0.0053). No association was observed for other symptom patterns or bronchial responsiveness. Significant association was observed for atopic dermatitis and rs11167761-A (OR 1.85, 95% CI 1.24-2.75, p=0.0026). Common variations in PCDH1 increase the risk of developing both transient early asthma and atopic dermatitis in early childhood. PMID- 23988764 TI - Grading the severity of airways obstruction: new wine in new bottles. AB - The objective of this study was to redesign the current grading of obstructive lung disease so that it is clinically relevant and free of biases related to age, height, sex and ethnic group. Spirometric records from 17 880 subjects (50.4% female) from hospitals in Australia and Poland, and 21 191 records (53.0% female) from two epidemiological studies (age range 18-95 years) were analysed. We adopted the American Thoracic Society(ATS)/European Respiratory Society (ERS) criteria for airways obstruction based on an forced expiratory volume in 1 s (FEV1)/(forced) vital capacity ((F)VC) ratio below the fifth percentile and graded the severity of pulmonary function impairment using z-scores for FEV1, which signify how many standard deviations a result is from the mean predicted value. Using the lower limit of normal for FEV1/(F)VC and z-scores for FEV1 of 2, -2.5, -3 and -4 to delineate severity grades of airflow limitation leads to close agreement with ATS/ERS severity classifications and removes age, sex and height related bias. The new classification system is simple, easily memorised and clinically valid. It retains previously established associations with clinical outcomes and avoids biases due to the use of per cent predicted FEV1. Combined with the Global Lung Function prediction equations it provides a worldwide diagnostic standard, free of bias due to age, height, sex and ethnic group. PMID- 23988765 TI - A review of paediatric tuberculosis in Denmark: 10-year trend, 2000-2009. AB - Paediatric tuberculosis (TB) is a key indicator for recent transmission and presents a reservoir for the disease. We describe trends in epidemiology, microbiological characteristics and treatment outcome in Denmark between 2000 and 2009. Data were retrieved from the national TB surveillance system and the International Reference Laboratory of Mycobacteriology. In total, 323 TB cases were reported in children aged <15 years, accounting for 7.6% of all notified cases in Denmark. The overall incidence rate of childhood TB declined from 4.1 per 100,000 to 1.9 per 100,000 in the study period. Immigrant children comprised 79.6% of all cases, with the highest incidence rate of 94.1 per 100,000 children in 2001. In contrast to immigrant children, the majority of Danish children were aged <5 years and had a known exposure to TB. Pulmonary TB was the commonest presentation. Only half of the cases were culture confirmed. We observed an overall decreasing trend in the child to adult notification ratio, but a slight increase in the ratio when calculated specifically for ethnic Danes. Childhood TB needs continuous attention with a special focus on risk groups. Emphasis on improving early TB case detection, contact tracing and further implementation of preventive treatment is necessary. PMID- 23988766 TI - Smoking resumption after lung transplantation: standardised screening and importance for long-term outcome. PMID- 23988767 TI - Detection and severity grading of COPD exacerbations using the exacerbations of chronic pulmonary disease tool (EXACT). AB - Uncertainty exists over the ability of the exacerbations of chronic pulmonary disease tool (EXACT) patient-reported outcome diary to quantify exacerbation severity and frequency. To clarify this, we investigated the ability of the EXACT to assess severity of exacerbations and examined the relationship between exacerbations diagnosed using London chronic obstructive pulmonary disease (COPD) cohort diary cards, physician review and symptom-defined events using the EXACT. 58 patients enrolled in the London Chronic Obstructive Pulmonary Disease (COPD) cohort prospectively completed the EXACT during 128 cohort diary card-defined exacerbations between January 2010 and April 2012. Mean +/- sd EXACT scores increased from 42.6 +/- 8.6 at baseline to 48.0 +/- 8.6 at exacerbation onset (p<0.001), and rose further to a maximum score of 54.1 +/- 8.9. Maximum EXACT scores were significantly higher in treated than untreated events. Time taken for EXACT scores to return to baseline was significantly related to symptom recovery time as judged by London COPD cohort diary cards, and to peak expiratory flow rate recovery. ~50% of both diary card-defined and healthcare utilisation exacerbations crossed the EXACT event threshold. However, only 27.9% of diary card-defined and 34.6% of healthcare utilisation exacerbations fully met the criteria for an EXACT event. Patients exhibited smaller rises in the EXACT score at exacerbation as baseline disease severity increased. The EXACT is an effective method of evaluating chronic obstructive pulmonary disease exacerbation severity. However, concerns remain about the ability of the EXACT to accurately detect exacerbations. PMID- 23988768 TI - Prediction of relapse after discontinuation of infliximab therapy in severe sarcoidosis. AB - Infliximab is effective as a third-line therapeutic for severe sarcoidosis; however, long-term efficacy is unknown. The aim of this study was to assess the relapse rate after discontinuation of infliximab in sarcoidosis patients and predict relapse by analysis of the activity marker soluble interleukin (IL)-2 receptor (sIL-2R) and maximum standardised uptake value (SUVmax) of (18)F fluorodeoxyglucose positron emission tomography (FDG PET). In this retrospective cohort study, the proportion of relapse was analysed using the Kaplan-Meier method and predicting factors were studied using Cox regression. 47 sarcoidosis patients who started infliximab therapy were included in the risk analysis. Kaplan-Meier analysis revealed a median time to relapse of 11.1 months and showed that 25% of the cohort relapsed within 4 months. Both mediastinal SUVmax >= 6.0 on FDG PET (hazard ratio 3.77, p<0.001) and serum sIL-2R >= 4000 pg . mL(-1) (hazard ratio 2.24, p=0.033) at start of therapy predicted relapse. In multivariate analysis, a mediastinal SUVmax >= 6.0 at initiation of therapy was an independent predictor of relapse (hazard ratio 4.33, p<0.001). The majority of patients that discontinued infliximab therapy relapsed. High serum sIL-2R and high SUVmax on FDG PET at initiation of therapy were significant predictors of relapse. These results suggest close monitoring of patients in this category when they discontinue infliximab treatment. PMID- 23988769 TI - The safety and feasibility of the inhaled mannitol challenge test in young children. PMID- 23988770 TI - Extensively drug-resistant tuberculosis: early access to bedaquiline for a UK patient. PMID- 23988771 TI - Neighbourhood air quality and snoring in school-aged children. AB - The prevalence of habitual snoring has been extensively explored in paediatric populations. Although exposure to cigarette smoke increases the risk of habitual snoring in a dose-dependent fashion, the potential contribution of air quality to habitual snoring remains unclear. 6000 questionnaires were distributed to 6- to 12-year-old children attending public schools in five distinct neighbourhoods within the city of Tehran, Iran, that were preselected based on air quality measures. Habitual snoring was defined as loud snoring >=3 nights per week. Information regarding clinical and family-related habitual snoring risk factors was also obtained. Descriptive statistics followed by adjusted risk assessments were conducted. Among the 4322 (72%) completed datasets, the prevalence of habitual snoring was 11.6%. Partition of habitual snoring rates according to neighbourhood air quality characteristics revealed significantly higher habitual snoring frequencies among children residing in neighbourhoods with greatest pollution (24.5% and 12.1% in South and Central neighbourhoods versus 7.0% and 7.7% in North and East neighbourhoods, respectively). The regional variance in habitual snoring was primarily accounted for by an integrated measure of air quality, even after controlling for other risk factors. Environmental air quality emerges as a significant and potentially modifiable contributor to the risk for developing habitual snoring during childhood. PMID- 23988772 TI - Bedaquiline in MDR/XDR-TB cases: first experience on compassionate use. PMID- 23988773 TI - Predictors of treatment outcome in multidrug-resistant tuberculosis in Portugal. PMID- 23988774 TI - Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis. AB - Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis. A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012. We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, co-trimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR TB treatment. PMID- 23988776 TI - EGFR, KRAS, BRAF and ALK gene alterations in lung adenocarcinomas: patient outcome, interplay with morphology and immunophenotype. AB - Numerous studies have been published on single aspects of pulmonary adenocarcinoma (ADC). To comprehensively link clinically relevant ADC characteristics, we evaluated established morphological, diagnostic and predictive biomarkers in 425 resected ADCs. Morphology was reclassified. Cytokeratin-7, thyroid transcription factor (TTF)1, napsin A, thymidylate synthase and excision repair cross-complementing rodent repair deficiency complementation group-1 expression, anaplastic lymphoma kinase rearrangements as well as epidermal growth factor receptor (EGFR), V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue (KRAS) and v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) mutations were analysed. All characteristics were correlated with clinical and survival parameters. Morphological ADC subtypes were significantly associated with smoking history and distinct patterns of diagnostic biomarkers. KRAS mutations were prevalent in male smokers, while EGFR mutations were associated with female sex, nonsmoking and lepidic as well as micropapillary growth patterns. TTF1 expression (hazard ratio (HR) for overall survival 0.61, p=0.021) and BRAF mutations (HR for disease-free survival 2.0, p=0.046) were found to be morphology- and stage-independent predictors of survival in multivariate analysis. Adjuvant radio-/chemotherapy, in some instances, strongly impacted on the prognostic effect of both diagnostic and predictive biomarkers. Our data draw a comprehensive picture of the prevalence and interplay of established histological and molecular ADC characteristics. These data will help to develop time- and cost-effective diagnostic and treatment algorithms for ADC. PMID- 23988775 TI - Variability of hospital resources for acute care of COPD patients: the European COPD Audit. AB - Studies have suggested that larger hospitals have better resources and provide better care than smaller ones. This study aimed to explore the relationship between hospital size, resources, organisation of care and adherence to guidelines. The European COPD Audit was designed as a pilot study of clinical care and a survey of resources and organisation of care. Data were entered by clinicians to a multilingual web tool and analysed centrally. Participating hospitals were divided into tertiles on the basis of bed numbers and comparisons made of the resources, organisation of care and adherence to guidelines across the three size groups. 13 national societies provided data on 425 hospitals. The mean number of beds per tertile was 220 (lower), 479 (middle), and 989 (upper). Large hospitals were more likely to have resources and increased numbers of staff; hospital performance measures were related in a minority of indicators only. Adherence to guidelines also varied with hospital size, but the differences were small and inconsistent. There is a wide variation in the size, resources and organisation of care across Europe for hospitals providing chronic obstructive pulmonary disease care. While larger hospitals have more resources, this does not always equate to better accessibility or quality of care for patients. PMID- 23988777 TI - Cells-nano interactions and molecular toxicity after delayed hypersensitivity, in guinea pigs on exposure to hydroxyapatite nanoparticles. AB - The aim of the study was to evaluate the cells-nanoparticle interactions and molecular toxicity after delayed hypersensitivity in Guinea pigs, exposed to hydroxyapatite nanoparticles (HANP). The study focuses on synthesizing and characterizing HANPs and gaining an insight into the cytotoxicity, molecular toxicity, hypersensitivity and oxidative stress caused by them in vitro and in vivo. HANP was synthesized by chemical method and characterized by standard methods. Cytotoxicity was assessed on L929 cells by MTT assay and in vitro studies were carried out on rat liver homogenate. In vivo study was carried out by topical exposure of Guinea pigs with HANP, repeatedly, and evaluating the skin sensitization potential, blood parameters, oxidative stress in liver and brain and DNA damage (8-hydroxyl-2-deoxyguanosine: 8-OHdG) in liver. The results of the study indicated that there was no cytotoxicity (up to 600MUg/mL) and oxidative damage (up to 100MUg/mL), when exposed to HANPs. It was also evident that, there was no skin sensitization and oxidative damage when HANP were exposed to Guinea pigs. PMID- 23988778 TI - Physicochemical approach to freshwater microalgae harvesting with magnetic particles. AB - Magnetic harvesting of microalgal biomass provides an attractive alternative to conventional methods. The approach to this issue has so far been pragmatic, focused mainly on finding cheap magnetic agents in combination with harvestable microalgae species. The aim of this work was to study experimentally and theoretically the mechanisms leading to cell-magnetic agent attachment/detachment using real experiments and predictions made by colloidal adhesion (XDLVO) model. Two types of well defined magnetic beads (MBs) carrying ion exchange functional groups (DEAE - diethylaminoethyl and PEI - polyethylenimine) were studied in connection with microalgae (Chlorella vulgaris). Optimal harvesting efficiencies (>90%) were found for DEAE and PEI MBs, while efficient detachment was achieved only for DEAE MBs (>90%). These findings were in accordance with the predictions by XDLVO model. Simultaneously there was found a discrepancy between the XDLVO prediction and the poor detachment of PEI MBs from microalgal surface. This can be ascribed to an additional interaction (probably covalent bonds) between PEI and algal surface, which the XDLVO model is unable to capture given by its non covalent nature. PMID- 23988779 TI - Potentiation of 5-fluorouracil encapsulated in zeolites as drug delivery systems for in vitro models of colorectal carcinoma. AB - The studies of potentiation of 5-fluorouracil (5-FU), a traditional drug used in the treatment of several cancers, including colorectal (CRC), were carried out with zeolites Faujasite in the sodium form, with different particle sizes (NaY, 700nm and nanoNaY, 150nm) and Linde type L in the potassium form (LTL) with a particle size of 80nm. 5-FU was loaded into zeolites by liquid-phase adsorption. Characterization by spectroscopic techniques (FTIR, (1)H NMR and (13)C and (27)Al solid-state MAS NMR), chemical analysis, thermal analysis (TGA), nitrogen adsorption isotherms and scanning electron microscopy (SEM), demonstrated the successful loading of 5-FU into the zeolite hosts. In vitro drug release studies (PBS buffer pH 7.4, 37 degrees C) revealed the release of 80-90% of 5-FU in the first 10min. To ascertain the drug release kinetics, the release profiles were fitted to zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas and Weibull kinetic models. The in vitro dissolution from the drug delivery systems (DDS) was explained by the Weibull model. The DDS efficacy was evaluated using two human colorectal carcinoma cell lines, HCT-15 and RKO. Unloaded zeolites presented no toxicity to both cancer cells, while all DDS allowed an important potentiation of the 5-FU effect on the cell viability. Immunofluorescence studies provided evidence for zeolite-cell internalization. PMID- 23988780 TI - Temporary dual-chamber pacing can stabilize hemodynamics during noncardiac surgery in a patient with left ventricular hypertrophy and outflow obstruction. PMID- 23988781 TI - Outcomes and biochemical parameters following cardiac surgery: effects of transfusion of residual blood using centrifugation and multiple-pass hemoconcentration. AB - OBJECTIVES: To determine whether or not there was a significant difference between the methods of centrifugation (CF) and multiple-pass hemoconcentration (MPH) of the residual cardiopulmonary-bypass volume in relation to biochemical measurements and patient outcomes. DESIGN: Prospective, randomized, and controlled. SETTING: Conducted at a western Canadian tertiary care hospital. PARTICIPANTS: Consisted of 61 consecutive male and female patients from ages 40 to 80 who were scheduled for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Either the centrifugation or multiple-pass hemoconcentration method was used to process the residual blood from the cardiopulmonary bypass circuit. RESULTS: The 12-hour postoperative levels of serum hemoglobin were not significantly different in the centrifugation group as compared to the multiple pass hemoconcentration group. However, the serum levels of total protein and albumin were significantly higher in the multiple-pass hemoconcentration group as compared to the centrifugation group. Additionally, after 12-hours postoperatively, the serum fibrinogen and platelet counts were significantly higher in the multiple-pass hemoconcentration group as compared to those of the centrifugation group. The allogeneic product transfusion index and the chest-tube blood drainage indices were lower in the multiple-pass hemoconcentration group as compared to the centrifugation group. CONCLUSION: Although the CF method provided a product in a shorter turnaround time, with consistent clearance of heparin, the MPH method trended towards enhanced biochemical and clinical patient outcomes over the 12-hour postoperative period. PMID- 23988782 TI - Comparison of mouse brain DTI maps using K-space average, image-space average, or no average approach. AB - Diffusion tensor imaging (DTI) is achieved by collecting a series of diffusion weighted images (DWIs). Signal averaging of multiple repetitions can be performed in the k-space (k-avg) or in the image space (m-avg) to improve the image quality. Alternatively, one can treat each acquisition as an independent image and use all of the data to reconstruct the DTI without doing any signal averaging (no-avg). To compare these three approaches, in this study, in vivo DTI data were collected from five normal mice. Noisy data with signal-to-noise ratios (SNR) that varied between five and 30 (before averaging) were then simulated. The DTI indices, including relative anisotropy (RA), trace of diffusion tensor (TR), axial diffusivity (lambda?), and radial diffusivity (lambda?), derived from the k avg, m-avg, and no-avg, were then compared in the corpus callosum white matter, cortex gray matter, and the ventricles. We found that k-avg and m-avg enhanced the SNR of DWI with no significant differences. However, k-avg produced lower RA in the white matter and higher RA in the gray matter, compared to the m-avg and no-avg, regardless of SNR. The latter two produced similar DTI quantifications. We concluded that k-avg is less preferred for DTI brain imaging. PMID- 23988783 TI - Injuries in pre-professional ballet dancers: Incidence, characteristics and consequences. AB - OBJECTIVES: Compared to other athletic activities, research on injury incidence and risk factors in dance is limited. There is also a need for more research evaluating the impact of intense training on elite adolescent athletes. The aim of this study was to evaluate the rates and risk of injuries, the hours of dance exposure and the characteristics and consequences of injuries among elite pre professional ballet students. DESIGN: Prospective epidemiological study. METHODS: 266 (112 male) full-time students aged 15-19 years from three elite pre professional ballet schools were followed prospectively over one school year. Injury rate was reported per 1000 h of dance and 1000 dance exposures (DEs). Injury details collected included type and anatomical location of injury. RESULTS: The clinical incidence of injury was 1.42 injuries per dancer and the risk of injury was 76% over the one-year period. The rate of injury was 1.38/1000 h of dance and 1.87/1000 DEs. Joints were the most commonly injured structures and the ankle was the most commonly injured body area. Overuse injuries were more common than traumatic injuries. Bony injuries (e.g. stress fractures), and injuries to the knee were associated with the greatest time loss per injury. Injury risk and rate increased as students progressed through their three years of training. CONCLUSIONS: In comparison with other adolescent athletic populations, participants in this study had a similar injury rate but a higher risk of injury. This may be attributable to the high level of training exposure in pre-professional ballet students. PMID- 23988784 TI - Are flexibility and muscle-strengthening activities associated with a higher risk of developing low back pain? AB - OBJECTIVES: To examine the association between participation in flexibility or muscle-strengthening activities with the development of low back pain. DESIGN: Observational cohort study. METHODS: The cohort included 4610 adults, 17% female, between 20 and 81 years of age (mean 46.6, standard deviation 4.96). The cohort was followed for a mean of 4.9 years for self-reported low back pain. All participants reported at baseline whether they performed flexibility or muscle strengthening activities, including specific sub-types. RESULTS: Neither general performance of flexibility or muscle-strengthening activities were associated with a higher incidence of low back pain compared to those who did not perform these activities. Those who reported stretching, as a specific flexibility activity were at a higher risk of developing low back pain compared with those who performed no flexibility exercises, reported callisthenic flexibility activities, or attended exercise classes. Those who reported using weight training machines, as part of muscle-strengthening activities, had a higher risk of reporting low back pain, compared with those who did not perform muscle strengthening activities or performed callisthenic or free weight activities. CONCLUSIONS: In this sample, stretching or use of weight training machines is associated with increased risk of developing low back pain compared to use of free weights, callisthenics or exercise classes. PMID- 23988785 TI - The descriptive epidemiology of sitting among US adults, NHANES 2009/2010. AB - OBJECTIVES: Using NHANES 2009/2010, to describe the amount of time a representative sample of the U.S. population spends sitting by age, sex, ethnicity, education, and body mass index. DESIGN: Cross-sectional analysis. METHODS: Participants (n=5911, >=20 years) self-reported demographic variables and the amount of time they spend sitting on a typical day. Body mass index was calculated from measured height and weight. RESULTS: Mean self-reported sitting time was 285min/day for males and 281min/day for females. Mexican-Americans reported sitting less than both non-Hispanic Whites and non-Hispanic Blacks (all p<0.0001). Non-Hispanic White males reported sitting more than non-Hispanic Black males, while Non-Hispanic White females reported sitting more than Other Hispanic females (both p<0.0001). No significant differences were found between sexes in any age group. There was a trend for increased sitting time with increasing age for females (p for trend=0.0045), for all Mexican-American and Hispanic participants and non-Hispanic Black males (all p<=0.006) and with increasing education (p for trend <0.0001). At the College Graduate level, females reported sitting less than males (p<0.0001). Obese females reported sitting more than normal weight and overweight females (p=0.0008). There were no significant differences in sitting time by body mass index for males. CONCLUSIONS: Self reported sitting time differed by ethnicity, age group, education and body mass index but there was no overall difference by sex. These results represent the most up to date prevalence of self-reported sitting for the US adult population. Certain groups should be targeted to reduce sitting time, for example those with higher educational attainment and obese females. PMID- 23988786 TI - The dose-response relationship between pseudoephedrine ingestion and exercise performance. AB - OBJECTIVES: The purpose of the present study was to examine a possible dose response between pre-exercise pseudoephedrine intake and cycling time trial performance. DESIGN: Randomised, double-blind, crossover trial. METHODS: Ten trained male endurance cyclists (26.5 +/- 6.2 years, 75.1 +/- 5.9 kg, 70.6 +/- 6.8 mL kg(-1)min(-1)) undertook three cycling time trials in which a fixed amount of work (7 kJ kg(-1) body mass) was completed in the shortest possible time. Sixty minutes before the start of exercise, subjects orally ingested either 2.3 mg kg(-1) or 2.8 mg kg(-1) body mass of pseudoephedrine or a placebo in a randomised and double-blind manner. Venous blood was sampled at baseline, pre- and post-warm up and post-exercise for the analysis of pH and lactate and glucose concentrations; plasma catecholamine and pseudoephedrine concentrations were measured at all times except post-warm up. RESULTS: Cycling time trial performance (~ 30 min) was not enhanced by pseudoephedrine ingestion. Plasma pseudoephedrine concentration increased from pre-warm up to post-exercise in both treatment conditions, with the 2.8 mg kg(-1) body mass dose producing the highest concentration at both time points (2.8 mg kg(-1)>2.3 mg kg(-1)>placebo; p<0.001). CONCLUSIONS: There was large individual variation in plasma pseudoephedrine concentration between subjects following pseudoephedrine administration. A number of factors clearly influence the uptake and appearance of pseudoephedrine in the blood and these are not yet fully understood. Combined with subsequent differences in plasma pseudoephedrine between individuals, this may partially explain the present findings and also the inconsistencies in performance following pseudoephedrine administration in previous studies. PMID- 23988787 TI - Does rating of perceived exertion result in target exercise intensity during interval training in cardiac rehabilitation? A study of the Borg scale versus a heart rate monitor. AB - OBJECTIVES: To assess whether rating of perceived exertion using the Borg 6-20 scale is a valid method for achieving target exercise intensity during high intensity interval training in cardiac rehabilitation. DESIGN: A single-group cross-over design. METHODS: Ten participants (56 (6.5) years) who were enrolled in a high-intensity interval training cardiac rehabilitation program were recruited. A target exercise intensity of Borg 17 (very hard) was used for exercise intensity guidance in the initial four exercise sessions that took place before a cardiopulmonary exercise test, as in usual care rehabilitation. The heart rate was recorded and blinded to the participants. After performing the test, the participants were then instructed using heart rate monitors openly for exercise guidance in four subsequent exercise sessions, at an intensity corresponding to 85-95% of peak heart rate. RESULTS: The mean exercise intensity during high-intensity bouts was 82% (6%) of peak heart rate for the rating of perceived exertion and 85% (6%) using heart rate monitors (p=0.005). Bland-Altman limits of agreement analysis with a mean bias showed a bias of 2.97 (-2.08, 8.02) percentage points for the two methods. Exercise intensity was highly repeatable with intra-class correlations of 0.95 (95% CI 0.86-0.99, p<0.001) and 0.96 (95% CI 0.88-0.99, p<0.001) in the exercise sessions using rating of perceived exertion and percentage of peak heart rate for intensity control, respectively. CONCLUSIONS: Rating of perceived exertion results in an exercise intensity below target during high-intensity interval training bouts in cardiac rehabilitation. Heart rate monitoring should be used for accurate intensity guidance. PMID- 23988788 TI - Proteome alteration in oxidative stress-sensitive methionine sulfoxide reductase silenced HEK293 cells. AB - Methionine sulfoxide reductases (Msr's) are key enzymes proficient in catalyzing the reduction of oxidized methionines. This reductive trait is essential to maintaining cellular redox homeostasis from bacteria to mammals and is also regarded as a potential mechanism to regulate protein activities and signaling pathways, considering the inactivating effects that can be induced by methionine oxidation. In this study, we have generated stable human embryonic kidney HEK293 clones with an altered Msr system by silencing the expression of the main Msr elements-MsrA, MsrB1, or MsrB2. The isolated clones--the single mutants MsrA, MsrB1, and MsrB2 and double mutant MsrA/B1-show a reduced Msr activity and an exacerbated sensitivity toward oxidative stress. A two-dimensional difference in gel electrophoresis analysis was performed on the Msr-silenced cells grown under basal conditions or submitted to oxidative stress. This proteomic analysis revealed that the disruption of the Msr system mainly affects proteins with redox, cytoskeletal or protein synthesis, and maintenance roles. Interestingly, most of the proteins found altered in the Msr mutants were also identified as potential Msr substrates and have been associated with redox or aging processes in previous studies. This study, through an extensive analysis of Msr-inhibited mutants, offers valuable input on the cellular network of a crucial maintenance system such as methionine sulfoxide reductases. PMID- 23988789 TI - Mitochondria are targets for peroxisome-derived oxidative stress in cultured mammalian cells. AB - Many cellular processes are driven by spatially and temporally regulated redox dependent signaling events. Although mounting evidence indicates that organelles such as the endoplasmic reticulum and mitochondria can function as signaling platforms for oxidative stress-regulated pathways, little is known about the role of peroxisomes in these processes. In this study, we employ targeted variants of the genetically encoded photosensitizer KillerRed to gain a better insight into the interplay between peroxisomes and cellular oxidative stress. We show that the phototoxic effects of peroxisomal KillerRed induce mitochondria-mediated cell death and that this process can be counteracted by targeted overexpression of a select set of antioxidant enzymes, including peroxisomal glutathione S transferase kappa 1, superoxide dismutase 1, and mitochondrial catalase. We also present evidence that peroxisomal disease cell lines deficient in plasmalogen biosynthesis or peroxisome assembly are more sensitive to KillerRed-induced oxidative stress than control cells. Collectively, these findings confirm and extend previous observations suggesting that disturbances in peroxisomal redox control and metabolism can sensitize cells to oxidative stress. In addition, they lend strong support to the ideas that peroxisomes and mitochondria share a redox sensitive relationship and that the redox communication between these organelles is not only mediated by diffusion of reactive oxygen species from one compartment to the other. Finally, these findings indicate that mitochondria may act as dynamic receivers, integrators, and transmitters of peroxisome-derived mediators of oxidative stress, and this may have profound implications for our views on cellular aging and age-related diseases. PMID- 23988790 TI - In vitro pharmacokinetics of antimicrobial cationic peptides alone and in combination with antibiotics against methicillin resistant Staphylococcus aureus biofilms. AB - Antibiotic therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections is becoming more difficult in hospitals and communities because of strong biofilm-forming properties and multidrug resistance. Biofilm-associated MRSA is not affected by therapeutically achievable concentrations of antibiotics. Therefore, we investigated the in vitro pharmacokinetic activities of antimicrobial cationic peptides (AMPs; indolicidin, cecropin [1-7]-melittin A [2 9] amide [CAMA], and nisin), either alone or in combination with antibiotics (daptomycin, linezolid, teicoplanin, ciprofloxacin, and azithromycin), against standard and 2 clinically obtained MRSA biofilms. The minimum inhibitory concentrations (MIC) and minimum biofilm-eradication concentrations (MBEC) were determined by microbroth dilution technique. The time-kill curve (TKC) method was used to determine the bactericidal activities of the AMPs alone and in combination with the antibiotics against standard and clinically obtained MRSA biofilms. The MIC values of the AMPs and antibiotics ranged between 2 to 16 and 0.25 to 512 mg/L, and their MBEC values were 640 and 512 to 5120 mg/L, respectively. The TKC studies demonstrated that synergistic interactions occurred most frequently when using nisin+daptomycin/ciprofloxacin, indolicidin+teicoplanin, and CAMA+ciprofloxacin combinations. No antagonism was observed with any combination. AMPs appear to be good candidates for the treatment of MRSA biofilms, as they act as both enhancers of anti-biofilm activities and help to prevent or delay the emergence of resistance when used either alone or in combination with antibiotics. PMID- 23988791 TI - Influence of cholecalciferol supplementation in hemodialysis patients on monocyte subsets: a randomized, double-blind, placebo-controlled clinical trial. AB - BACKGROUND/AIMS: Although most hemodialysis patients share a significant 25 hydroxyvitamin D [25(OH)D] deficiency, supplementation is controversially discussed. A potential influence on monocyte and T lymphocyte dysfunction advocates blood level-adapted supplementation as recommended by K/DOQI guidelines. This was a prospective double-blind randomized placebo controlled trial examining immune effects of 12 weeks of cholecalciferol supplementation. METHODS: We initiated serum level-adapted de novo cholecalciferol supplementation in 38 hemodialysis patients. Outcome measures were: monocyte subset cell counts (CD14+CD16++ vs. CD14++CD16+ vs. CD14++CD16-), lymphocyte Th1/Th2 differentiation frequencies, serum inflammatory proteins CRP and TNFalpha, parathyroid hormone (PTH), FGF-23, and alpha-Klotho. RESULTS: At baseline, the mean 25(OH)D serum level in the study population was 31.7 +/- 14.3 nmol/l, and only 3% of patients had levels within the normal range. At 12 weeks, 25(OH)D levels were normalized in the verum group (87.8 +/- 22.3 vs. placebo 24.6 +/- 8.0 nmol/l, p < 0.0001). In parallel, 1,25(OH)2D levels increased in the verum group. Monocyte subset cell counts as well as Th1 and Th2 lymphocyte frequencies did not change significantly after 12 weeks of cholecalciferol supplementation. There was also no significant difference in PTH, alkaline phosphatase, calcium, phosphate, TNFalpha, FGF-23, alpha-Klotho and CRP levels. CONCLUSIONS: Oral cholecalciferol supplementation according to the K/DOQI recommendations normalizes 25(OH)D levels without relevant side effects such as hyperphosphatemia or hypercalcemia. However, beneficial pleiotropic effects on monocyte subset cell counts, T cell differentiation, or cytokine production could not be confirmed at least at the used dosage. PTH and FGF23 levels were not affected during cholecalciferol administration. PMID- 23988792 TI - EXAFS and XANES investigation of (Li, Ni) codoped ZnO thin films grown by pulsed laser deposition. AB - Ni doped, Li doped and (Li, Ni) codoped ZnO thin films were successfully grown using a pulsed laser deposition technique. Undoped and doped ZnO thin films were investigated using extended x-ray absorption fine structure (EXAFS) and x-ray absorption near edge spectroscopy (XANES). Preliminary investigations on the Zn K edge of the undoped and doped ZnO thin films revealed that doping has not influenced the average Zn-Zn bond length and Debye-Waller factor. This shows that both Ni and Li doping do not appreciably affect the average local environment of Zn. All the doped ZnO thin films exhibited more than 50% of substitutional Ni, with a maximum of 77% for 2% Ni and 2% Li doped ZnO thin film. The contribution of Ni metal to the EXAFS signal clearly reveals the presence of Ni clusters. The Ni-Ni distance in the Ni(0) nanoclusters, which are formed in the film, is shorter with respect to the reference Ni metal foil and the Debye-Waller factor is higher. Both facts perfectly reflect what is expected for metal nanoparticles. At the highest doping concentration (5%), the presence of Li favors the growth of a secondary NiO phase. Indeed, 2% Ni and 5% Li doped ZnO thin film shows %Nisub = 75 +/- 11, %Nimet = 10 +/- 8, %NiO = 15 +/- 8. XANES studies further confirm that the substitutional Ni is more than 50% in all the samples. These results explain the observed magnetic properties. PMID- 23988793 TI - Protein subcellular localization in human and hamster cell lines: employing local ternary patterns of fluorescence microscopy images. AB - Discriminative feature extraction technique is always required for the development of accurate and efficient prediction systems for protein subcellular localization so that effective drugs can be developed. In this work, we showed that Local Ternary Patterns (LTPs) effectively exploit small variations in pixel intensities; present in fluorescence microscopy based protein images of human and hamster cell lines. Further, Synthetic Minority Oversampling Technique is applied to balance the feature space for the classification stage. We observed that LTPs coupled with data balancing technique could enable a classifier, in this case support vector machine, to yield good performance. The proposed ensemble based prediction system, using 10-fold cross-validation, has yielded better performance compared to existing techniques in predicting various subcellular compartments for both 2D HeLa and CHO datasets. The proposed predictor is available online at: http://111.68.99.218/Protein_SubLoc/, which is freely accessible to the public. PMID- 23988794 TI - Adaptive limiter control of unimodal population maps. AB - We analyse the adaptive limiter control (ALC) method, which was recently proposed for stabilizing population oscillations and experimentally tested in laboratory populations and metapopulations of Drosophila melanogaster. We thoroughly explain the mechanisms that allow ALC to reduce the magnitude of population fluctuations under certain conditions. In general, ALC is a control strategy with a number of useful properties (e.g. being globally asymptotically stable), but there may be some caveats. The control can be ineffective or even counterproductive at small intensities, and the interventions can be extremely costly at very large intensities. Based on our analytical results, we describe recipes how to choose the control intensity, depending on the range of population sizes we wish to target. In our analysis, we highlight the possible importance of initial transients and classify them into different categories. PMID- 23988795 TI - On dichotomic classes and bijections of the genetic code. AB - Dichotomic classes arising from a recent mathematical model of the genetic code allow to uncover many symmetry properties of the code, and although theoretically derived, they permitted to build statistical classifiers able to retrieve the correct translational frame of coding sequences. Herein we formalize the mathematical properties of these classes, first focusing on all the possible decompositions of the 64 codons of the genetic code into two equally sized dichotomic subsets. Then the global framework of bijective transformations of the nucleotide bases is discussed and we clarify when dichotomic partitions can be generated. In addition, we show that the parity dichotomic classes of the mathematical model and complementarity dichotomic classes obtained in the present article can be formalized in the same algorithmic way the dichotomic Rumer's degeneracy classes. Interestingly, we find that the algorithm underlying dichotomic class definition mirrors biochemical features occurring at discrete base positions in the decoding center of the ribosome. PMID- 23988796 TI - Coevolution of risk perception, sexual behaviour, and HIV transmission in an agent-based model. AB - Risk perception shapes individual behaviour, and is in turn shaped by the consequences of that behaviour. Here we explore this dynamics in the context of human immunodeficiency virus (HIV) spread. We construct a simplified agent-based model based on a partner selection game, where individuals are paired with others in the population, and through a decision tree, agree on unprotected sex, protected sex, or no sex. An individual's choice is conditioned on their HIV status, their perceived population-level HIV prevalence, and the preferences expressed by the individual with whom they are paired. HIV is transmitted during unprotected sex with a certain probability. As expected, in model simulations, the perceived population-level HIV prevalence climbs along with actual HIV prevalence. During this time, HIV- individuals increasingly switch from unprotected sex to protected sex, HIV+ individuals continue practicing unprotected sex whenever possible, and unprotected sex between HIV+ and HIV- individuals eventually becomes rare. We also find that the perceived population level HIV prevalence diverges according to HIV status: HIV- individuals develop a higher perceived HIV prevalence than HIV+ individuals, although this result is sensitive to how much information is derived from global versus local sources. This research illustrates a potential mechanism by which distinct groups, as defined by their sexual behaviour, HIV status, and risk perceptions, can emerge through coevolution of HIV transmission and risk perception dynamics. PMID- 23988797 TI - A hybrid computational model for the effects of maspin on cancer cell dynamics. AB - Cancer metastasis is a complex multistep process which allows cancer cells to establish new tumours in distant organs. The process of metastasis involves cell migration and invasion; it is what makes cancer a fatal disease. The efficiency of most cancer treatments depends on metastasis suppression. Maspin is a type II tumour metastasis suppressor which has multiple cellular effects. It has been described as a key regulatory protein in both the intracellular and extracellular environments. Maspin has been shown to reduce cell migration, invasion, proliferation and angiogenesis, and increase apoptosis and cell-cell adhesion in in vitro and in vivo experiments. The clinical data regarding the predictive effects of maspin expression are variable. To date, the whole cellular mechanisms that maspin uses to influence tumour cell behaviours have not been clearly defined. The diversity of the effects of maspin motivated us to develop an intelligent model to investigate its effects on cellular proliferation and migration. This paper reports a hybrid model of solid tumour growth in order to investigate the impact of maspin on the growth and evolutionary dynamics of the cancer cell. A feed-forward neural network was used to model the behaviours (proliferation, quiescence, apoptosis and/or movement) of each cell, which has been suggested as a suitable model of cell signalling pathways. Results show that maspin reduces migration by 10-40%, confirmed by published in vitro data. The model also shows a reduction in cell proliferation by 20-30% in the presence of maspin. So far, this is the first attempt to model the effect of maspin in a computational model to verify in vitro data. This will provide new insights into the tumour suppressive properties of maspin and inform the development of novel cancer therapies. PMID- 23988798 TI - iCDI-PseFpt: identify the channel-drug interaction in cellular networking with PseAAC and molecular fingerprints. AB - Many crucial functions in life, such as heartbeat, sensory transduction and central nervous system response, are controlled by cell signalings via various ion channels. Therefore, ion channels have become an excellent drug target, and study of ion channel-drug interaction networks is an important topic for drug development. However, it is both time-consuming and costly to determine whether a drug and a protein ion channel are interacting with each other in a cellular network by means of experimental techniques. Although some computational methods were developed in this regard based on the knowledge of the 3D (three dimensional) structure of protein, unfortunately their usage is quite limited because the 3D structures for most protein ion channels are still unknown. With the avalanche of protein sequences generated in the post-genomic age, it is highly desirable to develop the sequence-based computational method to address this problem. To take up the challenge, we developed a new predictor called iCDI PseFpt, in which the protein ion-channel sample is formulated by the PseAAC (pseudo amino acid composition) generated with the gray model theory, the drug compound by the 2D molecular fingerprint, and the operation engine is the fuzzy K nearest neighbor algorithm. The overall success rate achieved by iCDI-PseFpt via the jackknife cross-validation was 87.27%, which is remarkably higher than that by any of the existing predictors in this area. As a user-friendly web-server, iCDI-PseFpt is freely accessible to the public at the website http://www.jci bioinfo.cn/iCDI-PseFpt/. Furthermore, for the convenience of most experimental scientists, a step-by-step guide is provided on how to use the web-server to get the desired results without the need to follow the complicated math equations presented in the paper just for its integrity. It has not escaped our notice that the current approach can also be used to study other drug-target interaction networks. PMID- 23988799 TI - Parker Flex-It intubation stylet versus a 90-degree curved stylet during intubation with the McGrath videolaryngoscope performed by novices: a manikin study with 5 airway scenarios. AB - STUDY OBJECTIVE: To compare the Parker Flex-It intubation stylet with a 90-degree curved stylet using the McGrath videolaryngoscope in 5 airway scenarios (from easy to difficult) in a manikin. DESIGN: Prospective, randomized study. SETTING: Academic hospital. SUBJECTS: 20 staff anesthesiologists with no previous experience in videolaryngoscopy. MEASUREMENTS: Subjects performed a total of 200 intubations with the McGrath Series 5 videolaryngoscope and completed a questionnaire afterwards. RESULTS: Overall success rate was significantly higher with the Parker Flex-It intubation stylet (96 successful intubations with the Parker Flex-It vs 79 intubations in the 90 degrees curved stylet group; P < 0.05). Intubation time was not significantly different. Subjects rated the Parker Flex-It intubation stylet as the better device for intubation with the McGrath videolaryngoscope in routine or emergency situations. CONCLUSION: Intubation of the manikin with the McGrath videolaryngoscope had more success with the Parker Flex-It intubation stylet than a 90 degrees curved stylet. PMID- 23988800 TI - Tracheobronchopathia osteochondroplastica and difficult intubation: case report and perioperative recommendations for anesthesiologists. AB - Tracheobronchopathia osteochondroplastica is a rare disorder characterized by cartilaginous or ossified submucosal nodules that project into the tracheobronchial lumen. It is typically discovered in the evaluation of chronic upper respiratory symptoms. A case of a completely asymptomatic man diagnosed with extensive disease throughout his upper airway after unanticipated difficult endotracheal intubation for elective surgery, is presented. PMID- 23988801 TI - Incidence and predictors of postdischarge nausea and vomiting in a 7-day population. AB - STUDY OBJECTIVE: 1) To quantify the incidence and severity of postdischarge nausea and vomiting (PDNV) for 7 days in adults undergoing outpatient surgeries with general anesthesia; 2) to evaluate whether a risk model previously developed for the first two postoperative days may be used to predict the patient's risk of PDNV for 7 days; and 3) to verify whether the same risk factors are applicable in the 3 to 7 day period. DESIGN: Prospective study. SETTING: Two university affiliated centers. PATIENTS: 248 adult (>18 years) surgical outpatients undergoing ambulatory surgical procedures with general anesthesia between 2007 and 2008. MEASUREMENTS: The incidence and severity of PDNV and a simplified risk score for PDNV was assessed prospectively from discharge up to 7 postoperative days. MAIN RESULTS: The overall incidence of nausea was 56.9% and of emesis was 19.4%. The incidence of PDNV was highest on the day of surgery (DOS), with PDNV of 44.8% and decreasing over time to 6.0% on day 7. Using the simplified risk score for PDNV the area under the receiver operating characteristic (ROC) curve was 0.766 (0.707, 0.825). A previous history of postoperative nausea and vomiting (PONV; OR 3.51, CI 1.70 - 7.27), operating room time (odds ratio [OR] 2.19, 95% CI 1.34 - 3.60), use of ondansetron in the Postanesthesia Care Unit (PACU; OR 6.39, CI 1.65-24.79), and pain during days 3-7 (OR 1.67, CI 1.30 - 2.14) were the strongest predictors of PDNV on days 3-7. CONCLUSIONS: PDNV affects a significant number of patients after ambulatory surgery, and our simplified PDNV score may be applied to a 7-day population. Pain appears to be a factor in late PDNV. It is possible that the presence of PDNV during days 3-7 has different origins from the PDNV that resolved over the first 48 hours. PMID- 23988802 TI - The effect of epidural methylprednisolone acetate injection on the hypothalamic pituitary-adrenal axis. AB - STUDY OBJECTIVE: To evaluate the effect of an epidural corticosteroid injection of 80 mg and 40 mg of methylprednisolone acetate on the hypothalamic-pituitary adrenal axis and on back pain. DESIGN: Randomized, single-blinded prospective study. SETTING: Operating room of a university-affiliated hospital. PATIENTS: 42 patients with low back pain due to radiculopathy. INTERVENTIONS: Group 1 received an epidural corticosteroid injection of 80 mg of methylprednisolone acetate, and Group 2 received an epidural corticosteroid injection of 40 mg of methylprednisolone acetate. All study patients underwent a stimulation test of one MUg of adrenocorticotropin hormone (ACTH), and their pain levels were graded just prior to and following the epidural corticosteroid injection on weeks one, 3, and 4. MEASUREMENTS: Serum cortisol of the ACTH stimulation tests and back pain levels were rated using a visual analog scale (VAS). Serum cortisol levels lower than 18 ng/mL 30 minutes following the ACTH stimulation test were considered to be secondary adrenal insufficiency. MAIN RESULTS: 21 patients were enrolled in each group. The rate of secondary adrenal insufficiency in Group 1 was ~86%, ~ 22%, and ~17% of patients versus ~53% (P = 0.024), 15% (P = 0.874), and ~12% (P = 0.715) of Group 2 patients at weeks one, 3, and 4, respectively. About 62%, 56%, and 39% of Group 1 patients had a favorable clinical response as opposed to ~47% (P = 0362), 35% (P = 0.21), and ~6% (P = 0.049) of Group 2 patients at weeks one, 3, and 4, respectively. CONCLUSIONS: Epidural corticosteroid injection of methylprednisolone acetate in both groups was associated with very high rates of secondary adrenal insufficiency, but significantly more so in Group 1 at week one. This suppression was transient, with recovery of the gland in most patients noted over the ensuing weeks. An epidural corticosteroid injection of 80 mg had higher rates of favorable clinical response than a 40 mg injection, but significantly more so at week 4 only. This favorable response waned over a few weeks in both groups. PMID- 23988803 TI - Percutaneous radiofrequency ablation of hepatocellular lesions in segment II of the liver: a risk factor for cardiac tamponade. AB - Percutaneous radiofrequency ablation (PRFA) is a minimally invasive procedure used for the treatment of small hepatocellular carcinomas. PRFA is regarded as a much safer alternative to surgical resection or orthotopic liver transplantation. However, serious complications, including cardiac tamponade, have been reported. Two cases of severe cardiac tamponade during PRFA were successfully treated. PMID- 23988804 TI - Use of ultrasound-guided cryotherapy for the management of chronic pain states. AB - STUDY OBJECTIVE: To report the use of ultrasound for cyroablation of purely sensory nerves for long-term relief of pain because the use of ultrasound enhances accuracy while minimizing injury to surrounding structures. DESIGN: Case series of three patients with positive long-term outcomes. SETTING: Outpatient Pain Management Clinic associated with a large, university affiliated, tertiary care community hospital. PATIENTS: 3 ASA physical status 2 and 3 patients who were treated for intercostal neuralgia secondary to surgical incision or vertebral fractures. INTERVENTIONS: These patients had failed various medical therapies but had positive responses to diagnostic intercostal nerve blocks. They underwent lesioning of the culprit nerves (with the use of ultrasound). MEASUREMENTS AND MAIN RESULTS: Pain scores were recorded using a numeric rating scale (NRS), and were solicited preprocedurally and postprocedurally, and once again after longterm follow-up (> 2 mos). Longterm (> 2 mos) relief of symptoms from established, chronic pain conditions was achieved with cryotherapy with ultrasound guidance. CONCLUSIONS: Neuro-ablative procedures using cryotherapy have been well reported. The use of ultrasound with cryotherapy facilitates direct visualization of the anatomy and aids in avoidance of vital vascular and pleural structures. PMID- 23988805 TI - Drug testing physicians for substances of abuse: case report of a false-positive result. AB - The risk of a false-positive urine drug screen is one of the major impediments to widespread implementation of drug testing programs in anesthesiology. A case of a false-positive urine screen for ketamine in an anesthesia provider is presented, with recommendations for methods of managing such an event. PMID- 23988806 TI - Tracheal deviation secondary to massive cardiomegaly in a two month old child with newly diagnosed total anomalous pulmonary venous return. PMID- 23988807 TI - Refractory hypotension during spinal anesthesia for Cesarean delivery due to undiagnosed pheochromocytoma. AB - Profound hypotension and resistance to conventional vasopressor therapy following administration of spinal anesthesia for Cesarean delivery occurred in a multiparous parturient. Postpartum evaluation for secondary hypertension showed a diagnosis of pheochromocytoma. Pheochromocytoma was mistaken for preeclampsia with significant vasopressor requirement to treat hypotension from spinal anesthesia. If pheochromocytoma is diagnosed during pregnancy and Cesarean delivery is required, spinal anesthesia may not be the optimal choice of anesthesia. PMID- 23988808 TI - Etiology of valvular heart disease in the 21st century. AB - A metamorphosis in the etiology of valvular heart disease (VHD) has occurred over the last 6 decades. In this review, the factors contributing to this metamorphosis, the common causes of VHD today, the relationship of valvular calcification to atherosclerosis and the interrelationship of VHD with other systems/organs are presented. PMID- 23988809 TI - Nutrient composition of Cirina forda (Westwood)-enriched complementary foods. AB - BACKGROUND/AIMS: Dried Cirina forda (Westwood) larva is widely marketed, cheap, and commonly consumed in Southwestern Nigeria. Its powder was used in enriching two commonly used complementary food staples (maize and sorghum) as a source of protein and essential micronutrients in complementary foods for infants and young children. METHODS: Samples of soaked and dried sorghum and maize flours and C. forda powder were prepared, and C. forda powder was added to the dried soaked maize and sorghum flours at 5, 10, and 15% (w/w) inclusion levels and analyzed for proximate, mineral, and antinutrient compositions using standard methods of AOAC. RESULTS: One hundred grams of C. forda larva contained 52.6 g of protein, 16.8 g of lipids, 2.6 g of ash, 268.67 mg of calcium, 5.64 mg of iron, and 15.00 mg of zinc, and yielded 458.40 kcal energy with 4.40 mg of trypsin inhibitor. Sorghum and maize flours contained 9.2 and 8.3 g of protein, respectively. Addition of C. forda at 5, 10, and 15% levels to fermented sorghum and maize flours significantly increased both micro- and macronutrients of the complementary foods (p < 0.05), and the nutrient density and trypsin inhibitor increased with the inclusion level (p < 0.05). CONCLUSION: The trypsin inhibitor level was very low and cannot cause protein malabsorption. C. forda can serve as a good source of nutrients such as protein, fat, calcium, phosphorus, iron, and zinc in formulating nutrient-dense complementary foods. PMID- 23988810 TI - Social capital and loneliness among the very old living at home and in institutional settings: a comparative study. AB - OBJECTIVE: The aim of this study was to investigate the association between aspects of social capital and loneliness among the very old living at home and in institutional settings. METHOD: Half of those aged 85 years, and all 90- and 95 year-olds and older in urban and rural municipalities in northern Sweden and western Finland were invited to participate in a cross-sectional population-based study in 2005-2007. A sample of 483 participants who completed the study was included in the analyses. RESULTS: Loneliness was experienced by 55% percent of those living in institutional settings often or sometimes and 45% of those living in their own homes. Loneliness was closely related to living alone, to depression, and to region (northern Sweden). DISCUSSION: Social capital and loneliness are context dependent (i.e., geographical or living environment). Among the very old, the link between social capital resources and loneliness is also highly influenced by health status. PMID- 23988811 TI - Work-related injuries: an old problem revisited in the first representative U.S. sample of home health aides. AB - OBJECTIVE: To examine whether certain personal and workplace factors increase risk for work-related injuries among home health aides. METHOD: A cross-sectional analysis was conducted using data from the 2007 National Survey of Home Health Aides among workers who provided formal caregiving to older adults or people with disabilities (N = 3,377, weighted sample = 160,720). RESULTS: Multivariate logistic regression identified six factors associated with injury: White race (OR = 2.07, 95% CI 1.18, 3.63); inappropriate workload (OR = 3.27, 95% CI 1.55, 6.93); having multiple jobs (OR = 2.73, 95% CI 1.30, 5.71); job dissatisfaction (OR = 2.71, 95% CI 1.23, 5.96); higher hourly pay rate (OR = 2.38, 95% CI 1.31, 4.33); and working in two locations (inpatient facility and patient's home) compared with working in patient's home only (OR = 2.57, 95% CI 1.51, 4.40). DISCUSSION: Interventions should be developed to address preventable risk factors. Evaluations of candidate interventions should control for other related factors that are not modifiable. PMID- 23988812 TI - The relation between frequency of binge drinking and psychological distress among older adult drinkers. AB - OBJECTIVES: The present study examined the relation between past year frequency of binge drinking and psychological distress among older adult drinkers. METHOD: Data were obtained from the 2009 California Health Interview Survey (CHIS). Adults aged 60 and older who had consumed alcohol in the past year (n=13,265) were analyzed. Psychological distress was assessed using the Kessler 6 (K6) scale. Multiple regression analyses were conducted. RESULTS: A significant main effect of frequency of binge drinking was found in regression analyses, indicating that an increased frequency of binge drinking was significantly associated with increased psychological distress (B=.10, p<.001). Results from additional analyses showed that binge drinking was related to increased psychological distress when individuals were binge drinking more than once in the past year. DISCUSSION: The results suggest that binge drinking frequently may be related to increased experiences of psychological distress among older drinkers. Research and clinical implications are discussed. PMID- 23988813 TI - Second transurethral resection after Ta high-grade bladder tumor: a 4.5-year period at a single university center. AB - PURPOSE: We evaluated the results of second transurethral resections of the bladder (TURB) after pTa high-grade bladder cancer over a 4.5-year period. PATIENTS AND METHODS: From July 2007 to December 2011, 2,159 TURBs were performed at our institution, of which 1,143 were initial resections for primary bladder tumor or recurrence. Of these, 142 revealed pTa high-grade bladder cancer, and here we investigated tumor characteristics of initial TURB and results of second resection. RESULTS: The incidence of pTa high-grade tumor was 12.4% (n = 142). Of 87 patients who underwent a second resection, tumor was found in 36 (41.4%); tumors were multifocal in 25 (69.4%) and <3 cm in 29 (80.6%). Tumor was detected at the primary site in 38.9%, at other locations in 22.2%, and at both in 38.9%. Histology revealed pTa low-grade in 13 (14.9% of 87), pTa high-grade in 15 (17.2%), and pT1 in 5 (5.7%) patients. No muscle-invasive tumor was detected. A significant association was found for the number of tumors at initial TURB: in patients with tumor at second resection, 55.1% had had multiple tumors at first resection, more than twice those with solitary tumor (23.7%) (0.004). CONCLUSIONS: In our study, Ta high-grade tumors show a relevant rate of persistent tumor at second resection, most of them located at the primary tumor site. As recommended by the American and European clinical guidelines, patients with Ta high-grade tumor should undergo second resection. PMID- 23988814 TI - Adjuvant aromatase inhibitor therapy in patients with stage I breast cancer at a regional oncology center in Israel: implementation of a 'switching' policy in postmenopausal patients after initial tamoxifen. AB - OBJECTIVE: To analyze the implementation of a switching policy of adjuvant aromatase inhibitor (AI) therapy sequentially after tamoxifen in consecutively treated stage I (T1N0M0) hormone receptor (HR)-positive breast cancer (BC) patients. METHODS: The records of 279 consecutive HR-positive BC patients diagnosed between 2002 and 2006 and followed at the Soroka Medical Center were reviewed. RESULTS: Two-hundred-seventeen patients who initially received tamoxifen were suitable for switching and 28 received an AI as initial adjuvant treatment. The switch was accomplished in 82.5% of the 217 patients. Those who switched to an AI had a higher proportion of T1c stage than patients eligible who were not switched, but did not differ in age, histologic grade, or having received chemotherapy. Of the 179 patients who switched, 155 (86.6%) completed at least 4.5-5 years of adjuvant tamoxifen/AI therapy. Eighteen patients discontinued AI therapy prematurely because of toxicity. CONCLUSIONS: In this stage I BC population, despite the toxicities of AI therapy, >84% of eligible patients received an AI as adjuvant therapy. Measures to improve the management of AI toxicity, such as changing to a different AI, may reduce early stopping. PMID- 23988815 TI - Do circadian preferences influence the sleep patterns of night shift drivers? AB - OBJECTIVE: The objective of this study was to analyze the effect of individual circadian preferences of drivers with fixed night work schedules on sleep patterns. SUBJECTS AND METHODS: A total of 123 professional drivers, 32 indifferent preference drivers and 91 morning preference drivers of an intermunicipality and interstate bus transportation company were evaluated. All drivers underwent polysomnographic recordings after their shifts. Furthermore, they filled out a questionnaire that contained sociodemographic and health questions. The Horne and Ostberg questionnaire was used to assess the subjects' morningness-eveningness preference. RESULTS: The mean age was 42.54 +/- 6.98 years and 82 (66.66%) of the drivers had worked for >=15 years. A significant effect on rapid eye movement (REM) was observed in the morning preference drivers. They showed an increased sleep latency and an REM sleep percentage of 5% of the total REM time. This reveals a significant effect on sleep architecture associated with work time. CONCLUSION: The drivers reported that morning preference had a significant effect on their sleep pattern indicating less REM sleep and longer REM sleep latency in the morning preference group. Thus, it is important to evaluate interactions between individual aspects of health and other parameters, such as sleep quality and work organizational factors, to promote night shift workers' health and well-being. PMID- 23988816 TI - Cold finger: urban frostbite in the UK. AB - A 24-year-old man, presented to the accident and emergency (A&E) department 48 h after a social evening where excess alcohol had been consumed. He had fallen asleep outside then made a visit to the A&E department once his finger became painful. His diagnosis was frostbite. PMID- 23988817 TI - Retraction. Odontomas--silent tormentors of teeth eruption, shedding and occlusion. PMID- 23988818 TI - Bilateral ovarian malignant mixed Mullerian tumour: a rare entity. AB - A 52-year-old postmenopausal woman presented with abdominal distension for 2 months. She had no vaginal bleeding and no relevant medical history. A physical examination showed a large palpable pelvic mass. A CT scan showed an ill-defined, heterogeneously enhancing, soft tissue attenuation lesion in the lower abdomen and pelvis involving the right adnexal region with massive ascites, and the left ovary did not reveal any evidence of disease. The omentum was thickened and heterogeneous. The patient underwent a total hysterectomy with infracolic omentectomy. The diagnosis was bilateral ovarian malignant mixed Mullerian tumour (MMMT) with omental deposits. Aggressive treatment includes surgery and chemotherapy. Women with this tumour have a significant increased risk of death compared to women with epithelial ovarian cancer and very poor prognosis. We report a case of MMMT of the ovary with clinicopathological correlation and diagnostic difficulties as malignant epithelial tumour resemble ovarian stromal sarcoma in postmenopausal female. PMID- 23988820 TI - Giant pilomatricoma in a patient with tuberous sclerosis, both diagnosed in the adult life. AB - Pilomatricoma is a relatively common benign skin neoplasm originating from the hair follicle matrix cells. beta-Catenin is a subunit of the cadherin protein complex. It acts as an intracellular signal transducer that influences cell differentiation and proliferation. This protein was recently involved in the formation of hair follicle-related tumours, including pilomatricomas. Tuberous sclerosis (TS) is an inherited neurocutaneous disease, which is characterised by pleomorphic features involving many organs, hamartomas in multiple organ systems and by the fact that it is usually diagnosed early in life. We reported a case of a Caucasian patient with TS and a giant pilomatricoma, both diagnosed in the adult life. PMID- 23988819 TI - Listening to the head and not the heart: subarachnoid haemorrhage associated with severe acute left ventricular failure. AB - Headache is a very common presenting symptom in the emergency department, and distinguishing subarachnoid haemorrhage from more benign causes of headache can be challenging. This particular presentation of subarachnoid haemorrhage was made more difficult by concurrent-related cardiac pathophysiology. This case report describes the evolving differential diagnosis of a 54-year-old woman initially presenting with headache and confusion, with signs and investigations suggestive of ST elevation myocardial infarction and resultant left ventricular failure. The importance of prompt primary percutaenous coronary intervention left clinicians with a difficult decision about which specialty was most appropriate for the patient to be transferred to. Ultimately the symptoms were explained by radiographic confirmation of subarachnoid haemorrhage and subsequent adrenergic storm, causing myocyte injury and myocardial contractile dysfunction. This patient was transferred for coiling of a ruptured cerebral artery berry aneurysm. Her left ventricular failure improved from severe to mild within 48 h of presentation. PMID- 23988821 TI - Finger prosthesis: a boon to handicapped. AB - This is a clinical case report of a 52-year-old male patient with four partially missing fingers of the left hand. The article describes the clinical and laboratory procedure of making prosthesis with modern silicone material. A wax pattern was fabricated using the right hand of the patient. A special type of wax was formulated to make the pattern so that it can be easily moulded and carved. Intrinsic and extrinsic staining was also performed to match the adjacent skin colour. The patient was given the finger prosthesis and was asked to use a half glove (sports) to mask the junction between the prosthesis and the normal tissue. It also provides additional retention to the artificial fingers. The patient felt his social acceptance improved after wearing the finger prosthesis. PMID- 23988822 TI - Perimetric demonstration of spontaneous visual field recovery following occipital lobe haemorrhage. AB - A 45-year-old patient on lifelong warfarin therapy after a metal aortic valve replacement developed a homonymous visual field defect following an occipital lobe haemorrhage. The patient received only conservative management and yet described continued improvement in her visual field defect for up to 20 months following the initial cerebral insult. We present the first conclusive illustrative documentation of visual recovery in a patient with an occipital lobe haemorrhage with sequential automated perimetric assessments over an extended period of time. PMID- 23988823 TI - Fever, ulcers and joint pain: an incidental finding of oesophageal dysmotility. AB - A 41-year-old Bangladeshi man presented with a 2-month history of bilateral feet/hand swelling which intermittently resolved without medication. All blood tests performed by the general practitioner (GP) were unremarkable. Following admission to the accident and emergency department, a chest X-ray revealed a 'vail-like' opacification in the right side. High-resolution CT confirmed dilation of oesophagus with food debris and circumferential thickening of the lower oesophageal sphincter. PMID- 23988824 TI - An unexpected cause of right heart strain. AB - A 27-year-old woman was referred from her general practitioner (GP) 6 weeks postpartum with weight loss, dyspnoea and bilateral leg swelling. She had been treated by the GP for a chest infection the week before. On admission she was tachycardic, hypotensive and hypoxic with bilateral leg oedema and bibasal crackles. A chest radiograph showed diffuse multinodular opacification. A CT pulmonary angiogram showed dilated pulmonary artery. Echocardiogram confirmed right ventricular strain and dilation. Sputum microscopy was positive for acid fast bacilli. The patient developed confusion and low-grade fever and the CT head scan showed meningeal involvement. One year of antituberculous therapy was started and she made a clinical recovery after 10 days and was discharged with regular follow-up. An echocardiogram showed resolution of the right heart strain 4 months later. PMID- 23988825 TI - Cardiorespiratory arrest secondary to tracheostomy cuff herniation. AB - This report details the case of a 67-year-old man who required intubation following a fall and multiple rib fractures and underwent surgical tracheostomy. Postoperatively, he deteriorated on the intensive care unit with airway obstruction. Bronchoscopy demonstrated tracheostomy cuff herniation obstructing airflow necessitating conventional orotracheal reintubation. On inspection of the tracheostomy an unusual cuff deformation was noted. PMID- 23988826 TI - Yoga in the form of breathing exercises: a bane for some. PMID- 23988827 TI - Another rare cause of encephalopathy. PMID- 23988828 TI - The influence of angiotensin-(1-7) Mas receptor agonist (AVE 0991) on mitochondrial proteome in kidneys of apoE knockout mice. AB - Excessive action of angiotensin II on mitochondria has been shown to play an important role in mitochondrial dysfunction, a common feature of atherogenesis and kidney injury. Angiotensin-(1-7)/Mas receptor axis constitutes a countermeasure to the detrimental effects of angiotensin II on AT1 receptors. The aim of the study was to assess the effects of angiotensin-(1-7) peptidomimetic AVE0991 on the kidney mitochondrial proteome in widely used animal model of atherosclerosis (apoE(-/-) mice). Proteins changed in apoE(-/-) mice belonged to the groups of antioxidant enzymes, apoptosis regulators, inflammatory factors and metabolic enzymes. Importantly, AVE0991 partially reversed atherosclerosis related changes in apoE(-/-) mice. PMID- 23988831 TI - [Mental health of children and adolescents-challenges and potential actions]. PMID- 23988830 TI - Erysipelothrix bacteremia without endocarditis: rare event or under-reported occurrence? AB - A patient presented with inflamed hands and Erysipelothrix rhusiopathiae bacteremia. Because a high incidence of endocarditis has been reported with this organism, a transesophageal echocardiogram was obtained, which was normal. Treatment with oral moxifloxacin resolved all manifestations of illness. The association between E. rhusiopathiae bacteremia and endocarditis may be spurious. PMID- 23988832 TI - [Coping with everyday stress in different problem areas- comparison of clinically referred and healthy adolescents]. AB - OBJECTIVE: Studies are lacking that analyze how clinically referred adolescents and healthy adolescents cope with everyday stressors. METHODS: Clinically referred adolescents from three problematic domains (diverse disorders including delinquency, drug abuse, and depression) were compared to healthy adolescents using the Coping Across Situations Questionnaire (Seiffge-Krenke, 1995) and a short version of the Youth Self-Report (Achenbach, 1991). RESULTS: The different clinical groups (n = 469) showed unique patterns concerning their coping styles. The group of depressed youth altogether showed lower coping activities. The youth from institutions for drug abusive youth used more dysfunctional coping. The adolescents from youth welfare services (diverse disorders including delinquency) were more active in both dysfunctional and functional coping than the other two clinically referred groups. The control group showed more functional and less dysfunctional coping. The clinically referred adolescents did not differentiate in their coping behavior, depending on the type of stressor. Gender effects were apparent, albeit negligible. CONCLUSIONS: Clinically referred youth are unable to adapt their coping behavior according to the given situation. PMID- 23988833 TI - [Prevalence and intensity of nightmares in traumatized versus non-traumatized children and adolescents]. AB - OBJECTIVE: Nightmares may be seen as a symptom of traumatization in both children and adults. Nightmares are assumed to be more frequent and more distressing among traumatized children and adolescents than among those without trauma. A total of 38 traumatized and 40 nontraumatized children and adolescents were surveyed. METHOD: Nightmare-induced stress was measured with a questionnaire comprised of nine items (some of which concerned nightmare frequency and perceived intensity). RESULTS: Traumatized children and adolescents overall report a significantly higher number of nightmares, which they perceive in a more intense and frightening way than their control group counterparts. Traumatized children and adolescents reported an average of 9.7 nightmares per month compared to 1.7 in nontraumatized participants. The number of nightmares in traumatized girls was twice that in traumatized boys. CONCLUSIONS: Traumatized children and adolescents report fears of dream repetitions as well as feelings of helplessness during the nightmares and are thus influenced during the daytime significantly more often. Traumatized patients have more life-threatening and violent dreams. An increased frequency of nightmare and distress is also a specific feature in traumatized children and adolescents. PMID- 23988829 TI - Unintended consequences of Helicobacter pylori infection in children in developing countries: iron deficiency, diarrhea, and growth retardation. AB - Helicobacter pylori infection is predominantly acquired early in life. The prevalence of the infection in childhood is low in developed countries, whereas in developing countries most children are infected by 10 y of age. In poor resource settings, where malnutrition, parasitic/enteropathogen and H. pylori infection co-exist in young children, H. pylori might have potentially more diverse clinical outcomes. This paper reviews the impact of childhood H. pylori infection in developing countries that should now be the urgent focus of future research. The extra-gastric manifestations in early H. pylori infection in infants in poor resource settings might be a consequence of the infection associated initial hypochlorhydria. The potential role of H. pylori infection on iron deficiency, growth impairment, diarrheal disease, malabsorption and cognitive function is discussed in this review. PMID- 23988834 TI - [Interrater reliability of the "Diagnostic Interview bei psychischen Storungen im Kindes- und Jugendalter (Kinder-DIPS)]. AB - OBJECTIVE: This study investigates the interrater reliability of the "Diagnostisches Interview bei psychischen Storungen im Kindes- und Jugendalter" (Kinder-DIPS; Schneider, Unnewehr & Margraf, 2009) based on child and parent interviews. It further investigates differences in the interrater reliability depending on age or sex of the children. METHOD: 48 certified interviewers conducted 264 parent and 213 child interviews in various inpatient, outpatient, and research settings. RESULTS: There is a good interrater reliability for the parent and child interviews for the major diagnostic categories of conduct disorders, tic disorders, elimination disorders, mood disorders, eating disorders, sleeping disorders, the majority of the specific psychiatric disorders, and the exclusion of psychiatric disorders. Neither the sex nor the age of the children influenced interrater reliability. CONCLUSIONS: The second and expanded Kinder-DIPS proves to be a reliable parent and child interview for the assessment of mental disorders in both outpatient and inpatient settings. PMID- 23988835 TI - [The differential classification of school avoidance- a cluster-analytic investigation]. AB - OBJECTIVE: We investigated subtypes of school-avoiding children and adolescents in a German sample using cluster analysis. METHOD: 169 outpatients of a specialized outpatient unit for children and adolescents with school-avoiding behavior were subjected to cluster analysis using factor scores (principal factoring, varimax-rotation: measures of internalizing and externalizing symptoms, e.g., CBCL, YSR, and variables indicating the quality of school avoiding behavior, such as initial parental knowledge of school absence, activities during school absence). The resulting clusters were compared to other variables such as parental mental health problems, parental divorce, bullying in school, class repetition, and IQ. RESULTS: Three groups were identified: "school refusers" with low externalizing symptoms who mainly stayed at home with their parents and were informed about their school absence from the beginning. Second, the "truants" with strong externalizing symptoms who spent school time alone or together with peers outside their home and were absent in school without initial parental knowledge. In a third cluster, children showed more externalizing problems than the school refusers and less externalizing problems than the truants. Most of their parents were informed about the school absence from the beginning, although the dominant activity was staying at home alone. Internalizing symptoms had no impact on cluster formation. Comparisons of the three groups, however, showed higher internalizing problems for school refusers and the third cluster, which was then labeled "school avoidance with mixed symptoms." RESULTS AND CONCLUSIONS: In most cases, significant differences regarding potential stressors at home (e.g., parental mental health problems) or in school (e.g., bullying, class repetition) were not obtained. PMID- 23988837 TI - [Comment on J. Schmitt et al]. PMID- 23988836 TI - [On the relationship between executive functioning and social-emotional problems of deaf and hard-of-hearing students at general schools]. AB - PROBLEM: As part of inclusive efforts more and more deaf and hard-of-hearing (D/HH) children are attending general schools. This makes it important to consider significant developmental prerequisites necessary for this step. This study analyzed the socioemotional problems of hearing-impaired children from general schools with respect to their executive functioning and communicative competence. METHOD: The executive functions of a sample of 69 hearing-impaired students were assessed by their teachers with a German version of the Behavior Rating Inventory of Executive Functions (BRIEF). In addition, a questionnaire measuring communicative competence as well as a German version of the Strengths and Difficulties Questionnaire were administered. The data were compared with those from a hearing normative sample, and further correlation and regression analyses were performed. The relationships between executive functioning and sociodemographic variables were also analyzed. RESULTS: There was a significantly higher rate of problems in executive functions for the group of D/HH students than for a hearing normative sample on nearly all scales, with the prevalence rate for executive dysfunctions being on average about three times higher. In addition to the children's sex, the BRIEF index for behavior regulation proved best for predicting socioemotional problems. CONCLUSION: The consequences for practical work are discussed. The results from the study suggest that D/HH students at general schools benefit in their psychosocial development from educational concepts that, in addition to promoting language and communicative competences, explicitly include strengthening self-efficacy and self-control. PMID- 23988839 TI - Does tester experience influence the reliability with which 3D gait kinematics are collected in healthy adults? AB - OBJECTIVES: To determine whether tester experience influences the reliability of three-dimensional gait collections. DESIGN: Reliability study. PARTICIPANTS: Ten healthy subjects visited a university gait laboratory on two separate days and underwent a walking gait analysis. During each visit, kinematic data were collected by a biomechanist with 8 years of 3D gait analysis experience (EXP) and a physical therapist with no previous 3D gait analysis experience (NOV). MAIN OUTCOME MEASURES: Joint kinematic angles were calculated using either a functional or predictive joint identification method. Within-tester and between tester measures of reliability were determined by calculating the root mean square error (RMS) and coefficient of multiple correlations (CMC). RESULTS: Within-tester RMS and CMC values were not significantly different (P > 0.05) between the EXP and NOV testers using either a functional or predictive joint approach. Within-tester CMC values exceeded 0.90 for both testers across all kinematic variables. Between-tester CMC reliability values were greater than 0.85 for all variables measured. CONCLUSIONS: Following basic training, a physiotherapy clinician with no previous 3D gait experience is as reliable as an experienced gait biomechanist with respect to marker placement accuracy. In addition, reliability comparisons between an experienced and novice tester appear independent of the joint identification method chosen. PMID- 23988840 TI - Lack of nrf2 results in progression of proliferative lesions to neoplasms induced by long-term exposure to non-genotoxic hepatocarcinogens involving oxidative stress. AB - To explore the role of oxidative stress in chemical carcinogenesis driven by non genotoxic mechanisms, nrf2-deficient (nrf2(-/-)) and nrf2-wild-type (nrf2(+/+)) mice were exposed to pentachlorophenol (PCP) at concentrations of 600 or 1200 ppm for 60 weeks, or piperonyl butoxide (PBO) at concentrations of 3000 or 6000 ppm in the diet for 52 weeks, respectively. Additional studies were performed to examine 8-hydroxydeoxyguanosine (8-OHdG) levels in liver DNA and hepatotoxicological parameters in serum following 8 weeks of exposure of each group to PBO at the same doses as in the long-term study. Exposure to 600 ppm PCP caused cholangiofibrosis (CF) only in nrf2(-/-) mice, while 1200 ppm PCP induced CF in both genotypes. Moreover, cholangiocarcinomas were found with significant incidence only in nrf2(-/-) mice treated with 1200 ppm PCP. Short-term exposure to 6000 ppm PBO caused significant elevation of 8-OHdG levels in both genotypes, while exposure to 3000 ppm caused a significant increase in 8-OHdG only in nrf2( /-) mice. There were no inter-genotype changes in the incidences of regenerative hepatocellular hyperplasia (RHH) following long-term exposure to PBO. However, the incidence and multiplicity of hepatocellular adenomas, especially those observed in RHH, were much higher in nrf2-/- mice treated with 6000 ppm PBO than in nrf2+/+ mice treated with 6000 ppm PBO. Therefore, oxidative stress generated through PCP or PBO metabolism may promote the proliferation and progression of preneoplastic lesions to neoplasms. PMID- 23988841 TI - Direct measurement and modelling of internal strains in ion-implanted diamond. AB - We present a phenomenological model and finite element simulations to describe the depth variation of mass density and strain of ion-implanted single-crystal diamond. Several experiments are employed to validate the approach: firstly, samples implanted with 180 keV B ions at relatively low fluences are characterized using high-resolution x-ray diffraction; secondly, the mass density variation of a sample implanted with 500 keV He ions, well above its amorphization threshold, is characterized with electron energy loss spectroscopy. At high damage densities, the experimental depth profiles of strain and density display a saturation effect with increasing damage and a shift of the damage density peak towards greater depth values with respect to those predicted by TRIM simulations, which are well accounted for in the model presented here. The model is then further validated by comparing transmission electron microscopy-measured and simulated thickness values of a buried amorphous carbon layer formed at different depths by implantation of 500 keV He ions through a variable-thickness mask to simulate the simultaneous implantation of ions at different energies. PMID- 23988842 TI - The effects of astrocytes on differentiation of neural stem cells are influenced by knock-down of the glutamate transporter, GLT-1. AB - The majority of glutamate released during neurotransmission is uptaken into astrocytes through the glial glutamate transporter GLT-1, by which extracellular glutamate is inactivated. In this study, we determined whether GLT-1 mediated the astrocyte regulation of the cell fate of neural stem/progenitor cells (NSCs) by glutamate reuptake. The astrocytes stimulated neuronal lineage selection but inhibited glial lineage cells. However, all these effects were reversed after siRNA-targeting GLT-1 was delivered into astrocytes by lentiviral vectors. NSC and astrocyte co-culture also increased the synaptophysin protein levels of NSC derived new neurons through GLT-1. Glutamate was found to be present in the supernatants of the co-culture and astrocytes under different medium conditions, which may be attributed to the slower rate of clearance of the released glutamate. Dysfunctional glutamate reuptake may be the major consequence of GLT-1 functional silence in astrocytes. These results indicated that astrocytes regulated NSCs in reactive astrogliosis, neuronal generation, and synaptic function through GLT-1. PMID- 23988843 TI - In vitro models for the prediction of in vivo performance of oral dosage forms. AB - Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation...) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is anticipated that the innovative in vitro biopharmaceutical tools arising from the OrBiTo project will lead to improved predictions for in vivo behavior of drug formulations in the GI tract. PMID- 23988844 TI - Animal versus human oral drug bioavailability: do they correlate? AB - Oral bioavailability is a key consideration in development of drug products, and the use of preclinical species in predicting bioavailability in human has long been debated. In order to clarify whether any correlation between human and animal bioavailability exist, an extensive analysis of the published literature data was conducted. Due to the complex nature of bioavailability calculations inclusion criteria were applied to ensure integrity of the data. A database of 184 compounds was assembled. Linear regression for the reported compounds indicated no strong or predictive correlations to human data for all species, individually and combined. The lack of correlation in this extended dataset highlights that animal bioavailability is not quantitatively predictive of bioavailability in human. Although qualitative (high/low bioavailability) indications might be possible, models taking into account species-specific factors that may affect bioavailability are recommended for developing quantitative prediction. PMID- 23988845 TI - Regional intestinal drug permeation: biopharmaceutics and drug development. AB - Over the last 25 years, profound changes have been seen in both the development and regulation of pharmaceutical dosage forms, due primarily to the extensive use of the biopharmaceutical classification system (BCS) in both academia and industry. The BCS and the FDA scale-up and post-approval change guidelines were both developed during the 1990s and both are currently widely used to claim biowaivers. The development of the BCS and its wide acceptance were important steps in pharmaceutical science that contributed to the more rational development of oral dosage forms. The effective permeation (Peff) of drugs through the intestine often depends on the combined outcomes of passive diffusion and multiple parallel transport processes. Site-specific jejunal Peff cannot reflect the permeability of the whole intestinal tract, since this varies along the length of the intestine, but is a useful approximation of the fraction of the oral dose that is absorbed. It appears that drugs with a jejunal Peff>1.5*10( 4)cm/s will be completely absorbed no matter which transport mechanisms are utilized. In this paper, historical clinical data originating from earlier open, single-pass perfusion studies have been used to calculate the Peff of different substances from sites in the jejunum and ileum. More exploratory in vivo studies are required in order to obtain reliable data on regional intestinal drug absorption. The development of experimental and theoretical methods of assessing drug absorption from both small intestine and various sites in the colon is encouraged. Some of the existing human in vivo data are discussed in relation to commonly used cell culture models. It is crucial to accurately determine the input parameters, such as the regional intestinal Peff, as these will form the basis for the expected increase in modeling and simulation of all the processes involved in GI drug absorption, thus facilitating successful pharmaceutical development in the future. It is suggested that it would be feasible to use open, single-pass perfusion studies for the in vivo estimation of regional intestinal Peff, but that care should be taken in the study design to optimize the absorption conditions. PMID- 23988846 TI - Delivery of natural polyphenols by polymeric nanoparticles improves the resistance of endothelial progenitor cells to oxidative stress. AB - PURPOSE: Bone marrow-derived endothelial progenitor cells (EPCs) circulate into peripheral blood and significantly contribute to neo-vascularisation and re endothelialisation as part of the process of vascular repair. Several studies have reported decreased EPC number in the presence of oxidative stress. Aim of this study was to evaluate the validity of mucoadhesive polymeric nanoparticles as a delivery system of natural products able to protect EPCs from oxidative stress. METHODS: The total polyphenol content and antioxidant capacity of red grape seed extract (GSE) either pre-veraison (p-GSE) or ripe (r-GSE) were measured. Cell viability was evaluated by WST-1 assay. Nanoparticles were prepared by ionotropic crosslinking of two structurally different thiolated quaternary ammonium-chitosan conjugates. A hyaluronic acid solution, containing p GSE or r-GSE, was added to a stirred solution of each of the two chitosan derivatives to obtain p- or r-GSE loaded nanoparticles (NP) of two types. RESULTS: Both GSE types demonstrated strong antioxidant capacity. p-GSE showed a higher content in total polyphenols compared to r-GSE. NP size was in the 310-340 nm range, with 24 h stability, and nearly 100% encapsulation efficiency for both GSE types. NP were internalized by cells to an extent related directly with their surface charge intensity. GSE-NP uptake significantly improved cell viability and resistance to oxidation. CONCLUSIONS: Nanotechnology has a great potential in nutraceutical delivery. The present results suggest that NP is a highly promising polyphenol carrier system particularly useful to protect EPCs from oxidative stress, thus improving their survival. PMID- 23988847 TI - AFN-1252 in vitro absorption studies and pharmacokinetics following microdosing in healthy subjects. AB - OBJECTIVES: To investigate the absorption, distribution, metabolism and excretion of AFN-1252, a novel inhibitor of the essential FabI enzyme in Staphylococcus spp., in vitro and following microdosing in healthy adult male subjects following intravenous and oral administration. METHODS: Three ADME studies, comprising a Caco-2 assay, a rat intestinal perfusion model and a microdosing study in healthy human volunteers, were conducted. RESULTS: The Caco-2 assay indicated that AFN 1252 in solution is well-absorbed and undergoes insignificant efflux, and its transport across the intestinal wall is probably passive. In the rat intestinal perfusion model, AFN-1252 exhibited high permeability potential across three segments, in the rank order of jejunum=ileum>colon. Taken together with the low aqueous solubility, the data from these studies indicate that AFN-1252 is a BCS Class II molecule with solubility-limited absorption. Analysis of the [(14)C]-AFN 1252 radioactivity concentration-time data indicated similar pharmacokinetics following intravenous and oral administration in the microdosing study in healthy volunteers. These included long terminal half-lives of ~7 h and 83% bioavailability, indicating that there was little first-pass metabolism following oral dosing. AFN-1252 exhibited good distribution to skin and skin structures where its anti-staphylococcal activity may be required. Urinary and faecal excretion are major elimination routes for [(14)C]-AFN-1252 following intravenous or oral administration. CONCLUSIONS: AFN-1252 has the potential for both intravenous and oral administration, once- or twice-daily dosing and good tissue distribution in humans. Further safety, efficacy and pharmacokinetic studies in man are required to investigate therapeutically-relevant doses for this novel agent and its targeted selectivity and high potency against Staphylococcus spp. PMID- 23988848 TI - Determination of formal redox potentials in aqueous solution of copper(II) complexes with ligands having nitrogen and oxygen donor atoms and comparison with their EPR and UV-Vis spectral features. AB - Formal redox potentials in aqueous solution were determined for copper(II) complexes with ligands having oxygen and nitrogen as donor atoms. All the chosen copper(II) complexes have well-known stereochemistries (pseudo-octahedral, square planar, square-based pyramidal, trigonal bipyramidal or tetrahedral) as witnessed by their reported spectroscopic, EPR and UV-visible (UV-Vis) features, so that a rough correlation between the measured redox potential and the typical geometrical arrangement of the copper(II) complex could be established. Negative values have been obtained for copper(II) complexes in tetragonally elongated pseudo-octahedral geometries, when measured against Ag/AgCl reference electrode. Copper(II) complexes in tetrahedral environments (or flattened tetrahedral geometries) show positive redox potential values. There is a region, always in the field of negative redox potentials which groups the copper(II) complexes exhibiting square-based pyramidal arrangements. Therefore, it is suggested that a measurement of the formal redox potential could be of great help, when some ambiguities might appear in the interpretation of spectroscopic (EPR and UV-Vis) data. Unfortunately, when the comparison is made between copper(II) complexes in square-based pyramidal geometries and those in square planar environments (or a pseudo-octahedral) a little perturbed by an equatorial tetrahedral distortion, their redox potentials could fall in the same intermediate region. In this case spectroscopic data have to be handled with great care in order to have an answer about a copper complex geometrical characteristics. PMID- 23988849 TI - Gold(III) complexes with esters of cyclohexyl-functionalized ethylenediamine-N,N' diacetate. AB - Six novel gold(III) complexes containing O,O'-dialkyl-(S,S)-ethylenediamine-N,N' di-2-(3-cyclohexyl)propanoate ([AuCl2{(S,S)-R2eddch}]PF6, R=Me, Et, n-Pr, n-Bu, i Bu, i-Am; 1-6, respectively) were synthesized and characterized by elemental analysis, UV/Visible, IR and NMR spectroscopy, mass spectrometry and differential pulse voltammetry. Density functional theory (DFT) calculations confirmed that diastereoisomer with the N,N' atoms configured (S,S) was the most stable. In vitro antiproliferative activity was determined against human cervix adenocarcinoma HeLa and human myelogenous leukemia K562 tumor cell lines, as well as against rested and stimulated normal immunocompetent human peripheral blood mononuclear cells (PBMC) using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Complex 6 expressed the highest activity against K562 cells (IC50 = 3.8 +/- 0.5 MUM). Apoptosis, seen as condensation of HeLa cell nuclei was the mode of cell death induced by complexes 2-6. Complexes 3 6 induced death of K562 cells inhibiting cell entry in mitosis. PMID- 23988850 TI - The involvement of midbrain astrocyte in the development of morphine tolerance. AB - AIMS: Systemic administration of opiate analgesics such as morphine remains the most effective treatment for alleviating severe pain across a range of conditions including acute pain. However, chronic or repeated administration of opiate analgesics results in the development of analgesic tolerance. Glial cells such as microglia and astrocytes are known to release various inflammatory cytokines and neurotrophic factors leading to regulation of neuronal function. Recently, glial cells were reported to play important roles in the development of analgesic tolerance to morphine. Here, we focused on the involvement of midbrain glial cells, particularly astrocytes, in the development of analgesic tolerance to morphine. MAIN METHODS: Mice were treated with morphine (10mg/kg, s.c.) or vehicle once a day for 5 days. Pentoxifylline (an inhibitor of glial activation; 20mg/kg, i.p. or 50 and 100 MUg/mouse, i.c.v.) was administered 30 min before morphine treatment. Flavopiridol (a cyclin-dependent kinase inhibitor; 5 nmol/mouse, i.c.v.) was administered 10 min before and 10h after morphine treatment. The analgesic effect of morphine was measured using the tail flick method. KEY FINDINGS: The development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine for 5 days in mice. On days 1 and 3 after repeated morphine treatment, astrocyte marker glial fibrillary acidic protein expression levels were significantly increased, as determined by western blot analyses. These phenomena were significantly inhibited following pre treatment with pentoxifylline or flavopiridol. SIGNIFICANCE: We demonstrated that midbrain astrocytes play an important role in the development of analgesic tolerance to morphine. PMID- 23988851 TI - Endogenous opioids regulate alveolar bone loss in a periodontal disease model. AB - AIM: The anti-inflammatory effects of exogenous opioid compounds have been demonstrated in several conditions. Nevertheless, the function of endogenous opioid peptides released by the host during inflammatory processes deserves further characterization. The aim of this study was to verify whether endogenous opioids are involved in the progression of the inflammatory alveolar bone loss induced by ligature in rats. MAIN METHODS: The experimental model of periodontal disease (PD) induced by ligature in rats was used throughout the study. A silk ligature was placed around the 2nd upper molar of male Holtzman rats, for 7 days. Rats received different doses of either the non-selective opioid antagonist naloxone or vehicle, locally into the afflicted gingival tissue, from the 3rd to the 5th day after ligature placement. In the 7th experimental day, rats were euthanized and their maxillae were collected for evaluation of alveolar bone and fiber attachment loss, presence of neutrophils (myeloperoxidase assay), osteoclast amount, and levels of cytokines IL-6, TNF-alpha, IL-8 and IL-10 in periodontal tissues. KEY FINDINGS: Naloxone increased alveolar bone loss significantly, in a dose-dependent manner, in relation to vehicle-treated rats. In contrast, the opioid antagonist did not affect the loss of fiber attachment. The treatment with naloxone also induced a significant increase in myeloperoxidase levels, osteoclast number and cytokines in periodontal tissues of rats with ligature-induced PD. SIGNIFICANCE: Endogenous opioids protect the host from the progression of inflammatory alveolar bone loss that occurs in chronic periodontitis. PMID- 23988852 TI - Expression and function of PEPT2 during transdifferentiation of alveolar epithelial cells. AB - AIMS: The purpose of this study was to clarify the expression and function of peptide transporter 2 (PEPT2) in primary cultured alveolar type II epithelial cells and in transdifferentiated type I-like cells. MAIN METHODS: Real-time PCR analysis, uptake study of [(3)H]Gly-Sar, and immunostaining were performed in alveolar epithelial cells. KEY FINDINGS: The expression of PEPT2 mRNA in type II cells isolated from rat lungs was highest at day 0, and decreased rapidly during culture of the cells. In accordance with this change, PEPT2 activity estimated as cefadroxil-sensitive [(3)H]Gly-Sar uptake also decreased along with transdifferentiation. The expression of PEPT2 protein in type II cells was confirmed by immunostaining and Western blot analysis. The uptake of [(3)H]Gly Sar in type II cells was time- and pH-dependent. In contrast, minimal time dependence and no pH-dependence of [(3)H]Gly-Sar uptake were observed in type I like cells. The maximal [(3)H]Gly-Sar uptake was observed at pH6.0, and the uptake decreased at higher pHs in type II cells. The uptake of [(3)H]Gly-Sar in type II cells was inhibited by cefadroxil in a concentration-dependent manner, the IC50 value being 4.3 MUM. On the other hand, no significant inhibition by cefadroxil was observed in type I-like cells. In addition, [(3)H]Gly-Sar uptake in type II cells was saturable, the Km value being 72.0 MUM. SIGNIFICANCE: PEPT2 is functionally expressed in alveolar type II epithelial cells, but the expression decreases along with transdifferentiation, and PEPT2 would be almost completely lost in type I cells. PMID- 23988853 TI - Inhibition of monoamine oxidase isoforms modulates nicotine withdrawal syndrome in the rat. AB - AIMS: There have been many reports of monoamine oxidase (MAO) inhibition by non nicotine ingredients in tobacco smoke, persisting for days after smoking cessation. This study determined the effect of inhibiting MAO and its isoforms on nicotine withdrawal syndrome. MAIN METHODS: Rats were rendered nicotine-dependent by seven days of subcutaneous (s.c.) 9 mg/kg/day infusion of nicotine bitartrate. Twenty-two hours after termination of infusion, they were observed over 20 min for somatically expressed nicotine withdrawal signs. Three hours before observation, rats were injected intraperitoneally (i.p.) with 4 mg/kg each of the MAO A antagonist clorgyline and the MAO B antagonist deprenyl, or with saline alone. A similar experiment was performed with non-dependent, saline-infused rats. Another experiment compared nicotine-dependent rats that received injections of either saline or 4 mg/kg clorgyline alone. A further experiment compared rats receiving either saline or 4 mg/kg deprenyl alone. KEY FINDINGS: Combined treatment with both MAO inhibitors markedly and significantly exacerbated somatically expressed nicotine withdrawal signs in nicotine infused rats, while having no significant effects in saline-infused rats. Rats injected s.c. with 4 mg/kg clorgyline alone had significantly more withdrawal signs than saline-injected rats, while deprenyl-injected rats had significantly fewer signs than saline controls. Assays confirmed that clorgyline thoroughly reduced MAO A enzymatic activity and deprenyl thoroughly reduced MAO B activity. SIGNIFICANCE: The results suggest that inhibition of MAO A may contribute to the intensity of withdrawal syndrome in smoking cessation. PMID- 23988855 TI - Alpha-lipoic acid for the prevention of contrast-induced nephropathy in patients undergoing coronary angiography: the ALIVE study - a prospective randomized trial. AB - OBJECTIVES: alpha-Lipoic acid (ALA) is widely used for diabetic neuropathy due to its antioxidant properties. We evaluated its potential for preventing contrast induced nephropathy (CIN). METHODS: We conducted a prospective randomized controlled trial to evaluate the efficacy of ALA in CIN prevention. Two hundred and two patients with basal renal insufficiency who received elective coronary angiography were randomized to the ALA group [ALA treatment for 2 days (600 mg orally three times a day before and after coronary catheterization, n = 100)] or the control group (n = 102). The primary end point was the maximum increase in serum creatinine (sCr) and the secondary end point was the incidence of CIN defined as an increase in sCr of either >= 25% or >= 44.2 umol/l. RESULTS: Mean maximum increase in sCr was not different between the ALA and the control group ( 1.32 +/- 30.5 vs. -1.19 +/- 30.1 umol/l, respectively; p = 0.977). sCr did not significantly change from baseline (120.8 +/- 69.8 vs. 122 +/- 88.1 umol/l) in the ALA group and the simple saline hydration group (108.2 +/- 37.5 vs. 110 +/- 49 umol/l). There was a lower rate of CIN in the ALA group than in the control group, but the difference was not statistically significant (3.0 vs. 6.9%, respectively; p = 0.332). CONCLUSION: ALA showed no benefit in CIN prevention. PMID- 23988854 TI - Maternal endotoxin exposure results in abnormal neuronal architecture in the newborn rabbit. AB - Maternal intrauterine inflammation/infection is a potential risk factor for the development of neurologic disorders such as cerebral palsy (CP) in preterm and term infants. CP is associated with white matter and grey matter injury. In the current study, we used a rabbit model of CP in which pregnant rabbits are administered intrauterine injections of the endotoxin lipopolysaccharide. We then investigated the extent of neuronal damage in the newborn kit brain. We observed an overall decrease in the number of MAP2-stained neurons and an increase in Fluoro-Jade C-stained cells in the anterior thalamus of 1-day-old rabbit brain. We also observed an overall decrease in the number of branching points and spine density in the retrosplenial cortex, a major output region of the anterior thalamus that is involved in cognition and memory. The loss of spines and dendritic atrophy in the retrosplenial cortex may be caused by loss of presynaptic input from the thalamus. Our study indicates that the cognitive impairments seen in patients with CP may be related to the degeneration of neurons and abnormal arborization of the thalamic and cortical neurons. PMID- 23988856 TI - A consecutive and prospective stroke database covers the state of Baden Wuerttemberg with 10.8 million inhabitants in Germany. AB - BACKGROUND: In 1998 Baden-Wuerttemberg (BW), a federal state in southwest Germany with 10.8 million inhabitants, implemented a structured medical concept for the treatment of acute stroke. METHODS: Since 2004 participation in the BW stroke database is mandatory for all hospitals in BW involved in acute stroke care. The stroke database includes all inpatients >=18 years of age who have suffered an ischemic or hemorrhagic stroke within 7 days before hospitalization. This article presents methodological aspects and first results of the BW stroke database in the time period from 2007 to 2011. RESULTS: Annual inclusion numbers increased continuously (29,422 vs. 35,724, p < 0.001). Median age of stroke onset was stable over time. The proportion of stroke patients >=80 years increased from 36.9 to 38.8% (p < 0.001). Rates of patients treated in neurology departments rose from 50.7 to 60.9% (p < 0.001) and numbers of patients treated in stroke units rose from 59.1 to 68.4% (p < 0.001). Admission via emergency medical systems increased from 42.8 to 49.7% (p < 0.001) and arrival within 3 h increased from 29.8 to 34.4% (p < 0.001). CONCLUSION: We present results from a large, prospective and consecutive stroke patient database. This first analysis demonstrates a continuous increase of absolute and relative numbers of stroke patients who arrive within 3 h after onset, are hospitalized in neurology departments and treated in stroke units, and are aged >=80 years. PMID- 23988857 TI - Hepatocellular carcinoma size: platelets, gamma-glutamyl transpeptidase, and alkaline phosphatase. AB - BACKGROUND: Thrombocytopenia is a cirrhosis surrogate which is associated with hepatocellular carcinoma (HCC) development. AIMS: To compare the clinical characteristics of HCC in the presence and absence of thrombocytopenia. METHODS: The baseline clinical data of a large cohort of randomly presenting, biopsy proven HCC patients was examined for phenotypic patterns, after organizing the data by tumor size and subdivision into tumor size terciles. RESULTS: Small tumor size tercile I patients had the lowest platelet counts. Patients with higher platelets within each size tercile had the lowest bilirubin and prothrombin time and higher gamma-glutamyl transpeptidase (GGTP) and alkaline phosphatase (ALKP) levels. When patients with similar platelet and bilirubin levels were compared, alpha-fetoprotein, GGTP, and ALKP were significantly increased in patients with larger tumors and in the presence of portal vein thrombus. Large tumor size tercile III patients without thrombocytopenia had larger tumors, higher GGTP and ALKP, and lower bilirubin levels than did patients with thrombocytopenia. CONCLUSIONS: Thrombocytopenia occurred in 40.7% of patients with smaller tumors but only in 11.3% of patients with larger tumors. Patients without thrombocytopenia had elevated GGTP and ALKP and lower bilirubin levels, regardless of tumor size, but they also had larger tumors within the large tumor tercile. PMID- 23988858 TI - Using dual-polarization interferometry to study surface-initiated DNA hybridization chain reactions in real time. AB - In this study we used dual-polarization interferometry to investigate DNA hybridization chain reactions (HCRs) at solid-liquid interfaces. We monitored the effects of variations in mass, thickness, and density of the immobilized initiator on the subsequent HCRs at various salt concentrations. At low salt concentrations, the single-stranded DNA (ssDNA) initiator was attached uniformly to the chip surface. At high salt concentrations, it lay on the surface at the onset of the immobilization process, but the approaching ssDNA forced the pre immobilized ssDNA strands to extend into solution as a result of increased electrostatic repulsion between the pre-adsorbed and approaching ssDNA chains. Injection of a mixture of H1 and H2 increased the mass and thickness of the films initially, but thereafter the thickness decreased. These changes indicate that the long double-stranded DNA that formed lay on the surface, rather than extended into the solution, thereby suppressing the subsequent initiation activity of the released single-strand parts of H1 and H2. Increasing the salt concentration increased the HCR efficiency and reaction rate. The HCR efficiency of the initiator ssDNA immobilized on its 5' end was higher than that immobilized on its 3' end, suggesting that the released single-strand parts of H1 and H2 close to the chip surface decreased the initiation activity relative to those of the ones extending into solution. PMID- 23988859 TI - Cigarette brand variant portfolio strategy and the use of colour in a darkening market. AB - OBJECTIVES: To evaluate cigarette branding strategies used to segment a market with some of the toughest tobacco controls. To document brand variant and packaging portfolios and assess the role played by colour before plain packaging, as well as consider the threat that recently implemented legislation poses for tobacco manufacturers. DATA SOURCES: Brand variant and packaging details were extracted from manufacturer ingredient reports, as well as a retail audit of Australian supermarkets. Details were also collected for other product categories to provide perspective on cigarette portfolios. METHODS: Secondary and primary data sources were analysed to evaluate variant and packaging portfolio strategy. RESULTS: In Australia, 12 leading cigarette brands supported 120 brand variants. Of these 61 had names with a specific colour and a further 26 had names with colour connotation. There were 338 corresponding packaging configurations, with most variants available in the primary cigarette distribution channel in four pack size options. CONCLUSIONS: Tobacco companies microsegment Australian consumers with highly differentiated product offerings and a family branding strategy that helps ameliorate the effects of marketing restrictions. To date, tobacco controls have had little negative impact upon variant and packaging portfolios, which have continued to expand. Colour has become a key visual signifier differentiating one variant from the next, and colour names are used to extend brand lines. However, the role of colour, as a heuristic to simplify consumer decision-making processes, becomes largely redundant with plain packaging. Plain packaging's impact upon manufacturers' branding strategies is therefore likely to be significant. PMID- 23988860 TI - What is the role of tobacco control advertising intensity and duration in reducing adolescent smoking prevalence? Findings from 16 years of tobacco control mass media advertising in Australia. AB - OBJECTIVE: To examine how the intensity and duration of tobacco control advertising relate to adolescent smoking prevalence. METHODS: Australian students (aged 12-17 years) participating in a national survey conducted triennially between 1993 and 2008 (sample size range 12 314-16 611). The outcome measure was students' smoking in the previous 4 weeks collected through anonymous, self completed surveys. For each student, monthly targeted rating points (TRPs, a measure of television advertising exposure) for tobacco control advertising was calculated for the 3 and 12 months prior to surveying. For each time period, cumulative TRPs exposure and exposure to three intensity levels (>=100 TRPs/month; >=400 TRPs/month; >=800 TRPs/month) over increasing durations (eg, 1 month, 2 months, etc) were calculated. Logistic regression examined associations between TRPs and adolescent smoking after controlling for demographic and policy variables. RESULTS: Past 3-month cumulative TRPs were found to have an inverse relationship with smoking prevalence. Low TRPs exposure in the past 12 months was positively associated with adolescent smoking prevalence. However, smoking prevalence reduced with cumulative exposure levels above 5800 cumulative TRPs. Additionally, exposure to >=400 TRPs/month and >=800 TRPs/month were associated with reduced likelihood of smoking, although the duration needed for this effect differed for the two intensity levels. When intensity was >=400 TRPs/month, the odds of smoking only reduced with continuous exposure. When intensity was >=800 TRPs/month, exposure at levels less than monthly was associated with reductions in smoking prevalence. CONCLUSIONS: Both antismoking advertising intensity and duration are important for ensuring reductions in adolescent smoking prevalence. PMID- 23988861 TI - Relationship between knowledge about the harms of smoking and smoking status in the 2010 Global Adult Tobacco China Survey. AB - BACKGROUND: This analysis estimates the association between smoking-related knowledge and smoking behaviour in a Chinese context. To identify the specific knowledge most directly related to smoking status, we used a novel latent variable analysis approach to adjust for the high correlations between different measures of knowledge about tobacco smoking. METHOD: Data are from the Global Adult Tobacco China Survey, a nationally representative sample of 13 354 household-dwelling individuals 15 years of age or older. Multinomial logistic regressions estimated the association between smoking status (ie, never smoked, current smoker or past smoker) and four smoking-related beliefs: whether or not smoking causes lung cancer, heart attack and stroke, and whether or not low-tar cigarettes are less harmful. A latent variable approach reassessed these associations while taking into account the general level of knowledge about smoking. RESULTS: After demographic variables and general knowledge about smoking had been controlled for, the belief that low-tar cigarettes are not less harmful was more prevalent in persons who had never smoked than in current smokers (OR=1.3 (95% CI 1.0 to 1.7) in men and OR=2.8 (95% CI 1.3 to 5.9) in women); this association was even stronger when past smokers and current smokers were compared (OR=2.1 (95% CI 1.5 to 3.0) in men and OR=5.0 (95% CI 1.3 to 20.1) in women). CONCLUSIONS: Compared with those who have never smoked and those who have ceased smoking, current smokers in China are more likely to believe that low-tar cigarettes are less harmful than regular cigarettes. PMID- 23988862 TI - A comparative study of systemic carcinogen exposure in waterpipe smokers, cigarette smokers and non-smokers. AB - BACKGROUND: In the past decade, waterpipe smoking-also known as hookah, shisha, narghileh-has increased among youth. The scarcity of rigorous studies linking waterpipe smoking to smoking-related diseases has hindered policy and regulatory efforts to confront the waterpipe epidemic. This study compares systemic carcinogen exposure between independent groups of exclusive waterpipe smokers, cigarette smokers and non-smokers. METHODS: This study was conducted at the Syrian Center for Tobacco Studies (SCTS) in Aleppo, Syria, between 2010 and 2011. First morning urinary samples were collected from three groups of subjects; exclusive daily waterpipe smokers (n=24), exclusive daily cigarette smokers (n=23), and non-smokers (n=28). These samples were analysed for carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanol (NNAL) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Our results show that waterpipe smokers are exposed to about 5-10 times greater NNAL than non-smokers. Mean (95% CI) free and total NNAL was 0.7 (0.3 to 1. 4) and 3.9 (1.6 to 9.5) pg/mL urine for non-smokers, 8.4 (4.8 to 14.8) and 33.0 (21.6 to 50.6) pg/mL urine for waterpipe smokers, and 10.7 (5.0 to 22.6) and 46.8 (27.6 to 79.3) pg/mL urine for cigarette smokers (p<0.001 for all comparisons). Daily waterpipe smokers were less exposed to NNAL than daily cigarette smokers, although the difference did not reach statistical significance for all measurements. CONCLUSIONS: These results provide the clearest indication to date about systemic exposure to harmful carcinogens associated with long-term waterpipe smoking. Such evidence can support policy and regulatory efforts designed to confront the emerging global waterpipe epidemic, as well as drive interventions aimed at increasing the public awareness about the cancer risk associated with waterpipe smoking. PMID- 23988863 TI - Moyamoya syndrome as an unusual presenting manifestation of systemic lupus erythematosus in a young woman. AB - OBJECTIVE: To describe a rare case of moyamoya syndrome associated with systemic lupus erythematosus (SLE). PRESENTATION AND INTERVENTION: A 22-year-old woman presented with left-sided hemiparesis in addition to fever, fatigue and malar rash. Brain magnetic resonance imaging revealed acute infarction in the right middle cerebral artery territory. Cerebral angiography showed features of moyamoya syndrome. Brain biopsy showed evidence of vasculitis. She responded well to steroid therapy. CONCLUSION: This case represented a rare co-occurrence of SLE related vasculitis and moyamoya syndrome. Early vascular imaging is critical in patients with SLE and suspected ischemic stroke. PMID- 23988864 TI - Multifunctional PLGA particles containing poly(l-glutamic acid)-capped silver nanoparticles and ascorbic acid with simultaneous antioxidative and prolonged antimicrobial activity. AB - A water-soluble antioxidant (ascorbic acid, vitamin C) was encapsulated together with poly(l-glutamic acid)-capped silver nanoparticles (AgNpPGA) within a poly(lactide-co-glycolide) (PLGA) polymeric matrix and their synergistic effects were studied. The PLGA/AgNpPGA/ascorbic acid particles synthesized by a physicochemical method with solvent/non-solvent systems are spherical, have a mean diameter of 775 nm and a narrow size distribution with a polydispersity index of 0.158. The encapsulation efficiency of AgNpPGA/ascorbic acid within PLGA was determined to be >90%. The entire amount of encapsulated ascorbic acid was released in 68 days, and the entire amount of AgNpPGAs was released in 87 days of degradation. The influence of PLGA/AgNpPGA/ascorbic acid on cell viability, generation of reactive oxygen species (ROS) in HepG2 cells, as well as antimicrobial activity against seven different pathogens was investigated. The 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated good biocompatibility of these PLGA/AgNpPGA/ascorbic acid particles. We measured the kinetics of ROS formation in HepG2 cells by a DCFH-DA assay, and found that PLGA/AgNpPGA/ascorbic acid caused a significant decrease in DCF fluorescence intensity, which was 2-fold lower than that in control cells after a 5h exposure. This indicates that the PLGA/AgNpPGA/ascorbic acid microspheres either act as scavengers of intracellular ROS and/or reduce their formation. Also, the results of antimicrobial activity of PLGA/AgNpPGA/ascorbic acid obtained by the broth microdilution method showed superior and extended activity of these particles. The samples were characterized using Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, transmission electron microscopy, zeta potential and particle size analysis. This paper presents a new approach to the treatment of infection that at the same time offers a very pronounced antioxidant effect. PMID- 23988865 TI - Nutrient intake in infancy and body mass index at six years in two population based cohorts recruited before and after revision of infant dietary recommendations. AB - BACKGROUND/AIMS: The dietary intake in infancy can affect growth and the risk of childhood overweight. The aim of this study was to compare the nutrient intake in infancy and the body mass index (BMI) at age 6 years in two population-based cohorts recruited before and after the revision of infant dietary recommendations. METHODS: Two randomly selected population-based cohorts were recruited at birth and studied until 12 months of age and again at 6 years of age. Subjects were 90 and 170 children born in 1995-1996 and 2005, respectively. The dietary intake at 9 and 12 months was assessed via weighed food records. The height and weight from birth to age 12 months and at age 6 years were measured. RESULTS: The contribution of protein to the total energy intake (E%) was significantly lower in the 2005 cohort than in the 1995-1996 cohort [11.9 vs. 14.4 E% (p < 0.001) at 9 months and 14.6 vs. 15.6 E% (p = 0.016) at 12 months]. Relatively fewer children were classified as being overweight (including obese) in the 2005 cohort, i.e. 12 versus 21% (p = 0.045). CONCLUSION: The emphasis placed on the revised infant dietary recommendations resulted in a lower protein intake in the latter half of the first year. Changes in the infants' diets on the population level might have contributed to the lower overweight prevalence seen in the 2005 cohort. PMID- 23988866 TI - Maternal depression and infant development: theory and current evidence. AB - Maternal depression (MD) is a condition that has wide-ranging effects on the woman, her family, and the broader global society. It is generally agreed that MD is associated with untoward effects on the developmental trajectory of offspring. The aim of this article is to review the historical and theoretical underpinnings informing current thought linking MD with infant development, and to highlight some of the neuroendocrine and epigenetic processes related to MD and its sequelae. A broad understanding of the association between MD and infant developmental outcomes can inform nursing care of the childbearing family. PMID- 23988867 TI - Defects in 6 MeV H+ irradiated hydrothermal ZnO single crystal. AB - The effect of 6 MeV H(+) irradiation on hydrothermally grown ZnO single crystal has been investigated using high resolution x-ray diffraction (HRXRD) and optical absorption (ultraviolet-visible) spectroscopy. The increase of the diffuse scattering in the reciprocal space maps measured using HRXRD indicates an increase of the point defect density upon irradiation. Within the penetration depth of x-rays of several micrometres, the defect density increased with increasing distance from the sample surface. On the other hand, the near band gap optical absorption became sharper for the irradiated crystal. This reflects enhanced band to band absorption and reduced sub-band gap absorption due to defects. Temperature dependent photoluminescence spectra of the pristine sample show negative thermal quenching (NTQ) of the luminescence which is due to the presence of two or more donor related defects. Upon irradiation, a single dominant donor bound transition can be found without any temperature induced NTQ. Enhancement of the band edge luminescence and reduction of the defect related luminescence is observed at 10 K. Such changes have been discussed in the light of the hydrogen present in the as-grown state of hydrothermal ZnO. PMID- 23988868 TI - Feature-specific attention allocation modulates the generalization of recently acquired likes and dislikes. AB - We examined whether the generalization of recently acquired likes and dislikes depends on feature-specific attention allocation. Likes and dislikes were established by means of an evaluative-conditioning procedure in which participants were presented with several exemplars of two subordinate categories (e.g., young men vs. old women). Whereas exemplars of one category were consistently paired with negative stimuli, exemplars of the second category were consistently paired with positive stimuli. In addition, we manipulated feature specific attention allocation for specific stimulus dimensions (e.g., gender vs. age), either during (Experiments 1 and 2) or before the acquisition phase of the experiment (Experiment 3). Both direct and indirect attitude measures revealed a clear impact of this manipulation on attitude generalization. More specifically, only generalization stimuli that were similar to the CSs in terms of the stimulus dimension that was selectively attended to were evaluated in a manner that was congruent with the acquired liking of those CSs. PMID- 23988869 TI - Inhibition of return, but not facilitation, disappears under vigilance decrease due to sleep deprivation. AB - In this study, we assessed whether unspecific attention processes signaled by general reaction times (RTs), as well as specific facilitatory (validity or facilitation effect) and inhibitory (inhibition of return, IOR) effects involved in the attentional orienting network, are affected by low vigilance due to both circadian factors and sleep deprivation (SD). Eighteen male participants performed a cuing task in which peripheral cues were nonpredictive about the target location and the cue-target interval varied at three levels: 200 ms, 800 ms, and 1,100 ms. Facilitation with the shortest and IOR with the longest cue target intervals were observed in the baseline session, thus replicating previous related studies. Under SD condition, RTs were generally slower, indicating a reduction in the participants' arousal level. The inclusion of a phasic alerting tone in several trials partially compensated for the reduction in tonic alertness, but not with the longest cue-target interval. With regard to orienting, whereas the facilitation effect due to reflexive shifts of attention was preserved with sleep loss, the IOR was not observed. These results suggest that the decrease of vigilance produced by SD affects both the compensatory effects of phasic alerting and the endogenous component involved in disengaging attention from the cued location, a requisite for the IOR effect being observed. PMID- 23988870 TI - A bilateral advantage in controlling access to visual short-term memory. AB - Recent research on visual short-term memory (VSTM) has revealed the existence of a bilateral field advantage (BFA--i.e., better memory when the items are distributed in the two visual fields than if they are presented in the same hemifield) for spatial location and bar orientation, but not for color (Delvenne, 2005; Umemoto, Drew, Ester, & Awh, 2010). Here, we investigated whether a BFA in VSTM is constrained by attentional selective processes. It has indeed been previously suggested that the BFA may be a general feature of selective attention (Alvarez & Cavanagh, 2005; Delvenne, 2005). Therefore, the present study examined whether VSTM for color benefits from bilateral presentation if attentional selective processes are particularly engaged. Participants completed a color change detection task whereby target stimuli were presented either across both hemifields or within one single hemifield. In order to engage attentional selective processes, some trials contained irrelevant stimuli that needed to be ignored. Targets were selected based on spatial locations (Experiment 1) or on a salient feature (Experiment 2). In both cases, the results revealed a BFA only when irrelevant stimuli were presented among the targets. Overall, the findings strongly suggest that attentional selective processes at encoding can constrain whether a BFA is observed in VSTM. PMID- 23988871 TI - Past and future implications of near-misses and their emotional consequences. AB - The Reflection and Evaluation Model (REM) of comparative thinking predicts that temporal perspective could moderate people's emotional reactions to close counterfactuals following near-misses (Markman & McMullen, 2003). The experiments reported in this paper tested predictions derived from this theory by examining how people's emotional reactions to a near-miss at goal during a football match (Experiment 1) or a close score in a TV game show (Experiment 2) depended on the level of perceived future possibility. In support of the theory it was found that the presence of future possibility enhanced affective assimilation (e.g., if the near-miss occurred at the beginning of the game the players who had nearly scored were hopeful of future success) whereas the absence of future possibility enhanced affective contrast (e.g., if the near-miss occurred at the end of the game the players who had nearly scored were disappointed about missing an opportunity). Furthermore the experiments built upon our theoretical understanding by exploring the mechanisms which produce assimilation and contrast effects. In Experiment 1 we examined the incidence of present-oriented or future oriented thinking, and in Experiment 2 we examined the mediating role of counterfactual thinking in the observed effect of proximity on emotions by testing whether stronger counterfactuals (measured using counterfactual probability estimates) produce bigger contrast and assimilation effects. While the results of these investigations generally support the REM, they also highlight the necessity to consider other psychological mechanisms (e.g., social comparison), in addition to counterfactual thinking, that might contribute to the emotional consequences of near-miss outcomes. PMID- 23988872 TI - Contribution of degraded perception and insufficient encoding to decisions to mass or space study. AB - How do learners decide whether to mass or space an item during study? Results from Son (2004) indicate that these decisions are influenced by the degree to which an item is judged to be encoded sufficiently during an initial study episode, whereas others (Toppino, Cohen, Davis, & Moors, 2009) have proposed that degraded perceptual processing contributed to participants' decisions to mass or space study. To reconcile these conflicting conclusions, the current experiments used eye tracking technology to evaluate the contribution of degraded perception and insufficient encoding on learners' study decisions. Participants studied synonym pairs from the graduate record exam (GRE) that varied in item difficulty for 1 s (Experiment 1) or 5 s (Experiment 2) each while their eye movements were recorded. Participants then decided whether to mass, space, or drop each pair in future study. For pairs that were never fixated, and hence not perceived, participants overwhelmingly chose to mass their study, presumably so that they could read the target. For pairs that were processed sufficiently to be perceived, preference for massing and spacing pairs increased with item difficulty (i.e., both increased as pairs became less likely to be fully encoded). Taken together, these data demonstrate a contribution of degraded perception and insufficient encoding for learners' decisions to mass (or space) their study. PMID- 23988874 TI - GM crop co-existence: a question of choice, not prejudice. AB - The rapid uptake of biotech crops around the world demonstrates not only strong producer and consumer demand for the technology and its products, but also that where regulatory regimes function effectively and markets are allowed to operate as normal, co-existence between genetically modified (GM) and non-GM supply chains is readily achievable. However, the polarized debate over GMOs within the European Union over the past 15 years has resulted in a highly politicized and progressively impractical approach to the issue of GM crop co-existence, which in itself has become a further barrier to the technology's development. This article argues that co-existence should not be treated as a pro- or anti-GM issue, and that the aim of co-existence measures should be to permit consumer choice and freedom to operate whatever the production method involved. It suggests that supply chain-based solutions to co-existence, rather than Government prescription, offer the most pragmatic and flexible response to the commercial realities of servicing differentiated market demands. PMID- 23988873 TI - Clinical Pharmacogenetics Implementation Consortium guidelines for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. AB - The fluoropyrimidines are the mainstay chemotherapeutic agents for the treatment of many types of cancers. Detoxifying metabolism of fluoropyrimidines requires dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene), and reduced or absent activity of this enzyme can result in severe, and sometimes fatal, toxicity. We summarize evidence from the published literature supporting this association and provide dosing recommendations for fluoropyrimidines based on DPYD genotype (updates at http://www.pharmgkb.org). PMID- 23988875 TI - Recent advances on natriuretic peptide system: new promising therapeutic targets for the treatment of heart failure. AB - Since the discovery of the influence of the endocrine system on cardiac endocrine function 30 years ago, an increasing number of experimental and clinical studies have consolidated endocrine function of human heart as being a relevant component of a complex network including endocrine, nervous and immune systems. Many aspects, however, still remain unclear as to the production, secretion and peripheral degradation pathways of B- and C-type natriuretic peptides. In particular, the hypothesis that the circulating plasma pool of the pro-hormone can function as precursor of the active peptide hormone is yet to be fully demonstrated. According to recent studies, peripheral processing of circulating pro-hormone likely undergoes regulation pathways which seem to be impaired in patients with heart failure. This would open new perspectives also in the treatment of heart failure, and identify novel pharmacological targets for drugs inducing and/or modulating the maturation of the pro-hormone into active hormone. PMID- 23988876 TI - Alteration of the sublingual microvascular glycocalyx in critically ill patients. AB - Glycocalyx degradation may contribute to microvascular dysfunction and tissue hypoperfusion during systemic inflammation and sepsis. In this observational study we evaluated the alteration of the sublingual microvascular glycocalyx in 16 healthy volunteers and 50 critically ill patients. Sidestream Dark Field images of the sublingual microcirculation were automatically analyzed by dedicated software. The Perfused Boundary Region (PBR) was calculated as the dimensions of the permeable part of the glycocalyx allowing the penetration of circulating red blood cells, providing an index of glycocalyx damage. The PBR was increased in ICU patients compared to healthy controls (2.7 [2.59-2.88] vs. 2.46 [2.37-2.59]MUm, p<0.0001) and tended to be higher in the 32 septic patients compared to non-septics (2.77 [2.62-2.93] vs. 2.67 [2.55-2.75]MUm, p=0.05), suggesting more severe glycocalyx alterations. A PBR of 2.76 showed the best discriminative ability towards the presence of sepsis (sensitivity: 50%, specificity: 83%; area under the receiver operating characteristic curve: 0.67, 95% CI 0.52-0.82, p=0.05). A weak positive correlation was found between PBR and heart rate (r=0.3, p=0.03). In 17 septic patients, a correlation was found between PBR and number of rolling leukocytes in post-capillary venules (RL/venule) (r=0.55, p=0.02), confirming that glycocalyx shedding enhances leukocyte-endothelium interaction. PMID- 23988877 TI - Semi-automatic assessment of skin capillary density: proof of principle and validation. AB - BACKGROUND: Skin capillary density and recruitment have been proven to be relevant measures of microvascular function. Unfortunately, the assessment of skin capillary density from movie files is very time-consuming, since this is done manually. This impedes the use of this technique in large-scale studies. We aimed to develop a (semi-) automated assessment of skin capillary density. METHODS: CapiAna (Capillary Analysis) is a newly developed semi-automatic image analysis application. The technique involves four steps: 1) movement correction, 2) selection of the frame range and positioning of the region of interest (ROI), 3) automatic detection of capillaries, and 4) manual correction of detected capillaries. To gain insight into the performance of the technique, skin capillary density was measured in twenty participants (ten women; mean age 56.2 [42-72] years). To investigate the agreement between CapiAna and the classic manual counting procedure, we used weighted Deming regression and Bland-Altman analyses. In addition, intra- and inter-observer coefficients of variation (CVs), and differences in analysis time were assessed. RESULTS: We found a good agreement between CapiAna and the classic manual method, with a Pearson's correlation coefficient (r) of 0.95 (P<0.001) and a Deming regression coefficient of 1.01 (95%CI: 0.91; 1.10). In addition, we found no significant differences between the two methods, with an intercept of the Deming regression of 1.75 ( 6.04; 9.54), while the Bland-Altman analysis showed a mean difference (bias) of 2.0 (-13.5; 18.4) capillaries/mm(2). The intra- and inter-observer CVs of CapiAna were 2.5% and 5.6% respectively, while for the classic manual counting procedure these were 3.2% and 7.2%, respectively. Finally, the analysis time for CapiAna ranged between 25 and 35min versus 80 and 95min for the manual counting procedure. CONCLUSION: We have developed a semi-automatic image analysis application (CapiAna) for the assessment of skin capillary density, which agrees well with the classic manual counting procedure, is time-saving, and has a better reproducibility as compared to the classic manual counting procedure. As a result, the use of skin capillaroscopy is feasible in large-scale studies, which importantly extends the possibilities to perform microcirculation research in humans. PMID- 23988878 TI - Effect and mechanism of propofol on myocardial ischemia reperfusion injury in type 2 diabetic rats. AB - BACKGROUND: Propofol has been reported to have an inhibitory effect on ischemia/reperfusion (I/R) injury in various experimental models by reducing oxidative stress, protecting mitochondrial function and suppressing apoptosis. The aim of this study was to investigate the effect and mechanism of propofol on myocardial I/R injury in type 2 diabetic rats. METHODS: A total of 24 streptozotocin (STZ)-induced diabetic rats were randomly divided into three equal groups as follows: the DI group with myocardial I/R, which was induced by occluding the left anterior descending coronary artery for 30min, followed by 2h of reperfusion; the DP group, which underwent I/R and propofol infusion at 6mg.kg(-1).h(-1); and the DC group, which underwent sham operations without tightening of the coronary sutures. As a control, 24 healthy, age-matched, male Wistar rats were randomly divided into three equal groups: the CI, CP and CC groups. The injured cardiac tissues were removed for microscopic examination after reperfusion. The serum concentrations of nitric oxide (NO) and endothelin (ET-1); the expression of Bax, Bcl-2 and Caspase-3 within the cardiac structures; and the number of apoptotic myocardial cells were measured. RESULTS: Compared with the baseline levels before ischemia, the serum concentration of ET-1 after 2h of reperfusion was increased in the CI and DI groups, while the concentration of NO in these groups decreased after reperfusion. Compared with the I/R groups, propofol increased the content of NO and decreased the content of ET-1. Compared with the sham operation groups, I/R decreased the ratio of the anti-apoptotic protein Bcl-2 to the pro-apoptotic protein Bax, which resulted in an elevation of the index of apoptosis (AI). In contrast, compared with the I/R group, propofol increased the Bcl-2-to-Bax ratio and decreased the AI. I/R increased the expression of caspase-3 compared with the sham treatment groups, while treatment with propofol reduced caspase-3 expression relative to the I/R groups. CONCLUSIONS: These data suggest that propofol can protect against myocardial ischemia-reperfusion injury in both normal and type 2 diabetic rats, possibly by attenuating endothelial cell injury and inhibiting the apoptosis of cardiomyocytes. PMID- 23988879 TI - Implications of the Read-Write Genome view. PMID- 23988880 TI - Mechanisms of abiotic horizontal gene transfer: comment on "Lightning-triggered electroporation and electrofusion as possible contributors to natural horizontal gene transfer" by Tadej Kotnik. PMID- 23988881 TI - The value of a uniquely psychological approach to musical aesthetics: reply to the commentaries on 'A unified theory of musical emotions'. PMID- 23988885 TI - Application of a drug-interaction detection method to the Korean National Health Insurance claims database. AB - Drug interactions (DIs) constitute a serious problem and are considered to contribute to 6-30% of all adverse events (AEs). The use of existing data, including claims data, is expected to be helpful in detecting unknown DIs by complementing conventional spontaneous reporting systems. In the present study, an 'Omega shrinkage measure' was applied to the Korean National Health claims database to test the potential of the claims database as a DI surveillance resource. A well-known DI between non-steroidal anti-inflammatory drugs (NSAIDs) and diuretics was analyzed using the model. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) codes related to DIs were assigned to the AEs of the DIs: I50, I50.0, I50.1, I50.9, R60, R60.1, R60.9, and J81. An elevated occurrence of AEs versus the expected level was observed using a two-sided 95% lower credibility interval limit above zero, Omega025=0.245, which was the screening limit. The result was consistent with the actual DI between the two drugs. The finding indicates that the claims data have the potential to be used as a DI surveillance resource and that the Omega shrinkage measure may be a promising tool for detecting DIs in claims data. PMID- 23988886 TI - Mutagenic impurities in pharmaceuticals: a critique of the derivation of the cancer TTC (Threshold of Toxicological Concern) and recommendations for structural-class-based limits. AB - The cancer TTC (Threshold of Toxicological Concern) concept is currently employed as an aid to risk assessment of potentially mutagenic impurities (PMIs) in food, cosmetics and other sectors. Within the pharmaceutical industry the use of one default cancer TTC limit of 1.5 MUg/day for PMIs is being increasingly questioned. Its derivation, originally in the context of foodstuffs, can be broken down into five key elements: dataset composition; determination of carcinogenicity/mutagenicity status and carcinogenic potency (based on TD50s) of compounds in the dataset; linear extrapolation of carcinogenic potencies; evaluation of the more potent compounds in each structural category, and presence of representative structural alerts amongst the more potent compounds. A detailed evaluation reveals that the derivation process is distorted by the use of the lowest statistically significant TD50s (which can produce a false-carcinogen phenomenon) and by employing linear extrapolation for non-mutagenic carcinogens. By correcting for these two factors, it is concluded that only around 50% of conventional structural-alert categories were adequately addressed and that limits higher than the default value appear to be justified in many cases. Using similar criteria for PMIs in pharmaceuticals, four distinct potency categories of conventional structural alerts can be distinguished, ranging from alerts with questionable validity to those with high potency, which are considered to provide a range of flexible and pragmatic limits for such impurities. PMID- 23988887 TI - Tenc1-deficient mice develop glomerular disease in a strain-specific manner. AB - BACKGROUND/AIMS: Tenc1 (also known as tensin2) is an integrin-associated focal adhesion molecule that is broadly expressed in mouse tissues including the liver, muscle, heart and kidney. A mouse strain carrying mutated Tenc1, the ICR-derived glomerulonephritis (ICGN) strain, develops severe nephrotic syndrome. METHODS: To elucidate the function of Tenc1 in the kidney, Tenc1(ICGN) was introduced into 2 genetic backgrounds, i.e. DBA/2J (D2) and C57BL/6J (B6), strains that are respectively susceptible and resistant to chronic kidney disease. RESULTS: Biochemical and histological analysis revealed that homozygous Tenc1(ICGN) mice develop nephrotic syndrome on the D2 background (D2GN) but not on the B6 background (B6GN). Initially, abnormal assembly and maturation of glomerular basement membrane (GBM) were observed, and subsequently effacement of podocyte foot processes was noted in the kidneys of D2GN but not B6GN mice. These defects are likely to be involved in the integrin signaling pathway. CONCLUSION: This study suggests that Tenc1 contributes to the maintenance of GBM structures and that the genetic background influences the severity of nephrotic syndrome. PMID- 23988888 TI - The localized inflammatory response to bronchoscopic thermal vapor ablation. AB - BACKGROUND: Bronchoscopic thermal vapor ablation (BTVA) reduces lung volumes in emphysema patients by inducing a localized inflammatory response (LIR) leading to a healing process of fibrosis, but may also increase symptoms. OBJECTIVES: We sought to evaluate whether the clinical manifestation of LIR correlated with patient outcome. METHODS: Respiratory adverse events and inflammatory markers were analyzed from a multicenter trial of BTVA in patients with upper-lobe predominant emphysema. End points including changes in forced expiratory flow (FEV1), lobar volume, St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) and 6-minute-walk distance (6-MWD) were analyzed according to the presence or absence of a respiratory adverse event requiring treatment with an antibiotic or steroid. RESULTS: Forty-four patients received BTVA. Increases of inflammatory markers were observed with a peak between the second and fourth week. Eighteen respiratory adverse events occurred in 16 patients within 30 days of BTVA, requiring antibiotics and/or steroids. These patients had significantly greater lobar volume reduction (65.3 vs. 33.4%, p = 0.007) and a change in residual volume at 12 months (-933 vs. 13 ml, p < 0.001) associated with a greater improvement of exercise capacity and health-related quality of life than patients without respiratory adverse events. CONCLUSION: Patients with more prominent respiratory symptoms in the first 30 days following BTVA experience greater efficacy. The clinical manifestations of the LIR are predictive of long-term clinical benefits. PMID- 23988889 TI - Vitamin C: electron emission, free radicals and biological versatility. AB - The many-sided biological role of vitamin C (ascorbate) is briefly illustrated by specific examples. It is demonstrated that in aqueous solutions, vitamin C emits solvated electrons (e(aq)(-)), when excited in single state. Vitamin C can also react with e(aq)(-) as well as transfer them to other biological systems and thereby acts as efficient electron mediator. Based on its chemical and biological properties, it is clear that vitamin C plays a very important role in various functions in the organism alongside biochemical processes. PMID- 23988890 TI - Radioresistance of bone marrow stromal and hematopoietic progenitor cell lines derived from Nrf2-/- homozygous deletion recombinant-negative mice. AB - AIM: We determined whether bone marrow from Nrf2(-/-) compared with Nrf2(+/+) mice differed in response to the oxidative stress of continuous marrow culture, and in radiosensitivity of derived stromal and interleukin-3 (IL-3)-dependent hematopoietic progenitor cells. MATERIALS AND METHODS: Hematopoiesis longevity in Nrf2(-/-) was compared with Nrf2(+/+) mice in long-term bone marrow cultures. Clonogenic irradiation survival curves were performed on derived cell lines. Total antioxidant capacity at baseline in nonirradiated cells and at 24 hours after 5 Gy and 10 Gy irradiation was quantitated using an antioxidant reductive capacity assay. RESULTS: Long-term cultures of bone marrow from Nrf2(-/-) compared to Nrf2(+/+) mice demonstrated equivalent longevity of production of total cells and hematopoietic progenitor cells forming multi-lineage hematopoietic colonies over 26 weeks in culture. Both bone marrow stromal cell lines and Il-3-dependent hematopoietic progenitor cell lines derived from Nrf2(-/ ) mouse marrow cultures were radioresistant compared to Nrf2(+/+)-derived cell lines. Both DNA repair assay and total antioxidant capacity assay showed no defect in Nrf2(-/-) compared to Nrf2(+/+) stromal cells and IL-3-dependent cells. CONCLUSION: The absence of a functional Nrf2 gene product does not alter cellular interactions in continuous marrow culture, nor response to dsDNA damage repair and antioxidant response. However, lack of the Nrf2 gene does confer radioresistance on marrow stromal and hematopoietic cells. PMID- 23988891 TI - Curcumin suppresses N-methyl-N-nitrosourea-induced photoreceptor apoptosis in Sprague-Dawley rats. AB - AIM: Retinitis pigmentosa is a group of inherited neurodegenerative human diseases characterized by the loss of photoreceptor cells by apoptosis and lead to eventual blindness. A single intraperitoneal (i.p.) injection of N-methyl-N nitrosourea (MNU), an alkylating agent, causes photoreceptor cell apoptosis within seven days in rats. Curcumin is a polyphenolic natural product with pluripotent properties including antioxidant activity. The purpose of the present study was to evaluate the efficacy of curcumin against photoreceptor apoptosis in a MNU-induced retinal degeneration rat model. MATERIALS AND METHODS: Seven-week old female Sprague-Dawley rats received a single i.p. injection of 40 mg/kg MNU. Three days prior to MNU injection, daily i.p. injections of 100 or 200 mg/kg curcumin were started, and the injections were continued once daily until sacrifice. Rats were sacrificed at 6, 12, 24 and 72 h, and 7 days after MNU, and their eyes were examined morphologically and morphometrically to evaluate the photoreceptor cell ratio and retinal damage ratio in hematoxylin and eosin stained sections. Retinal 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were quantified by enzyme-linked immunosorbent assay (ELISA), and the apoptotic cell ratio in photoreceptor cells was determined in situ by TdT-mediated dUTP digoxigenin nick-end labeling (TUNEL). RESULTS: Curcumin (200 mg/kg) significantly (p<0.01) suppressed the loss of photoreceptor cells, as determined by the photoreceptor cell ratio at the central retina seven days after MNU, and this effect was dose-dependent. At 12 h after MNU injection, when the oxidative DNA damage caused by MNU peaked, curcumin significantly reduced the level of 8 OHdG (0.78 vs. 0.50 ng/ml) (p<0.05) and the percentage of TUNEL-positive photoreceptor cells (17.5% vs. 10.8%) (p<0.05) as compared with MNU-exposed, curcumin-untreated retina, respectively. CONCLUSION: Curcumin inhibited MNU induced photoreceptor cell apoptosis by suppressing DNA oxidative stress. These findings indicate that curcumin may help to suppress the onset and progression of human retinitis pigmentosa. PMID- 23988892 TI - Embolic encephalitis in a porcine model of endocarditis. AB - BACKGROUND: Endocarditis is a severe disease in which neurological complications are frequent and associated with increased mortality and complex disease management. In the present study, the pig was evaluated as a model of embolic encephalitis as a complication of experimental infective endocarditis. MATERIALS AND METHODS: Brains from pigs with experimental Staphylococcus aureus-associated infective endocarditis (IE; n=2), experimental non-bacterial thrombotic endocarditis (NBTE; n=5), experimental S. aureus sepsis without endocarditis (SNE; n=3) and saline controls (n=3), were used. The brains were examined for lesions macroscopically, histologically and immunohistochemically. RESULTS: Lesions of focal encephalitis were found in the IE and SNE pigs, at considerably higher numbers in the IE pigs. Furthermore, microabscesses were common in the IE pigs, which fits the association between brain abscesses and S. aureus-associated endocarditis in humans. CONCLUSION: Experimental porcine S. aureus-associated endocarditis is advantageous for studying neurological complications, such as brain abscess formation, as a result of endocardial bacterial seeding. PMID- 23988893 TI - A clinically relevant mouse model of canine osteosarcoma with spontaneous metastasis. AB - BACKGROUND/AIM: Many patients with osteosarcoma (OS) will succumb to distant metastasis, often involving the lungs. Effective therapies for treating lung metastases depend on the availability of a clinically relevant pre-clinical model. MATERIALS AND METHODS: Mice were surgically implanted with OS tumor fragments. The time course of primary tumor growth and subsequent spread to the lung were determined. RESULTS: Following development of a lytic and proliferative primary bone lesion, tumor metastasized to the lung in the majority of mice. There was no evidence of tumor at three weeks, but 10 out of 11 mice ultimately developed secondary OS in the lung within 12 weeks. CONCLUSION: Implantation of OS tumor fragments leads to the development of primary bone tumors and secondary lung metastases, recapitulating the clinical behavior of OS. This model offers an advantage over cell suspension injection models by precluding initial seeding of the lung with tumor cells. PMID- 23988894 TI - The in vitro activity of products formed from exposure of chlorpromazine to a 266 nm laser beam against species of mycobacteria of human interest. AB - Chlorpromazine (CPZ) was exposed to a 266 nm laser beam for different periods of time ranging from minutes to 24 h. At intervals, the products from irradiation were evaluated by thin-layer chromatography (TLC) and evaluated for their activity against mycobacteria of human interest (Mycobacterium tuberculosis, M. avium, M. intracellulare and their corresponding reference strains or clinical isolates). With the exception of the M. avium 47/07 clinical strain, the products produced from the irradiation of CPZ for 4 h had greater activity against M. intracellulare ATCC, M. avium ATCC, H37Rv and the Multidrug-resistant tuberculosis (MDR-TB) strains as opposed to that produced by the unirradiated control. The level of products from the 4-h exposure of CPZ remained the same throughout the next 20 h of irradiation. Of significant note is that the irradiation products of CPZ had lower in vitro cytotoxicity against human cells, suggesting that this approach may be useful for the development of compounds more bioactive than the parental species. PMID- 23988895 TI - Alteration of masticatory function by diet change induces stress responses in Wistar rats. AB - The occlusion-mastication system has extradigestive functions; however, whether liquid feeding evokes stress responses remains unclear. In this study, reactions to low masticatory performance were analyzed using a diet-alteration model in Wistar rats. Seven days after the diet of the rats was changed from solid to liquid, serum epinephrine and norepinephrine concentrations were found to be elevated by 205% and 158% compared to baseline values, respectively. Superoxide production by peritoneal neutrophils was higher in rats fed with a liquid diet than in those fed with a solid diet. Serum superoxide dismutase activity (i.e. the potential to eradicate serum superoxide) was lower in rats fed with liquid than in those fed with a solid diet, indicating that the former experienced oxidative stress. Conversely, the oxidative stress was removed following reversion of the liquid diet to solid diet. These results suggest that liquid diet mastication can cause mental stress, including an oxidative stress response. PMID- 23988896 TI - Sex differences of serum lipid profile in novel microminipigs. AB - Swine have been used extensively in biomedical research, with a significant increase in recent decades. Minipigs are increasingly becoming an especially attractive animal model in life science research because of their physiological and anatomical similarities to humans. The Microminipig (MMPig) has emerged as a novel and small minipig for non-clinical pharmacological/toxicological use. The MMPig is docile, weighs less than 10 kg in early maturity, and has an easily manageable size. In this study, we report on sex and age patterns in serum biochemistry parameters, including lipid analysis items and lipid profiles in healthy MMPigs. In total, 58 males and 67 females aged 0-34 months underwent serum biochemistry parameter measurements. Most parameters showed no effect of age or sex (although some did). Lipid analyses showed that the serum levels of total cholesterol, but not those of triglycerides (TG), were consistently higher in females at 0-34 months of age. Lipid profiles in 5-month-old MMPigs were investigated in greater detail. Serum low-density lipoprotein-cholesterol (LDL-C) values were higher in females. The percentage of LDL-C against total cholesterol was also higher, although high-density lipoprotein-cholesterol was lower, in females. There were no sex differences in the TG fraction. Although the sex difference in the serum lipid profile remains unexplained, the reference values obtained in this study could help facilitate the use of MMPigs in life science research. PMID- 23988897 TI - Oral administration of benzyl-isothiocyanate inhibits in vivo growth of subcutaneous xenograft tumors of human malignant melanoma A375.S2 cells. AB - A number of experiments have demonstrated that benzyl-isothiocyanate (BITC) induces cytotoxic cell death through the induction of apoptosis in various human cancer cell lines. In the present study, we investigated the effects of BITC on the growth of A375.S2 cell xenograft tumors in nude BALB/c mice in vivo. The A375.S2 cancer cells were inoculated subcutaneously into the lower flanks of each nude mouse. After cancer cell inoculation, all animals were maintained in the animal room for seven days and all mice produced one palpable tumor. Animals were randomly divided into two groups, each mouse was individually given intraperitoneal injections of BITC (20 mg/kg) or not (control). Results from the in vivo experiments indicated that BITC did not significantly affect the body weight of nude BALB/c mice bearing xenograft A375.S2 cell tumors but did significantly decrease the tumor weight. PMID- 23988898 TI - Epigallocatechin gallate (EGCG), influences a murine WEHI-3 leukemia model in vivo through enhancing phagocytosis of macrophages and populations of T- and B cells. AB - Epigallocatechin gallate (EGCG) is the major polyphenol in green tea, and has been reported to have anticancer effects on many types of cancer cells. However, there is no report to show its effects on the immune response in a murine leukemia mouse model. Thus, in the present study, we investigated the effects of EGCG on the immune responses of murine WEHI-3 leukemia cells in vivo. WEHI-3 cells were intraperitoneally injected into normal BALB/c mice to establish leukemic BALB/c mice, which were then oral-treated with or without EGCG at 5, 20 and 40 mg/kg for two weeks. The results indicated that EGCG did not change the weight of the animals, nor the liver or spleen when compared to vehicle (olive oil) -treated groups. Furthermore, EGCG increased the percentage of cluster of differentiation 3 (CD3) (T-cell), cluster of differentiation 19 (CD19) (B-cell) and Macrophage-3 antigen (Mac-3) (macrophage) but reduced the percentage of CD11b (monocyte) cell surface markers in EGCG-treated groups as compared with the untreated leukemia group. EGCG promoted the phagocytosis of macrophages from 5 mg/kg treatment and promoted natural killer cell activity at 40 mg/kg, increased T-cell proliferation at 40 mg/kg but promoted B-cell proliferation at all three doses. Based on these observations, it appears that EGCG might exhibit an immune response in the murine WEHI-3 cell line-induced leukemia in vivo. PMID- 23988899 TI - Effects of nebivolol on liver fibrosis induced by bile duct ligation in Wistar rats. AB - AIM: To study the effect of nebivolol on liver fibrosis induced by common bile duct ligation (BDL) in rats. MATERIALS AND METHODS: After BDL, Wistar rats were divided into three groups (n=24): SO, sham-operated animals; BDL, BDL rats without treatment; BDL+N, BDL rats treated with nebivolol for five weeks. Alanine aminotransferase, aspartate aminotransferase, gamma glutamyltransferase, total bilirubin and albumin levels were assessed. Liver samples collected were stained with hematoxylin-eosin, Masson's trichrom and reticulin. RESULTS: Mortality reached 37.5% in the BDL group, whereas no deaths were observed in the SO and BDL+N groups. The BDL group showed hepatic damage as evidenced by elevation in serum biochemical parameters and fibrosis scores. These pathophysiological changes were attenuated in the BDL+N group. However, there was no significant difference between these two groups. CONCLUSION: Nebivolol improved the survival rate of animals with BDL, but was unable to significantly improve liver function or reduce liver fibrosis. PMID- 23988900 TI - Profile of endocrinological derangements affecting PSA values in patients with COPD. AB - BACKGROUND/AIM: Chronic obstractive pulmonary disease (COPD) in men has been associated with testosterone deficiency, known as the late-onset hypogonadism. Prostate cancer becomes more prevalent when testosterone values decline in males. We sought to determine endocrinological derangements that may affect PSA values in male patients with COPD. MATERIALS AND METHODS: A total of 69 male patients with COPD and 82 healthy volunteers were divided into subgroups according to: their age: (i) <=60 years and (ii) >60 years; or disease severity: (i) FEV1<50% and (ii) FEV1>=50% predicted. RESULTS: There was a significant reduction in total and free testosterone in patients with COPD. Patients with COPD aged >60 years had significantly lower free PSA compared to the control group. CONCLUSION: Alterations of the male hormonal status in COPD are related with older age (>60 years) and poorer lung function (FEV1<50% predicted). This may have implications for the use of the PSA-based screening tests in the elderly male population with COPD. PMID- 23988901 TI - Risperidone-induced acute eosinophilic pneumonia. AB - BACKGROUND: Acute eosinophilic pneumonia (AEP) is a severe syndrome which can be induced for many reasons, including drugs. AEP has rarely been associated with first-generation antipsychotics and never been reported after use of second generation antipsychotics, such as risperidone. CASE REPORT: We report a case of a 64-year-old man with a medical history of alchoholism and paranoid symptoms, treated with risperidone at low doses. Following risperidone medication, he presented with respiratory distress. Bronchoalveolar lavage (BAL) specimen was indicated of AEP. All evidence indicated risperidone as the most probable causal factor. The syndrome rapidly resolved after discontinuation of the drug. DISCUSSION: Pathophysiological mechanisms implicated in the development of AEP in our patient seem to be associated with eotaxin and serotonin eosinophilic specific chemoattracting action, through the serotoninergic action of risperidone. CONCLUSION: To our knowledge, this is the first case report of a clinical adverse reaction of AEP from an atypical antipsychotic agent (risperidone). PMID- 23988902 TI - Usefulness of endobronchial ultrasound (EBUS) in the diagnosis of peripheral pulmonary lesions in a general hospital. AB - AIM: To investigate the efficiency of guided bronchoscopy compared to blind techniques in the study of non-visible pulmonary lesions. MATERIALS AND METHODS: A one-year, retrospective, study was conducted comparing two populations: Biopsies were either performed conventionally (FB-B) with the help of static images and the second where biopsies were performed after guidance (FB-EBUS). A 20-MHz radial-type ultrasound probe was used to obtain images. Sampling techniques, like bronchial brushing and transbronchial biopsies, were conducted in both populations by two separate bronchoscopists. If diagnosis was not achieved a surgical biopsy or observation followed. RESULTS: Forty patients appeared with non-visible lesions and were included in this study. Twenty were examined with the use of FB-EBUS and in 20 cases FB-B was conducted. At the FB EBUS population a pathologic lesion was visualized in 16 cases (80%) and in 15 cases (75%) a diagnosis was achieved. All lesions that weren't visualized had a diameter less than 30 mm. At the FB-B population a diagnosis was achieved in 11 cases (55%). In pulmonary lesions with a diameter more than 30 mm, the diagnostic yield was 87, 5% using guidance and 61, 5% using FB-B and in lesions less than 30 mm 66, 67% and 42, 85% respectively. Moreover, left lower lobe was the most promising to obtain a diagnosis. CONCLUSION: Our results suggest that in patients with a non-visible pulmonary lesion a diagnostic strategy involving the choice of EBUS-guided biopsy is a reasonable and effective choice. PMID- 23988903 TI - Cervical dilatation and curettage in elective caesarean section. A retrospective analysis. AB - BACKGROUND/AIM: To analyze the influence of intraoperative cervical dilatation and curettage during elective Caesarean section (CS) on maternal morbidity. PATIENTS AND METHODS: A total of 1,003 elective CS were retrospectively evaluated. Primary outcome measure was the influence of cervical dilatation and curettage on postpartum haemorrhage (PPH). Several subgroup analyses were performed and a multiple logistic regression model was used in order to identify risk factors affecting PPH. RESULTS: Multiple pregnancy (p=0.0025) and body mass index (p=0.0251) were identified as risk factors for PPH. Curettage, cervical dilatation, prior CS, age, and duration of pregnancy were statistically not significant at a level of alpha=0.10. There was a significantly higher proportion of women suffering from uterine sub-involution when the cervix was dilated (p=0.0482). The operating time was significantly longer when curettage and/or dilatation were performed (p<0.0001). CONCLUSION: Routine cervical dilatation and/or curettage in elective Caesarean section are not beneficial. Accomplishment of either or both of these measures led to a prolonged operating time, without improving the postoperative outcome. PMID- 23988904 TI - Relative effect of bioaugmentation with electrochemically active and non-active bacteria on bioelectrogenesis in microbial fuel cell. AB - Bioelectrogenic activity of microbial fuel cells (MFC) augmented with electrochemically active bacteria (EAB, Pseudomonas aeruginosa) and non-EAB (Escherichia coli) as biocatalysts was investigated. Anodic microflora augmented with P. aeruginosa (AMFCP) yielded higher electrogenic activity (418 mV; 3.87 mA) than E. coli (AMFCE; 254 mV; 1.67 mA) and non-augmented native microflora (MFCC; 235 mV; 1.37 mA). Higher redox currents along with lower Tafel-slopes were observed with AMFCP operation compared to AMFCE and MFCC due to manifestation of bioaugmentation thereby minimizing the losses. A fourfold and twofold increase in capacitance and exchange current was observed with AMFCP and AMFCE operation respectively, when compared to MFCC. Tracking of augmented biocatalyst by fluorescent in situ hybridization (FISH) with defined probes documented the survivability of Pseudomonas sp. in higher numbers than Enterobacteriaceae. Study corroborated enhanced electron transfer capability of mixed consortia owing to the synergistic interaction with EAB due to augmentation. PMID- 23988905 TI - Ultraviolet luminescence of ScPO4, AlPO4 and GaPO4 crystals. AB - The luminescence of self-trapped excitons (STEs) was previously observed and described for the case of tetragonal-symmetry ScPO4 single crystals. The subject band in this material is situated in the UV spectral range of ~210 nm or ~5.8 eV. In the present work, we are both expanding this earlier luminescence study and seeking to identify similar luminescence phenomena in other orthophosphate crystals, i.e., AlPO4 and GaPO4. These efforts have proven to be successful--in spite of the structural differences between these materials and ScPO4. Specifically we have found that for AlPO4 and GaPO4, in addition to an alpha quartz-like STE, there is a UV luminescence band that is similar in position and decay properties to that of ScPO4 crystals. Potentially this represents an STE in AlPO4 and GaPO4 crystals that is analogous to the STE of ScPO4 and other orthophosphates. The decay kinetics of the UV luminescence of ScPO4 was studied over a wide temperature range from 8 to 300 K, and they exhibited some unusual decay characteristics when subjected to pulses from an F2 excimer laser (157 nm). These features could be ascribed to a triplet state of the STE that is split in a zero magnetic field. A fast decay of the STE was detected as well, and therefore, we conclude that, in addition to the slow luminescence corresponding to a transition from the triplet state, there are singlet-singlet transitions of the STE. Time-resolved spectra of the slow and fast decay exhibit a small shift (~0.15 eV) indicating that the singlet-triplet splitting is small and the corresponding wavefunction of the STE is widely distributed over the atoms of the ScPO4 crystal where the STE is created. PMID- 23988906 TI - Characteristics of medically and surgically treated empyema patients: a retrospective cohort study. AB - BACKGROUND: The role of drainage, intrapleural fibrinolytics, and/or surgery in the management of thoracic empyema is controversial. OBJECTIVES: We aimed to investigate the operational practice of empyema management at our hospital. METHODS: Between January 2001 and December 2008, all patients with thoracic empyema were retrieved. After exclusion of patients with malignant effusion, traumatic or iatrogenic empyema, and a history of pleurodesis or tuberculosis, we compared the characteristics of medically versus surgically treated empyema patients. RESULTS: Seventy-eight of 215 retrieved patients were acute bacterial empyema cases. All received intravenous antibiotics. Fifty-eight (74.4%) initially received tube thoracostomy, 34 (43.6%) were treated with intrapleural urokinase, and 30 (38.5%) were operated on. Of 20 patients without initial tube thoracostomy, 15 (75%) were operated on, compared to 9 (37.5%) who were initially treated by tube thoracostomy without intrapleural fibrinolytics (OR 5; 95% CI 1.4 18.5, p = 0.01) and 6 (17.7%) who were initially treated with tube thoracostomy and intrapleural urokinase (OR 14; 95% CI 3.6-53.6, p < 0.001). The surgery patients were not different in demographic and clinical characteristics but were more likely to describe significant chest pain 12 months after discharge. CONCLUSIONS: In this retrospective cohort study of thoracic empyema patients, initial chest tube insertion and intrapleural fibrinolytics were associated with less surgical therapy. Other predictors of the need for surgery could not be identified. Surgery patients were more likely to suffer from residual chest pain 12 months after discharge. Initial treatment with IV antibiotics, chest tube, and intrapleural fibrinolytics was successful in the majority of patients. PMID- 23988907 TI - Long-term speech and language outcomes in prelingually deaf children, adolescents and young adults who received cochlear implants in childhood. AB - This study investigated long-term speech and language outcomes in 51 prelingually deaf children, adolescents and young adults who received cochlear implants (CIs) prior to 7 years of age and had used their implants for at least 7 years. Average speech perception scores were similar to those found in prior research with other samples of experienced CI users. Mean language test scores were lower than norm referenced scores from nationally representative normal-hearing, typically developing samples, although a majority of the CI users scored within 1 standard deviation of the normative mean or higher on the Peabody Picture Vocabulary Test, Fourth Edition (63%), and the Clinical Evaluation of Language Fundamentals, Fourth Edition (69%). Speech perception scores were negatively associated with a meningitic etiology of hearing loss, older age at implantation, poorer preimplant unaided pure-tone average thresholds, lower family income and the use of 'total communication'. Subjects who had used CIs for 15 years or more were more likely to have these characteristics and were more likely to score lower on measures of speech perception compared to those who had used CIs for 14 years or less. The aggregation of these risk factors in the >15 years of CI use subgroup accounts for their lower speech perception scores and may stem from more conservative CI candidacy criteria in use at the beginning of pediatric cochlear implantation. PMID- 23988908 TI - Two-year caries clinical study of the efficacy of novel dentifrices containing 1.5% arginine, an insoluble calcium compound and 1,450 ppm fluoride. AB - A 2-year double-blind randomized three-treatment controlled parallel-group clinical study compared the anti-caries efficacy of two dentifrices containing 1.5% arginine, an insoluble calcium compound (di-calcium phosphate or calcium carbonate) and 1,450 ppm fluoride (F), as sodium monofluorophosphate, to a control dentifrice containing 1,450 ppm F, as sodium fluoride, in a silica base. The 6,000 participants were from Bangkok, Thailand and aged 6-12 years initially. They were instructed to brush twice daily, in the morning and evening, with their randomly assigned dentifrice. Three trained and calibrated dentists examined the children at baseline and after 1 and 2 years using the National Institute of Dental Research Diagnostic Procedures and Criteria. The number of decayed, missing and filled teeth (DMFT) and surfaces (DMFS) for the three study groups were very similar at baseline, with no statistically significant differences among groups. After 1 year, there were no statistically significant differences in caries increments among the three groups. After 2 years, the two groups using the dentifrices containing 1.5% arginine, an insoluble calcium compound and 1,450 ppm F had statistically significantly (p < 0.02) lower DMFT increments (21.0 and 17.7% reductions, respectively) and DMFS increments (16.5 and 16.5%) compared to the control dentifrice. The differences between the two groups using the new dentifrices were not statistically significant. The results of this pivotal clinical study support the conclusion that dentifrices containing 1.5% arginine, an insoluble calcium compound and 1,450 ppm F provide significantly greater protection against caries lesion cavitation, in a low to moderate caries risk population, than dentifrices containing 1,450 ppm F alone. PMID- 23988909 TI - Expression and purification of the nucleocapsid protein of Schmallenberg virus, and preparation and characterization of a monoclonal antibody against this protein. AB - Schmallenberg virus (SBV) is a novel orthobunyavirus that primarily infects ruminants such as cattle, sheep and goats. The nucleocapsid (N) protein of SBV has been shown to be an ideal target antigen for serological detection. To prepare a monoclonal antibody (mAb) against the N protein, the full-length coding sequence of the SBV N gene was cloned into pET-28a-c(+) and pMAL-c5X vectors to generate two recombinant plasmids, which were expressed in Escherichia coli BL21 as histidine (His)-tagged (His-SBV-N) and maltose-binding protein (MBP)-tagged (MBP-SBV-N) fusion proteins, respectively. After affinity purification of His-SBV N with Ni-NTA agarose and MBP-SBV-N with amylose resin, His-SBV-N was used to immunize BALB/c mice, while MBP-SBV-N was utilized to screen for mAb-secreting hybridomas. Six hybridoma cell lines stably secreting mAbs against N were obtained. Clone 2C8 was selected for further study because of its rapid growth characteristics in vitro and good reactivity with recombinant SBV N proteins in enzyme-linked immunosorbent assays. The epitope recognized by 2C8 is located at amino acids 51-76 of the SBV N protein. Western blot analyses showed that 2C8 reacts with both recombinant SBV N proteins and SBV isolates. It is also cross reactive with the N proteins of genetically related Shamonda, Douglas and Akabane viruses, but not with the Rift Valley fever virus N protein. The successful preparation of recombinant N proteins and mAbs provides valuable materials that can be used in the serological diagnosis of SBV. PMID- 23988910 TI - An update of laparoscopy in cervical cancer staging: is it a useful procedure? AB - OBJECTIVE: It was the aim of this study to report on the role of laparoscopic staging in a large series of locally advanced cervical cancer (LACC) patients and its impact on prognosis. METHODS: Consecutive patients with LACC were considered for surgical staging: gynecological examination, cystoscopy and laparoscopy with peritoneal biopsies and peritoneal fluid cytology. RESULTS: Between February 2000 and September 2010, a total of 167 women were evaluated. In 5 patients, laparoscopy could not be performed. One hundred and sixty-two patients had correct laparoscopic staging: 49 International Federation of Gynecology and Obstetrics (FIGO) stage IB-IIA (>4 cm), 67 IIB, 39 III, and 7 IVA. Abdominal spread was found in 33 cases (20%). There was a minor laparoscopy complication rate of 1%. We found a significant difference in the distribution of peritoneal spread for tumor grade and FIGO stage (p = 0.01 and p < 0.0001, respectively), whereas no statistically significant difference for the histological type was found [p = not significant (NS)]. The median follow-up was 80 months (range 4 144). The median overall survival was 65 months. The patients without abdominal spread did not benefit from a significantly longer survival (median overall survival of 59 vs. 70 months; p = NS). CONCLUSIONS: Laparoscopic staging in cervical cancer is a safe and feasible technique but it does not modify the prognosis of LACC patients. PMID- 23988912 TI - Three-dimensional photon counting double-random-phase encryption. AB - In this Letter, we present a three-dimensional (3D) photon counting double-random phase encryption (DRPE) technique using passive integral imaging. A 3D photon counting DRPE can encrypt a 3D scene and provides more security and authentications due to photon counting Poisson nonlinear transformation on the encrypted image. In addition, 3D imaging allows verification of the 3D object at different depths. Preliminary results and performance evaluation have been presented. PMID- 23988913 TI - Compact fiber tip modal interferometer for high-temperature and transverse load measurements. AB - A compact fiber tip modal interferometer (FTMI) based on two-wave interference has been demonstrated. Its fabrication process is very simple, just involving fiber tapering by a fusion splicer. The effective sensing area of the FTMI has a small length of ~310 MUm. The interference spectra of the fiber tips with different size and profile have been analyzed. The FTMI has a good mechanical strength and high-temperature stability. It can be used for high-temperature and transverse load sensing simultaneously in a harsh environment when two different attenuation peaks are chosen to be monitored. PMID- 23988914 TI - Femtosecond digital lensless holographic microscopy to image biological samples. AB - The use of femtosecond laser radiation in digital lensless holographic microscopy (DLHM) to image biological samples is presented. A mode-locked Ti:Sa laser that emits ultrashort pulses of 12 fs intensity FWHM, with 800 nm mean wavelength, at 75 MHz repetition rate is used as a light source. For comparison purposes, the light from a light-emitting diode is also used. A section of the head of a drosophila melanogaster fly is studied with both light sources. The experimental results show very different effects of the pinhole size on the spatial resolution with DLHM. Unaware phenomena on the field of the DLHM are analyzed. PMID- 23988911 TI - p27kip1 maintains a subset of leukemia stem cells in the quiescent state in murine MLL-leukemia. AB - MLL (mixed-lineage leukemia)-fusion genes induce the development of leukemia through deregulation of normal MLL target genes, such as HOXA9 and MEIS1. Both HOXA9 and MEIS1 are required for MLL-fusion gene-induced leukemogenesis. Co expression of HOXA9 and MEIS1 induces acute myeloid leukemia (AML) similar to that seen in mice in which MLL-fusion genes are over-expressed. p27(kip1) (p27 hereafter), a negative regulator of the cell cycle, has also been defined as an MLL target, the expression of which is up-regulated in MLL leukemic cells (LCs). To investigate whether p27 plays a role in the pathogenesis of MLL-leukemia, we examined the effects of p27 deletion (p27(-/-)) on MLL-AF9 (MA9)-induced murine AML development. HOXA9/MEIS1 (H/M)-induced, p27 wild-type (p27(+/+)) and p27(-/-) AML were studied in parallel as controls. We found that LCs from both MA9-AML and H/M-AML can be separated into three fractions, a CD117(-)CD11b(hi) differentiated fraction as well as CD117(+)CD11b(hi) and CD117(+)CD11b(lo), two less differentiated fractions. The CD117(+)CD11b(lo) fraction, comprising only 1-3% of total LCs, expresses higher levels of early hematopoietic progenitor markers but lower levels of mature myeloid cell markers compared to other populations of LCs. p27 is expressed and is required for maintaining the quiescent and drug-resistant states of the CD117(+)CD11b(lo) fraction of MA9-LCs but not of H/M-LCs. p27 deletion significantly compromises the leukemogenic capacity of CD117(+)CD11b(lo) MA9-LCs by reducing the frequency of leukemic stem cells (LSCs) but does not do so in H/M-LCs. In addition, we found that p27 is highly expressed and required for cell cycle arrest in the CD117(-)CD11b(hi) fraction in both types of LCs. Furthermore, we found that c-Myc expression is required for maintaining LCs in an undifferentiated state independently of proliferation. We concluded that p27 represses the proliferation of LCs, which is specifically required for maintaining the quiescent and drug-resistant states of a small subset of MA9-LSCs in collaboration with the differentiation blockage function of c-Myc. PMID- 23988915 TI - Narrow linewidth Brillouin laser based on chalcogenide photonic chip. AB - We present, to the best of our knowledge, the first demonstration of a narrow linewidth, waveguide-based Brillouin laser that is enabled by large Brillouin gain of a chalcogenide chip. The waveguides are equipped with vertical tapers for low-loss coupling. Due to optical feedback for the Stokes wave, the lasing threshold is reduced to 360 mW, which is five times lower than the calculated single-pass Brillouin threshold for the same waveguide. The slope efficiency of the laser is found to be 30%, and the linewidth of 100 kHz is measured using a self-heterodyne method. PMID- 23988916 TI - Asymmetric light propagation in transverse separation modulated photonic lattices. AB - We investigate, both theoretically and numerically, the asymmetric light propagation in transverse separation modulated photonic lattices. The theoretical results show that the transmission contrast eta of the structure is determined only by the coupling strengths between the chirped lattice and the two boundary uniform lattice portions. The numerical studies demonstrate that eta is independent of the separation modulation function of the chirped lattice, which is in good agreement with the theory. PMID- 23988917 TI - Widely tunable 11 GHz femtosecond fiber laser based on a nonmode-locked source. AB - An 11 GHz fiber laser built on a modulated cw platform is described and characterized. This compact, vibration-insensitive, fiber-based system can be operated at wavelengths compatible with high-energy fiber technology, is driven by an RF signal directly, and is tunable over a wide range of drive frequencies. The demonstration system when operated at 1040 nm is capable of 50 ns bursts of 575 micropulses produced at a macropulse rate of 83 kHz where the macropulse and micropulse energies are 1.8 and 3.2 nJ, respectively. Micropulse durations of 850 fs are demonstrated. Extensions to shorter duration are discussed. PMID- 23988919 TI - Strengthening the longitudinal component of the sharply focused electric field by means of higher-order laser beams. AB - We study the sharp focusing of differently polarized low-order and high-order beams, including Bessel and Laguerre-Gaussian (LG) modes, to compare them using several criteria: the size of a light spot, the intensity ratio of the central peak and sidelobes, and the intensity of the longitudinal electric field component. The experiments performed using the near-field microscopy techniques are in general agreement with the results of the numerical simulation. We have validated the growth of the longitudinal component in the focus for high-order modes at moderate NA=0.6-0.8, and essential lower sidelobes of Bessel modes, in comparison with LG modes. PMID- 23988918 TI - Doubling the resolution of spatial-light-modulator-based differential interference contrast microscopy by structured illumination. AB - Recently developed spatial light modulator (SLM)-based differential interference contrast (DIC) microscopy [Opt. Lett. 34, 2988 (2009)] reveals flexibility on the implementation of DIC imaging. However, its numerical aperture (spatial resolution) is limited to maintain sufficient interference contrast, because it requires two beams to interfere. We present a structured illumination (SI) SLM based DIC microscopy to effectively improve the lateral resolution of the SLM based DIC microscopy. The SI field is generated and controlled by an adjustable grating displayed on an SLM. The SI SLM-based DIC expands the bandwidth of the coherent transfer function of the SLM-based DIC imaging system, thus improving the spatial resolution. The reconstructed SI SLM-based DIC image exhibits lateral resolution of approximately 208 nm, doubling that of the common SLM-based DIC image (approximately 415 nm). SI SLM-based DIC microscopy has the potential for achieving high-resolution quantitative phase images. PMID- 23988920 TI - Energy-efficient integral imaging with suppression of pseudo images. AB - The authors present an energy-efficient integral imaging system with suppression of pseudo images, which are caused by a leakage of rays from each elemental image to the adjacent elemental lenses. The leakage of rays can be decreased when the lens is paired with a segmented backlight with limited aperture, which consumes less electricity. To remove the leakage of rays completely without damaging the image to be presented, three modifications are implemented. First, a lens with a larger focal distance is used to decrease aberration. Second, a lens array composed of thick elemental lenses is used so that the leakage of rays can be blocked by the rough surface on the side of the thick lens. Third, the aperture of the segmented backlight is expanded to avoid loss of light in the right image. PMID- 23988921 TI - Complex field recovering from in-line digital holography. AB - This Letter presents an in-line digital holographic system that can provide full amplitude and phase reconstruction without any reference wave, with a single recorded hologram. This major capability is obtained by using a coherent mixing between several object waves generated by a pure spatial phase modulation. A scaling parameter permits us to reconstruct the phase without any unwrapping. The capability of the method to provide quantitative phase contrast measurement and numerical refocusing is demonstrated through experimental results. PMID- 23988922 TI - Graphene Q-switched 2.78 MUm Er3+-doped fluoride fiber laser. AB - We report a diode-pumped 2.78 MUm Er3+-doped ZBLAN fiber laser passively Q switched by a graphene saturable absorber, which was directly deposited onto a fiber dichroic mirror by the method of optically driven deposition. Stable Q switched operation with a pulse duration of 2.9 MUs and a pulse energy of 1.67 MUJ was achieved in a 10 m long gain fiber. The pulse duration was reduced to 1 MUs when the gain fiber length was shortened to 2 m. This Letter demonstrates that graphene is a promising and reliable saturable absorber for mid-infrared pulse generation at 3 MUm. PMID- 23988923 TI - Picosecond Raman compression laser at 1530 nm with aberration compensation. AB - A passively Q-switched Nd:YAG laser with a master-oscillator power-amplifier configuration based on Brillouin and Raman pulse compression has been developed. The laser operates at 100 Hz repetition rate, producing 50 mJ pulses of approximately 30 ps duration at 1530 nm wavelength with near-diffraction-limited beam quality (M2<=1.2). The effect of spherical aberration in thermally loaded Nd:YAG rods was studied, and efficient aberration compensation was achieved by use of a specially designed aspheric element. PMID- 23988924 TI - Design of Si/SiO2 micropillar cavities for Purcell-enhanced single photon emission at 1.55 MUm from InAs/InP quantum dots. AB - Numerical simulations were carried out on micropillar cavities consisting of Si/SiO2 distributed Bragg reflectors (DBRs) with an InP spacer layer. Owing to a large refractive index contrast of ~2 in DBRs, cavities with just 4/6.5 top/bottom DBR pairs that give a low pillar height (~4.5 MUm), have noticeable Purcell-enhancement effect in the 1.55-MUm band. With careful designs on cavities with diameters of ~2.30 MUm, a quality factor of up to 3300, a nominal Purcell factor of up to 110, and an output efficiency of ~60% are obtainable. These results ensure improvement of operation frequency and enhancement of photon indistinguishability for 1.55-MUm single photon sources based on InAs/InP quantum dots. PMID- 23988925 TI - True time-delay line with high resolution and wide range employing dispersion and optical spectrum processing. AB - True time-delay line with a high resolution and wide range is proposed and demonstrated. Tunable lasers and dispersion fibers are employed to control the time delay coarsely. An optical spectrum processor is utilized to realize high resolution time-delay control by adding a quadratic optical phase shift, which compensates the group velocity dispersion of the fiber simultaneously. A coarse tuning range of 1717 ps is realized by changing the wavelength of the optical carrier, and a high resolution of 0.67 ps is achieved by translating the symmetry axis of the quadratic phase shift. PMID- 23988927 TI - Holographic polymer-dispersed liquid crystal Bragg grating integrated inside a solid core photonic crystal fiber. AB - A polymer/liquid crystal-based fiber Bragg grating (PLC-FBG) is fabricated with visible two-beam holography by photo-induced modulation of a prepolymer/liquid crystal solution infiltrated into the hollow channels of a solid core photonic crystal fiber (PCF). The fabrication process and effects related to the photonic bandgap guidance into the infiltrated PCF, and characterization of the PLC-FBG, are discussed. Experimental data presented here demonstrate that the liquid crystal inclusions of the PLC-FBG lead to high thermal and bending sensitivities. The microscopic behavior of the polymer/liquid crystal phase separation inside the PCF capillaries is examined using scanning electron microscopy, and is discussed further. PMID- 23988926 TI - Pulsed-light imaging for fluorescence guided surgery under normal room lighting. AB - Fluorescence guided surgery (FGS) is an emerging technology that has demonstrated improved surgical outcomes. However, dim lighting conditions required by current FGS systems are disruptive to standard surgical workflow. We present a novel FGS system capable of imaging fluorescence under normal room light by using pulsed excitation and gated acquisition. Images from tissue-simulating phantoms confirm visual detection down to 0.25 MUM of protoporphyrin IX under 125 MUW/cm2 of ambient light, more than an order of magnitude lower than that measured with the Zeiss Pentero in the dark. Resection of orthotopic brain tumors in mice also suggests that the pulsed-light system provides superior sensitivity in vivo. PMID- 23988928 TI - Toward maximum transmittance into absorption layers in solar cells: investigation of lossy-film-induced mismatches between reflectance and transmittance extrema. AB - The mismatch in film thickness and incident angle between reflectance and transmittance extrema due to the presence of lossy film(s) is investigated toward the maximum transmittance design in the active region of solar cells. Using a planar air/lossy film/silicon double-interface geometry illustrates important and quite opposite mismatch behaviors associated with TE and TM waves. In a typical thin-film CIGS solar cell, mismatches contributed by TM waves in general dominate. The angular mismatch is at least 10 degrees in about 37%-53% of the spectrum, depending on the thickness combination of all lossy interlayers. The largest thickness mismatch of a specific interlayer generally increases with the thickness of the layer itself. Antireflection coating designs for solar cells should therefore be optimized in terms of the maximum transmittance into the active region, even if the corresponding reflectance is not at its minimum. PMID- 23988929 TI - Laser emission from the whispering gallery modes of a graded index fiber. AB - Whispering gallery mode (WGM) laser emission has been observed from rhodamine B doped polymer optical graded index (GI) fiber by transverse pumping with a frequency doubled Q-switched Nd:YAG laser. The propagation and confinement of these modes were also observed. A variation in the free spectral range from 0.29 to 1.24 nm is obtained along the length due to the confinement of WGMs in the GI fiber. PMID- 23988930 TI - Optical pulling force and conveyor belt effect in resonator-waveguide system. AB - We present the theoretical condition and actual numerical design that achieves an optical pulling force in resonator-waveguide systems, where the direction of the force on the resonator is in the opposite direction to the input light in the waveguide. We also show that this pulling force can occur in conjunction with the lateral optical equilibrium effect, such that the resonator is maintained at the fixed distance from the waveguide while experiencing the pulling force. PMID- 23988931 TI - Nyquist-WDM filter shaping with a high-resolution colorless photonic spectral processor. AB - We employ a spatial-light-modulator-based colorless photonic spectral processor with a spectral addressability of 100 MHz along 100 GHz bandwidth, for multichannel, high-resolution reshaping of Gaussian channel response to square like shape, compatible with Nyquist WDM requirements. PMID- 23988932 TI - Microwave photonic phase shifter based on birefringence effects in a semiconductor optical amplifier. AB - A continuously tunable microwave photonic (MWP) phase shifter based on birefringence effects in a semiconductor optical amplifier (SOA) is presented and the theoretical fundamentals of the design are explained. This proposed device provides a high efficiency phase-shift tuning range beyond 2pi rad by controlling the SOA launch power. A prototype of the MWP phase shifter with a frequency of 10 GHz and 2pi rad tuning range is experimentally demonstrated. PMID- 23988933 TI - Enhanced photoabsorption efficiency of incomplete nanoshells. AB - The rather low scattering or extinction efficiency of small nanoparticles, metallic and otherwise, is significantly enhanced when they are adsorbed on a larger core particle. But the photoabsorption by particles with varying surface area fractions on a larger core particle is found to be limited by saturation. It is found that the core-shell particle can have a lower absorption efficiency than a dielectric core with its surface partially nucleated with absorbing particles an "incomplete nanoshell" particle. We have both numerically and experimentally studied the optical efficiencies of titania (TiO2) nucleated in various degrees on silica (SiO2) nanospheres. We show that optimal surface nucleation over cores of appropriate sizes and optical properties will have a direct impact on the applications exploiting the absorption and scattering properties of such composite particles. PMID- 23988934 TI - Wideband switchable unidirectional transmission in a photonic crystal with a periodically nonuniform pupil. AB - Wideband switchable diode-like transmission can be exhibited by an asymmetric dielectric photonic crystal, when the host medium is changed from air to a coherent atomic gas (CAG), a strongly dispersive medium. Significant modification of diffraction-enabled one-way transmission due to the CAG is possible in both frequency and incidence-angle domains in the short-wave infrared regime. In particular, new one-way and high-contrast passbands, which are as much as 1.0 THz in bandwidth, can appear at fixed incidence angle within a stop band of the CAG free structure and tuned by varying the oscillator strength of the CAG. These passbands correspond to relatively small, either positive or negative, values of the dielectric susceptibility of the CAG. PMID- 23988935 TI - In-line microfluidic refractometer based on C-shaped fiber assisted photonic crystal fiber Sagnac interferometer. AB - We propose and demonstrate a highly sensitive in-line photonic crystal fiber (PCF) microfluidic refractometer. Ultrathin C-shaped fibers are spliced in between the PCF and standard single-mode fibers. The C-shaped fibers provide openings for liquid to flow in and out of the PCF. Based on a Sagnac interferometer, the refractive index (RI) response of the device is investigated theoretically and experimentally. A high sensitivity of 6621 nm/RIU for liquid RI from 1.330 to 1.333 is achieved in the experiment, which agrees well with the theoretical analysis. PMID- 23988936 TI - No guard-band wavelength translation of Nyquist OTDM-WDM signal for spectral defragmentation in an elastic add-drop node. AB - We demonstrate a seamless spectral defragmentation in an elastic all-optical add drop node based on wavelength division multiplexing (WDM) channels of Nyquist optical time division multiplexing (OTDM) signal. A 172 Gbaud Nyquist OTDM signal occupying a 215 GHz range is elastically shifted adjacent to its neighboring channel, completely filling a variable spectral gap caused by the dropped channel. The frequency shift is done in a dual-stage polarization-diversity four wave mixing-based converter using polarization-maintaining highly nonlinear fiber. The spectrally defragmented signals are successfully transmitted over a 80 km fiber link with BER<10(-9). PMID- 23988937 TI - Transverse-flow radio-frequency-excited amplifier seeded by a cavity-dumped CO2 laser for an extreme ultraviolet light source. AB - A transverse-flow radio-frequency-exited CO2 laser amplifier was evaluated by a short-pulse seed laser. We constructed a prototype transverse-flow amplifier for the extreme UV laser-produced-plasma source. The electrical power for the discharge was enhanced to 100 kW at a 100% duty cycle. A Q-switched cavity-dumped CO2 seed laser emitting 13 ns pulses with a repetition rate of 100 kHz was amplified along a fivefold optical path in the amplifier gain medium. As a result, the amplifier output an average power of 3.07 kW with an 8.5 W laser input. The electrical-to-optical efficiency was 3.1%, which was far higher than that of axial-flow amplifiers at the same laser input power. The pulse showed a slight stretch from an input duration of 13 ns to an output of 15 ns. PMID- 23988938 TI - Femtosecond-laser inscribed double-cladding waveguides in Nd:YAG crystal: a promising prototype for integrated lasers. AB - We report on the design and implementation of a prototype of optical waveguides fabricated in Nd:YAG crystals by using femtosecond-laser irradiation. In this prototype, two concentric tubular structures with nearly circular cross sections of different diameters have been inscribed in the Nd:YAG crystals, generating double-cladding waveguides. Under 808 nm optical pumping, waveguide lasers have been realized in the double-cladding structures. Compared with single-cladding waveguides, the concentric tubular structures, benefiting from the large pump area of the outermost cladding, possess both superior laser performance and nearly single-mode beam profile in the inner cladding. Double-cladding waveguides of the same size were fabricated and coated by a thin optical film, and a maximum output power of 384 mW and a slope efficiency of 46.1% were obtained. Since the large diameters of the outer claddings are comparable with those of the optical fibers, this prototype paves a way to construct an integrated single-mode laser system with a direct fiber-waveguide configuration. PMID- 23988939 TI - Robust moisture and thermally stable phosphor glass plate for highly unstable sulfide phosphors in high-power white light-emitting diodes. AB - Potential white light-emitting diode (LED) phosphor SrGa2S4, which remains superfluous due to its unstable nature in the presence of moisture, was successfully integrated in a high-power white LED system by developing a glass based phosphor plate. A glass system with softening temperature at around 600 degrees C, which lies far below the possible decomposition temperature of the sulfide phosphor, provides a stable shield. Physical properties such as thermal stability, transparency, and lower porosity along with chemical stability under operating conditions of the LEDs ensure long-term operability. H2S emission due to the decomposition of sulfide phosphors, which leads to corrosion of LED electrodes, was contained using the developed plate. Higher thermal resistivity of the developed glass system in comparison with conventional resins ensures lower thermal quenching of the luminescence and better color purity. PMID- 23988940 TI - Random fiber laser directly pumped by a high-power laser diode. AB - A random lasing based on Rayleigh scattering (RS) in a passive fiber directly pumped by a high-power laser diode (LD) has been demonstrated. Owing to the RS based random distributed feedback (RDFB) the low-quality LD beam (938 nm) is converted into the high-quality laser output (980 nm). Because of the relatively low excess above the threshold with the available LD, the RDFB laser output is not stationary and limited in power at the 0.5 W level. In the used gradient index fiber, the output beam has 4.5 lower divergence as compared with the pump beam thus demonstrating a new way for development of high-power fiber lasers with high-quality output. PMID- 23988941 TI - Distinct broadband third-harmonic generation on a thin amorphous medium-air interface. AB - We achieve a series of distinct broadband third-harmonic generation (THG) signals at the amorphous glass-air interface attributed to third-order and cascaded third order nonlinear processes. A novel THG laser sideband arises from cascaded interaction between fundamental pulses and the cascaded four-wave mixing signals. The spatially separated THG sidebands with distinct spectral profiles manifest femtosecond quantum beats. Using a versatile setup with two crossing near-IR pulses temporally delayed to each other, we design an incident pulse polarization control method on the THG sideband lasers and also acquire the low-frequency surface Raman spectrum of the amorphous medium. PMID- 23988942 TI - Fine tuning of micropillar cavity modes through repetitive oxidations. AB - Repetitive wet thermal oxidations of a tapered oxide aperture in a micropillar structure are demonstrated. After each oxidation step the confined optical modes are analyzed at room temperature. Three regimes are identified. First, the optical confinement increases when the aperture oxidizes toward the center. Then, the cavity modes shift by more than 30 nm when the taper starts to oxidize through the center, leading to a decrease in the optical path length. Finally, the resonance frequency levels off when the aperture is oxidized all the way through the micropillar, but confined optical modes with a high quality factor remain. This repetitive oxidation technique therefore enables precise control of the optical cavity volume or wavelength. PMID- 23988943 TI - Distributed dynamic large strain optical fiber sensor based on the detection of spontaneous Brillouin scattering. AB - A Brillouin-based distributed optical fiber dynamic strain sensor is described which converts strain-induced Brillouin frequency shift into optical intensity variations by using an imbalanced Mach-Zhender interferometer. A 3*3 coupler is used at the output of this interferometer to permit differentiate and cross multiply demodulation. The demonstrated sensor is capable of probing dynamic strain disturbances over 2 km of sensing length every 0.5 s up to a strain of 10 mepsilon with an accuracy of +/-50 MUepsilon and spatial resolution of 1.3 m. PMID- 23988944 TI - Structure of pump resonances during optical parametric oscillation in whispering gallery resonators. AB - In optical parametric oscillators, the line shape of the pump resonance becomes strongly distorted above the oscillation threshold. We model this behavior and find good agreement with the literature data and our original experimental data. A fit of the model to the data provides valuable information about the loss mechanisms in the parametric process. In particular, the modal properties of the parametric waves can be gained, which is important for both classical and quantum aspects of optical parametric oscillation. PMID- 23988945 TI - Experimental demonstration of five-beam-pumped optical parametric amplification. AB - We experimentally demonstrated optical parametric amplification with five pumps coming from two different oscillators. By spreading those partially mutually incoherent pumps at 532 nm over different phase-matching directions around a signal at 725 nm, we obtained a pumps-to-signal efficiency of 27%. PMID- 23988946 TI - Arbitrary-detuning asynchronous optical sampling pump-probe spectroscopy of bacterial reaction centers. AB - A recently reported variant of asynchronous optical sampling compatible with arbitrary unstabilized laser repetition rates is applied to pump-probe spectroscopy. This makes possible the use of a 5.1 MHz chirped pulse oscillator as the pump laser, thus extending the available time window to almost 200 ns with a time resolution as good as about 320 fs. The method is illustrated with the measurement in a single experiment of the complete charge transfer dynamics of the reaction center from Rhodobacter sphaeroides. PMID- 23988947 TI - Propagation-invariant beams with quantum pendulum spectra: from Bessel beams to Gaussian beam-beams. AB - We describe a new class of propagation-invariant light beams with Fourier transform given by an eigenfunction of the quantum mechanical pendulum. These beams, whose spectra (restricted to a circle) are doubly periodic Mathieu functions in azimuth, depend on a field strength parameter. When the parameter is zero, pendulum beams are Bessel beams, and as the parameter approaches infinity, they resemble transversely propagating one-dimensional Gaussian wave packets (Gaussian beam-beams). Pendulum beams are the eigenfunctions of an operator that interpolates between the squared angular momentum operator and the linear momentum operator. The analysis reveals connections with Mathieu beams, and insight into the paraxial approximation. PMID- 23988948 TI - Patterned flattened modes. AB - We show that field-flattened strands may be added to and arbitrarily positioned within a field-flattened shell to create patterned, flattened modes. Patterning does not alter the effective index or flatness of the flattened mode but does alter the characteristics of other modes; we show that it can improve a flattened mode's bend performance significantly. Patterning provides a new and potentially valuable waveguide design tool that may lead to higher-power transport and laser fibers. PMID- 23988949 TI - Fiber-based multiple-access optical frequency dissemination. AB - We demonstrate a fiber-based, multiple-access optical frequency dissemination scheme. Without using any additional laser sources, we reproduce the stable disseminated frequency at an arbitrary point along the fiber link. Relative frequency stabilities of 3*10(-16)/s and 4*10(-18)/10(4) s are obtained. A branching fiber network for high-precision synchronization of optical frequency is made possible by this method, and its applications are discussed. PMID- 23988950 TI - Coupled grating reflectors with highly angular tolerant reflectance. AB - We report on stacked high-contrast grating reflectors with virtually angular independent reflectance for transverse-magnetic polarized light. The investigated structure consists of two-layer pairs of amorphous silicon and silicondioxide that are designed for a wavelengths of 1550 nm. The large angular tolerance results from coupling of the two involved silicon gratings and is achieved if the modal fields in the reflectors are matched. With this approach, a reflectance of more than 96% in the entire angular spectrum is feasible. Experimentally we demonstrate a reflectance of more than 98% for incidence angles up to 60 degrees and more than 90% up to 80 degrees . PMID- 23988951 TI - Super-intense white upconversion emission of Yb2O3 polycrystals and its application on luminescence converter of dye-sensitized solar cells. AB - In this Letter, we present the observation of super-intense upconversion (UC) white emission of Yb2O3 under 980 nm excitation, its evolution on excitation power density, the UC mechanism, and its application on the luminescence converter of dye-sensitized solar cells (DSSCs). It is significant to observe that Yb2O3 demonstrates at least one order more intense UC luminescence than beta phase NaYF4:Yb3+, Er3+ and Yb2O3/DSSCs exhibit much better photovoltaic performance than beta-phase NaYF4:Yb3+, Er3+/DSSCs under strong excitation. This indicates that Yb2O3 would become a novel candidate of the solar energy converter, especially in the application of concentrator solar cells. PMID- 23988952 TI - Narrow-bandwidth, ~100 ps seeded optical parametric generation in CdSiP2 pumped by Raman-shifted pulses at 1198 nm. AB - Low-threshold, efficient optical parametric generation at ~4.64 MUm is demonstrated using CdSiP2 nonlinear crystal pumped by 150 ps Raman shifted pump pulses at 1198 nm in noncritical configuration at 1 kHz repetition rate. Maximum single pulse idler energy of 6 MUJ and total conversion efficiency of 30% are achieved. Seeding at the signal wavelength with a distributed feedback laser diode enables ~25 fold narrowing of the bandwidths down to ~10 GHz, resulting in a Fourier product of ~1 for the ~100 ps long signal (1615 nm) and idler (4.64 MUm) pulses. PMID- 23988953 TI - Subnanosecond, mid-IR, 0.5 kHz periodically poled stoichiometric LiTaO3 optical parametric oscillator with over 1 W average power. AB - We report a subnanosecond mid-IR tunable optical parametric oscillator based on periodically poled stoichiometric lithium tantalate (PPSLT), pumped by an amplified single frequency microchip laser at 1064 nm at a repetition rate of 0.5 kHz. Using a 20 mm long PPSLT crystal polled with three different domain periods (30.2, 30.3, and 30.4 MUm) and changing the temperature of the crystal from 20 degrees C to 265 degrees C, we achieved wavelength tuning between 2990 and 3500 nm. The high nonlinearity of the used medium and the large aperture (3.2 mm) ensure maximum idler output energy of ~2 mJ in the whole tuning range, corresponding to 18% idler conversion efficiency and more than 1 W of average power. 270 ps idler pulse durations were obtained as a result of the 818 ps pulse duration of the pump. PMID- 23988954 TI - Demonstration of reconfigurable optical generation of higher-order modulation formats up to 64 QAM using optical nonlinearity. AB - We demonstrate a reconfigurable optical transmitter of higher-order modulation formats including pulse-amplitude-modulation (PAM) signals and quadrature amplitude-modulation (QAM) signals. We generated six different modulation formats by multiplexing 10 Gbit/s on-off-keying (OOK) signals (10 Gbaud binary phase shift keying, 4-PAM, 8-PAM quadrature phase-shift keying (QPSK), 16-QAM and 16 star-QAM with error-vector magnitudes (EVMs) of 8.1%, 7.5%, 7.8%, 8.2%, 7.2%, and 6.9%, respectively) and 80 Gbit/s 16-QAM with an EVM of 8.5%, as well as 120 Gbit/s 64-QAM with an EVM of 7.1%, using two or three 40 Gbit/s QPSK signals, respectively. We also successfully transmitted the generated 16-QAM signals through a 100 km transmission line with negligible power penalty. PMID- 23988956 TI - Photonic microwave amplification for radio-over-fiber links using period-one nonlinear dynamics of semiconductor lasers. AB - For radio-over-fiber links, microwave-modulated optical carriers with high optical modulation depth are preferred because high optical modulation depth allows generation of high microwave power after photodetection, leading to high detection sensitivity, long transmission distance, and large link gain. This study investigates the period-one nonlinear dynamics of semiconductor lasers for optical modulation depth improvement to achieve photonic microwave amplification through modulation sideband enhancement. In our scheme, only typical semiconductor lasers are required as the amplification unit. The amplification is achieved for a broad microwave range, from less than 25 GHz to more than 60 GHz, and for a wide gain range, from less than 10 dB to more than 30 dB. The microwave phase quality is mainly preserved while the microwave power is largely amplified, improving the signal-to-noise ratio up to at least 25 dB. The bit-error ratio at 1.25 Gbits/s is better than 10(-9), and a sensitivity improvement of up to at least 15 dB is feasible. PMID- 23988957 TI - Polymer micro-fiber Bragg grating. AB - Polymer micro-fibers with inscribed Bragg gratings are reported in this Letter. Starting with a single-mode polymer optical fiber and implementing a two-stage tapering process, a 16 MUm diameter micro-fiber is fabricated and a Bragg grating is inscribed in it that exhibits a peak reflected wavelength circa 1530 nm. The growth dynamics of the polymer micro-fiber Bragg grating are also observed and analyzed. A maximum reflectivity of 5% is obtained after an exposure time of 3 min to a 50 mW power He-Cd laser of 325 nm wavelength. The temperature and strain characterization results of the micro-fiber Bragg grating with different diameters are also presented. Such polymer micro-fiber Bragg gratings can be used as sensors for high-sensitivity measurements in a number of application areas. PMID- 23988958 TI - Angular self-reconstruction of petal-like beams. AB - The self-reconstruction of superpositions of Laguerre-Gaussian (LG) beams has been observed experimentally, but the results appear anomalous and without a means to predict under what conditions this take place. In this Letter, we offer a simple equation for predicting the self-reconstruction distance of superpositions of LG beams, which we confirm by numerical propagation as well as by experiment. We explain that the self-reconstruction process is not guaranteed and predict its dependence on the obstacle location and obstacle size. PMID- 23988959 TI - Non-line-of-sight ultraviolet single-scatter propagation model in random turbulent medium. AB - Non-line-of-sight (NLOS) ultraviolet communication (UVC) uses the atmosphere as a propagation medium. In previous literature, various scatter propagation models have been derived based on the premise that atmospheric turbulence was ignored and the atmosphere was considered as a turbid medium, also called random scatterers. In this Letter, a NLOS single-scatter propagation model is proposed to describe the singly scattered radiation in a turbulent medium, also called a random continuum, such as the clear atmosphere. The model is established based on the relationship between the scattered power and the characteristics of the random turbulent medium. The scattering cross section is further investigated in terms of different correlation distances and wavelengths. The received power dependence for NLOS UVC is also analyzed for different factors, including refractive-index structure parameter and transceiver range. PMID- 23988960 TI - Light-emitting device with regularly patterned growth of an InGaN/GaN quantum well nanorod light-emitting diode array. AB - A light-emitting device consisting of a two-dimensional regularly patterned InGaN/GaN quantum well (QW) nanorod (NR) light-emitting diode (LED) array is implemented and characterized. The NR p-i-n structure includes n-GaN NR core and essentially conformal p-GaN shell. The active regions include nonpolar sidewall QWs and polar top-face QWs. A conformal layer of transparent GaZnO of low resistivity is deposited onto the NR LED structure for spreading the injection current over the sidewalls. It is found that the blue-shift range of the output spectral peak in increasing injection current is smaller than that of a planar LED of about the same operation wavelength in a similar variation range of injection current density although it is nonzero. The small blue-shift range is attributed to the mixed emission contributions from the nonpolar sidewall QWs and polar top-face QWs. PMID- 23988961 TI - Leakage radiation interference microscopy. AB - We present a proof of principle for a new imaging technique combining leakage radiation microscopy with high-resolution interference microscopy. By using oil immersion optics it is demonstrated that amplitude and phase can be retrieved from optical fields, which are evanescent in air. This technique is illustratively applied for mapping a surface mode propagating onto a planar dielectric multilayer on a thin glass substrate. The surface mode propagation constant estimated after Fourier transformation of the measured complex field is well matched with an independent measurement based on back focal plane imaging. PMID- 23988962 TI - Extra high reflection coating with negative extinction coefficient. AB - This Letter designed an extra high reflection filter by using multilayers with a negative k, commonly referred to as gain layers. The gain layer was fabricated by embedding CdS quantum dots in a dielectric layer. Experimental results indicated that the effective k value is around -0.0008. The associated optical and physical properties were also discussed. The application of gain layers is very forward looking. PMID- 23988963 TI - Finite-difference time-domain analysis of cholesteric blue phase II using the Landau-de Gennes tensor order parameter model. AB - We numerically calculated the photonic band structure of a cholesteric blue phase II (BPII) liquid crystal using two models, the tensor order parameter model and the double-twist cylinder (DTC) model. The tensor order parameter model was derived numerically from the Landau-de Gennes theory, whereas the DTC model simply assumed a three-dimensional stack of ordered cylinders. The two models yielded similar photonic band structures; however, the polarization dependence of the transmission spectrum through the (100) direction in BPII was different. The results from the tensor order parameter model gave a better qualitative agreement with experiments on the transmission spectrum. This demonstrates the importance of a precise orientation model in the analysis of the optical properties of cholesteric blue phases. PMID- 23988964 TI - Impedance calculation and equivalent circuits for metal-insulator-metal plasmonic waveguide geometries. AB - This Letter presents an analytical expression for the equivalent impedance of the fundamental mode of both 2D and 3D metal-insulator-metal (MIM) plasmonic waveguides. It also presents circuit models for passive 2D MIM waveguide components represented by additional parasitic circuit elements. Moreover, a modeling library for various 2D MIM waveguide structures is developed. The proposed analytical results have been verified and show great accuracy compared to the full-wave characterizations. PMID- 23988965 TI - Periodic self-accelerating beams by combined phase and amplitude modulation in the Fourier space. AB - We propose and demonstrate the generation of periodic self-accelerating beams through both phase and amplitude modulation in the Fourier space. For small amplitude variations, an accelerating beam still follows a smooth convex trajectory, which can be traced by acting on the spectral phase only. However, large modulations such as those generated from the Heaviside function with a zero amplitude distribution partially modify the convex trajectory due to the appearance of straight-line paths. Furthermore, periodic self-accelerating beams along convex trajectories are realized by employing an array of "spectral wells" in both the paraxial and nonparaxial regimes. PMID- 23988966 TI - Control of the soliton self-frequency shift dynamics using topographic optical fibers. AB - We demonstrate that the dynamics of the soliton self-frequency shift can be accurately controlled by using tapered optical fibers with optimized longitudinal profile shape (that we term topographic fibers). The tapering profiles tailored for a targeted soliton spectral trajectory through dispersion and nonlinearity management are determined by an inverse algorithm. This control is demonstrated experimentally with topographic photonic crystal fibers fabricated directly on a drawing tower. PMID- 23988967 TI - Nanoelectromechanical-systems-controlled bistability of double-coupled photonic crystal cavities. AB - In this Letter, we report an approach to controlling the bistability of double coupled photonic crystal cavities with a nanoelectromechanical comb drive, in which the optical force and thermo-optic effect form a feedback mechanism to the effective index of the cavities, and the gap width between the cavities is steered by the comb drive. A model based on temporal coupled mode theory is established to analyze this approach. Hysteresis loops characterizing the bistability are experimentally achieved by sweeping the gap width forward and in reverse. In addition, the experiments also demonstrate that the bistability is tunable by varying the input light power. PMID- 23988968 TI - Experimental and theoretical analysis for improved microscope design of optical projection tomographic microscopy. AB - We present theoretical and experimental results of axial displacement of objects relative to a fixed condenser focal plane (FP) in optical projection tomographic microscopy (OPTM). OPTM produces three-dimensional, reconstructed images of single cells from two-dimensional projections. The cell rotates in a microcapillary to acquire projections from different perspectives where the objective FP is scanned through the cell while the condenser FP remains fixed at the center of the microcapillary. This work uses a combination of experimental and theoretical methods to improve the OPTM instrument design. PMID- 23988969 TI - Laser-induced breakdown of an optically trapped gold nanoparticle for single cell transfection. AB - The cell selective introduction of therapeutic agents remains a challenging problem. Here we demonstrate spatially controlled cavitation instigated by laser induced breakdown of an optically trapped single gold nanoparticle of diameter 100 nm. The energy breakdown threshold of the gold nanoparticle with a single nanosecond laser pulse at 532 nm is three orders of magnitude lower than water, which leads to nanocavitation allowing single cell transfection. We quantify the shear stress to cells from the expanding bubble and optimize the pressure to be in the range of 1-10 kPa for transfection. The method shows transfection of plasmid DNA into individual mammalian cells with an efficiency of 75%. PMID- 23988970 TI - Diode-pumped Er:CaF2 ceramic 2.7 MUm tunable laser. AB - Spectroscopic and laser properties of a newly developed high optical quality Er:CaF2 hot-formed ceramic were investigated. Under pulsed 968 nm laser diode pumping, the mid-infrared (2.7 MUm) radiation was obtained with a slope efficiency of 3%. Laser tunability was reached using a birefringent filter and the laser tuning range of 118 nm, from 2687 up to 2805 nm, was demonstrated. The maximal output energy reached was 0.48 mJ at 2730 nm for the absorbed pumping energy 34 mJ. PMID- 23988971 TI - Experimental high numerical aperture focusing with high contrast gratings. AB - We demonstrate high aperture (up to NA~0.64) three-dimensional focusing in free space based on wavefront-engineered diffraction gratings. The grating lens' optical response is tailored by spatially varying the grating ridge and groove width in two dimensions to achieve focal lengths of order 100 MUm that are crucial for micro-optical applications. The phase profile of the lens includes multiple 2pi phase jumps and was obtained by applying an algorithm for finding the optimal path for both phase and amplitude. Experimental measurements reveal a lateral spot size of 5 MUm that is close to the size of a corresponding Airy disk. PMID- 23988972 TI - Dynamics of topological light states in spiraling structures. AB - We expose a mechanism for the dynamical generation and control of light states with diverse topologies in spiraling guiding structures. Specifically, we show that spiraling shallow refractive index landscapes induce coupling and periodic energy exchange between states with different topological charges. Such a resonant effect enables excitation of optical vortices by vortex-free inputs and allows the output topological charge of the beam to be controlled. The presence of nonlinearity results in a strong asymmetrization of the resonant curves and a shift of the resonant frequencies. Resonant vortex dynamic generation, including revivals, is shown to be possible not only in waveguides mediated by total internal reflection but also in Bragg-guiding hollow-core geometries. PMID- 23988973 TI - Compressive x-ray phase tomography based on the transport of intensity equation. AB - We develop and implement a compressive reconstruction method for tomographic recovery of refractive index distribution for weakly attenuating objects in a microfocus x-ray system. This is achieved through the development of a discretized operator modeling both the transport of intensity equation and the x ray transform that is suitable for iterative reconstruction techniques. PMID- 23988974 TI - Ultraviolet light detection using an optical microcavity. AB - Ultraviolet (UV) light exposure is connected to both physical and psychological diseases. As such, there is significant interest in developing sensors that can detect UV light in the mW/cm2 intensity range with a high signal-to-noise ratio. In this Letter, we demonstrate a UV sensor based on a silica integrated optical microcavity that has a linear operating response in both the forward and backward directions from 14 to 53 mW/cm2. The sensor response agrees with the developed predictive theory based on a thermodynamic model. Additionally, the signal-to noise ratio is above 100 at physiologically relevant intensity levels. PMID- 23988975 TI - Anisotropy of optical transitions in ordered ensemble of CdSe quantum rods. AB - We report on the observation of spectral dependence of absorption anisotropy in a CdSe quantum rod (QR) ensemble, which is aligned in a polymer film with a nanocrystal concentration of 2*10(-5) M. The experimental data on the polarization direction and anisotropy factor were obtained for the lowest excitonic transition and the second group of transitions in the QR. The nonzero constant value of anisotropy was investigated for the high-energy transitions, and is evidence of the one-dimensional confinement in the QR. PMID- 23988976 TI - Generating and measuring nondiffracting vector Bessel beams. AB - Nondiffracting vector Bessel beams are of considerable interest due to their nondiffracting nature and unique high-numerical-aperture focusing properties. Here we demonstrate their creation by a simple procedure requiring only a spatial light modulator and an azimuthally varying birefringent plate, known as a q plate. We extend our control of both the geometric and dynamic phases to perform a polarization and modal decomposition on the vector field. We study both single charged Bessel beams as well as superpositions and find good agreement with theory. Since we are able to encode nondiffracting modes with circular polarizations possessing different orbital angular momenta, we suggest these modes will be of interest in optical trapping, microscopy, and optical communication. PMID- 23988977 TI - In-fiber integrated chemiluminiscence online optical fiber sensor. AB - We report an in-fiber integrated chemiluminiscence (CL) sensor based on a kind of hollow optical fiber with a suspended inner core. The path of microfluid is realized by etching microholes for inlets and outlets on the surface of the optical fiber without damaging the inner core and then constructing a melted point beside the microhole of the outlet. When samples are injected into the fiber, the liquids can be fully mixed and form steady microflows. Simultaneously, the photon emitted from the CL reaction is efficiently coupled into the core and can be detected at the end of the optical fiber. In this Letter, the concentration of H2O2 samples is analyzed through the emission intensity of the CL reaction among H2O2, luminol, K3Fe(CN)6, and NaOH in the optical fiber. The linear sensing range of 0.1-4.0 mmol/L of H2O2 concentration is obtained. The emission intensity can be determined within 400 ms at a total flow rate of 150 MUL/min. Significantly, this work presents the information of developing in-fiber integrated online analyzing devices based on optical methods. PMID- 23988978 TI - Atmosphere characterization for simulation of the two optimal wireless terahertz digital communication links. AB - Our studies of terahertz pulse propagation in the atmosphere have identified the two most optimal communication channels. The potential of these channels is demonstrated by physically accurate linear dispersion theory calculations of digital pulse propagation, showing it is possible to have two high-performance, point-to-point digital terahertz links in the atmosphere: a direct 95 GHz, 20 km ground link at 9.5 Gb/s with power loss of 10 dB due to water vapor at RH 58% (10 g/m3) and 20 degrees C, and a direct 250 GHz, geosynchronous satellite link at 20.8 Gb/s with a 2 km zenith path with water vapor loss of 9 dB. PMID- 23988979 TI - Photonic generation of widely tunable and background-free binary phase-coded radio-frequency pulses. AB - We present a novel photonic approach to generating widely tunable and background free binary phase-coded radio-frequency (RF) pulses by cascading a polarization modulator (PolM) and a phase modulator (PM). The PolM is used to produce an optical carrier and two sidebands with orthogonal polarization states. The phase shift theta between the optical carrier and the sidebands is controlled by the electrical driving signal applied to the PM. For theta>pi/2 or 0.05). Following injection challenge with a virulent F. psychrophilum strain, mortality for injection vaccinated fish was significantly reduced compared to the control but did not differ by treatment (P > 0.05). Relative percent survival (RPS) was high in both treatments (90% in iron-replete, 98% in iron-limited medium). Fish immunized by immersion with CSF259-93B.17 grown in iron-replete medium exhibited lower mortality (29.3%; RPS 46%) when compared to mock immunized fish, but this was not significant. However, mortality was significantly lower in fish immunized with CSF259-93B.17 grown in iron-limited medium (14.7%; RPS 73%) when compared to mock immunized fish. The results demonstrate that the live-attenuated F. psychrophilum strain can confer protection to coho salmon and vaccine efficacy is enhanced by culturing the strain under iron-limited conditions. PMID- 23989040 TI - A C-type lectin could selectively facilitate bacteria clearance in red swamp crayfish, Procambarus clarkii. AB - C-type lectins function as pattern recognition receptors and play important roles in the innate immune system of crustaceans. In this study, we reported a new CTL gene (designated as PcLec5) from red swamp crayfish, Procambarus clarkii. PcLec5 was mainly distributed in hepatopancreas, gills and intestine, and the PcLec5 transcripts were up-regulated in all the three tissues after challenge with bacteria Vibrio anguillarum. For further functional analyses, PcLec5 was recombinantly expressed in Escherichia coli and anti-PcLec5 polyclonal antiserum was prepared. The results of bacteria binding assay revealed that PcLec5 could selectively bind to 5 of 9 kinds of bacteria we used and had a tendency to bind to Gram-negative bacteria. Sugar binding assay showed that PcLec5 could bind to peptidoglycan, lipoteichoic acid and lipopolysaccharide, with the highest affinity to LPS. Furthermore, bacteria-clearance experiment showed PcLec5 could selectively facilitate the clearance of injected bacteria in crayfish, and the bacteria-clearance facilitating spectrum of PcLec5 was totally in agreement with its bacteria binding spectrum. These results suggested PcLec5 function as a pattern recognition receptor in crayfish immune system and had certain selectivity on bacteria pathogens. PMID- 23989041 TI - Needle knife precut papillotomy and fistulotomy for difficult biliary cannulation during endoscopic retrograde cholangiopancreatography. AB - BACKGROUND: Although needle knife precut papillotomy and needle knife fistulotomy have been considered useful alternatives for achieving selective biliary cannulation, controversies remain regarding the technical proficiency for performing this procedure and safety concerns. AIM: This retrospective study evaluates the feasibility and safety of combining needle knife precut papillotomy and fistulotomy (NKPPF) to assist endoscopic retrograde cholangiopancreatography (ERCP) for difficult biliary cannulation. METHODS: Data were collected and analyzed for 48 patients who underwent NKPPF between January 2008 and September 2012 at our center. The operation success rate, mean procedure time, and post ERCP complications were investigated and compared with those of standard cannulation. RESULTS: The success rate for NKPPF was 96% (46/48) and the mean procedure time was 4.5 +/- 1.6 min based on our data set. The major complications included pancreatitis, which occurred in 2 of the 48 patients (4%), and acute cholangitis, which was observed in 1 patient (2%). There was no significant difference between the complication rate of NKPPF (6%) and standard cannulation therapeutic ERCP (4%). CONCLUSION: NKPPF is an effective method for accessing the biliary system after failed standard cannulation and is not associated with an increased risk of complications. PMID- 23989042 TI - [Oncological therapies - what are the patient relative outcomes?]. PMID- 23989043 TI - [Management of tumors with neuroendocrine differentiation]. PMID- 23989044 TI - Improving the safety of aging road users: a mini-review. AB - Older drivers are at greatest risk for injury or death as a result of a car crash. In this mini-review, we outline the normative age-related changes to perceptual, cognitive, and motor abilities that contribute to increased crash risk and decreased comfort with driving, and highlight specific driving scenarios and conditions that are particularly challenging for aging road users. Adopting a person-environment fit framework, we discuss how the roadway environment can be modified to better match the abilities of the aging driver. We also review evidence for the efficacy of training interventions that aim to change the abilities and strategies of the aging driver to better match the demands of the driving environment. Evidence suggests that specific changes to the roadway and driver training strategies can bring the abilities of the older driver back into alignment with the demands of the driving task. A focus on both approaches will help ensure the safety of all road users as the number of aging drivers greatly increases over the next few decades. PMID- 23989045 TI - Conversion from epoetin and darbepoetin to C.E.R.A. in non-dialysis CKD patients: a multicenter Italian prospective study in nephrology practice. AB - BACKGROUND: In non-dialysis patients (ND-CKD), C.E.R.A. has been extensively investigated in ESA-naive subjects but no data are available on its efficacy after switch from other ESA. METHODS: In this prospective, multicenter, open label study lasting 24 weeks, ND-CKD patients (n = 157) receiving ESA were converted to C.E.R.A. at doses lower than recommended. Primary outcome was the prevalence of Hb target (11-12.5 g/dl). RESULTS: Age was 73 +/- 13 years and GFR was 26.2 +/- 9.4 ml/min/1.73 m(2); male gender, diabetes and prior cardiovascular disease were 49, 33 and 19%, respectively. Doses of darbepoetin (25 +/- 16 ug/week, n = 124) and epoetin (5,702 +/- 3,190 IU/week, n = 33) were switched to low dose C.E.R.A. (87 +/- 17 ug/month). During the study, prevalence of Hb target increased from 60% to 68% at week-24, while that of Hb < 11 g/dl declined from 32% to 16% (p < 0.001). Hb increased from 11.3 +/- 0.8 at baseline to 11.7 +/- 0.9 g/dl at week-24 (p = 0.01) without changes in C.E.R.A. dose. Significant predictors of Hb increase were low BMI, low Hb and longer dosing intervals before switch. These factors also predicted the risk of Hb overshooting (Hb > 12.5 g/dl) occurring in 57 patients. CONCLUSIONS: In ND-CKD, conversion from other ESAs to C.E.R.A. is associated with a better anemia control induced by a greater Hb increase in patients previously treated with ESAs at extended dosing interval. This parameter should be considered when switching to long-acting ESA for its potential impact on the risk of overshooting. PMID- 23989046 TI - PROGRAMMABLE DIELECTROPHORETIC MUTAS SAMPLE HANDLING. AB - We present the concept of a general-purpose sample analysis platform (GSAP) based on dielectrophoretic methods. The platform architecture comprises integrated functional blocks that can be programmed to perform a diverse range of analysis steps, including the on-device preparation of real world samples. PMID- 23989047 TI - Continuous intraoperative temperature measurement and surgical site infection risk: analysis of anesthesia information system data in 1008 colorectal procedures. AB - OBJECTIVES: To investigate the association between intraoperative temperature and surgical site infection (SSI) in colorectal surgery with anesthesia information system data. METHODS: Continuously measured intraoperative anesthesia information system temperature data for adult abdominal colorectal surgery procedures at a large tertiary center for 1 year were linked to 30-day American College of Surgeons National Surgical Quality Improvement Program SSI outcomes. Univariable and multivariable analyses of SSI to descriptive temperature statistics, absolute and relative temperature threshold times, and other clinically relevant variables were performed. RESULTS: Overall, 1008 patients (48% female, median age: 53 years) underwent major colorectal procedures (7% emergent, 72% open, 173 +/- 95 minutes mean procedure time) with median intraoperative temperature 36.0 degrees C, using active rewarming in 92% and 1-hour presurgical antibiotic administration in 91%. Thirty-day overall and organ/space infection rates were 17.4% (175) and 8.5% (86). Maximum, minimum, ending, and median temperatures were similar for those with or without SSI (36.6 degrees C vs 36.5 degrees C, 34.9 degrees C vs 35.0 degrees C, 36.4 degrees C vs 36.2 degrees C, and 36.1 degrees C vs 36.0 degrees C, P = not significant) and percent minutes using incremental cutoffs failed to correlate SSI with temperature. Absolute minutes for higher temperature cutoffs correlated with SSI because of longer procedure times. On multivariable analysis, factors associated with SSI were preoperative diabetes [odds ratio: 1.81 (1.07-3.07), P = 0.022] and blood loss of more than 500 mL [odds ratio: 1.61 (1.01-2.58), P = 0.047]. CONCLUSIONS: Although active rewarming remains an accepted and valid process measure, highly granular anesthesia information system temperature data did not demonstrate a correlation between temperature measures and SSI. SSI prevention efforts should focus on more efficacious interventions as opposed to currently mandated publicly reported normothermia measures. PMID- 23989048 TI - Reply to letter: "laparoscopic sleeve gastrectomy in 108 obese children and adolescents ages 5 to 21 years". PMID- 23989049 TI - Health care reform: impact on American surgery and related implications. PMID- 23989050 TI - Long-term maturation of congenital diaphragmatic hernia treatment results: toward development of a severity-specific treatment algorithm. AB - OBJECTIVES: To assess the impact of varying approaches to congenital diaphragmatic hernia (CDH) repair timing on survival and need for ECMO when controlled for anatomic and physiologic disease severity in a large consecutive series of patients with CDH. BACKGROUND: Our publication of 60 consecutive patients with CDH in 1999 showed that survival was significantly improved by limiting lung inflation pressures and eliminating hyperventilation. METHODS: We retrospectively reviewed 268 consecutive patients with CDH, combining 208 new patients with the 60 previously reported. Management and ventilator strategy were highly consistent throughout. Varying approaches to surgical timing were applied as the series matured. RESULTS: Patients with anatomically less severe left liver down CDH had significantly increased need for ECMO if repaired in the first 48 hours, whereas patients with more severe left liver-up CDH survived at a higher rate when repair was performed before ECMO. Overall survival of 268 patients was 78%. Survival was 88% for those without lethal associated anomalies. Of these, 99% of left liver-down CDH survived, 91% of right CDH survived, and 76% of left liver-up CDH survived. CONCLUSIONS: This study shows that patients with anatomically less severe CDH benefit from delayed surgery whereas patients with anatomically more severe CDH may benefit from a more aggressive surgical approach. These findings show that patients respond differently across the CDH anatomic severity spectrum and lay the foundation for the development of risk specific treatment protocols for patients with CDH. PMID- 23989052 TI - Transient receptor potential ion channels: powerful regulators of cell function. AB - OBJECTIVE: This article reviews the current understanding of transient receptor potential ion channels (TRP channels) in health and disease. BACKGROUND: Transient receptor potential ion channels are a group of 27 channels that are expressed in all tissues. These channels play important roles in surgically important problems, such as chronic pain, susceptibility to infection, hypothermia, and some cancers. METHODS: A literature search was performed. This review focuses on the role of TRP channels in a few surgically important disease processes, such as pain, inflammation, airway diseases, and malignant melanomas. In addition, we discuss some of the structural properties that are important for the activation of TRP channels. RESULTS: TRPA1 and TRPV1 are expressed on pain fibers and play an important role in the development of chronic pain, such as chemotherapy-related neuropathic pain. Deletion of TRPA1 and TRPV1 suppresses the development of chronic pain, and blockers of TRPA1 and TRPV1 show promise as a new class of painkillers. Furthermore, several TRP channels are expressed on immune cells. Macrophages express at least 3 different TRP channels, and the properly balanced activation of all these channels together allows normal macrophage function. Deletion of any of these channels results in impaired macrophage function and increased susceptibility to infection. Because several of these TRP channels on macrophages are temperature sensitive, they may comprise the link for hypothermia-related infectious complications in trauma, and to a lesser degree, in elective surgical patients. CONCLUSIONS: Transient receptor potential ion channels are involved in several surgically important disease processes. Activation or blockade of these channels offers new therapeutic opportunities. Pharmacologic activation or blockade of TRP channels may offer new treatment options in surgical patients for the management of pain and infections. PMID- 23989051 TI - The role of aryl hydrocarbon receptor in interleukin-23-dependent restoration of interleukin-22 following ethanol exposure and burn injury. AB - OBJECTIVE: T-helper (Th)-17 lymphocytes play a crucial role in maintenance and regulation of gut immunity. Our laboratory has demonstrated that acute ethanol (EtOH) exposure before burn injury results in intestinal T cell suppression and enhanced bacterial translocation. BACKGROUND: To extend these studies, we examined the effects of EtOH exposure and burn injury on Th17 responses within intestinal lymphoid Peyer's patches (PP). We further investigated whether restitution of interleukin (IL)-23 enhances PP cell IL-17 and IL-22 after EtOH and burn injury. METHODS: Male mice, approximately 25 g, were gavaged with EtOH (2.9 mg/kg) before receiving an approximately 12.5% total body surface area full thickness burn. One day postinjury, PP mixed cells were cultured in the presence of plate-bound anti-CD3/soluble anti-CD28 in the presence or absence of IL-23 for 48 hours. Supernatants were harvested for IL-17 and IL-22 levels. RESULTS: When combined with EtOH intoxication, burn injury significantly decreased IL-17 and IL 22, as compared with sham injury. IL-23 treatment successfully increased levels of IL-22 but not IL-17. This restoration was prevented when PP cells were treated with CH-223191, an aryl hydrocarbon receptor inhibitor. To further delineate the mechanism of differential IL-17 and IL-22 suppression, PP cells were treated with phorbol 12-myristate 13-acetate (PMA) and ionomycin, which signal via protein kinase C (PKC) and calcium flux. Treatment with PMA and ionomycin significantly prevented the decrease in IL-17 but not IL-22 after EtOH exposure and burn injury. CONCLUSIONS: These findings suggest that IL-23-mediated restoration of IL 22 is aryl hydrocarbon receptor dependent, whereas IL-17 requires activation of protein kinase C and intracellular calcium signaling. PMID- 23989053 TI - Surgeon and breast unit volume-outcome relationships in breast cancer surgery and treatment. AB - OBJECTIVES: To determine whether surgeon case volume and Unit case volume affected specific recognized key performance indicators (KPIs) of breast cancer surgical management. BACKGROUND: An increasing body of evidence suggests that a higher standard of cancer care, demonstrated by improved outcomes, is provided in high-volume units or by high-volume surgeons. The volume-outcome relationship pertaining to screen-detected breast cancers has yet to be thoroughly established and remains a pertinent issue in view of the debate surrounding breast cancer screening. METHODS: The study population comprised all women with a new screen diagnosed breast cancer between 2004-2005 and 2009-2010. Surgeons' mean annual patient volumes were calculated and grouped as very low (<5), low (5-15), medium (16-49), or high volume (>50). The effect of breast screening unit volume was also evaluated. Statistical analyses were performed using Minitab V16.0 software (State College, PA) and R V2.13.0. RESULTS: There were 81,416 patients aged 61 (+/-6.8) years treated by 682 surgeons across 82 units. There were 209 very low-, 126 low-, 295 medium-, and 51 high-volume surgeons. The proportion of patients managed by very low-, low-, medium-, and high-volume surgeons was 1.2%, 6.9%, 65.5%, and 25.7%, respectively. Patients managed by high-volume surgeons were more likely to have breast-conserving surgery (BCS) than those managed by low volume surgeons (P < 0.001). There was a higher proportion of sentinel lymph node biopsies (SLNB) performed by high-volume surgeons in invasive cancers (P = 0.005). High-volume units performed more BCS and SLNB than low-volume units (P < 0.001 and P < 0.001, respectively). CONCLUSIONS: Even in a setting with established quality control measures (KPIs) surgeon and unit volume have potent influences on initial patient management and treatment. PMID- 23989054 TI - Early results of the Swiss Multicentre Bypass or Sleeve Study (SM-BOSS): a prospective randomized trial comparing laparoscopic sleeve gastrectomy and Roux en-Y gastric bypass. AB - OBJECTIVE: Laparoscopic sleeve gastrectomy (LSG) has been proposed as an effective alternative to the current standard procedure, laparoscopic Roux-en-Y gastric bypass (LRYGB). Prospective data comparing both procedures are rare. Therefore, we performed a randomized clinical trial assessing the effectiveness and safety of these 2 operative techniques. METHODS: Two hundred seventeen patients were randomized at 4 bariatric centers in Switzerland. One hundred seven patients underwent LSG using a 35-F bougie with suturing of the stapler line, and 110 patients underwent LRYGB with a 150-cm antecolic alimentary and a 50-cm biliopancreatic limb. The mean body mass index of all patients was 44 +/- 11.1 kg/m, the mean age was 43 +/- 5.3 years, and 72% were female. RESULTS: The 2 groups were similar in terms of body mass index, age, sex, comorbidities, and eating behavior. The mean operative time was less for LSG than for LRYGB (87 +/- 52.3 minutes vs 108 +/- 42.3 minutes; P = 0.003). The conversion rate was 0.9% in both groups. Complications (<30 days) occurred more often in LRYGB than in LSG (17.2% vs 8.4%; P = 0.067). However, the difference in severe complications did not reach statistical significance (4.5% for LRYGB vs 1% for LSG; P = 0.21). Excessive body mass index loss 1 year after the operation was similar between the 2 groups (72.3% +/- 22% for LSG and 76.6% +/- 21% for LRYGB; P = 0.2). Except for gastroesophageal reflux disease, which showed a higher resolution rate after LRYGB, the comorbidities and quality of life were significantly improved after both procedures. CONCLUSIONS: LSG was associated with shorter operation time and a trend toward fewer complications than with LRYGB. Both procedures were almost equally efficient regarding weight loss, improvement of comorbidities, and quality of life 1 year after surgery. Long-term follow-up data are needed to confirm these facts. PMID- 23989055 TI - The education, training, and specialization of surgeons: turn-of-the-century America and its postgraduate medical schools. AB - OBJECTIVES: To understand the institutions, personnel, and events that shaped postgraduate medical schools in late 19th- and early 20th-century America. BACKGROUND: In a little remembered chapter of American surgical medical history, postgraduate medical schools played a decisive role in surgery's march toward professionalization and specialization. While William Halsted was first establishing his training program in Baltimore, medical facilities such as the New York Polyclinic and the New York Post-Graduate were already turning out thousands of physicians who considered themselves "specialists" in surgery. METHODS: An analysis of the published and unpublished medical and lay literature relating to the nation's postgraduate medical schools. RESULTS: The founding of postgraduate medical schools in turn-of-the-century America was a key event in the acceptance of surgery as a legitimate specialty within the whole of medicine. These little remembered institutions laid the foundation for the blossoming of surgical care and the extraordinary clinical advances that followed. CONCLUSIONS: Postgraduate medical schools, particularly the New York Polyclinic and the New York Post-Graduate, were dominant influences in shaping the early history of surgery in America. These institutions brought the pressure for specialization in surgery to the forefront of discussions about medical education and training. For the first time, a large number of practitioners were offered a formalized surgical experience in a busy urban medical facility. As a result, and despite their being long forgotten, the importance of postgraduate medical schools in our nation's surgical history cannot be overstated. PMID- 23989056 TI - Treatment strategy for main duct intraductal papillary mucinous neoplasms of the pancreas based on the assessment of recurrence in the remnant pancreas after resection: a retrospective review. AB - OBJECTIVES: To clarify the recurrence pattern after resection of main duct intraductal papillary mucinous neoplasms (MD-IPMNs) using molecular analyses and determine the most adequate treatment strategy. BACKGROUND: The most appropriate resection line for MD-IPMNs remains an unresolved issue. METHODS: Medical records of 56 patients with pancreatectomy were retrospectively reviewed. Histological subtypes and Kras/GNAS mutations were assessed in patients with recurrence in the remnant pancreas. RESULTS: Forty-nine patients underwent partial pancreatectomy and 7 underwent total pancreatectomy. Thirty-six patients (64%) had malignant MD IPMNs. Recurrence was observed in 7 of 49 patients (14%), including 6 with malignant IPMNs and 1 with pancreatic ductal adenocarcinoma, all of whom underwent remnant pancreatectomy. The cumulative disease-specific survival rate of patients with pancreatic recurrence was greater than that of patients with extrapancreatic recurrence (P < 0.001). Although the pancreatic margin status at the initial operation did not affect the pancreatic recurrence rate, all 4 recurrent IPMNs examined had histological subtypes and Kras/GNAS mutations identical to those of the initial lesions. Four patients experienced recurrence in the remnant pancreas or systemic recurrence after resection of high-grade dysplasia of MD-IPMN. Three of the 56 patients had concomitant pancreatic ductal adenocarcinomas and MD-IPMNs. CONCLUSIONS: One-step total pancreatectomy can be avoided, and remnant total pancreatectomy would lead to favorable outcomes even in patients with pancreatic recurrence, some cases of which seem to involve residual lesions. Postoperative surveillance of high-grade dysplasia should be performed as if malignant, and close attention should be paid to the occurrence of concomitant pancreatic ductal adenocarcinomas in patients with MD-IPMNs. PMID- 23989057 TI - Mucinous and signet-ring cell colorectal cancers differ from classical adenocarcinomas in tumor biology and prognosis. AB - OBJECTIVES: To define the prognostic value of different histological subtypes of colorectal cancer. BACKGROUND: Most colorectal cancers are classical adenocarcinomas (AC). Less frequent subtypes include mucinous adenocarcinomas (MAC) and signet-ring cell carcinomas (SC). In contrast to established prognostic factors such as TNM and grading, the histological subtype has no therapeutical consequences so far, although it may reflect different biological behavior. METHODS: Between 1982 and 2012, a total of 3479 consecutive patients underwent surgery for primary colorectal cancer (AC, MAC, or SC). Clinical, histopathological, and survival data were analyzed. RESULTS: Of all 3479 patients, histological subtype was AC in 3074 cases (88%), MAC in 375 cases (11%), and SC in 30 cases (0.9%). MAC (51%, P < 0.001) and SC (50%, P = 0.029) occurred more frequently in right-sided tumors than AC (28%). Compared with AC, tumor stages and histological grading were higher in MAC and SC (P < 0.001 for each). Rates of angioinvasion were lower in MAC than in AC (5% vs 9%, P = 0.011). Rates of lymphatic invasion were higher in SC than in AC (67% vs 25%, P < 0.001). Five-year cause-specific survival was 67 +/- 1% for AC, 61 +/- 3% for MAC, and 21 +/- 8% for SC (P < 0.001 for difference between the groups). In multivariable analysis, survival did not differ significantly between AC and MAC after correction for tumor stage. However, SC remained an independent prognostic factor associated with worse survival (hazard ratio = 2.5, 95% confidence interval = 1.6 3.8, P < 0.001). CONCLUSIONS: MAC and SC are histological subtypes of colorectal cancer with different characteristics than classical AC. Both are diagnosed in more advanced tumor stages, but the dismal prognosis of SC seems to be caused by its intrinsic tumor biology. PMID- 23989058 TI - Towards design principles for determining the mechanical stability of proteins. AB - The successful integration of proteins into bionanomaterials with specific and desired functions requires an accurate understanding of their material properties. Two such important properties are their mechanical stability and malleability. While single molecule manipulation techniques now routinely provide access to these, there is a need to move towards predictive tools that can rationally identify proteins with desired material properties. We provide a comprehensive review of the available experimental data on the single molecule characterisation of proteins using the atomic force microscope. We uncover a number of empirical relationships between the measured mechanical stability of a protein and its malleability, which provide a set of simple tools that might be employed to estimate properties of previously uncharacterised proteins. PMID- 23989059 TI - Expanded clinical spectrum of enhanced S-cone syndrome. AB - IMPORTANCE: New funduscopic findings in patients with enhanced S-cone syndrome (ESCS) may help clinicians in diagnosing this rare autosomal recessive retinal dystrophy. OBJECTIVE: To expand the clinical spectrum of ESCS due to mutations in the NR2E3 gene. DESIGN: Retrospective, noncomparative case series of 31 patients examined between 1983 and 2012. SETTING: Academic and private ophthalmology practices specialized in retinal dystrophies. PARTICIPANTS: A cohort of patients diagnosed with ESCS and harboring known NR2E3 mutations. INTERVENTION: Patients had ophthalmic examinations including visual function testing that led to the original diagnosis. MAIN OUTCOMES AND MEASURES: New fundus features captured with imaging modalities. RESULTS: New clinical observations in ESCS include (1) torpedo-like, deep atrophic lesions with a small hyperpigmented rim, variably sized and predominantly located along the arcades; (2) circumferential fibrotic scars in the posterior pole with a spared center and large fibrotic scars around the optic nerve head; and (3) yellow dots in areas of relatively normal-appearing retina. CONCLUSIONS AND RELEVANCE: Enhanced S-cone syndrome has more pleiotropy than previously appreciated. While the nummular type of pigmentation at the level of the retinal pigment epithelium and cystoid or schisis-like maculopathy with typical functional findings remain classic hallmarks of the disease, changes such as circumferential fibrosis of the macula or peripapillary area and "torpedo like" lesions along the vascular arcades may also direct the clinical diagnosis and focus on screening the NR2E3 gene for a molecular diagnosis. PMID- 23989060 TI - Phospholipase D inhibitor enhances radiosensitivity of breast cancer cells. AB - Radiation and drug resistance remain the major challenges and causes of mortality in the treatment of locally advanced, recurrent and metastatic breast cancer. Dysregulation of phospholipase D (PLD) has been found in several human cancers and is associated with resistance to anticancer drugs. In the present study, we evaluated the effects of PLD inhibition on cell survival, cell death and DNA damage after exposure to ionizing radiation (IR). Combined IR treatment and PLD inhibition led to an increase in the radiation-induced apoptosis of MDA-MB-231 metastatic breast cancer cells. The selective inhibition of PLD1 and PLD2 led to a significant decrease in the IR-induced colony formation of breast cancer cells. Moreover, PLD inhibition suppressed the radiation-induced activation of extracellular signal-regulated kinase and enhanced the radiation-stimulated phosphorylation of the mitogen-activated protein kinases p38 and c-Jun N-terminal kinase. Furthermore, PLD inhibition, in combination with radiation, was very effective at inducing DNA damage, when compared with radiation alone. Taken together, these results suggest that PLD may be a useful target molecule for the enhancement of the radiotherapy effect. PMID- 23989061 TI - Kaempferol induces chondrogenesis in ATDC5 cells through activation of ERK/BMP-2 signaling pathway. AB - Endochondral bone formation occurs when mesenchymal cells condense to differentiate into chondrocytes, the primary cell types of cartilage. The aim of the present study was to identify novel factors regulating chondrogenesis. We investigated whether kaempferol induces chondrogenic differentiation in clonal mouse chondrogenic ATDC5 cells. Kaempferol treatment stimulated the accumulation of cartilage nodules in a dose-dependent manner. Kaempferol-treated ATDC5 cells stained more intensely with alcian blue staining than control cells, suggesting greater synthesis of matrix proteoglycans in the kaempferol-treated cells. Similarly, kaempferol induced greater activation of alkaline phosphatase activity than control cells, and it enhanced the expression of chondrogenic marker genes, such as collagen type I, collagen type X, OCN, Runx2, and Sox9. Kaempferol induced an acute activation of extracellular signal-regulated kinase (ERK) but not c-jun N-terminal kinase or p38 MAP kinase. PD98059, an inhibitor of MAPK/ERK, decreased in stained cells treated with kaempferol. Furthermore, kaempferol greatly expressed the protein and mRNA levels of BMP-2, suggesting chondrogenesis was stimulated via a BMP-2 pathway. Taken together, our results suggest that kaempferol has chondromodulating effects via an ERK/BMP-2 signaling pathway and could potentially be used as a therapeutic agent for bone growth disorders. PMID- 23989062 TI - Protective effects of 6-hydroxy-1-methylindole-3-acetonitrile on cisplatin induced oxidative nephrotoxicity via Nrf2 inactivation. AB - We previously demonstrated the ethanol extract of the roots of Brassica rapa protects against cisplatin-induced nephrotoxicity by attenuating oxidative stress. Here, we investigated the nephroprotective effects of 6-hydroxy-1 methylindole-3-acetonitrile (6-HMA), which was isolated from the roots of B. rapa, on cisplatin-induced toxicity in renal epithelial LLC-PK1 cells and in rats with acute renal injury. Pretreatment of LLC-PK1 cells with 6-HMA ameliorated cisplatin-induced cytotoxicity caused by oxidative stress, as was demonstrated by reductions in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increased levels of glutathione (GSH). In addition, 6-HMA inhibited cisplatin-induced heme oxygenase-1 (HO-1) expression, possibly due to the suppression of the nuclear translocation and binding activity of NF-E2-related factor 2 (Nrf2). Furthermore, 6-HMA administered rats showed lower levels of blood urea nitrogen (BUN), creatinine, and urinary lactate dehydrogenase (LDH) than cisplatin alone-treated rats in cisplatin-induced renal injury model. Moreover, 6-HMA inhibited the cisplatin-induced formation of MDA and GSH depletion and increased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GR). Taken together, these findings indicate 6 HMA is a major active constituent from the roots of B. rapa to have a protective effect against cisplatin-induced nephrotoxicity by attenuating oxidative stress. PMID- 23989064 TI - Nanophasic biodegradation enhances the durability and biocompatibility of magnesium alloys for the next-generation vascular stents. AB - Biodegradable metal alloys emerge as a new class of biomaterials for tissue engineering and medical devices such as cardiovascular stents. Deploying biodegradable materials to fabricate stents not only obviates a second surgical intervention for implant removal but also circumvents the long-term foreign body effect of permanent implants. However, these materials for stents suffer from an un-controlled degradation rate, acute toxic responses, and rapid structural failure presumably due to a non-uniform, fast corrosion process. Here we report that highly uniform, nanophasic degradation is achieved in a new Mg alloy with unique interstitial alloying composition as the nominal formula Mg-2.5Nd-0.2Zn 0.4Zr (wt%, hereafter, denoted as JDBM). This material exhibits highly homogeneous nanophasic biodegradation patterns as compared to other biodegradable metal alloy materials. Consequently it has significantly reduced degradation rate determined by electrochemical characterization. The in vitro cytotoxicity test using human vascular endothelial cells indicates excellent biocompatibility and potentially minimal toxic effect on arterial vessel walls. Finally, we fabricated a cardiovascular stent using JDBM and performed in vivo long-term assessment via implantation of this stent in an animal model. The results confirmed the reduced degradation rate in vivo, excellent tissue compatibility and long-term structural and mechanical durability. Thus, this new Mg-alloy with highly uniform nanophasic biodegradation represents a major breakthrough in the field and a promising material for manufacturing the next generation biodegradable vascular stents. PMID- 23989063 TI - Plasma functionalization of poly(vinyl alcohol) hydrogel for cell adhesion enhancement. AB - Tailoring the interface interactions between a biomaterial and the surrounding tissue is a capital aspect to consider for the design of medical devices. Poly(vinyl alcohol) (PVA) hydrogels present suitable mechanical properties for various biological substitutes, however the lack of cell adhesion on their surface is often a problem. The common approach is to incorporate biomolecules, either by blending or coupling. But these modifications disrupt PVA intra- and intermolecular interactions leading therefore to a loss of its original mechanical properties. In this work, surface modification by glow discharge plasma, technique known to modify only the surface without altering the bulk properties, has been investigated to promote cell attachment on PVA substrates. N2/H2 microwave plasma treatment has been performed, and the chemical composition of PVA surface has been investigated. X-ray photoelectron and Fourier transform infrared analyses on the plasma-treated films revealed the presence of carbonyl and nitrogen species, including amine and amide groups, while the main structure of PVA was unchanged. Plasma modification induced an increase in the PVA surface wettability with no significant change in surface roughness. In contrast to untreated PVA, plasma-modified films allowed successful culture of mouse fibroblasts and human endothelial cells. These results evidenced that the grafting was stable after rehydration and that it displayed cell adhesive properties. Thus plasma amination of PVA is a promising approach to improve cell behavior on contact with synthetic hydrogels for tissue engineering. PMID- 23989065 TI - The birth of the European Society for Vascular Medicine (ESVM) - a new step forward in the development of vascular medicine. PMID- 23989066 TI - Livedoid vasculopathy - a thrombotic disease. AB - Livedoid vasculopathy is a rare, chronic occlusive disease of vessels supporting the upper layers of the skin. It is characterized by purpuric maculae and recurrent painful ulcerations mostly affecting the lower leg. These ulcerations occur episodically especially in summer time and heal slowly, leaving characteristic porcelain-white scars called ?atrophie blanche?.This review is focused on the current knowledge on livedoid vasculopathy and modern therapy strategies resulting from its etiopathogenetic associations with prothrombotic states. Livedoid vasculopathy and its pathophysiology are clearly distinguished from inflammatory vasculitis and thus require a different therapeutic approach. The prevention of irreversible residual scarring and improving the quality of life of patients in this often misdiagnosed disease is one of the main treatment goals. PMID- 23989067 TI - How to asses and improve cardiopulmonary risk prior to vascular surgery? AB - Patients with peripheral arterial disease have a high rate of cardiac, cerebrovascular, or pulmonary comorbidities. Peripheral arterial surgical interventions are associated with a moderate to high perioperative cardiac risk. Simple clinical scoring systems for preoperative risk stratification can be used to identify high-risk patients. In these patients further diagnostic and therapeutic measures are required to reduce perioperative morbidity and mortality. In contrast, a group of patients can be identifed that do not require additional cardiopulmonary diagnostics and can immediately proceed to the intervention. According to evidence-based recommendations in patients at risk beta blocker should be uptitrated and statin therapy should be initiated preoperatively. Quitting smoking preoperatively also reduces perioperative complications and should be encouraged in all patients. PMID- 23989068 TI - Gene therapy for therapeutic angiogenesis in peripheral arterial disease - a systematic review and meta-analysis of randomized, controlled trials. AB - BACKGROUND: Beyond pharmacological, endovascular and surgical treatment strategies for peripheral arterial disease (PAD), therapeutic angiogenesis has been advocated to relieve symptoms and support limb salvage, in particular in patients with critical limb ischemia. We aimed to systematically review randomized controlled trials (RCTs) of gene therapy in PAD. PATIENTS AND METHODS: A systematic search of electronic databases was performed to identify RCTs studying local administration of pro-angiogenic growth factors (VEGF, FGF, HGF, Del-1, HIF-1alpha) using plasmid or viral gene transfer by intra-arterial or intra-muscular injections. Outcomes of interest comprised all-cause mortality, amputations, ulcer healing, walking distance and ankle-brachial index. If feasible, standard meta-analysis should be performed with subgroup analysis for claudicants and patients with critical limb ischemia (CLI). RESULTS: The systematic search yielded 12 RCTs for analysis from 1163 citations. In total, 1494 patients (29 % females) were included with the majority suffering from CLI (64 %). Various endpoints were improved by single studies, but none by a majority of studies. Meta-analysis showed neither a significant benefit nor harm for gene therapy when synthesizing data for all-cause mortality (OR 0.88, 95 % CI 0.62 - 1.26) amputations (OR 0.64, 95 % CI 0.31 - 1.31) or ulcer healing (OR 1.79, 95 % CI 0.8 - 4.01). No differences were seen between patients with intermittent claudication or CLI. CONCLUSIONS: Despite promising results in single studies, no clear benefit could be identified for gene therapy in PAD patients, irrespective of disease severity. PMID- 23989069 TI - Three year results of endovascular therapy with a new generation nitinol stent for femoro-popliteal artery lesions - a single-center outcome analysis of a subcohort of MISAGO 2 study. AB - BACKGROUND: Advances in stent technology have widened the field of indications for stent treatment of femoro-popliteal artery lesions, however the use of stents in bending arterial segments is restricted because some first- and second generation nitinol stent designs did not respond well to the mechanical forces of femoro-popliteal segments in motion which pose a substantial risk of stent fracture inducing in-stent-stenosis. New generation nitinol stents are supposed to overcome these limitations but long-term results are rare. PATIENTS AND METHODS: In forty-five patients (mean age 68 y, range 50 - 85) with peripheral arterial disease (TASC II A-C, Rutherford category 2 - 5) forty-six lesions of the superficial femoral artery (37) or popliteal artery (9) were treated [25 high grade stenoses, mean length 53 mm (range 30 - 145 mm); 21 chronic total occlusions, mean length 74 mm (range 30 - 180 mm)]. 74 % of lesions were located in the mobile bending arterial segments in the distal femoral or the popliteal segment. Clinical reevaluation performed at discharge, at 6, 12, 24, and 36 months included at least the measurement of ankle-brachial index (ABI) and duplex sonography. RESULTS: Procedural success rate was 100 %. At 6, 12, 24, and 36 months, cumulative primary patency rate was 93.5 %, 84.8 %, 80.5 %, and 74.3 % (SE<10); freedom from target lesion revascularization rate was 95.7 %, 89.2 %, 84.9 %, and 79.3 % (SE<10); Rutherford category and ABI improved in all patients and clinical success was maintained in more than 85 % of patients. CONCLUSIONS: Sustained technical and clinical success and good clinical long-term results were achieved with MisagoTM nitinol stent implantation in femoro-popliteal lesions with moderate risk for in-stent-stenosis, and in the distal femoral and popliteal mobile segment. PMID- 23989070 TI - Validation of the Walking Impairment Questionnaire for Spanish patients. AB - BACKGROUND: The Walking Impairment Questionnaire (WIQ) is a short, easy to complete, disease-specific questionnaire to assess intermittent claudication. A Spanish version of the WIQ for Hispanic Americans has recently been validated in Texas, but it needs to be validated for European Spanish people. PATIENTS AND METHODS: After translation and cultural adaptation of the WIQ, 920 patients with intermittent claudication (ankle brachial index < 0.9) completed two questionnaires (Spanish version of the WIQ and European Quality of Life 5 Dimension [EQ-5D]). The validity of the WIQ was determined by correlating WIQ and EQ-5D. Test-retest reliability and internal consistency were determined using the intra-class correlation coefficient (ICC) and Cronbach's alpha, respectively. RESULTS: The three domains of the WIQ were moderately correlated with the EQ-5D health outcome (r = 0.54 to 0.60; p < 0.001). Test-retest reliabilities ranged from ICC = 0.89 to 0.91 and internal consistency (Cronbach's alpha = 0.92) was high. CONCLUSIONS: The Spanish version of the WIQ for European Spanish patients was valid and reproducible, suggesting that it could be used in Spanish patients with intermittent claudication. PMID- 23989071 TI - Popliteal vein compression with the limb extended. AB - BACKGROUND: The aim of this study was to assess the haemodynamic significance of popliteal vein compression by full knee extension. PATIENTS AND METHODS: We examined patients without a history of previous deep vein thrombosis with the knee slightly flexed and then fully extended. The popliteal vein diameters and venous pressures in 61 subjects (116 limbs) were examined using duplex ultrasonography and photoplethysmography. The venous outflow in 50 patients was assessed using photoplethysmography. RESULTS: The diameter of the popliteal vein in semiflexion was 7.7 (+ 1,5) mm, in extension it was reduced to 4.3 (+ 1,7) mm (p < 0.001). Venous pressure in the big toe rose from 12.3 (+ 6,1) mmHg to 15.5 (+ 7,4) (p < 0.001). We have demonstrated the reduction of maximum venous outflow in 50 patients from 65.8 (+ 24) %/min to 60.1 (+ 23) %/min (p < 0.01) immediately after loosening the 2-minute venous occlusion, as well as outflow reduction during subsequent seconds. CONCLUSIONS: Our results provide evidence of haemodynamically significant popliteal vein compression in full extension of the limb. Clinically, the compression may play a role as a risk factor for venous thrombosis in immobilized patients, particularly during operations. PMID- 23989072 TI - Lymphedema - the long way to diagnosis and therapy. AB - BACKGROUND: Clinical experience indicates that edema often remain undiagnosed. The aim of this study was to examine how much time passes between important events in the 'patient journey' and what predicts delayed consultation and diagnosis. PATIENTS AND METHODS: 65 patients with secondary arm lymphedema and 161 patients with primary or secondary leg lymphedema were interviewed. The following latency times were computed: the time between (1) first symptoms and first visit to physician; (2) visit of physician and diagnosis; (3) diagnosis and lymph drainage therapy; (4) diagnosis and compression therapy. Associations of latency times with patient and clinical characteristics were analysed using t tests and multivariate linear regression. RESULTS: All arm edema patients had consulted a physician in the year after first symptoms at the latest, and everyone except two received the diagnosis in the following year at the latest. For secondary leg edema, the average latency until physician consultation was also short with 0.5 +/- 1.8 years, and latency until diagnosis was 1.7 +/- 3.8 years. In contrast, latencies in primary leg edema were significantly longer: The average time between first symptoms and physician consultation was 5.2 +/- 11.0 years, and edema diagnosis was made after further 6.7 +/- 11.4 years. On average, it took 13.5 years from first symptoms to lymph drainage therapy in these patients and 13.7 years until compression therapy. Predictors of late consultation and late diagnosis in primary leg edema were age < 40, positive family anamnesis, and female gender. CONCLUSIONS: Primary leg lymphedema is diagnosed late in many cases, especially in younger women. PMID- 23989073 TI - Comparison of fluorine-18-deoxyglucose positron emission tomography/computed tomography and contrast-enhanced ultrasound in a patient with chronic periaortitis. PMID- 23989074 TI - Giant cell arteriitis in critical bilateral lower limb ischemia. PMID- 23989075 TI - Iatrogenic pseudoaneurysm of the superior thyroid artery. PMID- 23989076 TI - Post-operative Staphylococcus aureus infection of a superficial femoral artery stent. PMID- 23989077 TI - A review of cord blood concentrations of iron status parameters to define reference ranges for preterm infants. AB - BACKGROUND: Iron plays an essential role in various tissue functions, and hence the reliable assessment of iron nutrition status of preterm infants appears to be mandatory. OBJECTIVES: To summarize available data on cord blood concentrations of iron status parameters as surrogate reference ranges for preterm infants until term-equivalent age. METHODS: Review of the literature searching PubMed for cord blood values of hemoglobin, mean corpuscular volume, ferritin, soluble transferrin receptor, ferritin index, transferrin saturation, reticulocyte hemoglobin content, zinc protoporphyrin/heme ratio, and hepcidin and comparison with reference ranges established for adults. RESULTS: Gestational age-specific cord blood concentration ranges at term were computed as weighted mean for hemoglobin [15.9 g/dl (13.3-18.4)], mean corpuscular volume [108.1 fl (97.8 118.5)] and transferrin saturation [61.2% (31.5-90.9)] and listed for ferritin, soluble transferrin receptor, ferritin index, zinc protoporphyrin/heme ratio, reticulocyte hemoglobin content and hepcidin. These surrogate reference ranges were markedly different from adult values. CONCLUSION: Reference ranges of iron status parameters established for adults are probably not suitable to define iron status in preterm infants. If iron supplementation in preterm infants should be individually adjusted based on iron status parameters, it may be necessary to aim for cord blood concentration ranges to enable optimal growth and development. PMID- 23989078 TI - The vitreous, the retinal interface in ocular health and disease. AB - The vitreous is a complex structure whose composition and appearance change with age. Anomalous adhesions between the posterior vitreous face and the retinal surface are the cause of numerous vitreoretinal complications, while the presence of an intact posterior hyaloid provides a scaffold for vascular growth and anteroposterior traction. This review summarizes what is known about the biochemistry of the vitreous, the process of posterior vitreous detachment (PVD) development, and the available clinical approaches to examining the vitreous and its interface. A pooled analysis of studies looking at the presence of a complete, partial or absent PVD in a number of macular and retinal diseases allows us to establish odds ratios for these various states. From this emerge both protective and disease-associated states in conditions such as proliferative diabetic retinopathy, macular edema, and age-related macular degeneration. With the emergence of pharmacological means to separate the posterior hyaloid, a better understanding of the possible role of the vitreous in tractional syndromes is required. PMID- 23989079 TI - Complications from surgery and hospital finances. PMID- 23989080 TI - Whales use distinct strategies to counteract solar ultraviolet radiation. AB - A current threat to the marine ecosystem is the high level of solar ultraviolet radiation (UV). Large whales have recently been shown to suffer sun-induced skin damage from continuous UV exposure. Genotoxic consequences of such exposure remain unknown for these long-lived marine species, as does their capacity to counteract UV-induced insults. We show that UV exposure induces mitochondrial DNA damage in the skin of seasonally sympatric fin, sperm, and blue whales and that this damage accumulates with age. However, counteractive molecular mechanisms are markedly different between species. For example, sperm whales, a species that remains for long periods at the sea surface, activate genotoxic stress pathways in response to UV exposure whereas the paler blue whale relies on increased pigmentation as the season progresses. Our study also shows that whales can modulate their responses to fluctuating levels of UV, and that different evolutionary constraints may have shaped their response strategies. PMID- 23989081 TI - A call for an end to the diet debates. PMID- 23989083 TI - In memoriam: Seymour Lieberman, hormonologist, chemist and humanist (1916-2012) National Academy of Sciences of the United States of America, member, and endocrine society, president, 1974-1975. PMID- 23989084 TI - Editorial: Molecular endocrinology articles in the Spotlight for September 2013. PMID- 23989086 TI - Cauda equina syndrome caused by spontaneous bleeding in the filum terminale myxopapillary ependymoma: a rare pediatric case. AB - The majority of the filum terminale ependymomas are of the myxopapillary type, which most commonly present as lumbago or sciatic pain, an insidious clinical condition, at times accompanied by paraparesis, bladder paresis and vesical alterations. We report the case of a 13-year-old patient who presented with acute cauda equina. He underwent total resection of the lesion, which resulted in progressive improvement. The clinical conditions, diagnoses and treatments of the medullary cone and cauda equina myxopapillary ependymomas are also discussed. PMID- 23989082 TI - PhenDisco: phenotype discovery system for the database of genotypes and phenotypes. AB - The database of genotypes and phenotypes (dbGaP) developed by the National Center for Biotechnology Information (NCBI) is a resource that contains information on various genome-wide association studies (GWAS) and is currently available via NCBI's dbGaP Entrez interface. The database is an important resource, providing GWAS data that can be used for new exploratory research or cross-study validation by authorized users. However, finding studies relevant to a particular phenotype of interest is challenging, as phenotype information is presented in a non standardized way. To address this issue, we developed PhenDisco (phenotype discoverer), a new information retrieval system for dbGaP. PhenDisco consists of two main components: (1) text processing tools that standardize phenotype variables and study metadata, and (2) information retrieval tools that support queries from users and return ranked results. In a preliminary comparison involving 18 search scenarios, PhenDisco showed promising performance for both unranked and ranked search comparisons with dbGaP's search engine Entrez. The system can be accessed at http://pfindr.net. PMID- 23989087 TI - Elevated removal of middle molecules without significant albumin loss with mixed dilution hemodiafiltration for patients unable to provide sufficient blood flow rates. AB - BACKGROUND: We examined the hypothesis that mixed-dilution online hemodiafiltration (MIXED) rather than predilution online hemodiafiltration (PRE) could enable patients with low blood flow rate (Qb) to benefit from advantages of convective therapies. METHODS: Thirty-eight patients were included in a prospective, randomized, crossover and multicenter study conducted with a view to comparing the equilibrated Kt/V, reduction ratio (RR) of phosphates, beta2 microglobulin (beta2-M) and myoglobin (myo) between PRE and MIXED, each at two Qb values of 250 and 300 ml/min during 4 h sessions with a FX1000HDF dialyzer. Albumin losses (Alb) were also measured in 12 patients. RESULTS: MIXED was always found to be more efficient compared to PRE notably for middle molecules (MM). RRbeta2-M: MIX250: 81.3 +/- 3.6 vs. PRE250: 75.2 +/- 5.9; MIX300: 82.7 +/- 3.6 vs. PRE300: 78.1 +/- 5.4; RRmyo: MIX250: 70.2 +/- 3.6 vs. PRE250: 42.6 +/- 2.6; MIX300: 70.6 +/- 3.6 vs. PRE300: 45.7 +/- 3.6 and with Alb <3.0 g/session. CONCLUSION: MIXED allows patients unable to provide sufficiently high Qb to achieve high levels of MM removal. PMID- 23989088 TI - The methodological approach used to develop the 2013 Pain, Agitation, and Delirium Clinical Practice Guidelines for adult ICU patients. AB - OBJECTIVE: In 2006, the American College of Critical Care Medicine assembled a 20 member task force to revise the 2002 guidelines for sedation and analgesia in critically ill adults. This article describes the methodological approach used to develop the American College of Critical Care Medicine's 2013 ICU Pain, Agitation, and Delirium Clinical Practice Guidelines. DESIGN: Review article. SETTING: Multispecialty critical care units. PATIENTS: Adult ICU patients. INTERVENTIONS: The task force was divided into four subcommittees, focusing on pain, sedation, delirium, and related outcomes. Unique aspects of this approach included the use of: 1) the Grading of Recommendations Assessment, Development and Evaluation method to evaluate the literature; 2) a librarian to conduct literature searches and to create and maintain the pain, agitation, and delirium database; 3) creation of a single web-based database; 4) rigorous psychometric analyses of pain, sedation, and delirium assessment tools; 5) the use of anonymous electronic polling; and 6) creation of an ICU pain, agitation, and delirium care bundle. RESULTS: The pain, agitation, and delirium database includes over 19,000 references. With the help of psychometric experts, members developed a scoring system and analyzed the psychometric properties of 6 behavioral pain scales, 10 sedation/agitation scales, and 5 delirium monitoring tools. A meta-analysis was performed to assess the overall impact of benzodiazepine versus nonbenzodiazepine sedation on ICU outcomes. The pain, agitation, and delirium guidelines include 54 evidence-based statements and recommendations. The quality of evidence and strength for each statement and recommendation was ranked. In the absence of sufficient evidence or group consensus, no recommendations were made. An ICU pain, agitation, and delirium care bundle was created to facilitate adoption of the pain, agitation, and delirium guidelines. It focuses on taking an integrated approach to assessing, treating, and preventing pain, agitation/sedation, and delirium in critically ill patients, and it links pain, agitation, and delirium management to spontaneous awakening trials, spontaneous breathing trials, and ICU early mobility and sleep hygiene programs in order to achieve synergistic benefits to ICU patient outcomes. CONCLUSIONS: The 2013 ICU pain, agitation, and delirium guidelines provide critical care providers with an evidence-based, integrated, and interdisciplinary approach to managing pain, agitation/sedation, and delirium. The methodological approach used to develop the guidelines ensures that they are rigorous, evidence-based, and transparent. Implementation of the ICU pain, agitation, and delirium care bundle is expected to have a significant beneficial impact on ICU outcomes and costs. PMID- 23989089 TI - Implementing the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle into everyday care: opportunities, challenges, and lessons learned for implementing the ICU Pain, Agitation, and Delirium Guidelines. AB - OBJECTIVE: The awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle is an evidence-based interprofessional multicomponent strategy for minimizing sedative exposure, reducing duration of mechanical ventilation, and managing ICU-acquired delirium and weakness. The purpose of this study was to identify facilitators and barriers to awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle adoption and to evaluate the extent to which bundle implementation was effective, sustainable, and conducive to dissemination. DESIGN: Prospective, before-after, mixed-methods study. SETTING: Five adult ICUs, one step-down unit, and a special care unit located in a 624-bed academic medical center SUBJECTS: : Interprofessional ICU team members at participating institution. INTERVENTIONS AND MEASUREMENTS: In collaboration with the participating institution, we developed, implemented, and refined an awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle policy. Over the course of an 18-month period, all ICU team members were offered the opportunity to participate in numerous multimodal educational efforts. Three focus group sessions, three online surveys, and one educational evaluation were administered in an attempt to identify facilitators and barriers to bundle adoption. MAIN RESULTS: Factors believed to facilitate bundle implementation included: 1) the performance of daily, interdisciplinary, rounds; 2) engagement of key implementation leaders; 3) sustained and diverse educational efforts; and 4) the bundle's quality and strength. Barriers identified included: 1) intervention-related issues (e.g., timing of trials, fear of adverse events), 2) communication and care coordination challenges, 3) knowledge deficits, 4) workload concerns, and 5) documentation burden. Despite these challenges, participants believed implementation ultimately benefited patients, improved interdisciplinary communication, and empowered nurses and other ICU team members. CONCLUSIONS: In this study of the implementation of the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle in a tertiary care setting, clear factors were identified that both advanced and impeded adoption of this complex intervention that requires interprofessional education, coordination, and cooperation. Focusing on these factors preemptively should enable a more effective and lasting implementation of the bundle and better care for critically ill patients. Lessons learned from this study will also help healthcare providers optimize implementation of the recent ICU pain, agitation, and delirium guidelines, which has many similarities but also some important differences as compared with the awakening and breathing coordination, delirium monitoring/management, and early exercise/mobility bundle. PMID- 23989090 TI - Contextual issues influencing implementation and outcomes associated with an integrated approach to managing pain, agitation, and delirium in adult ICUs. AB - OBJECTIVE: This pilot study was designed to identify which contextual factors facilitate/hinder the implementation of the awakening, breathing, coordination, delirium, and early mobility (ABCDE) bundle for guidance in future studies. DESIGN: The sources of data for this study included document review, planned site visits (including interviews and observations), a brief online contextual factors survey, and self-reported process and outcome data. PATIENTS: All patients in the four participating SF Bay Area ICUs were eligible to be included in this pilot study. SETTING: This study took place in the four San Francisco Bay Area ICUs participating in the ICU Clinical Impact Interest Group, funded by the Gordon and Betty Moore Foundation from January 2012 through June 2013. INTERVENTIONS: This was a pilot evaluation study to identify factors that facilitated/hindered the implementation of the ABCDE bundle, interventions designed to decrease the prevalence of ICU-acquired delirium and muscle weakness. The ABCDE bundle consists of spontaneous awakening trials, spontaneous breathing trials, coordination of awakening and breathing trials, choice of sedation, delirium screening and treatment, and early progressive mobility. MEASUREMENTS: Process data related to bundle element compliance were collected at baseline and monthly during the intervention period. Outcome data (average ICU length of stay and average days on mechanical ventilation) were collected at baseline and quarterly during the intervention period. Hospital-specific results of the online contextual factors survey and information gathered through interviews and observations during site visits also contributed to the analysis. MAIN RESULTS: Factors related to structural characteristics of the ICU, an organizational-wide patient safety culture, an ICU culture of quality improvement, implementation planning, training/support, and prompts/documentation are believed to have facilitated the rate and success of ABCDE bundle implementation. Excessive turnover (both in project and ICU leadership), staff morale issues, lack of respect among disciplines, knowledge deficits, and excessive use of registry staff are believed to have hindered implementation. CONCLUSIONS: Successful implementation of the elements of the ABCDE bundle can result in significant improvements in ICU patient care. The results of this study highlight specific structural and cultural elements of ICUs and hospitals that can positively and negatively influence the implementation of complex care bundles like the ABCDE bundle. Further research is needed to assess the influence of these contextual factors across a broader variety of ICUs and hospitals. PMID- 23989091 TI - Implementation of the Pain, Agitation, and Delirium Clinical Practice Guidelines and promoting patient mobility to prevent post-intensive care syndrome. AB - Surviving critical illness is associated with persistent and severe physical, cognitive, and psychological morbidities. The Society of Critical Care Medicine has developed pain, agitation, and delirium guidelines and promoted mobility to improve care of critically ill patients. A task force has developed tools to facilitate and rapidly implement the translation of guideline care recommendations into practice. The Society of Critical Care Medicine has also assembled a task force to assess the long-term consequences of critical illness. This article will explore relationships between the pain, agitation, and delirium guidelines, mobility recommendations, and post-intensive care syndrome initiative. Implementation of the pain, agitation, and delirium guidelines taking into account current data regarding post-intensive care syndrome outcomes and potential interventions are an important first step toward improving outcomes for patients and their families. Research is needed to reduce the impact of long-term negative consequences of critical illness and to fully understand the best within and post-ICU interventions, along with the optimal timing and dose of such interventions to produce the best long-term outcomes. PMID- 23989092 TI - Psychometric analysis of subjective sedation scales in critically ill adults. AB - OBJECTIVE: To describe and analyze the development and psychometric properties of subjective sedation scales developed for critically ill adult patients. DATA SOURCES: PubMed, MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, Scopus, ISI Web of Science, and the International Pharmaceutical Abstracts. STUDY SELECTION: English-only publications through December 2012 with at least 30 patients older than 18 years, which included the key words of adult, critically ill, subjective sedation scale, sedation scale, validity, and reliability. DATA EXTRACTION: Two independent reviewers evaluated the psychometric properties using a standardized sedation scale psychometric scoring system. DATA SYNTHESIS: Among the 19,000+ citations extracted for the 2013 Society of Critical Care Medicine's Clinical Practice Guidelines for the Management of Pain, Agitation and Delirium and from December 2010 to 2012, 36 articles were identified compassing 11 sedation scales. The scale development process, psychometric properties, feasibility, and implementation of sedation scales were analyzed using a 0-20 scoring system. Two scales demonstrated scores indicating "very good" published psychometric properties: Richmond Agitation-Sedation Scale (19.5) and the Sedation-Agitation Scale (19). Scores with "moderate" properties include the Vancouver Interaction and Calmness Scale (14.3), Adaptation to the Intensive Care Environment (13.7), Ramsay Sedation Scale (13.2), Minnesota Sedation Assessment Tool (13), and the Nursing Instrument for the Communication of Sedation (12.8). Scales with "low" properties included the Motor Activity Assessment Scale (11.5) and the Sedation Intensive Care Score (10.5). The New Sheffield Sedation Scale (8.5) and the Observer's Assessment of Alertness/Sedation Scale (3.7) demonstrated "very low" published properties. CONCLUSIONS: Based on the current literature, and using a predetermined psychometric scoring system, the Richmond Agitation-Sedation Scale and the Sedation-Agitation Scale are the most valid and reliable subjective sedation scales for use in critically ill adult patients. PMID- 23989093 TI - Benzodiazepine versus nonbenzodiazepine-based sedation for mechanically ventilated, critically ill adults: a systematic review and meta-analysis of randomized trials. AB - BACKGROUND: Use of dexmedetomidine or propofol rather than a benzodiazepine sedation strategy may improve ICU outcomes. We reviewed randomized trials comparing a benzodiazepine and nonbenzodiazepine regimen in mechanically ventilated adult ICU patients to determine if differences exist between these sedation strategies with respect to ICU length of stay, time on the ventilator, delirium prevalence, and short-term mortality. METHODS: We searched CINAHL, MEDLINE, the Cochrane databases, and the American College of Critical Care Medicine's Pain, Agitation, Delirium Management Guidelines' literature database from 1996 to 2013. Citations were screened for randomized trials that enrolled critically ill, mechanically ventilated adults comparing an IV benzodiazepine based to a nonbenzodiazepine-based sedative regimen and reported duration of ICU length of stay, duration of mechanical ventilation, delirium prevalence, and/or short-term mortality. Trial characteristics and results were abstracted in duplicate and independently, and the Cochrane risk of bias tool was used for quality assessment. We performed random effects model meta-analyses where possible. RESULTS: We included six trials enrolling 1,235 patients: midazolam versus dexmedetomidine (n = 3), lorazepam versus dexmedetomidine (n = 1), midazolam versus propofol (n = 1), and lorazepam versus propofol (n = 1). Compared to a benzodiazepine sedative strategy, a nonbenzodiazepine sedative strategy was associated with a shorter ICU length of stay (n = 6 studies; difference = 1.62 d; 95% CI, 0.68-2.55; I = 0%; p = 0.0007) and duration of mechanical ventilation (n = 4 studies; difference = 1.9 d; 95% CI, 1.70-2.09; I2 = 0%; p < 0.00001) but a similar prevalence of delirium (n = 2; risk ratio = 0.83; 95% CI, 0.61-1.11; I2 = 84%; p = 0.19) and short-term mortality rate (n = 4; risk ratio = 0.98; 95% CI, 0.76-1.27; I2 = 30%; p = 0.88). CONCLUSIONS: Current controlled data suggest that use of a dexmedetomidine- or propofol-based sedation regimen rather than a benzodiazepine-based sedation regimen in critically ill adults may reduce ICU length of stay and duration of mechanical ventilation. Larger controlled studies are needed to further define the impact of nonbenzodiazepine sedative regimens on delirium and short-term mortality. PMID- 23989094 TI - Daily sedation interruption versus targeted light sedation strategies in ICU patients. AB - OBJECTIVE: The updated clinical practice guidelines for the management of pain, agitation, and delirium recommend either daily sedation interruption or maintaining light levels of sedation as methods to improve outcomes for patients who are sedated in the ICU. We review the evidence supporting both methods and discuss whether one method is preferable or if they should be used concurrently. DATA SOURCE: Original research articles identified using the electronic PubMed database. STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials and large prospective cohort studies of mechanically ventilated ICU patients requiring sedation were selected. DATA SYNTHESIS: The methods of daily sedation interruption and targeting light sedation levels (including avoidance of deep sedation) are safe in critically ill patients with no increase, and a potential decrease, in long-term psychiatric disturbances. Randomized trials comparing these methods with standard care, which has traditionally involved moderate to heavy sedation, found that both methods reduced duration of mechanical ventilation and ICU length of stay. Additionally, one trial noted that daily sedation interruption paired with spontaneous breathing trials improved 1-year survival, whereas a large observational study found that deep sedation was associated with decreased 180-day survival. Two common characteristics of these interventions in trials showing benefits were avoidance of deep levels of sedation and significant reductions in sedative doses, especially benzodiazepines. Thus, combining targeted light sedation with daily sedation interruption may be more beneficial than either method alone if sedative doses are reduced and arousal and mobility are facilitated during the ICU stay. CONCLUSION: Daily sedation interruption and targeting light sedation levels are safe and proven to improve outcomes for sedated ICU patients when these approaches result in reduced sedative exposure and facilitate arousal. It remains unclear as to whether one approach is superior, and further studies are needed to evaluate which patients benefit most from either or both techniques. PMID- 23989095 TI - Top 10 myths regarding sedation and delirium in the ICU. AB - The management of pain, agitation, and delirium in critically ill patients can be complicated by multiple factors. Decisions to administer opioids, sedatives, and antipsychotic medications are frequently driven by a desire to facilitate patients' comfort and their tolerance of invasive procedures or other interventions within the ICU. Despite accumulating evidence supporting new strategies to optimize pain, sedation, and delirium practices in the ICU, many critical care practitioners continue to embrace false perceptions regarding appropriate management in these critically ill patients. This article explores these perceptions in more detail and offers new evidence-based strategies to help critical care practitioners better manage sedation and delirium, particularly in ICU patients. PMID- 23989096 TI - Alcohol, nicotine, and iatrogenic withdrawals in the ICU. AB - OBJECTIVES: The neurophysiology, risk factors, and screening tools associated with alcohol withdrawal syndrome in the ICU are reviewed. Alcohol withdrawal syndrome assessment and its treatment options are discussed. Description of nicotine withdrawal and related publications specific to the critically ill are also reviewed. A brief comment as to sedative and opiate withdrawal follows. DATA AND SUMMARY: The role of currently published alcohol withdrawal syndrome pharmacologic strategies (benzodiazepines, ethanol, clomethiazole, antipsychotics, barbiturates, propofol, and dexmedetomidine) is detailed. Studies on nicotine withdrawal management in the ICU focus mainly on the safety (mortality) of nicotine replacement therapy. Study characteristics and methodological limitations are presented. CONCLUSION: We recommend a pharmacologic regimen titrated to withdrawal symptoms in ICU patients with alcohol withdrawal syndrome. Benzodiazepines are a reasonable option; phenobarbital appears to confer some advantages in combination with benzodiazepines. Propofol and dexmedetomidine have not been rigorously tested in comparative studies of drug withdrawal treatment; their use as additional or alternative strategies for managing withdrawal syndromes in ICU patients should therefore be individualized to each patient. Insufficient data preclude recommendations as to nicotine replacement therapy and management of iatrogenic drug withdrawal in ICU patients. PMID- 23989097 TI - ICU early mobilization: from recommendation to implementation at three medical centers. AB - OBJECTIVE: To compare and contrast the process used to implement an early mobility program in ICUs at three different medical centers and to assess their impact on clinical outcomes in critically ill patients. DESIGN: Three ICU early mobilization quality improvement projects are summarized utilizing the Institute for Healthcare Improvement framework of Plan-Do-Study-Act. INTERVENTION: Each of the three ICU early mobilization programs required an interprofessional team based approach to plan, educate, and implement the ICU early mobility program. Champions from each profession-nursing, physical therapy, physician, and respiratory care-were identified to facilitate changes in ICU culture and clinical practice and to identify and address barriers to early mobility program implementation at each institution. SETTING: The medical ICU at Wake Forest University, the medical ICU at Johns Hopkins Hospital, and the mixed medical surgical ICU at the University of California San Francisco Medical Center. RESULTS: Establishing an ICU early mobilization quality improvement program resulted in a reduced ICU and hospital length of stay at all three institutions and decreased rates of delirium and the need for sedation for the patients enrolled in the Johns Hopkins ICU early mobility program. CONCLUSION: Instituting a planned, structured ICU early mobility quality improvement project can result in improved outcomes and reduced costs for ICU patients across healthcare systems. PMID- 23989098 TI - Cognitive dysfunction in ICU patients: risk factors, predictors, and rehabilitation interventions. AB - In contrast to other clinical outcomes, long-term cognitive function in critical care survivors has not been deeply studied. In this narrative review, we summarize the existing literature on the prevalence, mechanisms, risk factors, and prediction of cognitive impairment after surviving critical illness. Depending on the exact clinical subgroup, up to 100% of critical care survivors may suffer some degree of long-term cognitive impairment at hospital discharge; in approximately 50%, decrements in cognitive function will persist years later. Although the mechanisms of acquiring this impairment are poorly understood, several risk factors have been identified. Unfortunately, no easy means of predicting long-term cognitive impairment exists. Despite this barrier, research is ongoing to test possible treatments for cognitive impairment. In particular, the potential role of exercise on cognitive recovery is an exciting area of exploration. Opportunities exist to incorporate physical and cognitive rehabilitation strategies across a spectrum of environments (in the ICU, on the hospital ward, and at home, posthospital discharge). PMID- 23989099 TI - The pain, agitation, and delirium care bundle: synergistic benefits of implementing the 2013 Pain, Agitation, and Delirium Guidelines in an integrated and interdisciplinary fashion. AB - OBJECTIVE: In 2013, the American College of Critical Care Medicine published a revised version of the pain, agitation, and delirium guidelines. The guidelines included an ICU pain, agitation, and delirium care bundle designed to facilitate implementation of the pain, agitation, and delirium guidelines. DESIGN: Review article. SETTING: Multispecialty critical care units. PATIENTS: Adult ICU patients. INTERVENTIONS: This article describes: 1) the ICU pain, agitation, and delirium care bundle in more detail, linking pain, sedation/agitation, and delirium management in an integrated and interdisciplinary fashion; 2) pain, agitation, and delirium implementation strategies; and 3) the potential synergistic benefits of linking pain, agitation, and delirium management strategies to other evidence-based ICU practices, including spontaneous breathing trials, ICU early mobility programs, and ICU sleep hygiene programs, in order to improve ICU patient outcomes and to reduce costs of care. RESULTS: Linking the ICU pain, agitation, and delirium management strategies with spontaneous awakening trials, spontaneous breathing trials, and early mobility and sleep hygiene programs is associated with significant improvements in ICU patient outcomes and reductions in their costs of care. CONCLUSIONS: The 2013 ICU pain, agitation, and delirium guidelines provide critical care providers with an evidence-based, integrated, and interdisciplinary approach to managing pain, agitation/sedation, and delirium. The ICU pain, agitation, and delirium care bundle provides a framework for facilitating implementation of the pain, agitation, and delirium guidelines. Widespread implementation of the ICU pain, agitation, and delirium care bundle is likely to result in large-scale improvements in ICU patient outcomes and significant reductions in costs. PMID- 23989100 TI - Transition metal complexes of axially chiral tetrathioether bay-substituted perylene bisimide dyes. AB - Nucleophilic substitution of 1,6,7,12-tetrachloro perylene bisimide (PBI) with n butanethiol provided a novel, highly twisted PBI bearing four sulphur coordination sites at the bay positions, from which silver and palladium complexes were prepared. PMID- 23989102 TI - Investigating the order-disorder phase transition in Nd2-xYxZr2O7via diffraction and spectroscopy. AB - The pyrochlore-defect fluorite phase transition in the mixed-metal zirconate Nd2 xYxZr2O7 (0 <= x <= 2) solid solution was investigated using synchrotron X-ray and neutron diffraction, as well as X-ray absorption spectroscopy. Diffraction analysis revealed a two-phase region between 1.0 <= x <= 1.2. In the pyrochlore phase, Zr L3-edge XANES analysis demonstrated a gradual change in the local coordination environment of the B site with increasing Y content that was consistent with an increase in disorder. Although Y L3-edge XANES analysis suggested that the Y cations remained in an ordered coordination environment in the pyrochlore phase, disorder did gradually increase once the fluorite phase formed. It was found that Y cations prefer an ordered coordination environment near the phase boundary whereas Zr cations prefer a disordered coordination environment. PMID- 23989101 TI - Bifunctional coumarin derivatives that inhibit transthyretin amyloidogenesis and serve as fluorescent transthyretin folding sensors. AB - We describe coumarin derivatives that are non-fluorescent in aqueous buffers and that very selectively bind to transthyretin (TTR) in complex biological environments potently inhibiting TTR amyloidogenesis while also exhibiting sensitive off-on fluorescent sensing of the properly folded quaternary structure of TTR. PMID- 23989103 TI - Serum soluble ST2 as diagnostic marker of systemic inflammatory reactive syndrome of bacterial etiology in children. AB - BACKGROUND: Accurate and timely diagnosis of community-acquired bacterial versus viral infections in children with systemic inflammatory response syndrome (SIRS) remains challenging both for clinician and laboratory. In the quest of new biochemical markers to distinguish bacterial from viral infection, we have explored the possible role of the soluble secreted form of ST2 (sST2). METHODS: This explorative prospective cohort study included children with SIRS who were suspected of having community-acquired infections. Plasma samples for sST2 measurement were obtained from 64 hospitalized children, 41 of whom had SIRS of bacterial etiology and 23 SIRS of viral etiology, and from 20 healthy, age- and sex-matched control children. sST2 measurement was carried out by enzyme-linked immunosorbent assay in parallel with standard measurements of procalcitonin (PCT) and C reactive protein (CRP). RESULTS: Our findings demonstrate that children with SIRS associated with bacterial infection present significantly increased levels of sST2, when compared with patients with SIRS of viral etiology and healthy children. More important, receiver operating characteristic curve analysis indicated that sST2 has a significant diagnostic performance with respect to early identification of SIRS of bacterial etiology, which was similar to that of PCT and greater than that of CRP. Finally, the combination of sST2 plus PCT and/or CRP, and PCT plus CRP increased their sensitivity and negative predictive value compared with sST2, PCT and CRP alone. CONCLUSIONS: In conclusion, sST2 level may prove useful in predicting bacterial etiology in children with SIRS. PMID- 23989105 TI - Infective endocarditis at Costa Rica's children's hospital, 2000-2011. AB - Few reports of infective endocarditis in Latin American children have been published. We describe the epidemiology of infective endocarditis at the only pediatric tertiary hospital in Costa Rica. Methicillin-resistant Staphylococcus aureus rate was isolated in 44% of cases. The case fatality rate was 23%. PMID- 23989104 TI - Hospitalization for respiratory syncytial virus illness in Down syndrome following prophylaxis with palivizumab. AB - BACKGROUND: Down syndrome (DS) is a risk factor for respiratory syncytial virus (RSV) hospitalization, but little is known about prophylaxis in these children. METHODS: CARESS is a prospective registry of children who received >=1 dose of palivizumab during the 2006-2012 RSV seasons across 32 sites in Canada. The objective was to compare respiratory illness hospitalization and RSV hospitalization (RSVH) hazard ratios in DS children aged <2 years who received palivizumab versus children who received prophylaxis for standard indications (SI) and for other medical illnesses (MI). RESULTS: 13,310 children were enrolled; DS (600; 4.5%), SI (11,081; 83.3%) and MI (1629, 12.2%), with DS children increasing over the duration from 0.1% (2006) to 4.5% (2012). Participants were significantly different in mean birth weight, gestational and enrollment age and risk factors. Children in each group received an average of 4.3 +/- 1.4 (DS), 4.1 +/- 1.6 (SI) and 4.5 +/- 1.4 (MI) palivizumab injections per RSV season, with DS, differing significantly from SI [F(2, 13,307) = 43.6, P = 0.01] but not MI [F(2, 13 307) = 43.6, P = 0.07]. Compliance rates were similar across the groups. While a significantly greater proportion of SI children had RIHs compared with DS, [hazard ratio: 0.64 (0.48-0.84); P = 0.001] hazard ratios were similar for DS and MI. RSVH incidence rates were: 1.53%, 1.45% and 2.27% for DS, SI and MI, respectively. Neither group nor compliance affected time to RSVH. CONCLUSIONS: The proportion of DS children who received palivizumab in CARESS has increased almost 45-fold. RSVH rates were low in DS following prophylaxis and hazards were similar to those found in SI and MI. PMID- 23989106 TI - Short-course antibiotic treatment for community-acquired alveolar pneumonia in ambulatory children: a double-blind, randomized, placebo-controlled trial. AB - BACKGROUND: Studies on short-course treatment of childhood pneumonia in the developed world are lacking. We compared clinical and laboratory outcomes of a 3 day or a 5-day to a 10-day treatment in young children with community-acquired alveolar pneumonia. METHODS: A double-blind, randomized, placebo-controlled trial was conducted in 2 stages: (1) 3 days versus 10 days and (2) 5 days versus 10 days. Amoxicillin (80 mg/kg/d; divided into 3 daily doses) was used for all arms. Case definition was: age 6-59 months; radiologically confirmed community-acquired alveolar pneumonia; temperature >=38.5 degrees C; peripheral white blood cell count >=15,000/mm3; status permitting outpatient treatment. Scheduled visits were on days 4-5 and 10-14 with daily telephone interviews for 30 days. Treatment failure was defined by the need for a rescue treatment or hospitalization. Secondary outcomes were: duration of fever and symptoms and white blood cell and C-reactive protein responses. RESULTS: During Stage 1, 4/10 (40%) and 0/12 (0%) evaluable patients failed in the 3-day and 10-day arms, respectively (P = 0.16). Therefore, the 3-day arm was replaced by a 5-day arm (Stage 2). No failures occurred in the 5-day (n = 56) and 10-day (n = 59) arms. Overall, 4/10 (0%), 0/56 and 0/42 (0%) children failed in the 3-day, 5-day and 10-day arms, respectively (P < 0.001, 3-day versus 5-day or 10-day). Secondary outcomes were similar in the 5-day and 10-day arms. CONCLUSION: In 6- to 59-month-old outpatients with community-acquired alveolar pneumonia, a 5-day course with high-dose oral amoxicillin was not inferior to a 10-day course. The 3-day regimen may be associated with an unacceptable failure rate. PMID- 23989108 TI - Seasonal occurrence of human metapneumovirus infections in Croatia. AB - BACKGROUND: Human metapneumovirus (HMPV) is 1 of the commonest causes of viral ARI especially among pediatric patients. Its incidence varies from year to year in countries belonging to moderate climate zone. The aim of this study was to investigate epidemiologic characteristics of HMPV infections in Croatia. METHODS: During a 4-year period (January 1, 2009, through December 31, 2012), nasopharyngeal aspirates were collected from 2610 children <10 years who were admitted to hospitals with acute respiratory infections. Direct immunofluorescence assay was used to detect the virus from clinical samples. Demographics and clinical data were also analyzed. RESULTS: HMPV was detected in 8.4% of patients. While many of HMPV-infected children were 13-24 months of age (30.9% of all proven HMPV infections), the highest incidence of HMPV infection was recorded in 2- to 5-year-old children (11.4% of all children in this age group). HMPV caused 7.1% of upper respiratory tract infections and 11.7% of lower respiratory tract infections. Annual prevalence rates of HMPV infection varied significantly from year to year (P < 0.001). Peak incidence was detected in spring or winter months, depending on the year. CONCLUSIONS: This study indicates that HMPV infections in Croatia show a biennial outbreak pattern characterized by alternation of winter and spring activity. HMPV outbreaks alternate with respiratory syncytial virus outbreaks. PMID- 23989109 TI - Epidemiology of viral gastroenteritis in Iran. AB - Viruses are prominent causative agents of acute gastroenteritis in children <5 years of age per year. In the present review, all viral gastroenteritis studies in Iran were assessed, and the mean prevalences of rotaviruses, noroviruses, enteric adenoviruses, sapoviruses and astroviruses associated with acute gastroenteritis were 39.9%, 6%, 5.7%, 4.2% and 2.7%, respectively. In 2 studies, human bocavirus and human parechovirus were detected in 21.8% and 23.7% of children with acute gastroenteritis, respectively. PMID- 23989107 TI - Genetic variation of Helicobacter pylori in the oral cavity and stomach detected using thymine adenine cloning in children with chronic gastritis. AB - OBJECTIVES: To investigate the DNA sequence variations of Helicobacter pylori in the oral cavities and stomachs of children with chronic gastritis. METHODS: Dental plaques and gargle on 235 patients were obtained before gastroscopy. Gastric H. pylori infection was diagnosed using rapid urease test or Giemsa staining. H. pylori 16S rDNA and CagA gene were analyzed using PCR methods. Thymine adenine cloning-based sequencing was performed in patients with CagA gene positive from oral cavities. The sequence alignments and V1 variable region were evaluated by comparison with the sequence of the standard H. pylori 26695 strain. RESULTS: Totally, 46 out of the 235 patients were positive for gastric H. pylori infection. Of the 46 patients, 26 cases had amplified H. pylori 16S rDNA in both oral (plaque and gargle) and gastric samples. Of the 26 cases, 12 patients (46.1%) were positive for the H. pylori CagA gene in the oral samples, which was significantly lower than that in the gastric mucosa (80.8%; P = 0.010). The homology of the complete sequence alignment ranged from 74.0% to 92.1% in the oral and gastric samples. The V1 region alleles (positions 75-99) had 7-22 polymorphisms (homology from 12.0% to 72.0%) in 11 patients between the oral and gastric samples, but had 100% homology in 1 patient. CONCLUSIONS: Our study found that distinct H. pylori strains exist in the oral cavities of children, but we would not support the hypothesis that H. pylori in the oral cavities is an important reservoir of gastric H. pylori infections in children. PMID- 23989110 TI - In vivo degradation of magnesium alloy LA63 scaffolds for temporary stabilization of biological myocardial grafts in a swine model. AB - Synthetic or biological patch materials used for surgical myocardial reconstruction are often fragile. Therefore, a transient support by degradable magnesium scaffolds can reduce the risk of dilation or rupture of the patch until physiological remodeling has led to a sufficient mechanical durability. However, there is evidence that magnesium implants can influence the growth and physiological behavior of the host's cells and tissue. Hence, we epicardially implanted scaffolds of the magnesium fluoride-coated magnesium alloy LA63 in a swine model to assess biocompatibility and degradation kinetics. Chemical analysis of the pigs' organs revealed no toxic accumulation of magnesium ions in the skeletal muscle, myocardium, liver, kidney, and bone of the pigs 1, 3, and 6 months postimplantation. The implants were surrounded by a fibrous granulation tissue, but no signs of necrosis were histologically evaluable. A sufficiently slow degradation rate of the magnesium alloy scaffold can be demonstrated via micro-computed tomography investigation. We conclude that stabilizing scaffolds of the magnesium fluoride-coated magnesium alloy LA63 can be used for epicardial application because no significant adverse effects to myocardial tissue were noted. Thus, degradable stabilizing scaffolds of this magnesium alloy with a slow degradation rate can extend the indication of innovative biological and synthetic patch materials. PMID- 23989111 TI - Steroid profiling for congenital adrenal hyperplasia by tandem mass spectrometry as a second-tier test reduces follow-up burdens in a tertiary care hospital: a retrospective and prospective evaluation. AB - BACKGROUND: Newborn screening for congenital adrenal hyperplasia (CAH) based on measuring 17-hydroxyprogesterone (17-OHP) by immunoassay generates a number of false-positive results, especially in preterm neonates. We applied steroid profiling by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a second-tier test in newborns with positive CAH screening and evaluated its clinical utility in a tertiary care hospital setting. METHODS: By performing a 4 year retrospective data review, we were able to test 121 dried blood spots from newborns with positive CAH screening for 17-OHP, androstenedione and cortisol levels by LC-MS/MS. We prospectively evaluated the clinical utility of steroid profiling after the implementation of steroid profiling as a second-tier test in our routine clinical practice. During the 2-year prospective study period, 104 cases with positive initial screening by FIA were tested by LC-MS/MS. Clinical and laboratory follow-up were performed for at least 6 months. RESULTS: The preterm neonates accounted for 50.7% (76/150) and 70.4% (88/125) of screening positive cases in retrospective and prospective cohorts, respectively. By applying steroid profiling as a second-tier test for positive CAH screening, we eliminated all false-positive results and decreased the median follow-up time from 75 to 8 days. CONCLUSIONS: Our data showed that steroid profiling reduced the burden of follow-up exams by improving the positive predictive value of the CAH screening program. The use of steroid profiling as a second-tier test for positive CAH screening will improve clinical practice particularly in a tertiary care hospital setting where positive CAH screening from preterm neonates is frequently encountered. PMID- 23989112 TI - Amyloid beta peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Abeta-mediated toxicity in vitro. AB - The gradual accumulation and assembly of beta-amyloid (Abeta) peptide into neuritic plaques is a major pathological hallmark of Alzheimer disease (AD). Proteolytic degradation of Abeta is an important clearance mechanism under normal circumstances, and it has been found to be compromised in those with AD. Here, the extended substrate specificity and Abeta-degrading capacity of kallikrein 7 (KLK7), a serine protease with a unique chymotrypsin-like specificity, was characterized. Preferred peptide substrates of KLK7 identified using a bacterial display substrate library were found to exhibit a consensus motif of RXPhi(Y/F)?(Y/F)?(S/A/G/T) or RXPhi(Y/F)?(S/T/A) (Phi=hydrophobic), which is remarkably similar to the hydrophobic core motif of Abeta (K16L17V18F19F20 A21) that is largely responsible for aggregation propensity. KLK7 was found to cleave after both Phe residues within the core of Abeta42 in vitro, thereby inhibiting Abeta fibril formation and promoting the degradation of preformed fibrils. Finally, the treatment of Abeta oligomer preparations with KLK7, but not inactive pro-KLK7, significantly reduced Abeta42-mediated toxicity to rat hippocampal neurons to the same extent as the known Abeta-degrading protease insulin degrading enzyme (IDE). Taken together, these results indicate that KLK7 possesses an Abeta-degrading capacity that can ameliorate the toxic effects of the aggregated peptide in vitro. PMID- 23989113 TI - Association of the GCKR rs780094 polymorphism with metabolic traits including carotid intima-media thickness in Japanese community-dwelling men, but not in women. AB - BACKGROUND: The glucokinase regulator gene (GCKR) rs780094 has been shown to be strongly associated with some metabolic traits and atherosclerotic parameters, while the association between GCKR rs780094 and carotid intima-media thickness (CIMT) has not been fully investigated in the general population. The associations between the GCKR rs780094 genotype and metabolic traits including CIMT were examined in a Japanese community-dwelling population. METHODS: A total of 2491 Japanese adults (907 men and 1584 women) who participated in a medical screening program for the general population from 29 to 94 years of age during 2008 to 2010 were enrolled. GCKR rs780094 was genotyped by the TaqMan polymerase chain reaction method, and associations with metabolic markers including CIMT were evaluated. RESULTS: GCKR rs780094 AA genotype was significantly associated with higher TG (p<0.001 vs. GG), lower HDL-C (p=0.021 vs. GG), and lower HbA1c(p=0.023 vs. GG). The AA genotype showed significantly thinner CIMT (p=0.001 vs. GX). These associations were seen only in men. CONCLUSIONS: GCKR rs780094 was associated with TG, HDL-C, and HbA1c levels, as well as with CIMT in Japanese community-dwelling men, but not women. PMID- 23989114 TI - Cartilage splitting without stitches: technique and outcomes. AB - IMPORTANCE: Otoplasty procedures usually involve cartilage sparing, with stitches or cartilage scoring. These techniques have been widely reviewed in the literature. The technique reported in this study requires neither stitches nor rasping but rather a complete separation of the helix and antihelix, with nontransfixing incisions to break the cartilaginous springs. OBJECTIVES: To evaluate the technical details, aesthetic results, and complications in a series of otoplasty procedures involving cartilage splitting without stitches. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective review of patients who underwent otoplasty procedures between January 2004 and September 2010, by the same senior surgeon. MAIN OUTCOMES AND MEASURES: File data on complications, recurrences, and revision rates were collected. An aesthetic evaluation of the postoperative results was conducted by a panel of 3 plastic surgeons and 3 lay observers. RESULTS: Our series included 58 patients, with a mean age of 16 years. No recurrences were reported. Six patients (10%) experienced minor complications. No revisions were needed. No chondritis or skin necrosis was noted. The aesthetic results were very good for 36 patients (62%) by the plastic surgeons and 39 patients (68%) by lay observers. The remaining aesthetic results were judged as good. CONCLUSIONS AND RELEVANCE: The Jost otoplasty procedure described herein requires no nonabsorbable sutures to bend the cartilage, avoiding many complications. The technique is safe, reliable, and reproducible, with predictable and permanent outcomes. It is also useful for secondary otoplasty after failed Stenstrom or Mustarde otoplasty. LEVEL OF EVIDENCE: 4. PMID- 23989115 TI - Barriers and facilitators to CPR training and performing CPR in an older population most likely to witness cardiac arrest: a national survey. AB - BACKGROUND: Bystander CPR rates are lowest at home, where 85% of out-of-hospital cardiac arrests occur. We sought to identify barriers and facilitators to CPR training and performing CPR among older individuals most likely to witness cardiac arrest. METHODS: We selected independent-living Canadians aged >=55 using random-digit-dial telephone calls. Respondents were randomly assigned to answer 1 of 2 surveys eliciting barriers and facilitators potentially influencing either CPR training or performance. We developed survey instruments using the Theory of Planned Behavior, measuring salient attitudes, social influences, and control beliefs. RESULTS: Demographics for the 412 respondents (76.4% national response rate): Mean age 66, 58.7% female, 54.9% married, 58.0% CPR trained (half >10 years ago). Mean intentions to take CPR training in the next 6 months or to perform CPR on a victim were relatively high (3.6 and 4.1 out of 5). Attitudinal beliefs were most predictive of respondents' intentions to receive training or perform CPR (Adjusted OR; 95%CI were 1.81; 1.41-2.32 and 1.63; 1.26-2.04 respectively). Respondents who believed CPR could save a life, were employed, and had seen CPR advertised had the highest intention to receive CPR training. Those who believed CPR should be initiated before EMS arrival, were proactive in a group, and felt confident in their CPR skills had the highest intention to perform CPR. INTERPRETATION: Attitudinal beliefs were most predictive of respondents' intention to complete CPR training or perform CPR on a real victim. Behavioral change techniques targeting these specific beliefs are most likely to make an impact. PMID- 23989116 TI - Interventions for recurrent corneal erosion: a Cochrane Systematic review. PMID- 23989117 TI - Abusive head trauma and the eye in infancy. PMID- 23989118 TI - Response to Spitzer et al. PMID- 23989119 TI - Cranio-orbital primary intraosseous haemangioma. AB - PURPOSE: Primary intraosseous haemangioma (IOH) is a rare benign neoplasm presenting in the fourth and fifth decades of life. The spine and skull are the most commonly involved, orbital involvement is extremely rare. We describe six patients with cranio-orbital IOH, the largest case series to date. PATIENTS AND METHODS: Retrospective review of six patients with histologically confirmed primary IOH involving the orbit. Clinical characteristics, imaging features, approach to management, and histopathological findings are described. RESULTS: Five patients were male with a median age of 56. Pain and diplopia were the most common presenting features. A characteristic 'honeycomb' pattern on CT imaging was demonstrated in three of the cases. Complete surgical excision was performed in all cases with presurgical embolisation carried out in one case. In all the cases, histological studies identified cavernous vascular spaces within the bony tissue. These channels were lined by single layer of cytologically normal endothelial cells. DISCUSSION: IOCH of the cranio-orbital region is rare; in the absence of typical imaging features, the differential diagnosis includes chondroma, chondrosarcoma, bony metastasis, and lymphoma. Surgical excision may be necessary to exclude more sinister pathology. Intraoperative haemorrhage can be severe and may be reduced by preoperative embolisation. PMID- 23989120 TI - Lubricants to prevent recurrent corneal erosion: an error in the Cochrane review. PMID- 23989122 TI - Facile multifunctional plasmonic sunlight harvesting with tapered triangle nanopatterning of thin films. AB - Plasmonic absorbers have recently become important for a broad spectrum of sunlight-harvesting applications exploiting either heat generation, such as in thermal photovoltaics and solar thermoelectrics, or hot-electron generation, such as in photochemical and solid state devices. So far, despite impressive progress, combining the needed high performance with fabrication simplicity and scalability remains a serious challenge. Here, we report on a novel solar absorber concept, where we demonstrate and exploit simultaneously a host of absorption phenomena in tapered triangle arrays integrated in a metal-insulator-metal configuration to achieve ultrabroadband (88% average absorption in the range of 380-980 nm), wide angle and polarization-insensitive absorption. Furthermore, this absorber is subwavelength in thickness (260 nm) and its fabrication is based on a facile, low cost and potentially scalable method. In addition, the geometry of our design makes it compatible for both heat and hot electron generation. PMID- 23989121 TI - Long-term outcomes following the surgical repair of traumatic cyclodialysis clefts. AB - PURPOSE: To evaluate the long-term visual prognosis and intraocular pressure (IOP) control following direct and indirect cycloplexy for the surgical treatment of traumatic cyclodialysis clefts. METHODS: Retrospective consecutive case series of 17 eyes of 17 patients. All eyes showing signs of ocular hypotony were treated with either cleft cyclocryotherapy and/or direct surgical cycloplexy. Cycloplexy was performed by directly suturing the ciliary body to the scleral spur under a double-lamellar limbal-based scleral flap. The main outcome measures were IOP, best-corrected visual acuity (BCVA), and the occurrence of postoperative complications. RESULTS: The cyclodialysis clefts were post-traumatic in all the 17 eyes and extended for 2.1 +/- 1.6 clock-hours (range, 0.5-6 clock-hours). The mean follow-up time was 43.7 +/- 24.6 months (range, 12-110 months). Preoperatively, the mean IOP was 6.9 +/- 4.0 mm Hg (range, 2-14 mm Hg). Postoperatively, painful reversible IOP spikes of up to 70 mm Hg developed in 13 eyes. The final mean postoperative IOP was 12.2 +/- 4.1 mm Hg with no cases of secondary glaucoma. Preoperatively, BCVA was 6/12 or better in 4 eyes (24%), which rose to 12 eyes (71%) at final follow-up. Of the 12 patients who underwent direct cycloplexy, 75% achieved a final BCVA of 6/12 or better. There were no serious complications related to direct cycloplexy, including suprachoroidal haemorrhage or endophthalmitis. CONCLUSIONS: Successful cyclodialysis cleft repair can lead to a good long-term visual prognosis and stable IOP control, even in cases with a protracted history of ocular hypotony. PMID- 23989123 TI - Introduction to radiotherapy and standard teletherapy techniques. AB - Radiation was first discovered in the late 19th century by Wilhelm Roentgen and has since been used extensively to treat a variety of cancers. Over the last century, we have developed an extensive understanding of the physical properties of radiation as well as radiation biology. Technological advances in the last few decades in medical imaging and radiotherapy delivery have led to the development of highly complex radiation delivery systems such as intensity modulated radiotherapy, which can be utilized to conformally treat complex tumor shapes while minimizing radiation dose to the surrounding normal tissue. To completely appreciate the application of radiotherapy for ophthalmic cancers, it is important to have a basic understanding of radiation therapy. In this chapter, we will discuss the fundamentals of radiation and radioactive decay, the mechanism of tumor cell damage leading to tumor cell apoptosis, as well as radiation and treatment parameters that are relevant for an ophthalmic oncologist. We will also discuss the concept of tissue tolerance which is of critical importance when prescribing radiation treatment as well as introduce the principles of three dimensional conformal radiotherapy and intensity modulated radiotherapy. PMID- 23989124 TI - Teletherapy: advanced techniques. AB - Radiotherapy has been utilized as a treatment for ophthalmologic processes for more than one hundred years. Over this century, the field of ophthalmologic oncology has been revolutionized through medical discoveries, development of novel surgical interventions, and innovation of advanced radiotherapy techniques. In this chapter, novel radiotherapy techniques are considered. Material presented will build on basic radiation therapy principles, techniques, and treatment parameters established in the previous chapter through consideration of intensity modulated radiotherapy, stereotactic radiotherapy, and heavy ion therapy. Deliberation of matters common across advanced radiotherapy techniques including target delineation, treatment planning, and requisites for ensuring accurate, precise treatment delivery will precede discussion of advanced radiotherapy techniques as applied to the management ophthalmologic malignancies. PMID- 23989125 TI - Brachytherapy. AB - Brachytherapy is the preferred radiation treatment modality for various intraocular tumors, most commonly, uveal melanoma. Radioactive sources are placed directly onto or around the tumor with the aid of episcleral plaques, whereby the employed sources exhibit an extremely sharp fall-off of dosage outside the few millimeters around the tumor. With such high focality, radiation dose to vision critical structures is minimized. Various sources have been used over the years, with iodine-125 being the most common. This chapter will highlight the history of brachytherapy for the treatment of intraocular tumors, current practice including isotopes and plaques utilized, as well as a comprehensive treatment planning and physics review. PMID- 23989126 TI - Radiation therapy: uveal tumors. AB - Among primary uveal tumors, uveal melanoma is the most frequently occurring malignant neoplasm, albeit much less common than skin melanoma and indeed most other cancers. Traditionally, uveal melanoma was treated by enucleation of the globe, but is now increasingly been managed by an eye-preserving option, which saves vision without compromising the life of patients. More than 90% of eyes now preserved have some form of radiotherapy; most often episcleral brachytherapy that is easily accessible at many ophthalmic centers. Conversely, teletherapy in the form of charged particle irradiation, stereotactic radiotherapy or radiosurgery is only available at a comparatively small number of centers. Radiotherapy for uveal melanoma causes significant side effects and complications, but the vast majority of patients can keep their eye with some remaining function. This is of significant benefit to the quality of life for many patients. The side effects of radiotherapy are intimately related to the size of the irradiated tumor, hence early detection and identification of tumors that need to be treated is critical to improve the functional outcome. Experience gained from treating uveal melanoma has been expanded to treat benign uveal tumors such as choroidal hemangioma and other malignant tumors such as uveal lymphoma and uveal metastasis. PMID- 23989127 TI - Radiation therapy: retinal tumors. AB - The major retinal tumor that requires radiotherapy (RT) is retinoblastoma (RB); to a lesser degree, RT is used for some cases of retinal capillary hemangioma and lymphoma of the retina. Although there are concerns about the risk of RT-induced second malignancy in patients who carry a germline mutation in the RB1 gene, RT remains a very important part of our approach to intra-ocular and extra-ocular RB. Technical innovations in RT allow more precise targeting of retinal tumors and decreased exposure of adjacent normal tissue, an advance that is particularly significant for patients with hereditary RB who are at risk of additional malignancies. PMID- 23989128 TI - Radiation therapy: age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of severe irreversible vision loss in patients over the age of 50 years in the developed world. Neovascular AMD (NVAMD) is responsible for 90% of the cases with severe visual loss. In the last decade, the treatment paradigm for NVAMD has been transformed by the advent of anti-vascular endothelial growth factor therapy. Despite the excellent results of anti-vascular endothelial growth factor therapy, frequent injections remain a necessity for most patients. The burden of these frequent visits as well as the cumulative risks of indefinite intravitreal injections demand continued pursuit of more enduring therapy that provides similar functional results. Radiotherapy has been studied for two decades as a potential therapy for NVAMD. Because of its antiangiogenic properties, radiation therapy remains a promising potential adjunctive resource for the treatment of choroidal neovascularization secondary to NVAMD. This review considers the past, present and future of radiation as a treatment or combination treatment of NVAMD. PMID- 23989129 TI - Radiation therapy: conjunctival and eyelid tumors. AB - While the primary treatment of eyelid and conjunctival tumors is frequently surgical, several forms of ophthalmic radiation therapy have also been used to treat these malignancies. The goal of radiation therapy is to eradicate tumor burden in a manner that maintains visual function and preserves surrounding sensitive ocular tissues. Ophthalmic radiation may be used as a curative therapy, as adjuvant treatment following surgical excision, or as palliative therapy for advanced cases of eyelid and conjunctival tumors. The following review discusses the indications and outcomes of various modalities of radiation (external beam radiotherapy and brachytherapy) used to treat eyelid tumors (squamous cell carcinoma, basal cell carcinoma, sebaceous gland carcinoma, and melanoma) and conjunctival tumors (squamous cell carcinoma and melanoma). PMID- 23989130 TI - Radiation therapy: orbital tumors. AB - Orbital tumors are rare overall, comprising 0.1% of all tumors and less than 20% of all orbital diseases. Tumors may be benign, locally aggressive, or malignant. Of the malignant tumors, lymphomas and metastases are the most common and are primarily seen in the elderly population. While surgery and chemotherapeutic agents are often employed in the management of these lesions, not all patients are candidates for these therapies. Radiation therapy offers a noninvasive, well tolerated primary treatment modality, whereby vision-sparing is feasible in many cases. In this chapter, we review an array of non-neoplastic entities and orbital tumors, for which there exists a role for radiation, and the radiotherapeutic techniques and applications in their management. PMID- 23989131 TI - Radiation therapy: anterior segment complications. AB - The goal of radiotherapy is to produce maximal damage to the tumor yet at the same time produce minimal damage to the surrounding tissues. Here we discuss anterior chamber complications of radiotherapy. These can vary from ocular surface irritation to blindness and can be subdivided into acute (<4 weeks) and chronic (>4 weeks). Prevention and management is also discussed and subdivided by affected tissue. PMID- 23989132 TI - Radiation therapy: posterior segment complications. AB - Therapeutic radiation to the posterior segment of the eye is a common option for posterior segment tumors. Such tumors are often malignant, but sometimes, benign neoplasms are treated with ionizing radiation. Also, non-neoplastic intraocular lesions like wet age-related macular degeneration may be treated with radiotherapy. Orbital disease, both neoplastic lesions like optic nerve sheath meningioma and non-neoplastic entities like Graves' ophthalmopathy may be treated with radiotherapy and this may include radiation of the optic nerve and posterior segment of the eye. Occasionally, radiotherapy of extraocular malignant disease, involving, e.g. the paranasal sinuses, may cause significant radiation damage to the eye. Complications after radiation to the posterior segment of the eye are largely related to the radiation dose to the posterior segment. The amount of irradiated volume of normal tissue and fractionation are also important for the development of radiation complications to the posterior segment. Radiation retinopathy is the most common complication of the posterior segment, but radiation optic neuropathy also occurs frequently. Radiation scleral necrosis is less frequent probably due to the radioresistance of the scleral collagen. These complications have the potential to cause blindness (radiation retinopathy and optic neuropathy) or enucleation of the eye (scleral necrosis). Although numerous treatments have been advocated, management of radiation-induced damage remains controversial. Efficacy for any treatment still needs to be proven and, if possible, the best option by far is to minimize radiation changes to normal tissue. PMID- 23989133 TI - Agreement between time-domain and spectral-domain optical coherence tomography in the assessment of macular thickness in patients with idiopathic macular telangiectasia type 2. AB - PURPOSE: To estimate the conversion factors to transpose macular thickness measurements on time-domain (TD) to various spectral-domain (SD) optical coherence tomography (OCT) machines in patients with macular telangiectasia type 2a (MacTel). PROCEDURES: Macular scans on TD- and SD-OCT were performed on patients at the same visit. The retinal thickness values in various ETDRS subfields and macular volume were compared between different OCT machines. RESULTS: The macular thickness and volume were significantly greater (p < 0.0001, r = 0.678-0.822) on SD-OCT. The mean differences in macular thickness between TD Stratus and SD-OCT by Spectralis, Cirrus and Topcon were 62, 41 and 20 MUm, respectively. The conversion factor of macular thickness from TD-OCT to Spectralis, Cirrus and Topcon were +65, +39 and +25 MUm, respectively. CONCLUSION AND MESSAGE: The estimates of conversion of macular thickness from TD- to SD-OCT using simple mean differences between machines and those by linear regression were similar suggesting that the former may be used for the longitudinal follow up of MacTel patients. PMID- 23989134 TI - Pseudozyma aphidis induces ethylene-independent resistance in plants. AB - Species of the epiphytic fungus Pseudozyma are not pathogenic to plants and can be used as biocontrol agents against plant pathogens. Deciphering how they induce plant defense might contribute to their use for plant protection and expand our understanding of molecular plant-pathogen interactions. Here we show that Pseudozyma aphidis isolate L12, which is known to induce jasmonic acid- and salicylic acid-independent systemic resistance, can also activate local and systemic resistance in an ethylene-independent manner. We also show that P. aphidis localizes exclusively to the surface of the plant leaf and does not penetrate the mesophyll cells of treated leaves. We thus propose that P. aphidis acts via several mechanisms, and is an excellent candidate biocontrol agent. PMID- 23989135 TI - Polypill for cardiovascular disease prevention. PMID- 23989136 TI - Integrative transcriptome analysis reveals dysregulation of canonical cancer molecular pathways in placenta leading to preeclampsia. AB - We previously suggested links between specific XPD mutations in the fetal genome and the risk of placental maldevelopment and preeclampsia, possibly due to impairment of Transcription Factor (TF)IIH-mediated functions in placenta. To identify the underlying mechanisms, we conducted the current integrative analysis of several relevant transcriptome data sources. Our meta-analysis revealed downregulation of TFIIH subunits in preeclamptic placentas. Our overall integrative analysis suggested that, in the presence of hypoxia and oxidative stress, EGFR signaling deficiency, which can be caused by TFIIH impairment as well as by other mechanisms, results in ATF3 upregulation, inducing mediators of clinical symptoms of preeclampsia such as FLT1 and ENG. EGFR- and ATF3-dependent pathways play prominent roles in cancer development. We propose that dysregulation of these canonical cancer molecular pathways occurs in preeclampsia and delineate the relevance of TFIIH, providing etiologic clues which could eventually translate into a therapeutic approach. PMID- 23989137 TI - Using twitter to examine smoking behavior and perceptions of emerging tobacco products. AB - BACKGROUND: Social media platforms such as Twitter are rapidly becoming key resources for public health surveillance applications, yet little is known about Twitter users' levels of informedness and sentiment toward tobacco, especially with regard to the emerging tobacco control challenges posed by hookah and electronic cigarettes. OBJECTIVE: To develop a content and sentiment analysis of tobacco-related Twitter posts and build machine learning classifiers to detect tobacco-relevant posts and sentiment towards tobacco, with a particular focus on new and emerging products like hookah and electronic cigarettes. METHODS: We collected 7362 tobacco-related Twitter posts at 15-day intervals from December 2011 to July 2012. Each tweet was manually classified using a triaxial scheme, capturing genre, theme, and sentiment. Using the collected data, machine-learning classifiers were trained to detect tobacco-related vs irrelevant tweets as well as positive vs negative sentiment, using Naive Bayes, k-nearest neighbors, and Support Vector Machine (SVM) algorithms. Finally, phi contingency coefficients were computed between each of the categories to discover emergent patterns. RESULTS: The most prevalent genres were first- and second-hand experience and opinion, and the most frequent themes were hookah, cessation, and pleasure. Sentiment toward tobacco was overall more positive (1939/4215, 46% of tweets) than negative (1349/4215, 32%) or neutral among tweets mentioning it, even excluding the 9% of tweets categorized as marketing. Three separate metrics converged to support an emergent distinction between, on one hand, hookah and electronic cigarettes corresponding to positive sentiment, and on the other hand, traditional tobacco products and more general references corresponding to negative sentiment. These metrics included correlations between categories in the annotation scheme (phihookah-positive=0.39; phi(e-cigs)-positive=0.19); correlations between search keywords and sentiment (chi24=414.50, P<.001, Cramer's V=0.36), and the most discriminating unigram features for positive and negative sentiment ranked by log odds ratio in the machine learning component of the study. In the automated classification tasks, SVMs using a relatively small number of unigram features (500) achieved best performance in discriminating tobacco-related from unrelated tweets (F score=0.85). CONCLUSIONS: Novel insights available through Twitter for tobacco surveillance are attested through the high prevalence of positive sentiment. This positive sentiment is correlated in complex ways with social image, personal experience, and recently popular products such as hookah and electronic cigarettes. Several apparent perceptual disconnects between these products and their health effects suggest opportunities for tobacco control education. Finally, machine classification of tobacco-related posts shows a promising edge over strictly keyword-based approaches, yielding an improved signal-to-noise ratio in Twitter data and paving the way for automated tobacco surveillance applications. PMID- 23989138 TI - Neonatal non-invasive respiratory support: synchronised NIPPV, non-synchronised NIPPV or bi-level CPAP: what is the evidence in 2013? AB - Nasal continuous positive airway pressure (NCPAP) has proven to be an effective mode of non-invasive respiratory support in preterm infants; however, many infants still require endotracheal ventilation, placing them at an increased risk of morbidities such as bronchopulmonary dysplasia. Several other modes of non invasive respiratory support beyond NCPAP, including synchronised and non synchronised nasal intermittent positive pressure ventilation (SNIPPV and nsNIPPV) and bi-level positive airway pressure (BiPAP) are now also available. These techniques require different approaches, and the exact mechanisms by which they act remain unclear. SNIPPV has been shown to reduce the rate of reintubation in comparison to NCPAP when used as post-extubation support, but the evidence for nsNIPPV and BiPAP in this context is less convincing. There is some evidence that NIPPV (whether synchronised or non-synchronised) used as primary respiratory support is beneficial, but the variation in study methodology makes this hard to translate confidently into clinical practice. There is currently no evidence to suggest a reduction in mortality or important morbidities such as bronchopulmonary dysplasia, with NIPPV or BiPAP in comparison to NCPAP, and there is a lack of appropriately designed studies in this area. This review discusses the different approaches and proposed mechanisms of action of SNIPPV, nsNIPPV and BiPAP, the challenges of applying the available evidence for these distinct modalities of non-invasive respiratory support to clinical practice, and possible areas of future research. PMID- 23989139 TI - Crystallographic analysis of an RNA polymerase sigma-subunit fragment complexed with -10 promoter element ssDNA: quadruplex formation as a possible tool for engineering crystal contacts in protein-ssDNA complexes. AB - Structural studies of -10 promoter element recognition by domain 2 of the RNA polymerase sigma subunit [Feklistov & Darst (2011), Cell, 147, 1257-1269] reveal an unusual crystal-packing arrangement dominated by G-quartets. The 3'-terminal GGG motif of the oligonucleotide used in crystallization participates in G quadruplex formation with GGG motifs from symmetry-related complexes. Stacking between neighboring G-quadruplexes results in the formation of pseudo-continuous four-stranded columns running throughout the length of the crystal (G-columns). Here, a new crystal form is presented with a different arrangement of G-columns and it is proposed that the fortuitous finding of G-quartet packing could be useful in engineering crystal contacts in protein-ssDNA complexes. PMID- 23989140 TI - Structure of isochorismate synthase DhbC from Bacillus anthracis. AB - The isochorismate synthase DhbC from Bacillus anthracis is essential for the biosynthesis of the siderophore bacillibactin by this pathogenic bacterium. The structure of the selenomethionine-substituted protein was determined to 2.4 A resolution using single-wavelength anomalous diffraction. B. anthracis DhbC bears the strongest resemblance to the Escherichia coli isochorismate synthase EntC, which is involved in the biosynthesis of another siderophore, namely enterobactin. Both proteins adopt the characteristic fold of other chorismate utilizing enzymes, which are involved in the biosynthesis of various products, including siderophores, menaquinone and tryptophan. The conservation of the active-site residues, as well as their spatial arrangement, suggests that these enzymes share a common Mg(2+)-dependent catalytic mechanism. PMID- 23989141 TI - Structural analysis of DNA-protein complexes regulating the restriction modification system Esp1396I. AB - The controller protein of the type II restriction-modification (RM) system Esp1396I binds to three distinct DNA operator sequences upstream of the methyltransferase and endonuclease genes in order to regulate their expression. Previous biophysical and crystallographic studies have shown molecular details of how the controller protein binds to the operator sites with very different affinities. Here, two protein-DNA co-crystal structures containing portions of unbound DNA from native operator sites are reported. The DNA in both complexes shows significant distortion in the region between the conserved symmetric sequences, similar to that of a DNA duplex when bound by the controller protein (C-protein), indicating that the naked DNA has an intrinsic tendency to bend when not bound to the C-protein. Moreover, the width of the major groove of the DNA adjacent to a bound C-protein dimer is observed to be significantly increased, supporting the idea that this DNA distortion contributes to the substantial cooperativity found when a second C-protein dimer binds to the operator to form the tetrameric repression complex. PMID- 23989142 TI - Structure of formaldehyde dehydrogenase from Pseudomonas aeruginosa: the binary complex with the cofactor NAD+. AB - Formaldehyde dehydrogenase (FDH) is a member of the zinc-containing medium-chain alcohol dehydrogenase family which oxidizes toxic formaldehyde to formate using NAD(+) as an electron carrier. Three-dimensional structures have been reported for FDHs from several different species. Most FDHs are dependent on glutathione for catalysis, but the enzyme from Pseudomonas putida is an exception. In this structural communication, the recombinant production, crystallization and X-ray structure determination at 2.7 A resolution of FDH from P. aeruginosa are described. Both the tetrameric assembly and the NAD(+)-binding mode of P. aeruginosa FDH are similar to those of P. putida FDH, which is in good agreement with the high sequence identity (87.97%) between these two proteins. Preliminary enzymatic kinetics studies of P. aeruginosa FDH also revealed a conserved glutathione-independent 'ping-pong' mechanism of formaldehyde oxidization. PMID- 23989143 TI - The structure of amylosucrase from Deinococcus radiodurans has an unusual open active-site topology. AB - Amylosucrases (ASes) catalyze the formation of an alpha-1,4-glucosidic linkage by transferring a glucosyl unit from sucrose onto an acceptor alpha-1,4-glucan. To date, several ligand-bound crystal structures of wild-type and mutant ASes from Neisseria polysaccharea and Deinococcus geothermalis have been solved. These structures all display a very similar overall conformation with a deep pocket leading to the site for transglucosylation, subsite -1. This has led to speculation on how sucrose enters the active site during glucan elongation. In contrast to previous studies, the AS structure from D. radiodurans presented here has a completely empty -1 subsite. This structure is strikingly different from other AS structures, as an active-site-lining loop comprising residues Leu214 Asn225 is found in a previously unobserved conformation. In addition, a large loop harbouring the conserved active-site residues Asp133 and Tyr136 is disordered. The result of the changed loop conformations is that the active-site topology is radically changed, leaving subsite -1 exposed and partially dismantled. This structure provides novel insights into the dynamics of ASes and comprises the first structural support for an elongation mechanism that involves considerable conformational changes to modulate accessibility to the sucrose binding site and thereby allows successive cycles of glucosyl-moiety transfer to a growing glucan chain. PMID- 23989144 TI - Structure of the Aeropyrum pernix L7Ae multifunctional protein and insight into its extreme thermostability. AB - Archaeal ribosomal protein L7Ae is a multifunctional RNA-binding protein that directs post-transcriptional modification of archaeal RNAs. The L7Ae protein from Aeropyrum pernix (Ap L7Ae), a member of the Crenarchaea, was found to have an extremely high melting temperature (>383 K). The crystal structure of Ap L7Ae has been determined to a resolution of 1.56 A. The structure of Ap L7Ae was compared with the structures of two homologs: hyperthermophilic Methanocaldococcus jannaschii L7Ae and the mesophilic counterpart mammalian 15.5 kD protein. The primary stabilizing feature in the Ap L7Ae protein appears to be the large number of ion pairs and extensive ion-pair network that connects secondary-structural elements. To our knowledge, Ap L7Ae is among the most thermostable single-domain monomeric proteins presently observed. PMID- 23989145 TI - Structure of zebrafish MO25. AB - MO25, a conserved scaffold protein, activates the tumour suppressor LKB1 with the pseudokinase STRAD. MO25 also promotes the activities of the STE20-family kinases MST3, MST4, STK25, SPAK and OSR1. Zebrafish MO25 was purified and crystallized, and a crystal of zebrafish MO25 diffracted to 2.9 A resolution and belonged to space group P3221, with unit-cell parameters a = b = 156.665, c = 221.251 A. The structure of zebrafish MO25 was determined by molecular replacement. It is constituted of seven helical repeats. Structural comparison indicates that the overall structures of zebrafish and human MO25 are very similar, suggesting that MO25 has conserved functions in zebrafish. This work provides a structural basis for further functional and evolutionary studies of MO25. PMID- 23989146 TI - Expression, purification and crystallization of the ancestral androgen receptor DHT complex. AB - Steroid receptors (SRs) are a closely related family of ligand-dependent nuclear receptors that mediate the transcription of genes critical for development, reproduction and immunity. SR dysregulation has been implicated in cancer, inflammatory diseases and metabolic disorders. SRs bind their cognate hormone ligand with exquisite specificity, offering a unique system to study the evolution of molecular recognition. The SR family evolved from an estrogen sensitive ancestor and diverged to become sensitive to progestagens, corticoids and, most recently, androgens. To understand the structural mechanisms driving the evolution of androgen responsiveness, the ancestral androgen receptor (ancAR1) was crystallized in complex with 5alpha-dihydrotestosterone (DHT) and a fragment of the transcriptional mediator/intermediary factor 2 (Tif2). Crystals diffracted to 2.1 A resolution and the resulting structure will permit a direct comparison with its progestagen-sensitive ancestor, ancestral steroid receptor 2 (AncSR2). PMID- 23989147 TI - Crystallization studies of the keratin-like domain from Arabidopsis thaliana SEPALLATA 3. AB - In higher plants, the MADS-box genes encode a large family of transcription factors (TFs) involved in key developmental processes, most notably plant reproduction, flowering and floral organ development. SEPALLATA 3 (SEP3) is a member of the MADS TF family and plays a role in the development of the floral organs through the formation of multiprotein complexes with other MADS-family TFs. SEP3 is divided into four domains: the M (MADS) domain, involved in DNA binding and dimerization, the I (intervening) domain, a short domain involved in dimerization, the K (keratin-like) domain important for multimeric MADS complex formation and the C (C-terminal) domain, a largely unstructured region putatively important for higher-order complex formation. The entire K domain along with a portion of the I and C domains of SEP3 was crystallized using high-throughput robotic screening followed by optimization. The crystals belonged to space group P2(1)2(1)2, with unit-cell parameters a = 123.44, b = 143.07, c = 49.83 A, and a complete data set was collected to 2.53 A resolution. PMID- 23989148 TI - Purification, crystallization and preliminary X-ray diffraction analysis of the 23S rRNA methyltransferase RlmJ from Escherichia coli. AB - Methyltransferase RlmJ uses the cofactor S-adenosylmethionine to methylate the exocyclic nitrogen N6 of nucleotide A2030 in 23S rRNA during ribosome assembly in Escherichia coli. RlmJ with a C-terminal hexahistidine tag was overexpressed in E. coli and purified as a monomer using Ni(2+)-affinity and size-exclusion chromatography. The recombinant RlmJ was crystallized using the sitting-drop vapour-diffusion method and a full data set was collected to 1.85 A resolution from a single apo crystal. The crystals belonged to space group P2(1), with unit cell parameters a = 46.9, b = 77.8, c = 82.5 A, beta = 104 degrees . Data analysis suggested two molecules per asymmetric unit and a Matthews coefficient of 2.20 A(3) Da(-1). PMID- 23989149 TI - Crystallization and preliminary X-ray crystallographic analysis of the amylomaltase from Corynebacterium glutamicum. AB - Amylomaltase (AM; EC 2.4.1.25) belongs to the 4-alpha-glucanotransferase group of the alpha-amylase family. The enzyme can produce cycloamylose or large-ring cyclodextrin through intramolecular transglycosylation or cyclization reactions of alpha-1,4-glucan. Amylomaltase from the mesophilic bacterium Corynebacterium glutamicum (CgAM) contains extra residues at the N-terminus for which the three dimensional structure is not yet known. In this study, CgAM was overexpressed and purified to homogeneity using DEAE FF and Phenyl FF columns. The purified CgAM was crystallized by the vapour-diffusion method. Preliminary X-ray data showed that the CgAM crystal diffracted to 1.7 A resolution and belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 73.28, b = 82.61, c = 118.64 A. To obtain the initial phases, crystals of selenomethionyl-substituted amylomaltase were produced, and multiple-wavelength anomalous dispersion phasing and structure refinement are now in progress. PMID- 23989150 TI - Expression at 279 K, purification, crystallization and preliminary X-ray crystallographic analysis of a novel cold-active beta-1,4-D-mannanase from the Antarctic springtail Cryptopygus antarcticus. AB - The CaMan gene product from Cryptopygus antarcticus, which belongs to the glycoside hydrolase family 5 type beta-1,4-D-mannanases, has been crystallized using a precipitant solution consisting of 0.1 M Tris-HCl pH 8.5, 25%(w/v) polyethylene glycol 3350 by the microbatch crystallization method at 295 K. The CaMan protein crystal belonged to space group P212121, with unit-cell parameters a = 73.40, b = 83.81, c = 163.55 A. Assuming the presence of two molecules in the asymmetric unit, the solvent content was estimated to be about 61.29%. CaMan mannopentaose (M5) complex crystals that were isomorphous to the CaMan crystals were obtained using the same mother liquor containing 1 mM M5. PMID- 23989151 TI - Cloning, purification and preliminary crystallographic analysis of the Helicobacter pylori leucyl aminopeptidase-bestatin complex. AB - Helicobacter pylori is an important human pathogenic bacterium associated with numerous severe gastroduodenal diseases, including ulcers and gastric cancer. Cytosolic leucyl aminopeptidase (LAP) is an important housekeeping protein that is involved in peptide and protein turnover, catabolism of proteins and modulation of gene expression. LAP is upregulated in metronidazole-resistant H. pylori, which suggests that, in addition to having an important housekeeping role, LAP contributes to the mechanism of drug resistance. Crystals of H. pylori LAP have been grown by the hanging-drop vapour-diffusion method using polyethylene glycol as a precipitating agent. The crystals belonged to the primitive triclinic space group P1, with unit-cell parameters a = 97.5, b = 100.2, c = 100.4 A, alpha = 75.4, beta = 60.9, gamma = 81.8 degrees . An X-ray diffraction data set was collected to 2.8 A resolution from a single crystal. Molecular-replacement results using these data indicate that H. pylori LAP is a hexamer with 32 symmetry. PMID- 23989152 TI - Neutron diffraction studies towards deciphering the protonation state of catalytic residues in the bacterial KDN9P phosphatase. AB - The enzyme 2-keto-3-deoxy-9-O-phosphonononic acid phosphatase (KDN9P phosphatase) functions in the pathway for the production of 2-keto-3-deoxy-D-glycero-D-galacto nononic acid, a sialic acid that is important for the survival of commensal bacteria in the human intestine. The enzyme is a member of the haloalkanoate dehalogenase superfamily and represents a good model for the active-site protonation state of family members. Crystals of approximate dimensions 1.5 * 1.0 * 1.0 mm were obtained in space group P2(1)2(1)2, with unit-cell parameters a = 83.1, b = 108.9, c = 75.7 A. A complete neutron data set was collected from a medium-sized H/D-exchanged crystal at BIODIFF at the Heinz Maier-Leibnitz Zentrum (MLZ), Garching, Germany in 18 d. Initial refinement to 2.3 A resolution using only neutron data showed significant density for catalytically important residues. PMID- 23989153 TI - Expression, purification, crystallization and preliminary X-ray crystallographic analysis of human myosin 1c in complex with calmodulin. AB - Myosin 1c (Myo1c) is implicated in several cellular processes such as vesicle transport and the mediation of adaptation in the inner ear. Consequently, mutations impairing Myo1c motor activity lead to hearing loss in humans. To understand the role of Myo1c in this process on a molecular level, its crystal structure in complex with the light chain calmodulin was determined. A human Myo1c construct encompassing the motor domain and the first IQ motif was co expressed with calmodulin in Sf9 cells and purified to homogeneity. The protein complex crystallized readily, and the crystals belonged to space group P2(1) and diffracted to 3 A resolution. Attempts to determine the structure by molecular replacement are currently under way. PMID- 23989154 TI - Crystallization and preliminary X-ray crystallographic analysis of the variable domain of Scl2.3, a streptococcal collagen-like protein from invasive M3-type Streptococcus pyogenes. AB - Streptococcal collagen-like proteins (Scls) are widely expressed by the well recognized human pathogen Streptococcus pyogenes. These surface proteins contain a signature central collagen-like region and an amino-terminal globular domain, termed the variable domain, which is protruded away from the cell surface by the collagen-like domain. Despite their recognized importance in bacterial pathogenicity, no structural information is presently available on proteins of the Scl class. The variable domain of Scl2 from invasive M3-type S. pyogenes has successfully been crystallized using vapour-diffusion methods. The crystals diffracted to 1.5 A resolution and belonged to space group H32, with unit-cell parameters a = 44.23, b = 44.23, c = 227.83 A. The crystal structure was solved by single-wavelength anomalous dispersion using anomalous signal from a europium chloride derivative.| PMID- 23989155 TI - Preliminary X-ray crystallographic studies of the TRAF domain of human TRAF4. AB - TNF receptor-associated factor (TRAF) proteins were initially identified as tumour necrosis factor receptor (TNFR)-interacting proteins that perform critical functions in the regulation of inflammation, antiviral responses and apoptosis. Although TRAF4 is a canonical TRAF protein, it contains a unique domain boundary and functions differently in the cell. In this study, the human TRAF4 TRAF domain, corresponding to amino acids 290-470, was overexpressed in Escherichia coli using engineered C-terminal His tags. The TRAF4 TRAF domain was then purified to homogeneity and crystallized at 293 K. Finally, X-ray diffraction data were collected to a resolution of 2.3 A from a crystal belonging to space group P2(1)2(1)2(1), with unit-cell parameters a = 58.9, b = 87.9, c = 117.3 A, alpha = beta = gamma = 90 degrees . PMID- 23989156 TI - Cloning, expression, purification and preliminary X-ray analysis of the dimerization domain of ethylene response sensor 1 (ERS1) from Arabidopsis thaliana. AB - Ethylene signalling is initiated by a group of membrane-bound receptors with similarity to two-component systems. ERS1 belongs, together with ETR1, to subfamily 1, which plays a predominant role in ethylene signalling. The dimerization domain of ERS1 was crystallized in space groups C222(1) and P2(1)2(1)2, with two and four molecules per asymmetric unit, respectively. The crystals diffracted X-ray radiation to 1.9 A resolution. PMID- 23989157 TI - Purification, crystallization and preliminary X-ray analysis of adenylosuccinate synthetase from the fungal pathogen Cryptococcus neoformans. AB - With increasingly large immunocompromised populations around the world, opportunistic fungal pathogens such as Cryptococcus neoformans are a growing cause of morbidity and mortality. To combat the paucity of antifungal compounds, new drug targets must be investigated. Adenylosuccinate synthetase is a crucial enzyme in the ATP de novo biosynthetic pathway, catalyzing the formation of adenylosuccinate from inosine monophosphate and aspartate. Although the enzyme is ubiquitous and well characterized in other kingdoms, no crystallographic studies on the fungal protein have been performed. Presented here are the expression, purification, crystallization and initial crystallographic analyses of cryptococcal adenylosuccinate synthetase. The crystals had the symmetry of space group P2(1)2(1)2(1) and diffracted to 2.2 A resolution. PMID- 23989158 TI - Expression, crystallization and preliminary X-ray crystallographic analysis of alcohol dehydrogenase (ADH) from Kangiella koreensis. AB - Alcohol dehydrogenases (ADHs) are a group of dehydrogenase enzymes that facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of NAD(+) to NADH. In bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD(+). The adh gene from Kangiella koreensis was cloned and the protein (KkADH) was expressed, purified and crystallized. A KkADH crystal diffracted to 2.5 A resolution and belonged to the monoclinic space group P2(1), with unit-cell parameters a = 94.1, b = 80.9, c = 115.6 A, beta = 111.9 degrees . Four monomers were present in the asymmetric unit, with a corresponding VM of 2.55 A(3) Da(-1) and a solvent content of 51.8%. PMID- 23989159 TI - Expression, crystallization and preliminary X-ray crystallographic analysis of alanine racemase from Acinetobacter baumannii OXA-23. AB - Acinetobacter baumannii has received much attention owing to its exceptional ability to develop resistance to currently available antibiotics. Alanine racemase (ALR) catalyzes the racemization of L-alanine to D-alanine with pyridoxal 5'-phosphate (PLP) as a cofactor. The D-alanine product is an essential component of the bacterial cell wall and ALR is a potential target for the development of novel antibacterial drugs. The alr gene from A. baumannii was cloned and the protein (AbALR) was expressed, purified and crystallized. The AbALR crystal diffracted to 2.3 A resolution and belonged to the primitive orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 55.1, b = 85.0, c = 167.7 A. Two protomers were present in the asymmetric unit, with a corresponding V(M) value of 2.3 A(3) Da(-1) and a solvent content of 47.5%. PMID- 23989160 TI - Fibronectin type III domains engineered to bind CD40L: cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of two complexes. AB - Tn3 proteins are a novel class of binding molecules based on the third fibronectin type III domain of human tenascin C. Target-specific Tn3 proteins are selected from combinatorial libraries in which three surface-exposed loops have been diversified. Here, the cocrystallization of two different Tn3 proteins in complex with CD40L, a therapeutic target for immunological disease, is reported. These crystal structures are the first to be reported of Tn3 proteins and will help to reveal how these engineered molecules achieve specific recognition of a cognate target. PMID- 23989161 TI - Crystallization and preliminary X-ray diffraction analysis of human importin beta Snail zinc finger domain complex. AB - Snail is a C2H2-type zinc finger transcriptional repressor that induces epithelial-mesenchymal transition by repression of E-cadherin expression levels during embryonic development and tumour progression. Snail is imported into the nucleus by importin beta through direct binding with its four zinc finger domain. The complex between importin beta and Snail four zinc finger domain was crystallized in order to understand the nuclear transport mechanism of Snail. The constituents of the complex were separately expressed and were then co-purified and crystallized by the hanging-drop vapour-diffusion method. The crystals belonged to space group C2, with unit-cell parameters a = 228.2, b = 77.5, c = 72.0 A, beta = 100.9 degrees and diffracted to 2.5 A resolution. PMID- 23989162 TI - Crystallization of the HigBA2 toxin-antitoxin complex from Vibrio cholerae. AB - The genome of Vibrio cholerae encodes two higBA toxin-antitoxin (TA) modules that are activated by amino-acid starvation. Here, the TA complex of the second module, higBA2, as well as the C-terminal domain of the corresponding HigA2 antitoxin, have been purified and crystallized. The HigBA2 complex crystallized in two crystal forms. Crystals of form I belonged to space group P2(1)2(1)2, with unit-cell parameters a = 129.0, b = 119.8, c = 33.4 A, and diffracted to 3.0 A resolution. The asymmetric unit is likely to contain a single complex consisting of two toxin monomers and one antitoxin dimer. The second crystal form crystallized in space group P3(2)21, with unit-cell parameters a = 134.5, c = 55.4 A. These crystals diffracted to 2.2 A resolution and probably contain a complex with a different stoichiometry. Crystals of the C-terminal domain of HigA2 belonged to space group C2, with unit-cell parameters a = 115.4, b = 61.2, c = 73.8 A, beta = 106.7 degrees , and diffracted to 1.8 A resolution. PMID- 23989163 TI - Identifying ligand-binding hot spots in proteins using brominated fragments. AB - High-quality crystals of Thermus thermophilus EF-Tu in the GTP-bound conformation at 1.7-2.7 A resolution were used to test 18 small organic molecules, all brominated for confident identification in the anomalous difference maps. From this relatively small collection, it was possible to identify a small molecule bound in the functionally important tRNA CCA-end binding pocket. The antibiotic GE2270 A is known to interact with the same pocket in EF-Tu and to disrupt the association with tRNA. Bromide could be located from peaks in the anomalous map in data truncated to very low resolution without refining the structure. Considering the speed with which diffraction data can be collected today, it is proposed that it is worthwhile to collect the extra data from fragment screens while crystals are at hand to increase the knowledge of biological function and drug binding in an experimental structural context. PMID- 23989166 TI - Spectral domain optical coherence tomography findings in patients with retinitis pigmentosa. AB - BACKGROUND: To report the morphological macular findings detected by spectral domain optical coherence tomography (SD-OCT) and to determine their prevalence in patients with retinitis pigmentosa (RP). METHODS: SD-OCT scans of 176 eyes from 90 patients affected by RP were reviewed. A careful evaluation was carried out on photoreceptor inner/outer segment (IS/OS) junction, external limiting membrane (ELM), inner limiting membrane thickening (ILMT), epiretinal membranes (ERMs), retinal micropseudocysts (MPCs), cystoid macular edema (CME), macular holes (MHs) and choroidal neovascularization (CNV). RESULTS: The photoreceptor IS/OS junction was absent in the foveal region of 24 eyes (13.6%) and disrupted in 84 eyes (47.7%). The ELM was absent in 24 eyes (13.6%), whereas the ILMT was found in 118 eyes (67%). The presence of an ERM was detected in 48 eyes (27.3%). Some sort of vitreomacular alteration (ILMT and/or ERM) was identifiable in a total of 94.3% of eyes with RP. The presence of MPCs was detected in 32 eyes (18.2%). An evident CME was found in 22 eyes (12.5%). We also found MHs in 8 eyes (4.5%) and CNV in 3 eyes (1.7%). CONCLUSIONS: Our data indicate that RP is associated with alterations of many retinal layers. In particular, the vitreoretinal interface is affected in 94% of patients, and MPC can be identified in 18% of eyes. SD-OCT may contribute to the understanding of the pathophysiological mechanism involved in RP. PMID- 23989167 TI - Early detection and intervention in schizophrenia: a new therapeutic model. PMID- 23989164 TI - Serial femtosecond X-ray diffraction of 30S ribosomal subunit microcrystals in liquid suspension at ambient temperature using an X-ray free-electron laser. AB - High-resolution ribosome structures determined by X-ray crystallography have provided important insights into the mechanism of translation. Such studies have thus far relied on large ribosome crystals kept at cryogenic temperatures to reduce radiation damage. Here, the application of serial femtosecond X-ray crystallography (SFX) using an X-ray free-electron laser (XFEL) to obtain diffraction data from ribosome microcrystals in liquid suspension at ambient temperature is described. 30S ribosomal subunit microcrystals diffracted to beyond 6 A resolution, demonstrating the feasibility of using SFX for ribosome structural studies. The ability to collect diffraction data at near-physiological temperatures promises to provide fundamental insights into the structural dynamics of the ribosome and its functional complexes. PMID- 23989168 TI - [Current treatment of pelvic ring fractures]. AB - Pelvic injuries are often associated with multiple injuries of other body regions, neurovascular and visceral lesions, as well as hemodynamic instability. The use of a standardized classification characterizing the severity and stability of pelvic fractures and the early stabilization of pelvic ring injuries in appreciation of damage control principles has helped to improve the number of survivors. This is particularly necessary due to the higher number of older patients.Complex pelvic trauma still represents a life-threatening situation for the patient, particularly in multiple traumatized patients. Standardized clinical investigations and modern concepts even in the preclinical therapy of complex pelvic fractures make a contribution to enhancement of treatment options. Because of the still problematic long-term results after surgery of instable pelvic fractures, the need for modern treatment concepts has to be adapted to the requirements. PMID- 23989170 TI - Midline suboccipital osteoplastic craniotomy - 'cobra craniotomy'. AB - BACKGROUND: Midline suboccipital craniotomy has been proposed as an alternative to conventional craniectomy for removal of posterior fossa tumors. METHOD: We describe a modified technique for midline suboccipital osteoplastic craniotomy based on the atlantooccipital membrane for a 17-year-old boy with superior vermian astrocytoma. Osteoplastic craniotomy was performed safely in this patient. RESULT: The presence of the turned down, attached bone flap did not interfere with surgery. Reattachment of the bone flap was easy and stable. This technique was not associated with additional risks. CONCLUSION: Midline suboccipital osteoplastic craniotomy is a better option for superiorly placed midline posterior fossa tumor surgery. PMID- 23989171 TI - A greater analgesia, sedation, delirium order set quality score is associated with a decreased duration of mechanical ventilation in cardiovascular surgery patients. AB - OBJECTIVE: Protocols and order sets for the delivery of analgesia, sedation, and delirium care of the critically ill, mechanically ventilated patient have been shown to improve outcomes but are not uniform in hospitals across geographic areas. The extent to which greater order set quality is associated with improved patient outcomes is not known. We hypothesized that cardiac surgery patients cared for at hospitals with a greater analgesia, sedation, and delirium order set quality score (more guideline-concordant order sets) would have a shorter average duration of mechanical ventilation. DESIGN: Retrospective cohort study. SETTING: All Washington State non-federal hospitals providing cardiac surgery. PATIENTS: All mechanically ventilated cardiac surgery patients from January 1, 2008, until September 30, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We created a multivariable linear regression model to assess the relationship between a hospital's pain, agitation and delirium order set quality, as assessed by an expert-validated order set quality score, and the average duration of mechanical ventilation of its cardiac surgery patients, independent of other hospital and patient factors. A total of 19,561 patients underwent cardiac surgery at 16 Washington state hospitals during the study period. The order set quality scores ranged from 4 to 19 with a mean of 11.8 +/- 4.5. The mean duration of mechanical ventilation was 27.0 +/- 196.6 hours. In the multivariable model, independent of other patient and hospital factors, a 1-point increase in the order set quality score was associated with a 3.3 +/- 0.9 hour (p < 0.01) decrease in average duration of mechanical ventilation. CONCLUSIONS: Cardiac surgery hospitals with more guideline-adherent analgesia, sedation, and delirium order sets have patients with shorter mean durations of mechanical ventilation than hospitals with lower order set quality scores. PMID- 23989173 TI - Delayed medical emergency team calls and associated outcomes. AB - OBJECTIVE: To determine whether there was an association between delayed medical emergency team calls and mortality after a medical emergency team review. DESIGN: This was a prospective observational study. SETTING: A university-affiliated tertiary referral hospital in Porto Alegre, Brazil. PATIENTS: All patients were reviewed by the medical emergency team from July 2008 to December 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1,481 calls for 1,148 patients. Delayed medical emergency team calls occurred for 246 patients (21.4%). The criterion associated with delay was typically the same criterion for the subsequent medical emergency team call. Physicians had a greater prevalence of delayed medical emergency team calls (110 of 246 [44.7%]) than timely medical emergency team calls (267 of 902 [29.6%]; p < 0.001). The mortality at 30 days after medical emergency team review was higher among patients with delayed medical emergency team activation (152 [61.8%]) than patients receiving timely medical emergency team activation (378 [41.9%]; p < 0.001). In a multivariate analysis, delayed medical emergency team calls remained significantly associated with higher mortality. CONCLUSIONS: Delayed medical emergency team calls are common and are independently associated with higher mortality. This result reaffirms the concept and need for a rapid response system. PMID- 23989172 TI - Focused critical care echocardiography. AB - OBJECTIVE: Portable ultrasound is now used routinely in many ICUs for various clinical applications. Echocardiography performed by noncardiologists, both transesophageal and transthoracic, has evolved to broad applications in diagnosis, monitoring, and management of critically ill patients. This review provides a current update on focused critical care echocardiography for the management of critically ill patients. METHOD: Source data were obtained from a PubMed search of the medical literature, including the PubMed "related articles" search methodology. SUMMARY AND CONCLUSIONS: Although studies demonstrating improved clinical outcomes for critically ill patients managed by focused critical care echocardiography are generally lacking, there is evidence to suggest that some intermediate outcomes are improved. Furthermore, noncardiologists can learn focused critical care echocardiography and adequately interpret the information obtained. Noncardiologists can also successfully incorporate focused critical care echocardiography into advanced cardiopulmonary life support. Formal training and proctoring are important for safe application of focused critical care echocardiography in clinical practice. Further outcomes based research is urgently needed to evaluate the efficacy of focused critical care echocardiography. PMID- 23989174 TI - Acute respiratory failure in patients with toxic epidermal necrolysis: clinical features and factors associated with mechanical ventilation. AB - OBJECTIVES: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe adverse cutaneous drug reactions characterized by widespread skin and mucous membrane detachments, including bronchial mucosa, which may be associated with respiratory failure requiring mechanical ventilation. The presentation and outcome of patients requiring mechanical ventilation and the characteristics of bronchial epithelial lesions among ventilated patients are reported. Predictors of mechanical ventilation available on hospital admission were identified using univariate and multivariate logistic regressions. DESIGN: Retrospective cohort study. SETTING: Medical ICU and dermatology department of a tertiary care hospital, which hosts the French national referral center for toxic epidermal necrolysis. PATIENTS: Patients admitted for Stevens-Johnson syndrome/toxic epidermal necrolysis over a 14-year period were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 221 patients included in the study, 56 patients (25.3%) required mechanical ventilation. None of the patients received noninvasive ventilation. Patients requiring mechanical ventilation had a larger baseline detached body surface area, higher Logistic Organ Dysfunction score, and Simplified Acute Physiology Score II, and they presented more often with shock, pulmonary infiltrates, and renal dysfunction (p < 0.0001 for all comparisons). Among patients receiving mechanical ventilation, 57% of the patients died; those having bronchial epithelial lesions (22 of 56) required intubation earlier than others (1 [1-4] vs 4 [1-6] d after hospital admission; p = 0.027). Variables associated with mechanical ventilation in multivariate analysis included serum bicarbonates less than 20 mM (odds ratio, 4.9 [95% CI, 1.1-22.7]; p = 0.041), serum urea greater than 10 mM (odds ratio, 7.0 [95% CI, 2.2-22.8]; p < 0.001), a detached body surface area between 10% and 29% (odds ratio, 3.7 [95% CI, 1.0 13.8]; p = 0.048) or greater than or equal to 30% (odds ratio, 19.7 [95% CI, 4.4 87.4]; p < 0.0001), WBCs more than 12,000/mm3 (odds ratio, 11.6 [95% CI, 2.8 48.1]; p < 0.001), blood hemoglobin less than 8 g/dL (odds ratio, 8.1 [95% CI, 1.2-55.2]; p = 0.032), and more extensive pulmonary infiltrates (odds ratio, 9.7 [95% CI, 3.6-25.9]; p < 0.0001). CONCLUSIONS: Mechanical ventilation is required in one of four Stevens-Johnson syndrome/toxic epidermal necrolysis patients and is associated with a poor outcome. Prompt identification of Stevens-Johnson syndrome/toxic epidermal necrolysis patients at higher risk of intubation could help guide their early management, particularly for those having bronchial epithelial lesions. PMID- 23989175 TI - Sepsis and scientific revolutions. AB - HYPOTHESIS: The therapeutic approach to sepsis is following an evolutionary process of scientific discovery as articulated in the landmark work by Kuhn, The Structure of Scientific Revolutions, first published 50 years ago. BACKGROUND: Incremental advances, beginning with the introduction of antimicrobials and most recently highlighted by revised, evidence-based guidelines for the management of sepsis, have been accompanied by episodic paradigm shifts. Although some of these have shown success, there are numerous, noteworthy failures, largely involving immune- and coagulation-based therapeutic strategies. CONCLUSION: A sustained paradigm shift in the approach to treating sepsis has yet to emerge, but recent data suggest that an open-minded posture informed by novel pathobiologic findings may eventually bear fruit. PMID- 23989176 TI - Assessment of severity of ICU-acquired pneumonia and association with etiology. AB - OBJECTIVES: We evaluated the association between severity of illness and microbial etiology of ICU-acquired pneumonia to define if severity should be used to guide empiric antibiotic choices. DESIGN: Prospective observational study. SETTING: ICUs of a university hospital. PATIENTS: Three hundredy forty-three consecutive patients with ICU-acquired pneumonia clustered, according to the presence of multidrug resistant pathogens. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred eight patients had ventilator-associated pneumonia and 135 had nonventilator ICU-acquired pneumonia. We determined etiology in 217 patients (63%). The most frequent pathogens were Pseudomonas aeruginosa, Enterobacteriaceae, and methicillin-sensitive and methicillin-resistant Staphylococcus aureus. Fifty-eight patients (17%) had a multidrug-resistant causative agent. Except for a longer ICU stay and a higher rate of microbial persistence at the end of the treatment in the multidrug-resistant group, no differences were found in clinical and inflammatory characteristics, severity criteria, and mortality or survival between patients with and without multidrug resistant pathogens, even after adjusting for potential confounders. Patients with higher severity scores (Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment) and septic shock at onset of pneumonia had significantly lower 28- and 90-day survival and higher systemic inflammatory response. The results were similar when only patients with microbial diagnosis were considered, as well as when stratified into ventilator-associated pneumonia and nonventilator ICU-acquired pneumonia. CONCLUSIONS: In patients with ICU-acquired pneumonia, severity of illness seems not to affect etiology. Risk factors for multidrug resistant, but not severity of illness, should be taken into account in selecting empiric antimicrobial treatment. PMID- 23989177 TI - Critical care transition programs and the risk of readmission or death after discharge from an ICU: a systematic review and meta-analysis. AB - OBJECTIVE: To determine whether critical care transition programs reduce the risk of ICU readmission or death, when compared with standard care among adults who survived their incident ICU admission. DATA SOURCES: MEDLINE, EMBASE, CENTRAL, CINAHL, and two clinical trial registries were searched from inception to October 2012. STUDY SELECTION: Studies that examined the effects of critical care transition programs on the risk of ICU readmission or death among patients discharged from ICU were selected for review. A critical care transition program included any rapid response team, medical emergency team, critical care outreach team, or ICU nurse liaison program that provided follow-up for patients discharged from ICU. DATA EXTRACTION: Two reviewers independently extracted data on study characteristics, transition program characteristics, and outcomes (number of ICU readmissions and in-hospital deaths following discharge from ICU). DATA SYNTHESIS: From 3,120 citations, nine before-and-after studies were included. The studies examined medical-surgical populations and described transition programs that were a component of a hospital's outreach team (n = 6) or nurse liaison program (n = 3). Meta-analysis using a fixed-effect model demonstrated a reduced risk of ICU readmission (risk ratio, 0.87 [95% CI, 0.76 0.99]; p = 0.03; I2 = 0%) but no significant reduction in hospital mortality (risk ratio, 0.84 [95% CI, 0.66-1.05]; p = 0.1; I2 = 16%) associated with a critical care transition program. The risk of ICU readmission was similar whether the transition program was included within an outreach team or a nurse liaison program and did not depend on the presence of an intensivist. CONCLUSIONS: Critical care transition programs appear to reduce the risk of ICU readmission in patients discharged from ICU to a general hospital ward. Given methodological limitations of the included before-and-after studies, additional research should confirm these observations and explore the ideal model for these programs before recommending implementation. PMID- 23989178 TI - Timing of limitations in life support in acute lung injury patients: a multisite study*. AB - OBJECTIVE: Substantial variability exists in the timing of limitations in life support for critically ill patients. Our objective was to investigate how the timing of limitations in life support varies with changes in organ failure status and time since acute lung injury onset. DESIGN, SETTING, AND PATIENTS: This evaluation was performed as part of a prospective cohort study evaluating 490 consecutive acute lung injury patients recruited from 11 ICUs at three teaching hospitals in Baltimore, MD. INTERVENTIONS: None. MEASUREMENTS: The primary exposure was proportion of days without improvement in Sequential Organ Failure Assessment score, evaluated as a daily time-varying exposure. The outcome of interest was a documented limitation in life support defined as any of the following: 1) no cardiopulmonary resuscitation, 2) do not reintubate, 3) no vasopressors, 4) no hemodialysis, 5) do not escalate care, or 6) other limitations (e.g., "comfort care only"). MAIN RESULTS: For medical ICU patients without improvement in daily Sequential Organ Failure Assessment score, the rate of limitation in life support tripled in the first 3 days after acute lung injury onset, increased again after day 5, and peaked at day 19. Compared with medical ICU patients, surgical ICU patients had a rate of limitations that was significantly lower during the first 5 days after acute lung injury onset. In all patients, more days without improvement in Sequential Organ Failure Assessment scores was associated with limitations in life support, independent of the absolute magnitude of the Sequential Organ Failure Assessment score. CONCLUSIONS: Persistent organ failure is associated with an increase in the rate of limitations in life support independent of the absolute magnitude of Sequential Organ Failure Assessment score, and this association strengthens during the first weeks of treatment. During the first 5 days after acute lung injury onset, limitations were significantly more common in medical ICUs than surgical ICUs. PMID- 23989179 TI - The medical emergency team call: a sentinel event that triggers goals of care discussion. AB - OBJECTIVE: Several studies have questioned the effectiveness of rapid-response systems when measured by outcomes such as decreased overall hospital mortality or cardiac arrest rates. We studied an alternative outcome of rapid-response system implementation, namely, its effect on goals of care and designation of do not resuscitate. DESIGN: Retrospective chart review. SETTING: Veterans Administration Hospital in New York City. SUBJECTS: All patients requiring a medical emergency team call. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: : Monthly hospital census and discharge data, death occurrences, and do-not-resuscitate order placements were collected over an 8-year pre-medical emergency team and 5-year post-medical emergency team period. All medical emergency team calls and subsequent transfers to a critical care unit were reviewed and correlated to the placement and timing of do-not-resuscitate orders. Interrupted time-series analysis was used to evaluate the impact of the medical emergency team implementation on the change in trend of do-not-resuscitate orders and the hospital mortality. A total of 390 medical emergency team calls were associated with 109 do-not-resuscitate orders (28%). Of the 209 medical emergency team calls (54%) resulting in transfer to a critical care unit, 66 were associated with do not-resuscitate orders, 73% of which were obtained after transfer. The odds of becoming do not resuscitate for a patient going to the ICU after the medical emergency team call were 2.9 (95% CI, 1.6-5.5; p = 0.001) times greater than for patients staying on the floors after the medical emergency team call. The medical emergency team implementation significantly changed the trend of do-not resuscitate orders (p < 0.001) but had no impact on hospital mortality rate (p = 0.638). CONCLUSION: Implementation of a rapid-response system was associated with an increase in do-not-resuscitate order placement. As a sentinel event, medical emergency team activation and transfer to a critical care unit foster consideration of goals of care and frequently results in a transition to a palliative care strategy. PMID- 23989180 TI - Are autopsy findings still relevant to the management of critically ill patients in the modern era? AB - OBJECTIVES: The purpose of this study was to determine the accuracy of clinical diagnoses compared to autopsy findings in critically ill patients in the current medical era. DESIGN: We conducted a retrospective, blinded review of matched medical records and postmortem findings in patients who died between June 2006 and June 2011. SETTING: An ICU of a major university teaching hospital in Dublin, Ireland. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: A modification of the Goldman criteria was used to classify diagnostic error. There were 629 ICU deaths during the study period. Two hundred and seven patients underwent autopsy and 204 records were available for review. The mean age was 59 +/- 18.1 years, 62% were male, 70% were postoperative patients, and median length of ICU stay was 3 days. Admission diagnosis, admission source, and admission specialty were similar between autopsy and nonautopsy patients. Five patients (2.4%; CI, 0.8-5.6%) had a class I discrepancy and 11 patients (5.4%; CI, 2.4-9.7%) had a class II discrepancy. Minor missed diagnoses were present in 31 patients (15.2%; CI, 4.5 12.4%). There was complete concordance between clinical and postmortem findings (class V) in 161 patients (79%; CI, 72.7-84.3%). In more than half the cases of discrepancy, it was not possible for physicians to make the diagnosis antemortem in the time available, despite appropriate investigations. CONCLUSIONS: We detected a lower rate of clinicopathological discrepancy in critically ill patients than previously reported. Potential reasons for such findings include advances in diagnostic techniques and the use of a more robust definition to classify diagnostic discrepancies. Autopsy can still identify discrepancies in diagnosis even in patients who have undergone appropriate investigations. Prospective research is required to accurately define discrepancy rates in the critically ill population and to identify the patient subgroups in whom autopsy will continue to yield valuable information. PMID- 23989181 TI - Defining the practice of "no escalation of care" in the ICU. AB - OBJECTIVE: Withdrawal or withholding of life-sustaining therapies precedes most deaths in the modern ICU. As goals of care for critically ill patients change from curative to palliative, this transition often occurs abruptly, but a slower more staggered approach may also be used. One such approach is "no escalation of care", often the first step in this transition at the end-of-life. We aimed to determine the prevalence of no escalation of care designation for ICU decedents and identify which interventions are involved. DESIGN: We performed a retrospective medical record review of all patients who died over a two year period. Records with documentation of no escalation of care in physician orders or progress notes, or other instructions suggesting sequential or selective limitation of interventions were included. SETTING: Sixteen bed medical ICU at a single large academic hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of a total of 310 ICU decedents, 95 (30%) had a no escalation of care designation before death. Hemodialysis, vasopressors, and blood transfusions were the interventions more likely to be withheld. For ongoing therapies, hemodialysis, blood transfusions, and antibiotics were more likely to be withdrawn. Mechanical ventilation, hydration, and nutrition were less likely to be withheld or withdrawn. A minority had a palliative care consult (15%) or ethics consult (4%) while in the ICU. Time from no escalation of care designation to death averaged 0.8 days (range, 0-5 d). CONCLUSION: No escalation of care designation occurs in a significant proportion of ICU decedents shortly before death. Some interventions are more likely to be limited than others using a no escalation of care approach. PMID- 23989182 TI - Therapeutic hypothermia and the risk of infection: a systematic review and meta analysis. AB - OBJECTIVE: Observational studies suggest that infections are a common complication of therapeutic hypothermia. We performed a systematic review and meta-analysis of randomized trials to examine the risk of infections in patients treated with hypothermia. DATA SOURCES: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched for eligible studies up to October 1, 2012. STUDY SELECTION: We included randomized controlled clinical trials of therapeutic hypothermia induced in adults for any indication, which reported the prevalence of infection in each treatment group. DATA EXTRACTION: For each study, we collected information about the baseline characteristics of patients, cooling strategy, and infections. DATA SYNTHESIS: Twenty-three studies were identified, which included 2,820 patients, of whom 1,398 (49.6%) were randomized to hypothermia. Data from another 31 randomized trials, involving 4,004 patients, could not be included because the occurrence of infection was not reported with sufficient detail or not at all. The risk of bias in the included studies was high because information on the method of randomization and definitions of infections lacked in most cases, and assessment of infections was not blinded. In patients treated with hypothermia, the prevalence of all infections was not increased (rate ratio, 1.21 [95% CI, 0.95 1.54]), but there was an increased risk of pneumonia and sepsis (risk ratios, 1.44 [95% CI, 1.10-1.90]; 1.80 [95% CI, 1.04-3.10], respectively). CONCLUSION: The available evidence, subject to its limitations, strongly suggests an association between therapeutic hypothermia and the risk of pneumonia and sepsis, whereas no increase in the overall risk of infection was observed. All future randomized trials of hypothermia should report on this important complication. PMID- 23989183 TI - A comparison of the potential for acute cardiopulmonary adverse effects in dogs during continuous veno-venous hemofiltration with accusol 35 solution with and without induced calcium carbonate particles. AB - BACKGROUND: Baxter received reports of visible precipitate, identified as calcium carbonate, forming during hemofiltration with Accusol 35 solution. AIM: To evaluate the potential for acute cardiopulmonary adverse effects of Accusol 35 containing exaggerated calcium carbonate particles. METHODS: Anesthetized dogs underwent continuous veno-venous hemofiltration (CVVH) with Accusol 35 containing visible and subvisible particles (>=10 um) 36 times higher than the maximum concentration specified in the European Pharmacopoeia (P-Accusol), or Accusol 35 conforming to specification (Accusol). Select cardiovascular and blood gas parameters were evaluated during CVVH. Lung tissue samples were collected following CVVH. RESULTS: No differences were observed in cardiovascular and blood gas parameters or lung histology between P-Accusol and Accusol. CONCLUSION: Accusol 35 containing visible and subvisible particles (>=10 um) 36 times higher than the maximum concentration specified in the European Pharmacopoeia resulted in no acute cardiopulmonary adverse effects compared with Accusol 35 containing no visible particles and subvisible particles within European Pharmacopoeia specification. PMID- 23989185 TI - Remarkable thermoresponsive nanofibers from gamma-peptides. AB - Conformational analysis of gamma-peptides composed of 4,4-gem-dimethyl gamma amino acids, their spontaneous self-assembly into nanofibrillar superstructures and remarkable thermoreversible gelation properties in various organic solvents are studied. This new generation of gamma-peptides may serve as potential templates to design advanced biomaterials. PMID- 23989184 TI - Haloferax volcanii cells lacking the flagellin FlgA2 are hypermotile. AB - Motility driven by rotational movement of flagella allows bacteria and archaea to seek favourable conditions and escape toxic ones. However, archaeal flagella share structural similarities with bacterial type IV pili rather than bacterial flagella. The Haloferax volcanii genome contains two flagellin genes, flgA1 and flgA2. While FlgA1 has been shown to be a major flagellin, the function of FlgA2 is elusive. In this study, it was determined that although FlgA2 by itself does not confer motility to non-motile DeltaflgA1 Hfx. volcanii, a subset of these mutant cells contains a flagellum. Consistent with FlgA2 being assembled into functional flagella, FlgA1 expressed from a plasmid can only complement a DeltaflgA1 strain when co-expressed with chromosomal or plasmid-encoded FlgA2. Surprisingly, a mutant strain lacking FlgA2, but expressing chromosomally encoded FlgA1, is hypermotile, a phenotype that is accompanied by an increased number of flagella per cell, as well as an increased flagellum length. Site-directed mutagenesis resulting in early translational termination of flgA2 suggests that the hypermotility of the DeltaflgA2 strain is not due to transcriptional regulation. This, and the fact that plasmid-encoded FlgA2 expression in a DeltaflgA2 strain does not reduce its hypermotility, suggests a possible regulatory role for FlgA2 that depends on the relative abundance of FlgA1. Taken together, our results indicate that FlgA2 plays both structural and regulatory roles in Hfx. volcanii flagella-dependent motility. Future studies will build upon the data presented here to elucidate the significance of the hypermotility of this DeltaflgA2 mutant, and will illuminate the regulation and function of archaeal flagella. PMID- 23989186 TI - Dietary alpha-lipoic acid prevents UVB-induced corneal and conjunctival degeneration through multiple effects. AB - PURPOSE: This study investigated the effects of dietary alpha-lipoic acid (alpha LA) against ultraviolet B (UVB)-induced corneal and conjunctival degeneration in a mouse model. METHODS: Female CBA mice were randomly divided into five study groups, including blank control, UVB without alpha-LA, and UVB with dietary alpha LA at 1, 10, and 100 mg/kg body weight. Following UVB exposure, corneal surfaces were assessed along with immunohistochemistry for nuclear factor-kappaB (NF kappaB), cyclooxygenase-2 (COX-2), malondialdehyde (MDA) accumulation, and P63+ basal cell distribution. Matrix metalloproteinase (MMP)-2 and MMP-9 activities were determined by gelatin zymography. ELISA assay was performed to confirm the findings of immunohistochemistry for NF-kappaB, COX-2, and MDA, along with the levels of TNF-alpha and IL-6. Tear production and goblet cell density were determined after tear strip assay and periodic acid Schiff staining, respectively. RESULTS: The results showed that UVB irradiation caused corneal surface damage, polymorphonuclear leukocyte infiltration, and loss of P63+ basal cells. Dietary alpha-LA ameliorated the UVB-induced corneal damage while simultaneously reducing MDA accumulation and maintaining P63+ basal cell survival. NF-kappaB-p65, COX-2, TNF-alpha, IL-6, and MMP-9 activity were all reduced by dietary alpha-LA. In addition, alpha-LA helped to reverse aqueous tear reduction, conjunctival squamous epithelium metaplasia, and goblet cell loss after UVB exposure. CONCLUSIONS: Dietary alpha-LA can prevent UVB-induced corneal damage and can be used as a prophylactic agent prior to excessive UVB exposure. PMID- 23989187 TI - Overexpression of angiogenin in pterygium body fibroblasts and its association with proliferative potency. AB - PURPOSE: Angiogenin (ANG) originally was identified as an angiogenic tumor factor, and recently its biologic activity is extended to stimulating cell proliferation. With viewing pterygium as a tumorigenic mimicry, we investigated ANG profiles within pterygia. METHODS: Expression levels of ANG were assessed using immunohistochemistry, RT-PCR, and Western blotting through examination of excised specimens and cultured fibroblasts from pterygium and conjunctiva tissues. The phenotypes of pterygia were classified by four grading indices, including recurrence, growth activity, pterygium body translucency (T), and vascularity (V). Then, ANG levels in pterygia were differentiated according to phenotypes of pterygia, and were compared to levels in normal conjunctiva. Furthermore, to investigate ANG-related acquisition of proliferative potency in fibroblasts, the correlation between ANG and alpha-smooth muscle actin (alpha SMA) levels was evaluated. RESULTS: In immunohistochemistry, ANG was expressed strongly in pterygium stroma with all four severe phenotypes (with recurrence, active growth, thick body [T3], and marked vascularization [V3]), especially at the perivascular areas. There was a trend toward higher ANG expression in cultured fibroblasts of pterygia with severe phenotype, compared to those without and with normal conjunctiva. However, pterygium body V had a weak association with ANG expression. Additionally, Western blotting revealed a significant positive correlation between the expression levels of alpha-SMA and ANG. CONCLUSIONS: Overexpression of ANG in pterygium body fibroblasts might be involved in active pterygium growth with thick pterygium body formation and increased risk of recurrence. A possible mechanism for this finding includes ANG related transition of pterygium fibroblasts to the proliferative state. PMID- 23989188 TI - An investigative peptide-acyclovir combination to control herpes simplex virus type 1 ocular infection. AB - PURPOSE: To investigate the efficacy of a combination treatment composed of the cationic, membrane-penetrating peptide G2, and acyclovir (ACV) in both in vitro and ex vivo models of herpes simplex virus 1 (HSV-1) ocular infection. METHODS: The antiviral activity of a combined G2 peptide and ACV therapy (G2-ACV) was assessed in various treatment models. Viral entry, spread, and plaque assays were performed in vitro to assess the prophylactic efficacy of G2, G2-ACV, and ACV treatments. In the ex vivo model of HSV-1 infection, the level of viral inhibition was also compared among the three treatment groups via Western blot analysis and immunohistochemistry. The potential change in expression of the target receptor for G2 was also assessed using immunohistochemistry and RT-PCR. RESULTS: Statistically significant effects against HSV-1 infection were seen in all treatment groups in the viral entry, spread, and plaque assays. The greatest effects against HSV-1 infection in vitro were seen in the G2-ACV group. In the ex vivo model, statistically significant anti-HSV-1 effects were also noted in all control groups. At 24 hours, the greatest inhibitory effect against HSV-1 infection was seen in the ACV group. At 48 hours, however, the G2-ACV-treated group demonstrated the greatest antiviral activity. Syndecan-1, a target of G2, was found to be upregulated at 12-hours postinfection. CONCLUSIONS: This study shows that G2-ACV may be an effective antiviral against HSV-1 (KOS) strain when applied as single prophylactic applications with or without continuous doses postinfection. PMID- 23989189 TI - Bleb analysis by using anterior segment optical coherence tomography in two different methods of trabeculectomy. AB - PURPOSE: To investigate the correlation between bleb morphology and IOP control via the modified Indiana Bleb Appearance Grading Scale (IBAGS) and anterior segment optical coherence tomography (AS-OCT) in two different trabeculectomy (TLE) groups. METHODS: This study involved 94 eyes with primary open angle glaucoma that underwent two different TLE methods: limbal-based TLE (group I, 62 eyes) and fornix-based TLE (group II, 32). IOP control was defined as successful with an IOP <= 20 mm Hg and >=20% reduction of preoperative IOP. IBAGS and various parameters of the bleb height, extent, wall thickness, ciliochoroidal detachment (CCD), and lake under the scleral flap (LUSF) were obtained by slit lamp and AS-OCT, respectively. Correlation between IOP control and IBAGS/AS-OCT parameters were assessed by SAS. RESULTS: Both groups had the same success rate. As to correlation between IOP control and IBAGS, extent and Seidel were the best paired parameters in group I (Cp = 3.0402, R = 0.6401), yet no parameter was significant in group II (maximum R = 0.1599). As to correlation between IOP control and AS-OCT, the combinations of height, extent, and the minimum value of bleb wall thickness were significant (Cp = 0.2037, 0.2314, R = 0.4336, 0.4330) in group I. In group II, no parameter was significant, except CCD and/or LUSF (P = 0.032). As to coincidence of IBAGS and AS-OCT parameters, height and extent in group I (P = 0.000, P = 0.000) and height in group II were statistically significant (P = 0.020). CONCLUSIONS: IOP control in limbal-based TLE seemed to be more dependent on the large size and thinned-wall bleb than that in fornix based TLE. PMID- 23989191 TI - Development of a rat schematic eye from in vivo biometry and the correction of lateral magnification in SD-OCT imaging. AB - PURPOSE: Optical magnification in optical coherence tomography (OCT) depends on ocular biometric parameters (e.g., axial length). Biometric differences between eyes will influence scan location. A schematic model eye was developed to compensate for lateral magnification in OCT images of the healthy rat. METHODS: Spectral-domain optical coherence tomography images were acquired in 19 eyes of 19 brown Norway rats. Images were scaled using the OCT instrument's built-in scaling function and by calculating the micron per degree from schematic model eyes developed from in vivo biometry (immersion A-scan and videokeratometry). Mean total retinal thickness was measured 500 MUm away from the optic nerve head and optic nerve head diameter was measured. Corneal curvature, lens thickness, and axial length were modified to calculate their effects on OCT scan location and total retinal thickness. RESULTS: Mean total retinal thickness increased by 21 MUm and the SD doubles when images were scaled with the Built-in scaling (222 +/- 13 MUm) compared with scaling with individual biometric parameters (201 +/- 6 MUm). Optic nerve head diameter was three times larger when images were scaled with the Built-in scaling (925 +/- 97 MUm) than the individual biometric parameters (300 +/- 27 MUm). Assuming no other change in biometric parameters, total retinal thickness would decrease by 37 MUm for every millimeter increase in anterior chamber depth due to changes in ocular lateral magnification and associated change in scan location. CONCLUSIONS: Scaling SD-OCT images with schematic model eyes derived from individual biometric data is important. This approach produces estimates of retinal thickness and optic nerve head size that are in good agreement with previously reported measurements. PMID- 23989192 TI - Cluster analyses of grid-pattern display in macular parameters using optical coherence tomography for glaucoma diagnosis. AB - PURPOSE: Using spectral-domain optical coherence tomography (SD-OCT), we assessed the ability of cluster analyses, based on the grid-pattern of macular parameters, to detect glaucoma. METHODS: We enrolled 75 normal eyes, 64 early glaucomatous eyes (EG), and 40 preperimetric glaucomatous eyes (PPG). Each participant was imaged using 3-dimensional optical coherence tomography (3D-OCT) to examine the macular retinal nerve fiber layer (mRNFL) and the thickness of the ganglion cell layer, together with the inner plexiform layer (GCL/IPL). Diagnostic criteria based on the clustering of abnormal grids from the mRNFL and GCL/IPL measurements were applied. The sensitivity and specificity of glaucoma detection were compared between the cluster criteria (CC) and the average thickness criteria (ATC) of total and hemiretinal sectors, and the cut-off criteria were determined using receiver operating characteristic (ROC) curve analyses from our normal controls. RESULTS: The specificity values of CC and ATC from mRNFL measurements were 97% and 100%, respectively. The sensitivity of CC was 94% for EG and 68% for PPG. The sensitivity of ATC was 81% for EG and 38% for PPG. The specificity values of CC and ATC from GCL/IPL measurements were 96% and 100%, respectively. The sensitivity values of CC and ATC were 92% for EG and 63% for PPG. The sensitivity of ATC was 84% for EG and 25% for PPG. When compared to ATC and ROC-based cut-off criteria, CC showed a higher diagnostic capability. CONCLUSIONS: Judging abnormality based on a clustering of abnormal grids from macular OCT parameters may be a reliable approach for diagnosing early glaucoma. (http://www.umin.ac.jp/ctr/index/htm9 number, UMIN000006900.). PMID- 23989190 TI - BDNF treatment and extended recovery from optic nerve trauma in the cat. AB - PURPOSE: We examined the treatment period necessary to restore retinal and visual stability following trauma to the optic nerve. METHODS: Cats received unilateral optic nerve crush and no treatment (NT), treatment of the injured eye with brain derived neurotrophic factor (BDNF), or treatment of the injured eye combined with treatment of visual cortex for 2 or 4 weeks. After 1-, 2-, 4-, or 6-week survival periods, pattern electroretinograms (PERGs) were obtained and retinal ganglion cell (RGC) survival determined. RESULTS: In the peripheral retina, RGC survival for NT, eye only, and eye + cortex animals was 55%, 78%, and 92%, respectively, at 1 week, and 31%, 60%, and 93%, respectively, at 2 weeks. PERGs showed a similar pattern of improvement. After 4 weeks, RGC survival was 7%, 29%, and 53% in each group, with PERGs in the dual-treated animals similar to the 1- to 2-week animals. For area centralis (AC), the NT, eye only, and eye + cortex animals showed 47%, 78%, and 82% survival, respectively, at 2 weeks, and 13%, 54%, and 81% survival, respectively, at 4 weeks. Removing the pumps at 2 weeks resulted in ganglion cell survival levels of 76% and 74% in the AC at 4 and 6 weeks postcrush, respectively. The PERGs from 2-week treated, but 4- and 6-week survival animals were comparable to those of the 2-week animals. CONCLUSIONS: Treating the entire central visual pathway is important following optic nerve trauma. Long-term preservation of central vision may be achieved with as little as 2 weeks of treatment using this approach. PMID- 23989193 TI - Fluxional interconversion of divalent palladium complexes having NSNSN ligands between flexible SNS and rigid NNN-coordinated structures. AB - Mono- and dicationic divalent palladium complexes having 2,6-bis(N heteroarylsulfanylmethyl)pyridine ligands (NSNSN ligands) were synthesized and characterized. The NSNSN ligands were fixed in a rac-SNS tridentate coordination mode in the solid state, while the equilibria among meso-SNS, rac-SNS, and NNN isomers were observed in solution. The equilibrium between the SNS and NNN isomers could be modulated by temperature, as well as by the steric and electronic factors of the NSNSN and monodentate ligands. Lowering the temperature tended to make NNN isomers more predominant compared with SNS isomers. On the other hand, the steric demand between the ligands in the complexes shifted the equilibrium from NNN to SNS isomers. Introduction of pyridyl groups instead of pyrimidyl groups as N-heteroarenes also shifted the equilibrium to SNS isomers. DFT calculation indicated rapid ring inversion of the metallacycle moieties and relatively slow S-inversion in the SNS isomers, a result that was in good agreement with the experimentally observed dynamic behaviors. Both the experimental and theoretical results revealed that the SNS isomers had flexible structures in solution, whereas the NNN isomers were rigid and less dynamic. The mechanistic pathways for interconversion between SNS and NNN isomers were also calculated. Such calculations indicated that a pathway featuring a relatively unstable, distorted ax-SNN intermediate was plausible. The intermediate had an N heteroarene on the coordinated sulfur atom at an axial position. PMID- 23989195 TI - Time for a relook at Spitzer's laws of neonatology? AB - Thirty years ago, 20 tongue-in-cheek aphorisms relating to the practice of neonatology were published and became known as Spitzer's laws of neonatology (SLN). They became widely cited, perhaps because they resonated with some of the experiences of practicing neonatologists at that time. The purpose of this study was to see if Spitzer's laws still resonated with doctors currently practicing in neonatology. A questionnaire containing the 20 Spitzer's laws was distributed to 17 pediatric doctors during their neonatology placement. Each statement has the options of it being noted as rubbish, funny, intuitively correct or evidence based. Respondents were allowed to give more than one opinion for each statement. Less than a quarter (23.5%, n=4) of 17 doctors had previously heard of Spitzer's laws. Of the 355 opinions on Spitzer's statements, almost half (42%) were said to be rubbish, less than a third (31%) were intuitively correct and one-fifth (21%) were said to be funny. Only 5% were thought to be evidence based. Statement 7 'The milder the RDS, the sooner the infant will find himself on 100% oxygen and maximal ventilatory support', scored the highest as being the most rubbish statement (94%). It was also felt to be neither evidence based (0%), funny (0%) nor intuitively correct (6%). The aphorism,'The month you are on service always has three times as many days as any other month on the calendar', scored the highest (45%) as being the funniest. Statement 16, 'If they ain't breathin', they may be seizin'' was considered the aphorism most likely to be evidence based (35%, n=7). A third (35%) of the doctors said they would use Spitzer's laws for teaching future medical students. Many current neonatal practitioners still find SLN humorous but largely irrelevant and not evidence based. PMID- 23989194 TI - Prevalence of pediatric aspiration-associated extraesophageal reflux disease. AB - IMPORTANCE: The role of aspiration-associated extraesophageal reflux disease (AERD) in patients with chronic respiratory symptoms is not well defined. Identifying the frequency of AERD in these patients may provide guidance in their treatment. OBJECTIVE: To determine the prevalence of AERD in patients with chronic respiratory symptoms and to assess the utility of pepsin as a new marker for AERD. DESIGN: Case-control study performed from 2008 through 2012.Western blot analysis for pepsin and oil red O staining for lipid-laden macrophages (LLMs) was performed on bronchoalveolar lavage fluid specimens. SETTING: Tertiary referral center. PARTICIPANTS: Sixty-five patients (aged 4.5 months to 24 years) with chronic pulmonary disease, with or without tracheostomy, were compared with controls undergoing elective surgery who had no history of pulmonary disease. MAIN OUTCOMES AND MEASURES: Presence of pepsin and LLMs and quantity of LLMs in specimens. RESULTS: Seventy-six total patients participated: 34 patients who underwent bronchoscopy, 31 patients with tracheostomy, and 11 controls. Pepsin positive bronchoalveolar lavage fluid specimens were identified in 25 patients who underwent bronchoscopy (74%) and 22 patients with tracheostomy (71%). All specimens from controls were negative for pepsin. Presence of LLMs was identified in specimens from 31 patients in the bronchoscopy group (91%), 16 patients in the tracheostomy group (52%), and 7 controls (64%), with a similar distribution of the quantity of LLMs in each lavage fluid specimen among the groups. CONCLUSIONS AND RELEVANCE: Patients with chronic pulmonary disease have a high prevalence of AERD, which may have important treatment implications. The presence of pepsin was a better predictor of AERD in patients with respiratory symptoms compared with controls than presence of LLMs. Detection of pepsin in bronchoalveolar lavage fluid specimens can serve as a biomarker for AERD and is potentially superior to the current method of measuring LLMs. Whereas there is a significant association between AERD and the presence of chronic respiratory symptoms, this study does not verify causation. Additional study investigating the mechanism of pepsin on the respiratory epithelium may further our understanding of the pathophysiologic characteristics of this association and provide additional management options for these patients. PMID- 23989196 TI - Maternal and neonatal colonization in Bangladesh: prevalences, etiologies and risk factors. AB - OBJECTIVE: To estimate the prevalence of maternal colonizers in South Asia and their potential to colonize the umbilicus, an important precondition causing neonatal sepsis. STUDY DESIGN: We conducted a cross-sectional study at a maternity center in Dhaka with 1219 pregnant women and a subset of 152 newborns from 15 January to 31 October 2011. During labor, study paramedics collected vaginal swabs for bacterial culture and rectal swabs for Group B Streptococcus (GBS) testing. Community health workers collected neonatal umbilical swabs. Log binomial regression models were used to estimate risk ratios. RESULT: In all, 454 women (37.2%, 95% confidence interval (CI) 34.5 to 40.0%) were colonized. The most common organisms isolated were Staphylococcus aureus, Non-GBS and GBS. A total of 94 women (7.7%, 95% CI 6.2 to 9.2%) were colonized with GBS. The risk of GBS umbilical colonization was higher (RR=12.98, 95% CI 3.97 to 42.64) among newborns of mothers with GBS colonization. CONCLUSION: Newborns of mothers colonized with GBS are at higher risk of developing umbilical colonization. PMID- 23989199 TI - The total body burden of Dieldrin. PMID- 23989197 TI - Blood levels of saturated and monounsaturated fatty acids as markers of de novo lipogenesis and risk of prostate cancer. AB - De novo lipogenesis has been implicated in prostate carcinogenesis, and blood levels of specific saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) could reflect activity of this pathway. We used gas chromatography to measure blood SFA and MUFA levels in prediagnostic samples from 476 incident prostate cancer cases (1982-1995) in the Physicians' Health Study and an equal number of controls matched on age and smoking status. Five tagging polymorphisms in the fatty acid synthase (FASN) gene (rs1127678, rs6502051, rs4246444, rs12949488, and rs8066956) were related to blood SFA and MUFA levels. Conditional logistic regression was used to estimate the rate ratios, with 95% confidence intervals, of prostate cancer across quintiles of blood fatty acid levels. The polymorphisms rs6502051 and rs4246444 were associated with lower levels of 14:1n 5, 16:1n-7, and 18:1n-9. Blood levels of 16:1n-7 were associated with higher prostate cancer incidence, with rate ratios for men in increasing quintiles of 1.00, 1.40, 1.35, 1.44, and 1.97 (95% confidence interval: 1.27-3.06; Ptrend = 0.003). Furthermore, 16:1n-7 levels were positively related to incidence of high grade (Gleason score >=7) tumors (rate ratioQ5-Q1 = 3.92; 95% confidence interval: 1.72-8.94) but not low-grade tumors (rate ratioQ5-Q1 = 1.51; 95% confidence interval: 0.87-2.62) (Pheterogeneity = 0.02). Higher activity of enzymes involved in de novo lipogenesis, as reflected in blood levels of 16:1n-7, could be involved in the development of high-grade prostate cancer. PMID- 23989200 TI - Sources of error in the use of fish-brain acetylcholestrinase activity as a monitor for pollution. PMID- 23989198 TI - Prenatal exposure to traffic-related air pollution and risk of early childhood cancers. AB - Exposure to air pollution during pregnancy has been linked to the risk of childhood cancer, but the evidence remains inconclusive. In the present study, we used land use regression modeling to estimate prenatal exposures to traffic exhaust and evaluate the associations with cancer risk in very young children. Participants in the Air Pollution and Childhood Cancers Study who were 5 years of age or younger and diagnosed with cancer between 1988 and 2008 were had their records linked to California birth certificates, and controls were selected from birth certificates. Land use regression-based estimates of exposures to nitric oxide, nitrogen dioxide, and nitrogen oxides were assigned based on birthplace residence and temporally adjusted using routine monitoring station data to evaluate air pollution exposures during specific pregnancy periods. Logistic regression models were adjusted for maternal age, race/ethnicity, educational level, parity, insurance type, and Census-based socioeconomic status, as well as child's sex and birth year. The odds of acute lymphoblastic leukemia increased by 9%, 23%, and 8% for each 25-ppb increase in average nitric oxide, nitrogen dioxide, and nitrogen oxide levels, respectively, over the entire pregnancy. Second- and third-trimester exposures increased the odds of bilateral retinoblastoma. No associations were found for annual average exposures without temporal components or for any other cancer type. These results lend support to a link between prenatal exposure to traffic exhaust and the risk of acute lymphoblastic leukemia and bilateral retinoblastoma. PMID- 23989201 TI - Residues in two bald eagles suspected of pesticide poisoning. PMID- 23989202 TI - A method for estimating Diuron (N'-(3,4-dichlorophenyl)-NN-dimethyl urea) in surface water by electron capture gas chromatography. PMID- 23989203 TI - The inhibition of beef liver hydrolytic enzymes by organophosphorus pesticides -A comparison of the effects of several pesticides and their oxons on the inhibition response. PMID- 23989204 TI - Improved volatilization chamber for the kontes sweep co-destillation apparatus (K 50050). PMID- 23989205 TI - Detection of captan residues in prune fruits and blossoms by thin-layer chromatography. PMID- 23989206 TI - Nanoscale quantification of charge injection and transportation process in Si nanocrystal based sandwiched structure. AB - Si nanocrystals are formed by using KrF pulsed laser crystallization of an amorphous SiC/ultrathin amorphous Si/amorphous SiC sandwiched structure. Electrons and holes are injected into Si nanocrystals via a biased conductive AFM tip and the carrier decay and transportation behaviours at the nanoscale are studied by joint characterization techniques of Kelvin probe force microscopy (KPFM) and conductive atomic force microscopy (CAFM). Quantification of the surface charge density is realized by solving the Poisson equation based on KPFM measurements. Besides, the asymmetric barrier height for electrons and holes is considered to play a dominant role in controlling the charge retention and transportation characteristics. The methodology developed in this work is promising for studying the charge injection and transportation process in other materials and structures at the nanoscale. PMID- 23989207 TI - Creative compounding for the geriatric patient. PMID- 23989208 TI - Drug products and drug packaging for the elderly. PMID- 23989209 TI - Common diseases of the elderly. PMID- 23989210 TI - The use of computer technology in the compounding pharmacy. PMID- 23989211 TI - Parental admixture incompatibility: an introduction. PMID- 23989212 TI - Physical stability of urea topical formulations. AB - Urea is used in concentrations as high as 40% in different vehicles for numerous conditions. Ther purpose of this study was to observe the physical stability characteristics of urea incorporatted into several different dermatological bases. In particular, urea was incorporated, in concentrations ranging from 10% to 40%, into ten different vehicles or vehicle combinations; and the physical characteristics/stability were observed. The preparations with the best observable characteristics and apparent physical stability included Carbopol and combinations of Carbopol with Velvachol. PMID- 23989213 TI - The formulatiion development and stability of spironolactone suspension. AB - The purpose of this study was to extemporaneously formulate a liquid dosage form from commercially available tablets and establish the chemical stability of the drug. A suspension of spironolactone (5mg/mL) was formulated from 25-mg spironolactone tablets. Stability-indicating, high perfpromance liquid chromatography assay procedures were used to analyze the concentration of the drug. Chemical stability was predicted using accelerated stability studies. The stability studies were conducted at four temperatures, namely 5*, 30*, and 50*, and 60*C. The spironolactone suspension showed less than 10% degradation at all four temperatures for a period of three months. It appears that the formulation may be stable for longer periods of time; however, the investigation did not extend past this timeline and no recommendation should be implied. PMID- 23989214 TI - The formulation development and stability of metronidazole suspension. AB - The purpose of this study was to extemporaneously formulate a liquid dosage form from commercially available tablets and establish the chemical stability of the drug. A suspension of metronidazole (15 mg/mL) was formulated from 500-mg metronidazole tablets. Stability-indicating, high-performance liquid chromatography assay procedures were utilized to analyze the concentration of the drug. Chemical stability was predicted using accelerated stability studies conducted at four temperatures, namely, 40 deg, 50 deg, 60 deg, and 70 deg C for metronidazole. The Arrhenius plot was used to predict the shelf-life of the metronidazole suspension at room temperature. The shelf-life was calculated from the initial concentration and k0 was found to be 73 years. Howwever, it would be more reasonable to expect that a quantity lasting no more than 90 days should be prepared and dispensed. PMID- 23989215 TI - Stability of ketorolac tromethamine in 5% dextrose injection and 0.9% sodium chloride injections. AB - The stability of ketorolac tromethamine in 5% dextrose injection and 0.9% sodium cholride injection has been studied using a stability-indicating, high performance liquid chromatography assay method developed in our laboratory. This method is precise and accurate, with a percent relative standard deviation of 0.85% based on five readings. The admixtures were stable for at least 50 days when stored at 5 deg C. At 25 deg C the 0.9% sodium chloride admixture was stable for at least 35 days, and in 5% dextrose injection for only seven days. After 14 days of storage at 25 deg C the pH value of the admixture in 5% dextrose injection had decreased from 6.6 to 4.3. The changes in pH values of all other admixtures were less than 0.55. This assay method can be used to quantify ketorolac tromethamine in injections and tablets. PMID- 23989216 TI - Stability of cefmetazole sodium in 5% dextrose injection and 0.9% sodium chloride injection. AB - The stability of cefmetazole sodium in 5% dextrose injection and 0.9% sodium choloride injection has been studied using a stability-indicating, high performance liquid chromatography (HPLC) assay method developed in our laboratory. This HPLC method is precise and accurate, with a percent relative standard deviation of 1.4 based on five readings. The admixtures were stable for two days at 25 deg C and for 28 days at 5 deg C, and they remained clear throughout the study period. The pH values decreased from 4.7 to 4.0 in 0.9% sodium chloride injection and from 4.8 to 4.2 in 5% dextrose injection. The expiry date of seven days at 5 deg C recommended by the manufacturer appears to be conservative from a chemical-stability standpoint. PMID- 23989218 TI - New insights into the mechanisms of biomineralization. PMID- 23989217 TI - Advantages and clinical applications of natural killer cells in cancer immunotherapy. AB - The past decade has witnessed a burgeoning of research and further insight into the biology and clinical applications of natural killer (NK) cells. Once thought to be simple innate cells important only as cytotoxic effector cells, our understanding of NK cells has grown to include memory-like responses, the guidance of adaptive responses, tissue repair, and a delicate paradigm for how NK cells become activated now termed "licensing" or "arming." Although these cells were initially discovered and named for their spontaneous ability to kill tumor cells, manipulating NK cells in therapeutic settings has proved difficult and complex in part due to our emerging understanding of their biology. Therapies involving NK cells may either activate endogenous NK cells or involve transfers of exogenous cells by hematopoietic stem cell transplantation or adoptive cell therapy. Here, we review the basic biology of NK cells, highlighting characteristics which make NK cells particularly useful in cancer therapies. We also explore current treatment strategies that have been used for cancer as well as discuss potential future directions for the field. PMID- 23989219 TI - [Refractive changes after Descemet membrane endothelial keratoplasty]. AB - Penetrating keratoplasty has different refractive disadvantages in contrast to posterior lamellar keratoplasty. For example, a decentered corneal trephination and a tilted trephination or unevenly tightened corneal sutures can cause an uncontrolled high astigmatism as well as a refractive change. Also the postoperative refraction may change over time as a result of wound healing, suture loosening or suture removal. The aim of this retrospective study was to investigate a possible refractive change after Descemet membrane endothelial keratoplasty (DMEK). A total of 139 pseudophakic eyes from 125 patients with endothelial decompensation had undergone DMEK surgery at the Tubingen Eye Clinic. After a mean postoperative time of 13.15 +/- 2.98 months after DMEK discreet mean changes in the spherical equivalent of + 0.37 +/- 0.87 diopters and the cylinder to - 0.45 +/- 0.57 diopters were observed. The mean central corneal thickness decreased from 670 +/- 70 um to 544 +/- 55 um. In conclusion after DMEK a discreet induced hyperopic refractive shift due to the reversal of stromal swelling was observed. PMID- 23989220 TI - Induction of epidermal cell fate in Arabidopsis shoots. AB - Land plants have evolved a cuticle-bearing epidermis to protect themselves from environmental stress and pathogen attack. Despite its important role, little is known about the molecular mechanisms regulating shoot epidermal cell identity. In a recent study, we found that the Arabidopsis thaliana ATML1 gene is possibly a master regulator of shoot epidermal cell fate. We revealed that ATML1 has the ability to confer shoot epidermis-related traits to non-epidermal cells of the seedlings. These data are consistent with the previous loss-of-function mutant analyses, which implied a positive role of ATML1 in epidermal cell differentiation. Importantly, ectopic epidermal cells induced in ATML1 overexpressing lines provide a novel tool to assess the intrinsic properties of epidermal cells and to study epistatic interactions among genes involved in epidermal/mesophyll differentiation. Using this system, we obtained data revealing that ATML1 negatively influenced mesophyll cell fate. In addition, we provided a working model of how division planes in epidermal cells are determined. PMID- 23989221 TI - Ballistic parameters of .177 (4.5 mm) caliber plastic-sleeved composite projectiles compared to conventional lead pellets. AB - The capability of conventional air gun lead pellets (diabolo pellets) to cause severe injuries or fatalities even at low kinetic energy levels is well documented in medical literature. Modern composite hunting pellets, usually a metal core (made of steel, lead, zinc, or a zinc and aluminum alloy) encased in a plastic sleeve, are of special forensic and traumatological interest. These projectiles are advertised by the manufacturers to discharge at higher velocities than conventional air gun pellets, thus generating very high tissue-penetrating capabilities. Lack of experimental data on these uncommon air gun projectiles induced this work. Ballistic parameters of 12 different caliber .177 (4.5 mm) composite pellets, discharged from two spring-piston air guns (Weihrauch HW 35, Webley CUB) and three pneumatic air guns (Walther LGR, Walther LG400, Walther LP300), were investigated using a ballistic speed measurement system and compared to a conventional diabolo pellet (RWS Meisterkugel) as reference projectile. Although overall results were inconsistent, for some projectile-weapon combinations (particularly spring-piston air guns), a significant change of the kinetic energy (-53 up to +48 %) to the reference projectile was observed. The data provided in this work may serve as a basis for forensic investigation as well as traumatological diagnosis and treatment of injuries caused by these uncommon projectiles. PMID- 23989222 TI - Dry skull positioning device for extra-oral radiology and cone-beam CT. AB - Extra-oral radiographs of dry skulls on scientific or forensic context have head position as a critical procedure. The aims of this article are to present a multi purposed head-positioning device, and to describe the new method of image acquirement using the device to adequately keep the head in a correct and safe position during radiological or tomographic exam. The design was created from an average-sized skull and then tested in 20 others with different morphologies, sizes, weights, and structural state of preservation. A series of digital and analog orthopantomographies followed by a cone-beam computer tomography were obtained to assure that the correct positioning standards and anatomical visualization were achievable. The developed device properly kept adult skulls in position for all extra-oral radiographic exams, providing to operators a secure and facilitated way to achieve the proper position standards. The device did not impair the visualization of the anatomical structures neither on radiographs nor in cone-beam computer tomography. PMID- 23989223 TI - Bacterial populations associated with early-stage adipocere formation in lacustrine waters. AB - The preservation of soft tissue is a valuable evidence for forensic investigation as it may provide information about the cause and manner of death as well as the time since death. Adipocere forms from the conversion of triglycerides in the neutral fats into stable fatty acids producing a solid white product which aids tissue preservation. Adipocere will typically form in water-logged grave sites and aquatic environments. Documentation on the chemical and microbiological changes that cause adipocere formation in aquatic environments is scant and mostly based on observational case reports. The aim of this study was to monitor the early adipocere formation in lacustrine waters to investigate the effect of aquatic bacteria on adipocere formation. Tissue samples from pork (Sus scrofa domesticus) belly were submerged in water samples from Lake Ontario and deionised water (control). Bacteria samples from both water and tissue were harvested. Changes in the fatty acid composition of the tissue were determined using gas chromatography-mass spectrometry. Early-stage adipocere formation was confirmed on porcine tissue submerged in lake water but was not identified on porcine tissue submerged in deionised water. Adipocere formation required an abundance of gram-positive bacteria during the early postmortem period to assist in lipolysing the triglycerides into free fatty acids. Formation of adipocere in the lake water resulted in a decrease in bacterial concentrations in the tissue over time. PMID- 23989225 TI - Distribution ratio of some chlorinated hydrocarbon insecticides between hexane and water. PMID- 23989226 TI - Gas chromatographic characteristics of chlordane I. effect of an aqueous environment on the heptachlor component. PMID- 23989224 TI - All together now: Polo joins the kinase network controlling the spindle assembly checkpoint in Drosophila. AB - Maintenance of genomic stability during eukaryotic cell division relies on the Spindle Assembly Checkpoint (SAC), which has evolved as a surveillance mechanism that monitors kinetochore-microtubule attachment and prevents APC/C-mediated mitotic exit until all chromosomes are properly attached to the mitotic spindle. Reversible protein phosphorylation has long been accredited as a regulatory mechanism of the SAC. Nevertheless, knowledge of how several mitotic kinases act in concert within the signaling pathway to orchestrate SAC function is still emerging. In a recent study, we undertook a comprehensive dissection of the hierarchical framework controlling SAC function in Drosophila cells. We found that Polo lies at the top of the SAC pathway promoting the efficient recruitment of Mps1 to unattached kinetochores. This renders Mps1 fully active to control BubR1 phosphorylation that generates the 3F3/2 phosphoepitope at tensionless kinetochores. We have proposed that Polo is required for SAC function and that the molecular outcome of Mps1-dependent 3F3/2 formation is to promote the association of Cdc20 with BubR1 allowing proper kinetochore recruitment of Cdc20 and efficient assembly of the Mitotic Checkpoint Complex (MCC) required for a sustained SAC response. PMID- 23989227 TI - Conversion of heptachlor to its epoxide. PMID- 23989229 TI - The fate of phenyl N,N'-dimethylphosphor-diamidate in soil. PMID- 23989228 TI - A simple starch-gel electrophoretic method to investigate esterase inhibition by common organic insecticides. PMID- 23989230 TI - Degradation of p(32)-bromophos by microorganisms and seedlings. PMID- 23989231 TI - Delayed lethal effect of 2,4-Dichlorophenoxyacetic acid on bacteria. PMID- 23989232 TI - Activation and standardization of purified silica gel for column chromatographic cleanup of pesticide residue extracts. AB - Activation and standardization studies have been conducted with high purity grades 950 and 923 silica gel to obtain an effective adsorbent for cleanup of pesticide residue extracts. Activation of silica gel at 130 degrees C or 300 degrees C for a 2-hr period was very satisfactory for separating pesticides from biological materials with high recovery of pesticides. No gain in the activity of the adsorbent resulted from prolonging heat treatment beyond the 2-hr period. It was also found that the activity of the silica gel was not affected by storing it in an air-tight container for as long as 60 days. PMID- 23989233 TI - Two polyoxometalate-directed 3D metal-organic frameworks with multinuclear silver ptz cycle/belts as subunits. AB - Two new polyoxometalate (POM)-based metal-organic frameworks (MOFs) constructed from multinuclear silver-ptz cycle/belts, namely [Ag7(ptz)4(NO3)(H2O)][H4P2W18O62].5H2O () and [Ag6(ptz)4(H2O)2][HPMo12O40].3H2O () (ptzH = 5-(3-pyridyl)-1H-tetrazole), have been successfully synthesized under hydrothermal conditions via changing the polyoxoanions and adjusting the pH. Compound exhibits a 3D framework constructed from the Wells-Dawson [P2W18O62](6-) anion and a 2D layer based on two types of multinuclear Ag-ptz cycles. In compound , the 1D infinite multinuclear Ag-ptz belts consisting of repeated tetranuclear subunits [(Ag1)2(Ag2)2(ptz)4] are connected by Ag3 ions to form a 2D layer. The adjacent 2D layers are further linked by tetra-dentate Keggin [PMo12O40](3-) anions to construct a 3D framework. The structural analyses reveal that the different polyoxoanions have a great influence on the Ag(I)-ptz multinuclear cycle/belts and the whole structures. The influences of the pH and molar ratio of initial reactants in the hydrothermal process were also discussed. The electrochemical and photocatalytic properties of the title compounds have been studied in detail. PMID- 23989235 TI - Sex differences in sensation-seeking: a meta-analysis. AB - Men score higher than women on measures of sensation-seeking, defined as a willingness to engage in novel or intense activities. This sex difference has been explained in terms of evolved psychological mechanisms or culturally transmitted social norms. We investigated whether sex differences in sensation seeking have changed over recent years by conducting a meta-analysis of studies using Zuckerman's Sensation Seeking Scale, version V (SSS-V). We found that sex differences in total SSS-V scores have remained stable across years, as have sex differences in Disinhibition and Boredom Susceptibility. In contrast, the sex difference in Thrill and Adventure Seeking has declined, possibly due to changes in social norms or out-dated questions on this sub-scale. Our results support the view that men and women differ in their propensity to report sensation-seeking characteristics, while behavioural manifestations of sensation-seeking vary over time. Sex differences in sensation-seeking could reflect genetically influenced predispositions interacting with socially transmitted information. PMID- 23989236 TI - Cryptococcosis in a febrile renal transplant recipient. PMID- 23989237 TI - Ruthenium(II) complexes based on tridentate polypyridine ligands that feature long-lived room-temperature luminescence. AB - Integrating a matched organic chromophore and a Ru(II) complex with optimized tridentate polypyridine ligands instils reversible electronic energy transfer giving an unusually long room temperature luminescence lifetime (42 MUs) without compromising the emission quantum yield. PMID- 23989238 TI - Group B Streptococcus exposure and self-limited respiratory distress in late preterm and term neonates. AB - BACKGROUND: Self-limited respiratory distress is a common neonatal respiratory morbidity for which effective treatments are lacking. Supportive care with non invasive respiratory support is the norm. Animal models suggest that intrapartum exposure to group B Streptococcus (GBS) may cause mild pulmonary hypertension in the neonate, resulting in self-resolving respiratory distress. Treatments for pulmonary hypertension are currently not provided to neonates with self-limited respiratory distress empirically. OBJECTIVES: This study examines the hypothesis that the incidence and severity of self-limited respiratory distress are altered by intrapartum exposure to GBS and antibiotic prophylaxis (IAP) in a human population. METHODS: This is a 10-year single-center cohort study of retrospective data of late preterm and term neonates diagnosed with self-limited respiratory distress. Multiple logistic models were fitted to examine associations between exposure to GBS and IAP, and markers of self-limited respiratory distress severity. Additional linear regression models were fitted to examine the association between exposure to GBS and IAP, and duration of respiratory support for self-limited respiratory distress. Finally, crude and gestational age-adjusted incidence of self-limited respiratory distress among GBS exposed and -unexposed infants, as well as the odds of self-limited respiratory distress based on GBS exposure were calculated. RESULTS: 584 neonates met study criteria. Neither GBS exposure nor IAP exposure was associated with severity of self-limited respiratory distress in multiple models. Crude and adjusted incidence of self-limited respiratory distress among neonates did not differ by GBS exposure history. CONCLUSIONS: Although animal studies indicate that GBS mediated pulmonary hypertension may contribute to self-limited respiratory distress, neither exposure to GBS nor IAP was associated with an increased severity or incidence of self-limited respiratory distress in our human study population. Treatments for pulmonary hypertension are unlikely to speed symptom resolution for patients with self-limited respiratory distress. PMID- 23989241 TI - A High-Voltage Integrated Circuit Engine for a Dielectrophoresis-based Programmable Micro-Fluidic Processor. AB - A high-voltage (HV) integrated circuit has been demonstrated to transport droplets on programmable paths across its coated surface. This chip is the engine for a dielectrophoresis (DEP)-based micro-fluidic lab-on-a-chip system. This chip creates DEP forces that move and help inject droplets. Electrode excitation voltage and frequency are variable. With the electrodes driven with a 100V peak to-peak periodic waveform, the maximum high-voltage electrode waveform frequency is about 200Hz. Data communication rate is variable up to 250kHz. This demonstration chip has a 32*32 array of nominally 100V electrode drivers. It is fabricated in a 130V SOI CMOS fabrication technology, dissipates a maximum of 1.87W, and is about 10.4 mm * 8.2 mm. PMID- 23989242 TI - Disulfide bond reduction-triggered molecular hydrogels of folic acid-Taxol conjugates. AB - Molecular hydrogels of therapeutic agents are a novel kind of self-delivery system that can sustain release of drugs or pro-drugs. We have previously developed a molecular hydrogelator of folic acid (FA)-Taxol conjugate triggered by phosphatase. In this paper, we report a novel molecular hydrogelator system of FA-Taxol conjugates with improved synthetic strategy. The hydrogels are formed by the reduction of disulfide bond by glutathione (GSH). These hydrogels could sustain release of Taxol through ester bond hydrolysis. Compared with intravenous (i.v.) injection of clinically used Taxol(r) with four times the dosage, our hydrogel could inhibit tumor growth more efficiently by a single dose of intra tumor (i.t.) administration. These observations suggested the big potential of this novel gelation system of Taxol for cancer therapy. PMID- 23989243 TI - An ABI3-interactor of conifers responds to multiple hormones. AB - CnAIP2 (Callitropsis nootkatensis ABI3-Interacting Protein 2) was previously identified as a protein that interacts with the yellow-cedar ABI3 protein. CnAIP2 plays important roles during several key transitions of the plant lifecycle and acts as a global regulator with functions opposite to those of ABI3 proteins. Here we report that the CnAIP2 gene promoter is strongly upregulated by all of the major plant hormones. Young Arabidopsis seedlings expressing a chimeric CnAIP2pro-GUS construct were subjected to exogenously applied hormones; the maximum fold-enhancement of GUS activity was as high as 47-fold, and each hormone showed a distinctive cell/tissue-specific pattern of GUS induction. By far the greatest response was elicited by the synthetic auxin 2,4-D (47-fold induction); the other hormones tested stimulated GUS activities by 8- to 21-fold. The CnAIP2 promoter also responded to glucose and salt (NaCl), albeit to a lesser extent (2- to 3-fold induction). As well as acting in an antagonistic way to the global regulator ABI3, CnAIP2 appears to participate in multiple hormonal crosstalk pathways to carry out its functions. PMID- 23989244 TI - [Fiddler's neck]. AB - The fiddler's neck is an uncommon variant of acne mechanica in violinists and violists. It is a single firm red-brown dermal nodule usually on the left side of neck. This special form of acne mechanica represents a therapeutic challenge since the triggering mechanical factors persist, unless they can be corrected by changes in positioning or modifications of the chin pad. A 72-year-old woman who had played the violin since childhood presented with a red-brown nodule on her neck for 18 months. Cushioning provided no relief. Excision of the affected area with primary closure represented one therapeutic option. Further supportive measures include improved posture to reduce the pressure between skin and instrument and interposing a neck cloth. PMID- 23989245 TI - Surgical management of benign idiopathic osteonecrosis of the external auditory canal. AB - BACKGROUND/AIMS: Benign idiopathic osteonecrosis of the external ear canal remains a challenging management problem, with many patients experiencing a prolonged chronic course requiring frequent debridement. The technique of bony sequestrectomy, followed by rotation of a vascularized fascial flap and then a free full-thickness skin graft is presented. METHODS: Success with this technique is described in a retrospective case series format in addition to a review of the existing literature on surgical techniques for the treatment of this condition. RESULTS: The described technique was performed on 5 patients following prolonged periods of failed medical therapy (minimum 8 months). All 5 patients achieved a healed external auditory canal, with no ongoing skin ulceration or bony sequestration. Follow-up data (median 22 months) suggests that the technique provides a robust and long-lasting therapy. CONCLUSION: Symptomatic benign idiopathic osteonecrosis of the tympanic bone is well treated by provision of vascularized tissue to maximize the chance of bone healing and subsequent cure. It should be considered early in the management protocol to avoid lengthy symptomatic periods, the symptoms of which ultimately may not heal with medical therapy alone. PMID- 23989246 TI - A survey of current practices, attitudes, and knowledge regarding human papillomavirus-related cancers and vaccines among head and neck surgeons. AB - IMPORTANCE: Understanding head and neck surgeons' current knowledge, practices, and opinions regarding human papillomavirus (HPV) education and prevention will enable efforts to assist surgeons in this important endeavor. OBJECTIVE: To assess knowledge, attitudes, and beliefs of head and neck surgeons regarding HPV education and vaccination. DESIGN, SETTING, AND PARTICIPANTS: Online survey of members of the American Head and Neck Society (AHNS) in late 2011 and early 2012. MAIN OUTCOMES AND MEASURES: Knowledge, attitudes, and current practices regarding HPV education and vaccination. RESULTS: All 1081 members of the AHNS were approached via e-mail, and 297 members completed the survey, for an overall response rate of 27.5%. Most respondents were male (86.2%) fellowship-trained head and neck surgeons (80.4%), and most practice in an academic setting (77.1%) in the United States (78.1%). More than 90% of respondents discuss risk factors for head and neck cancer and HPV as a specific risk factor with their patients. However, only 49.1% discuss the importance of vaccinating preadolescents for HPV, most commonly citing that they do not do so because their patients are adults (38.7%). Of those respondents with daughters, 68.9% reported that their daughters had received or they intend their daughters to receive the HPV vaccine. Of those respondents with sons, only 55.8% reported that their sons had been vaccinated or they intend for them to be. Respondents reported divergent attitudes toward HPV vaccination safety and efficacy. However, respondents were overwhelmingly supportive of possible future ANHS activities to educate clinicians, increase public awareness, educate patients, and advocate for health policy related to HPV. CONCLUSIONS AND RELEVANCE: Head and neck surgeons are knowledgeable about HPV and show generally positive attitudes and beliefs about HPV education and vaccination. They endorse AHNS actions to improve public and patient education, as well as health policy on HPV. These findings support AHNS developing a strategic plan and actions to improve knowledge and reduce HPV infection among the American public. PMID- 23989247 TI - Chair rising time is longer in postmenopausal women with history of nonvertebral fracture. AB - The objective of the present study was to clarify the relationships between physical function, bone mass, biochemical markers, renal function, and a history of nonvertebral fracture in postmenopausal women with osteoporosis. In total, 143 postmenopausal women with osteoporosis (mean age: 71.2 years) and an osteoporosis treatment-naive status were recruited. Twenty-seven women had a history of nonvertebral fracture (nonvertebral fracture group) and 116 women did not (control group). The patients' bone mass, biochemical markers, estimated glomerular filtration rate (eGFR), unipedal standing time (index of body balance), and the five-repetition chair-rising time (index of muscle power) were compared between the two groups. Age, body mass index, bone mass, serum alkaline phosphatase, creatinine, albumin, urinary cross-linked N-terminal telopeptides of type I collagen, eGFR, and the unipedal standing time did not differ significantly between the two groups. However, the chair-rising time was significantly longer (12.3 sec vs. 9.6 sec) in the nonvertebral fracture group than in the control group. The odds ratio (95% confidence intervals) for nonvertebral fractures in subjects with a chair-rising time >10.1 sec (mean value) was 4.28 (1.78, 10.30). Thus, a significant association was found between the impairment of muscle power and a history of nonvertebral fracture in postmenopausal women with osteoporosis. PMID- 23989248 TI - Mid-femoral and mid-tibial muscle cross-sectional area as predictors of tibial bone strength in middle-aged and older men. AB - While it is widely acknowledged that bones adapt to the site-specific prevalent loading environment, reasonable ways to estimate skeletal loads are not necessarily available. For long bone shafts, muscles acting to bend the bone may provide a more appropriate surrogate of the loading than muscles expected to cause compressive loads. Thus, the aim of this study was to investigate whether mid-thigh muscle cross-sectional area (CSA) was a better predictor of tibial mid shaft bone strength than mid-tibia muscle CSA in middle aged and older men. 181 Caucasian men aged 50-79 years (mean+/-SD; 61+/-7 years) participated in this study. Mid-femoral and mid-tibial bone traits cortical area, density weighted polar moment of area and muscle CSA [cm(2)] were assessed with computed tomography. Tibial bone traits were positively associated with both the mid-femur (r=0.44 to 0.46, P<0.001) and the mid-tibia muscle CSA (r=0.35 to 0.37, P<0.001). Multivariate regression analysis, adjusting for age, weight, physical activity and femoral length, indicated that mid-femur muscle CSA predicted tibial mid shaft bone strength indices better than mid-tibia muscle CSA. In conclusion, the association between a given skeletal site and functionally adjacent muscles may provide a meaningful probe of the site-specific effect of loading on bone. PMID- 23989249 TI - Physical activity engendering loads from diverse directions augments the growing skeleton. AB - OBJECTIVE: An experiment was conducted to determine if modifying habitual activities to involve mechanical loading from more diverse directions can enhance the growing skeleton. METHODS: Growing female C57BL/6J mice were housed individually for 3 months in enclosures designed to accentuate either non-linear locomotion (diverse-orientation loading) or linear locomotion (stereotypic orientation loading) (n=10/cage type). Behavioral assessments were performed daily to quantify cage activity level. Following the experiment, trabecular and cortical bone structure in the humeral head and distal femoral metaphysis were analyzed with MUCT. RESULTS: Throughout the experiment, groups did not differ in cage activity level. Yet, following the experiment, the proximal humeri of mice that experienced increased diverse-orientation loading had significantly greater trabecular bone volume fraction (p=0.004), greater cortical bone area (p=0.005), greater cortical area fraction (p=0.0007), and thicker cortices (p=0.002). No significant group differences were detected in the distal femoral metaphysis. CONCLUSIONS: Diverting habitual activities to entail loading from more diverse orientations can augment the growing mouse skeleton. This study suggests that low intensity activities that produce loads from diverse directions may represent a viable alternative to vigorous, high-impact exercise as a means of benefiting skeletal health during growth. PMID- 23989250 TI - Changes over time in structural plasticity of trabecular bone in rat tibiae immobilized by reversible sciatic denervation. AB - OBJECTIVE: The present study aimed to clarify the structural recovery, and to compare the time course of morphological changes in trabeculae and the process of bone mass change in rat tibiae following temporary immobilization of hind limb by sciatic neurectomy or nerve freezing. METHODS: In 11-week-old male Fischer 344 rats, 4-5 mm of the sciatic nerve was removed (neurectomy group) or frozen by 5 second application of a stainless steel rod immersed in liquid nitrogen (nerve freezing group). Quantitative changes in cancellous bone were assessed by histomorphometry. RESULTS: The results clarified that: trabecular bone volume (BV/TV) decreases until 3 weeks after denervation, and in the nerve-freezing group, it then increases from week 4, recovering to pre-surgery levels by week 10 (no recovery was seen in the neurectomy group); in the initial phase of bone atrophy, the decrease in BV/TV is more gradual in the nerve-freezing group than in the neurectomy group; and changes in trabecular architecture in the bone atrophy-recovery process are strongly associated with changes in trabecular thickness. CONCLUSION: The findings suggested that after transient injury by nerve freezing and subsequent recovery of neuromuscular function, bone tissue undergoes recovery from bone loss, but that trabeculae may not show complete structural recovery. PMID- 23989251 TI - Reference data for jumping mechanography in healthy children and adolescents aged 6-18 years. AB - OBJECTIVES: To present gender-specific pediatric normative data on the main parameters of muscle function assessed using jumping mechanography. METHODS: The study population included 796 non-selected Caucasian children and adolescents (432 girls and 364 boys) aged 6-19 years recruited from 6 primary schools and 3 high schools. Maximum peak power (Pmax) was examined by a single two-legged jump, and maximum force (Fmax) was examined by a multiple one-legged hopping. All measurements were performed using a portable force platform (Leonardo Mechanograph, Novotec). Pmax, Pmax/mass, Fmax and Fmax/body weight were analyzed as the main outcome parameters. LMS method was used to generate age- and weight specific reference smooth curves. RESULTS: Both Pmax and Fmax were strongly dependent on age and weight in both genders (all p<0.001). In prepubertal children, there was no intergender difference in Pmax or Fmax. Both parameters steadily increased in boys and plateaued in girls aged >13 years. Whereas Pmax/mass was more dependent on anthropometric parameters, Fmax/BW remained nearly constant with respect to age and weight. CONCLUSIONS: These reference data are intended to assist clinicians in the assessment of muscle function by jumping mechanography in pediatric patients. PMID- 23989252 TI - Cross-sectional assessment of neuromuscular function using mechanography in women and men aged 20-85 years. AB - OBJECTIVES: The aim of this cross-sectional study was to examine the influence of age and sex on neuromuscular function of the lower limbs using mechanography. 704 adults aged 20-85 years from Germany participated in this study. METHODS: Ground reaction force and power were assessed with countermovement jumps and the chair rising test on a ground reactions force plate. RESULTS: While ground reaction force per unit body mass declined by about 20% from the third to the ninth decade, the decline of power per unit body mass was much greater, varying between 40-50%. Men and women are affected equally by the decline. Age and sex explained the variability of the power parameters to a much greater extent (R(2)=0.54 to R(2)=0.70) than the force parameters (R(2)=0.18 to R(2)=0.36). CONCLUSIONS: Our reference values can help to identify those who might be affected by the development of sarcopenia. Preventive exercise programs should focus on preserving muscle power in addition to the training of muscle force. PMID- 23989253 TI - Comparison of MRI and DXA to measure muscle size and age-related atrophy in thigh muscles. AB - OBJECTIVES: Magnetic resonance imaging (MRI) and dual-energy x-ray absorptiometry (DXA) were used to examine the thigh lean mass in young and old men and women. METHODS: A whole-body DXA scan was used to estimate thigh lean mass in young (20 men; 22.4+/-3.1y; 18 women; 22.1+/-2.0y) and older adults (25 men; 72.3+/-4.9y; 28 women; 72.0+/-4.5y). Thigh lean mass determined with a thigh scan on the DXA or full thigh MRI scans were compared. RESULTS: Although the thigh lean mass quantified by DXA and MRI in young and older participants were correlated (R(2)=0.88; p<0.001) the magnitude of the differences in thigh lean mass between young and old was smaller with DXA than MRI (old vs. young men 79.5+/-13.1% and 73.4+/-11.2%; old vs. young women 88.6+/-11.8% and 79.4+/-12.3%, respectively). Detailed analysis of MRI revealed 30% smaller quadriceps muscles in the older than young individuals, while the other thigh muscles were only 18% smaller. CONCLUSIONS: DXA underestimates the age-related loss of thigh muscle mass in comparison to MRI. The quadriceps muscles were more susceptible to age-related atrophy compared with other thigh muscles. PMID- 23989254 TI - Physical function and properties of quadriceps femoris muscle after bariatric surgery and subsequent weight loss. AB - OBJECTIVES: To investigate the effects of bariatric surgery-induced weight loss on physical function, the properties of quadriceps femoris muscle (QFM), and the subjective disabilities of the subjects with excessive weight. METHODS: Thirteen female and three male subjects were studied before and 8.8 months after Roux-en-Y gastric bypass (RYGP) operation. The health-related quality of life (RAND-36) and the self-reported disease-specific joint symptoms (WOMAC) were estimated. The objective physical function was evaluated with sock, repeated sit-to-stand, 6 minute walk, stair ascending and descending and timed up and go tests and the properties of the QFM were measured with ultrasound. RESULTS: The average weight loss was 27.3 kg. Objectively measured physical function improved after RYGP operation. Physical functioning, physical role functioning and general health domain scores of the RAND-36 were significantly improved. The stiffness and function scores were lower after RYGP operation in knee OA subjects. The subcutaneous fat thickness and the absolute muscle thickness of QFM decreased, but the ratio of muscle cross sectional area/total body weight did not change. The fat and connective tissue proportion in the QFM muscle were significantly increased. CONCLUSIONS: The RYPG-surgery-induced weight loss exerts a positive impact on physical function but a negative impact on a muscle structure. PMID- 23989255 TI - Decision making for osteoporotic treatment using FRAX or DVO risk algorithms in a clinical setting. AB - OBJECTIVES: To evaluate the therapy decisive clinical risk factors (CRFs) in tools provided by WHO (WHO-FRAX) and the Head Osteology Organization of Germany (DVO) in a clinical setting, and, the degree of agreement between them. METHODS: Three hundred subjects, 40 to 88 years of age, were consecutively referred for an evaluation of osteoporosis-related fracture risk, and therapy was possibly recommended. The evaluation used the 12 CRFs in the FRAX tool and the 21 CRFs in the DVO tool. We analyzed the degree of agreement and the strength of the CRFs in determining the therapy decision. RESULTS: Before evaluation, 52 (17.3%) of the patients took anti-osteoporotic medication. The FRAX tool indicated 36 (12.0%) patients suggested for treatment when hip density was included as a CRF, whereas the DVO tool indicated 80 (26.7%) and 91(30.3%), depending on bone density site. The pre- and post-test results agreed poorly to fair, whereas agreement was poor to good within both models and using the plain T-score to define the therapy intervention threshold. CONCLUSIONS: CRFs with debatable evidence reached significant influence on therapy decision. A considerably divergent number of patients were identified as treatment candidates, deserving further investigation to confirm the usefulness of some CRFs. PMID- 23989256 TI - Comparison of non-vertebral fracture between minodronate and risedronate therapy in elderly female patients with Alzheimer disease. AB - OBJECTIVES: Minodronate is a nitrogen-containing bisphosphonate that is commercially available for the treatment of osteoporosis in Japan. Preclinical studies demonstrated that minodronate is at least 10 times more potent than alendronate in inhibiting bone resorption in vivo. A high incidence of fractures, particularly of the hip, represents an important problem in Alzheimer disease (AD) patients who are prone to falls and may have osteoporosis. METHODS: A total of 256 elderly patients with AD were assigned to daily treatment with 1.0 mg of minodronate or a daily treatment with risedronate combined with daily 1000 IU ergocalciferol and 1200 mg elemental calcium, and followed up for 12 months. RESULTS: At baseline, patients of both groups showed low 25-hydroxyvitamin D with compensatory hyperparathyroidism. Non-vertebral fractures occurred in 5 patients in the minodronate group and 7 patients in the risedronate group (5 hip fractures; one fracture each at the distal forearm and pelvis). There was no difference in risk of hip fracture between the two groups (p=.70; odds ratio=0.8). CONCLUSIONS: The study medications were well tolerated with relatively few adverse events and were equivalent in reducing the risk of a fracture in elderly patients with AD. PMID- 23989257 TI - A long-term in vivo investigation on the effects of xenogenous based, electrospun, collagen implants on the healing of experimentally-induced large tendon defects. AB - AIM: This study was designed to investigate the effect of novel 3-dimensional (3 D) collagen implants on the healing of large, experimentally-induced, tendon defects in rabbits. METHODS: Forty mature male white New Zealand rabbits were divided randomly into treated and control groups. Two cm of the left Achilles tendon was excised and the gap was spanned by Kessler suture. In the treated group, a novel 3-D collagen implant was inserted between the cut ends of the tendon. No implant was used in the control group. During the course of the experiment the bioelectrical characteristics of the healing and normal tendons of both groups were investigated weekly. At 120 days post injury (DPI), the tendons were dissected and inspected for gross pathology, examined by transmission and scanning electron microscopy, and their biomechanical properties, percentage dry matter and hydroxyproline concentration assessed. RESULTS: The collagen implant significantly improved the bioelectrical characteristics, gross appearance and tissue alignment of the healed, treated tendons, compared to the healed, control scars. It also significantly increased fibrillogenesis, diameter and density of the collagen fibrils, dry matter content, hydroxyproline concentration, maximum load, stiffness, stress and modulus of elasticity of the treated tendons, as compared to the control tendons. Treatment also significantly decreased peri tendinous adhesions, and improved the hierarchical organization of the tendon from the collagen fibril to fibre-bundle level. 3-D xenogeneic-based collagen implants induced newly regenerated tissue that was ultrastructurally and biomechanically superior to tissue that was regenerated by natural unassisted healing. CONCLUSION: This type of bioimplant was biocompatible, biodegradable and appeared suitable for clinical use. PMID- 23989258 TI - Impact of exercise training on neuroplasticity-related growth factors in adolescents. AB - OBJECTIVES: We aimed to determine the effect of exercise training on plasma levels of brain-derived neurotrophic factor (BDNF), and serum insulin-like growth factor-1 (IGF-1) as well as cAMP response element-binding (CREB) activation in peripheral blood mononuclear cells (PBMCs) in adolescents. METHODS: Nine trained and seven sedentary male adolescents, matched in age (14.0+/-2.2 years), were recruited for the study. Trained boys performed higher physical activity levels (expressed both as total energy expenditure and as physical activity energy expenditure) and showed significant bradycardia when compared with sedentary ones. RESULTS: We found that BDNF and IGF-1 levels were significantly higher in trained adolescents than in sedentary ones. However, no effect of training was found in the activation of CREB in PBMCs. CONCLUSIONS: We demonstrated the increase of neuroplasticity-related proteins due to exercise training in adolescents. Our results emphasize the significance and impact of exercise in this developmental period. PMID- 23989260 TI - The effects of whole-body vibration on muscle strength and power: a meta analysis. AB - Exercise with whole-body vibration (WBV) is becoming popular as an alternative to conventional training or as supplementary training. However, despite increasing research efforts in this field, additive effects of WBV on muscle performance remain unclarified. In this review, we investigated the additive effects of long term WBV on muscle strength and power. This meta-analysis was restricted to randomized controlled trials lasting for at least 5 weeks comparing exercise with and without WBV, or comparing only WBV exposure and control. Data from a total of 314 participants in 10 studies on knee extension muscle strength, and 249 participants in 7 studies on countermovement jump height were pooled using random effect models. Meta-analysis showed significant additional effects of WBV on muscle strength (standardized mean difference [SMD]=0.76, 95% confidence interval [CI]=0.21-1.32; p=0.007) and countermovement jump (SMD=0.87, 95% CI=0.29-1.46; p=0.003). Based on these findings, we concluded that the use of WBV would lead to greater improvements in both knee extension muscle strength and countermovement jump than under identical conditions without WBV. PMID- 23989261 TI - Hip fracture leading to the diagnosis of autosomal dominant hypophosphatemic rickets. A case report. PMID- 23989259 TI - Rac1 mediates load-driven attenuation of mRNA expression of nerve growth factor beta in cartilage and chondrocytes. AB - OBJECTIVES: To determine effect of gentle loads applied to the knee on mRNA expression of nerve growth factor, particularly, the active beta subunit (NGFbeta) in cartilage and chondrocyte. METHODS: Cyclic compressive loads in vivo and fluid flow in vitro were used to determine the mRNA levels. Alteration of Rac1 GTPase as well as effect of salubrinal, a specific inhibitor of eIF2alpha phosphatase was assessed using fluorescence resonance energy transfer (FRET) based Rac1 biosensor. RESULTS: Knee loading at 1 N reduced mRNA levels of NGFbeta and its low affinity receptor, p75 in cartilage and subchondral bone. In cartilage, knee loading at 1 N reduced the phosphorylation level of p38 MAPK (p38 p) and activity of Rac1 GTPase. Consistent with in vivo results, fluid flow at 5 and 10 dyn/cm(2) reduced mRNA levels of NGFbeta and p75 in C28/I2 human chondrocytes. SB203580, which decreases p38-p, reduced the mRNA levels of NGFbeta and p75. Silencing Rac1 by siRNA decreased the levels of p38-p and NGFbeta mRNA but not p75. Furthermore, administration of salubrinal reduced FRET-based activity of Rac1 as well as the mRNA levels of NGFbeta and p75. CONCLUSIONS: These results provide evidence that mechanical stimulation and salubrinal may attenuate pain perception-linked NGFbeta signaling through Rac1-mediated p38 MAPK. PMID- 23989263 TI - Synthesis, characterization and structural investigation of novel meso-pyridyl BODIPY-cobaloxime complexes. AB - We report the synthesis of four boron-dipyrromethene (BODIPY) sensitized cobaloxime complexes as structural models of light-driven proton reduction catalysts. The BODIPY chromophore is covalently linked to the cobaloxime via a pyridine molecule in the meso-position of the BODIPY. Electron withdrawing or donating substituents on the pyridine (e.g. chloro- or methyl-groups) allow a comparison of the influence of these substituents on cobaloxime-BODIPY interactions. This includes altering the overall stability of the complexes and tuning the catalytically relevant Co(II/III) redox couple over a range of 220 mV, which will assist in the design of future cobaloxime-chromophore complexes. All complexes were characterized using electrochemistry, electronic absorption and fluorescence spectroscopy. Additionally, we present crystal structures of the four new BODIPY-cobaloxime complexes and elucidate the influence of the structural modifications. We found that these compounds produce sub stoichiometric quantities of hydrogen under standard photon-driven hydrogen evolving conditions. PMID- 23989262 TI - Minimally invasive hallux valgus surgery: a critical review of the evidence. AB - This systematic review aims to illustrate the published results of "minimally invasive" procedures for correction of hallux valgus. Based on former systematic reviews on that topic, the literature search was organised by two independent investigators. MEDLINE was systematically searched for available studies. The keywords used were "hallux valgus", "bunion", "percutaneous surgery", "minimally invasive surgery", "arthroscopy", "Bosch" and "SERI". Studies were assessed using the level of evidence rating. A total of 21 papers were included in this review. These studies described a total of 1,750 patients with 2,195 instances of percutaneous, minimally invasive or arthroscopic hallux valgus surgery. Clinical reports of results after minimally invasive hallux valgus surgery at meetings are common. Published results in peer-reviewed journals are less common and the majority of papers are level IV studies according to the level of evidence ratings. We found one level II and three level III studies. Reported complications seem to be less than one may see in one's own clinical practice. This possible bias may be related to the fact that most studies are published by centres performing primarily minimally invasive hallux valgus surgery. PMID- 23989265 TI - Eggshell thinning as influenced by method of DDT exposure. PMID- 23989264 TI - Transcription factors as potential participants in the signal transduction pathway of boron deficiency. AB - Boron (B) plays a well-known structural role in the cell wall, however the way of perceiving B deficiency by roots and transmitting this environmental signal to the nucleus to elicit a response is not well established. It is known that the direct interaction between Ca2+ sensors and transcription factors (TFs) is a necessary step to regulate the expression of downstream target genes in some signaling pathways. Interestingly, B deprivation affected gene expressions of several TFs belonging to MYB, WRKY, and bZIP families, as well as expressions of Ca2+ -related genes such as several CML (calmodulin-like protein) and CPK (Ca2+ dependent protein kinase) genes. Taken together, these results suggest that B deficiency could affect the expression of downstream target genes by alteration of a calcium signaling pathway in which the interaction between CMLs and/or CPKs with TFs (activator or repressor) would be a crucial step, which would explain why some genes are upregulated whereas others are repressed upon B deprivation. PMID- 23989267 TI - The toxity of polychlorinated biphenyls (PCB) in sea water toGrammarus oceanicus. PMID- 23989266 TI - Heptachlor induced changes in fenitrothion metabolism. AB - Pretreatment of rats with heptachlor administered in the food for 3 months increases the metabolism of fenitrothion. Comparison of oxon analogue levels in the blood and livers of pretreated and control animals suggests that the conversion of fenitrothion to its oxon analogue is enhanced and accelerated. This was studied by tracer methods, using P-fenitrothion. PMID- 23989268 TI - Fish avoidance reactions. PMID- 23989269 TI - Monitoring the purity of product in synthesis or production of compounds by gas chromatography as exemplified with methyl parathionS-Isomer production. PMID- 23989270 TI - Effects of some organophosphorous compounds and their metabolites on sorghum grain esterase and certain insects attacking sorghum grain. PMID- 23989271 TI - Low ambient level uptake of(14)C-DDT by three species of marine phytoplankton. PMID- 23989272 TI - The effect of putrefaction of eggs upon residue analysis of DDT and metabolites. PMID- 23989273 TI - Effects of pesticides on growth and survival ofEuglena gracilis Z. AB - Vapam and nabam were more toxic to cultures ofEuglena gracilis Z than malathion and parathion. Growth and survival of cells were affected by these compounds. Divalent metal ions did not offer protection against the killing action of nab. PMID- 23989275 TI - A simple agar gel electrophoretic method to investigate esterase inhibition in certain stored grain insects by malathion and its oxygen analogue. PMID- 23989274 TI - Residues of O,P'-DDD and O,P'-DDT in brown pelican eggs and mallard ducks. PMID- 23989276 TI - Insecticide residues in starlings in Idaho. PMID- 23989277 TI - Kelthane residues on almond hull meal exposed to ultraviolet light irradiation. PMID- 23989278 TI - Use of chromous chloride for the confirmation of heptachlor residues by derivatization. PMID- 23989279 TI - Biological fate studies of 2-nitro-1,1-bis-p-chlorophenylpropane. AB - CONCLUSION: The most significant conclusion from the data collected is that the 2 nitro-1,1-bis-p-chlorophenylpropane and/or its metabolites are very poorly absorbed from the surface of the leaf and accordingly are not translocated throughout the plant to any significant degree. No measurable amount of the insecticide was found in the roots or in the bean at any time intervals over the 40 day span of study following foliar application. Only minor amounts of the compound representing about 3 percent of that originally applied to the leaf was observed in the stem and untreated leaves, signifying a small amount of absorption and translocation within the first 9 days after application. PMID- 23989280 TI - Determination of DDT in the presence of toxaphene residues. PMID- 23989281 TI - Suitability of thin-layer chromatography, gas chromatography and bioassay for the determination of aldrin, dieldrin and DDT residues in different soils without cleanup. PMID- 23989282 TI - The heavy metal content of fruit juices and carbonated beverages by atomic absorption spectrophotometry. PMID- 23989283 TI - Simultaneous detection of some organophosphorous pesticides in whole wheat flour. PMID- 23989284 TI - Polychlorinated biphenyls (PCB) solubilized in water by nonionic surfactants for studies of toxity to aquatic animals. PMID- 23989285 TI - Complications from surgery and hospital finances--reply. PMID- 23989286 TI - Defining background DNA levels found on the skin of children aged 0-5 years. AB - There are currently no data available regarding the normal levels of DNA found on the skin of children engaging in routine day to day activities to assist with the forensic interpretation of DNA profiles generated from skin surface swabs. To address this deficit, skin surface swab samples were collected from 12 face/neck sites and 20 body sites on 50 children less than 5 years old. After exclusion of spoilt samples, 60 sets of swabs from 47 children (30 face/neck, 30 body) comprising of 944 individual samples were analysed. The number of alleles observed which could have originated from the child and the number which must have come from another source (non-child) were analysed. The following variables were evaluated: age, kissing, feeding and washing practices, number of contacts and application of cream. Overall, extremely small amounts of non-child DNA were retrieved from skin swabs. Child only (46.3%) or no DNA at all (18.6%) was observed for 64.9% of all swabbed samples. Low levels of non-child DNA (1-5 alleles) were observed on 31.6% of all swabs tested with only 3.4% of swabs showing six or more alleles. A great deal of variation between children and between sites in the levels of both child DNA and non-child DNA was observed. A multilevel model, taking account of clustering within children, showed that there was a strong direct association between the amounts of child and non-child DNA observed. There was no relationship between the amount of DNA recovered and the demographic and biographic variables analysed. These background data have the potential to assist the analysis of DNA from the skin of children during criminal investigation. PMID- 23989287 TI - Some like it cold: summer torpor by freetail bats in the Australian arid zone. AB - Bats are among the most successful groups of Australian arid-zone mammals and, therefore, must cope with pronounced seasonal fluctuations in ambient temperature (T a), food availability and unpredictable weather patterns. As knowledge about the energy conserving strategies in desert bats is scant, we used temperature telemetry to quantify the thermal physiology of tree-roosting inland freetail bats (Mormopterus species 3, 8.5 g, n = 8) at Sturt National Park over two summers (2010-2012), when T a was high and insects were relatively abundant. Torpor use and activity were affected by T a. Bats remained normothermic on the warmest days; they employed one "morning" torpor bout on most days and typically exhibited two torpor bouts on the coolest days. Overall, animals employed torpor on 67.9 % of bat-days and torpor bout duration ranged from 0.5 to 39.3 h. At any given T a, torpor bouts were longer in Mormopterus than in bats from temperate and subtropical habitats. Furthermore, unlike bats from other climatic regions that used only partial passive rewarming, Mormopterus aroused from torpor using either almost entirely passive (68.9 % of all arousals) or active rewarming (31.1 %). We provide the first quantitative data on torpor in a free-ranging arid-zone molossid during summer. They demonstrate that this desert bat uses torpor extensively in summer and often rewarms passively from torpor to maximise energy and water conservation. PMID- 23989288 TI - Progress towards water-soluble triazole-based selective MMP-2 inhibitors. AB - Water solubility is a key aspect that needs to be addressed to obtain drug-like compounds. In an effort to improve the water solubility of our recently reported nanomolar matrix metalloproteinase type 2 (MMP-2) inhibitors based on triazole substituted hydroxamates, we synthesized a new series of alpha-sulfone, alpha tetrahydropyran and alpha-piperidine, alpha-sulfone clicked hydroxamates and determined their inhibitory activities against both MMP-2 and MMP-9. The best results were found for 13e, a water-soluble compound that displays a low nanomolar activity against MMP-2 and is 26-fold less active against MMP-9. This finding allowed us to pursue in vitro permeability through the Caco-2 monolayer and opened the possibility of carrying out further preclinical investigations. Docking and MD simulations have been performed in order to rationalize the biological results. The inhibitory activity of this compound against a panel of ten MMPs was determined showing an interesting MMP-2/MMP-1, -8, and -14 selectivity profile. The cytotoxicity and anti-invasive activity of the compounds on highly metastatic human fibrosarcoma tumor cells (HT1080) were determined, showing, at 10 MUM concentration, a decrease in cell invasiveness up to 80%. PMID- 23989289 TI - Veterinary Compounding-A Bird's-eye View. PMID- 23989290 TI - Suggested flavors for veterinary medication. PMID- 23989291 TI - Animal drug-delivery systems. PMID- 23989292 TI - Compounding for Animals: The AVMA Perspective. PMID- 23989293 TI - Compounding for veterinary patients: pharmaceutical, biopharmaceutical, pharmacokinetic and physiologic considerations. PMID- 23989294 TI - Compounding for degenerative myelopathy in the german shepherd. PMID- 23989295 TI - Atropine overdosage with a suppository formulation containing atropine sulfate. AB - A reformulation of ergotamine tartrate and caffeine (Cafergot) suppositories was prescribed for a 55-year-old woman who suffered from severe attacks of migraine. The patient developed toxic effects similar to atropine poisoning soon after the first dose. Since each suppository contained a very small amount of atropine sulfate (0.25 mg), it was possible that a miscalculation occurred during compounding, resulting in atropine overdose. Therefore, a simple, sensitive and accurate analytical methold was developed for the quantitation of atropine sulfate in the suppositories and the samples were examined. It was found that the suppositories dispensed contained 25 mg of atropine sulfate each instead of 0.25 mg. This incident demonstrates how important and vital it is for the pharmacist to be vigilant in all aspects of compounding prescriptions. PMID- 23989296 TI - Development of clonidine hydrochloride injections for epidural intrathecal administration. AB - The purpose of this study was to describe and document the development of several concentrations of clonidine hydrochloride injection for evaluation as epidural and intrathecal injections in clinical trials for the control of intractable pain. Bulk clonidine hydrochloride prepared under Good Manufacturing Practices conditions was formulated as simple aqueous solutions in 0.9% sodium chloride injection having concentrations of 0.15, 0.5 and 1.5 mg/mL. The low concentration served as the starting concentration for low drug delivery, with the highter concentrations needed to accommodate increasing rates of drug delivery. All three concentrations exhibited natural pH values of about 6 to 6.5 and were adjusted to a target pH of 6.5 with sodium hydroxide, if necessary. The measured osmolalities were about 285 mOsm/kg, nearly isotonic. The injections were filtered through 0.22 micormeter filters and packaged in 20mL, Type-1, flint glass vials with rubber stoppers. The vials were terminally sterilized by autoclaving at 121 deg C and 15 psi for 30 minutes. Using a stability-indicating, high-performance liquid chromatography analytical technique based on the official USP method, we observed no loss of clonidine hydrochloride in any of the development vials at the concentrations of 0.15, 0.5 and 1.5 mg/mL after preparation and autoclaving. Similarly, shelf-life studies on two small batches each of the 0.15- and 0.5 mg/mL concentrations have shown little or no loss of clonidine hydrochloride after three months' storage at 37 deg C and for up to 24 months at 4 and 23 deg C. Shelf-life studies are continuing. Clonidine hydrochloride 0.15-, 0.5-, and 1.5-mg/mL injections have been developed as epidural and intrathecal injections in clinical trials to control intractable pain. The injections are easily formulated and stable during compounding and storage. PMID- 23989297 TI - Stability of bethanechol chloride in oral liquid dosage forms. AB - The chemical stability of bethanechol aqueous solutions prepared using either tablets, injection or powder was studied. For an aqueous solution prepared using tablets, the initial result was low (86.5%) and the pH value was 7.1. With storage at 25 deg C, the result increased to almost 100% in 12 days and the pH value decreased to about 3.4. For the solution prepared from the injection, the initial result was 100%. After 40 days' storage at 25*C, the pH value decreased from 7.0 to 6.0 and the result was still almost 100% of the label claim. The aqueous solutions prepared from powder in phosphate buffers (pH values between 3.0 and 6.8) retained almost 100% of the potency at all pH values. PMID- 23989298 TI - Stability of ceftriaxone sodium when mixed with metronidazole injection. AB - The chemical stabilities of ceftriaxone sodium and metronidazole in a mixture have been studied using a stability-indicating, high-performance liquid chromatography (HPLC) assay method. The HPLC method is precise and accurate, with a percent relative standard deviation of 1.4 based on five readings. Metronidazole did not lose any potency for four days when stored at 25+/-1 deg C. Ceftriaxone sodium lost less than 6% ofpotency in three days at 25+/-1 deg C. The products of decomposition did not interfere with the assay procedure. They eluted before the ceftriaxone peak. The solution remained clear (light yellow) throughout the study period, and the pH value did not change. Ceftriaxone sodium and metronidazole, when mixed together, were stable for three days at 25+/-1 deg C. PMID- 23989299 TI - Pregabalin abuse among opiate addicted patients. AB - PURPOSE: Pregabalin is a novel GABA-analogue approved for the treatment of partial onset seizures, neuropathic pain, and general anxiety disorder. Pregabalin has been classified as a Schedule V drug with a low risk of inflicting abuse or addiction. However, some publications have indicated that pregabalin may have a potential for abuse among patients with past or current opiate addiction. Thus, we hypothesized that pregabalin might be abused by patients who were undergoing an opiate replacement therapy and never had an indication for taking pregabalin on medical grounds. METHODS: Urine specimens from 124 patients with opiate dependency syndrome and from 111 patients with other addiction disorders (alcohol, benzodiazepines, cannabis, amphetamines) were screened for pregabalin by means of a mass spectrometer analysis. RESULTS: We found 12.1 % of all urine specimens from patients with opiate addiction to be positive for pregabalin. None of the patients concerned had a medical indication for using pregabalin. In the control group, 2.7 % of the patients were tested positively for pregabalin, due to their taking it regularly for chronic pain or general anxiety. CONCLUSIONS: Our data suggest that pregabalin is liable to be abused among individuals with opiate dependency syndrome Thus, vigilance and caution are called for when patients with a past or current opiate dependency are exposed to treatment with pregabalin. PMID- 23989301 TI - Neuropsychological effects of MRI-detected brain lesions after left atrial catheter ablation for atrial fibrillation: long-term results of the MACPAF study. AB - BACKGROUND: MRI-detected brain lesions are common after left atrial catheter ablation for symptomatic atrial fibrillation. The clinical relevance of these acute ischemic lesions is not fully understood, but ablation-related cerebral injury could contribute to cognitive dysfunction. METHODS AND RESULTS: In the prospective Mesh Ablator versus Cryoballoon Pulmonary Vein Ablation of Symptomatic Paroxysmal Atrial Fibrillation (MACPAF) study, serial 3-T brain MRIs and neuropsychological assessment were performed to analyze the rate of ablation related brain lesions and their effect on cognitive function. Thirty-seven patients with paroxysmal atrial fibrillation (median age, 63.0 [interquartile range, 57-68] years; 41% female; median CHA2DS2VASc score 2 [interquartile range, 1-3]) underwent 41 ablation procedures according to study criteria. None of these patients had overt neurological deficits after ablation. High-resolution diffusion-weighted imaging, performed within 48 hours after ablation, showed that new brain lesions (range, 1-17) were present in 16 (43.2%) patients after 18 (43.9%) left atrial catheter ablation procedures. Follow-up MRI at 6 months (median, 6.5; interquartile range, 6-7) revealed that 7 (12.5%) of the 56 total acute brain lesions after ablation formed a persistent glial scar in 5 (31.3%) patients. Large diffusion-weighted imaging lesions and a corresponding fluid attenuated inversion recovery lesion 48 hours after ablation predicted lesion persistence on 6-month follow-up. Neither persistent brain lesions nor the ablation procedure itself had a significant effect on attention or executive functions, short-term memory, or verbal and nonverbal learning after 6 months. CONCLUSIONS: Ablation-related acute ischemic brain lesions persist to some extent but do not cause cognitive impairment 6 months after the ablation procedure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01061931. PMID- 23989300 TI - Population pharmacokinetics of PEGylated liposomal CPT-11 (IHL-305) in patients with advanced solid tumors. AB - PURPOSE: To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK. METHODS: Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was administered as a 1 h IV infusion with doses ranging from 3.5 to 210 mg/m(2). Plasma concentrations of encapsulated CPT-11, released CPT-11 and SN-38 were used to develop a population PK model using NONMEM(r). RESULTS: PK of encapsulated CPT 11 was described by 1-compartment model with nonlinear clearance and PK of released CPT-11 was described by a 1-compartment model with linear clearance for all patients. PK of the active metabolite SN-38 was described by a 2-compartment model with linear clearance for all patients. Covariate analysis revealed that gender was a significant covariate for volume of distribution of encapsulated CPT 11. Vencap in male patients is 1.5-fold higher compared with female patients. CONCLUSIONS: The developed population PK modeling approach is useful to predict PK exposures of encapsulated and released drug and can be applied to the more than 300 other nanoparticle formulations of anticancer agents that are currently in development. The effect of gender on PK of IHL-305 needs to be further evaluated. PMID- 23989303 TI - DIELECTROPHORESIS BASED MICRO FLOW CYTOMETRY. AB - We report a simplified flow cytometer design that makes use of negative dielectrophoresis (DEP) for particle focusing and integrated optical and AC impedance detectors to enable an inexpensive, compact and robust system for cell and particle characterization. This straightforward, modular design could be applied as a standalone instrument or as a particle detector in an integrated micro total analysis system. PMID- 23989302 TI - Phosphatase of regenerating liver-3 induces angiogenesis by increasing extracellular signal-regulated kinase phosphorylation in endometrial adenocarcinoma. AB - OBJECTIVE: The aim of this study was to investigate the mechanism by which phosphatase of regenerating liver-3 (PRL-3) induces angiogenesis in endometrial adenocarcinoma tissues and cells. METHODS: We investigated the expression of PRL 3 and vascular endothelial growth factor (VEGF) in samples from 124 patients with endometrial adenocarcinoma using immunohistochemical staining. The relationship between PRL-3 expression and microvessel density (MVD), clinicopathological factors and surgical treatment outcome was also studied. Following this, we studied the effect on cell lines of blocking or upregulating PRL-3. RESULTS: PRL 3 expression in endometrial adenocarcinoma was high, and this overexpression is correlated with advanced clinical stage (p=0.008), lymph node metastasis (p=0.016) and poor postoperative survival. PRL-3 overexpression was associated with VEGF (p=0.001) expression and MVD (p=0.005). Upregulating PRL-3 expression promoted VEGF and phosphorylated extracellular signal-regulated kinase (pERK) expression. Blocking PRL-3 expression inhibited VEGF and pERK expression. Following inhibition of pERK, VEGF expression was downregulated. CONCLUSIONS: PRL 3 induces microvascular vessel formation by facilitating VEGF expression in endometrial adenocarcinoma tissues. PRL-3 upregulates pERK expression and activity, facilitating VEGF expression and accelerating angiogenesis. PMID- 23989304 TI - Acoustic-like dynamics of amorphous drugs in the THz regime. AB - The high frequency dynamics of Indomethacin and Celecoxib glasses has been investigated by inelastic x-ray scattering, accessing a momentum-energy region still unexplored in amorphous pharmaceuticals. We find evidence of phonon-like acoustic dynamics, and determine the THz behavior of sound velocity and acoustic attenuation. Connections with ordinary sound propagation are discussed, along with the relation between fast and slow degrees of freedom as represented by non ergodicity factor and kinetic fragility, respectively. PMID- 23989305 TI - A painless right supraclavicular mass. Chondroid lipoma (CL). PMID- 23989307 TI - An unusually unstable ortho-phosphinophenol and its use to prepare benzoxaphospholes having enhanced air-stability. AB - The primary phosphine 3,5-di-tert-butyl-2-phosphinophenol has been prepared and characterized. Oddly, the presence of a sterically demanding tert-butyl group adjacent to the PH2 centre renders the molecule very sensitive to loss of PH3 and formation of 3,5-di-tert-butyl-phenol in chloroform solutions in the presence of air. The process was catalyzed by HCl and dependent on the purity of CDCl3. Despite the instability of 3,5-di-tert-butyl-2-phosphinophenol, this material could be employed to produce a series of luminescent 2-R-4,6-di-tert-butyl-1,3 benzoxaphospholes having greater air stability than corresponding less bulky 2-R 1,3-benzoxaphospholes. PMID- 23989306 TI - Early detection of acute kidney injury by serum cystatin C in critically ill children. AB - BACKGROUND: We prospectively evaluated whether serum cystatin C (CysC) detected acute kidney injury (AKI) earlier than basal serum creatinine (Cr). METHODS: In 107 pediatric patients at high risk of developing AKI, serum Cr and serum CysC were measured upon admission. Baseline estimated creatinine clearance (eCCl) was calculated using a CysC-based glomerular filtration rate (GFR) equation from a serum Cr measured at the pediatric intensive care unit (PICU) entrance. RESULTS: The median age was 10 months (interquartile range, 3-36 months). Serum Cr, serum CysC, and eCCl (mean +/- standard deviation [range]) were 0.5 +/- 0.18 mg/dl (0.2 1.1 mg/dl), 0.53 +/- 0.78 (0.01-3.7 mg/l), and 72.55 +/- 28.72 (20.6-176.2) ml/min per 1.73 m(2), respectively. The serum CysC level in patients with AKI was significantly higher than children with normal renal function (p < 0.001). The values for the cut-off point, sensitivity, specificity, and the area under curve (AUC) were determined for CysC as 0.6 mg/l, 73.9 %, 78.9 %, and 0.92 [95 % confidence interval (0.82-1)], respectively, and for Cr the values were 0.4 mg/dl, 68 %, 46.2 %, and 0.39, [95 % confidence interval (0.24-0.54)], respectively. The receiver operating characteristics (ROC) curve analysis revealed that CysC had a significantly higher diagnostic accuracy than eCCl (p < 0.001). CONCLUSIONS: Our results identify that the sensitivity of serum CysC for detecting AKI is higher than that of serum Cr in a heterogeneous pediatric intensive care unit (PICU) population. PMID- 23989308 TI - Minimally invasive surgery for vertebral fracture and spinal infection. PMID- 23989309 TI - Current concepts of percutaneous balloon kyphoplasty for the treatment of osteoporotic vertebral compression fractures: evidence-based review. AB - Vertebral compression fractures constitute a major health care problem, not only because of their high incidence but also due to both direct and indirect consequences on health-related quality of life and health care expenditures. The mainstay of management for symptomatic vertebral compression fractures is targeted medical therapy, including analgesics, bed rest, external fixation, and rehabilitation. However, anti-inflammatory drugs and certain types of analgesics can be poorly tolerated by elderly patients, and surgical fixation often fails due to the poor quality of osteoporotic bone. Balloon kyphoplasty and vertebroplasty are two minimally invasive percutaneous surgical approaches that have recently been developed for the management of symptomatic vertebral compression fractures. The purpose of this study was to perform a comprehensive review of the literature and conduct a meta-analysis to compare clinical outcomes of pain relief and function, radiographic outcomes of the restoration of anterior vertebral height and kyphotic angles, and subsequent complications associated with these two techniques. PMID- 23989310 TI - Chemical and physical properties of bone cement for vertebroplasty. AB - Vertebral compression fracture is the most common complication of osteoporosis. It may result in persistent severe pain and limited mobility, and significantly impacts the quality of life. Vertebroplasty involves a percutaneous injection of bone cement into the collapsed vertebrae by fluorescent guide. The most commonly used bone cement in percutaneous vertebroplasty is based on the polymerization of methylmethacrylate monomers to polymethylmethacrylate (PMMA) polymers. However, information on the properties of bone cement is mostly published in the biomaterial sciences literature, a source with which the clinical community is generally unfamiliar. This review focuses on the chemistry of bone cement polymerization and the physical properties of PMMA. The effects of altering the portions and contents of monomer liquid and polymer powders on the setting time, polymerization temperature, and compressive strength of the cement are also discussed. This information will allow spine surgeons to manipulate bone cement characteristics for specific clinical applications and improve safety. PMID- 23989311 TI - Minimally invasive percutaneous endoscopic discectomy and drainage for infectious spondylodiscitis. AB - The primary goals for treating infectious spondylodiscitis are to make an accurate diagnosis, isolate the causative organism, and prescribe effective antibiotic therapy based on the culture data. A positive culture of the responsible organism is not required for diagnosis, although it is extremely important for successful treatment and prevention of further morbidity. Surgical intervention is usually reserved for cases that are unresponsive to antibiotic therapy and for patients who have developed progressive spinal deformity or instability, epidural abscesses, or neurological impairment. However, the incidence of perioperative morbidity is particularly increased in elderly patients or in those with poor general condition. With improved endoscopic instruments and techniques, our clinical experiences demonstrate that spinal infections can be successfully treated by minimally invasive percutaneous endoscopic debridement. Direct endoscopic observation and collection of sufficient quantities of samples for microbiological examinations from the infected region are usually possible. This article summarizes the diagnostic and therapeutic values of percutaneous endoscopic discectomy and drainage (PEDD) used to treat patients with spondylodiscitis. Our clinical evidence-based survey suggests that PEDD can provide adequate retrieval of specimens and has high diagnostic efficacy, thereby enabling prompt and sensitive antibiotic therapy to the offending pathogens. We propose that PEDD is an effective alternative for treating infectious spondylodiscitis and should be considered prior to extensive anterior surgery in selected cases. This method is particularly suitable for patients with early-stage spinal infection or serious medical conditions. PMID- 23989312 TI - Emergency medicine physicians performed ultrasound for pediatric intussusceptions. AB - BACKGROUND: Intussusception is the common acute abdomen in children with difficult clinical diagnosis. The routine ultrasound has recently been proposed as the initial diagnostic modality with high accuracy, but is not available for 24 h by gastroenterologists. We aimed to evaluate the validation of bedside ultrasound for intussusceptions performed by pediatric emergency physicians with ultrasound training during the night or holiday. METHODS: A retrospective study was conducted in children with suspected intussusceptions when routine ultrasounds by gastroenterologists were not available over the period from July 2004 to July 2008. Patients were divided into two groups: those diagnosed by emergency physicians with ultrasound training and without training. The clinical characteristics and course for all patients were reviewed and compared for seeking the difference. RESULTS: A total of 186 children were included. One hundred and thirteen (61%) children were diagnosed by pediatric emergency physician with ultrasound training. The clinical symptoms were not statistically different between the two groups. The diagnostic sensitivity of the ultrasound training group was significantly higher (90% vs. 79%, p = 0.034). Children of the training group also had significantly shorter hospital stay duration at emergency departments before reduction (2.41 +/- 2.01 vs. 4.58 +/- 4.80 h, p = 0.002). CONCLUSION: Bedside ultrasound performed by pediatric emergency physicians with ultrasound training is a sensitive test for detecting intussusceptions. Knowledge and use of bedside ultrasound can aid the emergency physician in the diagnosis of pediatric intussusceptions with less delay in treatment. PMID- 23989313 TI - Analysis of visual outcomes and complications following levator resection for unilateral congenital blepharoptosis without strabismus. AB - BACKGROUND: It is challenging to manage congenital blepharoptosis, especially unilateral, because symmetry is difficult to achieve under general anesthesia and age at which the ptosis should be corrected is still controversial. The aim of our study is to analyze visual and surgical outcomes after levator resection for unilateral congenital blepharoptosis. METHODS: Charts of patients with unilateral congenital blepharoptosis who underwent levator resection at the Chang Gung Memorial Hospital from 1991 through 2000 were reviewed. The resultant database was interrogated for demographic data, severity, surgical timing, visual outcomes, surgical outcomes, and complications. RESULTS: Eighty-four children underwent levator resection for unilateral congenital blepharoptosis: 16.7% of these patients had amblyopia and 84.5% had surgical success following levator resection. Severe ptosis (p = 0.0288, p < 0.05) and surgery at less than 2 years of age (p = 0.0126, p < 0.05) were the important factors contributing to surgical failure. Age at surgery (p = 0.0058, p < 0.01) and amblyogenic ametropia (p = 0.0001, p < 0.001) were found to be significantly associated with the postoperative visual results. CONCLUSION: The levator resection provides satisfactory results both in function and cosmesis in patients with unilateral congenital blepharoptosis. Amblyogenic ametropia is the leading cause of amblyopia in the patients with unilateral isolated congenital blepharoptosis. However, patients with unilateral congenital blepharoptosis should have cycloplegic refraction as early as possible, and their visual status monitored until visual maturity. PMID- 23989314 TI - Assessing medical students' performance in core competencies using multiple admission programs for colleges and universities: from the perspective of multi source feedback. AB - BACKGROUND: Since 1994, Taiwanese medical universities have employed the multiple application method comprising "recommendations and screening" and "admission application." The purpose of this study is to examine whether medical students admitted using different admission programs gave different performances. METHODS: To evaluate the six core competencies for medical students proposed by Accreditation Council for Graduate Medical Education (ACGME), this study employed various assessment tools, including student opinion feedback, multi-source feedback (MSF), course grades, and examination results.MSF contains self assessment scale, peer assessment scale, nursing staff assessment scale, visiting staff assessment scale, and chief resident assessment scale. In the subscales, the CronbachEs alpha were higher than 0.90, indicating good reliability. Research participants consisted of 182 students from the School of Medicine at Chang Gung University. RESULTS: Regarding studentsE average grade for the medical ethics course, the performance of students who were enrolled through school recommendations exceeded that of students who were enrolled through the National College University Entrance Examination (NCUEE) p = 0.011), and all considered "teamwork" as the most important. Different entry pipelines of students in the "communication," "work attitude," "medical knowledge," and "teamwork" assessment scales showed no significant difference. The improvement rate of the students who were enrolled through the school recommendations was better than that of the students who were enrolled through the N CUEE in the "professional skills," "medical core competencies," "communication," and "teamwork" projects of self assessment and peer assessment scales. However, the students who were enrolled through the NCUEE were better in the "professional skills," "medical core competencies," "communication," and "teamwork" projects of the visiting staff assessment scale and the chief resident assessment scale. CONCLUSION: Collectively, the performance of the students enrolled through recommendations was slightly better than that of the students enrolled through the NCUEE, although statistical significance was found in certain parts of the grades only. PMID- 23989315 TI - Pre-radiotherapy PSA level as a predictor. PMID- 23989316 TI - [Oncological and hematological emergencies: intensive care management]. PMID- 23989317 TI - Polypill for cardiovascular disease prevention--reply. PMID- 23989319 TI - Digestion of oysters for the determination of mercury. PMID- 23989318 TI - Identifying riparian buffer effects on stream nitrogen in southeastern coastal plain watersheds. AB - Within the Southeastern (SE) Coastal Plain of the U.S., numerous freshwaters and estuaries experience eutrophication with significant nutrient contributions by agricultural non-point sources (NPS). Riparian buffers are often used to reduce agricultural NPS yet the effect of buffers in the watershed is difficult to quantify. Using corrected Akaike information criterion (AICc) and model averaging, we compared flow-path riparian buffer models with land use/land cover (LULC) models in 24 watersheds from the SE Coastal Plain to determine the ability of riparian buffers to reduce or mitigate stream total nitrogen concentrations (TNC). Additional models considered the relative importance of headwaters and artificial agricultural drainage in the Coastal Plain. A buffer model which included cropland and non-buffered cropland best explained stream TNC (R (2) = 0.75) and was five times more likely to be the correct model than the LULC model. The model average predicted that current buffers removed 52 % of nitrogen from the edge-of-field and 45 % of potential nitrogen from the average SE Coastal Plain watershed. On average, 26 % of stream nitrogen leaked through buffered cropland. Our study suggests that stream TNC could potentially be reduced by 34 % if buffers were adequately restored on all cropland. Such estimates provide realistic expectations of nitrogen removal via buffers to watershed managers as they attempt to meet water quality goals. In addition, model comparisons of AICc values indicated that non-headwater buffers may contribute little to stream TNC. Model comparisons also indicated that artificial drainage should be considered when accessing buffers and stream nitrogen. PMID- 23989320 TI - Residues in cattle treated with DDT for control of horn flies on pasture. AB - Residues were analyzed in the fat of yearlings after exposure on pasture to continuous protection from horn flies with spray treatments of DDT. Eleven applications of 2 quarts of a 0.25 per cent suspension per head produced total residues of DDT, TDE and DDE that exceeded the acceptable tolerance of 7 p.p.m. when animals had reached the prime slaughterweight on a high-energy finishing ration. More information is needed on the mobilization of fat and the DDT stored within the depot to relate an acceptable tolerance for slaughter cattle to practical methods in beef production. PMID- 23989321 TI - Time response experiments with single dose and chronic treatment of dieldrin onTribolium castaneum. AB - After a single spray of dieldrin at different concentrations, insects die over a period of about 5 weeks, mostly in the first 3 weeks. The concentration of dieldrin in the insects decreases before the decline in mortality. After chronic poisoning some of the population tolerated the poison (at various concentration levels) and stayed alive. This final stage was reached after several weeks. For comparison, tests were also conducted with lindane, parathion and dichlofenthion. All produced an initial increase in mortality but subsequently the proportion of dead insects remained fairly constant up to 7 weeks. PMID- 23989322 TI - Effects of salinity on uptake of DDT, DDE and ODD by fish. PMID- 23989323 TI - The effect of a sublethal concentration of LAS on the acute toxicity of various phosphate pesticides to the fathead minnow (Pimephales promelas Rafinesque). PMID- 23989324 TI - A survey of salinity levels in the Indian River-Banana River Complex. PMID- 23989325 TI - Soil moisture and soil type influence initial penetration by organochlorine insecticides. PMID- 23989326 TI - Chromous chloride reductions. III. Identification of products obtained from prolonged contact of chlordene and heptachlor with chromous chloride solution. PMID- 23989327 TI - Chromous chloride reductions. IV. Reaction of endrin with chromous chloride solution. PMID- 23989328 TI - Effects of aerial sumithion spraying on juvenile atlantic salmon (Salmo salar L.) and brook trout (Salvelinus fontinalis Mitchill) in Newfoundland. AB - CONCLUSIONS: Forest sprays of the organophosphate pesticide, Sumithion, at 2 or 3 oz/acre were less acutely harmful to fish than sprays of the chlorinated hydrocarbon pesticide DDT have been in the past. Possible indirect or chronic effects cannot be discounted. PMID- 23989329 TI - A biopsy technique to obtain tissue for pesticide residue analysis from falconiform birds. PMID- 23989330 TI - The relationship of coliform populations to certain physico-chemical parameters in the Indian River-Banana River Complex. PMID- 23989331 TI - An electron capture detector bypass system. PMID- 23989332 TI - Studies on the assimilation of l,l,l-trichloro-2,2-bis (p-chlorophenyl) ethane (DDT) byCrassostrea virginica Gmelin. AB - CONCLUSIONS: The gills of the oyster are probably the primary entry site of DDT. The gut may be a DDT entry site also, but is of secondary importance. Further, mantle uptake of DDT has not been demonstrated. Hence, DDT found in the mantle is probably deposited there by the circulatory system after uptake across the gills. On the basis of the rapid rate of pesticide elimination from oyster tissue, the value of the oyster as an environmental integrator is questionable.Reported solubility values for DDT range from 0.1 ug/1 to 45 ug/1 (11,12,13). Although these values are contradictory, the fact remains that DDT has an extremely low solubility in water. This low solubility, as well as a tendency for sorption on particulate matter and/or equipment employed in sample handling, may make kinetic studies with DDT and similar compounds impossible. PMID- 23989333 TI - Environmental factors affecting dieldrin uptake by rye. PMID- 23989334 TI - Influence of dietary methionine on dieldrin metabolism in rats. PMID- 23989335 TI - Preliminary study of pesticide levels in the eggs of Iowa pheasants, blue wing teal and coots. PMID- 23989338 TI - Seasonal stress physiology and body condition differ among co-occurring tropical finch species. AB - Seasonal changes in avian hormonal stress responses and condition are well known for common species found at temperate and arctic latitudes, but declining and tropical species are poorly studied. This study compares stress and condition measures of co-occurring declining and non-declining tropical grass finch species in Australia. We monitored declining Gouldian finches (Erythrura gouldiae) and non-declining long-tailed and masked finches (Poepila acuticauda and P. personata) during two seasons that are potentially stressful: peak breeding (early dry season when food is plentiful) and moult (late dry to early wet season when food may be scarce). We measured body condition (muscle and fat), haematocrit, and stress response to capture using plasma corticosterone and binding globulin concentrations. All species had higher muscle and lower fat indices during breeding than moult. Haematocrit did not consistently differ between seasons. Long-tailed finches had higher stress responses during breeding than moult, similar to other passerines studied. Masked finches showed no seasonal changes in stress response. Gouldian finches had stress response patterns opposite to those of long-tailed finches, with higher stress responses during moult. However, seasonal trends in Gouldian and long-tailed finch stress responses sometimes differed between years or sites. The differences in stress response patterns between species suggest that the declining Gouldian finch is more sensitive to recent environmental changes which are thought to further reduce grass seed food resources during the late dry to early wet season. Retention of stress responsiveness during a protracted moult could increase the survival potential of Gouldian finches. This study highlights the utility of stress and condition indices to determine the sensitivity of co-occurring species to environmental conditions. PMID- 23989337 TI - The immunobiology of toll-like receptor 4 agonists: from endotoxin tolerance to immunoadjuvants. AB - Lipopolysaccharide (LPS, endotoxin) is a structural component of the gram negative outer membrane. The lipid A moiety of LPS binds to the LPS receptor complex expressed by leukocytes, endothelial cells, and parenchymal cells and is the primary component of gram-negative bacteria that is recognized by the immune system. Activation of the LPS receptor complex by native lipid A induces robust cytokine production, leukocyte activation, and inflammation, which is beneficial for clearing bacterial infections at the local level but can cause severe systemic inflammation and shock at higher challenge doses. Interestingly, prior exposure to LPS renders the host resistant to shock caused by subsequent LPS challenge, a phenomenon known as endotoxin tolerance. Treatment with lipid A has also been shown to augment the host response to infection and to serve as a potent vaccine adjuvant. However, the adverse effects associated with the pronounced inflammatory response limit the use of native lipid A as a clinical immunomodulator. More recently, analogs of lipid A have been developed that possess attenuated proinflammatory activity but retain attractive immunomodulatory properties. The lipid A analog monophosphoryl lipid A exhibits approximately 1/1,000th of the toxicity of native lipid A but retains potent immunoadjuvant activity. As such, monophosphoryl lipid A is currently used as an adjuvant in several human vaccine preparations. Because of the potency of lipid A analogs as immunoadjuvants, numerous laboratories are actively working to identify and develop new lipid A mimetics and to optimize their efficacy and safety. Based on those characteristics, lipid A analogs represent an attractive family of immunomodulators. PMID- 23989340 TI - Effects of chemical inhibitors and apyrase enzyme further document a role for apyrases and extracellular ATP in the opening and closing of stomates in Arabidopsis. AB - In Arabidopsis leaves there is a bi-phasic dose-response to applied nucleotides; i.e., lower concentrations induce stomatal opening, while higher concentrations induce closure. Two mammalian purinoceptor antagonists, PPADS and RB2, block both nucleotide-induced stomatal opening and closing. These antagonists also partially block ABA-induced stomatal closure and light-induced stomatal opening. There are two closely related Arabidopsis apyrases, AtAPY1 and AtAPY2, which are both expressed in guard cells. Here we report that low levels of apyrase chemical inhibitors can induce stomatal opening in the dark, while apyrase enzyme blocks ABA-induced stomatal closure. We also demonstrate that high concentrations of ATP induce stomatal closure in the light. Application of ATPgammaS and chemical apyrase inhibitors at concentrations that have no effect on stomatal closure can lower the threshold for ABA-induced closure. The closure induced by ATPgammaS was not observed in gpa1-3 loss-of-function mutants. These results further confirm the role of extracellular ATP in regulating stomatal apertures. PMID- 23989339 TI - Lizard thermal trait variation at multiple scales: a review. AB - Thermal trait variation is of fundamental importance to forecasting the impacts of environmental change on lizard diversity. Here, we review the literature for patterns of variation in traits of upper and lower sub-lethal temperature limits, temperature preference and active body temperature in the field, in relation to space, time and phylogeny. Through time, we focus on the direction and magnitude of trait change within days, among seasons and as a consequence of acclimation. Across space, we examine altitudinal and latitudinal patterns, incorporating inter-specific analyses at regional and global scales. This synthesis highlights the consistency or lack thereof, of thermal trait responses, the relative magnitude of change among traits and several knowledge gaps identified in the relationships examined. We suggest that physiological information is becoming essential for forecasting environmental change sensitivity of lizards by providing estimates of plasticity and evolutionary scope. PMID- 23989341 TI - Quality of life in fatal disease: the flawed judgement of the social environment. AB - Decisions to prolong or shorten life in fatal diseases like amyotrophic lateral sclerosis are strongly influenced by healthy individuals, such as caregivers and physicians. Furthermore, many believe that amyotrophic lateral sclerosis (ALS) patients should decide ahead of time on advanced directives to circumvent confounding effects of subsequent cognitive impairments. The ability of healthy persons (caregivers and age-matched healthy subjects) to anticipate patients' quality of life (QoL), depression and vital decisions was determined in a cross sectional approach. Eighty-nine ALS patients, 86 caregivers and 102 age-matched healthy subjects were asked to judge ALS patients' QoL and depression and the patients' wish for hastened death. Patients judged their own, the caregivers judged that of the patient under their care, healthy subjects were asked to judge that of a virtual patient. Additionally, healthy persons were asked to judge their own QoL and depression. Patients reported a satisfactory well-being and a low wish for hastened death. Healthy persons rated the patients' QoL significantly lower and the rate of depression significantly higher. The wish for hastened death was significantly lower in the patient group compared to what healthy subjects thought the patient would wish. The assessment by others was closely related to the persons' own well-being. Significant differences were identified between caregiver's perspectives and the patient's own perception of their psychological well-being. Our data suggest that caregivers and the general public significantly underestimate the QoL of ALS patients. A positive affective state can indeed be preserved in a progressive, fatal disease. PMID- 23989342 TI - Levodopa, vitamins, ageing and the neuropathy of Parkinson's disease. AB - Higher prevalence of neuropathy has been described in patients with Parkinson's disease (PD) in comparison with age and gender-matched controls. The cause of neuropathy may be levodopa-induced impairment of vitamin B12 metabolism, suggesting levodopa-naive subjects should be unaffected. There may, however, be other yet unidentified determinants of neuropathy in PD. We screened 33 consecutive levodopa-naive PD patients for neuropathy. Demographics, vitamin B12 and folate levels were studied. Findings were analyzed in the light of our previous available data on levodopa-treated PD patients. Four of 33 (12.1 %) levodopa-naive PD patients were diagnosed with neuropathy. This compared to 13/36 (36.1 %) previously evaluated levodopa-treated patients (p = 0.027) and 3/37 controls (p = 0.7). Analysis of our whole PD cohort consisting of a total of 70 subjects, including levodopa-naive and levodopa-treated patients, revealed that neuropathy correlated with use of levodopa (p = 0.041), cumulative levodopa exposure (p = 0.046), age at time of study (p = 0.005) and serum folate levels <10 MUg/L (p = 0.003). There was no association of neuropathy with PD duration. Multivariate regression analysis showed that neuropathy was only independently associated with age (p = 0.016) and serum folate levels <10 MUg/L (p = 0.012). We conclude that this study confirms the roles of levodopa usage and cumulative levodopa exposure in the neuropathy of PD. However, the effects of levodopa only appear contributory and are surpassed by age and lower folate levels. In view of the independent implication of lower folate levels, the need for preventative/protective supplementation including folate in addition to vitamin B12, probably irrespective of levodopa use, may deserve consideration in patients with PD. PMID- 23989343 TI - A TREX1 mutation causing cerebral vasculopathy in a patient with familial chilblain lupus. PMID- 23989344 TI - Gender differences in non-motor symptoms in early, drug naive Parkinson's disease. AB - Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naive PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naive PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naive PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the chi (2) exact test; multiple comparisons were corrected with the Benjamini Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naive PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients. PMID- 23989345 TI - Videogame-based coordinative training can improve advanced, multisystemic early onset ataxia. PMID- 23989346 TI - 4-aminopyridine improves freezing of gait in Parkinson's disease. PMID- 23989349 TI - Self-reported and performance-based functional outcomes after surgical repair of proximal hamstring avulsions. AB - BACKGROUND: Because a proximal hamstring avulsion results in residual loss of function, surgical repair is recommended. Few studies have investigated postoperative function with validated outcomes. PURPOSE: To examine lower extremity function after surgical repair of proximal hamstring avulsions using validated self-reported and performance-based functional outcomes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Operative records from 2006 to 2010 were retrospectively reviewed in 3 hospitals. A total of 39 patients who had undergone surgical repair of a proximal hamstring avulsion were identified, and 36 met the inclusion criteria. Thirty-one patients completed questionnaires with demographic background data and quality of life-related questions: the Lower Extremity Functional Scale (LEFS) and the Proximal Hamstring Injury Questionnaire (PHIQ). Thirty patients were evaluated using a Biodex dynamometer for isokinetic quadriceps and hamstring strength measurements at a velocity of 60 deg/s, and 27 patients performed 4 single-legged hop tests. RESULTS: Twenty-eight repairs were acute (<4 weeks), and 3 were chronic. There were complete ruptures of all 3 tendons in 17 (55%) cases. The mean follow-up was 30 months. Most patients experienced little or no pain or limitations during activities of daily living. The mean LEFS score was 89%, and 29 (94%) of the 31 patients were satisfied with the result after surgery. Eighteen (58%) of the 31 patients had returned to their preinjury activity level. Significant differences in the mean hamstring strength (peak torque) (P < .001) and single-legged hop test (P = .01) between the uninvolved and involved leg were found. Twenty-two (71%) of the 31 patients did not fully trust their operated leg during physical activities and feared sustaining a hamstring injury. Return to activity significantly correlated with the single-legged hop test, the LEFS score, and the questions regarding trust and fear. CONCLUSION: In this study, using both validated self-reported and performance-based outcome measures after surgical repair of proximal hamstring avulsions, minor pain and limitations to activities of daily living were seen. Isokinetic hamstring strength in the operated leg was significantly lower compared with the nonoperated leg, and a majority of the patients did not trust the operated leg completely during physical activity. PMID- 23989350 TI - Cystic adventitial disease of the popliteal artery causing intermittent exertional claudication in a young male athlete: a case report. PMID- 23989353 TI - Tissue protection by erythropoietin: new findings in a moving field. AB - Two groups elucidate novel mechanisms of tissue protection by erythropoietin (EPO). Hu et al. demonstrate that Klotho's protective effect against oxidant induced cytotoxicity is partially mediated by an increase in the endogenous expression of the classical EPO receptor (EpoR). While erythropoiesis is stimulated by the canonical EpoR homodimer, the tissue-protective effects of EPO are mediated through a heterodimeric 'tissue-protective' receptor. Coldewey et al. demonstrate a protective role of the 'tissue-protective' EpoR against acute kidney injury. PMID- 23989354 TI - Sevelamer and CKD-associated cardiovascular disease: going further, but far from there. AB - Cardiovascular disease is a major complication of chronic kidney disease (CKD), and current data support its link to mineral metabolism disturbances. However, there is an intense debate over whether CKD-mineral and bone disorder therapy could change the cardiovascular burden in CKD. The study by Maizel and colleagues shows the benefits of a phosphate binder, sevelamer, for the progression of aortic stiffness and endothelial dysfunction as well as left ventricular dysfunction and hypertrophy in mice with CKD. PMID- 23989355 TI - Genotypic variation and outcomes in kidney transplantation: donor and recipient effects. AB - The genetic composition of a donor impacts long-term allograft survival after kidney transplantation. Effects of the recipient's genetic make-up, particularly variation in immune response pathway genes, are less certain. Bay et al. reveal improved graft survival in transplant recipients with lower copy numbers of the complement 4 gene (C4) after receipt of deceased-donor kidneys. Genomics breakthroughs in nephrology and immunology will likely revolutionize the field of transplant medicine. PMID- 23989356 TI - Use of enoxaparin in end-stage renal disease. AB - Enoxaparin has become the treatment of choice for various thromboembolic diseases. In most patients with end-stage renal disease (ESRD), prophylactic dosage of enoxaparin does not appear to be associated with an increased bleeding risk and can be used without the need for monitoring and adjustment of regimens. Empirical dose adjustment and biological monitoring seem to be necessary along with therapeutic doses. Anti-factor Xa poorly predicts the degree of anticoagulation in ESRD patients given enoxaparin. PMID- 23989357 TI - Audit-based education: a potentially effective program for improving guideline achievement in CKD patients. AB - The achievement of treatment guidelines in patients with chronic kidney disease is poor, and more efforts are needed to improve this. Audit-based education is a program that may contribute to this improvement. de Lusignana et al. investigated whether audit-based education is effective in lowering systolic blood pressure in a primary-care setting. Although the program is inventive and promising, several adjustments are needed before it can be applied as an effective strategy. PMID- 23989358 TI - Unexpected effect of the appetite-stimulating hormone ghrelin on ENaC: hunger for sodium? AB - The orexigenic hormone ghrelin acts like a hunger signal, released by the stomach in response to nutritional status. However, ghrelin and its receptor in the kidney may play other biological roles. Kemp and colleagues identify that ghrelin stimulates renal Na+ absorption through cAMP-dependent trafficking of ENaC in the cortical collecting duct. While ghrelin seems to be a physiological regulator of ENaC, future studies are necessary to clarify its physiological and pathological roles in sodium homeostasis. PMID- 23989359 TI - Caution advised in interpreting nonsignificant results from ADVANCE post hoc analysis. PMID- 23989360 TI - The authors reply:. PMID- 23989361 TI - Metabolic acidosis may increase fibroblast growth factor-23 and cardiovascular mortality in the community. PMID- 23989362 TI - Comments on 'KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease'. PMID- 23989363 TI - The authors reply:. PMID- 23989364 TI - The authors reply:. PMID- 23989365 TI - The hidden secret of acute kidney injury: the urologist! PMID- 23989366 TI - The authors reply:. PMID- 23989367 TI - Selective bilirubin removal: a treatment of jaundice-related kidney injury? PMID- 23989369 TI - Retraction: Summary of KDIGO guideline: behind the scenes, need for guidance, and a framework for moving forward. PMID- 23989370 TI - Patent processus vaginalis in peritoneal dialysis. PMID- 23989371 TI - The case: fever, myalgia, visual disorders, and acute kidney failure in a pregnant woman. Diagnosis: Severe acute hantavirus infection. PMID- 23989372 TI - Home infusion alternate-site health care. PMID- 23989373 TI - Continued growth predicted for home infusion. PMID- 23989374 TI - Drug stability and compatibility: special considerations for home health care. PMID- 23989375 TI - Extemporaneous compounding in the hospital pharmacy. PMID- 23989376 TI - Assaying progesterone in extemporaneously prepared suppositories. PMID- 23989377 TI - Chemical stability of amiodarone hydrochloride in intravenous fluids. AB - The chemical stability of amiodarone hydrochloride in two intravenous (IV) fluids, 5% dextrose injection and 0.9% sodium chloride injection, was studied. Drug degradation was monitored using a stabiility-indicating, high-performance liquid chromatography assay method. The admixtures of amiodarone in the two IV fluids were found to be stable for 32 days when refrigerated (5 deg C) , and also at room temperature (25 deg C). All solutions remained clear during this period. The recommendations from the manufacturer are conservative. The admixtures are apparently physically and chemically stable for more than 24 hours, provided they are protected from microbiological contamination. However at 40 deg C, significant degradation was observed ater 18 days; and the solutions turned cloudy. Precautions must be taken to prevent temperature elevation during storage. PMID- 23989378 TI - The stability of lisinopril as an extemporaneous syrup. AB - The stability of lisinopril as an extemporaneous syrup compounded from powder was studied. The lisinopril syrup (2mg/mL) was prepared by incorporating lisinopril powder dissolved in water into simple syrup. Samples of the syrup were stored in amber-colored plastic bottles at 5 and 23 deg C. At various times during the 30 day study period, the concentration of lisinopril waas determined by a stability indicating high performance liquid chromatography assay procedure. Samples were also visually inspeceted for color and clarity. Over the 30-day study period, the percentage of the initial concentration remained between 97.46% and 100.54% for the 23 deg C samples and 98.15% and 100.74% for the 5 deg C samples. PMID- 23989379 TI - Compatibility of vancomycin hydrochloride and famotidine 5% dextrose injection. AB - The compatibility of vancomycin hydrochloride and famotidine in 5% dextrose injection stored at two temperatures was studied. Vancomycin hydrochloride and famotidine were reconstituted and diluted with 5% dextrose injection to form an admixture with a famotidine concentration of 0.2 mg/mL and a vancomycin concentration of 5 mg/mL. The admixture was stored in 100-mL vented intravenous containers in the dark at 4 and 25 deg C; three containers were stored at each temperature. A 2-mL sample was taken from each container after six and 12 hours and 1, 3, 5, 7, 10, 12, and 14 days of storage and visually inspected, tested for pH and assayed by a developed stability-indicating high performance liquid chromatographic method. Triplicate samples were prepared for each storage condition. No color change, precipitation or cloudiness was observed in any sample at any time during the study. Vancomycin 5 mg/mL and famotidine 0.2 mg/mL in admixtures in 5% dextrose injections are stable for 14 days at 4 and 25 deg C. PMID- 23989380 TI - Compatibility of warfarin sodium with selected drugs and large-volume parenteral solutions. AB - The objective of this study was to evaluate the compatibility of phosphate buffered warfarin sodium with several drugs and intravenous (IV) solutions previously tested with the unbuffered formulation. Warfarin sodium 0.1 mg/mL was tested for physical compatibility with seven common IV infusion solutions. Similarly, reconstituted warfarin sodium 2 mg/mL and diluted to 0.1 mg/mL in 5% dextrose injection and 0.9% sodium chloride injection were evaluated for physical compatibility with nine other drugs undiluted or admixed in 5% dextrose injection and 0.9% sodium chloride injection. Samples were evaluated initially and after one, four and 24 hours of storage at room temperature (about 23 deg C). Visual examinations were performed with the unaided eye in normal, diffuse room light as well as with a Tyndall beam (high-intensity monodirectional light source) (Dlan Jenner Industries, Woburn, MA) to enhance visualization of small particles and low-level turbidity. The turbidity of each sample was measured as well. Warfarin sodium (phosphate-buffered formulation) was physically compatible with all the common infusion solutions and with six of the nine drugs for at least 24 hours. This is very different than the reported results with the old, unbuffered formulation; previously, warfarin sodium (unbuffered) had been found to be incompatible with most of these drugs and solutions. However, the phosphate buffered formulation of warfarin sodium was physically incompatibe only with ammonium chloride, promazine hydrochloride, and vancomycin hydrochloride in at least some of the combinations tested. Warfarin sodium should not be mixed or administered simultaneously through the same line with the physically incompatible drugs. PMID- 23989381 TI - Concussion: purely a brain injury? PMID- 23989382 TI - Canadian Academy of Sport and Exercise Medicine position statement: osteoporosis and exercise. AB - The purpose of this paper is to look at the effects of exercise in the treatment and prevention of osteoporosis in athletes of all age groups. Recommendations for exercise programs will be discussed as a tool to improve bone health. Medical management of osteoporosis will be reviewed mainly as it pertains to postmenopausal women. PMID- 23989383 TI - Is there evidence in favor of surgical interventions for the subacromial impingement syndrome? AB - OBJECTIVE: To investigate the effectiveness of surgical and postsurgical interventions for the subacromial impingement syndrome (SIS). DATA SOURCES: Using terms including randomized controlled trial (RCT), shoulder impingement syndrome, rotator cuff impingement, and interventions, the Cochrane Library, PubMed, Embase, PEDro, and CINAHL were searched up to February 2009. STUDY SELECTION: Relevant systematic reviews and RCTs in any language that included patients with SIS that was not caused by systemic disease or acute trauma; that evaluated surgical or postsurgical treatment for SIS; that reported outcomes of pain, function, or recovery; and that had a follow-up of >= 2 weeks, were selected by 2 independent reviewers and confirmed by consensus. DATA EXTRACTION: Data on the study population, interventions, outcome measures, and length of follow-up (<3 months, 4 to 6 months, and >6 months) were extracted. Two reviewers assessed the methods of the RCTs that were included in reviews other than Cochrane reviews and in RCTs published more recently, rating RCTs that met 6 of 12 Furlan criteria as high quality. The effectiveness of the intervention was rated as moderate, limited, or no evidence, depending on the consistency and quality of the evidence. MAIN RESULTS: The included studies were 11 RCTs from a Cochrane review, an additional 2 RCTs that reported on the effectiveness of surgery for SIS, and 3 further RCTs that reported on postsurgical interventions. The quality of the studies was generally poor (10/11 RCTs in the Cochrane review had a high risk of bias; and 3 of the additional RCTs were rated moderate to low quality). Arthroscopic or open subacromial decompression compared with physiotherapy or exercise was investigated in 3 trials. No evidence for differences between the treatments in pain, function, or time to recovery was found in the short, medium, or long term. Five comparisons of arthroscopic versus open subacromial decompression showed no differences in pain or shoulder function scores at any follow-up assessment. One study found no difference in short- or long-term outcomes between arthroscopic versus open subacromial decompression for the removal of calcium deposits. A comparison of the Neer versus the modified Neer surgical technique found no verifiable difference between them in the short term. In a study comparing the techniques of electrocautery and holmium laser in arthroscopic subacromial decompression, differences favoring electrocautery were found for the short and medium term on one American shoulder rating scale but not on another. A high-quality study found no differences at any follow-up in pain or shoulder function scores when arthroscopic subacromial decompression was compared with radio-frequency-based plasma microtenotomy. A high-quality RCT compared injections of platelet-leukocyte gel given postoperatively with no injection. The additional intervention was effective at 6 weeks in reducing pain and improving shoulder function and range of motion, and in return to activities of daily living, but no differences were found in shoulder stability. Three low-quality studies compared the effectiveness of various postsurgical interventions. Early progressive exercises (range of motion, and strengthening exercises) resulted in greater improvements in range of motion at 3 and 12 months than later dynamic and strengthening exercise. Reductions in pain were similar for both groups. Patients taking ketoprofen (200 mg once daily for 6 weeks) compared with those taking placebo had less pain and better shoulder scale scores, active forward flexion, and active abduction, at 6 weeks but the groups did not differ after 2 years. The use of a pain pump (0.375% ropivacaine) after arthroscopic surgery was not effective in improving shoulder function scores at the 2-year follow-up. CONCLUSIONS: Studies of surgical interventions in subacromial impingement syndrome suggested that no technique is convincingly better than another or than conservative interventions. Evidence from the few better quality studies suggested that injections of platelet-leukocyte gel given postoperatively were effective in the short term for lessening pain and improving shoulder function, and that radio-frequency-based plasma microtenotomy was not more effective than arthroscopic subacromial decompression for improving any outcome measure. PMID- 23989384 TI - Neuromuscular training to prevent knee injuries in adolescent female soccer players. AB - OBJECTIVE: To evaluate the effectiveness of a neuromuscular warm-up program in preventing acute knee injury in adolescent female football (soccer) players. DESIGN: Cluster randomized (by team) controlled trial, stratified by geographical district. Sample size was calculated (n = 8118) with 80% power to show a reduction of 50% in an estimated 1.15% annual incidence of anterior cruciate ligament (ACL) injury at P <= 0.05. SETTING: Clubs in 8 regional districts of the Swedish Football Association, during the 2009 season (April through October). PARTICIPANTS: Female under-14 to under-18 football clubs (ages 12-17 years) were recruited. Reasons for the exclusion of clubs were lack of response, <2 training sessions per week, and the current use of an injury prevention program. INTERVENTION: The clubs were randomized to a neuromuscular warm-up intervention (Knakontroll, SISU Idrottsbocker, Sweden, 2005) or to a control group, who were instructed to continue with their usual training and playing practices. The neuromuscular training program included 6 exercises that focused on knee control and core stability (1- and 2-legged knee squats, a pelvic lift, the bench, the lunge, and jump/landing). The exercises were to be done twice per week and were to take about 15 minutes, after a brief running warm-up. They progressed through 4 levels of difficulty. The team coaches supervised the program after instruction from study therapists. MAIN OUTCOME MEASURES: The primary outcome was the rate of ACL injuries. Diagnosis was confirmed, as appropriate, by a physician and by magnetic resonance imaging. Secondary outcomes were the rates of serious knee injury and any acute knee injury, defined as those with sudden onset during play that led to a player being unable to participate in training or competition. Severe injuries were those that caused absences of >4 weeks. Two study therapists evaluated the injuries. The coaches recorded data, including when the intervention was performed, any injuries, individual playing times, and periods of absence. Assessment of the primary outcome was done by physicians blinded to group assignment. MAIN RESULTS: During 278 298 hours of play, 96 knee injuries occurred in 92 players (intervention group 48, control group 44). The rate did not differ between groups. Of the 21 ACL injuries, 7 occurred in the intervention group and 14 in the control group, giving a rate ratio (RR) of 0.36 (95% confidence interval [CI] 0.15-0.85; P = 0.02). Severe injuries (intervention group 26, control group 31) did not differ between groups. They included 22 collateral or capsular sprains, 21 ACL injuries, 7 patella dislocations or subluxations, 6 meniscal or chondral lesions, and 1 tibial plateau fracture. Compliant players (those who performed >= 1 exercise session per week; 1303 players) had a lower rate of ACL injury (RR, 0.17; 95% CI, 0.05-0.57), of severe knee injury (RR, 0.18; 95% CI, 0.07-0.45), and of any acute knee injury (RR, 0.53; 95% CI, 0.30-0.94) than the control group. CONCLUSIONS: A short weekly neuromuscular exercise program reduced the rate of ACL injuries among adolescent female football (soccer) players. Those who were compliant with the intervention had fewer severe knee injuries and fewer injuries overall. PMID- 23989385 TI - Children's physical activity and sedentary time and cardiometabolic risk factors. AB - OBJECTIVE: To examine the associations of moderate-to-vigorous physical activity (MVPA) and time spent sedentarily with cardiometabolic risk factors in children and adolescents. DESIGN: The data from 14 studies were pooled. This summary is of the associations between baseline activity levels and cardiometabolic risk factors measured in the cohort that was followed for a mean 2.1 years. SETTING: The data were drawn from studies (1998-2009) in Australia, Brazil, Europe, and the United States by the International Children's Accelerometry Database (ICAD) Collaborators. PARTICIPANTS: At baseline, the 20,871 participants in 14 studies were 4 to 18 years of age. Baseline and follow-up data on waist circumference were available for 6413 participants from 7 studies. ASSESSMENT OF RISK FACTORS: The children's time spent in activity and time spent sedentarily were objectively measured through the use of accelerometers (actigraphs) from which physical activity counts per minute (cpm) could be obtained in a standard way. Sedentary time was defined as all minutes showing <100 cpm, whereas MVPA time was minutes with >3000 cpm. Anthropometric and cardiometabolic measures were initially recorded at baseline. MAIN OUTCOME MEASURES: The main end points were the cardiometabolic outcomes of abdominal adiposity (waist circumference), glucose metabolism and lipid metabolism (fasting insulin, triglycerides, and HDL cholesterol), and resting systolic blood pressure (SBP). In each study the relations between cpm, MVPA, and sedentary time were adjusted for each other. Regression coefficients were calculated to allow cross-sectional random effects meta-analysis adjusted for sex, age, and monitor-wear time, and further adjusted in the prospective study by baseline values and follow-up time. MAIN RESULTS: At a median of 2.1 years of follow-up (range, 0.3-8.0 years), time spent in MVPA at baseline was not associated with waist circumference (beta = 0.00024; 95% confidence interval [CI] -0.0057 to 0.0062). Similarly, baseline sedentary time was not associated with follow-up waist circumference (beta = -0.0024; 95% CI, 0.0057 to 0.0010). A greater waist circumference at baseline was not associated with time spent in MVPA at follow-up (beta = -0.0037; 95% CI, -0.60 to 0.052), but was associated with more sedentary time at follow-up (beta = 0.40; 95% CI, 0.19-0.61). At baseline, total physical activity cpm and MVPA were negatively associated with baseline waist circumference, SBP, and serum levels of fasting insulin and triglycerides. Baseline time per day in sedentary activity was positively associated with fasting insulin level but not with any other cardiometabolic risk factor. CONCLUSIONS: Although children's level of physical activity and time spent sedentarily were cross-sectionally related to some baseline cardiometabolic risk factors, they did not predict waist circumference measured at follow-up. However, waist circumference at baseline did predict more sedentary time at follow-up. PMID- 23989386 TI - Marathon-related cardiac arrest. AB - OBJECTIVE: To investigate the incidence and assess the outcomes of cardiac arrest occurring in the context of participation in marathon or half-marathon races. DESIGN: Incidence study. SETTING: Data came from long-distance race records in the United States from January 1, 2001, to May 31, 2010. PARTICIPANTS: All participants were registered entrants in the long-distance races. Participation statistics (sex, participant identity numbers, and race distance) were publicly accessible from Running USA. ASSESSMENT OF RISK FACTORS: Data on possible risk factors for cases were obtained retrospectively through computer searches (age, sex, location of cardiac arrest, publicly released cause of death). Three attempts were made to obtain information from survivors or from the next-of-kin of deceased cases. This information included demographic characteristics, exercise and running history, and personal and family medical history. MAIN OUTCOME MEASURES: The main outcome measures were the incidence and characteristics of cases of cardiac arrest that occurred during the race, at the finish-line, or <= 1 hour after completion of a marathon or half marathon. Cardiac arrests were defined by a medical professional as an unconscious state and an absence of spontaneous respirations and pulse. Successful resuscitation and discharge from hospital defined a survivor, whereas a nonsurvivor was a person who was not successfully resuscitated in the field or who died before hospital discharge. Cases of cardiac arrest had to be independently identified in 3 separate sources of data or confirmed with official race medical staff. Further information, including details of the cardiac arrest, was obtained from medical records and autopsies and the survivors or next of kin. MAIN RESULTS: Among 10.9 million registered race participants there were 40 cardiac arrests in marathons and 19 in half marathons (overall incidence, 0.54 per 100,000; 95% confidence interval [CI], 0.41-0.70). The mean age of runners with cardiac arrest was 42 (SD 13) years and 86% were men. The incidence per 100,000 was higher in marathons (1.01; 95% CI, 0.72-1.38) than in half marathons (0.27; 95% CI, 0.17-0.43; and among men (0.90; 95% CI, 0.67-1.18) than among women (0.16; 95% CI, 0.07-0.31). More runners died than survived the cardiac arrest (42 [71%] vs 17[29%]); the incidence of sudden death was 0.39 per 100,000 participants (95% CI, 0.28-0.52). The mean age of the nonsurvivors was younger than that of the survivors (39 vs 49 years; P = 0.002). Complete clinical information on cause of death was available for 23 runners. The most common confirmed or possible cause of death was hypertrophic cardiomyopathy (15 cases, of whom 9 had an additional clinical factor). Among the 8 survivors with complete information, ischemic heart disease was the cause of cardiac arrest in 5. The survivors were older than nonsurvivors (53 vs 40 years), had completed more long-distance races, and were more likely to have known cardiac risk factors. The strongest predictors of survival were initiation of cardiopulmonary resuscitation by bystanders (P = 0.01) and an underlying diagnosis other than hypertrophic cardiomyopathy (P = 0.01) CONCLUSIONS:: The incidence of cardiac arrest and sudden death per 100,000 runner hours was 0.2 and 0.14. Risk factors for cardiac arrest were full marathon and male sex. Younger age and no previous knowledge of cardiovascular risk were associated with sudden death. PMID- 23989387 TI - Between red and yellow: evidence of intermediates in a vapochromic Pt(II) salt. AB - [Pt(tpy)Cl]ClO4.H2O (1.H2O) changes from red to yellow upon dehydration due to increased Pt...Pt distances. Spectroscopic, diffraction, gravimetric and calorimetric data demonstrate the presence of intermediates during hydration and dehydration which signifies surprising mechanistic complexity in the vapochromic response. PMID- 23989388 TI - Drug-induced hypothermia as beneficial treatment before and after cerebral ischemia. AB - OBJECTIVES: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when conditioning before (preconditioning) and after (postconditioning) experimental stroke. METHODS: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2 vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced either immediately or with 3 h delay. Rats survived ischemia for 2, 7 or 90 days. Infarct volumes were quantified by stereology. Additional experiments of methodological relevance were included in the study. RESULTS: Talipexole induced mild hypothermia (35.1+/-1.1 to 36.0+/-0.5 degrees C) for <20 h. Hypothermic pre- and postconditioning reduced infarct sizes by more than 60% as monitored during the first 90 days after experimental stroke (p<0.05). CONCLUSION: Talipexole is registered for use as a dopamine substitute in humans with Parkinson's disease. Although dosages cannot be directly translated to patients, our study exemplifies in an animal model that drug induced hypothermia in a clinical setting might reduce cerebral ischemic damage before neuro- and cardiac surgical procedures and after stroke. PMID- 23989389 TI - Copper(ii) chloride mediated (aza)oxindole synthesis by oxidative coupling of Csp(2)-H and Csp(3)-H centers: substrate scope and DFT study. AB - A CuCl2 mediated direct intramolecular oxidative coupling of Csp(2)-H and Csp(3) H centers gives access to 3,3-disubstituted oxindoles containing aromatic, heteroaromatic and alkyl substituents as well as a heteroatom at the quaternary center in good to excellent yields. The reaction is carried out in the presence of NaOtBu and CuCl2 in DMF at 110 degrees C. The key step of this reaction is the formation of an amidyl radical by one electron oxidation of amide enolate followed by an intramolecular radical cyclization reaction (homolytic aromatic substitution reaction). A detailed DFT study shows that the cyclization of the amidyl radical is the rate-limiting step in the oxindole synthesis, whereas the second single electron transfer (SET) becomes the rate-determining step in the aza-oxindole formation. Computational data are in agreement with the experimentally observed relative reactivity and regioselectivity. PMID- 23989390 TI - Intraoral mass causing obstructive sleep apnea. Venolymphatic malformation of the soft palate. PMID- 23989391 TI - Neural networks using two-component Bose-Einstein condensates. AB - The authors previously considered a method of solving optimization problems by using a system of interconnected network of two component Bose-Einstein condensates (Byrnes, Yan, Yamamoto New J. Phys. 13, 113025 (2011)). The use of bosonic particles gives a reduced time proportional to the number of bosons N for solving Ising model Hamiltonians by taking advantage of enhanced bosonic cooling rates. Here we consider the same system in terms of neural networks. We find that up to the accelerated cooling of the bosons the previously proposed system is equivalent to a stochastic continuous Hopfield network. This makes it clear that the BEC network is a physical realization of a simulated annealing algorithm, with an additional speedup due to bosonic enhancement. We discuss the BEC network in terms of neural network tasks such as learning and pattern recognition and find that the latter process may be accelerated by a factor of N. PMID- 23989392 TI - Cyanosis in a male Nigerian infant with acute kidney injury: questions. PMID- 23989393 TI - The nephrotic syndrome: pathogenesis and treatment of edema formation and secondary complications. AB - Nephrotic syndrome is an important clinical condition affecting both children and adults. Studies suggest that the pathogenesis of edema in individual patients may occur via widely variable mechanisms, i.e., intravascular volume underfilling versus overfilling. Managing edema should therefore be directed to the underlying pathophysiology. Nephrotic syndrome is also associated with clinically important complications related to urinary loss of proteins other than albumin. This educational review focuses on the pathophysiology and management of edema and secondary complications in patients with nephrotic syndrome. PMID- 23989394 TI - Cyanosis in a male Nigerian infant with acute kidney injury: answers. PMID- 23989395 TI - Subcutaneous nodules in a child on long-term dialysis. PMID- 23989397 TI - Engineering kidneys from simple cell suspensions: an exercise in self organization. AB - Increasing numbers of people approaching and living with end-stage renal disease and failure of the supply of transplantable kidneys to keep pace has created an urgent need for alternative sources of new organs. One possibility is tissue engineering of new organs from stem cells. Adult kidneys are arguably too large and anatomically complex for direct construction, but engineering immature kidneys, transplanting them, and allowing them to mature within the host may be more feasible. In this review, we describe a technique that begins with a suspension of renogenic stem cells and promotes these cells' self-organization into organ rudiments very similar to foetal kidneys, with a collecting duct tree, nephrons, corticomedullary zonation and extended loops of Henle. The engineered rudiments vascularize when transplanted to appropriate vessel-rich sites in bird eggs or adult animals, and show preliminary evidence for physiological function. We hope that this approach might one day be the basis of a clinically useful technique for renal replacement therapy. PMID- 23989398 TI - An unusual cause of abdominal ascites and acute kidney injury: questions. PMID- 23989400 TI - The effect of fatal carbon monoxide poisoning on the surface charge of blood cells. AB - The objective of this investigation was to evaluate postmortem changes of electric charge of human erythrocytes and thrombocytes after fatal carbon monoxide (CO) poisoning. The surface charge density values were determined on the basis of the electrophoretic mobility measurements of the cells carried out at various pH values of electrolyte solution. The surface charge of erythrocyte membranes after fatal CO poisoning as well as after sudden unexpected death increased compared to the control group in the whole range of experimental pH values. Also, a slight shift of the isoelectric point of erythrocyte membranes to high pH values was observed. The surface charge of thrombocyte membranes after fatal CO poisoning decreased at low pH compared to the control group. However, at high pH, the values increased compared to the control group. The isoelectric point of thrombocyte membranes after fatal CO poisoning was considerably shifted toward low pH values compared to the control group. The observed changes are probably connected with the destruction of blood cell structure. PMID- 23989401 TI - [Hemato-oncological diseases]. AB - Acquired inhibitors of coagulation cause a life-threatening disease. Clinically newly occurring hemorrhagic diathesis combined with prolonged activated partial thromboplastin time (aPTT) time is diagnostically indicative and can be confirmed by a positive plasma exchange test. For thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (TTP-HUS) the diagnosis of Coombs negative hemolytic anemia together with thrombocytopenia should lead to the detection of fragmentocytes in peripheral blood smears. Hairy cell leukemia is a rare subgroup of chronic B-cell neoplasia with the clinical signs of pancytopenia and splenomegaly which characteristically stain positive for CD103. The gastrointestinal stromal tumor (GIST) has nothing in common with classical soft tissue sarcoma based on the activating mutation of the KIT or PDGFRA gene (positivity for CD117). In all of these disorders the correct diagnosis has a major influence on patient outcome. For the case of acquired inhibitors of coagulation immunosuppressive therapy and substitution of coagulation factors (e.g. recombinant factor VIIa) or for TTP-HUS the immediate start of plasma exchange are mandatory. For hairy cell leukemia a very effective treatment exists with purine analogs (e.g. cladribine) and for metastatic inoperable GIST with tyrosine kinase inhibitors (e.g. imatinib). PMID- 23989402 TI - [Symptomatic diseases in pneumology]. AB - The diagnosis and treatment of granulomatous lung diseases is challenging. This article describes two of these entities: (1) eosinophilic vasculitis with polyangiitis which is clinically characterized as a combination of bronchial asthma and eosinophilic granulomatous vasculitis. Antoneutrophil cytoplasmic antibodies are present in approximately 40 % of patients. Treatment with steroids is sufficient in patients with isolated pulmonary manifestation but extrapulmonary manifestations, e.g. heart, central nervous system (CNS), kidneys and gastrointestinal tract warrant combined immunosuppression with prednisolone and cyclophosphamide. (2) In Germany tuberculosis is an orphan disease with an incidence of 5.3/100,000 in the year 2011. Prolonged cough, night sweats and weight loss should be considered suspicious of tuberculosis. Microbiological diagnosis has been improved by gene and PCR technology. The traditional Mendel Mantoux skin test has widely been replaced by the interferon gamma release assay (IGRA). Standard treatment of non-resistant mycobacterium tuberculosis is based on a combination of isonizide, rifampicine, pyrazinamide and ethambutol for 2 months followed by 4 months of isoniazide plus rifampicine. Therapy resistant, multiple drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis bacteria should be treated by experienced specialists. PMID- 23989403 TI - [Endocrine disease symptoms]. AB - Diseases of the endocrine system can be classified according to the prevalence into two categories: very frequent endocrinopathies, which affect a population of several millions in Germany and include diabetes mellitus, endemic goiter, osteoporosis and obesity. On the other hand there are a large number of rare endocrine diseases which share the paradox of other rare diseases: they are also often falsely suspected in patients who are not affected but at the same time there are sometimes long delays in diagnosis in those who do have the disease. In cases of adrenal insufficiency, absolute glucocorticoid deficiency can progress to an adrenal crisis which is fatal if not treated. Patients with de Quervain thyroiditis often suffer from prolonged episodes of fever with tender, diffuse goiter and neck pain. Pheochromocytomas should be recognized early in the course of disease because of life-threatening cardiovascular complications. This article highlights the essential characteristics in order to increase awareness. PMID- 23989404 TI - Temporal trends of PCBs, PCDD/Fs and PBDEs in soils from an E-waste dismantling area in East China. AB - The temporal trends of polychlorinated biphenyls (PCBs), polychlorinated dibenzo p-dioxins and dibenzofurans (PCDD/Fs) and polybrominated diphenyl ethers (PBDEs) were investigated in soils from an E-waste dismantling area in East China between 2005 and 2011. Isotope dilution high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS) was employed for the sample analysis. PCB levels declined as expected, while PCDD/Fs generally remained at a constant level during the sampling period, and PBDE concentrations tended to be slightly lower after 2007 although the decline was not statistically significant. The congener profiles indicated that lowly-halogenated congeners of these persistent organic pollutants (POPs) accounted for the decreasing levels and relative proportions of the POPs, suggesting that they have been gradually eliminated from the field soil over the years. However, the concentration levels of some heavy congeners (e.g., CB-209, OCDD and OCDF) showed different trends from those of the lighter ones. The general tendencies of the three types of POPs in soils were consistent with those reported in other studies in this area. The results implied that the enhanced regulations and centralized dismantling action introduced in 2005 might exert a limited influence on these three types of POPs in soils during the sampling period. PMID- 23989405 TI - Cytotoxicity, apoptosis, cell cycle arrest, reactive oxygen species, mitochondrial membrane potential, and Western blotting analysis of ruthenium(II) complexes. AB - Three new ruthenium(II) complexes-[Ru(bpy)2(adppz)](ClO4)2, [Ru(dmb)2(adppz)](ClO4)2, and [Ru(dmp)2(adppz)](ClO4)2 (bpy is 2,2'-bipyridine, adppz is 7-aminodipyrido[3,2-a:2',3'-c]phenazine, dmb is 4,4'-dimethyl-2,2' bipyridine, and dmp is 2,9-dimethyl-1,10-phenanthroline)-were synthesized. [Ru(dmp)2(adppz)](ClO4)2 exhibits higher cytotoxicity than cisplatin toward A549, MG-63, and SKBR-3 cells. The apoptosis and cellular uptake were studied by fluorescence microscopy. [Ru(dmp)2(adppz)](ClO4)2 enhances the level of reactive oxygen species (ROS) and decreases the mitochondrial membrane potential. These complexes induce cell cycle arrest in S phase in BEL-7402 cells, and inhibit the antiproliferation of SKBR-3 cells at G0/G1 phase. Western blotting analysis shows that [Ru(dmp)2(adppz)](ClO4)2 induces apoptosis in BEL-7402 cells through activation of caspase 3, caspase 7, and procaspase 7 and ROS-mediated mitochondrial dysfunction pathways. PMID- 23989407 TI - Spatial patterns of land use changes across a Mediterranean metropolitan landscape: implications for biodiversity management. AB - Land use and land cover change (LUCC) is an acknowledged cause of the current biodiversity crisis, but the link between LUCC and biodiversity conservation remains largely unknown at the regional scale, especially due to the traditional lack of consistent biodiversity data. We provide a methodological approach for assessing this link through defining a set of major pressures on biodiversity from LUCC and evaluating their extent, distribution, and association with a set of physical factors. The study was performed in the Metropolitan Region of Barcelona (MRB, NE of Spain) between 1956 and 2000. We generated a LUCC map for the time period, which was reclassified into a set of pressures on biodiversity (forestation, deforestation, crop abandonment, and urbanization). We then explored the association of these pressures with a set of physical factors using redundancy analysis (RDA). Pressures encompassed 38.8% of the MRB area. Urbanization and forestation were the dominating pressures, followed by crop abandonment and deforestation. RDA showed a significant distribution gradient of these pressures in relation to the studied physical factors: while forestation and deforestation are concentrated in remote mountain areas, urbanization mainly occurs in lowlands and especially on the coast, and close to previous urban centers and roads. Unchanged areas are concentrated in rainy and relatively remote mountain areas. Results also showed a dramatic loss of open habitats and of the traditional land use gradient, both featuring Mediterranean landscapes and extremely important for their biodiversity conservation. Implications of these results for biodiversity management are finally discussed. PMID- 23989406 TI - Human anamorsin binds [2Fe-2S] clusters with unique electronic properties. AB - The eukaryotic anamorsin protein family, which has recently been proposed to be part of an electron transfer chain functioning in the early steps of cytosolic iron-sulfur (Fe/S) protein biogenesis, is characterized by a largely unstructured domain (CIAPIN1) containing two conserved cysteine-rich motifs (CX8CX2CXC and CX2CX7CX2C) whose Fe/S binding properties and electronic structures are not well defined. Here, we found that (1) each motif in human anamorsin is able to bind independently a [2Fe-2S] cluster through its four cysteine residues, the binding of one cluster mutually excluding the binding of the second, (2) the reduced [2Fe 2S](+) clusters exhibit a unique electronic structure with considerable anisotropy in their coordination environment, different from that observed in reduced, plant-type and vertebrate-type [2Fe-2S] ferredoxin centers, (3) the reduced cluster bound to the CX2CX7CX2C motif reveals an unprecedented valence localization-to-delocalization transition as a function of temperature, and (4) only the [2Fe-2S] cluster bound to the CX8CX2CXC motif is involved in the electron transfer with its physiological protein partner Ndor1. The unique electronic properties of both [2Fe-2S] centers can be interpreted by considering that both cysteine-rich motifs are located in a highly unstructured and flexible protein region, whose local conformational heterogeneity can induce anisotropy in metal coordination. This study contributes to the understanding of the functional role of the CIAPIN1 domain in the anamorsin family, suggesting that only the [2Fe 2S] cluster bound to the CX8CX2CXC motif is indispensable in the electron transfer chain assembling cytosolic Fe/S proteins. PMID- 23989408 TI - Linear atrophoderma of moulin: report of 4 cases and 20th anniversary case review. AB - BACKGROUND: Linear atrophoderma of Moulin (LAM) is a rare clinical entity which was first described by Moulin et al. in 1992. The diagnosis is clinical, characterized by acquired unilateral hyperpigmented, depressed band-like skin lesions following Blaschko's lines. The disease typically affects children or adolescents and has a good prognosis without evidence of long-term progression. To date, the pathophysiology is unclear. Different authors hypothesize that the disease is secondary to a mosaic manifestation as a result of a post-zygotic mutational event. OBSERVATIONS: Four patients (2 men, 2 women) had a history of unilateral band-like skin lesions located on the lower legs (50%) or the trunk (50%). Physical examination showed atrophic and hyperpigmented skin lesions along Blaschko's lines, which appeared during childhood in 3 cases and at the age of 20 in the last case. Lesions had progressed rapidly but seemed to have stabilized so far except for 1 case who presented spontaneous improvement. Histopathological examination revealed a normal epidermis with a hyperpigmented basal layer and a perivascular lymphocytic infiltrate in the dermis. CONCLUSION: LAM is a rare disease with 32 reported cases and remains an exclusion diagnosis. Since the problem is mainly esthetic, treatments should not be too aggressive. PMID- 23989409 TI - Cryptococcosis in a febrile renal transplant recipient--reply. PMID- 23989410 TI - DDT in forest streams. AB - Water was sampled from a tributary of the Miramichi River of New Brunswick before, during, and up to two years after the final operational application of DDT to this area of forest. Gas chromatographic analysis of petroleum ether extracts of the water showed that only during and for a few hours after actual spray application did the DDT concentration in the stream exceed a steady background level of 0.5 ppb. pp 'DDT (<17 ppb.), and this DDT flush occurred mainly as a surface film associated with the formulating oil. Bottom sediments, extracted with hexane-acetone (2/1) for chromatographic analysis, showed a downstream dilution gradient of DDT residue from tributary to estuary, and these averaged only 12.5 per cent of the DDT concentration found in the soils of surrounding forests. Much of the pp' DDT applied in the original technical spray was decomposed to DDE and DDD in the bottom sediments of forest streams. PMID- 23989411 TI - Indentification of the major metabolic product of heptachlor epoxide in rat feces. PMID- 23989412 TI - Dieldrin poisoning of chickens during severe dietary restriction. AB - Two experiments were conducted to establish the effect of dieldrin on survival of chickens during severe dietary restriction. White Leghorn hens were fed rations containing 0, 1, 5, 10, and 20 ppm of dieldrin for 12 weeks. At this time, dieldrin had accumulated in the body fat in direct proportion to the amount fed. During subsequent feed restriction, survival of hens fed 10 or 20 ppm dieldrin was significantly shorter than that of hens fed 0, 1, or 5 ppm dieldrin. Dieldrin concentration in blood declined during the first and second weeks following feed removal, then it increased. Blood sampling was terminated at the end of 4 weeks because nearly all hens had died, but dieldrin concentration in the blood had not increased appreciably over the concentration observed in blood at the time that feed was removed. PMID- 23989413 TI - Comparison of mercury contents in maternal blood, umbilical cord blood, and placental tissues. PMID- 23989414 TI - Elimination rate and tissue residues of chloropropylate and chlorobenzilate in rats. PMID- 23989415 TI - Identification of the derivatives employed in the confirmation of dieldrin residues. PMID- 23989416 TI - Characterization of oxychlordane, animal metabolite of chlordane. PMID- 23989417 TI - Relationship between serum enzymes and histological changes in liver after administration of heptachlor in the rat. PMID- 23989418 TI - Microbial cometabolism of 2,4,5-Trichlorophenoxyacetic acid. PMID- 23989419 TI - Analysis of pesticides in water using silica gel column clean-up. PMID- 23989420 TI - Photolysis of pesticidal synergists. I. piperonyl butoxide. PMID- 23989421 TI - Primary production: Depression of oxygen evolution in algal cultures by organophosphorus insecticides. AB - Photosynthesis of four estuarine phytoplankters was inhibited by Baytex and Abate (organophosphates), Baygon (carbamate) and DDT (chlorinated hydrocarbon). Responses varied with the algal species and with the insecticide. The order from most to least toxic insecticide was Baytex, Baygon, DDT, Abate and the order from least to most sensitive alga wasC. nana,P. cornutum=S. costatum,D. euchlora. PMID- 23989422 TI - Determination of residual fuel oil contamination of aquatic animals. PMID- 23989423 TI - Phosphorimetry of chloro- and nitro-aromatic fungicides. AB - Low temperature fluorescence and phosphorescence properties of 19 chloro- and nitro-aromatic fungicides have been investigated. Five compounds (chloroneb, 1 chloro-2,4-dinitronaphthalene, daconil 2787, DCNA and dyrene) show luminescence, strong enough to be used for sensitive analytical procedures. The lowest detection limit (5*10(-9) g/ml) is shown by DCNA. In all cases phosphorescence was more intense than fluorescence suggesting the former as the preferred method. PMID- 23989424 TI - Effect of DDT on induction of microsomal enzymes and deposition of calcium in the domestic chicken. AB - These results show that PB pretreatment induced microsomal enzyme activity in all stages studied (as measured directly or by decreased sedation time), induction of microsomal enzymes by DDT was inconsistent in the enzyme assays and pretreatment with DDT and its analogs increased sedation time of PB inin vivo tests, an apparent inhibition of microsomal enzymes. Dieldrin and insecticides of a similar mode of action were found to decrease the sedation time of PB in young chicks, but dieldrin did not alter the sedation time of PB in mature birds. Addition of DDT-DDE to the food of laying hens had no effect on eggshell calcium. These experiments lend additional support to the hypothesis that alteration of oxidative enzyme activity and/or calcium deposition by chlorinated hydrocarbons does not appear to be a general phenomenon among the class Aves. PMID- 23989425 TI - Effects of nine insecticides on the numbers and biomass of earthworms in pasture. AB - The effects of nine insecticides on the numbers and biomass of earthworms were studied three weeks after plots in pasture were treated. Dursban, BAYER 37289 and DDT had very little effect, but Dasanit, carbofuran and Stauffer N-2596 drastically lessened numbers and biomass of earthworms sampled with formalin solution. BUX, endrin and carbaryl did not lessen numbers by more than 60% or the biomass by more than 68.3%. PMID- 23989426 TI - Identification of organochlorine pesticides in crude extracts by mass spectrometry. AB - A method is described for identifying a chlorinated pesticide in crude extracts (i) at 1 ppm by low resolution mass spectrometry with the aid of a recently developed temperature controlled probe and (ii) at 0.01 ppm by high resolution techniques using a photoplate record to determine the mass deficient ions containing chlorine.This analytical method is feasible wherever ions of the same elemental composition as those derived from an unknown are not otherwise present in the crude extract mass spectrum. PMID- 23989427 TI - Shunt dependency syndrome after cystoperitoneal shunting of arachnoid cysts. AB - PURPOSE: The goal of this study was to investigate the mechanisms, diagnosis, and treatment of shunt dependency syndrome in patients with temporal lobe arachnoid cysts who were initially treated with cystoperitoneal (CP) shunting. METHODS: Thirteen patients with temporal lobe arachnoid cysts who had initially been treated with CP shunt placement and had developed shunt dependency syndrome were treated by the senior author at Tiantan Hospital between April 2010 and January 2012. The clinical manifestations, neuroimaging findings, intracranial pressure (ICP) data, treatment methods, and therapeutic results were reviewed retrospectively. RESULTS: The study included ten males and three females. The mean age at the time of development of shunt dependency syndrome was 12.3 years (range 5.5-24 years). In most patients, neuroimaging findings showed a collapsed cyst (the cyst appeared almost unchanged in only one patient) and normal or small ventricles (only one patient had enlarged ventricles). Three patients underwent simple replacement of the shunt, four underwent ventriculoperitoneal shunt placement, and the other six underwent lumboperitoneal shunt placement. All patients experienced resolution of their symptoms postoperatively. The mean duration of follow-up was 20 months. CONCLUSIONS: Shunt dependency syndrome is a rare but serious complication of shunting an arachnoid cyst. This condition is similar to the slit ventricle syndrome, but also has some differences. ICP monitoring may confirm the diagnosis when there are no significant radiological findings. Achievement of a shunt-free state might be the ultimate goal for all shunted patients. PMID- 23989428 TI - Vertex cephaloceles: a review. AB - INTRODUCTION: Vertex cephaloceles (VCs), also known as midline parietal cephaloceles, are among the most common midline scalp masses. Usually composed by a meningeal wall herniating from a vertex skull defect and covered by skin, VCs may also contain both anomalous vessels and neural elements. In spite of their harmless appearance, VCs often hide complex intracranial venous and/or brain malformations so that they represent a "tip of the iceberg". Vertical embryonic positioned straight sinus, elongation of the vein of Galen, persistence of the falcine sinus, fenestration of the superior sagittal sinus, corpus callosum agenesis, intracranial cysts, tentorial malformations, cerebellar vermis agenesis, hydrocephalus, and gray matter heterotopia are some of such associated anomalies. METHODS: The treatment of VCs is surgical. It is indicated to prevent the rupture of the malformation or in case of pain or cosmetic impact. A careful preoperative radiological work up is mandatory to investigate the relationship between the VC and the sagittal sinus and/or the possible communication with the brain. The surgical procedure is usually carried out without significant complications. CONCLUSION: The prognosis of VCs is good even though the overall outcome is affected by the associated brain malformations. PMID- 23989429 TI - An operative technique combining endoscopic third ventriculostomy and long-term ICP monitoring. AB - Neuroendoscopy has been well established in the treatment of many neurological and neurosurgical diseases. Especially its application in occlusive hydrocephalus to restore a physiological cerebrospinal fluid circulation has been extensively examined in the past. Although such procedures are believed to be safe and effective, complication as well as failure rates up to 20% have been described pointing to the importance of long-term postoperative care. Therefore, different and partly invasive procedures as ventricular drain insertions or complex cranial imaging methods have been proposed; however, associated pitfalls and restrictions often limited their prognostic value and long-term benefit. An operative technique combining endoscopic third ventriculostomy and telemetric increased intracranial pressure monitoring has now been developed to optimize the postoperative care management. The main intention is to provide sufficient brain pressure data for long-term observation and early recognition of endoscopy failures and complications. The new operative technique was applied in a series with 24 patients suffering from occlusive hydrocephalus. Surgical technique and future perspectives are presented. PMID- 23989430 TI - The murine long-term multi-lineage renewal marrow stem cell is a cycling cell. AB - Prevailing wisdom holds that hematopoietic stem cells (HSCs) are predominantly quiescent. Although HSC cycle status has long been the subject of scrutiny, virtually all marrow stem cell research has been based on studies of highly purified HSCs. Here we explored the cell cycle status of marrow stem cells in un separated whole bone marrow (WBM). We show that a large number of long-term multi lineage engraftable stem cells within WBM are in S/G2/M phase. Using bromodeoxyuridine, we show rapid transit through the cell cycle of a previously defined relatively dormant purified stem cell, the long-term HSC (LT-HSC; Lineage(-)/c-kit(+)/Sca-1(+)/Flk-2(-)). Actively cycling marrow stem cells have continually changing phenotype with cell cycle transit, likely rendering them difficult to purify to homogeneity. Indeed, as WBM contains actively cycling stem cells, and highly purified stem cells engraft predominantly while quiescent, it follows that the population of cycling marrow stem cells within WBM are lost during purification. Our studies indicate that both the discarded lineage positive and lineage-negative marrow cells in a stem cell separation contain cycling stem cells. We propose that future work should encompass this larger population of cycling stem cells that is poorly represented in current studies solely focused on purified stem cell populations. PMID- 23989432 TI - Losing ALTITUDE? How should ASTRONAUT launch into ATMOSPHERE. PMID- 23989433 TI - Ambulatory care and the compounding pharmacist. PMID- 23989434 TI - Ambulatory care medicine: definition and scope of service. PMID- 23989435 TI - Compounding pharmacists play vital role in AIDS treatment. PMID- 23989431 TI - Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease. AB - The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT. PMID- 23989436 TI - Treating patients with asthma. PMID- 23989437 TI - Basic statistical concepts for evaluating pharmaceutical compounding literature. PMID- 23989438 TI - Stability of Two Concentrations of Heparin Sodium Prefilled in CADD-Micro* Pump Syringes. AB - The purpose of this study was to determine the stability of two concentrations (1000 units/mL and 40,000 units/mL) of heparin sodium when individually prefilled in CADD-Micro pump syringes (Sims Deltec, Inc., St Paul MN) and stored at near body (30 deg C) temperature for extended periods of time, up to 30 days. Three syringes were prepared for each sample period and each concentration. Following aseptic filling, the syringes were capped and stored under controlled temperatures for the duration of the study. The contents of each of three syringes per sample set were expelled individually into screw-cap, glass sample vials at designated sample times. Samples were immediately stored at -70 deg C until the time of analysis. The results of the study indicate that, when prefilled in CADD-Micro pump polypropylene syringes and maintained at 30 deg C for up to 30 days, both concentrations of heparin sodium studied retained greater thatn 95% of the intact drug. PMID- 23989439 TI - Stability of cefepime hydrochloride dextrose in 5% dextrose injection and 0.9% sodium chloride injection. AB - The stability of cefepime hydrochloride in 5% dextrose injection and 0.9% sodium chloride injection was studied using a stability-indicating assay method developed in our laboratory. This method is precise and accurate, with a percent relative standard deviation of 0.7% based on five readings. The admixtures were stable for two days at 25 deg C and 23 days at 5 deg C. The pH values of the admixtures did not change throughout this study, and the colors had changed from a very light yellow to a light yellow. The manufacturer recommends an expiry date of 24 hours at 20 to 25 deg C and seven days at 2 to 8 deg C. PMID- 23989440 TI - Short-term stability of atenolol in oral liquid formulations. AB - The objective of this study was to determine the stability of atenolol in extemporaneously compounded liquid formulations. Two sets of formulations were prepared using either pure atenolol powder or atenolol tablets. Vehicles used for preparation were simple syrup, a methylcellulose-based vehicle, Ora-Sweet, Ora Plus, and Ora-Sweet SF. The concentration of atenolol in the formulations was 2 mg/mL. Samples were collected at regular time intervals over a period of three months, and atenolol concentration was determined using a stability-indicating, high-performance liquid chromatography (HPLC) assay. All formulations were also visually observed for signs of settling. The HPLC results showed that all formulations prepared using the methylcellulose-based vehicle and Ora-Sweet SF were stable (ie, greater than 90% of atenolol remained unchanged) for more than 28 days. On the other hand, formulations prepared with simple syrup and Ora-Sweet were stable only for 14 days. Formulations prepared using simple syrup and Ora Sweet as vehicles were also placed at elevated temperatures in order to study the effect of temperature on the stability of atenolol. The concentration of atenolol that remained unchanged depended on the vehicle used and the temperature at which the formulations were stored. PMID- 23989441 TI - Stability of Clonazepam Suspension in HSC Vehicle. AB - The stability of clonazepam as an extemporaneous suspension compounded from tablets was studied. The clonazepam suspension (0.1 mg/mL) was prepared by incorporating pulverized 0.5-mg clonazepam tablets into the suspending Hospital for Sick children (HSC) Vehicle containing simple syrup and methylcellulose. This vehicle is also prepared extemporaneously. A clonazepam suspension and a clonazepam solution, both prepared in HSC Vehicle, were analyzed at various times during the 60-day study period against a clonazepam standard acetonitrile solutions stored in glass. These preparations using HSC Vehicle were stored at 4*C in a polyvinyl chloride (PVC) amber-colored plastic bottle. At various times during the 60 day study period, three samples from each bottle were removed and the concentration of clonazepam determined by a high-performance liquid chromatography assay procedure. This stability study demonstrates that storage of clonazepam suspension is safe for at least 60 days in a PVC bottle at 4*C, while the HSC solution rapidly loses the active ingredient by adsorption onto the plastic matrix due to the immediate availability towards the PVC. PMID- 23989442 TI - Feasibility and incremental benefit of puffed-cheek 18F-FDG PET/CT on oral cancer patients. AB - PURPOSE: The complexity of small oral cavity and intimate apposition of the oral cavity mucosal surfaces make CT identification of obvious masses difficult. Puffed-cheek CT improves the evaluation of oral cavity lesions. We used the puffed-cheek maneuver with 18F-FDG PET/CT scans to determine the feasibility and accuracy in clinical practice and to identify any benefits. PATIENTS AND METHODS: Twenty-two patients with oral cancer were included. They were instructed to perform the puffed-cheek maneuver after a conventional 18F-FDG PET/CT scan. Two physicians reviewed the puffed-cheek and conventional 18F-FDG PET/CT images and achieved consensus about the cancer extent, location, and dental artifacts before classifying and grading the oral cancers. Dichotomous results of localized or extended cancer and artifact grading scores from the puffed-cheek and conventional 18F-FDG PET/CT methods were compared using McNemar test and the Wilcoxon signed-rank test. P < 0.05 was considered significant. RESULTS: The puffed-cheek maneuver with 18F-FDG PET/CT was practical and had incremental benefits. The conventional 18F-FDG PET/CT classified 12 patients correctly as having localized or extended cancer, and the puffed-cheek 18F-FDG PET/CT classified 21 patients correctly. Puffed-cheek 18F-FDG PET/CT found a synchronous skip cancer and provided detailed cancer delineation. This method might reduce the effects of dental artifacts without undesirable muscular FDG uptake. CONCLUSIONS: Puffed-cheek PET/CT is feasible in the current clinical setting and can improve the delineation of oral cancer extent and location, with a potential benefit of reducing dental artifacts. PMID- 23989443 TI - Segmental hepatic concentration of 18F-FDG-labeled autologous leukocytes causing a "pseudo-lesion" on PET/CT in a patient with transient hepatic attenuation difference. AB - Labeled leukocyte scintigraphy has been described in the detection of infection in peripancreatic fluid collections in patients with acute pancreatitis. The authors describe a sectorial hepatic concentration of 18F-FDG-labeled autologous leukocytes forming a "pseudo-lesion" on PET/CT, matching the characteristic finding of transient hepatic attenuation difference on venous phase contrast enhanced computerized tomography. PMID- 23989444 TI - 111In-pentetreotide uptake in an ovarian teratoma and impact of SPECT/CT imaging. AB - We present a 19-year-old woman with a neuroendocrine tumor of the appendix diagnosed during an acute appendicitis. An 111In-pentetreotide scan was performed to establish the extension of the disease. Scintigraphy showed an abnormal focal uptake in the right side of the pelvis. The SPECT/CT images demonstrated a round shaped mass in the right ovary. Pathology revealed a benign cystic mature teratoma. In our case, hybrid imaging combining SPECT and CT contributed to localize the unusual 111In-pentetreotide accumulation within the anatomical context. PMID- 23989445 TI - Classic biphasic pulmonary blastoma demonstrated by 18F-FDG PET/CT. AB - A 75-year-old nonsmoker woman was referred for the evaluation of a nonsecretory left adrenal lesion. An abdominal contrast-enhanced CT showed an incidental left lower lobe mass, which was confirmed on a chest contrast-enhanced CT. A 18F-FDG PET/CT showed a hypermetabolic tumor without nodal or distant metastasis. She underwent a lobectomy, and the final pathology reported a classic biphasic pulmonary blastoma, which is an uncommon histological form of malignant lung neoplasm. This case highlighted the glucose avidity of this rare and aggressive cancer. PMID- 23989446 TI - The additional value of attenuation correction CT acquired during 18F-FDG PET/CT in differentiating mature from immature teratomas. AB - INTRODUCTION: Increased F-FDG uptake is often seen in soft-tissue components or in neuronal components of teratomas, which makes differentiation of mature and immature teratoma difficult using only F-FDG uptake. The distribution pattern of fat and calcification in teratomas is characteristic on CT, which can also be well seen on attenuation correction CT (AC-CT). We hypothesize that the fat and calcification distribution patterns on AC-CT taken during PET/CT will provide additional diagnostic information in differentiating between mature and immature teratomas. PATIENTS AND METHODS: This retrospective study included 34 patients (44 masses; mean age 32 +/- 16.3 years, range 0.2-70 years) who underwent F-FDG PET/CT before surgical resection for teratomas. F-FDG equal to or higher than the liver was visually considered positive. AC-CT images acquired during PET/CT were reviewed for calcification and fat distribution patterns. AC-CT findings for immature teratomas were scattered fat and/or disperse coarse calcification. Pathologic results were categorized into mature and immature teratomas. SUVmax and AC-CT findings were correlated with pathologic results. RESULTS: Out of the 44 lesions, 11 teratomas were immature, with higher F-FDG uptake in these tumors (7.8 +/- 4.10 vs. 2.1 +/- 2.28, P < 0.001). SUVmax higher than 2.8 were 91% accurate, but fat and/or calcification patterns on AC-CT were extremely helpful in reducing false-positive findings based on F-FDG uptake alone. CONCLUSION: Characteristic fat and calcification patterns on AC-CT of PET/CT were extremely helpful in differentiating mature from immature teratomas, especially in mature teratomas with increased F-FDG uptake. This can potentially reduce unnecessary radiation exposure from additional contrast-enhanced CT. PMID- 23989447 TI - 99mTc-sestamibi thigh SPECT/CT imaging for assessment of myopathy in cerebrotendinous xanthomatosis with histopathological and immunohistochemical correlation. AB - PURPOSE: The aim of this study was to determine the effectiveness of using Tc sestamibi thigh SPECT/CT imaging for evaluating myopathy in cerebrotendinous xanthomatosis (CTX). PATIENTS AND METHODS: Four genetically proven CTX patients (Family I, Cases I-1 and I-2; Family II, Cases II-1 and II-2) were included. They all underwent muscle biopsies for histopathologic and ultrastructural studies. Immunohistochemical staining for vinculin expression was also performed. Tc sestamibi thigh SPECT/CT imaging was conducted on all 4 CTX patients, and both visual interpretation and muscle-to-background (M/B) ratio count were applied for assessment. Correlation analysis of the imaging findings and results of the ultrastructural and immunohistochemical studies was done. RESULTS: In the Tc sestamibi thigh SPECT/CT imaging study, all 4 CTX cases had abnormal scores of visual interpretation and M/B ratios. The ultrastructural features of the skeletal muscle of the 4 CTX cases showed mitochondrial and membrane system abnormalities, with increased depositions of metabolites. They also had abnormal increases in vinculin expression after immunohistochemical staining of the skeletal muscle. CONCLUSIONS: This is the first report on the use of Tc-sestamibi thigh SPECT/CT imaging to assess the mitochondrial status of CTX. The imaging findings may have a correlation with the ultrastructural and immunohistochemical findings on skeletal muscle. Although the Tc-sestamibi thigh SPECT/CT imaging is not specific for CTX, this noninvasive in vivo assessment can be an important tool for the detection and follow-up study of skeletal muscle involvement in CTX. PMID- 23989448 TI - Comparison of coronary CT angiography and stress/rest myocardial perfusion SPECT imaging in a Chinese population. AB - INTRODUCTION: The relationship between luminal stenosis measured by coronary CT angiography and stress-induced ischemia by SPECT myocardial perfusion imaging is not clearly defined. The aims of this study were to evaluate the relationship between stenosis severity by coronary CT angiography and abnormal SPECT finding and to explore the impact of clinical factors on this relationship. PATIENTS AND METHODS: Seven hundred six consecutive patients with suspected coronary artery disease between January 2008 and October 2010 were prospectively enrolled. RESULTS: SPECT revealed 348 reversible and 58 fixed defects in 91 patients. Coronary CT angiography revealed that 339 patients had a maximal luminal stenosis 50% or greater. Total coronary artery calcium score was calculated in 428 patients, including 193 without calcification as well as 128 with mild, 59 with moderate, and 48 with severe-to-extensive calcification. Sensitivity, specificity, positive predictive value and negative predictive value (NPV) of coronary CT angiography for detecting abnormal SPECT finding were, respectively, 48.4%, 90.4%, 42.7%, and 92.2% on a patients' level and 40.2%, 95.6%, 33.6%, and 96.6% on vascular level when cutoff value of stenosis was set at 75%. Receiver operating characteristic analysis showed that the best cutoff value of stenosis for detecting abnormal SPECT finding was 55% on patients' level and 43% on vascular level. Patients with severe-to-extensive calcification had lowest specificity (56.3%) and NPV (69.2%). The sensitivity and positive predictive value of coronary CT angiography were not affected by any clinical factors (P = nonsignificant), whereas the specificity was higher in female patients, population younger than 60 years, and population without hypertension or family history of coronary artery disease (P < 0.05), and the NPV was higher among female patients and population without hypertension (P < 0.05). CONCLUSIONS: Coronary CT angiography has good agreement with stress/rest myocardial perfusion SPECT imaging. Coronary calcification and several clinical factors could affect the specificity and NPV of coronary CT angiography for detecting abnormal SPECT finding. PMID- 23989449 TI - ScFKBP12 bridges rapamycin and AtTOR in Arabidopsis. AB - FKBP12 encodes a prolyl isomerase and highly conserved in eukaryotic species. In yeasts and animals, FKBP12 can interact with rapamycin and FK506 to form rapamycin-FKBP12 and FK506-FKBP12 complex, respectively. In higher plants, FKBP12 protein lost its function to bind rapamycin and FK506. Early studies showed that yeast and human FKBP12 protein can restore the rapamycin sensitivity in Arabidopsis, but the used concentration is 100-1000 folds higher than that in yeast and animals. High concentration of drugs would increase the cost and cause the potential secondary effects on plant growth and development. Here we further discovered that BP12 plants generated in our previous study are hypersensitive to rapamycin at the concentration as low as that is effective in yeast and animals. It is surprising to observe that WT and BP12 plants are not sensitive to FK506 in normal growth condition. These findings advance the current understanding of rapamycin-TOR signaling in plants. PMID- 23989450 TI - Effect of sodium alginate on dextran sulfate sodium- and 2,4,6-trinitrobenzene sulfonic acid-induced experimental colitis in mice. AB - We evaluated the effects of sodium alginate (AL-Na) on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. DSS was added to the drinking water for 7 days. In another experiment, DSS was added to the drinking water for 5 days and DSS-free water was provided thereafter. In a separated study, colitis was induced by intrarectally administered TNBS. AL-Na, 5-aminosalicylic acid, or prednisolone was orally administered. These colitis models exhibited colonic damage and produced noticeable inflammatory responses and aggravated goblet cell damage. AL-Na significantly ameliorated DSS- and TNBS-induced experimental colitis and prevented goblet cell damage. Prednisolone also suppressed colitis but caused loss of body and spleen weight. In contrast, AL-Na did not provoke these symptoms. These data suggest that AL-Na may be a possible therapeutic agent for the treatment of inflammatory bowel disease. PMID- 23989451 TI - A real-time, fluorescence-based assay for measuring MU-opioid receptor modulation of adenylyl cyclase activity in Chinese hamster ovary cells. AB - Inhibition of adenylyl cyclase (AC) activity is frequently used to measure u opioid receptor (MOR) activation. We sought to develop a simple, rapid assay of AC activity in whole cells that could be used to study MOR signaling. Chinese hamster ovary cells expressing human MOR (CHO-MOR cells) were grown in 96-well plates and loaded with membrane potential-sensitive fluorescent dye. CHO-MOR cells were treated with the AC activator forskolin (FSK), with or without simultaneous application of MOR agonists, and the resulting change in fluorescence was measured. CHO-MOR cells hyperpolarized in response to application of FSK (pEC50, 7.3) or calcitonin (pEC50, 9.4). A submaximally effective concentration of FSK (300 nM) caused a 52% +/- 2% decrease in fluorescence. Simultaneous application of the opioids DAMGO (pEC50, 7.4; E(max), 56%), morphine (pEC50, 7.0; E(max), 61%); and buprenorphine (pEC50, 8.6; E(max), 24%) inhibited the FSK response in a dose-dependent manner while having no effect by themselves. The effects of DAMGO were blocked by pertussis toxin. This assay represents a simple, robust method for real-time observation of AC inhibition by MOR in CHO cells. It represents an appealing alternative to end-point assays that rely on cAMP accumulation and can avoid potential confounds associated with rapid desensitization of MOR signaling. PMID- 23989452 TI - Identification of Inhibitors of triacylglyceride accumulation in muscle cells: comparing HTS results from 1536-well plate-based and high-content platforms. AB - Excess caloric consumption leads to triacylglyceride (TAG) accumulation in tissues that do not typically store fat, such as skeletal muscle. This ectopic accumulation alters cells, contributing to the pathogenesis of metabolic syndrome, a major health problem worldwide. We developed a 1536-well assay to measure intracellular TAG accumulation in differentiating H9c2 myoblasts. For this assay, cells were incubated with oleic acid to stimulate TAG accumulation prior to adding compounds. We used Nile red as a fluorescent dye to quantify TAG content with a microplate reader. The cell nuclei were counterstained with DAPI nuclear stain to assess cell count and filter cytotoxic compounds. In parallel, we developed an image-based assay in H9c2 cells to measure lipid accumulation levels via high-content analysis, exploiting the dual-emission spectra characteristic of Nile red staining of neutral and phospholipids. Using both approaches, we successfully screened ~227,000 compounds from the National Institutes of Health library. The screening data from the plate reader and IC50 values correlated with that from the Opera QEHS cell imager. The 1536-well plate reader assay is a powerful high-throughout screening platform to identify potent inhibitors of TAG accumulation to better understand the molecular pathways involved in lipid metabolism that lead to lipotoxicity. PMID- 23989453 TI - A screening-based approach to circumvent tumor microenvironment-driven intrinsic resistance to BCR-ABL+ inhibitors in Ph+ acute lymphoblastic leukemia. AB - Signaling by the BCR-ABL fusion kinase drives Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Despite their clinical activity in many patients with CML, the BCR-ABL kinase inhibitors (BCR-ABL-KIs) imatinib, dasatinib, and nilotinib provide only transient leukemia reduction in patients with Ph+ ALL. While host-derived growth factors in the leukemia microenvironment have been invoked to explain this drug resistance, their relative contribution remains uncertain. Using genetically defined murine Ph+ ALL cells, we identified interleukin 7 (IL-7) as the dominant host factor that attenuates response to BCR-ABL-KIs. To identify potential combination drugs that could overcome this IL-7-dependent BCR-ABL-KI-resistant phenotype, we screened a small-molecule library including Food and Drug Administration-approved drugs. Among the validated hits, the well-tolerated antimalarial drug dihydroartemisinin (DHA) displayed potent activity in vitro and modest in vivo monotherapy activity against engineered murine BCR-ABL-KI resistant Ph+ ALL. Strikingly, cotreatment with DHA and dasatinib in vivo strongly reduced primary leukemia burden and improved long-term survival in a murine model that faithfully captures the BCR-ABL-KI-resistant phenotype of human Ph+ ALL. This cotreatment protocol durably cured 90% of treated animals, suggesting that this cell-based screening approach efficiently identified drugs that could be rapidly moved to human clinical testing. PMID- 23989454 TI - HIV cell fusion assay: phenotypic screening tool for the identification of HIV entry inhibitors via CXCR4. AB - The health and disease-related biology of the CXCR4 chemokine receptor presents the challenge of finding a small molecule that can bind CXCR4 and block T-cell tropic human immunodeficiency virus type 1 (HIV-1) cell entry, while preserving the ability of CXCR4 to respond to its native ligand, CXCL12. HIV entry into the host cell involves the interaction of the viral envelope glycoprotein gp120 binding to CD4, followed by a rearrangement in gp120, and subsequent interaction with the chemokine receptor CXCR4 or CCR5. These initial events can be re-created in a cell fusion assay that represents a surrogate system, mimicking the early stages of viral entry via these host cell receptors. In the current study, a T tropic HIV cell fusion assay was established using U2OS cells expressing the envelope glycoprotein gp160 from the T-tropic HIV NL4-3 and HeLa cells expressing CD4 and CXCR4. Detection of the cell fusion event was based on a Gal4/VP16 activated beta-lactamase signal and was measured by automated microscopy or laser scanning plate cytometry. Changes in morphology associated with cell fusion were combined with beta-lactamase activity to generate results with robust assay statistics in both 384-well and 1536-well plates. Compounds were subsequently characterized by CXCR4 signaling assays to eliminate functional antagonists and allow the identification of a function-sparing HIV entry inhibitor. PMID- 23989455 TI - Determining the relative efficacy of positive allosteric modulators of the GABAA receptor: design of a screening approach. AB - Gamma amino butyric acid receptors (GABA) are major therapeutic targets for the development of drugs in neurological and psychiatric disorders. The new generation of GABAA modulators is targeting subtype selectivity and low/partial efficacy on the receptor to potentially overcome the adverse effects described for drugs with full agonist profile. We evaluated a screening approach to measure the relative efficacy of GABAA positive allosteric modulators (PAM) using automated patch clamp and fluorescence membrane potential assays. We determined that the use of an internal comparator (zolpidem), tested on each cell in parallel to the test compound, provides a reliable approach to measure and compare the relative efficacy of PAM ligands. Patch clamp recordings on recombinant GABAA receptors, using a multiple drug addition protocol, allows us to rank PAM ligands with different levels of efficacies. We observed that fluorescence membrane potential assays are not predictive of the relative efficacies of GABAA PAM ligands. PMID- 23989456 TI - {110} Slip with {112} slip traces in bcc Tungsten. AB - While propagation of dislocations in body centered cubic metals at low temperature is understood in terms of elementary steps on {110} planes, slip traces correspond often with other crystallographic or non-crystallographic planes. In the past, characterization of slip was limited to post-mortem electron microscopy and slip trace analysis on the sample surface. Here with in-situ Laue diffraction experiments during micro-compression we demonstrate that when two {110} planes containing the same slip direction experience the same resolved shear stress, sharp slip traces are observed on a {112} plane. When however the {110} planes are slightly differently stressed, macroscopic strain is measured on the individual planes and collective cross-slip is used to fulfill mechanical boundary conditions, resulting in a zig-zag or broad slip trace on the sample surface. We anticipate that such dynamics can occur in polycrystalline metals due to local inhomogeneous stress distributions and can cause unusual slip transfer among grains. PMID- 23989457 TI - Relapsing papules on the antihelix of the left ear. Granuloma annulare (GA). PMID- 23989458 TI - Synthesis of saxitoxin derivatives bearing guanidine and urea groups at C13 and evaluation of their inhibitory activity on voltage-gated sodium channels. AB - Here, we describe the synthesis of the first C13-N-substituted STX derivatives 4, 5, and 6 bearing a guanidine, a urea group, and an acetamide, respectively, via the fully protected saxitoxinol derivative 8. These compounds are of interest because a previous docking study of saxitoxin (STX) with voltage-gated sodium channels (NaVCh) suggested that the C13 carbamoyl group of STX interacts with residue E403 in the pore region of NaVCh. In a cell-based assay with Neuro-2a cells, the NaVCh-inhibitory activities of 4 and 5 were more than 20- to 50-fold weaker than that of decarbamoyl-STX (3), which is 10-fold less potent than STX. On the other hand, 6 was 1000 times less potent than 3. The electrostatic analysis of C13 in STX and its analogs 4-6 using EON calculations suggested that the NaVCh-inhibitory activity of these derivatives is influenced by both the hydrophilicity and the charge balance of the substituent at C13. PMID- 23989459 TI - Dimerization of cyclopropenes to bifurans using tandem metal relay catalysis. AB - An efficient synthesis of bifurans via dimerization of cyclopropenes has been successfully developed using a copper-promoted cycloisomerization and palladium catalyzed dimerization cascade. These novel bifuran structures possess interesting optoelectronic properties. PMID- 23989460 TI - Provocative discography screening improves surgical outcome. AB - OBJECTIVE: The objective of this study was to compare the surgical outcomes of patients operated on, with or without discography prior to operation. METHODS: The study was designed as a randomized controlled trial, using power analysis with McNemar's test on two correlated proportions. The study comprised of 310 patients divided into trial (207) and control (103) groups. Inclusion criteria were low back pain resistant to nonsurgical treatment for more than 6 months and conventional radiological findings showing degenerative changes without a clear generator of pain. Exclusion criteria were red flags (tumor, trauma, and infection). After standard radiological diagnostic imaging (X-ray, CT, and MR), patients filled in the Oswestry Disability Index (ODI), SF-36, Zung, and MSP questionnaires. Depending on their radiological findings, patients were included and randomly placed in the trial or control group. At the 1-year follow-up examination, patients filled in the ODI, SF-36, and Likert scale questionnaires. RESULTS: The difference between preoperative and postoperative ODI in the control group degenerative disc disease (DDD) subgroup was 22.07 %. The difference between preoperative and postoperative ODI in the trial group DDD subgroup was 35.04 %. Differences between preoperative and postoperative ODI in the control group other indications subgroup was 26.13 %. Differences between preoperative and postoperative ODI in the trial group other indications subgroup was 28.42 %. CONCLUSIONS: DDD treated surgically without discography did not reach the clinically significant improvement of 15 ODI points for the patients treated with fusion. Provocative discography screening with psychological testing in the trial group made improvement following fusion clinically significant. PMID- 23989462 TI - Endovascular treatment with flow diverters may fail to occlude experimental bifurcation aneurysms. AB - INTRODUCTION: Animal models may explain how stents and flow diverters (FDs) may succeed or fail to treat bifurcation aneurysms. METHODS: In vitro studies were designed to anticipate device deformations in bifurcations. Large, wide-necked bifurcation aneurysms were constructed in 21 animals and treated 4-8 weeks later using stents and FDs in various combinations, forming four main groups: parent artery to right branch flow diversion (RBFD, n = 6), parent artery to left branch flow diversion (LBFD, n = 6), Y flow diversion (YFD, n = 4), and compared with high-porosity Y-stenting (YHPS, n = 4). The results include immediate and follow up angiography at 3 months, followed by grading of the extent of neointimal coverage of devices at pathology. RESULTS: In vitro, all braided devices showed varying porosities according to characteristic zones. FDs can be compacted to decrease porosities, but a limiting factor is the constant presence of a more porous transition zone. In vivo, 3/6 RBFD, 4/6 LBFD, and 2/4 YFD treated aneurysms had decreased in size by 3 months, while those treated with YHPS increased in size (P = 0.15). There was a significant correlation between device porosities and extent of neointimal coverage (r = 0.639, P = 0.002), and between porosities and angiographic evolution (r = -0.655, P = 0.002), but not between neointima formation and angiographic evolution (r = -0.278, P = 0.235). Failures could be explained in all cases by the presence of leaks or holes in the neointima at the level of the transition zones. CONCLUSION: FDs did not successfully treat most bifurcation aneurysms, at least in this animal model. PMID- 23989463 TI - A reply to the letter to the editor regarding "microstructural changes of the corticospinal tract in idiopathic normal pressure hydrocephalus: a comparison of diffusion tensor and diffusional kurtosis imaging". PMID- 23989464 TI - Can COPD patients who hyperinflate during daily life activities be identified by laboratory tests? AB - BACKGROUND: Identification of patients with chronic obstructive pulmonary disease (COPD) who develop dynamic hyperinflation (DH) during activities in daily life (ADL) is important, because of the association between DH and dyspnea and exercise limitation. OBJECTIVE: We aimed to answer the question whether measurements of DH during metronome-paced tachypnea (MPT) or cardiopulmonary exercise testing (CPET) can be used to identify patients who develop DH during ADL. METHODS: DH was measured by tracking changes in inspiratory capacity during CPET, MPT and ADL. Bland-Altman plots were used to evaluate agreement in DH between methods. With a receiver operating characteristic (ROC) analysis, the overall accuracy of MPT and CPET to identify patients who hyperinflate during ADL was assessed. RESULTS: There are broad limits of agreement in DH between methods. ROC curve analyses showed good overall accuracy of both CPET and MPT to identify patients who hyperinflate during ADL. For CPET, area under the curve (AUC) = 0.956 (95% CI 0.903-1.009). For MPT, AUC = 0.840 (95% CI 0.699-0.981). Sensitivity and specificity to identify patients who hyperinflate during ADL with CPET were 96 and 83%, respectively, and with MPT, they were 89 and 77%, respectively. CONCLUSION: Both CPET and MPT can serve as screening tools to identify patients who are susceptible to developing DH during ADL. In practice, MPT is the most simple and inexpensive surrogate. However, the sensitivity of MPT is not optimal. When DH does not occur during CPET, it is unlikely to occur during ADL. PMID- 23989465 TI - Editorial perspective: global surgery: measuring the impact. PMID- 23989466 TI - Early hard palate closure using a vomer flap in unilateral cleft lip and palate: effects on cleft width. AB - OBJECTIVES: Although no universal consensus exists on treatment of cleft palates, early hard palate closure is commonly performed. The aim of the present study was to determine the influence of a vomer flap for early hard palate closure on residual palatal cleft width in patients with a unilateral complete cleft lip and palate (UCLP). MATERIALS AND METHODS: Forty-seven UCLP patients were retrospectively divided into two groups. Group A consisted of 25 patients who underwent early lip closure and simultaneous hard palate closure using a vomer flap. Group B included 22 patients who had lip closure only at first surgery. Palatal cleft widths of both groups were measured at two time points and were compared using the Mann-Whitney U test to examine the influence of vomerplasty in this very early stage. RESULTS: No significant difference of baseline characteristics between the groups was found, and comparison of age at the time of surgeries was not significantly different. Mean age at the time of vomerplasty was 4.0 months. After the first surgery, a significantly greater total cleft width reduction of 5.0 mm average was found in group A compared to only 1.5 mm reduction in group B. This reduction took place after an average of 7.1 and 7.0 months, respectively. CONCLUSIONS: Lip closure accompanied by early hard palate closure using a vomer flap is associated with a significant postoperative reduction of the residual cleft when compared to lip closure only. CLINICAL RELEVANCE: This study shows another great advantage of performing early hard palate closure using a vomer flap. PMID- 23989467 TI - The outcome after surgical therapy of bisphosphonate-associated osteonecrosis of the jaw--results of a clinical case series with an average follow-up of 20 months. AB - OBJECTIVES: The present case series evaluates the success rate of osteotomy and primary wound closure in patients with bisphosphonate-associated osteonecrosis of the jaw (BRONJ). MATERIALS AND METHODS: Eighty patients suffering from BRONJ were included in the study. All patients received intravenous bisphosphonate therapy and underwent osteotomy and primary wound closure according to a standardised protocol. After discharge, the patients were reviewed on a regular basis over an average time period of 20 months. RESULTS: During follow-up in 11 patients, a recurrence of BRONJ occurred in the former operation field. Seventeen patients died due to their underlying disease. The success rate of osteotomy and primary wound closure in the treatment of BRONJ was calculated at 84.2 % 20 months after surgery. The results showed non-significant difference concerning the outcome of surgery in the different clinical stages of BRONJ. CONCLUSIONS: In accordance with previous studies, stage-independent osteotomy and primary wound closure combined with antibiotics shall be deemed a viable treatment option in patients suffering from BRONJ. CLINICAL RELEVANCE: With a high success rate, osteotomy in combination with primary wound closure seems to be a viable alternative to more conservative protocols in the treatment of BRONJ. PMID- 23989468 TI - Lability, solubility and speciation of Cd, Pb and Zn in alluvial soils of the River Trent catchment UK. AB - Alluvial soils can store a wide range of metal contaminants originating from point and diffuse sources. The biological health of these soils is important as they act as an interface between terrestrial and aquatic environments, therefore playing an important role in maintaining the quality of surface waters. The aim of this work was to examine the lability, solubility and bioavailability of Pb, Zn and Cd in the top (0-15 cm) and sub soil (35-50 cm) of metal contaminated alluvial soils from the Trent catchment, U.K. Samples (n = 46) were collected from within 10 m of the river bank. Sources of contamination include historical mining, industry, sewage treatment works and energy production. Enrichment factors based on total metal concentrations showed that contamination in soils declined with distance from the mining areas before rising again as a result of general urbanisation and identified point sources (e.g. river dredging activities). Pore waters were extracted and isotopic dilution and single extraction assays were undertaken on the soils to assess the lability and solubility of the metals. Multi-element isotopic dilution assays were used to determine the labile pool or E-value of these metals in the soil. E-value concentrations were found to range between 0.5 and 14 mg kg(-1), 11-350 mg kg(-1) and 25-594 mg kg(-1) for Cd, Pb and Zn, respectively. Comparison of the E-value assay with the EU standard extraction assay for trace element availability (0.05 M EDTA) showed that EDTA extractions generally over-estimated the E-value for Zn and Pb, with the difference being greater as contamination levels increased. Bioavailability of the metals was assessed by speciating the pore waters [MSol] using WHAM 7 to obtain estimates of free ion activities (M(2+)). Values of (M(2+)) were compared to published 'median critical limits' for soils that estimate levels of protection for 95% of biological species. For each of the three metals, (M(2+)) was found to exceed these critical limits at some sites. Solubility of the metals are reported using Kd values expressed using both the total and E-value as the solid phase. Finally we examine the use of different metal pools (total, E-value, EDTA-extractable) and different measures of Fe oxide pools (total, free total, free amorphous), in predicting [MSol] concentrations and (M(2+)) using WHAM 7 in assemblage modelling mode. Overall best simultaneous model predictions for the three metals were obtained using the E-values. Larger over-estimates of [MSol] and (M(2+)) were produced using the EDTA and total metal pools whereas a better fitting in the prediction was obtained when models used either the total or the free total FeOx pools. PMID- 23989469 TI - Task force: Evidence is lacking that screening for glaucoma in the general public leads to improved outcomes. PMID- 23989470 TI - [Bone transplantation with total hip endoprosthesis for diffuse pigmented villonodular synovitis]. AB - Pigmented villonodular synovitis (PVNS) is a rare benign but aggressive disease of the synovium. If the hip is involved early destruction of the joint is common due to the tight structure of the capsule and arthroplasty is unavoidable in these cases. We implanted a cemented total hip replacement in a 17-year-old female patient who had histologically confirmed PVNS. Because of massive bony destruction in the acetabulum a reconstruction with homologous bone (two femoral heads) from the bone bank was necessary. After 5 years the bone transplant had become integrated, there were no signs of recurrence and the patient was pain free with a normal joint function. There were no signs of loosening. PMID- 23989472 TI - [Clinical functional assessment of various surgical hand arthrodesis techniques]. AB - BACKGROUND: Total and partial arthrodesis of the wrist are currently sophisticated treatment options for many advanced pathological changes of the wrist. This retrospective study analyzed the subjective and objective outcome of different wrist arthrodesis techniques, e.g. total wrist arthrodesis, scaphotrapeziotrapezoid (STT) bone fusion and midcarpal arthrodesis. MATERIALS AND METHODS: Subjective physical and mental quality of life of 98 patients (total wrist arthrodesis n = 43, STT fusion n = 30 and midcarpal arthrodesis n = 25) was measured using the DASH questionnaire. The range of motion and grip strength were analyzed in 48 patients (total wrist arthrodesis n = 21, STT fusion n = 17 and midcarpal arthrodesis n = 10). RESULTS: Patients with partial wrist arthrodesis achieved a significantly better DASH score than patients with total wrist arthrodesis. Grip strength did not show any statistically significant differences between the two groups. Patients with STT fusion showed the best range of motion of the wrist. CONCLUSION: Partial arthrodesis seems to be superior to total wrist arthrodesis. Patients profit from a higher physical and mental quality of life. PMID- 23989471 TI - [Thromboembolic complications following ankle prosthesis implantation]. AB - BACKGROUND: Total ankle replacement is becoming an increasingly used treatment for patients with degenerative arthritis of the ankle; however, there is limited literature available addressing the incidence of thromboembolic complications after total ankle replacement. Therefore, we performed a systematic literature review addressing thrombosis prophylaxis and incidence of thromboembolic complications after total ankle replacement. Furthermore, we evaluated the incidence of thromboembolic complications in our clinic. METHODS: A systemic literature review was performed using established medical literature data bases. The following information was retrieved from the literature: thrombosis prophylaxis and duration and deep vein thrombosis/pulmonary embolism as postoperative complication. The incidence of thromboembolic complications was evaluated in our patient cohort including 964 total ankle replacement procedures. RESULTS: A total of 21 clinical studies were included in the systematic literature review. The range of incidence of thromboembolic complications was between 0.0 % and 4.8 %. In our patient cohort the incidence of symptomatic deep vein thrombosis was 3.4 %. There were no cases of pulmonary embolism. All patients received low molecular weight heparin prophylaxis. CONCLUSION: The incidence of thromboembolic complications in our patient cohort was comparable to that of symptomatic deep vein thrombosis in patients undergoing total knee or hip replacement or ankle fusion. We suggest the prophylactic use of low molecular weight heparin for patients after total ankle replacement. PMID- 23989473 TI - Induced pluripotent stem cells without c-Myc reduce airway responsiveness and allergic reaction in sensitized mice. AB - BACKGROUND: Allergic disorders have increased substantially in recent years. Asthma is characterized by airway damage and remodeling. Reprogramming induced pluripotent stem cells (iPSCs) from adult somatic cells transfected by Oct-4/Sox 2/Klf-4, but not c-Myc, has shown the potential of embryonic-like cells. These cells have potential for multilineage differentiation and provide a resource for stem cell-based utility. However, the therapeutic potential of iPSCs without c Myc (iPSC-w/o-c-Myc) in allergic diseases and airway hyperresponsiveness has not been investigated. The aim of this study was to evaluate the therapeutic effect of iPSC-w/o-c-Myc transplantation in a murine asthma model. METHODS: BALB/c mice were sensitized with alum-adsorbed ovalbumin (OVA) and then challenged with aerosolized OVA. Phosphate-buffered saline or iPSC-w/o-c-Myc was then intravenously injected after inhalation. Serum allergen-specific antibody levels, airway hyperresponsiveness, cytokine levels in spleen cells and bronchoalveolar lavage fluid (BALF), and cellular distribution in BALF were then examined. RESULTS: Treatment with iPSC-w/o-c-Myc effectively suppressed both Th1 and Th2 antibody responses, which was characterized by reduction in serum allergen specific IgE, IgG, IgG1, and IgG2a levels as well as in interleukin-5 and interferon-gamma levels in BALF and in OVA-incubated splenocytes. Meanwhile, regulatory cytokine, interleukin-10, was enhanced. Transplantation of iPSC-w/o-c Myc also significantly attenuated cellular infiltration in BALF and allergic airway hyperresponsiveness. However, no tumor formation was observed 6 months after transplantation. CONCLUSIONS: Administration of iPSC-w/o-c-Myc not only inhibited Th1 inflammatory responses but also had therapeutic effects on systemic allergic responses and airway hyperresponsiveness. iPSC-w/o-c-Myc transplantation may be a potential modality for treating allergic reactions and bronchial asthma. PMID- 23989474 TI - Neurological complication of non Hodgkin lymphoma in childhood: experience from a single center in Turkey. AB - PURPOSE: Lymphomas are the third most common childhood malignant disease after leukemia and central nervous system (CNS) tumors. Early diagnosis of these complications will reduce mortality and morbidity. In this study we aimed to review the neurological complications of childhood non Hodgkin Lymphoma (NHL). PATIENTS AND METHODS: Forty four children with NHL between 2006 and 2012 were investigated retrospectively and 14 cases with neurological complications were identified. RESULTS: The most common symptom was alteration of the consciousness (10 patients, 71.4 %) followed by convulsion (5 patients, 35.7 %), and hallucination (4 patients, 28.5 %); headache, eye pain, neurogenic bladder, speech disability and facial paralysis, and hemiplegia, were less common and each of them was seen in 1 (7.1 %) of the patients. The neurological complications were mostly seen in children with precursor T lymphoblastic lymphoma followed by anaplastic large cell lymphoma. The complications were secondary to medications (Eight patients) infection (two patients); CNS relapse (two patients); or CNS involvement of the primary disease (two patients). Chemotherapy-related neurologic complications were secondary to intrathecal methotrexate, L asparaginase, vincristine, and ifosfamide CONCLUSION: Advanced disease and PTLL subtype can be suggested as predictors of neurological complication. The survival rates of neurological complications are fairly good unless it is secondary to involvement of the primary disease. In patients with drug-induced neurological complications, the treatment can be safely re-administered after controlling the neurological complications. Therefore, clinicians managing children with NHL must be informative about neurological complications. PMID- 23989475 TI - The first total synthesis of the cyclodepsipeptide pipecolidepsin A. AB - Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered gamma-branched beta-hydroxy-alpha-amino acid D-allo-(2R,3R,4R)-2-amino-3 hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4 dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D allo-Thr and L-pipecolic acid. Here we describe the first total synthesis of a D allo-AHDMHA-containing peptide, pipecolidepsin A, thus allowing chemical structure validation of the natural product and providing a robust synthetic strategy to access other members of the relevant head-to-side-chain family in a straightforward manner. PMID- 23989476 TI - Unprecedented ortho-acylation of azoxybenzenes with alpha-oxocarboxylic acids by Pd-catalyzed C-H activation and decarboxylation. AB - A palladium-catalyzed ortho-acylation reaction of azoxybenzenes with alpha oxocarboxylic acids was developed in the presence of K2S2O8. The established methodology provides a direct approach to obtain acylated azoxybenzenes in good yields. PMID- 23989477 TI - Essential Truths about HRT. PMID- 23989478 TI - HRT and the Continuing Education of Health Care Professionals. PMID- 23989479 TI - Estrogen and Breast Cancer: Is there a Link? PMID- 23989480 TI - Estrogen in the treatment and prevention of Alzheimer's disease. PMID- 23989481 TI - The formulation and use of placebo dosage forms in pharmacy. PMID- 23989482 TI - Basic Statistical Concepts for Evaluating Pharmaceutical Compounding Lieterature, Part 2: Confidence Intervals and p Values. PMID- 23989483 TI - Extemporaneous lozenge formulations. PMID- 23989484 TI - The pH value of Urea Solutions in Purified Water. PMID- 23989485 TI - Physical compatibility and chemical stability of atracurium besylate and midazolam hydrochloride during intravenous coinfusion. AB - The objective of this study was to evaluate the physical stability and chemical compatibility of midazolam hydrochloride and atracurium besylate for intravenous coadministration at concentrations normally encountered in clinical practice. Commercially available midazolam hydrochloride injection (Versed) and atracurium besylate injection (Tracrium, Glaxo Wellcome) were used to prepare four different drug combinations in 5% dextrose injection. The final concentration of midazolam (as the hydrochloride salt) and of atracurium (as the besylate salt) was 0.1 or 0.5 mg/mL and or 5 mg/mL, respectively. The chemical stability of midazolam and atracurium in combination was evaluated using a stability-indicating high performance liquid chromatography assay, capable of simultaneous analysis of both compounds, developed in our laboratory Midazolam was detected using an ultraviolet detector and atracurium with a fluorescence detector. The analysis was done at room temperature under fluorescent lighting. All solutions were evaluated for physical stability by inspecting visually under normal fluorescent laboratory lighting for precipitate (against a black background) or gas formation and color change immediately following the admixture and then at one, two and three hours. The pH of these solutions was also measured at each time interval. Under the study conditions all test solutions retained greater than 90% of the initial concentration after three hours. There was no visible evidence of precipitation, color change, or gas formation in the test solution at any time following admixture; and the pH of the solutions was also unchanged during the three-hour study period. Midazolam hydrochloride and atracurium besylate are physicallly stable and chemically compatible for up to three hours at room temperature under normal fluorescent lighting at the concentrations used in this study and may be coinfused at a y-site without loss ofpotecncy. PMID- 23989486 TI - Ondansetron Suppositories: Extemporaneous Preparation, Drug Release, Stability and Flux through Rabbit Rectal Membrane. AB - The objective of this study was to determine the feasibility and develop a formulation for an extemporaneously prepared ondansetron suppository form Zofran 8-mg tablets. The stability of the formulation over 28 days of refrigerated storage and the initial and poststorage drug-release profiles were evaluated. The ondansetron flux in an in vitro model (a rabbit rectal membrane) from each formulation was determined. Suppositories containing 8 or 16 mg ondansetron were made using commercially available hydrophobic and hydrophilic suppository bases. A sensitive, stability-indication high-performance liquid chromatography assay was used for the analysis of ondansetron. The partition coefficient (octanol/water) of ondansetron and the displacement factor of tablets with each of the two bases were determined . The suppositories, formed in disposable molds, were kept in plastic wwrap and stored at 5 deg C in the refrigerator. The effect of storage on ondansetron release from the suppository base and the stability of ondansetron in the two suppository bases were evaluated over a period of 28 days. The dissolution study provided data on the release profile of the drug over 28 days, as well as the stabilty of the drug during the storage period. Ondansetron flux through rabbit rectal membrane from the various formulations was determined in vitro using modified Franz diffusion cells. Greater than 90% of the intiial amount (8 or 16 mg) of ondansetron was retained in the suppositories after 28-day storage at 5 deg C for both hydrophilic and hydrophobic formulations. There was no statistically siginificant difference in the drug-release profiles during this period. Ondansetron flux through the rabbit rectal membrane from 8- and 16-mg hydrophobic suppositories was 393 +/- 58 and 76.2 +/- 13.8 micrograms per centimeters squared -hour, respectively (n=6). The corresponding flux from 8- and 16-mg hydrophilic suppositories was 37.8 +/- 16 and 81.7 +/- 22.9 micrograms per centimeter squared - hour, respectively. The variablility in the flux required further study but the levels achieved indicated that extemporaneous preparation of ondansetron suppositories is reasonable using commercially available components. PMID- 23989487 TI - Stability of mechlorethamine hydrochloride 0.01% ointment in aquaphor base. AB - The purpose of this project was to evaluate the short-term shelf-life stability of an extemporaneously compounded mechlorethamine hydrochloride 0.01% topical ointment stored at room temperature. Mechlorethamine hydrochloreide injection 10 mg vials were reconstituted with 1 mL of dehydrated alcohol injection, USP, yielding a 10-mg/mL solution. One milliliter of the reconstituted liquid was incorporated by spatulation into 100 g of Aquaphor ointment base, yielding an ointment containing mechlorethamine hydrochloride 0.01%. The ointment was packaged in screw-cap ointment jars and stored at 23 deg C. Chemical stability was evaluated over a 90 day-period using derivatization and a stability indicating high-performance liquid chromatographic analytical method. Decomposition of the intact drug occurred at a mcuh slower rate than that observed in aqueous solutions. The loss appeared to be biphasic, occurring more rapidly during the first week and proceeding much more slowly thereafter. Mechlorethamine hydrochloride solubilized with dehydrated alcohol injection and incorporated into Aquaphor ointment base at a concentration of 0.01% lost 10% potency in seven days when stored at 23 deg C. PMID- 23989489 TI - Effects of physical fitness on relaxed G-tolerance and the exercise pressor response. AB - Fighter pilots are commonly recommended strength training as a means of improving the tolerance to withstand high gravitoinertial (G) loads. Previous studies on the effect of short-term strength-training regimens on G-endurance show equivocal results, with a majority of the studies suggesting improved G-endurance. The mechanisms underlying such improvement are unknown. Presumably, any change in G tolerance induced by physical training habits should be manifest following long term training. We also reasoned that during repeated straining maneuvers--as during certain G-endurance protocols--the relaxed G-tolerance and the exercise pressure response may play a significant role in maintaining adequate arterial pressure, and hence that different training modalities might alter G-endurance, by altering the exercise pressor response. Three groups of males were studied, long-term (>6 months) endurance-trained (E; n = 17), strength-trained (S; n = 16) and untrained (U; n = 17) individuals. The pressor response was studied during sustained (40 s) isometric knee extensions at 50 % of the maximal contraction level. Relaxed gradual onset-rate G-tolerance was determined. G-tolerance was similar in the E (4.6 +/- 0.5 G), S (4.9 +/- 0.8 G) and U (4.6 +/- 0.8 G) groups. The mean arterial pressure increase during isometric exercise was higher in the S (36 +/- 7 mmHg = mean +/- SD) and U (35 +/- 16 mmHg) groups than in the E group (28 +/- 8 mmHg). The results suggest that relaxed G-tolerance is unaffected by physical training habits, and that the training modality affects the magnitude of the exercise pressor response. However, it seems that the response is blunted by endurance training rather than enhanced by strength training. PMID- 23989490 TI - Intraparenchymal cyst development after deep brain stimulator placement. AB - Following deep brain stimulation (DBS) surgery, a variety of potential mechanical or functional complications ranging from perioperative events to hardware malfunction may occur. We present 2 patients who developed a unique complication of cyst formation at the tip of the DBS electrode in the absence of infection. One patient had a unilateral ventral intermediate lead placement for essential tremor, and the other had bilateral subthalamic nucleus (STN) placement for Parkinson's disease. After a period of symptom control, at 3 and 8 months after surgery, respectively, both patients developed new neurological deficits and were found to have a cyst at the left DBS lead tip. The right lead in the patient with the bilateral STN implant was without issue. Both affected leads were removed and the problematic symptoms regressed quickly over several days, though the lesion effect on the patients' initial tremor symptoms lasted for months. Bacteriological cultures of the removed electrodes and wounds were negative. We report a rare complication of DBS and show that simply removing the involved lead results in cyst resolution. PMID- 23989492 TI - beta-(Ethynylbenzoic acid)-substituted push-pull porphyrins: DSSC dyes prepared by a direct palladium-catalyzed alkynylation reaction. AB - The palladium-catalyzed oxidative alkynylation of beta-borylated porphyrins allows for concise preparation of push-pull structured ethynylbenzoic acid porphyrin derivatives. The resulting beta-singly- and doubly-substituted porphyrin dyes are regarded as isomeric derivatives of the corresponding meso substituted reference systems, and were found to give rise to nearly equal power conversion efficiencies when analyzed in DSSCs. PMID- 23989491 TI - Reduction-based iron uptake revisited: on the role of secreted iron-binding compounds. AB - With the exception of the grasses, plants rely on a reduction-based iron (Fe) uptake system that is compromised by high soil pH, leading to severe chlorosis and reduced yield in crop plants. We recently reported that iron deficiency triggers the production of secondary metabolites that are beneficial for Fe uptake in particular at high external pH when iron is present but not readily available. The exact function of these metabolites, however, remains enigmatic. Here, we speculate on the mechanism by which secondary metabolites secreted by roots from Fe-deficient plants improve Fe acquisition. We suggest that the production and excretion of Iron Binding Compounds (IBCs) constitute an integrative, pH-insensitive component of the reduction-based iron uptake strategy in plants. PMID- 23989493 TI - Discriminant analysis of functional optical topography for schizophrenia diagnosis. AB - Abnormal prefrontal function plays a central role in the cognition deficits of schizophrenic patients; however, the character of the relationship between discriminant analysis and prefrontal activation remains undetermined. Recently, evidence of low prefrontal cortex (PFC) activation in individuals with schizophrenia has also been found during verbal fluency tests (VFT) and other cognitive tests with several neuroimaging methods. The purpose of this study is to assess the hemodynamic changes of the PFC and discriminant analysis between schizophrenia patients and healthy controls during VFT task by utilizing functional optical topography. A total of 99 subjects including 53 schizophrenic patients and 46 age- and gender-matched healthy controls were studied. The results showed that the healthy group had larger activation in the right and left PFC than in the middle PFC. Besides, the schizophrenic group showed weaker task performance and lower activation in the whole PFC than the healthy group. The result of the discriminant analysis showed a significant difference with P value<0.001 in six channels (CH 23, 29, 31, 40, 42, 52) between the schizophrenic and healthy groups. Finally, 68.69% and 71.72% of subjects are correctly classified as being schizophrenic or healthy with all 52 channels and six significantly different channels, respectively. Our findings suggest that the left PFC can be a feature region for discriminant analysis of schizophrenic diagnosis. PMID- 23989494 TI - Biogeography revealed by mariner-like transposable element sequences via a Bayesian coalescent approach. AB - Genetic diversity of natural populations is useful in biogeographical studies. Here, we apply a Bayesian method based on the coalescent model to dating biogeographical events by using published DNA sequences of wild silkworms, Bombyx mandarina, and the domesticated model organisms B. mori, both of which categorized into the order of Lepidoptera, sampled from China, Korea, and Japan. The sequences consist of the BmTNML locus and the flanking intergenic regions. The BmTNML locus is composed of cecropia-type mariner-like element (MLE) with inverted terminal repeats, and three different transposable elements (TE), including L1BM, BMC1 retrotransposons, and BmamaT1, are inserted into the MLE. Based on the genealogy defined by TE insertions/deletions (indels), we estimated times to the most recent common ancestor and these indels events using the flanking, MLE, and indels sequences, respectively. These estimates by using MLE sequences strongly correlated with those by using flanking sequences, implying that cecropia-type MLEs can be used as a molecular clock. MLEs are thought to have transmitted horizontally among different species. By using a pair of published cecropia-type MLE sequences from lepidopteran insect, an emperor moth, and a coral in Ryukyu Islands, we demonstrated dating of horizontal transmission between species which are distantly related but inhabiting geographically close region. PMID- 23989495 TI - Endoscopic third ventriculostomy: can we predict success during surgery? AB - Endoscopic third ventriculostomy (ETV) is widely used as an alternative technique for hydrocephalus treatment. ETV success or failure may be influenced by numerous factors. In this study, we have analyzed preoperative and intraoperative risk factors and suggest an intraoperative scale to predict etV failure. Fifty-one patients (27 adults and 24 children) underwent an etV at Carlos Haya University Hospital, Malaga. Intraoperative video records were assessed and the following intraoperative findings were recorded: (1) abnormal ventricular anatomy, (2) intraoperative incident, (3) Liliequist membrane opening in a second endoscopic maneuver, (4) thickened or scarred membranes in the subarachnoid space, (5) absence or "weakness" of pulsation of third ventricle floor at etV completion, and (6) floppy premammillary membrane that needs edge coagulation. An intraoperative scale ranging from 0 to 6 points was performed. A significant relation was found between a higher result on the prognosis scale and etV failure (p < 0.0001). An absence or weakness of pulsation of the third ventricle floor at etV completion was significantly related to etV failure (p < 0.0001). The presence of thickened or scarred membranes in the subarachnoid space was significantly related to etV failure (p < 0.04) as well as the Liliequist membrane opening in a second endoscopic maneuver (p < 0.008). Intraoperative factors should be taken into account for prediction of etV success. More studies with larger case series are needed to determine the influence of all intraoperative factors over etV success. PMID- 23989496 TI - Alkaloid inspired spirocyclic oxindoles from 1,3-dipolar cycloaddition of pyridinium ylides. AB - Cycloaddition reactions between pyridinium ylides and 3-alkenyl oxindoles that proceed in high yield and with very good regio- and diastereoselectivity are reported. The resulting cycloadducts have the same stereochemistry of biologically active oxindole alkaloids, such as strychnofoline. PMID- 23989498 TI - Multimodal exercise training during myeloablative chemotherapy: a prospective randomized pilot trial. AB - PURPOSE: Cancer and its treatment-related side effects induce loss of physical performance. This study evaluated the effects of multimodal aerobic and strength exercises on physical performance in hospitalized cancer patients while receiving myeloablative chemotherapy. METHODS: In this prospective pilot study, 48 evaluable patients were randomly assigned to a training (TG, n = 24) or control (CG, n = 24) group. The TG performed an individually supervised exercise program five times a week with ergometer training and strength exercises for 20 min each during the hospitalization period for chemotherapy. The CG received standard physiotherapy. Physical performance was evaluated using spiroergometry, lung function, and muscle strength testing. Treatment-related side effects were assessed by daily interviews, quality of life by EORTC-QLQ-C30, and fatigue using the Modified Fatigue Impact Scale (MFIS) questionnaire. RESULTS: Physical performance significantly increased in the TG (8.96 +/- 24 W) and decreased in the CG (-7.24 +/- 20 W, p = 0.02). At 2-mmol/ml blood lactate concentration, the TG achieved significantly increased oxygen consumption (p = 0.03) and expiratory minute ventilation (p = 0.04) compared to the CG. Furthermore, physical functioning increased significantly in the TG (p = 0.04). Patients in the TG required less antiemetics (p = 0.01) and experienced significantly less fatigue (p = 0.04), although MFIS analysis was not able to detect this beneficial effect. Patients of the CG displayed higher impairments of cognitive (p = 0.02) and psychosocial function (p = 0.03) after chemotherapy. No adverse events due to the study intervention were observed. CONCLUSIONS: Multimodal exercise has beneficial effects on physical performance, physical functioning, and treatment-related symptoms even during myeloablative chemotherapy. We suggest an enhanced physical activity intervention program during hospitalization of cancer patients. PMID- 23989499 TI - Together and apart: providing psychosocial support for patients and families living with brain tumors. AB - PURPOSE: Brain tumors are associated with neurological sequelae and poor survival, contributing to distress in patients and their families. Our institution has conducted separate support groups for brain tumor patients and caregivers since 1999. This retrospective cohort study aimed to identify characteristics of brain tumor group participants in relation to attendance frequency, and compare themes of discussion in patient and caregiver groups. METHODS: Demographic and medical characteristics were obtained from patient and caregiver group registration sheets and medical chart review. We quantified discussion topics recorded by group facilitators between 1999 and 2006, extracted themes, and examined similarities and differences in the way these themes were expressed. RESULTS: A total of 137 patients and 238 caregivers attended the groups; about half attended more than one session. The chart review of a randomly selected subset of patient participants revealed that 57.5 % were married, 58.8 % had high-grade gliomas, and 55 % attended their first group within 3 months of diagnosis or at tumor progression. Both groups discussed physical and cognitive consequences, emotional reactions, relationships, coping, end of life, and practical issues. Caregivers discussed difficulties achieving self-care and caregiver burden. CONCLUSIONS: Brain tumor support group facilitators can expect to encounter a range of medical and psychosocial issues in accommodating patients' and caregivers' diverse concerns. Separate brain tumor patient and caregiver groups may allow participants to explore those concerns without worrying about effects on their friends or family. It remains to be seen whether the groups meet the needs of attendees, and whether those who do not attend the groups have unmet needs. PMID- 23989501 TI - The use of microwaves ablation in the treatment of epiphyseal osteoid osteomas. AB - OBJECTIVE: This study was designed to demonstrate the feasibility and the reliability of microwave ablation (MWA) of epiphyseal osteoid osteomas (OO). MATERIALS AND METHODS: From February to November 2012, 7 patients (4 males and 3 females; age range 16-30 years) with epiphyseal OOs were treated with MWA. The treatment was performed with 16 G antennas with a power of 20 W for 2 min. The OOs were approached by using coaxial needles inserted with hammer or with automatic drill. All patients underwent spinal anaesthesia, with posttreatment 6 8 h observation before discharging. We treated epiphyseal OOs placed away from nervous and vascular nontarget structures, located in: femoral head (n = 2), femoral lesser trochanter (n = 2), femoral neck (n = 2), and proximal tibial epiphysis (n = 1). CT was used to visualize the nidus and to insert the needle for thermal ablation and for postprocedure control. Technical success was considered the positioning of the antenna in the nidus, while the efficacy of treatment was clinically evaluated as the complete remission of pain after the procedure by using the visual analogue score (VAS). Follow-up was performed by using VAS score 1 day, 1 week, and 1, 3, and 6 months after the procedure, whereas MRI examination was performed immediately after the procedure, at 1 month, and in any case of recurrence. Complications were also recorded. RESULTS: All patients experienced resolution of the symptomatology (VAS = 0) in ~1 week until the last follow-up, with residual VAS < 2 points occurring only from 1 to 7 days after the procedure. No intraprocedural complication was noted, whereas one patient had back pain for 2 months after the procedure, likely due to spinal analgesic injection. CONCLUSIONS: In our experience, MWA can be safely performed with excellent results without complications in selected cases of epiphyseal OOs; however, the clinical significance of this report is limited because there were only few patients included in this study. Thus, these data must be confirmed by further and larger studies. PMID- 23989500 TI - Individual and dyadic development of personal growth in couples coping with cancer. AB - RATIONALE: Couples share distress as well as potential personal growth (PG) after a cancer diagnosis. It is essential for professionals to learn more about the ways couples cope together with adversity. Dyadic results may help to understand controversial results in the PG literature and inform clinicians in optimizing psychological support for couples. OBJECTIVE: We examine the temporal and dyadic development of PG among patients and their intimate partners. In addition, life threat is examined as a potential factor influencing PG after cancer diagnosis. METHODS: We assessed PG using the Personal Growth Inventory in a clinically representative, mixed-type and mixed-stage cancer cohort (N = 154 couples) 6 and 12 months after cancer diagnosis. Medical data on cancer diagnoses and treatments were collected from physicians. Actor-partner interdependence models were applied. RESULTS: PG was reported by patients and their partners. Women (either as patients or partners) reported more PG than male patients or partners. PG remained relatively stable over 6 months and was related to whether the patient was receiving curative or palliative treatment. Female patients experienced less PG 6 months after the cancer diagnosis and if treatment was curative. Male patients experienced less PG if their partners experienced PG, and the treatment was curative. CONCLUSIONS: Dyadic growth is a phenomenon not limited to breast cancer or female patient couples and may represent a form of dyadic coping. Patients and partners seem to develop individual and dyadic growth, depending on a combination of gender and life threat. Psycho-oncology services may want to promote both couple level coping and support in order to optimize cancer care. PMID- 23989502 TI - Anomalous unilateral single pulmonary vein mimicking pulmonary arteriovenous malformation. AB - Anomalies involving the pulmonary vein are so rare that most of them have been reported as a case or a series of several cases. Some of them often simulate pulmonary arteriovenous malformation (AVM), and patients undergo pulmonary angiography for embolization. Herein we report a case of anomalous unilateral single pulmonary vein that was confirmed on pulmonary angiography after initial diagnosis of pulmonary AVM on contrast medium-enhanced chest computed tomography. PMID- 23989503 TI - Minimally invasive ablation treatment for locally advanced pancreatic adenocarcinoma. AB - Pancreatic adenocarcinoma is an aggressive tumour with an extremely poor prognosis, which has not changed significantly during the last 30 years. Prolonged survival is achieved only by R0 resection with macroscopic tumour clearance. However, the majority of the cases are considered inoperable at diagnosis due to local spread or presence of metastatic disease. Chemoradiotherapy is not tolerated by all patients and still fails to prolong survival significantly; neoadjuvant treatment also has limited results on pain control or tumour downstaging. In recent years, there has been a growing interest in the use of ablation therapy for the treatment of nonresectable tumours in various organs. Ablation techniques are based on direct application of chemical, thermal, or electrical energy to a tumour, which leads to cellular necrosis. With ablation, tumour cytoreduction, local control, and relief from symptoms are obtained in the majority of the patients. Inoperable cases of pancreatic adenocarcinoma have been treated by various ablation techniques in the last few years with promising results. The purpose of this review is to present the current status of local ablative therapies in the treatment of pancreatic adenocarcinoma and to investigate on the efficiency and the future trends. PMID- 23989504 TI - Magnetoresistive emulsion analyzer. AB - We realize a magnetoresistive emulsion analyzer capable of detection, multiparametric analysis and sorting of ferrofluid-containing nanoliter-droplets. The operation of the device in a cytometric mode provides high throughput and quantitative information about the dimensions and magnetic content of the emulsion. Our method offers important complementarity to conventional optical approaches involving ferrofluids, and paves the way to the development of novel compact tools for diagnostics and nanomedicine including drug design and screening. PMID- 23989506 TI - Compounding for pain management. PMID- 23989505 TI - A randomized clinical trial to evaluate the impact of a dental care program in the quality of life of head and neck cancer patients. AB - OBJECTIVES: A randomized clinical trial (RCT) to evaluate the impact of dental care program on the quality of life (QOL) of head and neck cancer patients under oncological treatment. MATERIALS AND METHODS: The study design was a parallel RCT where 46 subjects with a diagnosis of head and neck primary neoplasy were randomly allocated to the control (CG) or test group (TG). Both groups received basic dental care but the TG received a complimentary care before and during, oncological therapy. Data related to general (WHOQOL-BREF) and specific (EORTC QLQ H&N 35) QOL were assessed before and 15 days after the conclusion of the oncological therapy. RESULTS: The TG showed an improvement in the general and specific QOL, while the CG showed a worsening in these indexes but without significant difference. The variation between the initial and final measures in the TG shows a tendency of significant improvement along the time. A reduction in candidiasis (p < 0.05) and muccositis was observed in the TG. CONCLUSION: In a short follow-up period, dental care was able to reduce damage from the oncological therapy especially related to muccositis and candidiasis, although the QOL was not significantly improved. However, a longer follow-up to measure the late side effects over the QOL of these patients is necessary. CLINICAL RELEVANCE: Provision of continuous dental care for head and neck cancer patients can reduce deleterious side effects of the oncological treatment. PMID- 23989507 TI - Opioids for noncancer pain; from controversy to consensus. PMID- 23989508 TI - Phonophoresis with hydrocortisone 10% in a highly viscous complant base. PMID- 23989509 TI - Managing pain in the terminally ill. PMID- 23989510 TI - The symptom relief kit for hospice patients. PMID- 23989511 TI - Dextromethorphan hydrobromide and opioid tolerance: a compounding opportunity for pharmacists with chronic pain patients. PMID- 23989512 TI - Clinical application of ketamine ointment in the treatment of sympathetically maintained pain. AB - The objective of this study was to determine the clinical efficacy of topical ketamine in relieving sympathectically maintained pain, including complex regional pain syndrome types I and II, involving the upper and/or lower extremities. In an open clinical pilot study of five referral patients diagnosed with sympathetically maintained pain who were unresponsive to conventional modalities, a single dose of topical ketamine was administered. Age, gender, duration or degree of disease and concurrent medication were not controlled. Ketamine was prepared for transdermal delivery in pluronic lethicin organogel (PLO) in calibrated applicators. Concentrations ranged from 10 to '50 mg/mL. Dosage ranged from 10 mg to 700 mg per single application. Each dosage was deternined clinically based on location and suface area of involvement. Pain intensity was measured using a validated mumeric analogue scale (NAS). Ketamine in PLO applied to the uper and/or lower extremities with sympathetically maintained pain resulted in significant pain reduction relative to pretreatment NAS of 65% to 100% . Initial response was within 20 seconds to three minutes, with NAS rating 15 minutes postapplication. No reported side effect occurred on patient follow-up at 24 and 48 hours. Single-dose, topical application of ketamine in PLO (patent pending) appears clinically effective in relieving sympathetically maintained pain of the extremities without apparent side effects. Further controlled studies are warranted to define patient selection, optimize dosage and validate the prominent analgesic effects obtained in this heretofore difficult-to-treat pain syndrome. This was an independent study in joint cooperation with representatives from the Univesity of California at Irvine, Loma Linda University Medical Center and private practice. PMID- 23989513 TI - Problems with third-party payments for compounded prescriptions. PMID- 23989514 TI - The pH Value of Common Household Products Using Meters, Papers and Sticks. PMID- 23989515 TI - Accuracy in prescriptions compounded by pharmacy students. AB - Most compounded prescriptions are not analyzed to determine the accuracy of the employed instruments and procedures. The assumption is that the compounded prescription will be +/- 5% the labeled claim. Two classes of School of Pharmcacy students who received repeated instruction and supervision on proper compounding techniques and procedures were assessed to determine their accuracy of compounding a diphenhydramine hydrochloride prescription. After two attempts, only 62% to 68% of the students could compound the prescription within +/- 5% the labeled claim; but 84% to 96% could attain an accuracy of +/- 10%. The results suggest that an accuracy of +/- 10% labeled claim is the least variation a pharmacist can expect when extemporaneously compounding prescriptions. PMID- 23989516 TI - Vehicles for compounding oral liquids: some practical considerations. PMID- 23989517 TI - Stability of indomethacin in 0.9% sodium chloride injection. AB - The stability of indomethacin (from indomethacin sodium trihydrate powder for injection) in preservative-free 0.9% sodium chloride injection has been studied using a stability-indicating high-performance liquid chromatography assay method. The method described is precise and accurate, with a percent relative standard deviation of 0.7% based on five readings. The 0.1-mg/mL solutions were stable for at least ten days when stored at roomtemperature in 10-mL plastic vials in which the sodium chloride injections are marketed. The solutions remained clear throughout the study;and pH values did increase by about 0.5 units, since the admixtures were not buffered. PMID- 23989518 TI - Stability of Milrinone Lactate 200 micrograms/mL in 5% Dextrose Injection and 0.9% Sodium Chloride Injection. AB - The stability of milrinone lactate 200 microgram/mL in either 5% dextrose injection or 0.9% sodium chloride injection was studied. The solutions were prepared in polyvinyl chloride bags and aliquots of 10 mL were withdrawn at times zero, one, three, seven and 14 days at room (20 to 25 deg C) and refrigerated (2 to 8 deg C) temperatures. The samples were then stored at -20 deg C and analyzed for potency using a stability-indicating high-performance liquid chromatography assay procedure. Stability was defined as 90% or greater of the original concentration remaining. Samples were inspected visually and no color change, haziness or precipitation was observed at any time during the study. Milrinone lactate 200 micrograms/mL mixed in either 5% dextrose injection or 0.9% sodium chloride injection is stable at room or refrigerated temperatures for 14 days. PMID- 23989519 TI - Palatability and chemical safety of apple juice fortified with pomegranate peel extract. AB - Pomegranate peel extract (PPE), a by-product of the pomegranate juice industry with potential health effects, was explored for use to fortify reconstituted apple juice in the concentration range 0.5 to 2.0% (w/w). Radical scavenging and antioxidative capacities of the fortified apple juices were evaluated using (i) electron spin resonance (ESR) to quantify their ability to scavenge the stable radical Fremy's salt and (ii) the Trolox equivalent antioxidant capacity (TEAC) assay and compared to apple juice without fortification as control. The highest antioxidative capacity was found in the apple juice fortified with the highest percentage of pomegranate peel extract, while the optimal sensory quality was found by addition of 0.5 g PPE per 100 mL. The Artemia salina assay was used as a fast screening method for evaluating overall toxicity, and showed little toxicity with up to 1.0 g per 100 mL addition of PPE, but increasing toxicity at higher concentrations. Accordingly, it is important to balance addition of PPE, when used for enrichment of apple juice in order to obtain a healthier product, without compromising the sensorial quality or toxicological safety of the apple juice. Concentrations between 0.5 and 1.0 g PPE per 100 mL seem to be acceptable. PMID- 23989520 TI - Microwave magnetoelectric effect via skyrmion resonance modes in a helimagnetic multiferroic. AB - Magnetic skyrmion, a topologically stable spin-swirling object, can host emergent electromagnetism, as exemplified by the topological Hall effect and electric current-driven skyrmion motion. To achieve efficient manipulation of nano-sized functional spin textures, it is imperative to exploit the resonant motion of skyrmions, analogously to the role of the ferromagnetic resonance in spintronics. The magnetic resonance of skyrmions has recently been detected with oscillating magnetic fields at 1-2 GHz, launching a search for new skyrmion functionality operating at microwave frequencies. Here we show a microwave magnetoelectric effect in resonant skyrmion dynamics. Through microwave transmittance spectroscopy on the skyrmion-hosting multiferroic crystal Cu2OSeO3 combined with theoretical simulations, we reveal nonreciprocal directional dichroism (NDD) at the resonant mode, that is, oppositely propagating microwaves exhibit different absorption. The microscopic mechanism of the present NDD is not associated with the conventional Faraday effect but with the skyrmion magnetoelectric resonance instead, suggesting a conceptually new microwave functionality. PMID- 23989521 TI - Hedgehog signal inhibitors suppress the invasion of human rhabdomyosarcoma cells. AB - PURPOSE: In the treatment of rhabdomyosarcoma (RMS), invasion and metastasis remain the most critical determinants of resectability and survival. The objective of this study was to determine whether Hedgehog (Hh) signaling plays a role in the invasion of RMS. METHODS: Two kinds of specific Hh signaling inhibitors, cyclopamine and forskolin, were used to suppress activated Hh signals in three RMS cell lines. The effects of the Hh signaling inhibitors on tumor cell invasion and motility were investigated using Matrigel invasion assays and wound closure assays, respectively. RESULTS: The number of invaded cells counted in six random microscopic fields in the Matrigel chambers was significantly decreased by both cyclopamine and forskolin in every RMS cell line. Furthermore, the wound closure assays revealed that a blockade of the Hh signaling pathway by the Hh inhibitors strongly impairs RMS cell motility, as visualized by the delayed closure of the gaps generated in the cultured cell monolayers of the three RMS cell lines. CONCLUSIONS: Both the invasive capacity and motility of RMS cells are significantly suppressed by Hh signaling inhibitors, demonstrating that the Hh pathway plays an important role in the invasion of RMS. Hh inhibitors may provide a new paradigm for the treatment of RMS. PMID- 23989522 TI - Multicenter randomized trial of postoperative corticosteroid therapy for biliary atresia. AB - PURPOSE: We aimed to evaluate early response to two different corticosteroids doses after Kasai portoenterostomy for biliary atresia (BA). METHODS: A prospective, randomized trial was performed in infants from the nationwide BA registry with type 3 BA. Sixty-nine infants were randomized to receive either 4 mg/kg/day (group A, n = 35) or 2 mg/kg/day prednisolone (group B, n = 34). The corticosteroids were started on postoperative day 7, and the dose was tapered toward day 30. Results of liver function tests on days 31 and 60 were compared between the groups. RESULTS: Mean bilirubin, AST, ALT, and GGT levels did not significantly differ between the groups. However, the levels of total and direct bilirubin of infants <70 days old at surgery significantly differed between the groups. Four patients from group A and five from group B, dropped out of the study. Complications during the first month after PE were comparable between the groups. CONCLUSIONS: An initial 4 mg/kg/day dose did not significantly improve liver function, except that bilirubin levels were lower in the subgroup of infants <70 days old at surgery. There were no significant complications with either dose of corticosteroids. PMID- 23989523 TI - Complex vascular anomalies. AB - The classification system for vascular anomalies now used by experts worldwide comprises two distinct disease entities that differ in their biologic and pathologic features: vascular tumors and vascular malformations. Vascular tumors include infantile and congenital hemangiomas, tufted angiomas, and kaposiform hemangioendotheliomas. Infantile hemangiomas, the most common vascular anomaly, generally have a predetermined life cycle (proliferation and subsequent involution). GLUT-1, a glucose transporter, is a marker for these specific lesions during all phases of development. Vascular malformations are classified according to their vascular tissue of origin and include capillary, venous, arteriovenous, lymphatic, and mixed malformations. Complex lymphatic malformations and complex mixed malformations, which may have most vascular components, are the most difficult vascular malformations to successfully treat. These lesions are present at birth and often expand or grow in response to trauma, infection, or hormonal changes. Imaging advancements have enabled more accurate assessments and improved management of vascular anomalies. In addition, many lesions are now being managed with targeted pharmacologic therapy. Propranolol and steroids are used for complex or disfiguring tumors, and new anti angiogenesis inhibitors such as sirolimus are selectively used to treat lymphatic and venous lymphatic malformations that are poorly responsive to sclerotherapy, embolization, and surgical excision. Multimodal therapies are often essential for complex lesions and require the combined expertise of an interdisciplinary team. PMID- 23989524 TI - Optimal surgical treatment and urological outcomes in boys with pelvic and urogenital rhabdomyosarcomas and soft tissue sarcomas. AB - BACKGROUND: Soft tissue sarcomas (STS) of pelvic origin in boys often involve the urogenital organs. The optimal extensiveness of radical surgery has long been an issue of discussion, since exenterative surgeries result in severe urogenital adverse effects. We conducted a retrospective review of patients with pelvic STS treated in two regional center hospitals and assessed the radicality of surgery and the functional outcome of the bladder. PATIENTS: Medical records and surgical reports of nine cases (embryonal rhabdomyosarcoma 6, malignant triton tumor 2, suspected rhabdomyosarcoma 1) treated within 1997-2012 were reviewed. Site of origin was prostate in seven, retroperitoneal in two. Average follow-up period was 96 months. TREATMENT AND OUTCOME: All cases were subjected to neoadjuvant chemotherapy. Response was PR in four, SD in two, and PD in two. Radical surgery resulted in gross total resection in eight, and partial resection in one. Three underwent cystoprostatectomy, two cases underwent prostatectomy, and bladder preserving tumor resection was carried out in four cases. At the last follow-up, three retained a functional bladder. Two required augmentation cystoplasty with intestinal conduits. CONCLUSIONS: The majority of the on-going clinical trials recommend conservative surgery for bladder/prostate rhabdomyosarcoma, and to preserve the bladder function particularly in chemosensitive tumors. Some other groups, however, advocate the importance of radical surgery to prevent local relapse. These reports include heterogenous group of patients in the cohort, and therefore it is difficult to draw a conclusion of which approach truly contributes to the survival of the patients better. Future studies should evaluate bladder and sexual function objectively to establish reliable evidence regarding the benefit and adverse effects of different surgical approaches. These data would be informative to optimize the treatment balance for children with pelvic rhabdomyosarcomas. PMID- 23989525 TI - The role of minimally invasive surgery in pediatric trauma: a collective review. AB - Although minimally invasive surgery (MIS) has been utilized in selective trauma patients, there a relative paucity of literature on its role in both blunt and penetrating trauma in the pediatric population. Our purpose is to review the current literature on the role of MIS in abdominal and thoracic pediatric trauma. A review of the literature, indications, risks, and benefits of MIS in trauma will be presented. Relevant literature was obtained from use of the PubMed database. PMID- 23989526 TI - Novel therapies for the management of short bowel syndrome in children. AB - Short bowel syndrome (SBS) is the most common cause of intestinal failure in children. It is defined as the inability to maintain adequate nutrition enterally as a result of a major loss of the small intestine. SBS is a life-threatening entity associated with potential significant morbidity and mortality. The etiology in the pediatric age group includes necrotizing enterocolitis (32%), atresia (20%), volvulus (18%), gastroschisis (17%), and aganglionosis (6%). It is characterized by substrate malabsorption, electrolyte imbalance, intestinal bacterial overgrowth, steatorrhea, and weight loss. Current medical management includes parenteral nutrition, progressive feeds as tolerated, various medications, and surgical manipulations. However, frequently this management is not successful in achieving the goal of attaining normal growth and development without parenteral nutrition. It has been known for decades that there is a normal physiologic response of the residual intestine to massive bowel resection referred to as intestinal adaptation. The mechanisms that control this process are unknown. Unfortunately, intestinal adaptation and the current management are not always successful. As a result of new knowledge regarding the pathophysiology of SBS over the past two decades, several novel strategies have been developed in experimental animal models as well as limited clinical trials in infants and children. They can be divided into several categories that potentially influence intestinal (1) absorption, (2) secretion, (3) motility, and (4) adaptation. More recently, newer modalities have been studied including small intestine transplantation, and the use of specific intestinal growth factors. Ultimately, tissue and organ engineering will become the treatment for infants and children with SBS. PMID- 23989527 TI - Education as a social determinant of health: issues facing indigenous and visible minority students in postsecondary education in Western Canada. AB - The level of educational attainment is increasingly being recognized as an important social determinant of health. While higher educational attainment can play a significant role in shaping employment opportunities, it can also increase the capacity for better decision making regarding one's health, and provide scope for increasing social and personal resources that are vital for physical and mental health. In today's highly globalized knowledge based society postsecondary education (PSE) is fast becoming a minimum requirement for securing employment that can afford young adults the economic, social and personal resources needed for better health. Canada ranks high among OECD countries in terms of advanced education, with 66% of Canadians having completed some form of postsecondary education. Yet youth from low income indigenous and visible minority (LIIVM) backgrounds continue to be poorly represented at PSE levels. The current study aimed to understand the reasons for this poor representation by examining the experiences of LIIVM students enrolled in a postsecondary program. Findings show that the challenges they faced during the course of their study had an adverse impact on their health and that improving representation of these students in PSE will require changes at many levels. PMID- 23989528 TI - Groups experiment with digital tools for patient consent. PMID- 23989529 TI - Cell-Free Protein Synthesis in Miniaturized Array Devices and Effects of Device Orientation. AB - Cell-free protein synthesis (CFPS) has been used as an alternative to cell-based recombinant technology for protein production in academic and industrial labs. The continuous-exchange format generally has higher expression yield by constantly supplying a nutrient solution and removing inhibitory by-products through a porous membrane. Because of the concern of possible membrane clogging by large molecules in the CFPS solution, we investigated the effects of membrane orientation on protein synthesis. We fabricated a miniaturized array device called Vertical-I with its membrane oriented vertically in reference to the table surface and found that the protein synthesis yield in the Vertical-I device was 144% higher than the Horizontal Device reported previously. The reaction time was also faster; beta-glucuronidase reached the synthesis yield plateau after 2 h in the Vertical-I device versus 4 h in the Horizontal Device. Possible clogging of membrane pores was confirmed by fluorescein diffusion measurement. Using these results, we designed a device called Vertical-II that would fit into a 96 well plate holder for compatibility with commercial reagent dispensers and microplate readers. The experimentally optimized device increased protein expression 406% over the Horizontal Device and consumes 5 times fewer reagents than a commercial device, showing the potential for high-throughput protein synthesis. PMID- 23989531 TI - [Conservative therapy in orthopedics and trauma surgery]. PMID- 23989532 TI - A highly sensitive near-infrared fluorescent probe for cysteine and homocysteine in living cells. AB - A near-infrared fluorescent probe (Cy-O-CHO) for the detection of endogenous Cys/Hcy in living cells was designed and synthesized. Cy-O-CHO exhibited high sensitivity and good selectivity to Cys/Hcy under physiological conditions with a detection limit of 7.9 nM for Cys. PMID- 23989534 TI - Morphological features of the P-waves at surface electrocardiogram as surrogate to mechanical function of the left atrium following a successful modified maze procedure. AB - AIMS: Absent left atrium (LA) mechanical contraction may occur following the modified Cox-maze operation, and was found to impose a potential risk for the occurrence of thrombo-embolic stroke. It is unknown whether certain morphological P-wave characteristics can surrogate absent LA mechanical activity. The aim of this study was to evaluate the morphological features of the P-waves on the surface electrocardiogram (ECG) of patients who underwent the maze operation and to relate them to the contractile profile of the LA. METHODS AND RESULTS: Electrocardiogram tracings of 150 consecutive patients that were in sustained sinus rhythm following the maze operation were evaluated. P-waves were scrutinized for morphology, duration, axis, and amplitude. Clinical, surgery related, and echocardiographic data were collected and analysed. Forty-seven patients (31%) had no evidence of LA contraction at 3 months after surgery (baseline assessment) and on follow-up echocardiography. Multivariate analysis showed that a positive-only P-wave deflection at lead V1 (P = 0.03), a negative only deflection at aVL, and a P-wave amplitude of <= 0.05 mV at the septal anterior leads (P < 0.001 for both) were associated with absent LA mechanical contraction. In a secondary analysis, a risk score involving the above three parameters was developed for the prediction of stroke occurrence. Patients at the high-risk score group had a 30% survival freedom of stroke compared with 70% for patients at intermediate risk (P < 0.001). CONCLUSION: Absent LA mechanical contraction following the modified maze operation may be accompanied by a distinguished pattern of the P-waves on the surface ECG. PMID- 23989533 TI - Beta-blockade and A1-adenosine receptor agonist effects on atrial fibrillatory rate and atrioventricular conduction in patients with atrial fibrillation. AB - AIMS: Reduced irregularity of RR intervals in permanent atrial fibrillation (AF) has been associated with poor outcome. It is not fully understood, however, whether modification of atrioventricular (AV) conduction using rate-control drugs affects RR variability and irregularity measures. We aimed at assessing whether atrial fibrillatory rate (AFR) and variability and irregularity of the ventricular rate are modified by a selective A1-adenosine receptor agonist tecadenoson, beta-blocker esmolol, and their combination. METHODS AND RESULTS: Twenty-one patients (age 58 +/- 7 years, 13 men) with AF were randomly assigned to either 75, 150, or 300 MUg intravenous tecadenoson. Tecadenoson was administered alone (Dose Period 1) and in combination (Dose Period 2) with esmolol (100 MUg/kg/min for 10 min then 50 MUg/kg/min for 50 min). Heart rate (HR) and AFR were estimated for every 10 min long recording segment. Similarly, for every 10 min segment, the variability of RR intervals was assessed, as standard deviation, pNN20, pNN50, pNN80, and the root of the mean squared differences of successive RR intervals, and irregularity was assessed by non linear measures such as regularity index (R) and approximate entropy. A marked decrease in HR was observed after both tecadenoson injections, whereas almost no changes could be seen in the AFR. The variability parameters were increased after the first tecadenoson bolus injection. In contrast, the irregularity parameters did not change after tecadenoson. When esmolol was infused, all the variability parameters further increased. CONCLUSION: Modification of AV node conduction can increase RR variability but does not affect regularity of RR intervals or AFR. PMID- 23989535 TI - Computational model of motor learning and perceptual change. AB - Motor learning in the context of arm reaching movements has been frequently investigated using the paradigm of force-field learning. It has been recently shown that changes to somatosensory perception are likewise associated with motor learning. Changes in perceptual function may be the reason that when the perturbation is removed following motor learning, the hand trajectory does not return to a straight line path even after several dozen trials. To explain the computational mechanisms that produce these characteristics, we propose a motor control and learning scheme using a simplified two-link system in the horizontal plane: We represent learning as the adjustment of desired joint-angular trajectories so as to achieve the reference trajectory of the hand. The convergence of the actual hand movement to the reference trajectory is proved by using a Lyapunov-like lemma, and the result is confirmed using computer simulations. The model assumes that changes in the desired hand trajectory influence the perception of hand position and this in turn affects movement control. Our computer simulations support the idea that perceptual change may come as a result of adjustments to movement planning with motor learning. PMID- 23989536 TI - Cleavage of sequestosome 1/p62 by an enteroviral protease results in disrupted selective autophagy and impaired NFKB signaling. AB - The adaptor protein, sequestosome 1 (SQSTM1)/p62, plays an essential role in mediating selective autophagy. It serves as an autophagy receptor targeting ubiquitinated proteins to autophagosomes for degradation. In addition, it functions as a scaffold protein to regulate signaling pathways. Here we explored the interplay between coxsackievirus B3 (CVB3) and SQSTM1-mediated selective autophagy. We reported that SQSTM1 was cleaved at glycine 241 following CVB3 infection through the activity of viral protease 2A(pro). The resulting cleavage fragments of SQSTM1 were no longer the substrates of autophagy, and their ability to form protein aggregates was greatly decreased. Although the C-terminal truncation sustained the binding activity of SQSTM1 to microtubule-associated protein 1 light chain (LC3), it failed to interact with ubiquitinated proteins. It was also found that colocalization between the C-terminal fragment of SQSTM1 (SQSTM1-C) and LC3 and ubiquitin within the punctate structures was markedly disrupted. Moreover, we observed that SQSTM1-C retained the ability of SQSTM1 to stabilize antioxidant transcription factor NFE2L2 [nuclear factor (erythroid derived 2)-like 2]; however, both the N-terminal fragment of SQSTM1 (SQSTM1-N) and SQSTM1-C lost the function of SQSTM1 in activating NFKB (the nuclear factor of kappa light polypeptide gene enhancer in B-cells) pathway. Collectively, our results suggest a novel model by which cleavage of SQSTM1 as a result of CVB3 infection impairs the function of SQSTM1 in selective autophagy and host defense signaling. PMID- 23989538 TI - Compounding ophthalmic preparations. PMID- 23989539 TI - Ophthalmic compounding: techniques for achieving sterility. PMID- 23989537 TI - Improved survival in patients with metastatic renal cell carcinoma undergoing cytoreductive nephrectomy in the era of targeted therapy. AB - BACKGROUND: We aimed to review our clinical experience of cytoreductive nephrectomy for patients with metastatic renal cell carcinoma (mRCC) and to identify factors associated with postoperative prognosis in these patients. METHODS: This study included a total of 164 Japanese patients with mRCC who underwent cytoreductive nephrectomy and subsequently received immunotherapy and/or molecular-targeted therapy between 2000 and 2010. RESULTS: Baseline characteristics of the 164 patients were as follows: median age was 66 years; metastatic sites included the lung in 133 (81.1 %), bone in 44 (26.8 %), and other in 37 (22.6 %); and 34 (20.7 %), 106 (64.7 %), and 24 (14.6 %) patients were classified into favorable, intermediate-risk, and poor-risk groups, respectively, according to the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model. As postoperative systemic therapy, 80 patients (48.8 %) were treated with immunotherapy alone; the remaining 84 (51.2 %) received molecular-targeted agents irrespective of previous treatment with immunotherapy. Median overall survival of these 164 patients was 25.8 months. Univariate analysis identified the MSKCC risk classification, preoperative C-reactive protein (CRP) level, metastatic site, nodal involvement, presence of sarcomatoid features, histological subtype, and introduction of molecular-targeted agents as significant predictors of overall survival, among which only the preoperative CRP level and introduction of molecular-targeted agents appeared to be independently associated with overall survival. CONCLUSIONS: Treatment with molecular-targeted agents following cytoreductive nephrectomy may contribute to improve the survival of patients with mRCC compared with immunotherapy alone, and it may be important to employ an aggressive systemic treatment for patients with an increased preoperative value of CRP. PMID- 23989540 TI - Buffer solutions for ophthalmic preparations. PMID- 23989541 TI - Preservation, sterilization, and sterility testing of ophthalmic preparations. PMID- 23989542 TI - Ophthalmic solutions in cataract surgery. PMID- 23989544 TI - Ophthalmic compounding for animals. PMID- 23989543 TI - An eye to success. PMID- 23989545 TI - Nutraceuticals: new opportunities for the pharmacist. PMID- 23989546 TI - An automated process for batch preparation of epidural solutions containing bupivacaine hydrochloride and fentanyl citrate. PMID- 23989547 TI - Basic statistical concepts for evaluating the pharmaceutical compounding literature. PMID- 23989548 TI - Making capsules using a solid oral dosage form of a different strength. PMID- 23989549 TI - Paclitaxel Compatibility with the IV Express Filter Unit. AB - The purpose of this project was to evaluate the compatibility of paclitaxel infusions with the IV Expres filter unit, a 0.22-micrometer intravenous solution filter (Millipore Corporation, Bedford, MA). The potential for extraction of diethylhexyl phthalate platicizer from the filter unit by the Cremaophor EL surfactant present in the paclitaxel injection and the potential for loss of paclitaxel to filter unit components due to sorption were evaluated. Plasticizer extraction was tested using the paclitaxel diluent at a concentration equivalent to 1.2 mg/mL over a three-hour simulated infusion. Paclitaxel delivery was evaluated in admixtures containing paclitaxel 0.3 mg/mL. All samples were prepared in triplicate in polyolefin bags of 5% dextrose injections and delivered through IV Express filter units attached to nonpolyvinyl chloride administration sets designed for the adminstration of paclitaxel infusions. The samples were collected in glass collection flasks. Both plasticizer and paclitaxel content were determined using specific high-performance liquid chromatographic methods. None of the admixtures delivered over three hours through the IV Express filter unit exhibited any detectable plasticizer. Further, no loss of paclitaxel due to soption to any filter commponent occurred; the full amount of paclitaxel was deliverd in the simulated ifusions. The IV Express filter unit tested in this study is suitable for the administration of paclitaxel infusions over three hours. PMID- 23989550 TI - Stability of Milrinone Lactate in 5% Dextrose Injection and 0.9% Sodium Chloride Injection at Concentrations of 400, 600, and 800 micrograms/mL. AB - Milirone lactate is a phosphodiesterase inhibitor that is used in the acute phase of congestive heart failure. It is available in ready-to-use intravenous piggybacks at a concentration of 200 micrograms/mL and in 10-mL and 20-mL vials at a concentration of 1 mg/mL. The stability of milrinone lactate at highter concentrations of 400, 600, and 800 micrograms/mL in 5% dextrose injection and 0.9% sodium chloride injection was studied. The solutions were prepared in polyvinyl chloride bags and aliquots of 10mL were withdrawn initially and after one, three and seven days at room and refrigerator temperatures under normal light. The aliquots were stored at -20 deg C and analyzed for potency using a high-performance liquid chromatography proceure. Both intraday and interday variations of the external standard were less than 4%. Stablility was defined as 90% or greater of the original concentration remaining. Milrinone lactate prepared in either 5% dextrose injection or 0.9% sodium chloride injection at concentrations of 400, 600, and 800 micrograms/mL is stable at room or refrigerated temperature for 14 days. PMID- 23989551 TI - Sorption of benzalkonium chloride to various filters used in processing ophthalmics. AB - Benzalkonium chloride is widely used as a preservative in ophthalmic formulations. The United Stated Pharmacopeia XXIII/National Formulary 18 states that "sterile membrane filtration under aseptic conditions is the preferred method" for sterilization of ophthalmic products, and sorption of benzalkonium chloride to filters has presented a problem in ophthalmic processing. The purpose of this study was to determine the extent of, and factors affecting, benzalkonium chloride sorption to filters. An aqueous solution of benzalkonium chloride 0.2 mg/mL was passed through syringe filters of various sizes, filter membrane media and manufacturers. The filters were of four sizes: 13- or 25-mm diameter with 0.2 or 0.45-micrometer pores. The filter membrane media were nylon, polyvinylidene fluoride (PVDF), polyethersulfone (PES) or polytetrafluoroethylene (PTFE) manufactured by Gelman Sciences or Micron Separations, Inc. A total volume of 3.6 mL in 0.6-mL increments was filtered, followed by a 1.8-mL water rinse. Samples were then analyzed by high-performance liquid chromatography. The results showed a significant difference in sorption based on all three variables. The 13-mm diameter filters absorbed less drug than the 25-mm filters, and filters with 0.45 micrometer pores adsorbed less drug than those with 0.2-micrometer pores because of smaller surface area exposed. The following sorption pattern was observed for the filter media: PVDF greater than PTFE greater than nylon greater than PES, with Micron Separations nylon filters showing a higher degree of sorption than Gelman Sciences nylon filters. The appropriate filter media and size should be chosen for ophthalmic product filtration to minimize loss of benzalkonium chloride in processing ophthalmic products. PMID- 23989552 TI - A label-free optical biosensor with microfluidics identifies an intracellular signalling wave mediated through the beta(2)-adrenergic receptor. AB - The canonical model of G protein-coupled receptor (GPCR) signalling states that it is solely initiated at the cell surface. In recent years, a handful of evidence has started emerging from high-resolution molecular assays that the internalized receptors can mediate the third wave of signalling, besides G protein- and beta-arrestin-mediated signalling both initiating at the cell surface. However, little is known about the functional consequences of distinct waves of GPCR signalling, in particular, at the whole cell system level. We here report the development of label-free biosensor antagonist reverse assays and their use to differentiate the signalling waves of an endogenous beta2-adrenergic receptor (beta2-AR) in A431 cells. Results showed that the persistent agonist treatment activated the beta2-ARs, leading to a long-term sustained dynamic mass redistribution (DMR) signal, a whole cell phenotypic response. Under the persistent treatment scheme in microplates, a panel of known beta-blockers all dose-dependently and completely reversed the DMR signal of epinephrine at a relatively low dose (10 nM), except for sotalol which partially reversed the DMR. Under the perfusion conditions with microfluidics, the subsequent perfusion with sotalol only reversed the DMR induced by epinephrine or isoproterenol at 10 nM, but not at 10 MUM. Furthermore, the degree of the DMR reversion by sotalol was found to be in an opposite relation with the duration of the initial agonist treatment. Together, these results suggest that the hydrophilic antagonist sotalol is constrained outside the cells throughout the assays, and the early signalling wave initiated at the cell surface dominates the DMR induced by epinephrine or isoproterenol at relatively low doses, while a secondary and late signalling wave is initiated once the receptors are internalized and contributes partially to the long-term sustainability of the DMR of epinephrine or isoproterenol at high doses. PMID- 23989553 TI - Direct growth of aligned graphitic nanoribbons from a DNA template by chemical vapour deposition. AB - Graphene, laterally confined within narrow ribbons, exhibits a bandgap and is envisioned as a next-generation material for high-performance electronics. To take advantage of this phenomenon, there is a critical need to develop methodologies that result in graphene ribbons <10 nm in width. Here we report the use of metal salts infused within stretched DNA as catalysts to grow nanoscopic graphitic nanoribbons. The nanoribbons are termed graphitic as they have been determined to consist of regions of sp(2) and sp(3) character. The nanoscopic graphitic nanoribbons are micrometres in length, <10 nm in width, and take on the shape of the DNA template. The DNA strand is converted to a graphitic nanoribbon by utilizing chemical vapour deposition conditions. Depending on the growth conditions, metallic or semiconducting graphitic nanoribbons are formed. Improvements in the growth method have potential to lead to bottom-up synthesis of pristine single-layer graphene nanoribbons. PMID- 23989554 TI - [The anticipated grieving before the awareness of finitude: life and the fear of "not being able to cope," "giving too much trouble" and dying]. AB - In their praxis, health professionals must deal with the grieving of patient, family and staff, but for the elderly anticipated grieving due to disease and the awareness of finitude can be as disturbing as the actual death of someone. This paper seeks to understand anticipated grieving in the interaction between old age and health-disease and disability processes from the viewpoint of the elderly in the community faced with their own finitude. This observational ethnographic study was conducted with 57 elderly people assisted by the Family Health Strategy. The collection and analysis of data in semi-structured interviews was based on the model of signs, meanings and actions. The final categories that were revealed were: experiences of death while alive; experiences of the elderly in health care; awareness of finitude and anticipated grieving that negate the meaning of life. In local culture aging is a disease, disability is "being unable to cope" with everyday activities, and "giving too much trouble" to others is worse than dying. The older they are, the greater the anticipated and real grieving and loss and awareness of finitude, which have been neglected in health care. Understanding this question is crucial for comprehensive and humane care of the elderly and their families. PMID- 23989555 TI - [Influence of age on the perception of finitude and quality of life]. AB - This cross-sectional study analyzed the influence of age on the perception of finitude and quality of life (QOL) of government employees, with a non probabilistic accessibility sample composed of 471 employees with an average age of 40. A self-administered questionnaire was used for the study. The results show that physical activity of group C had the highest average in all components and group B the lowest values, with the exception of walking. All the participants achieved good scores in the four domains of QOL (58% - 74%). In the perception of finitude, group B obtained better scores (positive perception) in the four areas, whereas groups A and C had a more negative perception, there being no significant difference between the variables. This study reveals the positive relation of finitude in the age group from 35 to 50. Positive QOL and a high level of physical activity were identified. PMID- 23989556 TI - [Illness and finitude: considerations about the interdisciplinary approach in the oncological Intensive Care Unit]. AB - Being afflicted with cancer involves a high degree of invasive and mutilating treatment, which has repercussions on the lives of individuals and harks back to the recollection of pain, limitations and fear of death, which requires the participation of the family or person responsible for the patient during treatment. Attention to the relatives or persons responsible for the patient is a very important evaluation issue of care in health institutions, as an integral aspect of the process of humanization of assistance, that requires the training of professionals to identify and meet their needs. Given the above, this study seeks to address some considerations regarding the interdisciplinary work of assisting the patients' families in the Adult Intensive Care Unit of Cancer Hospital I, as an efficient proposal with respect to attention to such clinical information requirements, as well as social, medical and/or psychological guidance. PMID- 23989557 TI - [Body and finitude--listening to suffering as a working tool in an oncological institution]. AB - Based on the day-to-day care of patients in the Pain Clinic of a Brazilian cancer hospital (INCA), this article seeks to examine the consequences upon the psychic dimension of the fact of pain being intimately linked to the body. Almost always profoundly affected by the illness, the concept of the subject's own body deeply modifies this identification. This not only causes suffering, but also prejudices oncological treatment. Conceptualizing the body from a psychoanalytical standpoint, this article emphasizes the importance of language and the spoken word in its constitution, as the body perceived by psychoanalysis does not coincide with the biological body. The importance of listening to what the patients say is therefore seen as an important tool in the work of professionals in an oncological institution. Two possible positions regarding professionals dealing with the imminence of death and the finitude of life are then outlined. The first is refraining from being affected by the finite and perishable dimension of life, feeling pity for the patients, resigning and distancing oneself from their predicament. The second involves listening to the patients with compassion, acknowledging the inexorable finitude common to all, such that they may not suffer alone and share some of the horror they are experiencing. PMID- 23989558 TI - [Palliative care: communication as a strategy of care for the terminal patient]. AB - Palliative care involves an approach in the field of care for terminal patients and their families that seeks to assure them better quality of life by establishing good communication. The scope of this study was to verify how nurses use communication in the field of palliative care when assisting patients in the terminal phase. This is exploratory research of a qualitative nature in which 28 nurses working in wards of a hospital in the city of Joao Pessoa in the State of Paraiba participated in the period from August to October 2012. A form was used for data collection that was then analyzed using the content analysis technique. Three categories emerged from the analysis of the material: "palliative care and communication - interpersonal relationship between the nurse and the terminal patient"; "communication in palliative care as a strategy for strengthening the bond between the nurse and the terminal patient"; and "the importance of communication between the nurse and the family of the terminal patient under palliative care." The conclusion reached was that communication is seen to be an effective element of care for the patient in the terminal phase and it is extremely important for the promotion of palliative care. PMID- 23989559 TI - [A qualitative study of cancer patients receiving palliative support in hospital care]. AB - This article focuses on patients with cancer during the terminal phase. It deals with the care that individuals need after trying to seek health solutions in different hospitals when the disease is deemed incurable and they then require palliative care (PC) to obtain welfare and assist them to die. In the Spanish health system these patients are cared for in palliative care units or services. The main objective of palliative care is to give comfort. Comforting is destined to alleviate and support patients and families during the process of health / disease / care / patient death. During this period, it is important to care for the ailing body. Similarly, when a disease is incurable, the pain and suffering runs its inexorable course and leaves perceptible traces. These signs can be an indication that death is nigh. Although scientific advances have produced positive results in the control of pain, in some cases there are critical moments when situations of misery and despair arise for the terminal patients. PMID- 23989560 TI - [Palliative care: between humanization and medicalization at the end of life]. AB - This paper analyzes the palliative care of terminal patients, examining the tensions between the humanization of care and the progressive medicalization at the end-of-life situation. The research upon which the article is based adopts a qualitative methodological approach derived from interviews with professionals and patients and ethnographic observations in a palliative care unit in the City of Buenos Aires, Argentina. The article describes the configuration of personalized and comprehensive health care based on the core values of more humanized end-of-life care promoted by palliative care supporters. Similarly, the paper analyzes how these practices are assisted by progress in the medicalization process in which the dimension of care is considered less an unprofessional area of medical practice than an area of care in which specific technical skills and know-how are employed. The articles explores how instead of being divergent, the logic of care and medicalization work in a complementary fashion. PMID- 23989561 TI - [The task of caring for terminally ill cancer patients]. AB - This is a study conducted in the palliative care unit of the INCA National Cancer Institute, in an attempt to understand the nature of the work and its effects on the health of the professionals. A qualitative approach is adopted, based on participant observation and semi-structured interviews with professionals from the hospital. Most of the professionals are female and were unaware of the concept of palliative care when they started their careers in the Unit. Teamwork is highly valued by the professionals who involve the families in the care actions and motivate the participation of patients and relatives in decision making. However, these workers experience high emotional stress due to their involvement in the suffering of patients and families. They are also exposed to considerable physical stress caused by the intense demand of the daily routine and the dependence of the majority of patients. The study revealed that there are many professionals on leave of absence due to musculoskeletal problems and psychiatric disorders. There is a pressing need for health support programs for these professionals and awareness of daily care measures for their own health. However, their suggestions for improvement of working and health conditions are merely passed on to be implemented by the institutions themselves. PMID- 23989562 TI - [Palliative care for HIV/AIDS patients: bioethical principles adopted by nurses]. AB - This study sought to investigate the principles of bioethics considered by nurses involved in research while caring for patients with HIV/Aids under palliative care. An exploratory study, with a qualitative approach, was conducted with twelve nurses in a public hospital in the municipality of Joao Pessoa in the State of Paraiba. A form was used for data collection and the empirical material was analyzed qualitatively using the content analysis technique. The following categories emerged from the qualitative analysis: Respect for the autonomy of HIV/Aids patients under palliative care; and Enhancement of the principles of charity, non-malevolence and justice in providing palliative care to HIV/Aids patients. The results revealed that the participants acknowledge the importance of bioethical principles while caring for patients with HIV/Aids under palliative care. The work provides a reflection on and elicits the pursuance of further studies which can contribute to improve the quality of life of these patients with care based on ethical principles. PMID- 23989563 TI - [Anticipated grieving in patients requiring Hematopoietic Stem Cell Transplantation]. AB - The scope of this study was to understand how the process of anticipated grieving is imbued in patients undergoing Hematopoietic Stem Cell Transplantation (HSCT). A cross-sectional clinical-qualitative study was conducted on a sample of 17 patients, mostly women, married, aged between 20 and 42 years and diagnosed with Chronic Myeloid Leukemia. Data was collected by semi-structured interviews applied individually and subjected to thematic content analysis. The results indicate that the loss of health imposes a new challenge in a life history already permeated by great hardships and premature losses. It was found that the expected reactions faced with normal grieving were expressed by the participants and that the most prevalent coping strategy was holding steadfast to their faith. Future plans involved being healed, returning to normality and vocational rehabilitation. The results may help the multidisciplinary teams to understand the emotional implications of the illness/treatment for implementing both preventive and intervention strategies. The critical aspect is that staff must be attentive as to how to communicate the diagnosis and the possibility of outlining a therapeutic plan, in order to augment the fighting spirit of the patient and strengthen the bond of trust with health professionals. PMID- 23989564 TI - [Palliative care: an approach based on the professional health categories]. AB - Palliative care has emerged as a humanitarian philosophy of caring for terminally ill patients, alleviating their pain and suffering. This care involves the action of an interdisciplinary team, in which all the professional recognize the limits of their performance will help the terminally ill patient to die with dignity. This article deals with the issue of death and dying, both from the traditional and the contemporary standpoint, and how palliative care have been treated in the job categories of medicine, social work, psychology and nursing. The methodology of this study consists of a literature review of articles in the SciELO database, electronic journals and technical books related to the topic. Analysis of the articles revealed a shortage of subjects that deal with the theme of death in professional curricula, as well as few palliative care services in Brazilian society and barriers faced by this new approach to the terminal patient. This research aims to broaden the discussion of palliative care in public health, and provide information for future studies that will address the theme. PMID- 23989565 TI - [The perception by nurses of the significance of palliative care in patients with terminal cancer]. AB - This study sought to assess the perception of nurses with respect to cancer patients under palliative care. It is an exploratory study with a qualitative approach conducted with nurses from a hospital attending cancer patients under palliative care located in the city of Joao Pessoa, State of Paraiba. The study included nine nurses who worked in the hospital. The empirical material was collected using the technique of semi-structured interviews and analyzed using the content analysis technique. The interpretative analysis of the interviews led to the definition of three categories: Improving the quality of life through the alleviation of pain and suffering; Palliative Care: a multi-professional study of terminal patients and their families in the grieving process; Communication: a source of dignity in the terminal care process. The conclusion reached is that the study revealed that the nurses involved acknowledge the importance of the multidisciplinary team. It enables the nurses to reflect on the use of communication as an essential element of care for patient and family under palliative care. It is hoped that the data obtained may foster further research on the topic. PMID- 23989566 TI - [Perceptions of the multi-professional team on the implementation of palliative care in intensive care units]. AB - The scope of this paper was to analyze the perceptions of the multi-professional team on the implementation of palliative care in an adult intensive care unit. An exploratory-descriptive study using a qualitative approach was conducted with 14 health professionals from a public teaching hospital. The information was collected between February and April 2012, by means of semi-structured interviews and non-participatory observation interpreted using content analysis. Three thematic categories were identified: Care for terminal patients in an ICU fostering physical comfort; Lack of preparation of the team in dealing with terminal patients; and Challenges of palliative care practices in the intensive care environment. The interviewed parties reported having some knowledge of the proposal for palliative care though divergences were observed in the therapeutic conduct of the team in the care provided, demonstrating a lack of interaction and communication among the professionals. The drafting of a national policy to promote care for terminally ill patients is necessary, as well as ongoing training of professionals and the creation of care protocols for promoting the comfort of the patients and their families during the end of life phase. PMID- 23989567 TI - [Difficult news: meanings attributed by family members of children with cystic fibrosis]. AB - This article studied some of the meanings that difficult news assumes when transmitted by health professionals to relatives of young cystic fibrosis patients undergoing treatment at a public hospital located in the south zone of the city of Rio de Janeiro, Brazil. It is the result of qualitative research and analysis of ten narratives collected during two months in 2010. These meanings are not understood by professionals and interfere with the evolution of the illness, the coping process and the care given to the children. It has been observed that the content of the news is perceived differently depending on: The clarity with which it is transmitted to each family member; The forthright way it is conveyed without the preparation of the listener; The consideration of the context in which people live and the consequences involved; The presence of a family member when the news is delivered; and the fragmentation of information. Results indicate the need to make professionals aware of the importance of communication aspects in clinical meetings and the inclusion of this training process in the medical curriculum as well as during physicians' professional lives. It seems that in delivery of the news the family expects a balance between technical efficiency and conversational tact from professionals. PMID- 23989568 TI - [Perception of family members and health professionals on end of life care within the scope of primary health care]. AB - The objective of this study is to reflect on care for people with terminal illnesses in primary health care. This study is relevant in the current context of demographic and epidemiological transition, in which there is an increase in the aging population and a rise in the prevalence of chronic degenerative diseases. By means of qualitative research with a critical hermeneutic focus, individual interviews were conducted with seven family members, three professionals from the Family Health Strategy and two professionals from the Home Care Program. The analysis established two empirical categories: end of life care from the perception of family members and that of health professionals. The results showed that, despite the humanization discourse, reflected in the prerogative of living the final moments of life with the family, a serious problem in the discontinuity of care is concealed. It was concluded that, despite the efforts, little is achieved in improving the quality of life for those who die from terminal diseases at home in the Unified Health System in municipalities distant from large centers. PMID- 23989569 TI - [The significance of death for doctors faced with end-of-life care of patients undergoing bone marrow transplants]. AB - This study sought to investigate the significance of death for doctors who work with terminally ill patients in the Bone Marrow Transplant (BMT) context. The research was based on a qualitative, methodological and collective case study approach, and used Dejours' psychodynamics of work as a theoretical framework. Five practitioners linked to a Bone Marrow Transplant Unit in a university hospital in Sao Paulo, Brazil, participated in the research. A semi-structured script was applied which addressed the personal, academic and professional experiences elicited by a terminal situation. Data were organized into two categories: "Work and professional identity: the doctor's battle against death" and "Vocation and medical training: it all begins at home." The results show that, in the medical and hospital context, death is almost always reduced to technical rationality and this must be avoided at all costs. The significances attributed to death are rooted in the values of contemporary society and subjectively perceived through the physician's life trajectory and academic training, which influence how these professionals experience the dying process of the patients. PMID- 23989570 TI - [The perception of death and dying of professionals working in a long-term care institution for the elderly]. AB - Population aging and a shortage of caregivers result in a growing demand for institutionalization, and finitude is one the reflections that permeates aging. Living with death is part of the daily routine of health professionals resulting in emotional overload. This study sought to ascertain the experiences of the process of dying and death of health care professionals in a long-stay institution for the elderly. Methodological and theoretical Grounded Data Theory and Symbolic Interaction were used, respectively. Twenty health professionals from varied backgrounds were interviewed. The core topic of the results was: reconstructing ways to deal with the circumstances of dying and death. This led to the following categories: seeing death as part of human existence; seeking to acquire knowledge to handle cases of death and dying; reflecting on one's own death. Without fertile ground for the systematic examination of the topic, the interaction among workers about the exchange of experiences on death and dying remain restricted to the subjective level. In the conclusion, the importance of a metamorphosis in the institutional context and in health education, with more specific focus on thanatology, is emphasized. PMID- 23989571 TI - [The knowledge, involvement and feelings of students graduating in medicine, nursing and psychology about orthothanasia]. AB - Orthothanasia involves the suspension of medical procedures for terminal phase patients, which leads to a natural death, relieving the symptoms that cause suffering. In this process, professionals such as physicians, nurses and psychologists, interact with patients and their families. Therefore, it is desirable that during undergraduate studies these professionals should take subjects geared to handle this aspect. The scope of this qualitative study was to evaluate the awareness with respect to orthothanasia of undergraduates in medicine, nursing and psychology courses in a university. Trigger questions in semi-structured interviews were conducted with 22 students. The interviews were recorded and transcribed for content analysis and core identification themes. Three categories were identified: knowledge about orthothanasia; who should be involved in this process; and feelings experienced when facing death. The data revealed that students have scant knowledge about the subject, consider the family involvement in the orthothanasia decision to be important and they do not feel prepared to deal with death situations. The conclusion points to the need to change the focus on the end-of-life issue in the undergraduate courses in the area of health care in order to prepare the future professional adequately. PMID- 23989572 TI - [The construction of a "good death" at different stages of life: reflections on the palliative care approach for adults and children]. AB - This article deals with the vision of Palliative Care leading to a "good death" for adults and children. The differences and similarities between the care of adults and children are examined based on the scrutiny of textbooks, manuals and articles, as well as the observation of courses and congresses within the specialty, which focus on patients diagnosed as "beyond therapeutic cure possibilities." Health teams seek to provide care for the "bio-psycho-social spiritual totality" of the patients and their family members, to offer "quality of life," with full autonomy and control of their symptoms. In accordance with the palliative care model, the social actors involved in care must accept the end of life inevitability. It is a question of ensuring a "good death," "with dignity," peaceful, accepted, transparent and socially shared, with the support of a multi-professional team. It is a complex configuration, as various factors and circumstances come into play. This is especially true in the case of children, when a paradox arises, since terminal illness at this stage of life - so highly valued in contemporary Western culture - constitutes a social drama. PMID- 23989573 TI - [Loss and grieving: the experiences of women who terminate a pregnancy due to lethal fetal malformations]. AB - The scope of this study was to investigate the grieving experiences of women who terminated pregnancies under judicial authorization, due to life-incompatible fetal malformation. Ten women attended in the Fetal Medicine Department of Botucatu Clinical Hospital participated in the study. Data collection was conducted by means of semi-structured interviews forty days after termination. The interviews were recorded and transcribed in full, with the data analyzed from the thematic content analysis perspective. The results revealed that the mothers sought explanations and meanings for the loss, with religious responses and self blame being very frequent. The reports were marked by feelings of sadness, longing and sensations of emptiness due to the loss of the child, revealing the need of the mothers to dwell on the issue. The mothers were and continued to be linked to their children; the termination of the pregnancy, although being a choice to minimize the pain of an inevitable loss, did not spare the women from experiences of great suffering.>The study includes input for the discussion and planning of health approaches and care for women who terminate their pregnancy due to lethal fetal malformation, by means of judicial authorization. PMID- 23989574 TI - [Falling ill and dying of a young woman with breast cancer]. AB - This study focused on the experience of a young woman with breast cancer and sought to understand the progression of her falling ill, dying and death based on the significance attributed to the events of her life. It concentrates on the idea that one dies from how one has lived and in the way that a new meaning is attributed to this life over the course of time. It is qualitative research that is presented as a situational study that enabled the construction of Beth's Life Line using her Life History in which, judging from her narratives, events considered significant by her and that confirmed her way of living, stand out and are reflected in her death. Besides the detailed description of how the interview meetings occurred, it also discusses two central categories of the study, called "Ebbing of life - the small deaths experienced by Beth" and "Beth living out her dying and death." The study emphasizes the need for the health professionals to assume responsibility for a kind of care that does not only seek a cure, but also focuses on the human dimension, aiming to ensure well-being and maintenance of life, while this is still possible. PMID- 23989575 TI - [Death as a process: an anthropological perspective]. AB - This article combines recent approximations that question the homology between death and biological demise from an anthropological perspective with the tradition of studies that review the death rituals in the Andean geographical area. In particular, it examines how in El Cajon, Catamarca, Northeast Argentina the dead are incorporated in the cosmologic scheme, and how death, being the initial step for this to occur, is not merely a biological event but also a highly dynamic social process. Based on ethnographical field work and using multiple-session open interviews and participant observation as methodological tools, it presents an analytical proposal that seeks to transcend the homology between death and biological demise, suggesting a notion that includes not only the organic dimension but also the social dimension: the process of death. PMID- 23989576 TI - [The right to live one's own death and its constitutionality]. AB - The article seeks to reflect on the legality of the early manifestation of will, established in Brazil through Resolution No. 1.995/12 of the Federal Council of Medicine in the face of the legislative omission and considering the possible linkage of physicians and relatives of terminally ill patients in drafting the Last Will and Testament. It examines the constitutionality of these policies and, therefore, the constitutionality of the resolution itself in light of the new Brazilian constitutional paradigm. PMID- 23989577 TI - [Procedures for dealing with the taboo of death]. AB - The more death is studied, the more it remains a mystery. Dealing with death is no easy matter and for that reason it is so frightening. All the fears of human beings are fundamentally related to the fear of death. This is because it is a mystery about which we know little or nothing, although it is natural to die. In view of this, religions give this topic a primary focus. Therefore, in this article an attempt is made to deal with the taboo surrounding death and reflect on issues associated with it. These themes are present in people's lives, especially when they have the experience of losing someone in their family or circle of friends. Among these subjects, the aspects of the Anointing of the Sick, the Funeral Mass, the Seventh Day Mass and the tradition of praying for the dead are all touched upon. These are all themes that help to deal with the taboo of death or losing a loved one. PMID- 23989578 TI - [The impact of a child's death on the marital relationship of the parents]. AB - The scope of this qualitative study was to understand the experience of the couple who lost a child stricken by cancer,focusing on the impact of death on the marital relationship. The methodological strategy used in this paper was the case study, seeking to describe the process of elaboration of mourning and the impact of the son's death on the parents' marital relationship. The couple who participated in the study had been together for 39 years and had lost their youngest son three years earlier. The spouses were interviewed individually and then together. Semi-structured interview scripts were used for this purpose. It was established that the religious community to which the couple belongs has been the main source of support in dealing with the mourning process, although its precepts may prevent the free expression of their suffering, particularly in the wife's case. Although the couple has remained together, the marital relationship was shaken after their son's death. The couple had difficulty in talking about their marriage, though the wife pointed to the absence of their son as one of the reasons for the change in their marital relationship. The marital relationship and religiosity/spirituality emerged as important dimensions to be addressed by health staff in attending bereaved families. PMID- 23989579 TI - [Experience in palliative care for children with leukemia: the professionals' viewpoint]. AB - Palliative care is developed through multi-professional assistance with actions to provide support and comfort for the children and their families. The support involves the alleviation of suffering by controlling the pain and its symptoms, as well as ensuring psychosocial and spiritual support. This is a qualitative case study which sought to understand the multidisciplinary view of the team vis a-vis a child with leukemia in palliative care, in a hospital in Belo Horizonte. The subjects of research were 17 health professionals of the direct assistance team to the child receiving such care and the data were analyzed using the content analysis technique. The professional experience in palliative care is intrinsic to the success and continuity of the patient's care. It was found that the professionals have little experience in this area and have difficulty dealing with their emotions, and sometimes become unable to act when faced with the anguish of those involved and with death. However, despite the fact that the area of activity causes suffering and anguish to the professional, the multi professional team still identifies with and likes the area, which is important for the children and their families to feel safe, respected and well cared for by the professionals. PMID- 23989580 TI - [A reappraisal of the works of Elisabeth Kubler-Ross]. AB - This article presents a reappraisal of part of the works of Elizabeth Kubler Ross, one of the most quoted authors addressing the end of life process, mourning and dying. Her work has contributed to a clearer understanding of these issues by health professionals, families, religious and lay people who handle and/or experience mourning. She has also been the subject of controversy related to ethical issues and the scientific rigor of her work. The books analyzed in this article are: On death and dying (1969); Questions and answers on death and dying (1971); Living with death and dying (1981); On children and death(1983); On life after death (1991) and Life lessons (2000). PMID- 23989581 TI - [Euthanasia, dysthanasia and orthothanasia: an integrative review of the literature]. AB - There is currently widespread concern among researchers in debating questions that generate ethical conflicts within the scope of health care geared to the human being in the terminal phase, especially euthanasia, dysthanasia and orthothanasia. This study sought to characterize the scientific production at the national level on euthanasia, dysthanasia and orthothanasia. It involves an integrative review of the literature. The study universe consisted of 41 publications related to the theme in question by means of a survey conducted online in the Virtual Health Library in the Capes Portal and in the Bioethical Magazine. Of these, 25 articles comprised the sample taking into consideration the established inclusion and exclusion criteria. Data collection occurred in March 2013, by means of an instrument containing information pertinent to the proposed objective. The key words used were euthanasia, dysthanasia and orthothanasia. With respect to the focus of the publications, three themes emerged: Theme I - Euthanasia; Theme II - Dysthanasia and Theme III - Orthothanasia. The studies analyzed reflected the current concern in terms of ethical dilemmas concerning care of the human being in the end of life phase. Thus, it is hoped that this research can contribute to bolster the critical reading with respect to the theme. PMID- 23989582 TI - [Difficult news and the standpoint of pediatric oncologists: a bibliographical review]. AB - In order to discuss and understand the experiences of oncologists faced with the task of communicating difficult news to children and their close family members, a bibliographical review was conducted in the Virtual Health Library databases containing the literature published by PubMed, Lilacs, Scielo, Scopus and SciVerse with input on the theme. The articles available evaluated by thematic analysis reveal the following aspects: the lack of studies focusing on the perception of professionals about imparting difficult news; communication as a strategy by which psychosocial, cultural, bioethical, legal and emotional aspects are handled; that more is expected from physicians than they were trained for. It was also seen that the information and training of professionals in strategies regarding how to handle the communication of difficult news needs to be ongoing in order to keep up with the dynamism of the occurrences and the physician patient relations in the oncological field in which patients tend to be or feel under constant life-threatening conditions. PMID- 23989583 TI - [The attitude among nursing professionals and students when facing death: a review of the scientific literature of the last decade]. AB - Nursing professionals are integral members of the healthcare team and they maintain the most direct and prolonged contact with patients experiencing a terminal illness. This integrative review of the literature sought to investigate the attitude towards death among nursing professionals and students. Data were collected through searches in Lilacs, Medline, PsycINFO and CINAHL databases using the key words "nurses" and "attitude to death" in the period from 2000 to 2011. Of the 1376 articles identified, 262 were selected for data extraction and 35 were downloaded in full, constituting the corpus of research. The results showed a predominance of articles published in Brazilian journals. Studies indicate that the subject of death and dying has been neglected in training institutions, which causes hardship among professionals and nursing students when faced with the issue in practice, in addition to inappropriate conduct when dealing with patients who are experiencing the end of life process. In conclusion, the need for future research that may provide more detailed clarifications on the subject and seek strategies to address the lack of preparation and support of the nursing staff when they cope with death and dying was emphasized. PMID- 23989584 TI - [The influence of mourning on feeding habits and its implications for nutritional behavior]. AB - The lack of preparation for dealing with death and the absence of the loved one may lead to organic and psychological reactions that, due to the adaptive capacity of the individual to the period of mourning, may result in interference in feeding habits and consequently on the person's nutritional status. This article addresses the effects of recent mourning on feeding behavior, followed by the analysis of the dietary interview from various standpoints. This includes the postmortem nutrition and feeding habits of the bereaved and the implications of this process on hunger, on thirst and on family cooking, with a focus on nutritional behavior and on the decisions that surround it. This is a review of the literature on the theme of death and mourning, which seeks to contextualize this theme around reflections based on this experience. It emphasizes the interaction of nutrition with the science of thanatology, which is an area still not properly examined and lacking study. The identification of this influence and its implications enables better planning of food strategies, contributing greatly to actions for coping and support during mourning. PMID- 23989587 TI - Low-level experimental selenite additions decrease mercury in aquatic food chains and fish muscle but increase selenium in fish gonads. AB - We investigated whether low-level addition of selenium (Se) could decrease mercury (Hg) in freshwater fish without imposing Se toxicity. Using a regression design, selenite was added to large mesocosms in a lake to achieve target concentrations <=1.6 MUg/L. (198)Hg (spike Hg) was added to mesocosms to determine changes in Hg bioaccumulation. Adding Se decreased spike total Hg (THg) in fish muscle, ambient THg in fish liver, and bioaccumulation of spike THg in muscle and spike methylmercury (MeHg) in zooplankton and Chironomid larvae relative to controls. Se decreased Hg in the food web but not in water, indicating that the dominant effect of Se on Hg cycling occurs in the food web. Concentrations of Se in gonads of fish were positively correlated with Se concentrations in water but did not exceed reproductive toxicity thresholds after 8 weeks. We conclude that low-level addition of Se decreases MeHg bioaccumulation and increases Se in gonads of fish; however, additions of Se to freshwater systems to decrease Hg in fish should be treated with caution because Se in fish gonads were likely to exceed toxic concentrations if exposed to increased Se for a longer period of time. PMID- 23989589 TI - Directly measuring of thermal pulse transfer in one-dimensional highly aligned carbon nanotubes. AB - Using a simple and precise instrument system, we directly measured the thermo physical properties of one-dimensional highly aligned carbon nanotubes (CNTs). A kind of CNT-based macroscopic materials named super aligned carbon nanotube (SACNT) buckypapers was measured in our experiment. We defined a new one dimensional parameter, the "thermal transfer speed" to characterize the thermal damping mechanisms in the SACNT buckypapers. Our results indicated that the SACNT buckypapers with different densities have obviously different thermal transfer speeds. Furthermore, we found that the thermal transfer speed of high-density SACNT buckypapers may have an obvious damping factor along the CNTs aligned direction. The anisotropic thermal diffusivities of SACNT buckypapers could be calculated by the thermal transfer speeds. The thermal diffusivities obviously increase as the buckypaper-density increases. For parallel SACNT buckypapers, the thermal diffusivity could be as high as 562.2 +/- 55.4 mm(2)/s. The thermal conductivities of these SACNT buckypapers were also calculated by the equation k = Cpalpharho. PMID- 23989591 TI - [Results-adapted operative treatment options for spinal metastases]. AB - The current operative approaches and technical possibilities in the operative treatment of spinal metastases are manifold which enables an individual operative strategy adapted to the patient's condition. Maintaining quality of life is the primary goal in the treatment of these patients. The therapeutic goals, such as pain control, avoidance of neurological deficits and the achievement of spinal stability have to be attained with as little morbidity as possible. From this perspective the available operative techniques ranging from minimally invasive approaches to complex reconstructive surgery will be addressed and discussed in this article. PMID- 23989590 TI - [Solitary spinal metastases. Is aggressive surgical management justified?]. AB - Advances in oncological and surgical therapies have led to a significant increase in life expectancy of cancer patients and also prolonged survival of patients with isolated or multiple metastases. Among the skeletal manifestations the spine is the most often affected site. Using novel imaging techniques with higher resolution and use of metabolic signatures, the screening of cancer patients has improved considerably. Consequently, the diagnosis of metastases is becoming increasingly more sensitive. Therefore, but also due to more effective polychemotherapy protocols, singular or solitary metastases are more frequently observed either in the early stages or as a result of a controlled malignant tumor entity (stable disease). The questions whether a solitary metastasis really exists (illusion or reality?) and its radical oncological and surgical treatment as a circumscribed singular tumor manifestation, is really relevant for the overall prognosis, remains controversial. However, it seems evident that a biologically favorable underlying tumor biology, radical treatment of the primary tumor and a long metastasis-free interval are valid predictors of a good oncological outcome. In the presence of a solitary metastasis under these circumstances (typical example: solitary metastasis of renal cell carcinoma many years after radical tumor nephrectomy) a radical surgical procedure (en bloc spondylectomy) can significantly improve the long-term prognosis of this patient group in combination with adjuvant chemotherapy and/or radiotherapy. However, a thorough evaluation of the overall survival prognosis, a detailed and complete staging followed by a treatment consensus in the interdisciplinary tumor board has to precede any therapeutical decisions. PMID- 23989592 TI - [Tumors and metastases of the upper cervical spine (C0-2). A special challenge]. AB - Tumors of the upper cervical spine are rare and represent less than 0.5 % of all spinal tumors. The types of tumor and the clinical presentation are as varied as the modalities used for treatment. The unique anatomy of the upper cervical spine with its high physical mobility means that biomechanical considerations and neighboring anatomical structures (e.g. vertebral artery, medulla oblongata, lower cranial nerves and pharynx) must be considered when creating a treatment plan. Finding a balance between complete tumor removal, the preservation and reestablishment of stability and function and the possible necessity for postoperative radiotherapy is of utmost importance and must be assessed on an individual basis. In this review paper some important points will be presented concerning the preparation of the patient, the planning of the operation and the surgical approach used in treating tumors of the craniocervical junction. PMID- 23989593 TI - [Indications and limitations of minimally invasive stabilization of metastatic spinal disease]. AB - The number of patients with symptomatic metastases increases from year to year. Especially spinal metastases often lead to severe pain which often cannot be treated adequately by conservative treatment. Surgeons are confronted with the risk of instability, pathological fractures and neurological failure and the surgical treatment necessary in most cases is nowadays becoming an even greater challenge. The surgical procedure has changed considerably in recent years. The therapy is patient-individualized, the selection of implants and technology is adapted to the physical condition of the patient and the progression of the underlying disease. The main targets of the surgical treatment of spinal metastases have to be sufficient pain reduction with restoration of mobility as well as with the prevention of neurological deficits caused by progressive osteolysis. There are two minimally invasive stabilization procedures which can basically be applied. Under certain circumstances a single kyphoplasty/vertebroplasty procedure can be sufficient, in contrast to the possibility of short or long percutaneous posterior stabilization in combination with selective decompression of neural structures. These percutaneous surgical procedures currently have an important place in the surgical treatment of spinal metastases. The advantages are a less traumatic intervention for patients with advanced malignant diseases and poor general condition. Low intraoperative loss of blood means less intraoperative stress for the patient and minor surgical approaches lead to rapid mobilization and effective pain relief. As a result the hospital stay is shorter, adjuvant therapy can be started earlier and patients can be discharged sooner. PMID- 23989595 TI - [Rheumatology]. PMID- 23989594 TI - [Learning and teaching abilities of a newly inaugurated operation technique. Analysis of learning curves and transferability exemplified by Kypho-IORT]. AB - The Kypho-IORT procedure is a recently developed surgical technique to combine intraoperative radiotherapy with cement augmentation of the vertebra for spinal metastases. The technical feasibility and the operation principle of this new method have been described. In the following article the refinement of the standard operation procedure and the technical development of the method are described. Not only the procedural improvements but also the learning curves of the inaugurators are pointed out. Moreover, the article presents the measures which were necessary to educate trainees during surgical master classes in this new method and to transfer the method. The learning success was quantified by recording the accuracy reached by the trainees in the key procedure during hands on cadaver exercises. Improvements of the standard operation procedure could be successfully transferred in a second master class. The method of Kypho-IORT and the demonstrated way of postgraduate education is feasible to instruct trainees. The Kypho-IORT procedure can be learnt and performed safely by running through the surgical master class. PMID- 23989596 TI - [Spondylarthrosis of the cervical spine. Therapy]. AB - Chronic neck pain is often associated with spondylarthrosis, whereby segments C4/C5 (C: cervical) are most frequently affected. Spondylarthrosis can be the sole complaint, but it is associated with a degenerative cascade of the spine. The umbrella term for neck pain is the so-called cervical syndrome, which can be differentiated into segmental dysfunction and/or morphological changes of the intervertebral discs and small joints of the vertebral column. Conservative therapy modalities include physical therapy, subcutaneous application of local anesthetics, muscle, nerve and facet joint injections in addition to adequate analgesic and muscle relaxant therapy. If surgery is required, various techniques via dorsal and ventral approaches, depending on the clinic and morphologic changes, can be applied. PMID- 23989598 TI - Obstructive sleep apnea syndrome as a novel cause for Meniere's disease. AB - PURPOSE OF REVIEW: Several recent reports have described the relation between sleep disorders and inner ear function. There are also many reports that insomnia is observed in Meniere's patients. However, the possibility that obstructive sleep apnea syndrome (OSAS) might affect Meniere's disease or other neurotological consequences was not noticed, until studies using polysomnography for these patients. RECENT FINDINGS: OSAS may cause not only vestibular but also auditory dysfunction. Several reports suggest that insufficient supply of blood via the vertebral basilar artery, which supplies the inner ear, may cause hydropic distension of the endolymphatic system and lead to Meniere's disease. However, few people noticed that in OSAS this insufficient supply might be exacerbated in the night while patients are sleeping. Even more, we should note that Meniere's patients may not only suffer from insomnia, but also that the impaired sleep might be caused by OSAS. SUMMARY: Physicians routinely prescribe benzodiazepines or other drugs that have hypnotic, muscle relaxing, antianxiety, and anticonvulsant properties for insomnia, but these properties may have the effect of aggravating OSAS symptoms. Continuous positive airway pressure (CPAP) is an effective therapy used worldwide for the treatment of OSAS. CPAP or surgeries for OSAS may also be useful as one aspect of treatment for Meniere's disease patients with OSAS. PMID- 23989597 TI - A 5-year follow-up study of adolescents who sought treatment for substance misuse in Sweden. AB - Previous studies have shown that substance misuse in adolescence is associated with increased risks of hospitalizations for mental and physical disorders, convictions for crimes, poverty, and premature death from age 21 to 50. The present study examined 180 adolescent boys and girls who sought treatment for substance misuse in Sweden. The adolescents and their parents were assessed independently when the adolescents first contacted the clinic to diagnose mental disorders and collect information on maltreatment and antisocial behavior. Official criminal files were obtained. Five years later, 147 of the ex-clients again completed similar assessments. The objectives were (1) to document the prevalence of alcohol use disorders (AUD) and drug use disorders (DUD) in early adulthood; and (2) to identify family and individual factors measured in adolescence that predicted these disorders, after taking account of AUD and DUD in adolescence and treatment. Results showed that AUD, DUD, and AUD + DUD present in mid-adolescence were in most cases also present in early adulthood. Prediction models detected no positive effect of treatment in limiting persistence of these disorders. Thus, treatment-as-usual provided by the only psychiatric service for adolescents with substance misuse in a large urban center in Sweden failed to prevent the persistence of substance misuse. Despite extensive clinical assessments of the ex-clients and their parents, few factors assessed in mid adolescence were associated with substance misuse disorders 5 years later. It may be that family and individual factors in early life promote the mental disorders that precede adolescent substance misuse. PMID- 23989599 TI - Evolution in surgical management of superior canal dehiscence syndrome. AB - PURPOSE OF REVIEW: This manuscript will review the progression of surgical techniques currently being used to repair a defect in the superior semicircular canal in symptomatic patients. Originally described via the middle cranial fossa route, larger series of patients have been demonstrated through less invasive approaches. These new innovative approaches will be discussed. RECENT FINDINGS: Recently, the surgical indications for the repair of superior canal dehiscence have been broadened. As a result, several surgical techniques have been demonstrated to limit inherent risks to patients while still adequately treating the symptoms known to be associated with superior canal dehiscence. Transmastoid plugging, transmastoid resurfacing, endoscopic resurfacing and endaural approaches will be described and recent results discussed. SUMMARY: Although the optimal surgical approach for superior canal dehiscence has yet to be determined, clearly a progression in techniques has been demonstrated. Surgical management of superior canal dehiscence syndrome began requiring a craniotomy but has now progressed to transmastoid and even endaural approaches. PMID- 23989600 TI - RASSF1A methylation indicates a poor prognosis in hepatoblastoma patients. AB - PURPOSE: The RAS association domain family protein 1 (RASSF1A) is known to be frequently inactivated by promoter hypermethylation in cancers. This study investigated the association of RASSF1A methylation with clinical outcomes in hepatoblastoma patients and whether it is correlated with the histological phenotype of hepatoblastoma tumors. METHODS: Seventy-four hepatoblastoma tumors were obtained from patients enrolled in the Japanese study group for pediatric liver tumor protocol-2. From nine formalin-fixed, paraffin-embedded specimens, we extracted DNA by dissection under a light microscope. We examined the methylation status of the RASSF1A promoter region by bisulfite pyrosequencing. RESULTS: Twenty-five (33.8 %) hepatoblastoma tumors were classified as having methylated RASSF1A. The RASSF1A methylation was significantly associated with metastatic tumors and a poor prognosis. Despite the complete resection, five pretreatment extent of disease II tumors showed recurrence or distant metastasis postoperatively. Among these cases, four tumors were found to show RASSF1A methylation. When compared to histologically different types of cell, RASSF1A methylation values in samples of the normal liver, fetal type, and embryonal type, were significantly elevated in ascending order. CONCLUSIONS: We confirmed that RASSF1A methylation is a significant prognostic indicator in hepatoblastomas, and it may become a promising molecular marker to stratify patients into appropriate risk groups. PMID- 23989602 TI - Reversible supra-channel effects: 3D kagome structure and catalysis via a molecular array of 1D coordination polymers. AB - Self-assembly of CuX2 (X(-) = ClO4(-) and BF4(-)) with 2,3 bis(nicotinoyloxy)naphthalene yields a 1D loop-chain skeleton. The loop-chains form an ensemble constituting a unique 3D kagome-type structure with both hexagonal and trigonal supra-channels. The unprecedented supra-channel effects on the catalytic oxidation of 3,5-di-tert-butylcatechol to 3,5-di-tert butylbenzoquinone were investigated. PMID- 23989601 TI - Laparoscopy-assisted surgery for male imperforate anus with rectourethral fistula. AB - Laparoscopically assisted anorectal pull-through (LAARP), first described by Georgeson, is now considered to be the radical surgical treatment of choice for rectourethral fistula (RUF) in boys with high/intermediate-type imperforate anus. Accurate positioning of the pull-through canal, with pelvic floor muscles surrounding it symmetrically, is well recognized as the most important prognostic factor irrespective of the procedure performed. Surgical intervention should be LAARP with intraoperative measurement of the RUF, with follow-up focused on bowel habit. Complications such as diverticulum formation, have been reported with increasing frequency after LAARP and are most likely related to incomplete excision of the RUF, especially in bulbar cases. Thus, complete excision, while technically challenging, is crucial. Based on the results of a multicenter study comparing LAARP with other surgery, the most reliable investigation for detecting the presence of a diverticulum is MRI. At Juntendo University Hospital in Tokyo, Japan, blunt dissection with mosquito forceps to identify the potential pull through canal, measuring the length of the RUF directly, and closer placement of trocars (in bulbar fistula cases) are homegrown refinements that we feel improve outcome and we present a review of our approach to the surgical management of ARM. PMID- 23989603 TI - Dieulafoy's lesion of the gallbladder. PMID- 23989604 TI - Prevention of carcinogenesis and development of gastric and colon cancers by 2 aminophenoxazine-3-one (Phx-3): direct and indirect anti-cancer activity of Phx 3. AB - 2-Aminophenoxazine-3-one (Phx-3), an oxidative phenoxazine, exerts strong anticancer effects on various cancer cell lines originating from different organs, in vitro. This article reviews new aspects for the prevention of carcinogenesis and development of gastric and colon cancers by Phx-3, based on the strong anticancer effects of Phx-3 on gastric and colon cancer cell lines (direct anticancer effects of Phx-3 for preventing development of cancer), the bacteriocidal effects of Phx-3 against Helicobacter pylori associated with carcinogenesis of gastric cancer (indirect anticancer effects for preventing carcinogenesis of gastric cancer), and the proapoptotic activity of Phx-3 against human neutrophils involved in the incidence of ulcerative colitis associated with a high colon cancer risk (indirect anticancer effects for preventing carcinogenesis of colon cancer). PMID- 23989605 TI - Nanoconfinement-induced structures in chiral liquid crystals. AB - We employ Monte Carlo simulations in a specialized isothermal-isobaric and in the grand canonical ensemble to study structure formation in chiral liquid crystals as a function of molecular chirality. Our model potential consists of a simple Lennard-Jones potential, where the attractive contribution has been modified to represent the orientation dependence of the interaction between a pair of chiral liquid-crystal molecules. The liquid crystal is confined between a pair of planar and atomically smooth substrates onto which molecules are anchored in a hybrid fashion. Hybrid anchoring allows for the formation of helical structures in the direction perpendicular to the substrate plane without exposing the helix to spurious strains. At low chirality, we observe a cholesteric phase, which is transformed into a blue phase at higher chirality. More specifically, by studying the unit cell and the spatial arrangement of disclination lines, this blue phase can be established as blue phase II. If the distance between the confining substrates and molecular chirality are chosen properly, we see a third structure, which may be thought of as a hybrid, exhibiting mixed features of a cholesteric and a blue phase. PMID- 23989606 TI - Capillary-seeding crystallization and preliminary crystallographic analysis of a solvent-tolerant elastase from Pseudomonas aeruginosa strain K. AB - Seeding is a versatile method for optimizing crystal growth. Coupling this technique with capillary counter diffusion crystallization enhances the size and diffraction quality of the crystals. In this article, crystals for organic solvent-tolerant recombinant elastase strain K were successfully produced through microseeding with capillary counter-diffusion crystallization. This technique improved the nucleation success rate with a low protein concentration (3.00 mg/mL). The crystal was grown in 1 M ammonium phosphate monobasic and 0.1 M sodium citrate tribasic dihydrate pH 5.6. The optimized crystal size was 1 * 0.1 * 0.05 mm3. Elastase strain K successfully diffracted up to 1.39 A at SPring-8, Japan, using synchrotron radiation for preliminary data diffraction analysis. The space group was determined to be monoclinic space group P12(1)1 with unit cell parameters of a = 38.99 A, b = 90.173 A and c = 40.60 A. PMID- 23989607 TI - Spin polarization and quantum spins in Au nanoparticles. AB - The present study focuses on investigating the magnetic properties and the critical particle size for developing sizable spontaneous magnetic moment of bare Au nanoparticles. Seven sets of bare Au nanoparticle assemblies, with diameters from 3.5 to 17.5 nm, were fabricated with the gas condensation method. Line profiles of the X-ray diffraction peaks were used to determine the mean particle diameters and size distributions of the nanoparticle assemblies. The magnetization curves M(H(a)) reveal Langevin field profiles. Magnetic hysteresis was clearly revealed in the low field regime even at 300 K. Contributions to the magnetization from different size particles in the nanoparticle assemblies were considered when analyzing the M(H(a)) curves. The results show that the maximum particle moment will appear in 2.4 nm Au particles. A similar result of the maximum saturation magnetization appearing in 2.3 nm Au particles is also concluded through analysis of the dependency of the saturation magnetization M(P) on particle size. The M(P)(d) curve departs significantly from the 1/d dependence, but can be described by a log-normal function. Magnetization can be barely detected for Au particles larger than 27 nm. Magnetic field induced Zeeman magnetization from the quantum confined Kubo gap opening appears in Au nanoparticles smaller than 9.5 nm in diameter. PMID- 23989608 TI - Oxidative stress and epigenetic regulation in ageing and age-related diseases. AB - Recent statistics indicate that the human population is ageing rapidly. Healthy, but also diseased, elderly people are increasing. This trend is particularly evident in Western countries, where healthier living conditions and better cures are available. To understand the process leading to age-associated alterations is, therefore, of the highest relevance for the development of new treatments for age-associated diseases, such as cancer, diabetes, Alzheimer and cardiovascular accidents. Mechanistically, it is well accepted that the accumulation of intracellular damage determined by reactive oxygen species (ROS) might orchestrate the progressive loss of control over biological homeostasis and the functional impairment typical of aged tissues. Here, we review how epigenetics takes part in the control of stress stimuli and the mechanisms of ageing physiology and physiopathology. Alteration of epigenetic enzyme activity, histone modifications and DNA-methylation is, in fact, typically associated with the ageing process. Specifically, ageing presents peculiar epigenetic markers that, taken altogether, form the still ill-defined "ageing epigenome". The comprehension of mechanisms and pathways leading to epigenetic modifications associated with ageing may help the development of anti-ageing therapies. PMID- 23989609 TI - Apigenin protects endothelial cells from lipopolysaccharide (LPS)-induced inflammation by decreasing caspase-3 activation and modulating mitochondrial function. AB - Acute and chronic inflammation is characterized by increased reactive oxygen species (ROS) production, dysregulation of mitochondrial metabolism and abnormal immune function contributing to cardiovascular diseases and sepsis. Clinical and epidemiological studies suggest potential beneficial effects of dietary interventions in inflammatory diseases but understanding of how nutrients work remains insufficient. In the present study, we evaluated the effects of apigenin, an anti-inflammatory flavonoid abundantly found in our diet, in endothelial cells during inflammation. Here, we show that apigenin reduced lipopolysaccharide (LPS) induced apoptosis by decreasing ROS production and the activity of caspase-3 in endothelial cells. Apigenin conferred protection against LPS-induced mitochondrial dysfunction and reestablished normal mitochondrial complex I activity, a major site of electron leakage and superoxide production, suggesting its ability to modulate endothelial cell metabolic function during inflammation. Collectively, these findings indicate that the dietary compound apigenin stabilizes mitochondrial function during inflammation preventing endothelial cell damage and thus provide new translational opportunities for the use of dietary components in the prevention and treatment of inflammatory diseases. PMID- 23989611 TI - PDIP38 is translocated to the spliceosomes/nuclear speckles in response to UV induced DNA damage and is required for UV-induced alternative splicing of MDM2. AB - PDIP38 (polymerase delta interacting protein 38) was originally discovered as a protein that interacts with DNA polymerase delta and PCNA. PDIP38 is present in multiple intracellular locations and is a multifunctional protein that has been implicated in several diverse cellular functions. We investigated the nuclear localization of PDIP38 in order to gain insights to its response to UV damage. PDIP38 was found to form distinct nuclear foci in response to UV irradiation in several cell lines, including HeLa S3 and A549 cells. However, these foci were not those associated with UV repair foci. Using various markers for different nuclear subcompartments, the UV-induced PDIP38 foci were identified as spliceosomes/nuclear speckles, the storage and assembly sites for mRNA splicing factors. To assess the role of PDIP38 in the regulation of splicing events, the effects of PDIP38 depletion on the UV-induced alternate splicing of MDM2 transcripts were examined by nested RT-PCR. Alternatively spliced MDM2 products were induced by UV treatment but were greatly reduced in cells expressing shRNA targeting PDIP38. These findings indicate that upon UV-induced DNA damage, PDIP38 is translocated to spliceosomes and contributes to the UV-induced alternative splicing of MDM2 transcripts. Similar results were obtained when cells were subjected to transcriptional stresses with actinomycin D or alpha-amanitin. Taken together, these studies show that PDIP38 is a protein regulated in a dynamic manner in response to genotoxic stress, as evidenced by its translocation to the spliceosomes. Moreover, PDIP38 is required for the induction of the alternative splicing of MDM2 in response to UV irradiation. PMID- 23989612 TI - Autophagy-dependent ATP release from dying cells via lysosomal exocytosis. AB - ATP not only represents a key molecule for the intracellular storage and utilization of energy, but also plays a central role in the extracellular milieu, as it both recruits and activates immune cells. The secretion of ATP in the course of immunogenic cell death (ICD), a peculiar type of apoptosis that elicits adaptive immune responses, critically relies on the molecular machinery for autophagy. We have recently demonstrated that autophagy allows for the ICD associated secretion of ATP as it contributes to the maintenance of lysosomal ATP stores. In addition, we found that ATP release in this setting is mediated by a molecular mechanism that involves lysosomal-associated membrane protein 1 (LAMP1) and pannexin 1 (PANX1)-dependent lysosomal exocytosis. PMID- 23989613 TI - Aspirin prolongs survival and reduces the number of Foxp3+ regulatory T cells in a genetically engineered mouse model of pancreatic cancer. AB - BACKGROUND AND AIMS: Gemcitabine became the reference regimen for advanced pancreatic cancer after a randomized trial showed significant improvement in the median overall survival. Since then, the combination of gemcitabine with a variety of cytotoxic and targeted agents has generally shown no significant survival advantage as compared with gemcitabine alone. Only the addition of erlotinib to gemcitabine resulted in a significant but very small improvement in overall survival, coming along with a very uncomfortable rash in the patients. Therefore, new adjuvant agents with very low toxic levels are needed. In this study, we used a genetically engineered mouse model of pancreatic cancer to evaluate the chemotherapeutic potential of aspirin as an adjuvant agent to gemcitabine. METHODS: Drug treatment was initiated at the age of 3 months. LsL Kras (G12D) ; Pdx1-Cre or LsL-Kras (G12D) ; LsL-Trp53 (R172H) ; Pdx1-Cre transgenic mice were randomly assigned to receive either mock treatment, gemcitabine, or a combination of gemcitabine and aspirin. All mice were treated until death. The effect of aspirin was evaluated by histopathological analyses and immunostaining. RESULTS: Gemcitabine prolonged overall median survival of LsL Kras (G12D) ; LsL-Trp53 (R172H) ; Pdx1-Cre mice by 31 days as compared to mock treated animals (median survival, 190 vs. 159 days; p = 0.396). Addition of aspirin to gemcitabine even extended the survival for ten more days, leading to a prolonged survival by 41 days, reaching virtually statistical significance versus the control group (median survival, 200 vs. 159 days; p = 0.05). Furthermore, we found that administration of aspirin in combination with gemcitabine reduced the number of Foxp3(+) regulatory T cells significantly. CONCLUSION: In conclusion, we identified aspirin as an effective adjuvant agent to gemcitabine in the treatment of PDAC. While fundamental differences in biology suggest the need for caution in equating mouse tumors with their human counterparts, mouse models nevertheless represent an important source of insight regarding human neoplasia. Further studies are necessary to confirm the hypothesis that aspirin might be an effective well-tolerated chemotherapeutic adjuvant agent for pancreatic cancer. PMID- 23989615 TI - Self-portrait: Beauford Delaney. PMID- 23989614 TI - Increased regional deformation of the left ventricle in normal children with increased body mass index: implications for future cardiovascular health. AB - The prevalence of obesity continues to increase in the developing world. The effects of obesity on the cardiovascular system include changes in systolic and diastolic function. More recently obesity has been linked with impairment of longitudinal myocardial deformation properties in children. We sought to determine the effect of increased body mass index (BMI) on cardiac deformation in a group of children taking part in the population-based Southampton Women's Survey to detect early cardiovascular changes associated with increasing BMI before established obesity. Sixty-eight children at a mean age of 9.4 years old underwent assessment of longitudinal myocardial deformation in the basal septal segment of the left ventricle (LV) using two-dimensional speckle tracking echocardiography. Parameters of afterload and preload, which may influence deformation, were determined from cardiac magnetic resonance imaging. BMI was determined from the child's height and weight at the time of echocardiogram. Greater pediatric BMI was associated with greater longitudinal myocardial deformation or strain in the basal septal segment of the LV (beta = 1.6, p < 0.001); however, this was not related to contractility or strain rate in this part of the heart (beta = 0.001, p = 0.92). The end-diastolic volume of the LV increased with increasing BMI (beta = 3.93, p < 0.01). In young children, regional deformation in the LV increases with increasing BMI, whilst normal contractility is maintained. This effect may be explained by the increased preload of the LV associated with increased somatic growth. The long-term implications of this altered physiology need to be followed-up. PMID- 23989616 TI - Stromal glycolysis and MCT4 are hallmarks of DCIS progression to invasive breast cancer. PMID- 23989617 TI - Decorin has an appetite for endothelial cell autophagy. AB - DCN (decorin), an extracellular matrix constituent and archetypical small leucine rich proteoglycan (SLRP), acts as a soluble tumor repressor. DCN exerts high affinity binding interactions with receptor tyrosine kinases and evokes receptor internalization consequent with lysosomal degradation for tumorigenic and angiogenic suppression. In our recent study, we discovered that DCN evokes synthesis of PEG3 (paternally expressed 3), an imprinted gene often silenced in various forms of cancer. Upon DCN stimulation, PEG3 relocalizes to BECN1- and LC3 positive phagophores. Importantly, PEG3 physically associates with BECN1- and LC3 containing supramolecular complexes, in a DCN-inducible manner, and PEG3 is necessary to maintain homeostatic levels of BECN1. Furthermore, DCN evokes a protracted autophagic program via transactivation of the BECN1 and MAPLC3A loci that is critically dependent on PEG3 expression. Mechanistically, DCN directly binds to the Ig domains 3-5 of the KDR/VEGFR2 ectodomain, in a region that partially overlaps with the canonical binding site for VEGFA. Therefore, we have unveiled a novel mechanism for a secreted proteoglycan to induce endothelial cell autophagy in a PEG3-dependent manner. These findings are consistent with earlier preclinical studies focusing on DCN-mediated tumorigenic and angiogenic suppression and may represent the mechanism of action to achieve these effects. Therefore, DCN and perhaps other members of this class of matrix constituents may represent a novel control of autophagy from the outside of the cells. PMID- 23989618 TI - Hair cell generation by notch inhibition in the adult mammalian cristae. AB - Balance disorders caused by hair cell loss in the sensory organs of the vestibular system pose a significant health problem worldwide, particularly in the elderly. Currently, this hair cell loss is permanent as there is no effective treatment. This is in stark contrast to nonmammalian vertebrates who robustly regenerate hair cells after damage. This disparity in regenerative potential highlights the need for further manipulation in order to stimulate more robust hair cell regeneration in mammals. In the utricle, Notch signaling is required for maintaining the striolar support cell phenotype into the second postnatal week. Notch signaling has further been implicated in hair cell regeneration after damage in the mature utricle. Here, we investigate the role of Notch signaling in the mature mammalian cristae in order to characterize the Notch-mediated regenerative potential of these sensory organs. For these studies, we used the gamma-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S phenylglycine t-butyl ester (DAPT), in conjunction with a method we developed to culture cristae in vitro. In postnatal and adult cristae, we found that 5 days of DAPT treatment resulted in a downregulation of the Notch effectors Hes1 and Hes5 and also an increase in the total number of Gfi1(+) hair cells. Hes5, as reported by Hes5-GFP, was downregulated specifically in peripheral support cells. Using lineage tracing with proteolipid protein (PLP)/CreER;mTmG mice, we found that these hair cells arose through transdifferentiation of support cells in cristae explanted from mice up to 10 weeks of age. These transdifferentiated cells arose without proliferation and were capable of taking on a hair cell morphology, migrating to the correct cell layer, and assembling what appears to be a stereocilia bundle with a long kinocilium. Overall, these data show that Notch signaling is active in the mature cristae and suggest that it may be important in maintaining the support cell fate in a subset of peripheral support cells. PMID- 23989620 TI - Single cell detection using 3D magnetic rolled-up structures. AB - A 3D rolled-up structure made of a SiO2 layer and a fishbone-like magnetic thin film was proposed here as a biosensor. The magnetoresistance (MR) measurement results of the sensor suggest that the presence of the stray field, which is induced by the magnetic nanoparticles, significantly increased the switching field. Comparing the performance of the 2D sensor and 3D sensor designed in this study, the response in switching field variation was 12.14% in the 2D sensor and 62.55% in the 3D sensor. The response in MR ratio variation was 4.55% in the 2D sensor and 82.32% in the 3D sensor. In addition, the design of the 3D sensor structure also helped to attract and trap a single magnetic cell due to its stronger stray field compared with the 2D structure. The 3D magnetic biosensor designed here can provide important information for future biochip research and applications. PMID- 23989619 TI - Cocaine-induced changes of synaptic transmission in the striatum are modulated by adenosine A2A receptors and involve the tyrosine phosphatase STEP. AB - The striatum is a brain area implicated in the pharmacological action of drugs of abuse. Adenosine A2A receptors (A2ARs) are highly expressed in the striatum and mediate, at least in part, cocaine-induced psychomotor effects in vivo. Here we studied the synaptic mechanisms implicated in the pharmacological action of cocaine in the striatum and investigated the influence of A2ARs. We found that synaptic transmission was depressed in corticostriatal slices after perfusion with cocaine (10 MUM). This effect was reduced by the A2AR antagonist ZM241385 and almost abolished in striatal A2AR-knockout mice (mice lacking A2ARs in striatal neurons, stA2ARKO). The effect of cocaine on synaptic transmission was also prevented by the protein tyrosine phosphatases (PTPs) inhibitor sodium orthovanadate (Na3VO4). In synaptosomes prepared from striatal slices, we found that the activity of striatal-enriched protein tyrosine phosphatase (STEP) was upregulated by cocaine, prevented by ZM241385, and absent in synaptosomes from stA2ARKO. The role played by STEP in cocaine modulation of synaptic transmission was investigated in whole-cell voltage clamp recordings from medium spiny neurons of the striatum. We found that TAT-STEP, a peptide that renders STEP enzymatically inactive, prevented cocaine-induced reduction in AMPA- and NMDA mediated excitatory post-synaptic currents, whereas the control peptide, TAT-myc, had no effect. These results demonstrate that striatal A2ARs modulate cocaine induced synaptic depression in the striatum and highlight the potential role of PTPs and specifically STEP in the effects of cocaine. PMID- 23989621 TI - [The health of workers: between science and ethics]. PMID- 23989623 TI - [Meanings and conceptualizations of nursing: the point of view of students from the nursing degree program at the Universidad Nacional de Lanus, 2008-2010]. AB - This work looks into the meanings of nursing from the point of view of the students in an undergraduate nursing degree program. The research took place at the Universidad Nacional de Lanus using semistructured interviews - eleven individual and seven group interviews - carried out between 2008 and 2010. A content analysis was then undertaken and the most relevant meanings in relation to four themes were selected: reasons for studying nursing, what nursing is, nursing as a profession, and working in nursing. Multiple and diverse ways of defining nursing were uncovered. Utilizing some conceptual developments from the sociology of the professions, the meanings were organized into four conceptualizations that represent ways of understanding nursing: as a vocation, as a profession, with a utilitarian perspective and with a community perspective. The conclusions reached indicate the need to broaden the debate regarding the types of nurses that are being trained. PMID- 23989622 TI - [Fatal work-related injuries and interpersonal violence in Brazil, 2000-2010]. AB - In this study, we present estimates of the proportionate mortality of work injuries involving interpersonal violence in Brazil from 2000 to 2010. Data come from the Mortality Information System based on death certificates from the Health Ministry, which in Brazil include a field for recording work-related injuries that must be completed in all deaths due to external causes. There were 1,368,732 deaths due to external causes, 31,576 (2.3%) due to work injuries, and only 226 (0.02%) due to work injuries involving interpersonal violence. Nearly 80% of the death certificates did not include data in the work injury field. Most cases occurred among males (94.3%) 25-34 years of age with less than high school education in the Southeast and Northeast country regions, primarily in the manufacturing and agricultural industries. The majority of cases were caused by firearms, followed by sharp instruments, with a relative increase in this last category during the study period. Findings suggest underrecording of diagnoses that recognize the work-related nature of the death. Better training on death certificate completion and studies to quantify the underrecording of work injuries and work injuries involving interpersonal violence are needed. PMID- 23989624 TI - [Social inequalities in cervical cancer mortality in the Autonomous City of Buenos Aires, 1999-2003 and 2004-2006]. AB - The aim of this study was to describe the spatial distribution of cervical cancer mortality in the Autonomous City of Buenos Aires during the period 1999-2003 and its relationship to the socioeconomic conditions of the population, as well as to compare the distribution during this period with that of the triennium 2004-2006. This ecological study used electoral districts as the unit of analysis. The selected socioeconomic indicators were educational deficit, lack of health insurance and the Material Deprivation of Households Index (Indice de Privacion Material de Hogares), taken from the National Population and Housing Census (Censo Nacional de Poblacion, Hogares y Viviendas) of 2001. The stratification of the city into areas according to these conditions and the analysis of standardized mortality ratios showed an increased risk of dying from cervical cancer associated with worse socioeconomic conditions. The stratification and death risks demonstrated a clear spatial pattern, with the south of the city presenting the highest death risks, and the northern and central areas presenting the lowest risks. PMID- 23989625 TI - [Bullying in the metropolitan area of Guadalajara, Mexico: prevalence and associated factors]. AB - This paper seeks to determine the prevalence of victims of school bullying among youth enrolled in public secondary schools in the metropolitan area of Guadalajara, Mexico and to identify the factors associated with being a victim of bullying in the period 2009-2011. An analytic cross-sectional study was carried out. A multistage probability sampling was designed for the public secondary schools, in which 1,706 students between 11 and 16 years old were studied. A questionnare with four sections was applied in order to identify victims of bullying. A logistic regression model was then used to measure the association between the factors analyzed and being a victim of bullying. The prevalence of school bullying was 17.6% (95% CI 15.8; 19.5). Personal factors, such as the feeling of not being accepted by peers or not spending much time with friends, were the factors with the strongest statistically significant association with being a victim of bullying. PMID- 23989626 TI - [Health and productivity? On the development of an "economic" analytics of the relationship between work and health (Argentina, 1900-1955)]. AB - This article seeks to demonstrate that the economic rationalization in health that characterizes the present, although possessing unique features, is inscribed within a longer historical process. Between 1900 and 1955, an "economic analytics" of the relationship between health and work was developed in Argentina, structured around the following focal points: reflections on the "price of a man"; thought that framed social medicine within the "human economy" program; the discourse of healthful and efficient living; the calculations of factory doctors and the conformation of an economic and utilitarian discourse within occupational medicine; and, finally, debates on productivity. These five central concepts define the emergence of a particular problematization regarding worker health and, in turn, raise questions about the relationship between capitalism, liberalism and biopower in occidental societies. PMID- 23989627 TI - [Prevention of cervical and breast cancer in health services and non-governmental organizations in the city of Buenos Aires]. AB - The article analyzes actions for the prevention of cervical and breast cancer in public, private, and employment-based health services and in non-governmental organizations in the city of Buenos Aires. The article seeks to reflect on the reach and limitations of the approaches implemented in the three subsectors of the health care system and the community to prevent women from suffering or eventually dying as a consequence of these diseases, in the fragmented context of a health system with great heterogeneity in access and deep social inequalities in the use of preventive actions. The study utilizes a broad definition of prevention which integrates education, awareness-building and early detection of pre-carcinogenic and carcinogenic lesions, among other medical and non-medical components. The results were obtained using semi-structured interviews with subjects from public hospitals, employment-based health care services, private medical companies and non-governmental organizations with work in cancer prevention. These results show that contrary to a comprehensive approach, each institution limits its actions to only one aspect of prevention, implementing predominately isolated or disconnected actions inadequate to generate an autonomous and well-informed demand for treatment and health care among women. PMID- 23989628 TI - [Legislation, knowledge and attitudes of health professionals in Mexico regarding abortion]. AB - The purpose of this study is to describe the knowledge and attitudes regarding abortion of a sample of health professionals in Mexico. In particular, we aim to explore their association with the practice of abortion and the care of post abortion complications, taking into consideration the present legal framework in Mexico. The data come from an anonymous and computerized survey applied to participants attending a national meeting of gynecology and obstetrics in Mexico in 2009 (n=418). The attitudes of health professionals in relation to abortion play a key role in promoting access to both medical and surgical abortion services. We did not find a statistical association between living in a largely restrictive federal entity and the practice of abortions, which may be explained by the lack of knowledge that these survey participants had about abortion laws in their federal entity. This lack of knowledge about abortion legislation can hinder a woman's access to these services even when the legal framework such access. PMID- 23989629 TI - [Occupational risks and health: perceptions of indigenous female agricultural workers in Northwestern Mexico]. AB - The objective of this study was to learn the perceptions of indigenous female day laborers regarding health-related risks in the workplace, based on their own characterization of the requirements of agricultural work. The concept of occupational risk is understood as a flexible construct in which work conditions and the different perceptions and lived experiences of social actors are interrelated. A microstructural model is employed to explain the occupational risks and their relationship to social inequalities and impacts in health. The methodology used was qualitative, employing non-participant observation, participatory workshops and group interviews during 2011-2012. Sixty indigenous women participated in the study. Results reveal that their perception regarding occupational risks is constructed from everyday practices in their place of work and that most of their work activities place them in situations of risk. PMID- 23989630 TI - [Salud Colectiva: report on editorial management 2011-2012]. PMID- 23989632 TI - pi-Conjugated polyHIPEs as highly efficient and reusable heterogeneous photosensitizers. AB - pi-Conjugated microporous polyHIPEs are synthesized via Suzuki cross-coupling. The polymeric backbone consists of electron donor and acceptor moieties with suitable energetic characteristics to promote the efficient photosensitizing ability for the activation of singlet oxygen, showing extraordinarily high stability. The reaction can be carried out in a continuous flow reaction set-up, realizing complete conversion of alpha-terpinene into ascaridole. PMID- 23989631 TI - Digital imprinting of RNA recognition and processing on a self-assembled nucleic acid matrix. AB - The accelerating progress of research in nanomedicine and nanobiotechnology has included initiatives to develop highly-sensitive, high-throughput methods to detect biomarkers at the single-cell level. Current sensing approaches, however, typically involve integrative instrumentation that necessarily must balance sensitivity with rapidity in optimizing biomarker detection quality. We show here that laterally-confined, self-assembled monolayers of a short, double stranded(ds)[RNA-DNA] chimera enable permanent digital detection of dsRNA specific inputs. The action of ribonuclease III and the binding of an inactive, dsRNA-binding mutant can be permanently recorded by the input-responsive action of a restriction endonuclease that cleaves an ancillary reporter site within the dsDNA segment. The resulting irreversible height change of the arrayed ds[RNA DNA], as measured by atomic force microscopy, provides a distinct digital output for each dsRNA-specific input. These findings provide the basis for developing imprinting-based bio-nanosensors, and reveal the versatility of AFM as a tool for characterizing the behaviour of highly-crowded biomolecules at the nanoscale. PMID- 23989634 TI - Compounding dermatological products. PMID- 23989635 TI - Malathion topical lotion: therapy for resistant head lice. PMID- 23989633 TI - Management of a fire in the operating room. AB - Operating room (OR) fires remain a significant source of liability for anesthesia providers and injury for patients, despite existing practice guidelines and other improvements in operating room safety. Factors contributing to OR fires are well understood and these occurrences are generally preventable. OR personnel must be familiar with the fire triad which consists of a fuel supply, an oxidizing agent, and an ignition source. Existing evidence shows that OR-related fires can result in significant patient complications and malpractice claims. Steps to reduce fires include taking appropriate safety measures before a patient is brought to the OR, taking proper preventive measures during surgery, and effectively managing fire and patient complications when they occur. Decreasing the incidence of fires should be a team effort involving the entire OR personnel, including surgeons, anesthesia providers, nurses, scrub technologists, and administrators. Communication and coordination among members of the OR team is essential to creating a culture of safety. PMID- 23989636 TI - Treatment of skin aging with topical estrogens. PMID- 23989637 TI - Dermatological compounds from the Caribbean. PMID- 23989638 TI - The rewards of treating decubitus ulcers. PMID- 23989639 TI - Tea tree oils. PMID- 23989640 TI - The stability of amphotericin B in a mixture of fungizone and optimoist. AB - The physical and chemical stability of amphotericin B in a mixture of Fungizone and Optimoist was studied. The mixture was prepared by mixing equal volumes of Fungizone and Optimoist. The rate of sedimentation of amphotericin B was evaluated in Fungizone, Fungizone:Optimoist (1:1) and Fungizone:distilled water (1:1) mixture. The chemical stability of amphotericin B in a mixture of Fungizone:Optimoist (1:1) was determined by high-performance liquid chromatography from samples stored at different temperatures. The rate of sedimentation was faster when Fungizone was mixed with distilled water as compared to Optimoist. Amphotericin B was stable for three weeks stored in the refrigerator (4 deg C) and for three weeks at room temperature (25 deg C). Fungizone can be diluted with Optimoist for topical application. The mixture should be shaken well before administration in order to disperse any sediment. PMID- 23989641 TI - Stability of ciprofloxacin in an extemporaneous oral liquid dosage form. AB - The stability of ciprofloxacin hydrochloride in an extemporaneously compounded oral liquid formulation was studied. A suspension was prepared by mixing four crushed, commercially available 750-mg tablets of ciprofloxacin hydrochloride with equal amounts of Ora Plus and simple syrup, NF to make a final volume of 60 mL. The final concentration of ciprofloxacin hydrochloride in the suspension was 50 mg/mL. Six identical suspensions were prepared, placed in amber, plastic prescription bottles and stored at room temperature (24 to 26 deg C) and under refrigeration (3 to 5 deg C). Immediately after preparation and at seven, 14, 28, and 56 days, samples were removed and assayed in duplicate by stability indicating high-performance liquid chromatography. Color, odor and pH did not change appreciably over the study period. At least 99% of the inital ciprofloxacin hydrochloride concentration remained in all suspensions througout the study period. Ciprofloxacin hydrochloride 50 mg/mL compounded extemporaneously in equal amounts of Ora Plus and simple syrup, NF was stable at room temperature and under refrigeration for at least 56 days in amber, plastic prescription bottles. PMID- 23989642 TI - Compatibility and stability of ranitidine hydrochloride with six cephalosporins during simulated y-site administration. AB - The purpose of this project was to determine the visual compatibility and stability of ranitidine hydrochloride in admixtures during simulated Y-site administration with six individual cephalosporins: ceftizoxime sodium, cefuzonam sodium, cefoperazone sodium, cefmenoxime hydrochloride, moxalactam disodium and flomoxef sodium. Dilutions of ranitidine hydrochloride 1 mg (as the free base)/mL were prepared in 0.9% sodium chloride injection. Two milliliters of the ranitidine solution (1mg/mL) was mixed with 2mL of each cephalosporin (20 mg/ml) in 10 mL glass test tubes. Concentrations of each drug were determined by stability-indicationg high-performance liquid chromatographic assay methods following zero, one, two, and four hours after mixing. All six cephalosporins retained greater than 95% of their original concentrations for four hours in the admixture with ranitidine. Ranitidine retained greater than 95% of its original concentration for four hours in the admixture with four of the tested cephalosporins and apporximately 90% with moxalactam and flomoxef. Solutions containing ranitidine may be coadministered with solutions either ceftizoxime, cefuzonam, cefoperazone or cefmenoxime via Y-injection site over four hours. While the ranitidine concentration may be reduced to near 90% after four hours with moxalactam and flomoxef, the tested antibiotics were not affected in the presence of ranitidine over four hours. PMID- 23989643 TI - Stability of Lorazepam in 5% dextrose injection. AB - The adsorption of lorazepam in intravenous admixtures onto 50-mL polyvinyl chloride (PVC) bags has been studied using a spectorphotometric assay method reported in the literature. This method indicated a loss of 7.7% to 9.5% versus a high-performance liquid chromatography (HPLC) assay method developed in our laboratory, which showed a loss of 4.9% to 5.5%. In the spectrophotometric assay method, benzyl alcohol (the preservative in the lorazepam injection) interfered with the assay procedure. The HPLC assay method separated the peak of lorazepam from the benzyl alcohol peak. It also showed that part of the loss as determined by spectrophotometric assay method was due to the absorption of benzyl alcohol. The adsorbed lorazepam was adsorbed in less than six hours and there was no more loss after that. By storing different volumes of the admixture (20, 30, 40, and 50 mL) vertically in 50-mL PVC bags, the loss of drug due to adsorption did not show any siginificant differences. PMID- 23989644 TI - Frontline health care workers and perceived career mobility: do high-performance work practices make a difference? AB - BACKGROUND: The use of high-performance work practices (HPWPs) related to career development (e.g., tuition remission, career ladders) is becoming more common in health care organizations, where skill shortages and concerns about quality of care have led to increasing investment in the frontline health care workforce. However, few studies have examined the effectiveness of these policies in shaping the career trajectories of health care workers. PURPOSES: The aim of this study is to examine how HPWPs that focus on career development are related to an individuals' perceived mobility with their current employer. We will also examine the relationships between perceived mobility, job satisfaction, and turnover intent. METHODOLOGY/APPROACH: We use confirmatory factor analysis and structural equation modeling to examine the relationships between HPWPs and perceived mobility in a sample of 947 frontline health care workers in 22 health care organizations across the United States. FINDINGS: The findings suggest that tuition remission and educational release time positively predict perceived mobility. Measures of perceived organizational support in one's current position (e.g., financial rewards, workload, and autonomy) and perceived supervisor support for career development are also significant predictors of perceived mobility. Finally, perceived mobility is a significant predictor of job satisfaction and intent to stay with current employer. PRACTICE IMPLICATIONS: Our findings suggest that HPWPs related to career development may be effective tools in improving workers' assessments of their own career potential and improving overall job satisfaction of frontline health care workers. Consequently, HPWPs related to career development may help employers both retain valuable workers and fill worker shortages. PMID- 23989645 TI - The economic crisis in Spain and its impact on the mental health of children and adolescents. PMID- 23989646 TI - A KCNQ1 mutation causes age-dependant bradycardia and persistent atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia. Gain-of-function mutations in KCNQ1, the pore-forming alpha-subunit of the slow delayed rectifier K current (IKs) channel, have been associated with AF. The purpose of this study was functional assessment of a mutation in KCNQ1 identified in a family with persistent AF and sinus bradycardia. We investigated whether this KCNQ1 missense mutation could form the genetic basis for AF and bradycardia simultaneously in this family. Sanger sequencing in a family with hereditary persistent AF identified a novel KCNQ1 variant (V241F) in a highly conserved region of S4 domain. The proband and her son developed bradycardia and persistent AF in an age dependent fashion. The other son was a mutation carrier but he showed sinus bradycardia and not AF. Whole-cell patch clamp electrophysiology showed that V241F mutation in KCNQ1 shifted the activation curve to the left and dramatically slowed deactivation, leading to a constitutively open-like phenotype. Computer modeling showed that V241F would slow pacemaker activity. Also, simulations of atrial excitation predicted that V241F results in extreme shortening of action potential duration, possibly resulting in AF. Our study indicates that V241F might cause sinus bradycardia by increasing IKs. Additionally, V241F likely shortens atrial refractoriness to promote a substrate for reentry. KCNQ1 mutations have previously been described in AF, yet this is the first time a mutation in KCNQ1 is associated with age-dependent bradycardia and persistent AF. This finding further supports the hypothesis that sinus node dysfunction contributes to the development of AF. PMID- 23989648 TI - Mapping of QTL conferring resistance to sharp eyespot (Rhizoctonia cerealis) in bread wheat at the adult plant growth stage. AB - KEY MESSAGE: Seven sharp eyespot resistance QTL were detected consistently across five environments and delimited to seven DNA marker intervals, respectively, six of which were independent of plant height and heading time. Sharp eyespot, caused mainly by the soil-borne fungus Rhizoctonia cerealis, is one of the important diseases of bread wheat (Triticum aestivum L.). This disease has escalated into a major threat to wheat production in some regions of the world. Wheat resistance to sharp eyespot can be a potential means to reduce the needs for application of fungicides and agricultural inputs. In the present study, the winter wheat lines, Luke and AQ24788-83, both of which possess quantitative resistance to sharp eyespot, were crossed and a population consisting 241 recombinant-inbred lines (RILs) was constructed. These RILs were assessed for sharp eyespot resistance by conducting five field and greenhouse trials during the period from 2008 to 2012, and they were genotyped with 549 simple-sequence repeat DNA markers. Seven quantitative trait loci (QTL) were detected consistently across the five trial environments to be associated with the sharp eyespot resistance. They were mapped on chromosomes 1A, 2B, 3B, 4A, 5D, 6B, and 7B. Four of these QTL are unequivocally novel, while it is possible that the other three might also be novel. Plant height and heading date of the 241 RILs were recorded in the four field trials. All of the seven disease resistance QTL were independent of plant height and heading time except one that was significantly associated with plant heading time. This association might be attributed genetically to a single QTL, or to different but closely linked QTL. In the case of single QTL, pleiotropism might be involved or the sharp eyespot resistance might be conferred in a physical instead of physiological nature. PMID- 23989649 TI - Induction of 4VS chromosome recombinants using the CS ph1b mutant and mapping of the wheat yellow mosaic virus resistance gene from Haynaldia villosa. AB - The wheat spindle streak mosaic virus (WSSMV) or wheat yellow mosaic virus (WYMV) resistance gene, Wss1, from Haynaldia villosa, was previously mapped to the chromosome arm 4VS by the development of 4V (4D) substitution and T4DL.4VS translocation lines. For better utilization and more accurate mapping of the Wss1, in this research, the CS ph1b mutant was used to induce new translocations with shortened 4VS chromosome fragments. Thirty-five homozygous translocations with different alien fragment sizes and breakpoints of 4VS were identified by GISH and molecular marker analysis. By field test, it was found that all the identified terminal translocations characterized as having smaller 4VS chromosome segments in the chromosome 4DS were highly resistant to WYMV, while all the interstitial translocations with 4VS inserted into the 4DS were WYMV susceptible. Marker analysis using 32 4VS-specific markers showed that both the terminal and interstitial translocations had different alien fragment sizes. Five specific markers could be detected in the WYMV-resistant terminal translocation line NAU421 with the shortest introduced 4VS fragment, indicating they can be used for marker-assisted selection in wheat breeding. Based on the resistance evaluation, GISH and molecular marker analysis of the available translocations, the gene(s) conferring the WYMV resistance on 4VS could be further cytologically mapped to the distal region of 4VS, immersed in the bin of FL 0.78-1.00. The newly developed small fragment translocations with WYMV resistance and 4VS specific markers have laid solid groundwork for the utilization in wheat breeding for WYMV resistance as well as further cloning of Wss1. PMID- 23989647 TI - Copy number polymorphism in plant genomes. AB - Copy number variants (CNVs) are genomic rearrangements resulting from gains or losses of DNA segments. Typically, the term refers to rearrangements of sequences larger than 1 kb. This type of polymorphism has recently been shown to be a key contributor to intra-species genetic variation, along with single-nucleotide polymorphisms and short insertion-deletion polymorphisms. Over the last decade, a growing number of studies have highlighted the importance of copy number variation (CNV) as a factor affecting human phenotype and individual CNVs have been linked to risks for severe diseases. In plants, the exploration of the extent and role of CNV is still just beginning. Initial genomic analyses indicate that CNVs are prevalent in plants and have greatly affected plant genome evolution. Many CNV events have been observed in outcrossing and autogamous species. CNVs are usually found on all chromosomes, with CNV hotspots interspersed with regions of very low genetic variation. Although CNV is mainly associated with intergenic regions, many CNVs encompass protein-coding genes. The collected data suggest that CNV mainly affects the members of large families of functionally redundant genes. Thus, the effects of individual CNV events on phenotype are usually modest. Nevertheless, there are many cases in which CNVs for specific genes have been linked to important traits such as flowering time, plant height and resistance to biotic and abiotic stress. Recent reports suggest that CNVs may form rapidly in response to stress. PMID- 23989650 TI - Natural and semisynthetic analogues of manadoperoxide B reveal new structural requirements for trypanocidal activity. AB - Chemical analysis of the Indonesian sponge Plakortis cfr. lita afforded two new analogues of the potent trypanocidal agent manadoperoxide B (1), namely 12 isomanadoperoxide B (2) and manadoperoxidic acid B (3). These compounds were isolated along with a new short chain dicarboxylate monoester (4), bearing some interesting relationships with the polyketide endoperoxides found in this sponge. Some semi-synthetic analogues of manadoperoxide B (6-8) were prepared and evaluated for antitrypanosomal activity and cytotoxicity. These studies revealed crucial structure-activity relationships that should be taken into account in the design of optimized and simplified endoperoxyketal trypanocidal agents. PMID- 23989651 TI - Supraventricular tachycardia with 'A-A-V' response upon ventricular entrainment and transient 2:1 AV conduction block. PMID- 23989652 TI - Epidemiology of Chagas disease in Europe: many calculations, little knowledge. AB - Chagas disease and its causative agent Trypanosoma cruzi are endemic in almost all countries in South and Middle America. Currently, there are more than 10 million affected people. It is the most common reason for heart failure and a frequent cause of intestinal problems in Latin America. The phenotype of the Chagas cardiomyopathy is varying. Dilative cardiomyopathy, often accompanied by an apical aneurysm is the most common finding in the end stage heart failure, but rhythm disorders like conduction blocks, ventricular or supraventricular forms of tachycardia or repolarization changes occur as well, mainly in the early stages. Migration of infected people leads to a distribution from the endemic countries to North America and Europe. Although more than 500,000 people of Latin American origin are currently living in Europe, Chagas disease is not considered as a public health problem, yet. Cases of transmission via blood donation, organ transplantation or from mother-to-child are reported for several European countries but there is no database for Germany. Current epidemiological data are mostly available from regional surveys from other countries or are extrapolated. Hence, there is a large variation in the estimated numbers on the incidence of Chagas. Robust and reliable data are lacking. This review gives an overview on the currently available data and calls for a German Chagas surveillance. PMID- 23989653 TI - An intragastric chest tube insertion. PMID- 23989654 TI - Association between urinary albumin excretion and coronary heart disease in black vs white adults. AB - IMPORTANCE: Excess urinary albumin excretion is more common in black than white individuals and is more strongly associated with incident stroke risk in black vs white individuals. Whether similar associations extend to coronary heart disease (CHD) is unclear. OBJECTIVE: To determine whether the association of urinary albumin excretion with CHD events differs by race. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of black and white US adults aged 45 years and older who were enrolled within the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study between 2003 and 2007 with follow-up through December 31, 2009. We examined race-stratified associations of urinary albumin-to-creatinine ratio (ACR) in 2 groups: (1) incident CHD among 23,273 participants free of CHD at baseline; and (2) first recurrent CHD event among 4934 participants with CHD at baseline. MAIN OUTCOMES AND MEASURES: Expert adjudicated incident and recurrent myocardial infarction and acute CHD death. RESULTS: A total of 616 incident CHD events (421 nonfatal MIs and 195 CHD deaths) and 468 recurrent CHD events (279 nonfatal MIs and 189 CHD deaths) were observed over a mean time of 4.4 years of follow-up. Among those free of CHD at baseline, age- and sex-adjusted incidence rates of CHD per 1000 person-years of follow-up increased with increasing categories of ACR in black and white participants, with rates being nearly 1.5-fold greater in the highest category of ACR (>300 mg/g) in black participants (20.59; 95% CI, 14.36-29.51) vs white participants (13.60; 95% CI, 7.60-24.25). In proportional hazards models adjusted for traditional cardiovascular risk factors and medications, higher baseline urinary ACR was associated with greater risk of incident CHD among black participants (hazard ratio [HR] comparing ACR >300 vs <10 mg/g, 3.21 [95% CI, 2.02-5.09]) but not white participants (HR comparing ACR >300 vs <10 mg/g, 1.49 [95% CI, 0.80-2.76]) (P value for interaction = .03). Among those with CHD at baseline, fully adjusted associations of baseline urinary ACR with first recurrent CHD event were similar between black participants (HR comparing ACR >300 vs <10 mg/g, 2.21 [95% CI, 1.22 4.00]) vs white participants (HR comparing ACR >300 vs <10 mg/g, 2.48 [95% CI, 1.61-3.78]) (P value for interaction = .53). CONCLUSIONS AND RELEVANCE: Higher urinary ACR was associated with greater risk of incident but not recurrent CHD in black individuals when compared with white individuals. These data confirm that black individuals appear more susceptible to vascular injury. PMID- 23989657 TI - Childhood obesity increases left-ventricular mass irrespective of blood pressure status. AB - Adults with a left-ventricular mass index (LVMI) in grams normalized to height in meters(2.7) (LVMI g/m(2.7)) >51 g/m(2.7) are more prone to cardiovascular and cerebrovascular events. We delineated the odds for cardiac structural sequelae amongst apparently normal white and African-American (AA) children with varying body mass indices (BMI) and office blood pressures. A total of 2,071 children with normal echocardiograms were categorized into risk groups based on BMI and systolic blood pressures (SBPs). Predictors of cardiac sequelae examined were age, sex, race, and z-scores (z) for BMI, SBP, and diastolic blood pressure. Cardiac sequelae measures included (LVMI g/m(2.7)) >51 g/m(2.7), (LVMI) (g/m(2.7)) z, left atrial size (LA(ht)) (mm) z, and relative wall thickness z. Mean age was 14 +/- 2 years with 56 % being male and 13 % being AA. Children were divided into "controls" (n = 1,059) and risk groups based on BMI and SBP. Odds ratio for LVMI (g/m(2.7)) > 51.0 g/m(2.7), varied from 5.3 up to 8.5 in children with increased BMI. Both increased BMI and SBP z were associated with increased LVMI (g/m(2.7)) z; however, BMI z had a stronger association. Increased BMI z and AA race were associated with greater LA(ht) (mm) z. AA controls had a nonsignificantly increased LVMI z and a significantly increased LA(ht) (mm) and RWT z. Being overweight or obese is associated with cardiac sequelae in children to the extent known to be associated with adverse outcomes in adults. Healthy AA children have unique cardiac structural differences. PMID- 23989658 TI - Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence. AB - Radiotherapy is one of the well-established therapeutic modalities for cancer treatment. However, the emergence of cells refractory to radiation is a major obstacle to successful treatment with radiotherapy. Many reports suggest that inhibitors targeting the mechanistic target of rapamycin (MTOR) can sensitize cancer cells to the effect of radiation, although by which mechanism MTOR inhibitors enhance the efficacy of radiation toward cancer cells remains to be elucidated. Our studies indicate that a potent and persistent activation of autophagy via inhibition of the MTOR pathway, even in cancer cells where autophagy is occurring, can trigger premature senescence, cellular proliferation arrest. Combined treatment of MTOR inhibitor and radiation induce heterochromatin formation, an irreversible growth arrest and an increase of senescence-associated GLB1 (beta-galactosidase) activity, which appear to result from a constant activation of TP53 and a restoration in the activity of retinoblastoma 1 protein (RB1)-E2F1. Thus, this study provides evidence that promoting cellular senescence via inhibition of the MTOR pathway may serve as an avenue to augment radiosensitivity in cancer cells that initiate an autophagy-survival mode to radiotherapy. PMID- 23989661 TI - Tissue-dependent regulation of RNAP II dynamics: the missing link between transcription and trinucleotide repeat instability in diseases? AB - More than 15 human genetic diseases, including Huntington's disease, result from the expansion of a trinucleotide repeat. The expansions are unstable in specific somatic tissues, which can lead to disease acceleration. Here we discuss the role of transcription elongation in tissue-selective trinucleotide repeat instability. PMID- 23989662 TI - Dose-dependent regulation of target gene expression and cell proliferation by c Myc levels. AB - The proto-oncogene c-myc encodes a basic helix-loop-helix leucine zipper transcription factor (c-Myc). c-Myc plays a crucial role in cell growth and proliferation. Here, we examined how expression of c-Myc target genes and cell proliferation depend on variation of c-Myc protein levels. We show that proliferation rates, the number of cells in S-phase, and cell size increased in a dose-dependent manner in response to increasing c-Myc levels. Likewise, the mRNA levels of c-Myc responsive genes steadily increased with rising c-Myc levels. Strikingly, steady-state mRNA levels of c-Myc target genes did not saturate even at highest c-Myc concentrations. These characteristics predestine c-Myc levels as a cellular rheostat for the control and fine-tuning of cell proliferation and growth rates. PMID- 23989663 TI - Topoisomerase II plays a role in dosage compensation in Drosophila. AB - In Drosophila, dosage compensation is mediated by the MSL complex, which binds numerous sites on the X chromosome in males and enhances the transcriptional rate of a substantial number of X-linked genes. We have determined that topoisomerase II (Topo II) is enriched on dosage compensated genes, to which it is recruited by association with the MSL complex, in excess of the amount that is present on autosomal genes with similar transcription levels. Using a plasmid model, we show that Topo II is required for proper dosage compensation and that compensated chromatin is topologically different from non-compensated chromatin. This difference, which is not the result of the enhanced transcription level due of X linked genes and which represents a structural modification intrinsic to the DNA of compensated chromatin, requires the function of Topo II. Our results suggest that Topo II is an integral part of the mechanistic basis of dosage compensation. PMID- 23989664 TI - Bacteriophage lambda repressor mediates the formation of a complex enhancer-like structure. PMID- 23989665 TI - Defective quality control mechanisms and accumulation of damaged mitochondria link Gaucher and Parkinson diseases. AB - Mutations in the GBA gene encoding glucocerebrosidase cause Gaucher disease (GD), the most prevalent of the lysosomal storage disorders (LSDs) and increase susceptibility to Parkinson disease (PD). Clinically the two disorders can present in a similar manner with analogous pathological features, suggesting mechanistic links between the two disease states. An increasing body of evidence implicates defects in quality control pathways in both, and suggests that LSDs, as a group, can be classed as disorders of autophagy. Using a mouse model of type II neuronopathic GD, we observed global defects in cellular quality control pathways in midbrain neurons and astrocytes. Our data suggest that downregulation of autophagy, mitophagy, and the ubiquitin-proteasome system (UPS) results in accumulation of dysfunctional and fragmented mitochondria, insoluble SNCA/alpha synuclein deposits and ubiquitinated proteins. These observations show that dysfunction of cellular quality control pathways lead to impaired energy and free radical homeostasis, providing new insights into the mechanisms of neurodegeneration in GD and illuminating the links between GD and PD. PMID- 23989666 TI - Simple network motifs can capture key characteristics of the floral transition in Arabidopsis. AB - The floral transition is a key decision during plant development. While different species have evolved diverse pathways to respond to different environmental cues to flower in the correct season, key properties such as irreversibility and robustness to fluctuating signals appear to be conserved. We have used mathematical modeling to demonstrate how minimal regulatory networks of core components are sufficient to capture these behaviors. Simplified models inevitably miss finer details of the biological system, yet they provide a tractable route to understanding the overall system behavior. We combined models with experimental data to qualitatively reproduce characteristics of the floral transition and to quantitatively scale the network to fit with available leaf numbers. Our study highlights the value of pursuing an iterative approach combining modeling with experimental work to capture key features of complex systems. PMID- 23989668 TI - The first chiral Raman spectrum report of a protein: a perspective of 20 years. AB - In 1990 the article on the first Raman spectrum of a protein using a circularly polarized light as excitation radiation, authored by the group of Prof. L. Barron, was published in ChemComm. In this viewpoint we analyze this pioneering work and we used it as a starting point to highlight, after 20 years since its publication, the most outstanding contributions in the application of the Raman Optical Activity to proteins and biological systems. PMID- 23989667 TI - RICE SALT SENSITIVE3 binding to bHLH and JAZ factors mediates control of cell wall plasticity in the root apex. AB - Plasticity of root growth in response to environmental cues and stresses is a fundamental characteristic of plants, in accordance with their sessile lifestyle. This is linked to the balance between plasticity and rigidity of cells in the root apex, and thus is coordinated with the control of cell wall properties. However, mechanisms underlying such harmonization are not well understood, in particular under stressful conditions. We have recently demonstrated that RICE SALT SENSITIVE3 (RSS3), a nuclear factor that mediates restrictive expression of jasmonate-induced genes, plays an important role in root elongation under saline conditions. In this study, we report that loss-of-function of RSS3 results in changes in cell wall properties such as lignin deposition and sensitivity to a cellulose synthase inhibitor, concomitant with altered expression of genes involved in cell wall metabolism. Based on these and previous phenotypic observations of the rss3 mutant, we propose that RSS3 plays a role in the coordinated control of root elongation and cell wall plasticity in the root apex. PMID- 23989669 TI - Refractory IGkappa/IRF4-positive DLBCL with CDKN2A/2B deletion. PMID- 23989670 TI - The simulation model of growth and cell divisions for the root apex with an apical cell in application to Azolla pinnata. AB - In contrast to seed plants, the roots of most ferns have a single apical cell which is the ultimate source of all cells in the root. The apical cell has a tetrahedral shape and divides asymmetrically. The root cap derives from the distal division face, while merophytes derived from three proximal division faces contribute to the root proper. The merophytes are produced sequentially forming three sectors along a helix around the root axis. During development, they divide and differentiate in a predictable pattern. Such growth causes cell pattern of the root apex to be remarkably regular and self-perpetuating. The nature of this regularity remains unknown. This paper shows the 2D simulation model for growth of the root apex with the apical cell in application to Azolla pinnata. The field of growth rates of the organ, prescribed by the model, is of a tensor type (symplastic growth) and cells divide taking principal growth directions into account. The simulations show how the cell pattern in a longitudinal section of the apex develops in time. The virtual root apex grows realistically and its cell pattern is similar to that observed in anatomical sections. The simulations indicate that the cell pattern regularity results from cell divisions which are oriented with respect to principal growth directions. Such divisions are essential for maintenance of peri-anticlinal arrangement of cell walls and coordinated growth of merophytes during the development. The highly specific division program that takes place in merophytes prior to differentiation seems to be regulated at the cellular level. PMID- 23989671 TI - Enzyme-controllable delivery of nitric oxide from a molecular hydrogel. AB - A beta-galactosidase-responsive molecular hydrogelator of a nitric oxide (NO) donor can release NO in a controllable manner to improve wound healing. PMID- 23989672 TI - Development of wheat-Aegilops speltoides recombinants and simple PCR-based markers for Sr32 and a new stem rust resistance gene on the 2S#1 chromosome. AB - KEY MESSAGE: Wheat- Aegilops speltoides recombinants carrying stem rust resistance genes Sr32 and SrAes1t effective against Ug99 and PCR markers for marker-assisted selection. Wild relatives of wheat are important resources for new rust resistance genes but underutilized because the valuable resistances are often linked to negative traits that prevent deployment of these genes in commercial wheats. Here, we report ph1b-induced recombinants with reduced alien chromatin derived from E.R. Sears' wheat-Aegilops speltoides 2D-2S#1 translocation line C82.2, which carries the widely effective stem rust resistance gene Sr32. Infection type assessments of the recombinants showed that the original translocation in fact carries two stem rust resistance genes, Sr32 on the short arm and a previously undescribed gene SrAes1t on the long arm of chromosome 2S#1. Recombinants with substantially shortened alien chromatin were produced for both genes, which confer resistance to stem rust races in the TTKSK (Ug99) lineage and representative races of all Australian stem rust lineages. Selected recombinants were back crossed into adapted Australian cultivars and PCR markers were developed to facilitate the incorporation of these genes into future wheat varieties. Our recombinants and those from several other labs now show that Sr32, Sr39, and SrAes7t on the short arm and Sr47 and SrAes1t on the long arm of 2S#1 form two linkage groups and at present no rust races are described that can distinguish these resistance specificities. PMID- 23989673 TI - Site-specific C-terminal and internal loop labeling of proteins using sortase mediated reactions. AB - Methods for site-specific modification of proteins should be quantitative and versatile with respect to the nature and size of the biological or chemical targets involved. They should require minimal modification of the target, and the underlying reactions should be completed in a reasonable amount of time under physiological conditions. Sortase-mediated transpeptidation reactions meet these criteria and are compatible with other labeling methods. Here we describe the expression and purification conditions for two sortase A enzymes that have different recognition sequences. We also provide a protocol that allows the functionalization of any given protein at its C terminus, or, for select proteins, at an internal site. The target protein is engineered with a sortase recognition motif (LPXTG) at the place where modification is desired. Upon recognition, sortase cleaves the protein between the threonine and glycine residues, facilitating the attachment of an exogenously added oligoglycine peptide modified with the functional group of choice (e.g., fluorophore, biotin, protein or lipid). Expression and purification of sortase takes ~3 d, and sortase mediated reactions take only a few minutes, but reaction times can be extended to increase yields. PMID- 23989674 TI - Site-specific N-terminal labeling of proteins using sortase-mediated reactions. AB - This protocol describes the use of sortase-mediated reactions to label the N terminus of any given protein of interest. The sortase recognition sequence, LPXTG (for Streptococcus aureus sortase A) or LPXTA (for Staphylococcus pyogenes sortase A), can be appended to a variety of probes such as fluorophores, biotin or even to other proteins. The protein to be labeled acts as a nucleophile by attacking the intermediate formed between the probe containing the LPXTG/A motif and the sortase enzyme. If sortase, the protein of interest and a suitably functionalized label are available, the reactions usually require less than 3 h. PMID- 23989675 TI - Production of unnaturally linked chimeric proteins using a combination of sortase catalyzed transpeptidation and click chemistry. AB - Chimeric proteins, including bispecific antibodies, are biological tools with therapeutic applications. Genetic fusion and ligation methods allow the creation of N-to-C and C-to-N fused recombinant proteins, but not unnaturally linked N-to N and C-to-C fusion proteins. This protocol describes a simple procedure for the production of such chimeric proteins, starting from correctly folded proteins and readily available peptides. By equipping the N terminus or C terminus of the proteins of interest with a set of click handles using sortase A, followed by a strain-promoted click reaction, unnatural N-to-N and C-to-C linked (hetero) fusion proteins are established. Examples of proteins that have been conjugated via this method include interleukin-2, interferon-alpha, ubiquitin, antibodies and several single-domain antibodies. If the peptides, sortase A and the proteins of interest are in hand, the unnaturally N-to-N and C-to-C fused proteins can be obtained in 3-4 d. PMID- 23989677 TI - Ultrasensitive microfluidic solid-phase ELISA using an actuatable microwell patterned PDMS chip. AB - Quantitative detection of low abundance proteins is of significant interest for biological and clinical applications. Here we report an integrated microfluidic solid-phase ELISA platform for rapid and ultrasensitive detection of proteins with a wide dynamic range. Compared to the existing microfluidic devices that perform affinity capture and enzyme-based optical detection in a constant channel volume, the key novelty of our design is two-fold. First, our system integrates a microwell-patterned assay chamber that can be pneumatically actuated to significantly reduce the volume of chemifluorescent reaction, markedly improving the sensitivity and speed of ELISA. Second, monolithic integration of on-chip pumps and the actuatable assay chamber allow programmable fluid delivery and effective mixing for rapid and sensitive immunoassays. Ultrasensitive microfluidic ELISA was demonstrated for insulin-like growth factor 1 receptor (IGF-1R) across at least five orders of magnitude with an extremely low detection limit of 21.8 aM. The microwell-based solid-phase ELISA strategy provides an expandable platform for developing the next-generation microfluidic immunoassay systems that integrate and automate digital and analog measurements to further improve the sensitivity, dynamic ranges, and reproducibility of proteomic analysis. PMID- 23989676 TI - Formation of microvascular networks in vitro. AB - This protocol describes how to form a 3D cell culture with explicit, endothelialized microvessels. The approach leads to fully enclosed, perfusable vessels in a bioremodelable hydrogel (type I collagen). The protocol uses microfabrication to enable user-defined geometries of the vascular network and microfluidic perfusion to control mass transfer and hemodynamic forces. These microvascular networks (MUVNs) allow for multiweek cultures of endothelial cells or cocultures with parenchymal or tissue cells in the extra-lumen space. The platform enables real-time fluorescence imaging of living engineered tissues, in situ confocal fluorescence of fixed cultures and transmission electron microscopy (TEM) imaging of histological sections. This protocol enables studies of basic vascular and blood biology, provides a model for diseases such as tumor angiogenesis or thrombosis and serves as a starting point for constructing prevascularized tissues for regenerative medicine. After one-time microfabrication steps, the system can be assembled in less than 1 d and experiments can run for weeks. PMID- 23989678 TI - Everyday clinical practice and its relationship to 2010 and 2011 GOLD guideline recommendations for the management of COPD. PMID- 23989679 TI - Improved blood pressure control associated with a large-scale hypertension program. AB - IMPORTANCE: Hypertension control for large populations remains a major challenge. OBJECTIVE: To describe a large-scale hypertension program in Northern California and to compare rates of hypertension control in that program with statewide and national estimates. DESIGN, SETTING, AND PATIENTS: The Kaiser Permanente Northern California (KPNC) hypertension program included a multifaceted approach to blood pressure control. Patients identified as having hypertension within an integrated health care delivery system in Northern California from 2001-2009 were included. The comparison group comprised insured patients in California between 2006-2009 who were included in the Healthcare Effectiveness Data and Information Set (HEDIS) commercial measurement by California health insurance plans participating in the National Committee for Quality Assurance (NCQA) quality measure reporting process. A secondary comparison group was included to obtain the reported national mean NCQA HEDIS commercial rates of hypertension control between 2001 2009 from health plans that participated in the NCQA HEDIS quality measure reporting process. MAIN OUTCOMES AND MEASURES: Hypertension control as defined by NCQA HEDIS. RESULTS: The KPNC hypertension registry included 349,937 patients when established in 2001 and increased to 652,763 by 2009. The NCQA HEDIS commercial measurement for hypertension control within KPNC increased from 43.6% (95% CI, 39.4%-48.6%) to 80.4% (95% CI, 75.6%-84.4%) during the study period (P < .001 for trend). In contrast, the national mean NCQA HEDIS commercial measurement increased from 55.4% to 64.1%. California mean NCQA HEDIS commercial rates of hypertension were similar to those reported nationally from 2006-2009 (63.4% to 69.4%). CONCLUSIONS AND RELEVANCE: Among adults diagnosed with hypertension, implementation of a large-scale hypertension program was associated with a significant increase in hypertension control compared with state and national control rates. Key elements of the program included a comprehensive hypertension registry, development and sharing of performance metrics, evidence-based guidelines, medical assistant visits for blood pressure measurement, and single pill combination pharmacotherapy. PMID- 23989680 TI - Vertebral artery injury and severely displaced odontoid fracture: the case for early reduction. AB - PURPOSE: To report a novel treatment method for vertebral artery occlusion. Vertebral artery injuries have a high association with specific cervical fractures including atlanto-axial fractures, displaced fracture patterns, and transverse foramen fractures. Optimal medical management of the occluded vertebral artery has yet to be determined; however, there is an extremely high complication rate with systemic anticoagulation in these patients. Furthermore, unlike appendicular skeleton fracture-dislocations with vascular injury, there is no clear consensus as to the optimal acute management of the displaced odontoid fracture with or without vertebral artery injury. METHODS: We report on a severely displaced odontoid fracture that was found to have a vertebral artery injury. Medical records and imaging were reviewed. RESULTS: An 82-year-old female presented to our hospital with a type IIb odontoid fracture after sustaining a ground-level fall. Pertinent physical exam findings were ecchymosis on the left side of her forehead and posterior cervical pain without neurologic deficits. An MRA showed an occluded left vertebral artery. The patient was placed in early cervical traction and the fracture was reduced within 12 h of presentation. Following surgical stabilization, an MR angiogram showed complete reperfusion of the vertebral artery without intimal tear. CONCLUSION: To our knowledge, this is the first report of a displaced odontoid fracture in which cervical traction was used to restore the perfusion of the vertebral artery. Cervical traction may obviate the need for systemic anticoagulation and should be considered in patients who have an identifiable compression of the vertebral artery even if neurologically intact. PMID- 23989681 TI - C6-C7 cervical disc arthroplasty in cervical disc herniation. PMID- 23989682 TI - Antibiotics for low back pain? PMID- 23989683 TI - Letter to the editor concerning: "Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized controlled trial of efficacy" by Albert HB et al. Eur Spine J (2013) 22:697-707. PMID- 23989685 TI - Three new phenolics and other constituents from the seeds of Lithocarpus pachylepis. AB - Twelve phenolics, including the three new compounds balanophonin C (1), balanophonin D (2), balanophonin E (3), were isolated from the seeds of Lithocarpus pachylepis. Their structures were elucidated by various spectroscopic techniques (UV, IR, MS, 1D and 2D NMR). Compounds 1-9 were evaluated for their anti-inflammatory activities on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 and showed moderate inhibitory activities, with IC50 values ranging from 10.9 to 34.7 MUM. PMID- 23989686 TI - Anti-inflammatory effects of total isoflavones from Pueraria lobata on cerebral ischemia in rats. AB - Puerariae radix, the dried root of Pueraria lobata Ohwi, is one of earliest and most important edible crude herbs used for various medical purposes in Oriental medicine. The aim of the present study was to determine the anti-inflammatory effects of Total Isoflavones from P. lobata (TIPL), which contains the unique isoflavone puerarin, in ischemia in vivo models. Oral administration of TIPL (100 mg/kg) reduced the brain infarct volume and attenuated ischemia-induced cyclooxygenase-2 (COX-2) up-regulation at 2 days after middle cerebral artery occlusion (MCAo) in rats. Moreover, TIPL reduced activation of glial fibrillary acid protein (GFAP) and CD11b antibody (OX-42) at 7 days after MCAo in hippocampal CA1 region. These results show that TIPL can protect the brain from ischemic damage after MCAo. Regarding the immunohistochemical study, the effects of TIPL may be attributable to its anti-inflammatory properties by the inhibition of COX-2 expression, astrocyte expression, and microglia. PMID- 23989687 TI - Two parallel needles with snare gastropexy device during gastrostomy in children. AB - A ferromagnetic T-fastener is often used in children during gastrostomy procedures. We describe the experience with the use of a new gastropexy device (two parallel needles with a snare) that uses a non-ferromagnetic anchor during primary percutaneous retrograde radiologic gastrostomy insertion in four children with a mean age of 6 years and 6 months (range: 2 years and 11 months to 9 years and 6 months). The new gastropexy device was safe and effective in children. It is advantageous for children requiring magnetic resonance (MR) examinations soon after gastrostomy insertion, especially in view of MR-related implications that result from the use of a ferromagnetic T-fastener. PMID- 23989689 TI - [Update]. PMID- 23989688 TI - Rationally designed porous polystyrene encapsulated zirconium phosphate nanocomposite for highly efficient fluoride uptake in waters. AB - Fluoride pollution in waters has engulfed worldwide regions and an excess of fluoride intake always causes skeletal fluorosis. Herein, a novel hybrid nanomaterial ZrP-MPN was fabricated for fluoride retention by encapsulating nano ZrP onto macroporous polystyrene materials modified with quaternary ammonium groups. The as-obtained materials exhibited favorable removal of fluoride ions from aqueous solution in presence of common anions (SO4(2-)/NO3(-)/Cl(-)) at high contents. Moreover outstanding sorption properties were also detected by involving series of commercial adsorbents (AA/magnetite/GFH/manganese sands) as references. Such satisfactory performances might be ascribed to the structural design of nanocomposite. (1) the CH2N(+)(CH3)3Cl groups enhances sorption diffusion and preconcentration in sorbent phase theoretically based on Donnan membrane principle; (2) the embedded ZrP nanoparticles also devotes to the efficient adsorption capacities due to its size-dependent specific properties. Additionally, the exhausted ZrP-MPN could be regenerated readily by alkaline solution. Thus, ZrP-MPN was a promising material for fluoride retention in waters. PMID- 23989690 TI - [Immune defect syndrome]. PMID- 23989691 TI - [Primary immunodeficiency]. AB - Primary (inborn) immunodeficiency is caused by gene defects that impact both the innate and the adaptive immune system. Individuals with an immunedeficiency primarily come to medical attention with recurrent infections. Most diagnoses are first made in childhood and include cellular immunodeficiency, defects of phagocyte function and other primary immunodeficiencies. Antibody deficiencies, particularly common variable immunodeficiency (CVID) and complement defects may, however, not become manifested until adulthood. A pathological susceptibility to infection in adults is defined as more than three infections per year that require treatment with antibiotics and last longer than 4 weeks each. Clinical clues for immunodeficiency are pathological susceptibility to infections and immune dysregulation. The former is characterized by frequent and severe infections with often unusual pathogens, localization, course and/or intensity. Immune dysregulation comprises granulomas, autoimmune diseases, recurrent fever/chronic inflammation, tendency to eczema, lymphoproliferation and chronic enteritis. There are evidence-based guidelines and consensus documents for the diagnosis and treatment of primary immunodeficiencies. Therapeutic approaches depend on the nature of the immune defect and range from immunoglobulin substitution for antibody deficiencies to bone marrow transplantation for severe cellular immune defects. PMID- 23989693 TI - [Communications of the DGRh]. PMID- 23989692 TI - [Pregnancy and inflammatory rheumatic diseases]. AB - Pregnancy in women with rheumatic diseases represents a challenge for patients and physicians and requires optimal shared decision-making strategies. However, the majority of women can have a successful pregnancy and the vast majority of babies are born healthy. Specific preconception care should be offered to women with rheumatic diseases to optimize and increase the chances of a successful pregnancy. A careful assessment of possible risks and the justified use of antirheumatic drugs before, during and after pregnancy are key issues. PMID- 23989694 TI - [German Rheumatism League uses campaign for better care]. PMID- 23989696 TI - Parenteral nutrition equipment and devices. PMID- 23989695 TI - Compounding nutritional solutions - a market overview. PMID- 23989697 TI - Catheter occlusion: causes and solutions. PMID- 23989698 TI - TPN Bulk Compounding from Bulk Drug Substances. PMID- 23989699 TI - The Feasibility and Benefits of TPN in Horses: A Review of the Findings. PMID- 23989700 TI - Required documentation for home infusion pharmacies - compounding records. PMID- 23989701 TI - Balances and weighing accuracy. PMID- 23989702 TI - Testing for bacterial endotoxins. PMID- 23989703 TI - Compatibility of Paclitaxel injection diluent with two reduced-phthalate administration sets for the acclaim pump. AB - The purpose of this project was to evaluate the compatibility of paclitaxel admixtures with the two reduced-phthalate administration sets designed for use with the Acclaim Infusion Control Device. The first is a nitroglycerin set composed of polyethylene tubing, while the second is made using tris(2-ethyl hexyl) trimellitate (TOTM)-plasticized polyvinyl chloride tubing. Both sets utilize a diethylhexyl phthalate (DEHP)-plasicized pumping segment. The potential for extraction of DEHP from the pumping segments and TOTM plasticizer from the plastic matrix by the Cremophor EL surfactant present in the paclitaxel injection was evaluated. Diethylhexyl phthalate and TOTM plasticizer extraction was tested using the paclitaxel diluent at concentrations equivalent to 0.3 and 1.2 mg/mL over three-hour and four-day infusions. All samples were prepared in triplicate in polyolefin bags of 5% dextrose injection and deliverd through the administration sets into glass collection flasks. Both DEHP and TOTM content were determined using high-performance liquid chromatographic methods. None of the admixtures delivered rapidly over three hours or slowly over four days through the TOTM-plasticized set exhibited any detectable TOTM. Similarly, no DEHP was detected in the effluent form either set with the simulated 0.3-mg/mL admixtures delivered over three hours. The simulated 1.2-mg/mL admixture delivered over three hours yielded only a barely detectable, but not quantifiable, trace of DEHP. However, slow delivery of both concentrations over four days through both sets resulted in leached DEHP in concentrations ranging from about 30 to 150 micrograms/mL at both one and four days. The two reduced-phthalate administration sets tested in this study are suitable for the administration of paclitaxel infusions of short duration, for up to three hours. However, the sets cannot be recommended for administration over longer-duration delivery times ranging from one to four days due to leaching of DEHP plasticizer from the pumping segments. PMID- 23989704 TI - Stability of Magnesium Sulfate in 0.9% Sodium Chloride and Lactated Ringers solutions. AB - Storage stability test were peformed on two extemporaneous formulation alternatives to the commercially available magnesium sulfate injection solutions that are in 5% dextrose or in water. Preparations of the commercial water for injection formulation and two alternative formulations in lactated Ringers and in 0.9% sodium chloride were stored at room temperature in glass bottles and in polyvinyl chloride bags over a three-month period. Solutions were monitored for gross precipitation and for changes in magnesium, sulfur and calcium levels as measured by elemental analysis using atomic absorption spectroscopy and inductively coupled plasma atomic emission spectroscopy. The results demonstrate no consistent decreases in measured elemental concentrations or gross signs of precipitation for any formulation tested. PMID- 23989705 TI - Ketorolac tromethamine and ketoprofen suppositories: release profiles and bioavailability of a cocoa butter base formula in rabbits. AB - Ketorolac tromethamine suppositories (30 mg) and ketoprofen suppositories (50 mg) were made by the fusion method with various bases such as cocoa butter, Witepsol H15, Witepsol W25, Witepsol W35, Witepsol E75, Suppocire AML and Hydrokote AP5-1. Also, ketorolac tromethamine and ketoprofen suppositories were prepared using Eudragit L100 and propylene glycol. The release rates for both ketorolac tromethamine and ketoprofen suppositories in Sorensen's phosphate buffer pH 7.4 were determined and found to be: cocoa butter greater than Witepsol H15 greater than Witepsol W25 greater than Suppocire AML greater than witepsol W35 greater than Hydrokote AP5-1> Witepsol E75. Drug-release studies showed that ketorolac tromethamine demonstrates faster release profiles from these selected bases in comparison to those seen for ketoprofen. Analysis of the relaease kinetics for ketorolac tromethamine and ketoprofen from the various bases suggests that a combination of release mechanisms such as melting of the base followed by partititoning of the drug, along with some diffusion of the drug from the base to the dissolution media, seems to be operative in these systems. The absolute bioavailabilty of the suppository formulaion made with ketorolac tromethamine in cocoa butter base was found to be 61% in rabbits. PMID- 23989706 TI - Stability of albuterol in continuous nebulization. AB - Due to the emergent nature of situations requiring continuous nebulization of albuterol a premixed albuterol solution would provide faster access to the therapy when required. The purpose of this study was to evaluate the stability of albuterol solutions at a concentration (200 micrograms/mL) used in continuous nebulization when stored in various containers of polyvinyl chloride bags, polyolefin bags, polypropylene syringes and tubes and borosilicate glass tubes. Solutions were prepared in triplicate in 0.9% sodium chloride stored under refrigerated and room temperatures for seven days. Samples were removed and analyzed using a stability-indicating high-performance liquid chromatrography assay method. Albuterol was found to be stable (greater than 90% of the initial concentration remaining) for at least seven days in all five types of containers under the conditions tested. PMID- 23989707 TI - Patient-specific instrumentation improves tibial component rotation in TKA. AB - PURPOSE: To compare the femoral and tibial components rotational alignment in total knee arthroplasty (TKA) performed either with conventional or with patient specific instrumentation. METHODS: Forty-five patients underwent primary TKA and were prospectively randomized into two groups: 22 patients into the conventional instrumentation group (group A) and 23 patients into the SignatureTM patient specific instrumentation group (group B). All patients underwent computed tomography of the operated knee in the first week after surgery to measure the components rotation. RESULTS: The femoral component rotation was 0.0 degrees ( 0.25, 1.0) in group A, and 0.0 degrees (0.0, 1.0) in group B. The tibial component rotation was -16.0 degrees (-18.5, 11.8) in group A, and -16.0 degrees (-19.0, -14.0) in group B. There were no significant differences between the two groups in tibial and femoral components rotation. The difference between the tibial component rotation and the neutral tibial rotation was similar in both groups [2.0 degrees (-0.5, 6.3) in group A and 2.0 degrees (-1.0, 4.0) in group B], but the dispersion around the median was different between the two groups. The amplitude of the difference between tibial rotation and neutral position was 27 degrees (-13, 14) in group A and 9 degrees (-3, 6) in group B. CONCLUSIONS: There is a smaller chance of internal malrotation of the tibial component with the SignatureTM patient-specific instrumentation system, with less dispersion and amplitude of the tibial component rotation around the neutral position. LEVEL OF EVIDENCE: II. PMID- 23989708 TI - On the potential of mass spectrometry-based metabolite profiling approaches to the study of biochemical adaptation in psychrophilic yeast. AB - To move beyond targeted approaches to the biochemical characterization of psychrophilic yeast and provide a more holistic understanding of the chemistry of physiological adaptation of psychrophiles at the molecular level, ultraperformance liquid chromatography combined with simultaneous acquisition of low- and high-collision energy mass spectra (UPLC/MS(e)) was employed for a preliminary comparative analysis of cell extracts of psychrophilic Antarctic yeasts Cryptococcus vishniacii CBS 10616 and Dioszegia cryoxerica CBS 10919 versus the mesophile Saccharomyces cerevisiae 'cry havoc'. A detailed workflow for providing high-confidence preliminary identifications of psychrophilic yeast specific molecular features is presented. Preliminary identifications of psychrophile-specific features in C. vishniacii and D. cryoxerica determined with the described method include the glycerophospholipids lysophosphatidylcholine 18:2, lysophosphatidylcholine 18:3, lysophosphatidylethanolamine 18:3, and lysophosphatidylethanolamine 18:2. In addition, levels of guanosine diphosphate appear significantly elevated in cell extracts of the psychrophilic yeasts as compared to Saccharomyces cerevisiae. Finally, five psychrophilic yeast-specific peptides have been discovered. All of these are demonstrated to be glycine- and/or proline-rich, a known structural characteristic of many naturally occurring bioactive peptides. The potential of this untargeted metabolite profiling approach as a tool for knowledge discovery and hypothesis generation in the study of biodiversity and microbial adaptation is highlighted. PMID- 23989709 TI - Innovations in health care and mortality trends from five cancers in seven European countries between 1970 and 2005. AB - OBJECTIVES: Although the contribution of health care to survival from cancer has been studied extensively, much less is known about its contribution to population health. We examine how medical innovations have influenced trends in cause specific mortality at the national level. METHODS: Based on literature reviews, we selected six innovations with proven effectiveness against cervical cancer, Hodgkin's disease, breast cancer, testicular cancer, and leukaemia. With data on the timing of innovations and cause-specific mortality (1970-2005) from seven European countries we identified associations between innovations and favourable changes in mortality. RESULTS: For none of the five specific cancers, sufficient evidence for an association between introduction of innovations and a positive change in mortality could be found. The highest association was found between the introduction of Tamoxifen and breast cancer mortality. CONCLUSIONS: The lack of evidence of health care effectiveness may be due to gradual improvements in treatment, to effects limited to certain age groups or cancer subtypes, and to contemporaneous changes in cancer incidence. Research on the impact of health care innovations on population health is limited by unreliable data on their introduction. PMID- 23989711 TI - Genetic cardiomyopathies causing heart failure. AB - Despite the striking advances in medical and surgical therapy, the morbidity, mortality, and economic burden of heart failure (HF) remain unacceptably high. There is increasing evidence that the risk and course of HF depend on genetic predisposition; however, the genetic contribution to HF is heterogeneous and complex. At one end of the spectrum are the familial monogenic HF syndromes in which causative mutations are rare but highly penetrant. At the other, HF susceptibility and course may be influenced by more common, less penetrant genetic variants. As detailed in this review, efforts to unravel the basis of the familial cardiomyopathies at the mendelian end of the spectrum already have begun to deliver on the promise of informative mechanisms, novel gene-based diagnostics, and therapies for distinct subtypes of HF. However, continued progress requires the differentiation of pathogenic mutations, disease modifiers, and rare, benign variants in the deluge of data emerging from increasingly accessible novel sequencing technologies. This represents a significant challenge and demands a sustained effort in analysis of extended family pedigrees, diligent clinical phenotyping, and systematic annotation of human genetic variation. PMID- 23989710 TI - Epidemiology of heart failure. AB - Heart failure (HF) has been singled out as an epidemic and is a staggering clinical and public health problem, associated with significant mortality, morbidity, and healthcare expenditures, particularly among those aged >= 65 years. The case mix of HF is changing over time with a growing proportion of cases presenting with preserved ejection fraction for which there is no specific treatment. Despite progress in reducing HF-related mortality, hospitalizations for HF remain frequent and rates of readmissions continue to rise. To prevent hospitalizations, a comprehensive characterization of predictors of readmission in patients with HF is imperative and must integrate the impact of multimorbidity related to coexisting conditions. New models of patient-centered care that draw on community-based resources to support HF patients with complex coexisting conditions are needed to decrease hospitalizations. PMID- 23989712 TI - Non-coding RNAs in cardiac remodeling and heart failure. AB - Heart failure is a leading cause of death in industrialized nations especially in an aging population. The recent improvements in cardiac revascularization therapy reduced death rates because of myocardial infarction but steadily increased the number of individuals developing cardiac remodeling and heart failure in the future. Conceptual novel approaches entering the clinics to treat cardiac remodeling and heart failure remain scarce. MicroRNAs emerged as powerful and dynamic modifiers of cardiovascular diseases. In this review, the current approaches using microRNAs as novel diagnostic and therapeutic strategies for cardiac remodeling and heart failure are highlighted. Other gene regulatory mechanisms presented include long (>200 bp) noncoding RNAs that function as an additional regulatory machinery of the genome controlling both transcriptional and post-transcriptional events also in the cardiovascular system. PMID- 23989714 TI - Cardiac metabolism in heart failure: implications beyond ATP production. AB - The heart has a high rate of ATP production and turnover that is required to maintain its continuous mechanical work. Perturbations in ATP-generating processes may therefore affect contractile function directly. Characterizing cardiac metabolism in heart failure (HF) revealed several metabolic alterations called metabolic remodeling, ranging from changes in substrate use to mitochondrial dysfunction, ultimately resulting in ATP deficiency and impaired contractility. However, ATP depletion is not the only relevant consequence of metabolic remodeling during HF. By providing cellular building blocks and signaling molecules, metabolic pathways control essential processes such as cell growth and regeneration. Thus, alterations in cardiac metabolism may also affect the progression to HF by mechanisms beyond ATP supply. Our aim is therefore to highlight that metabolic remodeling in HF not only results in impaired cardiac energetics but also induces other processes implicated in the development of HF such as structural remodeling and oxidative stress. Accordingly, modulating cardiac metabolism in HF may have significant therapeutic relevance that goes beyond the energetic aspect. PMID- 23989713 TI - Mechanisms of altered Ca2+ handling in heart failure. AB - Ca2+ plays a crucial role in connecting membrane excitability with contraction in myocardium. The hallmark features of heart failure are mechanical dysfunction and arrhythmias; defective intracellular Ca2+ homeostasis is a central cause of contractile dysfunction and arrhythmias in failing myocardium. Defective Ca2+ homeostasis in heart failure can result from pathological alteration in the expression and activity of an increasingly understood collection of Ca2+ homeostatic and structural proteins, ion channels, and enzymes. This review focuses on the molecular mechanisms of defective Ca2+ cycling in heart failure and considers how fundamental understanding of these pathways may translate into novel and innovative therapies. PMID- 23989715 TI - Integrating the myocardial matrix into heart failure recognition and management. AB - In contrast to public perception, the morbidity and mortality and the resultant healthcare costs associated with chronic heart failure (HF) are increasing and arguably reaching epidemic proportions. Although basic research efforts have provided unique insights into fundamental processes that govern myocardial extracellular matrix (ECM) growth and function, the translation of these findings to improved diagnostics and therapeutics for HF has not been as forthcoming. The factors that contribute to this relative paucity of new clinical tools for HF are multifactorial but likely include the need to recognize and differentiate HF phenotypes and to couple the use of biomarkers and multimodality imaging in early translational research studies. Recognizing the classification scheme of HF with a reduced ejection fraction (EF) to that of HF with a preserved EF and incorporating unique and differential measurements of ECM remodeling to these specific disease processes are warranted. For example, profiling pathways of ECM degradation such as the matrix metalloproteinases in patients with ischemic heart disease and HF with a reduced EF can provide prognostic information in terms of risk of progression to HF. In patients with chronic hypertensive disease and HF with a preserved EF, plasma profiling indexes of ECM synthesis and turnover, as well as advances in ECM imaging, have been shown to provide diagnostic and prognostic use. In terms of therapeutics, strategies to stabilize the ECM in HF with a reduced EF hold potential, whereas in contradistinction, selective antifibrotic agents may hold promise for HF with a preserved EF. PMID- 23989719 TI - Molecular changes after left ventricular assist device support for heart failure. AB - Heart failure is associated with remodeling that consists of adverse cellular, structural, and functional changes in the myocardium. Until recently, this was thought to be unidirectional, progressive, and irreversible. However, irreversibility has been shown to be incorrect because complete or partial reversal can occur that can be marked after myocardial unloading with a left ventricular assist device (LVAD). Patients with chronic advanced heart failure can show near-normalization of nearly all structural abnormalities of the myocardium or reverse remodeling after LVAD support. However, reverse remodeling does not always equate with clinical recovery. The molecular changes occurring after LVAD support are reviewed, both those demonstrated with LVAD unloading alone in patients bridged to transplantation and those occurring in the myocardium of patients who have recovered enough myocardial function to have the device removed. Reverse remodeling may be attributable to a reversal of the pathological mechanisms that occur in remodeling or the generation of new pathways. A reduction in cell size occurs after LVAD unloading, which does not necessarily correlate with improved cardiac function. However, some of the changes in both the cardiac myocyte and the matrix after LVAD support are specific to myocardial recovery. In the myocyte, increases in the cytoskeletal proteins and improvements in the Ca2+ handling pathway seem to be specifically associated with myocardial recovery. Changes in the matrix are complex, but excessive scarring appears to limit the ability for recovery, and the degree of fibrosis in the myocardium at the time of implantation may predict the ability to recover. PMID- 23989717 TI - Emerging paradigms in cardiomyopathies associated with cancer therapies. AB - The cardiovascular care of cancer patients (cardio-oncology) has emerged as a new discipline in clinical medicine, given recent advances in cancer therapy, and is driven by the cardiovascular complications that occur as a direct result of cancer therapy. Traditional therapies such as anthracyclines and radiation have been recognized for years to have cardiovascular complications. Less expected were the cardiovascular effects of targeted cancer therapies, which were initially thought to be specific to cancer cells and would spare any adverse effects on the heart. Cancers are typically driven by mutations, translocations, or overexpression of protein kinases. The majority of these mutated kinases are tyrosine kinases, though serine/threonine kinases also play key roles in some malignancies. Several agents were developed to target these kinases, but many more are in development. Major successes have been largely restricted to agents targeting human epidermal growth factor receptor-2 (mutated or overexpressed in breast cancer), BCR-ABL (chronic myelogenous leukemia and some cases of acute lymphoblastic leukemia), and c-Kit (gastrointestinal stromal tumor). Other agents targeting more complex malignancies, such as advanced solid tumors, have had successes, but have not extended life to the degree seen with chronic myelogenous leukemia. Years before the first targeted therapy, Judah Folkman correctly proposed that to address solid tumors one had to target the inherent neoangiogenesis. Unfortunately, emerging evidence confirms that angiogenesis inhibitors cause cardiac complications, including hypertension, thrombosis, and heart failure. And therein lies the catch-22. Nevertheless, cardio-oncology has the potential to be transformative as the human cardiomyopathies that arise from targeted therapies can provide insights into the normal function of the heart. PMID- 23989716 TI - Adrenergic nervous system in heart failure: pathophysiology and therapy. AB - Heart failure (HF), the leading cause of death in the western world, develops when a cardiac injury or insult impairs the ability of the heart to pump blood and maintain tissue perfusion. It is characterized by a complex interplay of several neurohormonal mechanisms that become activated in the syndrome to try and sustain cardiac output in the face of decompensating function. Perhaps the most prominent among these neurohormonal mechanisms is the adrenergic (or sympathetic) nervous system (ANS), whose activity and outflow are enormously elevated in HF. Acutely, and if the heart works properly, this activation of the ANS will promptly restore cardiac function. However, if the cardiac insult persists over time, chances are the ANS will not be able to maintain cardiac function, the heart will progress into a state of chronic decompensated HF, and the hyperactive ANS will continue to push the heart to work at a level much higher than the cardiac muscle can handle. From that point on, ANS hyperactivity becomes a major problem in HF, conferring significant toxicity to the failing heart and markedly increasing its morbidity and mortality. The present review discusses the role of the ANS in cardiac physiology and in HF pathophysiology, the mechanisms of regulation of ANS activity and how they go awry in chronic HF, methods of measuring ANS activity in HF, the molecular alterations in heart physiology that occur in HF, along with their pharmacological and therapeutic implications, and, finally, drugs and other therapeutic modalities used in HF treatment that target or affect the ANS and its effects on the failing heart. PMID- 23989718 TI - Electromechanical dyssynchrony and resynchronization of the failing heart. AB - Patients with heart failure and decreased function frequently develop discoordinate contraction because of electric activation delay. Often termed dyssynchrony, this further decreases systolic function and chamber efficiency and worsens morbidity and mortality. In the mid- 1990s, a pacemaker-based treatment termed cardiac resynchronization therapy (CRT) was developed to restore mechanical synchrony by electrically activating both right and left sides of the heart. It is a major therapeutic advance for the new millennium. Acute chamber effects of CRT include increased cardiac output and mechanical efficiency and reduced mitral regurgitation, whereas reduction in chamber volumes ensues more chronically. Patient candidates for CRT have a prolonged QRS duration and discoordinate wall motion, although other factors may also be important because ~30% of such selected subjects do not respond to the treatment. In contrast to existing pharmacological inotropes, CRT both acutely and chronically increases cardiac systolic function and work, yet it also reduces long-term mortality. Recent studies reveal unique molecular and cellular changes from CRT that may also contribute to this success. Heart failure with dyssynchrony displays decreased myocyte and myofilament function, calcium handling, beta-adrenergic responsiveness, mitochondrial ATP synthase activity, cell survival signaling, and other changes. CRT reverses many of these abnormalities often by triggering entirely new pathways. In this review, we discuss chamber, circulatory, and basic myocardial effects of dyssynchrony and CRT in the failing heart, and we highlight new research aiming to better target and implement CRT, as well as leverage its molecular effects. PMID- 23989720 TI - Heart failure gene therapy: the path to clinical practice. AB - Gene therapy, aimed at the correction of key pathologies being out of reach for conventional drugs, bears the potential to alter the treatment of cardiovascular diseases radically and thereby of heart failure. Heart failure gene therapy refers to a therapeutic system of targeted drug delivery to the heart that uses formulations of DNA and RNA, whose products determine the therapeutic classification through their biological actions. Among resident cardiac cells, cardiomyocytes have been the therapeutic target of numerous attempts to regenerate systolic and diastolic performance, to reverse remodeling and restore electric stability and metabolism. Although the concept to intervene directly within the genetic and molecular foundation of cardiac cells is simple and elegant, the path to clinical reality has been arduous because of the challenge on delivery technologies and vectors, expression regulation, and complex mechanisms of action of therapeutic gene products. Nonetheless, since the first demonstration of in vivo gene transfer into myocardium, there have been a series of advancements that have driven the evolution of heart failure gene therapy from an experimental tool to the threshold of becoming a viable clinical option. The objective of this review is to discuss the current state of the art in the field and point out inevitable innovations on which the future evolution of heart failure gene therapy into an effective and safe clinical treatment relies. PMID- 23989722 TI - The physical chemistry of cytoplasm and its influence on cell function: an update. AB - From the point of view of intermolecular interactions, the cytoplasmic space is more like a crowded party in a house full of furniture than a game of tag in an empty field. Understanding the physical chemical properties of cytoplasm is thus of key importance for understanding cellular function. This article attempts to provide an entree into the current literature on this subject and offers some general guidelines for thinking about intracellular biochemistry. PMID- 23989723 TI - Latanoprost effectively ameliorates glucose and lipid disorders in db/db and ob/ob mice. AB - AIMS/HYPOTHESIS: Improvement of glucose and lipid metabolic dysfunctions is a potent therapeutic strategy against type 2 diabetes mellitus, and identifying new functions for existing drugs may help accelerate the speed of new drug development. Here, we report that latanoprost, a clinical drug for treating primary open-angle glaucoma and intraocular hypertension, effectively ameliorated glucose and lipid disorders in two mouse models of type 2 diabetes. In addition, the glucose-lowering mechanisms of latanoprost were intensively investigated. METHODS: A binding-affinity assay and enzymatic tests were used to determine the targets of latanoprost. Cell-based assays on 3T3-L1 adipocytes and C2C12 myotubes and animal model-based assays with db/db and ob/ob mice were further performed to clarify the mechanisms underlying latanoprost-regulated glucose and lipid metabolism. RESULTS: Latanoprost functioned as both an indirect activator of AMP activated protein kinase and a selective retinoid X receptor alpha (RXRalpha) antagonist able to selectively antagonise the transcription of a RXRalpha/peroxisome proliferator-activated receptor gamma heterodimer. It promoted glucose uptake, inhibited pre-adipocyte differentiation and regulated the main genes responsible for glucose and lipid metabolism, including Fas, Scd1, Perilipin (also known as Plin1), Lpl and Pdk4. Chronic administration of latanoprost in mice potently decreased the levels of fasting blood glucose, HbA1c, fructosamine (FMN), NEFA and total cholesterol, and effectively improved glucose tolerance and glucose/lipid metabolism-related genes in vivo. CONCLUSIONS/INTERPRETATION: Our studies demonstrate that the existing eye drug latanoprost is both an indirect activator of AMP-activated protein kinase and a selective RXRalpha antagonist. Latanoprost effectively ameliorated glucose and lipid disorders in diabetic mice, which strongly highlights the potential of latanoprost in the treatment of type 2 diabetes mellitus. PMID- 23989724 TI - Ceramide accumulation in L6 skeletal muscle cells due to increased activity of ceramide synthase isoforms has opposing effects on insulin action to those caused by palmitate treatment. AB - AIMS/HYPOTHESIS: An accumulation of ceramides has been implicated in the generation of insulin resistance in skeletal muscle upon an oversupply of fatty acid. Different ceramide species are generated through the actions of ceramide synthases (CerSs), which incorporate specific acyl side chains. We tested whether particular CerS isoforms promoted insulin resistance through the generation of more inhibitory ceramide species, thus representing potential targets for intervention. METHODS: CerS isoforms CerS1, CerS2, CerS4, CerS5 and CerS6 were overexpressed in L6 myotubes using adenovirus, and cells were treated with palmitate and stimulated with insulin. Alternatively, CerS isoforms were knocked down using siRNAs. Sphingolipids were examined by mass spectrometry and tracer incorporation. Phosphorylation of IRS1 and Akt was measured by immunoblotting, while glucose disposal was assessed by measuring GLUT4 translocation and the incorporation of [(14)C]glucose into glycogen. RESULTS: Palmitate treatment increased the levels of several ceramides but reduced the levels of sphingomyelins, while insulin had no effect. The fatty acid also inhibited insulin-stimulated Akt phosphorylation and glycogen synthesis. Overexpression of CerS isoforms increased specific ceramides. Unexpectedly, the overexpression of CerS1 and CerS6 promoted insulin action, while no isoform had inhibitory effects. CerS6 knockdown had effects reciprocal to those of CerS6 overexpression. CONCLUSIONS/INTERPRETATION: Palmitate may increase intracellular ceramide levels through sphingomyelin hydrolysis as well as de novo synthesis, but no particular species were implicated in the generation of insulin resistance. The modulation of ceramides through an alteration of CerS expression does not affect the action of insulin in the same way as ceramide generation by palmitate treatment. Conversely, certain isoforms promote insulin action, indicating the importance of ceramides in cell function. PMID- 23989721 TI - Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. AB - Despite significant therapeutic advances, the prognosis of patients with heart failure (HF) remains poor, and current therapeutic approaches are palliative in the sense that they do not address the underlying problem of the loss of cardiac tissue. Stem cell-based therapies have the potential to fundamentally transform the treatment of HF by achieving what would have been unthinkable only a few years ago-myocardial regeneration. For the first time since cardiac transplantation, a therapy is being developed to eliminate the underlying cause of HF, not just to achieve damage control. Since the initial report of cell therapy (skeletal myoblasts) in HF in 1998, research has proceeded at lightning speed, and numerous preclinical and clinical studies have been performed that support the ability of various stem cell populations to improve cardiac function and reduce infarct size in both ischemic and nonischemic cardiomyopathy. Nevertheless, we are still at the dawn of this therapeutic revolution. Many important issues (eg, mechanism(s) of action of stem cells, long-term engraftment, optimal cell type(s), and dose, route, and frequency of cell administration) remain to be resolved, and no cell therapy has been conclusively shown to be effective. The purpose of this article is to critically review the large body of work performed with respect to the use of stem/progenitor cells in HF, both at the experimental and clinical levels, and to discuss current controversies, unresolved issues, challenges, and future directions. The review focuses specifically on chronic HF; other settings (eg, acute myocardial infarction, refractory angina) are not discussed. PMID- 23989725 TI - Evaluation of resveratrol sensitivities and metabolic patterns in human and rat glioblastoma cells. AB - PURPOSE: To further elucidate the correlation of resveratrol sensitivities with biotransformation activities of human and rat glioblastoma cells for personalized anti-glioblastoma therapy. METHODS: Resveratrol sensitivity of human U251 and rat RG2 and C6 glioblastoma cells was evaluated by 3-[4,5-dimethylthiazol-2-yl]-2, 5 diphenyltetrazolium bromide/MTT, flow cytometry, and TUNEL assays. The metabolic patterns of those cell lines were analyzed by high-performance liquid chromatography/HPLC coupled with tandem mass spectrum/MS/MS, and high-resolution mass spectrometry/HRMS. Immunocytochemical staining and Western blotting were employed to check resveratrol metabolic enzyme expression. RESULTS: Both rat RG2 and C6 and human U251 glioblastoma cells are sensitive to 100 MUM resveratrol in terms of growth arrest and increased apoptotic fraction. The main resveratrol metabolite in U251 cells is monosulfate biotransformed by sulfotransferases/SULTs and in RG2 and C6 cells is monoglucuronide generated by UDP glucuronosyltransferase/UGT. Both metabolites show lesser therapeutic efficacy. Although brain-associated UGTs (UGT1A6, 2B7, and 8) and SULTs (SULT1A1, 1C2, and 4A1) are expressed in rat and human glioma cells, the overall level of UGTs is predominant in the rat and SULTs in human glioblastoma cells. In similar to SULT expression pattern, UGT1A6, 2B7, and 8 are frequently downregulated (84.6 %, 82/97; 90.7 %, 88/97; 80.4 %, 78/97) in human glioblastoma tissues. CONCLUSION: Our results suggest (1) the decreased resveratrol biotransforming activity in rat and human resveratrol-sensitive glioblastoma cells; (2) the discrepant resveratrol metabolic patterns between human and rat glioblastoma cells; (3) the more powerful anti-glioblastoma efficacy of trans-resveratrol rather than resveratrol monoglucuronide or monosulfate; and (4) the value of RG2 and C6 cells in establishing resveratrol-based rat in vivo therapeutic model. PMID- 23989726 TI - Direct and selective tagging of cysteine residues in peptides and proteins with 4 nitropyridyl lanthanide complexes. AB - A cysteine-selective tagging method in water is reported, based on rapid displacement of a pyridyl nitro-substituent in simple pyridines and lanthanide complexes. The conjugation reaction creates a short link between the tag and peptide, holding the peptide closer to the Ln(3+) ion and with reduced flexibility compared to existing methods. PMID- 23989727 TI - Chemical and biosynthetic evolution of the antimycin-type depsipeptides. AB - Evolution of natural products, and particularly those resulting from microbial assembly line-like enzymes, such as polyketide (PK) and nonribosomal peptides (NRP), has resulted in a variety of pharmaceutically important and chemically diverse families of molecules. The antimycin-type depsipeptides are one such grouping, with a significant level of diversity and members that have noted activities against key targets governing human cellular apoptosis (e.g. Bcl-xL and GRP78). Chemical variance originates from ring size, with 9-, 12-, 15-, and 18-membered classes, and we show that such distinctions influence their molecular targeting. Further, we present here a systematic interrogation of the chemistry and assembly line evolution of antimycin-type analogues by conducting metabolomic profiling and biosynthetic gene cluster comparative analysis of the depsipeptide assembly lines for each member of the antimycin-group. Natural molecular evolution principles of such studies should assist in artificial re combinatorializing of PK and NRP assembly lines. PMID- 23989728 TI - When a healthy diet turns deadly. AB - The health benefits of a high fiber diet (HFD) result in part from the action of metabolic end products made by gut commensals on the host epithelium. Butyrate is one such beneficial metabolite; however, butyrate paradoxically enhances the capacity of Escherichia coli-produced Shiga toxin type 2 (Stx2) to kill tissue culture cells. We recently showed that mice fed an HFD exhibited increased butyrate in gut contents and had an altered intestinal microbiota with reduced numbers of Escherichia species. Furthermore, mice fed an HFD and infected with Stx-producing E. coli (STEC) were colonized to a higher degree, lost more weight and succumbed to infection at greater rates compared with STEC-infected low fiber diet animals. The HFD animals showed higher levels of the Stx receptor globotriaocylceramide (Gb3) in both the gut and kidneys. We speculate that an HFD that leads to increased intestinal butyrate and Gb3 in the intestines and kidneys may explain the higher rate of the hemolytic uremic syndrome in females over males. PMID- 23989730 TI - Signalling: Keeping TABs on p53. PMID- 23989729 TI - Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis. AB - IMPORTANCE: Infantile hypertrophic pyloric stenosis (IHPS) is a serious condition in which hypertrophy of the pyloric sphincter muscle layer leads to gastric outlet obstruction. Infantile hypertrophic pyloric stenosis shows strong familial aggregation and heritability, but knowledge about specific genetic risk variants is limited. OBJECTIVES: To search the genome comprehensively for genetic associations with IHPS and validate findings in 3 independent sample sets. DESIGN, SETTING, AND PARTICIPANTS: During stage 1, we used reference data from the 1000 Genomes Project for imputation into a genome-wide data set of 1001 Danish surgery-confirmed samples (cases diagnosed 1987-2008) and 2371 disease free controls. In stage 2, the 5 most significantly associated loci were tested in independent case-control sample sets from Denmark (cases diagnosed 1983-2010), Sweden (cases diagnosed 1958-2011), and the United States (cases diagnosed 1998 2005), with a total of 1663 cases and 2315 controls. MAIN OUTCOMES AND MEASURES: Association of genetic variation with the presence of infantile hypertrophic pyloric stenosis. RESULTS: We found a new genome-wide significant locus for IHPS at chromosome 11q23.3. The single-nucleotide polymorphism (SNP) with the lowest P value at the locus, rs12721025 (odds ratio [OR], 1.59; 95% CI, 1.38-1.83; P = 1.9 * 10(-10)), is located 301 bases downstream of the apolipoprotein A-I (APOA1) gene and is correlated (r2 between 0.46 and 0.80) with SNPs previously found to be associated with levels of circulating cholesterol. For these SNPs, the cholesterol-lowering allele consistently was associated with increased risk of IHPS. CONCLUSIONS AND RELEVANCE: This study identified a new genome-wide significant locus for IHPS. Characteristics of this locus suggest the possibility of an inverse relationship between levels of circulating cholesterol in neonates and IHPS risk, which warrants further investigation. PMID- 23989731 TI - Kidney disease and cardiovascular risk: whether black or white race matters. PMID- 23989733 TI - Rituximab effectiveness in a patient with juvenile systemic lupus erythematosus complicated with acquired Von Willebrand syndrome. AB - The acquired von Willebrand Syndrome (AvWS) is a bleeding disorder with laboratory findings similar to those of the congenital form. Its presentation is more common in adults than in children and is mainly associated with lymphoproliferative and myeloproliferative diseases and rarely with autoimmune diseases including systemic lupus erythematosus (SLE). Here, we report the case of a girl with SLE and AvWS with mucosal bleeding and low plasma levels of von Willebrand factor and factor VIII (FVIII) with failure to respond to treatment with first- and second-line therapies. The patient finally responded to rituximab. To our knowledge this is the first reported case of SLE associated with AvWS, that responded to rituximab. PMID- 23989732 TI - Respiratory symptom perception differs in obese women with strong or mild breathlessness during constant-load exercise. AB - BACKGROUND: During constant-load exercise, some otherwise healthy obese women report substantially more dyspnea on exertion (DOE) than do others. The objective of this study was to investigate whether qualitative differences exist between the sensations of dyspnea felt by these women. METHODS: Seventy-eight women were categorized based on their ratings of perceived breathlessness (RPBs) (Borg 0-10 scale) after 6 min of 60-W cycling. Thirty-four women rated RPB >= 4 (+DOE) (34 +/- 7 years, 36 +/- 5 kg/m2 BMI), and 22 women rated RPB <= 2 (-DOE) (32 +/- 7 years, 37 +/- 4 kg/m2 BMI). Twenty-two women rated RPB as 3 (RPB = 3) (34 +/- 7 years, 34 +/- 4 kg/m2 BMI) and were grouped separately to allow for a better delineation of the +DOE and the -DOE groups. After the exercise test, subjects were asked to pick three of 15 statements that best described their respiratory sensations. RESULTS: The +DOE and the -DOE groups were characterized differentially (P < .05) by the respiratory clusters "Breathing more" (82% of DOE vs 41% of +DOE), "Shallow" (36% vs 6%), and "Heavy" (14% vs 53%). All four descriptors in the cluster "Work/Effort" were chosen more frequently by women in the +DOE group than by women in the -DOE group. Although relative exercise intensity was higher in the +DOE women (75% +/- 13% vs 67% +/- 10% of oxygen uptake at peak exercise, 41 +/- 10 L/min vs 31 +/- 8 L/min as % maximal voluntary ventilation, 83% +/- 7% vs 76% +/- 7% of peak heart rate), none of these variables was significantly associated with RPB. CONCLUSIONS: Not only is the intensity of dyspnea significantly different between the +DOE and the -DOE groups, but so are the self-reported qualitative aspects of their dyspnea. Women in the +DOE group reported an increased sensation of the work of breathing relative to women in the -DOE group, which may be associated with the elevated RPB. PMID- 23989734 TI - Association of +3179G/A insulin-like growth factor-1 receptor polymorphism and insulin-like growth factor-1 serum level with systemic lupus erythematosus. AB - The insulin-like growth factor (IGF) system plays a prominent role in the regulation of immunity and inflammation. Inappropriate balance of IGF-1 signaling has been reported in autoimmune disorders. This study was designed to compare +3179G/A IGF-1R genotype distribution in 148 systemic lupus erythematosus (SLE) patients with a group of 240 healthy donors. We also investigated serum IGF-1 levels in SLE patients and healthy controls in an association to genotype. IGF-1 serum levels were measured by enzyme-linked immunosorbent assay and genotyping for the +3179G/A polymorphism was performed by restriction fragment length polymorphisms (RFLP)-polymerase chain reaction (PCR) assay. The higher frequency of homozygous genotype AA (22% vs. 17% with OR 1.319, 95% CI 0.71--2.44) and lower frequency of heterozygous genotype AG (42% vs. 46% with OR 0.698, 95% CI 0.38-1.27) were seen in cases versus controls. Serum IGF-1 levels were comparable between SLE patients and age- and sex-matched healthy donors, even when the groups was stratified according to +3179G/A IGF-1R genotypes. However, when patients were sub grouped according to the disease activity index (SLEDAI score), serum IGF-1 levels were increased in patients with severe disease activity. These results indicated that systemic lupus erythematosus activity is affected by a modulation of the insulin-like growth factor-1 signal pathway and +3179G/A IGF-1R polymorphism. PMID- 23989735 TI - Reflections on Lupus 2013: butterflies, wolves and prophecies. AB - The recently concluded Tenth International Congress on Systemic Lupus Erythematosus (SLE) held in Buenos Aires was a resounding success. This overview summarizes some of the origins of the First International Congress held in Calgary, Canada in 1986, predictions offered by past Congress Presidents, and a perspective on the trends in autoantibody testing, which remains one of the key approaches to the early and accurate diagnosis of SLE. The last few decades have witnessed a remarkable proliferation of new diagnostic technologies including addressable laser bead immunoassays and, more recently, chemiluminescence and lateral flow technologies that could find a clinical niche in point-of-care diagnostics. Against the backdrop of these constantly emerging technologies, indirect immunofluorescence has remained the platform of choice for many laboratories and diagnosticians. The notion that autoantibodies are pathogenic has been challenged by evidence that some autoantibodies are protective, some may have catalytic capacity while others may be neutral or have no function at all. The latter notion of functionless or "junk" autoantibodies needs to be taken under some advisement, because there was a time when a great proportion of the human genome was considered to include "junk DNA". The butterfly as a symbol of hope and progress in SLE research over the past 27 years since the First International Congress on SLE is almost certainly to be even more appropriate when future Congresses are held in Geneva (2015), Melbourne (2017) and eventually one in 2050. PMID- 23989736 TI - Bone mineral density in systemic lupus erythematosus women one year after rituximab therapy. AB - The objective of this study was to assess the effects of rituximab on bone mineral density (BMD) in women with systemic lupus erythematosus (SLE) 1 year after treatment. Thirty active female SLE patients treated with rituximab were compared with 43 SLE women not treated with rituximab. BMD was measured using dual energy X-ray absorptiometry (DEXA) before initiating biologic therapy and after 1 year. The mean age was 38.5 +/- 2.1 years; median disease duration was 7 years. In the rituximab group, after 1 year of follow-up, BMD at the femoral neck (FN) decreased from 0.980 +/- 0.130 g/cm(2) to 0.809 +/- 0.139 g/cm(2) (-17.4%; p=0.001). Similarly, BMD at the lumbar spine (LS) decreased from 1.062 +/- 0.137 g/cm(2) to 0.893 +/- 0.194 g/cm(2) (-15.8%; p=0.001). In control subjects, BMD at the FN decreased from 0.914 +/- 0.193 g/cm(2) to 0.890 +/- 0.135 g/cm(2) (-2.6%; p=0.001), and BMD at the LS decreased from 0.926 +/- 0.128 g/cm(2) to 0.867 +/- 0.139 g/cm(2) (-6.2%; p=0.09). After 1 year, SLE patients had lower BMD at both the FN and LS, but the loss was greater in postmenopausal patients who had received rituximab therapy. PMID- 23989737 TI - Health-related quality of life, fatigue and mood in patients with SLE and high levels of pain compared to controls and patients with low levels of pain. AB - Objective The objective of this paper is to investigate health-related quality of life (HRQoL), fatigue, anxiety and depression in patients with systemic lupus erythematosus (SLE) and higher levels of pain and to compare them to patients with lower levels of pain and controls. Method Patients were dichotomized into two groups based on SLE-related pain score on the visual analog scale (VAS): low pain group (76%, n=64, VAS 0-39 mm) and high-pain group (24%, n=20, VAS 40-100 mm). Sex- and age-matched controls were randomly selected from the general population. Participants were asked to complete questionnaires regarding self reported pain, HRQoL, fatigue, anxiety and depression. Medical assessments also were recorded. Result Fatigue score in the high-pain group (median, 36.5; interquartile range (IQR), 32.5-39.7) was significantly higher (p<0.001) compared to the low-pain group (median, 23; IQR, 14.6-34.1), as well as scores for anxiety (median, 9; IQR, 6.5-11.5) and depression (median, 7.5; IQR, 5.5-9) (p<0.001). The high-pain group had significantly lower scores compared to the low-pain group in all dimensions in the SF-36 (p <= 0.001-0.007). No statistical differences were detected between the low-pain group and controls in any measurement except for the dimensions physical function, general health, vitality and social function in SF-36. Conclusion Patients with SLE scoring higher degrees of pain were burdened with more fatigue, anxiety and depression and lower levels of HRQoL compared to patients with lower levels of pain who did not differ significantly from the general population in most dimensions. These results elucidate the importance of identifying patients with higher degrees of pain who are probably in need of more extensive multidimensional interventions to decrease symptom burden. PMID- 23989738 TI - Antibodies to phosphatidylserine/prothrombin complex in suspected antiphospholipid syndrome in the absence of antibodies to cardiolipin or Beta-2 glycoprotein I. AB - Antibodies to phosphatidylserine/prothrombin (aPS/PT) complex were measured in 728 serum specimens from patients suspected of having antiphospholipid syndrome (APS), but without diagnostic elevations in the levels of antibodies to cardiolipin or Beta-2 Glycoprotein 1 (beta2-GP1). Of the 728 specimens, 41 had elevated levels of aPS/PT. Thrombotic events occurred in 11 of the 22 patients with accessible medical histories. Six of the patients with accessible medical records also had laboratory evidence of the lupus anticoagulant. The identification of aPS/PT in patients without evidence of antibodies to cardiolipin, beta2-GP1, or the lupus anticoagulant can contribute to the identification of APS in patients that may go undetected with current testing methods. PMID- 23989739 TI - Total spondylectomy for solitary bone plasmacytoma of the lumbar spine in a young woman: a case report and review of literature. AB - INTRODUCTION: Solitary bone plasmacytoma (SP) is a rare diagnosis for which the primary treatment is local radiotherapy. There is no established consensus suggesting a total spondylectomy in spinal SP. MATERIALS AND METHODS: We report the case of a 43-year-old woman with solitary plasmacytoma of the lumbar spine treated with complete vertebral resection. Radiographs, CT scan and MRI showed a single osteolytic lesion of the third lumbar vertebra. Further diagnostics following recommended algorithm for tumour screening were negative. Two times, biopsy showed no histological pathologies. Due to the instability of the spine with suspicious unknown lesion, we decided to perform a dorsal lumbar approach and instrumentation with complete resection of the posterior parts to prepare for a complete resection if mandatory. Resamples were taken and the bone surfaces sealed. Consecutive findings were positive for plasma cell infiltration of the respective vertebra, however not on the first pass, but after diagnostic pathological reference. Surgery was completed by total spondylectomy. Reference histological findings with restaging and cytogenetic risk analysis confirmed a non-high-risk solitary bone plasmacytoma, and the patient was scheduled for localized radiotherapy with 40 Gy. RESULTS: Follow-up examinations (53 months) showed no local recurrence or disease progression. DISCUSSION: There is no consensus in the literature regarding appropriate surgical approach and perioperative strategies in the treatment of solitary plasmacytoma. The finding of a solitary plasmacytoma of the spine was the determining factor for our decision to perform radical surgery with subsequent radiotherapy. The rationale for the chosen approach was to minimize the risk of local recurrence and to avoid conversion into multiple myeloma. The follow-up with 53 months is limited. However, discussion remains, if radical surgery in addition to local radiotherapy could be an alternative therapeutic approach depending on paraclinical parameters, age and cytogenetic risk analysis. PMID- 23989740 TI - Expert's comment concerning Grand Rounds case entitled "Vertebral artery injury and severely displaced odontoid fracture: the case for early reduction" (by M.P. Sullivan, J.D. McCormick, V. Arlet). PMID- 23989742 TI - French door laminoplasty for cervical spondylotic myelopathy. PMID- 23989743 TI - Circumferential convex growth arrest by posterior approach for double cervicothoracic curves in congenital scoliosis. PMID- 23989744 TI - Spine Tango annual report 2012. AB - PURPOSE: Since the Spine Tango registry was founded over a decade ago it has become established internationally. An annual report has been produced using the same format as the SWEspine group to allow for first data comparisons between the two registries. METHODS: Data was captured with the latest generation of surgery and follow-up forms. Also, the Core Outcome Measures Index (COMI) from interventions performed in the year 2012 with follow-up to June 2013 was analyzed. Groups of patients with the most common degenerative lumbar spine diseases and a single group of patients with degenerative cervical spine diseases were created. The demographics, risk factors, previous treatments, current treatment, short-term outcomes, patient satisfaction and complications were analyzed. Pre- and postoperative pain and function scores were derived from the COMI. RESULTS: About 6,500 procedures were captured with Spine Tango in 2012. The definitions and composition of all the degenerative groups could not completely be matched between the two registries with the consequence that the age and sex distributions were partially different. Preoperative pain levels were similar. The short-term outcomes available did not allow for evaluation of the final result of surgical intervention. This will be possible with the longer term data in the next annual report. There was a distinct disparity in reported complication rates between surgeons and patients. CONCLUSIONS: This is a valuable first step in creating comparable reports for SWEspine and Spine Tango. The German spine registry may be able to collaborate in the future because of similar items and data structure as Spine Tango. There needs to be more work on understanding the harmonization of the different degenerative subgroups. The Spine Tango report is weakened by the short and incomplete follow-up. The visual presentation of data may be a useful model for aiding decision making for surgeons and patients in the future. PMID- 23989745 TI - Minimal-invasive stabilization and circumferential spinal cord decompression in metastatic epidural spinal cord compression (MESCC). PMID- 23989746 TI - Measurement of long-term outcome in patients with cervical spondylotic myelopathy treated surgically. AB - PURPOSE: The Myelopathy Disability Index and the Neck Disability Index are widely used to assess outcome in cervical spine surgery. Short Form (SF) 36 is a generic measure of health which can be used to measure health gains across a wide variety of conditions. The aim of the current study is to assess long-term outcomes using these measures in a cohort of patients with cervical spondylotic myelopathy (CSM). METHODS: Cohort study with prospective data collection. Patients with CSM being offered decompressive surgery were asked to complete a set of generic and condition-specific outcome measures. This was repeated post-operatively at 3, 12, 24 and 60 months. SF-36 was used as a generic outcome measure and the Myelopathy Index, Neck Disability Score and visual analogue scores for arm, neck and hand pain, paraesthesia and dysthaesia were used as condition-specific outcome measures. RESULTS: Significant improvements in all outcome measures were seen in 70% of the cohort. For SF-36, pre-operative scores were lower than age-matched controls in all domains and significant improvements were seen 3 months following surgery. This improvement in outcome was maintained at 5 years follow-up in approximately two-thirds of those with initial improvement. CONCLUSION: We have used generic and condition-specific outcome measures of health and shown that in patients with CSM treated surgically, up to 70% can expect improvement in their quality of life. These outcome measures are easy to collect and provide objective evidence of changes in quality of life and disability and can help quantify the potential health gains that can be achieved. PMID- 23989747 TI - An exploration of patients' expectation of and satisfaction with surgical outcome. AB - PURPOSE: The majority of studies of surgical outcome focus on measures of function and pain. Increasingly, however, the desire to include domains such as patients' satisfaction and expectations had led to the development of simple measures and their inclusion into clinical studies. The purpose of this study was to determine patients' pre-operative expectations of and post-operative satisfaction with the outcome of their spinal surgery. METHODS: As part of the FASTER randomised controlled trial, patients were asked pre-operatively to quantify their expected improvement in pain and health status at 6 weeks, 6 and 12 months following surgery using 100 mm visual analogue scales (VAS), and to indicate their confidence in achieving this result and also the importance of this recovery to them. Patients were then asked to rate their satisfaction with the improvement achieved at each post-operative review using 100 mm VAS. RESULTS: Although differences between patients' expectation and achievement were minimal 6 weeks post-operatively, there was a clear discrepancy at 6 months and 1 year, with patient expectations far exceeding achievement. There were significant correlations between failure to achieve expectations and the importance patients attached to this recovery at each post-operative assessment, but not with their confidence in achieving this result. Satisfaction levels remained high despite expectations not being met, with discectomy patients being more satisfied than decompression patients. CONCLUSIONS: Patients' pre-operative expectations of surgical outcome exceed their long-term achievement. The more importance the patient attached to a good outcome, the larger is the discrepancy between expectation and achievement. Despite this, satisfaction levels remained high. The impact of unrealistic expectations on outcome remains unclear. PMID- 23989748 TI - Lumbopelvic motion during seated hip flexion in subjects with low-back pain accompanying limited hip flexion. AB - PURPOSE: Limited hip flexion may lead to a poor lumbopelvic motion during seated active hip flexion in people with low-back pain (LBP). The purpose of this study was to compare lumbopelvic motion during seated hip flexion between subjects with and without LBP accompanying limited hip flexion. METHODS: Fifteen patients with LBP accompanying limited hip flexion and 16 healthy subjects were recruited. The subjects performed seated hip flexion with the dominant leg three times. A three dimensional motion-analysis system was used to measure lumbopelvic motion during seated hip flexion. RESULTS: During seated active hip flexion, the angle of hip flexion was significantly lower in patients with LBP accompanying limited hip flexion (17.4 +/- 4.4 in the LBP group, 20.8 +/- 2.6 in the healthy group; t = 2.63, p = 0.014). The angle of the lumbar flexion (4.8 +/- 2.2 in the LBP group, 2.6 +/- 2.0 in the healthy group; t = -2.96, p = 0.006) and posterior pelvic tilting (5.0 +/- 2.6 in the LBP group, 2.9 +/- 2.0 in the healthy group; t = 2.48 p = 0.019), however, were significantly greater in patients with this condition. CONCLUSIONS: The results of this study suggest that limited hip flexion in LBP can contribute to excessive lumbar flexion and posterior pelvic tilting during hip flexion in the sitting position. Further studies are required to confirm whether improving the hip flexion range of motion can reduce excessive lumbar flexion in patients with LBP accompanying limited hip flexion. PMID- 23989749 TI - Ultrastructural change of ligamentum flavum in galactosialidosis. AB - PURPOSE: Galactosialidosis is an autosomal recessive lysosomal storage disease caused by deficiency of both alpha-neuraminidase and beta-galactosidase due to a defect of the protective protein/cathepsin A. Three clinical subtypes have been described, depending on the age of onset and severity of the symptoms: the early infantile, late infantile and juvenile/adult form. We report an adult-type patient who underwent surgery for galactosialidosis-related spinal deformity, and showed a favorable course thereafter. METHODS: The patient was a 50-year-old male, and he consulted our hospital with pain of the bilateral anterior thigh. Lumbar radiograph showed applanation and horn-like deformity of the L2 vertebral body, which is characteristic of this disease, narrowing of the L1/2 intervertebral space, and topical kyphosis. Fenestration between the L1/2, decompression of the L2 nerve root, and posterolateral fusion involving the T12 to L3 were performed. RESULTS: Immediately after surgery, pain of the lower limbs disappeared. During the 2-year postoperative follow-up, bone assimilation was achieved, showing a favorable course. Histological examination of the ligamentum flavum (LF) collected during surgery showed that the elastic fibers were thin, whereas the collagen fibers were abundant and dense. The ligament cells were swollen, and there were a large number of vacuoles in the cytoplasm. CONCLUSION: This is the first report on spinal surgery for adult-type galactosialidosis and histological examination of spinal LF. PMID- 23989750 TI - Quantification and characterization of mucosa-associated and intracellular Escherichia coli in inflammatory bowel disease. AB - BACKGROUND: Mucosa-associated Escherichia coli are abundant in inflammatory bowel disease (IBD), but whether these bacteria gain intracellular access within the mucosa is uncertain. If E. coli does gain intracellular access, the contribution of bacterial pathogenicity to this requires further elucidation. This study aimed to quantify and characterize mucosa-associated and intracellular E. coli in patients with IBD and in healthy control subjects (HC). METHODS: Mucosal biopsies from 30 patients with Crohn's disease (CD), 15 with ulcerative colitis (UC), and 14 HC were cultured with or without gentamicin protection to recover intracellular or mucosa-associated E. coli, respectively. Overall, 40 strains (CD: n = 24, UC: n = 9, and HC: n = 7) were characterized by phylogenetic typing, adhesion and invasion assays, detection of virulence factors, antimicrobial resistance genes, and proteomic analysis. RESULTS: Mucosa-associated E. coli were more abundant in CD and UC than in HC (2750 versus 1350 versus 230 median colony forming units per biopsy; P = 0.01). Intracellular E. coli were more prevalent in CD (90%) than in UC (47%) or HC mucosal biopsies (0%) (P < 0.001). Of 24 CD strains, 2 were adherent and invasive, but there were no unifying pathogenicity determinants that could distinguish most CD strains from UC or HC strains, or intracellular isolates from mucosa-associated isolates. CONCLUSIONS: Intracellular E. coli are more common in CD than in UC and not identified in HC. Most intracellular E. coli did not have characterizing pathogenic features, suggesting a significant role for defects in mucosal immunity or barrier dysfunction in their ability to gain intracellular access. PMID- 23989751 TI - Imaging features of medulloepithelioma: report of four cases and review of the literature. AB - BACKGROUND: Intraocular medulloepithelioma is a childhood tumor arising from the nonpigmented primitive ciliary neuroepithelium. Although rarer than retinoblastoma, it remains the second most common primary intraocular neoplasm in children. The rarity of intraocular medulloepithelioma creates the challenge in establishing a clinical diagnosis, and radiologically the tumor is often confused with other intraocular masses. OBJECTIVE: To describe the clinical, imaging and pathological features of intraocular medulloepithelioma with emphasis on the role of imaging to enable its differentiation from more common intraocular pathology. MATERIALS AND METHODS: We retrospectively analyzed the clinical, histopathological and imaging data of four children with intraocular medulloepithelioma. RESULTS: All four children had medulloepithelioma arising from the ciliary body. The children were imaged with US (n = 3), MRI (n = 4), whole-body (99m)Tc-MDP scintigraphy (n = 2) and CT (n = 1). All four children had enucleation of the involved eye. One tumor was a malignant teratoid variant, two tumors were malignant nonteratoid variants and one was a nonteratoid variant of uncertain malignant potential. None of the tumors had extraocular extension on histopathology or imaging. Two children had associated retinal detachment on US and MRI examinations. All tumors were iso/hyperintense to vitreous on T1-weighted and hypointense on T2-weighted MRI and showed marked contrast enhancement of the solid components. No calcifications were identified on US or CT examinations. CONCLUSION: Our findings are consistent with previously reported cases of medulloepithelioma. This series emphasizes the roles of various imaging modalities, with pathological correlation, in differentiating the tumor from other ciliary body masses, in detecting tumor extension and in identifying associated ocular complications. In this series we also describe the results of postsurgical follow-up for tumor recurrence. PMID- 23989752 TI - Transition of refractive index contrast in course of grating growth. AB - Studies on the dynamics of holographic pattern formation in photosensitive polymers, gaining deeper insight into the specific material transformations, are essential for improvements in holographic recording as well as in integrated optics. Here we investigate the kinetics of volume hologram formation in an organic cationic ring-opening polymerization system. The time evolution of the grating strength and the grating phase is presented. We found two steps of growth, separated by a depletion of the light diffraction. Capable to explore this growing behavior, a transition-theory of the refractive index contrast is established. Accordingly the growth curves appear to be ruled by the interplay of polymerization and diffusion. Hence the grating formation mechanisms can be qualified as competing effects regarding the contribution to the refractive index change. We investigate the influence of the preparation and exposure procedure on the transition and consider the usability for integrated wave guide functions. PMID- 23989753 TI - Flavonoid bioavailability and attempts for bioavailability enhancement. AB - Flavonoids are a group of phytochemicals that have shown numerous health effects and have therefore been studied extensively. Of the six common food flavonoid classes, flavonols are distributed ubiquitously among different plant foods whereas appreciable amounts of isoflavones are found in leguminous plant-based foods. Flavonoids have shown promising health promoting effects in human cell culture, experimental animal and human clinical studies. They have shown antioxidant, hypocholesterolemic, anti-inflammatory effects as well as ability to modulate cell signaling and gene expression related disease development. Low bioavailability of flavonoids has been a concern as it can limit or even hinder their health effects. Therefore, attempts to improve their bioavailability in order to improve the efficacy of flavonoids are being studied. Further investigations on bioavailability are warranted as it is a determining factor for flavonoid biological activity. PMID- 23989756 TI - Sharp diffusion front in diffusion problem with change of state. AB - We propose an alternative model of diffusion in polymers, which may explain formation of propagating sharp diffusion fronts to be observed in some experiments. Differently from typical Case II or Stefan problem models, plasticisation of the polymer matrix is not necessarily required. Instead, diffusing small molecules are assumed to be captured by some specific sites of the polymer matrix for certain retention times. For example, they may become adsorbed at the surface of the holes and microvoids that are considered to be present in glassy polymer regions according to the well-known dual-sorption model and are attributed to excess free volume frozen into the glassy matrix. On the other hand, the small molecules may become bound to polymer chains. In this adsorbed/bound state they have much smaller movability and thus are effectively excluded from the diffusion. This adsorption/binding is considered to be a reversible process of state changing, but with asymmetric probabilities for direct and reverse events. With this assumption, taking into account that the amount of space available for such immobilised molecules is limited (limited free volume, limited number of anchoring sites) the model naturally results in the formation of sharp diffusion fronts or strong concentration gradients. Such a diffusion front is a region of effective immobilisation (adsorption/binding, though reversible) of the free diffusing molecules. For the simplest prescribed boundary conditions the diffusion front propagates linearly with the square root of time. By means of imposing generalised boundary conditions, it is possible to model other regimes of propagation of the diffusion front, including constant velocity. PMID- 23989755 TI - Tuning active emulsion dynamics via surfactants and topology. AB - We study water-in-oil emulsion droplets, running the Belousov-Zhabotinsky reaction, that form a new type of synthetic active matter unit. These droplets, stabilised by surfactants dispersed in the oil medium, are capable of internal chemical oscillations and self-propulsion. Here we present studies of networks of such self-propelled chemical oscillators and show that the resulting dynamics depend strongly on the topology of the active matter units and their connections. The chemical oscillations can couple via the exchange of promoter and inhibitor type of reaction intermediates across the droplets under precise conditions of surfactant bilayer formation between the droplets. The self-emerging synchronization dynamics are then characterized by the topology of the oscillator networks. Further, we show that the chemical oscillations inside the droplets cause oscillatory speed variations in the motion of individual droplets, extending our previous studies on such swimmers. Finally, we demonstrate that qualitatively new types of self-propelled motion can occur when simple droplet networks, for example two droplets connected by a bilayer, are set into motion. Altogether, these results lead to exciting possibilities in future studies of autonomous active matter. PMID- 23989754 TI - Life events and the onset of celiac disease from a patient's perspective. AB - Stressful events have been investigated in various immune-mediated diseases but not in celiac disease. Our aim was to examine the relationship of stressful events assessed by the standardized interview of Paykel with the diagnosis of celiac disease in comparison to patients, with a diagnosis of gastroesophageal reflux disease used as the control group. Adults with celiac disease (n = 186) reported more frequent and more severe life events in the years prior to the diagnosis than control patients (n = 96) (67.2% vs. 37.5%, p < 0.001, mean Paykel score 11.5 vs. 13.4, p = 0.001, respectively). Findings were not significantly different between celiac disease and control patients for the time lapse between the event and the diagnosis (mean 5.5 vs. 5.7 months). Pregnancy was defined as a negative event by 20.3% of celiac women, but never by control women. Findings were confirmed when analyses were repeated in the subgroup of patients of both groups with diagnosis made within one year of onset of symptoms. Data indicate that, before diagnosis, the number of stressful events in celiac disease was more frequent although less severe than in the control group suggesting that life events may favor the clinical appearance of celiac disease or accelerate its diagnosis. PMID- 23989757 TI - Explosively driven fragmentation of granular materials. AB - This paper investigates the explosively driven dynamics of dry and wet sand. Contrary to popular belief, wet sand under high strain rate loadings (10(4)s(-1)) is observed to have reduced resistance against flow compared to the dry sand, which is supported by a noticeably enhanced expansion before the breakup followed by an increased number of fragments. Even a small amount of interstitial oil (3.2 wt.%) suffices to substantially reduce the size of fragments whose average mass only amounts to 60% of the mass of the dry sand fragments. To predict the instability onset of the expanding sand shell, a kinetic instability model is proposed based on an instability criterion involving the opposing forces of stabilizing inertial pressures and destabilizing viscous resistance. The interstitial oil leads to a smaller viscous resistance of wet sand by the lubrication effect as well as lessening the degree of shock compaction. The dominance of viscous resistance thus commences later for the wet sand shell until a smaller thickness allows the inertial forces to be overtaken. Moreover, multi shear localizations rather than interface instability are identified as the dominant mechanism for the instability onset of the expanding sand shells. PMID- 23989758 TI - A simple model for the rotation of a trapped chiral nematic droplet under the action of a linearly polarized laser beam. AB - There have been recent reports of continuous rotation of chiral nematic droplets in restricted ranges of diameter/pitch (d /p) values, trapped by a linearly polarized laser beam. We have developed a simple model to calculate the distortion in the helical structure of a set of flat layers, caused by the action of the strong electric field of the propagating laser beam on the dielectric anisotropy of the medium. The resulting change in the polarization state of the beam passing through the sample is then used to calculate the torque on the sample as a function of the azimuthal angle of the first layer. The main results are: i) the torque tends to zero even with circularly polarized beam for samples with thicknesses around integral multiples of 0.5p ; ii) the undistorted sample takes an equilibrium orientation for linearly polarized beam, which jumps by pi/2 rad at the same sample thicknesses; iii) these samples will have a nonzero torque at all azimuthal angles of the first slice when the helical structure is distorted by the linearly polarized beam. The calculations show that a propagating accordion mode, in which the helical pitch alternately expands and contracts, gives rise to the nonzero torque. The theoretical predictions are in broad agreement with experimental results. PMID- 23989759 TI - Direct and inverse pumping in flows with homogeneous and non-homogeneous swirl. AB - The conditions in which meridional recirculations appear in swirling flows above a fixed wall are analysed. In the classical Bodewadt problem, where the swirl tends towards an asymptotic value away from the wall, the well-known "tea-cup effect" drives a flow away from the plate at the centre of the vortex. Simple dimensional arguments applied to a single vortex show that if the intensity of the swirl decreases away from the wall, the sense of the recirculation can be inverted, and that the associated flow rate scales with the swirl gradient. If the flow is quasi-2D, the classical tea-cup effect takes place. This basic theory is confirmed by numerical simulations of a square array of steady, electrically driven vortices. Experiments in the turbulent regimes of the same configuration reveal that these mechanisms are active in the average flow and in its fluctuating part. These mechanisms provide an explanation for previously observed phenomena in electrolyte flows. They also put forward a possible mechanism for the generation of helicity in flows close to two-dimensionality, which plays a key role in the transition between 2D and 3D turbulence. PMID- 23989762 TI - Maqdes A, Levy B, Klouche S, Hardy P. The feasibility and results of an arthroscopic removal of humeral locking plates and glenohumeral arthroylsis after proximal humeral fractures. Knee surg sports traumatol arthrosc 2013 Feb 9. [Epub ahead of print] Doi 10.1007/s00167-013-2437-8. PMID- 23989761 TI - The autodigestion hypothesis for shock and multi-organ failure. AB - An important medical problem with high mortality is shock, sepsis and multi-organ failure. They have currently no treatments other than alleviation of symptoms. Shock is accompanied by strong markers for inflammation and involves a cascade of events that leads to failure in organs even if they are not involved in the initial insult. Recent evidence indicates that pancreatic digestive enzymes carried in the small intestine after mixing with ingested food are a major cause for multi-organ failure. These concentrated and relatively non-specific enzymes are usually compartmentalized inside the intestinal lumen as requirement for normal digestion. But after breakdown of the mucosal barrier they leak into the wall of the intestine and start an autodigestion process that includes destruction of villi in the intestine. Digestive enzymes also generate cytotoxic mediators, which together are transported into the systemic circulation via the portal venous system, the intestinal lymphatics and via the peritoneum. They cause various degrees of cell and organ dysfunction that can reach the point of complete organ failure. Blockade of digestive enzymes in the lumen of the intestine in experimental forms of shock serves to reduce breakdown of the mucosal barrier and autodigestion of the intestine, organ dysfunctions and mortality. PMID- 23989764 TI - Pulmonary artery aneurysm in an octogenarian with operated secundum atrial septal defect. PMID- 23989763 TI - Tibiofemoral relationship following anatomic triple-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: The purpose of this study was to investigate the tibiofemoral relationship sequentially before and after anatomic triple-bundle (TB) anterior cruciate ligament (ACL) reconstruction in the same patients. METHODS: Nine patients with complete unilateral ACL rupture participated in this study. Anatomic TB ACL reconstruction was performed using autogenous semitendinosus tendon grafts. Computed tomography images were obtained before surgery as well as 3 weeks and 6 months afterwards. During image acquisition, the patient's knees were fully extended in the supine position. Using three-dimensional computer models, anterior-posterior and medial-lateral displacement of the tibia relative to the femur were evaluated for each period, as were internal-external and varus valgus rotation, followed by calculation of side-to-side differences in parameters. As the control group, 7 healthy volunteers were evaluated. RESULTS: The tibia was located anteriorly by 1.4 +/- 0.9 mm and rotated internally by 2.1 +/- 1.7 degrees before surgery, while the tibia was located posteriorly by 2.0 +/- 1.2 mm and rotated externally by 3.4 +/- 3.5 degrees 3 weeks after surgery. Six months after surgery, there was no significant difference between the patient and control groups. CONCLUSIONS: The anteriorly located and internally rotated tibia in ACL-deficient knees was over-constrained (posterior displacement and external rotation) 3 weeks after anatomic TB ACL reconstruction, but returned to the normal position 6 months afterwards. Therefore, anatomic tunnel placement, appropriate initial tension, and moderate rehabilitation can be the key for return to the normal tibiofemoral relationship after ACL reconstruction. LEVEL OF EVIDENCE: Therapeutic study, Level IV. PMID- 23989765 TI - Dense spontaneous echo contrast in the right heart chambers of a patient with autoimmune hemolytic anemia. PMID- 23989766 TI - Total left main coronary artery occlusion presenting with stable angina and normal ECG. PMID- 23989771 TI - Do coinage metal anions interact with substituted benzene derivatives? AB - The nature of the anion-pi interaction has been investigated by carrying out ab initio calculations of the complexes of coinage metal anions (Au(-), Ag(-), and Cu(-)) with different kinds of pi-systems. The binding energies indicate that gold anion has the highest and copper anion has the lowest affinity for interactions with pi-systems. Different aspects of the anion-pi interaction in these systems have been investigated, including charge-transfer effects (using the Merz-Kollman method), "atoms-in-molecules" (AIM) topological parameters, and interaction energies (using energy decomposition analysis, EDA). Our results indicated that, for most M(-)...pi interactions, the electrostatic term provides the dominant contribution, whereas polarization, charge transfer, and dispersion effects contribute less than 25 % of the interaction. We believe that the present results should lead to a greater understanding of the basis for anion-pi interactions of coinage metal anions. PMID- 23989772 TI - Stereoselectivity of chalcone isomerase with chalcone derivatives: a computational study. AB - Chalcone isomerase (CHI) catalyzes the intramolecular cyclization of chalcones into flavonoids. The activity of CHI is essential for the biosynthesis of flavonoids precursors of floral pigments and phenylpropanoid plant defense compounds. In the present study, we explored the detailed binding structures and binding free energies for two different active site conformations of CHI with s cis/s-trans conformers of three chalcone compounds by performing molecular dynamics (MD) simulations and binding free energy calculations. The computational results indicate that s-cis/s-trans conformers of chalcone compounds are orientated in the similar binding position in the active site of CHI and stabilized by the different first hydrogen bond network and the same second hydrogen bond network. The first hydrogen bond network results in much lower binding affinity of s-trans conformer of chalcone compound with CHI than that of s-cis conformer. The conformational change of the active site residue T48 from indirectly interacting with the substrate via the second hydrogen bond network to directly forming the hydrogen bond with the substrates cannot affect the binding mode of both conformers of chalcone compounds, but remarkably improves the binding affinity. These results show that CHI has a strong stereoselectivity. The calculated binding free energies for three chalcone compounds with CHI are consistent with the experimental activity data. In addition, several valuable insights are suggested for future rational design and discovery of high efficiency mutants of CHI. PMID- 23989773 TI - Impact of changes in metabolic control on progression to photocoagulation for clinically significant macular oedema: a 20 year study of type 1 diabetes. AB - AIMS/HYPOTHESIS: Although increasing hyperglycaemia, arterial hypertension and longer duration of diabetes raise the risk of progression of diabetic retinopathy, short-term benefits in terms of improved metabolic control and lowered blood pressure have not been demonstrated. We therefore examined the effect of changes in glycaemia and arterial blood pressure on the incidence of clinically significant macular oedema in a population of diabetic patients. METHODS: We performed a retrospective review of all patients with type 1 diabetes who attended the retinopathy screening clinic at the Steno Diabetes Center from 1988 to 2008, using the endpoint referral to first photocoagulation treatment for clinically significant diabetic macular oedema. The analysis included 1,878 patients (median observation, 8 years). Changes were defined as the inter-visit change; in the case of an event the last event-free interval before referral, where the median screening interval was 6 months. RESULTS: Risk of progression to photocoagulation for macular oedema increased with duration of diabetes (p < 0.001), current HbA1c (p < 0.0001) and with the magnitude of changes in HbA1c (p = 0.0002) and systolic blood pressure (p < 0.0001) in a multiple regression model. A recent decrease of >= 0.5 percentage points or an increase in HbA1c of >0.5 percentage points per 6 months was associated with HRs of 3.04 and 1.28, respectively, compared with lesser changes in HbA1c. CONCLUSIONS/INTERPRETATION: In this study, large recent changes in metabolic control and systolic blood pressure, irrespective of direction, were independent risk factors for progression to photocoagulation for diabetic macular oedema. The effects of metabolic and haemodynamic stability on diabetic retinopathy should be examined in prospective studies. PMID- 23989775 TI - Appropriate evidence for adaptive marketing authorization. PMID- 23989774 TI - Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms. AB - AIMS/HYPOTHESIS: In humans, disruption of the gene BSCL2, encoding the protein seipin, causes congenital generalised lipodystrophy (CGL) with severe insulin resistance and dyslipidaemia. While the causative gene has been known for over a decade, the molecular functions of seipin are only now being uncovered. Most pathogenic mutations in BSCL2 represent substantial disruptions including significant deletions and frameshifts. However, several more subtle mutations have been reported that cause premature stop codons or single amino acid substitutions. Here we have examined these mutant forms of seipin to gain insight into how they may cause CGL. METHODS: We generated constructs expressing mutant seipin proteins and determined their expression and localisation. We also assessed their capacity to recruit the key adipogenic phosphatidic acid phosphatase lipin 1, a recently identified molecular role of seipin in developing adipocytes. Finally, we used atomic force microscopy to define the oligomeric structure of seipin and to determine whether this is affected by the mutations. RESULTS: We show that the R275X mutant of seipin is not expressed in pre adipocytes. While the other premature stop mutant forms fail to bind lipin 1 appropriately, the point mutants T78A, L91P and A212P all retain this capacity. We demonstrate that wild-type human seipin forms oligomers of 12 subunits in a circular configuration but that the L91P and A212P mutants of seipin do not. CONCLUSIONS/INTERPRETATION: Our study represents the most comprehensive analysis so far of mutants of seipin causing lipodystrophy and reveals several different molecular mechanisms by which these mutations may cause disease. PMID- 23989776 TI - Irreversible kinase inhibitors gain traction. PMID- 23989777 TI - Patient-focused drug development programme takes first steps. PMID- 23989781 TI - Trial watch: Clinical trial boost for lentiviral gene therapy. PMID- 23989782 TI - Regulatory watch: Speedy validation sought for new cardiotoxicity testing strategy. PMID- 23989787 TI - An audience with... Tachi Yamada. Interviewed by Asher Mullard. PMID- 23989788 TI - The epigenetics pipeline. PMID- 23989789 TI - Kinase inhibitors: a molecular target for myelodysplastic syndromes. PMID- 23989794 TI - HIV: Efficacy through BibNAbs. PMID- 23989797 TI - Lateral wedge insoles as a conservative treatment for pain in patients with medial knee osteoarthritis: a meta-analysis. AB - IMPORTANCE: There is no consensus regarding the efficacy of lateral wedge insoles as a treatment for pain in medial knee osteoarthritis. OBJECTIVE: To evaluate whether lateral wedge insoles reduce pain in patients with medial knee osteoarthritis compared with an appropriate control. DATA SOURCES: Databases searched include the Cochrane Central Register of Controlled Trials, EMBASE, AMED, MEDLINE, CINAHL Plus, ScienceDirect, SCOPUS, Web of Science, and BIOSIS from inception to May 2013, with no limits on study date or language. The metaRegister of Controlled Trials and the NHS Evidence website were also searched. STUDY SELECTION: Included were randomized trials comparing shoe-based treatments (lateral heel wedge insoles or shoes with variable stiffness soles) aimed at reducing medial knee load, with a neutral or no wedge control condition in patients with painful medial knee osteoarthritis. Studies must have included patient-reported pain as an outcome. DATA EXTRACTION AND SYNTHESIS: Trial data were extracted independently by 2 researchers using a standardized form. Risk of bias was assessed using the Cochrane Risk of Bias tool by 2 observers. Eligible studies were pooled using a random-effects approach. MAIN OUTCOME AND MEASURES: Change in self-reported knee pain at follow-up. RESULTS: Twelve trials met inclusion criteria with a total of 885 participants of whom 502 received lateral wedge treatment. The pooled standardized mean difference (SMD) suggested a favorable association with lateral wedges compared with control (SMD, -0.47; 95% CI, -0.80 to -0.14); however, substantial heterogeneity was present (I2 = 82.7%). This effect size represents an effect of -2.12 points on the 20-point Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scale. Larger trials with a lower risk of bias suggested a null association. Meta-regression analyses showed that higher effect sizes (unstandardized beta, 1.07 [95% CI, 0.28 to 1.87] for trials using a no treatment control) were seen in trials using a no wedge treatment control group (n = 4 trials; SMD, -1.20 [95% CI, -2.09 to -0.30]) and lower effect sizes (unstandardized beta, 0.26 [95% CI, 0.002 to 0.52] for each bias category deemed low risk) when the study method was deemed at low risk of bias. Among trials in which the control treatment was a neutral insole (n = 7), lateral wedges showed no association (SMD, -0.03 [95% CI, -0.18 to 0.12] on WOMAC; this represents an effect of -0.12 points), and results showed little heterogeneity (I2 = 7.1%). CONCLUSIONS AND RELEVANCE: Although meta-analytic pooling of all studies showed a statistically significant association between use of lateral wedges and lower pain in medial knee osteoarthritis, restriction of studies to those using a neutral insole comparator did not show a significant or clinically important association. These findings do not support the use of lateral wedges for this indication. PMID- 23989798 TI - Pancreatic acinar cells--a normal finding at the gastroesophageal junction? Data from a prospective Central European multicenter study. AB - Pancreatic acinar cells are a well-recognized finding at the gastroesophageal junction, but their histogenesis and biological significance are unclear. From the prospective Central European multicenter histoGERD trial, we recruited 1,071 individuals undergoing gastroscopy for various non-selected reasons. Biopsy material was systematically sampled from the gastroesophageal junction and from the stomach. The study aimed to assess the prevalence of pancreatic acinar cells and to relate their presence to various histologic and clinical features. Overall, pancreatic acinar cells were observed in 184 (17.2%) participants. Individuals diagnosed with pancreatic acinar cells were slightly younger than those without (median 50 vs. 53 years; p = 0.009). There was no association with patients' symptoms and/or complaints or with an endoscopic diagnosis of esophagitis or Barrett's esophagus. Regarding histology, pancreatic acinar cells were not associated with features of the squamous epithelium indicating reflux disease, such as basal cell hyperplasia, papillary elongation, dilation of intercellular spaces, and inflammatory cell number, but were associated with the presence of cardiac mucosa (p < 0.001), oxyntocardiac mucosa (p < 0.001), and intestinal metaplasia (p = 0.038), respectively. No association with Helicobacter pylori infection or diagnosis of gastritis was noted. In conclusion, pancreatic acinar cells are a common finding at the gastroesophageal junction, and no association with either reflux disease (histologically or endoscopically) or diagnosis of gastritis was observed. These data suggest a congenital rather than an acquired (metaplastic) origin of pancreatic acinar cells at the gastroesophageal junction. This questions the term "pancreatic acinar metaplasia" which is currently widely used for their diagnosis. PMID- 23989796 TI - Targeting the unfolded protein response in disease. AB - Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a feature of specialized secretory cells and is also observed in many diseases, including cancer, diabetes, autoimmune conditions, liver disorders, obesity and neurodegenerative disorders. Cellular adaptation to ER stress is achieved by the activation of the unfolded protein response, which is an integrated signal transduction pathway that modulates many aspects of ER physiology. When these mechanisms of adaptation are insufficient to handle the unfolded protein load, cells undergo apoptosis. Here, we discuss recent advances in the design of novel compounds and therapeutic strategies to manipulate levels of ER stress in disease. PMID- 23989799 TI - Chitinolytic microorganisms and their possible application in environmental protection. AB - This paper provides a review of the latest research findings on the applications of microbial chitinases to biological control. Microorganisms producing these enzymes can inhibit the growth of many fungal diseases that pose a serious threat to global crop production. Currently, efforts are being made to discover producers of chitinolytic enzymes. The potential exists that natural biofungicides will replace chemical fungicides or will be used to supplement currently used fungicides, which would reduce the negative impact of chemicals on the environment and support the sustainable development of agriculture and forestry. PMID- 23989800 TI - Effect of protein hydrolysates on growth kinetics and aminopeptidase activities of Lactobacillus. AB - The goal of this study was to evaluate how two new hydrolysates from poultry by products act on ten lactobacilli growth kinetics when supplemented to the growth medium. These effects were compared with ones induced by two most common commercial hydrolysates, i.e., tryptone and peptone. Growth medium, supplemented with one of new hydrolysates, 78T, as only nitrogen source, can sustain the maximum growth rate and the biomass yield in the same way of MRS, reach of different nitrogen sources. Moreover aminopeptidase activities (AA) of each strain were determined to investigate the effect of the growth condition on the modulation of aminopeptidase pattern. Five cell extracts of each ten strains, obtained from their cultivation in MRS and in the presence of the two common hydrolysates and the two new ones, were considered. AA was investigated against five different chromogenic substrates: beta-naphthyl amide derivatives of L anomers of leucine, lysine, proline, glycine-proline, and phenilalanine-proline. A great variability of AA was observed among the strains: also strains belonging to the same species showed peculiar AA profile. PMID- 23989795 TI - 50 years of hurdles and hope in anxiolytic drug discovery. AB - Anxiety disorders are the most prevalent group of psychiatric diseases, and have high personal and societal costs. The search for novel pharmacological treatments for these conditions is driven by the growing medical need to improve on the effectiveness and the side effect profile of existing drugs. A huge volume of data has been generated by anxiolytic drug discovery studies, which has led to the progression of numerous new molecules into clinical trials. However, the clinical outcome of these efforts has been disappointing, as promising results with novel agents in rodent studies have very rarely translated into effectiveness in humans. Here, we analyse the major trends from preclinical studies over the past 50 years conducted in the search for new drugs beyond those that target the prototypical anxiety-associated GABA (gamma-aminobutyric acid) benzodiazepine system, which have focused most intensively on the serotonin, neuropeptide, glutamate and endocannabinoid systems. We highlight various key issues that may have hampered progress in the field, and offer recommendations for how anxiolytic drug discovery can be more effective in the future. PMID- 23989801 TI - Notch1 cardioprotection in myocardial ischemia/reperfusion involves reduction of oxidative/nitrative stress. AB - Oxidative/nitrative stress plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Notch1 participates in the regulation of cardiogenesis and cardiac response to hypertrophic stress, but the function of Notch1 signaling in MI/R has not been explored. This study aims to determine the role of Notch1 in MI/R, and investigate whether Notch1 confers cardioprotection. Notch1 specific small interfering RNA (siRNA, 20 MUg) or Jagged1 (a Notch ligand, 12 MUg) was delivered through intramyocardial injection. 48 h after injection, mice were subjected to 30 min of myocardial ischemia followed by 3 h (for cell apoptosis and oxidative/nitrative stress), 24 h (for infarct size and cardiac function), or 2 weeks (for cardiac fibrosis and function) of reperfusion. Cardiac specific Notch1 knockdown resulted in significantly aggravated I/R injury, as evidenced by enlarged infarct size, depressed cardiac function, increased myocardial apoptosis and cardiac fibrosis. Downregulation of Notch1 increased expression of inducible NO synthase (iNOS) and gp(91phox), enhanced the production of NO metabolites and superoxide, as well as their cytotoxic reaction product peroxynitrite. Moreover, Notch1 blockade also reduced phosphorylation of endothelial NO synthase (eNOS) and Akt, and increased expression of PTEN, a key phosphatase involved in the regulation of Akt phosphorylation. In addition, activation of Notch1 by Jagged1 or administration of peroxynitrite scavenger reduced production of peroxynitrite and attenuated MI/R injury. These data indicate that Notch1 signaling protects against MI/R injury partly though PTEN/Akt mediated anti-oxidative and anti-nitrative effects. PMID- 23989803 TI - Are albumin and total lymphocyte count significant and reliable predictors of mortality in fractured neck of femur patients? AB - Hip fractures are a significant cause of mortality and morbidity in the elderly. It is important to identify factors that predict an increased mortality following hip fracture. The aim of this study was to identify significant predictors of mortality at 6 and 12 months following hip fractures. Three hundred patients above the age of 65 were identified who were admitted in to the hospital with fracture neck of femur. Two hundred and seventy-four patients were operated and were included into the study. Variables collected were age, gender, significant comorbidities, admission albumin level and admission total lymphocyte count (TLC). Admission time and subsequent time to surgery were also analysed. Our study showed that albumin and TLC were found to be the only clearly significant mortality predictors at 12 months and a delay of up to 4 days to surgery does not significantly increase the mortality at 12 months. PMID- 23989804 TI - High-performance top-gated monolayer SnS2 field-effect transistors and their integrated logic circuits. AB - Two-dimensional (2D) layered semiconductors are very promising for post-silicon ultrathin channels and flexible electronics due to the remarkable dimensional and mechanical properties. Besides molybdenum disulfide (MoS2), the first recognized 2D semiconductor, it is also important to explore the wide spectrum of layered metal chalcogenides (LMCs) and to identify possible compounds with high performance. Here we report the fabrication of high-performance top-gated field effect transistors (FETs) and related logic gates from monolayer tin disulfide (SnS2), a non-transition metal dichalcogenide. The measured carrier mobility of our monolayer devices reaches 50 cm(2) V(-1) s(-1), much higher than that of the back-gated counterparts (~1 cm(2) V(-1) s(-1)). Based on a direct-coupled FET logic technique, advanced Boolean logic gates and operations are also implemented, with a voltage gain of 3.5 and output swing of >90% for the NOT and NOR gates, respectively. The superior electrical and integration properties make monolayer SnS2 a strong candidate for next-generation atomic electronics. PMID- 23989802 TI - Diet, microbial virulence, and Helicobacter pylori-induced gastric cancer. AB - Gastric adenocarcinoma is a leading cause of cancer-related death worldwide, and Helicobacter pylori infection is one of the strongest known risk factors for this malignancy. H. pylori strains exhibit a high level of genetic diversity, and the risk of gastric cancer is higher in persons carrying certain strain types (for example, those that contain a cag pathogenicity island or type s1 vacA alleles) than in persons carrying other strain types. Additional risk factors for gastric cancer include specific human genetic polymorphisms and specific dietary preferences (for example, a high-salt diet or a diet deficient in fruits and vegetables). Finally, iron-deficiency anemia is a risk factor for gastric cancer. Recent studies have provided evidence that several dietary risk factors for gastric cancer directly impact H. pylori virulence. In this review article, we discuss mechanisms by which diet can modulate H. pylori virulence and thereby influence gastric cancer risk. PMID- 23989805 TI - Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin only susceptible gram-negative bacteria. AB - BACKGROUND: The increasing frequency of ventilator-associated pneumonia (VAP) caused by colistin-only susceptible (COS) gram-negative bacteria (GNB) is of great concern. Adjunctive aerosolized (AS) colistin can reportedly increase alveolar levels of the drug without increasing systemic toxicity. Good clinical results have been obtained in patients with cystic fibrosis, but conflicting data have been reported in patients with VAP. METHODS: We conducted a retrospective, 1:1 matched case-control study to evaluate the efficacy and safety of AS plus IV colistin vs IV colistin alone in 208 patients in the ICU with VAP caused by COS Acinetobacter baumannii, Pseudomonas aeruginosa, or Klebsiella pneumoniae. RESULTS: Compared with the IV colistin cohort, the AS-IV colistin cohort had a higher clinical cure rate (69.2% vs 54.8%, P = .03) and required fewer days of mechanical ventilation after VAP onset (8 days vs 12 days, P = .001). In the 166 patients with posttreatment cultures, eradication of the causative organism was also more common in the AS-IV colistin group (63.4% vs 50%, P = .08). No between cohort differences were observed in all-cause ICU mortality, length of ICU stay after VAP onset, or rates of acute kidney injury (AKI) during colistin therapy. Independent predictors of clinical cure were trauma-related ICU admission (P = .01) and combined AS-IV colistin therapy (P = .009). Higher mean Simplified Acute Physiology Score II (P = .002) and Sequential Organ Failure Assessment (P = .05) scores, septic shock (P < .001), and AKI onset during colistin treatment (P = .04) were independently associated with clinical failure. CONCLUSIONS: Our results suggest that AS colistin might be a beneficial adjunct to IV colistin in the management of VAP caused by COS GNB. PMID- 23989806 TI - Health system-wide quality programs to improve blood pressure control. PMID- 23989807 TI - Laparoscopic urethrolysis followed by trans-obturator tape sling insertion for long standing voiding dysfunction after Burch colposuspension. AB - This case report describes laparoscopic urethrolysis followed by trans-obturator tape sling insertion for voiding dysfunction after colposuspension. A 50-year-old patient presented with predominant stress incontinence of urine 14 after Burch colposuspension. There was no anterior vaginal wall prolapse on examination and urodynamic assessment confirmed voiding dysfunction in the absence of urodynamic stress incontinence. Clean intermittent self-catheterisation was tried, but failed to improve the patient's symptoms. Laparoscopic urethrolysis was carried out, leading to the relief of voiding dysfunction, but was followed by recurrence of stress incontinence. A trans-obturator tape sling was subsequently inserted with significant improvement in stress incontinence and the patient was discharged. PMID- 23989808 TI - Anti-bioadhesion on hierarchically structured, superhydrophobic surfaces. AB - We prepared hierarchically structured, superhydrophobic surfaces, with single-, dual-, and triple-scale roughness, via a layer-by-layer (LbL) particle deposition approach. The dual-/triple-scale structured, superhydrophobic surfaces exhibited significantly reduced protein adsorption (up to a 90% decrease). Furthermore, platelet adhesion and activation was completely suppressed on the triple-scale structured surface. PMID- 23989810 TI - Robotically assisted hybrid coronary revascularization: does sequence of intervention matter? AB - OBJECTIVE: Hybrid coronary revascularization (HCR) is a treatment strategy for the revascularization of multivessel coronary disease that combines the advantages of both minimally invasive surgical techniques and percutaneous coronary intervention (PCI). The optimal sequence by which revascularization should be accomplished has not been determined. We investigated clinical outcomes in a series of patients planned for HCR via robotically assisted totally endoscopic coronary artery bypass (TECAB) and standard PCI based on revascularization sequence. METHODS: A total of 238 patients planned for HCR between 2001 and 2011 were divided into three groups based on treatment sequence: (a) TECAB before PCI, (b) PCI before TECAB, and (c) same-session procedure. Multiple procedural and clinical end points before discharge and up to 2 years after the procedure were compared between the three groups in an intention-to treat analysis. Demographic features were reviewed to determine baseline differences between each group. RESULTS: Of the 238 patients, 175 (73.5%) underwent TECAB before PCI, 38 patients (16.0%) underwent PCI before TECAB, and 25 (10.5%) underwent a simultaneous revascularization procedure. At baseline, the patients undergoing TECAB before PCI were significantly older. There was a significantly higher incidence of previous myocardial infarction in the PCI-first group (P < 0.001). There was a significant difference in intensive care unit (ICU) length of stay (LOS), with shorter ICU stays in the simultaneous revascularization group (P = 0.031) and shorter hospital LOS in the PCI before TECAB group (P = 0.021). CONCLUSIONS: In conclusion, revascularization sequence did not dramatically impact clinical outcomes in our observational study. The patients undergoing PCI-first and same-session interventions had shorter hospital and ICU LOS compared with the patients undergoing surgery first. Our findings suggest that no revascularization approach is arbitrarily superior and that revascularization sequence should be individualized on the basis of patient presentation and anatomical considerations. PMID- 23989811 TI - Navigating the pathway to robotic competency in general thoracic surgery. AB - OBJECTIVE: Although robotic technology has addressed many of the limitations of traditional videoscopic surgery, robotic surgery has not gained widespread acceptance in the general thoracic community. We report our initial robotic surgery experience and propose a structured, competency-based pathway for the development of robotic skills. METHODS: Between December 2008 and February 2012, a total of 79 robot-assisted pulmonary, mediastinal, benign esophageal, or diaphragmatic procedures were performed. Data on patient characteristics and perioperative outcomes were retrospectively collected and analyzed. During the study period, one surgeon and three residents participated in a triphasic, competency-based pathway designed to teach robotic skills. The pathway consisted of individual preclinical learning followed by mentored preclinical exercises and progressive clinical responsibility. RESULTS: The robot-assisted procedures performed included lung resection (n = 38), mediastinal mass resection (n = 19), hiatal or paraesophageal hernia repair (n = 12), and Heller myotomy (n = 7), among others (n = 3). There were no perioperative mortalities, with a 20% complication rate and a 3% readmission rate. Conversion to a thoracoscopic or open approach was required in eight pulmonary resections to facilitate dissection (six) or to control hemorrhage (two). Fewer major perioperative complications were observed in the later half of the experience. All residents who participated in the thoracic surgery robotic pathway perform robot-assisted procedures as part of their clinical practice. CONCLUSIONS: Robot-assisted thoracic surgery can be safely learned when skill acquisition is guided by a structured, competency-based pathway. PMID- 23989812 TI - Are there gender differences in outcomes after the Cox-Maze procedure for atrial fibrillation? AB - OBJECTIVE: Atrial fibrillation (AF) management suggests that women do not tolerate medication rhythm control strategies as well as men do; however, AF percutaneous catheter ablation has been found to be favorable. The study purpose was to compare the sex-based outcomes for patients who undergo the Cox-Maze procedure for AF. METHODS: Data were collected through our AF surgical ablation registry. Rhythm was verified by electrocardiogram and 24-hour holter at 6 and 12 months. General health-related quality of life (Short-Form 12) and specific AF symptom burden (Atrial Fibrillation Symptom Checklist: Frequency and Severity, version 3) were obtained at baseline and 12 months. RESULTS: Since 2005, a total of 540 patients have undergone a Cox-Maze procedure (34% were women). The women presented with higher operative risk [additive European System for Cardiac Operative Risk Evaluation (EuroSCORE), 6.71 +/- 2.61 vs 5.25 +/- 2.80, t = 5.85, P < 0.001], higher rates of congestive heart failure (49% vs 32%, P < 0.001), and more concomitant mitral valve procedures (32% vs 19%, P = 0.001). Perioperative outcomes were similar. Return to sinus rhythm off antiarrhythmics were not different at 6 and 12 months (78% vs 75%, P = 0.53, and 81% vs 80%, P = 1.00, respectively). Cumulative 2-year survival (93.9% for the men and 89.3% for the women) was not different for all-cause mortality (hazard ratio, 1.47; confidence interval, 0.68-3.21; P = 0.33) and cardiac-related mortality [women: 10/14 (71%) vs men 7/11 (64%), P = 1.00]. Health-related quality of life showed significant improvement; AF symptoms significantly decreased across the sexes. CONCLUSIONS: Outcomes after the Cox-Maze procedure are similar across sex. Atrial fibrillation surgical ablation should be considered a treatment option for women-it is safe and effective, improves general health-related quality of life, and reduces AF symptom burden. PMID- 23989813 TI - Evaluating the effect of three-dimensional visualization on force application and performance time during robotics-assisted mitral valve repair. AB - OBJECTIVE: The purpose of this study was to determine the effect of three dimensional (3D) binocular, stereoscopic, and two-dimensional (2D) monocular visualization on robotics-assisted mitral valve annuloplasty versus conventional techniques in an ex vivo animal model. In addition, we sought to determine whether these effects were consistent between novices and experts in robotics assisted cardiac surgery. METHODS: A cardiac surgery test-bed was constructed to measure forces applied during mitral valve annuloplasty. Sutures were passed through the porcine mitral valve annulus by the participants with different levels of experience in robotics-assisted surgery and tied in place using both robotics-assisted and conventional surgery techniques. RESULTS: The mean time for both the experts and the novices using 3D visualization was significantly less than that required using 2D vision (P < 0.001). However, there was no significant difference in the maximum force applied by the novices to the mitral valve during suturing (P = 0.7) and suture tying (P = 0.6) using either 2D or 3D visualization. The mean time required and forces applied by both the experts and the novices were significantly less using the conventional surgical technique than when using the robotic system with either 2D or 3D vision (P < 0.001). CONCLUSIONS: Despite high-quality binocular images, both the experts and the novices applied significantly more force to the cardiac tissue during 3D robotics assisted mitral valve annuloplasty than during conventional open mitral valve annuloplasty. This finding suggests that 3D visualization does not fully compensate for the absence of haptic feedback in robotics-assisted cardiac surgery. PMID- 23989814 TI - Pectus excavatum: a comparison of the Ravitch repair with the Nuss thoracoscopic technique with a standard metal bar or an absorbable bar. AB - OBJECTIVE: Although pectus excavatum repair has evolved to a minimally invasive technique in prepubescent patients, the best approach in adults is less clearly understood. The aim of this study was to identify the preoperative characteristics, operative variables, and postoperative outcomes in adult patients with pectus excavatum undergoing thoracoscopic repair using different bar stabilizers compared with the open surgical repair. METHODS: We conducted a prospective study between July 2009 and July 2012 in a single institution. Thirty one patients (26 men and 5 women) aged 18 to 35 years were randomly assigned into three groups: group A, 9 patients underwent modified Ravitch repair; group B, 11 patients underwent video-assisted thoracoscopic repair using metal stabilizers; and group C, 11 patients underwent video-assisted thoracoscopic repair using absorbable stabilizers. Preoperative, intraoperative, and postoperative variables are compared between all groups. RESULTS: In all groups, the preoperative variables were well matched for age, sex, and Haller index. Operative time was 2 hours longer in group A (P = 0.0001). There was no intraoperative complication. Length of hospital stay was 4 days shorter in group A. Morbidity was 23% and composed of pneumothorax (three), wound seroma (two), pleural effusion (one), and stabilizer break (one), occurring more frequently in groups B and C. There was no perioperative mortality. All patients were satisfied with the cosmetic results. CONCLUSIONS: Repair of pectus excavatum in adult patients can be performed effectively through either open surgical technique or thoracoscopy, with no intraoperative complications and with excellent immediate results. Although the operative time for the Ravitch repair was longer, the hospital stay was significantly shorter than that for the video-assisted method. PMID- 23989815 TI - Use of the eSVS Mesh: external vein support does not negatively impact early graft patency. AB - OBJECTIVE: The aim of this study was to assess early graft patency in eSVS Mesh covered saphenous vein grafts (SVGs) in patients undergoing coronary artery bypass grafting. METHODS: In 20 patients meeting criteria for double arterial grafting to the left-sided coronary system and eSVS Mesh-covered SVG to the right sided coronary system, patency was evaluated intraoperatively by transit time flow measurement and at 5 days postoperatively by computed tomographic angiography. RESULTS: Twenty patients underwent 49 arterial and 22 venous grafts (mean, 3.55/patient) using off-pump techniques. All grafts were determined to be patent intraoperatively. On computed tomographic angiography, arterial graft patency was 100%. In one venous anastomosis, the distal limb of a sequential graft was occluded, for an overall patency rate of 95%. CONCLUSIONS: The eSVS Mesh does not compromise early SVG patency. PMID- 23989816 TI - Thoracoscopic approach of the internal thoracic lymphatic chain. AB - OBJECTIVE: Few studies to date have evaluated the videothoracoscopic approach of the internal thoracic lymphatic chain. However, the histological evaluation of lymph nodes is essential for patients with breast cancer who show lymph node uptake at scintigraphy in the preoperative period and also for patients with lymphoma who have exclusive uptake in these lymph nodes at positron emission tomography for recurrence assessment. Our goal was to evaluate the safety and the change in oncologic approach through this minimally invasive technique. METHODS: This is a review of the prospectively collected data in a group of patients undergoing thoracoscopic biopsy of the thoracic lymphatic chain in patients with breast cancer and lymphoma carried out in our institution between September 2010 and June 2012. The analyzed variables include age, histological type, operated hemithorax, number of resected lymph nodes, neoplastic involvement of the resected lymph nodes, duration of chest tube drainage, length of hospital stay, and perioperative mortality. Complications such as subcutaneous emphysema and necessity for blood transfusion were also evaluated. RESULTS: Thoracoscopic biopsy was successfully performed in 16 patients, of whom 14 had breast cancer and 2 had lymphoma. The surgical biopsy results changed the treatment in the two patients with lymphoma and avoided radiotherapy in the eight patients with breast cancer who did not have metastases. CONCLUSIONS: The use of the thoracoscopic assessment of the internal thoracic lymphatic chain seems safe and resulted in therapy modification in more than half of our patients, suggesting that it is an effective technique for staging in selected breast cancer and lymphoma cases. PMID- 23989817 TI - Poststernotomy mediastinitis and the role of broken steel wires: retrospective study. AB - OBJECTIVE: Mediastinitis is a severe complication of cardiac surgery. Sternal instability is concomitantly present in most cases. Broken steel wires may cause sternal instability. In this study, the role of broken steel wires in sternal closure was evaluated in patients who developed poststernotomy mediastinitis. METHODS: Preoperative, perioperative, and postoperative data of patients who underwent thoracic surgery between 1996 and 2006 were retrieved from the SUMMIT registry database. Patients needing reoperation for mediastinitis were identified. Patients' charts and chest radiographs from initial surgery to reoperation for mediastinitis were reviewed. RESULTS: Forty-five patients developed postoperative mediastinitis needing reoperation (0.6%). Because of loss to follow-up, 31 patients were evaluated. Eight patients (25.8%) presented fractured steel wires. Most of the broken steel wires (87.5%) manifested at the cranial site of figure-of-eight configurations. In the patients without broken steel wires, mediastinitis manifested after 14 days compared with 38 days in the patients with broken wires. Time until mediastinitis was not significantly different (P = 0.229). The mean time until steel wire disruption was 14 days (range, 4-48 days). CONCLUSIONS: Broken steel wires were observed before mediastinitis became manifest. Fracturing occurred mainly at the cranial site of figure-of-eight configurations. The results of the present study emphasize that closure technique plays a prominent role in the development of mediastinitis. Because mediastinitis is associated with an increased risk for early morbidity, attention should be paid to patients presenting with broken steel wires. New techniques for median sternotomy closure are needed that are less prone to mechanical fatigue than are steel wires. PMID- 23989818 TI - Obesity should not deter a surgeon from selecting a minimally invasive approach for mitral valve surgery. AB - OBJECTIVE: Obesity is highly prevalent in modern patient populations. Several studies have published conflicting outcomes after minimally invasive surgery with regard to morbidity and mortality. Some instances consider obesity as a relative contraindication for this approach because of inadequate exposure of the surgical field. Our aim was to investigate the outcomes of minimally invasive mitral valve surgery through a right lateral minithoracotomy in patients with a body mass index (BMI) of 30 kg/m2 or greater. METHODS: We conducted a retrospective database review between January 1, 2009, and December 31, 2011. Preoperative, intraoperative, postoperative, and follow-up data of 225 consecutive patients were collected. RESULTS: The patients were stratified according to their BMI: 108 had a normal weight with a BMI of lower than 25 kg/m2 (18-24), 90 were overweight with a BMI of 25 to 29 kg/m2, and 27 were obese with a BMI of 30 kg/m2 (30-41) or greater. Statistical analysis showed significantly longer ventilation times in the obese group, whereas all other variables were similar. Survival, major adverse cardiac and cerebrovascular event-free survival, valve competency, and freedom from reoperation were also comparable. CONCLUSIONS: Our data suggest that obesity should not deter a surgeon from selecting a minimally invasive approach. Despite longer postoperative ventilation times, a BMI of 30 kg/m2 or greater does not influence short- and medium-term outcome. Obese patients may even benefit from this approach because it avoids the need for sternotomy and therefore reduces the risk for sternal wound infection. PMID- 23989819 TI - Impact of different surgical strategies on perioperative protein S100beta release in elderly patients undergoing coronary artery bypass grafting. AB - OBJECTIVE: This study was designed to compare neurological injury-associated protein S100beta release during three different treatment modalities, minimized closed circuit coronary artery bypass grafting (CABG) (MCABG), off-pump CABG (OPCAB), and conventional CABG (CCABG), comprising high-volume prime and cold crystalloid cardioplegia. Our working hypothesis was that fluid restriction as provided by MCABG may decrease neurological injury-associated protein S100beta release. METHODS: In this prospective trial, in a tertiary center, 30 surgical patients (aged >70 years, 25 men and 5 women) undergoing first-time elective CABG were enrolled. The inclusion criteria were three-vessel disease and elective surgery. The exclusion criteria were left ventricular ejection fraction of less than 30%, use of clopidogrel, carotid disease, or needing fewer than three distal anastomoses. Protein S100beta concentrations, hematocrit (Ht) levels, and PO2 levels were measured after induction of anesthesia, 10 minutes after reperfusion, upon arrival at the intensive care unit, 3 hours postoperatively at the intensive care unit, and the next morning. Statistics consisted of areas under the curve, peak levels, and correlation and variance tests. RESULTS: A significant negative correlation was found indicating higher S100beta release at lower Ht levels and at lower PO2 levels in all study groups. The lowest S100beta variance was measured during MCABG (Wilks Lambda P = 0.052). The perioperative Ht was significantly higher in the MCABG group and in the OPCAB group compared with the CCABG group (P = 0.04 vs P < 0.01). At all time points, the S100beta protein concentration showed no significant differences between the different surgical techniques. The mean (95% confidence interval) values of S100 area under the curve were the following: CCABG, 2.3 (1.06-3.5); MCABG, 1.44 (0.6-2.21); and OPCAB, 1.87 (1.5-2.19) [independent nonparametric Kruskal-Wallis test (P = 0.13)]. The mean (95% confidence interval) peak S100 values (calculated as the maximum value seen in a patient during the research period) were the following: CCABG, 1.07 (0.4-1.68); MCABG, 0.59 (0.28-0.90); and OPCAB, 0.83 (0.59-1.06) [independent nonparametric Kruskal-Wallis test (P = 0.22)]. CONCLUSIONS: Despite similar perioperative S100beta protein release for all techniques studied, higher Ht and PO2 levels correlated with lower S100beta release within all study groups. The low S100beta variance during the fluid restrictive MCABG technique may be due to more efficient oxygen transport to the brain provided by significantly higher perioperative Ht levels. Further prospective data are required to better understand this complex issue. PMID- 23989820 TI - Robotic multisegment triangular resections as an alternative to sliding leaflet plasty. AB - The sliding leaflet plasty of the posterior mitral leaflet is a complex procedure, both lengthy and technically challenging. A simple alternative is desirable, particularly for a minimally invasive approach. We report a distinct substitute to the conventional sliding leaflet plasty that included triangular resections of P2 and P3 using a robot. These multiple triangular resections enabled a successful mitral valve repair with satisfactory clinical and echocardiographic results. Recognizing the complexity of sliding leaflet plasties, we note that multisegment triangular resections seem to be an easy, expeditious, and effective alternative for the posterior leaflet that is readily performed via a robotic endoscopic approach. PMID- 23989821 TI - Combined heart transplantation and thoracic endovascular aortic repair for heart failure secondary to tricuspid atresia palliated with Potts shunt. AB - A 57-year-old-man with known tricuspid atresia previously palliated with a Potts shunt had developed progressive heart failure refractory to medical management. He underwent a combined thoracic endovascular stent graft procedure to eliminate the Potts shunt and orthotopic heart transplantation. At 3-month follow-up, right sided heart function and pulmonary artery pressures as well as pulmonary vascular resistance had normalized, and at 7 months, the patient had returned to normal activity. The surgical management and its principles as well as postoperative follow-up are described. PMID- 23989822 TI - Unipuncture double-access method in emergent endovascular procedures. AB - We describe a technique to gain an additional endovascular access in acute situations in which a large-bore introducer is already inserted or in situations in which multiple accesses are impaired because of other reasons. Using an existing percutaneous femoral artery access, a second guide wire is inserted into the introducer, which is later withdrawn and applied onto one of the two guide wires. A double-wire access is then achieved. This access can be used, for example, for angiography or embolization catheters. This method might be useful in situations in which a quick and unplanned extra access is needed. It is, for example, applicable in hemodynamically unstable patients in whom percutaneous access can be difficult to obtain or in aortic endovascular procedures when an unplanned access is needed to insert an additional catheter for angiography and embolization. PMID- 23989824 TI - Spectral-domain measurements of birefringence and sensing characteristics of a side-hole microstructured fiber. AB - We experimentally characterized a birefringent side-hole microstructured fiber in the visible wavelength region. The spectral dependence of the group and phase modal birefringence was measured using the methods of spectral interferometry. The phase modal birefringence of the investigated fiber increases with wavelength, but its positive sign is opposite to the sign of the group modal birefringence. We also measured the sensing characteristics of the fiber using a method of tandem spectral interferometry. Spectral interferograms corresponding to different values of a physical parameter were processed to retrieve the spectral phase functions and to determine the spectral dependence of polarimetric sensitivity to strain, temperature and hydrostatic pressure. A negative sign of the polarimetric sensitivity was deduced from the simulation results utilizing the known modal birefringence dispersion of the fiber. Our experimental results show that the investigated fiber has a very high polarimetric sensitivity to hydrostatic pressure, reaching -200 rad x MPa(-1) x m(-1) at 750 nm. PMID- 23989823 TI - Setting the bar high or setting up to fail? Interpretations and implications of the EXPLORE Study (HPTN 015). AB - Controlled studies show that HIV risk reduction counseling significantly increases condom use, reduces unprotected sex and prevents sexually transmitted infections. Nevertheless, without evidence of reducing HIV incidence, these interventions are generally discarded. One trial, the EXPLORE study, was designed to test whether ten sessions of risk reduction counseling could impact HIV incidence among men who have sex with men in six US cities. Based on epidemiologic models to define effective HIV vaccines, a 35 % reduction in HIV incidence was set a priori as the benchmark of success in this behavioral intervention trial. Results demonstrated a significant effect of the intervention, with more than a 35 % reduction in HIV incidence observed during the initial 12-18 months following counseling. Over an unprecedented 48-month follow-up, however, the effect of counseling on HIV incidence declined to 18 %. The current review examined how the scientific literature has thus far judged the outcomes of the EXPLORE study as well as the policy implications of these judgments. We identified 127 articles that cited the EXPLORE study since its publication. Among articles that discuss the HIV incidence outcomes, 20 % judged the intervention effective and 80 % judged the intervention ineffective. The overwhelmingly negative interpretation of the EXPLORE study outcomes is reflected in public policies and prevention planning. We conclude that using a vaccine standard to define success led to a broad discrediting of the benefits of behavioral counseling and, ultimately, adversely impacted policies critical to the field of HIV prevention. PMID- 23989825 TI - A linearization time-domain CMOS smart temperature sensor using a curvature compensation oscillator. AB - This paper presents an area-efficient time-domain CMOS smart temperature sensor using a curvature compensation oscillator for linearity enhancement with a -40 to 120 degrees C temperature range operability. The inverter-based smart temperature sensors can substantially reduce the cost and circuit complexity of integrated temperature sensors. However, a large curvature exists on the temperature-to-time transfer curve of the inverter-based delay line and results in poor linearity of the sensor output. For cost reduction and error improvement, a temperature-to-pulse generator composed of a ring oscillator and a time amplifier was used to generate a thermal sensing pulse with a sufficient width proportional to the absolute temperature (PTAT). Then, a simple but effective on chip curvature compensation oscillator is proposed to simultaneously count and compensate the PTAT pulse with curvature for linearization. With such a simple structure, the proposed sensor possesses an extremely small area of 0.07 mm2 in a TSMC 0.35-mm CMOS 2P4M digital process. By using an oscillator-based scheme design, the proposed sensor achieves a fine resolution of 0.045 degrees C without significantly increasing the circuit area. With the curvature compensation, the inaccuracy of -1.2 to 0.2 degrees C is achieved in an operation range of -40 to 120 degrees C after two-point calibration for 14 packaged chips. The power consumption is measured as 23 mW at a sample rate of 10 samples/s. PMID- 23989826 TI - A sparse representation-based deployment method for optimizing the observation quality of camera networks. AB - Deployment is a critical issue affecting the quality of service of camera networks. The deployment aims at adopting the least number of cameras to cover the whole scene, which may have obstacles to occlude the line of sight, with expected observation quality. This is generally formulated as a non-convex optimization problem, which is hard to solve in polynomial time. In this paper, we propose an efficient convex solution for deployment optimizing the observation quality based on a novel anisotropic sensing model of cameras, which provides a reliable measurement of the observation quality. The deployment is formulated as the selection of a subset of nodes from a redundant initial deployment with numerous cameras, which is an l0 minimization problem. Then, we relax this non convex optimization to a convex l1 minimization employing the sparse representation. Therefore, the high quality deployment is efficiently obtained via convex optimization. Simulation results confirm the effectiveness of the proposed camera deployment algorithms. PMID- 23989827 TI - Optimal oral health: a need to make a distinction. PMID- 23989828 TI - Ankylosed primary molars. PMID- 23989829 TI - Submerged primary molars. PMID- 23989830 TI - Authors' response. PMID- 23989831 TI - Monitoring TM disorders. PMID- 23989832 TI - TMD diagnostics. PMID- 23989833 TI - More about TMD diagnostics. PMID- 23989834 TI - Perceiving pain. PMID- 23989835 TI - Authors' response. PMID- 23989836 TI - How the introduction of the acid-etch technique revolutionized dental practice. PMID- 23989837 TI - Minimally invasive resin infiltration of arrested white-spot lesions: a randomized clinical trial. AB - BACKGROUND: The authors conducted a randomized, single-masked clinical trial involving patients who had completed orthodontic treatment to assess changes in the appearance of white-spot lesions (WSLs) that were treated with resin infiltration. METHODS: The authors divided affected teeth into control and treatment groups. In the treatment group, they restored teeth with WSLs by using resin infiltration. They evaluated changes in WSLs photographically by using a visual analog scale (VAS) (0 = no change, 100 = complete disappearance) and area measurements (in square millimeters). The authors analyzed the data by using two way analysis of variance. RESULTS: The mean VAS ratings for treated teeth demonstrated marked improvement relative to that for control teeth immediately after treatment (67.7 versus 5.2, P < .001) and eight weeks later (65.9 versus 9.2, P < .001). The results for treated teeth showed a mean reduction in WSL area of 61.8 percent immediately after treatment and 60.9 percent eight weeks later, compared with a -3.3 percent change for control teeth immediately after treatment and a 1.0 percent reduction eight weeks later. CONCLUSIONS: Resin infiltration significantly improved the clinical appearance of WSLs, with stable results seen eight weeks after treatment. PRACTICAL IMPLICATIONS: Resin infiltration, a minimally invasive restorative treatment, was shown to be effective for WSLs that formed during orthodontic treatment. PMID- 23989838 TI - Dental treatment for patients with neuropathic orofacial pain. PMID- 23989839 TI - Asymptomatic oral mucosal lesions. PMID- 23989840 TI - Adverse drug and device reactions in the oral cavity: surveillance and reporting. AB - BACKGROUND: According to the U.S. Centers for Disease Control and Prevention, 48 percent of Americans (roughly 144 million people) used at least one prescribed medication in the preceding month; 11 percent used five or more. The authors describe the U.S. Food and Drug Administration's (FDA's) MedWatch program, the safety surveillance system for drugs and devices in the United States, and the dentist's role with regard to voluntary reporting of adverse effects (AEs). They also identify the most frequent AEs in the oral cavity as reported in the FDA Adverse Event Reporting System (FAERS). METHODS: The authors reviewed the literature regarding MedWatch, and they mined data in the FAERS public database for the 100 most commonly prescribed medications and their associated AEs. RESULTS: Pharyngitis was the most common AE. Cough, dysgeusia and dysphagia also were common. CONCLUSION: The MedWatch program and its related databases contain useful information about AEs of pharmaceuticals and devices manifested in the oral cavity. Increased participation in the reporting of suspected adverse reactions will improve the national surveillance system and ultimately will protect patients' safety. PRACTICAL IMPLICATIONS: As pharmaceutical consumption increases exponentially for a growing segment of the population, and as innovation in dental technology and devices flourishes, dentists have a distinct role in safeguarding patients' well-being. Promptly reporting AEs in the oral cavity improves quality of care and protects patients' well-being. PMID- 23989841 TI - Dental care providers' and patients' perceptions of the effect of health information technology in the dental care setting. AB - BACKGROUND: The use of electronic health records (EHRs) in dental care and their effect on dental care provider-patient interaction have not been studied sufficiently. The authors conducted a study to explore dental care providers' interactions with EHRs during patient visits, how these interactions influence dental care provider-patient communication, and the providers' and patients' perception of EHR use in the dental clinic setting during patient visits. METHODS: The authors collected survey and interview data from patients and providers at three dental clinics in a health care system. The authors used qualitative and quantitative methods to analyze data obtained from patients and dental care providers. RESULTS: The provider survey results showed significant differences in perceptions of EHR use in patient visits across dental care provider groups (dentists, dental hygienists and dental assistants). Patient survey results indicated that some patients experienced a certain level of frustration and distraction because of providers' use of EHRs during the visit. CONCLUSIONS: The provider survey results indicated that there are different perceptions across provider groups about EHRs and the effect of computer use on communication with patients. Dental assistants generally reported more negative effects on communication with patients owing to computer use. Interview results also indicated that dental care providers may not feel comfortable interacting with the EHR without having any verbal or eye contact with patients during the patient's dental visit. PRACTICAL IMPLICATIONS: A new design for dental operatories and locations of computer screens within the operatories should be undertaken to prevent negative nonverbal communication such as loss of eye contact or forcing the provider and patient to sit back to back, as well as to enhance patient education and information sharing. PMID- 23989842 TI - Acceptance among and impact on dental practitioners and patients of American Heart Association recommendations for antibiotic prophylaxis. AB - BACKGROUND: The 2007 American Heart Association (AHA) guidelines for the prevention of infective endocarditis (IE) called for a major reduction in the number of patients recommended for antibiotic prophylaxis (AP) and redefined the dental procedures considered to put these patients at risk of acquiring the infection. The purpose of the authors' study was to determine the acceptance of these changes among and the impact of the changes on dentists and their patients. METHODS: The authors sent a survey to a random sample of 5,500 dentists in the United States. RESULTS: Ninety-five percent of the 878 respondents indicated that they saw patients who receive AP. More than 75 percent were either satisfied or very satisfied with the AHA guidelines, and the respondents indicated that they believed almost three-quarters of their patients also were pleased. Seventy percent of dentists, however, had patients who took antibiotics before a dental procedure even though the guidelines no longer recommend it. CONCLUSIONS: Acceptance of the 2007 guidelines appears to be high, but controversy remains. Additional scientific data are needed to resolve these issues. PRACTICAL IMPLICATIONS: The 2007 AHA guidelines have greatly simplified the identification of patients who need AP for dental procedures, given that, in general, far fewer people with cardiac abnormalities are considered to be at risk as a result of invasive procedures. Some physicians, however, continue to prescribe antibiotics for some patients whom the AHA no longer considers to need them. Patients also may choose to continue this practice themselves. There is ongoing controversy surrounding this common clinical question in dental practice, and the next guidelines from the AHA may change on the basis of data from future clinical studies. PMID- 23989843 TI - Use of chlorhexidine varnish to prevent root caries may benefit some patients. PMID- 23989847 TI - The four-step postrecession growth plan. PMID- 23989844 TI - The impact of the Great Recession on untreated dental caries among kindergarten students in North Carolina. AB - BACKGROUND: The authors conducted a study to determine the impact of the Great Recession on untreated dental caries in kindergarten-aged children in North Carolina (NC). METHODS: During the seven school years from 2003-2004 through 2009 2010, the state dental public health program assessed 608,339 kindergarten students for untreated decayed primary teeth (dt) as part of the statewide public health surveillance system. The authors aggregated observations to the school level and matched 7,660 school-year observations for 1,215 schools to National School Lunch Program (NSLP) participation rates, their primary economic indicator of the Great Recession. The authors included additional county-level economic indicators and measures of dentist supply and Medicaid enrollment. They used ordinary least squares regression with school-and year-fixed effects to examine the association of variables with the proportion of children with more than one dt for all schools and for schools with a greater than 10 percent increase in NSLP participation after 2006. RESULTS: The authors found a small but statistically significant association between the proportion of children in the schools participating in the NSLP and the proportion of kindergarten students who had more than one dt (beta, 0.031; 95 percent confidence interval [CI], 0.001 to 0.0604). This association was greater in schools that had a greater than 10 percent increase in NSLP participation (beta, 0.068; 95 percent CI, -0.007 to 0.143). Regression estimates indicate a 1.3- and 3.1-percentage point cumulative increase in the proportion of children with more than one dt during the period from 2008 through 2009 for all schools and high-risk schools, respectively. CONCLUSION: Increased NSLP enrollment was associated with less treatment for dental caries in 5-year-old children. PRACTICAL IMPLICATIONS: Fewer children are receiving needed dental treatment because of the Great Recession. Recent gains made in the treatment of dental caries in children in NC have slowed as a result. PMID- 23989848 TI - What are the ethical issues involved in providing a five-year treatment plan for a patient who is planning to retire in a year? PMID- 23989849 TI - For the dental patient: preventing and treating tooth sensitivity. PMID- 23989850 TI - Correlation of diffusion MRI findings with lesion progression in patients with traumatic intracerebral hemorrhage : diffusion MRI in traumatic intracerebral hemorrhages with progression. AB - PURPOSE: The aim of this study is to evaluate the association between lesion progression and the ischemic or edematous area that can develop around the hemorrhage in intraparenchymal hemorrhagic lesions originating after head trauma. METHODS: Thirty patients with intracerebral hemorrhage due to head trauma of a mild or intermediate degree were evaluated in this study. Brain diffusion MRI examinations were performed in the first 6 h after trauma in all patients. In addition, a computerized cranial tomography (CCT) was performed upon admission (in the first hour), and at 24 and 48 h after admission. Patients with or without progression of the lesion were compared. RESULTS: The increase in the risk of progression of the lesion in patients with an ischemia/hemorrhage rate > 2 identified in the diffusion MRIs by evaluation of the hemorrhagic and the surrounding ischemic area, obtained in the first 6 h after trauma was found to be statistically significant. The possibility of progression was found to be very low when this rate was less than two. CONCLUSIONS: As a result of the study, the ischemic area was found to be proportionally larger in patients with progression compared to nonprogressing patients with traumatic intracerebral hemorrhage. The ischemia/hemorrhage rate in the diffusion MRI is thought to be an important parameter, beneficial to identify the risk of lesion progression. PMID- 23989852 TI - MultiSig: a new high-precision approach to the analysis of complex biomolecular systems. AB - MultiSig is a newly developed mode of analysis of sedimentation equilibrium (SE) experiments in the analytical ultracentrifuge, having the capability of taking advantage of the remarkable precision (~0.1% of signal) of the principal optical (fringe) system employed, thus supplanting existing methods of analysis through reducing the 'noise' level of certain important parameter estimates by up to orders of magnitude. Long-known limitations of the SE method, arising from lack of knowledge of the true fringe number in fringe optics and from the use of unstable numerical algorithms such as numerical differentiation, have been transcended. An approach to data analysis, akin to 'spatial filtering', has been developed, and shown by both simulation and practical application to be a powerful aid to the precision with which near-monodisperse systems can be analysed, potentially yielding information on protein-solvent interaction. For oligo- and poly-disperse systems the information returned includes precise average mass distributions over both cell radial and concentration ranges and mass-frequency histograms at fixed radial positions. The application of MultiSig analysis to various complex heterogenous systems and potentially multiply interacting carbohydrate oligomers is described. PMID- 23989851 TI - Minute subsequent fracture at prophylactically treated adjacent vertebra after percutaneous vertebroplasty. PMID- 23989853 TI - The flavonoid apigenin improves glucose tolerance through inhibition of microRNA maturation in miRNA103 transgenic mice. AB - Polyphenols are representative bioactive substances with diverse biological effects. Here, we show that apigenin, a flavonoid, has suppressive effects on microRNA (miRNA) function. The effects were mediated by impaired maturation of a subset of miRNAs, probably through inhibition of the phosphorylation of TRBP, a component of miRNA-generating complexes via impaired mitogen-activated protein kinase (MAPK) Erk activation. While glucose intolerance was observed in miRNA103 (miR103)-overexpressing transgenic mice, administration of apigenin improved this pathogenic status likely through suppression of matured miR103 expression levels. These results suggest that apigenin may have favorable effects on the pathogenic status induced by overexpression of miRNA103, whose maturation is mediated by phosphorylated TRBP. PMID- 23989854 TI - Bilateral double osteotomy in severe torsional malalignment syndrome: 16 years follow-up. AB - BACKGROUND: Torsional malalignment syndrome (TMS) is a well defined condition consisting of a combination of femoral antetorsion and tibial lateral torsion. The axis of knee motion is medially rotated. This may lead to patellofemoral malalignment with an increased Q angle and chondromalacia, patellar subluxation and dislocation. Conservative management is recommended in all but the most rare and severest cases. In these cases deformity correction requires osteotomies at two levels per limb. MATERIALS AND METHODS: From 1987 to 2002 in our institution three patients underwent double femoral and tibial osteotomy for TMS bilateral correction (12 osteotomies). All patients were reviewed at mean follow-up of 16 years. RESULTS: At final follow-up no patients reported persistence of knee or hip pain. At clinical examination both lower limbs showed a normal axis and a normal patella anterior position. Pre-operative femoral version measurement showed an average hip internal rotation of 81.5 degrees (range 80 degrees -85 degrees ) and average hip external rotation of 27.2 degrees (10 degrees -40 degrees ). Thigh-foot angle measurement showed an average value of 38.6 degrees (32 degrees -45 degrees ). At final follow-up femoral version measurement showed an average hip internal rotation of 49 degrees (range 45 degrees -55 degrees ) and average hip internal rotation of 44.3 degrees (20 degrees -48 degrees ) (Figs. 1, 2, 3, 4, 5, 6). Thigh-foot angles measurement showed an average value of 21.6 degrees (18 degrees -24 degrees ) outward. CONCLUSION: We recommend a clinical, radiographical and CT scan evaluation of all torsional deformity. In cases of significant deformity, internally rotating the tibia alone is not sufficient. Ipsilateral outward femoral and inward tibial osteotomies are our current recommendation for TMS, both performed at the same surgical setting. PMID- 23989855 TI - Effectiveness of synthetic hydroxyapatite versus Persian Gulf coral in an animal model of long bone defect reconstruction. AB - BACKGROUND: There is a continuing search for bone substitutes to avoid or minimize the need for autogenous bone grafts. Hydroxyapatite, a crystalline phase of calcium phosphate found naturally in bone minerals, has shown tremendous promise as a graft material. Coral is an osteoconductive material used as a bone graft extender. This study examined the effect of hydroxyapatite and Persian Gulf coral on osteogenesis in vivo using a rabbit model of bone healing. MATERIALS AND METHODS: A critical-size defect of 10 mm elongation was created in the radial diaphysis of 36 rabbits and supplied with either hydroxyapatite or coral or left empty (control group). Radiographs of each forelimb were taken postoperatively on day 1 and then at 2, 4, 6, and 8 weeks postinjury to evaluate bone formation, union, and remodeling of the defect. The operated radiuses were removed on the 56th postoperative day and were grossly and histopathologically evaluated. In addition, biomechanical testing was conducted on the operated and normal forelimbs of half of the animals of each group. RESULTS: In radiological evaluation, bone formation and union were significantly superior in the coral and hydroxyapatite groups in comparison with the control group on the 42nd and 56th day postinjury (P < 0.05). There were no statistical differences between groups in remodeling criteria at the 56th day postinjury (P > 0.05). In histopathological evaluation, the union scores of the rabbits administered hydroxyapatite or coral were statistically superior to those of the animals of the control group on the 56th day postinjury (P < 0.05). In biomechanical evaluation, the control group showed weakness of biomechanical properties in comparison with the coral and hydroxyapatite groups (P < 0.05). CONCLUSIONS: According to this study, significant difference was not observed between hydroxyapatite and natural coral and these two materials were significantly better than the control group at 8 weeks postinjury. PMID- 23989856 TI - In-hospital complications following primary total hip and knee arthroplasty in octogenarian and nonagenarian patients. AB - BACKGROUND: As life expectancy of patients increases, more elderly patients are undergoing primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). There is a general perception of increased risk of complications in elderly patients. Our objective was to analyse the incidence of in-hospital medical and surgical complications following THA and TKA in octogenarian and nonagenarians. MATERIALS AND METHODS: This was a prospective review of 202 consecutive patients aged more than 80 years who underwent total hip and total knee arthroplasty (101 THA, 101 TKA) over an 18-month period. In this single centre observational study, collected data included patient demographics, American Society of Anethesiologists (ASA) grade, length of hospital stay and peri-operative medical and surgical complications during their hospital stay. RESULTS: Median age of patients was 83 years. Median ASA grade was 3. Mean length of hospital stay was 7.5 days. There were 14 major systemic complications in the THA group and 13 in the TKA group. While 1 major local complication occurred in each group, there were 6 minor local complications in THA and 7 in the TKA group. All the complications occurred within 5 post-operative days. There was no in hospital mortality. CONCLUSION: In our study, we found that the incidence of peri operative medical and surgical complications is higher in those over 80 years, compared to the published literature in patients of all age groups undergoing THA and TKA. Awareness of a higher incidence of major systemic complications should alert the treating surgeon to carry out comprehensive peri-operative management in this subset of patients, which could lead to better outcomes. PMID- 23989857 TI - Impact of specialty and level of training on CT measurement of femoral version: an interobserver agreement analysis. AB - BACKGROUND: To determine the interobserver agreement on femoral version measurements between an orthopedic attending, orthopedic senior and junior residents, and an attending radiologist. MATERIALS AND METHODS: Postoperative computed tomography (CT) scanograms of 267 patients who underwent femoral intramedullary (IM) nailing with corresponding radiology attending reads for femoral version were collected and de-identified. Femoral version measurements performed by a trauma fellowship-trained attending orthopedic surgeon (ORTHO), a senior orthopedic resident (PGY4), a junior orthopedic resident (PGY1), and a musculoskeletal fellowship-trained attending radiologist (RADS) were compared via Pearson's interclass correlation coefficient to assess interobserver level of agreement. RESULTS: Version measurements provided by the two attending physicians exhibited the highest level of agreement (r = 0.661, p < 0.01). The orthopedic attending and the senior resident had the next highest level of agreement (r = 0.543, p < 0.01). The first-year orthopedic resident had the weakest agreement across the board: with the orthopedic attending, the radiology attending, and the senior resident. CONCLUSION: Regardless of specialty, experience and higher levels of training produce stronger agreement when measuring femoral version. Residents in training, especially those who are junior, produce weak agreement when compared to their senior colleagues. LEVEL OF EVIDENCE: Level III, diagnostic study. PMID- 23989858 TI - Ulnar variance as a predictor of persistent instability following Galeazzi fracture-dislocations. AB - BACKGROUND: We investigated the radiographic parameters that may predict distal radial ulnar joint (DRUJ) instability in surgically treated radial shaft fractures. In our clinical experience, there are no previously reported radiographic parameters that are universally predictive of DRUJ instability following radial shaft fracture. MATERIALS AND METHODS: Fifty consecutive patients, ages 20-79 years, with unilateral radial shaft fractures and possible associated DRUJ injury were retrospectively identified over a 5-year period. Distance from radial carpal joint (RCJ) to fracture proportional to radial shaft length, ulnar variance, and ulnar styloid fractures were correlated with DRUJ instability after surgical treatment. RESULTS: Twenty patients had persistent DRUJ incongruence/instability following fracture fixation. As a proportion of radial length, the distance from the RCJ to the fracture line did not significantly differ between those with persistent DRUJ instability and those without (p = 0.34). The average initial ulnar variance was 5.5 mm (range 2-12 mm, SD = 3.2) in patients with DRUJ instability and 3.8 mm (range 0-11 mm, SD = 3.5) in patients without. Only 4/20 patients (20%) with DRUJ instability had normal ulnar variance (-2 to +2 mm) versus 15/30 (50%) patients without (p = 0.041). CONCLUSION: In the setting of a radial shaft fracture, ulnar variance greater or less than 2 mm was associated with a greater likelihood of DRUJ incongruence/instability following fracture fixation. PMID- 23989859 TI - Failing a student nurse: a new horizon of moral courage. AB - The factors preventing registered nurses from failing students in practice are multifaceted and have attracted much debate over recent years. However, writers rarely focus on what is needed to fail an incompetent pre-registration nursing student in their final placement. This hermeneutic study explored the mentor experience of failing a pre-registration nursing student in their final placement. A total of 19 mentors were recruited from 7 different healthcare organisations in both inner city and rural locations in the southeast of England. Participants took part in individual reflective interviews about their experience of failing a pre-registration nursing student in their final placement. These experiences were interpreted through a hermeneutic discovery of meaning. The new horizon of understanding which developed as a result of this research is framed within the context of moral stress, moral integrity and moral residue with the overall synthesis being that these mentors' stories presented a new horizon of moral courage. PMID- 23989860 TI - JAMA patient page. Male infant circumcision. PMID- 23989861 TI - Threshold dynamics in an SEIRS model with latency and temporary immunity. AB - A disease transmission model of SEIRS type with distributed delays in latent and temporary immune periods is discussed. With general/particular probability distributions in both of these periods, we address the threshold property of the basic reproduction number R0 and the dynamical properties of the disease free/endemic equilibrium points present in the model. More specifically, we 1. show the dependence of R0 on the probability distribution in the latent period and the independence of R0 from the distribution of the temporary immunity, 2. prove that the disease free equilibrium is always globally asymptotically stable when R0, and 3. according to the choice of probability functions in the latent and temporary immune periods, establish that the disease always persists when R0 < 1 and an endemic equilibrium exists with different stability properties. In particular, the endemic steady state is at least locally asymptotically stable if the probability distribution in the temporary immunity is a decreasing exponential function when the duration of the latency stage is fixed or exponentially decreasing. It may become oscillatory under certain conditions when there exists a constant delay in the temporary immunity period. Numerical simulations are given to verify the theoretical predictions. PMID- 23989862 TI - A review of the toxicology and pathology of the gastrointestinal tract. AB - The gastrointestinal tract of man and animals shows great specialization in structure and function for its primary role of digestion. There are many species differences in diet, anatomy and metabolism, and its neuroendocrine regulation has evolved into a complex field for investigation. Exposure of the tract from oral cavity, stomach, small and large intestine results in a range of toxicities covered by this review. Carcinogenesis of the gastrointestinal tract by a range of agents including pharmaceuticals is also discussed. PMID- 23989863 TI - Protective effects of agmatine against D-galactosamine and lipopolysaccharide induced fulminant hepatic failure in mice. AB - Fulminant hepatic failure (FHF) is a life-threatening syndrome characterized by massive hepatic necrosis and high mortality. There is no effective therapy for the disease other than liver transplantation. This study aimed to investigate the effect of agmatine, inducible nitric oxide synthase (iNOS) inhibitor, on D galactosamine and lipopolysaccharide (GalN/LPS)-induced FHF in mice and explore its possible mechanism(s). Male Swiss albino mice were injected with a single dose agmatine (14 mg/kg, IP) 8 h prior to challenge with a single intraperitoneal injection of both GalN (800 mg/kg) and LPS (50 MUg/kg). Agmatine significantly attenuated all GalN/LPS-induced biochemical and pathological changes in liver. It prevented the increase of serum transaminases and alkaline phosphatase (ALP). In addition, agmatine markedly attenuated GalN/LPS-induced necrosis and inflammation. Agmatine significantly reduced oxidative stress and enhanced antioxidant enzymes. Importantly, agmatine decreased total nitric oxide (NO) and pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha). These findings reveal that agmatine has hepatoprotective effects against GalN/LPS induced FHF in mice that may be related to its ability to suppress oxidative stress, NO synthesis and TNF-alpha production. Therefore, agmatine may serve as a novel therapeutic strategy for hepatic inflammatory diseases. PMID- 23989864 TI - Differences in insulin clearance between metabolically healthy and unhealthy obese subjects. AB - Metabolically healthy obese (MHO) are relatively insulin sensitive and have a favorable cardio-metabolic risk profile compared with metabolically abnormal obese (MAO). To evaluate whether MAO individuals have a decreased insulin clearance compared with MHO individuals, 49 MHO, 147 MAO, and 172 non-obese individuals were analyzed in this cross-sectional study. Insulin clearance and insulin sensitivity were assessed through euglycemic hyperinsulinemic clamp. MHO subjects exhibited significant lower triglycerides, total cholesterol, 2-h post challenge glucose, fasting and 2-h post-challenge insulin, steady-state plasma insulin, alanine aminotransferase, aspartate aminotransferase, and gamma glutamyltransferase as compared with MAO individuals. Disposition index was higher in MHO subjects as compared with MAO individuals after adjusting for gender and age (P = 0.04). Insulin clearance was significantly lower in MAO individuals as compared with MHO and non-obese individuals. The difference between the two obese subgroups remained significant after adjusting for gender, age, waist circumference, fat mass, and insulin-stimulated glucose disposal (P = 0.03). The hepatic insulin extraction (C-peptide/insulin) in the fasting state was significantly higher in MHO subjects as compared with MAO individuals (P < 0.0001). In univariate analysis adjusted for gender and age, insulin clearance was correlated with hepatic insulin extraction (P = 0.01). In conclusion, insulin clearance differs among obese subjects with different metabolic phenotypes. Impaired insulin clearance may contribute to sustained fasting and post-meal hyperinsulinemia observed in MAO individuals. PMID- 23989865 TI - Relationship between feed intake, feeding behaviors, performance, and ultrasound carcass measurements in growing purebred Angus and Hereford bulls. AB - The objectives of this study were to examine the growth, DMI, and feeding behaviors of Angus and Hereford bulls; identify the relationships between feeding behaviors and variation in DMI and residual feed intake (RFI); and determine the value of feeding behaviors in predicting DMI. Individual DMI was measured in Angus bulls (n=189; initial BW=427+/-3.4 kg) and Hereford bulls (n=146; initial BW=411+/-4.1 kg) fed a grower ration for 71 d in 2009, 78 d in 2010, and 74 d in 2011 using a GrowSafe intake monitoring system. Feeding frequency (FF, meals/d), head down duration (HDD, s/d), head down duration per meal (HDDM, HDD/FF, s/meal), average meal size [AMS, kg/(meal.d)], and feeding rate (FR, g/s) were also measured or calculated using behavior data collected by the GrowSafe system. Ultrasound measures of 12th-rib fat thickness (UFT), longissimus muscle area (ULMA), and intramuscular fat (IMF) were determined during the midtest-weight event of every trial. The data from 3 yr were pooled to generate mean differences between the breeds. Residual feed intake was calculated using a linear regression of DMI on ADG and midtest BW0.75 (MMWT). Animals were classified into 3 RFI groups based on their RFI score as Low (>0.5 SD below the mean), Average (+/-0.5 SD from the mean), or High RFI (>0.5 SD above the mean). Angus bulls in the Low RFI group consumed 17% (P<0.0001) less DM than the bulls in the High RFI group, while in the Hereford bulls there was a 14% (P<0.0001) difference in DMI between Low and High RFI groups. Significant phenotypic correlations were observed between RFI and DMI (0.83, 0.77), G:F (-0.65, -0.51), HDD (0.41, 0.59), HDDM (0.40, 0.53), AMS (0.52, 0.36), and FR (-0.31, -0.51) in Angus and Hereford bulls, respectively. The HDD, HDDM, and FR were significantly correlated with DMI. The feeding behavior traits, HDD, HDDM, and FR when added to the RFI base model, explained 18, 17, and 13%, respectively, of the variation in DMI not explained by ADG and MMWT in Angus bulls. Similarly, in Hereford bulls, HDD, HDDM, and FR explained 35, 26, and 24%, respectively, of the variation in DMI not explained by ADG and MMWT. These data suggest that feeding behaviors are related to DMI of growing Angus and Hereford bulls. PMID- 23989866 TI - Characterization of the genetic profile of five Danish dog breeds. AB - This investigation presents results from a genetic characterization of 5 Danish dog breeds genotyped on the CanineHD BeadChip microarray with 170,000 SNP. The breeds investigated were 1) Danish Spitz (DS; n=8), 2) Danish-Swedish Farm Dog (DSF; n=18), 3) Broholmer (BR; n=22), 4) Old Danish Pointing Dog (ODP; n=24), and 5) Greenland Dog (GD; n=23). The aims of the investigation were to characterize the genetic profile of the abovementioned dog breeds by quantifying the genetic differentiation among them and the degree of genetic homogeneity within breeds. The genetic profile was determined by means of principal component analysis (PCA) and through a Bayesian clustering method. Both the PCA and the Bayesian clustering method revealed a clear genetic separation of the 5 breeds. The level of genetic variation within the breeds varied. The expected heterozygosity (HE) as well as the degree of polymorphism (P%) ranked the dog breeds in the order DS>DSF>BR>ODP>GD. Interestingly, the breed with a tenfold higher census population size compared to the other breeds, the Greenland Dog, had the lowest within-breed genetic variation, emphasizing that census size is a poor predictor of genetic variation. The observed differences in variation among and within dog breeds may be related to factors such as genetic drift, founder effects, genetic admixture, and population bottlenecks. We further examined whether the observed genetic patterns in the 5 dog breeds can be used to design breeding strategies for the preservation of the genetic pool of these dog breeds. PMID- 23989867 TI - Heat stress and reduced plane of nutrition decreases intestinal integrity and function in pigs. AB - Heat stress can compromise intestinal integrity and induce leaky gut in a variety of species. Therefore, the objectives of this study were to determine if heat stress (HS) directly or indirectly (via reduced feed intake) increases intestinal permeability in growing pigs. We hypothesized that an increased heat-load causes physiological alterations to the intestinal epithelium, resulting in compromised barrier integrity and altered intestinal function that contributes to the overall severity of HS-related illness. Crossbred gilts (n=48, 43+/-4 kg BW) were housed in constant climate controlled rooms in individual pens and exposed to 1) thermal neutral (TN) conditions (20 degrees C, 35-50% humidity) with ad libitum intake, 2) HS conditions (35 degrees C, 20-35% humidity) with ad libitum feed intake, or 3) pair-fed in TN conditions (PFTN) to eliminate confounding effects of dissimilar feed intake. Pigs were sacrificed at 1, 3, or 7 d of environmental exposure and jejunum samples were mounted into modified Ussing chambers for assessment of transepithelial electrical resistance (TER) and intestinal fluorescein isothiocyanate (FITC)-labeled lipopolysaccharide (LPS) permeability (expressed as apparent permeability coefficient, APP). Further, gene and protein markers of intestinal integrity and stress were assessed. Irrespective of d of HS exposure, plasma endotoxin levels increased 45% (P<0.05) in HS compared with TN pigs, while jejunum TER decreased 30% (P<0.05) and LPS APP increased 2-fold (P<0.01). Furthermore, d 7 HS pigs tended (P=0.06) to have increased LPS APP (41%) compared with PFTN controls. Lysozyme and alkaline phosphatase activity decreased (46 and 59%, respectively; P<0.05) over time in HS pigs, while the immune cell marker, myeloperoxidase activity, was increased (P<0.05) in the jejunum at d 3 and 7. These results indicate that both HS and reduced feed intake decrease intestinal integrity and increase endotoxin permeability. We hypothesize that these events may lead to increased inflammation, which might contribute to reduced pig performance during warm summer months. PMID- 23989868 TI - Caspase-3 does not enhance in vitro bovine myofibril degradation by MU-calpain. AB - Tenderness is a key component of palatability, which influences consumers' perception of meat quality. There are a variety of factors that contribute to the tenderness of beef carcasses, including postmortem proteolysis. A more complete understanding of this biological mechanism regulating tenderness is needed to ensure consistently tender beef. Numerous reports indicate u-calpain is primarily responsible for the degradation of proteins postmortem. Meanwhile, it has been shown that caspase-3 can cleave calpastatin, the inhibitor of u-calpain. Therefore, the objective of this study was to determine if in vitro degradation of calpastatin by caspase-3 can enhance the postmortem breakdown of myofibrillar proteins by u-calpain. Bovine semitendinosus muscles were excised from two carcasses 20 min postmortem. Muscle strips were dissected from the semitendinosus, restrained to maintain length, and placed in a neutral buffer containing protease inhibitors. Upon rigor completion, myofibrils were isolated from each strip, and sarcomere length was determined. Samples with similar sarcomere lengths were selected to minimize the effect of sarcomere length on proteolysis. Myofibrils were then incubated at 22 degrees C with either u calpain, u-calpain+calpastatin, u-calpain+caspase-3+calpastatin, or caspase 3+calpastatin for 0.25, 1, 3, 24, 48, or 72 h at a pH of 6.8. Proteolysis of troponin T (TnT) and calpastatin was evaluated using SDS-PAGE and Western blotting techniques. Analysis of Western blots confirmed significant degradation of calpastatin by caspase-3 (P<0.05). Additionally, Western blots revealed intact calpastatin disappeared rapidly as a result of digestion by u-calpain. Although caspase-3 did not significantly degrade TnT (P>0.05), all u-calpain digestion treatments resulted in substantial TnT breakdown (P<0.05). Degradation of TnT did not differ between the u-calpain+calpastatin and u-calpain+caspase-3+calpastatin digestions (P>0.05). Results of this study indicate caspase-3 cleavage of calpastatin does not enhance in vitro degradation of TnT by u-calpain. PMID- 23989869 TI - Ergot alkaloids from endophyte-infected tall fescue decrease reticuloruminal epithelial blood flow and volatile fatty acid absorption from the washed reticulorumen. AB - An experiment was conducted to determine if ergot alkaloids affect blood flow to the absorptive surface of the rumen. Steers (n=8) were pair-fed alfalfa cubes and received ground endophyte-infected (Neotyphodium coenophialum) tall fescue (Lolium arundinaceum; E+) seed (0.015 mg ergovaline.kg BW(-1).d(-1)) or endophyte free tall fescue (E-) seed via the rumen cannula 2x daily for 7 d at thermoneutral (TN; 22 degrees C) and heat stress (HS; 32 degrees C) conditions. On d 8, the rumen was emptied and rinsed. A buffer containing VFA was incubated in the following sequence: control (CON), 15 MUg ergovaline.kg BW(-1) (1*EXT) from a tall fescue seed extract, and 45 MUg ergovaline.kg BW(-1) (3*EXT). For each buffer treatment there were two 30-min incubations: a 30-min incubation of a treatment buffer with no sampling followed by an incubation of an identical sampling buffer with the addition of Cr-EDTA and deuterium oxide (D2O). Epithelial blood flow was calculated as ruminal clearance of D2O corrected for influx of physiological water and liquid outflow. Feed intake decreased with dosing E+ seed at HS but not at thermoneutral conditions (TN; P<0.02). Dosing E+ seed decreased serum prolactin (P<0.005) at TN. At HS, prolactin decreased in both groups over the 8-d experiment (P<0.0001), but there was no difference in E+ and E- steers (P=0.33). There was a seed treatment*buffer treatment interaction at TN (P=0.038), indicating that E+ seed treatment decreased reticuloruminal epithelial blood flow at TN during the CON incubation, but the two groups of steers were not different during 1*EXT and 3*EXT (P>0.05). Inclusion of the extract in the buffer caused at least a 50% reduction in epithelial blood flow at TN (P=0.004), but there was no difference between 1*EXT and 3*EXT. There was a seed * buffer treatment interaction at HS (P=0.005), indicating that the reduction of blood flow induced by incubating the extract was larger for steers receiving E- seed than E+ seed. Volatile fatty acid flux was reduced during the 1*EXT and 3*EXT treatments (P<0.01). An additional experiment was conducted to determine the effect of time on blood flow and VFA flux because buffer sequence could not be randomized. Time either increased (P=0.05) or did not affect blood flow (P=0.18) or VFA flux (P>0.80), indicating that observed differences are due to the presence of ergot alkaloids in the rumen. A decrease in VFA absorption could contribute to the signs of fescue toxicosis including depressed growth and performance. PMID- 23989870 TI - Rest stops during road transport: impacts on performance and acute-phase protein responses of feeder cattle. AB - Angus*Hereford steers (n = 42) and heifers (n = 21) were ranked by gender and BW on d 0 of the experiment and randomly assigned to 1 of 3 treatments: 1) no transport and full access to feed and water (CON); 2) continuous road transport for 1,290 km (TRANS), or 3) road transport for 1,290 km, with rest stops every 430 km (STOP; total of 2 rest stops). Treatments were applied from d 0 to 1 of the experiment. Cattle from TRANS and STOP treatments were transported in separate commercial livestock trailers, within a single 2.1*7.2 m compartment, but through the exact same route. During each rest stop, STOP cattle were unloaded and offered mixed alfalfa-grass hay and water for ad libitum consumption for 2 h. Upon arrival of STOP and TRANS on d 1, cattle were ranked by sex and BW within each treatment and assigned to 21 feedlot pens (7 pens/treatment; 2 steers and 1 heifer/pen). Full BW was recorded before (d -1 and 0) treatment application and at the end of experiment (d 28 and 29). Total DMI was evaluated daily from d 1 to 28. Blood samples were collected on d 0 (before loading of TRANS and STOP cattle), 1 (immediately after unloading of TRANS and STOP cattle), 4, 7, 10, 14, 21, and 28. Body weight shrink from d 0 to d 1 was reduced (P<0.01) in CON compared to TRANS and STOP, and reduced in STOP compared to TRANS. Mean ADG was greater (P<0.05) in CON compared to TRANS and STOP, but similar (P=0.68) between TRANS and STOP. No treatment effects were detected (P>=0.18) on hay, concentrate, and total DMI. Mean G:F was greater (P=0.05) in CON compared to STOP, tended to be greater (P=0.08) in CON compared to TRANS, and similar (P=0.85) between TRANS and STOP. Plasma cortisol concentrations were greater (P<=0.04) in TRANS compared to CON and STOP on d 1, and greater (P=0.04) in TRANS compared to CON on d 4. Serum NEFA concentrations were greater (P<0.01) in TRANS compared to CON and STOP on d 1, and greater (P<=0.05) in TRANS compared to CON on d 4 and 7. Mean plasma ceruloplasmin concentrations were similar (P=0.19) among treatments. Plasma haptoglobin concentrations were greater (P<=0.04) in TRANS compared to CON and STOP on d 1, and in STOP compared to CON on d 1. In conclusion, inclusion of rest stops during a 1,290-km transport prevented the increase in circulating cortisol and alleviated the NEFA and haptoglobin response elicited by transport, but did not improve feedlot receiving performance of transported cattle. PMID- 23989871 TI - The influence of dietary restriction before and after 10 weeks of age on osteochondrosis in growing gilts. AB - Osteochondrosis (OC) is one of the main causes of leg weakness causing premature culling in breeding sows and develops in a short time frame in young growing gilts. Dietary restriction may have different effects on OC prevalence depending on the age of the gilts. The aim of this study is to investigate age-dependent effects of dietary restriction, ad libitum vs. restricted (80% of ad libitum), on the occurrence of OC in gilts at slaughter (26 wk of age). At weaning (4 wk of age), 211 gilts were subjected to one of 4 treatments of a feeding regime. Gilts were administered either ad libitum feeding from weaning until slaughter (AA); restricted feeding from weaning until slaughter (RR); ad libitum feeding from weaning until 10 wk of age, after which gilts were switched to restricted feeding (AR); or restricted feeding from weaning until 10 wk of age, after which gilts were switched to ad libitum feeding (RA). At slaughter, the elbow, hock, and knee joints were harvested. Joints were scored macroscopically for articular surface deformations indicative of OC. Gilts in the RA treatment had significantly higher odds of being affected by OC than gilts in the RR and AR treatments in the hock joint (OR=3.3, P=0.04 and OR=8.5, P=0.002, respectively) and at animal level (OR=2.5, P=0.001 and OR=1.9, P=0.01, respectively). Gilts in the AA treatment had higher odds of being affected by OC than gilts in the AR treatment in the hock joint (OR=5.3, P=0.01). The results indicate a possible pathway to reduce the prevalence of OC in breeding gilts that will have to last several parities. Switching from restricted feeding to ad libitum feeding after 10 wk of age increases OC prevalence as opposed to restricted feeding after 10 wk of age. PMID- 23989872 TI - Performance of Boer-Spanish and Spanish goats in Texas I: Body weights, fertility, prolificacy, and number of kids weaned. AB - Production records from 291 Boer-Spanish and Spanish does, collected between 1994 and 2004 in the Edwards Plateau region of West Texas, were examined to compare Boer-Spanish and Spanish does for body weights, fertility, prolificacy, and number of kids weaned. Traits were analyzed using single-trait mixed models. Boer Spanish does were heavier at birth than Spanish does (2.79 vs. 2.67 kg, P = 0.05) but similar weight at weaning (15.2 vs. 15.0 kg, P = 0.59). Boer-Spanish does had a heavier body weight at breeding than Spanish does (46.5 vs. 43.5 kg, P < 0.01). Boer-Spanish does had similar fertility over 8 annual breeding seasons (0.87 vs. 0.84, P = .22). Boer-Spanish does had an advantage over Spanish does for fertility to a 30-d breeding season (0.53 vs. 0.48; P = .09). Boer-Spanish does produced more kids than Spanish does (1.70 vs. 1.62, P = .09). Boer-Spanish does weaned a similar number of kids (1.30 vs. 1.31, P = .76). Age of doe significantly affected (P < 0.05) both number of kids born and number of kids weaned, with older does giving birth to, and weaning, more kids. Boer-Spanish does had greater birth weight, body weight at breeding, and number of kids born than Spanish does. Boer-Spanish does had a similar number of kids weaned as Spanish does. PMID- 23989873 TI - Response to capacitating stimuli indicates extender-related differences in boar sperm function. AB - Spermatozoa, especially those of the porcine species, are highly susceptible to in vitro chilling and ageing. Extenders are continuously developed to protect boar spermatozoa from chilling injury. New semen extenders and other modified preservation strategies require sensitive testing for essential sperm functions. The key process on the pathway of fertilization is capacitation. The aim of the present study was to examine whether the specific response to capacitating stimuli is sensitive enough to indicate different preservation capacities of extenders during hypothermic storage of boar spermatozoa. Semen was diluted in Beltsville Thawing Solution (BTS) and Androstar Plus and kept for 3 h at 22 degrees C or stored at 17 degrees C, 10 degrees C, and 5 degrees C. Semen was analyzed at 24 and 96 h of storage. Motility and membrane integrity remained at high levels, except for lower values when stored in BTS at 5 degrees C. Washed subsamples were incubated in capacitating medium (Tyrode) and control medium and were assessed for intracellular calcium concentration and integrity of plasma membranes using a flow cytometer. On the basis of the loss of low-calcium live cells in a kinetic approach, the specific response to capacitation stimuli was determined. There was a higher loss of response in semen stored hypothermically in the standard extender BTS compared to Androstar Plus. Assessment of the extent of phospholipid disorder under capacitating and control conditions by use of merocyanine staining did not reveal any significant extender-related differences. A field insemination trial with 778 sows was performed to relate in vitro results to fertility. Fertility parameters did not differ in semen stored up to 48 h at 10 degrees C in Androstar Plus compared to controls stored at 17 degrees C in BTS. In conclusion, assessment of specific reactivity to capacitating stimuli appears to be a sensitive tool for detection of extender-dependent alterations in functionality of chilled boar spermatozoa. PMID- 23989874 TI - Effects of acute heat stress on gene expression of brain-gut neuropeptides in broiler chickens. AB - Heat stress-induced reduction in feed intake is an annoyance of the poultry industry. Feed intake is regulated by complex mechanisms in which brain-gut neuropeptides are involved, but the changes in such neuropeptides in broiler chickens during heat exposure remain unclear. In this study, we investigated the effects of acute heat stress (35 degrees C, 6 h, and 65% relative humidity) on the gene expression of appetite-regulating peptides in the hypothalamus and gastrointestinal tract of broiler chickens at 42 d of age. The hypothalamic mRNA levels of neuropeptide Y, agouti-related peptide, pro-opiomelanocortin, cocaine- and amphetamine-regulated transcript, corticotropin-releasing hormone, melanocortin 4 receptor, melanin-concentrating hormone, prepro-orexin, cholecystokinin (CCK), and ghrelin did not significantly change (P>0.05) in the heat-exposed broiler chickens. However, the mRNA levels of ghrelin in the glandular stomach, duodenum, and jejunum significantly increased and the mRNA level of CCK in the duodenum significantly decreased. The results indicate that acute heat stress had no effect on the gene expression of central appetite regulating peptides under current experimental conditions; however, some gastrointestinal tract peptides (e.g., ghrelin and CCK) might play a role in the regulation of appetite in acute heat-exposed broiler chickens. Furthermore, ghrelin in the glandular stomach, duodenum, and jejunum might be the main regulative target of acute heat stress induced anorexia. PMID- 23989875 TI - Effects of TMEM154 haplotypes 1 and 3 on susceptibility to ovine progressive pneumonia virus following natural exposure in sheep. AB - Small ruminant lentiviruses (SRLV) adversely affect production and well-being of sheep and goats throughout much of the world. The SRLV, including ovine progressive pneumonia virus (OPPV) in North America, cause lifetime infections, and management procedures to eradicate or reduce disease prevalence are costly. Variants of ovine transmembrane protein 154 gene (TMEM154) affect susceptibility to OPPV. The primary experimental objective was to estimate additive and dominance effects of TMEM154 haplotypes 1 and 3 on susceptibility to OPPV infection following natural exposure. A group of 187 trial lambs was born and raised by mature, infected ewes to ensure natural exposure to OPPV. Parents of trial lambs were heterozygous for haplotypes 1 and 3, producing lambs with diplotypes "1 1," "1 3," and "3 3." A group of 20 sentinel lambs was born and raised by mature, uninfected ewes that were diplotype "1 1." Sentinel lambs had diplotypes "1 1" and "1 3," being sired by the same set of rams as trial lambs. Trial and sentinel lambs were comingled during the experiment. Lambs were weaned at 60 d of age, bled 1 wk after weaning, and thereafter at intervals of 4 or 5 wk until 9 mo of age when OPPV infection status was determined by use of a competitive enzyme-linked immunosorbent assay. Only 1 sentinel lamb became infected. Infection status of trial lambs was analyzed using logistic regression procedures to account for the binary nature of infection status and random effects of sires. Effects of sex, type of birth, type of rearing, age of dam, breed type of dam, and sires were not detected (P>0.20). Infection status was affected by diplotype of lamb (P=0.005), with additive (P=0.002) and dominance (P=0.052) effects identified. Predicted probabilities of infection for lambs with diplotypes "1 1," "1 3," and "3 3" were 0.094, 0.323, and 0.346, respectively. Confidence intervals for probabilities of infection for diplotypes "1 3" and "3 3" were similar, but distinct from diplotype "1 1." These results are consistent with complete dominance of haplotype 3 relative to haplotype 1. The probability of infection at 9 mo of age for lambs with either diplotype "1 3" or "3 3" averaged 3.56 times that of lambs with diplotype "1 1." Genetic susceptibility to OPPV infection can be reduced by selection to increase the frequency of haplotype 1, resulting in a greater proportion of lambs with diplotype "1 1." PMID- 23989876 TI - Effects of high fiber intake during late pregnancy on sow physiology, colostrum production, and piglet performance. AB - Dietary fiber given during pregnancy may influence sow endocrinology and increase piglet BW gain during early lactation. The aim of the current study was to determine whether dietary fiber given to sows during late pregnancy induces endocrine changes that could modulate sow colostrum production and, thus, piglet performance. From d 106 of pregnancy until parturition, 29 Landrace*Large White nulliparous sows were fed gestation diets containing 23.4 [high fiber (HF); n=15] or 13.3% total dietary fiber [low fiber (LF); n=14]. In the HF diet, wheat and barley were partly replaced by soybean hulls, wheat bran, sunflower meal (undecorticated), and sugar beet pulp. After parturition, sows were fed a standard lactation diet. Colostrum production was estimated during 24 h, starting at the onset of parturition (T0) and ending at 24 h after parturition (T24) based on piglet weight gains. Jugular blood samples were collected from sows on d 101 of pregnancy, daily from d 111 of gestation to d 3 of lactation, and then on d 7 and 21 of lactation (d 0 being the day of parturition). Postprandial kinetics of plasma glucose and insulin concentrations were determined on d 112 of pregnancy. The feeding treatment did not influence sow colostrum yield (3.9+/-0.2 kg) or piglet weight gain during the first day postpartum to d 21 of lactation. Colostrum intake of low birth weight piglets (<900 g) was greater in litters from HF sows than from LF sows (216+/-24 vs. 137+/-22 g; P=0.02). Preweaning mortality was lower in HF than LF litters (6.2 vs. 14.7%; P=0.01). Circulating concentrations of progesterone, prolactin, estradiol-17beta, and cortisol were not influenced by the treatment. Sows fed the HF diet had greater postprandial insulin concentrations than LF sows (P=0.02) whereas the postprandial glucose peak was similar. At T24, colostrum produced by HF sows contained 29% more lipid than colostrum produced by LF sows (P=0.04). Immunoglobulin A concentrations in colostrum were lower at T0 and T24 (P=0.02) in HF than LF sows (at T0: 8.6+/-1.1 vs. 11.9+/-1.1 mg/mL; at T24: 2.5+/-0.7 vs. 4.8+/-0.7 mg/mL). In conclusion, dietary fiber in late pregnancy affected sow colostrum composition but not colostrum yield, increased colostrum intake of low birth weight piglets, and decreased preweaning mortality, but these effects were not related to changes in peripartum concentrations of the main hormones involved in lactogenesis. PMID- 23989877 TI - Late gestation supplementation of beef cows differing in body condition score: effects on cow and calf performance. AB - A 2-yr study utilizing 120 mature, crossbred (Angus * Herford) cows/year, evaluated the influence of cow BCS and dried distillers grains with solubles (DDGS) supplementation during late gestation on cow performance and productivity of subsequent offspring. Treatments were arranged as a 2*2 factorial in a randomized complete block design with 2 BCS and with or without DDGS supplementation. Cows were nutritionally managed to enter the last trimester of gestation with a BCS of approximately 4 (LBCS) or 6 (HBCS) and were thereafter managed in a single herd (initial BCS were 4.4 and 5.7 for LBCS and HBCS treatments, respectively). During the last trimester, 12.7 kg/cow of low quality meadow hay (6.4% CP; DM basis) was provided each day. Supplemented cows were gathered and sorted into pens (12 pens; 5 cows/pen; 6 pens/BCS) every Monday, Wednesday, and Friday, and received the equivalent of 0.9 kg/cow daily of DDGS (31% CP; DM basis; supplement was consumed within 30 min on each supplementation day). Calf birth weight was greater for HBCS compared to LBCS (P=0.001) and for supplemented compared to nonsupplemented cows (P=0.04). Cow weight at weaning was greater for HBCS compared with LBCS (P<0.001); however, no differences were noted because of supplementation (P=0.16). Weaning weight was greater for the offspring of supplemented compared to nonsupplemented cows (P=0.02). There were no differences in postweaning calf performance (growing lot and feedlot) or carcass characteristics (P>0.05) due to treatments. Nevertheless, HBCS cows had approximately 10% more live calves at birth and at weaning (P<=0.01) compared to LBCS cows. Consequently, the total weaned calf weight per cow was 26 kg greater for HBCS compared with LBCS (P=0.004). Pregnancy rate was greater (P=0.05) for HBCS than LBCS cows (92% vs. 79%, respectively) but not affected by supplementation (P=0.94). This research demonstrates the potential consequences of not maintaining cows in adequate BCS at calving. Also, though it appears that supplementation of beef cows with DDGS during late gestation has a positive effect on weaning weight, there was no apparent developmental programming effect on feedlot performance and carcass characteristics of calves. PMID- 23989878 TI - Influence of experience on intake and feeding behavior of dairy sheep when offered forages from woody plants in a multiple-choice situation. AB - A satisfactory intake of novel low-quality forages by ruminants may require previous experience with this feed. Therefore, this study tested in sheep whether experience with forages from woody plants had an influence on feed intake, feeding behavior, and nutrient supply when offered in a multiple-choice arrangement. Two sheep experiments were conducted, 1 in Syria (Mediterranean region; Exp. 1) and the other in Switzerland (Central Europe; Exp. 2), that investigated 5 and 6 woody test plants, respectively. In Exp. 1, the test plants were Artemisia herba-alba, Atriplex leucoclada, Haloxylon articulatum, Noaea mucronata, and Salsola vermiculata. In Exp. 2, Betula pendula, Castanea sativa, and Juglans regia were used in addition to A. leucoclada, H. articulatum, and S. vermiculata (the plants most consumed in Exp. 1). In each experiment, 12 lactating sheep (Awassi sheep in Exp. 1 and East Friesian Milk sheep in Exp. 2) were allocated to 2 groups ("experienced" and "naive"). Experienced sheep subsequently were familiarized with each test plant during a learning period of binary choices (1 test plant vs. barley straw) for 4 h in the morning for 7 d each. The naive group received only straw. During the rest of the day, a basal diet composed of barley straw (ad libitum) and concentrate was offered to both groups. For the 2 wk following the learning period, the sheep were subjected to feeding of the basal diet to avoid carryover effects of the last offered test plant. In the following multiple-choice period, both groups were allowed to select from all test plants during 4 h in the morning for 14 d. Forage intake after 4 and 24 h and feeding behavior during the first 30 min of the test feeding were assessed. Milk yield and composition were measured at the end of the multiple-choice period. Nutrient intake was calculated using feed intake measurements and compositional analyses. Only in Exp. 2, group differences (P < 0.05) were found on d 1 of the multiple-choice period. The experienced sheep consumed more total forage, straw, OM, NDF, ADF, and ADL (nutrients without concentrate). However, across the entire multiple-choice period, there were no differences (P >= 0.05) in forage and nutrient intake, feeding behavior, and milk yield and composition between the groups in both experiments. This suggests that sheep can quickly adapt to previously unknown woody feeds of varying origin and quality offered as dried supplements. PMID- 23989879 TI - Dynamics of nitrogen retention in entire male pigs immunized against gonadotropin releasing hormone. AB - Immunization against GnRH reduces the occurrence of boar-taint-causing compounds in entire male pigs and is likely to alter growth performance, including whole body protein deposition (PD; N retention * 6.25). Thirty-six male pigs were used to determine the effects of immunization against GnRH with GnRH analog on N retention and plasma urea nitrogen (PUN; a measure of AA catabolism). Four treatments were used: 1) conventional, early castrates (EC), 2) entire male pigs (EM), 3) entire male pigs immunized with GnRH analog (IM), and 4) entire male pigs surgically castrated after 6 wk of age (between 25 and 40 kg BW; late castrates; LC). The GnRH analog was injected at 30 and 70 kg BW. Within each of 9 litters, 4 males were randomly assigned to the 4 treatments. Pigs were fed corn- and soybean-meal-based diets that were not limiting in essential nutrients for high PD. Five consecutive N balances were conducted between d -9 and -4, 1 and 7, 9 and 16, 20 and 26, and 30 and 36, relative to administration of the booster dose of GnRH analog at d 0. Blood was sampled on d -4, -1, 2, 5, 8, 11, 14, 19, 28, and 37. There was an interactive effect of treatment and time on N retention (P < 0.001). Across periods, N retention for EC and LC were similar (32.7 vs. 33.6 g/d) and lower than EM (39.2 g/d, P < 0.001). The N retention in EM and IM were similar up to d 7 (37.8 vs. 38.5 g/d), tended to be greater for EM than IM between d 9 and 16 (38.4 vs. 34.9 g/d, P = 0.07) and was greater for EM than IM after d 20 (40.9 vs. 34.9 g/d, P < 0.05). Between d 9 and 36, N retention in IM was similar to EC and LC. The PUN concentrations were similar in EC and LC across sampling times (15.50 vs. 15.86 mg/dL) and greater than EM (9.33 mg/dL, P < 0.05). The PUN concentrations were similar in EM and IM up to d 5 (9.88 vs. 9.59 mg/dL), tended to be less in EM than IM on d 8 (9.08 vs. 11.85 mg/dL, P < 0.10), and were lower in EM than IM from d 11 to 37 (8.94 vs. 14.80 mg/dL, P < 0.05). After d 8, PUN concentrations were similar for IM, EC, and LC (14.31, 15.13, and 15.55 mg/dL, respectively). In conclusion, the results of the current study show that N retention and PUN patterns in EC and LC are very similar and lower than those in EM. Between d 7 and 16 after administration of the booster dose of GnRH analog, N retention and PUN in IM changed gradually from EM levels to approach levels in EC and LC, which should be considered when developing feeding programs for IM. PMID- 23989880 TI - Combined effects of fungal alkaloids on intestinal motility in an in vitro rat model. AB - Diarrhea is caused by factors that alter absorption and secretion of water and ions across the intestinal epithelium and disrupt motility. Parasitic infection, stress, poor nutrition, and exposure to plant or fungal toxins predispose livestock to noninfectious diarrhea. This is more prevalent in sheep that graze pastures infected with wild-type endophytic fungus, suggesting the involvement of fungal alkaloids. These increase smooth muscle contraction: ergovaline/ergotamine (ergot alkaloid) activates serotonin (5-HT) receptors, and lolitrem B (indole diterpene) inhibits large-conductance Ca2+-activated K+ (BK) channels. Because of their separate mechanisms of action the objective of this study was to investigate whether they act synergistically to increase smooth muscle contraction. Effects of ergotamine (1 uM) and lolitrem B (0.1 uM) on the tension and frequency of spontaneous contractions were investigated in a longitudinal preparation of isolated distal colon. The compounds were dissolved in 0.1% dimethyl sulfoxide (DMSO) and applied separately or together for 1 h. Ergotamine increased contractile tension compared to the pretreatment control (P<0.01) and produced a short-lived increase in frequency (P<0.001). Lolitrem B increased contractile tension (P<0.05) but had no effect on frequency. When applied together, the contractile tension was greater than the sum of the compounds applied separately (P<0.05). The frequency of contractions was increased (P<0.05) but was not significantly different from that for ergotamine alone. The increased contractile tension when both compounds were applied together indicates that ergotamine and lolitrem B acted synergistically to increase smooth muscle contraction, suggesting that they would alter motility in vivo. PMID- 23989881 TI - Relationships between postweaning residual feed intake in heifers and forage use, body composition, feeding behavior, physical activity, and heart rate of pregnant beef females. AB - The objectives of this study were to determine if residual feed intake (RFI) classification of beef heifers affected efficiency of forage utilization, body composition, feeding behavior, heart rate, and physical activity of pregnant females. Residual feed intake was measured in growing Bonsmara heifers for 2 yr (n=62 and 53/yr), and heifers with the lowest (n=12/yr) and highest (n=12/yr) RFI were retained for breeding. Of the 48 heifers identified as having divergent RFI, 19 second-parity and 23 first-parity females were used in the subsequent pregnant female trial. Pregnant females were fed a chopped hay diet (ME=2.11 Mcal kg(-1) DM) in separate pens equipped with GrowSafe bunks to measure individual intake and feeding behavior. Body weights were measured at 7-d intervals and BCS and ultrasound measurements of 12th-rib fat depth, rump fat depth, and LM area obtained on d 0 and 77. Heart rate and physical activity were measured for 7 consecutive d. First-parity females had lower (P<0.05) initial BW, BW gain, and initial hip height and tended (P=0.07) to have lower DMI compared to second parity females. Females with low RFI as heifers consumed 17% less (P<0.01) forage compared to females with high RFI as heifers but maintained the same BW, BW gain, and body composition. Likewise, RFI classification did not affect calving date. An interaction (P=0.04) between heifer RFI classification and parity was found for calf birth weight. Calves from first-parity low-RFI females were lighter at birth (P<0.01) than calves from high-RFI females, but RFI classification did not affect BW of calves born to second-parity females. Residual feed intake classification did not affect bunk visit frequency, but low-RFI females spent 26% less time (P<0.01) at the bunk compared to high-RFI females. First-parity females had more (P<0.05) daily step counts and greater lying-bout frequencies compared to second-parity females, but physical activity was not affected by RFI classification. Heart rates of females classified as low RFI were 7% lower (P=0.03) compared to high-RFI females. Heifer postweaning RFI but not G:F or residual gain were positively correlated with forage intake (r=0.38) and RFI (r=0.42) of pregnant females. Results indicate that heifers identified as having low postweaning RFI have greater efficiency of forage utilization as pregnant females, with minimal impacts on growth, body composition, calving date, and calf birth BW, compared to their high-RFI counterparts. PMID- 23989882 TI - Effects of transport duration on maintenance behavior, heart rate and gastrointestinal tract temperature of market-weight pigs in 2 seasons. AB - Welfare and meat quality of market-weight pigs may be negatively affected by transport duration and environmental temperatures, which vary considerably between seasons. This study evaluated the effects of 3 transport durations (6, 12, and 18 h) on the physiology and behavior of pigs in summer and winter in western Canada. Market-weight pigs were transported using a pot-belly trailer at an average loading density of 0.375 m(2)/100 kg. Four replicates of each transport duration were conducted during each season. Heart rate and gastrointestinal tract temperature (GTT) were monitored from loading to unloading in 16 pigs from 4 selected trailer compartments (n = 96 groups, total of 384 animals, BW = 120.8 +/- 0.4 kg), namely top front (C1), top back (C4), middle front (C5), and bottom rear (C10). Behavior was recorded for pigs (948 and 924 animals, in summer and winter, respectively) in C1, C4, and C5 during transportation (standing, sitting, lying), and during 90 min in lairage (sitting, lying, drinking, latency to rest) for pigs in all 4 compartments. Transport was split into 7 periods: loading, pre-travel (PT), initial travel (IT), pre-arrival 1 (PA1) and 2 (PA2), unloading, and lairage. During IT and PA2, pigs spent less time lying in winter than summer (P < 0.05 and P < 0.05, respectively). During PA1, PA2, and unloading, a greater (P < 0.001) heart rate was found in pigs transported in winter compared with summer. During PA2, pigs subjected to the 18 h transport treatment in winter had a greater (P < 0.05) GTT than the other groups. In lairage, pigs transported for 18 h in winter drank more (P < 0.001) and took longer to rest (P < 0.01) than pigs from other groups. During PA1, pigs transported for 18 h had the greatest GTT (P < 0.001). At unloading, pigs transported for 6 h had the lowest GTT (P < 0.001). In lairage, pigs transported for 18 h spent less time lying than those transported for 6 or 12 h (P < 0.001). These results suggest that in winter, pigs increased their metabolism and were reluctant to rest on cold floors. Pigs transported for 18 h in winter showed greater evidence of thirst. It may be concluded that under western Canadian climatic conditions, long transports (18 h) in cold weather appear to be more detrimental to pig welfare. PMID- 23989883 TI - Relationship between pork quality and characteristics of muscle fibers classified by the distribution of myosin heavy chain isoforms. AB - A total of six fiber types, including four pure types (type I, IIA, IIX, and IIB) and two hybrid types (type IIAX and IIXB), were classified according to the expression of myosin heavy chain (MHC) isoforms by immunohistochemistry with MHC specific monoclonal antibodies. The comparison of the muscle fiber characteristics and pork quality between pork quality groups (DFD: dark, firm, and dry; PSE: pale, soft, and exudative; RFN: reddish pink, firm, and nonexudative; and RSE: reddish pink, soft, and exudative) classified by muscle pH, drip loss, and lightness was conducted and the relationship of myofiber characteristics to pork quality was investigated. The DFD group had the highest value of IIAX fiber density (P<0.05). The DFD group also showed the greatest fiber relative area of type I, IIA, and IIAX (P<0.05) whereas there were no significant differences in area composition for types I, IIA, and IIAX among the other groups including PSE, RFN, and RSE (P>0.05). The DFD group had the highest cross-sectional area (CSA) in types I, IIA, and IIX among the groups. The increase in density of type IIAX was related with the higher pH and the lower hue and drip loss. An increase in the fiber number composition of hybrid type IIXB increased the lightness and cooking loss and decreased sarcoplasmic protein solubility (SPS). Regarding fiber relative area, pure type I and IIA and hybrid type IIAX were greater in the DFD group and had lower lightness and drip loss. Hybrid type IIAX influences the desirability of the pork due to its association with low lightness and high pH and water-holding capacity (WHC). In contrast, type IIXB was related to poor quality pork, including pale color, low WHC in cooked meat, and low SPS. PMID- 23989884 TI - Effect of group size on behavior, health, production, and welfare of veal calves. AB - The objective of this study was to investigate the effect of group size on behavior, growth, health, and welfare of veal calves. Holstein-Friesian bull calves (n=168; 44+/-3 d of age) were assigned randomly to 1 of 3 treatments of group housing with 2, 4, or 8 calves per pen. The pens used for housing were 3 by 1.20 m (2 calves per pen), 3 by 2.40 m (4 calves per pen), and 3 by 4.80 m (8 calves per pen), supplying a total pen space allowance of 1.82 m2/calf, regardless of pen size. Behavior was recorded from video data throughout the day from 0700 to 1900 h during a single day each month for 5 mo using scan sampling every 5 min within 30-min observation sessions. On d 0, 1, 5, 14, 42, and 70 after grouping, continuous focal sampling around feeding time (30-min intervals before, during, and after feeding) focused on oral and aggressive behaviors. Calves housed in large groups (4 or 8 calves per pen) showed more (P<=0.001) conspecific contact, walking, and standing and less (P<0.001) manipulation of objects, self-licking, and lying when compared to calves housed in small groups (2 calves per pen). Group size had no effect on play behavior (P=0.11) throughout the experiment. During feeding times group size had no (P>=0.07) effect on any behavioral patterns except for duration of conspecific contact (P<0.01). Aggression at feeding time was not (P>0.23) affected by treatment. Group size treatments were similar for hip height change (P=0.41) and heart girth change (P=0.18) over the duration of the experiment; however, both hip height and heart girth increased (P=0.001) with calf age. During mo 1, calves in groups of 8 or 4 coughed more than calves in groups of 2 whereas calves in groups of 8 coughed more than calves in groups of 4 or 2 in mo 2 (treatment*month, P=0.03). Furthermore, during mo 4, calves in groups of 8 had less nasal discharge than calves in groups of 2 or 4 (treatment*month, P=0.02). Ocular discharge, ears, and fecal scores did not differ (P>=0.05) among treatments. Plasma cortisol was not (P>=0.37) affected by group size. The number of veal calves in a group when given the same space did not affect production and physiological indicators of welfare but had a transient effect on health during the 5-mo finishing period. If increased play and social contact and decreased aggression are considered as primary indicators of welfare, group size did not alter calf welfare. PMID- 23989885 TI - Cost-effectiveness of bariatric surgery. PMID- 23989888 TI - Serotonin transporter protein overexpression and association to Th17 and T regulatory cells in lupoid leishmaniasis. AB - The immunopathogenesis of chronic non-healing Old World cutaneous leishmaniasis is challenging. There is a bidirectional communication between the nervous and immune systems, serotonin being an important mediator in this respect. Our aim was to study the role of the serotonin transporter protein (SERT) and its relation to T cell-related immune responses in lupoid leishmaniasis. Paraffin embedded skin biopsies of 12 cases of lupoid and 12 cases of usual types of cutaneous leishmaniasis were investigated using immunohistochemistry regarding expression of SERT, Th1, Th2, Th17 and T regulatory cell (Treg) markers. SERT as well as Tregs and interleukin (IL)-17 positive cells were more prevalent while IL 5 (Th2) and interferon (IFN)-gamma (Th1) expressing cells were less numerous in the lupoid tissue compared to those from the usual type of leishmaniasis. The majority of the SERT(+) cells were also tryptase(+) (mast cells). There was a positive correlation between a higher number of SERT(+) and IL-17(+) cells in the lupoid type, while lower numbers of SERT(+) cells were significantly related to lower percentages of CD25(+) cells in the usual type of leishmaniasis. These results might indicate a role for SERT, Th17 and Tregs in the pathogenesis of lupoid leishmaniasis. PMID- 23989887 TI - Differential regulation of angiopoietin 1 and angiopoietin 2 during dengue virus infection of human umbilical vein endothelial cells: implications for endothelial hyperpermeability. AB - Infection with dengue virus (DV) can result in dengue hemorrhagic fever and dengue shock syndrome, where patients suffer from bleeding and plasma leakage involving endothelial cells. Angiopoietins (Ang) 1 and 2 are important angiogenic factors that affect endothelial barrier integrity. In this study, DV was observed to induce endothelial leakage at multiplicity of infection of 10 in primary human umbilical vein endothelial cells (HUVEC) with interendothelial gap formation. Immunostaining of vascular endothelial cadherin (VE-cadherin) and zona occludin 1 (ZO-1) showed the absence of these endothelial junctional proteins at the cell cell contact zones between adjacent cells. In addition, Ang1 that is required for protecting against endothelial hyperpermeability was found to be down-regulated during DV infection. Treatment with increasing concentrations of recombinant Ang1 was shown to prevent DV-induced endothelial hyperpermeability in a dose-dependent manner by preventing the down-regulation of VE-cadherin and ZO-1 at cell membrane. In contrast, the expression of Ang2, the natural antagonist of Ang1, was observed to be up-regulated during DV infection. Recombinant Ang2 added to HUVEC at non-toxic concentrations showed decreased in transendothelial electrical resistance reading and the down-regulation of VE-cadherin and ZO-1. These findings suggest that DV reduces the expression of Ang1 and enhances the expression of Ang2 in endothelial cells and that this imbalance of Ang 1 and Ang 2 may play a contributing role to the increased permeability of human primary endothelial cells during DV infection. PMID- 23989889 TI - Fundamental quantum noise mapping with tunnelling microscopes tested at surface structures of subatomic lateral size. AB - We present a measurement scheme that enables quantitative detection of the shot noise in a scanning tunnelling microscope while scanning the sample. As test objects we study defect structures produced on an iridium single crystal at low temperatures. The defect structures appear in the constant current images as protrusions with curvature radii well below the atomic diameter. The measured power spectral density of the noise is very near to the quantum limit with Fano factor F = 1. While the constant current images show detailed structures expected for tunnelling involving d-atomic orbitals of Ir, we find the current noise to be without pronounced spatial variation as expected for shot noise arising from statistically independent events. PMID- 23989891 TI - Differential modes of MHC class IIB gene evolution in cichlid fishes. AB - Cichlid fishes are emblematic models for the study of adaptive radiation, driven by natural and sexual selection. Parasite mediated selection is an important component in these processes, and the evolution of their immune system therefore merits special attention. In this study, light is shed on the phylogeny of the b family of cichlid major histocompatibility complex (MHC) class IIB genes. Full length coding sequences were used to reconstruct phylogenies using criteria of maximum parsimony, maximum likelihood and Bayesian inference. All analyses suggest monophyly of the b family of cichlid MHC class IIB genes, although sequences of the cichlid sister taxa are currently not available. Two evolutionary lineages of these genes, respectively encompassing the recently defined genomic regions DBB-DEB-DFB and DCB-DDB, show highly contrasting levels of differentiation. To explore putative causes for these differences, exon 2 sequences were screened for variation in recombination rate and strength of selection. The more diversified lineage of cichlid MHC class IIB b genes was found to have higher levels of both recombination and selection. This is consistent with the observation in other taxa that recombination facilitates the horizontal spread of positively selected sites across MHC loci and hence contributes to fast sequence evolution. In contrast, the lineage that showed low diversification might either be under stabilizing selection or is evolutionary constrained by its low recombination rate. We speculate whether this lineage might include MHC genes with non-classical functions. PMID- 23989890 TI - Recombinant Salmonella enterica serovar Typhimurium as a vaccine vector for HIV-1 Gag. AB - The HIV/AIDS epidemic remains a global health problem, especially in Sub-Saharan Africa. An effective HIV-1 vaccine is therefore badly required to mitigate this ever-expanding problem. Since HIV-1 infects its host through the mucosal surface, a vaccine for the virus needs to trigger mucosal as well as systemic immune responses. Oral, attenuated recombinant Salmonella vaccines offer this potential of delivering HIV-1 antigens to both the mucosal and systemic compartments of the immune system. So far, a number of pre-clinical studies have been performed, in which HIV-1 Gag, a highly conserved viral antigen possessing both T- and B-cell epitopes, was successfully delivered by recombinant Salmonella vaccines and, in most cases, induced HIV-specific immune responses. In this review, the potential use of Salmonella enterica serovar Typhimurium as a live vaccine vector for HIV-1 Gag is explored. PMID- 23989894 TI - Emission of spherical cesium-bearing particles from an early stage of the Fukushima nuclear accident. AB - The Fukushima nuclear accident released radioactive materials into the environment over the entire Northern Hemisphere in March 2011, and the Japanese government is spending large amounts of money to clean up the contaminated residential areas and agricultural fields. However, we still do not know the exact physical and chemical properties of the radioactive materials. This study directly observed spherical Cs-bearing particles emitted during a relatively early stage (March 14-15) of the accident. In contrast to the Cs-bearing radioactive materials that are currently assumed, these particles are larger, contain Fe, Zn, and Cs, and are water insoluble. Our simulation indicates that the spherical Cs-bearing particles mainly fell onto the ground by dry deposition. The finding of the spherical Cs particles will be a key to understand the processes of the accident and to accurately evaluate the health impacts and the residence time in the environment. PMID- 23989896 TI - Clinical impact of findings supporting an alternative diagnosis on CT pulmonary angiography in patients with suspected pulmonary embolism. AB - BACKGROUND: CT pulmonary angiography (CTPA) is commonly used as the first imaging test in the diagnostic workup of patients with suspected pulmonary embolism (PE). Other CTPA findings may provide an alternative explanation for signs and symptoms in these patients, but the clinical impact is not clear. METHODS: In 203 consecutive patients with suspected PE, we prospectively evaluated the clinical implication of abnormalities on CTPA. Alternative diagnoses were defined on clinical grounds before and after CTPA. Subsequent diagnostic tests and therapeutic consequences were assessed by criteria defined a priori. RESULTS: Sixty-one of the 203 patients (30%) had no abnormality on CTPA. Thirty-nine patients (19%) were given a diagnosis of PE. Before CTPA, alternative diagnoses were suspected in 97 patients (48%). Findings supporting an alternative diagnosis were detected in 88 patients (43%). In 28 patients, this was a new finding; in 18, a conclusive and previously unknown alternative diagnosis was made on the basis of the CTPA results. Overall, the findings supporting alternative diagnoses had therapeutic consequences in 10 patients (4.9%). Incidental findings (nodules and enlarged lymph nodes) requiring diagnostic procedures were present in 17 patients (8.4%), with one (0.5%) having a therapeutic consequence. CONCLUSIONS: In patients undergoing CTPA for suspected PE, findings supporting an alternative diagnosis were found in almost one-half of the patients. However, in only a few patients, the alternative diagnosis had therapeutic consequences. Hence, CTPA should principally be used to confirm or exclude PE in high-probability cases but not to establish an alternative diagnosis. PMID- 23989892 TI - Comprehensive analysis of medaka major histocompatibility complex (MHC) class II genes: implications for evolution in teleosts. AB - The major histocompatibility complex (MHC) class II molecules play central roles in adaptive immunity by regulating immune response via the activation of CD4 T cells. The full complement of the MHC class II genes has been elucidated only in mammalian species to date. To understand the evolution of these genes, we performed their first comprehensive analysis in nonmammalian species using a teleost, medaka (Oryzias latipes). Based on a database search, cDNA cloning, and genomic PCR, medaka was shown to possess five pairs of expressed class II genes, comprising one IIA and one IIB gene. Each pair was located on a different chromosome and was not linked to the class I genes. Only one pair showed a high degree of polymorphism and was considered to be classical class II genes, whereas the other four pairs were nonclassical. Phylogenetic analysis of all medaka class II genes and most reported teleost class II genes revealed that the IIA and IIB genes formed separate clades, each containing three well-corresponding lineages. One lineage contained three medaka genes and all known classical class II genes of Ostariophysi and Euteleostei and was presumed to be an original lineage of the teleost MHC class II genes. The other two lineages contained one nonclassical medaka gene each and some Euteleostei genes. These results indicate that multiple lineages of the teleost MHC class II genes have been conserved for hundreds of millions of years and that the tightly linked IIA and IIB genes have undergone concerted evolution. PMID- 23989897 TI - Directed multistep biocatalysis using tailored permeabilized cells. AB - : Recent developments in the field of biocatalysis using permeabilized cells are reviewed here, with a special emphasis on the newly emerging area of multistep biocatalysis using permeabilized cells. New methods of metabolic engineering using in silico network design and new methods of genetic engineering provide the opportunity to design more complex biocatalysts for the synthesis of complex biomolecules. Methods for the permeabilization of cells are thoroughly reviewed. We provide an extended review of useful available databases and bioinformatics tools, particularly for setting up genome-scale reconstructed networks. Examples described include phosphorylated carbohydrates, sugar nucleotides, and polyketides. PMID- 23989898 TI - Prediction of outcome in patients with liver dysfunction after left ventricular assist device implantation. AB - Although postoperative liver dysfunction (LD) following left ventricular assist device (LVAD) implantation is associated with high mortality, outcome is difficult to predict in patients with liver dysfunction. We aimed to clarify factors affecting recovery from LD after VAD implantation. A total of 167 patients underwent LVAD implantation, of whom 101 developed early postoperative LD, defined as maximum total bilirubin (max T-bil) greater than 5.0 mg/dl within 2 weeks. We set two different end-points, unremitting LD, and 90-day mortality. The rates of early mortality (90 days) and recovery from LD were 36 % (36/101) and 72 % (73/101), respectively. Univariate analysis showed that preoperative body weight, preoperative mechanical support, preoperative T-bil and creatinine, left ventricular diastolic dimension, right VAD (RVAD) insertion, cardiopulmonary bypass time, postoperative cardiac index, and postoperative T-bil and central venous pressure (CVP) on postoperative day (POD) 3 (non-recovered vs recovered, 12.4 +/- 4.5 vs 9.5 +/- 3.6 mmHg) were higher in patients with unremitting LD. Preoperative T-bil, RVAD insertion, and T-bil and CVP on POD 3 (non-survivor vs survivor, 12.4 +/- 4.4 vs 9.4 +/- 3.6 mmHg) were also higher in non-survivors. Multivariate analysis demonstrated that CVP on POD 3 was predictive of recovery from postoperative LD (OR 0.730, P < 0.05) and 90-day mortality (OR 0.730, P < 0.05). A key outcome factor in patients who developed early postoperative LD after LVAD implantation was postoperative liver congestion with high CVP. To overcome postoperative LD, appropriate management of postoperative CVP level is important. PMID- 23989899 TI - Is it possible? Predicting complications and morbidity in surgical patients on clopidogrel therapy with Thrombelastography Platelet Mapping. PMID- 23989900 TI - Structural and biomechanical responses of osseous healing: a novel murine nonunion model. AB - BACKGROUND: Understanding the biological mechanisms of why certain fractures are at risk for delayed healing or nonunion requires translational animal models that take advantage of transgenic and other genetic manipulation technologies. Reliable murine nonunion models can be an important tool to understand the biology of nonunion. In this study, we report the results of a recently established model for creating critical defects that lead to atrophic nonunions based on a unique fracture fixation technique. MATERIALS AND METHODS: Subcritical (0.6 mm long) and critical (1.6 mm long) defects were created in femurs of 10 week-old double transgenic (Col1/Col2) mice and stabilized using a custom designed plate and four screws. Four groups were used: normal, sham, subcritical, and critical. Histology (n = 3 for each group) was analyzed at 2 and 5 weeks, and micro-computed tomography (MUCT) and torsional biomechanics (n = 12 for each group) were analyzed at 5 weeks. RESULTS: Subcritical defects showed healing at 2 weeks and were completely healed by 5 weeks, with biomechanical properties not significantly different from normal controls. However, critical defects showed no healing by histology or MUCT. These nonunion fractures also displayed no torsional stiffness or strength in 10 of 12 cases. CONCLUSIONS: Our murine fracture model creates reproducible and reliable nonunions and can serve as an ideal platform for studying molecular pathways to contrast healing versus nonhealing events and for evaluating innovative therapeutic approaches to promote healing of a challenging osseous injury. PMID- 23989901 TI - Total parathyroidectomy with autotransplantation for a rare disease derived from uremic secondary hyperparathyroidism, the uremic leontiasis ossea. AB - SUMMARY: We described six uremic leontiasis ossea (ULO) patients who underwent total parathyroidectomy with autotransplantation. ULO demonstrated more a systemic disease than a simple craniofacial deformation. The surgery seemed an effective treatment to alleviate secondary hyperparathyroidism and to improve patients' quality of life. ULO may have a high postoperative recurrence tendency. INTRODUCTION: ULO is a rare disease derived from uremic secondary hyperparathyroidism (SHPT). Previous studies mostly focused on the craniofacial deformations. This study aims to investigate the systemic features of the disease and the surgical outcomes. METHODS: The present study retrospectively assessed six ULO patients who underwent total parathyroidectomy (TPTX) with autotransplantation (AT). Follow-up data were recorded. The follow-up status was considered as "effectiveness" if serum intact parathyroid hormone (iPTH) levels were <150 pg/mL in the first 3 days after surgery, or as "recurrence" if serum iPTH gradually increased >300 pg/mL during follow-up in patients whose status was initially considered as "effectiveness". RESULTS: Craniofacial deformations, short stature, thoracocyllosis, spine malformations, osteodynia, and muscle weakness were observed in all patients. Abnormal pulmonary functions were observed in five patients. After surgery, one patient died from respiratory failure. Surgery was effective in the remaining five patients with relieved osteodynia and stopped craniofacial deformation. A mean follow-up of 7.6 (4 to 12) months was available. Three patients suffered from recurrence of hyperparathyroidism originating from autografts. CONCLUSIONS: Our data suggests that ULO is not only a simple disease with craniofacial malformations but is a severe systemic disease leading to increased surgical risks. TPTX with AT seems an effective treatment to relieve SHPT and to improve quality of life. ULO may have a high postoperative recurrence tendency. PMID- 23989902 TI - A newly identified missense mutation of the EDA1 gene in a Hungarian patient with Christ-Siemens-Touraine syndrome. AB - Christ-Siemens-Touraine syndrome (CST; OMIM 305100) belongs to the group of ectodermal dysplasias and is characterized by the development of sparse hair, abnormal or missing teeth and sweating deficiency. CST is the consequence of mutations located in the ectodysplasin A (EDA1) gene. We have identified a 35 year-old Hungarian man with characteristic dysmorphic facial features, sparse hair, reduced sweating and missing teeth. Direct sequencing of the coding regions revealed a novel missense mutation in the eighth exon (c.971T/A, p.Val324Glu). The affected patient carries the mutation in a hemizygous form. Previous studies reported the association of missense mutations with non-syndromic tooth agenesis. However, the reported hemizygous patient exhibits hypodontia as well as hypotrichosis and reduced sweating. His daughter, an obligate heterozygous carrier of the identified missense mutation, exhibits only mild teeth abnormalities. As the novel missense mutation is located within the tumor necrosis factor (TNF) domain of the ectodysplasin protein, we hypothesize that this genetic variant affects the ectodysplasin/NFkappaB signaling pathway. PMID- 23989909 TI - The autism mental status exam: sensitivity and specificity using DSM-5 criteria for autism spectrum disorder in verbally fluent adults. AB - The phenotypic heterogeneity of adults suspected of autism spectrum disorder (ASD) requires a standardized diagnostic approach that is feasible in all clinical settings. The autism mental status exam (AMSE) is an eight-item observational assessment that structures the observation and documentation of social, communicative and behavioral signs and symptoms of ASD. Previous findings indicate high classification accuracy when compared to the autism diagnostic observation schedule in a non-stratified population of high-risk patients suspected of having ASD. This protocol investigates the sensitivity and specificity of AMSE scores using DSM-5 criteria for ASD in a sample of high-risk verbally fluent adults. Findings indicate an optimized sensitivity of 0.91 and a specificity of 0.93 for this group. Because of its high clinical utility, the AMSE holds promise as a diagnostic assessment tool that can support one's clinical diagnosis of ASD in high-risk adults. PMID- 23989911 TI - Plasmonic phase transition and phase retardation: essential optical characteristics of localized surface plasmon resonance. AB - Phase transition that occurs around the spectral position of localized surface plasmon resonance (LSPR) has various applications for light manipulation and refractive index sensing. Previous studies focused on phase responses of specific plasmonic structures, whereas the general theoretical analysis remains inadequate. In this study, we analytically modeled the phase spectra and the intensity spectra of silver nanodots with temporal coupled-mode theory. The phase transition occurs at the transmission dip, whereas the phase of reflection varies much more gradually. We further derived the equation for the slope of the phase at the transmission dip, which is a function of the rates of Ohmic dissipation and emission. The theoretical analysis is also applicable for wide varieties of LSPR systems and provides an intuitive physical mechanism for phase properties. Then, based on the fundamental discussion, we further investigated plasmonic phase retardation in anisotropic nanodots for the application of boosting the figure of merit (FOM) of refractive index sensing. The anisotropic nanodots induce plasmonic phase transitions, which spectrally split, for transmission waves polarized along the symmetric axes. Thus, anisotropy induces relative phase retardation in the narrow spectral region between the wavelengths of the LSPRs. We numerically manipulated the full width at half maximum of the ellipsometric spectra by adjusting the aspect ratio of the nanodots and observed an FOM of 24.3. In addition, experiments were performed to demonstrate the feasibility of this arrangement. PMID- 23989910 TI - Short-term intravenous antimicrobial prophylaxis for elective rectal cancer surgery: results of a prospective randomized non-inferiority trial. AB - PURPOSE: To investigate the non-inferiority of postoperative single-dose intravenous antimicrobial prophylaxis to multiple-dose intravenous antimicrobial prophylaxis in terms of the incidence of surgical site infections (SSIs) in patients undergoing elective rectal cancer surgery by a prospective randomized study. METHODS: Patients undergoing elective surgery for rectal cancer were randomized to receive a single intravenous injection of flomoxef (group 1) or five additional doses (group 2) of flomoxef after the surgery. All the patients had received preoperative oral antibiotic prophylaxis (kanamycin and erythromycin) after mechanical cleansing within 24 h prior to surgery, and had received intravenous flomoxef during surgery. RESULTS: A total of 279 patients (including 139 patients in group 1 and 140 in group 2) were enrolled in the study. The incidence of SSIs was 13.7% in group 1 and 13.6% in group 2 (difference [95% confidence interval]: -0.2% [-0.9 to 0.7%]). CONCLUSION: The incidence of SSIs was not significantly different in patients undergoing elective rectal surgery who were treated using a single dose of postoperative antibiotics compared to those treated using multiple-dose antibiotics when preoperative mechanical and chemical bowel preparations were employed. PMID- 23989908 TI - Effect of chronic treatment with conventional and organic purple grape juices (Vitis labrusca) on rats fed with high-fat diet. AB - Serra Gaucha is described as the most important wine region of Brazil. Regarding cultivars widespread in the Serra Gaucha, about 90 % of the area is occupied by vines of Vitis labrusca that is the most important specie used in grape juice production. The objective of this study was to investigate the antioxidant and neuroprotective effect of chronic intake of purple grape juice (organic and conventional) from Bordo variety (V. labrusca) on oxidative stress in different brain regions of rats supplemented with high-fat diet (HFD) for 3 months. A total of 40 male rats were randomly divided into 4 groups. Group 1 received a standard diet and water, group 2 HFD and water, group 3 HFD and conventional grape juice (CGJ), and group 4 HFD and organic grape juice (OGJ). All groups had free access to food and drink and after 3 months of treatment the rats were euthanized by decapitation and the cerebral cortex, hippocampus and cerebellum isolated and homogenized on ice for oxidative stress analysis. We observed that the consumption of calories in HFD and control groups, were higher than the groups supplemented with HFD and grape juices and that HFD diet group gain more weight than the other animals. Our results also demonstrated that HDF enhanced lipid peroxidation (TBARS) and protein damage (carbonyl) in cerebral cortex and hippocampus, reduced the non-enzymatic antioxidants defenses (sulfhydryl) in cerebral cortex and cerebellum, reduced catalase and superoxide dismutase activities in all brain tissues and enhanced nitric oxide production in all cerebral tissues. CGJ and OGJ were able to ameliorate these oxidative alterations, being OGJ more effective in this protection. Therefore, grape juices could be useful in the treatment of some neurodegenerative diseases associated with oxidative damage. PMID- 23989912 TI - Parameter non-identifiability of the Gyllenberg-Webb ODE model. AB - An ODE model introduced by Gyllenberg and Webb (Growth Develop Aging 53:25-33, 1989) describes tumour growth in terms of the dynamics between proliferating and quiescent cell states. The passage from one state to another and vice versa is modelled by two functions r0 and ri depending on the total tumour size. As these functions do not represent any observable quantities, they have to be identified from the observations. In this paper we show that there is an infinite number of pairs (r0, ri) corresponding to the same solution of the ODE system and the functions (r0, ri) will be classified in terms of this equivalence. Surprisingly, the technique used for this classification permits a uniqueness proof of the solution of the ODE model in a non-Lipschitz case. The reasoning can be widened to a more general setting including an extension of the Gyllenberg-Webb model with a nonlinear birth rate. The relevance of this result is discussed in a preclinical application scenario. PMID- 23989913 TI - An extension of the classification of evolutionarily singular strategies in Adaptive Dynamics. AB - The existing classification of evolutionarily singular strategies in Adaptive Dynamics (Geritz et al. in Evol Ecol 12:35-57, 1998; Metz et al. in Stochastic and spatial structures of dynamical systems, pp 183-231, 1996) assumes an invasion exponent that is differentiable twice as a function of both the resident and the invading trait. Motivated by nested models for studying the evolution of infectious diseases, we consider an extended framework in which the selection gradient exists (so the definition of evolutionary singularities extends verbatim), but where the invasion fitness may lack the smoothness necessary for the classification a la Geritz et al. We derive the classification of singular strategies with respect to convergence stability and invadability and determine the condition for the existence of nearby dimorphisms. In addition to ESSs and invadable strategies, we observe what we call one-sided ESSs: singular strategies that are invadable from one side of the singularity but uninvadable from the other. Studying the regions of mutual invadability in the vicinity of a one-sided ESS, we discover that two isoclines spring in a tangent manner from the singular point at the diagonal of the mutual invadability plot. The way in which the isoclines unfold determines whether these one-sided ESSs act as ESSs or as branching points. We present a computable condition that allows one to determine the relative position of the isoclines (and thus dimorphic dynamics) from the dimorphic as well as from the monomorphic invasion exponent and illustrate our findings with an example from evolutionary epidemiology. PMID- 23989914 TI - The patterns and criteria of vaginal douching and the risk of preterm labor among upper Egypt women: Retraction. PMID- 23989915 TI - Effect of azathioprine or mesalazine therapy on incidence of re-hospitalization in sub-occlusive ileocecal Crohn's disease patients. AB - BACKGROUND: Although the cost of Crohn's disease (CD) treatment differs considerably, hospitalization and surgery costs account for most of the total treatment cost. Decreasing hospitalization and surgery rates are pivotal issues in reducing health-care costs. MATERIAL/METHODS We evaluated the effect of azathioprine (AZA) compared with mesalazine on incidence of re-hospitalizations due to all causes and for CD-related surgeries. In this controlled, randomized study, 72 subjects with sub-occlusive ileocecal CD were randomized for AZA (2-3 mg/kg per day) or mesalazine (3.2 g per day) therapy during a 3-year period. The primary end point was the re-hospitalization proportion due to all causes, as well as for surgical procedures during this period evaluated between the groups. RESULTS: On an intention-to-treat basis, the proportion of patients re hospitalized within 36 months due to all causes was lower in patients treated with AZA compared to those on mesalazine (0.39 vs. 0.83, respectively; p=0.035). The AZA group had also significantly lower proportions of re-hospitalization for surgical intervention (0.25 vs. 0.56, respectively; p=0.011). The number of admissions (0.70 vs. 1.41, p=0.001) and the length of re-hospitalization (3.8 vs. 7.7 days; p=0.002) were both lower in AZA patients. CONCLUSIONS: Patients with sub-occlusive ileocecal CD treated with AZA had lower re-hospitalization rates due to all causes and for surgical management of CD compared to those treated with mesalazine during a 3-year period. The long-term use of AZA in ileocecal CD patients recovering from a sub-occlusion episode can save healthcare costs. PMID- 23989916 TI - Characteristics of undertreatment in COPD in the general population. AB - BACKGROUND: We wished to characterize undertreatment in COPD. METHODS: Among 5,812 individuals with COPD defined by FEV1/FVC < 0.7 participating in the Copenhagen General Population Study, we identified 920 individuals with FEV1 < 60% predicted. Prescriptions were identified in an all-inclusive nationwide registry. For each individual, we examined treatment with medication in the year before the day of the baseline examination, as well as treatment in the first year after the examination. Multivariable logistic regression analyses were applied in individuals with FEV1 < 60% predicted to identify predictors of treatment in the first year after baseline. RESULTS: Only 30% of individuals with COPD and FEV1 < 60% predicted were treated with medication in the year before the examination, whereas 42.2% were treated with medication in the first year after. Reporting six to 10 previous respiratory infections during the preceding 10 years that required consulting a doctor and/or staying home from work was the strongest predictor of treatment with medication (OR, 7.9; 95% CI, 3.5-19.8; P < .001). Breathlessness, low FEV1, previous admissions with a discharge diagnosis of COPD, and former smoking were also predictors of treatment with medication, whereas comorbidity predicted lack of treatment. In subgroup analysis, among individuals with FEV1 < 50% predicted, visits to the general practitioner and age were additional predictors of treatment, whereas male sex and being a widow/widower predicted lack of treatment. CONCLUSIONS: In this study, we observed important characteristics of a major undertreatment in individuals with COPD in the general population. Previous reported respiratory infections were the strongest predictors of treatment with medications, which indicates that most COPD treatment is initiated because of acute exacerbations. PMID- 23989917 TI - Dirigent proteins: molecular characteristics and potential biotechnological applications. AB - Dirigent proteins (DIRs) are thought to play important roles in plant secondary metabolism. They lack catalytic activity but direct the outcome of bimolecular coupling reactions toward regio- and stereospecific product formation. Functionally described DIRs confer specificity to the oxidative coupling of coniferyl alcohol resulting in the preferred production of either (+)- or (-) pinoresinol, which are the first intermediates in the enantiocomplementary pathways for lignan biosynthesis. DIRs are extracellular glycoproteins with high beta-strand content and have been found in all land plants investigated so far. Their ability to capture and orientate radicals represents a unique naturally evolved concept for the control of radical dimerization reactions. Although oxidative coupling is commonly used in biological systems, its wider application in chemical synthesis is often limited by insufficient selectivity. This minireview gives an overview of functionally described DIRs and their molecular characteristics and wants to inspire further research for their use in biotechnological applications. PMID- 23989918 TI - Isocitric acid production from rapeseed oil by Yarrowia lipolytica yeast. AB - Production of D S-threo-isocitric acid (ICA) by yeast meets serious difficulties since it is accompanied by a simultaneous production of citric acid (CA) in significant amounts that reduces the yield of desired product. In order to develop an effective process of ICA production, 60 yeast strains of different genera (Candida, Pichia, Saccharomyces, Torulopsis, and Yarrowia) were tested for their ability to produce ICA from rapeseed oil; as a result, wild-type strain Yarrowia lipolytica VKM Y-2373 and its mutant Y. lipolytica 704-UV4-A/NG50 were selected as promising ICA producers. The effects of temperature, pH, aeration, and concentrations of rapeseed oil, iron, and itaconic acid on ICA production by selected strains were studied. Under optimal conditions (pH 6.0; aeration 50-55 %; rapeseed oil concentration of 20-60 gl(-1), iron ion concentration of 1.2 mg l(-1), and itaconic acid amount of 30 mM), selected strains of Y. lipolytica produced predominantly ICA with a low amount of a by-product, CA. PMID- 23989919 TI - Use of a genetically-engineered Escherichia coli strain as a sample process control for quantification of the host-specific bacterial genetic markers. AB - Quantitative PCR (qPCR) assays targeting the host-specific Bacteroides-Prevotella 16S rRNA genetic markers have been proposed as one of the promising approaches to identify the source of fecal contamination in environmental waters. One of the concerns of qPCR assays to environmental samples is the reliability of quantified values, since DNA extraction followed by qPCR assays are usually performed without appropriate sample process control (SPC) and internal amplification controls (IACs). To check the errors in sample processing and improve the reliability of qPCR results, it is essential to evaluate the DNA recovery efficiency and PCR amplification efficiency of the target genetic markers and correct the measurement results. In this study, we constructed a genetically engineered Escherichia coli K12 strain (designated as strain MG1655 Deltalac::kan) as sample process control and evaluated the applicability to environmental water samples. The recovery efficiency of the SPC strain MG1655 Deltalac::kan was similar to that of Bacteroides fragilis JCM 11019, when DNA were extracted from water samples spiked with the two bacteria. Furthermore, the SPC was included in the qPCR assays with propidium monoazide (PMA) treatment, which can exclude the genetic markers from dead cells. No significant DNA loss was observed in the PMA treatment. The inclusion of both the SPC (strain MG1655 Deltalac::kan) and IAC in qPCR assays with PMA treatment gave the assurance of reliable results of host-specific Bacteroides-Prevotella 16S rRNA genetic markers in environmental water samples. PMID- 23989920 TI - [Critical incidents in preclinical emergency airway management : Evaluation of the CIRS emergency medicine databank]. AB - BACKGROUND: Many patients are victims of disastrous incidents during medical interventions. One of the obligations of physicians is to identify these incidents and to subsequently develop preventive strategies in order to prevent future events. Airway management and prehospital emergency medicine are of particular interest as both categories frequently show very dynamic developments. Incidents in this particular area can lead to serious injury but at the same time it has never been analyzed what kind of incidents might harm patients during prehospital airway management. MATERIALS AND METHODS: The German website http://www.cirs-notfallmedizin.de (CIRS critical incident reporting systems) offers anonymous reporting of critical incidents in prehospital emergency medicine. All incidents reported between 2005 and 2012 were screened to identify those which were concerned with airway management and four experts in this field analyzed the incidents and performed a root cause analysis. RESULTS: The database contained 845 reports. The authors considered 144 reports to be airway management related and identified 10 root causes: indications for intubation but no intubation performed (n = 8), no indications for intubation but intubation attempt performed (n = 7), wrong medication (n = 25), insufficient practical skills (n = 46), no use of alternative airway management (n = 7), insufficient handling before or after intubation (n = 27), defect equipment (n = 28), lack of equipment (n = 31), others (n = 18) and factors that cannot be influenced (n = 12). CONCLUSIONS: The incidents that were reported via the website http://www.cirs-notfallmedizin.de and that occurred during airway management in prehospital emergency medicine are described. To improve practical airway management skills of emergency physicians are one of the most important tasks in order to prevent critical incidents and are discussed in the article. PMID- 23989922 TI - Sugar as food. PMID- 23989921 TI - Observation of antiferromagnetic order collapse in the pressurized insulator LaMnPO. AB - The emergence of superconductivity in the iron pnictide or cuprate high temperature superconductors usually accompanies the suppression of a long-ranged antiferromagnetic (AFM) order state in a corresponding parent compound by doping or pressurizing. A great deal of effort by doping has been made to find superconductivity in Mn-based compounds, which are thought to bridge the gap between the two families of high temperature superconductors, but the AFM order was not successfully suppressed. Here we report the first observations of the pressure-induced elimination of long-ranged AFM order at ~ 34 GPa and a crossover from an AFM insulating to an AFM metallic state at ~ 20 GPa in LaMnPO single crystals that are iso-structural to the LaFeAsO superconductor by in-situ high pressure resistance and ac susceptibility measurements. These findings are of importance to explore potential superconductivity in Mn-based compounds and to shed new light on the underlying mechanism of high temperature superconductivity. PMID- 23989923 TI - A piece of my mind. Treat me like a child. PMID- 23989924 TI - Novel blood sampling method of an artificial endocrine pancreas via the cardiopulmonary bypass circuit. AB - We tried to perform continuous blood glucose monitoring during cardiovascular surgery involving cardiopulmonary bypass using an artificial endocrine pancreas (STG-22 or -55; Nikkiso, Tokyo, Japan); however, we often encountered problems during these procedures because insufficient blood was obtained for monitoring. Thus, we started performing the blood sampling via the venous side of the cardiopulmonary bypass circuit. As a result, continuous blood glucose monitoring using an artificial endocrine pancreas was proven to be stable and reliable during cardiovascular surgery involving cardiopulmonary bypass. PMID- 23989925 TI - Metabolic and transcriptional response of Escherichia coli with a NADP(+) dependent glyceraldehyde 3-phosphate dehydrogenase from Streptococcus mutans. AB - The NAD(+)-dependent glyceraldehyde-3-phosphate-dehydrogenase (NAD(+)-GAPDH) is a key enzyme to sustain the glycolytic function in Escherichia coli and to generate NADH. In the absence of NAD(+)-GAPDH activity, the glycolytic function can be restored through NADP(+)-dependent GAPDH heterologous expression. Here, some metabolic and transcriptional effects are described when the NAD(+)-GAPDH gene from E. coli (gapA) is replaced with the NADP(+)-GAPDH gene from Streptococcus mutans (gapN). Expression of gapN was controlled by the native gapA promoter (E. coliDeltagapA::gapN) or by the constitutive trc promoter in a multicopy plasmid (E. coliDeltagapA::gapN/pTrcgapN). The specific NADP(+)-GAPDH activity was 4.7 times higher in E. coliDeltagapA::gapN/pTrcgapN than E. coliDeltagapA::gapN. Growth, glucose consumption and acetic acid production rates increased in agreement with the NADP(+)-GAPDH activity level. Analysis of E. coliDeltagapA::gapN/pTrcgapN showed that although gapN expression complemented NAD(+)-GAPDH activity, the resulting low NADH levels decreased the expression of the respiratory chain and oxidative phosphorylation genes (ndh, cydA, cyoB and atpA). In comparison with the wild type strain, E. coliDeltagapA::gapN/pTrcgapN decreased the percentage of mole of oxygen consumed per mole of glucose metabolized by 40 % with a concomitant reduction of 54 % in the ATP/ADP ratio. The cellular response to avoid NADPH excess led to the overexpression of the transhydrogenase coded by udhA and the down-regulation of the pentose-phosphate and Krebs cycle genes, which reduced the CO2 production and increased the acetic acid synthesis. The E. coli strains obtained in this work can be useful for future metabolic engineering efforts aiming for the production of metabolites which biosynthesis depends on NADPH. PMID- 23989926 TI - An Lrp-type transcriptional regulator controls expression of the Bacillus subtilis chromate transporter. AB - The Bacillus subtilis strain 168 genome contains the chr3N-chr3C genes encoding the Chr3N/Chr3C protein pair of the chromate ion transporter (CHR) superfamily. Chr3N/Chr3C confers chromate resistance in Escherichia coli only when both proteins are expressed. Upstream of chr3N is the chrS gene encoding ChrS, a protein with homology to the Lrp/AsnC family of transcriptional regulators. When the chrS-chr3N-chr3C gene cluster was transferred to E. coli, a diminished level of chromate resistance was observed, as compared with E. coli transformants bearing only the chromate resistance genes, which displayed full resistance. These data suggested that the chrS gene product acts as negative regulator. RT PCR assays demonstrated that expression of chrS diminishes transcription of the chromate resistance genes in E. coli, and that this repression was overcome by chromate. Electrophoretic mobility shift assays showed that purified ChrS protein specifically binds to the 5' region of chrS. These results indicate that the chr gene cluster forms an operon regulated negatively by ChrS binding to its own gene's regulatory region, and positively by chromate ions. Sequence analysis revealed similar operons in many Bacillales strains, suggesting some adaptive advantage. This is the first example of a bacterial heavy-metal resistance system controlled by an Lrp-type transcriptional regulator. PMID- 23989927 TI - Sabulilitoribacter multivorans gen. nov., sp. nov., a polysaccharide-degrading bacterium of the family Flavobacteriaceae isolated from seashore sand. AB - A Gram-negative, aerobic, non-flagellated, non-gliding and rod-shaped bacterial strain, designated M-M16(T), was isolated from seashore sand around a seaweed farm on the South Sea, South Korea, and its taxonomic position was investigated by using a polyphasic study. Strain M-M16(T) grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 2 % (w/v) NaCl. Strain M-M16(T) exhibited the highest 16S rRNA gene sequence similarity values to the type strains of Gaetbulibacter lutimaris (96.5 %) and Flaviramulus basaltis (95.8 %). Neighbour joining and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences revealed that strain M-M16(T) clustered with the type strains of Gaetbulibacter species and F. basaltis. Strain M-M16(T) contained MK-6 as the predominant menaquinone and iso-C15:1 G, iso-C15:0 and iso-C17:0 3-OH as the major fatty acids. The major polar lipids detected in strain M-M16(T) were phosphatidylethanolamine and one unidentified lipid. The DNA G+C content of strain M-M16(T) was 37.4 mol%. The phylogenetic and chemotaxonomic data and other phenotypic properties revealed that strain M-M16(T) represents a novel genus and species within the family Flavobacteriaceae, for which the name Sabulilitoribacter multivorans gen. nov., sp. nov. is proposed. The type strain of S. multivorans is M-M16(T) (= KCTC 32326(T) = CCUG 63831(T)). PMID- 23989928 TI - Protein-protein association and cellular localization of four essential gene products encoded by tellurite resistance-conferring cluster "ter" from pathogenic Escherichia coli. AB - Gene cluster "ter" conferring high tellurite resistance has been identified in various pathogenic bacteria including Escherichia coli O157:H7. However, the precise mechanism as well as the molecular function of the respective gene products is unclear. Here we describe protein-protein association and localization analyses of four essential Ter proteins encoded by minimal resistance-conferring fragment (terBCDE) by means of recombinant expression. By using a two-plasmid complementation system we show that the overproduced single Ter proteins are not able to mediate tellurite resistance, but all Ter members play an irreplaceable role within the cluster. We identified several types of homotypic and heterotypic protein-protein associations among the Ter proteins by in vitro and in vivo pull-down assays and determined their cellular localization by cytosol/membrane fractionation. Our results strongly suggest that Ter proteins function involves their mutual association, which probably happens at the interface of the inner plasma membrane and the cytosol. PMID- 23989929 TI - Accumulation of serum lipids by vascular smooth muscle cells involves a macropinocytosis-like uptake pathway and is associated with the downregulation of the ATP-binding cassette transporter A1. AB - Vascular smooth muscle cells (VSMC) are present in arterial intima before atherosclerotic plaques develop and are likely to be exposed to unmodified serum lipids as they enter the vessel wall. We examined the effects of sera from mice on the morphology and function of mouse VSMC. Incubation of a mouse VSMC line (MOVAS) with sera from normocholesterolemic (C57BL/6J) or hypercholesterolemic (APOE(-/-)) mice caused concentration-dependent increases in lipid accumulation as measured by AdipoRed, with the extent of lipid uptake significantly greater with the latter sera type. Inhibition of c-Jun N-terminal kinases (SP600125), Src kinases (AG1879), and clathrin-dependent endocytosis (monodansylcadaverine) to disrupt scavenger receptor-mediated uptake of lipids had no effect on serum induced lipid accumulation by VSMC. By contrast, inhibition of macropinocytosis with antagonists of PI-3 kinase (LY294002) and actin (cytochalasin D) markedly reduced lipid accumulation. Serum exposure reduced the expression of the ATP binding cassette transporter A1, consistent with impaired cholesterol efflux, but had no effect on the expression of markers of VSMC differentiation. Moreover, the expression of several inflammation and foam cell markers was unchanged (CCL2, CCL5, and CD68) by mouse sera. The accumulation of unmodified serum lipids by VSMC involves a macropinocytosis-like uptake pathway and is associated with the downregulation of the ATP-binding cassette transporter. We speculate that VSMC may play an atheroprotective role in arterial intima by acting as a "sink" for unmodified lipids. PMID- 23989931 TI - Loss of a negative feedback loop involving pea3 and cyclin d2 is required for pea3-induced migration in transformed mammary epithelial cells. AB - The Ets family transcription factor Pea3 (ETV4) is involved in tumorigenesis especially during the metastatic process. Pea3 is known to induce migration and invasion in mammary epithelial cell model systems. However, the molecular pathways regulated by Pea3 are still misunderstood. In the current study, using in vivo and in vitro assays, Pea3 increased the morphogenetic and tumorigenic capacity of mammary epithelial cells by modulating their cell morphology, proliferation, and migration potential. In addition, Pea3 overexpression favored an epithelial-mesenchymal transition (EMT) triggered by TGF-beta1. During investigation for molecular events downstream of Pea3, Cyclin D2 (CCND2) was identified as a new Pea3 target gene involved in the control of cellular proliferation and migration, a finding that highlights a new negative regulatory loop between Pea3 and Cyclin D2. Furthermore, Cyclin D2 expression was lost during TGF-beta1-induced EMT and Pea3-induced tumorigenesis. Finally, restored Cyclin D2 expression in Pea3-dependent mammary tumorigenic cells decreased cell migration in an opposite manner to Pea3. As such, these data demonstrate that loss of the negative feedback loop between Cyclin D2 and Pea3 contributes to Pea3 induced tumorigenesis. IMPLICATIONS: This study reveals molecular insight into how the Ets family transcription factor Pea3 favors EMT and contributes to tumorigenesis via a negative regulatory loop with Cyclin D2, a new Pea3 target gene. PMID- 23989930 TI - Inhibition of hedgehog and androgen receptor signaling pathways produced synergistic suppression of castration-resistant prostate cancer progression. AB - Metastatic prostate cancer is initially treated with androgen ablation therapy, which causes regression of androgen-dependent tumors. However, these tumors eventually relapse resulting in recurrent castration-resistant prostate cancer (CRPC). Currently, there is no effective therapy for CRPC and the molecular mechanisms that lead to the development of CRPC are not well understood. Here, we evaluated the hypothesis that combined inhibition of Hedgehog (Hh) and androgen receptor (AR) signaling will synergistically attenuate the growth of CRPC in vitro and in vivo. Androgen deprivation induced full-length androgen receptor protein levels in CRPC cells, but decreased its nuclear localization and transcriptional activity. However, androgen deprivation also increased a truncated form of androgen receptor (lacking ligand-binding domain) that possessed transcriptional activity in CRPC cells. Androgen deprivation also promoted the expression of Hh signaling components in CRPC cells, xenograft tumors, and the prostate glands of castrated mice. Importantly, although inhibition of either Hh or androgen receptor signaling alone was only moderately effective in blocking CRPC cell growth, combination of an Hh pathway inhibitor and a noncompetitive androgen receptor inhibitor synergistically suppressed the growth of CRPC cells in vitro and in vivo. Finally, noncompetitive inhibition of androgen receptor, but not competitive inhibition, was effective at limiting the activity of truncated androgen receptor leading to the inhibition of CRPC. IMPLICATIONS: Combined therapy using Hh inhibitors and a non-competitive AR inhibitor may limit CRPC growth. PMID- 23989933 TI - Peripartum hysterectomy in 38 hospitals in China: a population-based study. AB - OBJECTIVE: To investigate the incidence, indications, risk factors and transfusions of peripartum hysterectomy in China. METHODS: A population-based study was conducted using inpatient records of 38 hospitals between 1 January 2011 and 31 December 2011; multivariate logistic regression analysis was used to identify independent risk factors for peripartum hysterectomy. RESULTS: During the study period, there were 43 peripartum hysterectomy cases out of 114,420 deliveries (0.380/00). Abnormal placentation was major indication for peripartum hysterectomy. Several factors significantly increased the risk of peripartum hysterectomy in this population: placenta previa/accreta [adjusted odds ratio (aOR) 49.7, 95 % CI 25.0-98.9], maternal age >=35 years (aOR 8.1, 95% CI 4.0 16.0), preeclampsia/eclampsia (aOR 7.5, 95% CI 2.6-21.7), cesarean delivery (aOR 3, 95% CI 1.1-8.0), and multiparity (aOR 2.7, 95% CI 1.2-5.4). In contrast, multiple gestations did not. CONCLUSIONS: Placenta previa/accreta, maternal age >=35 years, preeclampsia/eclampsia, cesarean delivery and multiparity were risk factors of peripartum hysterectomy. PMID- 23989934 TI - The testing of Sanocrysin: science, profit, and innovation in clinical trial design, 1926-31. AB - This article provides a detailed analysis of the origins and significance of the 1926 clinical trial of Sanocrysin, a gold compound thought at the time to be useful in the treatment of tuberculosis. This experiment is generally considered to be the first clinical trial in the United States that used a formal system of randomization to divide research subjects into treatment and nontreatment groups; it was probably also the first clinical trial in the United States to use placebo shams in a nontreatment control group to overcome the problem of what researchers at the time called "psychic influence." As such, it was an extremely important moment in the history of clinical trial design. Yet, as I argue, the Sanocrysin experiment also needs to be understood in terms of both the regulatory environment at the time and the commercial interests of Parke, Davis & Company, the pharmaceutical manufacturer that was intent on introducing the drug. Although some historians argue that therapeutic reformers in the twentieth century used experimental science to rein in the commercial forces of the market, this article suggests that, at least in this case, the promotion of rigorous clinical science and the pursuit of corporate profit were deeply intertwined. PMID- 23989935 TI - Alfred Russel Wallace's medical libertarianism: state medicine, human progress, and evolutionary purpose. AB - Alfred Russel Wallace (1823-1913), naturalist and explorer of South America and the Malay Archipelago, secured his place in history by independently discovering the theory of natural selection. His letter outlining the theory was sent from Ternate in eastern Indonesia and received at Down House, according to Charles Darwin (1809-82), on June 18, 1858, prompting the now-famed evolutionist to rush his languishing manuscript to press. Wallace's contributions to evolutionary biology, biogeography, and anthropology are well known, but his medical views have received far less attention. Within the context of a strident populist antivaccination movement and an ominous elitist eugenics campaign, Wallace took his stand, which revealed itself in a libertarianism that defended traditional socialist constituencies (the working poor, the lumpenproletariat, and feminist reformers) against state-mandated medical interventions. Rather than viewing Wallace as a heterodox contrarian, this article argues that his positions were logical outgrowths of his medical libertarianism and evolutionary and social theories. PMID- 23989936 TI - Gender and age differences in the core triad of impairments in autism spectrum disorders: a systematic review and meta-analysis. AB - Autism is an extensively studied disorder in which the gender disparity in prevalence has received much attention. In contrast, only a few studies examine gender differences in symptomatology. This systematic review and meta-analysis of 22 peer reviewed original publications examines gender differences in the core triad of impairments in autism. Gender differences were transformed and concatenated using standardized mean differences, and analyses were stratified in five age categories (toddlerhood, preschool children, childhood, adolescence, young adulthood). Boys showed more repetitive and stereotyped behavior as from the age of six, but not below the age of six. Males and females did not differ in the domain of social behavior and communication. There is an underrepresentation of females with ASD an average to high intelligence. Females could present another autistic phenotype than males. As ASD is now defined according to the male phenotype this could imply that there is an ascertainment bias. More research is needed into the female phenotype of ASD with development of appropriate instruments to detect and ascertain them. PMID- 23989937 TI - Alpha asymmetry in infants at risk for autism spectrum disorders. AB - An emerging focus of research on autism spectrum disorder (ASD) targets the identification of early-developing ASD endophenotypes using infant siblings of affected children. One potential neural endophenotype is resting frontal electroencephalogram (EEG) alpha asymmetry, a metric of hemispheric organization. Here, we examined the development of frontal EEG alpha asymmetry in ASD high-risk and low-risk infant populations. Our findings demonstrate that low and high-risk infants show different patterns of alpha asymmetry at 6 months of age and opposite growth trajectories in asymmetry over the following 12 months. These results support the candidacy of alpha asymmetry as an early neural ASD endophenotype. PMID- 23989938 TI - How does copayment for health care services affect demand, health and redistribution? A systematic review of the empirical evidence from 1990 to 2011. AB - This article reviews the quantitative evidence on the behavioural effects of copayment within the health area across a wide range of countries. The review distinguishes itself from previous similar reviews by having a high degree of transparency for the search strategy used to identify the studies included in the review as well as the criteria for inclusion and by including the most recent literature. Empirical studies were identified by performing searches in EconLit. The literature search identified a total of 47 studies of the behavioural effects of copayment. Considering the demand effects, the majority of the reviewed studies found that copayment reduces the use of prescription medicine, consultations with general practitioners and specialists, and ambulatory care, respectively. The literature found no significant effects of copayment on the prevalence of hospitalisations. The empirical evidence on whether copayment for some services, but not for others, causes substitution from the services that are subject to copayment to the 'free' services rather than lower total use is sparse and mixed. Likewise, the health effects of copayment have only been analysed empirically in a limited number of studies, of which half did not find any significant effects in the short term. Finally, the empirical evidence on the distributional consequences of copayment indicates that individuals with low income and in particular need of care generally reduce their use relatively more than the remaining population in consequence of copayment. Hence, it is clear that copayment involves some important economic and political trade-offs. PMID- 23989939 TI - The effect of sea anemone (H. magnifica) venom on two human breast cancer lines: death by apoptosis. AB - Venom from the sea anemone, Heteractis magnifica, has multiple biological effects including, cytotoxic, cytolytic and hemolytic activities. In this study, cytotoxicity induced by H. magnifica venom was investigated using the crystal violet assay on human breast cancer T47D and MCF7 cell lines and normal human breast 184B5 cell line. Apoptosis was also assayed via Annexin V-flourescein isothiocyanate and propidium iodide (PI) staining followed by flow cytometric analysis. Cell cycle progression and mitochondria membrane potential were studied via flow cytometry following PI and JC-1 staining respectively. H. magnifica venom induced significant reductions in viable cell numbers and increases in apoptosis in T47D and MCF7 in dose-dependent manners. A significant apoptosis related increase in the sub G1 peak of the cell cycle in both breast cancer cell lines was also observed. Moreover, treatment by venom cleaved caspase-8, caspase 9, and activated caspase-3. Overall, H. magnifica venom was highly cytotoxic to T47D and MCF7 human breast cancer cells, and the phenomenon could be the killing phenomenon via the death receptor-mediated and the mitochondria-mediated apoptotic pathways. Consequently, H. magnifica venom has potential for the development of a breast cancer therapeutic. PMID- 23989940 TI - Identification of the pivotal role of glutamate in enhancing insect cell growth using factor analysis. AB - Although the insect cell/baculovirus system is an important expression platform for recombinant protein production, our understanding of insect cell metabolism with respect to enhancing cell growth capability and productivity is still limited. Moreover, different host insect cell lines may have different growth characteristics associated with diverse product yields, which further hampers the elucidation of insect cell metabolism. To address this issue, the growth behaviors and utilization profiles of common metabolites among five cultured insect cell lines (derived from two insect hosts, Spodoptera frugiperda and Spodoptera exigua) were investigated in an attempt to establish a metabolic framework that can interpret the different cell growth behaviors. To analyze the complicated metabolic dataset, factor analysis was introduced to differentiate the crucial metabolic variations among these cells. Factor analysis was used to decompose the metabolic data to obtain the underlying factors with biological meaning that identify glutamate (a metabolic intermediate involved in glutaminolysis) as a key metabolite for insect cell growth. Notably, glutamate was consumed in significant amounts by fast-growing insect cell lines, but it was produced by slow-growing lines. A comparative experiment using cells grown in culture media with and without glutamine (the starting metabolite in glutaminolysis) was conducted to further confirm the pivotal role of glutamate. The factor analysis strategy allowed us to elucidate the underlying structure and inter-correlation between insect cell growth and metabolite utilization to provide some insights into insect cell growth and metabolism, and this strategy can be further extended to large-scale metabolomic analysis. PMID- 23989941 TI - Factors associated with time to diagnosis in early rheumatoid arthritis. AB - Early diagnosis and treatment yield optimal outcomes in rheumatoid arthritis (RA); thus, barriers to disease recognition must be identified and addressed. We determined the impact of sociodemographic factors, medical comorbidities, family history, and disease severity at onset on the time to diagnosis in early RA. The Canadian early ArThritis CoHort study data on 1,142 early RA patients were analyzed for predictors of time to diagnosis using regression analysis. Sociodemographic factors (age, sex, income strata, education, ethnicity), measures of disease activity (joint counts, DAS28 score, acute-phase reactants, patient global evaluation, function), family history, serology, chronic musculoskeletal and mental health conditions, and obesity at diagnosis were considered. In multivariate linear regression analysis, more swollen joints (beta = -0.047 per joint, 95 % CI -0.085, -0.010, p = 0.014), higher erythrocyte sedimentation rate (ESR) (beta = -0.012 per 1 mm/h, 95 % CI -0.022, -0.002, p = 0.0018), and worse patient global scores (beta = -0.082 per 1 unit on a visual analogue scale, 95 % CI -0.158, -0.006, p = 0.034) at baseline predicted a shorter time to diagnosis. Anti-cyclic citrullinated peptide (anti-CCP) antibody positivity (beta = 0.688, 95 % CI 0.261, 1.115, p = 0.002) and low income (annual <$20,000 beta = 1.185, 95 % CI 0.227, 2.143, p = 0.015; annual $20,000-50,000 beta = 0.933, 95 % CI 0.069, 1.798, p = 0.034) increased time to diagnosis. In the logistic regression models, the odds of being diagnosed within 6 months of symptom onset were increased for each swollen joint present [odds ratio (OR) 1.04, 95 % CI 1.02-1.06 per joint], each 1 mm/h elevation in the ESR (OR 1.01, 95 % CI 1.00-1.02), and decreased for patients who were either rheumatoid factor or anti-CCP positive compared to both factors being negative (OR 0.68, 95 % CI 0.51 0.91). Higher disease activity results in a more rapid diagnosis for Canadian patients with early RA, but those with lower income have delays in diagnosis. Strategies to identify patients with a less severe disease presentation and in lower socioeconomic strata are needed to ensure equal opportunity for optimal management. PMID- 23989942 TI - Long-term outcome of laparoscopic-assisted right-hemicolectomy with D3 lymphadenectomy versus open surgery for colon carcinoma. AB - PURPOSE: To investigate the applicability, safety, short-term and long-term outcomes of laparoscopic surgery in the treatment of right-sided colon carcinomas with D3 lymphadenectomy. METHODS: Between June 2003 and September 2010, 324 patients with right-sided colon carcinoma underwent surgical treatment in the same hospital, 177 cases were treated by laparoscopic surgery (LRH group) and 147 cases by open surgery (ORH group). We performed a retrospective analysis of the differences between the two groups in terms of the clinical data. RESULTS: There were no significant differences between the two groups in the demographic data; however, the recovery time was significantly shorter in the LRH group, the number of overall lymph nodes harvested and principle lymph nodes harvested in the LRH group was significantly higher than in the ORH group, the incidence of postoperative complications was 12.99 % in the LRH group and 22.45 % in the ORH group (P < 0.05), and the recurrence rate in the LRH group was lower than that in the ORH group, although the difference was not significant (15.25 vs 19.73 %). The cumulative overall survival for all stages at 1, 3 and 5 years in the LRH group (97.18, 83.73 and 70.37 %) were not significantly different compared to those in the ORH group (94.56, 77.84 and 66.97 %). CONCLUSIONS: Laparoscopic assisted right hemicolectomy with D3 lymphadenectomy for colon carcinomas is safe and effective, while it is also superior to open surgery regarding the short-term outcomes, and the long-term outcomes are similar to those of open surgery. PMID- 23989943 TI - Surgical strategies for esophageal cancer associated with head and neck cancer. AB - Esophageal cancer is frequently associated with squamous cell carcinoma in the head and neck. Both cigarette smoking and alcohol consumption are risk factors for multiple cancers of the head and neck, as well as the esophagus. Routine screening and close follow-up for second cancers are important in patients with esophageal cancer or head and neck cancer. For this purpose, endoscopy with Lugol's staining, as well as narrow-band imaging combined with magnifying endoscopy, is a powerful tool for the early detection of esophageal cancer. Multimodal therapy is essential for patients with double cancers. When considering surgical treatment, the curability of both cancers must be carefully evaluated. If both tumors are potentially curable, each lesion should be treated individually. In patients with metachronous double cancers, the prior treatment of the first primary carcinoma often affects the treatment of the second cancer. Close cooperation among medical staff members is essential for complicated surgeries for double cancers. Techniques that are appropriate for each case must be adopted, such as careful dissection, staged operations, muscular flaps and microvascular anastomosis. PMID- 23989945 TI - Is community treatment best? a randomised trial comparing delivery of cancer treatment in the hospital, home and GP surgery. AB - BACKGROUND: Care closer to home is being explored as a means of improving patient experience as well as efficiency in terms of cost savings. Evidence that community cancer services improve care quality and/or generate cost savings is currently limited. A randomised study was undertaken to compare delivery of cancer treatment in the hospital with two different community settings. METHODS: Ninety-seven patients being offered outpatient-based cancer treatment were randomised to treatment delivered in a hospital day unit, at the patient's home or in local general practice (GP) surgeries. The primary outcome was patient perceived benefits, using the emotional function domain of the EORTC quality of life (QOL) QLQC30 questionnaire evaluated after 12 weeks. Secondary outcomes included additional QOL measures, patient satisfaction, safety and health economics. RESULTS: There was no statistically significant QOL difference between treatment in the combined community locations relative to hospital (difference of -7.2, 95% confidence interval: -19.5 to +5.2, P=0.25). There was a significant difference between the two community locations in favour of home (+15.2, 1.3 to 29.1, P=0.033). Hospital anxiety and depression scale scores were consistent with the primary outcome measure. There was no evidence that community treatment compromised patient safety and no significant difference between treatment arms in terms of overall costs or Quality Adjusted Life Year. Seventy-eight percent of patients expressed satisfaction with their treatment whatever their location, whereas 57% of patients preferred future treatment to continue at the hospital, 81% at GP surgeries and 90% at home. Although initial pre-trial interviews revealed concerns among health-care professionals and some patients regarding community treatment, opinions were largely more favourable in post-trial interviews. INTERPRETATION: Patient QOL favours delivering cancer treatment in the home rather than GP surgeries. Nevertheless, both community settings were acceptable to and preferred by patients compared with hospital, were safe, with no detrimental impact on overall health-care costs. PMID- 23989944 TI - Tumour cell lysate-loaded dendritic cell vaccine induces biochemical and memory immune response in castration-resistant prostate cancer patients. AB - BACKGROUND: Recently, we produced a tumour antigen-presenting cells (TAPCells) vaccine using a melanoma cell lysate, called TRIMEL, as an antigen source and an activation factor. Tumour antigen-presenting cells induced immunological responses and increased melanoma patient survival. Herein, we investigated the effect of TAPCells loaded with prostate cancer cell lysates (PCCL) as an antigen source, and TRIMEL as a dendritic cell (DC) activation factor; which were co injected with the Concholepas concholepas haemocyanin (CCH) as an adjuvant on castration-resistant prostate cancer (CRPC) patients. METHODS: The lysate mix capacity, for inducing T-cell activation, was analysed by flow cytometry and Elispot. Delayed-type hypersensitivity (DTH) reaction against PCCL, frequency of CD8(+) memory T cells (Tm) in blood and prostate-specific antigen (PSA) levels in serum were measured in treated patients. RESULTS: The lysate mix induced functional mature DCs that were capable of activating PCCL-specific T cells. No relevant adverse reactions were observed. Six out of 14 patients showed a significant decrease in levels of PSA. DTH(+) patients showed a prolonged PSA doubling-time after treatment. Expansion of functional central and effector CD8(+) Tm were detected. CONCLUSION: Treatment of CRPC patients with lysate loaded TAPCells and CCH as an adjuvant is safe: generating biochemical and memory immune responses. However, the limited number of cases requires confirmation in a phase II clinical trial. PMID- 23989946 TI - An external validation study of nomograms designed to predict isolated loco regional and distant endometrial cancer recurrences: how applicable are they? AB - BACKGROUND: To externally validate and assess the robustness of two nomograms to predict the recurrence risk of women with endometrial cancer (EC). METHODS: Using an independent, multicentre external patient cohort we assessed the discrimination and calibration of two nomograms--the 3-year isolated loco regional (ILRR) and distant (DR) recurrence nomograms--in women with surgically treated stage I-III EC. RESULTS: Two hundred and seventy one eligible women were identified from two university hospital databases and the Senti-Endo trial. The median follow-up and initial recurrence time were 38.1 (range: 12-69) and 22.0 (range: 8.3-55) months, respectively. The overall recurrence rate was 13.8% (37 out of 271). Predictive accuracy according to the discrimination was 0.69 (95% CI, 0.58-0.79) and 0.66 (95% CI, 0.60-0.71) for the 3-year ILRR and DR nomograms, respectively. The correspondence between observed recurrence rate and the nomogram predictions suggests a moderate calibration of the nomograms in the validation cohort. CONCLUSION: The nomograms were externally validated and shown to be partly generalisable to a new and independent patient population. The tools need to be improved by including information on the lymph node status and adjuvant therapies. PMID- 23989947 TI - Phase I-II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma. AB - BACKGROUND: This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma. METHODS: The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single agent plitidepsin 3.2 mg m(-2) (n = 20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(-2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m( 2) q4wk (n = 38). RESULTS: The overall response rate with plitidepsin/DTIC was 21.4%; all responders had normal serum lactate dehydrogenase (LDH) levels and performance status <= 1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug-drug pharmacokinetic interactions were found. CONCLUSION: This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(-2) fortnightly and DTIC 800 mg m(-2) q4wk is recommended. PMID- 23989948 TI - Colorectal cancer screening: factors associated with colonoscopy after a positive faecal occult blood test. AB - BACKGROUND: Contextual socio-economic factors, health-care access, and general practitioner (GP) involvement may influence colonoscopy uptake and its timing after positive faecal occult blood testing (FOBT). Our objectives were to identify predictors of delayed or no colonoscopy and to assess the role for GPs in colonoscopy uptake. METHODS: We included all residents of a French district with positive FOBTs (n = 2369) during one of the two screening rounds (2007 2010). Multilevel logistic regression analysis was performed to identify individual and area-level predictors of delayed colonoscopy, no colonoscopy, and no information on colonoscopy. RESULTS: A total of 998 (45.2%) individuals underwent early, 989 (44.8%) delayed, and 102 (4.6%) no colonoscopy; no information was available for 119 (5.4%) individuals. Delayed colonoscopy was independently associated with first FOBT (odds ratio, (OR)), 1.61; 95% confidence interval ((95% CI), 1.16-2.25); and no colonoscopy and no information with first FOBT (OR, 2.01; 95% CI, 1.02-3.97), FOBT kit not received from the GP (OR, 2.29; 95% CI, 1.67-3.14), and socio-economically deprived area (OR, 3.17; 95% CI, 1.98 5.08). Colonoscopy uptake varied significantly across GPs (P=0.01). CONCLUSION: Socio-economic factors, GP-related factors, and history of previous FOBT influenced colonoscopy uptake after a positive FOBT. Interventions should target GPs and individuals performing their first screening FOBT and/or living in socio economically deprived areas. PMID- 23989949 TI - PTEN deficiency is associated with reduced sensitivity to mTOR inhibitor in human bladder cancer through the unhampered feedback loop driving PI3K/Akt activation. AB - BACKGROUND: Preclinical studies have shown that PTEN loss enhances sensitivity to mammalian target of Rapamycin (mTOR) inhibitors because of facilitated PI3K (phosphatidylinositol-3 kinase)/Akt activation and consecutive stimulation of the mTOR pathway. In patients with advanced transitional cell carcinoma (TCC) treated with the mTOR inhibitor everolimus, PTEN loss was, however, associated with resistance to treatment. METHODS: Transitional cell carcinoma specimens, human bladder cancer cells and derived mouse xenografts were used to evaluate how the PTEN status influences the activity of mTOR inhibitors. RESULTS: Transitional cell carcinoma patients with a shorter progression-free survival under everolimus exhibited PTEN deficiency and increased Akt activation. Moreover, PTEN-deficient bladder cancer cells were less sensitive to rapamycin than cells expressing wild type PTEN, and rapamycin strikingly induced Akt activation in the absence of functional PTEN. Inhibition of Akt activation by the PI3K inhibitor wortmannin interrupted this rapamycin-induced feedback loop, thereby enhancing the antiproliferative effects of the mTOR inhibitor both in vitro and in vivo. CONCLUSION: Facilitation of Akt activation upon PTEN loss can have a more prominent role in driving the feedback loop in response to mTOR inhibition than in promoting the mTOR pathway. These data support the use of both PI3K and mTOR inhibitors to treat urothelial carcinoma, in particular in the absence of functional PTEN. PMID- 23989951 TI - The latency period of mesothelioma among a cohort of British asbestos workers (1978-2005). AB - BACKGROUND: The Great Britain (GB) Asbestos Survey is a prospective cohort of asbestos workers in GB. The objective of this study was to investigate determinants of mesothelioma latency, paying particular attention to indicators of intensity of asbestos exposure such as occupation, sex, and presence of asbestosis. METHODS: The analysis included members of the cohort who died with mesothelioma between 1978 and 2005. The primary outcome was the latency period defined as the time from first occupational exposure to asbestos to death with mesothelioma. Generalised gamma accelerated failure-time models were used to estimate time ratios (TRs). RESULTS: After excluding missing data, there were 614 workers who died with mesothelioma between 1978 and 2005. Total follow-up time was 9280 person-years, with a median latency of 22.8 years (95% confidence interval (CI) 16.0-27.2 years). In the fully adjusted model, latency was around 29% longer for females compared with males (TR=1.29, 95% CI=1.18-1.42), and 5% shorter for those who died with asbestosis compared with those who did not (TR=0.95, 95% CI=0.91-0.99). There was no evidence of an association between latency and occupation. CONCLUSION: This study did not find sufficient evidence that greater intensity asbestos exposures would lead to shorter mesothelioma latencies. PMID- 23989950 TI - Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours. AB - BACKGROUND: Treatment options for patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs) are still limited. We investigated the antitumour activity and safety profile of pazopanib--a multitarget drug with anti angiogenic activity in patients with metastatic GEP NETs. METHODS: This was a nonrandomised, open-labeled, single-center phase II study. Pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The primary end point was an objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST). The secondary end points were progression-free survival (PFS), overall survival (OS) and safety. An independent review of objective response was planned. The trial is registered with ClinicalTrials.gov, NCT number 01099540. Correlative biomarker analyses were performed. RESULTS: Between April 2010 and February 2012, a total of 37 patients were enrolled. Thirty-two percent of the enrolled patients had pancreatic primary and 22% of the patients had colorectal primary NETs. This phase II study demonstrated an objective response rate of 18.9% (7 of the 37, 95% CI 8.0-35.2) and a disease control rate (CR+confirmed PR+stable disease) of 75.7% (28 of the 37, 95% CI, 58.8-88.2) in metastatic GEP NETs. The independent review demonstrated a higher overall response rate of 24.3% (95% CI, 11.8-41.2%) with nine confirmed PRs. CONCLUSION: Pazopanib showed a comparable efficacy to other targeted agents not only in pancreatic NETs but also in NETs originating from gastrointestinal (GI) tract. PMID- 23989953 TI - Evolution. What, where, and when? PMID- 23989954 TI - Observation of Dirac node formation and mass acquisition in a topological crystalline insulator. AB - In topological crystalline insulators (TCIs), topology and crystal symmetry intertwine to create surface states with distinct characteristics. The breaking of crystal symmetry in TCIs is predicted to impart mass to the massless Dirac fermions. Here, we report high-resolution scanning tunneling microscopy studies of a TCI, Pb(1-x)Sn(x)Se that reveal the coexistence of zero-mass Dirac fermions protected by crystal symmetry with massive Dirac fermions consistent with crystal symmetry breaking. In addition, we show two distinct regimes of the Fermi surface topology separated by a Van-Hove singularity at the Lifshitz transition point. Our work paves the way for engineering the Dirac band gap and realizing interaction-driven topological quantum phenomena in TCIs. PMID- 23989952 TI - Opposite feedbacks in the Hippo pathway for growth control and neural fate. AB - Signaling pathways are reused for multiple purposes in plant and animal development. The Hippo pathway in mammals and Drosophila coordinates proliferation and apoptosis via the coactivator and oncoprotein YAP/Yorkie (Yki), which is homeostatically regulated through negative feedback. In the Drosophila eye, cross-repression between the Hippo pathway kinase LATS/Warts (Wts) and growth regulator Melted generates mutually exclusive photoreceptor subtypes. Here, we show that this all-or-nothing neuronal differentiation results from Hippo pathway positive feedback: Yki both represses its negative regulator, warts, and promotes its positive regulator, melted. This postmitotic Hippo network behavior relies on a tissue-restricted transcription factor network including a conserved Otx/Orthodenticle-Nrl/Traffic Jam feedforward module-that allows Warts-Yki-Melted to operate as a bistable switch. Altering feedback architecture provides an efficient mechanism to co-opt conserved signaling networks for diverse purposes in development and evolution. PMID- 23989955 TI - Villification: how the gut gets its villi. AB - The villi of the human and chick gut are formed in similar stepwise progressions, wherein the mesenchyme and attached epithelium first fold into longitudinal ridges, then a zigzag pattern, and lastly individual villi. We find that these steps of villification depend on the sequential differentiation of the distinct smooth muscle layers of the gut, which restrict the expansion of the growing endoderm and mesenchyme, generating compressive stresses that lead to their buckling and folding. A quantitative computational model, incorporating measured properties of the developing gut, recapitulates the morphological patterns seen during villification in a variety of species. These results provide a mechanistic understanding of the formation of these elaborations of the lining of the gut, essential for providing sufficient surface area for nutrient absorption. PMID- 23989956 TI - Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. AB - Invasion of microbial DNA into the cytoplasm of animal cells triggers a cascade of host immune reactions that help clear the infection; however, self DNA in the cytoplasm can cause autoimmune diseases. Biochemical approaches led to the identification of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) as a cytosolic DNA sensor that triggers innate immune responses. Here, we show that cells from cGAS-deficient (cGas(-/-)) mice, including fibroblasts, macrophages, and dendritic cells, failed to produce type I interferons and other cytokines in response to DNA transfection or DNA virus infection. cGas(-/-) mice were more susceptible to lethal infection with herpes simplex virus 1 (HSV1) than wild-type mice. We also show that cGAMP is an adjuvant that boosts antigen-specific T cell activation and antibody production in mice. PMID- 23989957 TI - Structural and compositional properties of Er-doped silicon nanoclusters/oxides for multilayered photonic devices studied by STEM-EELS. AB - High resolution scanning transmission electron microscopy with an aberration corrected and monochromated instrument has been used for the assessment of the silicon-based active layer stack for novel optoelectronic devices. This layer contains a multilayer structure consisting of alternate thin layers of pure silica (SiO2) and silicon-rich silicon oxide (SRO, SiOx). Upon high temperature annealing the SRO sublayer segregates into a Si nanocluster (Si-nc) precipitated phase and a SiO2 matrix. Additionally, erbium (Er) ions have been implanted and used as luminescent centres in order to obtain narrow emission at 1.54 MUm. Our study exploits the combination of high angle annular dark field (HAADF) imaging with a sub-nanometer electron probe and electron energy loss spectroscopy (EELS) with an energy resolution below 0.2 eV. The structural and chemical information is obtained from the studied multilayer structure. In addition, the instrumental techniques for calibration, deconvolution, fitting and analysis of the EELS spectra are explained in detail. The spatial distribution of the Si-nanoclusters (Si-ncs) and the SiO2 barriers is accurately delimited in the multilayer. Additionally, the quality of the studied multilayer in terms of composition, roughness and defects is analysed and discussed. Er clusterization has not been observed; even so, blue-shifted plasmon and interband transition energies for silica are measured, in the presence of Er ions and sizable nanometer-size effects. PMID- 23989958 TI - Cytoplasmic RNA: a case of the tail wagging the dog. AB - The addition of poly(A) tails to eukaryotic nuclear mRNAs promotes their stability, export to the cytoplasm and translation. Subsequently, the balance between exonucleolytic deadenylation and selective re-establishment of translation-competent poly(A) tails by cytoplasmic poly(A) polymerases is essential for the appropriate regulation of gene expression from oocytes to neurons. In recent years, surprising roles for cytoplasmic poly(A) polymerase related enzymes that add uridylyl, rather than adenylyl, residues to RNA 3' ends have also emerged. These terminal uridylyl transferases promote the turnover of certain mRNAs but also modify microRNAs, their precursors and other small RNAs to modulate their stability or biological functions. PMID- 23989959 TI - Molecular control of the NEMO family of ubiquitin-binding proteins. AB - Research over the past decade has revealed how NF-kappaB essential modulator (NEMO; also known as IKKgamma) regulates the IKKalpha-IKKbeta signalling axis in the innate immune system. The discovery that NEMO is a polyubiquitin-binding protein and that the IKK complex is modulated by other protein kinases that are themselves controlled by polyubiquitin chains has provided a deeper molecular understanding of the non-degradative roles of ubiquitylation. New mechanistic insights of NEMO and related polyubiquitin-binding proteins have become a paradigm for how the interplay between phosphorylation and ubiquitylation controls cell signalling networks in health and disease. PMID- 23989961 TI - A novel approach to partition central and peripheral airway nitric oxide. AB - BACKGROUND: Determining the site of airways inflammation may lead to the targeting of therapy. Nitric oxide (NO) is a biomarker of airway inflammation and can be measured at multiple exhalation flow rates to allow partitioning into bronchial (large/central airway maximal nitric oxide flux [J'awno]) and peripheral (peripheral/small airway/alveolar nitric oxide concentration [Cano]) airway contributions by linear regression. This requires a minimum of three exhalations. We developed a simple and practical method to partition NO. METHODS: In 29 healthy subjects (FEV1, 97% +/- 3% predicted), 13 patients with asthma (FEV1, 90% +/- 4% predicted), 14 patients with COPD (FEV1, 59% +/- 3% predicted), and 12 patients with cystic fibrosis (CF) (FEV1, 60% +/- 3% predicted), we measured the area under the curve of the NO concentration/exhalation time plot (AUC-NO) at exhalation flow rates of 50, 100, 200, and 300 mL/s. We determined the change of the total AUC-NO production (DeltaAUC-NO) among the four different exhalation flow rates and compared these levels to Cano and J'awno indices measured conventionally by linear regression. RESULTS: The change in AUC-NO between increasing exhalation flow rates of 50 to 200 mL/s (DeltaAUC-NO50-200) was strongly correlated with J'awno in all patient groups as follows: healthy subjects (r = 0.94, P < .001), patients with asthma (r = 0.98, P < .001), patients with COPD (r = 0.93, P < .001), and patients with CF (r = 0.74, P < .05). In all subjects, AUC-NO at an exhalation flow rate of 200 mL/s (AUC-NO200) correlated with Cano (r = 0.69, P < .01). CONCLUSIONS: The bronchial production of NO can be determined by measuring DeltaAUC-NO50-200, whereas AUC-NO200 measures its peripheral concentration. This approach is simple, quick, and does not require sophisticated equipment or mathematical models. PMID- 23989960 TI - The RNA exosome and proteasome: common principles of degradation control. AB - Defective RNAs and proteins are swiftly degraded by cellular quality control mechanisms. A large fraction of their degradation is mediated by the exosome and the proteasome. These complexes have a similar architectural framework based on cylindrical, hollow structures that are conserved from bacteria and archaea to eukaryotes. Mechanistic similarities have also been identified for how RNAs and proteins are channelled into these structures and prepared for degradation. Insights gained from studies of the proteasome should now set the stage for elucidating the regulation, assembly and small-molecule inhibition of the exosome. PMID- 23989962 TI - [Pre-existing pain as comorbidity in postoperative acute pain service]. AB - BACKGROUND: Pre-existing or chronic pain is a relevant risk factor for severe postoperative pain. The prevalence of pre-existing and chronic pain in hospital depends on the time definition used and is approximately 44 % and 33%, at 3 or 6 months, respectively. The aim of this study was to determine the prevalence and importance of pre-existing pain in patients treated by a postoperative acute pain service (APS) and to evaluate the requirements for treatment and resources as well as its quality in this context. MATERIAL AND METHODS: This study involved an evaluation of all visits by the APS of the University Hospital in Gottingen over an 8-week period including patient subjective quality assessment on the basis of the quality improvement in postoperative pain therapy (QUIPS) questionnaire. Pre existing pain (>12 weeks) was assessed by recording patients history of pain by members of the APS. The results from patients with and without pre-existing pain were compared. RESULTS: A total of 128 patients (38% female, 62% male, aged 15-88 years old, mean age 59.8 +/- 14.4 years) were seen by the APS on 633 occasions. Of these patients 91% had been admitted to hospital for surgery (66% for tumor surgery, 8% joint replacement, 9% other joint surgery and 16% other interventions), 50% had acute postoperative pain without pre-existing pain, 50% had had pre-existing pain for at least 12 weeks, 31% had chronic non-cancer pain and 19% pain possibly related to cancer. Patients with pre-existing pain showed no significant differences in the treatment requirements (e.g. adjustment of medication), use of resources (e.g. number of visits to the APS and time spent in hospital) and quality of care (e.g. pain intensity, functional aspects, side effects and complications) in the setting of the APS. However, there was an additional subsequent support by chronic pain and palliative care services. CONCLUSION: Pre-existing pain is a common comorbidity in surgery patients treated by the APS. There were no significant differences in treatment requirements and quality of care between the patients. This is in contrast to other studies of postoperative pain management which showed that patients with pre-existing postoperative pain had higher pain intensity. This indicates indirectly that the presence of pre-existing pain should be further evaluated as a potentially useful indication for the support by an APS. However there is an urgent need for further studies to clarify whether this indirect effect can be replicated at other hospitals or in other patient collectives. Also it has to be clarified what benefits pain patients have from this kind of treatment: if they benefit from the APS in general or from the special technique, if there is a long-term effect lasting beyond treatment in the APS or if this group of patients would benefit in general from multiprofessional and non-invasive concepts of acute pain treatment. PMID- 23989963 TI - [Endovascular interventions in neuroradiology : New aspects]. AB - In the last 10 years interventional neuroradiology has become established especially in the endovascular treatment of aneurysms as the preferred treatment according to level 1 evidence and more recently in the treatment of acute ischemic stroke. These interventions are performed as routine procedures in an increasing number of centers. This, however, necessitates that anesthesiologists and neuroradiologists become increasingly more familiar with the complementary expectations and potential pitfalls in working together to maximise efficiency and patient safety. As a further challenge there are different aspects to be considered in elective procedures and emergency procedures where time is brain. This article highlights these aspects for the two most common procedures: aneurysm treatment and multimodal recanalization treatment for acute ischemic stroke. PMID- 23989964 TI - Diffusion of carbon monoxide through gypsum wallboard. PMID- 23989965 TI - Quantitative turbidity assay for lipolytic enzymes in microtiter plates. AB - A clearing assay for lipolytic enzymes has been realized in 96-well microtiter plates. A thin layer containing emulsified tributyrin as turbidity-generating substrate was placed on a thicker supporting aqueous layer. Both layers were stabilized by a gel-forming agent. Enzyme addition leads to clearing of the emulsion detected with a standard microtiter plate reader as a decrease of extinction. Dependencies of the signal kinetics on the substrate and enzyme concentrations were studied. For 0.5-1% tributyrin content the reaction rate is not substrate-limited. An initial slope of the signal kinetics is proportional to the lipase activity. A detailed characterization of the assay was performed. Lipolysis of tributyrin was confirmed by glycerol detection. Various gel-forming agents were compared and diffusion conditions in these gels were analyzed. Agar and agarose were found to be the most suitable gel-forming agents, which do not affect enzyme diffusion whereas polyacrylamide gels block lipase diffusion and therefore are not suitable for the assay. The optimized assay prepared from 1% tributyrin emulsion in 2% agar gel was tested with six microbial lipases and porcine pancreatic lipase. The detection limit is 20-60 ng/well which is equivalent to 30 MUU/well for T. lanuginosus lipase. PMID- 23989966 TI - Sputtered alumina as a novel stationary phase for micro machined gas chromatography columns. AB - Silica and graphite sputtering have previously been reported as novel solid stationary phase deposition techniques for micro gas chromatography columns. As a conventional solid stationary phase in gas chromatography, compatible with sputtering yet so far unreported, alumina was evaluated in this study. Alumina sputtered semi-packed micro columns were fabricated (including an activation step) and proved able to separate a mixture of volatile alkanes (C1-C4 with isomers) in less than 1 min. Kinetic and a thermodynamic evaluation led to calculation of 4,500 theoretical plates for ethane in 1.1 m (HETPmin = 250 MUm) and a Gibbs free energy for propane of 30.2 kJ mol(-1), making this stationary phase's properties very close to those observed with silica-sputtered micro columns. PMID- 23989967 TI - Pharmacokinetics of desmopressin administered as tablet and oral lyophilisate formulation in children with monosymptomatic nocturnal enuresis. AB - Desmopressin 120 MUg oral lyophilisate and 200 MUg tablet are considered bioequivalent, based on extrapolation of studies in a limited number of adults and on one dose-finding study of desmopressin oral lyophilisate in children. However, no comparative pharmacokinetic study in children was executed confirming this statement. No data are available on the influence of food intake on the bioavailability of desmopressin tablet in a pediatric setting, although studies in adults have documented that food intake results in a significantly lower desmopressin plasma concentration. In this study, we analyzed plasma concentrations of desmopressin oral lyophilisate and tablet with concomitant food intake. Twenty-three children with monosymptomatic nocturnal enuresis (mean age, 12.7 years) were recruited. Two tests were performed on two separate days in identical conditions with a standardized food and fluid intake. Desmopressin was administered as desmopressin tablet or desmopressin oral lyophilisate immediately after a meal. Desmopressin plasma concentration was measured at 1 h, 2 h, and 6 h postdosing. No significant difference in plasma concentration of 120 MUg desmopressin oral lyophilisate and 200 MUg tablet was demonstrated, even with concomitant food intake. A significant difference in variability was found, identifying a smaller variance for desmopressin oral lyophilisate plasma concentrations at all time points. This study demonstrates comparable plasma levels for desmopressin oral lyophilisate, despite the lower dose. The dosage for desmopressin oral lyophilisate is more predictable due to the significantly smaller variance. Therefore, desmopressin oral lyophilisate seems more suitable, especially in the younger age group for which time interval between dinner and drug administration is limited. PMID- 23989969 TI - Myoglobinuria as first clinical sign of a primary alpha-sarcoglycanopathy. AB - Myoglobinuria is a frequent complication of metabolic myopathies and may also occur in Duchenne and Becker dystrophies but is not a typical sign of limb-girdle muscular dystrophy. We describe an unusual presentation of alpha sarcoglycanopathy with myoglobinuria at the onset of the disease. The boy presented an episode of dark urine, identified as presence of blood by a urine dipstick, occurred 10 days after an episode of fever and sore throat treated with antibiotics. He was admitted to the hospital and investigated for post-infectious nephritis, but further analysis revealed the presence of myoglobinuria. Immunohistochemistry on muscle tissue revealed absent expression of alpha sarcoglycan confirmed by detection of a homozygous mutation in the alpha sarcoglycan gene. Myoglobinuria has been previously reported four times in sarcoglycanopathies but only once in alpha-sarcoglycanopathy. CONCLUSION: The present observation reinforces the idea that the myoglobinuria should be considered a manifestation of a primary sarcoglycanopathy even as the only recognizable sign at the debut of the disease. PMID- 23989970 TI - Manual lymphatic drainage in chronic venous disease: a duplex ultrasound study. AB - OBJECTIVES: To compare the effect of call-up and reabsorption maneuvers of manual lymphatic drainage on blood flow in femoral vein and great saphenous vein in patients with chronic venous disease and healthy controls. METHODS: Forty-one subjects participated in this study (mean age: 42.68(15.23)), 23 with chronic venous disease (chronic venous disease group) with clinical classification C1-5 of clinical-etiological-anatomical-pathological (CEAP) and 18 healthy subjects (control group). Call-up and reabsorption maneuvers were randomly applied in the medial aspect of the thigh. The cross-sectional areas, as well as the peak and the mean blood flow velocity at femoral vein and great saphenous vein, were assessed by Duplex ultrasound at the baseline and during maneuvers. The venous flow volume changes were calculated. RESULTS: The venous flow volume in femoral vein and great saphenous vein increased during both manual lymphatic drainage maneuvers and in both groups (P < 0.05). The two maneuvers had a similar effect on femoral vein and great saphenous vein hemodynamics, and in both the chronic venous disease and control groups. As a result of the call-up maneuver, the flow volume augmentations, as a result of call-up maneuver, decreased with the severity of chronic venous disease in those patients measured by the clinical classification of CEAP (r = -0.64; P = 0.03). CONCLUSIONS: Manual lymphatic drainage increases the venous blood flow in the lower extremity with a magnitude that is independent from the specific maneuver employed or the presence of chronic venous disease. Therefore, manual lymphatic drainage may be an alternative strategy for the treatment and prevention of venous stasis complications in chronic venous disease. PMID- 23989971 TI - 1064 nm Nd:YAG long pulse laser after polidocanol microfoam injection dramatically improves the result of leg vein treatment: a randomized controlled trial on 517 legs with a three-year follow-up. AB - OBJECTIVE: To assess the efficacy and safety of a new method of clearing varicose veins in the long term. It consists of applying the long-pulsed Nd:YAG laser following the injection of polidocanol microfoam, in two consecutive sessions, treating both legs in full in each session. METHOD: Randomized, Polidocanol controlled, blind evaluation clinical trial comparing the results between 79 legs treated with Polidocanol and 517 treated with Polidocanol + Laser. Photographs were taken preoperatively and at three months, two years and three years after treatment, as well as patient self-assessments. RESULTS: Polidocanol + Laser is much more effective than polidocanol microfoam in clearing venulectasias with a diameter under 4 mm (p < 0.001). After three years, clearing percentages of 89% (Class I veins), 94% (Class II veins) and 95% (Class III veins) are observed, in comparison to 15%, 18% and 17%, respectively when only polidocanol was applied. No unexpected adverse effects were found and 86% of patients stated they were Satisfied or Very Satisfied. CONCLUSION: The method leads to safe, fast and apparently permanent results. The treatment session lasts less than 1 h, and could become a first-choice treatment for the removal of all types of varicose veins with a diameter under 4 mm. PMID- 23989972 TI - Probing the transmembrane structure and topology of microsomal cytochrome-p450 by solid-state NMR on temperature-resistant bicelles. AB - Though the importance of high-resolution structure and dynamics of membrane proteins has been well recognized, optimizing sample conditions to retain the native-like folding and function of membrane proteins for Nuclear Magnetic Resonance (NMR) or X-ray measurements has been a major challenge. While bicelles have been shown to stabilize the function of membrane proteins and are increasingly utilized as model membranes, the loss of their magnetic-alignment at low temperatures makes them unsuitable to study heat-sensitive membrane proteins like cytochrome-P450 and protein-protein complexes. In this study, we report temperature resistant bicelles that can magnetically-align for a broad range of temperatures and demonstrate their advantages in the structural studies of full length microsomal cytochrome-P450 and cytochrome-b5 by solid-state NMR spectroscopy. Our results reveal that the N-terminal region of rabbit cytochrome P4502B4, that is usually cleaved off to obtain crystal structures, is helical and has a transmembrane orientation with ~17 degrees tilt from the lipid bilayer normal. PMID- 23989974 TI - In vivo efficacy and synergistic interaction of 16alpha-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide, a clerodane diterpene from Polyalthia longifolia against methicillin-resistant Staphylococcus aureus. AB - The Staphylococcus aureus bacterium, a nosocomial pathogen often causing untreatable and lethal infection in patients, mutated to become resistant to all the first-line drugs. The present study details the potential of clerodane diterpene 16alpha-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide (CD) isolated from Polyalthia longifolia against methicillin-resistant S. aureus (MRSA) through in vitro and in vivo assays. Minimum inhibitory concentration (MIC) of CD exhibited significant anti-MRSA activity (15.625-31.25 mg/l) against reference strain and seven clinical isolates, while time kill assays at graded MICs indicated 2.78-9.59- and 2.9-6.18-fold reduction in growth of reference strain and clinical isolates of S. aureus, respectively. The combined effect of the CD and 7.5 % NaCl resulted in significant reduction in microbial count within 24 h, indicating the loss of the salt tolerance ability of S. aureus. Further, release of 260-nm absorbing material and flow cytometric analysis revealed an increased uptake of propidium iodide. These assays may indicate the membrane-damaging potential of CD. The molecule CD was found to interact synergistically with clinically used antibiotics (FICI <= 0.5) against all clinical isolates. In infected mice, CD significantly (P < 0.001) lowered the systemic microbial load in blood, liver, kidney, lung and spleen tissues and did not exhibit any significant toxicity at 100 mg/kg body weight. PMID- 23989973 TI - Microbial community structure of a pilot-scale thermophilic anaerobic digester treating poultry litter. AB - The microbial community structure of a stable pilot-scale thermophilic continuous stirred tank reactor digester stabilized on poultry litter was investigated. This 40-m(3) digester produced biogas with 57% methane, and chemical oxygen demand removal of 54%. Bacterial and archaeal diversity were examined using both cloning and pyrosequencing that targeted 16S rRNA genes. The bacterial community was dominated by phylum Firmicutes, constituting 93% of the clones and 76% of the pyrotags. Of the Firmicutes, class Clostridia (52% pyrotags) was most abundant followed by class Bacilli (13% pyrotags). The bacterial libraries identified 94 operational taxonomic units (OTUs) and pyrosequencing identified 577 OTUs at the 97% minimum similarity level. Fifteen OTUs were dominant (>=2% abundance), and nine of these were novel unclassified Firmicutes. Several of the dominant OTUs could not be classified more specifically than Clostridiales, but were most similar to plant biomass degraders, including Clostridium thermocellum. Of the rare pyrotag OTUs (<0.5% abundance), 75% were Firmicutes. The dominant methanogen was Methanothermobacter which has hydrogenotrophic metabolism, and accounted for >99% of the archaeal clones. Based on the primary methanogen, as well as digester chemistry (high VA and ammonia levels), we propose that bacterial acetate oxidation is the primary pathway in this digester for the control of acetate levels. PMID- 23989976 TI - Development and characterization of essential oil component-based polymer films: a potential approach to reduce bacterial biofilm. AB - The development of new polymeric materials aimed to control the bacterial biofilm appears to be an important practical approach. The goal of the present study was to prepare and characterize poly(ethylene-co-vinyl acetate) copolymer (EVA) films containing citronellol, eugenol, and linalool and evaluate their efficiency on growth and biofilm formation of Listeria monocytogenes, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa in monospecies and dual species. The results showed that the addition of oil components influenced the elastic modulus (15 % decrease), the tensile stress (30 % decrease), the elongation at break (10 % increase), and the contact angle values (10-20 degrees decrease) while leaving the homogeneity of the surface unaltered. Among the polymeric films, EVA + citronellol and EVA + eugenol at 7 wt% had the best inhibitory effect. After 24-48 h of incubation, EVA + citronellol was more effective against the growth (30-60 % reduction) than EVA + eugenol (15-30 % inhibition). However, this inhibition decreased after 240 h of incubation. On the contrary, the biofilm evaluation revealed a strong inhibition trend also after prolonged incubation time: the amount of biomass per square centimeter formed on copolymer with oil components was significantly less (40-70 % decrease) than that on pure copolymer control for L. monocytogenes, S. aureus, and E. coli. When polymeric materials were simultaneously inoculated with combinations of S. aureus and E. coli, the biomass accumulated was higher for EVA + citronellol and lower for EVA + eugenol than that in monoculture biofilm. The findings were similar to the results obtained by 2,3-bis[2-methyloxy-4-nitro-5 sulfophenyl]-2H-tetrazolium-5-carboxanilide assay that measures the metabolic activity of viable cells. PMID- 23989975 TI - Changes in bacterial CO2 fixation with depth in agricultural soils. AB - Soils were incubated continuously in an atmosphere of (14)CO2 and the distribution of labeled C into soil organic carbon ((14)C-SOC) was determined at 0-1, 1-5, and 5-17 cm down the profile. Significant amounts of (14)C-SOC were measured in paddy soils with a mean of 1,180.6 +/- 105.2 mg kg(-1) at 0-1 cm and 135.3 +/- 47.1 mg kg(-1) at 1-5 cm. This accounted for 5.9 +/- 0.7% and 0.7 +/- 0.2%, respectively, of the total soil organic carbon at these depths. In the upland soils, the mean (14)C-SOC concentrations were 43 times (0-1 cm) and 11 times (1-5 cm) lower, respectively, than those in the paddy soils. The amounts of (14)C incorporated into the microbial biomass (MBC) were also much lower in upland soils (5.0 +/- 3.6% and 2.9 +/- 1.9% at 0-1 and 1-5 cm, respectively) than in paddy soils (34.1 +/- 12.4% and 10.2 +/- 2.1% at 0-1 and 1-5 cm, respectively). Similarly, the amount of (14)C incorporated into the dissolved organic carbon (DOC) was considerably higher in paddy soils (26.1 +/- 6.9% and 6.9 +/- 1.3% at 0-1 and 1-5 cm, respectively) than in upland soils (6.0 +/- 2.7% and 4.3 +/- 2.2%, respectively). The observation that the majority of the fixed (14)C-SOC, RubisCO activity and cbbL gene abundance were concentrated at 0-1 cm depth and the fact that light is restricted to the top few millimeters of the soil profiles highlighted the importance of phototrophs in CO2 fixation in surface soils. Phylogenetic analysis of the cbbL genes showed that the potential for CO2 fixation was evident throughout the profile and distributed between both photoautotrophic and chemoautotrophic bacteria such as Rhodopseudomonas palustris, Bradyrhizobium japonicum, Rubrivivax gelatinosus and Ralstonia eutropha. PMID- 23989977 TI - Chromosomal rearrangements in Tourette syndrome: implications for identification of candidate susceptibility genes and review of the literature. AB - Tourette syndrome (TS) is a childhood-onset complex neurobiological disorder characterized by a combination of persistent motor and vocal tics and frequent presence of other neuropsychiatric comorbidities. TS shares the fate of other complex disorders, where the genetic etiology is largely unknown, and identification of susceptibility genes through linkage and association studies has been complicated due to inherent difficulties such as no clear mode of inheritance, genetic heterogeneity, and apparently incomplete penetrance. Positional cloning through mapping of disease-related chromosome rearrangements has been an efficient tool for the cloning of disease genes in several Mendelian disorders and in a number of complex disorders. Through cytogenetic investigation of 205 TS patients, we identified three possibly disease-associated chromosome rearrangements rendering this approach relevant in chasing TS susceptibility genes. PMID- 23989978 TI - Nab-paclitaxel is an active drug in preclinical model of pediatric solid tumors. AB - PURPOSE: To investigate the antitumor effect of nab-paclitaxel, an albumin stabilized nanoparticle formulation of paclitaxel, on pediatric solid tumor models. EXPERIMENTAL DESIGN: A panel of three rhabdomyosarcoma, one osteosarcoma and seven neuroblastoma cell lines were exposed to increasing concentrations of nab-paclitaxel in vitro. Cell viability was evaluated using the Alamar Blue Assay. Antitumor effect was further assessed in vivo in NOD/SCID xenograft and metastatic neuroblastoma mouse models. Tumor sections were analyzed by immunohistochemistry for cleaved caspase-3 and phospho-histone H3. Plasma and intratumoral paclitaxel concentrations were measured by liquid chromatography mass spectrometry. Ratio of intratumoral and plasma concentration was compared between nab-paclitaxel and paclitaxel treatment groups. RESULTS: Nab-paclitaxel displayed significant cytotoxicity against most pediatric solid tumor cell lines in vitro in a dose-dependent manner. In vivo, nab-paclitaxel showed antitumor activity in both rhabdomyosarcoma (RH4 and RD) and neuroblastoma [SK-N-BE(2) and CHLA-20] xenograft models. In the SK-N-BE(2) metastatic model, nab-paclitaxel treatment significantly extended animal survival compared with control (P < 0.01). Nab-paclitaxel treatment induced tumor cell-cycle arrest and apoptosis in vivo. In the RH4 model, increased local relapse-free intervals were observed with nab-paclitaxel treatment (37.7 +/- 3.2 days) comparing with paclitaxel (13.6 +/- 2.07 days). Local relapsed tumors following paclitaxel treatment proved to be paclitaxel-resistant and remained responsive to nab-paclitaxel. Mechanistically, a higher tumor/plasma paclitaxel drug ratio in favor of nab-paclitaxel was observed. CONCLUSIONS: Nab-paclitaxel showed significant antitumor activity against all pediatric solid tumors associated with an enhanced drug intratumor delivery. Furthermore, testing of nab-paclitaxel in pediatric solid-tumor patient population is under development. PMID- 23989979 TI - A tumorigenic factor interactome connected through tumor suppressor microRNA-198 in human pancreatic cancer. AB - PURPOSE: The majority of pancreatic cancers overexpress mesothelin (MSLN), which contributes to enhanced proliferation, invasion, and migration. However, the MSLN regulatory network is still unclear. Here, we investigated the regulation of a panel of tumorigenic factors and explored the potential of MSLN-regulated miR-198 treatment in vivo. EXPERIMENTAL DESIGN: The expression and functional regulation of the tumorigenic factors MSLN, NF-kappaB, and the homeobox transcription factors (TF) POU2F2 (OCT-2), Pre-B-cell leukemia homeobox factor 1 (PBX-1), valosin-containing protein (VCP), and miR-198 were studied in pancreatic cancer cell lines, patient tumor samples, and xenograft pancreatic cancer mouse models. RESULTS: We found that miR-198 is downregulated in pancreatic cancer and is involved in an intricate reciprocal regulatory loop with MSLN, which represses miR-198 through NF-kappaB-mediated OCT-2 induction. Furthermore, miR-198 repression leads to overexpression of PBX-1 and VCP. The dysregulated PBX-1/VCP axis leads to increased tumorigenicity. Reconstitution of miR-198 in pancreatic cancer cells results in reduced tumor growth, metastasis, and increased survival through direct targeting MSLN, PBX-1, and VCP. Most interestingly, reduced levels of miR-198 in human tissue samples are associated with upregulation of these tumorigenic factors (MSLN, OCT-2, PBX-1, VCP) and predict poor survival. Reduced miR-198 expression links this tumor network signature and prognosticates poor patient outcome. High miR-198 disrupts the network and predicts better prognosis and increased survival. CONCLUSIONS: miR-198 acts as a central tumor suppressor and modulates the molecular makeup of a critical interactome in pancreatic cancer, indicating a potential prognostic marker signature and the therapeutic potential of attacking this tumorigenic network through a central vantage point. PMID- 23989980 TI - Inhibition of tumor growth and metastasis in non-small cell lung cancer by LY2801653, an inhibitor of several oncokinases, including MET. AB - PURPOSE: Lung cancer is the leading cause of cancer-related death worldwide. Sustained activation, overexpression, or mutation of the MET pathway is associated with a poor prognosis in a variety of tumors, including non-small cell lung cancer (NSCLC), implicating the MET pathway as a potential therapeutic target for lung cancer. Previously, we reported on the development of LY2801653: a novel, orally bioavailable oncokinase inhibitor with MET as one of its targets. Here, we discuss the evaluation of LY2801653 in both preclinical in vitro and in vivo NSCLC models. Experimental Design/ RESULTS: Treatment with LY2801653 showed tumor growth inhibition in tumor cell lines and patient-derived tumor xenograft models as a single agent (37.4%-90.0% inhibition) or when used in combination with cisplatin, gemcitabine, or erlotinib (66.5%-86.3% inhibition). Mechanistic studies showed that treatment with LY2801653 inhibited the constitutive activation of MET pathway signaling and resulted in inhibition of NCI-H441 cell proliferation, anchorage-independent growth, migration, and invasion. These in vitro findings were confirmed in the H441 orthotopic model where LY2801653 treatment significantly inhibited both primary tumor growth (87.9% inhibition) and metastasis (64.5% inhibition of lymph node and 67.7% inhibition of chest wall). Tumor-bearing animals treated with LY2801653 had a significantly greater survival time (87% increase compared with the vehicle-treated mice). In the MET independent NCI-H1299 orthotopic model, treatment with LY2801653 showed a significant inhibition of primary tumor growth but not metastasis. CONCLUSIONS: Collectively, these results support clinical evaluation of LY2801653 in NSCLCs and suggest that differences in the MET activation of tumors may be predictive of response. PMID- 23989982 TI - The link between past informal payments and willingness of the Hungarian population to pay formal fees for health care services: results from a contingent valuation study. AB - We examine the willingness of health care consumers to pay formal fees for health care use and how this willingness to pay is associated with past informal payments. We use data from a survey carried out in Hungary in 2010 among a representative sample of 1,037 respondents. The contingent valuation method is used to elicit the willingness to pay official charges for health care services covered by the social health insurance if certain quality attributes (regarding the health care facility, access to the services and health care personnel) are guaranteed. A bivariate probit model is applied to examine the relationship between willingness to pay and past informal payments. We find that 66% of the respondents are willing to pay formal fees for specialist examinations and 56% are willing to pay for planned hospitalizations if these services are provided with certain quality and access attributes. The act of making past informal payments for health care services is positively associated with the willingness to pay formal charges. The probability that a respondent is willing to pay official charges for health care services is 22% points higher for specialist examinations and 45% points higher for hospitalization if the respondent paid informally during the last 12 months. The introduction of formal fees should be accompanied by adequate service provision to assure acceptance of the fees. Furthermore, our results suggest that the problem of informal patient payments may remain even after the implementation of user fees. PMID- 23989983 TI - Streptacidiphilus hamsterleyensis sp. nov., isolated from a spruce forest soil. AB - Three acidophilic actinobacteria, isolates LSCA2, FGG8 and HSCA14(T), recovered from spruce litter were examined using a polyphasic approach. Chemotaxonomic and morphological properties of the isolates were found to be consistent with their classification in the genus Streptacidiphilus. The isolates were shown to have identical 16S rRNA gene sequences and were most closely related to Streptacidiphilus neutrinimicus DSM 41755(T) (99.9 % similarity). However, DNA:DNA relatedness between isolate HSCA14(T) and the type strain of S. neutrinimicus was found to be low at 44.0 (+/-14.1) %. A combination of phenotypic features, including degradative and nutritional characteristics were shown to distinguish the isolates from their nearest phylogenetic neighbours. Data from this study show that the isolates form a novel species in the genus for which the name S. hamsterleyensis sp. nov. is proposed. The type strain is HSCA 14(T) (=DSM 45900(T) = KACC 17456(T) = NCIMB 14865(T)). PMID- 23989984 TI - Does this patient have obstructive sleep apnea?: The Rational Clinical Examination systematic review. AB - IMPORTANCE: Obstructive sleep apnea is a common disease, responsible for daytime sleepiness. Prior to referring patients for definitive testing, the likelihood of obstructive sleep apnea should be established in the clinical examination. OBJECTIVE: To systematically review the clinical examination accuracy in diagnosing obstructive sleep apnea. DATA SOURCES: MEDLINE and reference lists from articles were searched from 1966 to June 2013. Titles and abstracts (n = 4449) were reviewed for eligibility and appraised for evidence levels. STUDY SELECTION: For inclusion, studies must have used full, attended nocturnal polysomnography for the reference standard (n = 42). MAIN OUTCOMES AND MEASURES: Community and referral-based prevalence of obstructive sleep apnea; accuracy of symptoms and signs for the diagnosis of obstructive sleep apnea. RESULTS: The prevalence of sleep apnea in community-screened patients is 2% to 14% (sample sizes 360-1741) and 21% to 90% (sample sizes 42-2677) for patients referred for sleep evaluation. The prevalence varies based on the apnea-hypopnea index (AHI) threshold used for the evaluation (>=5 events/h, prevalence 14%; >=15/h, prevalence 6%) and whether the disease definition requires symptoms in addition to an abnormal AHI (>=5/h with symptoms, prevalence 2%-4%). Among patients referred for sleep evaluation, those with sleep apnea weighed more (summary body mass index, 31.4; 95% CI, 30.5-32.2) than those without sleep apnea (summary BMI, 28.3; 95% CI, 27.6-29.0; P < .001 for the comparison). The most useful observation for identifying patients with obstructive sleep apnea was nocturnal choking or gasping (summary likelihood ratio [LR], 3.3; 95% CI, 2.1-4.6) when the diagnosis was established by AHI >=10/h). Snoring is common in sleep apnea patients but is not useful for establishing the diagnosis (summary LR, 1.1; 95% CI, 1.0-1.1). Patients with mild snoring and body mass index lower than 26 are unlikely to have moderate or severe obstructive sleep apnea (LR, 0.07; 95% CI, 0.03-0.19 at threshold of AHI >=15/h). CONCLUSIONS AND RELEVANCE: Nocturnal gasping or choking is the most reliable indicator of obstructive sleep apnea, whereas snoring is not very specific. The clinical examination of patients with suspected obstructive sleep apnea is useful for selecting patients for more definitive testing. PMID- 23989985 TI - Is TNF-alpha really involved in giant cell arteritis pathogenesis? PMID- 23989987 TI - Evidence in support of the validity of the TNF brake hypothesis. PMID- 23989990 TI - Multifunctional multisegmented Co/CoPt3 heterostructure nanowires. AB - Multisegmented (MS) Co/CoPt3 nanowires (NWs) have been successfully fabricated by a template-assisted pulsed electrodeposition process and the length of each Co and CoPt3 segment is controlled by the pulse durations. The MS NWs show both the characteristic surface plasmon absorption and catalytic properties of CoPt3 and the strong ferromagnetic properties of Co that are affected by the interactions between Co and CoPt3. Furthermore, the ferromagnetic, optical, and catalytic properties can be well modulated by mainly changing the length of the Co and CoPt3 segments, respectively. Such multifunction of MS nanowires can be exploited for recyclable catalysts and bioassays based on their magnetic-catalytic and magnetic-optical properties, respectively. PMID- 23989986 TI - A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip. AB - OBJECTIVES: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. METHODS: We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. RESULTS: We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9*10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6*10(-8)) and follow-up studies (p=7.3*10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9*10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2*10(-6), OR=1.27 in male specific analysis). CONCLUSIONS: Novel genetic loci for hip OA were found in this meta-analysis of GWAS. PMID- 23989995 TI - How I do it - selective amygdalohippocampectomy via subtemporal approach. AB - BACKGROUND: Surgery is superior over medicamentous treatment of pharmacoresistant mesial temporal lobe epilepsy caused by hippocampal sclerosis. The armamentarium of surgical procedures comprises standard temporal lobectomy and more selective procedures. Selective amygdalohippocampectomy can be performed via transcortical, transsylvian or subtemporal approach. METHOD: Describe the selective amygdalohippocampectomy through the subtemporal approach CONCLUSION: After the detailed preoperative epilepsy evaluation, surgery can be offered to pharmacoresistant epilepsy patient with hippocampal sclerosis. Selective amygdalohippocampectomy can be safely performed through the subtemporal approach. The good knowledge of the mesial temporal lobe anatomy is necessary when performing this procedure. PMID- 23989988 TI - An immunological biomarker to predict MTX response in early RA. AB - OBJECTIVES: The therapeutic goal for patients with rheumatoid arthritis (RA) is clinical remission. This is best achieved by early diagnosis and appropriate therapeutic intervention. RA is associated with dysregulation of T-cell subsets (naive, regulatory (Treg) and inflammation-related cells (IRC)) early in the disease. Our aim was to test the hypothesis that T-cell subset quantification can predict the achievement of clinical remission with early treatment in RA. METHODS: T-cell subsets were quantified in 108 drug-naive, early RA patients commencing methotrexate (MTX) or MTX+antitumor necrosis factor (anti-TNF) and in 105 healthy controls (HC). The primary outcome assessed was remission (DAS28<2.6). A pilot study used frozen cells (38 patients and 35 HCs, see online supplementary material) and was validated with fresh blood (70 patients and 70 HCs). RESULTS: Immune dysregulation in early RA was confirmed with an association between age and reduced naive cells compared with HCs (p=0.006), a lower age adjusted Treg and higher IRC frequency (p=0.001). Anticitrullinated peptide antibody (ACPA) positivity was associated with lower naive (p=0.031) and Treg frequencies (p=0.039). In 50 patients treated with MTX, ACPA/age-adjusted analysis demonstrated that higher naive cell frequency (relative to HC) was associated with remission (OR 5.90 (1.66 to 20.98), p=0.006, sensitivity/specificity 62%/79%, Positive Predictive Value (PPV)/Negative Predictive Value (NPV) 66%/76%). Remission with MTX+anti-TNF (n=20) was not found to be associated with naive cell frequency, and for patients with reduced naive cells the remission rate increased from 24% (MTX) to 42% (MTX+anti-TNF). CONCLUSIONS: Baseline T-cell subset analysis has a value in predicting early RA remission with first therapy with MTX. Immunological analysis could be used in conjunction with clinical/serological features to predict response to MTX and help select the most appropriate therapy at disease presentation. PMID- 23989996 TI - Gravity assisted vs. medium pressure valves for communicating hydrocephalus show similar valve-revision rates. AB - BACKGROUND: Two common valve types used to treat hydrocephalus include gravity assisted valves (GAV) and medium pressure valves (MPV). Despite their different mechanism of action, differentiated surgical indications per type are not well defined. One could assume that due to a higher complexity of the GAV system, it may be more prone to valve-related malfunction. The purpose of this retrospective study was to compare the valve-related complication rates of GAV and MPV in patients with communicating hydrocephalus. METHOD: Patients aged 16 years or older undergoing their first shunt implantation using GAV or MPV were included. We recorded demographic data, implantation diagnosis, outcome, complications, valve type and valve adjustments. Symptoms were documented at discharge and follow-up. Valve-related malfunctions were distinguished from other shunt complications. RESULTS: N = 252 patients (range 16.6-88.4, mean 65.0 years, 116 male and 136 female) underwent shunt placement for the first time. N = 122 GAV (48.4 %) and n = 130 MPV were implanted (51.6 %) over a period of 5 years. The most frequent diagnoses were normal pressure hydrocephalus (NPH) in 86 cases (34.1 %) and posthemorrhagic hydrocephalus in 114 cases (45.2 %). About two thirds of patients were free of hydrocephalus-related symptoms at follow-up. N = 66 subjects (26.2 %) underwent at least one shunt revision. N = 29 revisions (11.5 %) were due to valve-related malfunction. Valve-related revisions were the main cause for revision in 18/37 cases (48.6 %) in the GAV group and in 11/29 (37.9 %) in the MPV group. Neither clinical improvement nor valve-related malfunctions were found to be statistically different among groups. CONCLUSIONS: Despite their technical differences, GAV and MPV show similar valve-related revision rates in the treatment of communicating hydrocephalus. PMID- 23989997 TI - Is transplantation of cryopreserved ovarian tissue from patients with advanced stage breast cancer safe? A pilot study. AB - PURPOSE: To assess the safety of reimplantation of cryopreserved ovarian tissue from advanced-stage breast cancer patients. METHODS: Cryopreserved ovarian cortical fragments were obtained from 13 advanced-stage breast cancer patients aged 17-35 years. After thawing, part of the ovarian cortical tissue was grafted to severe combined immunodeficient mice for 6 months. The presence of malignant mammary cells in ovarian tissue was evaluated after thawing as well as after grafting by 1) histology and immunohistochemistry (epithelial membrane antigen, Her2/neu and gross cystic disease fluid protein 15 identification), and 2) detection of the MGB2 gene by qPCR. RESULTS: No malignant cells were evidenced by histology and immunohistochemistry. None of the mice died during the 6-month grafting period, nor developed macroscopically visible masses. MGB2 gene expression was detected by qPCR and confirmed by sequencing in frozen-thawed ovarian tissue in 4 cases and in grafts in 1 case. CONCLUSIONS: This pilot study is the first to evaluate the risk of contamination of cryopreserved ovarian tissue from advanced-stage breast cancer patients by xenotransplantation for 6 months to immunodeficient mice, associated with more conventional screening methods. Our xenografting results are reassuring, but caution needs to be exercised, as MGB2 gene expression was detected in some cases. Larger numbers of ovarian tissue samples from patients with advanced-stage breast cancer are required to confirm our findings before ovarian tissue transplantation can be contemplated in these patients. PMID- 23989998 TI - The association between thrombophilic gene mutations and recurrent pregnancy loss. AB - PURPOSE: To determine whether the Factor V (1691G/A), Factor V HR2 (4070A/G), Prothrombin (20210G/A), PAI-1 (-675 I/D, 5G/4G), ACE (intron 16 I/D), Factor VII (Gln353Arg), Factor XIII (Val34Leu), beta-fibrinogen (-455G/A), Glycoprotein Ia (807C/T), tPA (intron 8 D/I) gene mutations could be risk factors for recurrent pregnancy loss (RPL). METHODS: Genotyping of thrombophilic gene mutations were carried out by amplification Refractory Mutation System-PCR (ARMS-PCR) method after DNA extraction. RESULTS: We found that the mutant allele frequencies of Factor V (1691G/A), Factor V HR2 (4070A/G), Prothrombin (20210G/A), PAI-1 (-675 I/D, 5G/4G), Factor XIII (Val34Leu) and beta-fibrinogen (-455G/A) were more seen in the case group compared with the healthy control; However, the difference between the two group is not statistically significant (p > 0.05). Whilst the mutant allele frequencies of other studied genes were lower in the case in comparison to the fertile control women (p > 0.05). CONCLUSION: Taken together, our data has shown that the prevalence of thrombophilic gene mutations was similar in women with RPL and healthy controls. Therefore, it appears that further studies on large-scale population and other genetic variants will be needed to conclusively find candidate genes for RPL unknown etiology in the future. PMID- 23989999 TI - Percutaneous epididymal sperm aspiration and short time insemination in the treatment of men with obstructive azoospermia. AB - OBJECTIVE: To study the efficacy of percutaneous epididymal sperm aspiration (PESA) in combination with short time insemination to treat infertile men with obstructive azoospermia (OA). DESIGN: Paired randomized controlled trial in which each couple's cohort of oocytes was divided into two equal groups. SETTING: Center for reproductive care. PATIENTS: Twenty men with OA. INTERVENTIONS: Motile spermatozoa were collected using PESA. Half of the oocytes were used for intracytoplasmic sperm injection (ICSI). The rest were inseminated briefly with PESA sperm in vitro fertilization (IVF). After 4-5 h, the remaining cumulus cells were removed mechanically for second polar body observation to decide whether to apply "rescue" ICSI (RE-ICSI). MAIN OUTCOME MEASURES: Rates of oocyte maturation, fertilization, cleavage, and good quality embryos. Numbers of available embryos and good quality embryos were compared between PESA-IVF (using a short incubation protocol + rescue ICSI) group and PESA-ICSI group. RESULTS: In the short time insemination group, cumulus cells were dispersed by PESA spermatozoa. No second polar bodies were found, so RE-ICSI was done. PESA-IVF + RE-ICSI and PESA-ICSI outcomes were comparable in terms of fertilization rates, 2PN cleavage rate and good quality embryo rates with no statistically significant differences. CONCLUSIONS: PESA sperm without centrifugation could disperse the cumulus cells but were infertile and therefore could substitute for synthetic hyaluronidase. The outcomes of PESA-IVF with rescue ICSI were equivalent to PESA-ICSI. Using spermatozoa obtained by PESA and IVF before RE-ICIS is a viable treatment for men with OA. PMID- 23990000 TI - Dietary red meat aggravates dextran sulfate sodium-induced colitis in mice whereas resistant starch attenuates inflammation. AB - BACKGROUND: Although a genetic component has been identified as a risk factor for developing inflammatory bowel disease, there is evidence that dietary factors also play a role in the development of this disease. AIMS: The aim of this study was to determine the effects of feeding a red meat diet with and without resistant starch (RS) to mice with dextran sulfate sodium (DSS)-induced colitis. METHODS: Colonic experimental colitis was induced in Balb/c mice using DSS. The severity of colitis was evaluated based on a disease activity index (based on bodyweight loss, stool consistency, rectal bleeding, and overall condition of the animal) and a histological score. Estimations were made of numbers of a range of different bacteria in the treatment pools of cecal digesta using quantitative real-time PCR. RESULTS: Consumption of a diet high in red meat increased DSS induced colitis as evidenced by higher disease activity and histopathological scores. Addition of RS to the red meat diet exerted a beneficial effect in acute DSS-induced colitis. Subjective analysis of numbers of a range of bacterial targets suggest changes in the gut microbiota abundance were induced by red meat and RS treatments and these changes could contribute to the reported outcomes. CONCLUSIONS: A dietary intake of red meat aggravates DSS-induced colitis whereas co-consumption of resistant starch reduces the severity of colitis. PMID- 23990001 TI - Deep sedation or general anesthesia for ERCP? PMID- 23990002 TI - Complications from surgery and hospital finances. PMID- 23990003 TI - Inhaled corticosteroids and the risk of pneumonia in people with asthma: a case control study. AB - BACKGROUND: In clinical trials, the use of inhaled corticosteroids is associated with an increased risk of pneumonia in people with COPD, but whether the same is true for people with asthma is not known. METHODS: With the use of primary care data from The Health Improvement Network, we identified people with asthma, and from this cohort, we identified patients with pneumonia or lower respiratory tract infection and age- and sex-matched control subjects. Conditional logistic regression was used to determine the association between the dose and type of inhaled corticosteroid and the risk of pneumonia or lower respiratory tract infection. RESULTS: A dose-response relationship was found between the strength of inhaled corticosteroid dose and risk of pneumonia or lower respiratory tract infection (P < .001 for trend) such that after adjusting for confounders, people receiving the highest strength of inhaled corticosteroid (>= 1,000 MUg) had a 2.04 (95% CI, 1.59-2.64) increased risk of pneumonia or lower respiratory tract infection compared with those with asthma who did not have a prescription for inhaled corticosteroids within the previous 90 days. CONCLUSIONS: People with asthma receiving inhaled corticosteroids are at an increased risk of pneumonia or lower respiratory infection, with those receiving higher doses being at greater risk. Pneumonia should be considered as a possible side effect of inhaled corticosteroids, and the lowest possible dose of inhaled corticosteroids should be used in the management of asthma. PMID- 23990004 TI - Multidetector CT radiation dose optimisation in adults: short- and long-term effects of a clinical audit. AB - OBJECTIVE: To report short- and long-term effects of an audit process intended to optimise the radiation dose from multidetector row computed tomography (MDCT). METHODS: A survey of radiation dose from all eight MDCT departments in the state of Luxembourg performed in 2007 served as baseline, and involved the most frequently imaged regions (head, sinus, cervical spine, thorax, abdomen, and lumbar spine). CT dose index volume (CTDIvol), dose-length product per acquisition (DLP/acq), and DLP per examination (DLP/exa) were recorded, and their mean, median, 25th and 75th percentiles compared. In 2008, an audit conducted in each department helped to optimise doses. In 2009 and 2010, two further surveys evaluated the audit's impact on the dose delivered. RESULTS: Between 2007 and 2009, DLP/exa significantly decreased by 32-69 % for all regions (P < 0.001) except the lumbar spine (5 %, P = 0.455). Between 2009 and 2010, DLP/exa significantly decreased by 13-18 % for sinus, cervical and lumbar spine (P ranging from 0.016 to less than 0.001). Between 2007 and 2010, DLP/exa significantly decreased for all regions (18-75 %, P < 0.001). Collective dose decreased by 30 % and the 75th percentile (diagnostic reference level, DRL) by 20 78 %. CONCLUSIONS: The audit process resulted in long-lasting dose reduction, with DRLs reduced by 20-78 %, mean DLP/examination by 18-75 %, and collective dose by 30 %. KEY POINTS: * External support through clinical audit may optimise default parameters of routine CT. * Reduction of 75th percentiles used as reference diagnostic levels is 18-75 %. * The effect of this audit is sustainable over time. * Dose savings through optimisation can be added to those achievable through CT. PMID- 23990005 TI - Nasopharyngeal carcinoma: comparison of diffusion and perfusion characteristics between different tumour stages using intravoxel incoherent motion MR imaging. AB - OBJECTIVE: To explore intravoxel incoherent motion (IVIM) characteristics of nasopharyngeal carcinoma (NPC) and relationships with different tumour stages. METHODS: We prospectively recruited 80 patients with newly diagnosed undifferentiated NPC. Diffusion-weighted MR imaging was performed and IVIM parameters (D, pure diffusion; f, perfusion fraction; D*, pseudodiffusion coefficient) were calculated. Patients were stratified into low and high tumour stage groups based on American Joint Committee on Cancer (AJCC) and TNM staging for determination of the predictive powers of IVIM parameters using t test, multiple logistic regression and ROC curve analyses. RESULTS: D, f and D* were all statistically significantly lower in high-stage groups in AJCC, T and N staging. D, f and D* were all independent predictors of AJCC staging, f and D* were independent predictors of T staging, and D was an independent predictor of N staging. D was most powerful for AJCC and N staging, whereas f was most powerful for T staging. Optimal cut-off values (area under the curve, sensitivity, specificity, positive likelihood ratio, negative likelihood ratio) were as follows: AJCC stage, D = 0.782 * 10(-3) mm(2)/s (0.915, 93.3 %, 76.2 %, 3.92, 0.09); T staging, f = 0.133 (0.905, 80.5 %, 92.5 %, 10.73, 0.21); N staging, D = 0.761 * 10(-3) mm(2)/s (0.848, 87.5 %, 66.7 %, 2.62, 0.19). Multivariate analysis showed no diagnostic improvement. CONCLUSION: Nasopharyngeal carcinoma has distinctive intravoxel incoherent motion characteristics parameters in different tumour staging, potentially helping pretreatment staging. KEY POINTS: * Magnetic resonance imaging is increasingly used to assess nasopharyngeal carcinoma (NPC). * NPC has distinctive diffusion/perfusion characteristics at different stages. * Non-invasive MR imaging may help pretreatment staging prediction. * Diffusion properties of NPC best correlate with AJCC and N staging. * Perfusion properties of NPC best correlate with T staging. PMID- 23990011 TI - Synchrotron-based photoelectron spectroscopy provides evidence for a molecular bond between calcium and mineralizing organic phases in invertebrate calcareous skeletons. AB - Organic compounds have been extracted from calcium carbonate skeletons produced by three invertebrate species belonging to distinct phyla. The soluble parts of these skeleton matrices were isolated and analysed by synchrotron-based X-ray spectroscopy (XPS). The presence of calcium associated with these organic materials was revealed in every sample studied, with important variations in Ca 2p binding energy from species to species. Measured Ca 2p binding energy values are more related to compositional diversity of the mineralizing matrices of the skeletons, whose taxonomic dependence has long been established, than to the Ca carbonate polymorph selected to build the skeletal units. This suggests a physical bond between species-specific mineralizing organic assemblages and the associated calcium. Remarkably, the binding energy of 2p electrons in calcium associated with mineralizing matrices is consistently higher than Ca 2p values obtained in purely mineral carbonate (both calcite and aragonite). The ability both to identify and measure the effect of organic matrices on their mineral counterpart in calcareous biominerals opens a new perspective for a functional approach to the biomineralization process. PMID- 23990012 TI - Use of Boolean and fuzzy logics in lactose glycocluster research. AB - Fuzzy logic systems can be exploited for defining the degrees of true or false binding between calcium mediated multivalent lactose and peanut agglutinin lectin, which are difficult to define with Boolean logic. PMID- 23990013 TI - [Old and immobile in rural areas? Limited mobility of the elderly in the context of increasingly problematic health care in rural regions]. AB - Against the background of considerable population ageing processes in rural areas, it is expected that access to the health care system in these regions will deteriorate. Within this context, the question arises as to whether elderly people have the ability to overcome increasing distances in order to receive adequate medical care. Hence the objective of this study is an in-depth analysis of the everyday mobility of elderly people living in rural areas. The empirical analysis is based on the German National Travel Survey "Mobilitat in Deutschland 2008". Findings show that older women in particular experience limitations in their mobility options. Only 63% of mobility-impaired women (aged > 75 years) were mobile outside their homes, and only 37% had access to a car, which can be regarded as the crucial factor for being mobile. It follows that older and mobility-impaired women have to cope with everyday life under difficult conditions. In the context of the growing problem of access to the health care system in rural areas, the challenge is to ensure adequate primary health care for a large proportion of the immobile elderly. PMID- 23990014 TI - Laparoscopic versus open total gastrectomy with D2 dissection for gastric cancer: a meta-analysis. AB - OBJECTIVE: To elucidate the feasibility and safety of laparoscopic total gastrectomy with D2 dissection (LTGD2) for gastric cancer in comparison with open total gastrectomy with D2 dissection (OTGD2). BACKGROUND: More surgeons have chosen laparoscopic total gastrectomy as an alternative to open total gastrectomy. But no meta-analysis has been performed to evaluate the value of LTGD2. METHODS: Original articles compared LTGD2 and OTGD2 for gastric cancer, which published in English from January 1990 to March 2013 were searched in PubMed, Embase, and Web of Knowledge by two reviewers independently. Operative time, blood loss, harvested lymph nodes, analgesic medication, first flatus day, postoperative hospital stay, postoperative complications, and hospital mortality were compared using STATA version 10.1. RESULTS: 8 studies were selected in this analysis. A total of 1,498 patients were included (559 in LTG and 939 in OTG). LTGD2 showed longer operative time (WMD 39.29; 95 % CI 20.52, 58.06; P < 0.001), less blood loss (WMD -157.94; 95 % CI -245.25 -70.62; P < 0.001), fewer analgesic requirements (WMD -2.01; 95 % CI -3.10, -0.93; P < 0.001), earlier passage of flatus (WMD -0.73; 95 % CI -1.19, -0.27; P = 0.002), earlier hospital discharge (WMD -2.69; 95 % CI -3.42, -1.97; P < 0.001), and reduced postoperative morbidity (RR 0.70; 95 % CI 0.50, 0.98; P = 0.035). The number of harvested lymph nodes (WMD 0.27; 95 % CI -1.43, 1.98; P = 0.752) and hospital mortality rate (RR 0.57; 95 % CI 0.11, 3.09; P = 0.513) were similar. CONCLUSION: LTGD2 was associated with less blood loss, less postoperative pain, quicker bowel function recovery, shorter hospital stay, and reduced postoperative morbidity, at the expense of longer operative time. No statistical differences were observed in lymph node dissection, and hospital mortality, which indicated the similar ability of lymph nodes clearance and short-term outcomes with OTGD2. A positive trend was indicated toward LTGD2. So we encourage the experienced surgeons to achieve LTGD2 instead of OTGD2. Whereas, due to non-randomized control trails and lack of long term outcomes, more studies are required. PMID- 23990017 TI - Simulation of the contraction of the ventricles in a human heart model including atria and pericardium. AB - During the contraction of the ventricles, the ventricles interact with the atria as well as with the pericardium and the surrounding tissue in which the heart is embedded. The atria are stretched, and the atrioventricular plane moves toward the apex. The atrioventricular plane displacement (AVPD) is considered to be a major contributor to the ventricular function, and a reduced AVPD is strongly related to heart failure. At the same time, the epicardium slides almost frictionlessly on the pericardium with permanent contact. Although the interaction between the ventricles, the atria and the pericardium plays an important role for the deformation of the heart, this aspect is usually not considered in computational models. In this work, we present an electromechanical model of the heart, which takes into account the interaction between ventricles, pericardium and atria and allows to reproduce the AVPD. To solve the contact problem of epicardium and pericardium, a contact handling algorithm based on penalty formulation was developed, which ensures frictionless and permanent contact. Two simulations of the ventricular contraction were conducted, one with contact handling of pericardium and heart and one without. In the simulation with contact handling, the atria were stretched during the contraction of the ventricles, while, due to the permanent contact with the pericardium, their volume increased. In contrast to that, in the simulations without pericardium, the atria were also stretched, but the change in the atrial volume was much smaller. Furthermore, the pericardium reduced the radial contraction of the ventricles and at the same time increased the AVPD. PMID- 23990015 TI - Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society. AB - PURPOSE: The lethal effects of cancer are associated with the enhanced tumor aggressiveness in recurrent and metastatic lesions that show resistant phenotype to anti-cancer therapy, a major barrier to improving overall survival of cancer patients. The presence of heterogeneous populations of cancer cells within a specific tumor including the tumor-initiating cells or so-called cancer stem cells (CSCs) has linked the acquired resistance (AR, or adaptive resistance). Herein, we discuss the CSC-mediated tumor repopulation in AR of breast cancer in this review. METHODS: We emphasize a dynamic feature of gene induction in tumor cells that undergo long-term treatment, and describe a specific HER2-NF-kappaB HER2 pro-survival pathway that can be initiated in breast CSCs upon radiation therapy. RESULTS: Elucidation of HER2-induced pro-survival networks, specifically the force driving tumor repopulation due to radioresistant CSCs during anticancer therapies, will have a significant impact on the generation of new diagnostic and therapeutic targets to control of recurrent and metastatic breast tumors. PMID- 23990016 TI - Expression of E-cadherin, Twist, and p53 and their prognostic value in patients with oral squamous cell carcinoma. AB - PURPOSE: Epithelial-mesenchymal transition (EMT) and p53 play important roles in controlling cancer invasion and metastasis. However, discrepancies still exist in the relationship between the expression of an epithelial marker E-cadherin and predicting short survival of patients in many types of cancer. In this study, we aimed to determine the levels of E-cadherin, Twist, and p53 in tumor tissues from patients with oral squamous cell carcinoma (OSCC) and their clinical significances. METHODS: The protein expression of 112 OSCC tumor and 16 benign tissues was examined by immunohistochemistry staining. Overall survival rates of 112 OSCC patients were measured using Kaplan-Meier estimates and the log-rank tests. RESULTS: E-cadherin and p53 downregulation were found in 70 of 112 (62.5 %) and 66 of 112 (59.0 %), respectively, and Twist overexpression was found in 72 of 112 (64.3 %) studied cases of OSCC patients. Expression of E-cadherin was significantly associated with tumor location (P = 0.004) and mortality (P = 0.010). Patients with lower E-cadherin expression (P = 0.024), betel quid chewing (P = 0.006), smoking (P = 0.001), tumor size >2 cm (P = 0.001), advanced tumor stage (P = 0.043), and recurrence (P < 0.001) exhibited a poorer outcome. Multivariate analysis showed that E-cadherin is an independent marker for survival prediction. Additionally, low E-cadherin expression is significantly correlated with low p53 expression. CONCLUSIONS: E-cadherin is an independent marker for survival prediction in OSCC. Co-evaluation of E-cadherin and p53 expression might be a valuable tool for predicting OSCC patient outcome. PMID- 23990018 TI - A three-dimensional constitutive model for the stress relaxation of articular ligaments. AB - A new nonlinear constitutive model for the three-dimensional stress relaxation of articular ligaments is proposed. The model accounts for finite strains, anisotropy, and strain-dependent stress relaxation behavior exhibited by these ligaments. The model parameters are identified using published uniaxial stress stretch and stress relaxation data on human medial collateral ligaments (MCLs) subjected to tensile tests in the fiber and transverse to the fiber directions (Quapp and Weiss in J Biomech Eng Trans ASME 120:757-763, 1998; Bonifasi-Lista et al. in J Orthop Res 23(1):67-76, 2005). The constitutive equation is then used to predict the nonlinear elastic and stress relaxation response of ligaments subjected to shear deformations in the fiber direction and transverse to the fiber direction, and an equibiaxial extension. A direct comparison with stress relaxation data collected by subjecting human MCLs to shear deformation in the fiber direction is presented in order to demonstrate the predictive capabilities of the model. PMID- 23990019 TI - Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model. AB - Demyelinating disorders such as leukodystrophies and multiple sclerosis are neurodegenerative diseases characterized by the progressive loss of myelin that may lead toward a chronic demyelination of the brain's white matter, impairing normal axonal conduction velocity and ultimately causing neurodegeneration. Current treatments modifying the pathological mechanisms are capable of ameliorating the disease; however, frequently, these therapies are not sufficient to repress the progressive demyelination into a chronic condition and permanent loss of function. To this end, we analyzed the effect that bone marrow-derived mesenchymal stromal cell (BM-MSC) grafts exert in a chronically demyelinated mouse brain. As a result, oligodendrocyte progenitors were recruited surrounding the graft due to the expression of various trophic signals by the grafted MSCs. Although there was no significant reaction in the non-grafted side, in the grafted regions oligodendrocyte progenitors were detected. These progenitors were derived from the nearby tissue as well as from the neurogenic niches, including the subependymal zone and dentate gyrus. Once near the graft site, the cells matured to myelinating oligodendrocytes. Finally, electrophysiological studies demonstrated that axonal conduction velocity was significantly increased in the grafted side of the fimbria. In conclusion, we demonstrate here that in chronic demyelinated white matter, BM-MSC transplantation activates oligodendrocyte progenitors and induces remyelination in the tissue surrounding the stem cell graft. PMID- 23990020 TI - Pro-apoptotic miRNA-128-2 modulates ABCA1, ABCG1 and RXRalpha expression and cholesterol homeostasis. AB - Aberrant regulation of cholesterol homeostasis is associated with obesity as well as multiple types of cancer. However, the mechanism behind these is largely missing. Here, we show that microRNA (miRNA)-128-2 is not only a pro-apoptotic microRNA but it also alters the expression of genes involved in cellular cholesterol homeostasis. Cholesterol efflux via ATP-binding cassette transporters (ABCA1 and ABCG1) is a mechanism for cells to eliminate excess cholesterol and prevent cellular cholesterol accumulation. The regulation of these pathways is complex with transcriptional regulation by sterol-regulatory element-binding protein (SREBP) and liver X receptor/retinoid X receptor (RXR) transcription factors but poorly understood at the post-transcriptional levels. MiR-128-2 increases the expression of SREBP2 and decreases the expression of SREBP1 in HepG2, MCF7 and HEK293T cells independent of sirtuin 1 (SIRT1) status. MiR-128-2 inhibits the expression of ABCA1, ABCG1 and RXRalpha directly through a miR-128-2 binding site within their respective 3'untranslated regions. The administration of miR-128-2 leads to decline in the protein and mRNA levels of ABCA1, ABCG1 and RXRalpha. Conversely, anti-miRNA treatment leads to increased ABCA1, ABCG1 and RXRalpha expression. The inverse correlation between miR-128-2 and its targets viz. ABCA1 and ABCG1 was also established during high-fat diet in different mice tissues. Our data show that cholesterol efflux is attenuated by miR-128-2 overexpression and, conversely, stimulated by miR-128-2 silencing. Further, we also observed the induction of ER stress response by miR-128-2. In this study, we provide the first evidence of miR-128-2 to be a new regulator of cholesterol homeostasis. Our study shows dual role of miR-128-2, as a pro-apoptotic molecule as well as a regulator of cholesterol homeostasis. PMID- 23990021 TI - Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability. AB - Light toxicity is suspected to enhance certain retinal degenerative processes such as age-related macular degeneration. Death of photoreceptors can be induced by their exposure to the visible light, and although cellular processes within photoreceptors have been characterized extensively, the role of the retinal pigment epithelium (RPE) in this model is less well understood. We demonstrate that exposition to intense light causes the immediate breakdown of the outer blood-retinal barrier (BRB). In a molecular level, we observed the slackening of adherens junctions tying up the RPE and massive leakage of albumin into the neural retina. Retinal pigment epithelial cells normally secrete vascular endothelial growth factor (VEGF) at their basolateral side; light damage in contrast leads to VEGF increase on the apical side--that is, in the neuroretina. Blocking VEGF, by means of lentiviral gene transfer to express an anti-VEGF antibody in RPE cells, inhibits outer BRB breakdown and retinal degeneration, as illustrated by functional, behavioral and morphometric analysis. Our data show that exposure to high levels of visible light induces hyperpermeability of the RPE, likely involving VEGF signaling. The resulting retinal edema contributes to irreversible damage to photoreceptors. These data suggest that anti-VEGF compounds are of therapeutic interest when the outer BRB is altered by retinal stresses. PMID- 23990022 TI - CLL cells are resistant to smac mimetics because of an inability to form a ripoptosome complex. AB - In the lymph node (LN) environment, chronic lymphocytic leukemia (CLL) cells display increased NF-kappaB activity compared with peripheral blood CLL cells, which contributes to chemoresistance. Antagonists of cellular inhibitor of apoptosis proteins (cIAPs) can induce apoptosis in various cancer cells in a tumor necrosis factor-alpha (TNFalpha)-dependent manner and are in preclinical development. Smac-mimetics promote degradation of cIAP1 and cIAP2, which results in TNFR-mediated apoptosis via formation of a ripoptosome complex, comprising RIPK1, Fas-associated protein with death domain, FLICE-like inhibitory protein and caspase-8. CD40 stimulation of CLL cells in vitro is used as a model to mimic the LN microenvironment and results in NF-kappaB activation and TNFalpha production. In this study, we investigated the response of CLL cells to smac mimetics in the context of CD40 stimulation. We found that treatment with smac mimetics results in cIAP1 and cIAP2 degradation, yet although TNFalpha is produced, this did not induce apoptosis. Despite the presence of all components, the ripoptosome complex did not form upon smac-mimetic treatment in CLL cells. Thus, CLL cells seem to possess aberrant upstream NF-kappaB regulation that prevents ripoptosome formation upon IAP degradation. Unraveling the exact molecular mechanisms of disturbed ripoptosome formation may offer novel targets for treatment in CLL. PMID- 23990024 TI - Mechanistic insight into the hydrazine decomposition on Rh(111): effect of reaction intermediate on catalytic activity. AB - Periodic density functional theory (DFT) calculations have been performed to systematically investigate the effect of reaction intermediate on catalytic activity for hydrazine (N2H4) decomposition on Rh(111). Reaction mechanisms via intramolecular and NH2-assisted N2H4 decompositions are comparatively analyzed, including adsorption configuration, reaction energy and barrier of elementary step, and reaction network. Our results show that the most favorable N2H4 decomposition pathway starts with the initial N-N bond scission to the NH2 intermediate, followed by stepwise H stripping from adsorbed N2Hx (x = 1-4) species, and finally forms the N2 and NH3 products. Comparatively, the stepwise intramolecular dehydrogenation via N2H4-> N2H3-> N2H2-> N2H -> N2, and N2H4-> NH2 > NH -> N with or without NH2 promotion effect, are unfavorable due to higher energy barriers encountered. Energy barrier analysis, reaction rate constants, and electronic structures are used to identify the crucial competitive route. The promotion effect of the NH2 intermediate is structurally reflected in the weakening of the N-H bond and strengthening of the N-N bond in N2Hx in the coadsorption system; it results intrinsically from the less structural deformation of the adsorbate, and weakening of the interaction between dehydrogenated fragment and departing H in transition state. Our results highlight the crucial effect of reaction intermediate on catalytic activity and provide a theoretical approach to analyze the effect. PMID- 23990025 TI - Sulfonic acid functionalised ordered mesoporous materials as catalysts for fine chemical synthesis. AB - The synthesis of highly active acid catalysts supported on ordered mesoporous materials has eluded chemists until 1998, when Wim M. Van Rhijn et al. explored three different routes to tether sulfonic acid on mesoporous silica. This viewpoint sheds light on this landmark and explores its significant impact on material science and green catalysis. PMID- 23990023 TI - Cuprous oxide nanoparticles inhibit the growth and metastasis of melanoma by targeting mitochondria. AB - Metal and its oxide nanoparticles show ideal pharmacological activity, especially in anti-tumor therapy. Our previous study demonstrated that cuprous oxide nanoparticles (CONPs) selectively induce apoptosis of tumor cells in vitro. To explore the anti-tumor properties of CONPs in vivo, we used the particles to treat mouse subcutaneous melanoma and metastatic lung tumors, based on B16-F10 mouse melanoma cells, by intratumoral and systemic injections, respectively. The results showed that CONPs significantly reduced the growth of melanoma, inhibited the metastasis of B16-F10 cells and increased the survival rate of tumor-bearing mice. Importantly, the results also indicated that CONPs were rapidly cleared from the organs and that these particles exhibited little systemic toxicity. Furthermore, we observed that CONPs targeted the mitochondria, which resulted in the release of cytochrome C from the mitochondria and the activation of caspase-3 and caspase-9 after the CONPs entered the cells. In conclusion, CONPs can induce the apoptosis of cancer cells through a mitochondrion-mediated apoptosis pathway, which raises the possibility that CONPs could be used to cure melanoma and other cancers. PMID- 23990026 TI - Acute gouty arthritis complicated with acute ST elevation myocardial infarction is independently associated with short- and long-term adverse non-fatal cardiac events. AB - Large epidemiologic studies have associated gouty arthritis with the risk of coronary heart disease. However, there has been a lack of information regarding the outcomes for patients who have gout attacks during hospitalization for acute myocardial infarction. We reviewed the data of 444 consecutive patients who were admitted to our hospital between 2005 and 2008 due to acute ST elevation myocardial infarction (STEMI). The clinical outcomes were compared between patients with gout attack and those without. Of the 444, 48 patients with acute STEMI developed acute gouty arthritis during hospitalization. The multivariate analysis identified prior history of gout and estimated glomerular filtration rate as independent risk factors of gout attack for patients with acute STEMI (odds ratio (OR) 21.02, 95 % CI 2.96-149.26, p = 0.002; OR 0.92, 95 % CI 0.86 0.99, p = 0.035, respectively). The in-hospital mortality and duration of hospital stay did not differ significantly between the gouty group and the non gouty group (controls). During a mean follow-up of 49 +/- 28 months, all-cause mortality and stroke were similar for both groups. Multivariate Cox regression showed that gout attack was independently associated with short- and long-term adverse non-fatal cardiac events (hazard ratio (HR) 1.88, 95 % CI 1.09-3.24, p = 0.024; HR 1.82, 95 % CI 1.09-3.03, p = 0.022, respectively). Gout attack among patients hospitalized due to acute STEMI was independently associated with short term and long-term rates of adverse non-fatal cardiac events. PMID- 23990027 TI - Rheumatologists' opinions towards complementary and alternative medicine: a systematic review. AB - People with chronic musculoskeletal conditions are high users of complementary and alternative medicines (CAM). This systematic review was conducted to evaluate the attitudes of rheumatologists towards CAM and to identify whether these attitudes are affected by the personal or practice characteristics of the rheumatologists. A systematic search of electronic databases identified five eligible studies and one supplementary abstract, published before 1 December 2012. Outcomes measuring rheumatologists' attitudes towards CAM were extracted, as were any analysis of correlations with characteristics of the rheumatologist. Study quality was assessed using the STROBE checklist. Six studies from the USA, Canada and the Netherlands met inclusion criteria, with sample sizes ranging from 101 to 2,000. The studies were of variable methodological quality. Rheumatologists' opinions towards CAM varied according to therapy type. Many held favourable opinions towards bodywork and meditation, believed in their benefits and provided referrals for use. Other therapies, such as energy-based medicine, were regarded with scepticism. There were no demographic characteristics that consistently correlated with CAM attitudes or use. The limited data describing rheumatologist's attitudes to CAM is of varying quality but suggests that attitudes are influenced by the rheumatologist's familiarity with the CAM therapy and the degree to which a therapy has been assessed in a scientific manner. Given the high use of CAM amongst individuals seen in rheumatology clinics, physicians should undertake high-quality research to assess effectiveness of CAM therapy. PMID- 23990028 TI - Kinetic evidence of an apparent negative activation enthalpy in an organocatalytic process. AB - A combined kinetic and computational study on our tryptophan-based bifunctional thiourea catalyzed asymmetric Mannich reactions reveals an apparent negative activation enthalpy. The formation of the pre-transition state complex has been unambiguously confirmed and these observations provide an experimental support for the formation of multiple hydrogen bonding network between the substrates and the catalyst. Such interactions allow the creation of a binding cavity, a key factor to install high enantioselectivity. PMID- 23990030 TI - Insights into CO2/N2 separation through nanoporous graphene from molecular dynamics. AB - We show from molecular dynamics simulations that porous graphene of a certain pore size can efficiently separate carbon dioxide from nitrogen with high permeance, in agreement with the recent experimental finding (Koenig et al., Nat. Nanotechnol., 2012, 7, 728-732). The high selectivity is reflected in the much higher number of CO2 passing-through events than that of N2 from the trajectories. The simulated CO2 permeance is on the order of magnitude of 10(5) GPU (gas permeation unit). The selective trend is further corroborated by the free energy barriers of permeation. The predicted CO2/N2 selectivity is around 300. Overall, the combination of high CO2 flux and high CO2/N2 selectivity makes nanoporous graphene a promising membrane for post-combustion CO2 separation. PMID- 23990031 TI - Laryngeal injuries following endotracheal intubation in ENT surgery: predictive value of anatomical scores. AB - Endotracheal intubation has been associated with a threefold higher incidence of laryngopharyngeal complaints following anesthesia in comparison to laryngeal mask airway. Such complaints, including hoarseness and sore throat, have been reported in up to 90% of patients within 24 h of extubation. The purpose of this study was to determine which preoperatively documented clinical and anatomic parameters are predictive of laryngo-pharyngeal trauma resulting from elective endotracheal intubation. Fifty-three patients undergoing ENT procedures requiring general anesthesia with endotracheal intubation were recruited. Pre and postoperative laryngostroboscopic examination was performed and findings correlated to preoperative clinical and anatomic parameters. Readily assessed anatomic parameters including height (>180 cm) and weight (>80 kg) correlated significantly to the Eckerbom grade of intubation-associated acute laryngeal injury (rs = 0.374; p = 0.006 and rs = 0.278; p = 0.044, respectively). The mandibular protrusion test also correlated significantly to the Eckerbom grade (rs = 0.462, p = 0.001) while the upper-lip-bite test showed significant correlation to impaired vocal fold oscillation (rs = 0.288, p = 0.036), with injury prediction sensitivities of 37.5 and 39.4%, respectively. No parameters correlated to subjective complaints (n = 5, 9.2%). This study provides suggestions on how to improve the classification of intubation-associated laryngeal injuries as well as providing the basis for larger clinical trials in other surgical subspecialties. PMID- 23990032 TI - Clinical and molecular characteristics of HNSCC patients with brain metastases: a retrospective study. AB - Among the metastasis patterns of head and neck squamous cell carcinoma (HNSCC), intracranial spread is a rare but dreaded event. To date only very few cases have been reported and clinical and molecular data are sparse. We screened our archives for HNSCC patients from 1992 to 2005 who were diagnosed with brain metastases (BM). For retrospective analysis, all clinico-pathological data including disease-free survival (DFS), local progression-free survival (LPFS), and overall survival (OS) were compiled. Additionally, we assessed the mutational status of the TP53 gene and the prevalence of HPV serotypes by PCR and Sanger sequencing. Immunohistochemistry was applied to detect p16INK4A expression levels as surrogate marker for HPV infection. The prevalence rate of BM in our cohort comprising 193 patients with advanced HNSCC was 5.7%. Of 11 patients with BM, 3 were female and 9 were male. Seven of the primary tumors were of oropharyngeal origin (OPSCC). LPFS of the cohort was 11.8 months, DFS was 12.1 months and OS was 36.0 months. After the diagnosis of BM, survival was 10.5 months. Five tumors showed a mutation in the TP53 gene, while five of the seven OPSCC tumors had a positive HPV status displaying infection with serotype 16 in all cases. Compared with patients who harbored TP53wt/HPV-positive tumors, patients with TP53 mutations showed a poor prognosis. Compared with the whole cohort, the interval between diagnosis of the primary and the detection of BM was prolonged in the HPV infected OPSCC subgroup (26.4 vs. 45.6 months). The prognosis of HNSCC patients with BM is poor. In our cohort, most tumors were OPSCC with the majority being HPV positive. Our study points toward a putatively unusual metastatic behavior of HPV-positive OPSCC. PMID- 23990033 TI - PEPFAR's antiprostitution pledge: spending power and free speech in tension. PMID- 23990034 TI - Anatomical variation of superior petrosal vein and its management during surgery for cerebellopontine angle meningiomas. AB - No systematic study is yet available that focuses on the surgical anatomy of the superior petrosal vein and its significance during surgery for cerebellopontine angle meningiomas. The aim of the present study was to examine the variation of the superior petrosal vein via the retrosigmoid suboccipital approach in relation to the tumor attachment of cerebellopontine angle meningiomas as well as postoperative complications related to venous occlusion. Forty-three patients with cerebellopontine angle meningiomas were analyzed retrospectively. Based on the operative findings, the tumors were classified into four subtypes: the petroclival type, tentorial type, anterior petrous type, and posterior petrous type. According to a previous anatomical report, the superior petrosal veins were divided into three groups: Type I which emptied into the superior petrosal sinus above and lateral to the internal acoustic meatus, Type II which emptied between the lateral limit of the trigeminal nerve at Meckel's cave and the medial limit of the facial nerve at the internal acoustic meatus, and Type III which emptied into the superior petrosal sinus above and medial to Meckel's cave. In both the petroclival and anterior petrous types, the most common vein was Type III which is the ideal vein for a retrosigmoid approach. In contrast, the Type II vein which is at high risk of being sacrificed during a suprameatal approach procedure was most frequent in posterior petrous type, in which the superior petrosal vein was not largely an obstacle. Intraoperative sacrificing of veins was associated with a significantly higher rate of venous-related phenomena, while venous complications occurred even in cases where the superior petrosal vein was absent or compressed by the tumor. The variation in the superior petrosal vein appeared to differ among the tumor attachment subtypes, which could permit a satisfactory surgical exposure without dividing the superior petrosal vein. In cases where the superior petrosal vein was previously occluded, other bridging veins could correspond with implications for the crucial venous drainage system, and should thus be identified and protected whenever possible. PMID- 23990035 TI - Advanced disease, diuretic use, and marital status predict hospital admissions in an ambulatory cirrhosis cohort. AB - BACKGROUND AND AIMS: Hospital admissions in cirrhotic patients are a source of significant health care expenditure. Most studies to date have focused on readmissions in patients with decompensated cirrhosis. We sought to describe predictors of hospital admissions in an ambulatory cirrhosis cohort consisting of both compensated and decompensated patients to identify patients who could benefit from intensified outpatient chronic disease management. METHODS: We performed a retrospective cohort study of 395 cirrhotic patients followed at an academic medical center liver clinic. Inclusion criteria were documented cirrhosis and longitudinal care at our center during 2006-2008. Patients were followed until December 2011, death, or liver transplantation. The primary outcomes were non-elective cirrhosis-related hospital admissions within 1 year and time to admission. The secondary outcome was 2-year cirrhosis-related mortality. The study was approved by the Partners Human Research Committee (protocol 2012P001912). RESULTS: Seventy-eight patients (19.7 %) had at least one cirrhosis-related hospital admission within 1 year. The following were significant predictors in the multivariable model: model for end-stage liver disease score >=15 [OR 2.22, 95 % CI (1.21-4.07), p = 0.01], diagnosis of hepatocellular carcinoma [3.64 (1.42-9.35), 0.007], diuretic use [2.27 (1.23 4.17), 0.008], at least one cirrhosis-related admission during the baseline year [2.17 (1.21-3.89), 0.01], and being unmarried [1.92 (1.10-3.35), 0.02]. CONCLUSIONS: Advanced disease, diuretic use, and marital status were associated with cirrhosis-related hospital admissions in patients followed at an academic medical center liver clinic. Our findings suggest that patients with inadequately or overzealously treated ascites, as well as those with limited social supports, could benefit from intensified outpatient management. PMID- 23990036 TI - Effects of ischemia and reperfusion on subpopulations of rat enteric neurons expressing the P2X7 receptor. AB - BACKGROUND: Intestinal ischemia followed by reperfusion (I/R) may occur following intestinal obstruction. In rats, I/R in the small intestine leads to structural changes accompanied by neuronal death. AIM: To analyze the impact of I/R injury on different neuronal populations in the myenteric plexus of rat ileum. METHODS: The ileal artery was occluded for 35 min and animals were euthanized 6, 24, and 72 h, and 1 week later. Immunohistochemistry was performed with antibodies against the P2X7 receptor as well as nitric oxide synthase (NOS), calbindin, calretinin, choline acetyltransferase (ChAT), or the pan-neuronal marker anti HuC/D. RESULTS: Double immunolabeling demonstrated that 100% of NOS-, calbindin-, calretinin-, and ChAT-immunoreactive neurons in all groups expressed the P2X7 receptor. Following I/R, neuronal density decreased by 22.6% in P2X7 receptor immunoreactive neurons, and decreased by 46.7, 38, 39.8, 21.7, and 20% in NOS-, calbindin-, calretinin-, ChAT-, and HuC/D-immunoreactive neurons, respectively, at 6, 24, and 72 h and 1 week following injury compared to the control and sham groups. We also observed a 14% increase in the neuronal cell body profile area of the NOS-immunoreactive neurons at 6 and 24 h post-I/R and a 14% increase in ChAT immunoreactive neurons at 1 week following I/R. However, the average size of the calretinin-immunoreactive neurons was reduced by 12% at 6 h post-I/R and increased by 8% at 24 h post-I/R. CONCLUSIONS: This work demonstrates that I/R is associated with a significant loss of different subpopulations of neurons in the myenteric plexus accompanied by morphological changes, all of which may underlie conditions related to intestinal motility disorder. PMID- 23990037 TI - Facilitators and barriers to HIV activities in religious congregations: perspectives of clergy and lay leaders from a diverse urban sample. AB - This paper examines facilitators and barriers to HIV activities within religious congregations, the relative internal or external sources of these influences, and suggestive differences across congregational types. Results are based on in-depth interviews with clergy and lay leaders (n = 57) from 14 congregations in Los Angeles County, California, purposively selected to reflect diversity in racial ethnic composition, denomination, size, and HIV activity level. Many common facilitators and barriers were related to norms and attitudes, only a few of which appeared overtly associated with theological orientations. Clergy support was a facilitator particularly prevalent among congregations having higher HIV activity levels, indicating its importance in sustaining and expanding HIV programs. Resource issues were also prominent, with material resource barriers more frequently mentioned by smaller congregations and human resource barriers more among larger congregations. Organizational structure issues were mostly centered on external linkages with various social service, public health, and faith-based entities. Analysis of internal versus external sources highlights the roles of different stakeholders within and outside congregations in promoting HIV activities. Potential differences across congregational types represent fruitful areas for future research. PMID- 23990038 TI - Spirituality of chronic orofacial pain patients: case-control study. AB - The objective of this study was to investigate spirituality and blood parameters associated with stress in patients with facial musculoskeletal pain. Twenty-four women with chronic facial musculoskeletal pain (CFMP) and 24 healthy women were evaluated with a protocol for orofacial characteristics, research diagnostic criteria for temporomandibular disorders and the Spiritual Perspective Scale. Blood samples were collected to analyze blood count, cortisol, ACTH, C3, C4, thyroid hormones, total immunoglobulin, C-reactive protein and rheumatoid factor. The study group was more spiritualized than control group. Individuals with a high score of spirituality had less myofascial pain, less bruxism and fewer complaints. They also had lower levels of ACTH and IgE. Spirituality was higher in the study group and can be considered an important tool for coping with CFMP. PMID- 23990039 TI - Generalist red velvet mite predator (Balaustium sp.) performs better on a mixed diet. AB - Generalist predators have the potential advantage to control more than one pest and to be more persistent than specialist predators because they can survive on different foods. Moreover, their population growth rate may be elevated when offered a mixture of prey species. We studied a generalist predatory mite Balaustium sp. that shows promise for biological control of thrips and whiteflies in protected rose cultures in Colombia. Although starting its life in the soil, this predator makes excursions onto plants where it feeds on various arthropods. We quantified life history parameters of the predator, offering high densities of three pest species: first-instar larvae of Frankliniella occidentalis, eggs of Trialeurodes vaporariorum and Tetranychus urticae, either alone or in combination. The predators completed their life cycle on each diet. The egg-to egg period was c. 2 months. All eggs were laid in one batch in 1-2 days, indicating a pronounced semelparous reproduction pattern. In general, females reproduced earlier and laid more eggs on mixed diets, and these early reproducers consequently had higher population growth rates than late reproducers. The best diet in terms of egg-to-egg period and juvenile survival was the combination of eggs from whiteflies and spider mites. Spider mite eggs alone and western flower thrips larvae alone were the worst diets. It remains to be investigated whether mixed diets promote the population growth rate of Balaustium sufficiently for biocontrol of whiteflies and thrips in the presence of alternative prey, such as spider mites, to become effective. PMID- 23990040 TI - Leaf structures affect predatory mites (Acari: Phytoseiidae) and biological control: a review. AB - Because of their size, small arthropods can be highly affected by characteristics of the leaf surface. Leaf surfaces have various structures, such as trichomes and domatia, which add to the complexity of the microenvironment experienced by arthropods. Plant structure can affect the retention and performance of predators and parasitoids and it has been proposed that phylloplane characteristics be modified to improve the utility of these organisms as biological control agents. Phytoseiids have a long history as biological control agents of pest mite species in agricultural systems. In the past 30 years, extensive research has shown that trichomes and domatia influence phytoseiid populations and performance. Various reasons have been proposed to explain this relationship, including increased pollen capture for use as a food source, escape from predation, avoidance of adverse abiotic conditions, and increased/decreased ease of prey capture. There is potential for the manipulation of crops to improve biological control by phytoseiids, but incorporating beneficial traits into plants is likely to have lower priority than other breeding characteristics. The objectives of this review are to summarize the evidence for the relationship between phytoseiids and leaf surface structures, discuss possible hypotheses to explain this relationship, examine the potential of altering current crop varieties for the purpose of increasing phytoseiid populations or performance, and conduct a meta-analysis to quantify the effects of plant surface structures on phytoseiid and phytophagous mite densities. PMID- 23990041 TI - Effect of biotin on transcription levels of key enzymes and glutamate efflux in glutamate fermentation by Corynebacterium glutamicum. AB - Biotin is an important factor affecting the performance of glutamate fermentation by biotin auxotrophic Corynebacterium glutamicum and glutamate is over-produced only when initial biotin content is controlled at suitable levels or initial biotin is excessive but with Tween 40 addition during fermentation. The transcription levels of key enzymes at pyruvate, isocitrate and alpha ketoglutarate metabolic nodes, as well as transport protein (TP) of glutamate were investigated under the conditions of varied biotin contents and Tween 40 supplementation. When biotin was insufficient, the genes encoding key enzymes and TP were down-regulated in the early production phase, in particular, the transcription level of isocitrate dehydrogenase (ICDH) which was only 2% of that of control. Although the cells' morphology transformation and TP level were not affected, low transcription level of ICDH led to lower final glutamate concentration (64 g/L). When biotin was excessive, the transcription levels of key enzymes were at comparable levels as those of control with ICDH as an exception, which was only 3-22% of control level throughout production phase. In this case, little intracellular glutamate accumulation (1.5 mg/g DCW) and impermeable membrane resulted in non glutamate secretion into broth, even though the quantity of TP was more than 10-folds of control level. Addition of Tween 40 when biotin was excessive stimulated the expression of all key enzymes and TP, intracellular glutamate content was much higher (10-12 mg/g DCW), and final glutamate concentration reached control level (75-80 g/L). Hence, the membrane alteration and TP were indispensable in glutamate secretion. Biotin and Tween 40 influenced the expression level of ICDH and glutamate efflux, thereby influencing glutamate production. PMID- 23990042 TI - Characterizing the mode of action of Brevibacillus laterosporus B4 for control of bacterial brown strip of rice caused by A. avenae subsp. avenae RS-1. AB - Biological control efficacy of Brevibacillus laterosporus B4 associated with rice rhizosphere was assessed against bacterial brown stripe of rice caused by Acidovorex avenae subsp. avenae. A biochemical bactericide (chitosan) was used as positive control in this experiment. Result of in vitro analysis indicated that B. laterosporus B4 and its culture filtrates (70%; v/v) exhibited low inhibitory effects than chitosan (5 mg/ml). However, culture suspension of B. laterosporus B4 prepared in 1% saline solution presented significant ability to control bacterial brown stripe in vivo. Bacterization of rice seeds for 24 h yielded a greater response (71.9%) for controlling brown stripe in vivo than chitosan (56%). Studies on mechanisms revealed that B. laterosporus B4 suppressed the biofilm formation and severely disrupted cell membrane integrity of A. avenae subsp. avenae, causing the leakage of intracellular substances. In addition, the expression level of virulence-related genes in pathogen recovered from biocontrol agent-treated plants showed that the genes responsible for biofilm formation, motility, niche adaptation, membrane functionality and virulence of A. avenae subsp. avenae were down-regulated by B. laterosporus B4 treatment. The biocontrol activity of B. laterosporus B4 was attributed to a substance with protein nature. This protein nature was shown by using ammonium sulfate precipitation and subsequent treatment with protease. The results obtained from this study showed the potential effectiveness of B. laterosporus B4 as biocontrol agent in control of bacterial brown stripe of rice. PMID- 23990043 TI - Molecular dynamics simulation and linear interaction energy study of D-Glu-based inhibitors of the MurD ligase. AB - The biosynthetic pathway of the bacterial peptidoglycan, where MurD is an enzyme involved at the intracellular stage of its construction, represents a collection of highly selective macromolecular targets for novel antibacterial drug design. In this study as part of our investigation of the MurD bacterial target two recently discovered classes of the MurD ligase inhibitors were investigated resulting from the lead optimization phases of the N-sulfonamide D-Glu MurD inhibitors. Molecular dynamics simulations, based on novel structural data, in conjunction with the linear interaction energy (LIE) method suggested the transferability of our previously obtained LIE coefficients to further D-Glu based classes of MurD inhibitors. Analysis of the observed dynamical behavior of these compounds in the MurD active site was supported by static drug design techniques. These results complement the current knowledge of the MurD inhibitory mechanism and provide valuable support for the D-Glu paradigm of the inhibitor design. PMID- 23990044 TI - Strain changes on the cortical shell of vertebral bodies due to spine ageing: a parametric study using a finite element model evaluated by strain measurements. AB - The probability of fractures of the cortical shell of vertebral bodies increases as ageing progresses. Ageing involves all the spinal component changes. However, the effect of the spinal component ageing on the fracture risk of the cortical shell remains poorly understood. In this study, the influence of the ageing of the spinal components on cortical shell strain was investigated. A lumbar spinal specimen (L3-L5) was mechanically tested under a quasi-static axial compressive load. Clinical computed tomography images of the same specimen were used to create a corresponding finite element model. The material properties were determined by calibrating the finite element model using the L4 cortical shell strains of the anterior centre measurement site. The remaining experiment data (axial displacement, the intra-discal pressures, L4 cortical shell strain on the lateral measurement site) were used to evaluate the model. The individual ageing process of the six spinal components (cortical shell, cancellous bone, bony endplate, posterior elements, nucleus pulposus and annulus matrix) was simulated by changing their Young's moduli and Poisson's ratios, and the effect on cortical shell strain was investigated. Results show that the cortical shell strain is more sensitive to the ageing of the cortical shell and the cancellous bone than to the ageing of the nucleus pulposus, the annulus matrix, and the bony endplates and of the posterior elements. The results can help the clinicians focus on the aspects that mainly influence the vertebral cortex fracture risk factor. PMID- 23990046 TI - Morphological and phylogenetic description of a new xenoma-inducing microsporidian, Microsporidium aurata nov. sp., parasite of the gilthead seabream Sparus aurata from the Red Sea. AB - A new species of Microsporidia found in the marine teleost Sparus aurata collected from Hurghada coasts along the Red Sea, Egypt was described based on light and ultrastructural studies. Twenty three (30.6%) out of 75 of the examined fish were parasitized with a microsporidian parasite. Numerous macroscopic whitish cysts embedded in the peritoneal cavity were observed to infect many organs of the body including muscles, connective tissues, and the intestinal epithelium. The infection was developed as tumor-like masses of often up to 5 mm in diameter inducing an enormous hypertrophy to the infected organs. Fresh spores appeared mostly ovoid to pyriform in shape reaching a size of 1.7 +/- 0.5 (1.5 2.5) MUm * 1.3 +/- 0.4 (1-2) MUm; they possessed a large vacuole at the posterior end. These spores were located within a sporophorous vesicle which was bound by a thick amorphous wall. The ultrastructural features support the placement of the present species within the genus Microsporidium. The developmental stages were enclosed within a xenoma structure that was bounded by a double-layered cyst wall. The life cycle of the microsporidian pathogen described herein included four stages: proliferation (merogony), sporogony, sporoblast, spores, and liberation. Mature spores appeared electron dense, uninucleate, and were ellipsoidal in shape. At the anterior end of the spore, the anchoring disk was found in a central position. There was a definite number (5-11) of turns of the polar tube. A 538-bp region of the SSU rDNA gene of the studied species was sequenced (GenBank accession number: KF0220444). Multiple sequence alignment calculated a high degree of similarity (>92%) with six microsporidian species. The most closely related sequence was provided by the GenBank entry AF151529 for Microsporidium prosopium isolated from Hyperoplus lanceolatus differing in 67 nucleotide positions in its SSU rDNA with the highest percentage of identity (97.2%) and the lowest divergence value (0.20). Variations in the morphology of the spores and developmental stages between the two species revealed that the two species are different. The site of infection in the host and description of the onset of parasite development are strong criteria for the placement of the microsporidian parasite of the fish S. aurata within the genus Microsporidium as a new species, and we propose to name it Microsporidium aurata nov. sp. PMID- 23990047 TI - Rapid detection and identification of Theileria equi and Babesia caballi by high resolution melting (HRM) analysis. AB - The application of high-resolution melting (HRM) analysis in the differentiation between Theileria equi and Babesia caballi was evaluated using control samples from the United States Department of Agriculture and field samples collected from horses in Sudan and China. A region of the 18S rRNA gene, with four known nucleotide differences between the two parasites, was selected for primer design. HRM analysis successfully allowed the detection and differentiation of T. equi and B. caballi without the necessity of performing time-consuming and expensive post-PCR procedures such as sequencing or restriction digestion. Our results suggest that HRM could be an ideal method for rapid genotyping, which is required to determine a drug of choice or to administer an appropriate vaccine during an outbreak. PMID- 23990048 TI - Performance of EuroSCORE II compared to EuroSCORE I in predicting operative and mid-term mortality of patients from a single center after combined coronary artery bypass grafting and aortic valve replacement. AB - OBJECTIVE: The performance comparison of the recently introduced European System for Cardiac Operative Risk Evaluation II in predicting operative as well as mid term mortality, with its previous version in patients after combined aortic valve replacement and coronary artery bypass grafting surgery. METHODS: This retrospective analysis included 216 patients operated on at one institution from 01/1999 to 12/2005. Accuracy and calibration of EuroSCORE I and II were assessed by plotting the areas under the receiver operator curves and comparing observed and predicted mortalities. RESULTS: EuroSCORE II showed, regarding early mortality, a slightly higher discriminatory accuracy with an area under the receiver operator curve of 0.77, while additive and logistic EuroSCORE I areas were 0.749, 0.75, respectively. The highest specificity and sensitivity level was approached for EuroSCORE II at a predicted mortality of 4.4 %. Receiver operator curves concerning mid-term mortality revealed areas for additive, logistic EuroSCORE and EuroSCORE II of 0.745, 0.739 and 0.718 with the highest accuracy levels at predicted mortalities of 6.5, 6.48 and 3.88 %, respectively. Mean predicted mortalities by logistic EuroSCORE and EuroSCORE II were 8.35 and 3.99 %, respectively, while overall observed operative mortality was 6.3 %. In "high risk" patients (EuroSCORE > 13), EuroSCORE II underestimated early and mid-term outcomes. CONCLUSIONS: Regarding operative mortality, EuroSCORE II showed in this study a slightly higher discriminatory accuracy than EuroSCORE I. There were no significant differences in the calibration of the two model versions in "low-" and "moderate-risk" patients regarding early as well as mid-term mortality. Analyses in larger patient populations will contribute to further model improvement. PMID- 23990049 TI - One-stage bilateral pulmonary resections for pulmonary metastases. AB - OBJECTIVE: We analyze the safety and efficacy of one-stage bilateral pulmonary resections for pulmonary metastases via a bilateral approach. METHODS: We retrospectively analyzed 154 cases with pathologically verified pulmonary metastases which underwent curative pulmonary resection. Intraoperative and perioperative variables were evaluated. RESULTS: One hundred and thirty cases underwent unilateral pulmonary metastasectomy (group U), and the other 24 cases with bilateral pulmonary metastases underwent one-stage bilateral pulmonary resections (group B). Operation time in group B was significantly longer than in group U (354 +/- 132 vs. 203 +/- 110 min; p < 0.001), but was not longer than double that in group U (407 +/- 219 min; p = 0.540). Operative blood loss was not significantly greater in group B than group U (113 +/- 158 vs. 76 +/- 138 ml; p = 0.069). Neither duration of postoperative hospital stay nor incidence of postoperative complications differed between the two groups. Hospitalization costs in group B were significantly greater than in group U (257 +/- 120 * 10(4) vs. 168 +/- 69.2 * 10(4) yen; p < 0.001), but they were significantly less than double those in group U (336 +/- 138 * 10(4) yen; p < 0.001). CONCLUSIONS: We consider one-stage bilateral pulmonary metastasectomy to be safe for bilateral pulmonary metastases. Moreover, it may offer an economic benefit by avoiding the expenses associated with a two-stage operation. PMID- 23990045 TI - Acute abdominal and pelvic pain in pregnancy: ESUR recommendations. AB - Acute abdominal pain in pregnancy presents diagnostic and therapeutic challenges. Standard imaging techniques need to be adapted to reduce harm to the fetus from X rays due to their teratogenic and carcinogenic potential. Ultrasound remains the primary imaging investigation of the pregnant abdomen. Magnetic resonance imaging (MRI) has been shown to be useful in the diagnosis of gynaecological and obstetric problems during pregnancy and in the setting of acute abdomen during pregnancy. MRI overcomes some of the limitations of ultrasound, mainly the size of the gravid uterus. MRI poses theoretical risks to the fetus and care must be taken to minimise these with the avoidance of contrast agents. This article reviews the evolving imaging and clinical literature on appropriate investigation of acute abdominal and pelvic pain during established intrauterine pregnancy, addressing its common causes. Guidelines based on the current literature and on the accumulated clinico-radiological experience of the European Society of Urogenital Radiology (ESUR) working group are proposed for imaging these suspected conditions. PMID- 23990050 TI - Mesenchymal stromal cells versus betamethasone can dampen disease activity in the collagen arthritis mouse model. AB - The objective of this study was to compare between the effects of mesenchymal stem cell (MSC) and betamethasone in the treatment of rheumatoid arthritis. Sixty male albino mice were divided equally into 2 models. They are MSC model, group 1: saline control group, group 2: collagen-induced arthritis (CIA), group 3: induced arthritis mice that received intravenous injection of MSCs. Betamethasone model, group 1: phosphate buffer saline, group 2: CIA, group 3: induced arthritis mice that received intraperitoneal injection of betamethasone. Mice arthritis models were assessed by clinical paw edema and X-rays, at the proper time of sacrefaction, tissues were collected and examined using real-time PCR, and synovial tissue was examined for interleukin-10, tumor necrosis factor alpha, cartilage oligomeric matrix protein and matrix metalloproteinase 3. While serum levels of rheumatoid factor and C-reactive protein were detected by enzyme-linked immunosorbent assay kits. Also blood erythrocyte sedimentation rate was detected. Histopathological, paw edema and PCR results showed improvement in the groups that received MSC compared with the diseased group and the groups which received betamethasone. MSC significantly enhanced the effect of collagen-induced arthritis treatment, which is superior to betamethasone treatment, likely through the modulation of the expression of various cytokines. PMID- 23990051 TI - Evaluation of the Abelson gene as a control gene for real-time quantitative PCR in multiple myeloma. AB - The Abelson (ABL) gene was the best control gene for quantitative PCR (qPCR) based diagnosis and minimal residual disease detection in leukemic patients. However, there is still no concerted effort focused on the optimization of control genes in multiple myeloma (MM). The results of this study will provide a basis for the use of ABL as a control gene for the quantification of aberrantly expressed genes in MM. We analyzed ABL, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta-glucuronidase, and beta2-microglobulin genes expression in bone marrow samples of 62 MM patients and 31 healthy donors. MAGE-C1, the most commonly expressed cancer-testis antigen gene in MM, which is to be a potential clinical indicator for auxiliary diagnosis and prognostic evaluation in MM, was also detected. Our experimental results show that the copy numbers of the four control genes were well correlated in all samples detected. The quantitative data for MAGE-C1 using the four control genes also had high correlations. ABL and GAPDH genes were stably expressed in healthy donors and MM patients during therapy and did not vary with disease state. ABL is stable in the MM bone marrow mononuclear fraction, and it could be used as a reliable control gene for the normalization of qPCR studies in MM. PMID- 23990052 TI - Epigallocatechin-3-O-gallate, a green tea polyphenol, induces expression of pim-1 kinase via PPARgamma in human vascular endothelial cells. AB - Pim-1 is a serine/threonine kinase and involved in cell survival and proliferation. Recently, it has been shown that pim-1 signaling pathway plays an important role in cardiovascular protection and differentiation. In this study, we sought to explore the expression of pim-1 in human vascular endothelial cells (ECs) and its regulation by epigallocatechin-3-O-gallate (EGCG), a green tea polyphenol which has anti-oxidant, anti-inflammatory and vascular protective effects. By using quantitative reverse transcriptase PCR (qRT-PCR) and Western blotting, we showed that EGCG dose-dependently increased the expression of pim-1 in cultured umbilical vein endothelial cells. Next, we showed that EGCG activated a luciferase reporter driven by peroxisome proliferators-activated receptor (PPAR)-responsive elements. The induced expression of pim-1 was inhibited in ECs pretreated with GW9662, a specific antagonist of PPARgamma. In addition, pim-1 was also up-regulated in endothelial cells treated with rosiglitazone, a specific agonist for PPARgamma, or those infected with the adenovirus expressing a constitutively active PPARgamma. Collectively, our results provided new evidence that pim-1 can be up-regulated by EGCG via a PPARgamma-mediated mechanism and may mediate its vascular protective effects. PMID- 23990053 TI - Crimean-Congo hemorrhagic fever virus nucleoprotein suppresses IFN-beta-promoter mediated gene expression. AB - Crimean-Congo hemorrhagic fever virus (CCHFV) is a member of the family Bunyaviridae and is a causative agent of severe hemorrhagic disease. Knowledge regarding the pathogenesis of CCHFV is limited due to the requirement for high containment laboratories and the lack of an immunocompetent animal host. Previous studies have shown that CCHFV delays the activation of the human innate immune response, specifically, the type I interferon response. Our study results show that antagonism of the interferon-beta promoter is mediated by the nucleoprotein of CCHFV strain Hoti, while strains IbAr10200 and AP92 do not suppress the activity of the IFN-beta promoter. Our results also suggest that several viral factors may provide antagonistic action against the type I interferon response. PMID- 23990054 TI - Complete genome sequence analysis of human echovirus 30 isolated during a large outbreak in Guangdong Province of China, in 2012. AB - In May and June 2012, an outbreak of aseptic meningitis caused by Echovirus 30 (E30) occurred on a large scale in Luoding, Guangdong Province, China. Our team successfully isolated one subtype, strain 2012EM161, and its complete genome was sequenced. The phylogenetic tree of viral protein (VP) 1 gene sequences showed that the viral isolate was similar to the E30 strain prevalent in Fujian (2011), with identity of 98.05-99.32 % and 98.63-99.32 % for nucleotides and amino acids respectively. Whole genome-based phylogenetic analysis indicated that 2012EM161 contained the most proximate consensus to DQ246620 (Zhejiang, 2003) and FDJS03 (AY948442, Jiangsu, 2005), with nucleotide homogeneity of 87.09 % and 86.98 % respectively. The RDP4.16 and Simplot analysis showed that the newly discovered 2012EM161 was probably a recombinant, which was closely related to the strain of E30 (DQ246620) in the first half of the genome and the strain of E6 (JX976771) in genomic P3 region. The whole genome sequence of 2012EM161 will allow further study of the origin, evolution, and the molecular epidemiology of E30 strains. PMID- 23990055 TI - Immunization with an HPV-16 L1-based chimeric virus-like particle containing HPV 16 E6 and E7 epitopes elicits long-lasting prophylactic and therapeutic efficacy in an HPV-16 tumor mice model. AB - HPV L1-based virus-like particles vaccines (VLPs) efficiently induce temporary prophylactic activity through the induction of neutralizing antibodies; however, VLPs that can provide prophylactic as well as therapeutic properties for longer periods of time are needed. For this purpose, we generated a novel HPV 16 L1 based chimeric virus-like particle (cVLP) produced in plants that contains a string of T-cell epitopes from HPV 16 E6 and E7 fused to its C-terminus. In the present study, we analyzed the persistence of specific IgG antibodies with neutralizing activity induced by immunization with these cVLPs, as well as their therapeutic potential in a tumor model of C57BL/6 mice. We observed that these cVLPs induced persistent IgG antibodies for over 12 months, with reactivity and neutralizing activity for VLPs composed of only the HPV-16 L1 protein. Efficient protection for long periods of time and inhibition of tumor growth induced by TC 1 tumor cells expressing HPV-16 E6/E7 oncoproteins, as well as significant tumor reduction (57 %), were observed in mice immunized with these cVLPs. Finally, we discuss the possibility that chimeric particles of the type described in this work may be the basis for developing HPV prophylactic and therapeutic vaccines with high efficacy. PMID- 23990056 TI - Diversity and functional significance of cellulolytic microbes living in termite, pill-bug and stem-borer guts. AB - Arthropods living on plants are able to digest plant biomass with the help of microbial flora in their guts. This study considered three arthropods from different niches - termites, pill-bugs and yellow stem-borers - and screened their guts for cellulase producing microbes. Among 42 unique cellulase-producing strains, 50% belonged to Bacillaceae, 26% belonged to Enterobacteriaceae, 17% belonged to Microbacteriaceae, 5% belonged to Paenibacillaceae and 2% belonged to Promicromonosporaceae. The distribution of microbial families in the three arthropod guts reflected differences in their food consumption habits. Most of the carboxymethylcellulase positive strains also hydrolysed other amorphous substrates such as xylan, locust bean gum and beta-D-glucan. Two strains, A11 and A21, demonstrated significant activity towards Avicel and p-nitrophenyl-beta-D cellobiose, indicating that they express cellobiohydrolase. These results provide insight into the co-existence of symbionts in the guts of arthropods and their possible exploitation for the production of fuels and chemicals derived from plant biomass. PMID- 23990057 TI - Repair tissue quality after arthroscopic autologous collagen-induced chondrogenesis (ACIC) assessed via T2* mapping. AB - OBJECTIVE: A novel single-stage approach using arthroscopic microdrilling and atelocollagen/fibrin-gel application is employed for cartilage repair of the knee. The purpose of our study was to investigate the morphological and biochemical MRI outcome after this technique. MATERIALS AND METHODS: A retrospective case series of ten patients (mean age 45 years) with symptomatic chondral defects in the knee who were treated arthroscopically with microdrilling and atelocollagen application was analyzed. All defects were ICRS grade III or IV and the sizes were 2-8 cm(2) intra-operatively. All patients underwent morphological MRI and T2-star mapping at 1.5 T at 1-year follow-up. The magnetic resonance observation of cartilage repair tissue (MOCART) score was assessed. T2* relaxation time values of repair tissue and a healthy native cartilage area was assessed by means of region of interest analysis on the T2* maps. RESULTS: The mean MOCART score at 1-year follow-up was 71.7 +/- 21.0 ranging from 25 to 95. The mean T2* relaxation times were 30.6 +/- 11.3 ms and 28.8 +/- 6.8 ms for the repair tissue and surrounding native cartilage, respectively. The T2* ratio between the repair tissue and native cartilage was 105% +/- 30%, indicating repair tissue properties similar to native cartilage. CONCLUSIONS: An arthroscopic single-stage procedure using microdrilling in combination with atelocollagen gel and fibrin-glue can provide satisfactory MRI results at 1-year follow-up, with good cartilage defect filling. The T2* values in the repair tissue achieved similar values compared to normal hyaline cartilage. PMID- 23990058 TI - Why do the abundances of ions generated by MALDI look thermally determined? AB - In a previous study (J. Mass Spectrom. 48, 299-305, 2013), we observed that the abundance of each ion in a matrix-assisted laser desorption ionization (MALDI) spectrum looked thermally determined. To find out the explanation for the phenomenon, we estimated the ionization efficiency and the reaction quotient (QA) for the autoprotolysis of matrix, M + M -> [M + H](+) + [M - H](-), from the temperature-controlled laser desorption ionization spectra of alpha-cyano-4 hydroxycinnamic acid (CHCA) and 2,5-dihydroxybenzoic acid (DHB). We also evaluated the equilibrium constants (KA) for the autoprotolysis at various temperatures by quantum chemical calculation. Primary ion formation via various thermal models followed by autoprotolysis-recombination was compatible with the observations. The upper limit of the effective temperature of the plume where autoprotolysis-recombination occurs was estimated by equating QA with the calculated equilibrium constant. Figure ? PMID- 23990059 TI - Change in position dependency in non-responders after multilevel surgery for obstructive sleep apnea: analysis of polysomnographic parameters. AB - This study was aimed to evaluate the change in positional dependency by analyzing polysomnographic data in non-responders who previously underwent multilevel surgery for obstructive sleep apnea. A total of 48 consecutive patients who had a <50% reduction of apnea/hypopnea index (AHI) and a postoperative AHI of <=20 after multilevel surgery were enrolled in this study. Postoperative polysomnography (PSG) was carried out at least 6 months after surgical treatment, and both pre- and postoperative PSG data were analyzed. No significant differences were found in any of the measured polysomnographic parameters before and after multilevel surgery in non-responders. In position-dependent patients, supine AHI, non-supine AHI, supine oxygen desaturation index (ODI) and non supine ODI did not significantly improve after surgery. However, non-supine AHI and non-supine ODI in non-position-dependent patients (NPPs) improved significantly. Ten of 15 initially NPPs had position dependency after surgery, increasing the proportion of PPs from 68.8% (33/48) to 83.3% (40/48). These results suggest that positional therapy may be a useful adjuvant therapy in non responders with position dependency. PMID- 23990060 TI - The impact of laryngeal dysplasia on the development of laryngeal squamous cell carcinoma. AB - The aims of this study were to investigate the clinical course of patients with laryngeal dysplasia of various grades after surgical removal and analyze the percentage and time frame in which laryngeal dysplasia progresses to invasive carcinoma. The files of patients with surgical removal of laryngeal dysplasia and at least two microlaryngoscopies during a 10-year period were retrospectively reviewed. In total, 210 microlaryngoscopies of 70 adult patients were analyzed. Overall, of 295 biopsies taken 21 % showed no dysplastic alterations, 69 % showed dysplasia and 10 % showed invasive carcinoma, which had developed out of a laryngeal dysplasia. Dysplasia grades were equally distributed within the first three microlaryngoscopies (P = 0.31, P = 0.50, P = 0.55). The risk for developing laryngeal cancer out of laryngeal dysplasia showed no statistical correlation to the initial dysplasia grade (P = 0.26). On average, the malignant conversion took 127 weeks (mild dysplasia = 117 weeks; moderate dysplasia = 135 weeks; severe dysplasia = 82 weeks) (P = 0.27). Patients with laryngeal dysplasia are an inhomogeneous group and the grade of laryngeal dysplasia alone seems to be an insufficient prognostic factor for the development of laryngeal cancer. PMID- 23990061 TI - Sensorineural hearing loss: a complication of acute otitis media in adults. AB - We aim to evaluate the incidence and clinical manifestations of sensorineural hearing loss (SNHL) in adult patients with acute otitis media (AOM). Seventy-five patients (age > 18 years; 83 ears) diagnosed with AOM between January 2008 and March 2011 at our clinic were enroled and retrospectively reviewed. We detected audiometrically confirmed SNHL during the course of AOM in eight patients. The clinical course, treatment, and audiometric final outcome of each case were reviewed. SNHL was associated with AOM in 8 out of 83 ears (9.3%). The mean age of patients was 57.5 years, and the mean follow-up period was 21.1 months (range 0.6-46.3 months). The most common symptom was tinnitus. Mean bone conduction hearing threshold was 39.5 dB in pure tone audiometry. All patients showed high frequency HL, and three showed pan-frequency HL. All patients were treated with oral antibiotics at the initial visit. Seven ears were treated with a combination of oral steroids. Myringotomy was also performed. Seven of eight patients showed improvement; however, 8 kHz thresholds were not improved. This suggested that the inflammation spread through the round window. The mean duration of recovery was 18.6 days. SNHL associated with AOM in adult patients occurs during the early phases of the disease course. High-frequency hearing was commonly affected and was well treated with oral antibiotics, myringotomy, and steroid therapy. Audiometry can be helpful for treating adult patients with AOM. Active treatment, including myringotomy, should be performed during the early phase, if SNHL is suspected. PMID- 23990062 TI - Management of infected carotid artery rupture. AB - Carotid artery rupture (CAR) is a life-threatening complication of head and neck cancer, and infection complicates its management. The purpose of this study was to review our experience with the treatment of infected CAR and to summarize the existing literature on this topic. We retrospectively reviewed the medical records of patients treated in our department from 2000 to 2011 and re-analyzed cases reported in the literature during the same time period. We analyzed etiology, anatomic location, treatment, and rates of recurrent hemorrhage for each case. A total of 46 episodes of infected CAR occurred in the four patients in our own records and 27 patients described in the literature. Twenty-eight patients suffered from various head and neck cancers and underwent surgical resection, and 27 of them subsequently received radiotherapy or radiotherapy combined with chemotherapy (the 28th patient died before radiotherapy due to severe blood loss). The most common site of bleeding was the common carotid artery (33/46, 71.7%). Seventeen cases (17/45, 37.8%) were treated with surgical ligation, 20 (44.4%) with stent placement, and 7 (15.6%) with embolization. Surgical ligation had a lower rate of recurrent bleeding (2/17, 11.8%) than stent placement (12/20, 60.0%) when used for the treatment of infected CAR (P = 0.037, Chi squared test). Our results suggest that surgical ligation is an effective option in the management of infected CAR and may be the best choice to prevent recurrent hemorrhage. The complication rates, however, may be high when the common carotid or the internal carotid arteries are ligated. PMID- 23990064 TI - Perspectives on complementary and alternative medicine research. PMID- 23990063 TI - Self-generated sounds of locomotion and ventilation and the evolution of human rhythmic abilities. AB - It has been suggested that the basic building blocks of music mimic sounds of moving humans, and because the brain was primed to exploit such sounds, they eventually became incorporated in human culture. However, that raises further questions. Why do genetically close, culturally well-developed apes lack musical abilities? Did our switch to bipedalism influence the origins of music? Four hypotheses are raised: (1) Human locomotion and ventilation can mask critical sounds in the environment. (2) Synchronization of locomotion reduces that problem. (3) Predictable sounds of locomotion may stimulate the evolution of synchronized behavior. (4) Bipedal gait and the associated sounds of locomotion influenced the evolution of human rhythmic abilities. Theoretical models and research data suggest that noise of locomotion and ventilation may mask critical auditory information. People often synchronize steps subconsciously. Human locomotion is likely to produce more predictable sounds than those of non-human primates. Predictable locomotion sounds may have improved our capacity of entrainment to external rhythms and to feel the beat in music. A sense of rhythm could aid the brain in distinguishing among sounds arising from discrete sources and also help individuals to synchronize their movements with one another. Synchronization of group movement may improve perception by providing periods of relative silence and by facilitating auditory processing. The adaptive value of such skills to early ancestors may have been keener detection of prey or stalkers and enhanced communication. Bipedal walking may have influenced the development of entrainment in humans and thereby the evolution of rhythmic abilities. PMID- 23990065 TI - Visual outcomes after early vitreous surgery for aggressive posterior retinopathy of prematurity. AB - IMPORTANCE: Aggressive posterior retinopathy of prematurity (AP-ROP) rapidly progresses to retinal detachment despite application of photocoagulation. Early vitreous surgery might achieve prompt regression of neovascular activity and a high incidence of retinal reattachment. OBJECTIVE: To evaluate visual outcomes in eyes with AP-ROP after early vitreous surgery. DESIGN: Retrospective nonrandomized study of patients who underwent early vitreous surgery with lensectomy when retinal detachment developed despite photocoagulation. Aphakic correction with spectacles or contact lenses and the use of orthoptics were continued postoperatively. The best-corrected visual acuity (VA) was measured in eyes with a total retinal reattachment using the preferential looking technique in patients ranging in age from 8 months to no more than 3 years and a VA chart with Landolt rings or pictures for older children. The VA findings were converted to Snellen lines. SETTING: Institutional ophthalmology practice. PARTICIPANTS: Of the 103 eyes (57 patients) that underwent early vitreous surgery for AP-ROP, the VA was measured in 58 (32 patients) at a corrected age ranging from 8 months to 4 years. INTERVENTIONS: Early vitreous surgery and VA measurement using the preferential looking technique and a VA chart. MAIN OUTCOMES AND MEASURES: Postoperative VA, ROP stage, extent of fibrovascular tissue (FT) growth, and laterality of the eyes that underwent surgery. RESULTS: The VAs ranged from 20/2000 to 20/40. The VA may not be related to the preoperative ROP stage 4A or 4B but may depend on the preoperative extent of FT growth. In 39 of 58 eyes (67.2%), the FT had not reached the vitreous base preoperatively, and foveal formation occurred postoperatively with nearly age-appropriate VA (range, 20/250 to 20/40). In 17 of 58 eyes (29.3%), the FT had reached the vitreous base, and no fovea formed (VA range, 20/2000 to 20/250). Two of 58 eyes (3.4%) had deprivation amblyopia with a VA worse than 20/1600. The difference in VA between both eyes of patients who underwent bilateral vitreous surgery depended on ROP progression; patients who underwent a unilateral procedure in which the fellow eyes with ROP stabilized after photocoagulation tended to have poor vision because of deprivation amblyopia. CONCLUSIONS AND RELEVANCE: Early vitreous surgery may be beneficial for AP-ROP and should be performed before the FT reaches the vitreous base to facilitate foveal formation and good VA outcomes. The roles of photocoagulation, vitreous surgery, and anti-vascular endothelial growth factor therapy in the treatment of AP-ROP should be investigated in randomized trials regarding efficacy, safety, convenience, and cost. PMID- 23990066 TI - Plasmid pUPI126-encoded pyrrolnitrin production by Acinetobacter haemolyticus A19 isolated from the rhizosphere of wheat. AB - An Acinetobacter species identified as A. haemolyticus A19 produces an antibiotic and the enzyme chitinase. The antibiotic produced by A. haemolyticus A19 was extracellular and inducible by co-cultivation with Klebsiella pneumoniae in the optimum ratio 2:1, respectively. pH 7, temperature 28 degrees C, and addition of 2% (w/v) NaCl are the most suitable environmental conditions for production and activity of the antibiotic. The antibiotic was produced in the early stationary growth phase (48 h) of A. haemolyticus A19. It has a very broad spectrum of antimicrobial activity against plant and human pathogenic bacteria and fungi. The antibiotic was extracted with ethyl acetate and purified by column chromatography with further purification by preparative thin-layer chromatography. Yield of the antibiotic was 15 mg/l. The antibiotic was active at very low concentrations, for example 50 MUg/ml, and was water-soluble. It was stable at room temperature for up to 7 days. (1)H NMR analysis revealed the antibiotic was a pyrrolnitrin. It was found that pyrrolnitrin production by A. haemolyticus A19 was encoded by plasmid pUPI126 of molecular weight 25.7 kb. Plasmid pUPI126 was transferred to E. coli HB101 at a frequency of 5 * 10(-5) per MUg DNA. It was also conjugally transformed to E. coli HB101 rif (r) mutants at a frequency of 5.9 * 10(-8) per recipient cell. Plasmid pUPI126 was 100% stable in Acinetobacter and 95% stable in E. coli HB101. Transconjugants and transformants both produced the antibiotic. This is the first report of plasmid-mediated pyrrolnitrin production by A. haemolyticus A19 isolated from wheat rhizosphere. PMID- 23990067 TI - Effect of biofumigation and chemical fumigation on soil microbial community structure and control of pepper Phytophthora blight. AB - Soil biofumigation with brassica plant residues has been shown to significantly suppress soilborne pathogen. However, little published data reported the impact of biofumigation on microbial community structure in pepper (Capsicum annuum L.) production systems under field conditions. Biofumigation with rapeseed (Brassica napus 'Dwarf Essex') meal and chemical fumigation with dazomet were tested to control the pepper disease caused by Phytophthora capsici. BF treatment showed the lowest disease incidence among these treatments. Effects on soil bacterial and fungal communities were assessed by denaturating gradient gel electrophoresis and the results showed that the biofumigation increased bacterial diversity and decreased fungal diversity. There was a negative correlation between soil bacterial diversity and disease incidence and a positive correlation between soil fungal diversity and disease incidence. Cloning of the microbial community showed that the microbial community structures were altered by biofumigation. Soil was also evaluated for their chemical properties. Biofumigation increased soil content of total N, NO3(-)-N, available P and available K. A significant correlation between soil microbial community structures and soil chemical properties was found. Overall, these results indicated that biofumigation reduced disease incidence of pepper through altering soil microbial community structures. PMID- 23990068 TI - Cyanobacteria as a source of hydrogen for methane formation. AB - In a study during the 1970s co-variation of nitrogenase activity and methane formation associated with Sphagnum riparium was observed. This was suggested as evidence for a possible mechanism of hydrogen transfer from cyanobacteria to methanogens. We show experimentally that such a pathway is feasible. In a series of laboratory experiments, using a hydrogenase deficient strain of the heterocystous cyanobacterium Nostoc punctiforme and the hydrogenotrophic methanogen Methanospirillum hungateii in co-cultures, increasing light intensities resulted in elevated nitrogenase activity and methane production. The increase in methane production can be directly deduced from the nitrogenase activity of the N. punctiforme based on hydrogen balance calculations. These experimental results clearly suggest the possible existence of a novel photosynthetically regulated pathway for methane formation. PMID- 23990069 TI - Supercritical CO2 interpolymer complex encapsulation improves heat stability of probiotic bifidobacteria. AB - The probiotic industry faces the challenge of retention of probiotic culture viability as numbers of these cells within their products inevitably decrease over time. In order to retain probiotic viability levels above the therapeutic minimum over the duration of the product's shelf life, various methods have been employed, among which encapsulation has received much interest. In line with exploitation of encapsulation for protection of probiotics against adverse conditions, we have previously encapsulated bifidobacteria in poly (vinylpyrrolidone)-poly-(vinylacetate-co-crotonic acid) (PVP:PVAc-CA) interpolymer complex microparticles under supercritical conditions. The microparticles produced had suitable characteristics for food applications and also protected the bacteria in simulated gastrointestinal fluids. The current study reports on accelerated shelf life studies of PVP:PVAc-CA encapsulated Bifidobacterium lactis Bb12 and Bifidobacterium longum Bb46. Samples were stored as free powders in glass vials at 30 degrees C for 12 weeks and then analysed for viable counts and water activity levels weekly or fortnightly. Water activities of the samples were within the range of 0.25-0.43, with an average a(w) = 0.34, throughout the storage period. PVP:PVAc-CA interpolymer complex encapsulation retained viable levels above the recommended minimum for 10 and 12 weeks, for B. longum Bb46 and B. lactis Bb12, respectively, thereby extending their shelf lives under high storage temperature by between 4 and 7 weeks. These results reveal the possibility for manufacture of encapsulated probiotic powders with increased stability at ambient temperatures. This would potentially allow the supply of a stable probiotic formulation to impoverished communities without proper storage facilities recommended for most of the currently available commercial probiotic products. PMID- 23990070 TI - Effect of ionic liquids alkyl chain length on horseradish peroxidase thermal inactivation kinetics and activity recovery after inactivation. AB - The effects of different alkyl chain lengths of ionic liquids 1-ethyl-, 1-butyl- and 1-hexyl-3-methylimidazolium chloride, on the catalytic activity, thermal stability and deactivation kinetics of horseradish peroxidase were studied in the temperature range of 45-85 degrees C. The presence of 1-ethyl- and 1-butyl-ionic liquids up to 25% (w/v) did not affect significantly the enzyme activity at 25 degrees C, whereas the addition of 1-hexyl-solvent resulted in lower activity of enzyme. Typical biphasic deactivation profiles were obtained and adequately fitted by a bi-exponential equation. When increasing ionic liquids concentration up to 25% (w/v), the second phase of deactivation became more prominent, till leading to apparent first-order kinetics. Occurrence of activity regain, following thermal deactivation was found, reaching up 60-80% of the initial activity, especially in 1-hexyl-3-methylimidazolium chloride. Activity regain was particularly noticeable in the first phase of deactivation. Temperature sensitivity of the Soret band maxima indicated that the enzyme prepared in buffer or 1-hexyl-3-methylimidazolium chloride had similar conformational changes in the haem region, but no correlations were found with activity decrease. PMID- 23990071 TI - Culture-independent metagenomic approach to characterize the surface and subsurface soil bacterial community in the Brahmaputra valley, Assam, North-East India, an Indo-Burma mega-biodiversity hotspot. AB - Soil bacterial communities, which contain the highest level of prokaryotic diversity of any natural environment, are important for ecosystem functioning. A culture-independent metagenomic approach was employed in the present investigation to characterize the diversity of soil bacterial community composition in five geochemically and hydrologically different surface and subsurface soil habitats of Brahmaputra valley, Assam, North-East India, an Indo Burma mega-biodiversity hotspot. The diversity of soil bacterial community was determined through sequence analysis of 16S-23S intergenic spacer regions (ISR). Polymerase chain reaction (PCR) universal primers, 1406F (5'-TGYACACACCGCCCGT-3') and 155r (5'-GGGTTBCATTCRG-3') were used for amplification of 16S-23S ribosomal DNA intergenic spacers of bacteria. Amplification resulted in an intense array of PCR products approximately ranging in size from 200 to 900 bp. Clear banding patterns were observed in analysed samples using the primer set in combination. A clear change in microbial ISR profile was observed on visual analysis of gel electrophoresis profiles. Fast alignment database searches of PCR amplicons of 16S-23S ISR sequence data revealed that the isolated sequences resembled five major phylogenetic groups of bacteria, namely alpha-, beta- and gamma subdivisions of Proteobacteria, Acidobacterium and Comamonadaceae. PMID- 23990072 TI - Protective effect of Bacillus amyloliquefaciens against infections of Citrus aurantium seedlings by Phoma tracheiphila. AB - Isolate TEB1 an antagonistic endophytic bacterium, obtained from citrus leaves and identified as Bacillus amyloliquefaciens by 16S rDNA sequencing, was used for the biological control of mal secco disease of Citrus aurantium seedlings caused by the mitosporic fungus Phoma tracheiphila. The isolate TEB1 exhibited a good in vitro activity against P. tracheiphila in dual cultures as well as with the well diffusion method. C. aurantium seedlings watered with a suspension of TEB1 cells showed a reduction of 53.61 and 48.63% in disease severity and incidence, respectively. A PCR test with specific primers was performed 365 days after inoculation and P. tracheiphila was detected along the whole stem in inoculated control plant while no amplification product was obtained in TEB1 treated seedlings. Molecular analysis of TEB1 revealed a positive amplification of fenD and ituC genes responsible of the biosynthesis of fengycin and iturin lipopeptides, respectively. Moreover, observations by optical microscope showed that TEB1 reduced by 55% the germination of P. tracheiphila conidia and exhibited a marked effect on mycelia structure. Data suggest that lipopeptides produced by the bacterium interact with the cytoplasmic membrane of the fungus causing pore formation. TEB1 appears a potential candidate for the biological control of citrus mal secco disease. PMID- 23990073 TI - Nomograms to predict late urinary toxicity after prostate cancer radiotherapy. AB - OBJECTIVE: To analyze late urinary toxicity after prostate cancer radiotherapy (RT): symptom description and identification of patient characteristics or treatment parameters allowing for the generation of nomograms. METHODS: Nine hundred and sixty-five patients underwent RT in seventeen French centers for localized prostate cancer. Median total dose was 70 Gy (range, 65-80 Gy), using different fractionations (2 or 2.5 Gy/day) and techniques. Late urinary toxicity and the corresponding symptoms (urinary frequency, incontinence, dysuria/decreased stream, and hematuria) were prospectively assessed in half of the patients using the LENT-SOMA classification. Univariate and multivariate Cox regression models addressed patient or treatment-related predictors of late urinary toxicity (>=grade 2). Nomograms were built up, and their performance was assessed. RESULTS: The median follow-up was 61 months. The 5-year (>=grade 2) global urinary toxicity, urinary frequency, hematuria, dysuria, and urinary incontinence rates were 15, 10, 5, 3 and 1 %, respectively. The 5-year (>=grade 3) urinary toxicity rate was 3 %. The following parameters significantly increased the 5-year risk of global urinary toxicity (>=grade 2): anticoagulant treatment (RR = 2.35), total dose (RR = 1.09), and age (RR = 1.06). Urinary frequency was increased by the total dose (RR = 1.07) and diabetes (RR = 4). Hematuria was increased by anticoagulant treatment (RR = 2.9). Dysuria was increased by the total dose (RR = 1.1). Corresponding nomograms and their calibration plots were generated. Nomogram performance should be validated with external data. CONCLUSIONS: The first nomograms to predict late urinary toxicity but also specific urinary symptoms after prostate RT were generated, contributing to prostate cancer treatment decision. PMID- 23990074 TI - Identification and characterization of Rhipicephalus (Boophilus) microplus and Haemaphysalis bispinosa ticks (Acari: Ixodidae) of northeast India by ITS2 and 16S rDNA sequences and morphological analysis. AB - To investigate and identify the ticks prevalent in the North East part of India, scanning electron microscope (SEM) and DNA sequence of nuclear second internal transcribed spacer (ITS2) and mitochondrial 16S ribosomal DNA (rDNA) were used. Based on the morphological and molecular analysis, the ticks infesting cattle of North East India were found to be Rhipicephalus (Boophilus) microplus and Haemaphysalis bispinosa. ITS2 and 16S rDNA sequence from R. (B.) microplus and H. bispinosa were amplified using universal and gene specific primers, sequenced and analysed. The length of the amplified ITS2 sequence of R. (B.) microplus and H. bispinosa, were found to be approximately 1,500 and 1,700 bp, respectively. The length of the 16S rDNA sequences in both the ticks was found to be similar in size, but they differ in their base pair constitutions. This is the first report of the nucleotide sequences of ITS2 and 16S rDNA of H. bispinosa. Phylogenetic analysis revealed that H. bispinosa is a close relative of H. longicornis. A polymerase chain reaction-restriction fragment length polymorphism diagnostic tool was developed based on HindIII digestion of ITS2 in order to facilitate the identification of these two species which cannot be distinguished once it is fully-fed. Present study describes the use of SEM and 16S rDNA/ITS2 based molecular analysis in identification and differentiation of fully fed tick species. PMID- 23990075 TI - Diabetes risk in older Mexican Americans: effects of language acculturation, generation and socioeconomic status. AB - The effect of language acculturation, socioeconomic status (SES), and immigrant generation on development of diabetes among Mexican Americans was evaluated in the Hispanic Established Population for the Epidemiologic Study of the Elderly (HEPESE). HEPESE is a longitudinal cohort study of 3,050 non-institutionalized Mexican Americans aged 65 years at baseline (1993-1994) from 5 Southwestern states. Diabetes incidence was ascertained in 4 follow-up surveys to 2004-05 by respondent self-reported physician-diagnosis of diabetes, high blood glucose, or sugar in the urine. Language of interview, immigrant generation, gender, age, education, family history of diabetes, smoking status, alcohol use, health insurance type and self-reported height and weight were assessed. High socioeconomic status (SES) was defined by high school graduation and non-Medicaid insurance. Cox's proportional hazards models were fit to evaluate the effects of language acculturation, generation and SES on incident diabetes. 845 of 3,050 (27.7%) Mexican Americans had diabetes at baseline and were younger, more educated, and more likely to have health insurance than those without diabetes. Risk of developing diabetes increased for Spanish-speaking respondents with low SES from 1st to 3rd generation (HR = 1.76, 95% CI = 1.02-3.03) and from 2nd to 3rd generation (HR = 2.15, 95% CI = 1.20-3.84). Among English-speaking, high SES participants, generation had a protective effect on developing diabetes: HR = 0.45 (95% CI = 0.22-0.91) when comparing 3rd versus 1st generation. The effect of language acculturation and immigrant generation on incident diabetes is moderated by SES status in HEPESE participants. PMID- 23990076 TI - The effect of acid pH modifiers on the release characteristics of weakly basic drug from hydrophlilic-lipophilic matrices. AB - The solubility of weakly basic drugs within passage though GI tract leads to pH dependent or even incomplete release of these drugs from extended release formulations and consequently to lower drug absorption and bioavailability. The aim of the study was to prepare and evaluate hydrophilic-lipophilic (hypromellose montanglycol wax) matrix tablets ensuring the pH-independent delivery of the weakly basic drug verapamil-hydrochloride by an incorporation of three organic acidifiers (citric, fumaric, and itaconic acids) differing in their concentrations, pK a, and solubility. The dissolution studies were performed by the method of changing pH values, which better corresponded to the real conditions in the GI tract (2 h at pH 1.2 and then 10 h at pH 6.8). Within the same conditions, pH of matrix microenvironment was measured. To determine relationships between the above mentioned properties of acidifiers and the monitored effects (the amount of released drug and surface pH of gel layer in selected time intervals-360 and 480 min), the full factorial design method and partial least squares PLS-2 regression were used. The incorporation of the tested pH modifiers significantly increased the drug release rate from matrices. PLS components explained 75% and 73% variation in the X- and Y-data, respectively. The obtained results indicated that the main crucial points (p < 0.01) were the concentration and strength of acidifier incorporated into the matrix. Contrary, the acid solubility surprisingly did not influence the selected effects except for the surface pH of gel layer in time 480 min. PMID- 23990077 TI - Molecular inclusion complex of curcumin-beta-cyclodextrin nanoparticle to enhance curcumin skin permeability from hydrophilic matrix gel. AB - Curcumin (CUR) has various pharmacological effects, but its extensive first-pass metabolism and short elimination half-life limit its bioavailability. Therefore, transdermal application has become a potential alternative to delivery CUR. To increase CUR solubility for the development of a transparent homogenous gel and also enhance the permeation rate of CUR into the skin, beta-cyclodextrin-curcumin nanoparticle complex (BCD-CUR-N) was developed. CUR encapsulation efficiency was increased by raising the percentage of CUR to BCD up to 20%. The mean particle size of the best CUR loading formula was 156 nm. All evaluation data using infrared spectroscopy, Raman spectroscopy, powder X-ray diffractometry, differential thermal analysis and scanning electron microscopy confirmed the successful formation of the inclusion complex. BCD-CUR-N increased the CUR dissolution rate of 10-fold (p < 0.01). In addition, the improvement of CUR permeability acrossed skin model tissue was observed in gel containing the BCD CUR-N and was about 1.8-fold when compared with the free CUR gel (p < 0.01). Overall, CUR in the form of the BCD-CUR-N improved the solubility further on the penetration of CUR. PMID- 23990078 TI - Ion-pair chromatography for simultaneous analysis of ethionamide and pyrazinamide from their porous microparticles. AB - Ethionamide (ETA) and pyrazinamide (PZA) are considered the drugs of choice for the treatment of multidrug-resistant tuberculosis. Current methods available in the literature for simultaneous determination of ETA and PZA have low sensitivity or involve column modifications with lipophilic cations. The aim of this study was to develop a simple and validated reversed-phase ion-pair HPLC method for simultaneous determination of ETA and PZA for the characterization of polymeric based porous inhalable microparticles in in vitro and spiked human serum samples. Chromatographic separation was achieved on a Phenomenex C18 column (250 mm * 4.6 mm) using a Shimadzu LC 10 series HPLC. The mobile phase consisted of A: 0.01% trifluoroacetic acid in distilled water and B: ACN/MeOH at 1:1 v/v. Gradient elution was run at a flow rate of 1.5 mL/min and a fixed UV wavelength of 280 nm. The validation characteristics included accuracy, precision, linearity, analytical range, and specificity. Calibration curves at seven levels for ETA and PZA were linear in the analytical range of 0.1-3.0 MUg/mL with correlation coefficient of r (2) > 0.999. Accuracy for both ETA and PZA ranged from 94 to 106% at all quality control (QC) standards. The method was precise with relative standard deviation less than 2% at all QC levels. Limits of quantitation for ETA and PZA were 50 and 70 ng/mL, respectively. There was no interference from either the polymeric matrix ions or the biological matrix in the analysis of ETA and PZA. PMID- 23990080 TI - Brain imaging to be on track for improving diagnosis and pathophysiological insights in neuropsychiatric diseases. PMID- 23990079 TI - An fMRI study of reward circuitry in patients with minimal or extensive history of major depression. AB - Functional abnormalities in regions associated with reward processing are apparent in people with depression, but the extent to which disease burden impacts on the processing of reward is unknown. This research examined the neural correlates of reward processing in patients with major depressive disorder and varying degrees of past illness burden. Twenty-nine depressed patients and twenty five healthy subjects with no lifetime history of psychiatric illness completed the study. Subsets of fourteen patients were presenting for first lifetime treatment of a depressive episode, and fifteen patients had at least three treated episodes of depression. We used functional magnetic resonance imaging to study blood oxygen level-dependent signals during the performance of a contingency reversal reward paradigm. The results identified group differences in the response to punishers bilaterally in the orbitofrontal and medial prefrontal regions. In addition, areas such as the nucleus accumbens, anterior cingulate and ventral prefrontal cortices were activated greatest by controls during reward processing, less by patients early in the course of illness and least by patients with highly recurrent illness-suggesting that these areas are sensitive to the impact of disease burden and repeated episodes of depression. Reward processing in people with depression may be associated with diminished signaling of incentive salience, a reduction in the formation of reward-related associations and heightened sensitivities for negatively valenced stimuli, all of which could contribute to symptoms of depression. PMID- 23990081 TI - Time to disengage: holding an object influences the execution of rapid compensatory reach-to-grasp reactions for recovery from whole-body instability. AB - Rapid reach-to-grasp (RTG) reactions are important for balance recovery. Despite the benefit of having hands free to regain balance, people do not always release a handheld object. We investigated whether reluctance to release is related to central nervous system (CNS) processing delays that occur when the initial reaction is to drop the object rather than RTG. Young adults sat in a custom designed chair that tilted backwards. Participants regained balance by reaching to a handle with hands free or while holding onto (1) a chair-fixed object or (2) a SMALL or LARGE free-moving object (unbreakable plastic tubes). EMG was collected from the upper limb to determine onset of reaction. Kinematic data from a digitized wrist marker were used to determine movement time. 9 of 10 participants released the object in every trial. Extensor digitorum onset occurred significantly later than anterior deltoid onset in all conditions. LARGE object release induced further delays in extensor onset while both SMALL and LARGE object release increased response and movement time. Object disengagement led to delays in perturbation-evoked, RTG reactions, particularly in the focal muscle (extensor digitorum) and when the objects' properties posed greater risk for a failed RTG response. We propose that time required for cognitive disengagement accounts for the observed delays. This study offers a potential explanation for the tendency to avoid disengaging from a handheld object during balance recovery. Results also provide insight into the challenges imposed upon the CNS during temporally urgent movements. PMID- 23990082 TI - [Elimination of measles and rubella in Germany: Progress and hindrances]. PMID- 23990083 TI - [Progress in the elimination of measles and rubella in the WHO European Region]. AB - Substantial progress has been made in the World Health Organization (WHO) European Region toward reaching the goal of measles and rubella elimination. We analyzed the surveillance data of 2012 on measles and rubella for age-group, diagnosis confirmation status (clinical, laboratory-confirmed and epidemiologically linked), vaccination status, and measles-related deaths. For 2012, there were 23,871 measles cases and 29,361 rubella cases reported in the region, mostly among unvaccinated persons. Almost one in three patients with measles and one in five patients with rubella were aged 20 years and older. In a few countries, widespread outbreaks or indigenous transmission of measles persisted in 2012. While most countries in the region have controlled rubella, a small number still reported a high incidence and several outbreaks. Therefore, more efforts are required to achieve the goal of eliminating measles and rubella in the WHO European Region by 2015, particularly in high-incidence countries. The WHO measles and rubella elimination plan stipulates that all countries should achieve and maintain the required high vaccination coverage while conducting high quality surveillance. PMID- 23990084 TI - [Hot spot: epidemiology of measles and rubella in Germany and the WHO European region]. AB - The elimination of measles and rubella by 2015 is an important goal set by the World Health Organization European Region (WHO/Europa). Since 1991, the incidence of measles in WHO/Europa declined owing to routine childhood vaccination and supplementary immunization activities in the region. However, in many countries of Western Europe elimination of measles and rubella remains a challenge, and every year there are outbreaks with partly long-lasting transmission chains and dissemination of the virus internationally. In Germany, outbreaks occur because of the high proportion of susceptible individuals in specific population groups. In 2011, over 1,600 cases were reported (19.7 per 1,000,000 inhabitants, data from the Robert Koch Institute) whereas in 2012 only 167 cases were reported to the Robert Koch Institute (2 per 1,000,000 inhabitants). It is unclear whether the declining trend will continue in the following years due to improved vaccination coverage or whether number of cases will rise again because of the accumulation of susceptible groups. In Germany, there are currently no representative, country-wide data on rubella; however, data from the eastern federal states provide important epidemiological insights. Outbreaks are seldom reported, but statutory notification of rubella and congenital rubella syndrome was implemented in March 2013. As a result, it will be possible to better assess the epidemiology of rubella in Germany, although a considerable underreporting of rubella cases is anticipated. PMID- 23990085 TI - [Molecular surveillance shows progress in measles elimination process]. AB - Measles is a severe disease caused by infection with the measles virus. Complications after the onset of infection lead to 1-3 fatalities per 1,000 cases in industrialized countries. If more than 95 % of the global population were vaccinated twice with the measles, mumps, and rubella (MMR) vaccine, measles could be eliminated worldwide. The elimination of measles and rubella should be reached in the WHO Europe region in 2015. One important criterion for elimination of the measles virus consists in the analysis of the duration of transmission chains initiated by the import of measles virus. To assign measles viruses to outbreaks and transmission chains, genetic characterization is necessary. These investigations have been performed continually at the National Reference Center Measles, Mumps, Rubella since 1999, when the German Intervention Program was launched. This article summarizes our experiences with measles virus genotyping and new developments with respect to measles elimination in Germany. PMID- 23990086 TI - [Vaccination coverage against measles and sero-epidemiology of measles-specific IgG antibodies in German children and adolescents]. AB - BACKGROUND: Measles is a vaccine-preventable disease that could be eliminated by global vaccination strategies with two-dose measles vaccination. The World Health Organization (WHO) European Region aims at achieving measles elimination by 2015. Target control is mainly based on verification of 95 % vaccination coverage. In Germany, target verification cannot be based on data from centrally collected registers on vaccination and seroprevalence of measles-specific antibodies. OBJECTIVE: This paper provides an overview of measles vaccination coverage and the timeliness of measles vaccination in birth cohorts 1989-2008. In addition, factors associated with vaccination gaps are described. METHODS: Primary data on vaccination coverage (annual school entrance health examination) and on vaccination coverage and immune status (population-based German Health Interview and Examination Survey for Children and Adolescents - KiGGS) and secondary data (insurance refund claim data) are described and discussed. RESULTS AND CONCLUSION: The measles immunization coverage (two doses) obtained in the 2010 school entrance examinations was 91.5 %. The range was 87.6-95.3 % between Federal States. Regional differences were even more pronounced between districts. The timeliness of the two-dose measles immunization increased from 41 % (birth cohorts 2001/2002) to 66 % (birth cohorts 2006/2008). Despite progress in recent years, measles vaccination coverage is still inadequate in adolescents, young adults, and young children. The German Standing Committee on Vaccination (STIKO) recommends a combined MMR vaccination of adults who were born after 1970 and who were not fully vaccinated against measles during childhood. Successful implementation of this recommendation is crucial just as it is important to step up efforts to improve the timeliness of measles vaccination in young children. Regional vaccination gaps and susceptible clusters defined by age or sociodemographic parameters are of particular importance to the epidemiology of measles disease. Knowledge of the factors associated with nonimmunization should be used to tailor vaccination strategies. PMID- 23990087 TI - [Safety and tolerability of monovalent measles and combined measles, mumps, rubella, and varicella vaccines]. AB - Although effective monovalent and combined measles vaccines have been available for several decades in Germany, measles outbreaks continue to occur leading to severe cases of measles and even death. Possible reasons for the low acceptance of the measles vaccination are concerns about adverse events and serious complications following vaccination. In this report, we have summarized and assessed all adverse events reported in Germany from 2001 to 2012 after vaccination with monovalent- and combined measles-containing vaccines. A total of 1,696 suspected adverse reaction reports describing 5,297 adverse events were sent to the Paul Ehrlich Institute (PEI) between 1 January 2001 and 31 December 2012. The calculated mean reporting rate was 5.7 reports per 100,000 vaccine doses released by the PEI. Analysis of the reports indicates that measles containing vaccines are well tolerated with a constantly low rate of adverse events reported. Compared to the high rate of serious complications following wild-type measles infection, the benefit of measles-containing vaccines clearly outweighs the anticipated risks of adverse events. PMID- 23990088 TI - [Effectiveness, population-level effects, and heath economics of measles and rubella vaccination]. AB - Vaccination against measles and rubella has been included in national immunization programs worldwide for several decades. In this article, we present the evidence related to the effectiveness of measles and rubella vaccination based on published systematic reviews, and we describe the epidemiological and health economic effects of vaccination at a population level. Several observational studies demonstrate the high effectiveness (> 90 %) of both measles and rubella vaccination. The global measles mortality reduction and the dramatic decrease in rubella and measles incidences after introduction of routine immunization contribute to the very high quality of evidence. The countries of the Americas have proved that it is feasible to eliminate measles and rubella by strengthening infant immunization through routine vaccination services and by conducting supplemental immunization activities in other childhood age groups so as to close immunity gaps. An economic evaluation of measles and rubella vaccination specifically for the healthcare system in Germany does not exist. However, we conducted a systematic review and identified 11 health-economic studies from other industrialized countries and one for a hypothetical industrialized country. Results indicate that vaccination against measles and rubella had either a cost-effective or even a cost-saving potential, which could be assumed with some limitations also for the German setting. In conclusion, there is compelling evidence that the available vaccines are very effective and that measles and rubella elimination is feasible if adequate vaccination strategies are implemented. In Germany, catch-up vaccination programs are urgently needed for children, adolescents, and young adults specifically in the western federal states. PMID- 23990089 TI - [Knowledge, attitude, and practice concerning measles vaccination. Approaches for national vaccination education]. AB - Achievement of the goal to eliminate measles by 2015 set by the European region of the World Health Organization (WHO) necessitates an increase in the willingness of German nationals to get vaccinated. To identify influential factors on vaccination behavior as the basis for communication measures specific to target groups, the Federal Centre for Health Education (BZgA) has conducted two representative surveys on attitude, knowledge, and practice concerning vaccination among parents of children between 0 and 13 years as well as among adolescents and adults. The parents' survey (n = 3,002) revealed that more than one-third see measles as a harmless disease. The survey of adolescents and adults (n = 4,483, 16-85 years) also shows that about one-quarter of the interviewees between 16 and 44 years regarded vaccination against measles as not very important. Moreover, 81 % of adults born after 1970 without sufficient existing vaccine protection were not aware of the new measles vaccination recommendation for this age group. Personal consultation with the physician was regarded as the major source of vaccination information in both surveys. About half of all persons interviewed intended to obtain information about vaccinations on the Internet. The results of these studies were used for the development of a nationwide multilevel BZgA campaign on vaccination protection against measles, its goal being to support medical professionals with comprehensive information and to enable adolescents and young adults via different communication measures to make well-informed vaccination decisions. PMID- 23990090 TI - [The role of the Internet in eliminating infectious diseases. Managing perceptions and misperceptions of vaccination]. AB - BACKGROUND: The World Health Organization (WHO) has declared the elimination of measles as a global goal. According to the WHO, one critical challenge for countries such as Germany is managing perceptions and misperceptions about vaccination. Criticism and misinformation about vaccines are widespread, e.g., on the Internet, and they support the development of misperceptions, vaccine hesitancy, and fear. By contrast, owing to vaccination the actual incidence of measles is low and hardly anyone is familiar with measles as a severely infectious disease. This may lead to the incorrect perception of measles as a harmless children's disease. Education on the risks of infection and of vaccination should therefore be combined with effective debunking of misperceptions, both of which should govern the management of perceptions and misperceptions. AIM: The objective of this contribution is to propose and discuss several approaches with respect to the Janus-like role of the Internet: On the one hand, it serves as a source of anti-vaccination misinformation and is therefore responsible for the development of misperceptions. On the other hand, it can serve as the ideal platform for health agencies to educate the public and to debunk misinformation. CONCLUSION: This contribution suggests how an effective management of perceptions and misperceptions can take place on different levels of communication and how the Internet may be actively used to reach this goal. A collection of Internet links for patients and health-care personnel are recommended. PMID- 23990091 TI - [Outbreak management of measles. Requirement for official measures in light of the judgment of the Supreme Court]. AB - Measles outbreaks can be limited by consistent and timely management by the public health service. The aim of investigating outbreaks in the process of measles elimination is to prevent regional and also international spreading of the disease. The management of outbreaks is even more promising when the immunization coverage is already high. People without immunization can transmit the disease when they have taken contracted the measles virus. Hence, unvaccinated people are the focus of preventive measures according to the Protection Against Infection Act (Infektionsschutzgesetz). A judgment of the Federal Administrative Court of 22 March 2012 stated that individuals suspected of being contagious may be subject to a temporary prohibition of attending school so as to prevent the spread of a communicable disease. The court also pointed out which requirements are to be met by authorities before these measures are carried out. In compliance with the judgment, an outbreak investigation is thus also possible in future incidences of measles. The authority has to prove in each case that an unvaccinated person is suspected of being contagious. PMID- 23990092 TI - [The German National Verification Committee for Measles and Rubella Elimination]. AB - BACKGROUND: Since 1984, the World Health Organization (WHO) European Region has pursued the goal of eliminating measles. In 2005, it was decided to also stop the endemic transmission of rubellavirus, thereby eliminating congenital rubella syndrome. Both infections are to be eliminated by 2015. To document the progress and verify the elimination at country level, national verification committees should be established in WHO EU memberstates. PROCEDURE: In December 2012, the German Ministry of Health appointed the German National Verification Committee for Measles and Rubella Elimination. The commission meets at least twice a year to compile and analyze data on the epidemiology of measles and rubella in Germany and on the vaccination coverage/ immunity of the German population against these infections to assess progress in the elimination goals. Furthermore, the commission indicates whether the available data are sufficient or contain inconsistencies, evaluates the success of key strategies implemented, and advises on activities related to the verification of the elimination process in the country. A scientific report on the commission's findings is to be submitted annually to the WHO regional office. FUTURE PROSPECTS: Germany is committed to the aim of eliminating measles and rubella. Thus, every possible effort should be made to reach this goal by the responsible players in the German immunization system. The commission - as an independent group of experts - will critically accompany and evaluate this process. PMID- 23990093 TI - [Switzerland eliminates measles. National Strategy for the Elimination of Measles 2011-2015]. AB - The measles virus circulates within Switzerland in an endemic way leading to sporadic outbreaks. The most recent outbreak occurred in 2011. It lasted 9 months and had 687 reported cases. This is in contrast to 2012 when there were 66 cases,corresponding to an incidence of 8 cases per million inhabitants. During 2008-2010, the average national vaccination coverage for one or two doses of measles vaccine amounted to 92 and 83 % for 2-year-olds, 95 and 85 % for 8-year olds, and 95 and 85 % for 16-year-olds, respectively. To improve the national vaccination coverage, the Federal Council adopted the National Strategy for the Elimination of Measles 2011-2015 in 2011.The strategy was drawn up in a participative process led by the Federal Office for Public Health.The cantons as key partners were represented by the Conference of the Cantonal Directors for Public Health and the Association of Cantonal Health Officers. The strategy pursues the vision of eliminating measles in Switzerland in order to protect the population against measles and its complications, including all persons who may not be vaccinated for medical reasons. The strategy comprises six axes of intervention:(1)political engagement and support by all stakeholders, (2)a targeted >= 95 % two-dose vaccination coverage for all 2-year-olds, (3)easier access and incentives for the booster vaccination for everyone in the 2-year-old age group up to those born in 1964, (4)communication and promotion, (5)uniform national outbreak control, and (6)targeted surveillance. PMID- 23990094 TI - [Effects of the MMR vaccination on the epidemiology of mumps in Germany]. AB - Mumps is an acute viral infectious disease characterized by fever and swelling and tenderness of one or more salivary glands, usually the parotid gland. Since 1976, the German Standing Committee on Vaccination (STIKO) has recommended a mumps vaccination as part of the routine immunization schedule in former West Germany. In East Germany, the vaccination was only introduced in 1991 after reunification. In the preceding decades, no comprehensive surveillance system existed in Germany. However, for East Germany and the successional federal states of former East Germany, data on mumps incidence are available from different Eastern surveillance systems for the time period 1968-2012. According to these data, the incidence of mumps has dropped from > 200 cases/100,000 annually in the pre-vaccine era to currently <1/100,000. Recently, an age shift has been noted predominantly in the Western federal states. Based on data from school entry examinations and seroprevalence studies, the age shift is likely due to insufficient vaccination coverage and secondary vaccine failure ("waning immunity"). In view of the changes in mumps epidemiology and the increase of outbreaks among adolescents and young adults, the implementation of a nationwide mandatory notification was initiated and came into effect in March 2013. Mandatory notification enables the early detection of outbreaks and obtainment of comprehensive data for evaluation of the immunization program in place. Regarding the long-term prevention of mumps in Germany, it is hoped that--as part of the measles and rubella elimination effort--coverage rates for the second MMR dose among children will increase nationwide above 95% and existing vaccination gaps among adults will be closed. PMID- 23990095 TI - [Varicella vaccination in Germany. A provisional appraisal in the context of MMR vaccination]. AB - In 2004, a general varicella immunization was introduced in Germany for infants from the age of 11 months, followed by the subsequent recommendation in 2009 of a second vaccine dose. The vaccination is carried out at the same time as the immunization against measles, mumps, and rubella (MMR). Results of the nationwide sentinel surveillance of varicella and herpes zoster implemented by the Varicella Working Group (Arbeitsgemeinschaft Varizellen, AGV) show that the defined goals for varicella immunization (reduction of varicella-related morbidity, complications and hospitalizations) have been reached within a few years owing to the advances in vaccine coverage. Although coverage rates for varicella have not yet reached the same levels as for MMR, varicella immunization seems to have benefited from the established MMR immunization schedule. Moreover, there is no evidence for an adverse effect on the use and acceptance of the MMR vaccine. Lessons learnt in measles epidemiology (such as trends in the incidence of the disease in adolescents and infants), as well as in the history of MMR recommendations, may be useful for the evaluation of future epidemiological changes with respect to varicella and herpes zoster. In view of a rapidly waning immunity against the varicella zoster virus after vaccination with one dose and the lifelong persistence of the virus, achieving a robust and sustainable immunity in the general population seems to be an ambitious goal. However, this accomplishment will be indispensable in preventing breakthrough infections and a shift of varicella to older ages and in avoiding an increase in herpes zoster incidence. PMID- 23990096 TI - [Measles surveillance in Germany. From sentinel to mandatory surveillance]. AB - From September 1999 to March 2011, sentinel surveillance of measles was conducted by a self-selected sample of private physicians in Germany. From 2001, when mandatory surveillance for measles was established, two surveillance systems worked in parallel. The aim of this article is to summarize the strengths and limitations of sentinel versus mandatory surveillance. Active monthly reporting included case-based questionnaires on patients with (suspected) measles or zeroreporting. For confirmation of measles, the diagnostic patient specimens were sent to regional laboratories for serological tests or to the National Reference Laboratory (NRC). In the NRC in addition to serological tests measles-virus (MV) detection by PCR in urine, throat swabs, and oral fluid (since 2003) as well as MVgenotyping was offered. From January 2000 to December 2010, 934 out of 1,488 participating sentinel-practices did not see any measles case, while 554 reported 3,573 suspected cases. Measles was confirmed by laboratory testing in 801 cases, excluded in 473 cases, and the diagnosis remained uncertain in 215 cases. Of 3,100 analyzed cases, 2,712 (87 %) were unvaccinated, 217 (7 %) and 32 (1 %) were vaccinated with one or two doses, respectively, and for 139 (4 %) cases the vaccination status was unknown. The main reason for not being vaccinated against measles was refusal (n = 1,383). The confirmation rate was lower in the vaccinated than in the unvaccinated patients (19 % vs. 63 %). Since 2006, sentinel-cases have differed from notified cases by region and age. The proportion of sentinel cases from all NRC-investigated cases decreased from more than 50 % (2002) to less than 5 % (since 2007). Sentinel surveillance allowed for the detection of trends, delivered additional information for measles prevention, and played a major role in measles diagnostics. Since mandatory surveillance was established and sentinel surveillance no longer reflected the epidemiologic situation, the latter was abandoned in April 2011. PMID- 23990097 TI - [Gesundheitsziele.de. Selection of a new health target for Germany]. AB - In 2013, the forum gesundheitsziele.de selected "reduction of alcohol consumption" and "patient safety" as new health targets. Besides the two selected targets, three other topics were considered: health at work, health during pregnancy and childbirth, and health and migration. This paper describes the selection process, which followed several criteria: mortality, morbidity, prevalence, burden of disease, economic impact, potential for improvement, equity in health, empowerment of and priorities of health problems in the population. The analysis particularly focused on the assessment of the feasibility and the readiness of stakeholders to participate in the development and implementation of health targets. PMID- 23990098 TI - [Valid statements about violence in gender relations require gender-sensitive detection]. PMID- 23990099 TI - [Response of the Robert Koch Institute to the letter "Valid statements about violence in gender relations require gender-sensitive detection"]. PMID- 23990100 TI - [Temporary provision of blood donation in individuals with sexual risk behavior]. PMID- 23990103 TI - Classification of nAChRbeta2-immunoreactive retinal ganglion cells and their tectal projections in chicks. AB - The relationship between the type of retinal ganglion cell (RGC) and the retinoreceptive layer of the tectum is investigated by the immunostaining of RGCs with nicotinic acetylcholine receptorbeta2 (nAChRbeta2) antibody and intracellular staining by DiI and also by anterograde degeneration and biotinylated dextran amine labeling of retinotectal fibers in chicks. The results strongly suggest that many of the RGCs that express immunoreactivity to nAChRbeta2 send axons to tectal layer 7 and are mainly classified into the simple type of Groups II and III, which contain the cells providing middle-sized to large dendritic fields with simple dendritic arborization. These nAChRbeta2 immunoreactive RGCs receive visual information via the multiple sublayers of the inner plexiform layer. PMID- 23990104 TI - The impact of religiosity and individual prayer activities on advanced cancer patients' health: is there any difference in function of whether or not receiving palliative anti-neoplastic therapy? AB - Consecutive patients (n = 221) presenting for initial consultation at a palliative care outpatient clinic were prospectively interviewed and then followed until death. Individual prayer activity (IPA) and global religion scores were associated with quality of life, symptoms, inflammatory markers, and survival. Analyses were adjusted for whether patients were still receiving anti neoplastic therapies (ANTs) or not. Higher religion scores were associated with lower levels of inflammation in advanced cancer patients still undergoing ANTs. Additionally, higher IPA was an independent good prognostic factor in patients on active ANTs. Further studies are necessary to confirm these findings and to investigate possible biological mechanisms involved. PMID- 23990105 TI - Common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload gout, but not with all gout susceptibility. AB - Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, gout patients can be divided into those with renal overload (ROL) gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) gout. Recent genome wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 (MCT9/SLC16A9) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL gout (p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all gout cases (p = 0.10), non-ROL gout cases (p = 0.83), and RUE gout cases (p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of gout as well as the physiological roles of MCT9. PMID- 23990106 TI - Luteinizing hormone receptors are confined in mesoscale plasma membrane microdomains throughout recovery from receptor desensitization. AB - We examined the involvement of membrane microdomains during human luteinizing hormone (LH) receptor recovery from receptor desensitization after removal of bound hormone. Lateral motions of individual desensitized LH receptors expressed on the surface of Chinese hamster ovary cells and transient association of these receptors with detergent-resistant membrane (DRM) microdomains isolated using isopycnic sucrose gradient ultracentrifugation were assessed. Single particle tracking experiments showed untreated individual LH receptors to be confined within cell-surface membrane compartments with an average diameter of 199 +/- 17 nm and associated with membrane fractions characteristic of bulk plasma membrane. After brief exposure to human chorionic gonadotropin (hCG), LH receptors remained for several hours desensitized to hCG challenge. Throughout this period, significantly increased numbers of LH receptors were confined within smaller diameter (<120 nm) membrane compartments and associated with DRM fragments of characteristically low density. By 5 h, when cells again produced cAMP in response to hCG, unoccupied LH receptors were found in larger 169 +/- 22 nm diameter cell-surface membrane compartments and >90 % of LH receptors were again found in high-density membrane fragments characteristic of bulk plasma membrane. Taken together, these results suggest that, during recovery from LH receptor desensitization, LH receptors are both located with DRM lipid environments and confined within small, mesoscale (80-160 nm) cell-surface compartments. This may reflect hormone-driven translocation of receptors into DRM and formation there of protein aggregates too large or too rigid to permit effective signaling. Once bound hormone is removed, receptor structures would have to dissociate before receptors can again signal effectively in response to hormone challenge. Moreover, such larger protein complexes would be more easily constrained laterally by membrane structural elements and so appear resident in smaller cell surface compartments. PMID- 23990107 TI - Association between third molar agenesis patterns and agenesis of other teeth in a Japanese orthodontic population. AB - The purpose of this study was to investigate the patterns of third molar agenesis and incidence of agenesis of other permanent teeth in a Japanese orthodontic patient group. A total of 417 Japanese subjects (134 males and 283 females) with agenesis of one or more third molars were divided into four groups according to the agenesis pattern, and 874 other Japanese subjects (302 males and 572 females) without third molar agenesis were assigned to a control group. Panoramic radiographs and medical and dental records were used to examine for tooth agenesis. The Chi-square test and odds ratio were used to make statistical comparisons. The prevalence of third molar agenesis worked out at 32.3% with no statistically significant gender difference. A high prevalence rate of agenesis of third molars, unilateral or bilateral, could be considered characteristic of the Japanese orthodontic population. Significant increases in occurrence of oligodontia, and unilateral or bilateral agenesis of other teeth, including maxillary lateral incisors and maxillary and mandibular second premolars, were observed in all or almost all of the third molar agenesis groups, compared with the controls. A significantly increased prevalence rate of mandibular lateral incisor agenesis was observed in almost all of the third molar agenesis groups. The Japanese patients with third molar agenesis had a significantly increased occurrence of oligodontia, and unilateral or bilateral agenesis of maxillary and mandibular lateral incisors and second premolars, except for bilateral agenesis of mandibular lateral incisors. PMID- 23990108 TI - Proline and its metabolism enzymes in cucumber cell cultures during acclimation to salinity. AB - Proline is an important osmolyte appearing as the result of salt stress response of plants. In the present study, we measured the proline concentration, activities of pyrroline-5-carboxylate synthetase (P5CS), pyrroline-5-carboxylate reductase (P5CR), and proline dehydrogenase (PDH) key regulatory enzymes in the biosynthesis and degradation of proline in the acclimated (AC20) and the non acclimated (NAC) cucumber cell suspension cultures subjected to moderate (150 mM NaCl; AC20-150, NAC-150, respectively) and severe (200 mM NaCl; AC20-200, NAC 200, respectively) salt stress. The data showed that salt stress brought about a linear increase in proline content in both types of cultures. However, in the acclimated culture proline accumulation was observed earlier, in third hour after stress. Only in the acclimated culture moderate and severe stresses up-regulated P5CS activity throughout the experiment, whereas the activity of P5CR grew in response to both NaCl concentrations only in 24th and 48th hour. The severe salt stress resulted in decrease in P5CR in NAC-200 cultures. In response to salt stress, both types of cell suspension cultures reacted with decline in PDH activity below the spectrophotometrically detected level. Cell cultures vigor correlated with salt concentration and time of exposure to the stress factor. Both NaCl concentrations caused linear decline in vigor of the non-acclimated culture up to 80-90 % at the end of the experiment, whereas in the acclimated culture significant decrease by about 30-40 % was reached in 24th hour after stress. The presented data suggest that acclimation to salt stress up-regulated proline synthesis enzyme activity and caused intensive accumulations of proline by inhibiting its oxidation. PMID- 23990110 TI - Nuclear DNA content of Pongamia pinnata L. and genome size stability of in vitro regenerated plantlets. AB - Pongamia pinnata L. is a multipurpose versatile legume that is well known as a prospective feedstock biodiesel species. However, to date, there has been little genomic research aimed at the exploitation of the biotechnological potential of this species. Genetic characterization of any plant is a challenging task when there is no information about the genome size and organization of the species. Therefore, the genome size of P. pinnata was estimated by flow cytometry with respect to two standards (Zea mays and Pisum sativum), and compared with that of in vitro-raised plants (nodal segment, in vitro-rooted plantlets and acclimatized in vitro plants) to study the potential effect of somaclonal variation on genome size. This method can be used to support the establishment of true-to-type plants to encourage afforestation programs. Modified propidium iodide/hypotonic citrate buffer was used for isolation of the intact nuclei. The 2C DNA value of this species was estimated to be 2.51 +/- 0.01 pg. Statistically, there was no significant difference in the DNA content of the in vitro-grown plants and mother plant at alpha = 0.05. As a result of the low genome size of P. pinnata, a species that has adapted itself to a wide range of edaphic and ecological condition, we can now proceed for its next generation sequencing and genomic diversity studies. PMID- 23990109 TI - Cells in cells: morphogenetic and metabolic strategies conditioning rice infection by the blast fungus Magnaporthe oryzae. AB - The rice blast fungus Magnaporthe oryzae is a global food security threat due to its destruction of cultivated rice. Of the world's rice harvest, 10-30 % is lost each year to this pathogen, and changing climates are likely to favor its spread into new areas. Insights into how the fungus might be contained could come from the wealth of molecular and cellular studies that have been undertaken in order to shed light on the biological underpinnings of blast disease, aspects of which we review herein. Infection begins when a three-celled spore lands on the surface of a leaf, germinates, and develops the specialized infection structure called the appressorium. The mature appressorium develops a high internal turgor that acts on a thin penetration peg, forcing it through the rice cuticle and into the underlying epidermal cells. Primary then invasive hyphae (IH) elaborate from the peg and grow asymptomatically from one living rice cell to another for the first few days of infection before host cells begin to die and characteristic necrotic lesions form on the surface of the leaf, from which spores are produced to continue the life cycle. To gain new insights into the biology of rice blast disease, we argue that, conceptually, the infection process can be viewed as two discrete phases occurring in markedly different environments and requiring distinct biochemical pathways and morphogenetic regulation: outside the host cell, where the appressorium develops in a nutrient-free environment, and inside the host cell, where filamentous growth occurs in a glucose-rich, nitrogen-poor environment, at least from the perspective of the fungus. Here, we review the physiological and metabolic changes that occur in M. oryzae as it transitions from the surface to the interior of the host, thus enabling us to draw lessons about the strategies that allow M. oryzae cells to thrive in rice cells. PMID- 23990111 TI - Post-natalizumab clinical and radiological findings in a cohort of multiple sclerosis patients: 12-month follow-up. AB - There is an urgent need to identify the best strategies to prevent the loss of natalizumab (N) beneficial effects after its suspension. The objective is to evaluate the clinical and radiological disease activity and to test the efficacy of immunomodulatory/immunosuppressive drugs (IT) after N suspension. Clinical and radiological data from 54 patients 2 years before treatment (pre-N), during treatment (on-N) and after interruption, during 1-year follow-up (post-N) were retrospectively collected. Annualized relapse rate (ARR), expanded disability status scale (EDSS), presence of new T2 lesions and Gd+ (gadolinium enhancing) T1 lesions were evaluated. Pre-N ARR at 1 year was 1.74 while post-N ARR was 0.94 (p = 0.0053). We observed that post-N disease activity never raised over pre-N levels, neither post-N ARR nor post-N EDSS. In patients retreated with N after suspension, post-N ARR was significantly lower than pre-N ARR (p = 0.017), but not in patients treated with other IT or in patients not treated with any disease modifying drugs (DMD). The mean time of freedom from new T2 lesions and new Gd+ lesions was lower in post-N period compared to on-N (T2 lesions p = 0.0000, Gd+ lesions p = 0.0000). In conclusion, a "rebound" pattern was not identified in our cohort, though the disease activity rapidly returned after N, regardless of the treatment used. PMID- 23990112 TI - Intraosseous hemangioma arising in the clavicle. AB - Intraosseous hemangioma (IH) is commonly seen in the vertebral column and skull: however, IH occurring in the appendicular skeleton, including the clavicle, is uncommon. We herein report the case of a 69-year-old female presenting with IH of the left clavicle. The findings of preoperative imaging studies, including radiographs, computed tomography (CT), magnetic resonance imaging, fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography (PET)/CT and ultrasonography, are described. In particular, (18)F-FDG PET/CT showed an ill defined osteolytic lesion with abnormally high FDG uptake. Surgical en bloc resection with preoperative embolization was carried out and a histopathological examination confirmed the presence of an intraosseous cavernous hemangioma in the clavicle. PMID- 23990113 TI - In vitro and in vivo therapeutic efficacy of carfilzomib in mantle cell lymphoma: targeting the immunoproteasome. AB - Mantle cell lymphoma (MCL) remains incurable due to its inevitable pattern of relapse after treatment with current existing therapies. However, the promise of a cure for MCL lies in the burgeoning area of novel agents. In this study, we elucidated the therapeutic effect and mechanism of carfilzomib, a novel long acting second-generation proteasome inhibitor, in MCL cells. We found that carfilzomib induced growth inhibition and apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells was mediated by the activation of JNK, Bcl-2, and mitochondria-related pathways. In addition, carfilzomib inhibited the growth and survival signaling pathways NF kappaB and STAT3. Interestingly, we discovered that expression of immunoproteasome (i-proteasome) subunits is required for the anti-MCL activity of carfilzomib in MCL cells. In MCL-bearing SCID mice/primary MCL-bearing SCID-hu mice, intravenous administration of 5 mg/kg carfilzomib on days 1 and 2 for 5 weeks slowed/abrogated tumor growth and significantly prolonged survival. Our preclinical data show that carfilzomib is a promising, potentially less toxic treatment for MCL. Furthermore, an intact i-proteasome, especially LMP2, appears to be necessary for its anti-MCL activity, suggesting that i-proteasome could serve as a biomarker for identifying patients who will benefit from carfilzomib. PMID- 23990114 TI - SK-216, an inhibitor of plasminogen activator inhibitor-1, limits tumor progression and angiogenesis. AB - Plasminogen activator inhibitor-1 (PAI-1), which can be produced by host and tumor cells in the tumor microenvironment, is intimately involved in tumor progression. In the present study, to pursue the possibility that PAI-1 could be a therapeutic target in the management of malignancy, SK-216, a specific PAI-1 inhibitor, was orally administered to wild-type mice that were subcutaneously implanted or intravenously injected with either PAI-1-secreting Lewis lung carcinoma (LLC) or PAI-1-nonsecreting B16 melanoma cells. The systemic administration of SK-216 was found to reduce the size of subcutaneous tumors and the extent of metastases, regardless of PAI-1 secretion levels from the tumor cells. SK-216 also reduced the extent of angiogenesis in the tumors and inhibited VEGF-induced migration and tube formation by human umbilical vein endothelial cells in vitro. Then, to determine whether host or tumor PAI-1 was more crucial in tumor progression and angiogenesis, PAI-1-deficient or wild-type mice were subcutaneously implanted or intravenously injected with LLC or PAI-1 knockdown LLC cells. Tumor progression was shown to be controlled by the presence of host PAI-1 and not affected by the PAI-1 levels in the tumors. Similarly, host PAI-1 played a more crucial role in tumor angiogenesis than did tumor PAI-1. These observations suggest that regardless of the PAI-1 levels in the tumor, the systemic administration of SK-216 exerts an antitumor effect through its interaction with host PAI-1. This antitumor effect might be mediated by the antiangiogenic properties of SK-216. PMID- 23990115 TI - AMG 900, a small-molecule inhibitor of aurora kinases, potentiates the activity of microtubule-targeting agents in human metastatic breast cancer models. AB - Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubule targeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser(10), a proximal substrate of Aurora-B, and induced polyploidy and apoptosis. Furthermore, AMG 900 potentiated the antiproliferative effects of paclitaxel and ixabepilone at low nanomolar concentrations. In mice, AMG 900 significantly inhibited the growth of MDA-MB-231 (F(11); parental), MDA MB-231 (F(11)) PTX-r (paclitaxel-resistant variant), and DU4475 xenografts. The combination of AMG 900 with docetaxel enhanced tumor inhibition in MDA-MB-231 (F(11)) xenografts compared with either monotherapy. Notably, combining AMG 900 with ixabepilone resulted in regressions of MDA-MB-231 (F(11)) PTX-r xenografts, in which more than 50% of the tumors failed to regrow 75 days after the cessation of drug treatment. These findings suggest that AMG 900, alone and in combination with MTAs, may be an effective intervention strategy for the treatment of metastatic breast cancer and provide potential therapeutic options for patients with multidrug-resistant tumors. PMID- 23990116 TI - Investigation of the hostile attribution bias toward ambiguous facial cues in antisocial violent offenders. AB - Aggressive individuals exhibit a strong tendency to attribute hostile intent to the behavior of others, which may lead to provocation and aggravation of socially inappropriate reactions. Limited research has investigated the hostile attribution bias in the perception of facial affect. This study examined a hostile response bias to emotionally ambiguous faces in a population of 55 incarcerated antisocial violent offenders as compared to matched control subjects. Results suggest that aggression is associated with a strong preference to interpret ambiguous stimuli containing proportions of an angry expression as hostile, while there was no evidence for a generally biased interpretation of distress cues under conditions of uncertainty. Thus, the tendency to misinterpret nonverbal cues in social interactions may at least partly underlie aggressive impulsive behavior in susceptible individuals. PMID- 23990117 TI - Thoracic and cardiovascular surgery in Japan during 2011: Annual report by The Japanese Association for Thoracic Surgery. PMID- 23990118 TI - Successful repair of aortic annulus rupture during transcatheter aortic valve replacement using extracorporeal membrane oxygenation support. AB - Aortic annular rupture is a rare and much dreaded complication of transcatheter aortic valve replacement. Device oversizing to prevent post-procedural paravalvular leak is the most commonly identified cause of this complication. However, mechanical stress in a heavily calcified non-compliant vessel can also lead to annular rupture in this older population. We describe a case of aortic annular rupture with involvement of right coronary artery ostium leading to cardiac tamponade and cardiac arrest, successfully managed by extracorporeal membrane oxygenation support, open drainage of the pericardial space, pericardial patching of the defect and bypass of the affected vessel with excellent post procedural results. PMID- 23990119 TI - Comparative evaluation of porous versus nonporous mucoadhesive films as buccal delivery system of glibenclamide. AB - The present research work focused on the comparative assessment of porous versus nonporous films in order to develop a suitable buccoadhesive device for the delivery of glibenclamide. Both films were prepared by solvent casting technique using the 3(2) full factorial design, developing nine formulations (F1-F9). The films were evaluated for ex vivo mucoadhesive force, ex vivo mucoadhesion time, in vitro drug release (using a modified flow-through drug release apparatus), and ex vivo drug permeation. The mucoadhesive force, mucoadhesion time, swelling index, and tensile strength were observed to be directly proportional to the content of HPMC K4M. The optimized porous film (F4) showed an in vitro drug release of 84.47 +/- 0.98%, ex vivo mucoadhesive force of 0.24 +/- 0.04 N, and ex vivo mucoadhesion time of 539.11 +/- 3.05 min, while the nonporous film (NF4) with the same polymer composition showed a release of 62.66 +/- 0.87%, mucoadhesive force of 0.20 +/- 0.05 N, and mucoadhesive time of 510 +/- 2.00 min. The porous film showed significant differences for drug release and mucoadhesion time (p < 0.05) versus the nonporous film. The mechanism of drug release was observed to follow non-Fickian diffusion (0.1 < n < 0.5) for both porous and nonporous films. Ex vivo permeation studies through chicken buccal mucosa indicated improved drug permeation in porous films versus nonporous films. The present investigation established porous films to be a cost-effective buccoadhesive delivery system of glibenclamide. PMID- 23990120 TI - Stability of benzocaine formulated in commercial oral disintegrating tablet platforms. AB - Pharmaceutical excipients contain reactive groups and impurities due to manufacturing processes that can cause decomposition of active drug compounds. The aim of this investigation was to determine if commercially available oral disintegrating tablet (ODT) platforms induce active pharmaceutical ingredient (API) degradation. Benzocaine was selected as the model API due to known degradation through ester and primary amino groups. Benzocaine was either compressed at a constant pressure, 20 kN, or at pressure necessary to produce a set hardness, i.e., where a series of tablets were produced at different compression forces until an average hardness of approximately 100 N was achieved. Tablets were then stored for 6 months under International Conference on Harmonization recommended conditions, 25 degrees C and 60% relative humidity (RH), or under accelerated conditions, 40 degrees C and 75% RH. Benzocaine degradation was monitored by liquid chromatography-mass spectrometry. Regardless of the ODT platform, no degradation of benzocaine was observed in tablets that were kept for 6 months at 25 degrees C and 60% RH. After storage for 30 days under accelerated conditions, benzocaine degradation was observed in a single platform. Qualitative differences in ODT platform behavior were observed in physical appearance of the tablets after storage under different temperature and humidity conditions. PMID- 23990123 TI - Effects of anger, disgust, and sadness on sharing with others. AB - Although scholars have suggested that emotions are important for social dilemmas, extant research has neither documented, nor directly studied the influence of anger, disgust, or sadness on choices that involve social dilemmas. What is more, research that looks at social dilemmas typically examines public good dilemmas (e.g., giving resources to a group) and resource dilemmas (e.g., taking resources from a group) separately. Rarely are both dilemmas examined simultaneously, a potential oversight considering research on decision-making implicates give-and take differences. In this paper, we propose that an important part of cooperating in different social dilemmas involves emotionally guided goals, termed emotivations. For example, emotivations include: in anger, wanting to antagonize others; in disgust, wanting to expel objects and avoid taking anything new; and in sadness, wanting to change one's situation. We suggest that the amount of shared group resources that people give and take is associated with each of these particular emotivations. PMID- 23990122 TI - Challenging treatment decision-making in older urologic cancer patients. AB - PURPOSE: Cancer is the leading cause of death among patients aged 65 years and older. In this population, the cancer diagnosis is often made at a more advanced stage and worse prognosis than in younger patients. Specific mortality in older patients is superior to that reported in their younger counterparts. Moreover, the impact of curative treatment that has proven benefit in overall population may be not well studied in the sub-group of older patients. Thus, the management of cancer in the elderly is a major public health concern in most Western countries. METHODS/RESULTS: In this review, we summarize this challenging treatment decision-making in older urologic patients with prostate, kidney or bladder cancer. The estimation of life expectancy remains a difficult task. Chronological age should not be considered as the main decisive factor anymore when considering aggressive cancer treatment. Comorbidities increase the complexity of cancer management and affect survival. Multidisciplinary evaluation and comprehensive geriatrics assessment using specific scales are critical to improve the treatment decision-making and to minimize both overtreatment of low risk disease and undertreatment of high-risk disease. When an aggressive and potential quality-of-life-threatening treatment is scheduled after this comprehensive geriatrics assessment, personalized patient care must be early predefined by the geriatric team. CONCLUSIONS: In the elderly, an enhanced support including specific geriatric assessment and management optimizes the treatment course, including preoperative optimization, prevents treatment-related complications and loss of autonomy using or not geriatrics clinic or rehabilitation units, and limits the length of hospital stay and costs. PMID- 23990121 TI - Evaluation of the impacts of formulation variables and excipients on the drug release dynamics of a polyamide 6,10-based monolithic matrix using mathematical tools. AB - Drug release from hydrophilic matrices is regulated mainly by polymeric erosion, disentanglement, dissolution, swelling front movement, drug dissolution and diffusion through the polymeric matrix. These processes depend upon the interaction between the dissolution media, polymeric matrix and drug molecules, which can be significantly influenced by formulation variables and excipients. This study utilized mathematical parameters to evaluate the impacts of selected formulation variables and various excipients on the release performance of hydrophilic polyamide 6,10 (PA 6,10) monolithic matrix. Amitriptyline HCl and theophylline were employed as the high and low solubility model drugs, respectively. The incorporation of different excipient concentrations and changes in formulation components influenced the drug release dynamics as evidenced by computed mathematical quantities (t x%, MDT x%, f 1, f 2, k 1, k 2, and K F). The effects of excipients on drug release from the PA 6,10 monolithic matrix was further elucidated using static lattice atomistic simulations wherein the component energy refinements corroborates the in vitro and in silico experimental data. Consequently, the feasibility of modulating release kinetics of drug molecules from the novel PA 6,10 monolithic matrix was well suggested. PMID- 23990124 TI - Integrated environmental assessment of freshwater sediments: a chemical and ecotoxicological approach at the Alqueva reservoir. AB - In order to study the pollution of an aquatic ecosystem, it is necessary to analyze not only the levels of chemical pollutants in water, but also those accumulated in the sediment matrix, as well as to assess its ecotoxicological status. The Alqueva reservoir, the largest artificial lake in Europe, was chosen as case study as it constitutes the most important water supply source in southern Portugal. It is located in the Guadiana River Basin, in a semi-arid region with high levels of water scarcity and where agriculture is one of the main activities. The evaluation of sediments comprised: (1) physical and chemical analysis (grain size, pH, organic matter, nitrogen, phosphorus); (2) potentially toxic trace elements (Cu, As, Pb, Cr, Cd, Zn and Ni); and (3) ecotoxicological evaluation with Vibrio fischeri, Thamnocephalus platyurus, Daphnia magna, and Heterocypris incongruens. Total trace element concentrations indicated that As, Cd, and Pb surpassed the Canadian levels for the protection of aquatic life, in most of Alqueva's sites. The results of the toxicity assessment showed that some locations induced acute and chronic toxicity in the species used. Further, the H. incongruens was the most sensitive species as far as the contamination found in the sediment is concerned, followed by the bacteria V. fischeri. This integrative approach, together with the water column quality assessment, allowed a comprehensive evaluation of the environmental quality of this strongly modified water body and will allow the implementation of remediation strategies to obtain a good ecological potential as proposed in the Water Framework Directive. PMID- 23990125 TI - Characterization of indoor dust from Brazil and evaluation of the cytotoxicity in A549 lung cells. AB - Over the past decade, ambient air particulate matter (PM) has been clearly associated with adverse health effects. In Brazil, small and poor communities are exposed to indoor dust derived from both natural sources, identified as blowing soil dust, and anthropogenic particles from mining activities. This study investigates the physicochemical and mineralogical composition of indoor PM10 dust samples collected in Minas Gerais, Brazil, and evaluates its cytotoxicity and inflammatory potential. The mean PM10 mass concentration was 206 MUg/m(3). The high dust concentration in the interior of the residences is strongly related to blowing soil dust. The chemical and mineralogical compositions were determined by ICP-OES and XRD, and the most prominent minerals were clays, Fe-oxide, quartz, feldspars, Al(hydr)oxides, zeolites, and anatase, containing the transition metals Fe, Cr, V, Ni, Cu, Zn, Ti, and Mn as well as the metalloid As. The indoor dust samples presented a low water solubility of about 6 %. In vitro experiments were carried out with human lung alveolar carcinoma cells (A549) to study the toxicological effects. The influence of the PM10 dust samples on cell viability, intracellular formation of reactive oxygen species (ROS), and release of the pro inflammatory cytokine IL-8 was analysed. The indoor dust showed little effects on alamarBlue reduction indicating unaltered mitochondrial activity. However, significant cell membrane damage, ROS production, and IL-8 release were detected in dependence of dose and time. This study will support the implementation of mitigation actions in the investigated area in Brazil. PMID- 23990126 TI - Assessing human exposure to aluminium, chromium and vanadium through outdoor dust ingestion in the Bassin Minier de Provence, France. AB - The Western part of the "Bassin Minier de Provence", a former coal mining area, is still occupied by old polluting industries such as a coal-fired power plant and an alumina factory. The identified pollution sources that raise more concern in the population are the emission of gases and dusts, as well as the storage of raw and transformed materials. In 2011, a preliminary survey was carried out in the area as the first step to an exposure and health risk-assessment study. This first survey intends to assess human exposure through ingestion and health risk associated with potentially harmful elements (PHEs) in ground-level dusts collected in recreational areas used by children. Dust samples were taken at 19 sites distributed across the study area, depending on the location of public parks, public gardens, playgrounds and schools. Pseudo-total concentrations of 53 elements were determined by ICP-MS. Bioaccessible concentrations were estimated using the unified bioaccessibility method. This study presents the results obtained for Al, V and Cr, which seem to be related with industry and show similar distribution patterns. PHEs presumably related to traffic or other urban pollution sources are not discussed in this study. The highest total concentrations occur in dusts near the alumina plant that have significant amounts of Al mineral phases (gibbsite and alumina). However, in these dusts only small fractions of the elements under study are in bioaccessible forms. The highest bioaccessible fractions occur in dusts collected near the coal-fired power plant. Further investigation is required to assess potential pathways of exposure and health risk in this area. PMID- 23990127 TI - Arsenic input into the catchment of the River Caudal (Northwestern Spain) from abandoned Hg mining works: effect on water quality. AB - In Asturias (NW Spain) there are many abandoned mines, of which Hg mines are of particular significance from an environmental point of view, due to the presence of Hg and particularly As, which is found either in the form of specific (orpiment and realgar) or non-specific minerals (As-rich pyrite). The instability of these minerals leads to the presence of As-rich mine drainage and spoils heap leachates that enter surface waters or groundwaters. A study including the three most important Hg mines in the region (La Soterrana, Los Rueldos and El Terronal) has been conducted. Watercourses flowing through these mining areas are tributaries of the River Caudal, one of the most important rivers in the area. High concentrations of As were found in some of these waters, which were monitored over a period of three hydrological years and classified according to a water quality index. Those waters sampled close to the mines are generally of poor-to-bad quality, with low alkalinity and in some cases high metal content, but the quality of these waters improves with distance from the mines. The average mass load of As entering the River Caudal has been evaluated as: 200, 12 and 9,800 kg year(-1) from La Soterrana, Los Rueldos and El Terronal mine sites, respectively. Despite the constant input of about 10 tonnes of As per year, the total As concentration remains below analytical detection thresholds on account of the river's high water flow. Nevertheless, an important part of this As load is presumably retained in the river sediments, representing a potential risk of pollution of the aquatic ecosystems. PMID- 23990129 TI - Feasibility test of utilizing Saccharophagus degradans 2-40(T) as the source of crude enzyme for the saccharification of lignocellulose. AB - In the conversion of lignocellulose into high-value products, including fuels and chemicals, the production of cellulase and the enzymatic hydrolysis for producing fermentable sugar are the largest contributors to the cost of production of the final products. The marine bacterium Saccharophagus degradans 2-40(T) can degrade more than ten different complex polysaccharides found in the ocean, including cellulose and xylan. Accordingly, S. degradans has been actively considered as a practical source of crude enzymes needed for the saccharification of lignocellulose to produce ethanol by others including a leading commercial company. However, the overall enzyme system of S. degradans for hydrolyzing cellulose and hemicellulose has not been quantitatively evaluated yet in comparison with commercial enzymes. In this study, the inductions and activities of cellulase and xylanase of cell-free lysate of S. degradans were investigated. The growth of S. degradans cells and the activities of cellulase and xylanase were promoted by adding 2 % of cellulose and xylan mixture (cellulose:xylan = 4:3 in mass ratio) to the aquarium salt medium supplemented with 0.2 % glucose. The specific cellulase activity of the cell-free lysate of S. degradans, as determined by the filter paper activity assay, was approximately 70 times lower than those of commercial cellulases, including Celluclast 1.5 L and Accellerase 1000. These results imply that significant improvement in the cellulase activity of S. degradans is needed for the industrial uses of S. degradans as the enzyme source. PMID- 23990130 TI - Alteration in the balance of prosurvival and proapoptotic signalling pathways leads to sequence-dependent synergism between docetaxel and sorafenib in human non-small cell lung cancer cell lines. AB - To examine the antiproliferative effect of the combination of docetaxel and sorafenib, applied to the representative non-small cell lung cancer cell line A549 cells either wild type or with acquired resistance to docetaxel (A549/D). The aim of this study is to evaluate the synergistic effect of combination treatment on cell growth inhibition and to elucidate the involved molecular mechanisms. A549 cells with acquired resistance to docetaxel were established by continuous exposure to docetaxel. We examined the effect of different combinatorial treatment on cell proliferation and cell cycle distribution. In addition, the effect of combinatorial treatments on proliferative and apoptotic signalling pathway were studied. Our results showed that the synergistic effect presented when A549 cells were treated with docetaxel followed by sorafenib or when A549/D cells were treated in reverse sequence. Furthermore, we suggested that synergistic effect in A549/D cells was caused by inhibiting P-gp function and altering in the balance of growth and apoptotic signalling pathways. Our data suggested a potential role of sorafenib in chemosensitizing docetaxel-resistant cancer cells. This study also provides molecular evidence for applying different therapeutic strategies for patients with different genetic and proteomic profile. PMID- 23990131 TI - Dissociation of a population of Pectobacterium atrosepticum SCRI1043 in tobacco plants: formation of bacterial emboli and dormant cells. AB - The population dynamics of Pectobacterium atrosepticum SCRI1043 (Pba) within tobacco plants was monitored from the time of inoculation until after long-term preservation of microorganisms in the remnants of dead plants. We found and characterised peculiar structures that totally occlude xylem vessels, which we have named bacterial emboli. Viable but non-culturable (VBN) Pba cells were identified in the remnants of dead plants, and the conditions for resuscitation of these VBN cells were established. Our investigation shows that dissociation of the integrated bacterial population during plant colonisation forms distinct subpopulations and cell morphotypes, which are likely to perform specific functions that ensure successful completion of the life cycle within the plant. PMID- 23990128 TI - Serotonergic modulation of hippocampal theta activity in relation to hippocampal information processing. AB - Hippocampal theta activity is the result of the concerted activity of a group of nuclei located in the brain stem and the caudal diencephalic area, which are together referred to as the synchronizing ascending system. Serotonin is recognized as the only neurotransmitter able to desynchronize the hippocampal electroencephalographic. A theory has been developed in which serotonin, acting on medial septal neurons, modulates cholinergic/GABAergic inputs to the hippocampus and, thus, the cognitive processing mediated by this area. However, few studies have addressed the relationship between serotonin modulation of theta activity and cognition. In this review, we present a summary and analysis of the data relating serotonin and its theta activity modulation with cognition, and we also discuss the few works relating serotonin, theta activity and cognition as well as the theories regarding the serotonin regulation of memory processes organized by the hippocampus. We propose that serotonin depletion induces impairment of the relays coding the frequency of hippocampal theta activity, whereas depletion of the relays in which frequency is not coded induces improvements in spatial learning that are related to increased expression of high frequency theta activity. PMID- 23990132 TI - Insights into the roles of exogenous glutamate and proline in improving streptolydigin production of Streptomyces lydicus with metabolomic analysis. AB - The addition of precursors was one strategy to improve antibiotic production. The exogenous proline and glutamate, as precursors of streptolydigin, could significantly improve the streptolydigin production, but their underlying molecular mechanisms remain unknown. Herein, metabolomic analysis was carried out to explore the metabolic responses of Streptomyces lydicus to the additions of proline and glutamine. The significant differences in the quantified 53 metabolites after adding the exogenous proline and glutamate were enunciated by gas chromatography coupled to time-of-flight mass spectrometry. Among them, the levels of some fatty acids (e.g., dodecanoic acid, octadecanoic acid, hexadecanoic acid) were significantly decreased after adding glutamate and proline, indicating that the inhibition of fatty acid synthesis might be benefit for the accumulation of streptolydigin. Particularly, the dramatic changes of the identified metabolites, which are involved in glycolysis, the tricarboxylic acid cycle, and the amino acid and fatty acid metabolism, revealed that the additions of glutamate and proline possibly caused the metabolic cross-talk in S. lydicus. Additionally, the level of intracellular glutamate dramatically enhanced at 12 h after adding proline, showing that exogenous proline may be firstly convert into glutamate and consequently result in crease of the streptolydigin production. The high levels of streptolydigin at 12 and 24 h after adding glutamate unveiled that part glutamate were rapidly used to synthesize the streptolydigin. Furthermore, there is the significant difference in metabolomic characteristics of S. lydicus after adding glutamate and proline, uncovering that multiple regulatory pathways are involved in responses to the additions of exogenous glutamate and proline. Taken together, exogenous glutamate and proline not only directly provided the precursors of streptolydigin biosynthesis, but also might alter the metabolic homeostasis of S. lydicus E9 during improving the production of streptolydigin. PMID- 23990133 TI - Genome mining of the Streptomyces avermitilis genome and development of genome minimized hosts for heterologous expression of biosynthetic gene clusters. AB - To date, several actinomycete genomes have been completed and annotated. Among them, Streptomyces microorganisms are of major pharmaceutical interest because they are a rich source of numerous secondary metabolites. S. avermitilis is an industrial microorganism used for the production of an anthelmintic agent, avermectin, which is a commercially important antiparasitic agent in human and veterinary medicine, and agricultural pesticides. Genome analysis of S. avermitilis provides significant information for not only industrial applications but also understanding the features of this genus. On genome mining of S. avermitilis, the microorganism has been found to harbor at least 38 secondary metabolic gene clusters and 46 insertion sequence (IS)-like sequences on the genome, which have not been searched so far. A significant use of the genome data of Streptomyces microorganisms is the construction of a versatile host for heterologous expression of exogenous biosynthetic gene clusters by genetic engineering. Since S. avermitilis is used as an industrial microorganism, the microorganism is already optimized for the efficient supply of primary metabolic precursors and biochemical energy to support multistep biosynthesis. The feasibility of large-deletion mutants of S. avermitilis has been confirmed by heterologous expression of more than 20 exogenous biosynthetic gene clusters. PMID- 23990134 TI - The cryo-needle: a new tool for histological biopsies. A feasibility study. AB - PURPOSE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is a standard procedure for intrathoracic lymph node biopsies. The newly developed cryo-needle operates in a similar way to the EBUS-TBNA but is able to obtain specimens for histological evaluation. The purpose of this animal study was to evaluate the feasibility, effect, and safety of the cryo-needle biopsies. METHODS: Four EBUS-guided cryo-needle biopsies were obtained from a mediastinal lymph node of a healthy pig. In an open surgery approach, cryo-needle biopsies using activation times of 1, 2, and 3 s (A1/A2/A3) and needle biopsies using a 21 gauge EBUS-TBNA needle were obtained from mesenteric lymph nodes. Cryo-needle biopsies A2 were performed with (A2+) and without (A2-) an oversheath. The size, weight, percentage of lymphatic tissue and artefact-free area of each cryobiopsy were evaluated. Smears were made with the TBNA-needle aspirates to determine the number of lymphocytes per high-power field (HPF). The bleeding duration was measured. RESULTS: We successfully obtained EBUS-guided cryo-needle biopsies. The area and weight of the biopsies A3 and A2+ were significantly larger compared with A1 (1.7 +/- 0.8 and 1.4 +/- 0.3 vs. 0.9 +/- 0.4 mm(2); 5.2 +/- 2.4 and 3.4 +/- 1.8 vs. 1.5 +/- 0.7 mg). The percentage of lymphatic tissue of the cryobiopsies was 90 +/- 25 and 98 % of samples were artefact-free. The number of lymphocytes/HPF of TBNA-needle smears was 128 +/- 54.3. There was no difference in bleeding duration between the techniques. CONCLUSIONS: The cryo-needle yields large histological specimens of high quality. PMID- 23990135 TI - Shigellosis in Bay of Bengal Islands, India: clinical and seasonal patterns, surveillance of antibiotic susceptibility patterns, and molecular characterization of multidrug-resistant Shigella strains isolated during a 6-year period from 2006 to 2011. AB - This study aims to determine the clinical features and seasonal patterns associated with shigellosis, the antimicrobial resistance frequencies of the isolates obtained during the period 2006-2012 for 22 antibiotics, and the molecular characterization of multidrug-resistant strains isolated from endemic cases of shigellosis in the remote islands of India, with special reference to fluoroquinolone and third-generation cephalosporins resistance. During the period from January 2006 to December 2011, stool samples were obtained and processed to isolate Shigella spp. The isolates were evaluated with respect to their antibiotic resistance pattern and various multidrug resistance determinants, including resistance genes, quinolone resistance determinants, and extended spectrum beta-lactamase (ESBL) production. Morbidity for shigellosis was found to be 9.3 % among children in these islands. Cases of shigellosis occurred mainly during the rainy seasons and were found to be higher in the age group 2-5 years. A wide spectrum of resistance was observed among the Shigella strains, and more than 50 % of the isolates were multidrug-resistant. The development of multidrug resistant strains was found to be associated with various drug-resistant genes, multiple mutations in the quinolone resistance-determining region (QRDR), and the presence of plasmid-mediated quinolone-resistant determinants and efflux pump mediators. This report represents the first presentation of the results of long term surveillance and molecular characterization concerning antimicrobial resistances in clinical Shigella strains in these islands. Information gathered as part of the investigations will be instrumental in identifying emerging antimicrobial resistance, for developing treatment guidelines appropriate for that community, and to provide baseline data with which to compare outbreak strains in the future. PMID- 23990136 TI - Heterogeneity among septic shock patients in a set of immunoregulatory markers. AB - Immune activation is a regular feature of sepsis, but the incidence and nature of the ensuing inflammation-resolving and immunosuppressive component is less well understood. In this study, we compared immunoregulatory markers on blood leukocytes from patients with Gram-negative or Gram-positive sepsis or septic shock, and compared this to blood from patients with severe virosis or healthy controls. To this end, blood from 32 patients with sepsis, including ten cases with shock, and 12 patients with severe virosis were analysed by flow cytometry for the expression levels of monocyte HLA-DR, CD11c, CD14 and CD40, and for frequencies of CD163(+)-suppressive monocytes, HLA-DR(+) or CD40(+)-activated T cells and Tregs. Plasma cytokine levels were analysed as a functional measurement. Signs of immunosuppression dominated in the septic shock and Gram positive sepsis groups, whereas monocyte activation was common in Gram-negative sepsis patients without shock. However, the main finding was the large inter individual variation of immune activation and immunosuppression, with no correlation to prognosis among the shock patients. The pronounced inter individual variation in the analysed monocyte and lymphocyte markers forms a strong argument that, when immunomodulatory treatment is considered in a sepsis patient, it should be personalised and guided by a detailed immune status assessment. PMID- 23990137 TI - Pneumocystis jirovecii (Pj) quantitative PCR to differentiate Pj pneumonia from Pj colonization in immunocompromised patients. AB - Conventional polymerase chain reaction (PCR) in respiratory samples does not differentiate between Pneumocystis pneumonia (PCP) and Pneumocystis jirovecii (Pj) colonization. We used Pj real-time quantitative PCR (qPCR) with the objective to discriminate PCP from Pj colonization in immunocompromised patients. All positive Pj qPCR [targeting the major surface glycoprotein (MSG) gene] obtained in respiratory samples from immunocompromised patients presenting pneumonia at the Grenoble University Hospital, France, were collected between August 2009 and April 2011. Diagnoses were retrospectively determined by a multidisciplinary group of experts blinded to the Pj qPCR results. Thirty-one bronchoalveolar lavages and four broncho aspirations positive for the Pj qPCR were obtained from 35 immunocompromised patients. Diagnoses of definite, probable, and possible PCP, and pneumonia from another etiology were retrospectively made for 7, 4, 5, and 19 patients, respectively. Copy numbers were significantly higher in the "definite group" (median 465,000 copies/ml) than in the "probable group" (median 38,600 copies/ml), the "possible group" (median 1,032 copies/ml), and the "other diagnosis group" (median 390 copies/ml). With the value of 3,160 copies/ml, the sensitivity and specificity of qPCR for the diagnosis of PCP were 100 % and 70 %, respectively. With the value of 31,600 copies/ml, the sensitivity and specificity were 80 % and 100 %, respectively. The positive predictive value was 100 % for results with more than 31,600 copies/ml and the negative predictive value was 100 % for results with fewer than 3,160 copies/ml. qPCR targeting the MSG gene can be helpful to discriminate PCP from Pj colonization in immunocompromised patients, using two cut-off values, with a gray zone between them. PMID- 23990138 TI - Modest correlation between serum neopterin levels and Gensini scores in a cohort of patients undergoing coronary angiography. AB - OBJECTIVE: We initially tried to study the possible correlation between the severity of coronary artery disease (CAD) and serum neopterin levels in stable coronary artery disease patients. Also we tried to investigate the neopterin as an indicator for the extent of CAD using the Gensini score. METHODS: A total of 40 patients with stable angina pectoris who are chosen for coronary angiography were selected for the study. Before the angiography procedure, blood samples were taken for the measurement of serum neopterin levels and the results of the coronary angiography were scored according to the Gensini scoring system. RESULTS: Neopterin levels were correlated with the Gensini scores [p = 0.010, rho = 0.401] and a correlation between the age of patient population and Gensini score was also observed in the study [p = 0.016, rho = 0.380]. CONCLUSION: By the guidance of our results, we can confidently state that there is a correlation between serum neopterin levels and the severity and extent of CAD in stable coronary artery disease patients. PMID- 23990139 TI - Experience with a "hotline" service for outpatients on a ventricular assist device. AB - OBJECTIVES: With the growing number of outpatients on ventricular assist devices (VADs), there is an increasing need for "home discharge programs." One important feature is a 24-hour telephone service. In our center, the perfusionists run a so called "hotline" for all of our VAD patients. This study analyzes the hotline calls with regard to frequency, the reason for calling, and the type of action undertaken. PATIENTS AND METHODS: Over a period of 5 years, 16 (12 EXCOR and 4 INCOR; Berlin Heart, Berlin, Germany) of 33 VAD patients (48%) were discharged and instructed to use the "hotline" service. All the calls received by the perfusionists were reviewed. We classified the calls into three levels according to the severity of the problem: Level (L) 1 = assistance provided by the perfusionist alone; L2 = calls requiring discussion with the surgeon on duty and/or visit to the outpatient clinic ahead of time; and L3 = immediate action and/or admission to the hospital. RESULTS: Over a period of 2,890 outpatient days (7.9 years), a total of 26 calls were registered. There were 0.9 calls per 100 patient days and 1.6 calls per discharged patient. Out of the 26 calls, 14 calls (54%) were classified as L1, 8 (31%) as L2, and 4 (15%) as L3. The most frequent reasons for L1 or L2 calls were fibrin deposits in the EXCOR pump chamber (39%), followed by battery dysfunction (19%). L3 calls were related to dysfunction of the EXCOR driving units in three cases and to an EXCOR pump chamber disconnection, which the patient did not survive. CONCLUSIONS: The institution of a hotline is an essential component of a VAD outpatient program. It provides a certain level of safety for the patient, although a residual risk remains. PMID- 23990140 TI - Dual source computed tomography in patients with congenital heart disease. AB - OBJECTIVES: The objective of this study was to review our early experience with the dual source computed tomography (DSCT), a recently available scanner technique equipped with two X-ray tubes and two detectors, in the context of congenital cardiac malformations. PATIENTS AND METHODS: We reviewed 40 pediatric patients with congenital heart disease (CHD) who underwent DSCT between September 2009 and December 2011 as diagnostic imaging tool for surgical procedures. RESULTS: The median age was 0.36 years (range: 3 days to 44 years). Great vessels (n = 13), cardiac anatomy (n = 13), trachea and vascular rings (n = 7), pulmonary veins (n = 4), and coronary arteries (n = 3) were focused on, which revealed important information for surgery. Scanning quality was affected in only two cases (metal artifacts and tachycardia). Overall median age-specific dose was 1.47 mSv. In patients younger than 1 year (n = 26), median dose was 1.28 mSv. CONCLUSION: DSCT allows a very rapid scan speed, examinations are performed in spontaneously breathing patients, and the radiation exposure is relatively low. It is very valuable in the setting of complex surgery by revealing the position of anatomical structures in their relation to each other. Missing information can be acquired less invasively in addition to echocardiography and might replace cardiac catheterization for several morphological indications. PMID- 23990141 TI - Muscle flaps and thoracomyoplasty: alternative solution for unresectable primary pulmonary abscesses. AB - BACKGROUND: The objective of this study is to perform a retrospective analysis of our experience in using muscle flaps and thoracomyoplasty for unresectable primary pulmonary abscesses. MATERIALS AND METHODS: Between January 1, 2003, and January 1, 2012, we have used different muscle flaps and thoracomyoplasty in 15 patients with unresectable primary pulmonary abscesses. Muscle transposition was used alone (3 cases) or during thoracomyoplasty procedures for lung abscesses complicated with empyema (12 cases). The objective of the procedure was complete obliteration of the diseased space, with additional limited thoracoplasty being required in 12 out of 15 patients (average resected ribs: 3.7); bronchial fistula were encountered in 9 patients and were closed-reinforced using muscle flaps. The following parameters were followed: mortality, morbidity, intensive care and overall postoperative hospitalization, recurrence, and late sequelae. RESULTS: We have encountered one postoperative death (6.7%) and an overall 46.7% morbidity. Intensive-care unit stay ranged between 1 and 5 days with a median of 2. Overall postoperative hospitalization ranged between 22 and 46 days, with a median of 32 days. At late 1-year follow-up, we encountered no recurrence and no major chest deformity with a moderate limitation of shoulder mobility in two patients. CONCLUSION: Space-filling procedures are a valuable solution for unresectable primary pulmonary abscesses, allowing the avoidance of open drainage and pleuropneumonectomy. The extensive mobilization of the flaps offers a good quality biological material with considerable volume. PMID- 23990142 TI - The Arabidopsis thaliana RNA editing factor SLO2, which affects the mitochondrial electron transport chain, participates in multiple stress and hormone responses. AB - Recently, we reported that the novel mitochondrial RNA editing factor SLO2 is essential for mitochondrial electron transport, and vital for plant growth through regulation of carbon and energy metabolism. Here, we show that mutation in SLO2 causes hypersensitivity to ABA and insensitivity to ethylene, suggesting a link with stress responses. Indeed, slo2 mutants are hypersensitive to salt and osmotic stress during the germination stage, while adult plants show increased drought and salt tolerance. Moreover, slo2 mutants are more susceptible to Botrytis cinerea infection. An increased expression of nuclear-encoded stress responsive genes, as well as mitochondrial-encoded NAD genes of complex I and genes of the alternative respiratory pathway, was observed in slo2 mutants, further enhanced by ABA treatment. In addition, H2O2 accumulation and altered amino acid levels were recorded in slo2 mutants. We conclude that SLO2 is required for plant sensitivity to ABA, ethylene, biotic, and abiotic stress. Although two stress-related RNA editing factors were reported very recently, this study demonstrates a unique role of SLO2, and further supports a link between mitochondrial RNA editing events and stress response. PMID- 23990143 TI - Predictive value of pre-therapy (18)F-FDG PET/CT for the outcome of (18)F-FDG PET guided radiotherapy in patients with head and neck cancer. AB - PURPOSE: The aim of this study was to evaluate the predictive role of pre-therapy fluorodeoxyglucose (FDG) uptake parameters of primary tumour in head and neck cancer (HNC) patients undergoing intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) on FDG-positive volume-positron emission tomography (PET) gross tumour volume (PET-GTV). METHODS: This retrospective study included 19 patients (15 men and 4 women, mean age 59.2 years, range 23-81 years) diagnosed with HNC between 2005 and 2011. Of 19 patients, 15 (79 %) had stage III IV. All patients underwent FDG PET/CT before treatment. Metabolic indexes of primary tumour, including metabolic tumour volume (MTV), maximum and mean standardized uptake value (SUVmax, SUVmean) and total lesion glycolysis (TLG) were considered. Partial volume effect correction (PVC) was performed for SUVmean and TLG estimation. Correlations between PET/CT parameters and 2-year disease free survival (DFS), local recurrence-free survival (LRFS) and distant metastasis free survival (DMFS) were assessed. Median patient follow-up was 19.2 months (range 4-24 months). RESULTS: MTV, TLG and PVC-TLG predicting patients' outcome with respect to all the considered local and distant disease control endpoints (LRFS, DMFS and DFS) were 32.4 cc, 469.8 g and 547.3 g, respectively. SUVmean and PVC-SUVmean cut-off values predictive of LRFS and DFS were 10.8 and 13.3, respectively. PVC was able to compensate errors up to 25 % in the primary HNC tumour uptake. Moreover, PVC enhanced the statistical significance of the results. CONCLUSION: FDG PET/CT uptake parameters are predictors of patients' outcome and can potentially identify patients with higher risk of treatment failure that could benefit from more aggressive approaches. Application of PVC is recommended for accurate measurement of PET parameters. PMID- 23990145 TI - Perceptions of partner sexual satisfaction in heterosexual committed relationships. AB - Sexual script theory implies that partners' ability to gauge one another's level of sexual satisfaction is a key factor in determining their own sexual satisfaction. However, relatively little research has examined how well partners gauge one another's sexual satisfaction and the factors that predict their accuracy. We hypothesized that the degree of bias in partner judgments of sexual satisfaction would be associated with quality of sexual communication. We further posited that emotion recognition would ameliorate the biases in judgment such that poor communicators with good emotion recognition would make less biased judgments of partner satisfaction. Participants were 84 married or cohabiting heterosexual couples who completed measures of their own and their partners' sexual satisfaction, relationship satisfaction, quality of communication about sexual issues within their relationships, and emotion recognition ability. Results indicated that both men and women tended to be accurate in perceiving their partners' levels of sexual satisfaction (i.e., partner perceptions were strongly correlated with self-reports). One sample t-tests indicated that men's perceptions of their partners' sexual satisfaction were biased such that they slightly underestimated their partners' levels of sexual satisfaction whereas women neither over- nor underestimated their partners' sexual satisfaction. However, the gender difference was not significant. Bias was attenuated by quality of sexual communication, which interacted with emotion recognition ability such that when sexual communication was good, there was no significant association between emotion recognition ability and bias, but when sexual communication was poor, better emotion recognition ability was associated with less bias. PMID- 23990144 TI - SPECT/CT and tumour imaging. AB - Scintigraphic techniques are sensitive imaging modalities in the diagnosis and follow-up of cancer patients providing the functional and metabolic activity characteristics of the tumour. Hybrid SPECT/CT improves the diagnostic accuracy of these well-established imaging techniques by precise anatomical localization and characterization of morphological findings, differentiation between foci of physiological and pathological tracer uptake, resulting in a significant impact on patient management and more definitive interpretations. The use of SPECT/CT has been studied in a variety of applications in tumour imaging which are reviewed in this article. By combining functional and anatomical information in a single imaging session, SPECT/CT has become a one-stop cancer imaging modality. PMID- 23990146 TI - Cultivation and characterization of the MaMV-DC cyanophage that infects bloom forming cyanobacterium Microcystis aeruginosa. AB - The MaMV-DC cyanophage, which infects the bloom-forming cyanobacterium Microcystis aeruginosa, was isolated from Lake Dianchi, Kunming, China. Twenty one cyanobacterial strains were used to detect the host range of MaMV-DC. Microcystic aeruginosa FACHB-524 and plaque purification were used to isolate individual cyanophages, and culturing MaMV-DC with cyanobacteria allowed us to prepare purified cyanophages for further analysis. Electron microscopy demonstrated that the negatively stained viral particles are tadpole-shaped with an icosahedral head approximately 70 nm in diameter and a contractile tail approximately 160 nm in length. Using one-step growth experiments, the latent period and burst size of MaMV-DC were estimated to be 24-48 hours and approximately 80 infectious units per cell, respectively. Restriction endonuclease digestion and agarose gel electrophoresis were performed using purified MaMV-DC genomic DNA, and the genome size was estimated to be approximately 160 kb. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis revealed four major structural proteins. These results support the growing interest in using freshwater cyanophages to control bloom forming cyanobacterium. PMID- 23990147 TI - Scatter characterization and correction for simultaneous multiple small-animal PET imaging. AB - PURPOSE: The rapid growth and usage of small-animal positron emission tomography (PET) in molecular imaging research has led to increased demand on PET scanner's time. One potential solution to increase throughput is to scan multiple rodents simultaneously. However, this is achieved at the expense of deterioration of image quality and loss of quantitative accuracy owing to enhanced effects of photon attenuation and Compton scattering. The purpose of this work is, first, to characterize the magnitude and spatial distribution of the scatter component in small-animal PET imaging when scanning single and multiple rodents simultaneously and, second, to assess the relevance and evaluate the performance of scatter correction under similar conditions. METHODS: The LabPETTM-8 scanner was modelled as realistically as possible using Geant4 Application for Tomographic Emission Monte Carlo simulation platform. Monte Carlo simulations allow the separation of unscattered and scattered coincidences and as such enable detailed assessment of the scatter component and its origin. Simple shape-based and more realistic voxel based phantoms were used to simulate single and multiple PET imaging studies. The modelled scatter component using the single-scatter simulation technique was compared to Monte Carlo simulation results. PET images were also corrected for attenuation and the combined effect of attenuation and scatter on single and multiple small-animal PET imaging evaluated in terms of image quality and quantitative accuracy. RESULTS: A good agreement was observed between calculated and Monte Carlo simulated scatter profiles for single- and multiple-subject imaging. In the LabPETTM-8 scanner, the detector covering material (kovar) contributed the maximum amount of scatter events while the scatter contribution due to lead shielding is negligible. The out-of field-of-view (FOV) scatter fraction (SF) is 1.70, 0.76, and 0.11% for lower energy thresholds of 250, 350, and 400 keV, respectively. The increase in SF ranged between 25 and 64% when imaging multiple subjects (three to five) of different size simultaneously in comparison to imaging a single subject. The spill-over ratio (SOR) increases with increasing the number of subjects in the FOV. Scatter correction improved the SOR for both water and air cold compartments of single and multiple imaging studies. The recovery coefficients for different body parts of the mouse whole-body and rat whole-body anatomical models were improved for multiple imaging studies following scatter correction. CONCLUSIONS: The magnitude and spatial distribution of the scatter component in small-animal PET imaging of single and multiple subjects simultaneously were characterized, and its impact was evaluated in different situations. Scatter correction improves PET image quality and quantitative accuracy for single rat and simultaneous multiple mice and rat imaging studies, whereas its impact is insignificant in single mouse imaging. PMID- 23990149 TI - [Large vessel vasculitis and acral hypoperfusion]. PMID- 23990148 TI - In vitro evaluation of bioactive strontium-based ceramic with rabbit adipose derived stem cells for bone tissue regeneration. AB - The development of bone replacement materials is an important objective in the field of orthopaedic surgery. Due to the drawbacks of treating bone defects with autografts, synthetic bone graft materials have become optional. So in this work, a bone tissue engineering approach with radiopaque bioactive strontium incorporated calcium phosphate was proposed for the preliminary cytocompatibility studies for bone substitutes. Accumulating evidence indicates that strontium containing biomaterials promote enhanced bone repair and radiopacity for easy imaging. Hence, strontium calcium phosphate (SrCaPO4) and hydroxyapatite scaffolds have been investigated for its ability to support and sustain the growth of rabbit adipose-derived mesenchymal stem cells (RADMSCs) in vitro. They were characterized via Micro-CT for pore size distribution. Cells used were isolated from New Zealand White rabbit adipose tissue, characterized by FACS and via differentiation into the osteogenic lineage by alkaline phosphatase, Masson's trichome, Alizarin Red and von Kossa staining on day 28. Material-cell interaction was observed by SEM imaging of cell morphology on contact with material. Live-Dead analysis was done by confocal laser scanning microscopy and cell cluster analysis via MUCT. The in vitro biodegradation, elution and nucleation of apatite formation of the material was evaluated using simulated body fluid and phosphate buffered saline in static regime up to 28 days at 37 degrees C. These results demonstrated that SrCaPO4 is a good candidate for bone tissue engineering applications and with osteogenically-induced RADMSCs, they may serve as potential implants for the repair of critical-sized bone defects. PMID- 23990150 TI - [Diagnostics and stage-oriented therapy of keratoconus: introduction to the Homburg keratoconus center (HKC)]. PMID- 23990151 TI - [DALK and penetrating laser keratoplasty for advanced keratoconus]. AB - BACKGROUND: In cases of contact lens intolerance and/or central corneal scars, corneal transplantation is indicated for advanced keratoconus. This can be performed as deep anterior lamellar keratoplasty (DALK) or as penetrating keratoplasty (PKP). The German keratoplasty registry shows that the proportion of anterior lamellar grafts in Germany has remained stable at approximately 5 % in recent years. METHODS: Up to now DALK has not been technically standardized but can result in a good visual acuity using the big bubble technique if Descemet's membrane is laid bare intraoperatively. In 10-20 % a conversion to PKP is required if perforation of Descemet's membrane occurs. In cases of advanced keratoconus PKP is still the method of first choice especially after corneal hydrops due to rupture of Descemet's membrane. Non-contact excimer laser trephination seems to be especially beneficial for eyes with iatrogenic keratectasia after LASIK and those with repeat grafts in cases of keratoconus recurrence due to the graft being too small. For donor trephination from the epithelial side, an artificial chamber is used. Wound closure is achieved by a double running cross-stitch suture according to Hoffmann. Graft size is adapted individually depending on corneal size (as large as possible and as small as necessary). Limbal centration is given priority intraoperatively due to optical displacement of the pupil. RESULTS: Prospective clinical studies have shown that the technique of non-contact excimer laser PKP improves donor and recipient centration, reduces vertical tilt and horizontal torsion of the graft in the recipient bed, thus resulting in significantly less all-sutures-out keratometric astigmatism (2.8 D versus 5.7 D), higher regularity of the topography (SRI 0.80 vs. 0.98) and better visual acuity (0.80 vs. 0.63) in contrast to the motor trephine. The stage of the disease does not influence functional outcome after excimer laser PKP. CONCLUSIONS: In cases with optimal course DALK achieves the same visual outcome as mechanical PKP but the healthy endothelium can be preserved and endothelial immune reactions are prevented in keratoconus. In contrast to the undisputed clinical advantages of excimer laser keratoplasty with orientation teeth/notches in keratoconus, the major disadvantage of femtosecond laser application is still the necessity of suction and applanation of the cone during trephination. PMID- 23990152 TI - [Value of transretinal tumor biopsy as diagnostic and predictive instrument]. AB - Transretinal biopsy of intraocular tumors plays a decisive role as a diagnostic tool in ocular oncology. A biopsy is indicated to confirm a clinical diagnosis before treatment and allows identification of high risk melanomas of the uvea with a high potential of metastasis by molecular genetic evaluation of the specimen. This review will focus on the various biopsy techniques and indications for this method. PMID- 23990153 TI - [Sudden onset diplopia]. AB - Sudden onset diplopia may occur secondary to something as simple as uncorrected refractive error or as complicated as brainstem disorders in conjunction with other symptoms. Therefore, all complaints of diplopia must be a cause for concern. Ophthalmologists have to determine if diplopia is the first sign of a systemic or neurological disorder, which needs to be referred to a specialist or can be managed by the practitioner. In this paper the importance of the case history, primary diagnostic options, the indications for supplementary testing with computed tomography (CT) or magnetic resonance imaging (MRI) as well as treatment options when a patient complains of sudden onset diplopia are discussed. PMID- 23990155 TI - Solo-surgical laparoscopic cholecystectomy with a joystick-guided camera device: a case-control study. AB - BACKGROUND: This study aimed to evaluate the implementation of a joystick controlled camera holder (Soloassist; Actormed, Barbing, Germany) in laparoscopic cholecystectomy as so-called solo-surgery compared with the standard operation. METHODS: Of the 123 patients included in this study, 63 underwent laparoscopic cholecystectomy using the Soloassist system and were compared with 60 patients who underwent laparoscopic cholecystectomy with human assistance. The two groups did not differ significantly in terms of age, sex, body mass index, or American Society of Anesthesiology classification. The surgeons were divided into those highly experienced and those experienced with the new camera holder. The operation times were measured, including setup and dismantling of the system. The assessment also included complications, postoperative hospital stay, measurement of human resources in terms of personnel/minutes/operation, and subjective evaluation of the camera-guiding device by the surgeons. RESULTS: The hospital stay and operation-related complications were not enhanced in the Soloassist group. The differences in core operation time (p = 0.008) and total operating time (p = 0.001) significantly favored the human assistant. Whereas the absolute duration of surgery was longer, the relative operating time (in personnel/minutes/operation) was significantly shorter (p < 0.001). In 4.8 % of the cases, the operation could not be performed completely with the camera holding device. Clinically relevant postoperative complications did not occur. The experience of the surgeons did not differ significantly. The subjective evaluation regarding handling, image quality, effort, and satisfaction demonstrated high acceptance of the Soloassist system. CONCLUSIONS: The camera guiding device can be implemented without increased complications. The Soloassist system is safe and can be operated even by colleagues without system experience. All the surgeons rated their satisfaction with the system as very good to excellent. Although the operating times were longer than with the standard camera guidance, the absolute overall staff time was reduced. PMID- 23990156 TI - Feasibility of full-thickness gastric resection using master and slave transluminal endoscopic robot and closure by Overstitch: a preclinical study. AB - BACKGROUND: Gastric submucosal tumors are often treated by laparoscopic wedge resection. This study aimed to examine the feasibility of gastric full-thickness resection through a totally endoscopic approach using the master and slave transluminal endoscopic robot (MASTER), and closure of the luminal defect with an endoscopic suturing device. METHODS: The operation was performed in two live porcine models under general anesthesia. First, the anterior wall of the stomach was slung to the abdominal wall using a percutaneous suturing device. An imaginary 5-cm lesion was marked using a needle knife. After the initial mucosal incision was made using an IT knife, the MASTER was introduced through a long overtube. A circumferential mucosal incision was completed with the MASTER to expose the muscularis propria which was grasped and incised to the serosal layer by electrocautery applied through the hook of the MASTER. The full-thickness resection of the gastric wall was completed with retraction using the grasper and dissection using the hook. While the defect was being created, the luminal space was maintained with traction of the percutaneous sutures. The defect was closed with suture plication using an Apollo Overstitch device. RESULTS: Two full thickness gastric resections were performed in two nonsurvival porcine models (body weight = 30 and 35 kg, respectively) using the MASTER. The total procedure time was 56 min for the first model and 70 min for the second model. The luminal view was maintained during the whole procedure, and there was no damage to surrounding organs throughout the whole procedure. The gastric defects were closed successfully using Overstitch, with satisfactory gastric distension and no gas leakage afterward. CONCLUSION: The current experiment demonstrated the feasibility and safety of a totally endoscopic approach for the treatment of gastric submucosal tumors: full-thickness resection with the MASTER and successful closure of the defect using Overstitch. PMID- 23990157 TI - The influence of maternal health literacy and child's age on participation in social welfare programs. AB - The objective of this study is to determine the influence of maternal health literacy and child's age on participation in social welfare programs benefiting children. In a longitudinal prospective cohort study of 560 Medicaid-eligible mother-infant dyads recruited in Philadelphia, maternal health literacy was assessed using the test of functional health literacy in adults (short version). Participation in social welfare programs [Temporary Assistance to Needy Families (TANF), Supplemental Nutrition Assistance Program (SNAP), Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), child care subsidy, and public housing] was self-reported at child's birth, and at the 6, 12, 18, 24 month follow-up interviews. Generalized estimating equations quantified the strength of maternal health literacy as an estimator of program participation. The mothers were primarily African-Americans (83%), single (87%), with multiple children (62%). Nearly 24% of the mothers had inadequate or marginal health literacy. Children whose mothers had inadequate health literacy were less likely to receive child care subsidy (adjusted OR = 0.54, 95% CI 0.34-0.85) than children whose mothers had adequate health literacy. Health literacy was not a significant predictor for TANF, SNAP, WIC or housing assistance. The predicted probability for participation in all programs decreased from birth to 24 months. Most notably, predicted WIC participation declined rapidly after age one. During the first 24 months, mothers with inadequate health literacy could benefit from simplified or facilitated child care subsidy application processes. Targeted outreach and enrollment efforts conducted by social welfare programs need to take into account the changing needs of families as children age. PMID- 23990158 TI - Community-acquired Klebsiella pneumoniae liver abscess: the London experience. PMID- 23990159 TI - Supplementation with branched-chain amino acids to a low-protein diet regulates intestinal expression of amino acid and peptide transporters in weanling pigs. AB - This study determined the effects of dietary branched-chain amino acids (AA) (BCAA) on growth performance, expression of jejunal AA and peptide transporters, and the colonic microflora of weanling piglets fed a low-protein (LP) diet. One hundred and eight Large White * Landrace * Duroc piglets (weaned at 28 days of age) were fed a normal protein diet (NP, 20.9 % crude protein), an LP diet (LP, 17.1 % crude protein), or an LP diet supplemented with BCAA (LP + BCAA, 17.9 % crude protein) for 14 days. Dietary protein restriction reduced piglet growth performance and small-intestinal villous height, which were restored by BCAA supplementation to the LP diet to values for the NP diet. Serum concentrations of BCAA were reduced in piglets fed the LP diet while those in piglets fed the LP + BCAA diet were similar to values for the NP group. mRNA levels for Na(+)-neutral AA exchanger-2, cationic AA transporter-1, b(0,+) AA transporter, and 4F2 heavy chain were more abundant in piglets fed the LP + BCAA diet than the LP diet. However, mRNA and protein levels for peptide transporter-1 were lower in piglets fed the LP + BCAA diet as compared to the LP diet. The colonic microflora did not differ among the three groups of pigs. In conclusion, growth performance, intestinal development, and intestinal expression of AA transporters in weanling piglets are enhanced by BCAA supplementation to LP diets. Our findings provide a new molecular basis for further understanding of BCAA as functional AA in animal nutrition. PMID- 23990160 TI - Literature review on the role of dietary protein and amino acids in cognitive functioning and cognitive decline. AB - As the population of elderly people is growing rapidly, the number of individuals with dementia and cognitive impairment is also increasing. One of the preventive measures against cognitive decline is diet and different dietary factors have already been investigated. This review provides an overview of studies on dietary protein and cognitive functioning and cognitive decline. Also studies on the individual amino acids that are related to brain function, tryptophan and tyrosine, are discussed. Overall, the role of dietary protein intake on cognitive functioning as well as cognitive decline has hardly been studied; we found eight observational studies and three intervention studies. More studies investigated the role of tryptophan (14 studies) and tyrosine (nine studies) in relation to cognitive functioning, but all these studies were performed in young adult populations and mostly under special conditions. Research in elderly populations, in particular, is warranted. Also more research is needed to come to definitive conclusions and specific recommendations regarding protein intake or intake of specific amino acids for maintaining optimal cognitive functioning. PMID- 23990161 TI - Novel paradigms for dialysis vascular access: upstream hemodynamics and vascular remodeling in dialysis access stenosis. AB - Failure of hemodialysis access is caused mostly by venous intimal hyperplasia, a fibro-muscular thickening of the vessel wall. The pathogenesis of venous neointimal hyperplasia in primary arteriovenous fistulae consists of processes that have been identified as upstream and downstream events. Upstream events are the initial events producing injury of the endothelial layer (surgical trauma, hemodynamic shear stress, vessel wall injury due to needle punctures, etc.). Downstream events are the responses of the vascular wall at the endothelial injury that consist of a cascade of processes including leukocyte adhesion, migration of smooth muscle cells from the media to the intimal layer, and proliferation. In arteriovenous fistulae, the stenoses occur in specific sites, consistently related to the local hemodynamics determined by the vessel geometry and blood flow pattern. Recent findings that the localization of these sites matches areas of disturbed flow may add new insights into the pathogenesis of neointimal hyperplasia in the venous side of vascular access after the creation of the anastomosis. The detailed study of fluid flow motion acting on the vascular wall in anastomosed vessels and in the arm vasculature at the patient specific level may help to elucidate the role of hemodynamics in vascular remodeling and neointimal hyperplasia formation. These computational approaches may also help in surgical planning for the amelioration of clinical outcome. This review aims to discuss the role of the disturbed flow condition in acting as upstream event in the pathogenesis of venous intimal hyperplasia and in producing subsequent local vascular remodeling in autogenous arteriovenous fistulae used for hemodialysis access. The potential use of blood flow analysis in the management of vascular access is also discussed. PMID- 23990162 TI - Medication reconciliation and therapy management in dialysis-dependent patients: need for a systematic approach. AB - Patients with ESRD undergoing dialysis have highly complex medication regimens and disproportionately higher total cost of care compared with the general Medicare population. As shown by several studies, dialysis-dependent patients are at especially high risk for medication-related problems. Providing medication reconciliation and therapy management services is critically important to avoid costs associated with medication-related problems, such as adverse drug events and hospitalizations in the ESRD population. The Medicare Modernization Act of 2003 included an unfunded mandate stipulating that medication therapy management be offered to high-risk patients enrolled in Medicare Part D. Medication management services are distinct from the dispensing of medications and involve a complete medication review for all disease states. The dialysis facility is a logical coordination center for medication management services, like medication therapy management, and it is likely the first health care facility that a patient will present to after a care transition. A dedicated and adequately trained clinician, such as a pharmacist, is needed to provide consistent, high quality medication management services. Medication reconciliation and medication management services that could consistently and systematically identify and resolve medication-related problems would be likely to improve ESRD patient outcomes and reduce total cost of care. Herein, this work provides a review of available evidence and recommendations for optimal delivery of medication management services to ESRD patients in a dialysis facility-centered model. PMID- 23990163 TI - Albuminuria and cognitive decline in people with diabetes and normal renal function. AB - BACKGROUND AND OBJECTIVES: Diabetes mellitus is associated with increased risk of cognitive impairment. This study examines whether microvascular disease, as measured by albuminuria and decline in estimated GFR (eGFR), is associated with cognitive decline during 3.3 years of follow-up in individuals with diabetes with a normal baseline eGFR (approximately 90 ml/min per 1.73 m(2)). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Participants were from the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes study (N=2977; mean age 62.5 +/- 5.8 years; recruitment from August 2003 to December 2005, followed through June 2009), which examined the association of intensive versus standard glucose control on cognitive function. Participants underwent three neuropsychologic tests at baseline, 20 months, and 40 months. Tests included information processing speed, verbal memory, and executive function. Mixed-effects models were used to assess the association of albuminuria and eGFR on the percentage decline in each test. RESULTS: Participants with albuminuria at baseline and follow-up (persistent albuminuria) (-5.8% [95% confidence interval (CI), -7.3 to 4.2]) and participants with albuminuria at follow-up but none at baseline (progressive albuminuria) (-4.1% [95% CI, -5.6 to -2.7]) had greater percentage declines on information processing speed than participants without albuminuria at baseline and at follow-up (no albuminuria) (-2.6% [95% CI, -3.4 to -1.9]) (P=0.001 and P=0.10, respectively). There were borderline percentage changes in the test of verbal memory (4.8% [95% CI, 2.4 to 7.1] and 4.7% [95% CI, 2.5 to 7.0] versus 7.1% [95% CI, 6.0 to 8.3]; P=0.11 and P=0.08, respectively). On logistic regression analysis, persistent albuminuria (odds ratio, 1.37 [95% CI, 1.09 to 1.72]) and progressive albuminuria (odds ratio, 1.25 [95% CI, 1.02 to 1.56]) were associated with a >= 5% decline in information processing speed scores but not with verbal memory or executive function performance. A 1 ml/min per 1.73 m(2) per year eGFR decline had a borderline association with decline in tests of cognitive function. CONCLUSIONS: Persistent albuminuria and progressive albuminuria are associated with a decline in cognitive function in relatively young individuals with diabetes with unimpaired eGFR. These findings do not rule out the possibility of other processes causing cognitive decline. PMID- 23990164 TI - Efficacy and safety of a citrate-based protocol for sustained low-efficiency dialysis in AKI using standard dialysis equipment. AB - BACKGROUND AND OBJECTIVES: A simple anticoagulation protocol was developed for sustained low-efficiency dialysis (SLED) in patients with AKI, based on the use of anticoagulant citrate dextrose solution formulation A (ACD-A) and standard dialysis equipment. Patients' blood recalcification was obtained from calcium backtransport from dialysis fluid. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients treated with SLED (8- to 12-hour sessions) for AKI in four intensive care units of a university hospital were studied over a 30-month period, from May 1, 2008 to September 30, 2010. SLED interruptions and their causes, hemorrhagic complications, as well as coagulation parameters, ionized calcium, and blood citrate levels were recorded. RESULTS: This study examined 807 SLED sessions in 116 patients (mean age of 69.7 years [SD 12.1]; mean Acute Physiology and Chronic Health Evaluation II score of 23.8 [4.6]). Major bleeding was observed in six patients (5.2% or 0.4 episodes/100 person-days follow-up while patients were on SLED treatment). Citrate accumulation never occurred, even in patients with liver dysfunction. Intravenous calcium for ionized hypocalcemia (< 3.6 mg/dl or < 0.9 mmol/L) was needed in 28 sessions (3.4%); in 8 of these 28 sessions (28.6%), low ionized calcium was already present before SLED start. In 92.6% of treatments, SLED was completed within the scheduled time (median 8 hours). Interruptions of SLED by impending/irreversible clotting were recorded in 19 sessions (2.4%). Blood return was complete in 98% of the cases. In-hospital mortality was 45 of 116 patients (38.8%). CONCLUSIONS: This study protocol affords efficacious and safe anticoagulation of the SLED circuit, avoiding citrate accumulation and, in most patients, systematic calcium supplementation; it can be implemented with commercial citrate solutions, standard dialysis equipment, on-line produced dialysis fluid, and minimal laboratory monitoring. PMID- 23990165 TI - Glomerular diseases: FSGS. AB - FSGS is a lesion, not a disease. The separation into primary FSGS (a result of immunologic-mediated injury) versus secondary FSGS (related to a variety of causes) is often difficult. Even when this particular issue is carefully evaluated, the therapeutic implications are not always apparent. Newer literature on both biomarker discovery and on the genetic basis of FSGS is reviewed in this context. In addition, the thorny implications of obesity as it relates to the FSGS lesion are discussed. An overall practical algorithmic approach to the management and treatment of the FSGS lesion that integrates these controversial overlap areas is suggested. PMID- 23990166 TI - Novel paradigms for dialysis vascular access: downstream vascular biology--is there a final common pathway? AB - Vascular access dysfunction is a major cause of morbidity and mortality in hemodialysis patients. The most common cause of vascular access dysfunction is venous stenosis from neointimal hyperplasia within the perianastomotic region of an arteriovenous fistula and at the graft-vein anastomosis of an arteriovenous graft. There have been few, if any, effective treatments for vascular access dysfunction because of the limited understanding of the pathophysiology of venous neointimal hyperplasia formation. This review will (1) describe the histopathologic features of hemodialysis access stenosis; (2) discuss novel concepts in the pathogenesis of neointimal hyperplasia development, focusing on downstream vascular biology; (3) highlight future novel therapies for treating downstream biology; and (4) discuss future research areas to improve our understanding of downstream biology and neointimal hyperplasia development. PMID- 23990167 TI - Pollen baiting facilitates the isolation of marine thraustochytrids with potential in omega-3 and biodiesel production. AB - Marine heterotrophic microbes are capable of accumulating large amounts of lipids, omega-3 fatty acids, carotenoids, and have potential for biodiesel production. Pollen baiting using Pinus radiata pollen grain along with direct plating techniques were used in this study as techniques for the isolation of oil producing marine thraustochytrid species from Queenscliff, Victoria, Australia. Thirteen isolates were obtained using either direct plating or using pine pollen, with pine pollen acting as a specific substrate for the surface attachment of thraustochytrids. The isolates obtained from the pollen baiting technique showed a wide range of docosahexaenoic acid (DHA) accumulation, from 11 to 41 % of total fatty acid content (TFA). Direct plating isolates showed a moderate range of DHA accumulation, from 19 to 25 % of TFA. Seven isolates were identified on the basis of 18S rRNA sequencing technique as Thraustochytrium species, Schizochytrium species, and Ulkenia species. Although both methods appear to result in the isolation of similar strains, pollen baiting proved to be a simpler method for the isolation of these relatively slow-growing organisms. PMID- 23990169 TI - Efficient secretion of lipase r27RCL in Pichia pastoris by enhancing the disulfide bond formation pathway in the endoplasmic reticulum. AB - The lipase r27RCL from Rhizopus chinensis CCTCC M201021 was heterologously expressed in Pichia pastoris GS115 by simultaneous co-expression with two secretion factors ERO1p and PDI involved in the endoplasmic reticulum (ER). Compared to the expression of the lipase alone (12,500 U/ml), co-expression with these two proteins resulted in the production of larger total quantities of enzymes. The largest increase was seen when the combined ERO1p/PDI system was co expressed, resulting in approximately 30 % higher enzyme yields (16,200 U/ml) than in the absence of co-expressed secretion factors. The extracellular protein concentration of the recombinant strain Co XY RCL-5 reached 9.39 g/l in the 7-l fermentor. Simultaneously, the fermentation time was also shortened by about 8 h compared to that of the control. The substrate-specific consumption rate (Qs) and the product-specific production rate (Qp) were both investigated in this research. In conclusion, the space-time yield was improved by co-expression with ERO1p and PDI. This is a potential strategy for high level expression of other heterologous proteins in P. pastoris. PMID- 23990168 TI - Importance of microbial natural products and the need to revitalize their discovery. AB - Microbes are the leading producers of useful natural products. Natural products from microbes and plants make excellent drugs. Significant portions of the microbial genomes are devoted to production of these useful secondary metabolites. A single microbe can make a number of secondary metabolites, as high as 50 compounds. The most useful products include antibiotics, anticancer agents, immunosuppressants, but products for many other applications, e.g., antivirals, anthelmintics, enzyme inhibitors, nutraceuticals, polymers, surfactants, bioherbicides, and vaccines have been commercialized. Unfortunately, due to the decrease in natural product discovery efforts, drug discovery has decreased in the past 20 years. The reasons include excessive costs for clinical trials, too short a window before the products become generics, difficulty in discovery of antibiotics against resistant organisms, and short treatment times by patients for products such as antibiotics. Despite these difficulties, technology to discover new drugs has advanced, e.g., combinatorial chemistry of natural product scaffolds, discoveries in biodiversity, genome mining, and systems biology. Of great help would be government extension of the time before products become generic. PMID- 23990170 TI - The Dublin SURGE Project: geochemical baseline for heavy metals in topsoils and spatial correlation with historical industry in Dublin, Ireland. AB - The Dublin SURGE (Soil Urban Geochemistry) Project is Dublin's first baseline survey of heavy metals and persistent organic pollutants in topsoils and is part of a Europe-wide initiative to map urban geochemical baselines in ten cities. 1,058 samples were collected as part of a stratified random sampling programme in the greater Dublin area to give an overview of baseline conditions in the city. Samples were analysed for 31 inorganic elements including heavy metals. Analysis of results indicates that the concentrations of lead, copper, zinc and mercury are strongly influenced by human activities, with elevated concentrations in the city docklands, inner city and heavy industry areas. Sources of heavy metals in these areas may include historical industry, coal burning, re-use of contaminated soil, modern traffic and leaded paint and petrol. Concentrations of other inorganic elements in topsoil show patterns which are strongly related to regional bedrock parent material. The spatial distributions of heavy metals, in particular Pb and As, are explored in detail with respect to regional geology and the influence of historical industry on soil quality. Exploratory data, geostatistical and correlation analyses suggest that the concentrations of heavy metals tend to increase as the intensity of historical industrial activity increases. In particular, drinks production, power generation, oil/gas/coal, metals and textile historical industries appear to be the contamination source for several heavy metals. The data provide a geochemical baseline relevant to the protection of human health, compliance with environmental legislation, land use planning and urban regeneration. PMID- 23990171 TI - Biomonitoring of several toxic metal(loid)s in different biological matrices from environmentally and occupationally exposed populations from Panasqueira mine area, Portugal. AB - In the Panasqueira mine area of central Portugal, some environmental media show higher metal(loid) concentrations when compared with the local geochemical background and the values proposed in the literature for these environmental media. In order to evaluate the effect of the external contamination on selected indexes of internal dose, As, Cd, Cu, Cr, Fe, Hg, Mg, Mn, Mo, Ni, Pb, S, Se, Si, and Zn were quantified by inductively coupled plasma mass spectrometry and inductively coupled plasma optical emission spectrometry in blood, urine, hair and nail samples from individuals environmentally (N = 41) and occupationally exposed (N = 41). A matched control group (N = 40) was also studied, and data from the three groups were compared. Results obtained agreed with those reported by environmental studies performed in this area, pointing to populations living nearby and working in the mine being exposed to metal(loid)s originated from mining activities. Arsenic was the element with the highest increase in exposed populations. The concentration of other elements such as Cr, Mg, Mn, Mo, Ni, Pb, S, Se, and Zn was also increased, although at a lesser extent, specifically in the individuals environmentally exposed and in females. These findings confirm the need for competent authorities to act as soon as possible in this area and implement strategies aimed to protect exposed populations and the entire ecosystem. PMID- 23990172 TI - Clinical and epidemiological survey and analysis of the first case of human infection with avian influenza A(H7N9) virus in Hangzhou, China. AB - To investigate and report on the clinical and epidemiological characteristics of the first case of human infection with avian influenza A(H7N9) virus in Hangzhou, China. A field epidemiological survey was used to study the first case in Hangzhou. The patient was a 39-year-old male chef with a history of exposure to a farm product market and to poultry prior to the onset of disease on 15 March 2013. He had diarrhea, chills, pyrexia, and intermittent cough with freshly red foamy bloody sputum early in his disease. His fever > 39 degrees C continued for a week with rapid progression. Computed tomography findings showed extensive bilateral consolidation, followed by multiorgan failure. The patient died on the morning of 27 March. His infection was eventually confirmed 1 week later on 3 April. Flu-like symptoms including fever and cough were found in 46 of his 138 close contacts. This was the first case of human infection with avian influenza A(H7N9) virus in Hangzhou. None of the close contacts had onset of the disease. The case patient's condition progressed rapidly. The source of infection might be his exposure to the farm product market, but the mode of exposure remains unclear. PMID- 23990173 TI - Chronic inflammation and cancer: suppressing the suppressors. AB - Chronic inflammation typical to various chronic diseases is associated with immunosuppression, mediated primarily by immature myeloid-derived suppressor cells (MDSCs). A variety of factors induce MDSC differentiation arrest, thus manipulating the host's immune function and suppressing the innate and adaptive immune systems, as reflected by their impaired status associated with down regulated expression of the CD247 molecule. Such chronic inflammation-induced immunosuppressive features are also found in many tumors, generating tumor micro- and macro-environments that act as critical barriers to effective anti-tumor responses and therapies. This knowledge offers new and novel candidate immune targets for therapeutic interventions, in combination with more conventional approaches as chemotherapy, radiotherapy, and cancer cell targeted therapy. Therapeutic manipulation of chronic inflammation during cancer development is likely to enhance efficacy of treatments such as vaccinations, and adoptive T cell transfer, thus switching the chronic pro-cancer inflammatory environments into an anti-cancer milieu. Based on the functional relevance of immune networking in tumors, it is advantageous to merge monitoring immune biomarkers into the traditional patient's categorization and treatment regiments, which will provide new prognostic and/or predictive tools to clinical practice. A better identification of environmental and tumor-specific inflammatory mechanisms will allow directing the clinical management of cancer toward a more personalized medicine. PMID- 23990175 TI - Cognitive change in older women using a computerised battery: a longitudinal quantitative genetic twin study. AB - Cognitive performance is known to change over age 45, especially processing speed. Studies to date indicate that change in performance with ageing is largely environmentally mediated, with little contribution from genetics. We estimated the heritability of a longitudinal battery of computerised cognitive tests including speed measures, using a classical twin design. 324 (127 MZ, 197 DZ) female twins, aged 43-73 at baseline testing, were followed-up after 10 years, using seven measures of the Cambridge Automated Neuropsychological Test battery, four of which were measures of response latency (speed). Results were analysed using univariate and bivariate structural equation modelling. Heritability of longitudinal change was found in 5 of the 7 tests, ranging from 21 to 41%. The genetic aetiology was remarkably stable. The first principle component of change was strongly associated with age (p < 0.001) and heritable at 47% (27-62%). While estimates for heritability increased in all measures over time compared to baseline, these increases were statistically non-significant. This computerised battery showed significant heritability of age-related change in cognition. Focus on this form of change may aid the search for genetic pathways involved in normal and pre-morbid cognitive ageing. PMID- 23990177 TI - Gender differences in cardiac left ventricular mass and function: Clinical and experimental observations. AB - BACKGROUND: The aim of this study was to evaluate gender-associated impact on left ventricular mass (LVM) and on left ventricular function (LVF) in humans and rats with aging. METHODS: Myocyte area and collagen volume fraction (CVF) were studied in rats. LVM and LVF were evaluated in animals and humans by echocardiography and LVM index (LVMI) was obtained. RESULTS: LVMI, myocyte area and CVF were similar in males and females of 1-month-old rats. LVMI in children was similar in both genders. In contrast, in 6-month-old rats (5 males and 5 females), LVMI (17.7 +/- 0.7 mg/mm vs. 10.1 +/- 0.2 mg/mm; p < 0.01), and myocyte area (4572.5 +/- 72.6 MUm2 vs. 3293.85 +/- 57.8 MUm2, p < 0.01) were higher in male animals without differences in CVF. Men (n = 25) exhibited greater LVMI than women (n = 25) (77.4 +/- 3.2 g/m2 vs. 63.3 +/- 1.8 g/m2, p < 0.01), whereas the LVF was higher in women (105.9 +/- 2.9% vs. 95.3 +/- 3.5%, p < 0.01). CONCLUSIONS: There is a clear gender-associated impact on LVM with aging in humans and rats. Similar CVF and LVF associated to greater myocyte size and LVM in male rats suggest a process of physiological response. However, the increase in cardiac mass without an associated improved cardiac function in men in comparison to women could likely represent a potential disadvantage in the adaptive response during growth. PMID- 23990176 TI - Elevated prevalence of abnormal glucose metabolism in patients with primary aldosteronism: a meta-analysis. AB - OBJECTIVE: To conduct a meta-analysis of studies assessing abnormal glucose metabolism (AGM) prevalence among patients with primary aldosteronism (PA), calculating a combined pooled prevalence and summarizing metabolic parameters associated the pooled prevalence for comparative group. METHOD: Four electronic databases (PubMed, EMBASE, Cochrane CENTRAL, and ISI-Web of Science) were systematically retrieved with no language and time restriction. Studies about elevated level of glucose metabolism in primary aldosteronism were included. RESULT: Data were available in 16 studies. The pooled analysis revealed that the prevalence of elevated glucose in PA was 22.41 % (95 % CI 16.77-28.05 %), the retrospectively calculated prevalence was 31.20 % (95 % CI 15.81-46.60 %) for impaired fasting glucose, 26.19 % (95 % CI 15.17-37.21 %) for impaired glucose tolerance, 15.22 % (95 % CI 9.93-20.51 %) for diabetes mellitus. Prevalence of AGM in PA was higher than that in essential hypertension (OR = 1.55, 95 % CI 1.01 2.36, p = 0.04). From comparative groups, patients with primary aldosteronism had a lower level of insulin sensitivity indicators in comparison with normal group (p < 0.01). On the other hand, insulin resistance which presented by HOMA index was stronger in PA group than in normal control group (WMD = 0.41, 95 % CI 0.17, 0.65; p = 0.001), whereas it was weaker than that in EH group (WMD = -0.37, 95 % CI -0.62, -0.13; p = 0.003). CONCLUSION: There is a significant prevalence of elevated level of glucose metabolism in patients with PA. Awareness and treatment of this pre-diabetic or diabetic state are necessary. PMID- 23990178 TI - Electromechanical delay detected by tissue Doppler echocardiography is associated with the frequency of attacks in patients with lone atrial fibrillation. AB - BACKGROUND: Our main purpose in this study is to compare atrial (inter-atrial, intra-left atrial, intra-right atrial) electromechanical delays of patients with lone atrial fibrillation (LAF) with healthy individuals and examine the relationship of annual LAF attack frequency. METHODS: 32 entirely healthy individuals and 32 patients who have presented with tachycardia and complying with LAF criteria have been included in the study. The time passing from the beginning of the P wave on electrocardiography to the A' wave on tissue Doppler trace was accepted as the atrial conduction time (PA'). The PA' time difference between the mitral annulus of left ventricle (ML) and the tricuspid annulus of right ventricle (TL) was defined as inter-atrial electromechanical delay (IA EMD), the PA' time difference between the ML and septal mitral annulus (MS) as intra-left electromechanical delay (ILeft-EMD), the PA' time difference between MS and the TL as intra-right electromechanical delay (IRight-EMD). RESULTS: ILeft EMD (21.8 +/- 9.1 vs. 14.1 +/- 4.9, p < 0.001), IRight-EMD (9.3 +/- 6.8 vs. 5.9 +/- 4.9, p = 0.03) and IA-EMD times (24.7 +/- 11.2 vs. 11.9 +/- 7.1, p < 0.001) were significantly longer in LAF patients. In multivariate regression analysis, using a model including age, gender and left atrium (LA) volumes, ILeft-EMD times (OR 1.14, 95% CI 1.03-1.27,p = 0.012), IA-EMD times (OR 1.12, 95% CI 1.03-1.23, p = 0.007) and LA volumes (OR 1.18, 95% CI 1.05-1.32, p = 0.005) were independent predictors of LAF. In LAF group, the frequency of AF episodes was significantly correlated with ILeft-EMD (r = 0.90, p < 0.001) and IA-EMD times (r = 0.36, p < 0.004), whereas, IRight-EMD times and LA volumes were not correlated with recurrence rates. CONCLUSIONS: ILeft-EMD and IA-EMD may increase in the early stages of atrial fibrillation even without the left atrial dilation and may be more valuable than left atrial area and volume in predicting atrial fibrillation. PMID- 23990179 TI - Prognostic value of ACE I/D, AT1R A1166C, PAI-I 4G/5G and GPIIIa a1/a2 polymorphisms in myocardial infarction. AB - BACKGROUND: Coronary artery disease (CAD) has turned into a prevalent cause of morbi-mortality contributing some polymorphisms in the recurrence of major adverse cardiac events (MACE). METHODS: Three hundred and fifty six patients with first myocardial infarction (MI) were followed up during a 60-month period to find out if ACE I/D, AT1R A1166C, PAI-I 4G/5G and GPIIIa a1/a2 polymorphisms, in combination with other classical cardiovascular risk factors, can contribute to the relapse of MACE. RESULTS: Two hundred and eighty five (80.1%) men and 71 (19.9%) women were followed up after first MI. The primary clinical endpoint, a composite of MACE, was reached in 106 (29.8%) patients. In the Cox univariate survival analysis those risk factors influencing a poorer prognosis were age (p = 0.004), a positive family history of CAD (p = 0.007), diabetes (p = 0.004), smoking (p = 0.024), fibrinolytic therapy (p = 0.012) and having 2 or 3 vessels CAD (p = 0.046). Cox proportional hazards regression model showed that patients with the DD genotype had a 1.5 increased risk of having an unfavorable outcome when compared with No-DD genotype patients (RR 1.561, 95% CI 1.048-2.326, p = 0.028) and that patients with the ACE DD genotype plus the AT1R No-AA genotype, the GPIIIa No-a1a1 genotype or a combination of both, had a twice higher risk than any other genotype of MACE in the follow-up (RR 1.978, 95% CI 1.286-3.043, p = 0.002). CONCLUSIONS: Patients with the ACE DD genotype plus 1 or 2 unfavorable genotypes, the AT1R No-AA, the GPIIIa No-a1a1 or a combination of both, have twice higher the risk of MACE during their clinical follow-up. PMID- 23990180 TI - Sick euthyroid syndrome is associated with poor prognosis in patients with ST segment elevation myocardial infarction undergoing primary percutaneous intervention. AB - BACKGROUND: Concomitant thyroid and heart disease are frequently encountered in clinical practice. There are many studies evaluating thyroid function in acute and critical conditions. Information on thyroid dysfunction in ST-segment elevation myocardial infarction (STEMI) is limited; its correlation with short and long-term outcome is not fully known. METHODS: Four hundred and fifty seven patients diagnosed with STEMI in our emergency department were included in the study. Patients were divided into two groups: patients with normal thyroid function (euthyroid) and patients with thyroid dysfunction. STEMI was diagnosed with 12 derivation surface electrocardiogram. Thyroid hormone levels (TSH, free T3 and free T4) were measured. Patients with other acute coronary syndromes and endocrine pathologies except diabetes mellitus were excluded. Two patient groups were compared in terms of in-hospital and long-term outcome. RESULTS: Out of 457, 72 (15%) patients with thyroid dysfunction were detected. The other patients were euthyroid and constituted the control group. In-hospital cardiogenic shock (15% vs. 3% in the control group; p < 0.01) and death (7% vs. 1% in the control group; p < 0.01) were more frequently observed in the thyroid dysfunction group. In the subgroup analysis, it was observed that patients with sick euthyroid syndrome have the poorest outcome. Other markers for poor outcome were anemia and renal failure. CONCLUSIONS: Thyroid dysfunction, particularly sick euthyroid syndrome, was found to be related to in-hospital and long term mortality in patients with STEMI undergoing primary percutaneous intervention. PMID- 23990181 TI - The relationship between glycemic control and BNP levels in diabetic patients. AB - BACKGROUND: Glycemic control affects cardiovascular risk factors positively. The purpose of this study was to assess B-type natriuretic peptide (BNP) levels in patients with poorly controlled diabetes before and after glycemic regulation was achieved. METHODS: The study was performed in a prospective design. The study population consisted of 79 consecutive diabetic patients with poor glycemic control. All subjects underwent transthoracic echocardiography. Levels of fasting plasma glucose, glycosylated hemoglobin (HbA1c), lipid parameters, and BNP were measured before the onset of the treatment and after glycemic regulation was achieved. RESULTS: A significant decrease in BNP (95.0 [4.0-1807] ng/L vs. 52.0 [2.1-987.0] ng/L, p < 0.001) levels were observed, after improving glycemic control. The decrease in BNP levels was positively correlated with the decrease in HbA1c (r = 0.345, p = 0.003) and fasting plasma glucose (r = 0.366, p = 0.002). There was no correlation between the decrease in BNP levels and lipid parameters (p = NS). CONCLUSIONS: We conclude that poor glycemic control may cause high levels of BNP which may lead to overdiagnosis of congestive heart failure. We suggest that HbA1c and fasting plasma glucose should be checked in patients with high levels of BNP. PMID- 23990182 TI - Long-term outcomes of cardiac resynchronization therapy are worse in patients who require atrioventricular junction ablation for atrial fibrillation than in those with sinus rhythm. AB - BACKGROUND: The aim of the study was to assess the impact of atrial fibrillation (AF) with and without the need for atrioventricular junction (AVJ) ablation on outcomes in patients undergoing cardiac resynchronization therapy (CRT). METHODS: A single center cohort of 200 consecutive CRT patients was divided into three groups: 1) AF with CRT pacing < 95% in which AVJ ablation was performed (AF-ABL, n = 40; 20%), 2) AF without the need for AVJ ablation (AF-non ABL, n = 40; 20%), 3) sinus rhythm (SR, n = 120; 60%). All patients were assessed before CRT implantation and at 6-month follow-up. Positive clinical response to CRT was considered alive status without the need for heart transplantation and improvement >= 1 NYHA after 6 months. The comparative analysis among all study groups with respect to response-rate and long-term survival was performed. RESULTS: The 6-month response-rate in both AF-ABL and AF-nonABL was significantly lower than in SR (52.5 and 50 vs.77.5%, respectively; both p < 0.017), though there were no differences in baseline characteristics among study groups apart from higher baseline NT-proBNP levels in AF-ABL. However, after adjustment for this confounder, and despite optimal CRT pacing burden in study groups, the remote all-cause mortality during median follow-up of 36.1 months was significantly higher in AF-ABL than in SR (adjusted HR = 2.57, 95% CI 1.09-6.02, p = 0.03). What is more, no difference in long-term survival between SR and AF nonABL was observed. CONCLUSIONS: Despite the improvement of CRT pacing burden and thus response-rate up to the level of AF subjects without the need for ablation, the long-term survival of AF patients requiring AVJ ablation remains still worse than in SR. PMID- 23990183 TI - Novel algorithm for arrhythmogenic focus localization in patients with right ventricular outflow tract arrhythmias. AB - BACKGROUND: Previously presented new electrocardiography (ECG) algorithm for localization of arrhythmogenic focus (AFo) in right ventricular outflow tract (RVOT) was based on spontaneous arrhythmia QRS morphology analysis. The aim of this study was to estimate the clinical value of our RVOT algorithm in a prospective study. METHODS AND RESULTS: Algorithm validation was made on 62 patients with RVOT arrhythmias (45 women), mean age 41.6 +/- 14.3 years, scheduled for transcatheter ablation. Results of preablation ECG analysis with RVOT algorithm were matched with successful ablation sites and statistical indices: sensitivity (sens), specificity (spec), and positive and negative predictive values (PPV, NPV) were calculated for algorithm and for each of 9 RVOT zones (septal and free wall). An algorithm precisely localized AFo in 57 out of 62 patients (sens 91.3%, spec 99%, PPV 91%, NPV 98.8%). Sensitivity values for superior RVOT aspect (71% patients) varied from 88% to 100%, specificity from 95.9% to 100%; PPV values from 85.7% to 100%, NPV from 92.5% to 100%. Although the total number of patients was relatively small in the 2 remaining RVOT aspects (29% patients) high values (sens, spec, PPV, NPV) were gained for intermediate and inferior zones. CONCLUSIONS: On the basis of spontaneous arrhythmia QRS analysis, a novel algorithm was built for preablation localization of RVOT arrhythmia in 1 of the 9 RVOT zones. Prospective analysis of our ECG algorithm confirmed that it is a valuable tool to predict the site of successful ablation in patients with RVOT arrhythmias. PMID- 23990184 TI - Vernakalant: Perception of state of health in patients with a recent-onset atrial fibrillation. AB - BACKGROUND: Vernakalant is a new, safe and effective drug used intravenously, which has proved to be more rapid in converting recent onset atrial fibrillation (AF) to sinus rhythm compared to placebo, amiodarone, propafenone, and flecainide in clinical studies. Until now no study has been conducted comparing the perception of state of health in patients who received vernakalant versus propafenone or flecainide for conversion of recent-onset AF. The aim of our study is to compare the change of perception of state of health from screening to hour 2 in patients treated with vernakalant and propafenone or flecainide for conversion of recent-onset AF. METHODS: Eighty hemodynamically stable patients with recent onset AF without structural heart disease were prospectively included. A single oral dose of propafenone 600 mg was administered to 30 patients, 30 patients received intravenous vernakalant and the remaining 20 patients received a single oral dose of flecainide 300 mg. Clinical, laboratory variables and perception of state of health from screening to hour 2 treated with these drugs measured by the EQ-5 D quality-of-life assessments visual analog scale were recorded. RESULTS: Baseline characteristics were similar in the three groups. Treatment with vernakalant resulted in a significantly greater improvement in patient perception of state of health at hour 2 compared with propafenone and flecainide. In the vernakalant group, a mean increase (from baseline) of 12.1 points was seen compared with a mean increase of 5.4 points in the propafenone group or 5.2 points in flecainide group (p < 0.01). CONCLUSIONS: The change of perception of state of health from screening to hour 2 treated with vernakalant had a significantly statistical improvement compared with propafenone or flecainide for conversion recent-onset AF. PMID- 23990185 TI - Evaluation of the effect of mitral stenosis severity on the left ventricular systolic function using isovolumic myocardial acceleration. AB - BACKGROUND: Isovolumic acceleration (IVA) is a new tissue Doppler parameter in the assessment of systolic function of both left and right ventricles. It remains unaffected with the changes in pre- and after-load within the physiological range. The aim of our study was to assess the effect of mitral stenosis degree, which is determined by echocardiography, on the left ventricular (LV) function using IVA. METHODS: A total number of 62 patients with mitral stenosis (MS) and 32 healthy controls were examined. The severity of MS (mild, moderate, and severe) was determined on the basis of mitral valve area (MVA) and the mean diastolic mitral gradient findings. The peak myocardial velocities during isovolumic contraction, systole, early diastole and late diastole were measured by using tissue Doppler imaging (TDI). RESULTS: All TDI-derived global LV basal wall systolic (peak myocardial isovolumic contraction velocity, peak myocardial systolic velocity and IVA), and diastolic velocities (peak early and late diastolic velocities) were significantly decreased in the patients with MS, compared to the healthy patients (p < 0.001, for all). However, IVA was not different when the degree of MS was evaluated (p = 0.114). In addition, IVA was not correlated with the MVA (r = 0.185, p = 0.150). CONCLUSIONS: Left ventricular function is impaired in patients with MS regardless of the severity of the disease. PMID- 23990186 TI - Improving the efficiency of the cardiac catheterization laboratories through understanding the stochastic behavior of the scheduled procedures. AB - BACKGROUND: In this study, we sought to analyze the stochastic behavior of Catherization Laboratories (Cath Labs) procedures in our institution. Statistical models may help to improve estimated case durations to support management in the cost-effective use of expensive surgical resources. METHODS: We retrospectively analyzed all the procedures performed in the Cath Labs in 2012. The duration of procedures is strictly positive (larger than zero) and has mostly a large minimum duration. Because of the strictly positive character of the Cath Lab procedures, a fit of a lognormal model may be desirable. Having a minimum duration requires an estimate of the threshold (shift) parameter of the lognormal model. Therefore, the 3-parameter lognormal model is interesting. To avoid heterogeneous groups of observations, we tested every group-cardiologist-procedure combination for the normal, 2- and 3-parameter lognormal distribution. RESULTS: The total number of elective and emergency procedures performed was 6,393 (8,186 h). The final analysis included 6,135 procedures (7,779 h). Electrophysiology (intervention) procedures fit the 3-parameter lognormal model 86.1% (80.1%). Using Friedman test statistics, we conclude that the 3-parameter lognormal model is superior to the 2 parameter lognormal model. Furthermore, the 2-parameter lognormal is superior to the normal model. CONCLUSIONS: Cath Lab procedures are well-modelled by lognormal models. This information helps to improve and to refine Cath Lab schedules and hence their efficient use. PMID- 23990187 TI - Late gadolinium enhancement is common in patients with hypertrophic cardiomyopathy and no clinical risk factors for sudden cardiac death: A single center experience. AB - BACKGROUND: Cardiac magnetic resonance (CMR) is used in the diagnosis and risk stratification of hypertrophic cardiomyopathy (HCM) and can detect myocardial replacement fibrosis (anindependent predictor of adverse cardiac outcomes) using late gadolinium enhancement (LGE). METHODS: We retrospectively analysed CMR studies carried out over a 2 year period identifying those which were diagnostic of HCM. 117 cases were analysed. Mean age of subjects was 53 years and 78 (67%) were male. Mean ejection fraction (EF) was 68.3% with a mean left ventricular (LV) mass index of 89.4 g/m2. Hypertrophy was predominantly asymmetric in 94 (80%). RESULTS: All subjects received gadolinium and 80 (68%) had evidence of LGE. LVEF was lower (67 vs. 71%; p = 0.015) and LV mass index higher (94 vs. 81 g/m2; p = 0.007) in the LGE group. The proportion of patients with at least 1 clinical risk factor for sudden cardiac death (SCD) was similar in groups with and without LGE (48% vs. 32%; p = 0.160). In this study, a significant proportion (62%) of patients without clinical risk factors for SCD were found to have LGE on CMR. These patients would not currently be considered for therapy with an implantable cardiac defibrillator. CONCLUSIONS: 1. Patients with HCM are at increased risk of SCD, but identifying patients who may benefit from implantable defibrillators is difficult. 2. LGE is associated with adverse cardiovascular outcomes in HCM, but is present in a large proportion of patients. 3. Many patients without clinical risk factors for SCD have LGE and would not currently be considered for an implantable cardiac device. PMID- 23990188 TI - Systematic review and meta-analysis of chronic kidney disease as predictor of atrial fibrillation recurrence following catheter ablation. AB - BACKGROUND: Recent observational studies have shown that patients with chronic kidney disease (CKD) have higher risk of atrial fibrillation (AF) recurrence and, therefore, the value of catheter ablation therapy in patients with CKD has been doubted. The purpose of this meta-analysis was to systematically analyze the effect of CKD on recurrence of AF following catheter ablation. METHODS: PubMed and Cochrane clinical trials databases were searched until August 2012. Of the 1966 initially identified studies, 4 observational studies with 1379 patients were analyzed. RESULTS: The meta-analysis of these studies showed that CKD was associated with higher AF recurrence rate following single catheter ablation (HR = 1.96, 95% CI 1.35-2.85, p = 0.0004) while there were significant differences between individual trials (p = 0.07 and I2 = 58%). Sensitivity analysis suggested that this outcome was stable. A subgroup analysis showed that CKD has higher recurrent risk in patients with 100% paroxysmal AF (HR = 2.45, 95% CI 1.28-4.70, p = 0.007) than in patients with non 100% paroxysmal AF (HR = 1.65, 95% CI 1.15 2.36, p = 0.006). CONCLUSIONS: CKD was associated with higher AF recurrence rate following single catheter ablation. In addition, patients with 100% paroxysmal AF have higher risk than patients with non 100% paroxysmal AF that merits special consideration when evaluating patients for catheter-based AF ablation. Given that the CKD prevalence is rapidly increasing, there is an imperative need for better risk stratification of catheter ablation candidates. PMID- 23990189 TI - Intermittent heart rate-dependent early repolarization pattern (J-point ST elevation) demonstrated on Holter recordings. AB - The J-point elevation of the ST segment, the early repolarization (ER) pattern is diagnosed usually on a resting 12-lead ECG. We investigated the ER pattern on 24 h Holter recordings under physiological conditions in 9,200 consecutive cases. The patients' age varied between 14 days to 95 years. In 410 individuals (4.9% of the total) during at least one period of the 24-h recording J-point ST elevation of >= 1 mm was found in >= 2 of the 3 Holter leads, lasting for >= 3 min. In 382 patients (93.1% of the 410 with ER), the typical ER pattern was intermittent, i.e., seen only below heart rate (HR) of about 70/min, and as the HR climbed, beyond 65-75/min, the ER pattern disappeared and then reappeared when the HR slowed down again. This was observed during the 24 h period several times, usually 10-20 times during the 24-h period. In only 28 examinees (6.9% of the 410 cases with ER, 0.33% of the total 8,300 examinees included in the study) this pattern prevailed at HR faster than 75/min. Thus, if an ER pattern is seen on a "spot"-ECG recorded at slow HR, this does not ensure that this pattern will not disappear when HR rises. On the other hand, if no ER pattern is seen in a 12-lead ECG recorded on a relatively higher HR, we demonstrated that this pattern may temporarily appear when HR slows down. PMID- 23990190 TI - The association between coronary flow rate and impaired heart rate recovery in patients with metabolic syndrome: A preliminary report. AB - BACKGROUND: The aim of this study is to evaluate heart rate recovery (HRR) and association between coronary flow rate and HRR in patients with metabolic syndrome (MS) who had morphologically normal coronary angiogram. METHODS: Study population included 43 patients with MS and 37 control subjects without MS. All patients were selected from individuals who had recently undergone coronary angiography in our hospital and were diagnosed as having angiographically normal coronary arteries. Exercise stress test results obtained prior to coronary angiography were evaluated for calculating HRR and other parameters. In addition, coronary flow was objectively evaluated for each major coronary artery in each subject using TIMI frame count method. RESULTS: All HRR values calculated were detected significantly lower in MS group compared to controls (HRR first: 32 +/- 9 vs. 37 +/- 10; p = 0.01, second: 46 +/- 11 vs. 52 +/- 11; p = 0.03, third: 51 +/- 12 vs. 59 +/- 12; p = 0.00, fourth: 54 +/- 13 vs. 61 +/- 2; p = 0.02). TIMI frame counts for each major epicardial coronary artery and mean TIMI frame count were also found to be significantly higher in MS group compared to controls (left anterior descending artery:51 +/- 24 vs. 39 +/- 15; p = 0.009, left circumflex artery: 32 +/- 11 vs. 24 +/- 7; p = 0.001, right coronary artery: 33 +/- 14 vs. 24 +/- 10; p = 0.003, mean TIMI frame count: 38 +/- 15 vs. 29 +/- 9;p = 0.002). Additionally, significant negative correlations were also detected between HRR first minute and coronary TIMI frame count values in patients with MS. None of MS parameters did not affect HRR values, however mean TIMI frame count independently associated with HRR first minute (p = 0.04) in patients with MS. CONCLUSIONS: Impaired coronary blood flow occurring in MS might be a clue of autonomic dysfunction in addition to previously known endothelial dysfunction. PMID- 23990191 TI - Transcatheter closure of atrial septal defect in children up to 10 kg of body weight with Amplatzer device. AB - BACKGROUND: Transcatheter closure of atrial septal defect (ASD) in older children and adults is currently considered the first-choice therapeutic option. This approach remains challenging in younger children. The aim of the study was to evaluate feasibility, safety and midterm efficacy of percutaneous ASD closure in symptomatic infants <=10 kg body weight in our institution. METHODS: There were 28 children up to 10 kg of body weight, who were qualified for transcatheter closure of ASD. All patients but one showed overload of right atrium and right ventricle. Mean weight of patients who underwent transcatheter closure was 9.2 +/ 0.88 kg and age 1.59 +/- 0.58 years, respectively. Transcatheter closure of ASD was conducted using Amplatzer occluders (ASO). RESULTS: The devices were implanted successfully in 26/28 patients (93%). In 2 (7%) children the device repeatedly straddled the septum in relatively big ASD and the procedure was abandoned. Mean ASD diameter in patients, who underwent transcatheter closure, was 9.08 +/- 2.9 mm (transthoracic echocardiography) and mean implant size/weight ratio was 1.07 +/- 0.31. In the child with right-left shunt through ASD normalization of saturation occurred. Mean fluoroscopy time was 4.16 min. In 3 children minor complications occurred: transient arrhythmias (n = 1), fever after procedure (n = 2). The follow-up time was 6.1 (range 1.2-11) years. At follow-up, clinical condition and/or growth improved in all patients except 4 children with coexisting comorbidity. No arrhythmia nor conduction disturbances were observed during follow-up. CONCLUSIONS: In selected patients weighing less or equal to 10 kg, percutaneous closure of ASD is a safe and effective procedure. PMID- 23990192 TI - Antazoline for rapid termination of atrial fibrillation during ablation of accessory pathways. AB - BACKGROUND AND AIM: To assess safety and efficacy of antazoline for termination of atrial fibrillation (AF) occurring during ablation of accessory pathways (AP). METHODS: We analyzed electrophysiological mechanism of antazoline (changes in A-A interval) and the percentage of pre-excited QRS complexes before and after antazoline administration. The total dose administered and the time from the start of injection to sinus rhythm restoration were also measured. RESULTS: Out of consecutive 290 patients with Wolff-Parkinson-White syndrome undergoing radiofrequency (RF) ablation, 12 (4.1%) (4 females, mean age 36 +/- 20 years) developed sustained AF which did not stop spontaneously within 10 min, and antazoline in 100 mg repeated boluses was administered. In all 12 patients the drug restored sinus rhythm after a mean of 425 +/- 365 s (range 43-1245 s) using a mean cumulative dose of 176 +/- 114 mg (range 25-400 mg). The drug slightly prolonged R-R intervals during AF (from 383 +/- 106 to 410 +/- 70 ms) and reduced the percentage of fully pre-excited QRS complexes (from 35% to 26%). Intracardiac recordings showed gradual increase in A-A intervals, as well as regularization and decreasing fractionation of atrial activity following drug injection (mean A A interval of 162 +/- 30 ms at baseline vs. 226 +/- 26 ms shortly before sinus rhythm restoration, p < 0.001). AP was not completely blocked in any patient which enabled continuation of ablation. CONCLUSIONS: Antazoline safely and rapidly converts AF into sinus rhythm during ablation of AP. The drug does not block AP completely, enabling continuation of ablation. The drug converting AF into more organized atrial activity (atrial flutter/tachycardia) before sinus rhythm resumption. PMID- 23990193 TI - Impact of pulmonary vein isolation on obstructive sleep apnea in patients with atrial fibrillation. AB - BACKGROUND: Obstructive sleep apnea (OSA) has been identified as associated with the onset and propagation of atrial fibrillation (AF) and predicts recurrences of AF after pulmonary vein isolation (PVI). Vice versa, it has never been investigated whether PVI influences OSA. However, it has been controversial whether a restored atrial function can affect the course of OSA. There-fore, we have assessed whether PVI procedure modulates the prevalence and severity of OSA. METHODS AND RESULTS: We included 23 individuals with AF that were assigned to undergo PVI into this study. Patients were 65 +/- 7 years old, obese (BMI 29.9 +/ 5.4 kg/m2), white (100%) and had a normal left ventricular function (LVEF 64 +/- 9%). Polygraphic assessment was carried out before and 6 months after PVI. The prevalence of OSA, defined as an apnea-hypopnea index (AHI) >= 5 per hour of sleep, was 74% before PVI compared to 70% 6 months after the procedure (p > 0.05). Severity of OSA did not differ (AHI before vs. after: 18 +/- 18/h vs. 15 +/- 17/h, p > 0.05) as well as further polygraphic parameters did not differ before and after the procedure. CONCLUSIONS: Prevalence and severity of OSA are not affected by PVI in patients suffering from AF. PMID- 23990194 TI - Comprehensive cardiac resynchronization therapy optimization in the real world. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients suffering from chronic heart failure (CHF). Optimal device programming is crucial for maximum patient benefit. The goal of the present study was to assess device settings from CHF patients undergoing CRT optimization in a "real world" setting, and to delineate parameters most frequently requiring adjustment. METHODS: All patients who underwent CRT device implantation in the Cardiology Clinicat the University Hospital Zurich between January 2011 and September 2012 and in whom follow-up was available were included in this analysis. RESULTS: A total of 170 CHF patients were included in this analysis. True biventricular pacing was present in 44% of all patients, while QRS fusion was detected in 49.9%. The majority of the patients presented with suboptimal atrioventricular (AV) delays requiring adjustment. AV delays were therefore shortened due to the presence of QRS fusion in 53.3% and 38.1% of patients (sAV and pAV, respectively) or prolonged because of truncation of the A wave in the left ventricular inflow pulse wave Doppler measurement (17.5% and 28.4% for sAV and pAV, respectively). In contrast, interventricular delay (VV delay) was rarely changed (11.9%). CONCLUSIONS: In our "real world" cohort, a substantial proportion of patients presented to their first post-operative consultation with suboptimal device settings. Our data indicate that the opportunity to optimize device settings is frequently wasted in the "real world", underlining the necessity for expert device follow-up to deliver optimal care to this challenging group of heart failure patients. PMID- 23990195 TI - Regional differences among female patients with heart failure from the Cardiac Insufficiency BIsoprolol Study in ELDerly (CIBIS-ELD). AB - BACKGROUND: The aim of our study was to examine regional differences in the demographics, etiology, risk factors, comorbidities and treatment of female patients with heart failure (HF) in the Cardiac Insufficiency BIsoprolol Study in ELDerly (CIBIS-ELD) clinical trial. METHODS AND RESULTS: One hundred and fifty nine female patients from Germany and 169 from Southeastern (SE) Europe (Serbia, Slovenia and Montenegro) were included in this subanalysis of the CIBIS-ELD trial. Women comprised 54% of the study population in Germany and 29% in SE Europe. German patients were significantly older. The leading cause of HF was arterial hypertension in German patients, 71.7% of whom had a preserved ejection fraction. The leading etiology in SE Europe was the coronary artery disease; 67.6% of these patients had a reduced left ventricular ejection fraction (34.64 +/- 7.75%). No significant differences were found in the prevalence of traditional cardiovascular risk factors between the two regions (hypertension, diabetes, hypercholesterolemia, smoking and family history of myocardial infarction). Depression, chronic obstructive pulmonary disease and malignancies were the comorbidities that were noted more frequently in the German patients, while the patients from SE Europe had a lower glomerular filtration rate. Compared with the German HF patients, the females in SE Europe received significantly more angiotensin converting enzyme inhibitors, loop diuretics and less frequently angiotensin receptor blockers and mineralocorticoid receptor antagonists. CONCLUSIONS: Significant regional differences were noted in the etiology, comorbidities and treatment of female patients with HF despite similar risk factors. Such differences should be considered in the design and implementation of future clinical trials, especially as women remain underrepresented in large trial populations. PMID- 23990196 TI - Structural changes in the gray matter of unmedicated patients with obsessive compulsive disorder: a voxel-based morphometric study. AB - The aim of the current study was to use whole brain voxel-based morphometry (VBM) to assess the gray matter (GM) changes in unmedicated patients with obsessive compulsive disorder (OCD) compared with normal controls. We compared the GM volumes in 28 patients with 22 matched healthy controls using a 1.5T MRI. Three dimensional T1-weighted magnetic resonance images were obtained from all participants. VBM was performed to detect GM volume differences between the two groups. We detected increased regional GM volumes in the bilateral middle temporal gyri, bilateral middle occipital gyri, bilateral globus pallidus, right inferior parietal gyrus, left superior parietal gyrus, right parahippocampus, right supramarginal gyrus, right medial superior frontal gyrus, and left inferior frontal opercular cortex in the OCD patients relative to controls (P <0.001, uncorrected, cluster size >100 voxels). No decreased GM volume was found in the OCD group compared with normal controls. Our findings suggest that structural changes in the GM are not limited to fronto-striato-thalamic circuits in the pathogenesis of OCD. Temporo-parietal cortex may also play an important role. PMID- 23990197 TI - Heightened sensitivity to temperature cues in individuals with high anxious attachment: real or elusive phenomenon? PMID- 23990198 TI - It takes two to imitate: anticipation and imitation in social interaction. AB - Imitation is assumed to serve crucial functions in social interaction, such as empathy and learning, yet these functions apply only to the imitating observer. In the two experiments reported here, we revealed a distinct function of imitation for the action model: Anticipation of being imitated facilitates the production of overt motor actions. Specifically, anticipated motor responses of social counterparts serve as mental cues for the model to retrieve corresponding motor commands to orchestrate his or her own actions. PMID- 23990199 TI - Selectively dispersed isotope labeling for protein structure determination by magic angle spinning NMR. AB - The power of nuclear magnetic resonance spectroscopy derives from its site specific access to chemical, structural and dynamic information. However, the corresponding multiplicity of interactions can be difficult to tease apart. Complimentary approaches involve spectral editing on the one hand and selective isotope substitution on the other. Here we present a new "redox" approach to the latter: acetate is chosen as the sole carbon source for the extreme oxidation numbers of its two carbons. Consistent with conventional anabolic pathways for the amino acids, [1-(13)C] acetate does not label alpha carbons, labels other aliphatic carbons and the aromatic carbons very selectively, and labels the carboxyl carbons heavily. The benefits of this labeling scheme are exemplified by magic angle spinning spectra of microcrystalline immunoglobulin binding protein G (GB1): the elimination of most J-couplings and one- and two-bond dipolar couplings provides narrow signals and long-range, intra- and inter-residue, recoupling essential for distance constraints. Inverse redox labeling, from [2 (13)C] acetate, is also expected to be useful: although it retains one-bond couplings in the sidechains, the removal of CA-CO coupling in the backbone should improve the resolution of NCACX spectra. PMID- 23990201 TI - Design and exploratory data analysis of a second generation of dendrimer prodrugs potentially antichagasic and leishmanicide. AB - Chagas disease and leishmaniasis are neglected tropical diseases, considered as a serious public health. Also, the drugs available for their treatment are toxic and exhibit questionable efficacy. Consequently, the discovery and development of new drug candidates are currently necessary. Dendrimers are highly branched molecules with extremely controlled structure. Those molecular systems display several biological applications (i.e., drug carriers), especially when the focus is prodrug design. Herein, a second generation of dendrimer prodrugs was planned to obtain potentially antichagasic and leishmanicide delivery systems. These dendrimers were composed by myo-inositol (core), L-malic acid (spacer), and three bioactive agents [hydroxymethylnitrofurazone (NFOH), quercetin, 3 hydroxyflavone]. The major aim of this study was to investigate the molecular properties (thermodynamics, steric, steric/electronic, electronic, and hydrophobic) to further describe intersamples relationships through either similarity indices or linear combinations of the original variables. Then, an exploratory data analysis, which comprises hierarchical cluster analysis (HCA) and principal components analysis (PCA), was carried out. Complementary findings were observed for PCA and HCA. Steric, intrinsic/steric, steric/electronic, steric/hydrophobic, hydrophobic, and electronic properties influenced the discrimination process. In addition, these molecular properties can also contribute to enzymatic hydrolysis mechanism elucidation, which depends upon the approximation and a subsequent nucleophilic attack to release the drug from the dendrimer prodrugs. PMID- 23990200 TI - Practical considerations over spectral quality in solid state NMR spectroscopy of soluble proteins. AB - Great theoretical and methodological advances are pushing the limits of resolution and sensitivity in solid state NMR (SSNMR). However, sample preparation remains a critical issue for the success of an experiment. The factors affecting spectral quality in SSNMR samples are discussed, examining cases encountered in the literature and presenting new experimental data. A discussion on resolution and sensitivity in sedimented solutes is framed in this context. PMID- 23990203 TI - Association between urinary albumin excretion and low-density lipoprotein heterogeneity following treatment of type 2 diabetes patients with the dipeptidyl peptidase-4 inhibitor, vildagliptin: a pilot study. AB - BACKGROUND: Few data exist as to whether dipeptidyl peptidase (DPP)-4 inhibitors affect cardio-renal interaction, which is a strong independent prognostic factor for cardiovascular disease (CVD), in diabetic patients. We evaluated the effects of a DPP-4 inhibitor on atherogenic low-density lipoprotein (LDL) heterogeneity and albuminuria in diabetics as an indicator of the severity of diabetic nephropathy. METHODS: Type 2 diabetes patients (n = 47) inadequately controlled with diabetes therapy were treated with vildagliptin 50 mg bid for 8 weeks. LDL heterogeneity was evaluated on the basis of the patients' small dense (sd) LDL levels and sd-LDL proportion (sd-LDL/LDL cholesterol [LDL-C]). The level of albuminuria was evaluated on the basis of the urinary albumin-to-creatinine ratio (UACR). RESULTS: After 8 weeks of treatment, there was no significant change in serum LDL-C level, but the serum sd-LDL level had decreased significantly by 8.8 %, and the UACR had also decreased significantly by 44.6 %. Triglyceride (TG) metabolism-related markers (TG, remnant-like particle cholesterol, apolipoprotein [apo] B, apoC-2, and apoC-3) had decreased significantly. The Delta (absolute change from baseline) sd-LDL values correlated positively with DeltaTG-metabolism related markers, but not with the Delta hemoglobin (Hb) A1c or Delta fasting blood sugar (DeltaFBS). Furthermore, multivariate regression analysis revealed that Deltasd-LDL proportion, but not DeltaHbA1c or DeltaFBS, was an independent predictor of DeltaUACR (beta = 0.292, p = 0.0016). CONCLUSIONS: Although this was a single-arm study, treatment of type 2 diabetes with vildagliptin might prevent the progression of CVD complicating diabetes by improving LDL heterogeneity, and it might improve renal function by decreasing albuminuria. A randomized controlled trial is warranted. PMID- 23990204 TI - Warfarin induces cardiovascular damage in mice. AB - OBJECTIVE: Vascular calcification is an independent risk factor for cardiovascular disease. Once thought to be a passive process, vascular calcification is now known to be actively prevented by proteins acting systemically (fetuin-A) or locally (matrix Gla protein). Warfarin is a vitamin K antagonist, widely prescribed to reduce coagulation by inhibiting vitamin K dependent coagulation factors. Recently, it became clear that vitamin K antagonists also affect vascular calcification by inactivation of matrix Gla protein. Here, we investigated functional cardiovascular characteristics in a mouse model with warfarin-induced media calcification. APPROACH AND RESULTS: DBA/2 mice received diets with variable concentrations of warfarin (0.03, 0.3, and 3 mg/g) with vitamin K1 at variable time intervals (1, 4, and 7 weeks). Von Kossa staining revealed that warfarin treatment induced calcified areas in both medial layer of aorta and heart in a dose- and time-dependent fashion, which could be inhibited by simultaneous vitamin K2 treatment. With ongoing calcification, matrix Gla protein mRNA expression decreased, and inactive matrix Gla protein expression increased. TdT-mediated dUTP-biotin nick end labeling positive apoptosis increased, and vascular smooth muscle cell number was concomitantly reduced by warfarin treatment. On a functional level, warfarin treatment augmented aortic peak velocity, aortic valve-peak gradient, and carotid pulse-wave velocity. CONCLUSION: Warfarin induced significant calcification with resulting functional cardiovascular damage in DBA/2 wild-type mice. The model would enable future researchers to decipher mechanisms of vascular calcification and may guide them in the development of new therapeutic strategies. PMID- 23990206 TI - T-cell immunoglobulin and mucin domain 3 acts as a negative regulator of atherosclerosis. AB - OBJECTIVE: Atherosclerosis is a chronic autoimmune-like disease in which lipids and fibrous elements accumulate in the arterial blood vessels. T cells are present within atherosclerotic plaques, and their activation is partially dependent on costimulatory signals, which can either provide positive or negative signals that promote T-cell activation or limit T-cell responses, respectively. T cell immunoglobulin and mucin domain 3 (Tim-3) is a coinhibitory type 1 transmembrane protein that affects the function of several immune cells involved in atherosclerosis, such as monocytes, macrophages, effector T cells, and regulatory T cells. In the present study, we determined the role of Tim-3 in the development of atherosclerosis. APPROACH AND RESULTS: Western-type diet-fed low density lipoprotein receptor-deficient (LDLr(-/-)) mice were treated with an anti Tim-3 antibody for 3 and 8 weeks. Anti-Tim-3 administration increased fatty streak formation with 66% and increased atherosclerotic plaque formation after 8 weeks with 35% in the aortic root and with 50% in the aortic arch. Furthermore, blockade of Tim-3 signaling increased percentages of circulating monocytes with 33% and lesional macrophages with 20%. In addition, anti-Tim-3 administration increased CD4(+) T cells with 17%, enhanced their activation status, and reduced percentages of regulatory T cells with 18% and regulatory B cells with 37%. CONCLUSIONS: It is known that Tim-3 acts as a negative regulator of both innate and adaptive immune responses, and in the present study, we show that anti-Tim-3 treatment augments lesion development, accompanied by an increase in the number of monocytes/macrophages and CD4(+) T cells and by decreased regulatory T cells and regulatory B cells. PMID- 23990205 TI - Gene expression analyses of mouse aortic endothelium in response to atherogenic stimuli. AB - OBJECTIVE: Endothelial cells are central to the initiation of atherosclerosis, yet there has been limited success in studying their gene expression in the mouse aorta. To address this, we developed a method for determining the global transcriptional changes that occur in the mouse endothelium in response to atherogenic conditions and applied it to investigate inflammatory stimuli. APPROACH AND RESULTS: We characterized a method for the isolation of endothelial cell RNA with high purity directly from mouse aortas and adapted this method to allow for the treatment of aortas ex vivo before RNA collection. Expression array analysis was performed on endothelial cell RNA isolated from control and hyperlipidemic prelesion mouse aortas, and 797 differentially expressed genes were identified. We also examined the effect of additional atherogenic conditions on endothelial gene expression, including ex vivo treatment with inflammatory stimuli, acute hyperlipidemia, and age. Of the 14 most highly differentially expressed genes in endothelium from prelesion aortas, 8 were also perturbed significantly by >= 1 atherogenic conditions: 2610019E17Rik, Abca1, H2-Ab1, H2 D1, Pf4, Ppbp, Pvrl2, and Tnnt2. CONCLUSIONS: We demonstrated that RNA can be isolated from mouse aortic endothelial cells after in vivo and ex vivo treatments of the murine vessel wall. We applied these methods to identify a group of genes, many of which have not been described previously as having a direct role in atherosclerosis, that were highly regulated by atherogenic stimuli and may play a role in early atherogenesis. PMID- 23990202 TI - SUMO rules: regulatory concepts and their implication in neurologic functions. AB - Posttranslational modification of proteins by the small ubiquitin-like modifier (SUMO) is a potent regulator of various cellular events. Hundreds of substrates have been identified, many of them involved in vital processes like transcriptional regulation, signal transduction, protein degradation, cell cycle regulation, DNA repair, chromatin organization, and nuclear transport. In recent years, protein sumoylation increasingly attracted attention, as it could be linked to heart failure, cancer, and neurodegeneration. However, underlying mechanisms involving how modification by SUMO contributes to disease development are still scarce thus necessitating further research. This review aims to critically discuss currently available concepts of the SUMO pathway, thereby highlighting regulation in the healthy versus diseased organism, focusing on neurologic aspects. Better understanding of differential regulation in health and disease may finally allow to uncover pathogenic mechanisms and contribute to the development of disease-specific therapies. PMID- 23990207 TI - Bone marrow- or vessel wall-derived osteoprotegerin is sufficient to reduce atherosclerotic lesion size and vascular calcification. AB - OBJECTIVE: Osteoprotegerin (OPG) is a decoy receptor for the osteoclast differentiation factor receptor activator of NF-kappaB ligand. OPG regulates bone homeostasis, and its inactivation in mice results in severe osteoporosis. OPG deficiency in apolipoprotein E (ApoE)(-/-) mice results in increased atherosclerotic lesion size and calcification. Furthermore, receptor activator of NF-kappaB ligand enhances macrophage-dependent smooth muscle cell calcification in vitro. Here, we hypothesized that reconstitution of ApoE(-/-)OPG(-/-) mice with ApoE(-/-)OPG(+/+) bone marrow (BM) would be sufficient to rescue lesion progression and vascular calcification. Conversely, reconstitution of ApoE(-/ )OPG(+/+) mice with ApoE(-/-)OPG(-/-) BM may accelerate lesion progression and vascular calcification. APPROACH AND RESULTS: ApoE(-/-)OPG(-/-) mice transplanted with ApoE(-/-)OPG(+/+) BM developed smaller atherosclerotic lesions and deposited less calcium in the innominate artery than that of ApoE(-/-)OPG(-/-) mice transplanted with ApoE(-/-)OPG(-/-) BM. There were no differences in lesion size and calcification in ApoE(-/-)OPG(+/+) mice transplanted with BM from ApoE(-/ )OPG(-/-) or ApoE(-/-)OPG(+/+) mice. The large lesions observed in the ApoE(-/ )OPG(-/-) mice transplanted with OPG(-/-) BM were rich in chondrocyte-like cells, collagen, and proteoglycans. Importantly, the ApoE(-/-)OPG(-/-) mice transplanted with OPG(+/+) BM remained osteoporotic, and the ApoE(-/-)OPG(+/+) mice did not show signs of bone loss regardless of the type of BM received. In coculture experiments, macrophages and mesenchymal stem cells derived from ApoE(-/-)OPG(-/ ) BM induced more vascular smooth muscle cell calcification than cells derived from ApoE(-/-)OPG(+/+) mice. CONCLUSIONS: These results indicate that OPG derived either from the BM or from the vessel wall is sufficient to slow down lesion progression and vascular calcification independent of bone turnover. PMID- 23990208 TI - Hepatic cholesterol homeostasis: is the low-density lipoprotein pathway a regulatory or a shunt pathway? AB - OBJECTIVE: The hypothesis that cholesterol that enters the cell within low density lipoprotein (LDL) particles rapidly equilibrates with the regulatory pool of intracellular cholesterol and maintains cholesterol homeostasis by reducing cholesterol and LDL receptor synthesis was validated in the fibroblast but not in the hepatocyte. Accordingly, the present studies were designed to compare the effects of cholesterol that enters the hepatocyte within an LDL particle with those of cholesterol that enters via other lipoprotein particles. APPROACH AND RESULTS: We measured cholesterol synthesis and esterification in hamster hepatocytes treated with LDL and other lipoprotein particles, including chylomicron remnants and VLDL. Endogenous cholesterol synthesis was not significantly reduced by uptake of LDL, but cholesterol esterification (280%) and acyl CoA:cholesterol acyltransferase 2 expression (870%) were increased. In contrast, cholesterol synthesis was significantly reduced (70% decrease) with other lipoprotein particles. Furthermore, more cholesterol that entered the hepatocyte within LDL particles was secreted within VLDL particles (480%) compared with cholesterol from other sources. CONCLUSIONS: Much of the cholesterol that enters the hepatocyte within LDL particles is shunted through the cell and resecreted within VLDL particles without reaching equilibrium with the regulatory pool. PMID- 23990209 TI - Vasospasm of atherosclerotic coronary arteries precipitates acute ischemic myocardial damage in myocardial infarction-prone strain of the Watanabe heritable hyperlipidemic rabbits. AB - OBJECTIVE: This study tested the hypothesis that vasospasm can trigger coronary plaque injury and acute ischemic myocardial damage. APPROACH AND RESULTS: Myocardial infarction-prone strain of the Watanabe heritable hyperlipidemic rabbits received an intravenous bolus of ergonovine maleate (0.45 umol/kg) during intravenous infusion of norepinephrine (12 nmol/kg per minute) to provoke coronary spasm in vivo. After this treatment, coronary angiography demonstrated vasospasm, and the ECG showed ischemic abnormalities (ST depression/elevation and T-wave inversion) in 77% of animals (23/30). These changes normalized after nitroglycerin injection. In rabbits that demonstrated these ECG findings for >20 minutes, echocardiograms showed left ventricular wall motion abnormality. Serum levels of heart-type fatty acid-binding protein, cardiac troponin-I, and myoglobin increased markedly 4 hours after spasm provocation. In coronary lesions of myocardial infarction-prone strain of the Watanabe heritable hyperlipidemic rabbits with provoked coronary spasm, we observed intimal injury in 60.9% in the form of endothelial cell protrusions (39.1%), denudation (30.4%), and macrophage extravasation (56.5%). Plaque disruption with luminal thrombus, however, was only seen in 2 of 23 animals (8.7%), and mural microthrombus was rarely observed (4.3%). CONCLUSIONS: These observations show that provocation of vasospasm in myocardial infarction-prone strain of the Watanabe heritable hyperlipidemic rabbits associates with subsequent ischemic myocardial damage. Although treatment with spasmogens altered aspects of plaque morphology, for example, endothelial protrusion and macrophage emigration, thrombosis was rare in these animals with chronic atherosclerotic disease. PMID- 23990210 TI - Novel role of CD47 in rat microvascular endothelium: signaling and regulation of T-cell transendothelial migration. AB - OBJECTIVE: Although endothelial CD47, a member of the immunoglobulin superfamily, has been implicated in leukocyte diapedesis, its capacity for intracellular signaling and physical localization during this process has not been addressed in detail. This study examined endothelial CD47 spatiotemporal behavior and signaling pathways involved in regulating T-cell transendothelial migration. APPROACH AND RESULTS: By biochemical methods, transmigration assays, and live cell microscopy techniques, we show that endothelial CD47 engagement results in intracellular calcium mobilization, increased permeability, and activation of Src and AKT1/phosphoinositide 3-kinase in brain microvascular endothelial cells. These signaling pathways converge to induce cytoskeleton remodeling and vascular endothelial cadherin phosphorylation, which are necessary steps during T-cell transendothelial migration. In addition, during T-cell migration, transmigratory cups and podo-prints enriched in CD47 appear on the surface of the endothelium, indicating that the spatial distribution of CD47 changes after its engagement. Consistent with previous findings of intercellular adhesion molecule 1, blockade of CD47 results in decreased T-cell transmigration across microvascular endothelium. The overlapping effect of intercellular adhesion molecule 1 and CD47 suggests their involvement in different steps of the diapedesis process. CONCLUSIONS: These data reveal a novel role for CD47-mediated signaling in the control of the molecular network governing endothelial-dependent T-cell diapedesis. PMID- 23990211 TI - History of lifetime smoking, smoking cessation and cognitive function in the elderly population. AB - To examine potential associations of the history of lifetime smoking and smoking cessation with cognitive function in the elderly. In a population-based cohort study of older adults in Saarland, Germany, a detailed lifetime history of smoking was obtained using standardised questionnaires. Cognitive function was assessed with a validated telephone-based instrument (COGTEL) at the five-year follow-up in a subsample of n = 1,697 participants with a baseline age >65 years. Multiple linear regression models were employed to predict cognitive performance, adjusting for potential confounding factors. Ever-smokers with a higher cumulative dose of smoking in pack-years scored lower in the cognitive assessment than never-smokers, with the association being more pronounced in current smokers than in former smokers. In fully adjusted models, current smokers with 21-40 pack years scored 4.06 points lower (95 % CI -7.18 to -0.94) than never-smokers. In former smokers, a longer time since smoking cessation was associated with higher scores in the cognitive test with reference to current smokers, even after adjustment for pack-years. Former smokers who had quit for more than 30 years scored 4.23 points higher (95 % CI 1.75 to 6.71) than current smokers. Dose response-relationships of cognitive function with cumulative dose of smoking as well as with time since smoking cessation were substantiated by restricted cubic splines regression. Our results support suggestions that smokers are at an increased risk for cognitive impairment in older age; that the risk increases with duration and intensity of smoking, and subsides with time after smoking cessation. PMID- 23990212 TI - Do leukocyte telomere length dynamics depend on baseline telomere length? An analysis that corrects for 'regression to the mean'. AB - Leukocyte telomere length (LTL) shortens with age. Longitudinal studies have reported accelerated LTL attrition when baseline LTL is longer. However, the dependency of LTL attrition on baseline LTL might stem from a statistical artifact known as regression to the mean (RTM). To our knowledge no published study of LTL dynamics (LTL and its attrition rate) has corrected for this phenomenon. We illustrate the RTM effect using replicate LTL measurements, and show, using simulated data, how the RTM effect increases with a rise in stochastic measurement variation (representing LTL measurement error), resulting in spurious increasingly elevated dependencies of attrition on baseline values. In addition, we re-analyzed longitudinal LTL data collected from four study populations to test the hypothesis that LTL attrition depends on baseline LTL. We observed that the rate of LTL attrition was proportional to baseline LTL, but correction for the RTM effect reduced the slope of the relationship by 57% when measurement error was low (coefficient of variation ~2%). A modest but statistically significant effect remained however, indicating that high baseline LTL is associated with higher LTL attrition even when correcting for the RTM effect. Baseline LTL explained 1.3% of the variation in LTL attrition, but this effect, which differed significantly between the study samples, appeared to be primarily attributable to the association in men (3.7%). PMID- 23990213 TI - Bevacizumab in advanced NSCLC: chemotherapy partners and duration of use. AB - OPINION STATEMENT: Bevacizumab is an effective targeted therapy with demonstrated survival benefits for many patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Some patient populations are at higher risk for bleeding complications and bevacizumab should be avoided, but advanced age should not be used as the sole exclusion criterion for use. Bevacizumab is generally a well tolerated therapy that can be safely given in combination with multiple chemotherapy agents in the induction and maintenance phases of therapy. The optimal maintenance strategy is yet to be determined and is the focus of ongoing trials, such as ECOG 5508. Early use of bevacizumab in the adjuvant setting and continued use in the second-line setting are being investigated in current clinical trials. PMID- 23990214 TI - Molecular diagnosis of the tissue of origin in cancer of unknown primary site: useful in patient management. AB - OPINION STATEMENT: Cancer of unknown primary site (CUP) is a clinicopathologic syndrome consisting of many types of cancer and accounting for approximately 3 % of all patients with advanced cancers. This syndrome has frustrated patients and physicians for decades, because a primary site or tissue of origin has not been possible to identify clinically, despite the presence of metastatic tumor. Favorable subsets (approximately 20 % of all CUP) with a presumptive occult primary site have been recognized for several decades based on clinical and standard pathologic features; site-specific therapy in these patients improves their survival compared with the majority of other (approximately 80 %) CUP patients. These other patients, most with adenocarcinomas, have been difficult to treat because the tissue of origin was unknown. Broad-spectrum empiric chemotherapy became the standard approach for these patients in the past 30 years. More recently, new diagnostic technology (evolving immunohistochemistry and emergent gene-expression profiling) has enabled us to establish accurately a tissue of origin in most (90 %+) CUP patients. Gene-expression profiling assays complement standard pathology and for the majority of biopsy specimens accurately identify the primary site or tissue of origin; clinical studies have supported the value of site-directed therapy. When the tissue of origin is in doubt after standard pathologic examination, a gene expression assay is frequently diagnostic, and the outcome of many CUP patients is improved with site-specific therapy. The era of empiric therapy has ended in favor of site-specific therapy, based on the precise diagnosis of the tumor type present in each patient. PMID- 23990215 TI - Glutamine synthetase in astrocytes from entorhinal cortex of the triple transgenic animal model of Alzheimer's disease is not affected by pathological progression. AB - Astrocytes are fundamental for brain physiology and pathology, including Alzheimer's disease (AD). Among their functions, the maintenance of glutamate balance via the glutamate-glutamine (Glu-Gln) shuttle is critical for both normal cognitive functions and excitotoxicity relevant for AD progression. Astroglial glutamine synthetase (GS), converting glutamate to glutamine, is a key element in the Glu-Gln cycle. The entorhinal cortex (EC) is the brain area earliest affected in human AD. We have recently reported an early astrocytic atrophy in the EC in triple transgenic animal model of AD (3*Tg-AD). Here, we studied and analysed whether the changes in astrocytic morphology coincides with alterations of the Glu-Gln cycle by determining astrocytic GS. We found that the numerical density of GS-immunoreactive (GS-IR) cells as well as GS content (measured by optical density, OD) remained constant between 1 and 12 months of age, independent of the presence of senile plaques. Dual labelling images revealed GS-IR, GFAP-IR, GS/GFAP-IR subsets of astroglia. Despite the evident decrease in GFAP-IR surface and volume, the surface and volume of GS-IR and GS/GFAP-IR cells remained unchanged. Therefore, reduced GFAP presence obvious in the progression of AD from early stages does not impair upon glutamate homeostasis in the EC of 3*Tg-AD mice. Our data also indicate distinct functional populations of astrocytes, which may undergo specific remodelling during AD progression. PMID- 23990216 TI - Fasting can protect young and middle-aged Drosophila melanogaster flies against a severe cold stress. AB - Flies were starved with water before being subjected to various severe stresses (heat, cold, fungal infection, hydrogen peroxide) immediately after starvation or after a delay. Starvation of young and middle-aged flies increased resistance to a long cold stress (0 degrees C for up to 48 h), mainly if there was a 2-6 h delay between starvation and the cold stress, but positive effects in old flies were hardly observed. No positive effect was observed on resistance to the other stresses and starvation rather decreased resistance to them. It thus seems that fasting increases frailty but also puts at play mechanisms increasing resistance to cold. Starvation also increased learning scores but this could be linked to decreased positive phototaxis tendencies, and not to a better learning ability. Starvation appears to be a mild stress with limited hormetic effects, but studying the mechanisms of these effects is of interest because fasting is maybe of therapeutic value in human beings. PMID- 23990217 TI - Effect of LED-mediated-photobiomodulation therapy on orthodontic tooth movement and root resorption in rats. AB - The aim of this experimental study was to evaluate the effects of light-emitting diode-mediated-photobiomodulation therapy (LPT), on the rate of orthodontic tooth movement (TM) and orthodontically induced root resorption, in rats. Twenty male 12-week-old Wistar rats were separated into two groups (control and LPT) and 50 cN of force was applied between maxillary left molar and incisor with a coil spring. In the treatment group, LPT was applied with an energy density of 20 mW/cm(2) over a period of 10 consecutive days directly over the movement of the first molar teeth area. The distance between the teeth was measured with a digital caliper on days 0 (T0), 10 (T1), and 21 (T2) on dental cast models. The surface area of root resorption lacunae was measured histomorphometrically using digital photomicrographs. Mann-Whitney U and Wilcoxon tests were used for statistical evaluation at p < 0.05 level. TM during two different time intervals (T1-T0 and T2-T1) were compared for both groups and a statistically significant difference was found in the LPT group (p = 0.016). The TM amount at the first time period (1.31 +/- 0.36 mm) was significantly higher than the second time period (0.24 +/- 0.23 mm) in the LPT group. Statistical analysis showed significant differences between two groups after treatment/observation period (p = 0.017). The magnitude of movement in the treatment group was higher (1.55 +/- 0.33 mm) compared to the control group (1.06 +/- 0.35 mm). Histomorphometric analysis of root resorption, expressed as a percentage, showed that the average relative root resorption affecting the maxillary molars on the TM side was 0.098 +/- 0.066 in the LPT group and 0.494 +/- 0.224 in the control group. Statistically significant inhibition of root resorption with LPT was determined (p < 0.001) on the TM side. The LPT method has the potential of accelerating orthodontic tooth movement and inhibitory effects on orthodontically induced resorptive activity. PMID- 23990218 TI - The effects of low-level laser irradiation on bone tissue in diabetic rats. AB - Diabetes mellitus (DM) leads to a decrease in bone mass and increase the risk of osteoporosis and in this context, many treatments have shown to accelerate bone metabolism. It seems that low-level laser therapy (LLLT) is able of stimulating osteoblast activity and produced increased biomechanical properties. However, its effects on bone in diabetic rats are not fully elucidated. The aim of this study was to evaluate the effects of LLLT on bone formation, immunoexpression of osteogenic factors, biomechanical properties and densitometric parameters in diabetic rats. Thirty male Wistar rats were randomly distributed into three experimental groups: control group, diabetic group, and laser-treated diabetic group. DM was induced by streptozotocin (STZ) and after 1 week laser treatment started. An 830-nm laser was used, performed for 18 sessions, during 6 weeks. At the end of the experiment, animals were euthanized and tibias and femurs were defleshed for analysis. Extensive resorptive areas as a result of osteoclasts activity were noticed in DG when compared to control. Laser-treated animals showed an increased cortical area. The immunohistochemical analysis revealed that LLLT produced an increased RUNX-2 expression compared to other groups. Similar RANK-L immunoexpression was observed for all experimental groups. In addition, laser irradiation produced a statistically increase in fracture force, bone mineral content (BMC) and bone mineral density compared to DG. The results of this study indicate that the STZ model was efficient in inducing DM 1 and producing a decrease in cortical diameter, biomechanical properties and in densitometric variables. In addition, it seems that LLLT stimulated bone metabolism, decreased resorptive areas, increased RUNX-2 expression, cortical area, fracture force, BMD, and BMC. Further studies should be developed to provide additional information concerning the mechanisms of action of laser therapy in diabetic bone in experimental and clinical trials. PMID- 23990219 TI - Effect of low-level laser therapy on metalloproteinase MMP-2 and MMP-9 production and percentage of collagen types I and III in a papain cartilage injury model. AB - Osteoarthritis (OA) resulting from injury or disease is associated with increased levels of several matrix metalloproteinases (MMPs), which degrade all components of the complex extracellular matrix in the cartilage. The objective of this study is to investigate the effect of low-level laser therapy (LLLT) on papain-induced joint damage in rats by histopathology and analysis of metalloproteinase 2 and 9 production. Sixty male Wistar rats were randomly distributed into four groups of 15 animals: (1) non-injury negative control, (2) injury positive control, (3) treated with LLLT at 50 mW, and (4) treated with LLLT at 100 mW. OA was induced in animals using papain (4 % solution) followed by treatment with LLLT. After 7, 14, and 21 days, the animals were euthanized. The articular lavage was collected and centrifuged; then, the supernatant was stored prior to protein analysis by western blot. The material was stained with hematoxylin and eosin for histopathological analysis, and Picrosirius Red was used to estimate the percentage of collagen fibers. To determine normal distribution, ANOVA and Tukey's post hoc test were used for comparison between and within each group at each time period. All data are expressed as mean and standard deviation values, with the null hypothesis considered as p < 0.05. Both laser groups (50 and 100 mW) were effective in tissue repair, decreasing collagen type III expression and increasing type I expression in all experimental periods; however, LLLT at 50 mW reduced metalloproteinase 9 more than at 100 mW in 21 days. LLLT at 50 mW was more efficient in the modulation of matrix MMPs and tissue repair. PMID- 23990220 TI - Stimulus discrimination via responses of retinal ganglion cells and dopamine dependent modulation. AB - Neighboring retinal ganglion cells (RGCs) fire with a high degree of correlation. It has been increasingly realized that visual perception of the environment relies on neuronal population activity to encode and transmit the information contained in stimuli. Understanding how neuronal population activity contributes to visual information processing is essential for understanding the mechanisms of visual coding. Here we simultaneously recorded spike discharges from groups of RGCs in bullfrog retina in response to visual patterns (checkerboard, horizontal grating, and full-field illumination) using a multi-electrode array system. To determine the role of synchronous activity mediated by gap junctions, we measured the correct classification rates of single cells' firing patterns as well as the synchronization patterns of multiple neurons. We found that, under normal conditions, RGC population activity exhibited distinct response features with exposure to different stimulus patterns and had a higher rate of correct stimulus discrimination than the activity of single cells. Dopamine (1 MUmol/L) application did not significantly change the performance of single neuron activity, but enhanced the synchronization of the RGC population activity and decreased the rate of correct stimulus pattern discrimination. These findings suggest that the synchronous activity of RGCs plays an important role in the information coding of different types of visual patterns, and a dopamine-induced increase in synchronous activity weakens the population performance in pattern discrimination, indicating the potential role of the dopaminergic pathway in modulating the population coding process. PMID- 23990221 TI - Locomotor activity and anxiety status, but not spatial working memory, are affected in mice after brief exposure to cuprizone. AB - Chronic long-term exposure to cuprizone causes severe brain demyelination in mice, which leads to changes in locomotion, working memory and anxiety. These findings suggest the importance of intact myelin for these behaviors. This study aimed to investigate the possible behavioral changes in mice with mild oligodendrocyte/myelin damage that parallels the white matter changes seen in the brains of patients with psychiatric disporders. We used the cuprizone-treated mouse model to test both tissue changes and behavioral functions (locomotor activity, anxiety status, and spatial working memory). The results showed that mice given cuprizone in their diet for 7 days had no significant myelin breakdown as evaluated by immunohistochemical staining for myelin basic protein, while the number of mature oligodendrocytes was reduced. The number and length of Caspr protein clusters, a structural marker of the node of Ranvier, did not change. The locomotor activity of the cuprizone-treated mice increased whereas their anxiety levels were lower than in normal controls; spatial working memory, however, did not change. These results, for the first time, link emotion-related behavior with mild white matter damage in cuprizone-treated mice. PMID- 23990222 TI - Blockade of Na+/H+ exchanger type 3 causes intracellular acidification and hyperexcitability via inhibition of pH-sensitive K+ channels in chemosensitive respiratory neurons of the dorsal vagal nucleus in rats. AB - Extracellular pH (pHe) and intracellular pH (pHi) are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na(+)/H(+) exchanger 3 (NHE-3), a key pHi regulator in the brainstem, decreases the pHi, leading to membrane depolarization for the maintenance of respiration. However, how intracellular pH affects the neuronal excitability of respiratory neurons remains largely unknown. In this study, we showed that NHE-3 mRNA is widely distributed in respiration-related neurons of the rat brainstem, including the dorsal vagal nucleus (DVN). Whole-cell patch clamp recordings from DVN neurons in brain slices revealed that the standing outward current (Iso) through pH-sensitive K(+) channels was inhibited in the presence of the specific NHE-3 inhibitor AVE0657 that decreased the pHi. Exposure of DVN neurons to an acidified pHe and AVE0657 (5 MUmol/L) resulted in a stronger effect on firing rate and Iso than acidified pHe alone. Taken together, our results showed that intracellular acidification by blocking NHE-3 results in inhibition of a pH-sensitive K(+) current, leading to synergistic excitation of chemosensitive DVN neurons for the regulation of respiration. PMID- 23990223 TI - Hydroxysafflor yellow A protects against cerebral ischemia-reperfusion injury by anti-apoptotic effect through PI3K/Akt/GSK3beta pathway in rat. AB - Hydroxysafflor yellow A (HSYA) is the major active chemical component of the flower of the safflower plant, Carthamus tinctorius L. Previously, its neuroprotection against cerebral ischemia-reperfusion (I/R) injury was reported by anti-oxidant action and suppression of thrombin generation. Here, we investigate the role of HSYA in cerebral I/R-mediated apoptosis and possible signaling pathways. Male Wistar rats were subjected to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. HSYA was administered via tail-vein injection just 15 min after occlusion. The number of apoptotic cells was measured by TUNEL assay, apoptosis-related proteins Bcl-2, Bax and the phosphorylation levels of Akt and GSK3beta in ischemic penumbra were assayed by western blot. The results showed that administration of HSYA at the doses of 4 and 8 mg/kg significantly inhibited the apoptosis by decreasing the number of apoptotic cells and increasing the Bcl-2/Bax ratio in rats subjected to I/R injury. Simultaneously, HSYA treatment markedly increased the phosphorylations of Akt and GSK3beta. Blockade of PI3K activity by wortmannin dramatically abolished its anti-apoptotic effect and lowered both Akt and GSK3beta phosphorylation levels. Taken together, these results suggest that HSYA protects against cerebral I/R injury partly by reducing apoptosis via PI3K/Akt/GSK3beta signaling pathway. PMID- 23990224 TI - Effect of propofol post-treatment on blood-brain barrier integrity and cerebral edema after transient cerebral ischemia in rats. AB - Although propofol has been reported to offer neuroprotection against cerebral ischemia injury, its impact on cerebral edema following ischemia is not clear. The objective of this investigation is to evaluate the effects of propofol post treatment on blood-brain barrier (BBB) integrity and cerebral edema after transient cerebral ischemia and its mechanism of action, focusing on modulation of aquaporins (AQPs), matrix metalloproteinases (MMPs), and hypoxia inducible factor (HIF)-1alpha. Cerebral ischemia was induced in male Sprague-Dawley rats (n = 78) by occlusion of the right middle cerebral artery for 1 h. For post treatment with propofol, 1 mg kg(-1) min(-1) of propofol was administered for 1 h from the start of reperfusion. Nineteen rats undergoing sham surgery were also included in the investigation. Edema and BBB integrity were assessed by quantification of cerebral water content and extravasation of Evans blue, respectively, following 24 h of reperfusion. In addition, the expression of AQP 1, AQP-4, MMP-2, and MMP-9 was determined 24 h after reperfusion and the expression of HIF-1alpha was determined 8 h after reperfusion. Propofol post treatment significantly reduced cerebral edema (P < 0.05) and BBB disruption (P < 0.05) compared with the saline-treated control. The expression of AQP-1, AQP-4, MMP-2, and MMP-9 at 24 h and of HIF-1alpha at 8 h following ischemia/reperfusion was significantly suppressed in the propofol post-treatment group (P < 0.05). Propofol post-treatment attenuated cerebral edema after transient cerebral ischemia, in association with reduced expression of AQP-1, AQP-4, MMP-2, and MMP 9. The decreased expression of AQPs and MMPs after propofol post-treatment might result from suppression of HIF-1alpha expression. PMID- 23990225 TI - Microglial TNF-alpha-dependent elevation of MHC class I expression on brain endothelium induced by amyloid-beta promotes T cell transendothelial migration. AB - The blood-brain barrier (BBB) normally bars peripheral T lymphocytes from entering the cerebrum. Interestingly, activated T cells exist as infiltrates in the brains of Alzheimer's disease (AD) patients, but little is known about the mechanisms involved. In this study, we observed significantly higher MHC class I expression in rat brain endothelial cells compared with controls following the induction of experimental AD models. An in vitro BBB model, which was constructed with human brain microvascular endothelial cells, was established to study the mechanisms underlying the transendothelial migration of T cells. Using in vitro studies, we demonstrated that secretion of TNF-alpha from Abeta1-42-treated BV2 microglia contributes to the elevated expression of MHC class I on the brain microvessel endothelium. Transmigration assays and adhesion assays confirmed that the upregulation of MHC class I molecules was associated with T cell transendothelial migration. MHC class I knock-down in HBMECs significantly attenuated the migratory and adhesive capability of the T cells. Interestingly, a TNF-alpha neutralizing antibody effectively blocked the transendothelial migration of T cells triggered by treatment with the supernatant from Abeta1-42 treated BV2 microglia. We propose that microglia-derived TNF-alpha upregulates MHC class I molecule expression on brain endothelial cells, which represents a mechanism of T cell migration into the brain. This study may provide a new insight into the potential pathomechanism of Alzheimer's disease. PMID- 23990226 TI - The prevalence of abnormal echocardiographic findings in a sample of urban adult population. AB - BACKGROUND: Echocardiography has emerged as the test of choice for the evaluation of cardiac diseases. AIM: To assess the prevalence of a spectrum of cardiac abnormalities detected by echocardiography in a representative sample of an urban adult population. METHODS: Transthoracic echocardiography was performed in a random sample of 511 men (47%) and women (53%) aged 48-76 years selected from population registers in Krakow. Body surface area (BSA) was used to adjust echocardiographic parameters for variations in body size. Disease history and cardiovascular risk factors were assessed in all patients. RESULTS: Men smoked more frequently than women and had higher blood pressure and triglycerides and lower high density lipoprotein cholesterol. The most common finding was increased left ventricular (LV) end-diastolic diameter (EDd) (37%), followed by mitral (32%), aortic (24%), or tricuspid (17%) regurgitations, LV posterior wall (24.1%) and interventricular septum (17.5%) thickening, increased indexed LVEDd (23%), increased left atrial diameter (LAd; 15.7%), reduced LV ejection fraction (LVEF; 15.3%), segmental wall motion abnormalities (13.9%), increased indexed LAd (8.8%), dilation of the ascending aorta (8%), enlargement of the right ventricle (RV) (2%) and elevation of RV systolic pressure (0.6%). When adjusted for main cardiovascular risk factors and the presence of coronary artery disease, male sex was associated with a higher prevalence of enlargement of LV (LVEDd/BSA): OR = 1.8 (1.1-2.9), dilation of ascending aorta (aortic diameter/BSA): OR = 2.7 (1.3 5.8), and LA (LA/BSA) = OR 2.7 (1.3-5.6), as well as a decrease of LVEF: OR = 3.6 (1.9-6.5). CONCLUSIONS: Approximately a quarter of urban adults aged 48 to 76 can be expected to have some abnormalities on echocardiographic examination. Some of these abnormalities such as aortic dilation, LA enlargement, LV enlargement and decreased LVEF are more frequently found in males than in females, even after adjustment for BSA, main cardiovascular disease risk factors, and the presence of coronary artery disease. The use of raw instead of indexed LAd and LVEDd over estimates the prevalence of LA and LV enlargement. PMID- 23990227 TI - Anticoagulant and antiplatelet therapy for stroke prevention in atrial fibrillation patients in the clinical practice of a single district hospital in Poland. AB - BACKGROUND AND AIM: Retrospective evaluation of stroke risk in all patients with atrial fibrillation (AF) admitted to cardiology, internal medicine, and neurology wards in a single Polish district hospital in 2006 and 2010 using two risk stratification schemes, CHADS2 vs. CHA2DS2VASc risk scores and identification of independent predictors of guideline-compliant oral anticoagulant (OAC) treatment. METHODS: We analysed case records of 613 patients with AF (including 300 patients in 2006 and 313 patients in 2010) treated in a district hospital - the John Paul II Western Hospital (Szpital Zachodni) in Grodzisk Mazowiecki, to evaluate their stroke risk and therapy prescribed at discharge. RESULTS: The mean patient age in the overall study population (49% of men) was 74.3 years (74.8, 77.5, and 71.9 years, respectively, in patients with paroxysmal, permanent and persistent AF). Patients > 75 years old comprised 58.6% of the study group, and those < 65 years old comprised 16.6% of the study group. The most common concomitant diseases were hypertension (65.9%), chronic heart failure (61.7%), coronary artery disease (43.1%), at least moderate mitral and/or tricuspid regurgitation (36.4%), and peripheral arterial disease (36%). Indications for OAC treatment were present in 85% (using the CHADS2 score) or 95% (using the CHA2DS2VASc score) patients but this therapy was prescribed at discharge in only 39% of the study group (240 patients). Compared to patients who were not prescribed OAC, those prescribed OAC treatment were younger, more often male, with permanent AF, valvular heart disease, and hypertension. In patients without OAC treatment at discharge, the following conditions were found more frequently than in patients prescribed OAC treatment: paroxysmal AF(49.8% vs. 33.3% in OAC patients), established coronary artery disease (46.1% vs. 38.3%), previous myocardial infarction (27%vs. 18.7%), prior coronary revascularisation (11.2% vs. 6.6%), alcohol abuse (4.2% vs. 0.8%), renal failure (31.6% vs. 21.6%), and stroke or transient ischaemic attack (TIA; 19.3% vs. 12%). In multivariate logistic regression analysis, we identified 5 independent predictive factors associated with prescribing OAC at discharge, including persistent AF vs. paroxysmal AF (odd sratio [OR] = 5.27), permanent AF vs. paroxysmal AF (OR = 1.86), hypertension (OR = 1.50), previous stroke and/or TIA (OR = 0.59), and age > 75 years vs. < 65 years (OR = 0.53). CONCLUSIONS: Despite a high stroke risk as determined by both scores, only 39% of patients received OAC. In the studied population, independent predictors for prescribing OAC at discharge included arterial hypertension (in accordance with the guidelines) and younger patient age, no history of stroke/TIA, and AF other than paroxysmal. The practice of OAC and/or antiplatelet therapy use in AF patients discharged from a Polish district hospital was not compliant with the current ESC guidelines either in 2006 or in 2010. PMID- 23990228 TI - Analysis of risk factors and prospective evaluation of cardiovascular complications of Kawasaki disease in children: a single centre study. AB - BACKGROUND: Kawasaki disease (KD) remains a diagnostic challenge due to its nonspecific clinical symptoms. Delayed treatment initiation increases the risk of coronary complications. AIM: To evaluate the risk of coronary artery involvement and perform a prospective analysis of its course in children hospitalised due to KD. METHODS: KD was diagnosed in 38 children, including 25 boys and 13 girls, aged 1.5-118 months (median 37.5 months). We assessed the risk of cardiac complications in relation to the presence of a complete or incomplete form of the disease, age, gender and laboratory test results, as well as the timing of treatment initiation. Thirty-six children were followed for 1-9 years in a cardiology clinic. RESULTS: More than 80% of patients with KD were younger than 5 years. Eleven (29%) of them had an incomplete form of the disease. Coronary artery abnormalities were found in 10 (26%) children, insignificantly more often among those within complete KD. Each day of treatment delay increased the complication rate by almost 1.5 (OR 1.45, p = 0.009). Treatment initiated 10 days after the onset of the disease increased this risk almost nine times (OR 8.99, p = 0.007). No significant differences in respect to age (p = 0.431), gender (p = 0.744) and laboratory test results were found between the groups with and without coronary complications. A complete regression of coronary artery involvement was seen in 7 children, and partial regression was seen in one child. One child died and another needed coronary artery bypass grafting. CONCLUSIONS: Coronary artery aneurysms developed at a similar rate in both complete and incomplete forms of KD and the only significant risk factor was the timing of treatment initiation. In young children with fever of unknown cause lasting longer than 5 days, echocardiography is warranted. Despite a tendency for coronary artery aneurysms to regress, late complications may occur and all children require long-term follow up in a cardiology clinic. PMID- 23990229 TI - A new prognostic evaluation of patients with acute ST-elevation myocardial infarction undergoing primary angioplasty: combined Zwolle and Syntax score. AB - BACKGROUND: The Zwolle score (Zs) is a validated risk score used to identify low risk patients with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). The Syntax score (Ss) is an angiographic score that evaluates the complexity of coronary artery disease. AIM: We aimed to create a simple risk score by combining these two scores for risk stratification in patients with STEMI undergoing primary PCI. METHODS: 299 consecutive STEMI patients (mean age 57.4 +/- 11.7 years, 240 men) who underwent primary PCI were prospectively enrolled into the present study. The study population was divided into tertiles based on admission Zs and Ss. A high Zs (> 3) and high Ss (> 24) were defined as values in the third tertiles. A low Zs and low Ss were defined as values in the lower two tertiles. Patients were then classified into four groups: high Zs and high Ss (HZsHSs, n = 26), high Zs and low Ss (HZsLSs, n = 29), low Zs and high Ss (LZsHSs, n = 48), and low Zs and low Ss (LZsLSs, n = 196). In-hospital cardiacoutcomes were then recorded. RESULTS: In hospital cardiovascular mortality was higher in HZsHSs (50%) compared to the HZsLSs (27.5%), LZsHSs (0%), and LZsLSs (0.5%) groups. After adjustment for potentially confounding factors, HZsHSs (OR 77.6, 95% CI 6.69-113.1, p = 0.001), and HZsLSs (OR 28.9, 95% CI 2.77-56.2, p = 0.005) status, but not LZsHSs and LZsLSs status, remained independent predictors of in-hospital cardiovascular mortality. CONCLUSIONS: STEMI patients with HZsHSs represent the highest risk population for in-hospital cardiovascular mortality. PMID- 23990230 TI - Does heart failure determine the nutrition of patients? AB - BACKGROUND: Studies of the diet of heart failure (HF) patients, available in the literature, indicate that this diet is highly inadequate in light of the existing recommendations. AIM: To assess the nutrition of middle-aged patients with HF compared to a control group representing the general population without HF. METHODS: The study group comprised 70 patients with diagnosed HF, below 65 years, with NYHA class I/II/III. For the control group, we selected members of the general population with identical sex, age, body mass index and cigarette smoking parameters as the tested persons. Diet was evaluated on the basis of a dietary questionnaire and a 24-h dietary recall. RESULTS: The energy/ideal body weight ratio was significantly lower in the study group than in the control group (p < 0.005). Patients with HF had lower % kcal from fat, SAFA, MUFA (p < 0.05), omega 3 (p < 0.05), folic acid (p < 0.001) and dietary fibre (p < 0.01) consumption compared to the control group. No intergroup differences were found in the consumption of vitamins B6, C, A or E. The lowest energy, dietary fibre and vitamins intake (except vitamin A) was found in patients in NYHA class III. CONCLUSIONS: The diet of patients with HF seems to differ from the diet of persons without HF. These differences are manifested in a lower energy content of diet, lower intake of total fat, omega-3 fatty acids, folic acid and dietary fibre. Most patients with HF have ischaemic aetiology, and therefore should apply the dietary recommendations for patients with dyslipidaemia and high cardiovascular risk. However, their diet for certain parameters was inconsistent with ESC/EAS guidelines (high intake of saturated fatty acids, low intake of dietary fibre). PMID- 23990231 TI - Relations of diabetes mellitus, microvascular reperfusion and left ventricular remodelling in patients with acute myocardial infarction treated with primary coronary intervention. AB - BACKGROUND AND AIM: The aim of our study was to determine the influence of diabetes mellitus (DM) on myocardial reperfusion and left ventricular (LV) remodelling in patients with an acute myocardial infarction undergoing primary percutaneous coronary intervention. METHODS: The study population consisted of 218 patients with first anterior ST-segment elevation myocardial infarction (STEMI) successfully treated with primary coronary angioplasty. We evaluated microvascular reperfusion using angiographic (Myocardial Blush Grade [MBG]) as well as electrocardiographic methods (ST-segment resolution > 70%). LV remodelling was defined asan increase in end-diastolic volume >= 20%, based on repeated measurements in individual patients. The study population was divided into two groups according to the presence, n = 43 (20%), or absence, n = 175 (80%), of DM. RESULTS: Patients with DM showed a significantly higher rate of MBG <=2 (45.7% vs. 62.8%, p = 0.04) and lower incidence of ST-segment resolution > 70% (48% vs. 18.6%, p = 0.0003) compared to non-diabetics. Despite a similar incidence of LV remodelling in DM and non-DM groups (30.2% vs. 22.4%, p = 0.27), echocardiographic features of diastolic impairment and overt symptoms of heart failure were significantly more frequent in diabetic patients (55.2% vs. 27.1%, p = 0.006 and 36.1% vs. 18.3%, p = 0.02, respectively) at six-month follow-up. CONCLUSIONS: Despite worse microvascular reperfusion in STEMI patients with diabetes, the incidence of LV remodelling was similar compared to non-DM patients. DM was associated with the development of diastolic heart failure. PMID- 23990232 TI - TIMI myocardial perfusion grade and ST-segment resolution in the assessment of coronary reperfusion after primary angioplasty. AB - BACKGROUND: Angiographic coronary flow parameters and resolution of ST segment changes play an important role in the evaluation of reperfusion in patients with acute ST segment elevation myocardial infarction (STEMI). In previous studies on the relation between angiographic and electrocardiographic (ECG) parameters of coronary reperfusion, several alternative methods to assess ST segment resolution were used. Thus, the relation between the TIMI Myocardial Perfusion Grade (TMPG) and different methods to evaluate ST segment resolution seems to be of interest. AIM: To evaluate the relationship between TMPG and absolute and relative ST segment resolution after successful primary percutaneous coronary intervention (pPCI). METHODS: We studied a population of STEMI patients successfully treated with pPCI. Reperfusion of the coronary microcirculation was determined using 4 grade TMPG scale in coronary angiography performed after successful pPCI. ST segment resolution was analysed in two manners: 1) by calculating the sum of ST segment elevation in infarct leads and depression in reciprocal leads after pPCI (absolute resolution, SSTD); 2) as a percent reduction of summed ST segment deviation from the baseline value (relative resolution, SSTD%). Maximum ST segment elevation in a single lead on the postprocedural ECG was measured to categorise the risk of death. ST segment elevation > 1 mm for an inferior infarct or > 2 mm for an anterior infarct was considered the criterion of high risk (high risk ECG). RESULTS: The study population included 183 patients treated with pPCI. We found a significant but weak negative correlation between TMPG and SSTD (r = 0.27, p = 0.0002). Significant differences in median SSTD were observed between TMPG 0 vs. TMPG 2 and TMPG 3 groups (p = 0.0034 and 0.0121, respectively) and also between TMPG 1 and TMPG 2 (p = 0.02). A significant but very weak positive correlation was found between TMPG and SSTD% (r = 0.16,p = 0.0286). However, further analyses showed that differences in median SSTD% between patients with different TMPG values were statistically insignificant (p = 0.1756). In patients with TMPG 2/3, a high risk ECG was absent considerably more often (p = 0.0007). However, angiographic features of successfully vs. unsuccessfully reperfused microcirculation did not correspond to the presence of a high risk ECG in about 34% of cases. CONCLUSIONS: TMPG is more closely related to absolute compared to relative ST segment resolution. A high risk ECG was absent in most patients with TMPG 2 or 3. However, in about one third of cases TMPG did not correspond to the presence of ECG high risk features. These data suggest that TMPG is complementary to ST segment resolution in the assessment of coronary reperfusion. PMID- 23990233 TI - Intracoronary adenosine administered during aortocoronary vein graft interventions may reduce the incidence of no-reflow phenomenon. A pilot randomised trial. AB - BACKGROUND: The results of percutaneous coronary intervention (PCI) for saphenous vein graft (SVG) disease are limited by distal embolisation and no-reflow which occurs in 10-43% of cases. AIM: To examine the role of a new protocol of adenosine administration during PCI in SVG on immediate angiographic results and clinical course. METHODS: A prospective, single-centre, randomised placebo controlled pilot trial in 32 consecutive patients after coronary artery bypass graft (aged 71 +/- 12 years, 22 male) with stable and unstable angina (CCS II IV), who were admitted to our hospital for SVG PCI, was conducted. Patients were randomised to two groups. Group A (16 patients) received two times adenosine (2 mg + 2 mg) to the SVG during PCI procedure, and Group B (16 patients) received a placebo. RESULTS: No reflow was observed in one (6.25%) patient in the adenosine group and six (37.5%) patients in the placebo group (p = 0.0325). TIMI 3 flow (94% vs. 63%; p = 0.0322) and corrected TIMI frame count < 28 (94% vs. 63%; p = 0.0322) at the end of the procedure were better in patients who received adenosine. Myocardial blush grade 2 and 3 at the end of th eprocedure was observed in 15 patients in the adenosine group and ten patients in the placebo group (p = 0.083). A trend toward a lower rate of myocardial infarctions in the adenosine group was observed (6% vs. 25%; p = 0.144). CONCLUSIONS: Adenosine injections may be effective in preventing no-reflow in the setting of PCI of SVG. Adenosine administration seems to be associated with a more favourable clinical course. PMID- 23990234 TI - Dynamics of anxiety in women undergoing coronary angiography. AB - BACKGROUND: Anxiety is a common and serious problem in ischaemic heart disease. Anxiety-associated somatisation disorders may imitate symptoms of coronary artery disease or coexist with ischaemic heart disease. Despite multiple visits to various specialists, patients with somatisation are frequently misdiagnosed and therefore mistreated. Identification of patients with anxiety disorders among patients complaining of chest pain is a prerequisite for appropriate management. By its nature, coronary angiography is a diagnostic test that can give rise to anxiety. However, dynamics of anxiety in this setting may be variable depending on coexisting mental disorders. AIM: The purpose of this study was to determine whether the presence of significant atherosclerotic lesions in coronary arteries affects anxiety level changes following coronary angiography. METHODS: A group of 90 female patients who underwent coronary angiography was divided into two groups: the first one included 48 patients without significant coronary stenoses, and the other one included 42 patients with confirmed significant atherosclerotic lesions. Dynamics of anxiety level changes from the hospital admission, through the post-examination period, until 6 to 9 months after coronary angiography was evaluated with three-time measurement of anxiety using the Spielberger's State Trait Anxiety Inventory. In addition, intensity of anxiety as a trait was measured twice (at the first and the third examination). RESULTS: The highest intensity of anxiety as a state was noted in both groups at the first measurement. A significant reduction in anxiety was observed at the second measurement, more pronounced in the group without significant coronary lesions. At the third measurement, women with confirmed significant coronary lesions showed the lowest level of anxiety, while the level of anxiety increased compared to the second measurement in the group of patients without significant coronary lesions. At the third measurement, women without significant coronary lesions showed a significantly higher level of anxiety compared to the group with significant coronary lesions. Intensity of anxiety as a trait was significantly lower at the final measurement in the group of patients with confirmed significant coronary stenoses. CONCLUSIONS: In women demonstrating no significant atherosclerotic lesions in coronary angiography, anxiety does not resolve permanently but reappears after several months. In this group, is seems justified to consider a diagnosis of an anxiety disorder in the form of a somatoform disorder. Those patients should be offered psychiatric therapy. PMID- 23990235 TI - Cognitive impairment after appropriate implantable cardioverter-defibrillator therapy for ventricular fibrillation. AB - BACKGROUND: Short periods of cerebral ischaemia during ventricular defibrillation testing may be associated with neuropsychological impairment. However, the impact of out-of-hospital ventricular fibrillation (VF) converted by implantable cardioverter-defibrillator (ICD) shock on cognitive functioning is unknown. AIM: To assess the impact of out-of-hospital VF converted by ICD shock on cognitive functioning. METHODS: The study included 52 primary prevention ICD recipients. Patients with a history of stroke or other neurological impairment, previous head injury and individuals unable to see or speak to complete neuropsychological tests were not included.Initially, a Mini-Mental State Examination was performed in all patients and one patient with a result below 24 points was excluded from the study. The cognitive battery consisted of four tests (six measurements): 1) the Digit Span subtest of Wechsler Adult Intelligence Scale-Revised; 2) the Digit Symbol subtest of Wechsler Adult Intelligence Scale-Revised; 3) the Halstead Reitan Trail-Making Test A and B; and 4) the Ruff Figural Fluency Test. RESULTS: The mean time from ICD implantation to cognitive assessment was 26 months. During this period, 15 appropriate shocks for VF were observed in seven (14%) patients. The patients with appropriate ICD therapy were significantly worse in two out of the six neuropsychological measurements and had a significantly lower aggregate result. In multivariate linear regression analysis, defibrillation therapy was an independent factor of poor cognitive functioning, along with age and education. CONCLUSIONS: Short periods of out-of-hospital VF converted by ICD are associated with cognitive impairment in the recipients of primary prevention ICD. PMID- 23990236 TI - Comparison of the seven-year predictive value of six risk scores in acute coronary syndrome patients: GRACE, TIMI STEMI, TIMI NSTEMI, SIMPLE, ZWOLLE and BANACH. AB - BACKGROUND AND AIM: To compare the long-term predictive value of six risk scores in a seven-year follow-up of acute coronary syndrome (ACS) patients. METHODS: We followed 906 patients diagnosed with ACS for seven years prospectively. The following risk scores (RS) were calculated: TIMI STEMI, TIMI NSTEMI, GRACE, SIMPLE, ZWOLLE and BANACH. Based on the survival data, the predictive value for each RS was calculated with receiver operating characteristics (ROC) curve analysis and presented as area under curve (AUC). RESULTS: The seven-year survival was 71%. The RS showed diverse long-term predictive values and AUC. The best estimation was demonstrated by the TIMI STEMI (0.779 [95% CI 0.743-0.812]), GRACE RS (0.766 [95% CI 0.737-0.794]) and BANACHRS (0.743 [95% CI 0.713-0.771]). Other scores presented were SIMPLE (0.714 [95% CI 0.683-0.743], TIMI NSTEMI (0.635 [95% CI 0.580-0.688]) and ZWOLLE (0.739 [95% CI 0.697-0.779]. CONCLUSIONS: The predictive values of currently recommended RSs are good for long-term perspective (seven years). RSs with high usability, such as BANACH RS, demonstrate accuracy similar to the more advanced RS. PMID- 23990237 TI - Mapping cyclic stretch in the postpneumonectomy murine lung. AB - In many mammalian species, the removal of one lung [pneumonectomy (PNX)] is associated with the compensatory growth of the remaining lung. To investigate the hypothesis that parenchymal deformation may trigger lung regeneration, we used respiratory-gated micro-computed tomography scanning to create three-dimensional finite-element geometric models of the murine cardiac lobe with cyclic breathing. Models were constructed of respiratory-gated micro-computed tomography scans pre PNX and 24 h post-PNX. The computational models demonstrated that the maximum stretch ratio map was patchy and heterogeneous, particularly in subpleural, juxta diaphragmatic, and cephalad regions of the lobe. In these parenchymal regions, the material line segments at peak inspiration were frequently two- to fourfold greater after PNX; some regions of the post-PNX cardiac lobe demonstrated parenchymal compression at peak inspiration. Similarly, analyses of parenchymal maximum shear strain demonstrated heterogeneous regions of mechanical stress with focal regions demonstrating a threefold increase in shear strain after PNX. Consistent with previously identified growth patterns, these subpleural regions of enhanced stretch and shear strain are compatible with a mechanical signal, likely involving cyclic parenchymal stretch, triggering lung growth. PMID- 23990238 TI - Integrative pathway analysis of a genome-wide association study of (V)O(2max) response to exercise training. AB - We previously reported the findings from a genome-wide association study of the response of maximal oxygen uptake (Vo2max) to an exercise program. Here we follow up on these results to generate hypotheses on genes, pathways, and systems involved in the ability to respond to exercise training. A systems biology approach can help us better establish a comprehensive physiological description of what underlies Vo2maxtrainability. The primary material for this exploration was the individual single-nucleotide polymorphism (SNP), SNP-gene mapping, and statistical significance levels. We aimed to generate novel hypotheses through analyses that go beyond statistical association of single-locus markers. This was accomplished through three complementary approaches: 1) building de novo evidence of gene candidacy through informatics-driven literature mining; 2) aggregating evidence from statistical associations to link variant enrichment in biological pathways to Vo2max trainability; and 3) predicting possible consequences of variants residing in the pathways of interest. We started with candidate gene prioritization followed by pathway analysis focused on overrepresentation analysis and gene set enrichment analysis. Subsequently, leads were followed using in silico analysis of predicted SNP functions. Pathways related to cellular energetics (pantothenate and CoA biosynthesis; PPAR signaling) and immune functions (complement and coagulation cascades) had the highest levels of SNP burden. In particular, long-chain fatty acid transport and fatty acid oxidation genes and sequence variants were found to influence differences in Vo2max trainability. Together, these methods allow for the hypothesis-driven ranking and prioritization of genes and pathways for future experimental testing and validation. PMID- 23990239 TI - Disinhibition of RVLM neural circuits and regulation of sympathetic nerve discharge at peak hyperthermia. AB - Hyperthermia is a potent activator of visceral sympathetic nerve discharge (SND), and the functional integrity of the rostral ventral lateral medulla (RVLM) is critically important for sustaining sympathoexcitation at peak hyperthermia. However, RVLM mechanisms mediating SND activation to acute heat stress are not well understood. Because RVLM GABA is tonically inhibitory to sympathetic nerve outflow, it is plausible to hypothesize that disinhibition of RVLM sympathetic neural circuits, via withdrawal of GABAergic tone, may affect SND regulation at peak hyperthermia. The effect of RVLM bicuculline (BIC; GABAA receptor antagonist, 100-200 pmol) microinjections on the level of renal SND in anesthetized rats was determined after internal body temperature (Tc) had been increased to 41.5 degrees C. Temperature-control experiments involved RVLM BIC (100-200 pmol) microinjections, with Tc maintained at 38 degrees C. As expected, acute heating significantly increased renal SND from control levels. Bilateral RVLM BIC microinjections at 41.5 degrees C produced immediate and significant increases in renal SND above heating-induced levels of activation. Bilateral RVLM BIC microinjections at 38 degrees C increased renal SND to similar levels as produced by RVLM BIC microinjections after Tc had been increased to 41.5 degrees C (heating + RVLM BIC). These results demonstrate that a considerable level of RVLM GABAergic inhibition is sustained at peak hyperthermia, an interesting physiological response profile based on the significance of SND activation to cardiovascular regulation during heat stress. PMID- 23990240 TI - Brain mapping after prolonged cycling and during recovery in the heat. AB - The aim of this study was to determine the effect of prolonged intensive cycling and postexercise recovery in the heat on brain sources of altered brain oscillations. After a max test and familiarization trial, nine trained male subjects (23 +/- 3 yr; maximal oxygen uptake = 62.1 +/- 5.3 ml.min(-1).kg(-1)) performed three experimental trials in the heat (30 degrees C; relative humidity 43.7 +/- 5.6%). Each trial consisted of two exercise tasks separated by 1 h. The first was a 60-min constant-load trial, followed by a 30-min simulated time trial (TT1). The second comprised a 12-min simulated time trial (TT2). After TT1, active recovery (AR), passive rest (PR), or cold water immersion (CWI) was applied for 15 min. Electroencephalography was measured at baseline and during postexercise recovery. Standardized low-resolution brain electromagnetic tomography was applied to accurately pinpoint and localize altered electrical neuronal activity. After CWI, PR and AR subjects completed TT2 in 761 +/- 42, 791 +/- 76, and 794 +/- 62 s, respectively. A prolonged intensive cycling performance in the heat decreased beta activity across the whole brain. Postexercise AR and PR elicited no significant electrocortical differences, whereas CWI induced significantly increased beta3 activity in Brodmann areas (BA) 13 (posterior margin of insular cortex) and BA 40 (supramarginal gyrus). Self-paced prolonged exercise in the heat seems to decrease beta activity, hence representing decreased arousal. Postexercise CWI increased beta3 activity at BA 13 and 40, brain areas involved in somatosensory information processing. PMID- 23990241 TI - Quantitative assessment of muscle damage in the mdx mouse model of Duchenne muscular dystrophy using polarization-sensitive optical coherence tomography. AB - Minimally invasive, high-resolution imaging of muscle necrosis has the potential to aid in the assessment of diseases such as Duchenne muscular dystrophy. Undamaged muscle tissue possesses high levels of optical birefringence due to its anisotropic ultrastructure, and this birefringence decreases when the tissue undergoes necrosis. In this study, we present a novel technique to image muscle necrosis using polarization-sensitive optical coherence tomography (PS-OCT). From PS-OCT scans, our technique is able to quantify the birefringence in muscle tissue, generating an image indicative of the tissue ultrastructure, with areas of abnormally low birefringence indicating necrosis. The technique is demonstrated on excised skeletal muscles from exercised dystrophic mdx mice and control C57BL/10ScSn mice with the resulting images validated against colocated histological sections. The technique additionally gives a measure of the proportion (volume fraction) of necrotic tissue within the three-dimensional imaging field of view. The percentage necrosis assessed by this technique is compared against the percentage necrosis obtained from manual assessment of histological sections, and the difference between the two methods is found to be comparable to the interobserver variability of the histological assessment. This is the first published demonstration of PS-OCT to provide automated assessment of muscle necrosis. PMID- 23990242 TI - Spatiotemporal properties of high-speed calcium oscillations in the pedunculopontine nucleus. AB - The pedunculopontine nucleus (PPN) is a component of the reticular activating system (RAS), and is involved in the activated states of waking and rapid eye movement (REM) sleep. Gamma oscillations (approximately 30-80 Hz) are evident in all PPN neurons and are mediated by high-threshold voltage-dependent N- and P/Q type calcium channels. We tested the hypothesis that high-speed calcium imaging would reveal calcium-mediated oscillations in dendritic compartments in synchrony with patch-clamp recorded oscillations during depolarizing current ramps. Patch clamped 8- to 16-day-old rat PPN neurons (n = 67 out of 121) were filled with Fura 2, Bis Fura, or OGB1/CHR. This study also characterized a novel ratiometric technique using Oregon Green BAPTA-1 (OGB1) with coinjections of a new long stokes-shift dye, Chromeo 494 (CHR). Fluorescent calcium transients were blocked with the nonspecific calcium channel blocker cadmium, or by the combination of omega-agatoxin-IVA, a specific P/Q-type calcium channel blocker, and omega conotoxin-GVIA, a specific N-type calcium channel blocker. The calcium transients were evident in different dendrites (suggesting channels are present throughout the dendritic tree) along the sampled length without interruption (suggesting channels are evenly distributed), and appeared to represent a summation of oscillations present in the soma. We confirm that PPN calcium channel-mediated oscillations are due to P/Q- and N-type channels, and reveal that these channels are distributed along the dendrites of PPN cells. PMID- 23990243 TI - Respiratory system reactance is an independent determinant of asthma control. AB - The mechanisms underlying not well-controlled (NWC) asthma remain poorly understood, but accumulating evidence points to peripheral airway dysfunction as a key contributor. The present study tests whether our recently described respiratory system reactance (Xrs) assessment of peripheral airway dysfunction reveals insight into poor asthma control. The aim of this study was to investigate the contribution of Xrs to asthma control. In 22 subjects with asthma, we measured Xrs (forced oscillation technique), spirometry, lung volumes, and ventilation heterogeneity (inert-gas washout), before and after bronchodilator administration. The relationship between Xrs and lung volume during a deflation maneuver yielded two parameters: the volume at which Xrs abruptly decreased (closing volume) and Xrs at this volume (Xrscrit). Lowered (more negative) Xrscrit reflects reduced apparent lung compliance at high lung volumes due, for example, to heterogeneous airway narrowing and unresolved airway closure or near closure above the critical lung volume. Asthma control was assessed via the 6-point Asthma Control Questionnaire (ACQ6). NWC asthma was defined as ACQ6 > 1.0. In 10 NWC and 12 well-controlled subjects, ACQ6 was strongly associated with postbronchodilator (post-BD) Xrscrit (R(2) = 0.43, P < 0.001), independent of all measured variables, and was a strong predictor of NWC asthma (receiver operator characteristic area = 0.94, P < 0.001). By contrast, Xrs measures at lower lung volumes were not associated with ACQ6. Xrscrit itself was significantly associated with measures of gas trapping and ventilation heterogeneity, thus confirming the link between Xrs and airway closure and heterogeneity. Residual airway dysfunction at high lung volumes assessed via Xrscrit is an independent contributor to asthma control. PMID- 23990244 TI - Neural network versus activity-specific prediction equations for energy expenditure estimation in children. AB - The aim of this study was to compare the energy expenditure (EE) estimations of activity-specific prediction equations (ASPE) and of an artificial neural network (ANNEE) based on accelerometry with measured EE. Forty-three children (age: 9.8 +/- 2.4 yr) performed eight different activities. They were equipped with one tri axial accelerometer that collected data in 1-s epochs and a portable gas analyzer. The ASPE and the ANNEE were trained to estimate the EE by including accelerometry, age, gender, and weight of the participants. To provide the activity-specific information, a decision tree was trained to recognize the type of activity through accelerometer data. The ASPE were applied to the activity type-specific data recognized by the tree (Tree-ASPE). The Tree-ASPE precisely estimated the EE of all activities except cycling [bias: -1.13 +/- 1.33 metabolic equivalent (MET)] and walking (bias: 0.29 +/- 0.64 MET; P < 0.05). The ANNEE overestimated the EE of stationary activities (bias: 0.31 +/- 0.47 MET) and walking (bias: 0.61 +/- 0.72 MET) and underestimated the EE of cycling (bias: 0.90 +/- 1.18 MET; P < 0.05). Biases of EE in stationary activities (ANNEE: 0.31 +/- 0.47 MET, Tree-ASPE: 0.08 +/- 0.21 MET) and walking (ANNEE 0.61 +/- 0.72 MET, Tree-ASPE: 0.29 +/- 0.64 MET) were significantly smaller in the Tree-ASPE than in the ANNEE (P < 0.05). The Tree-ASPE was more precise in estimating the EE than the ANNEE. The use of activity-type-specific information for subsequent EE prediction equations might be a promising approach for future studies. PMID- 23990246 TI - Arousal from sleep: implications for obstructive sleep apnea pathogenesis and treatment. AB - Historically, brief awakenings from sleep (cortical arousals) have been assumed to be vitally important in restoring airflow and blood-gas disturbances at the end of obstructive sleep apnea (OSA) breathing events. Indeed, in patients with blunted chemical drive (e.g., obesity hypoventilation syndrome) and in instances when other defensive mechanisms fail, cortical arousal likely serves an important protective role. However, recent insight into the pathogenesis of OSA indicates that a substantial proportion of respiratory events do not terminate with a cortical arousal from sleep. In many cases, cortical arousals may actually perpetuate blood-gas disturbances, breathing instability, and subsequent upper airway closure during sleep. This brief review summarizes the current understanding of the mechanisms mediating respiratory-induced cortical arousal, the physiological factors that influence the propensity for cortical arousal, and the potential dual roles that cortical arousal may play in OSA pathogenesis. Finally, the extent to which existing sedative agents decrease the propensity for cortical arousal and their potential to be therapeutically beneficial for certain OSA patients are highlighted. PMID- 23990245 TI - Intermittent hypoxia and hypercapnia induce pulmonary artery atherosclerosis and ventricular dysfunction in low density lipoprotein receptor deficient mice. AB - Patients with obstructive sleep apnea, who experience episodic hypoxia and hypercapnia during sleep, often demonstrate increased inflammation, oxidative stress, and dyslipidemia. We hypothesized that sleep apnea patients would be predisposed to the development of atherosclerosis. To dissect the mechanisms involved, we developed an animal model in mice whereby we expose mice to intermittent hypoxia/hypercapnia (IHH) in normobaric environments. Two- to three month-old low-density lipoprotein receptor deficient (Ldlr(-/-)) mice were fed a high-fat diet for 8 or 16 wk while being exposed to IHH for either 10 h/day or 24 h/day. Plasma lipid levels, pulmonary artery and aortic atherosclerotic lesions, and cardiac function were then assayed. Surprisingly, atherosclerosis in the aorta of IHH mice was similar compared with controls. However, in IHH mice, atherosclerosis was markedly increased in the trunk and proximal branches of the pulmonary artery of exposed mice; even though plasma cholesterol and triglycerides were lower than in controls. Hemodynamic analysis revealed that right ventricular maximum pressure and isovolumic relaxation constant were significantly increased in IHH exposed mice and left ventricular % fractional shortening was reduced. In conclusion, 1) Intermittent hypoxia/hypercapnia remarkably accelerated atherosclerotic lesions in the pulmonary artery of Ldlr(-/ ) mice and 2) increased lesion formation in the pulmonary artery was associated with right and left ventricular dysfunction. These findings raise the possibility that patients with obstructive sleep apnea may be susceptible to atherosclerotic disease in the pulmonary vasculature, an observation that has not been previously recognized. PMID- 23990247 TI - Alpha 7 integrin preserves the function of the extensor digitorum longus muscle in dystrophin-null mice. AB - The dystrophin-associated glycoprotein complex (DGC) and the alpha7beta1-integrin complex are two independent protein complexes that link the extracellular matrix with the cytoskeleton in muscle cells. These associations stabilize the sarcolemma during force transmission. Loss of either one of these complexes leads to muscular dystrophy. Dystrophin is a major component of the DGC. Its absence results in Duchenne muscular dystrophy (DMD). Because alpha7-integrin overexpression has been shown to ameliorate muscle histopathology in mouse models of DMD, we hypothesize that the alpha7beta1-integrin complex can help preserve muscle function. To test this hypothesis, we evaluated muscle force, elasticity, and the viscous property of the extensor digitorum longus muscle in 19-day-old normal BL6, dystrophin-null mdx4cv, alpha7-integrin-null, and dystrophin/alpha7 integrin double knockout mice. While nominal changes were found in single knockout mice, contractility and passive properties were significantly compromised in alpha7-integrin double knockout mice. Our results suggest that DGC and alpha7beta1-integrin complexes may compensate each other to maintain normal skeletal muscle function. alpha7beta1-Integrin upregulation may hold promise to treat not only histological, but also physiological, defects in DMD. PMID- 23990249 TI - Ultrasound-guided fine-needle aspiration for solid thyroid nodules larger than 10 mm: correlation between sonographic characteristics at the needle tip and nondiagnostic results. AB - The objective of this study was to investigate the effect of the ultrasonographic (US) characteristics and ultrasound elastography (UE) patterns on the probability of a nondiagnostic result when performing ultrasound-guided fine-needle aspiration (UG-FNA) cytological sampling of solid thyroid nodules larger than 10 mm, to determine the efficacy of needle tip localization in UG-FNA. We retrospectively reviewed the cytological results of 710 samples from 355 patients. We compared the US characteristics and UE patterns between nodules with nondiagnostic and diagnostic results, using univariate and multivariate analyses. Among the 710 samples, 81 samples (11.4 %) from 41 patients had nondiagnostic results. According to multivariate analysis, the combinations of hypoechogenicity with avascularity [odds ratio (OR) = 2.42; 95 % confidence interval (CI) 1.37 3.72; p < 0.05], hypoechogenicity with the "hard pattern" (OR = 2.12; 95 % CI 1.58-4.59; p < 0.05), and hypoechogenicity with avascularity and the hard pattern (OR = 2.61; 95 % CI 1.40-5.21; p < 0.05) were risk factors that increased the incidence of nondiagnostic results in UG-FNA. UG-FNA was more likely to yield nondiagnostic results when the needle tip sampling region displayed hypoechogenicity and avascularity in US and the hard pattern in UE. PMID- 23990250 TI - Drug desensitization in the management of hypersensitivity reactions to monoclonal antibodies and chemotherapy. AB - Hypersensitivity reactions to monoclonal antibodies and chemotherapy, which may vary in severity from mild to life-threatening, can lead to their discontinuation and replacement by alternative agents that are often less effective, more toxic, and/or more expensive. Drug desensitization has emerged as the best treatment modality capable of allowing re-introduction of the hypersensitivity reaction inducing medication in highly sensitized patients in need of first line therapies. In recent years, the availability of new anti-neoplastic drugs and therapeutic monoclonal antibodies has increased, as has the potential for hypersensitivity reactions. Development of desensitization protocols for these new medications requires a careful assessment of the potential risks and benefits. The purposes of this review are to provide an overview of the presentation of hypersensitivity reactions amenable to desensitization and to increase awareness of the indications for and outcomes of desensitization protocols. Rapid drug desensitization has proven to be a safe and effective way of administering first line therapy to patients with hypersensitivity reactions, providing an extremely powerful treatment modality for patients for whom alternative drugs are deemed unacceptable. Rapid drug desensitization protocols should be administered only by highly trained allergists and nurses who have experience in determining which reactions are amenable to desensitization, and can identify high risk patients and provide them with appropriate care. Efforts should be made to increase awareness of the remarkable safety and efficacy of rapid drug desensitization among non-allergists, especially in the fields of oncology and rheumatology, so as to favor its universal application. Development of desensitization units to provide state-of-the-art care is possible only through coordinated teamwork. PMID- 23990248 TI - Muscle-bone interactions: basic and clinical aspects. AB - Muscle and bone are anatomically and functionally closely connected. The traditional concept that skeletal muscles serve to load bone and transform skeletal segments into a system of levers has been further refined into the mechanostat theory, according to which striated muscle is essential for bone development and maintenance, modelling and remodelling. Besides biomechanical function, skeletal muscle and bone are endocrine organs able to secrete factors capable of modulating biological function within their microenvironment, in nearby tissues or in distant organs. The endocrine properties of muscle and bone may serve to sense and transduce biomechanical signals such as loading, unloading or exercise, or systemic hormonal stimuli into biochemical signals. Nonetheless, given the close anatomical relationship between skeletal muscle and bone, paracrine interactions particularly at the periosteal interface can be hypothesized. These mechanisms can assume particular importance during bone and muscle healing after musculoskeletal injury. Basic studies in vitro and in rodents have helped to dissect the multiple influences of skeletal muscle on bone and/or expression of inside-organ metabolism and have served to explain clinical observations linking muscle-to-bone quality. Recent evidences pinpoint that also bone tissue is able to modulate directly or indirectly skeletal muscle metabolism, thus empowering the crosstalk hypothesis to be further tested in humans in vivo. PMID- 23990251 TI - The process leading to help seeking following childhood trauma. AB - In this article we explore the process leading to help seeking following childhood trauma among women who were currently in treatment. We interviewed 13 participants from six treatment groups for clients exposed to human-inflicted traumas. Transcripts were analyzed using a hermeneutical-phenomenological approach. Help seeking was initiated after a prolonged period of time (13 to 58 years after first trauma exposure), during which participants relied heavily on a strategy of managing on their own. Self-management contributed to delays in help seeking, but was also an important resource. High levels of distress were reported prior to help seeking, often without help seeking being considered as an option. The participants sought help when encountering situational demands exceeding available resources, resulting in experiences of exhaustion and loss of control. We present a model of the help-seeking process, underlining the importance of respecting and exploring the individual process of seeking help when offering trauma-specific treatment. PMID- 23990252 TI - Fractionation of heavy metals and assessment of contamination of the sediments of Lake Titicaca. AB - Chemical weathering is one of the major geochemical processes that control the mobilization of heavy metals. The present study provides the first report on heavy metal fractionation in sediments (8-156 m) of Lake Titicaca (3,820 m a.s.l.), which is shared by the Republic of Peru and the Plurinational State of Bolivia. Both contents of total Cu, Fe, Ni, Co, Mn, Cd, Pb, and Zn and also the fractionation of these heavy metals associated with four different fractions have been determined following the BCR scheme. The principal component analysis suggests that Co, Ni, and Cd can be attributed to natural sources related to the mineralized geological formations. Moreover, the sources of Cu, Fe, and Mn are effluents and wastes generated from mining activities, while Pb and Zn also suggest that their common source is associated to mining activities. According to the Risk Assessment Code, there is a moderate to high risk related to Zn, Pb, Cd, Mn, Co, and Ni mobilization and/or remobilization from the bottom sediment to the water column. Furthermore, the Geoaccumulation Index and the Enrichment Factor reveal that Zn, Pb, and Cd are enriched in the sediments. The results suggest that the effluents from various traditional mining waste sites in both countries are the main source of heavy metal contamination in the sediments of Lake Titicaca. PMID- 23990253 TI - Plant growth promotion by inoculation with selected bacterial strains versus mineral soil supplements. AB - In the process of remediation of mine sites, the establishment of a vegetation cover is one of the most important tasks. This study tests two different approaches to manipulate soil properties in order to facilitate plant growth. Mine waste from Ingurtosu, Sardinia, Italy rich in silt, clay, and heavy metals like Cd, Cu, and Zn was used in a series of greenhouse experiments. Bacteria with putative beneficial properties for plant growth were isolated from this substrate, propagated and consortia of ten strains were used to inoculate the substrate. Alternatively, sand and volcanic clay were added. On these treated and untreated soils, seeds of Helianthus annuus, of the native Euphorbia pithyusa, and of the grasses Agrostis capillaris, Deschampsia flexuosa and Festuca rubra were germinated, and the growth of the seedlings was monitored. The added bacteria established well under all experimental conditions and reduced the extractability of most metals. In association with H. annuus, E. pithyusa and D. flexuosa bacteria improved microbial activity and functional diversity of the original soil. Their effect on plant growth, however, was ambiguous and usually negative. The addition of sand and volcanic clay, on the other hand, had a positive effect on all plant species except E. pithyusa. Especially the grasses experienced a significant benefit. The effects of a double treatment with both bacteria and sand and volcanic clay were rather negative. It is concluded that the addition of mechanical support has great potential to boost revegetation of mining sites though it is comparatively expensive. The possibilities offered by the inoculation of bacteria, on the other hand, appear rather limited. PMID- 23990254 TI - Open-pit coal-mining effects on rice paddy soil composition and metal bioavailability to Oryza sativa L. plants in Cam Pha, northeastern Vietnam. AB - This study quantified Cd, Pb, and Cu content, and the soil-plant transfer factors of these elements in rice paddies within Cam Pha, Quang Ninh province, northeastern Vietnam. The rice paddies are located at a distance of 2 km from the large Coc Sau open-pit coal mine. Electron microprobe analysis combined with backscattered electron imaging and energy-dispersive spectroscopy revealed a relatively high proportion of carbon particles rimmed by an iron sulfide mineral (probably pyrite) in the quartz-clay matrix of rice paddy soils at 20-30 cm depth. Bulk chemical analysis of these soils revealed the presence of Cd, Cu, and Pb at concentrations of 0.146+/-0.004, 23.3+/-0.1, and 23.5+/-0.1 mg/kg which exceeded calculated background concentrations of 0.006+/-0.004, 1.9+/-0.5, and 2.4+/-1.5 mg/kg respectively at one of the sites. Metals and metalloids in Cam Pha rice paddy soils, including As, Cd, Cr, Cu, Hg, Mn, Ni, Pb, and Zn, were found in concentrations ranging from 0.2+/-0.1 to 140+/-3 mg/kg, which were in close agreement with toxic metal contents in mine tailings and Coc Sau coal samples, suggesting mining operations as a major cause of paddy soil contamination. Native and model Oryza sativa L. rice plants were grown in the laboratory in a growth medium to which up to 1.5 mg/kg of paddy soil from Cam Pha was added to investigate the effects on plant growth. A decrease in growth by up to 60% with respect to a control sample was found for model plants, whereas a decrease of only 10% was observed for native (Nep cai hoa vang variety) rice plants. This result suggests an adaptation of native Cam Pha rice plants to toxic metals in the agricultural lands. The Cd, Cu, and Pb contents of the native rice plants from Cam Pha paddies exceeded permitted levels in foods. Cadmium and Pb were highest in the rice plant roots with concentrations of 0.84+/-0.02 and 7.7+/ 0.3 mg/kg, suggesting an intake of these metals into the rice plant as shown, for example, by Cd and Pb concentrations of 0.09+/-0.01 and 0.10+/-0.04 mg/kg respectively in the rice grain endosperm. The adaptation of native rice plants, combined with bioaccumulation ratios of 1+/-0.6 to 1.4+/-0.7 calculated for Cd transfer to the rice grain endosperm, and maximum Cd transfer factors of 4.3+/ 2.1 to the plant roots, strongly suggest a continuous input of some toxic metals from coal-mining operations to agricultural lands in the region of Cam Pha. In addition, our results imply a sustained absorption of metals by native rice plant varieties, which may lead to metal accumulation (e.g., Cd) in human organs and in turn to severe disease. PMID- 23990255 TI - Mercury in the Mediterranean. Part 2: processes and mass balance. AB - Mass balance of contaminants can provide useful information on the processes that influence their concentrations in various environmental compartments. The most important sources, sinks and the equilibrium or non-equilibrium state of the contaminant in individual environmental compartments can also be identified. Using the latest mercury speciation data, the results of numerical models and the results of recent studies on mercury transport and transformation processes in the marine environment, we have re-evaluated the total mercury (HgT) mass balance in the Mediterranean Sea. New calculations have been performed employing three distinct marine layers: the surface layer, the thermocline and the deep sea. New transport mechanisms, deep water formation and density-driven sinking and upwelling, were included in the mass balance calculations. The most recent data have even enabled the calculation of an approximate methylmercury (MeHg) mass balance. HgT is well balanced in the entire Mediterranean, and the discrepancies between inputs and outputs in individual layers do not exceed 20 %. The MeHg balance shows larger discrepancies between gains and losses due to measurement uncertainties and gaps in our knowledge of Hg species transformation processes. Nonetheless, the main sources and sinks of HgT (deposition and evasion) and MeHg (fluxes from sediment, outflow through the Gibraltar Strait) are in accordance with previous studies on mercury in the Mediterranean Basin. Mercury in the Mediterranean fish harvest is the second largest MeHg sink; about 300 kg of this toxic substance is consumed annually with sea food. PMID- 23990256 TI - Occurrence and potential risk of triclosan in freshwaters of Sao Paulo, Brazil- the need for regulatory actions. AB - Triclosan (TCS) is a broad-spectrum bactericide, highly toxic to algae, which is released into the environment via wastewater effluents. Predicted no-effect concentrations (PNECs) for aquatic biota have been proposed in the literature, varying from 1.4 to 1,550 ng/L, reflecting contradicting protection goals. In this work, six rivers in the state of Sao Paulo were monitored for TCS and caffeine, a tracer for untreated sewage disposal, over a period of more than 1 year. From 71 samples analyzed, 32 contained TCS at concentrations above the limit of quantification, ranging from 2.2 to 66 ng/L, corresponding to a frequency of exceedance of the lowest PNEC of 86 % (six out of seven sites). No correlation between TCS and caffeine was observed, and one of the reasons for that could be the different use patterns in the local populations. Given the high values found in the investigated rivers, TCS seems to be a strong candidate in the priority list of compounds that should be regulated in Brazil to preserve the aquatic environment. PMID- 23990257 TI - Deposition and regional distribution of HCHs and p,p'-DDX in the western and southern Tibetan Plateau: records from a lake sediment core and the surface soils. AB - Tibetan Plateau is the world's highest plateau, which provides a unique location for the investigation of global fractionation of organochlorine pesticides (OCPs). In this study, deposition and regional distribution of HCHs and p,p'-DDX in the western and southern Tibetan Plateau were investigated by the records from a sediment core of Lake Zige Tangco and 24 surface soils. Concentration of SigmaHCHs in the surface soils of the western Tibetan Plateau was much higher than that of the southern part. Maximum fluxes of alpha-, beta-, and delta-HCH in the sediment core were 9.0, 222, and 21 pg cm(-2) year(-1), respectively, which appeared in the mid-1960s. Significant correlations were observed between concentrations of alpha- and beta-HCH in both the surface soils and the sediment core. Concentrations of both alpha- and beta-HCH increased with the inverse of the average annual temperature of these sites. gamma-HCH became the dominant isomer of HCHs after the late 1970s, and reached the maximum flux of 160 pg cm( 2) year(-1) in the early 1990s. There were no significant correlations between concentrations of gamma-HCH and the other isomers in both the surface soils and the sediment core. The results suggested that there was input of Lindane at scattered sites in this area. In contrast to SigmaHCHs, concentration of Sigmap,p'-DDX in the surface soils of the southern part was much higher than that of the western part. Maximum flux of Sigmap,p'-DDX was 44 pg cm(-2) year(-1), which appeared in the mid-1960s. Local emission of p,p'-DDT was found at scattered sites. This study provides novel data and knowledge for the OCPs in the western and southern Tibetan Plateau, which will help understand the global fractionation of OCPs in remote alpine regions. PMID- 23990258 TI - Challenges with tracing the fate and speciation of mine-derived metals in turbid river systems: implications for bioavailability. AB - The fast-flowing and highly turbid Lagaip River (0.5-10 g/L suspended solids) in the central highlands of Papua New Guinea receives mine-derived metal inputs in both dissolved and particulate forms. Nearest the mine, metal concentrations in suspended solids were 360, 9, 90, 740 and 1,300 mg/kg for As, Cd, Cu, Pb and Zn, while dissolved concentrations were 2.7, 0.6, 3.1, 0.1 and 25 MUg/L, respectively. This creates a significant metal exposure source for organisms nearer the mine. However, because the Lagaip River is diluted by a large number of tributaries, the extent to which mine-derived metals may affect biota in the lower catchments is uncertain. To improve our understanding of the forms of potentially bioavailable metals entering the lower river system, we studied the partitioning and speciation of metals within the Lagaip River system. Dissolved and particulate metal concentrations decreased rapidly downstream of the mine due to dilution from tributaries. As a portion of the particulate metal concentrations, the more labile dilute acid-extractable forms typically comprised 10-30% for As and Pb, 50-75% for Cu and Zn, and 50-100% for Cd. Only dissolved Cd, Cu and Zn remained elevated relative to the non-mine-impacted tributaries (<0.03, 0.5 and 0.3 MUg/L), but the concentrations did not appreciably change with increasing dilution downriver. This indicated that release of Cd, Cu and Zn was likely occurring from the more labile metal phases of the mine-derived particulates. Chelex-labile metal analyses and speciation modelling indicated that dissolved copper and lead were largely non-labile and likely complexed by naturally occurring organic ligands, while dissolved cadmium and zinc were predominantly present in labile forms. The study confirmed that mine-derived particulates may represent a significant source of dissolved metals in the lower river system; however, comparison with water quality guidelines indicates the low concentrations would not adversely affect aquatic life. PMID- 23990261 TI - Hyperparathyroidism. PMID- 23990259 TI - Mechanisms of chromium and arsenite adsorption by amino-functionalized SBA-15. AB - The adsorption of Cr(VI) and As(III) by amino-functionalized SBA-15 (NH2-SBA-15) from single and binary systems were investigated in this work. The effects of pH and temperature on the adsorption of NH2-SBA-15 were studied. Adsorption kinetics, isotherm model, and thermodynamics were studied to analyze the experimental data. pH 2 was the optimum condition for the adsorption of Cr(VI) and pH 4 for As(III) adsorption. Increasing temperature had a positive effect on the removal of both Cr(VI) and As(III). The Freundlich isotherm model can depict the adsorption process best. The pseudo-second-order kinetic model fitted well with the kinetic data of Cr(VI) and As(III) in the single-component system. In the binary system, the adsorption of As(III) by NH2-SBA-15 was slightly enhanced with the presence of Cr(VI); however, As(III) had no obvious effect on the removal of Cr(VI). Regeneration experiments indicated that 0.1 mol/L NaHCO3 was an efficient desorbent for the recovery of Cr(VI) and As(III) from NH2-SBA-15; the desorption rates for Cr(VI) and As(III) were 91.6 and 33.59 %, respectively. After five recycling cycles, the removal rates were 88 and 7 % for Cr(VI) and As(III) adsorption by NH2-SBA-15, respectively. PMID- 23990260 TI - Clinical aspects of primary hyperparathyroidism: clinical manifestations, diagnosis, and therapy. AB - Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia. An autonomous overproduction of parathyroid hormone leading to hypercalcemia, which is not downregulated by the calcium-sensing receptor, is the pathophysiological basis of the disease. The classical manifestations of PHPT include a generalized bone disease, kidney stones, and nephrocalcinosis, gastrointestinal, cardiovascular, neuromuscular and neuropsychiatric symptoms. Recently, the clinical presentation of PHPT, however, has changed in Western countries, it occurs oligo-asymptomatic in up to 80 %. Clinical examination, laboratory, and imaging techniques for the characterization of the disease and the localization include the diagnostic procedure. If possible, parathyroidectomy is the treatment of choice for clinically overt PHPT, for asymptomatic PHPT guidelines were developed in order to decide in individual cases between surgical and conservative approach; this consists of monitoring, adequate calcium and vitamin D intake, as well as hydration. Medical therapy includes bisphosphonates and calcimimetics. PMID- 23990262 TI - Substrate interactions in dehalogenation of 1,2-dichloroethane, 1,2 dichloropropane, and 1,1,2-trichloroethane mixtures by Dehalogenimonas spp. AB - When chlorinated alkanes are present as soil or groundwater pollutants, they often occur in mixtures. This study evaluated substrate interactions during the anaerobic reductive dehalogenation of chlorinated alkanes by the type strains of two Dehalogenimonas species, D. lykanthroporepellens and D. alkenigignens. Four contaminant mixtures comprised of combinations of the chlorinated solvents 1,2 dichloroethane (1,2-DCA), 1,2-dichloropropane (1,2-DCP), and 1,1,2 trichloroethane (1,1,2-TCA) were assessed for each species. Chlorinated solvent depletion and daughter product formation determined as a function of time following inoculation into anaerobic media revealed preferential dechlorination of 1,1,2-TCA over both 1,2-DCA and 1,2-DCP for both species. 1,2-DCA in particular was not dechlorinated until 1,1,2-TCA reached low concentrations. In contrast, both species concurrently dechlorinated 1,2-DCA and 1,2-DCP over a comparably large concentration range. This is the first report of substrate interactions during chlorinated alkane dehalogenation by pure cultures, and the results provide insights into the chlorinated alkane transformation processes that may be expected for contaminant mixtures in environments where Dehalogenimonas spp. are present. PMID- 23990263 TI - Update on lipoprotein(a) as a cardiovascular risk factor and mediator. AB - Recent genetic studies have put the spotlight back onto lipoprotein(a) [Lp(a)] as a causal risk factor for coronary heart disease. However, there remain significant gaps in our knowledge with respect to how the Lp(a) particle is assembled, the route of its catabolism, and the mechanism(s) of Lp(a) pathogenicity. It has long been speculated that the effects of Lp(a) in the vasculature can be attributed to both its low-density lipoprotein moiety and the unique apolipoprotein(a) component, which is strikingly similar to the kringle containing fibrinolytic zymogen plasminogen. However, the ability of Lp(a) to modulate either purely thrombotic or purely atherothrombotic processes in vivo remains unclear. The presence of oxidized phospholipid on Lp(a) may underlie many of the proatherosclerotic effects of Lp(a) that have been identified both in cell models and in animal models, and provides a possible avenue for identifying therapeutics aimed at mitigating the effects of Lp(a) in the vasculature. However, the beneficial effects of targeted Lp(a) therapeutics, designed to either lower Lp(a) concentrations or interfere with its effects, on cardiovascular outcomes remains to be determined. PMID- 23990264 TI - Metabolomics in the diagnosis of acute myocardial ischemia. AB - Despite recent advances in the diagnosis of myocardial ischemia, its biochemical identification in patients with acute chest pain is still a challenge, and alternative approaches for further improvement are needed. Metabolic alterations are the first consequences of acute myocardial ischemia. Metabolomics coupled with potent multivariate analyses allows for a simultaneous and relative quantification of thousands of different metabolites within a given sample. Thus, this discipline might exert a great impact on medical practice in cardiovascular medicine by providing a wealth of relevant biochemical data. Metabolomics is a promising tool to improve current, single biomarker-based approaches by identifying metabolic biosignatures that embody global biochemical changes in disease. This is especially relevant for conditions requiring early treatment like myocardial ischemia. This review discusses the potential application of metabolomics in the diagnosis of myocardial ischemia. PMID- 23990265 TI - Spinal-related malpractice suits against radiologists in the USA-rates, anatomic location, percent of adverse judgments, and average payments. AB - To present overall rates, anatomic location, percent of adverse settlements to the radiologists, and average payments to the plaintiff in spinal-related malpractice suits in a survey of 8,265 radiologists. The malpractice histories of 8,265 radiologists from 36 states were evaluated from credentialing data required of all radiologists participating in the network of One Call Medical Incorporated, a broker for CT/MR in workmen's compensation cases. Two hundred twenty-six of the 8,265 radiologists (31.5 %) had at least one suit. Of the 4,741 total claims, 627 (13.2 %) were related to the bones and adjacent soft tissue. Two hundred and ten (32.9 %) involved the spine. Of these, 70.2 % (134/191) were settled in favor of the plaintiff. One hundred and sixteen (68.2 %) involved the cervical spine with an average settlement of $483,156. Lumbar cases accounted for 28 (16.5 %) of spinal suits, with an average settlement of $119,272. Thoracic cases (26) accounted for only 15.3 % of spinal cases and had an average settlement of $481,608. An allegation of spinal malpractice resulting in a settlement or judgment against the radiologist occurred at a rate of 29.5 cases per 1,000 radiologists' person years. Of the three spinal regions, the cervical spine was the most frequent anatomic site of a malpractice suit and among all those cases settled incurred the highest payment in judgment to the plaintiff. PMID- 23990266 TI - Antipsychotics for acute and chronic pain in adults. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 4, 2008. The role of antipsychotics as adjuvant analgesics is a subject of longstanding controversy. Neuroleptanalgesia (that is a state of quiescence, altered awareness, and analgesia produced by a combination of taking an opioid analgesic and an antipsychotic), an established term for the management of acute pain, was shown to negatively influence disease course and total mortality in unstable angina patients. Nevertheless, antipsychotics are used to treat chronic pain (for example chronic headache, fibromyalgia and diabetic neuropathia). With atypical antipsychotics, a new class of antipsychotics, both fewer extrapyramidal side effects and additional benefits may be available. OBJECTIVES: To assess the analgesic efficacy and adverse effects of antipsychotics in acute or chronic pain in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, and EMBASE in October 2011 and January 2013. SELECTION CRITERIA: Randomised controlled trials (RCTs) of adults prescribed any dose of an oral antipsychotic for acute or chronic pain, where subjective pain assessment was described as either the primary or a secondary outcome, were included in this review. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent review authors, and results were compared for differences. Discrepancies were resolved by discussion. All trials were quality scored according to the methods set out in section six of the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: A total of 770 participants were involved in the 11 included studies. Data from five included randomised double-blind studies showed beneficial effects of antipsychotics in the treatment of acute and chronic pain. Quantitative analysis of these studies showed a significant reduction of mean pain intensity after administration of the antipsychotic compared to placebo or another active compound, weighted mean difference (WMD) -1.78 (95% CI -2.71 to -0.85) for the continuous data; and relative risk (RR) 0.43 (95% CI 0.25 to 0.73), number needed to treat to benefit (NNT) 2.6 for the dichotomous data. Nevertheless, the test for heterogeneity was significant for both the continuous data (P = 0.0007) and the dichotomous data (P = 0.04). Obviously this makes the calculated NNT less reliable and caution is warranted when interpreting these results.The most frequently reported adverse effects were extrapyramidal (that is involuntary movements, parkinsonism and akathisia) and sedating effects. AUTHORS' CONCLUSIONS: The recent search found five new studies which were all excluded, so the review remains the same as previously.Antipsychotics might be used as an add-on therapy in the treatment of painful conditions. Nevertheless, extrapyramidal and sedating side effects have to be considered before using antipsychotics for treating painful conditions.Results for antipsychotics in the treatment of different painful conditions are mixed and most sample sizes in the reviewed RCTs are small. Further studies on atypical antipsychotics in larger double-blind placebo controlled studies that include standardised pain assessment and documentation are warranted. PMID- 23990267 TI - Moving toward a better understanding of radioiodine action. PMID- 23990268 TI - A comprehensive overview of Infinium HumanMethylation450 data processing. AB - Infinium HumanMethylation450 beadarray is a popular technology to explore DNA methylomes in health and disease, and there is a current explosion in the use of this technique. Despite experience acquired from gene expression microarrays, analyzing Infinium Methylation arrays appeared more complex than initially thought and several difficulties have been encountered, as those arrays display specific features that need to be taken into consideration during data processing. Here, we review several issues that have been highlighted by the scientific community, and we present an overview of the general data processing scheme and an evaluation of the different normalization methods available to date to guide the 450K users in their analysis and data interpretation. PMID- 23990269 TI - An efficient approach to large-scale genotype-phenotype association analyses. AB - Modern molecular biotechnology generates a great deal of intermediate information, such as transcriptional and metabolic products in bridging DNA and complex traits. In genome-wide linkage analysis and genome-wide association study, regression analysis for large-scale correlated phenotypes is applied to map genes for those by-products that are regarded as quantitative traits. For a single trait, least absolute shrinkage and selection operator with coordinate descent step can be employed to efficiently shrink sparse non-zero genetic effects of quantitative trait loci (QTLs). However, regression analyses in a trait-by-trait basis do not take account of the correlations among the analyzed traits. In this study, conditional phenotype of each trait is defined, given other traits. Large-scale genotype-phenotype association analyses are therefore transformed to separate genotype-conditional phenotype ones. Meanwhile, the correlation architecture between each trait and other traits can also be provided by shrinkage estimation for each conditional phenotype. Simulation demonstrates that the proposed conditional mapping method is generally identical to joint mapping method based on multivariate analysis in terms of statistical detection power and parameter estimation. Application of the method is provided to locate eQTL in yeast. PMID- 23990270 TI - Simulating physiological interactions in a hybrid system of mathematical models. AB - Mathematical models can be deployed to simulate physiological processes of the human organism. Exploiting these simulations, reactions of a patient to changes in the therapy regime can be predicted. Based on these predictions, medical decision support systems (MDSS) can help in optimizing medical therapy. An MDSS designed to support mechanical ventilation in critically ill patients should not only consider respiratory mechanics but should also consider other systems of the human organism such as gas exchange or blood circulation. A specially designed framework allows combining three model families (respiratory mechanics, cardiovascular dynamics and gas exchange) to predict the outcome of a therapy setting. Elements of the three model families are dynamically combined to form a complex model system with interacting submodels. Tests revealed that complex model combinations are not computationally feasible. In most patients, cardiovascular physiology could be simulated by simplified models decreasing computational costs. Thus, a simplified cardiovascular model that is able to reproduce basic physiological behavior is introduced. This model purely consists of difference equations and does not require special algorithms to be solved numerically. The model is based on a beat-to-beat model which has been extended to react to intrathoracic pressure levels that are present during mechanical ventilation. The introduced reaction to intrathoracic pressure levels as found during mechanical ventilation has been tuned to mimic the behavior of a complex 19-compartment model. Tests revealed that the model is able to represent general system behavior comparable to the 19-compartment model closely. Blood pressures were calculated with a maximum deviation of 1.8 % in systolic pressure and 3.5 % in diastolic pressure, leading to a simulation error of 0.3 % in cardiac output. The gas exchange submodel being reactive to changes in cardiac output showed a resulting deviation of less than 0.1 %. Therefore, the proposed model is usable in combinations where cardiovascular simulation does not have to be detailed. Computing costs have been decreased dramatically by a factor 186 compared to a model combination employing the 19-compartment model. PMID- 23990271 TI - Organochlorine pesticides in the dust fall around Lake Chaohu, the fifth largest lake in China. AB - The residual levels of organochlorine pesticides (OCPs) in the dust fall around Lake Chaohu were measured using gas chromatography mass spectrometry from April 2010 to March 2011. The fluxes, components, temporal-spatial variations, and sources of OCPs were also analyzed. Twenty-one types of OCPs were detected in the dust fall samples around Lake Chaohu, with a total concentration of 51.54 +/- 36.31 ng/g and a total flux of 10.01 +/- 13.69 ng/(m(2) day). Aldrin (35.3 %), endosulfan (39.1 %), dichlorodiphenyltrichloroethanes (DDTs) (49.8 %), and isodrin (37.1 %) were the major OCPs in the spring, summer, autumn, and winter, respectively. Both the residual level and the flux were higher in the spring than in other seasons and higher at the outer lake sampling sites than inner lake sampling site. The potential source of the hexachlorcyclohexanes in the dust fall may be recent lindane usage. The DDTs mainly came from historical dicofol usage, and a significant input of DDT was found during April and June. The presence of endosulfan may be due to the present use of technical endosulfan. The aldrin in the dust might be due to its occasional usage, and isodrin may be a result of long-distance transport from other countries. PMID- 23990272 TI - Postoperative flat anterior chamber: incidence, risk factors, and effect on the long-term success of trabeculectomy. AB - PURPOSE: To investigate the long-term effects of postoperative flat anterior chamber (FAC) development on outcomes following trabeculectomy with mitomycin C. METHODS: This was a retrospective cohort study. Data on 383 consecutive patients (383 eyes) who underwent trabeculectomy at our institution between 1999 and 2009 were followed up. Patients who developed FAC after trabeculectomy and patients with maintained anterior chamber were evaluated. The primary outcome variable was the success of the initial trabeculectomy, which was defined at 3 different levels by the achievement of the following intraocular pressure (IOP)-related criteria without secondary IOP-lowering surgery: (a) IOP <= 12 mmHg and <=30 % reduction in IOP from the preoperative level; (b) IOP <= 16 mmHg and <=20 % reduction in IOP; and (c) IOP <= 21 mmHg. The hazard ratios (HRs) for the failure of trabeculectomy caused by FAC within 5 years of surgery were examined in conjunction with the Cox proportional hazards regression model. RESULTS: FAC was observed in 90 of the 383 eyes examined (23.4 %). Postoperative mild FAC was associated with the long-term success of trabeculectomy when evaluated according to our strictest success criterion, Criterion-A [HR = 0.72 (95 % CI 0.53-0.98); P = 0.04]. In contrast, severe FAC was inversely associated with the long-term success of the surgery when evaluated according to our most lenient criterion, Criterion-C [HR = 1.93 (95 % CI 1.16-3.22); P = 0.01]. CONCLUSION: Mild postoperative FAC after trabeculectomy is associated with a favorable long-term outcome, whereas severe postoperative FAC leads to an unfavorable prognosis. PMID- 23990273 TI - Coffee consumption and cardiovascular health: getting to the heart of the matter. AB - As coffee-consumption is a widespread tradition, its possible impact on health has been of considerable interest. This review examines the effects of coffee on cardiovascular risk, outlines underlying biological mechanisms, and discusses implications for public health. In the past, coffee was often viewed as a cardiovascular risk-factor. However, in meta-analyses of recent well-controlled prospective epidemiologic studies, coffee-consumption was not associated with risk of coronary heart disease and weakly associated with a lower risk of stroke and heart failure. Also, available evidence largely suggests that coffee consumption is not associated with a higher risk of fatal cardiovascular events. In randomized trials coffee-consumption resulted in small increases in blood pressure. Unfiltered coffee increased circulating LDL cholesterol and triglycerides concentrations, but filtered coffee had no substantial effects on blood lipids. In summary, for most healthy people, moderate coffee consumption is unlikely to adversely affect cardiovascular health. Future work should prioritize understanding the effects of coffee in at-risk populations. PMID- 23990274 TI - Renal artery stenosis: medical versus interventional therapy. AB - Reports from recent trials indicate little additional benefit from stent supported revascularization in patients with atherosclerotic renal artery stenosis. These data have been questioned, particularly on the basis of including subjects with modest occlusive disease and reports of clinical benefits to patients with episodic congestive heart failure. Nonetheless, these data have moved the pendulum away from renal revascularization as a primary maneuver to one reserved for refractory hypertension and/or progressive loss of renal function and circulatory congestion. Recent data emphasize the limits of the kidney adaptation to reduced blood flow, the eventual development of widespread renal hypoxia with activation of inflammatory and fibrogenic pathways. Experimental data now support developing adjunctive measures to support angiogenesis and anti inflammatory renal repair mechanisms, such as those observed with cell-based therapy with mesenchymal stem/stromal cells. PMID- 23990276 TI - Department of Dermatology was blessed with a wonderful psoriasis specialist. Foreword. PMID- 23990275 TI - Disability transitions in the oldest old in the general population. The Leiden 85 plus study. AB - Transitions between disability states in older people occur frequently. This study investigated predictors of disability transitions in the oldest old and was performed in the Leiden 85-plus study, a population-based prospective cohort study among 597 participants aged 85 years. At baseline (age 85 years), data on sociodemographic characteristics and chronic diseases were obtained. Disabilities in basic activities of daily living (BADL) and instrumental activities of daily living (IADL) were measured annually for 5 years with the Groningen Activities Restriction Scale (GARS). Mortality data were obtained. A statistical multi-state model was used to assess the risks of transitions between no disabilities, IADL disability, BADL disability, and death. At baseline, 299 participants (50.0 %) were disabled in IADL only, and 155 participants (26.0 %) were disabled in both BADL and IADL. During 5-year follow-up, 374 participants (62.6 %) made >1 transition between disability states, mostly deterioration in disability. Males had a lower risk of deterioration [hazard ratio (HR), 0.75 (95 % CI, 0.58-0.96)] compared to females. No gender differences were observed for improvement [HR, 0.64 (95 % CI, 0.37-1.11)]. Participants with depressive symptoms were less likely to improve [HR, 0.50 (95 % CI, 0.28-0.87)]. Participants with depressive symptoms [HR, 1.46 (95 % CI, 1.12-1.91)], >1 chronic disease [HR, 1.60 (95 % CI, 1.27-2.01)], and with cognitive impairment [HR, 1.60 (95 % CI, 1.20-2.13)] had the highest risk of deteriorating. Disability is a dynamic process in the oldest old. Deterioration is more common than improvement. Older men are less likely to deteriorate than women. The presence of depressive symptoms, chronic disease, and cognitive impairment predicts deterioration. PMID- 23990277 TI - Treatment of psoriasis and psoriatic arthritis. AB - Skin and joint manifestations associated with psoriasis and psoriatic arthritis (PsA) can significantly impact a patient's quality of life. Successful treatment is imperative in order to improve signs and symptoms of the disease, and to alleviate physical or psychological distress. For patients with mild psoriasis with or without PsA, topical agents and targeted phototherapy are appropriate treatments for psoriasis. Systemic therapies, such as methotrexate and phototherapy are recommended options for patients with more severe psoriasis, but their long-term use is hindered by safety concerns. Advancements in understanding the pathogenesis of psoriasis, including the role of T cells and cytokines, have been crucial to the development of biological therapies. These target the immune system and are suitable options for patients with extensive disease. Biological therapies for the treatment of psoriasis include targeted therapies (alefacept) and anti-cytokine therapies (anti-tumour necrosis factor [TNF] therapies [adalimumab, etanercept, infliximab] and a monoclonal antibody against interleukin [IL]-12 and IL-23 [ustekinumab]). Patients with PsA should be treated appropriately in order to improve symptoms and inhibit structural joint damage. Non-steroidal anti-inflammatory drugs or local intra-articular injections of corticosteroids can be used successfully in patients with mild PsA; however, neither treatment prevents the development of structural joint damage. For patients with moderate to severely active PsA, disease-modifying antirheumatic drugs (such as methotrexate), TNF inhibitor treatments (adalimumab, etanercept, infliximab and golimumab) or their combination are considered first-line treatment. This review provides a brief overview of treatment options for psoriasis and PsA, with an emphasis on the efficacy and safety of anti-TNF therapies. PMID- 23990278 TI - Infliximab in psoriasis and psoriatic arthritis. AB - Psoriasis is a chronic inflammatory disorder of the skin and joints. Although rarely life threatening, psoriasis can significantly impair quality of life (QOL) and cause considerable physical and psychological distress. Between 6 and 42% of patients with psoriasis develop psoriatic arthritis, which is characterized by stiffness, pain, swelling and tenderness of the joints. Nail psoriasis is highly prevalent in both plaque-type psoriasis and psoriatic arthritis and is found in approximately 50% of patients with psoriasis and in 80% of patients with psoriatic arthritis. Infliximab, a chimeric human-murine monoclonal antibody directed against tumour necrosis factor alpha, is approved in the USA and EU for the treatment of plaque psoriasis and psoriatic arthritis at a recommended dosage of 5 mg/kg administered by intravenous infusion at 0,2 and 6 weeks, then every 8 weeks thereafter. The EXPRESS and EXPRESS II trials demonstrated that infliximab is efficacious as induction and maintenance therapy in the treatment of moderate to severe plaque psoriasis and also improved health-related QOL. Infliximab is also efficacious in the treatment of psoriatic arthritis, as shown in the IMPACT and IMPACT II studies. Infliximab is generally well tolerated, with a similar adverse event profile in both psoriasis and psoriatic arthritis. The use of infliximab in three case reports is presented. The patients are similar to those normally seen by clinicians, and include a male patient with plaque psoriasis and a history of severe psoriatic arthritis who was corticosteroid dependent and in whom other systemic treatments were not effective or were not able to be used. This patient showed a rapid response to infliximab with no skin lesions or arthritis after 7 weeks' treatment. Infliximab was also safe and effective in the treatment of a female patient with plaque and nail psoriasis and a history of psoriatic arthritis. Importantly, this case report supports the efficacy of infliximab in psoriatic nail disease in the context of severe skin and joint involvement. Case 3 describes a young male patient with moderate plaque-type psoriasis associated with severe nail involvement and early signs of psoriatic arthritis. Treatment with infliximab improved nail psoriasis and appears to be an effective biological treatment for nail psoriasis. Importantly, ultrasound was able to diagnose joint involvement, as seen from the proliferative synovitis in the distal interphalangeal joint and mild enthesitis, despite there being no clinical evidence of psoriatic arthritis. This case report highlights the importance of early screening. If such abnormalities are detected early on in the course of psoriasis, clinicians may be able to predict which patients are more likely to develop psoriatic arthritis, and therefore offer effective and long term treatment that may reduce the disability and impairment of daily activities that can be associated with psoriatic arthritis. PMID- 23990279 TI - Role of a GATA-type transcriptional repressor Sre1 in regulation of siderophore biosynthesis in the marine-derived Aureobasidium pullulans HN6.2. AB - The GATA-type transcriptional repressor structural gene SRE1 was isolated from both the genomic DNA and mRNA of the marine yeast Aureobasidium pullulans HN6.2 by inverse PCR and RACE. An open reading frame (ORF) of 1,002 bp encoding a 334 amino acid protein (a calculated isoelectric point: 8.6) with a calculated molecular weight of 35.1 kDa was characterized. The corresponding gene had one single intron of 51 bp, and in its promoter two putative 5'-HGATAR-3' sequences could be recognized. The deduced protein from the cloned gene contained two conserved zinc-finger domains [Cys-(X2)-Cys-(X17)-Cys-(X2)-Cys)], nine sequences of Ser(Thr)-Pro-X-X which was characteristics of the regulator, and one cysteine rich central domain which was located between the two zinc fingers. The SRE1 gene in A. pullulans HN6.2 was disrupted by integrating the hygromycin B phosphotransferase gene into the ORF of the SRE1 gene using homologous recombination. Two hundreds of the disruptants (Deltasre1) (one of them was named R6) obtained still synthesized both intracellular and extracellular siderophores in the presence of added Fe(3+) and the expression of the SidA gene encoding L ornithine N(5)-oxygenase in the disruptant R6 was also partially derepressed in the presence of added Fe(3+). The colonies of the disruptant R6 grown on the iron replete medium with 1.5 and 2.0 mM Fe(3+) and also with 1.5 mM Fe(2+) became brown. In contrast, A. pullulans HN6.2 could not grow in the iron-replete medium with 1.5 mM and 2.0 mM Fe(3+). The brown-colored colonies of the disruptant R6 also had high level of siderophore and iron. PMID- 23990280 TI - Lynch Syndrome in high risk Ashkenazi Jews in Israel. AB - Lynch Syndrome is caused by mutations in DNA mismatch repair genes. Diagnosis is not always trivial and may be costly. Information regarding incidence, genotype phenotype correlation, spectrum of mutations and genes involved in specific populations facilitate the diagnostic process and contribute to clinical work-up. To report gene distribution, mutations detected and co-occurrence of related syndromes in a cohort of Ashkenazi Jews in Israel. Patients were identified in dedicated high risk clinics in 3 medical centers in Israel. Diagnostic process followed a multi-step scheme. It included testing for founder mutations, tumor testing, gene sequencing and MLPA. Lynch Syndrome was defined either by positive mutation testing, or by clinical criteria and positive tumor analysis. We report a cohort of 75 Ashkenazi families suspected of Lynch Syndrome. Mutations were identified in 51/75 (68%) families: 38 in MSH2, 9 in MSH6, and 4 in MLH1. 37/51 (73%) of these families carried one of the 3 'Ashkenazi' founder mutations in MSH2 or MSH6. Each of the other 14 families carried a private mutation. 3 (6%) were large deletions. Only 20/51 (39%) families were Amsterdam Criteria positive; 42 (82%) were positive for the Bethesda guidelines and 9 (18%) did not fulfill any Lynch Syndrome criteria. We report C-MMRD and co-occurrence of BRCA and Lynch Syndrome in our cohort. Mutation spectra and gene distribution among Ashkenazi Jews are unique. Three founder Lynch Syndrome mutations are found in 73% families with known mutations. Among the three, MSH2 and MSH6 are the most common. These features affect the phenotype, the diagnostic process, risk estimation, and genetic counseling. PMID- 23990281 TI - Illness perceptions, risk perception and worry in SDH mutation carriers. AB - Succinate dehydrogenase (SDH) mutation carriers are predisposed for developing paragangliomas. This study aimed to explore illness perceptions, risk perception and disease-related worry in these individuals. All consecutive SDHB and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center (LUMC), a tertiary referral center, were eligible for inclusion. Illness perceptions were assessed using the validated Illness Perception Questionnaire-Revised and compared to reference populations. Risk perception and worry were measured by two items each and associations with illness perceptions explored. Twenty SDHB and 118 SDHD mutation carriers responded. Compared with various reference groups, SDH mutation carriers perceived less controllability of their condition. SDHB mutation carriers considered their condition to be less chronic in nature (p = 0.005) and perceived more personal (p = 0.018) and treatment control (p = 0.001) than SDHD mutation carriers. Mutation carriers with manifest disease reported more negative illness perceptions and a higher risk perception of developing subsequent tumors than asymptomatic mutation carriers. Illness perceptions, risk perception and disease related worry were strongly correlated. Risk perception and disease-related worry may be assessed through illness perceptions. The development of interventions targeting illness perceptions may provide tools for genetic counseling. PMID- 23990282 TI - Genes encoding the production of extracellular polysaccharide bioflocculant are clustered on a 30-kb DNA segment in Bacillus licheniformis. AB - Bioflocculants are special high-molecular weight polymers produced by microorganisms. Despite the fact that several types of bioflocculants from different species of bacteria have been reported, there is a large gap in our knowledge regarding the molecular machine responsible for the production of bioflocculants. To investigate genes involved in bioflocculant synthesis, a fosmid library was generated from Bacillus licheniformis genomic DNA and screened for the production of bioflocculant. Four positive clones with distinct flocculation were isolated by a two-pooling scheme. The clone with 662 U ml(-1) flocculating activity was sequenced. As a result, a 30-kb fragment with 26 hypothetical genes was identified in the bioflocculant-producing clone. Most of the predicted proteins encoded by the inserted genes showed significant homology with enzymes involved in the biosynthesis of polysaccharide. Based on these homologies, a biosynthesis pathway and two gene clusters involved in the production of the polysaccharide bioflocculant were proposed with the integration of functional descriptions of individual genes by metabolic databases, and a glucose-sensitive glycosidases was predicted. This research supplied significant data for potential application of bioflocculant-producing strains in wastewater refining and industrial downstream treatments. PMID- 23990283 TI - The efficacy and safety of switching to ziprasidone from olanzapine in patients with bipolar I disorder: an 8-week, multicenter, open-label study. AB - BACKGROUND: Switching antipsychotic medication in patients undergoing combination therapy for bipolar I disorder is a common clinical practice because of suboptimal drug efficacy or tolerability. Despite the frequency of switching, little is known about the most appropriate switching options. Ziprasidone may be a good alternative for patients with bipolar disorder experiencing a suboptimal response or intolerance to olanzapine in combination with a mood stabilizer because of its mood-stabilizing effect and minimal propensity for clinically significant body weight gain and metabolic disturbances. However, no study has evaluated the efficacy, safety, and tolerability of switching to ziprasidone from olanzapine in combination with a mood stabilizer for treatment of bipolar disorder. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of switching to ziprasidone in patients with bipolar I disorder experiencing a suboptimal response or intolerance to olanzapine in combination with lithium or valproate. METHODS: An 8-week, prospective, open-label study was conducted among inpatients and outpatients with bipolar I disorder who were taking olanzapine combined with lithium or valproate to treat recent manic or mixed episodes. In subjects experiencing a suboptimal response [>=16 points on the Young Mania Rating Scale (YMRS) at screening and baseline] or intolerance, olanzapine was switched to ziprasidone while maintaining the same dose of their current combined mood stabilizer during the 8-week trial. The primary efficacy measure was the mean change in the YMRS total score. Metabolic parameters were measured to evaluate the improvement in metabolic syndrome. RESULTS: A total of 56 patients were enrolled, and 46 (82.1 %) completed this study. Switching to ziprasidone was effective and well-tolerated. YMRS total scores were significantly reduced over 8 weeks (mean change, -10.4 +/- 10.2). There were significant improvements in metabolic parameters, with mean changes of -0.4 +/- 0.8 kg/m(2) in body mass index (BMI), -1.2 +/- 2.5 kg in body weight, -21.3 +/- 62.7 mg/dL in the fasting triglyceride level, and -13.2 +/- 26.6 mg/dL in the total cholesterol level. Greater improvements in BMI, body weight, and dyslipidemia were positively correlated with a higher baseline BMI and abnormal lipid profile. CONCLUSIONS: Ziprasidone appears to be a good switching option for patients with bipolar I disorder experiencing suboptimal response or intolerance with olanzapine in combination with lithium or valproate. In addition, switching to ziprasidone improves metabolic parameters, especially in patients experiencing weight gain or dyslipidemia with olanzapine treatment. PMID- 23990284 TI - Long-term effects of intraperitoneal injection of estradiol-17beta on the growth and physiology of juvenile stellate sturgeon Acipenser stellatus. AB - Juvenile stellate sturgeon Acipenser stellatus were intraperitoneally injected with estradiol-17beta (E2; 0 and 5 mg/kg fish) to investigate the possibility of sex reversal and also determine the changes in biochemical parameters. Five-month old fish (40.9 +/- 1.1 g) were injected every 3-week interval during a 190-day trial. At the termination of the experiment, final weight and other growth parameters including weight gain and specific growth rate, hepatosomatic and viscerosomatic indices were not affected by repetitive injection of E2. Hematological features of E2-treated fish showed significant reductions in number of red blood cells, hemoglobin concentration, hematocrit value and mean corpuscular hemoglobin (P < 0.05), but no significant changes were observed in number of white blood cells, mean corpuscular volume and mean corpuscular hemoglobin concentration (P > 0.05). Calcium, phosphorus, glucose, triacylglycerol, cholesterol, total protein and estradiol concentrations were significantly increased in fish injected with E2 (P < 0.001). Plasma progesterone and testosterone levels were noticeably lower in fish injected with 5 mg/kg E2 rather than the control fish (P < 0.001). Histological observations of gonads showed that all fish injected with 5 mg/kg E2 apparently feminized, while 66.6 % of the control group was female. These results revealed that the injection of E2 is an effective method for feminization of stellate sturgeon without having significant inhibitory effects on growth and survival. PMID- 23990285 TI - Postprandial molecular responses in the liver of the barramundi, Lates calcarifer. AB - The regulation of gene expression by nutrients is an important mechanism governing energy storage and growth in most animals, including fish. At present, very few genes that regulate intermediary metabolism have been identified in barramundi, nor is there any understanding of their nutritional regulation. In this study, a partial barramundi liver transcriptome was assembled from next generation sequencing data and published barramundi EST sequences. A large number of putative metabolism genes were identified in barramundi, and the changes in the expression of 24 key metabolic regulators of nutritional pathways were investigated in barramundi liver over a time series immediately after a meal of a nutritionally optimised diet for this species. Plasma glucose and free amino acid levels showed a mild postprandial elevation which peaked 2 h after feeding, and had returned to basal levels within 4 or 8 h, respectively. Significant activation or repression of metabolic nuclear receptor regulator genes were observed, in combination with activation of glycolytic and lipogenic pathways, repression of the final step of gluconeogenesis and activation of the Akt-mTOR pathway. Strong correlations were identified between a number of different metabolic genes, and the coordinated co-regulation of these genes may underlie the ability of this fish to utilise dietary nutrients. Overall, these data clearly demonstrate a number of unique postprandial responses in barramundi compared with other fish species and provide a critical step in defining the response to different dietary nutrient sources. PMID- 23990286 TI - Reliable real-time calculation of heart-rate complexity in critically ill patients using multiple noisy waveform sources. AB - Heart-rate complexity (HRC) has been proposed as a new vital sign for critical care medicine. The purpose of this research was to develop a reliable method for determining HRC continuously in real time in critically ill patients using multiple waveform channels that also compensates for noisy and unreliable data. Using simultaneously acquired electrocardiogram (Leads I, II, V) and arterial blood pressure waveforms sampled at 360 Hz from 250 patients (over 375 h of patient data), we evaluated a new data fusion framework for computing HRC in real time. The framework employs two algorithms as well as signal quality indices. HRC was calculated (via the method of sample entropy), and equivalence tests were then performed. Bland-Altman plots and box plots of differences between mean HRC values were also obtained. Finally, HRC differences were analyzed by paired t tests. The gold standard for obtaining true means was manual verification of R waves and subsequent entropy calculations. Equivalence tests between mean HRC values derived from manually verified sequences and those derived from automatically detected peaks showed that the "Fusion" values were the least statistically different from the gold standard. Furthermore, the fusion of waveform sources produced better error density distributions than those derived from individual waveforms. The data fusion framework was shown to provide in real time a reliable continuously streamed HRC value, derived from multiple waveforms in the presence of noise and artifacts. This approach will be validated and tested for assessment of HRC in critically ill patients. PMID- 23990287 TI - Evaluation of point-of-care analyzers' ability to reduce bias in conductivity based hematocrit measurement during cardiopulmonary bypass. AB - Most point-of-care testing analyzers use the conductivity method to measure hematocrit (hct). During open-heart surgery, blood-conductivity is influenced by shifts in electrolyte and colloid concentrations caused by infusion media used, and this may lead to considerable bias in the hct measurement. We evaluated to what extent different analyzers correcting for 0, 1, 2, or 3 factors, respectively, compensated for this electrolyte/colloid interference: (1) the conductivity method with no correction (IRMA), (2) with a [Na(+)]-correction (GEM Premier 3000), (3) with a [Na(+)]/[K(+)]-correction (i-STAT), and (4) with a [Na(+)]/[K(+)]-correction in combination with an algorithm that estimates the protein dilution [i-STAT in cardiopulmonary bypass (CPB)-mode]. Bias in hct was measured during three consecutive stages of a CPB procedure: (I) before CPB, (II) start of CPB and (III) after cardioplegia. In order of high to low electrolyte/colloid interference: the analyzer with no correction, [Na(+)] correction, [Na(+)/]/[K(+)]-correction, and [Na(+)/]/[K(+)]/estimated protein correction showed a change of bias from stage I to stage III of -3.9 +/- 0.5, 3.4 +/- 0.4, -2.1 +/- 0.5, -0.3 +/- 0.5%. We conclude that correcting for more parameters (Na(+), K(+), estimated protein) gives less bias, but residual bias remains even after [Na(+)/]/[K(+)]/estimated protein-correction. This suggests that a satisfactory algorithm should also correct for other colloidal factors than protein. PMID- 23990288 TI - Peripheral tissue oximetry: comparing three commercial near-infrared spectroscopy oximeters on the forearm. AB - Estimation of regional tissue oxygenation (rStO2) by near infrared spectroscopy enables non-invasive end-organ oxygen balance monitoring and could be a valuable tool in intensive care. However, the diverse absolute values and dynamics of different devices, and overall poor repeatability of measurements are a problem. The aim of the present study is to test the hypothesis that INVOS 5100C, FORE SIGHT and NONIN EQUANOX 7600 have similar properties concerning absolute values, repeatability, and sensitivity to changes in rStO2. To test repeatability the sensors were repositioned 20 times during hemodynamic steady state on the adult forearm. Afterwards six vascular occlusions by inflation of an upper arm cuff were done to achieve low oxygenation in the forearm. Absolute values were compared by repeated-measures ANOVA, repeatability was estimated by the within subject standard deviation, Sw, and response to changing oxygenation by the down slope of rStO2 during vascular occlusion in the respective arm. 10 healthy adults, 21-29 years old, with double skinfolds on the forearm less than 10 mm participated. The median rStO2 was 70.7% (interquartile range (IQR) 7.7%), 68.4% (IQR 8.4%), and 64.6% (IQR 4.8) with INVOS, NONIN, and FORE-SIGHT, respectively, the median rate of decline was 13.2%/min (IQR 9.6), 22.8 %/min (IQR 18.0), and 10.8%/min (IQR 6.0), and the same-site repeatability was 2.9% (95% CI 2.4-3.3), 4.6% (CI 3.9-5.3), and 2.0% (CI 1.7-2.3). INVOS gave significantly higher steady state values than FORE-SIGHT, and NONIN had the steepest decline in rStO2, but the poorest repeatability. Two measures of signal-to-noise were similar among devices. This suggests that good repeatability comes at the expense of low sensitivity to changes in oxygenation. Values of rStO2 on the forearm from INVOS, NONIN and FORE-SIGTH cannot be used interchangeably. PMID- 23990289 TI - Morbidity and mortality of cytoreduction with intraperitoneal chemotherapy: outcomes from the ACS NSQIP database. AB - BACKGROUND: Cytoreduction with intraperitoneal chemotherapy (IPC) for treatment of peritoneal surface malignancies is increasingly utilized. However, the described morbidity and mortality rates are based predominantly on the experience at high-volume centers. We analyzed the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for a nationwide perspective on morbidity and mortality associated with IPC. METHODS: The NSQIP database was queried for all patients undergoing IPC and cytoreduction from 2005 to 2011. Univariate and forward stepwise multivariate regression identified factors associated with 30-day death and morbidity. RESULTS: A total of 795 patients underwent IPC. Patients underwent a median of seven operative procedures (range 2-13). Median hospital stay was 9 days (range 2-79 days). A total of 521 complications occurred in 249 (31 %) patients, and there were 19 (2.3 %) mortalities. The most common complications were bleeding (15.1 %) and sepsis (14.6 %). Univariate analysis identified age >=60 years, ascites, weight loss, recent prior operation, albumin <3 g/dl, bilirubin >=2 mg/dl, hematocrit <=30 %, colon, spleen, small bowel, liver, kidney, diaphragm, and gastric resections, wound classification, operative time, and intraoperative transfusion requirement as significantly associated with death and morbidity. By multivariate analysis, age >=60 years, preoperative albumin <3 g/dl, gastrectomy, operative time, and intraoperative transfusion requirement remained significantly associated with death and morbidity. Particularly high death and morbidity rates were associated with preoperative albumin <3 g/dl (58 %), gastrectomy (62 %), and operative time of >500 min (46 %). CONCLUSIONS: In this nationwide cohort, the death and morbidity rate associated with cytoreduction and IPC is consistent with other large series. Age >=60 years, albumin <3 g/dl, gastrectomy, operative time, and intraoperative transfusion requirement were associated with 30-day death and morbidity. These factors may help guide patient selection, counseling, and preoperative optimization before IPC. PMID- 23990290 TI - Molecular detection and genotyping of Fusarium oxysporum f. sp. psidii isolates from different agro-ecological regions of India. AB - Twenty one isolates of Fusarium oxysporum f. sp. psidii (Fop), causing a vascular wilt in guava (Psidium guajava L.), were collected from different agro-ecological regions of India. The pathogenicity test was performed in guava seedlings, where the Fop isolates were found to be highly pathogenic. All 21 isolates were confirmed as F. oxysporum f. sp. psidii by a newly developed, species-specific primer against the conserved regions of 28S rDNA and the intergenic spacer region. RAPD and PCR-RFLP were used for genotyping the isolates to determine their genetic relationships. Fifteen RAPD primers were tested, of which five primers produced prominent, polymorphic, and reproducible bands. RAPD yielded an average of 6.5 polymorphic bands per primer, with the amplified DNA fragments ranging from 200-2,000 bp in size. A dendrogram constructed from these data indicated a 22-74% level of homology. In RFLP analysis, two major bands (350 and 220 bp) were commonly present in all isolates of F. oxysporum. These findings provide new insight for rapid, specific, and sensitive disease diagnosis. However, genotyping could be useful in strain-level discrimination of isolates from different agro-ecological regions of India. PMID- 23990291 TI - Microbial community analysis of a coastal hot spring in Kagoshima, Japan, using molecular- and culture-based approaches. AB - Ibusuki hot spring is located on the coastline of Kagoshima Bay, Japan. The hot spring water is characterized by high salinity, high temperature, and neutral pH. The hot spring is covered by the sea during high tide, which leads to severe fluctuations in several environmental variables. A combination of molecular- and culture-based techniques was used to determine the bacterial and archaeal diversity of the hot spring. A total of 48 thermophilic bacterial strains were isolated from two sites (Site 1: 55.6 degrees C; Site 2: 83.1 degrees C) and they were categorized into six groups based on their 16S rRNA gene sequence similarity. Two groups (including 32 isolates) demonstrated low sequence similarity with published species, suggesting that they might represent novel taxa. The 148 clones from the Site 1 bacterial library included 76 operational taxonomy units (OTUs; 97% threshold), while 132 clones from the Site 2 bacterial library included 31 OTUs. Proteobacteria, Bacteroidetes, and Firmicutes were frequently detected in both clone libraries. The clones were related to thermophilic, mesophilic and psychrophilic bacteria. Approximately half of the sequences in bacterial clone libraries shared <92% sequence similarity with their closest sequences in a public database, suggesting that the Ibusuki hot spring may harbor a unique and novel bacterial community. By contrast, 77 clones from the Site 2 archaeal library contained only three OTUs, most of which were affiliated with Thaumarchaeota. PMID- 23990292 TI - Multiple gene genealogical analyses of a nematophagous fungus Paecilomyces lilacinus from China. AB - Paecilomyces lilacinus is a geographically widespread nematophagous fungus and a promising biological control agent against plant parasitic nematodes. However, relatively little is known about its patterns of genetic variation through its broad geographic and ecological contexts. In this study, we analyzed the genetic variation of 2 virulence-associated genes (PLS and PLC) and 4 housekeeping gene fragments (ITS, RPB1, RPB2, and beta-tubulin) among 80 P. lilacinus specimens collected from 7 locations in China. Various degrees of polymorphism and haplotype diversity were observed among the six gene fragments. However, no genetic differentiation was observed among the geographic populations, consistent with extensive gene flow among these geographic populations of P. lilacinus in China. Our analysis also suggested that clonal reproduction was the predominant mode of reproduction in natural populations of P. lilacinus. PMID- 23990294 TI - Bacterial diversity in the mountains of South-West China: climate dominates over soil parameters. AB - Certain patterns in soil bacterial diversity and community composition have become evident from metagenomics studies on a range of scales, from various parts of the world. For example, soil pH has generally been seen as dominating variation in bacterial diversity, above all other soil and climate parameters. It is important however to test the generality of these relationships by studying previously un-sampled areas. We compared soil bacterial diversity and community composition under a wide range of climatic and edaphic conditions in mountainous Yunnan Province, SW China. Soil samples were taken from a range of primary forest types and altitudes, reflecting the great variation of forest environments in this region. From each soil sample, DNA was extracted and pyrosequenced for bacterial 16S rRNA gene identification. In contrast to other recent studies from other parts of the world, pH was a weaker predictor of bacterial community composition and diversity than exchangeable Ca(2+) concentration, and also the more poorly defined environmental parameter of elevation. Samples from within each forest type clustered strongly, showing the distinctive pattern of their microbial communities on a regional scale. It is clear that on a regional scale in a very heterogeneous environment, additional factors beyond pH can emerge as more important in determining bacterial diversity. PMID- 23990295 TI - Phenotypic and genotypic analysis of clarithromycin-resistant Helicobacter pylori from Bogota D.C., Colombia. AB - Resistance of Helicobacter pylori to clarithromycin is the most common cause of treatment failure in patients with H. pylori infections. This study describes the MICs and the presence of 23S rRNA mutations of H. pylori isolates from Bogota, D.C., Colombia. H. pylori were isolated from gastric biopsies from patients with functional dyspepsia. Clarithromycin susceptibility was investigated by agar dilution and strains were considered resistant if the MIC was >= 1 MUg/ml. DNA sequences of the 23S rRNA gene of strains resistant and sensitive to clarithromycin were determined to identify specific point mutations. Clarithromycin resistance was present in 13.6% of patients by agar dilution. The A2143G, A2142G and A2142C mutations were found in 90.5, 7.1, and 2.4% of H. pylori strains with resistance genotype.The resistant phenotype was associated with 23S rRNA resistance genotype in 85.7% of isolates. The point mutations in 23S rRNA were well correlated with MICs values for clarithromycin. PMID- 23990296 TI - Screening and identification of ClpE interaction proteins in Streptococcus pneumoniae by a bacterial two-hybrid system and co-immunoprecipitation. AB - Hsp100/Clp proteins have crucial functions in the protein quality control, stress tolerance, and virulence of many pathogenic bacteria. ClpE is an important virulence factor involved in adherence and invasion in Streptococcus pneumoniae. To explore the underlying mechanism, we screened ClpE interaction proteins using a bacterial two-hybrid system and co-immunoprecipitation. We used ClpE as bait and constructed the pBT-ClpE bait plasmid for two-hybrid screening. Then, we constructed ClpE::GFP fusion for co-immunoprecipitation screening using anti-GFP monoclonal antibody. We obtained eight potential ClpE interaction proteins, including carbamoyl-phosphate synthase, pyruvate oxidase (SpxB), phosphoenolpyruvate-protein phosphotransferase, aminopeptidase N (pepN), L lactate dehydrogenase, ribosomal protein S4, sensor histidine kinase (SPD_2019), and FtsW (a cell division protein). FtsW, SpxB, pepN, and SPD_2019 were confirmed to interact with ClpE using Bacterial Two-hybrid or Co-immunoprecipitation. Morphologic observations found that DeltaclpE strain existed in abnormal division. beta-Galactosidase activity assay suggested that ClpE contributed to the degradation of FtsW. Furthermore, FtsW could be induced by heat shock. The results suggested that ClpE might affect cell division by regulating the level of FtsW. These data may provide new insights in studying the role of ClpE in S. pneumoniae. PMID- 23990297 TI - The pectate lyase encoded by the pecCl1 gene is an important determinant for the aggressiveness of Colletotrichum lindemuthianum. AB - Colletotrichum lindemuthianum is the causal agent of anthracnose in the common bean, and the genes that encode its cell-wall-degrading enzymes are crucial for the development of the disease. Pectinases are the most important group of cell wall-degrading enzymes produced by phytopathogenic fungi. The pecC1l gene, which encodes a pectate lyase in C. lindemuthianum, was isolated and characterized. Possible cis-regulatory elements and transcription factor binding sites that may be involved in the regulation of genetic expression were detected in the promoter region of the gene. pecCl1 is represented by a single copy in the genome of C. lindemuthianum, though in silico analyses of the genomes of Colletotrichum graminicola and Colletotrichum higginsianum suggest that the genome of C. lindemuthianum includes other genes that encode pectate lyases. Phylogenetic analysis detected two groups that clustered based on different members of the pectate lyase family. Analysis of the differential expression of pecCl1 during different stages of infection showed a significant increase in pecCl1 expression five days after infection, at the onset of the necrotrophic phase. The split maker technique proved to be an efficient method for inactivation of the pecCl1 gene, which allowed functional study of a mutant with a site-specific integration. Though gene inactivation did not result in complete loss of pectate lyase activity, the symptoms of anthracnose were reduced. Analysis of pectate lyases might not only contribute to the understanding of anthracnose in the common bean but might also lead to the discovery of an additional target for controlling anthracnose. PMID- 23990298 TI - Effect of pH on conjugated linoleic acid (CLA) formation of linolenic acid biohydrogenation by ruminal microorganisms. AB - Conventional beliefs surrounding the linolenic acid (LNA; cis-9 cis-12 cis-15 C18:3) biohydrogenation (BH) pathway propose that it converts to stearic acid (SA) without the formation of conjugated linoleic acid (CLA) as intermediate isomers. However, an advanced study (Lee and Jenkins, 2011) verified that LNA BH yields multiple CLAs. This study utilized the stable isotope tracer to investigate the BH intermediates of (13)C-LNA with different pH conditions (5.5 and 6.5). The (13)C enrichment was calculated as a (13)C/(12)C ratio of labeled minus unlabeled. After 24 h, eight CLA isomers were significantly enriched on both pH treatment, this result verifies that these CLAs originated from (13)C-LNA BH which supports the results of Lee and Jenkins (2011). The enrichment of cis cis double bond CLAs (cis-9 cis-11 and cis-10 cis-12 CLA) were significantly higher at low pH conditions. Furthermore, the concentration of cis-10 cis-12 CLA at low pH was four times higher than at high pH conditions after a 3 h incubation. These differences support the LNA BH pathways partial switch under different pH conditions, with a strong influence on the cis-cis CLA at low pH. Several mono-, di-, and tri-enoic fatty acid isomers were enriched during 24 h of incubation, but the enrichment was decreased or restricted at low pH treatment. Based on these results, it is proposed that low pH conditions may cause a changed or limited capacity of the isomerization and reduction steps in BH. PMID- 23990299 TI - Fumigant activity of volatiles from Streptomyces alboflavus TD-1 against Fusarium moniliforme Sheldon. AB - The fumigant activity of volatiles generated by Streptomyces alboflavus TD-1 against Fusarium moniliforme Sheldon was investigated. The results showed that the mycelial growth, sporulation, and spore germination of F. moniliforme were significantly suppressed, and that membrane permeability was disrupted in the presence of the volatiles. Gas chromatography-mass Spectrometry analysis revealed 31 kinds of volatile organic compound from the volatiles. Among them, two earthy smelling substances, namely, 2-methylisoborneol (50.97%) and trans-1,10-dimethyl trans-9-decalinol (3.10%) were found. The most abundant compound, 2 methylisoborneol, exhibited inhibitory activity against F. moniliforme by fumigation. All these results suggested that S. alboflavus TD-1 can be a promising starter for the inhibition of F. moniliforme through fumigant action. PMID- 23990300 TI - Antimicrobial effects of herbal extracts on Streptococcus mutans and normal oral streptococci. AB - Streptococcus mutans is associated with dental caries. A cariogenic biofilm, in particular, has been studied extensively for its role in the formation of dental caries. Herbal extracts such as Cudrania tricuspidata, Sophora flavescens, Ginkgo biloba, and Betula Schmidtii have been used as a folk remedy for treating diseases. The purpose of this study was to evaluate and compare the antibacterial activity of herbal extracts against normal oral streptococci, planktonic and biofilm of S. mutans. Streptococcus gordonii, Streptococcus oralis, Streptococcus salivarius, Streptococcus sanguinis, and S. mutans were cultivated with brain heart infusion broth and susceptibility assay for the herbal extracts was performed according to the protocol of Clinical and Laboratory Standard Institute. Also, S. mutans biofilm was formed on a polystyrene 12-well plate and 8-well chamber glass slip using BHI broth containing 2% sucrose and 1% mannose after conditioning the plate and the glass slip with unstimulated saliva. The biofilm was treated with the herbal extracts in various concentrations and inoculated on Mitis-Salivarius bacitracin agar plate for enumeration of viable S. mutans by counting colony forming units. Planktonic S. mutans showed susceptibility to all of the extracts and S. mutans biofilm exhibited the highest level of sensitivity for the extracts of S. flavescens. The normal oral streptococci exhibited a weak susceptibility in comparison to S. mutans. S. oralis, however, was resistant to all of the extracts. In conclusion, the extract of S. flavescens may be a potential candidate for prevention and management of dental caries. PMID- 23990293 TI - Bacterial and fungal diversity in the starter production process of Fen liquor, a traditional Chinese liquor. AB - Fermented foods and beverages are important parts of human diet. Fen liquor, a Chinese liquor is a fermented beverage that uses a traditional fermentation process. Starters are the main microbial source and also provide nutrients for microorganisms during fermentation. In this study, starters of Fen liquor were produced through a complex traditional fermentation process. To investigate the community structure and the composition of microorganisms in the starter production process, bacterial 16S rRNA and fungal internal transcribed spacer (ITS) regions were sequenced using clone libraries and pyrosequencing, respectively. There was much higher diversity among the bacteria than among the fungi in the starter production process. Bacteria on the surface of the starters belonged mostly to the Lactobacillaceae family, while members of the Bacillacae family were dominant in the interior of the samples that lacked access to air and water. In the fungi population, diversity was high only in the raw material. In all other samples, nearly all of the fungal sequences were from Pichia kudriavzevii, a member of the Saccharomycetaceae family. Nearly all samples showed similar fungal community structures, indicating that there was little change in the fungal community. To the best of our knowledge, this is the first report to reveal the whole process of the starter production of Chinese traditional liquor. The findings obtained in this study provide new insights into understanding the composition of the microbial community during the traditional Chinese liquor starter production process and information about the production process control and monitoring. PMID- 23990301 TI - Dysregulation of KSHV replication by extracts from Carthamus tinctorius L. AB - Carthamus tinctorius L. (CT) is traditionally used to reduce ailments from diseases of the musculoskeletal system and connective tissue and diseases of blood circulation and the cardiovascular system. Flower extracts from CT are known to have antibacterial activity, anti-inflammatory activity, and to inhibit tumor promotion in mouse skin carcinogenesis. In order to discover new antiviral agents from CT extracts, we tested whether CT extracts contain antiviral activity against gammaherpesvirus infection. This study demonstrated that treatment with CT extracts disrupted KSHV latency in the viral-infected host cells, iSLK-BAC16. n-Hexane and EtOH fractions of CT extracts critically affected at least two stages of the KHSV life-cycle by abnormally inducing KSHV lytic reactivation and by severely preventing KSHV virion release from the viral host cells. In addition to the effects on KSHV itself, CT extract treatments induced cellular modifications by dysregulating cell-cycle and producing strong cytotoxicity. This study demonstrated for the first time that CT extracts have antiviral activities that could be applied to development of new anti-gammaherpesviral agents. PMID- 23990302 TI - The N3 subdomain in a domain of fibronectin-binding protein B isotype I is an independent risk determinant predictive for biofilm formation of Staphylococcus aureus clinical isolates. AB - Fibronectin-binding proteins (FnBP), FnBPA and FnBPB, are purported to be involved in biofilm formation of Staphylococcus aureus. This study was performed to find which of three consecutive N subdomains of the A domain in the FnBP is the key domain in FnBP. A total of 465 clinical isolates of S. aureus were examined for the biofilm forming capacity and the presence of N subdomains of FnBP. In the biofilm-positive strains, N2 and N3 subdomains of FnBPA, and N1 and N3 subdomains of FnBPB were significantly more prevalent. Multivariate logistic regression analysis of 246 biofilm-positive and 123 biofilm-negative strains identified only the FnBPB-N3 subdomain as an independent risk determinant predictive for biofilm-positive strains of S. aureus (Odds ratio [OR], 13.174; P<0.001). We also attempted to delete each of the fnbA-N2 and -N3 and fnbB-N1 and -N3 from S. aureus strain 8325-4 and examined the biofilm forming capacity in the derivative mutants. In agreement with the results of the multivariate regression analysis, deletion of either the fnbA-N2 or -N3, or fnbB-N1 did not significantly diminish the capacity of strain 8325-4 to develop a biofilm, while deletion of the fnbB-N3 did. Therefore, it is suggested that the FnBPB-N3 subdomain of isotype I may be a key domain in FnBP which is responsible for the causing biofilm formation in S. aureus clinical isolates. PMID- 23990303 TI - Cell-surface expression of Aspergillus saitoi-derived functional alpha-1,2 mannosidase on Yarrowia lipolytica for glycan remodeling. AB - Expression of proteins on the surface of yeast has a wide range of applications, such as development of live vaccines, screening of antibody libraries, and use as whole-cell biocatalysts. The hemiascomycetes yeast Yarrowia lipolytica has been raised as a potential host for heterologous expression of recombinant proteins. In this study, we report the expression of Aspergillus saitoi alpha-1,2 mannosidase, encoded by the msdS gene, on the cell surface of Y. lipolytica. As the first step to achieve the secretory expression of msdS protein, four different signal sequences-derived from the endogenous Y. lipolytica Lip2 and Xpr2 prepro regions and the heterologous A. niger alpha-amylase and rice alpha amylase signal sequences-were analyzed for their secretion efficiency. It was shown that the YlLip2 prepro sequence was most efficient in directing the secretory expression of msdS in fully N-glycosylated forms. The surface display of msdS was subsequently directed by fusing GPI anchoring motifs derived from Y. lipolytica cell wall proteins, YlCwp1p and YlYwp1p, respectively, to the C terminus of the Lip2 prepro-msdS protein. The expression of actively functional msdS protein on the cell surface was confirmed by western blot, flow cytometry analysis, along with the alpha-1,2-mannosidase activity assay using intact Y. lipolytica cells as the enzyme source. Furthermore, the glycoengineered Y. lipolytica Deltaoch1Deltampo1 strains displaying alpha-1,2-mannosidase were able to convert Man8GlcNAc2 to Man5GlcNAc2 efficiently on their cell-wall mannoproteins, demonstrating its potential used for glycoengineering in vitro or in vivo. PMID- 23990304 TI - Functional characterization of Autographa californica multiple nucleopolyhedrovirus ORF43 and phenotypic changes of ORF43-knockout mutant. AB - ORF43 (ac43) of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is a highly conserved baculovirus gene of unknown function. To investigate the role of ac43 in the baculovirus lifecycle, we constructed an ac43-deleted mutant AcMNPV, Ac43KO. After transfection into Spodoptera frugiperda cells, Ac43KO produced polyhedra much larger in size than those of wild-type AcMNPV. Interestingly, some of the nucleocapsids were singly enveloped in the polyhedrin matrix while the nucleocapsids of AcMNPV are known to be multiply enveloped. Furthermore, Ac43KO led to a defect in the transcription and expression of polyhedrin, which resulted in reduced occlusion body production. However, Ac43KO did not affect production of budded virus as there was no remarkable difference in budded virus titer. These results suggest that ac43 plays an important role in the expression of polyhedrin, the morphogenesis of occlusion body, and the assembly of virions occluded in occlusion bodies. PMID- 23990305 TI - Comparative assessment of the intracellular survival of the Burkholderia pseudomallei bopC mutant. AB - Burkholderia pseudomallei, the causative agent of melioidosis, is a Gram-negative saprophytic bacterium capable of surviving within phagocytic cells. To assess the role of BopC (a type III secreted effector protein) in the pathogenesis of B. pseudomallei, a B. pseudomallei bopC mutant was used to infect J774A.1 macrophage like cells. The bopC mutant showed significantly reduced intracellular survival in infected macrophages compared to wild-type B. pseudomallei. In addition, the bopC mutant displayed delayed escape from endocytic vesicles compared with the wild-type strain. This indicates that BopC is important, and at least in part, needed for intracellular survival of B. pseudomallei. PMID- 23990306 TI - Glyoxal detoxification in Escherichia coli K-12 by NADPH dependent aldo-keto reductases. AB - Glyoxal (GO) and methylglyoxal (MG) are reactive carbonyl compounds that are accumulated in vivo through various pathways. They are presumably detoxified through multiple pathways including glutathione (GSH)-dependent/independent glyoxalase systems and NAD(P)H dependent reductases. Previously, we reported an involvement of aldo-ketoreductases (AKRs) in MG detoxification. Here, we investigated the role of various AKRs (YqhE, YafB, YghZ, YeaE, and YajO) in GO metabolism. Enzyme activities of the AKRs to GO were measured, and GO sensitivities of the corresponding mutants were compared. In addition, we examined inductions of the AKR genes by GO. The results indicate that AKRs efficiently detoxify GO, among which YafB, YghZ, and YeaE are major players. PMID- 23990307 TI - Pontibacter jeungdoensis sp. nov., isolated from a solar saltern in Korea. AB - A Gram-staining-negative, rod-shaped and red-pigmented bacterial strain, HMD3125(T), was isolated from a solar saltern in Jeungdo, Republic of Korea. A phylogenetic tree based on 16S rRNA gene sequences showed that strain HMD3125(T) formed a lineage within the genus Pontibacter and was similar to Pontibacter salisaro (96.1%) and P. korlensis (95.3%). The major fatty acids of strain HMD3125(T) were summed feature 4 (comprising iso-C17:1 I and/or anteiso-C17:1 B; 30.4%), iso-C15:0 (20.4%) and iso-C17:0 3OH (17.2%). The polar lipid profile of HMD3125(T) consisted of the phosphatidylethanolamine, four unidentified polar lipids, unidentified phospholipid, unidentified aminolipid and unidentified aminophospholipid. Strain HMD3125(T) contained MK-7 as the predominant menaquinone and sym-homospermidine as the major polyamine. The DNA G+C content of strain HMD3125(T) was 45.6 mol%. Strain HMD3125(T) assigned as a novel species in the genus Pontibacter, for which the name Pontibacter jeungdoensis sp. nov. is proposed. The type strain is HMD3125(T) (=KCTC 23156(T) =CECT 7710(T)). PMID- 23990308 TI - Penicillium daejeonium sp. nov., a new species isolated from a grape and schisandra fruit in Korea. AB - Two isolates of monoverticillate Penicillium species were collected from a grape and schisandra fruit in Korea. Multigene phylogenetic analyses with the nuclear ribosomal internal transcribed spacer (ITS) region and genes encoding beta tubulin (benA) and calmodulin (cmd), as well as morphological analyses revealed that the two isolates are members of the P. sclerotiorum complex in Penicillium subgenus Aspergilloides, but different from species of the P. sclerotiorum complex. The isolates are closely related to P. cainii, P. jacksonii, and P. viticola in terms of their multigene phylogeny, but their colony and conidiophore morphologies differ from those of closely related species. The name P. daejeonium is proposed for this unclassified new species belonging to the P. sclerotiorum complex in subgenus Aspergilloides. PMID- 23990309 TI - Evaluation of Fusarium head blight in barley infected by Fusarium graminearum. AB - Fusarium head blight, which is primarily caused by Fusarium graminearum, is a devastating disease in the barley field. A real-time PCR protocol was developed to evaluate the growth of this pathogen in the host plant tissues. All four strains harbored the gene encoding ATP-BINDING CASSETTE TRANSPORTER (FgABC; FGSG_00541) as a single copy within their genomes. Our Southern blot result was identical with the genomic data for F. graminearum strain PH-1. Based on the crossing point (CP) values obtained in our TaqMan real-time PCR analysis, two standard curves describing the relationship among the CP value, FgABC copy number, and amount of fungal DNA were constructed. Chronological enumeration of fungal growth was coincided with the symptom development. PMID- 23990311 TI - Febrile neutropenia in hematologic malignancies. AB - Febrile neutropenia (FN) can occur at any time during the course of a malignancy, especially hematologic malignancies, from diagnosis to end-stage disease. The majority of FN episodes are typically confined to the period of initial diagnosis and active treatment. Because of suppressed inflammatory responses, fever is often the sole sign of infection. As FN is a true medical emergency, prompt identification of and intervention in FN can prolong survival and improve quality of life. This article reviews FN in the setting of hematologic malignancies, specifically myelodysplastic syndromes and acute leukemias, providing an overview of the definition of fever and neutropenia, diagnostic approach, categories of risk/risk assessment, management in patients at low and high risk, and prophylaxis of infections. PMID- 23990312 TI - The importance of villous physiology and morphology in mechanistic physiologically-based pharmacokinetic models. AB - PURPOSE: Existing PBPK models incorporating intestinal first-pass metabolism account for effect of drug permeability on accessible absorption surface area by use of "effective" permeability, P eff , without adjusting number of enterocytes involved in absorption or proportion of intestinal CYP3A involved in metabolism. The current model expands on existing models by accounting for these factors. METHODS: The PBPK model was developed using SAAM II. Midazolam clinical data was generated at GlaxoSmithKline. RESULTS: The model simultaneously captures human midazolam blood concentration profile and previously reported intestinal availability, using values for CYP3A CLu int , permeability and accessible surface area comparable to literature data. Simulations show: (1) failure to distinguish absorbing from non-absorbing enterocytes results in overestimation of intestinal metabolism of highly permeable drugs absorbed across the top portion of the villous surface only; (2) first-pass extraction of poorly permeable drugs occurs primarily in enterocytes, drugs with higher permeability are extracted by enterocytes and hepatocytes; (3) CYP3A distribution along crypt-villous axes does not significantly impact intestinal metabolism; (4) differences in permeability of perpetrator and victim drugs results in their spatial separation along the villous axis and intestinal length, diminishing drug-drug interaction magnitude. CONCLUSIONS: The model provides a useful tool to interrogate intestinal absorption/metabolism of candidate drugs. PMID- 23990313 TI - Computational models for neglected diseases: gaps and opportunities. AB - Neglected diseases, such as Chagas disease, African sleeping sickness, and intestinal worms, affect millions of the world's poor. They disproportionately affect marginalized populations, lack effective treatments or vaccines, or existing products are not accessible to the populations affected. Computational approaches have been used across many of these diseases for various aspects of research or development, and yet data produced by computational approaches are not integrated and widely accessible to others. Here, we identify gaps in which computational approaches have been used for some neglected diseases and not others. We also make recommendations for the broad-spectrum integration of these techniques into a neglected disease drug discovery and development workflow. PMID- 23990314 TI - Carbon dioxide-mediated generation of hybrid nanoparticles for improved bioavailability of protein kinase inhibitors. AB - PURPOSE: A versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs). METHODS: The approach is based on nanoparticle precipitation by sub- or supercritical CO2 together with a matrix-forming polymer, incorporating surfactants either during or after nanoparticle formation. Notably, striking synergistic effects between hybrid PKI/polymer nanoparticles and surfactant added after particle formation is investigated. RESULTS: The hybrid nanoparticles, consisting of amorphous PKI embedded in a polymer matrix (also after 12 months), display dramatically increased release rate of nilotinib in both simulated gastric fluid and simulated intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. Similar results indicated flexibility of the approach regarding polymer identity, drug load, and choice of surfactant. The translation of the increased dissolution rate found in vitro into improved GI absorption and bioavalilability in vivo was demonstrated for male beagle dogs, where a 730% increase in the AUC0-24h was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs. CONCLUSIONS: Hybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration. PMID- 23990315 TI - Driving assessment for maintaining mobility and safety in drivers with dementia. AB - BACKGROUND: Demographic changes are leading to an increase in the number of older drivers: as dementia is an age-related disease, there is also an increase in the numbers of drivers with dementia. Dementia can impact on both the mobility and safety of drivers, and the impact of formal assessment of driving is unknown in terms of either mobility or safety. Those involved in assessment of older drivers need to be aware of the evidence of positive and negative effects of driving assessment. Cognitive tests are felt by some authors to have poor face and construct validity for assessing driving performance; extrapolating from values in one large-scale prospective cohort study, the cognitive test that most strongly predicted future crashes would, if used as a screening tool, potentially prevent six crashes per 1000 people over 65 years of age screened, but at the price of stopping the driving of 121 people who would not have had a crash. OBJECTIVES: PRIMARY OBJECTIVES: 1. to assess whether driving assessment facilitates continued driving in people with dementia;2. to assess whether driving assessment reduces accidents in people with dementia. SECONDARY OBJECTIVE: 1. to assess the quality of research on assessment of drivers with dementia. SEARCH METHODS: ALOIS, the Cochrane Dementia Group's Specialized Register was searched on 13 September 2012 using the terms: driving or driver* or "motor vehicle*" or "car accident*" or "traffic accident*" or automobile* or traffic. This register contains records from major healthcare databases, ongoing trial databases and grey literature sources and is updated regularly. SELECTION CRITERIA: We sought randomised controlled trials prospectively evaluating drivers with dementia for outcomes such as transport mobility, driving cessation or motor vehicle accidents following driving assessment. DATA COLLECTION AND ANALYSIS: Each review author retrieved studies and assessed for primary and secondary outcomes, study design and study quality. MAIN RESULTS: No studies were found that met the inclusion criteria. A description and discussion of the driving literature relating to assessment of drivers with dementia relating to the primary objectives is presented. AUTHORS' CONCLUSIONS: In an area with considerable public health impact for drivers with dementia and other road users, the available literature fails to demonstrate the benefit of driver assessment for either preserving transport mobility or reducing motor vehicle accidents. Driving legislation and recommendations from medical practitioners requires further research that addresses these outcomes in order to provide the best outcomes for both drivers with dementia and the general public. PMID- 23990316 TI - Modelling the risk of visual field loss arising from long-term exposure to the antiepileptic drug vigabatrin: a cross-sectional approach. AB - BACKGROUND: The antiepileptic drug vigabatrin has been used widely since 1989, but has only been approved for use in the US since 2009. The risk:benefit of vigabatrin is generally predicated upon an assumed frequency of associated visual field loss (VAVFL) of approximately 31 %. This estimate is based upon relatively short-term usage (up to 4-5 years) and it is essential to determine whether the frequency of VAVFL increases with longer-term usage. OBJECTIVE: The aim of this study was to model, from cross-sectional evidence, over greater ranges of treatment duration and cumulative dose than previously evaluated, the risk (frequency) of VAVFL with increasing exposure to vigabatrin. STUDY DESIGN AND SETTING: This was a retrospective cohort study undertaken in a regional hospital epilepsy clinic. PATIENTS: The cohort comprised 147 consecutive patients treated with vigabatrin for refractory complex partial (focal) seizures, who had all undergone ophthalmological examination and who had undertaken perimetry, reliably, according to a standard and robust protocol. The visual field plots were evaluated masked to treatment duration and dose. MAIN OUTCOME MEASURE: The risk (frequency) of VAVFL with increasing exposure to vigabatrin was modelled, from the cross-sectional evidence, by standard and plateau logistic regression. RESULTS: The cohort comprised 80 females and 67 males (mean age 40.3 years, standard deviation 13.7). The median duration of vigabatrin exposure was 7.9 years (interquartile range 3.6-11.0, range 0.2-16.1 years); 46 patients (31 %) had received vigabatrin for over 10 years. Eighty-seven patients (59 %) exhibited VAVFL; the proportion with VAVFL was higher in males (66 %) than females (54 %). The plateau model for duration and for cumulative dose exhibited a better fit than the standard model (both p < 0.001). The modelled frequency of VAVFL increased with increasing exposure up to approximately 6 years duration and 5 kg cumulative dose, and plateaued at approximately 76 % (95 % CI 67-85) and 79 % (95 % CI 70-87), respectively. Severity of VAVFL, classified in terms of the visual field index Mean Deviation, was not significantly associated with either duration or cumulative dose of therapy. CONCLUSION: Clinicians and patients, in enabling informed choice, should be alert to the possible substantial increased risk:benefit for VAVFL with increasing long-term exposure to vigabatrin and the ensuing increased cost:benefit resulting from the necessary additional visual assessments. PMID- 23990317 TI - The potential of dextran-based glycoconjugates for development of Helicobacter pylori vaccine. AB - We have recently demonstrated that synthetic glycoconjugates based on delipidated lipopolysaccharide (LPS) of Helicobacter pylori and containing an alpha(1-6) glucan chain induced broadly cross-reactive functional antibodies in immunized animals. To investigate the candidacy of alpha(1-6)-glucan as an alternative vaccine strategy we prepared glycoconjugates based on dextrans produced by lactic acid bacteria Leuconostoc mesenteroides B512F and consisting of linear alpha(1-6) glucan chains with limited branching. Three dextrans with averaged molecular masses of 5,000 Da, 3,500 Da and 1,500 Da, respectively, were modified with a diamino group-containing linker and conjugated to a carrier protein, tetanus toxoid (TT) or diphtheria toxoid (DT), and their immunological properties investigated. The conjugates were immunogenic in both rabbits and mice and induced specific IgG responses against alpha(1-6)-glucan-expressing H. pylori LPS. Studies performed with post-immune sera of mice and rabbits immunized with dextran-based conjugates demonstrated cross-reactivity with LPS from typeable and non-typeable strains of H. pylori and selected mutants. The post-immune sera from rabbits that received the conjugates exhibited functional activity against alpha(1-6)-glucan-positive strains of H. pylori. These data provide evidence that dextran-based conjugates may offer a simplified approach to the development of carbohydrate-based vaccines against H. pylori. PMID- 23990318 TI - From constraints to opportunities? Provision of psychosocial support in portuguese oncogenetic counseling services. AB - Although available guidelines for familial cancer risk counseling clearly state the need to provide adequate psychosocial assessments and support, this feature of care is only available in part for individuals and families in oncogenetic counseling protocols in Portugal. The purpose of this study was to examine the psychosocial aspects of oncogenetic counseling provided by a sample of Portuguese genetics professionals. We sought to ascertain perceived need for the provision of psychosocial services and ways to enhance the psychosocial focus in service delivery. A qualitative study was designed; semi-structured focus groups and individual interviews were performed with 30 professionals from Portuguese healthcare institutions where oncogenetic counseling is offered. Findings suggest: current practice is aligned with the teaching model, with a mainly information-based focus; use of psychosocial counseling techniques and psychosocial support is limited throughout the genetic counseling timeline; there is a limited workforce of adequately trained psychosocial professionals, who are disadvantaged by structural and organizational constraints. These factors are considered to be serious barriers for psychosocial delivery. Development of multidisciplinary teams working in oncogenetics, and need for further counselling skills and training for genetics healthcare professionals were identified as priorities. Implications for practice and policy are discussed. Portuguese genetic counselors who have recently completed their training, may therefore contribute to enhanced psychosocial services delivery. PMID- 23990319 TI - Predictive genetic testing of a bone marrow recipient-ethical issues involving unexpected results, gender issues, test accuracy, and implications for the donor. AB - We present a case where an apparently straightforward Lynch syndrome predictive genetic test of DNA from a blood sample from a woman yielded an unexpected result of X/Y chromosome imbalance. Furthermore, it demonstrates the complexities of genetic testing in people who have had bone marrow transplants. This highlights the potential for multiple ethical and counselling challenges, including the inadvertent testing of the donor. Good communication between clinics and laboratories is essential to overcome such challenges and to minimise the provision of false results. PMID- 23990320 TI - Genetic counselor perceptions of genetic counseling session goals: a validation study of the reciprocal-engagement model. AB - Although some researchers have attempted to define genetic counseling practice goals, no study has obtained consensus about the goals from a large sample of genetic counselors. The Reciprocal-Engagement Model (REM; McCarthy Veach, Bartels & LeRoy, 2007) articulates 17 goals of genetic counseling practice. The present study investigated whether these goals could be generalized as a model of practice, as determined by a larger group of clinical genetic counselors. Accordingly, 194 genetic counselors were surveyed regarding their opinions about the importance of each goal and their perceptions of how frequently they achieve each goal. Mean importance ratings suggest they viewed every goal as important. Factor analysis of the 17 goals yielded four factors: Understanding and Appreciation, Support and Guidance, Facilitative Decision-Making, and Patient Centered Education. Patient-Centered Education and Facilitative Decision-Making goals received the highest mean importance ratings. Mean frequency ratings were consistently lower than importance ratings, suggesting genetic counseling goals may be difficult to achieve and/or not applicable in all situations. A number of respondents provided comments about the REM goals that offer insight into factors related to implementing the goals in clinical practice. This study presents preliminary evidence concerning the validity of the goals component of the REM. PMID- 23990321 TI - A tutorial on data-driven methods for statistically assessing ERP topographies. AB - Dynamic changes in ERP topographies can be conveniently analyzed by means of microstates, the so-called "atoms of thoughts", that represent brief periods of quasi-stable synchronized network activation. Comparing temporal microstate features such as on- and offset or duration between groups and conditions therefore allows a precise assessment of the timing of cognitive processes. So far, this has been achieved by assigning the individual time-varying ERP maps to spatially defined microstate templates obtained from clustering the grand mean data into predetermined numbers of topographies (microstate prototypes). Features obtained from these individual assignments were then statistically compared. This has the problem that the individual noise dilutes the match between individual topographies and templates leading to lower statistical power. We therefore propose a randomization-based procedure that works without assigning grand-mean microstate prototypes to individual data. In addition, we propose a new criterion to select the optimal number of microstate prototypes based on cross-validation across subjects. After a formal introduction, the method is applied to a sample data set of an N400 experiment and to simulated data with varying signal-to-noise ratios, and the results are compared to existing methods. In a first comparison with previously employed statistical procedures, the new method showed an increased robustness to noise, and a higher sensitivity for more subtle effects of microstate timing. We conclude that the proposed method is well-suited for the assessment of timing differences in cognitive processes. The increased statistical power allows identifying more subtle effects, which is particularly important in small and scarce patient populations. PMID- 23990322 TI - Interventions to reduce alcohol use among HIV-infected individuals: a review and critique of the literature. AB - Alcohol use disorders are common among HIV-infected individuals and are associated with adverse physiological complications and increased engagement in other health risk behaviors. This paper provides a review and critique of interventions to reduce alcohol use among HIV-infected individuals, including a: (a) synthesis of core intervention components and trial designs; (b) summary of intervention efficacy to reduce alcohol use outcomes; and (c) methodological critique and guidance for future research. We reviewed 14 behavioral interventions that reported on alcohol use outcomes among HIV-infected individuals. Findings were mixed for intervention efficacy to reduce alcohol frequency and quantity. There was limited evidence that interventions reduced binge drinking frequency or alcohol abuse or dependence symptoms. Despite the prevalence of disordered alcohol use among HIV-infected individuals, there is lack of efficacious intervention approaches. Efficacious intervention approaches to reduce alcohol use among HIV-infected individuals are urgently needed. PMID- 23990323 TI - Grey matter volume in the cerebellum is related to the processing of grammatical rules in a second language: a structural voxel-based morphometry study. AB - The experience of learning and using a second language (L2) has been shown to affect the grey matter (GM) structure of the brain. Importantly, GM density in several cortical and subcortical areas has been shown to be related to performance in L2 tasks. Here, we show that bilingualism can lead to increased GM volume in the cerebellum, a structure that has been related to the processing of grammatical rules. Additionally, the cerebellar GM volume of highly proficient L2 speakers is correlated to their performance in a task tapping on grammatical processing in an L2, demonstrating the importance of the cerebellum for the establishment and use of grammatical rules in an L2. PMID- 23990324 TI - Interdomain contacts control folding of transcription factor RfaH. AB - Escherichia coli RfaH activates gene expression by tethering the elongating RNA polymerase to the ribosome. This bridging action requires a complete refolding of the RfaH C-terminal domain (CTD) from an alpha-helical hairpin, which binds to the N-terminal domain (NTD) in the free protein, to a beta-barrel, which interacts with the ribosomal protein S10 following RfaH recruitment to its target operons. The CTD forms a beta-barrel when expressed alone or proteolytically separated from the NTD, indicating that the alpha-helical state is trapped by the NTD, perhaps co-translationally. Alternatively, the interdomain contacts may be sufficient to drive the formation of the alpha-helical form. Here, we use functional and NMR analyses to show that the denatured RfaH refolds into the native state and that RfaH in which the order of the domains is reversed is fully functional in vitro and in vivo. Our results indicate that all information necessary to determine its fold is encoded within RfaH itself, whereas accessory factors or sequential folding of NTD and CTD during translation are dispensable. These findings suggest that universally conserved RfaH homologs may change folds to accommodate diverse interaction partners and that context-dependent protein refolding may be widespread in nature. PMID- 23990325 TI - The other face of restriction: modification-dependent enzymes. AB - The 1952 observation of host-induced non-hereditary variation in bacteriophages by Salvador Luria and Mary Human led to the discovery in the 1960s of modifying enzymes that glucosylate hydroxymethylcytosine in T-even phages and of genes encoding corresponding host activities that restrict non-glucosylated phage DNA: rglA and rglB (restricts glucoseless phage). In the 1980's, appreciation of the biological scope of these activities was dramatically expanded with the demonstration that plant and animal DNA was also sensitive to restriction in cloning experiments. The rgl genes were renamed mcrA and mcrBC (modified cytosine restriction). The new class of modification-dependent restriction enzymes was named Type IV, as distinct from the familiar modification-blocked Types I-III. A third Escherichia coli enzyme, mrr (modified DNA rejection and restriction) recognizes both methylcytosine and methyladenine. In recent years, the universe of modification-dependent enzymes has expanded greatly. Technical advances allow use of Type IV enzymes to study epigenetic mechanisms in mammals and plants. Type IV enzymes recognize modified DNA with low sequence selectivity and have emerged many times independently during evolution. Here, we review biochemical and structural data on these proteins, the resurgent interest in Type IV enzymes as tools for epigenetic research and the evolutionary pressures on these systems. PMID- 23990327 TI - The mycobacterial antibiotic resistance determinant WhiB7 acts as a transcriptional activator by binding the primary sigma factor SigA (RpoV). AB - Tuberculosis therapeutic options are limited by the high intrinsic antibiotic resistance of Mycobacterium tuberculosis. The putative transcriptional regulator WhiB7 is crucial for the activation of systems that provide resistance to diverse antibiotic classes. Here, we used in vitro run-off, two-hybrid assays, as well as mutagenic, complementation and protein pull-down experiments, to characterize WhiB7 as an auto-regulatory, redox-sensitive transcriptional activator in Mycobacterium smegmatis. We provide the first direct biochemical proof that a WhiB protein promotes transcription and also demonstrate that this activity is sensitive to oxidation (diamide). Its partner protein for transcriptional activation was identified as SigA, the primary sigma factor subunit of RNA polymerase. Residues required for the interaction mapped to region 4 of SigA (including R515H) or adjacent domains of WhiB7 (including E63D). WhiB7's ability to provide a specific spectrum of antibiotic-resistance was dependent on these residues as well as its C-terminal AT-hook module that binds to an AT-rich motif immediately upstream of the -35 hexamer recognized by SigA. These experimentally established constrains, combined with protein structure predictions, were used to generate a working model of the WhiB7-SigA-promoter complex. Inhibitors preventing WhiB7 interactions could allow the use of previously ineffective antibiotics for treatment of mycobacterial diseases. PMID- 23990326 TI - Both mature miR-17-5p and passenger strand miR-17-3p target TIMP3 and induce prostate tumor growth and invasion. AB - MicroRNAs (miRNA) precursor (pre-miRNA) molecules can be processed to release a miRNA/miRNA* duplex. In the canonical model of miRNA biogenesis, one strand of the duplex is thought to be the biologically active miRNA, whereas the other strand is thought to be inactive and degraded as a carrier or passenger strand called miRNA* (miRNA star). However, recent studies have revealed that miRNA* strands frequently play roles in the regulatory networks of miRNA target molecules. Our recent study indicated that miR-17 transgenic mice could abundantly express both the mature miR-17-5p and the passenger strand miR-17-3p. Here, we showed that miR-17 enhanced prostate tumor growth and invasion by increasing tumor cell proliferation, colony formation, cell survival and invasion. miRNA target analysis showed that both miR-17-5p and miR-17-3p repressed TIMP metallopeptidase inhibitor 3 (TIMP3) expression. Silencing with small interfering RNA against TIMP3 promoted cell survival and invasion. Ectopic expression of TIMP3 decreased cell invasion and cell survival. Our results demonstrated that mature miRNA can function coordinately with its passenger strand, enhancing the repressive ability of a miRNA by binding the same target. Within an intricate regulatory network, this may be among the mechanisms by which miRNA can augment their regulatory capacity. PMID- 23990328 TI - Sequence-specific microscopic visualization of DNA methylation status at satellite repeats in individual cell nuclei and chromosomes. AB - Methylation-specific fluorescence in situ hybridization (MeFISH) was developed for microscopic visualization of DNA methylation status at specific repeat sequences in individual cells. MeFISH is based on the differential reactivity of 5-methylcytosine and cytosine in target DNA for interstrand complex formation with osmium and bipyridine-containing nucleic acids (ICON). Cell nuclei and chromosomes hybridized with fluorescence-labeled ICON probes for mouse major and minor satellite repeats were treated with osmium for crosslinking. After denaturation, fluorescent signals were retained specifically at satellite repeats in wild-type, but not in DNA methyltransferase triple-knockout (negative control) mouse embryonic stem cells. Moreover, using MeFISH, we successfully detected hypomethylated satellite repeats in cells from patients with immunodeficiency, centromeric instability and facial anomalies syndrome and 5-hydroxymethylated satellite repeats in male germ cells, the latter of which had been considered to be unmethylated based on anti-5-methylcytosine antibody staining. MeFISH will be suitable for a wide range of applications in epigenetics research and medical diagnosis. PMID- 23990329 TI - Mutant DnaAs of Escherichia coli that are refractory to negative control. AB - DnaA is the initiator of DNA replication in bacteria. A mutant DnaA named DnaAcos is unusual because it is refractory to negative regulation. We developed a genetic method to isolate other mutant DnaAs that circumvent regulation to extend our understanding of mechanisms that control replication initiation. Like DnaAcos, one mutant bearing a tyrosine substitution for histidine 202 (H202Y) withstands the regulation exerted by datA, hda and dnaN (beta clamp), and both DnaAcos and H202Y resist inhibition by the Hda-beta clamp complex in vitro. Other mutant DnaAs carrying G79D, E244K, V303M or E445K substitutions are either only partially sensitive or refractory to inhibition by the Hda-beta clamp complex in vitro but are responsive to hda expression in vivo. All mutant DnaAs remain able to interact directly with Hda. Of interest, both DnaAcos and DnaAE244K bind more avidly to Hda. These mutants, by sequestrating Hda, may limit its availability to regulate other DnaA molecules, which remain active to induce extra rounds of DNA replication. Other evidence suggests that a mutant bearing a V292M substitution hyperinitiates by escaping the effect of an unknown regulatory factor. Together, our results provide new insight into the mechanisms that regulate replication initiation in Escherichia coli. PMID- 23990330 TI - Pregnancy complications and calculated cardiovascular risk in urban women: do we envisage an association? AB - Most researches related to pregnancy complications and future cardiovascular disease, and their risk factors have been equivocal. Existence and extent of these complications, as a contributing factor to CVD risks, with underlying mechanisms of these associations, still remain uncertain. Hence, the current study tends to examine associations between "complicated pregnancies" with obesity markers known to be coherent reflections of cardiovascular health in urban women. A cross-sectional sample of 631 Punjabi Khatri (mean age: 33 +/- 5.58 years) urban women was studied for associations of pregnancy diabetes mellitus, hypertensive disorders, preterm delivery, and size for GA with calculated 10-year CVD risk (based on the Framingham score). A wide range of obesity markers (BMI, waist circumference (WC), WHR, and WHtR) were measured 3-8 years postpregnancy to determine its association with complications during pregnancy. The association with the calculated 10-year CVD risk (>=10 %) based on the Framingham prediction score was 3.01 OR (2.11-3.72 CI) for pregnancy DM, 4.52 (3.68-4.93 CI) for preeclampsia/gestational hypertension, 2.16 (2.01-2.79 CI) for size at GA (SGA and LGA), 2.25 (1.91-2.85 CI) for preterm births, and 2.48 (2.08 3.98 CI) for abnormal birth weight when compared with women without pregnancy diabetes mellitus, preeclampsia/gestational hypertension, appropriate gestational age, full-term babies, and normal birth weight, respectively, in completely adjusted models. Therefore, HDP, pregnancy diabetes mellitus, and pregnancy outcomes are all associated with an increased risk of CVD 10 years later. Pregnancy may provide an opportunity to identify women at increased risk of CVD relatively early in life. PMID- 23990331 TI - An electromagnetic thermotherapy system with a deep penetration depth for percutaneous thermal ablation. AB - Thermal ablation has been a promising method to remove the cancerous tissues. Electromagnetic-based thermotherapy has been extensively investigated for a variety of medical applications recently. In this study, a prototype electromagnetic thermotherapy system has been developed with a new coil design and a two-section needle. The coil can generate an alternating electromagnetic field (EMF) with a deep penetration depth to remotely heat the needle which is located up to 15 cm away, enabling percutaneous thermal ablation. Several important parameters, including the heating effects of the needle at different positions, the intensity of the EMF and the induced temperature distribution on the surrounding tissue, are first explored. An in vitro animal experiment has also been performed which shows EMF-induced ablation in a porcine liver by the needle. Furthermore, an in vivo experiment on an animal model (a New Zealand white rabbit) is also conducted in the study. Thus, the two-section needle combined with the coil-generated EMF has been demonstrated to be a promising thermotherapy system for percutaneous thermal ablation. PMID- 23990332 TI - Issues potentially affecting quality of life arising from long-term medicines use: a qualitative study. AB - BACKGROUND: Polypharmacy is increasing and managing large number of medicines may create a burden for patients. Many patients have negative views of medicines and their use can adversely affect quality of life. No studies have specifically explored the impact of general long-term medicines use on quality of life. OBJECTIVE: To determine the issues which patients taking long-term medicines consider affect their day-to-day lives, including quality of life. SETTING: Four primary care general practices in North West England. METHODS: Face-to-face interviews with adults living at home, prescribed four or more regular medicines for at least 1 year. Interviewees were identified from primary care medical records and purposively selected to ensure different types of medicines use. Interviews were recorded, transcribed and analysed thematically. RESULTS: Twenty one interviews were conducted and analysed. Patients used an average of 7.8 medicines, 51 % were preventive, 40 % for symptom relief and 9 % treatment. Eight themes emerged: relationships with health professionals, practicalities, information, efficacy, side effects, attitudes, impact and control. Ability to discuss medicines with health professionals varied and many views were coloured by negative experiences, mainly with doctors. All interviewees had developed routines for using multiple medicines, some requiring considerable effort. Few felt able to exert control over medicines routines specified by health professionals. Over half sought additional information about medicines whereas others avoided this, trusting in doctors to guide their medicines use. Patients recognised their inability to assess efficacy for many medicines, notably those used for prophylaxis. All were concerned about possible side effects and some had poor experiences of discussing concerns with doctors. Medicines led to restrictions on social activities and personal life to the extent that, for some, life can revolve around medicines. CONCLUSION: There is a multiplicity and complexity of issues surrounding medicines use, which impact on day-to-day lives for patients with long-term conditions. While most patients adapt to long-term medicines use, others did so at some cost to their quality of life. PMID- 23990333 TI - Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. AB - BACKGROUND: Despite the widespread use of antenatal corticosteroids to prevent respiratory distress syndrome in preterm infants, there is currently no consensus as to the type of corticosteroid to use; nor the dose, frequency, timing of use or the route of administration. OBJECTIVES: To assess the effects of different corticosteroid regimens for women at risk of preterm birth. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013). SELECTION CRITERIA: All identified published and unpublished randomised controlled trials or quasi-randomised control trials comparing any two corticosteroids (dexamethasone or betamethasone or any other corticosteroid that can cross the placenta), comparing different dose regimens (including frequency and timing of administration) in women at risk of preterm birth were included. We planned to exclude cross-over trials and cluster-randomised trials. We included studies published as abstracts only along with studies published as full-text manuscripts DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data and assessed the risk of bias of included studies. Data were checked for accuracy. MAIN RESULTS: For this update, 12 trials (1557 women and 1661 infants) were included. Dexamethasone was associated with a reduced risk of intraventricular haemorrhage (IVH) compared with betamethasone (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.21 to 0.92; four trials, 549 infants). No statistically significant differences were seen for other primary outcomes: respiratory distress syndrome (RDS) (RR 1.06, 95% CI 0.88 to 1.27; five trials, 753 infants) and perinatal death (neonatal death RR 1.41, 95% CI 0.54 to 3.67; four trials, 596 infants). Similarly, very few differences were seen for secondary outcomes such as rate of admission to the neonatal intensive care unit (NICU) although in one trial, those infants exposed to dexamethasone, compared with betamethasone, had a significantly shorter length of NICU admission (mean difference (MD) -0.91 days, 95% CI -1.77 to -0.05; 70 infants). Results for biophysical parameters were inconsistent, but mostly no clinically important differences were seen.Compared with intramuscular dexamethasone, oral dexamethasone significantly increased the incidence of neonatal sepsis (RR 8.48, 95% CI 1.11 to 64.93) in one trial of 183 infants. No statistically significant differences were seen for other outcomes reported.Apart from a reduced maternal postpartum length of stay for women who received betamethasone at 12-hourly intervals compared to 24-hourly intervals in one trial (MD -0.73 days, 95% CI -1.28 to -0.18; 215 women), no differences in maternal or neonatal outcomes were seen between the different betamethasone dosing intervals assessed. Similarly, no significant differences in outcomes were seen when betamethasone acetate and phosphate was compared with betamethasone phosphate in one trial. AUTHORS' CONCLUSIONS: It remains unclear whether one corticosteroid (or one particular regimen) has advantages over another.Dexamethasone may have some benefits compared with betamethasone such as less IVH, and a shorter length of stay in the NICU. The intramuscular route may have advantages over the oral route for dexamethasone, as identified in one small trial. Apart from the suggestion that 12-hour dosing may be as effective as 24-hour dosing of betamethasone based on one small trial, few other conclusions about optimal antenatal corticosteroid regimens were able to be made. No long-term results were available except for a small subgroup of 18 month old children in one trial. Trials comparing the commonly used corticosteroids are most urgently needed, as are trials of dosages and other variations in treatment regimens. PMID- 23990335 TI - Situations of Choice: Configuring the Empowered Consumer of Hearing Technologies. AB - Focusing on the largest and, arguably, the least visible disability group, the hearing impaired, this paper explores present-day views and understandings of hearing impairment and rehabilitation in a Danish context, with particular focus on working-age adults with late onset of hearing impairment. The paper shows how recent changes in perception of the hearing impaired patient relate to the introduction of a new health care reform that turns audiological rehabilitation into a consumer issue. Ethnographic and interview data from hearing clinics provides evidence that the hearing technologies that are on offer stabilise in specific forms through processes of negotiation among a variety of social actors representing the interests of science, industry, government, and hearing-impaired people. The discussion critically considers the emergence of an "informed consumer" in audiological practices. PMID- 23990334 TI - 11beta-HSD1 inhibitors for the treatment of type 2 diabetes and cardiovascular disease. AB - Inhibition of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has been proposed as a novel therapeutic target for the treatment of type 2 diabetes mellitus. Over 170 new compounds targeting 11beta-HSD1 have been developed. This article reviews the current published literature on compounds that have reached phase II clinical trials in patients with type 2 diabetes, and summarises the preclinical evidence that such agents may be useful for associated conditions, including peripheral vascular disease, coronary artery disease and cognitive decline. In clinical trials, 11beta-HSD1 inhibitors have been well tolerated and have improved glycaemic control, lipid profile and blood pressure, and induced modest weight loss. The magnitude of the effects are small relative to other agents, so that further development of 11beta-HSD1 inhibitors for the primary therapeutic indication of type 2 diabetes has stalled. Ongoing programmes are focused on additional benefits for cognitive function and other cardiovascular risk factors. PMID- 23990336 TI - Automated monitoring to detect H1N1 symptoms among urban, Medicaid-eligible, pregnant women: a community-partnered randomized controlled trial. AB - In response to the H1N1 epidemic, we used community health workers to design and implement a randomized controlled trial to test the efficacy of a new automated call-monitoring system for second and third trimester predominantly Medicaid eligible pregnant women in an urban free standing birth center to promptly detect symptoms of influenza and assure rapid treatment to prevent adverse outcomes from influenza. Daily automated telephone call to second and third trimester pregnant women asking if the woman experienced flu-like symptoms. Calls continued daily until 38 weeks gestation. A community health worker's voice was used for the automated call recording. Positive responses triggered an immediate referral to a nurse-midwife for prompt treatment with anti-viral medication. Fifty pregnant participants were randomized into daily-automated call group (n = 26) or health information group (n = 24). The automated call group participants ranged in age from 14 to 36 (mean = 23.5, SD = 6.3), 84.7 % identified their race/ethnicity as African-American Non-Hispanic, and 80.7 % were Medicaid-Eligible. In the automated call group, 11.5 % chose to be immunized against H1N1. The mean percent of patients reached daily was 45.1 % (SD = 3.2 %) and at least once every 3 days was 65.1 % (SD = 3.1 %). One pregnant woman in the automated call group contracted H1N1 influenza and received prompt anti-viral treatment without any serious outcomes. Participation in daily-automated telephone calls did not differ significantly between patients younger than 18 years old versus patients 18 years or older. There was also no difference in participation between patients with parity of 0 versus patients with parity >=1. Participation in daily telephone calls significantly (alpha <=0.05) increased when a community health worker provided personal follow-up of non-responsive participants. 93.3 % of surveyed pregnant women, who received automated daily calls, recommended to use a similar daily call system in response to a future health crisis. Automated daily phone calls, designed and produced by community health workers, is a feasible, well received strategy to provide urgent health information to an urban, Medicaid eligible group of pregnant women, regardless of age or parity. PMID- 23990337 TI - Obesity and overweight in ethnic minorities of the Detroit metropolitan area of Michigan. AB - Race, ethnicity and socioeconomic factors influence the prevalence of obesity and overweight, which are major public health problems. Our objectives were (1) to calculate the prevalence of self-reported obesity and overweight in whites, blacks, Chaldeans, and Arabs in the Detroit metropolitan area; and (2) to examine the odds for self-reported overweight and obesity in the racial and ethnic minorities when compared to whites. The responses to a self-administered survey conducted among the adult residents (n = 2,883) of the Detroit metropolitan area of Michigan were analyzed. Prevalence of overweight and obesity were 47.4 and 34.6 % respectively for the whole sample, while it was 39.9 and 43.6 % for whites, 42.3 and 47.8 % for blacks, 46.2 and 30.3 % for Chaldeans, and 52.2 and 28.5 % for Arabs. The odds for obesity was significantly lower in Arabs [odds ratio (OR) 0.31; 95 % confidence interval (CI) 0.13-0.72] and Chaldeans (OR 0.14; 95 % CI 0.06-0.33) when compared to whites. Chaldeans (OR 0.36; 95 % CI 0.15 0.86) had significantly decreased likelihood for being overweight compared to whites. Odds for obesity and overweight can vary in the different ethnic minorities within whites. Sharing similar living conditions decreases the differences in the odds for overweight and obesity between whites and blacks. Taking into consideration the racial and ethnic differences of the target population may help in developing better programs for fighting overweight and obesity. PMID- 23990338 TI - Expression of ecto-nucleoside triphosphate diphosphohydrolase1-3 (NTPDase1-3) by cortical astrocytes after exposure to pro-inflammatory factors in vitro. AB - Nucleoside triphosphate diphosphohydrolases (NTPDases) are ecto-enzymes catalyzing the first step of sequential hydrolysis of extracellular ATP to adenosine, as the final product. Among eight members of NTPDase family, NTPDases1 3 have been shown to be expressed in the brain. Although altered NTPDase expression has been observed in relation to cell death and reactive gliosis in several experimentally induced neuropathologies, regulators of NTPDases expression and function are largely unknown. The present study explored the effects of several inflammatory factors (i.e., INF-gamma, TNF-alpha, LPS, peroxide, and glutamate) on NTPDase1-3 activity and expression by cultured cortical astrocytes. We were able to demonstrate that INF-gamma and TNF-alpha increased both ATP and ADP hydrolysis, while LPS specifically increased ATP hydrolysis. Consistent with the observed enhanced nucleotidase activity, INF gamma induced the upregulation of NTPDase1 at the mRNA and protein level. Furthermore, we were able to demonstrate that INF-gamma and TNF-alpha decreased the relative abundance of dominant astrocytic NTPDase2 in favor of NTPDase1. In summary, these results suggest that INF-gamma, TNF-alpha, and LPS may be relevant in vivo regulators of NTPDase expression in neuropathologies associated with neuroinflammation. PMID- 23990339 TI - Inflammation-induced catabolism of tryptophan and tyrosine in acute ischemic stroke. AB - Whether the inflammatory response that accompanies acute ischemic stroke induces the kynurenine pathway is currently a matter of conjecture. Activation of this pathway may disturb active metabolites. The aim of this study was thus to characterize the catabolism of tryptophan and tyrosine in acute ischemic stroke (AIS) patients, and its association with cytokines, C-reactive protein, and glucose. Serum levels of 5-hydroxytryptamine, tryptophan catabolites, and competing amino acids and significant ratios of these were measured in 45 AIS patients and compared to those of 40 control subjects. Furthermore, associations between the serum levels of these biomarkers and serum levels of cytokines, C reactive protein, and glucose were determined. Significantly lower levels of tryptophan and tyrosine in the stroke group indicate increased tryptophan and tyrosine oxidation in acute ischemic stroke, while significantly lowered tryptophan index and tyrosine index indicate a reduced capacity for the synthesis of 5-hydroxytryptamine and catecholamines in the brain, respectively. Furthermore, our findings indicate that the proinflammatory response in acute ischemic stroke may be responsible for a reduced capacity for the biosynthesis of brain catecholamines and mediate neurotoxic effects. Meanwhile, the anti inflammatory IL-10 may exert a neuroprotective effect and prevent the putative reduced capacity for 5-hydroxytryptamine synthesis in the brain. These mechanisms may be involved in several sequelae following stroke, such as cognitive impairment, depression, and fatigue. PMID- 23990340 TI - Generalized spike and waves: effect of discharge duration on brain networks as revealed by BOLD fMRI. AB - In the past decade, the possibility of combining recordings of EEG and functional MRI (EEG-fMRI), has brought a new insight into the brain network underlying generalized spike wave discharges (GSWD). Nevertheless, how GSWD duration influences this network is not fully understood. In this study we aim to investigate whether GSWD duration had a threshold (non-linear) and/or a linear effect on the amplitude of the associated BOLD changes in any brain regions. This could help in elucidating if there is an hemodynamic background supporting the differentiation between interictal and ictal events. We studied a population of 42 patients with idiopathic generalized epilepsies (IGE) who underwent resting state EEG-fMRI recordings in three centres (London, UK; Modena, Italy; Rome, Italy), applying a parametric analysis of the GSWD duration. Patients were classified as having Childhood Absence epilepsy, Juvenile Absence Epilepsy, or Juvenile Myoclonic Epilepsy. At the population level linear GSWD duration-related BOLD signal changes were found in a network of brain regions: mainly BOLD increase in thalami and cerebral ventricles, and BOLD decrease in posterior cingulate, precuneus and bilateral parietal regions. No region of significant BOLD change was found in the group analysis for the non-linear effect of GSWD duration. To explore the possible effect of both the different IGE sub-syndromes and the different protocols and scanning equipment used in the study, a full factorial ANOVA design was performed revealing no significant differences. These findings support the idea that the amplitude of the BOLD changes is linearly related to the GSWD duration with no universal threshold effect of spike and wave duration on the brain network supporting this activity. PMID- 23990341 TI - Safety and efficacy of daptomycin as first-line treatment for complicated skin and soft tissue infections in elderly patients: an open-label, multicentre, randomized phase IIIb trial. AB - BACKGROUND: Daptomycin has proven efficacy in patients with Gram-positive complicated skin and soft tissue infections (cSSTIs), including those caused by Staphylococcus aureus, regardless of methicillin susceptibility. OBJECTIVE: This study was undertaken to evaluate the efficacy and safety of daptomycin in elderly patients. STUDY DESIGN: This was an open-label, multicentre, randomized phase IIIb study conducted in hospitalized patients PATIENTS: Patients aged >=65 years with a diagnosis of Gram-positive cSSTIs with or without bacteraemia were included. In addition, infections were required to be of sufficient severity to require inpatient hospitalization and treatment with parenteral antibiotics for at least 96 h. The main exclusion criterion was the presence of a non-complicated SSTI that could heal by itself or be cured by surgical removal of the site of infection. INTERVENTION: Patients were randomized (2:1) to intravenous daptomycin or pooled intravenous standard therapies (semi-synthetic penicillin or vancomycin, referred to as the 'comparator'). Duration of treatment was between 5 and 14 days for cSSTIs without bacteraemia and between 10 and 28 days for cSSTIs with bacteraemia. MAIN OUTCOME MEASURE: The primary objective was descriptive comparison of clinical success in clinically evaluable patients at test of cure, 7-14 days post treatment. Secondary objectives were microbiological outcome, duration of treatment and safety. RESULTS: In total, 120 patients were randomized (81 to daptomycin; 39 to the comparator) and 102 patients completed the study. Baseline characteristics were similar between the two groups. Common infections included cellulitis, ulcers and abscesses; six patients had bacteraemia [five documented (daptomycin, n = 3; comparator, n = 2); and one suspected (daptomycin, n = 1)]. Test-of-cure clinical success rates were numerically higher for daptomycin than for the comparator [89.0 % (65/73) vs. 83.3 % (25/30); odds ratio 1.65 (95 % confidence interval 0.49-5.54)]. For patients with S. aureus infections, cure rates were 89.7 % (35/39) versus 69.2 % (9/13), respectively; percentage points difference, 20.5 (95 % confidence interval -12.2 to 50.9)]. Rates of adverse events (AEs) and serious AEs were similar in both treatment arms; however, discontinuation rates for AEs/serious AEs were lower for daptomycin than for the comparator (3.8 % vs. 10.0 %). Three serious AEs were considered to be related to the study drug: one case each of pancytopenia (semi synthetic penicillin), renal failure (vancomycin) and asymptomatic increase in creatine phosphokinase concentrations (daptomycin). CONCLUSION: In elderly patients, for whom data were previously limited, the efficacy and safety of daptomycin have been confirmed, including for infections caused by S. aureus, regardless of methicillin susceptibility. PMID- 23990342 TI - The Surviving Sepsis Campaign's Revised Sepsis Bundles. AB - The Surviving Sepsis Campaign (SSC) sepsis care bundles have recently been revised. The original 6-h resuscitation bundle which included rapid antibiotic administration and hemodynamic support with early goal-directed therapy (EGDT) has been divided into two bundles; one including antibiotic and fluid support to be completed within 3 h, and the other including vasopressor support and measures of central venous pressure and oxygen saturation to be completed within 6 h. The original 24-h management bundle targeting glucose control, administration of corticosteroids and recombinant human activated protein C (rhAPC), and limitation of plateau airway pressures during mechanical ventilation is no longer recommended. Past and recent reports by the SSC and others have suggested that compliance with the original bundles was low and their impact unclear. Examination of the revised bundles in the context of issues and questions arising with the original ones suggest that while compliance with new 3-h bundle will be high, compliance with the 6-h bundle will continue to be low. PMID- 23990343 TI - Drug-resistant tuberculosis: pediatric guidelines. AB - The World Health Organization estimates that there are 650,000 prevalent cases of multidrug-resistant (MDR) tuberculosis (TB) globally, and since children (<15 years of age) constitute up to 20 % of the TB caseload in high-burden settings, the number of children with drug-resistant (DR) TB is likely to be substantial. Because bacterial burden at the site of disease is often low, diagnosis involves collection of multiple specimens and a laboratory capable of performing culture, although the Xpert MTB/RIF assay has improved sensitivity over smear examination. The basic principles of treatment for children are the same as those for adults with MDR-TB; however, the treatment regimen is often empiric and based on the drug susceptibility pattern of the source case, if available, or on past history of treatment. Additional challenges arise when MDR-TB is diagnosed and managed in the context of HIV coinfection. HIV-infected children are also treated with antiretroviral therapy medications, which have the potential to interact with second-line anti-TB drugs. Lack of pediatric formulations of second-line drugs and paucity of pharmacokinetic data make dosage challenging. However, when treated appropriately, children with DR TB have good outcomes. PMID- 23990344 TI - City leadership for health and well-being: back to the future. AB - The new European Health Policy Framework and Strategy: Health 2020 of the World Health Organization, draws upon the experience and insights of five phases, spanning 25 years, of the WHO European Healthy Cities Network (WHO-EHCN). Applying the 2020 health lens to Healthy Cities, equity in health and human centered sustainable development are core values and cities have a profound influence on the wider determinants of health in the European population. "Making it Happen" relies on four action elements applied and tested by municipalities and their formal and informal partners: political commitment, vision and strategy, institutional change, and networking. In turn, the renewed commitment by member states of the WHO Regional Committee to work with all spheres and tiers of government is a new dawn for city governance, encouraging cities to redouble their investment in health and health equity in all policies, even in a period of austerity. For phase VI, the WHO-EHCN is being positioned as a strategic vehicle for implementing Health 2020 at the local level. Healthy Cities' leadership is more relevant than ever. PMID- 23990345 TI - The role of radionuclide imaging in heart failure. AB - The incidence of heart failure (HF) is increasing and it remains the only area in cardiovascular disease wherein hospitalization rates and mortalities have worsened in the past 25 years. This review is provided to assess the role of radionuclide imaging in HF. The focus is on three aspects: the value of nuclear imaging to distinguish ischemic from non-ischemic etiologies; risk stratification of patients with HF with evaluation of candidates for specific treatment strategies; and the role of cardiac neuronal imaging in patients with HF. Distinguishing ischemic from non-ischemic cardiomyopathy is important because patients with ischemic cardiomyopathy can potentially have dramatic improvement with revascularization. Single photon emission computed tomography (SPECT) has excellent reported sensitivity and negative predictive value in the detection of coronary artery disease in HF patients. SPECT imaging is also useful in establishing treatment strategies in patients with HF, including those with new onset CHF. Cardiac neuronal imaging of mIBG is particularly helpful in risk stratification of patients with HF. The modality can be used to monitor the response to therapy as dysfunctional mIBG uptake may show improvement with pharmacological treatment. PMID- 23990346 TI - Overexpression of PTP1B in human colorectal cancer and its association with tumor progression and prognosis. AB - Protein tyrosine phosphatase 1B (PTP1B) is a non-transmembrane protein tyrosine phosphatase that has been implicated in cancer pathogenesis. However, the expression level and the role of PTP1B in the development and prognosis of colorectal cancer (CRC) remain unclear. In this study, the expression of PTP1B in CRC tissues and matched noncancerous tissues were detected by using immunohistochemistry, real-time PCR and Western blotting. The correlations between PTP1B expression level and clinicopathologic characteristics and patient survival were analyzed. We found that PTP1B expression was significantly higher in CRC tissues compared with matched non-tumour tissues. Statistical analysis showed that the PTP1B expression was correlated with tumor differentiation, tumor invasion, lymph node metastasis, and TNM stage. Patients with higher expressions of PTP1B had the lower survival (P = 0.012). Taken together, our results suggest that PTP1B expression might play a critical role in the progression of CRC and may serve as a valuable prognostic biomarker for CRC. PMID- 23990347 TI - Idiopathic granulomatous hypophysitis: a systematic review of 82 cases in the literature. AB - Idiopathic granulomatous hypophysitis (IGH) is a rare inflammatory disease of the pituitary. There is debate in the scientific literature as to whether IGH represents a continuum of disease with lymphocytic hypophysitis or has a distinct pathogenesis. Due to the rare nature of the disease, previous descriptions have been limited to single case reports or small series. In the present study, a systematic review of the literature was performed for cases of IGH. 82 cases met inclusion criteria. Data was gathered on IGH clinical aspects, in order to elucidate any associations useful in determining pathogenesis, appropriate clinical treatment, or prognosis. Univariate and multivariate analysis was performed on available data. Female sex was significantly associated with IGH (p < 0.0001). Fever (p = 0.002), nausea or vomiting at presentation (p = 0.031), and histological evidence of necrosis (p = 0.022) correlated with reduced time to presentation. Panhypopituitarism at presentation predicted need for long term hormone replacement (p = 0.014). Hyperprolactinaemia (p = 0.032), normal gonadal (p = 0.037) and thyroid axes (p = 0.001) were associated with reduced likelihood of long-term hormone replacement. Anorexia (p = 0.017), cold intolerance (p = 0.046), and fatigue (p = 0.0033) were associated with death from IGH. Patients who had excisional surgery alone trended towards increased rates of symptom resolution, compared with patients who received corticosteroids as an adjunct to excisional surgery (p = 0.11). This article details the first systematic review of IGH, and presents evidence for a female predilection of the disease. Implications for pathogenesis, and a suggested clinical approach are discussed. An online disease registry has been established to facilitate further IGH research. PMID- 23990349 TI - Pituitary gland in psychiatric disorders: a review of neuroimaging findings. AB - In this paper, it was reviewed neuroimaging results of the pituitary gland in psychiatric disorders, particularly schizophrenia, mood disorders, anxiety disorders, and somatoform disorders. The author made internet search in detail by using PubMed database including the period between 1980 and 2012 October. It was included in the articles in English, Turkish and French languages on pituitary gland in psychiatric disorders through structural or functional neuroimaging results. After searching mentioned in the Methods section in detail, investigations were obtained on pituitary gland neuroimaging in a variety of psychiatric disorders. There have been so limited investigations on pituitary neuroimaging in psychiatric disorders including major psychiatric illnesses like schizophrenia and mood disorders. Current findings are so far from the generalizability of the results. For this reason, it is required to perform much more neuroimaging studies of pituitary gland in all psychiatric disorders to reach the diagnostic importance of measuring it. PMID- 23990348 TI - Characterization of persistent and recurrent Cushing's disease. AB - A case of possible recurrent Cushing's disease (CD) is presented and data on current definitions of CD remission, persistence, and recurrence are reviewed. While prevailing guidelines recommend the use of serum cortisol in the first post operative week for defining initial remission and predicting sustained remission, with the use of 24 h urinary free cortisol measurements if serum cortisol values are equivocal, there is debate as to which methods and thresholds best define CD remission and predict successful outcomes. Other methods used to define remission (and hence persistence and recurrence) include restoration of cortisol suppression after dexamethasone and physiologic diurnal cortisol rhythm as measured by midnight salivary free cortisol. However, the number and degree of abnormal test results needed to define recurrence, and the determination of which biochemical test has more significance when there are discrepancies between markers is inconsistent among studies. Further inquiry is warranted to examine if patients in apparent CD remission who have subtle hypothalamic pituitary adrenal (HPA) axis abnormalities represent distinctive remission subtypes versus mild or early recurrence. Additional investigation could also explore the degree to which these HPA axis abnormalities, such as alterations in cortisol circadian rhythm or partial resistance to dexamethasone, are associated with persistence of CD morbidities, including neuropsychiatric impairments, alterations in body composition, and cardiovascular risk. PMID- 23990350 TI - Combined corticosteroid and long-acting beta(2)-agonist in one inhaler versus inhaled corticosteroids alone for chronic obstructive pulmonary disease. AB - BACKGROUND: Both long-acting beta(2)-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens and to improve efficacy. Three preparations are currently available: fluticasone propionate/salmeterol (FPS). budesonide/formoterol (BDF) and mometasone furoate/formoterol (MF/F). OBJECTIVES: To assess the efficacy and safety of combined long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS) preparations, as measured by clinical endpoints and pulmonary function testing, compared with inhaled corticosteroids (ICS) alone, in the treatment of adults with chronic obstructive pulmonary disease (COPD). SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials, which is compiled from systematic searches of multiple literature databases. The search was conducted in June 2013. In addition, we checked the reference lists of included studies and contacted the relevant manufacturers. SELECTION CRITERIA: Studies were included if they were randomised and double-blind. Compared studies combined LABA/ICS with the ICS component. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. The primary outcomes were exacerbations, mortality and pneumonia. Health-related quality of life (as measured by validated scales), lung function and side effects were secondary outcomes. Dichotomous data were analysed as fixed-effect odds ratios with 95% confidence intervals (CIs), and continuous data as mean differences or rate ratios and 95% CIs. MAIN RESULTS: A total of 15 studies of good methodological quality met the inclusion criteria by randomly assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone. The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21 exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N = 7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this study was removed, no significant mortality difference was noted. The reduction in exacerbations did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements in health-related quality of life were measured on the St George's Respiratory Questionnaire (SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically important difference. Adverse event profiles were similar between the two treatments arms, and rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported in earlier trials. AUTHORS' CONCLUSIONS: Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. This review does not support the use of ICS alone when LABAs are available. Adverse events were not significantly different between treatments. Further long-term assessments using practical outcomes of current and new 24-hour LABAs will help determine their efficacy and safety. For robust comparisons as to their relative effects, long-term head-to-head comparisons are needed. PMID- 23990351 TI - Natural cycle in vitro fertilisation (IVF) for subfertile couples. AB - BACKGROUND: Subfertility affects 15% to 20% of couples trying to conceive. In vitro fertilisation (IVF) is one of the assisted reproduction techniques developed to improve chances of achieving pregnancy. In the standard IVF method with controlled ovarian hyperstimulation (COH), growth and development of multiple follicles are stimulated by using gonadotrophins, often combined with a gonadotrophin-releasing hormone (GnRH) agonist or antagonist. Although it is an established method of conception for subfertile couples, the treatment is expensive and has a high risk of adverse effects. Studies have shown that IVF in a natural cycle (NC) or a modified natural cycle (MNC) might be a promising low risk and low cost alternative to the standard stimulated IVF treatment since the available dominant follicle of each cycle is used. In this review, we included available randomised controlled studies comparing natural cycle IVF (NC and MNC) with standard IVF. OBJECTIVES: To compare the efficacy and safety of natural cycle IVF (including both NC-IVF and MNC-IVF) with controlled ovarian hyperstimulation IVF (COH-IVF) in subfertile couples. SEARCH METHODS: An extended search including of the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ClinicalTrials.gov, conference abstracts in the Web of Knowledge, the World Health Organization International Trials Registry Platform search portal, LILACS database, PubMed and the OpenSIGLE database was conducted according to Cochrane guidelines. The last search was on 31st July 2013. SELECTION CRITERIA: All randomised controlled trials (RCTs) comparing either natural cycle IVF or modified natural cycle IVF versus standard IVF in subfertile couples were included. DATA COLLECTION AND ANALYSIS: Data selection and extraction and risk of bias assessment were carried out independently by two authors (TA and AC). The primary outcome measures were live birth rate and ovarian hyperstimulation syndrome (OHSS) rate per randomised woman. We calculated Mantel-Haenszel odds ratios for each dichotomous outcome and either the mean difference or the standardised mean difference (SMD) for continuous outcomes, with 95% confidence intervals (CIs). A fixed effect model was used unless there was substantial heterogeneity, in which case a random effects model was used. MAIN RESULTS: Six randomised controlled trials with a total of 788 women were included. The largest of these trials included 396 women eligible for this review.No evidence of a statistically significant difference was found between natural cycle and standard IVF in live birth rates (OR 0.68, 95% CI 0.46 to 1.01, two studies, 425 women, I(2)= 0%, moderate quality evidence). The evidence suggests that for a woman with a 53% chance of live birth using standard IVF, the chance using natural cycle IVF would range from 34% to 53%. There was no evidence of a statistically significant difference between natural cycle and standard IVF in rates of OHSS (OR 0.19, 95% CI 0.01 to 4.06, one study, 60 women, very low quality evidence), clinical pregnancy (OR 0.52 95% CI 0.17 to 1.61, 4 studies, 351 women, I(2)=63%, low quality evidence), ongoing pregnancy (OR 0.72, 95% CI 0.50 to 1.05, three studies, 485 women, I(2)=0%, moderate quality evidence), multiple pregnancy (OR 0.76, 95% CI 0.25 to 2.31, 2 studies, 527 women, I(2)=0%, very low quality evidence), gestational abnormalities (OR 0.44 95% CI 0.03 to 5.93, 1 study, 18 women, very low quality evidence) or cycle cancellations (OR 8.98, 95% CI 0.20 to 393.66, 2 studies, 159 women, I(2)=83%, very low quality evidence). One trial reported that the oocyte retrieval rate was significantly lower in the natural cycle group (MD -4.40, 95% CI -7.87 to -0.93, 60 women, very low quality evidence). There were insufficient data to draw any conclusions about rates of treatment cancellation. Findings on treatment costs were inconsistent and more data are awaited. The evidence was limited by imprecision. Findings for pregnancy rate and for cycle cancellation were sensitive to the choice of statistical model: for these outcomes, use of a fixed effect model suggested a benefit for the standard IVF group. Moreover the largest trial has not yet completed follow up, though data have been reported for over 95% of women. AUTHORS' CONCLUSIONS: Further evidence from well conducted large trials is awaited on natural cycle IVF treatment. Future trials should compare natural cycle IVF with standard IVF. Outcomes should include cumulative live birth and pregnancy rates, the number of treatment cycles necessary to reach live birth, treatment costs and adverse effects. PMID- 23990352 TI - The effects of silencing of PI3K p85alpha on 5-FU-induced colorectal cancer cells apoptosis. AB - Colorectal cancer is the third most common malignancy worldwide. 5-fluorouracil (5-FU) is the commonly used chemotherapeutic agent, however, more patients develop resistance. Phosphatidylinositol 3-kinases (PI3Ks) play a crucial role in a wide range of cellular processes associated with malignant behavior including cell growth, migration, and survival. In this study, we show increased expression of PI3K p85alpha during the progression of colorectal cancer. Silencing of PI3K p85alpha in colorectal cancer cells increased disruption of mitochondrial membrane potential and enhanced 5-FU-induced apoptosis. Furthermore, PI3K p85alpha-depletion results in activated expression of apoptosis-associated genes Bcl-6, Bim, and Bax. Our results suggest that knockdown of PI3K p85alpha is a potential therapeutic strategy in the treatment of colorectal cancer. PMID- 23990353 TI - No evidence for shedding of circulating tumor cells to the peripheral venous blood as a result of mammographic breast compression. AB - This pilot study aimed to investigate whether mammographic compression procedures might cause shedding of tumor cells into the circulatory system as reflected by circulating tumor cell (CTC) count in peripheral venous blood samples. From March to October 2012, 24 subjects with strong suspicion of breast malignancy were included in the study. Peripheral blood samples were acquired before and after mammography. Enumeration of CTCs in the blood samples was performed using the CellSearch((r)) system. The pressure distribution over the tumor-containing breast was measured using thin pressure sensors. The median age was 66.5 years (range, 51-87 years). In 22 of the 24 subjects, breast cancer was subsequently confirmed. The difference between the average mean tumor pressure 6.8 +/- 5.3 kPa (range, 1.0-22.5 kPa) and the average mean breast pressure 3.4 +/- 1.6 kPa (range, 1.5-7.1 kPa) was statistically significant (p < 0.001), confirming that there was increased pressure over the tumor. The median pathological tumor size was 19 mm (range, 9-30 mm). Four subjects (17 %) were CTC positive before compression and two of these (8 %) were also CTC positive after compression. A total of seven CTCs were isolated with a mean size of 8 * 6 MUm(2) (range of the longest diameter, 5-12 MUm). The study supports the view that mammography is a safe procedure from the point of view of tumor cell shedding to the peripheral blood. PMID- 23990354 TI - What guidelines should or should not be: implications for guideline production. AB - European Renal Best Practice (ERBP) is the official guidance-providing body of the European Renal Association-European Dialysis and Transplant Association. This paper introduces the mission statement of ERBP, and provides insight on what this implies for guideline production. We will discuss that improving patient outcome does not only require attention to high-quality evidence, but also understanding of the processes of medical decision making. We will advocate that rigorous methodology is the cornerstone of guideline production, but in those cases where this does not retrieve quality evidence, consensus-based guidance might be suitable. Based on its mission statement, ERBP advocates that guidelines should encourage shared decision making. PMID- 23990355 TI - Variable selection in semi-parametric models. AB - We propose Bayesian variable selection methods in semi-parametric models in the framework of partially linear Gaussian and problit regressions. Reproducing kernels are utilized to evaluate possibly non-linear joint effect of a set of variables. Indicator variables are introduced into the reproducing kernels for the inclusion or exclusion of a variable. Different scenarios based on posterior probabilities of including a variable are proposed to select important variables. Simulations are used to demonstrate and evaluate the methods. It was found that the proposed methods can efficiently select the correct variables regardless of the feature of the effects, linear or non-linear in an unknown form. The proposed methods are applied to two real data sets to identify cytosine phosphate guanine methylation sites associated with maternal smoking and cytosine phosphate guanine sites associated with cotinine levels with creatinine levels adjusted. The selected methylation sites have the potential to advance our understanding of the underlying mechanism for the impact of smoking exposure on health outcomes, and consequently benefit medical research in disease intervention. PMID- 23990356 TI - Imaging the role of GABA in movement disorders. AB - Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. This paper reviews the current knowledge derived from positron emission tomography and single photon emission tomography studies quantifying GABAA receptor binding in movement disorders of extrapyramidal origin, focusing on essential tremor (ET), Parkinsonism (idiopathic PD and atypical parkinsonian syndromes), dystonia, and Huntington's disease (HD). In ET, there is evidence to suggest a specific disturbance at the level of the GABAA receptor and impairment of GABAergic inhibition to be a driving force for the development of rhythmic overactivity in cerebello-thalamo-cortical networks. In dystonia, GABAA receptor binding studies have been relevant for unraveling pathophysiological mechanisms causing sensorimotor disinhibition leading to dystonic movements. The role of GABA in idiopathic PD and atypical parkinsonian syndromes is less clear, despite the fact that GABAA receptors are expressed on virtually all striatal neurons and that GABA exerts important inhibitory influences upon basal outflow pathways. In HD, reductions of GABAA receptor have been reported in the basal ganglia but were found to be less extensive compared with concomitant metabolic reductions. PMID- 23990357 TI - Ranolazine reduces patient-reported angina severity and frequency and improves quality of life in selected patients with chronic angina. AB - BACKGROUND: Chronic stable angina negatively affects quality of life (QoL). American College of Cardiology/American Heart Association guidelines highlight maintaining/restoring a level of activity, functional capacity, and QoL that is satisfactory to the patient as an objective of treatment, and further define the treatment goal for most patients as maximizing survival and achieving prompt and complete (or near-complete) elimination of angina with a return to normal activities. OBJECTIVE: To assess self-reported angina severity, frequency, and QoL in patients with chronic stable angina who had not undergone revascularization and who were prescribed and remained on ranolazine. METHODS: Patients (N = 92) answered a survey evaluating their perceptions of angina prior to ranolazine initiation (based on recall of previous experience) and during ranolazine treatment. Change in QoL was assessed using the Patient Global Impression of Change scale. RESULTS: Most respondents were female (64%) and had taken ranolazine for >=6 months (89%); mean age was 64 years. The majority of respondents selected higher scores for angina severity before ranolazine treatment (54%), and lower scores for severity while on ranolazine (68%). Most respondents reported experiencing >=1 angina attack/week before ranolazine treatment (82%) and <1 attack/week while on ranolazine (73%). The effect of angina on daily activities was less while taking ranolazine than before ranolazine treatment; 52 and 8% of respondents, respectively, reported significant impact, and 12 and 67%, respectively, reported little/no impact. Most respondents reported noticeably improved angina-related QoL since starting ranolazine (79%). CONCLUSION: Patients who maintained ranolazine treatment for durations ranging from <6 months to >4 years reported substantial improvements in angina severity, frequency, and QoL. PMID- 23990358 TI - Prandial hypertriglyceridemia in metabolic syndrome is due to an overproduction of both chylomicron and VLDL triacylglycerol. AB - The aim was to determine whether fed VLDL and chylomicron (CM) triacylglycerol (TAG) production rates are elevated in metabolic syndrome (MetS). Eight men with MetS (BMI 29.7 +/- 1.1) and eight lean age-matched healthy men (BMI 23.1 +/- 0.4) were studied using a frequent feeding protocol. After 4 h of feeding, an intravenous bolus of (2)H5-glycerol was administered to label VLDL1, VLDL2, and TAG. (13)C-glycerol tripalmitin was administered orally as an independent measure of CM TAG metabolism. Hepatic and intestinal lipoproteins were separated by an immunoaffinity method. In MetS, fed TAG and the increment in TAG from fasting to feeding were higher (P = 0.03 and P = 0.04, respectively) than in lean men. Fed CM, VLDL1, and VLDL2 TAG pool sizes were higher (P = 0.006, P = 0.03, and P < 0.02, respectively), and CM, VLDL1, and VLDL2 TAG production rates were higher (P < 0.002, P < 0.05, and P = 0.06, respectively) than in lean men. VLDL1, VLDL2, and CM TAG clearance rates were not different between groups. In conclusion, prandial hypertriglyceridemia in men with MetS was due to an increased production rate of both VLDL and CM TAG. Since both groups received identical meals, this suggests that in MetS the intestine is synthesizing more TAG de novo for export in CMs. PMID- 23990360 TI - Hepatic notch signaling correlates with insulin resistance and nonalcoholic fatty liver disease. AB - Hepatic Notch signaling is inappropriately activated in obese/insulin-resistant mouse models. Genetic or pharmacologic inhibition of hepatic Notch signaling in obese mice simultaneously improves glucose tolerance and reduces hepatic triglyceride content. As such, we predicted that Notch signaling in human liver would be positively associated with insulin resistance and hepatic steatosis. Here, we systematically survey Notch signaling in liver biopsy specimens, and show active Notch signaling in lean and obese adults, with expression of multiple Notch receptors and ligands. In morbidly obese patients undergoing bariatric surgery, we show that Notch activation positively correlates with glucose-6 phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (PCK1) expression, key regulators of hepatic glucose output. We used immunofluorescence to identify active Notch signaling in hepatocytes and show highest activity in hyperglycemia, which we confirmed is a direct effect of hyperglycemia and insulin resistance. In a validation cohort of leaner individuals undergoing percutaneous liver biopsy for suspected nonalcoholic fatty liver disease (NAFLD), Notch activity showed independent positive association with insulin resistance and hepatic steatosis. Notably, Notch activity showed stronger correlation with the NAFLD activity score and alanine aminotransferase levels than with steatosis alone, suggesting that Notch activity is associated with nonalcoholic steatohepatitis. In summary, this study establishes that Notch signaling is activated in and may represent a therapeutic target for patients with obesity-related liver disease. PMID- 23990359 TI - PPARalpha and Sirt1 mediate erythropoietin action in increasing metabolic activity and browning of white adipocytes to protect against obesity and metabolic disorders. AB - Erythropoietin (EPO) has shown beneficial effects in the regulation of obesity and metabolic syndrome; however, the detailed mechanism is still largely unknown. Here, we created mice with adipocyte-specific deletion of EPO receptor. These mice exhibited obesity and decreased glucose tolerance and insulin sensitivity, especially when fed a high-fat diet. Moreover, EPO increased oxidative metabolism, fatty acid oxidation, and key metabolic genes in adipocytes and in white adipose tissue from diet-induced obese wild-type mice. Increased metabolic activity by EPO is associated with induction of brown fat-like features in white adipocytes, as demonstrated by increases in brown fat gene expression, mitochondrial content, and uncoupled respiration. Peroxisome proliferator activated receptor (PPAR)alpha was found to mediate EPO activity because a PPARalpha antagonist impaired EPO-mediated induction of brown fat-like gene expression and uncoupled respiration. PPARalpha also cooperates with Sirt1 activated by EPO through modulating the NAD+ level to regulate metabolic activity. PPARalpha targets, including PPARgamma coactivator 1alpha, uncoupling protein 1, and carnitine palmitoyltransferase 1alpha, were increased by EPO but impaired by Sirt1 knockdown. Sirt1 knockdown also attenuated adipose response to EPO. Collectively, EPO, as a novel regulator of adipose energy homeostasis via these metabolism coregulators, provides a potential therapeutic strategy to protect against obesity and metabolic disorders. PMID- 23990361 TI - TRIB3 mediates glucose-induced insulin resistance via a mechanism that requires the hexosamine biosynthetic pathway. AB - In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats, TRIB3 expression in skeletal muscle was increased after 10 days of hyperglycemia, and glycemia and muscle TRIB3 were both restored toward normal by insulin therapy. In L6 myocytes, the induction of TRIB3 by high glucose or glucosamine was reversible upon removal of these substrates. To assess the role of HBP in the induction of TRIB3, we demonstrated that the ability of high glucose to augment TRIB3 expression was prevented by azaserine, an inhibitor of glutamine: fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme in the HBP pathway. TRIB3 expression was also substantially stimulated by glucosamine, which bypasses GFAT, accompanied by a decrease in the insulin-stimulated glucose transport rate, and neither response was affected by azaserine. Further, knockdown of TRIB3 inhibited, and TRIB3 overexpression enhanced, the ability of both high glucose and glucosamine to induce insulin resistance. These data provide the mechanistic link between the HBP flux and insulin resistance and point to TRIB3 as a novel target for treatment of glucose-induced insulin resistance. PMID- 23990362 TI - Programmed cell death-4 deficiency prevents diet-induced obesity, adipose tissue inflammation, and insulin resistance. AB - Programmed cell death-4 (PDCD4), a selective protein translation inhibitor, has shown proinflammatory effect in some inflammatory diseases, but its roles in obesity remain unestablished. This study aims to investigate the effects of PDCD4 on obesity, inflammation, and insulin resistance. Surprisingly, high-fat diet (HFD)-fed PDCD4-deficient (PDCD4(-/-)) mice exhibited an absolutely lean phenotype together with improved insulin sensitivity. Compared with wild-type obese mice, HFD-fed PDCD4(-/-) mice showed higher energy expenditure, lower epididymal fat weight, and reduced macrophage infiltration inflammatory cytokine secretion in white adipose tissue (WAT). Alleviated hepatic steatosis along with decreased plasma levels of triglyceride and cholesterol was also observed in these mice. Importantly, PDCD4 appeared to disturb lipid metabolism via inhibiting the expression of liver X receptor (LXR)-alpha, a master modulator of lipid homeostasis, which was elevated in HFD-fed PDCD4(-/-) mice accompanied by upregulation of its target genes and relieved endoplasmic reticulum stress in WAT. These data demonstrate that PDCD4 deficiency protects mice against diet induced obesity, WAT inflammation, and insulin resistance through restoring the expression of LXR-alpha, thereby proposing PDCD4 as a potential target for treating obesity-associated diseases. PMID- 23990363 TI - Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages. AB - Chronic inflammation is a molecular element of the metabolic syndrome and type 2 diabetes. Saturated fatty acids (SFAs) are considered to be an important proinflammatory factor. However, it is still incompletely understood how SFAs induce proinflammatory cytokine expression. Hereby we report that activating transcription factor (ATF) 4, a transcription factor that is induced downstream of metabolic stresses including endoplasmic reticulum (ER) stress, plays critical roles in SFA-induced interleukin-6 (Il6) expression. DNA microarray analysis using primary macrophages revealed that the ATF4 pathway is activated by SFAs. Haploinsufficiency and short hairpin RNA-based knockdown of ATF4 in macrophages markedly inhibited SFA- and metabolic stress-induced Il6 expression. Conversely, pharmacological activation of the ATF4 pathway and overexpression of ATF4 resulted in enhanced Il6 expression. Moreover, ATF4 acts in synergy with the Toll like receptor-4 signaling pathway, which is known to be activated by SFAs. At a molecular level, we found that ATF4 exerts its proinflammatory effects through at least two different mechanisms: ATF4 is involved in SFA-induced nuclear factor kappaB activation; and ATF4 directly activates the Il6 promoter. These findings provide evidence suggesting that ATF4 links metabolic stress and Il6 expression in macrophages. PMID- 23990364 TI - Relationship of glycated albumin to blood glucose and HbA1c values and to retinopathy, nephropathy, and cardiovascular outcomes in the DCCT/EDIC study. AB - The association of chronic glycemia, measured by HbA(1c), with long-term complications of type 1 diabetes has been well established in the Diabetes Control and Complications Trial (DCCT) and other studies. The role of intermediate-term and acute glycemia and of glucose variability on microvascular and cardiovascular disease (CVD) is less clear. In order to examine the interrelationships among long-term, intermediate-term, and acute measures of glucose and its daily variability, we compared HbA(1c), glycated albumin (GA), and seven-point glucose profile concentrations measured longitudinally in a case cohort subpopulation of the DCCT. HbA(1c) and GA were closely correlated with each other and with the mean blood glucose (MBG) calculated from the seven-point profile. The associations of glucose variability and postprandial concentrations with HbA(1c) and GA were relatively weak and were further attenuated when MBG was included in multivariate models. In the case-cohort analyses, HbA(1c) and GA had similar associations with retinopathy and nephropathy, which were strengthened when both measures were considered together. Only HbA(1c) was significantly associated with CVD. The demonstrated interrelationships among different measures of glycemia will need to be considered in future analyses of their roles in the development of long-term complications of type 1 diabetes. PMID- 23990365 TI - Glucose-6-phosphate-mediated activation of liver glycogen synthase plays a key role in hepatic glycogen synthesis. AB - The liver responds to an increase in blood glucose levels in the postprandial state by uptake of glucose and conversion to glycogen. Liver glycogen synthase (GYS2), a key enzyme in glycogen synthesis, is controlled by a complex interplay between the allosteric activator glucose-6-phosphate (G6P) and reversible phosphorylation through glycogen synthase kinase-3 and the glycogen-associated form of protein phosphatase 1. Here, we initially performed mutagenesis analysis and identified a key residue (Arg(582)) required for activation of GYS2 by G6P. We then used GYS2 Arg(582)Ala knockin (+/R582A) mice in which G6P-mediated GYS2 activation had been profoundly impaired (60-70%), while sparing regulation through reversible phosphorylation. R582A mutant-expressing hepatocytes showed significantly reduced glycogen synthesis with glucose and insulin or glucokinase activator, which resulted in channeling glucose/G6P toward glycolysis and lipid synthesis. GYS2(+/R582A) mice were modestly glucose intolerant and displayed significantly reduced glycogen accumulation with feeding or glucose load in vivo. These data show that G6P-mediated activation of GYS2 plays a key role in controlling glycogen synthesis and hepatic glucose-G6P flux control and thus whole-body glucose homeostasis. PMID- 23990366 TI - Breast lesions with high signal intensity on T1-weighted MR images. AB - Magnetic resonance imaging of the breast supplies much information concerning the signal characteristics of a lesion. Among these, high signal intensity on non-fat saturated T1-weighted imaging (WI) is a special finding. Such a finding may result from different causes, such as a paramagnetic substance or fatty, bloody or proteinaceous content. In this article, we present hyperintense breast lesions on T1-WI. PMID- 23990367 TI - Imaging findings of parapharyngeal space pleomorphic adenoma in comparison with parotid gland pleomorphic adenoma. AB - PURPOSE: The purpose of this study was to assess imaging findings of parapharyngeal space (PPS) pleomorphic adenoma (PA) in comparison with parotid gland (PG) PA retrospectively. MATERIALS AND METHODS: Ten patients with PPS PAs and 66 with PG PAs were included. CT and MR images were reviewed for the size, presence of calcification or cystic degeneration, and MR signal intensity of solid components. RESULTS: The maximum diameter was greater in PPS PA (57.3 +/- 11.4 mm) than in PG PA (28.7 +/- 20.8 mm) (p < 0.01). The frequency of calcification was higher in PPS PA (50 %) than in PG PA (15 %) (p < 0.05). The frequency of cystic degeneration was marginally higher in PPS PA (60 %) than in PG PA (29 %) (p = 0.058). On T2-weighted images, solid components of PPS and PG PAs showed hyperintensity in 40 and 54 %, isointensity in 50 and 32 %, and hypointensity in 10 and 14 %, respectively. CONCLUSION: The size and the frequency of calcification or cystic degeneration were higher in PPS PAs than in PG PAs. Radiologists should recognize the difference in imaging features between PPS and PG PAs. PMID- 23990368 TI - A novel adenoviral vector-mediated mouse model of Charcot-Marie-Tooth type 2D (CMT2D). AB - Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS. Here, we report a novel GARS-associated mouse neuropathy model using an adenoviral vector system that contains a neuronal-specific promoter. In this model, we found that wild-type GARS is distributed to peripheral axons, dorsal root ganglion (DRG) cell bodies, central axon terminals, and motor neuron cell bodies. In contrast, GARS containing a G240R mutation was localized in DRG and motor neuron cell bodies, but not axonal regions, in vivo. Thus, our data suggest that the disease-causing G240R mutation may result in a distribution defect of GARS in peripheral nerves in vivo. Furthermore, a distributional defect may be associated with axonal degradation in GARS-associated neuropathies. PMID- 23990369 TI - A Novel Subgenotype of Torque teno Virus 1 (TTSuV1) in Slaughter Pigs in China. AB - TTsuV1 can cause persistent infection and unidentified clinical signs in pigs. In this study, a survey of TTsuV1 prevalence was conducted in slaughter pigs from Henan, Liaoning, and Shandong provinces in China. A total of 180 swine lymphoid tissues were assayed by PCR with primers targeting the conserved 5'-untranslated region (5'-UTR). The results showed that a 17.8 % positive rate, and different genotypes were detected. TTSuV1 presented higher viral load and prevalence in inguinal lymph node than in submandibular lymph node samples. All TTsuV1 isolates have 84-100 % nucleotide sequence homology in the 5'-UTR region and can be grouped into three subgenotypes (TTsuV1a-1, TTsuV1a-2, and TTsuV1b). Notably, the novel genetic subtype TTsuV1b was first reported in slaughter pigs. PMID- 23990370 TI - International conference on "Photosynthesis research for sustainability-2013: in honor of Jalal A. Aliyev", held during June 5-9, 2013, Baku, Azerbaijan. AB - In this brief report, we provide a pictorial essay on an international conference "Photosynthesis Research for Sustainability-2013 in honor of Jalal A. Aliyev" that was held in Baku, Azerbaijan, during June 5-9, 2013 ( http://photosynthesis2013.cellreg.org/ ). We begin this report with a brief note on Jalal Aliyev, the honored scientist, and on John Walker (1997 Nobel laureate in Chemistry) who was a distinguished guest and lecturer at the Conference. We briefly describe the Conference, and the program. In addition to the excellent scientific program, a special feature of the Conference was the presentation of awards to nine outstanding young investigators; they are recognized in this report. We have also included several photographs to show the pleasant ambience at this conference. (See http://photosynthesis2013.cellreg.org/Photo-Gallery.php ; https://www.dropbox.com/sh/qcr124dajwffwh6/TlcHBvFu4H?m ; and https://www.copy.com/s/UDlxb9fgFXG9/Baku for more photographs taken by the authors as well as by others.) We invite the readers to the next conferences on "Photosynthesis Research for Sustainability-2014: in honor of Vladimir A. Shuvalov" to be held during June 2-7, 2014, in Pushchino, Russia. Detailed information for this will be posted at the Website: http://photosynthesis2014.cellreg.org/ , and for the subsequent conference on "Photosynthesis Research for Sustainability-2015" to be held in May or June 2015, in Baku, Azerbaijan, at http://photosynthesis2015.cellreg.org/ . PMID- 23990371 TI - Regulation of the carbon-concentrating mechanism in the cyanobacterium Synechocystis sp. PCC6803 in response to changing light intensity and inorganic carbon availability. AB - Photosynthetic organisms possess regulatory mechanisms to balance the various inputs of photosynthesis in a manner that minimizes over-excitation of the light driven electron transfer apparatus, while maximizing the reductive assimilation of inorganic nutrients, most importantly inorganic carbon (Ci). Accordingly, the regulatory interactions coordinating responses to fluctuating light and responses to Ci availability are of fundamental significance. The inducible high affinity carbon-concentrating mechanism (CCM) in the cyanobacterium Synechocystis sp. PCC6803 has been studied in order to understand how it is integrated with the light and dark reactions of photosynthesis. To probe genetic regulatory mechanisms, genomic DNA microarrays were used to survey for differences in the expression of genes in response to a shift to high light conditions under conditions of either high or low Ci availability. Discrepancies in published experiments exist regarding the extent to which genes for the CCM are upregulated in response to high light treatment. These discrepancies may be due to critical differences in Ci availability existing during the different high light experiments. The present microarray experiments reexamine this by comparing high light treatment under two different Ci regimes: bubbling with air and bubbling with air enriched with CO2. While some transcriptional responses such as the downregulation of antenna proteins are quite similar, pronounced differences exist with respect to the differential expression of CCM and affiliated genes. The results are discussed in the context of a recent analysis revealing that small molecules that are intermediates of the light and dark reaction photosynthetic metabolism act as allosteric effectors of the DNA-binding proteins which modulate the expression of the CCM genes. PMID- 23990372 TI - Special issues on Photosynthesis Education honoring Govindjee. PMID- 23990373 TI - Endometrial resection and ablation techniques for heavy menstrual bleeding. AB - BACKGROUND: Heavy menstrual bleeding (HMB) is a significant health problem in premenopausal women; it can reduce their quality of life and cause anaemia. First line therapy has traditionally been medical therapy but this is frequently ineffective. On the other hand, hysterectomy is obviously 100% effective in stopping bleeding but is more costly and can cause severe complications. Endometrial ablation is less invasive and preserves the uterus, although long term studies have found that the costs of ablative surgery approach the cost of hysterectomy due to the requirement for repeat procedures. A large number of techniques have been developed to 'ablate' (remove) the lining of the endometrium. The gold standard techniques (laser, transcervical resection of the endometrium and rollerball) require visualisation of the uterus with a hysteroscope and, although safe, require skilled surgeons. A number of newer techniques have recently been developed, most of which are less time consuming. However, hysteroscopy may still be required as part of the ablative techniques and some of these techniques must be considered to be still under development, requiring refinement and investigation. OBJECTIVES: To compare the efficacy, safety and acceptability of of endometrial destruction techniques to reduce heavy menstrual bleeding (HMB) in premenopausal women. SEARCH METHODS: We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials CENTRAL), MEDLINE, EMBASE, CINAHL, and PsycInfo, (from inception to June 2013). We also searched trials registers, other sources of unpublished or grey literature and reference lists of retrieved studies, and made contact with experts in the field and pharmaceutical companies that manufacture ablation devices. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing different endometrial ablation techniques in women with a complaint of HMB without uterine pathology were eligible. The outcomes included reduction of HMB, improvement in quality of life, operative outcomes, satisfaction with the outcome, complications and need for further surgery or hysterectomy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trials for risk of bias and extracted data. Attempts were made to contact authors for clarification of data in some trials. Adverse events were only assessed if they were separately measured in the included trials. Comparisons were made with individual techniques and an overall comparison between first and second-generation ablation methods was also undertaken. MAIN RESULTS: Twenty five trials (4040 women) with sample sizes ranging from 20 to 372 were included in the review. A majority of the trials had a specified method of randomisation, adequate description of dropouts and no evidence of selective reporting. Less than half had adequate allocation concealment and most were unblinded.There was insufficient evidence to suggest superiority of a particular technique in the pairwise comparisons between individual ablation and resection methods.In the overall comparison of the newer 'blind' techniques (second-generation) with the gold standard hysteroscopic ablative techniques (first-generation) there was no evidence of overall differences in the improvement in HMB (12 RCTs) or patient satisfaction (11 RCTs).Surgery was an average of 15 minutes shorter (mean difference (MD) 14.9, 95% CI 10.1 to 19.7, 9 RCTs; low quality evidence), local anaesthesia was more likely to be employed (relative risk (RR) 2.8, 95% CI 1.8 to 4.4, 6 RCTs; low quality evidence) and equipment failure was more likely (RR 4.3, 95% CI 1.5 to 12.4, 3 RCTs; moderate quality evidence) with second-generation ablation. Women undergoing newer (second-generation) ablative procedures were less likely to have fluid overload, uterine perforation, cervical lacerations and hematometra than women undergoing the more traditional type of ablation and resection techniques (RR 0.18, 95% CI 0.04 to 0.79, 4 RCTs; RR 0.32, 95% CI 0.1 to 1.0, 8 RCTs; RR 0.22, 95% CI 0.08 to 0.61, 8 RCTs; and RR 0.32, 95% CI 0.12 to 0.85, 5 RCTs; all moderate quality evidence, respectively). However, women were more likely to have nausea and vomiting and uterine cramping (RR 2.0, 95% CI 1.3 to 3.0, 4 RCTs; and RR 1.2, 95% CI 1.0 to 1.4, 2 RCTs; both moderate quality evidence, respectively). The risk of requiring either further surgery of any kind or hysterectomy specifically was reduced with second-generation ablative methods compared to first-generation ablation up to 10 years after surgery (RR 0.69, 95% CI 0.48 to 0.99, 1 RCT; and RR 0.60, 95% CI 0.38 to 0.96, 1 RCT; both moderate quality evidence, respectively) but not at earlier follow up. Additional research is required to confirm this finding. AUTHORS' CONCLUSIONS: Endometrial ablation techniques offer a less invasive surgical alternative to hysterectomy. The rapid development of a number of new methods of endometrial destruction has made systematic comparisons between individual methods and with the 'gold standard' first-generation techniques difficult. Most of the newer techniques are technically easier to perform than traditional hysteroscopy-based methods but technical difficulties with the new equipment need to be addressed. Overall, the existing evidence suggests that success, satisfaction rates and complication profiles of newer techniques of ablation compare favourably with hysteroscopic techniques. PMID- 23990374 TI - Wnt signaling through the Ror receptor in the nervous system. AB - The receptor tyrosine kinase-like orphan receptor (Ror) proteins are conserved tyrosine kinase receptors that play roles in a variety of cellular processes that pattern tissues and organs during vertebrate and invertebrate development. Ror signaling is required for skeleton and neuronal development and modulates cell migration, cell polarity, and convergent extension. Ror has also been implicated in two human skeletal disorders, brachydactyly type B and Robinow syndrome. Rors are widely expressed during metazoan development including domains in the nervous system. Here, we review recent progress in understanding the roles of the Ror receptors in neuronal migration, axonal pruning, axon guidance, and synaptic plasticity. The processes by which Ror signaling execute these diverse roles are still largely unknown, but they likely converge on cytoskeletal remodeling. In multiple species, Rors have been shown to act as Wnt receptors signaling via novel non-canonical Wnt pathways mediated in some tissues by the adapter protein disheveled and the non-receptor tyrosine kinase Src. Rors can either activate or repress Wnt target expression depending on the cellular context and can also modulate signal transduction by sequestering Wnt ligands away from their signaling receptors. Future challenges include the identification of signaling components of the Ror pathways and bettering our understanding of the roles of these pleiotropic receptors in patterning the nervous system. PMID- 23990375 TI - Acute brain inflammation and oxidative damage are related to long-term cognitive deficits and markers of neurodegeneration in sepsis-survivor rats. AB - Survivors from sepsis present long-term cognitive deficits and some of these alterations resemble the pathophysiological mechanisms of neurodegenerative diseases. For this reason, we analyzed beta-amyloid peptide (Abeta) and synaptophysin levels in the brain of rats that survived from sepsis and their relation to cognitive dysfunction and to acute brain inflammation. Sepsis was induced in rats by cecal ligation and puncture, and 30 days after surgery, the hippocampus and prefrontal cortex were isolated just after cognitive evaluation by the inhibitory avoidance test. The immunocontent of Abeta and synaptophysin were analyzed by Western blot analysis. Abeta increased and synaptophysin decreased in septic animals both in the hippocampus and prefrontal cortex concurrent with the presence of cognitive deficits. Prefrontal levels of synaptophysin correlated to the performance in the inhibitory avoidance. Two different treatments known to decrease brain inflammation and oxidative stress when administered at the acute phase of sepsis decreased Abeta levels both in the prefrontal cortex and hippocampus, increased synaptophysin levels only in the prefrontal cortex, and improved cognitive deficit in sepsis-survivor animals. In conclusion, we demonstrated that brain from sepsis-survivor animals presented an increase in Abeta content and a decrease in synaptophysin levels and cognitive impairment. These alterations can be prevented by treatments aimed to decrease acute brain inflammation and oxidative stress. PMID- 23990376 TI - Inflammation: therapeutic targets for diabetic neuropathy. AB - There are still no approved treatments for the prevention or of cure of diabetic neuropathy, and only symptomatic pain therapies of variable efficacy are available. Inflammation is a cardinal pathogenic mechanism of diabetic neuropathy. The relationships between inflammation and the development of diabetic neuropathy involve complex molecular networks and processes. Herein, we review the key inflammatory molecules (inflammatory cytokines, adhesion molecules, chemokines) and pathways (nuclear factor kappa B, JUN N-terminal kinase) implicated in the development and progression of diabetic neuropathy. Advances in the understanding of the roles of these key inflammatory molecules and pathways in diabetic neuropathy will facilitate the discovery of the potential of anti-inflammatory approaches for the inhibition of the development of neuropathy. Specifically, many anti-inflammatory drugs significantly inhibit the development of different aspects of diabetic neuropathy in animal models and clinical trials. PMID- 23990378 TI - Night-time symptoms and their impact on sleep in patients with gastroesophageal reflux disease who have a partial response to proton pump inhibitors: a qualitative patient interview study. AB - BACKGROUND: Limited data exists about night-time symptoms that are generated directly from patients with gastroesophageal reflux disease (GERD) who have a partial response to proton pump inhibitor (PPI) therapy. This information is needed to select an appropriate instrument in studies in this patient population. OBJECTIVE: The objective of this qualitative interview study was to gain understanding of the night-time symptoms of patients with GERD who had a partial response to PPIs. The specific aims were (i) to evaluate whether GERD symptoms experienced during the night differ from those occurring during the day; and (ii) to understand the impact of night-time symptoms on sleep and next-day functioning. METHODS: Four US sites participated in this study of patients with GERD who, despite PPI therapy for at least 4 weeks, still experienced both daytime and night-time heartburn and/or regurgitation. Non-responders to PPIs were excluded. Patient statements were coded and grouped by concept. RESULTS: Twenty-nine patients were enrolled. The predominant and most troublesome symptoms during both the day and night were heartburn and regurgitation. At night-time only, expressions describing regurgitation were more frequent than those describing heartburn (62 vs. 26 %). During the daytime only, expressions describing regurgitation and heartburn occurred with similar frequency (21 vs. 27 %). Patients experienced greater severity of heartburn and regurgitation at night than during the day, and the difference was more pronounced for regurgitation. Patients focused on symptom frequency during the day but on symptom severity at night. Of expressions about the impact of night-time GERD symptoms, 46 % described impact on sleep and 41 % described compensatory behaviors when woken up by symptoms. Next-day impacts of night-time symptoms predominantly included changes in diet (53 %). CONCLUSIONS: Partial responders to PPI therapy experience similar GERD symptoms at night and during the day. However, regurgitation is more predominant at night than during the day, and at night patients focus more on symptom severity than symptom frequency. PMID- 23990377 TI - Introduction to deep sequencing and its application to drug addiction research with a focus on rare variants. AB - Through linkage analysis, candidate gene approach, and genome-wide association studies (GWAS), many genetic susceptibility factors for substance dependence have been discovered such as the alcohol dehydrogenase gene (ALDH2) for alcohol dependence (AD) and nicotinic acetylcholine receptor (nAChR) subunit variants on chromosomes 8 and 15 for nicotine dependence (ND). However, these confirmed genetic factors contribute only a small portion of the heritability responsible for each addiction. Among many potential factors, rare variants in those identified and unidentified susceptibility genes are supposed to contribute greatly to the missing heritability. Several studies focusing on rare variants have been conducted by taking advantage of next-generation sequencing technologies, which revealed that some rare variants of nAChR subunits are associated with ND in both genetic and functional studies. However, these studies investigated variants for only a small number of genes and need to be expanded to broad regions/genes in a larger population. This review presents an update on recently developed methods for rare-variant identification and association analysis and on studies focused on rare-variant discovery and function related to addictions. PMID- 23990379 TI - Construct an optimal triage prediction model: a case study of the emergency department of a teaching hospital in Taiwan. AB - The purpose of triage is to prevent the delay of treatment for patients in real emergencies due to excessive numbers of patients in the hospital. This study uses the data of patients of consistent triage to develop the triage prediction model. By integrating Principal Component Analysis (PCA) and Support Vector Machine (SVM), the anomaly detection (overestimate and underestimate) prediction accuracy rate can be 100%, which is better than the accuracy rate of SVM (about 89.2%) or Back- propagation Neural Networks (BPNN) (96.71%); afterwards, this study uses Support Vector Regression (SVR) to adopt Genetic Algorithm (GA) to determine three SVR parameters to predict triage. After using the scroll data predictive values, we calculate the Absolute Percentage Error (APE) of each scroll data. The resulting SVR's Mean Absolute Percentage Error (MAPE) is 3.78%, and BPNN's MAPE is 5.99%; therefore, the proposed triage prediction model of this study can effectively predict anomaly detection and triage. PMID- 23990380 TI - Non-steroidal anti-inflammatory drug use and brain tumour risk: a case-control study within the Clinical Practice Research Datalink. AB - PURPOSE: The aetiology of primary brain tumours is largely unknown; the role of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin use and glioma risk has been inconclusive, but few population-based studies with reliable prescribing data have been conducted, and the association with meningioma risk has yet to be assessed. METHODS: The UK Clinical Practice Research Datalink was used to assess the association between aspirin and non-aspirin NSAID use and primary brain tumour risk using a nested case-control study design. Conditional logistic regression analysis was performed on 5,052 brain tumour patients aged 16 years and over, diagnosed between 1987 and 2009 and 42,678 controls matched on year of birth, gender and general practice, adjusting for history of allergy and hormone replacement therapy use in the glioma and meningioma models, respectively. RESULTS: In conditional logistic regression analysis, excluding drug use in the year preceding the index date, there was no association with non-aspirin NSAID use (OR 0.96, 95 % CI 0.81-1.13) or glioma risk comparing the highest category of daily defined dose to non-users; however, non-aspirin NSAID use was positively associated with meningioma risk (OR 1.35, 95 % CI 1.06-1.71). No association was seen with high- or low-dose aspirin use irrespective of histology. CONCLUSIONS: This large nested case-control study finds no association between aspirin or non aspirin NSAID use and risk of glioma but a slight increased risk with non-aspirin NSAIDs and meningioma. PMID- 23990381 TI - Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. AB - BACKGROUND: Rebleeding is an important cause of death and disability in people with aneurysmal subarachnoid haemorrhage. Rebleeding is probably related to dissolution of the blood clot at the site of aneurysm rupture by natural fibrinolytic activity. This review is an update of a previously published Cochrane review. OBJECTIVES: To assess the effects of antifibrinolytic treatment in people with aneurysmal subarachnoid haemorrhage. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1948 to December 2012), and EMBASE (1947 to December 2012). In an effort to identify further published, unpublished, and ongoing studies we searched reference lists and trial registers, performed forward tracking of relevant references and contacted drug companies. SELECTION CRITERIA: Randomised trials comparing oral or intravenous antifibrinolytic drugs (tranexamic acid, epsilon amino-caproic acid, or an equivalent) with control in people with subarachnoid haemorrhage of suspected or proven aneurysmal cause. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted the data. Three review authors assessed trial quality. For the primary outcome we converted the outcome scales between good and poor outcome for the analysis. We scored death from any cause and rates of rebleeding, cerebral ischaemia, and hydrocephalus per treatment group. We expressed effects as risk ratios (RR) with 95% confidence intervals (CI). We used random-effects models for all analyses. MAIN RESULTS: We included 10 trials involving 1904 participants. The risk of bias was low in six studies. Four studies were open label and were rated as high risk of performance bias. One of these studies was also rated as high risk for attrition bias. Four trials reported on poor outcome (death, vegetative state, or severe disability) with a pooled risk ratio (RR) of 1.02 (95% confidence interval (CI) 0.91 to 1.15). All trials reported on death from all causes with a pooled RR of 1.00 (95% CI 0.85 to 1.18). In a trial that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for cerebral ischaemia the RR for poor outcome was 0.85 (95% CI 0.64 to 1.14). Antifibrinolytic treatment reduced the risk of re-bleeding reported at the end of follow-up (RR 0.65, 95% CI 0.44 to 0.97; 78 per 1000 participants), but there was heterogeneity (I2 = 62%) between the trials. The pooled RR for reported cerebral ischaemia was 1.41 (95% CI 1.04 to 1.91, 83 per 1000 participants), again with heterogeneity between the trials (I2 = 52%). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus in five trials (RR 1.11, 95% CI 0.90 to 1.36). AUTHORS' CONCLUSIONS: The current evidence does not support the use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage, even in those who have concomitant treatment strategies to prevent cerebral ischaemia. Results on short-term treatment are promising, but not conclusive. Further randomised trials evaluating short-term antifibrinolytic treatment are needed to evaluate its effectiveness. PMID- 23990382 TI - Origin of the dorsal scapular artery and its relation to the brachial plexus in Thais. AB - We investigated the variations of the origin of the dorsal scapular artery (DSA) and its relation to the brachial plexus in 252 sides of the posterior cervical triangles of Thais. The origin of this artery on each part of the subclavian artery or other arterial branches was examined with special reference to their course in relation to the brachial plexus. The results show that the DSA originated from three sites; most commonly from the transverse cervical artery (69%) followed by the direct branching from the second (2.8%) or the third part (28.2%) of the subclavian artery. When the DSA was branched from the transverse cervical artery, its course was always posterior or above the brachial plexus. When the DSA arose from the second or the third part of the subclavian artery, it always ran in the branches of the brachial plexus in various sites. The most frequent course was to pass between the upper and middle trunks of the brachial plexus (63.2%). Other courses were far less frequent and found to pass between the anterior division of the upper trunk and the middle trunk of brachial plexus or between the roots of C8 and T1 with the frequency of 1.3 and 2.6%, respectively. PMID- 23990383 TI - Acute promyelocytic leukemia: do we have a new front-line standard of treatment? AB - Since the introduction of all-trans retinoic acid, the use of this molecularly targeted treatment in combination with anthracycline-based chemotherapy has completely changed the prognosis of acute promyelocytic leukemia, turning it into the most curable myeloid leukemia. Also, the use of risk-adapted protocols has contributed to optimizing the drug combination and the most appropriate dose intensity for each subset of patients classified according to both the risk of relapse and vulnerability to drug toxicity. Recent developments have included the investigation of the role of arsenic trioxide as front-line treatment after its success in treating relapsed APL, both to minimize or even omit the use of cytotoxic agents and to improve the outcome of the conventional chemotherapy based approach. In this review, we discuss the current treatment approach for acute promyelocytic leukemia in newly diagnosed patients, particularly taking into account the latest developments with the use of the arsenic trioxide based regimen as targeted first-line treatment without chemotherapy. PMID- 23990384 TI - Croton antisyphiliticus Mart. attenuates the inflammatory response to carrageenan induced pleurisy in mice. AB - The aim of this study was to investigate the anti-inflammatory effect of the crude hydroalcoholic extract (CHE) from the aerial parts of Croton antisyphiliticus, its fractions and isolated compounds derived from it on the mouse model of pleurisy induced by carrageenan. The aerial parts of C. antisyphiliticus were dried, macerated and extracted with ethanol to obtain the CHE, which was fractionated by liquid-liquid extraction using solvents with increasing polarity to obtain hexane (Hex), ethyl acetate (EA) and aqueous (Aq) fractions. Vitexin and quinic acid were isolated from Aq fraction. Capillary electrophoresis analysis, physical characteristics and spectral data produced by infrared (IR), nuclear magnetic resonance ((1)H and (13)C NMR) and mass spectrometry analyses were used to identify and elucidate the structure of the isolated compounds. The experimental model of pleurisy was induced in mice by a single intrapleural injection of carrageenan (1 %). Leukocytes, exudate concentrations, myeloperoxidase (MPO) and adenosine-deaminase (ADA) activities and nitrate/nitrite (NOx), tumor necrosis factor-alpha (TNF-alpha) and interleukin-17 (IL-17) levels were determined in the pleural fluid leakage at 4 h after pleurisy induction. Animals pre-treated with CHE, Hex, EA, Aq, vitexin and quinic acid exhibited decreases in leukocytes, exudate concentrations, MPO and ADA activities and NOx levels (p < 0.05). Also CHE, Hex, EA and vitexin but not quinic acid inhibited TNF-alpha and IL-17 levels (p < 0.05). C. antisyphiliticus caused anti-inflammatory effect by inhibiting the activated leukocytes, exudate concentrations, NOx, TNF-alpha, and IL-17 levels. The compounds vitexin and quinic acid may be responsible for this anti-inflammatory action. PMID- 23990385 TI - Establishment and biological characteristics comparison of Chinese swamp buffalo (Bubalus bubalis) fibroblast cell lines. AB - To establish fibroblast cell lines from different tissues and to compare the biological characteristics of those cell lines, five fibroblast cell lines derived from Chinese swamp buffalo (Bubalus bubalis) were selected for comparative assays. Cell style and survival rate (before cryogenic preservation and after recovery) were tested, and karyotype, patterns of isoenzymes of lactic dehydrogenase, malic dehydrogenase, and cell cycle were analyzed. These cell lines had a healthy morphology with a typical spindle shape, and assessment of cell style showed these cells to be very pure fibroblasts. Cell growth curves showed a typical "S" shape. Results of microorganism contamination assays were negative, and isoenzyme analysis showed no cross-contamination. The number of chromosomes (2n) of swamp buffalo is 48. Between 28% and 46% of the cells were 2n, and cell apoptosis was not pronounced at 20th generation. Results showed that skin fibroblasts were more adaptable to tissue culture conditions than the ones from kidneys and ear margin, and they are more suitable for cellular manipulation in Chinese swamp buffalo. PMID- 23990386 TI - Differential effects of hypoxic and hyperoxic stress-induced hypertrophy in cultured chick fetal cardiac myocytes. AB - The adult heart responds to contraction demands by hypertrophy, or enlargement, of cardiac myocytes. Adaptive hypertrophy can occur in response to hyperoxic conditions such as exercise, while pathological factors that result in hypoxia ultimately result in heart failure. The difference in the outcomes produced by pathologically versus physiologically induced hypertrophy suggests that the cellular signaling pathways or conditions of myocytes may be different at the cellular level. The structural and functional changes in myocytes resulting from hyperoxia (simulated using hydrogen peroxide) and hypoxia (using oxygen deprivation) were tested on fetal chick cardiac myocytes grown in vitro. Structural changes were measured using immunostaining for alpha-sarcomeric actin or MyoD, while functional changes were assessed using immunostaining for calcium/calmodulin-dependent kinase (CaMKII) and by measuring intracellular calcium fluxes using live cell fluorescence imaging. Both hypoxic and hyperoxic stress resulted in an upregulation of actin and MyoD expression. Similarly, voltage-gated channels governing myocyte depolarization and the regulation of CaMK were unchanged by hyperoxic or hypoxic conditions. However, the dynamic features of calcium fluxes elicited by caffeine or epinephrine were different in cells subjected to hypoxia versus hyperoxia, suggesting that these different conditions differentially affect components of ligand-activated signaling pathways that regulate calcium. Our results suggest that changes in signaling pathways, rather than structural organization, may mediate the different outcomes associated with hyperoxia-induced versus hypoxia-induced hypertrophy, and these changes are likely initiated at the cellular level. PMID- 23990387 TI - Pea protein provides a promising matrix for microencapsulating iron. AB - Worldwide, the most prevalent nutritional deficiency is iron. The strategies for iron supplementation often fail due to poor adherence to supplementation methods contributed to unpleasant sensory characteristics. An alternative is the use of microencapsulated nutrients for home fortification in order to mask undesirable tastes and to allow its release in strategic sites of the gastrointestinal tract. Toward this end, pea protein concentrate was tested as a natural, edible and alternative material and the spray-drying technique was utilized for the preparation of microparticles containing ferrous sulfate. Their physical and chemical characteristics were evaluated. The microparticles had a spherical shape and grooves with an average size ranging between 2 and 3 MUm. Analysis by in vitro assays tested the release of iron in simulated salivary and gastric fluids and its intestinal absorption in Caco-2 cells. No dissolution of iron occurred in the salivary medium whereas the sensory analysis showed good acceptance of a product which incorporated 5.5 mg of iron per 100 g portion of food. Thus, the effectiveness of microencapsulation was demonstrated by utilizing a plant protein as an encapsulating matrix for the controlled release of iron and capable of preserving the bioaccessibility of ferrous sulfate. PMID- 23990388 TI - Psychological morbidity in children undergoing chemotherapy for acute lymphoblastic leukemia. AB - Diagnosis of leukemia causes severe stress in the child and family. Present work was carried out to study emotional and behavioral problems in children with acute lymphoblastic leukemia (ALL) undergoing chemotherapy. Psychopathology was assessed using childhood psychopathology measurement schedule (CPMS) in three groups of children aged 6-14 y: ALL, non-oncologic chronic disease (bronchial asthma) and minor ailment (control). Mean CPMS score in ALL group was 8.76 +/- 4.66 (range 1-20); in asthma group 5.72 +/- 3.13 (range 2-14) and 5.44 +/- 3.37 (range 1-13) in control group (p < 0.01). Fourteen of 40 (35.0 %) children with ALL had a CPMS score of >=10 as against 11 of 50 (22.0 %) in the chronic disease group. Children with ALL scored higher on the conduct disorder, depression and physical illness with emotional problems. Older age (10-14 y) and male gender had significant correlation with depression. Male children also had more conduct disorders. PMID- 23990389 TI - A person trade-off study to estimate age-related weights for health gains in economic evaluation. AB - BACKGROUND: An increasing body of literature is exploring whether the age of the recipient of health care should be a criterion in how health care resources are allocated. The existing literature is constrained both by the relatively small number of age comparison groups within preference-elicitation studies, and by a paucity of methodological robustness tests for order and framing effects and the reliability and transitivity of preferences that would strengthen confidence in the results. This paper reports the results of a study aimed at estimating granulated age-related weights for health gains across the age spectrum that can potentially inform health care decision-making. METHODS: A sample of 2,500 participants recruited from the health care consumer panels of a social research company completed a person trade-off (or 'matching') study designed to estimate age-related weights for 5- and 10-year life extensions. The results are presented in terms of matrices for alternative age comparisons across the age spectrum. RESULTS: The results revealed a general, although not invariable, tendency to give more weight to health gains, expressed in terms of life extensions, in younger age groups. In over 85% of age comparisons, the person trade-off exercises revealed a preference for life extensions by the younger of the two age groups that were compared. This pattern held regardless of the method of aggregating responses across study participants. Moreover, the relative weight placed on life extensions by the younger of the two age groups was generally, although not invariably, found to increase as the age difference between the comparator age groups increased. Further analyses revealed that the highest mean relative weight placed on life extensions was estimated for 30-year-olds when the ratio of means method was used to aggregate person trade-off responses across study participants. The highest mean relative weight placed on life extensions was estimated for 10-year-olds for 5-year life extensions and for 30-year-olds for 10-year life extensions, when the median of individual ratios method was used to aggregate person trade-off responses across study participants. Methodological tests framed around alternative referents in the person trade-off questions and the stability of preferences had no discernible effects on the study results. CONCLUSION: This study has produced new evidence on age-related weights for health gains that can potentially inform health care decision-making. PMID- 23990390 TI - The effect of iterative image reconstruction algorithms on the feasibility of automated plaque assessment in coronary CT angiography. AB - To evaluate the effect of adaptive statistical (ASIR) and model based (MBIR) iterative reconstruction algorithms on the feasibility of automated plaque assessment in coronary computed tomography angiography (CCTA) compared to filtered back projection reconstruction (FBPR) algorithm. Three ex vivo human donor hearts were imaged by CCTA and reconstructed with FBPR, ASIR and MBIR. Commercial plaque assessment software was applied for the automated delineation of the outer and inner vessel-wall boundaries. Manually corrections were performed where necessary and the percentages were compared between the reconstruction algorithms. In total 2,295 CCTA cross-sections with 0.5 mm increments were assessed (765 co-registered FBPR/ASIR/MBIR triplets). Any boundary corrections were performed in 31.0% of all cross-sections (N = 712). The percentage of corrected crosssections was lower for MBIR (24.1%) as compared to ASIR (32.4%, p = 0.0003) and FBPR (36.6%, p <0.0001), and marginal between ASIR/FBPR (p = 0.09). The benefit of MBIR over FBPR was associated with the presence of moderate and severe calcification (OR 2.9 and 5.7, p <0.0001; respectively). Using MBIR significantly reduced the need for vessel-wall boundary corrections compared to other reconstruction algorithms, particular at the site of calcifications. Thus, MBIR may improve the feasibility of automated plaque assessment in CCTA and potentially its clinical applicability. PMID- 23990391 TI - Physical conditioning as part of a return to work strategy to reduce sickness absence for workers with back pain. AB - BACKGROUND: Physical conditioning as part of a return to work strategy aims to improve work status for workers on sick leave due to back pain. This is the second update of a Cochrane Review (originally titled 'Work conditioning, work hardening and functional restoration for workers with back and neck pain') first published in 2003, updated in 2010, and updated again in 2013. OBJECTIVES: To assess the effectiveness of physical conditioning as part of a return to work strategy in reducing time lost from work and improving work status for workers with back pain. Further, to assess which aspects of physical conditioning are related to a faster return to work for workers with back pain. SEARCH METHODS: We searched the following databases to March 2012: CENTRAL, MEDLINE (from 1966), EMBASE (from 1980), CINAHL (from 1982), PsycINFO (from 1967), and PEDro. SELECTION CRITERIA: Randomized controlled trials (RCTs) and cluster RCTs that studied workers with work disability related to back pain and who were included in physical conditioning programmes. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included 41 articles reporting on 25 RCTs with 4404 participants. Risk of bias was low in 16 studies.Three studies involved workers with acute back pain, eight studies workers with subacute back pain, and 14 studies workers with chronic back pain.In 14 studies, physical conditioning as part of a return to work strategy was compared to usual care. The physical conditioning mostly consisted of graded activity with work-related exercises aimed at increasing back strength and flexibility, together with a set date for return to work. The programmes were divided into a light version with a maximum of five sessions, or an intense version with more than five sessions up to full time or as inpatient treatment.For acute back pain, there was low quality evidence that both light and intense physical conditioning programmes made little or no difference in sickness absence duration compared with care as usual at three to 12 months follow-up (3 studies with 340 workers).For subacute back pain, the evidence on the effectiveness of intense physical conditioning combined with care as usual compared to usual care alone was conflicting (four studies with 395 workers). However, subgroup analysis showed low quality evidence that if the intervention was executed at the workplace, or included a workplace visit, it may have reduced sickness absence duration at 12 months follow-up (3 studies with 283 workers; SMD -0.42, 95% CI -0.65 to -0.18).For chronic back pain, there was low quality evidence that physical conditioning as part of integrated care management in addition to usual care may have reduced sickness absence days compared to usual care at 12 months follow-up (1 study, 134 workers; SMD -4.42, 95% CI -5.06 to 3.79). What part of the integrated care management was most effective remained unclear. There was moderate quality evidence that intense physical conditioning probably reduced sickness absence duration only slightly compared with usual care at 12 months follow-up (5 studies, 1093 workers; SMD -0.23, 95% CI -0.42 to 0.03).Physical conditioning compared to exercise therapy showed conflicting results for workers with subacute and chronic back pain. Cognitive behavioural therapy was probably not superior to physical conditioning as an alternative or in addition to physical conditioning. AUTHORS' CONCLUSIONS: The effectiveness of physical conditioning as part of a return to work strategy in reducing sick leave for workers with back pain, compared to usual care or exercise therapy, remains uncertain. For workers with acute back pain, physical conditioning may have no effect on sickness absence duration. There is conflicting evidence regarding the reduction of sickness absence duration with intense physical conditioning versus usual care for workers with subacute back pain. It may be that including workplace visits or execution of the intervention at the workplace is the component that renders a physical conditioning programme effective. For workers with chronic back pain physical conditioning has a small effect on reducing sick leave compared to care as usual after 12 months follow-up. To what extent physical conditioning as part of integrated care management may alter the effect on sick leave for workers with chronic back pain needs further research. PMID- 23990392 TI - Methylene blue dye injection for identification of occult gastrointestinal bleeding. AB - The exact site of small bowel bleeding is difficult to detect intraoperatively. We present a simple method of on-table identification of the site of the bleed. A 55-year-old lady presented with recurrent episodes of melena and drop in hemoglobin. Digital subtraction angiography (DSA) revealed angiodysplasia of a vessel supplying the proximal jejunum. A microcatheter was placed at this site in the DSA suite, just prior to laparotomy. Two cubic centimeters of methylene blue dye was injected into the microcatheter on-table which demarcated the 6 in. of involved jejunum which was then resected. Patient is currently doing well over a 6-month follow up with no further episodes of melena. In conclusion, preoperative DSA and selective catheterization of the affected vessel allow for on-table localization of the exact site of bleed. This simple method avoids more invasive techniques of detection and enables limited segmental resection of the affected bowel. PMID- 23990393 TI - Effects of Ganfukang on expression of connective tissue growth factor and focal adhesion kinase/protein kinase B signal pathway in hepatic fibrosis rats. AB - OBJECTIVE: To investigate the effect of Ganfukang (GFK) on connective tissue growth factor (CTGF) and focal adhesion kinase (FAK)/protein kinase B (PKB or Akt) signal pathway in a hepatic fibrosis rat model and to explore the underlying therapeutic molecular mechanisms of GFK. METHODS: Fifty SD rats were randomly divided into five groups as follows: the control group, the model group (repeated subcutaneous injection of CCl4), and the three GFK treatment groups (31.25, 312.5, and 3125 mg/kg, intragastric administration). Reverse transcriptase polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry were used to examine the expression of CTGF, integrin alpha5, integrin beta1, FAK/Akt signal pathway, cyclinD1, and collagen in the different-treated rats. RESULTS: GFK attenuated the up-regulation of CTGF, integrin alpha5, and integrin beta1 in hepatic fibrosis rats and suppressed both the phosphorylation of FAK and the phosphorylation of Akt simultaneously (P<0.01). At the same time, the expression of cyclinD1, collagen I, and collagen III was decreased by GFK significantly (P<0.01). CONCLUSIONS: CTGF and FAK/Akt signal pathway were activated in the CCl4-induced hepatic fibrosis rats, which contribute to increased expression of cyclinD1 and collagen genes. The mechanisms of the anti fibrosis activity of GFK may be due to its effects against CTGF and FAk/Akt signal pathway. PMID- 23990394 TI - Metacognition: towards a new approach to quality of life. AB - PURPOSE: Recent studies have demonstrated that various diseases states (e.g., schizophrenia, Alzheimer's disease) and events (e.g., a stroke) alter a person's perception of their physical and mental status. Most often this involves alterations in a person's metacognitive capabilities, and this can question the conceptual model of quality of life (QoL) based on a "perspectivist" approach. METHODS: Using the example of schizophrenia, we applied a philosophical model, developed by Griffin, to deal with this potential threat to the validity of QoL assessment. RESULTS: Patients with schizophrenia are at risk for being impaired in their ability to assess their QoL. We hypothesise that metacognition (i.e., the ability to attribute mental states in terms of beliefs and goals to one's self and others) is a formal condition to assess QoL. This particular skill is important because self-reflection is necessary for making a qualitative judgment. A link between this psychological concept and the philosophical concept of reflexivity may be established. We propose a conceptual approach to QoL that takes into account the patient's reflexivity. This approach is derived from Griffin's theory based on the list of "prudential values" and the satisfaction of the informed desires of the individual. CONCLUSION: The ability of patients to evaluate and value their life should be considered to enrich the concept of QoL. The approach derived from Griffin's theory might constitute a new avenue for QoL research. PMID- 23990395 TI - Associations of cancer and other chronic medical conditions with SF-6D preference based scores in Medicare beneficiaries. AB - PURPOSE: Documenting the impact of different types of cancer on daily functioning and well-being is important for understanding burden relative to other chronic medical conditions. This study examined the impact of 10 different cancers and 13 other chronic medical conditions on health-related quality of life. METHODS: Health-related quality of life data were gathered on the Medicare Health Outcomes Survey (MHOS) between 1998 and 2002. Cancer information was ascertained using the National Cancer Institute's surveillance, epidemiology, and end results program and linked to MHOS data. RESULTS: The average SF-6D score was 0.73 (SD = 0.14). Depressive symptoms had the largest unique association with the SF-6D, followed by arthritis of the hip, chronic obstructive pulmonary disease/asthma, stroke, and sciatica. In addition, the majority of cancer types were significantly associated with the SF-6D score, with significant negative weights ranging from 0.01 to -0.02 on the 0-1 health utility scale. Distant stage of cancer was associated with large decrements in the SF-6D ranging from -0.04 (prostate) to 0.08 (female breast). CONCLUSION: A large number of chronic conditions, including cancer, are associated uniquely with decrements in health utility. The cumulative effects of comorbid conditions have substantial impact on daily functioning and well-being of Medicare beneficiaries. PMID- 23990396 TI - Recurrence of a functional adrenocortical oncocytoma of borderline malignant potential showing high FDG uptake on 18F-FDG PET/CT. AB - Adrenocortical oncocytoma is a very rare tumor, which is not malignant and nonfunctioning in most cases. We report a case of a 53-year-old male with a 9.8 cm sized hyperfunctioning, well-encapsulated adrenal mass, which exhibited by high FDG uptake on a PET/CT scan. The patient had complained of symptoms of Cushing's syndrome for 4 months. Laparoscopic adrenalectomy was performed and the mass was pathologically confirmed as adrenocortical oncocytoma of uncertain malignant potential. Four years after surgery, the tumor recurred with distant metastases, which was proven by subsequent biopsy. 18F-FDG PET/CT also showed hypermetabolism in the recurred tumor and multiple metastatic lesions. Adrenocortical oncocytoma of borderline malignant potential with high FDG uptake may require long-term follow-up with clinical, hormonal, and imaging evaluations. PMID- 23990397 TI - Novel Tc-99m labeled ELR-containing 6-mer peptides for tumor imaging in epidermoid carcinoma xenografts model: a pilot study. AB - OBJECTIVE: ELR-containing peptides targeting CXCR2 could be the excellent candidate for targeting ligand of molecular tumor imaging. In this study, we had developed two ELR-containing 6-mer peptides and evaluated the diagnostic performance of Tc-99m labeled 6-mer peptides as a molecular imaging agent in murine models bearing KB epidermoid carcinoma. METHODS: Peptides were synthesized using Fmoc solid phase peptide synthesis. Radiolabeling efficiency with Tc-99m was evaluated using instant thin-layer chromatography. In KB epidermoid cancer bearing mice, gamma images had acquired and tumor-to-muscle uptake ratio was calculated. Competition and biodistribution studies had performed. RESULTS: Two 6 mer peptides, ELR-ECG and ECG-ELR were successfully synthesized. After radiolabeling procedures with Tc-99m, the complex Tc-99m ELR-ECG and Tc-99m ECG ELR were prepared in high yield. In the gamma camera imaging of murine model, Tc 99m ELR-ECG was substantially accumulated in the subcutaneously engrafted tumor and tumor uptake had been suppressed by the free ELR co-injection. However, Tc 99m ECG-ELR was minimally accumulated in the tumor. CONCLUSIONS: Two ELR containing 6-mer peptides, ELR-ECG and ECG-ELR, were developed as a molecular imaging agent to target CXCR2 of epidermoid carcinoma. Tc-99m ELR-ECG had showed significant uptake in tumor and it was good candidate for a tumor imaging. PMID- 23990398 TI - Preadolescent drug use resistance skill profiles, substance use, and substance use prevention. AB - The aims of the current study were threefold: (1) specify the skills component of social influence prevention interventions for preadolescents, (2) examine the relationship between resistance skill profiles and substance use among preadolescents, and (3) evaluate whether subgroups of preadolescents based on their resistance skills and refusal confidence may be differentially impacted by the kiR prevention program. Latent class analysis showed a four-class model of 5th grader resistance skill profiles. Approximately half of preadolescents (53%) were familiar with four prototypical resistance skills and showed confidence to apply these skills in real-world settings (highly competent profile); 15% were familiar with resistance skills but had little confidence (skillful profile); 18% were confident yet had little knowledge (confident profile); while 15% had low knowledge and confidence (low competence profile). These skill profiles significantly predicted 8th grade recent substance use (2LL = -2,262.21, df = 3, p = .0005). As predicted by theory, the highly competent skill profile reported lower mean recent substance use than the population sample mean use. Latent transition analysis showed that although patterns of transiting into the highly competent skill profile over time were observed in the expected direction, this pattern was not significant when comparing treatment and control. Identifying skill profiles that predict recent substance use is theoretically consistent and has important implications for healthy and substance-free development. PMID- 23990399 TI - Polymorphism of HLA-B27: 105 subtypes currently known. AB - HLA-B27 has a high degree of genetic polymorphism, with 105 known subtypes, named HLA-B*27:01 to HLA-B*27:106, encoded by 132 alleles. The most common subtypes associated with ankylosing spondylitis are HLA-B*27:05 (Caucasians), HLA-B*27:04 (Chinese), and HLA-B*27:02 (Mediterranean populations). For Chinese populations, HLA-B*27:04 is associated with a greater ankylosing spondylitis risk than HLA B*27:05. Two subtypes, HLA-B27*06 and HLA-B27*09, seem to have no disease association. These differential disease associations of HLA-B27 subtypes, and the recent discovery that ERAP1 is associated with ankylosing spondylitis for patients with HLA-B27, have increased attempts to determine the function of HLA B27 in disease pathogenesis by studying hemodynamic features of its protein structure, alterations of its peptidome, aberrant peptide handling, and associated molecular events. However, after 40 years we still do not fully know how HLA-B27 predisposes to ankylosing spondylitis and related spondyloarthritis. PMID- 23990401 TI - Health needs assessment for congenital anomalies in middle-income countries: Examining the case for neural tube defects in Brazil. AB - Recent economic improvement in Brazil has been reflected in better maternal-child health indicators, with decreases in infant and perinatal mortality. However, under-five mortality due to congenital disorders remained unchanged, and congenital disorders have become the second leading cause of infant mortality. In the present study, we used the PHG Foundation Health Needs Assessment (HNA) Toolkit with the objective of first assessing the burden of disease caused by neural tube defects (NTDs) in Brazil and the impact of interventions already put in place to address the burden, and second to evaluate and prioritize further interventions and policies required for its prevention and treatment. The results from these two components of the HNA process are described in this paper. The published literature was reviewed to identify studies of NTDs (prevalence; morbidity; prenatal, perinatal, and postnatal mortality; treatment or prevention). Data on indicators of maternal and child health were obtained directly from the Brazilian Ministry of Health, through the online Live Births Information System (SINASC) and from the Mortality Information System (SIM). Descriptive analyses included reports of the rates of NTD in liveborns, fetal, and infant deaths. Differences between folic acid flour pre-fortification (2001 2004) and post-fortification (2006-2010) periods were expressed as prevalence rate ratios. Around 20 % of fetal deaths were related to congenital disorders with approximately 5 % of those being NTDs. For infant mortality, congenital disorders were notified in approximately 15 % of cases, with NTDs present in 10 % of the malformed children. Although statistically significant, the prevalence rate ratio (PRR) for spina bifida in live births was only 0.937 (95 % confidence interval (CI) 0.884-0.994), a decrease of 6.3 % when comparing the pre and post fortification periods. The impact of fortification seemed to be more visible in fetal deaths due to anencephaly (PRR = 0.727, 95 % CI 0.681-0.777) and for spina bifida (PRR = 0.700, 95 % CI 0.507-0.967) with associated decreases of 27.3 and 30 %. The lower impact of folic acid fortification in Brazil, compared to other Latin-American countries, can be due to differences in dietary habits, concentration of folic acid in flour, as well as characteristic population ethnic composition. The HNA led to the identification of the needs to be addressed in Brazil, including the improvement of reporting congenital disorders within the nationwide birth certification system, and revision of the policy of flour folic acid fortification. PMID- 23990400 TI - Assembly of adiponectin oligomers. AB - Adiponectin is among the most studied adipokines, the collection of molecules secreted from adipose tissue. It is also one of the most architecturally complex adipokines with its various oligomeric states that include trimers, hexamers, nonamers (9mers), dodecamers (12mers), and octadecamers (18mers). The importance of adiponectin in metabolic regulation is underscored by its strong positive associations with improvement in insulin action and also decreased risks for developing type 2 diabetes. Understanding the mechanisms involved in maintaining the steady-state concentrations of adiponectin oligomers in circulation is therefore likely to provide important insight into the development of insulin resistance. This review will discuss the current state of knowledge regarding the biochemical composition of adiponectin oligomers, the commonly used techniques to analyze them, and the known post-translational modifications that affect their assembly. Evidence based on in vitro oligomer assembly reactions in support of a "cystine ratchet" model of adiponectin oligomer formation will be considered along with limitations of the evidence. Secretory pathway proteins that have been shown to affect the distribution of adiponectin oligomers will also be discussed along with hypotheses regarding their potential involvement in the cystine ratchet model of adiponectin oligomerization. PMID- 23990402 TI - Pacing and awareness: brain regulation of physical activity. AB - The aim of this current opinion article is to provide a contemporary perspective on the role of brain regulatory control of paced performances in response to exercise challenges. There has been considerable recent conjecture as to the role of the brain during exercise, and it is now broadly accepted that fatigue does not occur without brain involvement and that all voluntary activity is likely to be paced at some level by the brain according to individualised priorities and knowledge of personal capabilities. This article examines the role of pacing in managing and distributing effort to successfully accomplish physical tasks, while extending existing theories on the role of the brain as a central controller of performance. The opinion proposed in this article is that a central regulator operates to control exercise performance but achieves this without the requirement of an intelligent central governor located in the subconscious brain. It seems likely that brain regulation operates at different levels of awareness, such that minor homeostatic challenges are addressed automatically without conscious awareness, while larger metabolic disturbances attract conscious awareness and evoke a behavioural response. This supports the view that the brain regulates exercise performance but that the interpretation of the mechanisms underlying this effect have not yet been fully elucidated. PMID- 23990403 TI - The role of glycogen synthase kinase-3beta in glioma cell apoptosis induced by remifentanil. AB - The aim of malignant glioma treatment is to inhibit tumor cell proliferation and induce tumor cell apoptosis. Remifentanil is a clinical anesthetic drug that can activate the N-methyl-D-aspartate (NMDA) receptor. NMDA receptor signaling activates glycogen synthase kinase-3beta (GSK-3beta). Discovered some 32 years ago, GSK-3beta was only recently considered as a therapeutic target in cancer treatment. The purpose of this study was to assess whether remifentanil can induce the apoptosis of C6 cells through GSK-3beta activation. 3-(4,5 Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) was used to detect cell viability. Hoechst 33342 staining and flow cytometry were used to detect cell apoptosis. The effect of GSK-3beta activation was detected using a GSK-3beta activation assay kit and 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD 8), a potent and selective small molecule inhibitor of GSK-3beta. The MTT assay indicated that remifentanil induced C6 cell death in a concentration- and time dependent manner. Hoechst 33342 staining and flow cytometry showed that remifentanil significantly induced C6 cell apoptosis. The measurement of GSK 3beta activation showed that remifentanil increased the cellular level of GSK 3beta. All of these toxic effects can be attenuated by treatment with TDZD-8. These results suggest that remifentanil is able to induce C6 cell apoptosis through GSK-3beta activation, which provides a basis for its potential use in the treatment of malignant gliomas. PMID- 23990404 TI - Heterogeneity in responses to a universal prevention program. AB - Because universal or primary prevention strategies often target heterogeneous populations, their effects may likewise be expected to be heterogeneous. We sought to explore the heterogeneity of outcomes of previously published results of a longitudinal Swedish study of a school-based socio-emotional learning program. By applying latent class regression analysis to two measures of well being, we found three significantly different classes with different change trajectories that yielded different outcomes. We conclude that restricting outcome analyses of primary prevention programs to sample means may conceal important heterogeneity regarding individual outcomes. PMID- 23990405 TI - Migraine prevalence, socioeconomic status, and social causation. AB - OBJECTIVE: To determine whether the known higher prevalence of migraine in lower household (HH) income groups is explained by a higher incidence rate or a lower remission rate. METHODS: We used data from the American Migraine Prevalence and Prevention Study, a US national sample of 132,674 females (with a 64.3% response rate) and 124,665 males (with a 62.0% response rate) 12 years of age and older. Data were previously collected on migraine symptoms, onset age, and demographics. Previously validated methods applied to the American Migraine Prevalence and Prevention Study data were used to simulate a cohort study. Incidence and remission rates were estimated within 3 sex-specific HH income groups (<$22,500, $22,500-$59,999, and >=$60,000). The chi2 test was used to determine whether the incidence or remission rates differed by HH income group as an explanation for differences in migraine prevalence by HH income. RESULTS: Migraine prevalence increased as HH income decreased for females (chi2, p < 0.01) and males (chi2, p < 0.01). Differences were not explained by race and other known confounders. Variation in prevalence was explained, in large part, by a higher incidence rate in the lower HH income groups for both females (chi2, p < 0.01) and males (chi2, p < 0.01). Migraine remission rates did not differ by HH income. CONCLUSIONS: The higher incidence of migraine in lower HH income groups is compatible with the social causation hypothesis. Once initiated, migraine remission is independent of HH income. Onset and remission may have etiologically distinct causes. PMID- 23990406 TI - Migraine and the social selection vs causation hypotheses: a question larger than either/or? AB - For decades, the question of social selection vs social causation has been raised by public health researchers and social scientists to explain the association between socioeconomic factors and mood disorders.(1,2) The social selection or "downward drift" theory postulates that the disease itself limits an individual's educational and occupational achievements, leading to a lower socioeconomic status (SES). In contrast, the social causation hypothesis suggests that factors associated with low SES (e.g., stressful life events, poor health care access) increase the likelihood of disease onset or prolonged disease duration.(3,4) Simply stated, the end result of each hypothesis is as follows: PMID- 23990407 TI - Role of hypothalamic autophagy in the control of whole body energy balance. AB - Autophagy is a catabolic process involving the rearrangement of subcellular membranes to sequester cytoplasm and organelles for delivery to lysosomes, where the sequestered material is degraded and recycled. Autophagy is important for maintenance of intracellular energy homeostasis and the quality control of organelles such as the endoplasmic reticulum (ER) and mitochondria, which suggests that dysregulated autophagy might play a role in the pathogenesis of metabolic disorders and diabetes. In an attempt to elucidate the role of autophagy in metabolic disorders, diverse in vivo and in vitro models have been employed. Site-specific autophagy knockout models that are autophagy-deficient specifically in pancreatic beta-cells, skeletal muscle, adipose tissues or liver have been produced. These models have generated valuable information regarding the role of autophagy in body metabolism. The role of autophagy in the hypothalamus, which controls whole body energy balance, appetite and energy expenditure, has also been investigated. Thus, mice with autophagy deficiency in the hypothalamus have shown diverse phenotypes (lean vs. obese) depending on the site of autophagy deficiency or the method of autophagy abrogation. PMID- 23990409 TI - Detecting and (not) dealing with plagiarism in an engineering paper: beyond CrossCheck-a case study. AB - In papers in areas such as engineering and the physical sciences, figures, tables and formulae are the basic elements to communicate the authors' core ideas, workings and results. As a computational text-matching tool, CrossCheck cannot work on these non-textual elements to detect plagiarism. Consequently, when comparing engineering or physical sciences papers, CrossCheck may return a low similarity index even when plagiarism has in fact taken place. A case of demonstrated plagiarism involving engineering papers with a low similarity index is discussed, and editor's experiences and suggestions are given on how to tackle this problem. The case shows a lack of understanding of plagiarism by some authors or editors, and illustrates the difficulty of getting some editors and publishers to take appropriate action. Consequently, authors, journal editors, and reviewers, as well as research institutions all are duty-bound not only to recognize the differences between ethical and unethical behavior in order to protect a healthy research environment, and also to maintain consistent ethical publishing standards. PMID- 23990410 TI - The chaperone protein clusterin may serve as a cerebrospinal fluid biomarker for chronic spinal cord disorders in the dog. AB - Chronic spinal cord dysfunction occurs in dogs as a consequence of diverse aetiologies, including long-standing spinal cord compression and insidious neurodegenerative conditions. One such neurodegenerative condition is canine degenerative myelopathy (DM), which clinically is a challenge to differentiate from other chronic spinal cord conditions. Although the clinical diagnosis of DM can be strengthened by the identification of the Sod1 mutations that are observed in affected dogs, genetic analysis alone is insufficient to provide a definitive diagnosis. There is a requirement to identify biomarkers that can differentiate conditions with a similar clinical presentation, thus facilitating patient diagnostic and management strategies. A comparison of the cerebrospinal fluid (CSF) protein gel electrophoresis profile between idiopathic epilepsy (IE) and DM identified a protein band that was more prominent in DM. This band was subsequently found to contain a multifunctional protein clusterin (apolipoprotein J) that is protective against endoplasmic reticulum (ER) stress-mediated apoptosis, oxidative stress, and also serves as an extracellular chaperone influencing protein aggregation. Western blot analysis of CSF clusterin confirmed elevated levels in DM compared to IE (p < 0.05). Analysis of spinal cord tissue from DM and control material found that clusterin expression was evident in neurons and that the clusterin mRNA levels from tissue extracts were elevated in DM compared to the control. The plasma clusterin levels was comparable between these groups. However, a comparison of clusterin CSF levels in a number of neurological conditions found that clusterin was elevated in both DM and chronic intervertebral disc disease (cIVDD) but not in meningoencephalitis and IE. These findings indicate that clusterin may potentially serve as a marker for chronic spinal cord disease in the dog; however, additional markers are required to differentiate DM from a concurrent condition such as cIVDD. PMID- 23990411 TI - A non-independent energy-based multiple sequence alignment improves prediction of transcription factor binding sites. AB - MOTIVATION: Multiple sequence alignments (MSAs) are usually scored under the assumption that the sequences being aligned have evolved by common descent. Consequently, the differences between sequences reflect the impact of insertions, deletions and mutations. However, non-coding DNA binding sequences, such as transcription factor binding sites (TFBSs), are frequently not related by common descent, and so the existing alignment scoring methods are not well suited for aligning such sequences. RESULTS: We present a novel multiple MSA methodology that scores TFBS DNA sequences by including the interdependence of neighboring bases. We introduced two variants supported by different underlying null hypotheses, one statistically and the other thermodynamically generated. We assessed the alignments through their performance in TFBS prediction; both methods show considerable improvements when compared with standard MSA algorithms. Moreover, the thermodynamically generated null hypothesis outperforms the statistical one due to improved stability in the base stacking free energy of the alignment. The thermodynamically generated null hypothesis method can be downloaded from http://sourceforge.net/projects/msa-edna/. CONTACT: dov.stekel@nottingham.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23990412 TI - Bayesian consensus clustering. AB - MOTIVATION: In biomedical research a growing number of platforms and technologies are used to measure diverse but related information, and the task of clustering a set of objects based on multiple sources of data arises in several applications. Most current approaches to multisource clustering either independently determine a separate clustering for each data source or determine a single 'joint' clustering for all data sources. There is a need for more flexible approaches that simultaneously model the dependence and the heterogeneity of the data sources. RESULTS: We propose an integrative statistical model that permits a separate clustering of the objects for each data source. These separate clusterings adhere loosely to an overall consensus clustering, and hence they are not independent. We describe a computationally scalable Bayesian framework for simultaneous estimation of both the consensus clustering and the source-specific clusterings. We demonstrate that this flexible approach is more robust than joint clustering of all data sources, and is more powerful than clustering each data source independently. We present an application to subtype identification of breast cancer tumor samples using publicly available data from The Cancer Genome Atlas. AVAILABILITY: R code with instructions and examples is available at http://people.duke.edu/%7Eel113/software.html. PMID- 23990408 TI - Brain regulation of energy balance and body weight. AB - Body weight is determined by a balance between food intake and energy expenditure. Multiple neural circuits in the brain have evolved to process information about food, food-related cues and food consumption to control feeding behavior. Numerous gastrointestinal endocrine cells produce and secrete satiety hormones in response to food consumption and digestion. These hormones suppress hunger and promote satiation and satiety mainly through hindbrain circuits, thus governing meal-by-meal eating behavior. In contrast, the hypothalamus integrates adiposity signals to regulate long-term energy balance and body weight. Distinct hypothalamic areas and various orexigenic and anorexigenic neurons have been identified to homeostatically regulate food intake. The hypothalamic circuits regulate food intake in part by modulating the sensitivity of the hindbrain to short-term satiety hormones. The hedonic and incentive properties of foods and food-related cues are processed by the corticolimbic reward circuits. The mesolimbic dopamine system encodes subjective "liking" and "wanting" of palatable foods, which is subjected to modulation by the hindbrain and the hypothalamic homeostatic circuits and by satiety and adiposity hormones. Satiety and adiposity hormones also promote energy expenditure by stimulating brown adipose tissue (BAT) activity. They stimulate BAT thermogenesis mainly by increasing the sympathetic outflow to BAT. Many defects in satiety and/or adiposity hormone signaling and in the hindbrain and the hypothalamic circuits have been described and are believed to contribute to the pathogenesis of energy imbalance and obesity. PMID- 23990413 TI - DIST: direct imputation of summary statistics for unmeasured SNPs. AB - MOTIVATION: Genotype imputation methods are used to enhance the resolution of genome-wide association studies, and thus increase the detection rate for genetic signals. Although most studies report all univariate summary statistics, many of them limit the access to subject-level genotypes. Because such an access is required by all genotype imputation methods, it is helpful to develop methods that impute summary statistics without going through the interim step of imputing genotypes. Even when subject-level genotypes are available, due to the substantial computational cost of the typical genotype imputation, there is a need for faster imputation methods. RESULTS: Direct Imputation of summary STatistics (DIST) imputes the summary statistics of untyped variants without first imputing their subject-level genotypes. This is achieved by (i) using the conditional expectation formula for multivariate normal variates and (ii) using the correlation structure from a relevant reference population. When compared with genotype imputation methods, DIST (i) requires only a fraction of their computational resources, (ii) has comparable imputation accuracy for independent subjects and (iii) is readily applicable to the imputation of association statistics coming from large pedigree data. Thus, the proposed application is useful for a fast imputation of summary results for (i) studies of unrelated subjects, which (a) do not provide subject-level genotypes or (b) have a large size and (ii) family association studies. AVAILABILITY AND IMPLEMENTATION: Pre compiled executables built under commonly used operating systems are publicly available at http://code.google.com/p/dist/. CONTACT: dlee4@vcu.edu . PMID- 23990414 TI - Identification of active transcription factor and miRNA regulatory pathways in Alzheimer's disease. AB - MOTIVATION: Alzheimer's disease (AD) is a severe neurodegenerative disease of the central nervous system that may be caused by perturbation of regulatory pathways rather than the dysfunction of a single gene. However, the pathology of AD has yet to be fully elucidated. RESULTS: In this study, we systematically analyzed AD related mRNA and miRNA expression profiles as well as curated transcription factor (TF) and miRNA regulation to identify active TF and miRNA regulatory pathways in AD. By mapping differentially expressed genes and miRNAs to the curated TF and miRNA regulatory network as active seed nodes, we obtained a potential active subnetwork in AD. Next, by using the breadth-first-search technique, potential active regulatory pathways, which are the regulatory cascade of TFs, miRNAs and their target genes, were identified. Finally, based on the known AD-related genes and miRNAs, the hypergeometric test was used to identify active pathways in AD. As a result, nine pathways were found to be significantly activated in AD. A comprehensive literature review revealed that eight out of nine genes and miRNAs in these active pathways were associated with AD. In addition, we inferred that the pathway hsa-miR-146a->STAT1->MYC, which is the source of all nine significantly active pathways, may play an important role in AD progression, which should be further validated by biological experiments. Thus, this study provides an effective approach to finding active TF and miRNA regulatory pathways in AD and can be easily applied to other complex diseases. PMID- 23990415 TI - A-clustering: a novel method for the detection of co-regulated methylation regions, and regions associated with exposure. AB - MOTIVATION: DNA methylation is a heritable modifiable chemical process that affects gene transcription and is associated with other molecular markers (e.g. gene expression) and biomarkers (e.g. cancer or other diseases). Current technology measures methylation in hundred of thousands, or millions of CpG sites throughout the genome. It is evident that neighboring CpG sites are often highly correlated with each other, and current literature suggests that clusters of adjacent CpG sites are co-regulated. RESULTS: We develop the Adjacent Site Clustering (A-clustering) algorithm to detect sets of neighboring CpG sites that are correlated with each other. To detect methylation regions associated with exposure, we propose an analysis pipeline for high-dimensional methylation data in which CpG sites within regions identified by A-clustering are modeled as multivariate responses to environmental exposure using a generalized estimating equation approach that assumes exposure equally affects all sites in the cluster. We develop a correlation preserving simulation scheme, and study the proposed methodology via simulations. We study the clusters detected by the algorithm on high dimensional dataset of peripheral blood methylation of pesticide applicators. AVAILABILITY: We provide the R package Aclust that efficiently implements the A-clustering and the analysis pipeline, and produces analysis reports. The package is found on http://www.hsph.harvard.edu/tamar sofer/packages/ CONTACT: tsofer@hsph.harvard.edu PMID- 23990416 TI - The MaSuRCA genome assembler. AB - MOTIVATION: Second-generation sequencing technologies produce high coverage of the genome by short reads at a low cost, which has prompted development of new assembly methods. In particular, multiple algorithms based on de Bruijn graphs have been shown to be effective for the assembly problem. In this article, we describe a new hybrid approach that has the computational efficiency of de Bruijn graph methods and the flexibility of overlap-based assembly strategies, and which allows variable read lengths while tolerating a significant level of sequencing error. Our method transforms large numbers of paired-end reads into a much smaller number of longer 'super-reads'. The use of super-reads allows us to assemble combinations of Illumina reads of differing lengths together with longer reads from 454 and Sanger sequencing technologies, making it one of the few assemblers capable of handling such mixtures. We call our system the Maryland Super-Read Celera Assembler (abbreviated MaSuRCA and pronounced 'mazurka'). RESULTS: We evaluate the performance of MaSuRCA against two of the most widely used assemblers for Illumina data, Allpaths-LG and SOAPdenovo2, on two datasets from organisms for which high-quality assemblies are available: the bacterium Rhodobacter sphaeroides and chromosome 16 of the mouse genome. We show that MaSuRCA performs on par or better than Allpaths-LG and significantly better than SOAPdenovo on these data, when evaluated against the finished sequence. We then show that MaSuRCA can significantly improve its assemblies when the original data are augmented with long reads. AVAILABILITY: MaSuRCA is available as open-source code at ftp://ftp.genome.umd.edu/pub/MaSuRCA/. Previous (pre-publication) releases have been publicly available for over a year. CONTACT: alekseyz@ipst.umd.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23990417 TI - A general species delimitation method with applications to phylogenetic placements. AB - MOTIVATION: Sequence-based methods to delimit species are central to DNA taxonomy, microbial community surveys and DNA metabarcoding studies. Current approaches either rely on simple sequence similarity thresholds (OTU-picking) or on complex and compute-intensive evolutionary models. The OTU-picking methods scale well on large datasets, but the results are highly sensitive to the similarity threshold. Coalescent-based species delimitation approaches often rely on Bayesian statistics and Markov Chain Monte Carlo sampling, and can therefore only be applied to small datasets. RESULTS: We introduce the Poisson tree processes (PTP) model to infer putative species boundaries on a given phylogenetic input tree. We also integrate PTP with our evolutionary placement algorithm (EPA-PTP) to count the number of species in phylogenetic placements. We compare our approaches with popular OTU-picking methods and the General Mixed Yule Coalescent (GMYC) model. For de novo species delimitation, the stand-alone PTP model generally outperforms GYMC as well as OTU-picking methods when evolutionary distances between species are small. PTP neither requires an ultrametric input tree nor a sequence similarity threshold as input. In the open reference species delimitation approach, EPA-PTP yields more accurate results than de novo species delimitation methods. Finally, EPA-PTP scales on large datasets because it relies on the parallel implementations of the EPA and RAxML, thereby allowing to delimit species in high-throughput sequencing data. AVAILABILITY AND IMPLEMENTATION: The code is freely available at www.exelixis lab.org/software.html. . PMID- 23990418 TI - Multiple alignment-free sequence comparison. AB - MOTIVATION: Recently, a range of new statistics have become available for the alignment-free comparison of two sequences based on k-tuple word content. Here, we extend these statistics to the simultaneous comparison of more than two sequences. Our suite of statistics contains, first, C(*)1 and C(S)1, extensions of statistics for pairwise comparison of the joint k-tuple content of all the sequences, and second, C(*)2, C(S)2 and C(geo)2, averages of sums of pairwise comparison statistics. The two tasks we consider are, first, to identify sequences that are similar to a set of target sequences, and, second, to measure the similarity within a set of sequences. RESULTS: Our investigation uses both simulated data as well as cis-regulatory module data where the task is to identify cis-regulatory modules with similar transcription factor binding sites. We find that although for real data, all of our statistics show a similar performance, on simulated data the Shepp-type statistics are in some instances outperformed by star-type statistics. The multiple alignment-free statistics are more sensitive to contamination in the data than the pairwise average statistics. AVAILABILITY: Our implementation of the five statistics is available as R package named 'multiAlignFree' at be http://www rcf.usc.edu/~fsun/Programs/multiAlignFree/multiAlignFreemain.html. CONTACT: reinert@stats.ox.ac.uk. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23990419 TI - Global status of fish-borne zoonotic trematodiasis in humans. AB - Fishborne zoonotic trematodes (FZT), infecting humans and mammals worldwide, are reviewed and options for control discussed. Fifty nine species belonging to 4 families, i.e. Opisthorchiidae (12 species), Echinostomatidae (10 species), Heterophyidae (36 species) and Nanophyetidae (1 species) are listed. Some trematodes, which are highly pathogenic for humans such as Clonorchis sinensis, Opisthorchis viverrini, O. felineus are discussed in detail, i.e. infection status in humans in endemic areas, clinical aspects, symptoms and pathology of disease caused by these flukes. Other liver fluke species of the Opisthorchiidae are briefly mentioned with information about their infection rate and geographical distribution. Intestinal flukes are reviewed at the family level. We also present information on the first and second intermediate hosts as well as on reservoir hosts and on habits of human eating raw or undercooked fish. PMID- 23990420 TI - Effects of Schistosoma mansoni infection on lutein and beta-carotene concentrations in Biomphalaria glabrata snails as determined by quantitative high performance reversed phase thin-layer chromatography. AB - High performance thin-layer chromatography was used to determine the concentration of beta-carotene and lutein in the whole body and digestive gland gonad complex (DGG) of uninfected Biomphalaria glabrata snails and those infected with Schistosoma mansoni for 6 and 8 weeks. Pigments were extracted from the snails using acetone and separated on EMD Millipore reversed phase C-18 plates with concentration zone using petroleum ether-acetonitrile-methanol (1:1:2) mobile phase. After development, two yellow pigment zones, lutein and beta carotene, were identified with respective Rf values of 0.55 and 0.13 and then quantified by densitometry. Statistical analysis of the weight percentages of each pigment showed a significant decrease (P < 0.05) in the concentration of beta-carotene in the DGGs of infected B. glabrata at 6 and 8 weeks post-infection compared to the uninfected snails. No significant differences were seen in the concentrations of beta-carotene in the whole body of the uninfected versus infected snail samples. Changes in the lutein concentration of the infected DGG and whole snail bodies were insignificant compared to the uninfected controls. In conclusion, larval S. mansoni infection caused a significant decrease in the beta carotene concentration of the DGG at 6 and 8 weeks post infection. PMID- 23990421 TI - Philometra johnii sp. nov. (Nematoda, Philometridae), a new gonad-infecting philometrid from the sin croaker Johnius dussumieri (Cuvier) (Perciformes, Sciaenidae) from marine waters of Iraq. AB - A new nematode species, Philometra johnii sp. nov. (Philometridae), is described from male and female specimens found in the ovary of the sin croaker, Johnius dussumieri (Cuvier) (Perciformes, Sciaenidae), in the Arabian Gulf, off the southern coast of Iraq. Based on light and scanning electron microscopical examination, the new species differs from all other gonad-infecting Philometra spp. with dorsal lamella-like structures on the distal tip of the gubernaculum in having a dorsal bipartite protuberance formed by two subdorsal lamellated parts separated from each other by a smooth longitudinal field. This gubernaculum structure is unique among all philometrids. Other distinguishing features include the structure of the male tail, number (6 pairs) and arrangement of genital papillae and the length of spicules (102-153 MUm). From eight congeneric, gonad infecting species with unknown males, the new species can be distinguished by some morphological and biometrical features found in gravid females (absence of caudal projections, length of oesophagus, moderately developed anterior oesophageal inflation, length of first-stage larvae) by the host type (fish family) and geographical distribution. Philometra johnii sp. nov. is the fourth known philometrid species recorded from marine waters of Iraq. PMID- 23990422 TI - Egg ultrastructure of the amabiliid cestode Tatria biremis Kowalewski, 1904 (Cyclophyllidea, Amabiliidae), with an emphasis on the oncospheral envelopes. AB - This is the first report on the ultrastructure of eggs in the cestode family Amabiliidae Braun, 1900. The gravid proglottides of Tatria biremis easily detach from the strobila. Their thick-walled saccate uterus contains numerous rounded or oval eggs measuring about 30-32 MUm in diameter. In the early preoncospheral phase, three primary embryonic envelopes are formed around the developing and differentiating embryos, namely: (1) vitelline capsule originating from vitellocyte material; (2) outer envelope formed by two macromeres, and (3) inner envelope originating from a fusion of three mesomeres. Thus, both the outer and inner envelopes of T. biremis eggs are cellular in origin and syncytial in nature. During egg maturation, the three primary embryonic envelopes undergo differentiation into fully formed oncospheral or egg envelopes. Most significant changes were observed in the inner envelope which becomes progressively subdivided into 3 sub-layers: the extra-embryophoral sub-layer, the embryophore, and the intra-embryophoral sub-layer, containing mesomere nuclei. The mature hexacanth is covered by a thin layer of the oncospheral tegument. Within the infective hexacanth larva, five cell types were distinguished: (1) a binucleated subtegumental cell; (2) U-shaped penetration gland; (3) nerve cells; (4) somatic cells representing the myocytons of both somatic and hook musculature, and (5) large germinative cells. Ultrastructural characteristics of T. biremis eggs are compared with those described in representatives of other cestode taxa. Since the functional ultrastructure of cestode egg envelopes is defined by multiple factors such as the type of life cycles, habitats and behaviour of the intermediate hosts, mode of the intermediate host infection, etc., ultrastructural studies of the greater diversity of cestodes are needed to obtain comparative data for fruitful analysis of cyclophyllidean cestode adaptations to their diverse life cycles. PMID- 23990423 TI - Follow-up study of prevalence and control of ascariasis in swine populations in Serbia. AB - The cause of the most significant helminth diseases in swine - Ascaris suum, can also causes infections in humans. The use of swine manure in agriculture renders the eggs of this ascaridida an accessible source of infection, thus posing a significant risk factor for human health. With the objective of proving the prevalence of infection with A. suum nematodes in the territory of Serbia, investigations were carried out in the period between 2007-2011 in the territories of five districts: North Backa, South Banat, Branicevo, Zlatibor and Nisava. The investigations covered coprological examinations of 1031 feces samples of swine originating from farms owned by individual breeders. The samples were examined using the standard flotation method with a saturated water solution of NaCl. The established prevalence of ascariasis infection amounted to 47.62% (1031/491). The biggest prevalence of infection was determined in the territory of the Branicevo District, 65.78% (301/198), and the smallest in the territory of the Nisava District, 32.24% (183/59). In spite of its prevalence and vast economic importance, there is still insufficient information about the key aspects of the biology and epidemiology of A. suum. Viewed from the aspect of epizootiology, it is very important to know the prevalence of swine infections with Ascaris because of the possible infection of humans by its migrating larvae. PMID- 23990424 TI - Redescriptions and comments on the validity of Acuaria subula and A. skrjabini (Nematoda, Spirurida, Acuariidae), parasites of passerine birds. AB - Acuaria subula (Dujardin, 1845) is redescribed by light microcopy (LM) and scanning electron microscopy (SEM) on the basis of specimens from its type host, Erithacus rubecula (Passeriformes, Muscicapidae), from Curonian Spit (Kaliningradskaya Oblast', Russia) and Bulgaria. Acuaria skrjabini (Ozerskaya, 1926) is redescribed by LM and SEM on the basis of specimens from Passer domesticus (type host) and P. hispaniolensis (Passeriformes, Passeridae) from Bulgaria. Contrary to previous opinions recognizing A. skrjabini as a junior synonym of A. subula, the present study confirms that they are distinct species. They can be distinguished on the basis of the ratio between the length of cordons and the body length, the ratio between the length of muscular oesophagus and glandular oesophagus, and the ratio between the total length of oesophagus and the body length. In addition, the plates forming the cordons in these two species exhibit different morphological characters. Another difference between these two species is associated with the particular irregular mosaic ornamentation of the cuticle on the ventral and lateral sides of body around the region of vulva of A. subula and its absence in A. skrjabini. Data on their host and geographical ranges are surveyed. The type series of Acuaria buttnerae Chabaud et Petter, 1961, described as a parasite of Calandrella brachydactyla (Passeriformes, Alaudidae) in France, is re-examined; the latter species is recognized as a junior synonym of A. skrjabini (new synonymy). PMID- 23990425 TI - Urinary creatinine to serum creatinine ratio and renal failure index in dogs infected with Babesia canis. AB - Urinary creatinine to serum creatinine (UCr/SCr) ratio and renal failure index (RFI) are useful indices of renal damage. Both UCr/SCr ratio and RFI are used in differentiation between prerenal azotaemia and acute tubular necrosis. In this work the authors calculated the UCr/SCr ratio and RFI in dogs infected with Babesia canis and the values of these indices in azotaemic dogs infected with the parasite. The results of this study showed significantly lower UCr/SCr ratio in dogs infected with B. canis than in healthy dogs. Moreover, in azotaemic dogs infected with B. canis the UCr/SCr ratio was significantly lower and the RFI was significantly higher than in non-azotaemic dogs infected with B. canis. The calculated correlation between RFI and duration of the disease before diagnosis and treatment was high, positive and statistically significant (r = 0.89, p < 0.001). The results of this study showed that during the course of canine babesiosis caused by B. canis in Poland acute tubular necrosis may develop. PMID- 23990426 TI - Susceptibility of Acanthamoeba to multipurpose lens-cleaning solutions. AB - The present study investigated the susceptibility of Acanthamoeba spp. trophozoites to two multipurpose systems for cleaning and maintenance of contact lenses. Three strains of trophozoites from the ATCC (A. castellani T4, A. castellani Neff, and A. polyphaga) and two Acanthamoeba isolates obtained from swimming pools (PT5 and PO1) were placed in monoxenic culture. To test their survival in cleaning solutions for contact lenses, the trophozoites were exposed for 4 and 24 h to two multipurpose solutions (A and B), and were then inoculated into a new monoxenic culture. Amoebic growth on the plates was observed after 72 h of incubation. Trophozoites from all three ATCC strains and one isolate from a swimming pool (PO1) grew in all plates after 4 h of exposure to solutions A and B. After 24 h, the ATCC strains and the PO1 isolate showed growth in most of the plates treated. Only the PT5 isolate showed susceptibility to both solutions over the time intervals tested. The two solutions were not completely effective against most strains and isolates over the time intervals tested. These results are important, since species of Acanthamoeba are widely distributed in the environment and are potential agents of eye pathologies. PMID- 23990427 TI - A new genus and species of pterodectine feather mite (Acari: Proctophyllodidae) from Tod-Tyrants in Brazil (Passeriformes: Tyrannidae). AB - A new genus and species of feather mite, Hemitriccodectes furcatus gen. nov., sp. nov., is described from passerines of the genus Hemitriccus from Brazil: Hemitriccus furcatus, H. margaritaceiventer and H. striaticollis (Tyrannidae). The new genus belongs to the Pterodectes generic complex and most clearly differs from previously established genera of this complex by the following combination of features: trochanteral setae sRIII are present, and solenidia sigma are absent from genua III. The new genus also lacks dorsal hysteroromal setae c1. PMID- 23990428 TI - The mutual influence of proteins from Varroa destructor extracts and from honeybee haemolymph on their proteolytic activity--in vitro study. AB - The influence of extracts from Varroa destructor, a parasitic mite of the honeybee Apis mellifera, on the proteinase activity of worker bee haemolymph was analysed in vitro, along with the influence of bee haemolymph on the proteolytic activity of V. destructor extract. The study was conducted in three different environments: pH 7.5 (high activity of bee enzymes and very low activity of parasite enzymes), pH 5 (moderate activity of enzymes from both sources) and pH 3.5 (limited activity of bee proteinases and high activity of mite proteinases). Based on electrophoretic studies, the inhibition of the activity of bee haemolymph proteinases by V. destructor extracts was observed at each pH. The study at pH 7.5 with commercial inhibitors of the 4 main classes of proteinases (pepstatin A, ethylenediaminetetraacetic acid (EDTA), E-64 (trans-epoxysuccinyl-L leucylamido-(4-guanidino)-butane), soybean trypsin inhibitor and Kunitz inhibitor) suggested that parasite extracts mainly inhibited serine proteinases and, to a lower degree, cysteine and aspartyl proteinases. At pH 3.5 and pH 5, a decrease of approximately 40% in parasite proteinase activity was also observed in the presence of bee haemolymph. The result points to the presence of aspartyl proteinase inhibitors in bee haemolymph, which may be an important defence element for bees during food intake by a mite. It was demonstrated that trypsin and trypsin inhibitors are active in the excretion/secretion products of V. destructor, the proteinases of which may assist the parasite in food suckling by preventing haemolymph coagulation, among other things. PMID- 23990429 TI - Peracreadium akenovae sp. nov. (Trematoda: Opecoelidae) parasitising the highfin moray eel Gymnothorax pseudothyrsoideus (Anguilliformes: Muraenidae) from Moreton Bay, Australia. AB - A new opecoelid trematode, Peracreadium akenovae sp. nov., is described from the highfin moray eel Gymnothorax pseudothyrsoideus (Bleeker) (Anguilliformes; Muraenidae), collected from Moreton Bay off southeast Queensland, Australia. The new species is distinctive in its body shape, transversely elongate irregular testes, vitelline follicles interrupted at the level of the ventral sucker, and diverticulate excretory vesicle. The Muraenidae is a new host family for Peracreadium Nicoll, 1909. Peracreadium is the seventh opecoelid genus reported from temperate eastern Australian marine fishes and this is its first report from Australian waters. PMID- 23990430 TI - Identification of public areas with potential toxocariasis transmission risk using geographical information systems. AB - Geographic information system (GIS) or Health geography is a geographical identification of the spatial variation of contagion disease and zoonosis risk in certain conditions. OBJECTIVE: Comparing the variation of environmental contamination of Toxocara spp. sands of lawns and public areas through the Geographic Information System. MATERIALS AND METHODS: Were investigated 98% of Parana recreational urban areas such as, schools, public parks and squares filled with sand and/or lawn. Samples were analyzed using zinc sulphate solution centrifuge-flotation, density 1.420, and water sedimentation. Maps were developed by ESRI Arc GIS 9.2. RESULTS: Total 77/98 (78,6%) of public spaces shown Toxocara spp. eggs presence. No significant difference was observed (p = 0,9999) between eggs prevalence in sand 44/56 (78,6%), and lawn 33/42 (78,6%), at school (p = 0,6898) and squares (p = 0,0616). Egg contamination prevailed in periphery areas in the sand 20/27 (74%) and lawn 18/21 (86%). However, no significant difference was observed between sand and lawn contamination from schools and parks to central and peripheral areas. Although schools 62/66 (93,9%) presented a higher number of enclosed spaces, did not provide a lower frequency of pollution (p = 0,3327). CONCLUSION: GIS observed a scattered pattern of zoonosis among schools and public squares sand and lawns, with predominance of contamination in the peripheral areas with presence of dogs/cats. PMID- 23990431 TI - Occurrence of antibodies to Toxoplasma gondii in water buffaloes and meat cattle in Rio Grande do Sul State, southern Brazil. AB - Serum samples from 169 water buffaloes and 121 beef cattle were analyzed for antibodies to T. gondii by an indirect fluorescent antibody test (IFAT). Positive results were obtained in 27.2% of water buffaloes and 17.4% of cattle. Statistical analysis indicated significant differences between the prevalence in cattle and buffalo (p <= 0.05). The highest titres found in positive animals were 1:256 (buffaloes) and 1:64 (cattle). In both bovine species, toxoplasmosis frequency in young animals (less than 2 years old) was lower compared to older individuals, although the differences seen in cattle were not statistically significant. PMID- 23990432 TI - The occurrence of Borrelia burgdorferi sensu lato in certain ectoparasites (Mesostigmata, Siphonaptera) of Apodemus flavicollis and Myodes glareolus in chosen localities in the Czech Republic. AB - Ticks represent the primary vectors of several serious diseases, including the Lyme disease caused by Borrelia burgdorferi sensu lato (Bbsl). In this study two dominant ectoparasitic groups of arthropods (Mesostigmata, Siphonaptera) were investigated for the presence of borrelian DNA in order to determine their potential role of vectors (or carriers) of this bacterium. All individuals (235) were collected from wild-living rodents obtained in three localities in the Czech Republic (Bazantula, Baba and Krizovice). The majority of parasites were members of the families Parasitidae and Dermanyssidae (Mesostigmata) and families Hystrichopsyllidae and Ceratophyllidae (Siphonaptera). The rodent host species was almost exclusively the yellow-necked mouse (Apodemus flavicollis). Bbsl was detected by the PCR method in the following ectoparasite species: Euryparasitus emarginatus (1), Eulaelaps stabularis (1), Haemogamassus nidi (1), Laelaps agilis (5), Myonyssus gigas (1) (Mesostigmata) and Ctenophthalmus agyrtes (1), C. solutus (3) (Siphonaptera). PMID- 23990433 TI - Molecular identification of cryptic species of Ceratomyxa Thelohan, 1892 (Myxosporea: Bivalvulida) including the description of eight novel species from apogonid fishes (Perciformes: Apogonidae) from Australian waters. AB - Ceratomyxa parasites from the gall bladders of 23 species of cardinalfishes (family Apogonidae) from Australian waters were examined for their taxonomic identity and phylogenetic relatedness. We identified 15 of the 23 apogonid fish species infected with species of Ceratomyxa. Although the majority of apogonid species harboured only a single Ceratomyxa species, four were found with multiple species of Ceratomyxa. This study describes eight novel species using a combination of morphological, small subunit ribosomal DNA (SSU rDNA) and biological characters. Six Ceratomyxa species are reported from single apogonid species, while two are reported from multiple host species. Molecular data were critical in identifying several morphologically cryptic species. However, our results suggest that SSU rDNA was not capable of distinguishing all the species present in the current study system and alternative genetic markers should be investigated in the future. PMID- 23990434 TI - Occurrence and genetic characterization of Toxoplasma gondii in naturally infected pigs. AB - The protozoan Toxoplasma gondii is an obligate intracellular parasite that infects a wide range of warm-blooded vertebrates. The data about the occurrence of toxoplasmosis in slaughter pigs in the Slovak Republic are still missing. The aim of our study was to estimate the prevalence of toxoplasmosis in pigs from Slovakia during the period of 2006-2010 by ELISA and PCR methods. In sera of 970 slaughter pigs, 2.16% seropositivity to T. gondii was detected. In tissue samples of seropositive pigs the presence of T. gondii DNA was confirmed. In six monitored Slovak regions the seropositivity varied between 1.11 and 3.48%. The statistically significant differences were recorded between the Kosice and Presov region. The seroprevalence of toxoplasmosis in sows (4.26%) was two times higher than that in slaughter pigs (2.06%) (OR = 2.12; 95% CI = 0.48-9.36). Presence of Toxoplasma gondii in tissues of seropositive pig isolates was confirmed by TGR1E and B1 genes and analysis of DNA polymorphism at SAG2 and ROP1 genes revealed the presence of virulent strain of genotype I in 85.7% of infected pigs and an avirulent strain (genotype II) in 14.3% of pigs. PMID- 23990435 TI - Redescription of Caligus serratus Shiino, 1965 (Copepoda: Caligidae) parasitic on eleven fish species from Chamela Bay in the Mexican Pacific. AB - Caligus serratus Shiino, 1965 (Copepoda: Caligidae), a parasite on 11 fish species caught in Chamela Bay off the Pacific Coast of Mexico, is redescribed based on material found on Pacific agujon needlefish Tylosurus pacificus (Steindachner, 1876). Caligus serratus can be distinguished from its congeners by the combination of the following characters: i) short abdomen (approximately 0.2 times as long as cephalothorax), ii) pointed posteromedial process on the first segment of the antenna, iii) sternal furca with bluntly pointed, diverging tines, and iv) leg 4 exopod bearing 3 unequal, distal spines (the shortest 0.2 times the length of the longest). Microphotographs of female and illustrations of both female and male are provided. The redescription of this species might be useful given its low host specificity. PMID- 23990436 TI - Ancylostoma ceylanicum metalloprotease 6 DNA vaccination induces partial protection against hookworm challenge infection. AB - Hookworms are blood feeding intestinal nematodes that infect more than 500 million people and cause iron deficiency anemia. Infected children suffer from physical and cognitive growth retardation. Because of potential anthelminthic drug resistance, the need for vaccine development is urgent. Numerous antigens have been tested in animal models as vaccines against hookworm infection, but there is no effective human vaccine. We cloned a cDNA encoding Ancylostoma ceylanicum metalloprotease 6 (Acemep-6). Ace-MEP-6 is a protein with a predicted molecular mass of 101.87 kDa and based on computational analysis it is very likely to be engaged in food processing via hemoglobin digestion. Groups of hamsters were immunized with an Ace-mep-6 cDNA vaccine, either once or three times. Animals that were administered one dose developed high resistance (80%, p < 0.01) against challenge infection, whereas triple immunization resulted in no worm burden reduction. These results suggest that DNA vaccines can be powerful tools in ancylostomiasis control, although the mechanisms through which protection is conferred remain unclear. PMID- 23990437 TI - Onchocerca lupi infection in Turkey: a unique case of a rare human parasite. AB - Onchocerpa lupi was first isolated from a wolf in Russia. Since then, canine ocular onchocercosis has been increasingly reported, particularly in Europe and the United States. It is thought that blackflies and midges are the vectors of transmission, and it is possible that these vectors could transmit the parasite to humans. The first human case of O. lupi in Turkey was reported in 2011. In this report we present the third human case of O. lupi infection in Turkey. Our patient was a 28-year-old male who displayed a painless, immobile mass under the conjunctiva. The mass measured 10 * 12 mm in size. Pathological examination of the surgically excised tissue was suggestive of infection by a filarial nematode. Subsequently, the parasite was identified as O. lupi through molecular analysis. All of the previously reported cases of O. lupi in both humans and dogs were more symptomatic than in our patient, Onchocerca infection should not be ruled out during the differential diagnosis of the subconjunctival and orbital cystic mass in instances where there is little to no inflammation. It is important to consider biopsy and carry out molecular analysis to identify the parasite. PMID- 23990438 TI - Morphometrical and genetic comparison of two nematode species: H. spumosa and H. dahomensis (Nematoda, Heterakidae). AB - Heterakis is a genus of parasitic nematodes, the majority of which are found in ground-feeding birds and only rarely in mammals. The best-known species is Heterakis spumosa, a parasite associated with the cosmopolitan invasive rodent Rattus rattus of Asiatic origin. Heterakis dahomensis was described in 1911 as a parasite of the Gambian giant rat (Cricetomys gambianus) from Benin (Africa), subsequently synonymized to H. spumosa by Hall (1916). The study of helminths in African rodents is scarce and patchy. Since the original description of H. dahomensis, there have been only a few reports from Africa of species belonging to the genus Heterakis and the validity of this species has never in fact been confirmed or rejected. In the present study individual Heterakis spp. were collected from C. gambianus from Senegal. The morphological data taken point to differences between Heterakis dahomensis and H. spumosa, specifically in the number of tail papillae in males and in the vulva cuticular processes of females. In addition, molecular data revealed differences between these taxa and so H. dahomensis should be considered as a valid species. Moreover, recent changes in the systematics of the genus Cricetomys mean that it is now necessary to study the morphology and genetics of the Heterakis specimens collected from Cricetomys spp. (previously assigned to C. gambianus) in order to determine their taxonomic status as either H. dahomensis o H. spumosa. PMID- 23990439 TI - Cross-sectional study of serum reactivity to Anisakis simplex in healthy adults in Niteroi, Brazil. AB - Although the incidence of anisakiasis is rising worldwide, its frequency is still unknown in Brazil. The aim of this study was to verify immunoreactivity to Anisakis simplex antigens in healthy adults and determine its possible relationship with frequency of fish consumption and allergy symptoms. A prospective cross-sectional study was carried out with 67 volunteers recruited from a military facility in Niteroi, Brazil. The subjects completed a structured questionnaire and serum titers of specific anti-Anisakis IgE and IgG antibodies were measured. The association between frequency of fish intake and IgE reactivity was evaluated by Fisher's exact test. Almost all subjects (97.0%, 65/67) that consumed seafood; 64.6% (42/65) ate fish at least once weekly. Of all seafood consumers, 56.9% (37/65) reported allergy symptoms, being gut allergies most often cited (35.5%). IgE seroreactivity to Anisakis simplex was found in 20.9% of subjects (14/67), with 13.4% (9/67) reacting exclusively to somatic antigen, 3.0% (2/67) exclusively to excretory/secretory antigens and 4.5% (3/67) to both antigens. There was a significant association between frequency of fish consumption and positive serology (p = 0.019). An immunoblot assay for Anisakis antigens showed different positive bands for IgG. The direct relationship between ELISA reactivity and frequency of fish intake and absence of association with allergy symptoms suggests previous contact with Anisakis simplex antigens. PMID- 23990440 TI - Barefoot running: does it prevent injuries? AB - Endurance running has evolved over the course of millions of years and it is now one of the most popular sports today. However, the risk of stress injury in distance runners is high because of the repetitive ground impact forces exerted. These injuries are not only detrimental to the runner, but also place a burden on the medical community. Preventative measures are essential to decrease the risk of injury within the sport. Common running injuries include patellofemoral pain syndrome, tibial stress fractures, plantar fasciitis, and Achilles tendonitis. Barefoot running, as opposed to shod running (with shoes), has recently received significant attention in both the media and the market place for the potential to promote the healing process, increase performance, and decrease injury rates. However, there is controversy over the use of barefoot running to decrease the overall risk of injury secondary to individual differences in lower extremity alignment, gait patterns, and running biomechanics. While barefoot running may benefit certain types of individuals, differences in running stance and individual biomechanics may actually increase injury risk when transitioning to barefoot running. The purpose of this article is to review the currently available clinical evidence on barefoot running and its effectiveness for preventing injury in the runner. Based on a review of current literature, barefoot running is not a substantiated preventative running measure to reduce injury rates in runners. However, barefoot running utility should be assessed on an athlete-specific basis to determine whether barefoot running will be beneficial. PMID- 23990441 TI - The role of leptospirosis in reproductive disorders in horses. AB - Leptospirosis is a zoonotic disease of global importance and has a worldwide distribution. This infection displays clear seasonal nature in some regions of the tropics, where the rainy season is marked by high temperatures. Household and wild animals carry leptospires and contribute to their dissemination in nature. Transmission mainly occurs by contact with water contaminated with the urine of infected animals, and consequently, it is quite widespread especially in times of rain, since many areas are subject to flooding and have poor sanitation. Serological tests demonstrate that Leptospira sp. infection in horses occurs worldwide and that the predominant serovar may vary depending on the region or infection sources. Besides systemic and ocular manifestations, leptospirosis in horses has been recognized as an important disease of the reproductive system, since it leads to the birth of weak foals, stillbirths or neonatal mortality, and mainly to abortion, usually after the sixth month of pregnancy. In this context, this review aims to gather and discuss information about the role of leptospirosis in reproductive disorders in horses. PMID- 23990443 TI - Association between SOD2 C47T polymorphism and lung cancer susceptibility: a meta analysis. AB - Lung cancer is one of the most common cancers worldwide, but its etiology is still unclear. Superoxide dismutase 2 (SOD2) plays an essential role in oxidative stress and may be involved in the development of lung cancer. The association between SOD2 C47T polymorphism and lung cancer risk has been widely investigated, but the results of previous studies are contradictory. We conducted a meta analysis to comprehensively assess the association between SOD2 C47T polymorphism and lung cancer. The association was estimated by odds ratio (OR) with 95 % confidence interval (95 % CI). A total of 10 studies with 5,146 cases and 6,173 controls were identified. The results showed that SOD2 C47T polymorphism was significantly associated with lung cancer (T versus C: OR = 0.88, 95 % CI = 0.83 0.93, P < 0.001; TT versus CC: OR = 0.74, 95 % CI = 0.66-0.83, P < 0.001; TT versus CC/CT: OR = 0.81, 95 % CI = 0.73-0.89, P < 0.001). Subgroup analysis by ethnicity suggested that SOD2 C47T polymorphism was significantly associated with lung cancer in both East Asians and Caucasians. Conclusively, this meta-analysis strongly suggests that SOD2 C47T polymorphism is significantly associated with lung cancer. PMID- 23990442 TI - IGF-1R and Bmi-1 expressions in lung adenocarcinoma and their clinicopathologic and prognostic significance. AB - IGF-1R and Bmi-1 play a critical role in cancer growth and survival. We explored the correlation between IGF-1R and Bmi-1, as well as their relationship with clinicopathological parameters and their impacts on outcomes in patients with lung adenocarcinoma resected. Tumors from 178 surgical lung adenocarcinoma patients were evaluated for IGF-1R and Bmi-1 expression by means of immunohistochemistry. The clinicopathological implications of these molecules were analyzed statistically. There was a significant correlation between the expression of IGF-1R and Bmi-1 (p = 0.011). The 5-year survival rate of patients with Bmi-1 positive was only 31.2%, but patients with Bmi-1 negative had a survival rate of 50.7% (p = 0.004). The pattern of survival curves showed that Bmi-1 was a significant prognostic factor of poor overall survival in lung adenocarcinoma patients. However, there was no obvious correlation between IGF-1R expression and patient survival. The results of multivariate Cox analysis revealed that the pathological stages and Bmi-1 expression were independent prognostic factors. Therefore, Bmi-1 may be a good biomarker to predict the prognosis of patients with completely resected lung adenocarcinoma. PMID- 23990444 TI - MicroRNA and transcription factor mediated regulatory network for ovarian cancer: regulatory network of ovarian cancer. AB - A better understanding on the regulatory interactions of microRNA (miRNA) target genes and transcription factor (TF) target genes in ovarian cancer may be conducive for developing early diagnosis strategy. Thus, gene expression data and miRNA expression data were downloaded from The Cancer Genome Atlas in this study. Differentially expressed genes and miRNAs were selected out with t test, and Gene Ontology enrichment analysis was performed with DAVID tools. Regulatory interactions were retrieved from miRTarBase, TRED, and TRANSFAC, and then networks for miRNA target genes and TF target genes were constructed to globally present the mechanisms. As a result, a total of 1,939 differentially expressed genes were identified, and they were enriched in 28 functions, among which cell cycle was affected to the most degree. Besides, 213 differentially expressed miRNAs were identified. Two regulatory networks for miRNA target genes and TF target genes were established and then both were combined, in which E2F transcription factor 1, cyclin-dependent kinase inhibitor 1A, cyclin E1, and miR 16 were the hub genes. These genes may be potential biomarkers for ovarian cancer. PMID- 23990445 TI - Editor's Spotlight/Take 5: Conditional survival greater than overall survival at diagnosis for Ewing's and osteosarcoma. PMID- 23990446 TI - Comparison of robotic-assisted and conventional acetabular cup placement in THA: a matched-pair controlled study. AB - BACKGROUND: Improper acetabular component orientation in THA has been associated with increased dislocation rates, component impingement, bearing surface wear, and a greater likelihood of revision. Therefore, any reasonable steps to improve acetabular component orientation should be considered and explored. QUESTIONS/PURPOSES: We therefore sought to compare THA with a robotic-assisted posterior approach with manual alignment techniques through a posterior approach, using a matched-pair controlled study design, to assess whether the use of the robot made it more likely for the acetabular cup to be positioned in the safe zones described by Lewinnek et al. and Callanan et al. METHODS: Between September 2008 and September 2012, 160 THAs were performed by the senior surgeon. Sixty-two patients (38.8%) underwent THA using a conventional posterior approach, 69 (43.1%) underwent robotic-assisted THA using the posterior approach, and 29 (18.1%) underwent radiographic-guided anterior-approach THAs. From September 2008 to June 2011, all patients were offered anterior or posterior approaches regardless of BMI and anatomy. Since introduction of the robot in June 2011, all THAs were performed using the robotic technique through the posterior approach, unless a patient specifically requested otherwise. The radiographic cup positioning of the robotic-assisted THAs was compared with a matched-pair control group of conventional THAs performed by the same surgeon through the same posterior approach. The safe zone (inclination, 30 degrees -50 degrees ; anteversion, 5 degrees -25 degrees ) described by Lewinnek et al. and the modified safe zone (inclination, 30 degrees -45 degrees ; anteversion, 5 degrees 25 degrees ) of Callanan et al. were used for cup placement assessment. Matching criteria were gender, age +/- 5 years, and (BMI) +/- 7 units. After exclusions, a total of 50 THAs were included in each group. Strong interobserver and intraobserver correlations were found for all radiographic measurements (r > 0.82; p < 0.001). RESULTS: One hundred percent (50/50) of the robotic-assisted THAs were within the safe zone described by Lewinnek et al. compared with 80% (40/50) of the conventional THAs (p = 0.001). Ninety-two percent (46/50) of robotic-assisted THAs were within the modified safe zone described by Callanan et al. compared with 62% (31/50) of conventional THAs p (p = 0.001). The odds ratios for an implanted cup out of the safe zones of Lewinnek et al. and Callanan et al. were zero and 0.142, respectively (95% CI, 0.044, 0.457). CONCLUSIONS: Use of the robot allowed for improvement in placement of the cup in both safe zones, an important parameter that plays a significant role in long-term success of THA. However, whether the radiographic improvements we observed will translate into clinical benefits for patients-such as reductions in component impingement, acetabular wear, and prosthetic dislocations, or in terms of improved longevity remains unproven. PMID- 23990447 TI - Changes in the adjacent segment 10 years after anterior lumbar interbody fusion for low-grade isthmic spondylolisthesis. AB - BACKGROUND: Adjacent segment degeneration is a long-term complication of arthrodesis. However, the incidence of adjacent segment degeneration varies widely depending on the patient's age and underlying disease and the fusion techniques and diagnostic methods used. QUESTIONS/PURPOSES: We determined (1) the frequency of adjacent segment degeneration and increased lordosis on imaging tests, (2) the frequency and severity of clinical sequelae of these findings, including revision surgery, and (3) the sequence of degeneration and risk factors for degeneration. METHODS: Seventy-three patients underwent anterior lumbar interbody fusion for low-grade isthmic spondylolisthesis at one institution between October 2000 and February 2002. Forty-nine (67%) of the original patients had complete radiographic and clinical followup for 10 years. CT and MRI were performed at 5 years and 10 years in all cases. The disc height, sagittal profiles, and facet and disc degeneration at adjacent levels were examined to identify radiographic and clinical adjacent segment degeneration. Mean followup was 134.2 months (range, 120-148 months). RESULTS: Cranial segment lordosis increased (from 14.8 degrees to 18.5 degrees ; p < 0.001), while caudal segment lordosis changed little (from 16.4 degrees to 17.3 degrees ). Radiographic and clinical adjacent segment degeneration occurred in 19 (38.8%) and six (12.2%) patients, respectively, and two patients (4.1%) underwent revision surgery. Patients with adjacent segment degeneration had more advanced preexisting facet degeneration than patients without adjacent segment degeneration (odds ratio: 18.6; 95% CI, 1.97-175.54, p = 0.01). Acceleration of disc and facet degeneration occurred in 4.1% and 10.2%, respectively. CONCLUSIONS: Adjacent segment degeneration requiring surgery is rare, although radiographic adjacent segment degeneration is common after anterior lumbar interbody fusion for isthmic spondylolisthesis. The only risk factor we found was preexisting facet degeneration of the cranial segment. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 23990448 TI - In vivo determination of cam-post engagement in fixed and mobile-bearing TKA. AB - BACKGROUND: Kinematics vary, sometimes in important ways, among the different types of total knee arthroplasty (TKA) designs, yet differences between the in vivo mechanisms of cam-post engagement in rotating-platform posterior-stabilized (PS) TKA, bicruciate-stabilized TKA, and fixed-bearing PS TKA designs remain largely uncharacterized. QUESTIONS/PURPOSES: The objective of this study was to determine the cam-post mechanism interaction for subjects implanted with three different TKA designs. METHODS: In vivo, analysis was conducted for patients implanted with nine rotating-platform PS TKAs, five knees with a fixed-bearing PS TKA, and 10 knees with a bicruciate-stabilized TKA while performing a deep knee bend. Three-dimensional kinematics of the implant components were determined by analysis of fluoroscopic images during flexion. The distances between the interacting surfaces were measured throughout flexion and instances and locations of contact were identified. RESULTS: Seven of the 10 bicruciate-stabilized knees analyzed had the femoral component engaged with the anterior aspect of the tibial post at full extension. Posterior cam-post engagement occurred at 34 degrees for the bicruciate-stabilized (range, 17 degrees -68 degrees ), 93 degrees for the fixed-bearing PS (range, 88 degrees -100 degrees ), and at 97 degrees (range, 90 degrees -104 degrees ) for rotating-platform PS TKA. In bicruciate-stabilized and fixed-bearing PS knees, the contact initially occurred on the medial aspect of the posterior surface of the tibial post and then moved centrally and superiorly with increasing flexion. For rotating-platform PS TKA, it was located centrally on the posterior surface of the post at all times. CONCLUSIONS: This study suggests that mobility of the polyethylene might play an important role in ensuring central cam-post interaction in PS TKA. The polyethylene insert rotates axially in accordance with the rotating femur, maintaining central cam-post contact. This phenomenon was not observed in the fixed-bearing PS TKAs analyzed in this study. CLINICAL RELEVANCE: We speculate that this centralized symmetrical contact between the cam and posterior surface of the post could be beneficial clinically in terms of reducing wear of the posterior surface and particularly at the medial extremes of it. PMID- 23990449 TI - Recombinant human BMP-2 increases the incidence and rate of healing in complex ankle arthrodesis. AB - BACKGROUND: Although its FDA-approved applications are limited, the pro osteogenic benefits of recombinant human BMP-2 (rhBMP-2) administration have been shown in off-label surgical applications. However, the effects of rhBMP-2 on ankle fusions are insufficiently addressed in the literature, which fails to include a case-control study of adequate sample size to evaluate the efficacy of rhBMP-2 treatment. QUESTIONS/PURPOSES: In this study we asked whether rhBMP-2 treatment (1) would increase the rate of successful ankle fusion in complex patients (patients with comorbidities associated with poor surgical healing) compared with a control group of patients undergoing ankle fusion who did not receive rhBMP-2; (2) would reduce total time wearing a frame when compared with the control group; (3) would result in a difference in the percentage of bone bridging between the group treated with rhBMP-2 and the control group, as determined by CT scans 3 months after surgery; and (4) would encounter an equal rate of complications different from untreated patients. METHODS: A retrospective chart study was performed on 82 patients who, because of a host of comorbidities associated with poor healing, required a complex ankle arthrodesis with the Ilizarov technique. The first 40 patients did not receive rhBMP-2, whereas the subsequent 42 patients received intraoperative rhBMP-2. Time wearing the frame was determined by chart review; decision to remove the frame was made by the surgeon based on quantitative bone bridging measured using a CT scan taken 3 months after fusion. RESULTS: Patients treated with rhBMP-2 were more likely to obtain fusion after the initial surgery (93% versus 53%, p < 0.001; OR, 11.76; 95% CI, 3.12-44.41), spent less total time wearing the frame (124 versus 161 days, p < 0.01), and showed more bone bridging on CT scans (48% versus 32%, p < 0.05). All patients with greater than 30% bone bridging observed on CT scans 3 months postoperatively achieved successful union without further intervention. CONCLUSIONS: Our findings suggest that rhBMP-2 is a beneficial adjunct for selected groups of patients undergoing complex ankle arthrodesis. CT is a promising modality in the assessment of bone healing in ankle fusion. A proper randomized controlled trial remains necessary to fully describe the efficacy of rhBMP-2 in accelerating bone healing. PMID- 23990450 TI - Golgi fragmentation induced by heat shock or inhibition of heat shock proteins is mediated by non-muscle myosin IIA via its interaction with glycosyltransferases. AB - The Golgi apparatus is a highly dynamic organelle which frequently undergoes morphological changes in certain normal physiological processes or in response to stress. The mechanisms are largely not known. We have found that heat shock of Panc1 cells expressing core 2 N-acetylglucosaminyltransferase-M (Panc1-C2GnT-M) induces Golgi disorganization by increasing non-muscle myosin IIA (NMIIA)-C2GnT-M complexes and polyubiquitination and proteasomal degradation of C2GnT-M. These effects are prevented by inhibition or knockdown of NMIIA. Also, the speed of Golgi fragmentation induced by heat shock is found to be positively correlated with the levels of C2GnT-M in the Golgi. The results are reproduced in LNCaP cells expressing high levels of two endogenous glycosyltransferases-core 2 N acetylglucosaminyltransferase-L:1 and beta-galactoside:alpha2-3 sialyltransferase 1. Further, during recovery after heat shock, Golgi reassembly as monitored by a Golgi matrix protein giantin precedes the return of C2GnT-M to the Golgi. The results are consistent with the roles of giantin as a building block of the Golgi architecture and a docking site for transport vesicles carrying glycosyltransferases. In addition, inhibition/depletion of HSP70 or HSP90 in Panc1-C2GnT-M cells also causes an increase of NMIIA-C2GnT-M complexes and NMIIA mediated Golgi fragmentation but results in accumulation or degradation of C2GnT M, respectively. These results can be explained by the known functions of these two HSP: participation of HSP90 in protein folding and HSP70 in protein folding and degradation. We conclude that NMIIA is the master regulator of Golgi fragmentation induced by heat shock or inhibition/depletion of HSP70/90. PMID- 23990451 TI - Aprepitant's prophylactic efficacy in decreasing postoperative nausea and vomiting in morbidly obese patients undergoing bariatric surgery. AB - BACKGROUND: Postoperative nausea and vomiting is a major cause of patient dissatisfaction towards surgery. For bariatric surgery, increased vomiting/retching is detrimental to surgical anastomosis. The present study evaluated the efficacy of aprepitant (neurokinin-1 inhibitor) as a prophylactic antiemetic in morbidly obese patients for laparoscopic bariatric surgery. METHODS: After institutional review board approval, 125 morbidly obese patients were recruited into this double-blind placebo-controlled trial. On random division, the patients received a tablet of aprepitant (80 mg) in group A, or a similar-appearing placebo in group P, an hour prior to surgery. All patients received intravenous ondansetron (4 mg) intraoperatively. Postoperatively, the patients were evaluated for nausea and vomiting by a blinded evaluator at 30 min, 1, 2, 6, 24, 48, and 72 h. RESULTS: Both groups were evenly distributed for age, body mass index, type, and length of surgery. Cumulative incidence of vomiting at 72 h was significantly lower in group A (3%) compared to group P (15%; p = 0.021). Odds ratio for vomiting in group P compared to group A was 5.47 times. On Kaplan-Meier plot, time to first vomiting was also significantly delayed in group A (p = 0.019). A higher number of patients showed complete absence of nausea or vomiting in group A compared to group P (42.18 vs. 36.67%). On the other hand, nausea scores were unaffected by aprepitant, and no significant difference between groups was found at any of the measured time points. CONCLUSIONS: In morbidly obese patients undergoing laparoscopic bariatric surgery, addition of aprepitant to ondansetron can significantly delay vomiting episodes simultaneously lowering the incidence of postoperative vomiting. PMID- 23990452 TI - Laparoscopic single-anastomosis duodenal-jejunal bypass with sleeve gastrectomy (SADJB-SG): short-term result and comparison with gastric bypass. AB - Laparoscopic duodeno-jejunal bypass with sleeve gastrectomy (DJB-SG) has been introduced as a novel metabolic surgery from Asia recently. It provides benefits of avoiding the risk of remnant gastric cancer, minimization of malnutrition from duodenal switch. Here, we introduce the technique of single-loop anastomosis duodeno-jejunal bypass with sleeve gastrectomy (SADJB-SG) and compare with other gastric bypass surgeries. Fifty morbid obese patients underwent our novel procedure, laparoscopic SADJB-S from 2011 to 2013. Operative complication, weight loss, and diabetes remission were followed. All procedures were completed laparoscopically. The mean operative time was 181.7 +/- 38.4 min, and the mean hospital stay was 3.8 days. Three minor early complications (6 %) were encountered but no major complication was noted. There was no significant difference in perioperative parameters between the SADJB-SG and gastric bypass except a longer operation time. The mean BMI decreased from 38.4 to 25.4 at 1 year after surgery with a mean weight loss of 32.7 % which is higher than gastric bypass. Laparoscopic SADJB-SG appears to be an ideal metabolic/bariatric surgery, whereas the efficacy is non-inferior to gastric bypass. PMID- 23990453 TI - Reply to R. Vilallonga et al. PMID- 23990454 TI - Clinical aspects and diagnostic relevance of neuroautonomic evaluation in patients with unexplained falls. AB - OBJECTIVE: To evaluate the diagnostic relevance of neuroautonomic evaluation in patients with unexplained falls compared to those with a syncope etiologically unexplained after initial evaluation. METHODS: It is an observational study, comparing 298 patients with unexplained fall with 989 patients with unexplained syncope. Each patient underwent supine and upright blood pressure measurement, tilt testing (TT) and carotid sinus massage (CSM). RESULTS: Patients with unexplained falls were older (75.3 +/- 11.1 vs. 63.2 +/- 19.2 years, p < 0.001), were more frequently hypertensive (66.1 vs. 47.2 %, p < 0.001) and more frequently prescribed antihypertensive drugs (62.4 vs. 48.7 %, p < 0.001) or benzodiazepines (15.7 vs. 10.6 %, p = 0.01), and in a greater proportion they experienced major traumatic injuries (77.5 vs. 29.6 %, p < 0.001) as a consequence of falls. The TT was less frequently positive in patients with unexplained falls (36 vs. 51.3 %, p < 0.001), whereas a Carotid Sinus Syndrome as suggested by CSM had a similar prevalence in the two groups (14.3 vs. 10.5 %, p = 0.074). Overall, either TT or CSM were positive in 61 % of patients with unexplained falls, and in 64 % of those with syncope (p = 0.346). After matching by age 298 patients with falls (75.3 +/- 11.1 years) and 298 patients with unexplained syncope (75.4 +/- 11.1 years), we found that the positivity prevalence of TT and CSM were similar in the two groups. CONCLUSIONS: The positivity prevalence of TT and CSM in patients with unexplained falls compared to patients with unexplained syncope is similar. Given its high diagnostic relevance, the neuroautonomic evaluation should be routinely performed in older patients with unexplained falls. PMID- 23990455 TI - Gender differences in orthostatic tolerance in the elderly. AB - BACKGROUND: Gender differences in orthostatic tolerance in the elderly are poorly studied and understood. METHODS: 48 healthy elderly over 65 years (24 women), free from medication and without chronic diseases, were subjected to head-up tilt (HUT) tests: 30 degrees for 10 min and 70 degrees for 40 min. Blood pressures, stroke volume, total peripheral resistance, blood pressure variability, heart rate variability and baroreceptor sensitivity were measured and test terminations due to vasovagal syncope or unbearable presyncopal symptoms were registered. RESULTS: Mean age was 72; women and men differed in body mass index; 22.2 versus 24.8, respectively (p < 0.01). Mean blood pressures were lower among women, with 88 and 98 mmHg, respectively (p < 0.01) (rest) and 86 and 96 mmHg (p < 0.01) (tilt 30 degrees ). Mean total peripheral resistance index was significantly higher among women during 70 degrees tilt, 13.5 versus 10.8 (p < 0.01); no gender differences in heart rate were seen. Women had lower LF/HF ratio (an index of sympathovagal balance) at rest and during 30 degrees tilt (both p < 0.05); other heart rate variability measures and baroreceptor sensitivity did not differ. Two women, 9 %, and 8 men, 33 %, terminated head-up tilt test due to vasovagal syncope or presyncopal symptoms. Gender difference was marginally significant (p = 0.05, log-rank test). Higher heart rate at rest (p < 0.01) was the only variable significantly associated with the risk of syncope. CONCLUSIONS: Our results indicate that elderly men have poorer orthostatic tolerance during protracted postural stress than women of the same age. The underlying reason might be differences in vascular rather than cardiac autonomic control. PMID- 23990458 TI - Predictive effect of XRCC3 Thr241Met polymorphism on platinum-based chemotherapy in lung cancer patients: meta-analysis. AB - Previous published data on the association between X-ray repair cross complementing group 3 (XRCC3) Thr241Met polymorphism and clinical outcome of platinum-based chemotherapy in patients with lung cancer reported conflicting results. A meta-analysis was performed to provide a systematic review of the published data. We retrieved the relevant studies from PubMed and Embase databases. The primary outcome was overall survival, and the hazard ratio (HR) with 95% confidence interval (95% CI) was estimated. Seven studies with a total of 1,514 patients were included into the meta-analysis. Overall, XRCC3 Thr241Met polymorphism had no influence on the overall survival of lung cancer patients receiving platinum-based chemotherapy (MetMet vs. ThrThr: HR = 0.82, 95% CI 0.52 1.31, P = 0.410; MetThr vs. ThrThr: HR = 0.93, 95% CI 0.79-1.10, P = 0.339; MetMet/MetThr vs. ThrThr: HR = 1.07, 95% CI 0.88-1.31, P = 0.480). There was no obvious risk of publication bias. Therefore, currently available data suggest that there is no predictive effect of XRCC3 Thr241Met polymorphism on platinum based chemotherapy in lung cancer patients. PMID- 23990456 TI - Apicidin-resistant HA22T hepatocellular carcinoma cells massively promote pro survival capability via IGF-IR/PI3K/Akt signaling pathway activation. AB - Despite rapid advances in the diagnostic and surgical procedures, hepatocellular carcinoma (HCC) remains one of the most difficult human malignancies to treat. This may be due to the chemoresistant behaviors of HCC. It is believed that acquired resistance could be overcome and improve the overall survival of HCC patients by understanding the mechanisms of chemoresistance in HCC. A stable HA22T cancer line, which is chronically resistant to a histone deacetylase inhibitor, was established. After comparing the molecular mechanism of apicidin-R HA22T cells to parental ones by Western blotting, cell cycle-regulated proteins did not change in apicidin-R cells, but apicidin-R cells were more proliferative and had higher tumor growth (wound-healing assay and nude mice xenograft model). Moreover, apicidin-R cells displayed increased levels of p-IGF-IR, p-PI3K, p-Akt, Bcl-xL, and Bcl-2 but also significantly inhibited the tumor suppressor PTEN protein and apoptotic pathways when compared to the parental strain. Therefore, the highly proliferative effect of apicidin-R HA22T cells was blocked by Akt knockdown. For all these findings, we believe that novel strategies to attenuate IGF-IR/PI3K/Akt signaling could overcome chemoresistance toward the improvement of overall survival of HCC patients. PMID- 23990457 TI - XRCC1 Arg399Gln variation and leukemia susceptibility: evidence from 2,647 cases and 5,518 controls. AB - Previous reports implicate XRCC1 Arg399Gln polymorphism as a possible risk factor for several cancers. Increasing studies have been conducted on the association of XRCC1 Arg399Gln polymorphisms with susceptibility to leukemia. However, conflicting results have been generated. The goal of the present study was to derive a more precise estimation of the relationship. Meta-analyses assessing the association of XRCC1 Arg399Gln variation with leukemia were conducted, and subgroup analyses on ethnicity and clinical types were further performed. Eligible studies were identified for the period up to February 2013. Consequently, 16 publications including 17 case-control studies with 2,647 cases and 5,518 controls were selected for analysis. The overall data indicated a significant association of XRCC1 Arg399Gln polymorphism with leukemia risk (Gln/Gln versus Arg/Arg: OR = 1.37, 95% confidence interval (CI) = 1.08-1.74; dominant model: OR = 1.23, 95%CI = 1.03-1.46; recessive model: OR = 1.23, 95%CI = 1.06-1.44). In the subgroup analysis by ethnicity, Gln allele may increase leukemia susceptibility among Asians (Gln/Gln versus Arg/Arg: OR = 1.82, 95%CI = 1.19-2.78; dominant model: OR = 1.53, 95%CI = 1.00-2.33; recessive model: OR = 1.51, 95%CI = 1.11-2.06), but not Caucasians or mixed ethnicities. In the subgroup analysis by clinical types, increased risk was observed in acute lymphocytic leukemia (ALL) subgroup (Gln/Gln versus Arg/Arg: OR = 1.45, 95%CI = 1.09-1.93; recessive model: OR = 1.30, 95%CI = 1.00-1.69), but not in acute myeloid leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia subgroups, respectively. Collectively, the results of the present study suggest that XRCC1 Arg399Gln polymorphism might be a low-penetrant risk factor for leukemia, particularly among Asians. Homozygous Gln/Gln alleles might have a correlation with increased ALL susceptibility. PMID- 23990459 TI - Ovarian evaluation of Girolando (Holstein * Gir) heifers submitted to a GnRH PGF2alpha-GnRH protocol in the dry or rainy seasons in the tropical savannah. AB - The Girolando breed is used in pasture-based dairy production systems in Brazil to associate the high production of Bos taurus to the rusticity and thermal adaptation of Bos indicus. This study was designed to evaluate the physiological response to a gonadotropin-releasing hormone (GnRH)-prostaglandin F2alpha (PGF2alpha)-GnRH protocol to synchronize the ovulation in 40 Girolando heifers of a pasture-based dairy production system and its relationships with the temperature and humidity index (THI) during the dry (DS) and rainy season (RS) in the tropical savannah-Brazil's cerrado biome. Responses were characterized by follicular and corpus luteum number and diameter, ovulation (D9), and pregnancy rates after first AI. Total follicle number (8.1 +/- 0.3 * 8.8 +/- 0.3), D9 ovulatory follicle diameter (11.9 +/- 0.4 * 10.1 +/- 0.4 mm), corpus luteum diameter (8.6 +/- 1.3 * 3.9 +/- 1.5 mm), corpus luteum score (3.7 +/- 0.8 * 1.8 +/- 1.0), corpus luteum diameter after AI (9.6 +/- 1.6 * 3.9 +/- 1.5 mm), and corpus luteum score after AI (3.2 +/- 0.4 * 0.9 +/- 0.6) in DS and RS differed (P < 0.01). D9 ovulation rate was 40 % (DS) and 20 % (RS), without differences (P > 0.05). Pregnancy rate was 45 % (DS) and 11 % (RS), with differences (P < 0.01). THI differed between DS and RS (P < 0.01). THI may interfere in the follicular and luteal dynamics and in the response of Girolando heifers to the GnRH PGF2alpha protocol in the tropical savannah, thus reducing the chances of pregnancy at the first artificial insemination. PMID- 23990460 TI - Functional specificity of CpG DNA-binding CXXC domains in mixed lineage leukemia. AB - The MLL CXXC domain binds nonmethylated CpG-containing DNA and is essential for the oncogenic properties of MLL fusion proteins. To determine potential functional promiscuity of similar DNA binding domains, we replaced the MLL CXXC domain in the context of the leukemogenic MLL-AF9 fusion with CXXC domains from DNMT1, CGBP (CFP1), and MBD1, or with a methyl-CpG-binding domain (MBD) from MBD1. MLL(DNMT1 CXXC)-AF9 shows robust in vitro colony forming activity and in vivo leukemogenesis, similar to MLL-AF9. However, colony forming ability and leukemogenicity are abrogated in MLL-AF9 containing either the CGBP or MBD1 CXXC domains or the MBD1 MBD domain. Direct comparison of in vitro DNA binding affinity of the isolated CXXC or MBD domains demonstrated that MLL, DNMT1, and CGBP CXXC domains could each bind to unmethylated DNA but with differing affinity. In contrast, the isolated MBD1 CXXC and MBD1 MBD domains were unable to bind to the same DNA. However, all substituted domains still allowed targeting of the MLL fusions to the functionally important Hoxa9 locus in primary bone marrow progenitor cells. In addition to DNA binding activity, it was critical that specific CpG residues in the Hoxa9 locus were protected from methylation for leukemia development. This ultimately prevented histone 3 lysine 9 trimethylation (H3K9me3) of the locus and enabled Hoxa9 expression. These were properties shared by MLL and DNMT1 CXXC domains but not by CGBP CXXC or the other swapped fusions tested. We demonstrate that similar CXXC domains can be mechanistically distinguished by specificity of CpG nucleotides preferentially protected from DNA methylation. PMID- 23990461 TI - Direct comparison of mice null for liver or intestinal fatty acid-binding proteins reveals highly divergent phenotypic responses to high fat feeding. AB - The enterocyte expresses two fatty acid-binding proteins (FABP), intestinal FABP (IFABP; FABP2) and liver FABP (LFABP; FABP1). LFABP is also expressed in liver. Despite ligand transport and binding differences, it has remained uncertain whether these intestinally coexpressed proteins, which both bind long chain fatty acids (FA), are functionally distinct. Here, we directly compared IFABP(-/-) and LFABP(-/-) mice fed high fat diets containing long chain saturated or unsaturated fatty acids, reasoning that providing an abundance of dietary lipid would reveal unique functional properties. The results showed that mucosal lipid metabolism was indeed differentially modified, with significant decreases in FA incorporation into triacylglycerol (TG) relative to phospholipid (PL) in IFABP(-/ ) mice, whereas LFABP(-/-) mice had reduced monoacylglycerol incorporation in TG relative to PL, as well as reduced FA oxidation. Interestingly, striking differences were found in whole body energy homeostasis; LFABP(-/-) mice fed high fat diets became obese relative to WT, whereas IFABP(-/-) mice displayed an opposite, lean phenotype. Fuel utilization followed adiposity, with LFABP(-/-) mice preferentially utilizing lipids, and IFABP(-/-) mice preferentially metabolizing carbohydrate for energy production. Changes in body weight and fat may arise, in part, from altered food intake; mucosal levels of the endocannabinoids 2-arachidonoylglycerol and arachidonoylethanolamine were elevated in LFABP(-/-), perhaps contributing to increased energy intake. This direct comparison provides evidence that LFABP and IFABP have distinct roles in intestinal lipid metabolism; differential intracellular functions in intestine and in liver, for LFABP(-/-) mice, result in divergent downstream effects at the systemic level. PMID- 23990462 TI - Endoplasmic reticulum protein quality control is determined by cooperative interactions between Hsp/c70 protein and the CHIP E3 ligase. AB - The C terminus of Hsp70 interacting protein (CHIP) E3 ligase functions as a key regulator of protein quality control by binding the C-terminal (M/I)EEVD peptide motif of Hsp/c70(90) with its N-terminal tetratricopeptide repeat (TPR) domain and facilitating polyubiquitination of misfolded client proteins via its C terminal catalytic U-box. Using CFTR as a model client, we recently showed that the duration of the Hsc70-client binding cycle is a primary determinant of stability. However, molecular features that control CHIP recruitment to Hsp/c70, and hence the fate of the Hsp/c70 client, remain unknown. To understand how CHIP recognizes Hsp/c70, we utilized a dominant negative mutant in which loss of a conserved proline in the U-box domain (P269A) eliminates E3 ligase activity. In a cell-free reconstituted ER-associated degradation system, P269A CHIP inhibited Hsc70-dependent CFTR ubiquitination and degradation in a dose-dependent manner. Optimal inhibition required both the TPR and the U-box, indicating cooperativity between the two domains. Neither the wild type nor the P269A mutant changed the extent of Hsc70 association with CFTR nor the dissociation rate of the Hsc70-CFTR complex. However, the U-box mutation stimulated CHIP binding to Hsc70 while promoting CHIP oligomerization. CHIP binding to Hsc70 binding was also stimulated by the presence of an Hsc70 client with a preference for the ADP-bound state. Thus, the Hsp/c70 (M/I)EEVD motif is not a simple anchor for the TPR domain. Rather CHIP recruitment involves reciprocal allosteric interactions between its TPR and U-box domains and the substrate-binding and C-terminal domains of Hsp/c70. PMID- 23990463 TI - Ion-specific effects on prion nucleation and strain formation. AB - Ordered, fibrous, self-seeding aggregates of misfolded proteins known as amyloids are associated with important diseases in mammals and control phenotypic traits in fungi. A given protein may adopt multiple amyloid conformations, known as variants or strains, each of which leads to a distinct disease pattern or phenotype. Here, we study the effect of Hofmeister ions on amyloid nucleation and strain generation by the prion domain-containing fragment (Sup35NM) of a yeast protein Sup35p. Strongly hydrated anions (kosmotropes) initiate nucleation quickly and cause rapid fiber elongation, whereas poorly hydrated anions (chaotropes) delay nucleation and mildly affect the elongation rate. For the first time, we demonstrate that kosmotropes favor formation of amyloid strains that are characterized by lower thermostability and higher frangibility in vitro and stronger phenotypic and proliferation patterns effectively in vivo as compared with amyloids formed in chaotropes. These phenomena point to inherent differences in the biochemistry of Hofmeister ions. Our work shows that the ionic composition of a solution not only influences the kinetics of amyloid nucleation but also determines the amyloid strain that is preferentially formed. PMID- 23990464 TI - Binding between the junctional proteins afadin and PLEKHA7 and implication in the formation of adherens junction in epithelial cells. AB - Adherens junction (AJ) is a specialized cell-cell junction structure that plays a role in mechanically connecting adjacent cells to resist strong contractile forces and to maintain tissue structure, particularly in the epithelium. AJ is mainly comprised of cell adhesion molecules cadherin and nectin and their associating cytoplasmic proteins including beta-catenin, alpha-catenin, p120(ctn), and afadin. Our series of studies have revealed that nectin first forms cell-cell adhesion and then recruits cadherin to form AJ. The recruitment of cadherin by nectin is mediated by the binding of alpha-catenin and p120(ctn) to afadin. Recent studies showed that PLEKHA7 binds to p120(ctn), which is associated with E-cadherin, and maintains the integrity of AJ in epithelial cells. In this study, we showed that PLEKHA7 bound to afadin in addition to p120(ctn) and was recruited to the nectin-3alpha-based cell-cell adhesion site in a manner dependent on afadin, but not on p120(ctn). The binding of PLEKHA7 to afadin was required for the proper formation of AJ, but not for the formation of tight junction, in EpH4 mouse mammary gland epithelial cells. These results indicate that PLEKHA7 plays a cooperative role with nectin and afadin in the proper formation of AJ in epithelial cells. PMID- 23990465 TI - Functional characterization of human myosin-18A and its interaction with F-actin and GOLPH3. AB - Molecular motors of the myosin superfamily share a generic motor domain region. They commonly bind actin in an ATP-sensitive manner, exhibit actin-activated ATPase activity, and generate force and movement in this interaction. Class-18 myosins form heavy chain dimers and contain protein interaction domains located at their unique N-terminal extension. Here, we characterized human myosin-18A molecular function in the interaction with nucleotides, F-actin, and its putative binding partner, the Golgi-associated phosphoprotein GOLPH3. We show that myosin 18A comprises two actin binding sites. One is located in the KE-rich region at the start of the N-terminal extension and appears to mediate ATP-independent binding to F-actin. The second actin-binding site resides in the generic motor domain and is regulated by nucleotide binding in the absence of intrinsic ATP hydrolysis competence. This core motor domain displays its highest actin affinity in the ADP state. Electron micrographs of myosin-18A motor domain-decorated F actin filaments show a periodic binding pattern independent of the nucleotide state. We show that the PDZ module mediates direct binding of myosin-18A to GOLPH3, and this interaction in turn modulates the actin binding properties of the N-terminal extension. Thus, myosin-18A can act as an actin cross-linker with multiple regulatory modulators that targets interacting proteins or complexes to the actin-based cytoskeleton. PMID- 23990466 TI - Mitotic regulation of SEPT9 protein by cyclin-dependent kinase 1 (Cdk1) and Pin1 protein is important for the completion of cytokinesis. AB - Precise cell division is essential for multicellular development, and defects in this process have been linked to cancer. Septins are a family of proteins that are required for mammalian cell division, but their function and mode of regulation during this process are poorly understood. Here, we demonstrate that cyclin-dependent kinase 1 (Cdk1) phosphorylates septin 9 (SEPT9) upon mitotic entry, and this phosphorylation controls association with the proline isomerase, Pin1. Both SEPT9 and Pin1 are critical for mediating the final separation of daughter cells. Expression of mutant SEPT9 that is defective in Pin1 binding was unable to rescue cytokinesis defects caused by SEPT9 depletion but rather induced dominant-negative defects in cytokinesis. However, unlike SEPT9 depletion, Pin1 was not required for the accumulation of the exocyst complex at the midbody. These results suggest that SEPT9 plays multiple roles in abscission, one of which is regulated by the action of Cdk1 and Pin1. PMID- 23990467 TI - Steap4 plays a critical role in osteoclastogenesis in vitro by regulating cellular iron/reactive oxygen species (ROS) levels and cAMP response element binding protein (CREB) activation. AB - Iron is essential for osteoclast differentiation, and iron overload in a variety of hematologic diseases is associated with excessive bone resorption. Iron uptake by osteoclast precursors via the transferrin cycle increases mitochondrial biogenesis, reactive oxygen species production, and activation of cAMP response element-binding protein, a critical transcription factor downstream of receptor activator of NF-kappaB-ligand-induced calcium signaling. These changes are required for the differentiation of osteoclast precursors to mature bone resorbing osteoclasts. However, the molecular mechanisms regulating cellular iron metabolism in osteoclasts remain largely unknown. In this report, we provide evidence that Steap4, a member of the six-transmembrane epithelial antigen of prostate (Steap) family proteins, is an endosomal ferrireductase with a critical role in cellular iron utilization in osteoclasts. Specifically, we show that Steap4 is the only Steap family protein that is up-regulated during osteoclast differentiation. Knocking down Steap4 expression in vitro by lentivirus-mediated short hairpin RNAs inhibits osteoclast formation and decreases cellular ferrous iron, reactive oxygen species, and the activation of cAMP response element binding protein. These results demonstrate that Steap4 is a critical enzyme for cellular iron uptake and utilization in osteoclasts and, thus, indispensable for osteoclast development and function. PMID- 23990469 TI - Lack of CD47 impairs bone cell differentiation and results in an osteopenic phenotype in vivo due to impaired signal regulatory protein alpha (SIRPalpha) signaling. AB - Here, we investigated whether the cell surface glycoprotein CD47 was required for normal formation of osteoblasts and osteoclasts and to maintain normal bone formation activity in vitro and in vivo. In parathyroid hormone or 1alpha,25(OH)2 vitamin D3 (D3)-stimulated bone marrow cultures (BMC) from CD47(-/-) mice, we found a strongly reduced formation of multinuclear tartrate-resistant acid phosphatase (TRAP)(+) osteoclasts, associated with reduced expression of osteoclastogenic genes (nfatc1, Oscar, Trap/Acp, ctr, catK, and dc-stamp). The production of M-CSF and RANKL (receptor activator of nuclear factor kappabeta ligand) was reduced in CD47(-/-) BMC, as compared with CD47(+/+) BMC. The stromal cell phenotype in CD47(-/-) BMC involved a blunted expression of the osteoblast associated genes osterix, Alp/Akp1, and alpha-1-collagen, and reduced mineral deposition, as compared with that in CD47(+/+) BMC. CD47 is a ligand for SIRPalpha (signal regulatory protein alpha), which showed strongly reduced tyrosine phosphorylation in CD47(-/-) bone marrow stromal cells. In addition, stromal cells lacking the signaling SIRPalpha cytoplasmic domain also had a defect in osteogenic differentiation, and both CD47(-/-) and non-signaling SIRPalpha mutant stromal cells showed a markedly reduced ability to support osteoclastogenesis in wild-type bone marrow macrophages, demonstrating that CD47 induced SIRPalpha signaling is critical for stromal cell support of osteoclast formation. In vivo, femoral bones of 18- or 28-week-old CD47(-/-) mice showed significantly reduced osteoclast and osteoblast numbers and exhibited an osteopenic bone phenotype. In conclusion, lack of CD47 strongly impairs SIRPalpha dependent osteoblast differentiation, deteriorate bone formation, and cause reduced formation of osteoclasts. PMID- 23990468 TI - The paired-box homeodomain transcription factor Pax6 binds to the upstream region of the TRAP gene promoter and suppresses receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast differentiation. AB - Osteoclast formation is regulated by balancing between the receptor activator of nuclear factor-kappaB ligand (RANKL) expressed in osteoblasts and extracellular negative regulatory cytokines such as interferon-gamma (IFN-gamma) and interferon beta (IFN-beta), which can suppress excessive bone destruction. However, relatively little is known about intrinsic negative regulatory factors in RANKL mediated osteoclast differentiation. Here, we show the paired-box homeodomain transcription factor Pax6 acts as a negative regulator of RANKL-mediated osteoclast differentiation. Electrophoretic mobility shift and reporter assays found that Pax6 binds endogenously to the proximal region of the tartrate acid phosphatase (TRAP) gene promoter and suppresses nuclear factor of activated T cells c1 (NFATc1)-induced TRAP gene expression. Introduction of Pax6 retrovirally into bone marrow macrophages attenuates RANKL-induced osteoclast formation. Moreover, we found that the Groucho family member co-repressor Grg6 contributes to Pax6-mediated suppression of the TRAP gene expression induced by NFATc1. These results suggest that Pax6 interferes with RANKL-mediated osteoclast differentiation together with Grg6. Our results demonstrate that the Pax6 pathway constitutes a new aspect of the negative regulatory circuit of RANKL-RANK signaling in osteoclastogenesis and that the augmentation of Pax6 might therefore represent a novel target to block pathological bone resorption. PMID- 23990470 TI - Zn2+ mediates high affinity binding of heparin to the alphaC domain of fibrinogen. AB - The nonspecific binding of heparin to plasma proteins compromises its anticoagulant activity by reducing the amount of heparin available to bind antithrombin. In addition, interaction of heparin with fibrin promotes formation of a ternary heparin-thrombin-fibrin complex that protects fibrin-bound thrombin from inhibition by the heparin-antithrombin complex. Previous studies have shown that heparin binds the E domain of fibrinogen. The current investigation examines the role of Zn(2+) in this interaction because Zn(2+) is released locally by platelets and both heparin and fibrinogen bind the cation, resulting in greater protection from inhibition by antithrombin. Zn(2+) promotes heparin binding to fibrinogen, as determined by chromatography, fluorescence, and surface plasmon resonance. Compared with intact fibrinogen, there is reduced heparin binding to fragment X, a clottable plasmin degradation product of fibrinogen. A monoclonal antibody directed against a portion of the fibrinogen alphaC domain removed by plasmin attenuates binding of heparin to fibrinogen and a peptide analog of this region binds heparin in a Zn(2+)-dependent fashion. These results indicate that the alphaC domain of fibrinogen harbors a Zn(2+)-dependent heparin binding site. As a consequence, heparin-catalyzed inhibition of factor Xa by antithrombin is compromised by fibrinogen to a greater extent when Zn(2+) is present. These results reveal the mechanism by which Zn(2+) augments the capacity of fibrinogen to impair the anticoagulant activity of heparin. PMID- 23990471 TI - Functions of class V myosins in neurons. AB - This minireview focuses on recent studies implicating class V myosins in organelle and macromolecule transport within neurons. These studies reveal that class V myosins play important roles in a wide range of fundamental processes occurring within neurons, including the transport into dendritic spines of organelles that support synaptic plasticity, the establishment of neuronal shape, the specification of polarized cargo transport, and the subcellular localization of mRNA. PMID- 23990472 TI - Reciprocal regulation of very low density lipoprotein receptors (VLDLRs) in neurons by brain-derived neurotrophic factor (BDNF) and Reelin: involvement of the E3 ligase Mylip/Idol. AB - BDNF positively influences various aspects of neuronal migration, maturation, and survival in the developing brain. Reelin in turn mediates inhibitory signals to migrating neuroblasts, which is crucial for brain development. The interplay between BDNF and Reelin signaling in neurodevelopment is not fully understood. We show here that BDNF increased the levels of the Reelin receptor (VLDL receptor (VLDLR)) in hippocampal neurons by increasing gene expression. In contrast, Reelin decreased VLDLRs, which was accompanied by an increase in the levels of the E3 ligase Mylip/Idol in neurons. Down-regulation of Mylip/Idol using shRNAs abrogated the decrease in VLDLRs induced by Reelin. These results show that VLDLRs are tightly regulated in hippocampal neurons by both transcriptional and post-transcriptional mechanisms. The regulation of VLDLR by BDNF and Reelin may affect the migration of neurons and contribute to neurodevelopmental disorders in the nervous system. PMID- 23990474 TI - Mediating role of stress reactivity in the effects of prenatal tobacco exposure on childhood mental health outcomes. AB - INTRODUCTION: Prenatal tobacco exposure, through maternal smoking during pregnancy, has been associated with adverse mental health outcomes in childhood. However, the mechanisms by which prenatal tobacco exposure compromises mental health later in life are unclear. We hypothesized that sensitized reactivity to stressful life events in early childhood mediates the effect of prenatal tobacco exposure on mental health outcomes in middle childhood, after accounting for earlier mental health outcomes. METHODS: Data were from 12,308 mothers and their children drawn from the Avon Longitudinal Study of Parents and Children, a large prospective population-based study. Mothers' self-reports of smoking during pregnancy, mothers' ratings of their child's reactivity to stressful life events, and teachers' and mothers' ratings of the Strengths and Difficulties Questionnaire assessing 5 domains of mental health outcomes were measured. RESULTS: A positive association was found between prenatal tobacco exposure and stress reactivity between the ages of 2 and 6. In turn, stress reactivity was positively associated with peer (isolation), hyperactivity, conduct, and emotional problems (but not prosocial behaviors) between the ages of 7 and 11, after accounting for the mental health outcome at age 4 and other confounders. CONCLUSIONS: Heightened stress reactivity in preschool ages mediated the effect of prenatal tobacco exposure on adverse mental health outcomes between the ages of 7 and 11. Interventions to assist children exposed to tobacco smoke during gestation in coping with stressful life events may help mitigate psychiatric symptoms in this population. PMID- 23990476 TI - Rapid extraction of total RNA from an anaerobic sludge biocoenosis. AB - In order to assess the activity of metabolic pathways during anaerobic biogas production, it is necessary to isolate total RNA from the anaerobic sludge. mRNA activity profiling complements the quantification of excreted metabolites for a comprehensive anaerobic digestion model (ADM1). Four non-commercial total RNA extraction protocols were examined to extract total RNA from suspended solids of anaerobic sludge. The most suitable protocol was identified and optimised. In relation to total RNA extraction efficiency, total RNA purity and RNA integrity, the best homogenisation method was a combined method of nitrogen grinding and bead beating. When bead beating or nitrogen grinding was used alone for homogenisation, total RNA extraction efficiency was lower than when both homogenisation methods were applied. Depending on the homogenisation method, the whole RNA extraction procedure takes approximately 2 to 3 h, which is as fast as when using commercial available soil RNA extraction kits. The proposed method is rapid in extracting total RNA from a biocoenosis present in an anaerobic sludge environment. Furthermore, we could apply any of the extracted homogenization methods for reverse transcription and subsequent PCR amplification of the gene for the methyl coenzyme M reductase alpha subunit (mcrA/mrtA). PMID- 23990473 TI - Membrane vesicles nucleate mineralo-organic nanoparticles and induce carbonate apatite precipitation in human body fluids. AB - Recent studies indicate that membrane vesicles (MVs) secreted by various cells are associated with human diseases, including arthritis, atherosclerosis, cancer, and chronic kidney disease. The possibility that MVs may induce the formation of mineralo-organic nanoparticles (NPs) and ectopic calcification has not been investigated so far. Here, we isolated MVs ranging in size between 20 and 400 nm from human serum and FBS using ultracentrifugation and sucrose gradient centrifugation. The MV preparations consisted of phospholipid-bound vesicles containing the serum proteins albumin, fetuin-A, and apolipoprotein A1; the mineralization-associated enzyme alkaline phosphatase; and the exosome proteins TNFR1 and CD63. Notably, we observed that MVs induced mineral precipitation following inoculation and incubation in cell culture medium. The mineral precipitates consisted of round, mineralo-organic NPs containing carbonate hydroxyapatite, similar to previous descriptions of the so-called nanobacteria. Annexin V-immunogold staining revealed that the calcium-binding lipid phosphatidylserine (PS) was exposed on the external surface of serum MVs. Treatment of MVs with an anti-PS antibody significantly decreased their mineral seeding activity, suggesting that PS may provide nucleating sites for calcium phosphate deposition on the vesicles. These results indicate that MVs may represent nucleating agents that induce the formation of mineral NPs in body fluids. Given that mineralo-organic NPs represent precursors of calcification in vivo, our results suggest that MVs may initiate ectopic calcification in the human body. PMID- 23990475 TI - Smoking antecedents: separating between- and within-person effects of tobacco dependence in a multiwave ecological momentary assessment investigation of adolescent smoking. AB - INTRODUCTION: Ecological momentary assessment (EMA) investigations have shown that the antecedents of smoking vary with individual differences in tobacco dependence. This has been interpreted as indicating that the transition to dependence is characterized by an erosion of external stimulus control over smoking. Rigorously testing this requires collecting multiple waves of EMA data, which permits separation of the influence of between- and within-person tobacco dependence variation in multilevel models. METHODS: Adolescents (n = 313, 9th or 10th grade at baseline) participated in up to 4 waves of week-long EMA assessment over the course of 2 years as part of a larger longitudinal, observational study. At each wave, participants recorded contextual features and subjective states in response to prompted diary assessments and when smoking. They completed a youth specific form of the Nicotine Dependence Syndrome Scale at each wave. RESULTS: In cross-sectional multilevel analyses, smoking was less contingent on alcohol/drug use and was more common at home and in the morning for adolescents with higher levels of dependence. Multiwave analyses demonstrated that these effects were largely attributable to between-person variation in dependence, although parameter estimates for intraindividual dependence * antecedent effects tended to be in the predicted direction. DISCUSSION: Findings provided partial support for the contention that the antecedents of smoking shift as an individual progresses to higher levels of dependence. Distinctive choices concerning smoking settings also appear to reflect between-person differences in propensity to dependence. More generally, the findings illustrate the value of using multilevel modeling and repeated EMA assessments to investigate the correlates of tobacco dependence at different levels of analysis. PMID- 23990477 TI - Parkin induces upregulation of 40S ribosomal protein SA and posttranslational modification of cytokeratins 8 and 18 in human cervical cancer cells. AB - Parkin was originally identified as a protein associated with Parkinson's disease. Recently, numerous research studies have suggested that parkin acts as a tumor suppressor. In accordance with these studies, we previously reported that overexpression of parkin in HeLa cells induced growth inhibition. To elucidate possible mechanisms by which parkin may inhibit cell growth, HeLa cells were infected with adenoviruses expressing either the parkin gene or adenovirus alone for 72 h and a total proteomic analysis was performed using 2-D gel electrophoresis followed by LC-MS/MS. We identified three proteins whose expression changed between the two groups: the 40S ribosomal protein SA (RPSA) was downregulated in parkin virus-infected cells, and cytokeratins 8 and 18 exhibited an acid shift in pI value without a change in molecular weight, suggesting that these proteins became phosphorylated in parkin virus-infected cells. The changes in these three proteins were first observed at 60 h postinfection and were most dramatic at 72 h postinfection. Because upregulation of RPSA and dephosphorylation of cytokeratins 8/18 have been linked with tumor progression, these data suggest that parkin may inhibit cell growth, at least in part, by decreasing RPSA expression and inducing phosphorylation of cytokeratin 8/18. PMID- 23990478 TI - Synthesis and biological activity of new resveratrol derivative and molecular docking: dynamics studies on NFkB. AB - Resveratrol (RVS) is a naturally occurring antioxidant, able to display an array of biological activities. In the present investigation, a new derivative of RVS, RVS(a), was synthesized, and its biological activity was determined on U937 cells. It was observed that RVS(a) showed pronounced activity on U937 cells than RVS. RVS(a) is able to induce apoptosis in tumor cell lines through subsequent DNA fragmentation. From the EMSA results, it was evident that RVS(a) was able to suppress the activity of NFkB by interfering its DNA binding ability. Furthermore, the molecular interaction analysis (docking and dynamics) stated that RVS(a) has strong association with the IkB-alpha site of NFkB compared with RVS; this binding nature of RVS(a) might be prevent the NFkB binding ability with DNA. The present findings represent the potential activity of propynyl RVS on U937 cells and signifying it as a one of putative chemotherapeutic drugs against cancer. PMID- 23990480 TI - Expanded criteria for endoscopic treatment of early gastric cancer: safe in the long term if feasible in the short term! PMID- 23990479 TI - Endoscopic stenting of gastric staple line leak following sleeve gastrectomy. AB - Laparoscopic sleeve gastrectomy is known to be associated with a risk of gastric staple line leak. We report on our experience with endoscopic stenting of the anomalous leaking tract. Three cases of post sleeve gastric leak confirmed by computed tomography scan were treated by endoscopic stenting of their leak with a plastic endoprosthesis under fluoroscopic and endoscopic guidance. Endoscopic stenting by means of biliary or pancreatic endoprosthesis was successful in the three patients. The median number of endoscopy procedures per patient was 1.3. Stents were extracted 6 to 10 weeks after their placement. Neither morbidity nor recurrence was noticed on follow-up. Endoscopic stenting of gastric staple line leak following sleeve gastrectomy proved to be an efficacious technique for leak healing. PMID- 23990481 TI - Short- and long-term outcomes of endoscopic submucosal dissection for undifferentiated early gastric cancer. AB - BACKGROUND AND STUDY AIMS: Intramucosal undifferentiated early gastric cancer (EGC) up to 2 cm in size without ulceration has been treated by endoscopic submucosal dissection (ESD) because the incidence of lymph node metastasis is negligible. The aim of this retrospective study was to clarify the short-term and long-term outcomes of ESD carried out to treat undifferentiated EGC. PATIENTS AND METHODS: Between January 1999 and September 2011, 113 patients with poorly differentiated adenocarcinoma or signet ring cell carcinoma on preoperative biopsy underwent ESD. In 16 patients differentiated EGC had been diagnosed after the ESD and these patients were excluded from the study. Short-term outcomes were evaluated in the remaining 97 patients with undifferentiated EGC, and long-term outcomes analyzed in the 79 patients with undifferentiated EGC who had undergone ESD between 1999 and 2008. RESULTS: En bloc and R0 resection were achieved in 99.0 % and 90.7 % of patients, respectively. Median procedure time was 45 minutes. Postoperative bleeding, perforation during the procedure, and delayed perforation were noted in 4.1 %, 3.1 %, and 1.0 % respectively. Curative resection was achieved in 63.9 %. Additional surgery was performed in 21 of 35 patients in whom resection was noncurative: one (4.8 %) had local residual tumor and two (9.5 %) had lymph node metastases. Of the 46 /79 patients in the long term outcome group who had curative resection, none had local recurrence or lymph node or distant metastasis during a median follow-up of 76.4 months. The 5-year overall mortality rate after curative resection was 7.0 %, and no patient died of gastric cancer. CONCLUSIONS: ESD for undifferentiated EGC can achieve curative resection with an excellent 5-year mortality rate. PMID- 23990482 TI - Risk of electrocoagulation syndrome after endoscopic submucosal dissection in the colon and rectum. AB - BACKGROUND AND STUDY AIMS: The risk of post endoscopic submucosal dissection electrocoagulation syndrome (PEECS) is unknown. We aimed to investigate the incidence and clinicopathologic risk factors associated with PEECS after colorectal endoscopic submucosal dissection (ESD). PATIENTS AND METHODS: All patients treated with colorectal ESD between 2009 and 2011 by a single expert ESD endoscopist at Gangnam Severance Hospital, Seoul, Korea were included in this retrospective study. Patients who had fever, regional rebound tenderness, or marked leukocytosis after ESD were defined as having PEECS. RESULTS: 89 patients were treated during the study period. Six patients with microperforation and one patient with overt perforation were excluded. Thus, 82 cases without perforation were analyzed. The risk of PEECS was 40.2 %. In the PEECS group, the mean size of resected specimens was larger and mean procedure time was longer than in the patients without PEECS. The risk of PEECS was significantly lower for patients with carcinoid tumors, and for ESD in the rectosigmoid area. Piecemeal resection was significantly associated with the development of PEECS. In multivariate analysis, lesion size larger than 3 cm (odds ratio [OR] 5.0, 95 % confidence interval [95 %CI] 1.2 - 21.7) and site other than rectosigmoid (OR 7.6, 95 %CI 2.1 - 27.9) were independent risk factors for PEECS. CONCLUSIONS: Large tumor size and tumor site other than rectosigmoid were independent risk factors related to PEECS. Patients with tumors larger than 3 cm, in colon areas other than the rectosigmoid, should be observed carefully after colorectal ESD. PMID- 23990483 TI - Esophageal disease. PMID- 23990484 TI - Endoscopic tumor diagnosis and treatment. PMID- 23990485 TI - Gastrointestinal bleeding. PMID- 23990486 TI - ERCP. PMID- 23990487 TI - EUS. PMID- 23990488 TI - Colonoscopy. PMID- 23990489 TI - Capsule endoscopy and deep enteroscopy. PMID- 23990490 TI - Endoscopic innovations. PMID- 23990491 TI - Capsule endoscopy in acute upper gastrointestinal bleeding: goodbye to nasogastric tube aspiration? PMID- 23990492 TI - Reply to Stanciu et al. and Weber et al. PMID- 23990493 TI - Capsule endoscopy for acute upper gastrointestinal bleeding: is the cherry ripe yet? PMID- 23990495 TI - The influence of expertise of the surgical pathologist to undergrading, upgrading, and understaging of prostate cancer in patients undergoing subsequent radical prostatectomy. AB - PURPOSE: The main objective of this retrospective study was to evaluate the influence of pathological experience in histological examination of prostate cancer (PCa) on preoperative understaging (UNS), undergrading (UNG), and upgrading (UPG). METHODS: Histopathological data of prostate biopsy (PB) and radical prostatectomy (RP) specimens of patients undergoing subsequent radical prostatectomy (n = 430) in our center were compared. Histological diagnoses of PB were provided either by corresponding academic pathology institute (Group 1: 322 patients) or by external (nonacademic) departments which had a lower number (<= 100/year) of PCa histopathological evaluations (Group 2 108 patients). The rate of UNG, UPG, and UNS in both groups and also the effects of institutional learning curve were analyzed in terms of grading and staging. RESULTS: Significant difference was detected between Group 1 and Group 2 in average preoperative Gleason score (GS) values and in the rate of well, moderately, and poorly differentiated cancers as well. There was also a significant difference in the rate of UNG (29.1 vs. 56.5 %, p < 0.0001). The mean preoperative and postoperative GS in Group 1 was significantly lower in the first 50 than in the last 50 patients, but the rates of UNG, UPG, and UNS did not differ significantly between the groups. CONCLUSIONS: The experience of pathologists has direct influence on grading concordance and on UNG and UPG, between PB and RP specimen; however, it has no significant effect on complete preoperative understaging. The bigger pathological experience improves the sensitivity of the histological diagnostic process. PMID- 23990496 TI - Procalcitonin: diagnostic value in systemic infections in chronic kidney disease or renal transplant patients. AB - PURPOSE: Although procalcitonin (PCT) has been described as a marker of infection and inflammation, it has not been extensively studied in patients with chronic kidney disease (CKD), end stage renal disease, or renal transplant. METHODS: PCT was routinely tested in 82 (56 dialyzed patients and 28 renal transplant recipients) consecutive cases with a strong clinical suspicion of infection, during a 6-month period, in a single referral unit. RESULTS: During the study period, 58/82 cases had confirmed infections as per definition. Patients with confirmed infections had higher values for PCT [median = 2.5 ng/mL, interquartile range (IR) = 0.9-5 ng/mL] than those without (median = 0.3 ng/mL, IR = 0.1-0.5 ng/mL), p < 0.001. Overall, for a cutoff value of 0.5 ng/mL, the sensitivity of the test was 93.1 % and the specificity 78.6. CONCLUSION: Our data indicate that significantly elevated PCT concentrations offer good sensitivity and specificity for the early diagnosis of systemic bacterial infection in patients with CKD. PMID- 23990497 TI - Adherence to therapies in patients with type 2 diabetes. AB - Adherence to therapy is defined as the extent to which a person's behavior in taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a healthcare provider. Patients presenting with type 2 diabetes mellitus are initially encouraged to maintain a healthy diet and exercise regimen, followed by early medication that generally includes one or more oral hypoglycemic agents and later may include an injectable treatment. To prevent the complications associated with type 2 diabetes, therapy frequently also includes medications for control of blood pressure, dyslipidemia and other disorders, since patients often have more than three or four chronic conditions. Despite the benefits of therapy, studies have indicated that recommended glycemic goals are achieved by less than 50% of patients, which may be associated with decreased adherence to therapies. As a result, hyperglycemia and long-term complications increase morbidity and premature mortality, and lead to increased costs to health services. Reasons for nonadherence are multifactorial and difficult to identify. They include age, information, perception and duration of disease, complexity of dosing regimen, polytherapy, psychological factors, safety, tolerability and cost. Various measures to increase patient satisfaction and increase adherence in type 2 diabetes have been investigated. These include reducing the complexity of therapy by fixed-dose combination pills and less frequent dosing regimens, using medications that are associated with fewer adverse events (hypoglycemia or weight gain), educational initiatives with improved patient-healthcare provider communication, reminder systems and social support to help reduce costs. In the current narrative review, factors that influence adherence to different therapies for type 2 diabetes are discussed, along with outcomes of poor adherence, the economic impact of nonadherence, and strategies aimed at improving adherence. PMID- 23990498 TI - Influence of fructose and fatty-rich diet combined with vanadium on bone marrow cells. AB - The aim of the study is to investigate the influence of diet treatment on bone marrow cells. Normal male Wistar rats were divided into six groups (n = 6 per group): control with normal diet (C), increased fructose (31 % w/w in fodder) (Fr) and high fatty (30 % w/w of animal fat in fodder) diet (Fa), and the same diets with vanadium complex ([VO(4,4' Me2-2,2' Bpy)2]SO4) . H2O (CV, FrV and FaV). During 5 weeks, the animals had unlimited access to food and water. Immediately after anaesthetizing and sacrificing the animals, bone marrow smears were prepared from the femurs. Different types of cell lines in the animal smears were examined under the microscope: erythroid line, myeloid line, monocytic line, megakariocytic line and lymphoid line. Addition of fructose or animal fat had evident influence on the proportional composition of the bone marrow cells. In erythroid precursors, addition of both investigated products resulted in a statistically significant increase of percentage of this type of cells. A reverse effect was observed for the lymphoid cell line where addition of both tested diets decreased quantity of these cells in comparison to the control diet. In the same lines, addition of vanadium intensified the observed changes. In the case of other types of cell lines, statistically significant changes were not observed. PMID- 23990499 TI - Effects of 5-fluorouracil on oxidative stress and calcium levels in the blood of patients with newly diagnosed colorectal cancer. AB - The administration of chemotherapeutic agents for colorectal carcinoma is associated with an increase in oxidative stress and a concomitant decrease in antioxidant and element levels in the blood. This study investigated the effects of 5-fluorouracil (5-FU) chemotherapy on the levels of lipid peroxidation, reduced glutathione (GSH), glutathione peroxidase (GSH-Px), antioxidant vitamins, and elements in colorectal cancer patients. Twelve patients with newly diagnosed colorectal carcinoma and 12 healthy subjects were included in this study. Blood samples were collected from both the healthy controls and patients. 5-FU was intravenously administered to the patients for 6 weeks, and blood samples were collected again from the treatment group. In the patient group, lipid peroxidation levels were increased in both the plasma and erythrocyte samples, whereas GSH-Px activity and concentrations of GSH, vitamin E, and beta-carotene in erythrocytes were decreased. The oxidant, antioxidant, and plasma calcium values were lower in 5-FU-treated patients than in the controls. Plasma vitamin A, chloride, sodium, and potassium concentrations did not change with 5-FU treatment. In conclusion, oxidative stress in patients with newly diagnosed colorectal cancer is attributable to the disease and not to 5-FU treatment. Blood vitamin E, beta-carotene, GSH, and GSH-Px levels could be useful as early biomarkers of the prognosis of colorectal cancer patients. PMID- 23990501 TI - 2012 AAPS National Biotech Conference Open Forum: a perspective on the current state of immunogenicity prediction and risk management. AB - The immunogenicity profile of a biotherapeutic is determined by multiple product , process- or manufacturing-, patient- and treatment-related factors and the bioanalytical methodology used to monitor for immunogenicity. This creates a complex situation that limits direct correlation of individual factors to observed immunogenicity rates. Therefore, mechanistic understanding of how these factors individually or in concert could influence the overall incidence and clinical risk of immunogenicity is crucial to provide the best benefit/risk profile for a given biotherapeutic in a given indication and to inform risk mitigation strategies. Advances in the field of immunogenicity have included development of best practices for monitoring anti-drug antibody development, categorization of risk factors contributing to immunogenicity, development of predictive tools, and development of effective strategies for risk management and mitigation. Thus, the opportunity to ask "where we are now and where we would like to go from here?" was the main driver for organizing an Open Forum on Improving Immunogenicity Risk Prediction and Management, conducted at the 2012 American Association of Pharmaceutical Scientists' (AAPS) National Biotechnology Conference in San Diego. The main objectives of the Forum include the following: to understand the nature of immunogenicity risk factors, to identify analytical tools used and animal models and management strategies needed to improve their predictive value, and finally to identify collaboration opportunities to improve the reliability of risk prediction, mitigation, and management. This meeting report provides the Forum participant's and author's perspectives on the barriers to advancing this field and recommendations for overcoming these barriers through collaborative efforts. PMID- 23990500 TI - A mathematical model of the effect of immunogenicity on therapeutic protein pharmacokinetics. AB - A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADA mediated drug clearance, the model provides an approach to characterize ADA generation during the study, including the maximum ADA response, sensitivity of ADA response to drug dose level, affinity maturation rate, time lag to observe an ADA response, and the elimination rate for ADA-drug complex. The model also provides a mean to estimate putative concentration-time profiles for ADA, ADA drug complex, and ADA binding affinity-time profile. When simulating ADA responses to various drug dose levels, bell-shaped dose-response curves were generated. The model contains simultaneous quantitative modeling and provides estimation of the characteristics of therapeutic protein drug PK and ADA responses in vivo. With further experimental validation, the model may be applied to the simulation of ADA response to therapeutic protein drugs in silico, or be applied in subsequent PK/PD models. PMID- 23990502 TI - Statistical and bioanalytical considerations for establishing a depletion criterion for specificity testing during immunogenicity assessment of a biotherapeutic. AB - Immunogenicity assessment of fully human monoclonal antibody-based biotherapeutics requires sensitive and specific ligand binding assays. One of the components of specificity is the depletion of signal by a relevant biotherapeutic that is commonly based on an arbitrary depletion criterion of inhibition of the original response or reduction of the signal below the screening assay cut point (ACP). Hence, there is a need to develop a statistically derived physiologically relevant specificity criterion. We illustrate an optimization approach to determine the concentration of biotherapeutic required for the specificity evaluation. Naive donor sample sets with and without circulating drug and antitherapeutic/drug antibody (ADA) were prepared. Next, a depletion cut point (DCP) using naive and ADA-containing donor sets with the optimized biotherapeutic concentration was evaluated. A statistically derived design of experiment was used to establish a validated DCP. A reliable DCP requires naive (no ADA) donors treated only with an optimized concentration of biotherapeutic. The additional DCPs generated using two distinct concentrations of ADA-spiked sample sets led to a physiologically irrelevant criterion that was not necessarily representative of real-time samples. This increased the risk of false positives or negatives. In this study, well-defined bioanalytical and statistical methods were employed to validate a DCP to confirm the presence of biotherapeutic specific ADA in human serum samples. A physiologically relevant and effective strategy to confirm specificity in immune reactive samples, especially those that are close to the ACP, is proposed through this study. PMID- 23990503 TI - Effect of PEG surface conformation on anticancer activity and blood circulation of nanoemulsions loaded with tocotrienol-rich fraction of palm oil. AB - Tocotrienol-rich fraction of palm oil, which contains the isomers of vitamin E, was shown to possess potent anticancer activity against mammary adenocarcinoma cell lines. Its clinical use, however, is limited by poor oral bioavailability and short half-life. Previously, we developed tocotrienol-rich lipid nanoemulsions for intravenous administration. The objective of this study was to investigate the effect of surface grafted polyethylene glycol (PEG) on the properties of the nanoemulsions. PEGylation was achieved by the addition of equimolar PEG groups using poloxamer or 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-[amino(polyethylene glycol)2000] (PEG2000-DSPE). The effect of PEG surface topography on the antiproliferative activity of nanoemulsions against mammary adenocarcinoma cells, their susceptibility to protein adsorption, and its effect on blood hemolysis and circulation time was investigated. Nanoemulsions PEGylated with poloxamer or PEG2000-DSPE were stable under physical stress. Poloxamer nanoemulsion, however, displayed higher uptake and potency against MCF-7 tumor cells in 2D and 3D culture and increased hemolytic effect and susceptibility to IgG adsorption, which was reflected in its rapid clearance and short circulation half-life (1.7 h). Conversely, PEGylation with PEG2000-DSPE led to a 7-fold increase in mean residence time (12.3 h) after IV injection in rats. Reduced activity in vitro and improved circulation time suggested strong shielding of plasma proteins from the droplets. Differences between the nanoemulsions were attributed to polymer imbibitions and the differences in PEG conformation and density on the surface of the droplets. PMID- 23990504 TI - Radionuclide decorporation: matching the biokinetics of actinides by transdermal delivery of pro-chelators. AB - The threat of nuclear terrorism by the deliberate detonation of a nuclear weapon or radiological dispersion device ("dirty bomb") has made emergency response planning a priority. The only FDA-approved treatments for contamination with isotopes of the transuranic elements Am, Pu, and Cm are the Ca and Zn salts of diethylenetriaminepentaacetic acid (DTPA). These injectable products are not well suited for use in a mass contamination scenario as they require skilled professionals for their administration and are rapidly cleared from the circulation. To overcome the mismatch in the pharmacokinetics of the DTPA and the biokinetics of these transuranic elements, which are slowly released from contamination sites, the penta-ethyl ester of DTPA (C2E5) was prepared and formulated in a nonaqueous gel for transdermal administration. When gels comprised of 40% C2E5, 40-45% Miglyol(r) 840, and 15-20% ethyl cellulose were spiked with [(14)C]-C2E5 and applied to rat skin; over 60% of the applied dose was absorbed within a 24-h period. Radioactivity was observed in urinary and fecal excretions for over 3 days after removal of the gel. Using an (241)Am wound contamination model, transdermal C2E5 gels were able to enhance total body elimination and reduce the liver and skeletal burden of (241)Am in a dose dependent manner. The efficacy achieved by a single 1,000 mg/kg dose to contaminated rats was statistically comparable to intravenous Ca-DTPA at 14 mg/kg. The effectiveness of this treatment, favorable sustained release profile of pro-chelators, and ease of administration support its use following radiological emergencies and for its inclusion in the Strategic National Stockpile. PMID- 23990506 TI - Left coronary artery fistula to right ventricle complicated heart failure in a patient on hemodialysis. PMID- 23990505 TI - A Markov chain model to evaluate the effect of CYP3A5 and ABCB1 polymorphisms on adverse events associated with tacrolimus in pediatric renal transplantation. AB - The SNP A6986G of the CYP3A5 gene (*3) results in a non-functional protein due to a splicing defect whereas the C3435T was associated with variable expression of the ABCB1 gene, due to protein instability. Part of the large interindividual variability in tacrolimus efficacy and toxicity can be accounted for by these genetic factors. Seventy-two individuals were examined for A6986G and C3435T polymorphism using a PCR-RFLP-based technique to estimate genotype and allele frequencies in the Jordanian population. The association of age, hematocrit, platelet count, CYP3A5, and ABCB1 polymorphisms with tacrolimus dose- and body weight-normalized levels in the subset of 38 pediatric renal transplant patients was evaluated. A Markov model was used to evaluate the time-dependent probability of an adverse event occurrence by CYP3A5 phenotypes and ABCB1 genotypes. The time dependent probability of adverse event was about double in CYP3A5 non-expressors compared to the expressors for the first 12 months of therapy. The CYP3A5 non expressors had higher corresponding normalized tacrolimus levels compared to the expressors in the first 3 months. The correlation trend between probability of adverse events and normalized tacrolimus concentrations for the two CYP3A5 phenotypes persisted for the first 9 months of therapy. The differences among ABCB1 genotypes in terms of adverse events and normalized tacrolimus levels were only observed in the first 3 months of therapy. The information on CYP3A5 genotypes and tacrolimus dose requirement is important in designing effective programs toward management of tacrolimus side effects particularly for the initial dose when tacrolimus blood levels are not available for therapeutic drug monitoring. PMID- 23990507 TI - Which patients are seen by an occupational psychiatry service? AB - BACKGROUND: Common mental disorders are the leading cause of sickness absence but are frequently misdiagnosed and undertreated. It is against this background that a specialist occupational psychiatry clinic was established at a London teaching hospital. AIMS: To explore the nature of patients and complaints seen in the clinic and investigate whether this form of service provision reached patients who may have otherwise been missed in the gap between primary and secondary care. METHODS: We reviewed the case notes of 51 consecutive new clinic assessments using a data extraction form, gathering information on socio-demographic and occupational details; the nature, duration and severity of symptoms [as assessed by Health of the Nation Outcome Scale (HoNOS)]; diagnosis; prior treatment and the outcome of the clinic appointment. RESULTS: Only half of those seen in the new clinic were currently on sick leave. The most common diagnosis was depression with most having symptoms lasting longer than 9 months. Sixty-five per cent had a medium or high HoNOS rating. Although 75% had received treatment from their general practitioner, the majority remained functionally impaired, and only 31% had been seen in secondary care. CONCLUSIONS: Specialist occupational psychiatry clinics do not replicate the work already being done by standard mental health services. Patients referred to a new specialist clinic within an occupational health department had chronic, debilitating psychiatric illnesses, which in many cases had failed to respond adequately to primary care treatment and were at risk of falling into the gap between primary and secondary services. PMID- 23990508 TI - Sutureless thyroidectomy with energy-based devices: Cerrahpasa experience. AB - Total thyroidectomy makes up the majority of all thyroidectomy cases. Energy based advanced vessel-sealing devices which were developed in recent years for the control of vascular pedicles allowed significant progress in thyroid surgery. This study is designed to compare the efficiency and safety of the two energy based vessel-sealing devices (LigasureTM LF1212 and Harmonic FOCUS((r))) in sutureless thyroidectomy. Two hundred and forty-five consecutive patients underwent sutureless total thyroidectomy. Patients were randomized for the LigasureTM LF1212 (n = 126) or Harmonic FOCUS((r)) (n = 119). The parameters of demographics, surgical indications, morbidity, incision length, duration of operation, weight of specimen, amount of drainage, postoperative pain, hospital stay, and histopathology of specimen were recorded. Mean duration of operation was 37.98 +/- 14.98 min (16-92 min) and was significantly shorter for Harmonic FOCUS((r)) (p < 0.001). Mean hospital stay was 1.09 +/- 0.3 (1-3) days. Morbidity rate was 9.8 % in total, whereas no mortality was observed. In terms of morbidity rates, no significant difference was determined between the two groups (p = 0.476). In both groups, there was no need for extra analgesic application other than the routine given after surgery. According to our experience, sutureless thyroidectomy can be performed with low morbidity rates in secure and efficient way. PMID- 23990509 TI - Influence of novel gallium complexes on the homeostasis of some biochemical and hematological parameters in rats. AB - The aim of this study was to detect possible homeostasis changes in some biochemical and hematological parameters after the administration of gallium (Ga) complexes C (24) and C (85) on an experimental animal model (Wistar strain rats). In order to observe chronobiological aspects, a morning (m) and an evening (e) animal series were constituted. Further on, each series were divided into three groups: control (C), experimental I (EI), and experimental II (EII). Both Ga complexes were solubilized in a carrier solution containing polyethylene glycol (PEG) 400, water, and ethanol. Animals of the C groups received the carrier solution by intraperitoneal injection, those from the EI groups received the solubilized C(24) gallium complex, and those of the EII groups received the solubilized C(85) gallium complex. At the end of the experiment, blood and tissue samples were taken and the following parameters were determined: serum concentration of the nonprotein nitrogenous compounds (uric acid, creatinine, and blood urea nitrogen), hematological parameters (erythrocytes, hemoglobin, leukocytes, and platelets), and the kidney tissue concentration of three essential trace elements (Fe, Cu, and Zn). With the exception of uric acid, the results revealed increased concentrations of the nonprotein nitrogenous compounds both in the morning and in the evening experimental groups. Hematological data showed increased levels of erythrocytes, hemoglobin, and leukocytes and decreased platelet levels in the experimental group given the C(24) gallium complex in the morning (EI-m) group; increased levels of leukocytes and decreased levels of the other parameters in the experimental group given the C(24) gallium complex in the evening (EI-e) group; and increased levels of all hematological parameters in the experimental groups receiving the C(85) gallium complex in the morning (EII-m) group and in the evening (EII-e) group. Decreased kidney tissue concentrations of metals were found in all the experimental groups. Fe levels were significantly decreased in the EI-m receiving the C(24) gallium complex and EII-m which received the C(85) gallium complex and in the EII-e group which received the C(85) gallium complex. In the EI-e group which received the C(24) gallium complex, a significant decrease of Cu concentration was reported. PMID- 23990510 TI - Analysis of chromosomal polymorphism in barley (Hordeum vulgare L. ssp. vulgare) and between H. vulgare and H. chilense using three-color fluorescence in situ hybridization (FISH). AB - The aim of the present work was to study chromosomal polymorphism within cultivated barley (Hordeum vulgare ssp. vulgare) using three-color fluorescence in situ hybridization (FISH). The physical distribution of the most frequently used, highly repetitive DNA sequences (GAA)7 specific for pericentromeric heterochromatic regions, the ribosomal DNA clone pTa71, specific for the 45S rDNA, and the barley-specific telomere-associated sequence HvT01, was investigated to reveal genetic diversity in metaphase spreads of ten barley genotypes with diverse geographical origin, growth habit and row number. A wild relative of barley, Hordeum chilense was also studied in order to compare the polymorphism between and within Hordeum species. Significant differences in the hybridization patterns of all three DNA probes could be detected between the two related species, but only probes pTa71 and HvT01 showed variation in the intensity and/or position of hybridization sites among genotypes of H. vulgare ssp. vulgare. The extent of polymorphism was less than that earlier reported for molecular markers and was restricted to the long chromosome arms, with differences between the chromosomes. 1H and 3H proved to be the most variable chromosomes and 4H and 6H the most conserved. PMID- 23990511 TI - Metabolomics reveals broad-scale metabolic perturbations in hyperglycemic mothers during pregnancy. AB - OBJECTIVE To characterize metabolites across the range of maternal glucose by comparing metabolomic profiles of mothers with high and low fasting plasma glucose (FPG). RESEARCH DESIGN AND METHODS We compared fasting serum from an oral glucose tolerance test at ~28 weeks' gestation from 67 Northern European ancestry mothers from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study with high (>90th percentile) FPG with 50 mothers with low (<10th percentile) FPG but comparable BMI. Metabolic data from biochemical analyses of conventional clinical metabolites, targeted mass spectrometry (MS)-based measurement of amino acids, and nontargeted gas chromatography/MS were subjected to per-metabolite analyses and collective pathway analyses using Unipathway annotation. RESULTS High-FPG mothers had a metabolic profile consistent with insulin resistance including higher triglycerides, 3-hydroxybutyrate, and amino acids including alanine, proline, and branched-chain amino acids (false discovery rate [FDR]-adjusted P < 0.05). Lower 1,5-anhydroglucitol in high-FPG mothers suggested recent hyperglycemic excursions (FDR-adjusted P < 0.05). Pathway analyses indicated differences in amino acid degradation pathways for the two groups (FDR-adjusted P < 0.05), consistent with population-based findings in nonpregnant populations. Exploratory analyses with newborn outcomes indicated positive associations for maternal triglycerides with neonatal sum of skinfolds and cord C-peptide and a negative association between maternal glycine and cord C-peptide (P < 0.05). CONCLUSIONS Metabolomics reveals perturbations in metabolism of major macronutrients and amino acid degradation pathways in high- versus low-FPG mothers. PMID- 23990513 TI - Toward defining a cutoff score for elevated fear of hypoglycemia on the hypoglycemia fear survey worry subscale in patients with type 2 diabetes. AB - OBJECTIVE To determine a cutoff score for clinically meaningful fear of hypoglycemia (FoH) on the Hypoglycemia Fear Survey Worry subscale (HFS-W). RESEARCH DESIGN AND METHODS Data on the HFS-W, history of hypoglycemia, emotional well-being (World Health Organization-5 well-being index), and distress about diabetes symptoms (Diabetes Symptom Checklist-Revised) were available from Dutch patients with type 2 diabetes who were treated with oral medication or insulin (n = 1,530). Four criteria were applied to define a threshold for clinically meaningful FoH: 1) modal score distribution (MD criterion), 2) scores 2 SDs above the mean (SD criterion), 3) concurrent validity with severe hypoglycemia and suboptimal well-being (CV criterion), and 4) an elevated score (>=3) on more than one HFS-W item (elevated item endorsement [EI criterion]). Associations between the outcomes of these approaches and a history of severe hypoglycemia and suboptimal well-being were studied. RESULTS Of the 1,530 patients, 19% had a HFS W score of 0 (MD criterion), and 5% reported elevated FoH (HFS-W >= mean + 2 SD; SD criterion). Patients with severe hypoglycemia reported higher HFS-W scores than those without (25 +/- 20 vs. 15 +/- 17; P < 0.001). Patients with suboptimal well-being reported higher HFS-W scores than those with satisfactory well-being (20 +/- 18 vs. 13 +/- 15; P < 0.001, CV criterion). Elevated FoH (defined by the EI criterion) was seen in 26% of patients. The SD and EI criteria were the strongest associated with history of severe hypoglycemia. The EI criterion was the strongest associated with suboptimal well-being. CONCLUSIONS Although no definite cutoff score has been determined, the EI criterion may be most indicative of clinically relevant FoH in this exploratory study. Further testing of the clinical relevance of this criterion is needed. PMID- 23990514 TI - Higher relative risk for multiple sclerosis in a pediatric and adolescent diabetic population: analysis from DPV database. AB - OBJECTIVE Type 1 diabetes and multiple sclerosis (MS) are typical autoimmune diseases in children and young adults. We assessed the co-occurrence of type 1 diabetes and MS by estimating the relative risk (RR) for MS in a pediatric and adolescent diabetic population and looked for possible influencing factors. RESEARCH DESIGN AND METHODS Within the Diabetes Patienten Verlaufsdokumentation (DPV)-Wiss Project, from January 1995 to October 2012, data from 56,653 patients with type 1 diabetes were collected in 248 centers in Germany and Austria. Published data on German and Mid-European MS prevalence were taken for comparison. Multivariable regression analysis was used to identify confounders for co-occurrence of type 1 diabetes and MS. RESULTS The RR for MS in patients with type 1 diabetes was estimated at 3.35-4.79 (95% CI 1.56-7.21 and 2.01-11.39, respectively). Immigration status in all patients (P < 0.05) and the presence of thyroid antibodies in male patients only (P = 0.05) were identified as influencing factors on MS incidence within the DPV database. The month-of-birth pattern revealed that risk was higher during the spring and summer months in the population with type 1 diabetes and MS in comparison with the population with type 1 diabetes. CONCLUSIONS The present cohort study demonstrates a higher risk of co-occurrence of MS in a pediatric and adolescent diabetic population. Immigration status and thyroid antibodies in male patients were independent risk indicators for the incidental rate of MS. Diabetic patients born during spring and summer had a higher risk for the development of MS. We suggest that environmental factors modulate the individual's risk for the co-occurrence of both diseases. PMID- 23990515 TI - Experiences, views, and support needs of family members of people with hypoglycemia unawareness: interview study. AB - OBJECTIVE Hypoglycemia unawareness (HU) affects ~25% of people with type 1 diabetes. People with HU are often reliant on family to detect hypoglycemia and treat severe episodes. We explored the impact of HU on family members' lives, their involvement in preventing and managing hypoglycemia, and their information and support needs. RESEARCH DESIGN AND METHODS This study employed an exploratory, qualitative design comprising in-depth interviews with 24 adult family members of persons with type 1 diabetes and HU. RESULTS Family members described restricting their lives so that they could help the person with HU detect and treat hypoglycemia. Some described being very physically afraid of their partner/relative when they had a hypoglycemic episode due to their aggressive and argumentative behavior and personality changes; this could also make treatment administration difficult. Family members also reported feeling anxious and worried about the safety of the person with HU, particularly when they were left unsupervised. These concerns were often precipitated by traumatic events, such as discovering the person with HU in a coma. Family members could neglect their own health and well-being to care for the person with HU and resentment could build up over time. Family members highlighted extensive, unmet needs for information and emotional support; however, some struggled to recognize and accept their own need for help. CONCLUSIONS Our findings reveal a caregiver group currently "in the shadow of the patient" and in urgent need of information and emotional support. Raising awareness among health care professionals is essential, and developing proactive support for family should be considered. PMID- 23990512 TI - Cardiovascular events and geriatric scale scores in elderly (70 years old and above) type 2 diabetic patients at inclusion in the GERODIAB cohort. AB - OBJECTIVE To analyze the relationships between cardiovascular complications and geriatric scale scores in French elderly (>=70 years of age) type 2 diabetic patients at inclusion in the GERODIAB cohort. RESEARCH DESIGN AND METHODS GERODIAB is the first French multicenter, prospective, observational survey designed to analyze the influence of glycemic control on morbidity/mortality in type 2 diabetic patients aged >=70 years during a 5-year follow-up period. This study analyzed the relationships between classical macroangiopathic complications and geriatric scale scores in 987 patients at baseline, using bivariate and multivariate analyses. RESULTS Cardiac ischemia (31.2%) was significantly associated with impaired activities of daily living (ADL) scores (P < 0.001). Stepwise logistic regression included hypercholesterolemia, ADL, sex, and hypertension successively (70.3% concordance; P < 0.001). Heart failure (10.1%) was associated with impaired Mini Mental State Examination (MMSE), instrumental ADL (IADL) (P < 0.05), and ADL scores (P < 0.001). With the logistic model, waist circumference, age, and HDL cholesterol were significant factors (70.7% concordance; P < 0.001). Arterial disease of the lower limbs (25.6%) was associated with impaired IADL and ADL scores (P < 0.001). Significant factors using the logistic model were duration of diabetes, IADL score, hypertension, and sex (62.8% concordance; P < 0.001). Cerebral ischemia (15.8%) was associated with impaired MMSE, Mini Nutritional Assessment, ADL, and IADL scores (P < 0.01). IADL, sex, hypertension, and ADL were included in the logistic model successively (65.6% concordance; P < 0.001). CONCLUSIONS In this specific population, impaired geriatric scale scores were found to be associated with classical macrovascular complications, notably using multivariate analyses. This suggests the benefits of thorough screening and management of cognitive and functional decline in elderly type 2 diabetic patients. PMID- 23990516 TI - Residual beta-Cell function 3-6 years after onset of type 1 diabetes reduces risk of severe hypoglycemia in children and adolescents. AB - OBJECTIVE: To determine the prevalence of residual beta-cell function (RBF) in children after 3-6 years of type 1 diabetes, and to examine the association between RBF and incidence of severe hypoglycemia, glycemic control, and insulin requirements. RESEARCH DESIGN AND METHODS: A total of 342 children (173 boys) 4.8 18.9 years of age with type 1 diabetes for 3-6 years were included. RBF was assessed by testing meal-stimulated C-peptide concentrations. Information regarding severe hypoglycemia within the past year, current HbA1c, and daily insulin requirements was retrieved from the medical records and through patient interviews. RESULTS: Ninety-two children (27%) had RBF >0.04 nmol/L. Patients with RBF <0.04 nmol/L were significantly more likely to have severe hypoglycemia than patients with RBF >0.04 nmol/L (odds ratio, 2.59; 95% CI, 1.10-7.08; P < 0.03). HbA1c was significantly higher in patients with RBF <0.04 nmol/L compared with patients with RBF >0.04 nmol/L (mean, 8.49 +/- 0.08% [69.3 +/- 0.9 mmol/mol] vs. 7.92 +/- 0.13% [63.1 +/- 1.4 mmol/mol]; P < 0.01), and insulin requirements were significantly lower in patients with RBF >0.2 nmol/L (mean +/- SE: 1.07 +/- 0.02 vs. 0.93 +/- 0.07 units/kg/day; P < 0.04). CONCLUSIONS: We demonstrated considerable phenotypic diversity in RBF among children after 3-6 years of type 1 diabetes. Children with RBF are at lower risk for severe hypoglycemia, have better diabetes regulation, and have lower insulin requirements compared with children without RBF. There appears to be a lower limit for stimulated RBF of ~0.04 nmol/L that confers a beneficial effect on hypoglycemia and metabolic control. PMID- 23990517 TI - Detection bias and overestimation of bladder cancer risk in type 2 diabetes: a matched cohort study. AB - OBJECTIVE: To investigate whether the risk of bladder cancer in individuals with newly diagnosed type 2 diabetes is influenced by the frequency of physician visits before diagnosis as a measure of detection bias. RESEARCH DESIGN AND METHODS: With the use of linked administrative databases from 1996 to 2006, we established a cohort of 185,100 adults from British Columbia, Canada, with incident type 2 diabetes matched one to one with nondiabetic individuals on age, sex, and index date. Incidence rates and adjusted hazard ratios (aHRs) for bladder cancer were calculated during annual time windows following the index date. Analyses were stratified by number of physician visits in the 2 years before diabetes diagnosis and adjusted for age, sex, year of cohort entry, and socioeconomic status. RESULTS: The study population was 54% men and had an average age of 60.7+/-13.5 years; 1,171 new bladder cancers were diagnosed over a median follow-up of 4 years. In the first year after diabetes diagnosis, bladder cancer incidence in the diabetic cohort was 85.3 (95% CI 72.0-100.4) per 100,000 person-years and 66.1 (54.5-79.4) in the control cohort (aHR 1.30 [1.02-1.67], P=0.03). This first-year increased bladder cancer risk was limited to those with the fewest physician visits 2 years before the index date (<=12 visits, aHR 2.14 [1.29-3.55], P=0.003). After the first year, type 2 diabetes was not associated with bladder cancer. CONCLUSIONS: The results suggest that early detection bias may account for an overestimation in previously reported increased risks of bladder cancer associated with type 2 diabetes. PMID- 23990518 TI - Adverse outcomes after noncardiac surgery in patients with diabetes: a nationwide population-based retrospective cohort study. AB - OBJECTIVE: To investigate whether diabetes affects perioperative complications or mortality and to gauge its impact on medical expenditures for noncardiac surgeries. RESEARCH DESIGN AND METHODS: With the use of reimbursement claims from the Taiwan National Health Insurance system, we performed a population-based cohort study of patients with and without diabetes undergoing noncardiac surgeries. Outcomes of postoperative complications, mortality, hospital stay, and medical expenditures were compared between patients with and without diabetes. RESULTS: Diabetes increased 30-day postoperative mortality (odds ratio 1.84 [95% CI 1.46-2.32]), particularly among patients with type 1 diabetes or uncontrolled diabetes and patients with preoperative diabetes-related comorbidities, such as eye involvement, peripheral circulatory disorders, ketoacidosis, renal manifestations, and coma. Compared with nondiabetic control patients, coexisting medical conditions, such as renal dialysis (5.17 [3.68-7.28]), liver cirrhosis (3.59 [2.19-5.88]), stroke (2.87 [1.95-4.22]), mental disorders (2.35 [1.71 3.24]), ischemic heart disease (2.08 [1.45-2.99]), chronic obstructive pulmonary disease (1.96 [1.29-2.97]), and hyperlipidemia (1.94 [1.01-3.76]) were associated with mortality for patients with diabetes undergoing noncardiac surgery. Patients with diabetes faced a higher risk of postoperative acute renal failure (3.59 [2.88-4.48]) and acute myocardial infarction (3.65 [2.43-5.49]). Furthermore, diabetes was associated with prolonged hospital stay (2.30 [2.16-2.44]) and increased medical expenditures (1.32 [1.25-1.40]). CONCLUSIONS: Diabetes increases postoperative 30-day mortality, complications, and medical expenditures in patients undergoing in-hospital noncardiac surgeries. PMID- 23990519 TI - GLP-1 responses are heritable and blunted in acquired obesity with high liver fat and insulin resistance. AB - OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45 80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults. PMID- 23990520 TI - The association between different A1C-based measures of glycemia and risk of cardiovascular disease hospitalization. AB - OBJECTIVE We tested whether average monthly glycemic burden (AMGB), a marker of hyperglycemia that is a function of the extent and duration that A1C exceeded 7%, indicated greater risk of cardiovascular disease (CVD) than traditional A1C measures. RESEARCH DESIGN AND METHODS Using a case-control design, we studied 2,456 members of Kaiser Permanente Northwest with type 2 diabetes: 1,228 who experienced a CVD hospitalization, matched on age, sex, and duration of diabetes to 1,228 patients who were not hospitalized for CVD. We calculated AMGB from diabetes diagnosis until CVD hospitalization as a function of the difference between each actual or interpolated A1C measurement and 7%, resulting in an area under the curve estimate of hyperglycemic exposure, adjusted for number of months of observation. We used conditional logistic regression to compare the association between several A1C-based measures of glycemia and CVD, controlling for clinical characteristics and comorbidities. RESULTS AMGB was associated with increased CVD risk of 29% (odds ratio 1.29 [95% CI 1.16-1.44]; P < 0.001), while mean A1C was associated with a 22% risk increase (1.22 [1.09-1.37]; P < 0.001). A1C ever exceeding 7% was associated with increased CVD risk of 39% (1.39 [1.08 1.79]; P = 0.010). No model with a glycemia measure provided substantially more information than an identical model without a glycemia measure. CONCLUSIONS AMGB demonstrated somewhat greater CVD risk than mean A1C, but its clinical usefulness may be limited. A1C ever rising above 7% (53 mmol/mol) was a simple predictor of CVD risk that may have important clinical ramifications for newly diagnosed patients. PMID- 23990521 TI - Haptoglobin 1-1 genotype is associated with poorer cognitive functioning in the elderly with type 2 diabetes. AB - OBJECTIVE: Haptoglobin (Hp) genotype (Hp 1-1, 1-2, or 2-2) is associated with risk for type 2 diabetes complications, but its relationship with cognitive compromise, a growing concern in type 2 diabetes, has rarely been studied. This study investigated whether Hp genotype is associated with cognitive function in cognitively normal elderly diabetic subjects. RESEARCH DESIGN AND METHODS: Relationships of Hp genotype with episodic memory, semantic categorization, attention/working memory and executive function, and an overall cognitive score were examined in subjects from the Israel Diabetes and Cognitive Decline (IDCD) study. RESULTS: In the present analysis, 812 subjects participated (84 with Hp 1 1, 335 with Hp 1-2, and 393 with Hp 2-2 genotypes). Average was 72.9 years of age (SD 4.7), and Mini-Mental State Exam (MMSE) was 28.0 (SD 1.8). Compared with subjects with Hp 1-2 genotype, Hp 1-1 subjects performed significantly worse in semantic categorization (F=7.03; P=0.008) and the overall cognitive score (F=5.57; P=0.02). A separate stepwise multiple regression analysis demonstrated that compared with subjects with Hp 2-2 genotype, Hp 1-1 subjects performed significantly worse in semantic categorization (F=4.18; P=0.04) and the overall cognitive score (F=4.70; P=0.03). The contribution of cardiovascular risk factors to cognition was significantly higher in subjects with Hp 1-1 genotype compared with Hp 2 carriers (Hp 1-2 and Hp 2-2) in the semantic categorization (P=0.009) and attention/working memory (P=0.002) cognitive domains. CONCLUSIONS: Compared with Hp 2 carriers, those with Hp 1-1 genotype present lower cognitive performance. Stronger relationships between cardiovascular risk factors and cognition in the latter group may suggest an underlying vascular mechanism. PMID- 23990522 TI - Diabetes in first-degree family members: a predictor of type 2 diabetes in 159 nonscreening Alabama hemochromatosis probands with HFE C282Y homozygosity. AB - OBJECTIVE We sought to identify predictors of diabetes diagnosed before hemochromatosis. RESEARCH DESIGN AND METHODS We studied these 16 variables in 159 nonscreening hemochromatosis probands with HFE C282Y homozygosity: age; sex; BMI; diabetes reports in first-degree family members (dichotomous); heavy ethanol consumption; cigarette smoking; elevated serum alanine aminotransferase/aspartate aminotransferase levels; nonalcoholic fatty liver; chronic viral hepatitis; cirrhosis; hand arthropathy; iron removed by phlebotomy; and positivity for HLA A*01, B*08; A*03, B*07; and A*03, B*14 haplotypes. We performed univariable and multivariable analyses. RESULTS Twenty-three probands (14.5%) had diabetes; 19 were men. Each of the 23 probands had type 2 diabetes. Mean BMI was greater in probands with diabetes (31.7 +/- 8.5 [SD] kg/m(2) vs. 27.6 +/- 5.1 kg/m(2); P = 0.032). Reports of any first-degree family member with diabetes were more prevalent in probands with than in probands without diabetes (69.6 vs. 17.6%; P < 0.0001). In probands with diabetes, the odds ratio (OR) of maternal diabetes was 6.7 (95% CI 2.3-19.7; P = 0.0005) and of sibling diabetes was 11.7 (3.0-45.5; P = 0.0004). In a logistic regression model, predictors of diabetes at hemochromatosis diagnosis in 159 probands were diabetes reports in family members (OR 8.5 [95% CI 2.9-24.8]; P < 0.0001) and BMI (1.1 [1.0-1.2]; P = 0.049). This model explained 26.0% of total deviance contributing to diabetes. CONCLUSIONS In nonscreening hemochromatosis probands with HFE C282Y homozygosity, a heritable factor(s) increases the risk of diabetes diagnosed before hemochromatosis. PMID- 23990523 TI - Low prepregnancy adiponectin concentrations are associated with a marked increase in risk for development of gestational diabetes mellitus. AB - OBJECTIVE: To examine whether circulating total and high-molecular weight (HMW) adiponectin concentrations, measured before pregnancy, are associated with subsequent risk of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: This was a nested case-control study among women who participated in the Kaiser Permanente Northern California Multiphasic Health Check-up exam (1984 1996) with a serum sample obtained and who had a subsequent pregnancy (1984 2009). Eligible women were free of recognized diabetes. Case subjects were the 256 women who developed GDM. Two control subjects were selected for each case and matched for year of blood draw, age at exam, age at pregnancy, and number of intervening pregnancies. RESULTS: Compared with the highest quartile of adiponectin, the risk of GDM increased with decreasing quartile (odds ratio [OR] 1.5 [95% CI 0.7-2.9], 3.7 [1.9-7.2], and 5.2 [2.6-10.1]; P(trend) <0.001) after adjustment for family history of diabetes, BMI, parity, race/ethnicity, cigarette smoking, and glucose and insulin concentrations. Similar estimates were observed for HMW (P(trend) <0.001). The combined effects of having total adiponectin levels below the median (<10.29 mg/mL) and being overweight or obese (BMI >=25.0 kg/m(2)) were associated with a sevenfold increased risk of GDM compared with normal-weight women with adiponectin levels above the median (OR 6.7 [95% CI 3.6 12.5]). CONCLUSIONS: Prepregnancy low adiponectin concentrations, a marker of decreased insulin sensitivity and altered adipocyte endocrine function, is associated with reduced glucose tolerance during pregnancy and may identify women at high risk for GDM to target for early intervention. PMID- 23990524 TI - Extending distributed lag models to higher degrees. AB - Distributed lag (DL) models relate lagged covariates to a response and are a popular statistical model used in a wide variety of disciplines to analyze exposure-response data. However, classical DL models do not account for possible interactions between lagged predictors. In the presence of interactions between lagged covariates, the total effect of a change on the response is not merely a sum of lagged effects as is typically assumed. This article proposes a new class of models, called high-degree DL models, that extend basic DL models to incorporate hypothesized interactions between lagged predictors. The modeling strategy utilizes Gaussian processes to counterbalance predictor collinearity and as a dimension reduction tool. To choose the degree and maximum lags used within the models, a computationally manageable model comparison method is proposed based on maximum a posteriori estimators. The models and methods are illustrated via simulation and application to investigating the effect of heat exposure on mortality in Los Angeles and New York. PMID- 23990526 TI - Could standardizing "commercial off-the-shelf" (COTS) monitors to the DICOM part 14: GSDF improve the presentation of dental images? A visual grading characteristics analysis. AB - OBJECTIVES: To investigate whether standardizing commercial off-the-shelf (COTS) display devices to the digital imaging and communications in medicine part 14: greyscale standard display function (DICOM part 14: GSDF) would affect the presentation of dental images. METHODS: Two COTS display devices from the radiology department of a dental teaching hospital and a laptop computer monitor for reference were calibrated to conform to DICOM part 14: GSDF. Four dental surgeons and two final-year students undertook a relative visual grading analysis of the two devices before and after calibration, under control of the viewing environment. RESULTS: Calibrating COTS display devices to conform to the DICOM part 14: GSDF and viewing under reduced ambient light result in a consistent, perceived visual sensation for the presented radiological image. The area under the visual grading characteristics curve (AUCVGC) before calibration is 0.62 CI (0.56, 0.68) and AUCVGC after calibration is 0.51 CI (0.45, 0.57). CONCLUSIONS: Standardizing COTS display devices to the DICOM part 14: GSDF can improve image presentation. PMID- 23990525 TI - Determination of intracellular unbound concentrations and subcellular localization of drugs in rat sandwich-cultured hepatocytes compared with liver tissue. AB - Prediction of clinical efficacy, toxicity, and drug-drug interactions may be improved by accounting for the intracellular unbound drug concentration (C(unbound)) in vitro and in vivo. Furthermore, subcellular drug distribution may aid in predicting efficacy, toxicity, and risk assessment. The present study was designed to quantify the intracellular C(unbound) and subcellular localization of drugs in rat sandwich-cultured hepatocytes (SCH) compared with rat isolated perfused liver (IPL) tissue. Probe drugs with distinct mechanisms of hepatocellular uptake and accumulation were selected for investigation. Following drug treatment, SCH and IPL tissues were homogenized and fractionated by differential centrifugation to enrich for subcellular compartments. Binding in crude lysate and cytosol was determined by equilibrium dialysis; the C(unbound) and intracellular-to-extracellular C(unbound) ratio (K(pu,u)) were used to describe accumulation of unbound drug. Total accumulation (K(pobserved)) in whole tissue was well predicted by the SCH model (within 2- to 3-fold) for the selected drugs. Ritonavir (K(pu,u) ~1) was evenly distributed among cellular compartments, but highly bound, which explained the observed accumulation within liver tissue. Rosuvastatin was recovered primarily in the cytosolic fraction, but did not exhibit extensive binding, resulting in a K(pu,u) >1 in liver tissue and SCH, consistent with efficient hepatic uptake. Despite extensive binding and sequestration of furamidine within liver tissue, a significant portion of cellular accumulation was attributed to unbound drug (K(pu,u) >16), as expected for a charged, hepatically derived metabolite. Data demonstrate the utility of SCH to predict quantitatively total tissue accumulation and elucidate mechanisms of hepatocellular drug accumulation such as active uptake versus binding/sequestration. PMID- 23990527 TI - Varenicline may reduce negative effect while aiding smoking cessation. PMID- 23990528 TI - Statin potency associated with incident diabetes in a real-world evaluation. PMID- 23990529 TI - Conservative management for low-risk prostate cancer improves quality-adjusted life expectancy at lower cost compared with initial treatment. PMID- 23990530 TI - Accelerating ocean exploration. PMID- 23990534 TI - Neurodevelopment. Lab dishes up mini-brains. PMID- 23990535 TI - Cell Biology. NIH effort gambles on mysterious extracellular RNAs. PMID- 23990537 TI - Planetary science. Taking the life out of Titan. PMID- 23990536 TI - Emerging infectious diseases. Link to MERS virus underscores bats' puzzling threat. PMID- 23990538 TI - Archaeology. European hunter-gatherers dined on domestic pigs. PMID- 23990539 TI - A teacher's quest. PMID- 23990540 TI - Medical research. The promise of poop. PMID- 23990541 TI - Medical research. Regulators grapple with an unorthodox therapy. PMID- 23990542 TI - Evidence-based environmental laws for China. PMID- 23990543 TI - Call for prudence in whole-genome testing. PMID- 23990544 TI - Data disclosure crucial after DNA patent verdict. PMID- 23990546 TI - Public health. Confronting the sorry state of U.S. health. PMID- 23990547 TI - Astronomy. The curious behavior of the milky way's central black hole. PMID- 23990548 TI - Cell biology. Strength under tension. PMID- 23990549 TI - Geophysics. Minimizing Caribbean tsunami risk. PMID- 23990550 TI - Materials science. A clear advance in soft actuators. PMID- 23990551 TI - Psychology. The poor's poor mental power. PMID- 23990552 TI - IBI* series winner. An inquiry into the water around us. PMID- 23990553 TI - Poverty impedes cognitive function. AB - The poor often behave in less capable ways, which can further perpetuate poverty. We hypothesize that poverty directly impedes cognitive function and present two studies that test this hypothesis. First, we experimentally induced thoughts about finances and found that this reduces cognitive performance among poor but not in well-off participants. Second, we examined the cognitive function of farmers over the planting cycle. We found that the same farmer shows diminished cognitive performance before harvest, when poor, as compared with after harvest, when rich. This cannot be explained by differences in time available, nutrition, or work effort. Nor can it be explained with stress: Although farmers do show more stress before harvest, that does not account for diminished cognitive performance. Instead, it appears that poverty itself reduces cognitive capacity. We suggest that this is because poverty-related concerns consume mental resources, leaving less for other tasks. These data provide a previously unexamined perspective and help explain a spectrum of behaviors among the poor. We discuss some implications for poverty policy. PMID- 23990554 TI - Dissecting x-ray-emitting gas around the center of our galaxy. AB - Most supermassive black holes (SMBHs) are accreting at very low levels and are difficult to distinguish from the galaxy centers where they reside. Our own Galaxy's SMBH provides an instructive exception, and we present a close-up view of its quiescent x-ray emission based on 3 megaseconds of Chandra observations. Although the x-ray emission is elongated and aligns well with a surrounding disk of massive stars, we can rule out a concentration of low-mass coronally active stars as the origin of the emission on the basis of the lack of predicted iron (Fe) Kalpha emission. The extremely weak hydrogen (H)-like Fe Kalpha line further suggests the presence of an outflow from the accretion flow onto the SMBH. These results provide important constraints for models of the prevalent radiatively inefficient accretion state. PMID- 23990555 TI - Stretchable, transparent, ionic conductors. AB - Existing stretchable, transparent conductors are mostly electronic conductors. They limit the performance of interconnects, sensors, and actuators as components of stretchable electronics and soft machines. We describe a class of devices enabled by ionic conductors that are highly stretchable, fully transparent to light of all colors, and capable of operation at frequencies beyond 10 kilohertz and voltages above 10 kilovolts. We demonstrate a transparent actuator that can generate large strains and a transparent loudspeaker that produces sound over the entire audible range. The electromechanical transduction is achieved without electrochemical reaction. The ionic conductors have higher resistivity than many electronic conductors; however, when large stretchability and high transmittance are required, the ionic conductors have lower sheet resistance than all existing electronic conductors. PMID- 23990556 TI - Reaction of O2 with subsurface oxygen vacancies on TiO2 anatase (101). AB - Oxygen (O2) adsorbed on metal oxides is important in catalytic oxidation reactions, chemical sensing, and photocatalysis. Strong adsorption requires transfer of negative charge from oxygen vacancies (V(O)s) or dopants, for example. With scanning tunneling microscopy, we observed, transformed, and, in conjunction with theory, identified the nature of O2 molecules on the (101) surface of anatase (titanium oxide, TiO2) doped with niobium. V(O)s reside exclusively in the bulk, but we pull them to the surface with a strongly negatively charged scanning tunneling microscope tip. O2 adsorbed as superoxo (O2(-)) at fivefold-coordinated Ti sites was transformed to peroxo (O2(2-)) and, via reaction with a VO, placed into an anion surface lattice site as an (O2)O species. This so-called bridging dimer also formed when O2 directly reacted with V(O)s at or below the surface. PMID- 23990557 TI - A Uranian Trojan and the frequency of temporary giant-planet co-orbitals. AB - Trojan objects share a planet's orbit, never straying far from the triangular Lagrangian points, 60 degrees ahead of (L4) or behind (L5) the planet. We report the detection of a Uranian Trojan; in our numerical integrations, 2011 QF99 oscillates around the Uranian L4 Lagrange point for >70,000 years and remains co orbital for ~1 million years before becoming a Centaur. We constructed a Centaur model, supplied from the transneptunian region, to estimate temporary co-orbital capture frequency and duration (to a factor of 2 accuracy), finding that at any time 0.4 and 2.8% of the population will be Uranian and Neptunian co-orbitals, respectively. The co-orbital fraction (~2.4%) among Centaurs in the International Astronomical Union Minor Planet Centre database is thus as expected under transneptunian supply. PMID- 23990558 TI - Paleofluvial mega-canyon beneath the central Greenland ice sheet. AB - Subglacial topography plays an important role in modulating the distribution and flow of basal water. Where topography predates ice sheet inception, it can also reveal insights into former tectonic and geomorphological processes. Although such associations are known in Antarctica, little consideration has been given to them in Greenland, partly because much of the ice sheet bed is thought to be relatively flat and smooth. Here, we present evidence from ice-penetrating radar data for a 750-km-long subglacial canyon in northern Greenland that is likely to have influenced basal water flow from the ice sheet interior to the margin. We suggest that the mega-canyon predates ice sheet inception and will have influenced basal hydrology in Greenland over past glacial cycles. PMID- 23990559 TI - Social learning of migratory performance. AB - Successful bird migration can depend on individual learning, social learning, and innate navigation programs. Using 8 years of data on migrating whooping cranes, we were able to partition genetic and socially learned aspects of migration. Specifically, we analyzed data from a reintroduced population wherein all birds were captive bred and artificially trained by ultralight aircraft on their first lifetime migration. For subsequent migrations, in which birds fly individually or in groups but without ultralight escort, we found evidence of long-term social learning, but no effect of genetic relatedness on migratory performance. Social learning from older birds reduced deviations from a straight-line path, with 7 years of experience yielding a 38% improvement in migratory accuracy. PMID- 23990560 TI - Nuclear Wave1 is required for reprogramming transcription in oocytes and for normal development. AB - Eggs and oocytes have a remarkable ability to induce transcription of sperm after normal fertilization and in somatic nuclei after somatic cell nuclear transfer. This ability of eggs and oocytes is essential for normal development. Nuclear actin and actin-binding proteins have been shown to contribute to transcription, although their mode of action is elusive. Here, we find that Xenopus Wave1, previously characterized as a protein involved in actin cytoskeleton organization, is present in the oocyte nucleus and is required for efficient transcriptional reprogramming. Moreover, Wave1 knockdown in embryos results in abnormal development and defective hox gene activation. Nuclear Wave1 binds by its WHD domain to active transcription components, and this binding contributes to the action of RNA polymerase II. We identify Wave1 as a maternal reprogramming factor that also has a necessary role in gene activation in development. PMID- 23990561 TI - Molecular basis of tubulin transport within the cilium by IFT74 and IFT81. AB - Intraflagellar transport (IFT) of ciliary precursors such as tubulin from the cytoplasm to the ciliary tip is involved in the construction of the cilium, a hairlike organelle found on most eukaryotic cells. However, the molecular mechanisms of IFT are poorly understood. Here, we found that the two core IFT proteins IFT74 and IFT81 form a tubulin-binding module and mapped the interaction to a calponin homology domain of IFT81 and a highly basic domain in IFT74. Knockdown of IFT81 and rescue experiments with point mutants showed that tubulin binding by IFT81 was required for ciliogenesis in human cells. PMID- 23990562 TI - Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis. AB - MraY (phospho-MurNAc-pentapeptide translocase) is an integral membrane enzyme that catalyzes an essential step of bacterial cell wall biosynthesis: the transfer of the peptidoglycan precursor phospho-MurNAc-pentapeptide to the lipid carrier undecaprenyl phosphate. MraY has long been considered a promising target for the development of antibiotics, but the lack of a structure has hindered mechanistic understanding of this critical enzyme and the enzyme superfamily in general. The superfamily includes enzymes involved in bacterial lipopolysaccharide/teichoic acid formation and eukaryotic N-linked glycosylation, modifications that are central in many biological processes. We present the crystal structure of MraY from Aquifex aeolicus (MraYAA) at 3.3 A resolution, which allows us to visualize the overall architecture, locate Mg(2+) within the active site, and provide a structural basis of catalysis for this class of enzyme. PMID- 23990563 TI - betaCaMKII in lateral habenula mediates core symptoms of depression. AB - The lateral habenula (LHb) has recently emerged as a key brain region in the pathophysiology of depression. However, the molecular mechanism by which LHb becomes hyperactive in depression remains unknown. Through a quantitative proteomic screen, we found that expression of the beta form of calcium/calmodulin dependent protein kinase type II (betaCaMKappaIotaIota) was significantly up regulated in the LHb of animal models of depression and down-regulated by antidepressants. Increasing beta-, but not alpha-, CaMKII in the LHb strongly enhanced the synaptic efficacy and spike output of LHb neurons and was sufficient to produce profound depressive symptoms, including anhedonia and behavioral despair. Down-regulation of betaCaMKII levels, blocking its activity or its target molecule the glutamate receptor GluR1 reversed the depressive symptoms. These results identify betaCaMKII as a powerful regulator of LHb neuron function and a key molecular determinant of depression. PMID- 23990564 TI - The chemistry and applications of metal-organic frameworks. AB - Crystalline metal-organic frameworks (MOFs) are formed by reticular synthesis, which creates strong bonds between inorganic and organic units. Careful selection of MOF constituents can yield crystals of ultrahigh porosity and high thermal and chemical stability. These characteristics allow the interior of MOFs to be chemically altered for use in gas separation, gas storage, and catalysis, among other applications. The precision commonly exercised in their chemical modification and the ability to expand their metrics without changing the underlying topology have not been achieved with other solids. MOFs whose chemical composition and shape of building units can be multiply varied within a particular structure already exist and may lead to materials that offer a synergistic combination of properties. PMID- 23990565 TI - Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. AB - Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but whether there is a systematic relationship between tissue mechanics and differentiation is unknown. Here, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, E, as did levels of collagens in the extracellular matrix that determine E. Stem cell differentiation into fat on soft matrix was enhanced by low lamin-A levels, whereas differentiation into bone on stiff matrix was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and, although lamin-A transcription was regulated by the vitamin A/retinoic acid (RA) pathway with broad roles in development, nuclear entry of RA receptors was modulated by lamin-A protein. Tissue stiffness and stress thus increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination. PMID- 23990567 TI - Effect of early antiretroviral therapy on sexual behaviors and HIV-1 transmission risk among adults with diverse heterosexual partnership statuses in Cote d'Ivoire. AB - BACKGROUND: The effect of early initiation of antiretroviral therapy (ART; ie, at CD4(+) T-cell counts >350 cells/mm(3)) on sexual behaviors and human immunodeficiency virus type 1 (HIV) transmission risk has not been documented in populations other than HIV-serodiscordant couples in stable relationships. METHODS: On the basis of data from a behavioral study nested in a randomized, controlled trial (Temprano-ANRS12136) of early ART, we compared proportions of risky sex (ie, unprotected sex with a partner of negative/unknown HIV status) reported 12 months after inclusion between participants randomly assigned to initiate ART immediately (hereafter, "early ART") or according to ongoing World Health Organization criteria. Group-specific HIV transmission rates were estimated on the basis of sexual behaviors and viral load-specific per-act HIV transmission probabilities. The ratio of transmission rates was computed to estimate the protective effect of early ART. RESULTS: Among 957 participants (baseline median CD4(+) T-cell count, 478 cells/mm(3)), 46.0% reported sexual activity in the past month; of these 46.0%, sexual activity for 41.5% involved noncohabiting partners. The proportion of subjects who engaged in risky sex was 10.0% in the early ART group, compared with 12.8% in the standard ART group (P = .17). After accounting for sexual behaviors and viral load, we estimated that the protective effect of early ART was 90% (95% confidence interval, 81%-95%). CONCLUSION: Twelve months after inclusion, patients in the early and standard ART groups reported similar sexual behaviors. Early ART decreased the estimated risk of HIV transmission by 90%, suggesting a major prevention benefit among seronegative sex partners in stable or casual relationships with seropositive individuals. PMID- 23990566 TI - Human milk oligosaccharides protect bladder epithelial cells against uropathogenic Escherichia coli invasion and cytotoxicity. AB - The invasive pathogen uropathogenic Escherichia coli (UPEC) is the primary cause of urinary tract infections (UTIs). Recurrent infection that can progress to life threatening renal failure has remained as a serious global health concern in infants. UPEC adheres to and invades bladder epithelial cells to establish infection. Studies have detected the presence of human milk oligosaccharides (HMOs) in urine of breast-fed, but not formula-fed, neonates. We investigated the mechanisms HMOs deploy to elicit protection in human bladder epithelial cells infected with UPEC CFT073, a prototypic urosepsis-associated strain. We found a significant reduction in UPEC internalization into HMO-pretreated epithelial cells without observing any significant effect in UPEC binding to these cells. This event coincides with a rapid decrease in host cell cytotoxicity, recognized by LIVE/DEAD staining and cell detachment, but independent of caspase-mediated or mitochondrial-mediated programmed cell death pathways. Further investigation revealed HMOs, and particularly the sialic acid-containing fraction, reduced UPEC mediated MAPK and NF-kappaB activation. Collectively, our results indicate that HMOs can protect bladder epithelial cells from deleterious cytotoxic and proinflammatory effects of UPEC infection, and may be one contributing mechanism underlying the epidemiological evidence of reduced UTI incidence in breast-fed infants. PMID- 23990568 TI - Protection against lethal Marburg virus infection mediated by lipid encapsulated small interfering RNA. AB - BACKGROUND: Marburg virus (MARV) infection causes severe morbidity and mortality in humans and nonhuman primates. Currently, there are no licensed therapeutics available for treating MARV infection. Here, we present the in vitro development and in vivo evaluation of lipid-encapsulated small interfering RNA (siRNA) as a potential therapeutic for the treatment of MARV infection. METHODS: The activity of anti-MARV siRNAs was assessed using dual luciferase reporter assays followed by in vitro testing against live virus. Lead candidates were tested in lethal guinea pig models of 3 different MARV strains (Angola, Ci67, Ravn). RESULTS: Treatment resulted in 60%-100% survival of guinea pigs infected with MARV. Although treatment with siRNA targeting other MARV messenger RNA (mRNA) had a beneficial effect, targeting the MARV NP mRNA resulted in the highest survival rates. NP-718m siRNA in lipid nanoparticles provided 100% protection against MARV strains Angola and Ci67, and 60% against Ravn. A cocktail containing NP-718m and NP-143m provided 100% protection against MARV Ravn. CONCLUSIONS: These data show protective efficacy against the most pathogenic Angola strain of MARV. Further development of the lipid nanoparticle technology has the potential to yield effective treatments for MARV infection. PMID- 23990569 TI - Relationship between domestic and wild birds in live poultry market and a novel human H7N9 virus in China. AB - To trace the source of the avian H7N9 viruses, we collected 99 samples from 4 live poultry markets and the family farms of 3 patients in Hangzhou city of Zhejiang province, China. We found that almost all positive samples came from chickens and ducks in live poultry markets. These results strongly suggest that the live poultry markets are the major source of recent human infections with H7N9 in Hangzhou city, Zhejiang province of China. Therefore, control measures are needed, not only in the domestic bird population, but also in the live poultry markets to reduce human H7N9 infection risk. PMID- 23990570 TI - Novel avian-origin human influenza A(H7N9) can be transmitted between ferrets via respiratory droplets. AB - The outbreak of human infections caused by novel avian-origin influenza A(H7N9) in China since March 2013 underscores the need to better understand the pathogenicity and transmissibility of these viruses in mammals. In a ferret model, the pathogenicity of influenza A(H7N9) was found to be less than that of an influenza A(H5N1) strain but comparable to that of 2009 pandemic influenza A(H1N1), based on the clinical signs, mortality, virus dissemination, and results of histopathologic analyses. Influenza A(H7N9) could replicate in the upper and lower respiratory tract, the heart, the liver, and the olfactory bulb. It is worth noting that influenza A(H7N9) exhibited a low level of transmission between ferrets via respiratory droplets. There were 4 mutations in the virus isolated from the contact ferret: D678Y in the gene encoding PB2, R157K in the gene encoding hemagglutinin (H3 numbering), I109T in the gene encoding nucleoprotein, and T10I in the gene encoding neuraminidase. These data emphasized that avian origin influenza A(H7N9) can be transmitted between mammals, highlighting its potential for human-to-human transmissibility. PMID- 23990571 TI - Genital herpes simplex virus type 2 infection in humanized HIV-transgenic mice triggers HIV shedding and is associated with greater neurological disease. AB - BACKGROUND: Epidemiological studies consistently demonstrate synergy between herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV 1). Higher HIV-1 loads are observed in coinfected individuals, and conversely, HIV-1 is associated with more-severe herpetic disease. A small animal model of coinfection would facilitate identification of the biological mechanisms underlying this synergy and provide the opportunity to evaluate interventions. METHODS: Mice transgenic for HIV-1 provirus and human cyclin T1 under the control of a CD4 promoter (JR-CSF/hu-cycT1) were intravaginally infected with HSV-2 and evaluated for disease progression, HIV shedding, and mucosal immune responses. RESULTS: HSV-2 infection resulted in higher vaginal HIV loads and genital tissue expression of HIV RNA, compared with HSV-uninfected JR-CSF/hu-cycT1 mice. There was an increase in genital tract inflammatory cells, cytokines, chemokines, and interferons in response to HSV-2, although the kinetics of the response were delayed in HIV-transgenic, compared with control mice. Moreover, the JR-CSF/hu cycT1 mice exhibited earlier and more-severe neurological disease. The latter was associated with downregulation of secretory leukocyte protease inhibitor expression in neuronal tissue, a molecule with antiinflammatory, antiviral, and neuroprotective properties. CONCLUSIONS: JR-CSF/hu-cycT1 mice provide a valuable model to study HIV/HSV-2 coinfection and identify potential mechanisms by which HSV-2 facilitates HIV-1 transmission and HIV modulates HSV-2-mediated disease. PMID- 23990573 TI - Cytokine and chemokine levels in patients infected with the novel avian influenza A (H7N9) virus in China. AB - H7N9 avian influenza is an emerging viral disease in China caused by avian influenza A (H7N9) virus. We investigated host cytokine and chemokine profiles in serum samples of H7N9 patients by multiplex-microbead immunoassays. Statistical analysis showed that IP-10, IL-6, IL-17, and IL-2 were increased in H7N9 infected patients. Furthermore, IL-6 and the chemokine IP-10 were significantly higher in severe H7N9 patients compared to nonsevere H7N9 cases. We suggest that proinflammatory cytokine responses, characterized by a combined Th1/Th17 cytokine induction, are partially responsible for the disease progression of patients with H7N9 infection. PMID- 23990574 TI - The DISCUSS Project: induced pluripotent stem cell lines from previously collected research biospecimens and informed consent: points to consider. AB - Human somatic cell reprogramming is a leading technology for accelerating disease modeling and drug discovery. Research organizations are sponsoring initiatives to create libraries of induced pluripotent stem cell (iPSC) lines for broad distribution and application. Donor informed consent plays a critical role in supporting the ethical conduct of iPSC research. To date, our organizations have focused on informed consent considerations for somatic cell collection intended specifically for iPSC derivation and distribution. This article considers how somatic cells obtained under general (biomedical) research protocols can be used for iPSC derivation. We present draft Points to Consider regarding the use of human somatic cells for iPSC research. Our goal is to initiate a process designed to develop consensus for the use of previously collected specimens for iPSC research. We anticipate publishing final considerations in early 2014. PMID- 23990575 TI - Complete nucleotide sequence of encephalomyocarditis virus isolated from South china tigers in china. AB - A strain of encephalomyocarditis virus (EMCV), strain FJ13, has been isolated from South China tigers in China, and its complete genome has been sequenced and analyzed. Phylogenetic analysis suggests that FJ13 belongs to the EMCV-1 serotype, and it is highly prevalent in China. PMID- 23990572 TI - Dependence of efavirenz- and rifampicin-isoniazid-based antituberculosis treatment drug-drug interaction on CYP2B6 and NAT2 genetic polymorphisms: ANRS 12154 study in Cambodia. AB - We investigated the population pharmacokinetics and pharmacogenetics of efavirenz in 307 patients coinfected with human immunodeficiency virus and tuberculosis and included in the Cambodian Early vs Late Initiation of Antiretrovirals trial (CAMELIA) in Cambodia. Efavirenz (600 mg/d) and stavudine plus lamivudine were administered in addition to standard antituberculosis treatment, including rifampicin and isoniazid. Blood samples were obtained a mean of 14 hours after efavirenz intake at weeks 2 and 6 after initiation of efavirenz and weeks 22 (efavirenz plus antituberculosis drugs) and 50 (efavirenz alone) after initiation of antituberculosis treatment. Ten patients participated in an extensive pharmacokinetic study after week 50. CYP2B6 G516T and C485-18T polymorphisms were the most significant covariates, with weight showing a significant minor effect. Change in efavirenz apparent clearance in patients taking both efavirenz and antituberculosis treatment was highly dependent on NAT2 polymorphism, as a possible surrogate of isoniazid exposure. Patients carrying the CYP2B6 516 TT genotype and slow-acetylation NAT2 phenotype had the lowest efavirenz apparent clearance. These data suggest that the inducing effect of rifampicin is counterbalanced by a concentration-dependant inhibitory effect of isoniazid on efavirenz clearance. PMID- 23990576 TI - Draft Genome Sequence of Mycobacterium massiliense Strain M159, Showing Phenotypic Resistance to beta-Lactam and Tetracycline Antibiotics. AB - Mycobacterium massiliense is a nontuberculous mycobacterium associated with human infections. We report here the draft genome sequence of M. massiliense strain M159, isolated from the bronchial aspirate of a patient who had a pulmonary infection. This strain showed genotypic and in vitro resistance to a number of tetracyclines and beta-lactam antibiotics. PMID- 23990577 TI - Complete Genome Sequence of a Thermophilic Hydrogenotrophic Methanogen, Methanothermobacter sp. Strain CaT2. AB - We isolated a thermophilic hydrogenotrophic methanogen, Methanothermobacter sp. strain CaT2, which is able to aggregate and utilize formate. Here, we report the complete genome sequence of this organism. PMID- 23990578 TI - High-Quality Draft Genome Sequences of Two Xanthomonas citri pv. malvacearum Strains. AB - We report high-quality draft genome sequences of two strains (race 18 and 20) of Xanthomonas citri pv. malvacearum, the causal agent of bacterial blight of cotton. Comparative genomics will help to decipher mechanisms provoking disease and triggering defense responses and to develop new molecular tools for epidemiological surveillance. PMID- 23990579 TI - Draft Genome Sequence of Lichen-Forming Fungus Caloplaca flavorubescens Strain KoLRI002931. AB - Here we report a draft genome sequence of Caloplaca flavorubescens strain KoLRI002931, isolated from the bark of a gingko tree at Mt. Deogyu, Muju, South Korea. The genome sequence is 34,455,815 bp, with a GC content of 41.89%, consisting of 36 scaffolds. PMID- 23990580 TI - Draft Genome Sequence of the Xanthomonas cassavae Type Strain CFBP 4642. AB - We report the draft genome sequence of the Xanthomonas cassavae type strain CFBP 4642, the causal agent of bacterial necrosis on cassava plants. These data will allow the comparison of this nonvascular pathogen with the vascular pathogen Xanthomonas axonopodis pv. manihotis, both infecting the same host, which will facilitate the development of diagnostic tools. PMID- 23990581 TI - Draft Genome Sequence of Sphingobium chinhatense Strain IP26T, Isolated from a Hexachlorocyclohexane Dumpsite. AB - Sphingobium chinhatense strain IP26(T) is a conducive hexachlorocyclohexane (HCH) degrader isolated from a heavily contaminated (450 mg HCH/g soil) HCH dumpsite. IP26(T) degrades alpha-, beta-, gamma-, and delta-HCH, which are highly persistent in the environment. Here we report the draft genome sequence (~5.8 Mbp) of this strain. PMID- 23990582 TI - Adolescent girls who experience abuse or neglect are at an increased risk of teen pregnancy. PMID- 23990583 TI - Calcium supplements associated with increased risk of cardiovascular death in men but not women. PMID- 23990584 TI - The South American Glabellar Experience Study (SAGE): a multicenter retrospective analysis of real-world treatment patterns following the introduction of incobotulinumtoxinA in Argentina. AB - BACKGROUND: IncobotulinumtoxinA was approved in Argentina in 2007 for the treatment of moderate to severe glabellar lines. OBJECTIVE: The authors evaluate real-world changes in facial aesthetic treatment patterns and patient satisfaction following the introduction of incobotulinumtoxinA in Argentina. METHODS: This multicenter, retrospective chart review conducted in Argentina included women who had received at least 2 treatment cycles of onabotulinumtoxinA (Allergan, Irvine, California) for glabellar lines (period 1) prior to switching to incobotulinumtoxinA (Merz Pharma, GmbH, Frankfurt, Germany (period 2). Subjects were given the option to continue with incobotulinumtoxinA treatments (captured in period 2) or switch back to onabotulinumtoxinA (documented as period 3). Medical records were reviewed for demographics, dosing, reason for switching between products, treatment satisfaction, and interval between injection cycles. RESULTS: One hundred ten women were enrolled and collectively received 662 treatment cycles with botulinum toxin. Subjects were switched to incobotulinumtoxinA at unit doses that were numerically and statistically similar to the onabotulinumtoxinA doses they received in period 1. Most subjects (92%) initially switched to incobotulinumtoxinA because of lower cost. Ninety-two subjects (84%) switched back to onabotulinumtoxinA in period 3, most commonly due to insufficient duration of effect with incobotulinumtoxinA (61/92; 66%). Subjects reported satisfaction with treatment in >90% of their onabotulinumtoxinA visits and in 34% of their incobotulinumtoxinA visits. Median interinjection intervals with onabotulinumtoxinA were 180.3 days (period 1) and 176.9 days (period 3) and 144.3 days with incobotulinumtoxinA in period 2. CONCLUSIONS: In this real-world setting, subjects did not appear to perceive the same facial aesthetic benefits from incobotulinumtoxinA as onabotulinumtoxinA when the products were administered at comparable doses. PMID- 23990585 TI - Draft Genome Sequences of Paenibacillus alvei A6-6i and TS-15. AB - Here, we report draft genomes of Paenibacillus alvei strains A6-6i and TS-15, which were isolated, respectively, from plant material and soil in the Virginia Eastern Shore (VES) tomato growing area. An array of genes related to antimicrobial biosynthetic pathways have been identified with whole-genome analyses of these strains. PMID- 23990586 TI - Draft Genome Sequence of the Human-Pathogenic Bacterium Vibrio alginolyticus E0666. AB - Vibrio alginolyticus is a Gram-negative halophilic bacterium with worldwide distribution. In this work, we report the draft genome sequence of a V. alginolyticus strain (E0666) isolated from Epinephelus coioides ascites in the Shantou city of Guangdong Province, China. PMID- 23990587 TI - Whole-Genome Sequences of Two Staphylococcus aureus ST398 Strains of Human Origin, S94 and S100. AB - Sequence type 398 (ST398) Staphylococcus aureus was originally associated with animal infection. We announce the complete genome sequences of two ST398 methicillin-susceptible S. aureus strains of human origin, S94 and S100. The genome sequences assist in the characterization of interesting ST398 features related to host specificities. PMID- 23990588 TI - Whole-Genome Sequence of the Ancestral Animal-Borne ST398 Staphylococcus aureus Strain S123. AB - Sequence type 398 (ST398) Staphylococcus aureus was originally reported in livestock. We announce the complete genome sequence of an ST398 methicillin susceptible S. aureus strain of animal origin, S123. The genome sequence reveals a wild-type genome that probably corresponds to an ancestral clone. PMID- 23990589 TI - Does serum albumin and creatinine predict survival of inpatient palliative care patients? AB - INTRODUCTION: Low creatinine and albumin are found among the chronically ill patients. This study retrospectively reviewed albumin and creatinine levels for survival in patients upon admission. METHODS: Records of patients admitted over 2 months were reviewed. Recursive partitioning analysis (RPA) identified cutpoints in albumin and creatinine that predicted survival. Kaplan-Meier survival, Cox proportional hazards, and stepwise Cox analyses identified prognostic factors. RESULTS: Of 83 patients, 81 were assessable. Variables for worse survival were albumin <3.1 g/dL, creatinine >0.93 mg/dL, and male gender. Albumin by continuous, median, RPA, and tertiles was significant; creatinine by RPA. Hazard ratio for albumin >3.1 was 0.28 (P < .001) and for creatinine >0.91 mg/dL was 1.8 (P = .046). DISCUSSION AND CONCLUSION: Albumin and creatinine are prognostically important. PMID- 23990590 TI - Reconnection: having the end-of-life discussion with mom. AB - Learning how to speak with patients about end-of-life topics is often anxiety provoking for medical trainees. However, it also provides a unique opportunity for personal growth. The surprising reward of having such a conversation is presented in this reflection. PMID- 23990591 TI - Unsafe to go home. PMID- 23990592 TI - Factors associated with utilization of an inpatient palliative care consultation service in an urban public hospital. AB - RATIONALE: To evaluate factors associated with palliative care consultation (PCC) in an urban public hospital. METHODS: A retrospective chart review of patients who died on inpatient medical services. RESULTS: Patients with a PCC were more likely to have a "do not resuscitate" (DNR) order at the time of death (p<0.001) and had a decreased likelihood of death in the ICU (p<0.001). Factors associated with PCC in a multivariate analysis included: cancer diagnosis (p=0.01), at least a high school education (p=0.04), older age (p=.003), and birth outside the US (p=0.03). CONCLUSION: The increased PCC utilization for immigrants is in contrast to previously reported literature. This increased use may be because access to services in a municipal hospital is not driven by demographic and socioeconomic factors. PMID- 23990593 TI - Surgical Process Improvement: Impact of a Standardized Care Model With Electronic Decision Support to Improve Compliance With SCIP Inf-9. AB - The absence of standardization in surgical care process, exemplified in a "solution shop" model, can lead to unwarranted variation, increased cost, and reduced quality. A comprehensive effort was undertaken to improve quality of care around indwelling bladder catheter use following surgery by creating a "focused factory" model within the cardiac surgical practice. Baseline compliance with Surgical Care Improvement Inf-9, removal of urinary catheter by the end of surgical postoperative day 2, was determined. Comparison of baseline data to postintervention results showed clinically important reductions in the duration of indwelling bladder catheters as well as marked reduction in practice variation. Following the intervention, Surgical Care Improvement Inf-9 guidelines were met in 97% of patients. Although clinical quality improvement was notable, the process to accomplish this-identification of patients suitable for standardized pathways, protocol application, and electronic systems to support the standardized practice model-has potentially greater relevance than the specific clinical results. PMID- 23990594 TI - Reply to "small dense low-density lipoprotein could be used as a therapeutic marker for treatment in patients with acute coronary syndrome". PMID- 23990595 TI - Protective role of statins in patients with acute coronary syndrome aged >= 75 years with low LDL-C who underwent percutaneous coronary intervention. AB - The effect of statins in patients with acute coronary syndrome (ACS) at advanced age with lower low-density lipoprotein cholesterol (LDL-C) levels undergoing percutaneous coronary intervention (PCI) remains unknown. We evaluated the effect of statins in 220 Chinese patients with ACS aged >= 75 years with low LDL-C undergoing PCI. Biomarkers were measured before and 6 hours after PCI, and patients were followed up for 1 year. Biomarkers in the statin group at 6 hours post-PCI were lower than controls (creatine kinase-myocardial band 14.2 +/- 5.78 vs 47.3 +/- 16.4 IU/L, P = .03; cardiac troponin I 0.36 +/- 0.12 vs 1.33 +/- 0.47 ng/mL, P = .01; and high-sensitivity C-reactive protein 7.6 +/- 4.3 vs 13.6 +/- 4.5 mg/L, P = .001, respectively). Significant differences were found in major adverse cardiac events at 1 year (P = .02-.01), while target lesion revascularization alone was less at 3 months between the 2 groups (P = .03). This study demonstrates that elderly patients with ACS having low LDL-C benefit from statins regardless of type, dosage, and duration of statin administration prior to PCI. PMID- 23990597 TI - Cusp thrombosis after transcatheter aortic valve replacement detected by computed tomography and echocardiography. PMID- 23990598 TI - Three-dimensional real-time MRI-guided intracardiac catheter navigation. PMID- 23990596 TI - Prevention of liver cancer cachexia-induced cardiac wasting and heart failure. AB - AIMS: Symptoms of cancer cachexia (CC) include fatigue, shortness of breath, and impaired exercise capacity, which are also hallmark symptoms of heart failure (HF). Herein, we evaluate the effects of drugs commonly used to treat HF (bisoprolol, imidapril, spironolactone) on development of cardiac wasting, HF, and death in the rat hepatoma CC model (AH-130). METHODS AND RESULTS: Tumour bearing rats showed a progressive loss of body weight and left-ventricular (LV) mass that was associated with a progressive deterioration in cardiac function. Strikingly, bisoprolol and spironolactone significantly reduced wasting of LV mass, attenuated cardiac dysfunction, and improved survival. In contrast, imidapril had no beneficial effect. Several key anabolic and catabolic pathways were dysregulated in the cachectic hearts and, in addition, we found enhanced fibrosis that was corrected by treatment with spironolactone. Finally, we found cardiac wasting and fibrotic remodelling in patients who died as a result of CC. In living cancer patients, with and without cachexia, serum levels of brain natriuretic peptide and aldosterone were elevated. CONCLUSION: Systemic effects of tumours lead not only to CC but also to cardiac wasting, associated with LV dysfunction, fibrotic remodelling, and increased mortality. These adverse effects of the tumour on the heart and on survival can be mitigated by treatment with either the beta-blocker bisoprolol or the aldosterone antagonist spironolactone. We suggest that clinical trials employing these agents be considered to attempt to limit this devastating complication of cancer. PMID- 23990599 TI - Tension gastrothorax mimicking acute coronary syndrome and causing cardiac arrest. PMID- 23990600 TI - An unusual case of systolic murmur and recurrent syncopes. PMID- 23990601 TI - Long-term adherence to therapy: the clue to prevent hypertension consequences. PMID- 23990602 TI - Epsilon waves in giant-cell myocarditis. PMID- 23990603 TI - Renal artery fibromuscular dysplasia: in vivo optical coherence tomography insights. PMID- 23990604 TI - Positional ventricular tachycardia in left ventricular assist device: a new frontier in ventricular tachycardia ablation. PMID- 23990605 TI - Lipid lowering in patients with treatment-resistant hypertension: an analysis from the Treating to New Targets (TNT) trial. AB - AIM: Patients with resistant hypertension are at high risk for adverse cardiovascular events. Efforts have been focused on lowering the surrogate endpoint of blood pressure (BP) with scant focus on reduction of hard cardiovascular endpoints. However, whether or not intensive lipid lowering is beneficial for reducing the risk of cardiovascular events in this high-risk cohort is not known. METHODS AND RESULTS: We evaluated 10 001 patients with coronary artery disease and a low-density lipoprotein cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the Treating to New Targets trial. Treatment-resistant hypertension (TRH) was defined as BP >=140 mmHg despite being on three antihypertensive agents or <140 mmHg on four or more agents. Subjects were followed up for a median duration of 4.9 years. The primary outcome was major cardiovascular events (composite of non-fatal myocardial infarction (MI), fatal coronary heart disease (CHD), resuscitated cardiac arrest, and stroke). Among the 10 001 patients in the trial, 1112 (11.1%) patients had TRH. Atorvastatin 80 mg, in patients with TRH, was associated with a significant reduction in the risk of the primary outcome (HR = 0.70; 95% CI 0.52-0.93; P = 0.01), driven largely by a significant reduction in CHD deaths (HR = 0.55; 95% CI 0.32-0.97; P = 0.04). In addition, atorvastatin 80 mg was associated with a reduction in major coronary events (HR = 0.67; 95% CI 0.49-0.93; P = 0.02), and any cardiovascular or coronary event and with a trend (P = 0.05) towards reduction in all-cause mortality (HR = 0.68; 95% CI 0.46-1.01) when compared with atorvastatin 10 mg. The results were similar when analysed for the two separate components of the TRH cohort. CONCLUSION: In subjects with TRH, intensive lipid lowering with atorvastatin 80 mg is associated with a significant reduction in cardiovascular events. PMID- 23990606 TI - The shared genomic architecture of human nucleolar organizer regions. AB - The short arms of the five acrocentric human chromosomes harbor sequences that direct the assembly and function of the nucleolus, one of the key functional domains of the nucleus, yet they are absent from the current human genome assembly. Here we describe the genomic architecture of these human nucleolar organizers. Sequences distal and proximal to ribosomal gene arrays are conserved among the acrocentric chromosomes, suggesting they are sites of frequent recombination. Although previously believed to be heterochromatic, characterization of these two flanking regions reveals that they share a complex genomic architecture similar to other euchromatic regions of the genome, but they have distinct genomic characteristics. Proximal sequences are almost entirely segmentally duplicated, similar to the regions bordering centromeres. In contrast, the distal sequence is predominantly unique to the acrocentric short arms and is dominated by a very large inverted repeat. We show that the distal element is localized to the periphery of the nucleolus, where it appears to anchor the ribosomal gene repeats. This, combined with its complex chromatin structure and transcriptional activity, suggests that this region is involved in nucleolar organization. Our results provide a platform for investigating the role of NORs in nucleolar formation and function, and open the door for determining the role of these regions in the well-known empirical association of nucleoli with pathology. PMID- 23990607 TI - H4K16 acetylation marks active genes and enhancers of embryonic stem cells, but does not alter chromatin compaction. AB - Compared with histone H3, acetylation of H4 tails has not been well studied, especially in mammalian cells. Yet, H4K16 acetylation is of particular interest because of its ability to decompact nucleosomes in vitro and its involvement in dosage compensation in flies. Here we show that, surprisingly, loss of H4K16 acetylation does not alter higher-order chromatin compaction in vivo in mouse embryonic stem cells (ESCs). As well as peaks of acetylated H4K16 and KAT8 histone acetyltransferase at the transcription start sites of expressed genes, we report that acetylation of H4K16 is a new marker of active enhancers in ESCs and that some enhancers are marked by H3K4me1, KAT8, and H4K16ac, but not by acetylated H3K27 or EP300, suggesting that they are novel EP300 independent regulatory elements. Our data suggest a broad role for different histone acetylation marks and for different histone acetyltransferases in long-range gene regulation. PMID- 23990608 TI - The influence of genomic context on mutation patterns in the human genome inferred from rare variants. AB - Understanding patterns of spontaneous mutations is of fundamental interest in studies of human genome evolution and genetic disease. Here, we used extremely rare variants in humans to model the molecular spectrum of single-nucleotide mutations. Compared to common variants in humans and human-chimpanzee fixed differences (substitutions), rare variants, on average, arose more recently in the human lineage and are less affected by the potentially confounding effects of natural selection, population demographic history, and biased gene conversion. We analyzed variants obtained from a population-based sequencing study of 202 genes in >14,000 individuals. We observed considerable variability in the per-gene mutation rate, which was correlated with local GC content, but not recombination rate. Using >20,000 variants with a derived allele frequency <= 10(-4), we examined the effect of local GC content and recombination rate on individual variant subtypes and performed comparisons with common variants and substitutions. The influence of local GC content on rare variants differed from that on common variants or substitutions, and the differences varied by variant subtype. Furthermore, recombination rate and recombination hotspots have little effect on rare variants of any subtype, yet both have a relatively strong impact on multiple variant subtypes in common variants and substitutions. This observation is consistent with the effect of biased gene conversion or selection dependent processes. Our results highlight the distinct biases inherent in the initial mutation patterns and subsequent evolutionary processes that affect segregating variants. PMID- 23990609 TI - Multiple RNA recognition patterns during microRNA biogenesis in plants. AB - MicroRNAs (miRNAs) derive from longer precursors with fold-back structures. While animal miRNA precursors have homogenous structures, plant precursors comprise a collection of fold-backs with variable size and shape. Here, we design an approach to systematically analyze miRNA processing intermediates and characterize the biogenesis of most of the evolutionarily conserved miRNAs present in Arabidopsis thaliana. We found that plant miRNAs are processed by four mechanisms, depending on the sequential direction of the processing machinery and the number of cuts required to release the miRNA. Classification of the precursors according to their processing mechanism revealed specific structural determinants for each group. We found that the complexity of the miRNA processing pathways occurs in both ancient and evolutionarily young sequences and that members of the same family can be processed in different ways. We observed that different structural determinants compete for the processing machinery and that alternative miRNAs can be generated from a single precursor. The results provide an explanation for the structural diversity of miRNA precursors in plants and new insights toward the understanding of the biogenesis of small RNAs. PMID- 23990610 TI - Interfering with histone demethylases in HSCs. PMID- 23990611 TI - Pinning down myeloma with Pim2 inhibitors! PMID- 23990612 TI - The ne plus ultra for deep BCR-ABL sequencing? PMID- 23990613 TI - No more sugar-coating it: mucins and platelet biology. PMID- 23990614 TI - A translational link between Fe and Epo. PMID- 23990615 TI - Ferritin and FerriScan in HCT recipients. PMID- 23990616 TI - A case of adenoid cystic carcinoma arising from the nasopharynx. PMID- 23990617 TI - Estimated disability-adjusted life year (DALY) in all cancers in GLOBOCAN 2008, in Asia by the country. PMID- 23990618 TI - CentriMag short-term ventricular assist as a bridge to solution in patients with advanced heart failure: use beyond 30 days. AB - OBJECTIVES: Left ventricular assist devices (LVADs) offer very valuable therapeutic options for patients with advanced heart failure. CentriMag (Thoratec, Pleasanton, CA, USA) is an extracorporeal short-term circulatory assist device Conformite Europeenne-marked in Europe for use up to 30 days. METHODS: Retrospective analysis of 41 patients with advanced heart failure who, from 2003 to 2011, were supported with CentriMag for >30 days as a bridge to recovery, long-term VAD or transplantation. RESULTS: Forty-one adult patients were supported with 46 CentriMag devices for a total of 2695 days with a mean support time of 59 (range: 31-167) days. Indications were post-cardiotomy cardiogenic shock (PC = 4), primary graft failure (PGF = 7) and refractory heart failure (RHF = 35). Six devices were used to support the left ventricle, 19 to support the right ventricle and 21 to support both the ventricles (biventricular support considered as single device unit). In the PC cohort, 3 (75%) patients were weaned from support, while 4 (57%) were weaned from support in the PGF cohort. In the RHF cohort, 8 patients were bridged to long-term VAD and 5 were bridged to transplantation; heart function recovered and device explanted in 14, while 8 patients died on support. There were no device failures. Overall, 34 (74%) patients were recovered or bridged, with a 1-year survival of 54%. CONCLUSIONS: CentriMag proved to be a versatile, safe and effective short-term circulatory support for patients with advanced heart failure as a bridge to solution. Its use over 30 days is associated with acceptable survival and does not increase device-related complications. PMID- 23990619 TI - Outcomes of mitral valve repair using artificial chordae. AB - OBJECTIVES: The use of artificial chordae techniques has increased the number of mitral valve lesions which are amenable to repair. Artificial chordae can be adapted for a wide range of mitral valve pathologies including restricting the motion of overly mobile 'floppy' Barlow disease leaflets, replacing diseased chordae and improving coaptation in degenerative disease. There is continuing concern about the long-term performance of artificial chordae, which become endothelialized over time and may exhibit complications during the early or late follow-up period. METHODS: To address these issues, we reviewed the literature and extracted 17 papers reporting outcomes following artificial chordae replacement. We discuss the evidence of the effect of artificial chordae on mortality, morbidity and valve performance as measured by echocardiography and complications related to the chordae. We discuss in detail studies comparing artificial chordae with more widely used quadrangular resection techniques. RESULTS: In general, outcomes with respect to mortality, morbidity, rates of reoperation, long-term function and complications of artificial chordae implantation are excellent in a range of pathological settings and in both children and adults. These results are comparable with classical Carpentier techniques and there is some evidence that chordal replacement techniques can in some respects improve the risk-benefit ratio for outcomes compared with the classical Carpentier techniques. CONCLUSIONS: A number of problems remain in the use of artificial chordae, especially the proper determination of their length. Techniques that solve these issues may enhance patient outcomes further. PMID- 23990621 TI - Long-term supports and services planning for the future: implications from a statewide survey of Baby Boomers and older adults. AB - PURPOSE OF THE STUDY: Little is known about adults' future planning for long-term supports and services (LTSS), and no studies have examined how LTSS planning compares between Baby Boomers and their parents' generation. The primary aim of this study is to examine the potential influences of birth cohort and gender on LTSS planning. Drawing on Andersen's Behavioral Model of Health Services Use, birth cohort and gender are viewed as predisposing characteristics, and several additional predisposing, enabling, and need characteristics are included as independent variables. DESIGN AND METHODS: Cross-sectional design; data obtained from a statewide survey of 2,522 randomly selected Baby Boomers (born between 1946 and 1964) and older adults (born before 1946). RESULTS: Two thirds of respondents expected to need LTSS, but few reported saving for such services. Controlling for other independent variables, compared with older adults, Baby Boomers were significantly more likely to plan to move to an apartment, live in a retirement community or assisted living, and live with an adult child. Conversely, women were more likely than men to report planning to use specific LTSS such as homecare, but specific LTSS plans did not vary by birth cohort. IMPLICATIONS: Policymakers and providers should prepare for a shift in community planning to accommodate the changing plans and expectations of Baby Boomers, large numbers of whom plan to age in existing homes and retirement communities, or live with adult children, with increasing demand for informal family support. The LTSS industry should also adapt to meet the need for formal services, which will likely continue to grow. PMID- 23990620 TI - Ikaros limits basophil development by suppressing C/EBP-alpha expression. AB - The Ikaros gene (Ikzf1) encodes a family of zinc-finger transcription factors implicated in hematopoietic cell differentiation. Here we show that Ikaros suppresses the development of basophils, which are proinflammatory cells of the myeloid lineage. In the absence of extrinsic basophil-inducing signals, Ikaros(-/ ) (Ik(-/-)) mice exhibit increases in basophil numbers in blood and bone marrow and in their direct precursors in bone marrow and the spleen, as well as decreased numbers of intestinal mast cells. In vitro culture of Ik(-/-) bone marrow under mast cell differentiation conditions also results in predominance of basophils. Basophil expansion is associated with an increase in basophil progenitors, increased expression of Cebpa and decreased expression of mast cell specifying genes Hes1 and microphthalmia-associated transcription factor (Mitf). Ikaros directly associates with regulatory sites within Cebpa and Hes1 and regulates the acquisition of permissive H3K4 tri-methylation marks at the Cebpa locus and reduces H3K4 tri-methylation at the Hes1 promoter. Ikaros blockade in cultured cells or transfer of Ik(-/-) bone marrow into irradiated Ik(+/+) recipients also results in increased basophils confirming a cell-intrinsic effect of Ikaros on basophil development. We conclude that Ikaros is a suppressor of basophil differentiation under steady-state conditions and that it acts by regulating permissive chromatin modifications of Cebpa. PMID- 23990622 TI - Older women in Appalachia: experiences with gynecological cancer. AB - PURPOSE OF THE STUDY: The purpose of this study was to explore how older women in rural Appalachia with gynecological cancer construct and interpret their experience with cancer. DESIGN AND METHODS: Grounded in social constructionist theory, semistructured in-depth interviews were conducted with 20 women, aged 51 82, who had been treated for gynecological cancer. Transcripts were analyzed using the constant comparative method. RESULTS: Although women narrated their experience along a common trajectory from symptoms to diagnosis to treatment, four distinct patterns of posttreatment perceptions were described: (a) positive: women believed they were cancer survivors, (b) cautious: women saw themselves as survivors but not risk free, (c) distanced: women viewed themselves as cured and equated survivor with victim, and (d) resigned: women refused more treatment. All of the women acknowledged an inner strength in how they experienced cancer, requiring a more nuanced framework for understanding how negative and positive feelings coexist with faith in a higher power and the capacity to endure a devastating threat to life and health. IMPLICATIONS: The findings expand the concept of survivor identity, suggesting that the women's perception that they had met life's challenges with fortitude and inner strength may have more resonance in later life than the concept of survivorship. Family members and medical and public health professionals need to support older women's individual response to cancer recovery and acknowledge their complicated reactions to a cancer diagnosis and prognosis. PMID- 23990624 TI - TLR2 & Co: a critical analysis of the complex interactions between TLR2 and coreceptors. AB - TLRs play a major role in microbe-host interactions and innate immunity. Of the 10 functional TLRs described in humans, TLR2 is unique in its requirement to form heterodimers with TLR1 or TLR6 for the initiation of signaling and cellular activation. The ligand specificity of TLR2 heterodimers has been studied extensively, using specific bacterial and synthetic lipoproteins to gain insight into the structure-function relationship, the minimal active motifs, and the critical dependence on TLR1 or TLR6 for activation. Different from that for specific well-defined TLR2 agonists, recognition of more complex ligands like intact microbes or molecules from endogenous origin requires TLR2 to interact with additional coreceptors. A breadth of data has been published on ligand induced interactions of TLR2 with additional pattern recognition receptors such as CD14, scavenger receptors, integrins, and a range of other receptors, all of them important factors in TLR2 function. This review summarizes the roles of TLR2 in vivo and in specific immune cell types and integrates this information with a detailed review of our current understanding of the roles of specific coreceptors and ligands in regulating TLR2 functions. Understanding how these processes affect intracellular signaling and drive functional immune responses will lead to a better understanding of host-microbe interactions and will aid in the design of new agents to target TLR2 function in health and disease. PMID- 23990623 TI - Fruit consumption and risk of type 2 diabetes: results from three prospective longitudinal cohort studies. AB - OBJECTIVE: To determine whether individual fruits are differentially associated with risk of type 2 diabetes. DESIGN: Prospective longitudinal cohort study. SETTING: Health professionals in the United States. PARTICIPANTS: 66,105 women from the Nurses' Health Study (1984-2008), 85,104 women from the Nurses' Health Study II (1991-2009), and 36,173 men from the Health Professionals Follow-up Study (1986-2008) who were free of major chronic diseases at baseline in these studies. MAIN OUTCOME MEASURE: Incident cases of type 2 diabetes, identified through self report and confirmed by supplementary questionnaires. RESULTS: During 3,464,641 person years of follow-up, 12,198 participants developed type 2 diabetes. After adjustment for personal, lifestyle, and dietary risk factors of diabetes, the pooled hazard ratio of type 2 diabetes for every three servings/week of total whole fruit consumption was 0.98 (95% confidence interval 0.97 [corrected] to 0.99). With mutual adjustment of individual fruits, the pooled hazard ratios of type 2 diabetes for every three servings/week were 0.74 (0.66 to 0.83) for blueberries, 0.88 (0.83 to 0.93) for grapes and raisins, 0.89 (0.79 to 1.01) for prunes, 0.93 (0.90 to 0.96) for apples and pears, 0.95 (0.91 to 0.98) for bananas, 0.95 (0.91 to 0.99) for grapefruit, 0.97 (0.92 to 1.02) for peaches, plums, and apricots, 0.99 (0.95 to 1.03) for oranges, 1.03 (0.96 to 1.10) for strawberries, and 1.10 (1.02 to 1.18) for cantaloupe. The pooled hazard ratio for the same increment in fruit juice consumption was 1.08 (1.05 to 1.11). The associations with risk of type 2 diabetes differed significantly among individual fruits (P<0.001 in all cohorts). CONCLUSION: Our findings suggest the presence of heterogeneity in the associations between individual fruit consumption and risk of type 2 diabetes. Greater consumption of specific whole fruits, particularly blueberries, grapes, and apples, is significantly associated with a lower risk of type 2 diabetes, whereas greater consumption of fruit juice is associated with a higher risk. PMID- 23990625 TI - Increased plasmacytoid dendritic cells and RORgammat-expressing immune effectors in cutaneous acute graft-versus-host disease. AB - The role of PDCs and Th17 cells is not well understood in the pathogenesis of aGVHD. We evaluated PDC and Th17 cells in skin biopsies of 38 patients at diagnosis of aGVHD. The biopsies were tested by immunohistochemistry for the expression of BDCA2, a typical marker of PDCs. We found an increase of BDCA2(+) cells in the skin of the patients with aGVHD. Moreover, we observed a strong expression of the type I IFN-inducible protein Mx1 in the skin of the patients with aGVHD, compared with that of those without it, suggesting that PDCs produce type I IFN. We also analyzed the expression of two Th17 surface markers-CD161 and CCR6-and RORgammat, the key transcription factor that orchestrates the differentiation of Th17 cells. Significantly higher numbers of RORgammat(+), CD161(+), and CCR6(+) cells were counted in the skin of the patients with aGVHD than in the skin of those who underwent allo-SCT and in whom aGVHD did not develop. This study provides evidence for a role of Th17-mediated responses and a potential new pathophysiological link between PDCs and Th17 in human cutaneous aGVHD. PMID- 23990627 TI - Requirement of TPO/c-mpl for IL-17A-induced granulopoiesis and megakaryopoiesis. AB - IL-17A is a critical, proinflammatory cytokine essential to host defense and is induced in response to microbial invasion. It stimulates granulopoiesis, leading to neutrophilia, neutrophil activation, and mobilization. TPO synergizes with other cytokines in stimulating and expanding hematopoietic progenitors, also leading to granulopoiesis and megakaryopoiesis, and is required for thrombocytopoiesis. We investigated the effects of in vivo expression of IL-17A on granulopoiesis and megakaryopoiesis in TPO receptor c-mpl-/- mice. IL-17A expression expanded megakaryocytes by 2.5-fold in normal mice but had no such effect in c-mpl-/- mice. The megakaryocyte expansion did not result in increased peripheral platelet counts. IL-17A expression did not impact bone marrow precursors in c-mpl-/- mice; however, it expanded splenic precursors, although to a lesser extent compared with normal controls (CFU-HPP). No peripheral neutrophil expansion was observed in c-mpl-/- mice. Moreover, in c-mpl-/- mice, release of IL-17A downstream cytokines was reduced significantly (KC, MIP-2, GM-CSF). The data suggest that IL-17A requires the presence of functional TPO/c-mpl to exert its effects on granulopoiesis and megakaryopoiesis. Furthermore, IL-17A and its downstream cytokines are important regulators and synergistic factors for the physiologic function of TPO/c-mpl on hematopoiesis. PMID- 23990628 TI - Bile acids PKA-dependently induce a switch of the IL-10/IL-12 ratio and reduce proinflammatory capability of human macrophages. AB - That cholestatic conditions are accompanied by an enhanced susceptibility to bacterial infection in human and animal models is a known phenomenon. This correlates with the observation that bile acids have suppressive effects on cells of innate and adaptive immunity. The present study provides evidence that in human macrophages, bile acids inhibit the LPS-induced expression of proinflammatory cytokines without affecting the expression of the anti inflammatory cytokine IL-10. This results in a macrophage phenotype that is characterized by an increased IL-10/IL-12 ratio. Correspondingly, bile acids suppress basal phagocytic activity of human macrophages. These effects of bile acids can be mimicked by cAMP, which is presumably induced TGR5-dependently. The data provided further suggest that in primary human macrophages, modulation of the macrophage response toward LPS by bile acids involves activation of CREB, disturbed nuclear translocation of NF-kappaB, and PKA-dependent enhancement of LPS-induced cFos expression. The increase in cFos expression is paralleled by an enhanced formation of a protein complex comprising cFos and the p65 subunit of NF kappaB. In summary, the data provided suggest that in human macrophages, bile acids induce an anti-inflammatory phenotype characterized by an increased IL 10/IL-12 ratio via activation of PKA and thereby, prevent their activation as classically activated macrophages. This bile acid-induced modulation of macrophage function may also be responsible for the experimentally and clinically observed anti-inflammatory and immunosuppressive effects of bile acids. PMID- 23990629 TI - Does the gut-brain axis control anticipatory food reward? Novel insights from bariatric surgery. PMID- 23990631 TI - India's problem with girls. PMID- 23990632 TI - Dyspepsia. PMID- 23990633 TI - Should the FDA regulate mobile medical apps? PMID- 23990634 TI - Do risks outweigh benefits in thrombolysis for stroke? PMID- 23990626 TI - Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. AB - Extensive research in the past decade has identified innate immune recognition receptors and intracellular signaling pathways that culminate in inflammatory responses. Besides its role in cytoprotection, the importance of cell stress in inflammation and host defense against pathogens is emerging. Recent studies have shown that proteins in cellular stress responses, including the heat shock response, ER stress response, and DNA damage response, interact with and regulate signaling intermediates involved in the activation of innate and adaptive immune responses. The effect of such regulation by cell stress proteins may dictate the inflammatory profile of the immune response during infection and disease. In this review, we describe the regulation of innate immune cell activation by cell stress pathways, present detailed descriptions of the types of stress response proteins and their crosstalk with immune signaling intermediates that are essential in host defense, and illustrate the relevance of these interactions in diseases characteristic of aberrant immune responses, such as chronic inflammatory diseases, autoimmune disorders, and cancer. Understanding the crosstalk between cellular stress proteins and immune signaling may have translational implications for designing more effective regimens to treat immune disorders. PMID- 23990635 TI - The judge as medical ethicist. PMID- 23990636 TI - Midwife led care delivers best outcomes, Cochrane review finds. PMID- 23990637 TI - Biological therapies improve inflammatory bowel disease symptoms, national audit finds. PMID- 23990638 TI - Proposals to charge migrants for NHS care are unworkable, says BMA. PMID- 23990639 TI - The infective endocarditis team: recommendations from an international working group. PMID- 23990640 TI - High-sensitivity cardiac troponin in patients with stable chronic obstructive pulmonary disease: looking beyond the lungs. PMID- 23990641 TI - The authors' reply. PMID- 23990643 TI - Statins and venous thromboembolism: the jury is still out. PMID- 23990642 TI - Twenty years of Cochrane reviews in menstrual disorders and subfertility. AB - The past three decades have seen considerable change in the understanding of clinical research methods. There has been an acceptance that RCTs are the best way of establishing treatment effectiveness and a recognition that, while single studies are useful, pooling knowledge from a complete body of work is likely to provide the best evidence. Advances in methodology have been mirrored by the many advances in the field of reproductive medicine, such as assisted reproduction, assessment of male fertility, ovulation induction and laparoscopic surgery. Together, they have led to welcome improvements in the outcomes of fertility treatments. In particular, systematic reviews have become important tools enabling clinicians and patients to make health-care decisions based on evidence from all the available high-quality studies. The move towards identifying and aggregating the highest quality evidence has been led by the Cochrane Collaboration, which this year celebrates 20 years of preparing and publishing systematic reviews. This paper outlines the achievements, progress and challenges of this enterprise to date, with a particular focus on systematic reviews of reproductive medicine. PMID- 23990644 TI - Beyond the ankle-brachial pressure index for the diagnosis of peripheral arterial disease--time for a new look at photoplethysmography. PMID- 23990645 TI - Further evaluations of functional communication training and chained schedules of reinforcement to treat multiple functions of challenging behavior. AB - We evaluated functional communication training (FCT) combined with a chained schedule of reinforcement procedure for the treatment of challenging behavior exhibited by two individuals diagnosed with Asperger syndrome and autism. Following functional analyses that suggested that challenging behavior served multiple functions for both participants, we implemented FCT in which mands for a discriminative stimulus (S(D); wristband) were reinforced with access to the S(D) and all three functional reinforcers. Next, we modified the procedure by incorporating delays to increase ease of implementation and promote toleration of delays to reinforcement. Last, we made additional modifications to the procedure by incorporating a chained schedule of reinforcement such that (a) mands for the wristband were reinforced with access to the wristband and (b) specific mands for respective functional reinforcers were reinforced in the presence of the wristband. The results showed that the procedure successfully treated challenging behavior with multiple functions. Future directions in the evaluation and development of treatments that simultaneously address multiple functions are discussed. PMID- 23990646 TI - Behavioral activation and problem-solving therapy for depressed breast cancer patients: preliminary support for decreased suicidal ideation. AB - Major depressive disorder (MDD) is the most common psychiatric disorder in breast cancer patients. The prevalence of suicidal ideation in breast cancer patients is considerable, and relative to the general population, the prevalence of completed suicide is elevated, particularly in cancer patients with MDD. A major component of suicide prevention is effective treatment of MDD. Although some research has explored the utility of psychotherapy with breast cancer patients, only three trials have explored the benefits of behavior therapy in patients with well diagnosed MDD and there has been no systematic investigation of the potential benefits of psychotherapy toward reducing suicidal ideation in breast cancer patients. As a follow-up to a recently completed randomized trial, this study examined the efficacy of 8 weeks of behavioral activation treatment for depression (BATD) and problem-solving therapy (PST) in reducing depression and suicidal ideation, as well as increasing hopefulness in breast cancer patients with MDD (n = 80). Across both treatments, GEE analyses revealed decreased depression and suicidal ideation and increased hopefulness at posttreatment, results that were maintained at 12-month follow-up. Moreover, follow-up patient contact at approximately 2 years posttreatment yielded no indication of completed suicide. Although these data are preliminary, BATD and PST may represent practical approaches to decrease suicidal ideation in depressed breast cancer patients. PMID- 23990647 TI - Pulmonary embolism and deep venous thrombosis following laparoscopic cholecystectomy. AB - There is considerable uncertainty related to the thromboembolic risk after laparoscopic cholecystectomy. Patients with pulmonary embolism (PE), deep venous thrombosis (DVT), or venous thromboembolism (VTE) at hospital discharge following laparoscopic cholecystectomy were identified from the Nationwide Inpatient Sample. From 1998 through 2009, 4 107 430 laparoscopic cholecystectomies were performed. The in-hospital prevalence of PE was 0.15%, DVT was 0.40%, and VTE was 0.53%. The prevalence of PE increased from 0.04% in patients aged 21 to 30 years to 0.31% in patients aged 71 to 80 years. Deaths due to in-hospital PE were 780 (0.02%) of the 4 107 430 laparoscopic cholecystectomies. The rate of death increased with age. The prevalence of VTE following laparoscopic cholecystectomy is low and fatal PE is rare. The risk of VTE increased with age, as did the risk of death in those who had PE. These data may be useful in assessing the use of thromboprophylaxis in patients undergoing laparoscopic cholecystectomy. PMID- 23990648 TI - Mycobacterium bourgelatii sp. nov., a rapidly growing, non-chromogenic species isolated from the lymph nodes of cattle. AB - Three independent strains of a rapidly growing, non-chromogenic member of the genus Mycobacterium were isolated from lymph nodes of French cattle. Identification of the isolates was carried out using a polyphasic approach. The nearly complete SSU rRNA gene sequences (>1200 bp) of the strains MLB-A23, MLB A30 and MLB-A84(T) were identical. A phylogenetic analysis of these unique SSU rRNA gene sequences showed that these strains were most closely related to Mycobacterium intermedium. Further phylogenetic analysis based on concatenated sequences (2854 bp) of four housekeeping genes (hsp65, rpoB, sodA and tuf), the transfer-messenger RNA (tmRNA) and SSU rRNA genes indicated that these three strains represented a distinct species that shares a common ancestor with M. intermedium. Phylogenetic and phenotypic data strongly indicate that the strains MLB-A23, MLB-A30 and MLB-A84(T) belong to a novel mycobacterial species for which the name Mycobacterium bourgelatii sp. nov. is proposed. The type strain is MLB A84(T) ( = CIP 110557(T) = DSM 45746(T)). PMID- 23990649 TI - Nocardioides endophyticus sp. nov. and Nocardioides conyzicola sp. nov., isolated from herbaceous plant roots. AB - Two Gram-stain-positive, non-motile, non-spore-forming, rod-shaped actinobacterial strains were isolated from the surface-sterilized roots of mugwort (Artemisia princeps) and horse-weed (Conyza canadensis), and subjected to taxonomic characterization. 16S rRNA gene sequence analysis indicated that the isolates, designated MWE 3-5(T) and HWE 2-02(T), should be placed in the genus Nocardioides of the family Nocardioidaceae. The strains were closely related to Nocardioides hankookensis DS-30(T), which exhibited 16S rRNA gene sequence similarity values of 97.99 and 99.09 % with strains MWE 3-5(T) and HWE 2-02(T), respectively. The genome relatedness of N. hankookensis DS-30(T) with strain MWE 3-5(T) was 35.8 %, and that with strain HWE 2-02(T) was 36.4 %, whereas that between the two isolates was 43.2 %. Strains MWE 3-5(T) and HWE 2-02(T) possessed MK-8(H4) as the major isoprenoid quinone, and ll-diaminopimelic acid in the cell wall peptidoglycan. The main fatty acids were iso-C16 : 0, iso-C17 : 0 and C18 : 1omega9c for strain MWE 3-5(T) and iso-C16 : 0, 10-methyl C18 : 0 and C18 : 1omega9c for strain HWE 2-02(T). Based on phenotypic, genotypic and phylogenetic studies, the following two novel species are proposed: Nocardioides endophyticus sp. nov. (type strain, MWE 3-5(T) = KCTC 29122(T) = JCM 18532(T)) and Nocardioides conyzicola sp. nov. (type strain, HWE 2-02(T) = KCTC 29121(T) = JCM 18531(T)). PMID- 23990650 TI - Bacillus paraflexus sp. nov., isolated from compost. AB - A Gram-stain-positive, rod-shaped, endospore-forming, aerobic bacterium capable of growing at 15-42 degrees C (optimum 30 degrees C) and at pH 5-11 (optimum pH 7) was isolated from compost. Its taxonomic position was deduced using a polyphasic approach and the strain was designated RC2(T). 16S rRNA gene sequence analysis showed that the isolate belongs to the division Firmicutes, forming a clade within the cluster containing Bacillus flexus IFO 15715(T), and showed highest similarity to B. flexus IFO 15715(T) (98.1 %). The cell wall contained meso-diaminopimelic acid as the diagnostic diamino acid. The major cellular fatty acids of the novel strain were iso-C15:0 (36.83 %), anteiso-C15:0 (49.19 %) and C16:0 (5.19 %). DNA-DNA hybridization between strain RC2(T) and B. flexus DSM 1320(T) showed a level of relatedness of 54.5 %. The polar lipid profile of strain RC2(T) showed the presence of phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine. The predominant isoprenoid quinone was MK-7 and the G+C content of strain RC2(T) was 37.6 mol%. On the basis of phenotypic characteristics, phylogenetic analysis and the results of biochemical and physiological tests, strain RC2(T) was clearly distinguished from closely related members of the genus, and the strain is assigned to a novel species, for which the name Bacillus paraflexus sp. nov. is proposed. The type strain is RC2(T) ( = MTCC 9831(T) = MCC 2100(T) = KCTC 13724(T) = CCM 7754(T)). PMID- 23990651 TI - Terriglobus aquaticus sp. nov., isolated from an artificial reservoir. AB - A pink-pigmented, chemo-organotrophic bacterium, designated strain 03SUJ4(T), was isolated from the freshwater of Juam reservoir, Republic of Korea (35 degrees 03' 43'' N 127 degrees 14' 15'' E). Cells were aerobic, Gram-reaction-negative and non-motile rods. Strain 03SUJ4(T) grew at pH 6-7 (optimum, pH 6) and at 15-30 degrees C (optimum, 25 degrees C). Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate belonged to the genus Terriglobus, showing sequence similarities of 97.09 % and 96.82 % to Terriglobus roseus DSM 18391(T) and Terriglobus saanensis SP1PR4(T), respectively. Low rpoB gene sequence similarity with members of the genus Terriglobus and different fingerprints with the repetitive primers BOX, ERIC and REP indicated that the isolate represented a novel species of the genus Terriglobus. The major cellular fatty acids were iso C15 : 0, C16 : 0, C20 : 1omega9c, C14 : 0 and summed feature 3 (C16 : 1omega7c/C16 : 1omega6c). The DNA G+C content of strain 03SUJ4(T) was 63.2+/-0.1 mol% (mean+/-sd of three determinations). The predominant menaquinone was MK-8. The major polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and two unidentified phospholipids. Several phenotypic characteristics served to differentiate the novel isolate from recognized members of the genus Terriglobus. On the basis of the evidence presented in this study, a novel species, Terriglobus aquaticus sp. nov. is proposed for strain 03SUJ4(T) ( = KCTC 23332(T) = JCM 17517(T)). PMID- 23990652 TI - Amnibacterium soli sp. nov., an actinobacterium isolated from grass soil. AB - A Gram-stain-positive, aerobic, non-motile, non-spore-forming, short rod-shaped actinobacterium, designated strain PB243(T), was isolated from grass soil sampled in Daejeon, Republic of Korea. Comparative 16S rRNA gene sequence studies showed the isolate was clearly affiliated with the class Actinobacteria, and most closely related to Amnibacterium kyonggiense KEMC 51201-037(T), showing 98.8 % 16S rRNA gene sequence similarity. Cells of strain PB243(T) formed yellow colonies on R2A agar, contained MK-11 and MK-12 as the predominant menaquinones, l-2,4-diaminobutyric acid as the diagnostic cell-wall diamino acid, and anteiso C15:0 and iso-C16:0 among the major fatty acids. The acyl type of the muramic acid was acetyl. The G+C content of the genomic DNA of strain PB243(T) was 71.5 mol%. Thus, the combined genotypic and phenotypic data supported the conclusion that strain PB243(T) represents a novel species of the genus Amnibacterium, for which the name Amnibacterium soli sp. nov. is proposed. The type strain is PB243(T) ( = KCTC 33147(T) = JCM 19015(T)). PMID- 23990653 TI - Streptomyces abietis sp. nov., a cellulolytic bacterium isolated from soil of a pine forest. AB - Cellulolytic bacteria A191(T), A192 and A193 isolated from the soil of Sakhalin fir forest in Hokkaido, Japan were studied phenotypically, genotypically and phylogenetically. Analysis of their 16S rRNA gene and gyrB sequences and DNA base composition suggested that these isolates were conspecific and members of the genus Streptomyces. However, levels of 16S rRNA gene and gyrB sequence similarity between the isolates and the type strains of their closest relatives in the genus Streptomyces were no higher than 97.9 and 95.0 %, respectively, implying that these isolates were distinctive. Moreover, the results of DNA-DNA hybridization experiments and physiological characterization clearly differentiated these isolates from their closest neighbours. It is therefore concluded that these isolates represent a novel species of the genus Streptomyces, for which the name Streptomyces abietis is proposed. The type strain is A191(T) ( = NBRC 109094(T) = DSM 42080(T)). PMID- 23990654 TI - Zhihengliuella flava sp. nov., an actinobacterium isolated from sea sediment, and emended description of the genus Zhihengliuella. AB - A novel Gram-staining-positive actinobacterium, designated H85-3(T), was isolated from a sea sediment sample and its taxonomic position was investigated by a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain H85-3(T) was closely related to the members of the genus Zhihengliuella with pairwise sequence similarities of 97.4-98.6 %. The peptidoglycan of strain H85-3(T) was found to be of the A4alpha type with lysine as the diagnostic diamino acid. The menaquinones were MK-9, MK-10 and MK-8 (56 : 30 : 14) and the major cellular fatty acids were anteiso-C15 : 0, iso-C15 : 0 and anteiso-C17 : 0. These data supported the affiliation of strain H85-3(T) to the genus Zhihengliuella. Meanwhile, the results of DNA-DNA hybridization, along with the differences in some phenotypic characteristics, indicated that strain H85 3(T) should be distinguished from the recognized species of the genus Zhihengliuella. Therefore, strain H85-3(T) represents a novel species of the genus Zhihengliuella, for which the name Zhihengliuella flava sp. nov. is proposed; the type strain is H85-3(T) ( = NBRC 109021(T) = DSM 26152(T)). An emended description of the genus Zhihengliuella is also proposed. PMID- 23990655 TI - Luteibaculum oceani gen. nov., sp. nov., a carotenoid-producing, lipolytic bacterium isolated from surface seawater, and emended description of the genus Owenweeksia Lau et al. 2005. AB - A yellow-pigmented, Gram-staining-negative, strictly aerobic, rod-shaped, non flagellated, non-spore-forming, lipolytic and gliding marine bacterium designated strain CC-AMWY-103B(T) was isolated from surface seawater collected at Kending, Taiwan. The strain shared the highest 16S rRNA gene sequence similarity of 89.4% with Owenweeksia hongkongensis JCM 12287(T) and Brumimicrobium mesophilum YH207(T), and established a distinct phyletic lineage associated with the members of the family Cryomorphaceae. The polar lipid profile of strain CC-AMWY-103B(T) consisted of phosphatidylethanolamine, ten unidentified lipids and four unidentified aminolipids. The major fatty acids (>5% of the total) were iso-C15 : 0, iso-C15 : 1 G, C15 : 1omega5c, iso-C17 : 0 3-OH and C15 : 1omega8c. The DNA G+C content was 44.2 +/- 0.3 mol%. The predominant respiratory quinone was menaquinone-6 (MK-6) and the major polyamine was spermidine. Based on its genetic, phylogenetic, phenotypic and chemotaxonomic distinctiveness, strain CC AMWY-103B(T) is proposed to represent a distinct member of the family Cryomorphaceae, for which the name Luteibaculum oceani gen. nov., sp. nov. is proposed; the type strain of Luteibaculum oceani is CC-AMWY-103B(T) ( = JCM 18817(T) = BCRC 80551(T)). An emended description of the genus Owenweeksia is also proposed. PMID- 23990656 TI - Posttraumatic growth and support among parents whose children have survived stem cell transplantation. AB - In the current study, we investigated the occurrence of posttraumatic growth (PTG) among parents whose children had had stem cell transplantation (SCT) and survived. Although SCT is well established, it remains stressful and dangerous, and SCT is only performed if there is no other choice of treatment to be considered. A questionnaire batteries including the Post-Traumatic Stress Disorder (PTSD) Check List-Civilian version and the Post-Traumatic Growth Inventory were sent out to a cross-sectional national sample of parents of children who had had SCT six months or more before the study. The response rate was 66% (n = 281). The data were analyzed in relation to parents' appraisal of the event, gender, and perceived social support. The results confirm that SCT in childhood is an event of extreme adversity for the parents. Indications of PTSD were found among an important minority of the parents. Nevertheless, a large proportion of the parents had experienced growth as a consequence of the child's illness. Appreciation of life and personal strength were the domains with the highest scores. Moreover, a higher level of PTG was correlated with a higher level of posttraumatic stress and with an experience of the trauma as more severe. In summary, the study indicates that PTG is a relevant concept for this group of parents. PMID- 23990657 TI - Consequences of caring for a child with a chronic disease: Employment and leisure time of parents. AB - Chronically ill children require several hours of additional care per day compared to healthy children. As parents provide most of this care, they have to incorporate it into their daily schedule, which implies a reduction in time for other activities. The study aimed to assess the effect of having a chronically ill child on parental employment and parental leisure activity time, and to explore the role of demographic, social, and disease-related variables in relation to employment and leisure activities. Outcomes of 576 parents of chronically ill children and 441 parents of healthy school children were analyzed with multivariate regression. Having a chronically ill child was negatively related with family employment, maternal labor force participation, and leisure activity time. Use of child care was positively related to family and maternal employment of the total group of parents. Within parents of chronically ill children, most important finding was the negative relation of dependency of the child on daily care and low parental educational level with family and maternal employment. In conclusion, parents of chronically ill children, mothers in particular, are disadvantaged in society probably due to the challenge of combining child care with work and leisure time. PMID- 23990658 TI - Editorial: Strangers with candy: policing the lungs with C-type lectins. PMID- 23990659 TI - Editorial: Pannexin-1--the hidden gatekeeper for HIV-1. PMID- 23990660 TI - Telemonitoring and self-management in the control of hypertension (TASMINH2): a cost-effectiveness analysis. AB - AIMS: Self-monitoring and self-titration of antihypertensives (self-management) is a novel intervention which improves blood pressure control. However, little evidence exists regarding the cost-effectiveness of self-monitoring of blood pressure in general and self-management in particular. This study aimed to evaluate whether self-management of hypertension was cost-effective. DESIGN AND METHODS: A cohort Markov model-based probabilistic cost-effectiveness analysis was undertaken extrapolating to up to 35 years from cost and outcome data collected from the telemonitoring and self-management in hypertension trial (TASMINH2). Self-management of hypertension was compared with usual care in terms of lifetime costs, quality adjusted life years and cost-effectiveness using a UK Health Service perspective. Sensitivity analyses examined the effect of different time horizons and reduced effectiveness over time from self-management. RESULTS: In the long-term, when compared with usual care, self-management was more effective by 0.24 and 0.12 quality adjusted life years (QALYs) gained per patient for men and women, respectively. The resultant incremental cost-effectiveness ratio for self-management was L1624 per QALY for men and L4923 per QALY for women. There was at least a 99% chance of the intervention being cost-effective for both sexes at a willingness to pay threshold of L20,000 per QALY gained. These results were robust to sensitivity analyses around the assumptions made, provided that the effects of self-management lasted at least two years for men and five years for women. CONCLUSION: Self-monitoring with self-titration of antihypertensives and telemonitoring of blood pressure measurements not only reduces blood pressure, compared with usual care, but also represents a cost effective use of health care resources. PMID- 23990661 TI - Cooperation between hepatic cholesteryl ester hydrolase and scavenger receptor BI for hydrolysis of HDL-CE. AB - Liver is the sole organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or bile acids. High density lipoprotein (HDL)-derived cholesterol is the major source of biliary sterols and represents a mechanism for the removal of cholesterol from peripheral tissues including artery wall-associated macrophage foam cells. Via selective uptake through scavenger receptor BI (SR-BI), HDL-cholesterol is thought to be directly secreted into bile, and HDL cholesteryl esters (HDL-CEs) enter the hepatic metabolic pool and need to be hydrolyzed prior to conversion to bile acids. However, the identity of hepatic CE hydrolase (CEH) as well as the role of SR-BI in bile acid synthesis remains elusive. In this study we examined the role of human hepatic CEH (CES1) in facilitating hydrolysis of SR-BI-delivered HDL-CEs. Over-expression of CEH led to increased hydrolysis of HDL-[3H]CE in primary hepatocytes and SR-BI expression was required for this process. Intracellular CEH associated with BODIPY-CE delivered by selective uptake via SR-BI. CEH and SR-BI expression enhanced the movement of [3H]label from HDL-[3H]CE to bile acids in vitro and in vivo. Taken together, these studies demonstrate that SR-BI-delivered HDL-CEs are hydrolyzed by hepatic CEH and utilized for bile acid synthesis. PMID- 23990662 TI - Role of the hydrophobic and charged residues in the 218-226 region of apoA-I in the biogenesis of HDL. AB - We investigated the significance of hydrophobic and charged residues 218-226 on the structure and functions of apoA-I and their contribution to the biogenesis of HDL. Adenovirus-mediated gene transfer of apoA-I[L218A/L219A/V221A/L222A] in apoA I-/- mice decreased plasma cholesterol and apoA-I levels to 15% of wild-type (WT) control mice and generated pre-beta- and alpha4-HDL particles. In apoA-I-/- * apoE-/- mice, the same mutant formed few discoidal and pre-beta-HDL particles that could not be converted to mature alpha-HDL particles by excess LCAT. Expression of the apoA-I[E223A/K226A] mutant in apoA-I-/- mice caused lesser but discrete alterations in the HDL phenotype. The apoA-I[218-222] and apoA I[E223A/K226A] mutants had 20% and normal capacity, respectively, to promote ABCA1-mediated cholesterol efflux. Both mutants had ~65% of normal capacity to activate LCAT in vitro. Biophysical analyses suggested that both mutants affected in a distinct manner the structural integrity and plasticity of apoA-I that is necessary for normal functions. We conclude that the alteration of the hydrophobic 218-222 residues of apoA-I disrupts apoA-I/ABCA1 interactions and promotes the generation of defective pre-beta particles that fail to mature into alpha-HDL subpopulations, thus resulting in low plasma apoA-I and HDL. Alterations of the charged 223, 226 residues caused milder but discrete changes in HDL phenotype. PMID- 23990663 TI - Differential diagnosis and the suspension of judgment. AB - In this paper I argue that ethics and evidence are intricately intertwined within the clinical practice of differential diagnosis. Too often, when a disease is difficult to diagnose, a physician will dismiss it as being "not real" or "all in the patient's head." This is both an ethical and an evidential problem. In the paper my aim is two-fold. First, via the examination of two case studies (late stage Lyme disease and Addison's disease), I try to elucidate why this kind of dismissal takes place. Then, I propose a potential solution to the problem. I argue that instead of dismissing a patient's illness as "not real," physicians ought to exercise a compassionate suspension of judgment when a diagnosis cannot be immediately made. I argue that suspending judgment has methodological, epistemic, and ethical virtues and therefore should always be preferred to patient dismissal in the clinical setting. PMID- 23990664 TI - New insights into von Hippel-Lindau function highlighted by investigation of the trichloroethylene-induced p.P81S hotspot mutation. PMID- 23990665 TI - Denosumab for patients with persistent or relapsed hypercalcemia of malignancy despite recent bisphosphonate treatment. AB - Hypercalcemia of malignancy (HCM), caused primarily by tumor-induced bone resorption, may lead to renal failure, coma, and death. Although HCM can be treated with intravenous bisphosphonates, patients may not respond or may relapse on therapy. Denosumab binds the bone resorption mediator RANKL. In this single arm, open-label, proof-of-concept study, HCM patients with albumin-corrected serum calcium (CSC) levels greater than 12.5mg/dL (Common Terminology Criteria for Adverse Events grade >= 3) despite recent intravenous bisphosphonate treatment received subcutaneous denosumab on days 1, 8, 15, and 29, and then every 4 weeks. The primary endpoint was the proportion of patients with CSC 11.5mg/dL or less (grade <= 1) within 10 days of denosumab initiation. In a prespecified interim analysis, 15 patients received denosumab (median CSC = 13.6 mg/dL). Time to response and response duration were analyzed with Kaplan-Meier methods. All statistical tests were two-sided. By day 10, 12 patients (80%; 95% exact confidence interval [CI] = 52% to 96%) responded (CSC <= 11.5mg/dL); median response duration was 26 days. Ten patients (67%; 95% exact CI = 38% to 88%) had complete responses (CSC <= 10.8 mg/dL) by day 10. Denosumab may offer a new treatment option for HCM. Clinicaltrials.gov identifier: NCT00896454. PMID- 23990666 TI - Pleiotropic effects of the trichloroethylene-associated P81S VHL mutation on metabolism, apoptosis, and ATM-mediated DNA damage response. AB - BACKGROUND: The risk relevance of the P81S von Hippel-Lindau (VHL) gene hotspot mutation identified in clear cell renal cell carcinoma from individuals exposed occupationally to trichloroethylene (TCE) is not known. VHL mutations in hereditary VHL syndrome strongly correlate with phenotypic associations, but specific sporadic mutations in VHL that uniquely alter its protein function may provide a selective growth advantage for somatic cells harboring these mutations. METHODS: VHL deficient (Vhl (-/-) ) mouse embryonic stem cells were generated that stably express wild-type, P81S, or R167Q human VHL protein. Under hypoxic conditions, cell lines were examined for hypoxia-inducible transcription factor family (HIF) stabilization and E3-ubiquitin ligase complex interactions. In vivo, teratomas were examined for tumor size, proliferation, apoptosis, and immunohistochemistry and subjected to gene expression analysis. Wild-type, R167Q, and P81S VHL-expressing teratomas were also exposed to 5 Gy ionizing radiation to quantify apoptotic response. Proliferation and apoptosis and teratoma growth were analyzed by either Student t test or analysis of variance with Bonferroni correction. All statistical tests were two-sided. RESULTS: The P81S VHL mutation produces deregulation of HIF factors in cell culture but exhibits a growth advantage in the tumor microenvironment, in part because of suppression of apoptosis (P81S mean = 0.9%, 95% confidence interval = 0.6 to 1.2%; WT mean = 7.6%; 95% confidence interval = 6.4 to 8.8%; P < .001) coupled with sustained proliferation. Transcriptional analysis of P81S teratomas revealed the induction of metabolic pathways, antiapoptotic genes, and global suppression of key DNA damage response genes not observed in VHL wild-type or R167Q mutants. In vivo irradiation exposure showed that P81S mutant is resistant to ionizing radiation induced apoptosis. CONCLUSIONS: The TCE-associated P81S VHL mutation can initiate a unique adaptive response required for selective tumor growth through pleiotropic effects on metabolic diversification, apoptosis suppression, and alteration of the DNA damage response. PMID- 23990670 TI - Shaking tobacco's residual grip: endgame strategies emerge. PMID- 23990668 TI - Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. AB - BACKGROUND: Cell migration is a critical determinant of cancer metastasis, and a better understanding of the genes involved will lead to the identification of novel targets aimed at preventing cancer dissemination. KIAA1199 has been shown to be upregulated in human cancers, yet its role in cancer progression was hitherto unknown. METHODS: Clinical relevance was assessed by examining KIAA1199 expression in human cancer specimens. In vitro and in vivo studies were employed to determine the function of KIAA1199 in cancer progression. Cellular localization of KIAA1199 was microscopically determined. SNAP-tag pull-down assays were used to identify binding partner(s) of KIAA1199. Calcium levels were evaluated using spectrofluorometric and fluorescence resonance energy transfer analyses. Signaling pathways were dissected by Western blotting. Student t test was used to assess differences. All statistical tests were two-sided. RESULTS: KIAA1199 was upregulated in invasive breast cancer specimens and inversely associated with patient survival rate. Silencing of KIAA1199 in MDA-MB-435 cancer cells resulted in a mesenchymal-to-epithelial transition that reduced cell migratory ability in vitro (75% reduction; P < .001) and decreased metastasis in vivo (80% reduction; P < .001). Gain-of-function assays further demonstrated the role of KIAA1199 in cell migration. KIAA1199-enhanced cell migration required endoplasmic reticulum (ER) localization, where it forms a stable complex with the chaperone binding immunoglobulin protein (BiP). A novel ER-retention motif within KIAA1199 that is required for its ER localization, BiP interaction, and enhanced cell migration was identified. Mechanistically, KIAA1199 was found to mediate ER calcium leakage, and the resultant increase in cytosolic calcium ultimately led to protein kinase C alpha activation and cell migration. CONCLUSIONS: KIAA1199 serves as a novel cell migration-promoting gene and plays a critical role in maintaining cancer mesenchymal status. PMID- 23990671 TI - Concerned about HPV-related cancer rise, researchers advocate boosting HPV vaccination rates. PMID- 23990667 TI - Impact of obesity on cancer survivorship and the potential relevance of race and ethnicity. AB - Evidence that obesity is associated with cancer incidence and mortality is compelling. By contrast, the role of obesity in cancer survival is less well understood. There is inconsistent support for the role of obesity in breast cancer survival, and evidence for other tumor sites is scant. The variability in findings may be due in part to comorbidities associated with obesity itself rather than with cancer, but it is also possible that obesity creates a physiological setting that meaningfully alters cancer treatment efficacy. In addition, the effects of obesity at diagnosis may be distinct from the effects of weight change after diagnosis. Obesity and related comorbid conditions may also increase risk for common adverse treatment effects, including breast cancer related lymphedema, fatigue, poor health-related quality of life, and worse functional health. Racial and ethnic groups with worse cancer survival outcomes are also the groups for whom obesity and related comorbidities are more prevalent, but findings from the few studies that have addressed these complexities are inconsistent. We outline a broad theoretical framework for future research to clarify the specifics of the biological-social-environmental feedback loop for the combined and independent contributions of race, comorbid conditions, and obesity on cancer survival and adverse treatment effects. If upstream issues related to comorbidities, race, and ethnicity partly explain the purported link between obesity and cancer survival outcomes, these factors should be among those on which interventions are focused to reduce the burden of cancer. PMID- 23990672 TI - A new mechanism for albuminuria-induced podocyte injury. PMID- 23990673 TI - Estimated GFR reporting influences recommendations for dialysis initiation. AB - Automated reporting of estimated GFR (eGFR) with serum creatinine measurement is now common. We surveyed nephrologists in four countries to determine whether eGFR reporting influences nephrologists' recommendations for dialysis initiation. Respondents were randomly allocated to receive a survey of four clinical vignettes that included either serum creatinine concentration only or serum creatinine and the corresponding eGFR. For each scenario, the respondent was asked to rank his or her likelihood of recommending dialysis initiation on a modified 8-point Likert scale, ranging from 1 ("definitely not") to 8 ("definitely would"). Analysis of the 822 eligible responses received showed that the predicted likelihood of recommending dialysis increased by 0.55 points when eGFR was reported (95% confidence interval, 0.33 to 0.76), and this effect was larger for eGFRs >5 ml/min per 1.73 m(2) (P<0.001). Subgroup analyses suggested that physicians who had been in practice >=13 years were more affected by eGFR reporting (P=0.03). These results indicate that eGFR reporting modestly increases the likelihood that dialysis is recommended, and physicians should be aware of this effect when assessing patients with severe CKD. PMID- 23990674 TI - Foretelling the future: predicting graft outcome by evaluating kidney baseline transplant biopsies. PMID- 23990675 TI - Stroke and the "stroke belt" in dialysis: contribution of patient characteristics to ischemic stroke rate and its geographic variation. AB - Geographic variation in stroke rates is well established in the general population, with higher rates in the South than in other areas of the United States. ESRD is a potent risk factor for stroke, but whether regional variations in stroke risk exist among dialysis patients is unknown. Medicare claims from 2000 to 2005 were used to ascertain ischemic stroke events in a large cohort of 265,685 incident dialysis patients. A Poisson generalized linear mixed model was generated to determine factors associated with stroke and to ascertain state-by state geographic variability in stroke rates by generating observed-to-expected (O/E) adjusted rate ratios for stroke. Older age, female sex, African American race and Hispanic ethnicity, unemployed status, diabetes, hypertension, history of stroke, and permanent atrial fibrillation were positively associated with ischemic stroke, whereas body mass index >30 kg/m(2) was inversely associated with stroke (P<0.001 for each). After full multivariable adjustment, the three states with O/E rate ratios >1.0 were all in the South: North Carolina, Mississippi, and Oklahoma. Regional efforts to increase primary prevention in the "stroke belt" or to better educate dialysis patients on the signs of stroke so that they may promptly seek care may improve stroke care and outcomes in dialysis patients. PMID- 23990676 TI - Should glucose-sparing prescriptions be expected to reduce the cardiovascular risk of peritoneal dialysis patients? PMID- 23990677 TI - Smac-mimetic-induced epithelial cell death reduces the growth of renal cysts. AB - Past efforts to pharmacologically disrupt the development and growth of renal cystic lesions focused primarily on normalizing the activity of a specific signaling molecule, but the effects of stimulating apoptosis in the proliferating epithelial cells have not been well studied. Although benign, ADPKD renal cysts created by the sustained proliferation of epithelial cells resemble tumors, and malignant cell death can be achieved by cotreatment with TNF-alpha and a mimetic of second mitochondria-derived activator of caspase (Smac). Notably, TNF-alpha accumulates to high levels in ADPKD cyst fluid. Here, we report that an Smac mimetic selectively induces TNF-alpha-dependent cystic renal epithelial cell death, leading to the removal of cystic epithelial cells from renal tissues and delaying cyst formation. In vitro, a Smac-mimetic (GT13072) induced the degradation of cIAP1 that is required but not sufficient for cell death. Cotreatment with TNF-alpha augmented the formation and activation of the RIPK1 dependent death complex and the degradation and cleavage of FLIP, an inhibitor of caspase-8, in renal cystic epithelial cells. This approach produced death specifically in Pkd1 mutant epithelial cells, with no effect on normal renal epithelial cells. Moreover, treatment with the Smac-mimetic slowed cyst and kidney enlargement and preserved renal function in two genetic strains of mice with Pkd1 mutations. Thus, our mechanistic data characterize an apoptotic pathway, activated by the selective synergy of an Smac-mimetic and TNF-alpha in renal cyst fluid, that attenuates cyst development, providing an innovative translational platform for the rational development of novel therapeutics for ADPKD. PMID- 23990678 TI - Analysis of a urinary biomarker panel for incident kidney disease and clinical outcomes. AB - Whether novel biomarkers improve the assessment of incident kidney disease and related adverse outcomes remains to be tested in longitudinal observational studies. We tested 14 urinary biomarkers for association with incident kidney, cardiovascular, and mortality outcomes in 2948 Framingham Heart Study participants. Baseline examinations were performed between 1995 and 1998; mean follow-up was 10.1 years for renal outcomes and 11.2 years for survival analyses. Primary outcomes were incident CKD, incident albuminuria, incident cardiovascular disease, and all-cause mortality. Secondary analyses assessed incident congestive heart failure (CHF) and mortality with coexistent kidney disease. Biomarkers were tested for association with renal end points using logistic regression and incident cardiovascular and mortality outcomes in proportional hazards models; alpha1-microglobulin, Kim-1, and TFF-3 predicted all-cause mortality (hazard ratio per SD increase in log-transformed biomarker [HR] range, 1.15 to 1.21; 95% confidence interval [CI] range, 1.04 to 1.34; P values=0.007 to <0.001), whereas alpha1-microglobulin, beta2-microglobulin, KIM-1, and TFF-3 associated with death with coexistent kidney disease (HR range, 1.72-2.25; 95% CI, 1.17 to 3.24; P values<0.01). KIM-1 also associated with the risk of incident CHF (HR, 1.32; 95% CI, 1.07 to 1.63; P=0.008). CTGF associated nominally with CKD (HR, 0.83; 95% CI, 0.71 to 0.98; P=0.03), but no other biomarkers associated with incident CKD or albuminuria. Addition of alpha1-microglobulin and TFF-3 resulted in a nonsignificant net reclassification index (NRI) of 3% for all-cause mortality beyond clinical risk factors. In conclusion, components of a panel of 14 subclinical biomarkers of kidney injury were associated with important clinical outcomes and merit additional investigation. PMID- 23990679 TI - The effect of race and income on living kidney donation in the United States. AB - Studies of racial disparities in access to living donor kidney transplantation focus mainly on patient factors, whereas donor factors remain largely unexamined. Here, data from the US Census Bureau were combined with data on all African American and white living kidney donors in the United States who were registered in the United Network for Organ Sharing (UNOS) between 1998 and 2010 (N=57,896) to examine the associations between living kidney donation (LKD) and donor median household income and race. The relative incidence of LKD was determined in zip code quintiles ranked by median household income after adjustment for age, sex, ESRD rate, and geography. The incidence of LKD was greater in higher-income quintiles in both African-American and white populations. Notably, the total incidence of LKD was higher in the African-American population than in the white population (incidence rate ratio [IRR], 1.20; 95% confidence interval [95% CI], 1.17 to 1.24]), but ratios varied by income. The incidence of LKD was lower in the African-American population than in the white population in the lowest income quintile (IRR, 0.84; 95% CI, 0.78 to 0.90), but higher in the African-American population in the three highest income quintiles, with IRRs of 1.31 (95% CI, 1.22 to 1.41) in Q3, 1.50 (95% CI, 1.39 to 1.62) in Q4, and 1.87 (95% CI, 1.73 to 2.02) in Q5. Thus, these data suggest that racial disparities in access to living donor transplantation are likely due to socioeconomic factors rather than cultural differences in the acceptance of LKD. PMID- 23990682 TI - Interhemispheric difference of pallidal local field potential activity in cervical dystonia. AB - BACKGROUND: Cervical dystonia (CD) produces involuntary neck muscle contractions that result in abnormal and often asymmetrical postures of the head and neck. Basal ganglia oscillatory activity in the 3-12 Hz band correlating with involuntary muscle activity suggests a role in the pathophysiology of primary dystonia. Despite the asymmetrical postures seen with CD, no comparison of interhemispheric differences of pallidal local field potential (LFP) activity has been reported. OBJECTIVE: The aim of this study was to examine the interhemispheric differences of LFP power in globus pallidus interna (GPi) in CD patients and compare these with their predominant head excursion identified as torticollis, laterocollis and retrocollis. METHODS: LFPs were recorded from bilateral GPi in 11 patients with CD using microelectrodes during deep brain stimulation surgery. LFP power was measured in right and left GPi separately. The mean percentage of total GPi LFP power in 4-30 Hz frequency band on each brain side was determined and related to their predominant CD symptoms. RESULTS: Interhemispheric difference in the mean percentage of LFP power in 4-12 Hz and 13 30 Hz band frequencies was found in patients with torticollis and laterocollis regardless of excursion direction. However, patients with retrocollis did not show interhemispheric difference in LFP activity in any band frequency. CONCLUSIONS: Interhemispheric differences in synchronisation of pallidal LFP activity in 4-12 Hz and 13-30 Hz bands are related to the CD clinical condition, suggesting that these frequencies are important in the pathophysiology of dystonia. PMID- 23990680 TI - LMX1B is essential for the maintenance of differentiated podocytes in adult kidneys. AB - Mutations of the LMX1B gene cause nail-patella syndrome, a rare autosomal dominant disorder affecting the development of the limbs, eyes, brain, and kidneys. The characterization of conventional Lmx1b knockout mice has shown that LMX1B regulates the development of podocyte foot processes and slit diaphragms, but studies using podocyte-specific Lmx1b knockout mice have yielded conflicting results regarding the importance of LMX1B for maintaining podocyte structures. In order to address this question, we generated inducible podocyte-specific Lmx1b knockout mice. One week of Lmx1b inactivation in adult mice resulted in proteinuria with only minimal foot process effacement. Notably, expression levels of slit diaphragm and basement membrane proteins remained stable at this time point, and basement membrane charge properties also did not change, suggesting that alternative mechanisms mediate the development of proteinuria in these mice. Cell biological and biophysical experiments with primary podocytes isolated after 1 week of Lmx1b inactivation indicated dysregulation of actin cytoskeleton organization, and time-resolved DNA microarray analysis identified the genes encoding actin cytoskeleton-associated proteins, including Abra and Arl4c, as putative LMX1B targets. Chromatin immunoprecipitation experiments in conditionally immortalized human podocytes and gel shift assays showed that LMX1B recognizes AT-rich binding sites (FLAT elements) in the promoter regions of ABRA and ARL4C, and knockdown experiments in zebrafish support a model in which LMX1B and ABRA act in a common pathway during pronephros development. Our report establishes the importance of LMX1B in fully differentiated podocytes and argues that LMX1B is essential for the maintenance of an appropriately structured actin cytoskeleton in podocytes. PMID- 23990683 TI - Performance evaluation of the small-animal nanoScan PET/MRI system. AB - nanoScan is a high-resolution integrated system for consecutive PET and MR imaging of small laboratory animals. We evaluated the performance of the system, using the NEMA NU 4-2008 protocol for the PET component and the NEMA MS 1-2007, MS 2-2008, and MS 3-2007 standards for the MR imaging component. METHODS: The imaging system uses magnetically shielded position-sensitive photomultiplier tubes and a compact 1-T permanent-magnet MR imaging platform. Spatial resolution, sensitivity, counting rate capabilities, and image quality parameters were evaluated in accordance with the aforementioned NEMA standards. Further in vivo evaluation experiments complement the physical validation results. RESULTS: The spatial resolution of the PET system enabled the 0.8-mm rods of a Derenzo phantom to be resolved. With point source and 2-dimensional filtered backprojection reconstruction, the resolution varied from 1.50 to 2.01 mm in full width at half maximum in the radial direction and from 1.32 to 1.65 mm in the tangential direction within the radius of 25 mm. Peak absolute sensitivity was 8.41%. Scatter fraction was 17.3% and 34.0%, and maximum noise-equivalent counting rate was 406 and 119 kcps in the mouselike and ratlike phantom, respectively. The image quality test found a nonuniformity of 3.52% and a spillover ratio of 6.2% and 5.8% in water and air, respectively. In testing of the MR imaging component, artifact-free images with high signal-to-noise ratio were recorded. Geometric distortion was below 5%, and image uniformity was at least 94.5% and 96.6% for the 60- and 35-mm radiofrequency coils, respectively. CONCLUSION: The nanoScan integrated small-animal PET/MR imaging system has excellent spatial resolution and sensitivity. The performance characteristics of the PET and the MR imaging components are not compromised as a result of their integration onto a single platform. Because of its combination of features and performance parameters, the system provides crucial advantages for preclinical imaging studies over existing PET/CT systems, especially in neurologic and oncologic research. PMID- 23990681 TI - TGF-beta1 promotes lymphangiogenesis during peritoneal fibrosis. AB - Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-beta1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-beta1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-beta type I receptor (TGFbetaR-I) inhibitor. TGF-beta1-induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFbetaR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-beta-VEGF-C pathway. PMID- 23990684 TI - 99mTc-sestamibi scintigraphy to monitor the long-term efficacy of enzyme replacement therapy on bone marrow infiltration in patients with Gaucher disease. AB - Assessing the skeletal response to enzyme replacement therapy (ERT) in Gaucher disease (GD) is problematic. We investigated the reliability of (99m)Tc-sestamibi scintigraphy in monitoring changes in bone marrow involvement induced by ERT. METHODS: In 52 GD patients, the efficacy of ERT on bone marrow disease was monitored using at least 2 sequential (99m)Tc-sestamibi scans; 17 patients were receiving ERT at enrollment, and 35 were ERT-naive. We elaborated a dose-response model by statistical analysis based on linear mixed models. RESULTS: Patients whose marrow disease improved had received a significantly higher ERT dose per month than patients who did not improve. Significantly more patients reached near disappearance of marrow disease if their disease burden at enrollment had been lower and the duration of clinical signs shorter. The response of the marrow scintigraphic score was more pronounced in ERT-naive patients. No relevant effect of ERT on marrow disease was observed until platelet count and splenomegaly had improved. CONCLUSION: Although based on localized evaluation, changes in the (99m)Tc-sestamibi score closely correlated with the main determinants of ERT, with a definite dose-response relationship. The threshold at which ERT induced any improvement in bone marrow disease was 35-36 U/kg/mo; in ERT-naive patients, the scintigraphic score declined by 1 unit after ERT at 28 U/kg/mo. PMID- 23990685 TI - Immigration Statistics for the 21st Century. AB - Of the three main contributors to population growth-fertility, mortality, and net migration-the latter is by far the most difficult to capture statistically. This article discusses the main sources of federal statistical data on immigration, each with its own characteristic set of strengths, weaknesses, possibilities, and limitations in the context of the interested social scientist. Among the key limitations, the article argues, are the elimination of parental birthplace from the Census and the lack of complete data concerning the legal statuses of the U.S. population. This article will conclude with suggestions on remedying such deficiencies, at relatively low marginal cost, such as the inclusion of questions on parental birthplace, instituting a regular survey of randomly selected legal immigrants, and the use of the "two-card method" in statistical data. PMID- 23990686 TI - Recent Economic Perspectives on Political Economy, Part I. AB - In recent years some of the best theoretical work on the political economy of political institutions and processes has begun surfacing outside the political science mainstream in high quality economics journals. This two-part paper surveys these contributions from a recent five-year period. In Part I, the focus is on elections, voting and information aggregation, followed by treatments of parties, candidates, and coalitions. In Part II, papers on economic performance and redistribution, constitutional design, and incentives, institutions, and the quality of political elites are discussed. Part II concludes with a discussion of the methodological bases common to economics and political science, the way economists have used political science research, and some new themes and arbitrage opportunities. PMID- 23990687 TI - On Not Knowing Zoonotic Diseases: Pastoralists' Ethnoveterinary Knowledge in the Far North Region of Cameroon. AB - In this article, we consider the implications of Murray Last's (1981)Knowing About Not Knowing for the study of ethnoveterinary knowledge of mobile pastoralists in the Far North Region of Cameroon. Specifically, we ask two interrelated questions: (1) what is the nature of this knowledge, and (2) what is the best way to study it? We conducted a study of pastoralists' knowledge of human and animal infectious diseases to evaluate the claim that mobile pastoralists in the Chad Basin do not have a concept for zoonotic diseases. We used a combination of free lists and semi-structured interviews to study pastoralists' knowledge. The results suggest that pastoralists do not have a concept for zoonotic diseases. Moreover, we found considerable variation in pastoralists' ethnoveterinary knowledge and examples of not knowing, which contrasts with previous studies that do not describe much variation in ethnoveterinary knowledge. In our discussion, we consider to what extent descriptions of ethnoveterinary knowledge are the product of researchers' conceptual framework and methodology. PMID- 23990689 TI - A Patient Focused Solution for Enrolling Clinical Trials in Rare and Selective Cancer Indications: A Landscape of Haystacks and Needles. AB - Participation of adult cancer patients in US based clinical trials has remained near 3% for decades. Traditional research methodology reaches a small fraction of the target population with a fixed number of predetermined sites. Solutions are needed to ethically increase patient participation and accelerate cancer trial completion. We compared enrollment outcomes of traditional and patient focused research methodologies. A patient prioritized method (Just-In-Time, JIT) was implemented in parallel with traditionally managed sites in three cancer trials. JIT research sites were initiated after candidate patients presented, while traditional sites were initiated in advance. JIT sites enrolled with mean rates no less than, and up to 2.75 fold greater than, traditional sites. Mean patients enrolled per site was comparable (JIT-1.82, traditional-1.78). There were fewer non-enrolling JIT sites (2/28, 7%) compared to traditional sites 19/52, 37%). This retrospective analysis supports JIT as a prospective solution to increase cancer clinical trial enrollment and the efficiency of clinical trial administrative activities. PMID- 23990688 TI - Light-Activated Pharmaceuticals: Mechanisms and Detection. AB - Photodynamic therapy relies on the interaction between light, oxygen and a photosensitizing agent. Its medical significance relates to the ability of certain agents, usually based on porphyrin or phthalocyanine structures, to localize somewhat selectively in neoplastic cells and their vasculature. Subsequent irradiation, preferably at a sufficiently high wavelength to have a significant pathway through tissues, results in a photophysical reaction whereby the excited state of the photosensitizing agent transfers energy to molecular oxygen and results in the formation of reactive oxygen species. Analogous reactive nitrogen species are also formed. These contain both nitrogen and oxygen atoms. The net result is both direct tumor cell death and a shutdown of the tumor vasculature. Other processes may also occur that promote the anti-tumor response but these are outside the scope of this review. PMID- 23990690 TI - Surgery in Space: Where are we at now? AB - In the coming decades, as we continue our path of space exploration beyond Earth's orbit, we will be required to provide sound medical and surgical care for the safety of space travellers and space flight participants. A few investigations have taken place in the field of surgery in space. In this paper, the authors review the present literature in order to identify possible limitations that currently exist and that could impair our ability to provide surgical care during spaceflight, from the pre-operative to the post-operative period. PMID- 23990691 TI - Bayesian Gaussian Copula Factor Models for Mixed Data. AB - Gaussian factor models have proven widely useful for parsimoniously characterizing dependence in multivariate data. There is a rich literature on their extension to mixed categorical and continuous variables, using latent Gaussian variables or through generalized latent trait models acommodating measurements in the exponential family. However, when generalizing to non Gaussian measured variables the latent variables typically influence both the dependence structure and the form of the marginal distributions, complicating interpretation and introducing artifacts. To address this problem we propose a novel class of Bayesian Gaussian copula factor models which decouple the latent factors from the marginal distributions. A semiparametric specification for the marginals based on the extended rank likelihood yields straightforward implementation and substantial computational gains. We provide new theoretical and empirical justifications for using this likelihood in Bayesian inference. We propose new default priors for the factor loadings and develop efficient parameter-expanded Gibbs sampling for posterior computation. The methods are evaluated through simulations and applied to a dataset in political science. The models in this paper are implemented in the R package bfa. PMID- 23990693 TI - Relative Importance of Emotional Dysregulation, Hostility, and Impulsiveness in Predicting Intimate Partner Violence Perpetrated by Men in Alcohol Treatment. AB - The current study employs dominance analysis to assess the relative importance of three constructs-hostility, impulsiveness, and emotional dysregulation (difficulties managing one's emotions when experiencing negative emotion or distress)-in explaining psychological, physical, and sexual intimate partner violence (IPV) perpetration by men seeking alcohol treatment. A sample of 121 predominantly White, heterosexual men (average age 33.28, range = 18 - 62) enrolled in residential substance abuse treatment completed measures of emotional dysregulation, hostility, and impulsiveness, which are three highly related constructs identified as risk factors for both substance use disorders and IPV. The constructs collectively accounted for 20-25% of the variance in each form of IPV. Because impulsiveness, hostility, and emotional dysregulation are highly correlated, dominance analysis was used to examine which factor most strongly predicted each form of IPV. Dominance analysis findings favored hostility as a predictor of physical IPV perpetration, and impulsiveness as a predictor of sexual and psychological IPV perpetration. Differential associations between the constructs and each form of IPV may be used to inform assessment and treatment planning of men who abuse alcohol. Better understanding, preventing, and treating male-to-female IPV will protect women from the far-reaching consequences of this violence. PMID- 23990692 TI - Heterolytic Cleavage of Dihydrogen by an Iron(II) PNP Pincer Complex via Metal Ligand Cooperation. AB - The bis-carbonyl Fe(II) complex trans-[Fe(PNP-iPr)(CO)2Cl]+ reacts with Zn as reducing agent under a dihydrogen atmosphere to give the Fe(II) hydride complex cis-[Fe(PNP-iPr)(CO)2H]+ in 97% isolated yield. A crucial step in this reaction seems to be the reduction of the acidic NH protons of the PNP-iPr ligand to afford H2 and the coordinatively unsaturated intermediate [Fe(PNPH-iPr)(CO)2]+ bearing a dearomatized pyridine moiety. This species is able to bind and heterolytically cleave H2 to give cis-[Fe(PNP-iPr)(CO)2H]+. The mechanism of this reaction has been studied by DFT calculations. The proposed mechanism was supported by deuterium labeling experiments using D2 and the N-deuterated isotopologue of trans-[Fe(PNP-iPr)(CO)2Cl]+. While in the first case deuterium was partially incorporated into both N and Fe sites, in the latter case no reaction took place. In addition, the N-methylated complex trans-[Fe(PNPMe iPr)(CO)2Cl]+ was prepared, showing no reactions with Zn and H2 under the same reaction conditions. An alternative synthesis of cis-[Fe(PNP-iPr)(CO)2H]+ was developed utilizing the Fe(0) complex [Fe(PNP-iPr)(CO)2]. This compound is obtained in high yield by treatment of either trans-[Fe(PNP-iPr)(CO)2Cl]+ or [Fe(PNP-iPr)Cl2] with an excess of NaHg or a stoichiometric amount of KC8 in the presence of carbon monoxide. Protonation of [Fe(PNP-iPr)(CO)2] with HBF4 gave the hydride complex cis-[Fe(PNP-iPr)(CO)2H]+. X-ray structures of both cis-[Fe(PNP iPr)(CO)2H]+ and [Fe(PNP-iPr)(CO)2] are presented. PMID- 23990694 TI - Molecular and Clinical Findings in Patients with LHX4 and OTX2 Mutations. AB - The pituitary gland produces hormones that play important roles in both the development and homeostasis of the body. Ontogeny of the anterior and posterior pituitary is orchestrated by inputs from neighboring tissues, cellular signaling molecules and transcription factors. Disruption of expression or function of these factors has been implicated in the etiology of combined pituitary hormone deficiency (CPHD). These include the transcription factors HESX1, PROP1, POU1F1, LHX3, LHX4, OTX2, SOX2, SOX3 and GLI2. This review focuses on summarizing most recent mutations in LHX4 and OTX2 responsible for pituitary hormone deficiency. In both genetic defects of LHX4 and OTX2, there is high variability in clinical manifestations even in the same family. In addition, there is no clear phenotype genotype correlation. These findings indicate that the other genetic and/or environmental factors influence the phenotype. In addition, the variability might reflect a plasticity during pituitary development and maintenance. Over the past two decades, a genetic basis for pituitary hormone deficiency and the mechanism of pituitary development have been clarified. It should be kept in mind that this review is not comprehensive, and defects of other transcriptional factors have been described in patients with CPHD. Furthermore, the causes in many patients with CPHD have not yet been determined. Therefore, continuing efforts for the clarification of the etiology are necessary. PMID- 23990695 TI - Assessment of Psychosocial Status among Short-stature Children with and without Growth Hormone Therapy and Their Parents. AB - To evaluate the psychosocial status of short children with and without growth hormone therapy (GHT) and that of their parents, self-administered questionnaires were collected from patients and parents who regularly visit the outpatient clinics participating in the Child Health and Development Network. Completed questionnaires were received for one hundred and thirteen patients with GHT and 67 patients without GHT. According to the parents, both children with GHT and without GHT have no difficulty in their daily lives (89% vs. 95%) and are positive (56% vs. 65%), respectively. Ninety-eight percent of parents of children with GHT and 83% of parents of children without GHT had expected the current treatment strategy to be effective. Parents of children with GHT are more satisfied with the current therapy than those without GHT (79% vs. 50%), and feel less anxiety about the on-going therapy than (31% vs. 58%, respectively). Children treated with or without equally reported having no difficulty in their daily lives (90% vs. 93%), and being positive in their lives (81% vs. 75%, respectively) despite their short stature. Although less than one third of the patients have been bullied in their classroom (26% with GHT vs. 29% without GHT), younger and shorter children tend to be bullied more often. Short children undergoing GHT and their parents have anxiety regarding their height and expectations of the effect of GHT. It is important for doctors to inform their patients regarding realistic height expectations before starting GHT. Additionally, medical consultation is recommended for patients who remain below 2 SD in height despite GHT. PMID- 23990696 TI - Development of endometrial carcinoma in a patient with leprechaunism (donohue syndrome). AB - Leprechaunism is a rare autosomal recessive disease that is characterized by severe insulin resistance. This disease is caused by a defective insulin receptor and features abnormal glucose metabolism and retarded intrauterine and postnatal growth. However, there are few reports on the long-term course of leprechaunism. We reported the long-term clinical course and rh-IGF-1 treatment in a patient with leprechaunism. During follow-up her diabetes gradually deteriorated despite of treatment of rh-IGF-1. Furthermore, she developed endometrioid adenocarcinoma at the age of 24 yr. The development of endometrial disease must be carefully followed up in this disease. PMID- 23990697 TI - Image stacking approach to increase sensitivity of fluorescence detection using a low cost complementary metal-oxide-semiconductor (CMOS) webcam. AB - Optical technologies are important for biological analysis. Current biomedical optical analyses rely on high-cost, high-sensitivity optical detectors such as photomultipliers, avalanched photodiodes or cooled CCD cameras. In contrast, Webcams, mobile phones and other popular consumer electronics use lower sensitivity, lower-cost optical components such as photodiodes or CMOS sensors. In order for consumer electronics devices, such as webcams, to be useful for biomedical analysis, they must have increased sensitivity. We combined two strategies to increase the sensitivity of CMOS-based fluorescence detector. We captured hundreds of low sensitivity images using a Webcam in video mode, instead of a single image typically used in cooled CCD devices.We then used a computational approach consisting of an image stacking algorithm to remove the noise by combining all of the images into a single image. While video mode is widely used for dynamic scene imaging (e.g. movies or time-lapse photography), it is not used to capture a single static image, which removes noise and increases sensitivity by more than thirty fold. The portable, battery-operated Webcam-based fluorometer system developed here consists of five modules: (1) a low cost CMOS Webcam to monitor light emission, (2) a plate to perform assays, (3) filters and multi-wavelength LED illuminator for fluorophore excitation, (4) a portable computer to acquire and analyze images, and (5) image stacking software for image enhancement. The samples consisted of various concentrations of fluorescein, ranging from 30 MUM to 1000 MUM, in a 36-well miniature plate. In the single frame mode, the fluorometer's limit-of-detection (LOD) for fluorescein is ~1000 MUM, which is relatively insensitive. However, when used in video mode combined with image stacking enhancement, the LOD is dramatically reduced to 30 MUM, sensitivity which is similar to that of state-of-the-art ELISA plate photomultiplier-based readers. Numerous medical diagnostics assays rely on optical and fluorescence readers. Our novel combination of detection technologies, which is new to biodetection may enable the development of new low cost optical detectors based on an inexpensive Webcam (<$10). It has the potential to form the basis for high sensitivity, low cost medical diagnostics in resource-poor settings. PMID- 23990698 TI - Frequency-Selective Fat Suppression Radiofrequency Pulse Train to Remove Olefinic Fats. AB - CHESS pulse can suppress the signal originating from aliphatic fat protons but cannot suppress the signal from olefinic fat protons, which is near the resonance frequency of water protons. Adipose tissue contains various fat species; aliphatic fat comprises about 90 % and olefinic fat about 10 % of adipose tissue. Thus, CHESS pulse cannot be used to suppress the signal from adipose tissue completely. The purpose of this study was to find a method to suppress the signal from adipose tissue completely. The Fatsat train pulse, created with an arbitrary flip angle and insensitive to B1 inhomogeneity, was used. Because B1 inhomogeneity is larger on higher field magnetic resonance imaging, the fat suppression radiofrequency pulse needs to be B1-insensitive. To investigate a percentage of olefinic fat in adipose tissues, the excitation frequency of the Fatsat train pulse was varied from -240 to +400 Hz and the images and fat suppressed images were obtained. The presence of olefinic fat comprising about 10 % of abdominal adipose tissue was identified. The result agreed with some previous papers. Complete fat suppression could be achieved by partial (10 %) inversion of longitudinal aliphatic fat magnetization and by canceling out the two fat magnetizations. The flip angle was identified to about 95 degrees . In conclusion, the cause that the signal from adipose tissues cannot be suppressed completely has been found. Improved images that signals from adipose tissues were suppressed completely have been demonstrated. This technique can also be applied to several pulse sequences. PMID- 23990699 TI - Regulation of immune cell infiltration into the CNS by regional neural inputs explained by the gate theory. AB - The central nervous system (CNS) is an immune-privileged environment protected by the blood-brain barrier (BBB), which consists of specific endothelial cells that are brought together by tight junctions and tight liner sheets formed by pericytes and astrocytic end-feet. Despite the BBB, various immune and tumor cells can infiltrate the CNS parenchyma, as seen in several autoimmune diseases like multiple sclerosis (MS), cancer metastasis, and virus infections. Aside from a mechanical disruption of the BBB like trauma, how and where these cells enter and accumulate in the CNS from the blood is a matter of debate. Recently, using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found a "gateway" at the fifth lumber cord where pathogenic autoreactive CD4+ T cells can cross the BBB. Interestingly, this gateway is regulated by regional neural stimulations that can be mechanistically explained by the gate theory. In this review, we also discuss this theory and its potential for treating human diseases. PMID- 23990700 TI - Transfer of auxinic herbicide resistance from Brassica kaber to Brassica juncea and Brassica rapa through embryo rescue. AB - Auxinic herbicides are widely used in agriculture to selectively control broadleaf weeds. Prolonged use of auxinic herbicides has resulted in the evolution of resistance to these herbicides in some biotypes of Brassica kaber (wild mustard), a common weed in agricultural crops. In this study, auxinic herbicide resistance from B. kaber was transferred to Brassica juncea and Brassica rapa, two commercially important Brassica crops, by traditional breeding coupled with in vitro embryo rescue. A high frequency of embryo regeneration and hybrid plant establishment was achieved. Transfer of auxinic herbicide resistance from B. kaber to the hybrids was assessed by whole-plant screening of hybrids with dicamba, a widely used auxinic herbicide. Furthermore, the hybrids were tested for fertility (both pollen and pistil) and their ability to produce backcross progeny. The auxinic herbicide-resistant trait was introgressed into B. juncea by backcross breeding. DNA ploidy of the hybrids as well as of the backcross progeny was estimated by flow cytometry. Creation of auxinic herbicide resistant Brassica crops by non-transgenic approaches should facilitate effective weed control, encourage less tillage, provide herbicide rotation options, minimize occurrence of herbicide resistance, and increase acceptance of these crops. PMID- 23990701 TI - Faith Pinnacle Moments: Stress, Miraculous Experiences, and Life Satisfaction in Young Adulthood. AB - Religious beliefs often persist among unaffiliated young adults, and certain beliefs about God have been shown to support subjective well-being. Yet we know much less about the persistence or psychological impact of religious experiences, specifically miracles from God. I conceive of such experiences as faith pinnacle moments which express and reinvigorate the individual's reciprocal bond with God, frequently occur in response to certain types of stress, and support well-being by solidifying one's sense of that bond. My results show that net of institutional religiosity, young adults who experience stress from traumas are more likely to report miracles. This suggests that these reports often refer to healings or similar interventions. Stress from family breakups, however, is negatively correlated with miracles, presumably since these disruptions damage the bond with God due to the established connection between parental relationships and perceived relationship with God. Finally, miracles are positively correlated with life satisfaction and partially protect against the negative effects of stress on life satisfaction. PMID- 23990702 TI - Spontaneous corneal perforation in an eye with Peters' anomaly. AB - A premature female infant underwent her first ophthalmologic examination at the age of 4 weeks. The initial examination of the baby was requested for evaluation of a 'white spot' on the surface of her right eye. She had been hospitalized in the neonatal intensive care unit because of systemic abnormalities, such as a right clavicle fracture and microcephaly. Slit-lamp examination of the right eye showed a central corneal opacity, corneal thinning, and an iridocorneal adhesion. The lens and fundus of the right eye could not be observed. We observed no pathologic findings in the left eye. The baby's parents were informed of the high risk for spontaneous corneal perforation without external pressure. At 42 days of age, an ophthalmologic examination of the infant was again requested for evaluation of 'tears' from her right eye 3 hours previously. Examination revealed corneal perforation, iris protrusion, and a fat anterior chamber. We performed emergent conjunctival flap surgery. Three months following surgery, the patient's right eye was successfully preserved with no sign of inflammation or leakage. PMID- 23990703 TI - Retrobulbar blood flow and visual field alterations after acute ethanol ingestion. AB - BACKGROUND: The purpose of this study was to test the effect of ethyl alcohol on the koniocellular and magnocellular pathway of visual function and to investigate the relationship between such visual field changes and retrobulbar blood flow in healthy subjects. METHODS: In 12 healthy subjects (mean age 32 +/- 4 years), color Doppler imaging, short-wavelength automated perimetry, and frequency doubling perimetry was performed before and 60 minutes after oral intake of 80 mL of 40 vol% ethanol. Mean and pattern standard deviations for short-wavelength automated and frequency doubling perimetry were assessed. End diastolic velocity (EDV) and peak systolic velocity (PSV) were measured in the central retinal and ophthalmic arteries using color Doppler imaging. Systemic blood pressure, heart rate, intraocular pressure, and blood alcohol concentration were determined. RESULTS: Mean PSV and EDV in the central retinal artery showed a significant increase after alcohol intake (P = 0.03 and P = 0.02, respectively). Similarly, we found a significant acceleration of blood flow velocity in the ophthalmic artery (P = 0.02 for PSV; P = 0.04 for EDV). Mean intraocular pressure decreased by 1.0 mmHg after alcohol ingestion (P = 0.01). Retinal sensitivity in short wavelength automated perimetry did not alter, whereas in frequency doubling perimetry, the mean deviation decreased significantly. Systolic and diastolic blood pressure did not change significantly. Mean blood alcohol concentration was 0.38 +/- 0.16 g/L. CONCLUSION: Although ethanol is known to cause peripheral vasodilation, our subjects had no significant drop in systemic blood pressure. However, a significant increase of blood flow velocity was seen in the retrobulbar vessels. Regarding visual function, moderate alcohol consumption led to reduced performance in the magnocellular visual system tested by frequency doubling perimetry, but had no effect on short-wavelength automated perimetry. PMID- 23990704 TI - Treatment and management of myelofibrosis in the era of JAK inhibitors. AB - Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment. PMID- 23990705 TI - Aflibercept in wet AMD: specific role and optimal use. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is a naturally occurring glycoprotein in the body that acts as a growth factor for endothelial cells. It regulates angiogenesis, enhances vascular permeability, and plays a major role in wet age-related macular degeneration. The consistent association between choroidal neovascularization and increased VEGF expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of this disorder. Blockade of VEGF activity is currently the most effective strategy for arresting choroidal angiogenesis and reducing vascular permeability, which is frequently the main cause of visual acuity deterioration. In recent years, a number of other molecules have been developed to increase the efficacy and to prolong the durability of the anti-VEGF effect. Aflibercept (EYLEA(r); Regeneron Pharmaceutical Inc and Bayer), also named VEGF Trap-eye, is the most recent member of the anti-VEGF armamentarium that was approved by the US Food and Drug Administration in November 2011. Because of its high binding affinity and long duration of action, this drug is considered to be a promising clinically proven anti-VEGF agent for the treatment of wet maculopathy. OBJECTIVE: This article reviews the current literature and clinical trial data regarding the efficacy and the pharmacological properties of VEGF-Trap eye and describes the possible advantages of its use over the currently used "older" anti VEGF drugs. METHODS: For this review, a search of PubMed from January 1989 to May 2013 was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, VEGF-Trap eye in wet AMD, VEGF-Trap eye in diabetic retinopathy, VEGF-Trap eye in retinal vein occlusions, aflibercept. Studies were limited to those published in English. RESULTS AND CONCLUSION: Two Phase III clinical trials, VEGF Trap-eye Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2, comparing VEGF Trap-eye to ranibizumab demonstrated the noninferiority of this novel compound. The clinical equivalence of this compound against ranibizumab is maintained even when the injections are administered at 8-week intervals, which indicates the potential to reduce the risk of monthly intravitreal injections and the burden of monthly monitoring. PMID- 23990706 TI - Clinical study of etomidate emulsion combined with remifentanil in general anesthesia. AB - BACKGROUND: The aim of this study was to investigate and evaluate the safety, recovery time, and side effects of general anesthesia with different doses of etomidate emulsion combined with remifentanil. METHODS: One hundred ten patients of American Society of Anesthesiologists class 1 or 2 who underwent gynecological general anesthesia with a 1-3-hour operation time were randomly divided into the following groups: etomidate emulsion group 1 ([E1] n = 30); etomidate emulsion group 2 ([E2] n = 30); etomidate emulsion group 3 ([E3] n = 20); and propofol group ([P group] n = 30). For induction of anesthesia, 0.3 mg/kg etomidate emulsion, and the continuous remifentanil infusion also to induce anesthesia (0.1~0.3 MUg . kg(-1) . min(-1)), was applied in all cases. Afterwards, continuous infusion of etomidate emulsion and remifentanil, respectively (E1: 10 MUg . kg(-1) . min(-1) and 0.1 MUg . kg(-1) . min(-1); E2: 15 MUg . kg(-1) . min( 1) and 0.2 MUg . kg(-1) . min(-1); E3: 20 MUg . kg(-1) . min(-1) and 0.2 MUg . kg(-1) . min(-1)), and propofol (P group: 6~10 mg . kg(-1) . h(-1)) were administered. Changes in blood flow kinetics and adverse reactions were noted and compared between the four groups. RESULTS: Both arterial blood pressure (BP) and heart rate (HR) decreased after induction of anesthesia (P < 0.05). Systolic (SBP) and diastolic (DBP) BP changed only slightly, and HRs were slightly infected in E1, E2, and E3. SBP, DBP, and HR during the operation all decreased significantly in P group (P < 0.05). Muscle tremor at the time of induction occurred in 13 cases (11.8%). Following etomidate emulsion anesthesia maintenance, postoperative agitation occurred in seven cases (8.75%), lethargy in 20 cases (25%), and vomiting in 19 cases (23.75%). No adverse reactions were found in P group. CONCLUSION: Continuous infusion of etomidate emulsion at 10 MUg . kg(-1) . minute(-1) combined with remifentanil during anesthesia has the advantages of hemodynamic stability, quick wake-up, and few adverse reactions. Increasing the dose of etomidate emulsion increases the incidence of adverse reactions. PMID- 23990707 TI - Update on rescue therapies in patients with lamivudine-resistant chronic hepatitis B. AB - Chronic hepatitis B continues to be a global problem, with an estimated 240 million cases according to the World Health Organization. Chronic infection with the hepatitis B virus (HBV) is associated with cirrhosis, hepatic decompensation, and hepatocellular carcinoma. There are currently several US Food and Drug Administration-approved medications for treating chronic hepatitis B, with Lamivudine (LAM) being the first oral agent made available. The major problem with LAM is significantly decreased effectiveness over time due to the development of anti-HBV resistance that can lead to virologic and biochemical breakthrough as well as hepatitis B flare, progression of liver disease, and decompensation of pre-existing cirrhosis. Despite its high anti-HBV resistant rate, LAM remains widely used in underdeveloped countries due to its wide availability and low cost compared to other antiviral medications, including those that are more effective. Therefore, it is still clinically important to learn how to prevent and treat LAM resistant strains of HBV. Several regimens with the other available antiviral agents have been studied, including switching to monotherapy with either Adefovir, Entecavir, or Tenofovir, adding Adefovir to LAM, and switching to a combination of Adefovir and Entecavir. This review article will examine molecular mechanisms and diagnosis of LAM anti-HBV resistance, risks for and approaches to reduce LAM anti-HBV resistance, and currently available rescue therapy regimens for LAM resistance. PMID- 23990708 TI - In silico identification of EGFR-T790M inhibitors with novel scaffolds: start with extraction of common features. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) is an attractive therapeutic target for a number of human tumors including non-small cell lung cancer (NSCLC). Most patients with NSCLC and somatic mutations have shown a dramatic initial clinical response to reversible EGFR inhibitors. The clinical efficacy of reversible inhibitors is, however, ultimately limited due to the emergence of drug resistance, which is usually conferred by the EGFR T790M mutation. Importantly, irreversible, synthetic small molecule inhibitors are currently evaluated and some of them have been shown to overcome the acquired resistance that is oftentimes observed in these patients. Thus far, irreversible EGFR inhibitors as a drug class have not received regulatory approval due in part to their poor effectiveness at clinically achievable concentrations. Therefore, there is an urgent need to discover and develop novel, potent irreversible inhibitors against the EGFR T790M mutation. MATERIAL AND METHODS: In the following study, we report a novel "hybrid strategy" to identify irreversible EGFR inhibitors with active scaffolds starting with the identification and extraction of a common chemical reactive feature and a pharmacophore feature. The chemical reactive feature was elucidated by investigating 138 currently known irreversible inhibitors at B3LYP/6-31G(d) level using the density function theory method. The pharmacophore feature was extracted from the same inhibitors using pharmacophore modeling. Based on these unique features, two constraints were set while calibrating the protocols of in silico screening. Compounds bearing these specific features were obtained from the National Cancer Institute diversity database to form our subsequent library. Finally, a structure based virtual screening against the library was conducted using standard protocols validated in our lab. RESULTS: Twenty-eight candidate compounds that demonstrated antitumor activity and that had novel scaffolds different from commonly known quinazoline/quinoline analogs were obtained. The interaction modes between three representative candidates and our model system are similar to that between the model system and the reference compound T-001, which has previously been reported to be one of the most potent of the 138 irreversible inhibitors. CONCLUSION: The hybrid strategy starting with the extraction of common features is an effective approach to design potential irreversible inhibitors with novel scaffolds and therefore to obtain lead molecules in the selection process. These candidates possessing unique scaffolds have a strong likelihood to act as further starting points in the preclinical development of potent irreversible T790M EGFR inhibitors. PMID- 23990709 TI - Bioequivalence study of two formulations of candesartan cilexetil tablet in healthy subjects under fasting conditions. AB - INTRODUCTION: The present study was conducted to compare the bioavailability of two candesartan cilexetil 16 mg tablet formulations (test and reference formulations). MATERIALS AND METHODS: This study was a randomized, single- blind, two-period, cross-over study which included 24 healthy adult male and female subjects under fasting conditions. The pharmacokinetic parameters were determined based on the concentrations of candesartan (CAS 139481-59-7), using ultra pressure high-performance liquid chromatography with a tandem mass spectrometer detector. In each of the two study periods (separated by a washout period of 1 week), a single dose of test or reference product was administered. The pharmacokinetic parameters assessed were area under the plasma concentration time curve (AUC) from time 0 hours to 24 hours, AUC from time zero to infinity, the peak plasma concentration of the drug (Cmax), time to achieve the Cmax, and the elimination half-life. RESULTS: The geometric mean ratios (90% confidence interval) of the test drug/reference drug for candesartan were 100.92% (92.15% 110.52%) for the AUC from 0 hours to 24 hours, 100.24% (92.24%-108.95%) for the AUC from time zero to infinity, and 106.71% (93.20%-122.18%) for the Cmax. The differences between the test and reference product in the time to achieve Cmax values and elimination half-life values were not statistically significant (P > 0.05). The 90% confidence intervals of the test/reference AUC ratio and Cmax ratio of candesartan were within the acceptance range for bioequivalence. There was no adverse event encountered during this bioequivalence study. CONCLUSION: It was concluded that the two candesartan tablet formulations (the test and reference product) were bioequivalent. PMID- 23990710 TI - A narrative approach to explore grief experiences and treatment adherence in people with chronic pain after participation in a pain-management program: a 6 year follow-up study. AB - OBJECTIVE: The aim of this study was to explore grief caused by chronic pain and treatment adherence, and how these experiences are integrated into ongoing life stories. METHODS: A 6-year follow-up using a qualitative mixed-methods design based on written narratives and image narratives was performed. Five women suffering from chronic pain comprised the purposive sample. They had completed an 8-week group pain-management program with two follow-ups, and thereafter continued as a self-help group. A narrative approach was used to analyze the written and image narratives guided by three analytic steps. RESULTS: Findings showed that experiences of grief over time were commonly associated with chronic pain. The participants' past experiences reflected their grief at having to abandon jobs and social networks, and revealed loneliness and despair. The present life situation seemed to reflect adaptation, and hope for the future had been established. Overall, forward progression means an ongoing struggle towards a reintegrated body and a meaningful life. CONCLUSION: Through such narratives, health-care workers can identify treatment adherence related to grief and pain, and learn how people might regain their lives beyond using traditional interviews. PMID- 23990711 TI - Transition experiences and health care utilization among young adults with type 1 diabetes. AB - BACKGROUND: The purpose of this study was to describe the current status of adult diabetes care in young adults with type 1 diabetes and examine associations between health care transition experiences and care utilization. METHODS: We developed a survey to assess transition characteristics and current care in young adults with type 1 diabetes. We mailed the survey to the last known address of young adults who had previously received diabetes care at a tertiary pediatric center. RESULTS: Of 291 surveys sent, 83 (29%) were undeliverable and three (1%) were ineligible. Of 205 surveys delivered, 65 were returned (response rate 32%). Respondents (mean age 26.6 +/- 3.0 years, 54% male, 91% Caucasian) transitioned to adult diabetes care at a mean age of 19.2 +/- 2.8 years. Although 71% felt mostly/completely prepared for transition, only half received recommendations for a specific adult provider. Twenty-six percent reported gaps exceeding six months between pediatric and adult diabetes care. Respondents who made fewer than three diabetes visits in the year prior to transition (odds ratio [OR] 4.5, 95% confidence interval [CI] 1.2-16.5) or cited moving/relocation as the most important reason for transition (OR 6.3, 95% CI 1.3-31.5) were more likely to report gaps in care exceeding six months. Patients receiving current care from an adult endocrinologist (79%) were more likely to report at least two diabetes visits in the past year (OR 6.0, 95% CI 1.5-24.0) compared with those receiving diabetes care from a general internist/adult primary care doctor (17%). Two thirds (66%) reported receiving all recommended diabetes screening tests in the previous year, with no difference according to provider type. CONCLUSION: In this sample, transition preparation was variable and one quarter reported gaps in obtaining adult diabetes care. Nevertheless, the majority endorsed currently receiving regular diabetes care, although visit frequency differed by provider type. Because locating patients after transition was incomplete, our findings suggest the need for standardized methods to track transitioning patients. PMID- 23990712 TI - Issues surrounding end-of-life decision-making. AB - End-of-life decision-making is a complex process that can be extremely challenging. We describe a 42-year-old woman in an irreversible coma without an advance directive. The case serves to illustrate the complications that can occur in end-of-life decision-making and challenges in resolving difficult futility disputes. We review the role of advance directives in planning end-of-life care, the responsibility and historical performance of patient surrogates, the genesis of futility disputes, and approaches to resolving disputes. PMID- 23990713 TI - Role of the levonorgestrel intrauterine system in effective contraception. AB - Norgestrel, a synthetic progestin chemically derived from 19-nortestosterone, is six times more potent than progesterone, with variable binding affinity to various steroid receptors. The levonorgestrel-releasing intrauterine system (LNG IUS) provides a long-acting, highly effective, and reversible form of contraception, with a pearl index of 0.18 per 100 women-years. The locally released hormone leads to endometrial concentrations that are 200-800 times those found after daily oral use and a plasma level that is lower than that with other forms of levonorgestrel-containing contraception. The contraceptive effect of the LNG IUS is achieved mainly through its local suppressive effect on the endometrium, leading to endometrial thinning, glandular atrophy, and stromal decidualization without affecting ovulation. The LNG IUS is generally well tolerated. The main side effects are related to its androgenic activity, which is usually mild and transient, resolving after the first few months. Menstrual abnormalities are also common but well tolerated, and even become desirable (eg, amenorrhea, hypomenorrhea, and oligomenorrhea) with proper counseling of the patient during the choice of the method of contraception. The satisfaction rates after 3 years of insertion are high, reaching between 77% and 94%. The local effect of the LNG IUS on the endometrium and low rates of systemic adverse effects have led to its use in other conditions rather than contraception, as for the treatment of endometrial hyperplasia, benign menorrhagia, endometriosis, adenomyosis, and uterine fibroids. PMID- 23990714 TI - Perspectives on medicine adherence in service users and carers with experience of legally sanctioned detention and medication: a qualitative study. AB - AIM: To explore and analyze perceptions of service users and caregivers on adherence and nonadherence to medication in a mental health care context. BACKGROUND: Mental health medication adherence is considered problematic and legal coercion exists in many countries. DESIGN: This was a qualitative study aiming to explore perceptions of medication adherence from the perspective of the service user (and their caregiver, where possible). PARTICIPANTS: Eighteen mental health service users (and six caregivers) with histories of medication nonadherence and repeated compulsory admission were recruited from voluntary sector support groups in England. METHODS: Data were collected between 2008 and 2010. Using qualitative coding techniques, the study analyzed interview and focus group data from service users, previously subjected to compulsory medication under mental health law, or their caregivers. RESULTS: The process of medication adherence or nonadherence is encapsulated in an explanatory narrative. This narrative constitutes participants' struggle to negotiate acceptable and effective routes through variable quality of care. Results indicated that service users and caregivers eventually accepted the reality of their own mental illness and their need for safety and treatment. They perceived the behavior of professionals as key in their recovery process. Professionals could be enabling or disabling with regard to adherence to medication. CONCLUSION: This study investigated service user and caregiver perceptions of medication adherence and compulsory treatment. Participants described a process perceived as variable and potentially doubly faceted. The behavior of professionals was seen as crucial in collaborative decision making on medication adherence. PMID- 23990715 TI - Ternary nanoparticles composed of cationic solid lipid nanoparticles, protamine, and DNA for gene delivery. AB - BACKGROUND: The objective of this research was to design an effective gene delivery system composed of cationic solid lipid nanoparticles (SLNs), protamine, and Deoxyribonucleic acid DNA. METHODS: Cationic SLNs were prepared using an aqueous solvent diffusion method with octadecylamine as the cationic lipid material. First, protamine was combined with DNA to form binary protamine/DNA nanoparticles, and the ternary nanoparticle gene delivery system was then obtained by combining binary protamine/DNA nanoparticles with cationic SLNs. The size, zeta potential, and ability of the binary and ternary nanoparticles to compact and protect DNA were characterized. The effect of octadecylamine content in SLNs and the SLNS/DNA ratios on transfection efficiency, cellular uptake and cytotoxicity of the ternary nanoparticles were also assessed using HEK293 cells. RESULTS: When the weight ratio of protamine to DNA reached 1.5:1, the plasmid DNA could be effectively compacted and protected. The average hydrodynamic diameter of the ternary nanoparticles when combined with protamine increased from 188.50 +/- 0.26 nm to 259.33 +/- 3.44 nm, and the zeta potential increased from 25.50 +/ 3.30 mV to 33.40 +/- 2.80 mV when the weight ratio of SLNs to DNA increased from 16/3 to 80/3. The ternary nanoparticles showed high gene transfection efficiency compared with LipofectamineTM 2000/DNA nanoparticles. Several factors that might affect gene transfection efficiency, such as content and composition of SLNs, post-transfection time, and serum were examined. The ternary nanoparticles composed of SLNs with 15 wt% octadecylamine (50/3 weight ratio of SLNs to DNA) showed the best transfection efficiency (26.13% +/- 5.22%) in the presence of serum. It was also found that cellular uptake of the ternary nanoparticles was better than that of the SLN/DNA and binary protamine/DNA nanoparticle systems, and DNA could be transported to the nucleus. CONCLUSION: SLNs enhanced entry of binary protamine/DNA nanoparticles into the cell, and protamine protected DNA from enzyme degradation and transported DNA into the nucleus. Compared with Lipofectamine 2000/DNA nanoparticles, these cationic ternary nanoparticles showed relatively durable and stable gene transfection in the presence of serum. PMID- 23990717 TI - Using poly(lactic-co-glycolic acid) microspheres to encapsulate plasmid of bone morphogenetic protein 2/polyethylenimine nanoparticles to promote bone formation in vitro and in vivo. AB - Repair of large bone defects is a major challenge, requiring sustained stimulation to continually promote bone formation locally. Bone morphogenetic protein 2 (BMP-2) plays an important role in bone development. In an attempt to overcome this difficulty of bone repair, we created a delivery system to slowly release human BMP-2 cDNA plasmid locally, efficiently transfecting local target cells and secreting functional human BMP-2 protein. For transfection, we used polyethylenimine (PEI) to create pBMP-2/PEI nanoparticles, and to ensure slow release we used poly(lactic-co-glycolic acid) (PLGA) to create microsphere encapsulated pBMP-2/PEI nanoparticles, PLGA@pBMP-2/PEI. We demonstrated that pBMP 2/PEI nanoparticles could slowly release from the PLGA@pBMP-2/PEI microspheres for a long period of time. The 3-15 MUm diameter of the PLGA@pBMP-2/PEI further supported this slow release ability of the PLGA@pBMP-2/PEI. In vitro transfection assays demonstrated that pBMP-2/PEI released from PLGA@pBMP-2/PEI could efficiently transfect MC3T3-E1 cells, causing MC3T3-E1 cells to secrete human BMP 2 protein, increase calcium deposition and gene expressions of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), SP7 and I type collagen (COLL I), and finally induce MC3T3-E1 cell differentiation. Importantly, in vivo data from micro-computed tomography (micro-CT) and histological staining demonstrated that the human BMP-2 released from PLGA@pBMP-2/PEI had a long-term effect locally and efficiently promoted bone formation in the bone defect area compared to control animals. All our data suggest that our PLGA-nanoparticle delivery system efficiently and functionally delivers the human BMP-2 cDNA and has potential clinical application in the future after further modification. PMID- 23990716 TI - Dry powder cationic lipopolymeric nanomicelle inhalation for targeted delivery of antitubercular drug to alveolar macrophage. AB - Excipients having self-assembling properties are less explored in the field of dry powder inhalation (DPI) technology. An amphiphilic lipopolymer system was developed using stearic acid (SA) and branched polyethyleneimine (BPEI) (1800 Dalton), at different proportions by covalent conjugation. A molecular dynamic (MD) simulation tool was employed for predicting the carrier behavior in a polar in vivo condition. The structural characterization was carried out using nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared (FTIR) spectroscopy. The physical nature of the lipopolymer was analyzed by differential scanning calorimetry. Determination of zeta potential and diameter of the micelles showed existence of cationic particles in the nano size range when a lower number of primary amino groups of BPEI was grafted with SA. The rifampicin (RIF)-loaded lipopolymer was also formulated further into spray-dried microparticles. Powder X-ray diffraction (PXRD) studies revealed that the RIF API (active pharmaceutical ingredient) exists as molecular dispersion in spray-dried microparticles. Topological analysis of the spray-dried nanomicelle was carried out using scanning electron microscopy (SEM). A large population of the drug carrying particles were found to be under the inhalable size range (fine particle fraction 67.88% +/- 3%). In vitro drug release kinetics from spray-dried nanomicelles were carried out at lung fluid pH. PMID- 23990718 TI - Enhanced transdermal bioavailability of testosterone propionate via surfactant modified ethosomes. AB - The current investigation aimed to evaluate the transdermal potential of novel testosterone propionate (TP) ethosomes and liposomes prepared by surfactant modification. The effect of hexadecyl trimethyl ammonium bromide and cremophor EL 35 on the particle size and zeta potential of the prepared vesicles was investigated. The entrapment efficiency and stability, as well as in vitro and in vivo skin permeation, were studied with the various techniques, such as differential scanning calorimetry, confocal laser scanning microscopy, transmission electron microscopy, dynamic light scattering, and so on. The results indicated that the ethosomes were defined as spherical, unilamellar structures with low polydispersity (0.100 +/- 0.015) and nanometric size (156.5 +/- 3.5 nm). The entrapment efficiency of TP in ethosomal and liposomal carriers was 92.7% +/- 3.7% and 64.7% +/- 2.1%, respectively. The stability profile of the prepared TP ethosomal system assessed for 120 days revealed very low aggregation and very low growth in vesicular size. TP ethosomes also provided an enhanced transdermal flux of 37.85 +/- 2.8 MUg/cm(2)/hour and a decreased lag time of 0.18 hours across mouse skin. The skin permeation efficiency of the TP ethosomes as further assessed by confocal laser scanning microscopy revealed enhanced permeation of rhodamine red-loaded formulations to the deeper layers of the skin (260 MUm) than that of the liposomal formation (120 MUm). PMID- 23990719 TI - Preparation and characterization of monomethoxy poly(ethylene glycol) poly(epsilon-caprolactone) micelles for the solubilization and in vivo delivery of luteolin. AB - Luteolin (Lu) is one of the flavonoids with anticancer activity, but its poor water solubility limits its use clinically. In this work, we used monomethoxy poly(ethylene glycol)-poly(e-caprolactone) (MPEG-PCL) micelles to encapsulate Lu by a self-assembly method, creating a water-soluble Lu/MPEG-PCL micelle. These micelles had a mean particle size of 38.6 +/- 0.6 nm (polydispersity index = 0.16 +/- 0.02), encapsulation efficiency of 98.32% +/- 1.12%, and drug loading of 3.93% +/- 0.25%. Lu/MPEG-PCL micelles could slowly release Lu in vitro. Encapsulation of Lu in MPEG-PCL micelles improved the half-life (t1/2 ; 152.25 +/ 49.92 versus [vs] 7.16 +/- 1.23 minutes, P = 0.007), area under the curve (0-t) (2914.05 +/- 445.17 vs 502.65 +/- 140.12 mg/L/minute, P = 0.001), area under the curve (0-infinity) (2989.03 +/- 433.22 vs 503.81 +/- 141.41 mg/L/minute, P = 0.001), and peak concentration (92.70 +/- 11.61 vs 38.98 +/- 7.73 mg/L, P = 0.003) of Lu when the drug was intravenously administered at a dose of 30 mg/kg in rats. Also, Lu/MPEG-PCL micelles maintained the cytotoxicity of Lu on 4T1 breast cancer cells (IC50 = 6.4 +/- 2.30 MUg/mL) and C-26 colon carcinoma cells (IC50 = 12.62 +/- 2.17 MUg/mL) in vitro. These data suggested that encapsulation of Lu into MPEG-PCL micelles created an aqueous formulation of Lu with potential anticancer effect. PMID- 23990721 TI - Nanostructured systems containing babassu (Orbignya speciosa) oil as a potential alternative therapy for benign prostatic hyperplasia. AB - The oil of babassu tree nuts (Orbignya speciosa) is a potential alternative for treatment and prophylaxis of benign prostatic hyperplasia. Improved results can be obtained by drug vectorization to the hyperplastic tissue. The main objective of this work was the preparation and characterization of poly(lactic-co-glycolic acid) (PLGA) nanoparticle and clay nanosystems containing babassu oil (BBS). BBS was extracted from the kernels of babassu tree nuts and characterized by gas chromatography-mass spectrometry as well as 1H and 13C nuclear magnetic resonance. BBS-clay nanosystems were obtained by adding polyvinylpyrrolidone, Viscogel B8(r), and BBS at a 2:1:1 mass ratio and characterized by X-ray diffraction, thermogravimetric analysis, infrared spectroscopy, and laser diffraction. The PLGA-BBS nanoparticles were prepared by the precipitation solvent evaporation method. Mean diameter, polydispersity, zeta potential, and scanning electron microscopic images of the nanosystems were analyzed. Thermogravimetric analysis showed successful formation of the nanocomposite. PLGA nanoparticles containing BBS were obtained, with a suitable size that was confirmed by scanning electron microscopy. Both nanostructured systems showed active incorporation yields exceeding 90%. The two systems obtained represent a new and potentially efficient therapy for benign prostatic hyperplasia. PMID- 23990720 TI - Critical evaluation of biodegradable polymers used in nanodrugs. AB - Use of biodegradable polymers for biomedical applications has increased in recent decades due to their biocompatibility, biodegradability, flexibility, and minimal side effects. Applications of these materials include creation of skin, blood vessels, cartilage scaffolds, and nanosystems for drug delivery. These biodegradable polymeric nanoparticles enhance properties such as bioavailability and stability, and provide controlled release of bioactive compounds. This review evaluates the classification, synthesis, degradation mechanisms, and biological applications of the biodegradable polymers currently being studied as drug delivery carriers. In addition, the use of nanosystems to solve current drug delivery problems are reviewed. PMID- 23990722 TI - Preparation and characteristics of lipid nanoemulsion formulations loaded with doxorubicin. AB - PURPOSE: Safe and effective lipid nanoemulsion (LNE) formulations for the antitumor delivery of doxorubicin is designed. METHODS: LNEs composed of medium chain triglyceride, soybean oil, lecithin, and doxorubicin are prepared by a solvent-diffusion method in an aqueous system. The effects of lipid material composition and polyethylene glycol (PEG)ylation on the size, drug encapsulation efficiency, and stability of LNEs are investigated. Based on in-vitro cytotoxicity and cellular uptake tests of A549 (human lung carcinoma) cells, in vivo biodistribution, antitumor activity, and cardiac toxicity are further examined using nude mouse bearing A549 tumor. RESULTS: The LNE size decreases from 126.4 +/- 8.7 nm to 44.5 +/- 9.3 nm with increased weight ratio of medium chain triglyceride to soybean oil from 1:4 to 3:2, whereas the encapsulation efficiency of doxorubicin is slightly reduced from 79.2% +/- 2.1% to 71.2% +/- 2.9%. The PEGylation of LNE by 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [carboxy(PEG)2000] (DSPE-PEG 2000) does not significantly change the size and drug encapsulation efficiency. Three-month storage at room temperature and lyophilization process does not affect the drug encapsulation efficiency, whereas the size slightly increases to almost 100 nm. The in-vitro drug-release profiles of LNEs suggest that the present formulation can prolong drug release for 48 hours. LNEs can be internalized into tumor cells in vitro and efficiently accumulate in tumor tissues in vivo by passive targeting. Analysis results of in vitro and in-vivo antitumor activities reveal that doxorubicin-loaded LNE exerts a therapeutic effect similar to that of the commercial Adriamycin. Moreover, the toxicity of doxorubicin, particularly its cardiac toxicity, is reduced. CONCLUSION: The present LNE formulation of doxorubicin can effectively suppress tumor growth and improve the safety of Adriamycin. PMID- 23990723 TI - Magnetic nanoparticles of Fe3O4 enhance docetaxel-induced prostate cancer cell death. AB - Docetaxel (DTX) is one of the most important anticancer drugs; however, the severity of its adverse effects detracts from its practical use in the clinic. Magnetic nanoparticles of Fe3O4 (MgNPs-Fe3O4) can enhance the delivery and efficacy of anticancer drugs. We investigated the effects of MgNPs-Fe3O4 or DTX alone, and in combination with prostate cancer cell growth in vitro, as well as with the mechanism underlying the cytotoxic effects. MgNPs-Fe3O4 caused dose dependent increases in reactive oxygen species levels in DU145, PC-3, and LNCaP cells; 8-hydroxydeoxyguanosine levels were also elevated. MgNPs-Fe3O4 alone reduced the viability of LNCaP and PC-3 cells; however, MgNPs-Fe3O4 enhanced the cytotoxic effect of a low dose of DTX in all three cell lines. MgNPs-Fe3O4 also augmented the percentage of DU145 cells undergoing apoptosis following treatment with low dose DTX. Expression of nuclear transcription factor kappaB in DU145 was not affected by MgNPs-Fe3O4 or DTX alone; however, combined treatment suppressed nuclear transcription factor kappaB expression. These findings offer the possibility that MgNPs-Fe3O4-low dose DTX combination therapy may be effective in treating prostate cancer with limited adverse effects. PMID- 23990724 TI - Evaluation of protective efficacy using a nonstructural protein NS1 in DNA vaccine-loaded microspheres against dengue 2 virus. AB - Dengue virus results in dengue fever or severe dengue hemorrhagic fever/dengue shock syndrome in humans. The purpose of this work was to develop an effective antidengue virus delivery system, by designing poly (dl-lactic-co-glycolic) acid/polyethylene glycol (PLGA/PEG) microspheres using a double-emulsion solvent extraction method, for vaccination therapy based on locally and continuously sustained biological activity. Nonstructural protein 1 (NS1) in deoxyribonucleic acid (DNA) vaccine-loaded PLGA/PEG microspheres exhibited a high loading capacity (4.5% w/w), yield (85.2%), and entrapment efficiency (39%), the mean particle size 4.8 MUm, and a controlled in vitro release profile with a low initial burst (18.5%), lag time (4 days), and continued released protein over 70 days. The distribution of protein on the microspheres surface, outer layer, and core were 3.0%, 28.5%, and 60.7%, respectively. A release rate was noticed to be 1.07 MUg protein/mg microspheres/day of protein release, maintained for 42 days. The cumulative release amount at Days 1, 28, and 42 was 18.5, 53.7, and 62.66 MUg protein/mg microspheres, respectively. The dengue virus challenge in mice test, in which mice received one dose of 20 MUg NS1 protein content of microspheres, in comparison with NS1 protein in Al(OH)3 or PBS solution, was evaluated after intramuscular immunization of BALB/c mice. The study results show that the greatest survival was observed in the group of mice immunized with NS1 protein loaded PLGA/PEG microspheres (100%). In vivo vaccination studies also demonstrated that NS1 protein-loaded PLGA/PEG microspheres had a protective ability; its steady-state immune protection in rat plasma changed from 4,443 +/- 1,384 pg/mL to 10,697 +/- 3,197 pg/mL, which was 2.5-fold higher than that observed for dengue virus in Al(OH)3 at 21 days. These findings strongly suggest that NS1 protein-loaded PLGA/PEG microspheres offer a new therapeutic strategy in optimizing the vaccine incorporation and delivery properties of these potential vaccine targeting carriers. PMID- 23990725 TI - An open-label, prospective study to evaluate social function and overall improvement of extended-release paliperidone treatment in Thai schizophrenia patients. AB - BACKGROUND: Previous studies with extended-release (ER) paliperidone have reported an effective outcome in terms of personal and social functioning improvement and also reported schizophrenia symptom improvement. The main objectives of this study were to further investigate improvements in symptom control and social functioning of paliperidone ER and acknowledge the safety profile of paliperidone ER in Thai patients with schizophrenia. PATIENTS AND METHODS: Patients with schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders criteria were allowed flexible 3-12 mg/day dosing during the 10-week study duration. Patients were interviewed and assessed in social functioning using the Personal and Social Performance (PSP) scale. Patients were also rated on overall severity of illness using the Clinical and Global Impressions - Severity (CGI-S) scale. RESULTS: In total, 40 patients were enrolled, 80% of enrolled patients (n = 32) completed the 10-week study period. Thirty-eight eligible patients were included in the intention-to-treat analysis set (male 39.5%, female 60.5%). One patient was lost to follow-up without postbaseline-efficacy measurements. Another patient was terminated early due to a change in diagnosis during the trial. Statistically significant improvements from baseline in PSP total score were observed at all time points. Clinically relevant improvement in PSP (increase of at least one 10-point category) was observed in 47.40% of patients at end point. Improvement in CGI-S was observed at end point (P < 0.001). The mean reduction +/- standard deviation at end point in CGI-S was 0.8 +/- 1.04 (95% confidence interval 0.48-1.16). The most commonly reported adverse events (>=5% of patients) were daytime drowsiness (15%) and headache (15%). Three subjects (7.5%) discontinued due to adverse events. CONCLUSION: This study suggests that paliperidone ER is well tolerated in Thai patients with schizophrenia. Paliperidone ER showed improvement in schizophrenic symptom control and social functioning. PMID- 23990727 TI - Role of once-daily glycopyrronium bromide (NVA237) in the management of COPD. AB - Progressive airflow limitation is a hallmark feature of chronic obstructive pulmonary disease (COPD) that ultimately leads to breathlessness, impaired quality of life, and reduced exercise capacity. Pharmacotherapy is used in patients with COPD to prevent and control symptoms, reduce both the frequency and severity of exacerbations, improve health status, and increase exercise tolerance. These strategies are intended to address management issues which promote both current disease control and a reduction in the risk of disease deterioration in the future. At the present time, long-acting beta2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are available for maintenance therapy in patients with persistent symptoms. Tiotropium was the first LAMA to be approved for management of COPD, and many studies have described its beneficial effects on multiple clinically relevant outcomes. Glycopyrronium bromide (NVA237), a new LAMA, has been developed and received regulatory approval for management of COPD in a number of countries around the world. Results from pivotal Phase III trials suggest that NVA237 is safe and well tolerated in patients with moderate to severe COPD, and provides rapid and sustained improvements in lung function. Further, these changes are associated with statistically and clinically meaningful improvements in dyspnea, health-related quality of life, and exercise tolerance. Treatment with NVA237 also results in a significant reduction in risk of exacerbations and the need for rescue medication, and has been comparable with tiotropium with respect to safety and efficacy outcomes. Finally, emerging data indicate that NVA237 is efficacious both as monotherapy and in combination with indacaterol. PMID- 23990728 TI - Over-the-counter suboptimal dispensing of antibiotics in Uganda. AB - BACKGROUND: Overuse and misuse of antibiotics is a serious global problem. While resistance to older antibiotics is increasing, development of newer molecules has stalled. Resistance to the existing antibiotics that is largely driven by their high-volume use is a global public health problem. Uganda is one of the countries where prescription-only drugs, including antibiotics, can be obtained over the counter. We determined the rate of antibiotic dispensing and use in Uganda. METHODS: The study utilized a descriptive cross-sectional study design to determine the number of antibiotic "prescribed" daily doses per 1,000 clients. Data were collected from one health center II, eight general/district hospitals, one national referral hospital, and 62 registered community pharmacies. From each study site, data were collected for five consecutive days over the months of November 2011 to January 2012. RESULTS: The overall antibiotic issue rate was 43.2%. Amoxicillin, metronidazole, ciprofloxacin, sulfamethoxazole-trimethoprim, cloxacillin, and ampicillin, belonging to the WHO anatomical therapeutic chemical classifications of penicillin with extended spectra, imidazole derivatives, fluoroquinolones, and sulfonamide-trimethoprim combinations, constituted 70% of the issued antibiotics. About 41% of antibiotics were issued over the counter. At community pharmacies, where 30% of antibiotic dispensing occurred, the number of prescribed daily doses/1,000 antibiotic clients was 4,169 compared to 6,220, 7,350 and 7,500 at general/district hospitals, the national referral hospital, and the health center, respectively. CONCLUSION: In Uganda, at least four in every ten individuals that visit a health-care facility are treated with an antibiotic. Antibiotics are largely given as over-the-counter drugs at community pharmacies. The number of antibiotic prescribed daily doses/1,000 antibiotic clients does not significantly differ between categories of health-care facilities except at community pharmacies, where lower doses are dispensed compared to other health-care facilities. PMID- 23990726 TI - Options for treating postherpetic neuralgia in the medically complicated patient. AB - Patients with postherpetic neuralgia (PHN) are often of advanced age or immunocompromised and likely to have >=1 comorbid medical condition for which they receive >=1 medication (polypharmacy). Comorbidities affecting renal or hepatic function can alter pharmacokinetics, thereby impacting the efficacy or tolerability of PHN analgesic therapies. Cardiovascular, cerebrovascular, or psychiatric comorbidities may increase patient vulnerability to potential adverse events associated with some PHN analgesic therapies. Because PHN is a localized condition, localized therapy with a topical analgesic (lidocaine patch 5% and capsaicin 8% patch or cream) may provide adequate efficacy while mitigating the risk of systemic adverse events compared with oral analgesics (eg, tricyclic antidepressants, anticonvulsants, opioids). However, combined therapy with a topical and an oral analgesic or with >1 oral analgesic may be needed for optimal pain management in some patients. This review summarizes how comorbidities and concomitant medications should be taken into account when selecting among available pharmacotherapies for PHN and provides recommendations for the selection of therapies that will provide analgesia while minimizing the risk of adverse events. PMID- 23990729 TI - Arsenic trioxide inhibits viability of pancreatic cancer stem cells in culture and in a xenograft model via binding to SHH-Gli. AB - OBJECTIVE: Overexpression of the sonic hedgehog (SHH) signaling pathway is an essential characteristic of pancreatic cancer stem cells (PCSCs) and arsenic trioxide (ATO) is described as a SHH inhibitor. This study evaluates whether ATO has the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins. METHODS: Cell counting kit-8 and flow cytometry were used for analyzing apoptosis in cells in vitro. The animal model was an athymic nude mouse model bearing subcutaneous xenografts of SW1990 pancreatic cancer cells. The terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry were used for tumor tissue analysis. The interaction between Gli1 and ATO was examined by a confocal system and an ultraviolet absorption spectrum assay. RESULTS: ATO induced apoptosis in pancreatic cancer cells, especially CD24(+)CD44(+) cells in vitro. Combination treatment of ATO and low dose gemcitabine inhibited tumor growth by 60.9% (P = 0.004), and decreased the expression of CD24, CD44, and aldehyde dehydrogenase 1 family, member A1 significantly in vivo. ATO changed the structure of the recombinant Gli1 zinc finger peptides in a cell-free condition and the binding action of ATO to recombinant Gli1 was observed in cultured pancreatic cancer cells. CONCLUSION: ATO may have the potential to inhibit viability of PCSCs via binding to SHH-Gli proteins in vitro and in vivo. PMID- 23990730 TI - Phenotypic and molecular characteristics of methicillin-resistant Staphylococcus aureus isolates from Ekiti State, Nigeria. AB - INTRODUCTION: The characteristics and antimicrobial resistance profiles of Staphylococcus aureus differs according to geographical regions and in relation to antibiotic usage. The aim of this study was to determine the biochemical characteristics of the prevalent S. aureus from Ekiti State, Nigeria, and to evaluate three commonly used disk diffusion methods (cefoxitin, oxacillin, and methicillin) for the detection of methicillin resistance in comparison with mecA gene detection by polymerase chain reaction. MATERIALS AND METHODS: A total of 208 isolates of S. aureus recovered from clinical specimens were included in this study. Standard microbiological procedures were employed in isolating the strains. Susceptibility of each isolate to methicillin (5 MUg), oxacillin (1 MUg), and cefoxitin (30 MUg) was carried out using the modified Kirby Bauer/Clinical and Laboratory Standard Institute disk diffusion technique. They were also tested against panels of antibiotics including vancomycin. The conventional polymerase chain reaction method was used to detect the presence of the mecA gene. RESULTS: Phenotypic resistance to methicillin, oxacillin, and cefoxitin were 32.7%, 40.3%, and 46.5%, respectively. The mecA gene was detected in 40 isolates, giving a methicillin-resistant S. aureus (MRSA) prevalence of 19.2%. The S. aureus isolates were resistant to penicillin (82.7%) and tetracycline (65.4%), but largely susceptible to erythromycin (78.8% sensitive), pefloxacin (82.7%), and gentamicin (88.5%). When compared to the mecA gene as the gold standard for MRSA detection, methicillin, oxacillin, and cefoxitin gave sensitivity rates of 70%, 80%, and 100%, and specificity rates of 76.2%, 69.1%, and 78.5% respectively. CONCLUSION: When compared with previous studies employing mecA polymerase chain reaction for MRSA detection, the prevalence of 19.2% reported in Ekiti State, Nigeria in this study is an indication of gradual rise in the prevalence of MRSA in Nigeria. A cefoxitin (30 MUg) disk diffusion test is recommended above methicillin and oxacillin for the phenotypic detection of MRSA in clinical laboratories. PMID- 23990731 TI - Isolated limb infusion chemotherapy for melanoma: an overview of early experience at the Adelaide Melanoma Unit. AB - BACKGROUND: Isolated limb infusion (ILI) using cytotoxic agents has been demonstrated to be an effective and less invasive alternative modality than isolated limb perfusion for the treatment of melanoma localized to a limb. Percutaneous catheters were inserted into the axial artery and vein of the affected limb while using a pneumatic cuff to restrict limb vascular flow proximally to "isolate" the limb from the body and enable delivery of high-dose intra-arterial chemotherapy selectively to the limb. The ILI technique was developed at the Sydney Melanoma Unit (now renamed the Melanoma Institute Australia), and only a few other centers have reported separate results. We report our early results using the ILI technique for management of locally recurrent surgically nonresectable melanoma. METHODS AND RESULTS: Twenty-eight ILI procedures were performed in 20 patients treated with one or more procedures between 1997 and 2007. Patient parameters and clinical responses were evaluated. The median follow-up duration was 15.9 months after the first ILI, with an overall response rate after one or more infusions of 70%, of which 35% were complete responders and 35% were partial responders, with a further 20% showing stable disease, giving a "clinically significant" response rate of 90%. After one ILI (n = 20), the overall response rate was 70%, with 20% complete responders and 50% partial responders, and 20% with stable disease. Low limb toxicities were generally observed, and no amputations were required. CONCLUSION: ILI chemotherapy is a useful technique, which can be readily repeated for control of melanoma in the limb. It is generally well tolerated, and is capable of achieving a cure, delayed progression, or effective palliation in selected cases. The longest survivors in this series were 8 and 10 years from the last ILI. PMID- 23990732 TI - Epidemiology of dengue: past, present and future prospects. AB - Dengue is currently regarded globally as the most important mosquito-borne viral disease. A history of symptoms compatible with dengue can be traced back to the Chin Dynasty of 265-420 AD. The virus and its vectors have now become widely distributed throughout tropical and subtropical regions of the world, particularly over the last half-century. Significant geographic expansion has been coupled with rapid increases in incident cases, epidemics, and hyperendemicity, leading to the more severe forms of dengue. Transmission of dengue is now present in every World Health Organization (WHO) region of the world and more than 125 countries are known to be dengue endemic. The true impact of dengue globally is difficult to ascertain due to factors such as inadequate disease surveillance, misdiagnosis, and low levels of reporting. Currently available data likely grossly underestimates the social, economic, and disease burden. Estimates of the global incidence of dengue infections per year have ranged between 50 million and 200 million; however, recent estimates using cartographic approaches suggest this number is closer to almost 400 million. The expansion of dengue is expected to increase due to factors such as the modern dynamics of climate change, globalization, travel, trade, socioeconomics, settlement and also viral evolution. No vaccine or specific antiviral therapy currently exists to address the growing threat of dengue. Prompt case detection and appropriate clinical management can reduce the mortality from severe dengue. Effective vector control is the mainstay of dengue prevention and control. Surveillance and improved reporting of dengue cases is also essential to gauge the true global situation as indicated in the objectives of the WHO Global Strategy for Dengue Prevention and Control, 2012-2020. More accurate data will inform the prioritization of research, health policy, and financial resources toward reducing this poorly controlled disease. The objective of this paper is to review historical and current epidemiology of dengue worldwide and, additionally, reflect on some potential reasons for expansion of dengue into the future. PMID- 23990733 TI - Allergy related to dental implant and its clinical significance. AB - The oral cavity provides an ideal and unique environment for study of biological processes involving metallic dental aids. Dental materials within the mouth interact continually with physiological fluids. Oral tissues are exposed to a veritable bombardment of both chemical and physical stimuli as well as the metabolism of many species of bacteria; yet, for the most part, oral tissues remain healthy. The pH of saliva varies from 5.2 to 7.8. Teeth, restorations, or any prosthesis including dental implants in the oral cavity have to function in one of the most inhospitable environments in the human body. They are subject to larger temperature and pH variations than most other parts of the body. Corrosion, the graded degradation of materials by electrochemical attack, is of concern particularly when dental implants are placed in the hostile electrolytic environment provided by the human mouth. Allergic reactions may occur from the presence of ions produced from the corrosion of implants. The present article describes various manifestations of allergic reactions due to implant material in the oral cavity. PMID- 23990734 TI - Serum selenium and skin diseases among Nigerians with human immunodeficiency virus/acquired immune deficiency syndrome. AB - BACKGROUND: The role of selenium as an antioxidant micronutrient has garnered the unprecedented focus of researchers in recent times. No clinical study has related serum selenium concentration to skin diseases in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. METHODS: In this study, 134 newly diagnosed HIV patients that satisfied the inclusion criteria were included. Skin diseases were clinically diagnosed and fasting venous blood was taken for assessment of serum selenium using an atomic absorption spectrophotometer. RESULTS: THE MEAN AGE OF HIV SUBJECTS WITH AND WITHOUT SKIN DISEASE WERE NOT SIGNIFICANTLY DIFFERENT: 32.72 +/- 9.21 versus 35.86 +/- 8.55 years, P = 0.077, respectively. The mean of serum selenium (0.51 +/- 0.48 versus 0.81 +/- 0.39), CD4+ count (228.06 +/- 212.89 versus 446.41 +/- 182.87), and body mass index (BMI; 21.09 +/- 3.58 versus 23.53 +/- 3.35) were significantly lower (P < 0.001) for HIV/AIDS participants with skin disease than those without skin disease. We found significant clustering of symptoms and signs: fever (P = 0.037), weight loss (P = 0.009), oral candidiasis (P = 0.038), pallor (P = 0.037) among HIV/AIDS subjects with skin diseases than those without. Low serum selenium concentration was significantly associated with primary skin disease of HIV/AIDS, such as pruritic papular eruption of AIDS (P = 0.003), xeroderma (P = 0.030), fluffy hair (P = 0.021), blue-black nail hyperpigmentation (P = 0.033) and secondary skin disease, such as oral candidiasis (P = 0.002). There was a significant association between low serum selenium concentration and increasing frequency of skin diseases (P = 0.002), but serum selenium was not significantly related to extents of distribution of skin diseases (P > 0.05). CONCLUSION: serum selenium concentration was lower among HIV subjects with skin diseases than those without skin disease. Pruritic papular eruption, xeroderma, fluffy hair, blue black nail hyper pigmentation, and oral candidiasis were significantly associated with low serum selenium concentration. PMID- 23990737 TI - Identification of Microdochium bolleyi Associated with Basal Rot of Creeping Bent Grass in Korea. AB - Symptoms of basal rot occurred sporadically on creeping bent grasses growing at a golf course in Hampyeong, Korea in April 2007. Ten isolates of Microdochium sp. were obtained from leaves and crowns of the diseased bent grasses. All isolates were identified as Microdochium bolleyi based on morphological, cultural, and molecular characteristics. This is the first report on M. bolleyi associated with basal rot on creeping bent grass in Korea. PMID- 23990736 TI - Development and initial validation of a computer-administered health literacy assessment in Spanish and English: FLIGHT/VIDAS. AB - Current measures of health literacy have been criticized on a number of grounds, including use of a limited range of content, development on small and atypical patient groups, and poor psychometric characteristics. In this paper, we report the development and preliminary validation of a new computer-administered and scored health literacy measure addressing these limitations. Items in the measure reflect a wide range of content related to health promotion and maintenance as well as care for diseases. The development process has focused on creating a measure that will be useful in both Spanish and English, while not requiring substantial time for clinician training and individual administration and scoring. The items incorporate several formats, including questions based on brief videos, which allow for the assessment of listening comprehension and the skills related to obtaining information on the Internet. In this paper, we report the interim analyses detailing the initial development and pilot testing of the items (phase 1 of the project) in groups of Spanish and English speakers. We then describe phase 2, which included a second round of testing of the items, in new groups of Spanish and English speakers, and evaluation of the new measure's reliability and validity in relation to other measures. Data are presented that show that four scales (general health literacy, numeracy, conceptual knowledge, and listening comprehension), developed through a process of item and factor analyses, have significant relations to existing measures of health literacy. PMID- 23990735 TI - Immunocytokines: a review of molecules in clinical development for cancer therapy. AB - The concept of therapeutically enhancing the immune system's responsiveness to tumors is long standing. Several cytokines have been investigated in clinical trials for their therapeutic activity in cancer patients. However, substantial side effects and unfavorable pharmacokinetic properties have been a major drawback hampering the administration of therapeutically relevant doses. The use of recombinant antibody-cytokine fusion proteins promises to significantly enhance the therapeutic index of cytokines by targeting them to the site of disease. This review aims to provide a concise and complete overview of the preclinical data and clinical results currently available for all immunocytokines having reached clinical development. PMID- 23990738 TI - Cultural Characteristics and Log-Mediated Cultivation of the Medicinal Mushroom, Phellinus linteus. AB - The optimal conditions for mycelial growth of Phellinus linteus ATCC 26710 were determined to be a log length of 20 cm, temperature of 30C and pH of 6.0. Mycelial growth was excellent on the mushroom complete medium, and was optimal when sucrose, mannose and glucose were supplied as carbon sources. Potassium nitrate and sodium nitrate as nitrogen sources supported good mycelial growth. To evaluate P. linteus mycelial colonization on logs, sterilized short log inoculation, drilling inoculation and log-end sandwich inoculation techniques were used. Only sterilized short log inoculation produced good mycelial colonization. Initial mycelial growth and full mycelial colonization were best on 20 cm logs having 42% moisture content. The initial mycelial growth of P. linteus was accelerated over 12 hr of sterilization. Basidiocarp formation was optimal using a burying method of logs after 5~6 months, and fruiting body formation was superior in cultivation house conditions of 31~35C and in excess of 96% relative humidity. PMID- 23990740 TI - Antibacterial and Antifungal Studies on Some Schiff Base Complexes of Zinc(II). AB - Two Schiff base ligands L1and L2 were obtained by the condensation of glycylglycine respectively with imidazole-2-carboxaldehyde and indole-3 carboxaldehyde and their complexes with Zn(II) were prepared and characterized by microanalytical, conductivity measurement, IR, UV-Vis., XRD and SEM. The molar conductance measurement indicates that the Zn(II) complexes are 1: 1electrolytes. The IR data demonstrate the tetradentate binding of L1and tridentate binding of L2. The XRD data show that Zn(II) complexes with L1and L2 have the crystallite sizes of 53 and 61nm respectively. The surface morphology of the complexes was studied using SEM. The in vitro biological screening effects of the investigated compounds were tested against the bacterial species Staphylococcus aureus, Escherichia coli, Klebsiella pneumaniae, Proteus vulgaris and Pseudomonas aeruginosa and fungal species Aspergillus niger, Rhizopus stolonifer, Aspergillus flavus, Rhizoctonia bataicola and Candida albicans by the disc diffusion method. A comparative study of inhibition values of the Schiff base ligands and their complexes indicates that the complexes exhibit higher antimicrobial activity than the free ligands. Zinc ions are proven to be essential for the growth-inhibitor effect. The extent of inhibition appeared to be strongly dependent on the initial cell density and on the growth medium. PMID- 23990739 TI - Vegetative Growth of Four Strains of Hericium erinaceus Collected from Different Habitats. AB - Vegetative growth of four different strains of Hericium erinaceus was observed. The temperature suitable for optimal mycelial growth was determined to be 25C, with growth observed in the extend temperature range of 20~30C. The different strains of this mushroom showed distinct pH requirements for their optimum vegetative growth, with the most favorable growth observed at pH 6. Considering vegetative mycelial growth, PDA, YM, Hennerberg, Hamada, and Glucose peptone were the most favorable media, and Czapek Dox, Hoppkins, Glucose tryptone, and Lilly were the most unfavorable media for these mushroom strains. With the exception of lactose, most of the carbon sources assayed demonstrated favorable vegetative growth of H. erinaceus. For mycelial growth, the most suitable nitrogen source was alanine and the most unsuitable was histidine. Oak sawdust medium supplemented with 10~20% rice bran was the best for mycelial growth of the mushroom. PMID- 23990741 TI - Antifungal Activity of Securinine against Some Plant Pathogenic Fungi. AB - The alkaloid securinine was assessed against spore germination of some plant pathogenic and saprophytic fungi (Alternaria alternata, Alternaria brassicae, Alternaria brassicicola, Curvularia lunata, Curvularia maculans, Curvularia pallenscens, Colletotrichum musae, Colletotrichum sp., Erysiphe pisi, Helminthosporium echinoclova, Helminthosporium spiciferum, Heterosporium sp.). Spore germinations of all the tested fungi were inhibited. Alternaria brassicicola, C. lunata, C. pallenscens and H. spiciferum were highly sensitive as complete inhibition of spore germination was observed at very low concentrations (200 ppm). PMID- 23990742 TI - Production of the Acetylcholinesterase Inhibitor from Yarrowia lipolytica S-3. AB - The acetylcholinesterase (AChE) inhibitor of Yarrowia lipolytica S-3 was maximally produced when it was incubated at 30C for 36 h in an optimal medium containing 1% yeast extract, 2% peptone and 2% glucose, with an initial pH 6.0. The final AChE inhibitory activity under these conditions was an IC50 value of 64 mg/ml. After partial purification of the AChE inhibitor by means of systematic solvent extraction, the final IC50 value of the partially purified AChE inhibitor was 0.75 mg/ml. We prepared a test product by using the partially purified AChE inhibitor and then determined its stability for the development of a new antidementia commercial product. The test product was stable at room temperature for 15 weeks. PMID- 23990743 TI - Anti-tumor Effects of Exo- and Endo-biopolymers Produced from Submerged Cultures of Three Different Mushrooms. AB - The anti-tumor effects of exo- (EX) and endo-biopolymers (EN) produced from submerged mycelial cultures of Ganoderma applanatum (GA), Collybia confluens (CC), and Pleurotus eryngii (PE) were studied using Sarcoma 180 bearing mice. Solid tumor growth was inhibited most effectively when 40 mg/kg body weight (BW) of GA-EX or PE-EN was administered to the intraperitoneal (i.p.) cavity of BALB/c mice. The spleen and liver indexes were increased in mice following i.p. administration of GA-EX and PE-EN fractions. GA-EX and PE-EN reduced the tumor formation by 30.7% and 29.4%, respectively. GA-EX and PE-EN increased the natural killer (NK) cell activity of splenocytes by 41.3% and 28.9%, respectively. PMID- 23990744 TI - Chemical Constituents of the Fruiting Bodies of Clitocybe nebularis and Their Antifungal Activity. AB - During a continuing search for antimicrobial substances from Korean native wild mushroom extracts, we found that the methanolic extract of the fruiting body of Clitocybe nebularis exhibited mild antifungal activity against pathogenic fungi. Therefore we evaluated the antifungal substances and other chemical components of the fruiting body of Clitocybe nebularis, which led to the isolation of nebularine, phenylacetic acid, purine, uridine, adenine, uracil, benzoic acid, and mannitol. Nebularine showed mild antifungal activity against Magnaphorthe grisea and Trichophyton mentagrophytes, and phenylacetic acid potently inhibited the growth of Pythium ultiumand displayed moderate antifungal activity against Magnaphorthe grisea, Botrytis cinerea, and Trichophyton mentagrophytes. The other isolated compounds showed no antimicrobial activity. PMID- 23990745 TI - Degradation of three aromatic dyes by white rot fungi and the production of ligninolytic enzymes. AB - This study was conducted to evaluate the degradation of aromatic dyes and the production of ligninolytic enzymes by 10 white rot fungi. The results of this study revealed that Pycnoporus cinnabarinus, Pleurotus pulmonarius, Ganoderma lucidum, Trametes suaveolens, Stereum ostrea and Fomes fomentarius have the ability to efficiently degrade congo red on solid media. However, malachite green inhibited the mycelial growth of these organisms. Therefore, they did not effectively decolorize malachite green on solid media. However, P. cinnabarinus and P. pulmonarius were able to effectively decolorize malachite green on solid media. T. suaveolens and F. rosea decolorized methylene blue more effectively than any of the other fungi evaluated in this study. In liquid culture, G. lucidum, P. cinnabarinus, Naematoloma fasciculare and Pycnoporus coccineus were found to have a greater ability to decolorize congo red. In addition, P. cinnabarinus, G. lucidum and T. suaveolens decolorized methylene blue in liquid media more effectively than any of the other organisms evaluated in this study. Only F. fomentarius was able to decolorize malachite green in liquid media, and its ability to do so was limited. To investigate the production of ligninolytic enzymes in media containing aromatic compounds, fungi were cultured in naphthalene supplemented liquid media. P. coccineus, Coriolus versicolor and P. cinnabarinus were found to produce a large amount of laccase when grown in medium that contained napthalene. PMID- 23990746 TI - Flavone Biotransformation by Aspergillus niger and the Characterization of Two Newly Formed Metabolites. AB - Aspergillus niger isolated from Allium sativum was used at large scale fermentation (150 mg flavone/200 ml medium) to obtain suitable amounts of the products, efficient for identification. Then spectral analysis (UV, IR, (1)H-NMR, (13)C-NMR) and mass spectrometry were performed for the two products, which contributed to the identification process. The metabolite (1) was identified as 2'-hydroxydihydrochalcone, and the metabolite (2) was identified as 2' hydroxyphenylmethylketone, which were more active than flavone itself. Antioxidant activities of the two isolated metabolites were tested compared with ascorbic acid. Antioxidant activity of metabolite (1) was recorded 64.58% which represented 79% of the antioxidant activity of ascorbic acid, and metabolite (2) was recorded 54.16% (67% of ascorbic acid activity). However, the antioxidant activity of flavone was recorded 37.50% which represented 46% of ascorbic acid activity. The transformed products of flavone have antimicrobial activity against Pseudomonas aeruginosa, Aspergillus flavus and Candida albicans, with MIC was recorded 250 ug/ml for metabolite (2) against all three organism and 500, 300, and 300 ug/ml for metabolite (1) against tested microorganisms (P. aeruginosa, Escherichia coli, Bacillus subtilis, and Klebsiella pneumonia, Fusarium moniliforme, A. flavus, Saccharomyces cerviceae, Kluveromyces lactis and C. albicans) at this order. PMID- 23990747 TI - Notes on species belonging to the genus coreomyces (laboulbeniales) collected from java island, indonesia. AB - Four species of Laboulbeniales collected from Java Island, Indonesia between August and September in 2006 are described. These species, which belong to the genus Coreomyces and were found on the family Corixidae of the order Hemiptera, were as follows; Coreomycus corixae Thaxter, Coreomyces micronectae Thaxter and Coreomyces orientalis Thaxter, which were found on Micronecta sedula Horvath, and Coreomyces recurvatus Thaxter, which was found on Micronecta sedula Horvath and Xenocorixa sp. C. corixae Thaxter and C. orientalis Thaxter were originally found on Micronecta, whereas C. recurvatus Thaxter was originally found on Xenocorixa. All species described herein are new to Java Island. The specimens were deposited in the Biological Herbarium, Division of Science Education, College of Education, Chosun University. PMID- 23990748 TI - Occurrence of Anthracnose on Chinese Mallow Caused by Colletotrichum malvarum. AB - Anthracnose symptoms were frequently observed on leaves, petioles, and stems of Chinese mallow grown in Namyangju, Korea, during a disease survey performed in November, 2007. The disease incidence was as high as 30% in the 12 greenhouses investigated. A total of 38 isolates of the Colletotrichum species were obtained from the anthracnose symptoms, and all the isolates were identified as Colletotrichum malvarum based on their morphological and culture characteristics. Three isolates of the fungus caused anthracnose symptoms on leaves and stems following artificial inoculation, which were similar to those observed during the greenhouse survey. In this study, mycological and pathological characteristics of C. malvarum identified as causing anthracnose of Chinese mallow were clarified. PMID- 23990749 TI - Biological reconstruction for sarcoma. PMID- 23990750 TI - A proposal for augmenting biological model construction with a semi-intelligent computational modeling assistant. AB - The translational challenge in biomedical research lies in the effective and efficient transfer of mechanistic knowledge from one biological context to another. Implicit in this process is the establishment of causality from correlation in the form of mechanistic hypotheses. Effectively addressing the translational challenge requires the use of automated methods, including the ability to computationally capture the dynamic aspect of putative hypotheses such that they can be evaluated in a high throughput fashion. Ontologies provide structure and organization to biomedical knowledge; converting these representations into executable models/simulations is the next necessary step. Researchers need the ability to map their conceptual models into a model specification that can be transformed into an executable simulation program. We suggest this mapping process, which approximates certain steps in the development of a computational model, can be expressed as a set of logical rules, and a semi intelligent computational agent, the Computational Modeling Assistant (CMA), can perform reasoning to develop a plan to achieve the construction of an executable model. Presented herein is a description and implementation for a model construction reasoning process between biomedical and simulation ontologies that is performed by the CMA to produce the specification of an executable model that can be used for dynamic knowledge representation. PMID- 23990751 TI - Size-driven ferroelectric-paraelectric phase transition in TGS nanocomposites. AB - Dielectric properties of porous glass nanocomposites with TGS crystals embedded into six porous matrices with average pore size from 5 to 312 nm were investigated in the temperature range from 280 to 380 K at selected frequencies. The results are discussed based on the effect of the particle size on the phase transition temperature of TGS nanocomposites. Temperature-size phase diagram of TGS composites was derived. Non-monotonic character of the temperature-driven phase transition (Tp) with the decreasing particle size was determined. The nature of the Tp variation can be ascribed to the size-effect theoretically predicted by Zhong et al. (Phys Rev B 50:698-703, 1994). PMID- 23990752 TI - Controllable functionalization and wettability transition of graphene-based films by an atomic oxygen strategy. AB - Though chemical modification of graphene based on Hummers method has been most widely used to tailor its properties and interfacial characteristics, a method which could achieve definitive and controllable groups and properties is still highly required. Here, we demonstrate a high-vacuum oxidation strategy by atomic oxygen (AO) and investigate the AO induced functionalization and wettability transition in films made from basal-defect- and oxide-free graphene dispersions. These graphene-based films are neither graphene nor graphite, but graphene blocks constituted by numerous randomly stacked graphene flakes. It is found that AO induced functionalization of these films through the formation of epoxy groups, sp3 configuration, ether, and double and triple C-O groups. The films turn to be hydrophilic after exposed to AO. The contact angle increases with AO exposure time. This phenomenon is attributed to the lower surface roughness induced by collision and/or edge erosion of energetic ions to the film surface and is further explained by the Wenzel model. The demonstrated strategy can overcome limitations of Hummers method, provide possibility to gain functionalization and wettability transition in liquid-phase exfoliated basal-defect- and oxide-free graphene in the dry environment, and may extend the study and application of this material in spacecraft in low earth orbit. PMID- 23990753 TI - Cytotoxicity evaluation of carbon-encapsulated iron nanoparticles in melanoma cells and dermal fibroblasts. AB - Carbon-encapsulated iron nanoparticles (CEINs) are emerging as promising biomedical tools due to their unique physicochemical properties. In this study, the cytotoxic effect of CEINs (the mean diameter distribution ranges 46-56 nm) has been explored by MTT, LDH leakage, Calcein-AM/propidium iodide (PI) and Annexin V-FITC/PI assays in human melanoma (HTB-140), mouse melanoma (B16-F10) cells, and human dermal fibroblasts (HDFs). The results demonstrated that CEINs produce mitochondrial and cell membrane cytotoxicities in a dose (0.0001-100 MUg/ml)-dependent manner. Moreover, the studies elucidated some differences in cytotoxic effects between CEINs used as raw and purified materials composing of the carbon surface with acidic groups. Experiments showed that HTB-140 cells are more sensitive to prone early apoptotic events due to raw CEINs as compared to B16-F10 or HDF cells, respectively. Taken together, these results suggest that the amount of CEINs administered to cells and the composition of CEINs containing different amounts of iron as well as the carbon surface modification type is critical determinant of cytotoxic responses in both normal and cancer (melanoma) cells. PMID- 23990754 TI - Solid-state MAS NMR, TEM, and TGA studies of structural hydroxyl groups and water in nanocrystalline apatites prepared by dry milling. AB - A series of nanocrystalline calcium hydroxyapatites was prepared by dry milling and characterized using proton and 31P MAS NMR, TEM, and TGA methods. The samples contained stubby rod-shaped crystals, which length and width varied in the 130-30 and 95-20 nm ranges, respectively. It was confirmed that concentration of structural hydroxyl groups in nanocrystalline apatites decreases with the decreasing crystal size. In the series of the studied apatites, the decrease was from 86 to ca. 50 % in reference to stoichiometric apatite. Water was found in the surface hydrated layer and in the c-axis channels, in which compartments existed as adsorbed and structural, respectively. Molecules of the adsorbed water were capable of moving from the crystal surface into the lattice c-axis channels of apatite. This process introduced considerable structural disorder within and around those channels and reduced the content of the structural hydroxyl groups, particularly in the region underneath the apatite crystal surface. PMID- 23990755 TI - A theoretical and empirical framework for constructing culture-specific stigma instruments for Chile. AB - Different cultural contexts contribute to substantial variation in the stigma faced by people with psychosis globally. We propose a new formulation of how culture affects stigma to create psychometrically-validated tools to assess stigma's culture-specific effects. We propose to construct culture-specific stigma measures for the Chilean context via: 1) open-ended administration of 'universal' stigma scales to a sample of individuals with psychosis, relatives, and community respondents; 2) qualitative analyses to identify how culture shapes stigma and to derive initial 'culture-specific' stigma items; 3) construction and pilot-testing of final 'culture-specific' stigma measures; 4) initial psychometric validation among a sample of individuals with psychosis. We identify initial hypotheses for how stigma might threaten the capacities to participate in fundamental activities that 'matter most' in the Chilean context. These include mental illness stigma threatening the man's ability to protect the honor of the family, and the woman's ability to be a 'holy and pure' mother. Mental illness stigma may further endanger the ability of the family to uphold reciprocal obligations within their social network. Developing such measures promises to aid efforts to address culture-specific forms of stigma, and to facilitate implementation of community mental health services, in Chile and other Latin American contexts. PMID- 23990756 TI - The Interplay of Employment Uncertainty and Education in explaining Second Births in Europe. AB - This paper analyzes how labor market instability since the late 1980s in Europe mediated decisions to second births. In particular, it examines which are the dimensions of economic uncertainty that affect women with different educational backgrounds. First, employing time varying measures of aggregate market conditions for women in twelve European countries as well as micro-measures of each woman's labor market history, it shows that delays in second births are significant in countries with high unemployment, among women who are unemployed, particularly the least educated, and who have temporary jobs. Holding a very short contract is more critical than unemployment for college graduates. Second, using the 2006 Spanish Fertility Survey, it presents remarkably similar findings for Spain, the country with the most dramatic changes in both fertility and unemployment in the last decades: a high jobless rate and the widespread use of limited-duration contracts were correlated with a substantial postponement of second births. PMID- 23990757 TI - Classification with Incomplete Data Using Dirichlet Process Priors. AB - A non-parametric hierarchical Bayesian framework is developed for designing a classifier, based on a mixture of simple (linear) classifiers. Each simple classifier is termed a local "expert", and the number of experts and their construction are manifested via a Dirichlet process formulation. The simple form of the "experts" allows analytical handling of incomplete data. The model is extended to allow simultaneous design of classifiers on multiple data sets, termed multi-task learning, with this also performed non-parametrically via the Dirichlet process. Fast inference is performed using variational Bayesian (VB) analysis, and example results are presented for several data sets. We also perform inference via Gibbs sampling, to which we compare the VB results. PMID- 23990758 TI - Polder effects on sediment-to-soil conversion: water table, residual available water capacity, and salt stress interdependence. AB - The French Atlantic marshlands, reclaimed since the Middle Age, have been successively used for extensive grazing and more recently for cereal cultivation from 1970. The soils have acquired specific properties which have been induced by the successive reclaiming and drainage works and by the response of the clay dominant primary sediments, that is, structure, moisture, and salinity profiles. Based on the whole survey of the Marais Poitevin and Marais de Rochefort and in order to explain the mechanisms of marsh soil behavior, the work focuses on two typical spots: an undrained grassland since at least 1964 and a drained cereal cultivated field. The structure-hydromechanical profiles relationships have been established thanks to the clay matrix shrinkage curve. They are confronted to the hydraulic functioning including the fresh-to-salt water transfers and to the recording of tensiometer profiles. The CE1/5 profiles supply the water geochemical and geophysical data by their better accuracy. Associated to the available water capacity calculation they allow the representation of the parallel evolution of the residual available water capacity profiles and salinity profiles according to the plant growing and rooting from the mesophile systems of grassland to the hygrophile systems of drained fields. PMID- 23990759 TI - Genetic diversity analysis of sugarcane parents in Chinese breeding programmes using gSSR markers. AB - Sugarcane is the most important sugar and bioenergy crop in the world. The selection and combination of parents for crossing rely on an understanding of their genetic structures and molecular diversity. In the present study, 115 sugarcane genotypes used for parental crossing were genotyped based on five genomic simple sequence repeat marker (gSSR) loci and 88 polymorphic alleles of loci (100%) as detected by capillary electrophoresis. The values of genetic diversity parameters across the populations indicate that the genetic variation intrapopulation (90.5%) was much larger than that of interpopulation (9.5%). Cluster analysis revealed that there were three groups termed as groups I, II, and III within the 115 genotypes. The genotypes released by each breeding programme showed closer genetic relationships, except the YC series released by Hainan sugarcane breeding station. Using principle component analysis (PCA), the first and second principal components accounted for a cumulative 76% of the total variances, in which 43% were for common parents and 33% were for new parents, respectively. The knowledge obtained in this study should be useful to future breeding programs for increasing genetic diversity of sugarcane varieties and cultivars to meet the demand of sugarcane cultivation for sugar and bioenergy use. PMID- 23990760 TI - On the connection coefficients of the Chebyshev-Boubaker polynomials. AB - The Chebyshev-Boubaker polynomials are the orthogonal polynomials whose coefficient arrays are defined by ordinary Riordan arrays. Examples include the Chebyshev polynomials of the second kind and the Boubaker polynomials. We study the connection coefficients of this class of orthogonal polynomials, indicating how Riordan array techniques can lead to closed-form expressions for these connection coefficients as well as recurrence relations that define them. PMID- 23990761 TI - Estimating the optimal control of zoonotic visceral leishmaniasis by the use of a mathematical model. AB - We argue that the strategy of culling infected dogs is not the most efficient way to control zoonotic visceral leishmaniasis (ZVL) and that, in the presence of alternative control strategies with better potential results, official programs of compulsory culling adopted by some countries are inefficient and unethical. We base our arguments on a mathematical model for the study of control strategies against ZVL, which allows the comparison of the efficacies of 5, alternative strategies. We demonstrate that the culling program, previously questioned on both theoretical and practical grounds is the less effective control strategy. In addition, we show that vector control and the use of insecticide-impregnated dog collars are, by far, more efficient at reducing the prevalence of ZVL in humans. PMID- 23990762 TI - Exceptional values of meromorphic function on annulus. AB - The main purpose of this paper is to study the exceptional values of meromorphic function and its derivative on annulus. We also give some theorems and corollaries about exceptional values of meromorphic function on the annulus, which are the improvement of the previous results given by Chen and Wu. PMID- 23990763 TI - Clinical and Cognitive Insight in a Compensatory Cognitive Training Intervention. AB - The impact of limited insight is a crucial consideration in the treatment of individuals with psychiatric illness. In the context of psychosis, both clinical and cognitive insight have been described. This study aimed to evaluate the relationships between clinical and cognitive insight and neuropsychological functioning, psychiatric symptom severity, and everyday functioning in patients with a primary psychotic disorder participating in a compensatory cognitive training (CT) intervention. Sixty-nine individuals diagnosed with a primary psychotic disorder were randomized to a 3-month CT intervention or to standard pharmacotherapy, and they completed a comprehensive neuropsychological, clinical, and functional battery at baseline, 3 months, and 6 months. The CT intervention focused on habit formation and compensatory strategy learning in four domains: prospective memory, attention and vigilance, learning and memory, and problem solving/cognitive flexibility. At baseline, better clinical insight was significantly related to better executive functioning and less severe negative symptoms. There was no significant association between cognitive insight and cognitive functioning, symptom severity, or everyday functioning ability. The CT intervention did not have an effect on clinical or cognitive insight, but better cognitive insight prior to participation in CT significantly predicted decreased positive and depressive symptom severity posttreatment, and better clinical insight predicted improved self-reported quality of life. Although clinical insight is related to executive functioning, the correlates of cognitive insight remain elusive. Intact insight appears to be beneficial in ameliorating clinical symptomatology like positive symptoms and depression, rather than augmenting cognition. It may be valuable to develop brief interventions aimed at improving clinical and cognitive insight prior to other psychosocial rehabilitation in order to maximize the benefit of treatment. PMID- 23990764 TI - From principal component to direct coupling analysis of coevolution in proteins: low-eigenvalue modes are needed for structure prediction. AB - Various approaches have explored the covariation of residues in multiple-sequence alignments of homologous proteins to extract functional and structural information. Among those are principal component analysis (PCA), which identifies the most correlated groups of residues, and direct coupling analysis (DCA), a global inference method based on the maximum entropy principle, which aims at predicting residue-residue contacts. In this paper, inspired by the statistical physics of disordered systems, we introduce the Hopfield-Potts model to naturally interpolate between these two approaches. The Hopfield-Potts model allows us to identify relevant 'patterns' of residues from the knowledge of the eigenmodes and eigenvalues of the residue-residue correlation matrix. We show how the computation of such statistical patterns makes it possible to accurately predict residue-residue contacts with a much smaller number of parameters than DCA. This dimensional reduction allows us to avoid overfitting and to extract contact information from multiple-sequence alignments of reduced size. In addition, we show that low-eigenvalue correlation modes, discarded by PCA, are important to recover structural information: the corresponding patterns are highly localized, that is, they are concentrated in few sites, which we find to be in close contact in the three-dimensional protein fold. PMID- 23990765 TI - Stochasticity, bistability and the wisdom of crowds: a model for associative learning in genetic regulatory networks. AB - It is generally believed that associative memory in the brain depends on multistable synaptic dynamics, which enable the synapses to maintain their value for extended periods of time. However, multistable dynamics are not restricted to synapses. In particular, the dynamics of some genetic regulatory networks are multistable, raising the possibility that even single cells, in the absence of a nervous system, are capable of learning associations. Here we study a standard genetic regulatory network model with bistable elements and stochastic dynamics. We demonstrate that such a genetic regulatory network model is capable of learning multiple, general, overlapping associations. The capacity of the network, defined as the number of associations that can be simultaneously stored and retrieved, is proportional to the square root of the number of bistable elements in the genetic regulatory network. Moreover, we compute the capacity of a clonal population of cells, such as in a colony of bacteria or a tissue, to store associations. We show that even if the cells do not interact, the capacity of the population to store associations substantially exceeds that of a single cell and is proportional to the number of bistable elements. Thus, we show that even single cells are endowed with the computational power to learn associations, a power that is substantially enhanced when these cells form a population. PMID- 23990766 TI - Nucleosome free regions in yeast promoters result from competitive binding of transcription factors that interact with chromatin modifiers. AB - Because DNA packaging in nucleosomes modulates its accessibility to transcription factors (TFs), unraveling the causal determinants of nucleosome positioning is of great importance to understanding gene regulation. Although there is evidence that intrinsic sequence specificity contributes to nucleosome positioning, the extent to which other factors contribute to nucleosome positioning is currently highly debated. Here we obtained both in vivo and in vitro reference maps of positions that are either consistently covered or free of nucleosomes across multiple experimental data-sets in Saccharomyces cerevisiae. We then systematically quantified the contribution of TF binding to nucleosome positioning using a rigorous statistical mechanics model in which TFs compete with nucleosomes for binding DNA. Our results reconcile previous seemingly conflicting results on the determinants of nucleosome positioning and provide a quantitative explanation for the difference between in vivo and in vitro positioning. On a genome-wide scale, nucleosome positioning is dominated by the phasing of nucleosome arrays over gene bodies, and their positioning is mainly determined by the intrinsic sequence preferences of nucleosomes. In contrast, larger nucleosome free regions in promoters, which likely have a much more significant impact on gene expression, are determined mainly by TF binding. Interestingly, of the 158 yeast TFs included in our modeling, we find that only 10-20 significantly contribute to inducing nucleosome-free regions, and these TFs are highly enriched for having direct interactions with chromatin remodelers. Together our results imply that nucleosome free regions in yeast promoters results from the binding of a specific class of TFs that recruit chromatin remodelers. PMID- 23990767 TI - A self-directed method for cell-type identification and separation of gene expression microarrays. AB - Gene expression analysis is generally performed on heterogeneous tissue samples consisting of multiple cell types. Current methods developed to separate heterogeneous gene expression rely on prior knowledge of the cell-type composition and/or signatures--these are not available in most public datasets. We present a novel method to identify the cell-type composition, signatures and proportions per sample without need for a-priori information. The method was successfully tested on controlled and semi-controlled datasets and performed as accurately as current methods that do require additional information. As such, this method enables the analysis of cell-type specific gene expression using existing large pools of publically available microarray datasets. PMID- 23990768 TI - On the importance of polar interactions for complexes containing intrinsically disordered proteins. AB - There is a growing recognition for the importance of proteins with large intrinsically disordered (ID) segments in cell signaling and regulation. ID segments in these proteins often harbor regions that mediate molecular recognition. Coupled folding and binding of the recognition regions has been proposed to confer high specificity to interactions involving ID segments. However, researchers recently questioned the origin of the interaction specificity of ID proteins because of the overrepresentation of hydrophobic residues in their interaction interfaces. Here, we focused on the role of polar and charged residues in interactions mediated by ID segments. Making use of the extended nature of most ID segments when in complex with globular proteins, we first identified large numbers of complexes between globular proteins and ID segments by using radius-of-gyration-based selection criteria. Consistent with previous studies, we found the interfaces of these complexes to be enriched in hydrophobic residues, and that these residues contribute significantly to the stability of the interaction interface. However, our analyses also show that polar interactions play a larger role in these complexes than in structured protein complexes. Computational alanine scanning and salt-bridge analysis indicate that interfaces in ID complexes are highly complementary with respect to electrostatics, more so than interfaces of globular proteins. Follow-up calculations of the electrostatic contributions to the free energy of binding uncovered significantly stronger Coulombic interactions in complexes harbouring ID segments than in structured protein complexes. However, they are counter balanced by even higher polar-desolvation penalties. We propose that polar interactions are a key contributing factor to the observed high specificity of ID segment-mediated interactions. PMID- 23990769 TI - Gause's principle and the effect of resource partitioning on the dynamical coexistence of replicating templates. AB - Models of competitive template replication, although basic for replicator dynamics and primordial evolution, have not yet taken different sequences explicitly into account, neither have they analyzed the effect of resource partitioning (feeding on different resources) on coexistence. Here we show by analytical and numerical calculations that Gause's principle of competitive exclusion holds for template replicators if resources (nucleotides) affect growth linearly and coexistence is at fixed point attractors. Cases of complementary or homologous pairing between building blocks with parallel or antiparallel strands show no deviation from the rule that the nucleotide compositions of stably coexisting species must be different and there cannot be more coexisting replicator species than nucleotide types. Besides this overlooked mechanism of template coexistence we show also that interesting sequence effects prevail as parts of sequences that are copied earlier affect coexistence more strongly due to the higher concentration of the corresponding replication intermediates. Template and copy always count as one species due their constraint of strict stoichiometric coupling. Stability of fixed-point coexistence tends to decrease with the length of sequences, although this effect is unlikely to be detrimental for sequences below 100 nucleotides. In sum, resource partitioning (niche differentiation) is the default form of competitive coexistence for replicating templates feeding on a cocktail of different nucleotides, as it may have been the case in the RNA world. Our analysis of different pairing and strand orientation schemes is relevant for artificial and potentially astrobiological genetics. PMID- 23990772 TI - International Society for Computational Biology welcomes its newest class of fellows. PMID- 23990771 TI - Transcriptional regulation of lineage commitment--a stochastic model of cell fate decisions. AB - Molecular mechanisms employed by individual multipotent cells at the point of lineage commitment remain largely uncharacterized. Current paradigms span from instructive to noise-driven mechanisms. Of considerable interest is also whether commitment involves a limited set of genes or the entire transcriptional program, and to what extent gene expression configures multiple trajectories into commitment. Importantly, the transient nature of the commitment transition confounds the experimental capture of committing cells. We develop a computational framework that simulates stochastic commitment events, and affords mechanistic exploration of the fate transition. We use a combined modeling approach guided by gene expression classifier methods that infers a time-series of stochastic commitment events from experimental growth characteristics and gene expression profiling of individual hematopoietic cells captured immediately before and after commitment. We define putative regulators of commitment and probabilistic rules of transition through machine learning methods, and employ clustering and correlation analyses to interrogate gene regulatory interactions in multipotent cells. Against this background, we develop a Monte Carlo time series stochastic model of transcription where the parameters governing promoter status, mRNA production and mRNA decay in multipotent cells are fitted to experimental static gene expression distributions. Monte Carlo time is converted to physical time using cell culture kinetic data. Probability of commitment in time is a function of gene expression as defined by a logistic regression model obtained from experimental single-cell expression data. Our approach should be applicable to similar differentiating systems where single cell data is available. Within our system, we identify robust model solutions for the multipotent population within physiologically reasonable values and explore model predictions with regard to molecular scenarios of entry into commitment. The model suggests distinct dependencies of different commitment-associated genes on mRNA dynamics and promoter activity, which globally influence the probability of lineage commitment. PMID- 23990770 TI - Causes and consequences of hyperexcitation in central clock neurons. AB - Hyperexcited states, including depolarization block and depolarized low amplitude membrane oscillations (DLAMOs), have been observed in neurons of the suprachiasmatic nuclei (SCN), the site of the central mammalian circadian (~24 hour) clock. The causes and consequences of this hyperexcitation have not yet been determined. Here, we explore how individual ionic currents contribute to these hyperexcited states, and how hyperexcitation can then influence molecular circadian timekeeping within SCN neurons. We developed a mathematical model of the electrical activity of SCN neurons, and experimentally verified its prediction that DLAMOs depend on post-synaptic L-type calcium current. The model predicts that hyperexcited states cause high intracellular calcium concentrations, which could trigger transcription of clock genes. The model also predicts that circadian control of certain ionic currents can induce hyperexcited states. Putting it all together into an integrative model, we show how membrane potential and calcium concentration provide a fast feedback that can enhance rhythmicity of the intracellular circadian clock. This work puts forward a novel role for electrical activity in circadian timekeeping, and suggests that hyperexcited states provide a general mechanism for linking membrane electrical dynamics to transcription activation in the nucleus. PMID- 23990773 TI - Predicting disease risk using bootstrap ranking and classification algorithms. AB - Genome-wide association studies (GWAS) are widely used to search for genetic loci that underlie human disease. Another goal is to predict disease risk for different individuals given their genetic sequence. Such predictions could either be used as a "black box" in order to promote changes in life-style and screening for early diagnosis, or as a model that can be studied to better understand the mechanism of the disease. Current methods for risk prediction typically rank single nucleotide polymorphisms (SNPs) by the p-value of their association with the disease, and use the top-associated SNPs as input to a classification algorithm. However, the predictive power of such methods is relatively poor. To improve the predictive power, we devised BootRank, which uses bootstrapping in order to obtain a robust prioritization of SNPs for use in predictive models. We show that BootRank improves the ability to predict disease risk of unseen individuals in the Wellcome Trust Case Control Consortium (WTCCC) data and results in a more robust set of SNPs and a larger number of enriched pathways being associated with the different diseases. Finally, we show that combining BootRank with seven different classification algorithms improves performance compared to previous studies that used the WTCCC data. Notably, diseases for which BootRank results in the largest improvements were recently shown to have more heritability than previously thought, likely due to contributions from variants with low minimum allele frequency (MAF), suggesting that BootRank can be beneficial in cases where SNPs affecting the disease are poorly tagged or have low MAF. Overall, our results show that improving disease risk prediction from genotypic information may be a tangible goal, with potential implications for personalized disease screening and treatment. PMID- 23990774 TI - Model-based analysis of HER activation in cells co-expressing EGFR, HER2 and HER3. AB - The HER/ErbB family of receptor tyrosine kinases drives critical responses in normal physiology and cancer, and the expression levels of the various HER receptors are critical determinants of clinical outcomes. HER activation is driven by the formation of various dimer complexes between members of this receptor family. The HER dimer types can have differential effects on downstream signaling and phenotypic outcomes. We constructed an integrated mathematical model of HER activation, and trafficking to quantitatively link receptor expression levels to dimerization and activation. We parameterized the model with a comprehensive set of HER phosphorylation and abundance data collected in a panel of human mammary epithelial cells expressing varying levels of EGFR/HER1, HER2 and HER3. Although parameter estimation yielded multiple solutions, predictions for dimer phosphorylation were in agreement with each other. We validated the model using experiments where pertuzumab was used to block HER2 dimerization. We used the model to predict HER dimerization and activation patterns in a panel of human mammary epithelial cells lines with known HER expression levels in response to stimulations with ligands EGF and HRG. Simulations over the range of expression levels seen in various cell lines indicate that: i) EGFR phosphorylation is driven by HER1-HER1 and HER1-HER2 dimers, and not HER1-HER3 dimers, ii) HER1-HER2 and HER2-HER3 dimers both contribute significantly to HER2 activation with the EGFR expression level determining the relative importance of these species, and iii) the HER2-HER3 dimer is largely responsible for HER3 activation. The model can be used to predict phosphorylated dimer levels for any given HER expression profile. This information in turn can be used to quantify the potencies of the various HER dimers, and can potentially inform personalized therapeutic approaches. PMID- 23990775 TI - Determinants of beat-to-beat variability of repolarization duration in the canine ventricular myocyte: a computational analysis. AB - Beat-to-beat variability of repolarization duration (BVR) is an intrinsic characteristic of cardiac function and a better marker of proarrhythmia than repolarization prolongation alone. The ionic mechanisms underlying baseline BVR in physiological conditions, its rate dependence, and the factors contributing to increased BVR in pathologies remain incompletely understood. Here, we employed computer modeling to provide novel insights into the subcellular mechanisms of BVR under physiological conditions and during simulated drug-induced repolarization prolongation, mimicking long-QT syndromes type 1, 2, and 3. We developed stochastic implementations of 13 major ionic currents and fluxes in a model of canine ventricular-myocyte electrophysiology. Combined stochastic gating of these components resulted in short- and long-term variability, consistent with experimental data from isolated canine ventricular myocytes. The model indicated that the magnitude of stochastic fluctuations is rate dependent due to the rate dependence of action-potential (AP) duration (APD). This process (the "active" component) and the intrinsic nonlinear relationship between membrane current and APD ("intrinsic component") contribute to the rate dependence of BVR. We identified a major role in physiological BVR for stochastic gating of the persistent Na(+) current (INa) and rapidly activating delayed-rectifier K(+) current (IKr). Inhibition of IKr or augmentation of INa significantly increased BVR, whereas subsequent beta-adrenergic receptor stimulation reduced it, similar to experimental findings in isolated myocytes. In contrast, beta-adrenergic stimulation increased BVR in simulated long-QT syndrome type 1. In addition to stochastic channel gating, AP morphology, APD, and beat-to-beat variations in Ca(2+) were found to modulate single-cell BVR. Cell-to-cell coupling decreased BVR and this was more pronounced when a model cell with increased BVR was coupled to a model cell with normal BVR. In conclusion, our results provide new insights into the ionic mechanisms underlying BVR and suggest that BVR reflects multiple potentially proarrhythmic parameters, including increased ion-channel stochasticity, prolonged APD, and abnormal Ca(2+) handling. PMID- 23990777 TI - Asparagine repeats in Plasmodium falciparum proteins: good for nothing? PMID- 23990778 TI - Host immune response to intestinal amebiasis. PMID- 23990779 TI - Kaposi's sarcoma-associated herpesvirus K-Rta exhibits SUMO-targeting ubiquitin ligase (STUbL) like activity and is essential for viral reactivation. AB - The small ubiquitin-like modifier (SUMO) is a protein that regulates a wide variety of cellular processes by covalent attachment of SUMO moieties to a diverse array of target proteins. Sumoylation also plays an important role in the replication of many viruses. Previously, we showed that Kaposi's sarcoma associated herpesvirus (KSHV) encodes a SUMO-ligase, K-bZIP, which catalyzes sumoylation of host and viral proteins. We report here that this virus also encodes a gene that functions as a SUMO-targeting ubiquitin-ligase (STUbL) which preferentially targets sumoylated proteins for degradation. K-Rta, the major transcriptional factor which turns on the entire lytic cycle, was recently found to have ubiquitin ligase activity toward a selected set of substrates. We show in this study that K-Rta contains multiple SIMs (SUMO interacting motif) and binds SUMOs with higher affinity toward SUMO-multimers. Like RNF4, the prototypic cellular STUbL, K-Rta degrades SUMO-2/3 and SUMO-2/3 modified proteins, including promyelocytic leukemia (PML) and K-bZIP. PML-NBs (nuclear bodies) or ND-10 are storage warehouses for sumoylated proteins, which negatively regulate herpesvirus infection, as part of the intrinsic immune response. Herpesviruses have evolved different ways to degrade or disperse PML bodies, and KSHV utilizes K-Rta to inhibit PML-NBs formation. This process depends on K-Rta's ability to bind SUMO, as a K-Rta SIM mutant does not effectively degrade PML. Mutations in the K-Rta Ring finger-like domain or SIM significantly inhibited K-Rta transactivation activity in reporter assays and in the course of viral reactivation. Finally, KSHV with a mutation in the Ring finger-like domain or SIM of K-Rta replicates poorly in culture, indicating that reducing SUMO-conjugates in host cells is important for viral replication. To our knowledge, this is the first virus which encodes both a SUMO ligase and a SUMO-targeting ubiquitin ligase that together may generate unique gene regulatory programs. PMID- 23990780 TI - Nuclear hormone receptor regulation of microRNAs controls innate immune responses in C. elegans. AB - Nuclear hormone receptors respond to small molecules such as retinoids or steroids and regulate development. Signaling in the conserved p38/PMK-1 MAP kinase pathway regulates innate immunity. In this study, we show that the Caenorhabditis elegans nuclear receptor DAF-12 negatively regulates the defense against pathogens via the downstream let-7 family of microRNAs, which directly target SKN-1, a gene downstream of PMK-1. These findings identify nuclear hormone receptors as components of innate immunity that crosstalk with the p38/PMK-1 MAP kinase pathway. PMID- 23990781 TI - The protein kinase double-stranded RNA-dependent (PKR) enhances protection against disease cause by a non-viral pathogen. AB - PKR is well characterized for its function in antiviral immunity. Using Toxoplasma gondii, we examined if PKR promotes resistance to disease caused by a non-viral pathogen. PKR(-/-) mice infected with T. gondii exhibited higher parasite load and worsened histopathology in the eye and brain compared to wild type controls. Susceptibility to toxoplasmosis was not due to defective expression of IFN-gamma, TNF-alpha, NOS2 or IL-6 in the retina and brain, differences in IL-10 expression in these organs or to impaired induction of T. gondii-reactive T cells. While macrophages/microglia with defective PKR signaling exhibited unimpaired anti-T. gondii activity in response to IFN-gamma/TNF-alpha, these cells were unable to kill the parasite in response to CD40 stimulation. The TRAF6 binding site of CD40, but not the TRAF2,3 binding sites, was required for PKR phosphorylation in response to CD40 ligation in macrophages. TRAF6 co immunoprecipitated with PKR upon CD40 ligation. TRAF6-PKR interaction appeared to be indirect, since TRAF6 co-immunoprecipitated with TRAF2 and TRAF2 co immunoprecipitated with PKR, and deficiency of TRAF2 inhibited TRAF6-PKR co immunoprecipitation as well as PKR phosphorylation induced by CD40 ligation. PKR was required for stimulation of autophagy, accumulation the autophagy molecule LC3 around the parasite, vacuole-lysosomal fusion and killing of T. gondii in CD40-activated macrophages and microglia. Thus, our findings identified PKR as a mediator of anti-microbial activity and promoter of protection against disease caused by a non-viral pathogen, revealed that PKR is activated by CD40 via TRAF6 and TRAF2, and positioned PKR as a link between CD40-TRAF signaling and stimulation of the autophagy pathway. PMID- 23990782 TI - The Merkel cell polyomavirus minor capsid protein. AB - The surface of polyomavirus virions is composed of pentameric knobs of the major capsid protein, VP1. In previously studied polyomavirus species, such as SV40, two interior capsid proteins, VP2 and VP3, emerge from the virion to play important roles during the infectious entry process. Translation of the VP3 protein initiates at a highly conserved Met-Ala-Leu motif within the VP2 open reading frame. Phylogenetic analyses indicate that Merkel cell polyomavirus (MCV or MCPyV) is a member of a divergent clade of polyomaviruses that lack the conserved VP3 N-terminal motif. Consistent with this observation, we show that VP3 is not detectable in MCV-infected cells, VP3 is not found in native MCV virions, and mutation of possible alternative VP3-initiating methionine codons did not significantly affect MCV infectivity in culture. In contrast, VP2 knockout resulted in a >100-fold decrease in native MCV infectivity, despite normal virion assembly, viral DNA packaging, and cell attachment. Although pseudovirus-based experiments confirmed that VP2 plays an essential role for infection of some cell lines, other cell lines were readily transduced by pseudovirions lacking VP2. In cell lines where VP2 was needed for efficient infectious entry, the presence of a conserved myristoyl modification on the N terminus of VP2 was important for its function. The results show that a single minor capsid protein, VP2, facilitates a post-attachment stage of MCV infectious entry into some, but not all, cell types. PMID- 23990783 TI - Replication vesicles are load- and choke-points in the hepatitis C virus lifecycle. AB - Hepatitis C virus (HCV) infection develops into chronicity in 80% of all patients, characterized by persistent low-level replication. To understand how the virus establishes its tightly controlled intracellular RNA replication cycle, we developed the first detailed mathematical model of the initial dynamic phase of the intracellular HCV RNA replication. We therefore quantitatively measured viral RNA and protein translation upon synchronous delivery of viral genomes to host cells, and thoroughly validated the model using additional, independent experiments. Model analysis was used to predict the efficacy of different classes of inhibitors and identified sensitive substeps of replication that could be targeted by current and future therapeutics. A protective replication compartment proved to be essential for sustained RNA replication, balancing translation versus replication and thus effectively limiting RNA amplification. The model predicts that host factors involved in the formation of this compartment determine cellular permissiveness to HCV replication. In gene expression profiling, we identified several key processes potentially determining cellular HCV replication efficiency. PMID- 23990784 TI - Crystal structure of vaccinia viral A27 protein reveals a novel structure critical for its function and complex formation with A26 protein. AB - Vaccinia virus envelope protein A27 has multiple functions and is conserved in the Orthopoxvirus genus of the poxvirus family. A27 protein binds to cell surface heparan sulfate, provides an anchor for A26 protein packaging into mature virions, and is essential for egress of mature virus (MV) from infected cells. Here, we crystallized and determined the structure of a truncated form of A27 containing amino acids 21-84, C71/72A (tA27) at 2.2 A resolution. tA27 protein uses the N-terminal region interface (NTR) to form an unexpected trimeric assembly as the basic unit, which contains two parallel alpha-helices and one unusual antiparallel alpha-helix; in a serpentine way, two trimers stack with each other to form a hexamer using the C-terminal region interface (CTR). Recombinant tA27 protein forms oligomers in a concentration-dependent manner in vitro in gel filtration. Analytical ultracentrifugation and multi-angle light scattering revealed that tA27 dimerized in solution and that Leu47, Leu51, and Leu54 at the NTR and Ile68, Asn75, and Leu82 at the CTR are responsible for tA27 self-assembly in vitro. Finally, we constructed recombinant vaccinia viruses expressing full length mutant A27 protein defective in either NTR, CTR, or both interactions; the results demonstrated that wild type A27 dimer/trimer formation was impaired in NTR and CTR mutant viruses, resulting in small plaques that are defective in MV egress. Furthermore, the ability of A27 protein to form disulfide linked protein complexes with A26 protein was partially or completely interrupted by NTR and CTR mutations, resulting in mature virion progeny with increased plasma membrane fusion activity upon cell entry. Together, these results demonstrate that A27 protein trimer structure is critical for MV egress and membrane fusion modulation. Because A27 is a neutralizing target, structural information will aid the development of inhibitors to block A27 self-assembly or complex formation against vaccinia virus infection. PMID- 23990785 TI - Phosphorylation of Calcineurin at a novel serine-proline rich region orchestrates hyphal growth and virulence in Aspergillus fumigatus. AB - The fungus Aspergillus fumigatus is a leading infectious killer in immunocompromised patients. Calcineurin, a calmodulin (CaM)-dependent protein phosphatase comprised of calcineurin A (CnaA) and calcineurin B (CnaB) subunits, localizes at the hyphal tips and septa to direct A. fumigatus invasion and virulence. Here we identified a novel serine-proline rich region (SPRR) located between two conserved CnaA domains, the CnaB-binding helix and the CaM-binding domain, that is evolutionarily conserved and unique to filamentous fungi and also completely absent in human calcineurin. Phosphopeptide enrichment and tandem mass spectrometry revealed the phosphorylation of A. fumigatus CnaA in vivo at four clustered serine residues (S406, S408, S410 and S413) in the SPRR. Mutation of the SPRR serine residues to block phosphorylation led to significant hyphal growth and virulence defects, indicating the requirement of calcineurin phosphorylation at the SPRR for its activity and function. Complementation analyses of the A. fumigatus DeltacnaA strain with cnaA homologs from the pathogenic basidiomycete Cryptococcus neoformans, the pathogenic zygomycete Mucor circinelloides, the closely related filamentous fungi Neurospora crassa, and the plant pathogen Magnaporthe grisea, revealed filamentous fungal-specific phosphorylation of CnaA in the SPRR and SPRR homology-dependent restoration of hyphal growth. Surprisingly, circular dichroism studies revealed that, despite proximity to the CaM-binding domain of CnaA, phosphorylation of the SPRR does not alter protein folding following CaM binding. Furthermore, mutational analyses in the catalytic domain, CnaB-binding helix, and the CaM-binding domains revealed that while the conserved PxIxIT substrate binding motif in CnaA is indispensable for septal localization, CaM is required for its function at the hyphal septum but not for septal localization. We defined an evolutionarily conserved novel mode of calcineurin regulation by phosphorylation in filamentous fungi in a region absent in humans. These findings suggest the possibility of harnessing this unique SPRR for innovative antifungal drug design to combat invasive aspergillosis. PMID- 23990786 TI - Determinants of GPI-PLC localisation to the flagellum and access to GPI-anchored substrates in trypanosomes. AB - In Trypanosoma brucei, glycosylphosphatidylinositol phospholipase C (GPI-PLC) is a virulence factor that releases variant surface glycoprotein (VSG) from dying cells. In live cells, GPI-PLC is localised to the plasma membrane where it is concentrated on the flagellar membrane, so activity or access must be tightly regulated as very little VSG is shed. Little is known about regulation except that acylation within a short internal motif containing three cysteines is necessary for GPI-PLC to access VSG in dying cells. Here, GPI-PLC mutants have been analysed both for subcellular localisation and for the ability to release VSG from dying cells. Two sequence determinants necessary for concentration on the flagellar membrane were identified. First, all three cysteines are required for full concentration on the flagellar membrane. Mutants with two cysteines localise predominantly to the plasma membrane but lose some of their flagellar concentration, while mutants with one cysteine are mainly localised to membranes between the nucleus and flagellar pocket. Second, a proline residue close to the C-terminus, and distant from the acylated cysteines, is necessary for concentration on the flagellar membrane. The localisation of GPI-PLC to the plasma but not flagellar membrane is necessary for access to the VSG in dying cells. Cellular structures necessary for concentration on the flagellar membrane were identified by depletion of components. Disruption of the flagellar pocket collar caused loss of concentration whereas detachment of the flagellum from the cell body after disruption of the flagellar attachment zone did not. Thus, targeting to the flagellar membrane requires: a titratable level of acylation, a motif including a proline, and a functional flagellar pocket. These results provide an insight into how the segregation of flagellar membrane proteins from those present in the flagellar pocket and cell body membranes is achieved. PMID- 23990787 TI - Aspergillus galactosaminogalactan mediates adherence to host constituents and conceals hyphal beta-glucan from the immune system. AB - Aspergillus fumigatus is the most common cause of invasive mold disease in humans. The mechanisms underlying the adherence of this mold to host cells and macromolecules have remained elusive. Using mutants with different adhesive properties and comparative transcriptomics, we discovered that the gene uge3, encoding a fungal epimerase, is required for adherence through mediating the synthesis of galactosaminogalactan. Galactosaminogalactan functions as the dominant adhesin of A. fumigatus and mediates adherence to plastic, fibronectin, and epithelial cells. In addition, galactosaminogalactan suppresses host inflammatory responses in vitro and in vivo, in part through masking cell wall beta-glucans from recognition by dectin-1. Finally, galactosaminogalactan is essential for full virulence in two murine models of invasive aspergillosis. Collectively these data establish a role for galactosaminogalactan as a pivotal bifunctional virulence factor in the pathogenesis of invasive aspergillosis. PMID- 23990788 TI - X-box binding protein 1 (XBP1s) is a critical determinant of Pseudomonas aeruginosa homoserine lactone-mediated apoptosis. AB - Pseudomonas aeruginosa infections are associated with high mortality rates and occur in diverse conditions including pneumonias, cystic fibrosis and neutropenia. Quorum sensing, mediated by small molecules including N-(3-oxo dodecanoyl) homoserine lactone (C12), regulates P. aeruginosa growth and virulence. In addition, host cell recognition of C12 initiates multiple signalling responses including cell death. To gain insight into mechanisms of C12 mediated cytotoxicity, we studied the role of endoplasmic reticulum stress in host cell responses to C12. Dramatic protection against C12-mediated cell death was observed in cells that do not produce the X-box binding protein 1 transcription factor (XBP1s). The leucine zipper and transcriptional activation motifs of XBP1s were sufficient to restore C12-induced caspase activation in XBP1s-deficient cells, although this polypeptide was not transcriptionally active. The XBP1s polypeptide also regulated caspase activation in cells stimulated with N-(3-oxo-tetradecanoyl) homoserine lactone (C14), produced by Yersinia enterolitica and Burkholderia pseudomallei, and enhanced homoserine lactone-mediated caspase activation in the presence of endogenous XBP1s. In C12 tolerant cells, responses to C12 including phosphorylation of p38 MAPK and eukaryotic initiation factor 2alpha were conserved, suggesting that C12 cytotoxicity is not heavily dependent on these pathways. In summary, this study reveals a novel and unconventional role for XBP1s in regulating host cell cytotoxic responses to bacterial acyl homoserine lactones. PMID- 23990789 TI - TRIM5 alpha drives SIVsmm evolution in rhesus macaques. AB - The antagonistic interaction with host restriction proteins is a major driver of evolutionary change for viruses. We previously reported that polymorphisms of the TRIM5alpha B30.2/SPRY domain impacted the level of SIVsmm viremia in rhesus macaques. Viremia in macaques homozygous for the non-restrictive TRIM5alpha allele TRIM5(Q) was significantly higher than in macaques expressing two restrictive TRIM5alpha alleles TRIM5(TFP/TFP) or TRIM5(Cyp/TFP). Using this model, we observed that despite an early impact on viremia, SIVsmm overcame TRIM5alpha restriction at later stages of infection and that increasing viremia was associated with specific amino acid substitutions in capsid. Two amino acid substitutions (P37S and R98S) in the capsid region were associated with escape from TRIM5(TFP) restriction and substitutions in the CypA binding-loop (GPLPA87 91) in capsid were associated with escape from TRIM5(Cyp). Introduction of these mutations into the original SIVsmE543 clone not only resulted in escape from TRIM5alpha restriction in vitro but the P37S and R98S substitutions improved virus fitness in macaques with homozygous restrictive TRIM(TFP) alleles in vivo. Similar substitutions were observed in other SIVsmm strains following transmission and passage in macaques, collectively providing direct evidence that TRIM5alpha exerts selective pressure on the cross-species transmission of SIV in primates. PMID- 23990790 TI - The secreted antifungal protein thionin 2.4 in Arabidopsis thaliana suppresses the toxicity of a fungal fruit body lectin from Fusarium graminearum. AB - Plants possess active defense systems and can protect themselves from pathogenic invasion by secretion of a variety of small antimicrobial or antifungal proteins such as thionins. The antibacterial and antifungal properties of thionins are derived from their ability to induce open pore formation on cell membranes of phytopathogens, resulting in release of potassium and calcium ions from the cell. Wheat thionin also accumulates in the cell walls of Fusarium-inoculated plants, suggesting that it may have a role in blocking pathogen infection at the plant cell walls. Here we developed an anti-thionin 2.4 (Thi2.4) antibody and used it to show that Thi2.4 is localized in the cell walls of Arabidopsis and cell membranes of F. graminearum, when flowers are inoculated with F. graminearum. The Thi2.4 protein had an antifungal effect on F. graminearum. Next, we purified the Thi2.4 protein, conjugated it with glutathione-S-transferase (GST) and coupled the proteins to an NHS-activated column. Total protein from F. graminearum was applied to GST-Thi2.4 or Thi2.4-binding columns, and the fungal fruit body lectin (FFBL) of F. graminearum was identified as a Thi2.4-interacting protein. This interaction was confirmed by a yeast two-hybrid analysis. To investigate the biological function of FFBL, we infiltrated the lectin into Arabidopsis leaves and observed that it induced cell death in the leaves. Application of FFBL at the same time as inoculation with F. graminearum significantly enhanced the virulence of the pathogen. By contrast, FFBL-induced host cell death was effectively suppressed in transgenic plants that overexpressed Thi2.4. We found that a 15 kD Thi2.4 protein was specifically expressed in flowers and flower buds and suggest that it acts not only as an antifungal peptide, but also as a suppressor of the FFBL toxicity. Secreted thionin proteins are involved in this dual defense mechanism against pathogen invasion at the plant-pathogen interface. PMID- 23990791 TI - Causal and synthetic associations of variants in the SERPINA gene cluster with alpha1-antitrypsin serum levels. AB - Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top ranking genotyped SNP rs4905179 was associated with an estimated effect of beta = -0.068 g/L per minor allele (P = 1.20*10(-12)). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1-5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population. PMID- 23990792 TI - Regulation of sister chromosome cohesion by the replication fork tracking protein SeqA. AB - Analogously to chromosome cohesion in eukaryotes, newly replicated DNA in E. coli is held together by inter-sister linkages before partitioning into daughter nucleoids. In both cases, initial joining is apparently mediated by DNA catenation, in which replication-induced positive supercoils diffuse behind the fork, causing newly replicated duplexes to twist around each other. Type-II topoisomerase-catalyzed sister separation is delayed by the well-characterized cohesin complex in eukaryotes, but cohesion control in E. coli is not currently understood. We report that the abundant fork tracking protein SeqA is a strong positive regulator of cohesion, and is responsible for markedly prolonged cohesion observed at "snap" loci. Epistasis analysis suggests that SeqA stabilizes cohesion by antagonizing Topo IV-mediated sister resolution, and possibly also by a direct bridging mechanism. We show that variable cohesion observed along the E. coli chromosome is caused by differential SeqA binding, with oriC and snap loci binding disproportionally more SeqA. We propose that SeqA binding results in loose inter-duplex junctions that are resistant to Topo IV cleavage. Lastly, reducing cohesion by genetic manipulation of Topo IV or SeqA resulted in dramatically slowed sister locus separation and poor nucleoid partitioning, indicating that cohesion has a prominent role in chromosome segregation. PMID- 23990793 TI - The genome of Spraguea lophii and the basis of host-microsporidian interactions. AB - Microsporidia are obligate intracellular parasites with the smallest known eukaryotic genomes. Although they are increasingly recognized as economically and medically important parasites, the molecular basis of microsporidian pathogenicity is almost completely unknown and no genetic manipulation system is currently available. The fish-infecting microsporidian Spraguea lophii shows one of the most striking host cell manipulations known for these parasites, converting host nervous tissue into swollen spore factories known as xenomas. In order to investigate the basis of these interactions between microsporidian and host, we sequenced and analyzed the S. lophii genome. Although, like other microsporidia, S. lophii has lost many of the protein families typical of model eukaryotes, we identified a number of gene family expansions including a family of leucine-rich repeat proteins that may represent pathogenicity factors. Building on our comparative genomic analyses, we exploited the large numbers of spores that can be obtained from xenomas to identify potential effector proteins experimentally. We used complex-mix proteomics to identify proteins released by the parasite upon germination, resulting in the first experimental isolation of putative secreted effector proteins in a microsporidian. Many of these proteins are not related to characterized pathogenicity factors or indeed any other sequences from outside the Microsporidia. However, two of the secreted proteins are members of a family of RICIN B-lectin-like proteins broadly conserved across the phylum. These proteins form syntenic clusters arising from tandem duplications in several microsporidian genomes and may represent a novel family of conserved effector proteins. These computational and experimental analyses establish S. lophii as an attractive model system for understanding the evolution of host-parasite interactions in microsporidia and suggest an important role for lineage-specific innovations and fast evolving proteins in the evolution of the parasitic microsporidian lifecycle. PMID- 23990794 TI - Identification of DSB-1, a protein required for initiation of meiotic recombination in Caenorhabditis elegans, illuminates a crossover assurance checkpoint. AB - Meiotic recombination, an essential aspect of sexual reproduction, is initiated by programmed DNA double-strand breaks (DSBs). DSBs are catalyzed by the widely conserved Spo11 enzyme; however, the activity of Spo11 is regulated by additional factors that are poorly conserved through evolution. To expand our understanding of meiotic regulation, we have characterized a novel gene, dsb-1, that is specifically required for meiotic DSB formation in the nematode Caenorhabditis elegans. DSB-1 localizes to chromosomes during early meiotic prophase, coincident with the timing of DSB formation. DSB-1 also promotes normal protein levels and chromosome localization of DSB-2, a paralogous protein that plays a related role in initiating recombination. Mutations that disrupt crossover formation result in prolonged DSB-1 association with chromosomes, suggesting that nuclei may remain in a DSB-permissive state. Extended DSB-1 localization is seen even in mutants with defects in early recombination steps, including spo-11, suggesting that the absence of crossover precursors triggers the extension. Strikingly, failure to form a crossover precursor on a single chromosome pair is sufficient to extend the localization of DSB-1 on all chromosomes in the same nucleus. Based on these observations we propose a model for crossover assurance that acts through DSB-1 to maintain a DSB-permissive state until all chromosome pairs acquire crossover precursors. This work identifies a novel component of the DSB machinery in C. elegans, and sheds light on an important pathway that regulates DSB formation for crossover assurance. PMID- 23990795 TI - The PSEN1, p.E318G variant increases the risk of Alzheimer's disease in APOE epsilon4 carriers. AB - The primary constituents of plaques (Abeta42/Abeta40) and neurofibrillary tangles (tau and phosphorylated forms of tau [ptau]) are the current leading diagnostic and prognostic cerebrospinal fluid (CSF) biomarkers for AD. In this study, we performed deep sequencing of APP, PSEN1, PSEN2, GRN, APOE and MAPT genes in individuals with extreme CSF Abeta42, tau, or ptau levels. One known pathogenic mutation (PSEN1 p.A426P), four high-risk variants for AD (APOE p.L46P, MAPT p.A152T, PSEN2 p.R62H and p.R71W) and nine novel variants were identified. Surprisingly, a coding variant in PSEN1, p.E318G (rs17125721-G) exhibited a significant association with high CSF tau (p = 9.2 * 10(-4)) and ptau (p = 1.8 * 10(-3)) levels. The association of the p.E318G variant with Abeta deposition was observed in APOE-epsilon4 allele carriers. Furthermore, we found that in a large case-control series (n = 5,161) individuals who are APOE-epsilon4 carriers and carry the p.E318G variant are at a risk of developing AD (OR = 10.7, 95% CI = 4.7 24.6) that is similar to APOE-epsilon4 homozygous (OR = 9.9, 95% CI = 7.2.9 13.6), and double the risk for APOE-epsilon4 carriers that do not carry p.E318G (OR = 3.9, 95% CI = 3.4-4.4). The p.E318G variant is present in 5.3% (n = 30) of the families from a large clinical series of LOAD families (n = 565) and exhibited a higher frequency in familial LOAD (MAF = 2.5%) than in sporadic LOAD (MAF = 1.6%) (p = 0.02). Additionally, we found that in the presence of at least one APOE-epsilon4 allele, p.E318G is associated with more Abeta plaques and faster cognitive decline. We demonstrate that the effect of PSEN1, p.E318G on AD susceptibility is largely dependent on an interaction with APOE-epsilon4 and mediated by an increased burden of Abeta deposition. PMID- 23990796 TI - Depletion of retinoic acid receptors initiates a novel positive feedback mechanism that promotes teratogenic increases in retinoic acid. AB - Normal embryonic development and tissue homeostasis require precise levels of retinoic acid (RA) signaling. Despite the importance of appropriate embryonic RA signaling levels, the mechanisms underlying congenital defects due to perturbations of RA signaling are not completely understood. Here, we report that zebrafish embryos deficient for RA receptor alphab1 (RARalphab1), a conserved RAR splice variant, have enlarged hearts with increased cardiomyocyte (CM) specification, which are surprisingly the consequence of increased RA signaling. Importantly, depletion of RARalphab2 or concurrent depletion of RARalphab1 and RARalphab2 also results in increased RA signaling, suggesting this effect is a broader consequence of RAR depletion. Concurrent depletion of RARalphab1 and Cyp26a1, an enzyme that facilitates degradation of RA, and employment of a novel transgenic RA sensor line support the hypothesis that the increases in RA signaling in RAR deficient embryos are the result of increased embryonic RA coupled with compensatory RAR expression. Our results support an intriguing novel mechanism by which depletion of RARs elicits a previously unrecognized positive feedback loop that can result in developmental defects due to teratogenic increases in embryonic RA. PMID- 23990797 TI - Brittle Culm1, a COBRA-like protein, functions in cellulose assembly through binding cellulose microfibrils. AB - Cellulose represents the most abundant biopolymer in nature and has great economic importance. Cellulose chains pack laterally into crystalline forms, stacking into a complicated crystallographic structure. However, the mechanism of cellulose crystallization is poorly understood. Here, via functional characterization, we report that Brittle Culm1 (BC1), a COBRA-like protein in rice, modifies cellulose crystallinity. BC1 was demonstrated to be a glycosylphosphatidylinositol (GPI) anchored protein and can be released into cell walls by removal of the GPI anchor. BC1 possesses a carbohydrate-binding module (CBM) at its N-terminus. In vitro binding assays showed that this CBM interacts specifically with crystalline cellulose, and several aromatic residues in this domain are essential for binding. It was further demonstrated that cell wall localized BC1 via the CBM and GPI anchor is one functional form of BC1. X-ray diffraction (XRD) assays revealed that mutations in BC1 and knockdown of BC1 expression decrease the crystallite width of cellulose; overexpression of BC1 and the CBM-mutated BC1s caused varied crystallinity with results that were consistent with the in vitro binding assay. Moreover, interaction between the CBM and cellulose microfibrils was largely repressed when the cell wall residues were pre-stained with two cellulose dyes. Treating wild-type and bc1 seedlings with the dyes resulted in insensitive root growth responses in bc1 plants. Combined with the evidence that BC1 and three secondary wall cellulose synthases (CESAs) function in different steps of cellulose production as revealed by genetic analysis, we conclude that BC1 modulates cellulose assembly by interacting with cellulose and affecting microfibril crystallinity. PMID- 23990798 TI - The intronic long noncoding RNA ANRASSF1 recruits PRC2 to the RASSF1A promoter, reducing the expression of RASSF1A and increasing cell proliferation. AB - The down-regulation of the tumor-suppressor gene RASSF1A has been shown to increase cell proliferation in several tumors. RASSF1A expression is regulated through epigenetic events involving the polycomb repressive complex 2 (PRC2); however, the molecular mechanisms modulating the recruitment of this epigenetic modifier to the RASSF1 locus remain largely unknown. Here, we identify and characterize ANRASSF1, an endogenous unspliced long noncoding RNA (lncRNA) that is transcribed from the opposite strand on the RASSF1 gene locus in several cell lines and tissues and binds PRC2. ANRASSF1 is transcribed through RNA polymerase II and is 5'-capped and polyadenylated; it exhibits nuclear localization and has a shorter half-life compared with other lncRNAs that bind PRC2. ANRASSF1 endogenous expression is higher in breast and prostate tumor cell lines compared with non-tumor, and an opposite pattern is observed for RASSF1A. ANRASSF1 ectopic overexpression reduces RASSF1A abundance and increases the proliferation of HeLa cells, whereas ANRASSF1 silencing causes the opposite effects. These changes in ANRASSF1 levels do not affect the RASSF1C isoform abundance. ANRASSF1 overexpression causes a marked increase in both PRC2 occupancy and histone H3K27me3 repressive marks, specifically at the RASSF1A promoter region. No effect of ANRASSF1 overexpression was detected on PRC2 occupancy and histone H3K27me3 at the promoter regions of RASSF1C and the four other neighboring genes, including two well-characterized tumor suppressor genes. Additionally, we demonstrated that ANRASSF1 forms an RNA/DNA hybrid and recruits PRC2 to the RASSF1A promoter. Together, these results demonstrate a novel mechanism of epigenetic repression of the RASSF1A tumor suppressor gene involving antisense unspliced lncRNA, in which ANRASSF1 selectively represses the expression of the RASSF1 isoform overlapping the antisense transcript in a location-specific manner. In a broader perspective, our findings suggest that other non-characterized unspliced intronic lncRNAs transcribed in the human genome might contribute to a location-specific epigenetic modulation of genes. PMID- 23990799 TI - The architecture of a prototypical bacterial signaling circuit enables a single point mutation to confer novel network properties. AB - Even a single mutation can cause a marked change in a protein's properties. When the mutant protein functions within a network, complex phenotypes may emerge that are not intrinsic properties of the protein itself. Network architectures that enable such dramatic changes in function from a few mutations remain relatively uncharacterized. We describe a remarkable example of this versatility in the well studied PhoQ/PhoP bacterial signaling network, which has an architecture found in many two-component systems. We found that a single point mutation that abolishes the phosphatase activity of the sensor kinase PhoQ results in a striking change in phenotype. The mutant responds to stimulus in a bistable manner, as opposed to the wild-type, which has a graded response. Mutant cells in on and off states have different morphologies, and their state is inherited over many generations. Interestingly, external conditions that repress signaling in the wild-type drive the mutant to the on state. Mathematical modeling and experiments suggest that the bistability depends on positive autoregulation of the two key proteins in the circuit, PhoP and PhoQ. The qualitatively different characteristics of the mutant come at a substantial fitness cost. Relative to the off state, the on state has a lower fitness in stationary phase cultures in rich medium (LB). However, due to the high inheritance of the on state, a population of on cells can be epigenetically trapped in a low-fitness state. Our results demonstrate the remarkable versatility of the prototypical two-component signaling architecture and highlight the tradeoffs in the particular case of the PhoQ/PhoP system. PMID- 23990800 TI - Hard selective sweep and ectopic gene conversion in a gene cluster affording environmental adaptation. AB - Among the rare colonizers of heavy-metal rich toxic soils, Arabidopsis halleri is a compelling model extremophile, physiologically distinct from its sister species A. lyrata, and A. thaliana. Naturally selected metal hypertolerance and extraordinarily high leaf metal accumulation in A. halleri both require Heavy Metal ATPase4 (HMA4) encoding a PIB-type ATPase that pumps Zn(2+) and Cd(2+) out of specific cell types. Strongly enhanced HMA4 expression results from a combination of gene copy number expansion and cis-regulatory modifications, when compared to A. thaliana. These findings were based on a single accession of A. halleri. Few studies have addressed nucleotide sequence polymorphism at loci known to govern adaptations. We thus sequenced 13 DNA segments across the HMA4 genomic region of multiple A. halleri individuals from diverse habitats. Compared to control loci flanking the three tandem HMA4 gene copies, a gradual depletion of nucleotide sequence diversity and an excess of low-frequency polymorphisms are hallmarks of positive selection in HMA4 promoter regions, culminating at HMA4-3. The accompanying hard selective sweep is segmentally eclipsed as a consequence of recurrent ectopic gene conversion among HMA4 protein-coding sequences, resulting in their concerted evolution. Thus, HMA4 coding sequences exhibit a network-like genealogy and locally enhanced nucleotide sequence diversity within each copy, accompanied by lowered sequence divergence between paralogs in any given individual. Quantitative PCR corroborated that, across A. halleri, three genomic HMA4 copies generate overall 20- to 130-fold higher transcript levels than in A. thaliana. Together, our observations constitute an unexpectedly complex profile of polymorphism resulting from natural selection for increased gene product dosage. We propose that these findings are paradigmatic of a category of multi copy genes from a broad range of organisms. Our results emphasize that enhanced gene product dosage, in addition to neo- and sub-functionalization, can account for the genomic maintenance of gene duplicates underlying environmental adaptation. PMID- 23990801 TI - The ribosomal protein Rpl22 controls ribosome composition by directly repressing expression of its own paralog, Rpl22l1. AB - Most yeast ribosomal protein genes are duplicated and their characterization has led to hypotheses regarding the existence of specialized ribosomes with different subunit composition or specifically-tailored functions. In yeast, ribosomal protein genes are generally duplicated and evidence has emerged that paralogs might have specific roles. Unlike yeast, most mammalian ribosomal proteins are thought to be encoded by a single gene copy, raising the possibility that heterogenous populations of ribosomes are unique to yeast. Here, we examine the roles of the mammalian Rpl22, finding that Rpl22(-/-) mice have only subtle phenotypes with no significant translation defects. We find that in the Rpl22(-/ ) mouse there is a compensatory increase in Rpl22-like1 (Rpl22l1) expression and incorporation into ribosomes. Consistent with the hypothesis that either ribosomal protein can support translation, knockdown of Rpl22l1 impairs growth of cells lacking Rpl22. Mechanistically, Rpl22 regulates Rpl22l1 directly by binding to an internal hairpin structure and repressing its expression. We propose that ribosome specificity may exist in mammals, providing evidence that one ribosomal protein can influence composition of the ribosome by regulating its own paralog. PMID- 23990802 TI - Genic intolerance to functional variation and the interpretation of personal genomes. AB - A central challenge in interpreting personal genomes is determining which mutations most likely influence disease. Although progress has been made in scoring the functional impact of individual mutations, the characteristics of the genes in which those mutations are found remain largely unexplored. For example, genes known to carry few common functional variants in healthy individuals may be judged more likely to cause certain kinds of disease than genes known to carry many such variants. Until now, however, it has not been possible to develop a quantitative assessment of how well genes tolerate functional genetic variation on a genome-wide scale. Here we describe an effort that uses sequence data from 6503 whole exome sequences made available by the NHLBI Exome Sequencing Project (ESP). Specifically, we develop an intolerance scoring system that assesses whether genes have relatively more or less functional genetic variation than expected based on the apparently neutral variation found in the gene. To illustrate the utility of this intolerance score, we show that genes responsible for Mendelian diseases are significantly more intolerant to functional genetic variation than genes that do not cause any known disease, but with striking variation in intolerance among genes causing different classes of genetic disease. We conclude by showing that use of an intolerance ranking system can aid in interpreting personal genomes and identifying pathogenic mutations. PMID- 23990803 TI - Combining quantitative genetic footprinting and trait enrichment analysis to identify fitness determinants of a bacterial pathogen. AB - Strains of Extraintestinal Pathogenic Escherichia c oli (ExPEC) exhibit an array of virulence strategies and are a major cause of urinary tract infections, sepsis and meningitis. Efforts to understand ExPEC pathogenesis are challenged by the high degree of genetic and phenotypic variation that exists among isolates. Determining which virulence traits are widespread and which are strain-specific will greatly benefit the design of more effective therapies. Towards this goal, we utilized a quantitative genetic footprinting technique known as transposon insertion sequencing (Tn-seq) in conjunction with comparative pathogenomics to functionally dissect the genetic repertoire of a reference ExPEC isolate. Using Tn-seq and high-throughput zebrafish infection models, we tracked changes in the abundance of ExPEC variants within saturated transposon mutant libraries following selection within distinct host niches. Nine hundred and seventy bacterial genes (18% of the genome) were found to promote pathogen fitness in either a niche-dependent or independent manner. To identify genes with the highest therapeutic and diagnostic potential, a novel Trait Enrichment Analysis (TEA) algorithm was developed to ascertain the phylogenetic distribution of candidate genes. TEA revealed that a significant portion of the 970 genes identified by Tn-seq have homologues more often contained within the genomes of ExPEC and other known pathogens, which, as suggested by the first axiom of molecular Koch's postulates, is considered to be a key feature of true virulence determinants. Three of these Tn-seq-derived pathogen-associated genes--a transcriptional repressor, a putative metalloendopeptidase toxin and a hypothetical DNA binding protein--were deleted and shown to independently affect ExPEC fitness in zebrafish and mouse models of infection. Together, the approaches and observations reported herein provide a resource for future pathogenomics-based research and highlight the diversity of factors required by a single ExPEC isolate to survive within varying host environments. PMID- 23990804 TI - Chromatin sampling--an emerging perspective on targeting polycomb repressor proteins. PMID- 23990807 TI - Fifty years on: GWAS confirms the role of a rare variant in lung disease. PMID- 23990805 TI - H2A.Z acidic patch couples chromatin dynamics to regulation of gene expression programs during ESC differentiation. AB - The histone H2A variant H2A.Z is essential for embryonic development and for proper control of developmental gene expression programs in embryonic stem cells (ESCs). Divergent regions of amino acid sequence of H2A.Z likely determine its functional specialization compared to core histone H2A. For example, H2A.Z contains three divergent residues in the essential C-terminal acidic patch that reside on the surface of the histone octamer as an uninterrupted acidic patch domain; however, we know little about how these residues contribute to chromatin structure and function. Here, we show that the divergent amino acids Gly92, Asp97, and Ser98 in the H2A.Z C-terminal acidic patch (H2A.Z(AP3)) are critical for lineage commitment during ESC differentiation. H2A.Z is enriched at most H3K4me3 promoters in ESCs including poised, bivalent promoters that harbor both activating and repressive marks, H3K4me3 and H3K27me3 respectively. We found that while H2A.Z(AP3) interacted with its deposition complex and displayed a highly similar distribution pattern compared to wild-type H2A.Z, its enrichment levels were reduced at target promoters. Further analysis revealed that H2A.Z(AP3) was less tightly associated with chromatin, suggesting that the mutant is more dynamic. Notably, bivalent genes in H2A.Z(AP3) ESCs displayed significant changes in expression compared to active genes. Moreover, bivalent genes in H2A.Z(AP3) ESCs gained H3.3, a variant associated with higher nucleosome turnover, compared to wild-type H2A.Z. We next performed single cell imaging to measure H2A.Z dynamics. We found that H2A.Z(AP3) displayed higher mobility in chromatin compared to wild-type H2A.Z by fluorescent recovery after photobleaching (FRAP). Moreover, ESCs treated with the transcriptional inhibitor flavopiridol resulted in a decrease in the H2A.Z(AP3) mobile fraction and an increase in its occupancy at target genes indicating that the mutant can be properly incorporated into chromatin. Collectively, our work suggests that the divergent residues in the H2A.Z acidic patch comprise a unique domain that couples control of chromatin dynamics to the regulation of developmental gene expression patterns during lineage commitment. PMID- 23990806 TI - Histone variant HTZ1 shows extensive epistasis with, but does not increase robustness to, new mutations. AB - Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact) to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA) lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1) to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be caused by loss of robustness, and therefore force reevaluation of prior claims based on that assumption. PMID- 23990809 TI - Nutrition economics: towards comprehensive understanding of the benefits of nutrition. AB - There has been an increase in the knowledge and interest on nutrition, and functional foods have gained popularity over the last few decades, and the trend is increasing. Probiotics and prebiotics are among the most studied functional foods. Nutrition economics has been defined as the discipline dedicated to researching and characterising health and economic outcomes in nutrition for the benefit of society. The concept and its application to probiotics and prebiotics will be discussed in terms of health and economic benefits and their evaluation. Health economics and concrete applications showing how to maximise long-term nutritional benefits will contribute to motivate consumers in making food choices based on a rational understanding of their own interest. We present a model that shows that nutrition economics can be used as an analytical tool for product and service network development. PMID- 23990810 TI - Correlations between Lumbricus terrestris survival and gut microbiota. AB - BACKGROUND: The interplay between diet, gut bacteria and health still remain enigmatic. Here, we addressed this issue through the investigation of the effect of crystalline cellulose on the earthworm Lumbricus terrestris gut microbiota composition and survival. METHODS: Earthworm gut contents were analyzed after 14 days of feeding using a mixed 16S rRNA gene sequencing approach, in addition to direct measurements of cellulase activity. The survival of earthworms was followed each week for 17 weeks. RESULTS: We found a tendency that the crystalline cellulose fed earthworms survived better than the high energy fed earthworms (p=0.08). Independent of feeding we found that the bacterial group related to Ferrimonadaceae was correlated to an increased lifespan (p=0.01). We also found a positive correlation between Ruminococcaceae related bacteria and cellulase activity in the earthworm gut (p=0.05). Surprisingly, however, the cellulase activity was not correlated to the feeding regime. CONCLUSION: Taken together, the interactions between diet, gut microbiota and lifespan seem complex. PMID- 23990808 TI - Neurobiological Underpinnings of the Estrogen - Mood Relationship. AB - Women are at a higher risk than men to develop mood disorders and depression. The increased risk is associated with fluctuating estrogen levels that occur during reproductive cycle events, particularly during the menopausal transition, a time characterized by drastic fluctuations in estrogen levels and increases in new onset and recurrent depression. Conversely, recent data show that hormone therapy, particularly transdermal estradiol formulations, may prevent mood disorders or even serve as a treatment regimen for women with diagnosed mood disturbances via estrogen regulation. While the exact mechanism is unknown, there is compelling scientific evidence indicating the neuromodulatory and neuroprotective effects of estrogen, which are directly relevant to mood symptomotology. Specifically, affective regulation has been linked to neural structures rich in estrogen receptors and estrogenic regulation of neurotransmitters. While a wealth of basic science, observational and clinical research support this rationale, potential mediating variables, such as estrogen formulation, proximity of administration to menopause, and the addition of progestins should be considered. Furthermore, the nature of postmenopausal exogenous hormone formulations in relation to premenopausal endogenous levels, as well as the ratio of estrone to estradiol warrant consideration. PMID- 23990811 TI - Gut indigenous microbiota and epigenetics. AB - This review introduces and discusses data regarding fundamental and applied investigations in mammalian epigenomics and gut microbiota received over the last 10 years. Analysis of these data enabled us first to come to the conclusion that the multiple low-molecular-weight substances of indigenous gut microbiota origin should be considered one of the main endogenous factors actively participating in epigenomic mechanisms that are responsible for the mammalian genome reprograming and post-translated modifications. Gut microecological imbalance caused by various biogenic and abiogenic agents and factors can produce different epigenetic abnormalities and the onset and progression of metabolic diseases associated. The authors substantiate the necessity to create an international project 'Human Gut Microbiota and Epigenomics' that facilitates interdisciplinary collaborations among scientists and clinicians engaged in host microbial ecology, nutrition, metagenomics, epigenomics, and metabolomics investigations as well as in disease prevention and treatment. Some priority scientific and applied directions in the current omic technologies coupled with gnotobiological approaches are suggested that can open a new era in characterizing the role of the symbiotic microbiota small metabolic and signal molecules in the host epigenomics. Although the discussed subject is only at an early stage its validation can open novel approaches in drug discovery studies. PMID- 23990813 TI - Foreword. PMID- 23990812 TI - Fermented milk containing Lactobacillus GG alleviated DSS-induced colitis in mice and activated epidermal growth factor receptor and Akt signaling in intestinal epithelial cells. AB - Lactobacillus rhamnosus GG was assessed for its ability to alleviate DSS-induced colitis in mice and activate epidermal growth factor receptor and Akt signaling in intestinal epithelial cells. In this study mice were treated with DSS to induce colitis and they were given Lactobacillus GG fermented milk to assess the effect of probiotic on colitis. Lactobacillus GG fermented milk significantly reduced the colitis associated changes suggesting a protective effect against DSS induced colitis. PMID- 23990815 TI - Prebiotics and probiotics - the importance of branding. AB - The costs of developing a probiotic or prebiotic ingredient have always been substantial. Ingredient characterization, evaluation of technological and physiological properties, and demonstrations of safety and clinical efficacy require expensive research. The demanding regulatory requirements imposed by EFSA raise the bar even higher so that the costs of acquiring the necessary clinical evidence to support labeling of these food ingredients is approaching that of pharmaceuticals. In order to justify investment in such expensive clinical development, companies require certainty that they can gain a return on investment. Patenting can provide some protection but is not always possible to patent ingredients, and the period of protection is limited. All ingredients eventually face the prospect of commoditization once patents expire. Branding strategies offer one means of maintaining adequate product differentiation to protect market share and margins over the long term. PMID- 23990814 TI - A ten years (2000-2009) surveillance of resistant Enterobacteriaceae in Zhejiang Province, China. AB - OBJECTIVE: In Zhejiang Province, there are several highly developed cities near the coast and several relatively under-developed mountain areas. Analysis of the composition of bacteria isolated from patients as well as their antibiotic resistance profile from various areas of this province, and tracing of such data year-by-year, will help to delineate the bacterial resistance profile of these areas and to understand how the stage of socio-economical development impacts on the composition of clinical micro-flora and their resistance profile. METHODS: In order to investigate variation in resistance rates and isolation rates of Enterobacteriaceae, from 2000 to 2009 in Zhejiang Province, China, Enterobacteriaceae isolated from 15 hospitals located in different regions of the province were surveyed. RESULTS: The total numbers of the Enterobacteriaceae isolated increased more than 20-fold from 2000 to 2009. Among the Enterobacteriaceae, Escherichia coli and Klebsiella pneumoniae were the dominant isolates. The percentage of E. coli and K. pneumoniae that produced detectable extended-spectrum beta-lactamases (ESBLs) increased from 2000 to 2007, and then declined slightly in 2008 and 2009. The percentages of K. pneumoniae and E. coli that were resistant to ceftazidime increased sharply from 2000 to 2009. There were remarkable increases in the carbapenem resistant rates during the decade, but they were much higher for the isolates from the developed cities than from the rural areas. In 2002, carbapenem-resistant E. coli was first found in Hangzhou, one of the highly developed cities in Zhejiang Province. By 2009, carbapenem-resistant bacteria were found for all species of Enterobacteriaceae surveyed in almost all areas of the province, although they were more frequently identified in developed areas than in rural areas. CONCLUSION: Much restrictive actions have to be taken in terms of rational use of antibiotics and nosocomial control to prevent the further spread of the drug-resistant pathogens. PMID- 23990816 TI - Intestinal cytochromes P450 regulating the intestinal microbiota and its probiotic profile. AB - Cytochromes P450 (CYPs) enzymes metabolize a large variety of xenobiotic substances. In this vein, a plethora of studies were conducted to investigate their role, as cytochromes are located in both liver and intestinal tissues. The P450 profile of the human intestine has not been fully characterized. Human intestine serves primarily as an absorptive organ for nutrients, although it has also the ability to metabolize drugs. CYPs are responsible for the majority of phase I drug metabolism reactions. CYP3A represents the major intestinal CYP (80%) followed by CYP2C9. CYP1A is expressed at high level in the duodenum, together with less abundant levels of CYP2C8-10 and CYP2D6. Cytochromes present a genetic polymorphism intra- or interindividual and intra- or interethnic. Changes in the pharmacokinetic profile of the drug are associated with increased toxicity due to reduced metabolism, altered efficacy of the drug, increased production of toxic metabolites, and adverse drug interaction. The high metabolic capacity of the intestinal flora is due to its enormous pool of enzymes, which catalyzes reactions in phase I and phase II drug metabolism. Compromised intestinal barrier conditions, when rupture of the intestinal integrity occurs, could increase passive paracellular absorption. It is clear that high microbial intestinal charge following intestinal disturbances, ageing, environment, or food-associated ailments leads to the microbial metabolism of a drug before absorption. The effect of certain bacteria having a benefic action on the intestinal ecosystem has been largely discussed during the past few years by many authors. The aim of the probiotic approach is to repair the deficiencies in the gut flora and establish a protective effect. There is a tentative multifactorial association of the CYP (P450) cytochrome role in the different diseases states, environmental toxic effects or chemical exposures and nutritional status. PMID- 23990818 TI - The gut: a triggering place for autism - possibilities and challenges. AB - BACKGROUND: During the recent years, a substantial amount of new data has underlined the importance of the gut as a triggering place for autism. Temporary improvements in clinical status following dietary alterations and the same that may occur after an antibiotic therapy are reported. Additionally, increasing numbers of bacteria belonging to certain groups, such as clostridia, desulfovibrios, and sutterella, have been reported. So far, however, presence of any bacterial group has never been causatively linked to autism, and every time a new candidate organism is introduced the same questions have to be asked: What is the cause? What is the consequence? What is the confounder? The possibilities of answering these questions are hampered by difficulties in obtaining adequate samples. Therefore, more efforts have been made to those biochemical methods that probe possible functional alterations in the gastrointestinal (GI) microbiota in autistic children. CONCLUSION: Autism is a disorder involving many organs and their functions, including the GI microbiota. More knowledge about the GI microbiota and its cross-talks with the host creates possibilities for future diagnostic and therapeutic improvements. PMID- 23990821 TI - Probiotics and prebiotics: health claim substantiation. AB - 'Probiotics' and 'prebiotics' by definition should have health benefits. Health claims on microorganisms proposed as probiotics and probiotic stimulating agents (prebiotics) suggest that there is a relationship between the specific food and maintaining good health or that the food can reduce the risk of a disease. The Health Claim Regulation in European Union aims at a level consumer protection. Thereby, health claim assessment focuses on defining the probiotics and prebiotics, assessing the health relationship and evaluating studies with emphasis on controlled human intervention studies. The challenges include the focus of claims for healthy populations while most intervention studies with probiotics and prebiotics have been conducted in patients or subjects at risk of specific diseases. Another challenge is the risk reduction claim, which requires demonstrated changes in biomarkers that are generally accepted as indicators of disease risk. Existing assessment opinions from EFSA illustrate the need for further research for probiotics and prebiotics in the future. PMID- 23990817 TI - Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. AB - Recent evidence suggests potential, but unproven, links between dietary, metabolic, infective, and gastrointestinal factors and the behavioral exacerbations and remissions of autism spectrum disorders (ASDs). Propionic acid (PPA) and its related short-chain fatty acids (SCFAs) are fermentation products of ASD-associated bacteria (Clostridia, Bacteriodetes, Desulfovibrio). SCFAs represent a group of compounds derived from the host microbiome that are plausibly linked to ASDs and can induce widespread effects on gut, brain, and behavior. Intraventricular administration of PPA and SCFAs in rats induces abnormal motor movements, repetitive interests, electrographic changes, cognitive deficits, perseveration, and impaired social interactions. The brain tissue of PPA-treated rats shows a number of ASD-linked neurochemical changes, including innate neuroinflammation, increased oxidative stress, glutathione depletion, and altered phospholipid/acylcarnitine profiles. These directly or indirectly contribute to acquired mitochondrial dysfunction via impairment in carnitine dependent pathways, consistent with findings in patients with ASDs. Of note, common antibiotics may impair carnitine-dependent processes by altering gut flora favoring PPA-producing bacteria and by directly inhibiting carnitine transport across the gut. Human populations that are partial metabolizers of PPA are more common than previously thought. PPA has further bioactive effects on neurotransmitter systems, intracellular acidification/calcium release, fatty acid metabolism, gap junction gating, immune function, and alteration of gene expression that warrant further exploration. These findings are consistent with the symptoms and proposed underlying mechanisms of ASDs and support the use of PPA infusions in rats as a valid animal model of the condition. Collectively, this offers further support that gut-derived factors, such as dietary or enteric bacterially produced SCFAs, may be plausible environmental agents that can trigger ASDs or ASD-related behaviors and deserve further exploration in basic science, agriculture, and clinical medicine. PMID- 23990820 TI - Defining microbiota for developing new probiotics. AB - The human body harbors complex communities of microbes that play a prominent role in human health. Detailed characterization of the microbiota in the target population forms the basis of probiotic use. Probiotics are defined as live bacterial preparations with clinically documented health effects in humans, and independent of their genus and species, probiotic strains are unique and their beneficial properties on human health have to be assessed in a case-by-case manner. Understanding the mechanisms by which probiotics influence microbiota would facilitate the use of probiotics for both dietary management and reduction in risk of specific diseases. The development of high throughput sequencing methods has allowed metagenomic approaches to study the human microbiome. These efforts are starting to generate an inventory of bacterial taxons and functional features bound to particular health or disease status that allow inferring aspects of the microbiome's function. In the future, this information will allow the rational design of dietary interventions aimed to improve consumer's health via modulation of the microbiota. PMID- 23990822 TI - A true case story. AB - Autism is not generally recognized as a condition which can be bio-medically influenced. As of today, there are no biomarkers for autism that are recognized by traditional medicine. Treating autism medically is a difficult and hopeless task according to official guidelines (even though it is seldom written in official documents). Parents of many children who have or had an ASD diagnosis have witnessed significant improvements in their children after dietary interventions as well as after interventions with vitamins, minerals and biogene substances which can be bought over the counter. The parents of individual children are their best observers. With a high degree of certainty, they are able to see which substances improve or weaken their children. Their observations are usually accurate, but their rationale for why is often wrong. Observations from parents can often be of greater importance for the child than advice from so called experts. This is a true story about a girl whose parents lost contact with her when she was only 6 months old. In her first 14 days she lost her ability to roll over, to babble and make sounds. She did not look at her parents any more - just stared up at the roof. At 9 months she did not respond to words such as, 'look at mommy'. Through the parents own experiences with her older siblings and 4 months of frantic searching for a diet that would agree with the child, she made a remarkable journey from 10 months of age to 18 months. There is one thing worth mentioning - she refused to eat solid food throughout this time. The story does not end there. Today she is 12 years old and has had to be regulated with diet and biogene substances every day since she was 4 years old. During the last 5 months she has shown more stability and can even go a day or two without biogene substances as long as she keeps to her dietary plan. If you had just met her and spent a day with her, you would never know. PMID- 23990823 TI - Nutrition economic evaluation of allergy treatment in infants and children: background for probiotic studies. AB - The treatment of food allergy is based on avoidance of the foods, which cause symptoms, and their replacement with nutritionally comparable foods. The cost of food allergy and elimination diets to families and society is poorly known. Our results suggest that estimation of dietary costs on the basis of dietary records was possible but challenging. In infancy, cost differences were small but vary depending on the age group with the reduction of median yearly costs around 180 240?. Thus, further studies are required for a more accurate cost estimate and an estimation of the impact of specific probiotics. PMID- 23990825 TI - Editorial: The gut and the brain - with focus on autism spectrum disorders. PMID- 23990824 TI - Enhancing probiotic stability in industrial processes. AB - BACKGROUND: Manufacture of probiotic products involves industrial processes that reduce the viability of the strains. This lost of viability constitutes an economic burden for manufacturers, compromising the efficacy of the product and preventing the inclusion of probiotics in many product categories. Different strategies have been used to improve probiotic stability during industrial processes. These include technological approaches, such as the modification of production parameters or the reformulation of products, as well as microbiological approaches focused on the strain intrinsic resistance. Among the later, both selection of natural strains with the desired properties and stress adaptation of strains have been widely used. CONCLUSION: During recent years, the knowledge acquired on the molecular basis of stress-tolerance of probiotics has increased our understanding on their responses to industrial stresses. This knowledge on stress-response may nowadays be used for the selection of the best strains and industrial conditions in terms of probiotic stability in the final product. PMID- 23990819 TI - Should autism be considered a canary bird telling that Homo sapiens may be on its way to extinction? AB - There has been a dramatic enhancement of the reported incidence of autism in different parts of the world over the last 30 years. This can apparently not be explained only as a result of improved diagnosis and reporting, but may also reflect a real change. The causes of this change are unknown, but if we shall follow T.C. Chamberlin's principle of multiple working hypotheses, we need to take into consideration the possibility that it partly may reflect an enhancement of the average frequency of responsible alleles in large populations. If this hypothesis is correct, it means that the average germline mutation rate must now be much higher in the populations concerned, compared with the natural mutation rate in hominid ancestors before the agricultural and industrial revolutions. This is compatible with the high prevalence of impaired human semen quality in several countries and also with what is known about high levels of total exposure to several different unnatural chemical mutagens, plus some natural ones at unnaturally high levels. Moreover, dietary deficiency conditions that may lead to enhancement of mutation rates are also very widespread, affecting billions of people. However, the natural mutation rate in hominids has been found to be so high that there is apparently no tolerance for further enhancement of the germline mutation rate before the Eigen error threshold will be exceeded and our species will go extinct because of mutational meltdown. This threat, if real, should be considered far more serious than any disease causing the death only of individual patients. It should therefore be considered the first and highest priority of the best biomedical scientists in the world, of research-funding agencies and of all medical doctors to try to stop the express train carrying all humankind as passengers on board before it arrives at the end station of our civilization. PMID- 23990826 TI - Commensal communication to the brain: pathways and behavioral consequences. PMID- 23990827 TI - Gut microbiota and infant distress - the association between compositional development of the gut microbiota and fussing and crying in early infancy. PMID- 23990828 TI - Autism spectrum disorder, functional MRI and MR spectroscopy: possibilities and challenges. AB - BACKGROUND: In this article we provide an overview of the use of the functional magnetic resonance imaging (fMRI) and MR spectroscopy (MRS) in studies of autism spectrum disorders (ASD). We moreover provide preliminary data using these measures in cases of children with ASD and healthy controls. A hypothesis was that ASD children would show aberrant brain activation in the prefrontal and parietal cortex in an oddball stimulus situation, with predictable and unpredictable deviant tone stimuli, as an index of resistance to change in the ASD children. We also hypothesized that glutamate and GABA metabolite levels would differ between the two groups. METHODS: fMRI images were acquired from a GE Signa HDx 3T MR scanner, as were the MRS data. Behavioral data were acquired as response accuracy to the deviant tone stimulus. The tone stimuli were presented in a standard fMRI ON-OFF box-car paradigim. RESULTS: The fMRI results showed reduced brain activation in the ASD cases compared to the controls, preferably in the inferior and superior frontal gyrus, posterior temporal lobe, and superior and inferior parietal lobule. These areas make up an effort mode network (EMN), being activated in response to cognitive effort. The MRS results also showed differences between the groups. DISCUSSION: The results are discussed in a theoretical framework of resistance to unexpected changes in the environment in ASD children, and how this could have a neurobiological underpinning. The results are also discussed in relation to the brain-gut link, and the possibility that ASD may have a microbial link. A limitation with the study is the few cases reported and the preliminary quality of the results. PMID- 23990829 TI - Isolation of bifidobacteria for blood group secretor status targeted personalised nutrition. AB - BACKGROUND: Currently, there is a constant need to find microbial products for maintaining or even improving host microbiota balance that could be targeted to a selected consumer group. Blood group secretor status, determining the ABO status, could be used to stratify the consumer group. OBJECTIVE: We have applied a validated upper intestinal tract model (TIM-1) and culturing methods to screen potential probiotic bacteria from faeces of blood secretor and non-secretor individuals. DESIGN: Faecal samples from healthy volunteers were pooled to age- and sex-matched secretor and non-secretor pools. Faecal pools were run through separate TIM-1 simulations, and bacteria were cultivated from samples taken at different stages of simulations for characterisation. RESULTS: Microbes in secretor pool survived the transit through TIM-1 system better than microbes of non-secretor pool, especially bifidobacteria and anaerobes were highly affected. The differences in numbers of bifidobacteria and lactobacilli isolates after plate cultivations and further the number of distinct RAPD-genotypes was clearly lower in non-secretor pool than in secretor pool. CONCLUSIONS: In the present study, we showed that microbiota of secretor and non-secretor individuals tolerate gastrointestinal conditions differently and that a combination of gastrointestinal simulations and cultivation methods proved to be a promising tool for isolating potentially probiotic bacteria. PMID- 23990831 TI - Let's do it! PMID- 23990830 TI - Probiotics and irritable bowel syndrome. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a major cause of abdominal discomfort and gut dysfunction worldwide. It is a poorly understood functional gastrointestinal disorder for which no effective medication is available. It is a benign condition, but its social and economic burden is significant. The symptoms consist of abdominal pain, bloating, flatulence, and irregular bowel movements. Alterations in the intestinal microbiota and mucosal inflammation may contribute to the development of IBS and probiotics could thus relieve the symptoms. This review gives an overview on the existing data on the effects of probiotics on the gastrointestinal symptoms of IBS. METHODS: A PUBMED search was made to review the relevant literature, and additional studies were obtained from the references of the selected articles. RESULTS: Clinical trials suggest that certain probiotics or combinations of bacteria have beneficial effects on the IBS symptoms. However the heterogeneity of studies, e.g. suboptimal study design, inadequate number of subjects, different doses and vehicles, inadequate length, make it difficult to compare the differences between probiotics and the effect may be strain-specific. CONCLUSIONS: Though evidence is very promising, no general recommendations on the use of probiotics in IBS can be given yet. Further clinical trials and data on the mechanisms of action are needed. Probiotics are considered safe and if future scientific data is able to substantiate their efficacy in IBS, they certainly could be a treatment option in relieving the symptoms in IBS. PMID- 23990832 TI - Concentration of circulating autoantibodies against HSP 60 is lowered through diving when compared to non-diving rats. AB - OBJECTIVE: Skin and ear infections, primarily caused by Pseudomonas aeruginosa (P. aeruginosa), are recurrent problems for saturation divers, whereas infections caused by P. aeruginosa are seldom observed in healthy people outside saturation chambers. Cystic fibrosis (CF) patients suffer from pulmonary infections by P. aeruginosa, and it has been demonstrated that CF patients have high levels of autoantibodies against Heat shock protein 60 (HSP60) compared to controls, probably due to cross-reacting antibodies induced by P. aeruginosa. The present study investigated whether rats immunised with P. aeruginosa produced autoantibodies against their own HSP60 and whether diving influenced the level of circulating anti-HSP60 antibodies. METHODS: A total of 24 rats were randomly assigned to one of three groups ('immunised', 'dived' and 'immunised and dived'). The rats in group 1 and 3 were immunised with the bacteria P. aeruginosa, every other week. Groups 2 and 3 were exposed to simulated air dives to 400 kPa (4 ata) with 45 min bottom time, every week for 7 weeks. Immediately after surfacing, the rats were anaesthetised and blood was collected from the saphenous vein. The amount of anti-HSP60 rat antibodies in the serum was analysed by enzyme linked immunosorbent assay. RESULTS: The immunised rats (group 1) showed a significant increase in the level of autoantibodies against HSP60, whereas no autoantibodies were detected in the dived rats (group 2). The rats both immunised and dived (group 3) show no significant increase in circulating autoantibodies against HSP60. A possible explanation may be that HSP60 is expressed during diving and that cross-reacting antibodies are bound. PMID- 23990833 TI - Probiotic viability - does it matter? AB - Probiotics are viable by definition, and viability of probiotics is often considered to be a prerequisite for the health benefits. Indeed, the overwhelming majority of clinical studies in the field have been performed with viable probiotics. However, it has also been speculated that some of the mechanisms behind the probiotic health effects may not be dependent on the viability of the cells and, therefore, is also possible that also non-viable probiotics could have some health benefits. The efficacy of non-viable probiotics has been assessed in a limited number of studies, with varying success. While it is clear that viable probiotics are more effective than non-viable probiotics and that, in many cases, viability is indeed a prerequisite for the health benefit, there are also some cases where it appears that non-viable probiotics could also have beneficial effects on human health. PMID- 23990834 TI - Fructophilic lactic acid bacteria inhabit fructose-rich niches in nature. AB - Fructophilic lactic acid bacteria (FLAB) are a special group of lactic acid bacteria (LAB), which prefer fructose but not glucose as growth substrate. They are found in fructose-rich niches, e.g. flowers, fruits, and fermented foods made from fruits. Quite recently, they were found in the gastrointestinal tracts of animals consuming fructose, which were bumblebees, tropical fruit flies, and Camponotus ants. These suggest that all natural sources that are rich in fructose are possible their habitats. Fructobacillus spp., formerly classified as Leuconostoc spp., are representatives of these microorganisms, and Lactobacillus kunkeei has also been classified as FLAB. They share several unique biochemical characteristics, which have not been found in LAB inhabited in other niches. FLAB grow well on fructose but very poor on glucose. These organisms grow well on glucose only when external electron accepters, e.g. pyruvate or oxygen, are available. LAB have been shown to have specific evolution to adapt to their niches and have several niche-specific characteristics. FLAB must have fructophilic evolution during adaptation to fructose-rich niches. FLAB are unique food-related LAB, suggesting a great potential for future food and feed applications. PMID- 23990835 TI - Peptides' role in autism with emphasis on exorphins. AB - PROBLEM: The nature of the peptides found increased in urine from autism needs verification of their structure, especially those that show opioid activity. METHODS: The peptides were separated on reverse phase C-18 HPLC in Trifluoroacetic acid-acetonitril gradients. Peaks eluting where synthetic opioids appear, and peaks that are common to most autistic children were analyzed by mass spectrometry and fragmentation pattern on a quadropole mass-spectrometer. RESULTS: We could demonstrate exorphins in the urine from autistic children, and their length varied from one patient to the next. CONCLUSION: Exorphins are found in urine of autistic children and may account for their symptoms. PMID- 23990837 TI - Molecular ecology in health and disease. PMID- 23990838 TI - Kiwifruit (Actinidia deliciosa) changes intestinal microbial profile. AB - BACKGROUND: Kiwifruit is high in pectic polysaccharides and dietary fiber. This study aimed to find out how the ingestion of kiwifruit will affect intestinal microbiota populations, namely Lactobacillus, Bacteroides, Clostridium, Bifidobacterium, and Enterococcus. METHODS: Freeze dried kiwifruit (equivalent of two fresh kiwifruits) was given to each of the six subjects daily for four days. Faecal samples were collected before, during and after kiwifruit consumption. The faecal bacteria were enumerated by qPCR and RT qPCR methods. RESULTS: The effect of the kiwifruit on intestinal microbiota profile varied between individuals; in general, the kiwifruit demonstrated a prebiotic effect of promoting the content of faecal lactobacilli and bifidobacteria (as compared to the baselines of the same individual before consumption) for as long as the fruit was consumed. The effect was however transient, the levels of the two bacteria returned near to that of the baselines upon cessation of consumption. CONCLUSION: Kiwifruit is a prebiotic in selectively enhancing the growth of intestinal lactic acid bacteria. PMID- 23990839 TI - Longitudinal high-risk sibling studies of autism spectrum disorder. PMID- 23990840 TI - The effect of a commercial probiotic drink on oral microbiota in healthy complete denture wearers. AB - BACKGROUND: It is acknowledged that oral and general health status declines with age. The global population of denture wearers is increasing, so is the incidence of denture biofilm-related problems, such as denture-associated stomatitis, aspiration pneumonia and malodour. It has been suggested that consumption of probiotic bacteria may improve oral health. However, the effects of probiotics on the oral microbiota of denture wearers have received little attention. METHODS: The aim of this study was to investigate the effect of consumption of a commercial probiotic product (Yakult) on microbiota of saliva, tongue and denture biofilm in healthy complete denture wearers. Eight healthy complete denture wearing National Health Service (NHS) patients undertook a 7-week trial comprising three phases: baseline; 4-week consumption of one bottle of Yakult per day, each containing a minimum 6.5*10(9) viable cells of Lactobacillus casei strain Shirota (LcS); 4-week washout period. The microbial viability and composition of saliva, tongue dorsum coating and denture biofilm were assessed using a range of solid selective and indicator media. Questionnaires were used to explore participants' denture cleaning habits and impact of wearing dentures on their life quality and well-being [modified oral health impact profile (OHIP-14)] prior to and after the study. RESULTS: Seven volunteers (1 male, 6 females) completed the trial. LcS temporarily colonised oral cavity and denture surface. There was no significant change in the viability of Streptococcus mutans, acidogenic microorganisms, total anaerobic species and Gram-negative obligate anaerobes between study phases. There was no obvious effect of LcS on occurrence and viability of Candida. Participants presented a good general knowledge of denture hygiene and their responses to OHIP-14 questionnaires improved after completing the study (p=0.16). CONCLUSION: It appeared that 4-week consumption of probiotic drink had no overall effect on selected oral parameters in healthy denture wearers despite temporary presence of LcS. PMID- 23990842 TI - Grand challenge: ELSI in a changing global environment. PMID- 23990841 TI - Metabiotics: novel idea or natural development of probiotic conception. AB - Traditionally, probiotics on the base of live microorganisms are considered to be both beneficial and safe. Unfortunately, their effects may have short-term success or are absent or uncertain. Some symbiotic (probiotic) microorganisms with known beneficial health affects may cause opportunistic infections, increase incidence of allergic sensitization and autoimmune disorders, produce microecological imbalance, modify gene expression, transfer antibiotic resistant and virulence genes, cause disorders in epigenome and genome integrity, induce chromosomal DNA damage, and activate signaling pathways associated with cancer and other chronic diseases. The commercially available probiotics should be considered as a first generation means of correcting microecological disorders. Further, their development will include the selection of natural metabiotics and/or working out the synthetic (or semi-synthetic) metabiotics that will be analogies or improved copies of natural bioactives, produced by symbiotic (probiotic) microorganisms. Metabiotics are the structural components of probiotic microorganisms and/or their metabolites and/or signaling molecules with a determined (known) chemical structure that can optimize host-specific physiological functions, regulator, metabolic and/or behavior reactions connected with the activity of host indigenous microbiota. Metabiotics have some advantages because of their exact chemical structure, well dosed, very safe and long shelf life. Thus, now metabiotics should not consider myth; they are the result of the natural evolution of probiotic conception. PMID- 23990844 TI - In adjuvant-induced arthritic rats, acupuncture analgesic effects are histamine dependent: potential reasons for acupoint preference in clinical practice. AB - This study investigated whether immediate acupuncture effects in the acupoint are histamine dependent. Both histamine injection and manual acupuncture stimulation increased the pain threshold (PT) after treatment compared with the model group (P < 0.01), producing an analgesic effect. After pretreatment with clemastine, an H1 receptor antagonist and an antipruritic, the increase in the animals' pain threshold after acupuncture was suppressed compared with the Acu group (P < 0.01); however, there was no interference with the acupuncture-induced degranulation of mast cells. Pretreatment with disodium cromolyn did not suppress the increase in PT induced by the histamine injection at Zusanli (ST-36). We conclude that in adjuvant-induced arthritic rats, acupuncture analgesic effects are histamine dependent, and this histamine dependence determines the acupoint preference of acupoints away from the target site in acupuncture practice. PMID- 23990843 TI - The added value of water, sanitation, and hygiene interventions to mass drug administration for reducing the prevalence of trachoma: a systematic review examining. AB - Trachoma is the leading cause of infectious blindness worldwide. The SAFE strategy, the World Health Organization-recommended method to eliminate blinding trachoma, combines developments in water, sanitation, surgery, and antibiotic treatment. Current literature does not focus on the comprehensive effect these components have on one another. The present systematic review analyzes the added benefit of water, sanitation, and hygiene education interventions to preventive mass drug administration of azithromycin for trachoma. Trials were identified from the PubMed database using a series of search terms. Three studies met the complete criteria for inclusion. Though all studies found a significant change in reduction of active trachoma prevalence, the research is still too limited to suggest the impact of the "F" and "E" components on trachoma prevalence and ultimately its effects on blindness. PMID- 23990845 TI - Intravenous laser blood irradiation increases efficacy of etanercept in selected subtypes of juvenile idiopathic arthritis: an innovative clinical research approach. AB - This single-blind, placebo-controlled study assesses the efficacy of synergic administration of intravenous laser blood irradiation (ILBI) and etanercept in selected subtypes of juvenile idiopathic arthritis (JIA). Etanercept is a tumor necrosis factor alpha blocking agent with recognized importance in JIA. Laser radiation has immunomodulatory effects in animal and human studies. Fourteen patients (Group I) received ILBI and 9 patients (Group II) received placebo laser. ILBI was performed in addition to ongoing JIA medication, including etanercept. ILBI was administrated in 3 sets of 5 consecutive daily sessions, with a 7-week interval between every set of sessions. Evaluation was performed using ACR (American College of Rheumatology) Pediatric Criteria (ACR Pedi) at study enrollment and at 10 and 20 weeks, respectively. After 10 weeks, 85.7% of the patients in Group I fulfilled Pedi 30 criteria, compared to only 55.6% of the patients in Group II. After 20 weeks, all patients in both groups had a Pedi 30 response. In Group I, 92.8% of the subjects met the Pedi 50 response, compared to only 55.6% in the placebo group. One patient in Group I responded best, fulfilling Pedi 70 criteria. If applied synergistically, ILBI and etanercept would have an increased efficacy in promoting JIA remission. PMID- 23990847 TI - Skimmin, a Coumarin from Hydrangea paniculata, Slows down the Progression of Membranous Glomerulonephritis by Anti-Inflammatory Effects and Inhibiting Immune Complex Deposition. AB - Skimmin is one of the major pharmacologically active molecules present in Hydrangea paniculata, a medical herb used in the traditional Chinese medicine as an anti-inflammatory agent. In the current study, we attempted to investigate its renoprotective activity and underlying mechanisms in a rat model of membranous glomerulonephritis induced by cationic bovine serum albumin (c-BSA). Sprague Dawley (SD) rats were divided into five groups, including normal control, model control, Mycophenolate Mofetil-treated group, and two skimming-treated groups (15 mg/kg and 30 mg/kg). Our research showed that treatment with skimmin significantly reduced the levels of blood urea nitrogen (BUN), urinary albumin excretion (UAE), and serum creatinine (Scr) as compared with model control after experimental induction of membranous glomerulonephritis (P < 0.01). Moreover, glomerular hypercellularity, tubulointerstitial injury, and glomerular deposition of IgG were less intense after skimmin treatment. By immunochemistry analysis, we demonstrated that skimmin could significantly inhibit interleukin-1 beta (IL1 beta ) and IL-6 expression (P < 0.05), reduce the loss of nephrin and podocin, and suppress the infiltration of renal interstitium by CD3-positive T cell and CD20-positive B cell. These results suggest that treatment with skimmin can significantly improve renal function and suppress the IgG deposition as well as the development of glomerular lesions in a rat model of membranous glomerulonephritis. PMID- 23990846 TI - Updates on Antiobesity Effect of Garcinia Origin (-)-HCA. AB - Garcinia is a plant under the family of Clusiaceae that is commonly used as a flavouring agent. Various phytochemicals including flavonoids and organic acid have been identified in this plant. Among all types of organic acids, hydroxycitric acid or more specifically (-)-hydroxycitric acid has been identified as a potential supplement for weight management and as antiobesity agent. Various in vivo studies have contributed to the understanding of the anti obesity effects of Garcinia/hydroxycitric acid via regulation of serotonin level and glucose uptake. Besides, it also helps to enhance fat oxidation while reducing de novo lipogenesis. However, results from clinical studies showed both negative and positive antiobesity effects of Garcinia/hydroxycitric acid. This review was prepared to summarise the update of chemical constituents, significance of in vivo/clinical anti-obesity effects, and the importance of the current market potential of Garcinia/hydroxycitric acid. PMID- 23990849 TI - Superior mesenteric vein thrombosis as a complication of acute appendicitis : report of a case. AB - Since superior mesenteric vein thrombosis (SMVT) is a relatively rare disease and shows no specific symptom, its diagnosis tends to be delayed. In this report, we present a patient in whom acute appendicitis was complicated by SMVT and portal vein thrombosis (PVT). A definitive diagnosis could be made by abdominal contrast enhanced CT, and acute appendicitis was surgically treated. Anticoagulant therapy was continued for about half a year after surgery. Abdominal contrast-enhanced CT after discharge showed no recurrence of SMVT or PVT. We consider that acute appendicitis induced SMVT or PVT caused by the effect of inflammation. There is the possibility that these conditions lead to intestinal congestion or necrosis and liver dysfunction; appropriate diagnosis and treatment are necessary. PMID- 23990848 TI - The time course effects of electroacupuncture on promoting skeletal muscle regeneration and inhibiting excessive fibrosis after contusion in rabbits. AB - The aim of this study was to investigate the longitudinal effects of electroacupuncture (EA) on Zusanli (ST36) and Ashi acupoints in promoting skeletal muscle regeneration and inhibiting excessive fibrosis after contusion in rabbits. Sixty rabbits were randomly divided into four groups: normal, contusion, EA, and recombinant human insulin-like growth factor-I (rhIGF-I). An acute skeletal muscle contusion was produced on the right gastrocnemius (GM) by an instrument-based drop-mass technique. EA was performed for 15 minutes every two days with 0.4 mA (2 Hz), and GM injections were executed with rhIGF-I (0.25 mL once a week). Rabbits treated with EA had a higher T-SOD and T-AOC serum activities and lower MDA serum level, the blood perfusion of which was also significantly higher. In the EA group, the diameter of the myofibril was uniform and the arrangement was regular, contrary to the contusion group. The number and diameter of regenerative myofibers and MHC expression were increased in the EA group. EA treatment significantly decreased fibrosis formation and reduced both GDF-8 and p-Smad2/3 expressions in injured muscle. Our data indicate that EA may promote myofiber regeneration and reduce excessive fibrosis by improving blood flow and antioxidant capacities. Additionally, EA may regulate signaling factor expression after contusion. PMID- 23990850 TI - Small intestinal obstruction resulting from ischemic enteritis: a case report. AB - A 69-year-old male was admitted to our institution because of a sudden onset of vomiting and abdominal distention. His past history of illness included femoral head fracture, congestive heart failure and ischaemic colitis. Plain abdominal computed tomography revealed extensively dilated small intestinal loops with a calibre change around the end of the ileum. Small intestinal obstruction was diagnosed and a transnasal ileus tube was placed. The ileus tube was constantly moved towards small intestine until it reached the distal ileum. Contrast medium from the ileus tube revealed a distal ileal stricture. Subsequently, transanal single balloon enteroscopy was performed to inspect the stricture, revealing a circumferential and afferent tubular ulcer in the distal ileum, 5 cm from the ileocecal valve; gastrofluorography confirmed the stricture. Although the stricture was dilated on several occasions using balloon catheters, the stricture could not be improved. However, during the treatment, his general condition worsened over time; thus, surgical treatment was decided. Operative findings revealed several circumferential ulcers with a clear margin 5-28 cm from the ileocecal valve: all lesions were successfully resected. Pathological findings were consistent with ischaemic enteritis. We report a case of small intestinal obstruction resulting from stenotic ischaemic enteritis. PMID- 23990851 TI - Usefulness of contrast-enhanced ultrasonography in the diagnosis of ruptured hepatocellular carcinoma. AB - The identification of bleeding sites of ruptured hepatocellular carcinoma (HCC) is important for immediate treatment. We experienced a case of ruptured HCC readily treated with transarterial embolization (TAE) after identification of the bleeding site using contrast-enhanced ultrasonography (CEUS) with Sonazoid. We report the case of a 61-year-old male with multiple HCCs caused by alcohol related cirrhosis, who was admitted for rapid development of abdominal fullness. The diagnosis was established by hemorrhagic ascites by abdominal paracentesis. No clear extravasation was found on contrast-enhanced computed tomography. CEUS using the re-injection method in the post-vascular phase showed active bleeding from a lesion close to the S5 gallbladder bed. Abdominal angiography was urgently performed. Based on CEUS findings, selective cannulation of the cystic artery was performed. Cystic angiography findings with carbon dioxide showed extravasation. He was treated by TAE. Our case had multiple HCCs, but CEUS was useful for the identification of bleeding sites. PMID- 23990852 TI - MULTIPLE IMPUTATION FOR SHARING PRECISE GEOGRAPHIES IN PUBLIC USE DATA. AB - When releasing data to the public, data stewards are ethically and often legally obligated to protect the confidentiality of data subjects' identities and sensitive attributes. They also strive to release data that are informative for a wide range of secondary analyses. Achieving both objectives is particularly challenging when data stewards seek to release highly resolved geographical information. We present an approach for protecting the confidentiality of data with geographic identifiers based on multiple imputation. The basic idea is to convert geography to latitude and longitude, estimate a bivariate response model conditional on attributes, and simulate new latitude and longitude values from these models. We illustrate the proposed methods using data describing causes of death in Durham, North Carolina. In the context of the application, we present a straightforward tool for generating simulated geographies and attributes based on regression trees, and we present methods for assessing disclosure risks with such simulated data. PMID- 23990866 TI - Circulating tumor cells: application as a biomarker for molecular characterization and predictor of survival in an all-comer solid tumor phase I clinical study. AB - PURPOSE: Clinical development of cancer drugs has a low success rate. Prognostic and predictive biomarkers using minimally invasive approaches hold promise for increasing the probability of success by enabling disease characterization, patient selection and early detection of drug treatment effect. Enumeration and molecular characterization of circulating tumor cells (CTC) may address some of these needs, and thus were evaluated for utility in a Phase I solid tumor clinical study. EXPERIMENTAL DESIGN: Blood samples for CTC analysis were obtained from 24 cancer patients in a multi-center all-comer Phase I study of MEDI-575, a novel anti-PDGFRalpha antibody. Samples were taken at screening and analyzed for enumeration of CTC using the CellSearch((r)) platform and for molecular characterization using a novel quantitative RT-PCR assay. RESULTS: Fifty-nine percent of the patients showed at least 1 CTC per 7.5 ml of blood at baseline. Progression-free survival (PFS) and overall survival (OS) of patients with 0 CTCs at baseline were longer than PFS and Os for patients with 1-3 and >3 CTCs (8.8 versus 1.4 and 1.3 months PFS, P = 0.02; 9.0 vs 7.4 and 3.5 months OS, P = 0.20, respectively). Patients with 0 CTC showed a greater percentage of stable disease than the other 2 groups with 1-3 and >3 CTCs (57% vs 29% and 0%). The multimarker qRT-PCR method detected CTC in 40% of the patients, and 80% of these patients were positive for pre-selected drug target genes. CONCLUSION: CTC enumeration of patients in an all-comer study is feasible and may allow for patient stratification for PFS and Os to evaluate the clinical response of investigational agents. Gene expression profiling of isolated CTC may provide a means for molecular characterization of selected tumor targets. PMID- 23990867 TI - Impact of STROBE statement publication on quality of observational study reporting: interrupted time series versus before-after analysis. AB - BACKGROUND: In uncontrolled before-after studies, CONSORT was shown to improve the reporting of randomised trials. Before-after studies ignore underlying secular trends and may overestimate the impact of interventions. Our aim was to assess the impact of the 2007 STROBE statement publication on the quality of observational study reporting, using both uncontrolled before-after analyses and interrupted time series. METHODS: For this quasi-experimental study, original articles reporting cohort, case-control, and cross-sectional studies published between 2004 and 2010 in the four dermatological journals having the highest 5 year impact factors (>= 4) were selected. We compared the proportions of STROBE items (STROBE score) adequately reported in each article during three periods, two pre STROBE period (2004-2005 and 2006-2007) and one post STROBE period (2008 2010). Segmented regression analysis of interrupted time series was also performed. RESULTS: Of the 456 included articles, 187 (41%) reported cohort studies, 166 (36.4%) cross-sectional studies, and 103 (22.6%) case-control studies. The median STROBE score was 57% (range, 18%-98%). Before-after analysis evidenced significant STROBE score increases between the two pre-STROBE periods and between the earliest pre-STROBE period and the post-STROBE period (median score2004-05 48% versus median score2008-10 58%, p<0.001) but not between the immediate pre-STROBE period and the post-STROBE period (median score2006-07 58% versus median score2008-10 58%, p = 0.42). In the pre STROBE period, the six monthly mean STROBE score increased significantly, by 1.19% per six-month period (absolute increase 95%CI, 0.26% to 2.11%, p = 0.016). By segmented analysis, no significant changes in STROBE score trends occurred (-0.40%; 95%CI, -2.20 to 1.41; p = 0.64) in the post STROBE statement publication. INTERPRETATION: The quality of reports increased over time but was not affected by STROBE. Our findings raise concerns about the relevance of uncontrolled before-after analysis for estimating the impact of guidelines. PMID- 23990868 TI - Attitudes toward family planning among HIV-positive pregnant women enrolled in a prevention of mother-to-child transmission study in Kisumu, Kenya. AB - BACKGROUND: Preventing unintended pregnancies among HIV-positive women through family planning (FP) reduces pregnancy-related morbidity and mortality, decreases the number of pediatric HIV infections, and has also proven to be a cost effective way to prevent mother-to-child HIV transmission. A key element of a comprehensive HIV prevention agenda, aimed at avoiding unintended pregnancies, is recognizing the attitudes towards FP among HIV-positive women and their spouse or partner. In this study, we analyze FP attitudes among HIV-infected pregnant women enrolled in a PMTCT clinical trial in Western Kenya. METHODS AND FINDINGS: Baseline data were collected on 522 HIV-positive pregnant women using structured questionnaires. Associations between demographic variables and the future intention to use FP were examined using Fisher's exact tests and permutation tests. Most participants (87%) indicated that they intended to use FP. However, only 8% indicated condoms as a preferred FP method, and 59% of current pregnancies were unintended. Factors associated with positive intentions to use FP were: marital status (p = 0.04), having talked to their spouse or partner about FP (p<0.001), perceived spouse or partner approval of FP (p<0.001), previous use of a FP method (p = 0.006), attitude toward the current pregnancy (p = 0.02), disclosure of a sexually transmitted infection (STI) diagnosis (p = 0.03) and ethnic group (p = 0.03). CONCLUSION: A significant gap exists between future FP intentions and current FP practices. Support and approval by the spouse or partner are key elements of FP intentions. Counseling services should be offered to both members of a couple to increase FP use, especially given the high number of unplanned pregnancies among HIV-positive women. Condoms should be promoted as part of a dual use method for HIV and STI prevention and for contraception. Integration of individual and couple FP services into routine HIV care, treatment and support services is needed in order to avoid unintended pregnancies and to prevent mother-to-child HIV transmission. PMID- 23990871 TI - Morpheme matching based text tokenization for a scarce resourced language. AB - Text tokenization is a fundamental pre-processing step for almost all the information processing applications. This task is nontrivial for the scarce resourced languages such as Urdu, as there is inconsistent use of space between words. In this paper a morpheme matching based approach has been proposed for Urdu text tokenization, along with some other algorithms to solve the additional issues of boundary detection of compound words, affixation, reduplication, names and abbreviations. This study resulted into 97.28% precision, 93.71% recall, and 95.46% F1-measure; while tokenizing a corpus of 57000 words by using a morpheme list with 6400 entries. PMID- 23990870 TI - Universal HIV screening at postnatal points of care: which public health approach for early infant diagnosis in Cote d'Ivoire? AB - BACKGROUND: Universal HIV pediatric screening offered at postnatal points of care (PPOC) is an entry point for early infant diagnosis (EID). We assessed the parents' acceptability of this approach in Abidjan, Cote d'Ivoire. METHODS: In this cross-sectional study, trained counselors offered systematic HIV screening to all children aged 6-26 weeks attending PPOC in three community health centers with existing access to HAART during 2008, as well as their parents/caregivers. HIV-testing acceptability was measured for parents and children; rapid HIV tests were used for parents. Both parents' consent was required according to the Ivorian Ethical Committee to perform a HIV test on HIV-exposed children. Free HIV care was offered to those who were diagnosed HIV-infected. FINDINGS: We provided 3,013 HIV tests for infants and their 2,986 mothers. While 1,731 mothers (58%) accepted the principle of EID, only 447 infants had formal parental consent 15%; 95% confidence interval (CI): [14%-16%]. Overall, 1,817 mothers (61%) accepted to test for HIV, of whom 81 were HIV-infected (4.5%; 95% CI: [3.5%-5.4%]). Among the 81 HIV-exposed children, 42 (52%) had provided parental consent and were tested: five were HIV-infected (11.9%; 95% CI: [2.1%-21.7%]). Only 46 fathers (2%) came to diagnose their child. Parental acceptance of EID was strongly correlated with prenatal self-reported HIV status: HIV-infected mothers were six times more likely to provide EID parental acceptance than mothers reporting unknown or negative prenatal HIV status (aOR: 5.9; 95% CI: [3.3-10.6], p = 0.0001). CONCLUSIONS: Although the principle of EID was moderately accepted by mothers, fathers' acceptance rate remained very low. Routine HIV screening of all infants was inefficient for EID at a community level in Abidjan in 2008. Our results suggest the need of focusing on increasing the PMTCT coverage, involving fathers and tracing children issued from PMTCT programs in low HIV prevalence countries. PMID- 23990869 TI - Genomic Grade Index (GGI): feasibility in routine practice and impact on treatment decisions in early breast cancer. AB - PURPOSE: Genomic Grade Index (GGI) is a 97-gene signature that improves histologic grade (HG) classification in invasive breast carcinoma. In this prospective study we sought to evaluate the feasibility of performing GGI in routine clinical practice and its impact on treatment recommendations. METHODS: Patients with pT1pT2 or operable pT3, N0-3 invasive breast carcinoma were recruited from 8 centers in Belgium. Fresh surgical samples were sent at room temperature in the MapQuant DxTM PathKit for centralized genomic analysis. Genomic profiles were determined using Affymetrix U133 Plus 2.0 and GGI calculated using the MapQuant Dx(r) protocol, which defines tumors as low or high Genomic Grade (GG-1 and GG-3 respectively). RESULTS: 180 pts were recruited and 155 were eligible. The MapQuant test was performed in 142 cases and GGI was obtained in 78% of cases (n=111). Reasons for failures were 15 samples with <30% of invasive tumor cells (11%), 15 with insufficient RNA quality (10%), and 1 failed hybridization (<1%). For tumors with an available representative sample (>= 30% inv. tumor cells) (n=127), the success rate was 87.5%. GGI reclassified 69% of the 54 HG2 tumors as GG-1 (54%) or GG-3 (46%). Changes in treatment recommendations occurred mainly in the subset of HG2 tumors reclassified into GG 3, with increased use of chemotherapy in this subset. CONCLUSION: The use of GGI is feasible in routine clinical practice and impacts treatment decisions in early stage breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01916837, http://clinicaltrials.gov/ct2/show/NCT01916837. PMID- 23990872 TI - Impact of thoracic surgery on cardiac morphology and function in small animal models of heart disease: a cardiac MRI study in rats. AB - BACKGROUND: Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies. METHODS: Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition. RESULTS: Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week (267.5+/-10.6 vs. 317.0+/-11.3 g, n<0.05) and 8 weeks (317.0+/-21.1 vs. 358.7+/-22.4 g, n<0.05) after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass (2.19+/ 0.30/0.83+/-0.13 vs. 1.85+/-0.22/0.70+/-0.07 mg left/right per g bw, p<0.05), or enddiastolic ventricular volume (1.31+/-0.36/1.21+/-0.31 vs. 1.14+/-0.20/1.07+/ 0.17 ul left/right per g bw, p<0.05). Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures (782.2+/-57.2/260.2+/-33.2 vs. 805.9+/ 84.8/310.4+/-48.5 mg, p<0.05 for left/right ventricular mass), but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease. CONCLUSION: Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients. PMID- 23990836 TI - Radiation protection following nuclear power accidents: a survey of putative mechanisms involved in the radioprotective actions of taurine during and after radiation exposure. AB - There are several animal experiments showing that high doses of ionizing radiation lead to strongly enhanced leakage of taurine from damaged cells into the extracellular fluid, followed by enhanced urinary excretion. This radiation induced taurine depletion can itself have various harmful effects (as will also be the case when taurine depletion is due to other causes, such as alcohol abuse or cancer therapy with cytotoxic drugs), but taurine supplementation has been shown to have radioprotective effects apparently going beyond what might be expected just as a consequence of correcting the harmful consequences of taurine deficiency per se. The mechanisms accounting for the radioprotective effects of taurine are, however, very incompletely understood. In this article an attempt is made to survey various mechanisms that potentially might be involved as parts of the explanation for the overall beneficial effect of high levels of taurine that has been found in experiments with animals or isolated cells exposed to high doses of ionizing radiation. It is proposed that taurine may have radioprotective effects by a combination of several mechanisms: (1) during the exposure to ionizing radiation by functioning as an antioxidant, but perhaps more because it counteracts the prooxidant catalytic effect of iron rather than functioning as an important scavenger of harmful molecules itself, (2) after the ionizing radiation exposure by helping to reduce the intensity of the post-traumatic inflammatory response, and thus reducing the extent of tissue damage that develops because of severe inflammation rather than as a direct effect of the ionizing radiation per se, (3) by functioning as a growth factor helping to enhance the growth rate of leukocytes and leukocyte progenitor cells and perhaps also of other rapidly proliferating cell types, such as enterocyte progenitor cells, which may be important for immunological recovery and perhaps also for rapid repair of various damaged tissues, especially in the intestines, and (4) by functioning as an antifibrogenic agent. A detailed discussion is given of possible mechanisms involved both in the antioxidant effects of taurine, in its anti-inflammatory effects and in its role as a growth factor for leukocytes and nerve cells, which might be closely related to its role as an osmolyte important for cellular volume regulation because of the close connection between cell volume regulation and the regulation of protein synthesis as well as cellular protein degradation. While taurine supplementation alone would be expected to exert a therapeutic effect far better than negligible in patients that have been exposed to high doses of ionizing radiation, it may on theoretical grounds be expected that much better results may be obtained by using taurine as part of a multifactorial treatment strategy, where it may interact synergistically with several other nutrients, hormones or other drugs for optimizing antioxidant protection and minimizing harmful posttraumatic inflammatory reactions, while using other nutrients to optimize DNA and tissue repair processes, and using a combination of good diet, immunostimulatory hormones and perhaps other nontoxic immunostimulants (such as beta-glucans) for optimizing the recovery of antiviral and antibacterial immune functions. Similar multifactorial treatment strategies may presumably be helpful in several other disease situations (including severe infectious diseases and severe asthma) as well as for treatment of acute intoxications or acute injuries (both mechanical ones and severe burns) where severely enhanced oxidative and/or nitrative stress and/or too much secretion of vasodilatory neuropeptides from C fibres are important parts of the pathogenetic mechanisms that may lead to the death of the patient. Some case histories (with discussion of some of those mechanisms that may have been responsible for the observed therapeutic outcome) are given for illustration of the likely validity of these concepts and their relevance both for treatment of severe infections and non-infectious inflammatory diseases such as asthma and rheumatoid arthritis. PMID- 23990873 TI - Association between XRCC1 and XRCC3 polymorphisms with lung cancer risk: a meta analysis from case-control studies. AB - Many studies have reported the association of X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln, Arg194Trp, Arg280His, -77T>C, and X-ray repair cross complementing group 3 (XRCC3) T241M polymorphisms with lung cancer risk, but the results remained controversial. Hence, we performed a meta-analysis to investigate the association between lung cancer risk and XRCC1 Arg399Gln (14,156 cases and 16,667 controls from 41 studies), Arg194Trp (7,426 cases and 9,603 controls from 23 studies), Arg280His (6,211 cases and 6,763 controls from 16 studies), -77T>C (2,487 cases and 2,576 controls from 5 studies), and XRCC3 T241M (8,560 cases and 11,557 controls from 19 studies) in different inheritance models. We found that -77T>C polymorphism was associated with increased lung cancer risk (dominant model: odds ration [OR] = 1.45, 95% confidence interval [CI] = 1.27-1.66, recessive model: OR = 1.73, 95% CI = 1.14-2.62, additive model: OR = 1.91, 95% CI = 1.24-1.94) when all the eligible studies were pooled into the meta-analysis. In the stratified and sensitive analyses, significantly decreased lung cancer risk was observed in overall analysis (dominant model: OR = 0.83, 95% CI = 0.78-0.89; recessive model: OR = 0.90, 95% CI = 0.81-1.00; additive model: OR = 0.82, 95% CI = 0.74-0.92), Caucasians (dominant model: OR = 0.82, 95% CI = 0.76-0.87; recessive model: OR = 0.89, 95% CI = 0.80-0.99; additive model: OR = 0.81, 95% CI = 0.73-0.91), and hospital-based controls (dominant model: OR = 0.81, 95% CI = 0.76-0.88; recessive model: OR = 0.89, 95% CI = 0.79-1.00; additive model: OR = 0.80, 95% CI = 0.71-0.90) for XRCC3 T241M. In conclusion, this meta-analysis indicates that XRCC1 -77T>C shows an increased lung cancer risk and XRCC3 T241M polymorphism is associated with decreased lung cancer risk, especially in Caucasians. PMID- 23990874 TI - Microbial products induce claudin-2 to compromise gut epithelial barrier function. AB - The epithelial barrier dysfunction is an important pathogenic feature in a number of diseases. The underlying mechanism is to be further investigated. The present study aims to investigate the role of tight junction protein claudin-2 (Cldn2) in the compromising epithelial barrier function. In this study, the expression of Cldn2 in the epithelial layer of mice and patients with food allergy was observed by immunohistochemistry. The induction of Cldn2 was carried out with a cell culture model. The Cldn2-facilitated antigen internalization was observed by confocal microscopy. The epithelial barrier function in the gut epithelial monolayer was assessed by recording the transepithelial resistance and assessing the permeability to a macromolecular tracer. The results showed that the positive immune staining of Cldn2 was observed in the epithelial layer of the small intestine that was weakly stained in naive control mice, and strongly stained in sensitized mice as well as patients with food allergy. Exposure to cholera toxin or Staphylococcal enterotoxin B induced the expression of Cldn2 in HT-29 or T84 cells. Cldn2 could bind protein antigen to form complexes to facilitate the antigen transport across the epithelial barrier. Blocking Cldn2 prevented the allergen-related hypersensitivity the intestine. We conclude that the tight junction protein Cldn2 is involved in the epithelial barrier dysfunction. PMID- 23990876 TI - Diagnostic application of targeted resequencing for familial nonsyndromic hearing loss. AB - Identification of causative genes for hereditary nonsyndromic hearing loss (NSHL) is important to decide treatment modalities and to counsel the patients. Due to the genetic heterogeneity in sensorineural genetic disorders, the high-throughput method can be adapted for the efficient diagnosis. To this end, we designed a new diagnostic pipeline to screen all the reported candidate genes for NSHL. For validation of the diagnostic pipeline, we focused upon familial NSHL cases that are most likely to be genetic, rather than to be infectious or environmental. Among the 32 familial NSHL cases, we were able to make a molecular genetic diagnosis from 12 probands (37.5%) in the first stage by their clinical features, characteristic inheritance pattern and further candidate gene sequencing of GJB2, SLC26A4, POU3F4 or mitochondrial DNA. Next we applied targeted resequencing on 80 NSHL genes in the remaining 20 probands. Each proband carried 4.8 variants that were not synonymous and had the occurring frequency of less than three among the 20 probands. These variants were then filtered out with the inheritance pattern of the family, allele frequency in normal hearing 80 control subjects, clinical features. Finally NSHL-causing candidate mutations were identified in 13(65%) of the 20 probands of multiplex families, bringing the total solve rate (or detection rate) in our familial cases to be 78.1% (25/32) Damaging mutations discovered by the targeted resequencing were distributed in nine genes such as WFS1, COCH, EYA4, MYO6, GJB3, COL11A2, OTOF, STRC and MYO3A, most of which were private. Despite the advent of whole genome and whole exome sequencing, we propose targeted resequencing and filtering strategy as a screening and diagnostic tool at least for familial NSHL to find mutations based upon its efficacy and cost-effectiveness. PMID- 23990875 TI - Giant hydrogen sulfide plume in the oxygen minimum zone off Peru supports chemolithoautotrophy. AB - In Eastern Boundary Upwelling Systems nutrient-rich waters are transported to the ocean surface, fuelling high photoautotrophic primary production. Subsequent heterotrophic decomposition of the produced biomass increases the oxygen depletion at intermediate water depths, which can result in the formation of oxygen minimum zones (OMZ). OMZs can sporadically accumulate hydrogen sulfide (H2S), which is toxic to most multicellular organisms and has been implicated in massive fish kills. During a cruise to the OMZ off Peru in January 2009 we found a sulfidic plume in continental shelf waters, covering an area >5500 km(2), which contained ~2.2*10(4) tons of H2S. This was the first time that H2S was measured in the Peruvian OMZ and with ~440 km(3) the largest plume ever reported for oceanic waters. We assessed the phylogenetic and functional diversity of the inhabiting microbial community by high-throughput sequencing of DNA and RNA, while its metabolic activity was determined with rate measurements of carbon fixation and nitrogen transformation processes. The waters were dominated by several distinct gamma-, delta- and epsilon-proteobacterial taxa associated with either sulfur oxidation or sulfate reduction. Our results suggest that these chemolithoautotrophic bacteria utilized several oxidants (oxygen, nitrate, nitrite, nitric oxide and nitrous oxide) to detoxify the sulfidic waters well below the oxic surface. The chemolithoautotrophic activity at our sampling site led to high rates of dark carbon fixation. Assuming that these chemolithoautotrophic rates were maintained throughout the sulfidic waters, they could be representing as much as ~30% of the photoautotrophic carbon fixation. Postulated changes such as eutrophication and global warming, which lead to an expansion and intensification of OMZs, might also increase the frequency of sulfidic waters. We suggest that the chemolithoautotrophically fixed carbon may be involved in a negative feedback loop that could fuel further sulfate reduction and potentially stabilize the sulfidic OMZ waters. PMID- 23990877 TI - Tolerance to copper and to salinity in Daphnia longispina: implications within a climate change scenario. AB - Considering IPPC climate change scenarios, it is pertinent to predict situations where coastal ecosystems already impacted with chemical contamination became exposed to an additional stressor under a future scenario of seawater intrusion. Accordingly, the present study aimed at evaluating if a negative association between tolerance to a metal and to saltwater exists among genotypes of a freshwater organism. For this, five clonal lineages of the cladoceran Daphnia longispina O.F. Muller, exhibiting a differential tolerance to lethal levels of copper, were selected. Each clonal lineage was exposed to lethal and sublethal concentrations of sodium chloride (assumed as a protective surrogate to evaluate the toxicity of increased salinity to freshwater organisms). Mortality, time to release the first brood and total number of neonates per female were monitored and the somatic growth rate and intrinsic rate of natural increase were computed for each clonal lineage. Data here obtained were compared with their lethal responses to copper and significant negative correlations were found. These results suggest that genetically eroded populations of D. longispina, due to copper or salinity, may be particularly susceptible to a later exposure to the other contaminant supporting the multiple stressors differential tolerance. PMID- 23990879 TI - Unintended consequences of invasive predator control in an Australian forest: overabundant wallabies and vegetation change. AB - Over-abundance of native herbivores is a problem in many forests worldwide. The abundance of native macropod wallabies is extremely high at Booderee National Park (BNP) in south-eastern Australia. This has occurred because of the reduction of exotic predators through an intensive baiting program, coupled with the absence of other predators. The high density of wallabies at BNP may be inhibiting the recruitment of many plant species following fire-induced recruitment events. We experimentally examined the post-fire response of a range of plant species to browsing by wallabies in a forest heavily infested with the invasive species, bitou bush Chrysanthemoides monilifera. We recorded the abundance and size of a range of plant species in 18 unfenced (browsed) and 16 fenced (unbrowsed) plots. We found the abundance and size of bitou bush was suppressed in browsed plots compared to unbrowsed plots. Regenerating seedlings of the canopy or middle storey tree species Eucalyptus pilularis, Acacia implexa, Allocasuarina littoralis, Breynia oblongifolia and Banksia integrifolia were either smaller or fewer in number in grazed plots than treatment plots as were the vines Kennedia rubicunda, Glycine tabacina and Glycine clandestina. In contrast, the understorey fern, Pteridium esculentum increased in abundance in the browsed plots relative to unbrowsed plots probably because of reduced competition with more palatable angiosperms. Twelve months after plots were installed the community structure of the browsed and unbrowsed plots was significantly different (P = 0.023, Global R = 0.091). The relative abundance of C. monilifera and P. esculentum contributed most to the differences. We discuss the possible development of a low diversity bracken fern parkland in Booderee National Park through a trophic cascade, similar to that caused by overabundant deer in the northern hemisphere. We also discuss its implications for broad scale fox control in southern Australian forests. PMID- 23990878 TI - Multifractal analysis for nutritional assessment. AB - The concept of multifractality is currently used to describe self-similar and complex scaling properties observed in numerous biological signals. Fractals are geometric objects or dynamic variations which exhibit some degree of similarity (irregularity) to the original object in a wide range of scales. This approach determines irregularity of biologic signal as an indicator of adaptability, the capability to respond to unpredictable stress, and health. In the present work, we propose the application of multifractal analysis of wavelet-transformed proton nuclear magnetic resonance ((1)H NMR) spectra of plasma to determine nutritional insufficiency. For validation of this method on (1)H NMR signal of human plasma, standard deviation from classical statistical approach and Hurst exponent (H), left slope and partition function from multifractal analysis were extracted from (1)H NMR spectra to test whether multifractal indices could discriminate healthy subjects from unhealthy, intensive care unit patients. After validation, the multifractal approach was applied to spectra of plasma from a modified crossover study of sulfur amino acid insufficiency and tested for associations with blood lipids. The results showed that standard deviation and H, but not left slope, were significantly different for sulfur amino acid sufficiency and insufficiency. Quadratic discriminant analysis of H, left slope and the partition function showed 78% overall classification accuracy according to sulfur amino acid status. Triglycerides and apolipoprotein C3 were significantly correlated with a multifractal model containing H, left slope, and standard deviation, and cholesterol and high-sensitivity C-reactive protein were significantly correlated to H. In conclusion, multifractal analysis of (1)H NMR spectra provides a new approach to characterize nutritional status. PMID- 23990880 TI - Incorporating disease and population structure into models of SIR disease in contact networks. AB - We consider the recently introduced edge-based compartmental models (EBCM) for the spread of susceptible-infected-recovered (SIR) diseases in networks. These models differ from standard infectious disease models by focusing on the status of a random partner in the population, rather than a random individual. This change in focus leads to simple analytic models for the spread of SIR diseases in random networks with heterogeneous degree. In this paper we extend this approach to handle deviations of the disease or population from the simplistic assumptions of earlier work. We allow the population to have structure due to effects such as demographic features or multiple types of risk behavior. We allow the disease to have more complicated natural history. Although we introduce these modifications in the static network context, it is straightforward to incorporate them into dynamic network models. We also consider serosorting, which requires using dynamic network models. The basic methods we use to derive these generalizations are widely applicable, and so it is straightforward to introduce many other generalizations not considered here. Our goal is twofold: to provide a number of examples generalizing the EBCM method for various different population or disease structures and to provide insight into how to derive such a model under new sets of assumptions. PMID- 23990881 TI - Tracking single cells in live animals using a photoconvertible near-infrared cell membrane label. AB - We describe a novel photoconversion technique to track individual cells in vivo using a commercial lipophilic membrane dye, DiR. We show that DiR exhibits a permanent fluorescence emission shift (photoconversion) after light exposure and does not reacquire the original color over time. Ratiometric imaging can be used to distinguish photoconverted from non-converted cells with high sensitivity. Combining the use of this photoconvertible dye with intravital microscopy, we tracked the division of individual hematopoietic stem/progenitor cells within the calvarium bone marrow of live mice. We also studied the peripheral differentiation of individual T cells by tracking the gain or loss of FoxP3-GFP expression, a marker of the immune suppressive function of CD4(+) T cells. With the near-infrared photoconvertible membrane dye, the entire visible spectral range is available for simultaneous use with other fluorescent proteins to monitor gene expression or to trace cell lineage commitment in vivo with high spatial and temporal resolution. PMID- 23990882 TI - LIM domains target actin regulators paxillin and zyxin to sites of stress fiber strain. AB - Contractile actomyosin stress fibers are critical for maintaining the force balance between the interior of the cell and its environment. Consequently, the actin cytoskeleton undergoes dynamic mechanical loading. This results in spontaneous, stochastic, highly localized strain events, characterized by thinning and elongation within a discrete region of stress fiber. Previous work showed the LIM-domain adaptor protein, zyxin, is essential for repair and stabilization of these sites. Using live imaging, we show paxillin, another LIM domain adaptor protein, is also recruited to stress fiber strain sites. Paxillin recruitment to stress fiber strain sites precedes zyxin recruitment. Zyxin and paxillin are each recruited independently of the other. In cells lacking paxillin, actin recovery is abrogated, resulting in slowed actin recovery and increased incidence of catastrophic stress fiber breaks. For both paxillin and zyxin, the LIM domains are necessary and sufficient for recruitment. This work provides further evidence of the critical role of LIM-domain proteins in responding to mechanical stress in the actin cytoskeleton. PMID- 23990883 TI - Interspecific introgression in cetaceans: DNA markers reveal post-F1 status of a pilot whale. AB - Visual species identification of cetacean strandings is difficult, especially when dead specimens are degraded and/or species are morphologically similar. The two recognised pilot whale species (Globicephala melas and Globicephala macrorhynchus) are sympatric in the North Atlantic Ocean. These species are very similar in external appearance and their morphometric characteristics partially overlap; thus visual identification is not always reliable. Genetic species identification ensures correct identification of specimens. Here we have employed one mitochondrial (D-Loop region) and eight nuclear loci (microsatellites) as genetic markers to identify six stranded pilot whales found in Galicia (Northwest Spain), one of them of ambiguous phenotype. DNA analyses yielded positive amplification of all loci and enabled species identification. Nuclear microsatellite DNA genotypes revealed mixed ancestry for one individual, identified as a post-F1 interspecific hybrid employing two different Bayesian methods. From the mitochondrial sequence the maternal species was Globicephala melas. This is the first hybrid documented between Globicephala melas and G. macrorhynchus, and the first post-F1 hybrid genetically identified between cetaceans, revealing interspecific genetic introgression in marine mammals. We propose to add nuclear loci to genetic databases for cetacean species identification in order to detect hybrid individuals. PMID- 23990886 TI - HIV-DNA in the genital tract of women on long-term effective therapy is associated to residual viremia and previous AIDS-defining illnesses. AB - OBJECTIVES: To assess the impact of long-term combined antiretroviral therapy (cART) on HIV-RNA and HIV-DNA levels in cervicovaginal secretions of HIV-1 infected women with sustained undetectable plasma RNA viral load (PVL); to explore factors predictive of residual viral shedding; and to evaluate the risk of heterosexual transmission. METHODS: Women with undetectable PVL (<50 copies/mL) for >6 months were included in this cross-sectional study. HIV-RNA and HIV-DNA were measured in blood and cervicovaginal lavage fluid (CVL). Women were systematically tested for genital infections. The risk of transmission to male partners during unprotected intercourse was estimated. RESULTS: Eighty-one women composed the study population: all had HIV-RNA <40 copies/mL in CVL. HIV-DNA was detectable in CVL of 29/78 patients (37%). There was a weak positive correlation between HIV-DNA levels in PBMCs and CVL (r = 0.20; p = 0.08). In multivariate analysis, two factors were associated with HIV-DNA detection in CVL: previous AIDS-defining illnesses (OR = 11; 95%CI = 2-61) and current residual viremia (200.20) across treatment arms. Baseline PHQ-9 scores were no significantly related to adherence to moodManager. CONCLUSIONS: TeleCoach produced significantly greater adherence to moodManager, relative to self directed moodManager. TeleCoached moodManager produced greater reductions in depressive symptoms relative to WLC, however, there were no statistically significant differences relative to self-directed moodManager. While greater use was associated with better outcomes, most users in both TeleCoach and self directed moodManager had dropped out of treatment by week 12. Even with telephone coaching, adherence to web-based interventions for depression remains a challenge. Methods of improving coaching models are discussed. TRIAL REGISTRATION: Clinicaltrials.gov NCT00719979. PMID- 23990897 TI - Tyrosinase inhibitory effects and antioxidative activities of saponins from Xanthoceras Sorbifolia nutshell. AB - Certain saponins are bioactive compounds with anticancer, antivirus and antioxidant activities. This paper discussed inhibitory effects of saponins from Xanthoceras Sorbifolia on tyrosinase, through the research of the rate of tyrosinase catalyzed L-DOPA oxidation. The inhibition rate of tyrosinase activity presented non-linear changes with the saponins concentration. The rate reached 52.0% when the saponins concentration was 0.96 mg/ml. Antioxidant activities of saponins from Xanthoceras Sorbifolia were evaluated by using hydroxyl and superoxide radical scavenging assays. The hydroxyl radical scavenging effects of the saponins were 15.5-68.7%, respectively at the concentration of 0.18-2.52 mg/ml. The superoxide radical scavenging activity reduced from 96.6% to 7.05% with the time increasing at the concentration of 1.44 mg/ml. All the above antioxidant evaluation indicated that saponins from Xanthoceras Sorbifolia exhibited good antioxidant activity in a concentration- dependent manner. PMID- 23990898 TI - The biological clock is regulated by adrenergic signaling in brown fat but is dispensable for cold-induced thermogenesis. AB - The biological clock plays an important role in integrating nutrient and energy metabolism with other cellular processes. Previous studies have demonstrated that core clock genes are rhythmically expressed in peripheral tissues, including the liver, skeletal muscle, pancreatic islets, and white and brown adipose tissues. These peripheral clocks are entrained by physiological cues, thereby aligning the circadian pacemaker to tissue functions. The mechanisms that regulate brown adipose tissue clock in response to physiological signals remain poorly understood. Here we found that the expression of core clock genes is highly responsive to cold exposure in brown fat, but not in white fat. This cold inducible regulation of the clock network is mediated by adrenergic receptor activation and the transcriptional coactivator PGC-1alpha. Brown adipocytes in mice lacking a functional clock contain large lipid droplets accompanied by dysregulation of genes involved in lipid metabolism and adaptive thermogenesis. Paradoxically, the "clockless" mice were competent in maintaining core body temperature during cold exposure. These studies elucidated the presence of adrenergic receptor/clock crosstalk that appears to be required for normal thermogenic gene expression in brown fat. PMID- 23990899 TI - Can yeast (S. cerevisiae) metabolic volatiles provide polymorphic signaling? AB - Chemical signaling between organisms is a ubiquitous and evolutionarily dynamic process that helps to ensure mate recognition, location of nutrients, avoidance of toxins, and social cooperation. Evolutionary changes in chemical communication systems progress through natural variation within the organism generating the signal as well as the responding individuals. A promising yet poorly understood system with which to probe the importance of this variation exists between D. melanogaster and S. cerevisiae. D. melanogaster relies on yeast for nutrients, while also serving as a vector for yeast cell dispersal. Both are outstanding genetic and genomic models, with Drosophila also serving as a preeminent model for sensory neurobiology. To help develop these two genetic models as an ecological model, we have tested if - and to what extent - S. cerevisiae is capable of producing polymorphic signaling through variation in metabolic volatiles. We have carried out a chemical phenotyping experiment for 14 diverse accessions within a common garden random block design. Leveraging genomic sequences for 11 of the accessions, we ensured a genetically broad sample and tested for phylogenetic signal arising from phenotypic dataset. Our results demonstrate that significant quantitative differences for volatile blends do exist among S. cerevisiae accessions. Of particular ecological relevance, the compounds driving the blend differences (acetoin, 2-phenyl ethanol and 3-methyl-1 butanol) are known ligands for D. melanogasters chemosensory receptors, and are related to sensory behaviors. Though unable to correlate the genetic and volatile measurements, our data point clear ways forward for behavioral assays aimed at understanding the implications of this variation. PMID- 23990900 TI - Integrating milk metabolite profile information for the prediction of traditional milk traits based on SNP information for Holstein cows. AB - In this study the benefit of metabolome level analysis for the prediction of genetic value of three traditional milk traits was investigated. Our proposed approach consists of three steps: First, milk metabolite profiles are used to predict three traditional milk traits of 1,305 Holstein cows. Two regression methods, both enabling variable selection, are applied to identify important milk metabolites in this step. Second, the prediction of these important milk metabolite from single nucleotide polymorphisms (SNPs) enables the detection of SNPs with significant genetic effects. Finally, these SNPs are used to predict milk traits. The observed precision of predicted genetic values was compared to the results observed for the classical genotype-phenotype prediction using all SNPs or a reduced SNP subset (reduced classical approach). To enable a comparison between SNP subsets, a special invariable evaluation design was implemented. SNPs close to or within known quantitative trait loci (QTL) were determined. This enabled us to determine if detected important SNP subsets were enriched in these regions. The results show that our approach can lead to genetic value prediction, but requires less than 1% of the total amount of (40,317) SNPs., significantly more important SNPs in known QTL regions were detected using our approach compared to the reduced classical approach. Concluding, our approach allows a deeper insight into the associations between the different levels of the genotype phenotype map (genotype-metabolome, metabolome-phenotype, genotype-phenotype). PMID- 23990901 TI - Balancing theory and practice in respondent-driven sampling: a case study of innovations developed to overcome recruitment challenges. AB - INTRODUCTION: Respondent-driven sampling (RDS) offers a recruitment strategy for hard-to-reach populations. However, RDS faces logistical and theoretical challenges that threaten efficiency and validity in settings worldwide. We present innovative adaptations to conventional RDS to overcome barriers encountered in recruiting a large, representative sample of men who have sex with men (MSM) who travel internationally. METHODS: Novel methodological adaptations for the "International Travel Research to Inform Prevention" or "I-TRIP" study were offering participants a choice between electronic and paper coupons referrals for recruitment and modifying the secondary incentives structure from small cash amounts to raffle entries for periodic large cash prize raffle drawings. Staged referral limit increases from 3 to 10 referrals and progressive addition of 70 seeds were also implemented. RESULTS: There were 501 participants enrolled in up to 13 waves of growth. Among participants with a choice of referral methods, 81% selected electronic referrals. Of participants who were recruited electronically, 90% chose to remain with electronic referrals when it was their turn to recruit. The mean number of enrolled referrals was 0.91 for electronic referrals compared to 0.56 for paper coupons. Median referral lag time, i.e., the time interval between when recruiters were given their referrals and when a referred individual enrolled in the study, was 20 days (IQR 10-40) for electronic referrals, 20 days (IQR 8-58) for paper coupons, 20 days (IQR 10-41) for raffle entries and 33 days (IQR 16-148) for small cash incentives. CONCLUSIONS: The recruitment of MSM who travel internationally required maximizing known flexible tools of RDS while at the same time necessitating innovations to increase recruitment efficiency. Electronic referrals emerged as a major advantage in recruiting this hard-to-reach population who are of high socio economic status, geographically diffuse and highly mobile. These enhancements may improve the performance of RDS in target populations with similar characteristics. PMID- 23990902 TI - Characterization of SLITRK1 variation in obsessive-compulsive disorder. AB - Obsessive compulsive disorder (OCD) is a syndrome characterized by recurrent and intrusive thoughts and ritualistic behaviors or mental acts that a person feels compelled to perform. Twin studies, family studies, and segregation analyses provide compelling evidence that OCD has a strong genetic component. The SLITRK1 gene encodes a developmentally regulated stimulator of neurite outgrowth and previous studies have implicated rare variants in this gene in disorders in the OC spectrum, specifically Tourette syndrome (TS) and trichotillomania (TTM). The objective of the current study was to evaluate rare genetic variation in SLITRK1 in risk for OCD and to functionally characterize associated coding variants. We sequenced SLITRK1 coding exons in 381 individuals with OCD as well as in 356 control samples and identified three novel variants in seven individuals. We found that the combined mutation load in OCD relative to controls was significant (p = 0.036). We identified a missense N400I change in an individual with OCD, which was not found in more than 1000 control samples (P<0.05). In addition, we showed the the N400I variant failed to enhance neurite outgrowth in primary neuronal cultures, in contrast to wildtype SLITRK1, which enhanced neurite outgrowth in this assay. These important functional differences in the N400I variant, as compared to the wildtype SLITRK1 sequence, may contribute to OCD and OC spectrum symptoms. A synonymous L63L change identified in an individual with OCD and an additional missense change, T418S, was found in four individuals with OCD and in one individual without an OCD spectrum disorder. Examination of additional samples will help assess the role of rare SLITRK1 variation in OCD and in related psychiatric illness. PMID- 23990903 TI - Hypomethylation of Alu elements in post-menopausal women with osteoporosis. AB - A decrease in genomic methylation commonly occurs in aging cells; however, whether this epigenetic modification leads to age-related phenotypes has not been evaluated. Alu elements are the major interspersed repetitive DNA elements in humans that lose DNA methylation in aging individuals. Alu demethylation in blood cells starts at approximately 40 years of age, and the degree of Alu hypomethylation increases with age. Bone mass is lost with aging, particularly in menopausal women with lower body mass. Consequently, osteoporosis is commonly found in thin postmenopausal women. Here, we correlated the Alu methylation level of blood cells with bone density in 323 postmenopausal women. Alu hypomethylation was associated with advanced age and lower bone mass density, (P<0.05). The association between the Alu methylation level and bone mass was independent of age, body mass, and body fat, with an odds ratio [1] = 0.4316 (0.2087-0.8927). Individuals of the same age with osteopenia, osteoporosis, and a high body mass index have lower Alu methylation levels (P = 0.0005, 0.003, and <=0.0001, respectively). Finally, when comparing individuals with the same age and body mass, Alu hypomethylation was observed in individuals with lower bone mass (P<0.0001). In conclusion, there are positive correlations between Alu hypomethylation in blood cells and several age-related phenotypes in bone and body fat. Therefore, reduced global methylation may play a role in the systemic senescence process. Further evaluation of Alu hypomethylation may clarify the epigenetic regulation of osteoporosis in post-menopausal women. PMID- 23990904 TI - Bovine mammary gene expression profiling during the onset of lactation. AB - BACKGROUND: Lactogenesis includes two stages. Stage I begins a few weeks before parturition. Stage II is initiated around the time of parturition and extends for several days afterwards. METHODOLOGY/PRINCIPAL FINDINGS: To better understand the molecular events underlying these changes, genome-wide gene expression profiling was conducted using digital gene expression (DGE) on bovine mammary tissue at three time points (on approximately day 35 before parturition (-35 d), day 7 before parturition (-7 d) and day 3 after parturition (+3 d)). Approximately 6.2 million (M), 5.8 million (M) and 6.1 million (M) 21-nt cDNA tags were sequenced in the three cDNA libraries (-35 d, -7 d and +3 d), respectively. After aligning to the reference sequences, the three cDNA libraries included 8,662, 8,363 and 8,359 genes, respectively. With a fold change cutoff criteria of >= 2 or <=-2 and a false discovery rate (FDR) of <= 0.001, a total of 812 genes were significantly differentially expressed at -7 d compared with -35 d (stage I). Gene ontology analysis showed that those significantly differentially expressed genes were mainly associated with cell cycle, lipid metabolism, immune response and biological adhesion. A total of 1,189 genes were significantly differentially expressed at +3 d compared with -7 d (stage II), and these genes were mainly associated with the immune response and cell cycle. Moreover, there were 1,672 genes significantly differentially expressed at +3 d compared with -35 d. Gene ontology analysis showed that the main differentially expressed genes were those associated with metabolic processes. CONCLUSIONS: The results suggest that the mammary gland begins to lactate not only by a gain of function but also by a broad suppression of function to effectively push most of the cell's resources towards lactation. PMID- 23990905 TI - Variation in the sodium-dependent vitamin C transporter 2 gene is associated with risk of acute coronary syndrome among women. AB - BACKGROUND: Vitamin C is associated with a lower risk of coronary heart disease possibly due to its anti-oxidative effects, beneficial effects on endothelial function and importance in collagen synthesis. The sodium-dependent vitamin C transporter 2 is responsible for the transport of vitamin C into various cells and malfunction of this protein leads to reduced vitamin C in tissue, including the arterial wall. We tested the hypothesis that candidate variations rs6139591 and rs1776964 in the gene coding for sodium-dependent vitamin C transporter 2 are associated with development of acute coronary syndrome. DESIGN: In the Danish Diet, Cancer and Health cohort study, we performed a case-cohort study among 57,053 subjects aged 50-64 years. RESULTS: During a mean follow-up period of 6.4 years, we identified 936 cases and randomly selected a sub-cohort (n = 1,580) with full information on genotypes and covariates. Using Cox proportional hazard models, we found that women with the rs6139591 TT genotype and a lower than median dietary vitamin C intake had a higher risk of acute coronary syndrome compared with those with the CC genotype (adjusted HR 5.39, 95% confidence interval, 2.01-14.50). We also observed a not as strong but positive although inconsistent association for women at a higher than median intake of vitamin C rich food. For the rs1776964 polymorphism, we found a higher risk (adjusted HR 3.45, 95% CI, 1.16-10.28) among TT-homozygous women with higher than median vitamin C intake compared with the CC genotype and low vitamin C intake. Among men, weaker and non-significant associations were observed for both polymorphisms. CONCLUSION: Genetic variation in the sodium-dependent vitamin C transporter 2 is associated with risk of incident acute coronary syndrome in women. The genotype effects may not be fully compensated by a higher intake of vitamin C rich food. PMID- 23990906 TI - Concentration addition, independent action and generalized concentration addition models for mixture effect prediction of sex hormone synthesis in vitro. AB - Humans are concomitantly exposed to numerous chemicals. An infinite number of combinations and doses thereof can be imagined. For toxicological risk assessment the mathematical prediction of mixture effects, using knowledge on single chemicals, is therefore desirable. We investigated pros and cons of the concentration addition (CA), independent action (IA) and generalized concentration addition (GCA) models. First we measured effects of single chemicals and mixtures thereof on steroid synthesis in H295R cells. Then single chemical data were applied to the models; predictions of mixture effects were calculated and compared to the experimental mixture data. Mixture 1 contained environmental chemicals adjusted in ratio according to human exposure levels. Mixture 2 was a potency adjusted mixture containing five pesticides. Prediction of testosterone effects coincided with the experimental Mixture 1 data. In contrast, antagonism was observed for effects of Mixture 2 on this hormone. The mixtures contained chemicals exerting only limited maximal effects. This hampered prediction by the CA and IA models, whereas the GCA model could be used to predict a full dose response curve. Regarding effects on progesterone and estradiol, some chemicals were having stimulatory effects whereas others had inhibitory effects. The three models were not applicable in this situation and no predictions could be performed. Finally, the expected contributions of single chemicals to the mixture effects were calculated. Prochloraz was the predominant but not sole driver of the mixtures, suggesting that one chemical alone was not responsible for the mixture effects. In conclusion, the GCA model seemed to be superior to the CA and IA models for the prediction of testosterone effects. A situation with chemicals exerting opposing effects, for which the models could not be applied, was identified. In addition, the data indicate that in non potency adjusted mixtures the effects cannot always be accounted for by single chemicals. PMID- 23990907 TI - Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens. AB - A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens. PMID- 23990908 TI - Adaptor identity modulates adaptation effects in familiar face identification and their neural correlates. AB - Adaptation-related aftereffects (AEs) show how face perception can be altered by recent perceptual experiences. Along with contrastive behavioural biases, modulations of the early event-related potentials (ERPs) were typically reported on categorical levels. Nevertheless, the role of the adaptor stimulus per se for face identity-specific AEs is not completely understood and was therefore investigated in the present study. Participants were adapted to faces (S1s) varying systematically on a morphing continuum between pairs of famous identities (identities A and B), or to Fourier phase-randomized faces, and had to match the subsequently presented ambiguous faces (S2s; 50/50% identity A/B) to one of the respective original faces. We found that S1s identical with or near to the original identities led to strong contrastive biases with more identity B responses following A adaptation and vice versa. In addition, the closer S1s were to the 50/50% S2 on the morphing continuum, the smaller the magnitude of the AE was. The relation between S1s and AE was, however, not linear. Additionally, stronger AEs were accompanied by faster reaction times. Analyses of the simultaneously recorded ERPs revealed categorical adaptation effects starting at 100 ms post-stimulus onset, that were most pronounced at around 125-240 ms for occipito-temporal sites over both hemispheres. S1-specific amplitude modulations were found at around 300-400 ms. Response-specific analyses of ERPs showed reduced voltages starting at around 125 ms when the S1 biased perception in a contrastive way as compared to when it did not. Our results suggest that face identity AEs do not only depend on physical differences between S1 and S2, but also on perceptual factors, such as the ambiguity of S1. Furthermore, short-term plasticity of face identity processing might work in parallel to object-category processing, and is reflected in the first 400 ms of the ERP. PMID- 23990909 TI - Suppressor of Cytokine Signaling (SOCS) 5 utilises distinct domains for regulation of JAK1 and interaction with the adaptor protein Shc-1. AB - Suppressor of Cytokine Signaling (SOCS)5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF) signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR). Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling. PMID- 23990910 TI - Phytoliths in pottery reveal the use of spice in European prehistoric cuisine. AB - Here we present evidence of phytoliths preserved in carbonised food deposits on prehistoric pottery from the western Baltic dating from 6,100 cal BP to 5750 cal BP. Based on comparisons to over 120 European and Asian species, our observations are consistent with phytolith morphologies observed in modern garlic mustard seed (Alliaria petiolata (M. Bieb) Cavara & Grande). As this seed has a strong flavour, little nutritional value, and the phytoliths are found in pots along with terrestrial and marine animal residues, these findings are the first direct evidence for the spicing of food in European prehistoric cuisine. Our evidence suggests a much greater antiquity to the spicing of foods than is evident from the macrofossil record, and challenges the view that plants were exploited by hunter-gatherers and early agriculturalists solely for energy requirements, rather than taste. PMID- 23990911 TI - Quantitative proteomic analysis of human lung tumor xenografts treated with the ectopic ATP synthase inhibitor citreoviridin. AB - ATP synthase is present on the plasma membrane of several types of cancer cells. Citreoviridin, an ATP synthase inhibitor, selectively suppresses the proliferation and growth of lung cancer without affecting normal cells. However, the global effects of targeting ectopic ATP synthase in vivo have not been well defined. In this study, we performed quantitative proteomic analysis using isobaric tags for relative and absolute quantitation (iTRAQ) and provided a comprehensive insight into the complicated regulation by citreoviridin in a lung cancer xenograft model. With high reproducibility of the quantitation, we obtained quantitative proteomic profiling with 2,659 proteins identified. Bioinformatics analysis of the 141 differentially expressed proteins selected by their relative abundance revealed that citreoviridin induces alterations in the expression of glucose metabolism-related enzymes in lung cancer. The up regulation of enzymes involved in gluconeogenesis and storage of glucose indicated that citreoviridin may reduce the glycolytic intermediates for macromolecule synthesis and inhibit cell proliferation. Using comprehensive proteomics, the results identify metabolic aspects that help explain the antitumorigenic effect of citreoviridin in lung cancer, which may lead to a better understanding of the links between metabolism and tumorigenesis in cancer therapy. PMID- 23990912 TI - Folic acid conjugated delta-valerolactone-poly(ethylene glycol) based triblock copolymer as a promising carrier for targeted doxorubicin delivery. AB - The aim of this study is to test the hypothesis that the newly synthesized poly(delta-valerolactone)/poly(ethylene glycol)/poly(delta-valerolactone) (VEV) copolymer grafted with folic acid would impart targetability and further enhance the anti-tumor efficacy of doxorubicin (DOX). Here, folic acid conjugated VEV (VEV-FOL) was synthesized by a modified esterification method and characterized using IR and NMR. DOX loaded VEV-FOL micelles were synthesized using a novel solvent evaporation method and were obtained with a mean diameter of 97 nm with high encapsulation efficiency and sustained in vitro release profile. Comparative studies of polymer micelles with and without folate for cellular uptake and cytotoxicity were done on folate receptor-positive breast cancer cell line, MDAMB231. The intracellular uptake tests showed significant increase in folate micellar uptake when compared to non-folate-mediated micelles. MTT assay followed by apoptosis assays clearly indicated that folate decorated micelles showed significantly better cytotoxicity (IC50 = 0.014 uM) and efficiency to induce apoptosis than other treated groups. Moreover, a significant G2/M arrest was induced by DOX loaded VEV-FOL micelles at a concentration where free drug failed to show any activity. Thus, our results show that the folic acid-labeled VEV copolymer is a promising biomaterial with controlled and sustainable tumor targeting ability for anticancer drugs which can open new frontiers in the area of targeted chemotherapy. PMID- 23990913 TI - jClustering, an open framework for the development of 4D clustering algorithms. AB - We present jClustering, an open framework for the design of clustering algorithms in dynamic medical imaging. We developed this tool because of the difficulty involved in manually segmenting dynamic PET images and the lack of availability of source code for published segmentation algorithms. Providing an easily extensible open tool encourages publication of source code to facilitate the process of comparing algorithms and provide interested third parties with the opportunity to review code. The internal structure of the framework allows an external developer to implement new algorithms easily and quickly, focusing only on the particulars of the method being implemented and not on image data handling and preprocessing. This tool has been coded in Java and is presented as an ImageJ plugin in order to take advantage of all the functionalities offered by this imaging analysis platform. Both binary packages and source code have been published, the latter under a free software license (GNU General Public License) to allow modification if necessary. PMID- 23990914 TI - A focus on the optical properties of the regenerated newt lens. AB - Lens regeneration studies in the adult newt suggest that molecular aspects of lens regeneration are complete within 5 weeks of lentectomy. However, very little is known about the optical properties of the regenerated lens. In an aquatic environment, the lens accounts for almost all of the refractive power of the eye, and thus, a fully functional lens is critical. We compared the optical properties of 9- and 26-week regenerated lenses in the red spotted newt, Notophthalmus viridescens, with the original lenses removed from the same eyes. At 9 weeks, the regenerated lenses are smaller than the original lenses and are histologically immature, with a lower density of lens proteins. The 9 week lenses have greater light transmission, but significantly reduced focal length and refractive index than the original lenses. This suggests that following 9 weeks of regeneration, the lenses have not recovered the functionality of the original lens. By 26 weeks, the transmission of light in the more mature lens is reduced, but the optical parameters of the lens have recovered enough to allow functional vision. PMID- 23990915 TI - Measuring social contacts in the emergency department. AB - BACKGROUND: Infectious individuals in an emergency department (ED) bring substantial risks of cross infection. Data about the complex social and spatial structure of interpersonal contacts in the ED will aid construction of biologically plausible transmission risk models that can guide cross infection control. METHODS AND FINDINGS: We sought to determine the number and duration of contacts among patients and staff in a large, busy ED. This prospective study was conducted between 1 July 2009 and 30 June 2010. Two 12-hour shifts per week were randomly selected for study. The study was conducted in the ED of an urban hospital. There were 81 shifts in the planned random sample of 104 (78%) with usable contact data, during which there were 9183 patient encounters. Of these, 6062 (66%) were approached to participate, of which 4732 (78%) agreed. Over the course of the year, 88 staff members participated (84%). A radiofrequency identification (RFID) system was installed and the ED divided into 89 distinct zones structured so copresence of two individuals in any zone implied a very high probability of contact <1 meter apart in space. During study observation periods, patients and staff were given RFID tags to wear. Contact events were recorded. These were further broken down with respect to the nature of the contacts, i.e., patient with patient, patient with staff, and staff with staff. 293,171 contact events were recorded, with a median of 22 contact events and 9 contacts with distinct individuals per participant per shift. Staff-staff interactions were more numerous and longer than patient-patient or patient-staff interactions. CONCLUSIONS: We used RFID to quantify contacts between patients and staff in a busy ED. These results are useful for studies of the spread of infections. By understanding contact patterns most important in potential transmission, more effective prevention strategies may be implemented. PMID- 23990916 TI - Antibiotic resistance of bacteria isolated from the internal organs of edible snow crabs. AB - Antibiotic resistance and microbiota within edible snow crabs are important for the Chionoecetes (snow crab) fishing industry. We investigated these parameters using culture methods and antibiotic susceptibility tests with six internal organs from three species of Chionoecetes. Each sample revealed many unexpected microbial species within Chionoecetes internal organs. On the basis of 16S rRNA sequence analysis of 381 isolates, the most abundant genera identified in Chionoecetes opilio were Acinetobacter spp. (24%), Bacillus spp. (4%), Pseudomonas spp. (34%), Stenotrophomonas spp. (28%), and Agreia spp. (11%). In Chionoecetes sp. crabs, Acinetobacter spp. (23%), Bacillus spp. (12%), and Psychrobacter spp. (20%) were most prevalent, while Agreia spp. (11%), Bacillus spp. (31%), Microbacterium spp. (10%), Rhodococcus spp. (12%), and Agrococcus spp. (6%) were most abundant in C. japonicus. Our antibiotic resistance test found resistance to all nine antibiotics tested in 19, 14, and two of the isolates from C. opilio, Chionoecetes sp., and, C. japonicus respectively. Our results are the first to show that microbes with antibiotic resistance are widely distributed throughout the internal organs of natural snow crabs. PMID- 23990917 TI - The prognostic significance of Wnt-5a expression in primary breast cancer is extended to premenopausal women. AB - Wnt-5a protein expression in primary tumors from unselected breast cancer patients has revealed a tumor suppressive function of the protein. However, in vitro experiments on human breast cancer cells have reported contradictory results, indicating both a tumor suppressive and promoting functions of Wnt-5a. This could be due to various functions of Wnt-5a in different subgroups of patients. The unselected cohorts analyzed to date for Wnt-5a protein expression contained few premenopausal patients. The aim of the present investigation was to evaluate the prognostic significance of Wnt-5a protein expression in a cohort of premenopausal women with comprehensive data on biomarkers, molecular subtypes and long-term outcome. In a randomized trial of adjuvant tamoxifen versus no adjuvant treatment, 564 premenopausal primary breast cancer patients were included. The median follow-up time was 14 years. A tumor tissue array was constructed and 361 samples were evaluated for Wnt-5a reactivity by immunohistochemistry. The primary end-point was recurrence-free survival. Wnt-5a protein expression was reduced or lost in 146/361 of tumors and correlated to younger age, estrogen receptor (ER) negativity and triple-negative phenotype. Wnt-5a was a prognostic factor in the whole cohort (p = 0.003). In patients with ER-positive tumors, Wnt-5a was an independent positive prognostic marker (HR 0.51 95% CI: 0.33-0.78 p = 0.002) and HER2 a negative prognostic marker (HR 2.84 95% CI: 1.51-5.31, p = 0.001) in a Cox multivariate analysis adjusted for standard prognostic markers and tamoxifen treatment. In the ER-negative subset, Wnt-5a added no prognostic information. In a subgroup analysis, Wnt-5a was significantly associated with better prognosis in patients with Luminal A tumors (p = 0.04). Conclusively, our results suggest that loss of Wnt-5a is a valuable prognostic marker in premenopausal breast cancer patients in particular in patients with ER-positive tumors and out-performed conventional prognostic factors in this subset of patients. PMID- 23990919 TI - Attitudes towards doping and related experience in Spanish national cycling teams according to different Olympic disciplines. AB - Attitudes towards doping are considered an influence of doping intentions. The aims of the present study were 1) to discover and compare the attitudes towards doping among Spanish national team cyclists from different Olympic disciplines, as well as 2) to get some complementary information that could better explain the context. The sample was comprised of seventy-two cyclists: mean age 19.67+/-4.72 years; 70.8% males (n = 51); from the different Olympic disciplines of Mountain bike -MTB- (n = 18), Bicycle Moto Cross -BMX- (n = 12), Track -TRA- (n = 9) and Road -ROA- (n = 33). Descriptive design was carried out using a validated scale (PEAS). To complement this, a qualitative open-ended questionnaire was used. Overall mean score (17-102) was 36.12+/-9.39. For different groups, the data were: MTB: 30.28+/-6.92; BMX: 42.46+/-10.74; TRA: 43.22+/-12.00; ROA: 34.91+/ 6.62, respectively. In relation to overall score, significant differences were observed between MTB and BMX (p = 0.002) and between MTB and TRA (p = 0.003). For the open-ended qualitative questionnaire, the most mentioned word associated with "doping" was "cheating" (48.83% of total sample), with "responsible agents of doping" the word "doctor" (52,77%), and with the "main reason for the initiation in doping" the words "sport achievement" (45.83%). The major proposed solution was "doing more doping controls" (43.05%). Moreover, 48.67% stated that there was "a different treatment between cycling and other sports". This study shows that Spanish national team cyclists from Olympic cycling disciplines, in general, are not tolerant in relation to doping. BMX and Track riders are a little more permissive towards the use of banned substances than MTB and Road. Results from the qualitative open-ended questionnaire showed interesting data in specific questions. These results empower the idea that, apart from maintaining doping controls and making them more efficient, anti-doping education programs are needed from the earliest ages. PMID- 23990918 TI - High-throughput sequencing and degradome analysis identify miRNAs and their targets involved in fruit senescence of Fragaria ananassa. AB - In non-climacteric fruits, the respiratory increase is absent and no phytohormone is appearing to be critical for their ripening process. They must remain on the parent plant to enable full ripening and be picked at or near the fully ripe stage to obtain the best eating quality. However, huge losses often occur for their quick post-harvest senescence. To understanding the complex mechanism of non-climacteric fruits post-harvest senescence, we constructed two small RNA libraries and one degradome from strawberry fruit stored at 20 degrees C for 0 and 24 h. A total of 88 known and 1224 new candidate miRNAs, and 103 targets cleaved by 19 known miRNAs families and 55 new candidatemiRNAs were obtained. These targets were associated with development, metabolism, defense response, signaling transduction and transcriptional regulation. Among them, 14 targets, including NAC transcription factor, Auxin response factors (ARF) and Myb transcription factors, cleaved by 6 known miRNA families and 6 predicted candidates, were found to be involved in regulating fruit senescence. The present study provided valuable information for understanding the quick senescence of strawberry fruit, and offered a foundation for studying the miRNA-mediated senescence of non-climacteric fruits. PMID- 23990920 TI - Human RNase H1 is associated with protein P32 and is involved in mitochondrial pre-rRNA processing. AB - Mammalian RNase H1 has been implicated in mitochondrial DNA replication and RNA processing and is required for embryonic development. We identified the mitochondrial protein P32 that binds specifically to human RNase H1, but not human RNase H2. P32 binds human RNase H1 via the hybrid-binding domain of the enzyme at an approximately 1?1 ratio. P32 enhanced the cleavage activity of RNase H1 by reducing the affinity of the enzyme for the heteroduplex substrate and enhancing turnover, but had no effect on the cleavage pattern. RNase H1 and P32 were partially co-localized in mitochondria and reduction of P32 or RNase H1 levels resulted in accumulation of mitochondrial pre ribosomal RNA [12S/16S] in HeLa cells. P32 also co-immunoprecipitated with MRPP1, a mitochondrial RNase P protein required for mitochondrial pre-rRNA processing. The P32-RNase H1 complex was shown to physically interact with mitochondrial DNA and pre-rRNA. These results expand the potential roles for RNase H1 to include assuring proper transcription and processing of guanosine-cytosine rich pre-ribosomal RNA in mitochondria. Further, the results identify P32 as a member of the 'RNase H1 degradosome' and the key P32 enhances the enzymatic efficiency of human RNase H1. PMID- 23990921 TI - Multiple host kinases contribute to Akt activation during Salmonella infection. AB - SopB is a type 3 secreted effector with phosphatase activity that Salmonella employs to manipulate host cellular processes, allowing the bacteria to establish their intracellular niche. One important function of SopB is activation of the pro-survival kinase Akt/protein kinase B in the infected host cell. Here, we examine the mechanism of Akt activation by SopB during Salmonella infection. We show that SopB-mediated Akt activation is only partially sensitive to PI3-kinase inhibitors LY294002 and wortmannin in HeLa cells, suggesting that Class I PI3 kinases play only a minor role in this process. However, depletion of PI(3,4) P2/PI(3-5) P3 by expression of the phosphoinositide 3-phosphatase PTEN inhibits Akt activation during Salmonella invasion. Therefore, production of PI(3,4) P2/PI(3-5) P3 appears to be a necessary event for Akt activation by SopB and suggests that non-canonical kinases mediate production of these phosphoinositides during Salmonella infection. We report that Class II PI3-kinase beta isoform, IPMK and other kinases identified from a kinase screen all contribute to Akt activation during Salmonella infection. In addition, the kinases required for SopB-mediated activation of Akt vary depending on the type of infected host cell. Together, our data suggest that Salmonella has evolved to use a single effector, SopB, to manipulate a remarkably large repertoire of host kinases to activate Akt for the purpose of optimizing bacterial replication in its host. PMID- 23990922 TI - Urinary uromodulin excretion predicts progression of chronic kidney disease resulting from IgA nephropathy. AB - BACKGROUND: Uromodulin, or Tamm-Horsfall protein, is the most abundant urinary protein in healthy individuals. Recent studies have suggested that uromodulin may play a role in chronic kidney diseases. We examined an IgA nephropathy cohort to determine whether uromodulin plays a role in the progression of IgA nephropathy. METHODS: A total of 344 IgA nephropathy patients were involved in this study. Morphological changes were evaluated with the Oxford classification of IgA nephropathy. Enzyme Linked Immunosorbent Assay (ELISA) measured the urinary uromodulin level on the renal biopsy day. Follow up was done regularly on 185 patients. Time-average blood pressure, time-average proteinuria, estimated glomerular filtration rate (eGFR) and eGFR decline rate were caculated. Association between the urinary uromodulin level and the eGFR decline rate was analyzed with SPSS 13.0. RESULTS: We found that lower baseline urinary uromodulin levels (P = 0.03) and higher time-average proteinuria (P = 0.04) were risk factors for rapid eGFR decline in a follow-up subgroup of the IgA nephropathy cohort. Urinary uromodulin level was correlated with tubulointerstitial lesions (P = 0.016). Patients that had more tubular atrophy/interstitial fibrosis on the surface had lower urinary uromodulin levels (P = 0.02). CONCLUSIONS: Urinary uromodulin level is associated with interstitial fibrosis/tubular atrophy and contributes to eGFR decline in IgA nephropathy. PMID- 23990923 TI - Demography and population dynamics of massive coral communities in adjacent high latitude regions (United Arab Emirates). AB - Individual massive coral colonies, primarily faviids and poritids, from three distinct assemblages within the southeastern Arabian Gulf and northwestern Gulf of Oman (United Arab Emirates) were studied from 2006-2009. Annual photographic censuses of approximately 2000 colonies were used to describe the demographics (size class frequencies, abundance, area cover) and population dynamics under "normal" environmental conditions. Size class transitions included growth, which occurred in 10-20% of the colonies, followed in decending order by partial mortality (3-16%), colony fission (<5%) and ramet fusion (<3%). Recruitment and whole colony mortality rates were low (<0.7 colonies/m(2)) with minimal interannual variation. Transition matrices indicated that the Arabian Gulf assemblages have declining growth rates (lambda<1) whereas the massive coral population is stable (lambda = 1) in the Gulf of Oman. Projection models indicated that (i) the Arabian Gulf population and area cover declines would be exacerbated under 10-year and 16-year disturbance scenarios as the vital rates do not allow for recovery to pre-disturbance levels during these timeframes, and (ii) the Gulf of Oman assemblage could return to its pre-disturbance area cover but its overall population size would not fully recover under the same scenarios. PMID- 23990924 TI - Association of systemic collagen type IV formation with survival among patients undergoing hemodialysis. AB - OBJECTIVE: The 7S domain of collagen type IV (P4NP_7S) assessed in plasma represents systemic collagen type IV formation. The objective of the study was to investigate the association of systemic collagen type IV formation with survival among patients undergoing hemodialysis. METHODS: We performed an observational cohort study of 371 hemodialysis patients. Plasma P4NP_7S was analyzed using a specific enzyme-linked immunosorbent assay detecting the amino-terminal propeptide of type IV procollagen. Association between categories of plasma P4NP_7S concentrations and survival was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model. RESULTS: For hemodialysis patients in the highest category of systemic collagen type IV formation, i.e. plasma P4NP_7S concentrations more than 775 pg/L, an increased risk for death was observed (highest P4NP_7S category vs all other categories, hazard ratio, 1.934; 95% confidence interval, 1.139 to 3.285). Survival analysis showed an increased risk of death in the highest P4NP_7S category compared to the other categories (Chi square 6.903; P = 0.032). Median survival was only 105 days in the highest P4NP_7S category whereas it was 629 days in the medium category, and 905 days in the lowest category. Multivariable-adjusted Cox regression showed increased odds for death with higher age and higher P4NP_7S categories. Systemic collagen type IV formation was associated with plasma concentrations of the collagen IV degradation product C4M (Spearman r = 0.764; P<0.0001) confirming extracellular matrix turnover. CONCLUSION: Among hemodialysis patients elevated systemic collagen type IV formation suggesting accelerating systemic fibrosis was associated with increased risk of death. PMID- 23990925 TI - Invasion dynamics of a fish-free landscape by brown trout (Salmo trutta). AB - Metapopulation dynamics over the course of an invasion are usually difficult to grasp because they require large and reliable data collection, often unavailable. The invasion of the fish-free freshwater ecosystems of the remote sub-Antarctic Kerguelen Islands following man-made introductions of brown trout (Salmo trutta) in the 1950's is an exception to this rule. Benefiting from a full long term environmental research monitoring of the invasion, we built a Bayesian dynamic metapopulation model to analyze the invasion dynamics of 85 river systems over 51 years. The model accounted for patch size (river length and connections to lakes), alternative dispersal pathways between rivers, temporal trends in dynamics, and uncertainty in colonization date. The results show that the model correctly represents the observed pattern of invasion, especially if we assume a coastal dispersal pathway between patches. Landscape attributes such as patch size influenced the colonization function, but had no effect on propagule pressure. Independently from patch size and distance between patches, propagule pressure and colonization function were not constant through time. Propagule pressure increased over the course of colonization, whereas the colonization function decreased, conditional on propagule pressure. The resulting pattern of this antagonistic interplay is an initial rapid invasion phase followed by a strong decrease in the invasion rate. These temporal trends may be due to either adaptive processes or environmental gradients encountered along the colonization front. It was not possible to distinguish these two hypotheses. Because invasibility of Kerguelen Is. freshwater ecosystems is very high due to the lack of a pre-existing fish fauna and minimal human interference, our estimates of invasion dynamics represent a blueprint for the potential of brown trout invasiveness in pristine environments. Our conclusions shed light on the future of polar regions where, because of climate change, fish-free ecosystems become increasingly accessible to invasion by fish species. PMID- 23990926 TI - Subtle population genetic structure in yelloweye rockfish (Sebastes ruberrimus) is consistent with a major oceanographic division in British Columbia, Canada. AB - The boundaries between oceanographic domains often function as dispersal barriers for many temperate marine species with a dispersive pelagic larval phase. Yelloweye rockfish (Sebastes ruberrimus, YR) are widely distributed across the northeastern Pacific Ocean, inhabiting coastal rocky reefs from the Aleutian Islands in Alaska through southern California. This species exhibits an extended pelagic larval duration and has the capacity for long distance larval transport. We assayed 2,862 YR individuals from 13 general areas in the northeast Pacific Ocean for allelic variation at nine microsatellite loci. Bayesian model-based clustering analyses grouped individuals from the Strait of Georgia (SG) into a distinct genetic cluster, while individuals from outer coastal water locations (OCLs) were partitioned equally across two genetic clusters, including the cluster associated with the SG fish. Pairwise FST values were consistently an order of magnitude higher for comparisons between the SG and OCLs than they were for all OCL-OCL comparisons (~0.016 vs. ~0.001). This same pattern was observed across two time points when individuals were binned into an "old" and "young" group according to birth year (old: ~0.020 vs. 0.0003; young: ~0.020 vs. ~0.004). Additionally, mean allelic richness was markedly lower within the SG compared to the OCLs (8.00 vs. 10.54-11.77). These results indicate that the Strait of Georgia "deep-basin" estuary oceanographic domain acts as a dispersal barrier from the outer coastal waters via the Juan de Fuca Strait. Alternatively, selection against maladapted dispersers across this oceanographic transition may underlie the observed genetic differentiation between the Georgia basin and the outer coastal waters, and further work is needed to confirm the SG-OCL divide acts as a barrier to larval dispersal. PMID- 23990927 TI - De novo transcriptome of Brassica juncea seed coat and identification of genes for the biosynthesis of flavonoids. AB - Brassica juncea, a worldwide cultivated crop plant, produces seeds of different colors. Seed pigmentation is due to the deposition in endothelial cells of proanthocyanidins (PAs), end products from a branch of flavonoid biosynthetic pathway. To elucidate the gene regulatory network of seed pigmentation in B. juncea, transcriptomes in seed coat of a yellow-seeded inbred line and its brown seeded near- isogenic line were sequenced using the next-generation sequencing platform Illumina/Solexa and de novo assembled. Over 116 million high-quality reads were assembled into 69,605 unigenes, of which about 71.5% (49,758 unigenes) were aligned to Nr protein database with a cut-off E-value of 10(-5). RPKM analysis showed that the brown-seeded testa up-regulated 802 unigenes and down regulated 502 unigenes as compared to the yellow-seeded one. Biological pathway analysis revealed the involvement of forty six unigenes in flavonoid biosynthesis. The unigenes encoding dihydroflavonol reductase (DFR), leucoantho cyanidin dioxygenase (LDOX) and anthocyanidin reductase (ANR) for late flavonoid biosynthesis were not expressed at all or at a very low level in the yellow seeded testa, which implied that these genes for PAs biosynthesis be associated with seed color of B. juncea, as confirmed by qRT-PCR analysis of these genes. To our knowledge, it is the first time to sequence the transcriptome of seed coat in Brassica juncea. The unigene sequences obtained in this study will not only lay the foundations for insight into the molecular mechanisms underlying seed pigmentation in B.juncea, but also provide the basis for further genomics research on this species or its allies. PMID- 23990928 TI - Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. AB - INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk. PMID- 23990929 TI - Tooth loss and risk of head and neck cancer: a meta-analysis. AB - BACKGROUND: Observational studies suggest an association between tooth loss and risk of head and neck cancer. However, whether tooth loss is an independent risk factor for head and neck cancer still remains controversial. The aim of this study is to assess the association between tooth loss and head and neck cancer risk. METHODS: Eligible studies were searched in PubMed and Embase databases from their inception to March 2013. A random-effects model or fixed-effects model was used to calculate the overall combined risk estimates. RESULTS: Eight case control studies and one cross-sectional study involving 5,204 patients and 5,518 controls were included in the meta-analysis. The overall combined odds ratio for tooth loss and head and neck cancer was 2.00 (95% confidence interval, 1.28 3.14). Similar results yielded both in the moderate and severe tooth loss group. Sensitivity analysis based on various exclusion criteria maintained this significance with respect to head and neck cancer individually. Little evidence of publication bias was observed. CONCLUSION: This meta-analysis suggests that tooth loss is associated with increased risk of head and neck cancer. This increase is probably independent of conventional head and neck cancer risk factors. PMID- 23990930 TI - Heat shock protein 27 is spatially distributed in the human placenta and decreased during labor. AB - Placental oxidative stress is a feature of human labor. Heat shock proteins (HSPs) play a key role in cellular stress. We hypothesized that placental expression of the small HSP 27 would be altered during labor and expression would vary in different regions of the placenta. Six women in labor who delivered vaginally and 6 women not in labor, who were delivered by Cesarean section, were recruited. Four equally spaced pieces were sampled from the inner, middle and outer regions of each placenta (total 12 samples per placenta). HSP 27 expression was investigated by Western blot analysis and RT-PCR. For non-labor, there was less HSP 27 protein in the inner placenta region compared with both the middle region (p<0.05) and outer region (p<0.05). For labor, there was also less HSP 27 protein in the inner region compared with both the middle (p<0.02) and outer region (p<0.01). When the 3 regions of the placenta were compared for non-labor versus labor there was less HSP 27 in the labor group at both the inner (p<0.05) and middle regions (p<0.005) compared to non-labor. Similar to HSP 27 protein, there was less HSP 27 mRNA in the labor group in both the inner region (p<0.05) and middle region (p<0.02) compared to non-labor. This study suggests that placental HSP 27 may play a role in labor and is spatially controlled. The results have important implications for how data obtained from studies in the placenta can be influenced by sampling methods. PMID- 23990931 TI - A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms. AB - Hierarchical organized tissue structures, with stem cell driven cell differentiation, are critical to the homeostatic maintenance of most tissues, and this underlying cellular architecture is potentially a critical player in the development of a many cancers. Here, we develop a mathematical model of mutation acquisition to investigate how deregulation of the mechanisms preserving stem cell homeostasis contributes to tumor initiation. A novel feature of the model is the inclusion of both extrinsic and intrinsic chemical signaling and interaction with the niche to control stem cell self-renewal. We use the model to simulate the effects of a variety of types and sequences of mutations and then compare and contrast all mutation pathways in order to determine which ones generate cancer cells fastest. The model predicts that the sequence in which mutations occur significantly affects the pace of tumorigenesis. In addition, tumor composition varies for different mutation pathways, so that some sequences generate tumors that are dominated by cancerous cells with all possible mutations, while others are primarily comprised of cells that more closely resemble normal cells with only one or two mutations. We are also able to show that, under certain circumstances, healthy stem cells diminish due to the displacement by mutated cells that have a competitive advantage in the niche. Finally, in the event that all homeostatic regulation is lost, exponential growth of the cancer population occurs in addition to the depletion of normal cells. This model helps to advance our understanding of how mutation acquisition affects mechanisms that influence cell-fate decisions and leads to the initiation of cancers. PMID- 23990932 TI - Evolutionary history of Triticum petropavlovskyi Udacz. et Migusch. inferred from the sequences of the 3-phosphoglycerate kinase gene. AB - Single- and low-copy genes are less likely to be subject to concerted evolution. Thus, they are appropriate tools to study the origin and evolution of polyploidy plant taxa. The plastid 3-phosphoglycerate kinase gene (Pgk-1) sequences from 44 accessions of Triticum and Aegilops, representing diploid, tetraploid, and hexaploid wheats, were used to estimate the origin of Triticum petropavlovskyi. Our phylogenetic analysis was carried out on exon+intron, exon and intron sequences, using maximum likelihood, Bayesian inference and haplotype networking. We found the D genome sequences of Pgk-1 genes from T. petropavlovskyi are similar to the D genome orthologs in T. aestivum, while their relationship with Ae. tauschii is more distant. The A genome sequences of T. petropavlovskyi group with those of T. polonicum, but its Pgk-1 B genome sequences to some extent diverge from those of other species of Triticum. Our data do not support for the origin of T. petropavlovskyi either as an independent allopolyploidization event between Ae. tauschii and T. polonicum, or as a monomendelian mutation in T. aestivum. We suggest that T. petropavlovskyi originated via spontaneous introgression from T. polonicum into T. aestivum. The dating of divergence among T. polonicum, T. petropavlovskyi, T. carthlicum, T. turgidum, and T. compactum indicates an age of 0.78 million years [corrected]. PMID- 23990933 TI - The prognostic value of SOX2 expression in non-small cell lung cancer: a meta analysis. AB - OBJECTIVE: To investigate the association of SOX2 expression in tumor with clinicopathological features and survival of non-small-cell lung carcinoma (NSCLC) patients. METHODS: Publications assessing the clinicopathological characteristics and prognostic significance of SOX2 in NSCLC were identified up to May 2013. A meta-analysis of eligible studies was performed using standard statistical methods to clarify the association between SOX2 expression and these clinical parameters. RESULTS: A total of eight studies met the inclusion criteria. Analysis of these data showed that SOX2 expression was positively associated with squamous histology, (pooled OR = 5.26, 95% CI: 1.08-25.6, P = 0.040). Simultaneously, we also found that SOX2 expression was positively associated with overall survival (pooled HR = 0.65, 95% CI: 0.47-0.89, P = 0.007, random-effect). CONCLUSIONS: SOX2 expression in tumor is a candidate positive prognostic biomarker for NSCLC patients. PMID- 23990934 TI - Emergence of daptomycin resistance in daptomycin-naive rabbits with methicillin resistant Staphylococcus aureus prosthetic joint infection is associated with resistance to host defense cationic peptides and mprF polymorphisms. AB - BACKGROUND: Previous studies of both clinically-derived and in vitro passage derived daptomycin-resistant (DAP-R) Staphylococcus aureus strains demonstrated the coincident emergence of increased DAP MICs and resistance to host defense cationic peptides (HDP-R). METHODS: In the present investigation, we studied a parental DAP-susceptible (DAP-S) methicillin-resistant Staphylococcus aureus (MRSA) strain and three isogenic variants with increased DAP MICs which were isolated from both DAP-treated and DAP-untreated rabbits with prosthetic joint infections. These strains were compared for: in vitro susceptibility to distinct HDPs differing in size, structure, and origin; i.e.; thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]; cell membrane (CM) phospholipid and fatty acid content; CM order; envelope surface charge; cell wall thickness; and mprF single nucleotide polymorphisms (SNPs) and expression profiles. RESULTS: In comparison with the parental strain, both DAP exposed and DAP-naive strains exhibited: (i) significantly reduced susceptibility to each HDP (P<0.05); (ii) thicker cell walls (P<0.05); (iii) increased synthesis of CM lysyl-phosphatidylglycerol (L-PG); (iv) reduced content of CM phosphatidylglycerol (PG); and (v) SNPs within the mprF locus No significant differences were observed between parental or variant strains in outer CM content of L-PG, CM fluidity, CM fatty acid contents, surface charge, mprF expression profiles or MprF protein content. An isolate which underwent identical in vivo passage, but without evolving increased DAP MICs, retained parental phenotypes and genotype. CONCLUSIONS: THESE RESULTS SUGGEST: i) DAP MIC increases may occur in the absence of DAP exposures in vivo and may be triggered by organism exposure to endogenous HDPs: and ii) gain-in-function SNPs in mprF may contribute to such HDP-DAP cross-resistance phenotypes, although the mechanism of this relationship remains to be defined. PMID- 23990935 TI - Crowdsourcing as a novel technique for retinal fundus photography classification: analysis of images in the EPIC Norfolk cohort on behalf of the UK Biobank Eye and Vision Consortium. AB - AIM: Crowdsourcing is the process of outsourcing numerous tasks to many untrained individuals. Our aim was to assess the performance and repeatability of crowdsourcing for the classification of retinal fundus photography. METHODS: One hundred retinal fundus photograph images with pre-determined disease criteria were selected by experts from a large cohort study. After reading brief instructions and an example classification, we requested that knowledge workers (KWs) from a crowdsourcing platform classified each image as normal or abnormal with grades of severity. Each image was classified 20 times by different KWs. Four study designs were examined to assess the effect of varying incentive and KW experience in classification accuracy. All study designs were conducted twice to examine repeatability. Performance was assessed by comparing the sensitivity, specificity and area under the receiver operating characteristic curve (AUC). RESULTS: Without restriction on eligible participants, two thousand classifications of 100 images were received in under 24 hours at minimal cost. In trial 1 all study designs had an AUC (95%CI) of 0.701(0.680-0.721) or greater for classification of normal/abnormal. In trial 1, the highest AUC (95%CI) for normal/abnormal classification was 0.757 (0.738-0.776) for KWs with moderate experience. Comparable results were observed in trial 2. In trial 1, between 64 86% of any abnormal image was correctly classified by over half of all KWs. In trial 2, this ranged between 74-97%. Sensitivity was >= 96% for normal versus severely abnormal detections across all trials. Sensitivity for normal versus mildly abnormal varied between 61-79% across trials. CONCLUSIONS: With minimal training, crowdsourcing represents an accurate, rapid and cost-effective method of retinal image analysis which demonstrates good repeatability. Larger studies with more comprehensive participant training are needed to explore the utility of this compelling technique in large scale medical image analysis. PMID- 23990936 TI - Temporal patterns of diversification across global cichlid biodiversity (Acanthomorpha: Cichlidae). AB - The contrasting distribution of species diversity across the major lineages of cichlids makes them an ideal group for investigating macroevolutionary processes. In this study, we investigate whether different rates of diversification may explain the disparity in species richness across cichlid lineages globally. We present the most taxonomically robust time-calibrated hypothesis of cichlid evolutionary relationships to date. We then utilize this temporal framework to investigate whether both species-rich and depauperate lineages are associated with rapid shifts in diversification rates and if exceptional species richness can be explained by clade age alone. A single significant rapid rate shift increase is detected within the evolutionary history of the African subfamily Pseudocrenilabrinae, which includes the haplochromins of the East African Great Lakes. Several lineages from the subfamilies Pseudocrenilabrinae (Australotilapiini, Oreochromini) and Cichlinae (Heroini) exhibit exceptional species richness given their clade age, a net rate of diversification, and relative rates of extinction, indicating that clade age alone is not a sufficient explanation for their increased diversity. Our results indicate that the Neotropical Cichlinae includes lineages that have not experienced a significant rapid burst in diversification when compared to certain African lineages (rift lake). Neotropical cichlids have remained comparatively understudied with regard to macroevolutionary patterns relative to African lineages, and our results indicate that of Neotropical lineages, the tribe Heroini may have an elevated rate of diversification in contrast to other Neotropical cichlids. These findings provide insight into our understanding of the diversification patterns across taxonomically disparate lineages in this diverse clade of freshwater fishes and one of the most species-rich families of vertebrates. PMID- 23990938 TI - Early prediction of movie box office success based on Wikipedia activity big data. AB - Use of socially generated "big data" to access information about collective states of the minds in human societies has become a new paradigm in the emerging field of computational social science. A natural application of this would be the prediction of the society's reaction to a new product in the sense of popularity and adoption rate. However, bridging the gap between "real time monitoring" and "early predicting" remains a big challenge. Here we report on an endeavor to build a minimalistic predictive model for the financial success of movies based on collective activity data of online users. We show that the popularity of a movie can be predicted much before its release by measuring and analyzing the activity level of editors and viewers of the corresponding entry to the movie in Wikipedia, the well-known online encyclopedia. PMID- 23990937 TI - Relative abundance of integral plasma membrane proteins in Arabidopsis leaf and root tissue determined by metabolic labeling and mass spectrometry. AB - Metabolic labeling of proteins with a stable isotope ((15)N) in intact Arabidopsis plants was used for accurate determination by mass spectrometry of differences in protein abundance between plasma membranes isolated from leaves and roots. In total, 703 proteins were identified, of which 188 were predicted to be integral membrane proteins. Major classes were transporters, receptors, proteins involved in membrane trafficking and cell wall-related proteins. Forty one of the integral proteins, including nine of the 13 isoforms of the PIP (plasma membrane intrinsic protein) aquaporin subfamily, could be identified by peptides unique to these proteins, which made it possible to determine their relative abundance in leaf and root tissue. In addition, peptides shared between isoforms gave information on the proportions of these isoforms. A comparison between our data for protein levels and corresponding data for mRNA levels in the widely used database Genevestigator showed an agreement for only about two thirds of the proteins. By contrast, localization data available in the literature for 21 of the 41 proteins show a much better agreement with our data, in particular data based on immunostaining of proteins and GUS-staining of promoter activity. Thus, although mRNA levels may provide a useful approximation for protein levels, detection and quantification of isoform-specific peptides by proteomics should generate the most reliable data for the proteome. PMID- 23990939 TI - Association between CD14 promoter -159C/T polymorphism and the risk of sepsis and mortality: a systematic review and meta-analysis. AB - BACKGROUND: Recent studies on the association between CD14-159C/T polymorphism and sepsis showed inconclusive results. Accordingly, we conducted a comprehensive literature search and a meta-analysis to determine whether the CD14-159C/T polymorphism conferred susceptibility to sepsis or was associated with increased risk of death from sepsis. METHODOLOGY: Data were collected from the following electronic databases: PubMed, Embase, Medline, Web of Knowledge, and HuGE Navigator, with the last report up to June 15, 2012. The odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of association. We summarized the data on the association between CD14-159C/T polymorphism and sepsis in the overall population and subgroup by ethnicity and sepsis subtype. PRINCIPAL FINDINGS: A total of 16 studies on sepsis morbidity (1369 cases and 2382 controls) and 4 studies on sepsis mortality (731 sepsis patients) met the inclusion criteria for meta-analysis. Overall analysis showed no strong evidences of association with sepsis susceptibility under any genetic model. However, slight associations were found in Asian populations (dominant model: OR = 1.38, 95%CI = 0.96-1.98, P = 0.08) and septic shock patients (dominant model: OR = 1.72, 95%CI 1.05-2.83, P = 0.03; allelic model: OR = 1.52, 95%CI 1.09-2.12, P = 0.01) in the stratified analysis. Moreover, there was borderline association between CD14-159C/T and sepsis mortality under the dominant genetic model (OR = 1.44, 95%CI = 0.98-2.11, P = 0.06). CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests that the CD14-159C/T polymorphism may not be a significant susceptibility factor in the risk of sepsis and mortality. Only weak associations were observed in Asian populations and septic shock patients. More studies based on larger sample sizes and homogeneous sepsis patients are needed to confirm these findings. PMID- 23990940 TI - Altered visual and feet proprioceptive feedbacks during quiet standing increase postural sway in patients with severe knee osteoarthritis. AB - OBJECTIVE: The objective was to investigate how postural control in knee osteoarthritis (KOA) patients, with different structural severities and pain levels, is reorganized under different sensory conditions. METHODS: Forty-two obese patients (BMI range from 30.1 to 48.7 kg*m(-2), age range from 50 to 74 years) with KOA were evaluated. One minute of quiet standing was assessed on a force platform during 4 different sensory conditions, applied 3 times at random: Eyes open (EO) and eyes closed (EC) standing on firm and soft (foam) surfaces (EO soft and EC-soft). Centre of pressure (Cop) standard deviation, speed, range and Cop mean position in both directions (anterior-posterior and medial-lateral) were extracted from the force platform data. Structural disease severity was assessed from semiflexed standing radiographs and graded by the Kellgren and Lawrence (KL) score. Pain intensity immediately before the measurements was assessed by numeric rating scale (range: 0-10). RESULTS: The patients were divided into "less severe" (KL 1 and 2, n = 24) and "severe" (KL>2, n = 18) group. The CoP range in the medial-lateral direction was larger in the severe group when compared with the less severe group during EC-soft condition (P<0.01). Positive correlation between pain intensity and postural sway (range in medial-lateral direction) was found during EC condition, indicating that the higher the pain intensity, the less effective is the postural control applied to restore an equilibrium position while standing without visual information. CONCLUSION: THE RESULTS SUPPORT THAT: (i) the postural reorganization under manipulation of the different sensory information is worse in obese KOA patients with severe degeneration and/or high pain intensity when compared with less impaired patients, and (ii) higher pain intensity is related to worse body balance in obese KOA patients. PMID- 23990941 TI - Electrospun poly(L-lactide)/poly(epsilon-caprolactone) blend nanofibrous scaffold: characterization and biocompatibility with human adipose-derived stem cells. AB - The essence of tissue engineering is the fabrication of autologous cells or induced stem cells in naturally derived or synthetic scaffolds to form specific tissues. Polymer is thought as an appealing source of cell-seeded scaffold owing to the diversity of its physicochemical property and can be electrospun into nano size to mimic natural structure. Poly (L-lactic acid) (PLLA) and poly (epsilon caprolactone) (PCL) are both excellent aliphatic polyester with almost "opposite" characteristics. The controlling combination of PLLA and PCL provides varying properties and makes diverse applications. Compared with the copolymers of the same components, PLLA/PCL blend demonstrates its potential in regenerative medicine as a simple, efficient and scalable alternative. In this study, we electrospun PLLA/PCL blends of different weight ratios into nanofibrous scaffolds (NFS) and their properties were detected including morphology, porosity, degradation, ATR-FTIR analysis, stress-stain assay, and inflammatory reaction. To explore the biocompatibility of the NFS we synthesized, human adipose-derived stem cells (hASCs) were used to evaluate proliferation, attachment, viability and multi-lineage differentiation. In conclusion, the electrospun PLLA/PCL blend nanofibrous scaffold with the indicated weight ratios all supported hASCs well. However, the NFS of 1/1 weight ratio showed better properties and cellular responses in all assessments, implying it a biocompatible scaffold for tissue engineering. PMID- 23990942 TI - RNA-mediated gene silencing of nicotinamide N-methyltransferase is associated with decreased tumorigenicity in human oral carcinoma cells. AB - Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. Despite progress in the treatment of OSCC, overall survival has not improved substantially in the last three decades. Therefore, identification of reliable biomarkers becomes essential to develop effective anti-cancer therapy. In this study, we focused on the enzyme Nicotinamide N-methyltransferase (NNMT), which plays a fundamental role in the biotransformation of many xenobiotics. Although several tumors have been associated with abnormal NNMT expression, its role in cancer cell metabolism remains largely unknown. In this report, 7 human oral cancer cell lines were examined for NNMT expression by Real-Time PCR, Western blot and HPLC-based catalytic assay. Subsequently, we evaluated the in vitro effect of shRNA-mediated silencing of NNMT on cell proliferation. In vivo tumorigenicity of oral cancer cells with stable knockdown of NNMT was assayed by using xenograft models. High expression levels of NNMT were found in PE/CA PJ-15 cells, in keeping with the results of Western blot and catalytic activity assay. PE/CA PJ-15 cell line was stably transfected with shRNA plasmids against NNMT and analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and soft agar Assays. Transfected and control cells were injected into athymic mice in order to evaluate the effect of NNMT silencing on tumor growth. NNMT downregulation resulted in decreased cell proliferation and colony formation ability on soft agar. In athymic mice, NNMT silencing induced a marked reduction in tumour volume. Our results show that the downregulation of NNMT expression in human oral carcinoma cells significantly inhibits cell growth in vitro and tumorigenicity in vivo. All these experimental data seem to suggest that NNMT plays a critical role in the proliferation and tumorigenic capacity of oral cancer cells, and its inhibition could represent a potential molecular approach to the treatment of oral carcinoma. PMID- 23990943 TI - The mitochondrial genome of Paramphistomum cervi (Digenea), the first representative for the family Paramphistomidae. AB - We determined the complete mitochondrial DNA (mtDNA) sequence of a fluke, Paramphistomum cervi (Digenea: Paramphistomidae). This genome (14,014 bp) is slightly larger than that of Clonorchis sinensis (13,875 bp), but smaller than those of other digenean species. The mt genome of P. cervi contains 12 protein coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 2 non-coding regions (NCRs), a complement consistent with those of other digeneans. The arrangement of protein-coding and ribosomal RNA genes in the P. cervi mitochondrial genome is identical to that of other digeneans except for a group of Schistosoma species that exhibit a derived arrangement. The positions of some transfer RNA genes differ. Bayesian phylogenetic analyses, based on concatenated nucleotide sequences and amino-acid sequences of the 12 protein-coding genes, placed P. cervi within the Order Plagiorchiida, but relationships depicted within that order were not quite as expected from previous studies. The complete mtDNA sequence of P. cervi provides important genetic markers for diagnostics, ecological and evolutionary studies of digeneans. PMID- 23990944 TI - Structural, antigenic, and evolutionary characterizations of the envelope protein of newly emerging Duck Tembusu Virus. AB - Since the first reported cases of ducks infected with a previously unknown flavivirus in eastern China in April 2010, the virus, provisionally designated Duck Tembusu Virus (DTMUV), has spread widely in domestic ducks in China and caused significant economic losses to poultry industry. In this study, we examined in detail structural, antigenic, and evolutionary properties of envelope (E) proteins of six DTMUV isolates spanning 2010-2012, each being isolated from individual farms with different geographical locations where disease outbreaks were documented. Structural analysis showed that E proteins of DTMUV and its closely related flavivirus (Japanese Encephalitis Virus) shared a conserved array of predicted functional domains and motifs. Among the six DTMUV strains, mutations were observed only at thirteen amino acid positions across three separate domains of the E protein. Interestingly, these genetic polymorphisms resulted in no detectable change in viral neutralization properties as demonstrated in a serum neutralization assay. Furthermore, phylogenetic analysis of the nucleotide sequences of the E proteins showed that viruses evolved into two distinct genotypes, termed as DTMUV.I and DTMUV.II, with II emerging as the dominant genotype. New findings described here shall give insights into the antigenicity and evolution of this new pathogen and provide guidance for further functional studies of the E protein for which no effective vaccine has yet been developed. PMID- 23990945 TI - Plasma levels of soluble urokinase-type plasminogen activator receptor associate with the clinical severity of acute Puumala hantavirus infection. AB - OBJECTIVES: Urokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to beta3-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease. DESIGN: A single-centre prospective cohort study. SUBJECTS AND METHODS: Plasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme linked immunosorbent assay (ELISA). RESULTS: The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0-18.2 ng/ml vs. median 4.7 ng/ml, range 2.4-12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = 0.325, p = 0.001) and minimum hematocrit (r = -0.369, p<0.001). CONCLUSION: Plasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates beta3-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease. PMID- 23990946 TI - Apical groove type and molecular phylogeny suggests reclassification of Cochlodinium geminatum as Polykrikos geminatum. AB - Traditionally Cocholodinium and Gymnodinium sensu lato clade are distinguished based on the cingulum turn number, which has been increasingly recognized to be inadequate for Gymnodiniales genus classification. This has been improved by the combination of the apical groove characteristics and molecular phylogeny, which has led to the erection of several new genera (Takayama, Akashiwo, Karenia, and Karlodinium). Taking the apical groove characteristics and molecular phylogeny combined approach, we reexamined the historically taxonomically uncertain species Cochlodinium geminatum that formed massive blooms in Pearl River Estuary, China, in recent years. Samples were collected from a bloom in 2011 for morphological, characteristic pigment, and molecular analyses. We found that the cingulum in this species wraps around the cell body about 1.2 turns on average but can appear under the light microscopy to be >1.5 turns after the cells have been preserved. The shape of its apical groove, however, was stably an open-ended anticlockwise loop of kidney bean shape, similar to that of Polykrikos. Furthermore, the molecular phylogenetic analysis using 18S rRNA-ITS-28S rRNA gene cistron we obtained in this study also consistently placed this species closest to Polykrikos within the Gymnodinium sensu stricto clade and set it far separated from the clade of Cochlodinium. These results suggest that this species should be transferred to Polykrikos as Polykrikos geminatum. Our results reiterate the need to use the combination of apical groove morphology and molecular phylogeny for the classification of species within the genus of Cochlodinium and other Gymnodiniales lineages. PMID- 23990947 TI - Association of STAT4 polymorphisms with susceptibility to type-1 autoimmune hepatitis in the Japanese population. AB - BACKGROUND/AIMS: Recent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study. METHODOLOGY/PRINCIPAL FINDINGS: Genomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR = 1.61, 95% CI = 1.23-2.11; P = 0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR = 1.50, 95%CI = 1.13-1.99; P = 0.005). Detailed genotype phenotype analysis of type-1 autoimmune hepatitis patients with (n = 44) or without liver cirrhosis (n = 186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies). CONCLUSIONS/SIGNIFICANCE: This is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases. PMID- 23990948 TI - Relationship between periodontitis and pre-eclampsia: a meta-analysis. AB - BACKGROUND: Studies have suggested controversial results regarding a possible association between pre-eclampsia (PE) and periodontal disease (PD) and no meta analysis has been performed to clarify this issue. METHODS: A literature search of electronic databases was performed for articles published through March 24, 2013, followed by a manual search of several dental and medical journals. The meta-analysis was conducted according to the recommendations of the Cochrane Collaboration and PRISMA. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Heterogeneity was assessed with the chi(2)-based Cochran Q test and I(2) statistic. The level of significance was set at P <0.05. RESULTS: Fifteen studies were included, including three cohort and 12 case-control studies. A positive association was found between PE and PD (OR 2.17, 95% CI 1.38 3.41, P = 0.0008). However, a high and significant heterogeneity was found (chi(2) = 62.42, P<0.00001, I(2) = 75%). In most cases, subgroup analysis had low power to detect significant differences between PE and non-PE groups. CONCLUSION: Based on the findings of the meta-analysis, PD appears to be a possible risk factor for PE. However, given the important differences in the definitions and diagnoses of PD and PE among the studies, as well as their lack of good methodological quality, future trials are needed to confirm the results of the present meta-analysis. PMID- 23990949 TI - The first peopling of South America: new evidence from Y-chromosome haplogroup Q. AB - Recent progress in the phylogenetic resolution of the Y-chromosome phylogeny permits the male demographic dynamics and migratory events that occurred in Central and Southern America after the initial human spread into the Americas to be investigated at the regional level. To delve further into this issue, we examined more than 400 Native American Y chromosomes (collected in the region ranging from Mexico to South America) belonging to haplogroup Q - virtually the only branch of the Y phylogeny observed in modern-day Amerindians of Central and South America - together with 27 from Mongolia and Kamchatka. Two main founding lineages, Q1a3a1a-M3 and Q1a3a1-L54(xM3), were detected along with novel sub clades of younger age and more restricted geographic distributions. The first was also observed in Far East Asia while no Q1a3a1-L54(xM3) Y chromosome was found in Asia except the southern Siberian-specific sub-clade Q1a3a1c-L330. Our data not only confirm a southern Siberian origin of ancestral populations that gave rise to Paleo-Indians and the differentiation of both Native American Q founding lineages in Beringia, but support their concomitant arrival in Mesoamerica, where Mexico acted as recipient for the first wave of migration, followed by a rapid southward migration, along the Pacific coast, into the Andean region. Although Q1a3a1a-M3 and Q1a3a1-L54(xM3) display overlapping general distributions, they show different patterns of evolution in the Mexican plateau and the Andean area, which can be explained by local differentiations due to demographic events triggered by the introduction of agriculture and associated with the flourishing of the Great Empires. PMID- 23990950 TI - Endogenous retrovirus EAV-HP linked to blue egg phenotype in Mapuche fowl. AB - Oocyan or blue/green eggshell colour is an autosomal dominant trait found in native chickens (Mapuche fowl) of Chile and in some of their descendants in European and North American modern breeds. We report here the identification of an endogenous avian retroviral (EAV-HP) insertion in oocyan Mapuche fowl and European breeds. Sequencing data reveals 100% retroviral identity between the Mapuche and European insertions. Quantitative real-time PCR analysis of European oocyan chicken indicates over-expression of the SLCO1B3 gene (P<0.05) in the shell gland and oviduct. Predicted transcription factor binding sites in the long terminal repeats (LTR) indicate AhR/Ar, a modulator of oestrogen, as a possible promoter/enhancer leading to reproductive tissue-specific over-expression of the SLCO1B3 gene. Analysis of all jungle fowl species Gallus sp. supports the retroviral insertion to be a post-domestication event, while identical LTR sequences within domestic chickens are in agreement with a recent de novo mutation. PMID- 23990951 TI - Association of genetic variants with isolated fasting hyperglycaemia and isolated postprandial hyperglycaemia in a Han Chinese population. AB - BACKGROUND: Though multiple single nucleotide polymorphisms (SNPs) associated with type 2 diabetes have been identified, the genetic bases of isolated fasting hyperglycaemia (IFH) and isolated postprandial hyperglycaemia (IPH) were still unclear. In present study, we aimed to investigate the association of genome-wide association study-validated genetic variants and IFH or IPH in Han Chinese. METHODS/PRINCIPAL FINDINGS: We genotyped 27 validated SNPs in 6,663 unrelated individuals comprising 341 IFH, 865 IPH, 1,203 combined fasting hyperglycaemia and postprandial hyperglycaemia, and 4,254 normal glycaemic subjects of Han ancestry. The distributions of genotype frequencies of FTO, CDKAL1 and GCKR were significant different between individuals with IFH and those with IPH (SNP(ptrend ): rs8050136(0.0024), rs9939609(0.0049), rs7756992(0.0122), rs780094(0.0037)). Risk allele of FTO specifically increased the risk of IFH (rs8050136: OR 1.403 [95% CI 1.125-1.750], p = 0.0027; rs9939609: 1.398 [1.120-1.744], p = 0.0030). G allele of CDKAL1 specifically increased the risk of IPH (1.217 [1.092-1.355], p = 0.0004). G allele of GCKR increased the risk of IFH (1.167 [0.999-1.362], p = 0.0513), but decreased the risk of IPH (0.891 [0.801-0.991], p = 0.0331). In addition, TCF7L2 and KCNQ1 increased the risk of both IFH and IPH. When combined, each additional risk allele associated with IFH increased the risk for IFH by 1.246-fold (p<0.0001), while each additional risk allele associated with IPH increased the risk for IPH by 1.190-fold (p<0.0001). CONCLUSION/SIGNIFICANCE: Our results indicate that genotype distributions of variants from FTO, GCKR, CDKAL1 were different between IPH and IFH in Han Chinese. Variants of genes modulating insulin sensitivity (FTO, GCKR) contributed to the risk of IFH, while variants of genes related to beta cell function (CDKAL1) increase the risk of IPH. PMID- 23990952 TI - Acute physiological stress down-regulates mRNA expressions of growth-related genes in coho salmon. AB - Growth and development in fish are regulated to a major extent by growth-related factors, such as liver-derived insulin-like growth factor (IGF) -1 in response to pituitary-secreted growth hormone (GH) binding to the GH receptor (GHR). Here, we report on the changes in the expressions of gh, ghr, and igf1 genes and the circulating levels of GH and IGF-1 proteins in juvenile coho salmon (Oncorhynchus kisutch) in response to handling as an acute physiological stressor. Plasma GH levels were not significantly different between stressed fish and prestressed control. Plasma IGF-1 concentrations in stressed fish 1.5 h post-stress were the same as in control fish, but levels in stressed fish decreased significantly 16 h post-stress. Real-time quantitative PCR (qPCR) analysis showed that ghr mRNA levels in pituitary, liver, and muscle decreased gradually in response to the stressor. After exposure to stress, hepatic igf1 expression transiently increased, whereas levels decreased 16 h post-stress. On the other hand, the pituitary gh mRNA level did not change in response to the stressor. These observations indicate that expression of gh, ghr, and igf1 responded differently to stress. Our results show that acute physiological stress can mainly down regulate the expressions of growth-related genes in coho salmon in vivo. This study also suggests that a relationship between the neuroendocrine stress response and growth-related factors exists in fish. PMID- 23990953 TI - Development of time sensitivity and information processing speed. AB - The aim of this study was to examine whether age-related changes in the speed of information processing are the best predictors of the increase in sensitivity to time throughout childhood. Children aged 5 and 8 years old, as well adults, were given two temporal bisection tasks, one with short (0.5/1-s) and the other with longer (4/8-s) anchor durations. In addition, the participants' scores on different neuropsychological tests assessing both information processing speed and other dimensions of cognitive control (short-term memory, working memory, selective attention) were calculated. The results showed that the best predictor of individual variances in sensitivity to time was information processing speed, although working memory also accounted for some of the individual differences in time sensitivity, albeit to a lesser extent. In sum, the faster the information processing speed of the participants, the higher their sensitivity to time was. These results are discussed in the light of the idea that the development of temporal capacities has its roots in the maturation of the dynamic functioning of the brain. PMID- 23990954 TI - New non-linear color look-up table for visualization of brain fractional anisotropy based on normative measurements - principals and first clinical use. AB - Fractional anisotropy (FA) is the most commonly used quantitative measure of diffusion in the brain. Changes in FA have been reported in many neurological disorders, but the implementation of diffusion tensor imaging (DTI) in daily clinical practice remains challenging. We propose a novel color look-up table (LUT) based on normative data as a tool for screening FA changes. FA was calculated for 76 healthy volunteers using 12 motion-probing gradient directions (MPG), a subset of 59 subjects was additionally scanned using 30 MPG. Population means and 95% prediction intervals for FA in the corpus callosum, frontal gray matter, thalamus and basal ganglia were used to create the LUT. Unique colors were assigned to inflection points with continuous ramps between them. Clinical use was demonstrated on 17 multiple system atrophy (MSA) patients compared to 13 patients with Parkinson disease (PD) and 17 healthy subjects. Four blinded radiologists classified subjects as MSA/non-MSA. Using only the LUT, high sensitivity (80%) and specificity (84%) were achieved in differentiating MSA subjects from PD subjects and controls. The LUTs generated from 12 and 30 MPG were comparable and accentuate FA abnormalities. PMID- 23990955 TI - Impact of Indian Total Sanitation Campaign on latrine coverage and use: a cross sectional study in Orissa three years following programme implementation. AB - BACKGROUND: Faced with a massive shortfall in meeting sanitation targets, some governments have implemented campaigns that use subsidies focused on latrine construction to overcome income constraints and rapidly expand coverage. In settings like rural India where open defecation is common, this may result in sub optimal compliance (use), thereby continuing to leave the population exposed to human excreta. METHODS: We conducted a cross-sectional study to investigate latrine coverage and use among 20 villages (447 households, 1933 individuals) in Orissa, India where the Government of India's Total Sanitation Campaign had been implemented at least three years previously. We defined coverage as the proportion of households that had a latrine; for use we identified the proportion of households with at least one reported user and among those, the extent of reported use by each member of the household. RESULTS: Mean latrine coverage among the villages was 72% (compared to <10% in comparable villages in the same district where the Total Sanitation Campaign had not yet been implemented), though three of the villages had less than 50% coverage. Among these households with latrines, more than a third (39%) were not being used by any member of the household. Well over a third (37%) of the members of households with latrines reported never defecating in their latrines. Less than half (47%) of the members of such households reported using their latrines at all times for defecation. Combined with the 28% of households that did not have latrines, it appears that most defecation events in these communities are still practiced in the open. CONCLUSION: A large-scale campaign to implement sanitation has achieved substantial gains in latrine coverage in this population. Nevertheless, gaps in coverage and widespread continuation of open defecation will result in continued exposure to human excreta, reducing the potential for health gains. PMID- 23990956 TI - The influence of bubbles on the perception carbonation bite. AB - Although many people naively assume that the bite of carbonation is due to tactile stimulation of the oral cavity by bubbles, it has become increasingly clear that carbonation bite comes mainly from formation of carbonic acid in the oral mucosa. In Experiment 1, we asked whether bubbles were in fact required to perceive carbonation bite. Subjects rated oral pungency from several concentrations of carbonated water both at normal atmospheric pressure (at which bubbles could form) and at 2.0 atmospheres pressure (at which bubbles did not form). Ratings of carbonation bite under the two pressure conditions were essentially identical, indicating that bubbles are not required for pungency. In Experiment 2, we created controlled streams of air bubbles around the tongue in mildly pungent CO2 solutions to determine how tactile stimulation from bubbles affects carbonation bite. Since innocuous sensations like light touch and cooling often suppress pain, we predicted that bubbles might reduce rated bite. Contrary to prediction, air bubbles flowing around the tongue significantly enhanced rated bite, without inducing perceived bite in blank (un-carbonated) solutions. Accordingly, though bubbles are clearly not required for carbonation bite, they may well modulate perceived bite. More generally, the results show that innocuous tactile stimulation can enhance chemogenic pain. Possible physiological mechanisms are discussed. PMID- 23990957 TI - Warfarin anticoagulant therapy: a Southern Italy pharmacogenetics-based dosing model. AB - BACKGROUND AND AIM: Warfarin is the most frequently prescribed anticoagulant worldwide. However, warfarin therapy is associated with a high risk of bleeding and thromboembolic events because of a large interindividual dose-response variability. We investigated the effect of genetic and non genetic factors on warfarin dosage in a South Italian population in the attempt to setup an algorithm easily applicable in the clinical practice. MATERIALS AND METHODS: A total of 266 patients from Southern Italy affected by cardiovascular diseases were enrolled and their clinical and anamnestic data recorded. All patients were genotyped for CYP2C9 2, 3, CYP4F2 3, VKORC1 -1639 G>A by the TaqMan assay and for variants VKORC1 1173 C>T and VKORC1 3730 G>A by denaturing high performance liquid chromatography and direct sequencing. The effect of genetic and not genetic factors on warfarin dose variability was tested by multiple linear regression analysis, and an algorithm based on our data was established and then validated by the Jackknife procedure. RESULTS: Warfarin dose variability was influenced, in decreasing order, by VKORC1-1639 G>A (29.7%), CYP2C9 3 (11.8%), age (8.5%), CYP2C9 2 (3.5%), gender (2.0%) and lastly CYP4F2 3 (1.7%); VKORC1 1173 C>T and VKORC1 3730 G>A exerted a slight effect (<1% each). Taken together, these factors accounted for 58.4% of the warfarin dose variability in our population. Data obtained with our algorithm significantly correlated with those predicted by the two online algorithms: Warfarin dosing and Pharmgkb (p<0.001; R(2) = 0.805 and p<0.001; R(2) = 0.773, respectively). CONCLUSIONS: Our algorithm, which is based on six polymorphisms, age and gender, is user-friendly and its application in clinical practice could improve the personalized management of patients undergoing warfarin therapy. PMID- 23990958 TI - Altered pattern of spontaneous brain activity in the patients with end-stage renal disease: a resting-state functional MRI study with regional homogeneity analysis. AB - PURPOSE: To investigate the pattern of spontaneous neural activity in patients with end-stage renal disease (ESRD) with and without neurocognitive dysfunction using resting-state functional magnetic resonance imaging (rs-fMRI) with a regional homogeneity (ReHo) algorithm. MATERIALS AND METHODS: rs-fMRI data were acquired in 36 ESRD patients (minimal nephro-encephalopathy [MNE], n = 19, 13 male, 37+/-12.07 years; non-nephro-encephalopathy [non-NE], n = 17, 11 male, 38+/ 12.13 years) and 20 healthy controls (13 male, 7 female, 36+/-10.27 years). Neuropsychological (number connection test type A [NCT-A], digit symbol test [DST]) and laboratory tests were performed in all patients. The Kendall's coefficient of concordance (KCC) was used to measure the regional homogeneity for each subject. The regional homogeneity maps were compared using ANOVA tests among MNE, non-NE, and healthy control groups and post hoc t -tests between each pair in a voxel-wise way. A multiple regression analysis was performed to evaluate the relationships between ReHo index and NCT-A, DST scores, serum creatinine and urea levels, disease and dialysis duration. RESULTS: Compared with healthy controls, both MNE and non-NE patients showed decreased ReHo in the multiple areas of bilateral frontal, parietal and temporal lobes. Compared with the non-NE, MNE patients showed decreased ReHo in the right inferior parietal lobe (IPL), medial frontal cortex (MFC) and left precuneus (PCu). The NCT-A scores and serum urea levels of ESRD patients negatively correlated with ReHo values in the frontal and parietal lobes, while DST scores positively correlated with ReHo values in the bilateral PCC/precuneus, MFC and inferior parietal lobe (IPL) (all P<0.05, AlphaSim corrected). No significant correlations were found between any regional ReHo values and disease duration, dialysis duration and serum creatinine values in ESRD patients (all P>0.05, AlphaSim corrected). CONCLUSION: Diffused decreased ReHo values were found in both MNE and non-NE patients. The progressively decreased ReHo in the default mode network (DMN), frontal and parietal lobes might be trait-related in MNE. The ReHo analysis may be potentially valuable for elucidating neurocognitive abnormalities of ESRD patients and detecting the development from non-NE to MNE. PMID- 23990959 TI - Research tools to investigate movements, migrations, and life history of sturgeons (Acipenseridae), with an emphasis on marine-oriented populations. AB - Worldwide, sturgeons (Acipenseridae) are among the most endangered fishes due to habitat degradation, overfishing, and inherent life history characteristics (long life span, late maturation, and infrequent spawning). As most sturgeons are anadromous, a considerable portion of their life history occurs in estuarine and marine environments where they may encounter unique threats (e.g., interception in non-target fisheries). Of the 16 marine-oriented species, 12 are designated as Critically Endangered by the IUCN, and these include species commercially harvested. We review important research tools and techniques (tagging, electronic tagging, genetics, microchemistry, observatory) and discuss the comparative utility of these techniques to investigate movements, migrations, and life history characteristics of sturgeons. Examples are provided regarding what the applications have revealed regarding movement and migration and how this information can be used for conservation and management. Through studies that include Gulf (Acipenser oxyrinchus desotoi) and Green Sturgeon (A. medirostris), we illustrate what is known about well-studied species and then explore lesser studied species. A more complete picture of migration is available for North American sturgeon species, while European and Asian species, which are among the most endangered sturgeons, are less understood. We put forth recommendations that encourage the support of stewardship initiatives to build awareness and provide key information for population assessment and monitoring. PMID- 23990960 TI - Time perception and depressive realism: judgment type, psychophysical functions and bias. AB - The effect of mild depression on time estimation and production was investigated. Participants made both magnitude estimation and magnitude production judgments for five time intervals (specified in seconds) from 3 sec to 65 sec. The parameters of the best fitting psychophysical function (power law exponent, intercept, and threshold) were determined individually for each participant in every condition. There were no significant effects of mood (high BDI, low BDI) or judgment (estimation, production) on the mean exponent, n = .98, 95% confidence interval (.96-1.04) or on the threshold. However, the intercept showed a 'depressive realism' effect, where high BDI participants had a smaller deviation from accuracy and a smaller difference between estimation and judgment than low BDI participants. Accuracy bias was assessed using three measures of accuracy: difference, defined as psychological time minus physical time, ratio, defined as psychological time divided by physical time, and a new logarithmic accuracy measure defined as ln (ratio). The ln (ratio) measure was shown to have approximately normal residuals when subjected to a mixed ANOVA with mood as a between groups explanatory factor and judgment and time category as repeated measures explanatory factors. The residuals of the other two accuracy measures flagrantly violated normality. The mixed ANOVAs of accuracy also showed a strong depressive realism effect, just like the intercepts of the psychophysical functions. There was also a strong negative correlation between estimation and production judgments. Taken together these findings support a clock model of time estimation, combined with additional cognitive mechanisms to account for the depressive realism effect. The findings also suggest strong methodological recommendations. PMID- 23990961 TI - Gene therapy model of X-linked severe combined immunodeficiency using a modified foamy virus vector. AB - X-linked severe combined immunodeficiency (SCID-X1) is an inherited genetic immunodeficiency associated with mutations in the common cytokine receptor gamma chain (gammac) gene, and characterized by a complete defect of T and natural killer (NK) cells. Gene therapy for SCID-X1 using conventional retroviral (RV) vectors carrying the gammac gene results in the successful reconstitution of T cell immunity. However, the high incidence of vector-mediated T cell leukemia, caused by vector insertion near or within cancer-related genes has been a serious problem. In this study, we established a gene therapy model of mouse SCID-X1 using a modified foamy virus (FV) vector expressing human gammac. Analysis of vector integration in a human T cell line demonstrated that the FV vector integration sites were significantly less likely to be located within or near transcriptional start sites than RV vector integration sites. To evaluate the therapeutic efficacy, bone marrow cells from gammac-knockout (gammac-KO) mice were infected with the FV vector and transplanted into gammac-KO mice. Transplantation of the FV-treated cells resulted in the successful reconstitution of functionally active T and B cells. These data suggest that FV vectors can be effective and may be safer than conventional RV vectors for gene therapy for SCID X1. PMID- 23990962 TI - Methods for generating year-round access to amphioxus in the laboratory. AB - Cephalochordates, commonly known as amphioxus, are key to understanding vertebrate origins. However, laboratory work suffers from limited access to adults and embryonic material. Here we report the design and experimental validation of an inland marine facility that allows establishing stable amphioxus colonies in the laboratory and obtaining embryos at any time of day and over almost the entire year, far exceeding natural conditions. This is achieved by mimicking the natural benthic environment, natural day- and moon- light, natural substrate and by providing a strictly controlled and seasonally fluctuating temperature regimen. Moreover, supplemented algae diets allow animals to refill their gonads in consecutive years. Spontaneous spawning, a major problem in previous setups, no longer occurs in our facility; instead, all breeding is induced and fertilization occurs fully in vitro. Our system makes amphioxus a standard laboratory animal model. PMID- 23990963 TI - The TRPA1 agonist, methyl syringate suppresses food intake and gastric emptying. AB - Transient receptor potential channel ankryn 1 (TRPA1) expressed in the gastrointestinal tract is associated with gastric motility, gastric emptying, and food intake. In this study, we investigated the effects of methyl syringate, a specific and selective TRPA1 agonist, on food intake, gastric emptying, and gut hormone levels in imprinting control region (ICR) mice. The administration of methyl syringate suppressed cumulative food intake and gastric emptying. In addition, treatment with ruthenium red (RR), a general cation channel blocker, and HC-030031, a selective TRPA1 antagonist, inhibited methyl syringate-induced reduction of food intake and delayed gastric emptying in ICR mice. Methyl syringate also increased plasma peptide YY (PYY) levels, but not glucagon-like peptide-1 (GLP-1) levels. The elevation in PYY was blocked by treatment with RR and HC-030031. The present findings indicate that methyl syringate regulates food intake and gastric emptying through a TRPA1-mediated pathway and, by extension, can contribute to weight suppression. PMID- 23990964 TI - Transcriptome and peptidome characterisation of the main neuropeptides and peptidic hormones of a euphausiid: the Ice Krill, Euphausia crystallorophias. AB - BACKGROUND: The Ice krill, Euphausia crystallorophias is one of the species at the base of the Southern Ocean food chain. Given their significant contribution to the biomass of the Southern Ocean, it is vitally important to gain a better understanding of their physiology and, in particular, anticipate their responses to climate change effects in the warming seas around Antarctica. METHODOLOGY/PRINCIPAL FINDINGS: Illumina sequencing was used to produce a transcriptome of the ice krill. Analysis of the assembled contigs via two different methods, produced 36 new pre-pro-peptides, coding for 61 neuropeptides or peptide hormones belonging to the following families: Allatostatins (A, B et C), Bursicon (alpha and beta), Crustacean Hyperglycemic Hormones (CHH and MIH/VIHs), Crustacean Cardioactive Peptide (CCAP), Corazonin, Diuretic Hormones (DH), the Eclosion Hormone (EH), Neuroparsin, Neuropeptide F (NPF), small Neuropeptide F (sNPF), Pigment Dispersing Hormone (PDH), Red Pigment Concentrating Hormone (RPCH) and finally Tachykinin. LC/MS/MS proteomics was also carried out on eyestalk extracts, which are the major site of neuropeptide synthesis in decapod crustaceans. Results confirmed the presence of six neuropeptides and six precursor-related peptides previously identified in the transcriptome analyses. CONCLUSIONS: This study represents the first comprehensive analysis of neuropeptide hormones in a Eucarida non-decapod Malacostraca, several of which are described for the first time in a non-decapod crustacean. Additionally, there is a potential expansion of PDH and Neuropeptide F family members, which may reflect certain life history traits such as circadian rhythms associated with diurnal migrations and also the confirmation via mass spectrometry of several novel pre-pro-peptides, of unknown function. Knowledge of these essential hormones provides a vital framework for understanding the physiological response of this key Southern Ocean species to climate change and provides a valuable resource for studies into the molecular phylogeny of these organisms and the evolution of neuropeptide hormones. PMID- 23990966 TI - Reduction of maternal mortality with highly active antiretroviral therapy in a large cohort of HIV-infected pregnant women in Malawi and Mozambique. AB - BACKGROUND: HIV infection is a major contributor to maternal mortality in resource-limited settings. The Drug Resource Enhancement Against AIDS and Malnutrition Programme has been promoting HAART use during pregnancy and postpartum for Prevention-of-mother-to-child-HIV transmission (PMTCT) irrespective of maternal CD4 cell counts since 2002. METHODS: Records for all HIV+ pregnancies followed in Mozambique and Malawi from 6/2002 to 6/2010 were reviewed. The cohort was comprised by pregnancies where women were referred for PMTCT and started HAART during prenatal care (n = 8172, group 1) and pregnancies where women were referred on established HAART (n = 1978, group 2). RESULTS: 10,150 pregnancies were followed. Median (IQR) baseline values were age 26 years (IQR:23-30), CD4 count 392 cells/mm(3) (IQR:258-563), Viral Load log10 3.9 (IQR:3.2-4.4), BMI 23.4 (IQR:21.5-25.7), Hemoglobin 10.0 (IQR: 9.0-11.0). 101 maternal deaths (0.99%) occurred during pregnancy to 6 weeks postpartum: 87 (1.1%) in group 1 and 14 (0.7%) in group 2. Mortality was 1.3% in women with